WO2011076687A1 - Pyridinone derivatives and pharmaceutical compositions thereof - Google Patents
Pyridinone derivatives and pharmaceutical compositions thereof Download PDFInfo
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- WO2011076687A1 WO2011076687A1 PCT/EP2010/070092 EP2010070092W WO2011076687A1 WO 2011076687 A1 WO2011076687 A1 WO 2011076687A1 EP 2010070092 W EP2010070092 W EP 2010070092W WO 2011076687 A1 WO2011076687 A1 WO 2011076687A1
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- 0 CCC[C@@](C)CC*CC(CCC1)=C[C@]1C(C)C Chemical compound CCC[C@@](C)CC*CC(CCC1)=C[C@]1C(C)C 0.000 description 13
- XNJYGSWFMACDTM-UHFFFAOYSA-N CC(C(Cc(c(F)ccc1)c1F)=C1SCC(CN(C)CCc2ncccc2)N11)=C(c(cc2)cc3c2OCO3)C1=O Chemical compound CC(C(Cc(c(F)ccc1)c1F)=C1SCC(CN(C)CCc2ncccc2)N11)=C(c(cc2)cc3c2OCO3)C1=O XNJYGSWFMACDTM-UHFFFAOYSA-N 0.000 description 1
- NNAZCVFXSLQPEW-UHFFFAOYSA-N CC(C(Cc1c(C(F)(F)F)cccc1F)=C1SCC(C(c2ccccc2)NCC=C)N11)=C(c(cccc2OC)c2F)C1=O Chemical compound CC(C(Cc1c(C(F)(F)F)cccc1F)=C1SCC(C(c2ccccc2)NCC=C)N11)=C(c(cccc2OC)c2F)C1=O NNAZCVFXSLQPEW-UHFFFAOYSA-N 0.000 description 1
- LIVWTWDADNSSJQ-UHFFFAOYSA-N CC(C(Cc1c(C(F)(F)F)cccc1F)=C1SCC(C(c2ccccc2)NCCCC(N)=O)N11)=C(c(cccc2OC)c2F)C1=O Chemical compound CC(C(Cc1c(C(F)(F)F)cccc1F)=C1SCC(C(c2ccccc2)NCCCC(N)=O)N11)=C(c(cccc2OC)c2F)C1=O LIVWTWDADNSSJQ-UHFFFAOYSA-N 0.000 description 1
- PPULPNXVCRSXRU-UHFFFAOYSA-N CC(C(Cc1c(C(F)(F)F)cccc1F)=C1SCC(C(c2ccccc2)NCCCO)N11)=C(c(cccc2OC)c2F)C1=O Chemical compound CC(C(Cc1c(C(F)(F)F)cccc1F)=C1SCC(C(c2ccccc2)NCCCO)N11)=C(c(cccc2OC)c2F)C1=O PPULPNXVCRSXRU-UHFFFAOYSA-N 0.000 description 1
- CKJKYMZEVDBTOI-UHFFFAOYSA-N CC(C)(C(C(c1ccccc1)=O)N12)SC1=C(Cc(c(F)ccc1)c1F)C(C)=C(c(cccc1OC)c1F)C2=O Chemical compound CC(C)(C(C(c1ccccc1)=O)N12)SC1=C(Cc(c(F)ccc1)c1F)C(C)=C(c(cccc1OC)c1F)C2=O CKJKYMZEVDBTOI-UHFFFAOYSA-N 0.000 description 1
- OWADRLFXNNZLSP-UHFFFAOYSA-N CC(NC(C(CSC1=C(Cc2c(C(F)(F)F)cccc2F)C(C)=C2c(cccc3OC)c3F)N1C2=O)c1ccccc1)=O Chemical compound CC(NC(C(CSC1=C(Cc2c(C(F)(F)F)cccc2F)C(C)=C2c(cccc3OC)c3F)N1C2=O)c1ccccc1)=O OWADRLFXNNZLSP-UHFFFAOYSA-N 0.000 description 1
- HOOADQLUNBWLSA-UHFFFAOYSA-N CC(c1cccc(B(O)O)c1F)(F)F Chemical compound CC(c1cccc(B(O)O)c1F)(F)F HOOADQLUNBWLSA-UHFFFAOYSA-N 0.000 description 1
- XXCDSNCSWHBOBO-UHFFFAOYSA-N CC1(C)OB(c(ccc2c3OCCO2)c3F)OC1(C)C Chemical compound CC1(C)OB(c(ccc2c3OCCO2)c3F)OC1(C)C XXCDSNCSWHBOBO-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
- A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Definitions
- the present invention refers generally to pyridinone derivatives as gonadotropin-releasing hormone (GnRH) receptor antagonists, pharmaceutical compositions containing a pyridinone derivative according to the invention and methods of treating disorders by administration of a pyridinone derivative according to invention to a mammal, particularly a human, in need thereof.
- GnRH gonadotropin-releasing hormone
- Gonadotropin-releasing hormone is a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu- Arg-Pro-Gly-NH 2 ) released from the hypothalamus, also known as luteinizing hormone- releasing hormone (LHRH). GnRH acts on the pituitary gland to stimulate the biosynthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
- LH released from the pituitary gland is responsible for the regulation of gonadal steroid production in both genders and late ovarian follicle development and ovulation in female mammals, FSH regulates spermatogenesis in males and early follicular development in females.
- GnRH plays a key role in human reproduction.
- peptidic GnRH agonists such as leuprorelin (pGlu-His-Trp-Ser-Tyr-d-Leu-Leu- Arg-Pro-NHEt), are described for the use in the treatment of such conditions (The Lancet 2001 , 358, 1793 - 1803; Mol. Cell. Endo. 2000, 166, 9 - 14). Said agonists initially induce the synthesis and release of gonadotropins, by binding to the GnRH receptor on the pituitary gonadotrophic cells ('flare-up').
- leuprorelin pGlu-His-Trp-Ser-Tyr-d-Leu-Leu- Arg-Pro-NHEt
- GnRH antagonists are supposed to suppress gonadotropins from the onset, offering several advantages, in particular a lack of side effects associated with the flare up seen under GnRH superagonist treatment.
- peptidic antagonists with low histamine release potential are known in the art. Said peptidic products show low oral bioavailability which limits their clinical use.
- GnRH receptor antagonists A number of nonpeptidic compounds have also been described for use as GnRH receptor antagonists, for example:
- GnRH receptor antagonists are still highly required in art as well as pharmaceutical compositions containing such GnRH receptor antagonists and methods relating to the use thereof to treat, for example, sex-hormone-related conditions in particular for the treatment of leiomyoma.
- the pyridinone derivatives according to the present invention meets these needs, and provide at the same time further related advantages.
- WO 01 36426 A1 refers to pyridinones and their derivatives which are described to be effective in treating or preventing Gram-negative bacterial infections.
- the pyridinones are stable and easily derivatized; the methods by which these derivatizations are accomplished are described.
- Two regioselective and functional group-tolerant methods for the synthesis of the novel pyridinones are also provided.
- One such synthetic method involves reacting an imine and a Meldrum's acid derivative in solution.
- the other synthetic method is a solid phase synthesis of the pyridinones in which an imine is prepared bound to a solid support and a Meldrum's acid derivative is reacted with the imine.
- Novel imine intermediates useful in the solid phase and solution methods of synthesizing the pyridinones are also described.
- WO 2008054290 A1 describes 1 H-pyridine-2-one derivatives, inhibitors of PAI-1 , processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
- the compounds of Formula I , I I and I I I may be used in the treatment of, for example, thrombosis, coronary heart disease, renal fibrosis, atherosclerotic plaque formation, cancer, diabetes and obesity.
- the aim of the present invention is to provide gonadotropin-releasing hormone (GnRH) receptor antagon ists, as wel l as the methods for their preparation and use, and pharmaceutical compositions containing the same.
- GnRH gonadotropin-releasing hormone
- the present invention relates to compounds of the general formula (I):
- R 2a and R represent independently of one another a hydrogen atom, a
- R 2a and R 2b joined, and taken together with the atom to which they are attached, form a C 3 -C 6 -cycloalkyl- group; represents a halogen atom, an aryl-, a heteroaryl-, a benzo[1 ,3]dioxolyl- 2,3-dihydro-1 ,4-benzodioxinyl group wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent R-n selected from :
- R 9 and R 10 represent, independently of one another, a hydrogen atom, a d-Ce-alkyl-, halo-C C 6 -alkyl-, Ci-C 6 -alkoxy-Ci-C 6 -alkyl-,
- R 8 represents one or more substituents independently selected from the group consisting of hydrogen, halogen, cyano, nitro,
- R-ia, and Ri b represent independently of one another a hydrogen atom, a CrC 6 -alkyl-, Ci-C 6 -alkoxy-Ci-C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, C 3 -C 8 -cycloalkyl-, aryl-, heteroaryl-, -Ci-C 6 -alkylene-aryl,
- R-ia and Ri b joined, and taken together with the atom to which they are attached, form a 3- to 10-membered heterocycloalkyl-, optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo-, hydroxyl-, cyano-, nitro-, oxo, CrC 6 -alkyl-, halo-CrC 6 -alkyl-, CrC 6 -alkoxy-, halo-CrC 6 -alkoxy-,
- R 9 and R 10 independently of one another or joined, and taken together with the atom to which they are attached, have the meaning given above, or
- R-ia and Ri b joined, and taken together with the atom to which they are attached, form a 3- to 10-membered heterocycloalkyl-, substituted with a group selected from : C 3 -Ci 0 -cycloalkyl-, aryl-, heteroaryl-,
- -CrC 6 -alkylene-C 3 -Cio-cycloalkyl 3- to 10-membered heterocycloalkyl-, -CrC 6 -alkylene-heterocycloalkyl-, said groups being optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo, cyano, CrC 6 -alkyl- and halo-CrC 6 -alkyl- ;
- Ric represents a hydrogen atom, a hydroxy group, a methoxy group or a CrC 6 -alkoxy-, a CrC 6 -alkyl-, Ci-C 6 -alkoxy-Ci-C 6 -alkyl-,
- R 3a and R 3b represent independently of one another a hydrogen atom, a d-Ce-alkyl-, Ci-C 6 -alkoxy-Ci-C 6 -alkyl-, C 2 -C 6 -alkenyl-,
- -CrC 6 -alkylene-C 3 -Cio-cycloalkyl, -CrC 6 -alkylene-(3- to 10-membered heterocycloalkyi) group; wherein said groups are optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo-, hydroxyl-, cyano-, nitro-, CrC 6 -alkyl-, halo-CrC 6 -alkyl-, CrC 6 -alkoxy-, halo-CrC 6 -alkoxy-, Ci-C 6 -alkoxy-Ci-C 6 -alkyl-, halo-Ci-C 6 -alkoxy-Ci-C 6 -alkyl-, aryl-, heteroaryl-, C 3 -Ci 0 -cycloalkyl-, 3- to 10-membered heterocycloalkyi-, -C( 0)OH, -
- Ria and R 3a or R 1b and R 3a , or R 3b and Ri a , or R 3b and Ri b joined, and taken together with the atom to which they are attached, form a 4- to 10-membered heterocycloalkyl- or 4- to 10-membered heterocycloalkenyl-, optionally substituted one or more times, in the same way or differently, with a substituent selected from :
- Compounds of the invention are the compounds of the formula (I) and the salts, solvates and solvates of the salts thereof, the compounds which are encompassed by formula (I) and are of the formulae mentioned hereinafter, and the salts, solvates and solvates of the salts thereof, and the compounds which are encompassed by formula (I) and are mentioned hereinafter as exemplary embodiments, and the salts, solvates and solvates of the salts thereof, insofar as the compounds encompassed by formula (I) and mentioned hereinafter are not already salts, solvates and solvates of the salts.
- Hydrates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with water, such as, for example, hemi-, mono-, or dihydrates.
- Solvates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with solvents.
- Solvates which are preferred for the purposes of the present invention are hydrates.
- Salts for the purposes of the present invention are preferably pharmaceutically acceptable salts of the compounds according to the invention (for example, see S. M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19).
- Pharmaceutically acceptable salts include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, maleic, fumaric, benzoic, ascorbic, succinic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, and glutamic acid.
- hydrochloric acid hydrobromic acid
- sulfuric acid sulfuric acid
- phosphoric acid methanesulfonic acid
- ethanesulfonic acid toluenesulfonic acid
- Pharmaceutically acceptable salts also include salts of customary bases, such as for example and preferably alkali metal salts (for example sodium, lithium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts), and ammonium salts derived from ammonia or organic amines, such as illustratively and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, benzylamine, dibenzylamine, N-methylmorpholine, N-methylpiperidine, dihydroabietyl- amine, argi ni ne, lysi ne, and ethylenediamine. Also encompassed are salts which are themselves unsuitable for pharmaceutical uses but can be used for example for isolating or purifying the compounds of the invention.
- alkali metal salts for example sodium,
- the present invention additionally encompasses prodrugs of the compounds of the invention.
- prodrugs encompasses compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body into compounds of the invention (for example by metabolism or hydrolysis).
- the compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers (enantiomers, diastereomers). Any isomer may be present in which the asymmetric center is in the (R)-, (S)-, or (Reconfiguration. It will also be appreciated that when two or more asymmetric centers are present in the compounds of the invention, several diastereomers and enantiomers of the exemplified structures will often be possible, and that pure diastereomers and pure enantiomers represent preferred embodiments. It is intended that pure stereoisomers, pure diastereomers, pure enantiomers, and mixtures thereof, are within the scope of the invention.
- the compounds of the invention may occur in tautomeric forms, the present invention encompasses all tautomeric forms.
- halogen atom or “halo” is to be understood as meaning a fluorine, chlorine, bromine or iodine atom.
- Ci-C 6 -alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g.
- said group has 1 , 2 or 3 carbon atoms ("Ci-C 3 -alkyl"), methyl, ethyl, n-propyl- or iso-propyl.
- halo-Ci-C 6 -alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "C"i-C 6 -alky is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in the same way or differently, i.e. one halogen atom being independent from another.
- said halogen atom is F.
- Said halo-CrC 6 -alkyl group is, in particular -CF 3 , -CHF 2 , -CH 2 F, -CF 2 CF 3 , -CF 2 CH 3 , or -CH 2 CF 3 .
- CrC 6 -alkoxy is to be understood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term “alkyl” is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof.
- halo-CrC 6 -alkoxy is to be understood as preferably meaning a linear or branched, saturated, monovalent CrC 6 -alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in the same way or differently, by a halogen atom.
- said halogen atom is F.
- Said halo-CrC 6 -alkoxy group is, for example, -OCF 3 , -OCHF 2 , -OCH 2 F, -OCF 2 CF 3 , or -OCH 2 CF 3 .
- C-i-Ce-alkoxy-C-i-Ce-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in the same way or differently, by a CrC 6 -alkoxy group, as defined supra, e.g.
- halo-Ci-C6-alkoxy-Ci-C 6 -alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent Ci-C 6 -alkoxy-Ci-C 6 -alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in the same way or differently, by a halogen atom.
- halogen atom is F.
- Said halo-Ci-C 6 -alkoxy-Ci-C 6 -alkyl group is, for example, -CH 2 CH 2 OCF 3 , -CH 2 CH 2 OCHF 2 , -CH 2 CH 2 OCH 2 F, -CH 2 CH 2 OCF 2 CF 3 , or -CH 2 CH 2 OCH 2 CF 3 .
- Alkylcarbonyl in general represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms which is bonded via a carbonyl group to the rest of the molecule.
- Non-limiting examples include acetyl, n-propionyl, n-butyryl, isobutyryl, pivaloyl.
- Alkoxycarbonylamino illustratively and preferably represents methoxycarbonylamino, ethoxy- carbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino and tert.-butoxycarbonylamino.
- Alkoxycarbonyl illustratively and preferably represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl and tert.-butoxycarbonyl.
- Alkylsulfonyl in general represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms which is bonded via a sulfonyl (-S0 2 -) group to the rest of the molecule.
- Non- limiting examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n- butylsulfonyl, tert.-butylsulfonyl.
- Non-limiting examples i n c l u d e S-methylsulfonimidoyl, S-ethylsulfonimidoyl, S-n-propylsulfonimidoyl, S-isopropylsulfonimidoyl, S-n-butylsulfonimidoyl, S-tert.-butylsulfonimidoyl.
- Monoalkylamino in general represents an amino radical having one alkyl residue attached to the nitrogen atom.
- radicals such as monoalkyl- aminocarbonyl.
- Dialkylamino in general represents an amino radical having two independently selected alkyl residues attached to the nitrogen atom.
- Non-limiting examples include ⁇ /,/V-dimethylamino, ⁇ /,/V-diethylamino, ⁇ /,/V-diisopropylamino, /V-ethyl-/V-methylamino, /V-methyl-/V-n-propylamino, /V-iso-propyl-/V-n-propylamino, /V-tert.-butyl-/V-methylamino.
- radicals such as di-alkylaminocarbonyl.
- Monoalkylaminocarbonyl illustratively and preferably represents methylaminocarbonyl, ethyl- aminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl and tert-butylaminocarbonyl.
- Dialkylaminocarbonyl illustratively and preferably represents ⁇ /,/V-dimethylaminocarbonyl, ⁇ /,/V-diethylaminocarbonyl, ⁇ /,/V-diisopropylaminocarbonyl, /V-ethyl-/V-methylaminocarbonyl, /V-methyl-/V-n-propylaminocarbonyl, /V-isopropyl-/V-n-propylaminocarbonyl and
- Non-limiting examples include acetyl- amino, n-propionylamino, n-butyrylamino, isobutyrylamino, pivaloylamino.
- C 2 -C 6 -alkeny is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3 , 4 , 5, 6 carbon atoms, particularly 2 or 3 carbon atoms ("C 2 -C 3 -alkenyr), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other.
- Said alkenyl group is, for example, a vinyl, allyl, (£)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (£)-but-2-enyl, (Z)-but-2-enyl, (£)-but-1-enyl, (Z)-but-l -enyl, pent-4-enyl,
- C 2 -C 6 -alkyny is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5, 6 carbon atoms, particularly 2 or 3 carbon atoms ("C 2 -C 3 -alkyny ).
- Said C 2 -Ci 0 -alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop-2-ynyl, but-1 -ynyl, but-2-ynyl, but-3-ynyl, pent-1 -ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1 -ynyl, hex-2-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1 -methylbut-2-ynyl, 3-methylbut-1 -ynyl, 1 -ethylprop-2-ynyl,
- alkynyl group is ethynyl, prop-1 -ynyl, or prop-2-ynyl.
- C 3 -Cio-cycloalkyl is to be u nderstood as preferably meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, particularly 3, 4, 5, or 6 carbon atoms ("C 3 -C 6 -cycloalky ).
- Said C 3 -Ci 0 -cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl group, or a bicyclic hydrocarbon ring, e.g. a perhydropentalenylene or decalin ring.
- Said cycloalkyl ring can optionally contain one or more double bonds e.g.
- cycloalkenyl such as a cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or cyclodecenyl group, wherein the bond between said ring with the rest of the molecule may be to any carbon atom of said ring, be it saturated or unsaturated.
- said ring can contain 2, 3, 4, or 5 carbon atoms, and one or more of the above- mentioned heteroatom-containing groups (a "3- to 6-membered heterocycloalkyl"), more particularly said ring can contain 4 or 5 carbon atoms, and one or more of the above- mentioned heteroatom-containing groups (a "5- to 6-membered heterocycloalkyl").
- Non-limiting examples include aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, sulfolanyl, 1 ,3-dioxolanyl, 1 ,3-oxazolidinyl,
- 5- to 7-membered monocyclic heterocycloalkyl radicals having up to 2 heteroatoms selected from the group consisting of N , O and S, such as illustratively and preferably tetrahydrofuranyl, 1 ,3-dioxolanyl, pyrrolidinyl, tetrahydropyranyl,
- aryl is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 carbon atoms (a "C 6 -Ci4-ary group), particularly a ring having 6 carbon atoms (a "C 6 -aryl” group), e.g. a phenyl group, or a biphenyl group, or a ring having 9 carbon atoms (a "C 9 -aryl” group), e.g. an indanyl or indenyl group, or a ring having 10 carbon atoms (a "Ci 0 -aryl” group), e.g.
- heteroaryl is understood as preferably meaning a monovalent, aromatic, mono- or bicycl ic aromatic ri ng system having 5, 6 , 7 , 8 , 9 , 1 0 , 1 1 , 1 2 , 1 3 or 1 4 ring atoms (a "5- to 14-membered heteroaryl” group), particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and can be monocyclic, bicyclic, or tricyclic, and in addition in each case can be benzocondensed .
- heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, tetrazolyl and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl,; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, tria
- alkylene is understood as preferably meaning an optionally substituted hydrocarbon chain (or “tether”) having 1 , 2, 3, 4, 5, or 6 carbon atoms, i.e. an optionally substituted -CH 2 - ("methylene” or “single membered tether” or, for example -C(Me) 2 -), -CH2-CH2- ("ethylene”, “dimethylene”, or “two-membered tether"), -CH2-CH2-CH2- ("propylene”, “trimethylene”, or “three-membered tether"), -CH2-CH2-CH2-CH2- ("butylene”, “tetramethylene”, or “four-membered tether"), -CH2-CH2-CH2-CH2- ("pentylene”, “pentamethylene” or “five-mem bered ether”), or -CH2-CH2-CH2-CH2-CH2- (“hexylene”, “hexamethylene”, or six-membered tether”) group.
- methylene or "s
- alkylenedioxy is understood as preferably meaning -0-CrC 6 alkylene-0- in particular methylenedioxy and ethylenedioxy as in the below exemplified formula:
- CrC 6 as used throughout this text, e.g. in the context of the definition of "Ci-C 6 -alkyl", “Ci-C 6 -haloalkyl", “CrC 6 -alkoxy”, or “CrC 6 -haloalkoxy” is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “Ci-C 6 " is to be interpreted as any sub-range comprised therein, e.g.
- C 2 -C 6 as used throughout this text, e.g. in the context of the definitions of "C2-C 6 -alkenyl” and “C2-C 6 -alkynyl”, is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C 2 -C 6 " is to be interpreted as any sub-range comprised therein, e.g. C 2 -C 6 , C 3 -C 5 , C 3 -C 4 , C 2 -C 3 , C 2 -C 4 , C 2 -C 5 ; particularly C 2 -C 3 .
- C3-C10 as used throughout this text, e.g. in the context of the definition of "C 3 -Ci 0 -cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 10, i.e. 3, 4 , 5, 6 , 7, 8, 9 or 10 carbon atoms, particularly 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C 3 -Ci 0 " is to be interpreted as any sub-range comprised therein, e.g. C3-C10 , C 4 -C 9 , C 5 -C 8 , C 6 -C 7 ; particularly C 3 -C 6 .
- Oxo represents a double-bonded oxygen atom.
- the term "one or more times”, e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning “one, two, three, four or five times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times".
- the use of singular language is given preference over plural language, but is generally meant to include the plural language if not otherwise stated . E .g.
- the expression "A method of treating a disease in a patient, comprising administering to a patient an effective amount of a compound of formula (I)" is meant to include the simultaneous treatment of more than one disease as well as the administration of more than one compound of formula (I)
- N represents a £- or Z-isomer, or a mixture thereof. * indicates the point of attachment to of a given group, for example a ring, to general formula in which said group is reported.
- R 1a , R 1b independently of one another or joined, and taken together with the atom to which they are attached, and R 3a , R3b independently of one another have the meaning as given with any of the above or below embodiments or definitions.
- compounds according to formula (I) are in particular those in which Y is any one of the following groups:
- R 3a , R 3b independently of one another have the meaning as given with any of the above or below embodiments and definitions.
- compounds according to formula (I) are in particular those in which Y is any one of the following groups:
- R 1a , R 1b independently of one another or R 1a , R 1b together, and R 3a , R 3b independently of one another have the meaning as given with any of the above or below embodiments and definitions.
- a further embodiment, in conjunction with any of the above or below embodiments, comprises compounds according to formula (I) in which R 6 is a 6 member heteroaryl group with at least a nitrogen atom and in which a group Rn, having the meaning as given with any of the above or below embodiments and definitions, is present one or more times.
- R-n having the meaning as given with any of the above or below embodiments and definitions, is present one or more times.
- a further particular embodiment, in conjunction with any of the above or below embodiments, refers to compounds according to fo in which R 6 is in which a group Rn has the meaning as given with any of the above or below embodiments and definitions and is present one or more times.
- a further detailed embodiment, in conjunction with any of the above or below embodiments, refers to compounds according to formula (I) in which R 6 is any one of the following groups:
- R 11a , R 11b , and Rn c have the meaning as given with any of the above or below embodiments and definitions.
- R 11a is an halogen, particularly a fluorine atom
- Rn b is a
- -CrC 6 -haloalkyl -0-CrC 6 -alkyl or -0-CrC 6 -haloalkylgroup, particularly -CF 2 -CH 3 , -OCH 3 or
- R 11a is an halogen, particularly a fluorine atom
- R 11b is a hydrogen
- Rn c is a -0-CrC 6 -alkyl or -0-CrC 6 -haloalkylgroup, particularly -OCH 3 or -OCF 3 .
- compounds according to formula (I) are in particular those in which R 6 is any one of the following groups: in which a group Rn a and R 12 have the meaning as given with any of the above or below embodiments and definitions, and R 12 is present one or more times; or R 11a , R 12a and Ri 2 b have the meaning as given with any of the above or below embodiments and definitions.
- R 9 and R 10 represent, independently from each other hydrogen, hydroxyl, CrC 6 -alkyl, halo-CrC 6 -alkyl, CrC 6 -alkoxy, halo-CrC 6 -alkoxy or R 9 and R 10 joined, and taken together with the atom to which they are attached, form 5- to 6-membered heterocycloalkyl-, optionally substituted one or two times, in the same way or differently, with a substituent selected from : oxo, CrC 6 -alkyl-, aryl-, heteroaryl-, -Ci-C 6 -alkylene-aryl,
- R 1a is hydrogen, a methyl or
- R-ia and Ri b joined, and taken together with the atom to which they are attached,form a 5- to 6-membered heterocycloalkyl-, optionally substituted one or more times, in the same way or differently, with a substituent selected from : oxo, CrC 6 -alkyl-, a optionally substituted aryl-, heteroaryl-, -Ci-C 6 -alkylene-aryl, -Ci-C 6 -alkylene-heteroaryl said groups being one or more times substituted, in the same way or differently, with a halo, cyano, CrC 6 -alkyl- and halo-CrC 6 -alkyl- group.
- R 1a and Ri b joined, and taken together with the atom to which they are attached form a piperidin-1 -yl or 4-phenyl-piperazin-1 -yl.
- R-ia and Ri b joined, and taken together with the atom to which they are attached, form a piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl group, optionally substituted one or more times.
- R 2a and R 2 b are both a hydrogen atom or a methyl group.
- R 3a and R 3 b are independently of one another hydrogen atom, a CrC 6 -alkyl-,
- R 3a is hydrogen and R 3 b is aryl, particularly phenyl and phenyl substituated one or more times with a fluorine atom, a chlorine atom, a methyl group or -CF 3 .
- R 7 is an hydrogen atom, -CH 3 , -CF 3 , -CH 2 CH 3 , -CH 2 CF 3 .
- R 8a and R 8 b are independently of one another a hydrogen atom, a halogen atom, a
- R 8a and R 8 b are both a hydrogen atom
- R 8a is a hydrogen atom and R 8b is selected from the group consisting of halogen, CrC 6 -alkyl-, halo-d-Ce-alkyl;
- R 8a is selected from the group consisting of halogen, CrC 6 -alkyl-, halo-CrC 6 -alkyl
- R 8b is selected from the group consisting of halogen, CrC 6 -alkyl-, halo-CrC 6 -alkyl
- R 8a and R 8b are in particular, independently of one another, a hydrogen atom, a fluorine atom or a fluorinated CrC 6 -alkyl group, more in particular a -CF 3 .
- R 9 and R 10 are independently selected from the group consisting of hydrogen, hydroxyl, CrC 6 -alkyl, halo-CrC 6 -alkyl, CrC 6 -alkoxy, halo-CrC 6 -alkoxy
- R 9 and R 10 joined, and taken together with the atom to which they are attached, form a 5- to 6-membered heterocycloalkyl-, optionally substituted one or more times, in the same way or differently, with a substituent selected from : oxo, CrC 6 -alkyl-, aryl-, heteroaryl-, -Ci-C 6 -alkylene-aryl, -Ci-C 6 -alkylene-heteroaryl.
- Rn , R 11a , R 11b and Rn c are independently of one another hydrogen, halogen, hydroxy, cyano, nitro, CrC 6 -alkyl, halo-CrC 6 -alkyl, CrC 6 -alkoxy, halo-CrC 6 -alkoxy with halogen, preferably fluorine atom.
- R-I2 , Ri2a and Ri 2 b are an hydrogen or an halogen atom, preferably a fluorine atom.
- R 2a and R 2 b are both a hydrogen atom or a methyl group
- R 8a and R 8 b are independently selected from the group consisting of hydrogen, halogen, CrC 6 -alkyl-, halo-CrC 6 -alkyl,
- Rii is present one or more times and is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, CrC 6 -alkyl,
- R 1a , R 1b , R3a , R3b have the meaning as given with any of the above or below embodiments or definitions.
- R 2a and R 2 b are both a hydrogen atom or a methyl group
- R 8a and R 8 b are independently selected from the group consisting of hydrogen, halogen, CrC 6 -alkyl-, halo-CrC 6 -alkyl
- Rii is present one or more times and is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, CrC 6 -alkyl,
- R 1a , R 1b , R3a , R3b have the meaning as given with any of the above or below embodiments or definitions.
- R 2a and R 2 b are both a hydrogen atom or a methyl group
- R 8a and R 8 b are independently selected from the group consisting of hydrogen, halogen, C C 6 -alkyl-, halo-C C 6 -alkyl
- Rii is present one or more times and is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, CrC 6 -alkyl, halo-CrC 6 -alkyl, CrC 6 -alkoxy, halo-CrC 6 -alkoxy, and in which R 1a , R 1b , R3a , R3b have the meaning as given with any of the above or below embodiments or definitions.
- R 1a , R 1b , R3a , R3b have the meaning as given with any of the above or below embodiments or definitions.
- R 2a and R 2 b are both a hydrogen atom or a methyl group
- R 8a and R 8 b are independently selected from the group consisting of hydrogen, halogen, CrC 6 -alkyl-, halo-CrC 6 -alkyl,
- Rii present one time and is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, CrC 6 -alkyl, halo-CrC 6 -alkyl,
- R 2a and R 2 b are both a hydrogen atom or a methyl group
- R 8a and R 8 b are independently selected from the group consisting of hydrogen, halogen, CrC 6 -alkyl-, halo-CrC 6 -alkyl,
- R 6 is any one of the following groups:
- R-n is present one to three times and is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, CrC 6 -alkyl, halo-CrC 6 -alkyl, CrC 6 -alkoxy, halo-CrC 6 -alkoxy and in which R 1a , R 1b , R3a , R3b have the meaning as given with any of the above or below embodiments or definitions.
- R 11a , R 11b , and Rn c are independently of one another hydrogen, halogen, hydroxy, cyano, nitro, CrC 6 -alkyl, halo-CrC 6 -alkyl, CrC 6 -alkoxy, halo-CrC 6 -alkoxy, and in wh ich all other grou ps have the mean i ng as given with any of th e a bove or below embodiments or definitions.
- R 11a is a halogen atom, particularly a fluorine atom
- Rn b is selected from the group consisting of
- R 2a and R 2 b are both a hydrogen atom
- R 8a is a hydrogen atom and R 8 b is selected from the group consisting of halogen atom, CrC 6 -alkyl-, halo-CrC 6 -alky; or
- R 8a is selected from the group consisting of halogen, CrC 6 -alkyl-, halo-CrC 6 -alky and R 8b is selected from the group consisting of halogen, CrC 6 -alkyl-, halo-CrC 6 -alkyl, Y is any one of the following groups:
- R 11a is an halogen, particularly a fluorine atom
- Rn b is selected from the group consisting of
- R 2a and R 2b are both a hydrogen atom
- R 8a and R 8b are both an halogen atom in particular a fluorine atom, or
- R 8a is an halogen atom, in particular a fluorine atom
- R 8b is a CrC 6 -alkyl-, or halo-CrC 6 -alkyl, in particular a -CF 3 .
- Y is any one of the following groups:
- R 11a is an halogen, particularly a fluorine atom, and Rn b is selected from the group consisting of
Abstract
Pyridinone derivatives, process for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for the manufacture of medicaments for the treatment and/or prophylaxis of diseases, especially sex-hormone-related conditions in both men and women, as well as a mammal in general (also referred to herein as a "subject"). For example, such conditions include endometriosis, uterine fibroids, polycystic ovarian disease, heavy menstrual bleeding, particularly menorrahagia and dysmenorrehea, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia such as cancers of the prostate, breast and ovary, gonadotrope pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, contraception and infertility (e.g., assisted reproductive therapy such as in vitro fertilization). The present application relates in particular to pyridinone derivatives as gonadotropin-releasing hormone (GnRH) receptor antagonists.
Description
Pyridinone derivatives and pharmaceutical compositions thereof
TECHNICAL FIELD The present invention refers generally to pyridinone derivatives as gonadotropin-releasing hormone (GnRH) receptor antagonists, pharmaceutical compositions containing a pyridinone derivative according to the invention and methods of treating disorders by administration of a pyridinone derivative according to invention to a mammal, particularly a human, in need thereof.
BACKGROUND ART
Gonadotropin-releasing hormone (GnRH) is a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu- Arg-Pro-Gly-NH2) released from the hypothalamus, also known as luteinizing hormone- releasing hormone (LHRH). GnRH acts on the pituitary gland to stimulate the biosynthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH released from the pituitary gland is responsible for the regulation of gonadal steroid production in both genders and late ovarian follicle development and ovulation in female mammals, FSH regulates spermatogenesis in males and early follicular development in females. Thus GnRH plays a key role in human reproduction.
As a consequence of its biological significance, synthetic antagonists and agonists to GnRH have been the center of several research activities, particularly in the field of endometriosis, uterine leiomyoma (fibroids), prostate cancer, breast cancer, ovarian cancer, prostatic hyperplasia, assisted reproductive therapy and precocious puberty.
For example, peptidic GnRH agonists, such as leuprorelin (pGlu-His-Trp-Ser-Tyr-d-Leu-Leu- Arg-Pro-NHEt), are described for the use in the treatment of such conditions (The Lancet 2001 , 358, 1793 - 1803; Mol. Cell. Endo. 2000, 166, 9 - 14). Said agonists initially induce the synthesis and release of gonadotropins, by binding to the GnRH receptor on the pituitary gonadotrophic cells ('flare-up'). However, chronic administration of GnRH agonists reduces gonadotropin release from the pituitary and results in the down-regulation of the receptor, with the consequence of suppressing sex steroidal hormone production after some period of treatment. GnRH antagonists, on the contrary, are supposed to suppress gonadotropins from the onset, offering several advantages, in particular a lack of side effects associated with the flare up seen under GnRH superagonist treatment. Several peptidic antagonists with low histamine
release potential are known in the art. Said peptidic products show low oral bioavailability which limits their clinical use.
A number of nonpeptidic compounds have also been described for use as GnRH receptor antagonists, for example:
Thieno [2,3-b]pyridin-4-ones {C o et al., J. Med. C em. 1998, 41, 4190 - 4195); substituted indoles (US 5,780, 437, US 5,849, 764, WO97/21 704, W098/55479, WO98/55470, W098/551 16, W098/551 1 9 , WO 97/21 707 , WO97/21 703 and W097/21435);
- tricyclic diazepines (WO 96/38438) and phenyl-substituted fused nitrogen-containing bicyclic compounds W099/33831 ;
quinoline and thienopyridine derivatives (W097/14682, W097/14697 and WO99/09033);
substituted quinolin-2-ones (WO97/44037 , WO97/44041 , W097/44321 and W097/44339);
indole derivatives and novel bicyclic and tricyclic pyrrolidine (WO02/066459 and WO02/1 1732).
Other compounds with a heterocyclic structure and their use as GnRH antagonists are included in WO00/69859, WO01 /29044, WO01 /551 1 9, WO03/01 3528, WO03/01 1870, WO03/01 1841 , WO03/01 1839, WO03/01 1293 and WO05/007164.
Nevertheless, effective small molecule GnRH receptor antagonists are still highly required in art as well as pharmaceutical compositions containing such GnRH receptor antagonists and methods relating to the use thereof to treat, for example, sex-hormone-related conditions in particular for the treatment of leiomyoma.
The pyridinone derivatives according to the present invention meets these needs, and provide at the same time further related advantages.
Pyridinone derivatives are known in the art as pharmaceutical active ingredients but their activity as GnRH receptor antagonists has not been described as state of the art, for example
WO 01 36426 A1 refers to pyridinones and their derivatives which are described to be effective in treating or preventing Gram-negative bacterial infections. The pyridinones are stable and easily derivatized; the methods by which these derivatizations are accomplished are described. Two regioselective and functional group-tolerant methods for the synthesis of
the novel pyridinones are also provided. One such synthetic method involves reacting an imine and a Meldrum's acid derivative in solution. The other synthetic method is a solid phase synthesis of the pyridinones in which an imine is prepared bound to a solid support and a Meldrum's acid derivative is reacted with the imine. Novel imine intermediates useful in the solid phase and solution methods of synthesizing the pyridinones are also described.
WO 2008054290 A1 describes 1 H-pyridine-2-one derivatives, inhibitors of PAI-1 , processes for their preparation, pharmaceutical compositions containing them and their use in therapy. The compounds of Formula I , I I and I I I may be used in the treatment of, for example, thrombosis, coronary heart disease, renal fibrosis, atherosclerotic plaque formation, cancer, diabetes and obesity.
DISCLOSURE OF THE INVENTION The aim of the present invention is to provide gonadotropin-releasing hormone (GnRH) receptor antagon ists, as wel l as the methods for their preparation and use, and pharmaceutical compositions containing the same.
In particular, the present invention relates to compounds of the general formula (I):
(I)
in which
R2a and R: represent independently of one another a hydrogen atom, a
CrC6-alkyl- or a C3-C6-cycloalkyl- group, or
R2a and R2b joined, and taken together with the atom to which they are attached, form a C3-C6-cycloalkyl- group; represents a halogen atom, an aryl-, a heteroaryl-, a benzo[1 ,3]dioxolyl- 2,3-dihydro-1 ,4-benzodioxinyl group wherein said group is optionally substituted one or more times, in the same way or differently, with a substituent R-n selected from :
hydrogen, halogen, hydroxy, cyano, nitro, CrC6-alkyl, halo-CrC6-alkyl,
CrC6-alkoxy, halo-CrC6-alkoxy, Ci-C6-hydroxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, Ci-C6-alkyl-C(=0)OH, C3-Ci0-cycloalkyl, 3- to 10-membered heterocycloalkyi, aryl, heteroaryl, aryloxy-, heteroaryloxy-, -C(=0)OH, -C(=0)0-CrC6-alkyl,
-N(H)C(=0)R9,
-N(H)S(=0)2R9, -N(CrC6-alkyl)S(=0)2R9,
-C(=0)N R9R10, -OC
-N(H)C(=0)N R9R10,
9, -S(=0)2N R9R10, -N R9R10 ; wherein
R9 and R10 represent, independently of one another, a hydrogen atom, a d-Ce-alkyl-, halo-C C6-alkyl-, Ci-C6-alkoxy-Ci-C6-alkyl-,
halo-Ci-C6-alkoxy-Ci-C6-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-,
C3-Ci0-cycloalkyl-, 3- to 10-membered heterocycloalkyi-, aryl-, heteroaryl-, Ci-C6-alkylene-aryl-, Ci-C6-alkylene-heteroaryl-,
-Ci-C6-alkylene-C3-Cio-cycloalkyl-, CrC6-alkylene-(3- to 10-membered heterocycloalkyi group ; wherein said C3-Ci0-cycloalkyl- and said 3- to 10- membered heterocycloalkyi- group are optionally substituted one or more times with a halogen atom, cyano, -OH , CrC6-alkyl, halo-CrC6-alkyl,
CrC6-alkoxy, C3-Ci0-cycloalkyl, aryl or a heteroaryl group ; or
R9 and R10 joined, and taken together with the atom to which they are attached, form a
3- to 10-membered heterocycloalkyi-, optionally substituted one or more times, in the same way or differently, with a substituent selected from the group consisting of halo-, hydroxyl-, cyano-, nitro-, oxo, CrC6-alkyl-,
halo-CrC6-alkyl-, CrC6-alkoxy-, halo-CrC6-alkoxy-, Ci-C6-alkoxy-Ci-C6-alkyl-, halo-Ci-C6-alkoxy-Ci-C6-alkyl-, C3-Ci0-cycloalkyl-,
3- to 10-membered heterocycloalkyi-, -C(=0)OH , -C(=0)0-C C6-alkyl, - C(=0)0-C3-Cio-cycloalkyl, -OC(=0)-C C6-alkyl, -OC(=O)-C3-Ci0-cycloalkyl, -N(H)C(=0)(CrC6)-alkyl, -N(Ci-C6-alkyl)C(=0)(Ci-C6)-alkyl,
-N(H)S(=0)2(CrC6)-alkyl, -N(Ci-C6-alkyl)S(=0)2(Ci-C6)-alkyl,
-C(=0)N((Ci-C6)-alkyl)((Ci-C6)-alkyl),
-OC(=0)N((Ci-C6)-alkyl)((Ci-C6)-alkyl), -N(H)C(=0)0(C C6)-alkyl,
-N(Ci-C6-alkyl)C(=0)0(Ci-C6)-alkyl, -N(H)C(=0)N ((Ci-C6)-alkyl)((Ci-C6)-alkyl), -N(Ci-C6-alkyl)C(=0)N((Ci-C6)-alkyl)((Ci-C6)-alkyl), -S(C C6)-alkyl,
-S(=0)(CrC6)-alkyl, -S(=0)2OH , -S(=0)2(C C6)-alkyl,
-S(=0)2N((C1-C6)-alkyl)((C1-C6)-alkyl), -P(=0)(OH)2,
-P(=0)(0(Ci-C6)-alkyl)(Ci-C6)-alkyl), -N((Ci-C6)-alkyl)((Ci-C6)-alkyl) and in which (CrC6)-alkyl is optionally substituted with one or more halogen atoms;
represents a hydrogen atom, CrC6-alkyl, halo-CrC6-alkyl or a C3-C6-cycloalkyl group;
W is O, S, S=0 or S(=0)2;
X is
in which
R8 represents one or more substituents independently selected from the group consisting of hydrogen, halogen, cyano, nitro,
a CrC6-alkyl-, halo-CrC6-alkyl-, CrC6-alkoxy-, Ci-C6-alkoxy-Ci-C6-alkyl-, halo-Ci-C6-alkoxy-Ci-C6-alkyl-, C2-C6-alkenyl-, a C2-C6-alkynyl- group, -C(=0)R9, -C(=0)OR9, -C(=0)NR9R10, -SR9, -S(=0)R9, -S(=0)2R9,
-S(=0)2NR9R10 or -NR9R10; wherein R9 and R10 independently of one another or joined, and taken together with the atom to which they are attached, have the meaning given above;
Y is
R-ia, and Rib represent independently of one another a hydrogen atom, a CrC6-alkyl-, Ci-C6-alkoxy-Ci-C6-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C8-cycloalkyl-, aryl-, heteroaryl-, -Ci-C6-alkylene-aryl,
-Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl, -CrC6-alkylene-(3- to 10-membered heterocycloalkyl),
-C(=0)-C C6-alkyl, -C(=0)-Ci-C6-alkylene-aryl,
-C(=0)-Ci-C6-alkylene-heteroaryl, -C(=0)0-C C6-alkyl,
-C(=0)0-Ci-C6-alkylene-aryl, -C(=0)0-Ci-C6-alkylene-heteroaryl,
-C(=0)NR9R10, -S(=0)2R9 group; wherein said groups are optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo-, hydroxy-, cyano-, nitro-, CrC6-alkyl-, halo-CrC6-alkyl-, CrC6-alkoxy-, halo-CrC6-alkoxy-,
Ci-C6-alkoxy-Ci-C6-alkyl-, halo-Ci-C6-alkoxy-Ci-C6-alkyl-,
C3-Ci0-cycloalkyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-, -C(=0)OH, -C(=0)0-CrC6-alkyl,
-OC(=0)-CrC6-alkyl,
-N(CrC6-alkyl)C(=0)
-C(=0)NR9R10, -OC(=0)NR9R10, -N(H)C(=0)OR9, -N(C C6-alkyl)C(=0)OR9,
-SR9, -S(=0)R9, -S(=0)2OH, -S(=0)2R9, -S(=0)2NR9R10, -P(=0)(OH)2, -P(=0)(OR9)(OR10), -NR9R10 , and wherein R9 and R10 independently of one another or joined, and taken together with the atom to which they are attached, have the meaning given above; or
R-ia and Rib joined, and taken together with the atom to which they are attached, form a 3- to 10-membered heterocycloalkyl-, optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo-, hydroxyl-, cyano-, nitro-, oxo, CrC6-alkyl-, halo-CrC6-alkyl-, CrC6-alkoxy-, halo-CrC6-alkoxy-,
Ci-C6-alkoxy-Ci-C6-alkyl-, halo-Ci-C6-alkoxy-Ci-C6-alkyl-,
-C(=0)OH, -C(=0)0-CrC6-alkyl,
-OC(=0)-CrC6-alkyl,
-N(H)C(=0)R9,
-N(CrC6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(C C6-alkyl)S(=0)2R9,
-C(=0)NR9R10, -OC(=0)NR9R10, -N(H)C(=0)OR9,
-N(CrC6-alkyl)C(=0)OR9, -N(H)C(=0)NR9R10, -N(H)C(=NH)NR9R10,
-SR9, -S(=0)R9, -S(=0)2OH, -S(=0)2R9, -S(=0)2NR9R10, -P(=0)(OH)2, -P(=0)(OR9)(OR10), -NR9R10
wherein R9 and R10 independently of one another or joined, and taken together with the atom to which they are attached, have the meaning given above, or
R-ia and Rib joined, and taken together with the atom to which they are attached, form a 3- to 10-membered heterocycloalkyl-, substituted with a group selected from : C3-Ci0-cycloalkyl-, aryl-, heteroaryl-,
-Ci-C6-alkylene-aryl, -Ci-C6-alkylene-heteroaryl,
-CrC6-alkylene-C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyl-, -CrC6-alkylene-heterocycloalkyl-, said groups being optionally substituted one
or more times, in the same way or differently, with a substituent selected from : halo, cyano, CrC6-alkyl- and halo-CrC6-alkyl- ;
Ric represents a hydrogen atom, a hydroxy group, a methoxy group or a CrC6-alkoxy-, a CrC6-alkyl-, Ci-C6-alkoxy-Ci-C6-alkyl-,
C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C8-cycloalkyl-, aryl-, heteroaryl-,
-Ci-C6-alkylene-aryl, -Ci-C6-alkylene-heteroaryl,
-Ci-C6-alkylene-C3-Cio-cycloalkyl, -CrC6-alkylene-(3- to 10-membered heterocycloalkyi) group; wherein said groups are optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo-, hydroxyl-, cyano-, nitro-, CrC6-alkyl-,
halo-CrC6-alkyl-, CrC6-alkoxy-, halo-CrC6-alkoxy-,
Ci-C6-alkoxy-Ci-C6-alkyl-, halo-Ci-C6-alkoxy-Ci-C6-alkyl-,
C3-Cio-cycloalkyl-, 3- to 10-membered heterocycloalkyi-, -C(=0)OH,
-C(=0)0-C C6-alkyl, -C(=O)O-C3-Ci0-cycloalkyl, -OC(=0)-C C6-alkyl,
-OC(=0)NR9R10, -N(H)C(=0)OR9, -N(C C6-alkyl)C(=0)OR9,
-SR9, -S(=0)R9, -S(=0)2R9, -S(=0)2NR9R10, -NR9R10 wherein R9 and R10 independently of one another or joined, and taken together with the atom to which they are attached, have the meaning given above;
R3a and R3b represent independently of one another a hydrogen atom, a d-Ce-alkyl-, Ci-C6-alkoxy-Ci-C6-alkyl-, C2-C6-alkenyl-,
C2-C6-alkynyl-, C3-C8-cycloalkyl-, 3- to 10-membered heterocycloalkyi-, aryl-, heteroaryl-, -Ci-C6-alkylene-aryl, -Ci-C6-alkylene-heteroaryl,
-CrC6-alkylene-C3-Cio-cycloalkyl, -CrC6-alkylene-(3- to 10-membered heterocycloalkyi) group; wherein said groups are optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo-, hydroxyl-, cyano-, nitro-, CrC6-alkyl-, halo-CrC6-alkyl-, CrC6-alkoxy-, halo-CrC6-alkoxy-, Ci-C6-alkoxy-Ci-C6-alkyl-, halo-Ci-C6-alkoxy-Ci-C6-alkyl-, aryl-, heteroaryl-, C3-Ci0-cycloalkyl-, 3- to 10-membered heterocycloalkyi-, -C(=0)OH, -C(=0)0-CrC6-alkyl,
-OC(=0)-CrC6-alkyl,
-N(H)C(=0)R9,
-N(CrC6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(C C6-alkyl)S(=0)2R9,
-C(=0)NR9R10, -OC(=0)NR9R10, -N(H)C(=0)OR9, -N(C C6-alkyl)C(=0)OR9,
-SR9, -S(=0)R9, -S(=0)2R9, -S(=0)2NR9R10, -NR9R10 wherein R9 and R10 independently of one another or joined, and taken together with the atom to which they are attached, have the meaning given above; or
Ria and R3a , or R1b and R3a , or R3b and Ria , or R3b and Rib joined, and taken together with the atom to which they are attached, form a 4- to 10-membered heterocycloalkyl- or 4- to 10-membered heterocycloalkenyl-, optionally substituted one or more times, in the same way or differently, with a substituent selected from :
halo-, hydroxyl-, cyano-, nitro-, CrC6-alkyl-, halo-CrC6-alkyl-,
CrC6-alkoxy-, halo-CrC6-alkoxy-, Ci-C6-alkoxy-Ci-C6-alkyl-,
halo-Ci-C6-alkoxy-Ci-C6-alkyl-, C3-Ci0-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, -C(=0)OH, -C(=0)0-C C6-alkyl,
-C(=0)0-C3-Cio-cycloalkyl, -OC(=0)-C C6-alkyl,
-OC(=0)NR9R10, -N(H)C(=0)OR9, -N(C C6-alkyl)C(=0)OR9,
-SR9, -S(=0)R9, -S(=0)2OH, -S(=0)2R9, -S(=0)2NR9R10, -P(=0)(OH)2,
-P(=0)(OR9)(OR10), -NR9R10 wherein R9 and R10 independently of one another or joined, and taken together with the atom to which they are attached, have the meaning given above, and
all the other substituents in Y have the meaning given above; with the proviso that Y is not -C(=0)H.
Compounds of the invention are the compounds of the formula (I) and the salts, solvates and solvates of the salts thereof, the compounds which are encompassed by formula (I) and are of the formulae mentioned hereinafter, and the salts, solvates and solvates of the salts thereof, and the compounds which are encompassed by formula (I) and are mentioned hereinafter as exemplary embodiments, and the salts, solvates and solvates of the salts thereof, insofar as the compounds encompassed by formula (I) and mentioned hereinafter are not already salts, solvates and solvates of the salts.
Hydrates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with water, such as, for example, hemi-, mono-, or dihydrates.
Solvates of the compounds of the invention or their salts are stoichiometric compositions of the compounds with solvents.
Solvates which are preferred for the purposes of the present invention are hydrates.
Salts for the purposes of the present invention are preferably pharmaceutically acceptable salts of the compounds according to the invention (for example, see S. M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19).
Pharmaceutically acceptable salts include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, maleic, fumaric, benzoic, ascorbic, succinic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, and glutamic acid.
Pharmaceutically acceptable salts also include salts of customary bases, such as for example and preferably alkali metal salts (for example sodium, lithium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts), and ammonium salts derived from ammonia or organic amines, such as illustratively and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, benzylamine, dibenzylamine, N-methylmorpholine, N-methylpiperidine, dihydroabietyl- amine, argi ni ne, lysi ne, and ethylenediamine. Also encompassed are salts which are themselves unsuitable for pharmaceutical uses but can be used for example for isolating or purifying the compounds of the invention.
The present invention additionally encompasses prodrugs of the compounds of the invention. The term "prodrugs" encompasses compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body into compounds of the invention (for example by metabolism or hydrolysis).
Furthermore, the compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers (enantiomers, diastereomers). Any isomer may be present in which the asymmetric center is in the (R)-, (S)-, or (Reconfiguration.
It will also be appreciated that when two or more asymmetric centers are present in the compounds of the invention, several diastereomers and enantiomers of the exemplified structures will often be possible, and that pure diastereomers and pure enantiomers represent preferred embodiments. It is intended that pure stereoisomers, pure diastereomers, pure enantiomers, and mixtures thereof, are within the scope of the invention.
Geometric isomers by nature of substituents about a double bond or a ring may be present in cis (= Z-) or trans (= £-) form, and both isomeric forms are encompassed within the scope of this invention.
All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this invention are encompassed within the scope of this invention. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art. For example, diastereomeric mixtures can be separated into the individual isomers by chromatographic processes or crystallization, and racemates can be separated into the respective enantiomers either by chromatographic processes on chiral phases or by resolution.
If the compounds of the invention may occur in tautomeric forms, the present invention encompasses all tautomeric forms.
Unless otherwise stated, the following definitions apply for the substituents and residues used throughout this specification and claims. The particularly named chemical groups and atoms (for example fluorine, methyl, methyloxy and so on) should be considered as particular forms of embodiment for the respective groups in compounds according to the invention.
The term "halogen atom" or "halo" is to be understood as meaning a fluorine, chlorine, bromine or iodine atom. The term "Ci-C6-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl,
1 ,1 -dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -methylpentyl,
2-ethylbutyl, 1 -ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1 ,1 -dimethylbutyl,
2,3-dimethylbutyl, 1 ,3-dimethylbutyl, or 1 ,2-dimethylbutyl group, or an isomer thereof.
Particularly, said group has 1 , 2 or 3 carbon atoms ("Ci-C3-alkyl"), methyl, ethyl, n-propyl- or iso-propyl.
The term "halo-Ci-C6-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "C"i-C6-alky is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in the same way or differently, i.e. one halogen atom being independent from another.
Particularly, said halogen atom is F. Said halo-CrC6-alkyl group is, in particular -CF3, -CHF2, -CH2F, -CF2CF3, -CF2CH3, or -CH2CF3.
The term "CrC6-alkoxy" is to be understood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term "alkyl" is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof.
The term "halo-CrC6-alkoxy" is to be understood as preferably meaning a linear or branched, saturated, monovalent CrC6-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in the same way or differently, by a halogen atom.
Particularly, said halogen atom is F. Said halo-CrC6-alkoxy group is, for example, -OCF3, -OCHF2, -OCH2F, -OCF2CF3, or -OCH2CF3.
The term "C-i-Ce-alkoxy-C-i-Ce-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in the same way or differently, by a CrC6-alkoxy group, as defined supra, e.g. methoxyalkyl, ethoxyalkyl, propyloxyalkyl, iso-propoxyalkyl, butoxyalkyl, iso-butoxyal kyl , tert-butoxyalkyl, sec-butoxyalkyl, pentyloxyalkyl, iso-pentyloxyalkyl, hexyloxyalkyl group, in which the term "C"i-C6-alky is defined supra, or an isomer thereof .
The term "halo-Ci-C6-alkoxy-Ci-C6-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent Ci-C6-alkoxy-Ci-C6-alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in the same way or differently, by a halogen atom.
Particularly, said halogen atom is F. Said halo-Ci-C6-alkoxy-Ci-C6-alkyl group is, for example, -CH2CH2OCF3, -CH2CH2OCHF2, -CH2CH2OCH2F, -CH2CH2OCF2CF3, or -CH2CH2OCH2CF3.
Alkylcarbonyl in general represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms which is bonded via a carbonyl group to the rest of the molecule. Non-limiting examples include acetyl, n-propionyl, n-butyryl, isobutyryl, pivaloyl. Alkoxycarbonylamino illustratively and preferably represents methoxycarbonylamino, ethoxy- carbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino and tert.-butoxycarbonylamino.
Alkoxycarbonyl illustratively and preferably represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl and tert.-butoxycarbonyl.
Alkylsulfonyl in general represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms which is bonded via a sulfonyl (-S02-) group to the rest of the molecule. Non- limiting examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n- butylsulfonyl, tert.-butylsulfonyl.
S-Alkylsulfonimidoyl in general represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms which is bonded via a sulfonimidoyi [-S(=0)(=NH)-] group to the rest of the molecule and which is attached to the sulfur atom of that group. Non-limiting examples i n c l u d e S-methylsulfonimidoyl, S-ethylsulfonimidoyl, S-n-propylsulfonimidoyl, S-isopropylsulfonimidoyl, S-n-butylsulfonimidoyl, S-tert.-butylsulfonimidoyl. Monoalkylamino in general represents an amino radical having one alkyl residue attached to the nitrogen atom. Non-l i m i ti n g exa m p l es i n cl u d e m eth yl a m i n o , ethyl a m i n o , n-propylamino, iso-propylamino, n-butylamino, tert-butylamino. The same applies to radicals such as monoalkyl- aminocarbonyl.
Dialkylamino in general represents an amino radical having two independently selected alkyl residues attached to the nitrogen atom. Non-limiting examples include Λ/,/V-dimethylamino, Λ/,/V-diethylamino, Λ/,/V-diisopropylamino, /V-ethyl-/V-methylamino, /V-methyl-/V-n-propylamino, /V-iso-propyl-/V-n-propylamino, /V-tert.-butyl-/V-methylamino. The same applies to radicals such as di-alkylaminocarbonyl.
Monoalkylaminocarbonyl illustratively and preferably represents methylaminocarbonyl, ethyl- aminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl and tert-butylaminocarbonyl.
Dialkylaminocarbonyl illustratively and preferably represents Λ/,/V-dimethylaminocarbonyl, Λ/,/V-diethylaminocarbonyl, Λ/,/V-diisopropylaminocarbonyl, /V-ethyl-/V-methylaminocarbonyl, /V-methyl-/V-n-propylaminocarbonyl, /V-isopropyl-/V-n-propylaminocarbonyl and
/V-tert-butyl-/V-methyl-aminocarbonyl.
Alkylcarbonylamino in general represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms which is bonded via a carbonylamino (-C(=0)-NH-) group to the rest of the molecule and which is attached to the carbon atom of that group. Non-limiting examples include acetyl- amino, n-propionylamino, n-butyrylamino, isobutyrylamino, pivaloylamino.
The term "C2-C6-alkeny is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3 , 4 , 5, 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkenyr), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other.
Said alkenyl group is, for example, a vinyl, allyl, (£)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (£)-but-2-enyl, (Z)-but-2-enyl, (£)-but-1-enyl, (Z)-but-l -enyl, pent-4-enyl,
(£)-pent-3-enyl, (Z)-pent-3-enyl, (£)-pent-2-enyl, (Z)-pent-2-enyl, (£)-pent-1 -enyl,
(Z)-pent-l -enyl, hex-5-enyl, (£)-hex-4-enyl, (Z)-hex-4-enyl, (£)-hex-3-enyl, (Z)-hex-3-enyl, (£)-hex-2-enyl, (Z)-hex-2-enyl, (£)-hex-1 -enyl, (Z)-hex-l -enyl, isopropenyl,
2- methylprop-2-enyl, 1 -methylprop-2-enyl, 2-methylprop-1 -enyl, (£)-1 -methylprop-1 -enyl, (Z)-1 -methylprop-1 -enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1 -methylbut-3-enyl,
3- methylbut-2-enyl, (£)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (£)-1 -methylbut-2-enyl, (Z)-1 -methylbut-2-enyl, (£)-3-methylbut-1 -enyl, (Z)-3-methylbut-1 -enyl,
(£)-2-methylbut-1 -enyl, (Z)-2-methylbut-1 -enyl, (£)-1 -methylbut-1 -enyl,
(Z)-1 -methylbut-1 -enyl, 1 ,1 -dimethylprop-2-enyl, 1-ethylprop-1 -enyl, 1 -propylvinyl,
1 -isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl,
1 -methylpent-4-enyl, 4-methylpent-3-enyl, (£)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl, (£)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl, (£)-1 -methylpent-3-enyl,
(Z)-1 -methylpent-3-enyl, (£)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl,
(£)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl, (£)-2-methylpent-2-enyl,
(Z)-2-methylpent-2-enyl, (£)-1 -methylpent-2-enyl, (Z)-1 -methylpent-2-enyl,
(£)-4-methylpent-1 -enyl, (Z)-4-methylpent-1 -enyl, (£)-3-methylpent-1 -enyl,
(Z)-3-methylpent-1 -enyl, (£)-2-methylpent-1 -enyl, (Z)-2-methylpent-1 -enyl,
(£)-1 -methylpent-1 -enyl, (Z)-1 -methylpent-1 -enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1 -ethylbut-3-enyl, (£)-3-ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (£)-2-ethylbut-2-enyl,
(Z)-2-ethylbut-2-enyl, (£)-1 -ethylbut-2-enyl, (Z)-1 -ethylbut-2-enyl, (£)-3-ethylbut-1 -enyl,
(Z)-3-ethylbut-1 -enyl, 2-ethylbut-l -enyl, (£)-1 -ethylbut-1 -enyl, (Z)-1 -ethylbut-1 -enyl,
2- propylprop-2-enyl, 1 -propylprop-2-enyl, 2-isopropylprop-2-enyl, 1 -isopropylprop-2-enyl, (£)-2-propylprop-1 -enyl, (Z)-2-propylprop-1 -enyl, (£)-1 -propylprop-1 -enyl,
(Z)-1 -propylprop-1 -enyl, (£)-2-isopropylprop-1 -enyl, (Z)-2-isopropylprop-1 -enyl,
(£)-1 -isopropylprop-1 -enyl, (Z)-1 -isopropylprop-1 -enyl, (£)-3,3-dimethylprop-1 -enyl,
(Z)-3,3-dimethylprop-1 -enyl, 1 -(1 ,1 -dimethylethyl)ethenyl, buta-1 ,3-dienyl, penta-1 ,4-dienyl, hexa-1 ,5-dienyl, or methylhexadienyl group. Particularly, said group is vinyl or allyl.
The term "C2-C6-alkyny is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5, 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkyny ).
Said C2-Ci0-alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop-2-ynyl, but-1 -ynyl, but-2-ynyl, but-3-ynyl, pent-1 -ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1 -ynyl, hex-2-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1 -methylbut-2-ynyl, 3-methylbut-1 -ynyl, 1 -ethylprop-2-ynyl,
3- methylpent-4-ynyl, 2-methylpent-4-ynyl, 1 -methylpent-4-ynyl, 2-methylpent-3-ynyl,
1 -methylpent-3-ynyl, 4-methylpent-2-ynyl, 1 -methylpent-2-ynyl, 4-methylpent-1 -ynyl,
3-methylpent-1 -ynyl, 2-ethylbut-3-ynyl, 1 -ethylbut-3-ynyl, 1 -ethylbut-2-ynyl,
1 -propylprop-2-ynyl, 1 -isopropylprop-2-ynyl, 2,2-dimethylbut-3-inyl, 1 ,1 -dimethylbut-3-ynyl, 1 ,1 -dimethylbut-2-ynyl, or 3,3-dimethylbut-1 -ynyl group. Particularly, said alkynyl group is ethynyl, prop-1 -ynyl, or prop-2-ynyl.
The term "C3-Cio-cycloalkyl" is to be u nderstood as preferably meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, particularly 3, 4, 5, or 6 carbon atoms ("C3-C6-cycloalky ).
Said C3-Ci0-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl group, or a bicyclic hydrocarbon ring, e.g. a perhydropentalenylene or decalin ring. Said cycloalkyl ring can optionally contain one or more double bonds e.g. cycloalkenyl, such as a cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or cyclodecenyl group, wherein the bond between said ring with the rest of the molecule may be to any carbon atom of said ring, be it saturated or unsaturated.
The term "3- to 10-membered heterocycloalkyi" is to be understood as preferably meaning a saturated or partially unsaturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, and one or more heteroatom-containing groups selected from C(=0), O, S, S(=0), S(=0)2, NH, NR', wherein R' represents a
d-Ce-alkyl, C3-C6-cycloalkyl, C3-C6 heterocycloalkyl, C(=0)R9, C(=O)NR10R11, -S(=0)2R9, -S(=O)2NR10R11 group as defined supra, it being understood that when said R' represents a C3-C6 heterocycloalkyl group, then said C3-C6 heterocycloalkyl group is present only once. Particularly, said ring can contain 2, 3, 4, or 5 carbon atoms, and one or more of the above- mentioned heteroatom-containing groups (a "3- to 6-membered heterocycloalkyl"), more particularly said ring can contain 4 or 5 carbon atoms, and one or more of the above- mentioned heteroatom-containing groups (a "5- to 6-membered heterocycloalkyl").
Non-limiting examples include aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, sulfolanyl, 1 ,3-dioxolanyl, 1 ,3-oxazolidinyl,
1 ,3-thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,
1 .3- dioxanyl,1 ,4-dioxanyl, morpholinyl, thiomorpholinyl, 1 ,1 -dioxidothiomorpholinyl, perhydro-azepinyl, perhydro-1 ,4-diazepinyl, perhydro-1 ,4-oxazepinyl, perhydroazocinyl, octahydropyrrolo-[3,4-b]pyrrolyl, octahydroisoindolyl, octahydropyrrolo[3,4-b]pyridyl, octahydropyrrolo[1 ,2-a]pyrazinyl, decahydroisochinolinyl, 7-azabicyclo[2.2.1]heptyl,
3-azabicyclo[3.2.0]heptyl, 7-azabicyclo-[4.1.0]heptyl, 2,5-diazabicyclo[2.2.1]heptyl,
2-oxa-5-azabicyclo[2.2.1 ]heptyl, 2-azabicyclo-[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl,
8-azabicyclo[3.2.1 ]octyl, 8-oxa-3-azabicyclo[3.2.1 ]octyl, 3-oxa-9-azabicyclo[3.3.1 ]nonyl.
Particular preference is given to 5- to 7-membered monocyclic heterocycloalkyl radicals having up to 2 heteroatoms selected from the group consisting of N , O and S, such as illustratively and preferably tetrahydrofuranyl, 1 ,3-dioxolanyl, pyrrolidinyl, tetrahydropyranyl,
1 .4- dioxanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, perhydro- azepinyl, perhydro-1 ,4-diazepinyl and perhydro-1 ,4-oxazepinyl.
The term "aryl" is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 carbon atoms (a "C6-Ci4-ary group), particularly a ring having 6 carbon atoms (a "C6-aryl" group), e.g. a phenyl group, or a biphenyl group, or a ring having 9 carbon atoms (a "C9-aryl" group), e.g. an indanyl or indenyl group, or a ring having 10 carbon atoms (a "Ci0-aryl" group), e.g. a tetralinyl, dihydronaphthyl, or naphthyl group, or a ring having 13 carbon atoms, (a "Ci3-aryl" group), e.g. a fluorenyl group, or a ring having 14 carbon atoms, (a "Ci4-aryl" group), e.g. an anthranyl group.
The term "heteroaryl" is understood as preferably meaning a monovalent, aromatic, mono- or bicycl ic aromatic ri ng system having 5, 6 , 7 , 8 , 9 , 1 0 , 1 1 , 1 2 , 1 3 or 1 4 ring atoms (a "5- to 14-membered heteroaryl" group), particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and can be monocyclic, bicyclic, or tricyclic, and in
addition in each case can be benzocondensed . Preference is given to 6-membered heteroaryl radicals having up to 2 nitrogen atoms, and to 5-membered heteroaryl radicals having up to 3 heteroatoms. Particularly, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, tetrazolyl and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl,; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, eic, and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, eic; or azocinyl, indolizinyl, purinyl and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl. More particularly, heteroaryl is selected from thienyl, oxazolyl, thiazolyl, 1 /-/-tetrazol-5-yl, pyridyl, benzothienyl, or furanyl.
The term "alkylene" is understood as preferably meaning an optionally substituted hydrocarbon chain (or "tether") having 1 , 2, 3, 4, 5, or 6 carbon atoms, i.e. an optionally substituted -CH2- ("methylene" or "single membered tether" or, for example -C(Me)2-), -CH2-CH2- ("ethylene", "dimethylene", or "two-membered tether"), -CH2-CH2-CH2- ("propylene", "trimethylene", or "three-membered tether"), -CH2-CH2-CH2-CH2- ("butylene", "tetramethylene", or "four-membered tether"), -CH2-CH2-CH2-CH2-CH2- ("pentylene", "pentamethylene" or "five-mem bered ether"), or -CH2-CH2-CH2-CH2-CH2-CH2- ("hexylene", "hexamethylene", or six-membered tether") group. Particularly, said alkylene tether has 1 , 2, 3, 4, or 5 carbon atoms, more particularly 1 or 2 carbon atoms.
The term "alkylenedioxy" is understood as preferably meaning -0-CrC6alkylene-0- in particular methylenedioxy and ethylenedioxy as in the below exemplified formula:
The term "CrC6", as used throughout this text, e.g. in the context of the definition of "Ci-C6-alkyl", "Ci-C6-haloalkyl", "CrC6-alkoxy", or "CrC6-haloalkoxy" is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term "Ci-C6" is to be interpreted as any sub-range comprised therein, e.g. Ci-C6 , C2-C5 , C3-C4 , Ci-C2 , C1-C3 , Ci-C4
C1-C5 , Ci-C6 ; particularly CrC2 , CrC3 , Ci-C4 , C1-C5 , Ci-C6 ; more particularly Ci-C4; in the case of "Ci-C6-haloalkyl" or "CrC6-haloalkoxy" even more particularly Ci-C2.
Similarly, as used herein, the term "C2-C6", as used throughout this text, e.g. in the context of the definitions of "C2-C6-alkenyl" and "C2-C6-alkynyl", is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term "C2-C6" is to be interpreted as any sub-range comprised therein, e.g. C2-C6 , C3-C5 , C3-C4 , C2-C3 , C2-C4 , C2-C5 ; particularly C2-C3.
Further, as used herein, the term "C3-C10", as used throughout this text, e.g. in the context of the definition of "C3-Ci0-cycloalkyl", is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 10, i.e. 3, 4 , 5, 6 , 7, 8, 9 or 10 carbon atoms, particularly 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term "C3-Ci0" is to be interpreted as any sub-range comprised therein, e.g. C3-C10 , C4-C9 , C5-C8 , C6-C7 ; particularly C3-C6.
Oxo represents a double-bonded oxygen atom. As used herein, the term "one or more times", e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning "one, two, three, four or five times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times". Throughout this document, for the sake of simplicity, the use of singular language is given preference over plural language, but is generally meant to include the plural language if not otherwise stated . E .g. , the expression "A method of treating a disease in a patient, comprising administering to a patient an effective amount of a compound of formula (I)" is meant to include the simultaneous treatment of more than one disease as well as the administration of more than one compound of formula (I)
indicates a non-specified sp2- or sp3-stereobond or a mixture of stereoisomers, for example, the group
OH
N represents a £- or Z-isomer, or a mixture thereof.
* indicates the point of attachment to of a given group, for example a ring, to general formula in which said group is reported.
Particular forms of embodiment of compounds of the general formula (I) as described above are going to be illustrated in the following.
In conjunction with the above or below definitions and embodiments, compounds according to formula (I) are in particular those in which X is
In a further embodiment, in conjunction with any of the above or below embodiments, compounds according to formula (I) are in particular those in which Y is
In a further embodiment, in conjunction with any of the above or below embodiments, compounds according to formula (I) are in particular those in which Y is any one of the following groups:
In a further embodiment, in conjunction with any of the above or below embodiments, compounds according to formula (I) are in particular those in which Y is any one of the following groups:
Another particular embodiment, in conjunction with any of the above or below embodiments, refers to compounds according to formula (I) in which Y is any one of the following groups:
More particularly a further embodiment, in conjunction with any of the above or below embodiments, refers to compounds according to formula (I) in which R6 is a pyridine ring optionally substituted one or more times in the same way or differently with a group Rn wherein R-n has the meaning as given with any of the above or below embodiments and definitions. In this respect particularly embodiments are any one of the following groups:
A further particular embodiment, in conjunction with any of the above or below embodiments, refers to compounds according to fo in which R6 is
in which a group Rn has the meaning as given with any of the above or below embodiments and definitions and is present one or more times.
A further detailed embodiment, in conjunction with any of the above or below embodiments, refers to compounds according to formula (I) in which R6 is any one of the following groups:
A further detailed embodiment, in conjunction with any of the above or below embodiments, refers to compounds according to formula (I) in which R6 is
and in which R11a is an halogen, particularly a fluorine atom, and Rnb is a
-CrC6-haloalkyl, -0-CrC6-alkyl or -0-CrC6-haloalkylgroup, particularly -CF2-CH3, -OCH3 or
A further detailed embodiment, in conjunction with any of the above or below embodiments, refers to compounds according to formula (I) in which R6 is
and in which R11a is an halogen, particularly a fluorine atom, R11b is a hydrogen and Rnc is a -0-CrC6-alkyl or -0-CrC6-haloalkylgroup, particularly -OCH3 or -OCF3.
In a further embodiment, in conjunction with any of the above or below embodiments, compounds according to formula (I) are in particular those in which R6 is any one of the following groups:
in which a group Rna and R12 have the meaning as given with any of the above or below embodiments and definitions, and R12 is present one or more times; or R11a , R12a and Ri2b have the meaning as given with any of the above or below embodiments and definitions.
More particularly, further forms of embodiment, in conjunction with any of the above or below embodiments, refer to compounds according to the invention comprising any one of the following groups with the following meaning:
Ria and Rib are independently of one another a hydrogen atom, a CrC6-alkyl-, d-C6-alkoxy- CrC6-alkyl-, -CrC6-alkenyl-, C3-C8-cycloalkyl-, aryl-, heteroaryl-, -Ci-C6-alkylene-aryl, -d-Ce-alkylene-heteroaryl, -C(=0)-C C6-alkyl, -C(=0)-Ci-C6-alkylene-aryl,
-C(=0)-Ci-C6-alkylene-heteroaryl, -C(=0)0-C C6-alkyl, -S(=0)2R9
optionally substituted one or more times, in the same way or differently, with a substituent selected from : halo-, hydroxy-, cyano, CrC6-alkyl-,
halo-CrC6-alkyl-,-C(=0)OH, -C(=0)NH2, -S(=0)2OH, -N(H)C(=0)NH2,
-N(H)C(=NH)NH2, -C(=0)0-CrC6-alkyl, -NR9R10 in which R9 and R10 represent, independently from each other hydrogen, hydroxyl, CrC6-alkyl, halo-CrC6-alkyl, CrC6-alkoxy, halo-CrC6-alkoxy or R9 and R10 joined, and taken together with the atom to which they are attached, form 5- to 6-membered heterocycloalkyl-, optionally substituted one or two times, in the same way or differently, with a substituent selected from : oxo, CrC6-alkyl-, aryl-, heteroaryl-, -Ci-C6-alkylene-aryl,
-Ci-C6-alkylene-heteroaryl; in particular R1a is hydrogen, a methyl or
n-propyl-C(=0)OH, n-butyl-C(=0)OH and Rib is hydrogen, 2-methoxyethyl- or
2-pyridin-2-yl-ethyk
R-ia and Rib joined, and taken together with the atom to which they are attached,form a 5- to 6-membered heterocycloalkyl-, optionally substituted one or more times, in the same way or differently, with a substituent selected from : oxo, CrC6-alkyl-, a optionally substituted aryl-, heteroaryl-, -Ci-C6-alkylene-aryl, -Ci-C6-alkylene-heteroaryl said groups being one or more times substituted, in the same way or differently, with a halo, cyano, CrC6-alkyl- and
halo-CrC6-alkyl- group. In particular, R1a and Rib joined, and taken together with the atom to which they are attached, form a piperidin-1 -yl or 4-phenyl-piperazin-1 -yl.
R-ia and Rib joined, and taken together with the atom to which they are attached, form a piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl group, optionally substituted one or more times.
R2a and R2b are both a hydrogen atom or a methyl group.
R3a and R3b are independently of one another hydrogen atom, a CrC6-alkyl-,
C2-C6-alkenyl-, aryl-, heteroaryl- wherein said groups are optionally substituted one or more times, in the same way or differently, with a substituent selected from halo-, -CN, CrC6-alkyl-, halo-CrC6-alkyl, d-C6-alkoxy- or halo-CrC6-alkoxy- . In particular, R3a is hydrogen and R3b is aryl, particularly phenyl and phenyl substituated one or more times with a fluorine atom, a chlorine atom, a methyl group or -CF3.
R7 is an hydrogen atom, -CH3, -CF3, -CH2CH3, -CH2CF3.
R8a and R8b are independently of one another a hydrogen atom, a halogen atom, a
CrC6-alkyl- or halo-CrC6-alkyl group, or
R8a and R8b are both a hydrogen atom; or
R8a is a hydrogen atom and R8b is selected from the group consisting of halogen, CrC6-alkyl-, halo-d-Ce-alkyl;
R8a is selected from the group consisting of halogen, CrC6-alkyl-, halo-CrC6-alkyl ,and R8b is selected from the group consisting of halogen, CrC6-alkyl-, halo-CrC6-alkyl;
R8a and R8b are in particular, independently of one another, a hydrogen atom, a fluorine atom or a fluorinated CrC6-alkyl group, more in particular a -CF3 .
R9 and R10 are independently selected from the group consisting of hydrogen, hydroxyl, CrC6-alkyl, halo-CrC6-alkyl, CrC6-alkoxy, halo-CrC6-alkoxy
R9 and R10 joined, and taken together with the atom to which they are attached, form a 5- to 6-membered heterocycloalkyl-, optionally substituted one or more times, in the same way or differently, with a substituent selected from : oxo, CrC6-alkyl-, aryl-, heteroaryl-, -Ci-C6-alkylene-aryl, -Ci-C6-alkylene-heteroaryl.
Rn , R11a , R11b and Rnc are independently of one another hydrogen, halogen, hydroxy, cyano, nitro, CrC6-alkyl, halo-CrC6-alkyl, CrC6-alkoxy, halo-CrC6-alkoxy with halogen, preferably fluorine atom.
R-I2 , Ri2a and Ri2b are an hydrogen or an halogen atom, preferably a fluorine atom.
In a further embodiment, in conjunction with any of the above or below embodiments, compounds according to formula (I) are in particular those represented according to the following general formula (II):
R8a and R8b are independently selected from the group consisting of hydrogen, halogen, CrC6-alkyl-, halo-CrC6-alkyl,
Rii is present one or more times and is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, CrC6-alkyl,
halo-CrC6-alkyl, CrC6-alkoxy, halo-CrC6-alkoxy, and in which R1a , R1b , R3a , R3b have the meaning as given with any of the above or below embodiments or definitions.
In a further embodiment, in conjunction with any of the above or below embodiments, compounds according to formula (I) are in particular those represented according to the following general formula (Ha)
R8a and R8b are independently selected from the group consisting of hydrogen, halogen, CrC6-alkyl-, halo-CrC6-alkyl
Rii is present one or more times and is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, CrC6-alkyl,
halo-CrC6-alkyl, CrC6-alkoxy, halo-CrC6-alkoxy, and in which R1a , R1b , R3a , R3b have the meaning as given with any of the above or below embodiments or definitions.
In a further embodiment, in conjunction with any of the above or below embodiments, compounds according to formula (I) are in particular those represented according to the following general formula (lib)
R8a and R8b are independently selected from the group consisting of hydrogen, halogen, C C6-alkyl-, halo-C C6-alkyl
Rii is present one or more times and is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, CrC6-alkyl,
halo-CrC6-alkyl, CrC6-alkoxy, halo-CrC6-alkoxy, and in which R1a , R1b , R3a , R3b have the meaning as given with any of the above or below embodiments or definitions. I n a further embodiment, in conjunction with any of the above or below embodiments, compounds according to formula (I) are in particular those represented according to the following general formula (III)
R8a and R8b are independently selected from the group consisting of hydrogen, halogen, CrC6-alkyl-, halo-CrC6-alkyl,
Rii present one time and is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, CrC6-alkyl, halo-CrC6-alkyl,
CrC6-alkoxy, halo-CrC6-alkoxy, and in which R1a , R1b , R3a , R3b have the meaning as given with any of the above or below embodiments or definitions.
In a further embodiment, in conjunction with any of the above or below embodiments, compounds according to formula (I) are in particular those represented according to the following general formula (IV)
R8a and R8b are independently selected from the group consisting of hydrogen, halogen, CrC6-alkyl-, halo-CrC6-alkyl,
R6 is any one of the following groups:
I n a further embodiment, in conjunction with any of the above or below embodiments, compounds according to formula (I) are in particular those represented according to the general formula (II), (Ha) and (lib) in which R6 is any one of the following groups:
In a further embodiment, in conjunction with any of the above or below embodiments, compounds according to formula (I) are in particular those represented according to the general formula (II), (Ha) and (lib) in which R6 is
-d-Ce-haloalkyl, -0-C C6-alkyl or -0-C C6-haloalkyl, particularly -CF2-CH3,
-OCH3, -OCF2H or -OCF3, and in which all other groups have the meaning as given with any of the above or below embodiments or definitions.
In a further embodiment, in conjunction with any of the above or below embodiments, compounds according to formula (I) are in particular those represented according to the general formula (II), (Ha) and (lib) in which
R2a and R2b are both a hydrogen atom,
R8a is a hydrogen atom and R8b is selected from the group consisting of halogen atom, CrC6-alkyl-, halo-CrC6-alky; or
R8a is selected from the group consisting of halogen, CrC6-alkyl-, halo-CrC6-alky and R8b is selected from the group consisting of halogen, CrC6-alkyl-, halo-CrC6-alkyl, Y is any one of the following groups:
Re is
wherein R11a is an halogen, particularly a fluorine atom, and Rnb is selected from the group consisting of
-d-Ce-haloalkyl, -0-C C6-alkyl or -0-C C6-haloalkyl, particularly -CF2-CH3, -OCH3 or -OCF3, and in which R1a , R1b , R3a , F½, have the meaning as given with any of the above or below embodiments or definitions.
In a further embodiment, in conjunction with any of the above or below embodiments, compounds according to formula (I) are in particular those represented according to the general formula (II), (Ha) and (lib) in which
R2a and R2b are both a hydrogen atom,
R8a and R8b are both an halogen atom in particular a fluorine atom, or
R8a is an halogen atom, in particular a fluorine atom, and R8b is a CrC6-alkyl-, or halo-CrC6-alkyl, in particular a -CF3.
Y is any one of the following groups:
Re is
-Ci-Ce-haloalkyl, -0-C C6-alkyl or -0-C C6-haloalkyl, particularly -CF2-CH3, -OCH3 or -OCF3, and in which R3a , R3b have the meaning as given with any of the above or below embodiments or definitions.
Compounds according to the invention are:
8-(2,6-difluoro-benzyl)-6-(2-fluoro -3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
6-(2-chloro-5-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-
2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
6-(2-fluoro-pyridin-3-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-6-(3-trifluoromethoxy-phenyl)-2,3- dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
6-(2,2-difluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
3-benzoyl-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3-dihydro- thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-3-(4-fluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(4-methoxy-benzoyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-trifluoromethoxy- benzoyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(thiophene-3-carbonyl)-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-(benzo[b]thiophene-3-carbonyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(furan-3-carbonyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(3-methyl-benzoyl)-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(3-trifluoromethyl-benzoyl)- 2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(2-methyl-benzoyl)-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-3-(2-fluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-(2-chloro-3-fluoro-benzoyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(3,5-difluoro-benzoyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-(2,3-difluoro-benzoyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-3-(3-fluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-(2,5-difluoro-benzoyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-(2-chloro-5-methyl-benzoyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(4-fluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-(4- trifluoromethoxy-benzoyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
[(2H5)phenylcarbonyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-(2-chloro-5-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-(2-fluoro-pyridin-3-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro- thiazolo[3,2-a]pyridin-5-one
3-(3,5-difluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(3-fluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(5-chloro-thiophene-2-carbonyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-(3- trifluoromethyl-benzoyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-8-(2-fluoro-6-trifluoromethyl-ben^
dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-(2,2-difluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(furan-2-carbonyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(3-fluoro-pyridine-2-carbonyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(5-methyl-thiazole-2- carbonyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-3-(3-fluoro-pyridine-2-carbonyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-(5-methyl- thiazole-2-carbonyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-8-(2!6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2!2!7-trimethyl-2,3-dihydro- thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(hydroxyimino-phenyl-methyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[(4-fluoro-phenyl)-hydroxyimino- methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[hydroxyimino-(4-methoxy-phenyl)- methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[hydroxyimino-(4-trifluoromethoxy- phenyl)-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(hydroxyimino-thiophen-3-yl-methyl)- 7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(furan-3-yl-hydroxyimino-methyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(hydroxyimino-o-tolyl-methyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(hydroxyimino-m-tolyl-methyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy
trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(hydroxyimino-phenyl- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-3-[(4-fluoro-phenyl)-hydroxyimino-methyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-[hydroxyimino-(4- trifluoromethoxy-phenyl)-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3- {(hydroxyimino)[(2H5)p enyl]methyl}-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(furan-2-yl- hydroxyimino-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-chloro-5-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(hydroxyimino phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-pyridin-3-yl)-8-(2-fluoro-6-trifluorom
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[hydroxyimino-(3-trifluoromethyl- phenyl)-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[(2-fluoro-phenyl)-hydroxyimino- methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[(2-chloro-3-fluoro-phenyl)-hydroxyimino-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[(3-fluoro-pyridin-2-yl)-hydroxyimino- methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[hydroxyimino-(5-methyl-thiazol-2-yl)- methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(benzo[b]thiophen-3-yl-hydroxyimino-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino-phenyl- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino-phenyl-methyl)-7-methyl-6-(3- trifluoromethoxy-phenyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino-phenyl- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino- phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2,2-difluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino- phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(allylimino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-benzyl-7-methyl-5-oxo-6-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid benzylamide
8-benzyl-7-methyl-5-oxo-6-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methoxy-amide
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridine-3-carboxylic acid pyridin-2-ylamide
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridine-3-carboxylic acid phenylamide
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridine-3-carboxylic acid methoxy-amide
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridine-3-carboxylic acid benzylamide
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridine-3-carboxylic acid cyclopropylamide
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridine-3-carboxylic acid methyl-(2-pyridin-2-yl-ethyl)-amide
8-benzyl-3-(benzylamino-methyl)-7-methyl-6-phenyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(benzylamino-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-pyridin-4-yl-piperazin-1 - ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[4-(1 -ethyl-propyl)-piperazin-1 -ylmethyl]-8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)- 7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-methyl-piperazin-1 -ylmethyl)- 2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(pyridin-4-ylaminomethyl)-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-phenyl-piperidin-1 -ylmethyl)- 2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-azetidin-1 -ylmethyl-8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3-dih thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-[(2-pyridin-4-yl-ethylamino)- methyl]-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-phenyl-piperazin-1 -ylmethyl)-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-{[(pyridin-2-ylmethyl)-amino]- methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-piperidin-1 -ylmethyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
2-(2-{[8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridin-3-ylmethyl]-amino}-ethyl)-piperidine-1 -carboxylic acid tert-butyl ester
2- (2-{[8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridin-3-ylmethyl]-amino}-ethyl)-pyrrolidine-1 -carboxylic acid tert-butyl ester
3- [(cyclopropylmethyl-amino)-methyl]-8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[4-(3,5-dimethyl-phenyl)-piperazin-1 -ylmethyl]-8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-{[(3-dimethylamino-propyl)-methyl-amino]-methyl}-8-(2-fluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-{[(2-dimethylamino-ethyl)-methyl-amino]-me
phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-cyclopropylaminomethyl-8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-phenylaminomethyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-((R)-3-dimethylamino-pyrrolidin-1 -ylmethyl)-8-(2-fluoro-benzyl)-6-(2-fluoro-3-metho
phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-((S)-3-dimethylamino-pyrrolidin-1 -ylmethyl)-8-(2-fluoro-benzyl)-6-(2-fluoro-3-meth
phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(4-benzyl-piperazin-1 -ylmethyl)-8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl^ 2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-{[(2-methoxy-ethyl)-methyl-amino]- methyl}-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[4-(3-dimethylamino-propyl)-piperazin-1 -ylmethyl]-8-(2-fluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
2-{[8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridin-3-ylmethyl]-methyl-amino}-N,N-dimethyl-acetamide
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(pyridin-2-ylaminomethyl)-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[(furan-2-ylmethyl-methyl-amino)- methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-pyridin-4-ylmethyl-piperazin- 1 -ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-benzo[1 ,3]dioxol-5-yl-8-(2-fluoro-benzyl)-7-methyl-3-{[methyl-(2-pyridin-2-yl-ethyl)-amino]- methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-3-[4-(1 -ethyl-propyl)-piperazin-1 -ylmethyl]-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-phenylaminomethyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2,2 ,7-trimethyl-3-(4-methyl-piperazin-1 - ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2!6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2,2J-trimethyl-3-{[methyl-(2-pyridin-2- yl-ethyl)-amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-6-(2-fluoro-3- methoxy-phenyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2,2 ,7-trimethyl-3-(4-pyridin-2-ylmethyl- piperazin-1 -ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-cyclopropylaminomethyl-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2,2,7- trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-[(methyl-phenethyl-amino)- methyl]-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-[(2-morpholin-4-yl- ethylamino)-methyl]-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-3-[4-(3,5-dimethyl-phenyl)-piperazin-1 -ylmethyl]-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(pyridin-4-ylaminomethyl)-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(phenethylamino-methyl)-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-cyclopropylaminomethyl-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methy
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-piperidin-1 -ylmethyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-methyl-piperazin-1 - ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-{[methyl-(2-morpholin-4-yl- ethyl)-amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-3-{[(3-dimethylamino-propyl)-methyl-amino]-methyl}-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-3-[4-(3-dimethylamino-propyl)-piperazin-1 -ylmethyl]-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(benzylamino-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2,2 ,7-trimethyl-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[(cyclopropylmethyl-amino)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(benzylamino-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-3-((S)-3-dimethylamino-pyrrolidin-1 -ylmethyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-7-methyl-3-{[methyl-(2-pyridin-2-yl-ethyl)-amino]-methyl}-6-(3- trifluoromethoxy-phenyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-pyridin-4-yl-piperazin-1 - ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-[(methyl-pyridin-4-ylmethyl- amino)-methyl]-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2,2 ,7-trimethyl-3-[(2-morpholin-4-yl- ethylamino)-methyl]-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(5-chloro-thiophen-2-yl)-8-(2,6-difluoro-benzyl)-7-methyl-3-{[methyl-(2-pyridin-2-yl-ethyl)- amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-3-((R)-3-dimethylamino-pyrrolidin-1 -ylmethyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-{[(2-methoxy-ethyl)-methyl-amino]- methyl}-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[(furan-2-ylmethyl-methyl-amin methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-pyridin-4-ylmethyl- piperazin-1 -ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[(benzyl-methyl-amino)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-{[methyl-(2-pyridin-2-yl- ethyl)-amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[4-(3,5-dimethyl-phenyl)-piperazin-1 -ylmethyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-{[(2-dimethylamino-ethyl)-methyl-amino]-me
6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-(4-methyl- piperazin-1 -ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-[(2-morpholin-
4-yl-ethylamino)-methyl]-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(benzylamino-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-{[(2-methoxy-ethyl)- methyl-amino]-methyl}-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-((R)-3-dimethylamino-pyrrolidin-1 -ylmethyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-{[methyl-(2- pyridin-2-yl-ethyl)-amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-({[2-(6-methoxy-pyridin-
2-yl)-ethyl]-methyl-amino}-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-({methyl-[2-(3- trifluoromethyl-pyridin-2-yl)-ethyl]-amino}-methyl)-2,3-dihydro-thiazolo[3,2-a]pyridi one
6-(2-fluoro-3-methoxy-phenyl)-3-({[2-(6-fluoro-pyridin-2-yl)-ethyl]-methyl-amino}-methy
fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-({[2-(5-chloro-pyridin-2-yl)-ethyl]-methyl-amino}-methyl)-6-(2-fluoro-3-methoxy-pheny
fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-({methyl-[2-(3- methyl-pyridin-2-yl)-ethyl]-amino}-methyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-3-({[2-(5-fluoro-pyridin-2-yl)-ethyl]-methyl-amino}-m
fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-({[2-(3-methoxy-pyridin-
2-yl)-ethyl]-methyl-amino}-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-({methyl-[2-(6- methyl-pyridin-2-yl)-ethyl]-amino}-methyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-({[2-(4-chloro-pyridin-2-yl)-ethyl]-methyl-amino}-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8 fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxy-phenyl)-3-({[2-(3-fluoro-pyridin-2-yl)-ethyl]-methyl-amino}-methyl)-^ fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-{[methyl-(2- quinolin-2-yl-ethyl)-amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[2-(piperidin-1 - yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[methyl(prop-2-yn-1 - yl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-3-({[4-(dimethylamino)phenyl]amino}methyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-({[2-(diethylamino)ethyl](methyl)amino}methyl)-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-{[4-(3-chlorophenyl)piperazin-1 -yl]methyl}-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[4-(pyrazin-2-yl)piperazin-1 - yl]methyl}-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[2-(1 -methylpyrrolidin-2- yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-{[4-(1 ,3-benzodioxol-5-yl)piperazin-1 -yl]methyl}-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(2-methyl-1 ,3-benzothiazol- 5-yl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({4-[3-(pyrrolidin-1 - yl)propyl]piperazin-1 -yl}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[3-
(trifluoromethyl)benzyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-{[(4-methoxyphenyl)amino]methyl}-7- methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3- [(tert-butylamino)methyl]-8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methy dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(4- methylbenzyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(3- phenylpropyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-3-({[2-(3,5-dimethoxyphenyl)ethyl]amino}methyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[3-(4-methylpiperidin-1 - yl)propyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
4- {[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3-dihydro-5H-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}-N,N-dimethylpiperazine-1 -carboxamide 8-(2,6-difluorobenzyl)-3-({[3-(dimethylamino)benzyl]amino}methyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-[(isoquinolin-8-ylamino)methyl]-7- methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
2- (4-{[8-(2!6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3-dihydro-5H-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}piperazin-1 -yl)-N-(2-phenylethyl)acetamide 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[4-(pyridin-3- ylmethyl)piperazin-1 -yl]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3- (azetidin-1 -ylmethyl)-8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-2,3- dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({4-[4-
(trifluoromethyl)phenyl]piperazin-1 -yl}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-5-one
2- (4-{[8-(2!6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3-dihydro-5H-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}piperazin-1 -yl)-N-(2-methoxyethyl)acetamide 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({4-[2-oxo-2-(pyrrolidin-1 - yl)ethyl]piperazin-1 -yl}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[2-(pyrrolidin-1 - yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3- {[(2-chlorobenzyl)amino]methyl}-8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7- methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-{[(4-fluorophenyl)amino]methyl}-7- methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-3-{[(3,5-dimethoxyben
7-methyl-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-({[2-(2- fluorophenyl)ethyl]amino}methyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin- 5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(2- phenoxyethyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-(morpholin-4-ylmethyl)-2,3- dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(pyridin-4- ylmethyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-{[(4-methoxybenzyl)amino]methyl}-7- methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-3-{[(2,2-diphenylethyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-7- methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-{[(2-chlorobenzyl)(methyl)amino]methyl}-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-({[4-(benzyloxy)phenyl]amino}methyl)-8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-
7-methyl-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-5-one
4-[(4-{[8-(2!6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3-dihydro-5H-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}piperazin-1 -yl)methyl]benzonitrile
8-(2,6-difluorobenzyl)-3-{[(3,5-dimethoxybenzyl)(methyl)amino]methyl}-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({4-[(1 -methylpiperidin-4- yl)methyl]piperazin-1 -yl}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one methyl 4-{[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3-dihydro-
5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}piperazine-1 -carboxylate
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[methyl(thiophen-3- ylmethyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[methyl(naphthalen-2- ylmethyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-{[(2- hydroxyethyl)(methyl)amino]methyl}-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(4- phenylbutyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxy^
methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3- {[4-(1 ,3-benzodioxol-5-ylmethyl)piperazin-1 -yl]methyl}-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-({[3-(diethylamino)propyl]amino}methyl)-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[4-(1 -methylpiperidin-4- yl)piperazin-1 -yl]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(3- methylbenzyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-(thiomorpholin-4-ylmethyl)- 2!3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
4- [2-({[8-(2!6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3-dihydro-5H-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}amino)ethyl]benzenesulfonamide
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({methyl[2-(pyridin-3- yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[4-(2- phenoxyethyl)piperazin-1 -yl]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-3-({[2-(dimethylamino)benzyl]amino}methyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[4-(methylsulfonyl)piperazin- 1 -yl]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
2- (4-{[8-(2!6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3-dihydro-5H-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}piperazin-1 -yl)-N-methylacetamide
3-({[2-(4-acetylpiperazin-1 -yl)ethyl]amino}methyl)-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(2- methylbenzyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({4-[3- (trifluoromethyl)phenyl]piperazin-1 -yl}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-5-one
3- [(1 ,3-benzodioxol-5-ylamino)methyl]-8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7- methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(thiophen-2- ylmethyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-(pyrrolidin-1 -ylmethy dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-({[3-(1 H-imidazol-1 - yl)propyl]amino}methyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 4-[({[8-(2!6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3-dihydro-5H-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}amino)methyl]benzonitrile
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({methyl[(1 -methyl-1 H- pyrazol-5-yl)methyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(thiophen-3- ylmethyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[(1 -methyl-1 H-imidazol-5- yl)methyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({4-[2-
(trifluoromethyl)phenyl]piperazin-1 -yl}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[2-(4- methylphenyl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-{[(2-methoxybenzyl)amino]methyl}-7- methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-[(3-methylpiperidin-1 - yl)methyl]-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[3-(2-oxopyrrolidin-1 - yl)propyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[4-(morpholin-4- yl)phenyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-({[2-(3- fluorophenyl)ethyl]amino}methyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-
5-one
N-[4-({[8-(2!6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3-dihydro-5H- [1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}amino)phenyl]methanesulfonamide
3-{[4-(2-chlorobenzyl)piperazin-1 -yl]methyl}-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(1 H-pyrazol-3- ylmethyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({4-[2-(pyridin-2- yl)ethyl]piperazin-1 -yl}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({4-[(1 -methylpiperidin yl)methyl]piperazin-1 -yl}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one N-cyclopropyl-2-(4-{[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3- dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}piperazin-1 -yl)acetamide
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[3-
(morpholin-4-yl)propyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(2- methylbenzyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-{[(3-chlorobenzyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-{[(2- hydroxyethyl)(methyl)amino]methyl}-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-(morpholin-4- ylmethyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(4- phenylbutyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-(1 !4'-bipiperidin-1 '-ylmethyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[methyl(prop- 2-yn-1 -yl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-{[(3- methoxybenzyl)amino]methyl}-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5- one
3-{[(4-chlorophenyl)(methyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3- {[4-(1 ,3-benzodioxol-5-ylmethyl)piperazin-1 -yl]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2- fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5- one
3-({[3-(dimethylamino)propyl]amino}methyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
4- {2-[({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5-oxo-2,3- dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)amino]ethyl}benzenesulfonamide 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(3!4,5- trimethoxybenzyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-{[tert-butyl(methyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[2-(pyridin-2- yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(pyridin-2- ylmethyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-{[(4- methoxyphenyl)amino]methyl}-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5- one
3-{[(2-chlorobenzyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 3-[(dibenzylamino)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzy ^
7-methyl-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-5-one
ethyl 4-({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5-oxo- 2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)piperazine-1 -carboxylate
6-(2-fluoro-3-methoxyphenyl)-3-{[(4-fluorophenyl)amino]methyl}-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 3-(azepan-1 -ylmethyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-[(4- methylpiperidin-1 -yl)methyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
1 -({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5-oxo-2,3- dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)piperidine-3-carboxamide
3-{[(1 ,3-benzodioxol-5-ylmethyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-[(prop-2-yn-1 - ylamino)methyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3- (3,4-dihydroisoquinolin-2(1 H)-ylmethyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(3!4,5- trimethoxyphenyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
4- [({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5-oxo-2,3- dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)amino]-N-phenylbenzamide ethyl {4-[({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5-oxo- 2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)amino]phenyl}acetate
-{[(4-chlorobenzyl)(methyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[3-(1 H- tetrazol-5-yl)phenyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[3-(piperidin-
1 - yl)propyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[2-(thiophen-
2- yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-[(4-methyl-1 ,4- diazepan-1 -yl)methyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
-[(4-ethylpiperazin-1 -yl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[2-(2- oxoimidazolidin-1 -yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5- one
-{[bis(pyridin-2-ylmethyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(2- phenylpropan-2-yl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-({4-[2-(dimethylamino)ethyl]piperazin-1 -yl^
6-(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({4-[2-
(morpholin-4-yl)ethyl]piperazin-1 -yl}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-
5-one
- {[(biphenyl-4-ylmethyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one- [4-({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5-oxo-2,3- dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)piperazin-1 -yl]benzonitrile
-[4-({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5-oxo-2,3- dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)piperazin-1 -yl]-N,N- dimethylacetamide
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({4-[2-
(pyrrolidin-1 -yl)ethyl]piperazin-1 -yl}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin- 5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[3-(5-methyl- 1 H-pyrazol-4-yl)propyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro
yl)phenyl]amino}methyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[(5- methylpyrazin-2-yl)methyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-[(quinolin-4- ylamino)methyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({methyl[(1 - methyl-1 H-pyrazol-4-yl)methyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(3- methylbenzyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
-{[benzyl(ethyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-({benzyl[2-(dimethylamino)ethyl]amino}methyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-[(isoquinolin-5- ylamino)methyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[4-
(morpholin-4-yl)phenyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-({[3-(1 H-imidazol-1 - yl)propyl]amino}methyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-{[(3,5-dimethoxybenzyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-[(4-acetylpiperazin-1 -yl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-[(isoquinolin-4- ylamino)methyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[4-(1 - phenylethyl)piperazin-1 -yl]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-[({2-[3-
(trifluoromethyl)phenyl]ethyl}amino)methyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-
5-one
-({[4-(dimethylamino)butyl]amino}methyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-[(1 ,3-benzothiazol-6-ylamino)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 3-{[(2,5-dichlorobenzyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(2- phenoxyethyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({methyl[2-
(pyridin-3-yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3- ({[4-(dimethylamino)benzyl]amino}methyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6^ (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
N-{4-[({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5-oxo-
2!3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}methyl)amino]phenyl}methanesulfonamide
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[4-(thieno[3,2- d]pyrimidin-4-yl)piperazin-1 -yl]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5- one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[4-(2- phenoxyethyl)piperazin-1 -yl]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[4- (phenylcarbonyl)piperazin-l -yl]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5- one
4- ({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5-oxo-2,3- dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)-N,N-dimethylpiperazine-1 - carboxamide
3-({[2-(4-benzylpiperidin-1 -yl)ethyl]amino}methyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro^^ (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[4-(pyrrolidin 1 -ylcarbonyl)piperazin-1 -yl]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[2-(3- methylphenyl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 3-({[2-(dimethylamino)benzyl]amino}methyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6^ (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
{[methyl(pyridin-4-yl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-[(isoquinolin-8- ylamino)methyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
-({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5-oxo-2,3- dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)-1 -(2-phenylethyl)piperazine-2,6- dione
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(2-methyl- 1 ,3-benzothiazol-5-yl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one- [4-({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5-oxo-2,3- dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)piperazin-1 -yl]-N-(2- phenylethyl)acetamide
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[(1 -methyl- 1 H-pyrazol-5-yl)methyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5- one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({methyl[(1 - methyl-I H-pyrazol-S-y methyllaminoJmethy ^.S-dihydro-SH-tl .S^hiazolo^^- a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(1 H-pyrazol-
3- ylmethyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[4-(3- phenylpropyl)piperazin-1 -yl]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[2-(4- methylpiperazin-1 -yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-^^ one
- {[4-({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5-oxo-2,3- dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)piperazin-1 -yl]methyl}benzonitrile-{[(3,5-dimethoxybenzyl)(methyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[2-(2- methylphenyl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-[(pyridazin-3- ylamino)methyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(thiophen-3- ylmethyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({4-[2-(pyridin-
4- yl)ethyl]piperazin-1 -yl}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one-{[4-(biphenyl-3-yl)piperazin-1 -yl]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-{[4-(3- methoxypropyl)piperazin-1 -yl]methyl}-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[4-(pyridin-3- ylmethyl)piperazin-1 -yl]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({4-[(1 - methylpiperidin-3-yl)methyl]piperazin-1 -yl}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({4-[(1 - methylpiperidin-4-yl)methyl]piperazin-1 -yl}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({4-[2- (trifluoromethyl)phenyl]piperazin-1 -yl}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[(1 -methyl- 1 H-pyrazol-4-yl)methyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5- one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
{[methyl(naphthalen-2-ylmethyl)amino]methyl}-2,3-dihydro-5H-[1 !3]thiazolo[3,2- a]pyridin-5-one
N-cyclopropyl-2-[4-({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)piperazin-1 - yl]acetamide
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({methyl[2- (pyrrolidin-1 -yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-({[2-(4-acetylpiperazin-1 -yl)ethyl]amino}methyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one N-(3-{[({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5-oxo-
2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)amino]methyl}phenyl)acetamide 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({methyl[2-(4- methylpiperidin-1 -yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5- one
8-(2,6-difluoro-benzyl)-6-iodo-7-methyl-3-{[methyl-(2-pyridin-2-yl-ethyl)-amino]-methyl}-2,3 dihydro-thiazolo[3,2-a]pyridin-5-one
6-(3-chloro-phenyl)-8-(2,6-difluoro-benzyl)-7-methyl-3-{[methyl-(2-pyridin-2-yl-ethyl)-amino] methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-benzo[1 ,3]dioxol-5-yl-8-(2,6-difluoro-benzyl)-7-methyl-3-{[methyl-(2-pyridin-2-yl-eth amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(R*)]}-3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(S*)]}-3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(S*)]}-3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)- 7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(4-fluoro-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(4-fluoro-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(4-methoxy-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(4-methoxy-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(4-trifluoromethoxy-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(4-trifluoromethoxy-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2,2,7- trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(4-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(4-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(4-trifluoromethoxy-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(S*)]-3-[amino-(4-trifluoromethoxy-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(S*)]-3-{amino[(2H5)p enyl]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(furan-2-yl- isopropylamino-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-(2-chloro-5-trifluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-(2-chloro-5-trifluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-pyridin-3-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-pyridin-3-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-6-(3- trifluoromethoxy-phenyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-6-(3- trifluoromethoxy-phenyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl^ benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethy benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-(2!2-difluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-(2!2-difluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[amino-(2-chloro-3-fluoro-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-m-tolyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-m-tolyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-thiophen-3-yl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(3-fluoro-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(3-fluoro-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(5-methyl-thiazol-2-yl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(5-methyl-thiazol-2-yl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(3-fluoro-pyridin-2-yl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(3-fluoro-pyridin-2-yl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-benzo[b]thiophen-3-yl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[amino(phenyl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-
7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 -oxide
[3a(R*)]-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-6-iodo-7-methyl-2,3-dihydro- thiazolo[3,2a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-7-methyl-6-thiophen-2-yl-2,3-dih thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(5-chloro-thiophen-2-yl)-8-(2,6-difluoro-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(3-chloro-phenyl)-8-(2,6-difluoro-benzyl)-7-methyl-2,3-dihydro- thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(6-chloro-pyridin-2-yl)-8-(2,6-difluoro-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-methoxy-pyridin-3-yl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(2-methoxy-pyridin-3-yl)-7^ methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(6-methoxy-pyridin-2-yl)-7^ methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(6-chloro-pyridin-2-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(2-chloro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)^
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-(2-chloro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-(2-chloro-3-m
benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-benzo[1 ,3]dioxol-5-yl-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-3-methyl-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-(2-fluoro
benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluorom
phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(2-chloro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(3-chloro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-6-yl]-2-fluoro-benzonitrile
[3a(S*)]-3-[3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-6-yl]-2-fluoro-benzonitrile
3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-6-thiophen-2-yl-2,3^ dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-6-(5-methyl-thioph
2-yl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(5-chloro-thiophen-2-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7 methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(3-chloro-thiophen-2-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7^ methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino(phenyl)(2H)methyl]-8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7- methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino(phenyl)(2H)methyl]-8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7- methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino(phenyl)(2H)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino(phenyl)(2H)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-(1 -amino-1 -phenyl-ethyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(1 -amino-1 -phenyl-but-3-enyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3S-[3a(R*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3R-[3a(S*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)^ butyric acid ethyl ester
{3S-[3a(S*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-acetic acid ethyl ester
3- ({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-propionic acid ethyl ester
4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo- 2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
5-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-pentanoic acid ethyl ester
4- ({[6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester 4-({[8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-6-(3-trifluoromethoxy-phenyl)-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester {3R-[3a(R*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)- 7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3S-[3a(R*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3R-[3a(S*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3S-[3a(S*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-acetic acid
3- ({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-propionic acid
4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo- 2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
5- ({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-pentanoic acid
4- ({[6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
4-({[8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-6-(3-trifluoromethoxy-phenyl)-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
{3R-[3a(R*)]}-sodium 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl] -
7-methyl-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
{3S-[3a(R*)]}-sodium 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl] -
7-methyl-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
{3R-[3a(S*)]}-sodium 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl] - 7-methyl-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
{3S-[3a(S*)]}-sodium 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl] - 7-methyl-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-(methylamino- phenyl-methyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(dimethylamino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(butylamino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6- (2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-[phenyl-(4,4,4- trifluoro-butylamino)-methyl]-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(allylamino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(1 -allylamino-1 -phenyl-but-3-enyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-(2-phenyl-
1 ,2,3,6-tetrahydro-pyridin-2-yl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
N-{[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-acetamide
3-bromo-2,2-difluoro-N-{[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- propionamide
2,2-difluoro-3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl- 5-0X0-2, 3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-propionic acid ethyl ester
2,2-difluoro-3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-meth 5-0X0-2, 3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-propionic acid
3-[(3,3-difluoro-2-oxo-azetidin-1 -y l)-phenyl-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-[(3-hydroxy- propylamino)-phenyl-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-[(4-hydroxy- butylamino)-phenyl-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-[(2,2-difluoro-3-hydroxy-propylamino)-phenyl-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3R-[3a(R*)]}-4-({[6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3S-[3a(R*)]}-4-({[6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3R-[3a(S*)]}-4-({[6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3S-[3a(S*)]}-4-({[6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3R-[3a(R*)]}-4-({[6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3S-[3a(R*)]H-({[6-[3-(1 lifluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3R-[3a(S*)]}-4-({[6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3S-[3a(S*)]}-4-({[6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({methyl[2-(pyridin-2- yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 -oxide 6-(4-chloro-2-fluoro-3-methoxyphenyl)-8-(2,6-difluorobenzyl)-7-methyl-3-({methyl[2-(pyridin-
2-yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 -oxide 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(hydroxy-phenyl- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one.
6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo- 2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
6-[3-(1 ,1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-
2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
6-(2-fluoro-4-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-hydroxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
6-(2-fluoro-4-phenoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
6-(4-fluoro-2,2-dideuterobenzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-
5-0X0-2, 3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester 6-(3-difluoromethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo- 2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
6-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihyd
5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
3-(2-fluoro-benzoyl)-6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(2-fluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-(thioph
carbonyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-(2-methy
benzoyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-(3-methy
benzoyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(2-chloro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(2,5-difluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7 methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(2,3-difluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7 methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(2-chloro-3-fluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-[3-(1 ,1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-(2-fluoro-4-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-hydroxy-phenyl)-7-methyl-2,3-dihydro- thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-(3-difluoromethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-(4-fluoro-2,2-dideutero-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-(2-fluoro-4-phenoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-benzoyl-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3- dihydro-oxazolo[3,2-a]pyridin-5-one
6-[3-(1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(hydroxyimino- phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-3-[(2-fluoro-phenyl)-hydroxyimino-methyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(hydroxyimino-thiophen
3-yl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(hydroxyimino-o-tolyl- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(hydroxyimino-m-tolyl- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[(2-chloro-phenyl)-hydroxyimino-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[(2,5-difluoro-phenyl)-hydroxyimino-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[(2,3-difluoro-phenyl)-hydroxyimino-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[(2-chloro-3-fluoro-phenyl)-hydroxyimino-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-
6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-[hydroxyimino-(5- methyl-thiazol-2-yl)-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3- (methoxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino- phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimin phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-[3-(1 ,1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-
(methoxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-4-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino-ph methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[(2-fluoro-phenyl)-methoxyimino-methyl]-6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-
6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-hydroxy-phenyl)-3-(methoxyimino-phenyl-methyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino-phenyl- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(3-difluoromethoxy-phenyl)-8-(2-fuoro-6-trifluoromethyl-benzyl)-3-(methoxyimino-phenyl- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(4-fluoro-2,2-dideutero-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-
(methoxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-4-phenoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino-phenyl- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-3-[(2-fluoro-phenyl)-methoxyimino-methyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[(3,5-difluoro-phenyl)-methoxyimino-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(3-difluoromethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino- phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino- phenyl-methyl)-7-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(2-fluoro-4-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[amino-(2-fluoro-phenyl)-methyl]-6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-hydroxy-ph
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-hydroxy-phenyl)-
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(4-fluoro-2!2-dideutero-benzo[1 ,3]dioxol-5-yl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(4-fluoro-2!2-dideutero-benzo[1 ,3]dioxol-5-yl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(4-fluoro-2!2-dideutero-benzo[1 ,3]dioxol-5-yl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(4-fluoro-2!2-dideutero-benzo[1 ,3]dioxol-5-yl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(2-fluoro-4-phenoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)- 7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-[amino-(2-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(R*)]}-3-[amino-(2-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(S*)]}-3-[amino-(2-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(S*)]}-3-[amino-(2-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[amino-(3,5-difluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-thiophen-3-yl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-thiophen-3-yl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-o-tolyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-o-tolyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-m-tolyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethy benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-m-tolyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluorometh benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(2-chloro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(2-chloro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(3-chloro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(3-chloro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(2,5-difluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(2,5-difluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(2,3-difluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(2,3-difluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(2-chloro-3-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one ) [3a(S*)]-3-[amino-(2-chloro-3-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(R*)]-3-[amino-(5-methyl-thiazol-2-yl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(5-methyl-thiazol-2-yl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(5-chloro-thiophen-2-yl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro- 6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(5-chloro-thiophen-2-yl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-
6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(3-difluoromethoxy-2-fluoro
benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one
{3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one
{3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one
{3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-2,2,7- trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-one
{3S-[3a(R*)]}-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-2,2,7- trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-one
{3R-[3a(S*)]}-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-2,2,7- trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-one
{3S-[3a(S*)]}-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-2,2,7- trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-one
-[3a(R*)]-3-(amino-phenyl-methyl)-6-[3-(1 , 1 -difluoro-ethyl)-phenyl]-8-(2-f luoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-[3a(S*)]-3-(amino-phenyl-methyl)-6-[3-(1 , 1 -difluoro-ethyl)-phenyl]-8-(2-f luoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(amino-phenyl-methyl)-6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluorometh benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-[3-(1 ,1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-[3-(1 , 1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-f luoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(3-acetyl-2-fluoro-phenyl)-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(2-fluoro-5-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluorometh benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluorom
3-yl)-7-methyl-2!3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(2-fluoro-4-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluorometh benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-methoxy-phenyl)-7-meth
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-(2-fluoro
benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-2,2 ,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(amino-phenyl-methyl)-6-(2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-2,2,7- trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-[3-(1 ,1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-[3-(1 , 1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-f luoro-6- trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-[3-(1 , 1 -difluoro-ethyl)-phenyl]-8-(2-f luoro-6- trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3R-[3a(R*)]}-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid methyl ester
{3S-[3a(R*)]}-[2-({[6-(2-fluoro-3-methoxy-ph
methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)^ ethoxy]-acetic acid methyl ester
{3R-[3a(S*)]}- [2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid methyl ester
{3S-[3a(S*)]}-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid methyl ester
6-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-hexanoic acid methyl ester
6-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-hexanoic acid amide
4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-3-hydroxy-butyric acid ethyl ester
2-tert-butoxycarbonylamino-4-({[6-(2-fluoro-3-m
benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid tert-butyl ester
4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyronitrile
{3R-[3a(R*)]}-4-({[6-(4-fluoro-benzo[1 !3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyronitrile
{3S-[3a(R*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyronitrile
{3R-[3a(S*)]}-4-({[6-(4-fluoro-benzo[1 !3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyronitrile
{3S-[3a(S*)]}-4-({[6-(4-fluoro-benzo[1 !3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyronitrile
4-({[8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-
5H-hiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester 4-({[6-(2-fluoro-4-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester 4-({[6-(3-acetyl-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2!3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester 4-({[6-(2-fluoro-5-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
{3R-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3S-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3R-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3S-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)^ butyric acid ethyl ester
{3R-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid ethyl ester
{3S-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid ethyl ester
{3R-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid ethyl ester
{3S-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid ethyl ester
4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyronitrile
4-({(2-fluoro-phenyl)-[6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-methyl}-amino)- butyronitrile
4-({[6-(2-fluoro-4-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-2,2,7-trimethyl-5-oxo- 2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
4-({[6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluorornethyl-benzyl)-2,2,7- trimethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
4-({[6-(2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-2!2J-trimethyl-5-oxo-2,3-dihydro- 5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
4-({[6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-2,2 ,7-trimethyl-5-oxo- 2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
[2-({[6-[3-(1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-ethoxy]-acet acid ethyl ester
4-({[6-[3-(1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
[2-({[6-[3-(1 , 1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-ethoxy]-acetic acid methyl ester
4-({[6-(2-fluoro-4-phenoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester {3R-[3a(R*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3S-[3a(R*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl- 5-0X0-2, 3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
{3R-[3a(S*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl- 5-0X0-2, 3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
{3S-[3a(S*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl- 5-0X0-2, 3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
{3R-[3a(R*)]}-[2-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid ethyl ester
{3S-[3a(R*)]}-[2-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid ethyl ester
{3R-[3a(S*)]}-[2-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid ethyl ester
{3S-[3a(S*)]}-[2-({[6-(3-difluoromethoxy
methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid ethyl ester
{3R-[3a(R*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)^ butyric acid ethyl ester
{3S-[3a(R*)]}-4-({[6-(4-fluoro-benzo[1 !3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3R-[3a(S*)]}-4-({[6-(4-fluoro-benzo[1 !3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3S-[3a(S*)]}-4-({[6-(4-fluoro-benzo[1 !3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3R-[3a(R*)]}-[2-({[6-(4-fluoro-benzo[1 !3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid methyl ester
{3S-[3a(R*)]}-[2-({[6-(4-fluoro-benzo[1 !3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid methyl ester
{3R-[3a(S*)]}-[2-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid methyl ester
{3S-[3a(S*)]}-[2-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid methyl ester
{3R-[3a(R*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]- amino}-butyric acid ethyl ester
{3S-[3a(R*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]- amino}-butyric acid ethyl ester
{3R-[3a(S*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]- amino}-butyric acid ethyl ester
{3S-[3a(S*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]- amino}-butyric acid ethyl ester
{3R-[3a(R*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]- amino}-ethoxy)-acetic acid ethyl ester
{3S-[3a(R*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]- amino}-ethoxy)-acetic acid ethyl ester
{3R-[3a(S*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]- amino}-ethoxy)-acetic acid ethyl ester
{3S-[3a(S*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]- amino}-ethoxy)-acetic acid ethyl ester
4-({(3,5-difluoro-phenyl)-[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-methyl}-amino)-butyric acid ethyl ester
{3R-[3a(R*)]}-4-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluororTiethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
{3S-[3a(R*)]}-4-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluororTiethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
{3R-[3a(S*)]}-4-({[6-(5-fluoro-2!3-dihydro-benzo[1 !4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
{3S-[3a(S*)]}-4-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluororTiethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
{3R-[3a(R*)]}-[2-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid ethyl ester
{3S-[3a(R*)]}-[2-({[6-(5-fluoro-2!3-dihydro-benzo[1 !4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid ethyl ester
{3R-[3a(S*)]}-[2-({[6-(5-fluoro-2!3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluorometh benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid ethyl ester
{3S-[3a(S*)]}-[2-({[6-(5-fluoro-2!3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluorometh benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid ethyl ester
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-[(2-hydroxy- ethylamino)-phenyl-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3- ({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-propane-1 -sulfonic acid
4- ({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butane-1 -sulfonic acid 2-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-
2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-ethyl]-isoindole-1 ,3- dione
2-[3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo- 2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-propyl]-isoindole- 1 ,3-dione
2-[4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-
2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyl]-isoindole-1 ,3- dione
{3R-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3S-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3R-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3S-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3R-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid ethyl ester
{3S-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid ethyl ester
{3R-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid ethyl ester
{3S-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid ethyl ester
{3R-[3a(R*)]}-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3S-[3a(R*)]}-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3R-[3a(S*)]}-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3S-[3a(S*)]}-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
6-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-hexanoic acid 4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-3-hydroxy-butyric acid
4-({[8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-
5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
4-({[6-(2-fluoro-4-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
4-({[6-(3-acetyl-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2!3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
4-({[6-(2-fluoro-5-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid {3R-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3S-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropo
methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino butyric acid
{3R-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3S-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3R-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3S-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3R-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3S-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
4-({[6-(2-fluoro-4-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid 4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-2,2 J-trimethyl-5-oxo-
2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
4-({[6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro
trimethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)^ butyric acid
4-({[6-(2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-2,2J-trimethyl-5-oxo-2,3-dihydro-
5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
4-({[6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-2,2 ,7-trimethyl-5-oxo-
2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
[2-({[6-[3-(1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-ethoxy]-acetic acid
4-({[6-[3-(1 ,1 -difluoro^thyl)-2-fluoro^henyl]^-(2-fluoro^-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid [2-({[6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-ethoxy]-acetic acid 4-({[6-(2-fluoro-4-phenoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
{3R-[3a(R*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3S-[3a(R*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl- 5-0X0-2, 3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid {3R-[3a(S*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-
5-0X0-2, 3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid {3S-[3a(S*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl- 5-0X0-2, 3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
{3R-[3a(R*)]}-[2-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3S-[3a(R*)]}-[2-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3R-[3a(S*)]}-[2-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3S-[3a(S*)]}-[2-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3R-[3a(R*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3S-[3a(R*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3R-[3a(S*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3S-[3a(S*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3R-[3a(R*)]}-[2-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3S-[3a(R*)]}-[2-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3R-[3a(S*)]}-[2-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3S-[3a(S*)]}-[2-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3R-[3a(R*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]- amino}-butyric acid
{3S-[3a(R*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]- amino}-butyric acid
{3R-[3a(S*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]- amino}-butyric acid
{3S-[3a(S*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]- amino}-butyric acid
{3R-[3a(R*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]- amino}-ethoxy)-acetic acid
{3S-[3a(R*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]- amino}-ethoxy)-acetic acid
{3R-[3a(S*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]- amino}-ethoxy)-acetic acid
{3S-[3a(S*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)-methyl]- amino}-ethoxy)-acetic acid
4-({(3,5-difluoro-phenyl)-[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-methyl}-amino)-butyric acid {3R-[3a(R*)]}-4-({[6-(5-fluoro-2!3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
{3S-[3a(R*)]}-4-({[6-(5-fluoro-2!3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
{3R-[3a(S*)]}-4-({[6-(5-fluoro-2!3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
{3S-[3a(S*)]}-4-({[6-(5-fluoro-2!3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
{3R-[3a(R*)]}-[2-({[6-(5-fluoro-2!3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid
{3S-[3a(R*)]}-[2-({[6-(5-fluoro-2!3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid
{3R-[3a(S*)]}-[2-({[6-(5-fluoro-2!3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid
{3S-[3a(S*)]}-[2-({[6-(5-fluoro-2!3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid
{3R-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3S-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3R-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3S-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3R-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3S-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3R-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
{3S-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- ethoxy]-acetic acid
4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyramide
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-{phenyl-[3-
(1 H-tetrazol-5-yl)-propylamino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(4-fluoro-1 ,3-benzo dioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-(phenyl{[3- (1 H-tetrazol-5-yl)propyl] amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo [3,2-a]pyridin-5- one 1 -oxide
6-(4-fluoro-benzo [1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-{phenyl-[3- (1 H-tetrazol-5-yl)-propylamino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
2- amino-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid 3-[(2-amino-ethylamino)-phenyl-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3- [(3-amino-propylamino)-phenyl-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[(4-amino-butylamino)-phenyl-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
N-[3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo- 2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-propyl]-guanidine
[1 £,3R(R)]-ethyl 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} butanoate
[1 £,3S(R)]-ethyl 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} butanoate
[1 £,3R(S)]-ethyl 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} butanoate
[1 £,3S(S)]-ethyl 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} butanoate
3-[amino(2 -fluorophenyl) methyl]-6-[2-fluoro-3-(trifluoromethoxy)phenyl]-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 - oxide
ethyl 4-{[{6-(2-fluoro-4-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 - oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoate
ethyl 4-{[(3,5-difluorophenyl){6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}methyl]amino}butanoate
ethyl 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 - oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(2 -fluorophenyl) methyl]amino}butanoate
ethyl 4-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl-1 - oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
[^,3R(R)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluororTiethyl)benzyl]-7-rTiethyl-1 oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanenitrile
[^,3S(R)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluororTiethyl)benzyl]-7-rTiethyl-1 oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanenitrile
[^,3R(S)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 - oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanenitrile
[^,3S(S)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 - oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanenitrile
[^!3R(R)]-4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanenitrile
[1
,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanenitrile
[^!3R(S)]-4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanenitrile
[^!3S(S)]-4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanenitrile
[^,3R(R)]-ethyl 4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoate
[^,3S(R)]-ethyl 4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoate
[1
4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoate
[^,3S(S)]-ethyl 4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoate
[^,3R(R)]-methyl (2-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]- 7-methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetate
[^,3S(R)]-methyl (2-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]- 7-methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetate
[1 £,3R(S)]-methyl (2-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]- 7-methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetate
[1 £,3S(S)]-methyl (2-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]- 7-methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetate
[1 £,3R(R)]-ethyl 4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-6-[3-
(trifluoromethoxy)phenyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoate
[1 £,3S(R)]-ethyl 4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-6-[3- (trifluoromethoxy)phenyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoate
[1 £,3R(S)]-ethyl 4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-6-[3- (trifluoromethoxy)phenyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoate
[1 £,3S(S)]-ethyl 4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-6-[3- (trifluoromethoxy)phenyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoate
[1 £,3R(R)]-ethyl 4-{[{6-(5-fluoro-2,3-dihydro-1 ,4-benzodioxin-6-yl)-8-[2-fluoro-6- (trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
[1 £,3S(R)]-ethyl 4-{[{6-(5-fluoro-2,3-dihydro-1 ,4-benzodioxin-6-yl)-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
[1 £,3R(S)]-ethyl 4-{[{6-(5-fluoro-2,3-dihydro-1 ,4-benzodioxin-6-yl)-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
[1 £,3S(S)]-ethyl 4-{[{6-(5-fluoro-2,3-dihydro-1 ,4-benzodioxin-6-yl)-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
[1 £,3R(R)]-ethyl (2-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} ethoxy)acetate
[1 £,3S(R)]-ethyl (2-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} ethoxy)acetate
[1 £,3 (S)]-ethyl (2-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} ethoxy)acetate
[1 £,3S(S)]-ethyl (2-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} ethoxy)acetate
[^,3R(R)]-3-[amino(phenyl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 - oxide
[1 ξ!3S(R)]-3-[amino(phenyl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 - oxide
[^,3R(S)]-3-[amino(phenyl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 - oxide
[^,3S(S)]-3-[amino(phenyl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 - oxide
3-[amino(3,5-difluorophenyl) methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 - oxide
3-[amino(2 -fluorophenyl) methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 - oxide
methyl (2-{[{6-[3-(1 , 1 -difluoroethyl)-2-fluorophenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} ethoxy)acetate
methyl (2-{[{6-[3-(1 ,1 -difluoroethyl)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl-1 - oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} ethoxy)acetate
3- [amino(phenyl)methyl]-6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-
7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 -oxide
4- {[{6-(2-fluoro-4-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5- oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoic acid
[^,3R(R)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 - oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoic acid
[^,3S(R)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 - oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoic acid
[^,3R(S)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 - oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoic acid
[1 ξ!3S(S)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 - oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoic acid
4-{[(3,5-difluorophenyl){6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}methyl]amino}butanoic acid
[^,3R(R)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 - oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(2-fluorophenyl)methyl] amino}butanoic acid
[^,3S(R)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 - oxido-5-oxo-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-3-yl}(2-fluorophenyl)methyl] amino}butanoic acid
[1 ξ, 3R(S)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl- 1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(2-fluorophenyl)methyl] amino}butanoic acid
[^,3S(S)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 - oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(2-fluorophenyl)methyl] amino}butanoic acid
[^,3R(R)]-4-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl- 1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoic acid
[^,3S(R)]-4-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl- 1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoic acid
[^,3R(S)]-4-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl- 1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoic acid
[^,3S(S)]-4-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl- 1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoic acid
[^!3R(R)]-4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoic acid
[^!3S(R)]-4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoic acid
[1
,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoic acid
[^!3S(S)]-4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoic acid
[^!3R(R)]-(2-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetic acid
[^!3S(R)]-(2-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetic acid
[^!3R(S)]-(2-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetic acid
[^!3S(S)]-(2-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetic acid
[^,3R(R)]-4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-6-[3- (trifluoromethoxy)phenyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoic acid
[^,3S(R)]-4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-6-[3- (trifluoromethoxy)phenyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoic acid
[^,3R(S)]-4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-6-[3- (trifluoromethoxy)phenyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoic acid
[^,3S(S)]-4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-6-[3- (trifluoromethoxy)phenyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoic acid
[^.SRCR^^-iKe-CS-fluoro^.S-dihydro-l ^-benzodioxin-e-y -S-p-fluoro-e-Ctrifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} butanoic acid
[^.SSCR^^-iKe-CS-fluoro^.S-dihydro-l ^-benzodioxin-e-yl^S-p-fluoro-e-Ctrifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} butanoic acid
[1 ξ,3Κ(8)]-4-{[{6-(5-ίΙυοι-ο-2,3^ίΙ^ ΐΌ-1 ,4-benzodioxin-6-yl)-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} butanoic acid
[^.SSCS^^-iKe-CS-fluoro^.S-dihydro-l ^-benzodioxin-e-yl^S-p-fluoro-e-Ctrifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} butanoic acid
[1 ξ,3Κ(Κ)]-(2-{[{6-[3-^ίΑυοΓθΓηΘΐΙ·^) phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetic acid
[1 ξ,38(Κ)]-(2-{[{6-[3-^ιΑυοΓθΓΤΐΘΐΙ·^) phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetic acid
[1 ξ,3Κ(8)]-(2-{[{6-[3-^ιΑυοΓθΓΤΐΘΐΙ·^) phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetic acid
[1 ξ!3S(S)]-(2-{[{6-[3-(difluoromethoxy) phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl- 1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetic acid
[^,3R*(R*)]-(2-{[{6-[3-(1 -difluoroethyl)-2-fluorophenyl]-8-[2-fluoro-6-(trifluoromethyl)benzyl]- 7-methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetic acid
[^,3R*(S*)]-(2-{[{6-[3-(1 -difluoroethyl)-2-fluorophenyl]-8-[2-fluoro-6-(trifluoromethyl)benzyl]- 7-methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetic acid
(2-{[{6-[3-(1 ,1 -difluoroethyl)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5- oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino}
ethoxy)acetic acid
Another embodiment of the present invention provides compounds according to general formula (I) and related specific embodiments for use as a medicament.
In another embodiment, the present invention provides a method of treating GnRH related disorder in a patient in need of such treatment, comprising administering to the patient an effective amount of a compound according to the invention as defined above. In still another aspect, the invention provides use of a compound according to the invention as defined above for manufacturing a pharmaceutical composition for the treatment or prevention of GnRH related disorders.
The term "treating" or "treatment" as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, rel ievi ng , i mprovi ng the cond ition of a d isease or d isorder, such as for example endometriosis and uterine fibroids.
The term "subject" or "patient" includes organisms which are capable of suffering from a disorder or who could otherwise benefit from the administration of a compound of the invention , such as human and non-human animals. Preferred humans include human patients suffering from or prone to sufferi ng from disorders, such as for example endometriosis and uterine fibroids. The term "non-human animals" includes vertebrates, e.g., mammals, such as non-human primates, sheep, cow, dog, cat and rodents, e.g., mice, and non-mammals, such as chickens, amphibians, reptiles, etc.
I n another aspect, the invention provides a pharmaceutical composition comprising a compound according to the invention, together with a pharmaceutically acceptable carrier. In still another aspect, the invention provides a process for preparing a pharmaceutical composition. The process includes the step of combining at least one compound according to the invention as defined above with at least one pharmaceutically acceptable carrier, and bringing the resulting combination into a suitable administration form. The compounds according to general formula (I) are used as a medicament. In particular, said compounds are used to treat sex-hormone-related conditions in both men and women, as well as a mammal in general (also referred to herein as a "subject"). For example, such
conditions include endometriosis, uterine fibroids, polycystic ovarian disease, heavy menstrual bleeding, particularly menorrahagia and dysmenorrehea, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia such as cancers of the prostate, breast and ovary, gonadotrope pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, contraception and infertility (e.g., assisted reproductive therapy such as in vitro fertilization).
The compounds of this invention are also useful as an adjunct to treatment of growth h ormone d eficiency a n d sh ort statu re , an d for th e treatment of system ic l u pus erythematosus.
According to a further embodiment of the present invention the compounds according to general formula (I) are also useful and can be used in combination with and rogens, estrogens, progestins, SERMs, antiestrogens and antiprogestins for the treatment of endometriosis, fibroids, and in contraception, as well as in combination with an angiotensin- converting enzyme inhibitor, an angiotensin I l-receptor antagonist, or a renin inhibitor for the treatment of uterine fibroids.
A combination of compounds according to general formula (I) with bisphosphonates and other agents for the treatment and/or prevention of disturbances of calcium, phosphate and bone metabolism, and in combination with estrogens, SERMs, progestins and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flushes during therapy with a GnRH antagonist is also part of the present invention.
The methods of this invention include administering an effective amount of a GnRH receptor antagonist, preferably in the form of a pharmaceutical composition, to a mammal in need thereof. Thus, in still a further embodiment, pharmaceutical compositions are disclosed containing one or more GnRH receptor antagonists of this invention in combination with a pharmaceutically acceptable carrier and/or diluent.
These and other aspects of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and/or compositions, and are each hereby incorporated by reference in their entirety.
The compounds of the present invention may generally be utilized as the free acid or free base. Alternatively, the compounds of this invention may be used in the form of acid or base addition salts.
Thus, the term "pharmaceutically acceptable salt" of compounds of general formula (I) is intended to encompass any and all acceptable salt forms.
In addition, prodrugs are also included within the context of this invention. Prodrugs are any covalently bonded carriers that release a compound of general formula (I) in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.
Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of general formula (I). Further, in the case of a carboxylic acid (-COOH), esters may be employed, such as methyl esters, ethyl esters, and the like.
With regard to stereoisomers, the compounds of general formula (I) may have chiral centers and may occu r as racemates , racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Furthermore, some of the crystalline forms of the compounds of general formula (I) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of general formula (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention. The effectiveness of a compound as a GnRH receptor antagonist may be determined by various assay techniques. Assay techniques well known in the field include the use of cultured pituitary cells for measuring GnRH activity (Vale et al., Endocrinology 1972, 91, 562 - 572) and the measurement of radioligand binding to rat pituitary membranes (Perrin et al., Mol. Pharmacol. 1983, 23, 44 - 51 ) or to membranes from cells expressing cloned receptors as described below. Other assay techniques include (but are not limited to) measurement of the effects of GnRH receptor antagonists on the inhibition of GnRH-stimulated calcium flux, modulation of phosphoinositol hydrolysis, and the circulating concentrations of gonadotropins in the castrate animal. Descriptions of these techniques, the synthesis of radiolabeled ligand, the employment of radiolabeled ligand in radioimmunoassay, and the measurement of the effectiveness of a compound as a GnRH receptor antagonist follow.
In another embodiment of the invention, pharmaceutical compositions containing one or more GnRH receptor antagonists are disclosed. For the purposes of administration, the compounds of the present invention may be formulated as pharmaceutical compositions. Pharmaceutical compositions of the present invention comprise a GnRH receptor antagonist of the present invention and a pharmaceutically acceptable carrier and/or diluent. The GnRH receptor antagonist is present in the composition in an amount which is effective to treat a particular disorder that is, in an amount sufficient to achieve GnRH receptor antagonist activity, and preferably with acceptable toxicity to the patient. Typically, the pharmaceutical compositions of the present invention may include a GnRH receptor antagonist in an amount from 0.1 mg to 500 mg per day dosage depending upon the route of administration, and more typically from 0.5 mg to 150 mg per day. Appropriate concentrations and dosages can be readily determined by one skilled in the art. Determination of a therapeutically effective amount or a prophylactically effective amount of the compounds of the invention can be readily made by the physician or veterinarian (the "attending clinician"), as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. The dosages may be varied depending upon the requirements of the patient in the judgment of the attending clinician; the severity of the condition being treated and the particular compound being employed. In determining the therapeutically effective amount or dose, and the prophylactically effective amount or dose, a number of factors are considered by the attending clinician, including, but not li m ited to: the specific G n RH med iated d isorder i nvolved ; pharmacodynam ic characteristics of the particular agent and its mode and route of administration; the desired time course of treatment; the species of mammal; its size, age, and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the kind of concurrent treatment (i.e., the interaction of the compound of the invention with other coadministered therapeutics); and other relevant circumstances.
Treatment can be initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
Pharmaceutically acceptable carrier and/or diluents are familiar to those skilled in the art. For compositions formulated as liquid solutions, acceptable carriers and/or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. The compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a GnRH receptor antagonist, diluents, dispersing and surface active agents, binders, and lubricants. One skilled in this art may further formulate the GnRH receptor antagonist in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed. , Mack Publishing Co., Easton, PA 1990.
In another embodiment, the present invention provides a method for treating sex-hormone- related conditions as discussed above. Such methods include administering of a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the condition. In this context, "treat" includes prophylactic administration. Such methods include systemic administration of a GnRH receptor antagonist of this invention, preferably in the form of a pharmaceutical composition as discussed above. As used herein , systemic administration includes oral and parenteral methods of administration. For oral administration, suitable pharmaceutical compositions of GnRH receptor antagonists include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives. For parental administration, the compounds of the present invention can be prepared in aqueous injection solutions which may contain, in addition to the GnRH receptor antagonist, buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.
MODE(S) FOR CARRYING OUT THE INVENTION
The following examples are provided for purposes of illustration, not limitation. In summary, the GnRH receptor antagonists of this invention may be assayed by the general methods disclosed above, while the following examples disclose the synthesis of representative compounds of this invention.
EXPERIMENTAL DETAILS AND GENERAL PROCESSES The following table lists the abbreviations used in this paragraph and in the examples section as far as they are not explained within the text body.
s singlet
sept septet
t or tr triplet
TBAF tetra-N-butylammonium fluoride
TEA triethylamine
TLC thin layer chromatography
TFA trifluoroacetic acid
THF tetrahydrofuran
Ts para-toluenesulfonyl
UPLC-MS ultra performance liquid chromatography mass spectrometry
NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. Chemical shifts are given in ppm; all spectra were calibrated to solvent residual peak. Integrals are given in integers, except for those cases atropisomerism was observed. Then non integer numbers were used; signals are marked with an asterisk (*), for example (0.5H*).
Ultra performance liquid chromatography / liquid chromatography mass spectrometry - methods:
The term "UPLC-MS (ESI+)" refers to the following condition:
Instrument: Waters Acquity UPLC-MS SQD 3001 ; column: Acquity UPLC BEH C18 1 .7 50x2.1 mm; eluent A: water + 0.1 % formic acid, eluent B: acetonitrile; gradient: 0-
1 .6 min 1 -99% B, 1 .6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; injection: 2 μΙ; DAD scan: 210-400 nm; or
Instrument: Waters Acquity UPLC-MS SQD 3001 ; column: Acquity UPLC BEH C18
1 .7 50x2.1 mm; Eluent A: water + 0.2% ammonia, eluent B: acetonitrile; gradient: 0- 1 .6 min 1 -99% B, 1 .6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; injection: 2 μΙ; DAD scan: 210-400 nm
The term "UPLC_MS (ESI+)" refers to the following condition:
Waters HPLC-MS: Micromass ZQ, PDA 2996 (210-350 nm), column: Waters XBridge 4.6x50 mm C18 3.5 μηι (20 °C), gradient: 0-8 min. 1 -99% acetonitrile in water (0.1 % formic acid), flow 2 mL/min.
Chemical names were generated according to the l U PAC rules [ACD/Name Batch ver. 12.00] or using AutoNom2000 as implemented in MDL ISIS Draw [MDL Information Systems Inc. (Elsevier MDL)]. In some cases generally accepted names of commercially available reagents were used in place of l U PAC names or AutoNom2000 generated names. Stereodescriptors are used according to chemical abstracts.
Reactions employing microwave irradiation may be run with a Biotage Initiator® microwave oven optionally equipped with a robotic unit. The reported reaction times employing microwave heating are intended to be understood as fixed reaction times after reaching the indicated reaction temperature.
The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. I n some cases, the compou nds may be pu rified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. from Separtis such as Isolute® Flash silica gel or Isolute® Flash NH2 silica gel in combination with a Flashmaster II autopurifier (Argonaut/Biotage) and eluents such as gradients of hexane/ethyl acetate or DCM/ethanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier eq u ipped with a d iode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid or aqueous ammonia.
In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the persion skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
The following schemes and general procedures illustrate general synthetic routes to the compounds of general formula (I) of the invention and are not intended to be limiting. It is obvious to the person skilled in the art that the order of transformations as exemplified in Schemes 1 to 4 can be modified in various ways. The order of transformations exemplified in
Schemes 1 to 4 is therefore not intended to be limiting. In addition, interconversion of substituents, for example of residues Ria, Rib, R2a, R2b, R3a, R3b, R6, R7 and R8 can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999).
Scheme 1
1 2 3 Scheme 1 General procedures for the preparation of a compounds of general formula 3 starting from an ester of general formula 1 , W, R1a, R1b, R2a, R2b, R6, R7 and R8 are as defined in the description and claims of this invention. The procedure is favourable for the synthesis of compounds of general formula (I) wherein Y is -C(=0)NR1aR1b. A compound of general formula 3 can be synthesized according to the procedure depicted in Scheme 1 from a suitably functionalized carboxylic acid of general formula 2 by reaction with an appropriate amine, HNR1aR1b. For amide formation, however, all processes that are known from peptide chemistry to the person skilled in the art are available. The acid of general formula 2, which can be obtained from the corresponding ester of general formula 1 by saponification, can be reacted with an appropriate amine in aprotic polar solvents, such as, for example, DMF, via an activated acid derivative, which is obtainable, for example, with hydroxybenzotnazole and a carbodiimide, such as, for example, diisopropylcarbodiimide, at temperatures between 0°C and the boil ing point of the solvent, preferably at room temperature, or else with preformed reagents, such as, for example, 0-(7-azabenzotriazol-1 - yl)-1 , 1 , 3, 3-tetramethyluronium hexafluorophosphate (see for example Chem. Comm. 1994,
201 - 203), at temperatures between 0°C and the boiling point of the solvent, preferably at room temperature, or else with activating agents such as dicyclohexylcarbodiimide / N,N- dimethylaminopyridine or /V-ethyl-/V',/V-dimethylaminopropylcarbodiimide / N,N- dimethylaminopyridine. The addition of a suitable base such as, for example, N- methylmorpholine, TEA, DIPEA may be necessary. Amide formation may also be accomplished via the acid halide (which can be formed from a carboxylic acid by reaction with e.g. oxalyl chloride, thionyl chloride or sulfuryl chloride), mixed acid anhydride (which can be formed from a carboxylic acid by reaction with e.g. isobutylchloroformate), imidazolide (which can be formed from a carboxylic acid by reaction with e.g. carbonyldiimidazole) or azide (which can be formed from a carboxylic acid by reaction with e.g. diphenylphosphorylazid).
Furthermore it is possible to react an appropriate amine with a suitably functionalized ester of general formula 1 according to a method described in J. Org. Chem.1995, 60, 8414 - 8416 in the presence of trimethylaluminum and in a suitable solvent, such as, for example toluene, at temperatures of 0°C to the boiling point of the solvent.
Scheme 2
A compound of general formula 6 can be synthesized according to the procedure depicted in Scheme 2 from a suitably functionalized activated precursor 5, wherein LG is an appropriate leaving group, such as, for example, a p-toluenesulfonyloxy (LG is OTs) or chlorine (LG is CI), in aprotic polar solvents, such as, for example, THF or DMF, with an appropriate amine, HNR1aR1b, at temperatures between 0°C and the boiling point of the solvent, preferably at 60°C. Further in situ activation of the chlorine precursor 5 (LG is CI), according to standard Finkelstein's procedure (S. D. Bowers Jr., J. M. Sturtevant, J. Am. Chem. Soc. 1955, 77, 4903 - 4907; M. Yonovich-Weiss, Y. Sasson, Synthesis 1984, 34 - 35) may be necessary. The activated precursor 5, is obtainable from the suitably functionalized alcohol 4 by reacting, for example, with p-toluenesulfonic anhydride and /V,/V-dimethylaminopyridine or p- toluenesulfonic acid chloride, a catalytic amount of /V,/V-dimethylaminopyridine and an appropriate base, such as, for example, Hunig's base or triethylamine in an aprotic polar solvent, such as, for example, dichloromethane at temperatures between -20°C and the boiling point of the solvent, preferably at room temperature.
Alternatively LG may comprise the Oxygen of an aldehyde moiety, i.e. a compound of general formula 6 can be synthesized by reductive amination of a suitably functionalized aldehyde 5 (LG is O) with an appropriate amine, HNR1aR1b, employing all methods available to the person skilled in the art. For example, a suitably functionalized aldehyde 5 (LG is O) can be reacted with an appropriate amine in the presence of an reducing reagent, such as, for example, sodium trisacetoxyborohydride in an appropriate solvent, such as, for example, toluene at temperatures between 0°C and the boiling point of the solvent, preferably at room temperature. The required suitably functionalized aldehyde can be obtained from an alcohol of general formula 4 by standard oxidation procedures, such as, for example Dess-Martin- oxidation (J. Prakt. Chem. 1996, 338, 588 - 590) or Swern-oxidation {Synthesis 1981 , 165 - 185) protocols.
A alcohol of general formula 4 can be obtained from the afore mentioned (see scheme 1 ) corresponding suitably functionalized ester 1 by reduction with an appropriate reducing reagent, such as, for example, lithium aluminum hydride or lithium borohydride in an aprotic polar solvent, such as, for example, THF at temperatures between -20°C and the boiling point of the solvent, preferably at room temperature.
Scheme 3
8 9 10
Scheme 3 General procedures for the preparation of a compound of the general formula 10 from an ester of general formula 1 , W, R1a, R1b,
R2b, R3a, R3b, R6, R7 and R8 are as defined in the description and claims of this invention. The procedure is favourable for the synthesis of compounds of general formula (I) wherein Y is -CR3aR3b-NR1aR1b.
A compound of general formula 10 can be synthesized according to the procedure depicted in Scheme 3 from a suitably functionalized imine and/or oxime 9. Since the process disclosed in scheme 3 can optionally deliver a compound of the general formula 10 wherein R-ia and Rib of general formula 10 comprises hydrogen, the latter compound may act as a precursor for the introduction of further substituents Ria and/or R1b different from hydrogen. The transformation primary amine (Ria and Rib of general formula 10 comprises hydrogen) to secondary or tertiary amine, amide, sulphonamide etc. can be achieved by any of the transformations known to a person skilled in the art. For example: reductive amination and/or alkylation introduces further substituents Ria and/or R1b different from hydrogen of general formula 10.
A primary amine of general formula 10 wherein R1a and Rib of general formula 10 comprises hydrogen, can be synthesized in analogy to the method described by Kano et al. (Synthesis 1980, 695 - 697) from a suitably functionalized oxime 9 wherein R1c is hydroxy or O-methyl by reduction with an appropriate reducing reagent, such as, for example lithium borohydride, in the presence of a lewis acid, such as, for example titanium tetrachloride, in a polar aprotic
solvent, such as, for example, dimethoxyethane at temperatures between -78°C and room temperature and the boiling point of the solvent, preferably at 0°C.
A primary amine of the general formula 10 wherein R1a and Rib of general formula 10 comprises Hydrogen and R3b is different from hydrogen or deuterium, can be synthesized in analogy to the method described by Kano et al. (Synthesis 1980, 695 - 697) from a suitably functionalized oxime 9 wherein R1c comprises hydroxyl or O-methyl by addition of an appropriate Grignard reagent, such as, for example, methyl magnesium chloride in the presence of a lewis acid, such as for example titanium tetrachloride, in a polar aprotic solvent, such as, for example, dimethoxyethane at temperatures between -78° C and room temperature and the boiling point of the solvent, preferably at 0°C.
Alternatively, a primary amine of the general formula 10 wherein R1a and Rib of general formula 10 comprises hydrogen and R3b is different from Hydrogen or deuterium, can be synthesized from a suitably functionalized secondary amine 10 (Ria is allyl) by deallylation using an appropriate catalyst, such as, for example, palladium on charcoal in an protic solvent, such as, for example, ethanol at temperatures between room temperature and the boiling point of the solvent, preferably at 80°C.
A secondary amine of the general formula 10 wherein R1a or R1b are different from hydrogen can - besides the formation from a primary amine (see above) - be synthesized in analogy to the method described by Kano et al. (Synthesis 1980, 695 - 697) from a suitably functionalized imine 9 wherein R1c comprises allyl by reduction with an appropriate reducing reagent, such as, for example, lithium borohydride, in a polar aprotic solvent, such as, for example, dimethoxyethane, at temperatures between -78°C and room temperature and the boiling point of the solvent, preferably at room temperature.
A secondary amine of the general formula 10 wherein R1a and R3b of general formula 10 are connected to form a N-heterocycle can be synthesized in analogy to the method described by Jenkins et al. (J. Org. Chem. 2009, 74, 1304 - 1313) from suitably functionalized aminodiene 10 wherein R1a and R3b are alkenyl by ring closing metathesis (RCM) with an appropriate catalyst, such as, for example, Grubbs second-generation catalyst, in an aprotic solvent, such as, for example, dichloromethane, at temperatures between room temperature and the boiling point of the solvent, preferably at 40°C.
The aminodiene 10 wherein R1a and R3b is alkenyl is obtainable by reacting suitably functionalized alkenyl imine 9 (Ric is alkenyl) in aprotic non-polar solvents, such as, for example, toluene, at temperatures between -78°C and the boiling point of the solvent, preferably at 0°C with an appropriate Grignard reagent or metallated alkane or alkene, which are commercially available or are obtainable, for example, from an alkyl halide or an alkenyl halide via halogen-metal-exchange by employing, for example, butyllithium or lithium metal in
an aprotic solvent, at temperatures between -100°C and the boiling point of the solvent, preferably at -20°C temperature.
The imine or oxime 9, is obtainable from the suitably functionalized ketone 8 by reacting with an appropriate amine, H2N-R1c, such as, for example, hydroxylamine hydrochloride or O-methylhydroxylamine or allylamine in a polar solvent, such as, for example, glacial acetic acid, alcohol or toluene or mixtures thereof at temperatures between room temperature and the boiling point of the solvent, preferably at 60°C. The addition of a suitable base, such as, for example, pyridine or triethylamine may be necessary. Some reactions may need the employment of a Dean-Stark apparatus and/or the addition of a suitable Lewis acid, such as, for example, titanium alkoxides. Ketone 8 can be synthesized in three different ways starting from suitably functionalized ester 1 :
1 .) Suitably functionalized thioester 7 can be reacted with an appropriate (hetero)aryl boronic acid in the presence of an appropriate catalytic system, such as, for example, as described by Liebeskind et al. {J. Am. Chem. Soc. 2000, 122, 1 1260 - 1 1261 ; and Org. Lett, 2000, 2 , 3229 - 3231 ) tris-(dibenzylidenaceton)-dipalladium (0) / 2- thiophenecarboxylic acid, copper(l) salt / phosphorous acid triethyl ester in an aprotic polar solvent, such as, for example, THF, at temperatures between room temperature and the boiling point of the solvent, preferably at 60°C. Furthermore an appropriate (hetero)aryl stannane in the presence of an appropriate catalytic system can be used instead of the boronic acid as described recently (Liebeskind et al., Org. Lett. 2003, 5,
3033 - 3035). Thioester 7 can be prepared from a suitably functionalized acid 2 (see scheme 1 ) by, however, all processes that are known for thioester formation to the person skilled in the art. The acid of general formula 2, which can be obtained from the corresponding ester of general formula 1 by saponification, can be reacted, for example, with thiophenol in an aprotic polar solvent, such as, for example, DMF, via an activated acid derivative, which is obtainable, for example, with hydroxybenzotriazole and a carbodiimide, such as, for example, N-ethyl-N',N'- dimethylaminopropylcarbodiimide / Ν,Ν-dimethylaminopyridine, at temperatures between 0°C and the boiling point of the solvent, preferably at room temperature. 2.) Suitably functionalized ester 1 can be directly transformed into ketone 8 in aprotic non-polar solvents, such as, for example, toluene, at temperatures between -78°C and the boiling point of the solvent, preferably at room temperature, by reacting with an appropriate metallated (hetero)aryl, which is commercially available or is obtainable, for example, from (hetero)aryl halide by halogen-metal-exchange or direct metallation of an (hetero)aromat, by employing, for example butyllithium or lithium metal in an aprotic solvent at temperatures between -100°C and the boiling point of the solvent, preferably at -20°C temperature.
3.) Furthermore suitably functionalized thioester 7 can also act as appropriate starting material for the above [bullet point 2.)] described transformation.
Scheme 4
15 16 1
Scheme 4 General procedures for the preparation of an ester of general formula 1 from an propionitrile of general formula 11 , W, R2a, F½b, R6, R7 and R8 are as defined in the description and claims of this invention. The procedure is favourable for the synthesis of compounds of general formula (I) wherein W is S.
An ester of general formula 1 can be synthesized according to the procedure depicted in Scheme 4 from a suitably functionalized 6-halo-pyridinone 16 and a suitable functionalized benzo[1 ,3]dioxolyl-, 2,3-dihydro-1 ,4-benzodioxinyl or (hetero)aryl boronic acid 17 (R is H) or an ester thereof. For carbon-carbon-bond formation, however, all methods that are known for Suzuki coupling to the person skilled in the art are available. For example, a suitably functionalized 6-iodo-pyridinone 16 (Hal is I) can be reacted with a suitable functionalized benzo[1 ,3]dioxolyl-, 2, 3-dihydro-1 ,4-benzodioxinyl or (hetero)aryl boronic acid 17 in the presence of an appropriate catalyst and base, such as, for example, dichlor(1 ,1 '- bis(diphenylphosphin)ferrocene) palladium dichloromethane complex an d aq ueous potassium carbonate, respectively, in an appropriate solvent, such as, for example, dioxane,
at temperatures between room temperature and the boiling point as well as above the boiling point of the solvent, preferably at 130°C temperature employing a microwave reactor. The synthesis of 6-halo-pyridinone 16 starts from corresponding suitably functionalized 6-H- pyridinone 15 in analogy to Almqvist et al. (J. Org. C em. 2004, 69, 7830 - 7835). N- iodosuccinimide and bromine, respectively, in a polar protic solvent, such as, for example, glacial acetic acid at temperatures between -20°C and the boiling point of the solvent, preferably at room temperature, can be used to introduce the desired halide at position C-6 of the pyridinone core. A pyridinone of general formula 15 can be synthesized starting from a suitably functionalized thiazoline 13 (W is S) and a suitably functionalized Meldrum's acid derivative 14 according to a method developed by Almqvist et al. (Molecular Diversity 2003, 7, 165 -169). Thiazoline of general formula 13 (W is S) and dihydrooxazole (W is O) can be synthesized via suitably functionalized iminoether 12 and readily available cystein methylester hydrochloride, penicillamine methylester hydrochloride (J. Org. Chem. 2001 , 66, 6756 - 6761 ) and derivatives thereof or serine methylester and derivatives thereof starting from a suitably functionalized propionitrile 11.
Scheme 5
18 14 Scheme 5 General procedure for the preparation of an Meldrum's acid of general formula 14 from Meldrum's acid 18, and R7 is as defined in the description and claims of this invention.
The Meldrum's acid derivative 14 can either be purchased (formula 14, scheme 5 with R7 is methyl, i . e . 5-acetyl-2,2-dimethyl-1 ,3-dioxane-4,6-dione, CAS-No. 72324-39-1 ) o r synthesized as depicted in scheme 5 starting from commercially available Meldrum's acid 18 (2,2-dimethyl-1 ,3-dioxan-4,6-dion, CAS-No. 2033-24-1 ) and an appropriate acylating reagent, such as, for example, 1 -(trifluoracetyl)-imidazole (R7 is trifluoromethyl) in an aprotic polar solvent, such as, for example, chloroform, at temperatures between -20°C and the boiling point of the solvent, preferably at room temperature, according to Yamamoto et al. (Chem. Commun. 1997, 359 - 360) or via an activated acetic acid derivative, which is obtainable, for example, from carbonyldiimidazole according to Duval et al. (Bioorganic and Medicinal Chemistry 1997, 5, 749 - 764).
Scheme 6
19 20 21 11
Scheme 6 General procedures for the preparation of an propionitrile of general formula 11 from benzaldehyde of general formula 19, and R8 is as defined in the description and claims of this invention.
A propionitrile of general formula 11 can either be purchased [e.g. 3-phenylpropionitrile (CAS-No. 645-59-0); or 3-(2-chloro-6-fluorophenyl)propionitrile from PARAGOS] or be synthesized as depicted in scheme 6 starting from a suitably functionalized benzaldehyde of general formula 19.
A suitable precursor of propionitrile 11 is a suitable functionalized cinnamon nitrile 21 which can be reduced by, however, all processes that are known for reduction of cinnamon nitriles to the person skilled in the art, such as, for example, reduction by magnesium in methanol or catalytic hydrogenation by employing palladium and hydrogen. For the synthesis of lower 2- fluoroalkyl-6-fluoro derivatives, in p ra ct i c e 6-difluoromethyl-2-f l u o ro a n d 2-fluoro-6- fluoromethyl, respectively, 2-fluoro-6-trifluoromethyl cinnamon nitrile acts as starting material. The reduction by magnesium in methanol has to be done under more harsh conditions, such as, for example extended reaction time.
A cinnamon nitrile of general formula 21 can by synthesized either direct from suitably functionalized benzaldehyde 19 by Wittig-Horner-reaction according to the literature (Robert M. Garbaccio et al., Bioorganic & Medicinal Chemistry Letters 2007, 17, 6280-6285) or by a two step procedure employing a Knoevenagel condensation / decarboxylation sequence as outlined in scheme 6. To do so, suitably functionalized benzaldehyde 19 is condensed with 50% aq. solution of sodium cyanoacetate (CAS-No. 1071 -36-9) and the acid 20 is subjected to copper-catalyzed decarboxylation (Fairhurst et al., Tetrahedron Lett. 1975, 44, 3843 - 3844).
Scheme 7
15 16 1
Scheme 7 General procedures for the preparation of an ester of general formula 1 from an benzaldehyde of general formula 19, and W, R2a, ί½, R6, 7 and R8 are as defined in the description and claims of this invention. The procedure is favourable for the synthesis of compounds of general formula (I) wherein W is O.
An esters of general formula 1 can be synthesized according to the alternate procedure depicted in Scheme 7. Synthetic steps for the introduction of the halogen (15→ 16) and the R6 moiety (16 → 1 ) are the same outlined in scheme 4. The 6-H-pyridinone 15 can be synthesized in a one pot protocol in analogy to Almqvist et al. (Tetrahedron 2008, 64, 9368 - 9376), or else via isolation of intermediate 13, from a suitable functionalized amide 26 of serine and cysteine and derivatives thereof, by employing the molybdenum-catalyzed
dehydrative cyclization developed by Is i ara et al. {Org. Lett. 2005, 7, 1971 - 1974; Tetrahedron 2009, 65, 2102 - 2109). Oxazolines and thiazolines 13 can be synthesized by dehydratisation of the respective amides 26 by any methode known to a person skilled in the art. For amide formation, however, all processes that are known from peptide chemistry to the person skilled in the art are available. The appropriate propionic acid of general formula 24, which can be obtained from the corresponding ester of general formula 23 by saponification, can be reacted with serine and cysteine and derivatives thereof in an aprotic polar solvent, such as, for example, DMF, via an activated acid derivative, which is obtainable, for example, with hydroxybenzotriazole and a carbodiimide, such as, for example, diisopropylcarbodiimide, at temperatures between 0°C and the boiling point of the solvent, preferably at room temperature, or else with preformed reagents, such as, for example, 0-(7- azabenzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (see for example Chem. Comm. 1994, 201 - 203), at temperatures between 0°C and the boiling point of the solvent, preferably at room temperature, or else with activating agents such as dicyclohexylcarbodiimide / Λ/,/V-dimethylaminopyridine or N-et y\-N',N'- dimethylaminopropylcarbodiimide / Λ/,/V-dimethylaminopyridine. The addition of a suitable base such as, for example, /V-methylmorpholine, TEA, DIPEA may be necessary.
Amide formation may also be accomplished via the acid halide 25 (which can be formed from a carboxylic acid by reaction with e.g. oxalyl chloride, thionyl chloride or sulfuryl chloride), mixed acid anhydride (which can be formed from a carboxylic acid 24 by reaction with e.g. isobutylchloroformate), imidazolide (which can be formed from a carboxylic acid by reaction with e.g. carbonyldiimidazole) or azide (which can be formed from a carboxylic acid by reaction with e.g. diphenylphosphorylazid. A suitable precursor of ester 23 is the suitable functionalized cinnamic acid ester 22 which can be reduced by, however, all processes that are known for reduction of cinnamic acids to the person skilled in the art. Such as, for example, reduction by magnesium in methanol or catalytic hydrogenation by employing palladium and hydrogen (see Hamilton et al. Journal of Medicinal Chemistry. 2002, 45, 3549 - 3557). Cinnamic acid ester of general formula 22 can by synthesized from a suitably functionalized benzaldehyde 19 by Wittig-Horner-reaction according to the literature employing Λ/,Λ/,Λ/',Λ/'-tetramethylguanidine (see Barrett et al. Organic Letters 1999, 4, 579 - 582), sodium hydride (see WO2007/93963) or butyl lithium (see Etemad-Moghadam et al. Tetrahedron 1984, 40, 5153 - 5166) as base and a suitable methyl phosphonoacetate, e.g. methyl diethylphosphonoacetate (CAS 1067-74-9). Compounds of general formula (I) wherein W is S(=0) (i.e. sulfoxides) and S(=0)2 (i.e. sulfones) can be synthesised from the corresponding sulfides (W is S) and sulfoxides [W is S(=0)], respectively, at any synthetic stage by any method known to the person skilled in the
art as well as according to the general procedures and examples which are outlined in this invention.
As above-mentioned the order of transformations as exemplified in Schemes 1 to 3 can be modified in various ways. The order of transformations exemplified in Schemes 1 to 3 is therefore not intended to be limiting.
Scheme 8
28 10
Scheme 8 General procedures for the preparation of a compound of the general formula 10 starting from an ester of general formula 15, W, R1a, R1b,
R2b, R3a, R3b, R6, R7 and R8 are as defined in the description and claims of this invention. A compound of general formula 10 can be synthesized by introducing benzo[1 ,3]dioxolyl- or (hetero)aryl moieties (R6 at C-6) in late stage of the synthesis starting from suitably functionalized 6-halopyridinones 28 as depicted in scheme 8 employing synthetic methods outlined for the transformation 16→ 1 in scheme 4.
As precursors of 28 act the corresponding suitably functionalized 6-H-pyridinones 27 which are halogenated in the same manner as outlined for the transformation 15→ 16 in scheme 4.
Suitably functionalized 6-H-pyridinones 27 are easily obtained from ester 15 by employing synthetic steps and methods outlined in schemes 1 , 2 and 3.
GENERAL PROCEDURES
I n the subsequent paragraphs detailed general proced ures for the synthesis of key intermediates and compounds of the present invention are described.
General Procedure 1 (GP 1 ): Wittig-Horner reaction (19→ 21 , scheme 6)
In analogy to Garbaccio et al., Bioorganic & Medicinal Chemistry Letters 2007, 17, 6280 - 6285.
At 0°C 1 ,8-diazabicyclo[5,4,0]undec-7en (1 - 2 eq.) is added dropwise to a stirred solution of the respective carbaldehyde 19, l ith i u m ch loride ( 1 - 2 eq.) and diethylcyanomethyl- phosphonate (1 - 2 eq.) in acetonitrile (app. 1 - 5 mL per mmol carbaldehyde) at such a rate that the temperature remained at about 0°C. The mixture is allowed to warm to room temperature under continued stirring. The mixture is concentrated and poured into ice-cooled water. After collection and washing of the crystals the crude product is used i n the subsequent reaction without further purification steps.
General Procedure 2 (GP 2): Knoevenagel reaction (19→ 20, scheme 6) In analogy to Lapworth & Baker, a-Cyano-fi-phenylacrylic acid. Organic Synthesis; Wiley: New York, 1941 ; Collect. Vol. 1, 181 - 183.
At 40°C the respective carbaldehyde 19 is added to a vigorously stirred solution of sodium cyanoacetate (50% aq. sol., 1 - 1 .5 eq.) and sodium hydroxide (0.5 - 1 % aq. sol., 0.1 - 0.2 eq.). After 30 - 60 minutes the heating bath is removed and the reaction is allowed to cool to room temperature. After TLC and/or LCMS indicate complete consumption of the starting material, pH is adjusted to 1 - 4 (cone. aq. hydrochloric acid), the precipitated acid 20 is filtered off, washed with cold water and dried in vacuum. The target compound is typically used in the subsequent reaction without further purification steps. General Procedure 3 (GP 3): Decarboxylation reaction, (20→ 21 , scheme 6)
In analogy to Fairhurst et al., Tetrahedron Lett. 1975, 44, 3843 - 3844.
Respective acid 20 and copper(ll)oxide (0.01 - 0.2 eq.) are mixed and stirred vigorously while heated to 120°C [some acids may require higher reaction temperatures (up to 200°C bath temperature)]. At app. 120°C the decarboxylation starts heavily with fuming. After the carbon dioxide evolution stops and TLC and/or LCMS indicate complete consumption of the starting material the oily suspension is filtered over silica gel. The target compound 21 is
isolated by distillation and/or flash column chromatography and/or preparative H PLC purification.
General Procedure 4a (GP 4a): Reduction of cinnamon nitrile, (21→ 11 , scheme 6) (conditions A)
In analogy to Montgomery et al., J. Med. Chem. 1993, 36, 55 - 69.
At room temperature magnesium turnings (3.0 - 50.0 eq.) are added to a stirred solution of respective cinnamon nitrile 21 in methanol (app. 2 - 10 mL per mmol cinnamon nitrile). After the reaction started (2-3 minutes) it is cooled immediately to 0°C and stirred at this temperature until TLC and/or LCMS indicate complete consumption of the starting material (usually 2 hours). The reaction is quenched by the addition of 6 N aqueous hydrochloric acid, solids are filtered off and a quantum of methanol is evaporated. The reaction mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum. The target compound 11 is isolated by distillation and/or flash column chromatography and/or preparative H PLC purification or is used in the su bseq uent reaction without fu rther purification steps. General Procedure 4b (GP 4b): Reduction of cinnamon nitrile, (21→ 11 , scheme 6) (conditions B)
In analogy to Bellamy et al., Journal of the Chemical Society, Perkin Transactions 2, 1982 161 - 168.
At room temperature the solution of respective cinnamon nitrile 21 in ethyl acetate (app. 2 - 10 mL per mmol cinnamon nitrile) and glacial acetic acid (5.0 - 10.0 eq.) is hydrogenated using palladium on charcoal (5 - 10% palladium, app. 2 - 50 weight-%) and hydrogen at normal or elevated pressure. After TLC and/or LCMS indicate completion of the reaction, filtration of the reaction mixture over celite®, washing with toluene, co-stripping of glacial acetic acid with toluene and chromatography and/or destination of the crude product, delivers the target propionitrile 11.
General Procedure 5a (GP 5a): Preparation of iminoether (11→ 12, scheme 4)
(conditions A)
In analogy to Almqvist et al., J. Org. Chem. 2001 , 66, 6756 - 6761 .
At 0°C dry hydrochloric acid (g) is passed through a solution of respective propionitrile 11 in dry ethanol (app. 0.2 - 1 0 m L per m mol nitrile) over 0.5 - 4 hours. The mixture is concentrated to give ethyl iminoether hydrochloride 12 as crystals or oil . The target compound is typically used in the subsequent reaction without further purification steps.
General Procedure 5b (GP 5b): Preparation of iminoether (11→ 12, scheme 4)
(conditions B)
At 0°C dry hydrochloric acid (g) is passed through a solution of respective propionitril 11 in dry ethanol (app. 0.2 - 1 0 m L per mmol n itrile) over 0.5 - 4 hours. After LCMS indicates completion of the reaction dry N2 is passed through the solution. The obtained ethanolic solution of iminoether hydrochloride 12 is directly used in the subsequent reaction.
General Procedure 6a (GP 6a): Preparation of thiazolines (12→ 13, W is S, scheme 4) (conditions A)
In analogy to Almqvist et al., J. Org. Chem. 2001 , 66, 6756 - 6761 .
At 0°C triethylamine (1 .0 - 10.0 eq.) is added to a suspension of cysteine methyl ester hydrochloride or penicillamin methyl ester hydrochloride (1.0 - 5 eq.) in dry DCM (app. 0.5 - 10 mL per mmol amino acid derivative). Then the respective iminoether 12 hydrochloride in DCM (0.5 - 10 mL per mmol iminoether) is added, and the mixture is allowed to warm up to room temperature while stirring until TLC and/or LCMS indicate complete consumption of the starting material. The reaction mixture is partitioned between DCM and water, the aqueous layer is extracted with DCM and the combined organic layers are washed , dried and concentrated in vacuum. The target compound 13 is isolated by crystallization and/or flash column chromatography and/or preparative HPLC purification.
General Procedure 6b (GP 6b): Preparation of thiazolines (12→ 13, W is S, scheme 4) (conditions B)
At 0°C an ethanolic solution (see GP 5b) of iminoether hydrochloride 12 (app. 0.2 - 10 mL per mmol iminoether) is added to a solution of cysteine methyl ester hydrochloride or penicillamin methyl ester hydrochloride (1 .0 - 5 eq.) in dry ethanol (app. 0.5 - 10 mL per mmol amino acid derivative). Triethylamine (1 .0 - 12 eq.) is added until the pH of the mixture turns basic. The mixture is allowed to warm up to room temperature while stirring until TLC and/or LCMS indicate complete consumption of the starting material. The reaction mixture is concentrated in vacuum and the obtained residue partitioned between DCM and aqueous
saturated sodium bicarbonate, the aqueous layer is extracted with DCM and the combined organic layers are washed, dried and concentrated in vacuum. The target compound 13 is isolated by crystallization and/or flash column chromatography and/or preparative H PLC purification.
General Procedure 7a (GP 7a): Preparation of pyridinones (13→ 15, W is S, scheme 4) (conditions A)
In analogy to Almqvist et al., Molecular Diversity 2003, 7, 165 - 169.
At room temperature 1 ,2-dichloroethane (app. 0.05 - 2.0 mL per mmol thiazoline), pre- saturated with hydrochloric acid (9), is added to the solution of the respective thiazoline 13 (W is S) and Meldrum's acid derivative 14 (1.0 - 5.0 eq.) in 1 ,2-dichloroethane (app. 0.5 - 10 mL per mmol thiazoline). The reaction mixture is heated to 140°C for 120 seconds in a Biotage Initiator microwave oven upon which TLC and/or LCMS analysis usually shows complete turnover (otherwise Meldrum's acid derivative 14 is added again and heating to 140°C is continued until TLC and/or LCMS analysis shows completion of turnover). After removal of the solvent the target compound 15 is isolated by crystallization and/or flash column chromatography and/or preparative HPLC purification. Alternatively the reaction mixture is concentrated in vacuum and the obtained residue taken up with DCM. The organic layer is washed with aqueous sodium bicarbonate and brine, dried and concentrated in vacuum. The target compound 15 is isolated by crystallization and/or flash column chromatography and/or preparative HPLC purification.
General Procedure 7b (GP 7b): Preparation of pyridinones (13→ 15, W is S, scheme 4) (conditions B)
At room temperature trifluoroacetic acid (1 eq.) is added to the solution of the respective thiazoline 13 (W is S) and Meldrum's acid derivative 14 (1 .0 - 5.0 eq.) in toluene or 1 ,2- dichloroethane (app. 0.5 - 10 mL per mmol thiazoline). The reaction mixture is refluxed for 2 hours upon which TLC and/or LCMS analysis usually shows complete turnover (otherwise Meldrum's acid derivative 14 is added again and refluxing is continued until TLC and/or LCMS analysis shows completion of turnover). After removal of the solvent the target compound 15 is isolated by crystallization and/or flash column chromatography and/or preparative HPLC purification. Alternatively the reaction mixture is concentrated in vacuum and the obtained residue taken up with DCM. The organic layer is washed with aqueous sodium bicarbonate and brine, dried and concentrated in vacuum. The target compound 15
is isolated by crystallization and/or flash column chromatography and/or preparative HPLC purification.
General Procedure 7c (GP 7c): Preparation of pyridinones (13→ 15, W is S, scheme 4) (conditions C)
At room temperature 1 ,2-dichloroethane (app. 0.05 - 2.0 mL per mmol thiazoline), pre- saturated with hydrochloric acid (9), is added to the solution of the respective thiazoline 13 (W is S) and Meldrum's acid derivative 14 (1.0 - 5.0 eq.) in 1 ,2-dichloroethane (app. 0.5 - 10 mL per mmol thiazoline). The reaction mixture is refluxed for 2 hours upon which TLC and/or LCMS analysis usually shows complete turnover (otherwise Meldrum's acid derivative 14 is added again and refluxing is continued until TLC and/or LCMS analysis shows completion of turnover). After removal of the solvent the target compound 15 is isolated by crystallization and/or flash column chromatography and/or preparative HPLC purification. Alternatively the reaction mixture is concentrated in vacuum and the obtained residue taken up with DCM. The organic layer is washed with aqueous sodium bicarbonate and brine, dried and concentrated in vacuum. The target compound 15 is isolated by crystallization and/or flash column chromatography and/or preparative HPLC purification. General Procedure 8 (GP 8): Preparation of 6-iod-pyridinones (15→ 16, Hal is I, scheme 4)
In analogy to Almqvist et al., J. Org. Chem. 2004, 69, 7830 - 7835.
At room temperature N-iodosuccinimide (1 .5 - 5.0 eq.) is added to a stirred solution of respective pyridinone 15 in acetic acid (app. 2 - 6 mL per mmol pyridinone) and TFA (app. 0.1 - 0.25 mL per mmol pyridinone). After TLC and/or LCMS indicate complete consumption of the starting material the reaction mixture is poured on ice-water and the precipitate is washed with aqueous saturated sodium bicarbonate. Alternatively the reaction mixture is partitioned between DCM and aqueous sodium thiosulfate, the aqueous layer is extracted with DCM and the combined organic layers are washed, dried and concentrated in vacuum. The target compound 16 (Hal is I) is isolated by crystallization and/or flash column chromatography and/or preparative HPLC purification.
General Procedure 9 (GP 9): Preparation of 6-brom-pyridinones (15→ 16, Hal is Br, scheme 4)
In analogy to Almqvist et al., J. Org. Chem. 2004, 69, 7830 - 7835.
At 10°C bromine (0.85 - 2.0 eq.) is added dropwise to a stirred solution of respective pyridinone 15 in acetic acid (app. 2 - 10 ml. per mmol pyridinone). After the mixture is allowed to warm to room temperature and TLC and/or LCMS indicate complete consumption of the starting material the reaction mixture is poured on ice-water and the precipitate is washed with aqueous saturated sodium bicarbonate. Alternatively the reaction mixture is partitioned between DCM and aqueous sodium thiosulfate, the aqueous layer is extracted with DCM and the combined organic layers are washed, dried and concentrated in vacuum. The target compound 16 (Hal is Br) is isolated by crystallization and/or flash column chromatography and/or preparative HPLC purification.
General Procedure 10a (GP 10a): Suzuki Coupling (16→ 1 , scheme 4) (conditions A)
At room temperature the respective boronic acid (1.0 - 5.0 eq.) and aqueous potassium carbonate (0.8 - 5.0 eq., 1 ,5 M) are added to a solution of 6-halo-pyridinone 16 in dioxane (app. 2 - 50 mL per mmol pyridinone). Then Argon is bubbled through the reaction mixture for several minutes followed by the addition of dichloro(1 ,1 '-bis(diphenylphosphin)ferrocene) palladium dichloromethane complex (0.1 - 0.5 eq.). The reaction mixture is heated to 130°C for 60 minutes in a Biotage Initiator microwave oven upon which TLC and/or LCMS analysis usually shows complete turnover (otherwise respective boronic acid and/or catalyst is added again and heating to 130°C is continued until TLC and/or LCMS analysis shows completion of turnover). After completion of the reaction the mixture is filtered through a pad of celite®, the filtrate is diluted with ethyl acetate and washed with water and brine. Drying of the organic layer, eva poration of the solvent and flash column chromatography and/or preparative HPLC yields the target compound 1.
General Procedure 10b (GP 10b): Suzuki Coupling (16→ 1 , scheme 4) (conditions B)
At room temperature the respective boronic acid (1 .0 - 5.0 eq.) is added to a solution of 6- halo-pyridinone 16 in dioxane (app. 2 - 50 mL per mmol pyridinone). Then Argon is bubbled through the reaction mixture for several minutes followed by the addition of aqueous potassium carbonate (0.8 - 5.0 eq., 1 .5 M) and dichloro(1 ,1 '-bis(diphenylphosphin)ferrocene) palladium (0.1 - 0.5 eq.). The reaction mixture is put in a preheated oilbath (80°C) and then heated under reflux until TLC and/or LCMS indicate complete consumption of the starting material. Further additions of respective boronic acid, aqueous potassium carbonate and dichloro(1 ,1 '-bis(diphenylphosphin)ferrocene)palladium may be necessary for complete conversion. After completion of the reaction the mixture is filtered through a pad of celite®, the filtrate is diluted with ethyl acetate and washed with water and brine. Drying of the
organic layer, evaporation of the solvent and flash column chromatography and/or preparative HPLC yields the target compound 1.
General Procedure 11 (GP 11 ): Saponification (1→ 2, scheme 1 )
At room temperature aqueous lithium hydroxide (1 - 10 eq., 0.5 - 1 M) is added to a stirred solution of respective ester 1 in THF (app. 1 - 10 mL per mmol ester) and/or methanol and /or alcohol (app. 1 - 10 mL per mmol ester) and stirred until TLC and/or LCMS indicate complete consumption of the starting material (usually 2 hours). Then pH is adjusted to 3-4 (aqueous citric acid or 2 N aqueous hydrochloric acid). The aqueous layer is extracted with ethyl acetate and the organic layer is dried and concentrated in vacuum. Prior to the extraction evaporation of some TH F and/or methanol might be necessary. The target compound 2 is isolated by flash column chromatography and/or preparative H PLC purification or is used in the subsequent reaction without further purification steps.
General Procedure 12 (GP 12): Amide formation (2→ 3, scheme 1 )
At room temperature 1 H-hydroxybenzotriazole (1.0 - 1 .5 eq.) and N-ethyl-N',N'- dimethylamino-propylcarbodiimide (1 .0 - 1.5 eq.) are added to a stirred solution of respective acid 2 in DMF (app. 1 - 10 mL per mmol acid). After 1 hour at room tempemperature a solution of the respective amine in DMF (app. 1 - 10 mL per mmol acid) is added and stirring is continued upon TLC and/or LCMS indicate complete consumption of the starting material. The reaction mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum. The target compound 3 is isolated by flash column chromatography and/or preparative HPLC purification or crystallization. Alternatively the product can by isolated by pouring the reaction mixture into ice-water and filtration of the target compound 3.
General Procedure 13 (GP 13): Reduction (1→ 4, scheme 2)
At -20°C lithium borohydride (1 .0 - 4.0 eq.; 2 M solution in THF) is added to a stirred solution of respective ester 1 in THF (app. 1 - 1 0 m L per mmol ester). After stirring at that temperature for 30 minutes, the reaction mixture is allowed to warm to room temperature. After TLC and/or LCMS indicate complete consumption of the starting material the reaction mixture is quenched by the addition of water. The reaction mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum. The target compound 4 is isolated by
flash column chromatography and/or preparative H PLC purification or is used in the subsequent reaction without further purification steps.
General Procedure 14 (GP 14): Formation of tosylate (4→ 5, LG is OTs, scheme 2)
At 0°C N,N-dimethylaminopyridine (2.0 - 5.0 eq.) and p-toluenesulfonic anhydride (1 .0 - 2.5 eq.) are added to a stirred solution of respective alcohol 4 in DCM (app. 1 - 20 mL per mmol alcohol). The reaction mixture is kept between 0 and 10°C upon TLC and/or LCMS indicate complete consumption of the starting material. The reaction mixture is partitioned between DCM and water, the aqueous layer is extracted with DCM and the combined organic layers are washed, dried and concentrated in vacuum. The target compound 5 (LG is OTs) is isolated by flash column chromatography and/or preparative HPLC purification or is used in the subsequent reaction without further purification steps. General Procedure 15 (GP 15): Formation of chloride (4→ 5, LG is CI, scheme 2)
At 0°C N,N-dimethylaminopyridine (0.1 - 1 .0 eq.) and p-toluenesulfonic chloride (1 .0 - 2.5 eq.) are added to a stirred solution of respective alcohol 4 in DCM (app. 1 - 10 mL per mmol alcohol). The reaction mixture is allowed to warm to room temperature and monitored until TLC and/or LCMS indicate complete consumption of the starting material. The reaction mixture is partitioned between DCM and water, the aqueous layer is extracted with DCM and the combined organic layers are dried and concentrated in vacuum. The target compound 5 (LG is CI) is isolated by flash column chromatography and/or preparative HPLC purification or is used in the subsequent reaction without further purification steps.
General Procedure 16a (GP 16a): Amine formation (5→ 6, LG is OTs, scheme 2)
(conditions A)
At room temperature the respective amine (1 .0 - 10.0 eq.) is added to a stirred solution of respective tosylate 5 (LG is OTs, scheme 2) in THF (app. 1 - 50 mL per mmol tosylate) and warmed up to 50°C until TLC and/or LCMS indicate complete consumption of the starting material. The reaction mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate, and the combined organic layers are washed, dried and concentrated in vacuum. The target compound 6 is isolated by flash column chromatography and/or preparative HPLC purification or crystallization.
General Procedure 16b (GP 16b): Amine formation (5→ 6, LG is OTs, scheme 2)
(conditions B; for parallel synthesis)
At room temperature the respective amine (1 .0 - 10.0 eq.) in DMF (app. 0.5 - 25 mL per mmol tosylate) is added to a stirred solution of respective tosylate 5 (LG is OTs, scheme 2) in DMF (app. 0.5 - 25 mL per mmol tosylate) and warmed up to 50°C for 15 hours. The reaction mixture is diluted with methanol (app. 1 - 50 mL per mmol tosylate) and concentrated in vacuum. The target compound 6 is isolated by preparative HPLC purification and lyophilization.
General Procedure 17 (GP 17): Amine formation (5→ 6, LG is CI, scheme 2)
At room temperature the respective amine (1 .0 - 30.0 eq.) is added in portions to a stirred solution of respective chloride 5 (LG is CI, scheme 2), sodium carbonate (1 .0 - 10.0 eq.) and sodium iodide (1 .0 - 10.0 eq) in DMF (app. 1 .0 - 75 mL per mmol chloride) and warmed up to 80-150°C until TLC and/or LCMS indicate complete consumption of the starting material. The reaction mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate, and the combined organic layers are washed, dried and concentrated in vacuum. The target compound 6 is isolated by flash column chromatography and/or preparative HPLC purification or crystallization.
General Procedure 18 (GP 18): Reductive amination [5→ 6, LG is O, scheme 2]
At room temperature sodium trisacetoxyborohydride (1 .0 - 10.0 eq.) is added in portions to a stirred solution of respective aldehyde 5 (LG is O, scheme 2) and respective amine (1 .0 - 5.0 eq.) in toluene (app. 1 - 50 mL per mmol aldehyde) and stirred at this temperature upon TLC and/or LCMS indicate complete consumption of the starting material. The reaction mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate, and the combined organic layers are washed, dried and concentrated in vacuum. The target compound 6 is isolated by flash column chromatography and/or preparative HPLC purification or crystallization.
General Procedure 19 (GP 19): Thioester formation (2→ 7, scheme 3) At room temperature 1 H-hydroxybenzotriazole (1 .0 - 1.5 eq.) and /V-ethyl-/V7V'- dimethylamino-propylcarbodiimide (1 .0 - 1.5 eq.) are added to a stirred solution of respective acid 2 in DMF (app. 1 - 15 mL per mmol acid). After 1 hour at room temperature the solution
of thiophenol in DMF (app. 1 - 35 mL per mmol acid) is added and stirring is continued upon TLC and/or LCMS indicate complete consumption of the starting material. The reaction mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum . Alternatively the reaction mixture is poured into a mixture of ice-water and aqueous saturated sodium bicarbonate. The formed precipitate is filtered off and washed excessively with toluene and water. The filtrate is separated and the aqueous layer extracted with toluene. The combined organic layers are washed, dried and concentrated in vacuum. The target compound 7 is isolated by flash column chromatography and/or preparative H PLC purification and/or crystallization or is used in the subsequent reaction without further purification steps.
General Procedure 20a (GP 20a): Liebeskind coupling (7→ 8, scheme 3) (conditions A) In analogy to Liebeskind et al., J. Am. Chem. Soc. 2000, 122, 1 1260 - 1 1261 .
At room temperature the respective thioester 7 in THF (app. 1 - 50 mL per mmol thioester, degassed with argon) is added to the respective boronic acid (1.0 - 1 .5 eq.), 2- thiophenecarboxylic acid, copper(1 +) salt (1 .0 - 1 .5 eq.) and tris-(dibenzylidenaceton)- dipalladium (0) (0.05 - 0.5 eq.). Then phosphorous acid triethyl ester (0.1 - 1 .0 eq.) is added and the reaction mixture is heated under reflux until TLC and/or LCMS indicate complete consumption of the starting material. Further additions of respective boronic acid , 2- thiophenecarboxylic acid , copper(1 +) salt, tris-(dibenzylidenaceton)-dipalladium (0) and phosphorous acid triethyl ester may be necessary for complete conversion. The reaction mixture is partitioned between ethyl acetate and aqueous sodium bicarbonate, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum. The target compound 8 is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization.
General Procedure 20b (GP 20b): Liebeskind coupling (7→ 8, scheme 3) (conditions B)
In analogy to Liebeskind et al., Org. Lett. 2003, 5, 3033 - 3035.
At room temperature and under Argon atmosphere the respective stannane (1 .0 - 2 eq.) is added to a stirred solution of the respective thioester 7 in THF (app. 1 - 25 mL per mmol thioester). Then copper(l)diphenylphosphinate (1 - 2.5 eq.), tri-(2-furyl)phosphin (0.04 - 0.8 eq.) and finally tris-(dibenzylidenaceton)-dipalladium (0) (0.005 - 0.1 eq.) are added and the reaction mixture is heated to 50°C until TLC and/or LCMS indicate complete consumption of the starting material. Further additions of respective stannane, copper(l)diphenylphosphinate,
tri-(2-furyl)phosphin and tris-(dibenzylidenaceton)-dipalladium (0) may be necessary for complete conversion. The reaction mixture is filtered through a pad of celite® and the filtrate concentrated in vacuum. The target compound 8 is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization.
General Procedure 21a (GP 21 a): Oxime formation (8→ 9, Ric is hydroxy or
hydroxymethyl; scheme 3) (conditions A)
At room temperature the respective hydroxylamine hydrochloride salt (1 .0 - 10.0 eq.) is added to a stirred solution of the respective ketone 8 in tert-butyl alcohol (app. 1 - 25 mL per mmol ketone) and ethanol (app. 1 - 25 mL per mmol ketone). Then titanium(IV) tert-butylat (2.0 - 8.0 eq.) is added and the reaction mixture is heated to 80°C until TLC and/or LCMS indicate complete consumption of the starting material. The reaction mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum. The target compound 9 is isolated by flash column chromatography and/or preparative H PLC purification and/or crystallization or is used in the subsequent reaction without further purification steps.
General Procedure 21 b (GP 21 b): Oxime formation (8→ 9, Ric is hydroxy or
hydroxymethyl; scheme 3) (conditions B)
At room temperature the respective hydroxylamine hydrochloride salt (1 .0 - 10.0 eq.) is added to a stirred solution of the respective ketone 8 in tert-butyl alcohol (app. 1 - 25 mL per mmol ketone) and toluene (app. 1 - 25 mL per mmol ketone). Then pyridine (app. 1 - 10 mL per mmol ketone) is added and the reaction mixture is heated to 100°C until TLC and/or LCMS indicate complete consumption of the starting material. The reaction mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum. The target compound 9 is isolated by flash column chromatography and/or preparative H PLC purification and/or crystallization or is used in the subsequent reaction without further purification steps.
General Procedure 22 (GP 22): Imine formation (8→ 9, scheme 3) In analogy to Capretta et al., Tetrahedron Lett. 2002, 43, 7687 - 7690
At room temperature the appropriate titanium(IV) Lewis acid (1 .0 - 8.0 eq.) is added to a stirred solution of the respective amine (1 .0 - 10.0 eq.) and the respective ketone 8 in
toluene (app. 1 - 50 mL per mmol ketone). Depending on the nature of the amine the reaction mixture is stirred at ambient temperature or is heated to elevated temperature or 100°C until TLC and/or LCMS indicate complete consumption of the starting material. The reaction mixture is partitioned between ethyl acetate and water, solids are filtered off, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum. The target compound 9 is isolated by flash column chromatography and/or preparative H PLC purification and/or crystallization or is used in the subsequent reaction without further purification steps. Alternatively, the reaction mixture is concentrated in vacuum and the obtained crude target compound 9 is used in the subsequent reaction without further purification steps.
General Procedure 23a (GP 23a): Reduction of oxime (9→ 10, Ric is hydroxy or
hydroxymethyl; scheme 3) (conditions A) At 0°C lithium borohydride (1.0 - 8.0 eq., 2 M solution in THF) is added slowly to a stirred solution of titanium(IV)chloride (1.0 - 4.0 eq.) in 1 ,2-dimethoxyethane (app. 1 - 50 mL per mmol oxime). After 10 minutes the respective oxime 9 in 1 ,2-dimethoxyethane (app. 1 - 20 mL per mmol oxime) is added and stirring is continued at 0°C for one hour. Then the reaction mixture is allowed to warm up to room temperature and stirred until TLC and/or LCMS indicate complete consumption of the starting material. After cooling to 0°C the reaction is quenched by the addition of water and aqueous ammonia (33 weight-%). The mixture is partitioned between DCM and water, solids are filtered off, the aqueous layer is extracted with DCM and the combined organic layers are dried and concentrated in vacuum. The target compound 10 is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization.
General Procedure 23b (GP 23b): Reduction of oxime (9→ 10, Ric is hydroxy or hydroxymethyl; scheme 3) (conditions B) In analogy to Ohhara et al., Acta Cryst. 2000, B56, 245 - 253.
At 0°C sodium borodeuteride (1 .0 - 25.0 eq.) is added slowly to a stirred solution of titanium(IV)chloride (1 .0 - 15.0 eq.) in 1 ,2-dimethoxyethane (app. 1 - 50 mL per mmol oxime). After 10 minutes the respective oxime 9 in 1 ,2-dimethoxyethane (app. 1 - 20 mL per mmol oxime) is added and stirring is continued at 0°C for one hour. Then the reaction mixture is allowed to warm up to room temperature and stirred until TLC and/or LCMS indicate complete consumption of the starting material. After cooling to 0°C the reaction is quenched by the addition of water and aqueous ammonia (33 weight-%). The mixture is
partitioned between DCM and water, solids are filtered off, the aqueous layer is extracted with DCM and the combined organic layers are dried and concentrated in vacuum . The target compound 10 is isolated by flash column chromatography and/or preparative H PLC purification and/or crystallization.
General Procedure 23c (GP 23c): Reduction of oxime (9→ 10, Ric is hydroxy or
hydroxymethyl; scheme 3) (conditions C)
In analogy to Kano et al., Synthesis 1980, 695 - 697.
At 0°C sodium borohydride (1 .0 - 8.0 eq . ) is ad d ed sl owly to a sti rred sol ution of titanium(IV)chloride (1 .0 - 4.0 eq.) in 1 ,2-dimethoxyethane (app. 1 - 50 mL per mmol oxime). After 10 minutes the respective oxime 9 in 1 ,2-dimethoxyethane (app. 1 - 20 mL per mmol oxime) is added and stirring is continued at 0°C for one hour. Then the reaction mixture is al lowed to warm u p to room tem peratu re and stirred u nti l TLC and/or LC MS indicate complete consumption of the starting material. After cooling to 0°C the reaction is quenched by the addition of water and aqueous ammonia (33 weight-%). The mixture is partitioned between DCM and water, solids are filtered off, the aqueous layer is extracted with DCM and the combined organic layers are dried and concentrated in vacuum. The target compound 10 is isolated by flash column chromatography and/or preparative H PLC purification and/or crystallization.
General Procedure 24a (GP 24a): Addition of C-nucleophiles to oxime (9→ 10, scheme 3) (conditions A) In analogy to Kano et al., Synthesis 1980, 695 - 697.
At -78°C titanium(IV)chloride (1 .0 - 10.0 eq., 1 M solution in CH2CI2) is added slowly to a stirred solution of the respective oxime 9 in 1 ,2-dimethoxyethane (app. 1 - 50 mL per mmol oxime). The respective Grignard reagent (1 .0 - 10.0 eq.) is subsequently added and stirring is continued while gradually warming the reaction mixture to 60°C until TLC and/or LCMS indicate complete consumption of the starting material. Subsequent additions of Lewis acid and/or Grignard reagent may be necessary to drive the reaction to completion. The reaction is quenched by the addition of water and aqueous sodium hydroxide (2 M). The mixture is partitioned between ethyl acetate and water, the aq ueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum. The target compound 10 is isolated by flash colu m n ch romatography and/or preparative H P LC purification and/or crystallization.
General Procedure 24b (GP 24b): Addition of C-nucleophiles to imine (9→ 10, scheme 3) (conditions B);
In analogy to Jenkins et al., J. Org. Chem. 2009, 74, 1304 - 1313.
At 0°C a solution of the respective Grignard reagent (1.0 - 10.0 eq.) is added slowly to a stirred solution of the respective imine 9 in toluene (app. 1 - 25 mL per mmol imine) and stirring is continued at 0°C or room temperature until TLC and/or LCMS indicate complete consumption of the starting material. The reaction is quenched by the addition of water, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum. The target compound 10 i s i solated by flas h col u m n chromatography and/or preparative HPLC purification and/or crystallization.
General Procedure 25a (GP 25a): N-alkylation or N-acylation of primary amines [10 wherein R-ia and Rib is Hydrogen→ 10 wherein R1a and/or R1b are different from hydrogen, scheme 3]. (conditions A)
At room temperature the solution of appropriate alkylation or acylation reagent (1 .0 - 10.0 eq.) is added to a stirred solution of the respective primary amine 10 and N-ethyl diisopropyl amine (1 .0 - 10.0 eq.) in a acetonitrile or DMF (app. 1 - 25 mL per mmol primary amine). The reaction mixture is stirred at ambient or elevated temperature as required until TLC and/or LCMS indicate complete consumption of the starting material. Subsequent additions of alkylation or acylation reagent and/or base may be necessary to drive the reaction to completion. The reaction mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum. The alkylated/acylated compound 10 is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization or is used in the subsequent reaction without further purification steps. Alternatively, the reaction mixture is concentrated in vacuum and the obtained crude alkylated/acylated compound 10 is used in the subsequent reaction without further purification steps or directly subjected to flash column chromatography and/or preparative HPLC purification.
General Procedure 25b (GP 25b): N-alkylation of primary amines via reductive amination
[10 wherein R1a and Rib comprises hydrogen→ 10 wherein R1a and/or R1b are different from hydrogen, scheme 3]. (conditions B)
At room temperature sodium trisacetoxyborohydride (1 .0 - 10.0 eq.) is added in portions to a stirred solution of respective aldehyde (1.0 - 5.0 eq.) and respective primary amine 10 in an
appropriate solvent, such as, for example toluene, THF or methanol (app. 1 - 50 mL per m mol amine) and stirred at this temperature until TLC and/or LCMS indicate complete consumption of the starting material . The reaction mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate, and the combined organic layers are washed, dried and concentrated in vacuum. The alkylated compound 10 is isolated by flash column chromatography and/or preparative HPLC purification or crystallization.
General Procedure 25c (GP 25c): N-acylation of primary amines [10 wherein R1a and Rib is hydrogen→ 10 wherein R1a and/or R1 b are different from hydrogen, scheme 3]. (conditions C, for parallel synthesis)
The amine (0.1 - 0.3 mmol in 0.2 - 0.6 mL DCM, TH F or DMF) is cooled to 0°C under inert gas, and triethylamine (0.1 - 0.6 mmol in 0.1 - 0.4 mL DCM, THF or DMF) and the acylating agent (carbonyl chloride, sulfonyl chloride, isocyanate or isothiocyanate; 0.1 - 0.6 mmol in 0.2 - 0.6 mL DCM, THF or DMF) are successively added. After additional 10 minutes at 0°C the mixture is warmed to 20 - 80°C, stirred at this temperature for 2 to 24 h, and concentrated. The target compound 10 is isolated by preparative H PLC purification and lyophilization.
General Procedure 26 (GP 26): Ring closing metathesis of aminodienes [10 wherein R1a comprises alkenyl and R3b comprises alkenyl→ 10 wherein R1a and R3b are connected to form a N-heterocycle, scheme 3]. At room temperature an appropriate RCM catalyst, such as, for example Grubbs second- generation catalyst (0.05 - 0.5 eq.) is added to a degassed and stirred solution of the respective aminodiene 10 in an appropriate solvent, such as for example dichloromethane (app. 1 - 50 mL per mmol aminodiene) and it is stirred at this temperature or it is heated to 40°C until TLC and/or LCMS indicate complete consumption of the starting material. The N- heterocycle compound 10 is isolated by flash column chromatography and/or preparative HPLC purification.
General Procedure 27a (GP 27a): Oxidation of sulfides (W is S) to sulfoxides [W is S(=0)] or sulfones [W is S(=0)2] and oxidation of sulfoxides [W is S(=0)] to sulfones [W is S(=0)2] (conditions A):
At -20°C to room temperature, preferentially at 0°C, meta-chloroperoxybenzoic acid (mCPBA) (1 .0 - 5.0 eq.) is added in portions to a stirred solution of the respective sulfide or sulfoxide in an appropriate solvent, such as for example dichloromethane or chloroform (app. 1 - 50 ml. per mmol sulfide/sulfoxide) and is stirred at this temperature until TLC and/or LCMS indicate complete consumption of the starting material. Successive additions of mCPBA and/or addition of solid sodium bicarbonate may be required. The reaction mixture is partitioned between ethyl acetate and aqueous sodium bicarbonate, the aqueous layer is extracted with ethyl acetate, and the combined organic layers are washed , dried and con cen trated i n vacu u m . Th e oxi d ated com pou n d i s i solated by flash column chromatography and/or preparative HPLC purification and/or crystallization.
General Procedure 27b (GP 27b): Oxidation of sulfides (W is S) to sulfoxides [W is S(=0)] or sulfones [W is S(=0)2] and oxidation of sulfoxides [W is S(=0)] to sulfones [W is S(=0)2] (conditions B):
At -20°C to 80°C, preferentially at room temperature, an appropriate oxidizing agent, such as for example, hydrogen peroxide or tert-butyl hydroperoxide (1 .0 - 10.0 eq.), is added to a stirred solution of the respective sulfide or sulfoxide in a polar protic solvent, such as for example acetic acid (app. 1 - 50 ml. per mmol sulfide/sulfoxide) and is stirred at this temperature until TLC and/or LCMS indicate complete consumption of the starting material. Successive additions of oxidizing agent and/or heating of the reaction mixture may be required. The reaction mixture is partitioned between ethyl acetate and aqueous sodium bicarbonate, the aqueous layer is extracted with ethyl acetate, and the combined organic layers are washed, dried and concentrated in vacuum. The oxidated compound is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization.
General Procedure 27c (GP 27c): Oxidation of sulfides (W is S) to sulfoxides [W is S(=0)] or sulfones [W is S(=0)2] and oxidation of sulfoxides [W is S(=0)] to sulfones [W is S(=0)2] (conditions C):
At -20°C to 80°C, preferentially at room temperature, an appropriate periodo agent, such as, for example, sodium (meta)periodate or (ortho)periodic acid (1 .0 - 7.0 eq.), is added to a stirred solution of the respective sulfide or sulfoxide in a polar solvent, such as for example acetonitrile or alcohol (app. 1 - 50 mL per mmol sulfide/sulfoxide) and is stirred at this temperature until TLC and/or LCMS indicate complete consumption of the starting material. The addition of catalytic amounds of an appropriate metal salt, such as iron (I I I) chloride and/or successive additions of periodo agent and/or heating of the reaction mixture may be
required. The reaction mixture is partitioned between ethyl acetate and aqueous sodium thiosulfate and/or aqueous hydrogen carbonate, the aqueous layer is extracted with ethyl acetate, and the combined organic layers are washed, dried and concentrated in vacuum. The oxidated compound is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization.
General Procedure 28a (GP 28a): Amide formation (24→ 26, W is O, scheme 7)
In analogy to Almqvist et al. {Tetrahedron 2008, 64, 9368 - 9376),
At room temperature chloro-1 ,1 ,3,3-tetramethyluronium hexachloroantimonate (ACTU) or 2- (7-azabenzotriazol-1 -yl)-/V,/V,/V',/V'-tetramethyluronium hexafluorophosphate (HATU) (0.5 - 4.0 eq) is added to a stirred solution of 1 H-hydroxybenzotriazole (1 .0 - 2.0 eq.), the respective propionic acid 24 (2.0 - 4.0 eq.) and 2,6-lutidin (2.0 - 6.0 eq.) in DMF (app. 1 - 50 mL per mmol amino acid). Then a solution of serine methyl ester (W is O) or the respective amino acid or a amino acid hydrochloride/triethylamine (1 :1 ) mixture in DMF or DCM (app. 1 - 10 mL per mmol amino acid) is added and stirring is continued upon TLC and/or LCMS indicate complete consumption of the starting material. Further addition of triethylamine may be required. The reaction mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum. The target compound 26 i s i solated by flas h col u m n chromatography and/or preparative HPLC purification or crystallization. Alternatively the product can by isolated by pouring the reaction mixture into ice-water and filtration of the target compound 26. General Procedure 28b (GP 28b): Amide formation (24→ 26, W is O, scheme 7)
Under nitrogen at -0°C the appropriate 2-amino acid ester (10 mmol) is added to a stirred solution of the appropriate acid chloride (16 mmol) and /V-ethyldiisopropylamine (2.7 mL, 16 mmol, 1.6 eq.; in case of using the amino acid ester hydrochloride the amount of base has to be adjusted accordingly) in acetonitrile or DCM (150 mL). After stirring until TLC and/or LCMS indicate complete consumption of the starting material the mixture is quenched with saturated ammoniumchloride solution (150 mL). The mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum to yield the desired amide.
General Procedure 29a (GP 29a): Pyridone formation (26→ 15, W is O, scheme 7)
In analogy to Ishihara et al. {Tetrahedron 2009, 65, 2102 - 2109) and Almqvist et al. {Tetrahedron 2008, 64, 9368 - 9376),
At room temperature ammonium molybdate [(NhU^MoCU] (0.005 - 0.50 eq.) is added to a stirred solution of amide 26 in toluene (10 - 100 mL per mmol amide). The solution is heated to reflux with removal of water using a Soxhiet apparatus containing activated 3 A molecular sieves. After TLC and/or LCMS indicate complete consumption of the starting material the reaction mixture is cooled to room temperature. Meldrum's acid derivative 14 (1 .0 - 3.0 eq.) followed by TFA (1 .0 - 10.0 eq.) is added. The solution is heated to reflux until TLC and/or LCMS indicate complete consumption of the starting material. Further additions of Meldrum's acid derivative 14 may be required. The solution is allowed to cool to room temperature, filtered through Celite and concentrated. The target compound 15 is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization. Alternatively the reaction mixture is partitioned between ethyl acetate and aqueous sodium bicarbonate, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum. The target compound 15 i s isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization. General Procedure 29b (GP 29b): Pyridone formation (13→ 15, W is O, scheme 7)
Meldrum's acid derivative 14 (1 .0 - 3.0 eq.) followed by TFA or pyridinium toluenesulfonate (1 .0 - 10.0 eq.) is added to a stirred solution of appropriate oxazoline or thiazoline 13 in toluene. The solution is heated to reflux until TLC and/or LCMS indicate complete consumption of the starting material. Further additions of Meldrum's acid derivative 14 may be required. The solution is allowed to cool to room temperature, filtered through Celite and concentrated. The target compound 15 is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization. Alternatively the reaction mixture is partitioned between ethyl acetate and aqueous sodium bicarbonate, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum. The target compound 15 is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization.
General Procedure 30 (GP 30): Synthesis of boronic acids 17 (scheme 4) (in the case of not being commercially available)
At -78°C tert-butyllithiium (1 .90 - 2.50 eq.) is added to a stirred solution of the respective aryl-, heteroaryl-, benzo[1 ,3]dioxolyl- or 2,3-dihydro-1 ,4-benzodioxinyl-halide (preferentially
bromide) in diethyl ether (10 - 100 mL per mmol halide). Stirring is continued for 30 minutes at -78°C. Then triisopropyl borate (2.00 - 4.00 eq.) is added and the mixture is allowed to warm to room temperature slowly. After the addition of hydrochloric acid (2N) the precipitated boronic acid 17 is filtered off. Alternatively the mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum. The boronic acid 17 is isolated by flash column chromatography and/or preparative HPLC purification and/or crystallization.
SYNTHESIS OF KEY INTERMEDIATES
Intermediate A.1
In an adaptation of GP 2: At 40°C commercially available 2-fluoro benzaldehyde (21 .2 ml_, 25.0 g, 201 mmol) was added to a vigorously stirred solution of sodium cyanoacetate (50% aq. sol., 18.5 ml_, 48.7 g, 227 mmol, 1 .13 eq.) and sodium hydroxide [1 % aq. sol., 1 .1 1 g, 28 mmol, 0.14 eq.]. After 60 minutes the heating bath was removed and the reaction was allowed to cool to room temperature. After TLC indicated complete consumption of the starting material, pH was adjusted to 3 - 4 (cone. aq. hydrochloric acid), the precipitated acid was filtered off, washed with cold water and dried in vacuum. Further adjustment of the pH to 1 yielded a second crop, which was washed with cold water and dried in vacuum. The target compound was used in the subsequent reaction without further purification steps (yield: 21 .8 g).
1H-N MR (d6-DMSO, 400 MHz): 7.36 - 7.44 (m, 2H); 7.63 - 7.70 (m, 1 H); 8.1 1 - 8.17 (m, 1 H); 8.33 (s, 1 H).
UPLC-MS (ESI+): [M + H]+ = 191 .
Table 1 : The following intermediate A.2 was prepared in analogy to intermediate A.1 and
GP 2 starting from commercially available 2,6-difluoro benzaldehyde.
Intermediate B.1
Preparation of 3-(2-fluoro-phenyl)-acrylonitrile
1H-NMR (CDCIs, 300 MHz): 5.56 (d, 1 H); 7.08 - 7.19 (m, 1 H); 7.20 - 7.30 (m, 1 H); 7.38 - 7.50 (m, 2H); 8.16 - 8.26 (m, 1 H). (Z-isomer)
MS (EI+): M+ = 147.
1H-NMR (CDCIs, 300 MHz): 6.04 (d, 1 H); 7.08 - 7.23 (m, 2H); 7.37 - 7.46 (m, 2H); 7.49 (d, 1 H). (E-isomer)
MS (EI+): M+ = 147. Table 2: The following intermediate B.2 was prepared in analogy to intermediate B.1 and GP 3 starting from intermediate A.2.
Intermediate B.3
Preparation of 3-(2-fluoro-6-trifluoromethyl-phenyl)-acrylonitrile
In an adaptation of GP 1 : At room temperature 1 ,8-diazabicyclo[5,4,0]undec-7en (79.78 g, 524 mmol , 2.0 eq .) was added dropwise to a stirred solution of commercially available 2-fluoro-6-(trifluoromethyl)benzaldehyde (50.34 g, 262 mmol), lithium chloride (21 .75 g, 513 mmol, 1 .95 eq.) and diethylcyanomethylphosphonate (90.51 g, 51 1 mmol, 1 .95eq.) in aceton itrile (500 m L) at such a rate that the tem peratu re remai ned at about room temperature. After TLC showed complete consumption of the starting material the mixture
was concentrated, poured into ice-cooled water (3 L) and stirred for 30 minutes. The precipitate was filtered off and washed with n-hexane. (yield: 32 g).
1H-NMR (CDCIs, 400 MHz): 5.89 (d, 1 H); 7.27 - 7.30 (m, 1 H); 7.36 - 7.64 (m, 3H). (Z- isomer).
1H-NMR (CDCI3, 400 MHz): 6.21 (d, 1 H); 7.36 - 7.64 (m, 4H). (E-isomer).
UPLC-MS (ESI+): [M + H]+ = 216.
Intermediate C.1
Preparation of 3-(2-fluoro-phenyl)-propionitrile
In an adaptation of GP 4a: At room temperature magnesium turnings (1 .64 g, 67 mmol, 40 eq .) were added to a stirred solution of 3-(2-fluoro-phenyl)-acrylonitrile (intermediate B.1 ) (248 mg, 1.69 mmol) in methanol (10 ml_). After the reaction had started (2-3 minutes) it was cooled immediately to 0°C and stirred at this temperature until TLC indicated complete consumption of the starting material. The reaction was quenched by the addition of 6 N aqueous hydrochloric acid. The mixture was partitioned between ethyl acetate and water, the aqueous layer was extracted with ethyl acetate and the combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuum. The target compound was used in the subsequent reaction without further purification steps (yield: 169 mg).
Table 3: The following intermediates C.2 to C.4 were prepared in analogy to intermediate C.1 and GP 4a starting from intermediates B.2 and B.3.
1H-NMR (CDCIs, 400 MHz):
F 3-(2-fluoro-6- 2.65 (t, 2H); 3.1 1 (t, 2H); 5.47 (d, 1 H); 7.10 fluoromethyl-
C.4 - 7.20 (m, 2H); 7.26 - 7.33 (m, 1 H).
phenyl)-
I T 19F-NMR (CDCIs, 400 MHz):
H propionitrile
-202.85 (t, 1 F); -1 16.77 (m, 1 F).
Intermediate C.5
Preparation of 3-(2-fluoro-6-trifluoromethyl-phenyl)-propionitrile
In an adaptation of GP 4b: At room temperature a solution of 3-(2-fluoro-6-trifluoromethyl- phenyl)-acrylonitrile (intermediate B.3) (27.1 g, 126 mmol) in ethyl acetate (541 mL) and glacial acetic acid (54 mL, 939 mmol, 7.5 eq .) was hydrogenated using palladium on charcoal (10% palladium, 5.4 g, 20 weight-%) and hydrogen at normal pressure for 4.5 hours. After filtration of the reaction mixture over celite®, washing with ethyl acetate, co-stripping of glacial acetic acid with toluene and flash column chromatography the target compound was obtained (yield: 20.9 g).
1H N M R (CDCIs, 400 MHz): 2.65 (t, 1 H); 3.21 (t, 1 H); 7.28 - 7.34 (m, 1 H); 7.38 - 7.44 (m, 1 H); 7.49 - 7.51 (m, 1 H).
UPLC-MS (ESI+): [M + H]+ = 218.
Intermediate D.1
Preparation of 3-phenyl-propionimidic acid ethyl ester hydrochloride
In an adaptation of GP 5a: At 0°C dry hydrochloric acid (g) was passed through a solution of commercially available 3-phenyl-propionitrile (25.0 g, 191 mmol) in dry ethanol (15 mL) over 2 hours. The mixture was concentrated to give target compound as crystals upon standing
over night. The target compound was used in the subsequent reaction without further purification steps (yield: 43.4 g).
1H-NMR (DMSO-d6, 300 MHz): 1 .32 (t, 3H); 2.95 (s, 4H), 4.37 (q, 2H); 7.21 - 7.37 (m, 5H); 10.80 - 12.06 (m, 2H).
MS (EI+): M+ = 177. (free base)
Table 4: The following intermediates D.2 to D.4 were prepared in analogy to intermediate D.1 and GP 5a or 5b starting from intermediates C.1 , C.2 and C.5.
Preparation of 2-phenethyl-4,5-dihydro-thiazole-4-carboxylic acid methyl ester
1H-NMR (CDCIs, 300 MHz): 2.82 - 2.91 (m, 2H); 2.94 - 3.04 (m, 2H); AB-Signal (δΑ = 3.51 , δΒ = 3.61 , 2 x 1 1-1); 3.81 (s, 3H); 5.03 - 5.1 1 (m, 1 H); 7.17 - 7.33 (m, 5H).
MS (EI+): M+ = 249. Table 5: The following intermediates E.2 to E.7 were prepared in analogy to intermediate E.1 an d G P 6a or 6b starting from intermediates D.1 to D.4 and cysteine methyl ester hydrochloride and penicillamine methyl ester hydrochloride, respectively.
Intermediate E.4 (alternative synthesis, see scheme 7)
Preparation of 2-[2-(2-fluoro-6-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-thiazole-4-carboxylic acid methyl ester
In analogy to Raman et al. Org Lett 2000, 2, 3289: At 0°C 2-[3-(2-fluoro-6-trifluoromethyl- phenyl)-propionylamino]-3-mercapto-propionic acid methyl ester (intermediate W.1 ) (4.75 g, 13.4 mmol) was dissolved in dichloromethane (200 mL) and 1 M titan (IV) chloride solution (40.32 ml , 40.32 mmol) was added. After 30 minutes the mixture was poured into saturated sodium bicarbonate and extracted several times with DCM. The combined extracts were dried over sodium sulphate, filtered and concentrated. Flash column chromatography give the desired thiazoline (yield: 2.35 g). Identical with the material described above.
Intermediate E.8
Preparation of 2-[2-(2-fluoro-6-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazole-4-carboxylic acid methyl ester
Method A, in an adaptation of WO2007/127173, example 6.f
Under nitrogen at -70°C diethyl amino sulphur trifluoride (DAST) (0.32 mL, 394 mg, 2.45 mmol, 1 .65 eq.) was added to a stirred solution of 2-[3-(2-fluoro-6-trifluoromethyl-phenyl)- propionylamino]-3-hydroxy-propionic acid methyl ester (intermediate W.2) (0.5 g, 1 .5 mmol) in DCM (15 mL). After stirring for 1 .5 hours the mixture was warmed to -20°C and anhydrous potassium carbonate (204.9 mg, 1 .48 mmol, 1 .0 eq.) was added. The mixture was then allowed to warm to room temperature. The mixture was poured into saturated sodium bicarbonate stirred for 1 hour and extracted several times with DCM. The combined extracts were dried over sodium sulphate, filtered and concentrated to give the desired oxazoline (yield: 456 mg).
1H-NMR (methanol-d4, 400 MHz): 2.57 (t, 2H); 3.12 (t, 2H); 3.75 (s, 3H); 4.44 - 4.55 (m, 2H); 4.75 (dd, 1 H); 7.37 (t, 1 H); 7.40 - 7.47 (m, 1 H); 7.48 - 7.53 (m, 1 H).
MS (ESI+): [M + H]+ = 320. Method B in an adaptation of WO2006/69063, example 3
At room temperature (methoxycarbonylsulphamoyl)triethylammonium hydroxide inner salt (Burgess reagent) (20.7 g, 86.7 mmol, 1 .1 eq.) was added in portions to a stirred solution of 2-[3-(2-fluoro-6-trifluoromethyl-phenyl)-propionylamino]-3-hydroxy-propionic acid methyl ester (intermediate W.2) (26.6 g, 78.8 mmol) in THF (450 mL). The reaction mixture was heated to 70°C for 1 hour. Concentration of the mixture and flash chromatography yielded the title compound (15.6 g). The product was identical with the material obtained described above.
Intermediate F.1
Preparation of 8-benzyl-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methyl ester
In an adaptation of GP 7a: At room temperature 1 ,2-dichloroethane (2 mL), pre-saturated with hydrochloric acid (g), was added to the solution of 2-phenethyl-4,5-dihydro-thiazole-4- carboxylic acid methyl ester (intermediate E.1 ) (446 mg, 1 .79 mmol) and commercially available Acetyl-Meldrum's acid (1 g, 5 mmol, 3.0 eq.) in 1 ,2-dichloroethane (13 mL). The reaction mixture was heated to 140°C for 120 seconds in a Biotage Initiator microwave oven. TLC analysis showed complete turnover. After removal of the solvent the target compound was isolated by filtration of the crude product over a pad of silica gel followed by flash column chromatography (yield: 500 mg).
1H-NMR (CDCIs, 300 MHz): 2.03 (d, 3H); AB-Signal (δΑ = 3.54, δΒ = 3.74, 2 x 1 H); 3.75 (s, 2H); 3.82 (s, 3H); 5.66 (dd, 1 H); 6.18 (d, 1 H); 7.09 - 7.15 (m, 2H); 7.17 - 7.24 (m, 1 H); 7.26 - 7.32 (m, 2H).
MS (EI+): M+ = 315.
Table 5a: The following intermediates F.2 to F.6 were prepared in analogy to intermediate F.1 and GP 7a starting from respective intermediates E.2 to E.7 and commercially available Acetyl-Meldrum's acid.
8-(2-fluoro-6-trifluoromethyl-
1H-NMR (CDCI3, 300 MHz): 1 .49 (s, 3H); 1.60 (s, 3H); 1.99 (s, 3H) benzyl)-2,2,7-trimethyl-5-oxo- 3.77 (s, 3H); 3.92 (br. s, 2H); 5.1 1 (s, 1 H); 6.12 (d, 1 H); 7.13 - 7.23 2,3-dihydro-5H-thiazolo[3,2- 1 H); 7.29 - 7.39 (m, 1 H); 7.46 - 7.51 (m, 1 H).
a]pyridine-3-carboxylic acid
UPLC-MS (ESI+): [M+H]+ = 430.
methyl ester
Intermediate F.7
Preparation of 8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H- oxazolo[3,2-a]pyridine-3-carboxylic acid methyl ester
In an adaptation of general procedure 29b: Acetyl meldrum's acid (27.4 g, 147 mmol, 3 eq.) and 2-[2-(2-fluoro-6-trifluoromethyl-phenyl)-ethyl]-4,5-dihydro-oxazole-4-carboxyl i c aci d methyl ester (intermediate E.8) (15.6 g, 49.0 mmol) in toluene (300 mL) were heated to reflux for 20 min. Then trifluoro acetic acid (18.9 mL, 27.9 g, 245 mmol, 5 eq.) was added and reflux was continued for 1 hour. The reaction mixture was partitioned between water and ethyl acetate. After phase separation, extraction of the aqueous layer with ethyl acetate, washing of the combined organic layers with brine and evaporation of the solvent flash chromatography yielded the desired title compound (yield: 4.7 g)
1H-NMR (methanol-d4, 300 MHz): 3.77 (s, 3H); 3.99 (s, 2H); 4.64 (dd, 1 H); 4.75 (t, 1 H); 5.23 (dd, 1 H); 5.96 (s, 1 H); 7.30 (m, 1 H); 7.38 - 7.47 (m, 1 H); 7.48 - 7.55 (m, 1 H).
MS (ESI+): [M + H]+ = 386.
Intermediate G.1
Preparation of 8-benzyl-6-iodo-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3- carboxylic acid methyl ester
In an adaptation of G P 8: At room temperature N-iodosuccinimide (342 mg, 1 .52 mmol, 2.4 eq.) was added to a stirred solution of 8-benzyl-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridine-3-carboxylic acid methyl ester (intermediate F.1 ) (200 mg, 0.63 mmol) in acetic acid (2 mL) and TFA (100 μί). After LCMS indicated complete consumption of the
starting material the reaction mixture was partitioned between DCM and aqueous sodium thiosulfate, the aqueous layer was extracted with DCM and the combined organic layers were washed with sodium bicarbonate, dried with sodium sulfate and concentrated in vacuum. The target compound was isolated by crystallization from ethyl acetate / tert-butyl methyl ether (yield: 185 mg).
1H-NMR (CDCIs, 300 MHz): 2.35 (d, 3H); AB-Signal (δΑ = 3.58, δΒ = 3.77, 2 x 1 H); 3.88 (s, 3H); 3.91 (s, 2H); 5.74 (dd, 1 H); 7.12 - 7.19 (m, 2H); 7.23 - 7.38 (m, 3H).
MS (EI+): M+ = 441 .
Table 6: The following intermediates G.2 to G.5 were prepared in analogy to intermediate G.1 and GP 8 starting from respective intermediates F.2 to F.5.
Intermediate G.6
Preparation of 8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-7-methyl-5-oxo-2,3-dihydro-5H- oxazolo[3,2-a]pyridine-3-carboxylic acid methyl ester
In an adaptation of GP 8: At 10°C temperature N-iodosuccinimide (7.01 g, 31 .4 mmol, 2.4 eq.) was added to a stirred solution of 8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridine-3-carboxylic acid methyl ester (intermediate F.7) (5.0 g, 13 mmol) in acetic acid (74 mL) and TFA (2.4 mL). The reaction was stirred over night and then partitioned between saturated aqueous sodium sulfite and ethyl acetate. After phase separation the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with sodium bicarbonate, dried and concentrated in vacuum. The target compound was isolated by crystallization from diethyl ether (yield: 4.69 g).
1H-NMR (DMSO-d6, 400 MHz): 2.36 (s, 3H); 3.70 (s, 3H); 4.00 (br. s, 2H); 4.69 - 4.78 (m, 1 H); 5.27 (dd, 1 H); 7.43 - 7.55 (m, 2H); 7.56 - 7.61 (m, 1 H).
MS (ESI+): [M + H]+ = 512.
Intermediate H.1
Preparation of 8-benzyl-6-bromo-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3- carboxylic acid methyl ester
In an adaptation of GP 9: At 10°C bromine (35 μί, 107 mg, 0.67 mmol, 1 .06 eq.) was added d ropwi se to a sti rred so l uti on of 8-benzyl-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2- a]pyridine-3-carboxylic acid methyl ester (intermediate F.1 ) (200 mg, 0.63 mmol) in acetic acid (6 mL). After the mixture was allowed to warm to room temperature and LCMS indicated
complete consumption of the starting material the reaction mixture was partitioned between DCM and aqueous sodium thiosulfate, the aqueous layer was extracted with DCM and the combined organic layers were washed with sodium bicarbonate, dried with sodium sulfate and concentrated in vacuum. The target compound was isolated by crystallization from ethyl acetate / tert-butyl methyl ether (yield: 147 mg).
1H-NMR (CDCIs, 300 MHz): 2.22 (s, 3H); AB-Signal (δΑ = 3.55, δΒ = 3.76, 2 x 1 H); 3.83 (s, 5H); 5.70 (dd, 1 H); 7.08 - 7.14 (m, 2H); 7.18 - 7.34 (m, 3H).
MS (EI+): M+ = 393 / 395. (Br isotope pattern) Intermediate 1.1
Preparation of 8-benzyl-7-methyl-5-oxo-6-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3- carboxylic acid methyl ester
1H-NMR (CDCI3, 400 MHz): 1 .90 (s, 3H); AB-Signal (δΑ = 3.53, δΒ = 3.76, 2 x 1 H); 3.83 (s, 5H); 5.67 (dd, 1 H); 7.15 - 7.25 (m, 5H); 7.27 - 7.40 (m, 5H).
MS (EI+): M+ = 391 .
Table 7: The following intermediates 1.2 to 1.25 were prepared in analogy to intermediate 1.1 and G P 10a or 10b starting from respective intermediates G.2 to G.5 and respective boronic acids.
3.70 - 1 H); -
3.72 - H); 6.94
3.64 - 6.75
3.70 - 2H);
6-(3-difluoromethoxy-2-fluoro-phenyl)-8-
1H-NMR (methanol-d4, 300 MHz): 1 .95 (s, 3H); 3.52 (dd, 1 H); 3.72 - o¾/ |j (2-fluoro-6-trifluoromethyl-benzyl)-7- 3.81 (m, 4H); 4.1 1 (br. s, 2H); 5.58 - 5.64 (m, 1 H); 6.89 (tr, 1 H); 6.96 -
1.24 methyl-5-oxo-2,3-dihydro-5H-
7.59 (m, 6H).
thiazolo[3,2-a]pyridine-3-carboxylic acid
-Hi UPLC-MS (ESI+): [M + H]+ = 562.
methyl ester
6-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro- 1H-NMR (methanol-d4, 300 MHz): 1.40 (m, 3H); 1 .95 (s, 3H); 3.52 (dd, 6-trifluoromethyl-benzyl)-7-methyl-5-oxo- 1 H); 3.72 - 3.82 (m, 4H); 4.1 1 (m, 4H); 5.62 (m, 1 H); 6.72 (m, 1 H); 7.00 -
1.25
2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3- 7.61 (m, 5H).
carboxylic acid methyl ester UPLC-MS (ESI+): [M + H]+ = 540.
Intermediate 1.26
Preparation of 6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridine-3-carboxylic acid methyl ester
In analogy to Guram A. S. et al. Org. Lett. 2006, 8, 1787: Argon was bubbled for 5 minutes through a solution of commercial available 2-fluoro-3-isopropoxyphenyl boronic acid (2.13 g. 10.7 mmol, 2.5 eq.), 8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-7-methyl-5-oxo-2,3-dihydro- 5H-oxazolo[3,2-a]pyridine-3-carboxylic acid methyl ester (intermediate G.6) (2.2 g, 4.3 mmol), pota ss i u m ca rbo n ate (1 .19 g, 8.61 mmol, 2.0 eq.) and bis(di-tert-butyl(4- dimethylaminophenyl)phosphin dichloropalladium (I I) (60.9 mg, 0.09 mmol, 0.02 eq.) in toluene / water (5:1 , 66 mL). Then the mixture was heated to reflux over night. Evaporation of the solvent and flash chromatography yielded the target compound (yield: 1.8 g).
1H-NMR (methanol-d4, 300 MHz): 1 .30 (m, 6H); 1 .95 (s, 3H); 3.76 (d, 3H); 4.06 (br. s, 2H); 4.50 - 4.62 (m, 1 H); 4.66 (dd, 1 H); 4.78 (dt, 1 H); 5.21 - 5.30 (m, 1 H); 6.66 - 6.79 (m, 1 H); 7.00 - 7.12 (m, 2H); 7.27 - 7.37 (m, 1 H); 7.38 - 7.47 (m, 1 H); 7.50 - 7.55 (m, 1 H).
MS (ESI+): [M + H]+ = 538. Intermediate K.1
Preparation of 8-benzyl-7-methyl-5-oxo-6-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3- carboxylic acid
I n an adaptation of GP 1 1 : At room temperature lithium hydroxide (18.3 mg, 0.77 mmol, 10 eq., 1 M solution in water) was added to a stirred solution of 8-benzyl-7-methyl-5-oxo-6- phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methyl ester (intermediate
1.1 ) (30 mg, 0.08 mmol) in THF (1 mL) and stirred until TLC indicate completed consumption of the starting material (1 hour). Then pH was adjusted to 4 (2 N aqueous hydrochloric acid). The aqueous layer was extracted with ethyl acetate and the organic layer was washed with water and brine, dried with sodium sulfate and concentrated in vacuum . The target compound was used in the subsequent reaction without further purification steps (yield: 29.4 mg).
1H-NMR (CDCIs, 300 MHz): 2.00 (s, 3H); AB-Signal (δΑ = 3.67, δΒ = 4.16, 2 x 1 H); AB-Signal (δΑ = 3.88, δΒ = 3.95, 2 x 1 H); 5.80 (d, 1 H); 7.16 - 7.50 (m, 10H).
MS (ESI+): [M+H]+ = 378.
Table 8: The following intermediates K.2 to K.20 were prepared in analogy to intermediate K.1 and GP 1 1 starting from respective intermediates 1.3 to I.25.
Intermediate L.1
Preparation of 8-benzyl-3-hydroxymethyl-7-methyl-6-phenyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
I n an adaptation of GP 13 (lithium aluminum hydride was used instead of lithium boron hydride): At room temperature lithium aluminum hydride (92.9 mg, 0.19 mmol, 1 .5 eq.) was added to a stirred solution of 8-benzyl-7-methyl-5-oxo-6-phenyl-2,3-dihydro-5H-thiazolo[3,2- a]pyridine-3-carboxylic acid methyl ester (intermediate 1.1 ) (50 mg, 0.13 mmol) in THF (2.5 mL). After stirring at that temperature for 1 .5 hours TLC indicated complete consumption of the starting material. The reaction mixture was quenched by the addition of water and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and were dried with sodium sulfate and concentrated in vacuum. The target compound was is used in the subsequent reaction without further purification steps (yield: 39.3 mg).
1H-NMR (CDCIs, 300 MHz): 1 .89 (s, 3H); AB-Signal (δΑ = 3.20, δΒ = 3.63, 2 x 1 H); 3.80 - 3.06 (m, 3H); 4.17 (dd, 1 H); 4.24 - 4.36 (m, 1 H); 5.39 (m, 1 H); 7.13 - 7.43 (m, 10H).
MS (ESI+): [M+H]+ = 364.
Table 9: The following intermediates L.2 to L.8 were prepared in analogy to intermediate L.1 and GP 13 starting from respective intermediates 1.2 to 1.8 employing lithium boron hydride.
Intermediate M.1
Preparation of toluene-4-sulfonic acid 8-benzyl-7-methyl-5-oxo-6-phenyl-2,3-dihydro-5H- thiazolo[3,2-a]pyridin-3-ylmethyl ester
In an adaptation of GP 14 (p-toluenesulfonic chloride was used instead of p-toluenesulfonic an hyd ride): At 0°C N , N-dimethylaminopyridine (8.9 mg, 0.07 mmol, 2.2 eq.) and p- toluenesulfonic chloride (6.9 mg, 0.04 mmol, 1 .1 eq.) were added to a stirred solution of 8- benzyl-3-hydroxymethyl-7-methyl-6-phenyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
(intermediate L.1 ) (12 mg, 0.03 mmol) in DCM (1 ml_). The reaction mixture was kept at 0°C for 1 .5 hours and at room temperature for 1 .5 hours upon which TLC indicated complete consumption of the starting material. The reaction mixture was partitioned between DCM and water, the aqueous layer was extracted with DCM and the combined organic layers were washed with sodium bicarbonate, dried over sodium sulfate and concentrated in vacuum. The target compound was used in the subsequent reaction without further purification steps (yield: 17.9 mg).
UPLC-MS (ESI+): [M + H]+ = 518.
Table 10: The following intermediates M.2 to M.8 were prepared in analogy to intermediate M.1 and GP 14 starting from respective intermediates
L.2 to L.8 employing p-toluenesulfonic anhydride.
toluene-4-sulfonic acid 8-(2,6-
1 H-NMR (methanol-d4, 300 MHz):
difluoro-benzyl)-7-methyl-5-oxo-6- 1.96 (s, 3H); 2.42 (s, 3H); 3.37 (d, 1 H); 3.72 (dd, 1 H); AB-Signal (δΑ = 3.83,
(3-trifluoromethoxy-phenyl)-2,3- δΒ = 3.90, 2x 1 H); AB-Signal (δΑ = 4.29, δΒ = 4.43, 2x 1 H); 5.24 - 5.34 (m, dihydro-5H-thiazolo[3,2-a]pyridin-3- 1 H); 6.90 - 7.01 (m, 4H); 7.20 - 7.52 (m, 5H); 7.67 - 7.75 (m, 2H). ylmethyl ester
Intermediate N.1
Preparation of 8-benzyl-7-methyl-5-oxo-6-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3- carbaldehyde
In analogy to the literature J. pra t. Chem. 1996, 338, 588 -590.
At 0°C Dess-Martin-Periodinane (77.0 mg, 0.165 mmol, 1 .5 eq.) was added in portions to a sti rred sol ution of 8-benzyl-3-hydroxymethyl-7-methyl-6-phenyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one (Intermediate L.1 ) (40.0 mg, 0.1 10 mmol) in DCM (2 ml_). After TLC indicated complete consumption of the starting material the reaction mixture was quenched by the addition of aqueous sodium bicarbonate / aqueous sodium thiosulfate (1 :1 ). After separation of phases the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuum . The target compou nd was used in the su bsequent reaction without further purification steps (yield: 40.4 mg).
1H-NMR (CDCIs, 300 MHz): 1 .93 (s, 3H); AB-Signal (δΑ = 3.59, δΒ = 3.67, 2 x 1 H); 3.83 (s, 3H); 5.54 - 5.60 (m, 1 H); 7.14 - 7.43 (m, 10H); 9.75 (s, 1 H).
UPLC-MS (ESI+): [M + H]+ = 362. Table 1 1 : The following intermediate N.2 was prepared in analogy to intermediate N.1 starting from intermediate L.3.
In an adaptation of GP 13: At -78°C lithium borohydride (3.75 mL, 2 M in THF, 7.5 mmol, 1.5 eq.) was added to a stirred solution of 8-(2,6-difluoro-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridine-3-carboxylic acid methyl ester (intermediate F.3) (1.75 g, 5.0 mmol) in THF (10 mL). After stirring at that temperature for 2.5 hours the reaction mixture was allowed to warm to 0°C. Stirring was continued until TLC indicated complete consumption of the starting material. The reaction mixture was quenched by the addition of aqueous sodium bicarbonate and was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and were dried with sodium sulfate and concentrated in vacuum. The target compound was is used in the subsequent reaction without further purification steps (yield: 1 .2 g).
1H-NMR (methanol-d4, 300 MHz): 2.14 (s, 3H); 3.45 - 3.53 (dd, 1 H); 3.57 - 3.91 (m, 5H); 5.08 - 5.19 (m, 1 H); 6.08 (s, 1 H); 6.85 - 6.98 (m, 2H); 7.21 - 7.34 (m, 1 H).
UPLC-MS (ESI+): [M + H]+ = 324. Intermediate P.1
Preparation of toluene-4-sulfonic acid 8-(2,6-difluoro-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridin-3-ylmethyl ester
In an adaptation of GP 14 (p-toluenesulfonic chloride was used instead of p-toluenesulfonic anhydride): At 0°C N,N-dimethylaminopyridine (997.4 mg, 8.16 mmol, 2.2 eq.) and p-
toluenesulfonic chloride (778.3 mg, 4.08 mmol, 1 .1 eq.) were added to a stirred solution of 8- (2,6-difluoro-benzyl)-3-hydroxymethyl-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (intermediate 0.1 ) (1 .2 g, 4 mmol) in DCM (33 mL). The reaction mixture was kept at 0°C for 0.5 hours and at room temperature for 2.5 hours upon TLC indicated complete consumption of the starting material. The reaction mixture was partitioned between DCM, water and sulfuric acid (1 % aqueous solution), the aqueous layer was extracted with DCM and the combined organic layers were washed with sodium bicarbonate, dried over sodium sulfate and concentrated in vacuum. The target compound was used in the subsequent reaction without further purification steps (yield: 2.1 g).
1H-NMR (methanol-d4, 400 MHz): 2.1 1 (s, 3H); 2.41 (s, 3H); 3.62 - 3.83 (m, 3H); 4.23 (dd, 1 H); 4.38 (dd, 1 H); 5.18 - 5.25 (m, 1 H); 5.90 (s, 1 H); 6.88 - 6.97 (m, 2H); 7.24 - 7.35 (m, 3H); 7.63 - 7.69 (m, 2H).
Intermediate Q.1
Preparation of 8-(2,6-difluoro-benzyl)-7-methyl-3-{[methyl-(2-pyridin-2-yl-ethyl)-amino]- methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
1H-NMR (methanol-d4, 300 MHz): 2.39 (s, 3H); 2.49 - 2.57 (m, 1 H); 2.63 - 2.80 (m, 2H); 2.87 - 3.01 (m, 5H); 3.35 - 3.46 (m, 1 H); AB-Signal (δΑ = 3.73, δΒ = 3.86, 2x 1 H); 5.06 - 5.16 (m, 1 H); 6.07 (d, 1 H); 6.86 - 6.97 (m, 2H); 7.19 - 7.38 (m, 3H); 7.67 - 7.79 (m; 1 H); 8.39 - 8.43 (m, 1 H).
UPLC-MS (ESI+): [M + H]+ = 442.
Intermediate R.1
Preparation of 8-(2-fluoro-6-trifluorpmethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridine-3-carboxylic acid
In an adaptation of GP 1 1 : At room temperature lithium hydroxide (1.34 g, 56.1 mmol, 1.5 eq., dissolved in 80 mL water) was added to a stirred solution of 8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methyl ester (intermediate F.4) (1 5 g, 37.4 mmol) in TH F (370 m L) and stirred until TLC indicated completed consumption of the starting material (2 hours). Then pH was adjusted to 4 (2 N aqueous hydrochloric acid). The THF was evaporated and the remains diluted with water. The solids were filtered off and washed with water to yield of the target compound (yield: 13.5 g).
1H-NMR (DMSO-de, 300 MHz): 2.05 (s, 3H); 3.38 (m, 1 H), 3.65 (m, 1 H), 3.88 (m, 2H), 5.33 (d, 1 H); 6.00 (s, 1 H), 7.40 - 7.60 (m, 3H).
MS (ESI+): [M + H]+ = 388.
Table 12: The following intermediates R.2 and R.3 were prepared in analogy to intermediate R.1 and in adaptation of GP 1 1 starting from intermediates F.3 and F.6, respectively.
Intermediate S.1
Preparation of 8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
1H-NMR (DMSO-de, 300 MHz): 2.10 (s, 3H); 3.50 (m, 1 H), 3.75 (m, 1 H), 3.92 (m, 2H), 5.69 (m, 1 H); 6.08 (s, 1 H), 7.30 - 7.60 (m, 8H).
MS (ESI+): [M + H]+ = 480.
Table 13: The following intermediates S.2 and S3 were prepared in analogy to intermediate S.1 and and in adaptation of GP 19 starting from intermediates R.2 and R.3 respectively.
Intermediate T.1
Preparation of 3-benzoyl-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro- thiazolo[3,2-a]pyridin-5-one
In an adaptation of GP 20b: At room temperature 8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester (intermediate S.1) (2.5 g, 5.21 mmol) was dissolved in THF (70 ml_). copper-(l)- diphenylphosphinate (1.95 g, 6.26 mmol, 1.2 eq.), tri-(2-furyl)-phosphin (97 mg, 0.42 mmol, 0.08 eq.), tris-(dibenzylidenaceton)dipalladium (48 mg, 52 μηιοΙ, 0.01 eq.) and phenyltnbutylstannane (2.68 g, 7.30 mmol, 1.4 eq.) were added and the resulting greenish suspension was stirred for 1.5 h at 50°C. After cooling the mixture was filtered over celite®, the filtrate concentrated and purified by flash chromatography (silica / hexane/ethyl acetate) to reisolate starting material (0.5 g) and to obtain the desired ketone (yield: 1.80 g).
1H-NMR (CDCIs, 300 MHz): 2.07 (s, 3H); 3.31 (dd, 1H), 3.78 (dd, 1H), 2.05 (dd, 2H), 6.16 (s, 1H); 6.47 (dd, 1H), 7.15-7.25 (m, 1H), 7.36 (m, 1H), 7.48-7.52 (m, 3H), 7.62 (m, 1H), 8.01 (dd, 1H).
MS (ESI+): [M + H]+ = 448.
Table 14: The following intermediates T.2 and T3 were prepared in analogy to intermediate S.1 and and in adaptation of GP 19 starting from intermediates S.2 and S.3 respectively.
Preparation of 3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
I n an adaptation of G P 21 a : 3-Benzoyl-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one (intermediate T.1 ) (1 .8 g, 4.02 mmol) was dissolved in toluene (65 mL) and tert-butanol (65 mL). Hydroxylamine hydrochloride (1 .34 g, 19.3 mmol, 4.8 eq.) and pyridine (17 mL, 220 mmol, 50 eq.) were added and and the mixture stirred at 100°C for 2 hours. UPLC-MS indicated complete conversion. After cooling the mixture was partitioned between water and ethyl acetate, the phases separated, the organic layer washed with water and brine, dried with sodium sulphate and concentrated to dryness. The resulting
£Z-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(hydroxyimino-phenyl-methy
dihydro-thiazolo[3,2-a]pyridin-5-one (yield: 1.7 g) was used without further purification.
In an adaptation of GP 23a: To titaniumtetrachloride (50 mg, 0.26 mmol, 1.2 eq), dissolved in dimethoxyethane (2 mL) were added at 0°C lithium borohydride (1.04 mmol, 4.8 eq., 2 M solution in THF) and stirred for 10 min. Then £Z-8-(2-fluoro-6-trifluoromethyl-benzyl)-3- (hydroxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-o n e (100 mg), dissolved in dimethoxyethane (2 mL), was added dropwise and the mixture stirred at room temp, for 16 hours. The reaction was stopped by the addition of 4 mL water and 1 mL ammonia (25% in water). The mixture was partitioned between water and dichloromethane, extracted with dichloromethane, the combined organic layers dried with sodium sulphate and the solvents removed in vacuum to yield 3-(amino-phenyl-methyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one as a mixture of diastereomers (1 : 2.5 by HPLC) (yield: 60 mg).
1H-NMR (CD3OD, 300 MHz): 2.10 and 2.16 (s, 3H); 3.30 - 3.45 (m, 2H), 3.85 and 4.01 (m, 2H), 4.53 and 4.66 (d, 1H), 5.27 (m, 1H), 6.07 and 6.22 (s, 1H), 7.10-7.60 (m, 8H).
MS (ESI+): [M + H]+ = 449.
Chiral HPLC (Chiralpak AD-H 5μηι 150x4.6 mm; hexane / ethanol 70:30 + 0.1% diethylamine; 1.0 mL/min):
diastereomer 1, enantiomer 1: RT = 5.46 min (15.4%)
diastereomer 1, enantiomer 2: RT = 7.48 min (13.2%)
diastereomer 2, enantiomer 1: RT = 8.94 min (36.3%)
diastereomer 2, enantiomer 2: RT = 13.42 min (35.1%) b) via reduction of methyl-oxime
In an adaptation of GP 21a: 3-Benzoyl-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one (intermediate T.1) (1.1 g, 2.46 mmol) was dissolved in toluene (27 mL) and tert-butanol (27 mL). O-Methyl-hydroxylamine hydrochloride (985 mg, 11.8 mmol, 4.8 eq.) and pyridine (10 mL, 123 mmol, 50 eq.) were added and and the mixture was stirred at 100°C for 3 hours. UPLC-MS indicated complete conversion. After cooling the mixture was partitioned between water and ethyl acetate, the phases separated, the organic layer washed with water and brine, dried with sodium sulphate and concentrated to dryness. The resulting £Z-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino-phenyl-methyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one was used without further purification (yield: (1.12 g)
To titaniumtetrachloride (50 mg, 0.26 mmol, 1 .2 eq), dissolved in to dimethoxyethane (2 mL) was added at 0°C sodium boron hydrid (33 mg 0.88 mmol, 4.2 eq.) and stirred for 5 min. Then E/Z-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino-phenyl-methyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one (100 mg), dissolved in dimethoxyethane (2 mL), was added dropwise and the mixture stirred at room temp, for 3 hours. The reaction was stopped by the addition of 4 m L water and 1 m L am mon ia (25% in water). The mixture was partitioned between water and dichloromethane, extracted with dichloromethane, the combined organic layers dried with sodium sulphate and the solvents removed in vacuum to obtain crude product (62 mg) which was further purified by chromatography (amino phase column, hexane/ethyl acetate) to yield 3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one as a mixture of diastereomers (9 : 1 by HPLC) (yield: 34 mg).
1H-NMR (CD3OD, 300 MHz), major isomer: 2.16 (s, 3H); 3.25 (m, 1 H), 3.44 (m, 1 H), 3.85 (m, 2H), 4.54 (d, 1 H), 5.30 (m, 1 H), 6.22 (s, 1 H), 7.10-7.60 (m, 8H).
MS (ESI+): [M + H]+ = 449.
Chiral HPLC (Chiralpak AD-H 5 μ ηι 1 50 x 4.6 mm; hexane / ethanol 70 : 30 + 0.1 % diethylamine; 1 .0 mL/min):
diastereomer 1 , enantiomer 1 : RT = 5.44 min (46.3%)
diastereomer 1 , enantiomer 2: RT = 7.45 min (44.0%)
diastereomer 2, enantiomer 1 : RT = 8.97 min (5.0%)
diastereomer 2, enantiomer 2: RT = 13.44 min (4.7%) c) via reductive amination
3-Benzoyl-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one (intermediate T.1 ) (205 mg, 560 mmol) was dissolved in methanol (10 mL), ammonium acetate (520 mg, 6.7 mmol, 12 eq.) and sodium cyano boronhydride (140 mg, 2.23 mmol, 4 eq.) were added and the mixture heated to reflux for 4 days. The methanol was evaporated, the residue redissolved in dichloromethane and aqueous sodium hydroxide (1 M), the phases separated, extracted with dichlormethane, washed with brine, dried with sodium sulphate and th e solven ts eva porated to yi eld 3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one as a m ixtu re of d i astereomers (1 : 3.6 by HPLC) (yield: 157 mg), which was further purified by chromatography (aminophase, hexane/ethyl acetate).
1H-NMR (CD3OD, 300 MHz), major isomer: 2.09 (s, 3H); 3.30-3.50 (m, 2H), 4.00 (m, 2H), 4.66 (d, 1 H), 5.30 (m, 1 H), 6.06 (s, 1 H), 7.10-7.60 (m, 8H).
MS (ESI+): [M + H]+ = 449.
Chiral HPLC (Chiralpak AD-H 5μηι 150x4.6 mm; hexane / ethanol 70:30 + 0.1% diethylamine; 1.0 mL/min):
diastereomer 1 , enantiomer 1 : RT = 5.47 min (11.2%)
diastereomer 1, enantiomer 2: RT = 7.47 min (10.4%)
diastereomer 2, enantiomer 1: RT = 8.91 min (38.1%)
diastereomer 2, enantiomer 2: RT = 13.39 min (40.3%)
Table 15: The following intermediate U.2 was prepared in analogy to intermediate U.1 and in adaptation of GP 23a via methyloxime starting from intermediate T.2. Intermediates U.3a&b were prepared in analogy to intermediate U.1 and in adaptation of GP 23a via hydroxyl oxime starting from intermediate T.3.
H),
H),
-
- -
enantiomer 2: RT = 6.07
Intermediate V.1
Preparation of [3-(1,1-difluoroethyl)phenyl]boronic acid
In an adaptation of GP 30: At -78°C tert-butyllithiium (1.33 mL, 144.9 mg, 2.26 mmol, 2.0 eq.) was added slowly to a stirred solution of commercially available 1-bromo-3-(1 ,1- difluoroethyl)benzene (250 mg, 1.13 mmol) in diethyl ether (2 mL). Stirring was continued for 20 minutes at -78°C. Then triisopropyl borate (531,8 mg, 2.83 mmol, 2.5 eq.) was added and the mixture was allowed to warm to room temperature over night. After the addition of hydrochloric acid (2N) (pH 1) the mixture was partitioned between ethyl acetate and water, the aqueous layer was extracted 3 times with ethyl acetate and the combined organic layers were washed with water, dried and concentrated in vacuum. The boronic acid was isolated by flash column chromatography (yield: 70 mg).
1H-NMR (CDCIs, 400 MHz): 2.03 (t, 3H); 7.57-7.66 (m, 1H); 7.73-7.81 (m, 1H); 8.27- 8.38 (m, 2H).
Intermediate V.2
Preparation of [3-(1,1-difluoroethyl)-2-fluorophenyl]boronic acid
Intermediate V.2a
Preparation of 1-bromo-3-(1,1-difluoro-ethyl)-2-fluoro-benzene
1H-NMR (methanol-d4, 300 MHz): 1 .95 (td, 3H); 7.10 (m, 1 H); 7.51 (m, 1 H); 7.70 (m, 1 H). Intermediate V.2b
Preparation of 2-[3-(1 ,1 -difluoroethyl)-2-fluorophenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane
1H-NMR (methanol-d4, 300 MHz): 1 .35 (s, 12H); 1 .96 (td, 3H); 7.23 (m, 1 H); 7.64 (m, 1 H); 7.77 (m, 1 H).
Intermediate V.2
Preparation of [3-(1 ,1 -difluoroethyl)-2-fluorophenyl]boronic acid
At room temperature ammon ium acetate (6.1 g, 80.2 mmol, 3.0 eq.) and sodium (meta)periodate (17.1 g, 80.2 mmol, 3.0 eq.) were added to a stirred solution of 2-[3-(1 ,1 - difluoroethyl)-2-fluorophenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (intermediate V.2b) (7.6 g, 26.7 mmol) in acetone / water (200 mL / 100 mL). The reaction mixture was stirred at 40°C for 4 hours. Then the acetone was evaporated an the aqueous phase was extracted with ethyl acetate 3 times. Washing with brine, filtration and evaporation of the solvent yielded the desired boronic acid , wh ich was use as crude product in the subsequent reactions (yield: 5.6 g).
1H-NMR (CDCIs, 400 MHz): 2.01 (t, 3H); 7.27 (m, 1 H); 7.72 (m, 1 H); 8.16 (m, 1 H).
Intermediate V.3
Preparation of (5-fluoro-2,3-dihydro-1 ,4-benzodioxin-6-yl)boronic acid
Intermediate V.3a
Preparation of 5-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3-dihydro-1 ,4- benzodioxine
1H-NMR (methanol-d4, 300 MHz): 1.30 (s, 12H); 4.26 (m, 4H); 6.61 (dd, 1 H); 7.07 (dd, 1 H).
Intermediate V.3
Preparation of (5-fluoro-2,3-dihydro-1 ,4-benzodioxin-6-yl)boronic acid
At room tem peratu re ammon iu m acetate (4.9 g, 63 mmol, 3.0 eq.) and sodium (meta)periodate (13.6 g, 63.4 mmol, 3.0 eq.) were added to a stirred solution of 5-fluoro-6- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3-dihydro-1 ,4-benzodioxine (intermediate V.3a) (5.9 g, 21 .1 mmol) in acetone / water (60 mL / 30 mL). The reaction mixture was stirred at 40 ° C fo r 4 h o u rs . Ammonium acetate (4.9 g, 63 mmol, 3.0 eq.) and sodium (meta)periodate (13.6 g, 63.4 mmol, 3.0 eq.) were added again and stirring was continued for another 4 hours at 50°C. Then the acetone was evaporated and the aqueous phase was treated with aqueous hydrochloric acid (2M) and extracted with ethyl acetate 3 times. Washing with brine, filtration and evaporation of the solvent yielded the desired boronic acid, wh ich was use as crude product in the subsequent reactions after toluene stripping (yield: 2.6 g).
1H-NMR (methanol-d4, 400 MHz): 4.26 (m, 4H); 6.63 (d, 1 H); 6.67 (m, 1 H).
Intermediate V.4
Preparation of 5-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,2-dideutero- benzo[1 ,3]dioxole
Intermediate V.4a
Preparation of 4-fluoro-2,2-dideutero-benzo[1 ,3]dioxole
A mixture of 3-fluorobenzene-1 ,3-diol (5 g, 39 mmol), cesiumcarbonate (19 g, 58 mmol) and methylenbromide-D2 (10 g, 175 mmol) in dimethylformamide (100 ml) was heated to 100 °C for 2 hours. After cooling, the reaction was filtered and the filtrate was partitionated between n-hexane and water. Separation of the organic layer, extraction of the aqueous layer with n- hexane and evaporation of the combined organic layers yielded the product.
1H-NMR (CDCIs, 300 MHz): 6.57 - 6.83 (m, 3H).
Intermediate V.4b
Preparation of 5-bromo-4-fluoro-2,2-dideutero-benzo[1 ,3]dioxole
At 0°C bromine (7 g, 159 mmol) was added to a stirred solution of 4-fluoro-2,2-dideutero- benzo[1 ,3]dioxole (intermediate V.4a) (5.2 g, 36 mmol) in methanol (95 ml_). The reaction mixture was stirred at room temperature overnight and was poured into a mixture of saturated sodiumhydrogencarbonate solution and crushed ice (1 :1 , 500 ml). The product was collected by filtration.
1H-NMR (methanol-d4, 400 MHz): 6.60 and 6.63 (2x d, 1 H); 7.01 and 7.04 (2x d, 1 H).
Intermediate V.4
Preparation of 5-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 2,2-dideutero- benzo[1 ,3]dioxole
At room temperature bis(pinacolato)diboron (33.5 g, 131 mmol), potassium acetate (19 g, 1 97 mmol) and d ichlor(1 , 1 '-bis(diphenylphosphin)ferrocene) palladium dichloromethane complex (4.8 g, 6.6 mmol) were added to a stirred solution of 5-bromo-4-fluoro-2,2-dideutero- benzo[1 ,3]dioxole (intermediate V.4b) (14.5 g, 221 mmol) in dioxane (470 mL). The reaction mixture was heated to 1 10°C for 2 hours. After cooling, the reaction was quenched by the addition of water and ethyl acetate. Separation of the organic layer, extraction of the aqueous layer with ethyl acetate, washing of the combined organic layers with brine and filtration yielded the crude boronic acid ester, which was further purified by flash chromatography . 1H-NMR (methanol-d4, 300 MHz): 1 .32 (s, 12H); 6.67 (d, 1 H); 7.20 (m, 1 H).
Intermediate V.5
Preparation of 5-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4-difluoromethoxy- benzene
Intermediate V.5a Preparation of 1 -bromo-3-difluoromethoxy-2-fluoro-benzene
1H-NMR (CDCIs, 300 MHz): 6.50 (t, 1 H); 6.85 (m, 1 H); 6.96 (dd, 1 H); 7.54 (t, 1 H). Intermediate V.5
Preparation of 5-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4-difluoromethoxy- benzene
1H-NMR (CDCI3, 300 MHz): 1 .36 (s, 12H); 6.54 (t, 1 H); 6.81 (dd, 1 H); 6.89 (dd, 1 H); 7.74 (t, 1 H).
Intermediate W.1
Preparation of 2-[3-(2-fluoro-6-trifluoromethyl-phenyl)-propionylamino]-3-mercapto-propionic acid methyl ester
Intermediate W.1 a
Preparation of (£)-3-(2-fluoro-6-trifluoromethyl-phenyl)-acrylic acid methyl ester
Under nitrogen at room temperature trimethylphosphonoacetate (355 g, 1 .95 mol) was added to a sti rred sol uti on of 2-fluoro-6-trifluoromethyl-benzaldehyde (250 g , 1 .3 mol) and lithiumhydroxide monohydrate (82 g, 1 .95 mol) in tetrahydrofurane (3 L). After stirring for 24 hours the mixture was partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate and the combined organic layers are dried and concentrated in vacuum to yield (£)-3-(2-fluoro-6-trifluoromethyl-phenyl)-acrylic acid methyl ester (329 g). 1H-NMR (CDCIs, 400 MHz): 3.82 (s , 3H); 6.57 - 6.66 (m , 1 H) 7.24 - 7.58 (m, 3H); 7.72 - 7.83 (m, 1 H).
UPLC-MS (ESI+): [M + H]+ = 249.
Intermediate W.1 b
Preparation of 3-(2-fluoro-6-trifluoromethyl-phenyl)-propionic acid methyl ester
(£)-3-(2-fluoro-6-trifluoromethyl-phenyl)-acrylic acid methyl ester (intermediate W.1 a) (248 g, 1 mol) was hydrogenated in ethanol (2,5 L) with a Pd/C catalyst ( 50 g , 10 % Pd , 50% water) until the hydrogen uptake stops (appr. 24 L hydrogen consumed). The catalyst was filtered off and filtrate was evaporated to yield 3-(2-fluoro-6-trifluoromethyl-phenyl)-propionic acid methyl ester (240 g).
1H-NMR (CDCIs, 400 MHz): 2.58 (m, 2H); 3.14 (m, 2H); 3.72 (s , 3H); 7.24 (m, 1 H); 7.32 (m, 1 H); 7.45 (m, 1 H).
Intermediate W.1 c
Preparation of 3-(2-fluoro-6-trifluoromethyl-phenyl)-propionic acid
Lithiumhydroxid monohydrate (83 g, 1 .98 mol) was added to a solution of 3-(2-fluoro-6- trifluoromethyl-phenyl)-propionic acid methyl ester (intermediate W.1 b) (240 g, 0.96 mol) in a mixture of water (2 L) and tetrahydrofurane (2 L) and stirred at room temperature overnight. The tetrahydrofurane was evaporated and the residue was acidified with concentrated hydrochloric acid to pH 2 while the product precipitates. The precipitate was filtered, washed with water and dried to give 3-(2-fluoro-6-trifluoromethyl-phenyl)-propionic acid (223 g).
1H-N MR (CDCIs, 400 MHz): 2.65 (m, 2H); 3.15 (m, 2H); 7.26 (m, 1 H); 7.34 (m, 1 H); 7.46 (m, 1 H).
Intermediate W.1 d
Preparation of 3-(2-fluoro-6-trifluoromethyl-phenyl)-propionyl chloride
Oxalylchloride (239 g, 1 .88 mol) was added to a solution of 3-(2-fluoro-6-trifluoromethyl- phenyl)-propionic acid (intermediate W.1 c) (222 g, 0.94 mol) in dichloromethane (2.2 L) at room temperature and stirred overnight. Then the mixture was evaporated to give 3-(2-fluoro- 6-trifluoromethyl-phenyl)-propionyl chloride (231 g).
1H-NMR (CDCIs, 400 MHz): 3.18 (m, 4H); 7.28 (m, 1 H); 7.37 (m, 1 H); 7.47 (m, 1 H).
Intermediate W.1
Preparation of 2-[3-(2-fluoro-6-trifluoromethyl-phenyl)-propionylamino]-3-mercapto-propionic acid methyl ester
Under nitrogen at -0°C 2-amino-3-mercapto-propionic-acid-methylester-hydrochloride (2.9 g, 17 mmol) was added to a stirred solution of 3-(2-fluoro-6-trifluoromethyl-phenyl)-propionyl chloride (intermediate W.1 d) (4 g, 16 mmol) and N-ethyldiisopropylamine (2.7 mL, 16 mmol) in acetonitrile (150 mL). After stirring for 30 minutes the mixture was quenched with saturated ammoniumchloride solution (150 mL). The mixture is partitioned between ethyl acetate and water, the aqueous layer is extracted with ethyl acetate and the combined organic layers are d ri ed a n d co n ce n tra ted i n va c u u m to yi e l d 2-[3-(2-fluoro-6-trifluoromethyl-phenyl)- propionylamino]-3-mercapto-propionic acid methyl ester (4.75 g).
1H-NMR (CDCIs, 400 MHz): 2.54 (m, 2H); 3.16 (m, 2H); 4.71 (m, 1 H); 6.39 (m, 1 H); 7.19 - 7.52 (m, 3H).
UPLC-MS (ESI+): [M + H]+ = 354.
Table 15a: The following intermediate W.2 was prepared in analogy to intermediate W.1 starting from intermediate W.1 d and serine methylester hydrochloride.
No Structure Name Analytical data
2-[3-(2-fluoro-6-
1H-NMR (methanol-d4, 300 MHz) 2.48 trifluoromethyl- - 2.60 (m, 2H); 3.03 - 3.17 (m, 2H), phenyl)-
W.2 3.74 (s, 3H), 3.75 - 3.92 (m, 2H), 4.53 propionylamino]-3- (t, 1 H), 7.31 - 7.55 (m, 3H);
hydroxy-propionic
UPLC-MS (ESI+): [M + H]+ = 338. acid methyl ester
SYNTHESIS OF EXAMPLE COMPOUNDS
Example 1.1
Preparation of 8-(2,6-difluoro-benzyl)-6-(2-fluoro -3-methoxy-phenyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
In an adaptation of GP 19: At room temperature 1 H-hydroxybenzotriazole (12.6 mg, 0.08 mmol, 1 .2 eq.) and N-ethyl-N',N'-dimethylamino-propylcarbodiimide (15.8 mg, 0.08 mmol, 1 .2 eq.) were added to a stirred solution of 8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid (intermediate K.2) (38 mg, 0.08 mmol, 1 .2 eq.) in DMF (2.5 mL). After 1 hour at room temp, a solution of thiophenol (7 μί, 7.6 mg, 68 μηιοΙ) in DMF (0.5 mL) was added and stirring was continued upon TLC indicated complete consumption of the starting material. The reaction mixture was poured into a mixture of ice/saturated sodium bicarbonate. The target compound was filtered off, washed with water and dryed in vacuum (yield: 40 mg).
1 H-NMR (methanol-d4, 400 MHz): 1 .97 (d, 3H); 3.54 - 3.68 (m, 1 H); 3.78 - 4.01 (m, 6H); 6.66 - 6.79 (m, 1 H); 6.86 - 6.98 (m, 3H); 7.03 - 7.15 (m, 2H); 7.21 - 7.36 (m, 2H); 7.37 - 7.50 (m, 3H).
UPLC-MS (ESI+): [M + H]+ = 554.
Table 16: The following examples 1.2 to 1.19 were prepared in analogy to example 1 .1 and GP 19 starting from respective intermediates K.3 to
K.20.
6-(3-difluoromethoxy-2-fluoro-phenyl)
8-(2-fluoro-6-trifluoromethyl-benzyl)-7 1H-NMR (methanol-d4, 300 MHz): 1 .91 (s, 3H); 3.50 (dd, 1 H); 3.73
methyl-5-oxo-2,3-dihydro-5H- (m, 1 H); 5.73 (m, 1 H); 6.82 (tr, 1 H); 6.90 - 7.50 (m,1 1 H).
thiazolo[3,2-a]pyridine-3-carbothioic UPLC-MS (ESI+): [M + Hf = 640.
acid S-phenyl ester
6-(3-ethoxy-2-fluoro-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7- 1H-NMR (methanol-d4, 300 MHz): 1.40 (m, 3H); 1.98 (m, 3H); 3.56 (m, 1 H); methyl-5-oxo-2,3-dihydro-5H- 3.84 (m, 1 H); 5.81 (m, 1 H); 6.70 - 6.79 (m, 1 H); 7.02 - 7.62 (m, 10H). thiazolo[3,2-a]pyridine-3-carbothioic UPLC-MS (ESI+): [M + H]+ = 618.
acid S-phenyl ester
Example 2.1
Preparation of 3-benzoyl-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-o
I n an adaptation of G P 20a : At room temperature 8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S- phenyl ester (example 1 .1 ) (100 mg) in TH F (5 ml_, degassed with argon prior use) was added to phenyl boronic acid (26.4 mg, 0.22 mmol, 1 .2 eq.), 2-thiophenecarboxylic acid copper(1 +) salt (41.3 mg, 0.22 mmol, 1.2 eq.) and tris-(dibenzylideneacetone)-dipalladium (0) (16.5 mg, 18 μηιοΙ, 0.1 eq.). Then phosphorous acid triethyl ester (12.5 μΙ_, 12.0 mg, 72 μηιοΙ, 0.4 eq.) was added and the reaction mixture was heated under reflux until TLC indicated complete consumption of the starting material. The reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate, the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried with sodium sulfate, filtered and concentrated in vacuum. The target compound was isolated by flash column chromatography (yield: 32.1 mg).
1H-NMR (CDCIs, 400 MHz): 1 .99 (mc, 3H); 3.33 - 3.42 (m, 1 H); 3.78 - 3.92 (m, 6H); 6.45 - 6.57 (m, 1 H); 6.75 - 6.84 (m, 1 H); 6.85 - 6.93 (m, 3H); 7.0 - 7.08 (m, 1 H); 7.16 - 7.25 (m, 1 H); 7.44 - 7.52 (m, 2H); 7.55 - 7.64 (m, 1 H); 7.97 - 8.05 (m, 2H).
UPLC-MS (ESI+): [M + H]+ = 522.
Table 17: The following examples 2.2 to 2.26 were prepared in analogy to example 2.1 and GP 20a starting from respective examples 1 .2 to 1.8 and respective boronic acids.
Example 2.27
Preparation of 3-benzoyl-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)- 7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
In an adaptation of GP 20b: At room temperature and under argon atmosphere tri-n-butyl- phenyl-stannane (335 mg, 0.91 mmol, 1 .1 eq.) was added to a stirred solution of 6-(2-fluoro- 3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thia- zolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester (example 1 .2) (500 mg, 0.83 mmol) in TH F ( 1 2 ml_). Then copper(l)diphenylphosphinate (310 mg, 0.99 mmol, 1 .2 eq.), tri-(2- furyl)phosphine (15.4 mg, 0.066 mmol, 0.080 eq.) and finally tris-(dibenzylideneacetone)- dipalladium (0) (7.6 mg, 0.008 mmol, 0.01 eq.) were added and the reaction mixture was heated to 50°C until LCMS indicated complete consumption of the starting material. The reaction mixture was filtered through a pad of celite® and the filtrate concentrated in vacuum. The target compound was isolated by flash column chromatography (yield: 369 mg).
1H NMR (CDCIs, 400 MHz): 1.95 - 1 .96 (m, 3H); AB-Signal (δΑ = 3.31 , δΒ = 3.79, 2 x 1 H); 3.86 - 3.87 (m, 3H); 4.08 - 4.09 (m, 2H); 6.47 - 6.56 (m, 1 H); 6.79 - 6.86 (m, 1 H); 6.88 - 6.93 (m, 1 H); 7.03 - 7.08 (m, 1 H); 7.23 - 7.25 (m, 1 H); 7.35 - 7.40 (m, 1 H); 7.45 - 7.52 (m, 3H); 7.57 - 7.62 (m, 1 H); 7.99 - 8.03 (m, 2H).
UPLC-MS (ESI+): [M + H]+ = 572.
Table 18: The following examples 2.28 to 2.36 were prepared in analogy to example 2.27 and GP 20b starting from respective examples 1.2 to 1.8 and respective stannanes.
Example 2.37
Preparation of 3-benzoyl-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2,2,7- trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
At 0°C phenyl lithium (0.53 mL, 1 .8 M in Bu20, 413 mg, 0.95 mmol, 1 .2 eq.) was added to a stirred solution of 8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2,2,7-trimethyl-5-oxo- 2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methyl ester (i ntermed iate 1.5) (400 mg, 0.79 mmol) in toluene (7 mL). After 30 minutes at that temperature the reaction mixture was allowed to warm to room tempemperature and stirring was continued for 18 hours. Then after cooling to 0°C phenyl lithium (0.44 mL, 1.8 M in Bu20, 344 mg, 0.79 mmol, 1 .0 eq.) was added. After 3.5 hours at room temp, the reaction was quenched by the addition of saturated aqueous ammonium hydrochloride and ice. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried with sodium sulfate, filtered and concentrated in vacuum. The target compound was isolated by repeated flash column chromatography (yield: 332 mg).
1H-NMR (methanol-d4, 400 MHz): 1 .60 (d, 6H); 1 .93 (d, 3H); 3.75 - 3.91 (m, 5H); 5.16 (d, 1 H); 6.24 - 6.29 (m, 1 H); 6.17 - 6.94 (m, 4H); 6.97 - 7.09 (m, 1 H); 7.13 - 7.24 (m, 1 H); 7.40 - 7.51 (m, 2H); 7.51 - 7.62 (m, 1 H); 7.99 - 8.08 (m, 2H).
MS (HPLC-ESI+): [M + H]+ = 550.
Table 17b (table 17 continued): The following examples 2.38 to 2.46 were prepared in analogy to example 2.1 and GP 20a starting from examples 1.2 and 1.1 1 , respectively, and respective boronic acids.
Table 18b (table 18 continued'): The following examples 2.47 to 2.57 were prepared in analogy to example 2.27 and GP 20b starting from respective examples 1 .3 to 1.19 and respective stannanes.
Example 2.58
Preparation of 3-benzoyl-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one
At -78°C phenylmagnesium bromide (3M in diethylether, 7.5 mL, 4.12 g, 22.7 mmol, 2.0 eq.) wa s a d d e d t o a s t i rre d s o l u t i o n of 6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridine-3-carboxylic acid methyl ester (intermediate 1.26) (6.1 g, 1 1 .4 mmol) in toluene (200 mL). After complete addition the reaction mixture was stirred for 5 hours maintaining the temperature below -70°C. Then the reaction was quenched by the addition of the pre-cooled (-70°C) mixture of methanol and water (20 mL, methanol / water = 9 / 1 ). Water was added and the mixture was allowed to warm to room temperature. Then ethyl acetate was added and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were concentrated in vacuum. The crude product was dissolved in THF and stirred with aqueous sulphuric acid (0.1 M) at room temperature for 2 hours. Then the mixture was partitioned between water and ethyl acetate. After phase separation the aqueous layer was extracted with ethyl acetate and the combined organic layers were concentrated in vacuum. The target compound was isolated by flash column chromatopgraphy (yield: 2.3 g).
1H-NMR (methanol-d4, 400 MHz): 1.25 - 1.34 (m, 6H); 1 .98 (s, 3H); 4.09 (s, 2H); 4.50 - 4.60 (m, 2H); 4.95 (t, 1 H); 6.32 - 6.38 (m, 1 H); 6.73 - 6.79 (m, 1 H); 6.99 - 7.12 (m, 2H); 7.29 - 7.37 (m, 1 H); 7.39 - 7.47 (m, 1 H); 7.49 - 7.58 (m, 3H); 7.63 - 7.70 (m, 1 H); 8.00 - 8.05 (m, 2H).
MS (ESI+): [M + H]+ = 584.
Example 3.1
Preparation of 8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(hydroxyimino-phenyl- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
I n an adaptation of GP 21 b: At room temperature hydroxylamine hydrochloride (417 mg, 6 mmol, 4.8 eq.) was added to a stirred solution of 3-benzoyl-8-(2,6-difluoro-benzyl)-6-(2- fluoro-3-methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (exa m pl e 2.1 ) (650 mg, 1 .24 mmol) in tert-butyl alcohol (20ml_) and toluene (20 mL). Then pyridine (5.5 mL) was added and the reaction mixture was heated to 100°C for 5.5 hours until LCMS indicated complete consumption of the starting material. The reaction mixture was partitioned between ethyl acetate and water, the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried and concentrated in vacuum. The target compound was isolated by flash column chromatography (yield: 603 mg).
1H-N MR (methanol-d4, 300 MHz): 1 .84 (d, 3H); 3.60 - 3.73 (m, 1 H); 3.75 - 3.96 (m, 5H); 3.97 - 4.08 (m, 1 H); 6.00 - 6.10 (m, 0.5H*); 6.40 - 6.50 (m, 1 H); 6.56 - 6.64 (m, 0.5H*); 6.87 - 7.40 (m, 1 1 H).
UPLC-MS (EI+): M+ = 536.
Table 19: The following examples 3.2 to 3.22 were prepared in analogy to example 3.1 and GP 21 b starting from respective examples 2.2 to 2.37 and hydroxylamine hydrochloride.
217
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- 1H-NMR (DMSO-d6, 300 MHz): 1 .76 (m, 3 H); 3.51 -3.61 (m, 1 methoxy-p enyl)-3-[hydroxyimino-(3- H); 3.77 (m, 1 H); 3.90 - 4.06 (m, 1 H); 5.98 - 6.07 (m, 0.55H*);
3.17 trifluoromethyl-phenyl)-methyl]-7- 6.17 - 6.28 (m, 1 H); 6.52 - 6.59 (m, 0.45H*); 6.92 - 7.02 (m, 4 methyl-2,3-dihydro-thiazolo[3,2- H); 7.23 - 7.49 (m, 4 H); 7.59 - 7.72 (m, 1 H).
a]pyridin-5-one UPLC-MS (ESI+): [M + H]+ = 605.
1H-NMR (methanol-d4, 300 MHz): 1.86 (m, 3H); 3.55 - 3.83 (m,
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-
3H); 3.84 - 3.89 (m, 3H); 3.92-4.07 (m, 1 H); 6.27 - 6.34 (m, methoxy-phenyl)-3-[(2-fluoro-phenyl)-
3.18 0.5H*); 6.46 - 6.59 (m, 1 H); 6.61 - 6.68 (m, 0.5H*); 6.81 - 7.39 hydroxyimino-methyl]-7-methyl-2,3-
(m, 9H)
dihydro-thiazolo[3,2-a]pyridin-5-one
F~ UPLC-MS (ESI+): [M + H]+ = 555
3-[(2-chloro-3-fluoro-phenyl)-
1H-NMR (methanol-d4, 300 MHz): 1.88 (m, 3H); 3.56 - 3.74 (m, hydroxyimino-methyl]-8-(2,6-difluoro- 2H); 3.86 - 3.91 (m, 3H); 6.50 - 6.57 (m, 0.4H*); 6.60 - 6.72 (m,
3.19 - benzyl)-6-(2-fluoro-3-methoxy- 1 ,6H*); 6.77 - 6.93 (m, 2H); 6.94 - 7.34 (m, 6H).
I phenyl)-7-methyl-2,3-dihydro- UPLC-MS (ESI+): M+ = 689
thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- 1H-NMR (methanol-d4, 300 MHz): 1.86 (m, 3H); 3.62 - 3.71 (m, methoxy-phenyl)-3-[(3-fluoro-pyridin- 1 H); 3.82 (m, 3H); 3.93 - 4.04 (m, 1 H); 6.31 (m, 0.5H*); 6.46 -
3.20 2-yl)-hydroxyimino-methyl]-7-methyl- 6.64 (m, 1 ,5H*); 6.85 - 7.08 (m, 4H); 7.23 - 7.35 (m, 2H); 7.38 - 2,3-dihydro-thiazolo[3,2-a]pyridin-5- 7.58 (m, 1 H); 8.04 - 8.12 (m, 1 H).
one
Example 3.23
Preparation of 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3- (methoxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
In an adaptation of GP 21 a: At room temperature O-methyl hydroxylamine hydrochloride salt (38 mg, 0.46 mmol, 4.0 eq.) was added to a stirred solution of 3-benzoyl-6-(2-fluoro-3- methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one (example 2.27) (65 mg, 0.1 1 mmol) in tert-butyl alcohol (2 mL) and ethanol (0.5 mL). Then titanium(IV) tert-butylat (170 μί, 0.46 mmol, 4.0 eq.) was added and the reaction mixture was heated to 80°C for 5 hours until TLC indicated complete consumption of the starting material. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried and concentrated in vacuum. The target compound was used in the subsequent reaction without further purification steps (yield: 76 mg).
1H-NMR (CDCIs, 400 MHz): 1 .82 (br. s, 2H*); 1 .92 (d, 1 H*); 3.41 - 3.51 (m, 0.6H*); 3.57 - 3.64 (m, 0.4H*); 3.71 - 4.09 (m, 8H); 6.00 - 6.07 (m, 0.3H*); 6.16 - 6.22 (m, 0.3H*); 6.33 - 6.42 (m, 0.5H*); 6.68 - 6.76 (m, 0.4H*); 6.80 - 7.58 (m, 10H).
UPLC-MS (ESI+): [M + H]+ = 601 .
Table 20: The following examples 3.24 to 3.27 were prepared in analogy to example 3.23 and GP 21a starting from respective examples 2.2 to 2.37 and O-methyl hydroxylamine hydrochloride salt.
223
Example 3.28
Preparation of 3-(allylimino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
In an adaptation of GP 22: At room temperature titanium(IV) isopropoxide (620 μΙ_, 2.1 1 mmol, 1 .0 eq.) was added to a stirred solution of allylamine (474 μΙ_, 6.33 mmol, 3.0 eq.) and 3-benzoyl-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one (example 2.27) (1 .21 g, 2.1 1 mmol) in toluene (12 ml_). The reaction mixture was stirred at room temperature for 2 days and then heated to 40°C for 6 hours until TLC indicated complete consumption of the starting material. The reaction mixture was concentrated in vacuum and the obtained crude target compound was used in the subsequent reaction without further purification steps (yield: 1 .75 g).
Table 19b (table 19 continued): The following examples 3.29 to 3.38 were prepared in analogy to example 3.1 and GP 21 b starting from respective examples 2.38 to 2.57 and hydroxylamine hydrochloride.
Table 20b (table 20 continued'): The following examples 3.39 to 3.53 were prepared in analogy to example 3.23 and GP 21 a starting from respective examples 2.38 to 2.58 and O-methyl hydroxylamine hydrochloride salt.
230
1 H-NMR (methanol-d4, 400 MHz): 1.27- 1.39 (m, 6H); 1.90, 1.92 &
6-(2-fluoro-3-isopropoxy-phenyl)-8
1.94 (3x s, 3H); 3.76 (s, 1.5H*); 3.90 - 4.08 (m, 6.5H*); 4.49 - 4.79 (2-fluoro-6-trifluoromethyl-benzyl)- (m, 4H); 4.89 - 5.00 (m, 1 H); 5.61 - 5.70 (m, 0.5H*); 5.98 - 6.06 (m, 3-(methoxyimino-p enyl-methyl)-7
1H); 6.18-6.27 (m, 0.5H*); 6.64-6.78 (m, 1H); 6.94-7.13 (m, 3H); methyl-2,3-dihydro-oxazolo[3,2-
7.21 -7.60 (m, 10H).
a]pyridin-5-one
UPLC-MS (ESI+): [M + H]+ = 613.
Example 4.1
Preparation of 8-benzyl-7-methyl-5-oxo-6-phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3- carboxylic acid benzylamide
In an adaptation of GP 12: At room temperature 1 H-hydroxybenzotriazole (16.8 mg, 0.1 1 mmol, 1 .2 eq.) and N-ethyl-N',N'-dimethylamino-propylcarbodiimide (21.0 mg, 0.1 1 mmol, 1 .2 eq.) were added to a stirred solution of 8-benzyl-7-methyl-5-oxo-6-phenyl-2,3-dihydro-5H- thiazolo[3,2-a]pyridine-3-carboxylic acid (intermediate K.1 ) (41 .4 mg, 0.1 1 mmol, 1 .2 eq.) in DMF (2 mL). After 1 hour at room temp, a solution of benzyl amine (10 μΙ_, 91 μηιοΙ) in DMF (0.5 mL) was added and stirring was continued upon TLC indicated complete consumption of the starting material. The reaction mixture was poured into ice / aqueous sodium bicarbonate. The target compound was filtered off and dried in vacuum (yield: 40.9 mg).
1H-NMR (DMSO-d6, 400 MHz): 1 .78 (s, 3H); AB-Signal (δΑ = 3.44, δΒ = 3.90, 2 x 1 H); 3.75 (s, 2H); 4.30 (d, 2H); 5.48 - 5.53 (m, 1 H); 7.06 - 7.36 (m, 15H); 8.68 - 8.73 (m, 1 H).
UPLC-MS (ESI+): [M + H]+ = 467.
Table 21 : The following examples 4.2 to 4.8 were prepared in analogy to example 4.1 and GP 12 starting from intermediates K.1 and K.2 and the respective amines.
Example 5.1
Preparation of 8-benzyl-3-(benzylamino-methyl)-7-methyl-6-phenyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
In an adaptation of GP 18: At room temperature sodium trisacetoxyboron hydride (46.7 mg, 0.22 mmol, 2.0 eq.) was added in portions to a stirred solution of 8-benzyl-7-methyl-5-oxo-6- phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carbaldehyde (intermediate N.1 ) (40 mg, 0.1 1 mmol) and benzyl amine (14.5 μΙ_, 14.2 mg, 0.13 mmol, 1 .2 eq) in DCM (3 ml.) and stirred at this temperature upon TLC indicated complete consumption of the starting material. The reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuum. The target compound was isolated by flash column chromatography (yield: 15 mg).
1H-NMR (CDCIs, 400 MHz): 1 .78 (s, 3H); AB-Signal (δΑ = 3.01 , δΒ = 3.20, 2 x 1 H); 3.51 (d, 1 H); 3.59 (m, 1 H); 3.75 - 3.92 (m, 4H); 5.22 - 5.29 (m, 1 H); 7.13 - 7.40 (m, 15H).
UPLC-MS (ESI+): [M + H]+ = 453.
Table 22: The following example 5.2 was prepared in analogy to example 5.1 and GP 18 starting from intermediate N.2 and benzyl amine.
Preparation of 8-benzyl-3-(benzylamino-methyl)-7-methyl-6-phenyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
In an adaptation of GP 16a: At room temperature benzyl amine (7.2 μΙ_, 7.1 mg, 66 μηιοΙ, 2.0 eq.) was added to a stirred solution of toluene-4-sulfonic acid 8-benzyl-7-methyl-5-oxo-6- phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-ylmethyl ester (intermediate M.1 ) in THF (1 .5 ml_). The reaction mixture was warmed up to 50°C until TLC indicated complete consumption of the starting material. The reaction mixture was analyzed by U PLC-MS showing the formation of the target compound which has been synthesized starting from the respective aldehyde as described above.
Table 23: The following examples 5.3 to 5.83 were prepared in analogy to example 5.1 and GP 16a starting from intermediates M.2 to M.8 and respective amines.
No Structure Name Analytical data
8-(2-fluoro-benzyl)-6-(2-fluoro- | 3-methoxy-phenyl)-7-methyl-3- UPLC-MS (ESI+):
5.3 (4-pyridin-4-yl-piperazin-1 - RT = 1.01
ylmethyl)-2,3-dihydro- [M + H]+ = 589.
thiazolo[3,2-a]pyridin-5-one
3-[4-(1-ethyl-propyl)-piperazin- 1 -ylmethyl]-8-(2-fluoro-benzyl)- UPLC-MS (ESI+):
5.4 6-(2-fluoro-3-methoxy-phenyl)- RT = 1.24
7-methyl-2,3-dihydro- [M + H]+ = 568.
o'CH* 8-(2-fluoro-benzyl)-6-(2-fluoro- o F- 3-methoxy-phenyl)-7-methyl-3- UPLC-MS (ESI+):
5.5 (4-methyl-piperazin-1 - RT = 1.14
ylmethyl)-2,3-dihydro- [M + H]+ = 512.
thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro- 3-methoxy-phenyl)-7-methyl-3- UPLC-MS (ESI+):
5.6 f |l (pyridin-4-ylaminomethyl)-2,3- RT = 1 .05
dihydro-thiazolo[3,2-a]pyridin- [M + H]+ = 507.
5-one
8-(2-fluoro-benzyl)-6-(2-fluoro- 3-methoxy-phenyl)-7-methyl-3- UPLC-MS (ESI+):
5.7 (4-phenyl-piperidin-1 - RT = 1 .24
ylmethyl)-2,3-dihydro- [M + H]+ = 574.
t iazolo[3,2-a]pyridin-5-one
3-azetidin-1 -ylmethyl-8-(2- fluoro-benzyl)-6-(2-fluoro-3- U PLC-MS (ESI-):
5.8 methoxy-phenyl)-7-methyl-2,3- RT = 1 .10
dihydro-thiazolo[3,2-a]pyridin- [M + HCOOH -H] = 513.
5-one
8-(2-fluoro-benzyl)-6-(2-fluoro- 3-methoxy-phenyl)-7-methyl-3- UPLC-MS (ESI+):
5.9 Γ [(2-pyridin-4-yl-ethylamino)- RT = 0.99
methyl]-2,3-di ydro- [M + H]+ = 534. thiazolo[3,2-a]pyridin-5-one
240
Table 24: The following examples 5.84 to 5.165 were prepared in analogy to GP 16b starting from intermediate M.3 and respective amines.
Table 25: The following examples 5.166 to 5.271 were prepared in analogy to GP 16b starting from intermediate M.4 and respective amines.
Example 5.272
Preparation of 8-(2,6-difluoro-benzyl)-6-iodo-7-methyl-3-{[methyl-(2-pyridin-2-yl-ethyl)- amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
I n an adaptation of GP 8: At room temperature N-iodosuccinimide (410 mg, 1 .97 mmol, 2.5 eq.) was added to a stirred solution 8-(2,6-difluoro-benzyl)-7-methyl-3-{[methyl-(2-pyridin- 2-yl-ethyl)-amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (intermediate Q.1 ) (331 mg, 0.75 mmol) in acetic acid (3 mL) and TFA (120 μΙ_). After LCMS indicated complete consumption of the starting material the reaction mixture was partitioned between DCM and aqueous sodium thiosulfate, the aqueous layer was extracted with DCM and the combined organic layers were washed with sodium bicarbonate, dried with sod iu m su lfate and concentrated in vacuum. The target compound was isolated by flash column chromatography (yield: 340 mg).
1H-NMR (CDCIs, 300 MHz): 2.36 (s, 3H); 2.39 (s, 3H); 2.50 - 2.58 (m, 1 H); 2.71 - 2.80 (m, 2H); 2.86 - 3.01 (m, 3H); AB-Signal (δΑ = 3.84, δΒ = 3.97, 2 x 1 H); 5.1 1 - 5.21 (m, 1 H); 6.85 - 6.97 (m, 2H); 7.18 - 7.38 (m, 3H); 7.68 - 7.78 (m, 1 H); 8.38 - 8.44 (m, 1 H).
UPLC-MS (ESI+): [M + H]+ = 568.
Example 5.273
Preparation of 6-(3-chloro-phenyl)-8-(2,6-difluoro-benzyl)-7-methyl-3-{[methyl-(2-pyridin-2-yl- ethyl)-amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
(example 5.272) (100 mg, 0.18 mmol) in dioxane (2 ml_). Then argon was bubbled through the reaction mixture for 10 minutes followed by the addition of dichlor(1,1'- bis(diphenylphosphin)ferrocene) palladium dichloromethane complex (16.8 mg, 0.02 mmol, 0.13 eq.). The reaction mixture was heated to 130°C for 60 minutes in a Biotage Initiator microwave oven upon which TLC analysis showed complete turnover. The mixture was filtered through a pad of celite® and washed with DCM. The organic phase was washed with water and dried with sodium sulfate. Evaporation of the solvent and flash column chromatography yielded the target compound (yield: 17 mg).
1H-NMR (methanol-d4, 400 MHz): 1.93 (s, 3H); 2.42 (s, 3H); 2.61 - 2.69 (m, 1 H); 2.77 - 3.01 (m, 4H); 3.42 - 3.51 (m, 1H); AB-Signal (δΑ = 3.81, δΒ = 3.94, 2x 1 H); 5.14-5.22 (m, 1H); 6.89 - 6.97 (m, 2H); 7.02 - 7.06 (m, 1H); 7.13 - 7.16 (m, 1H); 7.20 - 7.39 (m, 6H); 7.68 - 7.76 (m, 1 H); 8.36 - 8.42 (m, 1 H).
MS (CI+): M+ = 552 / 554 (CI isotope pattern).
Table 26: The following example 5.274 was prepared in analogy to example 5.273 and GP 10a starting from example 5.272 and 1 ,3-benzodioxol-5-ylboronic acid.
No Structure Name Analytical data
1H-NMR (methanol-d4, 400 MHz):
1.91 (s, 3H);2.37 (s, 3H); 2.52- benzo[1 ,3]dioxol- 2.60 (m, 1 H); 2.69 - 2.80 (m, 2H);
5-yl-8-(2,6-
2.85-2.98 (m, 3H); 3.37-3.45 difluoro-benzyl)-7- (m, 1 H); AB-Signal (δΑ = 3.77, δΒ = methyl-3-{[methyl- 3.90, 2x 1H); 5.09-5.18 (m, 1H);
5.274 (2-pyridin-2-yl-
5.91 (s, 2H); 6.49-6.55 (m, 1H); ethyl)-amino]-
6.55-6.60 (m, 1H); 6.76-6.83 methyl}-2,3- (m, 1H); 6.85-6.95 (m, 2H); 7.17 dihydro-
-7.36 (m, 3H); 7.66-7.74 (m, thiazolo[3,2- 1H); 8.36-8.42 (m, 1H). a]pyridin-5-one
MS (CI+): [M + H]+ = 562.
Examples 6.1 a & b
Preparation of 3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (diastereomer 1 & 2)
In an adaptation of GP 23a: At 0°C lithium borohydride (1 .79 mL, 2 M solution in THF, 3.58 mmol, 4.8 eq.) was added slowly to a stirred solution of titanium(IV)chloride (196 μΙ_, 1 .79 mmol, 2.4 eq.) in 1 ,2-dimethoxyethane (4 mL). After 10 minutes 8-(2,6-difluoro-benzyl)-6-(2- fluoro-3-methoxy-phenyl)-3-(hydroxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one (400 mg, 0.75 mmol) (example 3.1 ) in 1 ,2-dimethoxyethane (4 mL) was added and stirring was continued at 0°C for one hour. Then the reaction mixture was allowed to warm up to room temperature over 3 hours and stirred until TLC indicated complete consumption of the starting material. After cooling to 0°C the reaction was quenched by the addition of water and aqueous ammonia (33 weight-%). After stirring for 20 minutes the mixture was partitioned between DCM and water, solids were filtered off, the aqueous layer was 3 times extracted with DCM and the combined organic layers were dried over sodium sulfate and concentrated in vacuum. The target compounds were is isolated by flash column chromatography (147 mg & 83 mg).
Diastereomer 1 (example 6.1 a):
1H-NMR (methanol-d4, 300 MHz): 1 .91 (d, 3H); 3.38 - 3.63 (m, 2H); 3.76 - 4.00 (m, 5H); 4.62 (d, 0.5H*); 4.72 (d, 0.5H*); 5.27 - 5.38 (m, 1 H); 6.46 - 6.53 (m, 0.5H*); 6.64 - 6.71 (m, 0.5H*); 6.88 - 7.41 (m, 1 1 H).
UPLC-MS (ESI+): [M + H]+ = 523.
Chiral H PLC (Chiralpak IC 5μηι 150 x 4.6 mm; hexane / ethanol 50 : 50 + 0.1 % diethyl amine; 1.0 mL/min):
enantiomer 1 : RT = 6.20 min & 14.57 min (two peaks due to dynamic atropisomerism) enantiomer 2: RT = 10.66 min & 1 1 .17 min (two peaks due to dynamic atropisomerism) Diastereomer 2 (example 6.1 b):
1H-NMR (methanol-d4, 300 MHz): 2.00 (s, 3H); 3.47 - 3.63 (m, 2H); 3.63 - 3.76 (m, 2H); 3.86 - 3.93 (m, 3H); 4.56 (d, 0.5H*); 4.61 (d, 0.5H*); 5.32 - 5.41 (m, 1 H); 6.69 - 6.76 (m, 0.5H*); 6.80 - 6.92 (m, 2.5H*); 7.01 - 7.33 (m, 9H).
UPLC-MS (ESI+): [M + H]+ = 523.
Chiral H PLC (Chiralpak IC 5μηι 150 x 4.6 mm; hexane / ethanol 50 : 50 + 0.1 % diethyl amine; 1.0 mL/min):
enantiomer 1 : RT = 7.44 min & 8.74 min (two peaks due to dynamic atropisomerism) enantiomer 2: RT = 1 1 .42 min & 13.91 min (two peaks due to dynamic atropisomerism)
Table 27: The following examples 6.2a to 6.23 were prepared in analogy to examples 6.1 a & b and GP 23a starting from respective examples to 3.22.
317
322
Example 6.6b (via highly diastereoselective reduction) and example 6.24
Preparation of 3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (diastereomer 2) and 3-[amino(phenyl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 -oxide
At 0°C lithium borohydride (16.65 mL, 2 M solution in THF, 33.3 mmol, 4 eq.) was added slowly to a stirred solution of titanium(IV)chloride (33.3 mL, 1 M solution in dichloromethane, 33.3 m m ol , 4 eq . ) i n 1 ,2-d imethoxyethane (90 m L). After 1 0 m inutes 6-(2-fluoro-3- methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-[(methoxyimino)(phenyl)methyl]-7- methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one (example 3.23) (5 g, 8.32 mmol) in 1 ,2-dimethoxyethane (70 m L) was added and stirring was continued at 5°C until TLC indicated complete consumption of the starting material. The reaction was quenched by the addition of caesium carbonate (7.5 g) at room temperature. After stirring for 30 minutes water (0.3 mL in portions) was added and stirring is continued for additional 90 minutes. Then the mixture was filtered and the filtrate was evaporated. The residue was partitioned between ethyl acetate and water, the aqueous layer was 3 times extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated in vacuum. 3- (amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (diastereomer 2) was isolated by flash column chromatography (yield: 3.5 g).
Example 6.6b:
1H-NMR (methanol-d4, 400 MHz): 1 .94 (d, 3H); 3.44 - 3.53 (m, 1 H); 3.85 - 3.95 (m, 5H); 4.55 (d, 0.5H*); 4.60 (d, 0.5H*); 5.31 - 5.39 (m, 1 H); 6.71 - 6.76 (m, 0.5H*); 6.82 - 6.88 (m, 0.5H*); 7.07 - 7.51 (m, 10H).
MS (CI+): [M + H]+ = 573.
Chiral HPLC (Chiralpak I B 5μηι 1 50 x 4.6 mm ; hexane / ethanol 80 : 20 + 0.1 % diethyl amine; 1.0 mL/min):
enantiomer 1 : RT = 6.85 min & 7.43 min (two peaks due to dynamic atropisomerism)
enantiomer 2: RT = 9.01 min & 10.33 min (two peaks due to dynamic atropisomerism) Preparative HPLC (Chiralpak I B 5μηι 250 x 30 mm; hexane / ethanol 80 : 20 + 0.1 % diethyl amine; 50.0 mL/min):
enantiomer l : RT = 8.7 - 9.9 min & 9.9 - 10.9 min (two peaks due to dynamic atropisomerism) , optical rotation: [a]D 20 + 298.5° (C = 1 , methanol);
enantiomer 2: RT = 1 1 .7 - 13.8 min & 13.8 min - 16.5 min (two peaks due to dynamic atropisomerism) , optical rotation: [a]D 20 - 229.2° (C = 1 , methanol);
Example 6.24:
3-[Amino(phenyl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]- 7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-o n e 1 -oxide was isolated as side product of the above described separation (yield: 50 mg).
1H-NMR (methanol-d4, 400 MHz): 1 .83 (s, 3H); 3.85 - 3.93 (m, 4H); 4.06 - 4.18 (m, 1 H); 4.27 - 4.48 (m, 2H); 4.61 (d, 0.3H*); 4.67 (d, 0.7H*); 5.53 - 5.60 (m, 1 H); 6.70 - 6.78 (m, 1 H); 7.04 - 7.57 (m, 12H).
MS (ESI+): [M + H]+ = 589.
Example 6.24: (via direct oxidation of Sulfur)
In an adaptation of GP 27c: At room temperature iron (III) chloride (8.3 mg, 0.051 mmol) was added to a stirred solution of 3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-o n e (exa m p l e 6.6b) (250 mg, 0.437 mmol) in acetonitrile (10 mL). After 5 minutes (ortho)periodic acid (1 10 mg, 0.48 mmol) was added and stirring was continued over night. The reaction mixture was partitioned between ethyl acetate and aqueous sodium thiosulfate, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and brine, dried over sodium sulphate and concentrated in vacuum. The target compound was isolated by flash chromatography. Analytical data were identical with the ones described above.
Example 6.25a & b
Preparation of 3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-7-methyl- 2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (diastereomer 1 & 2)
I n an adaptation of G P 8: 3-(Amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (intermediate U.1 ) (557 mg, 1 .24 mmol) was dissolved in acetic acid (14 mL) and trifluoro acetic acid (290 mg, 2.5 mmol, 2 eq.) was added dropwise at room temperature. After 10 min N-iodo-succinimide (670 mg, 3.0 mmol, 2.4 eq.) was added. After 1 hour the mixture was diluted with 30 mL dichloromethane and 20 mL water and sat. aqueous sodium thiosulfate solution was added until the color turned from brown to yellow. After further 10 min of stirring the pH was adjusted to app. pH 8 by the addition of triethylamine, then the phases were separated, extracted with dichloromethane, washed with water and brine and dried with sodium sulfate. Evaporation of the solvents yielded crude 3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-7-methyl- 2,3-dihydro-thiazolo[3,2-a]pyridin-5-one as a mixture of stereoisomers. The diastereomers were separated by flash chromatography (Si02, dichloromethane/isopropanol 0 - 5%) (yield: 524 mg & 190 mg).
Diastereomer 1 (example 6.25a): 1H-NMR (CD3OD, 300 MHz): 2.37 (s, 3H); 3.35 (dd, 1 H), 3.46 (dd, 1 H), 4.1 1 (dd, 2H), 4.71 (br, 1 H), 5.33 (m, 1 H), 7.24 (m, 1 H), 7.32 (m, 3H), 7.38 (m, 2H), 7.48 (m, 1 H), 7.57 (m, 1 H).
MS (ESI+): [M + H]+ = 575.
Diastereomer 2 (example 6.25b): 1H-NMR (CD3OD, 300 MHz): 2.42 (s, 3H); 3.25 (m, 1 H), 3.49 (m, 1 H), 3.95 (dd, 2H), 4.56 (m, 1 H), 5.39 (m, 1 H), 7.15 (m, 2H), 7.20-7.56 (m, 6H). MS (ESI+): [M + H]+ = 575.
Table 28: The following example 6.26 was prepared in analogy to example 6.25 and in adaptation of GP 8 starting from intermediate U.2.
Example 6.6b (via changed order of synthetic steps)
In an adaptation of GP 10a: 3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6- iodo-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (example 6.25b) (155 mg, 270 mmol), 2-fluoro-3-methoxy phenylboronic acid (1 1 6 mg, 683 mmol, 2.5 eq.), dioxane (2.3 ml_), potassium carbonate solution (0.23 ml_, 1 .5 M in water) and (1 ,1 -bis(diphenyl- phosphino)ferrocen)dichlorpalladium(ll)complex with dichloromethane (10 mg, 23 μιτιοΙ, 0.085 eq.) were reacted under microwave irradiation (130°C / 1 00 W) for 20 min . After cooling the mixture was diluted with water, extracted with ethyl acetate, the combined organic layers washed with brine, dried with sodium sulphate and the solvents were evaporated. Chromatographic purification (silicagel, DCM / MeOH 0 - 5%) yielded the desired compound (yield: 97 mg). The product was identical with the material obtained described above.
Table 29: The following examples 6.27 to 6.46 were prepared in analogy to example 6.6b and GP 10a starting from examples 6.25 and 6.26 and respective boronic acids.
Examples 6.47a & b
Preparation of 3-[amino(phenyl)(2H)methyl]-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
(diastereomer 1 & 2)
In an adaptation of GP 23b: At 0°C sodium boron deuteride (thoroughly powdered, 145 mg, 3.46 mmol, 20.6 eq.) was added slowly to a stirred solution of titanium(IV)chloride (191 μΙ_, 1 .74 mmol, 10.4 eq .) in 1 ,2-dimethoxyethane (1 .8 ml_). After 1 0 minutes 8-(2,6-difluoro- benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(hydroxyimino-phenyl-methyl)-7-methyl-2,3-dihydro- thiazolo[3,2-a]pyridin-5-one (90 mg, 0.17 mmol) (example 3.1 ) in 1 ,2-dimethoxyethane (2 ml.) was added and stirring was continued at 0°C for two hours. Then the reaction mixture was allowed to warm up to room temperature and stirred until TLC indicated complete consumption of the starting material. After cooling to 0°C the reaction was quenched by the addition of water and aqueous ammonia (33 weight-%). After stirring for 20 minutes the mixture was partitioned between DCM and water, solids were filtered off, the aqueous layer was 3 times extracted with DCM and the combined organic layers were dried over sodium sulfate and concentrated in vacuum. The target compounds were isolated by flash column chromatography (yield: 12 mg & 16 mg).
Diastereomer 1 (example 6.47a):
1H-NMR (methanol-d4, 300 MHz): 1 .91 (d, 3H); 3.38 - 3.63 (m, 2H); 3.75 - 3.99 (m, 5H); 5.27 - 5.38 (m, 1 H); 6.47 - 6.54 (m, 0.5H*); 6.64 - 6.71 (m, 0.5H*); 6.86 - 7.50 (m, 1 1 H). MS (CI+): [M + H]+ = 524.
Diastereomer 2 (example 6.47b):
1H-NMR (methanol-d4, 300 MHz): 2.00 (s, 3H); 3.38 (dd, 1 H); 3.49 - 3.59 (m, 1 H); 3.64 - 3.77 (m, 2H); 3.89 (d, 3H); 5.33 - 5.41 (m, 1 H); 6.69 - 6.76 (m, 0.5H*); 6.79 - 6.92 (m, 2.5H*); 7.05 - 7.30 (m, 9H).
MS (CI+): [M + H]+ = 524.
Table 30: The following examples 6.48 a & b were prepared in analogy to examples 6.47 a & b and GP 23b starting from example 3.10.
Example 6.49
Preparation of 3-(1 -amino-1 -phenyl-ethyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
1H-NMR (methanol-d4, 300MHz): 1 .53 (s, 3H); 1 .91 - 1 .94 (m, 3H); 3.08 (dd, 1 H); 3.56 (dt, 1 H); 3.89 - 3.91 (m, 3H); 4.04 (br. s, 2H); 5.64 - 5.70 (m, 1 H); 6.70 - 6.75 (m, 0.5H*); 6.80 (ddd, 0.5H*); 7.07 - 7.19 (m, 2H); 7.22 - 7.27 (m, 1 H); 7.31 - 7.39 (m, 3H); 7.45 - 7.52 (m, 3H); 7.56 - 7.59 (m, 1 H).
UPLC-MS (ESI+): [M + H]+ = 587.
Example 6.50
Preparation of 3-(1 -amino-1 -phenyl-but-3-enyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
At room temperature palladium (21 mg, 20 μηηοΙ, 0.10 eq, 10% on charcoal) was added to a solution of 3-(1 -allylamino-1 -phenyl-but-3-enyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (130 mg, 198 μηηοΙ) (example 7.21 , see page 218) in ethanol (2.5 mL). The reaction mixture was heated to reflux for 4 hours and stirring continued at room temperature for 18 hours. Another amount of palladium (168 mg, 160 μηηοΙ, 0.80 eq, 10% on charcoal) was gradually added while heating the reaction mixture to reflux for another 5 hours. The catalyst was filtered off and the filtrate
concentrated in vacuum. The residue was purified by flash column chromatography to give the target compound (yield: 47 mg).
1H-NMR (methanol-d4, 600MHz): 1 .91 - 1 .93 (m, 3H); 2.43 - 2.49 (m, 1 H); 3.06 - 3.1 1 (m, 2H); 3.47 - 3.54 (m, 1 H); 3.89 - 3.90 (m, 3H); 4.04 (br. s, 2H); 4.92 - 4.95 (m, 1 H); 5.00 (d, 1 H); 5.29 - 5.39 (m, 1 H); 5.71 (dd, 1 H); 6.70 - 6.73 (m, 0.5H*); 6.80 - 6.83 (m, 0.5H*); 7.09 - 7.18 (m, 2H); 7.24 - 7.26 (m, 1 H); 7.32 - 7.36 (m, 3H); 7.46 - 7.52 (m, 3H); 7.56 (d, 1 H).
UPLC-MS (ESI+): [M + H]+ = 613. Example 6.51 b
Preparation of 3-(amino-phenyl-methyl)-6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
In an adaptation of GP 10a: 3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6- iodo-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (example 6.25b) (464 mg, 0.81 mmol), [3-(1 ,1 -difluoroethyl)phenyl]boronic acid (intermediate V.1 ) (380 mg, 2.04 mmol, 2.53 eq.), dioxane (7 ml_), potassium carbonate solution (0.6 ml_, 1 .5 M in water) and (1 ,1 -bis(diphenyl- phosphino)ferrocen)dichlorpalladium(ll)complex with dichloromethane (1 12.1 mg, 137 μιτιοΙ, 0.17 eq.) were degassed with argon for 10 min and reacted under microwave irradiation (130°C / 200 W) for 20 m i n . After cooling of the reaction mixture the solvents were evaporated. Repeated flash chromatography followed by HPLC purification yielded the target compound (yield: 200 mg).
1H-NMR (methanol-d4, 300 MHz): 1 .85 - 2.01 (m, 6H); 3.42 - 3.49 (m, 1 H); 3.93 (br. s, 2H); 4.55 (d, 1 H); 5.31 - 5.39 (m, 1 H); 7.17 - 7.56 (m, 12H).
MS (ESI+): [M + H]+ = 589
Table 27b (table 27 continued): The following examples 6.52a to 6.73b were prepared in analogy to examples 6.1a & b and GP 23a starting from respective examples 3.29 to 3.53.
nH-NMR (methanol-d4, 600 MHz): 1.32 - 1.41 (m, 6H); 1.93 (s, 3H); 3.64 - 3.79 (m, 2H); 4.38 - 4.47 (m, 1 H); 4.57 - 4.68 (m, 1 H); 4.73 - 4.82 (m, 2H); 4.99 - 5.05 (m, 1 H); 6.72 - 6.78 (m, 0.5H*); 6.82 - 6.87
3-(amino-phenyl-methyl)-6-(2- (m, 0.5H*); 7.07 - 7.26 (m, 8H); 7.31 - 7.39 (m, 1 H); 7.39 - 7.44 fluoro-3-isopropoxy-phenyl)-8 (m, 1 H).
(2-fluoro-6-trifluoromethyl- UPLC-MS (ESI+): [M + H]+ = 585.
benzyl)-7-methyl-2,3-dihydro- Chiral HPLC (Chiralpak IC 5μιη 150x4.6 mm, hexane / ethanol 80:20 oxazolo[3,2-a]pyridin-5-one + 0.1% diethyl amine; 1.0 mL/min):
(diastereomer 2) enantiomer 1 : RT = 5.95 min & 7.60 min (two peaks due to dynamic atropisomerism)
enantiomer 2: RT = 10.50 min & 15.13 min (two peaks due to dynamic atropisomerism)
Table 28b (table 28 continued): The following examples 6.74a & 6.74b were prepared in analogy to example 6.25 and in adaptation of GP 8 starting from intermediates U.3a and U.3b, respectively.
Table 29b (table 29 continued): The following examples 6.51 b to 6.90b were prepared in analogy to example 6.6b and GP 10a starting from examples 6.25a&b, 6.26 and 6.74a&b and respective boronic acids.
362
3-(amino-p enyl-methyl)-6-[3
(1 ,1-difluoro-ethyl)-phenyl]-8-
1H-NMR (methanol-d4, 400 MHz): 1.57 (s, 3H); 1.80 (s, 3H); 1.86 - (2-fluoro-6-trifluoromethyl- 2.05 (m, 6H); 3.84 (s, 2H); 5.06 (s, 1 H); 5.14 (s, 1 H); 7.17 -7.61 (m, benzyl)-2,2,7-trimethyl-2,3-
1 1 H).
dihydro-thiazolo[3,2-a]pyridin-
UPLC-MS (ESI+): [M + H]+ = 617.
5-one
(diastereomer 2)
Example 7.1 a
Preparation of 4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester (diastereomer 1 )
In an adaptation of GP 25a: At room temperature N-ethyl diisopropyl amine (24 μΙ_, 18 mg, 140 μηιοΙ, 1 eq.) was added to a stirred solution of ethyl 4-bromobutanoate (60 μΙ_, 82 mg, 41 9 μηιοΙ , 3 eq .) and 3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-o n e (d i a ste reom e r 1 ) (example 6.6a) (80 mg, 140 μηιοΙ) in acetonitrile (2 mL). The reaction mixture was heated to 80°C for 20 hours. Then a second portion of N-ethyl diisopropyl amine (24 μΙ_, 18 mg, 140 μηιοΙ, 1 eq.) and ethyl 4-bromobutanoate (60 μΙ_, 82 mg, 419 μηιοΙ, 3 eq.) were added and stirring was continued for 7 hours. Evaporation of the solvent and flash chromatography yielded the target compound (yield: 46,5 mg).
1H-NMR (methanol-d4, 400 MHz): 1.18 (dt, 3H); 1 .59 - 1 .69 (m, 2H); 1 .88 & 1 .91 (2 x s, 3H); 1 .95 (mc, 1 H); 2.02 - 2.14 (m, 1 H); 2.20 - 2.32 (m, 3H); 2.52 - 2.61 (m, 1 H); 3.33 - 3.46 (m, 2H); 3.83 - 3.92 (m, 4H); 3.99 - 4.16 (m, 5H); 4.38 (d, 0.5H*); 4.51 (d, 0.5H*); 5.21 - 5.31 (m, 1 H); 6.50 - 6.56 (m, 0.5H*); 6.67 - 6.73 (m, 0.5H*); 7.01 - 7.61 (m, 1 1 H).
MS (ESI+): [M + H]+ = 687.
Table 31 : The following examples 7.1 b to 7.7 were prepared in analogy to example 7.1 a and GP 25a starting from respective examples 6.6b to 6.50 and the respective ω-bromo carboxylic acid ethyl esters.
Example 7.8b
Preparation of 4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid (diastereomer 2)
At room temperature a solution of sodium hydroxide (32 μΙ_ of an 32% aq. sol, 33.7 mg, 843 μηιοΙ, 2 eq.) in water (30 μΙ_) was added to a stirred solution of 4-({[6-(2-fluoro-3-methoxy- phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2- a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester (diastereomer 2) (example 7.1 b) (289 mg, 421 μηιοΙ) in THF (6 ml.) and stirred at 45°C for 3 hours. Then sodium hydroxide (32 μΙ_ of an 32% aq. sol, 33.7 mg, 843 μηιοΙ, 2 eq.) in water (30 μΙ_) was added again and stirring at room temp, was continued for 48 hours. pH was adjusted to pH 5-6 by the addition of 10% aq. citric acid and the mixture was partitioned between ethyl acetate and water. The aqueous layer was 3 times extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated in vacuum. The target compound was isolated by flash column chromatography (yield: 215 mg).
1H-NMR (methanol-d4, 300 MHz): 1.66 - 1.82 (m, 2H); 1.94 (d, 3H); 2.26 - 2.40 (m, 2H); 2.59 - 2.82 (m, 2H); 3.20 (d, 0.5H*); 3.35 (d, 0.5H*); 3.49 - 3.58 (m, 1 H); 3.84 - 3.97 (m, 5H); 4.45 (d, 0.5H*); 4.53 (d, 0.5H*); 5.50 - 5.57 (m, 1 H); 6.70 - 6.76 (m, 0.5H*); 6.85 - 6.91 (m, 0.5H*); 7.07 - 7.35 (m, 8H); 7.38 - 7.55 (m, 2H).
MS (ESI+): [M + H]+ = 659.
enantiomer 1 : optical rotation: [a]D 20 + 204.5° (C = 1 , methanol).
Table 32: The following examples 7.8a to 7.14 were prepared in analogy to example 7.8b starting from examples 7.1a to 7.7.
370
4-({[8-(2-fluoro-6-trifluoromethyl-
1H-NMR (methanol-d4, 300 MHz): 1 .66 - 1.78 (m, 2H); 1.95 (s, 3H); benzyl)-7-methyl-5-oxo-6-(3- 2.19 (t, 2H); 2.52 (t, 2H); 3.32 (br. s, 1 H); 3.42 - 3.52 (m, 1 H); 3.91 (br. trifluoromethoxy-phenyl)-2,3- s, 2H); 4.37 (d, 1 H); 5.41 - 5.49 (m, 1 H); 7.1 1 - 7.33 (m, 9H); 7.37 - dihydro-5H-thiazolo[3,2-a]pyridin-
7.57 (m, 3H).
3-yl]-phenyl-methyl}-amino)- MS (ESI+): [M + H]+ = 695.
butyric acid
Example 7.15
Preparation of sodium 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]
-7-methyl-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
At room temperature sodium hydroxide (32% aq. solution, 61 .6 μηιοΙ, 1 .0 eq.) was added to a stirred solution of 4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid (diastereomer 2) (example 7.8b) (40.6 mg, 61.6 μηιοΙ) in tert butyl alcohol (0.5 mL) and water (0,5 mL). Lyophilization yielded the target compound (yield: 34.7 mg).
1H-NMR (methanol-d4, 400 MHz): 1 .65 - 1 .83 (m, 2H); 1 .91 (br. s, 3H); 2.07 - 2.19 (m, 2H); 2.41 - 2.57 (m, 2H); 3.35 - 3.55 (m, 2H); 3.79 - 3.95 (m, 5H); 4.32 (d, 0.5H*); 4.42 (d, 0.5H*); 5.39 - 5.48 (m, 1 H); 6.68 - 6.77 (m, 0.5H*); 6.83 - 6.91 (m, 0.5H*); 7.05 - 7.33 (m, 8H); 7.34 - 7.52 (m, 2H).
enantiomer 1 : optical rotation: [a]D 20 + 198.2° (C = 1 , methanol).
Example 7.16 & 7.17
Preparation of 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3- (methylamino-phenyl-methyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one and
3-(dimethylamino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
In an adaptation of GP 25a: At room temperature DIPEA (44 mg, 348 μηιοΙ, 2 eq.) was added to a stirred solution of methyliodide (40 mg, 283 μηιοΙ, 1.62 eq.) and 3-(amino-phenyl- methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one (diastereomer 2) (example 6.6b) (100 mg, 174 μηιοΙ) in acetonitrile (3 mL). The reaction mixture was heated to 50°C for 4 hours. Evaporation of the solvent and flash chromatography yielded the target compounds.
Example 7.16: 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl- 3-(methylamino-phenyl-methyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
1H-NMR (methanol-d4, 300MHz): 1 .93 (m, 3H); 2.28 (d, 3H); 3.89 (m, 3H); 4.23 - 4.30 (m, 1 H); 5.41 - 5.49 (m, 1 H); 6.70 - 6.77 (m, 0.5H*); 6.81 - 6.90 (m, 0.5H*); 7.06 - 7.53 (m, 1 1 H).
UPLC-MS (ESI+): [M + H]+ = 587.
Example 7.17: 3-(dimethylamino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
1H-NMR (methanol-d4, 300MHz): 1 .87 (m, 3H); 2.25 (d, 6H); 3.89 (m, 3H); 5.67 - 5.77 (m, 1 H); 6.67 - 6.74 (m, 0.5H*); 6.78 - 6.85 (m, 0.5H*); 7.06 - 7.49 (m, 1 1 H).
UPLC-MS (ESI+): [M + H]+ = 601 .
Table 33: The following examples 7.18 & 7.19 were prepared in analogy to example 7.16 and GP 25a starting from example 6.6b and the respective alkyl bromides.
5-one MS (ESI+): [M + H]+ = 683.
Example 7.20
P reparation of 3-(allylamino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
1H-NMR (methanol-d4, 600MHz): 1 .96 (s, 3H); 2.98 - 3.06 (m, 1 H); 3.10 - 3.16 (m, 1 H); 3.25 - 3.34 (m, 1 H); 3.48 (td, 1 H); 3.91 - 3.96 (m, 5H); 4.33 - 4.40 (m, 1 H); 5.02 - 5.05 (m, 1 H); 5.08 (ddd, 1 H); 5.45 (t, 1 H); 5.78 - 5.86 (m, 1 H); 6.74 - 6.76 (m, 0.55H*); 6.83 - 6.85 (m, 0.45H*); 7.1 1 - 7.31 (m, 8H); 7.42 - 7.47 (m, 1 H); 7.50 - 7.53 (m, 1 H).
UPLC-MS (ESI+): [M + H]+ = 613.
Example 7.21
Preparation of 3-(1 -allylamino-1 -phenyl-but-3-enyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro- 6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
In an adaptation of GP 24b: At 0°C a solution of allylmagnesium chloride (164 μΙ_, 2 M solution in TH F, 0.33 mmol, 4.0 eq .) was added slowly to a stirred solution of crude 3- (allylimino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)- 7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (example 3.28) (50 mg, 82 μηιοΙ) in toluene (0.5 ml_). Stirring was continued at 0°C for 20 min and at room temperature for 2.5 hours upon which the reaction mixture was cooled again to 0°C. Another amount of allylmagnesium chloride (164 μΙ_, 2 M solution in TH F, 0.33 mmol, 4.0 eq.) was added and the reaction quenched by the addition of water. The aqueous layer was extracted with ethyl acetate and
the combined organic layers were washed with brine, dried and concentrated in vacuum. The target compound was isolated by flash column chromatography (yield: 29 mg).
1H-N MR (methanol-d4, 300 MHz): 1 .96 (s, 3H); 2.60 - 2.68 (m, 1 H); 2.74 - 2.81 (m, 1 H); 2.97 - 3.21 (m, 3H); 3.48 - 3.59 (m, 1 H); 3.76 - 3.93 (m, 5H); 4.90 - 5.02 (m, 1 H); 5.12 - 5.35 (m, 3H); 5.65 - 5.70 (m, 1 H); 5.73 - 5.87 (m, 1 H); 5.96 - 6.08 (m, 1 H); 6.67 - 6.73 (m, 0.4H*); 6.90 (ddd, 0.6H*); 7.08 - 7.21 (m, 5H); 7.28 - 7.34 (m, 1 H); 7.39 - 7.50 (m, 4H). UPLC-MS (ESI+): [M + H]+ = 653.
Example 7.22
Preparation of 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3- (2-phenyl-1 ,2,3,6-tetrahydro-pyridin-2-yl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
1H-NMR (methanol-d4, 300MHz): 1 .98 - 2.00 (m, 3H); 2.88 - 2.99 (m, 1 H); 3.33 - 3.53 (m, 2H); 3.54 - 3.71 (m, 2H); 3.75 - 3.96 (m, 7H); 5.57 - 5.61 (m, 2H); 5.95 - 6.05 (m, 1 H); 6.74 - 6.79 (m, 0.5H*); 6.99 (ddd, 0.5H*); 7.16 - 7.36 (m, 7H); 7.38 - 7.46 (m, 2H); 7.48 - 7.51 (m, 1 H).
UPLC-MS (ESI+): [M + H]+ = 625.
Example 7.23
Preparation of N-{[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-acetamide
In an adaptation of GP 25a: At room temperature DIPEA (22 mg, 174 μηιοΙ, 1 eq.) was added to a stirred solution of acetylchloride (15.3 mg, 195 μηιοΙ, 1 .12 eq .) and 3-(amino- phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl- 2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (diastereomer 2) (example 6.6b) (100 mg, 174 μηιοΙ) in acetonitrile (3 mL). The reaction mixture was stirred at room temperature for 4 hours.
Evaporation of the solvent and flash chromatography yielded the target compound .
1H-NMR (methanol-d4, 300MHz): 1 .84 (m, 3H); 1 .93 (m, 3H); 3.89 (m, 3H); 5.46 - 5.61 (m,
2H); 6.67 - 6.80 (m, 1 H); 7.07 - 7.21 (m, 2H); 7.29 - 7.60 (m, 8H).
UPLC-MS (ESI+): [M + H]+ = 615.
Example 7.24 & 7.25
Preparation of 3-bromo-2,2-difluoro-N-{[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methylj-propionamide and
2,2-difluoro-3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl- 5-0X0-2, 3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-propionic acid ethyl ester
1H-NMR (methanol-d4, 300 MHz): 1.95 (s, 3H); 2.92 - 3.02 (m, 1 H); 3.47 - 3.60 (m, 1 H); 3.61 - 3.81 (m, 2H); 3.85 - 3.93 (m, 3H); 4.06 - 4.18 (m, 2H); 5.31 - 5.41 (m, 1 H); 5.57 - 5.70 (m, 1 H); 6.69 - 6.77 (m, 0.3H*); 6.83 - 6.91 (m, 0.7H*); 7.07 - 7.21 (m, 2H); 7.28 - 7.62 (m, 8H). MS (ESI+): [M + H]+ = 745. bromine isotope pattern
Example 7.25: 2,2-difluoro-3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- propionic acid ethyl ester (diastereomer 2)
UPLC-MS (ESI+): RT = 1 .64 min, [M + H]+ = 709.
Example 7.26 & 7.27
Preparation of 2,2-difluoro-3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- propionic acid and
3-[(3,3-difluoro-2-oxo-azetidin-1 -y l)-phenyl-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
At room temp, sodium hydride (60% in mineral oil, 30.7 mg, 769 μηιοΙ, 4.0 eq.) was added portionwise to a stirred solution of 3-bromo-2,2-difluoro-N-{[6-(2-fluoro-3-methoxy-phenyl)-8- (2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]- phenyl-methyl}-propionamide (example 7.24) (143 mg, 192 μηιοΙ) in DCM (1 .2 ml.) and DMF (150 μΙ_). After 22 hours at that temperature the solvents were evaporated and the residue was partitioned between ethyl acetate and saturated aq. ammonium chloride solution. After phase separation the aqueous layer was extracted with ethyl acetate and the combined organic layers were dried and concentrated in vacuum. The target compounds were isolated by flash column chromatography (yield: 109 mg & 8 mg).
Example 7.26: 2,2-difluoro-3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- propionic acid
1H-NMR (methanol-d4, 400MHz): 1 .92 (d, 3H); 2.85 - 3.14 (m, 2H); 3.33 - 3.53 (m, 2H); 3.76 - 3.93 (m, 5H); 4.45 (d, 0.5H*); 4.53 (d, 0.5H*); 5.40 - 5.47 (m, 1 H); 6.70 - 6.76 (m, 0.5H*); 6.86 - 6.93 (m, 0.5H*); 7.07 - 7.28 (m, 8H); 7.33 - 7.49 (m, 2H).
UPLC-MS (ESI+): [M + H]+ = 681 .
Example 7.27: 3-[(3,3-difluoro-2-oxo-azetidin-1 -y l)-phenyl-methyl]-6-(2-fluoro-3-methoxy- phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 1H-NMR (methanol-d4, 400MHz): 1 .90 - 1 .93 (m, 3H); 2.82 (d, 0.7H*); 3.01 (d, 0.3H*); 3.57 - 3.66 (m, 1 H); 3.83 - 3.92 (m, 4H); 4.00 - 4.16 (m, 3H); 5.44 (d, 0.3H*); 5.49 (d, 0.7H*); 5.80 - 5.88 (m, 1 H); 6.68 - 6.79 (m, 1 H); 7.04 - 7.15 (m, 2H); 7.25 - 7.59 (m, 9H).
UPLC-MS (ESI+): [M + H]+ = 663.
Example 7.28
Preparation of 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-[(3- hydroxy-propylamino)-phenyl-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
In an adaptation of GP 25a: At room temperature DIPEA (45 μΙ_, 34 mg, 266 μηιοΙ, 1 eq.) was added to a stirred solution of 3-bromo-propan-1 -ol (85 μΙ_, 131 mg, 798 μηιοΙ, 3 eq.) and 3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)- 7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (diastereomer 2) (example 6.6b) (152 mg, 266 μηιοΙ) in acetonitrile (3 mL). The reaction mixture was heated to 80°C for 12 hours and stirring continued at room temperature for two days. Evaporation of the solvent and flash chromatography yielded the target compound (yield: 148 mg).
1H-NMR (methanol-d4, 300MHz): 1 .68 - 1 .76 (m, 2H); 1 .97 (mc, 3H); 2.67 - 2.74 (m, 2H); 3.20 - 3.27 (m, 1 H); 3.50 - 3.63 (m, 3H); 3.91 - 4.01 (m, 5H); 4.49 - 4.54 (m, 1 H); 5.53 - 5.59 (m, 1 H); 6.73 - 6.78 (m, 0.5H*); 6.90 (ddd, 0.5H*); 7.10 - 7.21 (m, 3H); 7.27 - 7.38 (m, 5H); 7.41 - 7.56 (m, 2H).
UPLC-MS (ESI+): [M + H]+ = 631 . Example 7.29
Preparation of 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-[(4- hydroxy-butylamino)-phenyl-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
1H-NMR (methanol-d4, 400MHz): 1 .42 - 1 .54 (m, 4H); 1 .85 - 1 .94 (m, 3H); 2.32 - 2.57 (m, 2H); 3.43 - 3.55 (m, 4H); 3.83 - 3.91 (m, 3H); 3.98 - 4.13 (m, 2H); 4.38 (d, 0.6H*); 4.59 (s, 1 H); 5.25 - 5.31 (m, 1 H); 6.46 - 6.54 (m, 0.7H*); 6.67 - 6.74 (m, 0.3H*); 7.01 - 7.16 (m, 2H); 7.21 - 7.39 (m, 6H); 7.45 - 7.60 (m, 2H).
UPLC-MS (ESI+): [M + H]+ = 645.
Table 34: The following example 7.30 was prepared in analogy to example 7.29 starting from example 7.25.
Example 7.31
Preparation of 4-({[6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
In an adaptation of GP 25a: At room temperature N-ethyl diisopropyl amine (174 μΙ_, 131 mg, 1 .02 mmol, 3 eq.) was added to a stirred solution of ethyl 4-bromobutanoate (49 μΙ_, 66 mg, 340 μηιοΙ, 1 eq.) and 3-(amino-phenyl-methyl)-6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (example 6.51 ) (200 mg, 340 μηιοΙ) in acetonitrile (5 mL). The reaction mixture was heated to 80°C over night. Evaporation of the solvent and flash chromatography yielded the target compound (yield: 38 mg).
1H-NMR (methanol-d4, 400 MHz): 1.16 (t, 3H); 1 .60 - 1.74 (m, 2H); 1.87 - 2.00 (m, 6H); 2.28 (t, 2H); 2.33 - 2.49 (m, 2H); 3.18 (d, 1 H); 3.40 - 3.48 (m, 1 H); 3.90 - 4.08 (m, 4H); 4.20 (d, 1 H); 5.37 - 5.44 (m, 1 H); 7.19 - 7.56 (m, 12H).
MS (ESI+): [M + H]+ = 703.
Example 7.32
Preparation of 4-({[6-[3-(1 , 1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
At room temperature a solution of sodium hydroxide (210 μΙ_ of an 32% aq. sol, 284 mg, 2.28 mmol, 10 eq.) was added to a stirred solution of 4-({[6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]- phenyl-methyl}-amino)-butyric acid ethyl ester (example 7.31 ) (160 mg, 228 μηιοΙ) in ethanol (5 ml.) and stirred at room temperature over night. pH was adjusted to pH 7 by the addition of aqueous hydrochloric acid (2N) and the mixture was partitioned between ethyl acetate and water. The aqueous layer was 3 times extracted with ethyl acetate and the combined organic layers were washed with brine, dried and concentrated in vacuum. The target compound was isolated by HPLC chromatography (yield: 32 mg).
1H-NMR (methanol-d4, 300 MHz): 1 .62 - 1 .81 (m, 2H); 1 .84 - 2.03 (m, 6H); 2.26 - 2.36 (m, 2H); 2.58 - 2.68 (m, 2H); 3.19 (d, 1 H); 3.46 - 3.57 (m, 1 H); 3.88 - 4.02 (m, 2H); 4.44 (d, 1 H); 5.48 - 5.56 (m, 1 H); 7.22 - 7.57 (m, 12H).
MS (ESI+): [M + H]+ = 675.
Table 31 b (table 31 continued'): The following examples 7.33 to 7.73 were prepared in analogy to example 7.1 a and GP 25a starting from respective examples 6.1 to 6.90 and the respective ω-bromo/halo carboxylic acid esters and derivatives thereof.
Table 32b (table 32 continued'): The following examples 7.74 to 7.102 were prepared in analogy to example 7.8b starting from examples 7.33 to 7.73.
406
Example 7.103
Preparation of 4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyramide
At room temperature potassium hydroxid (4.6 mg. 82 μηιοΙ, 1 .5 eq.) was added to a stirred solution of 4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl- 5-0X0-2, 3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyronitrile
(example 7.38) (35 mg, 54 μηιοΙ) in ethanol (0.63 ml_). The reaction was stirred at room temp, for 3 days and at 40°C 7 days. Then the reaction mixture was partitioned between water and ethyl acetate and neutralized with citric acid (10% aq. solution). After phase separation the aqueous layer was extracted with ethyl acetate and the combined organic layers were concentrated in vacuum. The target compound was isolated by HPLC-chromatopgraphy (yield: 8 mg).
1H-N MR (methanol-d4, 400 MHz): 1.66 - 1 .81 (m, 2H); 1 .94 (d, 3H); 2.16 - 2.22 (m, 1 H); 2.27 - 2.37 (m, 1 H); 2.42 - 2.55 (m, 1 H); 2.59 - 2.82 (m, 2H); 3.21 (d, 0.5H*); 3.36 (d, 0.5H*); 3.45 - 3.58 (m, 1 H); 3.83 - 3.99 (m, 5H); 4.29 - 4.54 (m, 1 H); 5.40 - 5.56 (m, 1 H); 6.70 - 6.77 (m, 0.5H*); 6.81 - 6.91 (m, 0.5H*); 7.06 - 7.34 (m, 8H); 7.37 - 7.53 (m, 2H).
MS (ESI+): [M + H]+ = 659.
Example 7.104
Preparation of 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3- {phenyl-[3-(1 H-tetrazol-5-yl)-propylamino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
At room temperature trimethylsilyl azide (1 10 μΙ_, 96.5 mg, 820 μηιοΙ, 15 eq.) and dibutyltin (IV) oxide (20.8 mg, 82 μηιοΙ, 1 .5 eq.) were added to a stirred solution of 4-({[6-(2-fluoro-3- methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyronitrile (example 7.38) (35 mg, 54 μηιοΙ) in toluene (2 mL). The reaction was stirred at 80°C over night. Then the reaction mixture was partitioned between water and ethyl acetate. After phase separation the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium bicarbonat solution and concentrated in vacuum. The target compound was isolated by HPLC-chromatopgraphy (yield: 12 mg).
1H-NMR (methanol-d4, 300 MHz): 1 .85 - 2.03 (m, 5H); 2.63 - 2.77 (m, 2H); 2.86 - 2.99 (m, 2H); 3.12 - 3.24 (m, 1 H); 3.49 - 3.61 (m, 1 H); 3.89 (s, 3H); 3.91 - 4.04 (m, 2H); 4.52 (d, 1 H); 5.51 - 5.62 (m, 1 H); 6.70 - 6.83 (m, 1 H); 7.06 - 7.21 (m, 2H); 7.22 - 7.38 (m, 6H); 7.39 - 7.56 (m, 2H).
MS (ESI+): [M + H]+ = 683.
Table 37: The following examples 7.105 and 7.106 were prepared in analogy to example 7.104 starting from examples 8.10 and 7.39.
Example 7.107
Preparation of 2-amino-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
At room temperature a solution of hydrochloric acid (4M in dioxane, 1 14 μΙ_, 0.46 mmol, 2 eq. ) was add ed to a sti rred sol ution of 2-tert-butoxycarbonylamino-4-({[6-(2-fluoro-3- methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid tert-butyl ester (example 7.37) (1 90 mg, 0.23 mmol) in dioxane (5 m l_). The reaction was stirred ant 40°C over night. Evaporation of the solvent and HPLC-chromatographie yielded the target compound (yield: 34 mg).
1H-N MR (methanol-d4, 400 MHz): 1.78 - 1 .92 (m, 2H); 1 .95 (d, 3H); 1 .96 - 2.08 (m, 1 H); 2.64 - 2.79 (m, 2H); 3.17 - 3.27 (m, 1 H); 3.44 - 3.62 (m, 2H); 3.86 - 4.00 (m, 5H); 4.32 - 4.40 (m, 1 H); 5.42 - 5.49 (m, 1 H); 6.71 - 6.78 (m, 0.5H*); 6.83 - 6.91 (m, 0.5H*); 7.09 - 7.33 (m, 8H); 7.38 - 7.52 (m, 2H).
MS (ESI+): [M + H]+ = 674.
Example 7.108
Preparation of 3-[(2-amino-ethylamino)-phenyl-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
To a solution of 2-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-ethyl]- isoindole-1 ,3-dione (example 7.69) (181 mg, 0.24 mmol) in methanol (5 ml) at room temperature was added a 1 M solution of hydrazine hydrate in THF (1 .24 ml , 1 .2 mmol) and stirred overnight. The mixture was evaporated, triturated with dichloromethane and filtered off. To the filtrate added water and the pH was adjusted to pH14 while stirring. The organic layer was eva porated to yi el d 3-[(2-amino-ethylamino)-phenyl-methyl]-6-(2-fluoro-3-methoxy- phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one. 1H-NMR (methanol-d4, 400 MHz): 1 .92 (m , 3H ); 3.88 (m , 5H); 4.26 (m , 0.25H*); 4.36 (m, 0.75H*); 5.41 (m, 1 H); 6.74 (m, 0.5H*); 6.83 (m, 0.5H*); 7.02 - 7.57 (m, 10H).
UPLC-MS (ES+): [M + H]+ = 616.
Table 38: The following examples 7.109 and 7.1 10 were prepared in analogy to example 7.108 starting from examples 7.70 and 7.71 .
Preparation of N-[3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-propyl]- guanidine
At room temperature 1 /-/-pyrazole-1 -carboxamidine (40 mg, 0.27 mmol) was added to a stirred solution of 3-[(3-amino-propylamino)-phenyl-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-
(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridi (example 7.109) (100 mg, 0.16 mmol) in acetonitrile (5 mL) and Λ/,/V-diisopropylethylamine (0.083 ml, 0.47 mmol). The reaction mixture was stirred for 1 hour and evaporated. After chromatography the target compound was obtained.
1H-NMR (methanol-d4, 300 MHz): 1 .65 (m, 2H); 1 .95 (s, 3H); 2.46 (m, 2H); 3.89 (m, 3H); 4.22 (m, 1 H); 5.44 (m, 1 H); 6.77 (m, 1 H); 7.07 - 7.55 (m, 10H).
MS (ES+): [M + H]+ = 672.
Example 7.1 12
Preparation of [3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-propyl]-urea
1H-NMR (methanol-d4, 300 MHz): 1.60 (m, 2H); 1 .94 (s, 3H); 2.53 (m, 2H); 3.50 (m, 1 H); 3.90 (d, 3H); 4.33 (d, 0.5H*); 4.38 (d, 0.5H*); 5.47 (m, 1 H); 6.74 (m, 0.5H*); 6.84 (m, 0.5H*); 7.06 - 7.54 (m, 10H).
UPLC-MS (ESI+): [M + H]+ = 673.
Example 8.1 & 8.2
Preparation of 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({methyl[2- (pyridin-2-yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 -oxide and 6-(4-chloro-2-fluoro-3-methoxyphenyl)-8-(2,6-difluorobenzyl)-7-methyl-3-({methyl[2-(pyridin- 2-yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 -oxide
In an adaptation of GP 27c: At room temperature iron (I I I) chloride (0.3 mg, 0.002 mmol, 0.03 eq .) was added to a stirred solution of 8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-3-{[methyl-(2-pyridin-2-yl-ethyl)-amino]-methyl}-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one (example 5.64) (35 mg, 0.062 mmol) in acetonitrile (3 ml_). After 5 min . (ortho)periodic acid (15.5 mg, 0.068 mmol, 1 .1 eq.) was added and stirring was continued for 3.5 hours. Then iron (I I I) chloride (0.3 mg, 0.002 mmol, 0.03 eq.) and (ortho)periodic acid (15.5 mg, 0.068 mmol, 1.1 eq.) were added again and the mixture was stirred over night. The reaction mixture was partitioned between ethyl acetate and aqueous sodium thiosulfate, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and brine, dried over sodium sulphate and concentrated in vacuum. The target compounds were isolated by preparative HPLC purification (yield: 16 mg and 9 mg). Example 8.1 : 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({methyl[2- (pyridin-2-yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 -oxide 1H-NMR (methanol-d4, 400 MHz): 2.02 - 2.08 (m, 3H); 2.98 (d, 1 .5H*); 3.10 (d, 1.5H*); 3.36 - 3.70 (m, 4.5H*); 3.72 - 3.96 (m, 5H); 4.08 - 4.22 (m, 0.5H*); 4.26 - 4.46 (m, 2H); 5.76 - 5.93 (m, 1 H); 6.60 - 6.79 (m, 1 H); 6.90 - 7.04 (m, 2H); 7.13 - 7.43 (m, 5H); 7.74 - 7.86 (m, 1 H); 8.16 - 8.31 (m, 1 H).
MS (CI+): [M + H]+ = 582.
Example 8.2: 6-(4-chloro-2-fluoro-3-methoxyphenyl)-8-(2,6-difluorobenzyl)-7-methyl-3- ({methyl[2-(pyridin-2-yl)ethyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 -oxide
1H-NMR (methanol-d4, 300 MHz): 2.00 - 2.06 (m, 3H); 2.89 - 2.94 (m, 1 H); 3.02 - 3.09 (m, 2H); 3.56 - 3.73 (m, 3H); 3.85 - 3.96 (m, 4H); 4.28 - 4.46 (m, 2H); 5.78 - 5.94 (m, 1 H); 6.91 -7.04 (m, 2H); 7.15-7.47 (m, 5H); 7.76-7.88 (m, 1H); 8.26-8.36 (m 1H).
MS (CI+): [M + H]+ = 616.
Example 8.3
Preparation of ethyl 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1-oxido-5-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
4-({[6-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester (example 7.1) (350 mg, 0.5 mmol) was dissolved in acetonitrile (10 mL) and iron (III) chloride (10.5 mg, 0.06 mmol) and periodic acid (128 mg, 0.056 mmol) were added at room temperature. Additional amounts (each 128 mg, 0.056 mmol) of periodic acid were added (hourly) until the reaction is complete. Then the mixture was worked up and flash chromatography yielded the target compound.
1H-NMR (methanol-d4, 300 MHz): 1.18 (dt, 3H); 1.83 (m, 2H); 1.97 (s, 3H); 2.36 (m, 2H); 2.56 (m, 2H); 3.87 (d, 3H); 5.67 (m, 1 H); 7.02 - 7.59 (m, 11 H).
UPLC-MS (ESI+): [M + H]+ = 703.
Table 39: The following examples 8.4 to 8.21 were prepared in analogy to example 8.3 and GP 27c starting from appropriate sulfides.
3-[amino(phenyl)methyl]-6-[3- (difluoromethoxy)phenyl]-8-[2
1 H-NMR (methanol-d4, 300 MHz): 1.85 (s, 3H); 4.61 (d, 1 H); 5.58 fluoro-6-(trifluoromethyl)
(m, 1 H); 6.84 (t, 1 H); 6.95 - 7.58 (m, 1 1 H).
benzyl]-7-methyl-2,3-dihydro- UPLC-MS (ESI+): [M + H]+ = 607.
5H-[1 ,3]thiazolo[3,2-a]pyridin- 5-one 1 -oxide
Table 40: The following examples 8.22 to 8.33 were prepared by saponification of corresponding esters.
426
Preparation of 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(hydroxy- phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
At 0°C sodiumborohydride (51 mg, 1.338 mmol) was added to a stirred solution of 3-benzoyl- 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro- thiazolo[3,2-a]pyridin-5-one (example 2.27) (153 mg, 0.268 mmol) in methanol (5 mL). After 1 hr the pH was adjusted to 6 (1 N aqueous hydrochloric acid). The solution was extracted with ethyl acetate and the organic layer was washed with water and brine, dried with magnesium sulfate and concentrated in vacuum. The target compound was isolated by flash column chromatography (yield: 80 mg).
1H-N M R (Me3OD, 300 MHz): 1 .94 (m, 3H); 3.90 (m, 3H); 5.28 - 5.44 (m, 2H); 6.74 (m, 0.5H*); 6.85 (m, 0.5H*); 7.04 - 7.53 (m, 1 1 H).
UPLC-MS (ESI+): [M + H]+ = 574.
BIOLOGICAL ASSAYS
1 . MATERIALS Buserelin was purchased from Welding (Frankfurt/Main, Germany) or USbiological (#B8995, Swampscott, USA) for IP-One HTRF® assays and LHRH from Sigma-Aldrich® (Munich, Germany). Labelled cells, Tag-Lite buffer, labelled and unlabelled GnRHR binding peptide for Tag-lite® binding assay was purchased by Cisbio Bioassays (Bagnols-sur-Ceze Cedex, France). The radio labelling was performed in the Department of Isotope Chemistry of Bayer Schering Pharma AG (Berlin, Germany) by the iodogen method using [125l]sodium iodide (2000 Ci/mmol; PerkinElmer Life and Analytical Sciences, USA) yielding [125l]monoiodo- buserelin. The radio-tracer was purified by reversed phase HPLC on a Spherisorb ODS I I column (250 x 4 mm, particle size 3 pm) by elution with acetonitrile / water (34 : 66) containing 39 mM trifluoracetic acid at a flow rate of 1 mL / min.
The retention time of [125l]monoiodo-buserelin was approximately 17 min. All other chemicals were obtained from commercial sources at the highest purity grade available.
2. METHODS 2.1. RECEPTOR BINDING ASSAY USING RADIOLABELLED BUSERELIN
Binding studies for competition curves were run in triplicate samples in 96 well polypropylene microtiter plates (Nunc, New Jersey, USA). One assay sample contained 70μΙ of 300,000 cells for CHO cells stably transfected with the human GnRH receptor, 20 μΙ of 125l-labelled buserelin (100,000 cpm per sample for competition curves) and 10 μ I of assay buffer or test compound solution. Test compounds were dissolved in DMSO. Cetrorelix was dissolved in 0.1 M hydrochloric acid. Serial dilutions (5 x 10"6 M to 5 x 10"12 M) were prepared in assay buffer (DMEM or DMEM/Ham's F12 medium, 10 mM Hepes buffer pH 7.5, 0.5 % BSA). Nonspecific binding was determined in presence of excess unlabelled buserelin (10"5 M). Test samples were incubated for 60 min at room temperature. Bound and free ligand were separated by filtration over Unifilter GF/C filter microtiter plates (PerkinElmer, CT, USA) by applying negative pressure and washing twice with 200 mL of 0.02 M Tris/hydrochloric acid, pH 7.4. The filter plates were soaked with 0.3% polyethylenimine (Serva; Heidelberg, Germany) for 30 min prior to use in order to reduce nonspecific binding. The radioactivity retained by the filters was determined in a TopCount NXT HTS (PerkinElmer, CT, USA) using 20μΙΛ/νβΙΙ MicroScint40 scintillator cocktail (PerkinElmer, CT, USA). Competition curves
were obtained by plotting the measured radioactivity against the respective test compound concentration by using an in-house software.
2.2. TAG-LITE® RECEPTOR BINDING ASSAY
This binding assay is based on the fluorescence resonance energy transfer between fluorescence donor labelled human GnRHR and a green-labelled GnRHR binding peptide. Compounds interfering with the ligand binding side of the human GnRHR will replace the labelled peptide resulting in a signal decrease. The assay principle was established by Cisbio Bioassays (Bagnols-sur-Ceze Cedex, France) and further details are available on their homepage.
The assay procedure was further optimized for use in-house with reduced assay volumes. Frozen Hek293 cells, transiently transfected with human GnRHR and Terbium-labelling of the receptor, were supplied by Cisbio Bioassays as well as Tag-Lite buffer and green- labelled GnRHR binding peptide. Cells were thawed and transferred to cold Tag-Lite buffer. A volume of 8 μΙ of this cell suspension were added to 100 nl of a 1 60-fold concentrated solution of the test compound in DMSO pre-dispensed in a well of a white low-volume 384- well microtiter plate (Greiner Bio-One, Frickenhausen, Germany). The mixture was incubated for 5 min at room temperature. In the next step either 4 μΙ Tag-Lite buffer or as control 4 μΙ of an exceeding amount unlabelled binding peptide in Tag-Lite buffer were transferred to the mixture. The green-labelled GnRHR binding peptide was added in a final step at EC50 in a volume of 4 μΙ Tag-Lite buffer. After an incubation of 1 h at room temperature plates were measured in a microplate reader, e.g. a PHERAstar (BMG Labtechnologies, Offenburg, Germany) by using a specific optic module.
A ratio from the fluorescence emissions at 520 nm (green fluorescence) and at 490 nm (background signal of Terbium-labelled Gn RH R) was calculated and the data were normalized (reaction without test compound = 0% inhibition of binding of green-labelled peptide; reaction without test compound with exceeding amount unlabelled binding peptide = 100% inhibition of bind i ng of green-labelled peptide). On the same microtiter plate, compounds were tested at 10 different concentrations in the range of 12.5 μΜ to 0.64 nM (12.5 μΜ, 4.2 μΜ, 1 .4 μΜ, 0.46 μΜ, 0.15 μΜ, 51 ηΜ, 17 ηΜ, 5.7 ηΜ, 1 .9 nM and 0.64 ηΜ; dilution series prepared before the assay at the level of the 160-fold cone, stock solutions by serial 1 :3 dilutions in 100% DMSO) in duplicate values for each concentration. By using an in-house software, the IC50 values were calculated by a 4 parameter fit.
2.3. IP-ONE HTRF® ASSAY
By using homogenous time-resolved fluorescence resonance energy transfer (HTRF), the generation of one component of the GnRH-R signalling cascade can be measured. After stimulation of CHO cells stably expressing human GnRH receptor (established by Prof. Thomas Gudermann, currently University of Marburg, Germany; supplied as frozen cell aliquots by Cell Culture Services, Hamburg, Germany) with the EC8o of the GnRH agonist buserelin, Gq protein-coupled receptor signalling cascade is activated resulting in PLC- dependent cleavage of PI P2 to l nositol-1 ,4,5-triphosphate (I P3) and Diacylglycerol. The second messenger I P3 is degraded intracellular^ to myo-inositol. Inhibition of the final degradation step from lnositol-1 -phosphate (I P 1 ) to myo-inositol by addition of lithium chloride leads to accumulation of I P1 in the cells. In cell lysates, IP1 can be detected via an antibody-based HTRF detection technology, where IP1 can displace the FRET acceptor IP1 - d2 from binding by Terbium-labelled anti-IP1 antibody as donor resulting in a signal decrease. Compounds were tested for their capability of inhibiting GnRH-R activation by buserelin.
For all IP-One HTRF® assays reagents of Cisbio Bioassays (IP-One Tb J um bo kit, #62IPAPEJ; Cisbio Bioassays, Bagnols sur Ceze Cedex, France) were used.
For the assay, frozen cell aliquots were thawed and a cell suspension (3.33x106 cells/mL) containing IP1 -d2 (dilution 1 :40) was prepared and incubated at 37°C. After 1 h 3 μΙ of the cell suspension were added to 50 nl of a 100-fold concentrated solution of the test compound in DMSO pre-dispensed in a well of a white low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany). The mixture was incubated for 20 min at 22°C to allow for pre-binding of the test compound to the GnRH-R. The receptor signalling cascade was stimulated by addition of 2 μΙ buserelin or LHRH (at EC50 or EC8o) in stimulation buffer (10 mM Hepes pH 7.4, 1 mM CaCI2, 0.5 mM MgCI2, 4.2 mM KCI, 146 mM NaCI, 5.5 mM alpha-D-Glucose, 0.05% BSA, 125 mM LiCI (final assay concentration 50 mM) in aqua dest.). Plates were incubated for 1 h at 37°C and 5% C02 before the cells were lysed by adding 3 μΙ Terbium-labelled anti-IP1 antibody (1 :40) diluted in Conjugate & Lysis buffer as supplied with the kit. After an incubation for 1 h at 22°C to enable complete cell lysis and antibody binding to free I P 1 or I P 1 -d2, plates were measured in an HTRF reader, e.g. a RUBYstar, PHERAstar (both BMG Labtechnologies, Offenburg, Germany) or a Viewlux (PerkinElmer LAS, Rodgau-Jijgesheim, Germany).
From the fluorescence emissions at 665 nm (FRET) and at 620 nm (background signal of Terbium-antibody), the ratio (emission at 665 nm divided by emission at 620 nm) was calculated and the data were normalized (reaction without test compound = 0% inhibition; all other assay components except agonist = 100% inhibition). On the same microtiter plate,
compounds were tested at 10 different concentrations in the range of 20 μΜ to 1 nM (20 μΜ, 6.7 μΜ, 2.2 μΜ, 0.74 μΜ, 0.25 μΜ, 82 ηΜ, 27 ηΜ, 9.2 ηΜ, 3.1 nM and 1 nM; dilution series prepared before the assay at the level of the 100-fold cone, stock solutions by serial 1 :3 dilutions in 100% DMSO) in duplicate values for each concentration. By using an in-house software, the IC50 values were calculated by a 4 parameter fit.
2.4. IN VIVO ASSAY IN OVARIECTOMIZED CYNOMOLGUS MONKEYS
Studies of castrate animals provide a sensitive in vivo assay for the effects of GnRH antagonist (Andrology 1993, 25, 141 - 147). GnRH receptors in the pituitary gland mediate GnRH-stimulated LH release into the circulation. Castration results in elevated levels of circulating LH due to reduction of the negative feedback of gonadal steroids, leading to an enhancement of GnRH-stimulated LH release. Consequently, measurement of suppression of circulating LH levels in castrated macaques can be used as a sensitive in vivo measure of GnRH antagonism. Female macaques are surgically castrated and allowed to recover for four weeks at wh ich point elevated levels of LH are established. Animals are then administered the test compound as an oral, s.c, i.p or i.v. dose, and serial blood samples are taken for measurement of LH. Ovariectomized cynomolgus monkeys (3.5 - 6 kg b.w.) are treated i.p. and/or p.o. with a single dose of the respective compound dissolved in an appropriate vehicle, e.g. aqueous physiological sodium chloride solution. The administered doses are 10 and/or 30 and/or 100 mg/kg. Blood samples of are drawn 0; 0.5 hr; 1 hr; 2hrs; 4hrs; 7hrs; 24hrs post application. Serum LH levels are monitored by RIA. The biological reagents were provided by National H o rm o n e & P i t u i ta ry P ro g ra m , H U M C , CA. , U . S . A , P rof . D r . A . F . P a rl ow (Parlow(g)humc.edu). Cynomolgus monkey LH is radioiodinated using the Chloramine-T method as described in the RIA immunoreactant manual.
RESULTS
The data reveal that the compounds of the present invention have antagonist activities on the human GnRH receptor.
Within the meaning of the present invention the antagonist activity is reflected by the ability of a compound of the invention to antagonize human GnRH receptor stimulation in IP-One HTRF® assay at least three times the standard deviation over the background level.
Table 35: Potency in receptor binding assay using radiolabelled buserelin; the potency given as IC5o [μΜ].
Table 41 : Potency in receptor binding assay using TAG-LITE® technology; the potency is given as IC5o [μΜ].
5.115 14.5
5.122 3.76
5.142 14.0
5.145 >20.0
5.148 15.4
5.152 8.51
5.156 7.94
5.159 12.9
5.165 4.59
5.168 >20.0
5.169 14.5
5.170 11.0
5.175 >20.0
5.178 5.54
5.180 6.76
5.182 2.21
5.190 8.86
5.206 8.77
5.212 1.91
5.213 0.27
5.214 1.58
5.215 0.33
5.220 1.40
5.225 0.88
5.228 1.38
5.229 9.45
5.230 11.6
5.237 18.0
5.238 6.54
5.243 7.02
5.252 13.8
5.259 >20.0
5.260 6.34
5.270 9.53
6.12b 0.36
6.13a 1.69
6.13b 0.42
6.14a 0.53
6.14b 0.27
6.15 0.039
6.16a 1.56
6.16b 0.35
6.18a 0.34
6.18b 0.11
6.19 0.72
6.1a 0.43
Example Potency [μΜ] 6.1 b 0.08
6.20a 0.31
6.20b 0.16
6.21 b 0.29
6.22a 0.14
6.22b 0.58
6.23 0.25
6.24 0.003
6.27 2.54
6.2b 1 .00
6.30 4.27
6.33 0.58
6.34 0.45
6.35 0.83
6.36a 0.17
6.36b 0.022
6.37 0.18
6.38b 0.13
6.39 0.42
6.40 0.1 1
6.41 0.58
6.42b 0.14
6.43 0.51
6.44 0.28
6.45 0.99
6.46 0.26
6.47a 0.32
6.47b 0.12
6.48a 0.19
6.48b 0.021
6.49 0.13
6.4a 18.8
6.5 0.070
6.50 0.96
6.6a 0.15
6.6b 0.027
6.7a 0.95
6.7b 0.21
6.8a 18.7
6.9 0.043
7.10 0.68
7.1 1 0.056
7.12 0.19
7.13 0.050
7.14 0.095
7.15 0.019
7.16 0.021
Example Potency [μΜ] 7.17 0.59
7.18 1.94
7.1b 0.40
7.2 0.74
7.20 0.13
7.23 0.54
7.28 0.037
7.3 0.11
7.30 0.43
7.4 0.99
7.6 1.33
7.8b 0.031
7.9 0.79
8.1 1.88
9.1 0.25
Table 36a: Potency in IP-One HTRF® assay with buserelin (at EC8o) stimulation; the potency is given as IC50 [μΜ]. The new values given in the present tables may differ from those given in table 36 due to the fact that mesurament were repeated and the mean value provided. Values in italic and round brakets refer to the potency of single enantiomers, the values are given to enantiomer 1 and 2 subsequently (i.e. 6.6a: racemic mixture =0.16, enantiomer 1 =0.18, enantiomer 2=1.67). Values marked with an asterisk refer to the potency of the enantiomer derived from the most active enantiomer of the parent amine (see examples 6).
3.6 14.19 5.130 6.88
3.7 1.54 5.131 10.14
3.8 6.15 5.132 15.24
4.1 >20 5.133 >20
4.2 >20 5.134
4.3 >20 5.135 8.51
4.4 >20 5.136 4.05
4.5 18.72 5.137 6.18
4.6 13.39 5.138 7.7
4.7 11.33 5.139 1.83
4.8 5.81 5.14 >20
5.1 >20 5.140 7.73
5.10 >20 5.141 6.54
5.100 >20 5.142 14.04
5.101 6.1 5.143 8.57
5.102 8.59 5.144 18.84
5.103 2.66 5.145 >20
5.104 6.73 5.146
5.105 2.8 5.147 13.36
5.107 >20 5.148 15.39
5.108 4.33 5.149 10.57
5.109 4.74 5.15 >20
5.11 >20 5.150 4.85
5.110 7.85 5.151 2.84
5.111 7.34 5.152 8.51
5.112 >20 5.153 >20
5.113 15.73 5.154 15.05
5.114 9.77 5.155 3.82
5.115 14.52 5.156 7.94
5.116 10.01 5.157 12.05
5.118 >20 5.158 12.76
5.119 >20 5.159 12.95
5.12 >20 5.16 >20
5.120 4.7 5.160 7.97
5.121 >20 5.161 10.33
5.122 3.76 5.163 4.26
5.123 6.42 5.164 11.5
5.124 10.29 5.165 4.59
5.125 7.31 5.166 15.72
5.126 1.06 5.167 11.35
5.127 >20 5.168 >20
5.128 >20 5.169 14.5
5.129 14.15 5.17 >20
5.13 >20 5.170 10.99
Example: Potency [μΜ] Example Potency [ ]
5.171 >20 5.211 1.68
5.172 13.5 5.212 1.91
5.173 11.1 5.213 0.27
5.174 10.01 5.214 1.58
5.175 >20 5.215 0.33
5.176 8.63 5.216 2.23
5.177 8.32 5.217 3.94
5.178 5.54 5.218 4.8
5.179 9.28 5.219 >20
5.18 >20 5.22 17.52
5.180 6.76 5.220 1.4
5.181 4.44 5.221 6.32
5.182 2.21 5.222 5.2
5.183 >20 5.223 5.78
5.184 12.11 5.224 2.42
5.185 >20 5.225 0.88
5.186 13.38 5.226 7.19
5.187 >20 5.227 >20
5.188 9.71 5.228 I .38
5.189 15.13 5.229 9.45
5.19 >20 5.23 15.34
5.190 8.86 5.230 I I .57
5.191 14.48 5.231 7.16
5.192 10.86 5.232 4.21
5.193 5.89 5.233 15.27
5.194 >20 5.234 15.45
5.195 >20 5.235 13.39
5.196 >20 5.236 10.9
5.197 >20 5.237 18.03
5.199 9.77 5.238 6.54
5.2 4.97 5.239 15.53
5.20 >20 5.24 14.53
5.200 13.13 5.240 8.29
5.201 8.68 5.241 >20
5.202 6.73 5.242 5.17
5.203 4.95 5.243 7.02
5.204 4.65 5.244 1.21
5.205 10.86 5.245 5.15
5.206 8.77 5.246 >20
5.207 8.05 5.247 9.8
5.208 >20 5.248 8.96
5.209 14.64 5.249 5.59
5.21 18.11 5.25 14.18
5.210 1.03 5.250 12.42
Example: Potency [μΜ] Example Potency [ ]
5.251 >20 5.47 7.5
5.252 13.79 5.48 6.98
5.253 4.29 5.49 6.04
5.254 13.92 5.50 5.3
5.255 19.89 5.51 5.27
5.256 I .74 5.52 2.78
5.257 7.3 5.53 4.1
5.258 4.47 5.54 4.09
5.259 >20 5.55 3.64
5.26 I I .93 5.56 3.6
5.260 6.34 5.57 3.41
5.261 2.17 5.58 3.07
5.262 18.04 5.59 2.88
5.263 16.59 5.6 >20
5.264 >20 5.60 2.67
5.265 13.35 5.61 1.73
5.266 >20 5.62 1.52
5.267 5.94 5.63 1.16
5.268 12.2 5.64 0.43
5.269 10.14 5.65 >20
5.27 11.87 5.66 3.89
5.270 9.53 5.67 3.71
5.271 10.49 5.68 3.51
5.273 5.28 5.69 3.21
5.274 I .27 5.7 >20
5.28 I I .19 5.70 2.69
5.29 4.39 5.71 1.87
5.30 5.72 0.85
5.31 16.35 5.73 4.59
5.32 18.97 5.74 2.94
5.33 >20 5.75 4.92
5.34 >20 5.76 1.05
5.35 >20 5.77 0.22
5.36 >20 5.78 0.86
5.37 >20 5.79 1.31
5.38 >20 5.8 >20
5.39 >20 5.80 3.57
5.40 >20 5.81 3.47
5.41 19.35 5.82 1.36
5.42 13.16 5.83 10.05
5.43 13.15 5.84 4.09
5.44 12.29 5.85 10.48
5.45 11.27 5.86 16.96
5.46 10.38 5.87 14.28
Example: Potency [μΜ] Example Potency [ ]
5.88 16.17 6.2a 1.4
5.89 7.54 6.2b 1.01
5.9 >20 6.30 4.27
5.90 6.59 6.31 1 1.1 1
5.91 >20 6.32 1.52
5.92 >20 6.33 0.58
5.93 14.22 6.34 0.45
5.94 16.53 6.35 0.82
5.95 >20 6.36a 0.17
5.96 8.57 6.36b 0.02
5.97 12.69 6.37 0.18
5.98 19.88 6.38a 1.07
5.99 5.71 6.38b 0.12
6.10 1.05 6.39 0.42
6.1 1 a 17.99 6.3a 2.48
6.1 1 b 12.47 6.3b 3.1 1
6.12a 5.61 6.40 0.1 1
6.12b 0.36 6.41 0.58
6.13a 2.26 6.42a 1.77
6.13b 0.42 6.42b 0.14
6.14a 0.53 6.43 0.51
6.14b 0.27 6.44 0.28
6.15 0.04 (0.01,0.25) 6.45 0.99
6.16a 1.56 6.46 0.26
6.16b 0.35 6.47a 0.32
6.17 1.81 6.47b 0.12
6.18a 0.34 6.48a 0.19
6.18b 0.12 6.48b 0.02
6.19 0.72 6.49 0.13
6.1 a 0.43 6.4a 18.83
6.1 b 0.08 6.4b 18.75
6.20a 0.31 6.5 0.07
6.20b 0.21 6.50 0.96
6.21 a 1.15 6.51 b 0.86
6.21 b 0.29 6.51 a 2.51
6.22a 0.14 6.52a 0.98 (0.59,>20)
6.22b 0.58 6.52b 0.04 (0.06,0.56)
6.23 0.25 6.53 0.7
6.24 0.00379 6.54 0.12
6.25a >20 6.55a 14.1 1
6.25b 7.67 6.55b 1.54
6.27 2.54 6.56 0.09 (7.69,0.17)
6.28 2.19 6.57 0.02 (0.02,0.69) 6.29 2.06 6.58 0.03
Example Potency [μΜ] Example Potency [ ]
6.59 0.24 6.84b 0.02
6.60 0.05 (0.02,0.55) 6.85a 0.04
6.61 0.03 6.85b 0.02
6.62a 0.6 6.86a 0.18
6.62b 0.02 6.86b 0.12
6.63a 0.23 6.87 0.14
6.63b 0.08 6.88 0.28
6.64a 0.1 1 6.89a 0.21
6.64b 0.02 6.89b 0.44
6.65a 0.8 6.8a 18.74
6.65b 0.13 6.8b 10.82
6.66a 0.67 6.9 0.04
6.66b 0.04 6.90a 0.32
6.67a 0.28 6.90b 0.69
6.67b 0.05 7.10 0.68
6.68a 0.42 7.100 0.06 (0.05,0.62)
6.68b 0.09 7.101 (0.59,>20)
6.69a 0.39 7.102 (0.42,>20)
6.69b 0.13 7.103 0.05
6.6a 0.16 (0.18, 1.67) 7.104 0.1
6.6b 0.03 (0.08,0.27) 7.105 (0.07)*
6.70a 1.52 7.106 (0.14)*
6.70b 3.65 7.107 0.54
6.71 a 0.52 7.108 0.04
6.71 b 0.1 7.109 0.07
6.72 5.83 7.1 1 0.04
6.73a 0.37 7.1 10 0.41
6.73b 0.16 (0.18, 16) 7.1 1 1 0.07
6.74a (>20, 13) 7.1 12 0.03
6.74b (>20, 12.17) 7.12 0.19
6.75a 0.23 7.13 0.09
6.75b 0.04 (0.07,0.51) 7.14 0.1
6.76 0.07 7.15 0.02
6.77a 1.02 7.16 0.03
6.77b 0.14 7.17 0.59
6.78 0.1 1 7.18 1.94
6.79 2.51 7.19 3.57
6.7a 0.95 7.1 b 0.4 (0.11, 1.86)
6.7b 0.21 7.2 0.74
6.80 1.69 7.20 0.13
6.81 17.63 7.21 17.08
6.82 0.17 7.22 1.26
6.83 0.27 7.23 0.54
6.84a 0.02 7.24 3.46
Example: Potency [μΜ] Example Potency [ ]
7.26 2.1 7.73 (0.68)*
7.27 1.62 7.74 0.02 (0.02)*
7.28 0.04 7.75 1.25
7.29 1.09 7.76 0.03
7.3 0.1 1 7.78 0.19
7.30 0.52 7.79 0.04
7.31 3.69 7.80 0.38
7.32 0.1 1 7.81 0.05
7.33 0.08 7.82 (0.07)*
7.34 1.48 7.83 >20
7.35 0.86 7.84 1.49
7.38 0.03 7.85 2.64
7.39 (0.05)* 7.86 4.73
7.4 0.99 7.87 3.07
7.41 3.27 7.88 0.05
7.43 >20 7.89 0.18
7.44 2.01 7.8b 0.03 (0.01,0.44)
7.45 (0.66)* 7.9 0.79
7.46 0.19 7.90 0.06
7.47 0.14 7.91 0.27
7.49 0.26 7.92 0.03 (7.3,0.04)
7.5 1.33 7.93 (5.19,0.02)
7.50 2.65 7.94 0.04 (0.02)*
7.51 3.04 7.95 (0.02)*
7.52 2.55 7.96 0.03 (0.03, 1.21)
7.56 >20 7.97 (0.03, 1.3)
7.57 1.25 (15.4, 1.15) 7.98 0.05
7.58 (>20,0.39) 7.99 (0.03,0.5)
7.59 (0.26)* 8.1 1.88
7.6 1.33 8.10 (0.0064)*
7.60 (0.06)* 8.13 2.1 (>20,0.43)
7.61 (0.26)* 8.14 (0.17, 1.49)
7.62 (0.16)* 8.15 (0.13)*
7.63 0.15 8.16 (0.00186)*
7.64 (1.02)* 8.17 0.00353
7.65 0.51 (0.4, 1.66) 8.18 0.00547
7.66 0.02 8.2 18.85
7.67 0.34 8.21 0.02
7.68 0.07 8.22 0.1
7.69 0.92 8.23 0.009 (0.005,0.34)
7.7 4.24 8.24 0.01
7.70 0.27 8.25 0.02
7.71 2.58 8.26 0.03 (8.23,0.07) 7.72 (1.21)* 8.27 (0.01)*
Example Potency [μΜ]
8.28 (0.00678)*
8.29 (11.3,0.09)
8.3 0.04
8.30 (0.02,0.39)
8.31 (5.62,0.01)
8.32a 0.08
8.32b 0.24
8.33 0.09
8.4 4.46
8.6 0.02
8.7 0.06
8.8 (0.37)*
8.9a 0.02
8.9b 0.66
9.1 0.25
Claims
A compound having the following structure
(I)
in which
R2a and R2b represent independently of one another a hydrogen atom, a
CrC6-alkyl- or a C3-C6-cycloalkyl- group, or
R2a and R2b joined, and taken together with the atom to which they are attached, form a C3-C6-cycloalkyl- group;
Re represents a halogen atom, an aryl-, a heteroaryl-, a benzo[1 ,3]dioxolyl- or
2,3-dihydro-1 ,4-benzodioxinyl group wherein said group is optionally substituted one to three times, in the same way or differently, with a substituent R-n selected from :
hydrogen, halogen, hydroxy, cyano, nitro, CrC6-alkyl, halo-CrC6-alkyl, CrC6-alkoxy, halo-CrC6-alkoxy, CrC6-hydroxy, Ci-C6-alkoxy-Ci-C6-alkyl, halo-Ci-C6-alkoxy-Ci-C6-alkyl, C C6-alkyl-C(=0)OH, C3-Ci0-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, aryloxy-, heteroaryloxy-, -C(=0)OH, -C(=0)CrC6-alkyl, -C(=0)0-C C6-alkyl,
-N(CrC6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(C C6-alkyl)S(=0)2R9,
-C(=0)NR9R10, -OC(=0)NR9R10, -N(H)C(=0)OR9, -N(C C6-alkyl)C(=0)OR9,
-SR9, -S(=0)R9, -S(=0)2R9, -S(=0)2NR9R10, -NR9R10 ; wherein
R9 and R10 represent, independently of one another, a hydrogen atom, a Ci-Ce-alkyI-, halo-C C6-alkyl-, Ci-C6-alkoxy-Ci-C6-alkyl-,
halo-Ci-C6-alkoxy-Ci-C6-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-Cio-cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-, Ci-C6-alkylene-aryl-, Ci-C6-alkylene-heteroaryl-,
-CrC6-alkylene-C3-Cio-cycloalkyl-, CrC6-alkylene-(3- to 10-membered
heterocycloalkyi group ; wherein said C3-Ci0-cycloalkyl- and said 3- to 10- membered heterocycloalkyi- group are optionally substituted one or two times with a halogen atom, cyano, -OH, CrC6-alkyl, halo-CrC6-alkyl, CrC6-alkoxy, C3-Ci0-cycloalkyl, aryl, or a heteroaryl group ; or
R9 and R10 joined, and taken together with the atom to which they are attached, form a
3- to 10-membered heterocycloalkyi-, optionally substituted one or two times, in the same way or differently, with a substituent selected from the group consisting of halo-, hydroxyl-, cyano-, nitro-, oxo, CrC6-alkyl-,
halo-CrC6-alkyl-, CrC6-alkoxy-, halo-CrC6-alkoxy-, Ci-C6-alkoxy-Ci-C6-alkyl-, halo-Ci-C6-alkoxy-Ci-C6-alkyl-, C3-Ci0-cycloalkyl-,
3- to 10-membered heterocycloalkyi-, -C(=0)OH, -C(=0)0-C C6-alkyl, -C(=0)0-C3-Cio-cycloalkyl, -OC(=0)-C C6-alkyl,
-N(Ci-C6-alkyl)S(=0)2(Ci-C6)-alkyl -C(=0)N((Ci-C6)-alkyl)((Ci-C6)-alkyl), -OC(=0)N((Ci-C6)-alkyl)((Ci-C6)-alkyl), -N(H)C(=0)0(C C6)-alkyl,
-N(Ci-C6-alkyl)C(=0)0(Ci-C6)-alkyl, -N(H)C(=0)N((Ci-C6)-alkyl)((Ci-C6)-alkyl), -N(Ci-C6-alkyl)C(=0)N((Ci-C6)-alkyl)((Ci-C6)-alkyl), -S(C C6)-alkyl,
-S(=0)(CrC6)-alkyl, -S(=0)2OH,
-S(=0)2N((C1-C6)-alkyl)((C1-C6)-alkyl), -P(=0)(OH)2,
-P(=0)(0(Ci-C6)-alkyl)(Ci-C6)-alkyl), -N((Ci-C6)-alkyl)((Ci-C6)-alkyl) and in which (CrC6)-alkyl is optionally substituted with one to three halogen atoms; represents a hydrogen atom, CrC6-alkyl, halo-CrC6-alkyl or a
C3-C6-cycloalkyl group; is O, S, S=0 or S(=0)2; is
in which
R8 represents one to three substituents independently selected from the group consisting of hydrogen, halogen, cyano, nitro,
Ci-C6-alkyl-, halo-CrC6-alkyl-, CrC6-alkoxy-, Ci-C6-alkoxy-Ci-C6-alkyl-, halo-Ci-C6-alkoxy-Ci-C6-alkyl-, C2-C6-alkenyl-, a C2-C6-alkynyl-,
-C(=0)R9, -C(=0)OR9, -C(=0)N R9R10, -SR9, -S(=0)R9, -S(=0)2R9,
-S(=0)2N R9R10 or -N R9R10; wherein R9 and R10 independently of one another or joined, and taken together with the atom to which they are attached, have the meaning given above; is
R-ia, and Rib represent independently of one another a hydrogen atom, a CrC6-alkyl-, Ci-C6-alkoxy-Ci-C6-alkyl-, C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C8-cycloalkyl-, aryl-, heteroaryl-, -Ci-C6-alkylene-aryl,
-Ci-C6-alkylene-heteroaryl, -Ci-C6-alkylene-C3-Cio-cycloalkyl,
-CrC6-alkylene-(3- to 10-membered heterocycloalkyl),
-C(=0)-C C6-alkyl, -C(=0)-Ci-C6-alkylene-aryl,
-C(=0)-Ci-C6-alkylene-heteroaryl, -C(=0)0-C C6-alkyl,
-C(=0)0-Ci-C6-alkylene-aryl, -C(=0)0-Ci-C6-alkylene-heteroaryl,
-C(=0)N R9R10, -S(=0)2R9 group; wherein said groups are optionally substituted one to three times, in the same way or differently, with a substituent selected from : halo-, hydroxy-, cyano-, nitro-, CrC6-alkyl-, halo-CrC6-alkyl-, CrC6-alkoxy-, halo-CrC6-alkoxy-,
Ci-C6-alkoxy-Ci-C6-alkyl-, halo-Ci-C6-alkoxy-Ci-C6-alkyl-,
C3-Ci0-cycloalkyl-, aryl-, heteroaryl-, 3- to 10-membered heterocycloalkyl-, -C(=0)OH, -C(=0)0-CrC6-alkyl,
-OC(=0)-CrC6-alkyl,
-N(H)C(=0)R9,
-N(CrC6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(C C6-alkyl)S(=0)2R9,
-C(=0)N R9R10, -OC(=0)N R9R10, -N(H)C(=0)OR9, -N(C C6-alkyl)C(=0)OR9, -N(H)C(=0)N R9R10, -N(H)C(=N H)N R9R10, -N(Ci-C6-alkyl)C(=0)N R9R1°, -SR9, -S(=0)R9, -S(=0)2OH, -S(=0)2R9, -S(=0)2NR9R10, -P(=0)(OH)2, -P(=0)(OR9)(OR10), -N R9R10 , and wherein R9 and R10 independently of one
another or joined, and taken together with the atom to which they are attached, have the meaning given above; or
R-ia and Rib joined, and taken together with the atom to which they are attached, form a 3- to 10-membered heterocycloalkyi-, optionally substituted one to three times, in the same way or differently, with a substituent selected from : halo-, hydroxyl-, cyano-, nitro-, oxo, CrC6-alkyl-, halo-CrC6-alkyl-, CrC6-alkoxy-, halo-CrC6-alkoxy-,
Ci-C6-alkoxy-Ci-C6-alkyl-, halo-Ci-C6-alkoxy-Ci-C6-alkyl-,
-C(=0)OH, -C(=0)0-CrC6-alkyl,
-OC(=0)-CrC6-alkyl,
-N(CrC6-alkyl)C(=0)
-C(=0)NR9R10, -OC(=0)NR9R10, -N(H)C(=0)OR9,
-N(CrC6-alkyl)C(=0)OR9, -N(H)C(=0)NR9R10, -N(H)C(=NH)NR9R10,
-SR9, -S(=0)R9, -S(=0)2OH, -S(=0)2R9, -S(=0)2NR9R10, -P(=0)(OH)2, -P(=0)(OR9)(OR10), -NR9R10
wherein R9 and R10 independently of one another or joined, and taken together with the atom to which they are attached, have the meaning given above, or
R-ia and Rib joined, and taken together with the atom to which they are attached, form a 3- to 10-membered heterocycloalkyi-, substituted with a group selected from : C3-Ci0-cycloalkyl-, aryl-, heteroaryl-,
-Ci-C6-alkylene-aryl, -Ci-C6-alkylene-heteroaryl,
-Ci-C6-alkylene-C3-Cio-cycloalkyl, 3- to 10-membered heterocycloalkyi-, -CrC6-alkylene-heterocycloalkyl-, said groups being optionally substituted one to three times, in the same way or differently, with a substituent selected from : halo, cyano, CrC6-alkyl- and halo-CrC6-alkyl- ;
Ric represents a hydrogen atom, a hydroxy group, a methoxy group or a CrC6-alkoxy-, a CrC6-alkyl-, Ci-C6-alkoxy-Ci-C6-alkyl-,
C2-C6-alkenyl-, C2-C6-alkynyl-, C3-C8-cycloalkyl-, aryl-, heteroaryl-,
-Ci-C6-alkylene-aryl, -Ci-C6-alkylene-heteroaryl,
-CrC6-alkylene-C3-Cio-cycloalkyl, -CrC6-alkylene-(3- to 10-membered heterocycloalkyi) group; wherein said groups are optionally substituted one to three times, in the same way or differently, with a substituent selected from : halo-, hydroxyl-, cyano-, nitro-, CrC6-alkyl-,
halo-CrC6-alkyl-, CrC6-alkoxy-, halo-CrC6-alkoxy-,
Ci-C6-alkoxy-Ci-C6-alkyl-, halo-Ci-C6-alkoxy-Ci-C6-alkyl-,
C3-Cio-cycloalkyl-, 3- to 10-membered heterocycloalkyi-, -C(=0)OH,
-C(=0)0-C C6-alkyl, -C(=O)O-C3-Ci0-cycloalkyl, -OC(=0)-C C6-alkyl,
-OC(=0)NR9R10, -N(H)C(=0)OR9, -N(C C6-alkyl)C(=0)OR9,
-SR9, -S(=0)R9, -S(=0)2R9, -S(=0)2NR9R10, -NR9R10 wherein R9 and R10 independently of one another or joined, and taken together with the atom to which they are attached, have the meaning given above;
R3a and R3b represent independently of one another a hydrogen atom, a d-Ce-alkyl-, Ci-C6-alkoxy-Ci-C6-alkyl-, C2-C6-alkenyl-,
C2-C6-alkynyl-, C3-C8-cycloalkyl-, 3- to 10-membered heterocycloalkyi-, aryl-, heteroaryl-, -Ci-C6-alkylene-aryl, -Ci-C6-alkylene-heteroaryl,
-CrC6-alkylene-C3-Cio-cycloalkyl, -CrC6-alkylene-(3- to 10-membered heterocycloalkyi) group; wherein said groups are optionally substituted one to three times, in the same way or differently, with a substituent selected from : halo-, hydroxyl-, cyano-, nitro-, CrC6-alkyl-, halo-CrC6-alkyl-, CrC6-alkoxy-, halo-CrC6-alkoxy-, Ci-C6-alkoxy-Ci-C6-alkyl-, halo-Ci-C6-alkoxy-Ci-C6-alkyl-, aryl-, heteroaryl-, C3-Ci0-cycloalkyl-, 3- to 10-membered heterocycloalkyi-, -C(=0)OH, -C(=0)0-CrC6-alkyl,
-OC(=0)-CrC6-alkyl,
-N(H)C(=0)R9,
-N(CrC6-alkyl)C(=0)R9, -N(H)S(=0)2R9, -N(C C6-alkyl)S(=0)2R9,
-C(=0)NR9R10, -OC(=0)NR9R10, -N(H)C(=0)OR9, -N(C C6-alkyl)C(=0)OR9,
-SR9, -S(=0)R9, -S(=0)2R9, -S(=0)2NR9R10, -NR9R10 wherein R9 and R10 independently of one another or joined, and taken together with the atom to which they are attached, have the meaning given above; or
Ria and R3a , or R1b and R3a , or R3b and Ria , or R3b and Re joined, and taken together with the atom to which they are attached,form a 4- to 10-membered heterocycloalkyi- or 4- to 10-membered heterocycloalkenyl-, optionally substituted one to three times, in the same way or differently, with a substituent selected from :
halo-, hydroxyl-, cyano-, nitro-, CrC6-alkyl-, halo-CrC6-alkyl-,
CrC6-alkoxy-, halo-CrC6-alkoxy-, Ci-C6-alkoxy-Ci-C6-alkyl-,
halo-Ci-C6-alkoxy-Ci-C6-alkyl-, C3-Ci0-cycloalkyl-, 3- to 10-membered
heterocycloalkyh -C(=0)OH, -C(=0)0-CrC6-alkyl,
-C(=0)0-C3-Cio-cycloalkyl, -OC(=0)-Ci-C6-alkyl,
-SR9, -S(=0)R9, -S(=0)2OH, -S(=0)2R9, -S(=0)2NR9R10, -P(=0)(OH)2, -P(=0)(OR9)(OR10), -NR9R10 wherein R9 and R10 independently of one another or joined, and taken together with the atom to which they are attached, have the meaning given above and
all the other substituents in Y have the meaning given above; with the proviso that Y is not -C(=0)H.
2. A compound according to claim 1 in which X is
A compound according to claim 1 in which Y is
A compound according to claim 1 in which Y is
wherein R1a , R1b independently from one another or joined, and taken together with the atom to which they are attached have the meaning as given in claiml .
A compound according to claim 1 in which Y is
A compound according to claim 1 in which Y is
8. A compound according to claim 1 in which
Re is
a 6 member heteroaryl group with at least a nitrogen atom wherein R-n have the meaning as given in claim 1 .
9. A compound according to claim 1 in which
R6 is pyridine ring optionally substituted one to three times times, in the same way or differently, with a substituent selected from : hydrogen, halogen, hydroxy, cyano, nitro, CrC6-alkyl, halo-CrC6-alkyl, CrC6-alkoxy, halo-CrC6-alkoxy.
10. A compound according to claim 1 in which
Re is
where Rn has the meaning as given in claim 1 .
1 1 . A compound according to any one of claims 8 or 10 in which R-n is hydrogen, halogen, hydroxy, cyano, nitro, CrC6-alkyl, halo-CrC6-alkyl, CrC6-alkoxy,
halo-d-Ce-alkoxy, -C(=0)C C6-alkyl.
12. A compound according to claim 1 in which
Re is
13. A compound according to claim 1 in which
Re is
14. A compound according to claim 1 in which
Re is
15. A compound according to claim 1 in which
R7 is an hydrogen atom, -CH3, -CF3, -CH2CH3, -CH2CF3.
16. A compound of formula (II) according to claim 1 :
R2a and R2b are both a hydrogen atom or a methyl group,
R8a and R8b are independently selected from the group consisting of hydrogen, halogen, CrC6-alkyl-, halo-CrC6-alkyl,
Rii is present one to three times and is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, CrC6-alkyl, halo-CrC6-alkyl, CrC6-alkoxy, halo-CrC6-alkoxy, -C(=0)CrC6-alkyl, methylenedioxy- or ethylenedioxy group and in which
Ria , Rib , R3a , Rsb have the meaning as given in claim 1. 17. A compound of formula (Ha) according to claim 1 :
in which
R2a and R2b are both a hydrogen atom or a methyl group,
R8a and R8b are independently selected from the group consisting of hydrogen, a halogen, CrC6-alkyl-, halo-CrC6-alkyl,
Rii is present one to three times and is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, CrC6-alkyl, halo-CrC6-alkyl, CrC6-alkoxy, halo-CrC6-alkoxy, -C(=0)CrC6-alkyl, methylenedioxy- or ethylenedioxy group and in which
Ria , R1b , R3a , R3b have the meaning as given claim 1 .
A compound of formula (lib) according to clai
R2a and R2b are both a hydrogen atom or a methyl group,
R8a and R8b are independently selected from the group consisting of hydrogen, halogen, CrC6-alkyl-, halo-CrC6-alkyl,
Rii is present one to three times and is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, CrC6-alkyl, halo-CrC6-alkyl, CrC6-alkoxy, halo-CrC6-alkoxy, -C(=0)CrC6-alkyl, methylenedioxy- or ethylenedioxy group and in which
Ria , Rib , R3a , Rsb have the meaning as given claim 1 . 19. A compound of formula (III) according to claim 1 :
R8a and R8b are independently selected from the group consisting of hydrogen, halogen CrC6-alkyl-, halo-CrC6-alkyl,
Rii is present one time and is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, CrC6-alkyl, halo-CrC6-alkyl,
CrC6-alkoxy, halo-CrC6-alkoxy, and in which
Ria , Rib , R3a , Rsb have the meaning as given claim 1 .
20. A compound of formula (IV) according to claim 1 :
R2a and R2b are both a hydrogen atom or a methyl group,
R8a and R8b are independently selected from the group consisting of hydrogen, halogen, CrC6-alkyl-, halo-CrC6-alkyl,
R6 is any one of t
halo-CrC6-alkyl, CrC6-alkoxy, halo-CrC6-alkoxy,
and in which
Ria , Rib , R3a , Rsb have the meaning as given claim 1 .
21 . A compound according to any one of claim 1 or 16 to 20 in which
R2a and R2b are both a hydrogen atom or a methyl group.
22. A compound according to any one of claims 2, or 16 to 20 in which
R8a and R8b are both a hydrogen atom; or
R8a is a hydrogen atom and R8b is selected from the group consisting of halogen atom,Ci-C6-alkyl-, halo-CrC6-alky; or
R8a is selected from the group consisting of halogen, CrC6-alkyl-, halo-CrC6-alky and R8b is selected from the group consisting of halogen, CrC6-alkyl-, halo-CrC6-alkyl.
23. A compound according to any one of claims 2 or 16 to 20 in which R8a and R8b are independently of one another a hydrogen atom, a fluorine atom or a fluorinated CrC6-alkyl group, in particular a -CF3 .
24. A compound according to any one of claims 16 to 20 in which
R33 , R3b are both a hydrogen atom
R1a , R1 b independently of one another or joined, and taken together with the atom to which they are attached, have the meaning as given in claim 1 .
25. A compound according to claim 16 to 20 in which
Ria , Rib are both a hydrogen atom and
R3a , R3b have the meaning as given in claim 1 .
26. A compound according to any one of claims 16 to 20 in which
at least one of the substituents Ria , Rib , R3a , R3b is a hydrogen atom and all the others substituents have the meaning as given in claim 1 .
27. A compound according to any one of claim 1 , 3 to 4, 6 to 7 or 25 to 26, in which Ria , Rib, are independently of one another a hydrogen atom, a CrC6-alkyl-, Ci-C6-alkoxy-Ci-C6-alkyl-, -Ci-C6-alkenyl-, aryl-, heteroaryl-,
-Ci-C6-alkylene-aryl, -Ci-C6-alkylene-heteroaryl, -C(=0)-CrC6-alkyl,
optionally substituted one to three times times, in the same way or differently, with a substituent selected from : halo-, hydroxy-, cyano-, CrC6-alkyl-,
halo-d-Ce-alkyl-, -C(=0)OH, -C(=0)NH2, -S(=0)2OH, -N(H)C(=0)NH2,
-N(H)C(=NH)NH2, -C(=0)0-CrC6-alkyl, -NH2
28. A compound according to any one of claims 1 , 3, 5 to 7 or 25 to 26 in which
R33 , R3b are independently of one another hydrogen atom, a CrC6-alkyl-,
C2-C6-alkenyl-, aryl-, heteroaryl- wherein said groups are optionally substituted one to
three times times, in the same way or differently, with a substituent selected from halo-, cyano-, CrC6-alkyl-, halo-CrC6-alkyl, d-C6-alkoxy- or halo-CrC6-alkoxy-
29. A compound according to claim 27 in which
Ria, is an hydrogen and R1b is a -CH2-CH2-CH2-C(=0)0-CH2-CH3 ,
-CH2-CH2-0-CH2-C(=0)0-CH3 , -CH2-CH2-0-CH2-C(=0)0-CH2-CH3 ,
-CH2-CH2-CH2-C(=0)OH, -CH2-CH2-0-CH2-C(=0)OH , -CH2-CH2-CH2-C≡N , -CH2-CH2-CH2-1 H-tetrazol-5-yl
30. A compound according to any one of claims 28 in which
R3a is an hydrogen and R3b is a phenyl, thienyl, benzothienyl, furanyl, thiazolyl or pyridyl group optionally substituted one to three times with a halogen atom, cyano, CrC6-alkyl, halo-CrC6-alkyl, CrC6-alkoxy or halo-CrC6-alkoxy.
31 . 8-(2,6-difluoro-benzyl)-6-(2-fluoro -3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5H- thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-
2,3-dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester 6-(2-chloro-5-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-
5-0X0-2, 3-dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester 6-(2-fluoro-pyridin-3-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-6-(3-trifluoromethoxy-phenyl)-2,3- dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-
2,3-dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester 6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-
2,3-dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester 6-(2,2-difluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester 3-benzoyl-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3-dihydro- thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-3-(4-fluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(4-methoxy-benzoyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-trifluoromethoxy- benzoyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(thiophene-3- carbonyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(benzo[b]thiophene-3-carbonyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(furan-3-carbonyl)-7-methyl-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(3-methyl-benzoyl)-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(3-trifluoromethyl- benzoyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(2-methyl-benzoyl)-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-3-(2-fluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-chloro-3-fluoro-benzoyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(3,5-difluoro-benzoyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,3-difluoro-benzoyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-3-(3-fluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,5-difluoro-benzoyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-chloro-5-methyl-benzoyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(4-fluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-(4- trifluoromethoxy-benzoyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
[(2H5)phenylcarbonyl]-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
-benzoyl-6-(2-chloro-5-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-6-(2-fluoro-pyridin-3-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
-(3,5-difluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(3-fluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(5-chloro-thiophene-2-carbonyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-(3- trifluoromethyl-benzoyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-6-(3-trifluoromethoxy- phenyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-6-(2,2-difluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(furan-2- carbonyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(3-fluoro-pyridine-2-carbonyl)-
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(5-methyl-thiazole-2- carbonyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-3-(3-fluoro-pyridine-2-carbonyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-(5- methyl-thiazole-2-carbonyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-8-(2!6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2!2!7-trimethyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(hydroxyimino-phenyl- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[(4-fluoro-phenyl)- hydroxyimino-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[hydroxyimino-(4-methoxy- phenyl)-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[hydroxyimino-(4- trifluoromethoxy-phenyl)-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(hydroxyimino-thiophen-3-yl- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(furan-3-yl-hydroxyimino- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(hydroxyimino-o-tolyl-methyl)-
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(hydroxyimino-m-tolyl- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-(hydroxyimino-phenyl- methyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(hydroxyimino- phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-3-[(4-fluoro-phenyl)-hydroxyimino-methyl]-8-(2-fluoro-
6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-[hydroxyimino- (4-trifluoromethoxy-phenyl)-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-
{(hydroxyimino)[(2H5)p enyl]methyl}-7-rTiethyl-2!3-dihydro-5H-[1 !3]thiazolo[3!2- a]pyridin-5-one
-(2-Fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(furan-2-yl- hydroxyimino-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-(2-chloro-5-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-
(hydroxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-(2-fluoro-pyridin-3-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(hydroxyimino-phenyl- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[hydroxyimino-(3- trifluoromethyl-phenyl)-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[(2-fluoro-phenyl)- hydroxyimino-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-[(2-chloro-3-fluoro-phenyl)-hydroxyimino-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-
3-methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[(3-fluoro-pyridin-2-yl)- hydroxyimino-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[hydroxyimino-(5-methyl- thiazol-2-yl)-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-(benzo[b]thiophen-3-yl-hydroxyimino-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino- phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino-phenyl-methyl)-7-methyl-6-(3- trifluoromethoxy-phenyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino- phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-
(methoxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-(2,2-difluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-
(methoxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-(allylimino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-benzyl-7-methyl-5-oxo-6-phenyl-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carboxylic acid benzylamide
-benzyl-7-methyl-5-oxo-6-phenyl-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carboxylic acid methoxy-amide
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5/-/- thiazolo[3,2-a]pyridine-3-carboxylic acid pyridin-2-ylamide
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5/-/- thiazolo[3,2-a]pyridine-3-carboxylic acid phenylamide
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5/-/- thiazolo[3,2-a]pyridine-3-carboxylic acid methoxy-amide
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5/-/- thiazolo[3,2-a]pyridine-3-carboxylic acid benzylamide
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5/-/- thiazolo[3,2-a]pyridine-3-carboxylic acid cyclopropylamide
8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5/-/- thiazolo[3,2-a]pyridine-3-carboxylic acid methyl-(2-pyridin-2-yl-ethyl)-amide
8-benzyl-3-(benzylamino-methyl)-7-methyl-6-phenyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
3-(benzylamino-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-pyridin-4-yl-piperazin-
1 -ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[4-(1 -ethyl-propyl)-piperazin-1 -ylmethyl]-8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-methyl-piperazin-1 - ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(pyridin-4- ylaminomethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-phenyl-piperidin-1 - ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-azetidin-1 -ylmethyl-8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-[(2-pyridin-4-yl- ethylamino)-methyl]-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-phenyl-piperazin-1 - ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-{[(pyridin-2-ylmethyl)- amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-piperidin-1 -ylmethyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
2-(2-{[8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-
5H-thiazolo[3,2-a]pyridin-3-ylmethyl]-amino}-ethyl)-piperidine-1 -carboxylic acid tert-butyl ester
2- (2-{[8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-
5H-thiazolo[3,2-a]pyridin-3-ylmethyl]-amino}-ethyl)-pyrrolidine-1 -carboxylic acid tert-butyl ester
3- [(cyclopropylmethyl-amino)-methyl]-8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-[4-(3,5-dimethyl-phenyl)-piperazin-1 -ylmethyl]-8-(2-fluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-{[(3-dimethylamino-propyl)-methyl-amino]-methyl}-8-(2-fluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-8-(2-fluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-cyclopropylaminomethyl-8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-phenylaminomethyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
-((R)-3-dimethylamino-pyrrolidin-1 -ylmethyl)-8-(2-fluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-((S)-3-dimethylamino-pyrrolidin-1 -ylmethyl)-8-(2-fluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(4-benzyl-piperazin-1 -ylmethyl)-8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-{[(2-methoxy-ethyl)-methyl- amino]-methyl}-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-[4-(3-dimethylamino-propyl)-piperazin-1 -ylmethyl]-8-(2-fluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-{[8-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-5/-/- thiazolo[3,2-a]pyridin-3-ylmethyl]-methyl-amino}-/V,/V-dimethyl-acetamide-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(pyridin-2- ylaminomethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[(furan-2-ylmethyl-methyl-amino)- methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-pyridin-4-ylmethyl- piperazin-1 -ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzo[1 ,3]dioxol-5-yl-8-(2-fluoro-benzyl)-7-methyl-3-{[methyl-(2-pyridin-2-yl-ethyl)- amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-3-[4-(1 -ethyl-propyl)-piperazin-1 -ylmethyl]-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-phenylaminomethyl-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2!6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2!2,7-trimethyl-3-(4-methyl- piperazin-1 -ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2!6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2!2,7-trimethyl-3-{[methyl-(2- pyridin-2-yl-ethyl)-amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-(2,6-difluoro-benzyl)-3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-6-(2-fluoro-
3-methoxy-phenyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-(2!6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2!2,7-trimethyl-3-(4-pyridin-2- ylmethyl-piperazin-1 -ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-cyclopropylaminomethyl-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-
2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-[(methyl-phenethyl- amino)-methyl]-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-[(2-morpholin-4-yl- ethylamino)-methyl]-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-3-[4-(3,5-dimethyl-phenyl)-piperazin-1 -ylmethyl]-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(pyridin-4- ylaminomethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(phenethylamino- methyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-cyclopropylaminomethyl-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-piperidin-1 -ylmethyl-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-methyl-piperazin-
1 -ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-6-(2-fluoro-
3-methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-{[methyl-(2- morpholin-4-yl-ethyl)-amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-(2,6-difluoro-benzyl)-3-{[(3-dimethylamino-propyl)-methyl-amino]-methyl}-6-(2- fluoro-3-methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-(2,6-difluoro-benzyl)-3-[4-(3-dimethylamino-propyl)-piperazin-1 -ylmethyl]-6-(2- fluoro-3-methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-(benzylamino-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2,2,7- trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-[(cyclopropylmethyl-amino)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(benzylamino-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-3-((S)-3-dimethylamino-pyrrolidin-1 -ylmethyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-7-methyl-3-{[methyl-(2-pyridin-2-yl-ethyl)-amino]-methyl}-6-(3- trifluoromethoxy-phenyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-pyridin-4-yl- piperazin-1 -ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-[(methyl-pyridin-4- ylmethyl-amino)-methyl]-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2,2 ,7-trimethyl-3-[(2-morpholin-
4- yl-ethylamino)-methyl]-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(5-chloro-thiophen-2-yl)-8-(2,6-difluoro-benzyl)-7-methyl-3-{[methyl-(2-pyridin-2-yl- ethyl)-amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-3-((R)-3-dimethylamino-pyrrolidin-1 -ylmethyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-{[(2-methoxy-ethyl)-methyl- amino]-methyl}-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-3-[(furan-2-ylmethyl-methyl- amino)-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-(4-pyridin-4- ylmethyl-piperazin-1 -ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-[(benzyl-methyl-amino)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7-methyl-3-{[methyl-(2-pyridin-
2-yl-ethyl)-amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-[4-(3,5-dimethyl-phenyl)-piperazin-1 -ylmethyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-6-(2-fluoro-3-methoxy-phenyl)-8- (2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-
5- one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-(4- methyl-piperazin-1 -ylmethyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-[(2- morpholin-4-yl-ethylamino)-methyl]-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(benzylamino-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-{[(2-methoxy- ethyl)-methyl-amino]-methyl}-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-((R)-3-dimethylamino-pyrrolidin-1 -ylmethyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3- {[methyl-(2-pyridin-2-yl-ethyl)-amino]-methyl}-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-({[2-(6-methoxy- pyridin-2-yl)-ethyl]-methyl-amino}-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-
({methyl-[2-(3-trifluoromethyl-pyridin-2-yl)-ethyl]-amino}-methyl)-2,3-dihydro- thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-3-({[2-(6-fluoro-pyridin-2-yl)-ethyl]-methyl-amino}- methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
-({[2-(5-chloro-pyridin-2-yl)-ethyl]-methyl-amino}-methyl)-6-(2-fluoro-3-methoxy- phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-
({methyl-[2-(3-methyl-pyridin-2-yl)-ethyl]-amino}-methyl)-2,3-dihydro- thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-3-({[2-(5-fluoro-pyridin-2-yl)-ethyl]-methyl-amino}- methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-({[2-(3-methoxy- pyridin-2-yl)-ethyl]-methyl-amino}-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3- ({methyl-[2-(6-methyl-pyridin-2-yl)-ethyl]-amino}-methyl)-2,3-dihydro- thiazolo[3,2-a]pyridin-5-one
-({[2-(4-chloro-pyridin-2-yl)-ethyl]-methyl-amino}-methyl)-6-(2-fluoro-3-methoxy- phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-3-({[2-(3-fluoro-pyridin-2-yl)-ethyl]-methyl-amino}- methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3- {[methyl-(2-quinolin-2-yl-ethyl)-amino]-methyl}-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[2-(piperidin-1 - yl)ethyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[methyl(prop-2-yn-1 - yl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
-(2,6-difluorobenzyl)-3-({[4-(dimethylamino)phenyl]amino}methyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one-({[2-(diethylamino)ethyl](methyl)amino}methyl)-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one-{[4-(3-chlorophenyl)piperazin-1 -yl]methyl}-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[4-(pyrazin-2- yl)piperazin-1 -yl]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[2-(1 - methylpyrrolidin-2-yl)ethyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
-{[4-(1 ,3-benzodioxol-5-yl)piperazin-1 -yl]methyl}-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(2-methyl-1 ,3- benzothiazol-5-yl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({4-[3-(pyrrolidin-1 - yl)propyl]piperazin-1 -yl}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[3-
(trifluoromethyl)benzyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-{[(4- methoxyphenyl)amino]methyl}-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
3- [(tert-butylamino)methyl]-8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7- methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(4- methylbenzyl)amino]methyl}-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(3- phenylpropyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-3-({[2-(3,5-dimethoxyphenyl)ethyl]amino}methyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[3-(4- methylpiperidin-1 -yl)propyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
4- {[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3-dihydro-
5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}-/V,/\/-dimethylpiperazine-1 - carboxamide
8-(2,6-difluorobenzyl)-3-({[3-(dimethylamino)benzyl]amino}methyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-[(isoquinolin-8-ylamino)methyl]- 7-methyl-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-5-one
2- (4-{[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3- dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}piperazin-1 -yl)-/V-(2- phenylethyl)acetamide
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[4-(pyridin-3- ylmethyl)piperazin-1 -yl]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
3- (azetidin-1 -ylmethyl)-8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-
2!3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({4-[4-
(trifluoromethyl)phenyl]piperazin-1 -yl}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
2-(4-{[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3- dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}piperazin-1 -yl)-/V-(2- methoxyethyl)acetamide
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({4-[2-oxo-2-
(pyrrolidin-1 -yl)ethyl]piperazin-1 -yl}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[2-(pyrrolidin-1 - yl)ethyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-{[(2-chlorobenzyl)amino]methyl}-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-{[(4- fluorophenyl)amino]methyl}-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
8-(2,6-difluorobenzyl)-3-{[(3,5-dimethoxybenzyl)amino]methyl}-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-({[2-(2- fluorophenyl)ethyl]amino}methyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(2- phenoxyethyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-(morpholin-4- ylmethyl)-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(pyridin-4- ylmethyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-{[(4- methoxybenzyl)amino]methyl}-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
8-(2!6-difluorobenzyl)-3-{[(2,2-diphenylethyl)amino]methyl}-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-{[(2-chlorobenzyl)(methyl)amino]methyl}-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3- ({[4-(benzyloxy)phenyl]amino}methyl)-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
4- [(4-{[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3- dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}piperazin-1 - yl)methyl]benzonitrile
8-(2,6-difluorobenzyl)-3-{[(3,5-dimethoxybenzyl)(methyl)amino]methyl}-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({4-[(1 - methylpiperidin-4-yl)methyl]piperazin-1 -yl}methyl)-2,3-dihydro-5/-/- [1 ,3]thiazolo[3,2-a]pyridin-5-one
methyl 4-{[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3- dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}piperazine-1 -carboxylate
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[methyl(thiophen-3- ylmethyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[methyl(naphthalen- 2-ylmethyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-{[(2- hydroxyethyl)(methyl)amino]methyl}-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(4- phenylbutyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-{[(3- methoxybenzyl)amino]methyl}-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
3-{[4-(1 ,3-benzodioxol-5-ylmethyl)piperazin-1 -yl]methyl}-8-(2,6-difluorobenzyl)-6-(2- fluoro-3-methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
3- ({[3-(diethylamino)propyl]amino}methyl)-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[4-(1 -methylpiperidin-
4- yl)piperazin-1 -yl]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(3- methylbenzyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-(thiomorpholin-4- ylmethyl)-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-5-one
4- [2-({[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3- dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl]methyl}amino)ethyl]benzenesulfonamide
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({methyl[2-(pyridin-3- yl)ethyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[4-(2- phenoxyethyl)piperazin-1 -yl]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-
5- one
8-(2,6-difluorobenzyl)-3-({[2-(dimethylamino)benzyl]amino}methyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[4-
(methylsulfonyl)piperazin-1 -yl]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
2- (4-{[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3- dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}piperazin-1 -yl)-/V- methylacetamide
3- ({[2-(4-acetylpiperazin-1 -yl)ethyl]amino}methyl)-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(2- methylbenzyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({4-[3-
(trifluoromethyl)phenyl]piperazin-1 -yl}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
3- [(1 ,3-benzodioxol-5-ylamino)methyl]-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(thiophen-2- ylmethyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-(pyrrolidin-1 - ylmethyl)-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-({[3-(1 H-imidazol-1 - yl)propyl]amino}methyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
4- [({[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3-dihydro-
5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}amino)methyl]benzonitrile
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({methyl[(1 -methyl- 1 H-pyrazol-5-yl)methyl]amino}methyl)-2!3-dihydro-5H-[1 !3]thiazolo[3,2- a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(thiophen-3- ylmethyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[(1 -methyl-1 H- imidazol-5-yl)methyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin- 5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({4-[2-
(trifluoromethyl)phenyl]piperazin-1 -yl}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[2-(4- methylphenyl)ethyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-{[(2- methoxybenzyl)amino]methyl}-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-[(3-methylpiperidin-1 - yl)methyl]-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[3-(2-oxopyrrolidin- 1 -yl)propyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({[4-(morpholin-4- yl)phenyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-3-({[2-(3- fluorophenyl)ethyl]amino}methyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
/V-[4-({[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5-oxo-2,3- dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl]methyl}amino)phenyl]methanesulfonamide
3-{[4-(2-chlorobenzyl)piperazin-1 -yl]methyl}-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-{[(1 /-/-pyrazol-3- ylmethyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({4-[2-(pyridin-2- yl)ethyl]piperazin-1 -yl}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one 8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({4-[(1 - methylpiperidin-3-yl)methyl]piperazin-1 -yl}methyl)-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-5-one
/V-cyclopropyl-2-(4-{[8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3-yl]methyl}piperazin-1 - yl)acetamide
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[3- (morpholin-4-yl)propyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(2- methylbenzyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-{[(3-chlorobenzyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-{[(2- hydroxyethyl)(methyl)amino]methyl}-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
(morpholin-4-ylmethyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(4- phenylbutyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one 3-(1 !4'-bipiperidin-1 '-ylmethyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3- {[methyl(prop-2-yn-1 -yl)amino]methyl}-2!3-dihydro-5H-[1 !3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-{[(3- methoxybenzyl)amino]methyl}-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
3-{[(4-chlorophenyl)(methyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
3-{[4-(1 ,3-benzodioxol-5-ylmethyl)piperazin-1 -yl]methyl}-6-(2-fluoro-3- methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro- 5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3- ({[3-(dimethylamino)propyl]amino}methyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-
6-(trifluoromethyl)benzyl]-7-methyl-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin- 5-one
4- {2-[({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5- oxo^.S-dihydro-SH-tl .S^hiazolo^^-^pyridin-S- yl}methyl)amino]ethyl}benzenesulfonamide
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
{[(3!4!5-trimethoxybenzyl)amino]methyl}-2!3-dihydro-5H-[1 !3]thiazolo[3,2- a]pyridin-5-one
3-{[tert-butyl(methyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[2- (pyridin-2-yl)ethyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
{[(pyridin-2-ylmethyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin- 5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-{[(4- methoxyphenyl)amino]methyl}-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
3-{[(2-chlorobenzyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
3-[(dibenzylamino)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
ethyl 4-({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl- 5-0X0-2, 3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)piperazine-1 - carboxylate
6-(2-fluoro-3-methoxyphenyl)-3-{[(4-fluorophenyl)amino]methyl}-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
3-(azepan-1 -ylmethyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-[(4- methylpiperidin-1 -yl)methyl]-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
1 -({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5- oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)piperidine-3- carboxamide
3-{[(1 ,3-benzodioxol-5-ylmethyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2- fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2!3-dihydro-5H-[1 !3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-[(prop- 2-yn-1 -ylamino)methyl]-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
3- (3,4-dihydroisoquinolin-2(1 H)-ylmethyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
{[(3!4!5-trimethoxyphenyl)amino]methyl}-2!3-dihydro-5H-[1 !3]thiazolo[3,2- a]pyridin-5-one
4- [({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5- oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)amino]-/V- phenylbenzamide
ethyl {4-[({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2na]pyridin-3- yl}methyl)amino]phenyl}acetate
3-{[(4-chlorobenzyl)(methyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[3- (1 H-tetrazol-5-yl)phenyl]amino}methyl)-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[3-
(piperidin-1 -yl)propyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin- 5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[2- (thiophen-2-yl)ethyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin- 5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-[(4- methyl-1 ,4-diazepan-1 -yl)methyl]-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
3-[(4-ethylpiperazin-1 -yl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[2-(2- oxoimidazolidin-1 -yl)ethyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
3-{[bis(pyridin-2-ylmethyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-^ (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(2- phenylpropan-2-yl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
3-({4-[2-(dimethylamino)ethyl]piperazin-1 -yl}methyl)-6-(2-fluoro-3-methoxyphenyl)-8- [2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2!3-dihydro-5H-[1 !3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({4-[2- (morpholin-4-yl)ethyl]piperazin-1 -yl}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
3- {[(biphenyl-4-ylmethyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
4- [4-({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5- oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)piperazin-1 - yl]benzonitrile
2-[4-({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5- oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)piperazin-1 -yl]-/V,/\/- dimethylacetamide
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({4-[2- (pyrrolidin-1 -yl)ethyl]piperazin-1 -yl}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[3-(5- methyl-1 /-/-pyrazol-4-yl)propyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-({[4-(1 H- imidazol-1 -yl)phenyl]amino}methyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[(5- methylpyrazin-2-yl)methyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
[(quinolin-4-ylamino)methyl]-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
({methyl[(1 -methyl-1 H-pyrazol-4-yl)methyl]amino}methyl)-2,3-dihydro-5/-/- [1 ,3]thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(3- methylbenzyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one-{[benzyl(ethyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
-({benzyl[2-(dimethylamino)ethyl]amino}methyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2- fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2!3-dihydro-5H-[1 !3]thiazolo[3,2- a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-[(isoquinolin-5- ylamino)methyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[4- (morpholin-4-yl)phenyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-({[3-(1 H- imidazol-1 -yl)propyl]amino}methyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
-{[(3,5-dimethoxybenzyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
-[(4-acetylpiperazin-1 -yl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-[(isoquinolin-4- ylamino)methyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[4-(1 - phenylethyl)piperazin-1 -yl]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-[({2-[3- (trifluoromethyl)phenyl]ethyl}amino)methyl]-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
-({[4-(dimethylamino)butyl]amino}methyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
3-[(1 ,3-benzothiazol-6-ylamino)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
3-{[(2,5-dichlorobenzyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(2- phenoxyethyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
({methyl[2-(pyridin-3-yl)ethyl]amino}methyl)-2!3-dihydro-5H-[1 !3]thiazolo[3,2- a]pyridin-5-one
3- ({[4-(dimethylamino)benzyl]amino}methyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-
6-(trifluoromethyl)benzyl]-7-methyl-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin- 5-one
/V-{4-[({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5- oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2na]pyridin-3- yl}methyl)amino]phenyl}methanesulfonamide
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[4-
(thieno[3,2-d]pyrimidin-4-yl)piperazin-1 -yl]methyl}-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[4-(2- phenoxyethyl)piperazin-1 -yl]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-
5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[4- (phenylcarbonyl)piperazin-1 -yl]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
4- ({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5- oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2na]pyridin-3-yl}methyl)-A/,A/- dimethylpiperazine-1 -carboxamide
3-({[2-(4-benzylpiperidin-1 -yl)ethyl]amino}methyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2- fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2!3-dihydro-5H-[1 !3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[4-
(pyrrolidin-1 -ylcarbonyl)piperazin-1 -yl]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[2-(3- methylphenyl)ethyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
3- ({[2-(dimethylamino)benzyl]amino}methyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-
6-(trifluoromethyl)benzyl]-7-methyl-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin- 5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
{[methyl(pyridin-4-yl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin- 5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-[(isoquinolin-8- ylamino)methyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
4- ({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5- oxo-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-3-yl}methyl)-1 -(2- phenylethyl)piperazine-2,6-dione
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(2- methyl-1 !3-benzothiazol-5-yl)amino]methyl}-2!3-dihydro-5H-[1 !3]thiazolo[3,2- a]pyridin-5-one
2-[4-({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5- oxo-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-3-yl}methyl)piperazin-1 -yl]-/V-(2- phenylethyl)acetamide
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[(1 - methyl-1 H-pyrazol-5-yl)methyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
({methyl[(1 -methyl-1 H-pyrazol-3-yl)methyl]amino}methyl)-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[(1 H- pyrazol-3-ylmethyl)amino]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[4-(3- phenylpropyl)piperazin-1 -yl]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin- 5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[2-(4- methylpiperazin-1 -yl)ethyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
-{[4-({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-5- oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl)piperazin-1 - yl]methyl}benzonitrile
-{[(3,5-dimethoxybenzyl)(methyl)amino]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2- fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2!3-dihydro-5H-[1 !3]thiazolo[3,2- a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[2-(2- methylphenyl)ethyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
[(pyridazin-3-ylamino)methyl]-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3- {[(thiophen-3-ylmethyl)amino]methyl}-2!3-dihydro-5H-[1 !3]thiazolo[3,2- a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({4-[2- (pyridin-4-yl)ethyl]piperazin-1 -yl}methyl)-2!3-dihydro-5H-[1 !3]thiazolo[3,2- a]pyridin-5-one
-{[4-(biphenyl-3-yl)piperazin-1 -yl]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-3-{[4-(3- methoxypropyl)piperazin-1 -yl]methyl}-7-methyl-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-{[4-
(pyridin-3-ylmethyl)piperazin-1 -yl]methyl}-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({4-[(1 - methylpiperidin-3-yl)methyl]piperazin-1 -yl}methyl)-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({4-[(1 - methylpiperidin-4-yl)methyl]piperazin-1 -yl}methyl)-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({4-[2-
(trifluoromethyl)phenyl]piperazin-1 -yl}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-({[(1 - methyl-1 H-pyrazol-4-yl)methyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2- a]pyridin-5-one
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
{[methyl(naphthalen-2-ylmethyl)amino]methyl}-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-5-one
/V-cyclopropyl-2-[4-({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-3-yl}methyl)piperazin-1 -yl]acetamide
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
({methyl[2-(pyrrolidin-1 -yl)ethyl]amino}methyl)-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-5-one
3-({[2-(4-acetylpiperazin-1 -yl)ethyl]amino}methyl)-6-(2-fluoro-3-methoxyphenyl)-8-[2- fluoro-6-(trifluoromethyl)benzyl]-7-methyl-2!3-dihydro-5H-[1 !3]thiazolo[3,2- a]pyridin-5-one
/V-(3-{[({6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-
5-oxo-2!3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}methyl)amino]methyl}phenyl)acetamide
6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
({methyl[2-(4-methylpiperidin-1 -yl)ethyl]amino}methyl)-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-5-one
8-(2,6-difluoro-benzyl)-6-iodo-7-methyl-3-{[methyl-(2-pyridin-2-yl-ethyl)-amino]- methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(3-chloro-phenyl)-8-(2,6-difluoro-benzyl)-7-methyl-3-{[methyl-(2-pyridin-2-yl-ethyl)- amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-benzo[1 !3]dioxol-5-yl-8-(2,6-difluoro-benzyl)-7-methyl-3-{[methyl-(2-pyridin-2-yl- ethyl)-amino]-methyl}-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(R*)]}-3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(S*)]}-3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3S-[3a(S*)]}-3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(4-fluoro-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(4-fluoro-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(4-methoxy-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(4-methoxy-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(4-trifluoromethoxy-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2- fluoro-3-methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(S*)]-3-[amino-(4-trifluoromethoxy-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2- fluoro-3-methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-2,2,7- trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(4-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-
6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(S*)]-3-[amino-(4-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-
6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(R*)]-3-[amino-(4-trifluoromethoxy-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-
8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
[3a(S*)]-3-[amino-(4-trifluoromethoxy-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)- 8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
[3a(S*)]-3-{amino[(2H5)p enyl]methyl}-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(furan-2-yl- isopropylamino-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(R*)]-3-(amino-phenyl-methyl)-6-(2-chloro-5-trifluoromethoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
[3a(S*)]-3-(amino-phenyl-methyl)-6-(2-chloro-5-trifluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-pyridin-3-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-pyridin-3-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-6-(3- trifluoromethoxy-phenyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-6-(3- trifluoromethoxy-phenyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-
6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-(2!2-difluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-(2!2-difluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-[amino-(2-chloro-3-fluoro-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-m-tolyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-m-tolyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-thiophen-3-yl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)- 7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(R*)]-3-[amino-(3-fluoro- phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy-phenyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(3-fluoro-phenyl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(5-methyl-thiazol-2-yl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(5-methyl-thiazol-2-yl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino-(3-fluoro-pyridin-2-yl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino-(3-fluoro-pyridin-2-yl)-methyl]-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3- methoxy-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-benzo[b]thiophen-3-yl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-fluoro-3-methoxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[amino(phenyl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one 1 -oxide
[3a(R*)]-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-6-iodo-7-methyl-2,3-dihydro- thiazolo[3,2a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-7-methyl-6-thiophen-2-yl-2,3-dihydro- thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(5-chloro-thiophen-2-yl)-8-(2,6-difluoro-benzyl)-7-methyl-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(3-chloro-phenyl)-8-(2,6-difluoro-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(6-chloro-pyridin-2-yl)-8-(2,6-difluoro-benzyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2,6-difluoro-benzyl)-6-(2-methoxy-pyridin-3-yl)-7-meth
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(2-methoxy-pyridin-3- yl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(6-methoxy-pyridin-2- yl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(6-chloro-pyridin-2-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(2-chloro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-(2-chloro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-(2-chloro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(amino-phenyl-methyl)-6-benzo[1 ,3]dioxol-5-yl-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-3-methyl-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-3-methyl-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(2-fluoro-3- trifluoromethyl-phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(amino-phenyl-methyl)-6-(2-chloro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(3-chloro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-6-yl]-2-fluoro-benzonitrile
[3a(S*)]-3-[3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-6-yl]-2-fluoro-benzonitrile
3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-6-thiophen-2- yl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-6-(5-methyl- thiophen-2-yl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(5-chloro-thiophen-2-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(3-chloro-thiophen-2-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino(phenyl)(2H)methyl]-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-[amino(phenyl)(2H)methyl]-8-(2,6-difluorobenzyl)-6-(2-fluoro-3- methoxyphenyl)-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-[amino(phenyl)(2H)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
[3a(S*)]-3-[amino(phenyl)(2H)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one
3-(1 -amino-1 -phenyl-ethyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(1 -amino-1 -phenyl-but-3-enyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3R-[3a(R*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
{3S-[3a(R*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
{3R-[3a(S*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
{3S-[3a(S*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-
2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-acetic acid ethyl ester
3- ({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- propionic acid ethyl ester
4- ({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
5- ({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- pentanoic acid ethyl ester
4-({[6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
4-({[8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-6-(3-trifluoromethoxy- phenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid ethyl ester
{3R-[3a(R*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
{3S-[3a(R*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)- 7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
{3R-[3a(S*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)- 7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
{3S-[3a(S*)]}-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)- 7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo- 2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-acetic acid 3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-
methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-propionic acid
4- ({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
5- ({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- pentanoic acid
4-({[6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
4-({[8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-6-(3-trifluoromethoxy- phenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyric acid
{3R-[3a(R*)]}-sodium 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl] -7-methyl-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
{3S-[3a(R*)]}-sodium 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl] -7-methyl-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
{3R-[3a(S*)]}-sodium 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl] -7-methyl-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
{3S-[3a(S*)]}-sodium 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl] -7-methyl-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2- a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
6- (2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-
(methylamino-phenyl-methyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(dimethylamino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(butylamino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-
[phenyl-(4,4,4-trifluoro-butylamino)-methyl]-2,3-dihydro-thiazolo[3,2-a]pyridin- 5-one
3-(allylamino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(1 -allylamino-1 -phenyl-but-3-enyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-(2- phenyl-1 ,2,3,6-tetrahydro-pyridin-2-yl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one /V-{[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-acetamide 3-bromo-2,2-difluoro-/V-{[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methylj-propionamide
2,2-difluoro-3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-propionic acid ethyl ester
2,2-difluoro-3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-propionic acid
3-[(3,3-difluoro-2-oxo-azetidin-1 -y l)-phenyl-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-
(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-
5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-[(3-hydroxy- propylamino)-phenyl-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-[(4-hydroxy- butylamino)-phenyl-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[(2,2-difluoro-3-hydroxy-propylamino)-phenyl-methyl]-6-(2-fluoro-3-methoxy- phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
{3 ?-[3a( ?^]H-({[6-[3-(1 ,1-difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid ethyl ester
{3S-[3a(R*)]}-4-({[6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid ethyl ester
{3R-[3a(S*)]}-4-({[6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid ethyl ester
{3S-[3a(S*)]}-4-({[6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)- 7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
{3 ?-[3a( ?^]H-({[6-[3-(1 ,1-difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid
{3S-[3a(R*)]}-4-({[6-[3-(1 !1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid
{3R-[3a(S*)]}-4-({[6-[3-(1 !1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid
{3S-[3a(S*)]}-4-({[6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
8-(2,6-difluorobenzyl)-6-(2-fluoro-3-methoxyphenyl)-7-methyl-3-({methyl[2-(pyridin-2- yl)ethyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 -oxide
6-(4-chloro-2-fluoro-3-methoxyphenyl)-8-(2,6-difluorobenzyl)-7-methyl-3-({methyl[2- (pyridin-2-yl)ethyl]amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one 1 -oxide
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(hydroxy-phenyl- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one.
6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S- phenyl ester
6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-
2,3-dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester 6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester 6-[3-(1 ,1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-
5-0X0-2, 3-dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester 6-(2-fluoro-4-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-
2,3-dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester 8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-hydroxy-phenyl)-7-methyl-5-oxo-2,3-dihydro-
5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
-(2-fluoro-4-phenoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-
2,3-dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
-(4-fluoro-2,2-dideuterobenzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S- phenyl ester
-(3-difluoromethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3- dihydro-5H-thiazolo[3,2-a]pyridine-3-carbothioic acid S-phenyl ester
-(2-fluoro-benzoyl)-6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-(2-fluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-
(thiophene-3-carbonyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-(2- methyl-benzoyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-(3- methyl-benzoyl)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-chloro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,5-difluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2,3-difluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-chloro-3-fluoro-benzoyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-benzoyl-6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-6-[3-(1 ,1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-6-(2-fluoro-4-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-hydroxy-phenyl)-7-methyl-2,3- dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-6-(3-difluoromethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-6-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-
2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-6-(4-fluoro-2,2-dideutero-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-benzoyl-6-(2-fluoro-4-phenoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-benzoyl-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one
-[3-(1 ,1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-
(hydroxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-(2-fluoro-3-methoxy-phenyl)-3-[(2-fluoro-phenyl)-hydroxyimino-methyl]-8-(2-fluoro-
6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(hydroxyimino- thiophen-3-yl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(hydroxyimino-o- tolyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(hydroxyimino- m-tolyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-[(2-chloro-phenyl)-hydroxyimino-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-
6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-[(2,5-difluoro-phenyl)-hydroxyimino-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-[(2,3-difluoro-phenyl)-hydroxyimino-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-[(2-chloro-3-fluoro-phenyl)-hydroxyimino-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8- (2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-
5- one
-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-[hydroxyimino- (5-methyl-thiazol-2-yl)-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3- (methoxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-
(methoxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-
(methoxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-[3-(1 ,1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-
(methoxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-(2-fluoro-4-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino- phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-[(2-fluoro-phenyl)-methoxyimino-methyl]-6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-hydroxy-phenyl)-3-(methoxyimino-phenyl- methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino- phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(3-difluoromethoxy-phenyl)-8-(2-fuoro-6-trifluoromethyl-benzyl)-3-(methoxyimino- phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(4-fluoro-2,2-dideutero-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-
(methoxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
-(2-fluoro-4-phenoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-(methoxyimino- phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
-(2-fluoro-3-methoxy-phenyl)-3-[(2-fluoro-phenyl)-methoxyimino-methyl]-8-(2-fluoro-
6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[(3,5-difluoro-phenyl)-methoxyimino-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
6-(3-difluoromethoxy-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-
(methoxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-
(methoxyimino-phenyl-methyl)-7-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5- one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(amino-phenyl-methyl)-6-(2-fluoro-4-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[amino-(2-fluoro-phenyl)-methyl]-6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-
6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-hydroxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-hydroxy- phenyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(4-fluoro-2,2-dideutero-benzo[1 ,3]clioxol-5- yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
{3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(4-fluoro-2!2-dideutero-benzo[1 ,3]dioxol-5- yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
{3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(4-fluoro-2!2-dideutero-benzo[1 ,3]dioxol-5- yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
{3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(4-fluoro-2!2-dideutero-benzo[1 ,3]dioxol-5- yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(3-ethoxy-2-fluoro-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(amino-phenyl-methyl)-6-(2-fluoro-4-phenoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-[amino-(2-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
{3S-[3a(R*)]}-3-[amino-(2-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
{3R-[3a(S*)]}-3-[amino-(2-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
{3S-[3a(S*)]}-3-[amino-(2-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
3-[amino-(3,5-difluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-thiophen-3-yl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(S*)]-3-(amino-thiophen-3-yl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(R*)]-3-(amino-o-tolyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(S*)]-3-(amino-o-tolyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(R*)]-3-(amino-m-tolyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(S*)]-3-(amino-m-tolyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(R*)]-3-[amino-(2-chloro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
[3a(S*)]-3-[amino-(2-chloro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
[3a(R*)]-3-[amino-(3-chloro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
[3a(S*)]-3-[amino-(3-chloro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
[3a(R*)]-3-[amino-(2,5-difluoro-phenyl)-rnethyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
[3a(S*)]-3-[amino-(2,5-difluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
[3a(R*)]-3-[amino-(2,3-difluoro-phenyl)-rnethyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
[3a(S*)]-3-[amino-(2,3-difluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
[3a(R*)]-3-[amino-(2-chloro-3-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8- (2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin- 5-one )
[3a(S*)]-3-[amino-(2-chloro-3-fluoro-phenyl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8- (2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin- 5-one
[3a(R*)]-3-[amino-(5-methyl-thiazol-2-yl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
[3a(S*)]-3-[amino-(5-methyl-thiazol-2-yl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
[3a(R*)]-3-[amino-(5-chloro-thiophen-2-yl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8- (2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin- 5-one
[3a(S*)]-3-[amino-(5-chloro-thiophen-2-yl)-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8- (2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin- 5-one
3-(amino-phenyl-methyl)-6-(3-difluoromethoxy-2-fluoro-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one {3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one {3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one {3S-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one {3R-[3a(R*)]}-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-
2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-one
{3S-[3a(R*)]}-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-
2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-one
{3R-[3a(S*)]}-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-
2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-one
{3S-[3a(S*)]}-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-iodo-
2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-[3-(1 , 1 -difluoro-ethyl)-phenyl]-8-(2-f luoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one {3R-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-
8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
{3S-[3a(R*)]}-3-(amino-phenyl-methyl)-6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)- 8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
{3R-[3a(S*)]}-3-(amino-phenyl-methyl)-6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)- 8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
{3S-[3a(S^]^3-(amino^henyl-methyl)-6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)- 8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-[3-(1 ,1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-
6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(S*)]-3-(amino-phenyl-methyl)-6-[3-(1 , 1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-f luoro-
6-trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 6-(3-acetyl-2-fluoro-phenyl)-3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(2-fluoro-5-trifluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(6-methoxy-4-methyl- pyridin-3-yl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(2-fluoro-4-trifluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-8-(2-fluoro-6-trifluoro
methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(S*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(R*)]-3-(amino-phenyl-methyl)-6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-(5-fluoro-2!3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2- fluoro-6-trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one [3a(S*)]-3-(amino-phenyl-methyl)-6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-(amino-phenyl-methyl)-6-(2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-(amino-phenyl-methyl)-6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(R*)]-3-(amino-phenyl-methyl)-6-[3-(1 , 1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro- 6-trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
[3a(S*)]-3-(amino-phenyl-methyl)-6-[3-(1 , 1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-f luoro-
6- trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5- one
[3a(R*)]-3-(amino-phenyl-methyl)-6-[3-(1 , 1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6- trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
[3a(S*)]-3-(amino-phenyl-methyl)-6-[3-(1 , 1 -difluoro-ethyl)-phenyl]-8-(2-f luoro-6- trifluoromethyl-benzyl)-2,2,7-trimethyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
{3R-[3a(R*)]}-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid methyl ester
{3S-[3a(R*)]}-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid methyl ester
{3R-[3a(S*)]}- [2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid methyl ester
{3S-[3a(S*)]}-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid methyl ester
6-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- hexanoic acid methyl ester
6-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- hexanoic acid amide
4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-3- hydroxy-butyric acid ethyl ester
2-tert-butoxycarbonylamino-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-butyric acid tert-butyl ester
4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyronitrile
{3R-[3a(R*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyronitrile
{3S-[3a(R*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyronitrile
{3R-[3a(S*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyronitrile
{3S-[3a(S*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyronitrile
4-({[8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-methoxy-phenyl)-7-methyl-5-oxo-2,3- dihydro-5H-hiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
4-({[6-(2-fluoro-4-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
4-({[6-(3-acetyl-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo- 2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
4-({[6-(2-fluoro-5-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
{3R-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid ethyl ester
{3S-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid ethyl ester
{3R-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid ethyl ester
{3S-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid ethyl ester
{3R-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid ethyl ester
{3S-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid ethyl ester
{3R-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid ethyl ester
{3S-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid ethyl ester
4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyronitrile
4-({(2-fluoro-phenyl)-[6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-methyl}-amino)-butyronitrile
4-({[6-(2-fluoro-4-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-2!2,7- trimethyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
4-({[6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-2,2,7- trimethyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
4-({[6-(2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-2!2!7-trimethyl-5-oxo-2,3- dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
4-({[6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-2!2,7- trimethyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
[2-({[6-[3-(1 , 1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trif luoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid ethyl ester
4-({[6-[3-(1 ,1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
[2-({[6-[3-(1 , 1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-ethoxy]- acetic acid methyl ester
4-({[6-(2-fluoro-4-phenoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
{3R-[3a(R*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)- 7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
{3S-[3a(R*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
{3R-[3a(S*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
{3S-[3a(S*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid ethyl ester
{3R-[3a(R*)]}-[2-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid ethyl ester
{3S-[3a(R*)]}-[2-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid ethyl ester
{3R-[3a(S*)]}-[2-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid ethyl ester
{3S-[3a(S*)]}-[2-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid ethyl ester
{3R-[3a(R*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid ethyl ester
{3S-[3a(R*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid ethyl ester
{3R-[3a(S*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid ethyl ester
{3S-[3a(S*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid ethyl ester
{3R-[3a(R*)]}-[2-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid methyl ester
{3S-[3a(R*)]}-[2-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid methyl ester
{3R-[3a(S*)]}-[2-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid methyl ester
{3S-[3a(S*)]}-[2-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid methyl ester
{3R-[3a(R*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)- methyl]-amino}-butyric acid ethyl ester
{3S-[3a(R*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)- methyl]-amino}-butyric acid ethyl ester
{3R-[3a(S*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)- methyl]-amino}-butyric acid ethyl ester
{3S-[3a(S*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)- methyl]-amino}-butyric acid ethyl ester
{3R-[3a(R*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)- methyl]-amino}-ethoxy)-acetic acid ethyl ester
{3S-[3a(R*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)- methyl]-amino}-ethoxy)-acetic acid ethyl ester
{3R-[3a(S*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)- methyl]-amino}-ethoxy)-acetic acid ethyl ester
{3S-[3a(S*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)- methyl]-amino}-ethoxy)-acetic acid ethyl ester
4-({(3,5-difluoro-phenyl)-[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-methyl}- amino)-butyric acid ethyl ester
{3R-[3a(R*)]}-4-({[6-(5-fluoro-2!3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
{3S-[3a(R*)]}-4-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
{3R-[3a(S*)]}-4-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
{3S-[3a(S*)]}-4-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-butyric acid ethyl ester
{3R-[3a(R*)]}-[2-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-ethoxy]-acetic acid ethyl ester
{3S-[3a(R*)]}-[2-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-ethoxy]-acetic acid ethyl ester
{3R-[3a(S*)]}-[2-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-ethoxy]-acetic acid ethyl ester
{3S-[3a(S*)]}-[2-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-ethoxy]-acetic acid ethyl ester
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-3-[(2-hydroxy- ethylamino)-phenyl-methyl]-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3- ({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- propane-1 -sulfonic acid
4- ({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butane- 1 -sulfonic acid
2-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-ethyl]- isoindole-1 ,3-dione
2-[3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-propyl]- isoindole-1 ,3-dione
2-[4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyl]- isoindole-1 ,3-dione
{3R-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-oxazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid ethyl ester
{3S-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-oxazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid ethyl ester
{3R-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-oxazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid ethyl ester
{3S-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-oxazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid ethyl ester
{3R-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-oxazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid ethyl ester
{3S-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-oxazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid ethyl ester
{3R-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-oxazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid ethyl ester
{3S-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-oxazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid ethyl ester
{3R-[3a(R*)]}-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid
{3S-[3a(R*)]}-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid
{3R-[3a(S*)]}-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid
{3S-[3a(S*)]}-[2-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid
6-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- hexanoic acid
4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-3- hydroxy-butyric acid
4-({[8-(2-fluoro-6-trifluoromethyl-benzyl)-6-(3-methoxy-phenyl)-7-methyl-5-oxo-2,3- dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
4-({[6-(2-fluoro-4-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
4-({[6-(3-acetyl-2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5-oxo- 2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
4-({[6-(2-fluoro-5-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
{3R-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid
{3S-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid
{3R-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid
{3S-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid
{3R-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid
{3S-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid
{3R-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid
{3S-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid
4-({[6-(2-fluoro-4-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-2!2,7- trimethyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
4-({[6-(2-fluoro-3-trifluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-2,2,7- trimethyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
4-({[6-(2-fluoro-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-2!2!7-trimethyl-5-oxo-2,3- dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
4-({[6-(2-fluoro-5-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-2!2,7- trimethyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
[2-({[6-[3-(1 , 1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trif luoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid
4-({[6-[3-(1 ,1 -difluoro-ethyl)-2-fluoro-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
[2-({[6-[3-(1 ,1 -difluoro-ethyl)-phenyl]-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-ethoxy]- acetic acid
4-({[6-(2-fluoro-4-phenoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-butyric acid
{3R-[3a(R*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)- 7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
{3S-[3a(R*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
{3R-[3a(S*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
{3S-[3a(S*)]}-4-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
{3R-[3a(R*)]}-[2-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid
{3S-[3a(R*)]}-[2-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid
{3R-[3a(S*)]}-[2-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid
{3S-[3a(S*)]}-[2-({[6-(3-difluoromethoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-ethoxy]-acetic acid
{3R-[3a(R*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid
{3S-[3a(R*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid
{3R-[3a(S*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid
{3S-[3a(S*)]}-4-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid
{3R-[3a(R*)]}-[2-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid
{3S-[3a(R*)]}-[2-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid
{3R-[3a(S*)]}-[2-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid
{3S-[3a(S*)]}-[2-({[6-(4-fluoro-benzo[1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid
{3R-[3a(R*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)- methyl]-amino}-butyric acid
{3S-[3a(R*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)- methyl]-amino}-butyric acid
{3R-[3a(S*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)- methyl]-amino}-butyric acid
{3S-[3a(S*)]}-4-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)- methyl]-amino}-butyric acid
{3R-[3a(R*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)- methyl]-amino}-ethoxy)-acetic acid
{3S-[3a(R*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)- methyl]-amino}-ethoxy)-acetic acid
{3R-[3a(S*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)- methyl]-amino}-ethoxy)-acetic acid
{3S-[3a(S*)]}-(2-{[[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-
7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-(2-fluoro-phenyl)- methyl]-amino}-ethoxy)-acetic acid
4-({(3,5-difluoro-phenyl)-[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-methyl}- amino)-butyric acid
{3R-[3a(R*)]}-4-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-butyric acid
{3S-[3a(R*)]}-4-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-butyric acid
{3R-[3a(S*)]}-4-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-butyric acid
{3S-[3a(S*)]}-4-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-butyric acid
{3R-[3a(R*)]}-[2-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-ethoxy]-acetic acid
{3S-[3a(R*)]}-[2-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-ethoxy]-acetic acid
{3R-[3a(S*)]}-[2-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-ethoxy]-acetic acid
{3S-[3a(S*)]}-[2-({[6-(5-fluoro-2,3-dihydro-benzo[1 ,4]dioxin-6-yl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3- yl]-phenyl-methyl}-amino)-ethoxy]-acetic acid
{3R-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-oxazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid
{3S-[3a(R*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-oxazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid
{3R-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-oxazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid
{3S-[3a(S*)]}-4-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-oxazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-butyric acid
{3R-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-oxazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid
{3S-[3a(R*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-oxazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid
{3R-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-oxazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid
{3S-[3a(S*)]}-[2-({[6-(2-fluoro-3-isopropoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl- benzyl)-7-methyl-5-oxo-2,3-dihydro-5/-/-oxazolo[3,2-a]pyridin-3-yl]-phenyl- methyl}-amino)-ethoxy]-acetic acid
4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-5- oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)- butyramide
6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-
{phenyl-[3-(1 /-/-tetrazol-5-yl)-propylamino]-methyl}-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
6-(4-fluoro-1 ,3-benzo dioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3-
(phenyl{[3-(1 /-/-tetrazol-5-yl)propyl] amino}methyl)-2,3-dihydro-5/-/-[1 ,3]thiazolo
[3,2-a]pyridin-5-one 1 -oxide
6-(4-fluoro-benzo [1 ,3]dioxol-5-yl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl-3-
{phenyl-[3-(1 /-/-tetrazol-5-yl)-propylamino]-methyl}-2,3-dihydro-thiazolo[3,2- a]pyridin-5-one
2- amino-4-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7- methyl-5-oxo-2,3-dihydro-5/-/-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}- amino)-butyric acid
3- [(2-amino-ethylamino)-phenyl-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one 3-[(3-amino-propylamino)-phenyl-methyl]-6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6- trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
3-[(4-amino-butylamino)-phenyl-methyl]-6-(2-fluoro-3-methoxy
trifluoromethyl-benzyl)-7-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one
/V-[3-({[6-(2-fluoro-3-methoxy-phenyl)-8-(2-fluoro-6-trifluoromethyl-benzyl)-7-methyl^ oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-3-yl]-phenyl-methyl}-amino)-propyl]- guanidine
[1 £,3/?(/?)]-ethyl 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/- [1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
[1 ¾,3S( ?)]-ethyl 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/- [1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
[1 £,3/?(S)]-ethyl 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/- [1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
[1 £,3S(S)]-ethyl 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/- [1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
3-[amino(2 -fluorophenyl) methyl]-6-[2-fluoro-3-(trifluoromethoxy)phenyl]-8-[2-fluoro-6- (trifluoromethyl) benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one 1 -oxide
ethyl 4-{[{6-(2-fluoro-4-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl- 1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoate
ethyl 4-{[(3,5-difluorophenyl){6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl}methyl]amino}butanoate
ethyl 4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-
1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(2 -fluorophenyl) methyl]amino}butanoate
ethyl 4-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} butanoate
[^,3R(R)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanenitrile
[^,3S(R)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanenitrile
[^,3R(S)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanenitrile
[^,3S(S)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanenitrile
[^,3R(R)]-4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-
7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanenitrile
[^,3S(R)]-4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-
7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanenitrile
[^,3R(S)]-4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-
7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanenitrile
[^,3S(S)]-4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-
7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanenitrile
[1 ξ!3R(R)]-ethyl 4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoate
[1 ξ,35(/?)]-β%Ι 4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/- [1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoate
[1 ξ,3/?(5)]-β%Ι 4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/- [1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoate
[1 ξ!3S(S)]-ethyl 4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/- [1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoate
[1 ^3R{R)]-met y\ (2-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/- [1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetate
[1 £,3S(/?)]-methyl (2-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/- [1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetate
[1 £,3/?(S)]-methyl (2-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/- [1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetate
[1 ξ,35(5)]-ΓΤΐΘ%Ι (2-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/- [1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetate
[1 ^,3R{R)]-et y\ 4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-6-
[3-(trifluoromethoxy)phenyl]-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoate
[1 ξ,35(Α)]-Θ%Ι 4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-6-[3-
(trifluoromethoxy)phenyl]-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoate
[1 ξ,3Α(5)]-β%Ι 4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-6-[3-
(trifluoromethoxy)phenyl]-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoate
[1 ξ,35(5)]-β%Ι 4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-6-[3-
(trifluoromethoxy)phenyl]-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoate
[1 ^,3R{R)]-et y\ 4-{[{6-(5-fluoro-2,3-dihydro-1 ,4-benzodioxin-6-yl)-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
[1 ξ,35(/?)]-β%Ι 4-{[{6-(5-fluoro-2,3-dihydro-1 ,4-benzodioxin-6-yl)-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
[1 ξ,3/?(5)]-β%Ι 4-{[{6-(5-fluoro-2,3-dihydro-1 ,4-benzodioxin-6-yl)-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
[1 ξ,35(5)]-β%Ι 4-{[{6-(5-fluoro-2,3-dihydro-1 ,4-benzodioxin-6-yl)-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoate
[^,3R(R)]-ethyl (2-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} ethoxy)acetate
[1 £,3S(/?)]-ethyl (2-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} ethoxy)acetate
[1 ¾,3 ?(S)]-ethyl (2-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} ethoxy)acetate
[1 £,3S(S)]-ethyl (2-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} ethoxy)acetate
[^,3R(R)]-3-[amino(phenyl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one 1 -oxide
[^,3S(R)]-3-[amino(phenyl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one 1 -oxide
[^,3R(S)]-3-[amino(phenyl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one 1 -oxide
[^,3S(S)]-3-[amino(phenyl)methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl) benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one 1 -oxide
3-[amino(3,5-difluorophenyl) methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one 1 -oxide
3-[amino(2 -fluorophenyl) methyl]-6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-
(trifluoromethyl)benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5- one 1 -oxide
methyl (2-{[{6-[3-(1 , 1 -difluoroethyl)-2-f luorophenyl]-8-[2-f luoro-6-(trif luoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} ethoxy)acetate
methyl (2-{[{6-[3-(1 ,1 -difluoroethyl)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} ethoxy)acetate
3-[amino(phenyl)methyl]-6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-5-one 1 -oxide
4-{[{6-(2-fluoro-4-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 - oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}butanoic acid
[^,3R(R)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoic acid
[^,3S(R)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoic acid
[^,3R(S)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoic acid
[^,3S(S)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoic acid
4-{[(3,5-difluorophenyl){6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}methyl]amino}butanoic acid
[^,3R(R)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-3-yl}(2- fluorophenyl)methyl] amino}butanoic acid
[^,3S(R)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-3-yl}(2- fluorophenyl)methyl] amino}butanoic acid
[^,3R(S)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-3-yl}(2- fluorophenyl)methyl] amino}butanoic acid
[^,3S(S)]-4-{[{6-(2-fluoro-3-methoxyphenyl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-7- methyl-1 -oxido-5-oxo-2!3-dihydro-5H-[1 !3]thiazolo[3,2-a]pyridin-3-yl}(2- fluorophenyl)methyl] amino}butanoic acid
[^,3R(R)]-4-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} butanoic acid
[^,3S(R)]-4-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} butanoic acid
[^,3R(S)]-4-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} butanoic acid
[^,3S(S)]-4-{[{6-[3-(difluoromethoxy)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} butanoic acid
[^,3R(R)]-4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-
7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoic acid
[^,3S(R)]-4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-
7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoic acid
[^,3R(S)]-4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-
7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoic acid
[^,3S(S)]-4-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-
7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoic acid
[^!3R(R)]-(2-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-
7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}ethoxy)acetic acid
[^!3S(R)]-(2-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-
7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}ethoxy)acetic acid
[^!3R(S)]-(2-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-
7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}ethoxy)acetic acid
[^!3S(S)]-(2-{[{6-(4-fluoro-1 ,3-benzodioxol-5-yl)-8-[2-fluoro-6-(trifluoromethyl)benzyl]-
7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}ethoxy)acetic acid
[^,3R(R)]-4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-6-[3-
(trifluoromethoxy)phenyl]-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoic acid
[^,3S(R)]-4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-6-[3-
(trifluoromethoxy)phenyl]-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoic acid
[^,3R(S)]-4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-6-[3-
(trifluoromethoxy)phenyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoic acid
[^,3S(S)]-4-{[{8-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-6-[3-
(trifluoromethoxy)phenyl]-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}butanoic acid
[^^/^(^^-{[{e-CS-fluoro^^-dihydro-l ^-benzodioxin-e-yl^S-p-fluoro-e-
(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoic acid
[^.SS^^-iKe-CS-fluoro^.S-dihydro-l ^-benzodioxin-e-yl^-p-fluoro-e-
(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoic acid
[^^^(S^^-iKe-CS-fluoro^^-dihydro-l ^-benzodioxin-e-yl^-p-fluoro-e-
(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoic acid
[^.SSCS^^-iKe-CS-fluoro^.S-dihydro-l ^-benzodioxin-e-yl^-p-fluoro-e-
(trifluoromethyl) benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-
[1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl]amino} butanoic acid
[1 ξ,3/?(/?)]-(2-{[{6-[3-^ίίΙυοΓθΓΤΐΘΐΙ·^) phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-
7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}ethoxy)acetic acid
[1 ξ,35(Α)]-(2-{[{6-[3-^ίΑυοΓθΓΤΐΘΐΙ·^) phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-
7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}ethoxy)acetic acid
[1 ξ,3Α(5)]-(2-{[{6-[3-^ίΑυοΓθΓΤΐΘΐΙ·^) phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-
7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}ethoxy)acetic acid
[1 ξ,35(5)]-(2-{[{6-[3-^ιίΙυοΓθΓΤΐΘΐΙ·^) phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7- methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl] amino}ethoxy)acetic acid
[1 ξ,3/?*(/?*)]-(2-{[{6-[3-(1 , 1 -difluoroethyl)-2-f luorophenyl]-8-[2-f luoro-6- (trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/- [1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetic acid
[^,3R*(S*)]-(2-{[{6-[3-(1 ,1 -difluoroethyl)-2-fluorophenyl]-8-[2-fluoro-6- (trifluoromethyl)benzyl]-7-methyl-1 -oxido-5-oxo-2,3-dihydro-5/-/- [1 ,3]thiazolo[3,2-a]pyridin-3-yl}(phenyl)methyl] amino}ethoxy)acetic acid
(2-{[{6-[3-(1 ,1 -difluoroethyl)phenyl]-8-[2-fluoro-6-(trifluoromethyl) benzyl]-7-methyl-1 - oxido-5-oxo-2,3-dihydro-5H-[1 ,3]thiazolo[3,2-a]pyridin-3- yl}(phenyl)methyl]amino} ethoxy)acetic acid
32. A compound according to any one of the claims 1 to 31 for use as a medicament.
33. A compound according to any one of the claims 1 to 31 for use in the treatment of endometriosis, uterine fibroids, polycystic ovarian disease, heavy menstrual bleeding, particularly menorrahagia and dysmenorrehea, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia such as cancers of the prostate, breast and ovary, gonadotrope pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, contraception, infertility, assisted reproductive therapy such as in vitro fertilization, in the treatment of growth hormone deficiency and short stature, and in the treatment of systemic lupus erythematosus.
34. A pharmaceutical composition comprising a compound according to claims 1 to 31.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP09075567 | 2009-12-22 | ||
| EP09075567.9 | 2009-12-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2011076687A1 true WO2011076687A1 (en) | 2011-06-30 |
Family
ID=42076929
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2010/070092 WO2011076687A1 (en) | 2009-12-22 | 2010-12-17 | Pyridinone derivatives and pharmaceutical compositions thereof |
Country Status (4)
| Country | Link |
|---|---|
| AR (1) | AR079688A1 (en) |
| TW (1) | TW201130854A (en) |
| UY (1) | UY33128A (en) |
| WO (1) | WO2011076687A1 (en) |
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| WO2012175514A1 (en) * | 2011-06-21 | 2012-12-27 | Bayer Intellectual Property Gmbh | Pyridinone derivatives and pharmaceutical compositions thereof |
| WO2014185853A1 (en) * | 2013-05-14 | 2014-11-20 | Quretech Bio Ab | Compounds and methods for treatment of chlamydia infections |
| WO2015062391A1 (en) | 2013-10-30 | 2015-05-07 | 上海恒瑞医药有限公司 | Pyrazolopyrimidone or pyrrolotriazone derivatives, method of preparing same, and pharmaceutical applications thereof |
| EP2881391A1 (en) | 2013-12-05 | 2015-06-10 | Bayer Pharma Aktiengesellschaft | Spiroindoline carbocycle derivatives and pharmaceutical compositions thereof |
| WO2018086608A1 (en) | 2016-11-14 | 2018-05-17 | 江苏恒瑞医药股份有限公司 | Crystalline form of gnrh receptor antagonist and preparation method therefor |
| US10821152B2 (en) | 2014-08-26 | 2020-11-03 | Betanien Hospital | Methods, agents and compositions for treatment of inflammatory conditions |
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| UY33128A (en) | 2011-07-29 |
| AR079688A1 (en) | 2012-02-15 |
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