WO2011008302A1 - Certain chemical entities, compositions and methods - Google Patents
Certain chemical entities, compositions and methods Download PDFInfo
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- WO2011008302A1 WO2011008302A1 PCT/US2010/002020 US2010002020W WO2011008302A1 WO 2011008302 A1 WO2011008302 A1 WO 2011008302A1 US 2010002020 W US2010002020 W US 2010002020W WO 2011008302 A1 WO2011008302 A1 WO 2011008302A1
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- 0 C[n](c1ncn2)nc(*)c1c2I Chemical compound C[n](c1ncn2)nc(*)c1c2I 0.000 description 23
- ZNXJYWVYXSLDLL-UHFFFAOYSA-N CCC(N1c2ccccc2)=Cc2cccc(C)c2C1=O Chemical compound CCC(N1c2ccccc2)=Cc2cccc(C)c2C1=O ZNXJYWVYXSLDLL-UHFFFAOYSA-N 0.000 description 3
- RUQQCXITYHZNPM-ZDUSSCGKSA-N C[C@@H](C(N1c2ccccc2)=Cc(cccc2C)c2C1=O)N Chemical compound C[C@@H](C(N1c2ccccc2)=Cc(cccc2C)c2C1=O)N RUQQCXITYHZNPM-ZDUSSCGKSA-N 0.000 description 2
- SYMHUEFSSMBHJA-UHFFFAOYSA-N Cc1ncnc2c1nc[nH]2 Chemical compound Cc1ncnc2c1nc[nH]2 SYMHUEFSSMBHJA-UHFFFAOYSA-N 0.000 description 2
- JOYUQKYZHHDHMZ-WMZJFQQLSA-N C/C=N\c1c(C)nc(C)nc1N Chemical compound C/C=N\c1c(C)nc(C)nc1N JOYUQKYZHHDHMZ-WMZJFQQLSA-N 0.000 description 1
- AMWSEGBTTPQUKW-UHFFFAOYSA-N CC(C#C)NC(OC(C)(C)C)=O Chemical compound CC(C#C)NC(OC(C)(C)C)=O AMWSEGBTTPQUKW-UHFFFAOYSA-N 0.000 description 1
- CORUPKOVCCGBEJ-UHFFFAOYSA-N Cc(cccc1)c1N(C(CBr)=Cc1cccc(C)c11)C1=O Chemical compound Cc(cccc1)c1N(C(CBr)=Cc1cccc(C)c11)C1=O CORUPKOVCCGBEJ-UHFFFAOYSA-N 0.000 description 1
- XEJTYGQRSVAXKK-UHFFFAOYSA-N Cc(cccc1)c1N(C(C[n]1c2ncnc(N)c2nc1)=Cc1cccc(C)c11)C1=O Chemical compound Cc(cccc1)c1N(C(C[n]1c2ncnc(N)c2nc1)=Cc1cccc(C)c11)C1=O XEJTYGQRSVAXKK-UHFFFAOYSA-N 0.000 description 1
- MVNHBCGICJSKMD-UHFFFAOYSA-N Cc1cccc(C)c1C(Nc1ccccc1)=O Chemical compound Cc1cccc(C)c1C(Nc1ccccc1)=O MVNHBCGICJSKMD-UHFFFAOYSA-N 0.000 description 1
- HCBHQDKBSKYGCK-UHFFFAOYSA-N Cc1cccc(C)c1C(O)=O Chemical compound Cc1cccc(C)c1C(O)=O HCBHQDKBSKYGCK-UHFFFAOYSA-N 0.000 description 1
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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Definitions
- the activity of cells can be regulated by external signals that stimulate or inhibit intracellular events.
- the process by which stimulatory or inhibitory signals ard transmitted into and within a cell to elicit an intracellular response is referred to as signal transduction.
- cascades of signal transduction events have been elucidated and found to play a central role in a variety of biological responses. Defects in various components of signal transduction pathways have been found to account for a vast number of diseases, including numerous forms of cancer, inflammatory disorders, metabolic disorders, vascular and neuronal diseases (Gaestel et al. Current Medicinal Chemistry (2007) 14:2214-2234).
- Kinases represent a class of important signaling molecules. Kinases can generally be classified into protein kinases and lipid kinases, and certain kinases exhibit dual specificities. Protein kinases are enzymes that phosphorylate other proteins and/or themselves (i.e., autophosphorylation). Protein kinases can be generally classified into three major groups based upon their substrate utilization: tyrosine kinases which predominantly phosphorylate substrates on tyrosine residues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src, abl), serine/threonine kinases which
- phosphorylate substrates on serine and/or threonine residues e.g., mTorCl, mTorC2, ATM, ATR, DNA- PK, Akt), and dual-specificity kinases which phosphorylate substrates on tyrosine, serine and/or threonine residues.
- Lipid kinases are enzymes that catalyze the phosphorylation of lipids. These enzymes, and the resulting phosphorylated lipids and lipid-derived biologically active organic molecules, play a role in many different physiological processes, including cell proliferation, migration, adhesion, and differentiation. Certain lipid kinases are membrane associated and they catalyze the phosphorylation of lipids contained in or associated with cell membranes. Examples of such enzymes include phosphoinositide(s) kinases (such as PI3-kinases, PI4-Kinases), diacylglycerol kinases, and sphingosine kinases.
- PI3Ks phosphoinositide 3-kinases
- the phosphoinositide 3-kinases (PI3Ks) signaling pathway is one of the most highly mutated systems in human cancers.
- PI3K signaling is also a key factor in many other diseases in humans.
- PI3K signaling is involved in many disease states including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders related to diabetic complications, and inflammatory complications of the cardiovascular system such as acute coronary syndrome.
- PI3K& are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3 '-OH group on phosphatidylinositols or phosphoinositides.
- the PI3K family comprises 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation (Katso et al., 2001).
- the class I PDKs (pi 10a, pi lO ⁇ , pi 105, and pi lO ⁇ ) are typically activated by tyrosine kinases or G-protein coupled receptors to generate PIP3, which engages downstream effectors such as those in the Akt/PDKl pathway, mTOR, the Tec family kinases, and the Rho family GTPases.
- the class II and III PO-Ks play a key role in intracellular trafficking through the synthesis of PI(3)P and PI(3,4)P2.
- the PIKKs are protein kinases that control cell growth (mTORCl) or monitor genomic integrity (ATM, ATR, DNA-PK, and hSmg-1).
- PI3K ⁇ The delta ( ⁇ ) isoform of class I PI3K has been implicated, in particular, in a number of diseases and biological processes.
- PI3K ⁇ is expressed primarily in hematopoietic cells including leukocytes such as T-cells, dendritic cells, neutrophils, mast cells, B-cells, and macrophages.
- PI3K ⁇ is integrally involved in mammalian immune system functions such as T-cell function, B-cell activation, mast cell activation, dendritic cell function, and neutrophil activity.
- PI3K ⁇ Due to its integral role in immune system function, PI3K ⁇ is also involved in a number of diseases related to undesirable immune response such as allergic reactions, inflammatory diseases, inflammation mediated angiogenesis, rheumatoid arthritis, auto-immune diseases such as lupus, asthma, emphysema and other respiratory diseases.
- Other class I PI3K involved in immune system function includes PI3K ⁇ , which plays a role in leukocyte signaling and has been implicated in inflammation, rheumatoid arthritis, and autoimmune diseases such as lupus.
- Downstream mediators of the PI3K signal transduction pathway include Akt and mammalian target of rapamycin (mTOR).
- Akt possesses a plckstrin homology (PH) domain that binds PIP3, leading to Akt kinase activation.
- Akt phosphorylates many substrates and is a central downstream effector of PI3K for diverse cellular responses.
- One important function of Akt is to augment the activity of mTOR, through phosphorylation of TSC2 and other mechanisms.
- mTOR is a serine-threonine kinase related to the lipid kinases of the PI3K family.
- mTOR has been implicated in a wide range of biological processes including cell growth, cell proliferation, cell motility and survival. Disregulation of the mTOR pathway has been reported in various types of cancer.
- mTOR is a multifunctional kinase that integrates growth factor and nutrient signals to regulate protein translation, nutrient uptake, autophagy
- kinases particularly PI3Ks are prime targets for drug development.
- PI3K inhibitors suitable for drug development.
- the present invention addresses this need and provides related advantages as well by providing new classes of kinase inhibitors.
- the present invention provides compounds of Formula I below or pharmaceutically acceptable salts thereof, wherein
- W d is heterocycloalkyl, aryl or heteroaryl
- B is alkyl or a moiety of Formula II
- W c is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and q is an integer of 0, 1, 2, 3, or 4;
- X is absent or -(CH(R 9 )) Z -, and z is an integer of 1 ;
- Y is absent, or -N(R 9 )-;
- R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amido, alkoxycarbonyl, sulfonamido, halo, cyano, or nitro;
- R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy or nitro;
- R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, aryl or heteroaryl
- R 5 , R 6 , R 7 , and R 8 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, hetercycloalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxy or nitro; and
- each instance of R 9 is independently hydrogen, alkyl, cycloalkyl, or heterocycloalkyl.
- X is absent or -(CH(R 9 )) Z - and z is an integer of 1. In some embodiments, X is absent. In some embodiments, X is -(CH(R 9 )) Z -, and z is an integer of 1. In some embodiments, X is -CH 2 -, - CH(CH 2 CH 3 ), or -CH(CH 3 )-.
- Y is absent, or -N(R 9 )-. In some embodiments, Y is absent. In some embodiments, Y is -N(R 9 )-. In some embodiments, Y is -NH-, -N(CH 3 ), or -N(CH 2 CH 3 )-.
- X is absent or -(CH(R 9 )) 2 -, z is an integer of 1, and Y is absent or -N(R 9 )-. In certain embodiments, X is absent and Y is N(R 9 )-. In certain embodiments, Y is absent and X is -(CH(R 9 )) Z - wherein z is an integer of 1. In certain embodiments, neither X nor Y is absent.
- Y is -NH- (e.g., X is -(CH(R 9 )) Z - and Y is -NH-).
- X is -CH 2 -, -CH(CH 2 CH 3 ), or -CH(CH 3 )- and Y is -NH-.
- Y is -N(CH 3 )- (e.g., X is -(CH(R 9 )) Z - and Y is -N(CH 3 )-).
- X is -CH 2 -, -CH(CH 2 CH 3 ), or -CH(CH 3 )- and Y is - N(CH 3 )-.
- Y is— N(CH 2 CH 3 )- (e.g., X is -(CH(R 9 )) Z - and Y is -N(CH 2 CH 3 )-).
- X is -CH 2 -, -CH(CH 2 CH 3 ), or - CH(CH 3 )- and Y is - N(CH 2 CH 3 )-.
- the group X-Y is -CH 2 -N(CH 3 ), -CH 2 -N(CH 2 CH 3 ), -CH(CH 2 CH 3 )-NH- or -CH(CH 3 )-NH-.
- W d is a pyrazolopyrimidine of Formula I ⁇ I(a), or purine of Formula I ⁇ I(b), Formula III(c) or Formula I ⁇ I(d) below: 12
- R a of Formula I ⁇ I(d) is hydrogen, halo, phosphate, urea, a carbonate, amino, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, or heterocycloalkyl;
- R 11 of Formula I ⁇ I(a) is H, alkyl, halo, amino, amido, hydroxy, or alkoxy, and
- R 12 of Formula I ⁇ I(a), Formula III(c) or Formula I ⁇ I(d) is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl,
- W d is a pyrazolopyrimidine of Formula I ⁇ I(a), wherein R 11 is H, alkyl, halo, amino, amido, hydroxy, or alkoxy, and R 12 is cyano, amino, carboxylic acid, or amido.
- the compound of Formula I has the structure of Formula IV:
- R 11 is H, alkyl, halo, amino, amido, hydroxy, or alkoxy
- R 12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
- the compound of Formula I has the structure of Formula IV wherein R 11 is H, alkyl, halo, amino, amido, hydroxy, or alkoxy, and R 12 is cyano, amino, carboxylic acid, or amido.
- R 11 is amino.
- R 12 is alkyl, alkenyl, alkynyl, heteroaryl, aryl, or heterocycloalkyl.
- R 12 is cyano, amino, carboxylic acid, amido, monocyclic heteroaryl, or bicyclic heteroaryl.
- the compound of Formula I has the structure of Formula V:
- NR 9 is -N(CH 2 CH 3 )CH 2 - or N(CH 3 )CH 2 -.
- the compound has a structure of Formula VI:
- R 3 is-H, -CH 3 , -Cl, or -F, and R 5 , R 6 , R 7 , and R 8 are independently hydrogen.
- B is a moiety of Formula II
- W c is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and q is an integer of 0, 1, 2, 3, or 4.
- B is a moiety of Formula II
- W c in B is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and q is an integer of 0, 1, 2, 3, or 4;
- X is absent or -(CH(R 9 )) 2 -, and z is an integer of 1 ;
- Y is absent, or -N(R 9 )-;
- Wd when Y is absent, Wd is: , or when Y is present, Wd is: N — N
- R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amido, alkoxycarbonyl, sulfonamido, halo, cyano, or nitro;
- R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy or nitro;
- R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, aryl or heteroaryl;
- each instance of R 9 is independently hydrogen, Ci-Ci O alkyl, cycloalkyl, or hetercyclooalkyl; and R 12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
- a compound of Formula I or Formula 1-1 has the structure of Formula IV-A:
- R 12 is substituted benzoxazole.
- a compound of Formula I or Formula 1-1 has the structure of Formula V-A:
- a compound of Formula I or Formula 1-1 has the structure of Formula IV-A or Formula
- a compound of Formula I or Formula 1-1 has the structure of Formula V-B:
- a compound of Formula I or Formula 1-1 has the structure of Formula VI-A:
- a compound of Formula I or Formula 1-1 is the compound wherein B is a moiety of Formula II;
- W c is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl; q is an integer of 0 or 1 ; R 1 is hydrogen, alkyl, or halo; R 2 is alkyl or halo; andR 3 is hydrogen, alkyl, or halo, hi some embodiments, when both X and Y are present then Y is -NH-.
- R 3 is -H, -CH 3 , -CH 2 CH 3 , -CF 3 , -Cl or -F.
- R 3 is methyl or chloro.
- R 3 is haloalkyl.
- R 3 is -CF 3 , -CH 2 F or -CHF 2 .
- the compound of Formula I or Formula 1-1 is predominately in an (S)- stereochemical configuration.
- the compound has a structure of Formula V-A2:
- W c is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl
- q is an integer of 0, 1, 2, 3, or 4;
- R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amido, alkoxycarbonyl, sulfonamido, halo, cyano, or nitro;
- R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl, alkoxy, amino, halo, cyano, hydroxy or nitro;
- R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, aryl or heteroaryl;
- each instance of R 9 is independently hydrogen, alkyl, or heterocycloalkyl.
- B is a moiety of Formula II:
- W 0 is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl
- q is an integer of 0 or 1 ;
- R 1 is hydrogen, alkyl, or halo
- R 2 is alkyl or halo
- R 3 is hydrogen, alkyl, or halo.
- W 0 is aryl, such as phenyl.
- W c is cyclopropyl.
- W c is substituted by at least one of -CH 3 , -CH 2 CH 3 , -CF 3 , -Cl or -F.
- R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, alkoxycarbonyl sulfonamido, halo, cyano, hydroxy or nitro.
- R 3 is -
- R 3 is -CH 3 or -Cl. In other embodiments, R 3 is haloalkyl. For example, R 3 is -CF 3 , -CH 2 F or -CHF 2 .
- R 9 is -CH 3 . In other embodiments, R 9 is -CH 2 -CH 3 .
- the compound of Formula V-A2 has the Formula: or pharmaceutically acceptable salts thereof.
- R 2 is -H.
- the compound of Formula V-A2 has the Formula:
- R 1 and R 2 are independently selected from the group of hydrogen and halo.
- the compound is of the formula:
- R 1 is -H, e.g., of the formula:
- q is 1 and R 2 is provided in the meta position, e.g., of the formula: , or pharmaceutically acceptable salts thereof.
- R 1 is H and R 2 is H, e.g. of the formula:
- R 1 is H
- q is 1
- R 2 is halo (e.g., fluoro) of the formula:
- R 1 is H
- q is 1
- R 2 is halo (e.g., fluoro) in the meta position, e.g., of the formula:
- the compound of the Formula V-A2 has the Formula:
- the compound has the Formula:
- composition which comprises a
- the composition is a liquid, solid, semi-solid, gel, or an aerosol form.
- a method of inhibiting a phosphatidyl inositol-3 kinase comprising: contacting the PI3 kinase with an effective amount of one or more compounds disclosed herein.
- the step of contacting involves the use of one or more compounds of any formulae provided herien including but not limited to Formula 1, 1-1, IV, IV-A, V, V-A, V-A2, V-B, VI, and VI-A.
- the step of contacting comprises contacting a cell that contains said PI3 kinase.
- the inhibition takes place in a subject suffering from a disorder associated with malfunctioning of one or more types of PI3 kinase.
- Some exemplary diseases involving malfunctioning of one or more types of PI3 kinases are selected from the group consisting of autoimmune diseases, rheumatoid arthritis, respiratory disease, allergic reactions, and various types of cancers.
- the compound used in the method has the structure of Formula IV, wherein R 11 is amino and R 12 is substituted phenyl.
- the inhibition takes place in a subject suffering from rheumatoid arthritis or a respiratory disease, and wherein the compound has the structure of Formula IV, and wherein R 11 is amino and R 12 is bicyclic heteroaryl.
- the method comprises administering a second therapeutic agent to the subject.
- the present invention provides a method of treating a disease manifesting an undesired immune response.
- the method comprises the step of administering to a subject in need thereof, one or more compounds disclosed herein including compounds of Formula 1, 1-1, IV, IV-A, V, V-A, V-A2, V-B, VI, and/or VI-A, in an amount that is effective in ameliorating said undesired immune response.
- the one or more compounds inhibit T-cell independent B-cell activation as evidenced by a reduction in production of anti-TNP IgG3 by at least about five folds when administered in an amount less than about 30mg/kg BID dose to a test animal.
- the disease treated is associated with swelling or pain of a joint of a subject.
- the method can be effective in ameliorating one or more rheumatoid arthritis symptoms as evidenced by reduction in mean joint diameter by at least about 10% after 17 days and/or reduction in ankle diameter by at least 5-10% or more after several days to weeks of treatment, including for example reduction in ankle diameter by at least 5% after 7 days of treatment.
- the undesired immune response is evidenced by enhanced production of anti-type II collagen antibodies, and the use of one or more subject compounds reduces the serum anti-type II collagen level at an ED50 of less than about 10 mg/kg.
- FIG. 1 depicts an exemplary protocol for measuring T-cell independent production of TNP specific antibodies in vivo.
- FIG. 2 depicts the fold reduction in TNP specific IgG3 response to antigens provided by compounds 7 and 53 of formula IV as compared to a vehicle control, when administered orally.
- FIG. 3 depicts the dose-dependent effect of twice daily oral administration of compound 53 of formula IV in reducing the increase in ankle diameter over time in a collagen-induced developing arthritis model in rats. Also depicted are the results from non-arthritic control rats, arthritic control rats administered with a negative control vehicle, and arthritic control rats treated twice daily with methotrexate.
- FIG. 4 depicts the dose-dependent effect of compounds 7 and 53 of formula IV in improving ankle
- histopathology when administered in a collagen-induced developing arthritis model in rats are also depicted.
- results from arthritic control rats administered with negative control vehicle or methotrexate are also depicted.
- FIG. 5 depicts the dose-dependent effect of compounds 7 and 53 of formula IV in improving knee histopathology when administered in a collagen-induced developing arthritis model in rats. Also depicted are the results from arthritic control rats administered with negative control vehicle or positive control methotrexate.
- FIG. 6 depicts the dose-dependent effect of compounds 7 and 53 of formula IV in reducing the level of anti-type II collagen antibodies in vivo when administered to a collagen-induced developing arthritis rat model. Also depicted are the results from arthritic rats administered with negative control vehicle or methotrexate.
- FIG. 7 depicts the dose-dependent effect of compound 7 of formula IV on improving ankle histopathology when administered in collagen-induced developing arthritis model in rats. Also depicted are the results from arthritic vehicle control rats and methotrexate-treated arthritic rats.
- FIG. 8 depicts the dose-dependent effect of compound 53 of formula IV administered daily on ankle histopathology in a collagen-induced established arthritis model in rats. Also depicted are the results from arthritic arthritic vehicle control rats and Enbrel-treated arthritic rats.
- FIG. 9 depicts the dose-dependent effect of compound 53 of formula IV administered twice daily on ankle histopathology in a collagen-induced established arthritis model in rats. Also depicted are the results from arthritic vehicle control rats and Enbrel-treated arthritic rats.
- FIG. 10 depicts the dose-dependent effect of compound 53 of formula IV on the increase in average paw volume in an adjuvant induced arthritis model.
- FIG. 11 depicts the effect of compound 53 of formula IV on the average weight over time of rats in an adjuvant induced arthritis model in rats.
- FIG. 12 depicts the effect of compound 292 ("Cpd-A") of formula V- A2 on reducing the increase in ankle diameter over time in a collagen-induced developing arthritis model in rats.
- FIG. 13 depicts the effect of compound 292 ("Cpd-A") of formula V-A2 ankle histopathology in a collagen- induced established arthritis model in rats.
- FIG. 14 depicts the effect of compound 292 ("Cpd-A") of formula V-A2 on reducing the increase in ankle diameter over time in a rat adjuvant induced arthritis model in rats.
- FIG. 15 depicts the effect of compound 292 ("Cpd-A") of formula V- A2 of inhibiting LPS-induced total leukocyte neutrophil influx in a LPS-induced lung inflammation model in rats.
- FIG. 16 depicts the effect of compound 292 ("Cpd-A") of formula V- A2 of inhibiting eosinophil influx in a OVA-induced allergic lung inflammation model in rats.
- FIG. 17 depicts the effect of compound 200 ("Cpd-B") of formula V-A2 on reducing the increase in ankle diameter over time in a collagen-induced developing arthritis model in rats.
- FIG. 18 depicts the effect of compound 270 ("Cpd-C") of formula V- A2 on reducing the increase in ankle diameter over time in a collagen-induced developing arthritis model in rats.
- FIG. 19 depicts the effect of compound 196 ("Cpd-D") of formula V-A2 on reducing the increase in ankle diameter over time in a collagen-induced developing arthritis model in rats.
- agent refers to a biological, pharmaceutical, or chemical compound or other moiety.
- Non-limiting examples include simple or complex organic or inorganic molecule, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, antibody fragment, a vitamin derivative, a carbohydrate, a toxin, or a chemotherapeutic compound.
- Various compounds can be synthesized, for example, small molecules and oligomers (e.g., oligopeptides and oligonucleotides), and synthetic organic compounds based on various core structures.
- various natural sources can provide compounds for screening, such as plant or animal extracts, and the like. A skilled artisan can readily recognize that there is no limit as to the structural nature of the agents of the present invention.
- agonist refers to a compound having the ability to initiate or enhance a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the term “agonist” is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g. bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.
- antagonists are used interchangeably, and they refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the terms “antagonist” and “inhibitors” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g. bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition.
- a preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor, or an undesired immune response as manifested in autoimmune disease.
- an "anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent” refers to any agent useful in the treatment of a neoplastic condition.
- One class of anti-cancer agents comprises chemotherapeutic agents.
- “Chemotherapy” means the administration of one or more chemotherapeutic drugs and/or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation or in the form of a suppository.
- the term “cell proliferation” refers to a phenomenon by which the cell number has changed as a result of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal.
- co-administration encompass administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time.
- Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
- the term "effective amount” or “therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below.
- the therapeutically effective amount may vary depending upon the intended application ⁇ in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
- the term also applies to a dose that will induce a particular response in target cells, e.g. reduction of platelet adhesion and/or cell migration.
- the specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
- treatment or “treating,” or “palliating” or “ameliorating” is used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
- therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
- a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
- the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
- a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
- salts refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
- Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
- Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
- Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
- Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
- Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
- Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
- the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
- “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
- Signal transduction is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response.
- a modulator of a signal transduction pathway refers to a compound which modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway.
- a modulator may augment (agonist) or suppress (antagonist) the activity of a signaling molecule.
- selective inhibition or “selectively inhibit” as applied to a biologically active agent refers to the agent's ability to selectively reduce the target signaling activity as compared to off-target signaling activity, via direct or interact interaction with the target.
- B-ALL refers to B-cell Acute Lymphoblastic Leukemia.
- Subject refers to an animal, such as a mammal, for example a human.
- the methods described herein can be useful in both human therapeutics and veterinary applications.
- the patient is a mammal, and in some embodiments, the patient is human.
- Radionucleotides e.g., actinium and thorium
- radionuclides low linear energy transfer (LET) radiation emitters (i.e. beta emitters), conversion electron emitters (e.g. strontium-89 and samarium- 153-EDTMP, or high-energy radiation, including without limitation x-rays, gamma rays, and neutrons.
- LET linear energy transfer
- beta emitters i.e. beta emitters
- conversion electron emitters e.g. strontium-89 and samarium- 153-EDTMP
- high-energy radiation including without limitation x-rays, gamma rays, and neutrons.
- Prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein.
- prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
- a prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
- the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H.,
- prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
- Prodrugs of an active compound, as described herein may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
- Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
- Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
- in vivo refers to an event that takes place in a subject's body.
- in vitro refers to an event that takes places outside of a subject's body.
- an in vitro assay encompasses any assay run outside of a subject assay.
- In vitro assays encompass cell-based assays in which cells alive or dead are employed.
- In vitro assays also encompass a cell-free assay in which no intact cells are employed.
- structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
- compounds having the present structures wherein hydrogen is replaced by deuterium or tritium, or wherein carbon atom is replaced by 13 C- or 14 C-enriched carbon are within the scope of this invention.
- the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds.
- the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine- 125 ( 125 I) or carbon- 14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
- PI3-K Phosphoinositide 3-kinase
- PI phosphatidylinositol
- PDK Phosphoinositide Dependent Kinase
- DNA-PK Deoxyribose Nucleic Acid Dependent Protein Kinase
- PTEN Phosphatase and Tensin homolog deleted on chromosome Ten
- PIKK Phosphoinositide Kinase Like Kinase
- AIDS Acquired Immuno Deficiency Syndrome
- HIV Human Immunodeficiency Virus
- MeI Methyl Iodide
- POCl 3 Phosphorous Oxychloride
- KCNS Potassium IsoThiocyanate
- TLC Thin Layer Chromatography
- MeOH Methanol
- CHCl 3 Chloroform.
- Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., Ci-Ci 0 alkyl).
- a numerical range such as “1 to 10” refers to each integer in the given range; e.g., "1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated.
- Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, decyl, and the like.
- the alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (/.so-propyl), ⁇ ?-butyl, M-pentyl, 1,1-dimethylethyl (/-butyl), 3-methylhexyl,
- an alkyl group is optionally substituted by one or more of substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR", -
- Alkylaryl refers to an -(alkyl)aryl radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the subsituents described as suitable substituents for aryl and alkyl respectively.
- Alkylhetaryl refers to an -(alkyl)hetaryl radical where hetaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the subsituents described as suitable substituents for aryl and alkyl respectively.
- Alkylheterocycloalkyl refers to an -(alkyl) heterocycyl radical where alkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the subsituents described as suitable substituents for heterocycloalkyl and alkyl respectively.
- alkene refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
- an "alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon- carbon triple bond.
- the alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
- alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (ie. C 2 -Ci 0 alkenyl). Whenever it appears herein, a numerical range such as “2 to 10" refers to each integer in the given range; e.g., "2 to 10 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.In certain embodiments, an alkenyl comprises two to eight carbon atoms.
- an alkenyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkenyl).
- the alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-l,4-dienyl, and the like.
- an alkenyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , - SR a , -OC(O)-R 8 , -N(R a ) 2 , -C(O)R", -C(O)OR 8 , -OC(O)N(R a ) 2 , -C(O)N(R") 2 , -N(R a )C(O)OR a , -N(R 8 )C(O)R a , - N(R 8 )C(O)N(O)OR a ,
- alkenyl-cycloalkyl refers to an -(alkenyl)cycloalkyl radical where alkenyl and cyclo alkyl are as disclosed herein and which are optionally substituted by one or more of the subsituents described as suitable substituents for alkenyl and cycloalkyl respectively.
- Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (ie. C 2 -Ci 0 alkynyl).
- a numerical range such as “2 to 10” refers to each integer in the given range; e.g., "2 to 10 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
- an alkynyl comprises two to eight carbon atoms.
- an alkynyl has two to five carbon atoms (e.g., C 2 -C 5 alkynyl).
- the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
- an alkynyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR", -
- each R" is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
- Alkynyl-cycloalkyl refers to an -(alkynyl)cycloalkyl radical where alkynyl and cyclo alkyl are as disclosed herein and which are optionally substituted by one or more of the subsituents described as suitable substituents for alkynyl and cycloalkyl respectively.
- Cyano refers to a -CN radical.
- Cycloalkyl refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (ie. C 2 -Ci 0 cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10" refers to each integer in the given range; e.g.,
- 3 to 10 carbon atoms means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms. In some embodiments, it is a C 3 -C 8 cycloalkyl radical. In some embodiments, it is a C 3 -C 5 cycloalkyl radical.
- cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like.
- a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR", -
- R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,
- Cycloalkyl-alkenyl refers to a -(cycloalkyl) alkenyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the subsituents described as suitable substituents for heterocycloalkyl and cycloalkyl respectively.
- Cycloalkyl-heterocycloalkyl refers to a -(cycloalkyl) heterocycyl radical where cycloalkyl and
- heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the subsituents described as suitable substituents for heterocycloalkyl and cycloalkyl respectively.
- Cycloalkyl-heteroaryl refers to a -(cycloalkyl) heteroaryl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the subsituents described as suitable substituents for heterocycloalkyl and cycloalkyl respectively.
- alkoxy refers to the group -O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
- Lower alkoxy refers to alkoxy groups containing one to six carbons.
- Ci-C 4 alkyl is an alkyl group which encompasses both straight and branched chain alkyls of from 1 to 4 carbon atoms.
- substituted alkoxy refers to alkoxy wherein the alkyl constituent is substituted (i.e., - ⁇ -(substituted alkyl)).
- alkyl moiety of an alkoxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR 8 ,
- N(R 8 )C(O)N(R a ) 2) N(R a )C(NR a )N(R 8 ) 2 , -N(R 8 )S(O) t R 8 (where t is 1 or 2), -S(O) 1 OR 8 (where t is 1 or 2), -S(O),N(R°) 2
- each R 8 is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,
- a C r C 6 alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.
- Lower alkoxycarbonyl refers to an alkoxycarbonyl group wherein the alkoxy group is a lower alkoxy group.
- C r C 4 alkoxy is an alkoxy group which encompasses both straight and branched chain alkoxy groups of from 1 to 4 carbon atoms.
- substituted alkoxycarbonyl refers to the group (substituted alkyl)-O-C(O)- wherein the group is attached to the parent structure through the carbonyl functionality.
- alkyl moiety of an alkoxycarbonyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a ,
- each R 8 is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
- Acyl refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O)-, and
- (heterocycloalkyl)-C(O)- wherein the group is attached to the parent structure through the carbonyl functionality.
- it is a Ci-Ci 0 acyl radical which refers to the total number of chain or ring atoms of the alkyl, aryl, heteroaryl or heterocycloalkyl portion of the acyloxy group plus the carbonyl carbon of acyl, i.e three other ring or chain atoms plus carbonyl.
- the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms.
- R of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR 8 , SR 8 , -OC(O)-R 8 , -N(R a ) 2 , -C(O)R 0 , -C(O)OR 8 , -OC(O)N(R 8 ) 2 ,
- R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
- R of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -
- Amino refers to a -N(R 8 ) 2 radical group, where each R 8 is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification.
- R 8 is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification.
- a -N(R a ) 2 group has two Ra other than hydrogen they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring.
- -N(R") 2 is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl.
- an amino group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -
- carbocyclylalkyl aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of these moieties may be optionally substituted as defined herein.
- substituted amino also refers to N-oxides of the groups -NHR d , and NR d R d each as described above.
- N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid. The person skilled in the art is familiar with reaction conditions for carrying out the N-oxidation.
- Amide or “amido” refers to a chemical moiety with formula -C(O)N(R) 2 or -NHC(O)R, where R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), each of which moiety may itself be optionally substituted. In some embodiments it is a Ci-C 4 amido or amide radical, which includes the amide carbonyl in the total number of carbons in the radical.
- the R 2 of- N(R) 2 of the amide may optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6-, or 7-membered ring.
- an amido group is optionally substituted independently by one or more of the substituents as described herein for alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
- An amide may be an amino acid or a peptide molecule attached to a compound of Formula (I), thereby forming a prodrug. Any amine, hydroxy, or carboxyl side chain on the compounds described herein can be amidified.
- Aromatic or “aryl” refers to an aromatic radical with six to ten ring atoms (e.g., C 6 -C 10 aromatic or C 6 -C 10 aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl).
- Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.
- Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
- a numerical range such as “6 to 10” refers to each integer in the given range; e.g., "6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms.
- an aryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro,
- alkyl refers to an (aryl)alkyl— radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the subsituents described as suitable substituents for aryl and alkyl respectively.
- Ester refers to a chemical radical of formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). Any amine, hydroxy, or carboxyl side chain on the compounds described herein can be esterified. The procedures and specific groups to make such esters are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York, N. Y., 1999, which is incorporated herein by reference in its entirety.
- an ester group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR", -
- Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
- the alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.
- Halo means fluoro, chloro, bromo or iodo.
- haloalkyl means fluoro, chloro, bromo or iodo.
- haloalkenyl means fluoro, chloro, bromo or iodo.
- haloalkynyl means alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
- fluoroalkyl and fluoroalkoxy include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
- Heteroalkyl “heteroalkenyl” and “heteroalkynyl” include optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
- a numerical range may be given, e.g. CpC 4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long.
- a -CH 2 OCH 2 CH 3 radical is referred to as a "C 4 " heteroalkyl, which includes the heteroatom center in the atom chain length description.
- a heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR", - SR a , -OC(O)-R 8 , -N(R a ) 2 , -C(O)R 8 , -C(O)OR 8 , -C(O)N(R 8 ) 2) -N(R a )C(O)OR a , -N(R 8 )C(O)R 8 , -N(R a )S(O) t R
- Heteroalkylaryl refers to an -(heteroalkyl)aryl radical where heteroalkyl and aryl are as disclosed herein and which are optionally substituted by one or more of the subsituents described as suitable substituents for heteroalkyl and aryl respectively.
- Heteroalkylheteroaryl refers to an -(heteroalkyl)heteroaryl radical where heteroalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the subsituents described as suitable substituents for heteroalkyl and heteroaryl respectively.
- Heteroalkylheterocycloalkyl refers to an -(heteroalkyl)heterocycloalkyl radical where heteroalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the subsituents described as suitable substituents for heteroalkyl and heterocycloalkyl respectively
- Heteroalkylcycloalkyl refers to an -(heteroalkyl) cycloalkyl radical where heteroalkyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the subsituents described as suitable substituents for heteroalkyl and cycloalkyl respectively.
- Heteroaryl or, alternatively, “heteroaromatic” refers to a 5- to 18-membered aromatic radical (e.g., C 5 -C 13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system.
- a numerical range such as “5 to 18” refers to each integer in the given range; e.g., "5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms.
- Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding "-idene” to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene.
- An N-containing "heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
- the polycyclic heteroaryl group may be fused or non- fused.
- the heteroatom(s) in the heteroaryl radical is optionally oxidized.
- heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
- heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[£][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl,
- dibenzothiophenyl furanyl, furazanyl, fiiranonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9, lO-hexahydrocyclooctatdJpyridinyl.isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl,
- a heteraryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR a , -
- Substituted heteroaryl also includes ring systems substituted with one or more oxide (-0-) substituents, such as pyridinyl N-oxides.
- Heteroarylalkyl refers to a moiety having an aryl moiety, as described herein, connected to an alkylene moiety, as described herein, wherein the connection to the remainder of the molecule is through the alkylene group.
- Heterocycloalkyl refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as “3 to 18" refers to each integer in the given range; e.g., "3 to 18 ring atoms” means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. In some embodiments, it is a C 5 -C 10 heterocycloalkyl. In some embodiments, it is a C 4 -Ci 0 heterocycloalkyl. In some
- the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
- the heteroatoms in the heterocycloalkyl radical may be optionally oxidized.
- One or more nitrogen atoms, if present, are optionally quaternized.
- the heterocycloalkyl radical is partially or fully saturated.
- the heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s).
- heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
- a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR 8 , -
- Heterocycloalkyl also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.
- “Isomers” are different compounds that have the same molecular formula.
- Stepoisomers are isomers that differ only in the way the atoms are arranged in space, i.e. having a different stereochemical configuration.
- Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other.
- a 1 : 1 mixture of a pair of enantiomers is a "racemic” mixture.
- the term “(. ⁇ .)” is used to designate a racemic mixture where appropriate.
- “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by either R or S.
- Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
- Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
- the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
- Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
- the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
- Enantiomeric purity refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, which may potentially have an (R)- or an (S)- isomeric configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (R)- or (S)- isomer. If that compound has one isomeric form predominant over the other, for example, 80% (S)- and 20% (R)-, the enantiomeric purity of the compound with respect to the (S)-isomeric form is 80%.
- the enantiomeric purity of a compound can be determined in a number of ways known in the art, including but not limited to
- chromatography using a chiral support polarimetric measurement of the rotation of polarized light
- nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or the Pirkle alcohol, or derivatization of a compounds using a chiral compound such as Mosher's acid followed by chromatography or nuclear magnetic resonance spectroscopy.
- Moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
- Niro refers to the -NO 2 radical.
- Oxa refers to the -O- radical.
- Tautomers are structurally distinct isomers that interconvert by tautomerization.
- Tautomerization is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry.
- Prototropic tautomerization or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g. in solution), a chemical equilibrium of tautomers can be reached.
- An example of tautomerization is keto-enol tautomerization.
- keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
- tautomerization is phenol-keto tautomerization.
- phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers.
- an enantiomerically enriched preparation of the (S)-enantiomer means a preparation of the compound having greater than 50% by weight of the (S)-enantiomer relative to the (R)-enantiomer, more preferably at least 75% by weight, and even more preferably at least 80% by weight.
- the enrichment can be much greater than 80% by weight, providing a "substantially enantiomerically enriched,” “substantially enantiomerically pure” or a “substantially non- racemic” preparation, which refers to preparations of compositions which have at least 85% by weight of one enantiomer relative to other enantiomer, more preferably at least 90% by weight, and even more preferably at least 95% by weight.
- the enantiomerically enriched composition has a higher potency with respect to therapeutic utility per unit mass than does the racemic mixture of that composition.
- Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L.
- the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds.
- the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
- a "leaving group or atom” is any group or atom that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable examples of such groups unless otherwise specified are halogen atoms, mesyloxy, p-nitrobenzensulphonyloxy and tosyloxy groups.
- Protecting group has the meaning conventionally associated with it in organic synthesis, i.e. a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and such that the group can readily be removed after the selective reaction is complete.
- a variety of protecting groups are disclosed, for example, in T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999).
- a hydroxy protected form is where at least one of the hydroxy groups present in a compound is protected with a hydroxy protecting group.
- amines and other reactive groups may similarly be protected.
- Solvate refers to a compound (e.g., a compound selected from Formula I or a pharmaceutically acceptable salt thereof) in physical association with one or more molecules of a pharmaceutically acceptable solvent. It will be understood that "a compound of Formula I” encompass the compound of Formula I and solvates of the compound, as well as mixtures thereof.
- Substituted means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
- Di-substituted amino groups encompass those which form a ring together with the nitrogen of the amino group, such as for instance, morpholino.
- the substituents themselves may be substituted, for example, a cycloakyl substituent may have a halide substituted at one or more ring carbons, and the like.
- the protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references such as Greene and Wuts, above.
- Sulfanyl refers to the groups: -S-(optionally substituted alkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl), and -S-(optionally substituted heterocycloalkyl).
- Sulfinyl refers to the groups: -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-(optionally substituted amino), -S(O)-(optionally substituted aryl), -S(0)-(optionally substituted heteroaryl), and -S(O)-(optionally substituted heterocycloalkyl).
- Sulfonyl refers to the groups: -S(O 2 )-H, -S(O 2 )-(optionally substituted alkyl), -S(O 2 )-(optionally substituted amino), -S(O 2 )-(optionally substituted aryl), -S(O 2 )-(optionally substituted heteroaryl), and -S(O 2 )-(optionally substituted heterocycloalkyl).
- a sulfonamido group is optionally substituted by one or more of the subsituents described for alkyl, cycloalkyl, aryl, heteroaryl respectively
- R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
- a sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl respectively.
- substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -.
- Compounds of the present invention also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
- Crystal form may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.
- Chemical entities include, but are not limited to, compounds of Formula 1, 1-1, IV, IV-A, V, V-A, V- A2, V-B, VI or VI-A, and all pharmaceutically acceptable forms thereof.
- Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof.
- the compounds described herein are in the form of pharmaceutically acceptable salts.
- the terms "chemical entity” and “chemical entities” also encompass pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures.
- the compound of Formula I is obtained as an acid addition salt
- the free base can be obtained by basifying a solution of the acid salt.
- an addition salt particularly a
- pharmaceutically acceptable addition salt may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.
- the present invention provides a compound of Formula I:
- W d is heterocycloalkyl, aryl or heteroaryl
- B is alkyl, amino, heteroalkyl, or a moiety of Formula II;
- W c is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl
- q is an integer of 0, 1 , 2, 3, or 4;
- X is absent or is -(CH(R 9 )) 2 -and z is an integer of 1, 2, 3, or 4;
- R 1 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate;
- R 2 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate;
- R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, aryl, or heteroaryl;
- R 5 , R 6 , R 7 , and R 8 are independently hydrogen, C r C 4 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 5 cycloalkyl, C r C 4 heteroalkyl, Ci-C 4 alkoxy, CVQamido, amino, acyl, Ci-C 4 acyloxy, Ci-C 4 sulfonamido, halo, cyano, hydroxy or nitro; and [00203] each instance of R 9 is independently hydrogen, d-Cioalkyl, C 3 -C 7 cycloalkyl, heterocycloalkyl, or C 2 -
- Cioheteroalkyl isoheteroalkyl
- B is unsubstituted or substituted alkyl, including but not limited to -(CH 2 ) 2 -
- each R" is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, or NR a R a are combined together to form a cyclic moiety, which includes but is not limited to piperidinyl, piperazinyl, and morpholinyl.
- B is unsubstituted or substituted amino. In some embodiments, B is unsubstituted or substituted heteroalkyl.
- B is a moiety of Formula II and wherein W c is a member selected from the group consisting of unsubstituted or substituted aryl, substituted phenyl, unsubstituted or substituted heteroaryl including but not limited to pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, or pyrazin-2-yl, unsubstituted or substituted monocyclic heteroaryl, unsubstituted or substituted bicyclic heteroaryl, a heteroaryl comprising two heteroatoms as ring atoms, unsubstituted or substituted heteroaryl comprising a nitrogen ring atom, heteroaryl comprising two nitrogen ring atoms, heteroaryl comprising a nitrogen and a sulfur as ring atoms, unsubstituted or substituted heterocycloalkyl
- B is one of the following moieties:
- B is substituted by one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy,or sulfonamido, may itself be substituted.
- R 1 is a member selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl.
- R 1 is unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted heteroarylalkyl.
- R 1 is unsubstituted or substituted alkoxy, unsubstituted or substituted amido, unsubstituted or substituted amino. In some embodiments, R 1 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted alkoxycarbonyl, or unsubstituted or substituted sulfonamido. In some embodiments, R 1 is halo which includes -Cl, -F, -I, and -Br. In some embodiments, R 1 is selected from the group consisting of cyano, hydroxy, nitro, unsubstituted or substituted phosphate, unsubstituted or substituted urea, and carbonate.
- R 1 when R 1 is alkyl, R 1 is methyl, ethyl, propyl, isopropyl, n- butyl, tert- butyl, sec-butyl, pentyl, hexyl or heptyl.
- R 1 when R 1 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, or hydroxy, R 1 is substituted by phosphate, or unsubstituted urea, or substituted urea, or carbonic acid, or carbonate.
- R 1 when R 1 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfonamido, R 1 is substituted by one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido
- R 2 is a member selected from the group consisting of unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, and unsubstituted or substituted heterocycloalkyl.
- R 2 is unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl, or unsubstituted or substituted heteroarylalkyl.
- R 2 is unsubstituted or substituted alkoxy, unsubstituted or substituted amido, unsubstituted or substituted amino.
- R 2 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted alkoxycarbonyl, or unsubstituted or substituted sulfonamido.
- R 2 is halo, which is -I, -F, -Cl, or -Br.
- R 2 is selected from the group consisting of cyano, hydroxy, nitro, a carbonic acid, and a carbonate.
- R 2 is unsubstituted or substituted phosphate. In some embodiments, R 2 is unsubstituted or substituted urea. In some embodiments, when R 2 is alkyl, R 2 is methyl, ethyl, propyl, isopropyl, n- butyl, tert- butyl, sec-butyl, pentyl, hexyl or heptyl.
- R 2 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamide, or hydroxy, it is substituted by phosphate, substituted by urea, or substituted by carbonate.
- R 2 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfonamido
- it is substituted by one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido,
- q is an integer of 0. In some embodiments, q is an integer of 1. In some embodiments, q is an integer of 2. In some embodiments, q is an integer of 3. In some embodiments, q is an integer of 4.
- R 3 is a member selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, and unsubstituted or substituted alkynyl.
- R 3 is unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl.
- R 3 is unsubstituted or substituted alkoxy, unsubstituted or substituted amido, unsubstituted or substituted amino.
- R 3 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted alkoxycarbonyl, or unsubstituted or substituted sulfonamido.
- R 3 is halo, which is is -I, -F, -Cl, or -Br.
- R 3 is selected from the group consisting of cyano, hydroxy, and nitro.
- R 3 when R 3 is alkyl, R 3 is methyl, ethyl, propyl, isopropyl, n- butyl, tert- butyl, sec-butyl, pentyl, hexyl or heptyl.
- R 3 is -CF 3 , -CH 2 F or -CHF 2 .
- R 3 when R 3 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,or sulfonamido, it is substituted with one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,
- heterocycloalkyl aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfonamido may itself be substituted.
- R 5 is hydrogen, unsubstituted or substituted alkyl (including but not limited to unsubstituted or substituted Ci-C 4 alkyl). In some embodiments, R 5 is unsubstituted or substituted alkenyl including but not limited to unsubstituted or substituted C 2 -C 5 alkenyl. In some embodiments, R 5 is unsubstituted or substituted alkynyl including but not limited to unsubstituted or substituted C 2 -C 5 alkynyl.
- R 5 is unsubstituted or substituted cycloalkyl including but not limited to unsubstituted or substituted C 3 - C 5 cycloalkyl. In some embodiments, R 5 is unsubstituted or substituted heterocycloalkyl. In some embodiments, R 5 is unsubstituted or substituted heteroalkyl including but not limited to unsubstituted or substituted C r C 4 heteroalkyl. In some embodiments, R 5 is unsubstituted or substituted alkoxy including but not limited to unsubstituted or substituted C 1 - C 4 alkoxy.
- R 5 is unsubstituted or substituted amido including but not limited to unsubstituted or substituted C r C 4 amido. In some embodiments, R 5 is unsubstituted or substituted amino. In some embodiments, R 5 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C r C 4 acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted sulfonamido, or unsubstituted or substituted C 1 - C 4 sulfonamido.
- R 5 is halo, which is is -I, -F, -Cl, or -Br. In some embodiments, R 5 is selected from the group consisting of cyano, hydroxy, and nitro. In some other embodiments, R 5 is -CH 3 , -CH 2 CH 3 , n-propyl, isopropyl, -OCH 3 , -OCH 2 CH 3 , or -CF 3 .
- R 5 when R 5 is alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, acyl, alkoxy, amido, amino, acyloxy, alkoxycarbonyl, or sulfonamido, R 5 is optionally substituted with one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfonamido, halo,
- R 6 is hydrogen, unsubstituted or substituted alkyl (including but not limited to unsubstituted or substituted C r C 4 alkyl). In some embodiments, R 6 is unsubstituted or substituted alkenyl including but not limited to unsubstituted or substituted C 2 -C 5 alkenyl. In some embodiments, R 6 is unsubstituted or substituted alkynyl including but not limited to unsubstituted or substituted C 2 -C 5 alkynyl.
- R 6 is unsubstituted or substituted cycloalkyl including but not limited to unsubstituted or substituted C 3 - C 5 cycloalkyl. In some embodiments, R 6 is unsubstituted or substituted heterocycloalkyl. In some embodiments, R 6 is unsubstituted or substituted heteroalkyl including but not limited to unsubstituted or substituted Ci-C 4 heteroalkyl. In some embodiments, R 6 is unsubstituted or substituted alkoxy including but not limited to unsubstituted or substituted C 1 - C 4 alkoxy.
- R 6 is unsubstituted or substituted amido including but not limited to unsubstituted or substituted d-C 4 amido. In some embodiments, R 6 is unsubstituted or substituted amino. In some embodiments, R 6 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C t -Qacyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted sulfonamido, or unsubstituted or substituted C 1 - Qsulfonamido.
- R 6 is halo, which is is -I, -F, -Cl, or -Br. In some embodiments, R 6 is selected from the group consisting of cyano, hydroxy, and nitro. In some other embodiments, R 6 is -CH 3 , -CH 2 CH 3 , n-propyl, isopropyl, -OCH 3 , -OCH 2 CH 3 , or -CF 3 .
- R 6 when R 6 is alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, acyl, alkoxy, amido, amino, acyloxy, alkoxycarbonyl, or sulfonamido, R 6 is optionally substituted with one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfonamido, halo,
- R 7 is hydrogen, unsubstituted or substituted alkyl (including but not limited to unsubstituted or substituted C r C 4 alkyl). In some embodiments, R 7 is unsubstituted or substituted alkenyl including but not limited to unsubstituted or substituted C 2 -C 5 alkenyl. In some embodiments, R 7 is unsubstituted or substituted alkynyl including but not limited to unsubstituted or substituted C 2 -C 5 alkynyl.
- R 7 is unsubstituted or substituted cycloalkyl including but not limited to unsubstituted or substituted C 3 - C 5 cycloalkyl. In some embodiments, R 7 is unsubstituted or substituted heterocycloalkyl. In some embodiments, R 7 is unsubstituted or substituted heteroalkyl including but not limited to unsubstituted or substituted C r C 4 heteroalkyl. In some embodiments, R 7 is unsubstituted or substituted alkoxy including but not limited to unsubstituted or substituted C 1 - Qalkoxy.
- R 7 is unsubstituted or substituted amido including but not limited to unsubstituted or substituted C r C 4 amido. In some embodiments, R 7 is unsubstituted or substituted amino. In some embodiments, R 7 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C]-C 4 acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted sulfonamido, or unsubstituted or substituted C 1 - C 4 sulfonamido.
- R 7 is halo, which is is -I, -F, -Cl, or -Br. In some embodiments, R 7 is selected from the group consisting of cyano, hydroxy, and nitro. In some other embodiments, R 7 is -CH 3 , -CH 2 CH 3 , n-propyl, isopropyl, -OCH 3 , -OCH 2 CH 3 , or -CF 3 .
- R 7 when R 7 is alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, acyl, alkoxy, amido, amino, acyloxy, alkoxycarbonyl, or sulfonamide, R 7 is optionally substituted with one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfonamido may
- R 8 is hydrogen, unsubstituted or substituted alkyl (including but not limited to unsubstituted or substituted Ci-C 4 alkyl). In some embodiments, R 8 is unsubstituted or substituted alkenyl including but not limited to unsubstituted or substituted C 2 -C 5 alkenyl. In some embodiments, R 8 is unsubstituted or substituted alkynyl including but not limited to unsubstituted or substituted C 2 -C 5 alkynyl.
- R 8 is unsubstituted or substituted cycloalkyl including but not limited to unsubstituted or substituted C 3 - C 5 cycloalkyl. In some embodiments, R 8 is unsubstituted or substituted heterocycloalkyl. In some embodiments, R 8 is unsubstituted or substituted heteroalkyl including but not limited to unsubstituted or substituted In some embodiments, R 8 is unsubstituted or substituted alkoxy including but not limited to unsubstituted or substituted C r C 4 alkoxy. In some embodiments, R 8 is unsubstituted or substituted amido including but not limited to unsubstituted or substituted Q-Qamido.
- R 8 is unsubstituted or substituted amino. In some embodiments, R 8 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted Ci-C 4 acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted sulfonamido, or unsubstituted or substituted C 1 - C 4 sulfonamido. In some embodiments, R 8 is halo, which is is -I, -F, -Cl, or -Br. In some embodiments, R 8 is selected from the group consisting of cyano, hydroxy, and nitro. In some other embodiments, R 8 is -CH 3 , -CH 2 CH 3 , n-propyl, isopropyl, -OCH 3 , -OCH 2 CH 3 , or -CF 3 .
- R 8 when R 8 is alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, acyl, alkoxy, amido, amino, acyloxy, alkoxycarbonyl, or sulfonamido, R 8 is optionally substituted with one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, or sulfona
- R 5 , R 6 , R 7 , and R 8 are H and the compound has a structure of Formula I- 1:
- X is absent.
- X is -(CH(R 9 ))-, and z is an integer of 1, 2, 3 or 4.
- R 9 is unsubstituted or substituted alkyl including but not limited to unsubstituted or substituted Ci-Ci O alkyl.
- R 9 is unsubstituted or substituted cycloalkyl including but not limited to unsubstituted or substituted C 3 -C 7 cycloalkyl.
- R 9 is ethyl, methyl or hydrogen.
- R 9 is unsubstituted or substituted heterocycloalkyl including but not limited to unsubstituted or substituted C 2 -Ci 0 heteroalkyl.
- R 9 is unsubstituted or substituted heteroalkyl including but not limited to unsubstituted or substituted C 2 -C,oheteroalkyl.
- the invention also provides a compound of Formula I wherein R 9 is hydrogen, and X is -CH 2 -, -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -CH(CH 3 )-, or -CH(CH 2 CH 3 )-.
- X is -(CH(R 9 )) 2
- R 9 is not hydrogen
- z is an integer of 1.
- the compound can adopt either an (S)- or (R)- stereochemical configuration with respect to carbon X.
- the compound is a racemic mixture of (S)- and (R) isomers with respect to carbon X.
- the present invention provides a mixture of compounds of Formula I wherein individual compounds of the mixture exist predominately in an (S)- or (R)- isomeric configuration.
- the compound mixture has an (S)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more at the X carbon.
- the compound mixture has an (S)-enantiomeric purity of greater than about 55% to about 99.5%, greater than about about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.
- the compound mixture has an (R)-enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more at the X carbon.
- the compound mixture has an (R)- enantiomeric purity of greater than about 55% to about 99.5%, greater than about about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.
- the compound mixture contains identical chemical entities except for their stereochemical orientations, namely (S)- or (R)- isomers.
- the compounds of Formula I when X is -CH(R 9 )-, and R 9 is not hydrogen, then the -CH(R 9 )- is in an (S)- or (R)- sterochemical orientation for each of the identical chemical entities.
- the mixture of identical chemical entities of Formula I is a racemic mixture of (S)- and (R)- isomers at the carbon represented by X.
- the mixture of the identical chemical entities (except for their stereochemical orientations),contain predominately (S)-isomers or predominately (R)- isomers.
- the (S)- isomers in the mixture of identical chemical entities are present at about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% ,or more, relative to the (R)- isomers.
- the (S)- isomers in the mixture of identical chemical entities are present at an (S)-enantiomeric purity of greater than about 55% to about 99.5%, greater than about about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or more.
- the (R)- isomers in the mixture of identical chemical entities are present at about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about
- the (R)- isomers in the mixture of identical chemical entities are present at a (R)- enantiomeric purity greater than about 55% to about 99.5%, greater than about about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about
- the compound of Formula I, X is -CH(R 9 )-, R 9 is methyl or ethyl, and the compound is the
- At least one of X and Y is present. In some embodiments of the compound of Formula I, -
- XY- is -CH 2 -, -CH 2 -N(CH 3 ), -CH 2 -N(CH 2 CH 3 ), -CH(CH 3 )-NH-, (S) -CH(CH 3 )-NH-, or (R) -CH(CH 3 )-NH-.
- X-Y is -N(CH 3 ).CH 2 -, N(CH 2 CH 3 ) CH 2 -, -N(CH(CH 3 ) 2 )CH 2 -, or -NHCH 2 -.
- the invention provides other compounds of Formula I wherein when X-Y is X is -(CH(R 9 )) Z N(R 9 )-, z is an integer of 1, 2, 3 or 4, and -N(R 9 )- is not -
- W d in a formula disclosed herein including but not limited to 1, 1-1, IV, IV-A, V, V-A, V-
- A2, V-B, VI and VI-A is a member selected from the group consisting of unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.
- W d is unsubstituted or substituted monocyclic heteroaryl (including but not limited to pyrimidinyl, pyrrolyl, pyrazinyl, triazinyl, or pyridazinyl) or unsubstituted or substituted bicyclic heteroaryl.
- W d is a monocyclic heteroaryl of the following formula:
- R" is hydrogen, halo, phosphate, urea, a carbonate, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroalkyl, or unsubstituted or substituted heterocycloalkyl; and
- R 12 is H, unsubstituted or substituted alkyl, unsubstituted or substituted cyano, unsubstituted or substituted alkynyl, unsubstituted or substituted alkenyl, halo, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted amino, carboxylic acid, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, unsubstituted or substituted acyl, or unsubstituted or substituted sulfonamido.
- the invention provides monocyclic heteroaryl W d including but not limited to one of the following formulae:
- W d in a formula disclosed herein is a bicyclic heteroaryl having at least one heteroatom, e.g., a bicyclic heteroaryl having at least one nitrogen ring atom.
- W d is a bicyclic heteroaryl having at least two heteroatoms, e.g., a bicyclic heteroaryl having at least two nitrogen ring atoms.
- W d is a bicyclic heteroaryl having two heteroatoms in the ring which is connected to XY.
- W d is a bicyclic heteroaryl having two nitrogen ring atoms in the ring to which XY is connected. In some embodiments, W d is a bicyclic heteroaryl having four heteroatoms, e.g, a bicyclic heteroaryl having four nitrogen ring atoms. In some embodiments, W d is unsubstituted or substituted 4-amino-lH-pyrazolo[3,4-d]pyrimidin-l-yl, unsubstituted or substituted
- W d is one of the following:
- R" is hydrogen, halo, phosphate, urea, a carbonate, unsubstituted or substituted amino, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heteroalkyl, or unsubstituted or substituted heterocycloalkyl;
- R 1 ' is hydrogen, unsubstituted or substituted alkyl, halo (which includes -I, -F, -Cl, or -Br), unsubstituted or substituted amino, unsubstituted or substituted amido, hydroxy, or unsubstituted or substituted alkoxy, phosphate, unsubstituted or substituted urea, or carbonate; and
- R 12 is H, unsubstituted or substituted alkyl, unsubstituted or substituted cyano, unsubstituted or substituted alkynyl, unsubstituted or substituted alkenyl, halo, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted amino, carboxylic acid, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, unsubstituted or substituted acyl, or unsubstituted or substituted sulfonamido.
- W d of the compounds of Formula I whenR a is alkyl, alkynyl, cycloalkyl, heteroalkyl, or heterocycloalkyl, it is substituted by phosphate, urea, or carbonate.
- W d of the compounds of Formula I when R 11 is alkyl, amino, amido, hydroxy, or alkoxy, it is substituted by phosphate, urea, or carbonate.
- R 12 is a member of the group consisting of hydrogen, cyano, halo, unsubstituted or substituted alkyl, unsubstituted or substituted alkynyl, and unsubstituted or substituted alkenyl. In some embodiments, R 12 is unsubstituted or substituted aryl.
- R 12 is unsubstituted or substituted heteroaryl, which includes but is not limited to heteroaryl having a 5 membered ring, heteroaryl having a six membered ring, heteroaryl with at least one nitrogen ring atom, heteroaryl with two nitrogen ring atoms, monocylic heteroaryl, and bicylic heteroaryl.
- R 12 is unsubstituted or substituted heterocycloalkyl, which includes but is not limited to heterocycloalkyl with one nitrogen ring atom, heterocycloalkyl with one oxygen ring atom, R 12 is heterocycloalkyl with one sulfur ring atom, 5 membered heterocycloalkyl, 6 membered heterocycloalkyl, saturated heterocycloalkyl, unsaturated heterocycloalkyl, heterocycloalkyl having an unsaturated moiety connected to the heterocycloalkyl ring, heterocycloalkyl substituted by oxo, and heterocycloalkyl substituted by two oxo.
- R 12 is unsubstituted or substituted cycloalkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkyl substituted by one oxo, cycloalkyl having an unsaturated moiety connected to the cycloalkyl ring.
- R 12 is unsubstituted or substituted amido, carboxylic acid, unsubstituted or substituted acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted acyl, or unsubstituted or substituted sulfonamido.
- R 12 when R 12 is alkyl, alkynyl, alkenyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, it is substituted with phosphate. In some embodiments, when R 12 is alkyl, alkynyl, alkenyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, it is substituted with urea. In some embodiments, when R 12 is alkyl, alkynyl, alkenyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, it is substituted with carbonate.
- R 12 when R 12 is alkyl, alkynyl, alkenyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, alkoxycarbonyl, amido, acyloxy, acyl, or sulfonamido, it is substituted with one or more of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro, each of which alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, amido, amino, acyl, acyloxy, aloxycarbonyl, or sulfona
- R 12 of W d is one of the following moieties:
- W d is a pyrazolopyrimidine of Formula III:
- R 11 is H, alkyl, halo, amino, amido, hydroxy, or alkoxy
- R 12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
- R 11 is amino and R 12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
- R 11 is amino and R 12 is alkyl, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
- R 11 is amino and R 12 is monocyclic heteroaryl. In some embodiments, R 11 is amino and R 12 is bicyclic heteroaryl. In some embodiments, R 11 is amino and and R 12 is cyano, amino, carboxylic acid, acyloxy, alkoxycarbonyl,or amido.
- the compound of Formula I is a compound having a structure of Formula IV:
- R 11 is H, alkyl, halo, amino, amido, hydroxy, or alkoxy
- R 12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
- R 11 is amino and R 12 is alkyl, alkenyl, heteroaryl, aryl, or heterocycloalkyl.
- R 11 is amino and and R 12 is cyano, amino, carboxylic acid, alkoxycarbonyl, or amido.
- the compound of Formula IV is a compound of Formula IV-A:
- the invention also provides compounds of Formula I having a structure of any of Formulae V, V-Al, V- A2, V- B, VI, VI-A, VII-Al, VII- A2, VIII-Al, VIII- A2, IX-Al, IX- A2, X-Al, X- A2, XI-Al, XI- A2, XII-A, XII-Al, XII- A2, XIII-A, XIII-Al, XIII-A2, XIV-A, XIV-Al, XIV-A2, XV-A, XV-Al, XV-A2, XVI-A, XVI-Al, XVI-Al, XVI-A2, XVII-A, XVII- Al, XVII- A2, XVIII-A, XVIII-Al, or XVIII-A2:
- R 3 is H, CH 3 , CF 3 , Cl, or F; and B is a moiety of Formula II:
- W c is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl;
- R 1 is H, -F, -Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 , nitro, or phosphate;
- R 2 is halo, hydroxy, cyano, or nitro;
- q is an integer of 0, 1, 2, 3, or 4;
- R 5 , R 6 , R 7 , and R 8 are H;
- X is absent or (CH 2 ) Z ;
- z is 1;
- Y is absent or -N(R 9 )-;
- R 9 is hydrogen, Ci-Ci O alkyl, C 3 -C 7 cycloalkyl, or C 2 -C,oheteroalkyl; at least one of X and Y is present; and
- W d is pyrazolopyrimidine or purine. In some embodiments, when
- R 3 is H, CH 3 , CF 3 , Cl, or F;
- B is a moiety of Formula II which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, R 1 is H, -F, -Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 , nitro, or phosphate;
- R 2 is halo, hydroxy, cyano, or nitro; q is 0, 1 or 2;
- R 5 , R 6 , R 7 , and R 8 are H;
- X is absent or (CH 2 ) Z ;
- z is 1;
- Y is
- R 9 is hydrogen, methyl, or ethyl; at least one of X and Y is present; W d is: R 11 ; R 11 is amino; and R 12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
- W d is: R 11 ; R 11 is amino; and R 12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
- R 3 is H, CH 3 , CF 3 , Cl, or F;
- B is a moiety of Formula II, which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, R 1 is H, -F, -Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 , nitro, or phosphate;
- R 2 is halo, hydroxy, cyano, or nitro; q is 0, 1 or 2;
- X is (CH 2 ) Z ;
- z is 1 ;
- R 5 , R 6 , R 7 , and R 8 are H;
- Y is absent and
- W d is: ; R 11 is amino; and R 12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl.
- R 3 is H, CH 3 , CF 3 , Cl, or F;
- B is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl,
- R 1 is H, -F, -
- R 3 is aryl, heteroaryl, H, CH 3 , CF 3 , Cl, or F;
- B is alkyl or a moiety of Formula II;
- W c is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and q is an integer of 0, 1, 2, 3, or 4;
- R 1 is H, -F, - Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 , nitro, or phosphate;
- R 2 is halo, hydroxy, cyano, nitro, or phosphate; q is 0, 1 or 2;
- R 5 , R 6 , R 7 , and R 8 are H;
- X is absent or (CH(R 9 )) Z ;
- z is an integer of 1, 2, 3, or 4;
- Y is absent, -N(R 9 )-, or -N(R 9 ) CH(R 9 )-;
- R 9 is hydrogen, alkyl, cycloalkyl, or heteroalkyl; at least one of X and Y is present; and
- W d is
- R 3 is aryl, heteroaryl, H, CH 3 , CF 3 , Cl, or F;
- B is alkyl or a moiety of Formula II which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl,
- R 1 is H, -F, -Cl, -CN, -CH 3 , isopropyl, - CF 3 , -OCH 3 , nitro, or phosphate;
- R 2 is halo, hydroxy, cyano, nitro, or phosphate;
- q is 0, 1 or 2;
- R 5 , R 6 , R 7 , and R 8 are H;
- X is absent or (CH(R 9 )) Z ;
- z is an integer of 1 , 2, 3, or 4;
- Y is absent, -N(R 9 )-, or -N(R 9 ) CH(R 9 )-;
- R 9 is hydrogen, methyl, or
- R 3 is H, CH 3 , CF 3 , Cl, or F;
- B is alkyl or a moiety of Formula II which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl,
- R 1 is H, -F, -Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 , nitro, or phosphate;
- R 2 is halo, hydroxy, cyano, nitro, or phosphate;
- q is 0, 1 or 2;
- R 5 , R 6 , R 7 , and R 8 are H;
- X is (CH(R 9 )) Z ;
- z is an alkyl or a moiety of Formula II which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl
- R 1 is H, -F, -Cl, -CN, -CH 3 , isopropyl
- Y is absent-;
- R 9 is hydrogen, methyl, or ethyl;
- W d is: R 11 ;
- R 11 is amino; and
- R 12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, cyano, amino, carboxylic acid, alkoxycarbonyl, or amido.
- R 3 is aryl, heteroaryl, H, CH 3 , CF 3 , Cl, or F; B is a moiety of
- Formula II which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, R 1 is H, -F, -Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 , nitro, or phosphate; R 2 is halo, hydroxy, cyano, nitro, or phosphate; q is 0, 1 or 2; R 5 , R 6 , R 7 , and R 8 are H; X is absent or
- X and Y is present, and W d is: N .
- Y is -N(R 9 )-, and W d is purine, then Y is -NH-.
- R 3 is aryl, heteroaryl, H, CH 3 , CF 3 , Cl, or F;
- B is a moiety of Formula II which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl,
- R 1 is H, -F, -Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 , nitro, or phosphate;
- R 2 is halo, hydroxy, cyano, nitro, or phosphate;
- q is 0, 1 or 2;
- R 5 , R 6 , R 7 , and R 8 are H;
- X is absent;
- Y is aryl, heteroaryl, H, CH 3 , CF 3 , Cl, or F
- B is a moiety of Formula II which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl,
- R 1 is H, -F, -
- R 3 is aryl, heteroaryl, H, CH 3 , CF 3 , Cl, or F;
- B is alkyl or a moiety of Formula II which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl,
- R 1 is H, -F, -Cl, -CN, -CH 3 , isopropyl, - CF 3 , -OCH 3 , nitro, or phosphate;
- R 2 is halo, hydroxy, cyano, nitro, or phosphate;
- q is 0, 1 or 2;
- R 5 , R 6 , R 7 , and R 8 are H;
- X is absent or (CHCR 9 )) ⁇ z is an integer of 1, 2, 3, or 4;
- Y is absent, -N(R 9 )-, or -N(R 9 ) CH(R 9 )-;
- R 9 is hydrogen, methyl, or
- Y is -N(R 9 )-, and W d is purine, then Y is -NH-.
- Some illustrative compounds of the present invention having a structure of Formula IV-A include those in which R 3 is -H, -Cl, -F, or -CH 3 in combination with any B moiety described in Table 1, and any R 12 as described in Table 2.
- a compound of Formula IV-A includes any combination of R 3 , B, and R 12 . Additional exemplary compounds of Formula IV-A are illustrated in Table 4.
- Other illustrative compounds of the present invention have a structure of Formula V-A, V-Al, or V- A2, wherein B is a moiety described in Table 1, in combination with R 3 , which is -H, -Cl, -F, or CH 3 ,and R 9 , which is -H, CH 3 , or -CH 2 CH 3 .
- a compound of Formula V-A, V-Al, or V- A2 includes any combination of R 3 , B, and R 9 .
- the compound of Formula V- A2 is:
- R 1 is -H, e.g., of the formula:
- q is 1 and R 2 is provided as in the formula: , or pharmaceutically acceptable salts thereof.
- Rl is H and R2 is H, e.g. of the formula:
- Rl is H, q is 1 and R2 is halo (e.g., fluoro) of the formula:
- R is H, q is 1 and R is halo (e.g., fluoro) in the meta position, e.g., of the formula:
- R 3 is haloalkyl.
- R 3 is -CF 3 , -CH 2 F or -CHF 2 .
- Yet other illustrative compounds of the present invention have a structure of Formula V-B, wherein B is a moiety described in Table 1 , in combination with R 3 , which is -H, -Cl, -F, or CH 3 , and R 9 , which is -H, -CH 3 , or - CH 2 CH 3 .
- a compound of Formula V-B includes any combination of R 3 , B, and R 9 .
- Some other illustrative compounds of the present invention have a structure of Formula VI-A, wherein B is a moiety described in Table 1, in combination with R 3 , which is -H, -Cl, -F, or CH 3 ,and R 9 , which is -H, -CH 3 , or - CH 2 CH 3 .
- a compound of Formula VI-A includes any combination of R 3 , B, and R 9 .
- Further illustrative compounds of the invention have a structure of one of Formulae VII-Al, VII-A2, VIII-Al, VIII-A2, IX-Al, IX-A2, X-Al, X-A2, XI-Al, XI-A2, XII-A, XII-Al, XII-A2, XIII-A, XIII-Al, XIII-A2, XIV-A, XIV- Al, or XIV- A2: wherein B is a moiety described in Table 1, any R 12 as described in Table 2, in combination with R 3 , which is -H, -Cl, -F, or CH 3 , R 9 which is -H, -CH 3 , or -CH 2 CH 3> and R" ' which is -H, -Cl, -F, or -NH 2 .
- Additional exemplary compounds of the present invention include but are not limited to the following:
- reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -10 0 C to about 110 °C over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.
- solvent each mean a solvent inert under the conditions of the reaction being described in conjunction therewith including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone (“NMP”), pyridine and the like.
- solvents used in the reactions described herein are inert organic solvents. Unless specified to the contrary, for each gram of the limiting reagent, one cc (or mL) of solvent constitutes a volume equivalent.
- Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
- the (R)- and (S)-isomers of the compounds of the present invention may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
- a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents,
- the compounds of the invention can generally be synthesized by an appropriate combination of generally well known synthetic methods. Techniques useful in synthesizing these chemical entities are both readily apparent and accessible to those of skill in the relevant art, based on the instant disclosure.
- the compounds of the invention can be synthesized by an appropriate combination of known synthetic methods in the art.
- the discussion below is offered to illustrate certain of the diverse methods available for use in making the compounds of the invention and is not intended to limit the scope of reactions or reaction sequences that can be used in preparing the compounds of the present invention.
- Step 1 a compound of Formula 101, wherein X is N or CR 7 , is converted to a compound of Formula 103, for example, via a two step process of Heck coupling with a compound of Formula 102, followed by acid catalyzed cyclization in methanol.
- the product, a compound of Formula 103 is isolated.
- Step 2 a compound of Formula 103 is converted to a compound of Formula 404, for example, via reaction with an appropriately substituted aniline.
- the product, a compound of Formula 104 is isolated.
- Step 3 a compound of Formula 104 is converted to a compound of Formula 105, for example, though reduction with lithium aluminum hydride.
- a compound of Formula 105 is converted to a compound of Formula 106, for example, via reaction with thionyl chloride.
- the product, a compound of Formula 106 is isolated.
- Step 5 a compound of Formula 106 is converted to a compound of Formula 107, for example, via alkylation with a pyrrazolopyrimidine using a base such as potassium carbonate.
- the product, a compound of Formula 107 is isolated.
- Step 6 a compound of Formula 107 is converted to a compound of Formula 108, for example, via a Suzuki reaction.
- the product, a compound of Formula 108 is isolated and optionally purified.
- Step 1 a compound of Formula 201, wherein X is N or CR 7 , is converted to a compound of Formula 202, for example, with a reagent suitable for introduction of an acid chloride, for example, oxalyl chloride.
- a compound of Formula 202 is optionally isolated.
- Step 2 a compound of
- Formula 202 is converted to a compound of Formula 503 for example, reaction with, for example, an an aryl amine .
- the product, a compound of Formula 203 is isolated.
- Step 3 a compound of Formula 203 is converted to a compound of Formula 204, for example, via a Stille coupling using an appropriate vinyl-stannane.
- the product, a compound of Formula 204 is isolated.
- Step 4 a compound of Formula 204 is converted to a tertiary amide, a compoundof Formula 205, via reaction with chloroethyl acetate and sodium hydride base.
- the compound of Formula 205 is isolated.
- Step 5 a compound of Formula 205 is oxidized to an aldehyde, using, for example, osmonium tetraoxide and sodium periodinate.
- the product, a compound of Formula 206 is isolated.
- Step 6 a compound of Formula 206 is converted to a compound of Formula 104, for example, though aldol reaction in ethanol with a base, such as cesium carbonate. The product, a compound of Formula 104, is isolated.
- Step 7 a compound of Formula 104 is reduced to a primary alcohol via reduction with, for example, lithium aluminum hydride, to produce a compound of Formula 105, which is isolated.
- Step 8 a compound of Formula 105 is converted to a compound of Formula 207 via reaction with carbon tetrabromide and triphenylphosphine.
- the compound of Formula 207 is isolated. This compound can be a central intermediate in the synthesis of the compounds of the invention.
- Reaction Scheme 3 Reaction Scheme 3:
- Step 9 a compound of Formula 207, wherein X is N or CR 7 , is synthesized as described in Reaction Scheme 2 and is converted to a compound of Formula 107 via coupling with the compound of Formula 208 in the presence of base, for example, potassium t- butoxide.
- the compound of Formula 107 is isolated.
- Step 10 a compound of Formula 107 is converted to a compound of Formula 108 via coupling with, for example, an aryl boronic acid, in the presence of coupling catalysts and base, for example, palladium acetate, triphenylphosphine and sodium carbonate, for example.
- the compound of Formula 108 is isolated.
- Reaction Scheme 4 A which illustrates synthesis of a general class of purinyl substituted isoquinolones
- Step 1 iodo ester 401
- an alkyne of Formula 400-A in the presence of a palladium catalyst, copper iodide and triethylamine (TEA) to couple the alkyne to the aryl core of compound 401 to produce a compound of Formula 402.
- the compound of Formula 402 is optionally isolated.
- Step 2 a compound of Formula 402 is treated with potassium hydroxide base to obtain the carboxylic acid, a compound of Formula 403, if the reaction product is acidified, or its salt.
- the compound of Formula 403 is optionally isolated.
- Step 3 a compound of Formula 403 is treated with bis (acetonitrile)dichoropalladium (II) and TEA to effect intramolecular ring closure to produce a compound of Formula 404.
- the compound of Formula 404 is isolated.
- Step 4 a compound of Formula 404 is reacted with a primary amine to produce a compound of Formula 405.
- the compound of Formula 405 is optionally isolated.
- Step 5 a compound of Formula 405 is treated with hydrochoric acid, removing the protecting group on nitrogen, and to obtain a compound of Formula 406.
- the compound of Formula 406 is optionally isolated.
- Step 6 a compound of Formula 406 is reacted with a compound of Formula 407, to produce a compound of Formula 408.
- the compound of Formula 408 is isolated.
- Reaction Scheme 4B the synthesis of one subset of purinyl substituted isoquinolones, wherein R 9 is methyl and R a is hydrogen, is illustrated using the synthetic transformations described for Reaction Scheme 4 A.
- iodo ester 401 is reacted with alkyne 501 in the presence of palladium coupling catalyst, copper iodide, and TEA, to obtain a compound of Formula 502.
- the compound of Formula 502 is optionally isolated.
- the compound of Formula 502 is treated with potassium hydroxide base to obtain the carboxylate or free acid of a compound of Formula 503.
- the compound of Formula 503 is treated with bis (acetonitrile)dichoropalladium (II) and TEA to effect intramolecular ring closure to produce a compound of Formula 504.
- the compound of Formula 504 is optionally isolated.
- the compound of Formula 504 is treated with a primary amine to produce a compound of Formula 505.
- the compound of Formula 505 is isolated.
- Reaction Scheme 6A which illustrates synthesis of a general class of purinyl substituted isoquinolones
- Step 1 iodo ester 401 is reacted with alkyne 601 in the presence of palladium coupling catalyst, copper iodide, and TEA, to obtain a compound of Formula 602.
- the compound of Formula 602 is optionally isolated.
- Step 2 the compound of Formula 602 is treated with potassium hydroxide base to obtain the carboxylate or free acid of a compound of Formula 603.
- the compound of Formula 603 is treated with bis (acetonitrile)dichloropalladium (II) and TEA to effect intramolecular ring closure to produce a compound of Formula 604.
- the compound of Formula 604 is optionally isolated.
- the compound of Formula 604 is treated with a primary amine to produce a compound of Formula 605.
- the compound of Formula 605 is isolated.
- the compound of Formula 605 is treated with acid to remove the THP protecting group to obtain a compound of Formula 606.
- the compound of Formula 606 is isolated.
- Reaction Scheme 6B the synthesis of purinyl substituted isoquinolones, wherein R 9 is methyl and R a is hydrogen, is illustrated using the synthetic transformations described for Reaction Scheme 6A.
- Step 1 the compound of Formula 701 is synthesized by a variety of synthetic routes, including variations of Schemes 1 or 2 where, for example, a benzyl amine is used in the step of converting a compound of Formula 103 to a compound of Formula 104.
- the benzyl protecting group of the amine may be removed by standard deprotection chemistry to produce a compound of 701.
- Another example of a conversion of a compound of Formula 103 to a compoound of Formula 701 treatment of the compound of Formula 103 with ammonia produces the compound of Formula 701.
- the compound of Formula 701 is converted to a compound of Formula 702 by alkylation of the amide nitrogen with a number of 2-carbon containing synthons which can be deprotected, oxidized and reprotected as the respective ketal, the compound of Formula 702.
- the compound of Formula 702 is transformed by, for example, reductive amination of the ester moiety to introduce the purinyl moiety of a compound of Formula 703, or alternatively, is alkylated to so introduce a purinyl moiety and obtain a compound of Formula 703.
- the compound of Formula 703 is treated with acid to remove the ketal protecting group to produce a compound of Formula 704.
- the compound of Formula 704 is isolated.
- the compound of Formula 704 is reductively aminated with an amine to produce a compound of Formula 705.
- the compound of Formula 705 is isolated.
- the compound of Formula 702 is transformed by, steps 7 and 8 of Scheme 2 and step 9 of Scheme 3 to introduce the pyrazolopyrimidine moiety of a compound of Formula 706.
- the compound of Formula 706 is isolated.
- the compound of Formula 706 is treated with acid to remove the ketal protecting group to produce a compound of Formula 707.
- the compound of Formula 707 is isolated.
- Step 1 the compound of Formula 701 is synthesized as described in Scheme 7 or any other generally known chemistry.
- the compound of Formula 701 is tranformed by alkylation of the amide nitrogen with a number of 2-carbon containing synthons which can be deprotected, and converted to the alkoxy protected species as shown in the compond of Formula 801, which can be isolated.
- Step 2 the compound of Formula 801 is converted via chemistry described in Step 2-1 of Scheme 7 to introduce a purinyl moiety, and that resultant compound is transformed by deprotection, activation and amination with an amine to produce a compound of Formula 802, which is isolated.
- Step 3 the compound of Formula 801 is converted via chemistry described in Step 2-2 of Scheme 7 to introduce a pyrazolopyrimidine moiety, and that resultant compound is transformed by deprotection, activation and amination with an amine to produce a compound of Formula 803, which is isolated.
- Step 1 the compound of Formula 901 is treated with an amine to produce a compound of Formula 902.
- the compound of Formula 902 is isolated.
- Step 2 the compound of Formula 902 is treated with phosphorus oxychloride to generate a compound of Formula 903.
- the compound of Formula 903 is isolated.
- Step 3 the compound of Formula 903 is reacted with an amino purine of Formula 904 to obtain a compound of Formula 905.
- the compound of Formula 905 is isolated.
- Step 4 the compound of Formula 905 is treated with hydrochloric acid to remove the protecting group at nitrogen on the purine moiety to produce a compound of Formula 906.
- the compound of 906 is isolated.
- Step 1 the compound of Formula 1001 is treated with vinylogous ester 1002 using, for example a Heck reaction with subsequent cyclization, to produce a compound of Formula 1003.
- the compound of Formula 1003 is isolated.
- Step 2 the compound of Formula 1003 is reacted with 4- amino N-Boc piperidine to produce a compound of Formula 1004.
- the compound of Formula 1004 is isolated.
- the compound of Formula 1004 can be used as an intermediate in the synthesis of the compounds of the invention.
- Step 1 the compound of Formula 1101 is treated with an alkynyl alcohol, for example, of Formula 1102, in the presence of copper iodide and palladium on carbon catalyst, to produce a compound of Formula 1103.
- the compound of Formula 1103 is isolated.
- Step 1 the compound of Formula 1102 is reacted with 4- amino N-Boc piperidine to produce a compound of Formula 1103.
- the compound of Formula 1103 is isolated.
- the compound of Formula 1103 can be used as an intermediate in the synthesis of the compounds of the invention.
- Step 1 Another approach to synthesis of compounds of Formula I is illustrated in Scheme 12.
- the compound of Formula 1201 is treated with a chlorinating agent such as oxalyl chloride to produce an acid chloride of Formula 1202.
- Step 2 the compound of Formula 1202 is reacted with a compound of Formula R 1 NH 2 in the presence of a base such as triethylamine, to produce a compound of Formula 1203.
- the chlorinating agent used for the conversion of compound 1201 is thionyl chloride, for example thionyl chloride in toluene.
- step 1 and 2 may be combined to form a one-pot reaction.
- Step 3 the compound of Formula 1203 is treated with n-butyllithium and then reacted with an dialkyl oxalate such as diethyl oxalate to produce a compound of Formula 1204.
- Step 4 the compound of Formula 1204 is refluxed in an acidic solution, for example, hydrochloric acid in methanol to produce a compound of Formula 1205.
- Step 5 the compound of Formula 1205 is treated with a reducing agent such as lithium aluminum hydride to produce a compound of Formula 1206.
- Step 6 the compound of Formula 1206 is reacted with a brominating agent such as phosphorus tribromide, in the presence of dimethylformamide in acetonitrile to produce a bromo compound of Formula 1207.
- a brominating agent such as phosphorus tribromide
- Step 7 the compound of Formula 1207 is reacted with a heteroaryl compound, for example 3-iodo lH-pyrazolo[3,4-d]pyrimidin-4-amine, in the presence of a base such as potasssium tert-butoxide in dimethylformamide to produce a compound of Formula 1208.
- a heteroaryl compound for example 3-iodo lH-pyrazolo[3,4-d]pyrimidin-4-amine
- a base such as potasssium tert-butoxide in dimethylformamide
- Step 1 of Scheme 13 the compound of Formula 1301, (the S-isomer) is coupled to N, O- dimethylhydroxylamine using hydroxybenzotriazole (HOBt) and l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDCI) in the presence of triethylamine to produce a compound of Formula 1302.
- a compound of Formula 1203 which may be synthesized as described in Scheme 12, is deprotonated with n-butyllithium in THF and hexamethylphosphoramide at -78°C under an argon atmosphere.
- the compound of Formula 1302 is added and the reaction mixture is allowed to warm to -50 0 C, quenched with the addition of water and a compound of Formula 1303 is isolated.
- a weakly nucleophilic organomagnesium species such as iPrMgCl can be used to generate the magnesium anion of compound 1302 before its addition to the dianion.
- Step 3 the compound of Formula 1303 is treated with hydrochloric acid in methanol at reflux, and then the reaction mixture is basified with the addition of sodium carbonate solution to a pH of about 7- about 8, to produce a compound of Formula 1304.
- the compound of formula 1304 may be partly epimerized as a result of the preceding reaction steps.
- Highly enantiopure 1304 may be isolated by preparing the tartaric acid salt by dissolving the compound of Formula 1304 in methanol and adding D-tartaric acid. The resulting reaction mixture is refluxed for one hour, then stirred at room temperature for 16 hours, and permits isolation of the salt of the compound of Formula 1304 wherein the enantiomeric purity is greater than 90% of the (S)- isomer. The free amine of the compound of Formula 1304 is regenerated before its use in the next synthesis step.
- the compound of Formula 1304, which is substantially the (S)- enantiomer is coupled to a chloro substituted heteroaryl W d , a compound of Formula 1305, including but not limited to 6- chloro- 9(tetrahydro-2H-pyran-2-yl)-9H-purine, 2, 4, 5, -trichloropyrimidine, 4-chloro -7H-pyrrolo[2, 3-d] primidine, and 4-chloro-lH-pyrazolo[3,4-d]pyrimidine in the presence of base such as diisopropylethylamine or ammonia, to produce a compound of Formula 1306, and where the compound of Formula 1306 is the (S)- isomer.
- a compound of Formula 1305 including but not limited to 6- chloro- 9(tetrahydro-2H-pyran-2-yl)-9H-purine, 2, 4, 5, -trichloropyrimidine, 4-chloro -7H-pyrrolo[2, 3-d] primidine, and 4-ch
- the compounds of the present invention exhibits one or more functional characteristics disclosed herein.
- one or more subject compounds bind specifically to a PI3 kinase.
- the IC50 of a subject compound for pi 10a, pi lO ⁇ , pi lO ⁇ , or pi 105 is less than about 1 uM, less than about 100 nM, less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 0.5nM, less than about 10OpM, or less than about 50 pM.
- one or more of the subject compounds may selectively inhibit one or more members of type I or class I phosphatidylinositol 3-kinases (PI3-kinase) with an IC50 value of about 100 nM, 50 nM, 10 nM, 5 nM, 100 pM, 10 pM or 1 pM, or less as measured in an in vitro kinase assay.
- PI3-kinase phosphatidylinositol 3-kinases
- a compound of Formula having an (S)-enantiomeric configuration with respect to carbon X may exhibit greater potency against one or more target PI3-kinases than the corresponding compound having an (R)- enantiomeric configuration with respect to carbon X.
- the compound of the invention having an (S)- enantiomeric configuration with respect to carbon X may have a PI3-kinase IC50 value which is 1, 2, 3, or 4 orders of magnitude lower than the PI3-kinase IC50 value of the corresponding compound having an (R)-configuration.
- the compound of the invention is a compound of Formula V- A2 in an (S)-configuration with respect to carbon X which has a PI3-kinase IC50 value which is 1, 2, 3, or 4 orders of magnitude lower than the PI3-kinase IC50 value of the corresponding compound having an (R)-configuration.
- the compound of the invention is a compound of Formula V-A2 in an (S)-configuration with respect to carbon X which has a PI3-kinase IC50 value which is 4 orders of magnitude lower than a PI3-kinase IC50 value of the corresponding compound having an (Reconfiguration.
- the compound of the invention is a compound of Formula V- A2 wherein R 3 is C 1 -C 3 alkyl and B is phenyl, and where the compound is in an (S)-configuration with respect to carbon X and has a PI3-kinase IC50 value which is at least 3 orders of magnitude lower than the PI3-kinase IC50 value of the corresponding compound having an (Reconfiguration.
- the compound of the invention is a compound of Formula V- A2 wherein R 3 is halo and B is phenyl, and where the compound is in an (S)-configuration with respect to carbon X and has a PI3 -kinase IC50 value which is at least 3 orders of magnitude lower than the PI3 -kinase IC50 value of the corresponding compound having an (Reconfiguration.
- the compound of the invention is a compound of Formula V- A2 wherein R 3 is CpC 3 alkyl and B is cycloalkyl, and where the compound is in an (S)-configuration with respect to carbon X and has a PI3-kinase IC50 value which is 3 orders of magnitude lower than the PI3-kinase IC50 value of the corresponding compound having an (Reconfiguration.
- one or more of the subject compounds may selectively inhibit one or two members of type I or class I phosphatidylinositol 3-kinases (PI3-kinase) consisting of PI3-kinase ⁇ , PI3-kinase ⁇ , PI3-kinase ⁇ , and PI3-kinase ⁇ .
- PI3-kinase phosphatidylinositol 3-kinases
- some of the subject compounds selectively inhibit PI3-kinase ⁇ as compared to all other type I PI3-kinases.
- some of the subject compounds selectively inhibit PI3-kinase ⁇ and PI3-kinase ⁇ as compared to the rest of the type I PI3-kinases.
- some of the subject compounds selectively inhibit PI3-kinase ⁇ and PI3-kinase ⁇ as compared to the rest of the type I PI3-kinases. In still yet some other aspects, some of the subject compounds selectively inhibit PI3-kinase ⁇ and PI3-kinase ⁇ as compared to the rest of the type I PI3-kinases.
- some of the subject compounds selectively inhibit PI3-kinase ⁇ and PI3-kinase ⁇ as compared to the rest of the type I PI3 -kinases, or selectively inhibit PI3 -kinase ⁇ and PI3 -kinase ⁇ as compared to the rest of the type I PI3-kinases, or selectively inhibit PI3-kinase ⁇ and PI3-kinase y as compared to the rest of the type I PI3- kinases, or selectively inhibit PI3-kinase ⁇ and PI3-kinase ⁇ as compared to the rest of the type I PI3-kinases.
- one or more of the subject compounds selectively inhibit PI3-kinase ⁇ and PI3-kinase ⁇ as compared to the rest of the type I PI3-kinases.
- a compound of the invention exhibits an IC50 for PI3- kinase ⁇ which is less than 100, 90, 80, 70, 60, 50, 40, 30, 20, 10 or 5 times lower than the IC50 for PI3-kinase ⁇ .
- a compound of the invention exhibits an IC50 for PI3-kinase ⁇ which is less than 100, 90, 80, 70, 60, 50, 40, 30, 20, 10 or 5 times higher than the IC50 for PI3-kinase ⁇ . In some embodiments, the compound of the invention exhibits an IC50 for PI3-kinase ⁇ which is less than 10 times lower than the IC50 for PI3-kinase ⁇ . In other embodiments, the compound of the invention exhibits an IC50 for PI3-kinase ⁇ which is less than 10 times higher than the IC50 for PI3- kinase ⁇ .
- the compound of the invention exhibits an IC50 for PI3-kinase ⁇ which is less than 5 times higher or lower than the IC50 for PI3-kinase ⁇ .
- a subject compound has an IC50 for PI3-kinase ⁇ which is lower than the IC50 for PI3-kinase ⁇ by a factor of less than 20, 10, 5, or 2.
- a subject compound has an IC50 for PI3-kinase ⁇ which is lower than the IC50 for PI3-kinase ⁇ by a factor of less than 5.
- an inhibitor that selectively inhibits one or more members of type I PI3-kinases or an inhibitor that selectively inhibits one or more type I PI3 -kinase mediated signaling pathways, alternatively can be understood to refer to a compound that exhibits a 50% inhibitory concentration (IC50) with respect to a given type I PI3- kinase, that is at least at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 1000-fold, at least 10, 100- fold, or lower, than the inhibitor's IC50 with respect to the rest of the other type I PI3-kinases.
- IC50 50% inhibitory concentration
- one or more of the subject compounds inhibits pi 10a, pi lO ⁇ , DNAPK or mTor with an IC50 value of greater than 30 nM, and inhibits pi 105 and/or pi lO ⁇ with an IC50 value of less than 1 ⁇ M.
- the compound additionally shows selective inhibition of pi lO ⁇ and/or pi 1Oy relative to pi 10a, pi lO ⁇ , DNAPK and/or mTor by a factor of at least 3, 10, 100, 1000 or higher.
- a subject compound shows selective inhibition of pi lO ⁇ or pi lO ⁇ relative to pi 10a, pi lO ⁇ , DNAPK and/or mTor by a factor of at least 3.
- Exemplary compounds showing selective inhibition of pi lO ⁇ or pi lO ⁇ relative to pi 10a, pi lO ⁇ , DNAPK and/or mTor by a factor of at least 3 include, but are not limited to, compounds 328, 329, 330, 331, 332, 333, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 352, 354, 357 and 361 of Table 4.
- the invention provides pharmaceutical compositions comprising one or more compounds of the present invention.
- the invention provides pharmaceutical compositions for treating diseases or conditions related to an undesirable, over-active, harmful or deleterious immune response in a mammal.
- Such undesirable immune response can be associated with or result in, e.g., asthma, emphysema, bronchitis, psoriasis, allergy, anaphylaxsis, autoimmune diseases, rhuematoid arthritis, graft versus host disease, and lupus erythematosus.
- the pharmaceutical compositions of the present invention can be used to treat other respiratory diseases including but not limited to diseases affecting the lobes of lung, pleural cavity, bronchial tubes, trachea, upper respiratory tract, or the nerves and muscle for breathing.
- the invention provides pharmaceutical compositions for the treatment of disorders such as hyperproliferative disorder including but not limited to cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS related AIDS-Related (e.g.
- cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal
- bladder gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian,
- said pharmaceutical composition is for the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e. g., benign prostatic hypertrophy (BPH)).
- a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e. g., benign prostatic hypertrophy (BPH)).
- the invention also provides compositions for the treatment of liver diseases (including diabetes), pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes- induced renal disease) or pain in a mammal.
- liver diseases including diabetes
- pancreatitis or kidney disease including proliferative glomerulonephritis and diabetes- induced renal disease
- pain in a mammal.
- the invention further provides a composition for the prevention of blastocyte implantation in a mammal.
- the invention also relates to a composition for treating a disease related to vasculogenesis or angiogenesis in a mammal which can manifest as tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
- compositions are typically formulated to provide a therapeutically effective amount of a compound of the present invention as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
- the pharmaceutical compositions contain pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
- the subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions.
- the subject compounds and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.
- the concentration of one or more of the compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.
- the concentration of one or more of the compounds of the present invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%,
- the concentration of one or more of the compounds of the present invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v.
- the concentration of one or more of the compounds of the present invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.
- the amount of one or more of the compounds of the present invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g,
- the amount of one or more of the compounds of the present invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.
- the amount of one or more of the compounds of the present invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.
- the compounds according to the invention are effective over a wide dosage range.
- dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used.
- An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
- compositions for oral administration In some embodiments, the invention provides a pharmaceutical composition for oral administration containing a compound of the present invention, and a pharmaceutical excipient suitable for oral administration.
- the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the present invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration.
- the composition further contains: (iv) an effective amount of a third agent.
- the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption.
- Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
- Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients.
- compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
- a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent.
- Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds.
- water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time.
- Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
- Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
- An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.
- anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
- suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
- An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
- the carrier can take a wide variety of forms depending on the form of preparation desired for administration.
- any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose.
- suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.
- Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre- gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
- natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrol
- suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
- Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition.
- Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
- Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof.
- calcium stearate e.g., magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc
- hydrogenated vegetable oil e.g., peanut oil, cottonseed oil
- Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof.
- a lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.
- the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
- the tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
- Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
- Surfactant which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.
- a suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10.
- An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value).
- HLB hydrophilic-lipophilic balance
- Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
- Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
- lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10.
- HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
- Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides;
- glyceride derivatives of amino acids, oligopeptides, and polypeptides lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof;
- carnitine fatty acid ester salts salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di- acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
- ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides;
- succinylated mono- and di-glycerides succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
- Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine,
- phosphatidylethanolamine phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, lino
- Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides; alkylmaltosides;
- alkylthioglucosides lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copo
- hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG- 20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-10 glyce
- Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters;
- acetylated glycerol fatty acid esters lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof.
- preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.
- the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, e.g., compositions for injection.
- a solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
- solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG ; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone,
- solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
- the amount of solubilizer that can be included is not particularly limited.
- the amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art.
- the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients.
- very small amounts of solubilizer may also be used, such as 5%, 2%, 1% or even less.
- the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.
- the composition can further include one or more pharmaceutically acceptable additives and excipients.
- additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
- an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons.
- Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like.
- bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.
- a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids
- Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used.
- the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like.
- Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.
- Suitable acids are pharmaceutically acceptable organic or inorganic acids.
- suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.
- suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like.
- compositions for injection In some embodiments, the invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein.
- Aqueous solutions in saline are also conventionally used for injection.
- Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
- the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
- Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
- certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- Pharmaceutical compositions for topical (e.g.. transdermal) delivery In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery containing a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.
- compositions of the present invention can be formulated into preparations in solid, semi-solid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions.
- DMSO dimethylsulfoxide
- carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients.
- a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.
- compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin.
- suitable solid or gel phase carriers or excipients which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin.
- penetration-enhancing molecules known to those trained in the art of topical formulation.
- humectants e.g., urea
- glycols e.g., propylene glycol
- alcohols e.g., ethanol
- fatty acids e.g., oleic acid
- surfactants e.g., isopropyl myristate and sodium lauryl sulfate
- pyrrolidones e.g., isopropyl myristate and sodium lauryl sulfate
- pyrrolidones e.glycerol monolaurate, sulfoxides, terpenes (e.g., menthol)
- amines amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
- transdermal delivery devices patches
- Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, either with or without another agent.
- transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
- compositions for inhalation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
- the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
- the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
- Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
- compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art.
- Administration of the compounds or pharmaceutical composition of the present invention can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also abe administered intraadiposally or intrathecally.
- the amount of the compound administered will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician.
- an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day.
- dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. bydividing such larger doses into several small doses for administration throughout the day.
- a compound of the invention is administered in a single dose.
- administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly.
- other routes may be used as appropriate.
- a single dose of a compound of the invention may also be used for treatment of an acute condition.
- a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
- Administration of the agents of the invention may continue as long as necessary.
- an agent of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days.
- an agent of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day.
- an agent of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
- An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly,
- compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
- a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty.
- compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis.
- a compound of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent.
- a compound of the invention is admixed with a matrix.
- Such a matrix may be a polymeric matrix, and may serve to bond the compound to the stent.
- Polymeric matrices suitable for such use include, for eample, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides,
- polyaminoacids polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g. polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters.
- Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds.
- Compounds of the invention may be applied to the surface of the stent by various methods such as dip/spin coating, spray coating, dip- coating, and/or brush-coating.
- the compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent.
- the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall.
- Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent.
- compounds of the invention may be covalently linked to a stent or graft.
- a covalent linker may be used which degrades in vivo, leading to the release of the compound of the invention. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages.
- Compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis.
- the compounds of the invention may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation in light of the instant disclosure.
- the subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
- the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
- the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
- Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
- the activity of the compounds of the present invention may be determined by the following procedure, as well as the procedure described in the examples below.
- the activity of the kinase is assessed by measuring the incorporation of ⁇ - 33 P-phosphate from ⁇ - 33 P-ATP onto N-terminal His tagged substrate, which is expressed in E. coli and is purified by conventional methods, in the presence of the kinase.
- the assay is carried out in 96-well polypropylene plate.
- the incubation mixture (100, ⁇ L) comprises of 25 mM Hepes, pH 7.4, 10 mM MgCl 2 , 5 mM ⁇ -glycerolphosphate, 100 ⁇ M Na-orthovanadate, 5 mM DTT, 5 nM kinase, and 1 ⁇ M substrate.
- Inhibitors are suspended in DMSO, and all reactions, including controls are performed at a final concentration of 1% DMSO. Reactions are initiated by the addition of 10 ⁇ M ATP (with 0.5 ⁇ Ci ⁇ - 33 P- ATP/well) and incubated at ambient temperature for 45 minutes. Equal volume of 25% TCA is added to stop the reaction and precipitate the proteins.
- Precipitated proteins are trapped onto glass fiber B filterplates, and excess labeled ATP washed off using a Tomtec MACH III harvester. Plates are allowed to air-dry prior to adding 30 ⁇ L/well of Packard Microscint 20, and plates are counted using a Packard TopCount.
- kits include a compound or compounds of the present invention as described herein, in suitable packaging, and written material that can include instructions for use, discussion of clinical studies, listing of side effects, and the like.
- kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider.
- information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials.
- the kit may further contain another agent, hi some embodiments, the compound of the present invention and the agent are provided as separate compositions in separate containers within the kit. In some embodiments, the compound of the present invention and the agent are provided as a single composition within a container in the kit.
- Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer.
- the invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to diseases associated with malfunctioning of one or more types of PI3 kinase.
- diseases associated with malfunctioning of one or more types of PI3 kinase include diseases associated with malfunctioning of one or more types of PI3 kinase.
- a detailed description of conditions and disorders mediated by pi lO ⁇ kinase activity is set forth in Sadu et al., WO 01/81346, which is incorporated herein by reference in its entirety for all purposes.
- the treatment methods provided herein comprise administering to the subject a therapeutically effective amount of a compound of the invention.
- the present invention provides a method of treating an inflammation disorder, including autoimmune diseases in a mammal. The method comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
- autoimmune diseases includes but is not limited to acute disseminated encephalomyelitis (ADEM), Addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, coeliac disease, Crohn's disease, Diabetes mellitus (type 1), Goodpasture's syndrome, Graves' disease, Guillain-Barr ⁇ syndrome (GBS), Hashimoto's disease, lupus erythematosus, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, oemphigus, polyarthritis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis (also known as "giant cell arteritis”), warm autoimmune hemolytic anemia, Wegener
- the method of treating inflammatory or autoimmune diseases comprises administering to a subject (e.g. a mammal) a therapeutically effective amount of one or more compounds of the present invention that selectively inhibit PDK- ⁇ and/or PI3K- ⁇ as compared to all other type I PI3 kinases.
- a subject e.g. a mammal
- Such selective inhibition of PI3K-5 and/or PI3K- ⁇ may be advantageous for treating any of the diseases or conditions described herein.
- selective inhibition of PI3K-5 may inhibit inflammatory responses associated with inflammatory diseases, autoimmune disease, or diseases related to an undesirable immune response including but not limited to asthma, emphysema, allergy, dermatitis, rhuematoid arthritis, psoriasis, lupus erythematosus, or graft versus host disease.
- Selective inhibition of PI3K- ⁇ may further provide for a reduction in the inflammatory or undesirable immune response without a concomittant reduction in the ability to reduce a bacterial, viral, and/or fungal infection.
- one or more of the subject methods are effective in reducing antigen specific antibody production in vivo by about 2-fold, 3-fold, 4-fold, 5-fold, 7.5- fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold, 500-fold, 750-fold, or about 1000-fold or more.
- one or more of the subject methods are effective in reducing antigen specific IgG3 and/or IgGM production in vivo by about 2-fold, 3-fold, 4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold, 500-fold, 750-fold, or about 1000-fold or more.
- one of more of the subject methods are effective in ameliorating symptoms assoicated with rhuematoid arthritis including but not limited to a reduction in the swelling of joints, a reduction in serum anti-collagen levels, and/or a reduction in joint pathology such as bone resorption, cartilage damage, pannus, and/or inflammation.
- the subject methods are effective in reducing ankle inflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%, 60%, or about 75% to 90%.
- the subject methods are effective in reducing knee inflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%, 60%, or about 75% to 90% or more.
- the subject methods are effective in reducing serum anti-type II collagen levels by at least about 10%, 12%, 15%, 20%, 24%, 25%, 30%, 35%, 50%, 60%, 75%, 80%, 86%, 87%, or about 90% or more.
- the subject methods are effective in reducing ankle histopathology scores by about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, 90% or more.
- the subject methods are effective in reducing knee histopathology scores by about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, 90% or more.
- the present invention provides methods of using the compounds or pharmaceutical compositions to treat respiratory diseases including but not limited to diseases affecting the lobes of lung, pleural cavity, bronchial tubes, trachea, upper respiratory tract, or the nerves and muscle for breathing.
- respiratory diseases including but not limited to diseases affecting the lobes of lung, pleural cavity, bronchial tubes, trachea, upper respiratory tract, or the nerves and muscle for breathing.
- methods are provided to treat obstructive pulmonary disease.
- COPD chronic obstructive pulmonary disease
- COPD chronic obstructive pulmonary disease
- the compounds described herein are used for the treatment of asthma.
- the compounds or pharmaceutical compositions described herein may be used for the treatment of endotoxemia and sepsis.
- the compounds or pharmaceutical compositions described herein are used to for the treatment of rheumatoid arthritis (RA).
- the compounds or pharmaceutical compositions described herein is used for the treatment of contact or atopic dermatitis.
- Contact dermatitis includes irritant dermatitis, phototoxic dermatitis, allergic dermatitis, photoallergy dermatitis, contact urticaria, systemic contact-type dermatitis and the like.
- Irritant dermatitis can occur when too much of a substance is used on the skin of when the skin is sensitive to certain substance.
- Atopic dermatitis sometimes called eczema, is a kind of dermatitis, an atopic skin disease.
- the invention also relates to a method of treating a hyperproliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
- said method relates to the treatment of cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS-related (e.g. Lymphoma and Kaposi's Sarcoma) or viral-induced cancer.
- cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian, prostate,
- said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e. g., benign prostatic hypertrophy (BPH)).
- a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e. g., psoriasis), restenosis, or prostate (e. g., benign prostatic hypertrophy (BPH)).
- the invention also relates to a method of treating diseases related to vasculogenesis or angiogenesis in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
- said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
- a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma
- diabetes diabetic retinopathy, retinopathy of prematurity
- age-related macular degeneration hemangio
- Patients that can be treated with compounds of the present invention, or pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative of said compounds, according to the methods of this invention include, for example, patients that have been diagnosed as having psoriasis; restenosis; atherosclerosis; BPH; breast cancer such as a ductal carcinoma in duct tissue in a mammary gland, medullary carcinomas, colloid carcinomas, tubular carcinomas, and inflammatory breast cancer; ovarian cancer, including epithelial ovarian tumors such as adenocarcinoma in the ovary and an adenocarcinoma that has migrated from the ovary into the abdominal cavity; uterine cancer; cervical cancer such as adenocarcinoma in the cervix epithelial including squamous cell carcinoma and adenocarcinomas; prostate cancer, such as a prostate cancer selected from the following: an adenocarcinoma or an adenocarinom
- Patients that can be treated with compounds of the present invention, or pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative of said compounds, according to the methods of this invention include, for example, patients that have been diagnosed as having conditions including, but not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma,
- lymphangioendotheliosarcoma hemangiosarcoma
- benign monoclonal gammopathy biliary cancer
- cholangiocarcinoma bladder cancer
- breast cancer e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast
- brain cancer e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma
- bronchus cancer e.g., cervical adenocarcinoma
- cervical cancer e.g., cervical adenocarcinoma
- choriocarcinoma chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer, esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarinoma), Ewing sarcoma, familiar hypereosinophilia, gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC)), heavy chain disease (e.
- hepatocellular cancer HCC
- malignant hepatoma lung cancer
- lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
- leukemia e.g., acute lymphocytic leukemia (ALL), which includes B-lineage ALL and T-lineage ALL, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia (HLL) and Waldenstrom's macroglobulinemia (WM); peripheral T cell lymphomas (PTCL), adult T cell
- leukemia/lymphoma ATL
- CTL cutaneous T-cell lymphoma
- LGF large granular lymphocytic leukemia
- AML acute myelocytic leukemia
- CML chronic myelocytic leukemia
- CLL chronic lymphocytic leukemia
- lymphoma e.g., Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL)), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), multiple myeloma (MM), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia Vera (P) (e.g., polycythemia Vera (
- myelofibrosis MF
- chronic idiopathic myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)
- neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
- neuroendocrine cancer e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor
- osteosarcoma ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), Paget's disease of the vulva, Paget's disease of the penis, papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN)), pine
- the invention also relates to a method of treating diabetes in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
- the compounds described herein may be used to treat acne.
- arteriosclerosis is a general term describing any hardening of medium or large arteries.
- Atherosclerosis is a hardening of an artery specifically due to an atheromatous plaque.
- Glomerulonephritis is a primary or secondary autoimmune renal disease characterized by inflammation of the glomeruli. It may be asymptomatic, or present with hematuria and/or proteinuria. There are many recognized types, divided in acute, subacute or chronic glomerulonephritis. Causes are infectious (bacterial, viral or parasitic pathogens), autoimmune or paraneoplastic.
- the compounds described herein may be used for the treatment of bursitis, lupus, acute disseminated encephalomyelitis (ADEM), addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, coeliac disease, Crohn's disease, diabetes mellitus (type 1), goodpasture's syndrome, graves' disease, guillain-barr ⁇ syndrome (GBS), hashimoto's disease, inflammatory bowel disease, lupus erythematosus, myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, ord's thyroiditis,ostheoarthritis, uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis, reiter's syndrome, takayasu's arteritis, temporal arteritis, warm autoimmune hemo
- the compounds of the invention may be used for the treatment of Perennial allergic rhinitis, Mesenteritis, Peritonitis, Acrodermatitis, Angiodermatitis, Atopic dermatitis, Contact dermatitis, Eczema, Erythema multiforme, Intertrigo, Stevens Johnson syndrome, Toxic epidermal necrolysis, Skin allergy, Severe allergic reaction/anaphylaxis, Allergic granulomatosis, Wegener granulomatosis, Allergic conjunctivitis , Chorioretinitis, Conjunctivitis, Infectious keratoconjunctivitis, Keratoconjunctivitis, Ophthalmia neonatorum, Trachoma, Uveitis, Ocular inflammation,
- Blepharoconjunctivitis Mastitis, Gingivitis, Pericoronitis, Pharyngitis, Rhinopharyngitis, Sialadenitis, Musculoskeletal system inflammation, Adult onset Stills disease, Behcets disease, Bursitis, Chondrocalcinosis, Dactylitis, Felty syndrome, Gout, Infectious arthritis, Lyme disease, Inflammatory osteoarthritis, Periarthritis, Reiter syndrome, Ross River virus Infection, Acute Respiratory, Distress Syndrome, Acute bronchitis, Acute sinusitis, Allergic rhinitis, Asthma, Severe refractory asthma, Pharyngitis, Pleurisy, Rhinopharyngitis, Seasonal allergic rhinitis, Sinusitis, Status asthmaticus, Tracheobronchitis, Rhinitis, Serositis, Meningitis, Neuromyelitis optica, Poliovirus infection, Alport syndrome, Balanitis, Epi
- Lymphangiophlebitis Mondor disease, Periarteritis, or Pericarditis.
- the compounds of the invention are used for the treatment of Autoimmune hepatitis, Jejunitis, Mesenteritis, Mucositis, Non alcoholic steatohepatitis, Non viral hepatitis, Autoimmune pancreatitis, Perihepatitis, Peritonitis, Pouchitis, Proctitis, Pseudomembranous colitis, Rectosigmoiditis, Salpingoperitonitis, Sigmoiditis,
- Gastrointestinal inflammation Acute enterocolitis, Anusitis, Balser necrosis, Cholecystitis, Colitis, Crohns disease, Diverticulitis, Enteritis, Enterocolitis, Enterohepatitis, Eosinophilic esophagitis, Esophagitis, Gastritis, Hemorrhagic enteritis, Hepatitis, Hepatitis virus infection, Hepatocholangitis, Hypertrophic gastritis, Ileitis, Ileocecitis, Sarcoidosis, Inflammatory bowel disease, Ankylosing spondylitis, Rheumatoid arthritis, Juvenile rheumatoid arthritis, Psoriasis, Psoriatic arthritis, Lupus (cutaneous/systemic/ nephritis), AIDS, Agammaglobulinemia, AIDS related complex, Brutons disease , Chediak Higashi syndrome, Common variable immunodeficiency, DiGeorge syndrome,
- Dysgammaglobulinemia Immunoglobulindeficiency, Job syndrome, Nezelof syndrome, Phagocyte bactericidal disorder, Wiskott Aldrich syndrome, Asplenia, Elephantiasis, Hypersplenism, Kawasaki disease, Lymphadenopathy, Lymphedema, Lymphocele, Nonne Milroy Meige syndrome, Spleen disease, Splenomegaly, Thymoma, Thymus disease, Perivasculitis, Phlebitis, Pleuropericarditis, Polyarteritis nodosa, Vasculitis, Takayasus arteritis, Temporal arteritis, Thromboangiitis, Thromboangiitis obliterans, Thromboendocarditis, Thrombophlebitis, or COPD.
- the invention also relates to a method of treating a cardiovascular disease in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
- cardiovascular conditions include, but are not limited to, atherosclerosis, restenosis, vascular occlusion and carotid obstructive disease.
- the present invention provides methods of disrupting the function of a leukocyte or disrupting a function of an osteoclast.
- the method includes contacting the leukocyte or the osteoclast with a function disrupting amount of a compound of the invention.
- methods are provided for treating ophthalmic disease by administering one or more of the subject compounds or pharmaceutical compositions to the eye of a subject.
- Methods are further provided for administering the compounds of the present invention via eye drop, intraocular injection, intravitreal injection, topically, or through the use of a drug eluting device, microcapsule, implant, or microfluidic device.
- the compounds of the present invention are administered with a carrier or excipient that increases the intraocular penetrance of the compound such as an oil and water emulsion with colloid particles having an oily core surrounded by an interfacial film.
- the colloid particles include at least one cationic agent and at least one non-ionic sufactant such as a poloxamer, tyloxapol, a polysorbate, a polyoxyethylene castor oil derivative, a sorbitan ester, or a polyoxyl stearate.
- the cationic agent is an alkylamine, a tertiary alkyl amine, a quarternary ammonium compound, a cationic lipid, an amino alcohol, a biguanidine salt, a cationic compound or a mixture thereof.
- the cationic agent is a biguanidine salt such as chlorhexidine, polyaminopropyl biguanidine, phenformin, alkylbiguanidine, or a mixture thereof.
- the quaternary ammonium compound is a benzalkonium halide, lauralkonium halide, cetrimide, hexadecyltrimethylammonium halide, tetradecyltrimethylamr ⁇ onium halide, dodecyltrimethylammonium halide, cetrimonium halide, benzethonium halide, behenalkonium halide, cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide, benzododecinium halide, chlorallyl methenamine halide, rnyristylalkonium halide, stearalkonium halide or a mixture of two or more thereof.
- the oil phase is mineral oil and light mineral oil, medium chain triglycerides (MCT), coconut oil;
- hydrogenated oils comprising hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate castor oil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oil derivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60 hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil.
- the invention further provides methods of modulating kinase activity by contacting a kinase with an amount of a compound of the invention sufficient to modulate the activity of the kinase. Modulate can be inhibiting or activating kinase activity. In some embodiments, the invention provides methods of inhibiting kinase activity by contacting a kinase with an amount of a compound of the invention sufficient to inhibit the activity of the kinase. In some embodiments, the invention provides methods of inhibiting kinase activity in a solution by contacting said solution with an amount of a compound of the invention sufficient to inhibit the activity of the kinase in said solution.
- the invention provides methods of inhibiting kinase activity in a cell by contacting said cell with an amount of a compound of the invention sufficient to inhibit the activity of the kinase in said cell. In some embodiments, the invention provides methods of inhibiting kinase activity in a tissue by contacting said tissue with an amount of a compound of the invention sufficient to inhibit the activity of the kinase in said tissue. In some embodiments, the invention provides methods of inhibiting kinase activity in an organism by contacting said organism with an amount of a compound of the invention sufficient to inhibit the activity of the kinase in said organism.
- the invention provides methods of inhibiting kinase activity in an animal by contacting said animal with an amount of a compound of the invention sufficient to inhibit the activity of the kinase in said animal. In some embodiments, the invention provides methods of inhibiting kinase activity in a mammal by contacting said mammal with an amount of a compound of the invention sufficient to inhibit the activity of the kinase in said mammal. In some embodiments, the invention provides methods of inhibiting kinase activity in a human by contacting said human with an amount of a compound of the invention sufficient to inhibit the activity of the kinase in said human.
- the % of kinase activity after contacting a kinase with a compound of the invention is less than 1, 5, 10, 20, 30, 40, 50, 60, 70, 80 90, 95, or 99% of the kinase activity in the absence of said contacting step.
- the kinase is a lipid kinase or a protein kinase.
- the kinase is selected from the group consisting of PI3 kinase including different isorforms such as PI3 kinase ⁇ , PI3 kinase ⁇ , PI3 kinase ⁇ , PI3 kinase ⁇ ; DNA-PK; mTor; AbI, VEGFR, Ephrin receptor B4 (EphB4); TEK receptor tyrosine kinase (TIE2); FMS-related tyrosine kinase 3 (FLT-3); Platelet derived growth factor receptor (PDGFR); RET; ATM; ATR; hSmg-1 ; Hck; Src; Epidermal growth factor receptor (EGFR); KIT; Inulsin Receptor (IR) and IGFR.
- PI3 kinase including different isorforms such as PI
- the invention further provides methods of modulating PI3 kinase activity by contacting a PI3 kinase with an amount of a compound of the invention sufficient to modulate the activity of the PI3 kinase. Modulate can be inhibiting or activating PI3 kinase activity. In some embodiments, the invention provides methods of inhibiting PI3 kinase activity by contacting a PI3 kinase with an amount of a compound of the invention sufficient to inhibit the activity of the PI3 kinase. In some embodiments, the invention provides methods of inhibiting PI3 kinase activity.
- Such inhibition can take place in solution, in a cell expressing one or more PI3 kinases, in a tissue comprising a cell expressing one or more PI3 kinases, or in an organism expressing one or more PI3 kinases.
- the invention provides methods of inhibiting PI3 kinase activity in an animal (including mammal such as humans) by contacting said animal with an amount of a compound of the invention sufficient to inhibit the activity of the PI3 kinase in said animal.
- the present invention also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
- such therapy includes but is not limited to the combination of the subject compound with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect.
- the compounds or pharmaceutical compositions of the present invention may present synergistic or additive efficacy when administered in combination with agents that inhibit IgE production or activity. Such combination can reduce the undesired effect of high level of IgE associated with the use of one or more PI3K5 inhibitors, if such effect occurs. This may be particularly useful in treatment of autoimmune and inflammatory disorders (AIID) such as rheumatoid arthritis. Additionally, the administration of PI3K ⁇ or PI3K ⁇ / ⁇ inhibitors of the present invention in combination with inhibitors of mTOR may also exhibit synergy through enhanced inhibition of the PI3K pathway.
- AIID autoimmune and inflammatory disorders
- the present invention provides a combination treatment of a disease associated with PI3K ⁇ comprising administering to a PI3K ⁇ inhibitor and an agent that inhibits IgE production or activity.
- a PI3K ⁇ inhibitor and an agent that inhibits IgE production or activity.
- Other exemplary PI3K5 inhibitors are applicable and they are described, e.g., US Patent No. 6,800,620.
- Such combination treatment is particularly useful for treating autoimmune and inflammatory diseases (AIID) including but not limited to rheumatoid arthritis.
- AIID autoimmune and inflammatory diseases
- Agents that inhibit IgE production include but are not limited to one or more of TEI-9874, 2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid, rapamycin, rapamycin analogs (i.e. rapalogs), TORCl inhibitors, TORC2 inhibitors, and any other compounds that inhibit mTORCl and mTORC2.
- Agents that inhibit IgE activity include, for example, anti-IgE antibodies such as for example Omalizumab and TNX-901.
- the subject compounds or pharmaceutical compositions can be used in combination with commonly prescribed drugs including but not limited to Enbrel ® , Remicade ® , Humira ® , Avonex ® , and Rebif ® .
- the subject compounds or pharmaceutical compositions can be administered in combination with commonly prescribed drugs including but not limited to Xolair ® , Advair ® , Singulair ® , and Spiriva ® .
- the compounds of the invention may be formulated or administered in conjunction with other agents that act to relieve the symptoms of inflammatory conditions such as encephalomyelitis, asthma, and the other diseases described herein.
- agents include non-steroidal anti-inflammatory drugs (NSAIDs), e.g. acetylsalicylic acid; ibuprofen;
- naproxen indomethacin
- nabumetone tolmetin
- Corticosteroids are used to reduce inflammation and suppress activity of the immune system.
- the most commonly prescribed drug of this type is Prednisone.
- Chloroquine (Aralen) or hydroxychloroquine (Plaquenil) may also be very useful in some individuals with lupus. They are most often prescribed for skin and joint symptoms of lupus.
- Azathioprine (Imuran) and cyclophosphamide (Cytoxan) suppress inflammation and tend to suppress the immune system.
- Other agents e.g. methotrexate and cyclosporin are used to control the symptoms of lupus.
- Anticoagulants are employed to prevent blood from clotting rapidly. They range from aspirin at very low dose which prevents platelets from sticking, to heparin/coumadin. Other compounds used in the treatment of lupus include belimumab (Benlysta®).
- this invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, in combination with an amount of an anti-cancer agent (e.g. a biotherapeutic chemotherapeutic agent).
- an anti-cancer agent e.g. a biotherapeutic chemotherapeutic agent.
- Many chemotherapeutics are presently known in the art and can be used in combination with the compounds of the invention.
- Other cancer therapies can also be used in combination with the compounds of the invention and include, but are not limited to, surgery and surgical treatments, and radiation therapy.
- the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.
- chemotherapeutic agents include cytotoxic agents, and non-peptide small molecules such as Gleevec (Imatinib Mesylate), Velcade (bortezomib), Casodex (bicalutamide), Iressa (gef ⁇ tinib), and Adriamycin as well as a host of chemotherapeutic agents.
- Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXANTM); alkyl sulfonates such as busulfan, improsulfan and piposulfan;
- aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactin
- pirarubicin podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK.RTM ; razoxane; sizofiran; spirogermanium;
- chemotherapeutic cell conditioners include anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen
- NolvadexTM NolvadexTM
- raloxifene aromatase inhibiting 4(5)-imidazoles
- 4-hydroxytamoxifen Trihydroxytamoxifen
- trioxifene keoxifene
- LY 1 17018, onapristone and toremifene (Fareston)
- anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin
- chlorambucil gemcitabine
- 6-thioguanine mercaptopurine
- methotrexate platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine;
- the compounds or pharmaceutical composition of the present invention can be used in combination with commonly prescribed anti-cancer drugs such as Herceptin ® , Avastin ® , Erbitux ® , Rituxan ® , Taxol ® , Arimidex ® , Taxotere ® , and Velcade ® .
- chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g. goserelin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporf ⁇ n (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g.
- anti-estrogens e.g. tamoxifen, raloxifene, and megestrol
- LHRH agonists e.g. goserelin and leuprolide
- anti-androgens e.g. flutamide and bicalutamide
- photodynamic therapies e.g. vertoporf ⁇ n (BPD-MA), phthalo
- cyclophosphamide ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan
- nitrosoureas e.g. carmustine (BCNU) and lomustine (CCNU)
- alkylsulphonates e.g. busulfan and treosulfan
- triazenes e.g. dacarbazine, temozolomide
- platinum containing compounds e.g. cisplatin, carboplatin, oxaliplatin
- vinca alkaloids e.g. vincristine, vinblastine, vindesine, and vinorelbine
- taxoids e.g.
- paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (Abraxane), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG 1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-I), and glucose-conjugated paclitaxei, e.g., 2'- paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g.
- etoposide etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C
- anti-metabolites DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea and deferoxamine), uracil analogs (e.g.
- 5-fluorouracil 5-fluorouracil
- floxuridine doxifluridine, ratitrexed, tegafur-uracil, capecitabine
- cytosine analogs e.g. cytarabine (ara C), cytosine arabinoside, and fludarabine
- purine analogs e.g. mercaptopurine and Thioguanine
- Vitamin D3 analogs e.g. EB 1089, CB 1093, and KH 1060
- isoprenylation inhibitors e.g. lovastatin
- dopaminergic neurotoxins e.g. 1 -methyl-4-phenylpyridinium ion
- cell cycle inhibitors e.g.
- actinomycin e.g. actinomycin D, dactinomycin
- bleomycin e.g. bleomycin A2, bleomycin B2, peplomycin
- anthracycline e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone
- MDR inhibitors e.g. verapamil
- Ca2+ ATPase inhibitors e.g.
- thapsigargin imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTINTM, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI- 272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SUl 1248), toceranib
- axitinib AG01
- HERCEPTIN® bevacizumab
- AVASTIN® rituximab
- ERBITUX® panitumumab
- VECTIBIX® ranibizumab
- TASIGNA® nilotinib
- sorafenib NEXA VAR®
- everolimus AFINITOR®
- alemtuzumab CAMPATH®
- gemtuzumab ozogamicin MYLOTARG®
- temsirolimus TORISEL®
- biotherapeutic agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon ⁇ , interferon ⁇ ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-I, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g.
- Herceptin (trastuzumab), T-DMl, AVASTIN (bevacizumab), ERJBITUX (cetuximab), Vectibix (panitumumab), Rituxan (rituximab), Bexxar (tositumomab)).
- This invention further relates to a method for using the compounds or pharmaceutical composition in combination with radiation therapy in inhibiting abnormal cell growth or treating the hyperproliferative disorder in the mammal.
- Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein.
- the administration of the compound of the invention in this combination therapy can be determined as described herein.
- Radioactive isotopes e.g. At-211, 1-131, 1-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu.
- Suitable radiation sources for use as a cell conditioner of the present invention include both solids and liquids.
- the radiation source can be a radionuclide, such as 1-125, 1-131, Yb-169, Ir-192 as a solid source, I- 125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays.
- the radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of 1-125 or 1-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au- 198, Y-90.
- the radionuclide(s) can be embodied in a gel or radioactive micro spheres.
- the compounds of the present invention can render abnormal cells more sensitive to treatment with radiation for purposes of killing and/or inhibiting the growth of such cells. Accordingly, this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of the present invention or pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, which amount is effective is sensitizing abnormal cells to treatment with radiation.
- the amount of the compound, salt, or solvate in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein.
- compositions of the present invention can be used in combination with an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and
- Anti-angiogenesis agents such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix- metalloprotienase 9) inhibitors, and COX-1 1 (cyclooxygenase 11) inhibitors, can be used in conjunction with a compound of the present invention and pharmaceutical compositions described herein.
- MMP-2 matrix-metalloprotienase 2
- MMP-9 matrix- metalloprotienase 9
- COX-1 1 cyclooxygenase 11
- useful COX-II inhibitors include CELEBREXTM (alecoxib), valdecoxib, and rofecoxib.
- Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24,1996), WO 96/27583 (published March 7,1996), European Patent Application No.
- MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-I.
- MMP-2 and/or AMP-9 are those that selectively inhibit MMP-2 and/or AMP-9 relative to the other matrix- metalloproteinases (i. e., MAP-I, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP-8, MMP-IO, MMP-Il, MMP-12, andMMP-13).
- MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, and RS 13-0830.
- the invention also relates to a method of and to a pharmaceutical composition of treating a cardiovascular disease in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, or an isotopically-labeled derivative thereof, and an amount of one or more therapeutic agents use for the treatment of cardiovascular diseases.
- anti-thrombotic agents e.g., prostacyclin and salicylates
- thrombolytic agents e.g., streptokinase, urokinase, tissue plasminogen activator (TPA) and anisoylated plasminogen-streptokinase activator complex (APSAC)
- anti-platelets agents e.g., acetyl-salicylic acid (ASA) and clopidrogel
- vasodilating agents e.g., nitrates
- calcium channel blocking drugs anti-proliferative agents, e.g., colchicine and alkylating agents, intercalating agents, growth modulating factors such as interleukins, transformation growth factor- beta and congeners of platelet derived growth factor, monoclonal antibodies directed against growth factors, antiinflammatory agents, both steroidal and non-steroidal, and other agents that can modulate vessel tone, function, ar
- Antibiotics can also be included in combinations or coatings comprised by the invention. Moreover, a coating can be used to effect therapeutic delivery focally within the vessel wall. By incorporation of the active agent in a swellable polymer, the active agent will be released upon swelling of the polymer.
- tissue barriers also known as lubricants.
- tissue barriers include, but are not limited to, polysaccharides, polyglycans, seprafilm, interceed and hyaluronic acid.
- Medicaments which may be administered in conjunction with the compounds described herein include any suitable drugs usefully delivered by inhalation for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; antiallergics, e.g. cromoglycate, ketotifen or nedocromil; anti- infectives, e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines or pentamidine; antihistamines, e.g.
- analgesics e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine
- anginal preparations e.g. diltiazem
- antiallergics e.g. cromoglycate, ketotifen or nedocromil
- antiinflammatories e.g. beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide or fluticasone
- antitussives e.g. noscapine
- bronchodilators e.g.
- ephedrine adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin, isoetharine, tulobuterol, orciprenaline or (-)-4-amino-3,5-dichloro- ⁇ -[[[6-[2-(2-pyridinyl)ethoxy]hexyl]- amino]methyl]benzenemethanol; diuretics, e.g. amiloride; anticholinergics e.g.
- the medicaments may be used in the form of salts (e.g. as alkali metal or amine salts or as acid addition salts) or as esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) to optimize the activity and/or stability of the medicament.
- salts e.g. as alkali metal or amine salts or as acid addition salts
- esters e.g. lower alkyl esters
- solvates e.g. hydrates
- exemplary therapeutic agents useful for a combination therapy include but are not limited to agents as described above, radiation therapy, hormone antagonists, hormones and their releasing factors, thyroid and antithyroid drugs, estrogens and progestins, androgens, adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones, insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas, agents affecting calcification and bone turnover: calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitamins such as water-soluble vitamins, vitamin B complex, ascorbic acid, fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; anticholinesterase agents; agents acting at the neuromuscular junction and/or autonomic ganglia;
- catecholamines catecholamines, sympathomimetic drugs, and adrenergic receptor agonists or antagonists; and 5-hydroxytryptamine (5- HT, serotonin) receptor agonists and antagonists.
- 5-hydroxytryptamine 5-hydroxytryptamine (5- HT, serotonin) receptor agonists and antagonists.
- Therapeutic agents can also include agents for pain and inflammation such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances that are generated by biotransformation of the products of the selective hydrolysis of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory agents, analgesic-antipyretic agents, agents that inhibit the synthesis of prostaglandins and thromboxanes, selective inhibitors of the inducible cyclooxygenase, selective inhibitors of the inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, ⁇ -adrenergic agonists, i
- Additional therapeutic agents contemplated herein include diuretics, vasopressin, agents affecting the renal conservation of water, rennin, angiotensin, agents useful in the treatment of myocardial ischemia, anti-hypertensive agents, angiotensin converting enzyme inhibitors, ⁇ -adrenergic receptor antagonists, agents for the treatment of hypercholesterolemia, and agents for the treatment of dyslipidemia.
- Other therapeutic agents contemplated include drugs used for control of gastric acidity, agents for the treatment of peptic ulcers, agents for the treatment of gastroesophageal reflux disease, prokinetic agents, antiemetics, agents used in irritable bowel syndrome, agents used for diarrhea, agents used for constipation, agents used for inflammatory bowel disease, agents used for biliary disease, agents used for pancreatic disease.
- Therapeutic agents used to treat protozoan infections drugs used to treat Malaria, Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs used in the chemotherapy of helminthiasis.
- therapeutic agents include antimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, and agents for urinary tract infections, penicillins, cephalosporins, and other, ⁇ -Lactam antibiotics, an agent comprising an aminoglycoside, protein synthesis inhibitors, drugs used in the chemotherapy of tuberculosis, mycobacterium avium complex disease, and leprosy, antifungal agents, antiviral agents including nonretroviral agents and antiretroviral agents.
- therapeutic antibodies that can be combined with a subject compound include but are not limited to anti-receptor tyrosine kinase antibodies (cetuximab, panitumumab, trastuzumab), anti CD20 antibodies (rituximab, tositumomab), and other antibodies such as alemtuzumab, bevacizumab, and gemtuzumab.
- anti-receptor tyrosine kinase antibodies cetuximab, panitumumab, trastuzumab
- anti CD20 antibodies rituximab, tositumomab
- other antibodies such as alemtuzumab, bevacizumab, and gemtuzumab.
- therapeutic agents used for immunomodulation such as immunomodulators, immunosuppressive agents, tolerogens, and immunostimulants are contemplated by the methods herein.
- therapeutic agents acting on the blood and the blood-forming organs such as hematopoietic agents, growth factors, minerals, and vitamins, anticoagulant, thrombolytic, and antiplatelet drugs.
- the compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Hence, in some embodiments the compounds of the invention will be co-administer with other agents as described above.
- the compounds described herein may be administered with the second agent simultaneously or separately.
- This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the present invention and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations.
- a compound of the present invention can be administered just followed by and any of the agents described above, or vice versa.
- a compound of the present invention and any of the agents described above may be administered a few minutes apart, or a few hours apart, or a few days apart.
- Example 1 Synthesis of 3-((4-amino-3-(3-hydroxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)methyl)-8-methyI-2-o- toly1isoquinolin-l(2H)-one (Compound 1613), (method A).
- the mixture was allowed to warm to RT, filtered through silica gel (10 g), and the filtrate was concentrated in vacuo.
- the crude product was poured into H 2 O (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with brine (50 mL), dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo.
- the crude product was suspended in ethyl acetate (30 mL) and stirred for lOmin.
- Example 2 Synthesis of 3-((4-amino-3-(3-hydroxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)methyl)-8-methyl-2-o- tolylisoquinolin-l(2H)-one ( Compound 1613) (method B).
- the mixture was allowed to warm to RT, filtered through silica gel (10 g), and the filtrate was concentrated in vacuo.
- the crude product was poured into H 2 O (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with brine (50 mL), dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo.
- the crude product was suspended in ethyl acetate (30 mL) and stirred for lOmin.
- Example 6 Synthesis of 8-methyl-3-((methyl(9H-purin-6-yl)amino)methyl)-2-o-tolylisoquinolin-l(2H)-one.
- Example 7 Synthesis of 3-(l-(9H-purin-6-ylamino)ethyl)-8-methyl-2-o-tolylisoquinolin-l(2H)-one.
- Scheme 20 The synthesis of 3-(l-(9H-purin-6-ylamino)ethyl)-8-methyl-2-o-tolylisoquinolin-l(2H)-one (Compound 4106) is described.
- Example 8 Synthesis of 3-(4-amino-l-((8-methyl-l-oxo-2-o-tolyl-l,2-dihydroisoquinolin-3-yl)methyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)-5-fluorophenyl dihydrogen phosphate.
- TMSBr (0.34 mL, 2.64 mmol) was slowly added via a syringe and the resulting mixture was stirred from O 0 C to RT for 16 h.
- LC-MS showed small amount of staRT ing material left, additional amount of TMSBr (0.1 mL) was added and stirred at RT for 5 h.
- LC-MS showed the complete conversion.
- the mixture was concentrated in vacuo, and the residue was dissolved in Et 2 O (10 mL) and H 2 O (0.5 mL) and stirred for 30 min.
- the mixture was allowed to warm to room temperature, filtered through silica gel (10 g), and the filtrate was concentrated in vacuo.
- the crude product was poured into H 2 O (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with brine (50 mL), dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo.
- the crude product was suspended in ethyl acetate (30 mL) and stirred for lOmin.
- Example 10 Synthesis of 3-((4-amino-3-(fluoromethyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)methyl)-8-methyl-2-o- torylisoquinoIin-l(2H)-one ( compound 4504).
- Example 11 Synthesis of 4-amino-l-((8-methyl-l-oxo-2-o-tolyl-l,2-dihydroisoquinolin-3-yl)methyl)-lH- pyrazolo[3,4-d]pyrimidine-3-carboxamide ( compound 4602).
Abstract
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