WO2010126745A1

WO2010126745A1 - SUBSTITUTED IMIDAZO[1,2-A]PYRIDINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE AS β-SECRETASE INHIBITORS

Info

Publication number: WO2010126745A1
Application number: PCT/US2010/031781
Authority: WO
Inventors: Adnan M.M. Mjalli; Anitha Hari; Bapu Gaddam; Devi Reddy Gohimukkula; Dharma R. Polisetti; Hassan El Abdellaoui; Mohan Rao; Robert C. Andrews; Rongyuan Xie; Tan Ren
Original assignee: High Point Pharmaceuticals, Llc
Priority date: 2009-04-27
Filing date: 2010-04-20
Publication date: 2010-11-04
Also published as: EA201171306A1; KR20120028869A; IL215074A0; JP2012525390A; US20120101093A1; MX2011011396A; CN102414210A; CA2758958A1; EP2424866A1; SG174451A1; BRPI1012697A2; AU2010241929A1

Abstract

The present invention is directed to substituted imidazo[1,2-a]pyridine derivatives, pharmaceutically acceptable salts thereof, and tautomers of such compounds or salts, that inhibit β-site amyloid precursor protein-cleaving enzyme (BACE) and that may be useful in the treatment of diseases in which BACE is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which BACE is involved.

Description

Substituted lmidazo[1 ,2-a]pyridine Derivatives, Pharmaceutical Compositions, and Methods of Use as β-Secretase Inhibitors

CROSS-REFERENCE TO RELATED APPLICATION The present application claims priority under 35 U.S.C. § 119(e) and PCT Article 8(1) to U.S. Provisional Patent Application No. 61/173,180, filed April 27, 2009.

This specification hereby incorporates U.S. Provisional Patent Application No. 61/173,180 by reference in its entirety as though fully set forth herein.

BACKGROUND OF THE INVENTION

FIELD OF INVENTION

The present invention relates to substituted imidazo[1 ,2-a]pyridine derivatives useful as inhibitors of β-secretase, the β-site amyloid precursor protein-cleaving enzyme (BACE).

DESCRIPTION OF RELATED ART

Alzheimer's disease is characterized by the abnormal deposition of β-amyloid (Aβ) in the brain in the form of extra-cellular plaques and intra-cellular neurofibrillary tangles. The rate of amyloid accumulation is a combination of the rates of Aβ formation, aggregation, and egress from the brain. It is generally accepted that the main constituent of amyloid plaques is the 4kD amyloid protein (βA4, also referred to as Aβ, β-protein and βAP) which is a proteolytic product of a precursor protein of much larger size.

Amyloid precursor protein (APP) is a 695-770 amino acid glycoprotein, expressed in the neurons and glial cells in peripheral tissues. APP has a receptor-like structure with a large ectodomain, a membrane spanning region, and a short cytoplasmic tail. Aβ is a 39-42 amino acid peptide, constitutes part of the ectodomain of APP, and extends partly to the transmembrane domain of APP.

At least two secretory mechanisms exist which release APP from the membrane and generate soluble, truncated forms of APP (sAPP). Proteases that release APP and its fragments from the membrane are termed "secretases." Most sAPP is released by a putative α-secretase that cleaves within the Aβ protein to release sAPPα and precludes the release of intact Aβ. A smaller portion of sAPP is released by a β-secretase that cleaves near the NH₂-terminus of APP and produces COOH-terminal fragments (CTFs) which contain the complete Aβ domain.

Thus, the activity of β-secretase or β-site amyloid precursor protein-cleaving enzyme ("BACE") leads to the abnormal cleavage of APP, production of Aβ, and accumulation of β-amyloid plaques in the brain, which is characteristic of Alzheimer's disease. In addition, the processing of APP by β-secretase is thought to be the rate-determining step in Aβ production. Therefore, therapeutic agents that can inhibit BACE may be useful for the treatment of Alzheimer's disease.

The compounds of the present invention may be useful for treating Alzheimer's disease by inhibiting the activity of the BACE, thus preventing or reducing the rate of formation of insoluble Aβ.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to substituted imidazo[1 ,2-a]pyridine derivatives that inhibit the β-site amyloid precursor protein-cleaving enzyme (BACE) and that therefore may be useful in the treatment of diseases in which BACE is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising substituted imidazo[1 ,2-a]pyridine derivatives and the use of these compounds and pharmaceutical compositions in the treatment of diseases in which BACE is involved. In one aspect, the present invention provides compounds of Formula (I), pharmaceutically acceptable salts thereof, and tautomers of said compounds or salts, where the identity of individual substituents is set forth in greater detail below.

(I)

In another aspect, the present invention provides methods for the preparation of compounds of Formula (I), pharmaceutically acceptable salts thereof, and tautomers of said compounds or salts. In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a tautomer of said compound or salt. In one embodiment, the pharmaceutical composition comprises a compound of Formula (I)₁ a pharmaceutically acceptable salt thereof, or a tautomer of said compound or salt, and a pharmaceutically acceptable carrier, excipient, diluent, or mixture thereof. In another aspect, the present invention provides a method for the preparation of a pharmaceutical composition comprising a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a tautomer of said compound or salt. In another aspect, the present invention provides methods of treatment comprising administering a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a tautomer of said compound or salt, or a pharmaceutical composition comprising a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a tautomer of said compound or salt, to a subject who has a disease, disorder, or condition.

In another aspect, the present invention provides methods of treatment comprising administering a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a tautomer of said compound or salt, or a pharmaceutical composition comprising a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a tautomer of said compound or salt to a subject having a disease, disorder, or condition or a subject at risk for having a disease, disorder, or condition, wherein the disease, disorder, or condition is selected from the group consisting of: Alzheimer's disease, mild cognitive impairment, dementia of the Alzheimer's type, Down's syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type of Alzheimer's disease, and central or peripheral amyloid diseases.

Additional features of the present invention are described hereinafter.

BRIEF DESCRIPTION OF DRAWINGS

Not applicable.

DETAILED DESCRIPTION

The following definitions are meant to clarify the terms defined. If a particular term used herein is not specifically defined, the term should not be considered to be indefinite. Rather, such undefined terms are to be construed in accordance with their plain and ordinary meaning to skilled artisans in a field of art to which the invention is directed.

As used herein the term "alkyl" refers to a saturated straight or branched chain hydrocarbon having one to twelve carbon atoms, which may be optionally substituted, as herein further described, with multiple degrees of substitution being allowed. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n- butyl, sec-butyl, tert-butyl, isopentyl, n-pentyl, neopentyl, n-hexyl, and 2-ethylhexyl.

As used throughout this specification, the number carbon atoms in an alkyl group will be represented by the phrase "C_x-y alkyl," which refers to an alkyl group, as herein defined, containing from x to y, inclusive, carbon atoms. Thus, C_1-6 alkyl represents an alkyl chain having from 1 to 6 carbons as described above, and for example, includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, n- pentyl, neopentyl, and n-hexyl. Furthermore, the term "lower alkyl," as used herein, refers to an alkyl group, as herein defined, having from one to six carbon atoms, inclusive.

As used herein, the term "alkylene" refers to a saturated straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, which may be optionally substituted as herein further described, with multiple degrees of substitution being allowed.

Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, n-propylene, 1-methylethylene, 2-methylethylene, dimethylmethylene, n-butylene, 1-methyl- n-propylene, and 2-methyl-n-propylene.

As used throughout this specification, the number of carbon atoms in an alkylene group will be represented by the phrase "C_x._y alkylene," which refers to an alkylene group, as herein defined, containing from x to y, inclusive, carbon atoms. Thus, C_1-4 alkylene represents an alkylene chain having from 1 to 4 carbons as described above, and for example, includes, but is not limited to, methylene, ethylene, n-propylene, 1-methylethylene, 2-methylethylene, dimethylmethylene, n-butylene, 1-methyl-n-propylene, and 2-methyl-n- propylene.

As used herein, the term "alkenylene" refers to a straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, and containing at least one carbon- to-carbon double bond, which may be optionally substituted as herein further described, with multiple degrees of substitution being allowed. Examples of "alkenylene" as used herein include, but are not limited to, vinylene, allylene, and 2-propenylene.

As used throughout this specification, the number of carbon atoms in an alkenylene group will be represented by the phrase "C_x._y alkenylene," which refers to an alkenylene group, as herein defined, containing from x to y, inclusive, carbon atoms. Thus, C_1-4 alkenylene represents an alkenylene chain having from 1 to 4 carbons as described above, and for example, includes, but is not limited to, vinylene, allylene, and 2-propenylene.

As used herein, the term "alkynylene" refers to a straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, and containing at least one carbon- to-carbon triple bond, which may be optionally substituted as herein further described, with multiple degrees of substitution being allowed. Examples of "alkynylene" as used herein include, but are not limited to, ethynylene and propynylene.

As used throughout this specification, the number of carbon atoms in an alkynylene group will be represented by the phrase "C_x-y alkynylene," which refers to an alkynylene group, as herein defined, containing from x to y, inclusive, carbon atoms. Thus, C_1-4 alkynylene represents an alkynylene chain having from 1 to 4 carbons as described above, and for example, includes, but is not limited to, ethynylene and propynylene. As used herein, the term "cycloalkyl" refers to a three- to twelve-membered, cyclic hydrocarbon ring, which may be optionally substituted as herein further described, with multiple degrees of substitution being allowed. The term "cycloalkyl," as used herein, does not include ring systems which contain any aromatic rings, but does include ring systems that have one or more degrees of unsaturation. Examples of "cycloalkyl" groups as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-norbornyl, 2-norbomyl, 7-norbomyl, 1-adamantyl, and 2-adamantyl.

As used throughout this specification, the number of carbon atoms in a cycloalkyl group will be represented by the phrase "C_x-y cycloalkyl," which refers to a cycloalkyl group, as herein defined, containing from x to y, inclusive, carbon atoms. Similar terminology will apply for other terms and ranges as well. Thus, C_3-10 cycloalkyl represents a cycloalkyl group having from 3 to 10 carbons as described above, and for example, includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-norbornyl, 2-norbomyl, 7-norbornyl, 1-adamantyl, and 2-adamantyl. As used herein, the term "heterocycle" or "heterocyclyl" refers to a mono-, bi-, or tricyclic ring system containing one or more heteroatoms. Such "heterocycle" or "heterocyclyl" groups may be optionally substituted as herein further described, with multiple degrees of substitution being allowed. The terms "heterocycle" or "heterocyclyl," as used herein, do not include ring systems which contain any aromatic rings, but do include ring systems that have one or more degrees of unsaturation. Examples of heteroatoms include nitrogen, oxygen, or sulfur atoms, including N-oxides, sulfur oxides, and sulfur dioxides. Carbon atoms in the ring system can also be optionally oxidized to form heterocyclic rings such as, 2-oxo-pyrrolidin-1 -yl or 2-oxo-piperidin-1-yl. Typically, the ring is three- to twelve-membered. Such rings may be optionally fused to one or more of another heterocyclic ring(s) or cycloalkyl ring(s). Examples of

"heterocycle" or "heterocyclyl" groups, as used herein, include, but are not limited to, tetrahydrofuran, tetrahydropyran, 1 ,4-dioxane, 1 ,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, and tetrahydrothiophene, where attachment can occur at any point on said rings, as long as attachment is chemically feasible. Thus, for example, "morpholine" can refer to morpholin-2-yl, morpholin-3-yl, and morpholin-4-yl.

As used herein, when "heterocycle" or "heterocyclyl" is recited as a possible substituent, the "heterocycle" or "heterocyclyl" group can attach through either a carbon atom or any heteroatom, to the extent that attachment at that point is chemically feasible. For example, "heterocyclyl" would include pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3- yl. When "heterocycle" or "heterocyclyl" groups contain a nitrogen atom in the ring, attachment through the nitrogen atom can alternatively be indicated by using an "-ino" suffix with the ring name. For example, pyrrolidino refers to pyrrolidin-1-yl.

As used herein the term "halogen" refers to fluorine, chlorine, bromine, or iodine. As used herein the term "haloalkyl" refers to an alkyl group, as defined herein, that is substituted one or more times with halogen. Examples of branched or straight chained "haloalkyl" groups as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substituted independently with one or more halogens, for example, fluoro, chloro, bromo, and iodo. The term "haloalkyl" should be interpreted to include groups such as -CF₃ , -CH₂-CF₃, and -CF₂CI . As used herein, the term "aryl" refers to a six- to ten-membered cyclic, aromatic hydrocarbon, which may be optionally substituted as herein further described, with multiple degrees of substitution being allowed. Examples of "aryl" groups as used herein include, but are not limited to, phenyl and naphthyl. As used herein, the term "aryl" also includes ring systems in which a phenyl or naphthyl group is optionally fused with one to three non-aromatic, saturated or unsaturated, carbocyclic rings. For example, "aryl" would include ring systems such as indene, with attachment possible to either the aromatic or the non-aromatic ring(s).

As used herein, the term "heteroaryl" refers to a five- to fourteen-membered optionally substituted mono- or polycyclic ring system, which contains at least one aromatic ring and also contains one or more heteroatoms. Such "heteroaryl" groups may be optionally substituted as herein further described, with multiple degrees of substitution being allowed. In a polycyclic "heteroaryl" group that contains at least one aromatic ring and at least one non-aromatic ring, the aromatic ring(s) need not contain a heteroatom. Thus, for example, "heteroaryl," as used herein, would include indolinyl. Further, the point of attachment may be to any ring within the ring system without regard to whether the ring containing the attachment point is aromatic or contains a heteroatom. Thus, for example, "heteroaryl," as used herein, would include indolin-1 -yl, indolin-3-yl, and indolin-5-yl. Examples of heteroatoms include nitrogen, oxygen, or sulfur atoms, including N-oxides, sulfur oxides, and sulfur dioxides, where feasible. Examples of "heteroaryl" groups, as used herein include, but are not limited to, furyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1 ,2,4-triazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, indolyl, isoindolyl, benzo[b]thiophenyl, benzimidazolyl, benzothiazolyl, pteridinyl, and phenazinyl, where attachment can occur at any point on said rings, as long as attachment is chemically feasible. Thus, for example, "thiazolyl" refers to thiazol-2-yl, thiazol-4-yl, and thiaz-5-yl. As used herein, when "heteroaryl" is recited as a possible substituent, the "heteroaryl" group can attach through either a carbon atom or any heteroatom, to the extent that attachment at that point is chemically feasible.

As used herein, the term "direct bond", where part of a structural variable specification, refers to the direct joining of the substituents flanking (preceding and succeeding) the variable taken as a "direct bond". Where two or more consecutive variables are specified each as a "direct bond", those substituents flanking (preceding and succeeding) those two or more consecutive specified "direct bonds" are directly joined.

As used herein, the term "substituted" refers to substitution of one or more hydrogens of the designated moiety with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated, provided that the substitution results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature from about -80 ⁰C to about +40 °C, in the absence of moisture or other chemically reactive conditions, for at least a week, or a compound which maintains its integrity long enough to be useful for therapeutic or prophylactic administration to a patient. As used herein, the phrases "substituted with one or more..." or "substituted one or more times..." refer to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites, provided that the above conditions of stability and chemical feasibility are met.

As used herein, the various functional groups represented will be understood to have a point of attachment at the functional group having the hyphen or dash (-) or an asterisk (*).

In other words, in the case of -CH₂CH₂CH₃, it will be understood that the point of attachment is the CH₂ group at the far left. If a substituent group is recited without an asterisk or a dash, then its attachment point is the attachment point that skilled artisans would generally associate with that group. For example, "methyl" is -CH₃, as that conforms to the generally understood meaning of what a methyl group is.

When any variable occurs more than one time in any one constituent (e.g., R^a), or multiple constituents, its definition on each occurrence is independent of its definition on every other occurrence.

As used herein, multi-atom bivalent species are to be read from left to right. For example, if the specification or claims recite A-D-E and D is defined as -OC(O)-, the resulting group with D replaced is: A-OC(O)-E and not A-C(O)O-E.

As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur. As used herein, "administer" or "administering" means to introduce, such as to introduce to a subject a compound or composition. The term is not limited to any specific mode of delivery, and can include, for example, subcutaneous delivery, intravenous delivery, intramuscular delivery, intracisternal delivery, delivery by infusion techniques, transdermal delivery, oral delivery, nasal delivery, and rectal delivery. Furthermore, depending on the mode of delivery, the administering can be carried out by various individuals, including, for example, a health-care professional (e.g., physician, nurse, etc.), a pharmacist, or the subject (i.e., self-administration).

As used herein, "treat" or "treating" or "treatment" can refer to one or more of: delaying the progress of a disease, disorder, or condition; controlling a disease, disorder, or condition; delaying the onset of a disease, disorder, or condition; ameliorating one or more symptoms characteristic of a disease, disorder, or condition; or delaying the recurrence of a disease, disorder, or condition, or characteristic symptoms thereof, depending on the nature of the disease, disorder, or condition and its characteristic symptoms. As used herein, "subject" refers to any mammal such as, but not limited to, humans, horses, cows, sheep, pigs, mice, rats, dogs, cats, and primates such as chimpanzees, gorillas, and rhesus monkeys. In an embodiment, the "subject" is a human. In another embodiment, the "subject" is a human who exhibits one or more symptoms characteristic of a disease, disorder, or condition. In another embodiment, the "subject" is a human who has a disease, disorder, or condition in which BACE is involved. The term "subject" does not require one to have any particular status with respect to a hospital, clinic, or research facility (e.g., as an admitted patient, a study participant, or the like).

As used herein, the term "compound" includes free acids, free bases, and salts thereof. Thus, phrases such as "the compound of embodiment 1" or "the compound of claim 1 " are intended to refer to any free acids, free bases, and salts thereof that are encompassed by embodiment 1 or claim 1.

As used herein, "substituted imidazo[1 ,2-a]pyridines derivatives" refers to derivatives of 2-imidazo[1 ,2-a]pyridine carboxylic acid benzimidazol-2-yl amide or 3-imidazo[1 ,2- ajpyridine carboxylic acid benzimidazol-2-yl amide represented by Formula (I), as described in detail below.

As used herein, the term "pharmaceutical composition" is used to denote a composition that may be administered to a mammalian host, e.g., orally, topically, parenterally, by inhalation spray, or rectally, in unit dosage formulations containing conventional non-toxic carriers, diluents, adjuvants, vehicles and the like. The term "parenteral" as used herein, includes subcutaneous injections, intravenous, intramuscular, intracisternal injection, or by infusion techniques. As used herein, the term "tautomer," used in reference to compounds or salts of the invention, refers to tautomers that can form with respect to substituted benzimidazole groups, as shown below.

The present invention includes all such tautomers and methods of making and using the same. Throughout this specification, whenever a chemical formula (generic or otherwise) discloses a compound having a 1 H-benzimidazole moiety that is unsubstituted at the 1 position (as illustrated in the far left-hand structure shown immediately above), that chemical formula also implicitly discloses compounds that are otherwise identical except that the benzimidazole moiety undergoes tautomerization to form either of the other two benzimidazole tautomers shown immediately above. Thus, the phrase "a tautomer of a compound of Formula (I)" refers to compounds of Formula (I) where the R⁵ group of Formula (I) is hydrogen, and where said tautomer is related to a compound of Formula (I) according to the tautomeric relationship described immediately above. As used herein, the term "BACE inhibitor" or "inhibitor of BACE" is used to signify a compound having a structure, as defined herein, which is capable of interacting with BACE and inhibiting its enzymatic activity. Inhibiting BACE enzymatic activity means reducing the ability of BACE to cleave a peptide or protein. The peptide or protein may be APP, and a BACE inhibitor may reduce the ability of BACE to cleave APP near the NH₂ terminus of APP and produce COOH-terminal fragments (CTFs) that contain the complete Aβ domain. In various embodiments, such reduction of BACE activity is at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. In various embodiments, the concentration of BACE inhibitor required to reduce a BACE's enzymatic activity is less than about 30 μM, less than about 10 μM, or less than about 1 μM. As used herein, the term "pharmaceutical composition" is used to denote a composition that may be administered to a mammalian host, e.g., orally, topically, parenterally, by inhalation spray, or rectally, in unit dosage formulations containing conventional non-toxic carriers, diluents, adjuvants, vehicles and the like. The term "parenteral" as used herein, includes subcutaneous injections, intravenous, intramuscular, intracisternal injection, or by infusion techniques.

As used herein the terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable diluent", and pharmaceutically acceptable excipient" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Also included within the scope of the invention are the individual enantiomers of the compounds represented by Formula (I), pharmaceutically acceptable salts thereof, or tautomers of said compounds or salts, as well as any wholly or partially racemic mixtures thereof. The invention also covers the individual enantiomers of the compounds represented by Formula (I), pharmaceutically acceptable salts thereof, or tautomers of said compounds or salts, as well as mixtures with diastereoisomers thereof in which one or more stereocenters are inverted. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom by a ¹³C- or ¹⁴C-enriched carbon are within the scope of the invention.

In several aspects, the present invention relates to substituted imidazo[1 ,2-a]pyridine derivatives, pharmaceutical compositions comprising substituted imidazo[1 ,2-a]pyridine derivatives, methods of making substituted imidazo[1 ,2-a]pyridine derivatives, methods of making pharmaceutical compositions comprising substituted imidazo[1 ,2-a]pyridine derivatives, and methods of using substituted imidazo[1 ,2-a]pyridine derivatives or pharmaceutical compositions comprising substituted imidazo[1 ,2-a]pyridine derivatives, particularly for the treatment of diseases, disorders, or conditions that may be related to the enzymatic activity of BACE, such as Alzheimer's disease.

In a first aspect, the present invention provides substituted imidazo[1 ,2-a]pyridine derivatives, pharmaceutically acceptable salts thereof, and tautomers of said compounds or salts. Such compounds, salts, or tautomers thereof are useful in the reduction of the proteolytic activity of BACE, as discussed in more detail below.

In a first embodiment (i.e., embodiment 1), the present invention provides a compound of Formula (I), a tautomer of a compound of Formula (I), or a pharmaceutically acceptable salt of either of the foregoing:

(D wherein

G¹ is imidazo[1 ,2-a]pyridin-2-yl

or imidazo[1 ,2-a]pyridin-3-yl

wherein G¹ is optionally substituted with one or more substituents independently selected from the group consisting of: a) -halo, b) R^a, c) -J¹-R^b, d) -alkylene-J²-R^b, e) -alkynylene-R^f,

T) -alkenylene-R^f, g) -J¹-alkylene-J²-R^b, h) -alkylene-J¹-alkylene-J²-R^b, i) -N(R^d)(R^e), j) -alkylene-N(R^d)(R^e), k) -J¹-alkylene-N(R^d)(R^e),

I) -N(-alkylene-R^f)(-alkylene-R⁹), m) R^J, n) -J¹-alkylene-J²-R^J, o) -alkylene-J¹-alkylene-R^J, p) -alkylene-J¹-alkylene-J²-R^J, q) -C(O)R^d, r) -CO₂-R^d, s) -C(O)-N(R^d)(R^e), t) -SO₂-alkyl, u) -SO₂-OR^d, v) -SO₂-N(R^d)(R^e), w) -J²-alkylene-C(O)R^d, x) -J²-alkylene-CO₂R^d, y) -J²-alkylene-C(O)N(R^d)(R^e), z) -J²-alkylene-SO₂-alkyl, aa) -J²-alkylene-SO₂-OR^d, and bb) -J²-alkylene-SO₂-N(R^d)(R^e), wherein the alkylene, alkenylene, and alkynylene groups are optionally substituted with one or more substituents independently selected from R^c, and

J¹ is selected from the group consisting of: -O-, -NH-, and -S-, J² is selected from the group consisting of: a direct bond, -O-, -NH-, and -S-;

R¹ and R⁴ are independently selected from the group consisting of: a) -hydrogen, b) -halo, c) -alkyl, d) -haloalkyl, e) -O-alkyl, and f) -O-haloalkyl;

R² and R³ are independently selected from the group consisting of: a) -hydrogen, b) -halo, c) -alkyl, d) -haloalkyl, e) -O-alkyl, f) -O-haloalkyl, and g) -L²-D²-G², wherein at least one of R² and R³ is -L²-D²-G², and wherein

L² is selected from the group consisting of: direct bond, -O-, -NH-, and -N(R⁶)-; wherein R⁶ is -D³-G³, wherein D³ is selected from the group consisting of: direct bond, -alkylene-, and -alkenylene-; and

G³ is selected from the group consisting of: -phenyl and -cycloalkyl, wherein the phenyl and cycloalkyl groups are optionally substituted with one or more substituents independently selected from the group consisting of: -halo, -alkyl, -haloalkyl,

-OH, -NH₂, -phenyl, -cycloalkyl, -alkylene-phenyl, -alkylene- cycloalkyl, -O-alkyl, -O-haloalkyl, -O-phenyl, -O-cycloalkyl, -O- alkylene-phenyl, -O-alkylene-cycloalkyl, -C(O)alkyl, and - C(O)haloalkyl;

D² is selected from the group consisting of: direct bond, -alkylene-, and -alkenylene-; and

G² is selected from the group consisting of: -phenyl, -cycloalkyl, -heterocyclyl, and -heteroaryl, wherein the phenyl, cycloalkyl, heterocyclyl, and heteroaryl groups are optionally substituted with one or more substituents independently selected from the group consisting of: -halo, -alkyl, -haloalkyl, -OH, -NH₂, - NH-alkyl, -N(alkyl)₂, pyrrolidino, piperidino, piperazino, 4-methyl- piperazino, morpholino, -phenyl, -CN, -cycloalkyl, -alkylene-phenyl, - alkylene-cycloalkyl, -O-alkyl, -O-haloalkyl, -O-phenyl, -O-cycloalkyl, -O- alkylene-phenyl, -O-alkylene-cycloalkyl, -O-alkylene-O-alkyl, -C(O)alkyl, - C(O)haloalkyl, -CO₂-alkyl, and -SO₂-alkyl;

R⁵ is selected from the group consisting of: hydrogen, -haloalkyl, -alkyl, -alkylene-J³-R^d, -alkylene-N(R^d)(R^e), -alkylene-C(O)R^d, -alkylene-CO₂R^d, -alkylene-C(O)N(R^d)(R⁸), -alkylene-SO₂-alkyl, -alkylene-SO₂-OR^d, and -alkylene-SO₂-N(R^d)(R^Θ), wherein J³ is selected from the group consisting of: a direct bond, -O-, -NH-, and -S-;

R⁷ is -H or alkyl;

R^a is selected from the group consisting of: alkyl, haloalkyl, phenyl, cycloalkyl, piperidin-4-yl,

1-methyl-piperidin-4-yl, piperidin-3-yl, and pyrrolidin-3-yl, wherein the alkyl, phenyl, cycloalkyl, piperidin-4-yl, 1-methyl-piperidin-4-yl, piperidin-3-yl, and pyrrolidin-3-yl groups are optionally substituted with one or more substituents independently selected from R^c;

R^b is selected from the group consisting of: hydrogen, alkyl, haloalkyl, phenyl, cycloalkyl, piperidin-4-yl, 1-methyl-piperidin-4-yl, piperidin-3-yl, and pyrrolidin-3-yl, wherein the alkyl, phenyl, cycloalkyl, piperidin-4-yl, 1-methyl-piperidin-4-yl, piperidin-3-yl, and pyrrolidin-3-yl groups are optionally substituted with one or more substituents independently selected from R^c; R^c is selected from the group consisting of: halo, haloalkyl, alkyl, cycloalkyl, phenyl, -OH, - NH₂, -N(H)alkyl, -N(alkyl)₂, -O-haloalkyl, -O-alkyl, -O-cycloalkyl, -O-phenyl, and -O- alkylene-phenyl;

R^d and R^e are independently selected from the group consisting of: hydrogen, alkyl, phenyl, and cycloalkyl, wherein the alkyl, phenyl, and cycloalkyl groups are optionally substituted with one or more substituents independently selected from R^c, or R^d and R^e are taken together with the atom to which they are attached to form a ring, wherein R^d and R^e together have the formula -(CR^fR⁹)_s-X¹-(CR^fR⁹)_r, wherein s and t are independently 1 , 2, or 3, and the sum of s and t is equal to 3 or 4, and X¹ is selected from the group consisting of: direct bond, -CH₂-, -0-, -S-, and -NR⁷-;

R^f and R⁹ are independently selected from the group consisting of: hydrogen, halo, haloalkyl, alkyl, cycloalkyl, phenyl, -OH, -NH₂, -N(H)alkyl, -N(alkyl)₂, -O-haloalkyl, -O-alkyl, -O- cycloalkyl, -O-phenyl, and -O-alkylene-phenyl, wherein the alkyl, phenyl, cycloalkyl groups are optionally substituted with one or more substituents independently selected from R^c; and

R^J is heteroaryl or heterocyclyl, where each group is optionally substituted one or more times with substituents independently selected from R^c.

Embodiment 2: A compound according to embodiment 1 , wherein

G¹ is optionally substituted with one or more substituents independently selected from the group consisting of: a) -halo, b) R^a, c) -J¹-R^b, d) -alkylene-J²-R^b, e) -J¹-alkylene-J²-R^b, f) -N(R^d)(R^e), g) -alkylene-N(R^d)(R^Θ), h) -J¹-alkylene-N(R^d)(R^e), i) -N(-alkylene-R^f)(-alkylene-R⁹), j) -C(O)R^d, k) -CO₂-R^d,

I) -SO₂-alkyl, m) -SO₂-OR^d, n) -SO₂-N(R^d)(R^e), o) -J²-alkylene-C(O)R^d, p) -J²-alkylene-CO₂R^d, q) -J²-alkylene-C(O)N(R^d)(R^e), r) -J²-alkylene-SO₂-alkyl, s) -J²-alkylene-SO₂-OR^d, and t) -J²-alkylene-SO₂-N(R^d)(R^e), wherein the alkylene groups are optionally substituted with one or more substituents independently selected from R^c, and

J¹ is selected from the group consisting of: -O-, -NH-, and -S-,

J² is selected from the group consisting of: a direct bond, -O-, -NH-, and -S-;

G² is selected from the group consisting of: -phenyl and -cycloalkyl, wherein the phenyl and cycloalkyl groups are optionally substituted with one or more substituents independently selected from the group consisting of: -halo, - alkyl, -haloalkyl, -OH, -NH₂, -phenyl, -cycloalkyl, -alkylene-phenyl, -alkylene- cycloalkyl, -O-alkyl, -O-haloalkyl, -O-phenyl, -O-cycloalkyl, -O-alkylene- phenyl,-0-alkylene-cycloalkyl, -C(O)alkyl, and -C(O)haloalkyl;

R^a is selected from the group consisting of: alkyl, haloalkyl, phenyl, cycloalkyl, piperidin-4-yl, piperidin-3-yl, and pyrrolidin-3-yl, wherein the alkyl, phenyl, cycloalkyl, piperidin-4-yl, piperidin-3-yl, and pyrrolidin-3-yl groups are optionally substituted with one or more substituents independently selected from R^c;

R^b is selected from the group consisting of: hydrogen, alkyl, haloalkyl, phenyl, cycloalkyl, piperidin-4-yl, piperidin-3-yl, and pyrrolidin-3-yl, wherein the alkyl, phenyl, cycloalkyl, piperidin-4-yl, piperidin-3-yl, and pyrrolidin-3-yl groups are optionally substituted with one or more substituents independently selected from R^c; and

R⁷ is -H.

Embodiment 3: A compound according to embodiment 2, wherein R⁵ is hydrogen. Embodiment 4: A compound according to embodiment 2, wherein R⁵ is methyl. Embodiment 5: A compound according to embodiment 2, wherein R⁵ is -alkylene-J³-R^d. Embodiment 6: A compound according to embodiment 5, wherein R⁵ is -alkylene-O-R^d. Embodiment 7: A compound according to embodiment 2, wherein R⁵ is -alkylene-N(R^d)(R^e). Embodiment 8: A compound according to embodiment 2, wherein R⁵ is -alkylene-C(O)R^d. Embodiment 9: A compound according to embodiment 2, wherein R⁵ is -alkylene-CO₂R^d. Embodiment 10: A compound according to embodiment 2, wherein R⁵ is -alkylene-

C(O)N(R^d)(R^e). Embodiment 11 : A compound according to embodiment 2, wherein R⁵ is -alkylene-

SOa-alkyl. Embodiment 12: A compound according to embodiment 2, wherein R⁵ is -alkylene-

SO₂-OR^d. Embodiment 13: A compound according to embodiment 2, wherein R⁵ is -alkylene-

SO₂-N(R^d)(R^e).

Embodiment 14: A compound according to any one of embodiments 2 to 13, wherein G¹ is substituted once.

Embodiment 15: A compound according to any one of embodiment 2 to 13, wherein G¹ is substituted only at the 5-position. Embodiment 16: A compound according to any one of embodiments 2 to 13, wherein G¹ is substituted twice. Embodiment 17: A compound according to any one of embodiments 2 to 13, wherein G¹ is unsubstituted. Embodiment 18: A compound according to any one of embodiments 2 to 16, wherein G¹ is substituted with substituents independently selected from the group consisting of: - halo and R^a. Embodiment 19: A compound according to any one of embodiments 2 to 16, wherein G¹ is substituted with substituents independently selected from the group consisting of: a) -halo, b) -C_1-4 alkyl, c) -halo C_1-4 alkyl, d) -0-C_1-4 alkyl, e) -O-halo C_1-4 alkyl,

T) -0-C_1-4 alkylene-phenyl, g) -NH-C_1-4 alkyl, h) -NH-C_1-2 alkylene-phenyl, i) -N-(C_1-4 alkyl)₂, and j) -N-(C_1-2 alkylene-phenyl)₂. Embodiment 20: A compound according to any one of embodiments 2 to 16, wherein G¹ is substituted with substituents independently selected from the group consisting of: - halo, -C_1-4 alkyl, -halo C_1-4 alkyl, -0-C_1-4 alkyl, -O-halo C_1-4 alkyl, -J¹-R^b, -alkylene-J²-

R^b, and -J¹-alkylene-J²-R^b. Embodiment 21 : A compound according to any one of embodiments 2 to 16, wherein G¹ is substituted with substituents independently selected from the group consisting of: - halo, -C_1-4 alkyl, -halo C_1-4 alkyl, -0-C_1-4 alkyl, -O-halo C_1-4 alkyl, -N(R^d)(R^e),

-alkylene-N(R^d)(R^e), and -J¹-alkylene-N(R^d)(R^e).

Embodiment 22: A compound according to any one of embodiments 2 to 16, wherein G¹ is substituted with substituents independently selected from the group consisting of: - halo, -C_1-4 alkyl, -halo C_1-4 alkyl, -O-C_1-4 alkyl, -O-halo C_1-4 alkyl, -C(O)R^d, -CO₂-R^d,

-SO₂-alkyl, -SO₂-OR^d, and -SO₂-N(R^d)(R^e). Embodiment 23: A compound according to any one of embodiments 2 to 16, wherein G¹ is substituted with substituents independently selected from the group consisting of: - halo, -C_1-4 alkyl, -halo C_1-4 alkyl, -0-C_1-4 alkyl, -O-halo C-,.₄ alkyl, -J²-alkylene-

C(O)R^d, -J²-alkylene-CO₂R^d, -J²-alkylene-C(O)N(R^d)(R⁸), -J²-alkylene-SO₂-alkyl, -

J²-alkylene-SO₂-OR^d, and -J²-alkylene-SO₂-N(R^d)(R^e). Embodiment 24: A compound according to any one of embodiments 2 to 23, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl. Embodiment 25: A compound according to any one of embodiments 2 to 13, wherein G¹ is

5-methyl-imidazo[1 ,2-a]pyridin-2-yl. Embodiment 26: A compound according to any one of embodiments 2 to 23, wherein G¹ is imidazo[1 ,2-a]pyridin-3-yl.

Embodiment 27: A compound according to any one of embodiments 2 to 26, wherein R¹ and R⁴ are independently selected from the group consisting of: -hydrogen, -halo, - alkyl, -haloalkyl, -O-alkyl, and -O-haloalkyl. Embodiment 28: A compound according to embodiment 27, wherein at least one of R¹ and

R⁴ is hydrogen.

Embodiment 29: A compound according to embodiment 27, wherein R¹ and R⁴ are hydrogen.

Embodiment 30: A compound according to any one of embodiments 2 to 26, wherein R¹ and R⁴ are hydrogen, and one of R² and R³ is hydrogen and the other of R² and R³ is the group -L²-D²-G².

Embodiment 31 : A compound according to any one of embodiments 2 to 30, wherein one of R² and R³ is -L²-D²-G², wherein L² is a direct bond.

Embodiment 32: A compound according to embodiment 31, wherein D² is a direct bond. Embodiment 33: A compound according to embodiment 31 , wherein D² is -C_1-3 alkylene-. Embodiment 34: A compound according to embodiment 31 , wherein D² is -C(H)=C(H)-. Embodiment 35: A compound according to any one of embodiments 31 to 34, wherein G² is phenyl. Embodiment 36: A compound according to embodiment 35, wherein G² is -phenyl, wherein the phenyl group is unsubstituted. Embodiment 37: A compound according to embodiment 35, wherein G² is -phenyl, wherein the phenyl group is substituted with one or more substituents independently selected from the group consisting of: halo, -alkyl, -haloalkyl, -O-alkyl,-O-haloalkyl, and - C(O)-haloalkyl.

Embodiment 38: A compound according to embodiment 35, wherein G² is -phenyl, wherein the phenyl group is substituted with one or more substituents independently selected from the group consisting of: -F, -Cl, -C_1-3 alkyl, -CF₃, -OC_1-3 alkyl ,-0-CF₃, -CH₂-

CF₃, and -C(O)-CF₃. Embodiment 39: A compound according to any one of embodiments 31 to 34, wherein G² is

-cycloalkyl. Embodiment 40: A compound according to embodiment 39, wherein G² is -cycloalkyl, wherein the cycloalkyl group is unsubstituted.

Embodiment 41 : A compound according to embodiment 39, wherein G² is -cycloalkyl, wherein the cycloalkyl group is substituted with one or more substituents independently selected from the group consisting of: halo, -alkyl, -haloalkyl, -O- alkyl.-O-haloalkyl, and -C(O)-haloalkyl. Embodiment 42: A compound according to embodiment 39, wherein G² is -cycloalkyl, wherein the cycloalkyl group is substituted with one or more substituents independently selected from the group consisting of: -F, -Cl, -C_1-3 alkyl, -CF₃, -0-C_1-3 alkyl ,-0-CF₃, -CH₂-CF₃, and -C(O)-CF₃. Embodiment 43: A compound according to any one of embodiments 39 to 42, wherein G² is cyclopentyl or cyclohexyl.

Embodiment 44: A compound according to any one of embodiments 2 to 30, wherein one of R² and R³ is -L²-D²-G², wherein L² is -O- and D² is a direct bond or -alkylene-.

Embodiment 45: A compound according to embodiment 44, wherein D² is -CH₂- or -CH₂-

CH₂-.

Embodiment 46: A compound according to embodiment 44 or 45, wherein G² is phenyl. Embodiment 47: A compound according to embodiment 46, wherein G² is -phenyl, wherein the phenyl group is unsubstituted. Embodiment 48: A compound according to embodiment 46, wherein G² is -phenyl, wherein the phenyl group is substituted with one or more substituents independently selected from the group consisting of: halo, -alkyl, -haloalkyl, -O-alkyl, -O-haloalkyl, and - C(0)-haloalkyl. Embodiment 49: A compound according to embodiment 46, wherein G² is -phenyl, wherein the phenyl group is substituted with one or more substituents independently selected from the group consisting of: -F, -Cl, -C_1-3 alkyl, -CF₃, -0-C_1-3 alkyl , -0-CF₃, -CH₂- CF₃, and -C(O)-CF₃.

Embodiment 50: A compound according to embodiment 44 or 45, wherein G² is -cycloalkyl. Embodiment 51 : A compound according to embodiment 50, wherein G² is -cycloalkyl, wherein the cycloalkyl group is unsubstituted.

Embodiment 52: A compound according to embodiment 50, wherein G² is -cycloalkyl, wherein the cycloalkyl group is substituted with one or more substituents independently selected from the group consisting of: halo, -alkyl, -haloalkyl, -O-alkyl, -O-haloalkyl, and -C(0)-haloalkyl.

Embodiment 53: A compound according to embodiment 50, wherein G² is -cycloalkyl, wherein the cycloalkyl group is substituted with one or more substituents independently selected from the group consisting of: -F, -Cl, -C_1-3 alkyl, -CF₃, — O- CF₃, -CH₂-CF₃, and -C(O)-CF₃.

Embodiment 54: A compound according to any one of embodiments 50 to 53, wherein G² is a cyclopentyl or cyclohexyl group. Embodiment 55: A compound according to any one of embodiments 2 to 30, wherein one of

R² and R³ is -L²-D²-G², wherein L² is -NH- or -N(R⁶)- and D² is a direct bond or - alkylene-.

Embodiment 56: A compound according to embodiment 55, wherein D² is -CH₂- or -CH₂-

CH₂-, and R⁶ is -D³-G³, wherein D³ is -CH₂- or -CH₂-CH₂-. Embodiment 57: A compound according to embodiment 55 or 56, wherein G² and G³ are phenyl. Embodiment 58: A compound according to embodiment 57, wherein G² and G³ are -phenyl, wherein the phenyl groups are unsubstituted

Embodiment 59: A compound according to embodiment 57, wherein G² and G³ are -phenyl, wherein the phenyl groups are substituted with one or more substituents independently selected from the group consisting of: halo, -alkyl, -haloalkyl, -O-alkyl, -O-haloalkyl, and -C(O)-haloalkyl. Embodiment 60: A compound according to embodiment 57, wherein G² and G³ are -phenyl, wherein the phenyl groups are substituted with one or more substituents independently selected from the group consisting of: -F, -Cl, -C_1-3 alkyl, -CF₃, -0-C_1-3 alkyl , -0-CF₃, -CH₂-CF₃, and -C(O)-CF₃. Embodiment 61 : A compound according to embodiment 1 , wherein G¹ is imidazo[1 ,2- a]pyridin-2-yl, optionally substituted as described in embodiment 1. Embodiment 62: A compound according to embodiment 1 , wherein G¹ is imidazo[1 ,2- a]pyridin-3-yl, optionally substituted as described in embodiment 1. Embodiment 63: A compound according to embodiment 1 , 61 , or 62, wherein R⁵ is hydrogen.

Embodiment 64: A compound according to embodiment 1 , 61 , or 62, wherein R⁵ is alkyl. Embodiment 65: A compound according to embodiment 64, wherein R⁵ is methyl, ethyl, or isopropyl.

Embodiment 66: A compound according to embodiment 65, wherein R⁵ is methyl. Embodiment 67: A compound according to embodiment 1 , 61 , or 62, wherein R⁵ is - alkylene-J³-R^d, and J³ is -0-. Embodiment 68: A compound according to embodiment 67, wherein R⁵ is -alkylene-O-alkyl.

Embodiment 69: A compound according to embodiment 67, wherein R⁵ is -(CH₂)i_-3-(CH₂)o-i- CH₃.

Embodiment 70: A compound according to embodiment 67, wherein R⁵ is -(CH₂)₂-O-CH₃. Embodiment 71 : A compound according to embodiment 1 , 61 , or 62, wherein R⁵ is - alkylene-N(R^d)(R^e).

Embodiment 72: A compound according to embodiment 71 , wherein R⁵ is -CH₂CH₂- N(R^d)(R^e).

Embodiment 73: A compound according to embodiment 71 , wherein R⁵ is -CH₂CH₂- pyrrolidino, -CH₂CH₂-piperidino, -CH₂CH₂-morpholino, -CH₂CH₂-piperazino, - CH₂CH₂-(4-methyl-morpholino).

Embodiment 74: A compound according to any one of embodiments 1 and 61 to 73, wherein R¹ and R⁴ are both hydrogen.

Embodiment 75: A compound according to any one of embodiments 1 and 61 to 73, wherein one of R¹ and R⁴ is -halo, and the other is hydrogen. Embodiment 76: A compound according to any one of embodiments 1 and 61 to 73, wherein one of R¹ and R⁴ is alkyl, and the other is hydrogen or -halo. Embodiment 77: A compound according to any one of embodiments 1 and 61 to 76, wherein R³ is hydrogen. Embodiment 78: A compound according to any one of embodiments 1 and 61 to 76, wherein R³ is alkyl or haloalkyl. Embodiment 79: A compound according to any one of embodiments 1 and 61 to 76, wherein R³ is -halo. Embodiment 80: A compound according to any one of embodiments 1 and 61 to 79, wherein R² is -L²-D²-G². Embodiment 81 : A compound according to embodiment 80, wherein G² is -phenyl, which is optionally substituted as described in embodiment 1.

Embodiment 82: A compound according to embodiment 81 , wherein L² and D² are both a direct bond.

Embodiment 83: A compound according to embodiment 81 , wherein L² is -O- and D² is a direct bond. Embodiment 84: A compound according to embodiment 81 , wherein L² is a direct bond and

D² is -CH₂-. Embodiment 85: A compound according to embodiment 81 , wherein L² is -O- and D² is -

CH₂-. Embodiment 86: A compound according to embodiment 81 , wherein L² is -O- and D² is

-CH(CH₃)-.

Embodiment 87: A compound according to embodiment 81 , wherein L² is a direct bond and D² is -CH₂CH₂-.

Embodiment 88: A compound according to embodiment 81 , wherein L² is a direct bond and

D² is -CH=CH-. Embodiment 89: A compound according to any one of embodiments 81 to 88, wherein G² is

-phenyl, which is optionally substituted 1 or 2 times by substituents independently selected from the group consisting of halo, methyl, ethyl, isopropyl, tert-butyl, n- propyl, cyclopentyl, cyclohexyl, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n- propyloxy, -OH, -OCF₃, -OCH₂CF₃, cyclopentyloxy, cyclohexyloxy, pyrrolidino, piperidino, morpholino, piperazino, 4-methyl-piperazino, -O-(CH₂)₂-O-CH₃, -O-(CH₂)₃-

0-CH₃, -CN, -CO₂-CH₃, -CO₂-CH₂CH₃, and -SO₂CH₃. Embodiment 90: A compound according to any one of embodiments 81 to 88, wherein G² is

-phenyl, which is substituted 1 time by a substituent selected from the group consisting of halo, methyl, -CF₃, methoxy, and -OCF₃, and is also substituted 1 time by a substituent selected from the group consisting of halo, methyl, ethyl, isopropyl, tert-butyl, n-propyl, cyclopentyl, cyclohexyl, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -OH, -OCF₃, -OCH₂CF₃, cyclopentyloxy, cyclohexyloxy, pyrrolidino, piperidino, morpholino, piperazino, 4-methyl-piperazino, -O-(CH₂)₂-O- CH₃, -O-(CH₂)₃-O-CH₃, -CN, -CO₂-CH₃, -CO₂-CH₂CH₃, and -SO₂CH₃.

Embodiment 91 : A compound according to any one of embodiments 81 to 88, wherein G² is

-phenyl, which is substituted 1 time by a substituent selected from the group consisting of halo, methyl, ethyl, isopropyl, tert-butyl, n-propyl, cyclopentyl, cyclohexyl, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -OH, -

OCF₃, -OCH₂CF₃, cyclopentyloxy, cyclohexyloxy, pyrrolidino, piperidino, morpholino, piperazino, 4-methyl-piperazino, -O-(CH₂)₂-O-CH₃, -O-(CH₂)₃-O-CH₃, -CN₁ -CO₂-CH₃, -CO₂-CH₂CH₃, and -SO₂CH₃. Embodiment 92: A compound according to any one of embodiments 81 to 88, wherein G² is -phenyl, which is substituted 1 time by halo, and is also substituted 1 time by a substituent selected from the group consisting of halo, methyl, ethyl, isopropyl, tert- butyl, n-propyl, cyclopentyl, cyclohexyl, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -OH, -OCF₃, -OCH₂CF₃, cyclopentyloxy, cyclohexyloxy, pyrrolidino, piperidino, morpholino, piperazino, 4-methyl-piperazino, -O-(CH₂)₂-O-CH₃, -O-(CH₂)₃-

0-CH₃, -CN, -CO₂-CH₃, -CO₂-CH₂CH₃, and -SO₂CH₃.

Embodiment 93: A compound according to any one of embodiments 81 to 88, wherein G² is -phenyl, which is substituted 1 or 2 times by substituents independently selected from fluoro and chloro. Embodiment 94: A compound according to any one of embodiments 81 to 88, wherein G² is -phenyl, which is substituted once by methyl, ethyl, or isopropyl.

Embodiment 95: A compound according to any one of embodiments 81 to 88, wherein G² is -phenyl, which is substituted once by -CF₃.

Embodiment 96: A compound according to any one of embodiments 81 to 88, wherein G² is -phenyl, which is substituted once by -OCF₃.

Embodiment 97: A compound according to any one of embodiments 81 to 88, wherein G² is unsubstituted -phenyl.

Embodiment 98: A compound according to embodiment 80, wherein -L²-D²-G² is -cycloalkyl or -O-cycloalkyl, where the cycloalkyl group is optionally substituted as described in embodiment 1.

Embodiment 99: A compound according to embodiment 98, wherein -L²-D²-G² is cyclopentyl, cyclohexyl, cyclohexen-1-yl, cyclopentyloxy, or cyclohexyloxy, where each cycloalkyl group is optionally substituted one or more timed by substituents independently selected from the group consisting of halo, methyl, ethyl, isopropyl, - CF₃, -OCH₂CF₃, methoxy, -OCF₃, and -N(CH₃)₂. Embodiment 100: A compound according to embodiment 80, wherein -L²-D²-G² is - heterocyclyl, where the heterocyclyl group is optionally substituted as described in embodiment 1.

Embodiment 101 : A compound according to embodiment 100, wherein -L²-D²-G² is pyrrolidino, piperidino, or piperazino, where each heterocyclyl group is optionally substituted one or more times by substituents independently selected from the group consisting of halo, phenyl, methyl, ethyl, isopropyl, -CF₃, -OCH₂CF₃, methoxy, -OCF₃, and -N(CHs)₂.

Embodiment 102: A compound according to embodiment 80, wherein -L²-D²-G² is - heteroaryl, where the heteroaryl group is optionally substituted as described in embodiment 1.

Embodiment 103: A compound according to embodiment 102, wherein -L²-D²-G² is 2- pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl, 1 H-pyrrol-1- yl, 1 H-pyrrol-2-yl, 1 H-pyrrol-3-yl, 1 H-pyrazol-1-yl, 1 H-pyrazol-3-yl, 1 H-pyrazol-4-yl,

1 H-pyrazol-5-yl, 1 H-imidazol-1-yl, 1 H-imidazol-2-yl, 1 H-imidazol-4-yl, or 1H-imidazol- 5-yl, where each heteroaryl group is optionally substituted one or more timed by substituents independently selected from the group consisting of halo, phenyl, methyl, ethyl, isopropyl, -CF₃, -OCH₂CF₃, methoxy, -OCF₃, and -N(CH₃)₂. Embodiment 104: A compound according to any one of embodiments 1 and 62 to 103, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, optionally substituted as described in embodiment 1 , except that the substituent at the 3-position of the imidazo[1 ,2- a]pyridin-2-yl group is selected from the group consisting of hydrogen, halo, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -CF₃, -CH₂CF₃, -O-CF₃, -N(CH₃)₂, phenyl, and benzyl.

Embodiment 105: A compound according to embodiment 104, wherein G¹ is imidazo[1 ,2- a]pyridin-2-yl, optionally substituted as described in embodiment 1 , except that the substituent at the 3-position of the imidazo[1 ,2-a]pyridin-2-yl group is selected from the group consisting of hydrogen, halo, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -CF₃, -CH₂CF₃, -0-CF₃, and -N(CH₃)₂.

Embodiment 106: A compound according to embodiment 105, wherein G¹ is imidazo[1 ,2- a]pyridin-2-yl, optionally substituted as described in embodiment 1 , except that the substituent at the 3-position of the imidazo[1 ,2-a]pyridin-2-yl group is hydrogen.

Embodiment 107: A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is optionally substituted 1 or 2 times with substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n- propyloxy, -NH-CH₃, and -N(CH₃)₂.

Embodiment 108: A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with phenyl or benzyl; and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH-CH₃, and -N(CH₃)₂.

Embodiment 109: A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with -(CH₂)OH, -CH₂CH₂OH, or - OCH₂CH₂OH; and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, - CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH-CH₃, and -N(CH₃)₂. Embodiment 110: A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with -C≡C-C(CH₃)₂-OH or -C≡C-CH₂OH; and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH-CH₃, and -N(CH₃)₂. Embodiment 111 : A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with piperidin-4-yl, 1-methyl-piperidin-4-yl, - O-(piperidin-4-yl) or -O-(1-methyl-piperidin-4-yl); and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy,

-NH-CH₃, and -N(CH₃J₂.

Embodiment 112: A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with pyrrolidino, 3-hydroxyl-piperidino, 3- methoxy-piperidino, morpholino, piperazino, 4-methyl-piperazino, piperidino, or 4- hydroxypiperidino; and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, - CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH-CH₃, and -N(CH₃)₂. Embodiment 113: A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with -CH₂-pyrrolidino, -CH₂-(3-hydroxyl- piperidino), -CH₂-(3-methoxy-piperidino), -CH₂-morpholino, -CH₂-piperazino, -CH₂-(4- methyl-piperazino), -CH₂-piperidino, or -CH₂-(4-hydroxypiperidino); and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH-CH₃, and -N(CH₃)₂. Embodiment 114: A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with -0-CH₂-pyrrolidino, -O-CH₂-morpholino, -O-CH₂-piperazino, -O-CH₂-(4-methyl-piperazino), or -O-CH₂-piperidino; and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH-CH₃, and -N(CH₃)₂.

Embodiment 115: A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with -NH-(CH₂)_2-3-O-CH₃, -O-(CH₂)₂.₃-O-CH₃, or -O-(CH₂)₂.₃-N(CH₃)₂; and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, - CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH-CH₃, and -N(CH₃)₂. Embodiment 116: A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with -CH₂-NH-(CH₂)₂.₃-O-CH₃, -CH₂-NH- (CH₂)_2-3-OH, -CH₂-O-(CH₂)_2-3-O-CH₃, -CH₂-NH-(CH₂)_2-3-N(CH₃)_2l -CH₂-NH-(CH₂)₂.₃- morpholino, -CH₂-NH-(CH₂)_2-3-piperazino, -CH₂-NH-(CH₂)_2-3-(4-methyl-piperazino), or -CH₂-O-(CH₂)_2-3-N(CH₃)₂; and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2- yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, - CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH-CH₃, and -N(CH₃)₂. Embodiment 117: A compound according to any one of embodiments 104 to 106, wherein

G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with -CH₂-N(R^d)(R^e), where R^e is hydrogen or methyl, and R^d is methyl, ethyl, isopropyl, tert-butyl, n-propyl, isobutyl, phenyl, benzyl, 4-pyridyl, -CH₂-(4-pyridyl), cyclopentyl, or cyclohexyl; and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH-CH₃, and -N(CH₃)₂.

Embodiment 118: A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with -CH₂-N(R^d)(R^e), where R⁸ is hydrogen, and R^d is 2-hydroxyl-2-phenyl-ethyl or 1-hydroxyl-3-phenyl-prop-2-yl; and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH-CH₃, and -N(CH₃)₂. Embodiment 119: A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with 4-pyridyl or 1-methyl-pyrazol-4-yl; and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH-CH₃, and -N(CH₃)₂.

Embodiment 120: A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2-

^•— / NH *— / N— a]pyridin-2-yl group is substituted 1 time with > — / , \ — / , piperidin-4- yl, or 1-methyl-piperidin-4-yl; and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH-CH₃, and - N(CH₃)₂. Embodiment 121 : A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with R^a; and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH- CH₃, and -N(CH₃J₂.

Embodiment 122: A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with J¹-alkylene-J²-R^b; and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH-CH₃, and -N(CH₃)₂. Embodiment 123: A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with -CH₂-J¹-alkylene-J²-R^b; and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH-CH₃, and -N(CH₃)₂.

Embodiment 124: A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with -J¹-alkylene-N(R^d)(R^e); and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH-CH₃, and -N(CH₃)₂. Embodiment 125: A compound according to any one of embodiments 104 to 106, wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, and the pyridine ring portion of the imidazo[1 ,2- a]pyridin-2-yl group is substituted 1 time with -CO₂R^d or -C(O)-N(R^d)(R^e); and the pyridine ring portion of the imidazo[1 ,2-a]pyridin-2-yl group is also optionally substituted 1 time with a substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, tert-butyl, isobutyl, halogen, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -NH-CH₃, and -N(CH₃)₂. Embodiment 126: A compound according to any one of embodiments 1 to 125, wherein R⁵ is hydrogen and the benzimidazole exists in the following tautomeric form:

Embodiment 127: A compound according to any one of embodiments 1 to 125, wherein R⁵ is hydrogen and the benzimidazole exists in the following tautomeric form:

Embodiment 128: A compound according to any one of embodiments 1 to 125, wherein R⁵ is hydrogen and the benzimidazole exists in the following tautomeric form:

Embodiment 129: A compound according to any one of embodiments 1 to 128, wherein the compound exists in its free (non-salted) form. Embodiment 130: A compound according to any one of embodiments 1 to 128, wherein the compound exists as a pharmaceutically acceptable salt. Embodiment 131 : A compound according to embodiment 130, wherein the compound exists as a hydrochloride salt.

General Experimental Section

The routes below illustrate general methods of synthesizing compounds of Formula (I), tautomers of compounds of Formula (I), and/or pharmaceutically acceptable salts of either of the foregoing. The skilled artisan will appreciate that the compounds of the invention could be made by methods other than those specifically described herein, by adaptation of the methods described herein and/or by adaptation of methods known in the art. In general, compounds of the invention may be prepared in a multi-step synthesis, as shown below. All quantities shown are approximate, and are given solely for illustrative purposes. The following abbreviations may be used in describing reaction conditions, common reagents, common solvents, or methods of analysis.

AcOH = acetic acid

CDI = carbonyldiimidazole Cy = cyclohexyl

DBU = 1 ,8-diazabicyclo[5.4.0]undec-7-ene

DCE = 1 ,2-dichloroethane

DCM = dichloromethane

DIAD = diisopropylazodicarboxylate DIEA = diisopropylethylamine

DMAP = N,N'-dimethylamino pyridine

DME = 1 ,2-dimethoxyethane

DMF = N.N'-dimethylformamide

DMSO = dimethylsulfoxide DPPA = diphenylphosphoryl azide

EDCI = EDC = i-ethyl-S-CS-dimethylaminopropyOcarbodiimide hydrochloride

EtOAc = EA = ethyl acetate

EtOH = ethanol

¹H NMR = proton NMR analysis HBTU = 2-(1 H-benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate

HCI = hydrochloric acid hex = hexanes

HOBt = 1-hydroxybenzotriazole

LCMS = liquid chromatography- mass spectrometry analysis L-DOPA = l-3,4-dihydroxyphenylalanine

MTBE = methyl tert-butyl ether

MeOH = methanol

NEt₃ = triethylamine

NMM = N-methyl-morpholine PPh₃ = triphenylphosphine

Ph = phenyl

TEA = triethylamine

TBAF = tetrabutylammonium fluoride

TFA = trifluoroacetic acid THF = tetrahydrofuran

TLC = thin layer chromatography rt = r.t. = RT = room temperature h = hour min = minutes M = molar concentration N = normal concentration uL = ul = microliters eq. = eq = equiv = molar equivalents mL = ml = milliliters ug = micrograms mg = milligrams g = grams wt = wt. = weight

Synthesis of a substituted 2-aminobenzimidazole. General Procedure 1. To a mixture of 4-bromo-2-nitroaniline (1 mmol), a boronic acid (1.5 mmol), and Na₂CO₃ (3 mmol), toluene (10 mL) and water (5 mL) are added. The resulting mixture is purged with nitrogen for 10 minutes. Then, tetrakis(triphenylphosphine)palladium (0.05 mmol) is added, and the reaction mixture is heated at reflux for 4 hours under nitrogen. The reaction mixture is then cooled to room temperature and filtered through Celite, and then is washed with ethyl acetate. The organic layer is separated and dried over sodium sulfate, and then concentrated and purified by column chromatography using a silica gel stationary phase and ethyl acetate in hexanes as an eluent. The purified solution contains a 4-substituted-2-nitroaniline compound.

The 4-substituted-2-nitroaniline compound (1 mmol) is taken up into solution using an ethyl acetate-methanol mixture (about 1 :1). To this solution, Pd-C is added, and the resulting mixture is stirred under a hydrogen atmosphere for about 6 hours. Then, the solution is filtered on Celite, washed with methanol, and then concentrated until the characteristic dark-brown color of a diamine is apparent. The diamine compound is taken up into methanol, and CNBr (1 mmol) would be added. The resulting mixture is stirred at room temperature for about 30 minutes. The solution is then concentrated to dryness, and residual methanol is removed by co-evaporating with toluene about 3 times, followed by drying to obtain a substituted 2-aminobenzimidazole derivative as a hydrobromide salt. The reaction scheme below provides an illustration that accompanies this textual description. Suzuki

General Procedure 2. To a mixture of 4-bromo-benzene-1 ,2-diamine (1 mmol), a boronic acid (1.5 mmol), and Na₂CO₃ (3 mmol), toluene (10 ml_) and water (5 ml_) are added. The resulting mixture is purged with nitrogen for 10 minutes. Then, tetrakis(triphenylphosphine)palladium (0.05 mmol) is added, and the mixture is heated at reflux for 4 hours under nitrogen. The reaction mixture is then cooled to room temperature and filtered through Celite, and then is washed with ethyl acetate. The organic layer is separated and dried over sodium sulfate, and then concentrated and purified by column chromatography using a silica gel stationary phase and ethyl acetate in hexanes as an eluent. The purified solution contains a 4-substituted-1 ,2-diaminophenyl compound. The diamine compound is taken up into methanol, and CNBr (1 mmol) is added. The resulting mixture is stirred at room temperature for about 30 minutes. The solution is then concentrated to dryness, and residual methanol is removed by co-evaporating with toluene about 3 times, followed by drying to obtain a substituted 2-aminobenzimidazole derivative as hydrobromide salt. The reaction scheme below provides an illustration that accompanies this textual description.

General Procedure 3. A mixture of 5-fluoro-2-nitro-phenylamine (1 mmol), an alcohol (2 mmol), and potassium tert-butoxide (3 mmol) in THF (20 rmL) are heated at about 60 ⁰C overnight. After cooling the mixture to room temperature, water is added and then the mixture is extracted with ethyl acetate. The organic layer is washed with brine and dried over Na₂SO₄ and then concentrated. The crude material is purified on a silica gel column to yield a 5-alkyloxy-2-nitro-phenylamine. The 5-alkyloxy-2-nitro-phenylamine (1.0 mmol) is dissolved in an ethyl acetate-methanol mixture (about 1 :1 , 10 mL) in a round-bottom flask. To this solution Pd-C is added, and the mixture is stirred under a hydrogen atmosphere, while monitoring the reaction with thin-layer chromatography (TLC). After TLC shows substantial completion of the reaction, the solution is filtered on Celite and then washed with methanol and concentrated to obtain a 4-alkyloxy-benzene-1 ,2-diamine. The 4-alkyloxy- benzene-1 ,2-diamine (1 mmol) is dissolved in ethanol and CNBr (1.5 mmol) is added. The resulting dark brown solution would is at 60 ⁰C for 30 minutes. Thereafter, the mixture is cooled to room temperature, and the solvent is evaporated. Then the mixture is co- evaporated with toluene about two times to obtain a 5-alkyloxy-1 H-benzoimidazol-2-ylamine as a hydrobromide salt. The reaction scheme below provides an illustration that accompanies this textual description.

THF

General Procedure 4. A mixture of 5-fluoro-2-nitro-phenylamine (1 mmol), an amine (2 mmol) in THF (20 mL) is heated at about 60 °C overnight. After cooling the mixture to room temperature, the reaction mixture is concentrated. The crude material is purified on a silica gel column to yield a 5-amino-2-nitro-phenylamine. The 5-amino-2-nitro-phenylamine (1.0 mmol) is dissolved in an ethyl acetate-methanol mixture (about 1 :1 , 10 mL) in a round- bottom flask. To this solution Pd-C is added, and the mixture is stirred under a hydrogen atmosphere, while monitoring the reaction with thin-layer chromatography (TLC). After TLC shows completion of the reaction, the solution is filtered on Celite and then washed with methanol and concentrated to obtain a 4-amino-benzene-1 ,2-diamine. The 4-amino- benzene-1 ,2-diamine (1 mmol) is dissolved in ethanol and CNBr (1.5 mmol) is added. The resulting dark brown solution is heated at 60 ^°C for 30 minutes. Thereafter, the mixture is cooled to room temperature, and the solvent is evaporated. Then, the mixture is co- evaporated with toluene about two times to obtain a 5-amino-1 H-benzoimidazol-2-ylamine as a hydrobromide salt. The reaction scheme below provides an illustration that accompanies this textual description.

Synthesis of a substituted 2-aminobenzimidazole amide.

General Procedure 5. A mixture of a carboxylic acid (1 mmol), HBTU (1 mmol) and DIEA (3 mmol) in DMF (3 mL) are heated at 80 ^°C for 10 minutes. To this reaction mixture a substituted 2-aminobenzimidazole hydrobromide salt (1 mmol) is added, and the mixture continues to be heated at 80 ^"C for 30 minutes. After cooling the reaction mixture to room temperature, an aqueous sodium bicarbonate solution is added, and the mixture is stirred for 30 minutes. The mixture is then filtered, washed with water, and purified on silica gel column to yield a substituted 2-aminobenzimidazole amide. The reaction scheme below provides an illustration that accompanies this textual description.

Synthesis of substituted lmidazo[1 ,2-a]pyridine-2-carboxylic acid esters.

General Procedure 6. To the solution of a 2-amino-pyridine (10 mmol) in ethanol (50 mL) is added ethyl bromopyruvate (12.0 mmol), and refluxed for 2 hr. The reaction mixture is cooled to room temperature, and the volatiles are evaporated on rotavapor. Then, it is stirred in aqueous sodium bicarbonate solution for 1 hour. The resulting mixture is then filtered and the product is washed with water and dried to obtain an imidazo[1 ,2-a]pyridine-2- carboxylic acid ethyl ester.

Synthesis of substituted lmidazo[1 ,2-a]pyridine-2-carboxylic acids

General Procedure 7: Acid Hydrolysis. lmidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (50 mmol) is added to concentrated hydrochloric acid (50 mL) and dioxane (50 mL), and is refluxed over night. The resulting solution is concentrated under vacuum, washed with acetone, and dried to obtain the product, an imidazo[1 ,2-a]pyridine-2-carboxylic acid.

General Procedure 8: Basic Hydrolysis. To a solution of an imidazo[1 ,2-a]pyridine-2- carboxylic acid ethyl ester (1 mmol) in methanol/THF/water (v/v/v = 2/2/1 mL) is added NaOH (3 mmol), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is then neutralized with citric acid (1 mmol) and concentrated on a rotavapor. The obtained residue is stirred in DCM-methanol (1 :1), is then filter through a pad of Celite, and then washed with DCM-methanol (1 :1). The combined filtrates are concentrated, and the residues are purified by silica gel flash chromatography to obtain the product.

General Procedure 9. To a stirring solution of alcohol (4.0 mmol) in dry THF (5 mL) sodium hydride (60% dispersion in mineral oil, 6.0 mmol) is added, then a halo-imidazo[1 ,2- a]pyridine-2-carboxylic acid ethyl ester (3.0 mmol) is added and the reaction mixture is heated to 50 ⁰C for 1 hour. The reaction mixture is cooled to room temperature, quenched carefully with water, and extracted into ethyl acetate. The organic layer is washed with brine, dried on sodium sulfate, and evaporated. The resulting crude intermediate is hydrolyzed using General Procedure 8 to obtain an alkoxy-substituted imidazo[1 ,2-a]pyridine-2- carboxylic acid.

Synthesis of amino substituted lmidazo[1 ,2-a]pyridine-2-carboxylic acid amides.

General Procedure 10. A halo-imidazo[1 ,2-a]pyridine-2-carboxylic acid amide (0.1 mmol) and amine (0.5 mmol) in dry 1-methyl-2-pyrrolidinone are heated under nitrogen at 90 ^°C for 8-10 hours. The reaction mixture is then cooled to room temperature, water is added, and the mixture is then extracted into ethyl acetate. The organic layer is washed with brine, dried on sodium sulfate, and then concentrated and purified by silica gel flash chromatography using 10% methanol in DCM to obtain a 5-amino-imidazo[1 ,2-a]pyridine-2- carboxylic acid amide.

Synthesis of amino substituted lmidazo[1 ,2-a]pyridine-2-carboxylic acid esters

General Procedure 11. A mixture of bromo-imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (5.0 mmol) amine (5.0 mmol), palladium (O) bis(dibenzylideneacetone) (2.5 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.5 mmol) and cesium carbonate (10 mmol) in dry 1-methyl-2-pyrrolidinone (20 mL) is heated under nitrogen at 100 ⁰C for 8- 10 hours. The reaction mixture is then cooled to room temperature, water is added, and the resulting mixture is extracted into ethyl acetate. The organic layer is washed with brine, dried on sodium sulfate, concentrated and purified by silica gel flash chromatography using 10% of MeOH in DCM to obtain an amino-imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester.

Sonogashira reaction of halo-imidazo[1 ,2-a]pyridine-2-carboxylic acid ester.

General Procedure 12. To a bromo-imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (5.0 mmol) in THF (10 mL) and toluene (10 mL) is added bis(triphenylphosphine)palladium(ll) dichloride (1.0 mmol), copper (I) iodide (1.0 mmol), 1 ,8- diazabicyclo[5.4.0]undec-7-ene (10 mmol) and alkyne (10 mmol). The resulting mixture is stirred at 90 ^°C for 8-10 hours. The resulting mixture is condensed under vacuum, purified by silica gel flash chromatography using 10% of MeOH in DCM to yield an alkynyl- imidazo[1 ,2-ajpyridine-2-carboxylic acid ethyl ester.

Mitsunobu reaction of phenolic compounds

General Procedure 13. To a solution of an alcohol (5 mmol) in dry THF (10 mL), Ph₃P (7.5 mmol) and DIAD (7.5 mmol) are added at 0 ^°C . After stirring the reaction mixture for about 20 minutes, phenol is added in one portion. The dark-colored mixture is stirred at room temperature until LCMS shows substantial completion of the reaction. The reaction mixture is then concentrated on a rotavapor and is purified on silica gel column to obtain an ether.

Deprotection of alcohols

General Procedure 14. To a solution of a tetrahydro-pyran-2-yloxy derivative (0.1 mmol) in methanol (3 ml_), p-toluenesulfonic acid monohydrate (40 mg) is added. The reaction mixture is then stirred until LCMS shows substantial completion of the reaction. The resulting mixture is evaporated to remove substantially all of the volatiles. The mixture is then purified on a silica gel column using 2M ammonia-methanol in DCM as an eluent to obtain the an alcohol.

Preparation of silyloxymethyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid:

General Procedure 15. To a solution of pyridine-2-carboxylic acid (5 mmol) in methanol (20 mL), SOCI₂ (0.6 mL) is added. The resulting mixture is then refluxed overnight. Then, the reaction mixture is cooled to room temperature and concentrated on a rotavapor. To the resulting residue is added ethyl acetate (50 mL) and aqueous saturated sodium carbonate solution (50 mL). The organic phase is then separated, dried over sodium sulfate, concentrated, and then purified using a silica gel column to obtain a methyl ester.

To the ester (5 mmol) in dry THF (20 ml), a 2 M LiAIH₄ solution in THF (12 mmol) is added at -78 °C . The reaction mixture is slowly warmed to room temperature, and is stirred at the same temperature for 3 hours. The reaction mixture is then cooled in an ice bath and quenched by addition of saturated aqueous sodium sulfate solution. This reaction mixture is then stirred at room temperature for 15 minutes, the organic layer is decanted, and the residue is rinsed with ethyl acetate (50 mL). The combined organic layers are washed with brine, dried over Na₂SO₄, filtered and concentrated to obtain the product, which is used in the subsequent step without purification To a solution of 2-amino-pyridine (5 mmol) in ethanol (20 mL), ethyl bromopyruvate

(6.0 mol ) is added, and the reaction mixture is refluxed for 2 hours. The reaction mixture is then cooled to room temperature, the volatiles are evaporated on a rotavapor. The resulting product is purified by silica gel flash chromatography using ethyl acetate as an eluent to obtain the product. To a solution of hydroxymethyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (2 mmol) and imidazole (0.5g) in DMF (5 ml_), chloro-triisopropyl-silane (3 mL) is added slowly at room temperature. The reaction mixture is then heated at 70 °C for 2 hours. After the reaction mixture is cooled to room temperature, saturated sodium carbonate solution (50 mL) and extracted into ethyl acetate (50 mL) are added. The organic phase is washed with brine, dried over sodium sulfate and concentrated on rotavapor. The obtained residue is purified on a silica gel column to obtain a silyloxymethyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester.

To a solution of imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (2 mmol) in methanol/THF/water (v/v/v= 2/2/1) LiOH monohydrate (3 mmol) is added. The reaction mixture is then stirred at room temperature for 1 hour, and is then quenched by addition of acetic acid (0.4 mL). All of the volatiles are removed on rotavapor. The resulting residue is purified by silica gel flash chromatography to obtain an acid.

Synthesis of aminomethyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid amides

General Procedure 16. To a silyl derivative (1 mmol) in THF, 1 M TBAF in THF (2 mL) is added. The reaction mixture is stirred at room temperature overnight. After LCMS indicated the substantial completion of the reaction, all of the volatiles are evaporated on rotavapor. The obtained residue is purified by silica gel flash chromatography to obtain an alcohol.

The alcohol (0.5 mmol) is mixed with triethyl amine (0.4 mL) in DCM (3 mL), and the resulting mixture is cooled in an ice bath. Methanesulfonyl chloride (0.2 mL) is added slowly. The reaction mixture is slowly warmed to room temperature and is stirred at the same temperature for 1 hour. After LCMS indicates substantial completion of the reaction, an alkylamine (10 mmol) is added, and the mixture is stirred at room temperature until LCMS indicates substantial completion of the reaction. The volatiles are then evaporated on rotavapor and purified by silica gel flash chromatography to obtain the product.

To further illustrate how to make compounds of Formula (I), the following example syntheses are provided. These examples are provided as illustrations only. The procedures may be modified according to the knowledge of skilled artisans. Other compounds of the invention may be synthesized in an analogous manner to that shown for the examples below, although such compounds may be synthesized in other ways as well, according to the knowledge of skilled artisans.

Example 1

5-Methyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1 H- benzoimidazol-2-yl]~amide

Step 1. 4-Bromo-benzene-1 ,2-diamine (0.5 g), 3-(trifluoromethyl) phenylboronic acid (1.01 g) in DME (10 mL) and 2.0 N Na₂CO₃ (3.3 mL) was degassed with nitrogen for 15 minutes. Then, tetrakis(triphenylphosphine)palladium (0.15 g) was added and the mixture was heated at 90 ^"C overnight under nitrogen. The mixture was then cooled to room temperature, the organic layer was separated, washed with water, brine, dried (Na₂SO₄), filtered and concentrated under reduced pressure to get 3'-trifluoromethyl-biphenyl-3,4- diamine which was used in the next step without further purification. Step 2. The crude 3'-trifluoromethyl-biphenyl-3,4-diamine, CNBr (0.43 g), and H₂O

(2.0 mL) in ethanol (10 mL) was refluxed for 30 minutes. The mixture was then cooled to room temperature, and the solvent was evaporated. The resulting solid was washed with ethyl acetate, ether, and then dried to obtain 5-(3-trifluoromethyl-phenyl)-1 H-benzoimidazol- 2-ylamine dihydrobromide salt (0.45 g). LCMS (m/z): 278.7. Step 3. To a stirring solution of 5-(3-trifluoromethyl-phenyl)-1 H-benzoimidazol-2- ylamine dihydrobromide salt (0.095 g), 5-methyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid (0.042 g) and HBTU (0.1 g) in DMF, DIEA (0.051 g) was added. The reaction mixture was heated to 90 ⁰C for 2.0 hours. The mixture was cooled to room temperature, and then a saturated NaHCO₃ solution was added and the resulting solid was filtered and dried. The solid was dissolved in DCM and purified by silica gel flash chromatography using 1.5% of MeOH in DCM to obtain the title compound (20 mg). LCMS (m/z): 436.7. ¹H NMR (400 MHz, CD₃OD): δ 2.91 (3H, s), 7.42 (1 H, d), 7.09 (2H, t), 7.80 (2H, d), 7.83 (2H, d), 7.94-7.97 (3H, m), 7.98-8.02(1 H, m) 9.11 (1 H, s) ppm. Example 2

5-(Piperidin-4-yloxy)-imidazo[1 ,2-a]pyridine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-

1 H-benzoimidazol-2-yl]-amide trihydrochloride

Step 1. To 2-amino-6-chloropyridine (12.9 g) in ethanol (100 ml_) was added ethyl bromopyruvate (39.6 ml_) and stirred under reflux for 3 hours. The reaction mixture became a brown color. The reaction mixture was cooled to room temperature, and ethyl acetate was added to precipitate the product, which was filtered, washed with ethyl acetate and dried to give δ-chloro-imidazoli ^-ajpyridine^-carboxylic acid ethyl ester (17.2 g). LCMS (m/z): 225.2. Step 2. To a stirring solution of 4-hydroxy-piperidine-i-carboxylic acid tert-butyl ester

(804 mg) in dry THF (5 ml_) was added sodium hydride (60% dispersion in mineral oil, 240 mg), then 5-chloro-imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (674 mg) was added and the reaction mixture was heated to 50 ^°C for 1 hour. The resulting mixture was cooled to room temperature, quenched carefully with ice, and partitioned between ethyl acetate and water. The organic layers were evaporated and the resulting crude intermediate was hydrolyzed with lithium hydroxide (1.3 g) in 1 :1 methanol/water (10 mL) by heating to 100 °C for 0.5 hour. The resulting mixture was partitioned between ethyl acetate and water and organic layers were evaporated to give a solid, which was dissolved in DMF (5 mL), and to which was added 5-(3-trifluoromethyl-phenyl)-1 H-benzoimidazol-2-ylamine dihydrobromide salt (878 mg), HBTU (760 mg) and DIEA (0.70 mL). The resulting mixture was heated to 90 °C for 1 hour and then cooled to room temperature. Water was added and the resulting solid was filtered, dried, and purified by silica gel flash chromatography using 10% MeOH in DCM to obtain 4-{2-[5-(3-trifluoromethyl-phenyl)-1 H-benzoimidazol-2-ylcarbamoyl]-imidazo[1 ,2- a]pyridin-5-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (782 mg). LCMS (m/z): 621.8. Step 3. To a stirring solution of 4-{2-[5-(3-trifluoromethyl-phenyl)-1 H-benzoimidazol-

2-ylcarbamoyl]-imidazo[1 ,2-a]pyridin-5-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (780 mg) in DCM (2 mL) was added 4 N HCI in dioxane (2 mL). The mixture was stirred at room temperature for 1 hour, condensed, and triturated with hexanes to obtain the title compound (564 mg). LCMS (m/z): 521.9. ¹H NMR (400 MHz, DMSO-d6): δ 1.61-1.97 (4H, m), 2.88-3.63 (4H, m), 3.93 (1 H, m), 7.12 (1 H, d), 7.70-8.05 (10H, m), 8.70 (1 H, s) ppm.

Example 3

5-(1 -Methyl-piperidin-4-yloxy)-imidazo[1 ,2-a]pyridine-2-carboxylic acid [5-(3-trifluoromethyl- phenyl)-1 H-benzoimidazol-2-yl]-amide To a solution of 5-(piperidin-4-yloxy)-imidazo[1 ,2-a]pyridine-2-carboxylic acid [5-(3- trifluoromethyl-phenyl)-1 H benzoimidazol-2-yl]-amide trihydrochloride (315 mg) in dichloromethane (5 mL) was added formaldehyde solution in water (37%, 0.25 ml_), and 1 drop of acetic acid. Then sodium triacetoxyborohydride (530 mg) was added. Then, the mixture was stirred at room temperature for 0.5 hour, and then condensed. It was then diluted with water/EtOAc and neutralized with NaHCO₃ powder. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using 10% of MeOH in DCM to give the title compound (208 mg). LCMS (m/z): 535.9. ¹H NMR (400 MHz, DMSO- d6): δ 1.60-1.98 (4H, m), 2.79 (3H, s), 2.86-3.63 (4H, m), 3.93 (1 H, m), 7.12 (1 H, d), 7.72- 8.04 (10H, m), 8.70 (1 H, s) ppm.

Example 4

5-Methoxy-imidazo[1 ,2-a]pyridine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1 H- benzoimidazol-2-yl]-amide To a stirring solution of 5-chloro-imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester

(674 mg) in dry THF (5 mL) was added sodium methoxide (324 mg), and the reaction mixture was heated to 50 °C for 1 hour. The resulting mixture was cooled to room temperature, quenched with ice, and partitioned between ethyl acetate and water. The organic layers were evaporated and the resulting crude intermediate was hydrolyzed with lithium hydroxide (1.3 g) in 1 :1 methanol/water (10 mL) by heating to 100 ^°C for 0.5 hour. The resulting mixture was partitioned between ethyl acetate and water, and the organic layers were evaporated to give a solid, which was dissolved in DMF (5 mL), to which was added 5-(3-trifluoromethyl-phenyl)-1 H-benzoimidazol-2-ylamine dihydrobromide salt (878 mg), HBTU (760 mg) and DIEA (0.70 mL). The resulting mixture was heated to 90 ⁰C for 1 hour then cooled to room temperature. Water was added and the resulting solid was filtered, dried and purified by silica gel flash chromatography using 10% of MeOH in DCM to obtain the title compound (311 mg). LCMS (m/z): 452.9. ¹H NMR (400 MHz, CD3OD): δ 3.58 (3H, S)₁ 7.43 (1 H, d), 7.68-8.05 (9H, m), 9.17 (1 H, s) ppm.

Example 5

6-((R)-3-Hydroxy-pyrrolidin-1-yl)-5-methyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid [5-(3- chloro-5-fluoro-phenyl)-1 H-benzoimidazol-2-yl]-amide

Step 1. 6-Amino-3-bromo-2-methylpyridine (18.7 g) in ethanol (100 mL) was added ethyl bromopyruvate (39.6 mL) and stirred under reflux for 3 hour. The reaction mixture became a brown color. It was cooled to room temperature, and ethyl acetate was added to precipitate the product, which was filtered, washed with ethyl acetate and dried to give 6- bromo-5-methyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (22.9 g). LCMS (m/z): 283.6. ¹H NMR (400 MHz, DMSO-d6): δ 1.42 (3H₁ 1), 2.90 (3H, s), 4.47 (2H, q), 7.70 (1 H, d), 8.09 (1H, d), 8.95 (1H, s) ppm.

Step 2. 6-Bromo-5-methyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (1.42 g) in dry 1-methyl-2-pyrrolidinone (20 mL) was added (R)-(+)-3-pyrrolidinol (435 mg), palladium (0) bis(dibenzylideneacetone) (1.44 g), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (1.45 g) and cesium carbonate (3.26 g) and the mixture was heated under nitrogen at 100 ^"C for 8-10 hours. The mixture was then cooled to room temperature, partitioned between ethyl acetate and water, and the organic layer was evaporated and the resulting mixture was purified by silica gel flash chromatography using 10% of MeOH in

DCM to obtain 6-((R)-3-hydroxy-pyrrolidin-1-yl)-5-methyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester, which was suspended in 1 :1 methanol and water (5 mL), added sodium hydroxide (160 mg). The reaction mixture was heated to 100 ⁰C for 1 hour. The mixture was cooled to room temperature, neutralized with dilute aqueous hydrochloric acid to pH about 6-7. The solvents were evaporated, and the resulting solid was dissolved in THF and purified by silica gel flash chromatography using 10% of MeOH in DCM to obtain 6-((R)-3- hydroxy-pyrrolidin-i-yO-δ-methyl-imidazoti ^-alpyridine^-carboxylic acid (60 mg). LCMS (m/z): 262.3.

Step 3. To a stirring solution of 5-(3-chloro-5-fluoro-phenyl)-1 H-benzoimidazol-2- ylamine dihydrobromide salt (85 mg), 6-((R)-3-hydroxy-pyrrolidin-1-yl)-5-methyl-imidazo[1 ,2- a]pyridine-2-carboxylic acid (52 mg) and HBTU (83 mg) in DMF (1 mL), DIEA (51 mg) was added. Reaction mixture was heated to 90 ^°C for 1 hour. The mixture was cooled to room temperature, water was added and the resulting solid was filtered and dried and purified by silica gel flash chromatography using 10 % of MeOH in DCM to obtain the title compound (62 mg). LCMS (m/z): 505.8. ¹H NMR (400 MHz, DMSO-d6): δ 1.59-1.82 (2H, m), 2.65-2.95

(8H, m), 6.91 (1 H, d), 7.29 (1 H, d), 7.39 (1 H, t), 7.48-7.62 (5H, m), 7.81 (1 H, s), 8.60 (1 H, s) ppm.

Example 6

6-(3-Hydroxy-3-methyl-but-1-ynyl)-5-methyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid [5-(3- trifluoromethyl-phenyl)-1 H-benzoimidazol-2-yl]-amide

Step 1. 6-Bromo-5-methyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (1.42 g) in THF (10 mL) and toluene (10 mL) was added bis(triphenylphosphine)palladium(ll) dichloride (702 mg), copper (I) iodide (190 mg), 1 ,8-diazabicyclo[5.4.0]undec-7-ene (1.50 mL) and 2-methyl-3-butyn-2-ol (0.97 mL), stirred at 90 ^°C for 8-10 hours. The resulting mixture was condensed under vacuum, purified by silica gel flash chromatography using 10% of MeOH in DCM to give 6-(3-hydroxy-3-methyl-but-1-ynyl)-5-methyl-imidazo[1 ,2- a]pyridine-2-carboxylic acid ethyl ester (802 mg). LCMS (m/z): 287.4.

Step 2. To a stirring suspension of 6-(3-hydroxy-3-methyl-but-1-ynyl)-5-methyl- imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (593 mg) in 1 :1 methanol and water (10 ml_) was added sodium hydroxide (800 mg). The reaction mixture was heated to 100 ^°C for 1 hour. It was then cooled to room temperature, neutralized with dilute aqueous hydrochloric acid to a pH of about 6-7. The solvents were evaporated, and the resulting solid was dissolved in THF and purified by silica gel flash chromatography using 10% of MeOH in DCM to give 6-(3-hydroxy-3-methyl-but-1-ynyl)-5-methyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid (315 mg). LCMS (m/z): 259.3.

Step 3. To a stirring solution of 5-(3-trifluoromethyl-phenyl)-1 H-benzoimidazol-2- ylamine dihydrobromide salt (95 mg), 6-(3-hydroxy-3-methyl-but-1-ynyl)-5-methyl- imidazo[1 ,2-a]pyridine-2-carboxylic acid (57 mg) and HBTU (91 mg) in DMF (1 mL), DIEA (51 mg) was added. The reaction mixture was heated to 90 "C for 1 hour. It was then cooled to room temperature, water was added and the resulting solid was filtered, dried and purified by silica gel flash chromatography using 10% of MeOH in DCM to obtain the title compound (42 mg). LCMS (m/z): 518.9. ¹H NMR (400 MHz, DMSO-d6): δ 1.39 (6H, s), 2.81 (3H, s), 7.22 (1 H, d), 7.75-8.03 (9H, m), 8.68 (1 H, s) ppm.

Example 7

6-(2-Hydroxy-ethoxy)-5-methyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid [5-(3-trifluoromethyl- phenyi)-1 H-benzoimidazol-2-yl]-amide

Step 1. While maintaining a temperature of 0-5 "C with external ice cooling, 3- hydroxy-2-methylpyridine (20 g) was added gradually to concentrated sulfuric acid (140 mL); then a mixture of nitric acid (14 g) and concentrated sulfuric acid (33 g) was added over 2 hours. The resulting mixture was poured on to ice. Addition of a few milliliters of ammonium hydroxide caused precipitation of 3-hydroxy-6-nitro-2-methylpyridine as a solid (2.26 g), which was filtered, washed with water, dried and used directly in the next step without further purification. LCMS (m/z): 155.1. (See R.C. De Selms, J. Org. Chem., 1968, 33, 478-480). Step 2. To triphenylphosphine (5.2 g) in dry THF (10 mL) was added diisopropyl azodicarboxylate (3.94 mL) and 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (2.71 mL). Then the crude 3-hydroxy-6-nitro-2-methylpyridine (616 mg) was added and the mixture was heated at 70 ^°C for 5 hours. It was then cooled to room temperature, evaporated the solvent. Then, the resulting mixture was purified by silica gel flash chromatography using 10% of MeOH in DCM to get 2-methyl-6-nitro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-pyridine, which was reduced by 10% palladium-on-carbon catalyzed hydrogenation (hydrogen in balloon) in 1 :1 methanol and ethyl acetate to give 6-methyl-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-pyridin- 2-ylamine, which reacted further with ethyl bromopyruvate (2.64 mL) in ethanol under reflux for 3 hours to give 5-methyl-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-imidazo[1 ,2-a]pyridine-2- carboxylic acid ethyl ester after silica gel flash chromatography purification (140 mg). LCMS (m/z): 349.9.

Step 3. To a stirring suspension of 5-methyl-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]- imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (139 mg) in 1 :1 methanol and water (10 mL) was added sodium hydroxide (160 mg). The reaction mixture was heated to 100 ^°C for 1 hour. It was then cooled to room temperature, neutralized with dilute aqueous hydrochloric acid to a pH of about 6-7. The solvents were evaporated, and the resulting solid was dissolved in THF and purified by silica gel flash chromatography using 10% of MeOH in DCM to get 5-methyl-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-imidazo[1 ,2-a]pyridine-2- carboxylic acid (72 mg). LCMS (m/z): 321.8. Step 4. To a stirring solution of 5-(3-trifluoromethyl-phenyl)-1 H-benzoimidazol-2- ylamine dihydrobromide salt (95 mg), 5-methyl-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]- imidazo[1 ,2-a]pyridine-2-carboxylic acid (70 mg) and HBTU (91 mg) in DMF (1 mL), DIEA (51 mg) was added. The reaction mixture was heated to 90 ^"C for 1 hour. It was then cooled to room temperature, water was added and the resulting solid was filtered and dried to give 5-methyl-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-imidazo[1 ,2-a]pyridine-2-carboxylic acid [5-(3-trifluoro-methyl-phenyl)-1 H-benzoimidazol-2-yl]-amide. The crude solid was dissolved in methanol (5 mL) and added p-toluenesulfonic acid monohydrate (418 mg) and the mixture was stirred at room temperature for 2 hours. It was then concentrated and purified by silica gel flash chromatography using 10% of MeOH in DCM to obtain the title compound (45 mg). LCMS (m/z): 496.9. ¹H NMR (400 MHz, DMSO-d6): δ 2.77 (3H, s), 3.52 (1 H, m), 3.85 (2H, m), 4.40 (2H, t), 7.14 (1 H, d), 7.40 (1 H, d), 7.63-7.88 (6H, m), 8.05 (1 H, s), 8.17 (1 H₁ d), 8.90 (1 H₁ s) ppm. Example 8 5-((R)-3-Hydroxy-pyrrolidin-1-yl)-imidazo[1 ,2-a]pyridine-2-carboxylic acid [5-(3-chloro-5- fluoro-phenyl)-1 H-benzoimidazol-2-yl]-amide

Step 1. 2-Amino-6-chloropyridine (12.9 g) in ethanol (100 mL) was added ethyl bromopyruvate (39.6 mL) and stirred under reflux for 3 hours. The reaction mixture became a brown color. It was cooled to room temperature, and ethyl acetate was added to precipitate the product, which was filtered, washed with ethyl acetate and dried to give 5- chloro-imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester as a white solid (17.2 g). LCMS (m/z): 225.2. Step 2. 5-Chloro-imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (11.2 g) in concentrated hydrochloric acid (50 mL) and dioxane (50 ml_) was stirred under reflux overnight. The resulting solution was condensed under vacuum, washed with acetone and dried to obtain a solid, δ-chloro-imidazoπ^-ajpyridine^-carboxylic acid (6.7 g). LCMS (m/z): 197.2.

Step 3. To a stirring solution of 5-(3-chloro-5-fluoro-phenyl)-1 H-benzoimidazol-2- ylamine dihydrobromide salt (4.2 g), 5-chloro-imidazo[1 ,2-a]pyridine-2-carboxylic acid (2.0 g) and HBTU (3.8 g) in DMF (10 mL), DIEA (3.5 mL) was added. The reaction mixture was heated to 90 ^°C for 1 hour. It was then cooled to room temperature, water was added and the resulting solid was filtered, washed with 20% methanol in water and dried to give 5- chloro-imidazo[1 ,2-a]pyridine-2-carboxylic acid [5-(3-chloro-5-fluoro-phenyl)-1 H- benzoimidazol-2-yl]-amide (3.5 g). LCMS (m/z): 440.7.

Step 4. 5-Chloro-imidazo[1 ,2-a]pyridine-2-carboxylic acid [5-(3-chloro-5-fluoro- phenyl)-1 H-benzoimidazol-2-yl]-amide (44 mg) in dry 1-methyl-2-pyrrolidinone (1 mL) was added (R)-(+)-3-pyrrolidinol (44 mg) and the mixture was heated under nitrogen at 90 °C for 8-10 hours. It was then cooled to room temperature, partitioned between ethyl acetate and water, organic layer evaporated and the resulting mixture was purified by silica gel flash chromatography using 10 % methanol in DCM to obtain the title compound (25 mg). LCMS (m/z): 491.8. ¹H NMR (400 MHz, DMSO-d6): δ 1.95-2.12 (2H, m), 3.43-3.62 (5H, m), 7.05 (1 H, d), 7.30 (1 H, d), 7.48-7.92 (8H, m), 8.55 (1 H, s) ppm.

Example 9

6-(2-hydroxy-ethoxy)-imidazo[1 ,2-a]pyridine-2-carboxylic acid [5-(3-chloro-phenyl)-1 H- benzoimidazol-2-yl]-amide To a solution of 6-amino-pyridin-3-ol (0.6 g) in ethanol (20 mL) was added 3-bromo-

2-oxo-propionic acid ethyl ester (2 mL), the mixture was refluxed for 4 hours. After cooling to room temperature, the solvent was removed on rotavapor and purified by silica gel flash chromatography using DCM then 5% methanol in DCM as eluent to afford 6-hydroxy- imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (0.6 g), LCMS (m/z): 207.2. ¹H NMR (400 MHz, DMSO-de), δ 1.30 (3H, t), 4.29 (2H, q), 7.07 (1 H₁ d), 7.48 (1 H, d), 8.02 (1 H, s), 8.44 (1 H, s), 9.80 (1 H, bs).

To a solution of 2-(tetrahydro-pyran-2-yloxy)-ethanol (0.88g) in dry THF (10 mL) was added Ph₃P (2.35 g) and DIAD (1.5 mL) at 0 ^°C. After stirring for 20 min, 6-hydroxy- imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (0.6 g) was added in one portion. The dark-colored mixture was stirred at room temperature until LCMS showed substantial completion of the reaction (overnight). The reaction mixture was concentrated on a rotavapor and purified on silica gel column to obtain 6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]- imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (0.3 g). LCMS (m/z): 335.

To a solution of 6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-imidazo[1 ,2-a]pyridine-2- carboxylic acid ethyl ester (0.3 g) in methanol/THF/water (v/v/v = 2/2/2 ml.) was added NaOH (6 mmol), and stirred at room temperature for 1hour. The reaction mass was neutralized with citric acid (2 mmol) and concentrated on a rotavapor. The obtained residue was stirred in DCM-methanol (1 :1 , 30 ml_), filtered through a pad of Celite, and washed with DCM-methanol (1 :1). The combined filtrates were concentrated and the residues were purified by silica gel flash chromatography using DCM/methanol (v/v from 5:1 to 1 :1) to give 6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-imidazo[1 ,2-a]pyridine-2-carboxylic acid (0.2 g). LCMS (m/z): 307.7.

To a solution of 6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-imidazo[1 ,2-a]pyridine-2- carboxylic acid (40 mg) in DMF (1 mL) was added HBTU (60 mg) and DIEA (0.1 mL). The mixture was stirred for 10 minutes at room temperature, then 5-(3-chloro-phenyl)-1 H-benzo- imidazol-2-ylamine (20 mg) was added. The mixture was stirred at 80 C for 30 minutes, after cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with saturated sodium carbonate aqueous solution (10 ml). The organic phase was dried over sodium sulfate and concentrated. The residues were purified by silica gel flash chromatography using DCM/methanol (v/v from 100:1 to 100:5) to give an amide (18 mg). LCMS: 532.9.

To a solution 6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-imidazo[1 ,2-a]pyridine-2- carboxylic acid [5-(3-chloro-phenyl)-1 H-benzoimidazol-2-yl]-amide (18 mg ) in methanol (3 mL) was added p-toluenesulfonic acid monohydrate (40 mg) and the mixture was stirred until LCMS showed substantial completion of the reaction. Substantially all of the volatiles were evaporated and the product purified on silica gel column using 2M ammonia-methanol in DCM as an eluent. (10 mg). LCMS (m/z): 448.9.

Example 10

5-(4-Methyl-piperazin-1-ylmethyl)-imidazo[1 ,2-a]pyridine-2-carboxylic acid [5-(3- trifluoromethyl-phenyl)-1 H-benzoimidazol-2-yl]-amide

To a solution of 6-methyl-pyridine-2-carboxylic acid (5 g) in methanol (150 mL) was added SOCI₂ (4 mL), and the resulting mixture was refluxed overnight. The reaction mixture was then cooled to room temperature, concentrated on a rotavapor, and to the resulting residue was added ethyl acetate (250 mL) and aqueous saturated sodium carbonate solution (250 mL). The organic phase was separated, dried over sodium sulfate, concentrated and purified by silica gel column using ethyl acetate as eluent to give the desired methyl ester (4.4 g).

To the above a solution of 6-methyl-pyridine-2-carboxylic acid methyl ester (4.4 g) in dry THF (100 ml) was added 2M LiAIH₄ solution in THF (30 ml_) at -78 °C. The reaction mixture was slowly warmed to room temperature and stirred at the same temperature for 3 hours. The reaction mixture was cooled in an ice bath and quenched by addition of saturated aqueous sodium sulfate solution (10 ml_). This was stirred at room temperature for 15 minutes, decanted the organic layer and the residue was rinsed with ethyl acetate (50 ml_). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated to get desired product, which was used in the subsequent step without purification. LCMS (m/z): 125.1.

To a solution of (6-methyl-pyridin-2-yl)-methanol (from above reaction) in ethanol (100 mL) was added 3-bromo-2-oxo-propionic acid ethyl ester (6.6 mL), and was refluxed for 4 hours. The reaction mixture was cooled to room temperature. Then, the volatiles were evaporated on a rotavapor, and purified by silica gel flash chromatography using ethyl acetate as an eluent to get the desired product. ¹H NMR (400 MHz, DMSOd₆), δ 1.33 (3H, t), 4.39 ( 2H, q), 4.81 (2H, d), 5.75 (1 H, bt), 7.02 (1 H, d), 7.38 (1 H, dd), 7.60 (1 H, d), 8.45 (1 H₁ S).

To a solution of 5-hydroxymethyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (0.55 g) and imidazole (0.5g) in DMF (5 mL) was slowly added chloro-triisopropyl-silane (3 mL) at room temperature. The reaction mixture was heated at 70 °C for 2 hr. After cooling to room temperature, added saturated sodium carbonate solution (50 mL) and extracted into ethyl acetate (150 mL). The organic phase was washed with brine, dried over sodium sulfate and concentrated on rotavapor. Thus obtained residue was purified by silica gel flash chromatography using DCM/ethyl acetate (v/v = 1 : 1 ) as eluent to get the silyl derivative.

To a solution of 5-triisopropylsilanyloxymethyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid ethyl ester (0.6 g) in methanol/THF/water (v/v/v = 2/2/1) was added LiOH monohydrate (0.12 g), the mixture was stirred at room temperature for 1hour, then quenched by addition of acetic acid (0.4 mL). The solvent was removed under rotavapor. The residues were purified by silica gel flash chromatography using DCM/methanol (v/v from 10:1 to 5:1) to give the desired acid. LCMS (m/z): 350. ¹H NMR (400 MHz, DMSO-d₆), δ 1.03 (18H, d), 1.25 ( 3H, m), 5.07 (2H, s), 7.03 (1 H, d), 7.37 (1 H, dd), 7.57 (1 H, d), 8.35 (1 H₁ s).

To a solution of 5-triisopropylsilanyloxymethyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid (330 mg) in DMF (2.4 mL) was added HBTU (400 mg) and DIEA (0.2 mL). The mixture was stirred for 10 minutes then 5-(3-trifluoromethyl-phenyl)-1 H-benzoimidazol-2-ylamine

(220 mg) was added. The resulting mixture was heated at 80 °C for 30 minutes, then cooled to room temperature. The product was extracted with ethyl acetate (50 mL) and washed with saturated sodium carbonate solution (20 mL). The organic phase was dried over sodium sulfate and concentrated. The residues were purified by silica gel flash chromatography using DCM/methanol (v/v = 100:1 to 100: 5) as eluents. LCMS (m/z): 609.1. To the silyl derivative in THF added 1 M TBAF in THF (2 mL) and stirred at room temperature overnight. After LCMS indicated the completion of the reaction volatiles were evaporated on rotavapor. Thus obtained residue was purified by silica gel flash chromatography eluting with ethyl acetate then DCM/2M ammonia in methanol (v/v = 100:1 to 100:12) to give the desired alcohol (0.3 g). LCMS (m/z): 453. The solution of the above alcohol (200 mg) and triethylamine (0.4 mL) in DCM (3 mL) was cooled in an ice bath and slowly added methane sulfonyl chloride (0.2 mL). Slowly warmed the reaction mixture to room temperature and stirred at the same temperature for 1 hour. After LCMS indicated the completion of the reaction, added 1-methyl-piperazine (0.5 mL) and stirred at room temperature until LCMS indicated substantial completion of the reaction. Evaporated the volatiles on rotavapor and purified by silica gel flash chromatography to obtain the desired product. LCMS (m/z): 535.1.

Example 11

5-Methyl-imidazo[1 ,2-a]pyridine-2-carboxylic acid [1-methyl-5-(3-trifluoromethyl-phenyl)-1 H- benzoimidazol-2-yl]-amide

Step 1. 4-Bromo-2-fluoro-1-nitro-benzene (1.0 g), 3-(trifluoromethyl)phenylboronic acid (1.28 g) in DME (20 mL) and 2.0 N Na₂CO₃ (5.6 mL) were degassed with nitrogen for

10 minutes, then tetrakis(triphenylphosphine)palladium (0.26 g) was added and heated at 90

^°C for 3.0 hours. It was then cooled to room temperature, the organic layer was separated, washed with water, brine, dried (Na₂SO₄), filtered and concentrated under reduced pressure.

The product was purified by column chromatography using 3% ethyl acetate in hexanes to get 3-fluoro-4-nitro-3'-trifluoromethyl-biphenyl (0.8 g).

Step 2. 3-fluoro-4-nitro-3'-trifluoromethyl-biphenyl (0.5) was dissolved in 2.0 M methyl amine in THF. The reaction mixture was stirred at room temperature for overnight. The solvent was evaporated and the product was purified by column chromatography using ethyl acetate in hexanes to get methyl-(4-nitro-3'-trifluoromethyl-biphenyl-3-yl)-amine (0.3 g). Step 3. Methyl-(4-nitro-3'-trifluoromethyl-biphenyl-3-yl)-amine (0.25 g) was dissolved in MeOH (1OmL), 30 mg of Pd-C (10% by weight) was added and stirred under hydrogen atmosphere with balloon for 3 hours. It was then filtered through a pad of Celite and concentrated under reduced pressure to get N^*3*-methyl-3'-trifluoromethyl-biphenyl-3,4- diamine, which was used for the next step without further purification. Step 4. The above crude N^*3^*-methyl-3'-trifluoromethyl-biphenyl-3,4-diamine, CNBr (0.135 g) and H₂O (2.0 ml_) in ethanol (10 ml.) was refluxed for 30 minutes. It was then cooled to room temperature, and the solvent was evaporated; the resulting solid was washed with ether and dried to get 1 -methyl-5-(3-trifluoromethyl-phenyl)-1 H-benzoimidazol- 2-ylamine dihydrobromide salt (0.2 g). LCMS (m/z): 292.6.

Step 5. To a stirring solution of 1-methyl-5-(3-trifluoromethyl-phenyl)-1 H- benzoimidazol-2-ylamine dihydrobromide salt (0.125 g), 5-methyl-imidazo[1 ,2-a]pyridine-2- carboxylic acid (0.076 g) and HBTU (0.16 g) in DMF, DIEA (0.167 g) was added. The reaction mixture was heated to 90 ^°C for 2.0 hours. It was then cooled to room temperature, saturated NaHCO₃ solution was added and the resulting solid was filtered and dried. The solid was dissolved in DCM and purified by silica gel flash chromatography using 0.5% of MeOH in DCM to get the title compound (45 mg). LCMS (m/z): 450.7.

Example Compounds Table 1 shows examples of compounds of Formula (I) or pharmaceutically acceptable salts thereof that were synthesized. Each of the identified compounds constitutes a separate embodiment of the invention, where the embodiments include the compound in its free (non-salted) form, tautomers of the compound in its free (non-salted form), and pharmaceutically acceptable salts of either of the foregoing. In other embodiments, each of the recited compounds is in its free (non-salted) form constitutes a separate embodiment of the invention, including tautomers of each of the compounds. In other embodiments, the pharmaceutically acceptable salts of each of the recited compounds constitute a separate embodiment of the invention, including pharmaceutically acceptable salts of the tautomers of each of the compounds. In other embodiments, the hydrochloride salts of each of the recited compounds constitute a separate embodiment of the invention, including hydrochloride salts of the tautomers of said compounds. Table 1 shows LCMS data for each compound. The recorded m/z data are accurate to within about 1 amu. For some examples, proton NMR spectra were also recorded, although such data are not shown. Table 1 shows a generic structure, and identifies each compound by the identity of its substituents.

The LCMS (m/z) data are obtained using gradient elution on a parallel MUX™ system, running four Waters® 1525 binary HPLC pumps, equipped with a Mux-UV 2488 multichannel UV-Vis detector (recording at 215 and 254 nM) and a Leap Technologies HTS PAL Auto sampler using a Sepax GP-C18, 4.6 x 50 mm; 5 micron particle-size column. A three minute gradient is run from 25% B (97.5%acetonitrile, 2.5% water, 0.05% TFA) and 75% A (97.5% water, 2.5% acetonitrile, 0.05% TFA) to 100% B. The system is interfaced with a Waters Micromass ZQ mass spectrometer using electrospray ionization. MassLynx software is employed.

Table 1

Compounds in Table 1 having a basic group or acidic group are depicted as the free base or acid. Depending on the reaction conditions and purification conditions, various compounds in Table 1 having a basic group may have been isolated in either the free base form, as a salt (such as an HCI salt), or in both forms.

As shown in Table 2, below, compounds of the invention inhibit β-secretase enzyme activity. Compounds that inhibit β-secretase enzyme activity are potentially useful in treating diseases or conditions that may be associated with the build-up of β-amyloid plaques, including, but not limited to, Alzheimer's disease, mild cognitive impairment, dementia of Alzheimer's type, Down's syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type of Alzheimer's disease, and central or peripheral amyloid diseases.

The compounds of Formula (I), tautomers of compounds of Formula (I), and/or pharmaceutically acceptable salts of either of the foregoing, may therefore be useful in the treatment of one or more of these diseases.

In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I), a tautomer of a compound of Formula (I), or pharmaceutically acceptable salts of either of the foregoing. In another embodiment, the present invention provides a pharmaceutical composition comprising a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 (recited above). In another embodiment, the pharmaceutical composition comprises a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 and a pharmaceutically acceptable carrier, excipient, diluent, or a mixture thereof. In an embodiment, the pharmaceutical compositions containing a compound of

Formula (I), a tautomer of a compound of Formula (I), or a pharmaceutically acceptable salt of either of the foregoing, may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous, or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,356,108; 4,166,452; and 4,265,874, to form osmotic therapeutic tablets for controlled release. In another embodiment, formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. In another embodiment, the composition may comprise an aqueous suspension.

Aqueous suspensions may contain the active compounds in an admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl-eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Also, oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring, and coloring agents may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. In another embodiment, the pharmaceutical compositions of the present invention may comprise a syrup or elixir. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently employed as solvent or suspending medium. For this purpose, any bland fixed oil may be employed using synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The pharmaceutical compositions of the present invention may also be in the form of suppositories for rectal administration of the compounds of the invention. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols, for example.

In an embodiment, for topical use, creams, ointments, jellies, solutions of suspensions, etc., containing the compounds of the invention may be employed. For the purpose of this application, topical applications shall include mouth washes and gargles.

In an embodiment, the compounds of Formula (I), tautomers of compounds of Formula (I), or pharmaceutically acceptable salts of either of the foregoing may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

Pharmaceutically-acceptable salts of compounds of Formula (I) or tautomers of compound of Formula (I), where a basic or acidic group is present in the structure, are also included within the scope of the invention. The term "pharmaceutically acceptable salts" refers to salts of the compounds of this invention which are not biologically undesirable and are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. Representative salts include the following salts: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium, Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide, Trimethylammonium and Valerate. When an acidic substituent is present, such as -COOH, there can be formed the ammonium, morpholinium, sodium, potassium, barium, calcium salt, and the like, for use as the dosage form. When a basic group is present, such as amino or a basic heteroaryl radical, such as pyridyl, an acidic salt, such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartrate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate, ethanesulfonate, picrate and the like, and include acids related to the pharmaceutically-acceptable salts listed in the Journal of Pharmaceutical Science, 66, 2 (1977) p. 1-19. In another embodiment, the invention provides a pharmaceutical composition comprising a compound of Formula (I), a tautomer of a compound of Formula (I), or a pharmaceutically acceptable salt of either of the foregoing, and one or more pharmaceutically acceptable carriers, excipients, or diluents. In another embodiment, the invention provides a pharmaceutical composition comprising a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 and one or more pharmaceutically acceptable carriers, excipients, or diluents.

In another embodiment, the present invention provides a compound of Formula (I), a tautomer of a compound of Formula (I), or a pharmaceutically acceptable salt of either of the foregoing for use in medicine. In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in medicine.

The present invention further provides for the use of a compound of Formula (I), a tautomer of a compound of Formula (I), or a pharmaceutically acceptable salt of either of the foregoing, in combination with one or more medically effective active compounds for simultaneous, subsequent, or sequential administration. The invention also provides for the use of a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 in combination with one or more medically effective active compounds for simultaneous, subsequent, or sequential administration. Examples of such medically effective active ingredients include, but are not limited to, β-secretase inhibitors, γ-secretase inhibitors, HMG-CoA reductase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs) (including but not limited to ibuprofen, naproxen, and diclofenac), N-methyl-D-aspartate (NMDA) receptor agonists (including but not limited to memantine), cholinesterase inhibitors (including but not limited to galantamine, rivastigmine, donepezil, and tacrine), vitamin E₁ CB-1 receptor antagonists, CB-1 receptor inverse agonists, antibiotics (including but not limited to doxycycline and rifampin), agents that bind Aβ or that induce antibodies that bind Aβ, anti-Aβ antibodies, Aβ vaccines, RAGE/RAGE ligand interaction antagonists, and other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention. In one embodiment, the invention provides a pharmaceutical composition comprising a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 and at least one other medically effective active ingredient selected from β-secretase inhibitors, γ-secretase inhibitors, HMG- CoA reductase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs) (including but not limited to ibuprofen, naproxen, and diclofenac), N-methyl-D-aspartate (NMDA) receptor agonists (including but not limited to memantine), cholinesterase inhibitors (including but not limited to galantamine, rivastigmine, donepezil, and tacrine), vitamin E, CB-1 receptor antagonists, CB-1 receptor inverse agonists, antibiotics (including but not limited to doxycycline and rifampin), agents that bind Aβ or that induce antibodies that bind Aβ, anti-Aβ antibodies, Aβ vaccines, and RAGE/RAGE ligand interaction antagonists. In another embodiment, the invention provides for the use of a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 in combination with at least one other medically effective active ingredient selected from β-secretase inhibitors, v- secretase inhibitors, HMG-CoA reductase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs) (including but not limited to ibuprofen, naproxen, and diclofenac), N-methyl-D- aspartate (NMDA) receptor agonists (including but not limited to memantine), cholinesterase inhibitors (including but not limited to galantamine, rivastigmine, donepezil, and tacrine), vitamin E, CB-1 receptor antagonists, CB-1 receptor inverse agonists, antibiotics (including but not limited to doxycycline and rifampin), agents that bind Aβ or that induce antibodies that bind Aβ, anti-Aβ antibodies, Aβ vaccines, and RAGE/RAGE ligand interaction antagonists, for simultaneous, subsequent, or sequential administration.

Methods of Use

A compound of Formula (I) or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), a tautomer of a compound of Formula (I), or a pharmaceutically acceptable salt of either of the foregoing, may be used for the treatment of a disorder selected from Alzheimer's disease, mild cognitive impairment, dementia of Alzheimer's type, Down's syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type of Alzheimer's disease, and central or peripheral amyloid diseases.

In one embodiment, the invention provides a method of treatment comprising administering a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 to a human. In another embodiment, the invention provides a method of treatment comprising administering at least 0.1 milligrams of a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 to a human.

In another embodiment, the invention provides a method of treatment comprising administering a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 to a human, so as to treat at least one disorder selected from Alzheimer's disease, mild cognitive impairment, dementia of Alzheimer's type, Down's syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type of Alzheimer's disease, and central or peripheral amyloid diseases. In another embodiment, the invention provides a method of treatment comprising administering a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 to a human, so as to treat Alzheimer's disease. In another embodiment, the invention provides a method of treatment comprising administering a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 to a human, so as to treat mild cognitive impairment. In another embodiment, the invention provides a method of treatment comprising administering a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 to a human, so as to treat dementia of Alzheimer's type. In another embodiment, the invention provides a method of treatment comprising administering a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 to a human, so as to treat cerebral amyloid angiopathy.

As used herein, "Alzheimer's Disease" is a disorder that may be diagnosed by NINCDS and DSM criteria, Mini-Mental State Examination, and Clinical Dementia Rating within particular limits.

In another embodiment, the invention provides a method of treatment comprising administering a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 to a human, so as to improve cognitive performance. Cognitive performance may be assessed with the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), as is known in the art, which scores cognitive function on a 0 to 70 scale, with higher scores indicating greater cognitive impairment. Thus, a reduction in score demonstrates cognitive improvement. In another embodiment, the invention provides a method of treatment comprising administering a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 to a human, so as to reduce an ADAS-cog score in a subject with an abnormally high score. In another embodiment, the invention provides a method of treatment comprising administering a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 to a human so as to maintain an ADAS-cog score in a subject. In another embodiment, the invention provides a method of treatment comprising administering a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 to a human, so as to decrease the rate of increase in an ADAS-cog score in a subject. In each of these embodiments, the subject may be suffering from dementia of the Alzheimer's type. In a further embodiment, the subject may be suffering from dementia of the Alzheimer's type with early onset uncomplicated, dementia of the Alzheimer's type with early onset with delusions, dementia of the Alzheimer's type with early onset with depressed mood, dementia of the Alzheimer's type with late onset uncomplicated, dementia of the Alzheimer's type with late onset with delusions, or dementia of the Alzheimer's type with late onset with depressed mood.

In addition, the progression of Alzheimer's Disease may also be assessed through examination of four areas of patient function: General, Cognitive, Behavioral, and Activities of Daily Living. Such an assessment may be performed using a Clinician's Interview Based Impression of Change (CIBIC or CIBIC plus). In another embodiment, the present invention provides a method for improvement in a subject's function comprising administering a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 to a human. In an embodiment, the subject's function is one or more of general, cognitive, behavioral, and activities of daily living.

In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in medicine. In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in the treatment of at least one disorder selected from Alzheimer's disease, mild cognitive impairment, dementia of

Alzheimer's type, Down's syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type of Alzheimer's disease, and central or peripheral amyloid diseases. In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in the treatment of Alzheimer's disease. In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in the treatment of mild cognitive impairment. In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in the treatment of dementia of Alzheimer's type. In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in the treatment of cerebral amyloid angiopathy.

In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in the prevention of at least one disorder selected from Alzheimer's disease, mild cognitive impairment, dementia of Alzheimer's type, Down's syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type of Alzheimer's disease, and central or peripheral amyloid diseases. In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in the prevention of Alzheimer's disease. In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in the prevention of mild cognitive impairment. In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in the prevention of dementia of Alzheimer's type. In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in the prevention of cerebral amyloid angiopathy.

In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in the improvement of cognitive performance. In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in the reduction of an ADAS-cog score in a subject with an abnormally high score. In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in the maintenance of an ADAS-cog score in a subject. In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in decreasing the rate of increase in an ADAS-cog score in a subject. In another embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in the improvement of subject function in one or more of general, cognitive, behavioral, and activities of daily living.

In another embodiment, the invention provides for the use of a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for the preparation of a medicament. In another embodiment, the invention provides for the use of a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for the preparation of a medicament for the treatment of at least one disorder selected from Alzheimer's disease, mild cognitive impairment, dementia of Alzheimer's type, Down's syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type of Alzheimer's disease, and central or peripheral amyloid diseases. In another embodiment, the invention provides for the use of a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for the preparation of a medicament for the treatment of Alzheimer's disease. In another embodiment, the invention provides for the use of a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for the preparation of a medicament for the treatment of mild cognitive impairment. In another embodiment, the invention provides for the use of a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for the preparation of a medicament for the treatment of dementia of Alzheimer's type. In another embodiment, the invention provides for the use of a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for the preparation of a medicament for the treatment of cerebral amyloid angiopathy.

In another embodiment, the invention provides for the use of a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for the preparation of a medicament for improving cognitive performance. In another embodiment, the invention provides for the use of a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for the preparation of a medicament for reducing an ADAS-cog score in a subject with an abnormally high score. In another embodiment, the invention provides for the use of a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for the preparation of a medicament for the maintaining an ADAS-cog score in a subject. In another embodiment, the invention provides for the use of a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for the preparation of a medicament for decreasing the rate of increase in an ADAS-cog score in a subject. In another embodiment, the invention provides for the use of a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for the preparation of a medicament for improving subject function in one or more of general, cognitive, behavioral, and activities of daily living.

In another embodiment, the present invention provides a method for inhibiting the interaction of BACE with a physiological ligand. An example of a physiological ligand of BACE includes, but is not limited to, amyloid precursor protein (APP). In one embodiment, the invention provides a method for treating Alzheimer's Disease or dementia of the Alzheimer's type comprising: administering a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 to a human, so as to inhibit the interaction of BACE with a physiological ligand. In one embodiment, the physiological ligand is amyloid precursor protein (APP). In a further embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in the inhibition of the interaction of BACE with a physiological ligand. In a further embodiment, the invention provides for the use of a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for the preparation of a medicament for inhibiting the interaction of BACE with a physiological ligand.

In another embodiment, the present invention provides a method for increasing the α- secretory pathway in a human subject. In one embodiment, the invention provides a method for treating Alzheimer's Disease or dementia of the Alzheimer's type comprising: administering a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 to a human, so as to increase the α-secretory pathway. In a further embodiment, the invention provides a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for use in increasing the α-secretory pathway in a human subject. In a further embodiment, the invention provides for the use of a compound, tautomer, or pharmaceutically acceptable salt of any one of embodiments 1 to 131 for the preparation of a medicament for increasing the α-secretory pathway in a human subject.

In each of the methods or uses described above, a compound, tautomer, or pharmaceutically acceptable salt of any of embodiments 1 to 131 may be administered to a subject as part of a pharmaceutically formulation, as described above.

Examples of compounds of Formula (I), tautomers of compounds of Formula (I), or pharmaceutically acceptable salts of either of the foregoing, of the present invention having potentially useful biological activity are listed by name below in Table 3. The ability of compounds Formula (I), tautomers of compounds of Formula (I), or a pharmaceutically acceptable salt of either of the foregoing, to inhibit the proteolytic activity of BACE was established with the representative compounds of Formula (I) listed in Table 3 using the enzyme and cell based assays described below.

Biological Assays The following assay methods were used to identify and evaluate compounds of

Formula (I) that are effective in reducing the proteolytic activity of BACE.

BACE Fluorescence Resonance Energy Transfer (FRET) Assay

In the following assay, the proteolytic activity of BACE is measured by observing cleavage of a fluorescent group from a peptide substrate containing a rhodamine fluorescent donor and a quenching acceptor.

The inhibitory activity of compounds of Formula (I) may be compared to a statine derived control inhibitor STA200 (MP Biomedical Cat. # STA-200). The cleavage reaction occurs when a BACE-1 substrate (Invitrogen, Cat.# P2986) was added to a reaction mixture containing BACE-1 enzyme (R & D Systems, Cat.# 931AS) and allowed to proceed for about 1.5 hours. Fluorescence, used as a marker of BACE activity, is monitored using 540 nm excitation and 585 nm emission wavelengths (Envision, Perkin Elmer).

A typical assay reaction contains BACE-1 enzyme- in assay buffer (50 mM sodium acetate, pH 4-4.5, 0.01% CHAPS (3-[(3-Cholamidopropyl)dimethylammonio]-1- propanesulfonate), 0.0125% TritonX-100, 0.006% EDTA) which is pre-incubated for 30 minutes with test compound in 7.5% DMSO. The reaction is initiated with the addition of BACE-1 substrate in assay buffer and allowed to proceed for about 1.5 hours at room temperature. Assays are conducted in black 384-well microtiter plates and scanned at room temperature using 540 nm excitation and 585 nm emission wavelengths.

A test compound's activity is reported in Table 2 as the IC₅₀. In some instances, the percent inhibition at a given concentration is reported instead of the IC₅₀.

Aβ Cell Based Assay Procedure

In the following assay, the proteolytic activity of BACE in cells exposed to varying concentrations of a compound of interest is measured by observing the amount of Ap_1-40 secreted from HEK293 cells (Human Embryonic Kidney epithelial cell line) stably expressing wildtype human APP695 protein (HEK-APPwt cells).

HEK-APPwt cells were grown in high glucose DMEM (Dulbecco's Modified Eagles Medium SIGMA Cat.# D5796) supplemented with 25 mM HEPES (4-(2-hydroxyethyl)-1- piperazineethanesulfonic acid) (pH 7.4) (Invitrogen Cat.# 15630-114), 0.1 mM NEAA (Nonessential Amino Acids) (BioWhittaker Cat.#13-114E), 10% fetal bovine serum (SIGMA Cat.#F4135) and 250 μg/mL hygromycin (Invitrogen Cat.# 10687-010) in T-225 flasks at 37°C with 5% CO₂ and humidity control.

Test compounds were initially prepared in DMSO and diluted with DMEM media containing 2% FBS (Fetal bovine serum). Ten standard compound solutions were prepared having a range of concentrations. The standard compound solutions were used to determine the EC₅₀ of the test compound. The range of concentrations chosen may depend on the compound's predicted potency.

To prepare the cells for the assay, a flask containing HEK-APPwt cells were trypsinized briefly (1 mL trypsin), and once the cells detached, 4 ml. of 10% FBS-DMEM was added to the flask. The detached cells were centrifuged at 900 rpm for 5 min to form a pellet.

The HEK-APPwt cell pellet was re-suspended with 10 mL DMEM media containing 2% FBS. 80 μL of the cell suspension was added to each well of a 96-well cell culture plate to give 100 X 10⁴ cells/ml. 10 μL of a standard compound solution was added to each well of the 96-well cell culture plate followed by 10 μL of Alamar blue solution. The cells were incubated at 37 ^°C in a 5% CO₂ incubator for 6 hours.

At the end of the incubation, the plates were removed from incubator, and the supernatant was collected. Ap_1-40 concentration in the medium was measured by using a commercial Aβ_1-X ELISA kit (IBL, Japan Cat.# 27729). Briefly, the ELISA plates were coated with an anti-human Aβ (N)(82E1) mouse IgG monoclonal antibody. A horseradish peroxidase conjugated anti-human Aβ11-28 mouse IgG monoclonal antibody was used for detection. The cell culture supernatant was diluted with EIA buffer + protease inhibitors (kit buffer containing protease inhibitors (1 ml. Pl/ 30 ml_ buffer)). A 100 μL aliquot of the diluted supernatant was added to each well of the ELISA plate and incubated for 6 hrs at 4°C. The ELISA plate was washed 8 times with phosphate buffered saline (PBS) containing 0.05% Tween 20.

A 100 μL of detection antibody was then added and incubated for 1 hour at 4°C. The plate was washed 8 times with PBS buffer containing 0.05% Tween 20 followed by addition of 100 μL of the chromogen tetramethylbenzidine (TMB). The plate was incubated in the dark at room temperature for about 30 min and a stop solution (1 N H₂SO₄) was added.

The intensity of the color developed was measured at 450 nm. The optical density at 450 nm (OD450) is proportional to the concentration of human Ap_1-40 secreted by the cell. As a reference, N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT, a γ-secretase inhibitor) was used to indicate 100% inhibition of BACE activity. Thus, the assay measures the ability of a compound of interest to reduce Aβ_1-40 secretion. For select compounds, compound potency is reported in Table 3 as the EC₅₀ by calculating the percent inhibition at all concentration levels and the data were fit with non-linear curve fitting algorithm using GraphPad Prism.

Table 2

While the invention has been described and illustrated with reference to certain embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the dosages as set forth herein may be applicable as a consequence of variations in the responsiveness of the subject being treated. Likewise, the specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. Moreover, all compounds that are recited in the written description are contemplated as possibilities for any of the recited methods, processes, compositions, and/or compounds as appear in the written description and the appended claims.

Claims

CLAIMSWe claim:

1. A compound, where the compound is a compound of Formula (I), a tautomer of a compound of Formula (I), or a pharmaceutically acceptable salt of either of the foregoing:

wherein

G¹ is imidazo[1 ,2-a]pyridin-2-yl

or imidazo[1 ,2-a]pyridin-3-yl

wherein G¹ is optionally substituted with one or more substituents independently selected from the group consisting of: a) -halo, b) R^a, c) -J¹-R^b, d) -alkylene-J²-R^b, e) -alkenylene-R^f, f) -alkynylene-R^f, g) -J¹-alkylene-J²-R^b, h) -alkylene-J¹-alkylene-J²-R^b, i) -N(R^d)(R^e), j) -alkylene-N(R^d)(R^e), k) -J¹-alkylene-N(R^d)(R^e),

I) -N(-alkylene-R^f)(-alkylene-R⁹), m) R^J, n) -J¹-alkylene-J²-R^J, o) -alkylene-J¹-alkylene-R^J, p) -alkylene-J¹-alkylene-J²-R^J, q) -C(O)R^d, r) -CO₂-R^d, s) -C(O)-N(R^d)(R^Θ), t) -SO₂-alkyl, u) -SO₂-OR^d, v) -SO₂-N(R^d)(R^e), w) -J²-alkylene-C(O)R^d, x) -J²-alkylene-CO₂R^d, y) -J²-alkylene-C(O)N(R^d)(R^e), z) -J²-alkylene-SO₂-alkyl, aa) -J²-alkylene-SO₂-OR^d, and bb) -J²-alkylene-SO₂-N(R^d)(R^e), wherein the alkylene, alkenylene, and alkynylene groups are optionally substituted with one or more substituents independently selected from R^c, and J¹ is selected from the group consisting of: -O-, -NH-, and -S-, J² is selected from the group consisting of: a direct bond, -O-, -NH-, and -S-;

L² is selected from the group consisting of: direct bond, -O-, -NH-, and -N(R⁶)-; wherein R⁶ is -D³-G³, wherein

D³ is selected from the group consisting of: direct bond, -alkylene-, and -alkenylene-; and G³ is selected from the group consisting of: -phenyl and -cycloalkyl, wherein the phenyl and cycloalkyl groups are optionally substituted with one or more substituents independently selected from the group consisting of: -halo, -alkyl, -haloalkyl, -OH, -NH₂, -phenyl, -cycloalkyl, -alkylene-phenyl, -alkylene- cycloalkyl, -O-alkyl, -O-haloalkyl, -O-phenyl, -O-cycloalkyl, -O- alkylene-phenyl,-O-alkylene-cycloalkyl, -C(O)alkyl, and - C(O)haloalkyl;

D² is selected from the group consisting of: direct bond, -alkylene-, and -alkenylene-; and G² is selected from the group consisting of: -phenyl, -cycloalkyl, -heterocyclyl, and

-heteroaryl, wherein the phenyl, cycloalkyl, heterocyclyl, and heteroaryl groups are optionally substituted with one or more substituents independently selected from the group consisting of: -halo, -alkyl, -haloalkyl, -OH, -NH₂, - NH-alkyl, -N(alkyl)₂, pyrrolidino, piperidino, piperazino, 4-methyl- piperazino, morpholino, -phenyl, -CN, -cycloalkyl, -alkylene-phenyl, - alkylene-cycloalkyl, -O-alkyl, -O-haloalkyl, -O-phenyl, -O-cycloalkyl, -O- alkylene-phenyl, -O-alkylene-cycloalkyl, -O-alkylene-O-alkyl, -C(O)alkyl, -

C(O)haloalkyl, -CO₂-alkyl, and -SO₂-alkyl;

R⁵ is selected from the group consisting of: hydrogen, -haloalkyl, -alkyl, -alkylene-J³-R^d,

-alkylene-N(R^d)(R^e), -alkylene-C(O)R^d, -alkylene-CO₂R^d, -alkylene-C(O)N(R^d)(R^e), -alkylene-SO₂-alkyl, -alkylene-SO₂-OR^d, and -alkylene-SO₂-N(R^d)(R^e), wherein J³ is selected from the group consisting of: a direct bond, -O-, -NH-, and -S-;

R⁷ is -H or alkyl;

R^a is selected from the group consisting of: alkyl, haloalkyl, phenyl, cycloalkyl, piperidin-4-yl, 1-methyl-piperidin-4-yl, piperidin-3-yl, and pyrrolidin-3-yl, wherein the alkyl, phenyl, cycloalkyl, piperidin-4-yl, 1-methyl-piperidin-4-yl, piperidin-3-yl, and pyrrolidin-3-yl groups are optionally substituted with one or more substituents independently selected from R^c;

R^b is selected from the group consisting of: hydrogen, alkyl, haloalkyl, phenyl, cycloalkyl, piperidin-4-yl, 1-methyl-piperidin-4-yl, piperidin-3-yl, and pyrrolidin-3-yl, wherein the alkyl, phenyl, cycloalkyl, piperidin-4-yl, 1-methyl-piperidin-4-yl, piperidin-3-yl, and pyrrolidin-3-yl groups are optionally substituted with one or more substituents independently selected from R^c;

R^c is selected from the group consisting of: halo, haloalkyl, alkyl, cycloalkyl, phenyl, -OH, - NH₂, -N(H)alkyl, -N(alkyl)₂, -O-haloalkyl, -O-alkyl, -O-cycloalkyl, -O-phenyl, and -O- alkylene-phenyl;

R^d and R^e are independently selected from the group consisting of: hydrogen, alkyl, phenyl, and cycloalkyl, wherein the alkyl, phenyl, and cycloalkyl groups are optionally substituted with one or more substituents independently selected from R^c, or R^d and R^e are taken together with the atom to which they are attached to form a ring, wherein R^d and R^e together have the formula -(CR^fR⁹)_s-X¹-(CR^fR⁹)_r, wherein s and t are independently 1 , 2, or 3, and the sum of s and t is equal to 3 or 4, and X¹ is selected from the group consisting of: direct bond, -CH₂-, -O-, -S-, and -NR⁷-;

2. The compound according to claim 1 , wherein G¹ is imidazo[1 ,2-a]pyridin-2-yl, optionally substituted with one or more substituents independently selected from the group consisting of: a) -halo, b) R^a, c) -J¹-R^b, d) -alkylene-J²-R^b, e) -alkynylene-R⁹, f) -J¹-alkylene-J²-R^b, g) -alkylene-J¹-alkylene-J²-R^b, h) -N(R^d)(R^e), i) -alkylene-N(R^d)(R^e), j) -J¹-alkylene-N(R^d)(R^e), k) -N(-alkylene-R^f)(-alkylene-R⁹), I) R^J, m) -J¹-alkylene-J²-R^J, n) -alkylene-J¹-alkylene-R^J, o) -alkylene-J¹-alkylene-J²-R^J,

P) -C(O)R^d, q) -CO₂-R^d, r) -C(O)-N(R^d)(R^e), s) -SO₂-alkyl, t) -SO₂-OR^d, u) -SO₂-N(R^d)(R^e), v) -J²-alkylene-C(O)R^d, w) -J²-alkylene-CO₂R^d, x) -J²-alkylene-C(O)N(R^d)(R^e), y) -J²-alkylene-SO₂-alkyl, z) -J²-alkylene-SO₂-OR^d, and aa) -J²-alkylene-SO₂-N(R^d)(R^e), wherein the alkylene groups are optionally substituted with one or more substituents independently selected from R^c, and

J¹ is selected from the group consisting of: -O-, -NH-, and -S-, J² is selected from the group consisting of: a direct bond, -O-, -NH-, and -S-.

3. The compound according to claim 1 or 2, wherein R⁵ is hydrogen.

4. The compound according to claim 1 or 2, wherein R⁵ is methyl.

5. The compound according to any one of claims 1 to 4, wherein R¹ and R⁴ are both hydrogen.

6. The compound according to any one of claims 1 to 5, wherein R³ is hydrogen.

7. The compound according to any one of claims 1 to 6, wherein R² is -L²-D²-G².

8. The compound according to claim 7, wherein G² is -phenyl, optionally substituted with one or more substituents independently selected from the group consisting of: - halo, -alkyl, -haloalkyl, -OH, -NH₂, -NH-alkyl, -N(alkyl)₂, pyrrolidino, piperidino, piperazino, 4-methyl-piperazino, morpholino, -phenyl, -CN, -cycloalkyl, -alkylene- phenyl, -alkylene-cycloalkyl, -O-alkyl, -O-haloalkyl, -O-phenyl, -O-cycloalkyl, -O- alkylene-phenyl, -O-alkylene-cycloalkyl, -O-alkylene-O-alkyl, -C(O)alkyl, -

C(O)haloalkyl, -CO₂-alkyl, and -SO₂-alkyl.

9. The compound according to claim 8, wherein L² and D² are both a direct bond.

10. The compound according to claim 8, wherein L² is -O- and D² is -CH₂-.

11. The compound according to claim 9 or 10, wherein G² is -phenyl, which is optionally substituted 1 or 2 times by substituents independently selected from the group consisting of halo, methyl, ethyl, isopropyl, tert-butyl, n-propyl, cyclopentyl, cyclohexyl, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -OH, -OCF₃,

-OCH₂CF₃, cyclopentyloxy, cyclohexyloxy, pyrrolidino, piperidino, morpholino, piperazino, 4-methyl-piperazino, -O-(CH₂)₂-O-CH₃, -O-(CH₂)₃-O-CH₃, -CN, -CO₂-CH₃, -CO₂-CH₂CH₃, and -SO₂CH₃.

12. The compound according to claim 9 or 10, wherein G² is -phenyl, which is substituted 1 time by a substituent selected from the group consisting of halo, methyl, ethyl, isopropyl, tert-butyl, n-propyl, cyclopentyl, cyclohexyl, -CF₃, -CH₂CF₃, methoxy, ethoxy, isopropoxy, n-propyloxy, -OH, -OCF₃, -OCH₂CF₃, cyclopentyloxy, cyclohexyloxy, pyrrolidino, piperidino, morpholino, piperazino, 4-methyl-piperazino, - O-(CH₂)₂-O-CH₃, -O-(CH₂)₃-O-CH₃, -CN, -CO₂-CH₃, -CO₂-CH₂CH₃, and -SO₂CH₃.

13. The compound according to claim 9 or 10, wherein G² is -phenyl, which is substituted 1 or 2 times by substituents independently selected from fluoro or chloro.

14. The compound according to claim 9 or 10, wherein G² is -phenyl, which is substituted once by -CF₃.

15. The compound according to claim 9 or 10, wherein G² is -phenyl, which is substituted once by -OCF₃.

16. A pharmaceutical composition comprising a compound of any one of claims 1 to 15 and a pharmaceutically acceptable pharmaceutically acceptable carrier, excipient, diluent, or a mixture thereof.

17. The pharmaceutical composition according to claim 16 further comprising a medically effective active ingredient.

18. A method of treating dementia of the Alzheimer's type comprising administering to a human a compound or composition of any one of claims 1 to 17.

19. A method of treating Alzheimer's disease comprising administering to a human a compound or composition of any one of claims 1 to 17.

20. A method of reducing an ADAS-cog score in a human comprising administering to a human a compound or composition of any one of claims 1 to 17.

21. A method of inhibiting the interaction of BACE with a physiological ligand in a human comprising administering to a human a compound or composition of any one of claims 1 to 17.

22. A method of increasing the α-secretory pathway in a human comprising administering to a human a compound or composition of any one of claims 1 to 17.