WO2007096764A2 - Bicyclic heteroaryl derivatives as cannabinoid receptor modulators - Google Patents

Abstract

The present invention relates to; novel bicyclic derivatives of formula (I) : as cannabinoid receptor modulators, in particular cannabinoid 1 (CBl) or cannabinoid 2 (CB2) receptor modulators, and uses thereof for treating diseases, conditions and/or disorders modulated by a cannabinoid receptor (such as pain, neurodegenative disorders, eating disorders, weight loss or control, obesity, smoking cessation, alcohol dependency, depression, and attention deficit hyperactivity disorder). Pharmaceutical compositions containing the described compounds, which can be used for the treatment of diseases, condition and/or disorders mediated by a cannabinoid receptor (such as CBl or CB2) are further provided.

Description

BICYCLIC HETEROARYL DERIVATIVES AS CANNABINOID RECEPTOR

MODULATORS

This application claims the benefit of (i) Indian Application No. 275/MUM/2006, filed February 27, 2006, (ii) U.S. Provisional Application No. 60/781,055, filed March 10, 2006, (iii) Indian Application No. 1146/MUM/2006, filed My 18, 2006, (iv) U.S. Provisional Application No. 60/821,475, filed August 4, 2006, and (v) Indian Application No. 2088/MUM/2006, filed December 20, 2006, all of which are hereby incorporated by reference.

Field of the Invention

The present invention relates to novel bicyclic derivatives as cannabinoid receptor modulators, in particular cannabinoid 1 (CBl) or cannabinoid 2 (CB2) receptor modulators, and uses thereof for treating diseases, conditions and/or disorders modulated by a cannabinoid receptor (such as pain, neurodegenative disorders, eating disorders, weight loss or control, obesity, smoking cessation, alcohol dependency, depression, and attention deficit hyperactivity disorder). Pharmaceutical compositions containing the described compounds, which can be used for the treatment of diseases, condition and/or disorders mediated by a cannabinoid receptor (such as CBl or CB2) are further provided. _.

Background of the Invention

The endogenous cannabinoid system comprises two main receptors, CBl and CB2, and a number of ligands including anandamide and virodhamine which demonstrate the greatest activity at the cannabinoid receptor (Jonathan A W & Louis J A, Obes. Man., 5-19, 2005). Anandamide, which is produced postsynaptically, is the main fatty acid involved in the system. It gains access to the extra cellular space and activates CBl receptors located on presynaptic nerve terminals. This activation causes presynaptic inhibition of γ-aminobutyric acid or glutamate through inhibition of calcium channels, while simultaneously interfering with vesicle release and activating potassium channels. However, anandamide is prone to rapid enzymatic hydrolysis. This represents a serious drawback in its use as a drug because, inter alia, substances which are susceptible to hydrolytic cleavage may undergo changes in the gastrointestinal tract.

CBl receptors are predominantly located in the brain and other neurons, while CB2 receptors are predominantly located in immune cells. Stimulation of these receptors is known to affect the central and peripheral action on lipid and glucose metabolism in adipose tissue and most notably, helps to regulate food intake, energy balance and nicotine dependence as well as regulate fear and anxiety.

There is evidence suggesting that CBl agonists or antagonists, respectively, increase or decrease the motivation to work for palatable ingesta (Gallate J E and McGregor I S, Psychopharmacology, 142, 302-308, 1999 and Gallate J E, Saharov T, Mallet P E and McGregor I S, 1999, Eur. J. Pharmacol., 370, 233-240, 1999). Cannabinoids appear to directly stimulate eating by actions on appetitive processes, making food stimuli more salient and rapidly inducing eating even in satiated animals (Williams C M and Kirkham TC, Physiol Behav., 76, 241-250, 2002).

Current data reveals that cannabinoids mediate suppression of inflammation in vitro and in vivo through stimulation of CB2 receptors (Ehrhart J, et.al. J. Neuroinβammation, 2, 29, 2005). The inflammatory mediators such as nitric oxide, cytokines, and chemokines play an important role in microglial cell-associated neuron cell damage. Activated microglial cells have been implicated in a number of neurodegenerative disorders, including Alzheimer's disease, multiple sclerosis, HIV and dementia.

Compounds capable of modulating the cannabinoid (CB) receptor activity can be used in the treatment of CB receptor mediated syndromes, diseases or disorders which include appetite, metabolism, diabetes, obesity, dyslipidaemia, glaucoma associated intra-ocular pressure, mood disorders, seizures, substance abuse, learning disorders, cognition disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders, inflammation, cell growth disorders, eye- diseases, allergies and allergic reactions, pain, anxiety, psychotic afflictions, pathological states of brain, gastrointestinal disorders, nausea, vomiting, giddiness, urinary and fertility problems, cardiovascular diseases, neuroinflammatory pathologies, diseases of the central nervous system, neurodegenerative syndromes, diseases and disorders, sleep disorders, dermatological disorders, leukocyte activation-associated disorder, autoimmune diseases, nephrological pathologies, delayed or immediate hypersensitivity, infectious parasitic, and viral and bacterial diseases. At present, various CB modulators have been characterized as agonists, inverse agonists or antagonists to CBl and/or CB2 receptors. These modulators include naphthalen- lyl-(4-pentyloxy-naphthalen-l-yl) methanone (believed to be SAB-378), 4-(2,4-dichloro phenylamino)-N-(terahydro-pyran-4ylmethyl)-2-trifluromethyl-benzamide (GW-842166X), N-(l-piperidinyl)-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methylpyrazole-3-carbox- amide (SR141716A), 3-(4-chlorophenyl-N'-(4-chlorophenyl)sulfonyl-N-methyl-4-phenyl- 4,5-dihydro-lH-pyrazole-l-carboxamide (SLV-319) and N-[3-(4-chlorophenyl)-2(S)-(3- cyanophenyl)-l(S)-methylpropyl]-2-methyl-2-[5-(trifluoromethyl)pyridin-2- yloxy]propionamide (MK-0364).

These modulators have reached advanced stages of clinical trials for the treatment of pain, neurodegenerative disorders, psychotic disorders, neurological syndromes, diseases or disorders, eating disorders, Alzheimer's disease, alcohol dependency, diabetes, obesity and/or smoking cessation.

U.S. Patent Publication Nos. 2004/0082635 and 2003/0050320 disclose fused ring compounds useful as therapeutic agents for the treatment of hepatitis C. U.S. Patent Publication Nos. 2003/0018032 and 2002/0183327 disclose substituted bicyclic imidazo-3- yl-amines useful for the treatment of pain. European Patent Publication No. EP 0404190 discloses condensed heterocyclic compounds useful as plant fungicides. PCT Publication No. WO 2005/14598 discloses certain substituted imidazopyrimidines useful in the prevention and treatment of cancer. PCT Publication No. WO 2005/105798 discloses certain substituted imidazo[l,2-a]pyridine compounds useful in the production of drugs. PCT Publication No. WO 2000/08024 discloses substituted imidazo[l,2-a]azines as selective inhibitors of COX-2. JP 2001/043978 discloses diazaindolizine derivatives as components of organic electroluminescent elements.

Nevertheless, there still exists a need for safer and more effective therapeutic treatments for diseases, conditions and/or disorders modulated by cannabinoid receptors, including those modulated by CBl or CB2 receptors.

Summary of the Invention

The present invention relates to CB receptor modulators of the formula (I):

(D and analogs, N-oxides, tautomers, regioisomers, stereoisomers, prodrugs, polymorphs and pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein:

(i) X₁ is CR and X₂ is N, or (ii) Xj is N and X₂ is CR;

R, R¹H, R^, R² _a, R² _b, R² _C, R² _d, R² _e, R³ _a, R³ _b,R³ _c;R³ _dand R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR , -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_1n-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -0R^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R⁹, -C(0)NR^aR^b, -S(O)_m-R^a, -S(O)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is independently O, S or NR^a; 007/000459 each occurrence of R^a and R is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(O)NR^cR^d, -S(O)_1n-R⁰, -S(O)_m-NR°R^d, - NR°R^d ₅ -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^C or S; each occurrence of R^c and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; and each occurrence of m is independently 0, 1 or 2.

According to one embodiment, the compound meets one or more (or all) of criteria (l)-(6) below: (1) when X₁ is CR and X₂ is N, then

(a) when R² ₀ and R³ _C are OR⁴ (wherein R⁴ is methyl), then at least one of R^, R^ or R is not hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, nitro or hydroxy;

(b) when R^ is H and R² _C or R³ _C is — S(O)JR⁴, then R⁴ is not methyl, isopropyl or - NH₂;

(c) at least one of R, R^, or R^l _h is not hydrogen, halogen, hydroxy, SH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylsulfanyl, NR⁴R⁵ or NR⁴C(O)-R⁵ (wherein R⁴ and R⁵ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylmethyl, CH₂OCOH or CH₂OCO-alkyl), except when R and R*_b are each hydrogen, and R^ is bromine;

(d) when R, R^, or R^ is substituted or unsubstituted phenyl, then at least one of R² _a- R² _e or R³a~R³ _e is not hydrogen or substituted or unsubstituted alkyl; and/or

(e) at least one of R² _a-R² _e or R³ _a-R³ _e is halogen;

(2) when X₁ is N and X₂ is CR, then

(a) when R is -CONHR⁵, then R⁵ is not substituted or unsubstituted alkyl;

(b) R is not -COOH or a reactive derivative thereof; and

(c) when R^ is hydrogen then R³ _C is not -SO₂CH₃;

(3) when X₁ is CR and X₂ is N, then at least one of R _c and R _c is not substituted or unsubstituted alkoxy;

(4) when X₁ is CR and X₂ is N, then R² _C and R³ _C are not -S(O)_1nR⁴;

(5) at least one of R² _a-R² _e or R³ _a-R³ _e is halogen; and

(6) when R, R ₃, or R _b is substituted or unsubstituted phenyl, then at least one of R _a-R _e or R³ _a-R³ _e is not hydrogen or substituted or unsubstituted alkyl.

Preferred compounds include those of formula (I) wherein R is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or OR⁴.

Further preferred compounds include those of formula (I) wherein R is chlorine, bromine, methyl, CH₂NHC(CH₃)₃, CH₂OH, phenyl or -OCH₃.

Further preferred compounds include those of formula (I) wherein R*_a is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted alkynyl.

Further preferred compounds include those of formula (T) wherein K^l _a is selected from hydrogen, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3 -fluorophenyl, 4- fluorophenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3-trifluoromethylphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3,3-dimethyl-butynyl, 5-tert-butyl-l,3,4-oxadiazol-2-yl, 3-difiuoromethoxyphenyl, 3-hydroxyphenyl, 3-nitroρhenyl, benzamide, azeρan-1-yl- carbonyl, N-(2-hydroxyethyl)benzamide, N,Λf-dimethyl-carboxarnide, ΛζiV-dimethyl-3- benzamide, 3-phenylacetate, 3-benzoic acid, pyridyl, lH^"-tetrazole, thienyl, 3 ,3 -dimethyl- butyl, 4,4-dimethyl-4,5-dihydro-oxazol-2-yl, 2-ethynyl pyridine, and 1-ethynyl cyclohexanol.

Further preferred compounds include those of formula (I) wherein R*_b, R² _a, R²t_>, R²d, R² _e, R³ _a, R³b, R³ _C R³d and R³ _β are hydrogen. Further preferred compounds include those of formula (I) wherein R _c is hydrogen, halogen, thiol, substituted or unsubstituted alkyl, OR⁴, alkylsulfanyl or alkylsulfonyl.

Further preferred compounds include those of formula (I) wherein R² _C is chloro, bromo, fluoro, -OCH₃, -OH, methyl, ethyl, trifluoromethyl, or methylsulfanyl (-SMe) or methane sulfonyl (SO₂Me).

Further preferred compounds include those of formula (I) wherein R² _a, R\, R² _d, R³t_>, R c and R³ _e are hydrogen or halogen.

Further preferred compounds include those of formula (I) wherein R² _a, R² _t» R² _d and R b are fluoro

Further preferred compounds include those of formula (I) wherein R³ ₀ is chloro, bromo or fluoro.

Further preferred compounds include those of formula (I) wherein R³ _e is chloro, fluoro.

Further preferred compounds include those of formula (I) wherein R² _C and R³ ₀ are halogen.

Further preferred compounds include those of formula (I) wherein R _c and R _c are chloro.

Further preferred compounds include those of formula (I) wherein R² ₀, R³ _C, and at least one of R³ _a and R³ _e is chloro.

Further preferred compounds include those of formula (I) wherein X₁ is CH; X₂ is N; K\ is hydrogen; R² _a, R² _b, R² _C, R²d, R² _e, R³a, R³b, R³ _C, R³d and R³ _e are as defined above; and R*_a is 3-substituted phenyl wherein the substitutent(s) are as defined beløw.

Further preferred compounds include those of formula (I) wherein X₁ is CH; X₂ is N; R*b is hydrogen; R² _a, R² _b, R² _C, R²d, R²e, R³ _a,

R³e are as defined above; and R^l _a is 3-haloalkylρhenyl.

Further preferred compounds include those of formula (I) wherein X₁ is CH; X₂ is N; R*_b is hydrogen; R^is hydrogen, 3-haloalkylphenyl, 3,5-dihalophenyl, 3,3-dialkylbutynyl, 5- alkyloxadiazolyl, 3,3-dialkyl-butyl, 4,4-dialkyl-4,5-dihydro-oxazolyl, ethynyl heteroaryl, or ethynyl substituted or unsubstituted cycloalkyl; and R² _a, R² _b, R² _C, R²d, R²e, R³a, R³b,R³c,^R3d and R³ _e are independently hydrogen, halogen, alkyl, OR⁴ (wherein R⁴ is hydrogen or methyl), haloalkyl, methylsulfanyl and methanesulfonyl.

Representative compounds of the present invention include those specified below and analogs, N-oxides, tautomers, regioisomers, sterioiosmers, prodrugs, polymorphs, and pharmaceutically acceptable salts, solvates, and hydrates thereof. The present invention should not be construed to be limited to these compounds. 0459

2,3-bis-(4-chlorophenyl)-6-phenyl-imidazo-[l,2-a]-pyrazine (Compound No. 1),

2,3-bis-(4-chlorophenyl)-6-(3-trifluoromethyl-phenyl)-imidazo-[l₅2-a]-pyrimidine (Compound No. 2),

2,3-bis-(4-chlorophenyl)-6-(3-trifluoromethyl-phenyl)-imidazo-[l,2-a]-pyrimidine hydrochloride (Compound No. 2a),

8-Bromo-2,3 -bis-(4-chlorophenyl)-6-phenyl-imidazo-[l ,2-a]-pyrazine (Compound No. 3),

8-Bromo-2,3-bis-(4-chlorophenyl)-6-(4-fiuorophenyl)-imidazo-[l,2-a]pyrazine (Compound No. 4),

2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-6-(3-fluorophenyl)-8-methyl-imidazo- [l,2-a]pyrazine (Compound No. 5),

2,3-Bis-(4-chlorophenyl)-6-(2-chlorophenyl)-imidazo-[l,2-a]pyrazine (Compound No. 6),

2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-8-methyl-6-phenyl-imidazo-[l,2- ajpyrazine (Compound No. 7),

2-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-8-methyl-6-phenyl-imidazo-[l,2- a]pyrazine (Compound No. 8),

8-Bromo-2,3-bis-(4-chlorophenyl)-6-(3-fluorophenyl)-imidazo[l,2-a]pyrazine (Compound No. 9),

2, 3, 6-Tris-(4-chlorophenyl)-8-methyl-imidazo-[l,2-a]-pyrazine (Compound No. 10),

8-Chloro-2,3-bis-(4-Chlorophenyl)-6-phenyl-imidazo-[l,2-a]-pyrazine (Compound No. 11),

2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-phenyl-imidazo-[l,2-a]-pyrazine (Compound No. 12),

3-(4-Chlorophenyl)-2-(2,4-difluoro-phenyl)-7-methyl-6-phenyl-imidazo[l,2- ajpyrimidine (Compound No. 13),

2-(2,4-Difluoro-phenyl)-3-(4-methoxy-phenyl)-7-phenyl-imidazo[l,2-a]pyrimidine (Compound No. 14),

2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-(3-methoxyphenyl)-imidazo[l,2- a]pyrazine (Compound No. 15),

2,3-Bis-(4-chlorophenyl)-6-(3-chlorophenyl)-8-methoxy-imidazo-[l,2-a]ρyrazine (Compound No . 16),

2,3,6-Tris-(4-chloroρhenyl)-imidazo-[l,2-a]-pyrimidine (Compound No. 17), 2,3,6 Tris-(4-chlorophenyl)-imidazo-[l,2-a]-pyrimidine hydrochloride salt (Compound No. 18),

3-(4-Bromophenyl)-2,6-bis-(4-chlorophenyl)-imidazo-[l,2-a]pyrimidine (Compound No. 19),

2-(4-Bromophenyl)-3 -(2,4-dichlorophenyl)-6-(4-methoxyphenyl)-imidazo-[ 1 ,2- a]pyrimidine (Compound No. 20),

2-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-6-(4-methoxyphenyl)-imidazo-[l,2-a] pyrimidine hydrochloride (Compound No. 21),

2-(4-Bromoρhenyl)-3-(2,4-dichlorophenyl)-6-(4-fluorophenyl)-imidazo-[l,2- a]pyrimidine (Compound No. 22),

2-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-6-(4-fluorophenyl)-imidazo-[l,2- a]pyrimidine hydrochloride salt (Compound No. 23),

3-[2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-imidazo-[l,2-a]pyrimidin-6-yl]-phenol (Compound No. 24),

2,3-Bis-(4-chlorophenyl)-6-(3,5-difluorophenyl)-imidazo-[l,2-a]pyrimidine (Compound No. 25),

6-(3,5-Difluoro-phenyl)-3-(4-ethyl-phenyl)-2-(4-fluoro-phenyl)-imidazo [l,2- ajpyrimidine (Compound No. 26),

6-(3,5-Difluoro-phenyl)-2-(4-fluoro-phenyl)-3-p-tolyl-imidazo[l,2-a]pyrimidine (Compound No. 27),

2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-(3-nitrophenyl)-imidazo-[l,2- a]pyrimidine (Compound No. 28),

2,3-Bis-(4-chlorophenyl)-6-(3-fluorophenyl)-imidazo-[l,2-a]pyrimidine (Compound No. 29),

2,3-Bis-(4-chlorophenyl)-6-(pyridin-3-yl)-imidazo-[l ,2-a]pyrimidine (Compound No. 30),

2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-pyridin-3-yl-imidazo-[l,2-a]pyrimidine (Compound No. 31),

3-[2,3-Bis-(4-chlorophenyl)-imidazo-[l,2-a]pyrimidine-6-yl]-benzoic acid (Compound No. 32),

2,3-Bis-(4-chlorophenyl)-6-(3-nitrophenyl)-imidazo-[l ,2-a]pyrimidine (Compound

No. 33),

3-(2,4-Dichlorophenyl)-6-(3-methoxyphenyl)-2-phenyl-imidazo-[l,2-a]pyrimidine (Compound No. 34), B2007/000459

[2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo-[l,2-a]pyrimidin-6-yl]-pyrrolidin-l-yl- methanone (Compound No. 35),

3-.[2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-imidazo-[l,2-a]pyrimidine-6-yl]-N-(2- hydroxy-ethyl)-benzamide (Compound No. 36), ,

3-[2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-imidazo-[l,2-a]pyrimidine-6-yl]- benzamide (Compound No. 37),

3-[2,3-Bis-(4-chlorophenyl)-imidazo-[l,2-a]pyrimidine-6-yl]-N,N-dimethyl- benzamide (Compound No. 38),

2,3-Bis-(4-chlorophenyl)-6-(lH-tetrazol-5-yl)-imidazo[l,2-a]pyrimidine (Compound No. 39),

2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-(3-methoxyphenyl)-imidazo-[l,2- ajpyrimidine (Compound No. 40),

2-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-6-(3-methoxyphenyl)-imidazo-[l,2- a]pyrimidine (Compound No. 41),

2,3-Bis-(4-chlorophenyl)-6-(3-chlorophenyl)-imidazo_r[l,2-a]pyrimidine (Compound No. 42),

2,3-Bis-(4-chlorophenyl)-6-(2-chlorophenyl)-imidazo-[l,2-a]pyrimidine (Compound No. 43),

3-(2-Chlorophenyl)-2-(4-chlorophenyl)-6-(3-chlorophenyl)-imidazo[l,2-a]pyrimidine (Compound No. 44),

2,3-Bis-(4-chlorophenyl)-6-(3-methoxyphenyl)-imidazo-[l,2-a]pyrimidine (Compound No. 45),

Acetic acid 3-[2,3-Bis-(4-chlorophenyl)-imidazo-[l,2-a]pyrimidin-6-yl]-phenyl ester (Compound No. 46),

2-(4-Chlorophenyl)-3-(4-methoxyphenyl)-6-(3-trifluoromethyl-phenyl)-imidazo[l,2- a]pyrimidine (Compound No. 47),

2-(4-Chlorophenyl)-3-(4-methylsulfanylρhenyl)-6-(3-trifluoromethyl-phenyl)- imidazo[l,2-a]pyrimidine (Compound No. 48),

2-(2,4-Difluoro-phenyl)-3-p-tolyl-6-(3-trifluoromethyl-phenyl)-imidazo-[l,2-a]- pyrimidine (Compound No. 49),

2-(2,4-Difluoro-ρhenyl)-3-(4-methoxy-phenyl)-6-(3-trifluoromethyl-ρhenyl)-imidazo- [l,2-a]pyrimidine (Compound No. 50), 2-(3,4-Difluoro-phenyl)-3-(4-methoxy-phenyl)-6-(3-trifluoromethyl-phenyl)- imidazo[l,2-a]pyrimidine (Compound No. 51),

2-(4-Fluoro-phenyl)-3-(4-methoxy-phenyl)-6-(3-trifluoromethyl-phenyl)-imidazo[l,2- ajpyrimidine (Compound No. 52),

3-(4-Ethyl-phenyl)-2-(4-fluoro-phenyl)-6-(3-trifluoromethyl-plienyl)-imidazo[l,2- a]pyrimidine (Compound No. 53),

3-(3,5-Difluoro-phenyl)-2-(4-fluoro-phenyl)-6-(3-trifluoromethyl-phenyl)- imidazo[l,2-a]pyrimidine (Compound No. 54),

2-(4-Chlorophenyl)-6-(3-chlorophenyl)-3-(4-methoxyphenyl)-imidazo[l,2-a]- pyrimidine (Compound No. 55),

2,3-Bis-(4-chlorophenyl)-6-(3-difluoromethoxy-phenyl)-imidazo-[l,2-a]pyrimidine (Compound No. 56),

2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-(3-difluoromethyoxyphenyl)-imidazo- [l,2-a]pyrimidine (Compound No. 57),

3-[2,3-Bis-(4-chlorophenyl)-imidazo-[l ,2-a]pyrimidin-6-yl]-phenol (Compound No. 58),

2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-thiophen-3-yl-imidazo-[l,2- a]pyrimidine (Compound No. 59),

2,3-Bis-(4-chlorophenyl)-6-thiophen-3-yl-imidazo-[l,2-a]pyrimidine (Compound No. 60),

Azepan-l-yl-[2,3-bis-(4-chlorophenyl)-7-methyl-imidazo[l,2-a]pyrimidin-6-yl]- methaηone (Compound No. 61),

2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo[l,2-a]pyrimidine-6-carboxylic acid pentylamide (Compound No. 62),

[2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo[l,2-a]pyrimidin-6-yl]-piperidin-l-yl- methanone (Compound TSTo. 63),

2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo[ 1 ,2-a]pyrimidine-6-carboxylic acid dimethylamide (Compound No. 64),

2-(4-Chlorophenyl)-6-(3-chlorophenyl)-3-(4-methylsulfanylphenyl)-imidazo[l,2- ajpyrimidine (Compound No. 65),

2-(4-Chlorophenyl)-6-(3-chlorophenyl)-3-(4-methanesulfonylphenyl)-imidazo[l,2- ajpyrimidine (Compound No. 66),

2,3-Bis-(4-chlorophenyl)-6-m-tolyl-imidazo[l,2-a]ρyrimidine (Compound No. 67), 007/000459

2-(4-Chloroρhenyl)-3-(2, 4-dichloroρlienyl)-6-(4-methoxyplienyl) imidazo-[l ,2-a]- pyrimidine (Compound No. 68),

2-(4-Chlorophenyl)-3-(2, 4-dichlorophenyl)-6-(4-methoxyphenyl) imidazo-[l ,2-a]- pyrimidine hydrochloride (Compound No. 69),

3-[2, 3-Bis-(4-chlorophenyl)-imidazo[l ,2-a]pyrimidin-6-yl]-benzamide (Compound No. 70),

2,3-Bis-(4-chloro-phenyl)-6-(5,5-dimethyl-4,5-dihydro-oxazol-2-yl)-7-methyl- imidazo[l,2-a]pyrimidine (Compound No. 71),

2-(4-Fluorophenyl)-3-(4-trifluoromethylphenyl)-6-(3-trifluoromethylphenyl)-imidazo [l,2-a]-pyrimidine (Compound No. 72),

2-(4-Fluorophenyl)-3-(4-methylsulphanylphenyl)-6-(3-trifluoromethylphenyl)- imidazo[l,2-a]pyrimidine (Compound No. 73),

4-[2-(4-Chlorophenyl)-6-(3-trifluoromethylphenyl)-imidazo[l,2-a]pyrimidin-3-yl]- phenol (Compound No. 74),

4-[2-(4-Chlorophenyl)-3-p-tolyl-6-(3-trifluoromethylphenyl)-imidazo[l,2- a]pyrimidine (Compound No. 75),

6-(3,5-Dichlorophenyl)-2-(4-fluorophenyl)-3-(4-methylsulphanylphenyl)- imidazo[l,2-a]pyrimidine (Compound No. 76),

2,3-Bis-(4-fluoro-phenyl)-6-(3-trifluoromethyl-phenyl)-imidazo[l,2-a]pyrimidine (Compound No. 77),

2-(4-Fluoro-phenyl)-3-p-tolyl-6-(3-trifluoromethyl-phenyl)-imidazo[l,2-a]pyrimidine (Compound No. 78),

2,3 -Bis-(4-chlorophenyl)-6-(3 ,3 -dimethyl-but- 1 -ynyl)-imidazo [ 1 ,2-a]pyrimidine (Compound No. 79),

6-(5-tert-Butyl-[l, 3, 4]oxadiazol-2-yl)-2, 3-bis-(4-chlorophenyl)-7-methyl- imidazo[l,2-a]pyrimidine (Compound No. 80),

2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo[l₅2-a]pyrimidine (Compound No. 81),

2-(3,4-Difluoro-ρhenyl)-3-(4-methoxy-phenyl)-6-(3-trifluoromethyl-phenyl)- imidazo[l ,2-a]pyrimidine (Compound No. 82),

3-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-7-phenyl-imidazo[l_s2-a]pyrimidine (Compound No. 83),

2,3-Bis-(4-chloro-phenyl)-7-phenyl-imidazo[l,2-a]pyrimidine (Compound No. 84), [2,3-Bis-(4-cMoro-phenyl)-imidazo[l,2-a]pyrimidin-7-ylmethyl]-tert-butyl-ainine (Compound No. 85),

[3-Chloro-2-(2,4-difluoro-phenyl)-imidazo[l,2-a]pyrimidin-7-yl]-methanol (Compound No. 86),

2,3-Bis-(4-chloro-phenyl)-6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-7-methyl- imidazo[l,2-a]pyrimidine (Compound No. 87),

2,3 -Bis-(4-chloro-phenyl)-6-(3 ,3 -dimethyl-butyl)-imidazo[ 1 ,2-a]pyrimidine (Compound No. 88), l-[2,3-Bis-(4-chloro-phenyl)-imidazo[l,2-a]pyrimidin-6-yleihynyl]-cyclohexanol (Compound No. 89), and analogs, N-oxides, tautomers, regioisomers, stereoisomers, prodrugs, polymorphs, pharmaceutically acceptable salts, solvates and hydrates thereof.

Yet another embodiment is a selective CBl antagonist (i.e., a CBl antagonist that does not substantially inhibit or activate the CB2 receptor) having the formula:

(IA) and pharmaceutically acceptable salts thereof, solvates thereof, and hydrates thereof, wherein:

R, R^Ja, R² _a, R² _b, R²C, R²d, R² _e, R³a,

R³C, R³d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl^ substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_m-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -OR^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R³, -C(O)NR^aR^b, -S(O)_1n-R³, -S(O)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S or NR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(0)NR°R^d, -S(O)_1n-R⁰, -S(O)_m-NR°R^d, - TSfR°R^d, -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R⁰ and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; and each occurrence of m is 0, 1 or 2.

According to a preferred embodiment, R is hydrogen or methyl;

R¹ _J1 is substituted phenyl, -C(O)NR⁴R⁵, or substituted or unsubstituted alkyl; R² _a is hydrogen or halogen;

R²c is halogen, -S(O)_m-R^c, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;

R b, R d, and R _e are hydrogen;

R³ _a, R³b, R³d, and R³ _e are hydrogen; and

R³C is halogen. According to another preferred embodiment,

R is hydrogen;

R¹ _a is (i) unsubstituted alkyl or (ii) phenyl substituted with one or two substituents selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, hydroxy, and combinations thereof;

R a is hydrogen or halogen;

R² _C is halogen, -S(O)_m-R^c, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;

R b, R d, and R _e are hydrogen;

R³ _a, R³ _b, R³ _d, and R³ _e are hydrogen; and

R³c is halogen.

According to one embodiment, R^J _a is phenyl substituted with one or two substituents selected from -CF₃, chlorine, methyl, -OCHF₂, and nitro. R² _a is preferably hydrogen. R² _C is preferably methoxy, -SCH₃, chlorine, or hydroxy. R³ _C is preferably chlorine or fluorine and more preferably chlorine.

According to yet another preferred embodiment,

R is hydrogen;

R a is phenyl substituted at the 3 -position with a substituent selected from - CF₃, chlorine, methyl, -OCHF₂, and nitro.

R² _a, R² _b, R² _d, and R² _e are hydrogen;

R² _C is methoxy, -SCH₃, chlorine, or hydroxy;

R³ _a, R³b, R³ _d, and R³ _e are hydrogen; and

R³ _C is chlorine.

The compounds of formula (IA) are particularly useful in the treatment of disorders mediated by antagonizing the CBl receptor, including, but not limited to, appetite disorders, metabolism disorders, diabetes, obesity, glaucoma-associated intraocular pressure, social disorder, mood disorders, seizures, substance abuse, learning disorders, cognition disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders, locomotor^ activity disorders, movement disorders, immune disorders, inflammation, pain or neurodegenerative related syndromes, disorders or diseases. Accordingly, the present invention also includes methods of treating any of these disorders in a subject in need thereof by administering a therapeutically effective amount of one or more compounds of formula (IA). According to a preferred embodiment, the compounds of formula (IA) are administered to treat obesity, dyslipidemia, alcoholism, or tobacco abuse.

The compounds of formula (IA) can be administered with one or more additional therapeutic agents, such as anti-obesity agents, ACAT inhibitors, PDE IV inhibitors, DPP IV inhibitors, antidiabetic agents, dyslipidemic agents, CETP inhibitors, HMG-CoA reductase inhibitors, fibrates, guggle lipids and other CB 1 or CB2 modulators.

The invention also provides intermediates useful in the preparation of the compounds of the present invention having the formula (II)

(II) wherein X_1Λ X₂, R, R^! _a and R*_b are as defined above. According to one embodiment, R, R^! _a and R^! _b are independently hydrogen, substituted or unsubstituted phenyl, benzamide, azepan- lyl-carbonyl, N-(2-hydroxyethyl)benzamide, ΛζΛ/-dimethyl-carboxamide, JVyV-dimethyl-3- benzamide, 3-phenylacetate, 3-benzoic acid, pyridyl, lH-tetrazole, or thienyl. According to one preferred embodiment, at least one of R, R^! _a and R*_b is phenyl substituted with substituted or unsubstituted alkyl. According to another preferred embodiment, at least one of R, R¹ _a and R^ is selected from phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3- fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 3-trifluoromethylphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-difluoromethoxyphenyl, 3-hydroxyphenyl, 3- nitrophenyl, benzamide, azepan-lyl-carbonyl, iV-(2-hydroxyethyl)benzamide, iV^V-dimethyl- carboxamide, N,N-dimethyl-3 -benzamide, 3-ρhenylacetate, 3-benzoic acid, pyridyl, IH- tetrazole, and thienyl. According to yet another preferred embodiment, at least one of R, R*_a and R^ is phenyl substituted with trifluoromethyl (e.g., R^l _a can be phenyl substituted with trifluoromethyl). Further preferred compounds include those where R _a is phenyl substituted with trifluoromethyl and R and R¹I₃ are hydrogen.

The invention further provides intermediates useful in the preparation of the compounds of the present invention having the formula (III)

wherein

R³C₅ R³d, and R³ _e are as defined above. According to one embodiment, R³ _a, R³ _b, R³ _C, R³ _d, and R³ _β are independently hydrogen or halogen, and R^! _a and R'_b are independently hydrogen, substituted or unsubstituted phenyl, benzamide, azepan-lyl- carbonyl, JV-(2-hydroxyethyl)benzamide, ΛyV-dimethyl-carboxamide, ΛζiV-dimethyl-3- benzamide, 3-phenylacetate, 3-benzoic acid, pyridyl, lH-tetrazole, or thienyl. According to one preferred embodiment, R^! _a is phenyl substituted with substituted or unsubstituted alkyl. According to another preferred embodiment, at least one of R'_a and R _b is selected from phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 3,3-dimethylbutynyl, 5-fert-butyl-l,3,4-oxadiazol-2-yl, 3- difluoromethoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, benzamide, azepan-lyl-carbonyl, iV-(2-hydroxyethyl)benzamide, iV^V-dimethyl-carboxamide, ΛζiV-dimethyl-3 -benzamide, 3- phenylacetate, 3-benzoic acid, pyridyl, lH-tetrazole, and thienyl. According to yet another preferred embodiment, at least one of R*_a and R*_b is phenyl substituted with trifluoromethyl (e.g., R*_a can be phenyl substituted with trifluoromethyl). Further preferred compounds include those where R^ is 3-trifluoromethylphenyl; R³ _a, R\, R³d, R³ _e and R^ are each hydrogen, and R³ _C is halogen (e.g., Cl).

The invention further provides intermediates useful in the preparation of the compounds of the present invention having the formula (IV)

wherein R³ a, R³t_>, R³C, R³d, and R³ _e are as defined above. According to one embodiment, R³ _a, R\, R³ _C, R³ _d, and R³ _e are independently hydrogen or halogen, and R^! _a and R*_b are independently hydrogen, substituted or unsubstituted phenyl, benzamide, azepan-lyl- carbonyl, 7V-(2-hydroxyethyl)benzamide, λζJV-dimethyl-carboxamide, i\yV-dimethyl-3- benzamide, 3-phenylacetate, 3-benzoic acid, pyridyl, lH-tetrazole, or thienyl. According to one preferred embodiment, R^! _a is phenyl substituted with substituted or unsubstituted alkyl. According to another preferred embodiment, at least one of R^ and R^ is selected from phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3 -fluorophenyl, 4-fluorophenyl, , 3,5-difluorophenyl, 3,5-dichlorophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 3,3-dimethylbutynyl, 5-fer£-butyl-l,3,4-oxadiazol-2-yl, 3- difluoromethoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, benzamide, azepan-lyl-carbonyl, iV-(2-hydroxyethyl)benzamide, N^-dimethyl-carboxamide, NjN-dimethyl-3 -benzamide, 3- phenylacetate, 3-benzoic acid, pyridyl, lH-tetrazole, and thienyl. According to yet another preferred embodiment, at least one of R^! _a and R'_b is phenyl substituted with trifluoromethyl (e.g., R¹ _a can be phenyl substituted with trifluoromethyl). Further preferred compounds include those where R¹ _J1 is 3-trifluoromethylphenyl; R³ _a, R³t_>, R³a₅ R³e and R^!b are each hydrogen, and R³ _C is halogen (e.g., Cl).

The invention further provides intermediates useful in the preparation of the compounds of the present invention having the formula (V).

Another aspect of the invention is a pharmaceutical composition comprising at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of the compound(s) of the present invention.

The compounds and pharmaceutical compositions of the present invention are useful in the treatment of diseases, conditions and/or disorders modulated by cannabinoid receptors, and in particular CBl and/or CB2 receptors. These compounds are particularly useful in the treatment of appetite disorders, metabolism disorders, diabetes, obesity, glaucoma-associated intraocular pressure, social disorder, mood disorders, seizures, substance abuse, learning disorders, cognition disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders, inflammation, cell growth, pain or neurodegenerative related syndromes, disorders or diseases.

Yet another aspect of the invention is a method of treating a disease, condition and/or disorder modulated by a cannabinoid (CB) receptor, and in particular CBl and/or CB2 receptors, in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention. Any of the compounds of Formula (I) of any the embodiments specified above can be administered. For instance, a compound of formula (I) satisfying the conditional criteria of (1) a, b and d above can be administered.

A further preferred method of treatment includes administering a compound of formula (I) satisfying all of the criteria of (1) and (2) described above.

Preferred methods include one or more of the following embodiments. In one embodiment, the cannabinoid (CB) receptor modulator is a CBl or CB2 receptor modulator, hi another embodiment, the CB receptor modulator is an agonist, antagonist, partial agonist or inverse agonist. In another embodiment, the CB receptor mediated disease is obesity or dyslipidemia mediated by CBl . In yet another embodiment, the disease, condition and/or disorder is selected from appetite disorder, metabolism disorder, cardiovascular disease, catabolism disorder, diabetes, obesity, dyslipidemia, glaucoma-associated intraocular pressure, social related disorder, mood disorder, seizures, substance abuse, learning disorder, cognition disorder, memory disorder, organ contraction, muscle spasm, respiratory disorder, locomotor activity disorder, movement disorder, immune disorder (such as autoimmune disorder), inflammation, cell growth, pain and neurodegenerative related syndromes, disorders and diseases. Yet another aspect of the present invention provides a combination product or medicament comprising one or more compounds of the present invention and one or more of other therapeutic agents for treating a disease, disorder or condition described herein. Preferred combination products or medicaments comprise one or more compounds of the present invention and one or more antiobesity agents, ACAT inhibitors, PDE IV inhibitors, DPP IV inhibitors, antidiabetic agents, dyslipidemic agents, CETP inhibitors, HMG-COA reductase inhibitors, fibrates, guggle lipid or another CBl or CB2 modulator for treating a disease, disorder or condition described herein.

Yet another aspect of the present invention are processes for preparing the compounds described herein.

Detailed Description of the Invention

The present invention provides substituted bicylic derivatives, which can be used as cannabinoid receptor modulators, and processes for the synthesis of these compounds. Analogs, N-oxides, tautomers, regioisomers, sterioiosmers, prodrugs, polymorphs, and pharmaceutically acceptable salts, solvates, and hydrates of these compounds having the same type of activity are also provided. Pharmaceutical compositions containing the described compounds together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of diseases, conditions and/or disorders mediated by cannabinoid receptors (such as CBl or CB2) are further provided.

Definitions

The term "alkyl" refers to a straight or branched unsaturated hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).

The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl, and 2-butenyl.

The term "alkynyl" refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred), e.g., ethynyl, propynyl, and butynyl. The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule. Representative examples of such groups are -OCH₃ and -OC₂H₅.

The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic groups, e.g., spiro (4,4) non-2-yl.

The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group. The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

The term "cycloalkenyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.

The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH₂C₆H₅ and -C₂HsC₆H₅.

The term "heterocyclic ring" refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus,_. oxygen- and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxasolidinyl, triazolyl, indanyl, isoxazolyl, 9

isoxasolidinyl, morpholinyl, thiazqlyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term "heterocyclyl" refers to a heterocyclic ring radical as defined above. The heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

The term "heteroaryl" refers to an aromatic heterocyclic ring radical. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COOR^X, -C(O)R*, - C(S)R^X, -C(O)NR^xR^y ₅ -C(O)ONR^xR^y, -NR^xCONR^yR^z, -N(R^x)SOR^y, -N(R^x)SO₂R^y, -(=N- N(R^x)R^y), -NR^xC(0)0R^y, -NR^xR^y, -NR^xC(O)R^y, -NR^xC(S)R^y, -NR^xC(S)NR^yR^z, -SONR^xR^y, - SO₂NR^xR^y, -OR^X, -OR^xC(O)NR^yR^z, -0R^xC(0)0R^y, -OC(O)R^X, -OC(O)NR^xR^y, - R^xNR^yC(O)R^z, -R^xOR^y ₅ -R^xC(O)OR^y, -R^xC(0)NR^yR^z, -R^xC(O)R^y, -R^xOC(O)R^y, -SR^X, - SOR^X, -SO₂R*., and -ONO₂, wherein R^x, R^y and R^z are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted amino. The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" cannot be "substituted alkenyl".

The term "protecting group" or "PG" refers to a substituent that is employed to block or protect a particular functionality while other functional groups on the compound may remain reactive. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino- protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxy-protecting groups include, but are not limited to, acetyl, benzyl, tetrahydropyranyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Suitable carboxy-protecting groups include, but are not limited to, -CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl)ethyl, 2-(trimethyl silyl) ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p- nitrophenylsulfenyl)ethyl, 2-(diphenyl phosphino)-ethyl, and nitroethyl. For a general description of protecting groups and their use, see, T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

The term "reactive derivatives" at the carboxyl group include the acid anhydrides, active amides, active esters or the like. Specific examples of such reactive derivatives are as follows: 1) Acid anhydrides may be mixed anhydrides with halogenic acids (e.g., hydrochloric acid or hydrobroniic acid), mono-alkyl carbonates, aliphatic carboxylic acids (e.g., acetic acid, pivaloic acid, valeric acid, isovaleric acid or trichloroacetic acid) or aromatic carboxylic acids (e.g., benzoic acid), or symmetric acid anhydrides. 2) Active amides may be amides with pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole or benztriazole. 3) Active esters may be methyl ester, ethyl ester, methoxymethyl ester, 000459

propargyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester or mesylphenyl ester, or other esters with l-hydroxy-lH-2- pyrrolidone, N-hydroxysuccinimide or N- hydroxyphthalimide.

The term "cannabinoid receptor" refers to any one of the known or heretofore unknown subtypes of the class of cannabinoid receptors, including CBl and/or CB2 receptors, that may be bound by a cannabinoid modulator compound of the present invention.

The term "modulator" further refers to the use of a compound of the invention as a CB receptor agonist, partial agonist, antagonist or inverse-agonist.

The term "analog" refers to a compound that is a structural derivative of a parent compound that differs from it by a single element.

The term "prodrug" refers to a compound that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

The term "polymorph" refers to a compound that has the ability to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice.

The term "treating" or "treatment" of a state, disorder or condition includes:

(1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition;

(2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or

(3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

The benefit to a subject to be treated is either statistically significant or at least perceptible to the subject or to the physician.

The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife). A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.

Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), salts of organic bases (such as NjN'-diacetylethylenediamine, glucamine, triethylarnine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine), salts of chiral bases (such as alkylphenylamine, glycinol, and phenyl glycinol), salts of natural amino acids (such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine), salts of non-natural amino acids (such as D-isomers or substituted amino acids), salts of guanidine, salts of substituted guanidine (wherein the substituents are selected from nitro, amino, alkyl, alkenyl, or alkynyl), ammonium salts, substituted ammonium salts, and aluminum salts. Other pharmaceutically acceptable salts include acid addition salts (where appropriate) such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluroacetate), tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates. Yet other pharmaceutically acceptable salts include, but are not limited to, quaternary ammonium salts of the compounds of invention with alkyl halides or alkyl sulphates (such as MeI or (Me)₂SO₄). The pharmaceutically acceptable salts of the present invention may be prepared by any conventional technique known to a person of ordinary skill in the art, e.g., as described in the Handbook of Pharmaceutical Salts:Properties, Selection and Use, eds. P. Heinrich Stahl and Camille G. Wermuth, VHCA and WILEY-VCH, 2002.

Pharmaceutically acceptable solvates includes hydrates and other solvents of crystallization (such as alcohols). The compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.

The chemical names of the compounds described herein was determined by ISIS, Draw, version 2.4 (MDL information systems, Inc.).

For example, a compound of formula (1), as set forth above in the summary of the invention, wherein X₁ is nitrogen; X₂ is C-CH₃; R^! _a is phenyl; R*_b is hydrogen; R² _a, R² _C and R³ _C are each chlorine; R\, R² _d, R² _e, R³a, R³b, R³d and R³ _e are each hydrogen; i.e., a compound of the following formula,

is named herein as 2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-8-methyl-6-phenyl-imidazo- [l,2-a]pyrazine.

Pharmaceutical Compositions

The pharmaceutical composition of the present invention comprises at least one compound of the present invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of the compound(s) of the present invention. The cotnpound(s) of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.

Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone.

The carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention maybe formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing methods known in the art.

The pharmaceutical compositions of the present invention may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy. 20^th Ed., 2003 (Lippincott Williams & Wilkins). For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for example, in a sachet.

The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.

The route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment). The oral route is preferred.

Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.

A typical tablet that may be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mg microcrystalline cellulose (Avicel®), 70 mg modified cellulose gum (Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approx. 9 mg Mywacett 9-40 T and approx. 0.9 mg acylated monoglyceride

Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil. Methods of Treatment and Combination Therapies

The present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment, amelioration, and/or prevention of diseases, conditions and/or disorders modulated by a cannabinoid receptor (CB), especially those modulated by the CBl or CB2 receptor.

The present invention further provides a method of treating a disease, condition and/or disorder modulated by a cannabinoid receptor (CB), and in particular the CBl or CB2 receptor, in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.

Diseases, conditions, and/or disorders that are modulated by a CB receptor, include, but are not limited to, appetite disorders, metabolism disorders, catabolism disorders, diabetes, obesity, glaucoma-associated intraocular pressure, social related disorders, mood disorders, seizures, substance abuse, learning disorders, cognition disorders, memory disorders, organ contraction, muscle spasm, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders (such as autoimmune disorders), inflammation, cell growth, pain and neurodegenerative related syndromes, disorders and diseases.

Appetite related syndromes, disorders or diseases include, but are not limited to, obesity, overweight conditions, anorexia, bulimia, cachexia, dysregulated appetite and the like. Obesity related syndromes, disorders or diseases include, but are not limited to, obesity as a result of genetics, diet, food intake volume, metabolic syndrome, disorder or disease, hypothalmic disorder or disease, age, abnormal adipose mass distribution, abnormal adipose compartment distribution, compulsive eating disorders, motivational disorders which include the desire to consume sugars, carbohydrates, alcohols or drugs or any ingredient with hedonic value and the like. Symptoms associated with obesity related syndromes, disorders, and diseases include, but are not limited to, reduced activity.

Metabolism related syndromes, disorders or diseases include, but are not limited to, metabolic syndrome, dyslipidemia, elevated blood pressure, diabetes, insulin sensitivity or resistance, hyperinsulinemia, hypercholesterolemia, hyperlipidemias, hypertriglyceridemias, arteriosclerosis, atherosclerosis, other cardiovascular diseases, osteoarthritis, dermatological diseases, sleep disorders, cholelithiasis, hepatomegaly, steatosis, abnormal alanine aminotransferase levels, polycystic ovarian disease, inflammation, and the like. Diabetes related syndromes, disorders or diseases include, but are not limited to, glucose dysregulation, insulin resistance, glucose intolerance, hyperinsulinemia, dyslipidemia, hypertension, obesity, hyperglycemia and the like.

Catabolism related syndromes, disorders or diseases include, but are not limited to, catabolism in connection with pulmonary dysfunction and ventilator dependency; cardiac dysfunction, e.g., associated with valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure.

Social or mood related syndromes, disorders or diseases include, but are not limited to, depression, anxiety, psychosis, social affective disorders, cognitive disorders and the like.

Substance abuse related syndromes, disorders or diseases include, but are not limited to, drug abuse and drug withdrawal. Abused substances include, but are not limited to, alcohol, amphetamines (or amphetamine like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, opioids, heroin abuse, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics or benzodiazepines, combinations of any of the foregoing. The compounds and pharmaceutical compositions can also be used to treat withdrawal symptoms and substance-induced anxiety or mood disorder. Preferebaly, the compounds and compositions described herein may be used to treat alcoholism and tobacco abuse.

Learning, cognition or memory related syndromes, disorders or diseases include, but are not limited to, memory loss or impairment as a result of age, disease, side effects of medications (adverse events) or the like. Memory impairment is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld- Jakob disease, HIV, cardiovascular disease, and head trauma as well as age-related cognitive decline. Generally, dementias are diseases that include memory loss and additional intellectual impairment separate from memory. The compounds and pharmaceutical compositions of the present invention are also useful in treating cognitive impairments related to attentional deficits, such as attention deficit disorder.

Muscle spasm syndromes, disorders or diseases include, but are not limited to, multiple sclerosis, cerebral palsy and the like.

Locomotor activity and movement syndromes, disorders or diseases include, but are not limited to, stroke, Parkinson's disease, multiple sclerosis, epilepsy and the like.

Respiratory related syndromes, disorders or diseases include, but are not limited to, diseases of the respiratory tract, chronic pulmonary obstructive disorder, emphysema, asthma, bronchitis and the like. Autoimmune or inflammation related syndromes, disorders or diseases include, but are not limited to, psoriasis, lupus erythematosus, diseases of the connective tissue, Sjogren's syndrome, ankylosing spondylarthritis, rheumatoid arthritis, reactional arthritis, undifferentiated spondylarthritis, Behcet's disease, autoimmune hemolytic anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloses, graft rejection or diseases affecting the plasma cell line; allergic diseases: delayed or immediate hypersensitivity, allergic rhinitis, contact dermatitis or allergic conjunctivitis infectious parasitic, viral or bacterial diseases (such as AIDS and meningitis), inflammatory diseases (such as diseases of the joints including, but not limited to, arthritis, rhumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS)), osteoporosis, pain, chronic pain of the inflammatory type, allergies, rheumatoid arthritis, dermatitis, immunodeficiency, chronic neuropathic pain and the like.

Cell growth related syndromes, disorders or diseases include, but are not limited to, dysregulated mammalian cell proliferation, breast cancer cell proliferation, prostrate cancer cell proliferation and the like.

Pain related syndromes, disorders or diseases include, but are not limited to, central and peripheral pathway mediated pain, bone and joint pain, migraine headache associated pain, cancer pain, menstrual cramps, labor pain and the like.

Neurodegenerative related syndromes, disorders or diseases include, but are not limited to, Parkinson's disease, multiple sclerosis, epilepsy, ischemia or secondary biochemical injury collateral to traumatic head or brain injury, brain inflammation, eye injury or stroke, Alzheimer's disease, Huntington's disease, Tourett's syndrome, plaque sclerosis, spinal cord injury, and the like.

The compounds of this invention may also be used in conjunction with other pharmaceutical agents for the treatment of the diseases, conditions and/or disorders described herein. Therefore, methods of treatment that include administering compounds of the present invention in combination with other pharmaceutical agents are also provided. Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention include, but are not limited to, anti-obesity agents such as apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, llβ-hydroxy steroid dehydrogenase-1 (llβ-HSD type 1) inhibitors, PDEIV inhibitors, other CBl and CB2 modulators, peptide YY_3-36 or analogs thereof, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, β₃ adrenergic receptor agonists, dopamine receptor agonists (such as bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT_2c receptor agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as a bombesin agonist), neuropeptide-Y receptor antagonists, thyromimetic agents, dehydroepiandrosterone or an analog thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, glucagon-like peptide- 1 (GLP-I) receptor agonists, Protein Tyrosine Phosphatase (PTP-IB) inhibitors, dipeptidyl peptidase IV (DPP-IV) inhibitors, antidiabetic agents, ciliary neurotrophic factors (such as Axokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, N. Y. and Procter & Gamble Company, Cincinnati, Ohio), human agouti-related protein (AGRP) inhibitors, ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, and neuromedin U receptor agonists. Other anti-obesity agents, including the preferred agents set forth herein below, are well known, or will be readily apparent in light of the instant disclosure, to one of ordinary skill in the art.

Especially preferred are anti-obesity agents such as orlistat, sibutramine, bromocriptine, ephedrine, leptin, peptide YY_3-36 or an analog thereof (including the complete peptide YY), and pseudoephedrine. Preferably, compounds of the present invention and combination therapies are administered in conjunction with exercise and a sensible diet.

Anti-obesity agents for use in the combinations, pharmaceutical compositions, and methods of the invention can be prepared using methods known to one of ordinary skill in the art, for example, sibutramine can be prepared as described in U.S. Pat. No. 4,929,629; bromocriptine can be prepared as described in U.S. Pat. Nos. 3,752,814 and 3,752,888; orlistat can be prepared as described in U.S. Pat. Nos. 5,274,143, 5,420,305, 5,540,917, and 5,643,874; and PYY_3-36 (including analogs) can be prepared as described in U.S. Patent Publication No. 2002/0141985 and International Publication No. WO 03/027637. All of the above recited references are incorporated herein by reference.

Other suitable pharmaceutical agents that may be administered in combination with the compounds of the present invention include agents designed to treat tobacco abuse (e.g., nicotine receptor partial agonists, bupropion hypochlorite (also known under the traderiame Zyban™) and nicotine replacement therapies), agents to treat erectile dysfunction (e.g., dopaminergic agents, such as apomorphine), ADD/ADHD agents (e.g., Ritalin™ (methylphenidate hydrochloride), Strattera™ (atomoxetine hydrochloride), Concerta™ (methylphenidate hydrochloride) and Adderall™ (amphetamine aspartate; amphetamine sulfate; dextroamphetamine saccharate; and dextroamphetamine sulfate)), and agents to treat alcoholism, such as opioid antagonists (e.g., naltrexone (also known under the tradename ReVia™) and nalmefene), disulfiram (also known under the tradename Antabuse ™), and acamprosate (also known under the tradename Campral™)). In addition, agents for reducing alcohol withdrawal symptoms may also be co-administered, such as benzodiazepines, beta- blockers, clonidine, carbamazepine, pregabalin, and gabapentin (Neurontin™). Treatment for alcoholism is preferably administered in combination with behavioral therapy including such components as motivational enhancement therapy, cognitive behavioral therapy, and referral to self-help groups, including Alcohol Anonymous (AA).

Other pharmaceutical agents that may be useful include antihypertensive agents; antidepressants (e.g., fluoxetine hydrochloride (Prozac™)); cognitive improvement agents (e.g., donepezil hydrochloride (Aircept™.) and other acetylcholinesterase inhibitors); neuroprotective agents (e.g., memantine); antipsychotic medications (e.g., ziprasidone (Geodon ), risperidone (Risperdal ), and olanzapine (Zyprexa )); insulin and insulin analogs (e.g., LysPro insulin); GLP-I (7-37) (insulinotropin) and GLP-I (7-36)-NH₂; sulfonylureas and analogs thereof: chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, Glypizide^®, glimepiride, repaglinide, meglitinide; biguanides: metformin, phenformin, buformin; α2-antagonists and imidazolines: midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulin secretagogues: linogliride, A-4166; glitazones: ciglitazone, Actos^® (pioglitazone), englitazone, troglitazone, darglitazone, Avandia^® (BRL49653); fatty acid oxidation inhibitors: clomoxir, etomoxir; α-glucosidase inhibitors: acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945; β- agonists: BRL 35135, BRL 37344, RO 16-8714, ICI D7114, CL 316,243; phosphodiesterase inhibitors: L-386,398; lipid-lowering agents: benfluorex: fenfluramine; vanadate and vanadium complexes (e.g., Naglivan ) and peroxovanadium complexes; amylin antagonists; glucagon antagonists; gluconeogenesis inhibitors; somatostatin analogs; antilipolytic agents: nicotinic acid, acipimox, WAG 994, pramlintide (Symlin™), AC 2993, nateglinide, aldose reductase inhibitors (e.g., zopolrestat), glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, sodium-hydrogen exchanger type 1 (NHE-I) inhibitors and/or cholesterol biosynthesis inhibitors or cholesterol absorption inhibitors, especially a HMG- CoA reductase inhibitor, or a HMG-CoA synthase inhibitor, or a HMG-COA reductase or synthase gene expression inhibitor, dysliidemic agents, a CETP inhibitor, a bile acid sequesterant, a fibrate, an ACAT inhibitor, a squalene synthetase inhibitor, an anti-oxidant or niacin. The compounds of the present invention may also be administered in combination with a naturally occurring compound that acts to lower plasma cholesterol levels. Such naturally occurring compounds are commonly called nutraceuticals and include, for example, garlic extract, Hoodia plant extracts, niacin and guggle lipids.

The combination may have the following embodiments. For example, in one embodiment, there are provided combination comprising one or more compounds described herein and one or more of therapeutic agents selected from anti-obesity agents, dyslipidemic agents, CETP inhibitors, HMG-COA reductase inhibitors, fibrates, ACAT inhibitors, other CBl or CB2 modulators, PDE IV inhibitors, DPP-IV inhibitors, antidiabetic agents, guggle lipids for treating, preventing disease, disorder and/or conditions- mediated by CB receptors (such as CBl or CB2). In an another embodiment, there are provided combination comprising one or more compounds described herein and one or more therapeutic agents selected from antiobesity agents, dyslipidemic agents, CETP inhibitors, HMG-COA reductase inhibitors, fibrates or guggle lipids for treating, preventing disease, disorder and/or conditions mediated by CB receptors (such as CBl or CB2). The combination may optionally comprise one or more of pharmaceutically acceptable carriers, diluents or excipients.

The compounds of the present invention (including the pharmaceutical compositions and processes used therein) may be used alone or in combination with other pharmaceutical agents in the manufacture of a medicament for the therapeutic applications described herein.

Methods of preparation Scheme I

(2) O) (I)

According to one embodiment, a compound of Formula I is prepared by the above Scheme I. X₁, X₂, PΛ, PΛ, R² _a, R²b, R²c, R² _d, R² _e, R³a, R³b,R³ _c,R³d and R³ _e are as defined above.

A compound of Formula (2) is reacted with a compound of Formula (3) (wherein L₂ is a suitable leaving group, such as halogen), optionally in one or more suitable solvents (e.g., dimethylformamide, acetonitrile, dimethylacetamide, ethanol or a mixture thereof) to form the bicyclic compound of Formula (I). The reaction may be performed in the presence of one of more bases such as triethylamine, potassium carbonate, cesium carbonate, or a mixture thereof. Preferably, the reaction is performed at an elevated temperature (e.g., 60⁰C and above).

Scheme II

Step l:

(4) (5) (2)

Step 2:

In another embodiment, a compound of Formula (I), where R'_ais substituted or unsubstituted aryl, R^ is hydrogen, and R² _a to R² _e, R³ _a to R³ _e, X₁ and X₂ are as defined above, is synthesized as shown above in scheme II. L₂ is defined above.

A compound of Formula (4) is converted to a compound of Formula (5) (wherein L₁ is a suitable leaving group, such as halogen), for example by reacting the compound of Formula (4) with a halogenating agent (e.g., N-bromosuccinimide, N-iodosuccinimide, or the like), optionally in one or more suitable solvents (e.g., toluene, tetrahydofuran, diethylether, 1,4-dioxane or mixtures thereof). The compound of Formula (5) is converted to a compound of Formula (2) (wherein R^l _a is substituted or unsubstituted aryl and R'_b is hydrogen), for example by reacting the compound of Formula (5) with a compound having the formula RV B(OH)₂. The reaction may be performed in one or more suitable solvents (e.g., tetrahydofuran, diethylether, 1,4-dioxane or a mixture thereof). This reaction may optionally be performed in the presence of a catalyst (e.g., bis-(triarylphosphine) palladium (II) chloride) and/or a base (such as cesium fluoride, aqueous sodium carbonate or the like). Preferably, the reaction is performed at the reflux temperature of the solvent used.

The compound of Formula (2) can be reacted with a compound of Formula (3), optionally in one or more suitable solvents (e.g., dimethylformamide, dimethylsulfoxide, tetrahydofuran, diethylether, 1,4-dioxane or mixtures thereof), to form the compound of Formula (I).

Alternatively, the compound of Formula (2) can be reacted with a compound of Formula (2a) to form a compound of Formula (6). The reaction can be performed in one or more suitable solvents, such as aprotic polar solvents (e.g., dimethylformamide, tetrahydrofuran, carbon tetrachloride, acetonitrile and mixtures thereof), polar protic solvents (e.g., methanol, ethanol, isopropylalcohol and mixtures thereof) or a mixture thereof.

The compound of Formula (6) is converted to a compound of Formula (7) (wherein L₁ is as defined above), for example by reacting the compound of Formula (6) with a halogenating agent (e.g., N-bromosuccinimide, N-iodosuccinimide, or the like) optionally in one or more suitable solvents, such as aprotic polar solvents (e.g., dimethylformamide, tetrahydrofuran, acetonitrile, carbon tertrachloride, or a mixture thereof).

The compound of Formula (7) is reacted with a compound of Formula (7a) to form the compound of Formula (I). The reaction can be performed in the presence of a coupling agent (such as bis(triphenylphosphine)palladium(II) chloride, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) acetate, or a mixture thereof) and/or a base (such as sodium carbonate, cesium fluoride, or a mixture thereof). The reaction is performed in the presence of a suitable solvent (e.g., 1,4-dioxane, toluene, water or a combination thereof). Preferably, the reaction is performed at 100 ⁰C or above.

In yet another embodiment, a compound of Formula (I) is prepared by the above Scheme III. X₁, X₂, R¹,, R^l _h, R² _a, R² _b, R² _C, R² _d, R²e, R³ _a, R³b, R³ ₀₎ R³d, R³e, Li and L₂ are as defined above.

A compound of Formula (5) is reacted with a compound of Formula (3), optionally in of one or more suitable solvents (e.g., dimethylformamide, dimethylsulfoxide, tetrahydofuran, ethanol, acetonitrile, 1,4-diox.ane or mixtures thereof) and preferably at an elevated temperature (e.g., 60 ⁰C and above), to form a compound of Formula (8).

The compound of Formula (8) is converted to a compound of Formula (T), for example, by reaction with a compound having the formula R _aB(OH)2. Preferably, thee reaction is performed in the presence of a base (such as sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, potassium fluoride or a mixture thereof), and optionally in one or more solvents, such as aprotic polar solvents (e.g., tetrahydofuran, ethanol, toluene, 1,4-dioxane, water or a mixture thereof). cheme IV

In yet another embodiment, a compound of Formula (13) is prepared by the above Scheme IV. X₂ is N, and R² _a, R² _b, R² _C, R² _d, R² _e, R³ _a,

R³d, R³e and R⁴ are as defined above.

Ethylacetoacetate is converted to a compound of Formula (9), for example by reacting it with a suitable reagent, such as dimethylformamide acetal. The compound of Formula (9) is converted to a compound of Formula (10), for example by reacting the compound of Formula (9) with guanidine hydrochloride. The reaction can be performed in the presence of one or more bases (such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium hydroxide, sodium hydroxide or a mixture thereof) and/or in one or more suitable solvents (such as ethanol, methanol, isopropanol, t-butyl alcohol or a mixture thereof).

The compound of Formula (10) is reacted with a compound of Formula (3) to form a compound of Formula (11). The reaction can be performed in one or more suitable solvents, such as aprotic polar solvents (e.g., dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, ethanol or a mixture thereof).

The compound of Formula (11) is hydrolysed to form a compound of Formula (12). The hydrolysis can be performed in the presence of a base (such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or a mixture thereof) and/or in one or more suitable solvents (such as aprotic polar solvents (e.g., dimethylformamide, dimethylsulfoxide, dichloromethane, dichloroethane, tetrahydrofuran or a mixture thereof), polar solvents (e.g., methanol, ethanol, propanol, isopropanol, t-butanol, water or a mixture thereof) or a mixture thereof).

The compound of Formula (12) is converted to the compound of Formula (13), for example by reacting the compound of formula (12) with a compound having the formula R⁴- L² (wherein L² is as defined above and R⁴ is for example, NR^aR^b or -OR^a, where R^a and R^b are as defined above). The reaction is preferably performed in the presence of a coupling agent (such as benztriazoline-l-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate, N,N₎Λ'^'',iV^'-Tetramethyl-C>-(l/i^'-berizotriazol-l-yl)uronium hexafluorophosphate, N,N,N',N'- Tetramethyl-(9-(benzotriazol- 1 -yl)uronium tetrafluoroborate, N,N,ΛP//'-Tetramethyl-0-(7- azabenzotriazol-l-yl)uronium hexafluorophosphate or a mixture thereof) and/or one or more bases (such as triethylamine, disiopropylethylamine, pyridine, potassium carbonate, sodium carbonate or a mixture thereof). ^■ The reaction can be performed in one or more suitable solvents, such as aprotic polar solvents (e.g., dimethylformamide, dimethylsulfoxide, dichloromethane, dichloroethane, tetrahydrofuran or a mixture thereof).

Scheme V

In yet another embodiment, compounds of Formulas (19) and (20) are prepared by the above Scheme V. R^l _a, R² _a,

R² _C, R²d, R² _e, R³ _a, R³b,

R³d, R³e and L₁ are as defined above.

Pyrazin-2-yl-amine is reacted with a halogenating agent (e.g., N-bromosuccinimide, N-iodosuccinimide, or the like), optionally in one or more suitable solvents, such as aprotic polar solvents (e.g., tetrahydofuran, dimethyl formamide carbon tetrachloride, acetonitrile, 1,4-dioxane or a mixture thereof), to form a compound of Formula (14).

The compound of Formula (14) can be reacted with a compound of Formula (3), optionally in one or more suitable solvents, such as aprotic polar solvents (e.g., tetrahydofuran, dimethyl formamide, acetonitrile, ethanol, 1,4-dioxane or mixtures thereof), to form a compound of Formula (15). The compound of Formula (15) is converted to a compound of Formula (20), for example, by reaction with a compound having the formula R^B(OH)₂.

Alternatively, the compound of Formula (14) can be converted to a compound of Formula (16), for example, by reaction with a compound of Formula R^B(OH)₂ in the presence of one or more suitable solvents, such as aprotic polar solvents (e.g., dimethylformamide, tetrahydrofuran, 1,4-dioxane, ora mixture thereof), polar protic solvents (e.g., methanol, ethanol, isopropylalcohol or a mixture thereof) or a mixture thereof and/or in the presence of a catalyst (e.g., bis(triphenylphosphine)palladium(II) chloride or tetrakis(triphenylphosphine)palladium(0)). The compound of Formula (16) can be reacted with a compound of Formula (3) to form a compound of Formula (20). The reaction can be performed in one or more suitable solvents, such as aprotic polar solvents (e.g., tetrahydofuran, dimethyl formamide, and acetonitrile), polar protic solvents (e.g., ethanol, 1,4-dioxane or a mixture thereof) or a mixture thereof and/or at elevated temperature (60 ⁰C or above).

Alternatively, the compound of Formula (16) can be reacted with a halogenating agent (e.g., N-bromosuccinimide, N-iodosuccinimide, or the like), optionally in one or more suitable solvents (e.g., tetrahydofuran, carbon tetrachloride, 1,4-dioxane or mixtures thereof), to form a compound of Formula (17).

The compound of Formula (17) is methylated to form a compound of Formula (18). The reaction can be performed in the presence of one or more suitable bases (such as sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, potassium fluoride, or a mixture thereof) and/or a coupling agent (such as bis(triphenylphosphine)palladium(II) chloride, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) acetate, or a mixtureof ). The reaction can be performed in one or more suitable solvents, such as aprotic polar solvents (e.g., tetrahydofuran, dimethyl formamide, acetonitrile, or a mixture thereof) or polar protic solvents (e.g., ethanol, 1,4-dioxane or a mixture thereof).

The compound of Formula (18) is reacted with a compound of Formula (3), optionally in the presence of one or more suitable solvents (e.g., dimethylformamide, dimethylsulfoxide, tetrahydofuran, 1,4-dioxane, ethanol, acetonitrile or mixtures thereof), to form the compound of Formula (19).

Scheme VI

In yet another embodiment, a compound of Formula (22) is prepared by the above Scheme VI.

L₁ are as defined above and R⁴ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclic group.

A compound of Formula (17) is reacted with compound of Formula (3), optionally in one or more suitable solvents, such as dimethylformamide, dimethylsulfoxide, tetrahydofuran, 1,4-dioxane, ethanol, acetonitrile or a mixture thereof), to form a compound of Formula (21). The reaction is optionally performed in the presence of an organic or inorganic base such as triethyl amine, pyridine, or potassium carbonate and/or at an elevated temperature (e.g. 60 ⁰C or above). The compound of Formula (21) is reacted with a compound having the formula MOR (wherein M is an alkali metal) to form the compound of Formula (22). The reaction is optionally performed in one or more suitable solvents, such as polar protic solvents (e.g., methanol, ethanol, isopropanol, t-butanol or a mixture thereof), aprotic polar solvents (e.g., tetrahydrfuran, dimethyl formamide, 1,4-dioxane, diethyl ether or a mixture thereof) or a mixture thereof, either at room temperature or elevated temperature. Preferably, the reaction is performed at the reflux temperature of the solvent used.

In yet another embodiment, a compound of Formula (25) is prepared by the above Scheme VII. X₁, X₂, R\, R² _a, R² _b, R² _C, R² _d, R² _e, R³ _a, R³b,R³c,R³d, R³ _e and L₁ are as defined above, and HET is a substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl.

A compound of Formula (5) is converted to a compound of Formula (23) (e.g., by cyanation). For example, the compound of Formula (5) can be reacted with a cyanide source (e.g., trimethylsilylcyanide, copper cyanide, zinc cyanide or a mixture thereof), optionally in one or more suitable solvents, such as aprotic polar solvents (e.g., dimethylsulfoxide, N- methylpyrrolidone, dimethylformamide, quinoline, pyridine or a mixture thereof). The reaction can be performed at an elevated temperature (e.g., 100 ⁰C and above). The compound of Formula (23) is reacted with a compound of Formula (3), optionally in one or more suitable solvents (e.g., dimethylformamide, dimethylsulfoxide, tetrahydofuran, 1,4- dioxane, ethanol, acetonitrile or a mixture thereof), to form a compound of Formula (24). The compound of Formula (24) is converted into the compound of Formula (25), for example by reacting the compound of Formula (24) with a suitable reagent, such as sodium azide, substituted or unsubstituted diazonium compounds, or substituted or unsubstituted acyl halides. Optionally, the reaction is performed in the presence of a suitable reagent for example, ammonium chloride, or in the presence of a base such as sodium hydroxide, potassium hydroxide, or cesium hydroxide. The reaction can be performed in one or more suitable solvents, such as dimethylformamide, diethylformamide, acetonitrile, and the like, and either at room temperature or at an elevated temperature (e.g., 100 ⁰C and above).

007/000459

Scheme VIII

In yet another embodiment, a compound of Formula (28) is prepared by the above Scheme VIII. X₂ is N, and R^a, R² _a, R² _b, R² _C, R² _d, R² _e, R³ _a, R³b,R³ _c>R³ _d and R³ _e are as defined above.

A compound of Formula (11) is converted to a compound of Formula (26), for example, by reaction with hydrazine hydrochloride, optionally in one or more suitable solvents, such as methanol, ethanol, isopropanol or a mixture thereof). The compound of Formula (26) is reacted with a compound having the formula R^aCOLj (wherein L₁ is a leaving group such as halogen and R^a is as defined earlier) to form a compound of Formula (27). The reaction can be performed in one or more suitable solvents, such as aprotic polar solvents (e.g., dichloromethane, dichloroethane, chloroform or a mixture thereof),

The compound of Formula (27) is cyclized to form the compound of Formula (28), for example, by reaction with a suitable reagent, such as thionyl chloride, phosphorus oxychloride, or phosphorus pentoxide. The reaction can be performed in one or more suitable solvents, such as aprotic polar solvents (e.g., ethyl acetate, acetonitrile, dimethylformamide, diethylformamide or a mixture thereof). Scheme IX

(30)

In yet another embodiment, a compound of Formula (30) is prepared by the above Scheme IX. X₂ is N, and R² _a, R² _b, R² _C, R² _d, R² _e, R³ _a, R³b,R³c,^R3d, ^R3e, ^{R* and Ry are as} defined above.

A compound of Formula (12) is reacted with substituted or unsubstituted hydroxyamine to form a compound of Formula (29). The reaction can be performed in the presence of a coupling agent (such as benztriazoline-l-oxy-tris(dimethylamino)- phosphonium hexafluorophosphate, N,JV,iV,iV'-Tetramethyl-O-(lH-benzotriazol- 1 -yl)uronium hexafraorophosphate, N,N, N',iV-Tetramethyl-O-(benzotriazol-l -yl)uronium tetrafluoroborate, NJ\yV^l _;>iV^T-Tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate or a mixture thereof) and/or in the presence or one or more bases (such as triethylamine, disiopropylethylamine, pyridine, potassium carbonate, sodium carbonate or a mixture thereof). The reaction can also be performed in one or more suitable solvents, such as aprotic polar solvents (e.g., dimethylformamide, dimethylsulfoxide, dichloromethane, dichloroethane, tetrahydrofuran or a mixture thereof). The compound of Formula (29) is cyclized, for example, by reaction with a suitable reagent, such as phosphorus oxychloride or thionyl chloride to form a compound of Formula (30). The reaction can be performed in one or more suitable solvents, such as aprotic polar solvents (e.g., acetonitrile, dimethylformamide, diethylformainide or a mixture thereof), either at room temperature or at elevated temperature, to form the compound of Formula (30).

Scheme X

In yet another embodiment, a compound of formula (28) is prepared by the above Scheme X, wherein R^! _a is substituted or unsubstituted oxadiazole; R*_b is H; X₁ is C-CH₃; and R² _a-R²e, R³a-R³e and X₂ are as defined earlier.

A compound of formula (10) is converted to a compound of formula (31), for example, by reaction with hydrazine. The reaction can be perfomed in one or more suitable solvents, such as polar protic solvents (e.g, methanol, ethanol, isopropanol or a mixture thereof). Preferably, the reaction is performed at an elevated temperature.

The compound of formula (31) is converted to a compound of formula (32), for example, by reaction with pivaloyl chloride. The reaction can be performed in the presence of one or more bases (such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or a mixture thereof) and/or in one or more suitable solvents (e.g., dichloromethane, dichloroethane, dibromoethane, chloroform, carbon tetrachloride or a mixture thereof).

The compound of formula (32) is reacted with a compound of formula (3) to form a compound of formula (33). The reaction can be performed in one or more suitable solvents such as aprotic polar solvents (e.g., dimethylsulfoxide, N-methylpyrrolidone, dimethylformamide, acetonitrile, tetrahydofuran, 1,4-dioxane or a mixture thereof) or protic polar solvents (e.g., ethanol, methanol, isopropanol or a mixture thereof) and/or at elevated temperature (60⁰C and above). 000459

The compound of formula (33) is cyclized to form the compound of formula (28), for example, by reaction with phosphorous oxychloride. The reaction can be performed in one or more suitable solvents such as ethyl acetate, tetrahydrofuran, dichloromethane, dichloroethane, chloroform, ethanol, methanol, acetonitrile or a mixture thereof, and either at room temperature or at an elevated temperature. Preferably, the reaction is performed at the reflux temperature of the solvent used.

Scheme XI

Step I

(35)

In yet another embodiment, a compound of formula (39) is prepared by the above Scheme XI, wherein R is CN, -OR^a, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -NR⁴R⁵; and R^, R^, R² _a-R²e, R³ _a-R³e and X₁ are the same as defined earlier.

A compound of formula (34) is converted to a compound of formula (35) (wherein L₁ and L₃ are suitable leaving groups, such as halogen), for example by reacting the compound of Formula (34) with a halogenating agent (e.g., N-bromosuccinimide, N-iodosuccinimide, and the like). The reaction can be performed in one or more suitable solvents (e.g., tetrahydofuran, diethylether, acetonitrile, 1,4-dioxane or a mixture thereof).

The compound of formula (35) can be converted to a compound of formula (36) (wherein R is -CN, -OR^a, aryl, or -NR⁴R⁵ and L₁ is preferably chlorine and L₃ is preferably bromine), for example, by reaction with a suitable reagent. The reaction can be performed in one or more suitable solvents, for example, aprotic polar solvents (e.g., dimethylsulfoxide, N- methylpyrrolidone, dimethylformamide, pyridine or a mixture thereof) or polar protic solvents (e.g., methanol, ethanol, 2,2,2-trifluoroethanol, or a mixture thereof).

The compound of formula (36) is reacted with a compound of formula (3) to form a compound of formula (38). The reaction can be performed in the presence of one or more bases, for example, triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or a mixture thereof and/or in one or more suitable solvents (e.g., dimethylformamide, dimethylsulfoxide, tetrahydofuran, 1,4-dioxane, ethanol, acetonitrile or a mixture thereof).

The compound of formula (35) can alternatively be reacted with a compound of formula (3) to form a compound of formula (37). The reaction can be performed in the presence of one or more bases, for example, triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or a mixture thereof and/or in one or more suitable solvents (e.g., dimethylformamide, dimethylsulfoxide, tetrahydofuran, 1,4-dioxane, ethanol, acetonitrile or a mixture thereof).

The compound of formula (37) can be converted to a compound of formula (38) (wherein R is -CN, -OR^a, aryl, or -NR⁴R⁵ and L₁ is preferably chlorine and L₃ is preferably bromine or iodine), for example, with a suitable reagent. The reaction can be performed in one or more suitable solvents, for example, aprotic polar solvents (e.g., 1,4-dioxane, tetrahydrofuran, dimethylsulfoxide, N-methylpyrrolidone, dimethylformamide, pyridine or a mixture thereof), protic polar solvents (e.g., ethanol, methanol, isopropanol, t-butanol or a mixture thereof) or a mixture thereof.

For instrance, the compound of formula (37) (wherein L₁ is preferably chlorine and L₃ is preferably iodine) can be reacted with R-B(OH)₂ (wherein R is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl) to form a compound of formula (38). The reaction can be performed in the presence of a coupling agent, for example, bis(triphenylphosρhine)ρalladium(II) chloride, tetrakis(triphenylphosphine)palladium(0), bis(triρhenylphosphine)palladium(II) acetate or a mixture thereof, and/or in the presence of one or more bases, for example, triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, or a mixture thereof. The reaction can also be performed in one or more suitable solvents, for example, aprotic polar solvents (e.g., 1,4-dioxane, tetrahydrofuran, diethylether or a mixture thereof). The compound of formula (38) can be converted to a compound of formula (39). For example, when R*_a is CN, the compound of formula (38) can be cyanted (i.e., L¹ is converted to R¹ _Ji which is CN), for example, by reaction with a cyanide source, such as trimethylsilylcyanide, copper cyanide, zinc cyanide sodium cyanide or a mixture thereof. When R*_a is OR^a, the compound of formula (38) can be converted by reaction with a compound of the formula M0R^a (wherein M is metal). When R*_a is NR⁴R⁵, the compound of formula (38) can be converted by reaction with a compound of the formula L¹NR⁴R⁵ (wherein L¹ is a suitable leaving group). The reaction can be performed in one or more suitable solvents, for example, protic polar solvents (e.g., methanol, ethanol, isopropanol, t- butanol or a mixture thereof). Alternatively, the compound of formula (39) can be formed by reacting the compound of formula (38) with R^B(OH)₂, optionally in the presence of a coupling reagent (e.g. bis(triphenylphosphine)palladium(II) chloride or bis(triphenylphosphine)palladium(II) acetate).

Scheme XII

In another embodiment, a compound of formula (43) is prepared by the above scheme XII, wherein X₁ is CH₂R⁶ (wherein R⁶ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or -NR⁴R⁵) and R^, R\, R² _a-R² _e, R³ _a-R³ _e and X₂ are as defined earlier. A compound of formula (40) can be reacted with a compound of Formula (3) to form a compound of formula (41). The reaction can be performed in one or more solvents, for example, aprotic polar solvents (e.g., dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, diethylether, dioxane or a mixture thereof), polar protic solvents (e.g., ethanol, methanol, isopropanol, t-butanol, ethyl acetate, or a mixture thereof), or a mixture thereof. The reaction can also be performed in the presence or absence of one or more bases, for example, triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or a mixture thereof.

The compound of formula (41) can be reacted with a halogenating agent to form a compound of formula (42). Suitable halogenating agents include, but are not limited to, N- bromosuccinimide, N-iodosuccinimide, bromine, bromine-acetic acid, thionyl chloride, thionyl bromide, phosphorous trichloride or phosphorous oxychloride. Optionally, the reaction is performed in the presence of a radical initiator, such as azo compounds (e.g., azobisisobutyronitrile or l,l'-Azobis(cyclohexanecarbonitrile)), organic peroxide (e.g., benzoyl peroxide, methyl ethyl ketone peroxide, peroxyacetone, or triacetone triperoxide) or a mixture thereof and/or in one or more solvents, for example, carbon tetrachloride, dichloromethane, dichloroethane, dibromoethane, chloroform or a mixture thereof.

The compound of formula (42) is converted to a compound of formula (43), for example, by reaction with a compound of including an R⁶ moiety (e.g., a suitable grignard reagent, an aliphatic or aromatic alcohol, or -NR⁴R⁵). The reaction can be performed in the presence or absence of one or more bases (such as sodium hydride, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, sodium hydroxide, potassium hydroxide or triethylamine) optionally in one or more solvents (for example, aprotic polar solvents (e.g., dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, dioxane, tetrahydrofuran, diethylether or a mixture thereof), polar protic solvents (e.g., ethanol, methanol, isopropanol, t-butanol, ethyl acetate, or a mixture thereof), or a mixture thereof.

Alternatively, the compound of formula (41) can be directly converted to a compound of Formula (43), for example, by reaction with a compound of formula R⁶-X (wherein X is a suitable leaving group (e.g., halogen) and R⁶ is substituted or unsubstituted alkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl). The reaction can be performed in the presence or absence of one or more bases (such as sodium hydride, butyl lithium, lithium diisoprpylamide, or a mixture thereof) and/or in one or more solvents, for example, aprotic polar solvents (e.g., dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile, dioxane, tetrahydrofuran, diethylether or a mixture thereof). S

In another embodiment, a compound of Formula (46) can prepared by the above scheme XIII, wherein R*_a is -CH≡CR⁸ (where R⁸ is substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl) and R^! _b, R² _a-R² _e, R³ _a-R³ _e, L₁, X₁ and X₂ are as defined earlier.

The compound of formula (5) is reacted with a compound of formula (3) to form a compound of Formula (8). The reaction can be performed in one or more solvents, for example, aprotic polar solvents (e.g., dimethylformamide, dimethylacetamide, acetonitrile, tetrahydrofuran, diethylether, dioxane or a mixture thereof), polar protic solvents (e.g., ethanol, methanol, isopropanol, t-butanol, or a mixture thereof) and/or in the presence or absence of one or more bases, for example, triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide or a mixture thereof.

The compound of formula (8) is converted to a compound of formula (44), for example, by reaction with a compound of formula R⁷-C≡CH (wherein R⁷ is a protecting group, such as trimethylsilyl). The reaction can be performed in the presence or absence of one or more bases, for example, triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or a mixture thereof and/or one or more catalysts, for example, bis-(triarylphosphine) palladium(II) chloride, bis- (triarylphosphine) nickel (II) chloride, palladium (II) acetate, palladium (II) chloride, palladium on carbon, copper (II) acetate, tetrakis(triphenylphosphine)palladium (0), bis(benzonitrile)palladium (II) chloride or a mixture thereof. The reaction can be performed in one or more solvents, for example, polar protic solvents (e.g., ethanol, methanol, isopropanol, t-butanol, water, or a mixture thereof) or aprotic polar solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, tetrahydrofuran, diethylether, dioxane or a mixture thereof).

The compound of formula (44) is deprotected (e.g., desilylated) to form a compound of Formula (45). The reaction can be performed in the presence or absence of one or more bases, for example, potassium hydroxide, sodium hydroxide, triethylamine, sodium carbonate, potassium carbonate, cesium carbonate or a mixture thereof, or a suitable deprotecting reagent (e.g., tetrabutylammonium fluoride). The reaction can also be performed in one or more solvents, for example, polar protic solvents (e.g., ethanol, methanol, isopropanol, t-butanol, ethyl acetate, or a mixture thereof), or polar aprotic solvents (such as tetrahydrofuran or 1,4-dioxane).

The compound of formula (45) is converted to a compound of formula (46), for example, by reaction with a compound of formula R⁸ -X (wherein X is a suitable leaving group such as halogen and R is substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl). The reaction can be performed in the presence of (i) an amine (such as triethyl amine or the like) (ii) one or more catalysts (for example, bis-(triarylphosphine) palladium(II) chloride, bis-(triarylphosphine) nickel (II) chloride, palladium (II) acetate, palladium (II) chloride, palladium on carbon, copper (II) acetate, tetrakis(triphenylρhosρhine)palladium (0), bis(benzonitrile)palladium (II) chloride or a mixture thereof), and/or (iii) an organic or inorganic base. The reaction can also be performed in one or more solvents, for example, polar protic solvents (e.g., ethanol, methanol, isopropanol, £-butanol, or a mixture thereof) or aprotic polar solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, tetrahydrofuran, diethylether, dioxane or a mixture thereof). 000459

Scheme XIV

Step l

(54)

In another embodiment, compounds of formulas (53) and (54) can be prepared by the above scheme XIV, wherein R^, R^!b, R² _a-R² _e, R³ _a-R³ _e, Li, Xi and X₂ are as defined earlier.

A compound of formula (47) (wherein R⁸' is COOEt or CH(OMe)₂) is reacted with dimethylformamide dimethylacetal, optionally in one or more solvents (for example, polar protic solvents (e.g., ethanol, methanol, isopropanol, t-butanol, ethyl acetate, or a mixture thereof)) to form a compound of formula (48).

The compound of formula (48) is converted to a compound of formula (49), for example, by reaction with guanidine. The reaction can be performed in the presence or absence of one or more bases (for example, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium methoxide or a mixture thereof) and/or in one or more solvents (for example, polar protic solvents (e.g., ethanol, methanol, isopropanol, ^-butanol, ethyl acetate, or a mixture thereof)).

The compound of formula (49) (wherein R^8' is CH(OMe)₂) can be deprotected, for example, by reaction with one or more deprotecting agents (such as acids (e.g., hydrochloric acid, trifluoroacetic acid or a mixture thereof)) and further reduced with a reducing agent to form a compound of formula (50). Suitable reducing agents include, but are not limited to, sodium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminurn hydide or a mixture thereof.

The compound of formulas (49) or (50) can be converted to a compound of formula (51) (wherein R^8' is CH₂OH, CH(OMe)₂ or COOEt and X is halogen or hydrogen), for example, by reaction with a halogenating agent. Suitable halogenating agents include, but are not limited to, N-bromosucinimide and N-chlorosuccinimide. The reaction can be performed in one or more suitable solvents, such as aprotic polar solvents (e.g., acetonitrile, dimethylformamide, diethylformamide or a mixture thereof).

The compound of formula (51) is reacted with a compound of formula (3) optionally in one or more solvents to form a compound of formula (52). Suitable solvents include, but are not limited to, aprotic polar solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, diethylether, dioxane or a mixture thereof).

The compound of formula (52) (wherein R⁹ is COOEt) can be hydrolysed and then converted to a compound of formula (53) (wherein R¹⁰ is CONR⁴R⁵). The hydrolysis reaction can be performed in the presence of one or more bases (such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, or a mixture thereof) and/or in one or more solvents. Suitable solvents include, but are not limited to, polar protic solvents (e.g., ethanol, methanol, isopropanol, t-butanol, ethyl acetate, or a mixture thereof) or aprotic polar solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, diethylether, dioxane or a mixture thereof). The hydrolyzed compound can be converted to a compound of formula (53) by reaction with one or more reagents, such as oxalyl chloride, thionyl chloride, benztriazoline- l-oxy-tris(dimethylamino)phosphonium hexafluorophosphate or a mixture thereof. This reaction can be performed in the presence of one or more bases (for example, triethylamine, disiopropylethylamine, pyridine, potassium carbonate, sodium carbonate or a mixture thereof) and/or in one or more solvents (for example, aprotic polar solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, diethylether, dioxane or a mixture thereof).

The amide of formula (53) can be converted to a heteraryl group, for example, by reaction with a reagent, such as thionyl chloride, phosphorous oxychloride, thionyl bromide, phosphorous trichloride and the like, to form a compound of formula (53) (wherein R¹⁰ is heteroaryl].

Alternatively, the compound of formula (52) (wherein R⁹ is COOEt) can be converted to a compound of formula (53) (wherein R¹⁰ is heteroaryl, such as oxadiazole) according to the procedure as described in Scheme I.

The compound of formula (52) (wherein R is CH₂OH] can be deprotected, reduced, and converted to a compound of formula (54). For example, the compound of formula (52) can be reacted with one or more deprotecting agents (such as acids (e.g., hydrochloric acid, trifluoroacetic acid or mixtures thereof)), further reduced with a reducing agent (for example, sodium borohydride, sodium cyanoborohydride, lithium borohydride, boron trifluoride, lithium aluminum hydride, diisobutylaluminum hydide or a mixture thereof), and further reacted with a compound of formula R^B(OH)₂ to form a compound of formula (54).

Scheme XV Step

(57)

In another embodiment, a compound of formula (63) can be prepared by the above scheme XV, wherein R^ is H; R² _a-R² _e, R³ _a-R³ _e and X₂ are as defined earlier; Z is hydrogen or halogen (such as chlorine or bromine); and R¹⁰ is (i) alkyl substituted with hydroxy or alkoxy (e.g., CH₂OH and CH(OMe)₂), (ii) substituted or unsubstituted aryl, (iii) substituted or unsubstituted heteroaryl, or (iv) COOR^a, and R^a is as defined above.

A compound of formula (47a) (wherein R⁹ is trisubstituted alkyl, substituted or unsubstituted aryl or heteroaryl, COOR^a, or CH(OMe)₂) is reacted with dimethylformarnide dimethylacetal optionally in one or more solvents (for example, polar protic solvents (e.g., ethanol, methanol, isopropanol, t-butanol, ethyl acetate, or a mixture thereof)) to form a compound of formula (48a).

The compound of formula (48a) is cyclized to form a compound of formula (55), for example, by reaction with guanidine. The reaction may be performed in the presence or absence of one or more bases (for example, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium methoxide or a mixture thereof), and/or in one or more solvents (for example, polar protic solvents (e.g., ethanol, methanol, isopropanol, ϊ-butanol, ethyl acetate, or a mixture thereof)).

The compound of formula (55) (wherein R⁹ is CH(OMe)₂) can be deprotected, for example, with one or more deprotecting agents (for example, acids (e.g., hydrochloric acid, trifluoroacetic acid or a mixture thereof)) and further reduced to form a compound of formula (50). The compound can be further reduced with a reducing agent such as sodium borohydride, sodium cyanoborohydride, lithium borohydride, boron trifluoride, lithium aluminum hydride, diisobutylaluminum hydide or a mixture thereof.

The compounds of formulas (55) and (50) can be halogenated, for example, by reaction with a halogenating agent to form a compound of formula (57) (wherein R¹⁰ is CH₂OH, CH(OMe)₂, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, COOR^a and Z is halogen). Suitable halogenating agents include, but are not limited to, N-bromosucinimide and N-chlorosuccinimide. The reaction can be performed in one or more suitable solvents, such as aprotic polar solvents (e.g., acetonitrile, dimethylformamide, diethylforrnamide or a mixture thereof).1

The compound of formula (57a) (wherein Z is hydrogen or halogen such as chlorine or bromine, and R¹⁰ is CH₂OH, CH(OMe)₂, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or COOR^a) can be reacted with a compound of formula (3) to form a compound of formula (58). The reaction can be performed in one or more solvents, for example, aprotic polar solvents (e.g., dimethylformamide, dimethyacetamide, acetonitrile, dimethylsulfoxide, tetrahydrofuran, diethylether, dioxane or a mixture thereof).

The compound of formula (58) (wherein R¹⁰ is CH₂OH) can be oxidized to form a compound of Formula (59), for example, by reaction with one or more oxidizing agents, optionally in one or more solvents (for example, dichloromethane, dichloroethane, chloroform or a mixture thereof). Suitable oxidizing agents include, but are not limited to, pyridinium chlorochromate, pyridinium dichromate, chromium trioxide and dimethylsulfoxide-oxalyl chloride.

The compound of formula (59) can be reacted with an amine of formula NHR⁴R⁵ and reduced to form a compound of formula (63). The reaction can be performed in one or more solvents such as, dichloromethane, dichloroethane, ethanol, methanol, iospropanol or a mixture thereof and/or in the presence of one or more bases such as triethylamine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, or a mixture thereof. The compound can be reduced by reaction with a suitable reducing agent, such as sodium borohydride, lithium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride or a mxiture thereof.

Alternatively, the compound of formula (58) (wherein R¹⁰ is CH₂OH) can be converted to a compound of formula (61) (wherein L₂ is a suitable leaving group, for example, tosyl, mesyl, brosyl or triflate). For example, the compound of formula (58) can be reacted with a suitable reagent optionally in one or more solvents (such as, dichloromethane, dichloroethane, acetonitrile, dimethylformamide or a mixture thereof) and/or in the presence of one or more bases (such as, triethylamine, pyridine, sodium carbonate, sodium hydroxide, cesium carbonate, potassium hydroxide, or a mixture thereof).

The compound of formula (61) can be reacted with an amine of formula NHR⁴R⁵, optionally in one or more solvents (such as dichloromethane, dichloroethane, chloroform, acetonitrile, dimethylformamide or a mixture thereof) , optionally in the presence of one or more bases (such as, triethylamine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, or a mixture thereof), to form a compound of formula (63) (wherein R¹⁰ is CH₂NR⁴R⁵).

Alternatively, the compound of formula (57a), (wherein Z is halogen or hydrogen, and preferably chlorine or hydrogen) can be reacted with a compound of formula (2a) optionally in one or more solvents (for example, aprotic polar solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, ethanol, dioxane or a mixture thereof) and/or in the presence of one or more bases (for example, sodium carbonate, potassium carbonate, triethylamine, or a mixture thereof), to form a compound of formula (60).

The compound of formula (60) can be halogenated to form a compound of formula (62), for example, by reaction with a halogenating agent (e.g., N-bromosuccinimide or N- iodosuccinimide). The reaction can be performed in one or more suitable solvents, such as aprotic polar solvents (e.g., 1,4-dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, diethylformamide or a mixture thereof).

The compound of formula (62) can be reacted with a compound of formula (7a), optionally in the presence of a catalyst and/or one or more bases and optionally in one or more suitable solvents (, , which is further treated with a compound of formula (7a) optionally in the presence of a coupling agentto form the compound of formula (63). Suitable catalysts include, but are not limited to, bis-(triarylphosphine) palladium (II) chloride. Suitable bases include, but are not limited to, cesium fluoride, aqueous sodium carbonate, potassium carbonate, and mixtures thereof. Suitable solvents, but are not limited to, tetrahydofuran, diethylether, 1,4-dioxane and mixtures thereof. Suitable coupling agents, include, but are not limited to, bis(triphenylphosphine)palladium(II) chloride, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) acetate, and mixtures thereof.

Scheme XVI

(46) (64)

In another embodiment, a compound of formula (64) can be prepared by the above scheme XVI, wherein R*_b, R² _a-R² _e, R³ _a-R³ _e, R⁸, Xi and X₂ are as defined earlier.

The compound of formula (46) is reduced to form the compound of formula (64), for example, with a reducing agent, such as hydrogen/palladium-carbon or hydrogen/platinum- carbon, lithium aluminium hydride or the like. The reaction can be performed in one or more solvents (for example, ethanol, methanol, isopropanol, t-butanol, ethyl acetate, dioxane or a mixture thereof). Experimental Intermediate 1 : 5-Phenyl pyrazine-2-ylamine

Step 1: 2-Amino-5-bromo pyrazine: N-Bromosuccinimide (2.06 g, 11.56 mmol) was charged in portion to the solution of amino pyrazine (1.0 g, 10.51 mmol) in dry tetrahydrofuran (25 mL) at room temperature under nitrogen atmosphere and the reaction mixture was further stirred for 15 hr at the same temperature. The volatile matters were removed under reduced pressure, and the crude product thus obtained was purified using silica gel column chromatography using ethyl acetate and petroleum ether mixture as eluent in 60% yield (1.1 g). ¹H NMR (DMSO-d₆, 300 MHz, ppm): 68.03 (s, IH), 7.67 (s, IH), 6.66 (s, 2H).

Step 2: 5-Phenyl pyrazine-2-ylamine: 2-Amino-5-bromo pyrazine (600 mg, 3.44 mmol), phenyl boronic acid (461 mg, 3.79 mmol) and bis-(triphenylphosphine) palladium (II) chloride (121 mg, 0.17 mmol) in 1,4-dioxane (20 mL) was stirred at room temperature for 30 minutes under inert atmosphere followed by the addition of IM aqueous sodium carbonate solution (11 mL) and the resultant reaction mixture was heated to reflux. After completion of the reaction, the volatile matter was removed under reduced pressure and water was added. The organic components were extracted with ethyl acetate, and the ethyl acetate layer was washed with brine and dried over sodium sulfate followed by concentrated. The residue was subjected to silica gel column chromatography and the product was isolated using a mixture of ethyl acetate and petroleum ether in 84.8% yield (500 mg). ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.50 (s, IH), 7.95 (s, IH), 7.91 (d, J=7.8 Hz, 2H), 7.44-7.39 (m, 2H), 7.32-7.28 (m, IH), 6.57 (s, 2H).

The synthesis of the following derivatives was also carried out according to the procedure described above for the synthesis of 5-Phenyl pyrazine-2-yl amine.

5-(2-Chlorophenyl)-pyrazin~2ylamine

Yield: 84%. ¹HNMR (DMSOd₆, 300 MHz, ppm): 58.20 (s, IH); 7.97 (s, IH); 7.57-7.52 (m,

2H); 7.44-7.35 (m, 2H); 6.65 (b s, 2H).

5-(4-Fluorovhenyl)-pyrazin-2ylamine Yield: 79%. ¹HNMR (DMSOd₆, 300 MHz, ppm): 58.49 (d, J=I.5 Hz, IH); 7.97-7.92 (m,

3H); 7.24 (t, J=9.0 Hz, 2H); 6.57 (b s, 2H).

5-(3-Fluorophenyl)-pyrazin-2ylamine

Yield: 74%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 68.57 (d, J=I.5 Hz, IH); 7.96 (d, J=I.2

Hz, IH); 7.78 (d, J=7.8 Hz, IH); 7.74-7.69 (td, J=2.1 Hz and 11.1 Hz, IH); 7.49-7.42 (q,

J=8.1 Hz and 6.0 Hz, IH); 7.16-7.09 (dt, J-2.4 Hz and 8.4 Hz, IH); 6.69 (bs, 2H).

3-Methyl-5-phenylpyrazin-2ylamine

Yield: 95%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.38 (s, IH); 7.92 (dd, J=7.2 Hz and 1.5

Hz, 2H); 7.43-7.38 (t, J=7.5 Hz, 2H); 7.32-7.27 (m, IH); 6.33 (b s, 2H); 2.37 (s, 3H).

3-Bromo-5-(4-fluorophenyl)-pyrazin-2ylamine Y Yiieelldd:: 7700%%.. ¹¹HH NNMMRR ((DDMMSSOO- d₆, 300 MHz, ppm): 58.60 (s, IH); 7.96-7.91 (m, 2H); 7.28 (t, J=8.7 Hz, 2H); 6.88 (b s, 2H).

3-Bromo-5-(3-fluorophenyl)-pyrazin-2ylarnine

Yield: 68%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.66 (s, IH); 7.76 (d, J=7.8 Hz, IH); 7.72-7.68 (m, IH); 7.52-7.45 (q, J=8.1 Hz and 6.00 Hz, IH); 7.21-7.14 (dt, J=2.7 Hz and 8.1 Hz, IH); 7.00 (bs, 2H).

5-(3-Fluorophenyl)-3-metkyl-pyrazin-2ylamine

Yield: 48%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.44 (s, IH); 7.75-7.70 (m, 2H); 7.48-

7.40 (m, IH); 7.14-7.08 (m, IH); 6.46 (bs, 2H); 4.06 (s, 3H).

3-Chloro-5-(3~Chlorophenyl)-pyrazin-2ylamine

Yield: 71%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.66 (s, IH); 7.94 (s, IH); 7.88 (d, J=7.2

Hz, IH); 7.50-7.44 (t, J=7.8 Hz, IH); 7.40 (d, J=8.1 Hz, IH); 7.09 (b s, 2H).

3-Chloro-5-(4-fluorophenyl)pyrazine-2-ylamine

¹HNMR (DMSOd₆, 300 MHz, ppm): 58.57 (s, IH), 7.96-7.91 (m, 2H), 7.30-7.24 (t, J=9.0 & 8.7 Hz, 2H), 6.96 (s, 2H).

5-β-Methoxvvhenyl) vvrazine-2-vlamine ¹H NMR (DMSO-d₆, 300 MHz, ppm); 58.52 (d, J=1.5 Hz, IH), 7.95 (d, J=I .5 Hz, IH), 7.51- 7.47 (m, 2H), 7.35-7.30 (t, J=8.1 & 7.8 Hz, IH), 6.89-6.86 (dd, J=8.4 & 2.4 Hz, IH), 6.58 (s, 2H), 3.81 (s, 3H).

5-(4-Chlorophenyl)pyrazine-2-ylamine

This compound was prepared from 5-bromo pyrazine-2-yl amine following the procedure as described for 5-phenyl pyrazine-2-yl amine. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 58.53 (d, J=I.5 Hz, IH), 7.95 (d, J=I.5 Hz, IH), 7.94 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.7 Hz, 2H), 6.65 (s, 2H).

3-Bromo-5-(4-chlorophenyl) pyrazine-2-ylamine

¹H NMR (DMSO-d₆, 300 MHz, ppm): 58.63 (s, IH), 7.92 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4

Hz, 2H), 6.96 (s, 2H).

5-(4-chlorophenyl)~3-methylpyrazine-2-ylamme

¹H NMR (DMSOd₆, 300 MHz, ppm): 58.41 (s, IH), 7.95 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz₅ 2H), 6.43 (s, 2H), 2.36 (s, 3H).

Intermediate 2: 3-Bromo-5-phenylpyrazine-2-ylamine

3 -Bromo-5 -phenyl pyrazine-2-yl amine was prepared from Intermediate 1 following the procedure described in Step-1 for Intermediate 1.¹H NMR (DMSOd₆, 300 MHz, ppm): 5 8.60 (s, IH), 7.89 (d, J=7.2 Hz, 2H), 7.44-7.35 (m, 3H), 6.88 (s, 2H).

Intermediate 3: 5-(4-Chlorophenyl)pyrimidine-2-ylamine

Step 1: 2-Amino-5-bromo pyrimidine: was prepared according to the procedure described in step 1 for Intermediate 1. ¹H NMR (DMSOd₆, 300 MHz, ppm): δ 8.30 (s, 2H), 6.91 (s, 2H).

Step 2: 5-(4-Chlorophenyl)pynmidine-2-ylamine: was prepared according to the procedure described in step 1 for Intermediate 1. ¹H NMR (DMSOd₆, 300 MHz, ppm): 5 8.58 (s, 2H), 7.67-7.46 (AB quartet, J=8.4 Hz, 4H), 6.85 (s, 2H).

The synthesis of following derivatives was also carried out according to the procedure described above for the synthesis of 5-(4-Chlorophenyl) pyrimidine-2-yl amine.

5-(3-trifluoromethylvhenyl)-Oyrimidin-2ylamine Yield: 78%. ¹HNMR (DMSO-d₆, 300 MHz, ppm): 58.68 (s, 2H); 8.00-7.92 (m, 2H); 7.67 (d, J= 5.4 Hz, 2H); 6.93 (s, 2H).

5-(2~Chlorophenyl)-pyrimidin-2ylamine

Yield: 67%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.34 (s, 2H); 7.60-7.52 (m, IH); 7.46-

7.36 (m, 3H); 6.88 (b s, 2H).

5-β-Methoxyphenyl)-pyrimidin-2ylamine

Yield: 72%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 58.58 (s, 2H); 7.36-7.31 (t, J=7.5 Hz, .

IH); 7.19-7.16 (dd, J=I.2 Hz and 6.6 Hz, 2H); 6.90-6.87 (dd, J= 2.4 Hz and 6.6 Hz, IH); 6.79

(bs, 2H); 3.81 (s, 3H).

5-(3-Chlorophenyl)-pyrimidin-2ylamine

Yield: 81%. ¹HNMR (DMSO-d₆, 300 MHz, ppm): 58.61 (s, 2H); 7.72 (b s, IH); 7.60 (d,

J=7.8 Hz, IH); 1 Al-I Al (t, J=7.5 Hz and 8.1 Hz₅ IH); 7.36 (d, J=7.8 Hz, IH); 6.88 (b s, 2H).

5-(4-Chlorophenyl)-pyrimidin-2ylamine

Yield: 68%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.58 (s, 2H); 7.65 (d, J=8.4 Hz, 2H);

7.47 (d, J=8.4 Hz, 2H); 6.86 (b s, 2H).

5-(3,5-Difluorophenyl)-pyrimidin-2ylamine

Yield: 77%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.68 (s, 2H); 7.46 (d, J=7.2 Hz, 2H);

7.18-7.13 (t, J=8.7 Hz and 7.8 Hz, IH); 6.98 (s, 2H).

5-(3-Chlorophenyl)-pyrazin-2ylamine

Yield: 87%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.57 (s, IH); 7.96 (s, 2H); 7.89 (d, J=7.5

Hz, IH); 7.47-7.42 (t, J=7.8 Hz, IH); 7.36 (d, J=7.8 Hz, IH); 6.70 (s, 2H).

5-thiophen-3-yl-pyrimidin-2ylamine

Yield: 78%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.63 (s, 2H); 7.78 (s, IH); 7.64 (b s,

IH); 7.52 (d, J=4.2 Hz, IH); 6.74 (b s, 2H).

5-(4-Methoxyphenyl) pyrimidine-2-ylamine

¹H NMR (DMSOd₆, 300 MHz, ppm): 58.51 (s, 2H), 7.53 (d J=9.0 Hz, 2H), 6.99 (d, J=8.7

Hz, 2H), 6.68 (s, 2H), 3.77 (s, 3H). Intermediate 4: 2-Bromo-l-(4-chlorophenyl)-2-τ>henyl ethanone

To a solution of l,2-bis-(4-chlorophenyl) ethanone, prepared according to J. Med. Chem., 2004, 47, p. 627, (500 mg, 2.17 mmol) in benzene (15 mL), was added bromine (347 mg, 2.17 mmol) slowly at room temperature, and the resultant solution was continued to stir for 2 hr. at the same temperature. After removing the volatile matter on a rotary evaporator, the residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated. The residue was then subjected to silica gel column chromatography and the pure compound (450 mg, 67%) was isolated using ethyl acetate and petroleum ether as mixture.¹!! NMR (CDCl₃, 300 MHz, ppm): 58.08 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4Hz, 2H), 7.57 (d, J= 8.1 Hz, 2H), 7.47 (d, J=8.4 Hz, 2), 7.18 (s, lH).

The synthesis of following derivatives was also carried out according to the procedure described above 2-Bromo-l-(3,4-difluoro-phenyl)-ethanone

Yield: 98.6%. ¹H NMR [CDCl₃, 300 MHz, ppm]: 67.88-7.76 (m, 2H), 7.34-7.28 (m, IH), 4.39 (s, 2H).

2-Bromo-l-(2,4-difluoro-phenyl)-ethanone

Yield: 91.3%. ¹H NMR [CDCl₃, 300 MHz, ppm]: 58.04-7.96 (m, IH), 7.04-6.88 (m, 2H), 4.48 (s, 2H).

2-Bromo-l-(4-fluoro-phenyl)-ethanone

Yield: 99%. ¹H NMR [CDCl₃, 300 MHz, ppm]: 58.05-8.00 (m, 2H), 7.19-7.13 (m, 2H)₅ 4.41 (s, 2H).

Intermediate 5 : 5-(3-trifluoromethyl-phenyl)-pyrimidine-2-ylamine

Step 1: 2-Amino-5-bromo pyrimidine: N-Bromosuccinimide (2.06 g, 11.56 mmol) was added to a solution of 2-aminopyrimidine (1.0 g, 10.51 mmol) in dry tetrahydrofuran (25 mL) at room temperature under nitrogen atmosphere and continued to stirr for another 15 hr. The volatile matter was removed under reduced pressure, and the residue so obtained was subjected to silica gel column chromatography. The product was isolated using ethyl acetate and petroleum ether mixture as eluent in 60% yield (1.1 g). ¹H NMR (DMSOd₆₅ 300 MHz, ppm): 58.30 (s, 2H), 6.91 (s, 2H).

Step 2: 5-[3-(trifluoromethyl)phenyl]-pyrimidine-2-yl amine: 2-Amino-5-bromo pyrimidine (300 mg, 1.72 mmol), 3-(trifluoromethyl)phenylboronic acid (359 mg, 1.89 mmol) and bis-(triphenylphosphine) palladium (II) chloride (72 mg, 0.10 mmol) in 1,4- dioxane (15 mL) was stirred at room temperature for 30 minutes under inert atmosphere followed by the addition of IM aqueous sodium carbonate solution (5.2 mL). The resultant reaction mixture was heated to reflux for 5 hrs. After completion of reaction, the volatile matters were removed under reduced pressure and water was added. The organic components were extracted with ethyl acetate, the ethyl acetate layer was washed with brine and dried over sodium sulfate followed by concentrated. The residue was subjected ^• to column chromatography over silica gel and the product was isolated using a mixture of ethyl acetate and petroleum ether in 64.5% yield (265 mg). ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.67 (b s, 2H); 8.02-7.90 (b m, 2H); 7.70-7.62 (b m, 2H); 6.91 (b s, 2H).

Intermediate 6: 2-Bromo-l,2-bis(4-chlorophenyl)ethanone

To a solution of l,2-Bis-(4-Chlorophenyl) ethanone, prepared according to J Med. Chem., 2004, 47, p. 627, (500 mg, 2.17 mmol) in benzene (15 mL), was added bromine (347 mg, 2.17 mmol) slowly at room temperature and the resultant solution was continued to stir for 2 hrs. at the same temperature. After removing the volatile matter on a rotary evaporator, the residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated. The residue was then subjected to silica gel column chromatography, and the pure compound (450 mg, 67%) was isolated using ethyl acetate and petroleum ether as mixture.'H NMR (CDCl₃, 300 MHz, ppm): 58.08 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4Hz, 2H), 7.57 (d, J= 8.1 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.18 (s, lH).

Intermediate 7: 6-Bromo-2,3-bis-(4-chlorophenyl)-imidazo[l,2-a]pyrimidine

A mixture of 2-amino-5-bromopyrimidine (3 g, 17.23 mmol) and 2-bromo-l,2-bis-(4- chlorophenyl)-ethanone (6.52 g, 18.95 mmol) in dimethylformamide (35 mL) was heated at 110⁰C for 16 hrs. The cooled reaction mixture was poured into a saturated solution of sodium bicarbonate (300 mL) and stirred vigorously. The precipitated solid was filtered off, washed with water followed by petroleum ether and thoroughly dried. The crude mass was dissolved in a boiling mixture of ethyl acetate and tetrahydrofuran (8:1, 63 mL) followed by cooling to give the required compound that was further purified by column chromatography over silica gel using a mixture of ethyl acetate and petroleum ether as eluent to give a spectroscopically pure product (1.5 g, 20.8%). ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.76 (s, IH); 8.67 (s, IH); 7.67 (d, J=8.4 Hz, 2H); 7.58 (d, J=6.3 Hz, 4H); 7.44 (d, J=8.4 Hz, 2H). Purity [HPLC]: 99.1%. m.p.: 220-222 ⁰C.

The synthesis of following derivatives was also carried out according to the procedure described above for the synthesis of 6-bromo-2,3-bis-(4-chlorophenyl)-imidazo[l,2- ajpyrimidine.

6-Bromo-2-(4-chlorophenyl)-3-(2, 4-dichlorophenyl)-imidazo-fl , 2-a Ivyrimidine

Yield: 24%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 88.86 (d, J=2.1 Hz, IH); 8.72 (d, J=2.4 Hz, IH); 7.99 (s, IH); 7.70-7.62 (m, 2H); 7.57 (d, J=8.7 Hz, 2H); 7.46 (d, J=8.7 Hz, 2H).

6-Bromo-3-(2,4-dichlorophenyl)-2-phenyl-imidazo[l,2-a]pyrimidine

Yield: 19.94%. ¹HNMR (DMSOd₆, 300 MHz, ppm): 68.83 (s, IH); 8.70 (s, IH); 7.98 (s,

IH); 7.64 (s, 2H); 7.57 (d, J=6.6 Hz, 2H); 7.40-7.34 (m, 3H).

2,3-Bis-(4-chlorophenyl)-imidazo[L2-a]pyrimidine-6-carbonitrile

Yield: 17%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 68.68 (s, IH); 8.58 (s, IH); 7.67 (d, J=8.4

Hz, 2H); 7.62 (d, J=8.4 Hz₅ 2H); 7.40 (d, J=8.4 Hz, 2H); 7.32 (d, J=8.7 Hz, 2H).

8-Chloro-2,3-bis-(4-chlorophenyl)-6-(3-chlorophenyl)-imidazo-[l,2-a]pyrazine

Yield: 22%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 68.64 (s, IH); 8.07 (s, IH); 8.02-7.95 (b s, IH); 7.75-7.67 (m, 2H); 7.65-7.58 (m, 4H); 7.52-7.46 (m, 4H).

Intermediate 8 : 2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo-[ 1 ,2-a]pyrimidin-6-carboxyh^'c acid

Step 1: 2-[l-Dimethylamino-rneih-β)-ylidene]-3-oxo-butyric acid ethyl ester Yield: 64.1%. ¹H NMR (CDCl₃, 300 MHz, ppm): 57.69 (s, IH); 4.27-4.20 (q, J=6.9 Hz, 2H); 3.2-2.85 (b s, 6H); 2.33 (s, 3H); 1.35-1.30 (t, J=6.9 Hz, 3H).

Step 2: 2-Amino-4-methyl-pyrimidine-5-carboxylic acid etlhyl ester To a solution of sodium ethoxide (4.04 g, 59.45 mmol) in ethanol (100 mL) was added 2-[l- dimethylamino-meth-(Z)-ylidene]-3-oxo-butyric acid ethyl ester (10 g, 54.05 mmol) at room temperature followed by the addition of guanidine hydrochloride (5.66 g, 59.45 mmol). The mixture was then refluxed for 2 hrs. Ethyl acetate (750 mL) was added to the cooled reaction mixture, and the organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated under vacuum to give a spectroscopically homogenous title compound (6.5 g, 66.4%). ¹H NMR (CDCl₃, 300 MHz, ppm): 68.82 (s, IH); 5.41 (b s, 2H); 4.37-4.30 (q, J=6.9 Hz, 2H); 2.67 (s, 3H); 1.40-1.36 (t, J=7.5 Hz and 6.9 Hz, 3H).

Step 3: 2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo-[l,2-a]pyrimidin-6-carboxylic acid ethyl ester

A solution of 2-amino-4-methyl-pvrimidine-5-carboxylic acid ethyl ester (4.5 g, 24.86 mmol) and 2-bromo-l,2-bis-(4-chlorophenyl)-ethanone (10.26 g, 29.83 mmol) in dimethylformamide (20 mL) was heated at 110 ⁰C for 7 hrs. The cooled reaction mixture was diluted with ethyl acetate and the organic layer was washed with saturated solution of sodium bicarbonate, water and brine, followed by drying over sodium sulfate, and then concentrated. The crude mass was subjected to column chromatography over silica gel and the product was obtained using a mixture of ethyl acetate and petroleum ether as eluent in 16.9% yield (1.8 g). ¹HNMR (DMSOd₆, 300 MHz, ppm): 58.70 (s, IH); 7.72 (d, J=8.4 Hz, 2H); 7.63-7.59 (m, 4H); 7.46 (d, J=8.7 Hz, 2H); 4.35-4.28 (q, J=6.9 Hz, 2H); 2.80 (s, 3H); 1.32-1.28 (t, J=7.2 Hz and 6.6 Hz, 3H).

Step 4: 2, 3-Bis~(4-chlorophenyl)- 7-methyl-imidazo-[l, 2-a]pyrimidin-6-carboxylic acid

2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo-[l ,2-a]pyrimidin-6-carboxylic acid ethyl ester (1.0 g, 2.35 mmol) was dissolved in amixture of THF, ethanol and water (3:1:1, 50 mL) followed by the addition OfLiOH-H₂O (295 mg, 7.04 mmol). The resultant mixture was stirred vigorously for 2 hr. at room temperature. The usual workup was as follows: the volatile matter was removed under reduced pressure and the residue was suspended in water (10 mL) followed by acidification with glacial acetic acid to pH=4. The solid (760 mg) was then filtered off and washed thoroughly with water and dried, which was used in the next step without further purification. Yield: 81%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 68.46 (s, IH); 7.68 (d, J=8.4 Hz, 2H); 7.61-7.54 (AB q, J=9.0 Hz and 8.4 Hz, 4H); 7.42 (d, J=8.4 Hz, 2H); 2.80 (s, 3H).

Intermediate 9: 3-Bromo-2-(4-chlorophenvπ-6-(3-trifluoromethyl-phenyl)-imidazofl,2-al pyrimidine

Step 1 : 2-(4-Chlorophenyl)-6-(3~trifluoromethyl-phenyl)-imidazo[l, 2-a] pyrimidine A mixture of 5-(3-trifluoromethyl ρhenyl)-pyrimidin-2-yl-amine (275 mg, 1.15 mmol) and 4- chlorophenacyl bromide (295 mg, 1.26 mmol) in DMF (5 mL) was heated at 100 ⁰C for 5 hrs. The reaction mixture was cooled and quenched with saturated solution OfNaHCO₃ and the organic parts were extracted with ethyl acetate (2 X 25 ml). The combined ethyl acetate layer was then washed with water followed by brine and dried over Na₂SO₄ and concentrated. The product was purified by column chromatography using a mixture of ethyl acetate in petroleum ether as the eluent in 58% yield (250 mg). ¹H NMR (DMSOd₆, 300 MHz, ppm): 69.45 (s, IH); 9.00 (d, J=I.8 Hz, IH); 8.43 (s, IH); 8.19 (s, IH); 8.14 (d, J=7.8 Hz, IH); 8.09 (d, J=7.8 Hz, 2H); 7.85-7.75 (m, 2H); 7.55 (d, J=8.1 Hz, 2H).

The following compound was prepared according to the procedure described above for the synthesis of 2-(4-Chlorophenyl)-6-(3-trifluoromethyl-phenyl)-imidazo[l,2- a]pyrimidine 2-(4-Chlorophenyl)-6-(3-chlorophenylVimidazo-[l,2-a]pyrimidine

Yield: 32%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 59.39 (s, IH); 8.95 (s, IH); 8.41 (s, IH); 8.08 (d, J=8.4 Hz, 2H); 7.93 (s, IH); 7.80 (d, J=5.7 Hz, IH); 7.55 (d, J=7.8 Hz, 2H).

2-(2, 4-Difluoro-phenyl)- 7-methyl~6-phenyl-imidazo[l, 2-aJpyrimidine

Yield: 38.4%. ¹H NMR [DMSO-d₆, 300 MHz, ppm]: 58.85 (s, IH), 8.35-8.27 (m, IH), 8.17 (d, J=4.2 Hz, IH), 7.52-7.38 (m, 6H), 1.29-124 (b t, IH), 2.47 (s, 3H).

2-(3,4-Diβuoro-phenyl)-6-(3-trifluoromethyl-phenyl)-imidazo[l,2-a]pyrimidine Yield: 85%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: 69.46 (d, J=2.1 Hz, IH), 9.01 (d, J=2.1 Hz, IH), 8.45 (s, IH), 8.20-8.07 (m, 3H), 7.93 (b m, IH), 7.84-7.76 (m, 2H), 7.61-7.52 (q, J=8.7 Hz, IH).

2-(2,4-Difluoro-phenyl)-6-(3-trifluoromethyl-phenyl)-imidazo[l,2-a]pyrimidine

Yield: 25.5%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: 69.48 (s, IH), 9.04 (s, IH), 8.42-8.25 (m, 2H), 8.21-8.10 (m, 2H), 7.90-7.75 (m, 2H), 7.50-7.40 (b t, J=8.7 Hz, IH), 7.35-7.25 (b t, IH).

[2-(2,4-Difluoro-phenyl)-imidazo[l,2-a]pyrimidin-7-yl] -methanol

Yield: 40%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: 68.97 (d, J=7.2 Hz, IH), 8.33-8.24 (m, 2H), 7.46-7.39 (t, IH), 1.29-1.23 (t, IH), 7.19 (d, J=6.9 Hz, IH), 5.73-5.69 (t, J=6.0 Hz, IH), 4.60 (d, J=6.0 Hz, 2H).

6-(3,5-Difluoro-phenyl)-2-(4-fluoro-phenyl)-imidazo[l,2-a]pyrimidine

Yield: 60%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: 69.43 (s, IH), 8.97 (s, IH), 8.38 (s, IH), 8.12 (b t, 2H), 7.66 (d, J=6.9 Hz, 2H), 7.36-7.30 (m, 3H).

2-(2,4-Difluoro-phenyl)-7-phenyl-imidazo[l,2-a]pyrimidine

Yield: 33.46%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: 69.07 (d, J=6.9 Hz, IH), 8.35 (d, J=6.9 Hz, 2H), 8.30-8.25 (m, 2H), 7.77 (d, J=7.5 Hz, IH), 7.57 (s, 3H), 7.48-7.41 (dt, J=I 1.4 & 1.8 Hz, IH), 7.31-7.26 (t, J=6.9 Hz, IH). Step 2: 3-Bromo-2-(4-chlorophenyl)-6-(3-trifluoromethyl-phenyl)-imidazo[l, 2-a] pyrimidine

To a solution of 2-(4-chlorophenyl)-6-(3-trifluoromethyl-phenyl)-imidazo[l,2- a]pyrimidine (250 mg, 0.66 mmol) in dry THF (20 ml), under N₂ atm., was added N- bromosuccinimide (131 mg, 0.73 mmol) and stirred for 5 hrs. at room temperature. The volatile matter was then removed; the residue was diluted with ethyl acetate, washed, with water, followed by brine, dried over Na₂SO₄ and concentrated. The crude was subjected to silica gel column chromatography to obtain the required compound (290 mg, 96%). ¹H NMR (DMSO-d₆, 300 MHz₅ ppm): 59.12 (d, J=2.4 Hz, IH); 9.07 (s, IH); 8.29 (s, IH); 8.20-8.17 (m, 3H); 7.85 (d, J=8.1 Hz, IH); 7.82-7.76 (t, J=7.5 Hz and 8.1 Hz, IH); 7.64 (d, J=8.7 Hz₅ 2H).

The following intermediate was prepared according to the procedure described above for the synthesis of 3-bromo-2-(4-chlorophenyl)-6-(3-trifluoromethyl-phenyl)-imidazo[l,2- a]pyrimidine: S-Bromo^-^-chlorophenylVό-fS-chlorophenylVimidazo-fL∑-alpyrimidine

Yield: 48%. ¹H NMR (DMSOd₆, 300 MHz₅ ppm): 59.04 (d, J=3.3 Hz, 2H); 8.19 (d, J=8.4 Hz, 2H); 8.05 (s, IH); 7.92-7.84 (m, IH); 7.65 (d, J=8.4 Hz, 2H); 7.58 (d, J=7.5 Hz₅ 2H).

3-Bromo-2-(2, 4-difluoro-phenyl)- 7-methyl-6-phenyl-imidazo[l , 2-a] pyrimidine

Yield: 67.7%. ¹R NMR [DMSOd₆, 300 MHz, ppm]: 58.51 (s, IH), 7.79-7.71 (m, IH), 7.56- 7.43 (m, 6H), 7.32-7.26 (dt, IH).

3-Bromo-2-(3,4-difluoro-phenyl)-6-(3-trifluoromethyl-phenyI)-imidazo[l,2-Jpyrimidine

Yield: 45.5%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: 59.13 (d, J=I.5 Hz, IH), 9.08 (d, J=I.5 Hz, IH)₅ 8.29 (s, IH), 8.20 (d, J-7.2 Hz, IH), 8.15-8.02 (m, 2H), 7.87-7.77 (m, 2H), 7.70- 7.61 (q, J=8.7 Hz₅ IH).

3-Bromo-2-(2A-difluoro-phenyl)-6-(3-trifluoromethyl-phenyl)-imidazo[l,2-]pynmidine

Yield: 70.2%. ¹H NMR [DMSOd₆, 300 MHz₅ ppm]: 59.15 (s, IH), 9.09 (s, IH), 8.30 (d, J=I.5 Hz, IH), 8.21 (d, J=6.6 Hz, IH)₅ 7.90-7.74 (m, 3H)₅ 7.56-7.42 (b t, IH), 7.36-7.26 (b t, IH).

3-Bromo-6-(3,5-difluoro-phenyl)-2-(4-fluoro-phenyl)-imidazo[l,2-a]pyrimidine

Yield: 98.03%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: 59.11 (s, IH), 9.05 (s, IH), 8.23-8.18 (m, 2H)₅ 7.75 (d, J=7.8 Hz₅ 2H), 7.45-7.38 (m, 3H). 3-Bromo-2-(2,4-difluoro-phenyl)-7-phenyl-imidazo[l,2-a]pyrimidine

Yield: 67%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: 58.92 (d, J=6.9 Hz, IH), 8.29 (m, 2H), 7.90 (d, J=7.2 Hz, 2H), 7.84-7.76 (b q, IH), 7.59 (b s, 3H), 7.52-7.45 (t, J=9.6 Hz, IH), 7.33- 7.28 (t, J=8.1 Hz, IH).

[3-Bromo~2-(2, 4-difluoro~phenyl)-imidazo [1 , 2-aJpyήmidin- 7-yl] -methano

Yield: 97.1%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: δ8.85 (d, J=6.9 Hz, IH), 7.78-7.71 (m, IH), 7.49-7.43 (t, IH), 7.35 (d, J=6.9 Hz, IH), 7.31-7.25 (t, IH), 5.82-5.78 (t, J-5.7 Hz, IH), 4.65 (d, J=5.7 Hz, 2H).

Intermediate 10: 2-Amino-pyrimidine-5-carbonitrile

A mixture of 2-Amino-5-bromo-pyrimidine (6.Og, 34.48 mmol) and CuCN (3.4g, 37.93 mmol) in quinoline (20 mL) was heated to reflux for one hour. The cooled reaction mixture was then poured into boiling acetic acid (400 mL), and the slurry was filtered under hot condition. The filtrate was cooled and diluted with water (2 Lit). The precipitated solid was then filtered, washed with water thoroughly and dried under vacuum to give spectroscopically pure required compound (1.7g, 41%). ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.64 (s, 2H); 7.78 (s, 2H).

Intermediate 11 : 3-Bromo-5-chloro-pyrazin-2~ylamine

Step 1: 5-Chloro-pyra.zin-2-yla.mine: To an ice-cold (0 ^°C) solution of aminopyrazine (1 equiv.) in dry tetrahydrofuran about 50-70 mL, under nitrogen atmosphere, was added N- chlorosuccinimide (1.1 equiv.) in portions under stirring. The reaction mixture was left overnight allowing it to attain room temperature. The volatile matters were removed on a rotary evaporator and the crude was subjected to column chromatography to furnish the title compound. Yield: 2.1 g (51%). ¹H NMR (DMSOd₆, 300 MHz, ppm): 57.99 (s, IH); 7.67 (s, IH); 6.66 (b s, 2H).

Step 2: 3-Bromo-5-chloro-pyrazin-2-ylamine

To an ice-cold (0 C) solution of 5-chloro-pyrazin-2-ylamine (1 equiv.) in dry tetrahydrofuran, under nitrogen atmosphere, was added N-bromosuccinimide (1.1 equiv.) in portions under stirring. The reaction mixture was left overnight allowing it to attain room temperature. The volatile matters were removed on rotary evaporator and the crude was subjected to column chromatography to furnish the title compound. Yield: 2.5 g (77%). ¹H NMR (DMSOd₆, 300 MHz, ppm): 68.10 (s, IH); 6.98 (b s, 2H).

Intermediate 12: 5-Chloro-3-r2.2,2-trifluoro-ethoxyVpyrazin-2-ylamine To a round bottom flask [fitted with a reflux condenser and CaCl₂ guard tube] containing 2,2,2-trifluoroethanol (12 mL) was slowly added sodium metal (400 mg, 17.3 mmol) at room temperature. Once the metal was completely reacted, 3-bromo-5-chloro-pyrazin-2-ylamine (700 mg, 3.35 mmol) was charged and the resultant mixture was refluxed for 25 hr. The volatile matters were then removed under reduced pressure and the residue was dissolved in ethyl acetate (150 mL) followed by washing the organic layer with water (200 mL). The ethyl acetate layer was dried over sodium sulfate, filtered and concentrated to dryness to give the required spectroscopically homogenous compound (125 mg, 16.4%). ¹H NMR (DMSOd₆, 300 MHz, ppm): 57.69 (s, IH); 6.68 (b s, 2H), 5.03-4.94 (m, 2H). MS [m/z]: 228.45.

8-Bromo-6-chloro-2,3-bis-(4-chlorophenyl)-imidazo[l,2-a]pyrazine

Yield: 22%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): δ8.38 (s, IH); 7.70 (d, J=8.1 Hz, 2H); 7.59 (b s, 4H); 7.47 (d, J=7.8 Hz, 2H).

Interemdiate 13 : 2,3 -Bis-(4-chloro-phenyl)-6-trimethylsilanylethynyl-imidazo[ 1 ,2- alpyrirm^'dine

Yield: 71%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: 68.63-8.61 (m, 2H), 7.67 (d, J=8.4 Hz, 2H), 7.61-7.57 (m, 4H), 7.45 (d, J=8.7 Hz, 2H), 0.20 (s, 9H).

Intermediate 14: 2,3-Bis-(4-chloro-phenyl)-6-ethynyl-imidazo[l ,2-a]pyrimidine

Tetrabutylammonium fluoride (108 mg, 0.416 mmol, 1.0 M solution in THF, Aldrich®) was charged to a cold (10 ⁰C) solution of 2,3-bis-(4-chloro-phenyl)-6-trimethylsilanylethynyl- imidazo[l,2-a]pyrimidine (140 mg, 0.32 mmol) in tetrahydrofuran (15 mL) and the mixture was stirred for 1 hr allowing it to come to room temperature. The reaction mixture was once again cool to 0 ⁰C and acidified to pH=2 by IN HCl. The organic parts were then extracted with ethyl acetate (2x50 mL) from water and the combined organic phase was dried over sodium sulfate and concentrated. The residue was subjected to column chromatography and the required product was isolated using a mixture of ethyl acetate and petroleum ether mixture as eluent (50 mg, 43%). ¹H NMR [DMSOd₆, 300 MHz, ppm]: 68.67 (s, IH), 8.65 (s, IH), 7.66 (d, J=8.4 Hz, 2H), 7.61-7.59 (m, 4H), 7.44 (d, J=8.4 Hz, 2H), 4.51 (s, IH). Intermediate 15: 8-Bromo-6-chloro-2,3-bis-(4-chlorophenylVimidazo[l,2-a]pyrazine Step 3: 8-Bromo-6-chloro-2,3-bis-(4-chlorophenyl)-imidazo[l,2-a]pyrazine A solution of 3-bromo-5-chloro-pyrazin-2-ylamme (1 equiv.) and 2-bromo-l,2-bis-(4- chlorophenyl)~ethanone (1.21 equiv.) in dry dimethylformamide (about 4-8 mL) was heated at about 120 C, for about 48 h. The reaction mixture was poured into a saturated solution of sodium carbonate and the precipitated solid was filtered and washed with water. The required product was then purified by silica gel column chromatography. Yield: 0.48 g (22%). ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.38 (s, IH); 7.70 (d, 1=8.1 Hz, 2H); 7.59 (b s, 4H); 7.47 (d, J=7.8 Hz, 2H).

Intermediate 16: 4-Methyl-5-(3-trifluoromethyl-phenyl)-pyrimidin-2ylamine Step 1: 5-Bromo-4-methyl-pyrimidin-2-ylamine

To a cold (0 C) solution of 2-amino-4-methylpyrimidine (1.09 g, 10 mmol) in dry tetrahydrofuran (about 60-80 mL), under nitrogen atmosphere, was added N- bromosuccinimide (1.96 g, 11 mmol) in portions and the reaction mixture was stirred at room temperature overnight. The volatile matters were evaporated from the reaction mixture under reduced pressure and the residue was loaded on silica gel column chromatography to get spectroscopically homogenous product in 80% yield (1.5 g). ¹H NMR (DMSO-d₆, 300 MHz, ppm): 58.21 (s, IH); 6.78 (s, 2H); 2.32 (s, 3H).

Step 2: 4-Methyl-5-(3-trifluoromethyl-phenyl)-pyrimidin-2ylamine: A mixture of 5-bromo-4- methyl-pyrimidin-2-ylamine (0.75 g, 4.0 mmol), 3-trifluoromethylphenyl boronic acid (0.83 g, 4.39 mmol) and bis- (triphenylphosphine) palladium (II) chloride (0.14 g, 0.2 mmol) in 1, 4-dioxan (30 mL) was stirred for 20 min at room temperature. To the above was then added IM aqueous sodium carbonate solution (12 mL, 12 mmol) and the reaction mixture was refiuxed for 2 h. The solvent was then distilled off from the reaction mixture and the residue was diluted with water and the organic components were extracted with ethyl acetate. The ethyl acetate layer was then dried over Na₂SO₄ and concentrated. The product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent. Yield: 0.77g (76%). ¹H NMR (DMSO-d₆, 300 MHz, ppm): 58.11 (s, IH); 7.74-7.66 (b d, 4H); 6.74 (s, 2H); 2.25 (s, 3H).

The following compounds were prepared following the above procedure from 2- aminopyrimidine. Intermediate 17: 5-(3-trifluoromethylphenylVpyrimidin-2ylamine

Yield: 78%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 58.68 (s, 2H); 8.00-7.92 (m, 2H); 7.67 (d, J= 5.4 Hz₃ 2H); 6.93 (s, 2H).

Intermediate 18: 5-(3,5-DichlorophenylVρyrimidin-2-ylamine

Yield: 0.54 g (67%). ¹H NMR (DMSO-d₆, 300 MHz, ppm): 58.67 (s, 2H); 7.75 (d, J=I .2 Hz, 2H); 7.52 (s, IH); 6.98 (s, 2H).

Intermediate 19^': (2-Amino-pyrimidin-4-ylVmethanol

Step 1: 4-Dimethoxymethyl-pyrirnidin-2-ylamine: A mixture of pyruvic aldehyde dimethyl acetal (11.81 g, 0.10 mol) and N,N-dimethyl formamide dimethyl acetal (11.92 g, 0.1 mol) was heated at 100 C. The volatile matters were then evaporated from the reaction mixture and the product was obtained as an oil that was used without further purification in the next step. A solution of NaOH (4.4 g, 0.11 mol) in water (12 niL) was added to guanidine hydrochloride (10.46 g, 0.11 mol) in water (24 mL) and the resulting solution was added to the oil obtained above. The resultant reaction mixture was then stirred at room temperature for 48 h and the precipitated solid was filtered, washed with water and dried under vacuum to afford the title compound. Yield: 6.37 g (38%). ¹H NMR (CDCl₃, 300 MHz, ppm): 58.34 (d, J=4.8 Hz, IH); 6.84 (d, J=5.1 Hz, IH); 5.24 (b s, 2H); 5.15 (s, IH); 3.39 (s, 6H).

Step 2: (2-Amino-pyrimidin-4-yJ)-methanol: A solution of 4-dimethoxymethyl-pyrimidin-2- ylamine (1.0 g, 5.92 mmol) in 3N aqueous HCl (4.3 mL) was heated at 48 ^°C for 14 h. The reaction mass was cooled and was neutralized by the addition OfNaHCO₃. The organic parts were extracted with ethyl acetate and the combined organic layers were dried over Na₂SO₄ and concentrated (0.4 g, 3.25 mmol), which was dissolved in a mixture of methanol and THF followed by the addition OfNaBH₄ (61.5 mg, 1.63 mmol). The resultant mixture was stirred at room temperature for 2 h. The residue was diluted with ethyl acetate and the organic layer was washed with water followed by drying over Na₂SO₄. The volatile matters were removed under reduced pressure and the product was purified by column chromatography. Yield: 0.15 g (36%). ¹H NMR (DMSO-d₆, 300 MHz, ppm): 58.20 (d, J=5.1 Hz, IH); 6.66 (d, J=5.1 Hz, IH); 6.50 (b s, 2H); 5.39-5.35 (t, J=6.0 Hz, IH); 4.31 (d, J=6.0 Hz, 2H).

Intermediate 20: 2.3-Bis-(4-chlorophenyl)-7-methyl-imidazo[ 1 ,2-alpyrimidine-6-carboxylic acid N'-(2,2-dimethyl-propionylVhydrazide

Step 1: 2-[l-Dιmethylamino-meth-(Z)-ylidene]-3-oxo-butyric acid ethyl ester Yield: 64%. ¹H NMR (CDCl₃, 300 MHz, ppm): 57.69 (s, IH); 4.27-4.20 (q, J= 6.9 Hz, 2H); 3.2-2.85 (b s, 6H); 2.33 (s, 3H); 1.35-1.30 (t, J= 6.9 Hz₅ 3H).

Step 2: 2-Amino-4-methyl-pyrimidine-5-carboxylic acid ethyl ester

To a solution of sodium ethoxide (4.04 g, 59.45 mmol) in ethanol (100 mL) was added 2-[l- dimethylamino-meth-(Z)-ylidene]-3-oxo-butyric acid ethyl ester (10 g, 54.05 mmol) at room temperature followed by the addition of guanidine hydrochloride (5.66 g, 59.45 mmol). The mixture was then refluxed for 2 hrs. Ethyl acetate (750 mL) was added to the cooled reaction mixture, and the organic layer was washed with water followed by brine, dried over sodium sulfate and concentrated under vacuum to give a spectroscopically homogenous title compound (6.5 g, 66.4%). ¹H NMR (CDCl₃, 300 MHz): 58.82 (s, IH); 5.41 (b s, 2H); 4.37- 4.30 (q, J=6.9 Hz, 2H); 2.67 (s, 3H); 1.40-1.36 (t, J=7.5 Hz and 6.9 Hz, 3H).

Step 3: 2-Amino-4-methyl-pyήmidine-5-carboxylic acid hydrazide

To a suspension of 2-amino-4-methyl-pyrimidine-5-carboxylic acid etlhyl ester (0.6 g, 3.31 mmol) in absolute ethanol (10 mL) was added hydrazine hydrate (2.7 mL) and the reaction mixture was refluxed for 20 h. The reaction mixture was cooled and the resultant white precipitate was then filtered, washed with ethanol and dried under vacuum. Yield: 0.38 g (69%). ¹H NMR (DMSOd₆, 300 MHz, ppm): 59.36 (b s, IH); 8.19 (s, IH); 6.91 (b s, 2H); 4.39 (b s, 2H); 2.36 (s, 3H). MS [m/z]: 168.

Step 4: 2-Amino-4-methyl-pyrimidine-5-carboxylic acidN'-(2,2-dimethyl-propionyl)- hydrazide

To a suspension of 2-amino-4-methyl-pyrimidine-5-carboxylic acid hydrazide (0.37 g, 2.2 mmol) in dichloromethane (20 mL) was added triethylamine (0.27 g, 2.65 mmol) at 0 °C for 5 min. To the above was added pivaloyl chloride (0.32 g, 2.65 mmol), and the resultant mixture reaction mixture was stirred at room temperature for 3 h. The precipitate was then filtered, washed with dichloromethane and dried under vacuum to give spectroscopically pure product in 80% yield. (0.44 g). ¹H NMR (DMSO-d₆, 300 MHz, ppm): 59.83 (s, IH); 9.51 (s, IH); 8.30 (s, IH); 7.03 (b s, 2H); 2.40 (s, 3H); 1.18 (s, 9H). MS [m/z]: 252.29.

Step 5: 2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo[l,2-a]pyrimidine-6-carboxylic acid N'- (2, 2 -dimethyl-propionyl) -hydrazide

A solution of 2-amino-4-methyl-pyrimidme-5-carboxylic acid N'-(2,2-dimethyl-ρroρionyl)- hydrazide (0.15 g, 0.59 mmol) and 2-bromo-l,2-bis-(4-chloropheny)l-ethanone (0.25 g, 0.71 mmol) in dry DMF (4 mL) was heated at 110 ^°C for three and half hours. The reaction mixture was cooled and poured into a saturated solution of NaHCO₃, and the precipitated solid was filtered and washed with water. The crude material was then dissolved in chloroform and the chloroform layer was washed with water and then dried over Na₂SO₄ and concentrated. The crude material was subjected to silica gel column chromatography purification. Yield: 98 mg (33%). ¹H NMR (DMSO-d₆, 300 MHz, ppm): δlθ.27 (s, IH); 9.68' (s, IH); 8.41 (s, IH); 7.71 (d, J=8.4 Hz, 2H); 7.63 (d, J=2.7 Hz, 2H); 7.60 (d, J=3.0 Hz, 2H); 7.46 (d, J=8.4 Hz, 2H); 2.66 (s, 3H); 1.17 (s, 9H). MS [m/z]: 496.42

Intermediate 21 : 3-Bromo-2-(4-fluorophenyl)-6-(3-trifluoromethylphenyl)-imidazo[l,2- a]pyrimidine

Step 1 : 2-(4-Fluorophenyl)-6-(3-trifluoromethylphenyl)-imidazo[l, 2-aJpyrimidine A solution of Intermediate 17 (1.0 g, 4.2 mmol) and 4-fluoro phenacyl bromide (1.09 g, 5.01 mmol) in dry dimethylformamide (7 mL) was heated at 110 ^°C for 17 h. The reaction mixture was cooled and poured into a saturated solution of sodium bicarbonate and the precipitated solid was filtered and washed with water. The solid was dissolved in a boiling mixture of ethyl acetate and tetrahydrofuran (5:1). After cooling the precipitated solid was filtered and dried under vacuum. Yield: 0.65 g (43%). ¹H NMR (DMSO-d₆, 300 MHz, ppm): 59.45 (d, J=2.4 Hz, IH); 8.99 (d, J=2.1 Hz, IH); 8.38 (s, IH); 8.19 (s, IH); 8.17-8.07 (m, 3H); 7.85- 7.76 (m, 2H); 7.36-7.30 (t, J=9.0 Hz, 2H).

Step 2: 3-Bromo-2-(4-fluorophenyl)-6-(3-trifluoromethylphenyl)-imidazo[l,2-aJpyrimidine To a solution of 2-(4-fluorophenyl)-6-(3-trifluoromethylphenyl)-imidazo[l,2-a]pyrimidine (0.65 g, 1.82 mmol) in dry tetrahydrofuran (60 mL), under N₂ atmosphere, was added N- bromosuccinimide (0.49 g, 2.73 mmol) in portions at 0 C and the reaction mixture was stirred overnight at ambient temperature. Tetrahydrofuran was removed under reduced pressure and the residue was diluted with dichloromethane followed by washing with water. The DCM layer was then dried over sodium sulfate and concentrated and the crude was loaded on silica gel column chromatography to obtain the required title compound. Yield: 0.42 g (53%). ¹H NMR (DMSO-d₆, 300 MHz, ppm): 59.12 (d, J=I.8 Hz, IH); 9.06 (d, J=2.1 Hz, IH); 8.30 (s, IH); 8.23-8.16 (m, 3H); 7.88-7.75 (m, 2H); 7.45-7.39 (t, J=9.0 Hz, 2H).

The following compounds were prepared following the above procedure

Intermediate 22: 3-Bromo-2-r4-chlorophenylV6-(^"3-trifluoromethyl-phenyl)-imidazori ,2- alpyrimidine Step 1 : 2-(4-Chlorophenyl)-6-(3-trifluoromethyl-phenyl)-imidazo[l,2-a]pyrimidine The title compound was prepared analogously by the procedure described in step 1 of the synthesis of 3-Bromo-2-(4-fluorophenylV6-(3-trifluoromethylρhenylVimidazori,2- a]pyrimidine using Intermediate 17.

Yield: 58%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 89.45 (s, IH); 9.00 (d, J=I.8 Hz, IH); 8.43 (s, IH); 8.19 (s, IH); 8.14 (d, J=7.8 Hz, IH); 8.09 (d, J=7.8 Hz, 2H); 7.85-7.75 (m, 2H); 7.55 (d, J=8.1 Hz, 2H).

Step2: 3-Bromo-2-(4-chlorophenyl)-6-(3-trifluoromethyl-phenyl)-irnidazo[l,2-a]pyrimidine

Yield: 96%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 69.12 (d, J=2.4 Hz, IH); 9.07 (s, IH); 8.29 (s, IH); 8.25-8.15 (m, 3H); 7.85 (d, J=8.1 Hz, IH); 7.82-7.76 (t, J=7.5 Hz and 8.1 Hz, IH); 7.64 (d, J=8.7 Hz, 2H).

Intermediate 23 : 3-Bromo-6-(3,5-dichlorophenyl)-2-(4-fluorophenyl)-imidazo[l ,2- a]pyrimidine

Step 1 : 6-(3, 5-Dichlorophenyl)-2-(4-fluorophenyl)-imidazo[l, 2-aJpyrimidine

The title compound was prepared by following the procedure as described in step 1 of the synthesis of 3-Bromo-2-(4-fluorophenyl)-6-(3-trifluoromethylphenyl)-inύdazo[l,2- ajpyrimidine using Intermediate 18.

Yield: 59%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 69.45 (d, J=2.1 Hz, IH); 8.96 (d, J=2.7 Hz, IH); 8.36 (s, IH); 8.14-8.10 (m, 2H); 7.96 (d, J=I .5 Hz, 2H); 7.71 (s, IH); 7.36-7.30 (t, J=8.7 Hz, 2H).

Step 2: 3-Bromo-6-(3, 5-dichlorophenyl)-2-(4-fluorophenyl)-imidazo[l, 2-a]pyrimidine

Yield: 0.37 g. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 69.14 (d, J=2.1 Hz, IH); 9.04 (d, J=2.1 Hz, IH); 8.23-8.18 (m, 2H); 8.05 (b s, 2H); 7.73 (b s, IH); 7.45-7.39 (t, J=8.7 Hz, 2H).

Example 1 : 2,3-bis-(4-chlorophenyl)-6-phenyl-imidazo-[ 1.2-a^"|-pyrazme

A mixture of 5-phenyl pyrazine-2-yl amine (200 mg, 1.17 mmol) and 2-Bromo-l-(4- chlorophenyl)-2-phenyl ethanone (404.7 mg, 1.17 mmol) in dimethyl formammide (5 mL) was heated at 100-120 ⁰C for 3 hrs. The reaction mixture was diluted with ethyl acetate and the organic portion was washed with saturated sodium bicarbonate and water (3x40 mL) consecutively followed by drying over sodium sulfate. The extract was concentrated and the product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether followed by methanol and chloroform (184 mg). m.p.: 221-222 ⁰C. ¹H NMR (DMSOd₆, 300 MHz, ppm): 89.28 (bs, IH), 8.48 (bs, IH), 8.01 (d, J=8.1 Hz, 2H), 7.72-7.60 (m, 6H), 7.47-7.40 (m, 5H). Purity (HPLC): 99.8% Example 2: 2,3-bis-(4-chlorophenyl)-6-(3-trifluoromethyl-phenyl)-imidazo-[l,2-a]- pyrimidine

A mixture of 5-(3-trifluoromethyl-phenyl)-pyrimidine-2-yl amine (200 mg, 0.83 mmol) and 2-Bromo-l,2-bis(4-chlorophenyl)ethanone (316 mg, 0.92 mmol) in dimethyl formammide (5 mL) was heated at 100-120 ⁰C overnight. The reaction mixture was cooled and diluted with ethyl acetate and the organic portion was washed with saturated sodium bicarbonate and water (3x40 mL) consecutively followed by drying over sodium sulfate. The extract was concentrated and the product was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether (125 mg). Yield: 30.86%. m.p.: 212-213 ⁰C. ¹H NMR (DMSO-d₆, 300 MHz): 59.03 (d, J=2.4 Hz, IH); 8.78 (d, J=2.1 Hz, IH); 8.15 (s, IH); 8.08 (d, J=7.5 Hz, IH); 7.80 (d, J=8.1 Hz, 2H); 7.75 (d, J=7.8 Hz, IH); 7.66 (d, J=2.1 Hz, 4H); 7.62 (d, J=8.4 Hz, 2H); 7.46 (d, J=9.0 Hz, 2H). Purity [HPLC]: 97.09%. ESMS [m/e]: 484.46, 486.46.

Example 2a: 2,3-bis-(4-chlorophenyl)-6-(3-trifluoromethyl-phenyl)-imidazo-[l ,2-a]- pyrimidine hydrochloride

Yield: 94.97%. m.p.: 237-245 ⁰C. ¹H NMR (DMSOd₆, 300 MHz): 59.03 (d, J=2.4 Hz, IH); 8.78 (d, J=2.1 Hz, IH); 8.15 (s, IH); 8.08 (d, J=7.5 Hz, IH); 7.80 (d, J=8.1 Hz, 2H); 7.75 (d, J=7.8 Hz, IH); 7.66 (d, J=2.1 Hz, 4H); 7.62 (d, J=8.4 Hz, 2H); 7.46 (d, J=9.0 Hz, 2H). Purity [HPLC]: 99.6%. .

Example 3: 8-Bromo-2,3-bis-(4-chlorophenyl)-6-phenyl-imidazo-[l,2-a]-pyrazine

The compound was prepared according to the procedure of Example 1 using Intermediate 2 and Intermediate 4. m.p.: 199-200 ⁰C , ¹H NMR (DMSO-d₆, 300 MHz, ppm): 58.49 (s, IH), 7.98-7.95 (bd, 2H), 7.72-7.58 (m, 6H), 7.48-7.41 (m, 5H). Purity (HPLC): 89.5%.

The following compounds were prepared according to the procedure of Example 2, using appropriate (un)substituted pyrazine derivatives and appropriate (un)substituted phenyl ethanone derivatives.

Example 4: 8-Bromo-2.3 -bis-(4-chlorophenylV6-(4-fluoroρhenyl)-imidazo-[ 1 ,2-aipyrazine Yield: 20%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 68.51 (s, IH); 8.06-8.01 (m, 2H); 7.71 (d, J=8.7 Hz, 2H); 7.63 (d, J=8.4 Hz, 2H); 7.59 (d, J=9.0 Hz, 2H); 7.46 (d, J=8.7 Hz, 2H); 7.33- 7.27 (m, 2H). Purity [HPLC]: 91.33%. m.p.: 252-255 ⁰C.

Example 5: 2-r4-chlorophenyl)-3-(2,4-dichlorophenyl)-6-(3-fluorophenylV8-methyl-imidazo- [l,2-a]pyrazme

Yield: 11%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.46 (s, IH); 8.02 (d, J=I.5 Hz, 2H); 7.96-7.91 (m, 2H); 7.70-7.67 (m, 3H); 7.58 (d, J=8.4 Hz, 2H); 7.47 (d, J=8.7 Hz, 2H); 7.25- 7.19 (m, IH); 2.93 (s, 3H). Purity [HPLC]: 96.47%. m.p.: 221-223 ⁰C.

Example 6: 23-Bis-(4-chlorophenyl)-6-(2-chlorophenylVimidazo-[ 1 ,2-a]pyrazine

Yield: 17%. ¹H NMR (DMSOd₆, 300 MHz₅ ppm): 69.29 (s, IH); 8.33 (s, IH); 7.70-7.60 (m, 8H); 7.49-7.44 (m, 4H). Purity [HPLC]: 98.62%. m.p.: 196-199 ⁰C. MS [m/z]: 450.22 [M⁺].

Example 7: 2-(4-Chlorophenyl^')-3-(2,4-dichlorophenyl)-8-methyl-6-plienyl-imidazo-[l ,2- a]pyrazine

Yield: 17%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 67.87 (d, J=6.9 Hz, 2H); 7.74 (s, IH); 7.72 (d, J=I.8 Hz, IH); 7.58 (d, J=8.4 Hz, 2H); 7.48-7.38 (m, 4H); 7.35-7.28 (m, 3H); 3.06 (s, 3H). Purity [HPLC]: 98.15%. m.p.: 203-204 ⁰C.

Example 8 : 2-(4-Bromophenyl)-3-(2,4-dichlorophenylV8-methyl-6-phenyl-imidazo-[ 1 ,2- a]pyrazine

Yield: 24%. ¹HNMR (DMSOd₆, 300 MHz, ppm): 58.31 (s, IH); 8.05 (d, J=7.5 Hz, 2H); 8.01 (d, J=I.2 Hz, IH); 7.70-7.63 (m, 2H); 7.61 (d, J=8.7 Hz, 2H); 7.51 (d, J=9.0 Hz, 2H); 7.48-7.38 (m, 3H); 2.93 (s, 3H). Purity [HPLC]: 97.01%. m.p.: 227-229 ⁰C.

Example 9: 8-Bromo-2.3-bis-(4-chlorophenyl)-6-r3-fluorophenylVimidazo[L2-a]pyrazine

Yield: 8%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.62 (s, IH); 7.88-7.83 (m, 2H); 7.71 (d, J=8.4 Hz, 2H); 7.64 (d, J=8.7 Hz, 2H); 7.59 (d, J=8.4 Hz, 2H); 7.53-7.51 (m, IH); 7.47 (d, J=8.7 Hz, 2H); 7.30-7.22 (m, IH). Purity [HPLC]: 96.21%. m.p.: 240-242 ⁰C.

Example 10: 2, 3, 6-Tris-(4-chlorophenyl)-8-methyl-imidazo-[l,2-a]-pyrazine

Yield: 14.01%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 68.40 (s, IH), 8.06 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz₅ 2H)₅ 7.62 (d, J=8.4 Hz₅ 2H), 7.61 (d, J-8.4 Hz₅ 2H)₅ 7.51 (d, J=8.4 Hz₅ 2H), 7.46 (d, J=8.4 Hz₅ 2H)₅2.91 (s, 3H). m.p.: 237-241 ⁰C [decomposition]. Purity [HPLC]: 94.9%.

Example 11 : 8-Chloro-2,3-bis-(4-Chlorophenyl)-6-phenyl-imidazo-[l,2-a]-pyrazine 000459

Yield: 9.14%. ¹HNMR (DMSOd₆, 300 MHz, ppm): δ8.52 (s, IH), 8.07-8.03 (m, 2H), 7.71 (d, J-8.4 Hz, 2H), 7.65-7.59 (m, 4H), 7.47 (d, J=8.4 Hz, 2H), 7.33-7.27 (t, J=9.0 & 8.7 Hz, 4H). Purity [HPLC]: 90.8%. m.p.: 271-273 ⁰C.

Example 12: 2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-phenyl-imidazo-[l .2-a]-pyrazine

Yield: 15.4%. ¹HNMR (DMSO-d₆, 300 MHz, ppm): 58.32 (s, IH), 8.48 (s, IH), 8.06 (d, J=7.2 Hz, 2H), 8.02 (s, IH), 7.69 (s, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.48-7.40 (m, 5H). Purity [HPLC]: 92.8%. m.p.: 191-194 ⁰C.

Example 13: 3 -(4-Chlorophenyl)-2-(2,4-difluoro-phenyl>-7-methyl-6-phenyl-imidazo[ 1 ,2- a]pyrimidine

Yield: 11.4%. ¹H NMR [CDCl₃, 300 MHz, ppm]: δ 8.15 (s, IH), 7.88-7.80 (m, IH), 7.48- 7.41 (m, 4H), 7.34-7.28 (m, 5H), 7.00-6.95 (m, IH), 6.78-6.71 (m, IH), 2.57 (s, 3H). m.p.: 83-85 ⁰C. Purity [HPLC]: 97.13%.

Example 14j 2-(2,4-Difluoro-phenyl)-3-(4-methoxy-phenyl)-7-phenyl-imidazo[l,2- a]pyrimidine

Yield: 54%. ¹H NMR [DMSO-d₆, 300 MHz, ppm]: δ 8.71 (d, J=6.9 Hz, IH), 8.25 (b d, 2H), 7.74-7.58 (m, 5H), 7.39 (d, J=7.8 Hz, 2H), 7.29-7.20 (m, 2H), 7.08 (d, J-8.4 Hz, 2H), 3.82 (s, 3H). m.p.: 152-155 ⁰C. MS [m/z]: 414.44. Purity [HPLC]: 99.7%.

Example 15 : 2-(4-Chlorophenyl)-3 -(2 ,4-dichlorophenyl)-6-(3 -methoxyphenyl)-imidazo [1,2- a]pyrazine

Yield: 21.43%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 59.31 (s, IH), 8.48 (s, IH), 8.01 (s, IH), 7.69-7.56 (m, 6H), 7.48-7.46 (b d, 2H), 7.37 (b m, IH), 6.99 (b d, IH), 3.82 (s, 3H). Purity [HPLC]: 98.3%. MS [m/z]: 484.4. m.p.:182-185 ⁰C.

Example 16: 2,3-Bis-(4-chlorophenyl)-6-(3-chlorophenyl)-8-methoxy-imidazo-[ 1.2- a]pyrazine

A mixture of 2,3-bis-(4-chlorophenyl)-6-(3-chlorophenyl)-8-chloro-imidazo-[l,2- a]pyrazine (180 mg, 0.37 mmol) and sodium methoxide (40 mg, 0.74 mmol) in methanol (20 mL) was refluxed for 8 hrs. The volatile matters were removed under vacuum and the residue was diluted with ethyl acetate. The ethyl acetate layer was washed with water and brine followed by drying over sodium sulfate, and concentrated. The product was purified over silica gel column using a mixture of ethyl acetate and petroleum ether to give in 31% yield (55 mg). ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.25 (b s, IH); 8.10 (b s, IH); 8.05-7.95 (m, IH); 7.75-7.65 (m, 2H); 7.63-7.52 (m, 4H); 7.50-7.40 (m, 4H); 4.23 (s, 3H). Purity [HPLC]: 98.11%. m.p.: >250 ⁰C. MS [m/z]: 486.45 [M'+H]. Example 17: 2,3,6-Tris-f4-chlorophenylVimidazo-[l,2-a]-pyrimidine

The compound was prepared according to the procedure of Example 2 using Intermediate 3 and Intermediate 4. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 58.97 (bs, IH), 8.66(d, J=2.4 Hz₅ IH), 7.83-7.79 (dd, JM8.4 & 2.4 Hz, 2H), 7.79 (s, IH), 7.68-7.54 (m, 8H)₅ 7.45 (d, J-7.5 Hz, 2H).

Example 18: 2,3.6 Tris-(4-chlorophenylVimidazo-[l,2-a]-pyrimidine hydrochloride salt

2,3,6-Tris-(4-chlorophenyl)-imidazo-[l,2-a]-pyrimidine (68 mg) was dissolved in a mixture of tetrahydrofuran (5 mL) and methanol (5 mL) followed by the drop wise addition of saturated HCl solution in diethyl ether (5 mL). The mixture was stirred overnight at room temperature. The volatile matters were removed under reduced pressure and the solid was co- evaporated with benzene (1X10 mL). Diethyl ether was added to the residue and stirred and the precipitated solid was filtered off to give the title compound (60 mg). ¹H NMR (DMSO- d₆, 300 MHz₅ ppm); 69.09 (d₅ J=2.1 Hz, IH), 8.74(d, J=2.4 Hz, IH), 7.83 (d, J=8.4Hz, 2H), 7.74-7.55 (m, 8H), 7.48 (d, J=8.7 Hz, 2H); Purity (HPLC): 89.4%. m.p.: >275 ⁰C.

The following compounds were prepared according to the procedure of Example 2, using appropriate (un)substituted pyrimidine derivatives and appropriate (un)substituted phenyl ethanone derivatives.

Example 19: 3-(4-Bromophenyl)-2,6-bis-(^f4-chlorophenyl^')-imidazo-[l ,2-a]pyrimidine

Yield: %. ¹H NMR (DMSOd₆, 300 MHz₅ ppm): 58.96 (d, J=2.7 Hz₅ IH); 8.55 (d, J=2.4 Hz, IH); 7.78 (d, J=8.4 Hz₅ 2H); 7.63-7.54 (m, 8H); 7.42 (d, J=8.4 Hz₅ 2H). Purity [HPLC]: 89.1%. m.p.: >270 °C.

Example 20: 2-f4-BromophenylV3-(2,4-dichlorophenyl)-6-(4-methoxyphenyl)-imidazo-[L2- alpyrimidine

¹H NMR (DMSO-d₆, 300 MHz, ppm): 58.99 (d₅ J= 2.1 Hz, IH); 8.53 (d, J=2.4 Hz₅ IH); 7.98 (s, IH); 7.71 (d, J=8.4 Hz, 2H); 7.66 (s, 2H); 7.59 (d, J=8.4 Hz₅ 2H); 7.50 (d, J=8.4 Hz, 2H); 7.05 (d, J=9.0 Hz₅ 2H); 3.80 (s, 3H).

Example 21 : 2-(4-BromophenylV3-(2,4-dichlorophenyl)-6-f4-methoxyphenyl)-imidazo-[1.2- a] pyrimidine hydrochloride

Yield: 84%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 59.14 (d, J=2.4 Hz₅ IH); 8.69 (d₅ J-2.7 Hz₅ IH); 8.00 (s, IH); 7.74 (d, J=9.0 Hz, 2H); 7.66 (s, 2H); 7.63 (d, J=8.4 Hz₅ 2H); 7.49 (d, J=8.7 Hz₅ 2H); 7.06 (d₅ J=8.7 Hz₅ 2H); 3.80 (s₅ 3H). Purity [HPLC]: 97.86%. m.p.: 225-226 ⁰C. Example 22: 2-(4-Bromophenyl)-3-(2,4-dichlorophenyl)^6₌{4-fluoroρhenylVimidazo-[^'l ,2- ajpyrimidine

¹H NMR (DMSO-d₆, 300 MHz, ppm): 59.00 (d, 1=2.1 Hz, IH); 8.63 (d, 1=2.1 Hz, IH); 7.98-

7.97 (t, J=1.2 Hz, IH); 7.85-7.80 (q, J-5.1 and 8.7 Hz, 2H); 7.66 (d, J=1.5 Hz 2H); 7.59 (d,

J=9.0 Hz, 2H); 7.5 (d, J= 8.7 Hz, 2H); 7.36-7.30 (m, 2H).

Example 23: 2-(4-Bromophenyl)-3-(2₁4-dichlorophenyD-6-(^'4-fluorophenyl)-imidazo-[l,2- a]pyrimidine hydrochloride salt

Yield: 58%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 69.02 (d, J=2.7 Hz, IH); 8.64 (d, J=2.7 Hz₅ IH); 7.98 (d, J=0.9 Hz, IH); 7.85-7.81 (q, J=5.7 Hz, 2H); 7.66 (bs, 2H); 7.60 (d, J=8.4 Hz, 2H); 7.51 (d, J=8.7 Hz, 2H); 7.36-7.31 (m, 2H). Purity [HPLC]: 93.17%. m.p.: 257-259 ⁰C.

Example 24: 3-[2-(4-ChlorophenylV3-r2,4-dichlorophenyl)-imidazo-[ 1 ,2-a]pyrimidin-6-yl]- phenol

Yield: 27%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 59.67 (b s, IH); 8.95 (s, IH); 8.52 (s, IH); 7.98 (s, IH); 7.66 (s, 2H); 7.58 (d, J=8.4 Hz, 2H); 7.45 (d, J=8.1 Hz, 2H); 7.31-7.26 (b t, J=7.5 Hz, IH); 7.16 (d, J=7.8 Hz, IH); 7.09 (b s, IH); 6.83 (d, J=7.8 Hz, IH). Purity [HPLC]: 93.53%. m.ρ.: 255-256 ⁰C. MS [m/z]: 466.25 [M⁺].

Example 25 : 2,3-Bis-(4-chlorophenyl)-6-(3,5-difluorophenylVimidazo-[ 1 ,2-a]pyrimidine

Yield: 46%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 59.01 (d, J=2.7 Hz, IH); 8.79 (d, J=2.1 Hz, IH); 7.69-7.64 (m, 6H); 7.62-7.59 (dd, J=2.1 Hz and 9.0 Hz, 2H); 7.45 (d, J=8.7Hz, 2H); 7.35-7.29 (dt, J=2.1 Hz and 8.4 Hz, IH). Purity [HPLC]: 96.88%. m.p.: 252-255 ⁰C. MS [m/z]: 452.45 [M÷+H].

Example 26: 6-(3,5-Difluoro-phenyl)-3-(4-ethyl-phenyl)-2-(^'4-fluoro-phenyD-imidazo [L2- a]pyrimidine

Yield: 20.96%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: δ 8.97 (d, 1=2.1 Hz, IH), 8.69 (d, J=2.4 Hz₅ IH), 7.67-7.61 (m, 4H), 7.53-7.44 (AB q, J=8.7 & 8.1 Hz, 4H), 7.35-7.29 (b t, IH), 7.24-7.18 (t, J=9.0 & 8.7 Hz, 2H), 2.78-2.71 (q, J=7.8 Hz, 2H), 1.31-1.26 (t, J=7.8 Hz, 3H). m.p.: 195-196 ⁰C. Purity [HPLC]: 96.3%.

Example 27 : 6-f 3 ,5 -Diflυoro-phenyl)-2-(4-fluoro-phenylV3 -p-tolyl-imidazo [ 1 ,2-a]pyrimidine

Yield: 39%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: δ 8.97 (b s, IH), 8.66 (b s, IH), 7.68-7.60 (m, 4H), 7.50-7.41 (AB q, J=8.1 Hz, 4H), 7.34-7.28 (m, IH), 7.24-7.17 (m, 2H), 2.44 (s, 3H). m.p.: 194-197 ⁰C. Purity [HPLC]: 99.36%. MS [m/z]: 416.63.

Example 28 : 2-r4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-(3-nitrophenyl)-imidazo-[ 1 ,2- a]pyrimidine Yield: 34%. ¹H NMR (DMSO-d₆, 300 MHz₅ ppm): 59.09 (d, J=2.4 Hz, IH); 8.86 (d, J=2.4 Hz, IH); 8.59 (s, IH); 8.29 (d, J=9.9 Hz, IH); 8.24 (d, J=7.8 Hz, IH); 8.01 (s, IH); 7.82-7.77 (t, J=8.1 Hz, IH); 7.72-7.66 (m, 2H); 7.59 (d, J=9.0 Hz₃ 2H); 7.47 (d, J=8.4 Hz, 2H). Purity [HPLC]: 99.46%. m.p.: 214-218 ⁰C. MS [m/z]: 495.23 [M⁺+H].

Example 29: 2,3-Bis-r4-chlorophenyl)-6-(3-fluorophenylViniidazo-[l ,2-a]pyrimidine

To a mixture of 6-bromo-2,3-bis-(4-chlorophenyl)-imidazo[l,2-a]pyrimidine (200 mg, 0.47 mmol), 3-fluorophenylboronic acid (80.14 mg, 0.57 mmol) and bis-(triphenyl phosphine)-palladium (IΙ)-chloride (16 mg, 0.02 mmol) was added degassed 1,4-dioxane (10 mL). The mixture was stirred for 20 min followed by the addition of aqueous sodium carbonate (IM, 1.42 mL), and the resultant reaction mixture was refluxed for 2.5 hr . The volatile matters were removed under reduced pressure, the crude mass was diluted with ethyl acetate and the organic layer was washed with water followed by brine and dried over sodium sulfate and concentrated. The product was purified over silica gel column chromatography using a mixture of ethyl acetate and petroleum ether as eluent in 83% yield (172 mg). ¹H NMR (DMSO-d₆+ D₂O, 300 MHz, ppm): 59.01 (d, J=2.4 Hz, IH); 8.71 (d, J=2.1 Hz, IH); 7.73-7.50 (m, 9H); 7.45 (d, J-8.7 Hz, 2H); 7.30-7.24 (b t, J=8.4 Hz, IH). Purity [HPLC]: 99.18%. m.p.: 257-258 ⁰C. MS [m/z]: 434.0 [M⁺].

The following compounds were synthesized by following the procedure described above.

Example 30: 2,3-Bis-(4-chlorophenylV6-(pyridin-3-yl)-imidazo-[l ,2-a]pyrimidine Yield: 31%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 59.02 (d, J=2.1 Hz, IH); 8.99 (b s, IH); 8.80 (d, J=2.1 Hz, IH); 8.63 (d, J=3.9 Hz, IH); 8.20 (d, J=7.8 Hz, IH); 7.70-7.58 (m, 6H); 7.55-7.48 (m, IH); 7.46 (d, J=8.4 Hz, 2H). Purity [HPLC]: 97.87%. m.p.: >250⁰C. MS [m/z]: 417.54 [M⁺+H].

Example 31: 2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-pyridin-3-yl-imidazo-[l,2- a]pyrimidine

Yield: 56%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 59.07 (s, IH); 8.98 (s, IH); 8.82 (s, IH); 8.63 (b s, IH); 8.21 (d, J=6.9 Hz, IH); 7.99 (s, IH); 7.67 (b s, 2H); 7.59 (d, J=8.4 Hz, 2H); 7.55-7.45 (m, 3H). Purity [HPLC]: 99.24%. m.p.: 197-200 ⁰C. MS [m/z]: 451.40 [M⁺+H].

Example 32: 3-[^"2,3-Bis-(4-chlorophenyl)-imidazo-[l,2-a]pyrimidine-6-yl]-benzoic acid

Yield: 73%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.95 (b s, IH); 8.54 (b s, IH); 8.11 (s, IH); 7.91 (d, J=7.2 Hz, IH); 7.75-7.60 (m, 7H); 7.48-7.38 (m, 3H). Purity [HPLC]: 99.2%. m.ρ.: >260 ⁰C.

Example 33: 2.3-Bis-r4-chlorophenyl)-6-(3-nitroρhenyl)-imidazo-[1.2-a]pyrimidme Yield:15%. ¹HNMR (DMSO-d₆, 300 MHz, ppm): 59.05 (d, J=2.7 Hz₃ IH); 8.84 (d, J=2.1 Hz, IH); 8.60 (s, IH); 8.28 (d, J=8.4 Hz, IH); 8.24 (d, J=8.4 Hz, IH); 7.82-7.77 (t, J=7.8 Hz, IH); 7.70-7.60 (m, 6H); 7.46 (d, J=8.4 Hz, 2H). Purity [HPLC]: 98.52%. m.p.: >250 ⁰C. MS [m/z]: 461.25 [M*].

Example 34: 3-(2,4-DichlorophenylV6-(^'3-methoxyphenyl)-2-phenyl-imidazo-[1.2- a]pyrimidine

Yield: 20%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 59.01 (s, IH); 8.60 (s, IH); 7.98 (s, IH); 7.66 (s, 2H); 7.59 (d, J=6.6 Hz, 2H); 7.43-7.26 (m, 7H); 7.01 (d, J=7.8 Hz, IH); 3.82 (s, 3H). Purity [HPLC]: 93.22%. m.p.: 145-146.5 ⁰C

Example 35: [2,3-Bis-f4-chlorophenyl>7-methyl-imidazo-[l ,2-a]pyrimidin-6-yl]-pyrrolidin- 1-yl-methanone

To a solution of 2,3-bis-(4-chlorophenyl)-7-methyl-imidazo-[l,2-a]pyrimidin-6- carboxylic acid (60 mg, 0.15 mmol) in dimethylformamide (4 mL) was added benztriazoline- l-oxy-tris(dimethylamino)phosphonium hexafluorophosphate [BOP] (80 mg, 0.18 mmol) and triethylamine (45 mg, 0.45 mmol). The mixture was stirred for 1 hr at ambient temperature followed by the addition of pyrrolidine (12 μL, 0.18 mmol). The resultant clear solution was further stirred for 17 hrs at room temperature. The solution was diluted with ethyl acetate (75 mL) and the organic layer was washed with water followed by brine and dried over sodium sulfate and concentrated. The product was purified by preparative TLC (20 mg, 29%). ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.53 (s, IH); 7.65 (d, J=8.4 Hz, 2H); 7.60-7.54 (AB q, J-8.7 Hz, 4H); 7.44 (d, J=8.4 Hz, 2H); 3.50-3.42 (b t, 2H); 3.24-3.20 (b t, 2H); 1.90-1.75 (m, 4H); 1.23 (s, 3H). Purity [HPLC]:^' 96.68%. m.p.: 222-225 ⁰C. MS [m/z]: 451.4 [M⁺].

The following amides were also prepared according to the above procedure starting from 3-[2,3-Bis-(4-chlorpphenyl)-imidazo-[l ,2-a]pyrimidine-6-yl]-benzoic acid.

Example 36: 3-[2-(4-Chlorophenyl)-3-(2.4-dichlorophenylVimidazo-[1.2-a]pyrimidine-6-vn- N-(2-hydroxy-ethvQ-benzamide

Yield: 7%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 5, 9.10 (s, IH); 8.72 (s, IH); 8.61 (s, IH); 8.20 (s, IH); 8.05-7.85 (m, 3H); 1.15-1 A5 (m, 7H); 4.78 (s, IH); 3.53 (b s, 4H). Purity [HPLC]: 95.55%. m.p.: 238-240 ⁰C. MS [m/z]: 537.4 [M⁺].

Example 37: 3-[2-(4-Chlorophenyl^')-3-(2.4-dichloroρhenyl)-imidazo-[1.2-a]pyrimidine-6-yl]- benzamide

Yield: 39%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 5, 9.08 (s, IH); 8.70 (s, IH); 8.25-8.05 (m, 2H); 8.05-7.90 (m, 3H); 7.75-7.40 (m, 8H). Purity [HPLC]: 89.40%. m.p.: >260 ⁰C. MS [m/z]: 493.5 [M⁺]. Example 38: 3-f2,3-Bis-r4-chlorophenyl)-imidazo-[1.2-a1pyrimidine-6-yl1-N,N-dimethyl- benzamide

Yield: 34%. ¹H NMR (DMSOd₆, 300 MHz, ppm): δ, 8.99 (b s, IH); 8.68 (d, J=I.5 Hz, IH); 7.83 (d, J=7.5 Hz, IH); 7.79 (s, IH); 7.69-7.53 (m, 7H); 7.48-7.42 (m, 3H); 3.00 (s, 3H); 2.93 (s, 3H). Purity [HPLC]: 99.2%. m.p.: 260-262⁰C.

Example 39: 2,3-Bis-(4-chlorophenyl)-6-(lH-tetrazol-5-yl)-imidazo[l ,2-a]pyrimidine

A mixture of 2,3-bis-(4-chlorophenyl)-imidazo[l,2-a]-pyrimidine-6-carbonitrile (150 mg, 0.41 mmol), ammonium chloride (22 mg, 0.41 mmol) and sodium azide (27 mg, 0.41 mmol) in dry DMF (5 mL) was heated at 100⁰C for 5 hrs. The reaction mixture was then cooled and diluted with ethyl acetate (80 mL). The organic layer was washed with water (3 X 60 mL) and dried over Na₂SO₄ followed by concentrated. The product was then precipitated from ethyl acetate (10 mL) as a spectroscopically pure solid (22 mg, 13%). ¹H NMR (DMSOd₆, 300 MHz, ppm): 59.18 (d, 1=2.1 Hz, IH); 8.97 (b s, IH); 7.75 (d, J=8.4 Hz, 2H); 7.68-7.63 (m, 4H); 7.47 (d, J=8.4 Hz, 2H). Purity [HPLC]: 97.65%. m.p.: >270 ⁰C. MS [m/z]: 408.13 [M⁺].

Example 40: 2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-(3-methoxyphenyl)-imidazo-[l ,2- a]pyrimidine

Yield: 31%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 59.03 (d, J=2.4 Hz, IH); 8.62 (d, J=2.4 Hz, 2H); 7.99 (s, IH); 7.67 (d, J=I.5 Hz, 2H); 7.58 (d, J=9.0 Hz, 2H); 7.46 (d, J=9.0 Hz, 2H); 7.40 (d, J=8.1 Hz, IH); 7.33-7.31 (m, 2H); 7.03-7.00 (dd, J=1.8 Hz and 7.5 Hz, IH); 3.83 (s, 3H). Purity [HPLC]: 97.65%. m.p.: 189-191 ⁰C.

Example 41 : 2-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-6-(3-methoxyphenylVimidazo-[l,2- a]pyrimidine

Yield: 25%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 59.03 (d, J=2.7 Hz₅ IH); 8.62 (d, J=2.4 Hz, IH); 7.98 (s, IH); 7.67 (d, J=I.5 Hz, 2H); 7.60 (d, J=8.4 Hz, 2H); 7.51 (d, J=8.4 Hz, 2H); 7.40 (d, J=8.1 Hz, IH); 7.32 (d, J=6.6 Hz, 2H); 7.02 (bd, J=7.8 Hz, IH); 3.83 (s, 3H). Purity [HPLC]: 96.37%. m.p.:198-200⁰C.

Example 42: 2,3-Bis-(4-chloroρhenyl)-6-(3-chlorot)henvD-imidazo-[l ,2-a]pyrimidine

Yield: 43%. ¹HNMR (DMSOd₆, 300 MHz, ppm): 58.99 (d, J=2.4 Hz, IH); 8.72 (d, J=2.4 Hz, IH); 7.90 (s, IH); 7.76-7.74 (m, IH); 7.69-7.63 (m, 4H); 7.62 (d, J=8.4 Hz, 2H); 7.52 (d, J=6.6 Hz, 2H); 7.46 (d, J=8.7 Hz, 2H). Purity [HPLC]: 95.16%. m.p.: 231-233 ⁰C.

Example 43 : 2,3-Bis-(4-chlorophenyl)-6-(2-chlorophenylVimidazo-[ 1 ,2-a]pyrimidine Yield: 26%. ¹H NMR (DMSO-d₆, 300 MHz₅ ppm): δ8.74 (d, J=2.1 Hz, IH); 8.57 (d, J=2.7 Hz₅ IH); 7.66-7.59 (m, 8H); 7.52-7.45 (m, 4H). Purity [HPLC]: 98.74%. m.p.: 223 - 224 ⁰C. MS [m/z]: 450.27 [M⁺+H].

Example 44: 3-(2-Chlorophetiyl)-2-(4-chlorophenyl)-6-(3-chloroρhen^yl⁾-imidazo[l ,2- a]pyrimidine

Yield: 6%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): δ 9.02 (d, J=2.1 Hz, IH); 8.59 (d, J=2.1 Hz₅ IH); 7.88 (b s, IH); 7.79 (d, J=7.2 Hz, IH); 7.74-7.60 (m, 5H); 7.57 (d, J=8.4 Hz₅ 2H); 7.50 (d, J=6.3 Hz₅ IH); 7.43 (d, J=8.4 Hz₅ 2H). Purity [HPLC]: 95.98%. m.p.: 184-185 ⁰C. MS [m/z]: 452.28 [M>H].

Example 45: 2,3-Bis-(4-chlorophenyl)-6-(3-methoxyphenyπ-imidazo-[l ,2-a]pyrimidine

Yield: 33%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): δ8.99 (s, IH); 8.61 (s, IH); 7.70-7.60 (m, 6H); 7.50-7.38 (m, 3H); 7.35-7.28 (m, 2H); 7.01 (d, J=6.3 Hz, IH); 3.82 (s, 3H). Purity [HPLC]: 96.58%. m.p.: 226-227 ⁰CMS [m/z]: 446.42 [M⁺+H].

Example 46: Acetic acid 3-[2,3-Bis-(4-chlorophenyD-imidazo-[l,2-a]pyrimidin-6-yl]-phenyl ester

To a cold [0 ⁰C] solution of 3-[2,3-Bis-(4-chlorophenyl)-imidazo-[l,2-a]pyrimidin-6- yl]-phenol (150 mg, 0.34 mmol) in dichloromethane (10 mL) was charged triethylamine (0.053 mL, 0.37 mmol) followed by the addition of acetyl chloride (0.027 mL, 0.36 mmol). The resultant mixture was then stirred for 1 hr at 10-15 ⁰C. The volatile matter was removed under reduced pressure, and the crude mass was poured into water (100 mL) and the organic parts extracted with ethyl acetate (2x75 mL). The combined ethyl acetate layer was concentrated to dryness to give an analytically pure product (102 mg, 62.2%). ¹H NMR (DMSOd₆, 300 MHz, ppm): 88.97 (s, IH); 8.65 (s, IH); 7.75-7.50 (m, 9H); 7.44 (d, J=8.1 Hz, 2H); 7.21 (d, J=7.5 Hz, IH); 2.29 (s, 3H). Purity: 98.52%. m.p.: 229-234⁰C.

Example 47 : 2-(4-Chlorophenyl)-3 -(4-methoxyphenvD-6-(3 -trifluoromethyl-phenylV imidazo[l >2-a]pyrimidine

3-Bromo-2-(4-chlorophenyl)-6-(3-trifluoromethyl-phenyl)-imidazo[l,2-a] pyrimidine (145 mg, 0.32 mmol), 4-methoxyphenylboronic acid (53 mg, 0.35 mmol), bis-(triphenyl ρhosphine)palladium (II) chloride (13 mg, 0.06 mmol) were charged into degassed 1,4- dioxane (10 mL) and stirred at room temperature under N₂ for 45 min. Then degassed IM Na₂CO₃ solution (1 mL, 0.95 mmol) was added to it, and the resultant mixture was refluxed for 3 hrs. The solution was concentrated and the residue was diluted with ethyl acetate, and the ethyl acetate layer was washed with water followed by brine. The organic layer was then dried over Na₂SO₄ and concentrated. The product was then purified by silica gel column chromatography using ethyl acetate and petroleum ether mixture as a homogenous solid (90 mg, 58.8%). ¹H NMR (DMSO-d₆, 300 MHz₃ ppm): 58.99 (d, J=2.4 Hz, IH); 8.65 (d, J=2.7 Hz₅ IH); 8.13 (s, IH); 8.05 (d, J=7.8 Hz, IH); 7.80 (d, J=7.8 Hz, IH); 7.75-7.70 (t, 1=1.2 Hz and 7.8 Hz, IH); 7.65 (d, J-8,4 Hz, 2H); 7.53 (d, J=8.7 Hz, 2H); 7.43 (d, J=8.4 Hz, 2H); 7.17 (d, J=8.7 Hz, 2H); 3.86 (s, 3H). Purity [HPLC]: 97.24%. m.p.: 210-213 ⁰C. MS [m/z]: 480.45 [M^4--HH].

Example 48: 2-(4-Chlorophenyl)-3-(4-methylsulfanylphenyl)-6-(3-trifluoromethyl-phenylV imidazo [ 1 ,2-a]pyrimidine

The title compound was prepared according to the procedure described above for the synthesis of 2-(4-chlorophenyl)-3-(4-methoxyphenyl)-6-(3-trifluoromethyl-phenyl)- imidazo[l,2-a]pyrimidine starting from 3-Bromo-2-(4-chlorophenyl)-6-(3-trifluoromethyl- phenyl)-imidazo[l,2-a]pyrimidine and 4-methylthiophenylboronic acid. Yield: 44.3%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 59.00 (d, J=1.8 Hz, IH); 8.72 (d, J=1.8 Hz, IH); 8.14 (s, IH); 8.06 (d, J=6.6 Hz, IH); 7.85-7.70 (m, 2H); 7.64 (d, J=8.4 Hz, 2H); 7.54 (d, J=8.1 Hz, 2H); 7.50-7.40 (m, 4H); 2.56 (s, 3H). Purity [HPLC]: 97.59%. m.p.: 196-198 ⁰C. MS [m/z]: 496.43 [M⁺+H].

Example 49: 2-f2,4-Difluoro-phenyl)-3-p-tolyl-6-(3-trifluoromethyl-phenyl)-imidazo-[l,2-a]- pyrimidine

Yield: 42.3%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: δ 9.04 (s, IH)₅ 8.90 (s, IH)₅ 8.18 (s, IH), 8.10 (d, J=6.9 Hz, IH), 7.81-7.68 (m, 3H), 7.41 (d, J-7.5 Hz, 2H), 7.32 (d, J=7.8 Hz, 2H), 7.27-7.19 (m, 2H), 2.38 (s, 3H). m.p.: 190-193 ⁰C. Purity [HPLC]: 98.08%. MS [m/z]: 466.57.

Example 50: 2-(2,4-Difluoro-phenyl)-3-(4-methoxy-phenyl)-6-(3-trifluoromethyl-phenyl)- imidazo-[l ,2-a]pyrimidine

Yield: 35.86%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: δ 9.02 (d, J=2.4 Hz, IH), 8.86 (d, J=2.1 Hz, IH), 8.17 (s, IH), 8.09 (d, J=7.2 Hz, IH), 7.83-7.64 (m, 3H), 7.44 (d, J=8.4 Hz, 2H), 7.30-7.18 (m, 2H), 7.06 (d, J=8.4 Hz₅ 2H)₅ 3.81 (s, 3H). m.p.: 122.6 ⁰C. Purity [HPLC]: 99.8%. MS [m/z]: 482.63.

Example 51 : 2-(3,4-Difluoro-phenylV3-r4-methoxy-phenyl)-6-(3-trifluoromethyl-phenylV imidazo[ 1 ,2-a]pyrimidine

Yield: 9.47%. ¹H NMR [DMSO-d₆, 300 MHz, ppm]: δ 9.01 (s, IH), 8.65 (s, IH), 8.13 (s, IH), 8.05 (d, J=6.6 Hz, IH), 7.79-7.73 (m, 2H), 7.61-7.54 (m, 3H)₅ 7.44-7.42 (m, 2H), 7.19 (d, J=8.7 Hz₅ 2H), 3.87 (s, 3H). m.p.: 183-185 ⁰C. Purity [HPLC]: 95.6%. Example 52 : 2-(4-Fluoro-phenylV3 -f 4-methoxy-phenyiy6-C3 -trifluoromethyl-phenyl)- imidazo[l ,2-a]pyrirnidine

Yield: 44.7%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: δ 8.98 (s, IH), 8.63 (s, IH), 8.12 (s, IH), 8.04 (d, J=6.9 Hz, IH), 7.78-7.65 (m, 4H), 7.53 (d, J=8.7 Hz, 2H), 7.23-7.15 (m, 4H)₅ 3.86 (s, 3H). m.p.: 176-177 ⁰C. Purity [HPLC]: 97.6%. MS [m/z]: 464.5.

Example 53: 3-f4-Ethyl-phenyl)-2-f4-fluoro-phenyl)-6-(^'3-trifluoromethyl-phenyl)- imidazo[ 1 ,2-a^"jp yrimidine

Yield: 21.6%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: δ 9.00 (s, IH), 8.68 (s, IH), 8.14 (s, IH), 8.05 (d, J=7.8 Hz, IH), 7.82-7.64 (m, 4H), 7.53 (d, J=7.5 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.25-7.19 (t, J=8.7 Hz, 2H), 2.76-2.71 (q, J=7.8 Hz, 2H), 1.31-1.26 (t, J-7.8 Hz, 3H). m.p.: 108-110 ⁰C. Purity [HPLC]: 95.4%. MS [m/z]: 462.6.

Example 54: 3-(3,5-Difluoro-phenyl)-2-f4-fluoro-phenyl)-6-(3-trifluoromethyl-phenyl)- imidazo[ 1 ,2-a]pyrimidine

Yield: 37.2%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: δ 9.06 (s, IH), 8.73 (s, IH), 8.14 (s, IH), 8.07 (d, J=6.9 Hz, IH), 7.82-7.72 (m, 4H), 7.53-7.48 (t, J=9.0 & 8.4 Hz, 2H), 7.22-7.20 (b m, 3H). m.p.: 210-211 ⁰C. Purity [HPLC]: 99.5%. MS [m/z]: 470.48.

Example 55: 2-(4-Chlorophenyl)-6-(3-chloroplienyl)-3-(4-methoxyphenylVimidazo[l ,2-a]- pyrimidine

The title compound was prepared according to the procedure described above for the synthesis of 2-(4-chlorophenyl)-3 -(4-methoxyphenyl)-6-(3 -trifluoromethyl-phenyl)- imidazo[l,2-a]pyiimidme starting from 3-bromo-2-(4-chlorophenyl)-6-(3-chlorophenyl)- imidazo[l,2-a]pyrimidine and 4-methoxyphenylboronic acid. Yield: 29%. ¹H NMR (DMSO- d₆, 300 MHz, ppm): δ8.95 (s, IH); 8.58 (s, IH); 7.88 (s, IH); 7.71 (d, J=6.3 Hz, IH); 7.65 (d, J=8.4 Hz, 2H); 7.56-7.46 (m, 4H); 7.43 (d, J=8.4 Hz₅ 2H); 7.17 (d, J=7.5 Hz, 2H); 3.87 (s, 3H). Purity [HPLC]: 94.9%. m.p.: 217-222 ⁰C.

Example 56: 2,3-Bis-(4-chlorophenyl^')-6-(3-difluoromethoxy-phenylVimidazo-[l .2- a]pyrimidine

To a mixture of 3-[2,3-Bis-(4-chlorophenyl)-imidazo-[l,2-a]pyrimidin-6-yl]-phenol

(200 mg, 0.46 mmol) and potassium carbonate (191 mg, 1.38 mmol) in dimethylformamide (6 mL) was purged CHF₂Cl gas for 5 hrs. The reaction mixture was diluted with water (150 niL) and the organic components were extracted with ethyl acetate (150 mL). The ethyl acetate layer was washed with brine followed by drying over sodium sulfate, and concentrated. The crude was subjected to column chromatography over silica gel using a mixture of ethyl acetate and petroleum ether to give the title compound in 24.7% yield (55 mg). ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.99 (d, J=2.1 Hz, IH); 8.69 (d, J=2.1 Hz, IH); 7.74-7.50 (m, 9H); 7.45 (d, J=8.4 Hz, 2H); 7.52-7.10 (m, IH); 7.25 (d, J=8.1 Hz, IH). Purity [HPLC]: 99.14%. m.p.: 185-188 ⁰C. MS [m/z]: 482.51 [M⁺+H].

Example 57: 2-(4-ChlorophenyD-3-(2,4-dichlorophenylV6-r3-difluoromethyoxyphenyl)- imidazo-f 1 ,2-a]pyrimidine

This compound was prepared following the procedure described above for the synthesis of 2,3-Bis-(4-chlorophenyl)-6-(3-difluoromethoxy-phenyl)-imidazo-[l ,2-a] pyrimidine starting from 3-[2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-imidazo-[l,2- a]pyrimidin-6-yl]-phenol. Yield: 17%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 59.05 (d, J=2.1 Hz, IH); 8.70 (d, J=2.7 Hz, IH); 7.99 (s, IH); 7.68 (s, 4H); 7.64 (d, J=6.6 Hz, IH); 7.60-7.55 (m, 3H); 7.52-7.10 (t, J=74 Hz and 53 Hz, IH); 7.46 (d, J=8.4 Hz, 2H); 7.25 (d, J= 7.5 Hz, IH). Purity [HPLC]: 99.24%. m.p.: 153-159 ⁰C.

Example 58 : 3 - [2,3 -Bis-(4-chlorophenyl)-imidazo- [ 1 ,2-a]pyrimidin-6-yl] -phenol

Yield: 71.8%; ¹H NMR (DMSOd₆, 300 MHz, ppm): 59.67 (s, IH); 8.92 (d, J=2.4 Hz, IH); 8.51 (d, JM2.4 Hz, IH); 7.70-7.60 (m, 6H); 7.45 (d, J=8.1 Hz, 2H); 7.32-7.27 (t, J=7.8 Hz, IH); 7.16 (d, J=7.8 Hz, IH); 7.08 (d, J=1.5 Hz, IH); 6.83 (d, J=7.8 Hz, IH). Purity [HPLC]: 98.86%. m.p.: >260 ⁰C.

Example 59: 2-(4-Chlorophenyl)-3-(^'2,4-dichlorophenyl)-6-thiophen-3-yl-imidazo-[l,2- a]pyrimidine

Yield: 22.9%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 59.14 (d, J=2.1 Hz, IH); 8.67 (d, J=2.4 Hz, IH); 8.17 (s, IH); 8.00 (s, IH); 7.75-7.65 (m, 4H); 7.57 (d, J=8.4 Hz, 2H); 7.46 (d, J=8.4 Hz, 2H). Purity [HPLC]: 99.44%. m.p.: 243-246 ⁰C.

Example 60: 2,3-Bis-(4-chlorophenylV6-thiophen-3-yl-imidazo-[l,2-a]pyrimidine

Yield: 40%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 59.08 (d, J=2.4 Hz, IH); 8.68 (d, J=2.1 Hz, IH); 8.13 (b s, IH); 7.75-7.57 (m, 8H); 7.45 (d, J=9.0 Hz, 2H). Purity: 97.51%. m.p.: 250-251 ⁰C. MS [m/z]: 422.39 [M⁺+H].

Example 61 : Azepan-l-yl-[2,3-bis-r4-chlorophenyl)-7-methyl-imidazo[l,2-a]pyrimidin-6-yl]- methanone

Yield: 22.1%. ¹H NMR (CDCl₃, 300 MHz, ppm): 57.98 (s, IH); 7.66 (d, J=8.1 Hz, 2H); 7.55 (d, J=8.1 Hz, 2H); 7.36 (d, J=7.5 Hz, 2H); 7.29-7.26 (b d, 2H), 3.69 (b t, 2H); 3.30 (b s, 2H); 2.63 (s, 3H), 1.75-1.50 (m, 8H). Purity [HPLC]: 96.32%. m.p.: 194-196 ⁰C. MS [m/z]: 479.5 [M⁺]. Example 62: 2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo[^'l,2-a1pyrimidine-6-carboxylic acid pentylamide

Yield: 9%. ¹H NMR (CDCl₃ + D₂O, 300 MHz, ppm): 58.19 (s, IH); 7.62 (d, J=8.1 Hz, 2H); 7.54 (d, J=7.8 Hz₅ 2H); 7.35 (d, J=8.1 Hz, 2H); 7.29-7.26 (b d, 2H)₅ 3.40-3.36 (b q, 2H); 2.70 (s, 3H); 1.59 (b s, 2H), 1.34(b s, 4H); 0.91 (s, 3H). Purity [HPLC]: 97.45%. m.p.: 110-116 ⁰C. MS [m/z]: 467.4.

Example 63: [2,3-Bis-(4-chlorophenylV7-methyl-imidazo[l,2-a]pyrimidin-6-yl]-piperidin-l- yl-methanone

Yield: 19.9%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): δ8.44 (s, IH); 7.65-7.45 (m, 6H), 7.43 (d, J=7.5 Hz, 2H), 3.58 (b s, 2H), 3.35 (b s, 2H); 1.57-1.41 (m, 7H), 1.09 (b t, 2H). Purity [HPLC]: 96.75%. m.p.: 179-184 ⁰C. MS [m/z]: 465.41.

Example 64: 2_n3-Bis-(4-chlorophenyl)-7-methyl-imidazo[l,2-a]pyrimidine-6-carboxylic acid dimethylamide

Yield: 11%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.47 (s, IH); 7.70-7.40 (m, 8H), 2.98 (s, 3H), 2.86 (s, 3H), 2.49 (s, 3H). Purity [HPLC]: 96.9%. m.p.: 230-232 ⁰C. MS [m/z]: 425.39 [M¹H-H].

Example 65 : 2-f 4-Chlorophenyl)-6-f 3 -chlorophenyl)-3 -(4-methylsulfanylphenyl)- imidazo[l ,2-a]pyrimidine

Yield: 60.46%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 58.96 (s, IH); 8.65 (s, IH), 7.89 (s, IH), 7.72 (b d, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.56-7.40 (m, 8H), 2.56 (s, 3H). Purity [HPLC]: 93.57%. m.p.: 236-239 ⁰C. MS [m/z]: 462.43.

Example 66: 2-(4-Chlorophenyl)-6-(3-chlorophenyl)-3-(4-methanesulfonylphenyl)- imidazo[l ,2-a]pyrimidine

To a solution of 2-(4-chlorophenyl)-6-(3-chlorophenyl)-3-(4-methylsulfanylphenyl)- imidazo[l,2-a]pyrimidine (70 mg, 0.15 mmol) in dichloromethane (8 mL) was added drop wise a solution of 3-chloroperbenzoic acid (107 mg, 0.62 mmol) in dichloromethane (2 mL) at 0 ⁰C, and the resultant solution was stirred for 2 hrs at room temperature. The reaction mixture was then diluted further with dichloromethane (100 mL) and the organic layer was washed with 10% aqueous sodium bicarbonate solution. The dichloromethane layer was dried over sodium sulfate and concentrated and the crude was subjected to column chromatography over silica gel using a mixture of ethyl acetate and petroleum ether to give the title compound [40 mg, 51.9%]. ¹H NMR (DMSO-O₆, 300 MHz, ppm): 59.01 (d, J=I.8 Hz, IH); 8.83 (s, IH), 8.11 (d, J=8.1 Hz, 2H), 7.91 (s, 4H), 7.77-7.70 (m, 2H), 7.60 7.45 (m, 4H). Purity [HPLC]: 95.59%. m.p.: 232-236 ⁰C. MS [m/z]: 494.49 [M⁺+H]. Example 67: 2,3-Bis-(4-chlorophenylV6-m-tolyl-imidazo[l,2-a]pyrimidine

Yield: 84.44%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 58.96 (s, IH); 8.58 (s, IH), 7.68-7.53 (m, 8H)₃ 7.46-7.36 (m, 3H), 7.25 (b d, IH), 2.38 (s, 3H). m.p.: 217-220⁰C. MS [m/z]: 430.5 [M⁺].

Example 68: 2-(4-ChlorophenyD-3-f2, 4-dichlorophenyl)-6-f4-methoxyphenvD imidazo-[l,2- a]-pyrimidine

¹H NMR (DMSO-d₆, 300 MHz, ppm): δ8.99 (d, J=2.4 Hz, IH), 8.54 (d, J=2.1 Hz, IH), 7.98 (s, IH), 7.72 (d J=9.0 Hz, 2H), 7.66 (s, 2H), 7.58 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 3.80 (s, 3H).

Example 69: 2-(4-Chlorophenyl)-3-(2, 4-dichlorophenylV6-(4-methoxyphenvD imidazo-[l,2- a]-pyrimidine hydrochloride

Yield: 53.6%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 69.12 (d, J=2.7 Hz, IH), 8.67 (d, J=2.4 Hz, IH), 7.99 (bs, IH), 7.74 (d J=8.7 Hz, 2H), 7.66 (s, 2H), 7.58-7.48 (AB quartet, J=8.4 Hz, 4H), 7.06 (d, J=9.0 Hz, 2H), 3.80 (s, 3H). m.p.: 203-205 ⁰C. Purity [HPLC]: 98.47%.

Example 70: 3 -[2, 3-Bis-r4-chlorophenyl)-imidazo[l,2-a]pyrimidin-6-yl]-benzamide

Yield: 20.6%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 59.04 (d, J=2.1 Hz, IH), 8.71 (d, J=I.8 Hz, IH), 8.20 (s, IH), 7.91 (b d, 2H), 7.67-7.52 (m, 7H), 7.46 (d, J=8.7 Hz, 2H). Purity [HPLC]: 99.2%. MS [m/z]: 459.39. m.p.: 247-250⁰C.

Example 71 : 2.3-Bis-r4-chloro-phenyl)-6-(5.5-dimethyl-4.5-dihvdro-oxazol-2-yl)-7-methyl- imidazo[l ,2-a]pyrimidine

This compound can be prepared by following the procedure described in Example 87 using the appropriate starting materials.

Example 72 : 2-(4-Fluorophenyl>3 -(4-trifluoromethylphenyl)-6-(3 -trifluoromethylphenyl)- imidazo [L2-a]-pyrimidine

To a mixture of 3-bromo-2-(4-fluorophenyl)-6-(3-trifluoromethylphenyl)- imidazo[l,2-a]pyrimidine (0.12 g, 0.28 mmol), 4-(trifluoromethyl)-phenyl boronic acid (0.065 g, 0.34 mmol) and bis(triphenylphosphine)palladium(II)chloride (10 mg, 0.014 mmol) in degassed 1,4-dioxan (10 mL) were added and stirred at room temperature for 20 min. To the above was then added an aqueous solution of IM sodium carbonate (0.9 mL, 0.88 mmol), and the resultant mixture was refluxed for 4 h. The reaction mass was cooled and the volatile parts were evaporated from the reaction mixture. The residue was diluted with ethyl acetate and washed with water. The organic layer was then dried over sodium sulfate and concentrated. The product was isolated by column chromatography purification using ethyl acetate and petroleum ether mixture. Yield: 0.04 g (30%). ¹H NMR (DMSOd₆, 300 MHz, ppm): 69.04 (s, IH); 8.88 (s, IH); 8.16 (s, IH); 8.09 (d, J=8.1 Hz, IH); 7.96 (d, J=8.1 Hz₅ 2H); 7.86 (d, J=7.8 Hz, 2H); 7.82-7.70 (m, 2H); 7.65-7.58 (m, 2H); 7.27-7.22 (t, J=7.8 Hz, 2H). Purity [HPLC]: 97.69%. m.p.: 204-207 ⁰C. MS [m/z]: 502.76.

Example 73 : 2-(4-Fluorophenyl)-3-(4-methylsulphanylphenyl)-6-(3-trifluoromethylphenylV imidazo[ 1 ,2-a] -pyrimidine

The title compound was prepared by following the procedure as described for Example 72.

Yield: 11%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 59.00 (d, J=2.1 Hz, IH); 8.72 (d, J=2.1 Hz, IH); 8.15 (s, IH); 8.06 (d, J=7.8 Hz, IH); 7.81 (d, J=7.2 Hz, IH); 7.75 (d, J=7.8 Hz, IH); 7.72-7.65 (m, 2H); 7.55 (d, J=8.4 Hz, 2H); 7.46 (d, J=8.7 Hz, 2H); 7.26-7.20 (t, J=8.7 Hz, 2H); 2.56 (s, 3H). Purity [HPLC]: 97.95%. m.p.: 173-175 ⁰C. MS [m/z]: 480.39.

Example 74: 4-[2-(4-Chlorophenyl)-6-(3-trifluoromethylphenylVimidazo[ 1 ,2-a]-pyrimidin- 3-yl]-phenol

The title compound was prepared by following the procedure as described for Example 72.

Yield: 30%. ¹H NMR (DMSO-d₆, 300 MHz, ppm): 59.97 (s, IH); 8.98 (s, IH); 8.62 (s, IH); 8.12 (s, IH); 8.05 (d, J=6.9 Hz, IH); 7.78 (b s, IH); 7.74 (d, J=7.8 Hz, IH); 7.67 (d, J=7.8 Hz, 2H); 7.44-7.38 (t, J=8.7 Hz, 4H); 6.98 (d, J=8.1 Hz, 2H). Purity [HPLC]: 99.33%. m.p.: >250 ⁰C. MS [m/z]: 466.51.

Example 75: 2-(4-ChlorophenylV3-p-tolyl-6-(3-trifluoromethylphenyl)-imidazo[l,2- ajpyrimidine

The title compound was prepared by following the procedure as described for Example 72.

Yield: 18%. ¹H NMR (DMSOd₆, 300 MHz, ppm): 59.00 (s, IH); 8.66 (s, IH); 8.13 (s, IH); 8.05 (d, J=6.9 Hz, IH); 7.80 (d, J=7.5 Hz, IH); 7.75-7.70 (t, J=8.1 & 7.5 Hz, IH); 7.64 (d, J=8.7 Hz, 2H); 7.50 (d, J=8.1 Hz, 2H); 7.43 (d, J=8.4 Hz, 4H); 2.44 (s, 3H). Purity [HPLC]: 96.97%. m.p.: 179-181 ⁰C. MS [m/z]: 464.47.

Example 76: 6-(3,5-Dichlorophenyl)-2-(4-fluorophenyl)-3-(4-methylsulphanylphenyl)- imidazo[l ,2-a]pyrimidine

The title compound was prepared by following the procedure as described for Example 72.

Yield: 34%. ¹H NMR (DMSOd₆, 300 MHz₅ ppm): 58.96 (d, J=2.1 Hz, IH); 8.75 (d, J=2.4 Hz₅ IH); 7.90 (s, 2H); 7.70-7.62 (m, 3H); 7.53 (d, J=8.1 Hz₅ 2H); 7.46 (d, J-8.4 Hz, 2H); 7.26-7.20 (t, J=8.7 Hz₅ 2H); 2.57 (s, 3H). Purity [HPLC]: 93.83%. m.p.: 220-223 ⁰C. MS [m/z]: 480.47.

Example 77: 2,3-Bis-r4-fluoro-phenylV6-r3-trifluoromethyl-plienyD-iniidazo[ 1 ,2- ajpyrimidine

The title compound was prepared by following the procedure as described for Example 72.

Yield: 30%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: 59.01 (d, J=2.4 Hz, IH), 8.72 (d, J=2.4 Hz, IH), 8.07 (d, J=7.0 Hz, IH), 7.82-7.62 (m, 6H), 7.49-7.43 (t, J=9.0 & 8.7 Hz, 2H), 7.25- 7.19 (t, JM9.0 Hz & 8.7 Hz, 2H). Purity [HPLC]: 98.2%. m.p.: 183-186 ⁰C. MS [m/z]: 452.51.

Example 78: 2-(^"4-Fluoro-phenyl)-3-p-tolyl-6-(3-trifluoromethyl-phenyl)-imidazo[l 2- a]pyrimidine

The title compound was prepared by following the procedure as described for Example 13 by using 3-bromo-2-(4-fluorophenyl)-6-(3-trifluoromethylphenyl)-imidazo[l,2- a]pyrimidine.

Yield: 43.92%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: δ8.99 (s, IH), 8.66 (s, IH), 8.13 (s, IH), 8.05 (d, J=7.5 Hz, IH), 7.79-7.67 (m, 4H), 7.52-7.42 (AB q, J=6.6 & 6.9 Hz, 4H), 7.24- 7.22 (b t, 2H), 2.44 (s, 3H). Purity [HPLC]: 97.32%. m.p..: 194-197 ⁰C. MS [m/z]: 448.51.

Example 79: 2,3-Bis-(4-chlorophenyl)-6-(3,3-dimethyl-but-l-ynyl)-imidazo[l,2-a]pyrimidine

To a solution of 6-bromo-2,3-bis-(4-chlorophenyl)-imidazo[l,2-a]pyrimidine (0.21 g, 0.5 mmol) in dry dimethylformamide (4 mL), was added 3,3-dimethyl-but-l-yne (62 mg, 0.75 mmol) followed by triethylamine (0.21 ml, 1.5 mmol), copper(I)iodide (4.8 mg, 0.025 mmol) and &w-(triphenylphosphine)palladium (II) chloride (17.6 mg, 0.025 mmol), and the reaction mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with water and the organic parts were extracted with ethyl acetate. The ethyl acetate layer was then washed with water, followed by brine, and thendried over Na₂SO₄ and concentrated. The crude material was subjected to column chromatography over silica gel using a mixture of ethyl acetate in petroleum ether as the eluent. Yield: 0.13 g (62%). ¹H NMR (CDCl₃, 300 MHz, ppm): 58.54 (d, J=0.9 Hz, IH); 8.48 (b s, IH); 7.68 (d, J-8.4 Hz, 2H); 7.59 (d, J=5.4 Hz, 4H); 7.44 (d, J=8.4 Hz, 2H); 1.29 (s, 9H). Purity [HPLC]: 99.67%. m.p..: >260 ⁰C. MS [m/z]: 420.45.

Example 80: 6-f 5-tert-Butyl-|^" L 3, 4]oxadiazol-2-vD-2, 3-bis-f4-chlorophenylV7-methyl- imidazo[ 1 ,2-a]pyrimidine A mixture of 2,3 -bis-(4-chlorophenyl)-7-methyl-imidazo[ 1 ,2-a]pyrimidine-6- carboxylic acid N'-(2,2-dimethyl-propionyl)-hydrazide (90 nig, 0.18 mmol) and phosphorous oxychloride (1 mL) was heated to reflux for 30 min. The reaction mixture was then cooled, poured slowly into ice-cold water, the resultant mass was neutralized with sodium carbonate and then the organic parts were extracted with chloroform. The chloroform layer was dried over sodium sulfate and concentrated and the product was purified by preparative TLC. Yield: 18 mg (21%). ¹H NMR (DMSOd₆, 300 MHz, ppm): 58.79 (s, IH); 7.69-7.63 (m, 6H); 7.47 (d, J=6.9 Hz, 2H); 2.83 (s, 3H); 1.41 (s, 9H). MS [m/z]: 478.17.

Example 81 : 2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo[l,2-a]pyrimidine

The titled compound was prepared by following the procedure as described for 8- bromo-6-chloro-2,3-bis-(4-chlorophenyl)-imidazo[l ,2-a]pyrazine, intermediate 15.

Yield: 37%. ¹H NMR (δ, DMSO-d₆, 300 MHz): 8.05 (d, J=6.9 Hz, IH); 7.66 (d, J=8.7 Hz, 2H); 7.53 (d, J= 8.4 Hz, 2H); 7.37 (d, J= 8.4 Hz, 2H); 7.27 (d, J=6.9 Hz, 2H); 6.71 (d, J=6.9 Hz, IH); 2.65 (s, 3H). Purity [HPLC]: 99.71%. m.p.: >260⁰C.

Example 82 : 2-(3 ,4-Difluoro-phenyl)-3 -(4-methoxy-phenyD-6-(3 -trifluoromethyl-phenyl)- imidazofl ,2-a]pyrimidine

Yield: 9.4%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: 59.01 (b s, IH), 8.65 (b s, IH), 8.13 (b s, IH)₃ 8.05 (b d, IH), 7.85-7.30 (m, 7H), 7.19 (b d, J=8.7 Hz, 2H), 3.88 (s, 3H). Purity [HPLC]: 95.61%. m.p.: 183-185 ⁰C. MS [m/z]: 482.32.

Example 83 : 3-(4-Chloro-phenyl^')-2-(2-chloro-phenylV7-phenyl-imidazo[ 1 ,2-a]pyrimidine

Yield: 11%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: 58.90 (d, J=7.2 Hz, IH), 8.30-8.28 (b d, 2H), 7.78 (d, J=7.2 Hz, IH), 7.59-7.41 (m, HH). M.P.: 106⁰C.

Example 84: 2,3-Bis-(4-chloro-phenyl)-7-ρhenyl-imidazo[l ,2-a]pyrimidine

Yield: 33%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: 58.59 (b d, IH), 8.27 (b s, 2H), 7.68-7.59 (m, 10H), 7.47-7.44 (m, 2H). m.p.: 235-239⁰C.

Example 85: [2,3-Bis-(4-chloro-phenyl)-imidazo[l,2-a]pyrimidin-7-ylmethyl]-tert-butyl- amine

Step-I: [2, 3-Bis-(4-chloro-phenyl)-imidazo[l,2-a]pyrimidin-7-yl] -methanol

Yield: 19.9%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: 5 8.52 (d, J=6.9 Hz, IH), 7.67 (d, J=8.1 Hz, 2H), 7.61-7.55 (b t, 4H), 7.43 (d, J=8.1 Hz, 2H), 7.15 (d, J=6.9 Hz, IH), 5.73 (t, J=6.0 Hz, IH), 4.61 (d, J=6.0 Hz, 2H). Step-II: 2, 3-Bis-(4-chloro-phenyl)-imidazo[l, 2-aJpyrimidine- 7-carbaldehyde

To a suspension of pyridiniumdichromate (304 mg, 0.807 mmol) in dichloromethane (20 niL) was slowly added a solution of [2,3-bis-(4-chloro-phenyl)-imidazo[l,2-a]pyrimidin- 7-yl]-methanol (230 mg, 0.62 mmol) in dichloromethane (30 mL) under constant stirring at 0 ⁰C. After complete addition the reaction mixture was allowed to come to room temperature and stirred for 4 hr. The work up was done by diluting the mixture with diethyl ether and filtration over Celite® followed by washing with diethyl ether. The combined filtrate was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography. The product was isolated using a mixture of ethyl acetate and petroleum ether as eluent in 19.7% yield. ¹H NMR [DMSO-d₆, 300 MHz, ppm]: δ 9.96 (s, IH), 8.70 (d, J=6.9 Hz₅ IH), 7.71 (d, J=8.4 Hz, 2H), 7.66-7.61 (b t, 4H), 7.48 (d, J=8.4 Hz, 2H), 7.43 (d, J=6.9 Hz, IH).

Step-Ill: [2, 3-Bis-(4-chloro-phenyl)-imidazo[l, 2-aJpyrimidin- 7-ylmethylJ-tert-butyl-amine

A mixture of 2,3-bis-(4-chloro-phenyl)-imidazo[l,2-a]pyrimidine-7-carbaldehyde (58 mg, 0.157 mmol) and ter£-butylamine (17.3 mg, 0.236 mmol) in methanol (30 mL) was stirred for two days at room temperature followed by the addition of sodium borohydride (20.8 mg) and the resultant reaction mixture was further stirred for another 1 hr. at the same temperature. After removing the volatile matters under reduced pressure, the residue was dissolved in chloroform (50 mL) and the chloroform layer was washed with water (25 mL) followed by brine (25 mL). The organic layer was then dried over sodium sulfate and concentrated. The residue was then subjected to silica gel column chromatography and the product was isolated using a mixture of methanol and chloroform (12 mg, 18%). ¹H TSfMR [DMSOd₆, 300 MHz₃ ppm]: δ 8.46 (d, J=6.9 Hz, IH), 7.66 (d, J=8.4 Hz, 2H), 7.60-7.54 (b t, 4H), 7.43 (d, J=8.4 Hz, 2H), 7.16 (d, J=7.2 Hz, IH), 1.12 (s, 9H). m.p.: 146-150 ⁰C. MS [m/z]: 425.72.

Example 86: |[3-Chloro-2-f2,4-difluoro-phenyl)-imidazo[^' 1 ,2-a]pyrimidin-7-yl]-methanol

Yield: 45.4%. ¹H NMR [DMSOd₆, 300 MHz, ppm]: δ 8.75 (d, J=6.9 Hz, IH), 7.70-7.68 (m, IH), 7.57 (d, J=7.8 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.25-7.20 (m, 3H), 5.78 (b t, IH), 4.63 (d, J=6.0 Hz, 2H). m.p.: 188-190 ⁰C. Purity [HPLC]: 94.5%. MS [m/z]: 372.51.

Example 87: 2,3-Bis-(4-chloro-phenylV6-(4,4-dimethyl-4,5-dihydro-oxazol-2-ylV7-methyl- imidazo[ 1 ,2-a]pyrimidine Step —I: 2,3-Bis-(4-chloro-phenyl)-7-methyl-imidazo[l,2-a]pyrimidine-6-carhoxylic acid (2- hydroxy-1, 1 -dimethyl~ethyl)-amide:

To a solution of 2,3-bis-(4-chloro-phenyl)-7-memyl-imidazo[l,2-a]pyrimidine-6- carboxylic acid (260 mg, 0.65 mmol) in dimethylformamide (5.0 mL) was added BOP (346 mg, 0.78 mmol) followed by triethylamine (198.3 mg, 1.95 mmol) and the mixture was stirred at room temperature. After 2 hr., 2-amino-2-rnethyl-propan-l-ol (69.9 mg, 0.78 mmol) was added and the resultant mixture was further stirred for 17 hr. The reaction mixture was then diluted with water (25 mL) and the organic components were extracted with ethyl acetate (2x25 mL). The combined organic layer was washed with brine (1x50 mL), dried over sodium sulfate and concentrated to dryness (160 mg) that was used directly in the next step without further purification.

Step-II: 2, 3-Bis-(4-chloro-phenyl)-6-(4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl)-7-methyl- imidazofl, 2-qJpyrimidine:

A mixture of the crude residue (160 mg) obtained in step-I and thionyl chloride (0.285 mL) in ethyl acetate (20 mL) was refluxed for 7 hr. After cooling (0 ⁰C) the reaction mixture, the pH of the solution was adjusted to 8.0 with aqueous sodium bicarbonate solution. The organic parts were then extracted with ethyl acetate (2x75 mL) and the combined ethyl acetate layer was washed with brine (1x50 mL) and dried over sodium sulfate followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography and the product was isolated using a mixture of methanol and chloroform as eluent (15 mg, 5.1%). ¹H NMR [DMSOd₆, 300 MHz, ppm]: δ 8.35 (s, IH), 7.68 (d, J=8.4 Hz, 2H), 7.59 (d, 4H), 7.44 (d, J=8.4 Hz, 2H), 4.02 (s, 2H), 2.61 (s, 3H), 1.36 (s, 6H). m.p.: 152-157⁰C. Purity [HPCL]: 98.32%. MS [m/z]: 451.64.

Example 88: 2,3-Bis-(4-chloro-phenylV6-(3,3-dimethyl-butylVimidazo[l ,2-a]pyrimidine

To a solution of 2,3-bis-(4-chloro-phenyl)-6-(3,3-dimethyl-but-l-ynyl)-imidazo[l,2- ajpyrimidine (150 mg, 0.358 mmol) in 1,4-dioxane (25 mL) was charged Pd/C (10% wt/wt, 50 mg) and the mixture was stirred at room temperature under hydrogen atmosphere for 8 hrs. After completion of reaction, the catalyst was filtered on Celite® and was washed with 1,4-dioxane (25 mL). The combined filtrate was concentrated and the residue was subjected to silica gel column chromatography for purification and the title compound was isolated in 34.5% yield (52 mg). ¹H NMR [CDCl₃, 300 MHz, ppm]: 58.46 (d, J=2.1 Hz, IH), 7.93 (d, J=2.1 Hz₃ IH), 7.64 (dd, J=8.7 & 1.8 Hz, 2H), 7.56 (dd, J=8.7 & 1.8 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 7.28 (b d, 2H), 2.59-2.54 (m, 2H), 1.48-1.45 (m, 2H), 0.97 (s, 9H). m.p.: 217-218 ⁰C. Purity [HPLC]: 96.17%. MS [m/z]: 424.6.

Example 89: l-[2,3-Bis-(4-chloro-phenyl)-imidazori,2-a1pyrimidin-6-ylethvnyl]- cyclohexanol

Yield: 36.8%. ¹H NMR [DMSO-d₆, 300 MHz, ppm]: δ8.58 (s, IH), 8.53 (s, IH), 7.68 (b d, J=6.3 Hz, 2H), 7.61-7.58 (b d, 4H), 7.45 (b d, J=7.8 Hz, 2H), 5.52 (s, IH), 1.84 (b s, 2H), 1.60-1.53 (m, 8H). m.p.: 232-234 ⁰C. Purity [HPLC]: 99.78%. MS [m/z]: 462.56.

Example 90: In- vitro Protocol for rat CBl receptor binding using brain membrane

In this assay, [³H]SR141716A was used to bind the CBl receptor present in a rat brain membrane preparation which can be displaced by unlabeled ligands having affinity to the CBl receptor.

The assay was performed according to the modified method of Thomas et aL, 1998 (JPET 285: 285-292). The total reaction mixture (250 ml) contains Tris-BSA buffer (50 mM Tris, pH 7.4 with 1.5 % BSA) or unlabeled SR141716A (1 mM) or test samples (1 mM), [³H] SR141716A (2 nM) and 100 mg of rat brain membrane. The non-specific binding was defined by 1 mM of SR141716A. The assay mixture was incubated at 37⁰C for 1 hour. The reaction was then stopped by rapid filtration under vaccum using a Whatman GF/B-96 micro filter plate. A scintillation cocktail was added and radioactive counts were measured using Topcount beta scintillation counter.

The standard and test sample dilutions were made in an assay buffer containing either ethanol or DMSO at a final concentration of 1%.

The percent (%) displacement by a test ligand was calculated by comparing the specific bound values. The results of the assay are shown in Table II below.

Example 91 : Protocol for in-vitro assay using hCBl-CHO membranes

In this assay, [³H]-CP-55, 940 was used as the radioligand to bind human CBl receptors expressed on the membranes from CHO cells (the hCBl-CHO cell line was generated in-house) which can be displaced by unlabeled ligands having affinity to the CBl receptor.

The assay was performed according to the modified method of Ross et α/., 1999 (Br. J. Pharmacol. 128, 735-743). The reaction was set up in a total volume of 200 μl in PEI (Poly(ethyleneimine)) (0.2 %) precoated Millipore GFB (Glass Fibre-B) filter plates. ImM stocks of test compounds were prepared in DMSO and tested at a final concentration of 300 nM. The non-specific binding was determined by 0.5 μM CP-55, 940. The total reaction mixture contained Tris-BSA buffer (5OmM Tris, 5 mM MgCl₂, 1 mM EDTA, pH 7.4 with 0.1 % BSA), unlabelled CP-55, 940 (0.5 μM) or test samples, [³H]-CP-55, 940 (0.75 nM ) and 50 μg of human CBl receptor preparation. The assay mixture (with or without the test compound) was incubated at 37 ⁰C for 1 hour. The reaction was stopped by rapid filtration under vacuum and the radioactivity on the filters was measured by liquid scintillation counting. The results of the assay are shown in Table II below.

Example 92: In- vitro Protocol for rat CB2 receptor binding using spleen membrane

In this assay, [³H] CP 55, 940 was used to bind the CB2 receptor present in a rat spleen membrane preparation which can be displaced by unlabeled Hgands having affinity to the CB2 receptor.

The assay was performed according to the modified method of Rinaldi-Carmona et al, 1998 (JPET 284: 644-650). The total reaction mixture (250 ml) contains Tris-BSA buffer (50 mM Tris, pH 7.4 with 1.5 % BSA) or unlabeled SR144528 (1 mM) or test samples (300 nM), [³H]CP55,940 (1 nM) and 100 mg of rat brain membrane. The non-specific binding was defined by 1 mM of SR144528. The assay mixture was incubated at 37⁰C for 1 hour. The reaction was then stopped by rapid filtration under vaccum using a Whatman GF/B-96 micro filter plate. A scintillation cocktail was added and radioactive counts were measured using Topcount beta scintillation counter.

The standard and test sample dilutions were made in an assay buffer containing either ethanol or DMSO at a final concentration of 1%.

The percent (%) displacement by a test ligand was calculated by comparing the specific bound values. The results of the assay are shown in Table II below.

Example 93: Protocol for in- vitro assay using hCB2-CHO membranes m this assay, [³H]-CP-55, 940 was used as the radioligand to bind human CB2 receptor expressed on the membranes from CHO cells (hCB2-CHO cell line was procured form Euroscreen) which can be displaced by unlabeled ligands having affinity to the CB2 receptor.

The assay was performed according to the modified method of Ross et al.,1999 ( Br.

Jrnl. Pharmacol. 128, 735-743). The reaction was set up in a total volume of 200 μl in PEI (0.2 %) precoated Millipore GFB filter plates. ImM stocks of test compounds were prepared in DMSO and tested at a final concentration of 300 nM. The non-specific binding was determined by 0.5 μM CP-55, 940. The total reaction mixture contained Tris-BSA buffer(50mM Tris,5 mM MgCk₉I mM EDTA, pH 7.4 with 0.1 % BSA) , unlabelled CP-55, 940 (0.5 μM) or test samples, [³H]-CP-55, 940 (0.75 nM ) and 0.5 μg of human CB2 receptor preparation. The assay mixture (with or without the test compound) was incubated at 30 °C for 1 hour. The reaction was stopped by rapid filtration under vacuum and the radioactivity on the filters was measured by liquid scintillation counting.

AU patents, published patent applications, and references cited herein are incorporated ence.

Claims

We claim:

1. A compound of formula (I):

(I) and analogs, N-oxides, tautomers, regioisomers, stereoisomers, prodrugs, polymorphs and pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein:

(i) X₁ is CR and X₂ is N₅ or (ii) X₁ is N and X₂ is CR;

R, R^! _a, R^l _h, R² _a, R² _b, R² _C, R² _d, R² _e, R³ _a, R³ _b; R³ _C, R³ _d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_m-R⁴, or -S(O)_n-NR⁴R⁵; each occurrence of R and R⁵ is independently hydrogen, nitro, halo, cyano, -0R^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R³, -C(0)NR^aR^b, -S(O)_m-R^a, -S(0)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which 9

they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S orNR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, fαπnyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(0)NR°R^d, -S(O)_m-R^c, -S(O)_m-NR^cR^d, - NR^cR^d, -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or ^' unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R° and R is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; and each occurrence of m is 0, 1 or 2.

2. The compound according to claim 1, wherein when X₁ is CR, X₂ is N and R² _C and R³ _C are methoxy, then at least one of R^! _a, R^! _b or R is not hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, nitro or hydroxy.

3. The compound according to claim 1, wherein when X₁ is CR, X₂ is N, R\ is H, and R²c or R³ _c is -S(O)JR⁴, then R⁴ is not methyl, isopropyl or -NH₂.

4. The compound according to claim 1 , wherein when X₁ is CR and X₂ is N, then at least one of R, R*_a, or R^! _b is not hydrogen, halogen, hydroxy, SH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylsulfanyl, NR⁴R⁵

or NR⁴C(O)-R⁵ (wherein R⁴ and R⁵ are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylmethyl, CH₂OCOH or CH₂OCO-alkyl), except the compound where R and R^ are each hydrogen, and R¹ _a is bromine.

5. The compound according to claim 1, wherein when X₁ is CR, X₂ is N, and R, R*_a or R^J _b is substituted or unsubstituted phenyl, then at least one of R² _a-R² _e or R³ _a-R³ _e is not hydrogen or substituted or unsubstituted alkyl.

6. The compound according to claim 1 , wherein when X₁ is N, X₂ is CR and R is — CONHR⁵, then R⁵ is not substituted or unsubstituted alkyl.

7. The compound according to claim 1 , wherein when X₁ is N and X₂ is CR, then R is not a carboxyl group or a reactive derivative thereof.

8. The compound according to claim 1 , wherein when X₁ is N, X₂ is CR and R^ is hydrogen, then R³ _C is not -SO₂CH₃.

9. The compound according to claim 1, wherein when X₂ is N and X₁ is CR, then at least one ofR² _c and R³ _C is not substituted or unsubstituted alkoxy.

10. The compound according to claim 1 , wherein when X₂ is N and X₁ is CR, then R² _C and R³ _C are not -S(O)_1nR⁴.

11. The compound according to claim 1, wherein at least one of R² _a-R² _e or R³ _a-R³ _eis halogen.

12. The compound according to claim 1, wherein R is H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or OR⁴.

13. The compound according to claim 1 , wherein R is chlorine, bromine, methyl, methoxy, phenyl, CH₂OH or CH₂NHC(CH₃).

14. The compound according to claim 1, wherein R^! _a is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted alkynyl.

15. The compound according to claim 1, wherein R^J _a is substituted phenyl, -C(O)NR⁴R⁵, or substituted or unsubstituted alkyl.

16. The compound according to claim 1, wherein R^! _a is phenyl substituted with one or two substituents selected from -CF₃, chlorine, methyl, -OCHF₂, and nitro.

17. The compound according to claim 1, wherein R^x _a is selected from hydrogen, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 3,5- difluorophenyl, 3,5-dichlorophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 3,3-dimethyl-butynyl, 5-tert-butyl-l,3,4-oxadiazol-2-yl, 3- difluoromethoxyphenyl 3-hydroxyphenyl, 3-nitrophenyl, benzamide, azepan-lyl-carbonyl, N- (2-hydroxyethyl)benzamide, N,N-dimethyl-carboxamide, N,N-dimethyl-3 -benzamide, 3- phenylacetate, 3-benzoic acid, pyridyl, lH-tetrazole, thienyl, 3,3-dimethyl-butyl, 4,4- dimethyl-4,5-dihydro-oxazol-2-yl, 2-ethynyl pyridine, and 1-ethynyl.

18. The compound according to claim 1, wherein R 1 _b, τ R> 2_a, r R>2b, r R>2d, , R >3a, τ R»3b, R r>3d a „„nd j r R>3 are hydrogen.

19. The compound according to claim 1, wherein R² _C is hydrogen, halogen, S(O)_mR⁴, OR⁴, SR⁴, substituted or unsubstituted alkyl.

20. The compound according to claim 1, wherein R² _C is chloro, bromo, fluoro, SH, OCH₃, OH, -SCH₃, methyl, ethyl, trifluoromethyl.

21. The compound according to claim 1 , wherein R² _C and R³ _C are hydrogen or halogen.

22. The compound according to claim 1, wherein R³ _C is chloro, bromo or fluoro.

23. The compound according to claim 1, wherein R² _C and R³ _C are chloro.

24. The compound according to claim 1, wherein R² _C, R³ _C, and at least one of R³ _a and R³ _e is chloro.

25. The compound according to claim 1, wherein X₁ is CH, X₂ is N, R^ is hydrogen and R¹ _J1 is 3-substitutedphenyl.

26. The compound according to claim 1, wherein X₁ is CH, X₂ is N, R*_b is hydrogen and R¹ _J1 is 3-haloalkylphenyl.

27. The compound according to claim 1 , wherein R² _a, R² _b, R² _C, R² _d, R² _e, R³ _a,

and R _e are independently selected from hydrogen, halogen or alkyl.

28. The compound according to claim 1, wherein the compound is selected from: 2,3 -bis-(4-chlorophenyl)-6-phenyl-imidazo-[ 1 ,2-a] -pyrazine, 2,3-bis-(4-chlorophenyl)-6-(3-trifluoromethyl-phenyl)-imidazo-[l,2-a]-pyrimidine,

2,3-bis-(4-chlorophenyl)-6-(3-trifluoromethyl-phenyl)-imidazo-[l,2-a]-pyrimidine hydrochloride,

8-Bromo-2,3-bis-(4-chlorophenyl)-6-phenyl-imidazo-[l,2-a]-pyrazine, 8-Bromo-2,3-bis-(4-chlorophenyl)-6-(4-fluorophenyl)-imidazo-[l,2-a]pyrazine,

2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-6-(3-fluorophenyl)-8-methyl-imidazo- [l,2-a]pyrazine,

2,3-Bis-(4-chlorophenyl)-6-(2-chlorophenyl)-imidazo-[l,2-a]pyrazine,

2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-8-methyl-6-phenyl-imidazo-[l,2- ajpyrazine,

2-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-8-methyl-6-phenyl-imidazo-[l,2- a]pyrazine,

8-Bromo-2,3-bis-(4-chlorophenyl)-6-(3-fluorophenyl)-imidazo[l,2-a]pyrazine,

2, 3, 6-Tris-(4-chlorophenyl)-8-methyl-imidazo-[l,2-a]-pyrazine, 8-Chloro-2,3-bis-(4-Chlorophenyl)-6-phenyl-imidazo-[l,2-a]-pyrazine,

2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-phenyl-imidazo-[l,2-a]-pyrazine,

3-(4-Chlorophenyl)-2-(2,4-difluoro-phenyl)-7-methyl-6-phenyl-imidazo[l,2- a]pyrimidine,

2-(2,4-Difluoro-phenyl)-3-(4-methoxy-phenyl)-7-phenyl-imidazo[l,2-a]pyrimidine, 2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-(3-methoxyphenyl)-imidazo[l,2- ajpyrazine,

2,3-Bis-(4-chlorophenyl)-6-(3-chlorophenyl)-8-methoxy-imidazo-[l,2-a]pyrazine,

2,3,6-Tris-(4-chlorophenyl)-imidazo-[l,2-a]-pyrimidine,

2,3,6 Tris-(4-chlorophenyl)-imidazo-[l,2-a]-pyrimidine hydrochloride salt,

3-(4-Bromophenyl)-2,6-bis-(4-chlorophenyl)-imidazo-[l,2-a]pyrimidine,

2-(4-Bromophenyl)-3 -(2,4-dichlorophenyl)-6-(4-methoxyphenyl)-imidazo-[ 1 ,2- ajpyrimidine,

2-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-6-(4-methoxyphenyl)-imidazo-[l,2-a] pyrimidine hydrochloride,

2-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-6-(4-fluorophenyl)-imidazo-[l,2- ajpyrimidine,

2-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-6-(4-fluorophenyl)-imidazo-[l,2- ajpyrimidine hydrochloride salt,

3-[2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-imidazo-[l,2-a]pyrimidin-6-yl]-phenol, 2,3 -Bis-(4-chlorophenyl)-6-(3 ,5-difluorophenyl)-imidazo-[ 1 ,2-a]pyrimidine,

6-(3,5-Difluoro-phenyl)-3-(4-ethyl-phenyl)-2-(4-fluoro-phenyl)-imidazo [1,2- a]pyrimidine,

6-(3,5-Difluoro-phenyl)-2-(4-fluoro-phenyl)-3-p-tolyl-imidazo[l,2-a]pyrimidine,

2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-(3-nitrophenyl)-imidazo-[l,2- ajpyrimidine,

2,3-Bis-(4-chlorophenyl)-6-(3-fluorophenyl)-imidazo-[l,2-a]pyrimidine,

2,3 -Bis-(4-chlorophenyl)-6-(pyridin-3 -yl)-imidazo-[ 1 ,2-a]pyrimidine,

2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-pyridin-3-yl-imidazo-[l,2-a]pyrimidine,

3-[2,3-Bis-(4-chlorophenyl)-imidazo-[l,2-a]pyrimidine-6-yl]-benzoic acid,

2,3-Bis-(4-chlorophenyl)-6-(3-nitrophenyl)-imidazo-[l,2-a]pyrimidine,

3-(2,4-Dichlorophenyl)-6-(3-methoxyρhenyl)-2-phenyl-imidazo-[l,2-a]pyrimidine,

[2,3 -Bis-(4-chlorophenyl)-7-methyl-imidazo-[ 1 ,2-a]pyrimidin-6-yl] -pyrrolidin- 1 -yl- methanone, 3 -[2-(4-Chlorophenyl)-3 -(2,4-dichlorophenyl)-imidazo-[ 1 ,2-a]pyrimidine-6-yl] -N-(2- hydroxy-ethyl)-benzamide,

3-[2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-imidazo-[l,2-a]pyrimidine-6-yl]- benzamide,

3-[2,3-Bis-(4-chlorophenyl)-imidazo-[l,2-a]pyrimidine-6-yl]-N,N-dimethyl- benzamide,

2,3-Bis-(4-chlorophenyl)-6-(lH-tetrazol-5-yl)-imidazo[l,2-a]pyrimidine,

2-(4-Chlorophenyl)-3 -(2,4-dichlorophenyl)-6-(3 -methoxyphenyl)-imidazo-[ 1 ,2- a]pyrimidine,

2-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-6-(3-methoxyphenyl)-imidazo-[l,2-a]pyrimidine, 2,3-Bis-(4-chlorophenyl)-6-(3-chlorophenyl)-imidazo-[l,2-a]pyrimidine_:, 2,3-Bis-(4-chlorophenyl)-6-(2-chlorophenyl)-imidazo-[l,2-a]pyrimidine, 3-(2-Chlorophenyl)-2-(4-chlorophenyl)-6-(3-chlorophenyl)-imidazo[l,2-a]pyrimidine, 2,3 -Bis-(4-chlorophenyl)-6-(3 -methoxyphenyl)-imidazo-[ 1 ,2-a]pyrimidine, Acetic acid 3-[2,3-Bis-(4-chlorophenyl)-imidazo-[l,2-a]pyrimidin-6-yl]-phenyl ester,

2-(4-Chlorophenyl)-3-(4-methoxyphenyl)-6-(3-trifluoroniethyl-phenyl)-imidazo[l,2- a]pyrimidine,

2-(4-Chlorophenyl)-3-(4-methylsulfanylphenyl)-6-(3-trifluoromethyl-phenyl)- imidazo [ 1 ,2-a]pyrimidine,

2-(2,4-Difluoro-phenyl)-3-p-tolyl-6-(3-trifluoromethyl-phenyl)-imidazo-[l,2-a]- pyrimidine,

2-(2,4-Difluoro-phenyl)-3-(4-methoxy-phenyl)-6-(3-trifluoromethyl-phenyl)-imidazo- [l,2-a]pyrimidine,

2-(3 ,4-Difluoro-phenyl)-3 -(4-methoxy-phenyl)-6-(3 -trifluoromethyl-phenyl)- imidazo[ 1 ,2-a]pyrimidine,

2-(4-Fluoro-phenyl)-3 -(4-methoxy-phenyl)-6-(3 -trifluoromethyl-phenyl)-imidazo [1,2- ajpyrimidine,

3-(4-Etb.yl-phenyl)-2-(4-fluoro-phenyl)-6-(3-trifluoromethyl-phenyl)-imidazo[l,2- a]pyrimidine,

3-(3,5-Difluoro-phenyl)-2-(4-fluoro-ρhenyl)-6-(3-trifluorometliyl-plienyl)- imidazo[ 1 ,2-a]pyrimidine, IB2007/000459

2-(4-Chlorophenyl)-6-(3-chlorophenyl)-3-(4-methoxyphenyl)-imidazo[l,2-a]- pyrimidine,

2,3-Bis-(4-chlorophenyl)-6-(3-difluorometh.oxy-phenyl)-imidazo-[l,2-a]pyriniidine,

2-(4-Chlorophenyl)-3-(2,4-dichloiOphenyl)-6-(3-difluoromethyoxyphenyl)-imidazo- [ 1 ,2-a]pyrimidine,

3-[2,3-Bis-(4-chlorophenyl)-imidazo-[l,2-a]pyrimidin-6-yl]-phenol,

2-(4-Chlorophenyl)-3 -(2,4-dichlorophenyl)-6-thiophen-3 -yl-imidazo-[ 1 ,2- ajpyrimidiiie,

2,3-Bis-(4-chlorophenyl)-6-thiophen-3-yl-imidazo-[l,2-a]pyrimidine,

Azepan-l-yl-[2,3-bis-(4-chlorophenyl)-7-methyl-imidazo[l,2-a]pyrimidin-6-yl]- methanone,

2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo[l,2-a]pyrimidine-6-carboxylic acid pentylamide,

[2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo[l,2-a]pyrimidin-6-yl]-piperidin-l-yl- methanone,

2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo[l,2-a]pyrimidine-6-carboxylic acid dimethylamide,

2-(4-Chlorophenyl)-6-(3-chlorophenyl)-3-(4-meth.ylsulfanylphenyl)-imidazo[l,2- a]pyrimidine,

2-(4-Chlorophenyl)-6-(3-chlorophenyl)-3-(4-methanesulfonylphenyl)-imidazo[l,2- ajpyrimidine,

2,3-Bis-(4-chlorophenyl)-6-m-tolyl-imidazo[l,2-a]pyrimidine,

2-(4-Chlorophenyl)-3-(2, 4-dichlorophenyl)-6-(4-methoxyphenyl) imidazo-[l ,2-a]- pyrimidine,

2-(4-Chlorophenyl)-3-(2, 4-dichlorophenyl)-6-(4-methoxyphenyl) imidazo-[l ,2-a]- pyrimidine hydrochloride,

3-[2, 3-Bis-(4-chlorophenyl)-imidazo[l,2-a]pyrimidin-6-yl]-benzamide,

2,3-Bis-(4-chloro-phenyl)-6-(5,5-dimethyl-4,5-dihydro-oxazol-2-yl)-7-methyl- imidazo[ 1 ,2-a]pyrimidine,

2-(4-Fluorophenyl)-3-(4-trifluoromethylphenyl)-6-(3-trifluoromethylphenyl)-imidazo [ 1 ,2-a] -pyrimidine, 2-(4-Fluorophenyl)-3-(4-methylsulphanylphenyl)-6-(3-trifluoromethylρhenyl)- imidazo[ 1 ,2-a]pyrimidine,

^• 4-[2-(4-Chlorophenyl)-6-(3-trifluoromethylphenyl)-imidazo[l,2-a]pyrimidin-3-yl]- phenol,

4-[2-(4-Chlorophenyl)-3-p-tolyl-6-(3-trifluoromethylph.enyl)-imidazo[l,2- ajpyrimidine,

6-(3,5-Dichlorophenyl)-2-(4-fluorophenyl)-3-(4-methylsulphanylphenyl)- imidazo[ 1 ,2-a]pyrimidine,

2,3-Bis-(4-fluoro-phenyl)-6-(3-trifluoromethyl-phenyl)-imidazo[l,2-a]pyrimidine,

2-(4-Fluoro-phenyl)-3-p-tolyl-6-(3-trifluoromethyl-phenyl)-imidazo[l,2-a]pyrimidine,

2,3-Bis-(4-chlorophenyl)-6-(3,3-dimethyl-but-l-ynyl)-imidazo[l,2-a]pyrimidine,

6-(5-tert-Butyl-[l, 3, 4]oxadiazol-2-yl)-2, 3-bis-(4-chlorophenyl)-7-methyl- imidazo[ 1 ,2-a]pyrimidine,

2,3 -Bis-(4-chlorophenyl)-7-methyl-imidazo [ 1 ,2-a]pyrimidine,

2-(3,4-Difluoro-phenyl)-3-(4-methoxy-phenyl)-6-(3-trifluoromethyl-plienyl)- imidazo[l ,2-a]pyrimidine,

3-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-7-phenyl-imidazo[l,2-a]pyrimidine, 2,3-Bis-(4-chloro-phenyl)-7-phenyl-imidazo[l,2-a]pyriniidine, [2,3-Bis-(4-chloro-phenyl)-imidazo[l,2-a]pyrimidin-7-ylmethyl]-tert-butyl-ainine, [3-Chloro-2-(2,4-difluoro-phenyl)-irαidazo[l,2-a]pyrimidin-7-yl]-methanol,

2,3-Bis-(4-chloro-phenyl)-6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-7-methyl- imidazo[ 1 ,2-a]pyrimidine,

2,3 -Bis-(4-chloro-phenyl)-6-(3 ,3 -dimethyl-butyl)-imidazo[ 1 ,2-a]pyrimidine,

1 -[2,3-Bis-(4-chloro-phenyl)-imidazo[l ,2-a]pyrimidin-6-ylethynyl]-cyclohexanol, and analogs, N-oxides, tautomers, regioisomers, stereoisomers, prodrugs, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, and hydrates thereof.

29. A compound, which is selected from

2,3-bis-(4-chloroρhenyl)-6-(3-trifluoromethyl-ρhenyl)-imidazo-[l,2-a]-ρyrimidine,

2,3-bis-(4-chlorophenyl)-6-(3-trifluoromethyl-phenyl)-imidazo-[l,2-a]-pyrimidme hydrochloride, 3-(4-Chlorophenyl)-2-(2,4-difluoro-phenyl)-7-methyl-6-phenyl-imidazo[l,2- a]pyrimidine,

2-(2,4-Difluoro-phenyl)-3 -(4-methoxy-phenyl)-7-phenyl-imidazo [ 1 ,2-a]pyrimidine,

2,3 ,6-Tris-(4-chlorophenyl)-imidazo-[ 1 ,2-a] -pyrimidine,

2,3,6 Tris-(4-chlorophenyl)-imidazo-[l,2-a]-pyrimidine hydrochloride salt,

3 -(4-Bromophenyl)-2,6-bis-(4-chlorophenyl)-imidazo- [ 1 ,2-a]pyrimidine,

2-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-6-(4-methoxyphenyl)-imidazo-[l,2- a]pyrimidine,

2-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-6-(4-methoxyphenyl)-imidazo-[l,2-a] pyrimidine hydrochloride,

2-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-6-(4-fluorophenyl)-imidazo-[l,2- a]pyrimidine,

2-(4-Bromophenyl)-3 -(2,4-dichlorophenyl)-6-(4-fluorophenyl)-imidazo-[ 1 ,2- a]pyrimidine hydrochloride salt,

3-[2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-imidazo-[l,2-a]pyrimidin-6-yl]-phenol, 2,3-Bis-(4-chlorophenyl)-6-(3,5-difluorophenyl)-imidazo-[l,2-a]pyrimidine,

6-(3,5-Difluoro-phenyl)-3-(4-ethyl-phenyl)-2-(4-fluoro-phenyl)-imidazo [1,2- a]pyrimidine,

6-(3,5-Difluoro-phenyl)-2-(4-fluoro-phenyl)-3-p-tolyl-imidazo[l,2-a]pyrimidine,

2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-(3-nitrophenyl)-imidazo-[l,2- ajpyrimidine,

2,3-Bis-(4-chlorophenyl)-6-(3-fluorophenyl)-imidazo-[l,2-a]pyrimidine,

2,3-Bis-(4-chlorophenyl)-6-(pyridin-3-yl)-imidazo-[l,2-a]pyrimidine,

2-(4-Chlόrophenyl)-3-(2,4-dichlorophenyl)-6-pyridin-3-yl-imidazo-[l,2-a]pyrimidine,

3-[2,3-Bis-(4-chlorophenyl)-imidazo-[l,2-a]pyrimidine-6-yl]-benzoic acid,

2,3-Bis-(4-chlorophenyl)-6-(3-nitrophenyl)-imidazo-[l,2-a]pyrimidine,

3 -(2,4-Dichlorophenyl)-6-(3 -methoxyphenyl)-2-phenyl-imidazo-[ 1 ,2-a]pyrimidine,

[2,3 -Bis-(4-chlorophenyl)-7-methyl-imidazo-[ 1 ,2-a]pyrimidin-6-yl] -pyrrolidin- 1 -yl- methanone, 3-[2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-imidazo-[l,2-a]pyrimidine-6-yl]-N-(2- hydroxy-ethyl)-benzamide,

3-[2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-imidazo-[l,2-a]pyrimidine-6-yl]- benzamide,

3-[2,3-Bis-(4-chlorophenyl)-imidazo-[l,2-a]pyrimidine-6-yl]-N,N-dimethyl- benzamide,

2,3-Bis-(4-chlorophenyl)-6-(lH-tetrazol-5-yl)-imidazo[l,2-a]pyrimidine,

2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-(3-methoxyphenyl)-imidazo-[l,2- a]pyrimidine,

2-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-6-(3-methoxyphenyl)-imidazo-[l,2-a]pyrimidine, 2,3-Bis-(4-chlorophenyl)-6-(3 -chlorophenyl)-imidazo-[ 1 ,2-a]pyrimidine, 2,3-Bis-(4-chloiOphenyl)-6-(2-chlorophenyl)-imidazo-[l,2-a]pyrimidine, 3-(2-Chlorophenyl)-2-(4-chlorophenyl)-6-(3-chlorophenyl)-imidazo[l,2-a]pyrimidme, 2,3-Bis-(4-chlorophenyl)-6-(3-methoxyphenyl)-imidazo-[l,2-a]pyrimidine, Acetic acid 3-[2,3-Bis-(4-chlorophenyl)-imidazo-[l,2-a]pyrimidin-6-yl]-phenyl ester,

2-(4-Chlorophenyl)-3 -(4-methoxyphenyl)-6-(3 -Mfluoromethyl-phenyl)-imidazo [ 1 ,2- ajpyrimidine,

2-(4-Chlorophenyl)-3-(4-methylsulfanylphenyl)-6-(3-trifluoromethyl-phenyl)- imidazo[ 1 ,2-a]pyrimidine,

2-(2,4-Difluoro-phenyl)-3-p-tolyl-6-(3-trifluoromethyl-phenyl)-imidazo-[l,2-a]- pyrimidine,

2-(2,4-Difluoro-plienyl)-3-(4-metlioxy-phenyl)-6-(3-trifluorometliyl-phenyl)-imidazo- [l,2-a]pyrimidine,

2-(3 ,4-Difluoro-phenyl)-3 -(4-methoxy-phenyl)-6-(3 -trifluoromethyl-phenyl)- imidazo[ 1 ,2-a]pyrimidine,

2-(4-Fluoro-phenyl)-3-(4-methoxy-phenyl)-6-(3-trifluoromethyl-phenyl)-imidazo[l,2- a]pyrimidine,

3-(4-Ethyl-phenyl)-2-(4-fluoro-phenyl)-6-(3-trifluoromethyl-ρlienyl)-imidazo[l,2- ajpyrimidine,

3-(3,5-Difluoro-phenyl)-2-(4-fluoro-phenyl)-6-(3-trifluoroniethyl-phenyl)- imidazo [ 1 ,2-a]pyrimidine, B2007/000459

2-(4-Chlorophenyl)-6-(3-chlorophenyl)-3-(4-methoxyplienyl)-imidazo[l,2-a]- pyrimidine,

2,3-Bis-(4-chlorophenyl)-6-(3-difluoromethoxy-phenyl)-imidazo-[l,2-a]pyrimidine,

2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-(3-difluoromethyoxyphenyl)-imidazo- [ 1 ,2-a]pyrimidine,

3-[2,3-Bis-(4-chlorophenyl)-imidazo-[l,2-a]pyriniidin-6-yl]-phenol,

2-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-6-thiophen-3-yl-imidazo-[l,2- a]pyrimidine,

2,3-Bis-(4-chlorophenyl)-6-thiophen-3-yl-imidazo-[l,2-a]pyrimidine,

Azepan-l-yl-[2,3-bis-(4-chlorophenyl)-7-methyl-imidazo[l,2-a]pyrimidin-6-yl]- methanone,

2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo[l,2-a]pyrimidine-6-carboxylic acid pentylamide,

[2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo[l,2-a]pyrimidin-6-yl]-piperidin-l-yl- methanone,

2,3-Bis-(4-chlorophenyl)-7-methyl-imidazo[l,2-a]pyrimidine-6-carboxylic acid dimethylamide,

2-(4-Chlorophenyl)-6-(3-chlorophenyl)-3-(4-methylsulfanylphenyl)-imidazo[l,2- a]pyrimidine,

2-(4-Chloroplienyl)-6-(3-chlorophenyl)-3-(4-methanesulfonylphenyl)-imidazo[l,2- a]pyrimidine,

2,3-Bis-(4-chlorophenyl)-6-m-tolyl-imidazo[l,2-a]pyrimidine,

2-(4-Chlorophenyl)-3-(2, 4-dichlorophenyl)-6-(4-methoxyphenyl) imidazo-[l ,2-a]- pyrimidine,

2-(4-Chlorophenyl)-3-(2, 4-dichlorophenyl)-6-(4-methoxyphenyl) imidazo-[l ,2-a]- pyrimidine hydrochloride,

3-[2, 3-Bis-(4-chlorophenyl)-imidazo[l,2-a]pyrimidin-6-yl]-benzamide,

2,3-Bis-(4-chloro-phenyl)-6-(5,5-dimethyl-4,5-dihydro-oxazol-2-yl)-7-methyl- imidazo[l ,2-a]pyrimidine,

2-(4-Fluorophenyl)-3-(4-trifluoromethylphenyl)-6-(3-trifluoromethylρhenyl)-imidazo [1 ,2-a]-ρyrimidine, 2-(4-Fluorophenyl)-3-(4-methylsulphaiiylphenyl)-6-(3-trifluorometliylplienyl)- imidazo[l ,2-a]pyrimidine,

4-[2-(4-Chlorophenyl)-6-(3-trifluoromethylphenyl)-imidazo[l,2-a]pyrimidin-3-yl]- phenol,

4-[2-(4-Chlorophenyl)-3-p-tolyl-6-(3-trifluoromethylphenyl)-imidazo[l,2- ajpyrimidine,

6-(3,5-Dichlorophenyl)-2-(4-fluorophenyl)-3-(4-methylsulphanylphenyl)- imidazo[ 1 ,2-a]pyrimidine,

2,3-Bis-(4-fluoro-phenyl)-6-(3-trifluoronietliyl-phenyl)-imidazo[l,2-a]pyriniidine,

2-(4-Fluoro-phenyl)-3-p-tolyl-6-(3-trifluoromethyl-plienyl)-imidazo[l,2-a]pyrimidme, 2,3-Bis-(4-cnloiOphenyl)-6-(3,3-dimethyl-but-l-ynyl)-imidazo[l,2-a]pyrimidine,

6-(5-tert-Butyl-[l, 3, 4]oxadiazol-2-yl)-2, 3-bis-(4-chlorophenyl)-7-methyl- imidazo[ 1 ,2-a]pyrimidine,

2,3-Bis-(4-chlorophenyl)-7-nαethyl-imidazo[ 1 ,2-a]pyrimidine,

2-(3 ,4-Difluoro-phenyl)-3 -(4-methoxy-phenyl)-6-(3 -trifluoromethyl-phenyl)- imidazo[l ,2-a]pyrimidine,

3-(4-Chloro-phenyl)-2-(2-chloro-phenyl)-7-phenyl-imidazo[l,2-a]pyrimidine, 2,3 -Bis-(4-chloro-phenyl)-7-phenyl-imidazo [ 1 ,2-a]pyrimidine, [2,3-Bis-(4-chloro-phenyl)-imidazo[l,2-a]pyrimidin-7-ylmethyl]-tert-butyl-amine, [3-Chloro-2-(2,4-difluoro-phenyl)-imidazo[l,2-a]pyrimidin-7-yl]-methanol,

2,3-Bis-(4-chloro-phenyl)-6-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-7-methyl- imidazo[ 1 ,2-a]pyrimidine,

2,3-Bis-(4-chloro-phenyl)-6-(3,3-dimethyl-butyl)-imidazo[l,2-a]pyrimidine, l-[2,3-Bis-(4-chloro-phenyl)-imidazo[l,2-a]pyrimidin-6-ylethynyl]-cyclohexanol, and

analogs, N-oxides, tautomers, regioisomers, stereoisomers, prodrugs, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, and hydrates thereof.

30. A compound according to claim 1, wherein the pharmaceutically acceptable salt is (a) an inorganic acid addition salt selected from hydrochloride, sulphate, phosphate and nitrate, or (b) an organic acid addition salt selected from acetate, oxalate, maleate, tartarate, citrate, mesylate, succinate and cinnamate.

31. A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable excipient, diluent, carrier or combination thereof.

32. The composition according to claim 31, further comprising one or more therapeutic agents selected from antiobesity agents, ACAT inhibitors, PDE IV inhibitors, DPP IV inhibitors, antidiabetic agents, dyslipidemic agents, CETP inhibitors, HMG-COA reductase inhibitors, fibrates, guggle lipids or other CB 1 or CB2 modulators.

33. A method for treating a disease, disorder or syndrome mediated by cannabinoid (CB) receptors in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds according to claim 1 or a pharmaceutical composition according to claim 31.

34 The method according to claim 33, wherein the compound is a cannabinoid (CB) receptor modulator.

35. The method according to claim 33, wherein the CB receptor modulator is a CBl or CB2 receptor modulator.

36. The method according to any one of claims 34-35, wherein the CB receptor modulator is a CB receptor agonist, antagonist, partial agonist, inverse agonist or combination thereof.

37. The method according to claim 33, wherein the CB receptor mediated disease is obesity or dyslipidemia mediated by cannabinoid receptor 1 (CBl).

38. The method according to claim 33, wherein the disease, condition or disorder is selected from appetite disorder, metabolism disorder, cardiovascular disease, catabolism disorder, diabetes, obesity, dyslipidemia, glaucoma-associated intraocular pressure, social related disorder, mood disorder, seizures, substance abuse, learning disorder, cognition disorder, memory disorder, organ contraction, muscle spasm, respiratory disorder, locomotor activity disorder, movement disorder, immune disorder (such as autoimmune disorder), inflammation, cell growth, pain and neurodegenerative related syndrome, disorder or disease.

39. A method for treating obesity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds according to claim 1 or a pharmaceutical composition according to claim 31.

40. A method for treating dyslipidemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds according to claim 1 or a pharmaceutical composition according to claim 31.

41. A method for treating alcoholism and/or tobacco abuse in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds according to claim 1 or a pharmaceutical composition according to claim 31.

42. The method according to any of claims 33-41, further comprising administering one or more therapeutic agents selected from antiobesity agents, ACAT inhibitors, PDE IV inhibitors, DPP IV inhibitors, antidiabetic agents, dyslipidemic agents, CETP inhibitors, HMG-COA reductase inhibitors, fibrates, guggle lipids and other CB 1 or CB2 modulators.

43. A compound of formula (II)

(H) wherein

(i) X₁ is CR and X₂ is N, or (ii) X₁ is N and X₂ is CR; and

R, R*_a and R^ are independently substituted or unsubstituted phenyl, benzamide, azepan-lyl-carbonyl, N-(2-hydroxyethyl)benzamide, N,7V-dimethyl-carboxamide, N₅N- dimethyl-3 -benzamide, 3-phenylacetate, 3 -benzoic acid, pyridyl, 1/i-tetrazole, or thienyl, provided that R*_a is not phenyl substituted with -OR^XCOOH, wherein R^x is alkyl.

44. The compound according to claim 43, wherein at least one of R, R*_a and R^!b is selected from hydrogen, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3- fluorophenyl, 4-fmorophenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3- trifluoromethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,3-dimethyl-butynyl, 5-tert- butyl-l,3,4-oxadiazol-2-yl, 3-difluoromethoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, benzamide, azepan-lyl-carbonyl, JV-(2-hydiOxyethyl)benzamide, ΛζiV-dimethyl- carboxamide, ΛζN-dimethyl-3 -benzamide, 3-phenylacetate, 3 -benzoic acid, pyridyl, IH- tetrazole, and thienyl.

45. The compound according to claim 43, wherein at least one of R, R*_a and R^ is phenyl substituted with trifluoromethyl.

46. The compound according to claim 43, wherein the compound is 5-(3- (trifluoiOmethyl)phenyl)pyrimidin-2-amine.

47. A compound of formula (III)

wherein R³ _a,

R³ _C, R³d, and R³ _e are independently hydrogen or halogen; R^J _a and R¹ _I, are independently hydrogen, substituted or unsubstituted phenyl, benzamide, azepan-lyl- carbonyl, N-(2-hydroxyethyl)benzamide, ΛζiV-dimethyl-carboxamide, ΛζN-dimethyl-3- benzamide, 3-phenylacetate, 3-benzoic acid, pyridyl, Ii7-tetrazole, or thienyl.

48. The compound according to claim 47, wherein R^J _a is selected from phenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 3,5- difluorophenyl, 3,5-dichlorophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 3,3-dimethyl-butynyl, 5-tert-butyl-l,3,4-oxadiazol-2-yl, 3- difluoromethoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, benzamide, azepan-lyl-carbonyl, N-(2-hydroxyethyl)benzamide, ΛζN-dimethyl-carboxamide, N,N-dimethyl-3-benzamide, 3- phenylacetate, 3-benzoic acid, pyridyl, liJ-tetrazole, and thienyl.

49. The compound according to claim 47, wherein R^! _a is 3-trifluromethylphenyl; R³ _a, R³ _b, R³ _d, R³ _e and R^ are each hydrogen; and R³ _C is halogen.

50. A compound of formula (IV)

wherein R³ _a, R³ _b, R³ _C, R³ _d> and R³ _e are independently hydrogen or halogen; R^! _a and R*_b are independently hydrogen, substituted or unsubstituted phenyl, benzamide, azepan-lyl- carbonyl, JV-(2-hydroxyethyl)benzamide, N_^/V-dimethyl-carboxamide, iV,iV-dimethyl-3- benzamide, 3-phenylacetate, 3-benzoic acid, pyridyl, lH-tetrazole, or thienyl.

51. The compound according to claim 50, wherein R^ is selected from phenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 3,5- difluorophenyl, 3,5-dichlorophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, A- methoxyphenyl, 3,3-dimethyl-butynyl, 5-tert-butyl-l,3,4-oxadiazol-2-yl, 3- difluoromethoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, benzamide, azepan-lyl-carbonyl, N-(2-hydroxyethyl)benzamide, iV,N-dimethyl-carboxamide, ΛζiV-dimethyl-3 -benzamide, 3- phenylacetate, 3-benzoic acid, pyridyl, lH-tetrazole, and thienyl.

52. The compound according to claim 50, wherein

R³ _d, R³ _e and R^ are each hydrogen; and R³ _C is halogen.

53. A compound of formula (V)

54. A method of preparing a compound according to claim 1 comprising reacting a compound of formula (2)

(2) with a compound of formula (3)

wherein L₂ is a leaving group, to form the compound according to claim 1.

55. A method of preparing a compound according to claim 1, wherein R^J _a is substituted or unsubstituted aryl and RΛ is hydrogen, comprising (a) converting a compound of formula (4)

(4) to a compound of formula (5)

(5)

(b) converting the compound of formula (5) to a compound of formula (2)

⁽²⁾ ; and A (c) converting the compound of formula (2) to the compound according to claim 1.

56. The method according to claim 55, wherein step (a) comprises reacting the compound of formula (4) with a halogenating agent.

57. The method according to claim 55, wherein step (b) comprises reacting the compound of formula (5) with a compound having the formula R^-B(OH)₂.

58. The method according to claim 55, wherein step (c) comprises

(1) reacting the compound of formula (2) with a compound of formula (2a)

to form a compound of formula (6)

(2) converting the compound of formula (6) to a compound of formula (7)

(7) wherein L₁ is a leaving group; and

(3) reacting the compound of formula (7) with a compound of formula (7a)

(7a) to form the compound according to claim 1.

59. A method of preparing a compound according to claim 1 comprising (a) reacting a compound of formula (5)

(5) wherein L₁ is a leaving group, with a compound of formula (3)

wherein L₂ is a leaving group, to form a compound of formula (8)

(b) converting the compound of formula (8) to the compound according to claim 1.

60. A method of preparing a compound of formula (13)

wherein X₂ is N;

R¹B, R² _a, R² _b, R²C₃ R²d, R²e, R³a,

R³C, R³d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_m-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R and R⁵ is independently hydrogen, nitro, halo, cyano, -0R^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R^a, -C(0)NR^aR^b, -S(O)_m-R^a, -S(O)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two hetero atoms selected from O, NR^a or S; each occurrence of B is O, S or NR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(0)NR°R^d, -S(O)_m-R^c, -S(O)_m-NR^cR^d, - NR°R^d, -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstiruted alkynyl, substituted or unsubstiruted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^a or S; each occurrence of R° and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstiruted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; and each occurrence of m is 0, 1 or 2, the method comprising:

(a) converting ethylacetoacetate to a compound of formula (9)

(b) converting the compound of formula (9) to a compound of formula (10)

(10) •

(c) reacting the compound of formula (10) with a compound of formula (3)

wherein L₂ is a leaving group, to form a compound of formula (11)

(d) converting the compound of formula (11) to a compound of formula (12)

(12) ; and

(e) converting the compound of formula (12) to the compound of formula (13).

61. A method of preparing a compound of formula (20)

wherein

R³ _C) R³ _d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_1n-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -0R^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R^a, -C(0)NR^aR^b, -S(O)_1n-R³, -S(O)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S or NR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(0)NR°R^d, -S(O)₀₁-R⁰, -S(0)_in-NR°R^d, - NR°R^d, -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^a or S; each occurrence of R^c and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; and each occurrence of m is 0, 1 or 2, the method comprising:

(a) converting pyrazin-2-yl-amine to a compound of formula (14)

(14) wherein L₁ is a leaving group;

(b) reacting the compound of formula (14) with a compound of formula (3)

to form a compound of formula (15)

(c) converting the compound of formula (15) to the compound of formula (20).

62. A method of preparing a compound of formula (20)

wherein R*_a, R² _a, R² _b, R² _C, R²d, R²e, R³a, R³b, R³C, R³d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_1n-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -0R^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R^a, -C(0)NR^aR^b, -S(O)_m-R^a, -S(O)_ffi-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S orNR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R^C, -C(O)O-R^C, -C(0)NR^cR^d, -S(O)_m-R^c, -S(O)_m-NR°R^d, - NR^cR^d, -OR^C, -SR , a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R^c and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; and each occurrence of m is O, 1 or 2, the method comprising:

(a) converting pyrazin-2-yl-amine to a compound of formula (14)

(14) wherein L₁ is a leaving group;

(b) converting the compound of formula (14) to a compound of formula (16)

(c) reacting the compound of formula (16) with a compound of formula (3)

(3) to form the compound of formula (20).

63. A method of preparing a compound of formula (19)

wherein R^, R² _a, R² _b, R² _C, R² _d, R² _e, R³* R³b, R³O₁ R³d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_m-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -0R^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R³, -C(O)NR^aR^b, -S(O)_1n-R³, -S(O)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S or NR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(0)NR°R^d, -S(O)_m-R°, -S(0)_m-NR°R^d, - NR⁰R , -OR⁰, -SR , a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R° and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; and each occurrence of m is O, 1 or 2, the method comprising:

(a) converting pyrazin-2-yl-aniine to a compound of formula (14)

(14) wherein L₁ is a leaving group;

(b) converting the compound of formula (14) to a compound of formula (16)

(c) converting the compound of formula (16) to a compound of formula (17)

(d) converting the compound of formula (17) to a compound of formula (18)

(18) ; and

(e) reacting the compound of formula (18) with a compound of formula (3)

wherein L₂ is a leaving group, to form the compound of formula (19).

64. A method of preparing a compound of formula (22)

(22) wherein R*_a, R² _a, R² _b, R² _C, R² _d, R² _e, R³ _a, R³ _b, R³ _C, R³ _d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_1n-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -0R^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R³, -C(0)NR^aR^b, -S(O)_m-R^a, -S(0)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S or NR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(0)NR°R^d, -S(O)_m-R^c, -S(0)_m-NR^cR^d, - NR°R^d, -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R^c and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; each occurrence of m is 0, 1 or 2; and

R⁴ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclic group, the method comprising:

(a) reacting a compound of formula (17) with a compound of formula (3)

(17) wherein L₁ is a leaving group, to form a compound of formula (21)

(b) converting the compound of formula (21) to the compound of formula (22).

65. A method of preparing a compound of formula (25)

wherein (i) X₁ is CR and X₂ is N, or (ii) X₁ is N and X₂ is CR;

HET is a substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl;

R¹I,, R²a, R²b, R²C, R²d, R²e, R³a, R³b, R³C, R³d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, — C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_1n-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -0R^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R^a, -C(0)NR^aR^b, -S(O)_1n-R³, -S(O)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S or NR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(O)NR^cR^d, -S(O)_5n-R⁰, -S(O)_m-NR°R^d, - NR°R^d, -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R° and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; and each occurrence of m is 0, 1 or 2, the method comprising:

(a) converting a compound of formula (5)

(5) wherein L₁ is a leaving group, to a compound of formula (23)

(23) ;

(b) reacting the compound of formula (23) with a compound of formula (3)

wherein L₂ is a leaving group, to form a compound of formula (24)

(c) converting the compound of formula (24) to the compound of formula (25).

66. A method of preparing a compound of formula (28)

wherein X₂ is N;

R² _a, R²b, R²O, R²d, R²e, R³a, R\, R³ _C, R³d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, -C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)- R⁵, -S(O)_1n-R⁴, or -S(O)₀₁-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -OR^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetero arylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(0)0-R^a, -C(O)NR^aR^b, -S(O)_m-R^a, -S(O)_m-NR^aR^b, -NR^aR^b, or a protecting group or R and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S or NR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(0)NR^cR^d, -S(O)_1n-R⁰, -S(O)_in-NR°R^d, - NR°R^d, -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R^c and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; and each occurrence of m is 0, 1 or 2, the method comprising:

(a) converting a compound of formula (11)

to a compound of formula (26)

(b) reacting the compound of formula (26) with a compound of formula R⁸COL₁, wherein L₁ is a leaving group, to form a compound of formula (27)

(c) converting the compound of formula (27) to the compound of formula (28).

67. A method of preparing a compound of formula (30)

wherein X₂ is N; R² _a, R² _b, R²C, R²d, R² _e, R³ _a,

R³ _C) R³d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, -C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)- R⁵, -S(O)_1n-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -OR^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R^a, -C(0)NR^aR^b, -S(O)_1n-R³, -S(O)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S or NR^a; each occurrence ^; of R^a and R^b is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(0)-R^c, -C(O)O-R⁰, -C(O)NR°R^d, -S(O)_1n-R⁰, -S(O)_m-NR°R^d, - NR°R^d, -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R^c and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl;

R^xand R^y are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted amino; and each occurrence of m is 0, 1 or 2, the method comprising:

(a) reacting a compound of formula (12)

(12) with substituted or unsubstituted hydroxylamine to form a compound of formula (29)

⁽²⁹⁾ ; and

(b) converting the compound of formula (29) to the compound of formula (30).

68. A method of preparing a compound of formula (28)

wherein X₂ is N;

R² _a, R²b, R²O, R² _d, R² _e, R³ _a, R³b, R³O, R³ _d and R³ _e are independently hydrogen, cyano, foπnyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, -C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)- R⁵, -S(O)_m-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R and R⁵ is independently hydrogen, nitro, halo, cyano, -0R^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R³, -C(O)NR^aR^b, -S(O)_m-R^a, -S(O)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S or NR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, foπnyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(O)NR^cR^d, -S(O)_1n-R⁰, -S(0)_m-NR°R^d, - NR^cR^d, -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R° and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; and each occurrence of m is 0, 1 or 2, the method comprising:

(a) converting a compound of formula (10)

(10) to a compound of formula (31)

(31)

(b) converting the compound of formula (31 ) to a compound of formula (32);

(32)

(c) reacting the compound of formula (32) with a compound of formula (3)

wherein L₂ is a leaving group, to form a compound of formula (33)

(d) converting the compound of formula (33) to the compound of formula (28).

69. A method of preparing a compound of formula (39)

wherein X₁ is N;

R\ is CN; and R^l _h, R² _a, R² _b, R² _C, R² _d, R² _e, R³ _a, R³ _b, R³ _C, R³ _d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR R⁵, -C(=B)-R , - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_1n-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R and R⁵ is independently hydrogen, nitro, halo, cyano, -0R^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R³, -C(O)NR^aR^b, -S(O)_m-R^a, -S(0)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S or NR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(0)NR°R^d, -S(O)_m-R^c, -S(0)_m-NR°R^d, - NR°R^d, -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R° and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; each occurrence of m is 0, 1 or 2; and wherein R is -CN, -OR^a, aryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,or -NR⁴R⁵, the method comprising:

(a) converting a compound of formula (34)

(34) wherein L₁ is a leaving group, to a compound of formula (35)

(35)

(b) converting the compound of formula (35), wherein L₃ is a leaving group, to a compound of formula (36)

(36) (c) reacting the compound of formula (36) with a compound of formula (3)

wherein L₂ is a leaving group, to form a compound of formula {38)

(³⁸) ; and

(d) converting the compound of formula (38) to the compound of formula (39).

70. A method of preparing a compound of formula (39)

(39) wherein X₁ is N;

R¹I,, R²a, R²b, R²C, R²d, R²e, R³ a,

R³C, R³d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_1n-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R⁴ and R is independently hydrogen, nitro, halo, cyano, -0R^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R^a, -C(O)NR^aR^b, -S(O)_m-R^a, -S(O)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S orNR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, foπnyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(O)NR°R^d, -S(O)_1n-R⁰, -S(O)_m-NR°R^d, - NR⁰R , -OR⁰, -SR , a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^a or S; each occurrence of R° and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; each occurrence of m is 0, 1 or 2; and wherein R is -CN, -0R^a, aryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,or -NR⁴R⁵, the method comprising:

(a) reacting a compound of formula (35)

(35) wherein L₁ and L₃ are leaving groups, with a compound of formula (3)

wherein L₂ is a leaving group, form a compound of formula (37)

(b) converting the compound of formula (37) to a compound of formula (38)

(38) ; and

(C) converting the compound of formula (38) to the compound of formula (39).

A method of preparing a compound of formula (43)

wherein X₁ is N;

R¹ _a, RV R² _a, R² _b, R²O, R² _d, R² _e, R³ _a,

R³O, R³d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_1n-R⁴, or -S(O)₀₁-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -0R^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R^a, -C(0)NR^aR^b, -S(O)_m-R^a, -S(0)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S orNR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R^C, -C(O)O-R⁰, -C(0)NR^cR^d, -S(O)_m-R°, -S(0)_m-NR°R^d, - NR°R^d, -OR^C, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R^c and R is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; each occurrence of m is 0, 1 or 2; and

R⁶ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or -NR⁴R⁵, the method comprising:

(a) reacting a compound of formula (40) with a compound of formula (3)

wherein L₂ is a leaving group, to form a compound of formula (41)

(b) converting the compound of formula (41) to the compound of formula (43).

72. A method of preparing a compound of formula (43)

wherein X₁ is N;

R\, R¹I,, R² _a, R² _b, R²C, R²d, R² _e, R³a, R³b, R³C, R³d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR , -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_m-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -OR^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R³, -C(O)NR^aR^b, -S(O)_m-R^a, -S(O)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O₅ NR^a or S; each occurrence of B is O, S orNR^a; each occurrence of R^a and R is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R^C, -C(O)O-R⁰, -C(0)NR^cR^d, -S(O)_1n-R⁰, -S(0)_m-NR°R^d, - NR°R^d, -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^a or S, each occurrence of R^c and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; each occurrence of m is 0, 1 or 2; and

R⁶ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or -NR⁴R⁵, the method comprising:

(a) converting a compound of formula (41)

to a compound of formula (42)

(b) converting the compound of formula (42) to the compound of formula (43).

73. A method of preparing a compound of formula (46)

(46) wherein (i) X₁ is CR and X₂ is N, or (ii) X₁ is N and X₂ is CR;

K\, R² _a, R² _b, R²C, R² _d, R²e, R³a, R³b, R³C, R³d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_1n-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -OR^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R³, -C(0)NR^aR^b, -S(O)_m-R^a, -S(O)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S or NR^a; each occurrence of R^a and R is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(0)NR°R^d, -S(O)_1n-R⁰, -S(O)_m-NR°R^d, - NR°R^d, -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R⁰ and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; each occurrence of m is 0, 1 or 2; and

R is substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl, the method comprising:

(a) reacting a compound of formula (5) with a compound of formula (3)

wherein L₁ and L₂ are leaving groups, to form a compound of formula (8)

(8) (b) converting the compound of formula (8) to a compound of formula (44)

(44) wherein R⁷ is a protecting group;

( c) deprotecting the compound of formula (44) to form a compound of formula (45) T/IB2007/000459

<⁴⁵> ; and (d) converting the compound of formula (45) to the compound of formula (46).

74. A method of preparing a compound of formula (53)

wherein X is halogen or hydrogen, and X₂ is N;

R¹B, R² _a, R² _b, R²O, R²d, R² _e, R³a, R³b, R³C_; R³d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_1n-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -0R^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R³, -C(0)NR^aR^b, -S(O)_m-R^a, -S(O)_ffi-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O₅ NR^a or S; each occurrence of B is O, S or NR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R^C, -C(O)O-R⁰, -C(O)NR°R^d, -S(O)_1n-R⁰, -S(O)_ffl-NR^cR^d, - NR°R^d, -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R° and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; each occurrence of m is O, 1 or 2; and

R¹⁰ is CONR⁴R⁵, the method comprising:

(a) reacting a compound of formula (51) with a compound of formula (3)

wherein R⁸ is CH₂OH, CH(OMe)₂ or COOEt; and L₂ is a leaving group, to form a compound of formula (52)

wherein R⁹ is COOEt;

(b) converting the compound of formula (52) to a compound of formula (53).

75. A method of preparing a compound of formula (54)

(54) wherein X₂ is N;

R¹ _S, R\, R² _a, R² _b, R² _C, R² _d, R² _e, R³ _a, R³ _b, R³ ₀, R³d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, m^'tro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_1n-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R and R⁵ is independently hydrogen, nitro, halo, cyano, -0R^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R³, -C(O)NR^aR^b, -S(O)_1n-R³, -S(O)_ra-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S or NR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, foraiyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(0)NR^cR^d, -S(O)_1n-R⁰, -S(0)_m-NR°R^d, - NR⁰R , -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R° and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; and each occurrence of m is 0, 1 or 2, the method comprising: converting a compound of formula (52)

(52) (wherein R⁹ is CH₂OH) to the compound of formula (54).

76. A method of preparing a compound of formula (63)

wherein X₂ is N, and Z is hydrogen or halogen;

R¹I,, R² _a, R²b, R²C, R²d, R²e, R³a, R³b, R³C, R³a and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, -C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_m-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -OR^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R³, -C(0)NR^aR^b, -S(O)_m-R^a, -S(O)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S or NR^a; each occurrence of R^a and R is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(0)NR^cR^d, -S(O)_m-R^c, -S(O)_m-NR^cR^d, - NR^cR^d, -OR^C, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R° and R is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; each occurrence of m is 0, 1 or 2; and

R¹⁰ Is NR⁴R⁵, the method comprising:

(a) reacting a compound of formula (57a) with compound of formula (3)

wherein R is CH₂OH, and L₂ is a leaving group, to form a compound of formula (58)

(58) wherein R , 1¹0^U i •s CH₂OH; (b) oxidizing the compound of formula (58) to form a compound of formula (59)

(c) reacting the compound of formula (59) with an amine of formula NHR^ 4Rr, 5 to form the compound of formula (63).

77. A method of preparing a compound of formula (63)

wherein X₂ is N, and Z is hydrogen or halogen; R² _a, R² _b, R²C, R²d, R² _e, R³ _a,

R³C_; R³d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR R , — C(=B)-R , - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_m-R⁴, or -S(O)_m-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -OR^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R³, -C(0)NR^aR^b, -S(O)_m-R^a, -S(O)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S or NR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(0)NR°R^d, -S(O)_1n-R⁰, -S(O)_m-NR^cR^d, - NR^cR^d, -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R^b may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R^c and R is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; each occurrence of m is 0, 1 or 2; and

R¹⁰ is CH₂NR⁴R⁵, the method comprising:

(a) converting a compound of formula (58)

(58) wherein R¹⁰ is CH₂OH, to a compound of formula (61)

(61) wherein L₂ is a leaving group; and

(b) reacting the compound of formula (61) with an amine of formula NHR⁴R⁵ to form the compound of formula (63) (wherein R¹⁰ is CH₂NR⁴R⁵).

78. A method of preparing a compound of formula (63)

wherein X₂ is N, and Z is hydrogen or halogen;

K\, R² _a, R² _b, R²C, R²a, R² _e, R³a, R³b, R³C, R³d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR⁴, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR⁴R⁵, ~C(=B)-R⁴, - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_m-R⁴, or -S(O)_m-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -0R^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R³, -C(O)NR^aR^b, -S(O)_m-R^a, -S(O)_m-NR^aR^b, -NR^aR^b, or a protecting group or R and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S or NR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(0)NR°R^d, -S(O)_1n-R⁰, -S(0)_m-NR°R^d, - NR°R^d, -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^a or S; each occurrence of R° and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; each occurrence of m is 0, 1 or 2; and

R¹⁰ is CH₂OH, CH(OMe)₂, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, C00R^a, the method comprising:

(a) reacting the compound of formula (57a) with a compound of formula (2a)

wherein L₂ is a leaving group, to form a compound of formula (60)

(b) halogenating the compound of formula (60) to form a compound of formula (62)

wherein Hal represents halogen; and (c) reacting the compound of formula (62) with a compound of formula (7 a)

to form the compound of formula (63).

79. A method of preparing a compound of formula (64)

(64) wherein (i) X₁ is CR and X₂ is N, or (ii) X₁ is N and X₂ is CR;

R¹J,, R²a, R²b, R²C R²d, R²e, R³a, R³b, R³c, R³d and R³ _e are independently hydrogen, cyano, formyl, acetyl, thio, nitro, halogen, -OR⁴, -SR , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -NR R⁵, — C(=B)-R , - C(O)O-R⁴, -C(O)NR⁴R⁵, -NR⁴C(O)-R⁵, -S(O)_1n-R⁴, or -S(O)_1n-NR⁴R⁵; each occurrence of R⁴ and R⁵ is independently hydrogen, nitro, halo, cyano, -0R^a, - SR^a, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, -C(=B)-R^a, -C(O)O-R³, -C(O)NR^aR^b, -S(O)_m-R^a, -S(O)_m-NR^aR^b, -NR^aR^b, or a protecting group or R⁴ and R⁵ may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include at least two heteroatoms selected from O, NR^a or S; each occurrence of B is O, S orNR^a; each occurrence of R^a and R^b is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, -C(O)-R⁰, -C(O)O-R⁰, -C(O)NR°R^d, -S(O)_1n-R⁰, -S(O)_m-NR^cR^d, - NR°R^d, -OR⁰, -SR^d, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, or a substituted or unsubstituted heteroarylalkyl; or R^a and R may be joined together with the nitrogen atom to which they are attached to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include the heteroatoms selected from O, NR^aor S; each occurrence of R° and R^d is independently hydrogen, halogen, nitro, cyano, formyl, acetyl, oxo, thio, a protecting group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclylalkyl; each occurrence of m is 0, 1 or 2; and

R⁸ is substituted aryl, cycloalkyl, heterocyclyl or heteroaryl, the method comprising: reducing the compound of formula (46)

(46) . to form the compound of formula (64).

80. A compound having the formula:

(IA) or a pharmaceutically acceptable salt thereof, solvate thereof, or hydrate thereof, wherein:

R is hydrogen or methyl;

R¹ _S is substituted phenyl, -C(O)NR⁴R⁵, or substituted or unsubstituted alkyl;

R² _a is hydrogen or halogen;

R² _C is halogen, -S(O)_m-R°, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;

0 0 0

R b, R d, and R _e are hydrogen;

R³ _a, R³ _b, R³ _d, and R³ _e are hydrogen; and

R³ _C is halogen.

81. The compound of claim 8, wherein R is hydrogen;

R¹ _a is (i) unsubstituted alkyl or (ii) phenyl substituted with one or two substituents selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, halogen, hydroxy, and combinations thereof;

R² _a is hydrogen or halogen;

R² _C is halogen, -S(O)_m-R^c, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;

R² _b, R²a, and R² _e are hydrogen;

R³ _a, R³b, R³d, and R³ _e are hydrogen; and

R³ _C is halogen.

82. The compound of claim 80 or 81, wherein R*_a is phenyl substituted with one or two substituents selected from -CF₃, chlorine, methyl, -OCHF₂, and nitrø.

83. The compound of any of claims 80-82, wherein R² _a is hydrogen, R² _C is methoxy, -SCH₃, chlorine, or hydroxy, and R³ _C is chlorine or fluorine.

84. The compound of claim 80, wherein R is hydrogen;

R¹ _a is phenyl substituted at the 3 -position with a substituent selected from - CF₃, chlorine, methyl, -OCHF₂, and nitro.

R² _a, R²b, R²d, and R² _e are hydrogen;

R² _C is methoxy, -SCH₃, chlorine, or hydroxy;

"X ^ ¹X "\

R _a, R _b, R dj and R _e are hydrogen; and R³ ₀ is chlorine.

85. A method of treating obesity, dyslipidemia, alcoholism, or tobacco abuse in a subject in need thereof comprising admininstering a therapeutically effective amount of a compound of any of claims 80-84.

86. The method of claim 85, wherein the one or more additional therapeutic agents are co-administered, the additional therapeutic agents being selected from anti-obesity agents, ACAT inhibitors, PDE IV inhibitors, DPP IV inhibitors, antidiabetic agents, dyslipidemic agents, CETP inhibitors, HMG-CoA reductase inhibitors, fibrates, guggle lipids and other CB 1 or CB2 modulators.