EP2276748A1 - Bicyclic nitrogen containing heterocyclic compounds for use as stearoyl coa desaturase inhibitors - Google Patents

Abstract

The present invention discloses bicyclic nitrogen-containing heterocyclic compounds for use as inhibitors of stearoyl-CoA desaturase. The compounds are useful in treating and/or preventing various human diseases, mediated by stearoyl-CoA desaturase (SCD) enzymes, especially diseases related to abnormal lipid levels, cardiovascular disease, diabetes, obesity, oily skin conditions, metabolic syndrome, and the like.

Description

BICYCLIC NITROGEN-CONTAINING HETEROCYCLIC COMPOUNDS FOR USE AS STEAROYL CoA DESATURASE INHIBITORS

[0100] This application is a continuation-in-part application of U.S Patent Application serial no. 11/868,386, filed Oct. 5, 2007, which claims priority to U.S. Provisional Patent Application Serial No 60/849,648, filed October 5, 2006, each of which is incorporated herein by reference in their entireties.

Field of the Invention

[0101] The present invention relates generally to the field of inhibitors of stearoyl-CoA desaturase, such as pyπdine[2,3-b]pyrazone deπvatives, pyπdo[4,3-b]pyrazm-2(lH)-one derivatives, and qumoxalm-2(lH)-one deπvatives, and uses for such compounds in treating and/or preventing vaπous human diseases, mediated by stearoyl-CoA desaturase (SCD) enzymes, especially diseases related to elevated lipid levels, cardiovascular disease, cancer, diabetes, obesity, metabolic syndrome, oily skm conditions, and the like

Background

[0102] Stearoyl CoA desaturases (SCD's) are Δ9 fatty acid desaturases. The mammalian enzymes are localized to the endoplasmic reticulum and require molecular O₂ and NADH to desaturate saturated fatty acids at the Δ9 position and generate monounsaturated fatty acids and water in the process. The primary substrates for these enzymes are the acyl-CoA derivatives of steaπc (C 18) and palmitic acids (C 16) with the major reaction being the conversion of steaπc acid to oleic acid (C 18:1). Depending on the species, 2-4 isoforms of SCD exist. In rodents these isoforms are highly homologous and differ pπmaπly in tissue distribution In humans there are 2 known isoforms (SCDl and SCD5) and these isoforms function similarly, but SCD5 has reduced sequence homology to other SCD isoforms. Based on tissue distribution SCD5 appears to functionally analogous to rodent SCD2

[0103] The best characteπzed SCD isozyme is SCDl which is pπmaπly found in liver, adipose and skeletal muscle. Deletion, mutation or inhibition of SCDl in mice and rats results in decreased hepatic triglyceride secretion, decreased hepatic triglycerides and steatosis, resistance to weight gain and improvements m insulin sensitivity and glucose uptake (reviewed in Ntambi et al (2004) Prog Lipid Res 43, 91-104, (2005), Prostaglandins Leukot Essent Fatty Acids 73, 35-41; and (2005) Obes. Rev. 6, 169-174). These studies combined with studies in humans showing correlations between surrogates for SCD activity and metabolic syndrome, diabetes and obesity strongly implicate SCD inhibition as a means to treat obesity, diabetes, hypertryglyceridemia and associated diseases and co-morbidities. Studies done using antisense oligonucleotide inhibitors have also confirmed the results of the SCDl knockout and asebia mouse studies, and clearly shown that hepatic SCD inhibition may reduce elevated hepatic glucose output; see Jiang et al. (2005) J. Clin. Invest. H_5: 1030-1038G. and Gutierrez- Juarez et al. (2006) J. Clin. Invest. 116: 1686-1695 .

[0104] The present invention presents compounds that are useful in inhibiting SCD activity and thus regulating tissue and plasma lipid levels and fatty acid composition. These compounds are useful in the treatment of SCD-mediated diseases such as diseases related to dyslipidemia and disorders of lipid metabolism, including, but not limited to diseases related to elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome, fatty liver diseases, and the like.

SUMMARY OF THE INVENTION

[0105] It is an object of this invention to provide compounds that act as stearoyl-CoA desaturase inhibitors. Accordingly, in a first aspect, the invention relates to compounds of Formula I:

Formula I wherein

R is a) optionally substituted 4 to 6 membered nitrogen containing monocyclic heterocycle, b) -X-NR⁴R⁵, c) -X-C(O)NR⁴R⁵, d) -X-C(O)OR⁷, e) -X-OR⁷, or f) -X-NR⁸-C(O)NR⁴R⁵ wherein

R⁴ is hydrogen or lower alkyl, and

R⁵ is hydrogen, Ci_-4 lower alkyl, aryl, heteroaryl, C_)-4 alkoxy, -C(=NH)NH₂, - C(=O)R⁶ or -S(=O)₂R⁶, wherein

R⁶ is hydrogen, optionally substituted Ci_-4 alkyl, optionally substituted Ci_-4 alkenyl, Cj_-4 alkoxy, optionally substituted monocyclic aryl, or 5 or 6 membered optionally substituted monocyclic heteroaryl, or

R⁴ and R⁵ along with the nitrogen to which they are attached join to form a 5 or 6 membered monocyclic heteroaryl or heterocyclyl ring;

R⁷ is hydrogen, optionally substituted C_)-4 alkyl, optionally substituted alkenyl, optionally substituted monocyclic aryl, or 5 or 6 membered optionally substituted monocyclic heteroaryl;

R⁸ is hydrogen or Ci_-4 lower alkyl;

X is optionally substituted Ci_-4 linear or branched alkylene;

R² is optionally substituted mono or bicyclic heterocyclyl, mono or bicyclic aryl, or mono or bicyclic heteroaryl; wherein the aryl, heterocyclyl or heteroaryl moiety is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, heterocyclyl, aryl, heteroaryl, halo, NO₂, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, S(O)₃R²⁰, P(O)(OR²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂, NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, NR²⁰C(NR^2O)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²², SO₂NR²⁰CO₂R²², OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂, and further wherein each optional alkyl, heteroaryl, aryl, and heterocyclyl substituent is further optionally substituted with halo, NO₂, alkyl, CF₃, amino, mono- or di- alkylamino, alkyl or aryl or heteroaryl amide, NR²⁰COR²², NR²⁰SO₂R²², COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰),, OC(O)R²⁰, OC(O)N(R²⁰)₂, S(O)₃R²⁰, P(O)(OR²⁰)₂, SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰;

R³ is hydrogen, optionally substituted C_1-4 alkyl, 5 or 6 membered optionally substituted monocyclic cycloalkyl, optionally substituted monocyclic aryl, 5 or 6 membered optionally substituted monocyclic heterocycle, or 5 or 6 membered optionally substituted monocyclic heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl moiety is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, heterocyclyl, aryl, heteroaryl, halo, NO₂, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, S(O)₃R²⁰, P(O)(OR²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰);,, NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²², SO₂NR²⁰CO₂R²², OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂, and further wherein each optional alkyl, heteroaryl, aryl, and heterocyclyl substituent is further optionally substituted with halo, NO₂, alkyl, CF₃, amino, mono- or di- alkylamino, alkyl or aryl or heteroaryl amide, NR²⁰COR²², NR²⁰SO₂R²², COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰)₂, OC(O)R²⁰, OC(O)N(R²⁰)₂, S(O)₃R²⁰, P(O)(OR²⁰)₂, SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰;

R²⁰ and R²² are independently selected from the group consisting of hydrogen, C ₁.₁₅ alkyl, C_2-I5 alkenyl, C_2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl moieties are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O-Ci_₆ alkyl, CF₃, aryl, and heteroaryl;

Q is C_M alkylene which may optionally contain one or more -NH-, -O-, -S-, or carbonyl linking moieties;

W¹ is N or CH, or W¹ is C wherein said C is attached to the R²-Q-NH- moiety; and W² is N or CH with the proviso that W¹ and W² cannot both be N; wherein the R² -Q-NH- moiety is attached to the 'a' or 'b' position indicated in Formula I, provided that W¹ is C when the R²-Q-NH- moiety is attached to the 'a' position; or a pharmaceutically acceptable salt, ester, prodrug, or hydrate thereof.

[0106] In some embodiments the R² -Q-NH- moiety is attached to the 'a' position indicated in Formula I, and the compound has the structure of Formula Ia:

Formula Ia

[0107] In some embodiments the R² -Q-NH- moiety is attached to the 'b' position indicated in Formula I, and the compound has the structure of Formula Ib:

Formula Ib

[0108] In yet another aspect of the invention, pharmaceutical formulations are provided, comprising a therapeutically effective amount of an SCD inhibitory compound of Formula I, and at least one pharmaceutically acceptable carrier. In some embodiments the formulation is for oral administration, but in some embodiments the formulation may be provided for administration via other routes.

[0109] In a third embodiment of the invention, methods of using the compounds of Formula I in the treatment of a disease or condition in a mammal that can be treated with an SCD inhibitory compound are provided. The method comprises administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I. Such diseases include, but are not limited to, cardiovascular diseases (including, but not limited to, coronary artery disease, atherosclerosis, heart disease, hypertension , and peripheral vascular disease), cancer, cerebrovascular diseases (including, but not limited to, stroke, ischemic stroke and transient ischemic attack (TIA), and ischemic retinopathy), dyslipidemia, fatty liver diseases, obesity, diabetes, insulin resistance, decreased glucose tolerance, non-insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, and other diabetic complications.

[0110] At present, the preferred compounds for use in the invention include, but are not limited to:

[0111] N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0112] N-[2-(6-{[(4-fluorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0113] N-[2-(6-{[(3-chlorophenyl)methyl]ammo}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0114] N-[2-(6-{[(3-chloro-4-fluorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3- oxo-4-hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0115] 4-(2-ammoethyl)-6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4- methoxyphenyl)-4-hydropyridino[3,2-b]pyrazin-3-one;

[0116] N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]carboxamide;

[0117] N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-3-oxo-2-(3-pyridyl)-4- hydropyridino[2,3-b]pyrazm-4-yl)ethyl]acetamide;

[0118] 3-(6-{[(3 ,4-dichlorophenyl)methyl] amino } -2 -(4-methoxyphenyl)-3 -oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)propanamide;

[0119] N-{2-[2-(4-methoxyphenyl)-3-oxo-6-({[3-

(trifluoromethyl)phenyl]methyl}amino)-4-hydropyridino[2,3-b]pyrazin-4- yl]ethyl } acetami de ;

[0120] N-{2-[2-(4-methoxyphenyl)-3-oxo-6-({[4-

(trifluoromethyl)phenyl]methyl}amino)-4-hydropyridino[2,3-b]pyrazin-4- yl]ethyl}acetamide; [0121] N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methylthiophenyl)-3-oxo- 4-hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0122] N-fl-Cβ-lfCS^-dichlorophenyOmethyljaminoJ^^-methylphenyO-S-oxo^- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0123] 4-((3S)pyrrolidin-3-yl)-6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4- methoxyphenyl)-4-hydropyridino[3,2-b]pyrazin-3-one;

[0124] N-[2-(6-{[(3-chloro-4-fluorophenyl)methyl]amino}-3-oxo-2-(3-pyridyl)-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0125] ethyl 3-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo- 4-hydropyridino[2,3-b]pyrazin-4-yl)propanoate;

[0126] ethyl 4-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo- 4-hydropyridino[2,3-b]pyrazin-4-yl)butanoate;

[0127] 4-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)butanoic acid;

[0128] 3-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3 -b]pyrazin-4-yl)propanoic acid;

[0129] 3-(6-{[(3,4-dichlorophenyl)methyl]amino}-3-oxo-2-(3-pyridyl)-4- hydropyridino[2,3-b]pyrazin-4-yl)propanamide;

[0130] N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-3-oxo-2-(3-pyridyl)-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]carboxamide;

[0131 ] N- {2-[3 -oxo-2-(3 -pyridyl)-6-( { [3 -(trifluoromethyl)phenyl]methyl } amino)-4- hydropyridino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

[0132] N-[2-(6-{[(3-bromophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0133] N-{2-[6-({[3,5-bis(trifluoromethyl)phenyl]methyl}amino)-2-(4- methoxyphenyl)-3-oxo-4-hydropyridino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

[0134] N-{2-[6-({[4-fluoro-3-(trifluoromethyl)phenyl]methyl}amino)-2-(4- methoxyphenyl)-3-oxo-4-hydropyridino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

[0135] 4-(2-hydroxyethyl)-2-(4-methoxyphenyl)-6-({[3- (trifluoromethyl)phenyl]methyl}amino)-4-hydropyridino[3,2-b]pyrazin-3-one; [0136] N-{2-[2-(4-methoxyphenyl)-3-oxo-6-({[5-(trifluoromethyl)(3- pyridyl)]methyl}ammo)-4-hydropyridmo[2,3-b]pyrazin-4-yl]ethyl}acetamide;

[0137] N-{2-[2-(4-methoxyphenyl)-3-oxo-6-({[3-

(tπfluoromethyl)phenyl]methyl}amino)-4-hydropyridino[2,3-b]pyrazin-4- yl]ethyl } carboxamide;

[0138] N-{2-[3-oxo-2-(3-pyridyl)-6-({[3-(trifluoromethyl)phenyl]methyl}ammo)-4- hydropyridmo[2,3-b]pyrazm-4-yl]ethyl}carboxamide;

[0139] N-{2-[3-oxo-2-(tπfluoromethyl)-6-({[3-

(tnfluoromethyl)phenyl]methyl}amino)-4-hydropyπdino[2,3-b]pyrazin-4- yl]ethyl}acetamide;

[0140] N- {2-[2-methyl-3-oxo-6-( { [3-(trifluoromethyl)phenyl]methyl} amino)-4- hydropyridmo[2,3-b]pyrazm-4-yl]ethyl}acetamide;

[0141] N-P^ό-JtCS^-dichlorophenyOmethylJammol^-methyl^-oxo^- hydropyπdino[2,3-b]pyrazm-4-yl)ethyl]acetamide

[0142] 3-[3-oxo-2-(3-pyπdyl)-6-({[3-(trifluoromethyl)phenyl]methyl}amino)-4- hydropyπdino[2,3-b]pyrazm-4-yl]propanamide;

[0143] 3-[2-(4-methoxyphenyl)-3 -oxo-6-( { [3 -(tπfluoromethyl)phenyl]methyl } ammo)- 4-hydropyπdmo[2,3-b]pyrazm-4-yl]propanamide;

[0144] N- {2-[3 -oxo-6-( { [3 -(tπfluoromethyl)phenyl]methyl} ammo)-4- hydropyπdmo[2,3-b]pyrazm-4-yl]ethyl}acetamide;

[0145] N-(2-{2-(4-methoxyphenyl)-3-oxo-6-[benzylammo]-4-hydropyπdino[2,3- b]pyrazin-4-yl } ethyl)acetamide;

[0146] N-(2-{2-(4-methoxyphenyl)-3-oxo-6-[(3-pyπdylmethyl)amino]-4- hydropyπdmo[2,3-b]pyrazin-4-yl}ethyl)acetamide,

[0147] N-[2-(6-{[(3-fluorophenyl)methyl]ammo}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0148] 4-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo(4- hydropyridino[2,3-b]pyrazin-4-yl))-N-methylbutanamide;

[0149] 4-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)butanamide; [0150] 3-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo(4- hydropyπdino[2,3-b]pyrazin-4-yl))-N-methylpropanamide;

[0151] N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo(4- hydropyridmo[2,3-b]pyrazm-4-yl))ethyl](tert-butoxy)carboxamide;

[0152] N-[2-(6-{[(2-chlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridmo[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0153] N-(2-{2-(4-methoxyphenyl)-3-oxo-6-[(3-phenylpropyl)ammo]-4- hydropyridino[2,3-b]pyrazin-4-yl}ethyl)acetamide;

[0154] 4-((3R)pyrrolidin-3-yl)-6-{[(3,4-dichlorophenyl)methyl]ammo}-2-(4- methoxyphenyl)-4-hydropyπdino[3,2-b]pyrazin-3-one;

[0155] (3R)-3 -(6- { [(3 ,4-dichlorophenyl)methyl]amino} -2-(4-methoxyphenyl)-3 - oxo(4-hydropyndino[2,3-b]pyrazin-4-yl))pyrrohdmecarbaldehyde;

[0156] (3 S)-3 -(6- { [(3 ,4-dichlorophenyl)methyl]ammo} -2-(4-methoxyphenyl)-3 - oxo(4-hydropyπdmo[2,3-b]pyrazin-4-yl))pyrrolidmecarbaldehyde;

[0157] N- {2-[2-(4-methoxyphenyl)-3-oxo-6-( { [6-(trifluoromethyl)(2- pyπdyl)]methyl}ammo)-4-hydropyπdmo[2,3-b]pyrazin-4-yl]ethyl}acetamide;

[0158] N-[2-(2-(4-methoxyphenyl)-6-{[(5-methyl(l,2,4-oxadiazol-3- yl))methyl] ammo } -3 -oxo-4-hydropyπdino [2,3 -b]pyrazm-4-yl)ethyl] acetamide;

[0159] N-[2-(2-(4-methoxyphenyl)-6-{[(3-methoxyphenyl)methyl]ammo}-3-oxo-4- hydropyπdmo[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0160] N-[2-(6-{[(3,4-dichlorophenyl)methyl]ammo}-3-oxo-4-hydropyπdino[2,3- b]pyrazm-4-yl)ethyl]acetamide;

[0161] methyl 3-[({4-[2-(acetylammo)ethyl]-2-(4-methoxyphenyl)-3-oxo-4- hydropyπdmo[5,6-b]pyrazm-6-yl}ammo)methyl]benzoate;

[0162] 3-[({4-[2-(acetylamino)ethyl]-2-(4-methoxyphenyl)-3-oxo-4- hydropyridmo[5,6-b]pyrazm-6-yl}ammo)methyl]benzoic acid;

[0163] 3-[2-(4-methoxyphenyl)-3-oxo-6-({[3-

(tnfluoromethyl)phenyl]methyl}amino)(4-hydropyπdino[2,3-b]pyrazin-4-yl)]-N-

(phenylmethoxy)propanamide; [0164] N-methoxy-3 -[2-(4-methoxyphenyl)-3 -oxo-6-( { [3 -

(tπfluoromethyl)phenyl]methyl}ammo)(4-hydropyridino[2,3-b]pyrazm-4- yl)]propanamide;

[0165] ethyl 4-[2-(acetylammo)ethyl]-3-oxo-6-({[3- (tπfluoromethyl)phenyl]methyl}amino)-4-hydropyridino[2,3-e]pyrazine-2-carboxylate;

[0166] -[2-(2-(4-methoxyphenyl)-6-{[(3-methylphenyl)methyl]ammo}-3-oxo-4- hydropyπdino[2,3-b]pyrazm-4-yl)ethyl]acetamide;

[0167] 3-[2-(4-methoxyphenyl)-3-oxo-6-({[3-

(tnfluoromethyl)phenyl]methyl}amino)(4-hydropyridmo[2,3-b]pyrazm-4-yl)]-N- methylpropanamide;

[0168] 3-[2-(4-methoxyphenyl)-3 -oxo-6-( { [3 -(tπfluoromethyl)phenyl]methyl } amino)- 4-hydropyndino[2,3-b]pyrazm-4-yl]propanehydroxamic acid;

[0169] N-{2-[2-(4-methoxyphenyl)-3-oxo-6-({[3-

(tnfluoromethoxy)phenyl]methyl}amino)-4-hydropyridmo[2,3-b]pyrazin-4- yl]ethyl}acetamide;

[0170] N-(2-{2-(4-methoxyphenyl)-3-oxo-6-[(2-pyndylmethyl)amino]-4- hydropyridmo[2,3-b]pyrazin-4-yl}ethyl)acetamide;

[0171] 4-[2-(acetylamino)ethyl]-3-oxo-6-({[3-

(tnfluoromethyl)phenyl]methyl}amino)-4-hydropyπdino[2,3-b]pyrazme-2-carboxylic acid;

[0172] N-{2-[6-({[2-fluoro-5-(tπfluoromethyl)phenyl]methyl}ammo)-2-(4- methoxyphenyl)-3-oxo-4-hydropyridmo[2,3-b]pyrazin-4-yl]ethyl}acetamide;

[0173] (3R)-3-[2-(4-methoxyphenyl)-3-oxo-6-({[3- (tπfluoromethyl)phenyl]methyl } amino)(4-hydropyridino[2,3 -b]pyrazm-4- yl)]butanamide;

[0174] N-[2-(2-(4-methoxyphenyl)-6-{[(5-methylisoxazol-3-yl)methyl]amino}-3-oxo- 4-hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0175] N-{2-[2-[4-(2-methoxyethoxy)phenyl]-3-oxo-6-({[3-

(tπfluoromethyl)phenyl]methyl}amino)-4-hydropyridino[2,3-b]pyrazm-4- yl]ethyl}acetamide; [0176] N-{2-[3-oxo-2-(4-propylphenyl)-6-({[3-

(trifluoromethyl)phenyl]methyl}amino)-4-hydropyridino[2,3-b]pyrazin-4- yl]ethyl}acetamide;

[0177] N-{2-[2-[4-(acetylamino)phenyl]-3-oxo-6-({[3-

(trifluoromethyl)phenyl]methyl}amino)-4-hydropyridino[2,3-b]pyrazin-4- yl]ethyl}acetamide;

[0178] N-{2-[2-(4-methylphenyl)-3-oxo-6-({[3-

(trifluoromethyl)phenyl]methyl}amino)-4-hydropyridino[2,3-b]pyrazin-4- yl]ethyl} acetamide;

[0179] N-{2-[2-(4-ethylphenyl)-3-oxo-6-({[3-(trifluoromethyl)phenyl]methyl}amino)- 4-hydropyridino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

[0180] N-{2-[2-(4-fluorophenyl)-3-oxo-6-({[3-

(trifluoromethyl)phenyl]methyl}amino)-4-hydropyridino[2,3-b]pyrazin-4- yl]ethyl} acetamide;

[0181] 3-[2-(4-methylphenyl)-3-oxo-6-({[3-(trifluoromethyl)phenyl]methyl}amino)- 4-hydropyridino[2,3-b]pyrazin-4-yl]propanamide;

[0182] 3-[2-(4-ethylphenyl)-3 -oxo-6-( { [3 -(trifluoromethyl)phenyl]methyl } amino)-4- hydropyridino[2,3-b]pyrazin-4-yl]propanamide;

[0183] 3-[2-[4-(2-methoxyethoxy)phenyl]-3-oxo-6-({[3-

(trifluoromethyl)phenyl]methyl}amino)-4-hydropyridino[2,3-b]pyrazin-4- yljpropanamide;

[0184] 3-[3 -oxo-2-(4-propylphenyl)-6-( { [3 -(trifluoromethyl)phenyl]methyl } amino)-4- hydropyridino [2,3 -b]pyrazin-4-yl]propanamide;

[0185] N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo(4- hydropyridino[2,3-b]pyrazin-4-yl))ethyl]-2-(dimethylamino)acetamide;

[0186] {N-P-Cό-lfCS^-dichlorophenyOmethy^aminoJ^^-methoxypheny^-S-oxo^- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]carbamoyl}methyl acetate;

[0187] N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo(4- hydropyridino[2,3-b]pyrazin-4-yl))ethyl]-2-hydroxyacetamide;

[0188] 4-[2-(4-methoxyphenyl)-3-oxo-6-({[3-(trifluoromethyl)phenyl]methyl}amino)- 4-hydropyridino[2,3-b]pyrazin-4-yl]butanamide; [0189] 4-[2-methyl-3-oxo-6-({[3-(tπfluoromethyl)phenyl]methyl}amino)-4- hydropyπdino[2,3-b]pyrazin-4-yl]butanamide,

[0190] N-{2-[3-oxo-2-[4-(tπfluoromethyl)phenyl]-6-({[3-

(tπfluoromethyl)phenyl]methyl}amino)-4-hydropyridino[2,3-b]pyrazm-4- yl]ethyl}acetamide;

[0191] 3-[3-oxo-2-[4-(tπfluoromethyl)phenyl]-6-({[3-

(tπfluoromethyl)phenyl]methyl}amino)-4-hydropyridmo[2,3-b]pyrazin-4- yljpropanamide;

[0192] 2-[2-(4-methoxyphenyl)-3-oxo-6-({[3-(trifluoromethyl)phenyl]methyl}ammo)- 4-hydropyridino[2,3-b]pyrazm-4-yl]acetamide;

[0193] (3S)-3-[2-(4-methoxyphenyl)-3-oxo-6-({[3-

(tπfluoromethyl)phenyl]methyl}amino)(4-hydropyπdino[2,3-b]pyrazin-4- yl)]butanamide;

[0194] 2-amino-N-[2-(6-{[(3,4-dichlorophenyl)methyl]ammo}-2-(4-methoxyphenyl)- 3-oxo(4-hydropyπdmo[2,3-b]pyrazm-4-yl))ethyl]acetamide;

[0195] 2-(acetylamino)-N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4- methoxyphenyl)-3-oxo(4-hydropyπdino[2,3-b]pyrazin-4-yl))ethyl]acetamide;

[0196] N- {2-[3 -oxo-2-propyl-6-( { [3 -(tπfluoromethyl)phenyl]methyl} amino)-4- hydropyπdino[2,3 -b]pyrazm-4-yl] ethyl } acetamide ;

[0197] N-{2-[2-ethyl-3-oxo-6-({[3-(tπfluoromethyl)phenyl]methyl}ammo)-4- hydropyndmo[2,3-b]pyrazin-4-yl]ethyl}acetamide;

[0198] 3-(6-{[(3,4-dichlorophenyl)methyl]ammo}-2-(4-methoxyphenyl)-3-oxo(4- hydropyridino[2,3-b]pyrazm-4-yl))-N-(2-hydroxyethyl)propanamide;

[0199] N-{2-[3-oxo-2-(2-phenylethyl)-6-({[3-(trifluoromethyl)phenyl]methyl}ammo)- 4-hydropyridino[2,3-b]pyrazm-4-yl]ethyl}acetamide,

[0200] N-[2-(6-{[(3,4-dichlorophenyl)methyl]ammo}-2-[4-(methylsulfonyl)phenyl]-3- oxo-4-hydropyπdino[2,3-b]pyrazm-4-yl)ethyl]acetarmde;

[0201] 4-((3S)-6-oxo(3-pipeπdyl))-2-(4-methoxyphenyl)-6-({[3- (tπfluoromethyl)phenyl]methyl}ammo)-4-hydropyπdino[3,2-b]pyrazin-3-one;

[0202] N-[2-(2-(3,4-dichlorophenyl)-6-{[(3,4-dichlorophenyl)methyl]ammo}-3-oxo- 4-hydropyπdino[2,3-b]pyrazin-4-yl)ethyl]acetamide, [0203] N-[2-(6-{[3-(2,5-dichlorophenoxy)propyl]amino}-2-(4-methoxyphenyl)-3-oxo- 4-hydropyπdino[2,3-b]pyrazm-4-yl)ethyl]acetamide,

[0204] {N-[2-(4-methoxyphenyl)-3-oxo-6-({[3-

(tnfluoromethyl)phenyl]methyl}ammo)-4-hydropyridino[2,3-b]pyrazin-4- yl]carbamoyl}methyl acetate;

[0205] N-[2-(7- { [(3 ,4-dichlorophenyl)methyl]amino} -2-oxo-3-(3- pyπdyl)hydropyπdino[3,4-b]pyrazinyl)ethyl]acetamide;

[0206] N-[2-(7-{[(3,4-dichlorophenyl)methyl]amino}-3-(4-methylphenyl)-2- oxohydropyπdino[3,4-b]pyrazinyl)ethyl]acetamide,

[0207] N-[2-(7-{[(3,4-dichlorophenyl)methyl]amino}-3-(4-methoxyphenyl)-2- oxohydropyπdmo[3,4-b]pyrazinyl)ethyl]acetamide;

[0208] N-[2-(7-{[(3,4-dichlorophenyl)methyl]amino}-3-(4-chlorophenyl)-2- oxohydropyridino[3,4-b]pyrazinyl)ethyl]acetamide;

[0209] N-[2-(7- { [(3,4-dichlorophenyl)methyl]amino} -3-methyl-2- oxohydropyridmo[3,4-b]pyrazinyl)ethyl]acetamide,

[0210] N-[2-(7-{[(3,4-dichlorophenyl)methyl]amino}-3-(4-methoxyphenyl)-2- oxohydroquinoxahnyl)ethyl] acetamide ;

[0211] N-{2-[3-(4-methoxyphenyl)-2-oxo-7-({[3- (tπfluoromethyl)phenyl]methyl}ammo)hydroquinoxahnyl]ethyl}acetamide;

[0212] N-{2-[2-oxo-3-(3-pyπdyl)-7-({[3- (tπfluoromethyl)phenyl]methyl}ammo)hydroquinoxalmyl]ethyl}acetamide;

[0213] N-{2-[3-(4-methylphenyl)-2-oxo-7-({[3- (tπfluoromethyl)phenyl]methyl } ammo)hydroquinoxalmyl]ethyl } acetamide;

[0214] N-{2-[3-[4-(2-methoxyethoxy)phenyl]-2-oxo-7-({[3- (tπfluoromethyl)phenyl]methyl}amino)hydroquinoxahnyl]ethyl} acetamide;

[0215] N-{2-[3-methyl-2-oxo-7-({[3- (tπfluoromethyl)phenyl]methyl}amino)hydroquinoxalinyl]ethyl}acetamide;

[0216] (N- {2-[3 -methyl-2-oxo-7-( { [3 -

(tπfluoromethyl)phenyl]methyl}ammo)hydroquinoxahnyl]ethyl}carbamoyl)methyl acetate; [0217] 2-hydroxy-N-{2-[3-methyl-2-oxo-7-({[3- (trifluoromethyl)phenyl]methyl}amino)hydroquinoxalinyl]ethyl}acetamide;

[0218] N- {2-[3 -(4-ethylphenyl)-2-oxo-7-( { [3 - (trifluoromethyl)phenyl]methyl}amino)hydroquinoxalinyl]ethyl}acetamide;

[0219] N-(2-{3-(3,4-dichlorophenyl)-2-oxo-7- [(phenylmethoxy)carbonylamino]hydroquinoxalinyl } ethyl)acetamide; and

[0220] N-(2-{3-(4-methoxyphenyl)-2-oxo-7- [(phenylmethoxy)carbonylamino]hydroquinoxalinyl}ethyl)acetamide.

[0221] Additional compounds for use in the invention include, but are not limited to:

[0222] N-(2-(7-(3,4-dichlorobenzylammo)-2-(4-methoxyphenyl)-3-oxopyrido[2,3- b]pyrazin-4(3H)-yl)ethyl)acetamide;

[0223] N-(2-(2-(4-methoxyphenyl)-3-oxo-7-(3- (trifluoromethyl)benzylamino)pyrido[2,3-b]pyrazin-4(3H)-yl)ethyl)acetamide;

[0224] N-(2-(7-(4-chlorobenzylamino)-2-(4-methoxyphenyl)-3-oxopyrido[2,3- b]pyrazin-4(3H)-yl)ethyl)acetamide;

[0225] N-(2-(7-(3-chlorobenzylamino)-2-(4-methoxyphenyl)-3-oxopyrido[2,3- b]pyrazin-4(3H)-yl)ethyl)acetamide;

[0226] N-(2-(7-(4-methoxybenzylamino)-2-(4-methoxvphenyl)-3-oxopyrido[2,3- b]pyrazin-4(3H)-yl)ethyl)acetamide;

[0227] N-(2-(7-(3,4-dichlorobenzylamino)-3-oxo-2-(pyridin-3-yl)pyrido[2,3- b]pyrazin-4(3H)-yl)ethyl)acetamide;

[0228] N-(2-(7-(benzylamino)-2-methyl-3-oxopyrido[2,3-b]pyrazin-4(3H)- yl)ethyl)acetamide;

[0229] benzyl 4-(2-acetamidoethyl)-2-methyl-3-oxo-l,2,3,4-tetrahydropyrido[2,3- b]pyrazin-7-ylcarbamate;

[0230] N-(2-(7-(3,4-dichlorophenethylamino)-2-(4-methoxyphenyl)-3-oxopyrido[2,3- b]pyrazin-4(3H)-yl)ethyl)acetamide;

[0231] N-(2-(7-(3,4-dichlorobenzylamino)-2-(3,4-dichlorophenyl)-3-oxopyrido[2,3- b]pyrazin-4(3H)-yl)ethyl)acetamide; [0232] l-(2-acetamidoethyl)-N-(3,4-dichlorobenzyl)-3-(4-methoxyphenyl)-2-oxo-l,2- dihydroquinoxaline-6-carboxamide;

[0233] benzyl l-(2-acetamidoethyl)-3-(4-methoxyphenyl)-2-oxo-l,2- dihydroquinoxalin-6-ylcarbamate;

[0234] benzyl l-(2-acetamidoethyl)-3-(3,4-dichlorophenyl)-2-oxo-l,2- dihydroquinoxalin-6-ylcarbamate;

[0235] (S)-2-hydroxy-N-(2-(3-methyl-2-oxo-7-(3- (trifluoromethyl)benzylamino)quinoxalin-l(2H)-yl)ethyl)propanamide;

[0236] (R)-2-hydroxy-N-(2-(3-methyl-2-oxo-7-(3- (trifluoromethyl)benzylamino)quinoxalin-l(2H)-yl)ethyl)propanamide;

[0237] 3-hydroxy-N-(2-(3-methyl-2-oxo-7-(3- (trifluoromethyl)benzylamino)quinoxalin-l(2H)-yl)ethyl)propanamide;

[0238] N-(2-hydroxyethyl)-3-(3-methyl-2-oxo-7-(3- (trifluoromethyl)benzylamino)quinoxalin- 1 (2H)-yl)propanamide;

[0239] N-(2-(3-methyl-2-oxo-7-(3-(trifluoromethyl)benzylamino)quinoxalin-l(2H)- yl)ethyl)thiophene-3-carboxamide;

[0240] 2,3-dihydroxy-N-(2-(3-methyl-2-oxo-7-(3- (trifluoromethyl)benzylamino)quinoxalin-l(2H)-yl)ethyl)propanamide;

[0241] l-(2-(3-methyl-2-oxo-7-(3-(trifluoromethyl)benzylamino)quinoxalin-l(2H)- yl)ethyl)urea;

[0242] N-(2-(7-(3-chlorophenethylamino)-3-(4-methoxyphenyl)-2-oxoquinoxalin- 1 (2H)-yl)ethyl)acetamide;

[0243] N-(2-(7-(2-(2-chlorophenoxy)ethylamino)-3-(4-methoxyphenyl)-2- oxoquinoxalin- 1 (2H)-yl)ethyl)acetamide;

[0244] N-(2-(3 -(4-methoxyphenyl)-7-(3 -methylbenzylamino)-2-oxoquinoxalin- 1 (2H)- yl)ethyl)acetamide;

[0245] N-(2-(7-(3,4-dimethylbenzylamino)-3-(4-methoxyphenyl)-2-oxoquinoxalin- 1 (2H)-yl)ethyl)acetamide;

[0246] N-(2-(7-(4-chlorophenethylamino)-3-(4-methoxyphenyl)-2-oxoquinoxalin- 1 (2H)-yl)ethyl)acetamide; [0247] N-(2-(7-(4-chloro-3-(tnfluoromethyl)benzylammo)-3-(4-methoxyphenyl)-2- oxoquinoxalm- 1 (2H)-yl)ethyl)acetamide;

[0248] N-(2-(7-(4-fluoro-3-methylbenzylammo)-3-(4-methoxyphenyl)-2- oxoqumoxahn- 1 (2H)-yl)ethyl)acetamide;

[0249] N-(2-(3-(4-methoxyphenyl)-2-oxo-7-((4-(trifluoromethyl)pyπdm-2- yl)methylamino)quinoxahn- 1 (2H)-yl)ethyl)acetamide;

[0250] (±)-2,3-dihydroxy-N-(2-(3-methyl-2-oxo-7-(3-(trifluoromethyl)benzylammo)- qumoxalin- 1 (2H)-yl)ethyl)-propanamide;

[0251] N-(2-(7-(3,4-dichlorobenzylamino)-2-(4-methoxyphenyl)-3-oxopyπdo[3,2- b]pyrazin-4(3H)-yl)ethyl)acetamide;

[0252] N-(2-(7-(benzylamino)-2-methyl-3-oxopyπdo[3,2-b]pyrazin-4(3H)- yl)ethyl)acetamide;

[0253] N-(2-(7-(4-chloro-3-(trifluoromethyl)benzylamino)-3-(4- methoxyphenyl)-2-oxoquinoxalin- 1 (2H)-yl)ethyl)acetamide;

[0254] N-(2-(7-(4-fluoro-3-methylbenzylamino)-3-(4-methoxyphenyl)-2- oxoquinoxalin-1 (2H)-yl)ethyl)acetamide; and

[0255] N-(2-(3-(4-methoxyphenyl)-2-oxo-7-((4-(trifluoromethyl)pyridin-2- yl)methylamino)quinoxalin- 1 (2H)-yl)ethyl)acetamide.

DETAILED DESCRIPTION OF THE INVENTION Definitions and General Parameters

[0256] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0257] The term "alkyl" refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.

[0258] The term "substituted alkyl" refers to: 1) an alkyl group as defined above, having 1, 2, 3, 4 or 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO₂-alkyl, SO₂-aryl and -SO₂-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or

2) an alkyl group as defined above that is interrupted by 1-10 atoms independently chosen from oxygen, sulfur and NR₃-, where R₃ is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF₃, amino, substituted amino, cyano, or -S(O)_nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or

3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-10 atoms as defined above.

[0259] The term "lower alkyl" refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

[0260] The term "substituted lower alkyl" refers to lower alkyl as defined above having 1 to 5 substituents, preferably 1, 2, or 3 substituents, as defined for substituted alkyl, or a lower alkyl group as defined above that is interrupted by 1, 2, 3, 4, or 5 atoms as defined for substituted alkyl, or a lower alkyl group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1, 2, 3, 4, or 5 atoms as defined above.

[0261] The term "alkylene" refers to a diradical of a branched or unbranched saturated hydrocarbon chain, having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms. This term is exemplified by groups such as methylene (-CH₂-), ethylene (-CH₂CH₂-), the propylene isomers (e.g., -CH₂CH₂CH₂- and-CH(CH₃)CH₂-) and the like.

[0262] The term "lower alkylene" refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1, 2, 3, 4, 5, or 6 carbon atoms. [0263] The term "lower alkylene" refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from 1, 2, 3, 4, 5, or 6 carbon atoms.

[0264] The term" substituted alkylene" refers to:

(1) an alkylene group as defined above having 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO₂-alkyl, SO₂-aryl and - SO₂-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or

(2) an alkylene group as defined above that is interrupted by 1 -20atoms independently chosen from oxygen, sulfur and NR_a-, where R_a is chosen from hydrogen, optionally substituted alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycyl, or groups selected from carbonyl, carboxyester, carboxyamide and sulfonyl; or

(3) an alkylene group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-20 atoms as defined above. Examples of substituted alkylenes are chloromethylene (-CH(Cl)-), aminoethylene (-CH(NH₂)CH₂-), methylaminoethylene (-CH(NHMe)CH₂-), 2-carboxypropylene isomers(- CH₂CH(CO₂H)CH₂-), ethoxyethyl (-CH₂CH₂O-CH₂CH₂-), ethylmethylaminoethyl (- CH₂CH₂N(CH₃)CH₂CH₂-), 1 -ethoxy-2-(2-ethoxy-ethoxy)ethane (-CH₂CH₂O-CH₂CH₂- OCH₂CH₂-OCH₂CH₂-), and the like.

[0265] The term "aralkyl" refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein. "Optionally substituted aralkyl" refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group. Such aralkyl groups are exemplified by benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl, and the like.

[0266] The term "alkoxy" refers to the group R-O-, where R is optionally substituted alkyl or optionally substituted cycloalkyl, or R is a group -Y-Z, in which Y is optionally substituted alkylene and Z is optionally substituted alkenyl, optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined herein. Preferred alkoxy groups are optionally substituted alkyl-O- and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, trifluoromethoxy, and the like.

[0267] The term "alkylthio" refers to the group R-S-, where R is as defined for alkoxy.

[0268] The term "alkenyl" refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having 1 -6, preferably 1 , double bond (vinyl). Preferred alkenyl groups include ethenyl or vinyl (-CH=CH₂), 1- propylene or allyl (-CH₂CH=CH₂), isopropylene (-C(CH₃)=CH₂), bicyclo[2.2.1]heptene, and the like. In the event that alkenyl is attached to nitrogen, the double bond cannot be alpha to the nitrogen.

[0269] The term "lower alkenyl" refers to alkenyl as defined above having from 2 to 6 carbon atoms.

[0270] The term "substituted alkenyl" refers to an alkenyl group as defined above having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO₂-alkyl, SO₂-aryl and -SO₂-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0271] The term "alkynyl" refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1 -6 sites of acetylene (triple bond) unsaturation. Preferred alkynyl groups include ethynyl, (-C≡CH), propargyl (or prop-l-yn-3-yl, -CH₂C≡CH), and the like. In the event that alkynyl is attached to nitrogen, the triple bond cannot be alpha to the nitrogen.

[0272] The term "substituted alkynyl" refers to an alkynyl group as defined above having 1 , 2, 3, 4 or 5 substituents, and preferably 1 , 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, ammosulfonyl, ammocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO₂-alkyl, SO₂-aryl and -SO₂-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, ammo, substituted ammo, cyano, and -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0273] The term "aminocarbonyl" refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or where both R groups are joined to form a heterocyclic group (e.g., morphohno). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 -3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, ammo, substituted ammo, cyano, and -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0274] The term "acylammo" refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 -3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, ammo, substituted amino, cyano, and -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0275] The term "acyloxy" refers to the groups -O(O)C-alkyl, -O(O)C-cycloalkyl, -O(O)C- aryl, -O(O)C-heteroaryl, and -O(O)C-heterocyclyl. Unless otherwise constrained by the definition, all substituents may be optionally further substituted by alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, or -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0276] The term "aryl" refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl), or multiple condensed (fused) πngs (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.

[0277] The term "arylene" refers to a diradical of an aryl group as defined above. This term is exemplified by groups such as 1 ,4-phenylene, 1,3-phenylene, 1 ,2-phenylene, l,4'-biphenylene, and the like.

[0278] Unless otherwise constrained by the definition for the aryl or arylene substituent, such aryl or arylene groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylammo, acyloxy, ammo, aminocarbonyl, alkoxycarbonylammo, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylammo, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyammo, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO₂-alkyl, SO₂-aryl and -SO₂-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted ammo, cyano, and -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0279] The term "aryloxy" refers to the group aryl-O- wherein the aryl group is as defined above, and includes optionally substituted aryl groups as also defined above. The term "arylthio" refers to the group R-S-, where R is as defined for aryl.

[0280] The term "ammo" refers to the group -NH₂.

[0281] The term "substituted amino" refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, carboxyalkyl (for example, benzyloxycarbonyl), aryl, heteroaryl and heterocyclyl provided that both R groups are not hydrogen, or a group -Y-Z, in which Y is optionally substituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl, Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, ammo, substituted amino, cyano, and -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0282] The term "carboxyalkyl" refers to the groups -C(O)O-alkyl or -C(O)O-cycloalkyl, where alkyl and cycloalkyl, are as defined herein, and may be optionally further substituted by alkyl, alkenyl, alkynyl, alkoxy, halogen, CF₃, amino, substituted amino, cyano, or -S(O)_nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0283] The term "cycloalkyl¹' refers to carbocyclic groups of from 3 to 20 carbon atoms having a single cyclic πng or multiple condensed rings. Such cycloalkyl groups include, by way of example, single πng structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple πng structures such as adamantanyl, bicyclo[2.2.1]heptane, 1,3,3- tnmethylbicyclo[2.2.1]hept-2-yl, (2,3,3-tπmethylbicyclo[2.2.1]hept-2-yl), or carbocyclic groups to which is fused an aryl group, for example mdane, and the like

[0284] The term "substituted cycloalkyl" refers to cycloalkyl groups having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO₂-alkyl, SO₂-aryl and -Sθ₂-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0285] The term "halogen" or "halo" refers to fluoro, bromo, chloro, and iodo.

[0286] The term "acyl" denotes a group -C(O)R, in which R is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0287] The term "heteroaryl" refers to a radical derived from an aromatic cyclic group (i.e., fully unsaturated) having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazolyl, or benzothienyl). Examples of heteroaryls include, but are not limited to, [l,2,4]oxadiazole, [l,3,4]oxadiazole, [l,2,4]thiadiazole, [l,3,4]thiadiazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, and the like as well as N-oxide and N-alkoxy derivatives of nitrogen containing heteroaryl compounds, for example pyridine-N-oxide derivatives.

[0288] The term "heteroarylene" refers to a diradical of a heteroaryl group as defined above. This term is exemplified by groups such as 2,5-imidazolene, 3,5-[l,2,4]oxadiazolene, 2,4- oxazolene, 1,4-pyrazolene, and the like. For example, 1 ,4-pyrazolene is:

where A represents the point of attachment. [0289] Unless otherwise constrained by the definition for the heteroaryl or heteroarylene substituent, such heteroaryl or heterarylene groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, ammocarbonyl, alkoxycarbonylammo, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylammo, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyammo, alkoxyammo, mtro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO₂-alkyl, SO₂-aryl and -SO₂-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, ammocarbonyl, hydroxy, alkoxy, halogen, CF₃, ammo, substituted amino, cyano, and -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0290] The term "heteroaralkyl" refers to a heteroaryl group covalently linked to an alkylene group, where heteroaryl and alkylene are defined herein. "Optionally substituted heteroaralkyl" refers to an optionally substituted heteroaryl group covalently linked to an optionally substituted alkylene group. Such heteroaralkyl groups are exemplified by 3-pyπdylmethyl, quinohn-8-ylethyl, 4-methoxythiazol-2-ylpropyl, and the like.

[0291] The term "heteroaryloxy" refers to the group heteroaryl-O-.

[0292] The term "heterocyclyl" refers to a monoradical saturated or partially unsaturated group having a single nng or multiple condensed πngs, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1, 2, 3 or 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the nng. Heterocyclic groups can have a single nng or multiple condensed nngs, and include tetrahydrofuranyl, morpholmo, pipendinyl, piperazmo, dihydropyndmo, and the like.

[0293] Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1, 2, 3, 4 or 5, and preferably 1, 2 or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylammo, acyloxy, amino, ammocarbonyl, alkoxycarbonylammo, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylammo, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyammo, alkoxyammo, mtro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO₂-alkyl, SO₂-aryl and -SO₂- heteroaryl Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0294] The term "thiol" refers to the group -SH.

[0295] The term "substituted alkylthio" refers to the group -S-substituted alkyl.

[0296] The term "heteroarylthiol" refers to the group -S-heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above.

[0297] The term "sulfoxide" refers to a group -S(O)R, in which R is alkyl, aryl, or heteroaryl. "Substituted sulfoxide" refers to a group -S(O)R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.

[0298] The term "sulfone" refers to a group -S(O)₂R, in which R is alkyl, aryl, or heteroaryl. "Substituted sulfone" refers to a group -S(O)₂R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.

[0299] The term "keto" refers to a group -C(O)-. [0300] The term "thiocarbonyl" refers to a group -C(S)-. [0301] The term "carboxy" refers to a group -C(O)-OH.

[0302] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.

[0303] The term "compound of Formula I " is intended to encompass the compounds of the invention as disclosed, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, prodrugs, hydrates and polymorphs of such compounds. Additionally, the compounds of the invention may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of Formula I depends upon the number of asymmetric centers present (there are 2" stereoisomers possible where n is the number of asymmetric centers). The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound of Formula I by conventional means. The individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present invention, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated.

[0304] "Isomers" are different compounds that have the same molecular formula.

[0305] "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space.

[0306] "Enantiomers" are a pair of stereoisomers that are non-supeπmposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropπate.

[0307] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0308] The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown are designated (+) or (-) depending on the direction (dextro- or laevorotary) which they rotate the plane of polaπzed light at the wavelength of the sodium D line.

[0309] "Parenteral administration" is the systemic delivery of the therapeutic agent via injection to the patient.

[0310] The term "therapeutically effective amount" refers to that amount of a compound of Formula I that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the specific activity of the therapeutic agent being used, and the age, physical condition, existence of other disease states, and nutritional status of the patient. Additionally, other medication the patient may be receiving will effect the determination of the therapeutically effective amount of the therapeutic agent to administer.

[0311] The term "treatment" or "treating" means any treatment of a disease m a mammal, including:

(i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop;

(ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or (in) relieving the disease, that is, causing the regression of clinical symptoms.

[0312] In many cases, the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compounds of Formula I and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts deπved from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, tπalkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tπ(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tπ(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, tπsubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, tπsubstituted cycloalkenyl amines, aryl amines, diaryl amines, tπaryl amines, heteroaryl amines, diheteroaryl amines, tπheteroaryl amines, heterocyclic amines, diheterocyclic amines, tπheterocychc amines, mixed di- and tπ-ammes where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the ammo nitrogen, form a heterocyclic or heteroaryl group.

[0313] Specific examples of suitable amines include, by way of example only, isopropylamme, tπmethyl amine, diethyl amine, tπ(iso-propyl) amine, tπ(n-propyl) amine, ethanolamine, 2-dimethylammoethanol, tromethamine, lysine, argmine, histidme, caffeine, procaine, hydrabamme, choline, betaine, ethylenediamine, glucosamine, N-alkylglucammes, theobromine, purines, piperazme, pφeπdme, morpholme, N-ethylpipeπdme, and the like.

[0314] Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts deπved from inorganic acids include hydrochloπc acid, hydrobromic acid, sulfuπc acid, nitπc acid, phosphoπc acid, and the like. Salts denved from organic acids include acetic acid, propionic acid, glycohc acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citnc acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfomc acid, salicylic acid, and the like.

[0315] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, solubilizers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

Nomenclature

[0316] The naming and numbering of the compounds of the invention is illustrated with a representative compound of Formula I in which R¹ is 2-(acetylammo)ethyl, R² is 3,4- dichlorobenzyl, and R³ is 4-methoxyphenyl,

which is named:

N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide.

Pharmaceutical Compositions

[0317] When selected as the SCD inhibitor, the compounds of Formula I are usually administered in the form of pharmaceutical compositions. This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds of Formula I, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, earners, including inert solid diluents and fillers, diluents, including sterile aqueous solution and vaπous organic solvents, solubihzers and adjuvants. The compounds of Formula I may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known m the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co , Philadelphia, PA 17^lh Ed (1985) and "Modern Pharmaceutics", Marcel Dekker, Inc. 3^rd Ed. (G.S. Banker & CT Rhodes, Eds.). Synthetic Reaction Parameters

[0318] The terms "solvent", "inert organic solvent" or "inert solvent" mean a solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like]. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.

[0319] The term "q.s." means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).

Synthesis of the Compounds of Formula

[0320] One method of preparing compounds of Formula I (e.g. Formula Ib) is shown in Reaction Scheme I.

REACTION SCHEME I

Formula Ib Step 1 - Preparation of Formula (2)

[0321] The compound of formula (2) is made by replacing the halogen group adjacent to the nitro moiety on the commercially available formula (1) compound (i.e., 2,6-dichloro-3- nitropyridine, 2,4-dichloro-5-nitropyridine, 2,4-difluoro-nitrobenzene, or the like) with a compound of formula R¹NH₂ in the presence of a base. The reaction is earned out in a dipolar aprotic solvent such as tetrahydrofuran (THF), acetone, or ethylacetate, and the like, at a temperature of around -6O⁰C to around -90⁰C, for about 30 minutes to an hour. The reaction mixture is then allowed to warm to room temperature with continued stirring, approximately 2 to 5 hours. When the reaction is substantially complete, the product of formula (2) is isolated by conventional means, for example by removal of the solvent under reduced pressure, followed by chromatography of the residue on silica gel. Alternatively, the compound of formula (2) is used m the next step without purification.

Step 2 - Preparation of Formula (3)

[0322] The compound of formula (3) is made by replacing the remaining chloro group on the compound of formula (2) with a compound of formula R²NH₂ in the presence of a base. A similar procedure is used as descπbed with respect to step 2, however, the reaction is conducted at a temperature of approximately 50⁰C to approximately 80⁰C for 12 to 24 hours. When the reaction is substantially complete, the product of formula (3) may by isolated conventional means but is typically used in the next step without purification.

Step 3 - Preparation of Formula (4)

[0323] The formula (3) nitro compound is then reduced to the corresponding amine analog, compound (4), via conventional reduction techniques. Suitable methods include, but are not limited to, reaction with Na₂S₂O₄ and Na₂CO₃ at a temperature ranging from 20⁰C to 80⁰C for 10 minutes to 12 hours. After the reaction is allowed to cool to room temperature the product may be extracted by dilution with EtOAc followed by washing with saturated. NaHCO₄ solution and bnne. The combined organic phase can then be dried over MgSO₄ and concentrated to provide the compound of formula (4) in crude form which can be used in the next step without further purification.

[0324] Alternatively, the nitro group can be reduced by reaction with hydrazine and a Raney- Nickel catalyst. In this method, the nitro compound is placed in a methanol solution to which the hydrazine is added Then the reaction mixture is heated to approximately 50⁰C to 80⁰C and the Raney -Nickel catalyst gently added to insure even and steady evolution of the nitrogen gas The reaction proceeds for approximately 1 hour whereupon the reaction mixture is allowed to cool to room temperature, the catalyst filtered off, and the filter cake washed with methanol. The resulting solution may be concentrated and purified using conventional methods, i.e., chromatography using a methanol/dichloromethane gradient to provide the desired amine.

Step 4 - Preparation of Formula I

[0325] The final step in the synthesis involves the formation of the pyπmidme πng and the addition of the R³ substituent. This is achieved by reacting the amino compound of formula (4) with an ethyl oxoacetate derivative having the desired R³ moiety, i.e., a compound of formula (5). The compound of formula (4) is dissolved in 2% v/v AcOH in EtOH and then the compound of formula (5) is added. The reaction is stirred at 60⁰C to 90⁰C for 12 to 24 hours. The resulting suspension is cooled to room temperature and the final product extracted by the addition of a polar solvent such as methanol followed by filtration and washing with additional polar solvent. The compound of Formula I can then be dπed under vacuum to remove any remaining solvent.

[0326] Alternatively, the pyπmidine πng can be formed by first dissolving the ammo compound of formula (4) into acetonitπle followed by the addition of a catalytic drop of acid, such as glacial acetic acid. The oxoacetate deπvative is then added and the mixture heated for approximately 20 to 40 minutes in a microwave at 120⁰C. The reaction mixture may them be filtered, concentrated, and purified using column chromatography eluting with MeOH/dichloromethane gradient to provide the compound of Formula I.

Alternative Preparation - R¹ is a Nitrogen-Containing Heterocvcle

[0327] Compounds of Formula I wherein R¹ is a nitrogen-containing heterocycle may be prepared as described above with the additional requirement that the nitrogen atom in the R¹ heterocycle be protected by a suitable protecting group such as an N-terf-butoxycarbonyl group. If desired the protecting group may be removed after Step 4 using conventional techniques, i.e , heating at 60⁰C to 80⁰C in a mixture of acetonitnle and hydrochloπc acid. The acidic mixture is neutralized after cooling with an aqueous base such as KOH and the product extracted using dichloromethane Alternative Preparation - Secondary Modification of R¹

[0328] It will be appreciated that secondary modification may be made to the R¹ moiety after the compound of Formula I has been made. As was discussed in the R¹ heterocycles, this type of modification generally will involve the use of a protected terminal R¹ amino group. Once the protecting group is removed, the terminal R¹ amino group may be modified by reaction with any number of reactants allowing for the addition of a desired R⁵ or R⁷ substituent.

[0329] In one type of secondary modification, the deprotected compound of Formula I is dissolved m the appropπate non-protic solvent, i.e., acetomtπle or the like, and then an acidic version of the desired R⁵ substituent, R⁶-C(O)-OH, is added to the reaction mixture followed by 2-(lH-benzotπazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU) and diisopropylethyleneamme. After briefly heating to approximately 50° to 70⁰C, the reaction mixture is cooled to room temperature and the precipitated end product filtered off and washed with additional solvent to provide the final product of Formula I.

[0330] In another example of secondary modification, after the deprotected compound of Formula I is dissolved in the appropπate non-protic solvent, i.e., acetonitπle, it is placed in a microwave vessel with methyl formate and heated at 135°C to 150⁰C for 15 to 30 minutes. Cooling and filtration will provide the desired end product.

[0331] In still another example of secondary modification, the deprotected compound of Formula I is dissolved m acetonitπle and dichloromethane. A base such as diisopropylethyleneamme is then added along with{lH]-pyrazole-l-hydroxamidme hydrochloride. The reaction is heated at 30⁰C to 50⁰C for 15 to 30 minutes. Cooling and filtration will provide a compound of Formula I wherein R⁴ is -C(NH)NH₂.

Utility Testing and Administration

[0332] The present invention relates to compounds, pharmaceutical compositions and methods of using the compounds and pharmaceutical compositions for the treatment and/or prevention of diseases mediated by SCD. The methods and pharmaceutical compositions are particularly suitable for use in the treatment of diseases related to dyshpidemia and disorders of lipid metabolism, especially diseases related to elevated plasma and tissue lipid levels, such as cardiovascular disease, diabetes, obesity, metabolic syndrome, fatty liver diseases and the like.

[0333] In general, the compounds of the invention find utility in the treatment of a patient for, or protecting a patient from developing, a disease related to dyshpidemia and/or a disorder of lipid metabolism, wherein lipid levels in an animal, especially a human being, are outside the normal range (i e , abnormal lipid level, such as elevated plasma or tissue lipid levels or hepatic or peripheral tissue lipid accumulation), especially levels higher than normal, preferably where said lipid is a fatty acid, such as a free or complexed fatty acid, triglycerides, phospholipids, wax esters, cholesterol or cholesteryl ester, such as where VLDL, hepatic or peripheral tissue triglycerides are elevated, or any combination of these, where said hpid-related condition or disease is an SCD-mediated disease or condition, such as metabolic syndrome, diabetes, nonalcoholic fatty liver disease, obesity, cancer, oily skin and related diseases, comprising administering to an animal, such as a mammal, especially a human patient, a therapeutically effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention wherein the compound inhibits the activity of SCD.

[0334] The general value of the compounds of the invention m inhibiting the activity of SCD can be determined using the assay descπbed below m Example 20. Additionally, the general value of the compounds m treating disorders and diseases may be established in industry standard animal models for demonstrating the efficacy of compounds in treating obesity, diabetes, metabolic syndrome, or abnormal triglyceride or cholesterol levels or for improving glucose tolerance

Utility

[0335] The compounds of the instant invention are inhibitors of SCD and are useful for treating diseases and disorders in humans and other organisms, including all those human diseases and disorders which are the result of aberrant SCD biological activity or which may be ameliorated by inhibition of SCD biological activity.

[0336] As defined herein, an SCD-mediated disease or condition includes but is not limited to a disease or condition which is, or is related to, cardiovascular disease, dyshpidemias, fatty liver diseases, coronary artery disease, atherosclerosis, heart disease, cerebrovascular disease (including, but not limited, to stroke, ischemic stroke and transient ischemic attack (TIA), peπpheral vascular disease, ischemic retinopathy, cancer and skin conditions), cancers and oily skin

[0337] Dyshpidemia, as used herein, includes, but is not limited to, disorders related to the serum and tissue levels of triglycerides, i.e., hypertriglyceridemia, fatty liver diseases LDL, VLDL, and/or HDL, cholesterol, and total cholesterol Dyshpidemia also includes disorders related to the Δ9 fatty acid Desaturation Indexes (e g the ratio of SCD product fatty acids/SCD substrate fatty acids) Disorders of polyunsaturated fatty acid metabolism (PUFA) are also included as are cholesterol disorders such as familial combined hyperhpidemia and those disorders involving defective reverse cholesterol transport

[0338] SCD-mediated diseases or conditions relating to hypertriglyceridemia include, but are not limited to, hyperlipoproteinemias, familial histiocytic reticulosis, lipoprotein lipase deficiency, apohpoprotem deficiency (such as ApoCII deficiency or ApoE deficiency), and the like, or hypertriglyceridemia of unknown or unspecified etiology

[0339] Metabolic syndrome, Syndrome X and Pre-Diabetes are also within the scope of the term "SCD-mediated disease" including all of the vaπous component conditions that make up the syndromes such as, but not limited to, dyshpidemia, obesity, insulin resistance, hypeπnsulenemia, decreased glucose tolerance, hypertension, microalbuminemia, hyperuπcaemia, and hypercoagulability, diabetes, non-insulm-dependent diabetes melhtus, Type I diabetes, Type II diabetes, diabetic complications, body weight disorders such as overweight, cachexia and anorexia, and body mass index and leptin related diseases

[0340] As used herein, the term "metabolic syndrome" is a recognized clinical term used to describe a condition comprising combinations of Type II diabetes, impaired glucose tolerance, insulin resistance, hypeπnsulmemia, hypertension, obesity, increased abdominal girth, hypertriglyceridemia, low HDL, hyperuπcaemia, hypercoagulability and/or microalbuminemia

[0341] An SCD-mediated disease or condition also includes vaπous hepatic conditions such as hepatitis, hepatic steatosis, hepatic fibrosis, hepatic cirrhosis, non-alcoholic hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic hepatitis, fatty liver, non-alcoholic fatty liver disease (NAFLD), acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis, erythrohepatic protoporphyna, iron overload disorders, hereditary hemochromatosis, hepatoma and conditions related thereto

[0342] Vaπous skin and mucosal tissue disorders fall within the scope of an SCD-mediated disease or condition including, but not limited to, eczema, acne, psoπasis, keloid scar formation or prevention, diseases related to production or secretions from mucous membranes, such as monounsaturated fatty acids, wax esters, and the like Inflammation, sinusitis, asthma, pancreatitis, osteoarthπtis, rheumatoid arthπtis, cystic fibrosis, and pre-menstrual syndrome may also be considered SCD-mediated diseases or conditions as may diseases or conditions which is, or is related to cancer, neoplasm, malignancy, metastases, tumors (benign or malignant), carcinogenesis, hepatomas and the like SCD-mediated diseases or conditions also include diseases or conditions which are, or are related to, neurological diseases, psychiatric disorders, multiple sclerosis, eye diseases, and immune disorders An SCD-mediated disease or condition also includes a disease or condition which is, or is related to, viral diseases or infections.

[0343] An SCD-mediated disease or condition also includes a condition where increasing lean body mass or lean muscle mass is desired, such as is desirable in enhancing performance through muscle building. Myopathies and lipid myopathies such as carnitine palmitoyltransferase deficiency (CPT I or CPT II) are also included herein. Such treatments are useful in humans and in animal husbandry, including for administration to bovine, porcine or avian domestic animals or any other animal to reduce triglyceride production and/or provide leaner meat products and/or healthier animals.

[0344] The identification of compounds of the invention as SCD inhibitors was readily accomplished using the SCD enzyme and microsomal assay procedure described in Talamo and Bloch (1969) Analytical Biochemistry 29:300-304. When tested in this assay, compounds of the invention had less than 50% remaining SCD activity at 10 μM concentration of the test compound, preferably less than 40% remaining SCD activity at 10 μM concentration of the test compound, more preferably less than 30% remaining SCD activity at 10 μM concentration of the test compound, and even more preferably less than 20% remaining SCD activity at 10 μM concentration of the test compound, thereby demonstrating that the compounds of the invention are potent inhibitors of SCD activity.

[0345] Other methods of testing the compounds disclosed herein are also readily available to those skilled in the art. Thus, testing of the compounds may be accomplished in vivo. In one such embodiment, testing of the compounds is accomplished by administering the compound to an animal afflicted with a plasma or tissue, fatty acid or triglyceride (TG) related disorder or very low density lipoprotein (VLDL)-related disorder and subsequently detecting a change in plasma or tissue fatty acid composition or triglyceride level in said animal thereby identifying a therapeutic agent useful in treating a plasma or tissue, fatty acid or triglyceride (TG) related disorder or very low density lipoprotein (VLDL)-related disorder. In such embodiment, the animal may be a human, such as a human patient afflicted with such a disorder and in need of treatment of said disorder.

[0346] In specific embodiments of such in vivo processes, said change in SCD activity in said animal is a decrease in activity, preferably wherein said SCD modulating agent does not substantially directly inhibit the biological activity of a Δ5 desaturase, Δ6 desaturase, fatty acid synthetase, or other lipogenic enzymes. [0347] The model systems useful for compound evaluation may include, but not limited to, the use of liver microsomes, such as from mice or rats that have been maintained on a high carbohydrate or high-fat diet, or from human donors, including persons suffering from obesity. Immortalized cell lines, such as HepG2 (from human liver), MCF-7 (from human breast cancer) and 3T3-L1 (from mouse adipocytes) may also be used. . Primary cell lines, such as mouse primary hepatocytes, are also useful in testing the compounds of the invention. Where whole animals are used, mice or rats used as a source of primary hepatocyte cells may also be used wherein the mice or rats have been maintained on a high carbohydrate or other SCD inducing diet to increase SCD activity m microsomes and/or to elevate plasma and/or tissue triglyceride levels or Δ9 fatty acid desaturation indexes or Δ9 fatty acid desaturation indexes (e.g., the 18:1/18:0 ratio); alternatively mice on a normal diet or mice with normal triglyceride levels may be used. Mouse models having hypertriglyceridemia due to genetic or naturally occurring mutations are also available as is the mouse phenome database. Rabbits, hamsters and monkeys are also useful as animal models, especially those with diabetic and obesity phenotypes.

[0348] Another suitable method for determining the in vivo efficacy of the compounds of the invention is to indirectly measure their impact on inhibition of SCD enzyme by measuring changes in fatty acid composition. These include absolute or relative reductions in SCD product fatty acids such as 16:1 n-7, 18:1 n-7 or 18:1 n-9. As well fatty acid composition data may also be used to determine a subject's Δ9 Desaturation Index after administration of the compound. "Desaturation Index(s)" as employed in this specification means the ratio of the product over the substrate for the SCD enzyme as measured from a given tissue or plasma sample. This may be calculated using different equations, such as 18:ln-9/18:0; 16:ln-7/16:0; and/or (16:1 n-7+ 18: 1 n-7)/ 16:0. Desaturation Index(s) may be measured in plasma or tissues as well as specific lipid classes containing fatty acids such as triglycerides and phospholipids.

Administration

[0349] The compounds of Formula I may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as descπbed in those patents and patent applications incorporated by reference, including buccal, intranasal, intra-arteπal injection, intravenously, mtraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant

[0350] Oral administration is the preferred route for administration of the compounds of Formula I. Administration may be via capsule or enteric coated tablets, or the like. In making the pharmaceutical compositions that include at least one compound of Formula I, the active ingredient is usually diluted by an excipient and/or enclosed withm such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid mateπal (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or m a liquid medium), ointments containing, for example, up to 20% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and steπle packaged powders.

[0351] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, manmtol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, cyclodextrms, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.

[0352] The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known m the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902514; and 5,616,345.

[0353] In other embodiments, the compounds of the invention are incorporated into a pharmaceutical formulation containing a pharmaceutically acceptable earner that is generally suited to topical drug administration and compπsing any such mateπal known in the art. Suitable earners are well known to those of skill m the art and the selection of the earner will depend upon the form of the intended pharmaceutical formulation, e.g., as an ointment, lotion, cream, foam, microemulsion, gel, oil, solution, spray, salve, or the like, and may be comprised of either naturally occurnng or synthetic matenals. It is understood that the selected earner should not adversely affect the compound of Formula I other components of the pharmaceutical formulation.

[0354] Suitable earners for these types of formulations include, but are not limited to, vehicles including Shephard's Cream, Aquaphor^™, and Cetaphil lotion. Other preferred earners include ointment bases, e.g , polyethylene glycol-1000 (PEG-1000), conventional creams such as HEB cream, gels, as well as petroleum jelly and the like. Examples of suitable carriers for use herein include water, alcohols and other nontoxic organic solvents, glycerin, mineral oil, silicone, petroleum jelly, lanohn, fatty acids, vegetable oils, parabens, waxes, and the like. Particularly preferred formulations herein are colorless, odorless ointments, lotions, creams, microemulsions and gels.

[0355] Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. The specific ointment base to be used, as will be appreciated by those skilled in the art, is one that will provide for optimum drug delivery, and, preferably, will provide for other desired characteristics as well, e.g., emolliency or the like. As with other carriers or vehicles, an ointment base should be inert, stable, nonirntatmg and nonsensitizing. As explained in Remington 's Pharmaceutical Sciences, 20^th Ed. (Easton, Pa.: Mack Publishing Company, 2000), ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxysteaπn sulfate, anhydrous lanolin, and hydrophilic petrolatum. Emulsion ointment bases are either water-m-oil (W/O) emulsions or oil-m-water (OAV) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin, and steaπc acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols (PEGs) of varying molecular weight; again, reference may be had to Remington's, supra, for further information.

[0356] Lotions are preparations to be applied to the skin surface without friction, and are typically liquid or semiliquid preparations m which solid particles, including the active agent, are present in a water or alcohol base Lotions are usually suspensions of solids, and preferably, for the present purpose, compπse a liquid oily emulsion of the oil-m-water type. Lotions are preferred formulations herein for treating large body areas, because of the ease of applying a more fluid composition It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions will typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, e.g., methylcellulose, sodium carboxymethylcellulose, or the like. A particularly preferred lotion formulation for use in conjunction with the present invention contains propylene glycol mixed with a hydrophilic petrolatum such as that which may be obtained under the trademark Aquaphor^™ from Beiersdorf, Inc. (Norwalk, Conn.).

[0357] Creams containing the active agent are, as known in the art, viscous liquid or semisolid emulsions, either oil-m-water or water-in-oil. Cream bases are water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation, as explained in Remington's, supra, is generally a nonionic, anionic, cationic, or amphoteric surfactant.

[0358] Microemulsions are thermodynamically stable, isotropically clear dispersions of two immiscible liquids, such as oil and water, stabilized by an interfacial film of surfactant molecules (Encyclopedia of Pharmaceutical Technology (New York: Marcel Dekker, 1992), volume 9). For the preparation of microemulsions, a surfactant (emulsifier), a co-surfactant (co-emulsifier), an oil phase, and a water phase are necessary. Suitable surfactants include any surfactants that are useful in the preparation of emulsions, e.g., emulsifiers that are typically used in the preparation of creams. The co-surfactant (or "co-emulsifer") is generally selected from the group of polyglycerol derivatives, glycerol derivatives, and fatty alcohols. Preferred emulsifier/co-emulsifier combinations are generally although not necessaπly selected from the group consisting of: glyceryl monostearate and polyoxyethylene stearate; polyethylene glycol and ethylene glycol palmitostearate; and capπlic and capπc triglycerides and oleoyl macrogolglyceπdes. The water phase includes not only water but also, typically, buffers, glucose, propylene glycol, polyethylene glycols, preferably lower molecular weight polyethylene glycols (e.g., PEG 300 and PEG 400), and/or glycerol, and the like, while the oil phase will generally compπse, for example, fatty acid esters, modified vegetable oils, silicone oils, mixtures of mono- di- and triglycerides, mono- and di-esters of PEG (e.g., oleoyl macrogol glyceπdes), etc.

[0359] Gel formulations are semisolid systems consisting of either small inorganic particle suspensions (two-phase systems) or large organic molecules distributed substantially uniformly throughout a carrier liquid (single phase gels). Single phase gels can be made, for example, by combining the active agent, a earner liquid and a suitable gelling agent such as tragacanth (at 2 to 5%), sodium alginate (at 2-10%), gelatin (at 2-15%), methylcellulose (at 3-5%), sodium carboxymethylcellulose (at 2-5%), carbomer (at 0.3-5%) or polyvinyl alcohol (at 10-20%) together and mixing until a characteristic semisolid product is produced. Other suitable gelling agents include methylhydroxycellulose, polyoxyethylene-polyoxypropylene, hydroxyethylcellulose and gelatin. Although gels commonly employ aqueous earner liquid, alcohols and oils can be used as the carrier liquid as well.

[0360] Various additives, known to those skilled in the art, may be included in the topical formulations of the invention. Examples of additives include, but are not limited to, solubihzers, skm permeation enhancers, opacifiers, preservatives (e.g., anti-oxidants), gelling agents, buffeπng agents, surfactants (particularly nonionic and amphoteric surfactants), emulsifiers, emollients, thickening agents, stabilizers, humectants, colorants, fragrance, and the like Inclusion of solubilizers and/or skm permeation enhancers is particularly preferred, along with emulsifiers, emollients, and preservatives.

[0361] Examples of solubilizers include, but are not limited to, the following: hydrophilic ethers such as diethylene glycol monoethyl ether (ethoxydiglycol, available commercially as Transcutol^™) and diethylene glycol monoethyl ether oleate (available commercially as Softcutol^™); polyethylene castor oil deπvatives such as polyoxy 35 castor oil, polyoxy 40 hydrogenated castor oil, etc.; polyethylene glycol, particularly lower molecular weight polyethylene glycols such as PEG 300 and PEG 400, and polyethylene glycol deπvatives such as PEG-8 caprylic/capπc glyceπdes (available commercially as Labrasol ); alkyl methyl sulfoxides such as DMSO; pyrrohdones such as 2-pyrrolidone and N-methyl-2-pyrrolidone; and DMA. Many solubilizers can also act as absorption enhancers A single solubihzer may be incorporated into the formulation, or a mixture of solubilizers may be incorporated therein.

[0362] Suitable emulsifiers and co-emulsifiers include, without limitation, those emulsifiers and co-emulsifϊers descπbed with respect to microemulsion formulations. Emollients include, for example, propylene glycol, glycerol, isopropyl myristate, polypropylene glycol-2 (PPG-2) myπstyl ether propionate, and the like.

[0363] Other active agents may also be included in the formulation, e.g., anti-inflammatory agents, analgesics, antimicrobial agents, antifungal agents, antibiotics, vitamins, antioxidants, and sunblock agents commonly found m sunscreen formulations including, but not limited to, anthranilates, benzophenones (particularly benzophenone-3), camphor denvatives, cmnamates (e g , octyl methoxycmnamate), dibenzoyl methanes (e.g., butyl methoxydibenzoyl methane), p-aminobenzoic acid (PABA) and deπvatives thereof, and salicylates (e.g , octyl salicylate).

[0364] In the preferred topical formulations of the invention, the active agent is present in an amount in the range of approximately 0.25 wt. % to 75 wt % of the formulation, preferably in the range of approximately 0.25 wt. % to 30 wt. % of the formulation, more preferably in the range of approximately 0.5 wt. % to 15 wt. % of the formulation, and most preferably in the range of approximately 1.0 wt. % to 10 wt. % of the formulation

[0365] Also, the pharmaceutical formulation may be steπhzed or mixed with auxiliary agents, e g , preservatives, stabilizers, wetting agents, buffers, or salts for influencing osmotic pressure and the like. Sterile injectable solutions are prepared by incorporating the compound of Formula I or Formula II m the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered steπhzation. Generally, dispersions are prepared by incorporating the various steπhzed active ingredients into a steπle vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of steπle powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0366] Another formulation for use in the methods of the present invention employs transdermal delivery devices ("patches")- Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known m the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0367] SCD inhibitors such as the compounds of Formula I are effective over a wide dosage range and are generally administered in a pharmaceutically effective amount Typically, for oral administration, each dosage unit contains from 1 mg to 2 g of an SCD inhibitor, more commonly from 1 to 700 mg, and for parenteral administration, from 1 to 700 mg of a stearoyl- CoA desaturase inhibitor, more commonly about 2 to 200 mg. It will be understood, however, that the amount of the SCD inhibitor actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0368] For prepaπng solid compositions such as tablets, the pπncipal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules

[0369] The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeπc acids with such materials as shellac, cetyl alcohol, and cellulose acetate

[0370] Compositions for inhalation or insufflation include solutions and suspensions m pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as descπbed supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, e.g. orally or nasally, from devices that deliver the formulation in an appropriate manner.

[0371] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spiπt and scope of the invention.

EXAMPLE 1 Preparation of a Compound of Formula (2)

A. Preparation of a Compound of Formula (2) in which W¹ is CH, W² is N, R¹ is -

CH₂CH₂NHC(O)CH₁

[0372] To a solution of 3.Og (15 5 mmol) 2,6-dichloro-3-nitropyridine in 50 mL of THF at -78 ⁰C under Ar atmosphere was added 2 7 mL (15.5 mmol) of N,N-dnsopropylethylamine followed by 1 6 mL (15.5 mmol) of N-acetylethylenediamine. The mixture was stirred at -78 ⁰C for 30 min, allowed to warm to room temperature, and stirred for 72 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with MeOH/dichloromethane gradient (1 -> 10%) to provide N-(2-(6-chloro-3-nitropyridin-2- ylamino)ethyl)acetamide as pale yellow solid.

B. Preparation of Compounds of Formula (2) varying R¹

[0373] Similarly, following the procedure of Example IA above, but optionally substituting other compounds of formula (1) for 2,6-dichloro-3-nitropyridine, and optionally substituting other amines of formula R¹NH₂ for acetylethylenediamine, the following compound of formula (2) was prepared:

(tert-butoxy)-N-{2-[(6-chloro-3-nitro(2-pyridyl))amino]ethyl}carboxamide.

C. Preparation of Compounds of Formula (2) varying R¹

[0374] Similarly, following the procedure of Example 2A above, but optionally substituting other compounds of formula (1) for 2,6-dichloro-3-nitropyridine, and optionally substituting other amines of formula R¹NH₂ for acetylethylenediamine, other compounds of formula (2) are prepared.

EXAMPLE 2 Preparation of a Compound of Formula (3)

A. Preparation of a Compound of Formula (3) in which W¹ is CH. W² is N, R¹ is - CH₂CH₂NHC(O)OC(CH^₂. and R² is 3,4-Dichlorophenyl

[0375] 900 mg of (tert-butoxy)-N-{2-[(6-chloro-3-nitro(2-pyridyl))amino]ethyl}carboxamide, as prepared in Example 1, was combined with 990 μL of N,N-diisopropylethylamine and 760 μL of 3,4-dichlorobenzylamme in 10 mL of THF The mixture was stirred at 90 ⁰C for 16 h Significant precipitate had formed. The solution was concentrated down to form a yellow residue which was resuspended in MeOH. N-{2-[(6-{[(3,4-dichlorophenyl)methyl]amino}-3- nitro(2-pyridyl))ammo]ethyl}(tert-butoxy)carboxamide was filtered out as yellow precipitate. The product was used in the next step without further purification.

B Preparation of Compounds of Formula (3) varying R¹ and R²

[0376] Similarly, following the procedure of Example 2A above, but optionally substituting other compounds of formula (2) for (tert-butoxy)-N-{2-[(6-chloro-3-nitro(2- pyπdyl))amino]ethyl}carboxamide, and optionally substituting other amines of formula R²NH₂ for 3,4-dichlorobenzylamine, the following compounds of formula (3) were prepared:

[0377] N-{2-[(6-{[(3,4-dichlorophenyl)methyl]ammo}-3-nitπ>-2- pyπdyl)ammo] ethyl} acetamide;

[0378] N-{2-[(6-{[(4-fluorophenyl)methyl]amino}-3-mtro-2-pyπdyl)amino]ethyl}acetamide; [0379] N-{2-[(6-{[(3-chlorophenyl)methyl]amino}-3-nitro-2-pyridyl)ammo]ethyl}acetamide;

[0380] N-{2-[(6-{[(3-chloro-4-fluorophenyl)methyl]ammo}-3-nitro-2- pyridyl)ammo]ethyl}acetamide;

[0381] 3-[(6-{[(3,4-dichlorophenyl)methyl]ammo}-3-nitro-2-pyridyl)amino]propanamide;

[0382] N-(2-{[3-nitro-6-({[3-(tπfluoromethyl)phenyl]methyl}amino)-2- pyπdyl]amino} ethyl)acetamide;

[0383] N-(2-{[3-mtro-6-({[4-(tnfluoromethyl)phenyl]methyl}ammo)-2- pyπdyl]amino} ethyl)acetamide;

[0384] {6-[((3S)pyrrohdin-3-yl)ammo]-5-mtro(2-pyπdyl)} [(3,4- dichlorophenyl)methyl]amme;

[0385] ethyl 4-[(6- { [(3 ,4-dichlorophenyl)methyl]amino} -3 -mtro-2-pyπdyl)amino]butanoate; [0386] 3 4-[(6-{[(3,4-dichlorophenyl)methyl]amino}-3-mtro-2-pyridyl)amino]butanoic acid; [0387] ethyl 3-[(6-{[(3,4-dichlorophenyl)methyl]ammo}-3-nitro-2-pyridyl)ammo]propanoate; [0388] 3-[(6-{[(3,4-dichlorophenyl)methyl]amino}-3-mtro-2-pyridyl)amino]propanoic acid; [0389] N-{2-[(6-{[(3-bromophenyl)methyl]amino}-3-nitro-2-pyridyl)amino]ethyl}acetamide; [0390] N-(2-{[6-({[3,5-bis(trifluoromethyl)phenyl]methyl}amino)-3-nitro-2- pyπdyl]amino} ethyl)acetamide;

[0391] N-(2-{[6-({[4-fluoro-3-(tπfluoromethyl)phenyl]methyl}amino)-3-nitro-2- pyridyl]amino}ethyl)acetamide;

[0392] N-(2-{[3-nitro-6-({[6-(tπfluoromethyl)(2-pyridyl)]methyl}amino)-2- pyπdyl] ammo } ethyl)acetamide ;

[0393] N-(2-{[3-mtro-6-({[5-(trifluoromethyl)(3-pyπdyl)]methyl}amino)-2- pyπdyl]amino}ethyl)acetamide; and

[0394] 2- { [3 -mtro6-( { [3 -(tπfluoromethyl)phenyl]methyl } amino)-2-pyndyl]ammo} ethan- 1 - ol .

Preparation of Compounds of Formula (3) varying R and R²

[0395] Similarly, following the procedure of Example 2A above, but optionally substituting other compounds of formula (2) for (tert-butoxy)-N-{2-[(2-chloro-5-nitropyπmidm-4- yl)amino]ethyl}carboxamide, and optionally substituting other amines of formula R²NH₂ for 3,4-dichlorobenzylamine, other compounds of formula (3) are prepared.

EXAMPLE 3 Preparation of a Compound of Formula I

A. Preparation of a Compound of Formula I in which W¹ is CH, W² is N, R¹ is - CH₇CH^NHC(COCH,. R² IS 3.4- Dichlorophenyl. and R³ is 4-Methoxyphenvl

[0396] N-(2-(6-(3,4-dichlorobenzylamino)-3-nitropyridin-2-ylamino)ethyl)acetamide, as prepared in Example 2, was dissolved m 70 mL of 1 :1 mixture of dioxane and water and 1.7 g OfNa₂S₂O₄ (85% tech. grade, 2.9 mmol) and 1.1 g OfNa₂CO₃ (8.5 mmol) were added. The mixture was stirred at room temperature for 10 min under the blanket of nitrogen, diluted with 50 mL of water, and extracted 3 times with 20 mL portions of EtOAc. Combined organic layers were washed with 20 mL of brine and concentrated. The residue was dissolved in 20 mL of 2% v/v AcOH in EtOH containing 130 mg (1.2 mmol) of ethyl 2-(4-methoxyphenyl)-2- oxoacetate. The reaction mixture was stirred at 80 ⁰C for 6 h. The resulting suspension was concentrated down and subjected to chromatography eluting with 5% MeOH in dichloromethane. N-[2-(6- { [(3 ,4-dichlorophenyl)methyl]amino } -2-(4-methoxyphenyl)-3 -oxo- 4-hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetarnide was obtained as a yellow solid.

¹H NMR (δ, 400 MHz, CDCl₃) 8.27 (d, 2H); 7.90 (d, IH); 7.48 (m, IH); 7.43 (d, IH); 7.23 (dd, IH); 6.98 (d, 2H); 6.48 (d, IH); 6.20 (bs, IH); 5.44 (t, IH); 4.66 (d, 2H); 4.59 (t, 2H); 3.87 (s, 3H); 3.65 (q, 2H); 1.90 (s, 3H).

B. Preparation of Compounds of Formula I varying R¹. R², and R³

[0397] Similarly, following the procedure of Example 3 A above, but optionally substituting other compounds of formula (3) for N-(2-(6-(3,4-dichlorobenzylamino)-3-nitropyridin-2- ylamino)ethyl)acetamide, and optionally substituting other oxoacetate of formula (5) for ethyl 2-(4-methoxyphenyl)-2-oxoacetate, the following compounds of Formula I were prepared:

[0398] Ν-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo(4- hydropyridino[2,3-b]pyrazin-4-yl))ethyl](tert-butoxy)carboxamide;

[0399] N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0400] N-[2-(6-{[(4-fluorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0401] N-[2-(6-{[(3-chlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0402] N-[2-(6-{[(3-chloro-4-fluorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridmo[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0403] N- {2-[2-(4-methoxyphenyl)-3-oxo-6-( { [3-(trifluoromethyl)phenyl]methyl } amino)-4- hydropyridino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

[0404] N- {2-[2-(4-methoxyphenyl)-3-oxo-6-( { [4-(trifluoromethyl)phenyl]methyl} amino)-4- hydropyridino[2,3-b]pyrazin-4-yl]ethyl}acetamide; [0405] N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methylthiophenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0406] N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methylphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0407] N-[2-(6- { [(3-bromophenyl)methyl]amino} -2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0408] N-{2-[6-({[3,5-bis(trifluoromethyl)phenyl]methyl}amino)-2-(4-methoxyphenyl)-3- oxo-4-hydropyridino[2,3-b]pyrazin-4-yl]ethyl } acetamide;

[0409] N-{2-[6-({[4-fluoro-3-(trifluoromethyl)phenyl]methyl}amino)-2-(4-methoxyphenyl)-3- oxo-4-hydropyridino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

[0410] N-{2-[2-(4-methoxyphenyl)-3-oxo-6-({[5-(trifluoromethyl)(3-pyridyl)]methyl}amino)- 4-hydropyridino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

[0411] N-(2-{2-(4-methoxyphenyl)-3-oxo-6-[benzylamino]-4-hydropyridino[2,3-b]pyrazin-4- yl}ethyl)acetamide;

[0412] N-(2-{2-(4-methoxyphenyl)-3-oxo-6-[(3-pyridylmethyl)amino]-4-hydropyridino[2,3- b]pyrazin-4-yl} ethyl)acetamide;

[0413] N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-3-oxo-2-(3-pyridyl)-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide ;

[0414] N-[2-(6-{[(3-chloro-4-fluorophenyl)methyl]araino}-3-oxo-2-(3-pyridyl)-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

[0415] N- {2-[3 -oxo-2-(3 -pyridyl)-6-( { [3 -(trifluoromethyl)phenyl]methyl } amino)-4- hydropyridino[2,3-b]pyrazin-4-yl]ethyl} acetamide;

[0416] N-{2-[3-oxo-2-(trifluoromethyl)-6-({[3-(trifluoromethyl)phenyl]methyl}amino)-4- hydropyridino[2,3-b]pyrazin-4-yl]ethyl} acetamide;

[0417] N-{2-[2-methyl-3-oxo-6-({[3-(trifluoromethyl)phenyl]methyl}amino)-4- hydropyridino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

[0418] N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-methyl-3-oxo-4-hydropyridino[2,3- b]pyrazin-4-yl)ethyl]acetamide;

[0419] ethyl 3 -(6- { [(3 ,4-dichlorophenyl)methyl]amino } -2-(4-methoxyphenyl)-3 -oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)propanoate; [0420] ethyl 4-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyπdino[2,3-b]pyrazin-4-yl)butanoate,

[0421] 3-[3-oxo-2-(3-pyridyl)-6-({[3-(tnfluoromethyl)phenyl]methyl}amino)-4- hydropyridino[2,3-b]pyrazm-4-yl]propanamide,

[0422] 3-(6-{[(3,4-dichlorophenyl)methyl]ammo}-3-oxo-2-(3-pyridyl)-4-hydropyπdino[2,3- b]pyrazin-4-yl)propanamide;

[0423] 3-(6-{[(3,4-dichlorophenyl)methyl]ammo}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridmo[2,3-b]pyrazm-4-yl)propanamide;

[0424] 3 -[2-(4-methoxyphenyl)-3 -oxo-6-( { [3 -(trifluoromethyl)phenyl]methyl } ammo)-4- hydropyridino[2,3-b]pyrazin-4-yl]butanamide,

[0425] 4-(2-hydroxyethyl)-2-(4-methoxyphenyl)-6-({[3- (tπfluoromethyl)phenyl]methyl}amino)-4-hydropyπdmo[3,2-b]pyrazm-3-one; and

[0426] 3-[2-(4-methoxyphenyl)-3-oxo-6-({[3-(trifluoromethyl)phenyl]methyl}ammo)-4- hydropyridino[2,3-b]pyrazm-4-yl]propanamide.

C. Preparation of Compounds of Formula I varying R¹, R², and R³

[0427] Similarly, following the procedure of Example 3 A above, but optionally substituting other compounds of formula (3) for N-(2-(6-(3,4-dichlorobenzylammo)-3-nitropyridin-2- ylamino)ethyl)acetamide, and optionally substituting other oxoacetate of formula (5) for ethyl 2-(4-methoxyphenyl)-2-oxoacetate, other compounds of Formula I are prepared.

EXAMPLE 4 Preparation of a Compound of Formula I

A. Preparation of a Compound of Formula I in which W¹ is CH, W² is Ν, R¹ is - CH,CH,ΝH,. R² is 3.4- DichlorophenvL and R³ is 4-Methoxvphenvl

[0428] N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo(4- hydropyridino[2,3-b]pyrazin-4-yl))ethyl](tert-butoxy)carboxamide(150 mg, 0 26 mmol), prepared as descπbed in Example 3, was dissolved in dioxane (1 mL) and reacted with 4N HCl in dioxane (2 mL) at room temperature for 1 hour. The solution turned dark red and precipitate formed The precipitate was filtered off to provide 4-(2-ammoethyl)-6-{[(3,4- dichlorophenyl)methyl]ammo} -2-(4-methoxyphenyl)-4-hydropyridmo[3,2-b]pyrazm-3-one as a dark red solid.

B. Preparation of Compounds of Formula I varying R² and R³

[0429] Similarly, following the procedure of Example 4A above, but optionally substituting other compounds of Formula I having protected R¹ groups for N-[2-(2-{[(3,4- dichlorophenyl)methyl]amino}-6-(4-methoxyphenyl)-7-oxo(8-hydropteπdin-8-yl))ethyl](tert- butoxy)carboxamide, other compounds of Formula I are prepared.

EXAMPLE 5 Preparation of a Compound of Formula I

A. Preparation of a Compound of Formula I in which W¹ is CH, W² is N, R' is - CH,CH,NHCH(O), R² is 3.4- Dichlorophenyl. and R³ is 4-Methoxyphenyl

[0430] To a suspension of crude 4-(2-aminoethyl)-6-{[(3,4-dichlorophenyl)methyl]amino}-2- (4-methoxyphenyl)-4-hydropyridmo[3,2-b]pyrazin-3-one, as prepared in Example 4, (85 mg, 0.17 mmol) was reacted as a suspension in MeCN (2 mL) with dnsopropylethylamme (0.07 mL) and methyl formate (0.6 mL) in a microwave vessel at 150⁰C for 35 mm. After cooling off the mixture was concentrated and residue purified by chromatography (5% MeOH in dichloromethane) to provide N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4- methoxyphenyl)-3-oxo-4-hydropyridino[2,3-b]pyrazin-4-yl)ethyl]carboxamide as a yellow solid B. Preparation of Compounds of Formula I varying R¹, R , and R

[0431] Similarly, following the procedure of Example 5A above, but optionally substituting other compounds of Formula I having a terminal R¹ amino group for 8-(2-aminoethyl)-2- {[(3,4-dichlorophenyl)methyl]amino}-6-(4-methoxyphenyl)-8-hydropteπdin-7-one or optionally replacing methyl formate with other R⁵ derivatives, the following other compounds of Formula I were prepared:

[0432] N-{2-[2-(4-methoxyphenyl)-3-oxo-6-({[3-(trifluoromethyl)phenyl]methyl}ammo)-4- hydropyridino[2,3-b]pyrazin-4-yl]ethyl}carboxamide;

[0433] N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-3-oxo-2-(3-pyπdyl)-4- hydropyπdino[2,3-b]pyrazm-4-yl)ethyl]carboxamide; and

[0434] N-{2-[3-oxo-2-(3-pyπdyl)-6-({[3-(tπfluoromethyl)phenyl]methyl}ammo)-4- hydropyndmo[2,3-b]pyrazin-4-yl]ethyl}carboxamide.

Preparation of Compounds of Formula I varying R¹, R², and R³

[0435] Similarly, following the procedure of Example 5 A above, but optionally substituting other compounds of Formula I having a terminal R¹ ammo group for 8-(2-aminoethyl)-2- {[(3,4-dichlorophenyl)methyl]ammo}-6-(4-methoxyphenyl)-8-hydroptendm-7-one or optionally replacing methyl formate with other R⁵ deπvatives other compounds of Formula I are prepared.

EXAMPLE 6 Preparation of a Compound of Formula I

A. Preparation of a Compound of Formula I m which W¹ is CH, W² is N, R¹ is CH,CH,NHαC0OH. R² is 3.4- Dichlorophenyl, and R³ is 4-Methoxyphenyl

[0436] Crude starting material ethyl 3-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4- methoxyphenyl)-3-oxo-4-hydropyridmo[2,3-b]pyrazin-4-yl)propanoate, as made in Example 3, (20 mg, 0.038 mmol) was reacted with LiOH monohydrate (3.1 mg, 0.077 mmol) in 1: 1 1 THF/MeOH/water mixture (20 mL) overnight at room temperature. The reaction was diluted with water and IN HCl was added to acidify the mixture. The solution was extracted 3 times with EtOAc to afford 3-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo- 4-hydropyridino[2,3-b]pyrazin-4-yl)propanoic acid after concentration as a yellow solid.

B. Preparation of Compounds of Formula I varying R¹, R², and R³

[0437] Similarly, following the procedure of Example 6A above, but optionally substituting other compounds of Formula I having a R¹ ester group for ethyl 3 -(6- { [(3,4- dichlorophenyl)methyl]ammo}-2-(4-methoxyphenyl)-3-oxo-4-hydropyπdmo[2,3-b]pyrazm-4- yl)propanoate, the following other compound of Formula I was prepared:

4-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridmo[2,3-b]pyrazm-4-yl)butanoic acid.

C. Preparation of Compounds of Formula I varying R¹. R², and R³

[0438] Similarly, following the procedure of Example 6A above, but optionally substituting other compounds of Formula I having a R¹ ester group for ethyl 3-(6-{[(3,4- dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4-hydropyπdino[2,3-b]pyrazin-4- yl)propanoate, other compounds of Formula I are prepared.

EXAMPLE 7

Preparation of a Compound of Formula I

A Preparation of a Compound of Formula I in which W¹ is CH, W² is CH, R' is -CH,CHτNHC(O)NH,. R² IS 3-(trifluoromethyl)phenyl. and R³ is methyl

1 -(2-amιnoethyl)-3-methyl-7-(3-

(trιfluoromethyl)benzylamιno)quιn oxalιn-2(1H)-one

[0439] Compounds of Formula I in which R¹ includes a urea moiety can be synthesized from primary amines in a variety of ways using phosgene, tπphosgene, carbonyldiimidazole, and others as coupling reagents. One preferred way includes the use of the reagent phenyl carbamate (Young, RJ. et al, Bioorg. Med Chem Lett 2006, 16, 5953-7). Starting material 1- (2-ammoethyl)-3-methyl-7-(3-(tπfluoromethyl)benzyl-ammo)qumoxahn-2(lH)-one (50 mg) was heated to reflux in THF for 2 h m the presence of N-methyl morpholme (0.16 mmol) and phenyl carbamate (0.16 mmol). The reaction mixture was concentrated and purified by chromatography using 6% MeOH in dichloromethane as eluent. Product l-(2-(3-methyl-2-oxo- 7-(3-(tπfluoromethyl)benzyl-ammo)quinoxalin-l(2H)-yl)ethyl)urea was isolated as off-white solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 7 90 (s, IH); 7.80 (s, IH); 7.60 - 7.55 (m, 2H); 7.40 (d, IH); 7.12 (t, IH), 6 83 (s, IH); 6.69 (d, IH); 6.29 (broad t, IH); 5 64 (s, 2H); 4.57 (d, 2H); 4 09 (quartet, 2H); 3.19 (quartet, 2H); and 2.32 (s, 3H).

MS (ESI) m/z 420.2 (base peak)

EXAMPLE 8 Preparation of Compounds of Formula I

[0440] Other compounds of Formula I were obtained from l-(2-aminoethyl)-3 -methyl -7-(3- (tπfluoromethyl)benzylammo)qumoxalin-2(lH)-one by reaction with optionally substituted acid chloπdes in chloroform in the presence of tπethylamine at room temperature. In each case, the product was isolated by chromatography using 5% MeOH in dichloromethane. Compounds obtained in this fashion included

[0441] N-(2-(3-methyl-2-oxo-7-(3-(tnfluoromethyl)benzylamino)qumoxahn-l(2H)- yl)ethyl)thiophene-3-carboxamide; and

[0442] 3-(2-(3-methyl-2-oxo-7-(3-(trifluoromethyl)benzylammo)qumoxahn-l(2H)- yl)ethylamino)-3-oxopropane-l ,2-diyl diacetate.

EXAMPLE 9 Preparation of Compounds of Formula I

[0443] Hydrolysis of ester moieties in -(2-(3-methyl-2-oxo-7-(3-(tπfluoromethyl) benzylammo)quinoxahn-l(2H)-yl)ethylamino)-3-oxopropane-l,2-diyl diacetate with aid of LiOH in 1 :1 :1 mixture of water, THF, and methanol provided the following compound:

[0444] 2,3-dihydroxy-N-(2-(3-methyl-2-oxo-7-(3-(tπfluoromethyl)benzylammo) quinoxalm- 1 (2H)-yl)ethyl)propanamide.

EXAMPLE 10 Preparation of Compounds of Formula I

[0445] Other compounds of Formula I were obtained from l-(2-ammoethyl)-3-methyl-7-(3- (tπfluoromethyl)benzylammo)quinoxalm-2(lH)-one by reaction with optionally substituted carboxylic acids in the presence of EDC and HOBt in DMF at room temperature. In each case, the product was isolated by chromatography using 5% MeOH in dichloromethane. Compounds obtained in this fashion included:

[0446] 3-hydroxy-Ν-(2-(3-methyl-2-oxo-7-(3-(trifluoromethyl) benzylamino)qumoxalin- 1 (2H)-yl)ethyl)propanamide;

[0447] (R)-2-hydroxy-N-(2-(3-methyl-2-oxo-7-(3-(tπfluoromethyl) benzylamino)quinoxalin- l(2H)-yl)ethyl)propanamide, and

[0448] (S)-2-hydroxy-N-(2-(3-methyl-2-oxo-7-(3-(trifluoromethyl) benzylamino)quinoxalm- 1 (2H)-yl)ethyl)propanamide. EXAMPLE 11 Preparation of Compounds of Formula I

3-(3-methyl-2-oxo-7-(3-

(tπfluoromethyl)benzylamιno)quιn oxalιn-1 (2H)-yl)propanoιc acid

[0449] Compounds of Formula I in which R¹ includes an amide moiety may be made using well known coupling agents, such as N,N'-dicyclohexylcarbodnmide (DCC), l-ethyl-3-(3- dimethylammopropyl) carbodiimide hydrochloπde (EDC), O-(7-Azabenzotπazol-l-yl)- N,N,N',N'-tetramethyluromum hexafluorophosphate (HATU), O-Benzotπazole-N,N,N',N'- tetramethyluronium hexafluorophosphate (HBTU), or O-Benzotriazol-l-yl-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU).

[0450] In this example 3-(3-methyl-2-oxo-7-(3-(tπfluoromethyl)benzylamino)-quinoxahn- l(2H)-yl)propanoic acid (50 mg) was dissolved in chloroform (1 mL). HOBt (20 mg), EDC hydrochloπde (29 mg), tπethylamine (75 μL), and ethanolamine (9 μL) were added sequentially to the reaction flask and stirred overnight. Concentrated and residue chromatographed on silica gel using 5% MeOH in dichloromethane as eluent. Product N-(2- hydroxyethyl)-3 -(3 -methyl -2 -oxo-7-(3 -(tπfluoromethyl)benzylamino)-qumoxahn- 1 (2H)- yl)propanamide is isolated as yellow solid.

¹H ΝMR (DMSO-d₆, 400 MHz) δ 8.01 (t, IH); 8.12 (broad t, IH); 7.79 (s, IH); 7.76 (d, IH); 7.60 - 7.55 (m, 2H); 7.43 (d, IH); 7.18 (t, IH); 6.68 (dd, IH); 4.67 (t, IH); 4.51 (d, 2H); 4.26 (t, 2H); 3.40 (quartet, 2H); 3.15 (quartet, 2H); 2.39 (t, 2H); and 2.33 (s, 3H).

MS (ESI) m/z 449.2, 471.2, 919.4 (base peak).

EXAMPLE 12 Alternative Synthetic Scheme for Compounds of Formula I Formula I

[0451] The compound of formula (8) is obtained by reacting amine with the compound of formula (7) in appropπate organic solvent (THF, acetonitπle, DMF, or other). Heating may lead to faster completion of the reaction. The resulting nitro compound of formula (8) undergoes reaction with a reducing agent (hydrazine is preferred) in the presence of metal or metal salt. Raney Nickel is the preferred catalyst. The resulting aniline (9) may not need to be purified and may be used directly for cychzation with α-ketoester in organic solvent (ethanol is preferred) in the presence of acid catalyst (AcOH is the preferred catalyst) to produce compounds of Formula (10). Finally, compounds of Formula (10) can be coupled with an amine (R²-Q-NH²) using metal catalyst such as copper or palladium or other (palladium is preferred) in the presence of hgand (organic alcohol, or amine, or phenol, preferred hgand is BEST AP) in organic solvent (THF is preferred) to produce compounds of Formula I.

EXAMPLE 13

4-bromo-2-fluoro-

1 -nitrobenzene

A. Synthesis of Compound of Formula (8).

[0452] To a suspension of 4-bromo-2-fluoro-l -nitrobenzene (2.0 g) in ACN (15 mL) was added 0.56 g of N-acetylethylenediamine followed by 0.96 mL of NN-diisopropylethylamine. The mixture was stirred at 60 ⁰C for 1 h. After cooling down to room temperature N-(2-(5- bromo-2-nitrophenylamino)ethyl)acetamide was filtered out as yellow precipitate. Product was used in the next step without further purification.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.32 (broad t, IH); 8.12 (broad t, IH); 7.99 (d, IH); 7.38 (d, IH); 6.84 (dd, IH); 3.43 (quartet, 2H); 3.27 (quartet, 2H); and 1.82 (s, 3H).

MS (ESI) m/z 301.9, 628.9, 626.9 (base peak).

B. Further compounds of Formula (8).

[0453] Similarly, but optionally substituting N-acetylethylenediamine with N-Boc- ethylenediamine, the following compound was obtained:

[0454] tert-butyl 2-(5-bromo-2-nitrophenylamino)ethylcarbamate.

[0455] Similarly, but optionally substituting 4-bromo-2-fluoro-l -nitrobenzene with 5-bromo- 2-chloro-3-nitropyridine or 5-bromo-2-fluoro-l-nitrobenzene the following compounds were prepared:

[0456] Ν-(2-(5-bromo-3-nitropyridin-2-ylamino)ethyl)acetamide; and [0457] N-(2-(4-bromo-2-nitrophenylamino)ethyl)acetamide.

EXAMPLE 14

Λ/-(2- nitrop ethyl ^HAc

A. Synthesis of Compound Formula (9).

[0458] N-(2-(5-bromo-2-nitrophenylamino)ethyl)acetamide (1.0 g) was dissolved in MeOH (20 mL) by heating to 80 ⁰C. Hydrazine was added (1.6 mL) followed by Raney Nickel (50% slurry in water, 6 drops) and the reaction mixture was heated to reflux for 1 h. Filtered through Celite® and concentrated to amber oil containing mostly product by LC/MS. Used for next step without further purification. B Further compounds of Formula (9).

[0459] Similarly, but optionally substituting N-(2-(5-bromo-2-nitrophenylammo)ethyl)- acetamide with corresponding N-Boc derivative, the following compound was obtained:

[0460] tert-butyl 2-(2-amino-5-brornophenylamino)ethylcarbarnate.

[0461] Similarly, but optionally substituting N-(2-(5-bromo-2-nitrophenylamino)ethyl)- acetamide with N-(2-(5-bromo-3-nitropyπdm-2-ylamino)ethyl)acetamide or with N-(2-(4- bromo-2-nitrophenylamino)ethyl)acetamide, the following compounds were obtained:

[0462] Ν-(2-(3-amino-5-bromopyndin-2-ylamino)ethyl)acetamide; and [0463] N-(2-(2-ammo-4-bromophenylammo)ethyl)acetamide.

EXAMPLE 15

A Synthesis of Compound Formula (10)

[0464] To a solution of crude N-(2-(2-ammo-5-bromophenylammo)ethyl)acetamide from Example 14 m ethanol (0.74 mL) 870 mg of ethyl 2-(4-methoxyphenyl)-2-oxoacetate was added. To that mixture acetic acid was added resulting in of 1% v/v AcOH in EtOH solution. The reaction mixture was stirred at 80 ⁰C for 18 h and allowed to cool to room temperature. The yellow precipitate was collected by filtration and washed with two 5 mL portions of EtOH. The yellow solid was dπed under vacuum to provide N-(2-(7-bromo-3-(4-methoxyphenyl)-2- oxoquinoxahn- 1 (2H)-yl)ethyl)acetamide. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.36 (m, 2H); 8.12 (broad t, IH); 7.93 (d, IH); 7.79 (d, IH); 7.54 (dd, IH); 7.07 (m, 2H); 4.31 (t, 2H); 3.39 (quartet, IH); and 1.75 (s, 3H).

MS (ESI) m/z 418.0, 855.0 (base peak).

B. Further compounds of formula (10).

[0465] Similarly, but optionally substituting N-(2-(2-amino-5-brornophenylammo) ethyl)acetamide with corresponding N-Boc derivative, and substituting ethyl 2-(4- methoxyphenyl)-2-oxoacetate with other ketoesters the following compounds were obtained:

[0466] tert-butyl 2-(7-bromo-3 -methyl -2 -oxoquinoxalin-l(2H)-yl)ethylcarbamate; and [0467] tert-butyl 2-(7-bromo-2-oxo-3-(trifluoromethyl)quinoxalin-l (2H)-yl)ethylcarbamate.

[0468] Similarly, but optionally substituting N-(2-(2-amino-5-bromophenylamino) ethyl)acetamide with N-(2-(3-amino-5-bromopyridin-2-ylamino)ethyl)acetamide or with N-(2- (2-amino-4-bromophenylamino)ethyl)acetamide, the following compounds were obtained:

[0469] Ν-(2-(7-bromo-2-(4-methoxyphenyl)-3-oxopyrido[3,2-b]pyrazin-4(3H)- yl)ethyl)acetamide; and

[0470] N-(2-(6-bromo-3-(4-methoxyphenyl)-2-oxoquinoxalin-l(2H)-yl)ethyl)acetamide.

[0471] Similarly, but optionally substituting ethyl 2-(4-methoxyphenyl)-2-oxoacetate with other ketoesters, the following compounds were prepared:

[0472] N-(2-(7-bromo-2-methyl-3-oxopyrido[3,2-b]pyrazin-4(3H)-yl)ethyl)acetamide.

EXAMPLE 16

yl)ethyl)acetamide

A. Synthesis of Compound Formula I via Amine Coupling

[0473] In a 5 mL Smith Process™ vial 4-chloro-3-(trifluoromethyl)benzylamine (0.18 mmol) was dissolved in THF (3 mL) followed by, sequentially, N-(2-(7-bromo-3-(4-methoxyphenyl)- 2-oxoquinoxalin-l(2H)-yl)ethyl)acetamide (0.12 mmol), sodium tert-butoxide (0.18 mmol), Pd₂(dba)₃ (5.5 mg), and BIΝAP (7.5 mg). The mixture was heated for 5 min at 120 ⁰C in Emrys Optimizer™ microwave reactor. The reaction mixture was concentrated and dissolved in 0.6 mL DMSO without any intermediate workup. Purification was performed using Gilson™ preparatory HPLC system using Phenomenex reverse phase C(18) column and water/acetonitrile as mobile phase with no buffer. After high-vacuum drying product was obtained as tan powder. The product of the reaction, N-(2-(7-(4-chloro-3- (trifiuoromethyl)benzylamino)-3 -(4-methoxyphenyl)-2-oxoquinoxalin- 1 (2H)- yl)ethyl)acetamide, is a compound of formula I in which R¹ is -CH₂CH₂NHAc, R² is 4-chloro- 3-(trifluoromethyl)benzyl, R³ is 4-methoxyphenyl.

¹H NMR (DMSO-d₆, 400 MHz) δ 8.25 (m, 2H); 8.02 (broad s, IH); 7.75 (broad d, IH); 7.70 (d, IH); 7.54 (d, IH); 7.39 (t, IH), 7.00 (m, 2H); 6.77 (dd, IH); 6.72 (broad s, IH); 4.60 (d, 2H), 4.16 (t, 2H); 3.28 (quartet, 2H); and 1.83 (s, 3H).

MS (ESI) m/z 545.1 , 1111.2 (base peak). B Further compounds of Formula I.

[0474] Similarly, following the procedure of Example 16A above, but optionally substituting 4-chloro-3-(tπfiuoromethyl)benzylamine with other amines, the following compounds were prepared:

[0475] N-(2-(7-(3-chlorophenethylamino)-3-(4-methoxyphenyl)-2-oxoqumoxahn-l(2H)- yl)ethyl)acetamide;

[0476] N-(2-(7-(2-(2-chlorophenoxy)ethylamino)-3-(4-methoxyphenyl)-2-oxoquinoxalm- 1 (2H)-yl)ethyl)acetamide;

[0477] N-(2-(3-(4-methoxyphenyl)-7-(3-methylbenzylamino)-2-oxoqumoxalin-l(2H)- yl)ethyl)acetamide;

[0478] N-(2-(7-(3 ,4-dimethylbenzylamino)-3 -(4-methoxyphenyl)-2-oxoqumoxalm- 1 (2H)- yl)ethyl)acetamide;

[0479] N-(2-(7-(4-chlorophenethylammo)-3-(4-methoxyphenyl)-2-oxoqumoxalin-l(2H)- yl)ethyl)acetamide;

[0480] N-(2-(7-(4-fluoro-3 -methylbenzylammo)-3 -(4-methoxyphenyl)-2-oxoqumoxahn- l(2H)-yl)ethyl)acetamide; and

[0481] N-(2-(3-(4-methoxyphenyl)-2-oxo-7-((4-(tπfluoromethyl)pyridin-2- yl)methylamino)quinoxahn- 1 (2H)-yl)ethyl)acetamide.

EXAMPLE 17

oxo

A. Alternative Amine Coupling Procedure for Synthesis of Compounds of Formula I.

[0482] N-(2-(7-bromo-2-(4-methoxyphenyl)-3-oxopyrido[3,2-b]pyrazin-4(3H)- yl)ethyl)acetamide (100 mg), proline (6 mg), copper iodide (5 mg), potassium carbonate (69 mg), and 3,4-dichlorobenzylamine (62 mg) were all placed into a 7 mL PFA vessel and suspended in DMSO (2 mL). Heated for 60 mm at 130 °C Purification consisted of flash chromatography followed by preparative reverse -phase chromatography using C(18) column with water and acetonitrile as mobile phase.

B. Further compounds of Formula I.

[0483] Similarly, following the procedure of Example 17A above, but optionally substituting 4-chloro-3-(tπfluorornethyl)benzylamine with benzylamme, and substituting N-(2-(7-bromo-2- (4-methoxyphenyl)-3-oxopyrido[3,2-b]pyrazm-4(3H)-yl)ethyl)acetamide with N-(2-(7-bromo- 2-methyl-3-oxopyπdo[3,2-b]pyrazin-4(3H)-yl)ethyl)acetamide the following compound was prepared:

[0484] N-(2-(7-(benzylamino)-2-methyl-3-oxopyrido[3,2-b]pyrazin-4(3H)-yl)ethyl)acetamide.

EXAMPLE 18

13 14

Formula I

Alternative Synthesis of Compounds Formula I.

[0485] Compounds of Formula (14) are obtained from 4-chloro-3-nitroanihne (13) by reaction with electrophilic reagents, for example acyl chloπdes, one of them being benzyl chloroformate (CbzCl). An appropriate organic solvent and base such as tπethylamine, dπsopropylethylamme, or pyridine are needed. Conversion of compounds (14) into compounds

(15) is similar to procedure described in Example 13. Reduction of compounds (15) into compounds (16) is similar to procedure descπbed in Example 14 Cychzation of compounds

(16) into compounds of Formula I is similar to procedure descπbed in Example 15. EXAMPLE 19

A Synthesis of Compound of Formula I.

[0486] In one example, 4-chloro-3-mtroaniline reacted with CbzCl in dichloromethane in the presence of dnsopropylethylamme. The product benzyl 4-chloro-3-nitrophenylcarbamate was isolated following flash chromatography. Following procedures in Examples 12, 13, and 15, final product benzyl l-(2-acetamidoethyl)-3-(4-methoxyphenyl)-2-oxo-l,2-dihydroquinoxalm- 6-ylcarbamate was isolated following reverse-phase HPLC with C(18) column eluting with water and acetonitπle. The product of the reaction, benzyl l-(2-acetamidoethyl)-3-(4- methoxyphenyl)-2-oxo-l,2-dihydroqumoxalin-6-ylcarbamate, is a compound of formula I in which R¹ is -CH₂CH₂NHAc, R² is benzyloxycarbonyl, R³ is 4-methoxyphenyl.

B. Further compounds of Formula I.

[0487] Similarly, following the procedure of Example 13 A above, but optionally substituting 2-(4-methoxyphenyl)-2-oxoacetate with 2-(3,4-dichlorophenyl)-2-oxoacetate the following compound was prepared:

[0488] benzyl 1 -(2-acetamidoethyl)-3-(3,4-dichlorophenyl)-2-oxo-l ,2-dihydroqumoxalm-6- ylcarbamate EXAMPLE 20 CHARACTERIZATION OF STEAROYL-CoA DESATURASE INHIBITOR

Mateπals and Methods Matenals

[0489] [³H]stearoyl CoA and stercuhc acid were obtained from PerkmElmer and Planta Piloto de Quimica Fina, respectively. Commercial sources of other reagents are listed below:

Matenal Company

[³H]H₂O PerkinElmer

Stearoyl CoA Sigma

CoA Sigma

NADH Sigma

Tπs, IM Invitrogen

MgC12 Sigma

BSA Sigma

DMSO Sigma

ATP Sigma

96-well plates Corning

Bio-Beads SM-2 Bio-Rad

Preparation of Rat Liver Microsomes

[0490] The rat liver microsomes were collected according to the procedure descπbed m Ozols (1990) Methods Enzm, 182:225 .

In vivo expeπment (Liver perfusion and collection^')

[0491] Male Spraque Dawley Rats were placed on regimented fasting protocol for one week to stimulate SCD enzymatic activity. 48-hour periods were alternated between feeding and fasting to induce and down-regulate SCD activity with SCD activity being induced via carbohydrate πch diet pπor to liver perfusion and collection.

[0492] The rats were anesthetized with Isoflurane inhalation anesthetic, the liver perfused with cold phosphate buffered saline (PBS), weighed, and chilled in cold homogenization buffer (250 mM sucrose, 10 mM Tπs, 1 mM EDTA, pH 7.6. [0493] The livers were finely minced and placed in homogenization tube. 40 mL of homogenization buffer was added to the homogenization tube and the liver homogenized and centrifuged in a pre-chilled SLA-600 TC at 800G rotor for 10 mm at 4°C.

[0494] Following centrifugation, the supernatant was collected and the pellet removed and discarded. This supernatant was then centrifuged at 10,000G for 35 minutes. Following centrifugation, the supernatant was collected and the pellet discarded. The supernatant was further centrifuged in a pre-chilled 45-Ti rotor at 130,000G (41,000 RPM) for 90 minutes at 4°C. .

In vitro (Microsomal collection)

[0495] The supernatant was then aspirated off and the collected microsomal pellet washed m 25 mL of Glycerol PBS (IX PBS 7.4, 20% Glycerol) and resuspended in 4-5 volumes of Glycerol PBS.

[0496] The protein concentration of the microsomal preparation was determined by BCA assay (Pierce) and the microsomes were ahquoted and stored at -80 ⁰C.

Preparation of Hydrophobic Beads

[0497] Biobeads were ground to a smaller size in a mortar and pestle and filtered through 300 μM mesh and then resuspended in 3.6% TCA.

Stock Solutions

[0498] Stock solutions and their storage conditions are listed below:

Solution Storage condition

20 mg/ml Stearoyl CoA -80 ⁰C

2.8 mCi/ml [³H] Stearoyl CoA -80 ⁰C

CoA freshly prepared

Sterculic acid freshly prepared

0.2 M NADH -80 ⁰C

1 M Tπs, pH 7.2 room temperature

1 M MgC12 room temperature

100 mM ATP -20 ⁰C 10% BSA 4 ⁰C

10-20 mg/ml microsome -80 ⁰C

The SCD Assay Buffer

[0499] SCD was determined in the desaturase assay buffer. This assay buffer contained 0.1 M Tπs buffer, pH 7.2, 2 mM NADH, 4.8 mM ATP, 0.5 mM CoA, 4.8 mM MgCl₂, and 0.1% BSA.

The Procedure for the SCD Assay (Adapted from Talamo and Bloch (1969) Analytical Biochemistry 29:300-304)

[0500] lμl of each compound of Formula I was added to an assay plate by a low volume (0.5- lOμL) multichannel pipette. A DMSO control was also prepared. The microsomes were quickly thawed and added to assay buffer so that a concentration of 1-0.1 mg/ml was achieved (0.5- 0.05 mg/ml assay final). 50μl of the microsome suspension in assay buffer was then added into each well in the compound assay plate, the plate was covered, and the microsomes premcubated with the compounds for 30-60 minutes on the orbital shaker, 50-75rpm, at room temperature.

[0501] After preincubation, the reaction was initiated by the addition of 50 μl of substrate solution (20μM Stearoyl CoA, [3H]Stearoyl CoA, 74nCi) to the premcubated microsomes/compound suspensions in MiIhQ (Millrpore) H₂O. The reaction mixtures were then incubated for 45 minutes on the orbital shaker at 50-75 rpm at room temperature.

[0502] The reaction was terminated by the addition of 10 μl of 21% trichloroacetic acid (TCA) to the reaction mixture followed incubation on the orbital shaker for 30 minutes at 50-75 rpm at room temperature followed by centπfugation for 5 minutes at 3700 rpm.

[0503] 50μl of a 6% Bio-Bead suspension in H₂O was added to the reaction mixture and the assay plate was sealed. The Bio-Bead mixture was incubated on the orbital shaker for 1 to 24 hours, 100-150 rpm at room temperature, and then the mixture was centπfuged at 200Og for 5 minutes to pellet the Bio-Beads.

[0504] 25 μl of the supernatant was harvested from each well and transferred to a detection plate. lOOμl of OptiPhase SuperMix scinitillation cocktail (containing sufficient NaOH to neutralize the TCA) was added and the solutions mixed by vigorous shaking (300-400rpm) for 5 minutes at room temperature. The radioactivity was counted in a MicroBeta scintillation counter in order to determine the activity and IC₅₀ values for the compounds of Formula I. Table 1 presents the IC₅₀ data for a number of compounds of the invention for which the IC₅₀ as determined in the above assay was less than 30 μM.

Table 1

EXAMPLE 8 CHARACTERIZATION OF STEARO YL-CoA DESATURASE INHIBITOR

[0505] The procedures of Example 7 were followed to in order to determine the activity and IC₅₀ values for example compounds of Formula I. Table 1 presents the IC₅₀ data for a number of compounds of the invention for which the IC₅₀ as determined in the above assay was less than 30 μM

ADDENDUM

[0506] Due to different nomenclature conventions used, the following table is being provided to serve as a reference for various compounds mentioned herein. The compound named in column A is also known by the name given in Column B. Column B is the name given by the nomenclature convention generally used herein (i.e. ChemDraw v. 10 naming facility).

Claims

CLAIMS We Claim- 1. A compound having the structure of Formula T

Formula I wherein

R¹ IS a) optionally substituted 4 to 6 membered nitrogen containing monocyclic heterocycle, b) -X-NR⁴R⁵, c) -X-C(O)NR⁴R⁵, d) -X-C(O)OR⁷, e) -X-OR⁷, or f) -X-NR⁸-C(O)NR⁴R⁵ wherein

R⁴ is hydrogen or Ci_-4 lower alkyl, and

R⁵ is hydrogen, Ci_-4 lower alkyl, aryl, heteroaryl, C_M alkoxy, -C(=NH)NH₂, - C(=O)R⁶ or -S(=O)₂R⁶, wherein

R⁶ is hydrogen, optionally substituted C_M alkyl, optionally substituted Ci_-4 alkenyl, Ci_-4 alkoxy, optionally substituted monocyclic aryl, or 5 or 6 membered optionally substituted monocyclic heteroaryl, or

R⁴ and R⁵ along with the nitrogen to which they are attached join to form a 5 or 6 membered monocyclic heteroaryl or heterocyclyl πng; R⁷ is hydrogen, optionally substituted Ci_-4 alkyl, optionally substituted C_1-4 alkenyl, optionally substituted monocyclic aryl, or 5 or 6 membered optionally substituted monocyclic heteroaryl,

R⁸ is hydrogen or C₁.₄ lower alkyl;

X is optionally substituted Ci_-4 linear or branched alkylene;

R² is optionally substituted mono or bicyclic heterocyclyl, mono or bicyclic aryl, or mono or bicyclic heteroaryl; wherein the aryl, heterocyclyl or heteroaryl moiety is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, heterocyclyl, aryl, heteroaryl, halo, NO₂, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, S(O)₃R²⁰, P(O)(OR²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂, NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰),, NR^2OC(NR^2O)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²², SO₂NR²⁰CO₂R²², OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂, and further wherein each optional alkyl, heteroaryl, aryl, and heterocyclyl substituent is further optionally substituted with halo, NO₂, alkyl, CF₃, amino, mono- or di- alkylamino, alkyl or aryl or heteroaryl amide, NR²⁰COR²², NR²⁰SO₂R²², COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰),, OC(O)R²⁰, OC(O)N(R²⁰)₂, S(O)₃R²⁰, P(O)(OR²⁰)₂, SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰;

R³ is hydrogen, optionally substituted Ci_-4 alkyl, 5 or 6 membered optionally substituted monocyclic cycloalkyl, optionally substituted monocyclic aryl, 5 or 6 membered optionally substituted monocyclic heterocycle, or 5 or 6 membered optionally substituted monocyclic heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl moiety is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, heterocyclyl, aryl, heteroaryl, halo, NO₂, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, S(O)₃R²⁰, P(O)(OR²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂, NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²², SO₂NR²⁰CO₂R²², OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂, and further wherein each optional alkyl, heteroaryl, aryl, and heterocyclyl substituent is further optionally substituted with halo, NO₂, alkyl, CF₃, ammo, mono- or di- alkylamino, alkyl or aryl or heteroaryl amide, NR²⁰COR²², NR²⁰SO₂R²², COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰),, OC(O)R²⁰, OC(O)N(R²⁰)₂, S(O)₃R²⁰, P(O)(OR²⁰)₂, SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰;

R²⁰ and R²² are independently selected from the group consisting of hydrogen, C].₎₅ alkyl, C_2-I5 alkenyl, C_2-I5 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl moieties are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O-C_)-6 alkyl, CF₃, aryl, and heteroaryl;

Q is Ci_-4 alkylene which may optionally contain one or more -NH-, -0-, -S-, or carbonyl linking moieties;

W¹ is N or CH, or W¹ is C wherein said C is attached to the R²-Q-NH- moiety; and W² is N or CH with the proviso that W¹ and W² cannot both be N; wherein the R²-Q-NH- moiety is attached to the 'a' or 'b' position indicated in Formula I, provided that W¹ is C when the R²-Q-NH- moiety is attached to the 'a' position; or a pharmaceutically acceptable salt, ester, prodrug, or hydrate thereof.

2. The compound of claim 1 , wherein R¹ is -X-NR⁴R⁵, -X-C(O)NR⁴R⁵, -X-C(O)OR⁷, or - X-OR⁷ and R² is optionally substituted 5 or 6 membered monocyclic aryl or heteroaryl;

3. The compound of claim 1, wherein R¹ is -X-NR⁴R⁵ and R³ is optionally substituted monocyclic aryl.

4. The compound of claim 3, selected from the group consisting of: N-[2-(6- { [(3 ,4-dichlorophenyl)methyl]amino} -2-(4-methoxyphenyl)-3-oxo-4- hydropyπdino[2,3-b]pyrazm-4-yl)ethyl]acetamide,

N-[2-(6-{[(4-fluorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyπdino[2,3-b]pyrazm-4-yl)ethyl]acetamide;

N-[2-(6-{[(3-chlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

N-[2-(6-{[(3-chloro-4-fluorophenyl)methyl]ammo}-2-(4-methoxyphenyl)-3-oxo- 4-hydropyridmo[2,3-b]pyrazin-4-yl)ethyl]acetamide;

N-{2-[2-(4-methoxyphenyl)-3-oxo-6-({[3-

(tπfluoromethyl)phenyl]methyl}amino)-4-hydropyridmo[2,3-b]pyrazin-4- yljethyl} acetarmde;

N-{2-[2-(4-methoxyphenyl)-3-oxo-6-({[4-

(tnfluoromethyl)phenyl]methyl}amino)-4-hydropyπdmo[2,3-b]pyrazm-4- yl]ethyl} acetamide;

N-[2-(6-{[(3,4-dichlorophenyl)methyl]ammo}-2-(4-methylthiophenyl)-3-oxo-4- hydropyπdmo[2,3-b]pyrazm-4-yl)ethyl]acetamide;

N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methylphenyl)-3-oxo-4- hydropyridmo[2,3-b]pyrazm-4-yl)ethyl]acetamide;

N-[2-(6- { [(3-bromophenyl)methyl]amino} -2-(4-methoxyphenyl)-3-oxo-4- hydropyπdmo[2,3-b]pyrazm-4-yl)ethyl]acetamide;

N-{2-[6-({[3,5-bis(tπfluoromethyl)phenyl]methyl}amino)-2-(4-methoxyphenyl)- 3-oxo-4-hydropyπdmo[2,3-b]pyrazin-4-yl]ethyl}acetamide;

N- {2-[6-( { [4-fluoro-3 -(tπfluoromethyl)phenyl]methyl } ammo)-2-(4- methoxyphenyl)-3-oxo-4-hydropyπdino[2,3-b]pyrazm-4-yl]ethyl}acetamide;

N- {2-[2-(4-methoxyphenyl)-3 -oxo-6-( { [5 -(tπfluoromethyl)(3- pyπdyl)]methyl}ammo)-4-hydropyπdino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

N-(2-{2-(4-methoxyphenyl)-3-oxo-6-[benzylammo]-4-hydropyridino[2,3- b]pyrazin-4-yl}ethyl)acetamide;

N-(2-{2-(4-methoxyphenyl)-3-oxo-6-[(3-pyridylmethyl)amino]-4- hydropyridino[2,3-b]pyrazin-4-yl}ethyl)acetamide, N-[2-(6-{[(3-fluorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino [2 ,3 -b]pyrazin-4-yl)ethy 1] acetamide;

4-(2-aminoethyl)-6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)- 4-hydropyridino[3 ,2-b]pyrazin-3 -one;

N-[2-(6-{[(3 ,4-dichlorophenyl)methyl] amino } -2 -(4-methoxyphenyl)-3 -oxo(4- hydropyridino[2,3-b]pyτazin-4-yl))ethyl](tert-butoxy)carboxamide;

N-[2-(6-{[(2-chlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

N-(2-{2-(4-methoxyphenyl)-3-oxo-6-[(3-phenylpropyl)amino]-4- hydropyridino[2,3-b]pyrazin-4-yl}ethyl)acetamide;

N-{2-[2-(4-methoxyphenyl)-3-oxo-6-({[6-(trifluoromethyl)(2- pyridyl)]methyl}amino)-4-hydropyridino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

N-[2-(2-(4-methoxyphenyl)-6-{[(5-methyl(l,2,4-oxadiazol-3-yl))methyl]amino}- 3-oxo-4-hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

N-[2-(2-(4-methoxyphenyl)-6-{[(3-methoxyphenyl)methyl]amino}-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide; methyl 3-[( {4-[2-(acetylamino)ethyl]-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[5,6-b]pyrazin-6-yl}amino)methyl]benzoate;

3-[({4-[2-(acetylamino)ethyl]-2-(4-methoxyphenyl)-3-oxo-4-hydropyridino[5,6- b]pyrazin-6-yl} amino)methyl]benzoic acid;

N-[2-(2-(4-methoxyphenyl)-6-{[(3-methylphenyl)methyl]amino}-3-oxo-4- hydropyridmo[2,3-b]pyrazin-4-yl)ethyl]acetamide;

N- {2-[2-(4-methoxyphenyl)-3 -oxo-6-( { [3 -

(trifluoromethoxy)phenyl]methyl}amino)-4-hydropyridino[2,3-b]pyrazin-4- yl] ethyl } acetamide ;

N-(2-{2-(4-methoxyphenyl)-3-oxo-6-[(2-pyridylmethyl)amino]-4- hydropyridino[2,3-b]pyrazin-4-yl}ethyl)acetamide;

N-{2-[6-({[2-fluoro-5-(trifluoromethyl)phenyl]methyl}amino)-2-(4- methoxyphenyl)-3-oxo-4-hydropyridino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

N-[2-(2-(4-methoxyphenyl)-6-{[(5-methylisoxazol-3-yl)methyl]amino}-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide; N-{2-[2-[4-(2-memoxyethoxy)phenyl]-3-oxo-6-({[3- (trifluoromethyl)phenyl]methyl}amino)-4-hydropyridino[2,3-b]pyrazin-4- yl]ethyl } acetamide;

N-{2-[3-oxo-2-(4-propylphenyl)-6-({[3-(trifluoromethyl)phenyl]methyl}amino)- 4-hydropyridino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

N-{2-[2-[4-(acetylamino)phenyl]-3-oxo-6-({[3-

(trifluoromethyl)phenyl]methyl}amino)-4-hydropyridino[2,3-b]pyrazin-4- yl]ethyl}acetamide;

N-{2-[2-(4-methylphenyl)-3-oxo-6-({[3-(trifluoromethyl)phenyl]methyl}amino)- 4-hydropyridino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

N- {2-[2-(4-ethylphenyl)-3 -oxo-6-( { [3 -(trifluoromethyl)phenyl]methyl } amino)-4- hydropyridino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

N- {2-[2-(4-fluorophenyl)-3-oxo-6-( { [3 -(trifluoromethyl)phenyl]methyl } amino)- 4-hydropyridino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo(4- hydropyridino[2,3-b]pyrazin-4-yl))ethyl]-2-(dimethylamino)acetamide;

{N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]carbamoyl} methyl acetate;

N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo(4- hydropyridino[2,3-b]pyrazin-4-yl))ethyl]-2-hydroxyacetamide;

2-amino-N-[2-(6- { [(3 ,4-dichlorophenyl)methyl]amino} -2-(4-methoxyphenyl)-3- oxo(4-hydropyridino[2,3-b]pyrazin-4-yl))ethyl]acetamide

2-(acetylamino)-N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4- methoxyphenyl)-3-oxo(4-hydropyridino[2,3-b]pyrazin-4-yl))ethyl]acetamide;

N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-[4-(methylsulfonyl)phenyl]-3- oxo-4-hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

N-[2-(2-(3,4-dichlorophenyl)-6- { [(3 ,4-dichlorophenyl)methyl] amino} -3 -oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

N-[2-(6-{[3-(2,5-dichlorophenoxy)propyl]amino}-2-(4-methoxyphenyl)-3-oxo- 4-hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide; {N-[2-(4-methoxyphenyl)-3-oxo-6-({[3-(trifluoromethyl)phenyl]methyl}amino)- 4-hydropyridino[2,3-b]pyrazin-4-yl]carbamoyl}methyl acetate;

N-{2-[3-oxo-2-[4-(tπfluoromethyl)phenyl]-6-({[3- (tπfluoromethyl)phenyl]methyl}amino)-4-hydropyπdmo[2,3-b]pyrazin-4- yl]ethyl}acetamide;

N-[2-(7-{[(3,4-dichlorophenyl)methyl]ammo}-3-(4-methylphenyl)-2- oxohydropyπdmo [3 ,4-b]pyrazinyl)ethyl] acetamide ;

N-[2-(7-{[(3,4-dichlorophenyl)methyl]ammo}-3-(4-methoxyphenyl)-2- oxohydropyridino[3,4-b]pyrazmyl)ethyl]acetamide;

N-[2-(7-{[(3,4-dichlorophenyl)methyl]amino}-3-(4-chlorophenyl)-2- oxohydropyπdino[3,4-b]pyrazmyl)ethyl]acetamide;

N-[2-(7- { [(3 ,4-dichlorophenyl)methyl]amino} -3 -(4-methoxyphenyl)-2- oxohydroqumoxahnyl)ethyl]acetamide;

N- {2-[3 -(4-methoxyphenyl)-2-oxo-7-( { [3 - (tπfluoromethyl)phenyl]methyl}amino)hydroquinoxahnyl]ethyl}acetamide;

N-{2-[3-(4-methylphenyl)-2-oxo-7-({[3- (tπfluoromethyl)phenyl]methyl}amino)hydroquinoxalinyl]ethyl}acetamide;

N-{2-[3-[4-(2-methoxyethoxy)phenyl]-2-oxo-7-({[3- (tπfluoromethyl)phenyl]methyl } ammo)hydroquinoxalinyl] ethyl } acetamide ,

N-{2-[3-(4-ethylphenyl)-2-oxo-7-({[3- (tπfluoromethyl)phenyl]methyl}ammo)hydroquinoxalinyl]ethyl}acetamide;

N-(2-{3-(3,4-dichlorophenyl)-2-oxo-7- [(phenylmethoxy)carbonylamino]hydroquinoxalmyl}ethyl)acetamide;

N-(2-{3-(4-methoxyphenyl)-2-oxo-7- [(phenylmethoxy)carbonylamino]hydroquinoxalmyl}ethyl)acetarmde;

N-(2-(7-(3,4-dichlorobenzylamino)-2-(4-methoxyphenyl)-3-oxopyrido[2,3- b]pyrazm-4(3H)-yl)ethyl)acetamide;

1 -(2-acetamidoethyl)-N-(3 ,4-dichlorobenzyl)-3 -(4-methoxyphenyl)-2-oxo- 1 ,2- dihydroquinoxahne-6-carboxamide;

N-(2-(2-(4-methoxyphenyl)-3-oxo-7-(3- (tπfluoromethyl)benzylamino)pyπdo[2,3-b]pyrazm-4(3H)-yl)ethyl)acetamide; N-(2-(7-(4-chlorobenzylamino)-2-(4-methoxyphenyl)-3-oxopyrido[2,3- b]pyrazin-4(3H)-yl)ethyl)acetamide,

N-(2-(7-(3-chlorobenzylamino)-2-(4-methoxyphenyl)-3-oxopyπdo[2,3- b]pyrazm-4(3H)-yl)ethyl)acetamide,

N-(2-(7-(4-methoxybenzylammo)-2-(4-methoxyphenyl)-3-oxopyπdo[2,3- b]pyrazm-4(3H)-yl)ethyl)acetamide; benzyl 1 -(2-acetamidoethyl)-3-(4-methoxyphenyl)-2-oxo-l ,2-dihydroquinoxalm- 6-ylcarbamate; benzyl 1 -(2-acetamidoethyl)-3-(3,4-dichlorophenyl)-2-oxo-l ,2- dihydroqumoxalm-6-ylcarbamate,

N-(2-(7-(3,4-dichlorophenethylamino)-2-(4-methoxyphenyl)-3-oxopyrido[2,3- b]pyrazm-4(3H)-yl)ethyl)acetamide;

N-(2-(7-(3,4-dichlorobenzylamino)-2-(3,4-dichlorophenyl)-3-oxopyrido[2,3- b]pyrazin-4(3H)-yl)ethyl)acetamide,

N-(2-(7-(3-chlorophenethylammo)-3-(4-methoxyphenyl)-2-oxoqumoxalm- 1 (2H)-yl)ethyl)acetamide;

N-(2-(7-(2-(2-chlorophenoxy)ethylammo)-3-(4-methoxyphenyl)-2- oxoqumoxalm-l(2H)-yl)ethyl)acetamide;

N-(2-(3 -(4-methoxyphenyl)-7-(3 -methylbenzylammo)-2-oxoqumoxalm- 1 (2H)- yl)ethyl)acetamide;

N-(2-(7-(3,4-dimethylbenzylammo)-3-(4-methoxyphenyl)-2-oxoquinoxalin- 1 (2H)-yl)ethyl)acetamide;

N-(2-(7-(4-chlorophenethylammo)-3-(4-methoxyphenyl)-2-oxoqumoxahn- 1 (2H)-yl)ethyl)acetamide;

N-(2-(7-(4-chloro-3-(tπfluoromethyl)benzylammo)-3-(4-methoxyphenyl)-2- oxoqumoxalm- 1 (2H)-yl)ethyl)acetamide;

N-(2-(7-(4-fluoro-3-methylbenzylamino)-3-(4-methoxyphenyl)-2-oxoquinoxahn- l(2H)-yl)ethyl)acetamide; and

N-(2-(3-(4-methoxyphenyl)-2-oxo-7-((4-(tnfluoromethyl)pyπdin-2- yl)methylammo)qmnoxalin-l(2H)-yl)ethyl)acetamide.

5. The compound of claim 2, wherein R¹ is -X-NR⁴R⁵ and R³ is 5 or 6 membered optionally substituted monocyclic heteroaryl.

6. The compound of claim 5, selected from the group consisting of:

N-[2-(6-{[(3,4-dichlorophenyl)methyl]amino}-3-oxo-2-(3-pyridyl)-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

N-[2-(6-{[(3-chloro-4-fluorophenyl)methyl]amino}-3-oxo-2-(3-pyridyl)-4- hydropyridino[2,3-b]pyrazin-4-yl)ethyl]acetamide;

N- {2-[3 -oxo-2-(3 -pyridyl)-6-( { [3 -(trifluoromethyl)phenyl]methyl } amino)-4- hydropyridino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

N-[2-(7-{[(3,4-dichlorophenyl)methyl]amino}-2-oxo-3-(3- pyridyl)hydropyridino[3,4-b]pyrazinyl)ethyl]acetamide;

N-{2-[2-oxo-3-(3-pyridyl)-7-({[3- (trifluoromethyl)phenyl]methyl } amino)hydroquinoxalmyl] ethyl } acetamide ; and

N-(2-(7-(3,4-dichlorobenzylammo)-3-oxo-2-(pyridin-3-yl)pyrido[2,3- b]pyrazin-4(3H)-yl)ethyl)acetamide.

7. The compound of claim 2, wherein R¹ is -X-NR⁴R⁵ and R³ is hydrogen.

The compound of claim 7, selected from the group consisting of:

N-{2-[3-oxo-6-({[3-(trifluoromethyl)phenyl]methyl}amino)-4- hydropyridino[2,3-b]pyrazin-4-yl]ethyl} acetamide; and

N-[2-(6-{[(3 ,4-dichlorophenyl)methyl] amino } -3 -oxo-4-hydropyridino [2,3 - b]pyrazin-4-yl)ethyl]acetamide.

9. The compound of claim 2, wherein R³ is optionally substituted alkyl.

10. The compound of claim 9, selected from the group consisting of: N-{2-[3-oxo-2-(trifluoromethyl)-6-({[3-

(trifluoromethyl)phenyl]methyl}amino)-4-hydropyπdino[2,3-b]pyrazm-4- yl]ethyl}acetamide;

N-{2-[2-methyl-3-oxo-6-({[3-(trifluoromethyl)phenyl]methyl}ammo)-4- hydropyridino[2,3-b]pyrazm-4-yl]ethyl}acetamide;

N-[2-(6-{[(3,4-dichlorophenyl)methyl]ammo}-2-methyl-3-oxo-4- hydropyridmo[2,3-b]pyrazin-4-yl)ethyl]acetamide; ethyl 4-[2-(acetylammo)ethyl] -3-oxo-6-( { [3 - (tπfluoromethyl)phenyl]methyl}ammo)-4-hydropyπdino[2,3-e]pyrazme-2-carboxylate;

4-[2-(acetylammo)ethyl]-3-oxo-6-({[3-

(tnfluoromethyl)phenyl]methyl}ammo)-4-hydropyndino[2,3-b]pyrazine-2-carboxylic acid;

N- {2-[3 -oxo-2-propyl-6-( { [3 -(trifluoromethyl)phenyl]methyl } amino)-4- hydropyπdino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

N- {2-[2-ethyl-3 -oxo-6-( { [3 -(trifluoromethyl)phenyl]methyl } amino)-4- hydropyπdino[2,3-b]pyrazin-4-yl]ethyl}acetamide;

N- {2-[3 -oxo-2-(2-phenylethyl)-6-( { [3 -(trifluoromethyl)phenyl]methyl } amino)- 4-hydropyπdmo[2,3-b]pyrazm-4-yl]ethyl}acetamide;

N-[2-(7- {[(3,4-dichlorophenyl)methyl]ammo} -3-methyl-2- oxohydropyπdino[3,4-b]pyrazinyl)ethyl]acetamide;

N- {2-[3-methyl-2-oxo-7-( { [3- (tπfluoromethyl)phenyl]methyl}amino)hydroquinoxalmyl]ethyl}acetamide;

(N-{2-[3-methyl-2-oxo-7-({[3-

(tπfluoromethyl)phenyl]methyl}amino)hydroqumoxahnyl]ethyl}carbamoyl)methyl acetate;

2-hydroxy-N-{2-[3-methyl-2-oxo-7-({[3- (tπfluoromethyl)phenyl]methyl}amino)hydroquinoxalinyl]ethyl}acetamide;

4-[2-methyl-3-oxo-6-({[3-(trifluoromethyl)phenyl]methyl}ammo)-4- hydropyridmo[2,3-b]pyrazin-4-yl]butanamide;

N-(2-(7-(benzylamino)-2-methyl-3-oxopyrido[2,3-b]pyrazin-4(3H)- yl)ethyl)acetamide; benzyl 4-(2-acetamidoethyl)-2-methyl-3-oxo-l,2,3,4-tetrahydropyπdo[2,3- b]pyrazin-7-ylcarbamate;

(S)-2-hydroxy-N-(2-(3-methyl-2-oxo-7-(3- (tπfluoromethyl)benzylammo)qumoxalm-l(2H)-yl)ethyl)propanamide;

(R)-2-hydroxy-N-(2-(3-methyl-2-oxo-7-(3- (tπfluoromethyl)benzylamino)qumoxalin-l(2H)-yl)ethyl)propanamide;

3-hydroxy-N-(2-(3-methyl-2-oxo-7-(3- (tπfluoromethyl)benzylamino)qmnoxalm-l(2H)-yl)ethyl)propanamide;

N-(2-hydroxyethyl)-3 -(3 -methyl-2-oxo-7-(3 - (tπfluoromethyl)benzylamino)qumoxalm- 1 (2H)-yl)propanamide;

N-(2-(3-methyl-2-oxo-7-(3-(tnfluoromethyl)benzylamino)qumoxahn-l(2H)- yl)ethyl)thiophene-3 -carboxamide; and

2,3-dihydroxy-N-(2-(3-methyl-2-oxo-7-(3- (tπfluoromethyl)benzylammo)qumoxalin-l(2H)-yl)ethyl)propanamide.

11. The compound of claim 2, wherein R¹ is -X-C(O)NR⁴R⁵ and R³ is optionally substituted monocyclic aryl.

12. The compound of claim 11 , selected from the group consisting of:

3-(6- { [(3,4-dichlorophenyl)methyl]amino} -2-(4-methoxyphenyl)-3-oxo-4- hydropyπdmo[2,3-b]pyrazin-4-yl)propanamide;

3-[2-(4-methoxyphenyl)-3-oxo-6-({[3-(trifluoromethyl)phenyl]methyl}ammo)- 4-hydropyridmo[2,3-b]pyrazm-4-yl]propanamide;

4-(6- { [(3,4-dichlorophenyl)methyl]amino} -2-(4-methoxyphenyl)-3-oxo(4- hydropyndino[2,3-b]pyrazm-4-yl))-N-methylbutanamide;

4-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridmo[2,3-b]pyrazm-4-yl)butanamide; and

3-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo(4- hydropyridino[2,3-b]pyrazin-4-yl))-N-methylpropanamide; 3-[2-(4-methoxyphenyl)-3-oxo-6-({[3-

(tπfluoromethyl)phenyl]methyl}amino)(4-hydropyridino[2,3-b]pyrazin-4-yl)]-N- (phenylmethoxy)propanamide ;

N-methoxy-3 -[2-(4-methoxyphenyl)-3 -oxo-6-( { [3 - (trifluoromethyl)phenyl]methyl}amino)(4-hydropyridmo[2,3-b]pyrazm-4- yl)]propanamide,

3-[2-(4-methoxyphenyl)-3-oxo-6-({[3-

(tπfluoromethyl)phenyl]methyl}amino)(4-hydropyπdino[2,3-b]pyrazin-4-yl)]-N- methylpropanamide ;

3-[2-(4-methoxyphenyl)-3-oxo-6-({[3-(tπfluoromethyl)phenyl]methyl}ammo)- 4-hydropyridmo[2,3 -b]pyrazm-4-yl]propanehydroxamic acid;

(3R)-3-[2-(4-methoxyphenyl)-3-oxo-6-({[3-

(tπfluoromethyl)phenyl]methyl}amino)(4-hydropyπdmo[2,3-b]pyrazm-4- yl)]butanamide;

3-[2-(4-methylphenyl)-3-oxo-6-({[3-(tπfluoromethyl)phenyl]methyl}amino)- 4-hydropyπdmo[2,3-b]pyrazm-4-yl]propanamide;

3-[2-(4-ethylphenyl)-3-oxo-6-({[3-(tτifluoromethyl)phenyl]methyl}amino)-4- hydropyπdino[2,3-b]pyrazm-4-yl]propanamide;

3-[2-[4-(2-methoxyethoxy)phenyl]-3-oxo-6-({[3-

(tπfluoromethyl)phenyl]methyl}ammo)-4-hydropyridino[2,3-b]pyrazm-4- yljpropanamide;

3-[3 -oxo-2-(4-propylphenyl)-6-( { [3 -(trifluoromethyl)phenyl]methyl } ammo)-4- hydropyridino[2,3-b]pyrazm-4-yl]propanamide;

4-[2-(4-methoxyphenyl)-3-oxo-6-({[3-(trifluoromethyl)phenyl]methyl}ammo)- 4-hydropyridmo[2,3-b]pyrazin-4-yl]butanamide;

3-[3-oxo-2-[4-(tnfluoromethyl)phenyl]-6-({[3-

(tπfluoromethyl)phenyl]methyl}amino)-4-hydropyτidino[2,3-b]pyrazin-4- yl]propanamide;

2-[2-(4-methoxyphenyl)-3 -oxo-6-( { [3 -(tπfluoromethyl)phenyl]methyl } amino)- 4-hydropyridino[2,3-b]pyrazin-4-yl]acetamide; (3S)-3-[2-(4-methoxyphenyl)-3-oxo-6-({[3-

(trifluoromethyl)phenyl]methyl}amino)(4-hydropyridino[2,3-b]pyrazin-4- yl)]butanamide; and

3 -(6- { [(3 ,4-dichlorophenyl)methyl] amino } -2 -(4-methoxyphenyl)-3 -oxo(4- hydropyridino[2,3-b]pyrazin-4-yl))-N-(2-hydroxyethyl)propanamide.

13. The compound of claim 2, wherein R¹ is -X-C(O)NR⁴R⁵ and R³ is 5 or 6 membered optionally substituted monocyclic heteroaryl.

14. The compound of claim 13, selected from the group consisting of:

3-(6-{[(3,4-dichlorophenyl)methyl]amino}-3-oxo-2-(3-pyridyl)-4- hydropyridino[2,3-b]pyrazin-4-yl)propanamide; and

3-[3-oxo-2-(3-pyridyl)-6-({[3-(trifluoromethyl)phenyl]methyl}amino)-4- hydropyridino[2,3-b]pyrazin-4-yl]propanamide.

15. The compound of claim 2, wherein R¹ is -X-C(O)OR⁷ and R³ is optionally substituted monocyclic aryl.

16. The compound of claim 15, selected from the group consisting of: ethyl 3 -(6- { [(3 ,4-dichlorophenyl)methyl] amino } -2-(4-methoxyphenyl)-3 -oxo- 4-hydropyridino[2,3-b]pyrazin-4-yl)propanoate; ethyl 4-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo- 4-hydropyridino[2,3-b]pyrazm-4-yl)butanoate;

4-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)butanoic acid; and

3-(6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4-methoxyphenyl)-3-oxo-4- hydropyridino[2,3-b]pyrazin-4-yl)propanoic acid.

17. The compound of claim 2, wherein R¹ is -X-OR⁷.

18. The compound of claim 17, wherein X is ethylene, R² is 3-(trifluoromethyl), R³ is 4-methoxyphenyl, and R⁵ is hydrogen, namely 4-(2-hydroxyethyl)-2-(4-methoxyphenyl)-6- ({[3-(trifluoromethyl)phenyl]methyl}amino)-4-hydropyridino[3,2-b]pyrazin-3-one.

19. The compound of claim 2, wherein R¹ is -X-NR -C(O)NR 4⁴rR> 5⁵.

20. A compound according to claim 19, namely l-(2-(3-methyl-2-oxo-7-(3- (trifluorornethyl)benzylamino)quinoxalin- 1 (2H)-yl)ethyl)urea.

21 The compound of claim 1 , wherein W is CH and W is N.

22. The compound of claim 1, wherein W is N and W is CH.

23. The compound of claim 1, wherein both W¹ and W² are CH.

24. The compound of claim 1 wherein R¹ is a 4 to 6 membered nitrogen containing monocyclic heterocycle.

25. The compound of claim 24, selected from the group consisting of:

4-((3R)pyrrolidin-3-yl)-6-{[(3,4-dichlorophenyl)methyl]amino}-2-(4- methoxyphenyl)-4-hydropyridino[3,2-b]pyrazin-3-one;

(3R)-3-(6-{[(3 ,4-dichlorophenyl)methyl] amino } -2-(4-methoxyphenyl)-3 - oxo(4-hydropyridino[2,3-b]pyrazin-4-yl))pyrrolidinecarbaldehyde;

(3 S)-3 -(6- { [(3 ,4-dichlorophenyl)methyl]amino} -2-(4-methoxyphenyl)-3 - oxo(4-hydropyridino[2,3-b]pyrazin-4-yl))pyrrolidinecarbaldehyde; and

4-((3S)-6-oxo(3-piperidyl))-2-(4-methoxyphenyl)-6-({[3- (trifluoromethyl)phenyl]methyl}amino)-4-hydropyridino[3,2-b]pyrazin-3-one.

26. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt, ester, prodrug, or hydrate thereof.

27. A method for treating a disease or condition in a mammal that can be treated with an stearoyl-CoA desaturase inhibitory compound comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of claim 1 or a pharmaceutically acceptable salt, ester, prodrug, or hydrate thereof .