US 200800 19978A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0019978A1 Palani et al. (43) Pub. Date: Jan. 24, 2008

(54) NITROGEN-CONTAINING HETEROCYCLIC (57) ABSTRACT COMPOUNDS AND METHODS OF USE The present invention provides compounds of Formula (I): THEREOF (75) Inventors: Anandan Palani, Bridgewater, NJ (US); Jing Su, Scotch Plains, NJ (US); (I) Dong Xiao, Warren, NJ (US); Xianhai Huang, Warren, NJ (US); Ashwin U. Rao, Avenel, NJ (US); Xiao Chen, Edison, NJ (US); Haiqun Tang, Belle Mead, NJ (US); Jun Qin, Edison, NJ (US); Ying R. Huang, Berkeley Heights, NJ (US); Robert G. Aslanian, Rockaway, NJ (US); Brian A. and pharmaceutically acceptable salts, Solvates, esters, and McKittrick, New Vernon, NJ (US); tautomers thereof, wherein: Sylvia J. Degrado, Scotch Plains, NJ Q is selected from the group consisting of: (US) Correspondence Address: SCHERING-PLOUGH CORPORATION PATENT DEPARTMENT (K-6-1, 1990) 2000 GALLOPNG HILL ROAD KENILWORTH, NJ 07033-0530 (US) (73) Assignee: Schering Corporation (21) Appl. No.: 11/771.538 (22) Filed: Jun. 29, 2007 (b) Related U.S. Application Data (63) Continuation-in-part of application No. 1 1/600,216, filed on Nov. 15, 2006, which is a continuation-in-part of application No. 11/432,133, filed on May 11, 2006. (60) Provisional application No. 60/681,848, filed on May 17, 2005. Provisional application No. 60/715,565, filed on Sep. 9, 2005. Provisional application No. 60/731,039, filed on Oct. 28, 2005. (c) Publication Classification (51) Int. Cl. A 6LX 3/59 (2006.01) A 6LX 3L/397 (2006.01) A6 IK 3/56 (2006.01) A6 IK 3L/60 (2006.01) A6 IK 38/16 (2006.01) A 6LX 39/395 (2006.01) (d) A6IP I/00 (2006.01) A6IP II/00 (2006.01) A6IP 3/00 (2006.01) A6IP 3/10 (2006.01) A6IP 35/00 (2006.01) A6IP 9/00 (2006.01) C07D 239/70 (2006.01) (52) U.S. Cl...... 424/158.1: 514/12: 514/165; 514/171; 514/210.02; 514/210.05; 514/260.1; 544/278 US 2008/0019978 A1 Page 2

-continued -continued (g) (e) b R3 R O s Ra

* R4. (h) i N O y s and O I. and f (i) L is selected from the group consisting of O ey (f) I. O O s pharmaceutically compositions comprising one or more compounds of formula (I), and methods of using the com pounds of formula (I). US 2008/00 19978 A1 Jan. 24, 2008

NITROGEN-CONTAINING HETEROCYCLC 0006 WO 2005/000217 describes combination therapies COMPOUNDS AND METHODS OF USE THEREOF for the treatment of dyslipidemia comprising the adminis tration of a combination of an anti-obesity agent and an REFERENCE TO PRIORITY APPLICATIONS anti-dyslipidemic agent. However, WO 2005/000217 fails to 0001. This application is a continuation-in-part of U.S. describe nicotinic acid receptor agonists, or combinations of patent application Ser. No. 1 1/600,216, filed Nov. 15, 2006, one or more nicotinic acid receptor agonists with a second which is a continuation-in-part of U.S. patent application therapeutic agent. Ser. No. 11/4327,133, filed May 11, 2006, which claims the benefit of priority from U.S. provisional patent applications, 0007 WO 2004/110375 describes combination therapies Ser. Nos. 60/681,848 filed May 17, 2005; 60/715,565 filed for the treatment of diabetes comprising the administration Sep. 9, 2005; and 60/731,039 filed Oct. 28, 2005, each of of a combination of an anti-obesity agent and an anti which is incorporated herein by reference in its entirety. diabetic agent. However, WO 2004/110375 fails to describe nicotinic acid receptor agonists, or combinations of one or FIELD OF THE INVENTION more nicotinic acid receptor agonists with a second thera 0002 The present invention relates to nicotinic acid peutic agent. receptor agonist compounds useful for treating metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders 0008 US 2004/0122033 describes combination therapies of the peripheral and central nervous system, hematological for the treatment of obesity comprising the administration of diseases, cancer, inflammation, respiratory diseases, gastro a combination of an appetite Suppressant and/or metabolic enterological diseases, diabetes, and non-alcoholic fatty rate enhancers and/or nutrient absorption inhibitors. How liver disease; pharmaceutical compositions comprising Such ever, US 2004/0122033 fails to describe nicotinic acid compounds; pharmaceutical compositions comprising nico receptor agonists, or combinations of one or more nicotinic tinic acid receptor agonist compounds in combination with acid receptor agonists with a second therapeutic agent. US other therapeutic agents; and methods of treatment using the 2004/0229844 describes combination therapies for treating compounds and compositions to treat conditions such as atherosclerosis comprising the administration of a combi metabolic syndrome, dyslipidemia, cardiovascular diseases, nation of nicotinic acid or another nicotinic acid receptor disorders of the peripheral and central nervous system, agonistanda DP receptor antagonist. However, the nicotinic hematological diseases, cancer, inflammation, respiratory acid agonists of US 2004/02298.44 are quite different from diseases, gastroenterological diseases, diabetes, hepatic Ste those of the present invention. atosis and non-alcoholic fatty liver disease. 0009 WO2005/077950 describes xanthine derivatives BACKGROUND OF THE INVENTION which are agonists of the nicotinic acid receptor HM74A. However, the xanthine derivatives of WO2005/077950 are 0003 Nicotinic acid has been used to treat metabolic quite different from the compounds of the present invention. syndrome and dyslipidemia. However, nicotinic acid has undesirable side effects such as flushing and diarrhea. It is therefore desirable to provide improved nicotinic acid recep SUMMARY OF THE INVENTION tor agonists with improved efficacy at treating metabolic 0010. In one embodiment, the present invention is syndrome and dyslipidemia, yet without the undesirable side directed to a compound of Formula (I): effects. The compounds of the present invention provide Such improved nicotinic acid receptor agonists. 0004) M. Ridi, Gazzetta Chim. Ital. (1950) vol. 80, p. 121 (I) and M. Ridi, Gazzetta Chim. Ital. (1952) vol. 82, p 23 disclose syntheses of barbituric acid derivatives. FR 2563223 discloses nucleoside analogs. T. Paterson et al. J. Chem. Soc., Perkins Trans. I (1972), vol. 8, pp. 1041-1050 discloses the synthesis of 8-substituted pyrido 2,3-dipyrim idines. S. Rao, Indian J. Chem. (1974), 12(10), pp. 1028 1030 discloses the synthesis of pyrano 2,3-dipyrimidines. M. Skof, Heterocycles, (1999), 51(5), pp. 1051-1058 dis and pharmaceutically acceptable salts, Solvates, esters, and closes one step transformations of (S)-1-benzoyl-3-(E)- tautomers thereof, wherein: dimethylaminomethylidene-5-methoxycarbonyl-pyrroli 0011 Q is selected from the group consisting of: din-2-one into quinolizinyl- and 2H-2-pyranonyl-substituted alanine derivatives. R. Toplak J. Heterocyclic Chem. (1999), 36(1), pp. 225-235 discloses the synthesis of pyran-2-ones. (a) However, the compounds of the above references differ from those of the present invention. * R4 0005 WO 2004/110368 describes combination therapies for the treatment of hypertension comprising the combina tion of an anti-obesity agent and an anti-hypertensive agent. ins s However, WO 2004/110368 fails to describe nicotinic acid receptor agonists, or combinations of one or more nicotinic O acid receptor agonists with a second therapeutic agent. US 2008/00 19978 A1 Jan. 24, 2008

-continued -continued (b) (i)

0013) R' is selected from the group consisting of H, alkyl, arylalkyl, -alkylene-S-alkyl, alkenyl, alkynyl, haloalkyl, wherein an alkyl group can be optionally Substituted with one or more of the following groups, (c) which can be the same or different: —OH, cycloalkyl, —C(O)-alkyl, -alkylene-C(O) O-alkyl, -O-R', -alkylene-O-alkyl, aryl, -alkylene-aryl, heteroaryl, -alkylene-heteroaryl, halogen, -(CH2), N(R), -alkylene-cycloalkyl, or -alkylene-cycloalkenyl, 0014 wherein the cycloalkyl or the cycloalkyl por tion of said -alkylene-cycloalkyl of R' is unsubsti tuted or Substituted with one or more X groups, said aryl or the aryl portion of said -alkylene-aryl of R' is (d) unsubstituted or substituted with one or more Y groups, and said heteroaryl or the heteroaryl portion of said -alkylene-heteroaryl of R is unsubstituted or substituted with one or more Y groups: yer and 0015 R is selected from the group consisting of H, halogen, alkyl, haloalkyl, alkyl substituted with one or more —OH, - C(O)-alkyl, —C(O) O-alkyl, —C(O)—OH, - O R', -alkylene-O-alkyl, unsubsti tuted aryl, aryl substituted with one or more Ygroups, unsubstituted heteroaryl, heteroaryl substituted with one or more Y groups, and halogen; or (e) 0016) R' and R together with the ring carbon atoms to which they are shown attached, form a 5- or 6-mem bered cycloalkenyl ring or a 5- or 6-membered hetero cyclic ring having 1 or 2 heteroatoms; 0017 R is selected from the group consisting of H, alkyl, alkyl substituted with one or more hydroxyl groups, -alkylene-O-alkyl, cycloalkyl, -alkylene-cy cloalkyl, -alkylene-C(O) O-alkyl, -alkylene-O- C(O)-alkyl, alkenyl, aryl, and heteroaryl, 0018 wherein the cycloalkyl or the cycloalkyl por 0012 L is selected from the group consisting of: tion of said -alkylene-cycloalkyl of R is unsubsti tuted or Substituted with one or more X groups, said aryl of R is unsubstituted or substituted with one or (f) more Y groups, and said heteroaryl of R is unsub stituted or substituted with one or more Y groups: 0019 R is selected from the group consisting of H, halogen, alkyl, haloalkyl, —O-cycloalkyl, —O-alky (g) nyl, —O R', —C(O) O-alkyl, - S(O), R. - N(R), N(R) NH-C(O)-alkyl, - N(R)- NH C(O) O-alkyl, - O N=C(R') - N(R)- N=C(R'), C(O)-alkyl, unsubstituted heterocyclyl, (h) heterocyclyl Substituted with one or more X groups, —O N(R) C(O) O-alkyl, —C(O) N(R), —CN, N, and —O C(O)-alkyl: 0020 R is selected from the group consisting of H, sy alkyl, -OH, haloalkyl, arylalkyl, —O-alkyl, O-aryl, cycloalkyl, heterocyclyl. —O-cycloalkyl, -O-hetero US 2008/00 19978 A1 Jan. 24, 2008

cyclyl. —O-arylalkyl or -alkylene-O-alkyl-alkylene aryl of R" is unsubstituted or substituted with one or C(O)—R, -alkylene-C(O) N(R') -alkylene more Y groups; and the heteroaryl portion of said C(=N O-alkyl)-aryl, cycloalkyl, -alkylene -alkylene-heteroaryl of R" is unsubstituted or sub cycloalkyl, -alkylene-C(O)—O-alkyl, -alkylene-O- stituted with one or more Z groups; C(O)-alkyl, -alkylene-C(O)-heterocyclyl, and alkenyl, 0034) R' is selected from the group consisting of H, 0021 wherein the cycloalkyl or the cycloalkyl por alkyl, and aryl, tion of said -alkylene-cycloalkyl of R is unsubsti tuted or Substituted with one or more X groups, and 0035) wherein the aryl of R' is unsubstituted or the aryl portion of said -alkylene-C(=N O-alkyl)- substituted with one or more Y groups; or aryl of R is unsubstituted or substituted with one or 0036) two R' groups,group together9. with the N atom to more Y groups; which they are attached, form a heterocyclyl: 0022 R is selected from the group consisting of H, 0037l each R' is independently selected from the alkyl, alkenyl, alkyl substituted with one or more p y hydroxyl groups, -alkylene-O-alkyl, —O R', halo group consisting of alkyl, aryl, and heteroaryl, gen, aryl, heteroaryl, and —N(R), 0038 wherein the aryl of R' is unsubstituted or Substituted with one or more Y groups and said 0023 wherein the aryl of R is unsubstituted or heteroaryl of R' is unsubstituted or substituted with Substituted with one or more Y groups, and said one or more Z groups; or wherein both R" groups, heteroaryl of R is unsubstituted or substituted with together with the carbon atom to which they are one or more Z groups; attached, combine to form a heterocyclyl group; 0024) each R" is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, —C(O)-alkyl, 0039) R' and Rare each independently selected from and —C(O)-aryl, the group consisting of H. alkyl, aryl, and heteroaryl, 0.025 wherein the cycloalkyl of R is unsubstituted 0040 wherein the aryl of R and R is unsubstituted or Substituted with one or more X groups, and the or Substituted with one or more Y groups, and said aryl portion of said —C(O)-aryl or said aryl of R is heteroaryl of R and R is unsubstituted or substi unsubstituted or substituted with one or more Y tuted with one or more Z groups; groups: 0041 R is selected from the group consisting of H, 0026 two R' groups, together with the N atom to alkyl, alkylene-aryl, and —C(O)-alkyl, which they are bonded form a heterocyclyl: 0042 wherein the aryl portion of said alkylene-aryl 0027) R is selected from the group consisting of aryl, of R is unsubstituted or substituted with one or more —OH, and heterocyclyl, Y groups; 0028) wherein the heterocyclyl of R is unsubsti tuted or Substituted with one or more X groups, and 0043) R' is selected from the group consisting of H, said aryl of R is unsubstituted or substituted with alkyl, and alkylene-aryl, one or more Y groups; 0044 wherein the aryl portion of said alkylene-aryl 0029) R is selected from the group consisting of alkyl, of R is unsubstituted or substituted with one or more -alkylene-cycloalkyl, alkenyl, -N(R'), and -alky Y groups; lene-aryl, 0045 each X is independently selected from the group 0030 wherein the cycloalkyl portion of said alky consisting of halogen, alkyl, haloalkyl, -O-alkyl, lene-cycloalkyl of R is unsubstituted or substituted —O-haloalkyl, and —OH: with one or more X groups, and the aryl portion of 0046 each Y is independently selected from the group said -alkylene-aryl of R is unsubstituted or substi consisting of halogen, alkyl, haloalkyl, -O-alkyl, tuted with one or more Y groups, and —O-haloalkyl, —CN, NO. —OH, -S(O)-alkyl, 0.031) with the proviso that when R is N(R'), m —S(O)-aryl, —S(O)—NH —S(O) NH-alkyl, is 1 or 2; —S(O) NH-aryl, - S(O) N(alkyl). —S(O)— N(aryl), —S(O)—N(alkyl)(aryl), and aryl; 0032) R' is selected from the group consisting of H, alkyl, cycloalkyl, arylalkyl, haloalkyl, -alkylene-O- 0047 each Z is independently selected from the group alkyl, -alkylene-aryl, -alkenylene-aryl, -alkylene-het consisting of alkyl, haloalkyl, halogen, —O-alkyl, eroaryl, alkenyl, —C(O)-alkyl, alkynyl, and -alkylene —O-haloalkyl, —CN, —OH, aryl, and N-oxide: cycloalkyl, 0.048 n is 0, 1, 2, or 3: 0033 wherein an the alkynyl portion of an —O- alkynyl group can be optionally Substituted with 0049 m is 0, 1, or 2; and with the proviso that when L —OH or alkoxy; the cycloalkyl portion of an —O- is (f), and R, R and R are each H, then cycloalkyl group can be optionally Substituted with an -alkylene-O-alkylene-aryl group; the cycloalkyl 0050 R is not CH. portion of said -alkylene-cycloalkyl of R' is unsub 0051. In another embodiment, the present invention is stituted or substituted with one or more X groups; the directed to a pharmaceutical composition comprising a aryl portion of said -alkylene-aryl or -alkenylene therapeutically effective amount of at least one compound of US 2008/00 19978 A1 Jan. 24, 2008

Formula (I), or a pharmaceutically acceptable salt, Solvate, antidiabetic agents, anti-hypertensive agents, anti-dyslipi ester, or tautomer thereof, and at least one pharmaceutically demic agents, DP receptor antagonists, apolipoprotein-B acceptable carrier. secretion/microsomal triglyceride transfer protein (apo-B/ 0.052 In another embodiment, the present invention is MTP) inhibitors, sympathomimetic agonists, dopamine ago directed to a method of treating a disease or disorder in a nists, melanocyte-stimulating hormone receptor analogs, patient, Such as metabolic syndrome, dyslipidemia, cardio melanin concentrating hormone antagonists, leptons, gala vascular diseases, disorders of the peripheral and central nin receptor antagonists, bombesin agonists, neuropeptide-Y nervous system, hematological diseases, cancer, inflamma antagonists, thyromimetic agents, dehydroepiandrosterone, tion, respiratory diseases, gastroenterological diseases, dia analogs of dehydroepiandrosterone, urocortin binding pro betes, and non-alcoholic fatty liver disease. The method tein antagonists, glucagons-like peptide-1 receptor agonists, comprises administering to the patient an effective amount human agouti-related proteins (AGRP), neuromedin U of at least one compound of Formula (I), or a pharmaceu receptor agonists, noradrenergic anorectic agents, appetite tically acceptable salt, Solvate, ester, or tautomer thereof. Suppressants, hormone sensitive lipase antagonists, MSH receptor analogs, C-glucosidase inhibitors, apo A1 milano 0053. In another embodiment, the present invention is reverse cholesterol transport inhibitors, fatty acid binding directed to a method of treating a disease or disorder in a patient, Such as metabolic syndrome, dyslipidemia, cardio protein inhibitors (FABP), and fatty acid transporter protein vascular diseases, disorders of the peripheral and central inhibitors (FATP). nervous system, hematological diseases, cancer, inflamma DETAILED DESCRIPTION OF THE tion, respiratory diseases, gastroenterological diseases, dia INVENTION betes, hepatic Steatosis, and non-alcoholic fatty liver disease. The method comprises administering to the patient an effec 0054 The nicotinic acid receptor agonist compounds of tive amount of at least one compound of Formula (I), or a the present invention are useful for treating conditions such pharmaceutically acceptable salt, Solvate, ester, or tautomer as metabolic syndrome, dyslipidemia, cardiovascular dis thereof, in combination with at least one additional active eases, disorders of the peripheral and central nervous sys ingredient selected from the group consisting of hydroxy tem, hematological diseases, cancer, inflammation, respira Substituted aZetidinone compounds, Substituted B-lactam tory diseases, gastroenterological diseases, diabetes, hepatic compounds, HMG CoA reductase inhibitor compounds, Steatosis, and non-alcoholic fatty liver disease and other HMG CoA synthetase inhibitors, squalene synthesis inhibi diseases listed herein. One or more compounds of the tors, squalene epoxidase inhibitors, sterol biosynthesis present invention can be administered alone or in combina inhibitors, nicotinic acid derivatives, bile acid sequestrants, tion with one or more other therapeutic agents as described inorganic cholesterol sequestrants, AcylCoA:Cholesterol herein. O-acyltransferase inhibitors, cholesteryl ester transfer pro tein inhibitors, fish oils containing Omega 3 fatty acids, 0055. The present invention provides compound of For natural water soluble fibers, plant stanols and/or fatty acid mula (I): esters of plant stanols (e.g., Omacor R) from Pronova Bio care, Oslo, Norway), low-density lipoprotein receptor acti vators, anti-oxidants, PPAR C agonists, PPAR Y-agonists, (I) FXR receptor modulators, LXR receptor agonists, lipopro tein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport protein inhibitors, bile acid reabsorption inhibitors, PPAR 8 agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low den sity lipoprotein receptor inducers, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR 8 partial ago and pharmaceutically acceptable salts, Solvates, esters, and nists, niacin or niacin receptor agonists, 5HT transporter tautomers thereof, wherein L. Q. R' and R are defined inhibitors, NE transporter inhibitors, CB antagonists/in above for the compound of formula (I). verse agonists, ghrelin antagonists, H antagonists/inverse agonists, MCH1R antagonists, MCH2R agonists/antago 0056. In one embodiment, R' is alkyl. nists, NPY 1 antagonists, NPY5 antagonists, NPY2 agonists, 0057. In another embodiment, R' is haloalkyl. NPY4 agonists, mGluR5 antagonists, leptins, leptin ago nists/modulators, leptin derivatives, opioid antagonists, 0058. In another embodiment, R' is arylalkyl. orexin receptor antagonists, BRS3 agonists, CCK-A ago 0059. In still another embodiment, R' is -alkylene-S- nists, CNTF, CNTF derivatives, CNTF agonists/modulators, alkyl. 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 agonists, 0060) In yet another embodiment, R is -alkylene-cy phentermine, topiramate, phytopharm compound 57, ghrelin cloalkyl. antibodies, Mc3r agonists, ACC2 inhibitors, B3 agonists, 0061. In another embodiment, R' is -alkylene-cyclopro DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE pyl, -alkylene-cyclobutyl, -alkylene-cyclopentyl or -alky inhibitors, thyroid hormone Bagonists, UCP-1 activators. lene-cyclohexyl. UCP-2 activators, UCP-3 activators, acyl-estrogens, gluco 0062) In a further embodiment, R' is -alkylene-cycloalk corticoid agonists/antagonists, 11B HSD-1 inhibitors, enyl. SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose 0063) In another embodiment, R' is a straight chain alkyl transporter inhibitors, phosphate transporter inhibitors, having from 1 to 6 carbon atoms. US 2008/00 19978 A1 Jan. 24, 2008

0.064 In one embodiment, R' is methyl. 0105. In still another embodiment, R is O-alkynylene 0065 In another embodiment, R' is ethyl. cycloalkyl. 0066) In another embodiment, R' is n-propyl. 0106. Inin yyet anotherh embodiment,bodi R 1Sis haloalkvlalCa 0067 In still another embodiment, R' is n-butyl. 0107. In a further embodiment, R is - O N=C(R). 0068 In one embodiment, R' is n-pentyl. 0108). In one embodiment, R is is —CHF. 0069 In another embodiment, R' is n-hexyl. 0070). In yet another embodiment, R' is a branched chain 0109) In another embodiment, R is CH(F). alkyl having from 3 to 6 carbon atoms. 0110. In another embodiment, R is CF. 0071) In a further embodiment, R' is isopropyl. 0111. In another embodiment, R is —OCH2C=CCH.H. 0072) In one embodiment, R' is isobutyl. 0112) In another embodiment, R4 is 0073) In another embodiment, R' is isopentyl. —OCH2C=C(CH2)CH. 0074) In another embodiment, R' is sec-butyl. 0113. In still another embodiment, R is 0075) In still another embodiment, R' is tert-butyl. –OCHC=CCHCHCH. 0076) In yet another embodiment, R' is haloalkyl, having 0114. In yet another embodiment, R is —OCHC=C- from 1 to 3 F atoms. cyclopropyl. 0077. In another embodiment, R' is -(CH2)CF. 0115) In a further embodiment, R4 is 0078 In one embodiment, R is H. –OCHC=CCH(OCH)CH. 0079 In another embodiment, R is —CN. 0116. In O embodiment, R4 is 0080) In another embodiment, R is NHC(O)-alkyl. OCHC=CCH(OH)CH. 0081) In still another embodiment, R is NHC(O)CHs. 0.117). In another embodiment, R4 is 0082 In one embodiment, R is H. OCHC=CCH(OH)CHCH 0083) In another embodiment, R is —OH. 0118. In another embodiment, R4 is 0084) In another embodiment, R is alkyl. –OCHC=CCHCHOCH. 0085 In another embodiment, R is haloalkyl. 0119). In still another embodiment, R is 0086) In still another embodiment, R is O-alkyl. –OCHC=CCHCH-OH. 0087 In yet another embodiment, R is cycloalkyl. 0120) In yet another embodiment, R is –OCHC=C(CH)OH. 0088) In a further embodiment, R is heterocyclyl. 0089) In one embodiment, R is —O-arylalkyl. 0121. In a further embodiment, R is 0090) In another embodiment, R is -alkylene-O-alkyl. 0122) In another embodiment, R is —OCH2C=C-cyclo 0091) In one embodiment, R is —OCHs. hexyl. 0092) In another embodiment, R is cyclobutyl. 0123) In one embodiment, R is —O-cyclobutyl. 0093) In another embodiment, R is ethyl. 0124) In another embodiment, R is: 0094) In still another embodiment, R is N-morpholinyl. O095 In one embodiment, R is —O-benzyl. 0096) In another embodiment, R is —CHCHOCH. 0097 In yet another embodiment, R is —OCHCHs. 0098) In another embodiment, R is —CHF. -O-cloch-K) 0099) In one embodiment, R is —CH2CH.F. 0100 In another embodiment, R is —OH. in KO-isoch-K) O 0101 In one embodiment, R is CF. 0102) In another embodiment, R is H. 0103) In another embodiment, R is —O-cycloalkyl. -O-isoci-( ) 0104) In another embodiment, R O-alkynyl. US 2008/00 19978 A1 Jan 24, 2008

0125) In one embodiment, R is: 0.155. In another embodiment, Q is: (b) y R3 0126) In one embodiment, R is H. O127) In another embodiment, R is —OH. ns. 0128 In another embodiment, R is alkyl. O 0129 In another embodiment, R is haloalkyl. 0.156. In another embodiment, Q is: 0130 In still another embodiment, R is O-alkyl. 0131) In yet another embodiment, R is cycloalkyl. (c) 0132) In a further embodiment, R is heterocyclyl. 0133) In one embodiment, R is —O-arylalkyl. 0134) In another embodiment, R is -alkylene-O-alkyl. 0135) In one embodiment, R is —OCH. 0136 In another embodiment, R is cyclobutyl. 0137) In another embodiment, R is ethyl. 0138) In still another embodiment, R is N-morpholinyl. 0157. In still another embodiment, Q is: 0139) In one embodiment, R is —O-benzyl. 0140 In another embodiment, R is —CH2CHOCHs. (d) 0141) In yet another embodiment, R is —OCHCHs. 0142) In another embodiment, R is —CHF. 0143) In one embodiment, R is —CH2CH.F. 0144) In another embodiment, R is —OH. 0145) In one embodiment, R is alkoxy. 0146) In another embodiment, R is O-alkylene-O- alkyl. 0147) In another embodiment, R is —O-arylalkyl. 0158. In yet another embodiment, Q is: 0148 in still another embodiment, R is —O-haloalkyl. 0149) In yet another embodiment, R is —OCH-(4- (e) methoxyphenyl). R3 0150. In one embodiment, R is OCHF. 0151. In another embodiment, R is OCHCHF. y R.

0152) In another embodiment, R is OCHCH. N 0153. In still another embodiment, R is –OCHCHOCH. 0154) In one embodiment, Q is: (a) 0159) In one embodiment, L is: y (f) US 2008/00 19978 A1 Jan. 24, 2008

0160 In another embodiment, L is: 0169) wherein the (C-C)cycloalkyl or the (C- C7)cycloalkyl portion of said —(C-C)alkylene (C-C)cycloalkyl of R is unsubstituted or substi (g) tuted with one or more X groups; R O (0170) R' is selected from the group consisting of Ra halogens - O R', —C(O)—O (C-C)alkyl, —S(O), R, N(R), -O-N=C(R), - N(R) NH-C(O)-O-(C-C)alkyl and —C(O)-(C-C)alkyl: 0161 In another embodiment, L is: 0171) R' is selected from the group consisting of H, —(C-C)alkyl, -(C-C)alkylene-C(O) R. —(C- C.)alkylene-C(=N-O-(C-C)alkyl)-(C-C)aryl, (h) (C-C7)cycloalkyl, —(C-C)alkylene-(C- C7)cycloalkyl, —(C-C)alkylene-C(O)-O-(C- C.)alkyl, and (C-C)alkenyl 0172 wherein the (C-C,)cycloalkyl or the (C- C7)cycloalkyl portion of said -(C-C)alkylene (C-C)cycloalkyl of R is unsubstituted or substi tuted with one or more X groups, and the (C- 0162. In still another embodiment, L is: Co)aryl portion of said —(C-C)alkylene C(N=O (C-C)alkyl)-(C-C)aryl of R is (i) unsubstituted or substituted with one or more Y groups: (0173) R' is selected from the group consisting of -O-R', halogen, and N(R'); 0174) each R" is independently selected from the group consisting of H., (C-C)alkyl, (C-C)cycloalkyl, and (Co-Co)aryl, 0163) In another embodiment of the compounds of For mula (I), 0175 wherein the (C-C)cycloalkyl of R is unsub (0164) R' is selected from the group consisting of stituted or substituted with one or more X groups, —(C-C)alkyl, -(C-C)alkenyl, -(C-C)alkynyl. and said (Co-Co)aryl of R is unsubstituted or sub —(C-C)haloalkyl, —(C-C)alkyl substituted with stituted with one or more Y groups; one hydroxyl group, —(C-C7)cycloalkyl, -(C- (0176) R is selected from the group consisting of Co.)alkylene-O-(C-C)alkyl, -(C-C)alkylene-(C- unsubstituted (Co-Co)aryl, (C-C)aryl substituted Co)aryl, -C-C)alkylene-(C-Co)heteroaryl, -(C- with one or more Y groups. -OH, unsubstituted (C- C.)alkylene-C(O) O (C-C)alkyl, -(CH2) - Co)heterocyclyl, and (C-C)heterocyclyl substituted N(R), —(C-C)alkylene-(C-C)cycloalkyl, and with one or more X groups: —(C-C)alkylene-(C-C7)cycloalkenyl 0177 R’ is selected from the group consisting of 0165 wherein the —(C-C)cycloalkyl or the (C- (C-C)alkyl, -(C-C)alkylene-(C-C7)cycloalkyl, C7)cycloalkyl portion of said —(C-C)alkylene (C-C)alkenyl, and —(C-C)alkylene-(C-C)aryl, (C-C7)cycloalkyl is unsubstituted or substituted 0178 wherein the (C-C)cycloalkyl portion of said with one or more X groups, the (C-C)aryl portion —(C-C)alkylene-(C-C)cycloalkyl of R is of said —(C-C)alkylene-(Co-Co)aryl is unsubsti unsubstituted or substituted with one or more X tuted or substituted with one or more Y groups, and groups, and the (C-C)aryl portion of said —(C- the (C-Co)heteroaryl portion of said —(C- C.)alkylene-(Co-Co)aryl of R is unsubstituted or C.)alkylene-(C-C)heteroaryl is unsubstituted or substituted with one or more groups Y: substituted with one or more Z groups; 0179) R' is selected from the group consisting of H, 0166 R is H, halogen, unsubstituted aryl, aryl substi (C-C)alkyl, -(C-C)alkylene-(Co-Co)aryl, -(C- tuted with one or more independently selected Y Co.)alkenylene-(Co-Co)aryl, -(C-C)alkylene-(C- groups, unsubstituted heteroaryl, heteroaryl substituted Co)heteroaryl, (C-C)alkenyl, (C-C)alkynyl, and with one or more independently selected Ygroups; or —(C-C)alkylene-(C-C,)cycloalkyl, (0167) R' and R together with the ring carbonatoms to 0180 wherein the (C-C)cycloalkyl portion of said which they are shown attached, form a 5- or 6-mem —(C-C)alkylene-(C-C)cycloalkyl of R' is bered cycloalkenyl ring: unsubstituted or substituted with one or more X (0168 R is selected from the group consisting of H, groups, and the (C-C)aryl portion of said —(C- (C-C)alkyl, -(C-C)alkylene-O-(C-C)alkyl, Co.)alkylene-(Cs-Co)aryl or -(C-C)alkenylene (C-C)cycloalkyl, —(C-C)alkylene-(C- (Co-Co.)aryl of R" is unsubstituted or substituted C7)cycloalkyl, -(C-C)alkylene-C(O) O-alkyl, and with one or more Y groups, and the (C- (C-C)alkenyl, Co)heteroaryl portion of said -(C-C)alkylene

US 2008/00 19978 A1 Jan. 24, 2008

0206 each Y is independently selected from the group of R" is unsubstituted or substituted with one or consisting of F, Cl, Br, —CH, —CF, —O—CH, more groups Y, and the (C-C)heteroaryl of said —O—CF, —CN, OH, and phenyl; and —(C-C)alkylene-(C-Co)heteroaryl of R' is 0207 each Z is independently selected from the group unsubstituted or Substituted with one or more groups consisting of —CH, —CF, F, Br, and Cl. —O—CH, Z: —CN. —OH, phenyl, and N-oxide. 0220 each R' is independently selected from the group consisting of (C-C)alkyl, (C-Co)aryl, and 0208. In another embodiment of the compounds of For (C-Co)heteroaryl, mula (I), 0221 wherein the (C-C)aryl is unsubstituted or 0209 Q is: Substituted with one or more Y group, and said (C-C)heteroaryl is unsubstituted or substituted (a) with one or more Z group; 0222 each Y is independently selected from the group ". R4 consisting of halogen, (C-C)alkyl, (C-C)haloalkyl, —O—(C-C)haloalkyl, —O—(C-C)alkyl, —CN, —NO. —OH, -S(O)—(C-C)alkyl, - S(O)— (Co-Co)aryl, S(O)—NH, S(O)—NH (C- Ns. C.)alkyl. —S(O)—NH-(C-C)aryl, - S(O)— O N((C-C)alkyl). —S(O)—N((C-Co)aryl), —S(O)—N((C-C)alkyl)((C-C)aryl), and (C- Co)aryl; and 0210 L is: 0223) each Z is independently selected from the group consisting of (C-C)alkyl, (C-C)haloalkyl, halogen, —O-alkyl, —O—(C-C)haloalkyl, —CN, —OH, (C- (f) Co)aryl, and, and N-oxide. 0224. In another embodiment of the compounds of For y mula (I), 0225. Q is: 0211) R' is selected from the group consisting of —(C-C)alkyl, —(C-C)alkylene-O-(C-C)alkyl, unsubstituted (C-C)aryl, and (C-C)aryl Substi (a) tuted with one or more substituents Y: ". n R4 0212 R is H or halogen: 0213) R' is selected from the group consisting of halogen. —O R', —C(O)-O-(C-C)alkyl, ns. —S(O), R, - N(R), - O N=C(R'), N(R) NH CO) O (C-C)alkyl, and O —C(O)—(C-C)alkyl; 0214) R is H or (C-C)alkyl: 0226 L is: 0215 each R" is independently selected from the group consisting of H., (C-C)alkyl, (C-C)cycloalkyl, unsubstituted (C-C)aryl, and (C-C)aryl Substi tuted with one or more Y groups; 0216), R is selected from the group consisting of Sry (C-C)alkyl, —(C-C)alkylene-(C-C)cycloalkyl, (C-C)alkenyl, and —(C-C)alkylene-(Co-Co)aryl, 0217 wherein the (C-C)aryl of said —(C- 0227) R' is —OHOH, butyl, pentyl, —CH, CH C.)alkylene-(Co-Co)aryl of R is unsubstituted or CH2-cyclopropyl; substituted with one or more groups Y: 0228), R is H, Br, unsubstituted aryl, aryl substituted 0218) R' is selected from the group consisting of H, with one or more Y groups, unsubstituted heteroaryl, (C-C)alkyl, —(C-C)alkylene-(Co-Co.)aryl, —(C- heteroaryl substituted with one or more Y groups; C.)alkenylene-(C-C)aryl, -(C-C)alkylene-(C- Co)heteroaryl, (C-C)alkenyl, (C-C)alkynyl, and 0229) R' is selected from the group consisting of C1, —(C-C)alkylene-(C-C)cycloalkyl 0219 wherein the aryl of said —(C-C)alkylene (Co-Co.)aryl or —(C-C)alkenylene-(C-C)aryl CH=CH, -S(O) CH-phenyl, -S(O)-CH(CH)-

US 2008/00 19978 A1 Jan. 24, 2008

0292 each Z is independently selected from the group 0305 R is selected from the group consisting of H, consisting of —CH, F, Br, and Cl. —O—CH –CN, —(C-C)alkylene-(C-C)cycloalkyl, —(C- —OH, phenyl, and N-oxide. C.)alkylene-C(O)—O—(C-C)alkyl, —(C- C)cycloalkyl, (C-C)alkyl, (C-C)alkenyl, and 0293. In another embodiment of the compounds of For —(C-C)alkylene-O-(C-C)alkyl; and mula (I), 0306 R is - O N=C((C-C)alkyl). 0294. Q is: 0307 In another embodiment of the compounds of For (d) R3 mula (I), w O; 0308 Q is: (b) R3 2 N

R6 w O

0295) L is: N NR5 O

O (f) (c) N R4; y n

2 N 0296) R' is —(C-C)alkyl: 0297 R is H: R6 0298 R is H or —(C-C)alkenyl; and 0299 R is -OH or - O (C-C)alkylene-(C- 0309 L is selected from the group consisting of: C.)cycloalkyl. 0300. In another embodiment of the compounds of For (g) mula (I), 0301 Q is: (h) (e) R3 w R4. sy | (i)

O

0302) L is: 0310 R and Rare each independently selected from the group consisting of H. (C-C)alkyl, (C-C)aryl, and (C-C)heteroaryl, (f) 0311 wherein the (C-C)aryl of R and R is unsubstituted or substituted with one or more Y y s groups, and said (C-Clo)heteroaryl of R" and R is unsubstituted or substituted with one or more Z groups: 0303) R' is —(C-C)alkyl or —(C-C)haloalkyl: 0312 R is selected from the group consisting of H, (C-C)alkyl, —(C-C)alkylene-(C-C)aryl, and 0304 R is H: —C(O)—(C-C)alkyl,

US 2008/00 19978 A1 Jan. 24, 2008

which they are attached, form an azetidinyl, pyrrolidinyl, consisting of —CH, -CF, F, Br, and Cl. —O—CH, piperidinyl, piperazinyl, morpholinyl, pyrrolidinonyl, triaz —O CF, —CN, -OH, phenyl, and N-oxide. olyl, or pyrrolyl ring. 0347. Non-limiting illustrative examples of the com 0334. In another embodiment of the compound of For mula (I), R is —CH, unsubstituted phenyl, phenyl substi pounds of formula (I), include the following compounds: tuted with one or more Y groups, piperidyl, and —OH. 0335) In another embodiment of the compound of For mula (I), R is —CH, —CHCH. —CH(CH), —C(CH), —CH2-cyclopropyl. —CH2—CH=CH2. (allyl), —CH-phenyl, and —CH(CH)-phenyl. 0336. In another embodiment of the compound of For mula (I), R' is H. —CH2C=CCH, -CH2-cyclopropyl, —CH-CH=CH2. —CH2-phenyl, —CH(CH)-phenyl, —CH(CH-CH-)-phenyl, —CH(CH(CH))-phenyl, —CH-pyridyl, —CH-thiazolyl, -CH(CH)-thiazolyl, —CH2-pyrimidyl, —CH(CH-CH=CH-)-phenyl, —CH(CHCHCH)-phenyl, wherein the phenyl portion of —CH2-phenyl, —CH(CH)-phenyl, -CH(CH2CH)-phe nyl, —CH(CH(CH))-phenyl, —CH(CH-CH=CH-)-phe nyl, and —CH(CH2CH2CH)-phenyl of R'' are unsubsti tuted or substituted with one or more Y groups, and the pyridyl, thiazolyl, and pyrimidyl portion of said —CH pyridyl, —CH-thiazolyl, —CH(CH)-thiazolyl, —CH-py rimidyl are unsubstituted or substituted with one or more Z groups. 0337. In another embodiment of the compound of For mula (I), R'' is H. —CH, or phenyl, wherein the phenyl is unsubstituted or substituted with one or more Y groups. Alternatively, two groups R', together with the Natom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinonyl, triaz olyl, or pyrrolyl ring. 0338. In another embodiment of the compound of For mula (I), R is H, —CH, -CHCH, or unsubstituted pyridyl or pyridyl Substituted with one or more Z groups. 0339. In another embodiment of the compound of For mula (I), R is H or —CH. 0340. In another embodiment of the compound of For mula (I), R is H or —CHs. 0341 In another embodiment of the compound of For mula (I), R and Rare both —CHs. 0342. In another embodiment of the compound of For mula (I), R is H or —CH. 0343. In another embodiment of the compound of For mula (I), R is H, CH, or -CH2-phenyl, wherein the phenyl portion of said —CH2-phenyl of R is unsubstituted or substituted with one or more Y groups as defined herein. 0344) In another embodiment of the compound of For mula (I), each X is independently selected from the group consisting of CH, -CF, F, Br, and Cl. —O—CH, —O CF, —CN, -OH, phenyl, and N-oxide: 0345. In another embodiment of the compound of For mula (I), each Y is independently selected from the group consisting of F, Cl, Br, —CH, —CF, —O—CH, —O CF, —CN, OH, and phenyl; and 0346. In another embodiment of the compound of For mula (I), each Z is independently selected from the group US 2008/00 19978 A1 Jan. 24, 2008 16

-continued -continued

O O N NHNHCO.Me,

NHNHCO.Me, US 2008/00 19978 A1 Jan. 24, 2008 17

-continued -continued

US 2008/00 19978 A1 Jan. 24, 2008 18

-continued -continued O O N O H NY O O N O, O O N O,

S N-N-CO.Me, S. NH S NS O O O O O O N rNulls l

O Ph, O O N O is N- NH N- N

SP is D. Dil O O N O, rsr s H N1arr -NH N--rt) N Y1.O.

O

V O O O O O N O, rsr r N N N NH Y> O O

O O O O O N O, rsr N 1a1 -NHr sus O

O

r O O O O O N O, r S 1 NHr s--- l

O r O O N O O s O N NH N N

O O US 2008/00 19978 A1 Jan. 24, 2008 19

-continued -continued

US 2008/00 19978 A1 Jan. 24, 2008 20

-continued -continued H Ns N Yy 2N s Br OH US 2008/00 19978 A1 Jan. 24, 2008 21

-continued -continued

US 2008/00 19978 A1 Jan. 24, 2008 22

-continued -continued

US 2008/00 19978 A1 Jan. 24, 2008 23

-continued -continued

US 2008/00 19978 A1 Jan. 24, 2008 24

-continued -continued

US 2008/00 19978 A1 Jan. 24, 2008 25

-continued -continued

US 2008/00 19978 A1 Jan. 24, 2008 26

-continued -continued

US 2008/00 19978 A1 Jan. 24, 2008 27

-continued -continued

O O, O Y NH

C

US 2008/00 19978 A1 Jan. 24, 2008 28

-continued -continued US 2008/00 19978 A1 Jan. 24, 2008 29

-continued -continued H H O O N O O NY

S O O

H O O N O H F O O N O n N Nulls N NS-F. F O O

H O O N O F S N Suk.F, H H O O NY O O NY O N N F, N NS-1 H O O N O O F O NY F N Nulls F, H O O NY O S. N-1-

O US 2008/00 19978 A1 Jan. 24, 2008 30

0348. In one embodiment, the compounds of formula (I)

-continued have the formula (II): (II) O. O | 1N1-1 RI and pharmaceutically acceptable salts, Solvates, esters, and tautomers thereof, wherein: 0349 Q is selected from the group consisting of:

and

R6 0350) R' is —H, alkyl, haloalkyl, arylalkyl, -alkylene-S- alkyl or -alkylene-cycloalkyl; 0351 R is H, CN, or NHC(O)-alkyl; 0352) R' is —O-cycloalkyl, -O-alkynyl, -O-alky nylene-cycloalkyl, haloalkyl or —O N=C(R'), wherein both R" groups, together with the carbon atom to which they are attached, combine to form a heterocyclyl group, and wherein the alkynyl portion of an —O-alkynyl group can be optionally substituted with —OH oralkoxy; and wherein the cycloalkyl portion of an —O-cycloalkyl group can be optionally substituted with an -alkylene-O-alkylene-aryl group; 0353 R is -H, -OH, alkyl, haloalkyl, arylalkyl, -O- alkyl, —O-aryl, cycloalkyl, heterocyclyl. —O-cycloalkyl, —O-heterocyclyl, —O-arylalkyl or -alkylene-O-alkyl; and 0354) R is alkoxy, O-alkylene-O-alkyl, -O-arylalkyl or —O-haloalkyl. 0355 The following embodiments refer to the com pounds of formula (II), wherein Q is: ". R4 ns. O and pharmaceutically acceptable salts, Solvates, esters, or 0356) In one embodiment, R' is alkyl. tautomers thereof. 0357) In another embodiment, R' is haloalkyl. US 2008/00 19978 A1 Jan. 24, 2008

0358) In another embodiment, R' is arylalkyl. 0392) In a further embodiment, R4 is 0359 In still another embodiment, R' is -alkylene-S- –OCHC=CCH(OCH)CH. alkyl. 0393) In O embodiment, R4 is 0360) In yet another embodiment, R' is -alkylene-cy OCHC=CCH(OH)CH. cloalkyl. 0394). In another embodiment, R4 is 0361). In another embodiment, R' is -alkylene-cyclopro OCHC=CCH(OH)CHCH pyl, -alkylene-cyclobutyl, -alkylene-cyclopentyl or -alky 0395. In another embodiment, R4 is lene-cyclohexyl. –OCHC=CCHCHOCH. 0362 In a further embodiment, R' is -alkylene-cycloalk 0396) In still another embodiment, R is enyl. –OCHC=CCHCH-OH. 0363) In another embodiment, R' is a straight chain alkyl 0397. In yet another embodiment, R is having from 1 to 6 carbon atoms. –OCHC=C(CH)OH. 0364 In one embodiment, R' is methyl. 0398. In a further embodiment, R is 0365) In another embodiment, R' is ethyl. 0399. In another embodiment, R is OCH2C=C-cyclo 0366) In another embodiment, R' is n-propyl. hexyl. 0367) In still another embodiment, R' is n-butyl. 04.00 In one embodiment, R is —O-cyclobutyl. 0368 In one embodiment, R' is n-pentyl. 0401) In another embodiment, R is: 0369) In another embodiment, R' is n-hexyl. 0370. In yet another embodiment, R' is a branched chain alkyl having from 3 to 6 carbon atoms. 0371) In a further embodiment, R' is isopropyl. 0372) In one embodiment, R' is isobutyl. -O-cloch-K) 0373) In another embodiment, R' is isopentyl. 0374) In another embodiment, R' is sec-butyl. -KO-isoci-( ) O 0375) In still another embodiment, R' is tert-butyl. 0376) In yet another embodiment, R' is haloalkyl, having from 1 to 3 F atoms. O-g :-not-( ) 0377. In another embodiment, R' is -(CH2)CF. 0378. In one embodiment, R is CF. 0402 In one embodiment, R is: 0379) In another embodiment, R is H. O380) In another embodiment, R is —O-cycloalkyl. 0381 In another embodiment, R O-alkynyl. 0382) In still another embodiment, Ris-O-alkynylene cycloalkyl. 0383) In yet another embodiment, R is haloalkyl. 0403) In one embodiment, R is H. 0384) In a further embodiment, R is -O-N=C(R7). 04.04 In another embodiment, R is —OH. 0385) In one embodiment, R is is —CH.F. 0405 In another embodiment, R is alkyl. 0386 In another embodiment, R is —CH(F). 0406) In another embodiment, R is haloalkyl. 0387) In another embodiment, R is CF. 0407 In still another embodiment, R is —O-alkyl. 0388. In another embodiment, R4 is –OCHC=CCHCH. 04.08 In yet another embodiment, R is cycloalkyl. 0389). In another embodiment, R4 is 04.09 In a further embodiment, R is heterocyclyl. —OCH2C=C(CH2)CH. 0410 In one embodiment, R is —O-arylalkyl. 0390. In still another embodiment, R is In another embodiment, R is -alkylene-O-alkyl. –OCHC=CCHCHCH. 0411 0391) In yet another embodiment, R is —OCHC=C- 0412 In one embodiment, R is —OCHs. cyclopropyl. 0413 In another embodiment, R is cyclobutyl. US 2008/00 19978 A1 Jan. 24, 2008 32

0414) In another embodiment, R is ethyl. 0444 The following embodiments refer to the com 0415) In still another embodiment, R is N-morpholinyl. pounds of formula (II), wherein Q is: 0416) In one embodiment, R is O-benzyl. 0417. In another embodiment, R is CHCHOCH. 0418) In yet another embodiment, R is —OCHCHs. 0419. In another embodiment, R is CHF. 0420. In one embodiment, R is CHCHF. 0421) In another embodiment, R is —OH. 0422) In one embodiment, R' is alkyl and R is —H. 0445. In one embodiment, R' is alkyl. 0423) In another embodiment, R' is haloalkyl and R is 0446. In another embodiment, R' is haloalkyl. —H. 0447. In another embodiment, R' is arylalkyl. 0424) In another embodiment, R' is arylalkyl and R is 0448. In still another embodiment, R' is -alkylene-S- —H. alkyl. 0425) In still another embodiment, R' is -alkylene-S- 0449) In yet another embodiment, R' is -alkylene-cy alkyl and R is —H. cloalkyl. 0426) In yet another embodiment, R' is -alkylene-cy 0450. In another embodiment, R' is -alkylene-cyclopro cloalkyl and R is —H. pyl, -alkylene-cyclobutyl, -alkylene-cyclopentyl or -alky 0427. In one embodiment, R' is alkyl and R is H. lene-cyclohexyl. 0428. In another embodiment, R' is haloalkyl and R is 0451 In a further embodiment, R' is -alkylene-cycloalk —H. enyl. 0429. In another embodiment, R' is arylalkyl and R is 0452) In another embodiment, R' is a straight chain alkyl —H. having from 1 to 6 carbon atoms. 0430). In still another embodiment, R' is -alkylene-S- 0453 In one embodiment, R' is methyl. alkyl and R is —H. 0454) In another embodiment, R' is ethyl. 0431) In yet another embodiment, R' is -alkylene-cy cloalkyl and R is —H. 0455) In another embodiment, R' is n-propyl. In still another embodiment, R' is n-butyl. 0432) In one embodiment, R' is alkyl, R is H and R' 0456) is —O-alkynyl. 0457) In one embodiment, R is n-penty1. 0433) In another embodiment, R' is alkyl, R is Hand 0458) In another embodiment, R' is n-hexyl. R" is O-alkynylene-cycloalkyl. 0459). In yet another embodiment, R' is a branched chain 0434) In another embodiment, R' is alkyl, R is Hand alkyl having from 3 to 6 carbon atoms. R" is haloalkyl. 0460) In a further embodiment, R' is isopropyl. 0435) In still another embodiment, R' is alkyl, R is H In one embodiment, R is isobutyl. and R is - O N=C(R). 0461) 0436. In one embodiment, R' is haloalkyl, R is Hand 0462) In another embodiment, R' is isopentyl. R" is O-alkynyl. 0463 In another embodiment, R' is sec-butyl. 0437. In another embodiment, R' is haloalkyl, R is H 0464) In still another embodiment, R' is tert-butyl. and R is —O-alkynylene-cycloalkyl. 0465) In yet another embodiment, R' is haloalkyl, having 0438. In another embodiment, R' is haloalkyl, R is H from 1 to 3 F atoms. and R is haloalkyl. 0466) In another embodiment, R' is —(CH2)CF. 0439. In still another embodiment, R' is haloalkyl, R is In one embodiment, R is H. -H and R is -O-N=C(R). 0467 0440. In one embodiment, R is -alkylene-cycloalkyl, R 0468 In another embodiment, R is —CN. is – H and R is —O-alkynyl. 0469 In another embodiment, R is NHC(O)-alkyl. 0441. In another embodiment, R is -alkylene-cycloalkyl, 0470) In still another embodiment, R is NHC(O)CH. R is H and R is O-alkynylene-cycloalkyl. 0471) In one embodiment, R is CF. 0442.) In yet another embodiment, R is -alkylene-cy cloalkyl, R is H and R is haloalkyl. 0472) In another embodiment, R is H. 0443) In still another embodiment, R' is -alkylene-cy 0473) In another embodiment, R is —O-cycloalkyl. cloalkyl, R is -H and R is -O-N=C(R). 0474) In another embodiment, R O-alkynyl. US 2008/00 19978 A1 Jan. 24, 2008

0475). In still another embodiment, Ris-O-alkynylene 0496) In one embodiment, R is alkoxy. cycloalkyl. 0497 In another embodiment, R is O-alkylene-O- 0476) In yet another embodiment, R is haloalkyl. alkyl. 0477) In a further embodiment, R is -O-N=C(R). 0498. In another embodiment, R is —O-arylalkyl.arylal Ky 0478) In one embodiment, R is is —CHF. 0499. In still another embodiment, R is —O-haloalkyl. 0479. In another embodiment, R is CH(F). 0500. In yet another embodiment, R is —OCH-(4- 0480. In another embodiment, R is CF. methoxyphenyl). 0481. In another embodiment, R4 is –OCHC=CCHCH. 0501) In one embodiment, R is OCHF. 0482 In another embodiment, R4 is 0502. In another embodiment, R is OCHCHF. —OCH2C=C(CH2)CH. 0483. In still another embodiment, R is 0503) In another embodiment, R is OCHCH. –OCHC=CCHCHCH. 0504) In still another embodiment, R is 0484) In yet another embodiment, is —OCH2C=C- –OCHCHOCH. cyclopropyl. 0505) In one embodiment, R' is alkyl and R is —O- 0485. In a further embodiment, R is alkynyl. –OCH=CCH(OCH)CH. 0506. In another embodiment, R' is alkyl and R is 0486 In O embodiment, R4 is —O-alkynylene-cycloalkyl. OCHC=CCH(OH)CH. 0507. In another embodiment, R' is alkyl and R is 0487. In another embodiment, R4 is haloalkyl. OCHC=CCH(OH)CHCH 0488. In another embodiment, R4 is 0508. In still another embodiment, R' is alkyl and R is OCHC=CCHCHOCH. -O-N=C(R). 0489. In still another embodiment, R is 0509. In one embodiment, R' is haloalkyl and R is –OCHC=CCHCH-OH. —O-alkynyl. 0490. In yet another embodiment, R is 0510) In another embodiment, R' is haloalkyl and R is –OCHC=C(CH)OH. —O-alkynylene-cycloalkyl. 0491. In a further embodiment, R is 0511). In another embodiment, R' is haloalkyl and R is haloalkyl. 0492) In another embodiment, R is —OCH-C=C-cyclo 0512) In still another embodiment, R' is haloalkyl and R' hexyl. is —O N=C(R). 0493) In one embodiment, R is —O-cyclobutyl. 0513) In one embodiment, R' is -alkylene-cycloalkyl and 0494 In another embodiment, R is: R" is O-alkynyl. 0514) In another embodiment, R is -alkylene-cycloalkyl and R is O-alkynylene-cycloalkyl. 0515) In yet another embodiment, R' is -alkylene-cy –{O-cloch-K) s cloalkyl and R is haloalkyl. 0516) In still another embodiment, R' is -alkylene-cy -K)-isoch-K) O cloalkyl and R is - O N=C(R). 0517 Non-limiting illustrative examples of the com pounds of formula (II), include the following compounds: -O-isoci-O) 0495) In one embodiment, R is: US 2008/00 19978 A1 Jan. 24, 2008 34

-continued -continued

US 2008/00 19978 A1 Jan. 24, 2008 35

-continued -continued

US 2008/00 19978 A1 Jan. 24, 2008 36

-continued -continued

US 2008/00 19978 A1 Jan. 24, 2008 37

-continued -continued

US 2008/00 19978 A1 Jan. 24, 2008 38

-continued -continued

and pharmaceutically acceptable salts, Solvates, esters, or tautomers thereof. 0518. In one embodiment, the compounds of formula (I) have the formula (III):

(III) O O | r 1S R1

and pharmaceutically acceptable salts, Solvates, esters, or tautomers thereof, wherein: 0519 Q is selected from the group consisting of: R3 R3 'N' and 's ins As O R6 0520) R' is -H, alkyl, haloalkyl, arylalkyl, -alkylene-S- alkyl or -alkylene-cycloalkyl; 0521) R' is -H, - CN, or - NHC(O)-alkyl: 0522 R is —H, -OH, alkyl, haloalkyl, arylalkyl, -O- alkyl, —O-aryl, cycloalkyl, heterocyclyl. —O-cycloalkyl, —O-heterocyclyl, —O-arylalkyl or -alkylene-O-alkyl: 0523 R is —H, -OH, alkyl, haloalkyl, arylalkyl, -O- alkyl, —O-aryl, cycloalkyl, heterocyclyl. —O-cycloalkyl, —O-heterocyclyl, —O-arylalkyl or -alkylene-O-alkyl; and 0524) R is alkoxy, O-alkylene-O-alkyl, -O-arylalkyl or —O-haloalkyl. 0525) The following embodiments refer to the com pounds of formula (III),y wherein Q is: As O US 2008/00 19978 A1 Jan. 24, 2008 39

0526) In one embodiment, R' is alkyl. 0567. In yet another embodiment, R is OCHCH. 0527 In another embodiment, R' is haloalkyl. 0568. In another embodiment, R is CHF. 0528) In another embodiment, R' is -alkylene-S-alkyl. 0569. In one embodiment, R is CHCHF. 0529) In still another embodiment, R' is -arylalkyl. 0570). In another embodiment, R is OH. 0530) In yet another embodiment, R' is -alkylene. 0571. In one embodiment, R is H. 0531) In a further embodiment, R' is cycloalkyl. 0572. In another embodiment, R is OH. 0532) In one embodiment, R' is -alkylene-cycloalkenyl. 0573. In another embodiment, R is alkyl. 0533) In another embodiment, R' is a straight chain alkyl In another embodiment, R is haloalkyl. having from 1 to 6 carbon atoms. 0574) In still another embodiment, R is —O-alkyl. 0534) In one embodiment, R' is methyl. 0575) 0535) In another embodiment, R' is ethyl. 0576) In yet another embodiment, R is cycloalkyl. 0536) In another embodiment, R' is n-propyl. 0577) In a further embodiment, R is heterocyclyl. 0537) In still another embodiment, R' is n-butyl. 0578. In one embodiment, R is O-arylalkyl. 0538) In one embodiment, R' is n-pentyl. 0579. In another embodiment, R is -alkylene-O-alkyl. 0539 In another embodiment, R' is n-hexyl. 0580. In one embodiment, R is OCH. 0540) In yet another embodiment, R is a branched chain 0581). In another embodiment, R is cyclobutyl. alkyl having from 3 to 6 carbon atoms. 0582. In another embodiment, R is ethyl. 0541) In a further embodiment, R' is isopropyl. 0583. In still another embodiment, R is N-morpholinyl. 0542) In one embodiment, R' is isobutyl. 0584) In one embodiment, R is O-benzyl. 0543) In another embodiment, R' is isopentyl. 0585. In another embodiment, R is CHCHOCH. 0544 In another embodiment, R' is sec-butyl. 0586. In yet another embodiment, R is OCHCH. 0545) In still another embodiment, R' is tert-butyl. 0587. In another embodiment, R is CHF. 0546) In yet another embodiment, R' is haloalkyl, having from 1 to 3 F atoms. 0588. In one embodiment, R is CHCHF. 0547 In another embodiment, R' is —(CH2)CF. 0589. In another embodiment, R is OH. 0590. In one embodiment, R' is alkyl, and each of R. R. 0548 In one embodiment, R is H. and R is H. 0549) In another embodiment, R is —CN. 0591) In another embodiment, R' is alkyl, R is -H, and 0550) In another embodiment, R is NHC(O)-alkyl. one, but not both of R and R is H. 0551) In still another embodiment, R is NHC(O)CH. 0592) In another embodiment, R' is alkyl, R is -H, and 0552) In one embodiment, R is H. one of R and R is H and the other is alkyl. 0553) In another embodiment, R is —OH. 0593. In still another embodiment, R is alkyl, R is -H, 0554 In another embodiment, R is alkyl. and one of R and R is H and the other is —O-alkyl. 0594) In yet another embodiment, R' is alkyl, R is -H, 0555) In another embodiment, R is haloalkyl. and one of R and R is H and the other is -cycloalkyl. 0556) In still another embodiment, R is O-alkyl. 0595. In one embodiment, R is alkyl, R is -H, and one 0557) In yet another embodiment, R is cycloalkyl. of R and R is H and the other is -heterocyclyl. 0558) In a further embodiment, R is heterocyclyl. 0596) In one embodiment, R' is alkyl, R is —H, and one 0559) In one embodiment, R is —O-arylalkyl. of R and R is H and the other is -alkylene-O-alkyl. 0597. In one embodiment, R' is -alkylene-cycloalkyl, and 0560) In another embodiment, R is -alkylene-O-alkyl. each of R, R and R is H. 0561) In one embodiment, R is —OCHs. 0598. In another embodiment, R is -alkylene-cycloalkyl, 0562 In another embodiment, R is cyclobutyl. R’ is -H, and one, but not both of R and R is H. 0563) In another embodiment, R is ethyl. 0599. In another embodiment, R' is -alkylene-cycloalkyl, 0564) In still another embodiment, R is N-morpholinyl. R’ is -H, and one of RandR is Hand the other is alkyl. 0600). In still another embodiment, R' is -alkylene-cy 0565) In one embodiment, R is —O-benzyl. cloalkyl, R is —H, and one of R and R is H and the 0566) In another embodiment, R is —CH2CHOCHs. other is —O-alkyl. US 2008/00 19978 A1 Jan. 24, 2008 40

0601) In yet another embodiment, R' is -alkylene-cy 0629. In a further embodiment, R' is isopropyl. cloalkyl, R is —H, and one of R and R is H and the other is -cycloalkyl. 0630 In one embodiment, R' is isobutyl. 0602) In one embodiment, R is -alkylene-cycloalkyl, R 0631 In another embodiment, R' is isopentyl. is -H, and one of R and R is H and the other is 0632) In another embodiment, R' is sec-butyl. -heterocyclyl. 0633) In still another embodiment, R' is tert-butyl. 0603) In one embodiment, R' is -alkylene-cycloalkyl, R' is —H, and one of R and R is —H and the other is 0634) In yet another embodiment, R' is haloalkyl, having -alkylene-O-alkyl. from 1 to 3 F atoms. 0604 The following embodiments refer to the com 0635) In another embodiment, R' is —(CH2)CF. pounds of formula (III), wherein Q is: 0636) In one embodiment, R is H. 0637. In another embodiment, R is CN. 0638. In another embodiment, R is NHC(O)-alkyl. y 0639. In still another embodiment, R is NHC(O)CH. 0640). In one embodiment, R is H. 0641) In another embodiment, R is —OH. A R6 0642) In another embodiment, R is alkyl. 0643) In another embodiment, R is haloalkyl. 0605) In one embodiment, R is alkoxy. 0644) In still another embodiment, R is —O-alkyl. 0606) In another embodiment, R is —O-alkylene-O- alkyl. 0645) In yet another embodiment, R is cycloalkyl. 0607) In another embodiment, R is O-arylalkyl. 0646) In a further embodiment, R is heterocyclyl. 0608. In still another embodiment, R is —O-haloalkyl. 0647) In one embodiment, R is O-arylalkyl. 0609. In yet another embodiment, R is —OCH-(4- 0648) In another embodiment, R is -alkylene-O-alkyl. methoxyphenyl). 0649) In one embodiment, R is —OCHs. 0610. In one embodiment, R is OCHF. 0650) In another embodiment, R is cyclobutyl. 0611. In another embodiment, R is —OCHCHF. 0651) In another embodiment, R is ethyl. 0612) In another embodiment, R is —OCHCH. 0652) In still another embodiment, R is N-morpholinyl. 0613) In still another embodiment, R is 0653) In one embodiment, R is —O-benzyl. –OCHCHOCH. 0654) In another embodiment, R is —CH2CHOCHs. 0614) In one embodiment, R' is alkyl. 0615) In another embodiment, R' is haloalkyl. 0655) In yet another embodiment, R is —OCHCH. 0616) In another embodiment, R' is -alkylene-S-alkyl. 0656) In another embodiment, R is —CHF. 0617) In still another embodiment, R' is -arylalkyl. 0657) In one embodiment, R is —CHCHF. 0618. In yet another embodiment, R' is -alkylene. 0658 In another embodiment, R is H. 0659. In one embodiment, R is alkoxy, R' is alkyl, and 0619. In a further embodiment, R' is -cycloalkyl. each of R and R is H. 0620. In one embodiment, R' is -alkylene-cycloalkenyl. (0660) In another embodiment, R is alkoxy, R is alkyl, 0621) In another embodiment, R' is a straight chain alkyl R is -H, and R is alkyl. having from 1 to 6 carbon atoms. 0661). In still another embodiment, R is alkoxy, R is 0622) In one embodiment, R' is methyl. alkyl, R is -H, and R is —O-alkyl. 0623) In another embodiment, R' is ethyl. 0662) In yet another embodiment, R is alkoxy, R is 0624 In another embodiment R' is n-propyl. alkyl, R is -H, and R is -cycloalkyl. 0663) In one embodiment, R is alkoxy, R is alkyl, R is 0625 In still another embodiment, R' is n-butyl. —H, and and R is -heterocyclyl. 0626) In one embodiment, R' is n-pentyl. 0664) In one embodiment, R is aikoxy, R is alkyl, R is 0627) In another embodiment, R' is n-hexyl. —H, and R is -alkylene-O-alkyl. 0628. In yet another embodiment, R' is a branched chain 0665) In one embodiment, R is alkoxy, R is -alkylene alkyl having from 3 to 6 carbon atoms. cycloalkyl, and each of R and R is H. US 2008/00 19978 A1 Jan. 24, 2008

0666) In another embodiment, R is alkoxy, R is -alky 0690. In another embodiment, R is O-arylalkyl, R' is lene-cycloalkyl, R is H, and R is alkyl. -alkylene-cycloalkyl, R is —H, and R is alkyl. 0667. In still another embodiment, R is alkoxy, R' is 0.691). In still another embodiment, R is O-arylalkyl, -alkylene-cycloalkyl, R is —H, and R is —O-alkyl. R is -alkylene-cycloalkyl, R is —H, and R is —O-alkyl. 0668). In yet another embodiment, R is alkoxy, R' is 0692) In yet another embodiment, R is O-arylalkyl, R' -alkylene-cycloalkyl, R is —H, and R is -cycloalkyl. is -alkylene-cycloalkyl, R is -H, and R is -cycloalkyl. 0669. In one embodiment, R is alkoxy, R is -alkylene 0693. In one embodiment, R is O-arylalkyl, R' is cycloalkyl, R is —H, and R is -heterocyclyl. -alkylene-cycloalkyl, R is -H, and R is -heterocyclyl. 0670). In one embodiment, R is alkoxy, R is -alkylene 0694) In one embodiment, R is —O-arylalkyl, R' is cycloalkyl, R is —H, and R is -alkylene-O-alkyl. -alkylene-cycloalkyl, R is -H, and R is -alkylene-O-alkyl. 0671). In one embodiment, R is —O-alkylene-O-alkyl, 0695) In one embodiment, R is -O-haloalkyl, R' is R is alkyl, and each of R and R is H. alkyl, and each of R and R is H. 0672) In another embodiment, R is O-alkylene-O- 0696) In another embodiment, R is —O-haloalkyl, R' is alkyl, R' is alkyl, R is —H, and R is alkyl. alkyl, R is -H, and R is alkyl. 0673) In still another embodiment, R is —O-alkylene (0697). In still another embodiment, R is —O-haloalkyl, O-alkyl, R' is alkyl, R is H, and R is —O-alkyl. R is alkyl, R is -H, and R is —O-alkyl. 0674) In yet another embodiment, R is O-alkylene-O- (0.698). In yet another embodiment, R is —O-haloalkyl, alkyl, R' is alkyl, R is —H, and R is -cycloalkyl. R is alkyl, R is -H, and R is -cycloalkyl. 0675). In one embodiment, R is —O-alkylene-O-alkyl, 0699. In one embodiment, R is -O-haloalkyl, R' is R is alkyl, R is —H, and and R is -heterocyclyl. alkyl, R is -H, and and R is -heterocyclyl. 0676). In one embodiment, R is —O-alkylene-O-alkyl, 0700. In one embodiment, R is -O-haloalkyl, R' is R is alkyl, R is —H, and R is -alkylene-O-alkyl. alkyl, R is -H, and R is -alkylene-O-alkyl. (0.677). In one embodiment, R is —O-alkylene-O-alkyl, 0701. In one embodiment, R is -O-haloalkyl, R' is R is -alkylene-cycloalkyl, and each of R and R is H. -alkylene-cycloalkyl, and each of R° and R is H. 0678. In another embodiment, R is O-alkylene-O- 0702) In another embodiment, R is —O-haloalkyl, R' is alkyl, R' is -alkylene-cycloalkyl, R is —H, and R is alkyl. -alkylene-cycloalkyl, R is —H, and R is alkyl. (0703) In still another embodiment, R is —O-haloalkyl, 0679. In still another embodiment, R is —O-alkylene R is -alkylene-cycloalkyl, R is —H, and R is —O-alkyl. O-alkyl, R' is -alkylene-cycloalkyl, R is —H, and R is —O-alkyl. (0704) In yet another embodiment, R is —O-haloalkyl, R is -alkylene-cycloalkyl, R is -H, and R is cycloalkyl. 0680 In yet another embodiment, R is —O-alkylene-O- alkyl, R' is -alkylene-cycloalkyl, R is -H, and R is 0705 Non-limiting illustrative examples of the com -cycloalkyl. pounds of formula (III), include the following compounds: 0681) In one embodiment, R is —O-alkylene-O-alkyl, R is -alkylene-cycloalkyl, R is —H, and R is -heterocy clyl. (0.682). In one embodiment, R is —O-alkylene-O-alkyl, R is -alkylene-cycloalkyl, R is -H, and R is -alkylene Sn N YOMe, N N YOMe, O-alkyl. 0683) In one embodiment, R is —O-arylalkyl, R' is O O alkyl, and each of R and R is H. 0684) In another embodiment, R is —O-arylalkyl, R' is alkyl, R is -H, and R is alkyl. (0.685). In still another embodiment, R is —O-arylalkyl, R is alkyl, R is -H, and R is O-alkyl. (M. (M. 0686) In yet another embodiment, R is O-arylalkyl, R' O O NY O O NY is alkyl, R is -H, and R is -cycloalkyl. S NH N N 0687 In one embodiment, R is O-arylalkyl, R' is alkyl, R is -H, and and R is -heterocyclyl. O O 0688. In one embodiment, R is —O-arylalkyl, R' is alkyl, R is -H, and R is -alkylene-O-alkyl. 0689. In one embodiment, R is O-arylalkyl, R' is -alkylene-cycloalkyl, and each of R and R is H. US 2008/00 19978 A1 Jan. 24, 2008 42

-continued -continued H H H O O NY O O NY O O N N N YOMe, N N YOMe, MeOCHN N NH

O O O

H H O O N O , O O N O,

OMe OMe N N N N O O N O, O O N O, Yy r r O O N NH N NH

O O

H H N O O NY O O N N N N N H O O NY O O N Some

CN H O O N O, O O N O s s OMe n H N NH N n O O N O, O O N O, n O O Null N NH NC S NH

O

H H O O N O O N O O N N NH S NH N NH NC NC US 2008/00 19978 A1 Jan. 24, 2008 43

-continued -continued OEt

O

US 2008/00 19978 A1 Jan. 24, 2008 44

and and pharmaceutically acceptable salts, Solvates, esters, -continued and tautomers thereof, wherein: OH H 0707) R" is haloalkyl; and O O N O O NY s 0708) R’ is H or cycloalkyl. NH N 0709. In one embodiment, R' is fluoroalkyl. S S YOH 0710) In another embodiment, R' is -alkylene-F. O O 0711) In another embodiment, R' is -alkylene-CF. 0712) In still another embodiment, R' is —(CH) CF.

H 0713) In another embodiment, R' is —(CH) CF. O O N 0714) In another embodiment, R' is —(CH) CF. NH 0715) In yet another embodiment, R is —(CH) CF. 1S 0716) In still another embodiment, R' is —(CH), F. O 0717) In another embodiment, R' is —(CH) F. 0718) In another embodiment, R' is —(CH2)5 F. O O NH O, No s O 0719. I h bodi R i CH F O O N O n yet another embodiment, 1S — 216 1. 0720. In one embodiment, R is H. us N N NH H N NH O721. I in anotherh embodiment,bodi R2 1S cyclopropyl.1 1 O 0722) In another embodiment, R is cyclobutyl. O O723. Inin St1llSt11 anotherh embodiment,bodi R’ is1S cyclopentylCWCOWI. 0724) In another embodiment, R is cyclohexyl.

H 0725) In one embodiment, R' is fluoroalkyl and R is H. 0726) In another embodiment, R is fluoroalkyl and R is O O NY cycloalkyl. N NS 1. and 0727. In another embodiment, R' is -alkylene-CF, and R' is H. 0728) In another embodiment, R' is -alkylene-CF, and R' is cycloalkyl.

0729 Non-limiting examples of compounds of formula (IV) include compounds 834, 835 and 837-841 as depicted in the Examples section below, and and pharmaceutically acceptable salts, Solvates, esters, and tautomers thereof. 0730. In another embodiment, the compounds of formula (I) are compounds of formula (V): (V) O O Ns R2 N NH and pharmaceutically acceptable salts, Solvates, esters, or RI O tautomers thereof. and and pharmaceutically acceptable salts, Solvates, esters, 0706. In one embodiment, the compounds of formula (I) are compounds of formula (IV): and tautomers thereof, wherein: 0731) R" and R are each, independently, haloalkyl. (IV) 0732) In one embodiment, R is fluoroalkyl. 0733) In another embodiment, R' is -alkylene-F. 0734) In another embodiment, R' is -alkylene-CF. 0735) In still another embodiment, R' is —(CH) CF. 0736) In another embodiment, R' is —(CH) CF. US 2008/00 19978 A1 Jan. 24, 2008 45

0737. In another embodiment, R' is —(CH) CF. 0738). In yet another embodiment, R' is —(CH-)s CF. -continued 0739. In still another embodiment, R is —(CH) F. Com 0740) In another embodiment, R' is —(CH) F. red Structure 0741. In another embodiment, R' is —(CH2)5 F. 0742) In yet another embodiment, R' is —(CH) F. 847 0743) In one embodiment, R is fluoroalkyl. 0744) In another embodiment, R is —CHF. 0745) In one embodiment, R is fluoroalkyl and R is fluoroalkyl. 0746) In another embodiment, R is fluoroalkyl and R is —CHF. 0747. In another embodiment, R' is -alkylene-CF, and R' is fluoroalkyl. 848 0748). In still another embodiment, R' is -alkylene-CF and R is —CHF. 0749 Non-limiting examples of compounds of formula N (V) include compounds 836 and 842-844 as depicted in the \ Examples section below, and and pharmaceutically accept able salts, Solvates, esters, and tautomers thereof. o 0750 Additional non-limiting examples of compounds of formula (I) include compounds 845-911 as depicted in the 849 following table:

Com pound No. Structure

845 F

F 850 H O O NY N NH

O

851 H O O N O 846 Y N NH F O US 2008/00 19978 A1 Jan. 24, 2008 46

-continued -continued

Com Com pound pound No Structure No Structure 856

852 O O

853

857

854

858

855

859

US 2008/00 19978 A1 Jan. 24, 2008 47

-continued -continued

Com pound Com No. Structure pound No. Structure 860 F

865 F F O O N n F S NH

O

861 866 F

F F

862 F

F

867 F

F

863 F

O O N n F N NH

O

864 F 868 F

US 2008/00 19978 A1 Jan. 24, 2008 48

-continued -continued

Com Com pound pound No Structure No Structure 873 F

869 F

874

F

870

875 F

F 871

872 876

US 2008/00 19978 A1 Jan. 24, 2008

-continued -continued

Com- Com pound pound No. Structure No. Structure 878 F

883 F F

F

879 F

884 F

F

88O F

F 885 F

F

881 F

F

886 F

F

882 F US 2008/00 19978 A1 Jan. 24, 2008 50

-continued -continued

Com Com pound pound No. Structure No Structure 887 F 891

888 F

892

893 886 F

890 F 894

N NH

OH O

895 NullO N. US 2008/00 19978 A1 Jan. 24, 2008 51

-continued -continued

Com Com pound pound No. Structure

896 H 900 O O N S NH

O

O 901

897

902

898 903

899

904 US 2008/00 19978 A1 Jan. 24, 2008 52

-continued -continued

Com Com pound pound No. Structure No. Structure

905 910 H O O O O N N N NH

906 O O 911 N

s S le

907 O O

N and and pharmaceutically acceptable salts, Solvates, esters, and tautomers thereof. 0751. In all embodiments of the present invention, when L is (f), and R. Rand Rare each H, then R is not —CH. One of skill in the art will recognize that the present invention does not include the following compound, or 908 tautomeric forms thereof: O O N

C

909 0752 The moiety L of Formula (I) of the present inven O O tion can have any chemically stable orientation. That is, when L is (f), the compounds of Formula (I) of the present N invention can include the following: US 2008/00 19978 A1 Jan. 24, 2008 53

-continued O Rd in 21 Q, Q O 1S U1 R2 N-Ul/ R1 R1 or salts, Solvates, esters, or tautomers thereof. When L is (g), Rd the compounds of Formula (I) of the present invention can o1 include the following: N21 Rb | y, O N-Ul/ Ra

R2 N U of R or salts, Solvates, esters, or tautomers thereof. Ra Rb 0753. The compounds of Formula (I) can be purified to a O degree Suitable for use as a pharmaceutically active Sub | y, stance. That is, the compounds of Formula (I) can have a R2 N U1 purity of 95 wt % or more (excluding adjuvants such as pharmaceutically acceptable carriers, solvents, etc., which R1 are used in formulating the compound of Formula (I) into a conventional form, such as a pill, capsule, IV solution, etc. or salts, solvates, esters, or tautomers thereof. When L is (h), suitable for administration into a patient). The purity can be the compounds of Formula (I) of the present invention can 97 wt % or more, or, 99 wt % or more. A purified compound include the following: of Formula (I) includes a single isomer having a purity, as discussed above, of 95 wt % or more, 97 wt % or more, or

99 wt % or more, as discussed above. 0754). Alternatively, the purified compound of Formula (I) can include a mixture of isomers, each having a structure O according to Formula (I), where the amount of impurity (i.e., compounds or other contaminants, exclusive of adjuvants as discussed above) is 5 wt % or less, 3 wt % or less, or 1 wt % or less. For example, the purified compound of Formula (I) can be an isomeric mixture of compounds of Structure (I), where the ratio of the amounts of the two isomers is approximately 1:1, and the combined amount of the two isomers is 95 wt % or more, 97 wt % or more, or 99 wt % O. O. 0755 Compounds of Formula (I), and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All Such or salts, solvates, esters, or tautomers thereof. When L is (i), tautomeric forms are contemplated herein as part of the the compounds of Formula (I) of the present invention can present invention. For example, the compounds of the include the following: present invention include tautomeric forms as shown below:

O O N OH H H O O N NY O O N ne al r re 1S R2 N 2 = - R2 N

R1 O RI OH RI O US 2008/00 19978 A1 Jan. 24, 2008 54

-continued

Rb O O; Ra s s N NH R2

N NH

RI O

H N N O; 2 Y N NH US 2008/00 19978 A1 Jan. 24, 2008

-continued RC RC H O N l N R4 O N N." R2 N D.C. RI O RI O Rdo N N R4 Rdo N N R4 Rdo N R4

R2 S 2 N s R2 N NH s R2 N N

RI OH RI O R1 O

Such tautomeric forms are considered equivalent. 0784 “t-BuOK' means potassium tertiary-butoxide. 0756. As used above, and throughout this disclosure, the 0785. “TFA' means trifluoroacetic acid. following terms, unless otherwise indicated, shall be under stood to have the following meanings: 0786) “TfGH' means trifluromethanesulfonic acid. 0757. “AcOH” means acetic acid. 0787. “THF means tetrahydrofuran. 0758 “Bn” means benzyl. 0788 “TLC’ means thin layer chromatography. 0759) “BnBr” means benzyl bromide. 0789) “PMBOH” means 4-methoxybenzyl alcohol. 0760 “BnOH” means benzyl alcohol. 0790) “PMBCI means 4-methoxybenzyl chloride. 0791) “Prep TLC' means preparative thin layer chroma 0761) “CDI means carbodiimide. tography. 0762 “DCM” means dichloromethane (CHCl). 0792 “Patient' includes both human and animals. 0763 “DIAD' means diisopropyl azodicarboxylate. 0793 “Mammal means humans and other mammalian 0764) “DIEA' means N,N-diisopropylethylamine. animals. 0765) “DMF means dimethylformamide. 0794 “Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 0766) “Et” means ethyl. to about 20 carbon atoms in the chain. Preferred alkyl groups 0767) “EtO,” means diethyl ether. contain about 1 to about 12 carbonatoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon 0768 “EtOAc' means ethylacetate. atoms in the chain. Branched means that one or more lower 0769) “HATU” means O-(7-azabenzotriazol-1-yl)-NN, alkyl groups such as methyl, ethyl or propyl, are attached to N',N'-tetramethylammonium hexafluorophosphate. a linear alkyl chain. "Lower alkyl means a group having “HOAc' means acetic acid. about 1 to about 6 carbon atoms in the chain which may be 0770 straight or branched. “Alkyl may be unsubstituted or 0771) “IBMX” means 3-isobutyl-1-methylxanthine. optionally substituted by one or more substituents which may be the same or different, each substituent being inde 0772) “m-CPBA” means m-chloroperoxybenzoic acid. pendently selected from the group consisting of halo, alkyl, 0773) “Me” means methyl. aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl). —NH(cycloalkyl). —N(alkyl), carboxy and 0774) “MeCN' means acetonitrile. —C(O)C-alkyl. Non-limiting examples of suitable alkyl 0775 “MeI” means iodomethane. groups include methyl, ethyl, n-propyl, isopropyl and t-bu tyl. 0776 “MeS” means dimethyl sulfide. 0795 “Alkenyl' means an aliphatic hydrocarbon group 0777 “MeOH” means methanol. containing at least one carbon-carbon double bond and 0778 “NaOEt” means sodium ethoxide. which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl 0779) “NaOMe” means sodium methoxide. groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the 0780 “NBS” means N-bromosuccinimide. chain. Branched means that one or more lower alkyl groups 0781) “NEt” means triethylamine. Such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. “Lower alkenyl means about 2 to about 6 0782 “NIS’ means N-iodosuccinimide. carbon atoms in the chain which may be straight or 0783) “t-Bu' means tertiary-butyl. branched. “Alkenyl may be unsubstituted or optionally US 2008/00 19978 A1 Jan. 24, 2008 56 substituted by one or more substituents which may be the Suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thie same or different, each Substituent being independently nyl, pyrimidinyl, pyridone (including N-Substituted pyri selected from the group consisting of halo, alkyl. aryl, dones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl pyra cycloalkyl, cyano, alkoxy and —S(alkyl). Non-limiting Zolyl, furazanyl, pyrrolyl pyrazolyl, triazolyl, 1,2,4- examples of Suitable alkenyl groups include ethenyl, prope thiadiazolyl pyrazinyl, pyridazinyl, quinoxalinyl, nyl. n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and phthalazinyl, oxindolyl, imidazol-2-alpyridinyl, imidazo decenyl. 2,1-bithiazolyl, benzofurazanyl, indolyl azaindolyl, benz imidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopy 0796 “Alkylene' means a difunctional group obtained ridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, by removal of a hydrogen atom from an alkyl group that is imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-tri defined above. Non-limiting examples of alkylene include azinyl, benzothiazolyl and the like. The term "heteroaryl methylene, ethylene and propylene. also refers to partially saturated heteroaryl moieties such as, 0797 “Alkenylene' means a difunctional group obtained for example, tetrahydroisoquinolyl, tetrahydroquinolyl and by removal of a hydrogen from an alkenyl group that is the like. defined above. Non-limiting examples of alkenylene include 0802 “Aralkyl or “arylalkyl means an aryl-alkyl CH=CH C(CH)=CH , and CH=CHCH group in which the aryl and alkyl are as previously 0798 “Alkylene-aryl (or aryl-alkylene-) means a group described. Preferred aralkyls comprise a lower alkyl group. in which the aryl and alkylene are as previously described. Non-limiting examples of Suitable aralkyl groups include The bond to the parent moiety is through the alkylene. The benzyl, 2-phenethyl and naphthalenylmethyl. The bond to alkylene moiety can be bonded to one or more aryl moieties. the parent moiety is through the alkyl. Alkylene-aryls can comprise a lower alkylene group. Non 0803 “Alkylaryl means an alkyl-aryl- group in which limiting examples of Suitable alkylene-aryl groups include the alkyl and aryl are as previously described. Preferred benzyl, 2-phenethyl, 2,2-diphenylethylene and naphthale alkylaryls comprise a lower alkyl group. Non-limiting nylmethyl. example of a suitable alkylaryl group is tolyl. The bond to 0799. “Alkynyl' means an aliphatic hydrocarbon group the parent moiety is through the aryl. containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 0804 “Cycloalkyl means a non-aromatic mono- or mul 15 carbon atoms in the chain. Preferred alkynyl groups have ticyclic ring system comprising about 3 to about 10 carbon about 2 to about 12 carbon atoms in the chain; and more atoms, preferably about 5 to about 10 carbon atoms. Pre preferably about 2 to about 4 carbon atoms in the chain. ferred cycloalkyl rings contain about 5 to about 7 ring atoms. Branched means that one or more lower alkyl groups such The cycloalkyl can be optionally substituted with one or as methyl, ethyl or propyl, are attached to a linear alkynyl more “ring system substituents' which may be the same or chain. “Lower alkynyl means about 2 to about 6 carbon different, and are as defined above. Non-limiting examples atoms in the chain which may be straight or branched. of Suitable monocyclic cycloalkyls include cyclopropyl. Non-limiting examples of Suitable alkynyl groups include cyclopentyl, cyclohexyl, cycloheptyl and the like. Non ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. “Alky limiting examples of Suitable multicyclic cycloalkyls nyl' may be unsubstituted or optionally substituted by one include 1-decalinyl, norbornyl, adamanty1 and the like. or more substituents which may be the same or different, 0805 “Cycloalkylalkyl means a cycloalkyl moiety as each substituent being independently selected from the defined above linked via an alkyl moiety (defined above) to group consisting of alkyl, aryl and cycloalkyl. a parent core. Non-limiting examples of Suitable cycloalky 0800 “Aryl means an aromatic monocyclic or multicy lalkyls include cyclohexylmethyl, adamantylmethyl and the clic ring system comprising about 6 to about 14 carbon like. atoms, preferably about 6 to about 10 carbon atoms. The aryl 0806 “Cycloalkenyl' means a non-aromatic mono or group can be optionally Substituted with one or more “ring multicyclic ring system comprising about 3 to about 10 system substituents’ which may be the same or different, carbon atoms, preferably about 5 to about 10 carbon atoms and are as defined herein. Non-limiting examples of Suitable which contains at least one carbon-carbon double bond. aryl groups include phenyl and naphthyl. Preferred cycloalkenyl rings contain about 5 to about 7 ring 0801) “Heteroaryl means an aromatic monocyclic or atoms. The cycloalkenyl can be optionally substituted with multicyclic ring system comprising about 5 to about 14 ring one or more “ring system substituents’ which may be the atoms, preferably about 5 to about 10 ring atoms, in which same or different, and are as defined above. Non-limiting one or more of the ring atoms is an element other than examples of Suitable monocyclic cycloalkenyls include carbon, for example nitrogen, oxygen or Sulfur, alone or in cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the combination. Preferred heteroaryls contain about 5 to about like. Non-limiting example of a suitable multicyclic 6 ring atoms. The "heteroaryl' can be optionally substituted cycloalkenyl is norbornylenyl. by one or more “ring system substituents’ which may be the 0807 “Cycloalkenylalkyl means a cycloalkenyl moiety same or different, and are as defined herein. The prefix aza, as defined above linked via an alkyl moiety (defined above) oxa or thia before the heteroaryl root name means that at to a parent core. Non-limiting examples of Suitable cycloalk least a nitrogen, oxygen or Sulfur atom respectively, is enylalkyls include cyclopentenylmethyl, cyclohexenylm present as a ring atom. A nitrogen atom of a heteroaryl can ethyl and the like. be optionally oxidized to the corresponding N-oxide. “Het eroaryl' may also include a heteroaryl as defined above 0808 “Halogen' means fluorine, chlorine, bromine, or fused to an aryl as defined above. Non-limiting examples of iodine. Preferred are fluorine, chlorine and bromine. US 2008/00 19978 A1 Jan. 24, 2008 57

0809. The term “haloalkyl as used herein refers to an one or more “ring system substituents’ which may be the alkyl group, as defined above, wherein one or more of the same or different, and are as defined herein. The nitrogen or alkyl group's hydrogen atoms is independently replaced sulfur atom of the heterocyclyl can be optionally oxidized to with a halogen. In one embodiment, a haloalkyl group is a the corresponding N-oxide, S-oxide or S.S.-dioxide. Non “fluoroalkyl group.” limiting examples of Suitable monocyclic heterocyclyl rings 0810) The term “fluoroalkyl group’ as used herein, refers include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, to an alkyl group, wherein one or more of the alkyl group's thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydro hydrogen atoms are replaced with a —F atom. In various furanyl, tetrahydrothiophenyl, lactam, lactone, and the like. embodiments, a fluorooalkyl group contains one Fatom, two “Heterocyclyl may also mean a single moiety (e.g., carbo Fatoms or three Fatoms. Illustrative example of fluoroalkyl nyl) which simultaneously replaces two available hydrogens groups include, but are not limited to, —CH2F, —CH(F), on the same carbon atom on a ring system. Example of Such CHCHF, —CF, and —(CH2)CF. moiety is pyrrolidone: 0811 “Ring system substituent’ means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system Substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, O. aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, het eroarylalkenyl, alkylheteroaryl, hydroxy, hydroxyalkyl, 0814) “Heterocyclylalkyl means a heterocyclyl moiety alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, as defined above linked via an alkyl moiety (defined above) carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbo to a parent core. Non-limiting examples of Suitable hetero nyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alky cyclylalkyls include piperidinylmethyl, piperazinylmethyl lthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio. and the like. cycloalkyl, heterocyclyl, C(=N CN) NH, C(=NH) NH, C(=NH) NH(alkyl), YYN . 0815) “Heterocyclenyl' means a non-aromatic monocy YY-N-alkyl-, YYNC(O) , YYNSO and clic or multicyclic ring system comprising about 3 to about —SONYY, wherein Y and Y can be the same or 10 ring atoms, preferably about 5 to about 10 ring atoms, in different and are independently selected from the group which one or more of the atoms in the ring system is an consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. element other than carbon, for example nitrogen, oxygen or "Ring system Substituent may also mean a single moiety Sulfur atom, alone or in combination, and which contains at which simultaneously replaces two available hydrogens on least one carbon-carbon double bond or carbon-nitrogen two adjacent carbon atoms (one H on each carbon) on a ring double bond. There are no adjacent oxygen and/or Sulfur system. Examples of Such moiety are methylene dioxy, atoms present in the ring system. Preferred heterocyclenyl ethylenedioxy, —C(CH) - and the like which form moi rings contain about 5 to about 6 ring atoms. The prefix aza, eties such as, for example: oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or Sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally Substituted by one or more ring system Substituents, wherein “ring system substituent” is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S.S.- to Co. b dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1.2.3,4-tetrahydropyridinyl, 1,2-dihydropy 0812 “Heteroarylalkyl means a heteroaryl moiety as ridinyl, 1,4-dihydropyridinyl, 1.2.3,6-tetrahydropyridinyl, defined above linked via an alkyl moiety (defined above) to 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, a parent core. Non-limiting examples of Suitable heteroaryls 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihy include 2-pyridinylmethyl, quinolinylmethyl and the like. drooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-di 0813 “Heterocyclyl means a non-aromatic saturated hydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, monocyclic or multicyclic ring system comprising about 3 to 7-Oxabicyclo2.2.1]heptenyl, dihydrothiophenyl, dihy about 10 ring atoms, preferably about 5 to about 10 ring drothiopyranyl, and the like. “Heterocyclenyl' may also atoms, in which one or more of the atoms in the ring system mean a single moiety (e.g., carbonyl) which simultaneously is an element other than carbon, for example nitrogen, replaces two available hydrogens on the same carbon atom oxygen or Sulfur, alone or in combination. There are no on a ring system. Example of Such moiety is pyrrolidinone: adjacent oxygen and/or Sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocy clyl root name means that at least a nitrogen, oxygen or Sulfur atom respectively is present as a ring atom. Any —NH in a heterocyclyl ring may exist protected Such as, for example, as an —N(Boc), —N(CBZ), —N(ToS) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by US 2008/00 19978 A1 Jan. 24, 2008

0816) “Heterocyclenylalkyl means a heterocyclenyl 0822 “Hydroxyalkyl means a HO-alkyl-group in which moiety as defined above linked via an alkyl moiety (defined alkyl is as previously defined. Preferred hydroxyalkyls con above) to a parent core. tain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hy 0817 “Cycloalkylene' means a difunctional group droxyethyl. obtained by removal of a hydrogen atom from a cycloalkyl group that is defined above. Non-limiting examples of 0823 “Acyl' means an H C(O)—, alkyl-C(O)— or cycloalkylene include cycloalkyl-C(O)—, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of Suitable acyl groups include formyl, acetyl and propanoyl. 0824 “Aroyl means an aryl-C(O)—group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of Suitable groups include benzoyl and 1-naphthoyl. 0825 "Alkoxy' means an alkyl-O group in which the alkyl group is as previously described Non-limiting examples of Suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen. 0818. It should be noted that in hetero-atom containing 0826 “Aryloxy' means an aryl-O group in which the ring systems of this invention, there are no hydroxyl groups aryl group is as previously described. Non-limiting on carbon atoms adjacent to a N, O or S, as well as there are examples of Suitable aryloxy groups include phenoxy and no N or S groups on carbon adjacent to another heteroatom. naphthoxy. The bond to the parent moiety is through the Thus, for example, in the ring: ether oxygen. 0827 “Aralkyloxy' means an aralkyl-O group in which the aralkyl group is as previously described. Non limiting examples of Suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen. 0828 “Alkylthio’ means an alkyl-S group in which the alkyl group is as previously described. Non-limiting examples of Suitable alkylthio groups include methylthio there is no —OH attached directly to carbons marked 2 and and ethylthio. The bond to the parent moiety is through the 5. sulfur. 0819. It should also be noted that tautomeric forms such 0829 "Arylthio’ means an aryl-S group in which the as, for example, the moieties: aryl group is as previously described. Non-limiting examples of Suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.

rs r 2 0830) “Aralkylthio’ means an aralkyl-S group in N O N OH which the aralkyl group is as previously described. Non limiting example of a suitable aralkylthio group is ben h and Zylthio. The bond to the parent moiety is through the sulfur. 0831 “Alkoxycarbonyl' means an alkyl-O CO are considered equivalent in certain embodiments of this group. Non-limiting examples of Suitable alkoxycarbonyl invention. groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl. 0820) “Alkynylalkyl means an alkynyl-alkyl-group in which the alkynyl and alkyl are as previously described. 0832 “Aryloxycarbonyl' means an aryl-O C(O)— Alkynylalkyls can contain a lower alkynyl and a lower alkyl group. Non-limiting examples of Suitable aryloxycarbonyl group. The bond to the parent moiety is through the alkyl. groups include phenoxycarbonyl and naphthoxycarbonyl. Non-limiting examples of Suitable alkynylalkyl groups The bond to the parent moiety is through the carbonyl. include propargylmethyl. 0833 “Aralkoxycarbonyl' means an aralkyl-O C(O)— 0821) “Heteroaralkyl means a heteroaryl-alkyl-group in group. Non-limiting example of a suitable aralkoxycarbonyl which the heteroaryl and alkyl are as previously described. group is benzyloxycarbonyl. The bond to the parent moiety Preferred heteroaralkyls contain a lower alkyl group. Non is through the carbonyl. limiting examples of suitable aralkyl groups include pyridyl 0834 “Alkylsulfonyl means an alkyl-S(O)— groups methyl, and quinolin-3-ylmethyl. The bond to the parent Preferred groups are those in which the alkyl group is lower moiety is through the alkyl. alkyl. The bond to the parent moiety is through the sulfonyl. US 2008/00 19978 A1 Jan. 24, 2008 59

0835 "Arylsulfonyl means an aryl-S(O)—group. The through hydrolysis in blood. A discussion of the use of bond to the parent moiety is through the sulfonyl. prodrugs is provided by T. Higuchi and W. Stella, “Pro 0836. The term “substituted” means that one or more drugs as Novel Delivery Systems.” Vol. 14 of the A.C.S. hydrogens on the designated atom is replaced with a selec Symposium Series, and in Bioreversible Carriers in Drug tion from the indicated group, provided that the designated Design, ed. Edward B. Roche, American Pharmaceutical atom’s normal valency under the existing circumstances is Association and Pergamon Press, 1987. not exceeded, and that the substitution results in a stable 0844. For example, if a compound of Formula (I) or a compound. Combinations of Substituents and/or variables pharmaceutically acceptable salt, hydrate or Solvate of the are permissible only if such combinations result in stable compound contains a carboxylic acid functional group, a compounds. By “stable compound or “stable structure' is prodrug can comprise an ester formed by the replacement of meant a compound that is sufficiently robust to Survive the hydrogen atom of the acid group with a group Such as, isolation to a useful degree of purity from a reaction mixture, for example, (C-Cs)alkyl, (C-C)alkanoyloxymethyl, and formulation into an efficacious therapeutic agent. 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon 0837. The term “optionally substituted” means optional atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon Substitution with the specified groups, radicals or moieties. atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 car 0838. The term “Purified”, “in purified form” or “in bon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having isolated and purified form” for a compound refers to the from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl physical state of said compound after being isolated from a having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbony synthetic process (e.g. from a reaction mixture), or natural l)amino)ethyl having from 4 to 10 carbon atoms, 3-phtha source or combination thereof. Thus, the term “purified, “in lidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N- purified form” or “in isolated and purified form” for a (C-C)alkylamino(C-C)alkyl (such aS compound refers to the physical state of said compound after f3-dimethylaminoethyl), carbamoyl-(C-C)alkyl, N.N- being obtained from a purification process or processes di (C-C)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, described herein or well known to the skilled artisan (e.g., pyrrolidino- or morpholino(C-C)alkyl, and the like. chromatography, recrystallization and the like), in Sufficient purity to be characterizable by standard analytical tech 0845 Similarly, if a compound of Formula (I) contains an alcohol functional group, a prodrug can be formed by the niques described herein or well known to the skilled artisan. replacement of the hydrogen atom of the alcohol group with 0839. It should also be noted that any carbon as well as a group Such as, for example, (C-C)alkanoyloxymethyl, heteroatom with unsatisfied Valences in the text, schemes, 1-((C-C)alkanoyloxy)ethyl, 1-methyl-1-((C- examples and Tables herein is assumed to have the sufficient C.)alkanoyloxy)ethyl, (C-C)alkoxycarbonyloxymethyl, number of hydrogen atom(s) to satisfy the Valences. N-(C-C)alkoxycarbonylaminomethyl, succinoyl, (C- 0840 When a functional group in a compound is termed C.)alkanoyl, C.-amino(C-C)alkanyl, arylacyl and C-ami “protected’, this means that the group is in modified form to noacyl, or CL-aminoacyl-C-aminoacyl, where each C-ami preclude undesired side reactions at the protected site when noacyl group is independently selected from the naturally the compound is subjected to a reaction. Suitable protecting occurring L-amino acids, P(O)(OH), -P(O)(O(C- groups will be recognized by those with ordinary skill in the C.)alkyl) or glycosyl (the radical resulting from the art as well as by reference to standard textbooks such as, for removal of a hydroxyl group of the hemiacetal form of a example, T. W. Greene et al. Protective Groups in organic carbohydrate), and the like. Synthesis (1991), Wiley, N.Y. 0846. If a compound of Formula (I) incorporates an amine functional group, a prodrug can be formed by the 0841 When any variable (e.g., aryl, heterocycle, R, etc.) replacement of a hydrogen atom in the amine group with a occurs more than one time in any constituent or in Formula group Such as, for example, R-carbonyl, RO-carbonyl, I, its definition on each occurrence is independent of its NRR'-carbonyl where R and R' are each independently definition at every other occurrence. (C-Co.)alkyl, (C-C) cycloalkyl, benzyl, or R-carbonyl is 0842. As used herein, the term “composition' is intended a natural (-aminoacyl or natural C-aminoacyl, -C(O- to encompass a product comprising the specified ingredients HC(O)OY, wherein Y' is H. (C-C)alkyl or benzyl, in the specified amounts, as well as any product which —C(OY)Y wherein Y is (C-C) alkyl and Y is (C- results, directly or indirectly, from combination of the speci C.)alkyl, carboxy (C-C)alkyl, amino(C-C)alkyl or fied ingredients in the specified amounts. mono-N- or di-N,N-(C-C)alkylaminoalkyl, -C(Y)Y wherein Y is H or methyl and Y is mono-N or di-N. 0843 Prodrugs and solvates of the compounds of the N—(C-C)alkylamino morpholino, piperidin-1-yl or pyr invention are also contemplated herein. A discussion of rolidin-1-yl, and the like. prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Sympo 0847 One or more compounds of the invention may exist sium Series, and in Bioreversible Carriers in Drug Design, in unsolvated as well as Solvated forms with pharmaceuti (1987) Edward B. Roche, ed., American Pharmaceutical cally acceptable solvents such as water, ethanol, and the like, Association and Pergamon Press. The term “prodrug means and it is intended that the invention embrace both solvated a compound (e.g., a drug precursor) that is transformed in and unsolvated forms. "Solvate” means a physical associa Vivo to yield a compound of Formula (I) or a pharmaceu tion of a compound of this invention with one or more tically acceptable salt, hydrate or Solvate of the compound. Solvent molecules. This physical association involves vary The transformation may occur by various mechanisms (e.g., ing degrees of ionic and covalent bonding, including hydro by metabolic or chemical processes). Such as, for example, gen bonding. In certain instances the Solvate will be capable US 2008/00 19978 A1 Jan. 24, 2008 60 of isolation, for example when one or more solvent mol of Pharmaceutics (1986) 33 201-217: Anderson et al. The ecules are incorporated in the crystal lattice of the crystalline Practice of Medicinal Chemistry (1996), Academic Press, solid. “Solvate” encompasses both solution-phase and iso New York; and in The Orange Book (Food & Drug Admin latable solvates. Non-limiting examples of suitable solvates istration, Washington, D.C. on their website). These disclo include ethanolates, methanolates, and the like “Hydrate' is sures are incorporated herein by reference thereto. a solvate wherein the solvent molecule is H.O. 0852 Exemplary basic salts include ammonium salts, 0848. One or more compounds of the invention may alkali metal salts such as sodium, lithium, and potassium optionally be converted to a solvate. Preparation of solvates salts, alkaline earth metal salts such as calcium and magne is generally known. Thus, for example, M. Caira et al., J. sium salts, salts with organic bases (for example, organic Pharmaceutical Sci., 93(3), 601-611 (2004) describe the amines) such as dicyclohexylamines, t-butyl amines, and preparation of the Solvates of the antifungal fluconazole in salts with amino acids such as arginine, lysine and the like. ethyl acetate as well as from water. Similar preparations of Basic nitrogen-containing groups may be quarternized with solvates, hemisolvate, hydrates and the like are described by agents such as lower alkyl halides (e.g. methyl, ethyl, and E. C. van Tonder etal, AAPS PharmSciTech., 5(1), article 12 butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. (2004); and A. L. Bingham et al. Chem. Commun., 603-604 dimethyl, diethyl, and dibutyl sulfates), long chain halides (2001). A typical, non-limiting, process involves dissolving (e.g. decyl, lauryl, and Stearyl chlorides, bromides and the inventive compound in desired amounts of the desired iodides), aralkyl halides (e.g. benzyl and phenethyl bro Solvent (organic or water or mixtures thereof) at a higher mides), and others. than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by stan 0853 All such acid salts and base salts are intended to be dard methods. Analytical techniques such as, for example I. pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equiva R. spectroscopy, show the presence of the solvent (or water) lent to the free forms of the corresponding compounds for in the crystals as a Solvate (or hydrate). purposes of the invention. 0849) “Effective amount” or “therapeutically effective 0854 Pharmaceutically acceptable esters of the present amount' is meant to describe an amount of compound or a compounds include the following groups: (1) carboxylic composition of the present invention effective in inhibiting acid esters obtained by esterification of the hydroxy groups, the above-noted diseases and thus producing the desired in which the non-carbonyl moiety of the carboxylic acid therapeutic, ameliorative, inhibitory or preventative effect. portion of the ester grouping is selected from straight or 0850. The compounds of Formula I can form salts which branched chain alkyl (for example, acetyl. n-propyl, t-butyl, are also within the scope of this invention. Reference to a or n-butyl), alkoxyalkyl (for example, methoxymethyl), compound of Formula I herein is understood to include aralkyl (for example, benzyl), aryloxyalkyl (for example, reference to salts thereof, unless otherwise indicated. The phenoxymethyl), aryl (for example, phenyl optionally Sub term "salt(s)', as employed herein, denotes acidic salts stituted with, for example, halogen, Calkyl, or Calkoxy formed with inorganic and/or organic acids, as well as basic or amino); (2) Sulfonate esters, such as alkyl- or aralkylsul salts formed with inorganic and/or organic bases. In addi fonyl (for example, methanesulfonyl); (3) amino acid esters tion, when a compound of Formula I contains both a basic (for example, L-Valyl or L-isoleucyl); (4) phosphonate esters moiety, Such as, but not limited to a pyridine or imidazole, and (5) mono-, di- or triphosphate esters. The phosphate and an acidic moiety, Such as, but not limited to a carboxylic esters may be further esterified by, for example, a Co acid, Zwitterions (“inner salts') may be formed and are alcohol or reactive derivative thereof, or by a 2,3-di(C. included within the term "salt(s) as used herein. Pharma 24)acyl glycerol. ceutically acceptable (i.e., non-toxic, physiologically 0855 Compounds of Formula I, and salts, solvates, esters acceptable) salts are preferred, although other salts are also and prodrugs thereof, may exist in their tautomeric form (for useful. Salts of the compounds of the Formula I may be example, as an amide or imino ether). All Such tautomeric formed, for example, by reacting a compound of Formula I forms are contemplated herein as part of the present inven with an amount of acid or base, such as an equivalent tion. amount, in a medium Such as one in which the salt precipi tates or in an aqueous medium followed by lyophilization. 0856. The compounds of Formula (I) may contain asym metric or chiral centers, and, therefore, exist in different 0851 Exemplary acid addition salts include acetates, stereoisomeric forms. It is intended that all stereoisomeric ascorbates, benzoates, benzenesulfonates, bisulfates, forms of the compounds of Formula (I) as well as mixtures borates, butyrates, citrates, camphorates, camphorsul thereof, including racemic mixtures, form part of the present fonates, fumarates, hydrochlorides, hydrobromides, invention. In addition, the present invention embraces all hydroiodides, lactates, maleates, methanesulfonates... naph geometric and positional isomers. For example, if a com thalenesulfonates, nitrates, oxalates, phosphates, propi onates, Salicylates. Succinates, Sulfates, tartarates, thiocyan pound of Formula (I) incorporates a double bond or a fused ates, toluenesutfonates (also known as tosylates.) and the ring, both the cis- and trans-forms, as well as mixtures, are like. Additionally, acids which are generally considered embraced within the scope of the invention. suitable for the formation of pharmaceutically useful salts 0857 Diastereomeric mixtures can be separated into their from basic pharmaceutical compounds are discussed, for individual diastereomers on the basis of their physical example, by P. Stahl et al., Camille G. (eds.) Handbook of chemical differences by methods well known to those skilled Pharmaceutical Salts. Properties, Selection and Use. (2002) in the art, such as, for example, by chromatography and/or Zurich: Wiley-VCH. S. Berge et al., Journal of Pharmaceu fractional crystallization. Enantiomers can be separated by tical Sciences (1977) 66(1) 1-19; P. Gould, International J. converting the enantiomeric mixture into a diastereomeric US 2008/00 19978 A1 Jan. 24, 2008 mixture by reaction with an appropriate optically active ing procedures analogous to those disclosed in the Schemes compound (e.g., chiral auxiliary Such as a chiral alcohol or and/or in the Examples hereinbelow, by substituting an Mosher's acid chloride), separating the diastereomers and appropriate isotopically labelled reagent for a non-isotopi converting (e.g., hydrolyzing) the individual diastereomers cally labelled reagent. to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., Sub 0863 Polymorphic forms of the compounds of Formula stituted biaryls) and are considered as part of this invention. I, and of the salts, Solvates, esters and prodrugs of the Enantiomers can also be separated by use of chiral HPLC compounds of Formula I, are intended to be included in the column. present invention. 0864. The term “pharmaceutical composition' is also 0858. It is also possible that the compounds of Formula intended to encompass both the bulk composition and indi (I) may exist in different tautomeric forms, and all Such vidual dosage units comprised of more than one (e.g., two) forms are embraced within the scope of the invention. Also, pharmaceutically active agents such as, for example, a for example, all keto-enol and imine-enamine forms of the compound of the present invention and an additional agent compounds are included in the invention. selected from the lists of the additional agents described 0859 All stereoisomers (for example, geometric isomers, herein, along with any pharmaceutically inactive excipients. optical isomers and the like) of the present compounds The bulk composition and each individual dosage unit can (including those of the salts, Solvates, esters and prodrugs of contain fixed amounts of the afore-said “more than one the compounds as well as the salts, Solvates and esters of the pharmaceutically active agents'. The bulk composition is prodrugs). Such as those which may exist due to asymmetric material that has not yet been formed into individual dosage carbons on various Substituents, including enantiomeric units. An illustrative dosage unit is an oral dosage unit Such forms (which may exist even in the absence of asymmetric as tablets, pills and the like. Similarly, the herein-described carbons), rotameric forms, atropisomers, and diastereomeric method of treating a patient by administering a pharmaceu forms, are contemplated within the scope of this invention, tical composition of the present invention is also intended to as are positional isomers (such as, for example, 4-pyridyl encompass the administration of the afore-said bulk com and 3-pyridyl). (For example, if a compound of Formula (I) position and individual dosage units. incorporates a double bond or a fused ring, both the cis- and 0865 The compounds of Formula (I), or pharmaceuti trans-forms, as well as mixtures, are embraced within the cally acceptable salts, Solvates, or esters thereof according to Scope of the invention. Also, for example, all keto-enol and the invention have pharmacological properties; in particular, imine-enamine forms of the compounds are included in the the compounds of Formula (I) can be nicotinic acid receptor invention.) agonists. 0860 Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other 0866 The compounds of Formula (I) of the present isomers, or may be admixed, for example, as racemates or invention, or pharmaceutically acceptable salts, Solvates, or with all other, or other selected, stereoisomers. The chiral esters thereof are useful in treating diseases or conditions centers of the present invention can have the S or R including dyslipidemia and metabolic syndrome. configuration as defined by the IUPAC 1974 Recommenda 0867. The compounds of Formula (I), or pharmaceuti tions. The use of the terms “salt”, “solvate”, “ester”, “pro cally acceptable salts, Solvates, or esters thereof, can be drug and the like, is intended to equally apply to the salt, administered in any Suitable form, e.g., alone, or in combi Solvate, ester and prodrug of enantiomers, Stereoisomers, nation with a pharmaceutically acceptable carrier, excipient rotamers, tautomers, positional isomers, racemates or pro or diluent in a pharmaceutical composition, according to drugs of the inventive compounds. standard pharmaceutical practice. The compounds of For 0861. The present invention also embraces isotopically mula (I), or pharmaceutically acceptable salts, Solvates, or labelled compounds of the present invention which are esters thereof, can be administered orally or parenterally, identical to those recited herein, but for the fact that one or including intravenous, intramuscular, interperitoneal, Sub more atoms are replaced by an atom having an atomic mass cutaneous, rectal, or topical routes of administration, or if so or mass number different from the atomic mass or mass selected, by a combination of one or more of the above number usually found in nature. Examples of isotopes that shown methods. can be incorporated into compounds of the invention include 0868 Pharmaceutical compositions comprising at least isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, one compound of Formula (I), or a pharmaceutically accept fluorine and chlorine, such as H, H, C, C, N, O, able salt, solvate, ester, or tautomer thereof can be in a form '7O, P, P, S, F, and C1, respectively. Suitable for oral administration, e.g., as tablets, troches, capsules, lozenges, aqueous or oily Suspensions, dispersible 0862 Certain isotopically-labelled compounds of For powders or granules, emulsions, syrups, or elixirs. Oral mula (I) (e.g., those labeled with H and ''C) are useful in compositions may be prepared by any conventional phar compound and/or Substrate tissue distribution assays. Triti ated (i.e., H) and carbon-14 (i.e., "C) isotopes are particu maceutical method, and may also contain Sweetening agents, larly preferred for their ease of preparation and detectability. flavoring agents, coloring agents, and preserving agents. Further, substitution with heavier isotopes such as deuterium 0869. The amount of compound of Formula (I), or a (i.e., H) may afford certain therapeutic advantages resulting pharmaceutically acceptable salt, Solvate, ester, or tautomer from greater metabolic Stability (e.g., increased in vivo thereof, administered to a patient can be determined by a half-life or reduced dosage requirements) and hence may be physician based on the age, weight, and response of the preferred in some circumstances. Isotopically labelled com patient, as well as by the severity of the condition treated. pounds of Formula (I) can generally be prepared by follow For example, the amount of compound of Formula I, or a US 2008/00 19978 A1 Jan. 24, 2008 62 pharmaceutically acceptable salt, Solvate, ester, or tautomer hormone receptor analogs, melanin concentrating hormone thereof, administered to the patient can range from about 0.1 antagonists, leptons, galanin receptor antagonists, bombesin mg/kg body weight per day to about 60 mg/kg/d. In one agonists, neuropeptide-Y antagonists, thyromimetic agents, embodiment, the amount is from about 0.5 mg/kg/d to about dehydroepiandrosterone, analogs of dehydroepiandroster 40 mg/kg/d. In another embodiment, the amount is from one, urocortin binding protein antagonists, glucagons-like about 0.5 mg/kg/d to about 10 mg/kg/d. In another embodi peptide-1 receptor agonists, human agouti-related proteins ment, the amount is from about 1 mg/kg/d to about 5 (AGRP), neuromedin U receptor agonists, noradrenergic mg/kg/d. In still another embodiment, the amount is from anorectic agents, appetite Suppressants, hormone sensitive about 1 mg/kg/d to about 3 mg/kg/d. In a specific embodi lipase antagonists, MSH-receptor analogs, C-glucosidase ment, the amount is about 1 mg/kg/d. In another specific inhibitors, apo A1 milano reverse cholesterol transport embodiment, the amount is about 3 mg/kg/d. In another inhibitors, fatty acid binding protein inhibitors (FABP), and specific embodiment, the amount is about 5 mg/kg/d. In fatty acid transporter protein inhibitors (FATP). another specific embodiment, the amount is about 7 mg/kg/ d. In still another specific embodiment, the amount is about 0871. Non-limiting examples of hydroxy-substituted aze 10 mg/kg/d. tidinone compounds and Substituted B-lactam compounds useful in combination with the nicotinic acid receptor ago 0870. The compounds of Formula (I), or pharmaceuti nists of the present invention are those disclosed in U.S. Pat. cally acceptable salts, Solvates, or esters thereof, can also be Nos. 5,767,115, 5,624,920, 5,668,990, 5,656,624 and 5,688, administered in combination with other therapeutic agents. 787, 5,756,470, U.S. Patent Application Nos. 2002/0137690 For example one or more compounds of Formula (I) or and 2002/0137689 and PCT Patent Application No. WO pharmaceutically acceptable salts, Solvates, or esters thereof, 2002/066464, each of which is incorporated herein by can be administered with one or more additional active reference in their entirety. A preferred azetidinone com ingredients selected from the group consisting of hydroxy pound is eZetimibe (for example, ZETIAR) which is avail Substituted aZetidinone compounds, Substituted B-lactam able from Schering-Plough Corporation). compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibi 0872. Non-limiting examples of HMG CoA reductase tors, squalene epoxidase inhibitors, sterol biosynthesis inhibitor compounds useful in combination with the nico inhibitors, nicotinic acid derivatives, bile acid sequestrants, tinic acid receptor agonists of the present invention are inorganic cholesterol sequestrants, AcylCoA:Cholesterol lovastatin (for example MEVACORR) which is available O-acyltransferase inhibitors, cholesteryl ester transfer pro from Merck & Co.), simvastatin (for example ZOCOR(R) tein inhibitors, fish oils containing Omega 3 fatty acids, which is available from Merck & Co.), pravastatin (for natural water soluble fibers, plant stanols and/or fatty acid example PRAVACHOL(R) which is available from Bristol esters of plant stanols, anti-oxidants, PPAR C agonists, Meyers Squibb), atorvastatin, fluvastatin, cerivastatin, PPAR Y-agonists, FXR receptor modulators, LXR receptor CI-981, rivastatin (sodium 7-(4-fluorophenyl)-2,6-diisopro agonists, lipoprotein synthesis inhibitors, renin angiotensin pyl-5-methoxymethylpyridin-3-yl)-3,5-dihydroxy-6-hep inhibitors, microsomal triglyceride transport protein inhibi tanoate), rosuvastatin calcium (CRESTOR(R) from AstraZen tors, bile acid reabsorption inhibitors, PPAR 8 agonists, eca Pharmaceuticals), pitavastatin (such as NK-104 of triglyceride synthesis inhibitors, squalene epoxidase inhibi Negma Kowa of Japan). tors, low density lipoprotein receptor inducers or activators, 0873. A non-limiting example of a HMG CoA synthetase platelet aggregation inhibitors, 5-LO or FLAP inhibitors, inhibitor useful in combination with the nicotinic acid PPAR 8 partial agonists, niacin or niacin receptor agonists, receptor agonists of the present invention is, for example, 5HT transporter inhibitors, NE transporter inhibitors, CB L-659,699 ((E.E)-11-3'R-(hydroxy-methyl)-4'-oxo-2R-ox antagonists/inverse agonists, ghrelin antagonists, Hantago etanyl-3,5,7R-trimethyl-2,4-undecadienoic acid). nists/inverse agonists, MCH1R antagonists, MCH2R ago nists/antagonists, NPY 1 antagonists, NPY5 antagonists, 0874) A non-limiting example of a squalene synthesis NPY2 agonists, NPY4 agonists, mGluR5 antagonists, lep inhibitor useful in combination with the nicotinic acid tins, leptin agonists/modulators, leptin derivatives, opioid receptor agonists of the present invention is, for example, antagonists, orexin receptor antagonists, BRS3 agonists, squalestatin 1. CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/ modulators, 5HT2c agonists, Mc4r agonists, monoamine 0875. A non-limiting example of a squalene epoxidase reuptake inhibitors, serotonin reuptake inhibitors, GLP-1. inhibitor useful in combination with the nicotinic acid GLP-1 agonists, GLP-1 mimetics, phentermine, topiramate, receptor agonists of the present invention is, for example, phytopharm compound 57, ghrelin antibodies, Mc3r ago NB-598 ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3- nists, ACC inhibitors, B3 agonists, DGAT1 inhibitors, (3,3'-bithiophen-5-yl)methoxybenzene-methanamine DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hydrochloride). hormone? agonists, UCP-1 activators, UCP-2 activators, 0876. A non-limiting example of a sterol biosynthesis UCP-3 activators, acyl-estrogens, glucocorticoid agonists/ inhibitor useful in combination with the nicotinic acid antagonists, 11B HSD-1 inhibitors, SCD-1 inhibitors, lipase receptor agonists of the present invention is, for example, inhibitors, fatty acid transporter inhibitors, dicarboxylate DMP-565. transporter inhibitors, glucose transporter inhibitors, phos phate transporter inhibitors, anti-diabetic agents, anti-hyper 0877. Non-limiting examples of nicotinic acid deriva tensive agents, anti-dyslipidemic agents, DP receptor tives (e.g., compounds comprising a pyridine-3-carboxylate antagonists, apolipoprotein-B secretion/microsomal triglyc structure or a pyrazine-2-carboxylate structure, including eride transfer protein (apo-B/MTP) inhibitors, sympathomi acid forms, salts, esters, Zwitterions and tautomers) useful in metic agonists, dopamine agonists, melanocyte-stimulating combination with the nicotinic acid receptor agonists of the US 2008/00 19978 A1 Jan. 24, 2008

present invention are niceritrol, nicofuranose and acipimox described in Kuo et al. J. Am. Chem. Soc., 117, 10629-34 (5-methyl pyrazine-2-carboxylic acid 4-oxide). (1995), herein incorporated by reference; the compounds described in Pietzonka et al. Bioorg, Med. Chem. Lett. 6, 0878. Non-limiting examples of bile acid sequestrants 1951-54 (1996), herein incorporated by reference; the com useful in combination with the nicotinic acid receptor ago pounds described in Lee et al. J. Antibiotics, 49, 693-96 nists of the present invention are cholestyramine (a styrene (1996), herein incorporated by reference; the compounds divinylbenzene copolymer containing quaternary ammo described by Busch et al. Lipids, 25, 216-220, (1990), herein nium cationic groups capable of binding bile acids, such as incorporated by reference; the compounds described in QUESTRANR) or QUESTRAN LIGHTR) cholestyramine Morton and Zilversmit J. Lipid Res., 35, 836-47 (1982), which are available from Bristol-Myers Squibb), colestipol herein incorporated by reference; the compounds described (a copolymer of diethylenetriamine and 1-chloro-2,3-ep in Connolly et al. Biochem. Biophys. Res. Comm., 223, oxypropane, such as COLESTID(R) tablets which are avail 42-47 (1996), herein incorporated by reference; the com able from Pharmacia), colesevelam hydrochloride (such as pounds described in Bisgaier et al. Lipids, 29, 811-8 (1994), WelCholR) Tablets (poly(allylamine hydrochloride) cross herein incorporated by reference; the compounds described linked with epichlorohydrin and alkylated with 1-bromode in EP 818448, herein incorporated by reference; the com cane and (6-bromohexyl)-trimethylammonium bromide) pounds described in JP 10287662, herein incorporated by which are available from Sankyo), water soluble derivatives reference; the compounds described in PCT applications Such as 3.3-ioene, N-(cycloalkyl)alkylamines and poli WO 98/35.937, WO 9914174, WO 9839299, and WO glusam, insoluble quaternized polystyrenes, Saponins and 9914215, each of which is herein incorporated by reference: mixtures thereof. the compounds of EP applications EP 796846, EP 801060, 0879 Non-limiting examples of inorganic cholesterol 818448, and 818197, each of which is herein incorporated sequestrants useful in combination with the nicotinic acid by reference; probucol or derivatives thereof, such as AGI receptor agonists of the present invention are bismuth Sali 1067 and other derivatives disclosed in U.S. Pat. Nos. cylate plus montmorillonite clay, aluminum hydroxide and 6,121.319 and 6,147.250, herein incorporated by reference: calcium carbonate antacids. low-density lipoprotein (LDL) receptor activators such as HOE-402, an imidazolidinyl-pyrimidine derivative that 0880. Non-limiting examples of AcylCoA:Cholesterol directly stimulates LDL receptor activity, described in M. O-acyltransferase (“ACAT) inhibitors useful in combina Huettinger et al., “Hypolipidemic activity of HOE-402 is tion with the nicotinic acid receptor agonists of the present Mediated by Stimulation of the LDL Receptor Pathway'. invention are avasimibe (2,4,6-tris(1-methylethyl)phenyl Arterioscler. Thromb. 1993: 13:1005-12, herein incorpo acetylsulfamic acid, 2,6-bis(1-methylethyl)phenyl ester, rated by reference: 4-carboxyamino-2-substituted-1,2,3,4- formerly known as CI-1011), HL-004, lecimibide (DuP tetrahydroquinolines, e.g., torcetrapib, described in WO 128) and CL-277082 (N-(2,4-difluorophenyl)-N-4-(2,2- 00/017164, WO 00/017166, WO 00/1401.90, WO dimethylpropyl)phenyl)methyl-N-heptylurea), and the 00/213797, and WO 2005/033082 (each of which is herein compounds described in P. Chang et al., “Current, New and incorporated by reference). Torcetrapib can be combined Future Treatments in Dyslipidaemia and Atherosclerosis'. with HMG-CoA reductase inhibitors such as atorvastatin Drugs July 2000; 60(1): 55-93, which is incorporated by (WO 00/213797, WO 2004/056358, WO 2004/056359, and reference herein. WO2005/011634). 0881. Non-limiting examples of cholesteryl ester transfer 0882. A non-limiting example of a fish oil containing protein (“CETP) inhibitors useful in combination with the Omega 3 fatty acids useful in combination with the nicotinic nicotinic acid receptor agonists of the present invention are acid receptor agonists of the present invention is 3-PUFA. those disclosed in PCT Patent Application No. WO 00/38721, U.S. Pat. Nos. 6,147,090, 6,958,346, 6,924.313 0883. Non-limiting examples of GLP-1 mimetics useful 6,906,082, 6,861,561, 6,803,388, 6,794,396, 6,787,570, in combination with the nicotinic acid receptor agonists of 6,753,346, 6,723,752, 6,723,753, 6,710,089, 6,699,898, the present invention include exendin-3, exendin-4, Byetta 6,696,472, 6,696,435, 6,683,113, 5,519,001, 5,512,548, Exanatide, Liraglutinide, CJC-1131 (ConjuChem), 6,410,022, 6,426,365, 6,448,295, 6,387,929, 6,683,099, Exanatide-LAR (Amylin) BIM-51077 (Ipsen/LaRoche), 6,677,382, 6,677,380, 6,677,379, 6,677,375, 6,677,353, ZP-10 (Zealand Pharmaceuticals), and compounds disclosed 6,677,341, 6,605,624, 6,586,433, 6,451,830, 6,451,823, in International Publication No. WOOO/07617. 6,462,092, 6,458,849, 6,458,803, 6,455,519, 6,583,183, 0884. Non-limiting examples of natural water soluble 6,562,976, 6,555,113, 6,544,974, 6,521,607, 6,489,366, fibers useful in combination with the nicotinic acid receptor 6,482,862, 6,479,552, 6,476,075, 6,476,057, and 6,897,317, agonists of the present invention are psyllium, guar, oat and each of which are incorporated herein by reference; com pectin. pounds described in Yan Xia et al., “Substituted 1,3,5- Triazines. As Cholesteral Ester Transfer Protein Inhibitors', 0885. A non-limiting example of a plant stanol and/or Bioorganic & Medicinal Chemistry Letters, vol. 6, No. 7, fatty acid ester of plant stanols useful in combination with 1996, pp. 919-922, herein incorporated by reference; natural the nicotinic acid receptor agonists of the present invention products described in S. Coval et al., “Wiedendiol-A and -B, is the sitostanol ester used in BENECOLR) margarine. Cholesteryl Ester Transfer Protein Inhibitors From The Marine Sponge Xestosponga Wiedenmayeri'. Bioorganic & 0886. A non-limiting example of an anti-oxidant useful in Medicinal Chemistry Letter, vol. 5, No. 6, pp. 605-610, combination with the nicotinic acid receptor agonists of the 1995, herein incorporated by reference; the compounds present invention includes probucol. described in Barrett et al. J. Am. Chem. Soc., 188, 7863-63 0887. Non-limiting examples of PPAR C. agonists useful (1996), herein incorporated by reference; the compounds in combination with the nicotinic acid receptor agonists of US 2008/00 19978 A1 Jan. 24, 2008 64 the present invention include beclofibrate, benzafibrate, (melanin-concentrating hormone 2 receptor) agonists/an ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfi tagonists useful in combination with the nicotinic acid brozil. receptor agonists of the present invention include those 0888. Non-limiting examples of lipoprotein synthesis described in WO 01/82925, WO 01/87834, WO 02/06245, inhibitors useful in combination with the nicotinic acid WO 02/04433, WO 02/51809, and JP 13226269 (each of the receptor agonists of the present invention include niacin or preceding references is herein incorporated by reference), nicotinic acid. and T-226296 (Takeda). 0889 Non-limiting examples of 5HT (serotonin) trans 0895. Non-limiting examples of NPY1 antagonists useful port inhibitors useful in combination with the nicotinic acid in combination with the nicotinic acid receptor agonists of receptor agonists of the present invention include paroxet the present invention include those described in U.S. Pat. ine, fluoxetine, fenfluramine, fluvoxamine, Sertraline, and No. 6,001,836, WO 96/14307, WO 01/23387, WO imipramine. 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528 (each of the preceding references is herein 0890. Non-limiting examples of NE (norepinephrine) incorporated by reference); and BIBP3226, J-115814, BIBO transport inhibitors useful in combination with the nicotinic 3304, LY-357897, CP-671906, and GI-264879A. acid receptor agonists of the present invention include GW 320659, despiramine, talsupram, and nomifensine. 0896) Non-limiting examples of NPY5 antagonists useful in combination with the nicotinic acid receptor agonists of 0891. Non-limiting examples of CB antagonists/inverse the present invention include those described in U.S. Pat. agonists useful in combination with the nicotinic acid recep No. 6,140,354, U.S. Pat. No. 6,191,160, U.S. Pat. No. tor agonists of the present invention include rimonabant, 6,258,837, U.S. Pat. No. 6,313,298, U.S. Pat. No. 6,337,332, SR-147778 (Sanofi Aventis), and the compounds described U.S. Pat. No. 6,329,395, U.S. Pat. No. 6,340,683, U.S. Pat. in U.S. Pat. No. 5,532,237, U.S. Pat. No. 4,973,587, U.S. No. 6,326,375, U.S. Pat. No. 6,335,345, EP-01010691, Pat. No. 5,013,837, U.S. Pat. No. 5,081,122, U.S. Pat. No. EP-01044970, WO 97/19682, WO 97/20820, WO 97/20821, 5,112,820, U.S. Pat. No. 5,292,736, U.S. Pat. No. 5,624,941, WO 97/20822, WO 97/20823, WO 98/27063, WO U.S. Pat. No. 6,028,084, WO 96/33159, WO 98/33765, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, 98/43636, WO 98/43635, WO 01/09120, WO 98/31227, WO 01/85714, WO 01/85730, WO 01/07409, WO WO 98/41519, WO 98/37061, WO 00/10967, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, 00110968, WO 97/29079, WO 99/02499, WO 01/58869, WO 01/44201, WO 01/62737, WO 01/62738, WO WO 02/076949, and EP-658546 (each of the preceding 01/09120, WO 02/22592, WO 0248152, WO 02/49648, WO references is herein incorporated by reference). 01/14376, WO 04/110375, WO 05/000217 and Norman et 0892. Non-limiting examples of ghrelin antagonists use al., J. Med. Chem. 43:4288-4312 (2000) (each of the pre ful in combination with the nicotinic acid receptor agonists ceding references is herein incorporated by reference); and of the present invention include those described in WO 152,804, GW-569180A, GW-594884A, GW-587081X, 01/87335 and WO 02/08250 (each of the preceding refer GW-548118X; FR226928, FR 24.0662, FR252384; ences is herein incorporated by reference). Ghrelin antago 1229U91, GI-264879A, CGP71683A, LY-377897, nists are also known as GHS (growth hormone secretagogue PD-160170, SR-120562A, SR-120819A and JCF-104. receptor) antagonists. The pharmaceutical combinations and methods of the present invention therefore comprehend the 0897. Non-limiting examples of NPY2 agonists useful in use GHS antagonists in place of ghrelin antagonists (in combination with the nicotinic acid receptor agonists of the combination with the nicotinic acid receptor agonists of the present invention include PYY3-36 as described in Batter ham, et al., Nature. 418:650-654 (2003), NPY3-36, and present invention). other Y2 agonists such as Nacetyl Leu(28.31) NPY 24-36 0893. Non-limiting examples of H antagonists/inverse (White-Smith and Potter, Neuropeptides 33:526-33 (1999)), agonists useful in combination with the nicotinic acid recep TASP-V (Malis et al., Br. J. Pharmacol. 126:989-96 (1999)), tor agonists of the present invention include thioperamide, cyclo-(28/32)-Ac-Lys28-Glu32-(25-36)-pNPY (Cabrele 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, and Beck-Sickinger J-Pept-Sci. 6:97-122 (2000)) (each of clobenpropit, iodophenpropit, imoproxifan, and GT2394 the preceding references is herein incorporated by refer (Gliatech), those described in: WO 02/15905 (herein incor porated by reference); O-3-(1H-imidazol-4-yl)propanol ence). carbamates described in Kiec-Kononowicz, K. et al., Phar 0898) Non-limiting examples of NPY4 agonists useful in mazie, 55:349-55 (2000) (herein incorporated by reference), combination with the nicotinic acid receptor agonists of the piperidine-containing histamine H-receptor antagonists present invention include pancreatic peptide (PP) as described in Lazewska, D. et al., Pharmazie, 56:927-32 described in Batterham et al., J. Clin. Endocrinol. Metab. (2001) (herein incorporated by reference), benzophenone 88:3989-3992 (2003), and other Y4 agonists such as derivatives and related compounds described in Sasse, A. et 1229U91 (Raposinho et al., Neuroendocrinology. 71:2- al., Arch. Pharm. (Weinheim) 334:45-52 (2001) (herein 7(2000) (both references are herein incorporated by refer incorporated by reference), substituted N-phenylcarbamates ence). described in Reidemeister, S. et al., Pharmazie, 55:83-6 0899) Non-limiting examples of mGluR5 (Metabotropic (2000) (herein incorporated by reference), and proxifan glutamate Subtype 5 receptor) antagonists useful in combi derivatives described in Sasse, A. et al., J. Med. Chem. nation with the nicotinic acid receptor agonists of the present 43:3335-43 (2000) (each of the preceding references is invention include 2-methyl-6-(phenylethynyl)-pyridine herein incorporated by reference). (MPEP) and (3-(2-methyl-1,3-thiazol-4-yl)ethynylpyri 0894 Non-limiting examples of MCH1R (melanin-con dine) (MTEP) and those compounds described in Anderson centrating hormone 1 receptor) antagonists and MCH2R J. et al., J, Eur J Pharmacol. Jul. 18, 2003:473(1):35-40: US 2008/00 19978 A1 Jan. 24, 2008

Cosford N. et al., Bioorg Med Chem Lett. Feb. 10, Pat. No. 4,806,570, U.S. Pat. No. 5,436,272, and US 2002/ 2003:13(3):351-4; and Anderson J. et al., J Pharmacol Exp 0006964 (each of which is herein incorporated by refer Ther. December 2002:303(3):1044-51 (each of the preced ence). ing references is herein incorporated by reference). 0908. Non-limiting examples of serotonin reuptake 0900. Non-limiting examples of leptins, leptin deriva inhibitors useful in combination with the nicotinic acid tives, and leptin agonists/modulators useful in combination receptor agonists of the present invention include dexfen with the nicotinic acid receptor agonists of the present fluramine, fluoxetine, and those described in U.S. Pat. No. invention include recombinant human leptin (PEG-OE, 6,365,633, WO 01/27060, and WO 01/162341 (each of Hoffman La Roche) and recombinant methionyl human which is herein incorporated by reference). leptin (Amgen). Leptin derivatives (e.g., truncated forms of 0909. A non-limiting example of an acyl-estrogen useful leptin) useful in the present invention include those in combination with the nicotinic acid receptor agonists of described in U.S. Pat. No. 5,552,524, U.S. Pat. No. 5,552, the present invention includes oleoyl-estrone. 523, U.S. Pat. No. 5,552,522, U.S. Pat. No. 5,521,283, WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, 0910 Non-limiting examples of 11 B HSD-1 inhibitors WO 96/23517, WO 96/23518, WO 96/23519, and WO useful in combination with the nicotinic acid receptor ago 96/23520 (each of the preceding references is herein incor nists of the present invention include those described in WO porated by reference). 03/065983 and WO 03/104207 (both of which are herein 0901. Non-limiting examples of opioid antagonists useful incorporated by reference). in combination with the nicotinic acid receptor agonists of 0911) A non-limiting example of a lipase inhibitor useful the present invention include nalmefene (RevexTM), 3-meth in combination with the nicotinic acid receptor agonists of oxynaltrexone, naloxone, and naltrexone, as well as opioid the present invention include orlistat. antagonists described in WO 00/21509 (herein incorporated 0912 Anti-diabetic agents useful in combination with the by reference). nicotinic acid receptor agonists of the present invention 0902. Non-limiting examples of orexin receptor antago include Sulfonylureas, meglitinides, C.-amylase inhibitors, nists useful in combination with the nicotinic acid receptor C-glucoside hydrolase inhibitors, PPAR-Y agonists, agonists of the present invention include SB-334867-A, as PPAROfy agonists, biguanides, PTP-1B inhibitors, DP-IV well as those described in WO 01/96302, WO 01/68609, inhibitors, DPP-IV inhibitors, insulin secretagogues, fatty WO 02/51232, and WO 02/51838 (each of the preceding acid oxidation inhibitors, A2 antagonists, c-jun amino-ter references is herein incorporated by reference). minal kinase inhibitors, insulin, insulin mimetics, glycogen phosphorylase inhibitors, VPAC2 receptor agonists, glu 0903) Non-limiting examples of CNTF (specific ciliary cokinase activators, and non-thiazolidinedione PPAR neurotrophic factors) useful in combination with the nico ligands. Non-limiting examples of Sulfonylureas useful in tinic acid receptor agonists of the present invention include combination with the nicotinic acid receptor agonists of the GI-181771 (Glaxo-SmithKline); SR146131 (Sanofi Aven present invention include acetohexamide, chlorpropamide, tis); butabindide; PD170,292, PD 149164 (Pfizer). diabinese, glibenclamide, glipizide, glyburide, glimepiride, 0904) Non-limiting examples of CNTF derivatives and gliclazide, glipentide, gliquidone, glisolamide, tolaZamide, CNTF agonists/modulators useful in combination with the and tolbutamide. nicotinic acid receptor agonists of the present invention 0913 Non-limiting examples of meglitinides useful in include axokine (Regeneron) and those described in WO combination with the nicotinic acid receptor agonists of the 94/09134, WO 98/22128, and WO99/43813 (each of which present invention include repaglinide, mitiglinide and nateg is herein incorporated by reference). linide. 0905. Non-limiting examples of 5HT2c agonists useful in 0914 Non-limiting examples of C.-amylase inhibitors combination with the nicotinic acid receptor agonists of the useful in combination with the nicotinic acid receptor ago present invention include BVT933, DPCA37215, nists of the present invention include tendamistat, trestatin, WAY161503, and R-1065, as well as those described in U.S. and AI-3688. Pat. No. 3,914,250, WO 02/6396, WO 02/48124, WO 0915 Non-limiting examples of C-glucoside hydrolase 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, inhibitors useful in combination with the nicotinic acid WO 02/40456, and WO 02/40457 (each of which is herein receptor agonists of the present invention include acarbose, incorporated by reference). adipose, camiglibose, emiglitate, miglitol, Voglibose, 0906) Non-limiting examples of Mc4ragonists useful in pradimicin-Q, salbostatin, CDK-711, MDL-25,637, MDL combination with the nicotinic acid receptor agonists of the 73,945, and MOR 14. present invention include CHIR86036 (Chiron); ME-10142, 0916 Non-limiting examples of PPAR-Yagonists useful and ME-10145 (Melacure), as well as those described in in combination with the nicotinic acid receptor agonists of WO 01/991752, WO 01/74844, WO 02/12166, WO the present invention include balaglitaZone, ciglitaZone, 02/11715, and WO 02/12178 (each of which is herein dargilitaZone, englitaZone, isaglitaZone (MCC-555), piogli incorporated by reference). taZone, rosiglitaZone, troglitaZone, tesaglitazar, netoglita 0907. Non-limiting examples of monoamine reuptake Zone, GW-409544, GW-501516, CLX-0921, 5-BTZD, inhibitors useful in combination with the nicotinic acid GW-0207, LG-100641, LY-300512, LY-519818, R483 receptor agonists of the present invention include Sibutra (Roche), and T131 (Tularik). mine (MeridiaTM/ReductilTM), as well as those described in 0917 Non-limiting examples of PPARO/Yagonists useful WO 01/27068, WO 01/62341, U.S. Pat. No. 4,746,680, U.S. in combination with the nicotinic acid receptor agonists of US 2008/00 19978 A1 Jan. 24, 2008 66 the present invention include CLX-0940, GW-1536, dichlorophenamide, hydroflumethiazide, indapamide, GW-1929, GW-2433, KRP-297, L-796449, LR-90, hydrochlorothiazide, bumetanide, ethacrynic acid, furo MK-0767, and SB 219994. semide, torsemide, amiloride, triamterene, Spironolactone, 0918 Non-limiting examples of biguanides useful in and epirenone. combination with the nicotinic acid receptor agonists of the 0929 Non-limiting examples of B-adrendergic blockers present invention include buformin, metformin, and phen useful in combination with the nicotinic acid receptor ago formin. nists of the present invention include acebutolol, atenolol. betaxolol, bevantolol, bisoprolol, bopindolol, carteolol, 0919) Non-limiting examples of PTP-1B inhibitors (pro carvedilol, celiprolol, esmolol, indenolol, metaprolol, nad tein tyrosine phosphatase-1B inhibitors) useful in combina olol, nebivolol, penbutolol, pindolol, propanolol, Sotalol, tion with the nicotinic acid receptor agonists of the present tertatolol, tilisolol, and timolol. invention include A-401,674, KR 61639, OC-060062, 0930 Non-limiting examples of alpha 1 blockers useful OC-83839, OC-297962, MC52445, and MC52453. in combination with the nicotinic acid receptor agonists of 0920 Non-limiting examples of DPP-IV inhibitors the present invention include teraZosin, urapidil, praZosin, (dipeptidyl peptidase IVi inhibitors) useful in combination bunaZosin, trimaZosin, doxazosin, naftopidil, indoramin, with the nicotinic acid receptor agonists of the present WHIP 164, and XENO10. invention include Sitagliptin, saxagliptin, denagliptin, Vilda 0931. Non-limiting examples of calcium channel block gliptin, alogliptin, alogliptin benzoate, Galvus (Novartis), ers useful in combination with the nicotinic acid receptor ABT-279 and ABT-341 (Abbott), ALS-2-0426 (Alantos), agonists of the present invention include amlodipine, arani ARI-2243 (Arisaph), BI-A and BI-B (Boehringer Ingel dipine, azelnidipine, barnidipine, benidipine, bepridil, cinal heim), SYR-322 (Takeda), MP-513 (Mitsubishi), DP-893 dipine, clevidipine, diltiazem, efonidipine, felodipine, gal (Pfizer) and RO-0730699 (Roche), isoleucine thiazolidide, lopamil, isradipine, lacidipine, lemildipine, lercanidipine, NVP-DPP728, P32/98, LAF 237, TSL 225, valine pyrroli nicardipine, nifedipine, nilvadipine, nimodepine, nisol dide, TMC-2A/2B/2C, CD-26 inhibitors, and SDZ 274-444. dipine, nitrendipine, manidipine, pranidipine, and Vera 0921 Non-limiting examples of insulin secretagogues pamil. useful in combination with the nicotinic acid receptor ago 0932. Non-limiting examples of angiotensin converting nists of the present invention include linogliride and A-4166. enzyme inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include 0922 Non-limiting examples of fatty acid oxidation alacepril, benazepril, ceronapril, captopril, cilaZapril, dela inhibitors useful in combination with the nicotinic acid pril, enalapril, fosinopril, imidapril, losinopril, moveltopril, receptor agonists of the present invention include clomoxir moexipril, quinapril, quinaprilat, ramipril, perindopril, peri and etomoxir. dropril, quanipril, spirapril, temocapril, trandolapril, and 0923 Non-limiting examples of A2 antagonists useful in Zofenopril. combination with the nicotinic acid receptor agonists of the 0933. Non-limiting examples of neutral endopeptidase present invention include midaglizole, isaglidole, derigli inhibitors useful in combination with the nicotinic acid dole, idaZOXan, earoxan, and fluparoxan. receptor agonists of the present invention include omapat 0924 Non-limiting examples of insulin mimetics useful rilat, cadoxatril, ecadotril, fosidotril, sampatrilat, AVE7688, in combination with the nicotinic acid receptor agonists of and ER4030. the present invention include biota, LP-100, novarapid, 0934 Non-limiting examples of angiotensin II receptor insulin detemir, insulin lispro, insulin glargine, insulin Zinc antagonists useful in combination with the nicotinic acid suspension (lente and ultralente), Lys-Pro insulin, GLP-1 receptor agonists of the present invention include cande (73-7) (insulintropin), and GLP-1 (7-36)-NH). Sartan, eprosartan, irbesartan, losartan, pratosartan, tasosar 0925 Non-limiting examples of glycogen phosphorylase tan, telisartan, valsartan, EXP-3137, F16828K, RNH6270, inhibitors useful in combination with the nicotinic acid losartan monopotassium, and losartan potassium-hydrochlo receptor agonists of the present invention include CP-368, rothiazide. 296, CP-316,819, and BAYR3401. 0935 Non-limiting examples of endothelin antagonists useful in combination with the nicotinic acid receptor ago 0926 Non-limiting examples of non-thiazolidinedione nists of the present invention include tezosentan, A308165, PPAR ligands useful in combination with the nicotinic acid and YM62899. receptoragonists of the present invention include JT-501 and 0936 Non-limiting examples of vasodilators useful in fargilitazar (GW-2570/GI-262579). combination with the nicotinic acid receptor agonists of the 0927. Anti-hypertensive agents useful in combination present invention include hydralazine (apresoline), cloni with the nicotinic acid receptor agonists of the present dine (catapres), minoxidil (loniten), and nicotinyl alcohol invention include diuretics, B-adrendergic blockers, C.-adr (roniacol). energic blockers, aldosterone inhibitors, alpha 1 blockers, 0937. Non-limiting examples of alpha 2a agonists useful calcium channel blockers, angiotensin converting enzyme in combination with the nicotinic acid receptor agonists of inhibitors, neutral endopeptidase inhibitors. angiotensin II the present invention include lofexidine, tiamenidine, moX receptor antagonists, endothelin antagonists, vasodilators, onidine, rillmenidine, and guanobenz. alpha 2a agonists, and C/B adrenergic blockers. 0938) Non-limiting examples of C/B adrenergic blockers 0928 Non-limiting examples of diuretics useful in com useful in combination with the nicotinic acid receptor ago bination with the nicotinic acid receptor agonists of the nists of the present invention include nipradillol, arotinolol. present invention include chlorthalidone, chlorthiazide, and amoSulalol. US 2008/00 19978 A1 Jan. 24, 2008 67

0939 DP receptor antagonists useful in combination with Novartis), felodipine (from Pierre Fabre SA), 2-methox the nicotinic acid receptor agonists of the present invention yestradiol (from PR Pharmaceuticals), C.1 adrenoreceptor include those described in US 2004/0229844 (herein incor antagonists (erg., from Recordati SpA), lercanidipine-enala porated by reference). pril combination (from Recordati SpA). NO donors 9 e.g., 0940. Non-limiting examples of additional agents that from Renopharm), CR-3834 (from Rottapharm Gr), iloprost can be combined with the nicotinic acid receptor agonists of (from Schering AG), SPP-1100 (from The Speedel Group), the present invention include aspirin, Niaspan, NorvsacR) angiotensinogen, MC-4232 (from Medicure), ACE inhibitor (amlodipine), NSAIDS agents (e.g., Celecoxib (CelebrexR), (from Servier), LCP-Feno/Stat. (from LifeCycle Pharma), Diclofenac (Cataflam(R), VoltarenR), Arthrotec(R).) Diflunisal APA-01 statin combination (from Phosphagenics Ltd), (DolobidR), Etodolac (Lodine(R). Fenoprofen (NalfonR), KH-01502 (from Kos), KS-01019 (from Kos), niacin-lov Flurbirofen (AnsaidR), Ibuprofen (Motrin R, ADVIL(R), astatin combination (from Kos/Merck KGaA), MK-0524/ NUPRINR, Tab-Profen R, Vicoprofen R, CombunoX(R) extended release niacin/simvastatin combination (from Indornethacin (Indocin R, Indo-Lemmon R, Indorneth Merck), MK-0524/extended release combination (from agan R) Ketoprofen (Oruvail(R), Ketorolac (Toradol(R), Merck), Pro-NAD (from Niadyne Inc), beraprost, perin Mefenamic acid (Ponstel(R), commercially available from dopril erbumine, barnidipine, irbesartan, Valsartan, Valsar First Horizon Pharmaceutical), flufenamic acid (N-(3-trif tan-HCTZ combination, meclinertant, TAK-536, luoromethylphenyl)anthranilic acid), Meloxicam SR-121463, irbesatran+HCTZ combination, darusentan, (MobicR), Naburnetone (Relafen R), Naproxen PMD-2850, CR-2991, SLV-306, bisoprolol fumarate+ (NaprosynR), ALEVER, Anaprox(R), Naprelan R, Napra HCTZ combination, NV-04, FG-3019, TRC-4149, AVE pacR), Oxaprozin (Day proR), Piroxicam (FeldeneR), 7688, PV-903, diltiazem, QC-BT16, cardiotherpay (from Sulindac (ClinorillR) and Tolimetin (TolectinR)), antihyper Cytopia), treprostinil Sodium, enalapril--diltiazem combina tensive agents (Prazosin(R), Propranolol, nadolol, timolol. tion, eprosartan mesylate+HCTZ combination, renin inhibi metoprolol, pindolol, labetalol, guanethidine, reserpine, tor (from Vitae), LG-105 inhibitors (from Lexicon(, LG-844 clonidine, methyldopa, guanabenz, captopril, enalapril, lisi inhibitors (from Lexicon), NO-enhancing PDE inhibitors, nopril, losartan, Verapamil, diltiazem, nifedipine, hydrochlo hyaluronidase, propranolol hydrochloride, BIO-236, RWJ rothiazide, chlorothalidone, furosemide, triamterene, 351647, metoprolol, YM-222546, bLN-5, olmesartan+ hydralazine, minoxidil), PGE2 receptor antagonists (e.g., azelnidipine combination (from Sanyo), moxonidine--HCTZ EP2 and EP4). combination, NS-304, BIO-123, aldosterone antagonists, clonidine, BIO-003 and CR-3834. 0941 Non-limiting examples of additional agents that can be combined with the nicotinic acid receptor agonists of 0942. In addition, the nicotinic acid receptor agonists of the present invention include homocysteinase, orphan the present invention can also be used in combination with GPCR modulator, HRE-based gene therapy, gene therapy, two or more therapeutic agents. A non-limiting example of dual PPARO/Y agonists, recombinant FGF-1, VRI-1, CRX two or more therapeutic agents useful in combination with 150, VEGF-114 based therapy, CT-500, regadenosan, the nicotinic acid receptor agonists of the present invention CK-1827452, JAK2 tyrosine kinase inhibitors, adipose is the combination of a compound of the present invention derived regenerative cells, STARBURST dendrimer-based with VYTORINR) (a combination of simvastatin and MRI contrast agents, TBC-11299, HEMOxygenation, hep eZetimibe). arin, GO-EPO, IDN-6734, ISIS-301012, HIF-alpha gene 0943. The invention disclosed herein is exemplified by therapy, C2b adrenoceptor antagonists, KI-0002, adenosine the following preparations and examples which should not modulators, Ki-23095, PR-5 (Melacure), L-364373, histone be construed to limit the scope of the disclosure. Alternative deacetylase inhibitors, adenylate cyclase inhibitors (E.g., mechanistic pathways and analogous structures will be HI-30435 from Millennium), MITO-0139 (from MitoKor), NV-04 (from Novogen), M-118 (Momenta), hypoxia apparent to those skilled in the art. response element, PI-99 (from progen), NEXVAS (from Resverlogix). CS-207) from Shenzhen Chipscreen Bio EXAMPLES Sciences), estrogen-regulated gene therapy, SLV-327 (from 0944. In the examples and tables that follow, the exem Solvay), TNX-832 (from Sunol Molecular Corp), SLX-2101 plary compounds of the invention are referred to by number. (from Surface Logix), recombinant human annexin (from In some instances, the compounds of the invention are SurroMed), Chymase inhibitors (e.g., from Toa Eiyo), referred to as “Example X,” wherein “X” would be the VM-202 (from ViroMed), liver X receptor modulators (erg. representative number of that particular compound. In other from Exelixis/Bristol Myers Squibb), Heberkinasa (from Y. instances, the compounds of the invention are referred to as M. Biosciences), atorvastatin-amlodipine combination, “compound X, wherein “X” would be the representative AGN-195795 (Allergan), angiotensisn (1-7) agonists (erg. number of that particular compound. In other instances, a from Arena), Toprol XL/hydrochlorothiazide (from Astra compound of the invention may simply be referred to by its Zeneca), Teczem (Aventis), SGC stimulators, calcium chan number. It is to be understood that these terms are used nel blockers, CYT-006-AngCb (CytosBiotechnology), renin interchangeably. For example, the compound labeled inhibitors (e.g., from Rochef Speedel), Coxagen (from gen “Example 1 can also be referred to as “compound 1’ and eRx+ Inc), MC-4262 (from Medicure), VNP-489 (from Vice versa. US 2008/00 19978 A1 Jan. 24, 2008 68

Preparative Example 1 0952) H NMR (CDOD): & 2.41 (s, 3 H) 5.75 (s, 1 H) 0945) 0953) Mass for CHNO (MH)": 195, Found: 195. Preparative Example 3 H 0954) O O NY N NH Example 3

O

Example 1 Step A:

H O O O N O -- NH Ho 0955 Example 3 was prepared by a method analogous to the method used to prepare Example 1, except that methyl O butanoylacetate was used instead of methyl propionylac H etate. O O N 0956) "H NMR (CDOD): ) 0.96 (t, 3 H, J-7.6 Hz), 1.57 N NH (m, 2 H), 2.86 (m, 2 H), 5.75 (s, 1 H) 0957) Mass for CHNO (MH)"; 223. Found: 223. O Preparative Example 4 Example 1 0958)

0946 Methyl propionylacetate (12.5g, 96.1 mmol. 1.23 Example 4 eq.) and barbituric acid (10g, 78.1 mmol. 1 eq.) were mixed together and without solvent, the mixture was heated to 195° C. in air for 2 hr., at which time all of the liquids had evaporated. The solid was washed with boiling distilled water twice. The remaining solid was recrystallized with 2-methoxyethanol/water to give 4 g of Example 1 as a yellow solid (20% yield). 0947 "H NMR (CDOD): & 1.20 (t, 3 H, J=7.3 Hz), 3.00 (q, 2 H, J=7.3 Hz), 580 (s, 1 H) 0959 Example 4 was prepared by a method analogous to 0948 °C NMR (CDOD): & 12.6, 27.4, 92.0, 104.2, the method used to prepare Example 1, except that ethyl 149.5, 158.4, 161.8, 162. 1, 164.1 isobutylacetate was used instead of methyl propionylacetate, and Example 4 was purified by HPLC (5% acetonitrile in 0949) Mass for CHNO (MH)": 209. Found: 209. water to 95% acetonitrile in 10 min). Preparative Example 2 0960 "H NMR (CDOD): & 1.14 (d. 6 H, J=6.8 Hz), 4.03 (m. 1 H), 5.86 (s, 1 H) 0950) 0961) Mass for CHNO (MH)"; 223. Found: 223.

Example 2 Preparative Example 5 0962)

0951 Example 2 was prepared by a method analogous to the method used to prepare Example 1, except that methyl acetonylacetate was used instead of methyl propionylac Example 5 etate. US 2008/00 19978 A1 Jan. 24, 2008 69

removed and the residue was purified by prep TLC with 25% -continued EtOAc/hexane as the eluting solvent to give desired product Step A: as first fraction (7 mg, 4% yield). O O O 0968 H NMR (CDOD): & 1.27 (t, 3 H, J=7.2 Hz), 3.05 Y (m, 2 H), 6.11 (s, 1 H), 7.11 (t, 1 H, J=7.6 Hz), 7.34 (m. 2 -- POCl3 H), 7.48 (brs, 1 H), 7.60 (d. 2 H, J=8.0 Hz) S NH 0969 Mass for CHCINO (MH)": 302. Found: 302. O Preparative Example 7 Example 1 0970)

Example 5 0963) Example 1 (5g, 24.04 mmol. 1 eq), POCl (36.86 g, 240 mmol. 10 eq.) and pyridine (0.95 g, 12 mmol. 0.5 eq) were mixed and heated to 115° C. for 8 hours. After cooling to room temperature, the solvent was removed and the brownish residue was purified using flash chromatography with 20% EtOAc/hexane as the eluting solvent. The desired PhNH --- product (4 g) was obtained in 68% yield. 0964) H NMR (CDOD): & 1.29 (t, 3 H, J=7.2 Hz), 3.12 (m, 2 H), 6.39 (s, 1 H) Example 5 0965) Mass for CHC1.N.O. (MH)": 245. Found: 245. Preparative Example 6 0966)

Example 7

0971 Example 7 was prepared using the method used to prepare Example 6, except that Example 7 was obtained as the second fraction by prep TLC (8 mg, 4% yield).

0972) H NMR (CDOD): & 1.43 (t, 3 H, J=7.2 Hz), 2.96 (m, 2 H), 6.22 (s, 1 H), 7.37-7.48 (m, 5H) -- PhNH2 He- 0973) Mass for CHCINO, (MH)": 302. Found: 302. Preparative Example 8 0974) Example 5

H O O NY N NH

O O Example 6 0967 Compound 1 (0.15g, 0.61 mmol. 1 eq.) and aniline OEt (0.06 g., 0.64 mmol. 1.05 eq) were mixed in 3 mL of Example 8 anhydrous THF and stirred for 12 hours. Solvent was US 2008/00 19978 A1 Jan. 24, 2008 70

-continued Step A: Step B: O OEt H O N O O "Sk 1, Pyridine, CH2Cl2 Her 2. MeOH O Y --- F.C1 Ncoc -- t -- NH

O O O OEt

O H --> O O N O O Compound 9a N NH

O O 0981 Into a solution of Meldrums acid (2,2-dimethyl 4,6-dioxo-1,3-dioxane; 9 g, 62 mmol) and pyridine (9.8 g. OEt 68 mmol) in anhydrous CHCl (10 mL), which cooled to 0° Example 8 C., was added 3,3,3-trifluoropropionyl chloride (10 g. 68 mmol). The resulting reaction mixture was stirred under N 0975 Example 8 was prepared using a method analogous at 0°C. for 1 hour then at room temperature for 2 hours. The to the method used to prepare Example 1, except that diethyl reaction mixture was then concentrated under reduced pres 1,3-acetonedicarboxylate was used instead of methyl pro sure. The resulting paste was mixed with MeOH (20 mL), pionylacetate. and heated to 80° C. for 5 hours. The solvent was removed 0976) "H NMR (CDOD): & 1.20 (t, 3 H, J=7.3 Hz), 3.88 and the resulting mixture was distilled under reduced pres (s, 2 H), 4.10 (q, 2 H, J=7.3 Hz), 5.81 (s, 1 H) sure to give Compound 9a (6.2 g, 54%). 0977 °C NMR (CDOD): & 13.4, 39.6, 61.2, 92.2, H 108.1, 149.7, 153.1, 157.8, 1617, 1620, 170.3 N O 0978 Mass for HRMS for CHNO (MH)": calcd O Y + FC N 180° C. 267.0617, found 267.0623. NH O O Preparative Example 9 O Compound 9a 0979)

Example 9 H H O O N O O N N NH N NH O O CF CF Example 9

Step A: 0982) A mixture of Compound 9a (2.2 g 12 mmol) and SOCl barbituric acid was heated to 180° C. for 1 hour to provide Ec1Ncoh - - Ec1Ncoc a black Solid. After cooling to room temperature, the black solid was dissolved into hot water (70 mL). The resulting 0980 A mixture of 3,3,3,-trifluoropropionic acid (16 g. mixture was extracted with ethyl acetate (4x50 mL). The 125 mmol), thionyl chloride (29.75g, 250 mmol), and DMF organic solution was dried (Na2SO4) and concentrated under (0.5 mL) was heated to 70° C. for 4 hours. The reaction reduced pressure. The crude product was purified by reverse mixture was distilled under reduced pressure to give 3,3,3- phase HPLC eluting with formic acid (0.1%)/acetonitrile to trifluoropropionyl chloride (11.5 g., 72%). give Example 9 (0.17g, 5%). Electrospray MSM+1263. US 2008/00 19978 A1 Jan. 24, 2008 71

Preparative Example 10 0983 Step C: O O N SMe Example 10 O O N SOMe r r N NH ... mCPBA "le N NH O Compound 10b O Step A H OMe HO N S 1. Y O O 2N 1659 C. Example 10 OH O O N 0986) m-CPBA (3.1 g, 70%, 12.6 mmol) was added to a suspension of Compound 10b (2.0 g, 8.4 mmol) in CH2Cl2 N NH (150 mL) at room temperature. The solvent was removed from the suspension after 3 hours and the crude product was purified using silica gel flash column chromatography, elut ing first with hexane/EtOAc (v/v=1/1) then CHCl2/MeOH Compound 10a (v/v=2/1) to give Example 10 (2.09 g, 94%). Electrospray MS M+1) 255.1. 0984. A mixture of 4,6-dihydroxy-2-mercapto-pyrimi Preparative Example 11 dine (20.0 g, 138.7 mmol) and methyl propionylacetate 0987) (21.8 mL, 173.4 mmol) was heated at 165° C. until the ester was completely reacted. The reaction mixture was cooled down and poured into water (75 mL) and then filtered Example 11 through a sintered funnel. The solid residue was washed with water (2x20 mL) and dried under vacuum to yield Compound 10a (11.6 g., 37%).

Step B: H O O NY N NH + MeI DMF

O

Compound 10a Example 10 O O N SMe

S r NH

O

Compound 10b Example 11 0985 Mel (2.23 mL, 35.72 mmol) was added to a sus pension of Compound 10a (4.0 g. 17.86 mmol) in DMF (40 0988) Example 10 (0.35 g, 1.37 mmol) in MeOH (40 mL) mL) at room temperature. The reaction mixture was stirred was heated at reflux overnight. After cooling to room at room temperature overnight. The reaction mixture was temperature, the solvent was removed under reduced pres then poured into water (250 mL) and filtered through a sure and the crude product was purified using silica gel flash sintered funnel. The solid residue was washed with water column chromatography eluting with CH2Cl2/MeOH (V/v= (2x50 mL) and dried under vacuum to give Compound 10b 50/1) to give Example 11 (0.23 g, 76%). Electrospray MS (4.1 g, 96%). M+1' 223.1. US 2008/00 19978 A1 Jan. 24, 2008 72

Preparative Example 12 -continued 0989)

Example 12

Compound 13a

0992 Cyclopropyl methyl bromide (1.30 mL, 13.4 mmol) was added to a suspension of Compound 10a (0.5 g. CHCN 2.24 mmol) in DMF (5.0 mL) at room temperature. The + BnOH + NEt2 TA - reaction mixture was stirred at 85° C. for two days. The reaction mixture was cooled down and poured into water (75 mL) and then filtered through a sintered funnel. The solid Example 10 residue was washed with water (2x20 mL) and dried under vacuum to give Compound 13a (0.55 g, 88%).

Step B:

Example 12 CHCl2 + mCPBA ->

0990 BnOH (2.46 mL, 23.76 mmol) was added to a solution of Example 10 (0.404g, 1.58 mmol) and NEt (0.22 mL, 1.58 mmol) in CHCN (12.0 mL) at room temperature. The reaction mixture was heated at 85°C. overnight. After cooling to room temperature, HOAc (0.09 mL, 1.58 mmol) was added and the solvent was removed under reduced pressure. The crude product was purified using silica gel flash column chromatography eluting with CHCl/MeOH (v/v=50/1) to give Example 12 (0.20 g. 42%). Electrospray MS M+1 299.1. Preparative Example 13 Example 13 0991) 0993 m-CPBA (0.33 g, 70%, 1.35 mmol) was added to a suspension of Compound 13a (0.25 g, 0.9 mmol) in Example 13 CHCl (30 mL) at room temperature. Solvent was removed after 3 hours, and the crude product was purified using silica gel flash column chromatography eluting with EtOAC/ CHC1/MeOH (v/v=4/1/2) to give Example 13 (0.15 g, 57%). Electrospray MS M+1) 295.1. Preparative Example 14

Step A: 0994)

O O N S Example 14 NHNHCOMe DMF S Her850 C. s NH

Compound 10a US 2008/00 19978 A1 Jan. 24, 2008

Preparative Example 16 -continued 0998) SOMe

Example 16 CHCN + NHNHCOMe ->

NHNHCOMe

Example 14

0995) A mixture of Example 10 (0.205 g, 0.804 mmol) and NH-NHCOMe (0.145 g, 1.608 mmol) in MeCN (4.0 mL) was heated at reflux for 3 hours. After cooling to room temperature, the solvent was removed under reduced pres sure and the crude product was washed with water (3x25 mL) with filtration. The solid was dried under vacuum to give Example 14 (0.2 g, 89%). Electrospray MS M+1 2811.

Preparative Example 15 Example 16 0996) 0999 Cyclopropyl carbinol (0.79 mL. 9.8 mmol) was Example 15 O O N S added to a solution of Example 10 (0.050 g, 0.196 mmol) in CHCN (0.8 mL) at room temperature. The reaction mixture was heated at 85° C. overnight. After cooling to room S NH temperature, the solvent was removed under reduced pres Sure. The crude product was purified using silica gel flash O column chromatography eluting with hexane/EtOAc (V/v= Step A: 1/1) to give Example 16 (0.027 g, 52%). Electrospray MS H M+1 263.1. O O N N NH Br N DMF Preparative Example 17 1000 O

Example 17 Compound 10a O O Nn S N-1s N NH

O Example 15

0997 Allyl bromide (1.74 mL, 20.1 mmol) was added to a suspension of Compound 10a (1.5 g. 6.7 mmol) in DMF (15.0 mL) at room temperature. The reaction mixture was CHCN stirred at 45° C. overnight. The reaction mixture was cooled down and poured into water (200 mL) and then filtered through a sintered funnel. The solid residue was washed with water (2x40 mL) and dried under vacuum to give Example 10 Example 15 (1.55g, 92%). Electrospray MS M+1" 265.1. US 2008/00 19978 A1 Jan. 24, 2008 74

-continued -continued Step A: H O O NY N NH + Eti -DMF -

Compound 17a Compound 10a

1001) A mixture of Example 10 (0.10g, 0.392 mmol) and t-BuSH (0.66 mL, 5.88 mmol) in 1,4-dioxane (2.0 mL) was heated at reflux overnight. After cooling to room tempera ture, the solvent was removed under reduced pressure. The crude product was purified using silica gel flash column chromatography eluting with hexane/EtOAc (v/v=1/1) to Compound 18a give Compound 17a (0.045 g, 41%). 1004 Et (2.1 g, 13.4 mmol) was added to a suspension of Compound 10a (1.5 g. 6.7 mmol) in DMF (20 mL). After stirring at room temperature overnight, the reaction mixture was poured into water (50 mL) and filtered through a Buchner funnel. The solid residue was washed with water CHCl2 (2x50 mL) and dried under vacuum to give Compound 18a rk + mCPBA --> (1.3 g, 76%). Step B:

Compound 17a CHCl2

Compound 18a

Example 17

1002 m-CPBA (0.049 g, 70%, 0.20 mmol) was added to Example 18 a suspension of Compound 17a (0.040 g, 0.143 mmol) in 1005 m-CPBA (74 mg, 70%, 3 mmol) was added to a CHCl (2.5 mL) at room temperature. Solvent was removed suspension of Compound 18a (0.5g, 2 mmol) in CHCl (50 after 3 hours and the crude product was purified using silica mL) at room temperature. After stirring at room temperature gel flash column chromatography eluting first with hexane/ 3 hours, the solvent was removed, and the crude product was EtOAc (v/v=1/1) then with CHC1/MeCH (v/v=5/1) to give purified using silica gel flash column chromatography elut Example 17 (0.030 g, 71%). Electrospray MSM+1297.1. ing with AcOH/MeOH/CHCl (v/v/v=0.1/4.9/95) to give Example 18 (0.4g, 74%). Electrospray MS M+1" 269. Preparative Example 18 Preparative Example 19 1003) 1006) Example 19

Example 18 US 2008/00 19978 A1 Jan. 24, 2008 75

Preparative Example 20 -continued 1009) Step A: Example 20 H Br

O O NY O DMF N NH -- Hs

O Compound 10a Step A:

O

DMF N NH | Br --C.

Compound 19a

1007 Benzyl bromide (1.54 g, 9 mmol) was added to a suspension of Compound 10a (1 g, 4.5 mmol) in DMF (20 mL). After stirring at room temperature overnight, the reaction mixture was poured into water (50 mL) and filtered through a Buchner funnel. The solid residue was washed with water (2x50 mL) and dried under vacuum to give Compound 19a (1.3 g 92%). Compound 20a 1010 (1-Bromoethyl)benzene (3.4 g, 18 mmol) was added to a Suspension of Compound 10a (1 g, 4.5 mmol) in Step B: DMF (20.0 mL) at room temperature The reaction mixture was stirred at 70° C. for one day. The reaction mixture was cooled down and poured into water (50 mL) and then filtered through a Buchner funnel. The solid residue was washed CHCl2 with water (2x20 mL) and dried under vacuum to Com -- ImCPBA -ss pound 20a (1.3 g, 87%). Electrospray MS M+1 329. Step B:

Compound 19a

O CHCl2 | -- ImCPBA -ss O O N S

N r NH Compound 20a O Example 19 O N. s 1008 m-CPBA (72 mg, 70%, 3 mmol) was added to a S NH suspension of Compound 19a (0.5g, 2 mmol) in CHCl (50 mL) at room temperature. After stirring at room temperature O 3 hours, the solvent was removed, and the crude product was Example 20 purified using silica gel flash column chromatography elut ing with AcOH/MeOH/CHCl (v/v/v=0.1/2.9/97) to give 1011 m-CPBA (0.3 g, 70%, 1.2 mmol) was added to a Example 19 (0.5 g, 76%). Electrospray MS M+1' 331. suspension of Compound 20a (0.33 g, 1 mmol) in CHCl, US 2008/00 19978 A1 Jan. 24, 2008 76

(30 mL) at room temperature. Solvent was removed after 3 (30 mL) at room temperature. Solvent was removed after 3 hours and the crude product was purified using silica gel hours, the crude product was purified using a silica gel flash flash column chromatography eluting with 5% EtOH in column chromatography eluting with 0.1% AcOH in MeOH/ EtOAc/hexanes (v/v=1:1) to give Example 20 (0.1 g, 50%). CHC1, (v/v=2:98) to give Example 21 (0.45 g, 80%). Electrospray MS M+1" 345. Efectrospray MS M+1" 283. Preparative Example 21 Preparative Examples 22 and 23 1012) 1015)

Example 21

Step A: Example 23 H O O N S

DMF N NH He80° C. DMF + Etl + K2CO3 -> O Compound 10a

Compound 21a Example 22 Example 23 1013 2-lodopropane (1.53 g, 9 mmol) was added to a suspension of Compound 10a (1 g, 4.5 mmol) in DMF (20 mL). The reaction mixture was stirred at 80°C. for one day. The reaction mixture was cooled down and poured into 1016 KCO (36.7 mg, 0.266 mmol) was added to a water (50 mL) and then filtered through a Buchner funnel. mixture of Example 11 (29.6 mg, 0.133 mmol) and EtI The solid residue was washed with water (2x20 mL) and (0.064 mL, 0.8 mmol) in DMF (1.0 mL) at room tempera dried under vacuum to give Compound 21a (1.05 g, 88%). ture. The reaction was stirred over night before it was diluted with by the addition of EtOAc (50 mL) and water (10 mL). Step B: The organic phase was washed with water (3x15 mL), brine (15 mL), and dried over MgSO. After filtration and con centration, the crude product was purified using preparative TLC with hexane/CH.Cl/EtOAc (v/v/v=7/3/1) as eluent to give Example 22 (7.0 mg, 21%) and Example 23 (20 mg. 60%). Electrospray MS M+1 251.1. Preparative Example 24 1017

Example 24 O O N-N-N Example 21 1S NH 1014 m-CPBA (0.74 g., 70%, 3 mmol) was added to a O Suspension of Compound 21a (0.53 g, 2 mmol) in CH2Cl2 US 2008/00 19978 A1 Jan. 24, 2008 77

-continued -continued Step A: H O O N O Br CH3CN S NH -- -- EtN - -

O Example 10 Example 1

Compound 24a 1018. Example 10 (0.216 g., 0.847 mmol) in allyl alcohol O O N (3.0 mL) was heated at reflux overnight. After cooling to room temperature, the solvent was removed under reduced N NH pressure and the crude product was purified using silica gel flash column chromatography eluting with EtOAc/MeOH O (v/v=5/1) to give Compound 24a (0.1 g, 48%). Example 25 Step B: O O Ns O N-1S 1021 Example 1 (0.5 g. 2.4 mmol) was taken up in CHCI CHCN (10 mL). Triethylamine (0.33 mL, 2.4 mmol) was S NH + NBS E added to the suspension followed by cyclopropyl methyl bromide (0.26 mL, 2.64 mmol) and NaI(0.36 g. 2.4 mmol). O The reaction mixture was heated to reflux overnight. After cooling to room temperature, the solvent was evaporated in Compound 24a vacuo. The crude product was purified by crystallization O O N O from EtOAc/hexanes to give Example 25 (0.25 g, 40%).

Br S NH Preparative Example 26

O 1022) Example 24 Example 26 1019 NBS (36 mg, 0.202 mmol) was added to a solution of Compound 24a (0.040 g, 0.161 mmol) in CHCl (2.0 lo mL) at room temperature. Solvent was removed over 1 hour and the crude product was purified using silica gel flash O O NY column chromatography eluting with hexane/EA (V/v=1/1) N NH to give Example 24 (0.025 g, 48%). Electrospray MS M+1327.1. O Preparative Example 25 1020 Example 25 Step A: H O O N O CHCN O O N N NH + BrCHCOMe + EtN -> N NH O Example 1 US 2008/00 19978 A1 Jan. 24, 2008 78

-continued O Step B: OMe OMe r O O N O O O N O Br NaH N r N r DMF

O O Example 26 Compound 27a 1023 Example 1 (0.1 g, 0.48 mmol) was taken up in CHCN (3.0 mL). Triethylamine (0.067 mL. 0.48 mmol) was added to the suspension followed by methyl bromoac O O N etate (0.046 mL, 0.48 mmol). The reaction mixture was allowed to stir overnight at room temperature. The solvent N- uA was removed under reduced pressure and the crude mixture was purified by column chromatography eluting with O EtOAc/hexanes (2/3:v/v) to yield Example 26 (0.06 g, 45%). Compound 27b Preparative Example 27 1026 Sodium hydride (0.058 g, 1.46 mmol) was added to 1024 a mixture of Compound 27a (0.335 g, 1.33 mmol) in 8 mL DMF at 0° C. followed by cyclopropyl methyl bromide (0.142 mL, 1.46 mmol). The suspension was allowed to stir Example 27 H at room temperature overnight before being diluted with EtOAc (10 mL) and quenched by the addition of water (5 O O NY mL). The aqueous phase was extracted with EtOAc (2x5 mL). The organic layers were combined, dried over MgSO, Nuu-A and concentrated to give the crude product. The crude mixture was purified by column chromatography eluting O with EtOAc/hexanes (2/3:v/v) to yield Compound 27b Step A: (0.175 g, 43%). H O O N O Step C: CHCN N NH + MeOCHBr + EtN -- s O O N O DCM, -789 C. O + BBr - > Example 1 S N

O Compound 27b H O Nuu-AO N Compound 27a O Example 27 1025) Example 1 (1.0 g, 4.8 mmol) was taken up in CHCN (20 mL). Triethylamine (0.67 mL, 4.8 mmol) was 1027 Boron tribromide (2.85 mL, 2.85 mmol, 1.0 M added to the suspension followed by bromomethyl methyl solution in DCM) was added to a solution of Compound 27b ether (0.44 mL, 4.8 mmol). The reaction mixture was (0.175 g, 0.57 mmol) in CHC1 (8.0 mL) at -78° C. The allowed to stir at room temperature for 10 min after which reaction was allowed to stir for 2 h before being quenched it was concentrated. The crude mixture was purified by with water (5.0 mL). The reaction mixture was extracted column chromatography eluting with EtOAC/hexanes with EtOAc (2x5 mL). The organic layers were combined, (2/3:V/v) to yield Compound 27a (0.6 g. 50%). dried over MgSO, and concentrated to give the crude US 2008/00 19978 A1 Jan. 24, 2008 79 product. The crude mixture was purified by column chro matography eluting with EtOAc/hexanes (2/3:v/v) to yield -continued Example 27 (0.1 g, 67%). H O O N Preparative Example 28 N N-N-CO:Me 1028 O H Example 28 Example 28 O O NY 1030) Boron tribromide (1.1 mL, 1.1 mmol, 1.0 M solu N N-CO:Me tion in DCM) was added to a solution of Compound 28a (0.07 g., 0.22 mmol) in CHC1 (3.0 mL) at -78° C. The O reaction was allowed to stir for 2 h before being quenched Step A: with water (5.0 mL). The reaction mixture was extracted with EtOAc (2x5 mL). The organic layers were combined, dried over MgSO, and concentrated to give the crude l product. The crude mixture was purified by column chro O O N O matography eluting with EtOAc/hexanes (2/3:v/v) to yield Example 28 (0.02 g, 33%). NaH S NH + BrCH2COMe DMF Preparative Example 29

O 1031) Compound 27a Example 29 H O O N O s Y O O O N O N Null Ph r O N OMe Nulls Step A: O Compound 28a O O N O Br

1029 Sodium hydride (0.016g, 0.396 mmol) was added NaH -- to a mixture of Compound 27a (0.100 g, 0.396 mmol) in 2 N NH -- DMF mL DMF at 0°C. followed by methyl bromoacetate (0.041 mL, 0.44 mmol). The Suspension was allowed to stir at room O temperature overnight before being diluted with EtOAc (5 mL) and quenched by the addition of water (5 mL). The Compound 27a aqueous phase was extracted with EtOAc (2x5 mL). The organic layers were combined, dried over MgSO, and s concentrated to give the crude product. The crude mixture O O N O was purified by column chromatography eluting with NY O EtOAc/hexanes (2/3:v/v) to yield Compound 28a (0.07 g. N Null Ph 54%). O Step B: Compound 29a s 1032 Sodium hydride (0.080 g, 1.98 mmol) was added to O O N O O DCM, -789 C. a mixture of Compound 27a (0.500 g, 1.98 mmol) in 8 mL sus + BBr --> DMF at 0°C. followed by 2-bromoacetophenone (0.434 g. N 1.98 mmol). The suspension was allowed to stir at room N OMe temperature overnight before being diluted with EtOAc (5 O mL) and quenched by the addition of water (5 mL). The aqueous phase was extracted with EtOAc (2x5 mL). The Compound 28a organic layers were combined, dried over MgSO4, and concentrated to give the crude product. The crude mixture US 2008/00 19978 A1 Jan. 24, 2008 was purified by column chromatography eluting with EtOAc/hexanes (2/3:v/v) to yield Compound 29a (0.37 g. -continued 50%). H O NY Step B:

s Compound 30b O O N O O DCM, -789 C. sus + BBr --> 1035. To a CHCl solution of cyclopentylamine was S N Ph added trimethylsilyl isocyanate. The reaction mixture was stirred overnight. To this was added 200 ml of CH-OH, and O the mixture was stirred for another 2 hrs. The reaction Compound 29a mixture was concentrated and was titrated using diethyl H ether to give an off-white precipitate. The precipitate was O O N O filtered through a Buchner funnel to give cyclopentyl urea Compound 30a as a white crystalline solid compound (13.0 r g, 86%). To this urea Compound 30a (5.0 g, 38.7 mmol) in N Nulls Ph acetic acid (11 mL), was added malonic acid (4.0 g, 38.7 mmol) followed by acetic anhydride (18 mL) and the O reaction was stirred at 70° C. for 12 hrs. The reaction mixture was concentrated, cooled in an ice bath and titrated Example 29 using 4/1 EtO/EtOAc. A pale yellow crystalline solid precipitated out. The precipitate was filtered and washed 2-3 times using cold diethyl ether to obtain a pale yellow solid 1033 Boron tribromide (4.7 mL, 4.7 mmol, 1.0 M solu Compound 30b (2.5g, 33%). tion in DCM) was added to a solution of Compound 29a (0.350 g., 0.95 mmol) in CHCl (10.0 mL) at -78°C. The Step B: reaction was allowed to stir for 2 h before being quenched H with water (5.0 mL). The reaction mixture was extracted with EtOAc (2x15 mL). The organic layers were combined, O NY dried over MgSO, and concentrated to give the crude N -- product. The crude mixture was purified by column chro matography eluting with EtOAc/hexanes (2/3:v/v) to yield Example 29 (0.175 g, 56%). Compound 30b Preparative Example 30 and 31 O N Sulfamic Acid Hess 140° C. 1034) O O

H O O N O O N O O N O O s N NH S N S NH S. N

O O i) Example 30 Example 31 Example 30 Example 31 1036 Compound 30b (0.75 g, 1.0 equiv. 3.82 mmol) was Step A: condensed with methyl propional acetate (0.48 mL, 3.82 O mmol) in the presence of sulfamic acid and heated to 140° HN C. for 6 hrs, forming a dark brown solid. The reaction mixture was diluted with EtOAc, washed with HO, dried NH2 NH using Na2SO and concentrated to give a crude mixture. TMSNCO Malonic acid Her He Prep TLC purification of the crude mixture in 95/5 CHCl/ Ac2O, AcOH CH-OH yielded both the N and N isomers. Example 30 LCMS: (M+1)277.1 and Example 31 LCMS: (M+1). 277.1 Compound 30a 1037. A similar two-step procedure was used to synthe size Examples 32-43. US 2008/00 19978 A1 Jan. 24, 2008

LCMS: LCMS: (M + 1) of (M + 1) of Substituents N-1 products N-1 products N-3 products N-3 products cyclopropyl 249.1 H 249.1 O O NY O O N N N N NH O

O Example 33

Example 32 cyclobutyl 263.1 H 263.1 O O N

On O. N. O N

S rNH O Example 35 O Example 34

Pr 2S1.1 H 2S1.1 O O N

O O N O N r O N NH Example 37 O Example 36

Et 237.1 H 237.1 r O O N O O O N O Y N N S NH O

O Example 38 Example 38

Me H 223.0 O O N O

O O N N N NH S N

O O Example 41 Example 40 US 2008/00 19978 A1 Jan. 24, 2008 82

-continued

LCMS: LCMS: (M + 1) of (M + 1) of Substituents N-1 products N-1 products N-3 products N-3 products allyl 249.1 H 249.1

N O O N N O N NH N Example 43 O Example 42

1038. Using the procedure set forth above for making the compound of Example 30, and Substituting the appropriate -continued reagents and intermediates, compounds 780-785 were pre Electrospray pared: Compound LCMS No. Structure IM + 1 + 783 291.2 Electrospray Compound LCMS No. Structure IM + 1 + 78O H 303.1 O N-O NY-

O

784 317.2

781 H 305.2 O N!O N-

O

Preparative Example 44

782 291.2 1039)

Example 44 US 2008/00 19978 A1 Jan. 24, 2008 83

-continued -continued H O O N O Y Allyl Bromide, LiOH Electrospray S NH CH-OH:HO3 2O (1:1(1:1) PREPARATIVE LCMS EXAMPLE IM + 1 +

O 317.1 Example 1

Example 44

1040. To Example 1 (0.456 g, 2.2 mmol) in MeOH:HO N (1:1) was added allyl bromide followed by LiOH, and the reaction mixture was heated to 82° C. for 8 hours. The progress of the reaction was monitored by TLC which indicated presence of some starting material. The reaction mixture was then heated for another 6 hours. An orange-red precipitate was produced, which was filtered from the solu Example 51 tion using diethyl ether. The filtrate was purified using prep TLC 95/5 CHC1/CH-OH to give Example 44 LCMS: 359.1 (M+1).249.0 MeO

1041. The following Examples 45-47, 51, 61-64, 66-67, N O 69-79 were prepared by a procedure similar to that used for the preparation of Example 12, using Example 10 and the s appropriate corresponding alcohol. NH OMe

Electrospray PREPARATIVE LCMS EXAMPLE IM + 1 + 391.1 367.1

O N O s Br NH CF

CF 367.1 327.1

Example 46 Example 63 US 2008/00 19978 A1 Jan. 24, 2008

-continued -continued

Electrospray Electrospray PREPARATIVE LCMS PREPARATIVE LCMS EXAMPLE IM + 1 + EXAMPLE IM + 1 +

327.1 21 316.1 N-N,N

Example 64 Example 71

21 3OO.1 21 3.14.1

Sa Sa N N

Example 66 Example 72

2n -- 1 O 316.1 313.1 S

Example 67 Example 73

391.2 317.1

F

Example 69 Example 74

21 3.14.1 383.1 O O Ns O N N NH OCF

O Example 70 Example 75 US 2008/00 19978 A1 Jan. 24, 2008 85

-continued -continued Electrospray PREPARATIVE LCMS EXAMPLE IM + 1 +

333.1 + BOH + DIAD +

Compound 10b C O O Ns S N THF PPh. -- S 2N

375.1 OB Compound 48a

1043) DIAD (0.488 mL, 2.52 mmol) was added dropwise to a solution of Compound 10b (0.5g, 2.10 mmol), BnOH (0.261 mL, 2.52 mmol) and PPhs (0.661 g, 2.52 mmol) in THF (6.0 mL) at room temperature. The resulting reaction mixture was stirred for 5 hours before it was worked up by 320.1 silica gel flash column chromatography using a solid sample loading method, eluting with hexane/EtOAc (v/v=5/1) to give Compound 48a (0.25 g, 36%).

Step B: O O N S N N CPBA CHCl2 Example 78 N 2 N -- l- He

Br 469.1 OB Compound 48a.

O Br O O N ga2

S. 2 N

OB Example 79 Compound 48b

Preparative Example 48 104.4 m-CPBA (0.384 g, 1.55 mmol. 60-70%) was added 1042 at room temperature to a solution of Compound 48a (0.17 g. 0.518 mmol) in CHCl (5 mL). The reaction mixture was stirred for 5 hours before it was quenched with addition of Example 48 MeS (76 ul, 1.55 mmol). The mixture was then diluted with EtOAc and washed with NaHCO solution. The organic phase was washed with water, brine, and dried (NaSO). Solvent was removed under reduced pressure, and the crude product was purified by Silica gel flash column chromatog raphy eluting with hexane/CH2Cl2/EtOAc (v/v/v=7/3/2) to give Compound 48b (0.15 g, 80%). US 2008/00 19978 A1 Jan. 24, 2008 86

Preparative Example 49 Step C: 1047

O O O N ga2 n N -- NaCN DMF S 2 N 8. Hess

OB Compound 48b

Compound 48c

1045 NaCN (14.0 mg, 0.286 mmol) was added to a solution of Compound 48b (85.8 mg, 0.238 mmol) in DMF (1.5 mL) at room temperature. The reaction mixture was Example 10 stirred at room temperature for 2 hours before it was worked up by dilution with EtOAc and water. The organic phase was NaH washed with water (2x), brine, and dried (MgSO). Solvent He was removed under reduced pressure, and the crude product HO THFDMF was purified by silica gel flash column chromatography, eluting with hexane/CHCl2/EtOAc (v/v/v=5/1/1) to give Compound 48c (37 mg, 50%).

HCI, MeOH

Example 49 Compound 48c

1048 (R)-Phenethanol (0.24 mL, 2.0 mmol) was added dropwise to a suspension of NaH (87.4 mg, 2.0 mmol. 55% in mineral oil) in THF (3.0 mL) at room temperature. The mixture was stirred for 2 hours until the solution was clear. The alkoxide thus formed was then added dropwise to a solution of the Compound 10 (0.27 g, 1.0 mmol) in DMF (3.0 mL) at room temperature. The reaction mixture was Compound 48 stirred for 2 hours before it was quenched by the addition of HOAc (0.11 mL 2.0 mmol). The reaction mixture was taken up in EtOAc/CHCl (8/2), washed with diluted HCl (0.1 1046. A solution of Compound 48c (10 mg, 0.0326 M), water and brine, then dried (MgSO). The solvent was mmol) in 4.0 M HCl in dioxane (0.7 mL) and MeOH (0.7 removed under reduced pressure. The crude product was mL) in a sealed tube was heated at 70° C. for 7 hours. The purified using silica get flash column chromatography elut mixture was cooled to room temperature and solvent was ing with hexane/CH.Cl/EtOAc (v/v/v=7/3/2) to give Com removed under reduced pressure to give crude product. The pound 49 (0.25 g, 80%). Electrospray MS M+1' 313.1. crude product was purified with preparative thin layer silica gel chromatography eluting with hexane/CH2Cl2/MeOH 1049. Using the method set forth above and substituting (v/v/v=6/4/1) to give Example 48 (5 mg, 61%). Electrospray the appropriate reagents and intermediates, compounds 791 MS M+1 251.1. 795 were prepared: US 2008/00 19978 A1 Jan. 24, 2008

Electrospray Compound LCMS No. Structure IM + 1 +

791 411.2

792 411.2

793 437.2

794 O O N O a 437.2

795 291.2 US 2008/00 19978 A1 Jan. 24, 2008 88

Preparative Example 50 Preparative Example 54 1050 1056)

Example 50 O O O OMe H O O N O r r S. sul Ph N N O

O Example 54

F Step A: H O O N O

1051 Example 50 was prepared by a procedure similar to r -- that used to prepare Example 29, using Compound 27a and N Nulls Ph the appropriate corresponding bromide Electrospray MS M+1 345.1. O Example 29 Preparative Example 52 NaOAc, EtOH 1052) NHOMe-HCl Her H O O N O OMe Example 52 r N Null Ph

O

Example 54

1057 Example 29 (0.05 g, 0.153 mmol) was taken up in ethanol (3.0 mL), Methoxylamine hydrochloride (0.051 g, 0.61 mmol) was added to the mixture followed by sodium acetate (0.038 g., 0.46 mmol). The reaction mixture was 1053 Example 52 was prepared by a procedure similar to stirred at 60° C. overnight. After being cooled to room that used to prepare Example 49, using Example 10 and temperature, the solvent was removed under reduced pres (S)-phenethanol. Electrospray MS M-1' 3.13.1. sure, diluted with CHCl (5 mL) and water (5 mL). The product was extracted from CHCl (2x5 mL), dried over Preparative Example 53 MgSO concentrated. The crude product was dissolved in minimum CHCl, diluted with hexanes and filtered to give 1054) Example 54. Electrospray MS M+1' 356.1. Preparative Example 55 Example 53 O O MOMr O 1058) N N lo O CF O O NK N 2N

1055 Example 53 prepared by a procedure similar to that OPMB used in Step A of the preparation of Example 29, using Compound 27a and the appropriate corresponding bromide. Example 55 Electrospray MS M+1" 439.4. US 2008/00 19978 A1 Jan. 24, 2008

phase was washed with water, brine, and dried (Na2SO). -continued Solvent was removed under reduced pressure, crude product was purified with silica gel flash column chromatography eluting with hexane/CH.Cl/EtOAc (v/v/v=7/3/2) to give Example 55 (0.15g, 80%). Electrospray MS M+1' 391.1. Preparative Example 56 1061

Compound 10b O -(- NENX-0 y- + PMBOH + O O O O N S n N PPh F- N 2N

OPMB

Compound 55a

1059. Di-t-butyl diazodicarboxylate (2.32 g, 10.08 mmol) was added to a solution of Compound 10b (2.0 g, 8.4 Example 10 mmol), 4-methoxybenzyl alcohol (1.39 g, 10.08 mmol) and PPhs (2.64 g, 10.08 mmol) in THF (20.0 mL) at room temperature. The resulting reaction mixture was stirred for 4 hours before it was worked up by direct silica gel flash column chromatography using a solid sample loading HN CH3CN method, eluting with hexane/CH.Cl/EtOAc (v/v/v=9/1/1) He to give Compound 55a (1.6 g. 53%). Yy

Step B: Example 56 O O N S n N -- l-CPBA HeSCSI: 1062 Cyclobutylamine (0.14g, 2 mmol) was added to a N 2 N suspension of Example 10 (0.25 g, 1 mmol) in CHCN (15 mL). The reaction mixture was stirred at room temperature OPMB for 16 hours. Solvent was removed and the crude product was purified using silica gel flash column chromatography Compound 55a eluting with 10% NH-OH in MeOH/CHCl (v/v=3:97) to give Example 56 (0.045 g, 17%). Electrospray MS M+1" 2 O O O Ns S N 262.1 Preparative Example 57 1063) OPMB

MOM Example 55 O O rO 1060 m-CPBA (0.47g, 1.92 mmol. 60-70%) was added N OH at room temperature to a solution of Compound 55a (0.287 g, 0.80 mmol) in CHCl (8 mL). The reaction mixture was O stirred for 5 hours before it was quenched by the addition of MeS (124 uL, 1.92 mmol). The mixture was then diluted Example 57 with EtOAc and washed with NaHCO solution. The organic US 2008/00 19978 A1 Jan. 24, 2008 90

stirred at room temperature for 4 hours. Removal of solvent -continued and excess trifluoroacetic acid gave Example 57 (0.89 g, Step A: 100%). Electrospray MS M+1' 3.11.2 OMe Preparative Example 58 O a 1066) Br NaH O -- CC DMF H O -N O O N Compound 27a N- y O Example 58 Step A:

O O O

Compound 57a

1064. A mixture of Compound 27a (2 g, 7.9 mmol) in DMF (100 mL), t-butyl bromoacetate (1.7g, 8.7 mmol), and H diisopropyl ethylamine (1.1 g, 8.7 mmol) was stirred at 40° O O N O C. for 4 hours, then at room temperature for 16 hours. The 140-145° C. Y reaction mixture was mixed with water (200 mL), and then Sulfamic acid Her extracted with ethyl acetate (100 mLX3). The organic solu N y tion was dried (NaSO) and concentrated. The crude prod uct was purified using silica gel flash column chromatogra O phy eluting with MeOH/CHCl (v/v=2:98) to give Compound 57a (1.8 g. 62%). Electrospray MS M+1 Example 58 367.2. 1067 To a mixture of mono-cyclobutylbarbituric acid Step B: (300 mg, 1.6 mmol) and 2-Methyl-3-oxo-pentanoic acid ethyl ester (1.041 g, 6.59 mmol) was added sulfamic acid (77 mg, 0.8 mmol). The mixture was heated at 140-145° C. s for 48 h. The residue was loaded onto preparative silica gel O O N O O plates and eluted with 5% MeOH/CHCl to afford Example TFA 58 (42 mg, 9%). LCMS: M+1: 277.1 N N O Preparative Example 59 O - 1068) Compound 57a s Example 59 O O N rO N Nulls OH O CN

Example 57 1069) EXAMPLE 59 was prepared using a two step procedure similar to that used for the preparation of 1065. A mixture of Compound 57a (0.95g, 2.6 mmol) in Example 29, using Compound 27a and the appropriate CHCl (5 mL) and trifluoroacetic acid (1.5 g., 13 mmol) was corresponding bromide. Electrospray MS M+1 252.1. US 2008/00 19978 A1 Jan. 24, 2008 91

Preparative Example 60 -continued H 1070) O O N O Y O OH H O O N O N N Y O OH O N N Compound 60 O Compound 60 1072 Boron tribromide (1.3 mL, 1.31 mmol, 1.0 M Step A: solution in DCM) was added to a solution of Compound 60a OMe (0.105 g, 0.262 mmol) in CHC1 (5.0 mL) at -78° C. The reaction mixture was allowed to stir for 2 h before being r O quenched with water (5.0 mL). The reaction mixture was O O N O extracted with EtOAc (2x5 mL). The organic layers were NaH -- He combined, dried over MgSO4, and concentrated to give the N NH DMF crude product. The crude mixture was purified by column chromatography eluting with EtOAc/hexanes (2/3:v/v) to OMe O yield Compound 60. Electrospray MS M+1" 343.1. Compound 27a Preparative Example 65 s 1073) O O N O O OMe

N N

O Compound 60a

1071 Sodium hydride (0.035 g, 0.869 mmol) was added to a mixture of Compound 27a (0.200 g, 0.79 mmol) in 3 mL DMF at 0°C. followed by 2-methoxyphenacyl bromide (0.2 g, 0.87 mmol). The suspension was allowed to stir at room temperature overnight before being diluted with EtOAc (10 mL) and quenched by the addition of water (5 mL). The aqueous phase was extracted with EtOAc (2x5 mL). The Compound 12 organic layers were combined, dried over MgSO4, and concentrated to give the crude product. The crude mixture was purified by column chromatography eluting with EtOAc/hexanes (2/3:v/v) to yield Compound 60a. He

Step B: OMe Compound 65a

O O ( . 1074 KCO (64.7 mg, 0.47 mmol) was added to a r OMe mixture of Example 12 (70 mg, 0.235 mmol) and cyclopro N- N -- pyl methyl bromide (0.068 mL, 0.705 mmol) in DMF (2.0 mL) at room temperature. The reaction mixture was stirred overnight before it was diluted by the addition of EtOAc (50 O mL) and water (10 mL). The organic phase was washed with Compound 60a water (3x15 mL), brine (15 mL), and dried over MgSO. DCM, -789 C. After filtration and concentration, the crude product was BBr: He purified using preparative TLC with hexane/CH.Cl/EtOAc (v/v/v=7/3/1) as eluent to give Compound 65a (26 mg, 31%) US 2008/00 19978 A1 Jan. 24, 2008 92

-continued Electrospray Compound LCMS No. IM + + 788 269.1

Compound 65a

789 295.2

Example 65

1075 Compound 65a (26 mg, 0.074 mmol) in EtOH (5.0 mL) was treated at room temperature with Pd/C (7.8 mg, 10 wt %) and was hydrogenated with a H. balloon for 30 minutes. The reaction mixture was filtered through a short pad of Celite and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the crude product was purified using preparative TLC with 790 283.2 hexane/CH.Cl/MeOH (v/v/v=3/7/1) as eluent to give Example 65 (6 mg, 30%). Electrospray MS M+1' 263.1. 1076. Using the method set forth above and substituting the appropriate reagents and intermediates, compounds 786 790 were prepared:

Electrospray Compound LCMS

No. IM + + Preparative Example 68 786 291.2 1077)

H O O N O Y O N Nulls, O Example 68 787 295.2 Step A: MOM O O N O N sus, O O Example 57 CHCl2 HATU + NEts --> US 2008/00 19978 A1 Jan. 24, 2008 93

-continued -continued MOM Step A: O O N O MOM r O O N O N Nulls, N HerCHC1, 70° C. S. N + NBS O Compound 68a O Compound 27b 1078. The mixture of Example 57 (0.1 g, 0.32 mmol) in MOM CHCl (5 mL), piperidine (0.027 g., 0.32 mmol), HATU (0.24g, 0.64 mmol), and triethylamine (0.098 g. 0.96 mmol) O O N was stirred at room temperature for 2 hours. The reaction mixture was mixed with water (20 mL), and then extracted N- uA with CHCL (10 mLx2). The organic solution was dried (NaSO) and concentrated. The crude product was purified Br using silica gel flash column chromatography eluting with Compound 80a EtOAc/hexanes (v/v=1:1) to give Compound 68a (0.065 g, 54%). Electrospray MS M+1' 378.2. Step B: 1081 Compound 27a (0.1 g, 0.33 mmol) was taken up in MOM CH2Cl at room temperature. NBS was then added and the O O N O reaction was stirred for 4 hours. After no progress in the reaction was observed, a mixture of NBS (0.061 g, 0.34 r mmol) in chloroform (4 mL) was added. The reaction N Nulls, mixture was heated for 12 hrs at 70° C. Both the TLC (30/70 O EtOAC/Hexane) and mass spectrogram indicated that the reaction was complete. The reaction mixture was cooled to Compound 68a room temperature and diluted with CHC1 and washed with

BBr: HeDCM, -789 C. HO. The organic phase was dried with NaSO and solvent H was removed to give the crude product. Preparative silica gel O O N O chromatography purification in EtOAc/Hexane (v/v=30/70) r yielded Compound 80a (0.075 g, 60%). N Nulls, Step B: MOM O O O N O Example 68 Y BBr: DCM,-78° C. S N 1079) 1MBBr solution in CHCl (0.75 mL, 0.75 mmol) was added to a solution of Compound 68a (0.056 g., 0.15 O mmol) at -78° C. After the reaction mixture was stirred at Br -78° C. for 2 hours, water (5 mL) was added. The organic Compound 80a solution was dried (NaSO) and concentrated. The crude H product was purified using silica gel flash column chroma O O N. tography eluting with 10% NHOH in MeOH/CHCl (v/v= 3:97) to give Example 68 (0.01 g, 20%). Electrospray MS Nuu-A M+1334.2. O Preparative Example 80 Br Example 80 1080 H 1082 Compound 80a (0.070 g., 0.18 mmol) was taken up in CH2Cl and the mixture was cooled to -78°C. 1M BBr O O NY (0.909 mL, 0.9 mmol) was added. The reaction mixture was stirred for 4 hours. Upon completion of the reaction, the nulus-A mixture was diluted with CHCl, washed with H2O, dried O with NaSO, and then solvent was removed to give crude Br product. The crude product was purified by preparative silica Example 80 gel chromatography using 30/70 EtOAc/Hexane, to give Example 80. Electrospray MS M+1 341.2. US 2008/00 19978 A1 Jan. 24, 2008 94

Preparative Example 81 -continued 1083

O O N N

N 2 N

OPMB Compound 92a

1086 Isopropenyl magnesium bromide (0.95 mL, 0.475 mmol. 0.5 M in THF) was added dropwise to a solution of Example 55 (0.133 g, 0.341 mmol) in THF (4.0 mL) at 0° C. The mixture was stirred at 0°C. for 2 hours before it was quenched with HCl (0.2 M). The mixture was taken up in EtOAc and washed with water and brine. The organic phase Example 5 was dried over MgSO. Solvent was removed under reduced pressure and the crude product was purified with silica gel flash column chromatography eluting with hexane/CH2Cl2/ EtOAc (v/v/v=4/1/1) to give Compound 92a (59 mg, 49%). DIEA --

Step B:

Example 81 O O N n

1084) To a mixture of Example 5 (84 mg. 0.34 mmol) and S 2 N + OsO4SU4 + acetone oxime (27.5 mg 0.37 mmol) was added DIEA (0.09 ml, 0.52 mmol) and the mixture was stirred for 3 days. The OPMB mixture was concentrated and was subjected to silica gel column chromatography to give Example 81 (30 mg, 31%) Compound 92a LCMS: M-1: 282.1

Preparative Example 92 O O O N 1085 N THF/H2O O NaIO4 - - - S. 2 N

OPMB Compound 92b

1087 NaIO (70.1 mg, 0.328 mmol) was added to a Step A: solution of Compound 92a (46.2 mg, 0.131 mmol) and 0504 (22.2 LL, 4 wt % in water) in THF (5.0 mL) and water (5.0 mL) at room temperature. The reaction mixture was stirred O O overnight before it was quenched by the addition of MeS THF (20 uL, 0.328 mmol). The mixture was diluted with EtOAc N He and washed with HCl (0.5 M), water and brine. The organic phase was dried over MgSO. Solvent was removed under OPMB reduced pressure and the crude product was purified by silica gel flash column chromatography eluting with hexane/ Example 55 CHC1/EtOAc (v/v/v=2/1/1) to give Compound 92b (39 mg, 84%). US 2008/00 19978 A1 Jan. 24, 2008 95

Step C: -continued O Electrospray O O N N PREPARATIVE LCMS CHCN/HO EXAMPLE IM + 1 + N 2 N - CAN -->

OPMB 341.1

Compound 92b

Example 92 341.1

1088 Ceric ammonium nitrate (70.9 mg, 0.129 mmol) was added to a solution of Compound 92b (20.8 mg, 0.059 mmol) in MeCN (3.0 mL) and water (0.3 mL) at room temperature. The reaction mixture was stirred for 2 hours before it was diluted with EtOAc. The organic phase was washed with HCl (0.5 M), water, brine and dried over MgSO4. Solvent was removed under reduced pressure and Example 85 crude product was purified using preparative TLC with hexane/CH.Cl/MeOH (v/v/v=2/8/1) as eluent to give N Ph 391.1 Example 92 (8 mg, 58%). Electrospray MS M+1 235.1. 21

1089 Examples 82-91 were prepared by procedures N O N similar to those used for the preparation of Example 49, s S using Example 10 and the appropriate corresponding alco hols. NH

O Electrospray Example 86 PREPARATIVE LCMS EXAMPLE IM + 1 + 264.1 Ph 389.1

N-s-ss's NH

339.1 327.1

Example 88 Example 83 US 2008/00 19978 A1 Jan. 24, 2008 96

-continued -continued H Electrospray PREPARATIVE LCMS O O NY EXAMPLE IM + 1 + N NH

349.1 O HO Example 92

1091 Example 2 (0.71 g, 3.66 mmol. 1 eq) and SeO. (0.46g, 1.1 eq) were mixed together in 1,4-dioxane (10.5 mL) and THF (1.5 mL) and the mixture was heated to 90° C. in air for 24 hr. 5% of the resulting crude product was purified by directly loading it onto a reverse-phase HPLC column to afford the desired product Example 92 (7.4 mg) as a white solid. 331.1 1092) "H NMR (CDOD): 8 4.80 (s, 2 H) 6.20 (s, 1 H) 1093 Mass of CHNOs (MH)": 211. Found: 211. Preparative Example 93 1094)

341.1

Example 91 Example 93 Step A: H O O N O Preparative Example 92 NY HeSeO 1090) S NH

O H Example 2 O O N S NH S NH O HO CHO O Example 92 Compound 93a H O O N O SeO He 1095 Compound 93a was prepared by a procedure simi N NH lar to that used to prepare alcohol Example 92, except that the alcohol was allowed to oxidize further to the correspond ing aldehyde. After purification several times using reverse O phase HPLC, Compound 93a (90 mg) was obtained. Example 92 1096 Mass of CHNO (MH)": 209. Found: 209. US 2008/00 19978 A1 Jan. 24, 2008 97

-continued Step B: H H O O N O O O NY N NH N rrNH O HO CHO O Example 94 Compound 93a

1101 Example 94 was prepared by a procedure similar to that used to prepare Example 92, except that Example 1 was oxidized instead of Example 2. 1102) H NMR (CDOD): & 1.38 (d. 2 H, J=6.8 Hz) 5.50 (q, 1 H, J=6.8 Hz) 6.20 (s, 1 H) 1103 Mass of CHNO (MH)": 225. Found: 225. Preparative Example 95 1104) Example 93

1097 Compound 93b (90 mg, 0.43 mmol. 1 eq)) was O O N ous mixed with 3-methoxyaniline (109 mg, 2 equiv.) and sodium r triacetoxyborohydride (185 mg, 2 equiv.) in 2 mL of THF. N NH After stirring overnight, the reaction mixture was quenched with methanol. Preparative TLC afforded 15.3 mg of the O desired product Example 93. Example 95 1098 H NMR (CDOD): 83.60 (s, 3 H)4.60 (s, 2 H) 5.75 (s, 1 H) 6.20 (m, 3 H) 6.95 (m, 1 H) O O NN 1099 Mass of CHNOs (MH)": 316. Found: 316. N NH Preparative Example 94 O 1100 Example 10

H O O N ous O O N N r NH S NH

O O HO Example 95 Example 94 1105 2-butyn-1-ol (140 mg, 2 mmol. 2 equiv.) in 4 mL of H O O N O THF was treated with 1.6 Mn-BuLi (1.2 mL, 2 equiv.) at 0° C. for 5 min to provide an alkoxide solution. Example 10 SeO2 (0.25 g, 1 mmol. 1 equiv.) was then added to the alkoxide S NH Her Solution. After stirring 1.5 hr, 0.12 g of acetic acid (2 equiv.) was added to the solution. The solvent was removed and O extraction with diethyl ether and water provided a white solid. The solid was washed with cold diethyl ether and dried Example 1 under vacuum. 80 mg of the desired product Example 95 was obtained. US 2008/00 19978 A1 Jan. 24, 2008 98

1106 H NMR (CDC1): 8 1.20 (t, 2 H, J=6.8 Hz) 1.83 2-oxo-cyclopentanecarboxylic acid methyl ester, respec (s, 3 H)3.00 (q, 2 H, J=6.98 Hz) 5.00 (s, 2 H) 6.00 (s, 1 H) tively, were used instead of methylpropionylacetate. 1107) Mass of CHNO (MH)": 261. Found: 261. 11131 Electrospravpray MS IM+1l '96 and 97 are 235.1. Preparative Example 96 Preparative Example 99 1108) 1114) Bn H H O N N O O NY N NH Sr NH

O O Example 96 H Example 99 O N O O Y TEA NH Na2CO3 NH + CHCOCH -reflux - EtO HC --

OEt O H Compound 99a O O N NH2 o NHCI Na2CO3 N NH EtO He- - - EtOH OEt O Compound 99b Example 96 O O O

EtO o NH2 NulusO 1. 1109 Barbituric acid (1.0 g, 7.81 mmol) was taken up in excess acetone. Triethylamine (2 mL) was added, and the NH2 reaction mixture was refluxed overnight after which it was Compound 99c cooled and filtered. The crude solid was purified by pre H parative TLC (8:1:1/EtOAc:DCM:MeOH) to yield the O N NH2 desired product, Example 96. 1110 Electrospray MS M+1" for Example 96 is 209.0 N OEt Preparative Examples 97 and 98 O 1111 Compound 99d 1115 Commercially available (Aldrich) Compound 99a Example 97 H (75 g, 383 mmol) was stirred with cold aqueous NaCO (15%, 450 mL) for 2 h. Extraction with EtOAc and drying O O N over NaCO provided Compound 99b as a colorless oil, which was immediately treated with NHCl (19.5 g., 364 N NH mmol) in 200 mL of dry EtOH at 50° C. for 60 h. The crude product mixture was cooled and the solvent was removed. O The resulting light yellow solid was treated with cold Example 98 KCO, (30%, 300 mL HO) for 0.5 h. Extraction with H EtOAc gave Compound 99c as a light yellow solid (37.92 g). This solid was reacted with methyl propionylacetate (38.0 g, O O N 292 mmol), 2 mL pyridine, in 400 mL of dry EtOH at 100° N NH C. for 24 h. After cooling and filtration, the solid was washed with EtOH and 18 g of Compound 99d as a white solid was O obtained (22% yield from Compound 99a). 1116) "H NMR (CDC1): 8 1.20 (t, 3 H, J=7.3 Hz) 1.40 (t, 1112) Examples 97 and 98 were prepared by methods 3 H, J=7.1 Hz) 2.90 (q, 2 H, J=7.3 Hz) 4.30 (q, 2 H, J=7.1 analogous to the method used to prepare Example 1, except Hz) 5.75 (s, 1 H) that 2-oxo-cyclohexanecarboxylic acid methyl ester and 1117 Mass of CHNO (MH)": 211. Found: 211.