AU2013203726A1 - Nitrogen-containing heterocyclic compounds and methods of use thereof - Google Patents

Abstract

The present invention provides compounds of Formula (1) and pharmaceutically acceptable salts, solvates, esters, and tautomers thereof, s wherein: Q is selected from the group consisting of: (a), (b), (c), (d) and (e); and L is selected from the group consisting of: (f), (g), (h), and (i); pharmaceutically compositions comprising one or more compounds of formula (I), and methods of using the compounds of formula (1). w:\nrportbl\GHMatters\KIRSTENA\4245447_1.DOCX11/04/13

Description

1 NITROGEN-CONTAINING HETEROCYCC COMPOUNDS AND METHODS OF USETHEREOF This application is a divisional application of Australian patent application no. 2007319940 which is herein incorporated by reference. Field of the Invention The present invention relates to nicotinic acid receptor agonist compounds useful for treating metabolic syndrome, dyslipidemia, cardiovascular diseases, 5 disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, and non-alcoholic fatty liver disease; pharmaceutical compositions comprising such compounds; pharmaceutical compositions comprising nicotinic acid receptor agonist compounds in combination with other therapeutic agents; and methods of treatment 10 using the compounds and compositions to treat conditions such as metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, hepatic steatosis and non-alcoholic fatty liver disease. 15 Background of the Invention Nicotinic acid has been used to treat metabolic syndrome and dyslipidemia. However, nicotinic acid has undesirable side effects such as flushing and diarrhea. It is therefore desirable to provide improved nicotinic acid receptor agonists with 20 improved efficacy at treating metabolic syndrome and dyslipidemia, yet without the undesirable side effects. The compounds of the present invention provide such improved nicotinic acid receptor agonists. M. Ridi, Gazzetta Chim. Ital. (1950) vol. 80, p. 121 and M. Ridi, Gazzetta Chim. 25 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. (1972), vol. 8, pp. 1041-1050 discloses the synthesis of 8-substituted pyrido[2,3-dlpyrimidines. S. Rao, Indian J. Chem. (1974), 12(10), pp. 1028-1030 discloses the synthesis of pyrano[2,3-d]pyrimidines. M. Skof, Heterocycles, (1999), 2 51(5), pp. 1051-1058 discloses one step transformations of (S)-1-benzoyl-3-[(E) dimethylaminomethylidene]-5-methoxycarbonyl-pyrrolidin-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. However, the 5 compounds of the above references differ from those of the present invention. WO 2004/110368 describes combination therapies for the treatment of hypertension comprising the combination of an anti-obesity agent and an anti hypertensive agent. However, WO 2004/110368 fails to describe nicotinic acid receptor agonists, or combinations of one or more nicotinic acid receptor agonists with 10 a second therapeutic agent. WO 2005/000217 describes combination therapies for the treatment of dyslipidemia comprising the administration of a combination of an anti-obesity agent and an anti-dyslipidemic agent. However, WO 2005/000217 fails to describe nicotinic acid receptor agonists, or combinations of one or more nicotinic acid receptor agonists 15 with a second therapeutic agent. WO 2004/110375 describes combination therapies for the treatment of diabetes comprising the administration of a combination of an anti-obesity agent and an anti-diabetic agent. However, WO 2004/110375 fails to describe nicotinic acid receptor agonists, or combinations of one or more nicotinic acid receptor agonists with 20 a second therapeutic agent. US 2004/0122033 describes combination therapies for the treatment of obesity comprising the administration of a combination of an appetite suppressant and/or metabolic rate enhancers and/or nutrient absorption inhibitors. However, US 2004/0122033 fails to describe nicotinic acid receptor agonists, or combinations of 25 one or more nicotinic acid receptor agonists with a second therapeutic agent. US 2004/0229844 describes combination therapies for treating atherosclerosis comprising the administration of a combination of nicotinic acid or another nicotinic acid receptor agonist and a DP receptor antagonist. However, the nicotinic acid agonists of US 2004/0229844 are quite different from those of the present invention. 30 W02005/077950 describes xanthine derivatives which are agonists of the nicotinic acid receptor HM74A. However, the xanthine derivatives of W02005/077950 are quite different from the compounds of the present invention.

3 Summary of the Invention In one embodiment, the present invention is directed to a compound of Formula (I): L R2 Q R1 5 (I) and pharmaceutically acceptable salts, solvates, esters, and tautomers thereof, wherein: Q is selected from the group consisting of:

R

3 R3 N R4 N O, .Ny R4 NN 0 NR4 N 5R5S' N N- N 0 0 R (a) (b) (C) (d) and (e) 10 L is selected from the group consisting of: RC Rd O rO Ra OI I (f) , (9) , (h) ,and (i)

R

1 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, which can be the same or different: 15 OH, cycloalkyl, -C(O)-alkyl, -alkylene-C(O)-O-alkyl, -O-R 1 0, -alkylene-O-alkyl, aryl, -alkylene-aryl, heteroaryl, -alkylene-heteroaryl, halogen, -(CH 2 )n-N(R 7

)

2 , -alkylene-cycloalkyl, or -alkylene-cycloalkenyl, wherein the cycloalkyl or the cycloalkyl portion of said -alkylene-cycloalkyl of

R

1 is unsubstituted or substituted with one or more X groups, said aryl or 20 the aryl portion of said -alkylene-aryl of R1 is unsubstituted or substituted with one or more Y groups, and said heteroaryl or the heteroaryl portion 4 of said -alkylene-heteroaryl of R' is unsubstituted or substituted with one or more Y groups;

R

2 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 10 , 5 -alkylene-O-alkyl, unsubstituted aryl, aryl substituted with one or more Y groups, unsubstituted heteroaryl, heteroaryl substituted with one or more Y groups, and halogen; or

R

1 and R 2 together with the ring carbon atoms to which they are shown attached, form a 5- or 6-membered cycloalkenyl ring or a 5- or 6-membered heterocyclic 10 ring having 1 or 2 heteroatoms;

R

3 is selected from the group consisting of H, alkyl, alkyl substituted with one or more hydroxyl groups, -alkylene-O-alkyl, cycloalkyl, -alkylene-cycloalkyl, alkylene-C(O)-O-alkyl, -alkylene-O-C(O)-alkyl, alkenyl, aryl, and heteroaryl, wherein the cycloalkyl or the cycloalkyl portion of said -alkylene-cycloalkyl of 15 R 3 is unsubstituted or substituted with one or more X groups, said aryl of

R

3 is unsubstituted or substituted with one or more Y groups, and said heteroaryl of R 3 is unsubstituted or substituted with one or more Y groups;

R

4 is selected from the group consisting of H, halogen, alkyl, haloalkyl, -0 20 cycloalkyl, -0-alkynyl, -O-R 1 0 , -C(O)-O-alkyl, -S(O)m-R 9 , -N(R 7

)

2 ,

-N(R

7 )-NH-C(O)-alkyl, -N(R 7 )-NH-C(O)-O-alkyl, -O-N=C(R12) 2 , -N(R 7

)

N=C(R 12)2, -C(O)-alkyl, unsubstituted heterocyclyl, heterocyclyl substituted with one or more X groups, -O-N(R 7 )-C(O)-O-alkyl, -C(O)-N(R 7

)

2 , -CN, -N 3 , and -0-C(O)-alkyl; 25 R 5 is selected from the group consisting of H, alkyl, -OH, haloalkyl, arylalkyl, -0 alkyl, -0-aryl, cycloalkyl, heterocyclyl, -0-cycloalkyl, -0-heterocyclyl, -0 arylalkyl or -alkylene-O-alkyl -alkylene-C(O)-R 8 , -alkylene-C(O)-N(R' 1 )2, -alkylene-C(=N-0-alkyl)-aryl, cycloalkyl, -alkylene-cycloalkyl, -alkylene-C(O)-O-alkyl, -alkylene-O-C(O)-alkyl, -alkylene-C(O)-heterocyclyl, 30 and alkenyl, wherein the cycloalkyl or the cycloalkyl portion of said -alkylene-cycloalkyl of

R

5 is unsubstituted or substituted with one or more X groups, and the 5 aryl portion of said -alkylene-C(=N-O-alkyl)-aryl of R 5 is unsubstituted or substituted with one or more Y groups;

R

6 is selected from the group consisting of H, alkyl, alkenyl, alkyl substituted with one or more hydroxyl groups, -alkylene-O-alkyl, -O-R 10 , halogen, aryl, 5 heteroaryl, and -N(R 7

)

2 , wherein the aryl of R 6 is unsubstituted or substituted with one or more Y groups, and said heteroaryl of R 6 is unsubstituted or substituted with one or more Z groups; each R 7 is independently selected from the group consisting of H, alkyl, cycloalkyl, 10 aryl, -C(O)-alkyl, and -C(O)-aryl, wherein the cycloalkyl of R 7 is unsubstituted or substituted with one or more X groups, and the aryl portion of said -C(O)-aryl or said aryl of R 7 is unsubstituted or substituted with one or more Y groups; two R 7 groups, together with the N atom to which they are bonded form a 15 heterocyclyl;

R

8 is selected from the group consisting of aryl, -OH, and heterocyclyl, wherein the heterocyclyl of R 8 is unsubstituted or substituted with one or more X groups, and said aryl of R 8 is unsubstituted or substituted with one or more Y groups; 20 R 9 is selected from the group consisting of alkyl, -alkylene-cycloalkyl, alkenyl,

-N(R'

1

)

2 , and -alkylene-aryl, wherein the cycloalkyl portion of said -alkylene-cycloalkyl of R 9 is unsubstituted or substituted with one or more X groups, and the aryl portion of said -alkylene-aryl of R 9 is unsubstituted or substituted with 25 one or more Y groups, and with the proviso that when R 9 is -N(R' 1

)

2 , m is 1 or 2;

R

10 is selected from the group consisting of H, alkyl, cycloalkyl, arylalkyl, haloalkyl, -alkylene-O-alkyl, -alkylene-aryl, -alkenylene-aryl, -alkylene-heteroaryl, alkenyl, -C(O)-alkyl, alkynyl, and -alkylene-cycloalkyl, 30 wherein an the alkynyl portion of an -0-alkynyl group can be optionally subsituted with -OH or alkoxy; the cycloalkyl portion of an -0-cycloalkyl group can be optionally substituted with an -alkylene-O-alkylene-aryl 6 group; the cycloalkyl portion of said -alkylene-cycloalkyl of R 10 is unsubstituted or substituted with one or more X groups; the aryl portion of said -alkylene-aryl or -alkenylene-aryl of R 10 is unsubstituted or substituted with one or more Y groups; and the heteroaryl portion of said 5 -alkylene-heteroaryl of R 10 is unsubstituted or substituted with one or more Z groups; R" is selected from the group consisting of H, alkyl, and aryl, wherein the aryl of R" is unsubstituted or substituted with one or more Y groups; or 10 two R" groups, together with the N atom to which they are attached, form a heterocyclyl; each R 12 is independently selected from the group consisting of alkyl, aryl, and heteroaryl, wherein the aryl of R 12 is unsubstituted or substituted with one or more Y 15 groups and said heteroaryl of R 12 is unsubstituted or substituted with one or more Z groups; or wherein both R 12 groups, together with the carbon atom to which they are attached, combine to form a heterocyclyl group; Ra and Rb are each independently selected from the group consisting of H, alkyl, aryl, and heteroaryl, 20 wherein the aryl of Ra and Rb is unsubstituted or substituted with one or more Y groups, and said heteroaryl of Ra and Rb is unsubstituted or substituted with one or more Z groups; Rc is selected from the group consisting of H, alkyl, alkylene-aryl, and -C(O)-alkyl, wherein the aryl portion of said alkylene-aryl of Rc is unsubstituted or 25 substituted with one or more Y groups; Rd is selected from the group consisting of H, alkyl, and alkylene-aryl, wherein the aryl portion of said alkylene-aryl of Rd is unsubstituted or substituted with one or more Y groups; each X is independently selected from the group consisting of halogen, alkyl, 30 haloalkyl, -0-alkyl, -0-haloalkyl, and -OH; each Y is independently selected from the group consisting of halogen, alkyl, haloalkyl, -0-alkyl, -0-haloalkyl, -CN, -NO 2 , -OH, -S(0 2 )-alkyl, -S(02)-aryl, 7 -S(0 2

)-NH

2 , -S(0 2 )-NH-alkyl, -S(0 2 )-NH-aryl, -S(0 2 )-N(alkyl) 2 , -S(0 2 )-N(aryl) 2 , -S(0 2 )-N(alkyl)(aryl), and aryl; each Z is independently selected from the group consisting of alkyl, haloalkyl, halogen, -0-alkyl, -0-haloalkyl, -CN, -OH, aryl, and N-oxide; 5 n is 0, 1,2, or 3; m is 0, 1, or 2; and with the proviso that when L is (f), and R 2 , R 3 and R 5 are each H, then R 1 is not

-CH

3 . In another embodiment, the present invention is directed to a pharmaceutical 10 composition comprising a therapeutically effective amount of at least one compound of Formula (1), or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, and at least one pharmaceutically acceptable carrier. In another embodiment, the present invention is directed to a method of treating a disease or disorder in a patient, such as metabolic syndrome, dyslipidemia, 15 cardiovascular diseases, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, and non-alcoholic fatty liver disease. The method comprises administering to the patient an effective amount of at least one compound of Formula (1), or a pharmaceutically acceptable salt, solvate, ester, or 20 tautomer thereof. In another embodiment, the present invention is directed to a method of treating a disease or disorder in a patient, such as metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders of the peripheral and central nervous system, hematological diseases, cancer, inflammation, respiratory diseases, 25 gastroenterological diseases, diabetes, hepatic steatosis, and non-alcoholic fatty liver disease. The method comprises administering to the patient an effective amount of at least one compound of Formula (1), or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, in combination with at least one additional active ingredient selected from the group consisting of hydroxy-substituted azetidinone compounds, 30 substituted p-lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives, bile acid 8 sequestrants, inorganic cholesterol sequestrants, AcylCoA:Cholesterol 0 acyltransferase inhibitors, cholesteryl ester transfer protein inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stanols and/or fatty acid esters of plant stanols (e.g., Omacor* from Pronova Biocare, Oslo, norway), low 5 density lipoprotein receptor activators, anti-oxidants, PPAR a agonists, PPAR y agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport protein inhibitors, bile acid reabsorption inhibitors, PPAR 6 agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers, 10 platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR 6 partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors,

CB

1 antagonists/inverse agonists, ghrelin antagonists, H 3 antagonists/inverse agonists, MCH1 R antagonists, MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptins, 15 leptin agonists/modulators, leptin derivatives, opioid antagonists, orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 agonists, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC2 inhibitors, P3 agonists, 20 DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone p agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11 P HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, anti 25 hypertensive agents, anti-dyslipidemic agents, DP receptor antagonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons, galanin receptor antagonists, bombesin agonists, neuropeptide-Y antagonists, 30 thyromimetic agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin binding protein antagonists, glucagons-like peptide-1 receptor agonists, human agouti-related proteins (AGRP), neuromedin U receptor agonists, 9 noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists, MSH-receptor analogs, a-glucosidase inhibitors, apo Al milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP). 5 DETAILED DESCRIPTION OF THE INVENTION The nicotinic acid receptor agonist compounds of the present invention are useful for treating conditions such as metabolic syndrome, dyslipidemia, cardiovascular diseases, disorders of the peripheral and central nervous system, 10 hematological diseases, cancer, inflammation, respiratory diseases, gastroenterological diseases, diabetes, hepatic steatosis, and non-alcoholic fatty liver disease and other diseases listed herein. One or more compounds of the present invention can be administered alone or in combination with one or more other therapeutic agents as described herein. 15 The present invention provides compound of Formula (1): L R2 Q (I) and pharmaceutically acceptable salts, solvates, estesr, and tautomers thereof, wherein L, Q, R' and R 2 are defined above for the compound of formula (1). 20 In one embodiment, R' is alkyl. In another embodiment, R 1 is haloalkyl. In another embodiment, R 1 is arylalkyl. In still another embodiment, R' is -alkylene-S-alkyl. In yet another embodiment, R' is -alkylene-cycloalkyl. 25 In another embodiment, R' is -alkylene-cyclopropyl, -alkylene-cyclobutyl, -alkylene-cyclopentyl or -alkylene-cyclohexyl. In a further embodiment, R' is -alkylene-cycloalkenyl. In another embodiment, R 1 is a straight chain alkyl having from 1 to 6 carbon atoms. 30 In one embodiment, R 1 is methyl.

10 In another embodiment, R' is ethyl. In another embodiment, R' is n-propyl. In still another embodiment, R' is n-butyl. In one embodiment, R1 is n-pentyl. 5 In another embodiment, R 1 is n-hexyl. In yet another embodiment, R 1 is a branched chain alkyl having from 3 to 6 carbon atoms. In a further embodiment, R1 is isopropyl. In one embodiment, R1 is isobutyl. 10 In another embodiment, R' is isopentyl. In another embodiment, R' is sec-butyl. In still another embodiment, R' is tert-butyl. In yet another embodiment, R 1 is haloalkyl, having from 1 to 3 F atoms. In another embodiment, R 1 is -(CH 2

)

3

CF

3 . 15 In one embodiment, R 2 is -H. In another embodiment, R 2 is -CN. In another embodiment, R 2 is -NHC(O)-alkyl. In still another embodiment, R 2 is -NHC(O)CH 3 . In one embodiment, R 3 is -H. 20 In another embodiment, R 3 is -OH. In another embodiment, R 3 is alkyl. In another embodiment, R 3 is haloalkyl. In still another embodiment, R 3 is -0-alkyl. In yet another embodiment, R 3 is cycloalkyl. 25 In a further embodiment, R 3 is heterocyclyl. In one embodiment, R 3 is -0-arylalkyl. In another embodiment, R 3 is -alkylene-O-alkyl. In one embodiment, R 3 is -OCH 3 . In another embodiment, R 3 is cyclobutyl. 30 In another embodiment, R 3 is ethyl. In still another embodiment, R 3 is N-morpholinyl. In one embodiment, R 3 is -O-benzyl.

11 In another embodiment, R 3 is -CH 2

CH

2 0CH 3 . In yet another embodiment, R 3 is -OCH 2

CH

3 . In another embodiment, R 3 is -CH 2 F. In one embodiment, R 3 is -CH 2

CH

2 F. 5 In another embodiment, R 3 is -OH. In one embodiment, R 4 is -CF 3 . In another embodiment, R 4 is -H. In another embodiment, R 4 is -0-cycloalkyl. In another embodiment, R 4 -O-alkynyl. 10 In still another embodiment, R 4 is -0-alkynylene-cycloalkyl. In yet another embodiment, R 4 is haloalkyl. In a further embodiment, R 4 is -O-N=C(R 7

)

2 . In one embodiment, R 4 is is -CH 2 F. In another embodiment, R 4 is -CH(F) 2 . 15 In another embodiment, R 4 is -CF 3 . In another embodiment, R 4 is -OCH 2

CECCH

2

CH

3 . In another embodiment, R 4 is -OCH 2

C=C(CH

2

)

3

CH

3 . In still another embodiment, R 4 is -OCH 2 CsCCH 2

CH

2

CH

3 . In yet another embodiment, R 4 is -OCH 2 CEC-cyclopropyt. 20 In a further embodiment, R 4 is -OCH 2

CECCH(OCH

3

)CH

3 . In one embodiment, R 4 is -OCH 2

C-CCH(OH)CH

3 . In another embodiment, R 4 is -OCH 2

C=CCH(OH)CH

2

CH

3 . tn another embodiment, R 4 is -OCH 2

CECCH

2

CH

2 0CH 3 . In still another embodiment, R 4 is -OCH 2

C=CCH

2

CH

2 OH. 25 In yet another embodiment, R 4 is -OCH 2

C=C(CH

2

)

3 oH. In a further embodiment, R 4 is -OCH(CH 3

)CCCH

2

CH

3 . In another embodiment, R 4 is -OCH 2 C=C-cyclohexyl. In one embodiment, R 4 is -O-cyclobutyl. In another embodiment, R 4 is- 12 0

CH

2 0CH 2 000QXs

CH

2 0CH 2 or O CH 2

CH

2 in one embodiment, R4 is: ONO In one embodiment, R 5 is -H. 5 In another embodiment, R 5 is -OH. In another embodiment, R 5 is alkyl. In another embodiment, R 5 is haloalkyl. In still another embodiment, R 5 is -0-alkyl. In yet another embodiment, R 5 is cycloalkyl. 10 In a further embodiment, R 5 is heterocyclyl. In one embodiment, R 5 is -0-arylalkyl. In another embodiment, R 5 is -alkylene-O-alkyl. In one embodiment, R 5 is -OCH 3 . In another embodiment, R 5 is cyclobutyl. 15 In another embodiment, R 5 is ethyl. In still another embodiment, R 5 is N-morpholinyl. In one embodiment, R 5 is -O-benzyl. In another embodiment, R 5 is -CH 2

CH

2 0CH 3 . In yet another embodiment, R 5 is -OCH 2

CH

3 . 20 In another embodiment, R 5 is -CH 2 F. In one embodiment, R 5 is -CH 2

CH

2 F. In another embodiment, R 5 is -OH. In one embodiment, R 6 is alkoxy. In another embodiment, R 6 is -O-alkylene-O-alkyl. 25 In another embodiment, R 6 is -0-arylalkyl. In still another embodiment, R 6 is -0-haloalkyl.

13 In yet another embodiment, R 6 is -OCH 2 -(4-methoxyphenyl). In one embodiment, R 6 is -OCH 2 F. In another embodiment, R 6 is -OCH 2

CH

2 F. In another embodiment, R 6 is -OCH 2

CH

3 5 In still another embodiment, R 6 is -OCH 2

CH

2 0CH 3 . In one embodiment, Q is: O; N R 4 v' N* ,R5 0 (a) In another embodiment, Q is: R3 tSKNN 5 0 10 (b) In another embodiment, Q is: 5SYN

R

6 (C) In still another embodiment, Q is: R3 ~NyO R 15 (d).

14 In yet another embodiment, Q is: R3 N R4 0 (e) In one embodiment, L is: 5 () In another embodiment, L is: Rb RaO (g) In another embodiment, L is: Rc O NN? (h) 10 In still another embodiment, L is: Rd 0 N> (i), In another embodiment of the compounds of Formula (1),

R

1 is selected from the group consisting of -(Cr 1

C

6 )alkyl, -(0 1

-C

6 )alkenyl, -(Ci 15 C 6 )alkynyl, -(C-C 6 )haloalkyl, -(0 1

-C

6 )alkyl substituted with one hydroxyl group,

-(C

3 -C7)cycloalkyl, -(C-Ce)alkylene-O-(0 1

-C

6 )alkyl, -(Ci- 15 Ce)alkylene-(C 6

-C

1 0o)aryl, -(C-Ce)alkylene-(C 2 -Clo)heteroaryl, -(C-Ce)alkylene-C(O)-O-(C-Ce)alkyl, -(CH 2 )n-N(R 7

)

2 , -(C-C 6 )alkylene-(C 3 C 7 )cycloalkyl, and -(C-C 6 )alkylene-(C 3

-C

7 )cycloalkenyl wherein the -(C 3

-C

7 )cycloalkyl or the (C 3

-C

7 )cycloalkyl portion of said 5 -(C-Ce)alkylene-(C 3

-C

7 )cycloalkyl is unsubstituted or substituted with one or more X groups, the (C6-C 1 o)aryl portion of said -(C

C

6 )alkylene-(Ce-C 10 )aryl is unsubstituted or substituted with one or more Y groups, and the (C 2

-C

10 )heteroaryl portion of said -(C-C 6 )alkylene

(C

2

-C

10 )heteroaryl is unsubstituted or substituted with one or more Z 10 groups;

R

2 is H, halogen, unsubstituted aryl, aryl substituted with one or more independently selected Y groups, unsubstituted heteroaryl, heteroaryl substituted with one or more independently selected Y groups; or R' and R 2 together with the ring carbon atoms to which they are shown attached, 15 form a 5- or 6-membered cycloalkenyl ring;

R

3 is selected from the group consisting of H, (C-C 6 )alkyl,

-(C

3

-C

6 )alkylene-O-(C-C 6 )alkyl, (C 3

-C

7 )cycloalkyl,

-(C-C

6 )alkylene-(C 3

-C

7 )cycloalkyl, -(C-C6)alkylene-C(O)-O-alkyl, and (C-Ce)alkenyl, 20 wherein the (C 3

-C

7 )cycloalkyl or the (C 3

-C

7 )cycloalkyl portion of said

-(C

3 -C)alkylene-(C 3

-C

7 )cycloalkyl of R 3 is unsubstituted or substituted with one or more X groups;

R

4 is selected from the group consisting of halogen, -O-R' 0 , -C(O)-O-(C-C 6 )alkyl, -S(O)m-R 9 , -N(R 7

)

2 , -O-N=C( R 1 2)2, -N(R 7

)-NH-C(O)-O-(C-C

6 )alkyl and 25 -C(O)-(C-C 6 )alkyl;

R

5 is selected from the group consisting of H, -(C-C 6 )alkyl, -(C-C 6 )alkylene-C(O)

R

8 , -(C-C 6 )alkylene-C(=N-O-(C-Ce)alkyl)-(C 6

-C

10 )aryl, (C 3 -C7)cycloalkyl, -(C -C 6 )alkylene-(C 3 -C7)cycloalkyl, -(C-Ce)alkylene-C(O)-O-(C-C 6 )alkyl, and

(C

2

-C

6 )alkenyl 30 wherein the (C 3

-C

7 )cycloalkyl or the (C 3 -C7)cycloalkyl portion of said

-(C-C

6 )alkylene-(C 3

-C

7 )cycloalkyl of R 5 is unsubstituted or substituted with one or more X groups, and the (Ce-C 10 )aryl portion of said 16

-(C-C

6 )alkylene-C(=N-O-(Cr-C 6 )alkyl)-(C 6

-C

1 o)aryl of R 5 is unsubstituted or substituted with one or more Y groups;

R

6 is selected from the group consisting of -O-R 10 , halogen, and -N(R 7

)

2 ; each R 7 is independently selected from the group consisting of H, (C-C 6 )alkyl, (C3 5 CO)cycloalkyl, and (Ce-C1o)aryl, wherein the (C 3

-C

7 )cycloalkyl of R 7 is unsubstituted or substituted with one or more X groups, and said (C 6

-C

10 )aryl of R 7 is unsubstituted or substituted with one or more Y groups;

R

8 is selected from the group consisting of unsubstituted (Co-C1o)aryl, (C6-C1o)aryl 10 substituted with one or more Y groups, -OH, unsubstituted (C 2

-C

10 )heterocyclyl, and (C 2

-C

10 )heterocyclyl substituted with one or more X groups;

R

9 is selected from the group consisting of (C-C6)alkyl, -(C-C 6 )alkylene-(C 3 C 7 )cycloalkyl, (C 2 -Ce)alkenyl, and -(C-C 6 )alkylene-(C 6 -C1o)aryl, wherein the (C 3

-C

7 )cycloalkyl portion of said 15 -(C-C6)alkylene-(C 3

-C

7 )cycloalkyl of R 9 is unsubstituted or substituted with one or more X groups, and the (C 6

-C

1 o)aryl portion of said -(C-C6)alkylene-(C 6 -C1o)aryl of R 9 is unsubstituted or substituted with one or more groups Y;

R'

0 is selected from the group consisting of H, (CrC 6 )alkyl, -(C-Ce)alkylene 20 (C6-Clo)aryl, -(C 2 -Ce)alkenylene-(C 6 -C1o)aryl, -(C-C 6 )alkylene

(C

2 -C1o)heteroaryl, (C 2

-C

6 )alkenyl, (C 2 -Ce)alkynyl, and -(C-C 6 )alkylene-(C 3 C 7 )cycloalkyl, wherein the (C 3

-C

7 )cycloalkyl portion of said

-(C-C

6 )alkylene-(C 3

-C

7 )cycloalkyt of R 1 0 is unsubstituted or substituted 25 with one or more X groups, and the (C 6 -C1o)aryl portion of said (C-C 6 )alkylene-(C 6

-C

1 o)aryl or -(C 2

-C

6 )alkenylene-(C 6

-C

1 o)aryl of R' 0 is unsubstituted or substituted with one or more Y groups, and the

(C

2

-C

1 o)heteroaryl portion of said -(C-C 6 )alkylene-(C 2

-C

1 o)heteroaryl of

R

10 is unsubstituted or substituted with one or more Z groups; 30 each R 12 is independently a (C 1

-C

6 )alkyl; Ra and Rb are each independently a (C-C6)alkyl; R4 is H; 17 Rd is selected from the group consisting of H, (0 1

-C

6 )alkyl, and -(C-C 6 )alkylene

(C

6

-C

1 o)aryl, wherein the (C 6

-C

10 )aryl portion of said -(C-Ce)alkylene-(C 6

-C

10 )aryl of Rd is unsubstituted or substituted with one or more Y groups; 5 each X is independently selected from the group consisting of F, Cl, Br, (Cr-C 6 )alkyl, (C-C 6 )haloalkyl, -0-(C-C 6 )alkyl, -O-(C-Ce)haloalkyl, and -OH; each Y is independently selected from the group consisting of F, Br, Cl, (C C)alkyl, (C-C)haloalkyl, -O-(0 1

-C

6 )alkyl, -O-(C-Ce)haloalkyl, -CN, -NO 2 , -OH, , -S(0 2

)-(C-C

6 )alkyl, -S(O 2

)-(C

6 -C1o)aryl, -S(0 2

)-NH

2 , -S(0 2 )-NH-(Cr-C 6 )alkyl, 10 -S(0 2

)-NH-(C

6

-C

1 o)aryl, -S(0 2 )-N((C-Ce)alkyl) 2 , -S(0 2

)-N((C

6

-C

1 o)aryl) 2 , -S(0 2

)-N((C-C

6 )alkyl)((C6-C 10 )aryl), and (C6-C1o)aryl; and each Z is independently selected from the group consisting of (C-Ce)alkyl, (C

C

6 )haloalkyl, F, Br, and Cl, -O-(C-C6)alkyl, -CN, -OH, (Ce-C 10 )aryl, and N oxide. 15 In another embodiment of the compounds of Formula (1), R' is selected from the group consisting of -CH 3 , -CH 2

CH

3 , -CH 2

CH

2

CH

3 ,

-CH

2

CH

2

CH

2

CH

3 , -CH 2

CH

2

CH

2

CH

2

CH

3 , -CH 2

CH

2

CH

2

CH

2

CH

2

CH

3 ,

-CH

2

CH

2

CH(CH

3

)

2 , -CH 2

CH

2

CH

2

CH(CH

3

)

2 , -CH(CH 3

)

2 , -CH 2

CH

2

CH=CH

2 ,

-CH

2

CH

2

CH=CHCH

3 , -CH 2

CH

2

CH

2

CH

2

CH=CH

2 , -CH 2

CH

2

CH

2

CH=CH

2 , 20 -CH 2 -OH, -CH(CH 3 )-OH, cyclobutyl, -CH 2

-C(O)-O-CH

2

CH

3 ,

-CH

2

CH

2

CH

2 -0-CH 3 , -CH 2

CF

3 , -CHBrCH 3 , -CH 2

CH

2

CF

3 , -CH 2

CH

2

CH

2

CF

3 ,

-CH

2

CH

2

CH

2

CH

2

CF

3 , -CH 2

CH

2

CH

2 CI, , -CH 2 -(2-thiophenyl), -CH 2

CH

2

CH

2 -(2 thiophenyl), -CH 2 -cyclopropyl, -CH 2

CH

2 -cyclopropyl, -CH 2

CH

2

CH

2 -cyclopropyl,

-CH

2

CH

2

CH

2

CH

2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2

CH

2 -cyclobutyl, 25 -CH 2

CH

2

CH

2 -cyclobutyl, -CH 2

CH

2

CH

2

CH

2 -cyclobutyl, -CH 2 -cyclopentyl,

-CH

2

CH

2 -cyclopentyl, -CH 2

CH

2

CH

2 -cyclopentyl, -CH 2

CH

2

CH

2

CH

2 -cyclopentyl,

-CH

2 -cyclohexyl, -CH 2 -(4-methylcyclohexyl), -CH 2

CH

2 -cyclohexyl,

-CH

2 -cycloheptyl, -CH 2 -(2-cyclopentenyl, -CH 2

CH

2 C=CH, -CH 2

CH

2

CH

2 CECH,

-CH

2 -phenyl, -CH 2 -(2-fluorophenyl), -CH 2 -(3-fluorophenyl), and -CH 2 -NH(3 30 methoxyphenyl); 18

R

2 is selected from the group consisting of H, F, Cl, Br, unsubstituted aryl, aryl substituted with one or more Y groups, unsubstituted heteroaryl, heteroaryl substituted with one or more Y groups; or

R

1 and R 2 together with the ring carbon atoms to which they are shown attached, 5 form a cyclopentenyl or cyclohexenyl ring;

R

3 is selected from the group consisting of H, -CH 2 -cyclopropyl, -CH 2

-C(O)-O-CH

3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, -CH 3 , -CH 2

CH

3 , -CH 2

CH

2

CH

3 ,

-CH

2

CH=CH

2 , and -CH 2 -0-CH 3 ;

R

4 is selected from the group consisting of Cl, -O-R 1 0 , -C(O)-O-CH 3 , -S(O) 2

-CH

3 , 10 -S(O)-CH 3 , -S(O)-CH 2

CH

3 , -S(O)-CH(CH 3

)

2 , -S(O)-C(CH 3

)

3 ,

-S(O)-CH

2 -cyclopropyl, -S(O)-CH 2 -phenyl, -S(O)-CH(CH 3 )-phenyl,

-S-CH

2

-CH=CH

2 , -N(R 7

)

2 , -O-N=C(CH 3

)

2 , -NH-NH-C(O)-O-CH 3 , and

-C(O)-CH

3 , wherein the phenyl portion of said -S(O)-CH 2 -phenyl, or 15 -S(O)-CH(CH 3 )-phenyl of R 4 is unsubstituted or substituted with one or more groups Y;

R

5 is selected from the group consisting of H, -CH 3 , -CH 2

CH

3 , -CH 2

CH

2

CH

3 , -CH 2 C(O)-phenyl, -CH 2 -C(O)-OH, -CH 2 -C(=N--0CH 3 )-phenyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH 2 -C(O)-piperidyl, -CH 2 -cyclopropyl, 20 -CH 2

-C(O)-O-CH

3 , and -CH 2

-CH=CH

3 , wherein the phenyl portion of said -CH 2 -C(O)-phenyl is unsubstituted or substituted with one or more Y groups;

R

6 is selected from the group consisting of -OR 10 , Cl, and -N(R 7

)

2 ; each R 7 is independently selected from the group consisting of H, cyclobutyl, 25 unsubstituted phenyl, and phenyl substituted with one or more Y groups;

R'

0 is selected from the group consisting of H, -CH 3 , -CH 2 -cyclopropyl,

-CH

2

-CH=CH

3 , -CH 2

C=C-CH

3 , -CH 2 -phenyl, -CH(CH 3 )-phenyl,

-CH(CH

2

CH

3 )-phenyl, -CH(CH 2

CH

2

CH

3 )-phenyl, -CH(CH(CH 3

)

2 )-phenyl,

-CH(CH

2

CH=CH

2 )-phenyl, -CH 2 -pyridyl, -CH(CH 3 )-thiazolyl, and 30 -CH 2 -pyrimidinyl, wherein the phenyl portion of said -CH 2 -phenyl, -CH(CH 3 )-phenyl,

-CH(CH

2

CH

3 )-phenyl, -CH(CH 2

CH

2

CH

3 )-phenyl, -CH(CH(CH 3

)

2 )-phenyl, 19 or -CH(CH 2

CH=CH

2 )-phenyl of R1 0 is unsubstituted or substituted with one or more groups Y, and the pyridyl, thiazolyl, or pyrimidinyl portion of said -CH 2 -pyridyl, -CH 2 -thiazolyl, or -CH 2 -pyrimidinyl of R 10 is unsubstituted or substituted with one or more groups Z; 5 Ra and Rb are each -CH 3 ; Rc is H; Rd is selected from the group consisting of H, -CH 3 , and -CH 2 -phenyl, wherein the phenyl portion of said -CH 2 -phenyl of Rd is unsubstituted or substituted with one or more Y groups; 10 each Y is independently selected from the group consisting of F, Cl, Br, -CH 3 , CF 3 , -0-CH 3 , -0-CF 3 , -CN, -OH, and phenyl; and each Z is independently selected from the group consisting of -CH 3 , -CF 3 , F, Br, and Cl, -0-CH 3 , -CN, -OH, phenyl, and N-oxide. In another embodiment of the compounds of Formula (I), 15 Qis: ( N R4 f"' Y R5 0 (a) L is: oYo (f);

R

1 is selected from the group consisting of -(Cr 1

C

6 )alkyl, -(Cr-Ce)alkylene-O-(C 20 C 6 )alkyl, unsubstituted (C 6

-C

1 o)aryl, and (Ce-C 10 )aryl substituted with one or more substituents Y;

R

2 is H or halogen;

R

4 is selected from the group consisting of halogen, -0-R 0 , -C(O)-O-(CrC 6 )alkyl, -S(O)m-R 9 , -N(R 7

)

2 , -O-N=C(R12) 2 , -N(R 7 )-NH-C(O)-0-(Cr-C 6 )alkyl, and 25 -C(O)-(Cr -C 6 )alkyl;

R

5 is H or (Cr 1 Ce)alkyl; 20 each R 7 is independently selected from the group consisting of H, (C-C 6 )alkyl, (C3 Ce)cycloalkyl, unsubstituted (C 6

-C

10 )aryl, and (C 6

-C

10 )aryl substituted with one or more Y groups;

R

9 is selected from the group consisting of (C-C 6 )alkyl, -(C-C 6 )alkylene-(C 3 5 C 6 )cycloalkyl, (C 2

-C

6 )alkenyl, and -(C-C 6 )alkylene-(C6-C 10 )aryl, wherein the (C 6

-C

10 )aryl of said -(C-C6)alkylene-(Ce-C 1 o)aryl of R 9 is unsubstituted or substituted with one or more groups Y; R1 0 is selected from the group consisting of H, (C-Ce)alkyl,

-(C-C

6 )alkylene-(C 6

-C

1 o)aryl, -(C-C 6 )alkenylene-(C 6

-C

10 )aryl, -(C-C 6 )alkylene 10 (C 2

-C

10 )heteroaryl, (C 2

-C

6 )alkenyl, (C 2 -C6)alkynyl, and

-(C-C

6 )alkylene-(C 3

-C

6 )cycloalkyl wherein the aryl of said -(C-C 6 )alkylene-(C 6

-C

10 )aryl or -(C-Ce)alkenylene-(C 6

-C

10 )aryl of R' 0 is unsubstituted or substituted with one or more groups Y, and the (C 2

-C

10 )heteroaryl of said -(C 15 C 6 )alkylene-(C 2

-C

10 )heteroaryl of R1 0 is unsubstituted or substituted with one or more groups Z; each R 12 is independently selected from the group consisting of (CrC 6 )alkyl, (C6

C

1 o)aryl, and (C 2

-C

10 )heteroaryl, wherein the (C 6

-C

10 )aryl is unsubstituted or substituted with one or more Y 20 group, and said (C 2

-C

10 )heteroaryl is unsubstituted or substituted with one or more Z group; each Y is independently selected from the group consisting of halogen, (C Ce)alkyl, (C-C)haloalkyl, -O-(C-C 6 )haloalkyl, -O-(C-Ce)alkyl, -CN, -NO 2 , -OH,

-S(O

2

)-(C-C

6 )alkyl, -S(0 2

)-(C

6

-C

1 o)aryl, -S(0 2

)-NH

2 , -S(0 2 )-NH-(C-Ce)alkyl, 25 -S(0 2

)-NH-(C

6

-C

10 )aryl, -S(O 2

)-N((C-C

6 )alkyl) 2 , -S(0 2

)-N((C

6

-C

1 o)aryI) 2 , -S(0 2

)-N((C-C

6 )alkyl)((C 6

-C

1 o)aryl), and (C 6

-C

1 o)aryl; and each Z is independently selected from the group consisting of (CrCO)alkyl, (C

C

6 )haloalkyl, halogen, -0-alkyl, -O-(C-C)haloalkyl, -CN, -OH, (C 6

-C

10 )aryl, and, and N-oxide. 30 In another embodiment of the compounds of Formula (1), Q is: 21 N YR4 0 (a) L is: (f);

R

1 is -CH 2

CH

3 , butyl, pentyl, -CH2-CH 2

-CH

2 -cyclopropyl; 5 R 2 is H, Br, unsubstituted aryl, aryl substituted with one or more Y groups, unsubstituted heteroaryl, heteroaryl substituted with one or more Y groups;

R

4 is selected from the group consisting of Cl, -O-R' 0 , -C(O)-O-CH 3 , -S(O)-CH 3 ,

-S(O)-CH

2

CH

3 , -S(O)-CH(CH 3

)

2 , -S(O)-C(CH 3

)

3 , -S(O)-CH 2 -cyclopropyl,

-S-CH

2

-CH=CH

2 , -S(O)-CH 2 -phenyl, -S(O)-CH(CH 3 )-phenyl, -N(R 7

)

2 , -0 10 N=C(CH 3

)

2 , -NH-NH-C(O)-0-CH 3 , and -C(O)-CH 3 , wherein the phenyl portion of said -S(O)-CH 2 -phenyl, or

-S(O)-CH(CH

3 )-phenyl of R 4 is unsubstituted or substituted with one or more groups Y;

R

5 is H or -CH 2

CH

3 ; 15 each R 7 is independently selected from the group consisting of H and cyclobutyl;

R

10 is selected from the group consisting of H, -CH 3 , -CH 2 -cyclopropyl,

-CH

2

-CH=CH

2 , -CH 2

C=C-CH

3 , -CH 2 -phenyl, -CH(CH 3 )-phenyl,

-CH(CH

2

CH

3 )-phenyl, -CH(CH(CH 3

)

2 )-phenyl, -CH(CH 2

CH

2

CH

3 )-phenyl,

-CH(CH

2

CH=CH

2 )-phenyl, -CH 2 -pyridyl, -CH(CH 3 )-thiazolyl, -CH 2 -pyrimidinyl, 20 wherein the phenyl portion of said -CH 2 -phenyl, -CH(CH 3 )-phenyl,

-CH(CH

2

CH

3 )-phenyl, -CH(CH(CH 3

)

2 )-phenyl,

-CH(CH

2

CH=CH

2 )-phenyl, or -CH(CH 2

CH

2

CH

3 )-phenyl, of R 10 is unsubstituted or substituted with one or more groups Y, and the pyridyl, thiazolyl, or pyrimidinyl portion of said -CH 2 -pyridyl, 25 -CH(CH 3 )-thiazolyl, or -CH 2 -pyrimidinyl of R 10 is unsubstituted or substituted with one or more groups Z; 22 each Y is independently selected from the group consisting of F, Cl, Br, -CH 3 ,

-CF

3 , -0-CH 3 , -0-CF 3 , and phenyl; and each Z is independently selected from the group consisting of -CH 3 , phenyl, and N-oxide. 5 In another embodiment of the compounds of Formula (1), Q is: R3 R5 0 (b) L is: (f); 10 is selected from the group consisting of -(COe)alkyl, -(Cr 1

C

6 )alkenyl, -(C Ce)alkynyl, -(Cr -C 6 )alkylene-C(O)-0-(C-C 6 )alkyl, -(C 3 -C7)cycloalkyl, -(Ci

C

6 )alkylene-O-(0 1

-C

6 )alkyl, -(Cr C 6 )alkylene-(C 6

-C

1 o)aryl, -(C -Ce)alkylene

(C

2

-C

10 )heteroaryl, -(Oi-C6)alkylene-(C 3 -C7)cycloalkyl,

-(C-C

6 )alkylene-(C 3

-C

7 )cycloalkenyl, (0 1

-C

6 )alkyl substituted with one or more 15 hydroxyl groups, -(CH 2 )n-N(R 7

)

2 , and -(Cr 1

C

6 )haloalkyl wherein the -(C 3 -C7)cycloalkyl or the (C 3

-C

7 )cycloalkyl portion of said -(Cr 1

C

6 )alkylene-(C 3

-C

7 )cycloalkyl is unsubstituted or substituted with one or more X groups, the (C 6

-C

10 )aryl portion of said -(C Ce)alkylene-(CO-C 10 )aryl is unsubstituted or substituted with one or more 20 Y groups, and the (C 2

-C

10 )heteroaryl portion of said -(Cr 1 Ce)alkylene

(C

2

-C

10 )heteroaryl is unsubstituted or substituted with one or more Z groups;

R

2 is H; 23

R

3 is selected from the group consisting of H, (C-Ce)alkyl, (C 3

-C

6 )cycloalkyl, -(C-Ce)alkylene-(C 3

-C

6 )cycloalkyl, -(C-C 6 )alkylene-C(O)-O-(C-C 6 )alkyl,

(C

2

-C

6 )alkenyl, and -(C-Ce)alkylene-O-(C-C 6 )alkyl;

R

5 is selected from the group consisting of H, -(C-C 6 )alkyl, (C 2

-C

6 )alkenyl, 5 -(C-C 6 )alkylene-C(O)-R , -(C-C6)alkylene-C(=N-O-(C-C 6 )alkyl)-(C 6

-C

1 o)aryl,

(C

3

-C

6 )cycloalkyl, -(C-C 6 )alkylene-(C 3

-C

6 )cycloalkyl, and

-(C-C

6 )alkylene-C(O)-O-(C-C 6 )alkyl; each R 7 is independently selected from the group consisting of H and aryl, wherein the aryl of R 7 is unsubstituted or substituted with one or more Y 10 groups;

R

8 is selected from the group consisting of unsubstituted (C 6

-C

10 )aryl, (C 6

-C

10 )aryl substituted with one or more Y groups, -OH, unsubstituted (C 2

-C

10 )heterocyclyl and (C 2

-C

10 )heterocyclyl substituted with one or more X groups; each X is independently selected from the group consisting of halogen, (C 15 C 6 )alkyl, (C-C)haloalkyl, -O-(C-C 6 )alkyl, -O-(C-C 6 )haloalkyl, and -OH; each Y is independently selected from the group consisting of halogen, (C

C

6 )alkyl, (C-C 6 )haloalkyl, -O-(C-C 6 )haloalkyl, -O-(C-C 6 )alkyl, -CN, -NO 2 , -OH, -S(0 2 )-(C-Ce)alkyl, -S(0 2 )-(Ce-C 1 o)aryl, -S(0 2

)-NH

2 , -S(0 2 )-NH-(C-Ce)alkyl, -S(0 2 )-NH-(C6-C 1 o)aryl, -S(0 2 )-N((0 1 -C)alkyl) 2 , -S(0 2

)-N((C

6

-C

1 o)aryl) 2 , 20 -S(0 2

)-N((C-C

6 )alkyl)((Ce-C 10 )aryl), and (Ce-Clo)aryl; and each Z is independently selected from the group consisting of (C-C 6 )alkyl, (C

C

6 )haloalkyl, F, Br, and Cl, -O-(C-C 6 )alkyl, -CN, -OH, (C6-C 10 )aryl, and N oxide. In another embodiment of the compounds of Formula (1), 25 Qis: R3 NyO N s R5 0 (b) 24 L is: (0 ; R' is selected from the group consisting of -CH 3 , -CH 2

CH

3 , -CH 2

CH

2

CH

3 ,

-CH

2

CH

2

CH

2

CH

3 , -CH 2

CH

2

CH

2

CH

2

CH

3 , -CH 2

CH

2

CH

2

CH

2

CH

2

CH

3 , 5 -CH 2

CH

2

CH(CH

3

)

2 , -CH 2

CH

2

CH

2

CH(CH

3

)

2 , -CH(CH 3

)

2 , -CH 2

-C(O)-O-CH

2

CH

3 ,

-CH

2

CF

3 , -CH 2

CH

2

CH=CH

2 , -CH 2

CH

2

CH=CHCH

3 , -CH 2

CH

2

CH

2

CH

2

CH=CH

2 ,

-CH

2

CH

2

CH

2

CH=CH

2 , -CH 2 OH, -CH(CH 3 )OH, -CH 2

N(R

7

)

2 , cyclobutyl,

-CH

2

CH

2

CH

2 -0-CH 3 , -CH 2

CH

2

CF

3 , -CH 2

CH

2

CH

2

CF

3 , -CH 2

CH

2

CH

2

CH

2

CF

3 ,

-CH

2

CH

2

CH

2 CI, , -CH 2 -(2-thiophenyl), -CH 2

CH

2

CH

2 -(2-thiophenyl), 10 -CH 2 -cyclopropyl, -CH 2

CH

2 -cyclopropyl, -CH 2

CH

2

CH

2 -cyclopropyl,

-CH

2

CH

2

CH

2

CH

2 -cyclopropyl, -CH 2 -cyclopentyl, -CH 2

CH

2 -cyclopentyl,

-CH

2 -cyclohexyl, -CH 2 -(4-methylcyclohexyl), -CH 2

CH

2 -cyclohexyl,

-CH

2 -cycloheptyl, -CH 2 -(2-cyclopentenyl, -CH 2

CH

2 C=CH, -CH 2

CH

2

CH

2 C=CH,

-CH

2 -phenyl, -CH 2 -(2-fluorophenyl), -CH 2 -(3-fluorophenyl), and -CHBrCH 3 ; 15 R 2 is H; or R' and R 2 together with the ring carbon atoms to which they are shown attached, form a cyclopentenyl or cyclohexenyl ring;

R

3 is selected from the group consisting of H, -CH 2 -cyclopropyl, -CH 2

-C(O)-O-CH

3 , -cyclopropyl, cyclobutyl, cyclopentyl, -CH 3 , -CH 2

CH

3 , -CH 2

CH

2

CH

3 , 20 CH 2

CH=CH

2 , and -CH 2 -0-CH 3 ;

R

5 is selected from the group consisting of H, -CH 2 -cyclopropyl, -CH 2

-C(O)-O-CH

3 ,

-CH

2 -C(O)-R", -CH 2 -C(=N--0CH 3 )-phenyl, cyclopropyl, cyclobutyl, cyclopentyl,

-CH

3 , -CH 2

CH

3 , -CH 2

CH

2

CH

3 , and -CH 2

CH=CH

2 ; each R 7 is independently H or phenyl, 25 wherein the phenyl of R 7 is unsubstituted or substituted with one or more Y groups;

R

8 is selected from the group consisting of unsubstituted phenyl, phenyl substituted with one or more Y groups, -OH, and piperidyl; and . each Y is independently selected from the group consisting of F, -CF 3 , -OCH 3 , 30 -CN, and-OH.

25 In another embodiment of the compounds of Formula (I), Q is: N R4 N

R

6 (C) L is: 0 0 5 (f)

R

1 is selected from the group consisting of -(C-Ce)alkyl, -(C-C 6 )alkenyl, -(C Ce)alkynyl, -(Cr C 6 )alkylene-C(O)-O-(C-C 6 )alkyl, -(C3-C 7 )cycloalkyl, -(C

C

6 )alkylene-O-(C-C 6 )alkyl, -(C-C 6 )alkylene-(C 6

-C

1 o)aryl, -(C-Ce)alkylene (C2-Clo)heteroaryl, -(C-C6)alkylene-(C 3 -C7)cycloalkyl, 10 -(C-Ce)alkylene-(C 3

-C

7 )cycloalkenyl, -(C-C 6 )alkyl substituted with one or more hydroxyl groups, -(CH 2 )n-N(R 7

)

2 , and -(C-C 6 )haloalkyl wherein the -(C 3

-C

7 )cycloalkyl or the (C 3 -C7)cycloalkyl portion of said -(C-C6)alkylene-(C 3

-C

7 )cycloalkyl is unsubstituted or substituted with one or more X groups, the (Ce-C 10 )aryl portion of said -(C 15 C 6 )alkylene-(C6-C 10 )aryl is unsubstituted or substituted with one or more Y groups, and the (C 2

-C

10 )heteroaryl portion of said -(C-C 6 )alkylene

(C

2

-C

10 )heteroaryl is unsubstituted or substituted with one or more Z groups;

R

2 is H; or 20 R 1 and R 2 together with the ring carbon atoms to which they are shown attached, form a 5- or 6-membered cycloalkenyl ring;

R

4 is selected from the group consisting of halogen, -O-R' 0 , -C(O)-O-(C-C 6 )alkyl, -S(O)m-R 9 , -N(R 7

)

2 , -O-N=C(R12 )2, -N(R 7 )-NH-C(O)-O-(C-Ce)alkyl, and

-C(O)-(C-C

6 )alkyl; 25 R 6 is selected from the group consisting of -O-R1 0 , halogen, and -N(R 7

)

2

;

26 each R 7 is independently selected from the group consisting of H, (0 1

-C

6 )alkyl, (C3

C

6 )cycloalkyl, unsubstituted (C6-C1O)aryl, and (C 6

-C

10 )aryl substituted with one or more Y groups;

R

9 is selected from the group consisting of (C-Ce)alkyl, -(C-C 6 )alkylene-(C 3 5 C 6 )cycloalkyl, (C 2

-C

6 )alkenyl, and -(C-Ce)alkylene-(C6-C 10 )aryl, wherein the (C-C 10 )aryl portion of said -(C-Ce)alkylene-(C 6

-C

1 o)aryl of R 9 is unsubstituted or substituted with one or more groups Y;

R'

0 is selected from the group consisting of H, (C-Ce)alkyl,

-(C-C

6 )aikylene-(Ce-C1o)aryI, -(C-C6)alkenylene-(C 6

-C

10 )aryl, -(C-C 6 )alkylene 10 (C 2

-C

10 )heteroaryl, (C 2

-C

6 )alkenyl, (C 2

-C

6 )alkynyl, and -(C-C 6 )alkylene-(C 3 C 6 )cycloalkyl, wherein the (Ce-C 10 )aryl portion of said -(C-C 6 )alkylene-(C 6 -C1o)aryl or

-(C-C

6 )alkenylene-(C 6

-C

10 )aryl of R1 0 is unsubstituted or substituted with one or more groups Y, and the (C 2

-C

10 )heteroaryl portion of said 15 -(C-C 6 )alkylene-(C 2

-C

10 )heteroaryl of R 10 is unsubstituted or substituted with one or more groups Z; each Y is independently selected from the group consisting of F, Br, Cl, (C

C

6 )alkyl, (C-C 6 )haloalkyl, -0-(C-Ce)alkyl, -O-(C-C 6 )haloalkyl, -CN, -NO 2 , -OH, , -S(0 2

)-(C-C

6 )alkyl, -S(0 2 )-(Ce-C 10 )aryl, -S(0 2

)-NH

2 , -S(0 2

)-NH-(C-C

6 )alkyl, 20 -S(0 2

)-NH-(C

6

-C

1 O)aryl, -S(0 2 )-N((Cr-C 6 )alkyl) 2 , -S(0 2

)-N((C

6 -C1o)aryl) 2 , -S(0 2 )-N((C-C6)alkyl)((C 6

-C

10 )aryl), and (C 6

-C

10 )aryl; and each Z is independently selected from the group consisting of (CrC 6 )alkyl, (C

C

6 )haloalkyl, F, Br, and Cl, -O-(C-Ce)alkyl, -CN, -OH, (C 6

-C

10 )aryl, and N oxide. 25 In another embodiment of the compounds of Formula (I), Q is: C N R 4 i" N R6 (c) L is: 27 0 0 (f);

R

1 is selected from the group consisting of -CH 3 , -CH 2

CH

3 , -CH 2

CH

2

CH

3 ,

-CH

2

CH

2

CH

2

CH

3 , -CH 2

CH

2

CH

2

CH

2

CH

3 , -CH 2

CH

2

CH

2

CH

2

CH

2

CH

3 ,

-CH

2

CH

2

CH(CH

3

)

2 , -CH 2

CH

2

CH

2

CH(CH

3

)

2 , -CH(CH 3

)

2 , -CH 2

-C(O)-O-CH

2

CH

3 , 5 -CH 2 -OH, -CH(CH 3 )-OH, -CH 2

CH

2

CH=CH

2 , -CH 2

CH

2

CH=CHCH

3 ,

-CH

2

CH

2

CH

2

CH

2

CH=CH

2 , -CH 2

CH

2

CH

2

CH=CH

2 , cyclobutyl,

-CH

2

CH

2

CH

2 -0-CH 3 , -CH 2

CH

2

CF

3 , -CH 2

CH

2

CH

2

CF

3 , -CH 2

CH

2

CH

2

CH

2

CF

3 ,

-CH

2

CH

2

CH

2 CI, , -CH 2 -(2-thiophenyl), -CH 2

CH

2

CH

2 -(2-thiophenyl),

-CH

2 -cyclopropyl, -CH 2

CH

2 -cyclopropyl, -CH 2

CH

2

CH

2 -cyclopropyl, 10 -CH 2

CH

2

CH

2

CH

2 -cyclopropyl, -CH 2 -cyclopentyl, -CH 2

CH

2 -cyclopentyl,

-CH

2 -cyclohexyl, -CH 2 -(4-methylcyclohexyl), -CH 2

CH

2 -cyclohexyl,

-CH

2 -cycloheptyl, -CH 2 -(2-cyclopentenyl, -CH 2

CH

2 C=CH, -CH 2

CH

2

CH

2 CECH,

-CH

2 -phenyl, -CH 2 -(2-fluorophenyl), -CH 2 -(3-fluorophenyl), -CHBrCH 3 and

-CH

2

CF

3 ; 15 R 2 is H; or R' and R 2 together with the ring carbon atoms to which they are shown attached, form a cyclopentenyl or cyclohexenyl ring

R

4 is selected from the group consisting of Cl, -O-R 10 , -C(O)-O-CH 3 , -S(O) 2

-CH

3 ,

-S(O)-CH

3 , -S(O)-CH 2

CH

3 , -S(O)-CH(CH 3

)

2 , -S(O)-C(CH 3

)

3 , 20 -S(O)-CH 2 -cyclopropyl, -S-CH 2

-CH=CH

2 , -S(O)-CH 2 -phenyl,

-S(O)-CH(CH

3 )-phenyl, -N(R 7

)

2 , -O-N=C(CH 3

)

2 , -NH-NH-C(O)-O-CH 3 , and

-C(O)-CH

3 , wherein the phenyl portion of said -S(O)-CH 2 -phenyl, or

-S(O)-CH(CH

3 )-phenyl of R 4 is unsubstituted or substituted with one or 25 more groups Y;

R

6 is selected from the group consisting of -O-R1 0 , -N(R 7

)

2 , and Cl; each R 7 is independently selected from the group consisting of H, unsubstituted phenyl, phenyl substituted with one or more Y groups, and cyclobutyl;

R

10 is selected from the group consisting of H, CH 3 , -CH 2 -cyclopropyl, 30 -CH 2

-C=C-CH

3 , -CH 2

-CH=CH

2 , -CH 2 -phenyl, -CH(CH 3 )-phenyl, 28

-CH(CH

2

CH

3 )-phenyl, -CH(CH(CH 3

)

2 )-phenyl, -CH(CH 2

CH

2

CH

3 )-phenyl,

-CH(CH

2

CH=CH

2 )-phenyl, -CH 2 -pyridyl, -CH(CH 3 )-thiazolyl, -CH 2 -pyrimidinyl, wherein the phenyl portion of said -CH 2 -phenyl, -CH(CH 3 )-phenyl,

-CH(CH

2

CH

3 )-phenyl, -CH(CH 2

CH=CH

2 )-phenyl, or 5 -CH(CH 2

CH

2

CH

3 )-phenyl of R 10 is unsubstituted or substituted with one or more groups Y, and the pyridyl, thiazolyl, or pyrimidinyl portion of said

-CH

2 -pyridyl, -CH(CH 3 )-thiazolyl, or -CH 2 -pyrimidinyl of R1 0 is unsubstituted or substituted with one or more groups Z; each Y is independently selected from the group consisting of F, Cl, Br, -CH 3 , 10 CF 3 , -0-CH 3 , -0-CF 3 , -CN, -OH, and phenyl; and each Z is independently selected from the group consisting of -CH 3 , F, Br, and CI, -0-CH 3 , -CN, -OH, phenyl, and N-oxide. In another embodiment of the compounds of Formula (I), 0 is: R3

R

6 15 (d) L is: oYo (f); R1 is -(C1-C 6 )alkyl;

R

2 is H; 20 R 3 is H or -(C 2

-C

6 )alkenyl; and

R

6 is -OH or -O-(C1-C 6 )alkylene-(C1-C 6 )cycloalkyl. In another embodiment of the compounds of Formula (I), Q is: 29

R

3 N1R4 N 0 (e) L is: OY O (f); R1 is -(C 1

-C

6 )alkyl or -(C 1 -Ce)haloalkyl; 5 R 2 is H;

R

3 is selected from the group consisting of H, -(C 1

-C

6 )alkylene-(C 1

-C

6 )cycloalkyl, -(C1-C 6 )alkylene-C(O)-O-(C 1 -Ce)alkyl, -(C1-C)cycloalkyl, (C 1

-C

6 )alkyl,

(C

2 -Ce)alkenyl, and -(C1-C 6 )alkylene-O-(C 1

-C

6 )alkyl; and

R

4 is -O-N=C((C-C 6 )alkyl) 2 . 10 In another embodiment of the compounds of Formula (I), Qis: R 3 N ON R4 RKN 5 VS .Y N 0

R

6 (b) or (C) L is selected from the group consisting of: RC Rd R b Ij Ra 0>O N 0 N 15 (g) , (h) ,and (i) Ra and Rb are each independently selected from the group consisting of H, (C

C

6 )alkyl, (C 6

-C

1 o)aryl, and (C 2

-C

10 )heteroaryl, 30 wherein the (C 6

-C

10 )aryl of Ra and Rb is unsubstituted or substituted with one or more Y groups, and said (C 2

-C

10 )heteroaryl of Ra and Rb is unsubstituted or substituted with one or more Z groups; Rc is selected from the group consisting of H, (C-C 6 )alkyl, -(C-C 6 )alkylene-(C 6 5 C 10 )aryl, and -C(O)-(C-C 6 )alkyl, wherein the (C 6

-C

10 )aryl portion of said -(C-Ce)alkylene-(C 6 -C1o)aryl of Rc is unsubstituted or substituted with one or more Y groups; Rd is selected from the group consisting of H, (C-Ce)alkyl, and

-(C-C

6 )aIkyIene-(C 6

-C

1 o)aryI, 10 wherein the (C 6

-C

1 o)aryl portion of said -(C-Ce)alkylene-(Ce-C1o)aryl of Rd is unsubstituted or substituted with one or more Y groups; R' is (C-C 6 )alkyl or or -(C-C 6 )haloalkyl;

R

2 is H;

R

3 is H; 15 R 4 is -O-R 10 ;

R

5 is H or -(C-Ce)alkylene-(C 3

-C

6 )cycloalkyl;

R

6 is -O-R 10 ;

R

10 is H, (C-CE)alkyl, or -(C 1

-C

6 )alkylene-(C 6

-C

10 )aryl; and each Y is independently selected from the group consisting of F, Br, CI, (C 20 C 6 )alkyl, (C-C 6 )haloalkyl, -O-(C-C 6 )alkyl, -O-(C-Ce)haloalkyl, -CN, -NO 2 , -OH, , -S(O 2 )-(C-Ce)alkyl, -S(0 2 )-(C6-Clo)aryl, -S(0 2

)-NH

2 , -S(0 2

)-NH-(C-C

6 )alkyl, -S(0 2

)-NH-(C

6

-C

1 o)aryl, -S(0 2

)-N((C-C

6 )alkyl) 2 , -S(0 2

)-N((C

6

-C

1 o)aryl) 2 ,

-S(O

2

)-N((C-C

6 )alkyl)((C 6

-C

10 )aryl), and (C 6

-C

1 o)aryl; and each Z is independently selected from the group consisting of (C-Ce)alkyl, (C 25 C 6 )haloalkyl, F, Br, and Cl, -O-(C-C 6 )alkyl, -CN, -OH, (C6-C 1 o)aryl, and N oxide. In another embodiment of the Formula (1), R' is -CH 3 , -CH 2

CH

3 , -CH 2

CH

2

CH

3 ,

-CH

2

CH

2

CH

2

CH

3 , -CH(CH 3

)

2 , -CH 2

-C(O)-O-CH

2

CH

3 , -CH 2

CF

3 , -CH 2 -OH,

-CH(CH

3 )OH, -CH 2

-N(R

7

)

2 , -CH 2 -NH(3-methoxyphenyl), -CH 2

CH

2

CH

2

CH

2

CH

3 , 30 -CH 2

CH

2

CH

2

CH

2

CH

2

CH

3 , -CH 2

CH

2

CH(CH

3

)

2 , -CH 2

CH

2

CH

2

CH(CH

3

)

2 ,

-CH

2

CH

2

CH=CH

2 , -CH 2

CH

2

CH=CHCH

3 , -CH 2

CH

2

CH

2

CH

2

CH=CH

2 ,

-CH

2

CH

2

CH

2

CH=CH

2 , cyclobutyl, -CH 2

CH

2

CH

2

-O-CH

3 , -CH 2

CF

3 , -CHBrCH 3

,

31

-CH

2

CH

2

CF

3 , -CH 2

CH

2

CH

2

CF

3 , -CH 2

CH

2

CH

2

CH

2

CF

3 , -CH 2

CH

2

CH

2 CI, , -CH2-(2 thiophenyl), -CH 2

CH

2

CH

2 -(2-thiophenyl), -CH 2 -cyclopropyl, -CH 2

CH

2 -cyclopropyl,

-CH

2

CH

2

CH

2 -cyclopropyl, -CH2CH2CH 2

CH

2 -cyclopropyl, -CH 2 -cyclopentyl,

-CH

2

CH

2 -cyclopentyl, -CH 2 -cyclohexyl, -CH2-(4-methylcyclohexyl), -CH 2

CH

2 5 cyclohexyl, -CH 2 -cycloheptyl, -CH2-(2-cyclopentenyl, -CH 2

CH

2 CCH,

-CH

2

CH

2

CH

2 CCH, -CH 2 -phenyl, -CH 2 -(2-fluorophenyl), -CH 2 -(3-fluorophenyl), or -CHBrCH 3 . In another embodiment of the Formula (I), R 2 is H. in another embodiment of the Formula (I), R 2 is Br. 10 In another embodiment, R' and R 2 together with the ring carbon atoms to which they are shown attached in Formula (I), form a cyclopentenyl or cyclohexenyl ring. In another embodiment of the Formula (1), R 3 is H, -CH 2 -cyclopropyl,

-CH

2

-C(O)-O-CH

3 , -cyclopropyl, cyclobutyl, cyclopentyl, -CH 3 , -CH 2

CH

3 ,

-CH

2

-CH

2

CH

3 , -CH 2

CH=CH

2 , or -CH 2 -0-CH 3 . 15 In another embodiment of the Formula (I), R 4 is CI, -OH, -0-CH 3 ,

-O-CH

2 -cyclopropyl, -CH 2

-C=C-CH

3 , -O-CH 2 -phenyl, -O-CH(CH 3 )-phenyl,

-O-CH(CH

2

CH

3 )-phenyl, -O-CH(CH 2

CH

2

CH

3 )-phenyl, -O-CH(CH(CH 3

)

2 )-phenyl,

-O-CH(CH

2

CH=CH

2 )-phenyl, -O-CH 2 -pyridyl, -O-CH 2 -thiazolyl, -O-CH(CH 3 )-thiazolyl,

-O-CH

2 -pyrimidinyl, -C(O)-O-CH 3 , -S(0 2 ) -CH 3 , -S(O)-CH 3 , -S(O)-CH 2

CH

3 , 20 -S(O)-CH(CH 3

)

2 , -S(O)-C(CH 3

)

3 , -S(O)-CH 2 -cyclopropyl, -S(O)-CH 2 -phenyl,

-S(O)-CH(CH

3 )-phenyl, -S(O)-N(R' 1 )2, -S(0 2 )-N(R")2, -S-CH 2

-CH=CH

2 , -N(H)cyclobutyl, -N(H)phenyl, -NH-NH-C(O)-O-CH 3 , -O-CH 2

-CH=CH

2 , -O-N=C(CH 3

)

2 , or -C(O)-CH 3 , wherein the phenyl portions of any of these groups can be unsubstituted or substituted with one or more Y groups as defined herein, the 25 cyclobutyl portions of any of these groups may be unsubstituted or substituted with one or more X groups as defined herein, and the pyridyl, thiazolyl, or pyrimidinyl portions of any of these groups can be unsubstituted or substituted with one or more Z groups as defined herein. In another embodiment of the compound of Formula (1), R 5 is H, -CH 3 , 30 -CH 2

CH

3 , -CH 2

CH

2

CH

3 , -CH 2 -C(O)-phenyl, -CH 2 -C(O)-OH,

-CH

2 -C(=N-0-CH 3 )-phenyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH 2 -C(O)-piperidyl,

-CH

2 -cyclopropyl, -CH 2

-C(O)-O-CH

3 , or -CH 2

-CH=CH

3 , wherein the phenyl of said 32

-CH

2 -C(O)-phenyl of R 5 is unsubstituted or substituted with one or more Y groups as defined herein, said cyclopropyl, the cyclopropyl of said -CH 2 -cyclopropyl, cyclobutyl, cyclopentyl, or the piperidyl of said -CH 2 -C(O)-piperidyl of R are unsubstituted or substituted with one or more X groups as defined herein. 5 In another embodiment of the compound of Formula (I), R 6 is -OH, Cl, -0-CH 3 , -0-CH2-cyclopropyl, -0-CH 2

-CH=CH

3 , -0-CH 2 -phenyl, -0-CH(CH 3 )-phenyl, -0-CH(CH 2

CH

3 )-phenyl, -0-CH(CH 2

CH

2

CH

3 )-phenyl, -0-CH(CH(CH 3

)

2 )-phenyl,

-O-CH(CH

2

CH=CH

2 )-phenyl, -0-CH 2 -pyridyl, -0-CH 2 -thiazolyl, -0-CH 2 -pyrimidinyl, and -N(H)cyclobutyl, -N(H)phenyl, -NH-NH-C(O)-0-CH 3 , wherein the phenyl of said 10 -0-CH 2 -phenyl, -O-CH(CH 3 )-phenyl, -O-CH(CH 2

CH

3 )-phenyl, -0-CH(CH 2

CH

2

CH

3 )-phenyl, -0-CH(CH(CH 3

)

2 )-phenyl, or -O-CH(CH 2

CH=CH

2 )-phenyI of R 6 is unsubstituted or substituted with one or more groups Y as defined herein, and the pyridyl, thiazolyl , or pyrimidinyl of said -0-CH 2 -pyridyl, -O-CH 2 -thiazolyl, or -0-CH 2 -pyrimidinyl of R 6 is unsubstituted or substituted with one or more groups Z as 15 defined herein. In another embodiment of the compound of Formula (I), each R 7 is independently H, -CH 3 , -CH 2

CH

3 , -CH 2

CH

2

CH

3 , unsubstituted phenyl, phenyl substituted with one or more Y groups, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C(O)-CH 3 , and -C(O)-phenyl. Alternatively, two groups R , together with 20 the N atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinonyl, triazolyl, or pyrrolyl ring. In another embodiment of the compound of Formula (I), R 8 is -CH 3 , unsubstituted phenyl, phenyl substituted with one or more Y groups, piperidyl, and -OH. 25 In another embodiment of the compound of Formula (1), R" is -CH 3 , -CH 2

CH

3 ,

-CH(CH

3

)

2 , -C(CH 3

)

3 , -CH 2 -cyclopropyl, -CH 2

-CH=CH

2 (allyl), -CH 2 -phenyl, and

-CH(CH

3 )-phenyl. In another embodiment of the compound of Formula (1), R 1 0 is H, -CH 2

C=CCH

3 ,

-CH

2 -cyclopropyl, -CH 2

CH=CH

2 , -CH 2 -phenyl, -CH(CH 3 )-phenyl, 30 -CH(CH 2

CH

3 )-phenyl, -CH(CH(CH 3

)

2 )-phenyl, -CH 2 -pyridyl, -CH 2 -thiazolyl, -CH(CH 3

)

thiazolyl, -CH 2 -pyrimidyl, -CH(CH 2

CH=CH

2 )-phenyl, -CH(CH 2

CH

2

CH

3 )-phenyl, wherein the phenyl portion of -CH 2 -phenyl, -CH(CH 3 )-phenyl, -CH(CH2CH 3 )-phenyl, 33

-CH(CH(CH

3

)

2 )-phenyl, -CH(CH 2

CH=CH

2 )-phenyl, and -CH(CH 2

CH

2

CH

3 )-phenyl of R30 are unsubstituted or substituted with one or more Y groups, and the pyridyl, thiazolyl, and pyrimidyl portion of said -CH 2 -pyridyl, -CH 2 -thiazolyl, -CH(CH 3 )-thiazolyl,

-CH

2 -pyrimidyl are unsubstituted or substituted with one or more Z groups. 5 In another embodiment of the compound of Formula (I), R 11 is H, -CH 3 , or phenyl, wherein the phenyl is unsubstituted or substituted with one or more Y groups. Alternatively, two groups R", together with the N atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinonyl, triazolyl, or pyrrolyl ring. 10 In another embodiment of the compound of Formula (I), R 12 is H, -CH 3 ,

-CH

2

CH

3 , or unsubstituted pyridyl or pyridyl substituted with one or more Z groups. In another embodiment of the compound of Formula (1), Ra is H or -CH 3 . In another embodiment of the compound of Formula (I), Rb is H or -CH 3 . In another embodiment of the compound of Formula (1), Ra and Rb are both 15 CH 3 . In another embodiment of the compound of Formula (I), Rc is H or -CH 3 . In another embodiment of the compound of Formula (I), Rd is H, -CH 3 , or

-CH

2 -phenyl, wherein the phenyl portion of said -CH 2 -phenyl of Rd is unsubstituted or substituted with one or more Y groups as defined herein. 20 In another embodiment of the compound of Formula (1), each X is independently selected from the group consisting of -CH 3 , -CF 3 , F, Br, and Cl, -0-CH 3 , , -0-CF 3 , -CN, -OH, phenyl, and N-oxide; In another embodiment of the compound of Formula (1), each Y is independently selected from the group consisting of F, Cl, Br, -CH 3 , -CF 3 , -0-CH 3 , 25 O-CF 3 , -CN, -OH, and phenyl; and In another embodiment of the compound of Formula (1), each Z is independently selected from the group consisting of -CH 3 , -CF 3 , F, Br, and Cl, -0-CH 3 , -0-CF 3 , -CN, -OH, phenyl, and N-oxide. 30 Non-limiting illustrative examples of the compounds of formula (1), include the following compounds: 34 H H 0 0 N 00 0 1N, OH H 0 0 Ne 000 NyOH 00 Ne 000 NyOHO0ON ca NNH N yN NH N .N 0 OH N NH N -NN N OOH 0 OH cl H O 0 N 00 0 NyOH 0 H NHh' H N N0 N 0 0 N 0 NH~ 0Ph 0 O 5 h Ost 0 QEt OHCF 3 0 CF O H 00 1N 0r0 N yOH N' NH N N H H O 0 Ny 00 0 N OHO N 00 0 N OH 0 OH 1 I NH NH 'N , N H N~ N' N H ' N . N 0 OH 0 OH 'NI 'OHNb OHOH OH O 0H 3

,,CXH

3 '0 0N. 0 0 N 0,, 0 0~o~ 0 N, 0 Y~ N H(fNNH N NH OOH 0 OH 0 00NyOMe 00 NyOBn 0 0 NyOBn 0 Nys..-A0O S -NN NH N N N NH N - N 5OH 0 OH 0 OH O Ny NHNHCOMe 0 0 NINH,, M 00. N -S- 0 0 NS~ y~ N NH N~- N NH N - N NH 0 OH 0 OH 0 0 0 0 0 N 01-~A.0 0 N0,0 NyS,,-0 SOEt 0 14N SOEt N 5N N NH 1 N N NH N .

OH 0 OH 0 OH 5I 1tI 9,0-9,0 - 0 -0 N, ,0 0 Nii y sNA 0 ONySONy< 00 N N NY0 0 N N'N N N N NH N - NH 1 OOH 0 OH 0 y I -N N NEt B N NH r N ,-NN NH N NH OH 0 0 OH 0 0 H H H9 H 7 0 0 N y 0 0 NO 00 N y0 0 No0 0, NO 00 NO "A .IC0me l N_ N'P 0 NH N NN' NH 100 1 1 0 0 0 0 35 HH H KH 00 NO 0 00 N 0 N 01 N 00 1ON 00 0 1N o00 NO0 III N NH 1 NH N y N> N 00N 0 NH,0 H 0 N 00 0H[ H 0 0 N 0 00 0 N o0 0ON yo y 0 ON < N N'NH N NH CF, 00 0 0 N0 S C 3 CF 3 F 0 N N4 b r___p 0 N,0 N , y"a ~ N CF 3 N NHN N N NH OH 0 OH 0 0" 0 0 NO N 0 0 NONrke -0 O0 N' 0 0 NO N N N N NH N - N NH N .

OH 0 OH 0 OH 0 0N N00 NO NN N N O N0 N,,,,, Kr Kro O0 NH N .- N NH 5 F 0OH 0 Oz 0Ny ,o 0 0 NO H 0 0 00 0 N 00 N NNN N NN -N OCH 3 OH 0CF3F 0 0 N H H 0 N NO000 Ny 00 NO0 N00 NO0 ~T< O ~Y f0 f 0 OH N N\ , 3 N 0 N 0 0 N N N N N N OH00 , 0 OH, CN,

H

3 CO HC0 0 0 1NyO N 00 N N 000 NyO N0 0 NO N 1 0 N H0 C 3 N N O C H 3 N I,- N r N L N H B r 0 OH OH 0 O, Ny0 00 NyO NO0 NON 0 0 0 N Oc§II00ON0_oN NHN N N NHKN NK 0 01 : OH 0, OH 0 0 N O H N NN 0Oil0 0 0 0 0,,OnN,, 0 0 NO N0 0N NH N~ N NH 100 H 0 100 5I 36 00 NO O N 00 N 0 0 NO N 0 NO N O N O O N Br O NH Br O OH 0 00 N0 O NN 0 N 0 NNON ON 0 ON00 NO O '0 NH OH, NOH, N NH N O OH 0 OH 00 N O 00,NO 00 NO 00 NO 0-Y N N NH N F N H N C O OH 0 OH 00 NO N O NO O 00 NyO 0 NO N NH F N N F N NH 00F 3 N -N 0F 3 OH 0 OH N,: O Br ON , O Br o 0 N O 0 Br N O Br O NH 0 N O NH 0 O O O OON O0 OHH N ")O O N O Oy N ON O O NH O N NH N ON OH 0 NOH 0 0 Ny 0 0 NO, L& 0 0 NON 0I 0 NO NyB NIBr:NNNHN l O OH 0 OH H 0 0 0 NI Br:-00 0 N yO N' Br 0 0 N 0 N0Br 0 N YO 0 B NIHNI N N NH N .N Br OH C 0 OH H N NNN 0 0 N N 000=ON 0 NONO 0Ny0 N NN NH N NN 00 N1O 00OHNO 37 0 0N1 0 ) 0 0 Ny 0 N N 0 NO- N 7~TT NH I NY 'o NN)CNH OH 0 OH 0 N N N N 0 0 N yo 0 0 N O,, 00N 0 NN 0 0 NyO-N N K N N H/ NH N ~ OH 0 0 OH 0 0 NyO 0 N O ON N 00 N 0,o~Q0 0 NyO N NH N~ N N N NH OOH 0 OH 0 NH F F OH OH 0 OH 0 0 NO N 0 NO N 0 NyO N 0 N o"N NH N NNH F 5 0 O OHCO 0 H 0 0 NyO N 00 NO Ny0 NO N 00 N OHN N H F N NH N y-N N OH 0 OH 0 0 OH 0 0H H 0 0 N OH H N0 N 00 0 N u0 N OH 0 N0N 0 N y N NH NN 0 0NHOHNY N OHNH 0 11 0OOH0 , OH0 OH 0 OH 0 1OH0 H H H H H 0 0 NO 00 N I, 0 uY N OH 0 N 0 N NyOHNH N NH 01 0 AN - 3 N 00 2 2 2 2 0 H H H 0 H O N 0 H 0 0 N0 00 H 0O 0 N 0 00 NO0 T,0 N 0 NN 0 N0 0N0 0 N0 0H 0 000F F F F 10 F F 38 H H H 0 0 NO 0 01 N %f-O000 N 0 H H H T0 OON O OO N,0NH 00 0 N 0ONH N NH Ifw0 . f0 0i N HH 0N0 NHF F s 0 ONH C0F NO " I,0INH I ON O O NH H 00NNH00 N H O N O O N0 FO O N 0 0 NO NH NHFNO NH ON O NH 0 O0NH OONN H0 NF O NH 0 N NH O0N0FNNH0NN H H H 0 NQ 0 N OHN H 00 NO O N O,. 00 N yF H ONO OH NH HN000 O NNH 0 00N000N0 0 0 H H H H iio 00ONO0 0 0N H 0 0 N 0 0 0 N0K NH 0 0 N 0 NH 0ONfO y NH N NH ~ 0N 0 ~~IIlNH 0 N:0 1 11 I F , Fs F 0 0 N, 00 0 0 N k FF0 0 N, 0 eH NH .. NH " F N 0 0 NO NH0 NH 0 ""~ N NH 0 10 F F 00 ,, 0 N F F 0 0 N) 0 ON N H F 0 FNH NH N N F 00 NH0 F 0OF

H

3 C0 CI I I H 0 0 NO 0 NH 0 % N0 y F O 0 0 F0 70 1 39 H R H H0 NF 0 0 NH O ON F0 Fi 0 H H0N N NH N NNN O F O0FF 0 N 0 H H H H N 00 FNO H 0 0 NO 0 0 N 0 0 0QF N 0 0 NO Y F YN FFN 0 0 HNO H H 0 0 N ,rO0 0 N N 0N-N Kr NNNN 0 NO NN F0 FII)F 5 F,wheFre H 0 N.O H 0 0 NO N 0N0N R F>IF 0) Fanand and pharmaceutically acceptable salts, solvates, esters, or tautomers thereof. 10 In one embodiment, the compounds of formula (I) have the formula (11): o 0 R 2 R' (11) and pharmaceutically acceptable salts, solvates, esters, and tautomers thereof, 15 wherein: o is selected from the group consisting of: o and R

R

1 is -H, alkyl, haloalkyl, arylalkyl, -alkylene-S-alkyl or -alkylene-cycloalkyl; 40

R

2 is -H, -CN, or -NHC(O)-alkyl;

R

4 is -0-cycloalkyl, -0-alkynyl, -0-alkynylene-cycloalkyl, haloalkyl or -0 N=C(R12) 2 , wherein both R 12 groups, together with the carbon atom to which they are attached, combine to form a heterocyclyl group, and wherein the alkynyl portion of an 5 -0-alkynyl group can be optionally subsituted with -OH or alkoxy; and wherein the cycloalkyl portion of an -0-cycloalkyl group can be optionally substituted with an alkylene-O-alkylene-aryl group;

R

5 is -H, -OH, alkyl, haloalkyl, arylalkyl, -0-alkyl, -0-aryl, cycloalkyl, heterocyclyl, -0-cycloalkyl, -0-heterocyclyl, -0-arylalkyl or -alkylene-O-alkyl; and 10 R 6 is alkoxy, -O-alkylene-O-alkyl, -0-arylalkyl or -0-haloalkyl. The following embodiments refer to the compounds of formula (II), wherein Q is: N, R 4 l" N%%%R5 0. 15 In one embodiment, R1 is alkyl. In another embodiment, R' is haloalkyl. In another embodiment, R1 is arylalkyl. In still another embodiment, R1 is -alkylene-S-alkyl. In yet another embodiment, R1 is -alkylene-cycloalkyl. 20 In another embodiment, R1 is -alkylene-cyclopropyl, -alkylene-cyclobutyl, -alkylene-cyclopentyl or -alkylene-cyclohexyl. In a further embodiment, R1 is -alkylene-cycloalkenyl. In another embodiment, R' is a straight chain alkyl having from 1 to 6 carbon atoms. 25 In one embodiment, R' is methyl. In another embodiment, R 1 is ethyl. In another embodiment, R' is n-propyl. In still another embodiment, R' is n-butyl. In one embodiment, R' is n-pentyl.

41 In another embodiment, R' is n-hexyl. In yet another embodiment, R' is a branched chain alkyl having from 3 to 6 carbon atoms. In a further embodiment, R' is isopropyl. 5 In one embodiment, R' is isobutyl. In another embodiment, R' is isopentyl. In another embodiment, R 1 is sec-butyl. In still another embodiment, R 1 is tert-butyl. In yet another embodiment, R' is haloalkyl, having from 1 to 3 F atoms. 10 in another embodiment, R' is -(CH 2

)

3

CF

3 . In one embodiment, R 4 is -CF 3 . In another embodiment, R 4 is -H. In another embodiment, R 4 is -0-cycloalkyl. In another embodiment, R 4 -O-alkynyl. 15 In still another embodiment, R 4 is -0-alkynylene-cycloalkyl. In yet another embodiment, R 4 is haloalkyl. In a further embodiment, R 4 is -O-N=C(R 7

)

2 . In one embodiment, R 4 is is -CH 2 F. In another embodiment, R 4 is -CH(F) 2 . 20 In another embodiment, R 4 is -CF 3 . In another embodiment, R 4 is -OCH 2

CECCH

2

CH

3 . In another embodiment, R 4 is -OCH 2

C=C(CH

2

)

3

CH

3 . In still another embodiment, R 4 is -OCH 2

CCCH

2

CH

2

CH

3 . In yet another embodiment, R 4 is -OCH 2 CEC-cyclopropyI. 25 In a further embodiment, R 4 is -OCH 2

CECCH(OCH

3

)CH

3 . In one embodiment, R 4 is -OCH 2 C CCH(OH)CH 3 . In another embodiment, R 4 is -OCH 2

CECCH(OH)CH

2

CH

3 . In another embodiment, R 4 is -OCH 2

C=CCH

2

CH

2 0CH 3 . In still another embodiment, R 4 is -OCH 2

C=CCH

2

CH

2 OH. 30 In yet another embodiment, R 4 is -OCH 2

CEC(CH

2

)

3 0H. In a further embodiment, R 4 is -OCH(CH 3

)C(CCH

2

CH

3 . In another embodiment, R 4 is -OCH 2 CEC-cyclohexyl.

42 In one embodiment, R 4 is -0-cyclobutyl. In another embodiment, R 4 is: F OCH 2

CH

2 -Olit, CH 2

OCH

2 4 or 0 CH 2 0CH 2 In one embodiment, R 4 is: 0 O*NO In one embodiment, R 5 is -H. In another embodiment, R 5 is -OH. In another embodiment, R 5 is alkyl. In another embodiment, R 5 is haloalkyl. 10 In still another embodiment, R 5 is -0-alkyl. In yet another embodiment, R 5 is cycloalkyl. In a further embodiment, R 5 is heterocyclyl. In one embodiment, R 5 is -0-arylalkyl. In another embodiment, R 5 is -alkylene-O-alkyl. 15 In one embodiment, R 5 is -OCH 3 . In another embodiment, R 5 is cyclobutyl. In another embodiment, R 5 is ethyl. In still another embodiment, R 5 is N-morpholinyl. In one embodiment, R 5 is -O-benzyl. 20 In another embodiment, R 5 is -CH 2

CH

2

OCH

3 . In yet another embodiment, R 5 is -OCH 2

CH

3 . In another embodiment, R 5 is -CH 2 F. In one embodiment, R 5 is -CH 2

CH

2 F. In another embodiment, R 5 is -OH. 25 In one embodiment, R 1 is alkyl and R 5 is -H. In another embodiment, R' is haloalkyl and R 5 is -H.

43 In another embodiment, R 1 is arylalkyl and R 5 is -H. In still another embodiment, R' is -alkylene-S-alkyl and R 5 is -H. In yet another embodiment, R 1 is -alkylene-cycloalkyl and R 5 is -H. In one embodiment, R' is alkyl and R 5 is -H. 5 In another embodiment, R' is haloalkyl and R 5 is -H In another embodiment, R' is arylalkyl and R 5 is -H. In still another embodiment, R' is -alkylene-S-alkyl and R 5 is -H. In yet another embodiment, R' is -alkylene-cycloalkyl and R 5 is -H. In one embodiment, R 1 is alkyl, R 5 is -H and R 4 is -0-alkynyl. 10 In another embodiment, R 1 is alkyl, R 5 is -H and R 4 is -0-alkynylene-cycloalkyl. In another embodiment, R' is alkyl, R 5 is -H and R 4 is haloalkyl. In still another embodiment, R 1 is alkyl, R 5 is -H and R 4 is -O-N=C(R 7

)

2 . In one embodiment, R 1 is haloalkyl, R is -H and R 4 is -0-alkynyl. In another embodiment, R' is haloalkyl, R 5 is -H and R 4 is -0-alkynylene 15 cycloalkyl. In another embodiment, R' is haloalkyl, R 5 is -H and R 4 is haloalkyl. In still another embodiment, R 1 is haloalkyl, R 5 is -H and R 4 is -O-N=C(R 7

)

2 . In one embodiment, R' is -alkylene-cycloalkyl, R 5 is -H and R 4 is -0-alkynyl. In another embodiment, R 1 is -alkylene-cycloalkyl, R 5 is -H and R 4 is -0 20 alkynylene-cycloalkyl. In yet another embodiment, R 1 is -alkylene-cycloalkyl, R 5 is -H and R 4 is haloalkyl. In still another embodiment, R1 is -alkylene-cycloalkyl, R 5 is -H and R 4 is -0

N=C(R

7

)

2 . 25 The following embodiments refer to the compounds of formula (II), wherein Q is: YR4 R 6. In one embodiment, R1 is alkyl.

44 In another embodiment, R1 is haloalkyl. In another embodiment, R' is arylalkyl. In still another embodiment, R' is -alkylene-S-alkyl. In yet another embodiment, R 1 is -alkylene-cycloalkyl. 5 In another embodiment, R' is -alkylene-cyclopropyl, -alkylene-cyclobutyl, -alkylene-cyclopentyl or -alkylene-cyclohexyl. In a further embodiment, R' is -alkylene-cycloalkenyl. In another embodiment, R' is a straight chain alkyl having from 1 to 6 carbon atoms. 10 In one embodiment, R' is methyl. In another embodiment, R1 is ethyl. In another embodiment, R 1 is n-propyl. In still another embodiment, R 1 is n-butyl. In one embodiment, R' is n-pentyl. 15 In another embodiment, R' is n-hexyl. In yet another embodiment, R1 is a branched chain alkyl having from 3 to 6 carbon atoms. In a further embodiment, R1 is isopropyl. In one embodiment, R' is isobutyl. 20 In another embodiment, R 1 is isopentyl. In another embodiment, R' is sec-butyl. In still another embodiment, R1 is tert-butyl. In yet another embodiment, R 1 is haloalkyl, having from 1 to 3 F atoms. In another embodiment, R' is -(CH 2

)

3

CF

3 . 25 In one embodiment, R 2 is -H. In another embodiment, R 2 is -CN. In another embodiment, R 2 is -NHC(O)-alkyl. In still another embodiment, R 2 is -NHC(O)CH 3 . In one embodiment, R 4 is -CF 3 . 30 In another embodiment, R 4 is -H. In another embodiment, R 4 is -0-cycloalkyl. In another embodiment, R 4 -0-alkynyl.

45 In still another embodiment, R 4 is -0-alkynylene-cycloalkyl. In yet another embodiment, R 4 is haloalkyl. In a further embodiment, R 4 is -O-N=C(R 7

)

2 . In one embodiment, R 4 is is -CH 2 F. 5 In another embodiment, R 4 is -CH(F) 2 . In another embodiment, R 4 is -CF 3 . In another embodiment, R 4 is -OCH 2 C2CCH 2

CH

3 . In another embodiment, R 4 is -OCH 2

C=C(CH

2

)

3

CH

3 . In still another embodiment, R 4 is -OCH 2

CCCH

2

CH

2

CH

3 . 10 In yet another embodiment, R 4 is -OCH2CEC-cyclopropy. In a further embodiment, R 4 is -OCH 2

CECCH(OCH

3

)CH

3 . In one embodiment, R 4 is -OCH 2

C=CCH(OH)CH

3 . In another embodiment, R 4 is -OCH 2

C=CCH(OH)CH

2

CH

3 . In another embodiment, R 4 is -OCH 2

CCCH

2

CH

2 0CH 3 . 15 In still another embodiment, R 4 is -OCH 2

CCCH

2

CH

2 OH. In yet another embodiment, R 4 is -OCH 2

CC(CH

2

)

3 0H. In a further embodiment, R 4 is -OCH(CH 3

)CCCH

2

CH

3 . In another embodiment, R 4 is -OCH 2 C=C-cyclohexy. In one embodiment, R 4 is -O-cyclobutyl. 20 In another embodiment, R 4 is: O

CH

2

OCH

2 01% iij~CH 2 0CH 2 -KI or O CH 2

OCH

2 -~ In one embodiment, R 4 is: In one embodiment, R is alkoxy. 25 In another embodiment, R4 is -O-alkylene-O-alkyl. In another embodiment, R 6 is -0-arylalkyl.

46 in still another embodiment, R 6 is -0-haloalkyl. In yet another embodiment, R 6 is -OCH 2 -(4-methoxyphenyl). In one embodiment, R 6 is -OCH 2 F. In another embodiment, R 6 is -OCH 2

CH

2 F. 5 In another embodiment, R 6 is -OCH 2

CH

3 In still another embodiment, R 6 is -OCH 2

CH

2

OCH

3 . In one embodiment, R 1 is alkyl and R 4 is -0-alkynyl. In another embodiment, R' is alkyl and R 4 is -0-alkynylene-cycloalkyl. In another embodiment, R 1 is alkyl and R 4 is haloalkyl. 10 In still another embodiment, R' is alkyl and R 4 is -O-N=C(R 7

)

2 In one embodiment, R' is haloalkyl and R 4 is -0-alkynyl. In another embodiment, R 1 is haloalkyl and R 4 is -0-alkynylene-cycloalkyl. In another embodiment, R 1 is haloalkyl and R 4 is haloalkyl. In still another embodiment, R' is haloalkyl and R 4 is -O-N=C(R 7

)

2 . 15 In one embodiment, R' is -alkylene-cycloalkyl and R 4 is -0-alkynyl. In another embodiment, R 1 is -alkylene-cycloalkyl and R 4 is -0-alkynylene cycloalkyl. In yet another embodiment, R1 is -alkylene-cycloalkyl and R 4 is haloalkyl. In still another embodiment, R1 is -alkylene-cycloalkyl and R 4 is -O-N=C(R 7

)

2 . 20 Non-limiting illustrative examples of the compounds of formula (11), include the following compounds: O 0 N 0,,O 1_ 0 0 N 0 0,0 10 N 0 ONO NH NH H 0 0N 00 4 0 N 04'1100 NyO, 0 y O ,/ NHH NH 4 0Y 250,,0 0 0 NO 4' 0 0 N 04' 0 0 Ny04' -. NH -. NH '-. NH 0 $0 10 47 0 N0O O 00 NO N 00 NO F/ NHO N H NH ON 0 0 0 a F 00 FO0 F N F F 0 N 0 O00 N O NO N )F 0 0 y F 0, 1 F NH NHHNH N H 0 0- 0 0 OMe 5 0F F 0 e 0 0 N 0 0 N 0 0 OH0 N OF N O 0 0N 0 N 0N 0 0 Y N H 0 0NHON N NH OH OH O We 0 0 1N YON 0 0 NO0,.0 0 NO0,. N NH N NH N NH 00 0 OH O0 0 N o 0OH00 ONyO < O 1 NH NH N NH N NH 10 5 0 0 ' 0 0 0 NO 0 00Ny0 <. 0 0 N 0, N H N NH N NH 0O 0 0 0O0ONOY K, 0 0 N Y0,,,0 0 -0 N Y0 K N NH N NH N NH 0 0 0 48 OH OH 0 0 N O 0 0 N O NH NH 0 0 N0 0 0 F NH 0 F 0 0 N 0 O N00 N F 0 FN F N NHN H N HF O O0 H 00N0NH 0 0 > 01NFNH N. N F 0 N CF 3 0 O N OCF, N C F 0 0 HN N NH NH 0 0 0 F O N, F 0 0 R NNH ~NH N , 00 5 0 NH 0 N 0 N , 0 0N 0 0 0NF 00NY NH 0 0 NO o N NH 0 N YN 0 F 10 a a, F F 0CONIF 0 0NF0 0 0 ONyCF 3 FO0N0 F N NH N NH N NH N NH N NH 0 0 0 0 I; , and F and pharmaceutically acceptable salts, solvates, esters, or tautomers thereof. 15 In one embodiment, the compounds of formula (1) have the formula (Ill): 49 0 0 2r

R

1 (Ill) and pharmaceutically acceptable salts, solvates, esters, or tautomers thereof, wherein: 5 0 is selected from the group consisting of: R 3 R3 N ON O N"1N.R 5 N 0 and R ; R' is -H, alkyl, haloalkyl, arylalkyl, -alkylene-S-alkyl or -alkylene-cycloalkyl;

R

2 is -H, -CN, or -NHC(O)-alkyl; 10 R 3 is -H, -OH, alkyl, haloalkyl, arylalkyl, -0-alkyl, -0-aryl, cycloalkyl, heterocyclyl, -0-cycloalkyl, -0-heterocyclyl, -0-arylalkyl or -alkylene-O-alkyl;

R

5 is -H, -OH, alkyl, haloalkyl, arylalkyl, -0-alkyl, -0-aryl, cycloalkyl, heterocyclyl, -0-cycloalkyl, -0-heterocyclyl, -0-arylalkyl or -alkylene-O-alkyl; and

R

6 is alkoxy, -O-alkylene-O-alkyl, -0-arylalkyl or -0-haloalkyl. 15 The following embodiments refer to the compounds of formula (Ill), wherein Q is:

R

3 ~NyO NR5 0 In one embodiment, R1 is alkyl. 20 In another embodiment, R' is haloalkyl. In another embodiment, R 1 is -alkylene-S-alkyl. In still another embodiment, R 1 is -arylalkyl.

50 In yet another embodiment, R' is -alkylene. In a further embodiment, R 1 is -cycloalkyl. In one embodiment, R' is -alkylene-cycloalkenyl. In another embodiment, R 1 is a straight chain alkyl having from 1 to 6 carbon 5 atoms. In one embodiment, R' is methyl. In another embodiment, R' is ethyl. In another embodiment, R' is n-propyl. In still another embodiment, R 1 is n-butyl. 10 In one embodiment, R' is n-pentyl. In another embodiment, R 1 is n-hexyl. In yet another embodiment, R' is a branched chain alkyl having from 3 to 6 carbon atoms. In a further embodiment, R' is isopropyl. 15 In one embodiment, R' is isobutyl. In another embodiment, R' is isopentyl. In another embodiment, R 1 is sec-butyl. In still another embodiment, R' is tert-butyl. In yet another embodiment, R 1 is haloalkyl, having from 1 to 3 F atoms. 20 In another embodiment, R' is -(CH 2

)

3

CF

3 . In one embodiment, R 2 is -H. In another embodiment, R 2 is -CN. In another embodiment, R 2 is -NHC(O)-alkyl. In still another embodiment, R 2 is -NHC(O)CH 3 . 25 In one embodiment, R 3 is -H. In another embodiment, R 3 is -OH. In another embodiment, R 3 is alkyl. In another embodiment, R 3 is haloalkyl. In still another embodiment, R 3 is -0-alkyl. 30 In yet another embodiment, R 3 is cycloalkyl. In a further embodiment, R 3 is heterocyclyl. In one embodiment, R 3 is -0-arylalkyl.

51 In another embodiment, R 3 is -alkylene-O-alkyl. In one embodiment, R 3 is -OCH 3 . In another embodiment, R 3 is cyclobutyl. In another embodiment, R 3 is ethyl. 5 In still another embodiment, R 3 is N-morpholinyl. In one embodiment, R 3 is -O-benzyl. In another embodiment, R 3 is -CH 2

CH

2 0CH 3 . In yet another embodiment, R 3 is -OCH 2

CH

3 . In another embodiment, R 3 is -CH 2 F. 10 In one embodiment, R 3 is -CH 2

CH

2 F. In another embodiment, R 3 is -OH. In one embodiment, R 5 is -H. In another embodiment, R 5 is -OH. In another embodiment, R 5 is alkyl. 15 In another embodiment, R 5 is haloalkyl. In still another embodiment, R 5 is -0-alkyl. In yet another embodiment, R 5 is cycloalkyl. In a further embodiment, R 5 is heterocyclyl. In one embodiment, R is -0-arylalkyl. 20 In another embodiment, R 5 is -alkylene-O-alkyl. In one embodiment, R 5 is -OCH 3 . In another embodiment, R 5 is cyclobutyl. In another embodiment, R 5 is ethyl. In still another embodiment, R 5 is N-morpholinyl. 25 In one embodiment, R 5 is -O-benzyl. In another embodiment, R 5 is -CH 2

CH

2 0CH 3 . In yet another embodiment, R 5 is -OCH 2

CH

3 . In another embodiment, R is -CH 2 F. In one embodiment, R 5 is -CH 2

CH

2 F. 30 In another embodiment, R 5 is -OH. In one embodiment, R' is alkyl, and each of R 2 , R 3 and R 5 is -H.

52 In another embodiment, R' is alkyl, R 2 is -H, and one, but not both of R 3 and R 5 is -H. In another embodiment, R' is alkyl, R 2 is -H, and one of R 3 and R 5 is -H and the other is alkyl. 5 In still another embodiment, R' is alkyl, R 2 is -H, and one of R 3 and R 5 is -H and the other is -0-alkyl. In yet another embodiment, R' is alkyl, R 2 is -H, and one of R 3 and R 5 is -H and the other is -cycloalkyl. In one embodiment, R' is alkyl, R 2 is -H, and one of R 3 and R 5 is -H and the 10 other is -heterocyclyl. In one embodiment, R' is alkyl, R 2 is -H, and one of R 3 and R 5 is -H and the other is -alkylene-O-alkyl. In one embodiment, R' is -alkylene-cycloalkyl, and each of R 2 , R 3 and R 5 is -H. In another embodiment, R 1 is -alkylene-cycloalkyl, R 2 is -H, and one, but not 15 both of R 3 and R 5 is -H. In another embodiment, R' is -alkylene-cycloalkyl, R 2 is -H, and one of R 3 and

R

5 is -H and the other is alkyl. In still another embodiment, R' is -alkylene-cycloalkyl, R 2 is -H, and one of R 3 and R 5 is -H and the other is -0-alkyl. 20 In yet another embodiment, R 1 is -alkylene-cycloalkyl, R 2 is -H, and one of R 3 and R 5 is -H and the other is -cycloalkyl. In one embodiment, R 1 is -alkylene-cycloalkyl, R 2 is -H, and one of R 3 and R 5 is -H and the other is -heterocyclyl. In one embodiment, R 1 is -alkylene-cycloalkyl, R 2 is -H, and one of R 3 and R 5 25 is -H and the other is -alkylene-O-alkyl. The following embodiments refer to the compounds of formula (111), wherein Q is: 53 R3 N

R

6 In one embodiment, R 6 is alkoxy. In another embodiment, R 6 is -O-alkylene-O-alkyl. In another embodiment, R 6 is -0-arylalkyl. 5 In still another embodiment, R4 is -0-haloalkyl. In yet another embodiment, R 6 is -OCH 2 -(4-methoxyphenyl). In one embodiment, R 6 is -OCH 2 F. In another embodiment, R 6 is -OCH 2

CH

2 F. In another embodiment, R 6 is -OCH 2

CH

3 10 In still another embodiment, R is -OCH 2

CH

2 0CH 3 . In one embodiment, R 1 is alkyl. In another embodiment, R' is haloalkyl. In another embodiment, R' is -alkylene-S-alkyl. In still another embodiment, R' is -arylalkyl. 15 In yet another embodiment, R' is -alkylene. In a further embodiment, R 1 is -cycloalkyl. In one embodiment, R 1 is -alkylene-cycloalkenyl. In another embodiment, R 1 is a straight chain alkyl having from 1 to 6 carbon atoms. 20 In one embodiment, R 1 is methyl. In another embodiment, R' is ethyl. In another embodiment, R 1 is n-propyl. In still another embodiment, R' is n-butyl. In one embodiment, R 1 is n-pentyl. 25 In another embodiment, R1 is n-hexyl. In yet another embodiment, R 1 is a branched chain alkyl having from 3 to 6 carbon atoms. In a further embodiment, R' is isopropyl.

54 In one embodiment, R' is isobutyl. In another embodiment, R 1 is isopentyl. In another embodiment, R' is sec-butyl. In still another embodiment, R 1 is tert-butyl. 5 In yet another embodiment, R 1 is haloalkyl, having from 1 to 3 F atoms. In another embodiment, R' is -(CH 2

)

3

CF

3 . In one embodiment, R 2 is -H. In another embodiment, R 2 is -CN. In another embodiment, R 2 is -NHC(O)-alkyl. 10 In still another embodiment, R 2 is -NHC(O)CH 3 . In one embodiment, R 3 is -H. In another embodiment, R 3 is -OH. In another embodiment, R 3 is alkyl. In another embodiment, R 3 is haloalkyl. 15 In still another embodiment, R 3 is -0-alkyl. In yet another embodiment, R 3 is cycloalkyl. In a further embodiment, R 3 is heterocyclyl. In one embodiment, R 3 is -0-arylalkyl. In another embodiment, R 3 is -alkylene-O-alkyl. 20 In one embodiment, R 3 is -OCH 3 . In another embodiment, R 3 is cyclobutyl. In another embodiment, R 3 is ethyl. In still another embodiment, R 3 is N-morpholinyl. In one embodiment, R 3 is -O-benzyl. 25 In another embodiment, R 3 is -CH 2

CH

2 0CH 3 . In yet another embodiment, R 3 is -OCH 2

CH

3 . In another embodiment, R 3 is -CH 2 F. In one embodiment, R 3 is -CH 2

CH

2 F. In another embodiment, R 3 is -OH. 30 In one embodiment, R 6 is alkoxy, R' is alkyl, and each of R 2 and R 3 is -H. In another embodiment, R5 is alkoxy, R 1 is alkyl, R 2 is -H, and R 3 is alkyl.

55 In still another embodiment, R 6 is alkoxy, R' is alkyl, R 2 is -H, and R 3 is -0 alkyl. In yet another embodiment, R 6 is alkoxy, R' is alkyl, R 2 is -H, and R 3 is cycloalkyl. 5 In one embodiment, R 6 is alkoxy, R1 is alkyl, R 2 is -H, and and R 3 is heterocyclyl. In one embodiment, R 6 is alkoxy, R' is alkyl, R 2 is -H, and R 3 is -alkylene-0 alkyl. In one embodiment, R 6 is alkoxy, R 1 is -alkylene-cycloalkyl, and each of R 2 and 10 R 3 is -H. In another embodiment, R 6 is alkoxy, R 1 is -alkylene-cycloalkyl, R 2 is -H, and R 3 is alkyl. In still another embodiment, R 6 is alkoxy, R 1 is -alkylene-cycloalkyl, R 2 is -H, and R 3 is -0-alkyl. 15 In yet another embodiment, R 6 is alkoxy, R 1 is -alkylene-cycloalkyl, R 2 is -H, and R 3 is -cycloalkyl. In one embodiment, R is alkoxy, R' is -alkylene-cycloalkyl, R 2 is -H, and R 3 is -heterocyclyl. In one embodiment, R 6 is alkoxy, R' is -alkylene-cycloalkyl, R 2 is -H, and R 3 is 20 -alkylene-0-alkyl. In one embodiment, R 6 is -0-alkylene-0-alkyl, R' is alkyl, and each of R 2 and

R

3 is -H. In another embodiment, R 6 is -0-alkylene-0-alkyl, R' is alkyl, R 2 is -H, and R 3 is alkyl. 25 In still another embodiment, R 6 is -O-alkylene-0-alkyl, R 1 is alkyl, R 2 is -H, and

R

3 is -0-alkyl. In yet another embodiment, R 6 is -0-alkylene-0-alkyl, R 1 is alkyl, R 2 is -H, and

R

3 is -cycloalkyl. In one embodiment, R 6 is -0-alkylene-0-alkyl, R 1 is alkyl, R 2 is -H, and and R 3 30 is -heterocyclyl. In one embodiment, R 6 is -0-alkylene-0-alkyl, R 1 is alkyl, R 2 is -H, and R 3 is alkylene-0-alkyl.

56 In one embodiment, R 6 is -O-alkylene-O-alkyl, R' is -alkylene-cycloalkyl, and each of R 2 and R 3 is -H. In another embodiment, R 6 is -O-alkylene-O-alkyl, R' is -alkylene-cycloalkyl, R 2 is -H, and R 3 is alkyl. 5 In still another embodiment, R6 is -O-alkylene-O-alkyl, R' is -alkylene cycloalkyl, R 2 is -H, and R 3 is -0-alkyl. In yet another embodiment, R 6 is -O-alkylene-O-alkyl, R 1 is -alkylene cycloalkyl, R 2 is -H, and R 3 is -cycloalkyl. In one embodiment, R 6 is -O-alkylene-O-alkyl, R' is -alkylene-cycloalkyl, R 2 is _ 10 H, and R 3 is -heterocyclyl. In one embodiment, R 6 is -O-alkylene-O-alkyl, R' is -alkylene-cycloalkyl, R 2 is _ H, and R 3 is -alkylene-O-alkyl. In one embodiment, R 6 is -0-arylalkyl, R' is alkyl, and each of R 2 and R 3 is -H. In another embodiment, R 6 is -0-arylalkyl, R 1 is alkyl, R 2 is -H, and R 3 is alkyl. 15 In still another embodiment, R 6 is -0-arylalkyl, R 1 is alkyl, R 2 is -H, and R 3 is 0-alkyl. In yet another embodiment, R 6 is -0-arylalkyl, R' is alkyl, R 2 is -H, and R 3 is cycloalkyl. In one embodiment, R 6 is -0-arylalkyl, R 1 is alkyl, R 2 is -H, and and R 3 is 20 heterocyclyl. In one embodiment, R 6 is -0-arylalkyl, R 1 is alkyl, R 2 is -H, and R 3 is -alkylene O-alkyl. In one embodiment, R 6 is -0-arylalkyl, R' is -alkylene-cycloalkyl, and each of

R

2 and R 3 is -H. 25 In another embodiment, R 6 is -0-arylalkyl, R' is -alkylene-cycloalkyl, R 2 is -H, and R 3 is alkyl. In still another embodiment, R 6 is -0-arylalkyl, R is -alkylene-cycloalkyl, R 2 is H, and R 3 is -0-alkyl. In yet another embodiment, R 6 is -0-arylalkyl, R' is -alkylene-cycloalkyl, R 2 is 30 H, and R 3 is -cycloalkyl. In one embodiment, R 6 is -0-arylalkyl, R' is -alkylene-cycloalkyl, R 2 is -H, and

RA

3 is -heterocyclyl.

57 In one embodiment, R 6 is -0-arylalkyl, R' is -alkylene-cycloalkyl, R 2 is -H, and

R

3 is -alkylene-O-alkyl. In one embodiment, Re is -0-haloalkyl, R' is alkyl, and each of R 2 and R 3 is -H. In another embodiment, R5 is -0-haloalkyl, R1 is alkyl, R 2 is -H, and R 3 is alkyl. 5 In still another embodiment, R 6 is -0-haloalkyl, R' is alkyl, R 2 is -H, and R 3 is _ O-alkyl. In yet another embodiment, R 6 is -0-haloalkyl, R 1 is alkyl, R 2 is -H, and R 3 is cycloalkyl. In one embodiment, R 6 is -0-haloalkyl, R 1 is alkyl, R 2 is -H, and and R 3 is 10 heterocyclyl. In one embodiment, R 6 is -0-haloalkyl, R' is alkyl, R 2 is -H, and R 3 is alkylene-O-alkyl. In one embodiment, R 6 is -0-haloalkyl, R' is -alkylene-cycloalkyl, and each of

R

2 and R 3 is -H. 15 In another embodiment, R is -0-haloalkyl, R' is -alkylene-cycloalkyl, R 2 is -H, and R 3 is alkyl. In still another embodiment, R 6 is -0-haloalkyl, R' is -alkylene-cycloalkyl, R 2 is -H, and R 3 is -0-alkyl. In yet another embodiment, R 6 is -0-haloalkyl, R' is -alkylene-cycloalkyl, R 2 is 20 -H, and R 3 is -cycloalkyl. Non-limiting illustrative examples of the compounds of formula (II1), include the following compounds: H OMe 00ON O NO OONOH H N,O eOMe NHOONO ON NO O N,OMe N, eNH O o 0 O , O 25 H OMe H OMe 00 NO O OMe 0 0 N0 00 NO 0 0N 0 Y 0 0 NHYIY N'OMe NH N N'OMe N NH 0 0 0 0 O : NH O O O 0 58 H H 0 0 N. ~ H 0 0 NO eH O N O O 0 N 0 |N O 0O N O N NH 0 H MeOCHN N NH 0 NC NH 00 NO 0N 0 NC: NH O H H H O1) 0 0 N 0 00 N 0 0 N 0 H 0 I 0 Ny 00NO0 00 NO N 0N N 0O1 N NH N,N ")NH 0 0 O O 5 OMe H HH H 0 0 N, IH0 0 NO 00N O NOON 0t0 N0 000 N NONHNOt O N O OH O NO Y N0- N N N 0 OM OO II , F NOONO H O 0 0 N NF NY0H O NN0 00 N0N00 NNHNOONE t O N H 0 OHONN 0 0 0 N OEt 0100 0 H H 0Q0NI O H H 0 0 N 0 H 00N N 0 N ~ 0 0 0 OF 10 , ndF H H 0ONO OH H0Q N 0e N ~ lI1 HHNNN NNH 0: NN 0 N 00 0H 0' NC 0 0 0 H 0ONO 0 0 NO 0 0 1NON N NH N No00 0 and F 15 and pharmaceutically acceptable salts, solvates, esters, or tautomers thereof.

59 In one embodiment, the compounds of formula (1) are compounds of formula (IV): H O O N O Ns, R2 R1 O (IV) 5 and and pharmaceutically acceptable salts, solvates, esters, and tautomers thereof, wherein: R' is haloalkyl; and

R

2 is H or cycloalkyl. 10 In one embodiment, R 1 is fluoroalkyl. In another embodiment, R' is -alkylene-F. In another embodiment, R' is -alkylene-CF 2 . In still another embodiment, R' is -(CH 2

)

2

-CF

2 . In another embodiment, R1 is -(CH 2

)

3

-CF

2 . 15 In another embodiment, R 1 is -(CH 2

)

4

-CF

2 . In yet another embodiment, R 1 is -(CH 2

)

5

-CF

2 . In still another embodiment, R 1 is -(CH 2

)

3 -F. In another embodiment, R' is -(CH 2

)

4 -F. In another embodiment, R 1 is -(CH 2

)

5 -F. 20 In yet another embodiment, R 1 is -(CH 2

)

6 -F. In one embodiment, R 2 is H. In another embodiment, R 2 is cyclopropyl. In another embodiment, R 2 is cyclobutyl. In still another embodiment, R 2 is cyclopentyl. 25 In another embodiment, R 2 is cyclohexyl. In one embodiment, R 1 is fluoroalkyl and R 2 is H. In another embodiment, R' is fluoroalkyl and R 2 is cycloalkyl.

60 In another embodiment, R 1 is -alkylene-CF 2 and R 2 is H. In another embodiment, R 1 is -alkylene-CF 2 and R 2 is cycloalkyl. Non-limiting examples of compounds of formula (IV) include compounds 834, 5 835 and 837-841 as depicted in the Examples section below, and and pharmaceutically acceptable salts, solvates, esters, and tautomers thereof. In another embodiment, the compounds of formula (1) are compounds of formula (V): o O N R2 NH 10 R1 O (V) and and pharmaceutically acceptable salts, solvates, esters, and tautomers thereof, wherein: R' and R 2 are each, independently, haloalkyl. 15 In one embodiment, R 1 is fluoroalkyl. In another embodiment, R 1 is -alkylene-F. In another embodiment, R' is -alkylene-CF 2 . In still another embodiment, R1 is -(CH 2

)

2

-CF

2 . 20 In another embodiment, R' is -(CH 2

)

3

-CF

2 . In another embodiment, R1 is -(CH 2

)

4

-CF

2 . In yet another embodiment, R' is -(CH 2

)

5

-CF

2 . In still another embodiment, R1 is -(CH 2

)

3 -F. In another embodiment, R1 is -(CH 2

)

4 -F. 25 In another embodiment, R' is -(CH 2

)

5 -F. In yet another embodiment, R' is -(CH 2

)

6 -F. In one embodiment, R 2 is fluoroalkyl. In another embodiment, R 2 is -CHF 2

.

61 In one embodiment, R 1 is fluoroalkyl and R 2 is fluroalkyl. In another embodiment, R' is fluoroalkyl and R 2 is -CHF 2 . In another embodiment, R 1 is -alkylene-CF 2 and R 2 is fluoroalkyl. In still another embodiment, R' is -alkylene-CF 2 and R2 is -CHF 2 . 5 Non-limiting examples of compounds of formula (V) include compounds 836 and 842-844 as depicted in the Examples section below, and and pharmaceutically acceptable salts, solvates, esters, and tautomers thereof. 10 Additional non-limiting examples of compounds of formula (1) include compounds 845-911 as depicted in the following table: Compound No. Structure 845 F 0ON F NH 0 N N 0 \N 846 F O O N F NH 847 ON N NH N 0 N 848 OON 0 N NH N o N 849 O o N O N . NH N O N 62 850 0 NH 0 851 H 0O0NW0 NH 0 852____F F H 85 0 853 F O0ON~ F 854F 0 N F NH 855F 0 0NN F NH 0 856 F O ONN F NH 0 63 857 F OONN F NH 0 858 0 NH 0 0 859 F 0 0 N, F 0 NH 0 860 F 0 IN F NH 0 F 861 F 00NN F NH 0 862 F 0 0 N Nt O NH :0 863 F O N NH 64 864 F OON F NH o 0 N0 o N- 0 865 F 00NI F N NH 0 866 F 0 0 N F NH 0 867 F N F NH 0 0 868 F 0 0 N F NH 0 F 869 F 00N' F NH N0 65 870 F 0 0 N N'IF N NH F 0 F 871 F NH 0 872 F 0 0N F NH 0 873 F 0 0 NN F 0N0NH 0 874 F 0 0 N ''F N NH 0 Ph 875 F 0F 0 0NH 66 876 F NH 0 CI 878 F 0 0 N F 0 NH 879 F o0 N.% F NH F 0 880 F o0 N, F NH 0 881 F O O N F HO 0 882 F 00NN F NH 0 883 F . O NH 0 67 884 F NN F NH 0 885 F o o NN NH 0 886 F o a N F NH 0 887 F 0 0 N '"F NH F 0 F 888 F o O N F NH 0 886 F o O N F 0 wN NH 0 68 890 F o o NN F NH 0 891 F o 0 N lz F SNH 0 892 0 0 N 0 NNH 893 0 840 0 N,, 0 NH 894H 895 0 0 N N NH OHO 8960H 0 0 N O N NH 0 0 69 897 0 0 NH 0 898 H NNH NH 0 900 0O0Nfo KNH 0 F 901 00H~ F NNH F 0 FN 902 H NH 0 70 9030H NH 0 F F 904 00 o NH 0 905 0 H0 NH 0 906 H S 0 9070 W NH 0o 908 OONH NH 0 CI 9090 N NH 0 71 9100 H NH 0 911 H NH F 0 and and pharmaceutically acceptable salts, solvates, esters, and tautomers thereof. 5 In all embodiments of the present invention, when L is (f), and R 2 , R 3 and R 5 are each H, then R 1 is not -CH 3 . One of skill in the art will recognize that the present invention does not include the following compound, or tautomeric forms thereof: The moiety L of Formula (1) of the present invention can have any chemically 10 stable orientation. That is, when L is (f), the compounds of Formula (I) of the present invention can include the following: 0 O 0 R 2R2N Ror , or salts, solvates, esters, or tautomers thereof. When L is (g), the compounds of Formula (I) of the present invention can include the following: 72 Rb Ra Rb 0 Ra 0 I Q 0Q R2 R2 R, or R 1 , or salts, solvates, esters, or tautomers thereof. When L is (h), the compounds of Formula (1) of the present invention can include the following: O N Rc o' N R2 R2 R or R1 , or salts, solvates, esters, or tautomers 5 thereof. When L is (i), the compounds of Formula (1) of the present invention can include the following: Rd O'Rd O N Q Q R2 R2 R or R' , or salts, solvates, esters, or tautomers thereof. The compounds of Formula (1) can be purified to a degree suitable for use as a 10 pharmaceutically active substance. That is, the compounds of Formula (1) can have a purity of 95 wt% or more (excluding adjuvants such as pharmaceutically acceptable carriers, solvents, etc., which are used in formulating the compound of Formula (1) into a conventional form, such as a pill, capsule, IV solution, etc. suitable for administration into a patient). The purity can be 97 wt% or more, or, 99 wt% or more. A purified 15 compound of Formula (1) 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. Alternatively, the purified compound of Formula (1) can include a mixture of isomers, each having a structure according to Formula (1), where the amount of impurity (i.e., compounds or other contaminants, exclusive of adjuvants as discussed 20 above) is 5 wt% or less, 3 wt% or less, or 1 wt% or less. For example, the purified 73 compound of Formula (I) can be an isomeric mixture of compounds of Structure (1), 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% or more. 5 Compounds of Formula (1), and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention. For example, the compounds of the present invention include tautomeric forms as shown below: H H O ON OH 0 0 N OH 0 0 N O 0 0 10R2H NR ONH R -N R ONH 10 R 1 OH R 1 0 R' OH R' 0 Rb Rb Rb HR H O) N N OH 0 N OH 0 NO O 0NN Y 0 R2 N R 2 NH R2 -N R2 NH

R

1 OH R 1 0 R' OH R 1 0 RCRc RC RC R RO N N OH RON N OH RON N O RO N N O R2 1, N R 2 N NH R 2 N N R2N NH

R

1 OH R 1 0 R 1 OH R 0 AdO N OH RdO N N OH RdO N R N N NO AdO N N 0

R

1 OHRaR0OHH

OHR

1 0 H O 0 N OH 0 0 N 0

R

1 R 6

R

1

R

6 Rb0 NOH 0Rb 0 Ra Y R Kr

A

2 N R 2 N R 2 R 15 R 1

A

6

R

1

RA

6 I I H 0 N NY OH 0 N N Y0 R2N.R2N RA RA 6 o R 'R 6 74 Rd H RdO N NyOH RdO N N 0 Y R2N R2

R

1

R

6 R1 R 6 44 H 4 O O N R 0 0 N R 4 0 0 N R 4 -NH N R 2 2 NH N R1 OH R 1 0 R 0 RHR O R R2 N R2 NH R2N R OH R 0 R' 0 ac eACtAc 1n mNa n 0 N N R 0 N N

A

2 ' ,,,' N R2 N NH R2 N N R' OH R 0 Rby c0 Ado N sr 4 Adicab 4 odoNxat 4

A

2 mns NA 2 pNHroyl2ethaN 5 R' OH R 1 0 A' 0 Such tautomeric forms are considered equivalent. As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings: "AcOH" means acetic acid. 10"Bn" means benzyl. "BnBr" means benzyl bromide. "BnOH" means benzyl alcohol. "CDI" means carbodiimide. "DOM" means dichloromethane (CH 2

CI

2 ). 15 "D AD" means diisopropyl azodicarboxylate. "DIEA" means N, N-diisopropylethylamine. "DMF means dimethylformamide. "Et" means ethyl. "EtO 2 " means diethyl ether. 20 "EtOAc" means ethylacetate. "HATU" means O-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethylammonium hexafluorophosphate.

75 "HOAc" means acetic acid. "IBMX" means 3-isobutyl-1-methylxanthine. "m-CPBA" means m-chloroperoxybenzoic acid. "Me" means methyl. 5 "MeCN" means acetonitrile. "Mel" means iodomethane. "Me 2 S" means dimethyl sulfide. "MeOH" means methanol. "NaOEt" means sodium ethoxide. 10 "NaOMe" means sodium methoxide. "NBS" means N-bromosuccinimide. "NEtV' means triethylamine. "NIS" means N-iodosuccinimide. "t-Bu" means tertiary-butyl. 15 "t-BuOK" means potassium tertiary-butoxide. "TFA" means trifluoroacetic acid. "TfOH" means trifluromethanesulfonic acid. "THF" means tetrahydrofuran. "TLC" means thin layer chromatography. 20 "PMBOH" means 4-methoxybenzyl alcohol. "PMBCI" means 4-methoxybenzyl chloride. "Prep TLC" means preparative thin layer chromatography. "Patient" includes both human and animals. "Mammal" means humans and other mammalian animals. 25 "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a 30 linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. "Alkyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, 76 each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), N(alkyl) 2 , carboxy and -C(O)O-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. 5 "Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl 10 or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. "Alkenyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl). Non-limiting 15 examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut 2-enyl, n-pentenyl, octenyl and decenyl. "Alkylene" means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene. 20 "Alkenylene" means a difunctional group obtained by removal of a hydrogen from an alkenyl group that is defined above. Non-limiting examples of alkenylene include -CH=CH-, -C(CH 3 )=CH-, and -CH=CHCH 2 -. "Alkylene-aryl" (or aryl-alkylene-) means a group in which the aryl and alkylene are as previously described. The bond to the parent moiety is through the alkylene. 25 The alkylene moiety can be bonded to one or more aryl moieties. Alkylene-aryls can comprise a lower alkylene group. Non-limiting examples of suitable alkylene-aryl groups include benzyl, 2-phenethyl, 2,2-diphenylethylene and naphthalenylmethyl. "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon carbon triple bond and which may be straight or branched and comprising about 2 to 30 about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl 77 or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3 methylbutynyl. "Alkynyl" may be unsubstituted or optionally substituted by one or more 5 substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl. "Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" 10 which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example 15 nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A 20 nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. "Heteroaryl" may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4 25 thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2 a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated 30 heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

78 "Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl. 5 "Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising 10 about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and 15 the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1 -decalinyl, norbornyl, adamantyl and the like. "Cycloalkylalkyl" means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like. 20 "Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or 25 different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl. "Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable 30 cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like. "Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.

79 The term "haloalkyl" as used herein refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms is independently replaced with a halogen. In one embodiment, a haloalkyl group is a "fluoroalkyl group." The term "fluoroalkyl group" as used herein, refers to an alkyl group, wherein 5 one or more of the alkyl group's hydrogen atoms are replaced with a -F atom. In various embodiments, a fluorooalkyl group contains one F atom, two F atoms or three F atoms. Illustrative example of fluoroalkyl groups include, but are not listed to, CH 2 F, -CH(F) 2 , CH 2

CH

2 F, -CF 3 , and -(CH 2

)

3

CF

3 . "Ring system substituent" means a substituent attached to an aromatic or non 10 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, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, 15 nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -C(=N-CN)-NH 2 , -C(=NH)-NH 2 , -C(=NH) NH(alkyl), Y 1

Y

2 N-, Y 1

Y

2 N-alkyl-, Y 1

Y

2 NC(O)-, Y 1

Y

2

NSO

2 - and -SO 2

NY

1

Y

2 , wherein Y, and Y 2 can be the same or different and are independently selected from the group 20 consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH 3

)

2 - and the like which form moieties such as, for example: 0 25 0 and "Heteroarylalkyl" means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like. "Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring 30 system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring 80 atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no 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 5 the heterocyclyl 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 one or more "ring system substituents" which may be the 10 same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4 dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. 15 "Heterocyclyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidone: H N 0. "Heterocyclylalkyl" means a heterocyclyl moiety as defined above linked via an 20 alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like. "Heterocyclenyl" means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, 25 for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, 81 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 5 be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non limiting examples of suitable heterocyclenyl groups include 1,2,3,4 tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6 tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2 imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, 10 dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7 oxabicyclo[2.2.1 ]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclenyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidinone: H N 15 0. "Heterocyclenylalkyl" means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. "Cycloalkylene" means a difunctional group obtained by removal of a hydrogen atom from a cycloalkyl group that is defined above. Non-limiting examples of 20 cycloalkylene include v ,-, , and It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, 0 or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for 25 example, in the ring: 82 4 2 5 N H there is no -OH attached directly to carbons marked 2 and 5. It should also be noted that tautomeric forms such as, for example, the moieties: NO 5 H and H are considered equivalent in certain embodiments of this invention. "Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Alkynylalkyls can contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of 10 suitable alkynylalkyl groups include propargylmethyl. "Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3 ylmethyl. The bond to the parent moiety is through the alkyl. 15 "Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. "Acyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through 20 the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl. "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. 25 "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.

83 "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen. "Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as 5 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. "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and 10 ethylthio. The bond to the parent moiety is through the sulfur. "Arylthio" means an aryl-S- group in which the 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. "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as 15 previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur. "Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl. 20 "Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl. "Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety 25 is through the carbonyl. "Alkylsulfonyl" means an alkyl-S(0 2 )- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl. "Arylsulfonyl" means an aryl-S(0 2 )- group. The bond to the parent moiety is 30 through the sulfonyl. The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the 84 designated atom's normal valency under the existing circumstances is not-exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently 5 robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties. The term "purified", "in purified form" or "in isolated and purified form" for a 10 compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan 15 (e.g., chromatography, recrystallization and the like) , in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the 20 sufficient number of hydrogen atom(s) to satisfy the valences. When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard 25 textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York. When any variable (e.g., aryl, heterocycle, R 2 , etc.) occurs more than one time in any constituent or in Formula 1, its definition on each occurrence is independent of its definition at every other occurrence. 30 As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product 85 which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, 5 Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (1) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. 10 The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and 15 Pergamon Press, 1987. For example, if a compound of Formula (1) or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C-C8)alkyl, (C2 20 C 12 )alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 25 1 -(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4 crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C-C 2 )alkylamino(C 2

-C

3 )alkyl (such as @-dimethylaminoethyl), carbamoyl-(C-C 2 )alkyl, N,N-di (C-C 2 )alkylcarbamoyl-(C1 C2)alkyl and piperidino-, pyrrolidino- or morpholino(C 2

-C

3 )alkyl, and the like. Similarly, if a compound of Formula (1) contains an alcohol functional group, a 30 prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Cr 1

C

6 )alkanoyloxymethyl, 1-((Cl

C

6 )alkanoyloxy)ethyl, 1-methyl-1-((C-C 6 )alkanoyloxy)ethyl, (C- 86

C

6 )alkoxycarbonyloxymethyl, N-(C-C6)alkoxycarbonylaminomethyl, succinoyl, (C

C

6 )alkanoyl, a-amino(C-C 4 )alkanyl, arylacyl and a-aminoacyl, or a-aminoacyl-a aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , -P(O)(O(C 1

-C

6 )alkyl) 2 or glycosyl (the radical 5 resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like. If a compound of Formula (I) incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' 10 are each independently (C-Cl 0 )alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural a-aminoacyl or natural a-aminoacyl, -C(OH)C(O)OY' wherein Y 1 is H, (C

C

6 )alkyl or benzyl, -C(OY 2 )y 3 wherein Y 2 is (C1C4) alkyl and Y 3 is (C-C 6 )alkyl, carboxy (C-C 6 )alkyl, amino(C-C 4 )alkyl or mono-N-or di-N,N-(C-Ce)alkylaminoalkyl,

-C(Y

4

)Y

5 wherein Y 4 is H or methyl and Y 5 is mono-N- or di-N,N-(C-C 6 )alkylamino 15 morpholino, piperidin-1 -yl or pyrrolidin-1 -yl, and the like. One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with 20 one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable 25 solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H 2 0. One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates 30 of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et 87 al, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard 5 methods. Analytical techniques such as, for example 1. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate). "Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, 10 inhibitory or preventative effect. The compounds of Formula I can form salts which are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as 15 basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) 20 salts are preferred, although other salts are also useful. Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Exemplary acid addition salts include acetates, ascorbates, benzoates, 25 benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are 30 generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.

88 (2002) Zurich: Wiley-VCH; S. Berge et a, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) .33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). 5 These disclosures are incorporated herein by reference thereto. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, 10 lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. 15 All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention. Pharmaceutically acceptable esters of the present compounds include the 20 following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, 25 phenyl optionally substituted with, for example, halogen, Cl 4 alkyl, or Cl 4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C-20 alcohol or reactive derivative thereof, 30 or by a 2,3-di (C 6

-

24 )acyl glycerol.

89 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 tautomeric forms are contemplated herein as part of the present invention. The compounds of Formula (1) may contain asymmetric or chiral centers, and, 5 therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (1) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, 10 as well as mixtures, are embraced within the scope of the invention. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture 15 into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (1) may be atropisomers (e.g., substituted biaryls) and are considered as 20 part of this invention. Enantiomers can also be separated by use of chiral HPLC column. It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are 25 included in the invention. All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including 30 enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 90 3-pyridyl). (For example, if a compound of Formula (1) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.). 5 Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the 10 like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds. The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one 15 or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3 H, 130C14C 15 N, 180 17O 31 p 32 p 35 18 F, and 36CI, respectively. 20 Certain isotopically-labelled compounds of Formula (1) (e.g., those labeled with 3 H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from 25 greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formula (I) can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled 30 reagent.

91 Polymorphic forms of the compounds of Formula 1, and of the salts, solvates, esters and prodrugs of the compounds of Formula I, are intended to be included in the present invention. The term "pharmaceutical composition" is also intended to encompass both the 5 bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore 10 said "more than one pharmaceutically active agents". The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said 15 bulk composition and individual dosage units. The compounds of Formula (1), or pharmaceutically acceptable salts, solvates, or esters thereof according to the invention have pharmacological properties; in particular, the compounds of Formula (I) can be nicotinic acid receptor agonists. The compounds of Formula (1) of the present invention, or pharmaceutically 20 acceptable salts, solvates, or esters thereof are useful in treating diseases or conditions including dyslipidemia and metabolic syndrome. The compounds of Formula (1), or pharmaceutically acceptable salts, solvates, or esters thereof, can be administered in any suitable form, e.g., alone, or in combination with a pharmaceutically acceptable carrier, excipient or diluent in a 25 pharmaceutical composition, according to standard pharmaceutical practice. The compounds of Formula (1), or pharmaceutically acceptable salts, solvates, or esters thereof, can be administered orally or parenterally, including intravenous, intramuscular, interperitoneal, subcutaneous, rectal, or topical routes of administration, or if so selected, by a combination of one or more of the above-shown 30 methods. Pharmaceutical compositions comprising at least one compound of Formula (I), or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof can be in a 92 form suitable for oral administration, e.g., as tablets, troches, capsules, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, syrups, or elixirs. Oral compositions may be prepared by any conventional pharmaceutical method, and may also contain sweetening agents, flavoring agents, coloring agents, 5 and preserving agents. The amount of compound of Formula (1), or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, administered to a patient can be determined by a physician based on the age, weight, and response of the patient, as well as by the severity of the condition treated. For example, the amount of compound of Formula 1, 10 or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, administered to the patient can range from about 0.1 mg/kg body weight per day to about 60 mg/kg/d. In one embodiment, the amount is from about 0.5 mg/kg/d to about 40 mg/kg/d. In another embodiment, the amount is from about 0.5 mg/kg/d to about 10 mg/kg/d. In another embodiment, the amount is from about 1 mg/kg/d to about 5 15 mg/kg/d. In still another embodiment, the amount is from about 1 mg/kg/d to about 3 mg/kg/d. In a specific embodiment, the amount is about 1 mg/kg/d. In another specific embodiment, the amount is about 3 mg/kg/d. In another specific embodiment, the amount is about 5 mg/kg/d. In another specific embodiment, the amount is about 7 mg/kg/d. In still another specific embodiment, the amount is about 10 mg/kg/d. 20 The compounds of Formula (1), or pharmaceutically acceptable salts, solvates, or esters thereof, can also be administered in combination with other therapeutic agents. For example one or more compounds of Formula (1) or pharmaceutically acceptable salts, solvates, or esters thereof, can be administered with one or more additional active ingredients selected from the group consisting of anti-flushing agents, 25 hydroxy-substituted azetidinone compounds, substituted p-lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives, bile acid sequestrants, inorganic cholesterol sequestrants, AcylCoA:Cholesterol 0-acyltransferase inhibitors, cholesteryl ester transfer protein 30 inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stanols and/or fatty acid esters of plant stanols, anti-oxidants, PPAR a agonists, PPAR y-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis 93 inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport protein inhibitors, bile acid reabsorption inhibitors, PPAR 6 agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR 6 partial 5 agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CB 1 antagonists/inverse agonists, ghrelin antagonists, H 3 antagonists/inverse agonists, MCH1R antagonists, MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptin agonists/modulators, leptin derivatives, opioid antagonists, 10 orexin receptor antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1, GLP-1 agonists, GLP-1 mimetics, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC inhibitors, 03 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS 15 inhibitors, PDE inhibitors, thyroid hormone P agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11p HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, anti-diabetic agents, anti-hypertensive agents, anti-dyslipidemic 20 agents, DP receptor antagonists, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons, galanin receptor antagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone, analogs 25 of dehydroepiandrosterone, urocortin binding protein antagonists, glucagons-like peptide-1 receptor agonists, human agouti-related proteins (AGRP), neuromedin U receptor agonists, noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists, MSH-receptor analogs, a-glucosidase inhibitors, apo Al milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors 30 (FABP), and fatty acid transporter protein inhibitors (FATP). Non-limiting examples of hydroxy-substituted azetidinone compounds and substituted P-lactam compounds useful in combination with the nicotinic acid receptor 94 agonists of the present invention are those disclosed in U.S. Patents Nos. 5,767,115, 5,624,920, 5,668,990, 5,656,624 and 5,688,787, 5,756,470, U.S. Patent Application Nos. 2002/0137690 and 2002/0137689 and PCT Patent Application No. WO 2002/066464, each of which is incorporated herein by reference in their entirety. A 5 preferred azetidinone compound is ezetimibe (for example, ZETIA* which is available from Schering-Plough Corporation). In one embodiment, the additional agent is an anti-flushing agent. Non-limiting examples of HMG CoA reductase inhibitor compounds useful in combination with the nicotinic acid receptor agonists of the present invention are 10 lovastatin (for example MEVACOR* which is available from Merck & Co.), simvastatin (for example ZOCOR* which is available from Merck & Co.), pravastatin (for example PRAVACHOL* which is available from Bristol Meyers Squibb), atorvastatin, fluvastatin, cerivastatin, CI-981, rivastatin (sodium 7-(4-fluorophenyl)-2,6-diisopropyl 5-methoxymethylpyridin-3-yl)-3,5-dihydroxy-6-heptanoate), rosuvastatin calcium 15 (CRESTOR® from AstraZeneca Pharmaceuticals), pitavastatin (such as NK-1 04 of Negma Kowa of Japan). A non-limiting example of a HMG CoA synthetase inhibitor useful in combination with the nicotinic acid receptor agonists of the present invention is, for example, L-659,699 ((E,E)-11-[3'R-(hydroxy-methyl)-4'-oxo-2'R-oxetanyl]-3,5,7R 20 trimethyl-2,4-undecadienoic acid). A non-limiting example of a squalene synthesis inhibitor useful in combination with the nicotinic acid receptor agonists of the present invention is, for example, squalestatin 1. A non-limiting example of a squalene epoxidase inhibitor useful in combination 25 with the nicotinic acid receptor agonists of the present invention is, for example, NB 598 ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophen-5 yl)methoxy]benzene-methanamine hydrochloride). A non-limiting example of a sterol biosynthesis inhibitor useful in combination with the nicotinic acid receptor agonists of the present invention is, for example, DMP 30 565. Non-limiting examples of nicotinic acid derivatives (e.g., compounds comprising a pyridine-3-carboxylate structure or a pyrazine-2-carboxylate structure, including acid 95 forms, salts, esters, zwitterions and tautomers) useful in combination with the nicotinic acid receptor agonists of the present invention are niceritrol, nicofuranose and acipimox (5-methyl pyrazine-2-carboxylic acid 4-oxide). Non-limiting examples of bile acid sequestrants useful in combination with the 5 nicotinic acid receptor agonists of the present invention are cholestyramine (a styrene divinylbenzene copolymer containing quaternary ammonium cationic groups capable of binding bile acids, such as QUESTRAN* or QUESTRAN LIGHT® cholestyramine which are available from Bristol-Myers Squibb), colestipol (a copolymer of . diethylenetriamine and 1 -chloro-2,3-epoxypropane, such as COLESTID* tablets which 10 are available from Pharmacia), colesevelam hydrochloride (such as WelChol* Tablets (poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1 bromodecane and (6-bromohexyl)-trimethylammonium bromide) which are available from Sankyo), water soluble derivatives such as 3,3-ioene, N-(cycloalkyl) alkylamines and poliglusam, insoluble quaternized polystyrenes, saponins and mixtures thereof. 15 Non-limiting examples of inorganic cholesterol sequestrants useful in combination with the nicotinic acid receptor agonists of the present invention are bismuth salicylate plus montmorillonite clay, aluminum hydroxide and calcium carbonate antacids. Non-limiting examples of AcylCoA:Cholesterol O-acyltransferase ("ACAT") 20 inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention are avasimibe ([[2,4,6-tris(1-methylethyl)phenyl]acetyl]sulfamic acid, 2,6 bis(1-methylethyl)phenyl ester, formerly known as CI-1011), HL-004, lecimibide (DuP 128) and CL-277082 (N-(2,4-difluorophenyl)-N-[[4-(2,2-dimethylpropyl)phenyl]methyl] N-heptylurea), and the compounds described in P. Chang et al., "Current, New and 25 Future Treatments in Dyslipidaemia and Atherosclerosis", Drugs 2000 Jul; 60(1); 55 93, which is incorporated by reference herein. Non-limiting examples of cholesteryl ester transfer protein ("CETP") inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention are those disclosed in PCT Patent Application No. WO 00/38721, U.S. Patent Nos. 30 6,147,090, 6,958,346, 6,924,313 6,906,082, 6,861,561, 6,803,388, 6,794,396, 6,787,570, 6,753,346, 6,723,752, 6,723,753, 6,710,089, 6,699,898, 6,696,472, 6,696,435, 6,683,113, 5,519,001, 5,512,548, 6,410,022, 6,426,365, 6,448,295, 96 6,387,929, 6,683,099, 6,677,382, 6,677,380, 6,677,379, 6,677,375, 6,677,353, 6,677,341, 6,605,624, 6,586,433, 6,451,830, 6,451,823, 6,462,092, 6,458,849, 6,458,803, 6,455,519, 6,583,183, 6,562,976, 6,555,113, 6,544,974, 6,521,607, 6,489,366, 6,482,862, 6,479,552, 6,476,075, 6,476,057, and 6,897,317, each of which 6 are incorporated herein by reference; compounds described in Yan Xia et al., "Substituted 1,3,5-Triazines As Cholesteral Ester Transfer Protein Inhibitors", Bloorganic & Medicinal Chemistry Letters, vol. 6, No. 7, 1996, pp. 919-922, herein incorporated by reference; natural products described in S. Coval et al., "Wiedendiol-A and-B, Cholesteryl Ester Transfer Protein Inhibitors From The Marine Sponge 10 Xestosponga Wiedenmayeri", Bioorganic & Medicinal Chemistry Letter, vol. 5, No. 6, pp. 605-610, 1995, herein incorporated by reference; the compounds described in Barrett et al. J. Am. Chem. Soc., 188, 7863-63 (1996), herein incorporated by reference; the compounds described in Kuo et al. J. Am. Chem. Soc., 117, 10629-34 (1995), herein incorporated by reference; the compounds described in Pietzonka et al. 15 Bioorg. Med. Chem. Lett., 6, 1951-54 (1996), herein incorporated by reference; the compounds described in Lee et al. J. Antibiotics, 49, 693-96 (1996), herein incorporated by reference; the compounds described by Busch et al. Lipids, 25, 216 220, (1990), herein incorporated by reference; the compounds described in Morton and Zilversmit J. Lipid Res., 35, 836-47 (1982), herein incorporated by reference; the 20 compounds described in Connolly et al. Biochem. Biophys. Res. Comm., 223, 42-47 (1996), herein incorporated by reference; the compounds described in Bisgaier et al. Lipids, 29, 811-8 (1994), herein incorporated by reference; the compounds described in EP 818448, herein incorporated by reference; the compounds described in JP 10287662, herein incorporated by reference; the compounds described in PCT 25 applications WO 98/35937, WO 9914174, WO 9839299, and WO 9914215, each of which is herein incorporated by reference; the compounds of EP applications EP 796846, EP 801060, 818448, and 818197, each of which is herein incorporated by reference; probucol or derivatives thereof, such as AGI-1 067 and other derivatives disclosed in U.S. Patents Nos. 6,121,319 and 6,147,250, herein incorporated by 30 reference; low-density lipoprotein (LDL) receptor activators such as HOE-402, an imidazolidinyl-pyrimidine derivative that directly stimulates LDL receptor activity, described in M. Huettinger et al., "Hypolipidemic activity of HOE-402 is Mediated by 97 Stimulation of the LDL Receptor Pathway", Arterioscler. Thromb. 1993; 13:1005-12, herein incorporated by reference; 4-carboxyamino-2-substituted- 1,2,3,4 tetrahydroquinolines, e.g., torcetrapib, described in WO 00/017164, WO 00/017166, WO 00/140190, WO 00/213797, and WO 2005/033082 (each of which is herein 5 incorporated by reference). Torcetrapib can be combined with HMG-CoA reductase inhibitors such as atorvastatin (WO 00/213797, WO 2004/056358, WO 2004/056359, and W02005/011634). A non-limiting example of a fish oil containing Omega 3 fatty acids useful in combination with the nicotinic acid receptor agonists of the present invention is 3 10 PUFA. Non-limiting examples of GLP-1 mimetics useful in combination with the nicotinic acid receptor agonists of the present invention include exendin-3, exendin-4, Byetta-Exanatide, Liraglutinide, CJC-1 131 (ConjuChem), Exanatide-LAR (Amylin), BIM-51077 (Ipsen/LaRoche), ZP-10 (Zealand Pharmaceuticals), and compounds 15 disclosed in International Publication No. WO 00/07617. Non-limiting examples of natural water soluble fibers useful in combination with the nicotinic acid receptor agonists of the present invention are psyllium, guar, oat and pectin. A non-limiting example of a plant stanol and/or fatty acid ester of plant stanols 20 useful in combination with the nicotinic acid receptor agonists of the present invention is the sitostanol ester used in BENECOL* margarine. A non-limiting example of an anti-oxidant useful in combination with the nicotinic acid receptor agonists of the present invention includes probucol. Non-limiting examples of PPAR a agonists useful in combination with the 25 nicotinic acid receptor agonists of the present invention include beclofibrate, benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil. Non-limiting examples of lipoprotein synthesis inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include niacin or nicotinic acid. 30 Non-limiting examples of 5HT (serotonin) transport inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include paroxetine, fluoxetine, fenfluramine, fluvoxamine, sertraline, and imipramine.

98 Non-limiting examples of NE (norepinephrine) transport inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include GW 320659, despiramine, talsupram, and nomifensine. Non-limiting examples of CB 1 antagonists/inverse agonists useful in 5 combination with the nicotinic acid receptor agonists of the present invention include rimonabant, SR-147778 (Sanofi Aventis), and the compounds described in US 5,532,237, US 4,973,587, US 5,013,837, US 5,081,122, US 5,112,820, US 5,292,736, US 5,624,941, US 6,028,084, WO 96/33159, WO 98/33765, WO 98/43636, WO 98/43635, WO 01/09120, WO 98/31227, WO 98/41519, WO 98/37061, 10 WO 00/10967, WO 00/10968, WO 97/29079, WO 99/02499, WO 01/58869, WO 02/076949, and EP-658546 (each of the preceding references is herein incorporated by reference). Non-limiting examples of ghrelin antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include those described in WO 15 01/87335 and WO 02/08250 (each of the preceding references is herein incorporated by reference). Ghrelin antagonists are also known as GHS (growth hormone secretagogue receptor) antagonists. The pharmaceutical combinations and methods of the present invention therefore comprehend the use GHS antagonists in place of ghrelin antagonists (in combination with the nicotinic acid receptor agonists of the 20 present invention). Non-limiting examples of H 3 antagonists/inverse agonists useful in combination with the nicotinic acid receptor agonists of the present invention include thioperamide, 3-(1 H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, and GT2394 (Gliatech), those described in WO 02/15905 (herein 25 incorporated by reference); O-[3-(1H-imidazol-4-yl)propanol]carbamates described in Kiec-Kononowicz, K. et al., Pharmazie, 55:349-55 (2000) (herein incorporated by reference), piperidine-containing histamine H 3 -receptor antagonists described in Lazewska, D. et al., Pharmazie, 56:927-32 (2001) (herein incorporated by reference), benzophenone derivatives and related compounds described in Sasse, A. et al., Arch. 30 Pharm.(Weinheim) 334:45-52 (2001)(herein incorporated by reference), substituted N phenylcarbamates described in Reidemeister, S. et al., Pharmazie, 55:83-6 (2000)(herein incorporated by reference), and proxifan derivatives described in Sasse, 99 A. et al., J. Med. Chem. 43:3335-43 (2000)( each of the preceding references is herein incorporated by reference). Non-limiting examples of MCH1 R (melanin-concentrating hormone 1 receptor) antagonists and MCH2R (melanin-concentrating hormone 2 receptor) 5 agonists/antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include those described in WO 01/82925, WO 01/87834, WO 02/06245, WO 02/04433, WO 02/51809, and JP 13226269 (each of the preceding references is herein incorporated by reference), and T-226296 (Takeda). Non-limiting examples of NPY1 antagonists useful in combination with the 10 nicotinic acid receptor agonists of the present invention include those described in US 6,001,836, WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528 (each of the preceding references is herein incorporated by reference); and BIBP3226, J-1 15814, BIBO 3304, LY-357897, CP-671906, and GI-264879A. 15 Non-limiting examples of NPY5 antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include those described in US 6,140,354, US 6,191,160, US 6,258,837, US 6,313,298, US 6,337,332, US 6,329,395, US 6,340,683, US 6,326,375, US 6,335,345, EP-01010691, EP-01044970, WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, 20 WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0248152, WO 02/49648, WO 01/14376, WO 04/110375, WO 05/000217 and Norman et al., J. Med. Chem. 43:4288-4312 (2000) (each of the preceding references is herein 25 incorporated by reference); and 152,804, GW-569180A, GW-594884A, GW-587081 X, GW-548118X; FR226928, FR 240662, FR252384; 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104. Non-limiting examples of NPY2 agonists useful in combination with the nicotinic acid receptor agonists of the present invention include PYY3-36 as described in 30 Batterham, et al., Nature. 418:650-654 (2003), NPY3-36, and other Y2 agonists such as N acetyl [Leu(28,31)] NPY 24-36 (White-Smith and Potter, Neuropeptides 33:526 33 (1999)), TASP-V (Malis et al., Br. J. Pharmacol. 126:989-96 (1999)), cyclo-(28/32)- 100 Ac-[Lys28-Glu32]-(25-36)-pNPY (Cabrele and Beck-Sickinger J-Pept-Sci. 6:97-122 (2000)) (each of the preceding references is herein incorporated by reference). Non-limiting examples of NPY4 agonists useful in combination with the nicotinic acid receptor agonists of the present invention include pancreatic peptide (PP) as 5 described in Batterham et al., J. Clin. Endocrinol. Metab. 88:3989-3992 (2003), and other Y4 agonists such as 1229U91 (Raposinho et al., Neuroendocrinology. 71:2 7(2000) (both references are herein incorporated by reference). Non-limiting examples of mGluR5 (Metabotropic glutamate subtype 5 receptor) antagonists useful in combination with the nicotinic acid receptor agonists of the 10 present invention include 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and (3-[(2 methyl-1,3-thiazol-4-yl)ethynyl]pyridine) (MTEP) and those compounds described in Anderson J. et al., J, Eur J Pharmacol. Jul. 18, 2003;473(1):35-40; Cosford N. et al., Bioorg Med Chem Lett. Feb. 10, 2003;13(3):351-4; and Anderson J. et al., J Pharmacol Exp Ther. December 2002:303(3):1044-51 (each of the preceding 15 references is herein incorporated by reference). Non-limiting examples of leptins, leptin derivatives, and leptin agonists/modulators useful in combination with the nicotinic acid receptor agonists of the present invention include recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen). Leptin derivatives (e.g., 20 truncated forms of leptin) useful in the present invention include those described in US 5,552,524, US 5,552,523, US 5,552,522, US 5,521,283, WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO 96/23517, WO 96/23518, WO 96/23519, and WO 96/23520 (each of the preceding references is herein incorporated by reference). Non-limiting examples of opioid antagonists useful in combination with the 25 nicotinic acid receptor agonists of the present invention include nalmefene (Revex

TM

), 3-methoxynaltrexone, naloxone, and naltrexone, as well as opioid antagonists described in WO 00/21509 (herein incorporated by reference). Non-limiting examples of orexin receptor antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include SB-334867-A, as 30 well as those described in WO 01/96302, WO 01/68609, WO 02/51232, and WO 02/51838 (each of the preceding references is herein incorporated by reference).

101 Non-limiting examples of CNTF (specific ciliary neurotrophic factors) useful in combination with the nicotinic acid receptor agonists of the present invention include GI-1 81771 (Glaxo-SmithKline); SR146131 (Sanofi Aventis); butabindide; PD1 70,292, PD 149164 (Pfizer). 5 Non-limiting examples of CNTF derivatives and CNTF agonists/modulators useful in combination with the nicotinic acid receptor agonists of the present invention include axokine (Regeneron) and those described in WO 94/09134, WO 98/22128, and WO 99/43813 (each of which is herein incorporated by reference). Non-limiting examples of 5HT2c agonists useful in combination with the 10 nicotinic acid receptor agonists of the present invention include BVT933, DPCA37215, WAY161503, and R-1 065, as well as those described in US 3,914,250, WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457 (each of which is herein incorporated by reference). Non-limiting examples of Mc4r agonists useful in combination with the nicotinic 15 acid receptor agonists of the present invention include CHIR86036 (Chiron); ME 10142, and ME-10145 (Melacure), as well as those described in WO 01/991752, WO 01/74844, WO 02/12166, WO 02/11715, and WO 02/12178 (each of which is herein incorporated by reference). Non-limiting examples of monoamine reuptake inhibitors useful in combination 20 with the nicotinic acid receptor agonists of the present invention include sibutramine (MeridiaTm/ReductilTM), as well as those described in WO 01/27068, WO 01/62341, US 4,746,680, US 4,806,570, US 5,436,272, and US 2002/0006964 (each of which is herein incorporated by reference). Non-limiting examples of serotonin reuptake inhibitors useful in combination 25 with the nicotinic acid receptor agonists of the present invention include dexfenfluramine, fluoxetine, and those described in US 6,365,633, WO 01/27060, and WO 01/162341 (each of which is herein incorporated by reference). A non-limiting example of an acyl-estrogen useful in combination with the nicotinic acid receptor agonists of the present invention includes oleoyl-estrone. 30 Non-limiting examples of 111P HSD-1 inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include those described in WO 03/065983 and WO 03/104207 (both of which are herein incorporated by reference).

102 A non-limiting example of a lipase inhibitor useful in combination with the nicotinic acid receptor agonists of the present invention include orlistat. Anti-diabetic agents useful in combination with the nicotinic acid receptor agonists of the present invention include sulfonylureas, meglitinides, a-amylase 5 inhibitors, a-glucoside hydrolase inhibitors, PPAR-y agonists, PPARa/y agonists, biguanides, PTP-1B inhibitors, DP-IV inhibitors, DPP-IV inhibitors, insulin secretagogues, fatty acid oxidation inhibitors, A2 antagonists, c-jun amino-terminal kinase inhibitors, insulin, insulin mimetics, glycogen phosphorylase inhibitors, VPAC2 receptor agonists, glucokinase activators, and non-thiazolidinedione PPAR ligands. 10 Non-limiting examples of sulfonylureas useful in combination with the nicotinic acid receptor agonists of the present invention include acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide. Non-limiting examples of meglitinides useful in combination with the nicotinic 15 acid receptor agonists of the present invention include repaglinide, mitiglinide and nateglinide. Non-limiting examples of a-amylase inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include tendamistat, trestatin, and Al-3688. 20 Non-limiting examples of a-glucoside hydrolase inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include acarbose, adipose, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, salbostatin, CDK 711, MDL-25,637, MDL-73,945, and MOR 14. Non-limiting examples of PPAR-y agonists useful in combination with the 25 nicotinic acid receptor agonists of the present invention include balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone (MCC-555), pioglitazone, rosiglitazone, troglitazone, tesaglitazar, netoglitazone, GW-409544, GW-501516, CLX-0921, 5-BTZD, GW-0207, LG-100641, LY-300512, LY-519818, R483 (Roche), and T131 (Tularik). 30 Non-limiting examples of PPARa/y agonists useful in combination with the nicotinic acid receptor agonists of the present invention include CLX-0940, GW-1 536, GW-1 929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB 219994.

103 Non-limiting examples of biguanides useful in combination with the nicotinic acid receptor agonists of the present invention include buformin, metformin, and phenformin. Non-limiting examples of PTP-1 B inhibitors (protein tyrosine phosphatase-1 B 5 inhibitors) useful in combination with the nicotinic acid receptor agonists of the present invention include A-401,674, KR 61639, OC-060062, OC-83839, OC-297962, MC52445, and MC52453. Non-limiting examples of DPP-IV inhibitors (dipeptidyl peptidase IVi inhibitors) useful in combination with the nicotinic acid receptor agonists of the present invention 10 include sitagliptin, saxagliptin, denagliptin, vildagliptin, alogliptin, alogliptin benzoate, Galvus (Novartis), ABT-279 and ABT-341 (Abbott), ALS-2-0426 (Alantos), ARI-2243 (Arisaph), BI-A and 1-B (Boehringer Ingelheim), SYR-322 (Takeda), MP-513 (Mitsubishi), DP-893 (Pfizer) and RO-0730699 (Roche), isoleucine thiazolidide, NVP DPP728, P32/98, LAF 237, TSL 225, valine pyrrolidide, TMC-2A/2B/2C, CD-26 15 inhibitors, and SDZ 274-444. Non-limiting examples of insulin secretagogues useful in combination with the nicotinic acid receptor agonists of the present invention include linogliride and A-4166. Non-limiting examples of fatty acid oxidation inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include clomoxir and 20 etomoxir. Non-limiting examples of A2 antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include midaglizole, isaglidole, deriglidole, idazoxan, earoxan, and fluparoxan. Non-limiting examples of insulin mimetics useful in combination with the 25 nicotinic acid receptor agonists of the present invention include biota, LP-100, novarapid, insulin detemir, insulin lispro, insulin glargine, insulin zinc suspension (lente and ultralente), Lys-Pro insulin, GLP-1 (73-7) (insulintropin), and GLP-1 (7-36)

NH

2 ). Non-limiting examples of glycogen phosphorylase inhibitors useful in 30 combination with the nicotinic acid receptor agonists of the present invention include CP-368,296, CP-316,819, and BAYR3401.

104 Non-limiting examples of non-thiazolidinedione PPAR ligands useful in combination with the nicotinic acid receptor agonists of the present invention include JT-501 and farglitazar (GW-2570/GI-262579). Anti-hypertensive agents useful in combination with the nicotinic acid receptor 5 agonists of the present invention include diuretics, p-adrendergic blockers, a adrenergic blockers, aldosterone inhibitors, alpha 1 blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, angiotensin II receptor antagonists, endothelin antagonists, vasodilators, alpha 2a agonists, and a/P adrenergic blockers. 10 Non-limiting examples of diuretics useful in combination with the nicotinic acid receptor agonists of the present invention include chlorthalidone, chlorthiazide, dichlorophenamide, hydroflumethiazide, indapamide, hydrochlorothiazide, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, triamterene, spironolactone, and epirenone. 15 Non-limiting examples of p-adrendergic blockers useful in combination with the nicotinic acid receptor agonists of the present invention include acebutolol, atenolol, betaxolol, bevantolol, bisoprolol, bopindolol, carteolol, carvedilol, celiprolol, esmolol, indenolol, metaprolol, nadolol, nebivolol, penbutolol, pindolol, propanolol, sotalol, tertatolol, tilisolol, and timolol. 20 Non-limiting examples of alpha 1 blockers useful in combination with the nicotinic acid receptor agonists of the present invention include terazosin, urapidil, prazosin, bunazosin, trimazosin, doxazosin, naftopidil, indoramin, WHIP 164, and XEN010. Non-limiting examples of calcium channel blockers useful in combination with 25 the nicotinic acid receptor agonists of the present invention include amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, bepridil, cinaldipine, clevidipine, diltiazem, efonidipine, felodipine, gallopamil, isradipine, lacidipine, lemildipine, lercanidipine, nicardipine, nifedipine, nilvadipine, nimodepine, nisoldipine, nitrendipine, manidipine, pranidipine, and verapamil. 30 Non-limiting examples of angiotensin converting enzyme inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include alacepril, benazepril, ceronapril, captopril, cilazapril, delapril, enalapril, fosinopril, 105 imidapril, losinopril, moveltopril, moexipril, quinapril, quinaprilat, ramipril, perindopril, peridropril, quanipril, spirapril, temocapril, trandolapril, and zofenopril. Non-limiting examples of neutral endopeptidase inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include omapatrilat, 5 cadoxatril, ecadotril, fosidotril, sampatrilat, AVE7688, and ER4030. Non-limiting examples of angiotensin Il receptor antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include candesartan, eprosartan, irbesartan, losartan, pratosartan, tasosartan, telisartan, valsartan, EXP-3137, Fl6828K, RNH6270, losartan monopotassium, and losartan 10 potassium-hydrochlorothiazide. Non-limiting examples of endothelin antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include tezosentan, A308165, and YM62899. Non-limiting examples of vasodilators useful in combination with the nicotinic 15 acid receptor agonists of the present invention include hydralazine (apresoline), clonidine (catapres), minoxidil (loniten), and nicotinyl alcohol (roniacol). Non-limiting examples of alpha 2a agonists useful in combination with the nicotinic acid receptor agonists of the present invention include lofexidine, tiamenidine, moxonidine, rilmenidine, and guanobenz. 20 Non-limiting examples of a/s adrenergic blockers useful in combination with the nicotinic acid receptor agonists of the present invention include nipradilol, arotinolol, and amosulalol. DP receptor antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include those described in US 2004/0229844 (herein 25 incorporated by reference). Non-limiting examples of additional agents that can be combined with the nicotinic acid receptor agonists of the present invention include aspirin, Niaspan, Norvsac* (amlodipine), NSAIDS agents (e.g., Celecoxib (Celebrex*), Diclofenac (Cataflam*, Voltaren*, Arthrotec*,) Diflunisal (Dolobid*), Etodolac (Lodine), 30 Fenoprofen (Nalfon*), Flurbirofen (Ansaid*), Ibuprofen (Motrin®, ADVIL, NUPRIN*, Tab-Profen*, Vicoprofen®, Combunox), Indornethacin (Indocin*, Indo-Lemmon*, Indornethagan), Ketoprofen (Oruvail), Ketorolac (Toradol), Mefenamic acid 106 (Ponstel*, commercially available from First Horizon Pharmaceutical), flufenamic acid ([N-(3-trifluoromethylphenyl)anthranilic acid]), Meloxicam (Mobic*), Naburnetone (Relafen*), Naproxen (Naprosyn, ALEVE*, Anaprox*, Naprelan®, Naprapac), Oxaprozin (Daypro), Piroxicam (Feldene), Sulindac (Clinoril®) and Tolmetin 5 (Tolectin*)), antihypertensive agents (Prazosin®, Propranolol, nadolol, timolol, metoprolol, pindolol, labetalol, guanethidine, reserpine, clonidine, methyldopa, guanabenz, captopril, enalapril, lisinopril, losartan, verapamil, diltiazem, nifedipine, hydrochlorothiazide, chlorothalidone, furosemide, triamterene, hydralazine, minoxidil), PGE2 receptor antagonists (e.g., EP2 and EP4). 10 Non-limiting examples of additional agents that can be combined with the nicotinic acid receptor agonists of the present invention include homocysteinase, orphan GPCR modulator, HRE-based gene therapy, gene therapy, dual PPARa/y agonists, recombinant FGF-1, VRI-1, CRx-150, VEGF-1 14 based therapy, CT-500, regadenosan, CK-1827452, JAK2 tyrosine kinase inhibitors, adipose-derived 15 regenerative cells, STARBURST dendrimer-based MRI contrast agents, TBC-1 1299, HEMOxygenation, heparin, GO-EPO, IDN-6734, ISIS-301012, HIF-alpha gene therapy, a2b adrenoceptor antagonists, KI-0002, adenosine modulators, Ki-23095, PR-5 (Melacure), L-364373, histone deacetylase inhibitors, adenylate cyclase inhibitors (E.g., HI-30435 from Millennium), MITO-0139 (from MitoKor), NV-04 (from 20 Novogen), M-1 18 (Momenta), hypoxia response element, PI-99 (from progen), NEXVAS (from Resverlogix), CS-207 )from Shenzhen Chipscreen Biosciences), estrogen-regulated gene therapy, SLV-327 (from SolvaY), TNX-832 (from Sunol Molecular Corp), SLx-21 01 (from Surface Logix), recombinant human annexin (from SurroMed), Chymase inhibitors (e.g, from Toa Eiyo), VM-202 (from ViroMed), liver x 25 receptor modulators (e.g., from Exelixis/Bristol Myers Squibb), Heberkinasa (from Y. M. Biosciences), atorvastatin-amlodipine combination, AGN-195795 (Allergan), angiotensisn (1-7) agonists (e.g., from Arena), Toprol XL/hydrochlorothiazide (from AstraZeneca), Teczem (Aventis), sGC stimulators, calcium channel blockers, CYT 006-AngQb (CytosBiotechnology), renin inhibitors (e.g., from Roche/Speedel), 30 Coxagen (from geneRx+ Inc), MC-4262 (from Medicure), VNP-489 (from Novartis), felodipine (from Pierre Fabre SA), 2-methoxyestradiol (from PR Pharmaceuticals), al adrenoreceptor antagonsists (e.g., from Recordati SpA), lercanidipine-enalapril 107 combination (from Recordati SpA). NO donors 9e.g., from Renopharm), CR-3834 (from Rottapharm Gr), iloprost (from Schering AG), SPP-1 100 (from The Speedel Group), angiotensinogen, MC-4232 (from Medicure), ACE inhibitor (from Servier), LCP-Feno/Stat. (from LifeCycle Pharma), APA-01/statin combination (from 5 Phosphagenics Ltd), KH-01 502 (from Kos), KS-01 019 (from Kos), niacin-lovastatin combination (from Kos/Merck KGaA), MK-0524/extended release niacin/simvastatin combination (from Merck), MK-0524/extended release combination (from Merck), Pro NAD (from Niadyne Inc), beraprost, perindopril erbumine, barnidipine, irbesartan, valsartan, valsartan-HCTZ conmbination, meclinertant, TAK-536, SR-121463, 10 irbesatran + HCTZ combination, darusentan, PMD-2850, CR-2991, SLV-306, bisoprolol fumarate+ HCTZ combination, NV-04, FG-3019, TRC-4149, AVE-7688, PV 903, diltiazem, QC-BT1 6, cardiotherpay (from Cytopia), treprostinil sodium, enalapril+diltiazem combination, eprosartan mesylate +HCTZ combination, renin inhibitor (from Vitae), LG-105 inhibitors (from Lexicon(, LG-844 inhibitors (from 15 Lexicon), NO-enhancing PDE inhibitors, hyaluronidase, propranolol hydrochloride, BlO-236, RWJ-351647, metoprolol, YM-222546, bLN-5, olmesartan+azelnidipine combination (from Sanyo), moxonidine + HCTZ combination, NS-304, BIO-1 23, aldosterone antagonists, clonidine, BIO-003 and CR-3834. In addition, the nicotinic acid receptor agonists of the present invention can also 20 be used in combination with two or more therapeutic agents. A non-limiting example of two or more therapeutic agents useful in combination with the nicotinic acid receptor agonists of the present invention is the combination of a compound of the present invention with VYTORIN* (a combination of simvastatin and ezetimibe). The invention disclosed herein is exemplified by the following preparations and 25 examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art. EXAMPLES 30 In the examples and tables that follow, the exemplary compounds of the invention are referred to by number. In some instances, the compounds of the invention are referred to as "Example X," wherein "X" would be the representative 108 number of that particular compound. In other instances, the compounds of the invention are referred to as "compound X," wherein "X" would be the representative number of that particular compound. In other instances, a compound of the invention may simply be referred to by it's number. It is to be understood that these terms are 5 used interchangeably. For example, the compound labeled "Example 1" can also be referred to as "compound 1" and vice versa. PREPARATIVE EXAMPLE 1 H 0O0Ner 0 Example 1 10 Step A: H H~0 0 NO + NNH 0 NH 0 0 Example 1 Methyl propionylacetate (12.5 g, 96.1 mmol, 1.23 eq.) and barbituric acid (10 g, 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 15 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). 1H NMR (CD 3 0D): 6 1.20 (t, 3 H, J = 7.3 Hz), 3.00 (q, 2 H, J = 7.3 Hz), 5.80 (s, 1 H) 13C NMR (CD 3 0D): 6 12.6, 27.4, 92.0,104.2, 149.5,158.4, 161.8, 162.1, 164.1 Mass for C 9

H

9

N

2 0 4 (MH)*: 209. Found: 209. 20 PREPARATIVE EXAMPLE 2 H Example 2 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 25 propionylacetate. 'H NMR (CD 3 0D): 6 2.41 (s, 3 H) 5.75 (s, 1 H) Mass for C 8

H

7

N

2 0 4 (MH)*: 195. Found: 195. PREPARATIVE EXAMPLE 3 109 H 0O 1N YO ;NH 0 Example 3 Example 3 was prepared by a method analogous to the method used to 5 prepare Example 1, except that methyl butanoylacetate was used instead of methyl propionylacetate. 'H NMR (CD 3 0D): 6 0.96 (t, 3 H, J = 7.6 Hz), 1.57 (m, 2 H), 2.86 (m, 2 H), 5.75 (s, 1 H) Mass for C 10 HjjN 2 0 4 (MH)*: 223. Found: 223. 10 PREPARATIVE EXAMPLE 4 H 0 0 N::O '. NH 0 Example 4 Example 4 was prepared by a method analogous to the method used to 15 prepare Example 1, except that ethyl isobutylacetate was used instead of methyl propionylacetate, and Example 4 was purified by HPLC (5% acetonitrile in water to 95% acetonitrile in 10 min). 1 H NMR (CD 3 0D): 6 1.14 (d, 6 H, J = 6.8 Hz), 4.03 (m, 1 H), 5.86 (s, 1 H) Mass for C 10 HiN 2 0 4 (MH)*: 223. Found: 223. 20 PREPARATIVE EXAMPLE 5 0 0 N Cl O"CN C, Example 5 Step A: H 0 0 NO 0 0 N C1 NH + POC1 3 -O 25 Example 1 Example 5 Example 1 (5 g, 24.04 mmol, 1 eq), POCl 3 (36.86g, 240 mmol, 10 eq.) and pyridine (0.95g, 12 mmol, 0.5 eq) were mixed and heated to 1150C for 8 hours. After cooling to room temperature, the solvent was removed and the brownish residue was 110 purified using flash chromatography with 20% EtOAc/hexane as the eluting solvent. The desired product (4 g) was obtained in 68% yield. 1 H NMR (CD 3 0D): 6 1.29 (t, 3 H, J = 7.2 Hz), 3.12 (m, 2 H), 6.39 (s, 1 H) Mass for C 9

H

7 Cl 2

N

2 0 2 (MH)*: 245. Found: 245. 5 PREPARATIVE EXAMPLE 6 0 0 N NHPh N C, Example 6 Step A: 0 0 N C 0 0 N NHPh O N + PhNH 2 N O N 10 Example 5 Example 6 Compound 1 (0.15 g, 0.61 mmol, 1 eq.) and aniline (0.06g, 0.64 mmol, 1.05 eq) were mixed in 3 mL of anhydrous THF and stirred for 12 hours. Solvent was removed and the residue was purified by prep TLC with 25% EtOAc/hexane as the 15 eluting solvent to give desired product as first fraction (7 mg, 4% yield). 1 H NMR (CD 3 0D): 6 1.27 (t, 3 H, J = 7.2 Hz), 3.05 (m, 2 H), 6.11 (s, 1 H), 7.11 (t, 1 H, J = 7.6 Hz), 7.34 (m, 2 H), 7.48 (br s, 1 H), 7.60 (d, 2 H, J = 8.0 Hz) Mass for C 15

H

13

CIN

3 0 2 (MH)*: 302. Found: 302.

111 PREPARATIVE EXAMPLE 7 0 0 N Ct N NHPh Example 7 Step A: 0 0 N Cl 0 0 N Cl N + PhNH 2 . N C1 NHPh 5 Example 5 Example 7 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). 10 1 H NMR (CD 3 0D): 6 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) Mass for C 1

H

13

CIN

3 0 2 (MH)*: 302. Found: 302. PREPARATIVE EXAMPLE 8 H 00 NO -. NH 0 0 OEt 15 Example 8 Step A: H H 00 NO 0OQEt + 0 N NH 0 NH O 0 0 0 OEt OEt Example 8 20 Example 8 was prepared using a method analogous to the method used to prepare Example 1, except that diethyl 1,3-acetonedicarboxylate was used instead of methyl propionylacetate. 1 H NMR (CD 3 0D): 6 1.20 (t, 3 H, J = 7.3 Hz), 3.88 (s, 2 H), 4.10 (q, 2 H, J = 7.3 Hz), 5.81 (s, 1 H) 25 13C NMR (CD 3 0D): 6 13.4, 39.6, 61.2, 92.2, 108.1, 149.7, 153.1,157.8,161.7, 162.0, 170.3 Mass for HRMS for C, 1

H

11

N

2 0 6 (MH)*: calcd 267.0617, found 267.0623.

112 PREPARATIVE EXAMPLE 9 H 0 0 1N0 CF, Example 9 Step A: Socl 2

F

3 C CO 2 H r F 3 C COOl 5 70oC A mixture of 3,3,3,-trifluoropropionic acid (16 g, 125 mmol), thionyl chloride (29.75 g, 250 mmol), and DMF (0.5 mL) was heated to 70 0 C for 4 hours. The reaction mixture was distilled under reduced pressure to give 3,3,3,-trifluoropropionyl chloride 10 (11.5 g, 72%). Step B: O 1, Pyridine,

CH

2 Cl2 O F3C COUl + O F3C" 2. MeOH 0 0 O Compound 9a 15 Into a solution of Meldrum's acid (2,2-dimethyl-4,6-dioxo-1,3-dioxane; 9 g, 62 mmol) and pyridine (9.8 g, 68 mmol) in anhydrous CH 2

C

2 (10 mL), which cooled to 0*C, was added 3,3,3,-trifluoropropionyl chloride (10 g, 68 mmol). The resulting reaction mixture was stirred under N 2 at 0*C for 1 hour then at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure. The 20 resulting paste was mixed with MeOH (20 mL), and heated to 80*C for 5 hours. The solvent was removed and the resulting mixture was distilled under reduced pressure to give Compound 9a (6.2 g, 54%). H H 0 N +0 F C O 180 C 0 0 N NH +FC NHJN 0 0

CF

3 Compound 9a Example 9 A mixture of Compound 9a (2.2 g, 12 mmol) and barbituric acid was heated to 25 180*C for 1 hour to provide a black solid. After cooling to room temperature, the black solid was dissolved into hot water (70 mL). The resulting mixture was extracted with ethyl acetate (4 x 50 mL). The organic solution was dried (Na 2

SO

4 ) and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC 113 eluting with formic acid (0.1%)/acetonitrile to give Example 9 (0.17 g, 5 %). Electrospray MS [M+1 ]*263. PREPARATIVE EXAMPLE 10 0 0 N SOMe NH 0 5 Example 10 Step A: HO H SHOMe H -N NH OH 1650C0 Compound 10a A mixture of 4,6-dihydroxy-2-mercapto-pyrimidine (20.0 g, 138.7 mmol) and 10 methyl propionylacetate (21.8 mL, 173.4 mmol) was heated at 1650C until the ester was completely reacted. The reaction mixture was cooled down and poured into water (75 mL) and then filtered through a sintered funnel. The solid residue was washed with water (2 x 20 mL) and dried under vacuum to yield Compound 1Oa (11.6 g, 37%). 15 Step B: 0O0NS +l DMF 00 NSMe N1y NH + Mel N1 NH Compound 10a Compound 10b Mel (2.23 mL, 35.72 mmol) was added to a suspension of Compound 10a (4.0 g, 17.86 mmol) in DMF (40 mL) at room temperature. The reaction mixture was stirred 20 at room temperature overnight. The reaction mixture was then poured into water (250 mL) and filtered through a sintered funnel. The solid residue was washed with water (2 x 50 mL) and dried under vacuum to give Compound 1Ob (4.1 g, 96%). Step C: O 0 N SMe 0 0 N SOMe

CH

2

CI

2 N NH + mCPBA 'NH 0 0 25 Compound10b Example 10 m-CPBA (3.1 g, 70%, 12.6 mmol) was added to a suspension of Compound 1 Ob (2.0 g; 8.4 mmol) in CH 2 0 2 (150 mL) at room temperature. The solvent was removed from the suspension after 3 hours and the crude product was purified using 114 silica gel flash column chromatography, eluting first with hexane/EtOAc (v/v = 1/1) then CH 2

CI

2 /MeOH (v/v = 2/1) to give Example 10 (2.0 g, 94%). Electrospray MS [M+1]* 255.1. PREPARATIVE EXAMPLE 11 0 0 N OMe NH 0 5 Example 11 Step A: 0 0 N ,,,SOMe 0 0 Nz ,OMe O S eNH MeOH OOH Example 10 Example 11 10 Example 10 (0.35 g, 1.37 mmol) in MeOH (40 mL) was heated at reflux overnight. After cooling to room temperature, the solvent was removed under reduced pressure and the crude product was purified using silica gel flash column chromatography eluting with CH 2

CI

2 /MeOH (v/v = 50/1) to give Example 11 (0.23 g, 76%). Electrospray MS [M+1]* 223.1. 15 PREPARATIVE EXAMPLE 12 0 0 N OBn NH Example 12 Step A: 0, 0 N S,OMe 0 0 N,OBn NH S +BnOH + NEt NCHN NH 0 0 20 Example 10 Example 12 BnOH (2.46 mL, 23.76 mmol) was added to a solution of Example 10 (0.404 g, 1.58 mmol) and NEt 3 (0.22 mL, 1.58 mmol) in CH 3 CN (12.0 mL) at room temperature. The reaction mixture was heated at 85*C overnight. After cooling to room 25 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 CH 2 C1 2 /MeOH (v/v = 50/1) to give Example 12 (0.20 g, 42%). Electrospray MS [M+1]* 299.1.

115 PREPARATIVE EXAMPLE 13 0 0N NH 0 Example 13 Step A: HA 00 NS 0 0N N S + BrI D 51 0 85 "C0 5 Compound10a Compound 13a Cyclopropyl methyl bromide (1.30 mL, 13.4 mmol) was added to a suspension of Compound 10a (0.5 g, 2.24 mmol) in DMF (5.0 mL) at room temperature. The 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 10 solid residue was washed with water (2 x 20 mL) and dried under vacuum to give Compound 13a (0.55 g, 88%). Step B: 0A O N S - CH 2

C

2 O N 0' 0 1NyS.ACl 0 0 Nkrl, NH + mCPBA NH 0 0 Compound 13a Example 13 15 m-CPBA (0.33 g, 70%, 1.35 mmol) was added to a suspension of Compound 13a (0.25 g, 0.9 mmol) in CH 2 Cl 2 (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/CH 2

C

2 /MeOH (v/v = 4/1/2) to give Example 13 20 (0.15 g, 57%). Electrospray MS [M+1]* 295.1. PREPARATIVE EXAMPLE 14 0 0 N NHNHCO 2 Me NH 0 Example 14 Step A: 25 N SOMe 0 N NHNHCO 2 Me NH CHaCN 0N,_NHHOM + NH 2

NHCO

2 Me CNNH 0 0 Example 10 Example 14 116 A mixture of Example 10 (0.205 g, 0.804 mmol) and NH 2

NHCO

2 Me (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 pressure and the crude product was washed with water (3 x 25 mL) with filtration. The solid was dried under vacuum 5 to give Example 14 (0.2 g, 89%). Electrospray MS [M+1]* 281.1. PREPARATIVE EXAMPLE 15 00 NS NH 0 Example 15 Step A: 10 H 00 N S DMF 00 NH + B N NH 0 0 Compound 10a Example 15 Allyl bromide (1.74 mL, 20.1 mmol) was added to a suspension of Compound 1Oa (1.5 g, 6.7 mmol) in DMF (15.0 mL) at room temperature. The reaction mixture 15 was stirred at 450C 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 (2 x 40 mL) and dried under vacuum to give Example 15 (1.55 g, 92%). Electrospray MS [M+1J 265.1. PREPARATIVE EXAMPLE 16 20 0 0 N O NH Example 16 Step A: 0 Os 0 0 NrL' N SONH + H O A CH3CN OO Example 10 Example 16 25 Cyclopropyl carbinol (0.79 mL, 9.8 mmol) was added to a solution of Example 10 (0.050 g, 0.196 mmol) in CH 3 CN (0.8 mL) at room temperature. The reaction mixture was heated at 85*C overnight. After cooling to room temperature, the solvent was removed under reduced pressure. The crude product was purified using silica gel 117 flash column chromatography eluting with hexane/EtOAc (v/v = 1/1) to give Example 16 (0.027 g, 52%). Electrospray MS [M+1]* 263.1. PREPARATIVE EXAMPLE 17 0 00 N S NH 0 Example 17 5 Step A: 0NSOMe CH0CN ONS NH + HS'. 51CN NHY 00 Example 10 Compound 17a A mixture of Example 10 (0.10 g, 0.392 mmol) and t-BuSH (0.66 mL, 5.88 10 mmol) in 1,4-dioxane (2.0 mL) was heated at reflux overnight. After cooling to room temperature, 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 give Compound 17a (0.045 g, 41%). Step B: 15 0 0 NYS,. CH~cI 2 0 0 N Sl SN + mCPBA CNH Compound 17a Example 17 m-CPBA (0.049 g, 70%, 0.20 mmol) was added to a suspension of Compound 17a (0.040 g, 0.143 mmol) in CH 2 Cl 2 (2.5 mL) at room temperature. Solvent was 20 removed after 3 hours and the crude product was purified using silica gel flash column chromatography eluting first with hexane/EtOAc (v/v = 1/1) then with CH 2

C

2 /MeOH (v/v = 5/1) to give Example 17 (0.030 g, 71%). Electrospray MS [M+1]* 297.1. PREPARATIVE EXAMPLE 18 0 0 N SOEt N10NH 0 25 Example 18 Step A: H 0 0 N Y S DF 0 0 N SEt N NH + Etl DMF N 0 C 0 Compound 10a Compound 18a 118 Etl (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 5 solid residue was washed with water (2 x 50 mL) and dried under vacuum to give Compound 18a (1.3 g, 76%). Step B 0 0 N SEt 0 0 N SOEt NH + mCPBA CH2CI OONH 0 0 Compound 18a Example 18 10 m-CPBA (74 mg, 70%, 3 mmol) was added to a suspension of Compound 18a (0.5g, 2 mmol) in CH 2 Cl 2 (50 mL) at room temperature. After stirring at room temperature 3 hours, the solvent was removed, and the crude product was purified using silica gel flash column chromatography eluting with AcOH/MeOH/CH 2 Cl 2 (v/v/v 15 = 0.1/4.9/95) to give Example 18 (0.4 g, 74%). Electrospray MS [M+1]* 269. PREPARATIVE EXAMPLE 19 0 K 0 0 NH N NH 0 Example 19 20 Step A: 0O0 S Br 0 0DNMSN NH+DMF N0NH Compound 10a Compound 19a Benzyl bromide (1.54 g, 9 mmol) was added to a suspension of Compound 25 1Oa (1g, 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 (2 x 50 mL) and dried under vacuum to give Compound 19a (1.3 g, 92%).

119 Step B: 00 S CH 2

C

2 00 NS NH + mCPBA NH 0 0 Compound 19a Example 19 5 m-CPBA (72 mg, 70%, 3 mmol) was added to a suspension of Compound 19a (0.5g, 2 mmol) in CH 2

CI

2 (50 mL) at room temperature. After stirring at room temperature 3 hours, the solvent was removed, and the crude product was purified using silica gel flash column chromatography eluting with AcOH/MeOH/CH 2

CI

2 (v/v/v 0.1/2.9/97) to give Example 19 (0.5 g, 76%). Electrospray MS [M+1]* 331. 10 PREPARATIVE EXAMPLE 20 0 ' 0 1N O Ny NH 0 Example 20 Step A: H 00 S MF 0 0 N S N O S + Br O N 51 0 -T-0 70 0 C0 15 Compound10a Compound 20a (1 -Bromoethyl)benzene (3.4 g, 18 mmol) was added to a suspension of Compound 10a (1 g, 4.5 mmol) in DMF (20.0 mL) at room temperature. The reaction mixture was stirred at 700C for one day. The reaction mixture was cooled down and 20 poured into water (50 mL) and then filtered through a Buchner funnel. The solid residue was washed with water (2 x 20 mL) and dried under vacuum to Compound 20a (1.3 g, 87%). Electrospray MS [M+1 ]*329. Step B: 0 0 N S H 00 N S NH + mCPBA NH 0 0 25 Compound 20a Example 20 m-CPBA (0.3 g, 70%, 1.2 mmol) was added to a suspension of Compound 20a (0.33 g, 1 mmol) in CH 2 C1 2 (30 mL) at room temperature. Solvent was removed 120 after 3 hours and the crude product was purified using silica gel flash column chromatography eluting with 5 % EtOH in EtOAc/hexanes (v/v = 1:1) to give Example 20 (0.1 g, 50%). Electrospray MS [M+1]* 345. PREPARATIVE EXAMPLE 21 5 0 0 0 N S'T Example 21 Step A: H 0 0 N S00 Y'.' O S ~DMFOS N~NH + I .NH 80 OC 0 0 Compound 1Oa Compound 21a 10 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 water (50 mL) and then filtered through a Buchner funnel. The solid residue was washed with water (2 x 20 mL) and dried under vacuum to give Compound 21a (1.05 g, 88%). 15 Step B 0 00 N OHCI,0 0 Nz SI, NH + mCPBA CH2C NH 0 5 0 Compound 21a Example 21 m-CPBA (0.74 g, 70%, 3 mmol) was added to a suspension of Compound 21a (0.53 g, 2 mmol) in CH 2

C

2 (30 mL) at room temperature. Solvent was removed after 3 20 hours, the crude product was purified using a silica gel flash column chromatography eluting with 0.1% AcOH in MeOH/CH 2 Cl 2 (v/v = 2:98) to give Example 21 (0.45 g, 80%). Electrospray MS [M+1]* 283. PREPARATIVE EXAMPLES 22 and 23 0 0 N OMe 0 N OMe N~NEt N N 0- QEt 25 Example 22 Example 23 Step A: 121 o 0 N O~le 0 0 N OMe 0 0 NlOe DMF O NH +Eli+ K 2 CO DFONEt + N ON 0 0 QEt Example 11 Example 22 Example 23

K

2

CO

3 (36.7 mg, 0.266 mmol) was added to a mixture of Example 11 (29.6 mg, 0.133 mmol) and Etl (0.064 mL, 0.8 mmol) in DMF (1.0 mL) at room temperature. 5 The reaction was stirred over night before it was diluted with by the addition of EtOAc (50 mL) and water (10 mL). The organic phase was washed with water (3x1 5 mL), brine (15 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using preparative TLC with hexane/CH 2

C

2 /EtOAc (v/v/v = 7/3/1) as eluent to give Example 22 (7.0 mg, 21 %) and Example 23 (20 mg, 60%). 10 Electrospray MS [M+1I* 251.1. PREPARATIVE EXAMPLE 24 00 N O Br NH 0 Example 24 Step A: 15 0 0 N SOMe 0 0 N 0 NH +CHCN r SNH + H NH 0 0 Example 10 Compound 24a Example 10 (0.216 g, 0.847 mmol) in allyl alcohol (3.0 mL) was heated at reflux overnight. After cooling to room temperature, the solvent was removed under 20 reduced pressure and the crude product was purified using silica gel flash column chromatography eluting with EtOAc/MeOH (v/v = 5/1) to give Compound 24a (0.1 g, 48%). Step B: 0 '~N0 0 N0 O NH + NBS CH 2 CB B 25 Compound 24a Example 24 NBS (36 mg, 0.202 mmol) was added to a solution of Compound 24a (0.040 g, 0.161 mmol) in CH 2 Cl 2 (2.0 mL) at room temperature. Solvent was removed over 1 hour and the crude product was purified using silica gel flash column chromatography 122 eluting with hexane/EA (v/v = 1/1) to give Example 24 (0.025 g, 48%). Electrospray MS [M+1]* 327.1. PREPARATIVE EXAMPLE 25 NO 0 5 Example 25 Step A: H 0 0 NO 0Q0NO O '~ + ~Br + Et 3 N CH 3 CN O 0Nal 0 Example 1 Example 25 10 Example 1 (0.5 g, 2.4 mmol) was taken up in CH 3 CN (10 mL). Triethylamine (0.33 mL, 2.4 mmol) was added to the suspension followed by cyclopropyl methyl bromide (0.26 mL, 2.64 mmol) and Nal (0.36 g, 2.4 mmol). The reaction mixture was 15 heated to reflux overnight. After cooling to room temperature, the solvent was evaporated in vacuo. The crude product was purified by crystallization from EtOAc/hexanes to give Example 25 (0.25 g, 40%). PREPARATIVE EXAMPLE 26 rCO 2 Me 0 0 NO O NH 0 20 Example 26 Step A: 0 H ( OMe 0 0 N O 0C0 NHCN I CHCN NH + BrCH 2 COMe + Et 3 N NH 0 0 Example 1 Example 26 25 Example 1 (0.1 g, 0.48 mmol) was taken up in CH 3 CN (3.0 mL). Triethylamine (0.067 mL, 0.48 mmol) was added to the suspension followed by methyl bromoacetate 123 (0.046 mL, 0.48 mmol). The reaction mixture was allowed to stir overnight at room temperature. The solvent was removed under reduced pressure and the crude mixture was purified by column chromatography eluting with EtOAc/hexanes (2/3: v/v) to yield Example 26 (0.06 g, 45%). 5 PREPARATIVE EXAMPLE 27 0 Example 27 Step A: 10 OMe 0 0 N O CH 3 CN 0 0 N 0 NH + MeOCH 2 Br + Et 3 N NH 0 0 Example 1 Compound 27a Example 1 (1.0 g, 4.8 mmol) was taken up in CH 3 CN (20 mL). Triethylamine (0.67 mL, 4.8 mmol) was added to the suspension followed by bromomethyl methyl 15 ether (0.44 mL, 4.8 mmol). The reaction mixture was allowed to stir at room temperature for 10 min after which it was concentrated. The crude mixture was purified by column chromatography eluting with EtOAc/hexanes (2/3: v/v) to yield Compound 27a (0.6 g, 50%). Step B: 20 OMe MeO0 r NOe 0 0 N0 + Br NaH N. OHO MF N OM 0 0 Compound 27a Compound 27b Sodium hydride (0.058 g, 1.46 mmol) was added to a mixture of Compound 27a (0.335 g, 1.33 mmol) in 8 mL DMF at 00C followed by cyclopropyl methyl bromide 25 (0.142 mL, 1.46 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 (2 x 5 mL). The organic layers were combined, dried over MgSO 4 , and concentrated to give the crude product.

124 The crude mixture was purified by column chromatography eluting with EtOAc/hexanes (2/3: v/v) to yield Compound 27b (0.175 g, 43%). Step C: MeO 0 0 N0 0 0 N 0 O + BBr, DCM, -78*C 0 0 5 Compound 27b Example 27 Boron tribromide (2.85 mL, 2.85 mmol, 1.0 M solution in DCM) was added to a solution of Compound 27b (0.175 g, 0.57 mmol) in CH 2 Cl 2 (8.0 mL) at -78*C. The reaction was allowed to stir for 2 h before being quenched with water (5.0 mL). The 10 reaction mixture was extracted with EtOAc (2 x 5 mL). The organic layers were combined, dried over MgSO 4 , 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 Example 27 (0.1 g, 67%). PREPARATIVE EXAMPLE 28 15 H 0 0 NO O N ,,C0 2 Me 0 Example 28 Step A: OMe MeO 0 YON ON 0 N + BrCH 2

CO

2 Me NNOMe 0 0 Compound 27a Compound 28a 20 Sodium hydride (0.016 g, 0.396 mmol) was added to a mixture of Compound 27a (0.100 g, 0.396 mmol) in 2 mL DMF at 00C followed by methyl bromoacetate (0.041 mL, 0.44 mmol). The suspension was allowed to stir at room temperature overnight before being diluted with EtOAc (5 mL) and quenched by the addition of 25 water (5 mL). The aqueous phase was extracted with EtOAc (2 x 5 mL). The organic layers were combined, dried over MgSO 4 , 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 28a (0.07 g, 54%). Step B: 125 MeO 0 0 NO 0000WNO O + BBr 3 DCM, -78 *C N C0 2 Me 0 0 Compound 28a Example 28 Boron tribromide (1.1 mL, 1.1 mmol, 1.0 M solution in DCM) was added to a 5 solution of Compound 28a (0.07 g, 0.22 mmol) in CH 2 0 2 (3.0 mL) at -78*C. The reaction was allowed to stir for 2 h before being quenched with water (5.0 mL). The reaction mixture was extracted with EtOAc (2 x 5 mL). The organic layers were combined, dried over MgSO 4 , and concentrated to give the crude product. The crude mixture was purified by column chromatography eluting with EtOAc/hexanes (2/3: v/v) 10 to yield Example 28 (0.02 g, 33%). PREPARATIVE EXAMPLE 29 H 0 0 N0 NkPh 0 Example 29 Step A: 15 OMe MeO 0 0 NO 0 0 NOY0 NH + K Br NaH O Br NDMF Ph Compound 27a Compound 29a Sodium hydride (0.080 g, 1.98 mmol) was added to a mixture of Compound 27a (0.500 g, 1.98 mmol) in 8 mL DMF at 00C followed by 2-bromoacetophenone 20 (0.434 g, 1.98 mmol). The suspension was allowed to stir at room temperature overnight before being diluted with EtOAc (5 mL) and quenched by the addition of water (5 mL). The aqueous phase was extracted with EtOAc (2 x 5 mL). The organic layers were combined, dried over MgSO 4 , and concentrated to give the crude product. The crude mixture was purified by column chromatography eluting with 25 EtOAc/hexanes (2/3: v/v) to yield Compound 29a (0.37 g, 50%). Step B: 126 MeO~ 0 0 N0 0 0 NO0 O+ BDC M ,-78 C PhI 0 N P + BBr 3 .,), 0 0 Compound 29a Example 29 Boron tribromide (4.7 mL, 4.7 mmol, 1.0 M solution in DCM) was added to a 5 solution of Compound 29a (0.350 g, 0.95 mmol) in CH 2

CI

2 (10.0 mL) at -78 0 C. The reaction was allowed to stir for 2 h before being quenched with water (5.0 mL). The reaction mixture was extracted with EtOAc (2 x 15 mL). The organic layers were combined, dried over MgSO 4 , and concentrated to give the crude product. The crude mixture was purified by column chromatography eluting with EtOAc/hexanes (2/3: v/v) 10 to yield Example 29 (0.175 g, 56%). PREPARATIVE EXAMPLE 30 and 31 00 NO 00 NO 0 NO Example 30 Example 31 Step A: 0 H

NH

2 TMSNCO H2N ANH Malonic acid 0 N O 6 MN Ac 2 O, AcOH N 15 Compound 30a Compound30b To a CH 2 0 2 solution of cyclopentylamine was added trimethylsilyl isocyanate. The reaction mixture was stirred overnight. To this was added 200 ml of CH 3 OH, and the mixture was stirred for another 2 hrs. The reaction mixture was concentrated and 20 was titrated using diethyl ether to give an off-white precipitate. The precipitate was filtered through a Buchner funnel to give cyclopentyl urea Compound 30a as a white crystalline solid compound (13.0 g, 86%). To this urea Compound 30a (5.0 g, 38.7 mmol) in acetic acid (11 mL), was added malonic acid (4.0g, 38.7 mmol) followed by acetic anhydride (18 mL) and the reaction was stirred at 70*C for 12 hrs. The 25 reaction mixture was concentrated, cooled in an ice bath and titrated using 4/1 EtO 2 /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 Compound 30b (2.5 g, 33%).

127 Step B: H9 0 NO 0 NO 0 O,+. O Sulfamic Acid NHO O Compound 30b0 0 Example 30 Example 31 5 Compound 30b (0.75 g, 1.0 equiv., 3.82 mmol) was condensed with methyl propional acetate (0.48mL, 3.82 mmol) in the presence of sulfamic acid and heated to 140 0 C for 6 hrs, forming a dark brown solid. The reaction mixture was diluted with EtOAc, washed with H 2 0, dried using Na 2

SO

4 and concentrated to give a crude mixture. Prep TLC purification of the crude mixture in 95/5 CH 2 Cl 2

/CH

3 0H yielded 10 both the N 1 and N 3 isomers, Example 30 LCMS: (M+1) 277.1 and Example 31 LCMS: (M+1). 277.1 A similar two-step procedure was used to synthesize Examples 32-43. substituents N-1 products LCMS: (M+1) N-3 products LCMS: (M+1) of N-1 of N-3 products products cyclopropyl Yf249.1o O N o 249.1 00 NO N NH 0 O Example 33 Example 32 H cyclobutyl 263.1 0 0 N a 263.1 001N O N NH N Example 35 Example 34_R Pr 251.1 0 o NO N251.1 O N Y0N NHO Example 37 0 Example 36 H Et 237.1 O0 N O 237.1 0 N 0 Example 3a Example 38 E xample 39 1 H Me 0 0 N 0 0 No 223.0 a 0 _______________ Example 40 Example 41 128 substituents N-1 products LCMS: (M+1) N-3 products LCMS: (M+1) of N-1 of N-3 products products H allyl 249.1 o o NYo 249.1 0 0 N 0N Oa 43 Example 43 0 ____________________ Example 42 ___________ ______________________ Using the procedure set forth above for making the compound of Example 30, and substituting the appropriate reagents and intermediates, compounds 780-785 5 were prepared: Compound Electrospray ComounStructure LCMS No' [M+1]+ H 0 0 NO 780 0 N' 303.1 H 0 0 N rO N 781 0 305.2 H 0 0 NO 782 0 291.2 H 0 0 NO NN 783 o0291.2 H 0 0 NO 7N 784 o317.2 129 PREPARATIVE EXAMPLE 44 H 00NH 01O Example 44 S N O Allyl Bromide, 1OH 0 0 N 0 0 NH 00NeN 0" H

CH

3 0H:HO (1 NH 0 0 Example 1 Example 44 5 To Example 1 (0.456 g, 2.2 mmol) in MeOH:H 2 0 (1:1) was added allyl bromide followed by LiOH, and the reaction mixture was heated to 820C 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 10 orange-red precipitate was produced, which was filtered from the solution using diethyl ether. The filtrate was purified using prep TLC 95/5 CH 2 Cl 2

/CH

3 0H to give Example 44 LCMS: (M+1).249.0 The following Examples 45-47, 51, 61-64, 66-67, 69-79 were prepared by a procedure similar to that used for the preparation of Example 12, using Example 10 15 and the appropriate corresponding alcohol. PREPARATIVE Electrospray PREPARATIVE Electrospray EXAMPLE LCMS [M+1]+ EXAMPLE LCMS [M+1]* SN 367.1367.1 NH CF 3 NH 0 0 Example 45 Exa le 46 317.1 I300.1 F00 NO N NH NH 0, 0 Example 47 Example 51 359.1 1391.1 NON O Ny NH OW NH Br 0 0 Exml 61 Example 62 130 PREPARATIVE Electrospray PREPARATIVE Electrospray EXAMPLE LCMS [M+1]+ EXAMPLE LCMS [M+1]+ 327.1 327.1 NHNH ~ o 0 Example 63 Example 64 300.1 316.1 NH NH o 0 Example 66 Example67 391.2 314.1 S NH Br N NH o O Example 69 Example70 o O 316.1 N3141 0 y0N o N 1y 314.1 NHN NH o 0 Example 71 Example 72 S313.1317.1 N NH N NH F o 0 Example 73 Example 74 N383.1333.1 oN O N. NO NH OCF 3 NH Cl o 0 Example 75 Example 76 O 4NY N375.1 01 NY320.1 ONO H Example 77 Example 78 Br 469.1 O N N Br N NH 0 Example 79 PREPARATIVE EXAMPLE 48 O 0 N CO 2 Me N NH 0 Example 48 5 SteQ A: 131 OSMe + BnOH + DIAD + PPh T O N 0 n Compound 10b Coond48 DIAD (0.488 mL, 2.52 mmol) was added dropwise to a solution of Compound 10b (0.5 g, 2.10 mmol), BnOH (0.261 mL, 2.52 mmol) and PPh 3 (0.661 g, 2.52 mmol) 5 in THF (6.0 mL) at room temperature. The resulting reaction mixture was stirred for 5 hours before it was worked up by 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: 10 CNCI, 0 0 NY NySN CH 2

C

2 N N+N n-CPBA N OBn Compound 48a Compound 48b m-CPBA (0.384 g, 1.55 mmol, 60-70%) was added at room temperature to a solution of Compound 48a (0.17 g, 0.518 mmol) in CH 2

CI

2 (5 mL). The reaction 15 mixture was stirred for 5 hours before it was quenched with addition of Me 2 S (76 uL, 1.55 mmol). The mixture was then diluted with EtOAc and washed with NaHCO 3 solution. The organic phase was washed with water, brine, and dried (Na 2

SO

4 ). Solvent was removed under reduced pressure, and the crude product was purified by silica gel flash column chromatography eluting with hexane/CH 2 Cl 2 /EtOAc (v/v/v = 20 7/3/2) to give Compound 48b (0.15 g, 80%). Step C: 01% NRM 0 0 IN, CN DMF NC 0 0N + NaCN N OBn OBn Compound 48b Compound 48c 25 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 stirred at room temperature for 2 hours before it was worked up by dilution with EtOAc and water. The organic phase was washed with water (2x), brine, and dried (MgSO 4 ). Solvent was removed under reduced pressure, and the crude product was purified by 132 silica gel flash column chromatography, eluting with hexane/CH 2

CI

2 /EtOAc (v/v/v = 5/1/1) to give Compound 48c (37 mg, 50%). Step D: S0HC/MeN

CO

2 Me OBn 5 Compound 48c Example 48 A solution of Compound 48c (10 mg, 0.0326 mmol) in 4.0 M HCI in dioxane (0.7 mL) and MeOH (0.7 mL) in a sealed tube was heated at 70 0 C for 7 hours. The mixture was cooled to room temperature and solvent was removed under reduced 10 pressure to give crude product. The crude product was purified with preparative thin layer silica gel chromatography eluting with hexane/CH 2 Cl 2 /MeOH (v/v/v = 6/4/1) to give Example 48 (5 mg, 61%). Electrospray MS [M+1]* 251.1. PREPARATIVE EXAMPLE 49 00 1NO '-. NH 0 15 Example 49 Step A: 0 0 N,, SOMe 0 o Nz O N NH + HO NaH NH O THF/DMF Example 10 Example 49 20 (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 stirred for 2 25 hours before it was quenched by the addition of HOAc (0.11 mL, 2.0 mmol). The reaction mixture was taken up in EtOAc/CH 2 Cl 2 (8/2), washed with diluted HCI (0.1 M), water and brine, then dried (MgSO 4 ). The solvent was removed under reduced pressure. The crude product was purified using silica gel flash column chromatography eluting with hexane/CH 2 Cl 2 /EtOAc (v/v/v = 7/3/2) to give Compound 30 49 (0.25 g, 80%). Electrospray MS [M+1]* 313.1.

133 Using the method set forth above and substituting the appropriate reagents and intermediates, compounds 791-795 were prepared: Compound Electrospray No. Structure LCMS [M+1]+ N N O,O 791 411.2 ON 792 0411.2 793 0437.2 N OYO 794 0 437.2 O NH 795 291.2 5 PREPARATIVE EXAMPLE 50 H N Example 50 F 10 Example 50 was prepared by a procedure similar to that used to prepare Example 29, using Compound 27a and the appropriate corresponding bromide. Electrospray MS [M+1] J345.1.

134 PREPARATIVE EXAMPLE 52 0 0 NyOJZIJ O NH 0 Example 52 5 Example 52 was prepared by a procedure similar to that used to prepare Example 49, using Example 10 and (S)-phenethanol. Electrospray MS [M+1] 313.1. PREPARATIVE EXAMPLE 53 MOM 0 0 1NO NN 0 CF, Example 53 10 Example 53 prepared by a procedure similar to that used in Step A of the preparation of Example 29, using Compound 27a and the appropriate corresponding bromide. Electrospray MS [M+1]* 439.1. PREPARATIVE EXAMPLE 54 15 00 ON'OMe Ph 0 Example 54 Step A: H 00 0N 0 0 H O N APh + NH2OMe.HCI NaOAc, EtOH O Ph 0 0 20 Example 29 Example 54 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 stirred at 60*C 25 overnight. After being cooled to room temperature, the solvent was removed under reduced pressure, diluted with CH 2

CI

2 (5 mL) and water (5 mL). The product was extracted from CH 2

CI

2 (2 x 5 mL), dried over MgSO 4 , concentrated. The crude product was dissolved in minimum CH 2 C1 2 , diluted with hexanes and filtered to give Example 54. Electrospray MS [M+1 ]* 356.1.

135 PREPARATIVE EXAMPLE 55 0O 0 0 N o "N OPMB Example 55 Step A: 0 NH. + 5- 0 THF 0 N=N + PMBOH + PPh -H O . SN 0 0 OPMB 5 Compound 10b) Compound 55a Di-t-butyl diazodicarboxylate (2.32 g, 10.08 mmol) was added to a solution of Compound 1Ob (2.0 g, 8.4 mmol), 4-methoxybenzyl alcohol (1.39 g, 10.08 mmol) and PPh 3 (2.64 g, 10.08 mmol) in THF (20.0 mL) at room temperature. The resulting 10 reaction mixture was stirred for 4 hours before it was worked up by direct silica gel flash column chromatography using a solid sample loading method, eluting with hexane/CH 2

CI

2 /EtOAc (v/v/v = 9/1/1) to give Compound 55a (1.6 g, 53%). Step B: 0 00N SN C 0 r% I CH 2

CI

2 N + m-CPBA 'N OPMB OPMB Compound 55a Example 55 15 m-CPBA (0.47 g, 1.92 mmol, 60-70%)was added at room temperature to a solution of Compound 55a (0.287 g, 0.80 mmol) in CH 2

CI

2 (8 mL). The reaction mixture was stirred for 5 hours before it was quenched by the addition of Me 2 S (124 pL, 1.92 mmol). The mixture was then diluted with EtOAc and washed with NaHCO 3 20 solution. The organic phase was washed with water, brine, and dried (Na 2

SO

4 ). Solvent was removed under reduced pressure, crude product was purified with silica gel flash column chromatography eluting with hexane/CH 2

CI

2 /EtOAc (v/v/v = 7/3/2) to give Example 55 (0.15 g, 80%). Electrospray MS [M+1]* 391.1. 25 PREPARATIVE EXAMPLE 56 H 0 0 "NYN N NH 0 Example 56 Step A: 136 NSOMe0H0 N NH + H 2 N NCH,C NH" Example 10 Example 56 Cyclobutylamine (0.14 g, 2 mmol) was added to a suspension of Example 10 5 (0.25 g, 1 mmol) in CH 3 CN (15 mL). The reaction mixture was stirred at room temperature for 16 hours. Solvent was removed and the crude product was purified using silica gel flash column chromatography eluting with 10% NH 4 OH in MeOH/CH 2 Cl 2 (v/v = 3:97) to give Example 56 (0.045 g, 17%). Electrospray MS [M+1]* 262.1 10 PREPARATIVE EXAMPLE 57 MOM 0 0 NOY0 N N OH 0 Example 57 15 Step A: COMeO N O Br NaH N0 0 DMF N O O O 0 Compound 27a Compound 57a A mixture of Compound 27a (2 g, 7.9 mmol) in DMF (100 mL), t-butyl bromoacetate (1.7 g, 8.7 mmol), and diisopropyl ethyl amine (1.1 g, 8.7 mmol) was 20 stirred at 40 0 C for 4 hours, then at room temperature for 16 hours. The reaction mixture was mixed with water (200 mL), and then extracted with ethyl acetate (100 mL x 3). The organic solution was dried (Na 2

SO

4 ) and concentrated. The crude product was purified using silica gel flash column chromatography eluting with MeOH/CH 2

CI

2 (v/v = 2:98) to give Compound 57a (1.8 g, 62%). Electrospray MS [M+1 ]* 367.2. 25 Step B: MeO MeO O0 N 0 0 TFA 0 0 N 0 0 N,,)I.. N_. OH O 0 Compound 57a Example 57 137 A mixture of Compound 57a (0.95g, 2.6 mmol) in CH 2

CI

2 (5 mL) and trifluoroacetic acid (1.5g, 13 mmol) was stirred at room temperature for 4 hours. Removal of solvent and excess trifluoroacetic acid gave Example 57 (0.8g, 100%). 5 Electrospray MS [M+1 ]*311.2 PREPARATIVE EXAMPLE 58 H 00NO NI Example 58 10 Step A: 00H O o 140-145 C N O O0+ 1 N + sulfamic acid 5- N + 0"N Example 58 To a mixture of mono-cyclobutylbarbituric acid (300 mg, 1.6 mmol) and 2 15 Methyl-3-oxo-pentanoic acid ethyl ester (1.041g, 6.59 mmol) was added sulfamic acid (77 mg, 0.8 mmol). The mixture was heated at 140-145*C for 48h. The residue was loaded onto preparative silica gel plates and eluted with 5% MeOH/CH 2 0 2 to afford Example 58 (42 mg, 9%). LCMS: M+1: 277.1 20 PREPARATIVE EXAMPLE 59 H 0 0 1NO OCN Example 59 EXAMPLE 59 was prepared using a two step procedure similar to that used for 25 the preparation of Example 29, using Compound 27a and the appropriate corresponding bromide. Electrospray MS [M+1]* 252.1. PREPARATIVE EXAMPLE 60 138 H O, N YO0O0OH 0 0 N Compound 6 Step A: NO0 Me OTNHO Br NaH N{O O 0NH e DMF N_ CompouCompound 6 5 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 00C 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 10 water (5 mL). The aqueous phase was extracted with EtOAc (2 x 5 mL). The organic layers were combined, dried over MgSO 4 , 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. Step B: 15 O NyO 0 OMe D.-7800 0 NO O0OH O N + Mra O N 0 Compound Oa Compound 60 Boron tribromide (1.3 mL, 1.31 mmol, 1.0 M solution in DCM) was added to a solution of Compound 60a (0.105 g, 0.262 mmol) in CH 2 Cl 2 (5.0 mL) at -78*C. The 20 reaction mixture was allowed to stir for 2 h before being quenched with water (5.0 mL). The reaction mixture was extracted with EtOAc (2 x 5 mL). The organic layers were combined, dried over MgSO 4 , 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 60. Electrospray MS [M+1]* 343.1.

139 PREPARATIVE EXAMPLE 65 H N Example 65 Step A: 5 0 N,,OBn Yn O NH n+ Br A + K2CO+DM O N Compound 12 Compound 65

K

2

CO

3 (64.7 mg, 0.47 mmol) was added to a mixture of Example 12 (70 mg, 0.235 mmol) and cyclopropyl methyl bromide (0.068 mL, 0.705 mmol) in DMF (2.0 10 mL) at room temperature. The reaction mixture was stirred overnight before it was diluted by the addition of EtOAc (50 mL) and water (10 mL). The organic phase was washed with water (3x15 mL), brine (15 mL), and dried over MgSO 4 . After filtration and concentration, the crude product was purified using preparative TLC with hexane/CH 2

CI

2 /EtOAc (v/v/v = 7/3/1) as eluent to give Compound 65a (26 mg, 31%). 15 Step B: H 0 N OBn 0P0 N 0 N H/PdCN Compound 65a Example 65 Compound 65a (26 mg, 0.074 mmol) in EtOH (5.0 mL) was treated at room 20 temperature with Pd/C (7.8 mg, 10 wt%) and was hydrogenated with a H 2 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 hexane/CH 2

CI

2 /MeOH (v/v/v = 3/7/1) as eluent to give Example 65 (6 mg, 30%). 25 Electrospray MS [M+1]* 263.1. Using the method set forth above and substituting the appropriate reagents and intermediates, compounds 786-790 were prepared: 140 Compound Electrospray No. Structure LCMS [M+1]+ H 00 NO N 786 0 291.2 H 00 N O N 787 0 295.2 0 0 0 OO O 788 269.1 F H 723N I N 789 0295.2 F H 790 283.2 0 PREPARATIVE EXAMPLE 68 H 00 1NO: N'-A OO Example 68 Step A: 5 0 0 N ~ 0 CHC 2 0 0 NO0 O OH)+ + HATU + NEt, CH2CN Example 57 Compound 68a The mixture of Example 57 (0.1g, 0.32 mmol) in CH 2

CI

2 (5 mL), piperidine (0.027 g, 0.32 mmol), HATU (0.24g, 0.64 mmol), and triethylamine (0,098 g, 0.96 10 mmol) was stirred at room temperature for 2 hours. The reaction mixture was mixed with water (20 mL), and then extracted with CH 2

CI

2 (10 mL x 2). The organic solution was dried (Na 2

SO

4 ) and concentrated. The crude product was purified using silica gel 141 flash column chromatography eluting with EtOAc/hexanes (v/v = 1:1) to give Compound 68a (0.065 g, 54%). Electrospray MS [M+11* 378.2. Step B: MOM 00 0 0 N 0H O 0N + BBr DCM, .- 78 *C 0 5 Compound 68a Example 68 1M BBr 3 solution in CH 2 Cl 2 (0.75 mL, 0.75 mmol) was added to a solution of Compound 68a (0.056 g, 0.15 mmol) at -78*C. After the reaction mixture was stirred at -78 0 C for 2 hours, water (5 mL) was added. The organic solution was dried 10 (Na 2

SO

4 ) and concentrated. The crude product was purified using silica gel flash column chromatography eluting with 10% NH 4 0H in MeOH/CH 2

C

2 (v/v = 3:97) to give Example 68 (0.01 g, 20%). Electrospray MS [M+1]* 334.2. PREPARATIVE EXAMPLE 80 H 00 Sr 15 Example 80 Step A: MOMMO 00NO000 N0 NNOSCHCI,.70 *C N NZ + NBS NA 0 Br 0 Compound 27b Compound 80a Compound 27a (0.1 g, 0.33 mmol) was taken up in CH 2 Cl 2 at room 20 temperature. NBS was then added and the reaction was stirred for 4 hours. After no progress in the reaction was observed, a mixture of NBS (0.061 g, 0.34 mmol) in chloroform (4 mL) was added. The reaction mixture was heated for 12 hrs at 70 0 C. Both the TLC (30/70 EtOAc/ Hexane) and mass spectrogram indicated that the reaction was complete. The reaction mixture was cooled to room temperature and 25 diluted with CH 2 Cl 2 and washed with H 2 0. The organic phase was dried with Na 2

SO

4 and solvent was removed to give the crude product. Preparative silica gel chromatography purification in EtOAc/Hexane (v/v = 30/70) yielded Compound 80a (0.075 g, 60 %). Step B: 30 142 0 0 NO00 0 N0 BBr 3 DCM,- 78 *C Br.

0

B

0 Compound 80a Example 80 Compound 80a (0.070g, 0.18 mmol) was taken up in CH 2

CI

2 and the mixture was cooled to -78*C. 1 M BBr 3 (0.909 mL, 0.9 mmol) was added. The reaction mixture 5 was stirred for 4 hours. Upon completion of the reaction, the mixture was diluted with

CH

2

C

2 , washed with H 2 0, dried with Na 2

SO

4 , and then solvent was removed to give crude product. The crude product was purified by preparative silica gel chromatography using 30/70 EtOAc/ Hexane, to give Example 80. Electrospray MS [M+1]* 341.2. 10 PREPARATIVE EXAMPLE 81 N Cl Example 81 Step A: 0 0 N Cl Y ~0 0 NyO O N + HO, N + DIEA -N C1 51Cl Example 5 Example 81 15 To a mixture of Example 5 (84 mg, 0.34 mmol) and 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 mixture was concentrated and was subjected to silica gel column chromatography to give Example 81 (30 mg, 31%). LCMS: M+1: 282.1 20 PREPARATIVE EXAMPLE 92 0 00N -. NH 0 Example 92 Step A: O B MgB THF OPMBp Com B 25 Example 55 Compound 92a 143 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 00C. The mixture was stirred at 00C for 2 hours before it was quenched with HCI (0.2 M). The mixture was taken up in EtOAc and washed with water and brine. The organic 5 phase was dried over MgSO 4 . Solvent was removed under reduced pressure and the crude product was purified with silica gel flash column chromatography eluting with hexane/CH 2

C

2 /EtOAc (v/v/v = 4/1/1) to give Compound 92a (59 mg, 49%). Step B: 0 0 NF4 0 N N THF/H 2 OI N + OsO 4 + NalO4,N OPMB OPMB 10 Compound 92 Compound 92b NalO 4 (70.1 mg, 0.328 mmol) was added to a solution of Compound 92a (46.2 mg, 0.131 mmol) and Os04 (22.2 pL, 4 wt% in water) in THF (5.0 mL) and water (5.0 mL) at room temperature. The reaction mixture was stirred overnight before it was 15 quenched by the addition of Me 2 S (20 pL, 0.328 mmol). The mixture was diluted with EtOAc and washed with HCI (0.5 M), water and brine, The organic phase was dried over MgSO 4 . Solvent was removed under reduced pressure and the crude product was purified by silica gel flash column chromatography eluting with hexane/CH 2 Cl 2 /EtOAc (v/v/v = 2/1/1) to give Compound 92b (39 mg, 84%). 20 Step C: 0 0 00 ) N 0 ON CH 3

CN/H

2 0 0 ,N +CAN NH OPMB 0 Compound 92b Example 92 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 25 temperature. The reaction mixture was stirred for 2 hours before it was diluted with EtOAc. The organic phase was washed with HCI (0.5 M), water, brine and dried over MgSO 4 . Solvent was removed under reduced pressure and crude product was purified using preparative TLC with hexane/CH 2 Cl 2 /MeOH (v/v/v = 2/8/1) as eluent to give Example 92 (8 mg, 58%).Electrospray MS [M+1]* 235.1.

144 Examples 82-91 were prepared by procedures similar to those used for the preparation of Example 49, using Example 10 and the appropriate corresponding alcohols. PREPARATIVE Electrospray PREPARATIVE Electrospray EXAMPLE LCMS [M+1 ]* EXAMPLE LCMS [M+1]* 389.1 1327.1 NH N NH O 0 Example 82 Example 83 341.1 341.1 NH' NH O 0 Example 84 Example 85 "' Y, 391.1 00 Ny 0, 264.1 11NO -NH N NHO 0 0 Example 87 Example86 ___________ 339.1 F-349.1 NH NH F 0. 0 Example 88 Example 89 1 331.1 0 1341.1 O N 0Ny NH F N NH o 0 Example 90 Example 91 5 PREPARATIVE EXAMPLE 92 H 0 0 1NOY N N H HO0 Example 92 H H 00 N 0 0 NO0 S0 2 OH NH N NH 0 HO Example 2 Example 92 Example 2 (0.71 g, 3.66 mmol, 1 eq) and SeQ 2 (0.46 g, 1.1 eq) were mixed 10 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 145 it onto a reverse-phase HPLC column to afford the desired product Example 92 (7.4 mg) as a white solid. 'H NMR (CD 3 OD): 8 4.80 (s, 2 H) 6.20 (s, 1 H) Mass of C 8

H

7

N

2 0 5 (MH)*: 211. Found: 211. 5 PREPARATIVE EXAMPLE 93 HN 0 N NH 0 Example 93 Step A: H H 0 0 NO 0eo, 0 1NOt O O~ Se0 2 0 CHO 0 Example 2 Compound 93a Compound 93a was prepared by a procedure similar to that used to prepare 10 alcohol Example 92, except that the alcohol was allowed to oxidize further to the corresponding aldehyde. After purification several times using reverse-phase HPLC, Compound 93a (90 mg) was obtained. Mass of C 8

H

5

N

2 0 5 (MH)*: 209. Found: 209. Step B: 15 H H 00 NO 00 CHOO HN 0 Compound 93a Example 93 Compound 93b (90 mg, 0.43 mmol, 1 eq)) was mixed with 3-methoxyaniline (109 mg, 2 equiv.) and sodium triacetoxyborohydride (185 mg, 2 equiv.) in 2 mL of THF. After stirring overnight, the reaction mixture was quenched with methanol. 20 Preparative TLC afforded 15.3 mg of the desired product Example 93. 'H NMR (CD 3 OD): 8 3.60 (s, 3 H) 4.60 (s, 2 H) 5.75 (s, 1 H) 6.20 (m, 3 H) 6.95 (m, 1 H) Mass of C1 5

H

4

N

3 0 5 (MH)*: 316. Found: 316. PREPARATIVE EXAMPLE 94 146 H 0 0 N 0 'NH Example 94 H H 0 0 N O 0 0 H N NH SeO 2 NNH Example 1 Example 94 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. 5 'H NMR (CD 3 0D): 8 1.38 (d, 2 H, J = 6.8 Hz) 5.50 (q, 1 H, J = 6.8 Hz) 6.20 (s, 1 H) Mass of C 9 HqN 2 0 5 (MH)*: 225. Found: 225. PREPARATIVE EXAMPLE 95 0O0 N O-' O~ NH 0 Example 95 0 00N O ONO NH NH 0 0 Example 10 Example 95 10 2-butyn-1 -ol (140 mg, 2 mmol, 2 equiv.) in 4 mL of THF was treated with 1.6 M n-BuLi (1.2 mL, 2 equiv.) at 0*C for 5 min to provide an alkoxide solution. Example 10 (0.25 g, 1 mmol, 1 equiv.) was then added to the alkoxide solution. After stirring 1.5 hr, 0.12 g of acetic acid (2 equiv.) was added to the solution. The solvent was removed and extraction with diethyl ether and water provided a white solid. The solid 15 was washed with cold diethyl ether and dried under vacuum. 80 mg of the desired product Example 95 was obtained. 1 H NMR (CDC13): 5 1.20 (t, 2 H, J = 6.8 Hz) 1.83 (s, 3 H) 3.00 (q, 2 H, J = 6.98 Hz) 5.00 (s, 2 H) 6.00 (s, 1 H) Mass of C 13

H

1 3

N

2 0 4 (MH)*: 261. Found: 261.

147 PREPARATIVE EXAMPLE 96 0 NO + CHCOCH T NH reftuNH 100 Example 96 Barbituric acid (1.0 g, 7.81 mmol) was taken up in excess acetone. 5 Triethylamine (2 mL) was added, and the reaction mixture was refluxed overnight after which it was cooled and filtered. The crude solid was purified by preparative TLC (8:1:1/EtOAc:DCM:MeOH) to yield the desired product, Example 96. Electrospray MS [M+1]* for Example 96 is 209.0 PREPARATIVE EXAMPLES 97 and 98 H H 0 0 N 0 00,,N/ 0 NNH 3100 10 Example 97 Example 98 Examples 97 and 98 were prepared by methods analogous to the method used to prepare Example 1, except that 2-oxo-cyclohexanecarboxylic acid methyl ester and 2-oxo-cyclopentanecarboxylic acid methyl ester, respectively, were used instead of methylpropionylacetate. 15 Electrospray MS [M+1 ]* for 96 and 97 are 235.1. PREPARATIVE EXAMPLE 99 Bn I H O N NO, 1 N H 510 Example 99 0 H 0 0\/ 0 0H NH HCI Na 2 CO, ' -Et NH 2

NH

4 C Na 2 CO EtO - NH 2 0 NH t HO EtOt EOEt OEt OEt NH 2 0 Compound 99a Compound 99b Compound 99c Compound 99d Commercially available (Aldrich) Compound 99a (75 g, 383 mmol) was stirred 20 with cold aqueous Na 2

CO

3 (15%, 450 mL) for 2 h. Extraction with EtOAc and drying over Na 2

CO

3 provided Compound 99b as a colorless oil, which was immediately 148 treated with NH 4 CI (19.5 g, 364 mmol) in 200 mL of dry EtOH at 500C for 60 h. The crude product mixture was cooled and the solvent was removed. The resulting light yellow solid was treated with cold K 2 C0 3 (30 %, 300 mL H 2 0) for 0.5 h. Extraction with EtOAc gave Compound 99c as a light yellow solid (37.92 g). This solid was 5 reacted with methyl propionylacetate (38.0 g, 292 mmol), 2 mL pyridine, in 400 mL of dry EtOH at 1 00*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 obtained (22% yield from Compound 99a). 1 H NMR (CDCI 3 ): 5 1.20 (t, 3 H, J = 7.3 Hz) 1.40 (t, 3 H, J = 7.1 Hz) 2.90 (q, 2 H,J= 10 7.3 Hz) 4.30 (q, 2 H, J = 7.1 Hz) 5.75 (s, 1 H) Mass of C 1 0

H

15

N

2 0 3 (MH)*: 211. Found: 211. Bn Bn H I I H O N NH 2 0N NHON N Bn~r EtN NH 3 ~ O O OEt O 2 HOEt Coc NNtBuOK 0 00 Compound 99d Compound 99e Example 99 Compound 99d (3.0 g, 14.28 mmol) was treated with BnBr (2.44 g, 1 eq) and K2CO3(3.94 g, 2 eq) in 100 mL acetone at 70*C for 17 h. The solvent was removed 15 and chromatographic purification (5% EtOAc in hexane) provided 2.53 g pure Compound 99e in 58% yield. Compound 99e (0.3 g, 1 mmol) was treated with Et 3 N (0.22 g, 2.2 eq), COC12 (1.9 M in toluene, 0.53 mL, 1 equiv) in 5 mL DCM at -78*C for 45 min. The reaction mixture was warmed to room temperature in 1 h. NH 3 (0.5 M in 1,4-dioxane, 2 mL, 1 20 eq) was added and the reaction mixture was stirred overnight. The solvent was then removed, 3 mL anhydrous THF was added along with t-BuOK (1 M in THF, 1 mL, 1 equiv), and the mixture was stirred overnight. The solvent was removed, hexane and a small amount of MeOH were added and the resulting white solid was collected. The solid was further washed with anhydrous diethyl ether to give 3.8 mg of Example 99 25 as a white solid. 'H NMR (CDCI 3 ): 8 1.20 (t, 3 H, J = 7.3 Hz) 3.10 (q, 2 H, J = 7.3 Hz) 5.40 (s, 2 H) 6.40 (s, 1 H) 7.20-7.40 (m, 4 H) 8.30 (m, 2 H) Mass of C1 6

H

16

N

3 0 3 (MH)*: 298. Found: 298.

149 PREPARATIVE EXAMPLE 100 Me I H O N INOY 510 Example 100 Example 100 was prepared following procedures similar to those used to prepare Example 99, except that methyl iodide was used instead of BnBr, and 5 cyclopropylmethylamine was used instead of ammonia. 'H NMR (CDC1 3 ): 8 0.40 (m, 4 H) 1.18-1.25 (m, 4 H) 3.10 (q, 2 H, J = 7.2 Hz) (3.82 (d, 2 H, J = 7.4 Hz) 3.90 (s, 3 H) 6.38 (s, 1 H) 8.10 (br s, 1 H) Mass of C1 4

H

18

N

3 0 3 (MH)*: 276. Found: 276. PREPARATIVE EXAMPLE 101 H H O 0P 10 Example 101 Bn H H H 0, N N 0___ N N 0 YO O '~ N N Compound 101a Example 101 Intermediate Compound 101a was prepared using procedures similar to those used to prepare Example 99, except that cyclobutylamine was used instead of ammonia. 15 'H NMR (CDCl 3 ): S 1.20 (t, 2 H, J = 7.3 Hz) 1.60-1.80 (m, 2 H) 2.10 (m, 2 H) 3.00 (m, 2 H) 3.10 (q, 2 H, J = 7.3 Hz) 5.30 (m, 1 H) 5.40 (s, 2 H) 6.40 (s, 1 H) 7.20-7.40 (m, 5 H) 8.20 (br s, 1 H) Mass of C 20

H

22

N

3 0 3 (MH)*: 352. Found: 352. Compound 101a (70 mg) was treated with 3% Pd/C (50 mg), 10 mL MeOH 20 under a hydrogen atmosphere (hydrogen balloon) overnight. After filtration, prep HPLC purification provided 1.2 mg of Example 101. 'H NMR (CDCl 3 ): 5 1.20 (t, 2 H, J = 7.3 Hz) 1.60-1.80 (m, 2 H) 2.10 (m, 2 H) 2.95 (m, 2 H) 3.20 (q, 2 H, J = 7.3 Hz) 5.30 (m, 1 H) 6.40 (s, 1 H) 8.00 (br s, 1 H). Mass of C 1 4

H

7

N

3 0 3 (MH)*: 276. Found: 276.

150 PREPARATIVE EXAMPLE 102 0 N O NH 0 Example 102 H H a00 NO ON 0 00 acetic acid ONH NH ~ Me N NH reflux 16 h 0 0 Example 102 In a 25 mL round bottomed flask equipped with a magnetic stirring bar and a 5 nitrogen balloon was placed 1.0 g of barbituric acid (7.8 mmol) and 1.52 mL of 3 oxoheptanoic acid methyl ester (9.6 mmol, 1.23 equiv.). 8 mL of acetic acid was added to the reaction mixture and was refluxed for 16 h after which the reaction was cooled to room temperature. The excess acetic acid was concentrated and dried in vacuo to give crude product Example 102 along with unreacted starting materials. 10 The crude product was stirred with 20 mL of boiling water for a few minutes and filtered. The precipitate was washed with boiling water (2 x 10 mL) and dried to yield 0.65 g (35% yield) of Example 102. 1 H NMR (DMSO): 8 0.9 (t, 3 H, J = 7.5 Hz) 1.32-1.40 (m, 2 H) 1.45-1.51 (m, 2 H) 15 2.84-2.87 (t, 2 H, J = 7.5 Hz) 5.82 (s, 1 H) 11.34 (s, 1 H) 12.72 (br s, 1 H) Mass of C 1 H1 2

N

2 0 4 (MH)*: 236.22. Found: 237.1. EXAMPLES 103-135 H H H H H 0 0 N. 00 0N 0 0 Oi O0 0 N 000 N 00O N 000 YONHO O NHY NH NH NH 0NH NH0NH O O0O ;00 F F Example 103 Example 104 Example 105 Example 106 Example 107 Example 108 Example 109 HH H H 0 0 N 0 H 0 0 N00 NO N 00 e00 0 O N 0 NHN NNH O NO N NH H ON ONH NHNH NH 0N0 F 0 F F FI Example 110 Example 111 Example 112 Example 113 Example 114 Example 115 Example 116 151 H H H NH 00N0 0 0 NO H HN 0 0 NHNH N 0NfO H NHH N NH N NH NH S NH 0 0 0 NH 0 NH 00 Example 117 Example 118 Example 119 Example 120 Example 121 Example 122 Example 123 OH H 00NN0 0 0O N|O H HO O 0 N NH NHNHNH N 1 0 O H0 F ~ N 0 0 N NH HNH N0 %,N '1 NHN 0 0N NH 0 NH 0F 0 00 S Example 124 Example 125 Example 126 Example 127 Example 128 Example 129 Example 130 HH H 0 0 N 0 00.PIN 0 0 0 NOH0 NH 0 0 NO0 0 ~~~H NNH N 0 0 N NH F F S Example 131 Example 132 Example 133 Example 134 Example 135 Examples 103-135 where prepared using procedures similar to those used to 5 prepare Example 102, except that an appropriately substituted keto-ester was used instead of 3-oxoheptanoic acid methyl ester. The examples 200, 210, 241, 242, 245, 246, 252-260, 274-278, 280, 281, 282, 284, 285, 291 were prepared by a procedure similar to that used for the preparation of Example 30 and 31. 10 The examples 201, 202, 204-209, 211-218, 224-240, 243, 244, 247-251,261 273, 279, 283, 286-290, 293, 294-297 were prepared by a procedure similar to that used for the preparation of example 102, using barbituric acid and the corresponding keto ester. The preparation of ketoesters starting material where appropriate is shown 15 below. The preparation of keto ester starting material for examples 247 is as follows 152 Preparative example 247a 00 OEt 247a 0 CDI, MgCl 2 0 0 O H O0 OOE t EtO)AOK 247a 5 4-Methylhexanoic acid (3.0 g, 23.08 mmol) was taken in 40 mL THF. 1,1' Carbonyldiimidazole (4.49 g, 27.69 mmol) was added and the reaction was stirred at room temperature for 1 h after which MgC1 2 (2.2 g, 23.08 mmol) and ethyl potassium malonate (5.89 g, 34.62 mmol) was added. The reaction was allowed to run at room temperature overnight. The crude reaction mixture was filtered through a short pad of 10 silica gel and eluted with EtOAc/hexanes (1:3) to yield compound 247a. Preparative example 223a 0 0 F F 223a The starting material for the preparation of example 223 is as follows. 0

CO

2 Et + (Et)2-P-CH 2

CO

2 Et NaHMDS,THF 0 0 223b 15 Step A: A solution of triethyl phosphonate (44.8g, 200 mmol) in THF (30 ml) at 00*C was treated with a 1 M solution (200 ml) of sodium bis(trimethylsilylamide) in THF. The resulting mixture was stirred at room temperature for 0.5 hour, and then cooled to 0 *C. A solution of 1,4-cyclohexanedione mono ethylene ketal (15.6g, 200 mmol) in THF (50 ml) was added dropwise, and the resulting solution was stirred at room 20 temperature for 18 hours. The reaction mixture was then cooled to 0O0C, treated with cold aqueous citric acid, and the mixture was extracted with EtOAc. The extract was washed with satd. aqueous NaHCO 3 , brine, dried over Na 2

SO

4 , filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with a gradient of CH 2 Cl 2 /EtOAc to afford 223b (21g, 91%).

153

CO

2 Et CO 2 Et Pd/C, EtOH 223b 223c Step B: The compound 223b (20g) was dissolved in EtOH (150 ml) and treated with 10% Pd/C under 1 atm of hydrogen for 3 days. The mixture was filtered and the filtrate was evaporated to 223c (20.3g, 100%). COEt COEt Formic acid 700*C 0 5 223c 223d Step C: The compound 223c (7g) was dissolved in formic acid (50 ml) and heated at 70 0C for 1 h. The solution was concentrated and the residue was taken up in EtOAc and washed with satd. aqueous NaHCO 3 , brine, dried over Na 2

SO

4 and concentrated. The residue was chromatographed on silica gel to afford 223d (5g).

CO

2 Et

CO

2 Et DAST, CH 2

CI

2 0 F F 10 223d 223e Step D: The compound 223d (4.6 g) was dissolved in CH2C2 (10 ml) and treated with diethylaminosulfur trifluoride (DAST, 5 ml) at room temperature for 3 hours. The reaction mixture was poured into ice/water (30 ml) and extracted with CH 2 C1 2 . The extract was washed with satd. aqueous NaHCO 3 , brine, dried over Na 2

SO

4 and 15 concentrated to afford 223e as brown oil (3.2 g, 62%).

CO

2 Et CO2H 6 LiOH, MeOH 6 223e 223f Step E: The compound 223e (3.2 g, 15.5 mmol) was dissolved in MeOH (5 ml) and treated with LiOH (559 mg, 23.3 mmol) overnight. The reaction mixture was acidified by 3 N HCI to pH 4 and extracted with CH 2

C

2 . The extract was dried over Na 2

SO

4 and 20 concentrated to afford 223f as brown oil (3 g, 100%).

CO

2 H 0 0 3 0KOMgCI 2 , CDI + K23O THF 223f F F 223a 154 Step F: The compound 223f (900 mg, 5.0 mmol) was dissolved in THF (15 ml), added with CDI (972 mg, 6.0 mmol) and stirred for 45 min. Then methyl malonate potassium salt (1.02 g, 6.0 mmol) and MgCI 2 (570 mg, 6.0 mmol) were added into the above 5 solution. The resulting mixture was stirred overnight and filtered through a short pad of silica gel and washed with EtOAc. The filtrate was concentrated and chromatographed on silica gel to afford 223a as colorless oil (400 mg, 34%). The starting materials for structures 262, 263 were prepared in a manner similar to 218a. 10 Preparative example 262a OEt 262a OH CDI. MgCI 2 O 0 >)- - OH ~ ~ ~ 0 O EtOA OK 22 262a Prepared in the same manner as in example 218a. Preparative example 263a 00 OEt 15 263a 0 C01, MgCI 2 0 0 OH O0 O0OEt EtO OK 23 263a Prepared in the same manner as in example 218a. Preparative example 266a 00 OMe 266a SBr 0 0 NaH, n-BuU 0 0 Br + OMe THF OMe 20 266a Sodium hydride (1.42 g, 35.56 mmol) was taken in THF (20 mL) in a round bottomed flask equipped with a stirring bar and nitrogen balloon. It was cooled to 0 *C 155 and methyl acetoacetate (3.84 mL, 35.56 mmol) dissolved in 10 mL THF was added dropwise. The reaction mixture was stirred at 00*C for 30 min after which n-BuLi (2.5 M solution in hexanes, 14.2 mL, 35.56 mmol) was added dropwise. The reaction was allowed to run for 30 min at 00*C and then cooled to - 25 *C. Bromomethylcyclobutane 5 (4.82 g, 32.32 mmol) dissolved in 20 mL THF was added dropwise and the reaction was stirred at - 25 0C for 4 h followed by room temperature overnight. It was quenched with the addition of sat. NH 4 CI, extracted with EtOAc (2 x 30 mL), dried over MgSO 4 , concentrated in vacuo. The crude product was purified by biotage (5% EtOAc/hexanes) to yield compound 266a. 10 Preparative example 267a O Et 267a OH CDI, MgCI 2 QEt 0 00 00 EtO 0OK 267a Prepared in the same manner as in example 218a. Preparative example 268a O 0 15 268a 0 0 One On~0e 268b Trifluoroacetic acid (7.84 mL, 105.48 mmol) and diiodomethane (8.5 mL, 105.48 mmol) in 50 mL DCM was cooled to 0 *C. Diethylzinc (1.0 M solution in hexanes, 105.5 mL, 105.48 mmol) was added dropwise. The reaction was allowed to 20 stir at 00*C for 20 min after which 5-Methyl-5-hexenoic acid methyl ester (5.0 g, 35.16 mmol) in 20 mL DCM was added dropwise. The reaction was allowed to stir at room temperature overnight. The reaction was quenched by the addition of sat. NH 4 CI, extracted with DCM (2 x 30 mL), dried over MgSO 4 , concentrated in vacuo to yield compound 268b which was carried over to the next step without further purification. OMe OH 25 268b 268c 156 Ester 268b (5.0 g, 32 mmol) was taken in MeOH (50 mL) and NaOH (3.2 g, 80 mmol) was added to it. The reaction was allowed to stir at room temperature overnight. The reaction was diluted with water (50 mL) and acidified with conc HCl. It was extracted with Et 2 O ( 2 x 30 mL), washed with brine, dried over MgSO 4 , and 5 concentrated in vacuo. The crude product 268c was used as such without any further purification. 0 0 0 7 OH OEt 268c 268a Prepared in the same manner as in example 262a. Preparative example 269a 00 OMe 10 269a 0 0 NaH, n-BuU 0 0 Br + OMe THF OMe 269a Prepared in the same manner as in example 266a. Preparative example 279a 00 EtO OMe 279a CH(OMe)0 0 O~ MeON, HSO.

4 Mo 0 15 279b 5,5-Dimethyl-dihydro-furan-2-one (5.0 g, 43.8 mmol), trimethyl orthoformate (11.5 mL, 105.12 mmol), and sulfuric acid (0.43 g, 4.38 mmol) were taken in MeOH (50 mL). The reaction mixture was heated to 50 0C overnight. After cooling, the solvent was removed in vacuo, quenched with sat. NaHCO 3 and extracted with EtOAc 20 (2 x 30 mL). The organic layer was washed with brine, dried over MgSO 4 and concentrated in vacuo to yield compound 279b which was used without any further purification.

157 0 0 MeO O e HO O 279b 279c Prepared in the same manner as in example 268c. 0 CDI, MgCl 2 O o HO OMe EtO OMe EtO.K>OK 279c 279a Prepared in the same manner as in example 262a. 5 Preparative example 288a NCY"O1 t 288a )NCN Br OBn LDA NC> OBn THF 288b Lithium diisopropylamide (2.0 M solution in THF/heptane/ethyl benzene, 43.4 mL, 86.82 mmol) was taken in THF (30 mL) and cooled to - 78 *C. Isobutyronitrile (6 10 g, 86.82 mmol) in THF (10 mL) was added dropwise and the reaction was stirred at 78 0C for 1 h and 0 0C for 2 h. Benzyl 4-bromobutyl ether (21.1 g, 86.82 mmol) in THF (10 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched by the addition of saturated NH 4 CI and extracted with Et 2 0. The organic layer was washed with brine, dried over MgSO 4 15 and concentrated in vacuo. The crude compound obtained was purified by biotage (5% EtOAc/hexanes) to yield compound 288b. NCXI O 01n eNCX - OH 288b 288c Compound 288b was taken up in CH 2 Cl 2 (25 mL) in a 100 mL round bottomed flask equipped with a stirring bar and nitrogen balloon and cooled to - 78 *C. Boron 20 trichloride (1.0 M solution in hexanes, 43.2 mL, 43.2 mmol) was added dropwise and the reaction was allowed to gradually warm to 0 OC. After 1 h the reaction was quenched by the addition of sat. NaHCO 3 , extracted with CH 2 Cl 2 . The organic layer was washed with brine, dried over MgSO 4 , and concentrated in vacuo to yield the 158 crude compound which was purified by filtering through a short pad of silica gel eluting with 50% EtOAc/hexanes to yield compound 288c. NC OH NCX< )OH 288c 288d Compound 288c (3.0 g, 21.2 mmol) was taken in acetone (20 mL) and cooled 5 to 0 0C. Jones reagent was added dropwise until there was no change in color to green upon addition of the reagent. The excess reagent was quenched by the addition of i-PrOH, and water (20 mL) extracted with Et 2 0. The organic layer was washed with brine, dried over MgSO 4 , and concentrated in vacuo to yield compound 288d which was used without further purification. 0 ~CDI, MgC12 NCX" OH CI g4 NC OEt 00 10 288d EtO OK 288a Prepared in the same manner as in example 262a. Preparative example 293a 0 0 OEt 2938 O CHO 293b 15 Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 108.9 mL, 108.9 mmol) was taken up in 100 mL THF in a 500 mL round bottomed flask equipped with a stirring bar and nitrogen balloon. The solution was cooled to 0 0C and (methoxymethyl)triphenylphosphonium chloride (37.3 g, 108.9 mmol) was added portionwise and the dark red solution was stirred at 00*C for 45 min. Dicyclopropyl 20 ketone (10 g, 90.78 mmol) in THF (10 mL) was added dropwise and the reaction was stirred at 0 0C for 3 h after which the reaction mixture was poured into hexane. The mixture was filtered through silica gel eluting with hexane. Solvent removal gave the crude enol ether. The crude enol ether was taken up in THF (100 mL) and 10 % HCI (100 mL) was 25 added. The reaction was refluxed overnight. Upon cooling, diluted with water and 159 extracted with Et 2 0 (2 x 50 mL), washed with brine, dried over MgSO 4 , concentrated in vacuo. The crude mixture 293b was used as such without further purification. COEt CHO 293b 293c Sodium hydride (6.44 g, 161 mmol) was taken in THF (30 mL) in a 250 mL 5 round bottomed flask equipped with a magnetic stirring bar and nitrogen balloon. The mixture was cooled to 0 *C. Triethylphosphonoacetate (36.1 g, 161 mmol) in 20 mL THF was added dropwise and the mixture was stirred at room temperature for 1 h after which it was cooled back to 0O0C and compound 293b (10 g, 80.5 mmol) in 20 mL THF was added dropwise and the reaction was allowed to stir at room 10 temperature for 2 h. The reaction was quenched by the addition of water and was extracted with Et20. The organic layer was washed with brine, dried over MgSO 4 , and concentrated in vacuo. The crude was purified by biotage (2% EtOAc/haxanes) to yield compound 293c.

CO

2 Et CO 2 Et 293c 293d 15 Compound 293c was taken up in 100 mL EtOH in a 200 mL round bottomed flask. To the solution was added Pd/C (10 wt%, 7.0 g, 5.7 mmol) and the mixture was hydrogenated using a hydrogen balloon under ambient temperature for 12 h. The mixture was filtered through celite and eluted with EtOH which upon solvent removal gave crude compound 293d.

CO

2 Et CO 2 H 20 293d 293e Prepared in the same manner as in example 268c. C02H CDI,MgCI2 0 0OEt EtOOOK 293e 293a Prepared in the same manner as in example 262a. Preparative example 294a 160 NCO'N'0Et 2948 0 CDI, MgCl2 N 0 00 EtO'A OK29 Prepared in the same manner as in example 288a. Preparative example 295a 0 0 OEt 5 2958 0 CDI, MgCO 2 0 0 OH O OEt EtO0t< OK 295a Prepared in the same manner as in example 262a. Preparative example 292a 0 292a 10 The starting material for the preparation of example 292 is as follows. 0 0 0 0 Cul-prollne O- O Cs 2

CO

3 , DMSO 40'C zN. 292a Into the solution of iodobenzene (10.2 g, 50 mmol) in anhydrous DMSO (150 mL) and 3-oxoenanthic acid methyl ester (15.8 g, 100 mmol) was added copper(l) iodide 15 (1.9 g, 10 mmol), L-proline (2.3g, 20 mmol), and cesium carbonate (65.2g, 200 mmol). After stirred under N 2 at 40 4C for 18 hours, the reaction mixture was dissolved into ethyl acetate (250 mL), washed with water (4 x 150 ml). The organic solution was dried with sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified using silica gel flash column chromatography eluting with ethyl 20 acetate/hexanes (v/v = 5/95) to give compound 292a (4.5 g, 38%). Preparative example 297a 161 00 297a The starting material for the preparation of example 297 is as follows. OH 1. MsCI, CH 2 Cl, EtN 2. Nal, acetone 297b To a solution of 2-cyclopentyl ethanol (11.4 g, 100 mmol), anhydrous CH 2

CI

2 5 (80 mL), and triethyl amine(12 g, 120 mmol), which cooled to 00C, was added via syringe MsCl ( 13.7 g, 120 mmol). After stirring under N 2 at 0 C for 1 hour then at room temperature for 18 hours, the reaction mixture was washed with water (2 x 100 mL), dried with sodium sulfate, and concentrated under reduced pressure to give a clear oil (1 9g, 100%). The oil was dissolved into anhydrous CH 2 Cl 2 (250 mL) and 10 mixed with Nal (20g, 200 mmol). After stirring at room temperature for 18 hours, the reaction mixture was filtered from solid. The resulting filtrate was concentrated under reduced pressure to give a brown paste. The paste was dissolved into diethyl ether (300 mL), washed with water (2 x 150 mL), dried with sodium sulfate, concentrated under reduced pressure to give compound 297b (20g, 89%). o0 + NaH, BuU 15 297b THF 297a To a solution of methyl acetoacetate (5.8 g, 50 mmol) and anhydrous THF (100 mL), which cooled to 0 C, was added NaH (60%, 2.4g, 60 mmol). After stirring under

N

2 at 0 OC for 0.5 hour, n-BuLi (2.5 M in hexanes, 20 mL) was added via syringe. After stirring at 0 OC for 0.5 hour, the reaction mixtures was cooled to -25 C, the compound 20 297b was added via syringe. The reaction mixture was stirred at 0 OC for 0.5 hour, then room temperature for 18 hours. The reaction mixture was quenched with saturated ammonium chloride (200 mL) and extracted with ethyl acetate ( 2 x 200 mL)washed with water (2 x 100 mL). The organic solution was dried with sodium sulfate, and concentrated under reduced pressure to give a brown oil, which purified using silica gel 25 flash column chromatography eluting with ethyl acetate/hexanes (v/v = 7/93) to give compound 297a (3.2 g, 32%). Preparative example 214 162 H 0 0 NO N NH 0 214 HH 0 0 N 0 NIS, DMF 0 N 0 NH1 N NH 214. 214b Compound 214a (10 g, 48.04 mmol) was taken in DMF (50 mL) in a round bottomed flask equipped with a magnetic stirring bar. N-lodosuccinimide (22 g, 97.79 5 mmol) was added portionwise and the reaction mixture was heated to 500C overnight. After cooling to ambient temperature, H 2 0 (100 mL) was added. The product was filtered, washed with water followed by ether to give a white powdery mixture (> 95% yield). The product 214b was used as such for the next step without any further purification. H H 00 0 0 NyO I I NH NH 10 214b 214 Compound 214b (0.1 g, 0.3 mmol) was taken in C 6

H

6 (1 mL) in a 10 mL round bottomed flask. Pd(OAc) 2 (0.004 g, 0.018 mmol), PPh 3 (0.014 g, 0.054 mmol), and Na 2

CO

3 (0.5 mL, 2M solution) was added and the reaction mixture was allowed to stir at room temperature for 30 min. trans-1-Hexen-1 -ylboronic acid (0.042 g, 0.33 mmol) 15 in EtOH (0.5 mL) was added and the reaction mixture was allowed to reflux (80 *C) overnight. After cooling, the mixture was diluted with H 2 0 (2 mL), extracted with EtOAc (2 x 10 mL), dried over MgSO 4 , concentrated and dried to yield the crude compound 214. Purification by preparative TLC (10% MeOH/DCM) to yield compound 214.

163 Preparative example 219 N H Ph0 0 219 H H 0 0 Ny 0 0 N -O I NH NH 51 0 Ph 0 214b 219 Compound 214b (0.1 g, 0.3 mmol) was taken in DMF (3.0 mL) in a 10 mL 5 round bottomed flask. PdCl 2 (PPh 3

)

2 (0.011 g, 0.015 mmol), phenylacetylene (0.061 g, 0.6 mmol), Cut (0.006 g, 0.03 mmol), and triethylamine (0.091 g, 0.9 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (5 mL), neutralized with 1 N HCI, and extracted with EtOAc (2 x 10 mL), dried over MgSO 4 , concentrated and dried to yield 10 crude 219. The crude product was taken in ether and filtered to yield pure compound 219. Preparative example 220 H 0 0 NyO N NH 0 220 Ph H H HO N O O N O O O + OMe NH 0 0 0 0 220a 220b 220c 15 Barbituric acid 220a (1.0 g, 7.81 mmol) and keto ester 220b (1.45 g, 9.4 mmol) was taken in glacial acetic acid (8 mL) and the reaction mixture was heated to reflux overnight. After cooling to room temperature, the acetic acid was removed in vacuo and hot water was added to remove excess barbituric acid. The procedure was repeated a few times until no starting material was left. It was followed by washing 20 with ether. The product 220c was dried and needed no further purification.

164 H H 00 NO 0 0 NO 0 0 220C 220 Ph Compound 220c (0.1 g, 0.431 mmol) was taken in DMF (1 mL) in a 10 mL round bottomed flask. lodobenzene (0.053 g, 0.258 mmol), PdCl 2 (PPh 3

)

2 (0.003 g, 0.0043 mmol), Cul (0.002 g, 0.0086 mmol), and Et 2 NH (0.157 g, 2.15 mmol) was 5 added and the reaction mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc (2 mL), neutralized with 1 N HCI and extracted with EtOAc (2 x 10 mL). It was dried over MgSO 4 , concentrated in vacuo. The crude product was purified by preparative TLC (20 % MeOH/DCM) to yield compound 220. Preparative example 216 H 0 0 NO NH 0 10 EtO 0 216 H NOOO 0 001 NH + EtO OEt _ _NH 0 0 00 216a EtO 0 216 Barbituric acid (1.0 g, 7.81 mmol) and Diethyl #-ketoadipate 216a (2.03 g, 9.4 mmol) was taken in glacial acetic acid (8 mL) and the reaction mixture was heated to reflux overnight. After cooling to room temperature, the acetic acid was removed in 15 vacuo and hot water was added to remove excess barbituric acid. The procedure was repeated a few times until no starting material was left. It was followed by washing with ether. The product 216 was dried and needed no further purification. The starting material for the preparation of example 203 is as follows. Preparative example 203 V1N Ph O N0 0 H 20 203 Step A: 165 1) LHMDS 0 2) PropfnicC02Et anhydride 203a To a solution of ethylphenylacetate (8.2g, 0.05 mol) in THF at -78 0 C was added LHMDS (1M in THF, 100 ml, 0.10 mol) and stirred for 20 min. Propionic anhydride (6.5 ml, 0.05 mol) was added rapidly. The mixture was allowed to warm up 5 to 0 0C and stirred for 30 min. It was quenched with NH 4 CI (aq.) and extracted with EtOAc. Usual work up afforded the crude material which was chromatographed on silica gel to obtain product. Step B: 0 co 2 Et 0 Ph N P hN P O NO sulfamic acid O N 0 0 H H400O H 10 Compound 203 was obtained by normal condensation procedure with cyclobutylbarbituric acid. Preparative example 209 0 0 NH 0 1 209 166 Step A: UOH 0Me-.4OH 0 0 209A 209B Starting material 209a (9.9 g, 75 mmol) was dissolved in THF (100 mL) and water (25 mL). LiOH (3.4 g, 80.9 mmol), the resulting mixture was stirred at room 5 temperature overnight. 1 N HCI (100 mL) was added and extracted with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO 4 ) to give compound 209b (8.8 g, 93%). Step B: 00 MOO I 0O _ P__O__O 0 CDI 209B MgCI, 209C 10 Compound 209c (1.9 g, 16.1 mmol) was dissolved in THF (50 mL), CDI (12.3 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. MgC 2 (1.5 g, 16.1 mmol) and KOCOCH 2

CO

2 Me (3.8 g, 24.2 mmol) were added, the resulting mixture was stirred at room temperature overnight. EtOAc (100 mL), water (50 mL) were added. The aqueous layer was separated and extracted with EtOAc. 15 The aqueous layer was extracted with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO 4 ), filtered and concentrated. The residue was separated by silica gel chromatography, with Biotage 40S+ column, eluted with EtOAc: hexanes, 1:10, to give 2.1 g (74%) yellow liquid as Compound 209d. Step B: H O O OH OO O N O 0 0 0 H0NN MeO O0 + N" HOAc NH 125*C0 209C 0 0 20 Y1 209 Compound 209c (1.13 g, 6.49 mmol) and barbituric acid (0.5 g, 3.90 mmol) was mixed with HOAc (2 mL) in a sealed tube, and heated in an oil bath at 125 0 C overnight. The mixture was cooled to room temperature, HOAc was removed and the residue was taken up in MeOH, and filtered. The volume of the mother liquid was 25 reduced until solid started to come out, the beige solid was collected to give Compound 209 (153 mg, 10%). Electrospray MS [M+1]: 253.1.

167 Compound 208 was prepared in a similar fashion as in Compound 209, from the commercially available Compound 208a. H 0 0H 00 N O NH 0 00 compound 208A compound 208 Preparative example 270 5 Step A: O KOH 0 8Br 270a Starting lactone (10 g, 116 mmol) was mixed with allylbromide (30 mL, 346 mmol), toluene (75 mL), and KOH (19.5 g, 348 mmol). The mixture was heated 110C overnight. The mixture was cooled to room temperature; water (100 mL) was 10 added. The aqueous layer was extracted with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO 4 ), filtered and concentrated to give a yellow liquid as the desired Compound 270a (11.8 g, 55.2%). Step B: 0 H/PdO O 270a 270b 15 Compound 270a (3.0 g, 16.3 mmol) was dissolve in EtOH (20 mL), 10 % Pd/C (300 mg) was added. The slurry was stirred under H 2 overnight. The mixture was filtered through Celite, and the filtrate was concentrated to give a yellow liquid as the desired Compound 270b (2.5 g, 81%). Step C: 0 LIOH 0 Me0 'K 0 0 20 H0C Compound 270b (3.0 g, 16.3 mmol) was dissolve in THF (20 mL)-H 2 0 (7 mL), LiOH (1.66 g, 39.5 mmol) was added. The resulting mixture was stirred at room temperature overnight. 1 N HCI (75 mL) was added, and extracted with Et 2 0. The organic extracts were combined, dried (MgSO 4 ) filtered and concentrated. The 168 residue was dissolved in THF (50 mL), CDI(12.3 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. MgCl2 (1.3 g, 13.6 mmol) and

KOCOCH

2

CO

2 Me (2.9 g, 18.5 mmol) were added, the resulting mixture was stirred at room temperature overnight. EtOAc (100 mL), water (50 mL) were added. The 5 aqueous layer was separated and extracted with EtOAc. The aqueous layer was extracted with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO 4 ), filtered and concentrated. The residue was separated by silica gel chromatography, with Biotage 40S+ column, eluted with EtOAc: hexanes, 1:10, to give 1.5 g (46%) yellow liquid as Compound 270d. 10 Step D: H 0 0 NeO 0 0 O010 0 +M0NHHOAc NH 125*C 0 270d 0 0 270 Compound 270d (448 mg, 2.22 mmol) and barbituric acid (340 mg, 2.65 mmol) was mixed with HOAc (2 mL) in a sealed tube, and heated in an oil bath at 125 0C overnight. The mixture was cooled to room temperature, HOAc was removed and 15 the residue was taken up in MeOH, and filtered. The mother liquid was concentrated and separated by preparative TLC, eluted with 1:10:10, HOAc:DCM:EtOAc, to give desired Compound 270 (72 mg, 11.4%) as a white solid. Electrospray MS [M+1]: 281.2.

169 Preparative example 271 StepA: MsCI BnO,. OH Et3N Bn,9 % OMs 271a Starting alcohol (5.2 g, 28.0 mmol) was dissolved in DCM (100 mL), 5 triethylamine (6 mL, 42.7 mmol) and MsCI (2.6 mL, 33.6 mmol) was added. The resulting solution was stirred at room temperature for 1 h. The mixture was diluted with EtOAc and washed with 1 N HCI (50 mL x 2). The aqueous layers were combined, extracted with EtOAc. The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated to give Compound 271a (7.26 g, 10 100%). Step B: HO NaH 271a 271b Cyclopentanol (3.8 mL, 42 mmol) was dissolved in THF (50 mL) under nitrogen. NaH (0.85 g, 95% oil dispersion, 33.7 mmol) was added. The resulting 15 slurry was stirred at room temperature for 1 h. A solution of mesylate 271 a (7.26 g, 28 mmol) in DMF (30 mL) was added via syringe. The resulting mixture was heated at 85 4C overnight. The mixture was cooled to room temperature, and diluted with EtOAc, and washed with water (50 mL x 3). The aqueous layers were combined and extracted with EtOAc. The organic extracts were combined, washed with brine, dried 20 (MgSO 4 ), filtered and concentrated in vacuo. The residue was purified over silica gel column, eluted with EtOAc-hexanes (1:10) to give 4.95 g (71%) of Compound 271b as an amber liquid. Step B: B n , - O H 2 / P d H O HO 271b 271c 25 Compound 271b (4.95 g, 20 mmol) was dissolved in EtOH (100 mL), 10% Pd/C (0.55 g) was added and stirred under 1 atm of hydrogen balloon overnight. Filtered through Celite, the filtrate was concentrated in vacuo. The residue was 170 purified over silica gel column, eluted with EtOAc-hexanes (1:3) to give 3.1 g (98%) of Compound 271c as a colorless liquid. StepC: CrO 3 0 HO OH 271c 271d 5 Cr0 3 was mixed with 4.7 mL of conc. H 2

SO

4 . The mixture was diluted with water to 36 mL. Compound 271 c was dissolved in acetone (30 mL), and Jones reagent was added. The mixture was stirred at room temperature for 1 h, diluted with water and extracted with DCM. The organic extracts were combined, washed with brine, dried (MgSO 4 ), filtered and concentrated to give 1.99 g (71 %). 10 Step D: 0 O O OH MeO OK' Me 0 O 0 CDI 271d M9C2 271e Compound 271d (2.40 g, 14.0 mmol) dissolved in THF (50 mL), CDI (2.48 g, 15.3 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. MgC 2 (1.5 g, 15.3 mmol) and KOCOCH 2

CO

2 Me (3.3 g, 20.9 mmol) were added, the 15 resulting mixture was stirred at room temperature overnight. EtOAc (100 mL), water (50 mL) were added. The aqueous layer was separated and extracted with EtOAc. The aqueous layer was extracted with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO4), filtered and concentrated. The residue was filtered through a pad of silica gel, eluted with EtOAc: hexanes, 1:3, to give 2.2 g (69%) yellow 20 liquid as Compound 270e. Step D: H 00 N 0 OO0HNNH MeOHOAc NH 125 0 C 271e 0 271 Compound 271e (448 mg, 2.22 mmol) and barbituric acid (340 mg, 2.65 mmol) was mixed with HOAc (2 mL) in a sealed tube, and heated in an oil bath at 25 125 0 C overnight. The mixture was cooled to room temperature, HOAc was removed 171 and the residue was taken up in MeOH, and filtered. The mother liquid was concentrated and separated by preparative TLC, eluted with 1:10:10, HOAc:DCM:EtOAc, to give desired Compound 271 (55 mg, 4%) as a white solid. Electrospray MS [M+1]: 307.2. 5 Compound 273, Compound 287 and Compound 290 are prepared in a similar fashion as Compound 271 from the corresponding alcohols. Preparative example 205 O O O B (OH)a O NH 00H 1 ~0 0 NyO 0 0 N H N N H 0 Pd(dppf) 2

CI

2 0 BrjK F 205a 205 Compound 205a (50 mg, 0.14 mmol) was dissolved in DMF (2 mL) and H 2 0 (2 10 mL), Pd(dppf) 2 Cl 2 and K2CO3 were added. The resulting mixture was heated at 85 0C under nitrogen for 5 h. The mixture was cooled to room temperature and filtered through Celite. The filtrated was concentrated. The residue was dissolved in MeOH, and DCM was added until precipitation persisted. The solid was collected as the desired Compound 205 (21 mg, 40%). Electrospray MS [M+1]: 481.5. 15 Compound 207 was prepared in a similar fashion as Compound 205, using the corresponding boronic acid. Several compounds of the invention are shown in the Table below as well as in the Tables presented later in this specification. The compounds shown in the table below were made using methods described in the preparative examples presented 20 above herein. The LCMS data is also shown wherever available. The activity (EC 50 ) data is also shown, wherever measured and available, and is designated A, B or C, where A = 0.001 nM to 100 nM; B is >100 <1000 nM and C is >1000 nM. Compound STRUCTURE NA EC50 Electrospray No. camp (nM) LCMS [M+1]+ H 200 N B 331.2 172 201N NH C 289.2 0 NHO 202 B 311.2 203N C 339.1 204N NH C 265.1 ONO r NH 205 O B 365.2 0N,, FH 206 NH B 235.1 0 H ON N O 0 207 C 377.2 H 00 NYO 208NH C 316.2 0 H 209 N B 253.1 N0 210 0BN 331.2 0 H 0 Ne0 211 N NH C263.1 0 173 212 NHk~ 1 B 263.1 0e N NH 2130 B 345.2 CF3 H NO 214 NH c 291.2 H O NOe 215 NH c 343.2 0 216N NH B 267.1 0 H 217__ I NHC 247.1 H 218HNB 251.1 0 O NYO 219 NH c 309.2 N 0 H NO 220 NNH c 309.2 NN,, H 221 0 c 378.2 0 H O N,,e 222 0 N~H C281.2 EtO 174 H 0 NH0 223 0 A 313 0 Y FH 224 y NA 317.2 225 NH A 269.1 H 226 NH A 261.1 0 227 H C 249.1 0 H 00 N 228 0 C 372.2 0 Ne~ 229 NH A 391.2 H 230 B 301.2 N 0 2312 C 368.2 (M+Na) 0 H NH 2H 232 0c 368.2 (M+Na) 0 0 N 0 NNH 233 C398 175 H 234 O N O C 426 ON ''NH 0 H O NO 235A NH 275.2 E0 HH ON 0 238 HB 349.2 239 N NH A 267.1 H 240 C 251 H 2418 OB 331.2 243 oB 380 H 1:5 NH 244 C 264 0

-

-~

176 245 NA 305.2 246 ~x ~ C 345.2 H 247 N A 235.2 0 249 FN 35. H N N 248 NH A 293.2 0 H N Ne 253NH C 37.2 0 H 25400 N7,2 N'H 251 0 B38 00 NO 0 254C 3762 0 177 0 O N O 255 N H C 359.2 0 H 00 N 0 N 256 0 C 359.2 00 No 257 NH C 291.2 0 00 NO 258 B 291.2 0 00 NyO 259 NH C 305.2 0 260 N NN.A C 305.2 0 . H 00 NY N 261 0 B 396 0 \ N0 H NH 262 0 A 279.2 0 0 1Ne O NHO 263 NH C 265.1 0 178 H 264 0 C 329.2 O o ____ H 0 0 NO NNH 265 o C 321.2 0 o N O NH 266 0 A 263.1 H 00 Ne0 267 c 265.1 0 H 00 N,O NHo 268 0 A 277.2 271 'NH 0 0 H 00 NO 27 9NHB21.2 0 H 00 NO 271 BH 3078.2 Ku 0 00 N H 272 NHB 23.1 0 0 0 NO NNH 2730 B 293.2 _ _ _ Q N _ _ _ _ 179 N O 274 Nl NH B 303.2 0 O. O N O 275 00 NH B 263.1 0 00 N O 276 N B 263.1 00 N O 277 NHc277.2 0 278 ~N B 277.2 H 020 N0 N 279 C 281.2 0 N 281 BH 3598.2 0 00' 0Ne 280 0 373.2 s 03B21 N 35 . 281 0B35. 0 0 N y0 282 0 3 B 345.2 H 0 0 Ne0 283 NH B 221.1 0 180 0 0 N,e 284 B 333.1 284 0 00 N O N 285 0 B 331.2 H 00 N O NH 286 0 A 277.2 H 0 N O NH 287 0 C 321.2 O 00 0 6 H 0 N O NH 288C900B 315.2 N 289 C 223.1 0 00 N O NH 2900 B 315.2 (M+Na) 291 0 , fC 223.1 292 NHB 313.2 6 0 NH 293 0 B 303.2 181 H 00 N,,0 NH 294 0 B 288.2 N H 0 0 NO 296 NH 295 0 B 263.1 H N N H 2960 B 249.1 0 0 01 297 0 A 291.2 The compounds 500 to 690 were prepared by a procedure similar to that used for the preparation of Example 49, using Example 10, and the appropriate corresponding alcohol. 5 Compounds 691 and 698 were prepared by a procedure similar to Example 49, using appropriate oxyaminocarbamate and sulfoxide which was prepared using Example 10. Compound NA EC50 Electrospray No. Structure camp LCMS [M+1]+ (nM) 0 0N M N, 500 NH B 363.1 501 5 0NH A 363.1 182 0- 0 ONy o N 502 N H B 343 503 0 ONyO: 503N1 HcB 368 O 0N O 0 0 NyOJIIZJ 504 NH B 327 510 505 NH B 327 510 0 00 N :,zr," F 506 FN C 335 N0 NH 0 507N NH c A 363 510 0 0 1NOz, N 508 N 381.1 0F 0 0 NO N 509 N H B 400 051 C3 N YN 510 N NH C393

F

183 511NH N C 358.2 0 0 NYO 512 NH A 275 0 0 0 Nyo 513 NNHB 304 1C40 FF 00 N O ONC 5141 N c435 NH6 F F 0 0 0 1NOY 0 jIJ 515 NH B 363 0 0 0 1NYO NF 516NH F 381 0 0 0 NO 517 , NC 375.2 518N NH FB39. 0 0 0 NO Nr 519 N NH c295.1 0 184 0 0 NO" YO 520NN C 376.2 0 00 0 M0y CIF 521 NH F B 401.2 0 522 0NH B 323 0 00 0NyO NI~ 523 NH A 300.2 0 524 NH B 267.1 0 0 0 Iy0_O 525 N NH B 329.2 0 0 0 0 NO N 526 N H AB 380 0 N N 527 NH B 350 0 0 N8oB3 N2 B 350 528 NH N 0 185 N--N 00 NO O 529 NH B 317 0 0 0 N 0" WN 530 NH B 317 0 00 NH 5312 NHB38 0 N N 0 0 N 0 N 53 NH B 380 0 N O' 00 NOr 0 00 0 S Br N3NH B 379 05C3 0 0 0 N3 NH B 380 0 -N 5365N NHB38 0 K0 0 N37NH C363 0 186 0 0 N 0 538 NH B 355 510 00 0NO N 5391NB 327 N==\ 0 0 NO 540 H B 366 O 0 O N 541 N NH B 388 O0NO 542 N NH c 379 00 N OJ2 N N3NH B 354 0 00 NO N 0 NOOHB 330.2 545NN 0 - F 0 0 N Br 546 NH B 369.99 187 00 0NO N 547NB 447 0 00 0NO 548 5"NH B 405 HO 549 w B 419 055N , 0 0 NrON 550 N NH c 389 50N 0 0 NrON 551 NH H B 432 0 NN l 0 0 0 NOrN 552 NH B 446 0 0 0 NO Nr N NH 5530H C 458 0 0 MNON 554 zNH C 409 0 N i 0 0 N r0 ;O 555N NH B 247 0 188 0 0 556 N NH C314.2 0 o 0 Ny0 557 ~ . NH A 289 0 0 0 mNO CI 558 N NH F c 427 0 0 0 NO 0 N NH B 393 0 0 0 NO I 560 N NH K C426 0 0 0N N N 561N NH B 405 0 0N 0 0 N 0 N 562N NH ~ > B 406 0 00 0 N ~ 7 563 N YNH-N 7 510 0 0 NyON N 564N NH ~ B 409 0 189 0 0 NO Nr 565 NH B 435 0 00 0NO Nr 566N NH F c 393 0 00 0NO No 567 NH B 400 N 00 rO -N F 568N NH F F B 368.2 0 569 Y A 407.2 N NH F 00 N N, 570 N' -,- B 365.1 00 0NO 51N NH N B 366.1 0 0 0 0 NON 572 NH B 423.1 0 NF 573 0 01 yF B 461.1 N NH F 0 190 -N 0 0 NyON 574 I HY FB 394.1 0 N N 0 0 NON 575 B 395.1 N NH F 0 0I y.0 a 576 N NH c 343.2 0r0 N#,FNH d ~ B 343.2 0 58 0 0 Ny - CN 578NH K> 320.2 0 0 0 NyO,~N 579 NHc 306.2 0 0 0 NYO-,-O,, 580 NHc 281.2 510 0 0 NYO,-ek 581 NH No c 279.2 0 0 0 N0Yo-JkNH N582 NH B 266.1 510 191 00 NO 583 NH N B 379.2 0 O N 584 NH B 418 O N F 0 0 NyON NO 55 5 NH y H B 418 585 N 0 N NO 00 000 586 NH A 383.1 0 0 0 y0" ac 587 NH c379.1 0 588 NH 00C 315.1 0 0 0 N O 589 NH A 287 0 0 0 NyO "' 590 NH B 275 0 591N NH 00 A 411.1 0 192 o 0 592 B 320.2 5 N O 0 0N 0 0 593 1" o-nH c 307.2 ,,3 NH 0 00 NO 594 NH c320.2 0 0 0~ 595 N HB 295.2 596 N H B 343.2 510 597 0 0 N 0 C 398.1 N NH 0 0 0 NO, N 598 0yB 343.1 N 0NH 0 0 NO 0,,N 599N B 343.1 0 Br 060 NO _ 600 NH ~ C409.1 0 193 00 N O 601 NH C 293.1 1 0 0 HaC F F 602 0 NyO O IN B 398.1 N ONH

H

3 C 0 0 00 0NO y O L 603 NoNH B 327.2

H

3 C 0 0 N0 604 NH 0 B 387.2 0 0 yo 605 sN 0 309.2

H

3 0 0 0 N 0O 606 NH C 321 HC 0 0 NO0- IH 607 N NH CB 281.2

H

3 C Br SNO N 608 NH B 384.2 HC 0 H 3 C 0 0 NO N O O N NO CH 3 609 N NH c 376.1 N 0 194 0 0Nr 610 NN NH C 335

H

3 00 NyO 611 NH N9C 324.2

H

3 0 0 0 NyO N, 612 H -OHc364.2 H3C K 613 00 N O 0 B 412.1 NH lyo HaC 0O 1N Y0,,,Oy 614 NH F B 347.1 0 H3C 0 0 N O <' CH 3 N NH 615N 0 B 337.1 10 00 NO N 616 NH F B 379.2 N O0 00 . N F 617 NH B 397.2 HaC 0 68 0 0 NZ0 ..

0 .. CH 3 618 NH B 343.2

H

3

C

195 0 N 0 N CH 3 619 N NH CHa B 342.2 H N 0 0 o 0 N0,-N.J 620 N NH C 322.2

H

3 C 0 0 o O N

CH

3 621 NHHC B322.2 HC 0 CH3 6220 NH0HO k 20B 389.2 H NH 623 HCl A 357.2 H3C 624H0 N O B 365.2 NH o 0 N 0 625 NH F B 318.2 N NH

H

3 C 0 64 0 0 N0YOB36. 626N NH A 358 H5,,0y 0 0 NyON NH O 0 N 0 6267 NH A358 196 I N 00 N O N 628 C 366.2 HH H, 0 0N0 N 629 H B 334.2

H

3 C 00 NO0N N O 630 N NH C 324.2

H

3 0 0 0 N 0 OH 631 NH B 277

H

3 C CHa O 0 NO O CHa 632 NH B 281.2 HC 0 633N NH HB 329.2

H

3 C 00 NYO 634 NH B 405

H

3 C N OH 0 OH 635 NH C 395

H

3 C 0 0 N 0 O'CH3 636 NH B 291

H

3

C

197 o 0oy - sPH 3 637 6NH OH, B 309.2 HC o0 N 0 638 NH B 329

H

3 ,c 0 o0 N O CH 3 639 NH CH, B 283 Ha0 CI I~N 640 00 N 0 0;B 400.1 Tw NH

H

3 0 0H0, N 0C r-OH 641N O C 641 NH A 304

H

3 0 0 N yO; S H 3 0 0 N Y0O,-,_S,'CH3 642 NH B 297.2 HaC 00N 0 OH 643 T NH B 253.1

H

3 H H 0 0 N O CH 3 644 NH A 291

H

3 0 0 N OH 645 NH A 305 HC 0 198 CH3 CI1 646 N O 44HgC 73. N H N H yo 3 N O~ 6480 N O NHB 38.2 Ol -N , 69NH CHB 0 650 0B329. 0 0 N 0 \ .O 61 NH B 382.2 0 0 -N SN 0 N" Br 649 NH B 368 0 6500 N9 65 0 NNBa329.2 0 0 1NO0 651 0 N 2 0 0 1N O', 652N NH I A 280.1 0N 00 0NyO NN 653 N NH 6<c 399.2 510 0 0 Ny0 654 NH A M+Na 391.2 10 199 655 0 NHO N B346.2 0 00 N O N 656 NH c 332 0 00 N yON 657 NH c 290 0 OH O0 N 0 658N NH 00 NO N 65 N NHI C 3 .2 NH O 0o 652 NH H 99-2 00 N NH 660 c 317.2 (M+Na) O 0 N 0 0 O CH3 N63NH C B 371.2 F 0 0 NO ,-- N 662 N H~ A 399.2 00NO N63NH c 439.2 663l 200 O 00N 0 - OCHa 664 NH B 305 665 N 304 O0 ON 0 666NH A 332 0 0 0 NyO N 667 NH B 346 0 0 NyN 668 NH304 0" 0 0 0 N4Y0""~ OCH, 669 N NH B 319 0 0 0 N 0K 0 670 N A 319.2 OH O 00N O K 671 NH A 305 :0 O 00 N 0 K OCHa 672 N NH B 305 201 o o N 0,,N 673 Y B 359 0 o00N O 674 NH 303 0 o o Nyo 675 N NH B 346 510 0_-0z0 N N 676 NHB 360 NHO 0 677 NH A 315 0 0 0 NO , 678 NH B 331 0 OH 0 0 N O 679 NH A 333 0 OH 0 0 N O 680 NH A 319 0 + 01 O 0 N 0 ' 681 NH 0 344.2 0 202 0 0 NO N NHO 682 CH328.2 0 o 0 N 0 -. NH 683 C 360.2 F O 0N OCH 3 NH 684 A 371.2 F N 685N B 412.2 F 0 0NO NH 686 B 279.2 0 0 N N NH 687 0 B 305.2 SN, 0 0 N O 688 NONH B 374.2 0 0 0 N 0 0 B4NH 689 B 400.2 0 203 s 690 C 241.1 SNH 0 o o N 0-1 691 NH HA 350.2 0 O 0 NAL HNH 692 O A 352.2 O 00N Ol NHNH 693 0 B 364.2 0 O 0 N N AO 694 NH c338.2 0 O 0 N': 0,AL. NH 695 A 338.2 0 0 O0 0 ,N 0 . 696H NH B 336.2 0 0 O 0 N 0 ALN 0N 698 NH -- 295.2 0 204 Preparative example 699 H 0 0 NO NH N NH 0 699 H O NH 0 NH 0 0 699a 699b 5 Compound 699a (0.925 g, 3.53 mmol) was taken in DMF (10 mL) in a round bottomed flask equipped with a magnetic stirring bar. N-lodosuccinimide (1.59 g, 7.05 mmol) was added portionwise and the reaction mixture was heated to 50*C overnight. After cooling to ambient temperature, H 2 0 (25 mL) was added. The product was filtered, washed with water followed by ether to give a white powdery mixture (> 95% 10 yield). The product 699b was used as such for the next step without any further purification. H H 00 00N0 NO I NH I N NH 00,N 699b 69 Compound 699b (0.1 g, 0.258 mmol) was taken in 5 mL DME/H 2 0 (4:1) in a 10 mL round bottomed flask. PdC1 2 (PPh 3

)

2 (0.018 g, 0.0258 mmol), Na 2

CO

3 (0.082 g, 15 0.774 mmol), and phenylboronic acid (0.057 g, 0.464 mmol) was added, and the reaction mixture was allowed to reflux (80 *C) for 6 h. After cooling, the mixture was concentrated and purified by flash chromatography (CH 2

CI

2 to 5% MeOH/CH 2

CI

2 ) to yield compound 699. O O N Oe NH F 00 700 700 20 Compound 700 was prepared in the same manner as in example 699.

205 H 00 NO NH F, 0 701 Compound 701 was prepared in the same manner as in example 699. H 0NO NH NC 702 Compound 702 was prepared in the same manner as in example 699. H 0 0 Ne0 NH EtO 0 5 703 Compound 703 was prepared in the same manner as in example 699. H 0 0 NO AN 0 H 704 Compound 704 was prepared in the same manner as in example 699. H 0 0 N NIS, DMF 0 0 0O NH NI NH 0 0 705a 705b 10 Compound 705b was prepared in the same manner as in example 699b. 0 0 NO NH CI 0 705 Compound 705 was prepared in the same manner of compound 699. 0 0 N O NH F 0 706 206 The compound 706 was prepared in the same manner of compound 699. H o O N 0 O NH 0 707 The compound 707 was prepared in the same manner of compound 699. H o 0 N 0 NH

F

3 C 0 708 5 The compound 708 was prepared in the same manner of compound 699. H o 0 N 0 NH NC 0 709 The compound 709 was prepared in the same manner of compound 699. H o 0 N 0 0 NH N 0 H 710 The compound 710 was prepared in the same manner of compound 699. 10 Compound STRUCTURE NA EC 50 camp Electrospray No. (nM) LCMS [M+1]+ H 00 N NH 699 0 C 339.2 207 700 F C 357.2 00 0 NH 701F 3 C 0 407.2 H FNeC 00NO 702 0 c 364.2 0 O N O NH 703 Et c383.2 EOj H 0 0 1Ne 0 NH 704N0 C 396.2 H H 0 0 N 0 706NH 705 c 347.2 CF 0 H O 0 N 0 706 ICNH331.2 F 0 MeO NNH 707 Ic 343.2 0 0 N~ N IN. NH 708 B 381.2 F, 0 208 H 0 0 N 0 709 0H338.2 NC 0 O O NO 710 0N370.2 H Preparative example 711 O O N YO" NH 0 5 711 Step A:

C

2 Me + Et 2 Zn + TFA + CH 2 1 CH2C 2 C0 2 Me 10 711 A To a solution of diethyl zinc (3.0 eq, 1.0 M in THF) in CH 2 Cl 2 (0.2 M) at 0 0C was added TFA (3.0 equiv, dropwise via an addition funnel). The resulting mixture was allowed to stir at 00*C for 15 minutes after the addition was complete. CH 2 1 2 (3.0 15 equiv) was then added to the reaction mixture dropwise via syringe and the resulting reaction was allowed to stir at 00*C for 10 minutes. To the resulting reaction was added hex-5-enoic acid methyl ester (1.0 equiv) and the reaction mixture was stirred for about 15 hours, allowing the mixture to increase to room temperature. The reaction was then quenched by careful addition of aqueous 1 N HCI and the the aqueous layer 20 was extracted with CH 2 0 2 (3x). The combined organic phases were washed with water, then brine, then dried over MgSO 4 and concentrated in vacuo to provide compound 711A in quantitative yield.

209 Step B:

CO

2 Me NaOH CO 2 H 711A 711B 5 Aqueous NaOH solution (2.0 equiv, 2.0 N) was added to a solution of 711A (1.0 equiv) in THF and MeOH (v/v = 2/1, 0.2 M) at room temperature. The mixture was allowed to stir for 4 hours and the solvent was then removed in vacuo. The resulting aqueous solution was extracted with ether and the resulting solution was then acidified using 5 M HCl. The aqueous layer was extracted with ether (3x) and the 10 combined organic phases were washed with water, then brine, then dried over MgSO 4 and concentrated in vacuo to provide compound 711B in quantitative yield. Step C: C0 2 H + MeO 2

CCH

2 C0 2 K + CDI + MgC 2 aOMe 15 711B 711C CDI (1.2 equiv) was added to a solution of 711 B in THF (0.5 M) at room temperature. The reaction mixture was allowed to stir for 1 hour, then monomethyl melonate ester potassium salt (1.5 equiv) and MgCl 2 (1.0 equiv) were added. The resulting reaction was allowed to stir for about 15 hours and was then quenched with 20 aqueous HCI (1.0 N). The aqueous layer was extracted with EtOAc (3x). The combined organic phases were washed with water, then brine, then dried over MgSO 4 and concentrated in vacuo to provide compound 711C in quantitative yield. Step D: H H H 00 N S OMe 0 S HOAc N 0 0 + NH N 25 711C 711 D A mixture of 4,6-dihydroxy-2-mercapto-pyrimidine (1.0 eq) and 711C (1.25 equiv) in HOAc (1.0 M) was heated to reflux and allowed to stir at this temperature for about 15 hours. The reaction mixture was then cooled and concentrated in vacuo and 210 the resulting residue was purified using flash column chromatography on silica gel to provide compound 711D (37% yield). Step E: H 0 0 N S 0 0 N SMe DMF NH + Mel NH 50 0 5 711 D 711 E Mel (1.8 equiv) was added to a suspension of 711 D (4.0 g, 17.86 mmol) in DMF (0.3 M) at room temperature. The reaction mixture was allowed to stir at room temperature for about 15 hours, then poured into water and the resulting solution was 10 filtered through a sintered funnel. The collected solid material was washed with water and dried under vacuum to provide compound 711 E (96% yield). Step F: o 0 N SMe 0 0 N SOMe and SO 2 Me CHeCl 2 NH + m-CPBA - , NH 0 70 15 711 E 711F m-CPBA (2.0 equiv) was added to a suspension of 711 E (1.0 equiv) in CH 2 Cl 2 (0.15 M) at room temperature. After stirring for 3 hours, the reaction was quenched with Me 2 S (3.0 eq) and concentrated in vacuo to provide a crude product which was washed with Hexane/EtOAc (v/v = 3/1) to provide compound 711 F as a mixture of 20 sulfone and sulfoxide (90% yield, w/w = 1/2).

211 Step G: 0 0 N SOMe and SO 2 Me O00 N O K NH NaHTHF/DMF NH + ______NH 0 HO O 711F 711G 5 Pent-2-yne-1 -ol (2.0 equiv) was added dropwise to a suspension of NaH (2.0 equiv) in THF at room temperature. The reaction mixture was stirred for 1 hour to provide a clear solution to which was then added dropwise a solution of 711IF (1.0 equiv) in DMF. The reaction mixture was stirred for about 2 hours at room temperature and was then quenched with HOAc (2.0 equiv). The resulting solution 10 was diluted with EtOAc and washed sequentially with 0.1 M HCI, water and brine, then dried over MgSO 4 and concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel (eluent: hexane/CH 2

CI

2 /EA (v/v/v = 7/3/2)) to provide compound 711 (50% yield). Electrospray MS [M+1 ]*329.2. 15 Using the method described above, and appropriate materials, Compounds 712-739 were prepared: Compound Structure Electrospray No. LCMS [M+1] O 00N 0 71 2 NH 329.2 O0, N 0O 713 ".y NH 329.2 714 NH 317.2 0 0 0 N O4' 715 NH 331.2 0 0 212 O0 N 0J 716 N NH 343.2 01 717 NH 315.2 0 o0 N 0 718 NH 343.2 0 o 0 Nyo0 4' 719 NH 357.2 73 0 o700N 0 Y 720 NH315.2 0 721 N NH 329.2 0 722 01N 4' 327.2 N NH 0 ; OMe 723 00 NYO 305 O N OH 0 OH 724 N O 0 OH 725 0 0 N y O 319 N NH OMe 00 NYO O 726 NH 305 0 213 727 NH 291 0 O0 N 'O ",OH 728 NH 305 0 OH 729 00 NY O291 NH 0 O Ny O 730 N NH 289 731 0 0 1 NYO O 329 510NH N 4 732 NH 275 0 00 NyO 733N NH 39 0 0 O NYO' 734 NH30 0 ON Y0O. 735 NH 315 0 OH 00 Ny0 736 NH 333 0 214 OH 00 NyO 737 N NH 319 0 00 Ny 0 ', 738NH287 0 0 N 0 739N NH 337.1 0 Preparative example 740 F 0 0 N F NH 0 5 740 Step:1 F H2N LNH + F NaOEt 1 EtOH HO N F

H

2 N JI NH 2 +

-IO"

F ref luxr OH 740A 10 A mixture of malonamide (40.00 g, 392.22 mmol) and NaOEt (21%, 292.00 ml, 784.53 mmol) in MeOH (1 L) was stirred at room temperature for 1 hour. Difluoroacetic acid ethyl ester (58.00 g, 467.74 mmol) was then added to the reaction mixture and the reaction was heated to ref lux and allowed to stir at this temperature 15 for about 15 hours. The reaction mixture was cooled to room temperature and the solid product was collected by filtration and washed sequentially with EtOH, EtOAc 215 and hexane, then sucked dry under vacuum to provide 45.0 g product as white powder (71% yield). Step:2 F 0 0 NF HO N OF sulfamic acid N F N + .. .. NH 1;-16500 0 OH 5 740A 740B 740 A mixture of compound 740A (10.50g, 64.81 mmol), compound 740B (14.90g, 80.98 mmol), and sulfamic acid (6.29g, 64.84 mmol) was heated to 1650*C and 10 allowed to stir at this temperature for 30 minutes. The reaction mixture was then cooled to about 70 0C, then poured into into a mixture of CH 2 Cl 2 /MeOH (1:1, 50 mL) and the resulting solution was filtered. The solid collected by filtration was then washed repeatedly with CH 2

CI

2 /MeOH (1:1) and the eluates were combined and concentrated in vacuo to provide compound 740 as white crystals (3.30 g, 17%). 15 Using the method described above, and appropriate materials, Compounds 742, 743, 745, 746, 748, 750, 752, 754, 757 and 812 were prepared: Compound Structure Electrospray No. LCMS [M+1]* 0 0 1Nr-F N F N -N 742 0 405.2 O e O O N TJ'F NH 743 0285.1 216 F O N N O N 0F 745N431.2 F 00 N F N NH 746 0 311.2 F 7500NH 752 F 0 O NY--F NH 748 0 297.2 F 080 NH 750N NH 271.1 0 F 752N NH 283.2 0 F 0 0 N Y)"F NNH 754 0 299.2 IF NNH 770 325.2 IF 812N NH 299.2 0 Preparative example 758 217 H 0 NYO NCN NH 0 758 Step A: 0 0 N5SMe NIS,0DMF 1 SMe NH NS DF INH 5 0 0; 758A 758B NIS (6.72 g, 29.9 mmol) was added to a solution of 758A (5 g, 21 mmol) in DMF (70 mL). The reaction mixture was heated to 50 *C and allowed to stir at this 10 temperature for about 15 hours. The reaction mixture was then cooled to room temperature and water (100 mL) was added. The resulting solution was filtered, and the collected solid was washed with water then ether to provide compound 758B as a yellow powder (65% yield) which was used without further purification. 15 Step B: o0 N SMe 0 0 N SMe NH CuCN, DMF NC NH 00 758B 758C 20 CuCN (0.246 g, 2.75 mmol) was added to a solution of 758B (1.0 g, 2.75 mmol) in DMF (10 mL). The reaction was refluxed for 2 h, under N 2 . After cooling to room temperature, H 2 0 (50 mL) was added. The precipitated product was filtered, washed with water then ether to afford 16 (95% yield). 25 Step C: 218 H 0 0 N SMe 0 0 N 0 NC N SNH 1. m-CPBA NC 02. H 2 0/ MeCN NC 0NH 758C 758 m-CPBA (0.936 g, 4.18 mmol) was added to a solution of 758C (0.55 g, 2.09 mmol) in CH 2

CI

2 (15 mL). The resulting reaction was allowed to stir at room 5 temperature for 4 hours, then Me 2 S was added and the resulting solution was allowed to stir for an additional 10 minutes and concentrated in vacuo. The resulting residue was diluted with 10 mL CH 3 CN/ H 2 0 (1:1) and the resulting solution was stirred at room temperature for 12 hours then concentrated in vacuo and purified by preparative TLC (15% MeOH/DCM) to provide compound 758. Electrospray MS: [MH*] = 262.1 10 Using the method described above, and appropriate materials, compounds 759 and 760 were prepared: Compound Structure Electrospray No. LCMS [M+1]* H 0 0 NO 759 C 0288.2 760 NCO NH 262.1 0 15 Preparative example 761 H O O 0 N O N NH HO 761 219 Step A: H H 00 N0 HNO 00 N O NH NH 0 AcOH 0 2 N 0 761 A 761 B 5 Fuming HNO 3 (0.9 mL) was added drop wise to a solution of 761A (0.5 g, 1.81 mmol) in HOAc (1.8 mL) under N 2 . The reaction was heated to 100 *C and allowed to stir at this temperature for 30 minutes, then the reaction mixture was poured into cold water (5 mL). The precipitate formed was isolated and washed with acetonitrile (1 mL) to afford compound 761 B (0.3 g, 51%). Electrospray MS: [MH*] = 322.2 10 Step B: H H O O 1N o0 0 01N YO 0 2 N NH 1. Zn/AcOH ANH 2. Et 3 N/acetic anhydride 761 761 15 Zn dust (0.47 g, 7.2 mmol) was added to a solution of 7618 (0.23 g, 0.72 mmol) in HOAc (3 mL) and MeOH (2 mL), and the resulting reaction was stirred at room temperature for about 18 hours. The reaction was filtered and the filtrate was concentrated in vacuo to provide a residue which was dissolved in CH 2 Cl 2 (2 mL). To the resulting solution was added Et 3 N (2 mL) followed by acetic anhydride (2 mL). 20 The resulting reaction was allowed to stir at room temperature for 24 hours, then was concentrated in vacuo and the resulting residue was purified using flash column chromatography on silica gel (eluent: MeOH/CH 2

CI

2 (v/v = 10/97)) to provide compound 761 (0.15 g, 62%). Electrospray MS: [MH] = 334.2 25 Preparative example 762 220 0 0 N CF 3 0 NH 762 Step A: o 0 NaOEt 0 N CF 3

F

3 C 0 , +

H

2 N NH 2 EtOH NH 0 5 0 762A Trifluoroacetic acid ethyl ester (8.8 ml, 73.5 mmol) was slowly added to a suspension of malonamide (5 g, 49 mmol) and NaOEt (21% in EtOH, 36.5 ml, 98 mmol) in EtOH (50 mL). The resulting reaction was put under nitrogen atmosphere, 10 heated to ref lux, and allowed to stir at this temperature for about 20 hours. The reaction mixture was then filtered and the collected yellow solid was washed with EtOAc, then EtOH to provide compound 762A. Step B: 0 NyCF3 711C 0 0 N CF 3 NH HOAc 'N NH O01200 *C0 15 762A 762 Compound 711C (0.8g, 4.2 mmol, prepared as described above in preparative example 711, step C) was added to a solution of 762A (0.5g, 2.8 mmol) in HOAc (1.5 mL). The resulting reaction was heated to 120 *C and allowed to stir at this 20 temperature for 20 hours, then the reaction was cooled to room temperature and concentrated in vacuo. The resulting residue was purified using flash column 221 chromatography on silica gel (eluent: 3% MeOH/CH 2 Cl 2 ) followed by preparative TLC (5% MeOH/CH 2

CI

2 ) to to provide compound 762. Using the method described above, and appropriate materials, compounds 5 763 and 764 were prepared: Compound Structure Electrospray No. LCMS [M+1]* 0o 0N CF NH 763 o 329.2 0 0 N CF NH 764 0289.2 Preparative example 765 O H MeN N 0 NH 10 0 765 Step A: O H O H MeO MeO O~ H H I H 0 15 765A 765B N-iodosuccinimide (40 g, 177 mmol) was added to a solution of 765A (15 g, 88 mmol) in a mixture of TFA-TFAA (300 mL, 30 mL) and the resulting reaction was heated heated to 85 *C and allowed to stir at this temperature for about 15 hours. The reaction was then cooled to room temperature and concentrated in vacuo. The 20 resulting residue was partitioned between 200 mL of H 2 0 and 100 mL of EtOAc. The 222 precipitate was collected and washed with H 2 0 and EtOAc, then dried in vacuo to afford compound 765B (20.2 g, 78%). Step B: 0 H 0 PMB %N NO0 MeO NMeOM I H I PMB 5 0 0 765B 765C Na 2

CO

3 (27g, 300 mmol) and PMBCI (34 mL, 300 mmol) were added to a solution of 765B (20 g, 100 mmol) in DMF (300 mL). The resulting slurry was heated to 50 *C and allowed to stir at this temperature for about 15 hours. The reaction was 10 then cooled to room temperature and partitioned between H 2 0 (250 mL) and EtOAc (500 mL). The organic layer was separated and washed with H 2 0, then brine, then dried over MgSO 4 , filtered and concentrated in vacuo. The resulting residue was filtered through a pad of silica gel, eluted with EtOAc-heaxanes (1:10) followed by EtOAc-hexanes (1:1). The filtrate was concentrated in vacuo and the residue was 15 recrystalized from DCM and hexanes to afford 765C (16.6 g, 31%). Step C: O PMB 0 PMB NONO MeO N HO N I PMB I PMB 0 0 765C 765D 20 Lithium iodide (15.3 g, 114 mmol) was added to a solution of 765C (15.3 g, 28.5 mmol) in EtOAc (300 mL). The resulting slurry was stirred heated to 85*OC and allowed to stir at this temperature for about 15 hours. The reaction mixture was cooled to room temperature; then water (100 mL) was added and the resulting solution was transferred to a separatory funnel. The aqueous layer was separated 25 and brought to a basic pH by the addition of 1 N NaOH, then the basified solution was washed with ether. The aqueous layer was then adjusted to pH = 1 by addition of 1 N HCI and the resulting acidic solution was extracted with EtOAc. The combined 223 organic extracts were washed with 1 N sodium thiosulfate solution, dried over MgSO 4 , then filtered and concentrated in vacuo to provide compound 765D (13.5 g, 90%). Step D: 0 PMB 0 PMB HO NOHN N I PMB I NPMB 5 0 0 765D 765E Oxalyl chloride (0.2 mL, 2.32 mmol) was added to a solution of 765D (1.0 g, 1.91 mmol) in CH 2 Cl 2 (10 mL), followed by addition of a drop of DMF. The resulting mixture was allowed to stir at room temperature for 30 minutes, then concentrated in 10 vacuo. The resulting residue was dissolved in CH 2 0 2 (10 mL), and to the resulting solution was added allylamine (0.2 mL, 19.8 mmol) . The resulting reaction was allowed to stir at room temperature for about 15 hours, then the reaction mixture was diluted with CH 2 C1 2 (10 mL) and washed with 1 N HCI. The organic layer was separated, washed with brine, dried over MgSO 4 , and concentrated in vacuo. The 15 resulting residue was purified using flash column chromatography on silica gel (eluent: EtOAc-hexanes, 1:1), to provide compound 765E (0.61 g, 60%). Step E: 0 PMB 0 PMB HN NO HN N,PMB N'PMB 20 765E 765F In a sealed tube, Et 3 N (0.42 ml, 2.99 mmol) and Pd(OAc) 2 (38 mg, 0.17 mmol) were added to a solution of 765E (1.0 g, 1.91 mmol) in DMF (6 mL). The resulting reaction was heated at 85 *C and allowed to stir at this temperature for about 15 hours, then cooled to room temperature and filtered through Celite. The filtrate was 25 concentrated in vacuo and the resulting residue was purified using flash column chromatography on silica gel (eluent: EtOAc-hexanes, 1:1) to provide compound 765F (0.27 g, 36%).

224 Step F: 0 PMB OMePMB 0 PMB HN MB N N 0 MeN MB N MNPMB N, PMB 0 0 0 765F 765G 765H 5 A solution of 765F (262 mg, 0.60 mmol) in DMF/THF (1:1, 12 mL) was cooled to 0O0C and NaH (30 mg, 1.18 mmol, 95% oil dispersion) was added. The resulting reaction was allowed to stir at 0 *C was stirred for about 30 minutes, then iodomethane (0.1 mL, 1.60 mmol) was added and the reaction was allowed to stir at room temperature for about 15 hours. The reaction was quenched with water, and the 10 aqueous layer was separated and extracted with CH 2 0 2 . The combined organic extracts were dried over MgSO 4 and concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel (eluent: EtOAc-hexanes, 1:1) to provide compounds 765G (5 mg, 4% yield) and 765H (121 mg, 90%). 15 Step G: o PMB H 0 0 MeN NYOMeN NY N' PMB N NH 765H 765 TFA (0.5 mL) and TfOH (0.1 mL) were added to a solution of 765H (100 mg, 20 0.22 mmol) in CH 2

CI

2 (6 mL). The resulting reaction was allowed to stir at room temperature for about 15 hours, then concentrated in vacuo to provide a crude residue which was purified using preparatory TLC (eluent: acetic acid/CH 2 Cl 2 /EtOAc, 1:10:10) to provide compound 765 (12 mg, 26%). Electrospray MS [M+1]* 208.1 225 Preparative examples 766 and 767 0 0 0, N HN 0 'N00 0 N 0 0 H 766 767 5 Step A: 1) Et 2 N-polymer 0 TMSNCO 0.N MeONH 2 -HCI 2) malonic acid O$N O HOAc,Ac 2 O ,H 70 *C 766A Diethylaminomethyl-polystyrene (40 g, 3.2 mmol/g,128 mmol) was added to a solution of methoxylamine hydrochloride (5.0 g, 60 mmol) in MeOH (300 mL). The 10 reaction mixture was stirred for 1 h. Then, TMSNCO (8.1 mL, 60 mmol) was added and the solution was stirred for 4 h. The polymer was filtered and washed twice with MeOH (50 mL, each). The volatiles were removed and the residue was dissolved in acetic acid (40 mL) then malonic acid (5.1 g, 60 mmol) and Ac 2 0 (40 mL) were added. The mixture was heated at 70 *C for 10h. The reaction was concentrated in vacuo 15 and the residue was dissolved in MeOH (100 mL), stirred for 10 min. and concentrated. The resulting residue was triturated in 1:1 EtOAc/Et2O and filtered to obtain 34 (4.2 g). Step B: O0 0 NO,.'NHN 0 N OOO OIN 0 O + O7N 0 0 H sulfamic acid H 20 140 *C 766A 766 767 Sulfamic acid (613 mg, 6.32 mmol) was added to a mixture of 3-oxo-heptanoic acid methyl ester (2.0 g, 12.6 mmol) and 766A (1.0 g, 6.32 mmol). The mixture was 226 heated at 140 *C for 4 hours. The resulting residue was dissolved in 10 mL of MeOH, filtered and separated using a Gilson HPLC to obtain pure 766 and 767. Electrospray MS [M+1]* 267.1 5 Using the method described above, and appropriate materials, compounds 768-779 were prepared: Compound Structure Electrospray No. LCMS [M+1]* 0 N0 O 768 N N, OMe 239.1 0 H 00 N)N r0 769 0 OMe 293.1 OMe 770 NH293.1 OMe 0 NyO NH 771 292.2 0 772 OMe 306.3 OMe 00 NyO NH 773 0 306.31 227 H O0 N yO 774 0Ne NA Oe 00 NO NH 775 NA 0 OEt 00 NO 8N NH 776 0307.1 H 00 , N O 77 0NOEt 307.1 00 NO 778 NH 281.1 0 779 QN,OEt 281.1 0 NA = not available Other illustrative compounds of formula (I), include but are not listed to compounds 796-810, which are depicted below: 5 Compound Structure Electrospray No. LCMS [M+1 ]* 228 00NO 796 Iy322.2 0 H 797N 798 00N0343.2 0 H 00 NO 799 NON343.2 0 0N 800 01N e 307.2 0OMe NON 801 N 307.2 0 H 0 O N O NNF 802 295 ~e30.2 QONO 803 2693071 0 H ONO 804 30 29.2 229 OH 0ONO 805 NH 253.1 0 R 0 NO0 806 NI OH 253.1 0 0 N 807 N 0NH 193.1 1 H O N NO 808 NH222.2 0 809 1 "F 253.1 01 810 NYNH211.1 Preparative example 811 000 O O N F NH 0 811 5 0 0 NH HO N + F N .HCI NaOMe, MeOH F EtO"OEt +NH 2 N reflux OH 811 A Step A: 10 A solution of diethylmalonate (2.96 g, 18.48 mmol) and NaOMe (25 wt % in MeOH, 10.75 g, 49.76 mmol) was added to a solution of 2-fluoroacetamidine hydrochloride (2.0 g, 17.77 mmol) in MeOH (20 mL). The resulting reacton was heated to reflux and allowed to stir at this temperature for about 15 hours. The 230 reaction mixture was cooled to room temperature, concentrated in vacuo, and the resulting residue was diluted with water (20 mL). The resulting solution was neutralized using concentrated HCI and the solid formed was collected by filtration, washed sequentially with H 2 0 and Et 2 0, then sucked dry to provide compound 811 A 5 as a pale brown powder (1.8 g, 69%). Step B HO N 0F + 0 sulfamic acid NH 1300 *C OH 10 811A 811B 811 A mixture of compound 811A (0.1 g, 0.694 mmol), compound 811B (0.295 g, 1.39 mmol) and sulfamic acid (0.034 g, 0.347 mmol) was heated to 1300*C and allowed to stir at this temperature for about 2 hours. The reaction mixtures was then cooled to room temperature and poured into into a mixture of CH 2 Cl 2 /MeOH (1:1, 1 15 mL). The resulting solution was purified using flash column chromatography (eluent: gradient of from 20% to 50% EtOAc/hexanes) to provide compound 811 product as a white solid. Using the method described above, and appropriate materials, Compounds 20 741, 744, 747, 749, 751, 753, 755 and 756 were prepared: Compound Structure Electrospray No. LCMS [M+1]* NH 741 o 279 0 0 N F NH 744 0 267.1 231 I NH 747 o 293.2 00 I NH 749 o 279.2 I NH 751 o 285.2 s I 0O0O1N F NNH 753 0 265.1 1 NH 755 0 281.2 O 0N :, F NH 756 O 307.2 F Preparative example 813 F"" 00 N 0 NH 0 5 813 Step A: H F H 0O N O BrCH 2 F, K 2

CO

3 O N O NH NH O OF 232 102 813

K

2

CO

3 (0.35 g, 2.54 mmol) was added to a solution of compound 102 (0.4 g, 1.69 mmol) and BrCH 2 F (0.21 g, 1.86 mmol) in DMF (5.0 mL) at room temperature. The resulting mixture was stirred overnight. The reaction mixture was diluted with 5 ethyl acetate and neutralized with aqueous HCI solution (0.5 N). The organic phase was washed with water (3x), dried (Mg 2

SO

4 ), and concentrated under vacuo to provide crude product which was purified with PTLC (CH2Cl2/MeOH = 20/1) to give product 813 (5 mg), Electrospray MS [M+1 1269.1. 10 Preparative example 814 H 00 N O N YF OF 814 15 Step A: 0 0 N SMe BrcHF 2 , Cs 2 CO 0 O N SMe NHO y DMFN" N F 0 O F 711E 814A Cs 2

CO

3 (1.30 g, 3.99 mmol) was added to a solution of compound 711E (0.39 g, 1.33 mmol) and BrCHF 2 (0.79 g, 6.05 mmol) in DMF (5.0 mL) at room 20 temperature. The resulting mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and neutralized with aqueous HCl solution (0.5 N). The organic phase was washed with water (3x), dried (Mg 2

SO

4 ), and concentrated under vacuo to provide crude product which was purified with silica gel column chromatography (EtOAc/hexane gradient) to provide compound 814A (0.15 g). 25 233 Step B: H O O N SMe 3 O2C2; 0 o 1No 1) CH CQ 3 H, CH0c0a N F 2) Cs 2 CO/DMF O F OF 814A 814

CH

3

CO

3 H (0.30 mL, 1.4 mmol) was added at room temperature to a solution of 5 814A (80 mg, 0.234 mmol) in CH 2

CI

2 (2.0 mL). The mixture was stirred for 3 hours before it was quenched with Me 2 S (10.0 eq.). The reaction mixture was diluted with ethyl acetate and washed with water (3x). The organic phase was washed with brine, dried (Mg 2

SO

4 ), and concentrated under vacuo to provide crude product which was taken up in DMF (2.0 mL) and treated with Cs 2

CO

3 (91.6 mg, 0.281 mmol). The 10 mixture was stirred for 1 hour before it was diluted with ethyl acetate and neutralized with aqueous HCI solution (0.5 N). The organic phase was washed with water (3x), dried (Mg 2

SO

4 ), and concentrated under vacuo to provide crude product which was purified with reverse phase Gilson separation to provide compound 814 (60 mg), Electrospray MS [M+1 ]*313.2. 15 Using the method described above in Preparative Examples 813 and 814, and substituting the appropriate bromo compound in Step A, Compounds 815-833 were prepared: Compound Structure Electrospray No. LCMS [M+1]* H 815 O 297.2 816 NINF 287.2

OF

234 H o N,,e N O 817 NyF 255.1 H 0 N 0 0 818 F283.2 0 819 N ""F 255.1 0 H 0 0 NO 820 F 269.1 0 0 NNOF 821 30. H N O 8224N ")F 309.2 0 R N0F 823 0N327.2 F 0N 824 0309.2 H NO 8254N X329.1 0 ,F H 827 _NN283.2 0 _________________ ____________________ 235 H 0NO 828 N 301.2 0 gF 00 NO N 829 0 319.2 FF H 0 NO -N 830 327.2 H 0 N O 831 0 N327.2 0 0 N 831F 832 N 255.1 O) F H 0 N O 833 O)297.2 Preparative Example 834 00 N0 NH 0 F F 5 834 Step: 0 C2H BnOH 834A EDC 834B >90% 236 To a solution of 4-pentenoic acid (834A, 60 g, 0.594 mol) and benzyl alcohol (56 mL, 0.54 mol) in dichloromethane (1 L) was added EDC (207 g, 1.08 mol) at 0*C and the reaction was stirred until homogeneous (-5 min). DMAP (6.7 g, 0.054 mol) 5 was then added and reaction mixture was allowed to warm to room temperature, then stirred under nitrogen for an additional 2 hours. The reaction mixture was washed with 1 N HCl (aq.), then saturated NaHCO 3 (aq.), then dried over sodium sulfate and concentrated in vacuo to provide compound 834B in nearly quantitative yield (>95%). 10 Step2: 0 0 0OsO4(cat.) O O 4 '- 0Bn Na1O4 0Bn 834B 67% 834C To a solution of compound 834B (2.3 g, 0.012 mol) and 4% osmium tetraoxide 15 in water (3 mL, 0.04 eq) in 3:1 (v/v) THF/H 2 0 (45 mL:15 mL) was added sodium periodate (7.7 g, 0.036 mol) and the resulting reaction was stirred under nitrogen at room temperature overnight. Sodium periodate was then added and a precipiate formed from the resulting exotherm. The reaction mixture was filtered, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified using 20 flash column chromatograpy on silica gel (0-20% EtOAc/Hexane) to provide compound 834C (1.6 g, 0.083 mol, 67%). Step 3: O CF 2 Br 2 F O OBn 834C P(NMe 2

)

3 F O OBn 25 63% 834D To a solution of hexamethyl phosphorous triamide (25.4 g, 0.156 mol) in THF (300 mL) at -78*C was added dibromodifluoromethane (16.4 g, 0.078 mol) and the resulting suspension was allowed to warm to room temperature. Compound 834C 30 (7.5 g, 0.039 mol) was added and RM refluxed at 660C under nitrogen overnight. The 237 reaction mixture was filtered, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified using flash column chromatograpy on silica gel ( 0 10% EtOAc/Hexane) to provide compound 834D (5.5 g, 0.024 mol, 62 %). 5 Step 4: F 0 H2, Pd/C F O F O OBn near 100% F OH 834D 834E To a solution of compound 834D (5.5 g, 0.024 mol) in EtOAc (120 mL) was 10 added 10% Pd/C (1.3 g, 0.05 eq) and the resulting solution was placed on Parr shaker under 50 psi hydrogen gas overnight. The reaction mixture was then filtered and the filtrate was concentrated in vacuo to provide compound 834E (3.3 g, 0.024 mol, >99%). 15 Step 5 F 0 CDI, MgCI2 F 00 F< AOH KO2CCH2CO2Me F O", O Me 834E 834F To solution of compound 834E (6 g, 0.0434 mol) in THF (150 mL) was added 20 CDI (8.5 g, 1.2 eq) and the resulting reaction was stirred at room temperature under nitrogen for 1 hour. MgCI2 (4.1 g, 1 eq) and monomethyl malonate potassium salt (10.2 g, 1.5 eq) were than added and the resulting reaction was stirred at room temperature under nitrogen overnight. The reaction mixture was then partitioned between 1 N HCI (aq.) (200 mL) and EtOAc (200 mL). The aqueous layer was 25 collected and extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue obtained was purified using flash chromatography on silica gel (0-20% EtOAc/Hexane) to provide compound 834F (6.7 g, 0.0347, 80%) 30 Step 6: 238 F 0 F H F 0O0O0oNo0F FO OeNH sulfamic acid 834F EtOCH2CH2OH 0 0 N O 145 C 834 H To a solution of barbituric acid (7 g, 1.1 eq) and compound 834F (9.7 g, 0.05 5 mol) in EtOEtOH (15 mL) was added sulfamic acid (2.4 g, 0.5 eq) and the resulting reaction was stirred at 1470C for 4 hours. The reaction mixture was concentrated in vacuo and the resulting residue triturated with hot water three times to provide compound 834 (2 g, 0.007 mol, 15 %). 10 Preparative Example 835 H 0 N F F 835 N F F O 0O1O F 'N~Me H .J" / N 834F sulfamic acid N 834F145C 835 15 N-cyclobutyl barbituric acid (782, 4.3 mmol) and compound 834F (1 g, 1.2 eq) were heated at 140*C for 2 hours in the presence of sulfamic acid (417 mg, 1 eq). The mixture was suspended in 10 mL DMF and the suspension was then filtered. The filtrate was injected into a Gilson HPLC in twenty injections and purified on a C18 column eluted with 0.1% TFA in water/acetonitrile (gradient 10-100% 20 water/acetonitrile at a flow rate of 25 mL/min) to provide compound 835 (retention time: 10.1 min; 120 mg, 0.037 mmol, 9%).

239 Preparative Example 836 F 00 Nr F NH F 0 F F 5 836 F 0 F 0 O 0 CHF 2 F 0 H sulfamic acid 834F acetic acid 0 0 N CHF 2 1200 *C836 H To a mixture of difluorobarbituric acid (1 g) and compound 834F (1 g) in a 15 mL microwave vial was added acetic acid (3 mL). The vial was sealed and the 10 resuting solution was microwaved at 180 0C for 20 minutes. The reaction mixture was then concentrated in vacuo and purified using flash chromatography on silica gel (gradient elution of 0-80% EtOAC/Hexane). The blue UV band that eluted off the column was collected and concentrated in vacuo and the resulting residue was purified using preparative TLC (2:1 EtOAc/Hexane) to provide compound 836 (40 mg, 15 3%). Using the methods described above in Preparative Examples 834-836 with the approrpriate difluoro p-keto ester and barbituric acid or barbituric acid derivative, Compounds 837-844 were prepared: 20 240 Compound Structure No. H 0 0 1NYO 837 O F F H 00 NO NH 838 0 F H 0 0 N 839 NH 0 F H 0 NO 840 NH 0 F F H O O N Oe NH 841 0 F F 0 N CHF, NH 0 842 F F 0 0NCHF, NH 843 0 F 0 0 N CHF 2 'N NH 844? 0 F F 241 Nicotinic Acid Receptor Assay The nicotinic acid receptor agonist activity of the inventive compounds was determined by following the inhibition of forskolin-stimulated cAMP accumulation in cells using the MesoScale Discovery cAMP detection kit following the manufacturer's 5 protocol. Briefly, Chinese Hamster Ovary (CHO) cells expressing recombinant human nicotinic acid receptor (NAR) were harvested enzymatically, washed 1 X in phosphate buffered saline (PBS) and resuspended in PBS containing 0.5 mM IBMX at 3x10 6 cells/mL. Ten gL of cell suspension was added to each well of a 384-well plate which contained 10 gL of test compounds. Test compounds were diluted with PBS 10 containing 6 pM of forskolin. Plates were incubated for 30 minutes at room temperature after the addition of cells. Lysis buffer containing cAMP-Tag was added to each well (10 L/well) as per the manufacturer's protocol. Plates were then incubated from 45 minutes to overnight. Prior to reading, 10 pL of read buffer was added to each well, and the plate was read in a Sector 6000 plate imager. The signal 15 was converted to cAMP concentration using a standard curve run on each plate. Compound EC 50 values were determined from concentration gradients of test compounds. Compounds of Formula (1) of the present invention, and salts, solvates, or esters thereof, have cAMP EC 50 values of less than about 10,000 nM, preferably 20 about 1000 nM or less, more preferably about 500 nM or less, even more preferably about 100 nM or less. Examples 1, 5,10, 29, 39, 71,101-116, and 118-135 have cAMP EC 50 values of 100 nM or less. The activity of selected illustrative compounds of the invention as determined 25 using the above-described assay is presented in the following Table: 242 Nicotinic Recepor Agnst Activity of Selected Illustrative Compounds of the Invention Compound Structure NA ECso No. camp (nM) 11 125.0 0 H 35 N NO9.0 90 N1H F475.3 0 0 NyO Nz 74 N H ~183.0 0 H 102 NN 31.0 0 H 0NN~ 103 NH74.3 0 H 00 NYO 104 NNH 47.0 0 H NO 107 NN 18.7 0 H 00 NO 108N NH 28.0 0 H 0 N,, 12NH 14.4

F

3 ,0 243 H 116 ONHO12.6 H O0NO 117, NNH 155.0 0 118 NH4.2 0 H ON,0 119 ~ NH 10.1 0 H 122 NH 5.3 0 H NO 123NH4.3 0 H O0 NeO 124N NH 78.5 0 H 125N NH 1.2 0 H 126 yNNH 26.5 0 H 127 N NH 57.3 0 H N,e 128N NH 6.3 0 H 0 0 NyO 19NH 106.5 0 244 135 o NH 4.8 0 H N 'N NH 223 026.45 F 229 47. H 241 O TO12.95 2621 NH41.2 0 H 00NO 2686'N H12 0 0 H 0 0 NO0 292 ~NH30 0 H 00NH 297 ' H56.75 0 512N 1NH 26.2 00 245 666 00 1ONy ~r 063.3 N NH 0 o o N 4, NH O 691 N47.5 0 o N 0O 712 NH 57.0 713 "Y22.0 7140 0 NH 66.0 0 0 o N O, 715 NH 671.0 0 N O o 0 N Y0,/ 716 N0NH 171.5 0 o 0 N 0 4, 717 NH 259.0 0 o0 N 0 4, 718 NH 162.5 0 N O o0 Ny0 , 719 NH 152.0 0 7200 0 N- 0 4 720NJHy89.5 00 246 721N 225.5 0 722 00111.5 N NH 0 0 OMe 723 00 NYO 296 NH 0 OH 00 NO O y2459.5 724 N. NH 50 OH 725 00 NY 675 NH 50 OR 0 0 N O O 727 NH 79 O 0 N ' "O " OH 728 NH 26-2 0 OH 0 0 N 0 730 NH 155.8 0 247 731 0 0 N 0,-"177.4 NH 0 00 NO 732 NH 95.5 0 0 0 N O 733 NH 52.6 0 00 NYO 734N1 NH 71.8 00 N0 735 NH 94 0 OH 00NYO 736 NH 32.9 0 OH 00 Ny0 737 NH 59.5 0 738 0y 0<,33.8 N NH 50 0 0 1N Y Ol 739 NH 136.8 O 1_-

-,_-_-II

248 F 0 N OION F NH 740 130 0 0 N NrF NH 741 0 123 ONF 0 N F NH 742 1068 00N 0 O N F 746 NH 743 0 212.5 F 00 N'Zr N H 745 0 1233 0 0 0 N N N 0 N NH 747 0 1233 249 F 00 N F N NH 748 0 286 00 0 0 N F N NH 749 0 182.5 F 0 0 N~yl N F 750 NH 1892.5 0 O NH 751 0 487 s o O Nl F 752 NH 248 0 753 00 F NH o 228 7540 N F N NH 0 308 755 0 0 F NH 0 286 00N H 0 0 1NOy 759 NC 11NH2326 760 NC NH 10000 0 250 0 O N CF3 763 N NH 0 7734 0 0 N PCF3 N NH 764 0 8922 H 0 0 NO 768 N, %Me 383.5 0 H 0 0 NO o oMo 769 19 OMe 770 0 NH908 0 OMe 00 1N f0 NH 771 17 0 H O O N yO NOMe 772 0N39 OMe 0 0 N,~ NH 773 0 48.5 H 0 0N1O 774 0NOMe 28.0 251 OEt 7760 1 N y0 NH 776010000 H 00 NyO 777 0 OEt 5600 0 OEt 778 NH 9150 0 H 0 0 NO1 779 NEt 2851 0 0 00 NO 780 N036 H 00 NO 781 0N68 H 00 NO 782 o 194 00 N 0Ne 783 oN64 00 NO 784 0 17.9 252 H 0 0 NO 786 05331 00 NO 787 N1681.5 H oNO 788 Nj38.5 F ONO 789 N088 F sIN OI 791 50 05 IN O 792 0 44 796 0 >10000 0 797NN 798 0 0 N 0O>10000 NNH 0 H 00 NO 799 NN>1000 0 253 H 080 NO 800 N >10000 Oe 80 NO 801 F >10000 0 804 F H NyO 802 0 12 H 0 0 N y F 803 3450 810 0 H 804 0 178 OH 805 " NH 2063 0 H 806 N 'OH 256 0 0 0 N 807 NH > 10000 0 H O N NO 808 NH >10000 0 NNH 809 0 187 810 N'NH> 10000 254 811 0 0 NN F O 22

H

3 C 812 O0N F NH 40 0 0 O 813 H 256 0 H 814 161 N F H 0 I N0 815 O 10000 816 NyF 291 O F H 817 NF 1450 0 F0 818 ~N >308 0 819 N ,- F1536 0 H 0 0 NOe 820 KN F10000 0 255 R 0 0 1NO 821 N NJF 142 0 H 00 NO0 822 N ">(F 10000 0 H 823 0 10000 NO 824 91 F 825 N 616 F

N

0 N O 826 N 3251 0 O1F 0 NO 827 _N 690 0 HIF H N 0 828 N 407 O F> 00 NO 829 0 882 F F H 00 NyO 830 112 _____2XF

____

256 H NO 831 F 531 F 00 0 832 N304 HF 0 N O N 833 o0 511 F The activity of compounds 834-844 was also determined using the above described assay and the EC 50 values measured ranged from about 3 nM to about 1600 nM. Several selected compounds demonstrated EC 50 values ranging from 5 about 3 nM to about 100 nM. The activity of several other compounds of the present invention is shown earlier in this specification as A, B or C. It will be appreciated by those skilled in the art that the herein-described inventive compounds exhibit excellent nicotinic acid receptor 10 agonist activity. While the present invention has been described with in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention. 15

Claims (34)

1. 2. The compound of claim 1, having the formula: 10 o 0 R2 R1 (11) or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein: Q is selected from the group consisting of: 1 NyR4 NY R4 N%,R5 1N 15 0 and R 6 R 1 is -H, alkyl, haloalkyl, arylalkyl, -alkylene-S-alkyl or -alkylene-cycloalkyl; R 2 is -H, -CN, or -NHC(O)-alkyl; R 4 is -0-cycloalkyl, -0-alkynyl, -0-alkynylene-cycloalkyl, haloalkyl or -0 N=C(R12) 2 , wherein both R 12 groups, together with the carbon atom to which they are 20 attached, combine to form a heterocyclyl group, and wherein the alkynyl portion of an -0-alkynyl group can be optionally subsituted with -OH or alkoxy; and wherein the cycloalkyl portion of an -0-cycloalkyl group can be optionally substituted with an alkylene-O-alkylene-aryl group; R 5 is -H, -OH, alkyl, haloalkyl, arylalkyl, -0-alkyl, -0-aryl, cycloalkyl, 25 heterocyclyl, -0-cycloalkyl, -0-heterocyclyl, -0-arylalkyl or -alkylene-O-alkyl; and R 6 is alkoxy, -O-alkylene-O-alkyl, -0-arylalkyl or -0-haloalkyl. 262
2. 3. The compound of claim 1, having the formula: o 0 R2 Ill or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein: 5 Q is selected from the group consisting of: R3 R3 NON TO INR 5 N 0 and R ; R' is -H, alkyl, haloalkyl, arylalkyl, -alkylene-S-alkyl or -alkylene-cycloalkyl; R 2 is -H, -CN, or -NHC(O)-alkyl; 10 R 3 is -H, -OH, alkyl, haloalkyl, arylalkyl, -0-alkyl, -0-aryl, cycloalkyl, heterocyclyl, -0-cycloalkyl, -0-heterocyclyl, -0-arylalkyl or -alkylene-O-alkyl; R 5 is -H, -OH, alkyl, haloalkyl, arylalkyl, -0-alkyl, -0-aryl, cycloalkyl, heterocyclyl, -0-cycloalkyl, -0-heterocyclyl, -0-arylalkyl or -alkylene-O-alkyl; and R 6 is alkoxy, -O-alkylene-O-alkyl, -0-arylalkyl or -0-haloalkyl. 15
3. 4. The compound of claim 1, wherein Q is: tLNy R4 ry N %%R5 0
4. 5. The compound of claim 1, wherein Q is: R 3 NR 5 0. 263
5. 6. The compound of claim 1, wherein Q is: N R4 ss N N R 6 5 7. The compound of claim 1, wherein Q is: R 3 OSyN R 6 10
6. 9. The compound of claim 1, wherein R' is -H, alkyl, haloalkyl, arylalkyl, -alkylene-S-alkyl or -alkylene-cycloalkyl; R 2 is -H, -ON, or -NHC(O)-alkyl; R 3 is -H, -OH, alkyl, haloalkyl, arylalkyl, -O-alkyl, -0-aryl, cycloalkyl, 15 heterocyclyl, -O-cycloalkyl, -O-heterocyclyl, -O-arylalkyl or -alkylene-O-alkyl; R 4 is -O-cycloalkyl, -- alkynyl, -O-alkynylene-cycloalky, haloalkyl or - N=C(R 12 ) 2 , wherein both R1 2 groups, together with the carbon atom to which they are attached, combine to forrn a heterocyclyl group, and wherein the alkynyl portion of an -- alkynyl group can be optionally subsituted with -OH or alkoxy; and wherein the 20 cycloalkyl portion of an -0-cycloalkyl group can be optionally substituted with an alkylene-O-alkylene-aryl group; and 264 R 5 is -H, -OH, alkyl, haloalkyl, arylalkyl, -0-alkyl, -0-aryl, cycloalkyl, heterocyclyl, -0-cycloalkyl, -0-heterocyclyl, -0-arylalkyl or -alkylene-O-alkyl; and R 6 is alkoxy, -O-alkylene-O-alkyl, -0-arylalkyl or -0-haloalkyl. 5 10. . The compound of claim 9, wherein Q is: H H N 4N O N R l NR5 y NR5 y N a , 0 or 0 R' is alkyl, haloalkyl or -alkylene-cycloalkyl; R 2 is -H; and R 5 is -H or alkyl. 10 11. The compound of claim 9, wherein Q is: R 3 S I 1N SR4 1N O Y RN NS~ R 6 (c) or (d) R' is alkyl, haloalkyl or -alkylene-cycloalkyl; and R 2 is -H. 15 12. The compound of claim 10, wherein Q is: 4 H C<N N R4 N O 51YNH 0yNH 0 or 0 and R 4 is -0-alkynyl or -0-alkynylene-cycloalkyl, wherein the alkynyl portion of an -0 alkynyl group can be optionally subsituted with -OH or alkoxy. 20
7. 13. The compound of claim 10, wherein 265 Q is: 4H N R4 N O ,Y NH S4 rrNH o or 0 and R 4 is haloalkyl. 5 14. The compound of claim 10, wherein Q is: 4H 54"y NH y NH o or 0 and R 4 is -O-N=C(R12) 2 , wherein both R1 2 groups, together with the carbon atom to 10 which they are attached, combine to form a heterocyclyl group.
8. 15. The compound of claim 13, wherein R 4 is -CH 2 F or -CH(F) 2 .
9. 16. The compound of claim 14, wherein R 4 is: 15
10. 17. The compound of claim 2, wherein Q is: N R4 IJK(NH 0 20 R1 is alkyl, haloalkyl, or -alkylene-cycloalkyl, and R 2 is -H. 266
11. 18. The compound of claim 17, wherein R 4 is -0-alkynyl or -0-alkynylene cycloalkyl, wherein the alkynyl portion of an -0-alkynyl group can be optionally subsituted with -OH or alkoxy. 5 19. The compound of claim 17, wherein R 4 is haloalkyl.
12. 20. The compound of claim 17, wherein R 4 is -O-N=C(R12) 2 , wherein both R12 groups, together with the carbon atom to which they are attached, combine to form a heterocyclyl group. 10
13. 21. The compound of claim 17, wherein R 4 is -CH 2 F, -CH(F) 2 , -CF 3 , OCH 2 C=CCH 2 CH 3 ,-OCH 2 C=C(CH 2 ) 3 CH 3 ,-OCH 2 CECCH 2 CH 2 CH 3 , -OCH2C=C-cyclopropyl, -OCH 2 C=CCH(OCH 3 )CH 3 ,-OCH 2 C=CCH(OH)CH 3 , -OCH 2 C-CCH(OH)CH 2 CH 3 ,-OCH 2 C=CCH 2 CH 2 OCH 3 , 15 OCH 2 C=CCH 2 CH 2 OH, -OCH 2 C=C(CH 2 ) 3 0H, -OCH(CH 3 )C=CCH 2 CH 3 ,-OCH 2 C=C-cyclohexyl, -0-cyclobutyl, 0 cH 2 OCH 2 - hos CH 2 CH 2 O.CH2OCH2 or \0N=~~ O or 20
14. 22. The compound of claim 21, wherein R 4 is -CH 2 F, -CH(F) 2 or O1N ~~~ C O 25 23. The compound of claim 2, wherein Q is: 267 c N rR 4 R 6 R' is alkyl, haloalkyl, or -alkylene-cycloalkyl, and R 2 is -H.
15. 24. The compound of claim 23, wherein R 4 is -CH 2 F, -CH(F) 2 , -CF 3 , 5 OCH 2 C=CCH 2 CH 3 , -OCH 2 C=C(CH 2 ) 3 CH 3 , -OCH 2 C=CCH 2 CH 2 CH 3 , -OCH 2 C=C-cyclopropyl, -OCH 2 C=CCH(OCH 3 )CH 3 , -OCH 2 CECCH(OH)CH 3 , -OCH 2 C=CCH(OH)CH 2 CH 3 ,-OCH 2 CECCH 2 CH 2 OCH 3 , OCH 2 C=CCH 2 CH 2 OH, -OCH 2 C=C(CH 2 ) 3 0H, -OCH(CH 3 )C=CCH 2 CH 3 , -OCH 2 C=C-cyclohexyl, -0-cyclobutyl, 0 CH2OCH20Q<" CH 2 CH 2 10 CH 2 0CH 2 -0 N=orN O or NO
16. 25. The compound of claim 24, wherein R 4 is -CH 2 F, -CH(F) 2 or 15( N~~~ O
17. 26. The compound of claim 24, wherein R' is a straight chain alkyl having from 1 to 6 carbon atoms. 20 27. The compound of claim 24, wherein R' is -(CH2) 3 -cyclopropyl or -(CH 2 ) 2 cyclobutyl.
18. 28. The compound of claim 3, wherein Q is: 268 R 3 ~N O NR5 0.
19. 29. The compound of claim 28, wherein R1 is alkyl, haloalkyl, or -alkylene-cycloalkyl; and R 2 , R 3 and R 5 are each -H. 5
20. 30. The compound of claim 28, wherein R1 is alkyl, haloalkyl, or -alkylene-cycloalkyl; R 2 is -H and one, but not both of R 3 and R 5 are -H.
21. 31. The compound of claim 29, wherein R' is a straight chain alkyl having from 1 to 10 6 carbon atoms.
22. 32. The compound of claim 1, wherein Q is: R3 N -''R4 NY R4 N JR4 NIR5N SNN 0 R6 0 (a) (c) or (e) 15 R' is alkyl or -alkylene-cycloalkyl and R 2 is -H.
23. 33. The compound of claim 32, wherein R 4 is haloalkyl or -O-N=C(R12) 2 , wherein both R 12 groups, together with the carbon atom to which they are attached, combine to 20 form a heterocyclyl group.
24. 34. The compound of claim 33, wherein R 4 is -CH 2 F or -CH(F) 2 . 269
25. 35. The compound of claim 30, wherein R 1 is methyl, ethyl, n-butyl, n-phenyl, (CH 2 ) 3 -cyclopropyl or -(CH 2 ) 2 -cyclobutyl, R 2 is -H, and R 4 is -CH 2 F, -CH(F) 2 , -CF 3 , OCH 2 C=CCH 2 CH 3 , -OCH 2 C=C(CH 2 ) 3 CH 3 , -OCH 2 C=CCH 2 CH 2 CH3, OCH 2 C=C-cyclopropyl, -OCH 2 C=CCH(OCH 3 )CH 3 , -OCH 2 C=CCH(OH)CH 3 , 5 OCH 2 C=CCH(OH)CH 2 CH 3 , -OCH 2 C=CCH 2 CH 2 0CH 3 , OCH 2 CECCH 2 CH 2 OH, -OCH 2 C=C(CH 2 ) 3 OH, -OCH(CH 3 )C=CCH 2 CH 3 , -OCH 2 C=C cyclohexyl, -0-cyclobutyl, O < CH20CH2OlCH 2 CH 2 OK CH 2 OCH 2 4 or ON- O or 10
26. 36. The compound of claim 1, wherein Qis: R3 R3 N 0N O R6 (b) or (d) 15 R' is alkyl or -alkylene-cycloalkyl and R 2 is -H.
27. 37. The compound of claim 36, wherein one, but not both, of R 3 and R 5 is -H.
28. 38. The compound of claim 37, wherein one of R 3 and R 5 is -H and the other is 20 OH, alkyl, haloalkyl, arylalkyl, -0-alkyl, -0-aryl, cycloalkyl, heterocyclyl, -0-cycloalkyl, 0-heterocyclyl, -0-arylalkyl or -alkylene-O-alkyl. 270
29. 39. The compound of claim 38, wherein one of R 3 and R 5 is -H and the other is OCH 3 , cyclobutyl, ethyl, N-morpholinyl, -O-benzyl, -CH 2 CH 2 0CH 3 , -OCH 2 CH 3 , CH 2 F, -CH 2 CH 2 F or -OH. 5
30. 40. A compound having the structure: 0 0 N Y0 ,/62 01N 0 0 N 0,,,, N NH '.. NHY -. NH 100 0 NO 00 NO O 0 N O2 NHN NH 10 0 ,0 00No/ 000N 60 0 0 NO,,, NO 0O -. NH --. NH N NH O0V:3 0 0 0 NyO,,62/ 00 NyO 0 0 -NO 06. NHN 0;N H NH 0 0 f 0 15 F F O F F 00 N 0F O O NF N O0 N F 0 ONF NH NH 0-NH NH O 0 0 0 OMe 0 ON F O00 N F 0 N F OMe N 0 N NH N NH 0 N O 0N 0 0Y NH 0 271 OH OH 00 NO 001NO 00 N0 O Oe O NH O NH NH 0 0 0 OH O 0 O 0~ OH 00 NO < 0 ONO ' OONH NH NH H O 0 0 N 0 N0YONO 0 0 NK"., 00N 0NH N NH N NH 0 0 0 OH OH 00 NO 0 0 NO 00 NO N NH NH NH 0 0 0 F O 0 0 1 N F0 N O F OF NH N H N O NHF ONH 0 0N 00 1 " NH 100 141 :7 :1 1 0 0 N'yF 0 0 NyCF 3 O0:0 1 NyCF 3 O O N F N NH N H NH H 0 C N NH 0 0 0 F O 00 N F 0 0 Rr NNH N NH 0 N0, 0 0 N H 10y7y 0Q0NO04,-%0 0 N ~F 0 0 N 0' Y \'KO NH N N,01 NH 0 NH0 H 3 0 272 O0 F FzH N 0 Y CFO ON< 0 0 N NH Y 0H 0 N&0 1 NH 0 N NH 0N 0 F Or F Y , F F 0 0 N, 0 0 N F O0 O N<F 00 N CF 3 N F F NH F NH ONH NH O0 Nz F 0 0 0 NNH 0 IF N NH 0 or F or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof. 5
31. 41. A compound having the structure: H OMe 0 N000 NO 0 H IYO 0N0 0 NO0 H OMe I IY 0 0 1NY0 0 0 0 NOY 0N0NOMe ' N, NI 0N0 0 ONOe0 N OMe e H I H I~ 0 0 NO OMe 00 N 0 ~0 N 0 0 0 NO0 N , %Me 0 YN0 NH NOMe N NH'~ 0 N NH 0 00 0 10 H H 00 O0 0 NO H 0 0 NO NCN 0 HNC NNH 0 H MeOCHN 0H 0 NNC 0 ~00 273 H H H0) NrO 0 N 00 0 OOHN N N " 0 1 NI 00 0 NO 00 NO 0: N ~ N NH N , NH 0 0 0O O O O O~e O O H H H 00 N HO N00 N0 00 NOH10 O 0 0 N NI Y00I I N ONOO NH ENH I ,I 00 Et I H H 0 0 N 00 0 N 0 Et 0F0 NO 00 N 00N NKN . NH N, OBt lY N0 0 NHNQEt 0 5 1 0 0 H H 00NO H H 00 NO H NFOO0NY 0 NO N 0 0 ~.F N F N 0N0 N O F 0 F F 2 H H 0 0 Ny0 OH H 0 0 0 N 0 N 0 0 0 N, 0 H1 NH '-'-NH-NF00N H HN 0 o 0r 0 0 NC N 0 H 0 H 0 0 W 0 0-0 0 0 '01N H0~ 10 ,or F or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof.
32. 42. A compound having the structure: 274 0 0 N F 0 0 K H 0 o 0 N F 0 0 N F 0Oo N O NH NH 0 0 N F N 0 0 NH 0 0 F H H 0FF 00 N F O N OO N OON F NH F NH N NF ' N H INHNH 00NH 0 F O F 0 0 0 N O or 5 or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof.
33. 43. A compound having the formula: H o 0 N O N,'R2 R1 O (IV) 10 or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is haloalkyl; and R 2 is H or cycloalkyl. 15 44. A compound having the formula:
34. 275. 0 N R2 NH R1 O (V) or a pharmaceutically acceptable salt or solvate thereof, wherein: 5 R1 and R 2 are each, independently, haloalkyl. 45. The compound of claim 43, wherein R 1 is fluoroalkyl. 46. The compound of claim 44, wherein R' is -alkylene-CF 2 . 10 47. The compound of claim 44, wherein R1 is -alkylene-F. 48. The compound of claim 46, wherein R 1 is -(CH 2 )3-CF 2 , -(CH 2 ) 4 -CF 2 or -(CH 2 ) 5 CF 2 . 15 49. The compound of claim 43, wherein R 2 is H. 50. The compound of claim 43, wherein R 2 is cycloalkyl. 20 51. The compound of claim 50, wherein R 2 is cyclobutyl. 52. The compound of claim 44, wherein R 2 is H. 53. The compound of claim 45, wherein R 2 is H. 25 54. The compound of claim 44, wherein R 2 is cycloalkyl. 55. The compound of claim 45, wherein R 2 is cycloalkyl. 276 56. A compound having the structure: H H F H 00 N 000 N O 00 Nl 0F O N O NH N NH NH 0O 0 0 F F F F , F , F ,F F 5 H 0 0 NO0 HOO 00 NO H HNH 0 0 N 000 NO INH O O N O O O N0 O N NH NH O O F 00 F ,F ,F F , F 00 N CHF 2 NH 0 0 N CHF 2 0 0 N O O 0 N CHF 2 ON NH NH NH "N O 0 00 F F ,F OF F 10 or a pharmaceutically acceptable salt or solvate thereof. 57. A composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier. 15 58. A composition comprising at least one compound of claim 40 and a pharmaceutically acceptable carrier. 59. A composition comprising at least one compound of claim 41 and a pharmaceutically acceptable carrier. 20 277 60. A composition comprising at least one compound of claim 42 and a pharmaceutically acceptable carrier. 61. A composition comprising at least one compound of claim 43 and a 5 pharmaceutically acceptable carrier. 62. A composition comprising at least one compound of claim 44 and a pharmaceutically acceptable carrier. 10 63. A composition comprising at least one compound of claim 56 and a pharmaceutically acceptable carrier. 64. The composition of any one of claims 57-63, further comprising at least one additional therapeutic agent selected from the group consisting of anti-flushing agents, 15 hydroxy-substituted azetidinone compounds, substituted p-lactam compounds, HMG CoA reductase inhibitor compounds, HMG CoA synthetase inhibitors, squalene synthesis inhibitors, squalene epoxidase inhibitors, sterol biosynthesis inhibitors, nicotinic acid derivatives, bile acid sequestrants, aspirin, NSAID agents, Vytorin, ezetimibe, inorganic cholesterol sequestrants, AcylCoA:Cholesterol 0 20 acyltransferaseinhibitors, cholesteryl ester transfer protein inhibitors, fish oils containing Omega 3 fatty acids, natural water soluble fibers, plant stanols and/or fatty acid esters of plant stanols, anti-oxidants, PPAR a agonists, PPAR y-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport inhibitors, bile acid 25 reabsorption inhibitors, PPAR 6 agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR 6 partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CB 1 antagonists/inverse agonists, ghrelin antagonists, H 3 antagonists/inverse agonists, 30 MCH1 R antagonists, MCH2R agonists/antagonists, NPY1 antagonists, NPY5 antagonists, NPY2 agonists, NPY4 agonists, mGluR5 antagonists, leptins, leptin agonists/modulators, leptin derivatives, opioid antagonists, orexin receptor 278 antagonists, BRS3 agonists, CCK-A agonists, CNTF, CNTF derivatives, CNTF agonists/modulators, 5HT2c agonists, Mc4r agonists, monoamine reuptake inhibitors, serotonin reuptake inhibitors, GLP-1 mimetics, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC inhibitors, P3 agonists, DGAT1 5 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone P agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11(P HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, anti 10 hypertensive agents, anti-dyslipidemic agents, DPP-IV inhibitors, apolipoprotein-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitors, sympathomimetic agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogs, melanin concentrating hormone antagonists, leptons, galanin receptor antagonists, bombesin agonists, neuropeptide-Y antagonists, thyromimetic 15 agents, dehydroepiandrosterone, analogs of dehydroepiandrosterone, urocortin binding protein antagonists, glucagons-like peptide-1 receptor agonists, human agouti-related proteins (AGRP), neuromedin U receptor agonists, noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists, MSH receptor analogs, a-glucosidase inhibitors, apo Al milano reverse cholesterol 20 transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP). 65. The composition of claim 64, wherein the at least one additional therapeutic agent is an HMG CoA reductase inhibitor selected from the group consisting of 25 lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatin calcium, and pitavastatin. 66. The composition of claim 65, wherein the at least one additional therapeutic agent is simvastatin. 30 67. The composition of claim 64, wherein the at least one additional therapeutic agent is a cholesteryl ester transfer protein inhibitor. 279 68. The composition of claim 67, wherein the at least one additional therapeutic agent is an anti-flushing agent. 5 69. The composition of claim 64, wherein the at least one additional therapeutic agent is Vytorin*, ezetimibe, aspirin, ibuprofen or acetaminophen or a combination thereof. 70. The composition of claim 64, wherein the at least one additional therapeutic 10 agent is DPP-IV inhibitor or a GLP-1 mimetic.