US20100227873A1

US20100227873A1 - Nitrogen-containing heterocyclic compounds and methods of use thereof

Info

Publication number: US20100227873A1
Application number: US12/770,931
Authority: US
Inventors: Anandan Palani; Jing Su; Dong Xiao; Xianhai Huang; Ashwin U. Rao; Xiao Chen; Haiqun Tang; Jun Qin; Ying R. Huang; Robert G. Aslanian; Brian A. McKittrick; Syliva J. Degrado
Original assignee: Schering Corp
Current assignee: Merck Sharp and Dohme LLC
Priority date: 2005-05-17
Filing date: 2010-04-30
Publication date: 2010-09-09
Also published as: JP2010509397A; AU2007319940A1; NO20092286L; US20080019978A1; EP2059519B1; US7737155B2; MX2009005217A; TW200825090A; US20110152259A1; WO2008060476A3; JP5020331B2; RU2009122245A; CA2669670A1; EP2059519A2; WO2008060476A2; CL2007003265A1; AR063800A1; CN101589041A; ECSP099335A; KR20090083461A

Abstract

The present invention provides compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, esters, and tautomers thereof, wherein:
- Q is selected from the group consisting of:

and
- L is selected from the group consisting of:

pharmaceutically compositions comprising one or more compounds of formula (I), and methods of using the compounds of formula (I).

Description

REFERENCE TO PRIORITY APPLICATIONS

This application is a continuation-in-part of U.S. patent application Ser. No. 11/600,216, filed Nov. 15, 2006, which is a continuation-in-part of U.S. patent application Ser. No. 11/432,133, filed May 11, 2006, which claims the benefit of priority from U.S. provisional patent applications, Ser. Nos. 60/681,848 filed May 17, 2005; 60/715,565 filed Sep. 9, 2005; and 60/731,039 filed Oct. 28, 2005, each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to nicotinic acid receptor agonist compounds useful for treating metabolic syndrome, dyslipidemia, 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; pharmaceutical compositions comprising such compounds; pharmaceutical compositions comprising nicotinic acid receptor agonist compounds in combination with other therapeutic agents; and methods of treatment 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.

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 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. Ital. (1952) vol. 82, p. 23 disclose syntheses of barbituric acid derivatives. FR 2563223 discloses nucleoside analogs. T. Paterson et al., J. Chem. Soc., Perkins Trans. I (1972), vol. 8, pp. 1041-1050 discloses the synthesis of 8-substituted pyrido[2,3-d]pyrimidines. S. Rao, Indian J. Chem. (1974), 12(10), pp. 1028-1030 discloses the synthesis of pyrano[2,3-d]pyrimidines. M. Skof, Heterocycles, (1999), 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 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 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 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 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 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.
WO2005/077950 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.

SUMMARY OF THE INVENTION

In one embodiment, the present invention is directed to a compound of Formula (I):
and pharmaceutically acceptable salts, solvates, esters, and tautomers thereof, wherein:

- Q is selected from the group consisting of:

- L is selected from the group consisting of:

- R¹is 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: —OH, cycloalkyl, —C(O)-alkyl, -alkylene-C(O)—O-alkyl, -alkylene-O-alkyl, aryl, -alkylene-aryl, heteroaryl, -alkylene-heteroaryl, halogen, —(CH₂)_n—N(R⁷)₂, -alkylene-cycloalkyl, or -alkylene-cycloalkenyl,
  - wherein the cycloalkyl or the cycloalkyl portion of said -alkylene-cycloalkyl of R¹is unsubstituted or substituted with one or more X groups, said aryl or the aryl portion of said -alkylene-aryl of R¹is unsubstituted or substituted with one or more Y groups, and said heteroaryl or the heteroaryl portion of said -alkylene-heteroaryl of R¹is unsubstituted or substituted with one or more Y groups;
- R²is 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—R¹⁰, -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
- R¹and R²together 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 ring having 1 or 2 heteroatoms;
- R³is 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 R³is unsubstituted or substituted with one or more X groups, said aryl of R³is unsubstituted or substituted with one or more Y groups, and said heteroaryl of R³is unsubstituted or substituted with one or more Y groups;
- R⁴is selected from the group consisting of H, halogen, alkyl, haloalkyl, —O-cycloalkyl, —O-alkynyl, —O-R¹⁰, —C(O)—O-alkyl, —S(O)_m—R⁹, —N(R⁷)₂, —N(R⁷)—NH—C(O)-alkyl, —N(R⁷)—NH—C(O)—O-alkyl, —O—N═C(R¹²)₂, —N(R⁷)—N═C(R¹²)₂, —C(O)-alkyl, unsubstituted heterocyclyl, heterocyclyl substituted with one or more X groups, —O—N(R⁷)—C(O)—O-alkyl, —C(O)—N(R⁷)₂, —CN, —N₃, and —O—C(O)-alkyl;
- R⁵is selected from the group consisting of H, alkyl, —OH, haloalkyl, arylalkyl, —O-alkyl, —O-aryl, cycloalkyl, heterocyclyl, —O-cycloalkyl, —O-heterocyclyl, —O-arylalkyl or -alkylene-O-alkyl-alkylene-C(O)—R⁸, -alkylene-C(O)—N(R¹¹)₂, -alkylene-C(═N—O-alkyl)-aryl, cycloalkyl, -alkylene-cycloalkyl, -alkylene-C(O)—O-alkyl, -alkylene-O—C(O)-alkyl, -alkylene-C(O)-heterocyclyl, and alkenyl,
  - wherein the cycloalkyl or the cycloalkyl portion of said -alkylene-cycloalkyl of R⁵is unsubstituted or substituted with one or more X groups, and the aryl portion of said -alkylene-C(═N—O-alkyl)-aryl of R⁵is unsubstituted or substituted with one or more Y groups;
- R⁶is selected from the group consisting of H, alkyl, alkenyl, alkyl substituted with one or more hydroxyl groups, -alkylene-O-alkyl, —O—R¹⁰, halogen, aryl, heteroaryl, and —N(R⁷)₂, wherein the aryl of R⁶is unsubstituted or substituted with one or more Y groups, and said heteroaryl of R⁶is unsubstituted or substituted with one or more Z groups;

each R⁷is independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, —C(O)-alkyl, and —C(O)-aryl, wherein the cycloalkyl of R⁷is unsubstituted or substituted with one or more X groups, and the aryl portion of said —C(O)-aryl or said aryl of R⁷is unsubstituted or substituted with one or more Y groups;

- two R⁷groups, together with the N atom to which they are bonded form a heterocyclyl;
- R⁸is selected from the group consisting of aryl, —OH, and heterocyclyl,
  - wherein the heterocyclyl of R⁸is unsubstituted or substituted with one or more X groups, and said aryl of R⁸is unsubstituted or substituted with one or more Y groups;
- R⁹is selected from the group consisting of alkyl, -alkylene-cycloalkyl, alkenyl, —N(R¹¹)₂, and -alkylene-aryl,
  - wherein the cycloalkyl portion of said -alkylene-cycloalkyl of R⁹is unsubstituted or substituted with one or more X groups, and the aryl portion of said -alkylene-aryl of R⁹is unsubstituted or substituted with one or more Y groups, and
  - with the proviso that when R⁹is —N(R¹¹)₂, m is 1 or 2;
- R¹⁰is 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, wherein an the alkynyl portion of an —O-alkynyl group can be optionally subsituted with —OH or alkoxy; the cycloalkyl portion of an —O-cycloalkyl group can be optionally substituted with an -alkylene-O-alkylene-aryl group; the cycloalkyl portion of said -alkylene-cycloalkyl of R¹⁰is unsubstituted or substituted with one or more X groups; the aryl portion of said -alkylene-aryl or -alkenylene-aryl of R¹⁰is unsubstituted or substituted with one or more Y groups; and the heteroaryl portion of said -alkylene-heteroaryl of R¹⁰is unsubstituted or substituted with one or more Z groups;
- R¹¹is selected from the group consisting of H, alkyl, and aryl,
  - wherein the aryl of R¹¹is unsubstituted or substituted with one or more Y groups; or
- two R¹¹groups, together with the N atom to which they are attached, form a heterocyclyl;
- each R¹²is independently selected from the group consisting of alkyl, aryl, and heteroaryl,
  - wherein the aryl of R¹²is unsubstituted or substituted with one or more Y groups and said heteroaryl of R¹²is unsubstituted or substituted with one or more Z groups; or wherein both R¹²groups, together with the carbon atom to which they are attached, combine to form a heterocyclyl group;
- R^aand R^bare each independently selected from the group consisting of H, alkyl, aryl, and heteroaryl,
  - wherein the aryl of R^aand R^bis unsubstituted or substituted with one or more Y groups, and said heteroaryl of R^aand R^bis unsubstituted or substituted with one or more Z groups;
- R^cis selected from the group consisting of H, alkyl, alkylene-aryl, and —C(O)-alkyl,
  - wherein the aryl portion of said alkylene-aryl of R^cis unsubstituted or substituted with one or more Y groups;
- R^dis selected from the group consisting of H, alkyl, and alkylene-aryl,
  - wherein the aryl portion of said alkylene-aryl of R^dis unsubstituted or substituted with one or more Y groups;
- each X is independently selected from the group consisting of halogen, alkyl, haloalkyl, —O-alkyl, —O-haloalkyl, and —OH;
- each Y is independently selected from the group consisting of halogen, alkyl, haloalkyl, —O-alkyl, —O-haloalkyl, —CN, —NO₂, —OH, —S(O₂)-alkyl, —S(O₂)-aryl, —S(O₂)—NH₂, —S(O₂)—NH-alkyl, —S(O₂)—NH-aryl, —S(O₂)—N(alkyl)₂, —S(O₂)—N(aryl)₂, —S(O₂)—N(alkyl)(aryl), and aryl;
- each Z is independently selected from the group consisting of alkyl, haloalkyl, halogen, —O-alkyl, —O-haloalkyl, —CN, —OH, aryl, and N-oxide;
- n is 0, 1, 2, or 3;
- m is 0, 1, or 2; and
  - with the proviso that when L is (f), and R², R³and R⁵are each H, then
- R¹is not —CH₃.

In another embodiment, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula (I), 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, 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 (I), or a pharmaceutically acceptable salt, solvate, ester, or 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, 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 (I), 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, substituted β-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 O-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-density lipoprotein receptor activators, anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport protein inhibitors, bile acid reabsorption inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR 6 partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CB, antagonists/inverse agonists, ghrelin antagonists, H₃antagonists/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, 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, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone β agonists, UCP-1 activators,
UCP-2 activators, UCP-3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11β HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, anti-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, 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, noradrenergic anorectic agents, appetite suppressants, hormone sensitive lipase antagonists, MSH-receptor analogs, α-glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP).

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, 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.
The present invention provides compound of Formula (I):
and pharmaceutically acceptable salts, solvates, estesr, and tautomers thereof, wherein L, Q, R¹and R²are defined above for the compound of formula (I).
In one embodiment, R¹is alkyl.
In another embodiment, R¹is haloalkyl.
In another embodiment, R¹is arylalkyl.
In still another embodiment, R¹is -alkylene-S-alkyl.
In yet another embodiment, R¹is -alkylene-cycloalkyl.
In another embodiment, R¹is -alkylene-cyclopropyl, -alkylene-cyclobutyl, -alkylene-cyclopentyl or -alkylene-cyclohexyl.
In a further embodiment, R¹is -alkylene-cycloalkenyl.
In another embodiment, R¹is a straight chain alkyl having from 1 to 6 carbon atoms.
In one embodiment, R¹is methyl.
In another embodiment, R¹is ethyl.
In another embodiment, R¹is n-propyl.
In still another embodiment, R¹is n-butyl.
In one embodiment, R¹is n-pentyl.
In another embodiment, R¹is n-hexyl.
In yet another embodiment, R¹is a branched chain alkyl having from 3 to 6 carbon atoms.
In a further embodiment, R¹is isopropyl.
In one embodiment, R¹is isobutyl.
In another embodiment, R¹is isopentyl.
In another embodiment, R¹is sec-butyl.
In still another embodiment, R¹is tert-butyl,
In yet another embodiment, R¹is haloalkyl, having from 1 to 3 F atoms.
In another embodiment, R¹is —(CH₂)₃CF₃.
In one embodiment, R²is —H.
In another embodiment, R²is —CN.
In another embodiment, R²is —NHC(O)-alkyl.
In still another embodiment, R²is —NHC(O)CH₃.
In one embodiment, R³is —H.
In another embodiment, R³is —OH.
In another embodiment, R³is alkyl.
In another embodiment, R³is haloalkyl.
In still another embodiment, R³is —O-alkyl.
In yet another embodiment, R³is cycloalkyl.
In a further embodiment, R³is heterocyclyl.
In one embodiment, R³is —O-arylalkyl.
In another embodiment, R³is -alkylene-O-alkyl.
In one embodiment, R³is —OCH₃.
In another embodiment, R³is cyclobutyl.
In another embodiment, R³is ethyl.
In still another embodiment, R³is N-morpholinyl.
In one embodiment, R³is —O-benzyl.
In another embodiment, R³is —CH₂CH₂OCH₃.
In yet another embodiment, R³is —OCH₂CH₃.
In another embodiment, R³is —CH₂F.
In one embodiment, R³is —CH₂CH₂F.
In another embodiment, R³is —OH.
In one embodiment, R⁴is —CF₃.
In another embodiment, R⁴is —H.
In another embodiment, R⁴is —O-cycloalkyl.
In another embodiment, R⁴—O-alkynyl.
In still another embodiment, R⁴is —O-alkynylene-cycloalkyl.
In yet another embodiment, R⁴is haloalkyl.
In a further embodiment, R⁴is —O—N═C(R⁷)₂.
In one embodiment, R⁴is is —CH₂F.
In another embodiment, R⁴is —CH(F)₂.
In another embodiment, R⁴is —CF₃.
In another embodiment, R⁴is —OCH₂C≡CCH₂CH₃.
In another embodiment, R⁴is —OCH₂C≡C(CH₂)₃CH₃.
In still another embodiment, R⁴is —OCH₂C≡CCH₂CH₂CH₃.
In yet another embodiment, R⁴is —OCH₂C≡C-cyclopropyl.
In a further embodiment, R⁴is —OCH₂C≡CCH(OCH₃)CH₃.
In one embodiment, R⁴is —OCH₂C≡CCH(OH)CH₃.
In another embodiment, R⁴is —OCH₂C≡CCH(OH)CH₂CH₃.
In another embodiment, R⁴is —OCH₂C≡CCH₂CH₂OCH₃.
In still another embodiment, R⁴is —OCH₂C≡CCH₂CH₂OH.
In yet another embodiment, R⁴is —OCH₂C≡C(CH₂)₃OH.
In a further embodiment, R⁴is —OCH(CH₃)C≡CCH₂CH₃.
In another embodiment, R⁴is —OCH₂C≡C-cyclohexyl.
In one embodiment, R⁴is —O-cyclobutyl.
In another embodiment, R⁴is:
In one embodiment, R⁴is:
In one embodiment, R⁵is —H.
In another embodiment, R⁵is —OH.
In another embodiment, R⁵is alkyl.
In another embodiment, R⁵is haloalkyl.
In still another embodiment, R⁵is —O-alkyl.
In yet another embodiment, R⁵is cycloalkyl.
In a further embodiment, R⁵is heterocyclyl.
In one embodiment, R⁵is —O-arylalkyl.
In another embodiment, R⁵is -alkylene-O-alkyl.
In one embodiment, R⁵is —OCH₃.
In another embodiment, R⁵is cyclobutyl.
In another embodiment, R⁵is ethyl.
In still another embodiment, R⁵is N-morpholinyl.
In one embodiment, R⁵is —O-benzyl.
In another embodiment, R⁵is —CH₂CH₂OCH₃.
In yet another embodiment, R⁵is —OCH₂CH₃.
In another embodiment, R⁵is —CH₂F.
In one embodiment, R⁵is —CH₂CH₂F.
In another embodiment, R⁵is —OH.
In one embodiment, R⁶is alkoxy.
In another embodiment, R⁶is —O-alkylene-O-alkyl.
In another embodiment, R⁶is —O-arylalkyl.
In stilt another embodiment, R⁶is —O-haloalkyl.
In yet another embodiment, R⁶is —OCH₂-(4-methoxyphenyl).
In one embodiment, R⁶is —OCH₂F.
In another embodiment, R⁶is —OCH₂CH₂F.
In another embodiment, R⁶is —OCH₂CH₃
In still another embodiment, R⁶is —OCH₂CH₂OCH₃.
In one embodiment, Q is:
In another embodiment, Q is:
In another embodiment, Q is:
In still another embodiment, Q is:
In yet another embodiment, Q is:
In one embodiment, L is:
In another embodiment, L is:
In another embodiment, L is:
In still another embodiment, L is:
In another embodiment of the compounds of Formula (I),

- R¹is selected from the group consisting of —(C₁-C₆)alkyl, —(C₁-C₆)alkenyl, —(C₁-C₆)alkynyl, —(C₁-C₆)haloalkyl, —(C₁-C₆)alkyl substituted with one hydroxyl group, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, —(C₁-C₆)alkylene-(C₆-C₁₀)aryl, —(C₁-C₆)alkylene-(C₂-C₁₀)heteroaryl, —(C₁-C₆)alkylene-C(O)—O—(C₁-C₆)alkyl, —(CH₂)_n—N(R⁷)_{2l , —(C} ₁-C₆)alkylene-(C₃-C₇)cycloalkyl, and —(C₁-C₆)alkylene-(C₃-C₇)cycloalkenyl
  - wherein the —(C₃-C₇)cycloalkyl or the (C₃-C₇)cycloalkyl portion of said —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl is unsubstituted or substituted with one or more X groups, the (C₆-C₁₀)aryl portion of said —(C₁-C₆)alkylene-(C₆-C₁₀)aryl is unsubstituted or substituted with one or more Y groups, and the (C₂-C₁₀)heteroaryl portion of said —(C₁-C₆)alkylene-(C₂-C₁₀)heteroaryl is unsubstituted or substituted with one or more Z groups;
- R²is 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
- R¹and R²together with the ring carbon atoms to which they are shown attached, form a 5- or 6-membered cycloalkenyl ring;
- R³is selected from the group consisting of H, (C₁-C₆)alkyl, —(C₃-C₆)alkylene-O—(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-C(O)—O-alkyl, and (C₁-C₆)alkenyl,
  - wherein the (C₃-C₇)cycloalkyl or the (C₃-C₇)cycloalkyl portion of said —(C₃-C₆)alkylene-(C₃-C₇)cycloalkyl of R³is unsubstituted or substituted with one or more X groups;
- R⁴is selected from the group consisting of halogen, —O—R¹⁰, —C(O)—O—(C₁-C₆)alkyl, —S(O)_m—R⁹, —N(R⁷)₂, —O—N═C(R¹²)₂, —N(R⁷)—NH—C(O)—O—(C₁-C₆)alkyl and —C(O)—(C₁-C₆)alkyl;
- R⁵is selected from the group consisting of H, —(C₁-C₆)alkyl, —(C₁-C₆)alkylene-C(O)—R⁸, —(C₁-C₅)alkylene-C(═N—O—(C₁-C₆)alkyl)-(C₆-C₁₀)aryl, (C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-C(O)—O—(C₁-C₆)alkyl, and (C₂-C₆)alkenyl
  - wherein the (C₃-C₇)cycloalkyl or the (C₃-C₇)cycloalkyl portion of said —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl of R⁵is unsubstituted or substituted with one or more X groups, and the (C₆-C₁₀)aryl portion of said —(C₁-C₆)alkylene-C(═N—O—(C₁-C₆)alkyl)-(C₆-C₁₀)aryl of R⁵is unsubstituted or substituted with one or more Y groups;
- R⁶is selected from the group consisting of —O—R¹⁰, halogen, and —N(R⁷)₂;
- each R⁷is independently selected from the group consisting of H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, and (C₆-C₁₀)aryl,
  - wherein the (C₃-C₇)cycloalkyl of R⁷is unsubstituted or substituted with one or more X groups, and said (C₆-C₁₀)aryl of R⁷is unsubstituted or substituted with one or more Y groups;
- R⁸is selected from the group consisting of unsubstituted (C₆-C₁₀)aryl, (C₆-C₁₀)aryl substituted with one or more Y groups, —OH, unsubstituted (C₂-C₁₀)heterocyclyl, and (C₂-C₁₀)heterocyclyl substituted with one or more X groups;
- R⁹is selected from the group consisting of (C₁-C₆)alkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, (C₂-C₆)alkenyl, and —(C₁-C₆)alkylene-(C₆-C₁₀)aryl,
  - wherein the (C₃-C₇)cycloalkyl portion of said —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl of R⁹is unsubstituted or substituted with one or more X groups, and the (C₆-C₁₀)aryl portion of said —(C₁-C₆)alkylene-(C₆-C₁₀)aryl of R⁹is unsubstituted or substituted with one or more groups Y;
- R¹⁰is selected from the group consisting of H, (C₁-C₆)alkyl, —(C₁-C₆)alkylene-(C₆-C₁₀)aryl, —(C₂-C₆)alkenylene-(C₆-C₁₀)aryl, —(C₁-C₆)alkylene-(C₂-C₁₀)heteroaryl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, and —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl,
  - wherein the (C₃-C₇)cycloalkyl portion of said —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl of R¹⁰is unsubstituted or substituted with one or more X groups, and the (C₆-C₁₀)aryl portion of said —(C₁-C₆)alkylene-(C₆-C₁₀)aryl or —(C₂-C₆)alkenylene-(C₆-C₁₀)aryl of R¹⁰is unsubstituted or substituted with one or more Y groups, and the (C₂-C₁₀)heteroaryl portion of said —(C₁-C₆)alkylene-(C₂-C₁₀)heteroaryl of R¹⁰is unsubstituted or substituted with one or more Z groups;
- each R¹²is independently a (C₁-C₆)alkyl;
- R^aand R^bare each independently a (C₁-C₆)alkyl;
- R^cis H;
- R^dis selected from the group consisting of H, (C₁-C₆)alkyl, and —(C₁-C₆)alkylene-(C₆-C₁₀)aryl,
  - wherein the (C₆-C₁₀)aryl portion of said —(C₁-C₆)alkylene-(C₆-C₁₀)aryl of R^dis unsubstituted or substituted with one or more Y groups;
- each X is independently selected from the group consisting of F, Cl, Br, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —O—(C₁-C₆)haloalkyl, and —OH;
- each Y is independently selected from the group consisting of F, Br, Cl, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —O—(C₁-C₆)haloalkyl, —CN, —NO₂, —OH, —S(O₂)—(C₁-C₆)alkyl, —S(O₂)—(C₆-C₁₀)aryl, —S(O₂)—NH₂, —S(O₂)—NH—(C₁-C₆)alkyl, —S(O₂)—NH—(C₆-C₁₀)aryl, —S(O₂)—N((C₁-C₆)alkyl)₂, —S(O₂)—N((C₆-C₁₀)aryl)₂, —S(O₂)—N((C₁-C₆)alkyl)((C₆-C₁₀)aryl), and (C₆-C₁₀)aryl; and
- each Z is independently selected from the group consisting of (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, F, Br, and Cl, —O—(C₁-C₆)alkyl, —ON, —OH, (C₆-C₁₀)aryl, and N-oxide.

In another embodiment of the compounds of Formula (I),

- R¹is selected from the group consisting of —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH(CH₃)₂, —CH(CH₃)₂, —CH₂CH₂CH═CH₂, —CH₂CH₂CH═CHCH₃, —CH₂CH₂CH₂CH₂CH═CH₂, —CH₂CH₂CH₂CH═CH₂, —CH₂—OH, —CH(CH₃)—OH, cyclobutyl, —CH₂—C(O)—O—CH₂CH₃, —CH₂CH₂CH₂—O—CH₃, —CH₂CF₃, —CHBrCH₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂Cl, —CH₂-(2-thiophenyl), —CH₂CH₂CH₂-(2-thiophenyl), —CH₂-cyclopropyl, —CH₂CH₂-cyclopropyl, —CH₂CH₂CH₂-cyclopropyl, —CH₂CH₂CH₂CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂CH₂-cyclobutyl, —CH₂CH₂CH₂-cyclobutyl, —CH₂CH₂CH₂CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂CH₂-cyclopentyl, —CH₂CH₂CH₂-cyclopentyl, —CH₂CH₂CH₂CH₂-cyclopentyl, —CH₂-cyclohexyl, —CH₂-(4-methylcyclohexyl), —CH₂CH₂-cyclohexyl, —CH₂-cycloheptyl, —CH₂-(2-cyclopentenyl, —CH₂CH₂CH≡CH, —CH₂CH₂CH₂C≡CH, —CH₂-phenyl, —CH₂-(2-fluorophenyl), —CH₂-(3-fluorophenyl), and —CH₂—NH(3-methoxyphenyl);
- R²is 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
- R¹and R²together with the ring carbon atoms to which they are shown attached, form a cyclopentenyl or cyclohexenyl ring;
- R³is selected from the group consisting of H, —CH₂-cyclopropyl, —CH₂—C(O)—O—CH₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH═CH₂, and —CH₂—O—CH₃;
- R⁴is selected from the group consisting of Cl, —O—R¹⁰, —C(O)—O—CH₃, —S(O)₂—CH₃, —S(O)—CH₃, —S(O)—CH₂C H₃, —S(O)—CH(CH₃)₂, —S(O)—C(CH₃)₃, —S(O)—CH₂-cyclopropyl, —S(O)—CH₂-phenyl, —S(O)—CH(CH₃)-phenyl, —S—CH₂—CH═CH₂, —N(R⁷)₂, —O—N═C(CH₃)₂, —NH—NH—C(O)—O—CH₃, and —C(O)—CH₃,
  - wherein the phenyl portion of said —S(O)—CH₂-phenyl, or —S(O)—CH(CH₃)-phenyl of R⁴is unsubstituted or substituted with one or more groups Y;
- R⁵is selected from the group consisting of H, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂—C(O)-phenyl, _13 CH₂—C(O)—OH, —CH₂—C(═N—O—CH₃)-phenyl, cyclopropyl, cyclobutyl, cyclopentyl, —CH₂—C(O)-piperidyl, —CH₂-cyclopropyl, —CH₂—C(O)—O—CH₃, and —CH₂—CH═CH₃,
  - wherein the phenyl portion of said —CH₂—C(O)-phenyl is unsubstituted or substituted with one or more Y groups;
- R⁶is selected from the group consisting of —OR¹⁰, Cl, and —N(R⁷)₂;
- each R⁷is independently selected from the group consisting of H, cyclobutyl, unsubstituted phenyl, and phenyl substituted with one or more Y groups;
- R¹⁰is selected from the group consisting of H, —CH₃, —CH₂-cyclopropyl, —CH₂—CH═CH₃, —CH₂C≡C—CH₃, —CH₂-phenyl, —CH(CH₃)-phenyl, —CH(CH₂CH₃)-phenyl, —CH(CH₂CH₂CH₃)-phenyl, —CH(CH(CH₃)₂)-phenyl, —CH(CH₂CH═CH₂)-phenyl, —CH₂-pyridyl, —CH(CH₃)-thiazolyl, and —CH₂-pyrimidinyl,
  - wherein the phenyl portion of said —CH₂-phenyl, —CH(CH₃)-phenyl, —CH(CH₂CH₃)-phenyl, —CH(CH₂CH₂CH₃)-phenyl, —CH(CH(CH₃)₂)-phenyl, or —CH(CH₂CH═CH₂)-phenyl of R¹⁰is unsubstituted or substituted with one or more groups Y, and the pyridyl, thiazolyl, or pyrimidinyl portion of said —CH₂-pyridyl, —CH₂-thiazolyl, or —CH₂-pyrimidinyl of R¹⁰is unsubstituted or substituted with one or more groups Z;
- R^aand R^bare each —CH₃;
- R^cis H;
- R^dis selected from the group consisting of H, —CH₃, and —CH₂-phenyl,
  - wherein the phenyl portion of said —CH₂-phenyl of R^dis unsubstituted or substituted with one or more Y groups;
- each Y is independently selected from the group consisting of F, Cl, Br, —CH₃, —CF₃, —O—CH₃, —O—CF₃, —CN, —OH, and phenyl; and
- each Z is independently selected from the group consisting of —CH₃, —CF₃, F, Br, and Cl, —O—CH₃, —CN, —OH, phenyl, and N-oxide.

In another embodiment of the compounds of Formula (I),

- Q is:

- L is:

- R¹is selected from the group consisting of —(C₁-C₆)alkyl, —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, unsubstituted (C₆-C₁₀)aryl, and (C₆-C₁₀)aryl substituted with one or more substituents Y;
- R²is H or halogen;
- R⁴is selected from the group consisting of halogen, —O—R¹⁰—C(O)—O—(C₁-C₆)alkyl, —S(O)_m—R⁹, —N(R⁷)₂, —O—N═C(R¹²)₂, —N(R⁷)—NH—C(O)—O—(C₁-C₆)alkyl, and —C(O)—(C₁-C₆)alkyl;
- R⁵is H or (C₁-C₆)alkyl;
- each R⁷is independently selected from the group consisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, unsubstituted (C₅-C₁₀)aryl, and (C₆-C₁₀)aryl substituted with one or more Y groups;
- R⁹is selected from the group consisting of (C₁-C₆)alkyl, —(C₁-C₆)alkylene-(C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, and —(C₁-C₆)alkylene-(C₆-C₁₀)aryl,
  - wherein the (C₆-C₁₀)aryl of said —(C₁-C₆)alkylene-(C₆-C₁₀)aryl of R⁹is unsubstituted or substituted with one or more groups Y;
- R¹⁰is selected from the group consisting of H, (C₁-C₆)alkyl, —(C₁-C₆)alkylene-(C₅-C₁₀)aryl, —(C₁-C₆)alkenylene-(C₆-C₁₀)aryl, —(C₁-C₆)alkylene-(C₂-C₁₀)heteroaryl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, and —(C₁-C₆)alkylene-(C₃-C₆)cycloalkyl
  - wherein the aryl of said —(C₁-C₆)alkylene-(C₆-C₁₀)aryl or —(C₁-C₆)alkenylene-(C₆-C₁₀)aryl of R¹⁰is unsubstituted or substituted with one or more groups Y, and the (C₂-C₁₀)heteroaryl of said —(C₁-C₆)alkylene-(C₂-C₁₀)heteroaryl of R¹⁰is unsubstituted or substituted with one or more groups Z;
- each R¹²is independently selected from the group consisting of (C₁-C₆)alkyl, (C₆-C₁₀)aryl, and (C₂-C₁₀)heteroaryl,
  - wherein the (C₆-C₁₀)aryl is unsubstituted or substituted with one or more Y group, and said (C₂-C₁₀)heteroaryl is unsubstituted or substituted with one or more Z group;
- each Y is independently selected from the group consisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —O—(C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —CN, —NO₂, —OH, —S(O₂)—(C₁-C₆)alkyl, —S(O₂)—(C₆-C₁₀)aryl, —S(O₂)—NH₂, —S(O₂)—NH—(C₁-C₆)alkyl, —S(O₂)—NH—(C₆-C₁₀)aryl, —S(O₂)—N((C₁-C₆)alkyl)₂, —S(O₂)—N((C₆-C₁₀)aryl)₂, —S(O₂)—N((C₁-C₆)alkyl)((C₆-C₁₀)aryl), and (C₆-C₁₀)aryl; and
- each Z is independently selected from the group consisting of (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, halogen, —O-alkyl, —O—(C₁-C₆)haloalkyl, —CN, —OH, (C₆-C₁₀)aryl, and, and N-oxide.

In another embodiment of the compounds of Formula (I),

- Q is:

- L is:

- R¹is —CH₂CH₃, butyl, pentyl, —CH₂—CH₂—CH₂-cyclopropyl;
- R²is H, Br, unsubstituted aryl, aryl substituted with one or more Y groups, unsubstituted heteroaryl, heteroaryl substituted with one or more Y groups;
- R⁴is selected from the group consisting of Cl, —O—R¹⁰, —C(O)—O—CH₃, —S(O)—CH₃, —S(O)—CH₂CH₃, —S(O)—CH(CH₃)₂, —S(O)—C(CH₃)₃, —S(O)—CH₂-cyclopropyl, —S—CH₂—CH═CH₂, —S(O)—CH₂-phenyl, —S(O)—CH(CH₃)-phenyl, —N(R⁷)₂, —O—N═C(CH₃)₂, —NH—NH—C(O)—O—CH₃, and —C(O)—CH₃,
  - wherein the phenyl portion of said —S(O)—CH₂-phenyl, or —S(O)—CH(CH₃)-phenyl of R⁴is unsubstituted or substituted with one or more groups Y;
- R⁵is H or —CH₂CH₃;
- each R⁷is independently selected from the group consisting of H and cyclobutyl;
- R¹⁰is selected from the group consisting of H, —CH₃, —CH₂-cyclopropyl, —CH₂—CH═CH₂, —CH₂C≡C—CH₃, —CH₂-phenyl, —CH(CH₃)-phenyl, —CH(CH₂CH₃)-phenyl, —CH(CH(CH₃)₂)-phenyl, —CH(CH₂CH₂CH₃)-phenyl, —CH(CH₂CH═CH₂)-phenyl, —CH₂-pyridyl, —CH(CH₃)-thiazolyl, —CH₂-pyrimidinyl,
  - wherein the phenyl portion of said —CH₂-phenyl, —CH(CH₃)-phenyl, —CH(CH₂CH₃)-phenyl, —CH(CH(CH₃)₂)-phenyl, —CH(CH₂CH═CH₂)-phenyl, or —CH(CH₂CH₂CH₃)-phenyl, of R¹⁰is unsubstituted or substituted with one or more groups Y, and the pyridyl, thiazolyl, or pyrimidinyl portion of said —CH₂-pyridyl, —CH(CH₃)-thiazolyl, or —CH₂-pyrimidinyl of R¹⁰is unsubstituted or substituted with one or more groups Z;
- each Y is independently selected from the group consisting of F, Cl, Br, —CH₃, —CF₃, —O—CH₃, —O—CF₃, and phenyl; and
- each Z is independently selected from the group consisting of —CH₃, phenyl, and N-oxide.

In another embodiment of the compounds of Formula (I),

- Q is:

- L is:

- is selected from the group consisting of —(C₁-C₆)alkyl, —(C₁-C₆)alkenyl, —(C₁-C₆)alkynyl, —(C₁-C₆)alkylene-C(O)—O—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, —(C₁-C₆)alkylene-(C₆-C₁₀)aryl, —(C₁-C₆)alkylene-(C₂-C₁₀)heteroaryl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkenyl, (C₁-C₆)alkyl substituted with one or more hydroxyl groups, —(CH₂)_n—N(R⁷)₂, and —(C₁-C₆)haloalkyl
  - wherein the —(C₃-C₇)cycloalkyl or the (C₃-C₇)cycloalkyl portion of said —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl is unsubstituted or substituted with one or more X groups, the (C₆-C₁₀)aryl portion of said —(C₁-C₆)alkylene-(C₆-C₁₀)aryl is unsubstituted or substituted with one or more Y groups, and the (C₂-C₁₀)heteroaryl portion of said —(C₁-C₆)alkylene-(C₂-C₁₀)heteroaryl is unsubstituted or substituted with one or more Z groups;
- R²is H;

1R³is selected from the group consisting of H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₆)cycloalkyl, —(C₁-C₆)alkylene-C(O)—O—(C₁-C₆)alkyl, (C₂-C₆)alkenyl, and —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl;

- R⁵is selected from the group consisting of H, —(C₁-C₆)alkyl, (C₂-C₆)alkenyl, —(C₁-C₆)alkylene-C(O)—R⁸, —(C₁-C₆)alkylene-C(═N—O—(C₁-C₆)alkyl)-(C₆-C₁₀)aryl, (C₃-C₆)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₆)cycloalkyl, and —(C₁-C₆)alkylene-C(O)—O—(C₁-C₆)alkyl;
- each R⁷is independently selected from the group consisting of H and aryl,
  - wherein the aryl of R⁷is unsubstituted or substituted with one or more Y groups;
- R⁸is selected from the group consisting of unsubstituted (C₆-C₁₀)aryl, (C₆-C₁₀)aryl substituted with one or more Y groups, —OH, unsubstituted (C₂-C₁₀)heterocyclyl and (C₂-C₁₀)heterocyclyl substituted with one or more X groups;
- each X is independently selected from the group consisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —O—(C₁-C₆)haloalkyl, and —OH;
- each Y is independently selected from the group consisting of halogen, (C₁-C₆)alkyl, (C₁-C₈)haloalkyl, —O—(C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —CN, —NO₂, —OH, —S(O₂)—(C₁-C₆)alkyl, —S(O₂)—(C₆-C₁₀)aryl, —S(O₂)—NH₂, —S(O₂)—NH—(C₁-C₆)alkyl, —S(O₂)—NH—(C₆-C₁₀)aryl, —S(O₂)—N((C₁-C₆)alkyl)₂, —S(O₂)—N((C₆-C₁₀)aryl)₂, —S(O₂)—N((C₁-C₆)alkyl)((C₆-C₁₀)aryl), and (C₆-C₁₀)aryl; and
- each Z is independently selected from the group consisting of (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, F, Br, and Cl, —O—(C₁-C₆)alkyl, —CN, —OH, (C₆-C₁₀)aryl, and N-oxide.

In another embodiment of the compounds of Formula (I),

- Q is:

- L is:

- R¹is selected from the group consisting of —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH(CH₃)₂, —CH(CH₃)₂, —CH₂—C(O)—O—CH₂CH₃, —CH₂CF₃, —CH₂CH₂CH═CH₂, —CH₂CH₂CH═CHCH₃, —CH₂CH₂CH₂CH₂CH═CH₂, —CH₂CH₂CH₂CH═CH₂, —CH₂OH, —CH(CH₃)OH, —CH₂N(R⁷)₂, cyclobutyl, —CH₂CH₂CH₂—O—CH₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂Cl, —CH₂-(2-thiophenyl), —CH₂CH₂CH₂-(2-thiophenyl), —CH₂-cyclopropyl, —CH₂CH₂-cyclopropyl, —CH₂CH₂CH₂-cyclopropyl, —CH₂CH₂CH₂CH₂-cyclopropyl, —CH₂-cyclopentyl, —CH₂CH₂-cyclopentyl, —CH₂-cyclohexyl, —CH₂-(4-methylcyclohexyl), —CH₂CH₂-cyclohexyl, —CH₂-cycloheptyl, —CH₂-(2-cyclopentenyl, —CH₂CH₂C≡CH, —CH₂CH₂CH₂C≡CH, —CH₂-phenyl, —CH₂-(2-fluorophenyl), —CH₂-(3-fluorophenyl), and —CHBrCH₃;
- R²is H; or
- R¹and R²together with the ring carbon atoms to which they are shown attached, form a cyclopentenyl or cyclohexenyl ring;
- R³is selected from the group consisting of H, —CH₂-cyclopropyl, —CH₂—C(O)—O—CH₃, -cyclopropyl, cyclobutyl, cyclopentyl, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH═CH₂, and —CH₂—O—CH₃;
- R⁵is selected from the group consisting of H, —CH₂-cyclopropyl, —CH₂—C(O)—O—CH₃, —CH₂—C(O)—R⁸, —CH₂—C(═N—O—CH₃)-phenyl, cyclopropyl, cyclobutyl, cyclopentyl, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, and —CH₂CH═CH₂;
- each R⁷is independently H or phenyl,
  - wherein the phenyl of R⁷is unsubstituted or substituted with one or more Y groups;
- R⁸is 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, —CF₃, —OCH₃, —CN, and —OH.

In another embodiment of the compounds of Formula (I),

- Q is:

- L is:

- R¹is selected from the group consisting of —(C₁-C₆)alkyl, —(C₁-C₆)alkenyl, —(C₁-C₆)alkynyl, —(C₁-C₆)alkylene-C(O)—O—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, —(C₁-C₆)alkylene-(C₆-C₁₀)aryl, —(C₁-C₆)alkylene-(C₂-C₁₀)heteroaryl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylene-(C₃-C₇)cycloalkenyl, —(C₁-C₆)alkyl substituted with one or more hydroxyl groups, —(CH₂)_n—N(R⁷)₂, and —(C₁-C₆)haloalkyl
  - wherein the —(C₃-C₇)cycloalkyl or the (C₃-C₇)cycloalkyl portion of said —(C₁-C₆)alkylene-(C₃-C₇)cycloalkyl is unsubstituted or substituted with one or more X groups, the (C₆-C₁₀)aryl portion of said —(C₁-C₆)alkylene-(C₆-C₁₀)aryl is unsubstituted or substituted with one or more Y groups, and the (C₂-C₁₀)heteroaryl portion of said —(C₁-C₆)alkylene-(C₂-C₁₀)heteroaryl is unsubstituted or substituted with one or more Z groups;
- R²is H; or
- R¹and R²together with the ring carbon atoms to which they are shown attached, form a 5- or 6-membered cycloalkenyl ring;
- R⁴is selected from the group consisting of halogen, —O—R¹⁰, —C(O)—O—(C₁-C₆)alkyl, —S(O)_m—R⁹, —N(R⁷)₂, —O—N═C(R¹²)₂, —N(R⁷)—NH—C(O)—O—(C₁-C₆)alkyl, and —C(O)—(C₁-C₆)alkyl;
- R⁶is selected from the group consisting of —O—R¹⁰, halogen, and —N(R⁷)₂;
- each R⁷is independently selected from the group consisting of H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, unsubstituted (C₆-C₁₀)aryl, and (C₆-C₁₀)aryl substituted with one or more Y groups;
- R⁹is selected from the group consisting of (C₁-C₆)alkyl, —(C₁-C₆)alkylene-(C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, and —(C₁-C₆)alkylene-(C₆-C₁₀)aryl,
  - wherein the (C₆-C₁₀)aryl portion of said —(C₁-C₆)alkylene-(C₆-C₁₀)aryl of R⁹is unsubstituted or substituted with one or more groups Y;
- R¹⁰is selected from the group consisting of H, (C₁-C₆)alkyl, —(C₁-C₆)alkylene-(C₆-C₁₀)aryl, —(C₁-C₆)alkenylene-(C₆-C₁₀)aryl, —(C₁-C₆)alkylene-(C₂-C₁₀)heteroaryl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, and —(C₁-C₆)alkylene-(C₃-C₆)cycloalkyl,
  - wherein the (C₆-C₁₀)aryl portion of said —(C₁-C₆)alkylene-(C₆-C₁₀)aryl or —(C₁-C₆)alkenylene-(C₆-C₁₀)aryl of R¹⁰is unsubstituted or substituted with one or more groups Y, and the (C₂-C₁₀)heteroaryl portion of said —(C₁-C₆)alkylene-(C₂-C₁₀)heteroaryl of R¹⁰is unsubstituted or substituted with one or more groups Z;
- each Y is independently selected from the group consisting of F, Br, Cl, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —O—(C₁-C₆)haloalkyl, —CN, —NO₂, —OH, —S(O₂)—(C₁-C₆)alkyl, —S(O₂)—(C₆-C₁₀)aryl, —S(O₂)—NH₂, —S(O₂)—NH—(C₁-C₆)alkyl, —S(O₂)—NH—(C₆-C₁₀)aryl, —S(O₂)—N((C₁-C₆)alkyl)₂, —S(O₂)—N((C₆-C₁₀)aryl)₂, —S(O₂)—N((C₁-C₆)alkyl)((C₆-C₁₀)aryl), and (C₆-C₁₀)aryl; and
- each Z is independently selected from the group consisting of (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, F, Br, and Cl, —O—(C₁-C₆)alkyl, —CN, —OH, (C₆-C₁₀)aryl, and N-oxide.

In another embodiment of the compounds of Formula (I),

- Q is:

- L is:

- R¹is selected from the group consisting of —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH(CH₃)₂, —CH(CH₃)₂, —H₂—C(O)—O—CH₂CH₃, —CH₂—OH, —CH(CH₃)—OH, —CH₂CH₂CH═CH₂, —CH₂CH₂CH═CHCH₃, —CH₂CH₂CH₂CH₂CH═CH₂, —CH₂CH₂CH₂CH═CH₂, cyclobutyl, —CH₂CH₂CH₂—O—CH₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂Cl, —CH₂-(2-thiophenyl), —CH₂CH₂CH₂-(2-thiophenyl), —CH₂-cyclopropyl, —CH₂CH₂-cyclopropyl, —CH₂CH₂CH₂-cyclopropyl, —CH₂CH₂CH₂CH₂-cyclopropyl, —CH₂-cyclopentyl, —CH₂CH₂-cyclopentyl, —CH₂-cyclohexyl, —CH₂-(4-methylcyclohexyl), —CH₂CH₂-cyclohexyl, —CH₂-cycloheptyl, —CH₂-(2-cyclopentenyl, —CH₂CH₂C≡CH, —CH₂CH₂CH₂C≡CH, —CH₂-phenyl, —CH₂-(2-fluorophenyl), —CH₂-(3-fluorophenyl), —CHBrCH₃and —CH₂CF₃;
- R²is H; or
- R¹and R²together with the ring carbon atoms to which they are shown attached, form a cyclopentenyl or cyctohexenyl ring
- R⁴is selected from the group consisting of Cl, —O—R¹⁰, —C(O)—O—CH₃, —S(O)₂—CH₃, —S(O)—CH₃, —S(O)—CH₂CH₃, —S(O)—CH(CH₃)₂, —S(O)—C(CH₃)₃, —S(O)—CH₂-cyclopropyl, —S—CH₂—CH═CH₂, —S(O)—CH₂-phenyl, —S(O)—CH(CH₃)-phenyl, —N(R⁷)₂, —O—N═C(CH₃)₂, —NH—NH—C(O)—O—CH₃, and —C(O)—CH₃,
  - wherein the phenyl portion of said —S(O)—CH₂-phenyl, or —S(O)—CH(CH₃)-phenyl of R⁴is unsubstituted or substituted with one or more groups Y;
- R⁶is selected from the group consisting of —O—R¹⁰, —N(R⁷)₂, and Cl;
- each R⁷is independently selected from the group consisting of H, unsubstituted phenyl, phenyl substituted with one or more Y groups, and cyclobutyl;
- R¹⁰is selected from the group consisting of H, CH₃, —CH₂-cyclopropyl, —CH₂—C≡C—CH₃, —CH₂—CH═CH₂, —CH₂-phenyl, —CH(CH₃)-phenyl, —CH(CH₂CH₃)-phenyl, —CH(CH(CH₃)₂)-phenyl, —CH(CH₂CH₂CH₃)-phenyl, —CH(CH₂CH═CH₂)-phenyl, —CH₂-pyridyl, —CH(CH₃)-thiazolyl, —CH₂-pyrimidinyl,
  - wherein the phenyl portion of said —CH₂-phenyl, —CH(CH₃)-phenyl, —CH(CH₂CH₃)-phenyl, —CH(CH₂CH═CH₂)-phenyl, or —CH(CH₂CH₂CH₃)-phenyl of R¹⁰is unsubstituted or substituted with one or more groups Y, and the pyridyl, thiazolyl, or pyrimidinyl portion of said —CH₂-pyridyl, —CH(CH₃)-thiazolyl, or —CH₂-pyrimidinyl of R¹⁰is unsubstituted or substituted with one or more groups Z;
- each Y is independently selected from the group consisting of F, Cl, Br, —CH₃, —CF₃, —O—CH₃, —O—CF₃, —CN, —OH, and phenyl; and
- each Z is independently selected from the group consisting of —CH₃, F, Br, and Cl, —O—CH₃, —CN, —OH, phenyl, and N-oxide.

In another embodiment of the compounds of Formula (I),

- Q is:

- L is:

- R¹is —(C₁-C₆)alkyl;
- R²is H;
- R³is H or —(C₂-C₆)alkenyl; and
- R⁶is —OH or —O—(C₁-C₆)alkylene-(C₁-C₆)cycloalkyl.

In another embodiment of the compounds of Formula (I),

- Q is:

- L is:

- R¹is —(C₁-C₆)alkyl or —(C₁-C₆)haloalkyl;
- R²is H;
- R³is selected from the group consisting of H, —(C₁-C₆)alkylene-(C₁-C₆)cycloalkyl, —(C₁-C₆)alkylene-C(O)—O—(C₁-C₆)alkyl, —(C₁-C₆)cycloalkyl, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, and —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl; and
- R⁴is —O—N═C((C₁-C₆)alkyl)₂.

In another embodiment of the compounds of Formula (I),

- Q is:

- L is selected from the group consisting of:

- R^aand R^bare each independently selected from the group consisting of H, (C₁-C₆)alkyl, (C₆-C₁₀)aryl, and (C₂-C₁₀)heteroaryl,
  - wherein the (C₆-C₁₀)aryl of R^aand R^bis unsubstituted or substituted with one or more Y groups, and said (C₂-C₁₀)heteroaryl of R^aand R^bis unsubstituted or substituted with one or more Z groups;
- R^cis selected from the group consisting of H, (C₁-C₆)alkyl, —(C₁-C₆)alkylene-(C₆-C₁₀)aryl, and —C(O)—(C₁-C₆)alkyl,
  - wherein the (C₆-C₁₀)aryl portion of said —(C₁-C₆)alkylene-(C₆-C₁₀)aryl of R^cis unsubstituted or substituted with one or more Y groups;
- R^dis selected from the group consisting of H, (C₁-C₆)alkyl, and —(C₁-C₆)alkylene-(C₆-C₁₀)aryl,
  - wherein the (C₆-C₁₀)aryl portion of said —(C₁-C₆)alkylene-(C₆-C₁₀)aryl of R^dis unsubstituted or substituted with one or more Y groups;
- R¹is (C₁-C₆)alkyl or or —(C₁-C₆)haloalkyl;
- R²is H;
- R³is H;
- R⁴is —O—R¹⁰;
- R⁵is H or —(C₁-C₆)alkylene-(C₃-C₆)cycloalkyl;
- R⁶is —O—R¹⁰;
- R¹⁰is H, (C₁-C₆)alkyl, or —(C₁-C₆)alkylene-(C₆-C₁₀)aryl; and
- each Y is independently selected from the group consisting of F, Br, Cl, (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, —O—(C₁-C₆)alkyl, —O—(C₁-C₆)haloalkyl, —CN, —NO₂, —OH, —S(O₂)—(C₁-C₆)alkyl, —S(O₂)—(C₆-C₁₀)aryl, —S(O₂)—NH₂, —S(O₂)—NH—(C₁-C₆)alkyl, —S(O₂)—NH—(C₆-C₁₀)aryl, —S(O₂)—N((C₁-C₆)alkyl)₂, —S(O₂)—N((C₆-C₁₀)aryl)₂, —S(O₂)—N((C₁-C₆)alkyl)((C₆-C₁₀)aryl), and (C₆-C₁₀)aryl; and
- each Z is independently selected from the group consisting of (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, F, Br, and Cl, —O—(C₁-C₆)alkyl, —CN, —OH, (C₆-C₁₀)aryl, and N-oxide.

In another embodiment of the Formula (I), R¹is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂—C(O)—O—CH₂CH₃, —CH₂CF₃, —CH₂—OH, —CH(CH₃)OH, —CH₂—N(R⁷)₂, —CH₂—NH(3-methoxyphenyl), —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH═CH₂, —CH₂CH₂CH═CHCH₃, —CH₂CH₂CH₂CH₂CH═CH₂, —CH₂CH₂CH₂CH═CH₂, cyclobutyl, —CH₂CH₂CH₂—O—CH₃, —CH₂CF₃, —CHBrCH₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂Cl, —CH₂-(2-thiophenyl), —CH₂CH₂CH₂-(2-thiophenyl), —CH₂-cyclopropyl, —CH₂CH₂-cyclopropyl, —CH₂CH₂CH₂-cyclopropyl, —CH₂CH₂CH₂CH₂-cyclopropyl, —CH₂-cyclopentyl, —CH₂CH₂-cyclopentyl, —CH₂-cyclohexyl, —CH₂-(4-methylcyclohexyl), —CH₂CH₂-cyclohexyl, —CH₂-cycloheptyl, —CH₂-(2-cyclopentenyl, —CH₂CH₂C≡CH, —CH₂CH₂CH₂C≡CH, —CH₂-phenyl, —CH₂-(2-fluorophenyl), —CH₂-(3-fluorophenyl), or —CHBrCH₃.
In another embodiment of the Formula (I), R²is H.
In another embodiment of the Formula (I), R²is Br.
In another embodiment, R¹and R²together 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 (I), R³is H, —CH₂-cyclopropyl, —CH₂—C(O)—O—CH₃, -cyclopropyl, cyclobutyl, cyclopentyl, —CH₃, —CH₂CH₃, —CH₂—CH₂CH₃, —CH₂CH═CH₂, or —CH₂—O—CH₃.
In another embodiment of the Formula (I), R⁴is Cl, —OH, —O—CH₃, —O—CH₂-cyclopropyl, —CH₂—C≡C—CH₃, —O—CH₂-phenyl, —O—CH(CH₃)-phenyl, —O—CH(CH₂CH₃)-phenyl, —O—CH(CH₂CH₂CH₃)-phenyl, —O—CH(CH(CH₃)₂)-phenyl, —O—CH(CH₂CH═CH₂)-phenyl, —O—CH₂-pyridyl, —O—CH₂-thiazolyl, —O—CH(CH₃)-thiazolyl, —O—CH₂-pyrimidinyl, —C(O)—O—CH₃, —S(O₂)—CH₃, —S(O)—CH₃, —S(O)—CH₂CH₃, —S(O)—CH(CH₃)₂, —S(O)—C(CH₃)₃, —S(O)—CH₂-cyclopropyl, —S(O)—CH₂-phenyl, —S(O)-CH(CH₃)-phenyl, —S(O)—N(R¹¹)₂, —S(O₂)—N(R¹¹)₂, —S—CH₂—CH═CH₂, —N(H)cyclobutyl, —N(H)phenyl, —NH—NH—C(O)—O—CH₃, —O—CH₂—CH═CH₂, —O—N═C(CH₃)₂, or —C(O)—CH₃, wherein the phenyl portions of any of these groups can be unsubstituted or substituted with one or more Y groups as defined herein, the 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 (I), R⁵is H, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂—C(O)-phenyl, —CH₂—C(O)—OH, —CH₂—C(═N—O—CH₃)-phenyl, cyclopropyl, cyclobutyl, cyclopentyl, —CH₂—C(O)-piperidyl, —CH₂-cyclopropyl, —CH₂—C(O)—O—CH₃, or —CH₂—CH═CH₃, wherein the phenyl of said —CH₂—C(O)-phenyl of R⁵is unsubstituted or substituted with one or more Y groups as defined herein, said cyclopropyl, the cyclopropyl of said —CH₂-cyclopropyl, cyclobutyl, cyclopentyl, or the piperidyl of said —CH₂—C(O)-piperidyl of R⁵are unsubstituted or substituted with one or more X groups as defined herein.
In another embodiment of the compound of Formula (I), R⁶is —OH, Cl, —O—CH₃, —O—CH₂-cyclopropyl, —O—CH₂—CH═CH₃, —O—CH₂-phenyl, —O—CH(CH₃)-phenyl, —O—CH(CH₂CH₃)-phenyl, —O—CH(CH₂CH₂CH₃)-phenyl, —O—CH(CH(CH₃)₂)-phenyl, —O—CH(CH₂CH═CH₂)-phenyl, —O—CH₂-pyridyl, —O—CH₂-thiazolyl, —O—CH₂-pyrimidinyl, and —N(H)cyclobutyl, —N(H)phenyl, —NH—NH—C(O)—O—CH₃, wherein the phenyl of said —O—CH₂-phenyl, —O—CH(CH₃)-phenyl, —O—CH(CH₂CH₃)-phenyl, —O—CH(CH₂CH₂CH₃)-phenyl, —O—CH(CH(CH₃)₂)-phenyl, or —O—CH(CH₂CH═CH₂)-phenyl of R⁶is unsubstituted or substituted with one or more groups Y as defined herein, and the pyridyl, thiazolyl , or pyrimidinyl of said —O—CH₂-pyridyl, —O—CH₂-thiazolyl, or —O—CH₂-pyrimidinyl of R⁶is unsubstituted or substituted with one or more groups Z as defined herein.
In another embodiment of the compound of Formula (I), each R⁷is independently H, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, unsubstituted phenyl, phenyl substituted with one or more Y groups, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —C(O)—CH₃, and —C(O)-phenyl. Alternatively, two groups R⁷, together with 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), R⁸is —CH₃, unsubstituted phenyl, phenyl substituted with one or more Y groups, piperidyl, and —OH.
In another embodiment of the compound of Formula (I), R⁹is —CH₃, —CH₂CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH₂-cyclopropyl, —CH₂—CH═CH₂(allyl), —CH₂-phenyl, and —CH(CH₃)-phenyl.
In another embodiment of the compound of Formula (I), R¹⁰is H, —CH₂C≡CCH₃, —CH₂-cyclopropyl, —CH₂CH═CH₂, —CH₂-phenyl, —CH(CH₃)-phenyl, —CH(CH₂CH₃)-phenyl, —CH(CH(CH₃)₂)-phenyl, —CH₂-pyridyl, —CH₂-thiazolyl, —CH(CH₃)-thiazolyl, —CH₂-pyrimidyl, —CH(CH₂CH═CH₂)-phenyl, —CH(CH₂CH₂CH₃)-phenyl, wherein the phenyl portion of —CH₂-phenyl, —CH(CH₃)-phenyl, —CH(CH₂CH₃)-phenyl, —CH(CH(CH₃)₂)-phenyl, —CH(CH₂CH═CH₂)-phenyl, and —CH(CH₂CH₂CH₃)-phenyl of R¹⁰are unsubstituted or substituted with one or more Y groups, and the pyridyl, thiazolyl, and pyrimidyl portion of said —CH₂-pyridyl, —CH₂-thiazolyl, —CH(CH₃)-thiazolyl, —CH₂-pyrimidyl are unsubstituted or substituted with one or more Z groups.
In another embodiment of the compound of Formula (I), R¹¹is H, —CH₃, or phenyl, wherein the phenyl is unsubstituted or substituted with one or more groups. Alternatively, two groups R¹¹, together with 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), R¹²is H, —CH₃, —CH₂CH₃, or unsubstituted pyridyl or pyridyl substituted with one or more Z groups.
In another embodiment of the compound of Formula (I), R^ais H or —CH₃.
In another embodiment of the compound of Formula (I), R^bis H or —CH
In another embodiment of the compound of Formula (I), R^aand R^bare both —CH₃.
In another embodiment of the compound of Formula (I), R^cis H or —CH₃.
In another embodiment of the compound of Formula (I), R^dis H, —CH₃, or —CH₂-phenyl, wherein the phenyl portion of said —CH₂-phenyl of R^dis unsubstituted or substituted with one or more Y groups as defined herein.
In another embodiment of the compound of Formula (I), each X is independently selected from the group consisting of —CH₃, —CF₃, F, Br, and Cl, —O—CH₃, —O—CF₃, —CN, —OH, phenyl, and N-oxide;
In another embodiment of the compound of Formula (I), each Y is independently selected from the group consisting of F, Cl, Br, —CH₃, —CF₃, —O—CH₃, —O—CF₃, —CN, —OH, and phenyl; and
In another embodiment of the compound of Formula (I), each Z is independently selected from the group consisting of —CH₃, —CF₃, F, Br, and Cl, —O—CH₃, —O—CF₃, —CN, —OH, phenyl, and N-oxide.
Non-limiting illustrative examples of the compounds of formula (I), include the following compounds:
and pharmaceutically acceptable salts, solvates, esters, or tautomers thereof.
In one embodiment, the compounds of formula (I) have the formula (II):
and pharmaceutically acceptable salts, solvates, esters, and tautomers thereof, wherein:
Q is selected from the group consisting of:
R¹is —H, alkyl, haloalkyl, arylalkyl, -alkylene-S-alkyl or -alkylene-cycloalkyl;
R²is —H, —CN, or —NHC(O)-alkyl;
R⁴is —O-cycloalkyl, —O-alkynyl, —O-alkynylene-cycloalkyl, haloalkyl or —O—N═C(R¹²)₂, wherein both R¹²groups, together with the carbon atom to which they are attached, combine to form a heterocyclyl group, and wherein the alkynyl portion of an —O-alkynyl group can be optionally subsituted with —OH or alkoxy; and wherein the cycloalkyl portion of an —O-cycloalkyl group can be optionally substituted with an -alkylene-O-alkylene-aryl group;
R⁵is —H, —OH, alkyl, haloalkyl, arylalkyl, —O-alkyl, —O-aryl, cycloalkyl, heterocyclyl, —O-cycloalkyl, —O-heterocyclyl, —O-arylalkyl or -alkylene-O-alkyl; and
R⁶is alkoxy, —O-alkylene-O-alkyl, —O-arylalkyl or —O-haloalkyl.
The following embodiments refer to the compounds of formula (II), wherein Q is:
In one embodiment, R¹is alkyl.
In another embodiment, R¹is haloalkyl.
In another embodiment, R¹is arylalkyl.
In still another embodiment, R¹is -alkylene-S-alkyl.
In yet another embodiment, R¹is -alkylene-cycloalkyl.
In another embodiment, R¹is -alkylene-cyclopropyl, -alkylene-cyclobutyl, -alkylene-cyclopentyl or -alkylene-cyclohexyl.
In a further embodiment, R¹is -alkylene-cycloalkenyl.
In another embodiment, R¹is a straight chain alkyl having from 1 to 6 carbon atoms.
In one embodiment, R¹is methyl.
In another embodiment, R¹is ethyl.
In another embodiment, R¹is n-propyl.
In still another embodiment, R¹is n-butyl.
In one embodiment, R¹is n-pentyl.
In another embodiment, R¹is n-hexyl.
In yet another embodiment, R¹is a branched chain alkyl having from 3 to 6 carbon atoms.
In a further embodiment, R¹is isopropyl.
In one embodiment, R¹is isobutyl.
In another embodiment, R¹is isopentyl.
In another embodiment, R¹is sec-butyl.
In still another embodiment, R¹is tert-butyl.
In yet another embodiment, R¹is haloalkyl, having from 1 to 3 F atoms.
In another embodiment, R¹is —(CH₂)₃CF₃.
In one embodiment, R⁴is —CF₃.
In another embodiment, R⁴is —H.
In another embodiment, R⁴is —O-cycloalkyl.
In another embodiment, R⁴—O-alkynyl.
In still another embodiment, R⁴is —O-alkynylene-cycloalkyl.
In yet another embodiment, R⁴is haloalkyl.
In a further embodiment, R⁴is —O—N═C(R⁷)₂.
In one embodiment, R⁴is is —CH₂F.
In another embodiment. R⁴is —CH(F)₂.
In another embodiment, R⁴is —CF₃.
In another embodiment, R⁴is —OCH₂C≡CCH₂CH₃.
In another embodiment, R⁴is —OCH₂C≡C(CH₂)₃CH₃.
In still another embodiment, R⁴is —OCH₂C≡CCH₂CH₂CH₃.
In yet another embodiment, R⁴is —OCH₂C≡C-cyclopropyl.
In a further embodiment, R⁴is —OCH₂C≡CCH(OCH₃)CH₃.
In one embodiment, R⁴is —OCH₂C≡CCH(OH)CH₃.
In another embodiment, R⁴is —OCH₂C≡CCH(OH)CH₂CH₃.
In another embodiment, R⁴is —OCH₂C≡CCH₂CH₂OCH₃.
In still another embodiment, R⁴is —OCH₂C≡CCH₂CH₂OH.
In yet another embodiment, R⁴is —OCH₂C≡C(CH₂)₃OH.
In a further embodiment, R⁴is —OCH(CH₃)C≡CCH₂CH₃.
In another embodiment, R⁴is —OCH₂C≡C-cyclohexyl.
In one embodiment, R⁴is —O-cyclobutyl.
In another embodiment, R⁴is:
In one embodiment, R⁴is:
In one embodiment, R⁵is —H.
In another embodiment, R⁵is —OH.
In another embodiment, R⁵is alkyl.
In another embodiment, R⁵is haloalkyl.
In still another embodiment, R⁵is —O-alkyl.
In yet another embodiment, R⁵is cycloalkyl.
In a further embodiment, R⁵is heterocyclyl.
In one embodiment, R⁵is —O-arylalkyl.
In another embodiment, R⁵is -alkylene-O-alkyl.
In one embodiment, R⁵is —OCH₃.
In another embodiment, R⁵is cyclobutyl.
In another embodiment, R⁵is ethyl.
In still another embodiment, R⁵is N-morpholinyl.
In one embodiment, R⁵is —O-benzyl.
In another embodiment, R⁵is —CH₂CH₂OCH₃.
In yet another embodiment, R⁵is —OCH₂CH₃.
In another embodiment, R⁵is —CH₂F.
In one embodiment, R⁵is —CH₂CH₂F.
In another embodiment, R⁵is —OH.
In one embodiment, R¹is alkyl and R⁵is —H.
In another embodiment, R¹is haloalkyl and R⁵is —H.
In another embodiment, R¹is arylalkyl and R⁵is —H.
In still another embodiment, is -alkylene-S-alkyl and R⁵is —H.
In yet another embodiment, R¹is -alkylene-cycloalkyl and R⁵is —H.
In one embodiment, R¹is alkyl and R⁵is —H.
In another embodiment, R¹is haloalkyl and R⁵is —H
In another embodiment, R¹is arylalkyl and R⁵is —H.
In still another embodiment, R¹is -alkylene-S-alkyl and R⁵is —H.
In yet another embodiment, R¹is -alkylene-cycloalkyl and R⁵is —H.
In one embodiment, R¹is alkyl, R⁵is —H and R⁴is —O-alkynyl.
In another embodiment, R¹is alkyl, R⁵is —H and R⁴is —O-alkynylene-cycloalkyl.
In another embodiment, R¹is alkyl, R⁵is —H and R⁴is haloalkyl.
In still another embodiment, R¹is alkyl, R⁵is —H and R⁴is —O—N═C(R⁷)₂.
In one embodiment, R¹is haloalkyl, R⁵is —H and R⁴is —O-alkynyl.
In another embodiment, R¹is haloalkyl, R⁵is —H and R⁴is —O-alkynylene-cycloalkyl.
In another embodiment, R¹is haloalkyl, R⁵is —H and R⁴is haloalkyl.
In still another embodiment, R¹is haloalkyl, R⁵is —H and R⁴is —O—N═C(R⁷)₂.
In one embodiment, R¹is -alkylene-cycloalkyl, R⁵is H and R⁴is —O-alkynyl.
In another embodiment, R¹is -alkylene-cycloalkyl, R⁵is —H and R⁴is —O-alkynylene-cycloalkyl.
In yet another embodiment, R¹is -alkytene-cycloalkyl, R⁵is —H and R⁴is haloalkyl.
In still another embodiment, R¹is -alkylene-cycloalkyl, R⁵is —H and R⁴is —O—N═C(R⁷)₂.
The following embodiments refer to the compounds of formula (II), wherein Q is:
In one embodiment, R¹is alkyl.
In another embodiment, R¹is haloalkyl.
In another embodiment, R¹is arylalkyl.
In still another embodiment, R¹is -alkylene-S-alkyl.
In yet another embodiment, R¹is -alkylene-cycloalkyl.
In another embodiment, R¹is -alkylene-cyclopropyl, -alkylene-cyclobutyl, -alkylene-cyclopentyl or -alkylene-cyclohexyl.
In a further embodiment, R¹is -alkylene-cycloalkenyl.
In another embodiment, R¹is a straight chain alkyl having from 1 to 6 carbon atoms.
In one embodiment, R¹is methyl.
In another embodiment, R¹is ethyl.
In another embodiment, R¹is n-propyl.
In still another embodiment, R¹is n-butyl.
In one embodiment, R¹is n-pentyl.
In another embodiment, R¹is n-hexyl.
In yet another embodiment, R¹is a branched chain alkyl having from 3 to 6 carbon atoms.
In a further embodiment, R¹is isopropyl.
In one embodiment, R¹is isobutyl.
In another embodiment, R¹is isopentyl.
In another embodiment, R¹is sec-butyl.
In still another embodiment, R¹is tert-butyl.
In yet another embodiment, R¹is haloalkyl, having from 1 to 3 F atoms.
In another embodiment, R¹is —(CH₂)₃CF₃.
In one embodiment, R²is —H.
In another embodiment, R²is —CN.
In another embodiment, R²is —NHC(O)-alkyl.
In still another embodiment, R²is —NHC(O)CH₃.
In one embodiment, R⁴is —CF₃.
In another embodiment, R⁴is —H.
In another embodiment, R⁴is —O-cycloalkyl.
In another embodiment, R⁴—O-alkynyl.
In still another embodiment, R⁴is —O-alkynylene-cycloalkyl.
In yet another embodiment, R⁴is haloalkyl.
In a further embodiment, R⁴is —O—N═C(R⁷)₂.
In one embodiment, R⁴is is —CH₂F.
In another embodiment, R⁴is —CH(F)₂.
In another embodiment, R⁴is —CF₃.
In another embodiment, R⁴is —OCH₂C≡CCH₂CH₃.
In another embodiment, R⁴is —OCH₂C≡C(CH₂)₃CH₃.
In still another embodiment, R⁴is —OCH₂C≡CCH₂CH₂CH₃.
In yet another embodiment, R⁴is —OCH₂C≡C-cyclopropyl.
In a further embodiment, R⁴is —OCH₂C≡CCH(OCH₃)CH₃.
In one embodiment, R⁴is —OCH₂C≡CCH(OH)CH₃.
In another embodiment, R⁴is —OCH₂C≡CCH(OH)CH₂CH₃.
In another embodiment, R⁴is —OCH₂C≡CCH₂CH₂OCH₃.
In still another embodiment, R⁴is —OCH₂C≡CCH₂CH₂OH.
In yet another embodiment, R⁴is —OCH₂C≡C(CH₂)₃OH.
In a further embodiment, R⁴is —OCH(CH₃)C≡CCH₂CH₃.
In another embodiment, R⁴is —OCH₂C≡C-cyclohexyl.
In one embodiment, R⁴is —O-cyclobutyl.
In another embodiment, R⁴is:
In one embodiment, R⁴is:
In one embodiment, R⁶is alkoxy.
In another embodiment, R⁶is —O-alkylene-O-alkyl.
In another embodiment, R⁶is —O-arylalkyl.
In still another embodiment, R⁶is —O-haloalkyl.
In yet another embodiment, R⁶is —OCH₂-(4-methoxyphenyl).
In one embodiment, R⁶is —OCH₂F.
In another embodiment, R⁶is —OCH₂CH₂F.
In another embodiment, R⁶is —OCH₂CH₃
In still another embodiment, R⁶is —OCH₂CH₂OCH₃.
In one embodiment, R¹is alkyl and R⁴is —O-alkynyl.
In another embodiment, R¹is alkyl and R⁴is —O-alkynylene-cycloalkyl.
In another embodiment, R¹is alkyl and R⁴is haloalkyl.
In still another embodiment, R¹is alkyl and R⁴is —O—N═C(R⁷)₂.
In one embodiment, R¹is haloalkyl and R⁴is —O-alkynyl.
In another embodiment, R¹is haloalkyl and R⁴is —O-alkynylene-cycloalkyl.
In another embodiment, R¹is haloalkyl and R⁴is haloalkyl.
In still another embodiment, R¹is haloalkyl and R⁴is —O—N═C(R⁷)₂.
In one embodiment, R¹is -alkylene-cycloalkyl and R⁴is —O-alkynyl.
In another embodiment, R¹is -alkylene-cycloalkyl and R⁴is —O-alkynylene-cycloalkyl.
In yet another embodiment, R¹is -alkylene-cycloalkyl and R⁴is haloalkyl.
In still another embodiment, R¹is -alkylene-cycloalkyl and R⁴is —O—N═C(R⁷)₂.
Non-limiting illustrative examples of the compounds of formula (II), include the following compounds:
and pharmaceutically acceptable salts, solvates, esters, or tautomers thereof.
In one embodiment, the compounds of formula (I) have the formula (III).
and pharmaceutically acceptable salts, solvates, esters, or tautomers thereof, wherein:
Q is selected from the group consisting of:
R¹is —H, alkyl, haloalkyl, arylalkyl, -alkylene-S-alkyl or -alkylene-cycloalkyl;
R²is —H, —CN, or —NHC(O)-alkyl;
R³is —H, —OH, alkyl, haloalkyl, arylalkyl, —O-alkyl, —O-aryl, cycloalkyl, heterocyclyl, —O-cycloalkyl, —O-heterocyclyl, —O-arylalkyl or -alkylene-O-alkyl;
R⁵is —H, —OH, alkyl, haloalkyl, arylalkyl, —O-alkyl, —O-aryl, cycloalkyl, heterocyclyl, —O-cycloalkyl, —O-heterocyclyl, —O-arylalkyl or -alkylene-O-alkyl; and
R⁶is alkoxy, —O-alkylene-O-alkyl, —O-arylalkyl or —O-haloalkyl.
The following embodiments refer to the compounds of formula (III), wherein Q is:
In one embodiment, R¹is alkyl.
In another embodiment, R¹is haloalkyl.
In another embodiment, R¹is -alkylene-S-alkyl.
In still another embodiment, R¹is -arylalkyl.
In yet another embodiment, R¹is -alkylene.
In a further embodiment, R¹is -cycloalkyl.
In one embodiment, R¹is -alkylene-cycloalkenyl.
In another embodiment, R¹is a straight chain alkyl having from 1 to 6 carbon atoms.
In one embodiment, R¹is methyl.
In another embodiment, R¹is ethyl.
In another embodiment, R¹is n-propyl.
In still another embodiment, R¹is n-butyl.
In one embodiment, R¹is n-pentyl.
In another embodiment, R¹is n-hexyl.
In yet another embodiment, R¹is a branched chain alkyl having from 3 to 6 carbon atoms.
In a further embodiment, R¹is isopropyl.
In one embodiment, R¹is isobutyl.
In another embodiment, R¹is isopentyl.
In another embodiment, R¹is sec-butyl.
In still another embodiment, R¹is tert-butyl.
In yet another embodiment, R¹is haloalkyl, having from 1 to 3 F atoms.
In another embodiment, R¹is —(CH₂)₃CF₃.
In one embodiment, R²is —H.
In another embodiment, R²is —CN.
In another embodiment, R²is —NHC(O)-alkyl.
In still another embodiment, R²is —NHC(O)CH₃.
In one embodiment, R³is —H.
In another embodiment, R³is —OH.
In another embodiment, R³is alkyl.
In another embodiment, R³is haloalkyl.
In still another embodiment, R³is —O-alkyl.
In yet another embodiment, R³is cycloalkyl.
In a further embodiment, R³is heterocyclyl.
In one embodiment, R³is —O-arylalkyl.
In another embodiment, R³is -alkylene-O-alkyl.
In one embodiment, R³is —OCH₃.
In another embodiment, R³is cyclobutyl.
In another embodiment, R³is ethyl.
In still another embodiment, R³is N-morpholinyl.
In one embodiment, R³is —O-benzyl.
In another embodiment, R³is —CH₂CH₂OCH₃.
In yet another embodiment, R³is —OCH₂CH₃.
In another embodiment, R³is —CH₂F.
In one embodiment, R³is —CH₂CH₂F.
In another embodiment, R³is —OH.
In one embodiment, R⁵is —H.
In another embodiment, R⁵is —OH.
In another embodiment, R⁵is alkyl.
In another embodiment, R⁵is haloalkyl.
In still another embodiment, R⁵is —O-alkyl.
In yet another embodiment, R⁵is cycloalkyl.
In a further embodiment, R⁵is heterocyclyl.
In one embodiment, R⁵is —O-arylalkyl.
In another embodiment, R⁵is -alkylene-O-alkyl.
In one embodiment, R⁵is —OCH₃.
In another embodiment, R⁵is cyclobutyl.
In another embodiment, R⁵is ethyl.
In still another embodiment, R⁵is N-morpholinyl.
In one embodiment, R⁵is —O-benzyl.
In another embodiment, R⁵is —CH₂CH₂OCH₃.
In yet another embodiment, R⁵is —OCH₂CH₃.
In another embodiment, R⁵is —CH₂F.
In one embodiment, R⁵is —CH₂CH₂F.
In another embodiment, R⁵is —OH.
In one embodiment, R¹is alkyl, and each of R², R³and R⁵is —H.
In another embodiment, R¹is alkyl, R²is —H, and one, but not both of R³and R⁵is —H.
In another embodiment, R¹is alkyl, R²is —H, and one of R³and R⁵is —H and the other is alkyl.
In still another embodiment, R¹is alkyl, R²is —H, and one of R³and R⁵is —H and the other is —O-alkyl.
In yet another embodiment, R¹is alkyl, R²is —H, and one of R³and R⁵is —H and the other is -cycloalkyl.
In one embodiment, R¹is alkyl, R²is —H, and one of R³and R⁵is —H and the other is -heterocyclyl.
In one embodiment, R¹is alkyl, R²is —H, and one of R³and R⁵is —H and the other is -alkylene-O-alkyl.
In one embodiment, R¹is -alkylene-cycloalkyl, and each of R², R³and R⁵is —H.
In another embodiment, R¹is -alkylene-cycloalkyl, R²is —H, and one, but not both of R³and R⁵is —H.
In another embodiment. R¹is -alkylene-cycloalkyl, R²is —H, and one of R³and R⁵is —H and the other is alkyl.
In still another embodiment, R¹is -alkylene-cycloalkyl, R²is —H, and one of R³and R⁵is —H and the other is —O-alkyl.
In yet another embodiment, R¹is -alkylene-cycloalkyl, R²is —H, and one of R³and R⁵is —H and the other is cycloalkyl.
In one embodiment, R¹is -alkylene-cycloalkyl, R²is —H, and one of R³and R⁵is —H and the other is -heterocyclyl.
In one embodiment, R¹is -alkylene-cycloalkyl, R²is —H, and one of R³and R⁵is —H and the other is -alkylene-O-alkyl.
The following embodiments refer to the compounds of formula (III), wherein Q is:
In one embodiment, R⁶is alkoxy.
In another embodiment, R⁶is —O-alkylene-O-alkyl.
In another embodiment, R⁶is —O-arylalkyl.
In still another embodiment, R⁶is —O-haloalkyl.
In yet another embodiment, R⁶is —OCH₂-(4-methoxyphenyl).
In one embodiment, R⁶is —OCH₂F.
In another embodiment, R⁶is —OCH₂CH₂F.
In another embodiment, R⁶is —OCH₂CH₃
In still another embodiment, R⁶is —OCH₂CH₂OCH₃.
In one embodiment, R¹is alkyl.
In another embodiment, R¹is haloalkyl.
In another embodiment, R¹is -alkylene-S-alkyl.
In still another embodiment, R¹is -arylalkyl.
In yet another embodiment, R¹is -alkylene.
In a further embodiment, R¹is -cycloalkyl.
In one embodiment, R¹is -alkylene-cycloalkenyl.
In another embodiment, R¹is a straight chain alkyl having from 1 to 6 carbon atoms.
In one embodiment, R¹is methyl,
In another embodiment, R¹is ethyl.
In another embodiment. R¹is n-propyl.
In still another embodiment, R¹is n-butyl.
In one embodiment, R¹is n-pentyl.
In another embodiment, R¹is n-hexyl.
In yet another embodiment, R¹is a branched chain alkyl having from 3 to 6 carbon atoms.
In a further embodiment, R¹is isopropyl.
In one embodiment, R¹is isobutyl.
In another embodiment, R¹is isopentyl.
In another embodiment, R¹is sec-butyl.
In still another embodiment, R¹is tert-butyl.
In yet another embodiment, R¹is haloalkyl, having from 1 to 3 F atoms.
In another embodiment, R¹is —(CH₂)₃CF₃.
In one embodiment, R²is —H.
In another embodiment, R²is —CN.
In another embodiment, R²is —NHC(O)-alkyl.
in still another embodiment, R²is —NHC(O)CH₃.
In one embodiment, R³is —H.
In another embodiment, R³is —OH.
In another embodiment, R³is alkyl.
In another embodiment, R³is haloalkyl.
In still another embodiment, R³is —O-alkyl.
In yet another embodiment, R³is cycloalkyl.
In a further embodiment, R³is heterocyclyl.
In one embodiment, R³is —O-arylalkyl.
In another embodiment, R³is -alkylene-O-alkyl.
In one embodiment, R³is —OCH₃.
In another embodiment, R³is cyclobutyl.
In another embodiment, R³is ethyl.
In still another embodiment, R³is N-morpholinyl.
In one embodiment, R³is —O-benzyl.
In another embodiment, R³is —CH₂CH₂OCH₃.
In yet another embodiment, R³is —OCH₂CH₃.
In another embodiment, R³is —CH₂F.
In one embodiment, R³is —CH₂CH₂F.
In another embodiment, R³is —OH.
In one embodiment, R⁶is alkoxy, R¹is alkyl, and each of R²and R³is —H.
In another embodiment, R⁶is alkoxy, R¹is alkyl, R²is —H, and R³is alkyl.
In still another embodiment, R⁶is alkoxy, R¹is alkyl, R²is —H, and R³is —O-alkyl.
In yet another embodiment, R⁶is alkoxy, R¹is alkyl, R²is —H, and R³is -cycloalkyl.
In one embodiment, R⁶is alkoxy, R¹is alkyl, R²is —H, and and R³is -heterocyclyl.
In one embodiment, R⁶is alkoxy, R¹is alkyl, R²is —H, and R³is -alkylene-O-alkyl.
In one embodiment, R⁶is alkoxy, R¹is -alkylene-cycloalkyl, and each of R²and R³is —H.
In another embodiment, R⁶is alkoxy, R¹is -alkylene-cycloalkyl, R²is —H, and R³is alkyl.
In still another embodiment, R⁶is alkoxy, R¹is -alkylene-cycloalkyl, R²is —H, and R³is —O-alkyl,
In yet another embodiment, R⁶is alkoxy, R¹is -alkylene-cycloalkyl, R²is —H, and R³is -cycloalkyl.
In one embodiment, R⁶is alkoxy, R¹is -alkylene-cycloalkyl, R²is —H, and R³is -heterocyclyl.
In one embodiment, R⁶is alkoxy, R¹is -alkylene-cycloalkyl, R²is —H, and R³is -alkylene-O-alkyl.
In one embodiment, R⁶is —O-alkylene-O-alkyl, R¹is alkyl, and each of R²and R³is —H.
In another embodiment, R⁶is —O-alkylene-O-alkyl, R¹is alkyl, R²is —H, and R³is alkyl.
In still another embodiment, R⁶is —O-alkylene-O-alkyl, R¹is alkyl, R²is —H, and R³is —O-alkyl.
In yet another embodiment, R⁶is —O-alkylene-O-alkyl, R¹is alkyl, R²is —H, and R³is -cycloalkyl.
In one embodiment, R⁶is —O-alkylene-O-alkyl, R¹is alkyl, R²is —H, and and R³is -heterocyclyl.
In one embodiment, R⁶is —O-alkylene-O-alkyl, R¹is alkyl, R²is —H, and R³is -alkylene-O-alkyl.
In one embodiment, R⁶is —O-alkylene-O-alkyl, R¹is -alkylene-cycloalkyl, and each of R²and R³is —H.
In another embodiment, R⁶is —O-alkylene-O-alkyl, R¹is -alkylene-cycloalkyl, R²is —H, and R³is alkyl.
In still another embodiment, R⁶is —O-alkylene-O-alkyl, R¹is -alkylene-cycloalkyl, R²is —H, and R³is —O-alkyl.
In yet another embodiment, R⁶is —O-alkylene-O-alkyl, R¹is -alkylene-cycloalkyl, R²is —H, and R³is -cycloalkyl.
In one embodiment, R⁶is —O-alkylene-O-alkyl, R¹is -alkylene-cycloalkyl, R²is —H, and R³is -heterocyclyl.
In one embodiment, R⁶is —O-alkylene-O-alkyl, R¹is -alkylene-cycloalkyl, R²is —H, and R³is -alkylene-O-alkyl.
In one embodiment, R⁶is —O-arylalkyl, R¹is alkyl, and each of R²and R³is —H.
In another embodiment, R⁶is —O-arylalkyl, R¹is alkyl, R²is —H, and R³is alkyl.
In still another embodiment, R⁶is —O-arylalkyl, R¹is alkyl, R²is —H, and R³is —O-alkyl.
In yet another embodiment, R⁶is —O-arylalkyl, R¹is alkyl, R²is —H, and R³is -cycloalkyl.
In one embodiment, R⁶is —O-arylalkyl, R¹is alkyl, R²is —H, and and R³is -heterocyclyl.
In one embodiment, R⁶is —O-arylalkyl, R¹is alkyl, R²is —H, and R³is -alkylene-O-alkyl.
In one embodiment, R⁶is —O-arylalkyl, R¹is -alkylene-cycloalkyl, and each of R²and R³is —H.
In another embodiment, R⁶is —O-arylalkyl, R¹is -alkylene-cycloalkyl, R²is —H, and R³is alkyl.
In still another embodiment, R⁶is —O-arylalkyl, R¹is -alkylene-cycloalkyl, R²is —H, and R³is —O-alkyl.
In yet another embodiment, R⁶is —O-arylalkyl, R¹is -alkylene-cycloalkyl, R²is —H, and R³is -cycloalkyl.
In one embodiment, R⁶is —O-arylalkyl, R¹is -alkylene-cycloalkyl, R²is —H, and R³is -heterocyclyl.
In one embodiment, R⁶is —O-arylalkyl, R¹is -alkylene-cycloalkyl, R²is —H, and R³is -alkylene-O-alkyl.
In one embodiment, R⁶is —O-haloalkyl, R¹is alkyl, and each of R²and R³is —H.
In another embodiment, R⁶is —O-haloalkyl, R¹is alkyl, R²is —H, and R³is alkyl.
In still another embodiment, R⁶is —O-haloalkyl, R¹is alkyl, R²is —H, and R³is —O-alkyl,
In yet another embodiment, R⁶is —O-haloalkyl, R¹is alkyl, R²is —H, and R³is -cycloalkyl.
In one embodiment, R⁶is —O-haloalkyl, R¹is alkyl, R²is —H, and and R³is -heterocyclyl.
In one embodiment, R⁶is —O-haloalkyl, R¹is alkyl, R²is —H, and R³is -alkylene-O-alkyl.
In one embodiment, R⁶is —O-haloalkyl, R¹is -alkylene-cycloalkyl, and each of R²and R³is —H.
In another embodiment, R⁶is —O-haloalkyl, R¹is -alkylene-cycloalkyl, R²is —H, and R³is alkyl.
In still another embodiment, R⁶is —O-haloalkyl, R¹is -alkylene-cycloalkyl, R²is —H, and R³is —O-alkyl.
In yet another embodiment, R⁶is —O-haloalkyl, R¹is -alkylene-cycloalkyl, R²is —H, and R³is -cycloalkyl.
Non-limiting illustrative examples of the compounds of formula (III), include the following compounds:
and pharmaceutically acceptable salts, solvates, esters, or tautomers thereof.
In one embodiment, the compounds of formula (I) are compounds of formula (IV):
and and pharmaceutically acceptable salts, solvates, esters, and tautomers thereof,

wherein:

R¹is haloalkyl; and
R²is H or cycloalkyl.
In one embodiment, R¹is fluoroalkyl.
In another embodiment, R¹is -alkylene-F.
In another embodiment, R¹is -alkylene-CF₂.
In still another embodiment, R¹is —(CH₂)₂—CF₂.
In another embodiment, R¹is —(CH₂)₃—CF₂.
In another embodiment, R¹is —(CH₂)₄—CF₂.
In yet another embodiment, R¹is —(CH₂)₅—CF₂.
In still another embodiment, R¹is—(CH₂)₃—F.
In another embodiment. R¹is —(CH₂)₄—F.
In another embodiment, R¹is —(CH₂)₅—F.
In yet another embodiment, R¹is —(CH₂)₅—F.
In one embodiment, R²is H.
In another embodiment, R²is cyclopropyl.
in another embodiment, R²is cyclobutyl.
In still another embodiment, R²is cyclopentyl.
In another embodiment, R²is cyclohexyl.
In one embodiment, R¹is fluoroalkyl and R²is H.
In another embodiment, R¹is fluoroalkyl and R²is cycloalkyl.
In another embodiment, R¹is -alkylene-CF₂and R²is H.
In another embodiment, R¹is -alkylene-CF₂and R²is cycloalkyl.
Non-limiting examples of compounds of formula (IV) include compounds 834, 835 and 837-841 as depicted in the Examples section below, and and pharmaceutically acceptable salts, solvates, esters, and tautomers thereof.
In another embodiment, the compounds of formula (I) are compounds of formula (V):
and and pharmaceutically acceptable salts, solvates, esters, and tautomers thereof,

wherein:

R¹and R²are each, independently, haloalkyl.
In one embodiment, R¹is fluoroalkyl.
In another embodiment, R¹is -alkylene-F.
In another embodiment, R¹is -alkylene-CF₂.
In still another embodiment, R¹is —(CH₂)₂—CF₂.
In another embodiment, R¹is —(CH₂)₃—CF₂.
In another embodiment, R¹is —(CH₂)₄—CF₂.
In yet another embodiment, R¹is —(CH₂)₅—CF₂.
In still another embodiment, R¹is —(CH₂)₃—F.
In another embodiment, R¹is —(CH₂)₄—F.
In another embodiment, R¹is —(CH₂)₅—F.
In yet another embodiment, R¹is —(CH₂)₆—F.
In one embodiment, R²is fluoroalkyl.
In another embodiment, R²is —CHF₂.
In one embodiment, R¹is fluoroalkyl and R²is fluroalkyl.
In another embodiment, R¹is fluoroalkyl and R²is —CHF₂.
In another embodiment, R¹is -alkylene-CF₂and R²is fluoroalkyl.
In still another embodiment, R¹is -alkylene-CF₂and R²is —CHF₂.
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.
Additional non-limiting examples of compounds of formula (I) include compounds 845-911 as depicted in the following table:


Compound No.	Structure

845

846

847

848

849

850

851

852

853

854

855

856

857

858

859

860

861

862

863

864

865

866

867

868

869

870

871

872

873

874

875

876

878

879

880

881

882

883

884

885

886

887

888

886

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

and and pharmaceutically acceptable salts, solvates, esters, and tautomers thereof.

In all embodiments of the present invention, when L is (f), and R², R³and R⁵are each H, then R¹is not —CH₃. 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 (I) of the present invention can have any chemically stable orientation. That is, when L is (f), the compounds of Formula (I) of the present invention can include the following:
or salts, solvates, esters, or tautomers thereof. When L is (g), the compounds of Formula (I) of the present invention can include the following:
or salts, solvates, esters, or tautomers thereof. When L is (h), the compounds of Formula (I) of the present invention can include the following:
or salts, solvates, esters, or tautomers thereof. When L is (i), the compounds of Formula (I) of the present invention can include the following:
or salts, solvates, esters, or tautomers thereof.
The compounds of Formula (I) can be purified to a degree suitable for use as a pharmaceutically active substance. That is, the compounds of Formula (I) 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 (I) 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 compound of Formula (I) includes a single isomer having a purity, as discussed above, of 95 wt % or more, 97 wt % or more, or 99 wt % or more, as discussed above.
Alternatively, the purified compound of Formula (I) can include a mixture of isomers, each having a structure according to Formula (I), where the amount of impurity (i.e., compounds or other contaminants, exclusive of adjuvants as discussed above) is 5 wt % or less, 3 wt % or less, or 1 wt % or less. For example, the purified compound of Formula (I) can be an isomeric mixture of compounds of Structure (I), where the ratio of the amounts of the two isomers is approximately 1:1, and the combined amount of the two isomers is 95 wt % or more, 97 wt % or more, or 99 wt % or more.
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. For example, the compounds of the present invention include tautomeric forms as shown below:
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.
“Bn” means benzyl.
“BnBr” means benzyl bromide.
“BnOH” means benzyl alcohol.
“CDI” means carbodiimide.
“DCM” means dichloromethane (CH₂Cl₂)
“DIAD” means diisopropyl azodicarboxylate.
“DIEA” means N,N-diisopropylethylamine.
“DMF” means dimethylformamide.
“Et” means ethyl.
“EtO₂” means diethyl ether.
“EtOAc” means ethylacetate.
“HATU” means O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylammonium hexafluorophosphate.
“HOAc” means acetic acid.
“IBMX” means 3-isobutyl-1-methylxanthine.
“m-CPBA” means m-chloroperoxybenzoic acid.
“Me” means methyl.
“MeCN” means acetonitrile.
“MeI” means iodomethane.
“Me₂S” means dimethyl sulfide.
“MeOH” means methanol.
“NaOEt” means sodium ethoxide.
“NaOMe” means sodium methoxide.
“NBS” means N-bromosuccinimide.
“NEt₃” means triethylamine.
“NIS” means N-iodosuccinimide.
“t-Bu” means tertiary-butyl.
“t-BuOK” means potassium tertiary-butoxide.
“TFA” means trifluoroacetic acid.
“TfOH” means trifluromethanesulfonic acid.
“THF” means tetrahydrofuran.
“TLC” means thin layer chromatography.
“PMBOH” means 4-methoxybenzyl alcohol,
“PMBCl” means 4-methoxybenzyl chloride.
“Prep TLC” means preparative thin layer chromatography.
“Patient” includes both human and animals.
“Mammal” means humans and other mammalian animals.
“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 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, 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.
“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 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 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.
“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(CH₃)═CH—, and —CH═CHCH₂—.
“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. 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 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 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 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” 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 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 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-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 heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
“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.
“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 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 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.
“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 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 cycloalkenylalkyls include cyclopentenylmethyl, cyciohexenylmethyl and the like.
“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
The term “haloaikyl” 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 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 limted to, —CH₂F, —CH(F)₂, CH₂CH₂F, —CF₃, and —(CH₂)₃CF₃.
“Ring system substituent” means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, —C(═N—CN)—NH₂, —-C(═NH)—NH₂, C(═NH)—NH(alkyl), Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)—, Y₁Y₂NSO₂— and —SO₂NY₁Y₂, wherein Y₁and Y₂can be the same or different and are independently selected from the group 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(CH₃)₂— and the like which form moieties such as, for example:
“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 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, 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 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 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. “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:
“Heterocyclylalkyl” means a heterocyclyl moiety as defined above linked via an 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, 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, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein “ring system substituent” is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-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, 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:
“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 cycloalkylene include
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, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:
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:
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 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.
“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 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.
“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.
“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 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 alkyfthio groups include methylthio and 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 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.
“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 is through the carbonyl.
“Alkylsulfonyl” means an alkyl-S(O₂)— 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(O₂)— group. The bond to the parent moiety is 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 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 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 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 (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 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 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, R², etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence.
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 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, 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 (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. 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 Pergamon Press, 1987.
For example, if a compound of Formula (I) 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, (C₁-C₈)alkyl, (C₂-C₁₂)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, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as 3-dimethylaminoethyl), carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C1-C2)alkyl and piperidine, pyrrolidine- or morpholino(C₂-C₃)alkyl, and the like.
Similarly, if a compound of Formula (I) contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl, N-(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂or glycosyl (the radical 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′ are each independently (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, or R-carbonyl is a natural a-aminoacyl or natural α-aminoacyl, —C(OH)C(O)OY¹wherein Y¹is H, (C₁-C₆)alkyl or benzyl, —C(OY²)Y³wherein Y²is (C₁-C₄) alkyl and Y³is (C₁-C₆)alkyl, carboxy (C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— or di-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵wherein Y⁴is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₆)alkylamino 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 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 solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H₂O.
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 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 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 methods. Analytical techniques such as, for example I. 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, 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 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) 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, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, rnaleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are 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. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; 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). 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, 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.
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 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, phenyl optionally substituted with, for example, halogen, C_1-4alkyl, or C_1-4alkoxy 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_1-20alcohol or reactive derivative thereof, or by a 2,3-di (C_6-24)acyl glycerol.
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 (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) 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 (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.
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 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 (I) may be atropisomers (e.g., substituted biaryis) and are considered as 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 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 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 3-pyridyl). (For example, if a compound of Formula (I) 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.).
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 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 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, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸ _F, and ³⁶Cl, respectively.
Certain isotopically-labelled compounds of Formula (I) (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) 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., ²H) may afford certain therapeutic advantages resulting from 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 reagent.
Polymorphic forms of the compounds of Formula I, 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 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-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 bulk composition and individual dosage units.
The compounds of Formula (I), 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 acceptable salts, solvates, or esters thereof are useful in treating diseases or conditions including dyslipidemia and metabolic syndrome.
The compounds of Formula (I), 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 pharmaceutical composition, according to standard pharmaceutical practice. The compounds of Formula (I), 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 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 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, and preserving agents.
The amount of compound of Formula (I), 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 I, 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 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 g/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.
The compounds of Formula (I), 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 (I) or pharmaceutically acceptable salts, solvates, or esters thereof, can be administered with one or more additional active ingredients selected from the group consisting of hydroxy-substituted azetidinone compounds, substituted β-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 O-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, anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport protein inhibitors, bile acid reabsorption inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CB₁antagonists/inverse agonists, ghrelin antagonists, H₃antagonists/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, orexia 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, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone β agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 1β 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 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 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, α-glucosidase inhibitors, apo Al milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP).
Non-limiting examples of hydroxy-substituted azetidinone compounds and substituted β-lactam compounds useful in combination with the nicotinic acid receptor agonists of the present invention are those disclosed in U.S. Pat. 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. 200210137690 and 2002/0137689 and PCT Patent Application No. WO 2002/066464, each of which is incorporated herein by reference in their entirety. A preferred azetidinone compound is ezetimibe (for example, ZETIA® which is available from Schering-Plough Corporation).
Non-limiting examples of HMG CoA reductase inhibitor compounds useful in combination with the nicotinic acid receptor agonists of the present invention are lovastatin (for example MEVACO® 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 (CRESTOR® from AstraZeneca Pharmaceuticals), pitavastatin (such as NK-104 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-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 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-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 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 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 OUESTRAN® 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 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.
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”) 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 Future Treatments in Dyslipidaemia and Atherosclerosis”, Drugs 2000 July; 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. Pat. Nos. 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, 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 are incorporated herein by reference; compounds described in Yan Xia et al., “Substituted 1,3,5-Triazines As Cholesteral Ester Transfer Protein Inhibitors”, Bioorganic & 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 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. 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 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 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-1067 and other derivatives disclosed in U.S. Pat. Nos. 6,121,319 and 6,147,250, herein incorporated by 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 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 incorporated by reference). Torcetrapib can be combined with HMG-CoA reductase inhibitors such as atorvastatin (WO 00/213797, WO 20041056358, WO 2004/056359, and WO2005/011634).
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-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-1131 (ConjuChem), Exanatide-LAR (Amylin), BIM-51077 (Ipsen/LaRoche), ZP-10 (Zealand Pharmaceuticals), and compounds 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 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 α agonists useful in combination with the 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.
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.
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 CB₁antagonists/inverse agonists useful in combination with the nicotinic acid receptor agonists of the present invention include rimonabant, SR-147778 (Sanofi Aventis), and the compounds described in U.S. Pat. No. 5,532,237, U.S. Pat. No. 4,973,587, U.S. Pat. No. 5,013,837, U.S. Pat. No. 5,081,122, U.S. Pat. No. 5,112,820, U.S. Pat. No. 5,292,736, U.S. Pat. No. 5,624,941, U.S. Pat. No. 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, 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 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 present invention).
Non-limiting examples of N₃antagonists/inverse agonists useful in combination with the nicotinic acid receptor agonists of the present invention include thioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, and GT2394 (Gliatech), those described in WO 02/15905 (herein 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 H₃-receptor antagonists described in Lazewska, D. et al., Pharmazie, 56:927-32 (2001) (herein incorporated by reference), benzophenone derivatives and related compounds described in Sasso, A. et al., Arch. 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, A. et al., J. Med. Chem. 43:3335-43 (2000)(each of the preceding references is herein incorporated by reference).
Non-limiting examples of MCH1R (melanin-concentrating hormone 1 receptor) antagonists and MCH2R (melanin-concentrating hormone 2 receptor) 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 nicotinic acid receptor agonists of the present invention include those described in U.S. Pat. No. 6,001,836, WO 96/14307, WO 01/23387, WO 99151600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01189528 (each of the preceding references is herein incorporated by reference); and BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, and GI-264879A.
Non-limiting examples of NPY5 antagonists useful in combination with the nicotinic acid receptor agonists of the present invention include those described in U.S. Pat. No. 6,140,354, U.S. Pat. No. 6,191,160, U.S. Pat. No. 6,258,837, U.S. Pat. No. 6,313,298, U.S. Pat. No. 6,337,332, U.S. Pat. No. 6,329,395, U.S. Pat. No. 6,340,683, U.S. Pat. No. 6,326,375, U.S. Pat. No. 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, 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 incorporated by reference); and 152,804, GW-569180A, GW-594884A, GW-587081X, GW-548118X; FR226928, FR 240662, FR252384; 1229091, 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 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 (Malin et al., Br. J. Pharmacol. 126:989-96 (1999)), cyclo-(28/32)-Ac-[Lys28-G1u32]-(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 described in Batterham et at, J. Clin. Endocrinol. Metab. 88:3989-3992 (2003), and other Y4 agonists such as 1229U91 (Raposinho et at, Neuroendocrinology. 71:2-7(2000) (both references are herein incorporated by reference).
Non-limiting examples of mG.luR5 (Metabotropic glutamate subtype 5 receptor) antagonists useful in combination with the nicotinic acid receptor agonists of the 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 at, J, Eur J Pharmacol. Jul. 18, 2003; 473(1):35-40; Cosford N. et at, Bioorg Med Chem Lett. Feb. 10, 2003; 13(3):351-4; and Anderson J. et at, J Pharmacol Exp Ther. December 2002: 303(3):1044-51 (each of the preceding 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., truncated forms of leptin) useful in the present invention include those described in U.S. Pat. No. 5,552,524, U.S. Pat. No. 5,552,523, U.S. Pat. No. 5,552,522, U.S. Pat. No. 5,521,283, WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, 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 nicotinic acid receptor agonists of the present invention include nalmefene (Revex™), 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 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).
Non-limiting examples of CNTF (specific ciliary neurotrophic factors) useful in combination with the nicotinic acid receptor agonists of the present invention include GI-181771 (Glaxo-SmithKline); SR146131 (Sanofi Aventis); butabindide; PD170,292, PD 149164 (Pfizer).
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 nicotinic acid receptor agonists of the present invention include BVT933, DPCA37215, WAY161503, and R-1065, as well as those described in U.S. Pat. No. 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 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 with the nicotinic acid receptor agonists of the present invention include sibutramine (Meridia™/Reductil™), as well as those described in WO 01/27068, WO 01/62341, U.S. Pat. No. 4,746,680, U.S. Pat. No. 4,806,570, U.S. Pat. No. 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 with the nicotinic acid receptor agonists of the present invention include dexfenfluramine, fluoxetine, and those described in U.S. Pat. No. 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.
Non-limiting examples of 11β 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).
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 inhibitors, a-glucoside hydrolase inhibitors, PPAR-γ agonists, PPARα/γ 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. 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 acid receptor agonists of the present invention include repaglinide, mitiglinide and nateglinide.
Non-limiting examples of α-amylase inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include tendamistat, trestatin, and AI-3688.
Non-limiting examples of α-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-γ agonists useful in combination with the 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).
Non-limiting examples of PPARα/γ agonists useful in combination with the nicotinic acid receptor agonists of the present invention include CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB 219994.
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-1B inhibitors (protein tyrosine phosphatase-1B 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 include sitagliptin, saxagliptin, denagliptin, vildagliptin, alogliptin, alogliptin benzoate, Galvus (Novartis), ABT-279 and ABT-341 (Abbott), ALS-2-0426 (Alantol), ARI-2243 (Arisaph), BI-A and BI-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 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 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 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)-NH₂).
Non-limiting examples of glycogen phosphorylase inhibitors useful in combination with the nicotinic acid receptor agonists of the present invention include CP-368,296, CP-316,819, and BAYR3401.
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 agonists of the present invention include diuretics, β-adrendergic blockers, α-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 α/β adrenergic blockers.
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.
Non-limiting examples of β-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.
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 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.
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, imidapril, losinopril, moveltopril, moexipril, quinapril, quinaprilat, ramipril, perindopril, peridropril, quanipril, spiraprit, 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, cadoxatril, ecadotril, fosidotril, sampatrilat, AVE7688, and ER4030.
Non-limiting examples of angiotensin II 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, F16828K, RNH6270, losartan monopotassium, and losartan 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 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.
Non-limiting examples of α/β 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 200410229844 (herein 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 (Celebre®), Diclofenac (Cataflam®, Voltaren®, Arthrotec®,) Diflunisal (Dolobid®), Etodolac (Lodine®), Fenoprofen (Nalfon®), Flurbirofen (Ansaid®), Ibuprofen (Motrin®, ADVIL®, NUPRIN®, Tab-Profen®, Vicoprofen®, Combunox®), Indornethacin (Indocin®, Indo-Lemmon®, Indornethagan®), Ketoprofen (Oruvail®), Ketorolac (Toradol®), Mefenamic acid (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 (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).
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-114 based therapy, CT-500, regadenosan, CK-1827452, JAK2 tyrosine kinase inhibitors, adipose-derived regenerative cells, STARBURST dendrimer-based MRI contrast agents, TBC-11299, HEMOxygenation, heparin, GO-EPO, IDN-6734, ISIS-301012, HIF-alpha gene therapy, α2b 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 Novogen), M-118 (Momenta), hypoxia response element, PI-99 (from progen), NEXVAS (from Resveriogix), CS-207)from Shenzhen Chipscreen Biosciences), estrogen-regulated gene therapy, SLV-327 (from SolvaY), TNX-832 (from Sunol Molecular Corp), SLx-2101 (from Surface Logix), recombinant human annexin (from SurroMed), Chymase inhibitors (e.g, from Toa Eiyo), VM-202 (from ViroMed), liver x 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), 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 combination (from Recordati SpA). NO donors 9e.g., from Renopharm), CR-3834 (from Rottapharm Gr), iloprost (from Schering AG), SPP-1100 (from The Speedel Group), angiotensinogen, MC-4232 (from Medicure), ACE inhibitor (from
Servier), LCP-Feno/Stat. (from LifeCycle Pharma), APA-01/statin combination (from Phosphagenics Ltd), KH-01502 (from Kos), KS-01019 (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, 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-BT16, 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 Lexicon), NO-enhancing PDE inhibitors, hyaluronidase, propranolol hydrochloride, BIO-236, RWJ-351647, metoprolol, YM-222546, bLN-5, olmesartan+azelnidipine combination (from Sanyo), moxonidine+HCTZ combination, NS-304, BIO-123, aldosterone antagonists, clonidine, BIO-003 and CR-3834.
In addition, the nicotinic acid receptor agonists of the present invention can also 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 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

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 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 used interchangeably. For example, the compound labeled “Example 1” can also be referred to as “compound 1” and vice versa.

Preparative Example 1

Step A:

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 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 (CD₃OD): δ 120 (t, 3H, J=7.3 Hz), 3.00 (q, 2 H, J=7.3 Hz), 5.80 (s, 1H)
¹³C NMR (CD₃OD): δ 12.6, 27,4, 92.0, 104.2, 149.5, 158.4, 161.8, 162.1, 164.1
Mass for C₉H₉N₂O₄(MH)⁺: 209. Found: 209.

Preparative 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 propionylacetate.
¹H NMR (CD₃OD): δ 2.41 (s, 3H) 5.75 (s, 1H)
Mass for C₈H₇N₂O₄(MH)⁺: 195. Found: 195.

Preparative Example 3

Example 3 was prepared by a method analogous to the method used to prepare Example 1, except that methyl butanoylacetate was used instead of methyl propionylacetate.
¹H NMR (CD₃OD): δ 0.96 (t, 3H, J=7.6 Hz), 1.57 (m, 2H), 2.86 (m, 2H), 5.75 (s, 1H)
Mass for C₁₀H₁₁N₂O₄(MH)⁺: 223. Found: 223.

Preparative Example 4

Example 4 was prepared by a method analogous to the method used to 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).
¹H NMR (CD₃OD): δ 1.14 (d, 6H, J=6.8 Hz), 4.03 (m, 1H), 5.86 (s. 1H)
Mass for C₁₀H₁₁N₂O₄(MH)⁺: 223. Found: 223.

Preparative Example 5

Step A:

Example 1 (5 g, 24.04 mmol, 1 eq), POCK (36.86 g, 240 mmol, 10 eq.) and pyridine (0.95 g, 12 mmol, 0.5 eq) were mixed and heated to 115° C. for 8 hours. After cooling to room temperature, the solvent was removed and the brownish residue was purified using flash chromatography with 20% EtOAc/hexane as the eluting solvent. The desired product (4 g) was obtained in 68% yield.
¹H NMR (CD₃OD): δ 1.29 (t, 3H, J=7.2 Hz), 3.12 (m, 2H), 6.39 (s, 1H)
Mass for C₉H₇Cl₂N₂O₂(MH)⁺: 245. Found: 245.

Preparative Example 6

Step A:

Compound 1 (0.15 g, 0.61 mmol, 1 eq.) and aniline (0.06 g, 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 eluting solvent to give desired product as first fraction (7 mg, 4% yield).
¹H NMR (CD₃OD): δ 1.27 (t, 3H, J=7.2 Hz), 3.05 (m, 2H), 6.11 (s, 1H), 7.11 (t, 1H, J=7.6 Hz), 7.34 (m, 2H), 7.48 (br s, 1H), 7.60 (d, 2H, J=8.0 Hz)
Mass for C₁₅H₁₃ClN₃O₂(MH)⁺: 302. Found: 302.

Preparative Example 7

Step A:

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).
¹H NMR (CD₃OD): δ 1.43 (t, 3H, J=7.2 Hz), 2.96 (m, 2H), 6.22 (s, 1H), 7.37-7.48 (m, 5H)
Mass for C₁₅H₁₃ClN₃O₂(MH)⁺: 302. Found: 302.

Preparative Example 8

Step A:

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.
¹H NMR (CD₃OD): δ 1.20 (t, 3H, J=7.3 Hz), 3.88 (s, 2H), 4.10 (q, 2H, J=7.3 Hz), 5.81 (s, 1H)
¹³C NMR (CD₃OD): δ 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 C₁₁H₁₁N₂O₆(MH)⁺: calcd 267.0617, found 267.0623.

Preparative Example 9

Step A:

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° C. for 4 hours. The reaction mixture was distilled under reduced pressure to give 3,3,3,-trifluoropropionyl chloride (11.5 g, 72%).

Step B:

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 CH₂Cl₂(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 N₂at 0° C. for 1 hour then at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure. The 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%).
A mixture of Compound 9a (2.2 g, 12 mmol) and barbituric acid was heated to 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 (4×50 mL). The organic solution was dried (Na₂SO₄) and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC eluting with formic acid (0.1%)/acetonitrile to give Example 9 (0.17 g, 5%). Electrospray MS [M₊1]⁺ 263.

Preparative Example 10

Step A:

A mixture of 4,6-dihydroxy-2-mercapto-pyrimidine (20.0 g, 138.7 mmol) and methyl propionylacetate (21.8 mL, 173.4 mmol) was heated at 165° C. until the ester was completely reacted. The reaction mixture was cooled down and poured into water (75 mL) and then filtered through a sintered funnel. The solid residue was washed with water (2×20 mL) and dried under vacuum to yield Compound 10a (11.6 g, 37%).

Step B:

MeI (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 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 (2×50 mL) and dried under vacuum to give Compound 10b (4.1 g, 96%).

Step C:

m-CPBA (3.1 g, 70%, 12.6 mmol) was added to a suspension of Compound 10b (2.0 g, 8.4 mmol) in CH₂Cl₂(150 mL) at room temperature. The solvent was removed from the suspension after 3 hours and the crude product was purified using silica gel flash column chromatography, eluting first with hexane/EtOAc (v/v =1/1) then CH₂Cl₂/MeOH (v/v=2/1) to give Example 10 (2.0 g, 94%). Electrospray MS [M+1]⁺ 255.1.

Preparative Example 11

Step A:

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 CH₂Cl₂/MeOH (v/v=50/1) to give Example 11 (0.23 g, 76%). Electrospray MS [M₊1]⁺ 223.1.

Preparative Example 12

Step A:

BnOH (2.46 mL, 23.76 mmol) was added to a solution of Example 10 (0.404 g, 1.58 mmol) and NEt₃(022 mL, 1.58 mmol) in CH₃CN (12.0 mL) at room temperature. The reaction mixture was heated at 85° C. overnight. After cooling to room temperature, HOAc (0.09 mL, 1.58 mmol) was added and the solvent was removed under reduced pressure. The crude product was purified using silica gel flash column chromatography eluting with CH₂Cl₂/MeOH (v/v 50/1) to give Example 12 (0.20 g, 42%). Electrospray MS [M₊1]⁺ 299.1.

Preparative Example 13

Step A:

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 solid residue was washed with water (2×20 mL) and dried under vacuum to give Compound 13a (0.55 g, 88%).

Step B:

m-CPBA (0.33 g, 70%, 1.35 mmol) was added to a suspension of Compound 13a (0.25 g, 0.9 mmol) in CH₂Cl₂(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/CH₂Cl₂/MeOH (v/v=4/1/2) to give Example 13 (0.15 g, 57%). Electrospray MS [M₊1]⁺ 295.1.

Preparative Example 14

Step A:

A mixture of Example 10 (0.205 g, 0.804 mmol) and NH₂NHCO₂Me (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 (3×25 mL) with filtration. The solid was dried under vacuum to give Example 14 (0.2 g, 89%). Electrospray MS [M+1]⁺ 281.1.

Preparative Example 15

Step A:

Allyl bromide (1.74 mL, 20.1 mmol) was added to a suspension of Compound 10a (1.5 g, 6.7 mmol) in DMF (15.0 mL) at room temperature. The reaction mixture was stirred at 45° C. overnight. The reaction mixture was cooled down and poured into water (200 mL) and then filtered through a sintered funnel. The solid residue was washed with water (2×40 mL) and dried under vacuum to give Example 15 (1.55 g, 92%). Electrospray MS [M+1]⁺ 265.1.

Preparative Example 16

Step A:

Cyclopropyl carbinol (0.79 mL. 9.8 mmol) was added to a solution of Example 10 (0.050 g, 0.196 mmol) in CH₃CN (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 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

Step A:

A mixture of Example 10 (0.10 g, 0.392 mmol) and t-BuSH (0.66 mL, 5.88 mmol) in 1,4-dioxane (2.0 mL) was heated at reflux overnight. After cooling to room 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:

m-CPBA (0.049 g, 70%, 0.20 mmol) was added to a suspension of Compound 17a (0.040 g, 0.143 mmol) in CH₂Cl₂(2.5 mL) at room temperature. Solvent was 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 CH₂Cl₂/MeOH (v/v=5/1) to give Example 17 (0.030 g, 71%). Electrospray MS [M+1]⁺ 297.1.

Preparative Example 18

Step A:

EtI (2.1 g, 13.4 mmol) was added to a suspension of Compound 10a (1.5 g, 6.7 mmol) in DMF (20 mL). After stirring at room temperature overnight, the reaction mixture was poured into water (50 mL) and filtered through a Buchner funnel. The solid residue was washed with water (2×50 mL) and dried under vacuum to give Compound 18a (1.3 g, 76%).

Step B

m-CPBA (74 mg, 70%, 3 mmol) was added to a suspension of Compound 18a (0.5 g, 2 mmol) in CH₂Cl₂(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/CH₂Cl₂(v/v/v=0.1/4.9/95) to give Example 18 (0.4 g, 74%). Electrospray MS [M+1]⁺ 269.

Preparative Example 19

Step A:

Benzyl bromide (1.54 g, 9 mmol) was added to a suspension of Compound 10a (1 g, 4.5 mmol) in DMF (20 mL). After stirring at room temperature overnight, the reaction mixture was poured into water (50 mL) and filtered through a Buchner funnel. The solid residue was washed with water (2×50 mL) and dried under vacuum to give Compound 19a (1.3 g, 92%).

Step B:

m-CPBA (72 mg, 70%, 3 mmol) was added to a suspension of Compound 19a (0.5 g, 2 mmol) in CH₂Cl₂(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/CH₂Cl₂(v/v/v=0.1/2.9/97) to give Example 19 (0.5 g, 76%). Electrospray MS [M+1]₊ 331.

Preparative Example 20

Step A:

(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 70° C. for one day. The reaction mixture was cooled down and poured into water (50 mL) and then filtered through a Buchner funnel. The solid residue was washed with water (2×20 mL) and dried under vacuum to Compound 20a (1.3 g, 87%). Electrospray MS [M+1]⁺ 329.

Step B:

m-CPBA (0.3 g, 70%, 1.2 mmol) was added to a suspension of Compound 20a (0.33 g, 1 mmol) in CH₂Cl₂(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 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

Step A:

2-Iodopropane (1.53 9, 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 (2×20 mL) and dried under vacuum to give Compound 21a (1.05 g, 88%).

Step B

m-CPBA (0.74 g, 70%, 3 mmol) was added to a suspension of Compound 21a (0.53 g, 2 mmol) in CH₂Cl₂(30 mL) at room temperature. Solvent was removed after 3 hours, the crude product was purified using a silica gel flash column chromatography eluting with 0.1% AcOH in MeOH/CH₂Cl₂(v/v=2:98) to give Example 21 (0.45 g, 80%). Electrospray MS [M+1]⁺ 283.

Prepartive Examples 22 and 23

Step A:

K₂CO₃(36.7 mg, 0.266 mmol) was added to a mixture of Example 11 (29.6 mg, 0.133 mmol) and EtI (0.064 mL, 0.8 mmol) in DMF (1.0 mL) at room temperature. 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 (3×15 mL), brine (15 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using preparative TLC with hexane/CH₂Cl₂/EtOAc (v/v/v=7/3/1) as eluent to give Example 22 (7.0 mg, 21%) and Example 23 (20 mg, 60%). Electrospray MS [M+1]⁺ 251.1.

Preparative Example 24

Step A:

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 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:

NBS (36 mg, 0.202 mmol) was added to a solution of Compound 24a (0.040 g, 0.161 mmol) in CH₂Cl₂(2.0 mL) at room temperature, Solvent was removed over 1 hour and the crude product was purified using silica gel flash column chromatography 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

Step A:

Example 1 (0.5 g, 2.4 mmol) was taken up in CH₃CN (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 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

Step A:

Example 1 (0.1 g, 0.48 mmol) was taken up in CH₃CN (3.0 mL). Triethylamine (0.067 mL, 0.48 mmol) was added to the suspension followed by methyl bromoacetate (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%).

Preparative Example 27

Step A:

Example 1 (1.0 g, 4.8 mmol) was taken up in CH₃CN (20 mL).
Triethylamine (0.67 mL, 4.8 mmol) was added to the suspension followed by bromomethyl methyl 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:

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 0° C. followed by cyclopropyl methyl bromide (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 (2×5 mL). The organic layers were combined, dried over MgSO₄, and concentrated to give the crude product. The crude mixture was purified by column chromatography eluting with EtOAc/hexanes (2/3: v/v) to yield Compound 27b (0.175 g, 43%).

Step C:

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 CH₂Cl₂(8.0 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 (2×5 mL). The organic layers were combined, dried over MgSO₄, and concentrated to give the crude product. The crude mixture was purified by column chromatography eluting with EtOAc/hexanes (2/3: v/v) to yield Example 27 (0.1 g, 67%).

Preparative Example 28

Step A:

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 0° C. 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 water (5 mL). The aqueous phase was extracted with EtOAc (2×5 mL). The organic layers were combined, dried over MgSO₄, and concentrated to give the crude product. The crude mixture was purified by column chromatography eluting with EtOAc/hexanes (2/3: v/v) to yield Compound 28a (0.07 g, 54%).

Step B:

Boron tribromide (1.1 mL, 1.1 mmol, 1.0 M solution in DCM) was added to a solution of Compound 28a (0.07 g, 0.22 mmol) in CH₂Cl₂(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 (2×5 mL). The organic layers were combined, dried over MgSO₄, and concentrated to give the crude product. The crude mixture was purified by column chromatography eluting with EtOAc/hexanes (2/3: v/v) to yield Example 28 (0.02 g, 33%).

Preparative Example 29

Step A:

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 0° C. followed by 2-bromoacetophenone (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 (2×5 mL). The organic layers were combined, dried over MgSO₄, and concentrated to give the crude product. The crude mixture was purified by column chromatography eluting with EtOAc/hexanes (2/3: v/v) to yield Compound 29a (0.37 g, 50%).

Step B:

Boron tribromide (4.7 mL, 4.7 mmol, 1.0 M solution in DCM) was added to a solution of Compound 29a (0.350 g, 0.95 mmol) in CH₂Cl₂(10.0 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 (2×15 mL). The organic layers were combined, dried over MgSO₄, and concentrated to give the crude product. The crude mixture was purified by column chromatography eluting with EtOAc/hexanes (2/3: v/v) to yield Example 29 (0.175 g, 56%).

Preparative Examples 30 and 31

Step A:

To a CH₂Cl₂solution of cyclopentylamine was added trimethylsilyl isocyanate. The reaction mixture was stirred overnight. To this was added 200 ml of CH₃OH. and the mixture was stirred for another 2 hrs. The reaction mixture was concentrated and 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 (4.0 g, 38.7 mmol) followed by acetic anhydride (18 mL) and the reaction was stirred at 70° C. for 12 hrs. The reaction mixture was concentrated, cooled in an ice bath and titrated using 4/1 EtO₂/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%).

Step B:

Compound 30b (0.75 g, 1.0 equiv., 3.82 mmol) was condensed with methyl propional acetate (0.48 mL, 3.82 mmol) in the presence of sulfamic acid and heated to 140° C. for 6 hrs, forming a dark brown solid. The reaction mixture was diluted with EtOAc, washed with H₂O, dried using Na₂SO₄and concentrated to give a crude mixture. Prep TLC purification of the crude mixture in 95/5 CH₂Cl₂/CH₃OH yielded both the N₁and N₃isomers, 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.


		LCMS:		LCMS:
		(M + 1) of N-		(M + 1) of N-
substituents	N-1 products	1 products	N-3 products	3 products

cyclopropyl	Example 32	249.1	Example 33	249.1

cyclobutyl	Example 34	263.1	Example 35	263.1

Pr	Example 36	251.1	Example 37	251.1

Et	Example 38	237.1	Example 39	237.1

Me	Example 40		Example 41	223.0

allyl	Example 42	249.1	Example 43	249.1

Using the procedure set forth above for making the compound of Example 30, and substituting the appropriate reagents and intermediates, compounds 780-785 were prepared:


		Electrospray
Compound		LCMS
No.	Structure	[M + 1]+

780		303.1

781		305.2

782		291.2

783		291.2

784		317.2

Preparative Example 44

To Example 1 (0.456 g, 2.2 mmol) in MeOH:H₂O (1:1) was added allyl bromide followed by LiOH, and the reaction mixture was heated to 82° C. for 8 hours. The progress of the reaction was monitored by TLC which indicated presence of some starting material. The reaction mixture was then heated for another 6 hours. An orange-red precipitate was produced, which was filtered from the solution using diethyl ether. The filtrate was purified using prep TLC 95/5 CH₂Cl₂/CH₃OH 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 and the appropriate corresponding alcohol.


PREPARATIVE	Electrospray
EXAMPLE	LCMS [M + 1]⁺

Example 45	367.1

Example 46	367.1

Example 47	317.1

Example 51	300.1

Example 61	359.1

Example 62	391.1

Example 63	327.1

Example 64	327.1

Example 66	300.1

Example 67	316.1

Example 69	391.2

Example 70	314.1

Example 71	316.1

Example 72	314.1

Example 73	313.1

Example 74	317.1

Example 75	383.1

Example 76	333.1

Example 77	375.1

Example 78	320.1

Example 79	469.1

Preparative Example 48

Step A:

DIAD (0.488 mL, 2.52 mmol) was added dropwise to a solution of Compound 10b (0.5 g, 2.10 mmol), BnOH (0261 mL, 2.52 mmol) and PPh₃(0.661 g, 2.52 mmol) in THF (6.0 mL) at room temperature. The resulting reaction mixture was stirred for 5 hours before it was worked up by 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:

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 CH₂Cl₂(5 mL). The reaction mixture was stirred for 5 hours before it was quenched with addition of Me₂S (76 uL, 1.55 mmol). The mixture was then diluted with EtOAc and washed with NaHCO₃solution. The organic phase was washed with water, brine, and dried (Na₂SO₄). Solvent was removed under reduced pressure, and the crude product was purified by silica gel flash column chromatography eluting with hexane/CH₂Cl₂/EtOAc (v/v/v=7/3/2) to give Compound 48b (0.15 g, 80%).

Step C:

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 (2×), brine, and dried (MgSO₄). Solvent was removed under reduced pressure, and the crude product was purified by silica gel flash column chromatography, eluting with hexane/CH₂Cl₂/EtOAc (v/v/v=5/1/1) to give Compound 48c (37 mg, 50%).

Step D:

A solution of Compound 48c (10 mg, 0.0326 mmol) in 4.0 M HCl in dioxane (0.7 mL) and MeOH (0.7 mL) in a sealed tube was heated at 70° C. for 7 hours. The mixture was cooled to room temperature and solvent was removed under reduced pressure to give crude product. The crude product was purified with preparative thin layer silica gel chromatography eluting with hexane/CH₂Cl₂/MeOH (v/v/v=6/4/1) to give Example 48 (5 mg, 61%). Electrospray MS [M+1]⁺ 251.1.

Preparative Example 49

Step A:

(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 hours before it was quenched by the addition of HOAc (0.11 mL, 2.0 mmol). The reaction mixture was taken up in EtOAc/CH₂Cl₂(812), washed with diluted HCl (0.1 M), water and brine, then dried (MgSO₄). The solvent was removed under reduced pressure. The crude product was purified using silica gel flash column chromatography eluting with hexane/CH₂Cl₂/EtOAc (v/v/v=7/3/2) to give Compound 49 (0.25 g, 80%). Electrospray MS [M+1]⁺ 313.1.
Using the method set forth above and substituting the appropriate reagents and intermediates, compounds 791-795 were prepared:


		Electrospray
Compound		LCMS
No.	Structure	[M + 1]+

791		411.2

792		411.2

793		437.2

794		437.2

795		291.2

Preparative Example 50

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]⁺ 345.1.

Preparative Example 52

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

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

Step A:

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. overnight. After being cooled to room temperature, the solvent was removed under reduced pressure, diluted with CH₂Cl₂(5 mL) and water (5 mL). The product was extracted from CH₂Cl₂(2×5 mL), dried over MgSO₄, concentrated. The crude product was dissolved in minimum CH₂Cl₂, diluted with hexanes and filtered to give Example 54. Electrospray MS [M+1]⁺ 356.1.

Preparative Example 55

Step A:

Di-t-butyl diazodicarboxylate (2.32 g, 10.08 mmol) was added to a solution of Compound 10b (2.0 g, 8.4 mmol), 4-methoxybenzyl alcohol (1.39 g, 10.08 mmol) and PPh₃(2.64 g, 10.08 mmol) in THE (20.0 mL) at room temperature. The resulting reaction mixture was stirred for 4 hours before it was worked up by direct silica gel flash column chromatography using a solid sample loading method, eluting with hexane/CH₂Cl₂/EtOAc (v/v/v=9/1/1) to give Compound 55a (1.6 g, 53%).

Step B:

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 CH₂Cl₂(8 mL). The reaction mixture was stirred for 5 hours before it was quenched by the addition of Me₂S (124 μL, 1.92 mmol). The mixture was then diluted with EtOAc and washed with NaHCO₃solution. The organic phase was washed with water, brine, and dried (Na₂SO₄). Solvent was removed under reduced pressure, crude product was purified with silica gel flash column chromatography eluting with hexane/CH₂Cl₂/EtOAc (v/v/v=7/3/2) to give Example 55 (0.15 g, 80%). Electrospray MS [M+1]⁺ 391.1.

Preparative Example 56

Step A:

Cyclobutylamine (0.14 g, 2 mmol) was added to a suspension of Example 10 (0.25 g, 1 mmol) in CH₃CN (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% NH₄OH in MeOH/CH₂Cl₂(v/v=3:97) to give Example 56 (0.045 g, 17%). Electrospray MS [M+1]⁺ 262.1

Preparative Example 57

Step A:

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 stirred at 40° 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×3). The organic solution was dried (Na₂SO₄) and concentrated. The crude product was purified using silica gel flash column chromatography eluting with MeOH/CH₂Cl₂(v/v=2:98) to give Compound 57a (1.8 g, 62%). Electrospray MS [M+1]⁺ 367.2.

Step B:

A mixture of Compound 57a (0.95g, 2.6 mmol) in CH₂Cl₂(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 (0.8 g, 100%). Electrospray MS [M+1]⁺ 311.2

Preparative Example 58

Step A:

To a mixture of mono-cyclobutylbarbituric acid (300 mg, 1.6 mmol) and 2-Methyl-3-oxo-pentanoic acid ethyl ester (1.041 g, 6.59 mmol) was added sulfamic acid (77 mg, 0.8 mmol). The mixture was heated at 140-145° C. for 48 h. The residue was loaded onto preparative silica gel plates and eluted with 5% MeOH/CH₂Cl₂to afford Example 58 (42 mg, 9%). LCMS: M+1: 277.1

Preparative Example 59

EXAMPLE 59 was prepared using a two step procedure similar to that used for the preparation of Example 29, using Compound 27a and the appropriate corresponding bromide. Electrospray MS [M+1]⁺ 252.1.

Preparative Example 60

Step A:

Sodium hydride (0.035 g, 0.869 mmol) was added to a mixture of Compound 27a (0.200 g, 0.79 mmol) in 3 mL DMF at 0° C. followed by 2-methoxyphenacyl bromide (0.2 g, 0,87 mmol). The suspension was allowed to stir at room temperature overnight before being diluted with EtOAc (10 mL) and quenched by the addition of water (5 mL). The aqueous phase was extracted with EtOAc (2×5 mL). The organic layers were combined, dried over MgSO₄, and concentrated to give the crude product. The crude mixture was purified by column chromatography eluting with EtOAc/hexanes (2/3: v/v) to yield Compound 60a.

Step B:

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 CH₂Cl₂(5.0 mL) at −78° C. The reaction mixture was allowed to stir for 2 h before being quenched with water (5.0 mL). The reaction mixture was extracted with EtOAc (2×5 mL). The organic layers were combined, dried over MgSO₄, and concentrated to give the crude product. The crude mixture was purified by column chromatography eluting with EtOAc/hexanes (2/3: v/v) to yield Compound 60. Electrospray MS [M+1]⁺ 343.1.

Preparative Example 65

Step A:

K₂CO₃(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, 0705 mmol) in DMF (2.0 mL) at room temperature. The reaction mixture was stirred overnight before it was diluted by the addition of EtOAc (50 mL) and water (10 mL). The organic phase was washed with water (3×15 mL), brine (15 mL), and dried over MgSO₄. After filtration and concentration, the crude product was purified using preparative TLC with hexane/CH₂Cl₂/EtOAc (v/v/v=7/3/1) as eluent to give Compound 65a (26 mg, 31%).

Step B:

Compound 65a (26 mg, 0.074 mmol) in EtOH (5.0 mL) was treated at room temperature with Pd/C (7.8 mg, 10 wt %) and was hydrogenated with a H₂balloon 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/CH₂Cl₂/MeOH (v/v/v=3/7/1) as eluent to give Example 65 (6 mg, 30%). Electrospray MS [M+1]⁺ 263.1.
Using the method set forth above and substituting the appropriate reagents and intermediates, compounds 786-790 were prepared:


		Electrospray
Compound		LCMS
No.	Structure	[M + 1]+

786		291.2

787		295.2

788		269.1

789		295.2

790		283.2

Preparative Example 68

Step A:

The mixture of Example 57 (0.1 g, 0.32 mmol) in CH₂Cl₂(5 mL), piperidine (0.027 g, 0.32 mmol), HATU (0.24 g, 0.64 mmol), and triethylamine (0.098 g, 0.96 mmol) was stirred at room temperature for 2 hours. The reaction mixture was mixed with water (20 mL), and then extracted with CH₂Cl₂(10 mL×2). The organic solution was dried (Na₂SO₄) and concentrated. The crude product was purified using silica gel flash column chromatography eluting with EtOAc/hexanes (v/v=1:1) to give Compound 68a (0.065 g, 54%). Electrospray MS [M+1]⁺ 378.2.

Step B:

1M BBr₃solution in CH₂Cl₂(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° C. for 2 hours, water (5 mL) was added. The organic solution was dried (Na₂SO₄) and concentrated. The crude product was purified using silica gel flash column chromatography eluting with 10% NH₄OH in MeOH/CH₂Cl₂(v/v=3:97) to give Example 68 (0.01 g, 20%). Electrospray MS [M+1]⁺ 334.2.

Preparative Example 80

Step A:

Compound 27a (0.1 g, 0.33 mmol) was taken up in CH₂Cl₂at room 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° 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 diluted with CH₂Cl₂and washed with H₂O. The organic phase was dried with Na₂SO₄and 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:

Compound 80a (0.070 g, 0.18 mmol) was taken up in CH₂Cl₂and the mixture was cooled to −78° C. 1M BBr₃(0.909 mL, 0.9 mmol) was added. The reaction mixture was stirred for 4 hours. Upon completion of the reaction, the mixture was diluted with CH₂Cl₂, washed with H₂O, dried with Na₂SO₄, 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.

Preparative Example 81

Step A:

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

Preparative Example 92

Step A:

Isopropenyl magnesium bromide (0.95 mL, 0.475 mmol, 0.5 M in THF) was added dropwise to a solution of Example 55 (0.133 g, 0.341 mmol) in THF (4.0 mL) at 0° C. The mixture was stirred at 0° C. for 2 hours before it was quenched with HCl (0.2 M). The mixture was taken up in EtOAc and washed with water and brine. The organic phase was dried over MgSO₄. Solvent was removed under reduced pressure and the crude product was purified with silica gel flash column chromatography eluting with hexane/CH₂Cl₂/EtOAc (v/v/v=4/1/1) to give Compound 92a (59 mg, 49%).

Step B:

NaIO₄(70.1 mg, 0.328 mmol) was added to a solution of Compound 92a (46.2 mg, 0.131 mmol) and OsO₄(22.2 μL, 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 quenched by the addition of Me₂S (20 μL, 0.328 mmol). The mixture was diluted with EtOAc and washed with HCl (0.5 M), water and brine. The organic phase was dried over MgSO₄. Solvent was removed under reduced pressure and the crude product was purified by silica gel flash column chromatography eluting with hexane/CH₂Cl₂/EtOAc (v/v/v=2/1/1) to give Compound 92b (39 mg, 84%).

Step C:

Ceric ammonium nitrate (70.9 mg, 0.129 mmol) was added to a solution of Compound 92b (20.8 mg, 0.059 mmol) in MeCN (3.0 mL) and water (0.3 mL) at room temperature. The reaction mixture was stirred for 2 hours before it was diluted with EtOAc. The organic phase was washed with HCl (0.5 M), water, brine and dried over MgSO₄. Solvent was removed under reduced pressure and crude product was purified using preparative TLC with hexane/CH₂Cl₂/MeOH (v/v/v=2/8/1) as eluent to give Example 92 (8 mg, 58%).Electrospray MS [M+1]⁺ 235.1.
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
EXAMPLE	LCMS [M + 1]⁺

Example 82	389.1

Example 83	327.1

Example 84	341.1

Example 85	341.1

Example 86	391.1

Example 87	264.1

Example 88	339.1

Example 89	349.1

Example 90	331.1

Example 91	341.1

Preparative Example 92

Example 2 (0.71 g, 3.66 mmol, 1 eq) and SeO₂(0.46 g, 1.1 eq) were mixed together in 1,4-dioxane (10.5 mL) and THF (1.5 mL) and the mixture was heated to 90° C. in air for 24 hr. 5% of the resulting crude product was purified by directly loading it onto a reverse-phase HPLC column to afford the desired product Example 92 (7.4 mg) as a white solid.
NMR (CD₃OD): δ 4.80 (s, 2H) 620 (s, 1H)
Mass of C₈H₇N₂O₅(MH)⁺: 211. Found: 211.

Preparative Example 93

Step A:

Compound 93a was prepared by a procedure similar to that used to prepare 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 C₈H₅N₂O₅(MH)⁺: 209. Found: 209.

Step B:

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. Preparative TLC afforded 15.3 mg of the desired product Example 93.
¹H NMR (CD₃OD): δ 3.60 (s, 3H) 4.60 (s, 2H) 5.75 (s, 1H) 6.20 (m, 3H) 6.95 (m, 1H)
Mass of C₁₅H₁₄N₃O₅(MH)⁺: 316. Found: 316.

Preparative 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.
¹H NMR (CD₃OD): δ 1.38 (d, 2H, J=6.8 Hz) 5.50 (q, 1H, J=6.8 Hz) 6.20 (s, 1H)
Mass of C₉H₉N₂O₅(MH)⁺: 225. Found: 225.

Preparative Example 95

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 was washed with cold diethyl ether and dried under vacuum. 80 mg of the desired product Example 95 was obtained.
¹H NMR (CDCl₃): δ 1.20 (t, 2H, J=6.8 Hz) 1.83 (s, 3H) 3.00 (q, 2H, J=6.98 Hz) 5.00 (s, 2H) 6.00 (s, 1H)
Mass of C₁₃H₁₃N₂O₄(MH)⁺: 261. Found: 261.

Preparative Example 96

Barbituric acid (1.0 g, 7.81 mmol) was taken up in excess acetone. 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

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.
Electrospray MS [M+1]⁺ for 96 and 97 are 235.1.

Preparative Example 99

Commercially available (Aldrich) Compound 99a (75 g, 383 mmol) was stirred with cold aqueous Na₂CO₃(15%, 450 mL) for 2 h. Extraction with EtOAc and drying over Na₂CO₃provided Compound 99b as a colorless oil, which was immediately treated with NH₄Cl (19.5 g, 364 mmol) in 200 mL of dry EtOH at 50° C. for 60 h. The crude product mixture was cooled and the solvent was removed. The resulting light yellow solid was treated with cold K₂CO₃(30%, 300 mL H₂O) for 0.5 h. Extraction with EtOAc gave Compound 99c as a light yellow solid (37.92 g). This solid was reacted with methyl propionylacetate (38.0 g, 292 mmol), 2 mL pyridine, in 400 mL of dry EtOH at 100° 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).
¹H NMR (CDCl₃): δ 1.20 (t, 3H, J=7.3 Hz) 1.40 (t, 3H, J=7.1 Hz) 2.90 (q, 2H, J=7.3 Hz) 4.30 (q, 2H, J=7.1 Hz) 5.75 (s, 1H)
Mass of C₁₀H₁₅N₂O₃(MH)⁺: 211. Found: 211.
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 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 Et₃N (0.22 g, 2.2 eq), COCl₂(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. NH₃(0.5 M in 1,4-dioxane, 2 mL, 1 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 as a white solid.
¹H NMR (CDCl₃): δ 1.20 (t, 3H, J=7.3 Hz) 3.10 (q, 2H, J=7.3 Hz) 5.40 (s, 2H) 6.40 (s, 1H) 7.20-7.40 (m, 4H) 8.30 (m, 2H)
Mass of C₁₆H₁₆N₃O₃(MH)⁺: 298. Found: 298.

Preparative 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 cyclopropylmethylamine was used instead of ammonia.
¹H NMR (CDCl₃): δ 0.40 (m, 4H) 1.18-1.25 (m, 4H) 3.10 (q, 2H, J=7.2 Hz) (3.82 (d, 2H, J=7.4 Hz) 3.90 (s, 3H) 6.38 (s, 1H) 8.10 (br s, 1H)
Mass of C₁₄H₁₈N₃O₃(MH)⁺: 276. Found: 276.

Preparative 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.
¹H NMR (CDCl₃): δ 1.20 (t, 2H, J=7.3 Hz) 1.60-1.80 (m, 2H) 2.10 (m, 2H) 3.00 (m, 2H) 3.10 (q, 2H, J=7.3 Hz) 5.30 (m, 1H) 5.40 (s, 2H) 6.40 (s, 1H) 7.20-7.40 (m, 5H) 8.20 (br s, 1H)
Mass of C₂₀H₂₂N₃O₃(MH)⁺: 352. Found: 352.
Compound 101a (70 mg) was treated with 3% Pd/C (50 mg), 10 mL MeOH under a hydrogen atmosphere (hydrogen balloon) overnight. After filtration, prep HPLC purification provided 1.2 mg of Example 101.
¹H NMR (CDCl₃): δ 1.20 (t, 2H, J=7.3 Hz) 1.60-1.80 (m, 2H) 2.10 (m, 2H) 2.95 (m, 2H) 3.20 (q, 2H, J=7.3 Hz) 5.30 (m, 1H) 6.40 (s, 1H) 8.00 (br s, 1H).
Mass of C₁₄H₁₇N₃O₃(MH)⁺: 276. Found: 276.

Preparative Example 102

In a 25 mL round bottomed flask equipped with a magnetic stirring bar and a 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. The crude product was stirred with 20 mL of boiling water for a few minutes and filtered. The precipitate was washed with boiling water (2×10 mL) and dried to yield 0.65 g (35% yield) of Example 102.
¹H NMR (DMSO): δ 0.9 (t, 3H, J=7.5 Hz) 1.32-1.40 (m, 2H) 1.45-1.51 (m, 2H) 2.84-2.87 (t, 2H, J=7.5 Hz) 5.82 (s, 1H) 11.34 (s, 1H) 12.72 (br s, 1H)
Mass of C₁₁H₁₂N₂O₄(MH)⁺: 236.22. Found: 237.1.

Examples 103-135

Examples 103-135 where prepared using procedures similar to those used to 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.
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 below.
The preparation of keto ester starting material for examples 247 is as follows

Preparative Example 247a

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 MgCl₂(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 silica gel and eluted with EtOAc/hexanes (1:3) to yield compound 247a.

Preparative Example 223a

The starting material for the preparation of example 223 is as follows.
Step A: A solution of triethyl phosphonate (44.8 g, 200 mmol) in THF (30 ml) at 0° C. was treated with a 1M 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 (15.6 g, 200 mmol) in THF (50 ml) was added dropwise, and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was then cooled to 0° C., treated with cold aqueous citric acid, and the mixture was extracted with EtOAc. The extract was washed with satd. aqueous NaHCO₃, brine, dried over Na₂SO₄, filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with a gradient of CH₂Cl₂/EtOAc to afford 223b (21 g, 91%).
Step 8: The compound 223b (20 g) 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 (20.3 g, 100%).
Step C: The compound 223c (7 g) was dissolved in formic acid (50 ml) and heated at 70° C. for 1 h. The solution was concentrated and the residue was taken up in EtOAc and washed with satd. aqueous NaHCO₃, brine, dried over Na₂SO₄and concentrated. The residue was chromatographed on silica gel to afford 223d (5 g).
Step D: The compound 223d (4.6 g) was dissolved in CH₂Cl₂(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 CH₂Cl₂. The extract was washed with satd. aqueous NaHCO₃, brine, dried over Na₂SO₄and concentrated to afford 223e as brown oil (32 g, 62%).
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 HCl to pH 4 and extracted with CH₂Cl₂. The extract was dried over Na₂SO₄and concentrated to afford 223f as brown oil (3 g, 100%).
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 MgCl₂(570 mg, 6.0 mmol) were added into the above 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.

Preparative Example 262a

Prepared in the same manner as in example 218a.

Preparative Example 263a

Prepared in the same manner as in example 218a.

Preparative Example 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. and methyl acetoacetate (3.84 mL, 35.56 mmol) dissolved in 10 mL THF was added dropwise. The reaction mixture was stirred at 0° 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 0° C. and then cooled to −25° C. Bromomethylcyclobutane (4.82 g, 32.32 mmol) dissolved in 20 mL THF was added dropwise and the reaction was stirred at −25° C. for 4 h followed by room temperature overnight. It was quenched with the addition of sat. NH₄Cl, extracted with EtOAc (2×30 mL), dried over MgSO₄, concentrated in vacuo. The crude product was purified by biotage (5% EtOAc/hexanes) to yield compound 266a.

Preparative Example 267a

Prepared in the same manner as in example 218a.

Preparative Example 268a

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 stir at 0° 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. NH₄Cl, extracted with DCM (2×30 mL), dried over MgSO₄, concentrated in vacuo to yield compound 268b which was carried over to the next step without further purification.
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 Et₂O (2×30 mL), washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude product 268c was used as such without any further purification.
Prepared in the same manner as in example 262a.

Preparative Example 269a

Prepared in the same manner as in example 266a.

Preparative Example 279a

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° C. overnight. After cooling, the solvent was removed in vacuo, quenched with sat. NaHCO₃and extracted with EtOAc (2×30 mL). The organic layer was washed with brine, dried over MgSO₄and concentrated in vacuo to yield compound 279b which was used without any further purification.
Prepared in the same manner as in example 268c.
Prepared in the same manner as in example 262a.

Preparative Example 288a

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 g, 86.82 mmol) in THF (10 mL) was added dropwise and the reaction was stirred at −78° C. for 1 h and 0° C. 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 NH₄Cl and extracted with Et₂O. The organic layer was washed with brine, dried over MgSO₄and concentrated in vacuo. The crude compound obtained was purified by biotage (5% EtOAc/hexanes) to yield compound 288b.
Compound 288b was taken up in CH₂Cl₂(25 mL) in a 100 mL round bottomed flask equipped with a stirring bar and nitrogen balloon and cooled to −78° C. Boron 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° C. After 1 h the reaction was quenched by the addition of sat. NaHCO₃, extracted with CH₂Cl₂. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo to yield the crude compound which was purified by filtering through a short pad of silica gel eluting with 50% EtOAc/hexanes to yield compound 288c.
Compound 288c (3.0 g, 212 mmol) was taken in acetone (20 mL) and cooled to 0° C. 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 Et₂O. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo to yield compound 288d which was used without further purification.
Prepared in the same manner as in example 262a.

Preparative Example 293a

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° C. and (methoxymethyl)triphenylphosphonium chloride (37.3 g, 108.9 mmol) was added portionwise and the dark red solution was stirred at 0° C. for 45 min. Dicyclopropyl ketone (10 g, 90.78 mmol) in THF (10 mL) was added dropwise and the reaction was stirred at 0° C. 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 end ether. The crude end ether was taken up in THF (100 mL) and 10% HCl (100 mL) was added. The reaction was refluxed overnight. Upon cooling, diluted with water and extracted with Et₂O (2×50 mL), washed with brine, dried over MgSO₄, concentrated in vacuo. The crude mixture 293b was used as such without further purification.
Sodium hydride (6.44 g, 161 mmol) was taken in THF (30 mL) in a 250 mL 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 0° C. and compound 293b (10 g, 80.5 mmol) in 20 mL THF was added dropwise and the reaction was allowed to stir at room temperature for 2 h. The reaction was quenched by the addition of water and was extracted with Et₂O. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude was purified by biotage (2% EtOAc/haxanes) to yield compound 293c.
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.
Prepared in the same manner as in example 268c.
Prepared in the same manner as in example 262a.

Preparative Example 294a

Prepared in the same manner as in example 288a.

Preparative Example 295a

Prepared in the same manner as in example 262a.

Preparative Example 292a

The starting material for the preparation of example 292 is as follows.
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(I) iodide (1.9 g, 10 mmol), L-proline (2.3 g, 20 mmol), and cesium carbonate (65.2 g, 200 mmol). After stirred under N₂at 40° C. for 18 hours, the reaction mixture was dissolved into ethyl acetate (250 mL), washed with water (4×150 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 acetate/hexanes (v/v=5/95) to give compound 292a (4.5 g, 38%).

Preparative Example 297a

The starting material for the preparation of example 297 is as follows.
To a solution of 2-cyclopentyl ethanol (11.4 g, 100 mmol), anhydrous CH₂Cl₂(80 mL), and triethyl amine(12 g, 120 mmol), which cooled to 0° C., was added via syringe MsCl (13.7 g, 120 mmol). After stirring under N₂at 0° C. for 1 hour then at room temperature for 18 hours, the reaction mixture was washed with water (2×100 mL), dried with sodium sulfate, and concentrated under reduced pressure to give a clear oil (19 g, 100%). The oil was dissolved into anhydrous CH₂Cl₂(250 mL) and mixed with NaI (20 g, 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 (2×150 mL), dried with sodium sulfate, concentrated under reduced pressure to give compound 297b (20q, 89%).
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%, 2.4 g,. 60 mmol). After stirring under N₂at 0° C. for 0.5 hour, n-BuLi (2.5 M in hexanes, 20 mL) was added via syringe. After stirring at 0° C. for 0.5 hour, the reaction mixtures was cooled to −25° C., the compound 297b was added via syringe. The reaction mixture was stirred at 0° C. 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 (2×200 mL)washed with water (2×100 mL). The organic solution was dried with sodium sulfate, and concentrated under reduced pressure to give a brown oil, which purified using silica gel flash column chromatography eluting with ethyl acetate/hexanes (v/v=7/93) to give compound 297a (32 g, 32%).

Preparative Example 214

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-Iodosuccinimide (22 g, 97.79 mmol) was added portionwise and the reaction mixture was heated to 50° C. overnight. After cooling to ambient temperature, H₂O (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.
Compound 214b (0.1 g, 0.3 mmol) was taken in C₆H₆(1 mL) in a 10 mL round bottomed flask. Pd(OAc)₂(0.004 g, 0.018 mmol), PPh₃(0.014 g, 0.054 mmol), and Na₂CO₃(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) 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 H₂O (2 mL), extracted with EtOAc (2×10 mL), dried over MgSO₄, concentrated and dried to yield the crude compound 214. Purification by preparative TLC (10% MeOH/DCM) to yield compound 214.

Preparative Example 219

Compound 214b (0.1 g, 0.3 mmol) was taken in DMF (3.0 mL) in a 10 mL round bottomed flask. PdCl₂(PPh₃)₂(0.011 g, 0.015 mmol), phenylacetylene (0.061 g, 0.6 mmol), CuI (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 1N HCl, and extracted with EtOAc (2×10 mL), dried over MgSO₄, concentrated and dried to yield crude 219. The crude product was taken in ether and filtered to yield pure compound 219.

Preparative Example 220

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 with ether, The product 220c was dried and needed no further purification.
Compound 220c (0.1 g, 0.431 mmol) was taken in DMF (1 mL) in a 10 mL round bottomed flask. Iodobenzene (0.053 g, 0.258 mmol), PdCl₂(PPh₃)₂(0.003 g, 0.0043 mmol), CuI (0.002 g, 0.0086 mmol), and Et₂NH (0.157 g, 2.15 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was diluted with EtOAc (2 mL), neutralized with 1N HCl and extracted with EtOAc (2×10 mL). It was dried over MgSO₄, concentrated in vacuo. The crude product was purified by preparative TLC (20% MeOH/DCM) to yield compound 220.

Preparative Example 216

Barbituric acid (1.0 g, 7.81 mmol) and Diethyl β-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 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

Step A:

To a solution of ethylphenylacetae (8.2 g, 0.05 mol in THF at −78° 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 to 0° C. and stirred for 30 min. It was quenched with NH₄Cl (aq.) and extracted with EtOAc. Usual work up afforded the crude material which was chromatographed on silica gel to obtain product.

Step B:

Compound 203 was obtained by normal condensation procedure with cyclobutylbarbituric acid.

Preparative Example 209

Step A:

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 temperature overnight. 1 N HCl (100 mL) was added and extracted with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO₄) to give compound 209b (8.8 g, 93%).

Step B:

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. MgCl₂(1.5 g, 16.1 mmol) and KOCOCH₂CO₂Me (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. The aqueous layer was extracted with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO₄), 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:

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° 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 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.
Compound 208 was prepared in a similar fashion as in Compound 209, from the commercially available Compound 208a.

Preparative Example 270

Step A:

Starting lactone (10 g, 116 mmol) was mixed with allylbromide (30 mL, 346 mmol), toluene (75 and KOH (19.5 g, 348 mmol). The mixture was heated 110° C. overnight. The mixture was cooled to room temperature; water (100 mL) was added. The aqueous layer was extracted with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO₄), filtered and concentrated to give a yellow liquid as the desired Compound 270a (11.8 g, 55.2%).

Step B:

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 H₂overnight. 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:

Compound 270b (3.0 g, 16.3 mmol) was dissolve in THF (20 mL)-H₂O (7 mL), LiOH (1.66 g, 39.5 mmol) was added. The resulting mixture was stirred at room temperature overnight. 1 N HCl (75 mL) was added, and extracted with Et₂O. The organic extracts were combined, dried (MgSO₄) filtered and concentrated. The 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 KOCOCH₂CO₂Me (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 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 separated by silica gel chromatography, with Biotage 405+ column, eluted with EtOAc: hexanes, 1:10, to give 1.5 g (46%) yellow liquid as Compound 270d.

Step D:

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° C. overnight. The mixture was cooled to room temperature, HOAc was removed 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 270 (72 mg, 11.4%) as a white solid. Electrospray MS [M+1]: 281.2.

Preparative Example 271

Step A:

Starting alcohol (5.2 g, 28.0 mmol) was dissolved in DCM (100 mL), triethylamine (6 mL, 42.7 mmol) and MsCl (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 HCl (50 mL×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, 100%).

Step B:

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 slurry was stirred at room temperature for 1 h. A solution of mesylate 271a (7.26 g, 28 mmol) in DMF (30 mL) was added via syringe. The resulting mixture was heated at 85° C. overnight. The mixture was cooled to room temperature, and diluted with EtOAc, and washed with water (50 mL×3). The aqueous layers were combined and extracted with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO₄), 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:

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 purified over silica gel column, eluted with EtOAc-hexanes (1:3) to give 3.1 g (98%) of Compound 271c as a colorless liquid.

Step C:

CrO₃was mixed with 4.7 mL of conc. H₂SO₄. The mixture was diluted with water to 36 mL. Compound 271c 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 (MgSO₄), filtered and concentrated to give 1.99 g (71%).

Step D:

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. MgCl₂(1.5 g, 15.3 mmol) and KOCOCH₂CO₂Me (3.3 g, 20.9 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. 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 liquid as Compound 270e.

Step D:

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 125° C. overnight. The mixture was cooled to room temperature, HOAc was removed 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.
Compound 273, Compound 287 and Compound 290 are prepared in a similar fashion as Compound 271 from the corresponding alcohols.

Preparative Example 205

Compound 205a (50 mg, 0.14 mmol) was dissolved in DMF (2 mL) and H₂O (2 mL), Pd(dppf)₂Cl₂and K₂CO₃were added. The resulting mixture was heated at 85° C. 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.
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 LCMS data is also shown wherever available. The activity (EC50) 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		NA EC50	Electrospray
No.	STRUCTURE	camp (nM)	LCMS [M + 1]+

200		B	331.2

201		C	289.2

202		B	311.2

203		C	339.1

204		C	265.1

205		B	365.2

206		B	235.1

207		C	377.2

208		C	316.2

209		B	253.1

210		B	331.2

211		C	263.1

212		B	263.1

213		B	345.2

214		C	291.2

215		C	343.2

216		B	267.1

217		C	247.1

218		B	251.1

219		C	309.2

220		C	309.2

221		C	378.2

222		C	281.2

223		A	313

224		A	317.2

225		A	269.1

226		A	261.1

227		C	249.1

228		C	372.2

229		A	391.2

230		B	301.2

231		C	318.2 (M + Na)

232		C	368.2 (M + Na)

233		C	398

234		C	426

235		A	275.2

236		C	309.2

237		C	280.2

238		B	349.2

239		A	267.1

240		C	251

241		A	331.2

242		C	331.2

243		B	380

244		C	264

245		A	305.2

246		C	345.2

247		A	265.1

248		C	293.2

249		B	434

250		C	376

251		B	380

252		A	249.1

253		C	317.2

254		C	317.2

255		C	359.2

256		C	359.2

257		C	291.2

258		B	291.2

259		C	305.2

260		C	305.2

261		B	396

262		A	279.2

263		C	265.1

264		C	329.2

265		C	321.2

266		A	263.1

267		C	265.1

268		A	277.2

269		B	279.2

270		A	281.2

271		B	307.2

272		B	263.1

273		B	293.2

274		B	303.2

275		B	263.1

276		B	263.1

277		C	277.2

278		B	277.2

279		C	281.2

280		C	373.2

281		B	359.2

282		B	345.2

283		B	221.1

284		B	333.1

285		B	331.2

286		A	277.2

287		C	321.2

288		C	290.2

289		C	223.1

290		B	315.2 (M + Na)

291		C	223.1

292		B	313.2

293		B	303.2

294		B	288.2

295		B	263.1

296		B	249.1

297		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.

Compounds 691 and 698 were prepared by a procedure similar to Example 49, using appropriate oxyaminocarbamate and sulfoxide which was prepared using Example 10.


		NA EC50
Compound		camp	Electrospray
No.	Structure	(nM)	LCMS [M + 1]+

500		B	363.1

501		A	363.1

502		B	343

503		B	368

504		B	327

505		B	327

506		C	335

507		A	363

508		C	381.1

509		B	400

510		C	393

511		C	358.2

512		A	275

513		B	304

514		C	435

515		B	363

516		C	381

517		C	375.2

518		B	393.2

519		C	295.1

520		C	376.2

521		B	401.2

522		B	323

523		A	300.2

524		B	267.1

525		B	329.2

526		B	380

527		B	350

528		B	350

529		B	317

530		B	317

531		B	380

532		B	383

533		C	370

534		B	384

535		B	380

536		B	379

537		C	363

538		B	355

539		B	327

540		B	366

541		B	388

542		C	379

543		B	354

544		B	330.2

545		B	368.2

546		B	369.99

547		B	447

548		B	405

549		B	419

550		C	389

551		B	432

552		B	446

553		C	458

554		C	409

555		B	247

556		C	314.2

557		A	289

558		C	427

559		B	393

560		C	426

561		B	405

562		B	406

563		B	376

564		B	409

565		B	435

566		C	393

567		B	400

568		B	368.2

569		A	407.2

570		B	365.1

571		B	366.1

572		B	423.1

573		B	461.1

574		B	394.1

575		B	395.1

576		C	343.2

577		B	343.2

578		C	320.2

579		C	306.2

580		C	281.2

581		C	279.2

582		B	266.1

583		B	379.2

584		B	418

585		B	418

586		A	383.1

587		C	379.1

588		C	315.1

589		A	287

590		B	275

591		A	411.1

592		B	320.2

593		C	307.2

594		C	320.2

595		B	295.2

596		B	343.2

597		C	398.1

598		B	343.1

599		B	343.1

600		C	409.1

601		C	293.1

602		B	398.1

603		B	327.2

604		B	387.2

605		C	309.2

606		C	321

607		B	281.2

608		B	384.2

609		C	376.1

610		C	335

611		C	324.2

612		C	364.2

613		B	412.1

614		B	347.1

615		B	337.1

616		B	379.2

617		B	397.2

618		B	343.2

619		B	342.2

620		C	322.2

621		B	322.2

622		B	389.2

623		A	357.2

624		B	365.2

625		B	318.2

626		A	358

627		C	361.2

628		C	366.2

629		B	334.2

630		C	324.2

631		B	277

632		B	281.2

633		B	329.2

634		B	405

635		C	395

636		B	291

637		B	309.2

638		B	329

639		B	283

640		B	400.1

641		A	304

642		B	297.2

643		B	253.1

644		A	291

645		A	305

646		C	373.2

647		B	448.2

648		B	382.2

649		B	368

650		B	329.2

651		B	520

652		A	280.1

653		C	399.2

654		A	M + Na 391.2

655		B	346.2

656		C	332

657		C	290

658		B	291

659		C	399.2

660		C	317.2 (M + Na)

661		B	371.2

662		A	399.2

663		C	439.2

664		B	305

665		C	304

666		A	332

667		B	346

668		C	304

669		B	319

670		A	319.2

671		A	305

672		B	305

673		B	359

674		A	303

675		B	346

676		B	360

677		A	315

678		B	331

679		A	333

680		A	319

681		C	344.2

682		C	328.2

683		C	360.2

684		A	371.2

685		B	412.2

686		B	279.2

687		B	305.2

688		B	374.2

689		B	400.2

690		C	241.1

691		A	350.2

692		A	352.2

693		B	364.2

694		C	338.2

695		A	338.2

696		B	336.2

697		—	324.2

698		—	295.2

Preparative Example 699

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-Iodosuccinimide (1.59 g, 7.05 mmol) was added portionwise and the reaction mixture was heated to 50° C. overnight. After cooling to ambient temperature, H₂O (25 mL) was added. The product was filtered, washed with water followed by ether to give a white powdery mixture (>95% yield). The product 699b was used as such for the next step without any further purification.
Compound 699b (0.1 g, 0.258 mmol) was taken in 5 mL DME/H₂O (4:1) in a 10 mL round bottomed flask. PdCl₂(PPh₃)₂(0.018 g, 0.0258 mmol), Na₂CO₃(0.082 g, 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 (CH₂Cl₂to 5% MeOH/CH₂Cl₂) to yield compound 699.
Compound 700 was prepared in the same manner as in example 699.
Compound 701 was prepared in the same manner as in example 699.
Compound 702 was prepared in the same manner as in example 699.
Compound 703 was prepared in the same manner as in example 699.
Compound 704 was prepared in the same manner as in example 699.
Compound 705b was prepared in the same manner as in example 699b.
Compound 705 was prepared in the same manner of compound 699.
The compound 706 was prepared in the same manner of compound 699.
The compound 707 was prepared in the same manner of compound 699.
The compound 708 was prepared in the same manner of compound 699.
The compound 709 was prepared in the same manner of compound 699.
The compound 710 was prepared in the same manner of compound 699.


Compound		NA EC₅₀camp	Electrospray
No.	STRUCTURE	(nM)	LCMS [M + 1]+

699		C	339.2

700		C	357.2

701		C	407.2

702		C	364.2

703		C	383.2

704		C	396.2

705		C	347.2

706		C	331.2

707		C	343.2

708		B	381.2

709		C	338.2

710		C	370.2

Preparative Example 711

Step A:

To a solution of diethyl zinc (3.0 eq, 1.0 M in THF) in CH₂Cl₂(0.2 M) at 0° C., was added TFA (3.0 equiv, dropwise via an addition funnel). The resulting mixture was allowed to stir at 0° C. for 15 minutes after the addition was complete. CH₂I₂(3.0 equiv) was then added to the reaction mixture dropwise via syringe and the resulting reaction was allowed to stir at 0° 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 HCl and the aqueous layer was extracted with CH₂Cl₂(3×). The combined organic phases were washed with water, then brine, then dried over MgSO₄and concentrated in vacuo to provide compound 711A in quantitative yield.

Step B:

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 (3×) and the combined organic phases were washed with water, then brine, then dried over MgSO₄and concentrated in vacuo to provide compound 711B in quantitative yield.

Step C:

CDI (1.2 equiv) was added to a solution of 711B 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 MgCl₂(1.0 equiv) were added. The resulting reaction was allowed to stir for about 15 hours and was then quenched with aqueous HCl (1.0 N). The aqueous layer was extracted with EtOAc (3×). The combined organic phases were washed with water, then brine, then dried over MgSO₄and concentrated in vacuo to provide compound 711C in quantitative yield.

Step 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 the resulting residue was purified using flash column chromatography on silica gel to provide compound 711D (37% yield).

Step E:

Mel (1.8 equiv) was added to a suspension of 711D (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 filtered through a sintered funnel. The collected solid material was washed with water and dried under vacuum to provide compound 711E (96% yield).

Step F:

m-CPBA (2.0 equiv) was added to a suspension of 711E (1.0 equiv) in CH₂Cl₂(0.15 M) at room temperature. After stirring for 3 hours, the reaction was quenched with Me₂S (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 711F as a mixture of sulfone and sulfoxide (90% yield, w/w=1/2).

Step G:

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 711F (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 was diluted with EtOAc and washed sequentially with 0.1 M HCl, water and brine, then dried over MgSO₄and concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel (eluent: hexane/CH₂Cl₂/EA (v/v/v=7/3/2)) to provide compound 711 (50% yield). Electrospray MS [M+1]⁺329.2.
Using the method described above, and appropriate materials, Compounds 712-739 were prepared:


Compound		Electrospray
No.	Structure	LCMS [M + 1]⁺

712		329.2

713		329.2

714		317.2

715		331.2

716		343.2

717		315.2

718		343.2

719		357.2

720		315.2

721		329.2

722		327.2

723		305

724		305

725		319

726		305

727		291

728		305

729		291

730		289

731		329

732		275

733		289

734		303

735		315

736		333

737		319

738		287

739		337.1

Preparative Example 740

Step 1

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 reflux and allowed to stir at this temperature 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 and hexane, then sucked dry under vacuum to provide 45.0 g product as white powder (71% yield).

Step:2

A mixture of compound 740A (10.50 g, 64.81 mmol), compound 740B (14.90 g, 80.98 mmol), and sulfamic acid (6.29 g, 64.84 mmol) was heated to 165° C. and allowed to stir at this temperature for 30 minutes. The reaction mixture was then cooled to about 70° C., then poured into into a mixture of CH₂Cl₂/MeOH (1:1, 50 mL) and the resulting solution was filtered. The solid collected by filtration was then washed repeatedly with CH₂Cl₂/MeOH (1:1) and the eluates were combined and concentrated in vacua to provide compound 740 as white crystals (3.30 g, 17%).
Using the method described above, and appropriate materials, Compounds 742, 743, 745, 746, 748, 750, 752, 754, 757 and 812 were prepared:


		Electrospray
Compound		LCMS
No.	Structure	[M + 1]⁺

742		405.2

743		285.1

745		431.2

746		311.2

748		297.2

750		271.1

752		283.2

754		299.2

757		325.2

812		299.2

Preparative Example 758

Step A:

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 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.

Step B:

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 N₂. After cooling to room temperature, H₂O (50 mL) was added. The precipitated product was filtered, washed with water then ether to afford 16 (95% yield).

Step C:

m-CPBA (0.936 g, 4.18 mmol) was added to a solution of 758C (0.55 g, 2.09 mmol) in CH₂Cl₂(15 mL). The resulting reaction was allowed to stir at room temperature for 4 hours, then Me₂S 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 CH₃CN/H₂O (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
Using the method described above, and appropriate materials, compounds 759 and 760 were prepared:


Compound		Electrospray
No.	Structure	LCMS [M + 1]⁺

759		288.2

760		262.1

Preparative Example 761

Step A:

Fuming HNO₃(0.9 mL) was added drop wise to a solution of 761A (0.5 g, 1.81 mmol) in HOAc (1.8 mL) under N₂. 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 761B (0.3 g, 51%). Electrospray MS: [MH⁺]=322.2

Step B:

Zn dust (0.47 g, 7.2 mmol) was added to a solution of 761B (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 vacua to provide a residue which was dissolved in CH₂Cl₂(2 mL). To the resulting solution was added Et₃N (2 mL) followed by acetic anhydride (2 mL). The resulting reaction was allowed to stir at room temperature for 24 hours, then was concentrated in vacua and the resulting residue was purified using flash column chromatography on silica gel (eluent: MeOH/CH₂Cl₂(v/v=10/97)) to provide compound 761 (0.15 g, 62%). Electrospray MS: [MH⁺]=334.2

Preparative Example 762

Step A:

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, heated to reflux, 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:

Compound 711C (0.8 g, 4.2 mmol, prepared as described above in preparative example 711, step C) was added to a solution of 762A (0.5 g, 2.8 mmol) in HOAc (1.5 mL). The resulting reaction was heated to 120° C. and allowed to stir at this temperature for 20 hours, then the reaction was cooled to room temperature and concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel (eluent: 3% MeOH/CH₂Cl₂) followed by preparative TLC (5% MeOH/CH₂Cl₂) to to provide compound 762.
Using the method described above, and appropriate materials, compounds 763 and 764 were prepared:


Compound		Electrospray
No.	Structure	LCMS [M + 1]⁺

763		329.2

764		289.2

Preparative Example 765

Step A:

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 resulting residue was partitioned between 200 mL of H₂O and 100 mL of EtOAc. The precipitate was collected and washed with H₂O and EtOAc, then dried in vacuo to afford compound 765B (20.2 g, 78%).

Step B:

Na₂CO₃(27 g, 300 mmol) and PMBCl (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 then cooled to room temperature and partitioned between H₂O (250 mL) and EtOAc (500 mL). The organic layer was separated and washed with H₂O, then brine, then dried over MgSO₄, 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 recrystalized from DCM and hexanes to afford 765C (16.6 9, 31%).

Step C:

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° C. 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 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 HCl and the resulting acidic solution was extracted with EtOAc. The combined organic extracts were washed with 1 N sodium thiosulfate solution, dried over MgSO₄, then filtered and concentrated in vacuo to provide compound 765D (13.5 g, 90%).

Step D:

Oxalyl chloride (0.2 mL, 2.32 mmol) was added to a solution of 765D (1.0 g, 1.91 mmol) in CH₂Cl₂(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 vacuo. The resulting residue was dissolved in CH₂Cl₂(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 CH₂Cl₂(10 mL) and washed with 1 N HCl. The organic layer was separated, washed with brine, dried over MgSO₄, and concentrated in vacuo. The 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:

In a sealed tube, Et₃N (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 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%).

Step F:

A solution of 765F (262 mg, 0.60 mmol) in DMF/THF (1:1, 12 mL) was cooled to 0° C. 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 aqueous layer was separated and extracted with CH₂Cl₂. The combined organic extracts were dried over MgSO₄and concentrated in vacua 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%).

Step G:

TFA (0.5 mL) and TfOH (0.1 mL) were added to a solution of 765H (100 mg, 0.22 mmol) in CH₂Cl₂(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/CH₂Cl₂/EtOAc, 1:10:10) to provide compound 765 (12 mg, 26%). Electrospray MS [M+1]⁺208.1

Preparative Examples 766 and 767

Step A:

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 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 Ac₂O (40 mL) were added. The mixture was heated at 70° C. for 10 h. The reaction was concentrated in vacuo 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:

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 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
Using the method described above, and appropriate materials, compounds 768-779 were prepared:


Compound		Electrospray
No.	Structure	LCMS [M + 1]⁺

768		239.1

769		293.1

770		293.1

771		292.2

772		306.3

773		306.31

774		NA

775		NA

776		307.1

777		307.1

778		281.1

779		281.1

NA = not available

Other illustrative compounds of formula (I), include but are not limited to compounds 796-810, which are depicted below:


Com-		Electrospray
pound		LCMS
No.	Structure	[M + 1]⁺

796		322.2

797		322.2

798		343.2

799		343.2

800		307.2

801		307.2

802		295.2

803		269.1

804		309.2

805		253.1

806		253.1

807		193.1

808		222.2

809		253.1

810		211.1

Preparative Example 811

Step A:

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 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 HCl and the solid formed was collected by filtration, washed sequentially with H₂O and Et₂O, then sucked dry to provide compound 811A as a pale brown powder (1.8 9, 69%).

Step B

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 130° 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 CH₂Cl₂/MeOH (1:1, 1 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 741, 744, 747, 749, 751, 753, 755 and 756 were prepared:


Compound		Electrospray
No.	Structure	LCMS [M + 1]⁺

741		279

744		267.1

747		293.2

749		279.2

751		285.2

753		265.1

755		281.2

756		307.2

Preparative Example 813

Step A:

K₂CO₃(0.35 g, 2.54 mmol) was added to a solution of compound 102 (0.4 g, 1.69 mmol) and BrCH₂F (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 ethyl acetate and neutralized with aqueous HCl solution (0.5 N). The organic phase was washed with water (3×), dried (Mg₂SO₄), 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]⁺269.1.

Preparative Example 814

Step A:

Cs₂CO₃(1.30 g, 3.99 mmol) was added to a solution of compound 711E (0.39 g, 1.33 mmol) and BrCHF₂(0.79 g, 6.05 mmol) in DMF (5.0 mL) at room 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 (3×), dried (Mg₂SO₄), 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).

Step B:

CH₃CO₃H (0.30 mL, 1.4 mmol) was added at room temperature to a solution of 814A (80 mg, 0.234 mmol) in CH₂Cl₂(2.0 mL). The mixture was stirred for 3 hours before it was quenched with Me₂S (10.0 eq.). The reaction mixture was diluted with ethyl acetate and washed with water (3×). The organic phase was washed with brine, dried (Mg₂SO₄), and concentrated under vacua to provide crude product which was taken up in DMF (2.0 mL) and treated with Cs₂CO₃(91.6 mg, 0.281 mmol). The mixture was stirred for 1 hour before it was diluted with ethyl acetate and neutralized with aqueous HCl solution (0.5 N). The organic phase was washed with water (3×), dried (Mg₂SO₄), and concentrated under vacua to provide crude product which was purified with reverse phase Gilson separation to provide compound 814 (60 mg), Electrospray MS [M+1]⁺313.2.
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:


		Electrospray
Compound		LCMS
No.	Structure	[M + 1]⁺

815		297.2

816		287.2

817		255.1

818		283.2

819		255.1

820		269.1

821		301.2

822		319.2

823		327.2

824		309.2

825		269.1

826		339.2

827		283.2

828		301.2

829		319.2

830		327.2

831		327.2

832		255.1

833		297.2

Preparative Example 834

Step1:

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) 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 1N HCl (aq.), then saturated NaHCO₃(aq.), then dried over sodium sulfate and concentrated in vacuo to provide compound 834B in nearly quantitative yield (>95%).

Step2:

To a solution of compound 834B (23 g, 0.012 mol) and 4% osmium tetraoxide in water (3 mL, 0.04 eq) in 3:1 (v/v) THF/H₂O (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 vacua. The resulting residue was purified using flash column chromatograpy on silica gel (0-20% EtOAc/Hexane) to provide compound 834C (1.6 g, 0.083 mol, 67%).

Step 3:

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 (7.5 g, 0.039 mol) was added and RM refluxed at 66° C. under nitrogen overnight. The reaction mixture was filtered, dried over sodium sulfate and concentrated in vacua. 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%).

Step 4:

To a solution of compound 834D (5.5 g, 0.024 mol) in EtOAc (120 mL) was 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%).

Step 5

To solution of compound 834E (6 g, 0.0434 mol) in THF (150 mL) was added CDI (8.5 g, 1.2 eq) and the resulting reaction was stirred at room temperature under nitrogen for 1 hour, MgCl2 (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 1N HCl (aq.) (200 mL) and EtOAc (200 mL). The aqueous layer was collected and extracted with EtOAc (3×100 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%)

Step 6:

To a solution of barbituric acid (7 g, 1.1 eq) and compound 834F (9.7 g, 0.05 mol) in EtOEtOH (15 mL) was added sulfamic acid (2.4 g, 0.5 eq) and the resulting reaction was stirred at 147° C. 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%).

Preparative Example 835

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% 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%).

Preparative Example 836

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 resulting solution was microwaved at 180° C. 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, 3%).
Using the methods described above in Preparative Examples 834-836 with the approrpriate difluoro β-keto ester and barbituric acid or barbituric acid derivative, Compounds 837-844 were prepared:


	Compound
	No.	Structure

	837

	838

	839

	840

	841

	842

	843

	844

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 protocol. Briefly, Chinese Hamster Ovary (CHO) cells expressing recombinant human nicotinic acid receptor (NAR) were harvested enzymatically, washed 1× in phosphate buffered saline (PBS) and resuspended in PBS containing 0.5 mM IBMX at 3×10⁶cells/mL. Ten μL of cell suspension was added to each well of a 384-well plate which contained 10 μL of test compounds. Test compounds were diluted with PBS containing 6 μM 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 μL/well) as per the manufacturer's protocol. Plates were then incubated from 45 minutes to overnight. Prior to reading, 10 μt of read buffer was added to each well, and the plate was read in a Sector 6000 plate imager. The signal was converted to cAMP concentration using a standard curve run on each plate. Compound EC₅₀values were determined from concentration gradients of test compounds.
Compounds of Formula (I) of the present invention, and salts, solvates, or esters thereof, have cAMP EC₅₀values of less than about 10,000 nM, preferably 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 EC₅₀values of 100 nM or less.
The activity of selected illustrative compounds of the invention as determined using the above-described assay is presented in the following Table:

Nicotinic Receptor Agonist Activity of Selected Illustrative Compounds of the Invention


Compound		NA EC₅₀
No.	Structure	camp (nM)

11		125.0

35		9.0

90		475.3

74		183.0

102		31.0

103		74.3

104		47.0

107		18.7

108		28.0

112		14.4

116		12.6

117		155.0

118		4.2

119		10.1

122		5.3

123		4.3

124		78.5

125		1.2

126		26.5

127		57.3

128		6.3

129		106.5

135		4.8

223		26.45

229		47.4

241		12.95

262		49.9

266		1.2

268		2.1

292		300

297		56.75

512		95.5

589		33.8

645		26.2

666		63.3

691		47.5

712		57.0

713		22.0

714		66.0

715		671.0

716		171.5

717		259.0

718		162.5

719		152.0

720		89.5

721		225.5

722		111.5

723		296

724		59.5

725		675

726		219

727		179

728		26.2

729		49.9

730		155.8

731		177.4

732		95.5

733		52.5

734		71.8

735		94

736		32.9

737		59.5

738		33.8

739		136.8

740		130

741		123

742		1068

743		212.5

744		128

745		10000

746		1402

747		1233

748		286

749		182.5

750		1892.5

751		487

752		248

753		228

754		308

755		286

759		2326

760		10000

763		7734

764		8922

768		383.5

769		19

770		908

771		17

772		39

773		48.5

774		28.0

776		10000

777		5600

778		9150

779		2851

780		36

781		68

782		94

783		64

784		17.9

786		5331

787		681.5

788		38.5

789		88

791		50

792		44

796		>10000

797		>1000

798		>10000

799		>10000

800		>10000

801		>10000

802		12

803		3450

804		178

805		2063

806		256

807		>10000

808		>10000

809		187

810		>10000

811		22

812		40

813		256

814		161

815		10000

816		291

817		1450

818		308

819		1536

820		10000

821		142

822		10000

823		10000

824		91

825		616

826		3251

827		690

828		407

829		882

830		112

831		531

832		304

833		511

The activity of compounds 834-844 was also determined using the above-described assay and the EC₅₀values measured ranged from about 3 nM to about 1600 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 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.

Claims

1. A compound having the formula:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

R¹is haloalkyl; and

R²is H or cycloalkyl.

2. A compound having the formula:

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

R¹and R²are each, independently, haloalkyl.

3. The compound of claim 1, wherein R¹is fluoroalkyl.

4. The compound of claim 2, wherein R¹is -alkylene-CF₂.

5. The compound of claim 2, wherein R¹is -alkylene-F.

6. The compound of claim 4, wherein R¹is —(CH₂)₃—CF₂, —(CH₂)₄—CF₂or —(CH₂)₅—CF₂.

7. The compound of claim 1, wherein R²is H.

8. The compound of claim 1, wherein R²is cycloalkyl.

9. The compound of claim 8, wherein R²is cyclobutyl.

10. The compound of claim 2, wherein R²is H.

11. The compound of claim 3, wherein R²is H.

12. The compound of claim 2, wherein R²is cycloalkyl.

13. The compound of claim 3, wherein R²is cycloalkyl.

14. A compound having the structure:

or a pharmaceutically acceptable salt or solvate thereof.

15. A composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier.

16.-38. (canceled)

39. A method of treating metabolic syndrome, dyslipidemia, a cardiovascular disease, a disorder of the peripheral and central nervous system, a hematological disease, cancer, inflammation, a respiratory disease, a gastroenterological disease, diabetes or non-alcoholic fatty liver disease in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof.

40. The method of claim 39, wherein the treating is for dyslipidemia.

41. The method of claim 39, further comprising administering at least one additional therapeutic agent selected from the group consisting of hydroxy-substituted azetidinone compounds, substituted β-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, aspirin, NSAID agent, ezetimibe, Vytorin®, AcylCoA:Cholesterol O-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, Omacor®, anti-oxidants, PPAR α agonists, PPAR γ-agonists, FXR receptor modulators, LXR receptor agonists, lipoprotein synthesis inhibitors, renin angiotensin inhibitors, microsomal triglyceride transport protein inhibitors, bile acid reabsorption inhibitors, PPAR δ agonists, triglyceride synthesis inhibitors, squalene epoxidase inhibitors, low density lipoprotein receptor inducers or activators, platelet aggregation inhibitors, 5-LO or FLAP inhibitors, PPAR δ partial agonists, niacin or niacin receptor agonists, 5HT transporter inhibitors, NE transporter inhibitors, CB₁antagonists/inverse agonists, ghrelin antagonists, H₃antagonists/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, 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 mimetics, phentermine, topiramate, phytopharm compound 57, ghrelin antibodies, Mc3r agonists, ACC inhibitors, β3 agonists, DGAT1 inhibitors, DGAT2 inhibitors, FAS inhibitors, PDE inhibitors, thyroid hormone β agonists, UCP-1 activators, UCP-2 activators, UCP-3 activators, acyl-estrogens, glucocorticoid agonists/antagonists, 11β HSD-1 inhibitors, SCD-1 inhibitors, lipase inhibitors, fatty acid transporter inhibitors, dicarboxylate transporter inhibitors, glucose transporter inhibitors, phosphate transporter inhibitors, antidiabetic agents, anti-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 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, α-glucosidase inhibitors, apo A1 milano reverse cholesterol transport inhibitors, fatty acid binding protein inhibitors (FABP), and fatty acid transporter protein inhibitors (FATP).

42. The method of claim 41, wherein the at least one additional active ingredient is an HMG CoA reductase inhibitor selected from: lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin, rosuvastatin calcium, and pitavastatin.

43. The method of claim 41, wherein the additional active ingredient is simvastatin.

44.-53. (canceled)