Novel Tricyclic Compounds

• US 20110190489A1
• Filed: 12/01/2010
• Published: 08/04/2011
• Est. Priority Date: 12/01/2009
• Status: Active Grant

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbott Laboratories Incorporated
• Inventors: Woller, Kevin R., Frank, Kristine E., Fiamengo, Bryan R., Friedman, Michael, Goedken, Eric R., Breinlinger, Eric C., Morytko, Michael J., Li, Biqin C., Josephsohn, Nathan S., Calderwood, David J., Mullen, Kelly D., Somal, Gagandeep, Argiriadi, Maria A., Stewart, Kent D., Wang, Lu, George, Dawn M., Ericsson, Anna M., Voss, Jeffrey W., Wishart, Neil, Wallace, Grier A.
• Granted Patent: US 8,785,639 B2
• Time in Patent Office: Days
• US Class Current: 544/115
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/14 Ortho-condensed systems
• CPC Class Codes: C07D 487/14 Ortho-condensed systems
• CPC Class Codes: C07D 498/14 Ortho-condensed systems
• CPC Class Codes: C07D 513/14 Ortho-condensed systems
• CPC Class Codes: C07F 9/06 without P—C bonds

Abstract

The invention provides a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), or (Il) as defined herein, pharmaceutically acceptable salts, pro-drugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variable are defined herein. The compounds of the invention are useful for treating immunological and oncological conditions.

Claims

1. A compound of formula

2. The compound of claim 1 wherein

R¹ is H, halogen, CF₃, CN, OH, N(R^a)(R^b), OCF₃, —

C(O)-optionally substituted (C₁-C₆)alkyl, —

C(O)-optionally substituted (C₃-C₆)cycloalkyl, —

S-optionally substituted (C₁-C₆)alkyl, —

S(O)₂-optionally substituted (C₁-C₆)alkyl, —

S(O)₂N(R^a)(R^b), optionally substituted (C₁-C₆)alkoxy, optionally substituted azaindolyl, optionally substituted azepinyl, optionally substituted azetidinyl, optionally substituted benzo(b)thienyl, optionally substituted benzofuranyl, optionally substituted benzimidazolyl, optionally substituted benzoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted benzoxadiazolyl, optionally substituted 6,7-dihydro-5H-cyclopentapyrimidinyl, optionally substituted furanyl, optionally substituted imidazolyl, imidazopyridinyl, 5,6,7,8-tetrahydro-imidazo[1,2-c]pyrazinyl, 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazinyl, 5,6,7,8-tetrahydro[1,2,4]-triazolo[4,3-a]pyrazinyl, optionally substituted indazolyl, optionally substituted indolinyl, optionally substituted indolyl, optionally substituted isoindolinyl, optionally substituted isoxazolyl, optionally substituted isothiazolyl, optionally substituted morpholinyl, optionally substituted oxadiazolyl, optionally substituted oxazolyl, optionally substituted phenyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted purinyl, optionally substitute pyranyl, optionally substituted pyrazolyl, optionally substituted pyrazolo[3,4-d]pyrimidinyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, optionally substituted pyrrolyl, optionally substituted pyrrolo[3,2-c]pyrimidinyl, optionally substituted pyrrolo[2,3-d]pyrimidinyl, optionally substituted pyrrolo[2,3-b]pyridinyl, optionally substituted octahydropyrrolo[3,4-c]pyrrolyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, optionally substituted quinucludinyl, optionally substituted quinoxalinyl, optionally substituted optionally substituted thiomorpholinyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydroindolyl, optionally substituted thiazolyl, optionally substituted thienyl, optionally substituted tetrazolyl, optionally substituted thiadiazolyl, optionally substituted[1,3,5]triazinyl, optionally substituted thiomorpholinyl, optionally substituted triazolyl, or optionally substituted tropanyl;

or

R¹ is —

Z¹⁰¹-L¹-Z¹⁰² wherein

Z¹⁰¹ is H, optionally substituted (C₁-C₆)alkylene, optionally substituted (C₁-C₁₀)heteroarylene, optionally substituted (C₁-C₁₀)heterocyclylene, or optionally substituted (C₆-C₁₀)arylene;

L¹ is a bond, optionally substituted (C₁-C₄)alkylene, —

CH₂C(O), —

C(O)—

, —

C(O)CH₂—

, —

O—

, -optionally substituted (C₁-C₄)alkylene-N(R^a)C(O)—

, -optionally substituted (C₁-C₄)alkylene-C(O)N(R^a)—

, —

C(O)N(R^a)—

, —

N(R^a)C(O)—

, —

C(O)N(R^a)-optionally substituted (C₁-C₄)alkylene-, —

N(R^a)C(O)-optionally substituted (C₁-C₄)alkylene-, -optionally substituted (C₁-C₄)alkylene-N(R^a)C(O)—

, -optionally substituted (C₁-C₄)alkylene-N(R^a)C(O)-optionally substituted (C₁-C₄)alkylene-, -optionally substituted (C₁-C₄)alkylene-C(O)N(R^a)—

optionally substituted (C₁-C₄)alkylene-, -optionally substituted (C₁-C₄)alkylene-N(R^a)S(O)₂—

, -optionally substituted (C₁-C₄)alkylene-S(O)₂N(R^a)—

, —

N(R^a)S(O)₂CH₂—

, —

S(O)₂N(R^a)-optionally substituted (C₁-C₄)alkylene-, —

S(O)₂—

, —

S(O)₂N(R^a)—

, —

N(R^a)S(O)₂—

or —

O—

(C₁-C₄)alkylene-; and

Z¹⁰² is —

N(R^a)(R^b), -optionally substituted (C₁-C₄)alkyl, optionally substituted (C₁-C₄)alkoxy, optionally substituted (C₁-C₁₀)heteroaryl, or optionally substituted (C₁-C₁₀)heterocyclyl.

3. The compound of claim 2 wherein R¹ is H, halogen, CF₃, CN, OH, N(R^a)(R^b), OCF₃, —

C(O)-optionally substituted (C₁-C₆)alkyl, —

C(O)-optionally substituted (C₃-C₆)cycloalkyl, —

S-optionally substituted (C₁-C₆)alkyl, —

S(O)₂-optionally substituted (C₁-C₆)alkyl, —

S(O)₂N(R^a)(R^b), optionally substituted (C₁-C₆)alkoxy, optionally substituted benzofuranyl, optionally substituted benzo(b)thienyl, optionally substituted furanyl, optionally substituted imidazolyl, imidazopyridinyl, 5,6,7,8-tetrahydro-imidazo[1,2-c]pyrazinyl, 5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazinyl, 5,6,7,8-tetrahydro[1,2,4]-triazolo[4,3-a]pyrazinyl, optionally substituted indazolyl, optionally substituted indolinyl, optionally substituted indolyl, optionally substituted isoxazolyl, optionally substituted oxadiazolyl, optionally substituted oxazolyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyrazolo[3,4-d]pyrimidinyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolyl, optionally substituted octahydropyrrolo[3,4-c]pyrrolyl, optionally substituted pyrrolo[2,3-c]pyridinyl, optionally substituted quinolinyl, optionally substituted thiazolyl, optionally substituted thienyl, or optionally substituted tetrazolyl;

or

R¹ is —

Z¹⁰¹-L¹-Z¹⁰² wherein

Z¹⁰¹ is H, optionally substituted (C₁-C₆)alkylene, optionally substituted (C₁-C₁₀)heteroarylene, optionally substituted (C₁-C₁₀)heterocyclylene, or optionally substituted (C₆-C₁₀)aryenel;

L¹ is a bond, optionally substituted (C₁-C₄)alkylene, —

CH₂C(O), —

C(O)—

, —

C(O)CH₂—

, —

O—

, -optionally substituted (C₁-C₄)alkylene-N(R^a)C(O)—

, -optionally substituted (C₁-C₄)alkylene-C(O)N(R^a)—

, —

C(O)N(R^a)—

, —

N(R^a)C(O)—

, —

C(O)N(R^a)-optionally substituted (C₁-C₄)alkylene-, —

N(R^a)C(O)-optionally substituted (C₁-C₄)alkylene-, —

C(O)N(R^a)—

optionally substituted (C₁-C₄)alkylene-C(O), —

N(R^a)C(O)-optionally substituted (C₁-C₄)alkylene-C(O)—

, —

C(O)-optionally substituted (C₁-C₄)alkylene-N(R^a)C(O)—

, —

C(O)-optionally substituted (C₁-C₄)alkylene-C(O)N(R^a)—

, -optionally substituted (C₁-C₄)alkylene-N(R^a)C(O)-optionally substituted (C₁-C₄)alkylene-, -optionally substituted (C₁-C₄)alkylene-C(O)N(R^a)-optionally substituted (C₁-C₄)alkylene-, -optionally substituted (C₁-C₄)alkylene-N(R^a)S(O)₂—

, -optionally substituted (C₁-C₄)alkylene-S(O)₂N(R^a)—

, —

N(R^a)S(O)₂CH₂—

, —

S(O)₂N(R^a)-optionally substituted (C₁-C₄)alkylene —

C(O)N(R^a)S(O)₂—

, —

S(O)₂N(R^a)C(O—

), —

S(O)₂—

, —

S(O)₂N(R^a)—

, —

N(R^a)S(O)₂—

or —

O—

(C₁-C₄)alkylene-; and

Z¹⁰² is, —

N(R^a)(R^b), -optionally substituted (C₁-C₄)alkyl, optionally substituted (C₁-C₄)alkoxy, optionally substituted (C₁-C₁₀)heteroaryl, or optionally substituted (C₁-C₁₀)heterocyclyl.

4. The compound of claim 3 wherein Z¹⁰¹ is optionally substituted indazolyl, optionally substituted indolyl, optionally substituted phenyl, optionally substituted pyrazolyl, or optionally substituted pyrrolyl.

5. The compound of claim 4 wherein Z¹⁰² is —

N(R^a)(R^b), -optionally substituted (C₁-C₄)alkyl, optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl,

6. The compound of claim 1 wherein R² is H, halogen, CF₃, CN, OR^a, N(R^a)(R^b), OCF₃, —

C(O)-optionally substituted (C₁-C₆)alkyl, —

C(O)-optionally substituted (C₃-C₆)cycloalkyl, —

S-optionally substituted (C₁-C₆)alkyl, —

S(O)₂-optionally substituted (C₁-C₆)alkyl, —

S(O)₂N(R^a)(R^b), optionally substituted (C₁-C₆)alkyl, optionally substituted (C₁-C₆)alkoxy, —

C(O)N(R^a)(R^b), optionally substituted (C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl, optionally substituted (C₂-C₆)alkynyl, optionally substituted (C₃-C₁₀)cycloalkyl, optionally substituted azetidinyl, optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substitute pyranyl, optionally substituted pyrrolidinyl, optionally substituted optionally substituted thiomorpholinyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydroindolyl, optionally substituted tetrahydropyridinyl or optionally substituted tropanyl.

7. The compound of claim 1 wherein R³ is H, CF₃, —

C(O)OR^a, N(R^a)(R^b), optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₆)cycloalkyl, optionally substituted azepinyl, optionally substituted azetidinyl, optionally substituted dihydrobenzofuranyl, optionally substituted benzo[b]thienyl, optionally substituted isoquinolinyl, optionally substituted morpholinyl, optionally substituted phenyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyranyl, optionally substituted pyridinyl, optionally substituted pyrrolidinyl, optionally substituted thiomorpholinyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydroindolyl, or optionally substituted tropanyl.

8. The compound of claim 1 wherein R³ is -A-D-E-G, wherein:

A is a bond, —

C(O)—

, optionally substituted (C₁-C₆)alkylene, optionally substituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene, optionally substituted (C₃-C₈)cycloalkylene, optionally substituted azetidinyl, optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substitute pyranyl, substituted pyrrolidinyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydroindolyl, optionally substituted thiomorpholinyl, -optionally substituted (C₁-C₆)alkylene-N(R^a)—

, —

R^e—

C(O)N(R^a)—

R^e—

, —

R^e—

N(R^a)C(O)—

R^e—

, —

O—

R^e—

, —

N(R^a)—

R^e—

, —

S—

R^e—

, —

S(O)₂—

R^e—

, —

S(O)R^e—

, —

C(O—

R^a)(R^b)—

R^e—

, —

S(O)₂N(R^a)—

R^e—

, —

N(R^a)S(O)₂—

R^e—

or —

N(R^a)C(O)N(R^b)—

R^e—

.

9. The compound of claim 1 wherein R³ is -A-D-E-G, wherein

D is a bond, an optionally substituted (C₁-C₈)alkylene, optionally substituted adamantanylene, optionally substituted (C₃-C₈)cycloalkylene, optionally substituted (C₃-C₁₀)cycloalkenylene, optionally substituted azaindolyl, optionally substituted azepanyl, optionally substituted azetidinyl, optionally substituted benzo(b)thienyl, optionally substituted benzofuranyl, optionally substituted benzimidazolyl, optionally substituted benzofuranyl, optionally substituted benzoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted benzoxadiazolyl, optionally substituted 6,7-dihydro-5H-cyclopentapyrimidinyl, optionally substituted furanyl, optionally substituted imidazolyl, imidazopyridinyl, optionally substituted indazolyl, optionally substituted indolinyl, optionally substituted indolyl, optionally substituted isoindolinyl, optionally substituted isoxazolyl, optionally substituted isothiazolyl, optionally substituted morpholinyl, optionally substituted oxadiazolyl, optionally substituted oxazolyl, optionally substituted phenylene, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted purinyl, optionally substitute pyranyl, optionally substituted pyrazolyl, optionally substituted pyrazolo[3,4-d]pyrimidinyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, optionally substituted pyrrolyl, optionally substituted pyrrolo[2,3-d]pyrimidinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, optionally substituted quinucludinyl, optionally substituted quinoxalinyl, optionally substituted thiomorpholinyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydroindolyl, optionally substituted thiazolyl, optionally substituted thienyl, optionally substituted tetrazolyl, optionally substituted thiadiazolyl, optionally substituted [1,3,5]triazinyl, optionally substituted thiomorpholinyl, optionally substituted triazolyl, or optionally substituted tropanyl.

10. The compound of claim 1 wherein R³ is -A-D-E-G, wherein E is a bond, —

R^e—

, —

R^e—

C(O)—

R^e—

, —

R^e—

C(O)C(O)—

R^e—

, —

R^e—

C(O)O—

R^e—

, —

R^e—

C(O)N(R^a)C(O)R^e—

, —

R^e—

O—

R^e—

, —

R^e—

S(O)₂—

R^e—

, —

R^e—

S(O)—

R^e—

, —

R^e—

S—

R^e—

, —

R^e—

N(R^a)—

R^e—

, —

R^e—

N(R^a)C(O)—

R^e—

, —

R^eC(O)N(R^a)R^e—

, —

R^e—

OC(O)N(R^a)—

R^e—

, —

R^e—

N(R^a)C(O)OR^e—

, —

R^e—

N(R^a)C(O)N(R^b)—

R^e—

, —

R^e—

N(R^a)S(O)₂—

R^e—

, or —

R^e—

S(O)₂N(R^a)—

R^e—

;

where in all cases, E is linked to either a carbon or a nitrogen atom in D.

11. The compound of claim 10 wherein E is a bond, (C₁-C₆)alkylene, —

C(O)—

, —

CH₂—

C(O)—

, —

C(O)CH₂—

, —

C(O)N(R^a)C(O)—

, —

O—

, —

S(O)₂—

, —

S(O)—

, —

S—

, —

N(R^a)—

, —

N(R^a)C(O)—

, —

C(O)N(R^a)—

, —

OC(O)N(R^a)—

, —

N(R^a)C(O)O—

, —

N(R^a)C(O)N(R^b)—

, —

N(R^a)S(O)₂—

, or —

S(O)₂N(R^a)—

.

12. The compound of claim 1 wherein R³ is -A-D-E-G, wherein G is H, deuterium, —

N(R^a)(R^b), halogen, —

OR^a, —

SR^a, —

S(O)R^a, —

S(O)₂R^a, —

NO₂, —

C(O)OR^a, —

CN, —

C(O)_N(R^a)(R^b), —

N(R^a)C(O)R^b, —

N(R^a)C(O)OR^b, —

OC(O)N(R^a), —

N(R^a)C(O)N(R^b)₂, —

C(O—

R^a)(R^b)₂, —

C(O)R^a, —

CF₃, —

OCF₃, —

N(R^a)S(O)₂R^b, —

S(O)₂N(R^a)(R^b), —

S(O)₂N(R^a)C(O)R^b, an optionally substituted —

(C₁-C₆)alkyl, an optionally substituted —

(C₂-C₆)alkenyl, an optionally substituted —

(C₂-C₆)alkynyl, an optionally substituted —

(C₃-C₈)cycloalkyl, optionally substituted azaindolyl, optionally substituted azepinyl, optionally substituted azetidinyl, optionally substituted benzo(b)thienyl, optionally substituted benzofuranyl, optionally substituted benzimidazolyl, optionally substituted benzoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted benzoxadiazolyl, optionally substituted 6,7-dihydro-5H-cyclopentapyrimidinyl, optionally substituted furanyl, optionally substituted imidazolyl, optionally substituted imidazopyridinyl, optionally substituted indazolyl, optionally substituted indolinyl, optionally substituted indolyl, optionally substituted isoindolinyl, optionally substituted isoxazolyl, optionally substituted isothiazolyl, optionally substituted morpholinyl, optionally substituted oxadiazolyl, optionally substituted oxazolyl, optionally substituted phenyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted purinyl, optionally substitute pyranyl, optionally substituted pyrazolyl, optionally substituted pyrazolo[3,4-d]pyrimidinyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, optionally substituted pyrrolyl, optionally substituted pyrrolo[2,3-d]pyrimidinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, optionally substituted quinucludinyl, optionally substituted quinoxalinyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydroindolyl, optionally substituted thiazolyl, optionally substituted thienyl, optionally substituted tetrazolyl, optionally substituted thiadiazolyl, optionally substituted [1,3,5]triazinyl, optionally substituted thiomorpholinyl, optionally substituted triazolyl, optionally substituted tropanyl, an optionally substituted —

(C₁-C₆)alkyl-(C₃-C₈)cycloalkyl, an optionally substituted —

(C₁-C₆)alkyl-phenyl, an optionally substituted —

(C₁-C₆)alkyl-(C₁-C₁₀)heteroaryl, or an optionally substituted —

(C₁-C₆)alkyl-(C₁-C₁₀)heterocyclyl.

13. The compound of claim 12 wherein G is H, deuterium, —

N(R^a)(R^b), halogen, —

OR^a, —

SR^a, —

S(O)R^a, —

S(O)₂R^a, —

NO₂, —

C(O)OR^a, —

CN, —

C(O)N(R^a)(R^b), —

N(R^a)C(O)R^b, —

N(R^a)C(O)OR^b, —

OC(O)N(R^a), —

N(R^a)C(O)N(R^b)₂, —

C(O—

R^a)(R^b)₂, —

C(O)R^a, —

CF₃, —

OCF₃, —

N(R^a)S(O)₂R^b, —

S(O)₂N(R^a)(R^b), —

S(O)₂N(R^a)C(O)R^b, an optionally substituted —

(C₁-C₆)alkyl, an optionally substituted —

(C₂-C₆)alkenyl, an optionally substituted —

(C₂-C₆)alkynyl, an optionally substituted —

(C₃-C₈)cycloalkyl, optionally substituted azetidinyl, optionally substituted furanyl, optionally substituted imidazolyl, optionally substituted indolyl, optionally substituted isoindolinyl, optionally substituted isoxazolyl, optionally substituted morpholinyl, optionally substituted phenyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, optionally substituted pyrrolyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrofuranyl, optionally substituted thiazolyl, optionally substituted thienyl, optionally substituted tetrazolyl, optionally substituted thiadiazolyl, optionally substituted [1,3,5]triazinyl, optionally substituted thiomorpholinyl, optionally substituted triazolyl, an optionally substituted —

(C₁-C₆)alkyl-(C₃-C₈)cycloalkyl, or an optionally substituted —

(C₁-C₆)alkyl-phenyl.

14. The compound of claim 1 wherein R⁴ is H, CF₃, N(R^a)(R^b), optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₆)cycloalkyl, optionally substituted azaindolyl, optionally substituted azepinyl, optionally substituted azetidinyl, optionally substituted morpholinyl, optionally substituted phenyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyranyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, optionally substituted thiomorpholinyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydroindolyl, or optionally substituted tropanyl.

15. The compound of claim 1 wherein R⁴ is -J-L-M-Q, wherein:

J is a bond, —

C(O)—

, optionally substituted (C₁-C₆)alkylene, optionally substituted (C₂-C₆)alkenylene, optionally substituted (C₂-C₆)alkynylene, optionally substituted (C₃-C₈)cycloalkylene, optionally substituted azetidinyl, optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substitute pyranyl, optionally substituted pyrrolidinyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydroindolyl, -optionally substituted (C₁-C₆)alkylene-N(R^a)—

, —

R^e—

C(O)N(R^a)—

R^e—

, —

R^e—

N(R^a)C(O)—

R^e—

, —

O—

R^e—

, —

N(R^a)—

R^e—

, —

S—

R^e—

, —

S(O)₂—

R^e—

, —

S(O)R^e—

, —

C(OR^a)(R^b)—

R^e—

, —

S(O)₂N(R^a)—

R^e—

, —

N(R^a)S(O)₂—

R^e—

or —

N(R^a)C(O)N(R^b)—

R^e—

.

16. The compound of claim 1 wherein R⁴ is -J-L-M-Q, wherein

L is a bond, an optionally substituted (C₁-C₈)alkylene, optionally substituted adamantanylene, optionally substituted (C₃-C₈)cycloalkylene, optionally substituted (C₃-C₁₀)cycloalkenylene, optionally substituted azaindolyl, optionally substituted azepinyl, optionally substituted azetidinyl, optionally substituted benzo(b)thienyl, optionally substituted benzofuranyl, optionally substituted benzimidazolyl, optionally substituted benzofuranyl, optionally substituted benzoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted benzoxadiazolyl, optionally substituted 6,7-dihydro-5H-cyclopentapyrimidinyl, optionally substituted furanyl, optionally substituted imidazolyl, imidazopyridinyl, optionally substituted indazolyl, optionally substituted indolinyl, optionally substituted indolyl, optionally substituted isoindolinyl, optionally substituted isoxazolyl, optionally substituted isothiazolyl, optionally substituted morpholinyl, optionally substituted oxadiazolyl, optionally substituted oxazolyl, optionally substituted phenylene, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted purinyl, optionally substitute pyranyl, optionally substituted pyrazolyl, optionally substituted pyrazolo[3,4-d]pyrimidinyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, optionally substituted pyrrolyl, optionally substituted pyrrolo[2,3-d]pyrimidinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, optionally substituted quinucludinyl, optionally substituted quinoxalinyl, optionally substituted thiomorpholinyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydroindolyl, optionally substituted thiazolyl, optionally substituted thienyl, optionally substituted tetrazolyl, optionally substituted thiadiazolyl, optionally substituted [1,3,5]triazinyl, optionally substituted thiomorpholinyl, optionally substituted triazolyl, or optionally substituted tropanyl.

17. The compound of claim 1 wherein R⁴ is -J-L-M-Q, wherein M is a bond, —

R^e—

, —

R^e—

C(O)—

R^e—

, —

R^e—

C(O)C(O)—

R^e—

, —

R^e—

C(O)O—

R^e—

, —

R^e—

C(O)N(R^a)C(O)R^e—

, —

R^e—

O—

R^e—

, —

R^e—

S(O)₂—

R^e—

, —

R^e—

S(O)—

R^e—

, —

R^e—

S—

R^e—

, —

R^e—

N(R^a)—

R^e—

, —

R^e—

N(R^a)C(O)—

R^e—

, —

R^eC(O)N(R^a)R^e—

, —

R^e—

OC(O)N(R^a)—

R^e—

, —

R^e—

N(R^a)C(O)OR^e—

, —

R^e—

N(R^a)C(O)N(R^b)—

R^e—

, —

R^e—

N(R^a)S(O)₂—

R^e—

, or —

R^e—

S(O)₂N(R^a)—

R^e—

;

where in all cases, M is linked to either a carbon or a nitrogen atom in L.

18. The compound of claim 17 wherein M is a bond, (C₁-C₆)alkylene, —

C(O)—

, —

CH₂—

C(O)—

, —

C(O)CH₂—

, —

C(O)N(R^a)C(O)—

, —

O—

, —

S(O)₂—

, —

S(O)—

, —

S—

, —

N(R^a)—

, —

N(R^a)C(O)—

, —

C(O)N(R^a)—

, —

OC(O)N(R^a)—

, —

N(R^a)C(O)O—

, —

N(R^a)C(O)N(R^b)—

, —

N(R^a)S(O)₂—

, or —

S(O)₂N(R^a)—

.

19. The compound of claim 1 wherein R⁴ is -J-L-M-Q, wherein Q is H, deuterium, —

N(R^a)(R^b), halogen, —

OR^a, —

SR^a, —

S(O)R^a, —

S(O)₂R^a, —

NO₂, —

C(O)OR^a, —

CN, —

C(O)N(R^a)(R^b), —

N(R^a)C(O)R^b, —

N(R^a)C(O)OR^b, —

OC(O)N(R^a), —

N(R^a)C(O)N(R^b)₂, —

C(O—

R^a)(R^b)₂, —

C(O)R^a, —

CF₃, —

OCF₃, —

N(R^a)S(O)₂R^b, —

S(O)₂N(R^a)(R^b), —

S(O)₂N(R^a)C(O)R^b, an optionally substituted —

(C₁-C₆)alkyl, an optionally substituted —

(C₂-C₆)alkenyl, an optionally substituted —

(C₂-C₆)alkynyl, an optionally substituted —

(C₃-C₈)cycloalkyl, optionally substituted azaindolyl, optionally substituted azepinyl, optionally substituted azetidinyl, optionally substituted benzo(b)thienyl, optionally substituted benzofuranyl, optionally substituted benzimidazolyl, optionally substituted benzoxazolyl, optionally substituted benzothiazolyl, optionally substituted benzothiadiazolyl, optionally substituted benzoxadiazolyl, optionally substituted 6,7-dihydro-5H-cyclopentapyrimidinyl, optionally substituted furanyl, optionally substituted imidazolyl, optionally substituted imidazopyridinyl, optionally substituted indazolyl, optionally substituted indolinyl, optionally substituted indolyl, optionally substituted isoindolinyl, optionally substituted isoxazolyl, optionally substituted isothiazolyl, optionally substituted morpholinyl, optionally substituted oxadiazolyl, optionally substituted oxazolyl, optionally substituted phenyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted purinyl, optionally substitute pyranyl, optionally substituted pyrazolyl, optionally substituted pyrazolo[3,4-d]pyrimidinyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, optionally substituted pyrrolyl, optionally substituted pyrrolo[2,3-d]pyrimidinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, optionally substituted quinucludinyl, optionally substituted quinoxalinyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrofuranyl, optionally substituted tetrahydroindolyl, optionally substituted thiazolyl, optionally substituted thienyl, optionally substituted tetrazolyl, optionally substituted thiadiazolyl, optionally substituted [1,3,5]triazinyl, optionally substituted thiomorpholinyl, optionally substituted triazolyl, optionally substituted tropanyl, an optionally substituted —

(C₁-C₆)alkyl-(C₃-C₈)cycloalkyl, an optionally substituted —

(C₁-C₆)alkyl-phenyl, an optionally substituted —

(C₁-C₆)alkyl-(C₁-C₁₀)heteroaryl, or an optionally substituted —

(C₁-C₆)alkyl-(C₁-C₁₀)heterocyclyl.

20. The compound of claim 19 wherein Q is H, deuterium, —

N(R^a)(R^b), halogen, —

OR^a, —

SR^a, —

S(O)R^a, —

S(O)₂R^a, —

NO₂, —

C(O)OR^a, —

CN, —

C(O)N(R^a)(R^b), —

N(R^a)C(O)R^b, —

N(R^a)C(O)OR^b, —

OC(O)N(R^a), —

N(R^a)C(O)N(R^b)₂, —

C(O—

R^a)(R^b)₂, C(O)R^a, —

CF₃, —

OCF₃, N(R^a)S(O)₂R^b, —

S(O)₂N(R^a)(R^b), —

S(O)₂N(R^a)C(O)R^b, an optionally substituted —

(C₁-C₆)alkyl, an optionally substituted —

(C₂-C₆)alkenyl, an optionally substituted —

(C₂-C₆)alkynyl, an optionally substituted —

(C₃-C₈)cycloalkyl, optionally substituted azetidinyl, optionally substituted furanyl, optionally substituted imidazolyl, optionally substituted indolyl, optionally substituted isoindolinyl, optionally substituted isoxazolyl, optionally substituted morpholinyl, optionally substituted phenyl, optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrrolidinyl, optionally substituted pyrrolyl, optionally substituted tetrahydropyranyl, optionally substituted tetrahydrofuranyl, optionally substituted thiazolyl, optionally substituted thienyl, optionally substituted tetrazolyl, optionally substituted thiadiazolyl, optionally substituted [1,3,5]triazinyl, optionally substituted thiomorpholinyl, optionally substituted triazolyl, an optionally substituted —

(C₁-C₆)alkyl-(C₃-C₈)cycloalkyl, or an optionally substituted —

(C₁-C₆)alkyl-phenyl.

21. The compound of claim 1 wherein R⁶ is optionally substituted (C₁-C₆)alkyl, optionally substituted (C₂-C₆)alkenyl, optionally substituted (C₃-C₆)cycloalkyl, optionally substituted dihydrobenzofuranyl, optionally substituted benzo(b)thienyl, optionally substituted furanyl, optionally substituted indolyl, optionally substituted isoquinolinyl, optionally substituted phenyl, optionally substituted piperidinyl, optionally substituted pyridinyl, optionally substituted pyrido[3,2-b]oxazin-3-(4H)-one, optionally substituted pyrimidinyl, optionally substituted pyrazolyl, optionally substituted quinolinyl, optionally substituted quinoxalinyl, optionally substituted tetrahydropyridinyl, or optionally substituted thienyl;

or

R⁶ is —

Z²⁰¹-L²-Z²⁰² wherein

Z²⁰¹ is optionally substituted (C₁-C₆)alkylene, optionally substituted phenyl, optionally substituted piperidinyl, optionally substituted pyrazolyl, optionally substituted thienyl, or optionally substituted tetrhydropyridinyl;

L² is a bond, —

CH₂C(O)—

, —

C(O)CH₂, —

C(O)—

, —

C(O)N(R^a)—

, —

N(R^a)C(O), —

S(O)₂, optionally substituted (C₁-C₆)alkylene, -optionally substituted (C₁-C₄)alkylene-S(O)₂N(R^a)—

, -optionally substituted (C₁-C₄)alkylene-N(R^a)S(O)₂—

S(O)₂N(R^a)-optionally substituted (C₁-C₄)alkylene-, or —

O—

(C₁-C₄)alkylene-; and

Z²⁰² is —

N(R^a)(R^b), —

OR^a, optionally substituted (C₁-C₆)alkyl, optionally substituted (C₃-C₆)cycloalkyl, optionally substituted morpholinyl, optionally substituted oxetanyl, optionally substituted piperazinyl or optionally substituted piperidinyl.