Methylene linked quinolinyl modulators of RORγt

1. A compound of Formula I wherein:

R 1 is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, tetrahydropyranyl, phenyl, oxazolyl, isoxazolyl, thiophenyl, benzoxazolyl, or quinolinyl; wherein said piperidinyl, pyridyl, pyridyl N-oxide, imidazolyl, phenyl, thiophenyl, benzoxazolyl, and pyrazolyl are optionally substituted with SO 2 CH 3 , C(O)CH 3 , C(O)NH 2 , CH 3 , CH 2 CH 3 , CF 3 , Cl, F, —CN, OCH 3 , N(CH 3 ) 2 , —(CH 2 ) 3 OCH 3 , SCH 3 , OH, CO 2 H, CO 2 C(CH 3 ) 3 , or OCH 2 OCH 3 ; and optionally substituted with up to two additional substituents independently selected from the group consisting of Cl, OCH 3 , and CH 3 ; and wherein said triazolyl, oxazolyl, isoxazolyl, and thiazolyl are optionally substituted with one or two CH 3 groups; and wherein said azetidinyl is optionally substituted with CO 2 C(CH 3 ) 3 , C(O)NH 2 , CH 3 , SO 2 CH 3 , or C(O)CH 3 ;

R 2 is 1-methyl-1,2,3-triazolyl, pyridyl, pyridyl-N-oxide, 1-methyl pyrazol-4-yl, pyrimidin-5-yl, pyridazyl, pyrazin-2-yl, oxazolyl, isoxazolyl, N-acetyl-azetidin-3-yl, N-methylsulfonyl-azetidin-3-yl, N-Boc-azetidin-3-yl, N-methyl-azetidin-3-yl, N-acetamidyl-azetidin-3-yl, 1-H-azetidin-3-yl, N-acetyl piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl, N—C (1-2) alkyl-piperidinyl, thiazol-5-yl, 1-(3-methoxypropyl)-imidazol-5-yl, or 1-C (1-2) alkyl imidazol-5-yl; wherein said 1-C (1-2) alkyl imidazol-5-yl is optionally substituted with up to two additional CH 3 groups, or one substituent selected from the group consisting of SCH 3 , and Cl; and said pyridyl, and pyridyl-N-oxide are optionally substituted with up to two substituents independently selected from the group consisting of C(O)NH 2 , —CN, OCH 3 , CF 3 , Cl, and CH 3 ; and said thiazol-5-yl, oxazolyl, and isoxazolyl are optionally substituted with up to two CH 3 groups; and said 1-methyl pyrazol-4-yl is optionally substituted with up to two additional CH 3 groups;

R 3 is H, OH, OCH 3 , NHCH 3 , N(CH 3 ) 2 , or NH 2 ;

R 4 is H, or F;

R 5 is H, Cl, —CN, CF 3 , SCH 3 , OC (1-3) alkyl, OH, C (1-4) alkyl, N(CH 3 )OCH 3 , NH(C (1-2) alkyl), N(C (1-2) alkyl) 2 , NH-cyclopropyl, OCHF 2 , 4-hydroxy-piperidinyl, azetidin-1-yl, or fur-2-yl;

R 6 is pyridyl, pyrimidinyl, phenyl, benzothiophenyl, or thiophenyl; wherein said pyridyl or phenyl is optionally substituted with N(CH 3 ) 2 , SCH 3 , OCF 3 , SO 2 CH 3 , CF 3 , CHF 2 , imidazol-1-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl, CH 3 , OCH 3 , Cl, F, or —CN; and said thiophenyl is optionally substituted with CF 3 ;

R 7 is H, Cl, —CN, C (1-4) alkyl, OCH 2 CF 3 , OCH 2 CH 2 OCH 3 , CF 3 , SCH 3 , SO 2 CH 3 , OCHF 2 , NA 1 A 2 , C(O)NHCH 3 , N(CH 3 )CH 2 CH 2 NA 1 A 2 , OCH 2 CH 2 NA 1 A 2 , OC (1-3) alkyl, OCH 2 -(1-methyl)-imidazol-2-yl, imidazol-2-yl, fur-2-yl, pyrazol-1-yl, pyrazol-4-yl, pyrid-3-yl, or pyrimidin-5-yl; thiophen-3-yl, 1-methyl-indazol-5-yl, 1-methyl-indazol-6-yl, phenyl, or

wherein said imidazolyl or pyrazolyl can be optionally substituted with a CH 3 group;

A 1 is H or C (1-4) alkyl;

A 2 is H, C (1-4) alkyl, cyclopropyl, C (1-4) alkylOC (1-4) alkyl, C (1-4) alkylOH, C(O)C (1-2) alkyl, or OCH 3 ; or A 1 and A 2 may be taken together with their attached nitrogen to form a ring selected from the group consisting of:

R a is H, F, OCH 3 , or OH;

R b is CH 3 , or phenyl;

R 8 is H, CH 3 , OCH 3 , or F;

R 9 is H, or F;

and pharmaceutically acceptable salts thereof;

provided that (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)bis(1,2,5-trimethyl-1H-imidazol-4-yl)methanol, N-(2-((3-(4-(1H-pyrazol-1-yl)benzyl)-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-4-hydroxyquinolin-2-yl)oxy)ethyl)acetamide, and (3-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-(4-methylpiperazin-1-yl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol are excluded from the claim.

2. A compound of claim 1 wherein:

R 1 is oxazolyl, azetidinyl, imidazolyl, pyrimidinyl, triazolyl, tetrahydropyranyl, thiazolyl, pyridyl, phenyl, or isoxazolyl; wherein said pyridyl, imidazolyl, and phenyl are optionally substituted with CH 3 , CF 3 , Cl, F, —CN, or OCH 3 ; and optionally substituted with up to one additional group independently selected from the group consisting of Cl, OCH 3 , and CH 3 ; and wherein said oxazolyl, triazolyl, isoxazolyl, and thiazolyl are optionally substituted with one or two CH 3 groups; and wherein said azetidinyl is optionally substituted with CO 2 C(CH 3 ) 3 , or C(O)CH 3 ;

R 2 is 1-methyl-1,2,3-triazol-5-yl, pyrid-3-yl, N-acetyl-piperidin-4-yl, N-Boc-azetidin-3-yl, N-acetyl-azetidin-3-yl, N-methyl-azetidin-3-yl, N-acetamidyl-azetidin-3-yl, 1-H-azetidin-3-yl, 1,2-dimethyl imidazol-5-yl, or 1-methyl imidazol-5-yl;

R 3 is OH, NHCH 3 , N(CH 3 ) 2 , or NH 2 ;

R 4 is H;

R 5 is H, Cl, OH, —CN, N(CH 3 )OCH 3 , NH-cyclopropyl, OCHF 2 , or OCH 3 ;

R 6 is phenyl, pyrimidin-5-yl, 2-trifluoromethyl-pyrid-5-yl, 2-trifluoromethyl-thiophen-5-yl, or benzothiophenyl; wherein said phenyl is optionally substituted with pyrazol-1-yl, 1,2,4-triazol-1-yl, imidazol-1-yl, SO 2 CH 3 , CH 3 , F, CF 3 , OCF 3 , N(CH 3 ) 2 , —CN, or SCH 3 ;

R 7 is Cl, —CN, CF 3 , C (1-4) alkyl, SO 2 CH 3 , OCHF 2 , NA 1 A 2 , OCH 2 CH 2 OCH 3 , 1-methyl imidazol-2-yl, pyrazol-1-yl, 1-methyl pyrazol-4-yl, or OCH 3 ;

A 1 is H, or C (1-2) alkyl;

A 2 is C (1-2) alkyl, cyclopropyl, CH 2 CH 2 OCH 3 , or OCH 3 ; or A 1 and A 2 may be taken together with their attached nitrogen to form a ring which is:

R a is H, OH, OCH 3 , or F;

R 8 is H, or CH 3 ;

R 9 is H;

and pharmaceutically acceptable salts thereof.

3. A compound of claim selected from the group consisting of:

Another embodiment of the invention is a compound selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

4. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

5. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

6. A process for making a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

7. A method for treating or ameliorating a RORγt mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , wherein the disease is selected from the group consisting of: inflammatory bowel diseases, rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis, ankylosing spondylitis, neutrophilic asthma, steroid resistant asthma, multiple sclerosis, and systemic lupus erythematosus.

8. The method of claim 7 , wherein the disease is psoriasis.

9. The method of claim 7 , wherein the disease is rheumatoid arthritis.

10. The method of claim 7 , wherein the inflammatory bowel disease is ulcerative colitis.

11. The method of claim 7 , wherein the inflammatory bowel disease is Crohn's disease.

12. The method of claim 7 , wherein the disease is multiple sclerosis.

13. The method of claim 7 , wherein the disease is neutrophilic asthma.

14. The method of claim 7 , wherein the disease is steroid resistant asthma.

15. The method of claim 7 , wherein the disease is psoriatic arthritis.

16. The method of claim 7 , wherein the disease is ankylosing spondylitis.

17. The method of claim 7 , wherein the disease is systemic lupus erythematosus.

18. The method of claim 7 , wherein the disease is chronic obstructive pulmonary disorder.

19. A method of treating or ameliorating a syndrome, disorder or disease, in a subject in need thereof comprising administering to the subject an effective amount of a compound of claim 1 or composition or medicament thereof in a combination therapy with one or more anti-inflammatory agents, or immunosuppressive agents, wherein said syndrome, disorder or disease is selected from the group consisting of: rheumatoid arthritis, and psoriasis.

20. A method for treating or ameliorating a RORγt mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , wherein the disease is selected from the group consisting of: rheumatoid arthritis and psoriasis.

21. A method of inhibiting production of interleukin-17, comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .