Phenyl linked quinolinyl modulators of RORγt

• US 9,309,222 B2
• Filed: 10/15/2013
• Issued: 04/12/2016
• Est. Priority Date: 10/16/2012
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Leonard, Kristi A., Barbay, Kent, Edwards, James P., Kreutter, Kevin D., Kummer, David A., Maharoof, Umar, Nishimura, Rachel, Urbanski, Maud, Venkatesan, Hariharan, Wang, Aihua, Wolin, Ronald L., Woods, Craig R., Fourie, Anne, Xue, Xiaohua, Mirzadegan, Taraneh, Ganamet, Kelly
• Primary Examiner(s): Seaman, D M
• Application Number:
  US14/053,707
• Publication Number:
  US 20140107097A1
• Time in Patent Office: 910 Days
• Field of Search: 546/159, 514/312
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

The present invention comprises compounds of Formula I.

wherein:

• R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are defined in the specification.

The invention also comprises a method of treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is rheumatoid arthritis or psoriasis. The invention also comprises a method of modulating RORγt activity in a mammal by administration of a therapeutically effective amount of at least one compound of claim 1.

Claims

1. The compounds of Formula I:

2. The compounds of claim 1, wherein:

R¹ is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, tetrahydropyranyl, phenyl, oxazolyl, isoxazolyl, thiophenyl, benzoxazolyl, or quinolinyl;

wherein said piperidinyl, imidazolyl, phenyl, thiophenyl, benzoxazolyl, pyrazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, or quinolinyl are optionally substituted with C(O)C_(1-4)alkyl, C(O)NH₂, C_(1-4)alkyl, CF₃, CH₂CF₃, Cl, F, —

CN, OC_(1-4)alkyl, N(C_(1-4)alkyl)₂, —

(CH₂)₃OCH₃, SC_(1-4)alkyl, OH, CO₂H, CO₂C_(1-4)alkyl, OCF₃, OCHF₂, SO₂CH₃, SO₂NH₂, or OCH₂OCH₃; and

optionally substituted with up to two additional substituents independently selected from the group consisting of Cl, C_(1-2)alkyl, SCH₃, OC_(1-2)alkyl, CF₃, —

CN, and F; and

wherein said triazolyl, oxazolyl, isoxazolyl, pyrrolyl, and thiazolyl are optionally substituted with up to two substituents independently selected from the group consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —

CN, OC_(1-2)alkyl, (CH₂)_(2-3)OCH₃, SCH₃, CF₃, F, Cl, and C_(1-2)alkyl; and

said pyridyl, and pyridyl-N-oxide are optionally substituted with up to three additional substituents independently selected from the group consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —

CN, OC_(1-4)alkyl, (CH₂)_(2-3)OCH₃, SC_(1-4)alkyl, CF₃, F, Cl, and C_(1-4)alkyl;

R² is 1-methyl triazolyl, pyridyl, pyridyl-N-oxide, 1-methyl pyrazolyl, pyrimidinyl, oxazolyl, isoxazolyl, N-acetyl piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl, N—

C_(1-3)alkyl-piperidinyl, thiazolyl, pyridazyl, pyrazinyl, 1-(3-methoxypropyl)-imidazolyl, or 1-C_(1-2)alkyl imidazolyl;

wherein said 1-C_(1-2)alkyl imidazolyl is optionally substituted with up to two additional substituents independently selected from the group consisting of C_(1-2)alkyl, SCH₃, OC_(1-2)alkyl, CF₃, —

CN, F, and Cl; and

said pyridyl, and pyridyl-N-oxide are optionally substituted with up to three additional substituents independently selected from the group consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —

CN, OC_(1-2)alkyl, (CH₂)_(2-3)OCH₃, SCH₃, CF₃, F, Cl, and C_(1-2)alkyl; and

said thiazolyl, oxazolyl and isoxazolyl are optionally substituted with up to two substituents independently selected from the group consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —

CN, OC_(1-2)alkyl, (CH₂)_(2-3)OCH₃, SCH₃, CF₃, F, Cl, and C_(1-2)alkyl; and

said 1-methyl pyrazolyl is optionally substituted with up to two additional CH₃ groups;

R⁶ is pyridyl, pyrimidinyl, pyridazyl, pyrazinyl, or phenyl, any of which is optionally substituted with —

CN, CH₃, OC_(1-4)alkyl, N(C_(1-2)alkyl)₂, SONH₂, SON(CH₃)2, OCH₂CF₃, SO₂CH₃, CF₃, Cl, F, or OCF₃;

R⁷ is H, Cl, —

CN, C_(1-4)alkyl, OC_(1-4)alkylCF₃, OCH₂CH₂OC_(1-4)alkyl, CF₃, SCH₃, CH₂NA¹A², CH₂OC_(2-3)alkylNA¹A², NA¹A², C(O)NA¹A², N(CH₃)C_(2-4)alkylNA¹A², OC_(2-4)alkylNA¹A², OC_(1-4)alkyl, OCH₂-(1-methyl)-imidazol-2-yl, furyl, pyrazolyl, imidazolyl, pyridyl, pyridazyl, pyrazinyl, or pyrimidinyl;

wherein said imidazolyl or pyrazolyl is optionally substituted with one CH₃ group;

A¹ is H, or C_(1-4)alkyl;

A² is H, C_(1-4)alkyl, C_(1-4)alkylOC_(1-4)alkyl, C_(1-4)alkylOH, C(O)C_(1-4)alkyl, or OC_(1-4)alkyl;

or A¹ and A² may be taken together with their attached nitrogen to form a ring selected from the group consisting of;

3. The compounds of claim 2, wherein:

R¹ is 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 C(O)C_(1-4)alkyl, C(O)NH₂, C_(1-4)alkyl, CF₃, CH₂CF₃, Cl, F, —

CN, OC_(1-4)alkyl, N(C_(1-4)alkyl)₂, —

(CH₂)₃OCH₃, SC_(1-4)alkyl, OH, CO₂H, CO₂C_(1-4)alkyl, OCF₃, OCHF₂, SO₂CH₃, SO₂NH₂, or OCH₂OCH₃; and

optionally substituted with up to two additional substituents independently selected from the group consisting of Cl, OCH₃, and CH₃; and

wherein said triazolyl, oxazolyl, isoxazolyl, and thiazolyl are optionally substituted with one or two CH₃ groups;

R² is 1-methyl triazolyl, pyridyl, pyridyl-N-oxide, 1-methyl pyrazolyl, pyrimidinyl, pyrazinyl, oxazolyl, isoxazolyl, N-acetyl piperidinyl, 1-H-piperidinyl, N-Boc-piperidinyl, N—

C_(1-2)alkyl-piperidinyl, thiazolyl, pyridazyl, 1-(3-methoxypropyl)-imidazolyl, or 1-C_(1-2)alkyl imidazolyl;

wherein said 1-C_(1-2)alkyl imidazolyl is optionally substituted with up to two additional CH₃ groups, or one substituent selected from the group consisting of SCH₃, and Cl; and

said pyridyl, and pyridyl-N-oxide are optionally substituted with up to two subsitutents independently selected from the group consisting of SO₂CH₃, SO₂NH₂, C(O)NH₂, —

CN, OCH₃, CF₃, Cl, and CH₃; and

said thiazolyl, oxazolyl and isoxazolyl are optionally substituted with up to two CH₃ groups; and

said 1-methyl pyrazolyl is optionally substituted with up to two additional CH₃ groups;

R⁶ is pyridyl or phenyl, either of which is optionally substituted with —

CN, CH₃, OCH₃, N(CH₃)₂, SONH₂, SO₂CH₃, CF₃, Cl, F, or OCF₃;

R⁷ is H, Cl, —

CN, C_(1-4)alkyl, OC_(1-4)alkylCF₃, OCH₂CH₂OC_(1-4)alkyl, CF₃, SCH₃, NA¹A², C(O)NA¹A², N(CH₃)C_(2-4)alkylNA¹A², OC_(2-4)alkylNA¹A², OC_(1-4)alkyl, OCH₂-(1-methyl)-imidazol-2-yl, imidazolyl, furyl, pyrazolyl, pyridyl, or pyrimidinyl;

wherein said imidazolyl or pyrazolyl is optionally substituted with one CH₃ group;

A^1is H, or C_(1-4)alkyl;

A² is H, C_(1-4)alkyl, C_(1-4)alkylOC_(1-4)alkyl, C_(1-4)alkylOH, C(O)C_(1-4)alkyl, or OC_(1-4)alkyl;

or A¹ and A² may be taken together with their attached nitrogen to form a ring selected from the group consisting of;

4. The compounds of claim 3, wherein:

R¹ is 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 SO₂CH₃, C(O)CH₃, C(O)NH₂, CH₃, CH₂CH₃, CF₃, Cl, F, —

CN, OCH₃, N(CH₃)₂, —

(CH₂)₃OCH₃, SCH₃, OH, CO₂H, CO₂C(CH₃)₃, or OCH₂OCH₃; and

optionally substituted with up to two additional substituents independently selected from the group consisting of Cl, OCH₃, and CH₃; and

wherein said triazolyl, oxazolyl, isoxazolyl, and thiazolyl are optionally substituted with one or two CH₃ groups;

R² is 1-methyl-1,2,3-triazolyl, pyridyl, pyridyl-N-oxide, 1-methyl pyrazol-4-yl, pyrimidin-5-yl, pyridazyl, pyrazin-2-yl, isoxazolyl, 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 CH₃ groups, or one substituent selected from the group consisting of SCH₃, 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)NH₂, —

CN, OCH₃, CF₃, Cl, and CH₃; and

said thiazol-5-yl, and said isoxazolyl are optionally substituted with up to two CH₃ groups; and

said 1-methyl pyrazol-4-yl is optionally substituted with up to two additional CH₃ groups;

R⁵ is H, Cl, —

CN, CF₃, SCH₃, OC_(1-3)alkyl, OH, C_(1-4)alkyl, N(CH₃)OCH₃, NH(C_(1-2)alkyl), N(C_(1-2)alkyl)₂, or 4-hydroxy-piperidinyl;

R⁶ is pyridyl or phenyl, either of which is optionally substituted with Cl, F, CF₃, SO₂CH₃, —

CN, or OCF₃;

R⁷ is H, Cl, —

CN, C_(1-4)alkyl, OCH₂CF₃, OCH₂CH₂OCH₃, CF₃, SCH₃, NA¹A², C(O)NHCH₃, N(CH₃)CH₂CH₂NA¹A², OCH₂CH₂NA¹A², OC_(1-3)alkyl, OCH₂-(1-methyl)-imidazol-2-yl, imidazol-2-yl, fur-2-yl, pyrazol-4-yl, pyrid-3-yl, or pyrimidin-5-yl;

wherein said imidazolyl or pyrazolyl is optionally substituted with one CH₃ group;

A¹ is H, or C_(1-4)alkyl;

A² is H, C_(1-4)alkyl, C_(1-4)alkylOC_(1-4)alkyl, C_(1-4)alkylOH, C(O)C_(1-2)alkyl, OCH₃;

or A¹ and A² may be taken together with their attached nitrogen to form a ring selected from the group consisting of;

5. The compounds of claim 4 wherein:

R¹ is pyrrolyl, triazolyl, imidazolyl, thiazolyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, phenyl, isoxazolyl, thiophenyl, benzoxazolyl, pyrazolyl or quinolinyl;

wherein said piperidinyl, pyridyl, imidazolyl, phenyl, thiophenyl, benzoxazolyl, and pyrazolyl are optionally substituted with C(O)CH₃, C(O)NH₂, CH₃, CH₂CH₃, CF₃, Cl, F, —

CN, OCH₃, N(CH₃)₂, —

(CH₂)₃OCH₃, SCH₃, OH, CO₂H, CO₂C(CH₃)₃, or OCH₂OCH₃; and

optionally substituted with up to two additional CH₃ groups, or one additional chloro group; and

wherein said triazolyl, isoxazolyl, and thiazolyl are optionally substituted with one or two CH₃ groups;

R² is 1-methyl-1,2,3-triazolyl, pyridyl, pyridyl-N-oxide, 1-methyl pyrazol-4-yl, pyrimidin-5-yl, pyridazyl, pyrazin-2-yl, isoxazol-4-yl, isoxazol-5-yl, N-acetyl piperidin-3-yl, N-acetyl piperidin-4-yl, 1-H-piperidin-3-yl, 1-H-piperidin-4-yl, N-Boc-piperidin-3-yl, N-Boc-piperidin-4-yl, N—

C_(1-2)alkyl-piperidin-3-yl, N—

C_(1-2)alkyl-piperidin-4-yl, 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 CH₃ groups, or one substituent selected from the group consisting of SCH₃, and Cl; and

said pyridyl is optionally substituted with up to two subsitutents selected from the group consisting of C(O)NH₂, —

CN, OCH₃, CF₃, Cl, and CH₃; and

said thiazol-5-yl, isoxazol-4-yl, and isoxazol-5-yl are optionally substituted with up to two CH₃ groups; and

said 1-methyl pyrazol-4-yl is optionally substituted with up to two additional CH₃ groups;

R⁶ is pyridyl or phenyl, wherein said phenyl is optionally substituted with Cl, F, CF₃, SO₂CH₃, or OCF₃;

R⁷ is H, Cl, —

CN, C_(1-3)alkyl, OCH₂CF₃, OCH₂CH₂OCH₃, CF₃, SCH₃, NA¹A², N(CH₃)CH₂CH₂N(CH₃)₂, OCH₂CH₂NH₂, OCH₂CH₂—

N-aziridinyl, OCH₂CH₂NHC(O)CH₃,OC_(1-3)alkyl, OCH₂-(1-methyl)-imidazol-2-yl, pyrid-3-yl, or pyrimidin-5-yl;

A¹ is H, or C_(1-4)alkyl;

A² is H, C_(1-4)alkyl, C_(1-4)alkylOC_(1-4)alkyl, C_(1-4)alkylOH, C(O)C_(1-2)alkyl, or OCH₃;

or A and A² may be taken together with their attached nitrogen to form a ring selected from the group consisting of;

6. The compounds of claim 5, wherein:

R¹ is pyrrolyl, triazolyl, imidazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazyl, piperidinyl, phenyl, isoxazolyl, thiophenyl, benzoxazolyl, or quinolinyl;

wherein said piperidinyl, pyridyl, phenyl, thiophenyl, and benzoxazolyl, are optionally substituted with C(O)CH₃, CH₃, CF₃, Cl, F, OCH₃, N(CH₃)₂, OH, or OCH₂OCH₃; and

optionally substituted with CH₃; and

wherein said triazolyl, imidazolyl, isoxazolyl, and thiazolyl are optionally substituted with one or two CH₃ groups;

R⁵ is H, Cl, —

CN, CF₃, OC_(1-3)alkyl, OH, C_(1-4)alkyl, NH(CH₃), N(C_(1-2)alkyl)₂, or 4-hydroxy-piperidinyl;

R⁶ is phenyl, or pyridyl, wherein said phenyl is optionally substituted with Cl, F, or OCF₃;

R⁷ is H, Cl, —

CN, C_(1-2)alkyl, CF₃, NA¹A², N(CH₃)CH₂CH₂N(CH₃)₂, OC_(1-3)alkyl, pyrid-3-yl, or pyrimidin-5-yl;

A¹ is C_(1-2)alkyl;

A² is C_(1-4)alkyl, or CH₂CH₂OCH₃;

or A¹ and A² may be taken together with their attached nitrogen to form a ring selected from the group consisting of;

7. A compound of claim 1 selected from the group consisting of:

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

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

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

11. A method for treating or ameliorating a RORγ

t 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, psoriasis, chronic obstructive pulmonary disorder, psoriatic arthritis, ankylosing spondylitis, Crohn'"'"'s disease, neutrophilic asthma, steroid resistant asthma, multiple sclerosis, systemic lupus erythematosus, and ulcerative colitis.

12. The method of claim 11, wherein the disease is psoriasis.

13. The method of claim 11, wherein the disease is rheumatoid arthritis.

14. The method of claim 11, wherein the disease is ulcerative colitis.

15. The method of claim 11, wherein the disease is Crohn'"'"'s disease.

16. The method of claim 11, wherein the disease is multiple sclerosis.

17. The method of claim 11, wherein the disease is neutrophilic asthma.

18. The method of claim 11, wherein the disease is steroid resistant asthma.

19. The method of claim 11, wherein the disease is psoriatic arthritis.

20. The method of claim 11, wherein the disease is ankylosing spondylitis.

21. The method of claim 11, wherein the disease is systemic lupus erythematosus.

22. The method of claim 11, wherein the disease is chronic obstructive pulmonary disorder.

23. 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.

24. A method for treating or ameliorating a RORγ

t mediated inflammatory syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of claim 7, wherein the disease is selected from the group consisting of;

rheumatoid arthritis and psoriasis.

25. 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.