Quinolinyl modulators of RORγt

• US 10,201,546 B2
• Filed: 03/02/2017
• Issued: 02/12/2019
• Est. Priority Date: 10/15/2013
• 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, Cummings, Maxwell D., McClure, Kelly, Tanis, Virginia
• Primary Examiner(s): Chandrakumar, Nizal S
• Application Number:
  US15/447,917
• Publication Number:
  US 20170182056A1
• Time in Patent Office: 712 Days
• Field of Search: 51421018
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5365 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• 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 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

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. A method for treating or ameliorating a RORγ

t mediated inflammatory syndrome, disorder or disease 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, comprising administering to a subject in need thereof an effective amount of a compound of Formula I, wherein;

2. The method of claim 1, wherein in said compound:

R¹ is imidazolyl, triazolyl, tetrahydropyranyl, thiazolyl, pyridyl, or phenyl;

wherein said pyridyl, imidazolyl, and phenyl are optionally substituted with one substituent selected from the group consisting of CH₃, CF₃, Cl, and —

CN; and

optionally substituted with up to one additional CH₃; and

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

R² is H, CH₃, 1-methyl-1,2,3-triazol-5-yl, pyrid-3-yl, 2-trifluoromethyl-pyrid-4-yl, 1,3,5-trimethyl-pyrazol-4-yl, N-acetyl-azetidin-3-yl, N-methylsulfonyl-azetidin-3-yl, N-Boc-azetidin-3-yl, N-acetyl-piperidin-4-yl, N-methylsulfonyl-piperidin-4-yl, N-Boc-piperidin-4-yl, 1-H-piperidin-4-yl, 1,2-dimethyl-imidazol-5-yl, or 1-methyl-imidazol-5-yl, provided that R² is not H when R⁵ is H;

R⁵ is H, Cl, —

CN, CF₃, C_(1-2)alkyl, OCH₃, azetidin-1-yl, or fur-2-yl;

provided that R⁵ is not H if R⁷ is OCH₃;

R⁷ is Cl, CF₃, CH₂CH₃, cyclopropyl, OCH₃, pyrimidin-5-yl, thiophen-3-yl, 1-methyl-indazol-5-yl, 1-methyl-indazol-6-yl, fur-2-yl, azetidin-1-yl, phenyl, or

3. A method of claim 1, wherein the compound is selected from the group consisting of:

4. A method of claim 1, wherein in the compound:

R¹ is imidazolyl, triazolyl, tetrahydropyranyl, thiazolyl, pyridyl, or phenyl;

wherein said pyridyl, imidazolyl, and phenyl are optionally substituted with one substituent selected from the group consisting of CH₃, CF₃, Cl, and —

CN; and

optionally substituted with up to one additional CH₃; and

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

R² is 1-methyl-1,2,3-triazol-5-yl, pyrid-3-yl, 2-trifluoromethyl-pyrid-4-yl, 1,3,5-trimethyl-pyrazol-4-yl, N-acetyl-azetidin-3-yl, N-methylsulfonyl-azetidin-3-yl, N-Boc-azetidin-3-yl, N-acetyl-piperidin-4-yl, N-methylsulfonyl-piperidin-4-yl, N-Boc-piperidin-4-yl, 1-H-piperidin-4-yl, 1,2-dimethyl-imidazol-5-yl, or 1-methyl-imidazol-5-yl;

R³ is OH;

R⁴ is H;

R⁵ is Cl, —

CN, CF₃, C_(1-2)alkyl, OCH₃, azetidin-1-yl, or fur-2-yl;

R⁶ is C_(1-4)alkylene-Q, OC_(1-4)alkylene-Q, C(O)NA³A⁴, C(O)OC_(1-4)alkyl, O-tetrahydropyranyl, —

O—

(N-methyl)piperidinyl, cyclopentyl, cyclohexyl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl, or tetrahydropyran-4-yl;

provided that R⁶ is not CH₂-phenyl, CH₂-pyridinyl, nor CH₂-pyrimidinyl;

Q is H, CF₃, OH, SO₂CH₃, NA³A⁴, OC_(1-4)alkyl, cyclopropyl, 1-methyl-cyclopropyl, oxetanyl, 3-methyl-oxetanyl, tetrahydrofuranyl, 1,3-dimethyl-pyrazol-5-yl, 3,5-dimethyl-isoxazol-4-yl, thiazol-2-yl, N-methyl-pyrrolidin-2-yl, cyclohexyl, N-acetyl-piperidin-4-yl, N-Boc-piperidin-4-yl, 1-H-piperidin-4-yl, tetrahydropyran-4-yl, 1,1-dioxo-tetrahydrothiopyran-4-yl, tetrahydrothiopyran-4-yl, phenyl, pyridin-3-yl, or pyrimidin-2-yl;

wherein said cyclopropyl, and said cyclohexyl are optionally substituted with up to two fluorine atoms;

wherein

A³ is H, or CH₃;

A⁴ is CH₃, CH₂-cyclopropyl, cyclopropyl, C_(1-3)alkylCF₃, CH₂CH₂OCH₂CF₃, C(O)C_(1-2)alkylCF₃,

5. A method of claim 4, wherein the compound is selected from the group consisting of:

6. A method of claim 4, wherein in the compound, R⁸ is H.

7. The method of claim 1, wherein the disease is psoriasis.

8. The method of claim 1, wherein the disease is rheumatoid arthritis.

9. The method of claim 1, wherein the inflammatory bowel disease is ulcerative colitis.

10. The method of claim 1, wherein the inflammatory bowel disease is Crohn'"'"'s disease.

11. The method of claim 1, wherein the disease is multiple sclerosis.

12. The method of claim 1, wherein the disease is neutrophilic asthma.

13. The method of claim 1, wherein the disease is steroid resistant asthma.

14. The method of claim 1, wherein the disease is psoriatic arthritis.

15. The method of claim 1, wherein the disease is ankylosing spondylitis.

16. The method of claim 1, wherein the disease is systemic lupus erythematosus.

17. The method of claim 1, wherein the disease is chronic obstructive pulmonary disorder.

18. 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 Formula I, wherein: