IP Library › Granted Patent US 8,445,518
Granted Patent B2
US 8,445,518 · App. 12/708,900 · Granted May 21, 2013

Triazolyl pyridyl benzenesulfonamides

Inventors: Trevor T. Charvat (San Jose, CA); Cheng Hu (Menlo Park, CA); Jeff Jin (Fremont, CA); Yandong Li (San Jose, CA); Anita Melikian (San Francisco, CA); Andrew M. K. Pennell (San Francisco, CA); Sreenivas Punna (Sunnyvale, CA); Solomon Ungashe (Fremont, CA); Yibin Zeng (San Mateo, CA)
Assignee: ChemoCentryx, Inc.
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Quick Facts
Patent No.
US 8,445,518
App. No.
12/708,900
Granted
May 21, 2013
Kind
B2
Abstract

Compounds are provided that act as potent antagonists of the CCR2 or CCR9 receptor. Animal testing demonstrates that these compounds are useful for treating inflammation, a hallmark disease for CCR2 and CCR9. The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR2-mediated diseases, CCR9-mediated diseases, as controls in assays for the identification of CCR2 antagonists and as controls in assays for the identification of CCR9 antagonists.

Claims (88)

1. A compound of the formula (I), or a salt thereof:

wherein

Ar is selected from the group consisting of substituted or unsubstituted C 6-10 aryl;

Y 1 is —CR 3a —;

Y 2 is —CR 3b —;

Y 3 is —CR 3c —;

Y 4 is —N—;

R 3a , R 3b , and R 3c are each independently selected from the group consisting of hydrogen, halogen, —CN, —C(O)R 4 , —CO 2 R 4 , —C(O)NR 4 R 5 , —OR 4 , —OC(O)R 4 , —OC(O)NR 4 R 5 , —SR 4 , —S(O)R 4 , —S(O) 2 R 4 , —S(O) 2 NR 4 R 5 , —NO 2 , —NR 4 R 5 , —NR 4 C(O)R 5 , —NR 4 C(O)OR 5 , —NR 4 S(O) 2 R 5 , —NR 4 C(O)NR 5 R 6 , substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;

R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;

R 4 and R 5 , R 5 and R 6 or R 4 and R 6 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring;

R 1 is selected from the group consisting of hydrogen, —C(O)R 7 , —CO 2 R 7 , —C(O)NR 7 R 8 , —S(O)R 7 , —S(O) 2 R 7 , —S(O) 2 NR 7 R 8 , substituted or unsubstituted C 1-8 alkyl, C 1-8 substituted or unsubstituted cycloalkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, and substituted or unsubstituted C 6-10 aryl;

R 2 is selected from the group consisting of hydrogen, halogen, —CN, —C(O)R 7 , —CO 2 R 7 , —C(O)NR 7 R 8 , —OR 7 , —OC(O)R 7 , —OC(O)NR 7 R 8 , —SR 7 , —S(O)R 7 , —S(O) 2 R 7 , —S(O) 2 NR 7 R 8 , —NO 2 , —NR 7 R 8 , —NR 7 C(O)R 8 , —NR 7 C(O)OR 8 , —NR 7 S(O) 2 R 8 , —NR 7 C(O)NR 8 R 9 , substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, and substituted or unsubstituted C 6-10 aryl; and

R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, and substituted or unsubstituted C 6-10 aryl.

2. The compound of claim 1 , which is represented by formula (II) or a salt thereof:

wherein

Y 5 , Y 6 and Y 7 are each independently selected from the group consisting of hydrogen, halogen, —CN, —C(O)R 15 , —CO 2 R 15 , —C(O)NR 15 R 16 , —OR 15 , —OC(O)R 15 , —OC(O)NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , —S(O) 2 NR 15 R 16 , —NO 2 , —NR 15 R 16 , —NR 15 C(O)R 16 , —NR 15 C(O)OR 16 , —NR 15 S(O) 2 R 16 , —NR 15 C(O)NR 16 R 17 , substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, and substituted or unsubstituted C 6-10 aryl;

R 15 , R 16 and R 17 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl.

3. The compound of claim 2 , which is represented by formula (III) or a salt thereof:

wherein

X 1 , X 2 , X 3 , X 4 , and X 5 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, —CN, —NO 2 , —C(O)R 18 , —CO 2 R 18 , —C(O)NR 18 R 19 , —OR 18 , —OC(O)R 19 , —C(O)NR 18 R 19 , —NO 2 , —NR 18 C(O)R 19 , —NR 18 C(O)NR 19 R 20 , —NR 18 R 19 , —NR 18 CO 2 R 19 , —NR 18 S(O) 2 R 19 , —SR 18 , —S(O)R 18 , —S(O) 2 R 18 , —S(O) 2 NR 18 R 19 , and substituted or unsubstituted C 6-10 aryl;

R 18 , R 19 and R 20 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, and substituted or unsubstituted C 6-10 aryl.

4. The compound of claim 3 , which is represented by formula (IV), or a salt thereof:

wherein X 1 and X 2 are each independently from the group consisting of halogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, —CN, —CO 2 R 18 , —OR 18 , —OC(O)R 19 , —OC(O)NR 18 R 19 , —NR 18 C(O)R 19 , —NR 18 C(O)NR 19 R 20 , —NR 18 R 19 , —NR 18 CO 2 R 19 , —NR 18 S(O) 2 , —NO 2 , and —SR 18 ;

Y 6 is selected from the group consisting of halogen, —CN, —OR 18 , and substituted or unsubstituted C 1-8 alkyl;

R 1 is selected from the group consisting of hydrogen, —C(O)R 7 , —CO 2 R 7 , —C(O)NR 7 R 8 , —S(O)R 7 , —S(O) 2 R 7 , —S(O) 2 NR 7 R 8 , substituted or unsubstituted C 1-8 alkyl, C 1-8 substituted or unsubstituted cycloalkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, and substituted or unsubstituted C 6-10 aryl;

R 2 is selected from the group consisting of hydrogen, halogen, —CN, —C(O)R 7 , —CO 2 R 7 , —C(O)NR 7 R 8 , —OR 7 , —OC(O)R 7 , —OC(O)NR 7 R 8 , —SR 7 , —S(O)R 7 , —S(O) 2 R 7 , —S(O) 2 NR 7 R 8 , —NO 2 , —NR 7 R 8 , —NR 7 C(O)R 8 , —NR 7 C(O)OR 8 , —NR 7 S(O) 2 R 8 , —NR 7 C(O)NR 8 R 9 , substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, and substituted or unsubstituted C 6-10 aryl;

R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, and substituted or unsubstituted C 6-10 aryl;

R 18 , R 19 and R 20 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, and substituted or unsubstituted C 6-10 aryl.

5. The compound of claim 3 , which is represented by formula (V), or a salt thereof:

6. The compound of claim 3 , which is represented by formula (VII), or a salt thereof:

wherein Z is 0, 1, 2, 3, 4, or 5 substituents selected from the group consisting of halogen, substituted or unsubstituted C1-8 alkyl, and substituted or unsubstituted C1-8 alkoxy.

7. The compound of claim 3 wherein Y 6 is selected from the group consisting of halogen and methyl.

8. The compound of claim 3 wherein X 1 and X 2 are independently selected from the group consisting of hydrogen, halogen, substituted and unsubstituted C 1 -C 4 alkyl, and OR 18 .

9. The compound of claim 8 wherein X 1 is Cl and X 2 is CF 3 .

10. The compound of claim 9 wherein R 1 is C 1 -C 4 alkyl.

11. The compound of claim 3 which is represented by formula (VIII), or a salt thereof:

12. A compound which is represented by formula (IX), or a salt thereof:

wherein R 3 and R 4 are each independently hydrogen, unsubstituted or substituted C 1-8 alkyl, or R 3 and R 4 together with the carbon which they substitute form a 3-10 membered carboxylic;

R 2 is selected from the group consisting of hydrogen, halogen, —CN, —C(O)R 7 , —CO 2 R 7 , —C(O)NR 7 R 8 , —OR 7 , —OC(O)R 7 , —OC(O)NR 7 R 8 , —SR 7 , —S(O)R 7 , —S(O) 2 R 7 , —S(O) 2 NR 7 R 8 , —NO 2 , —NR 7 R 8 , —NR 7 C(O)R 8 , —NR 7 C(O)OR 8 , —NR 7 S(O) 2 R 8 , —NR 7 C(O)NR 8 R 9 , substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl; and

R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;

R 7 and R 8 , R 8 and R 9 or R 7 and R 9 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring; and

where R 1 and R 2 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring.

13. The compound of claim 12 wherein R 2 is hydrogen.

14. The compound of claim 3 wherein R 2 is hydrogen.

15. A compound selected from the following:

ethyl 5-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxylate;

5-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-N,N-dimethyl-4H-1,2,4-triazole-3-carboxamide;

5-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-N-methyl-4H-1,2,4-triazole-3-carboxamide;

N-(5-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-4H-1,2,4-triazol-3-yl)acetamide;

4-tert-butyl-N-(5-chloro-2-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;

4-tert-butyl-N-(5-chloro-2-(4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;

4-tert-butyl-N-(5-chloro-2-(4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;

4-tert-butyl-N-(5-chloro-2-(4-ethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;

4-tert-butyl-N-(5-chloro-2-(4-ethyl-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;

4-tert-butyl-N-(5-chloro-2-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;

4-tert-butyl-N-(5-chloro-2-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;

4-tert-butyl-N-(5-chloro-2-(4-isopropyl-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;

4-tert-butyl-N-(5-chloro-2-(4-isopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3yl)benzenesulfonamide;

4-tert-butyl-N-(5-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;

4-tert-butyl-N-(5-chloro-2-(4-phenyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;

4-tert-butyl-N-(5-chloro-2-(5-(2-hydroxypropan-2-yl)-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;

4-tert-butyl-N-(5-chloro-2-(5-(methoxymethyl)-4-(tetrahydro-2H-pyran-4-yl)-4-H

4-tert-butyl-N-(5-chloro-2-(5-(methoxymethyl)-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;

4-tert-butyl-N-(5-chloro-2-(5-isopropyl-4-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;

N-(2-(5-amino-4-isopropyl-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide;

ethyl-5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxylate;

5-(3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-5-methylpyridin-2-yl)-4-phenyl-4H-1,2,4-triazole-3-carboxamide;

5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxamide;

5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-isopropyl-N,N-dimethyl-4H-1,2,4-triazole-3-carboxamide;

(S)-4-chloro-N-(5-chloro-2-(4-(1-hydroxypropan-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;

4-chloro-N-(5-chloro-2-(4-(1-(dimethylamino)propan-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;

4-chloro-N-(5-chloro-2-(4-(4-hydroxybutan-2-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;

4-chloro-N-(5-chloro-2-(4-o-tolyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;

4-chloro-N-(5-chloro-2-(4-phenyl-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;

4-chloro-N-(5-chloro-2-(4-propyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;

4-chloro-N-(5-chloro-2-(5-((dimethylamino)methyl)-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;

4-chloro-N-(5-chloro-2-(5-(hydroxymethyl)-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;

4-chloro-N-(5-chloro-2-(5-chloro-4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;

N-(2-(5-amino-4-isopropyl-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide; and

N-(2-(5-bromo-4-isopropyl-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide.

16. A method for treating a CCR2-mediated condition or disease or a CCR9-mediated condition or disease comprising administering to a subject an effective amount of a compound of claim 1 or a salt thereof.

17. The method of claim 16 , where the disease or condition is selected from the group consisting of atherosclerosis, restenosis, multiple sclerosis, inflammatory bowel disease, renal fibrosis, rheumatoid arthritis, obesity, diabetes, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, idiopathic pneumonia syndrome, pulmonary fibrosis, transplantation rejection, graft-versus-host disease, cancer, and neuropathic pain.

18. The method of claim 16 , where the administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical.

19. The method of claim 16 , further comprising administering an anti-inflammatory or analgesic agent.

20. A method of modulating CCR2 function in a cell, comprising contacting the cell with a CCR2 modulating amount of the compound of claim 1 .

21. A method of modulating CCR9 function in a cell, comprising contacting the cell with a CCR9 modulating amount of the compound of claim 1 .

22. A method for treating a CCR9-mediated condition or disease comprising administering to a subject an effective amount of the compound of claim 1 .

23. A method for treating a CCR2-mediated condition or disease comprising administering to a subject an effective amount of the compound of claim 1 .

Assignments (2)
ASSIGNEE CHANGE OF ADDRESS Recorded Jun 27, 2023
From: CHEMOCENTRYX, INC.
To: CHEMOCENTRYX, INC.
Reel/Frame 064144/0685 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 19, 2010
From: CHARVAT, TEVOR T.; HU, CHENG; JIN, JEFF; LI, YANDONG; MELIKIAN, ANITA; PENNELL, ANDREW M.K.; PUNNA, SREENIVAS; UNGASHE, SOLOMON; ZENG, YIBIN
To: CHEMOCENTRYX, INC.
Reel/Frame 023962/0791 →
Continuity (4)
Division 11775601 · Jul 10, 2007
Provisional Application 60831042 · Jul 14, 2006
Provisional Application 60945854 · Jun 22, 2007
Related Publication 20100152186A1 · Jun 17, 2010