Triazolyl pyridyl benzenesulfonamides
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.
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 3b ;
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, and substituted or unsubstituted C 6-10 aryl;
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, and substituted or unsubstituted C 6-10 aryl;
R 1 is an unsubstituted isoxazolyl or an isoxazolyl substituted with 1 or 2 substituents independently selected from the group consisting of halogen, —CN, —CO 2 R′, —C(O)R′, —C(O)NR′R″, —OR′, —OC(O)R′, —OC(O)NR′R″, —NO 2 , —NR′C(O)R″, —NR″′C(O)NR′R″, —NR′R″, —NR′CO 2 R″, —NR′S(O)R″, —NR′S(O) 2 R″′, —NR″′S(O)NR′R″, —NR″′S(O) 2 NR′R″, —SR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NR′—C(NHR″)═NR″′, —SiR′R″R″′, —N 3 , and 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;
wherein said substituted C 1-8 alkyl, substituted C 2-8 alkenyl, and substituted C 2-8 alkynyl have 1 to (2m′=1) substituents, where the substituents are independently selected from the group consisting of halogen, —CN, —CO 2 R′, —C(O)R′, —C(O)NR′R″, —OR′, —OC(O)R′, —OC(O)NR′R″, —NO 2 , —NR′C(O)R″, —NR″′C(O)NR′R″, —NR′R″, —NR′CO 2 R″, —NR′S(O)R″, —NR′S(O) 2 R″′, —NR″′S(O)NR′R″, —NR″′S(O) 2 NR′R″, —SR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NR′—C(NHR″)═NR″′, —SiR′R″R″′, —N 3 , and unsubstituted C 6-10 aryl;
wherein m′ is the total number of carbons in said substituted alkyl, substituted alkenyl, and substituted alkynyl;
wherein said substituted C 6-10 aryl have 1 to 5 substituents independently selected from the group consisting of halogen, —CN, —CO 2 R′, —C(O)R′, —C(O)NR′R″, oxo(=O or —O − ), —OR′, —OC(O)R′, —OC(O)NR′R″, —NO 2 , —NR′C(O)R″, —NR″′C(O)NR′R″, —NR′R″, —NR′CO 2 R″, —NR′S(O)R″, —NR′S(O) 2 R″′, —NR″′S(O)NR′R″, —NR″′S(O) 2 NR′R″, —SR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NR′—C(NHR″)═NR″′, —SiR′R″R″′, —N 3 , and unsubstituted C 6-10 aryl; and
wherein R′, R″and R″′ are each independently selected from the group consisting of: hydrogen, unsubstituted C 1-8 alkyl, unsubstituted C 2-8 alkenyl, unsubstituted C 2-8 alkynyl, and unsubstituted C 6-10 aryl.
2. A compound which is represented by formula (II) or a salt thereof:
wherein
Ar is selected from the group consisting of substituted or unsubstituted C 6-10 aryl;
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; and
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, and substituted or unsubstituted C 6-10 aryl R 1 is an unsubstituted isoxazolyl or an isoxazolyl substituted with 1 or 2 substituents independently selected from the group consisting of halogen, —CN, —CO 2 R′, —C(O)R′, —C(O)NR′R″, —OR′, —OC(O)R′, —OC(O)NR′R″, —NO 2 , —NR′C(O)R″, —NR″′C(O)NR′R″, —NR′R″, —NR′CO 2 R″, —NR′S(O)R″, —NR′S(O) 2 R″′, —NR″′S(O)NR′R″, —NR″′S(O) 2 NR′R″, —SR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NR′—C(NHR″)═NR″′, —SiR′R″R″′, —N 3 , and 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;
wherein said substituted C 1-8 alkyl, substituted C 2-8 alkenyl, and substituted C 2-8 alkynyl have 1 to (2m′=1) substituents, where the substituents are independently selected from the group consisting of halogen, —CN, —CO 2 R′, —C(O)R′, —C(O)NR′R″, —OR′, —OC(O)R′, —OC(O)NR′R″, —NO 2 , —NR′C(O)R″, —NR″′C(O)NR′R″, —NR′R″, —NR′CO 2 R″, —NR′S(O)R″, —NR′S(O) 2 R″′, —NR″′S(O)NR′R″, —NR″′S(O) 2 NR′R″, —SR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NR′—C(NHR″)═NR″′, —SiR′R″R″′, —N 3 , and unsubstituted C 6-10 aryl;
wherein m′ is the total number of carbons in said substituted alkyl, substituted alkenyl, and substituted alkynyl;
wherein said substituted C 6-10 aryl have 1 to 5 substituents independently selected from the group consisting of halogen, —CN, —CO 2 R′, —C(O)R′, —C(O)NR′R″, oxo(=O or —O − ), —OR′, —OC(O)R′, —OC(O)NR′R″, —NO 2 , —NR′C(O)R″, —NR″′C(O)NR′R″, —NR′R″, —NR′CO 2 R″, —NR′S(O)R″, —NR′S(O) 2 R″′, —NR″′S(O)NR′R″, —NR″′S(O) 2 NR′R″, —SR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NR′—C(NHR″)═NR″′, —SiR′R″R″′, —N 3 , and unsubstituted C 6-10 aryl; and
wherein R′, R″ and R″′ are each independently selected from the group consisting of: hydrogen, unsubstituted C 1-8 alkyl, unsubstituted C 2-8 alkenyl, unsubstituted C 2-8 alkynyl, and 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 , —OC(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; and
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 R 19 , —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 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; and
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 5 wherein Y 6 is selected from the group consisting of halogen and methyl.
7. The compound of claim 5 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 .
8. The compound of claim 7 wherein X 1 is Cl and X 2 is CF 3 .
9. The compound of claim 2 which is represented by formula (VIII), or a salt thereof:
10. The compound of claim 9 which is represented by formula (IX), or a salt thereof:
R 3 and R 4 together with the carbon which they substitute form a unsubstituted or substituted isoxazolyl.
11. The compound of claim 10 wherein R 2 is hydrogen.
12. The compound of claim 3 which is represented by formula (XI), 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 R 19 , —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;
E is O;
R 10 and R 11 are each independently selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C 1-8 alkyl;
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; and
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.
13. The compound of claim 11 which is represented by formula (IX), or salts thereof wherein R 2 is hydrogen.
14. A compound selected from the following:
ethyl 5-(5-chloro-3-(4-chloro-3-(trifluoromethyl) phenylsulfonamido)pyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxylate;
5-(3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-5-methylpyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;
5-(5-chloro-3-(3,4-dichlorophenylsulfonamido)pyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;
5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido) pyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;
5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido) pyridin-2-yl)-4-(isoxazol-3-yl)-N,N-dimethyl-4H-1,2,4-triazole-3-carboxamide;
5-(5-chloro-3-(4-chloro-3-(trifluoromethyl) phenylsulfonamido) pyridin-2-yl)-N-ethyl-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;
5-(5-chloro-3-(4-chloro-3-(trifluoromethyl) phenylsulfonamido) pyridin-2-yl)-N-ethyl-4-(isoxazol-3-yl)-N-methyl-4H-1,2,4-triazole-3-carboxamide;
5-(5-chloro-3-(4-chloro-3-(trifluoromethyl) phenylsulfonamido) pyridin-2-yl)-N-isopropyl-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;
5-(5-chloro-3-(4-methyl-3-(trifluoromethyl) phenylsulfonamido) pyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide;
3,4-dichloro-N-(5-chloro-2-(4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)benzenesulfonamide;
4-chloro-N-(5-chloro-2-(4-(isoxazol-3-yl)-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;
4-chloro-N-(5-chloro-2-(5-(hydroxymethyl)-4-(isoxazol-3 -yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide;
N-(2-(5-bromo-4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloropyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide; and
N-(5-bromo-2-(4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide; or a salt thereof.
15. A compound that is 5-(3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-5-methylpyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide, or a salt thereof.
16. A compound that is 5-(3-(4-chloro-3-(trifluoromethyl) phenylsulfonamido)-5-methylpyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide.
17. A compound that is 5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide, or a salt thereof.
18. A compound that is 5-(5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)pyridin-2-yl)-4-(isoxazol-3-yl)-4H-1,2,4-triazole-3-carboxamide.