Triazolyl phenyl 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 method for treating a CCR2-mediated condition or disease or a CCR9-mediated condition or disease selected from the group consisting of: atherosclerosis, restenosis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, renal fibrosis, rheumatoid arthritis, obesity, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, idiopathic pneumonia syndrome, pulmonary fibrosis, transplantation rejection, graft-versus-host disease, and neuropathic pain, comprising:
administering to a subject an effective amount of a compound of formula (I), or a salt thereof:
where
Ar is selected from the group consisting of: substituted or unsubstituted C 6-10 aryl and substituted or unsubstituted 5- to 10-membered heteroaryl;
Y 4 , 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, 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 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, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; and
R 15 and R 16 , R 16 and R 17 , or R 15 and R 17 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 1-17 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 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;
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, 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.
2. The method of claim 1 , wherein the compound or a salt thereof is of formula (II):
where
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 , —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 , 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 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, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; and
R 18 and R 19 , R 19 and R 20 , or R 18 and R 20 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring.
3. The method of claim 2 , where
X 1 is selected from the group consisting of: halogen, substituted or unsubstituted C 1-8 alkyl, —OR 18 , —NR 18 R 19 , and substituted or unsubstituted 3- to 10-membered heterocyclyl;
Y 7 is hydrogen;
Y 4 , Y 5 , and Y 6 are each independently selected from the group consisting of: hydrogen, halogen, —CN, —CO 2 R 15 , and —C(O)NR 15 R 16 ;
R 1 is selected from the group consisting of substituted or unsubstituted C 1-17 alkyl, 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 2 is selected from the group consisting of: hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl.
4. The method of claim 2 , wherein the compound or a salt thereof is of formula (III):
where at least one of X 1 and X 2 is other than hydrogen and at least one of Y 4 and Y 5 is other than hydrogen.
5. The method of claim 4 , where X 2 is hydrogen or halogen; Y 4 is hydrogen, halogen or —CN; and X 1 and Y 5 are other than hydrogen.
6. The method of claim 5 , where
X 1 is selected from the group consisting of: substituted or unsubstituted C 1-8 alkyl, —OR 18 , —NR 18 R 19 , and substituted or unsubstituted 3- to 10-membered heterocyclyl;
Y 5 is selected from the group consisting of: halogen, —CN, —CO 2 R 15 , and —C(O)NR 15 R 16 ;
R 1 is selected from the group consisting of: substituted or unsubstituted C 1-13 alkyl, 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 2 is hydrogen.
7. The method of claim 6 , wherein the compound or a salt thereof is of formula (VIII):
where W is NH or O; and n is 0, 1, or 2.
8. The method of claim 4 , where
X 1 is halogen;
X 2 is halogen or —CF 3 ;
Y 4 is halogen;
Y 5 is hydrogen or halogen;
R 2 is hydrogen or substituted or unsubstituted C 1-8 alkyl.
9. The method of claim 8 , wherein the compound or a salt thereof is of formula (V):
10. The method of claim 2 , wherein the compound or a salt thereof is of formula (IV):
where Y 4 is hydrogen or halogen; and X 1 and Y 5 are other than hydrogen.
11. The method of claim 10 , where
X 1 is selected from the group consisting of: substituted or unsubstituted C 1-8 alkyl, —OR 18 , —NR 18 R 19 , and substituted or unsubstituted 3- to 10-membered heterocyclyl;
Y 5 is selected from the group consisting of: halogen, —CN, —CO 2 R 15 , and —C(O)NR 15 R 16 ;
R 1 is selected from the group consisting of: substituted or unsubstituted C 1-17 alkyl, 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 2 is selected from the group consisting of: hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl.
12. The method of claim 11 , wherein the compound or a salt thereof is of formula (VI):
13. The method of claim 12 , wherein the compound or a salt thereof is of formula (VII):
where
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 member carbocyclic, 4-10 member heterocyclic, 5-10 member heteroaryl ring or 6-10 membered aryl ring.
14. The method of claim 13 , where R 2 is hydrogen.
15. A method for treating a CCR2-mediated condition or disease or a CCR9-mediated condition or disease selected from the group consisting of: atherosclerosis, restenosis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, renal fibrosis, rheumatoid arthritis, obesity, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, idiopathic pneumonia syndrome, pulmonary fibrosis, transplantation rejection, graft-versus-host disease, and neuropathic pain, comprising administering to a subject an effective amount of a compound selected from the group consisting of:
4-tert-butyl-N-(4-chloro-2-(4,5-diisopropyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-cyclopentyl-5-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-isopropyl-5-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-methyl-5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-phenyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-(methoxymethyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-ethyl-4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-isopropyl-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
N-(4-chloro-2-(4-isopropyl-5-methyl-4H-1,2,4-triazol-3-yl)phenyl)-4-isopropoxybenzenesulfonamide;
N-(2-(3-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-5-methyl-4H-1,2,4-triazol-4-yl)ethyl)acetamide;
(R)-4-tert-butyl-N-(4-chloro-2-(4-methyl-5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4,5-difluoro-2-(4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-2-(4-(1-hydroxypropan-2-yl)-5-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-2-(4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-2-(4-methyl-5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(2-(4-ethyl-4H-1,2,4-triazol-3-yl)-4,5-difluorophenyl)benzenesulfonamide;
4-tert-butyl-N-(2-(4-ethyl-4H-1,2,4-triazol-3-yl)-5-fluorophenyl)benzenesulfonamide;
4-tert-butyl-N-(4,5-difluoro-2-(4-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4,5-diethyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-3-fluorophenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-5-fluorophenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-ethyl-4H-1,2,4-triazol-3-yl)-3-fluorophenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-ethyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-ethyl-5-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)-3-fluorophenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-isobutyl-5-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-methyl-5-(oxazol-4-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-((dimethylamino)methyl)-4-methyl-4H-1,2,4-triazol-3-yl)-5-fluorophenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-(2-methoxyethyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-(methoxymethyl)-4-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-(piperidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(5-chloro-2-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(5-chloro-2-(4-isopropyl-5-(4-methyltetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(5-fluoro-2-(4-isopropyl-5-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
N-(4-chloro-2-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)phenyl)-4-isopropoxybenzenesulfonamide;
ethyl 2-(5-(2-(4-tert-butylphenylsulfonamido)-5-chloro-4-fluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)acetate;
5-(2-(4-tert-butylphenylsulfonamido)-5-chloro-4-fluorophenyl)-4-methyl-4H-1,2,4-triazole-3-carboxamide;
5-(2-(4-tert-butylphenylsulfonamido)-5-chloro-4-fluorophenyl)-N,4-dimethyl-4H-1,2,4-triazole-3-carboxamide;
(R)-4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-(1-hydroxyethyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-2-(4-(piperidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-2-(4-(tetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(piperidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-(piperidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-(1-hydroxyethyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-methyl-4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)—N-(4-chloro-2-(4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)-4-isopropoxybenzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-isopropyl-5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-methyl-5-(5-methyloxazol-4-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-((cyclopropylamino)methyl)-4-methyl-4H-1,2,4-triazol-3-yl)-5-fluorophenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-((ethylamino)methyl)-4-methyl-4H-1,2,4-triazol-3-yl)-5-fluorophenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-ethyl-4-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)-5-fluorophenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-ethyl-4-methyl-4H-1,2,4-triazol-3-yl)-5-fluorophenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-ethyl-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-(tetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-isopropyl-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-5-((methylamino)methyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-5-(methylsulfonylmethyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-5-(oxazol-4-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-5-(pyrrolidin-1-ylmethyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-5-(tetrahydro-2H-pyran-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-((isopropylamino)methyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-(1-hydroxyethyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-(2-hydroxy-2-methylpropyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-(2-hydroxypropan-2-yl)-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-(2-methoxyethyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-(hydroxymethyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-(methoxymethyl)-4-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-(methoxymethyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
N-(2-(5-(azetidin-1-ylmethyl)-4-methyl-4H-1,2,4-triazol-3-yl)-4-chloro-5-fluorophenyl)-4-tert-butylbenzenesulfonamide;
N-(2-(5-acetyl-4-methyl-4H-1,2,4-triazol-3-yl)-4-chloro-5-fluorophenyl)-4-tert-butyl benzenesulfonamide;
(S)-4-tert-butyl-N-(4,5-difluoro-2-(5-methyl-4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-2-(5-ethyl-4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-2-(5-isopropyl-4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(2-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-5-fluorophenyl)benzenesulfonamide;
4-tert-butyl-N-(2-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)-4,5-difluorophenyl)benzenesulfonamide;
4-tert-butyl-N-(2-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)-5-fluorophenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-methyl-5-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-isopropyl-5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-5-(5-methyloxazol-4-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-isopropyl-4-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-methyl-4-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
N-(4-chloro-2-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)phenyl)-4-isopropoxybenzenesulfonamide;
N-(4-chloro-2-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)-4-isopropoxybenzenesulfonamide,
(S)-4-tert-butyl-N-(4-chloro-2-(5-ethyl-4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)-5-fluorophenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-(2-oxopyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-isopropyl-4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)—N-(4-chloro-2-(4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)-4-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-cyclobutyl-5-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-ethyl-5-isopropyl-4H-1,2,4-triazol-3-yl)-5-fluorophenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-isopropyl-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(1-methylpiperidin-4-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-5-(2-(methylsulfonyl)ethyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
N-(2-(4-(1-acetylpiperidin-4-yl)-5-methyl-4H-1,2,4-triazol-3-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;
N-(2-(4-(2-aminoethyl)-5-methyl-4H-1,2,4-triazol-3-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;
N-(2-(4-(azetidin-3-yl)-4H-1,2,4-triazol-3-yl)-4-chloro-5-fluorophenyl)-4-tert-butylbenzenesulfonamide;
(R)-4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(2-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)-4,5-difluorophenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-isopropyl-5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-methyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-methyl-5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-((dimethylamino)methyl)-4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-(isopropoxymethyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-(3-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-5-methyl-4H-1,2,4-triazol-4-yl)piperidine-1-carboxamide;
4-tert-butyl-N-(4-chloro-2-(4-(2-(dimethylamino)ethyl)-5-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(1-(methylsulfonyl)piperidin-4-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(2-(methylamino)ethyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(5-chloro-2-(4-isopropyl-5-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
N-(2-(4-(1-acetylpyrrolidin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;
N-(2-(5-amino-4-isopropyl-4H-1,2,4-triazol-3-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;
(R)-4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(R)-4-tert-butyl-N-(4-chloro-2-(4-(pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-cyano-2-(5-ethyl-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-(4-tert-butylphenylsulfonamido)-3-(5-ethyl-4-methyl-4H-1,2,4-triazol-3-yl)benzamide;
4-(4-tert-butylphenylsulfonamido)-3-(5-ethyl-4-methyl-4H-1,2,4-triazol-3-yl)benzoic acid;
N-(2-(4-(azetidin-3-yl)-4H-1,2,4-triazol-3-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-methyl-5-((methylamino)methyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
methyl 4-(4-tert-butylphenylsulfonamido)-3-(5-ethyl-4-methyl-4H-1,2,4-triazol-3-yl)benzoate;
N-(4-chloro-2-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)phenyl)-3-fluoro-4-morpholinobenzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-(2-hydroxyethyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(5-((isopropylamino)methyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-(1-methoxyethyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(R)-4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-5-(pyrrolidin-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-2-(4-(1-isopropylpyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-3-(3-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-4H-1,2,4-triazol-4-yl)pyrrolidine-1-carboxamide;
4-tert-butyl-N-(4-chloro-2-(4-methyl-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-5-(piperidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-5-(piperazin-1-ylmethyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-5-((tetrahydrofuran-3-ylamino)methyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(5-(((2-methoxyethyl)(methyl)amino)methyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-2-(4-isopropyl-5-(4-methyltetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-5-((4-methylpiperazin-1-yl)methyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-methyl-5-((tetrahydro-2H-pyran-4-ylamino)methyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
(S)-4-tert-butyl-N-(4-chloro-2-(4-(1-(methylsulfonyl)pyrrolidin-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
4-tert-butyl-N-(4-chloro-5-fluoro-2-(4-isopropyl-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)phenyl)benzenesulfonamide;
N-(2-(4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chlorophenyl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;
4-chloro-N-(5-chloro-2-(5-methyl-4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)phenyl)-3-(trifluoromethyl)benzenesulfonamide;
4-chloro-N-(5-chloro-2-(4-phenyl-4H-1,2,4-triazol-3-yl)phenyl)-3-(trifluoromethyl)benzenesulfonamide;
N-(2-(4-(1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-chloro-4-fluorophenyl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide;
5-(4-chloro-2-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-5-fluorophenyl)-4-(1H-pyrazol-3-yl)-4H-1,2,4-triazole-3-carboxamide; and
N-(2-([1,2,4]triazolo[4,3-a]pyrimidin-3-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide.
16. The method of claim 1 , where the administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical.
17. The method of claim 1 , further comprising administering an anti-inflammatory or analgesic agent.
18. The method of claim 1 for treating the CCR2- or CCR9-mediated condition or disease wherein the condition or disease is Crohn's disease or ulcerative colitis.
19. The method of claim 1 for treating the CCR2- or CCR9-mediated condition or disease wherein the condition or disease is inflammatory bowel disease.
20. A method for treating a CCR2-mediated condition or disease or a CCR9-mediated condition or disease selected from the group consisting of: atherosclerosis, restenosis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, renal fibrosis, rheumatoid arthritis, obesity, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, idiopathic pneumonia syndrome, pulmonary fibrosis, transplantation rejection, graft-versus-host disease, and neuropathic pain, comprising:
administering to a subject an effective amount of a compound of formula (I), or a salt thereof:
where
Ar is selected from the group consisting of: substituted or unsubstituted C 6-10 aryl and substituted or unsubstituted 5- to 10-membered heteroaryl;
Y 4 , 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, 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 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, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; and
R 15 and R 16 , R 16 and R 17 , or R 15 and R 17 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: —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 2-17 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 8-10 aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;
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;
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, 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.
21. The method of claim 20 , wherein the compound or a salt thereof is of formula (II):
where
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 , —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 , 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 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, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; and
R 18 and R 19 , R 19 and R 20 , or R 18 and R 20 may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring.
22. The method of claim 21 , wherein the compound or a salt thereof is of formula (III):
where at least one of X 1 and X 2 is other than hydrogen and at least one of Y 4 and Y 5 is other than hydrogen.
23. The method of claim 22 , wherein the compound or a salt thereof is of formula (VIII):
where W is NH or O; and n is 0, 1, or 2.
24. The method of claim 20 , wherein the compound or a salt thereof is of formula (VI):