초록 ▼

Compounds are provided that act as potent antagonists of the CCR9 receptor. Animal testing demonstrates that these compounds are useful for treating inflammation, a hallmark disease for CCR9. The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, meth

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

대표청구항 ▼

1. A compound, salt, or N-oxide of the formula (I): where Ar1 is a substituted or unsubstituted C6-10 aryl or substituted or unsubstituted 5- to 10-membered heteroaryl; each having 0 to 5 substituents selected from the group consisting of halogen, substituted or unsubstituted C1-8 alkyl, substituted

1. A compound, salt, or N-oxide of the formula (I): where Ar1 is a substituted or unsubstituted C6-10 aryl or substituted or unsubstituted 5- to 10-membered heteroaryl; each having 0 to 5 substituents selected from the group consisting of halogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, —CN, —NO2, ═O, —C(O)R3, —CO2R3, —C(O)NR3R4, —OR3, —OC(O)R3, —OC(O)NR3R4, —NR5C(O)R3, —NR5C(O)NR3R4, —NR3R4, —NR5CO2R3, —NR5S(O)2R3, —SR3, —S(O)R3, —S(O)2R3, —S(O)2NR3R4, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl;A is N;X1X2X3 are selected from the group consisting of:N—N═NN—C(R6)═NN—N═C(R7)N—C(R6)═C(R7)C═N—C(R7)C═C(R6)—N(R5)R1 is hydrogen or C1-8 alkyl;each R2, R3, R4, R6 and R7, when present, are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, —CN, ═O, —NO2, —OR′, —OC(O)R′, —CO2R′, —C(O)R′, —C(O)NR″R′, —OC(O)NR″R′, —NR′″C(O)R′, —NR′″C(O)NR″R′, —NR″R′, —NR′″CO2R′, —SR′, —S(O)R′, —S(O)2R′, —S(O)2NR″R′, —NR″S(O)2R′, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl and substituted or unsubstituted 3- to 10-membered heterocyclyl; orR2 and R3 together with the atoms which they substitute form a substituted or unsubstituted 5-, 6-, or 7-membered ring;each R5 is independently selected from group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, —CO2R′, —C(O)R′, —C(O)NR″R′, —S(O)R′, —S(O)2R′, —S(O)2NR″R′, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; andR′, R″ and R′″ are each independently hydrogen or unsubstituted C1-4 alkyl; or R′ and R″ together with the atoms which they substitute form a substituted or unsubstituted 5-, 6-, or 7-membered ring. 2. The compound of claim 1, which is of the formula (II), or a salt thereof: where R8, R9, R10, R11, and R12 are each independently selected from the group consisting of hydrogen, halogen, C1-8 alkoxy, C1-8 alkyl, —CN, or C1-8 haloalkyl. 3. The compound of claim 2, which is of the formula (IV), or a salt thereof: 4. The compound of claim 2, which is of the formula (V), or a salt thereof: 5. A composition comprising a pharmaceutically acceptable carrier and a compound of claim 1. 6. The compound of claim 2, which is of the formula (VI), or a salt thereof: 7. The compound of claim 1, which is of the formula (CCI), or a salt thereof: where R1 is a halogen, C1-8 alkoxy, C1-8 alkyl, —CN, or C1-8 haloalkyl;each R2 is independently hydrogen, halogen, C1-8 alkyl, —CN, or C1-8 haloalkyl;R3 is hydrogen or C1-8 alkyl;R4 is halogen or C1-8 alkyl;R5 is hydrogen, halogen or C1-8 alkyl;R6, R7, R8 and R9 are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C2-8 alkenyl, substituted or unsubstituted C2-8 alkynyl, —CN, ═O, —NO2, —OR′, —OC(O)R′, —C(O)R′, —C(O)NR″R′, —OC(O)NR″R′, —NR′″C(O)R′, —NR′″C(O)NR″R′, —NR″R′, —NR′″CO2R′, —SR′, —S(O)R′, —S(O)2R′, —S(O)2NR″R′, —NR″S(O)2R′, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl and substituted or unsubstituted 3- to 10-membered heterocyclyl; orR6 and R7 together with the atoms which they substitute form a substituted or unsubstituted 5-, 6-, or 7-membered ring;X3 is CR8 or N; andX2 is CR9 or N. 8. The compound of claim 7, which is of the formula (CCII), or a salt thereof: 9. The compound of claim 7, which is of the formula of (CCIII), or a salt thereof: 10. The compound of claim 7, which is of the formula of (CCIV), or a salt thereof: 11. The compound of claim 7, which is of the formula of (CCV), or a salt thereof: 12. The compound of claim 7, which is of the formula of (CCVI), or a salt thereof: 13. The compound of claim 1, which is: 4-tert-butyl-N-(5-chloro-2-(1H-pyrazolo[4,3-b]pyridine-1-yl)pyridine-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(5-methyl-1H-pyrazolo[4,3-b]pyridine-1-yl)pyridine-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(1H-imidazo[4,5-b]pyridine-1-yl)pyridine-3-yl)benzenesulfonamide; and4-tert-butyl-N-(5-chloro-2-(3H-imidazo[4,5-b]pyridine-3-yl)pyridine-3-yl)benzenesulfonamide;N-(2-(5-amino-1H-pyrrolo[3,2-b]pyridin-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide;N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide;ethyl 1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-1H-pyrazole-4-carboxylate;N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-5-methylpyridin-3-yl)-4-tert-butylbenzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-phenyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(2-methyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(2-isopropyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(2-phenyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(2-ethyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(1H-indol-1-yl)pyridin-3-yl)benzenesulfonamide;N-(2-(1H-benzo[d]imidazol-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(1H-indazol-1-yl)pyridin-3-yl)benzenesulfonamide;N-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(9H-purin-9-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(2,4-dimethyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-(piperidine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-(morpholine-4-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-(pyrrolidine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-(4-methylpiperazine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;N-(2-(4-(azetidine-1-carbonyl)-1H-pyrazol-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide;1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N-isopropyl-N-methyl-1H-pyrazole-4-carboxamide;4-tert-butyl-N-(5-chloro-2-(4-(4-isopropylpiperazine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;4-tert-butyl-N-(5-chloro-2-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N-(2-(dimethylamino)ethyl)-N-methyl-1H-pyrazole-4-carboxamide;4-tert-butyl-N-(5-chloro-2-(4-(1,2,3,6-tetrahydropyridine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N-methyl-1H-pyrazole-4-carboxamide;1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide;1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N,3-dimethyl-1H-pyrazole-4-carboxamide;1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N,N,3-trimethyl-1H-pyrazole-4-carboxamide;1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-1H-pyrazole-4-carboxylic acid;N-(2-(4-amino-1H-pyrazol-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide;N-(1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-1H-pyrazol-4-yl)acetamide; and4-tert-butyl-N-(5-chloro-2-(4-(oxazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;or a salt thereof. 14. The composition of claim 5, further comprising an anti-inflammatory or analgesic agent.