Pyrrolo[2,3-b]pyridin-4-yl-amines and pyrrolo[2,3-b]pyrimidin-5-yl-amines as Janus kinase inhibitors
The present invention provides pyrrolo[2,3-b]pyridine-4-yl amines pyrrolo[2,3-b]pyrimidin-4-yl amines that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases and cancer.
1. A method of inhibiting an activity of JAK2 comprising contacting said JAK2 with a compound of Formula I:
or pharmaceutically acceptable salt form thereof, wherein:
R 1 , R 2 , and R 3 are each, independently, H, halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R d , NR c C(O)OR a , S(O)R b , S(O)NR c R d , S(O) 2 R b , or S(O) 2 NR c R d ;
R 4 is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, S(O) 2 R 9 , SOR 9 , cycloalkyl, or heterocycloalkyl, wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cycloalkyl, heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c R(O)R d , NR c R(O)OR a , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ;
R 5 is 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -L-(3-8 membered cycloalkyl), -L-(3-8 membered heterocycloalkyl), each substituted by one R 6 and 0, 1 or 2 R 7 ;
L is C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, O, S, NR 14 , CO, COO, OCO, NR 14 C(O)O, CONR 14 , SO, SO 2 , SONR 14 , SO 2 NR 14 , or NR 14 CONR 14 ;
R 6 is —W 1 —W 2 —W 3 —W 4 —W 5 —W 6 —R 13 ;
W 1 is absent, C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted by 1, 2 or 3 halo, CN, NO 2 , OH, ═NH, ═NOH, ═NO—(C 1-4 alkyl), C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino or C 2-8 dialkylamino;
W 2 is absent, C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, O, S, NR 12 , CO, COO, OCO, C(S), C(S)NR 12 , —C(═N—CN)—, NR 12 C(O)O, CONR 12 , SO, SO 2 , SONR 12 , SO 2 NR 12 , or NR 12 CONR 12 , wherein said C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, are each optionally substituted by 1, 2 or 3 halo, OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino or C 2-8 dialkylamino;
W 3 is absent, C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, CN, NO 2 , OH, ═NH, ═NOH, ═NO—(C 1-4 alkyl), C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino or C 2-8 dialkylamino;
W 4 is absent, C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, O, S, NR 12 , CO, COO, OCO, —C(═N—CN)—, NR 12 C(O)O, CONR 12 , SO, SO 2 , SONR 12 , SO 2 NR 12 , or NR 12 CONR 12 , wherein said C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, are each optionally substituted by 1, 2 or 3 halo, CN, NO 2 , OH, ═NH, ═NOH, ═NO—(C 1-4 alkyl), C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino or C 2-8 dialkylamino;
W 5 is absent, C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, CN, NO 2 , OH, ═NH, ═NOH, ═NO—(C 1-4 alkyl), C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino or C 2-8 dialkylamino;
W 6 is absent, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, O, S, NR 12 , CO, COO, OCO, —C(═N—CN)—, NR 12 C(O)O, CONR 12 , SO, SO 2 , SONR 12 , SO 2 NR 12 , or NR 12 CONR 12 , wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl are each optionally substituted by 1, 2 or 3 CN, NO 2 , OH, ═NH, ═NOH, ═NO—(C 1-4 alkyl), C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino or C 2-8 dialkylamino;
R 7 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO 2 , OR a″ , SR a″ , C(O)R b″ , C(O)NR c″ R d″ , C(O)OR a″ , OC(O)R b″ , OC(O)NR c″ R d″ , NR c″ R d″ , NR c″ C(O)R d , NR c″ C(O)OR a″ , S(O)R b″ , S(O)NR c″ R d″ , S(O) 2 R b″ , S(O) 2 NR c″ R d″ , —(C 1-6 alkyl)-CN, —(C 1-6 alkyl)-NO 2 , —(C 1-6 alkyl)-OR a″ , —(C 1-6 alkyl)-SR a″ , —(C 1-6 alkyl)-C(O)R b″ , —(C 1-6 alkyl)-C(O)NR c″ R d″ , —(C 1-6 alkyl)-C(O)OR a″ , —(C 1-6 alkyl)-OC(O)R b″ , —(C 1-6 alkyl)-OC(O)NR c″ R d″ , —(C 1-6 alkyl)-NR c″ R d″ , —(C 1-6 alkyl)-NR c″ C(O)R d″ , —(C 1-6 alkyl)-NR c″ C(O)OR a″ , —(C 1-6 alkyl)-S(O)R b″ , —(C 1-6 alkyl)-S(O)NR c″ R d″ , —(C 1-6 alkyl)-S(O) 2 R b″ , or —(C 1-6 alkyl)-S(O) 2 NR c″ R d″ ;
R 9 is C 1-4 alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, or 3 substituents selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a′ , SR a′ , C(O)R b′ , C(O)NR c′ R d′ , C(O)OR a′ , OC(O)R b′ , OC(O)NR c′ R d′ , NR c′ R d′ , NR c′ C(O)R d , NR c′ C(O)OR a′ , S(O)R b′ , S(O)NR c′ R d′ , S(O) 2 R b′ , and S(O) 2 NR c′ R d′ ;
R 12 and R 14 are each, independently, H or C 1-6 alkyl optionally substituted by 1, 2 or 3 substituents selected from OH, CN, NO 2 , amino, (C 1-4 alkyl)amino, (C 2-8 dialkyl)amino, C 1-6 haloalkyl, C 1-6 acyl, C 1-6 acyloxy, C 1-6 acylamino, —(C 1-6 alkyl)-CN, and —(C 1-6 alkyl)-NO 2 ;
R 13 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO 2 , OR a″ , SR a″ , C(O)R b″ , C(O)NR c″ R d″ , C(O)OR a″ , OC(O)R b″ , OC(O)NR c″ R d″ , NR c″ R d″ , NR c″ C(O)R d″ , NR c″ C(O)OR a″ , S(O)R b″ , S(O)NR c″ R d″ , S(O) 2 R b″ , S(O) 2 NR c″ R d″ , —(C 1-6 alkyl)-CN, —(C 1-6 alkyl)-NO 2 , —(C 1-6 alkyl)-OR a″ , —(C 1-6 alkyl)-SR a″ , —(C 1-6 alkyl)-C(O)R b″ , —(C 1-6 alkyl)-C(O)NR c″ R d″ , —(C 1-6 alkyl)-C(O)OR a″ , —(C 1-6 alkyl)-OC(O)R b″ , —(C 1-6 alkyl)-OC(O)NR c″ R d″ , —(C 1-6 alkyl)-NR c″ R d″ , —(C 1-6 alkyl)-NR c″ C(O)R d″ , —(C 1-6 alkyl)-NR c″ C(O)OR a″ , —(C 1-6 alkyl)-S(O)R b″ , —(C 1-6 alkyl)-S(O)NR c″ R d″ , —(C 1-6 alkyl)-S(O) 2 R b″ , or —(C 1-6 alkyl)-S(O) 2 NR c″ R d″ , wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from:
C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO 2 , OR a″ , SR a″ , C(O)R b″ , C(O)NR c″ R d″ , C(O)OR a″ , OC(O)R b″ , OC(O)NR c″ R d″ , NR c″ R d″ , NR c″ C(O)R d″ , NR c″ C(O)OR a″ , S(O)R b″ , S(O)NR c″ R d″ , S(O) 2 R b″ , S(O) 2 NR c″ R d″ , —(C 1-6 alkyl)-CN, —(C 1-6 alkyl)-NO 2 , —(C 1-6 alkyl)-OR a″ , —(C 1-6 alkyl)-SR a″ , —(C 1-6 alkyl)-C(O)R b″ , —(C 1-6 alkyl)-C(O)NR c″ R d″ , —(C 1-6 alkyl)-C(O)OR a″ , —(C 1-6 alkyl)-OC(O)R b″ , —(C 1-6 alkyl)-OC(O)NR c″ R d″ , —(C 1-6 alkyl)-NR c″ R d″ , —(C 1-6 alkyl)-NR c″ C(O)R d″ , —(C 1-6 alkyl)-NR c″ C(O)OR a″ , —(C 1-6 alkyl)-S(O)R b″ , —(C 1-6 alkyl)-S(O)NR c″ R d″ , —(C 1-6 alkyl)-S(O) 2 R b″ , and —(C 1-6 alkyl)-S(O) 2 NR c ″R d″ ;
R a , R a′ and R a″ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;
R b , R b′ and R b″ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;
R c and R d are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;
or R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
R c′ and R d′ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;
or R c′ and R d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; and
R c″ and R d″ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;
or R c″ and R d″ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group.
2. The method of claim 1 wherein said compound is a selective inhibitor of JAK2 over JAK1, JAK2, JAK3 and TYK2.
3. A method of treating a skin disorder in a patient comprising topically administering to said patient a therapeutically effective amount of a compound of Formula II:
or pharmaceutically acceptable salt form thereof, wherein:
A is N or CR 1 ;
R 1 , R 2 , and R 3 are each, independently, H, halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c R(O)R d , NR c R(O)OR a , S(O)R b , S(O)NR c R d , S(O) 2 R b , or S(O) 2 NR c R d ;
R 4 is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, S(O) 2 R 9 , SOR 9 , cycloalkyl, or heterocycloalkyl, wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cycloalkyl, heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c R(O)R d , NR c R(O)OR a , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ;
R 5 is 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -L-(3-8 membered cycloalkyl), -L-(3-8 membered heterocycloalkyl), each substituted by one R 6 and 0, 1 or 2 R 7 ;
L is C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, O, S, NR 14 , CO, COO, OCO, NR 14 C(O)O, CONR 14 , SO, SO 2 , SONR 14 , SO 2 NR 14 , or NR 14 CONR 14 ;
R 6 is —W 1 —W 2 —W 3 —W 4 —W 5 —W 6 —R 13 ;
W 1 is absent, C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted by 1, 2 or 3 halo, CN, NO 2 , OH, ═NH, ═NOH, ═NO—(C 1-4 alkyl), C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino or C 2-8 dialkylamino;
W 2 is absent, C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, O, S, NR 12 , CO, COO, OCO, C(S), C(S)NR 12 , —C(═N—CN)—, NR 12 C(O)O, CONR 12 , SO, SO 2 , SONR 12 , SO 2 NR 12 , or NR 12 CONR 12 , wherein said C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, are each optionally substituted by 1, 2 or 3 halo, OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino or C 2-8 dialkylamino;
W 3 is absent, C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, CN, NO 2 , OH, ═NH, ═NOH, ═NO—(C 1-4 alkyl), C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino or C 2-8 dialkylamino;
W 4 is absent, C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, O, S, NR 12 , CO, COO, OCO, —C(═N—CN)—, NR 12 C(O)O, CONR 12 , SO, SO 2 , SONR 12 , SO 2 NR 12 , or NR 12 CONR 12 , wherein said C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, are each optionally substituted by 1, 2 or 3 halo, CN, NO 2 , OH, ═NH, ═NOH, ═NO—(C 1-4 alkyl), C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino or C 2-8 dialkylamino;
W 5 is absent, C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, CN, NO 2 , OH, ═NH, ═NOH, ═NO—(C 1-4 alkyl), C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino or C 2-8 dialkylamino;
W 6 is absent, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, O, S, NR 12 , CO, COO, OCO, —C(═N—CN)—, NR 12 C(O)O, CONR 12 , SO, SO 2 , SONR 12 , SO 2 NR 12 , or NR 12 CONR 12 , wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl are each optionally substituted by 1, 2 or 3 CN, NO 2 , OH, ═NH, ═NOH, ═NO—(C 1-4 alkyl), C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino or C 2-8 dialkylamino;
R 7 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO 2 , OR a″ , SR a″ , C(O)R b″ , C(O)NR c″ R d″ , C(O)OR a″ , OC(O)R b″ , OC(O)NR c″ R d″ , NR c″ R d″ , NR c″ C(O)R d″ , NR c″ C(O)OR a″ , S(O)R b″ , S(O)NR c″ R d″ , S(O) 2 R b″ , S(O) 2 NR c″ R d″ , —(C 1-6 alkyl)-CN, —(C 1-6 alkyl)-NO 2 , —(C 1-6 alkyl)-OR a″ , —(C 1-6 alkyl)-SR a″ , —(C 1-6 alkyl)-C(O)R b″ , —(C 1-6 alkyl)-C(O)NR c″ R d″ , —(C 1-6 alkyl)-C(O)OR a″ , —(C 1-6 alkyl)-OC(O)R b″ , —(C 1-6 alkyl)-OC(O)NR c″ R d″ , —(C 1-6 alkyl)-NR c″ R d″ , —(C 1-6 alkyl)-NR c″ C(O)R d″ , —(C 1-6 alkyl)-NR c″ C(O)OR a″ , —(C 1-6 alkyl)-S(O)R b″ , —(C 1-6 alkyl)-S(O)NR c″ R d″ , —(C 1-6 alkyl)-S(O) 2 R b″ , or —(C 1-6 alkyl)-S(O) 2 NR c″ R d″ ;
R 9 is C 1-4 alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, or 3 substituents selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , OR a′ , SR a′ , C(O)R b′ , C(O)NR c′ R d′ , C(O)OR a′ , OC(O)R b′ , OC(O)NR c′ R d′ , NR c′ R d′ , NR c′ C(O)R d′ , NR c′ C(O)OR a′ , S(O)R b′ , S(O)NR c″ R d′ , S(O) 2 R b′ , and S(O) 2 NR c′ R d′ ;
R 12 and R 14 are each, independently, H or C 1-6 alkyl optionally substituted by 1, 2 or 3 substituents selected from OH, CN, NO 2 , amino, (C 1-4 alkyl)amino, (C 2-8 dialkyl)amino, C 1-6 haloalkyl, C 1-6 acyl, C 1-6 acyloxy, C 1-6 acylamino, —(C 1-6 alkyl)-CN, and —(C 1-6 alkyl)-NO 2 ;
R 13 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO 2 , OR a″ , SR a″ , C(O)R b″ , C(O)NR c″ R d″ , C(O)OR a″ , OC(O)R b″ , OC(O)NR c″ R d″ , NR c″ R d″ , NR c″ C(O)R d″ , NR c″ C(O)OR a″ , S(O)R b″ , S(O)NR c″ R d″ , S(O) 2 R b″ , S(O) 2 NR c″ R d″ , —(C 1-6 alkyl)-CN, —(C 1-6 alkyl)-NO 2 , —(C 1-6 alkyl)-OR a″ , —(C 1-6 alkyl)-SR a″ , —(C 1-6 alkyl)-C(O)R b″ , —(C 1-6 alkyl)-C(O)NR c″ R d″ , —(C 1-6 alkyl)-C(O)OR a″ , —(C 1-6 alkyl)-OC(O)R b″ , —(C 1-6 alkyl)-OC(O)NR c″ R d″ , —(C 1-6 alkyl)-NR c″ R d″ , —(C 1-6 alkyl)-NR c″ C(O)R d″ , —(C 1-6 alkyl)-NR c″ C(O)OR a″ , —(C 1-6 alkyl)-S(O)R b″ , —(C 1-6 alkyl)-S(O)NR c″ R d″ , —(C 1-6 alkyl)-S(O) 2 R b″ , or —(C 1-6 alkyl)-S(O) 2 NR c″ R d″ , wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from:
C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO 2 , OR a″ , SR a″ , C(O)R b″ , C(O)NR c″ R d″ , C(O)OR a″ , OC(O)R b″ , OC(O)NR c″ R d″ , NR c″ R d″ , NR c″ C(O)R d″ , NR c″ C(O)OR a″ , S(O)R b″ , S(O)NR c″ R d″ , S(O) 2 R b″ , S(O) 2 NR c″ R d″ , —(C 1-6 alkyl)-CN, —(C 1-6 alkyl)-NO 2 , —(C 1-6 alkyl)-OR a″ , —(C 1-6 alkyl)-SR a″ , —(C 1-6 alkyl)-C(O)R b″ , —(C 1-6 alkyl)-C(O)NR c″ R d″ , —(C 1-6 alkyl)-C(O)OR a″ , —(C 1-6 alkyl)-OC(O)R b″ , —(C 1-6 alkyl)-OC(O)NR c″ R d″ , —(C 1-6 alkyl)-NR c″ R d″ , —(C 1-6 alkyl)-NR c″ C(O)R d″ , —(C 1-6 alkyl)-NR c″ C(O)OR a″ , —(C 1-6 alkyl)-S(O)R b″ , —(C 1-6 alkyl)-S(O)NR c″ R d″ , —(C 1-6 alkyl)-S(O) 2 R b″ , and —(C 1-6 alkyl)-S(O) 2 NR c″ R d″ ;
R a , R a′ and R a″ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;
Rb, R b′ and R b″ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;
R c and R d are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;
or R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
R c′ and R d′ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;
or R c′ and R d″ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; and
R c″ and R d″ are each, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;
or R c″ and R d″ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group.
4. The method of claim 3 wherein said skin disorder is atopic dermatitis or psoriasis.
5. The method of claim 3 wherein said skin disorder is skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.
6. The method of claim 3 wherein said compound of Formula II is administered in the form of a transdermal patch, ointment, lotion, cream, or gel.
7. The method of claim 3 wherein A is CR 1 .
8. The method of claim 3 wherein A is N.
9. The method of claim 3 , wherein the disorder is an inflammatory skin disorder.