IP Library › Granted Patent US 8,053,433

Granted Patent B2

US 8,053,433 · App. 11/980,314 · Granted Nov 8, 2011

Pyrrolo[2,3-b]pyridin-4-yl-amines and pyrrolo[2,3-b]pyrimidin-5-yl-amines as janus kinase inhibitors

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 8,053,433
App. No.: 11/980,314
Granted: Nov 8, 2011
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

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.

Claims (91)

1. A method of inhibiting an activity of JAK comprising contacting said JAK 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 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 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. A method of treating psoriasis in a patient, the method 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 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 ;

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 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.

3. The method of claim 2 wherein said compound of Formula II, or pharmaceutically acceptable salt form thereof, is administered in the form of a transdermal patch, ointment, lotion, cream, or gel.

4. The method of claim 2 wherein A is CR 1 .

5. The method of claim 2 wherein A is N.

6. A method of treating cancer in a patient, the method comprising administering to said patient a therapeutically effective amount of a compound of Formula I:

or pharmaceutically acceptable salt form thereof, wherein:

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 ;

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 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)OR 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: