PYRROLO[2,3-b]PYRIDIN-4-YL-AMINES AND PYRROLO[2,3-b]PYRIMIDIN-5-YL-AMINES AS JANUS KINASE INHIBITORS

摘要

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.

主权项

1. A compound of Formula I:or pharmaceutically acceptable salt form or prodrug thereof, wherein:
R1, R2, and R3 are each, independently, H, halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd; R4 is H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, S(O)2R9, SOR9, cycloalkyl, or heterocycloalkyl, wherein said C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd; R5 is 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -L-(3-8 membered cycloalkyl), -L-(3-8 membered heterocycloalkyl), each substituted by one R6 and 0, 1 or 2 R7; L is C1-4 alkylenyl, C2-4 alkenylenyl, C2-4 alkynylenyl, O, S, NR14, CO, COO, OCO, NR14C(O)O, CONR14, SO, SO2, SONR14, SO2NR14, or NR14CONR14; R6 is —W1—W2—W3—W4—W5—W6—R13; W1 is absent, C1-4 alkylenyl, C2-4 alkenylenyl, C2-4 alkynylenyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted by 1, 2 or 3 halo, CN, NO2, OH, ═NH, ═NOH, ═NO—(C1-4 alkyl), C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino; W2 is absent, C1-4 alkylenyl, C2-4 alkenylenyl, C2-4 alkynylenyl, O, S, NR12, CO, COO, OCO, C(S), C(S)NR12, —C(═N—CN)—, NR12C(O)O, CONR12, SO, SO2, SONR12, SO2NR12, or NR12CONR12, wherein said C1-4 alkylenyl, C2-4 alkenylenyl, C2-4 alkynylenyl, are each optionally substituted by 1, 2 or 3 halo, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino; W3 is absent, C1-4 alkylenyl, C2-4 alkenylenyl, C2-4 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C1-4 alkylenyl, C2-4 alkenylenyl, C2-4 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, CN, NO2, OH, ═NH, ═NOH, ═NO—(C1-4 alkyl), C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino; W4 is absent, C1-4 alkylenyl, C2-4 alkenylenyl, C2-4 alkynylenyl, O, S, NR12, CO, COO, OCO, —C(═N—CN)—, NR12C(O)O, CONR12, SO, SO2, SONR12, SO2NR12, or NR12CONR12, wherein said C1-4 alkylenyl, C2-4 alkenylenyl, C2-4 alkynylenyl, are each optionally substituted by 1, 2 or 3 halo, CN, NO2, OH, ═NH, ═NOH, ═NO—(C1-4 alkyl), C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino; W5 is absent, C1-4 alkylenyl, C2-4 alkenylenyl, C2-4 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C1-4 alkylenyl, C2-4 alkenylenyl, C2-4 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, CN, NO2, OH, ═NH, ═NOH, ═NO—(C1-4 alkyl), C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino; W6 is absent, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, O, S, NR12, CO, COO, OCO, —C(═N—CN)—, NR12C(O)O, CONR12, SO, SO2, SONR12, SO2NR12, or NR12CONR12, wherein said C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl are each optionally substituted by 1, 2 or 3 CN, NO2, OH, ═NH, ═NOH, ═NO—(C1-4 alkyl), C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino; R7 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO2, ORa, SRa″, C(O)Rb″, C(O)NRc″Rd″, C(O)ORa″, OC(O)Rb″, OC(O)NRc″Rd″, NRc″Rd″, NRc″C(O)Rd″, NRc″C(O)ORa″, S(O)Rb″, S(O)NRc″Rd″, S(O)2Rb″, S(O)2NRc∴Rd″, —(C1-6 alkyl)-CN, —(C1-6 alkyl)-NO2, —(C1-6 alkyl)-ORa″, —(C1-6 alkyl)-SRa″, —(C1-6 alkyl)-C(O)Rb″, —(C1-6 alkyl)-C(O)NRc″Rd″, —(C1-6 alkyl)-C(O)ORa″, —(C1-6 alkyl)-OC(O)Rb″, —(C1-6 alkyl)-OC(O)NRc″Rd″, —(C1-6 alkyl)-NRc″Rd″, —(C1-6 alkyl)-NRc″C(O)Rd″, —(C1-6 alkyl)-NRc″C(O)ORa″, —(C1-6 alkyl)-S(O)Rb″, —(C1-6 alkyl)-S(O)NRc″Rd″, —(C1-6 alkyl)-S(O)2Rb″, or —(C1-6 alkyl)-S(O)2NRc″Rd″; R9 is C1-4 alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, or 3 substituents selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa′, SRa′, C(O)Rb′, C(O)NRc′Rd′, C(O)ORa′, OC(O)Rb′, OC(O)NRc′Rd′, NRc′Rd′, NRc′C(O)Rd′, NRc′C(O)ORa′, S(O)Rb′, S(O)NRc′Rd′, S(O)2Rb′, and S(O)2NRc′Rd′; R12 and R14 are each, independently, H or C1-6 alkyl optionally substituted by 1, 2 or 3 substituents selected from OH, CN, NO2, amino, (C1-4 alkyl)amino, (C2-8 dialkyl)amino, C1-6 haloalkyl, C1-6 acyl, C1-6 acyloxy, C1-6 acylamino, —(C1-6 alkyl)-CN, and —(C1-6 alkyl)-NO2; R13 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, CN, NO2, ORa″, SRa″, C(O)Rb″, C(O)NRc″Rd″, C(O)ORa″, OC(O)Rb″, OC(O)NRc″Rd″, NRc″Rd″, NRc″C(O)Rd, NRc″C(O)ORa″, S(O)Rb″, S(O)NRc″Rd″, S(O)2Rb″, S(O)2NRc″Rd″, —(C1-6 alkyl)-CN, —(C1-6 alkyl)-NO2, —(C1-6 alkyl)-0Ra″, —(C1-6 alkyl)-SRa″, —(C1-6 alkyl)-C(O)Rb″, —(C1-6 alkyl)-C(O)NRc″Rd″, —(C1-6 alkyl)-C(O)ORa″, —(C1-6 alkyl)-OC(O)Rb″, —(C1-6 alkyl)-OC(O)NRc″Rd″, —(C1-6 alkyl)-NRc″Rd″, —(C1-6 alkyl)-NRc″C(O)Rd″, —(C1-6 alkyl)-NRc″C(O)ORa″, —(C1-6 alkyl)-S(O)Rb″, —(C1-6 alkyl)-S(O)NRc″Rd″, —(C1-6 alkyl)-S(O)2Rb″, or —(C1-6 alkyl)-S(O)2NRc″Rd″, wherein each of said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from: C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO2, ORa″, SRa″, C(O)Rb″, C(O)NRc″Rd″, C(O)ORa″, oC(O)Rb″, OC(O)NRc″Rd″, NRc″Rd″, NRc″C(O)Rd″, NRc″C(O)ORa″, S(O)Rb″, S(O)NRc″Rd″, S(O)2Rb″, S(O)2NRc″Rd″, —(C1-6 alkyl)-CN, —(C1-6 alkyl)-NO2, —(C1-6 alkyl)-oRa″, —(C1-6 alkyl)-SRa″, (C1-6 alkyl)-C(O)Rb″, —(C1-6 alkyl)-C(O)NRc″Rd″, —(C1-6 alkyl)-C(O)ORa″, —(C1-6 alkyl)-OC(O)Rb″, —(C1-6 alkyl)-OC(O)NRc″Rd″, —(C1-6 alkyl)-NRc″Rd″, —(C1-6 alkyl)-NRc″C(O)Rd″, —(C1-6 alkyl)-NRc″C(O)ORa″, —(C1-6 alkyl)-S(O)Rb″, —(C1-6 alkyl)-S(O)NRc″Rd″, —(C1-6 alkyl)-S(O)2Rb″, and —(C1-6 alkyl)-S(O)2NRc″Rd″; Ra, Ra′and Ra″ are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; Rb, Rb′ and Rb″ are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; Rc and Rd are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; Rc′ and Rd′ are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or Rc′and Rd′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; and Rc″ and Rd″ are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl; or Rc″ and Rd″ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group.