Substituted heterocycles as janus kinase inhibitors

A compound of Formula I:

• or a pharmaceutically acceptable salt form thereof, wherein:
• Cya is selected from arylene, heteroarylene, cycloalkylene, and heterocycloalkylene, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-6alkyl, C2-6 alkenyl, C2-6alkynyl, Cy, C1-6haloalkyl, halosulfanyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(═NRi)NRc1Rd1, NRc1C(═NRi)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;
• wherein said C1-6alkyl, C2-6alkenyl, or C2-6alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Cy, C1-6haloalkyl, halosulfanyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(═NRi)NRc1Rd1, NRc1C(═NRi)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;
• Cyb is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Cy, C1-6haloalkyl, halosulfanyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(═NRi)NRc2Rd2, NRc2C(═NRi)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2;
• wherein said C1-6alkyl, C2-6alkenyl, or C2-6alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, Cy, C1-6haloalkyl, halosulfanyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(═NRi)NRc2Rd2, NRc2C(═NRi)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2;
• L is a divalent moiety selected from C1-6alkylene, C2-6alkenylene, C2-6alkynylene, (C1-6alkylene)p-(C3-10cycloalkylene)-(C1-6alkylene)q, (C1-6alkylene)p-(C3-10heterocycloalkylene)-(C1-6alkylene)q, (C1-6alkylene)p-(C6-10 arylene)-(C1-6alkylene)q, (C1-6alkylene)p-(C3-10 heteroarylene)-(C1-6alkylene)q, (C1-6alkylene)p-C(O)—(C1-6alkylene) (C1-6alkylene)p-S—(C1-6alkylene)q, (C1-6alkylene)p-NRc3—(C1-6alkylene)q, (C1-6alkylene)p-C(O)—(C1-6alkylene)q, (C1-6alkylene)p-OC(O)—(C1-6alkylene)q, (C1-6alkylene)p-C(O)NRc3—(C1-6alkylene)q, (C1-6alkylene)p-OC(O)NRc3—(C1-6alkylene)q, (C1-6alkylene)p-S(O)—(C1-6alkylene)q, (C1-6alkylene)p-S(O)2—(C1-6alkylene)q, (C1-6alkylene)p-S(O)NRc3—(C1-6alkylene)q, (C1-6alkylene)p-S(O)2NRc3—(C1-6alkylene)q, (C1-6alkylene)p-NRc3C(O)NRd3—(C1-6alkylene)q, (C1-6alkylene)p-NRc3S(O)NRd3—(C1-6alkylene)q, and (C1-6alkylene)p-NRc3S(O)2NRd3—(C1-6alkylene)q, wherein each of the C1-6alkylene, C2-6alkenylene, C2-6alkynylene, cycloalkylene, arylene, heterocycloalkylene, and heteroarylene is optionally substituted by 1, 2 or 3 substituents independently selected from C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4hydroxyalkyl, C1-4cyanoalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, CN, NO2, SCN, OH, C1-4haloalkyl, halosulfanyl, C1-4alkoxy-C1-4alkyl, C1-4alkoxy, C1-4 haloalkoxy, amino, C1-4alkylamino, and C2 dialkylamino;
• wherein L is oriented in either direction with respect to its attachment to Cya and Cyb;
• Y1 is selected from CR3 and N;
• Y2 is selected from CR4 and N;
• Y3 is selected from CR5 and N;
• provided that at least one of Y1 and Y2 is other than N;
• Z1 is selected from CR6 and N;
• Z2 is selected from CR7 and N;
• R1 is selected from H, C1-6alkyl, C(O)C1-6alkyl, and C(O)aryl;
• R2, R3, R4, R5, R6, and R7 are independently selected from H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, halosulfanyl, CN, NO2, ORa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(═NRi)NRc4Rd4, NRc4C(═NRi)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4;
• wherein said C1-6alkyl, C2-6alkenyl, or C2-6alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from CN, NO2, Cy1, Cy1—(C1-6alkyl)-, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, C(═NRi)NRc4Rd4, NRc4C(═NRi)NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4;
• Cy, Cy1, and Cy2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocyclo-alkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, halosulfanyl, CN, NO2, N3, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)NRc5Rd5, NRc5C(O)ORa5, C(═NRi)NRc5Rd5, NRc5C(═NRi)NRc5Rd5, P(Rf5)2, P(ORe5)2, P(O)Re5Rf5, P(O)ORe5ORf5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, NRc5S(O)2Rb5, and S(O)2NRc5Rd5, wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C1-6haloalkyl, halosulfanyl, CN, NO2, N3, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)NRc5Rd5, NRc5C(O)ORa5, C(═NRI)NRe5Rd5, NRc5C(═NRi)NRc5Rd5, P(Rf5)2, P(ORe5)2, P(O)Re5Rf5, P(O)ORe5ORf5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, NRc5S(O)2Rb5, and S(O)2NRc5Rd5;
• Ra1, Ra2, and Ra4 are independently selected from H, Cy2, —(C1-6alkyl)-Cy2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, and C(O)—C1-7 hydrocarbyl, wherein said C1-6alkyl, C2-6alkenyl, hydrocarbyl, or C2-6alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, C1-6alkoxy, CN, amino, alkylamino, dialkylamino, halo, C1-6alkyl, C1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
• Rb1, Rb2, and Rb4 are independently selected from H, Cy2, —(C1-6alkyl)-Cy2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, wherein said C1-6alkyl, C2-6alkenyl, or C2-6alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, C1-6alkoxy, CN, amino, alkylamino, dialkylamino, halo, C1-6alkyl, C1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
• Rc1, Rc2, and Rc4 are independently selected from H, Cy2, —(C1-6alkyl)-Cy2, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C2-6alkenyl, C2-6alkynyl, wherein said C1-6alkyl, C2-6alkenyl, or C2-6 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from OH, C1-6alkoxy, CN, amino, alkylamino, dialkylamino, halo, C1-6alkyl, C1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
• Rd1, Rd2, and Rd4 are independently selected from H, Cy2, —(C1-6alkyl)-Cy2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, wherein said C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from OH, C1-6alkoxy, CN, amino, alkylamino, dialkylamino, halo, C1-6alkyl, C1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
• or,
• one or more of Rc1 and Rd1, Rc2 and Rd2, and Rc4 and Rd4 together with the N atom to which they are attached, optionally form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, C1-6alkoxy, CN, amino, alkylamino, dialkylamino, halo, C1-6alkyl, C1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
• Rc3 and Rd3 are independently selected from H, Cy2, —(C1-6alkyl)-Cy2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, wherein said C1-6alkyl, C2-6alkenyl, or C2-6alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, C1-6alkoxy, CN, amino, alkylamino, dialkylamino, halo, C1-6alkyl, C1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
• Ra5 is H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy;
• Rb5 is H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein said C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy;
• Rc5 and Rd5 are independently selected from H, C1-10alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C1-10alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy;
• or
• Rc5 and Rd5 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, and C1-6haloalkoxy;
• Re5 is H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, (C1-6alkoxy)-C1-6alkyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclo-alkylalkyl;
• Rf5 is H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl;
• R1 is H, CN, NO2, C(O)NH2, or C1-6alkyl;
• p is 0 or 1;
• and
• q is 0 or 1;
• provided that when Cya is a piperazine ring, R2 is other than halo.