Substituted heterocycles as janus kinase inhibitors

1. A compound of Formula IIC:

or a pharmaceutically acceptable salt form thereof, wherein:

R is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(═NR i )NR c1 R d1 , NR c1 C(═NR i )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(═NR i )NR c1 R d1 , NR c1 C(═NR i )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ;

Q 1 , Q 2 , and Q 3 are independently selected from CR Q and N;

R Q is independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(═NR i )NR c1 R d1 , NR c1 C(═NR i )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(═NR i )NR c1 R d1 , NR c1 C(═NR i )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ;

Cy b is a substituted aryl or substituted heteroaryl ring according to Formula IF:

wherein:

W 1 and W 2 are independently selected from CR W and N;

A 1 and A 2 are independently selected from CR W and N; or the group A 1 =A 2 is S, O, or NH; and

each R W is independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(═NR i )NR c2 R d2 , NR c2 C(═NR i )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(═NR i )NR c2 R d2 , NR c2 C(═NR i )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;

L is a divalent moiety selected from C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, (C 1-6 alkylene) p -(C 3-10 cycloalkylene)-(C 1-6 alkylene) q , (C 1-6 alkylene) p -(C 3-10 heterocycloalkylene)-(C 1-6 alkylene) q , (C 1-6 alkylene) p -(C 6-10 arylene)-(C 1-6 alkylene) q , (C 1-6 alkylene) p -(C 3-10 heteroarylene)-(C 1-6 alkylene) q , (C 1-6 alkylene) p -O-(C 1-6 alkylene) q , (C 1-6 alkylene) p -S-(C 1-6 alkylene) q , (C 1-6 alkylene) p -NR c3 —(C 1-6 alkylene) q , (C 1-6 alkylene) p -C(O)—(C 1-6 alkylene) q , (C 1-6 alkylene) p -OC(O)—(C 1-6 alkylene) q , (C 1-6 alkylene) p -C(O)NR c3 —(C 1-6 alkylene) q , (C 1-6 alkylene) p -OC(O)NR c3 —(C 1-6 alkylene) q , (C 1-6 alkylene) p -S(O)—(C 1-6 alkylene) q , (C 1-6 alkylene) p -S(O) 2 —(C 1-6 alkylene) q , (C 1-6 alkylene) p -S(O)NR c3 —(C 1-6 alkylene) q , (C 1-6 alkylene) p -S(O) 2 NR c3 —(C 1-6 alkylene) q , (C 1-6 alkylene) p -NR c3 C(O)NR d3 —(C 1-6 alkylene) q , (C 1-6 alkylene) p -NR c3 S(O)NR d3 —(C 1-6 alkylene) q , and (C 1-6 alkylene) p -NR c3 S(O) 2 NR d3 —(C 1-6 alkylene) q , wherein each of the C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, cycloalkylene, arylene, heterocycloalkylene, and heteroarylene is optionally substituted by 1, 2 or 3 substituents independently selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, CN, NO 2 , SCN, OH, C 1-4 haloalkyl, halosulfanyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, and C 2-8 dialkylamino;

wherein L is oriented in either direction with respect to its attachment to Cy b and the ring containing Q 1 , Q 2 , and Q 3 ;

Z 1 is CR 6 ;

Z 2 is CR 7 ;

R 1 is selected from H, C 1-6 alkyl, C(O)C 1-6 alkyl, and C(O)aryl;

R 2 , R 3 , R 4 , and R 5 are independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy 1 , C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , C(═NR i )NR c4 R d4 , NR c4 C(═NR i )NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O) 2 R b4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , and S(O) 2 NR c4 R d4 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from CN, NO 2 , Cy 1 , Cy 1 -(C 1-6 alkyl)-, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , C(═NR i )NR c4 R d4 , NR c4 C(═NR i )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , and S(O) 2 NR c4 R d4 ;

R 6 is H;

R 7 is H;

Cy, Cy 1 , and Cy 2 are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR i )NR c5 R d5 , NR c5 C(═NR i )NR c5 R d5 , P(R f5 ) 2 , P(OR e5 ) 2 , P(O)R e5 R f5 , P(O)OR e5 OR f5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , and S(O) 2 NR c5 R d5 , wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)NR c5 R d5 , NR c5 C(O)OR a5 , C(═NR i )NR c5 R d5 , NR c5 C(═NR i )NR c5 R d5 , P(R f5 ) 2 , P(OR e5 ) 2 , P(O)R e5 R f5 , P(O)OR e5 OR f5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , and S(O) 2 NR c5 R d5 ;

R a1 , R a2 , and R a4 are independently selected from H, Cy 2 , —(C 1-6 alkyl)-Cy 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C(O)—C 1-7 hydrocarbyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 1-7 hydrocarbyl, or C 2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, C 1-6 alkoxy, CN, amino, alkylamino, dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;

R b1 , R b2 , and R b4 are independently selected from H, Cy 2 , —(C 1-6 alkyl)-Cy 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, C 1-6 alkoxy, CN, amino, alkylamino, dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;

R c1 , R c2 , and R c4 are independently selected from H, Cy 2 , —(C 1-6 alkyl)-Cy 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from OH, C 1-6 alkoxy, CN, amino, alkylamino, dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;

R d1 , R d2 , and R d4 are independently selected from H, Cy 2 , —(C 1-6 alkyl)-Cy 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from OH, C 1-6 alkoxy, CN, amino, alkylamino, dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or,

one or more of R c1 and R d1 , R c2 and R d2 , and R c4 and R d4 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, C 1-6 alkoxy, CN, amino, alkylamino, dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;

R c3 and R d3 are independently selected from H, Cy 2 , —(C 1-6 alkyl)-Cy 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, C 1-6 alkoxy, CN, amino, alkylamino, dialkylamino, halo, C 1-6 alkyl, C 1-6 haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;

R a5 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 halo alkoxy;

R b5 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

R c5 and R d5 are independently selected from H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; or

R c5 and R d5 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, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

R e5 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, (C 1-6 alkoxy)-C 1-6 alkyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocycloalkylalkyl;

R f5 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl;

R i is H, CN, NO 2 , C(O)NH 2 , or C 1-6 alkyl;

p is 0 or 1; and

q is 0 or 1.

2. A compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R 1 is H, C 1-6 alkyl, or C(O)C 1-6 alkyl.

3. A compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R is selected from H, halo, CN, C 1-6 alkyl and OR a1 .

4. A compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Q 3 is CR Q .

5. A compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Q 3 is N.

6. A compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Cy b is a substituted aryl according to Formula IG:

wherein each R W is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(═NR i )NR c2 R d2 , NR c2 C(═NR i )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Cy, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(═NR i )NR c2 R d2 , NR c2 C(═NR i )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 .

7. A compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein L is C(O)NH.

8. A composition comprising a compound according to claim 1 , or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

9. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is 4-methyl-3-(9H-pyrido[2,3-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide.

10. A method of treating myeloproliferative disorder in a patient, the method comprising, administering to said patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 , wherein said myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD).

12. A method of treating acute lymphoblastic leukemia (ALL), chronic myelomonocytic leukemia (CMML), or chronic myeloid leukemia (CML), in a patient, the method comprising, administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

13. A method of treating Type I diabetes in a patient, the method comprising, administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

14. A method of treating psoriasis in a patient, the method comprising, administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.