IP Library › Granted Patent US 9,315,501

Granted Patent B2

US 9,315,501 · App. 14/554,263 · Granted Apr 19, 2016

Bicyclic heterocycles as BET protein inhibitors

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Quick Facts

Patent No.: US 9,315,501
App. No.: 14/554,263
Granted: Apr 19, 2016
Kind: B2

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Abstract

The present invention relates to bicyclic heterocycles which are inhibitors of BET proteins such as BRD2, BRD3, BRD4, and BRD-t and are useful in the treatment of diseases such as cancer.

Claims (149)

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

represents a single or double bond;

Ring B is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, C 5 -cycloalkyl, C 6 -cycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 R B ;

L is absent, —(CR a R b ) p —, —(CR a R b ) n —O—(CR a R b ) m —, —(CR a R b ) n —S—(CR a R b ) m —, —(CR a R b ) n —S(═O)—(CR a R b ) m —, —(CR a R b ) n —S(═O) 2 —(CR a R b ) m —, —(CR a R b ) n —C(═O)—(CR a R b ) m —, —(CR a R b ) n —C(═O)O—(CR a R b ) m —, —(CR a R b ) n —OC(═O)—(CR a R b ) m —, —(CR a R b ) n —NR c —(CR a R b ) m —, —(CR a R b ) n —C(═O)NR c —(CR a R b ) m —, —(CR a R b ) n —NR c C(═O)—(CR a R b ) m —, or —(CR a R b ) n —NR c C(═O)NR d —(CR a R b ) m —;

A1 is CR 3 or N;

A2 is C or N;

A3 is C or N;

A4 is CR 4 or N;

wherein when one of A2 and A3 is N, then the other of A2 and A3 is C;

W is CR 5 ;

X is CR 6 or N;

Y is CR 7 or N;

Z is C 6-10 aryl, C 3-10 cycloalkyl, or 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 R Z ;

R 1 is H or C 1-4 alkyl;

R 2 is C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl;

R 3 and R 4 are each independently selected from H, halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R 5 is H, halo, C 1-6 alkyl, or C 1-6 haloalkyl;

R 6 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , or S(O) 2 NR c1 R d1 , wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-4 haloalkyl, 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 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , C(═NR c1 )R b1 , C(═NR c1 )NR c1 R d1 , NR c1 C(═NR c1 )NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ;

R 7 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , or S(O) 2 NR c2 R d2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-4 haloalkyl, 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 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(═NR c2 )R b2 , C(═NR c2 )NR c2 R d2 , NR c2 C(═NR c2 )NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;

each R B is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(═NR c3 )R b3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 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, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, —NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 ;

each R Z is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, 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 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , C(═NR e4 )R b4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 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 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 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, 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 e4 )NR c4 R d4 , NR c4 C(═NR e4 )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 , NR c4 S(O) 2 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 ;

each R a and R b is independently selected from H, halo, OH, methyl, and ethyl;

each R c and R d is independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, and cyclopropyl;

each R a1 , R b1 , R c1 , R d1 , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , R d3 , R a4 , R b4 , R c4 , and R d4 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl, C 3-10 cycloalky-C 1-6 alkyl, (5-10 membered heteroaryl)-C 1-6 alkyl, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl, C 3-10 cycloalky-C 1-6 alkyl, (5-10 membered heteroaryl)-C 1-6 alkyl, and (4-10 membered heterocycloalkyl)-C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, CN, 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 e5 )NR c5 R d5 , NR c5 C(═NR e5 )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 ;

or any R c1 and R d1 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, 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 e5 )NR c5 R d5 , NR c5 C(═NR e5 )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 , wherein said C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, 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 e5 )NR c5 R d5 , NR c5 C(═NR e5 )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 ;

or any R c2 and R d2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, 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 e5 )NR c5 R d5 , NR c5 C(═NR e5 )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 , wherein said C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, 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 e5 )NR c5 R d5 , NR c5 C(═NR e5 )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 ;

or any R c3 and R d3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, 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 e5 )NR c5 R d5 , NR c5 C(═NR e5 )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 , wherein said C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, 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 e5 )NR c5 R d5 , NR c5 C(═NR e5 )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 ;

or any R c4 and R d4 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, 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 e5 )NR c5 R d5 , NR c5 C(═NR e5 )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 , wherein said C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, 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 e5 )NR c5 R d5 , NR c5 C(═NR e5 )NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , and S(O) 2 NR c5 R d5 ; each R e1 , R e2 , R e3 , and R e4 is independently selected from H, C 1-4 alkyl, CN, OR a5 , SR b5 , S(O) 2 R b5 , C(O)R b5 , S(O) 2 NR c5 R d5 , and C(O)NR c5 R d5 ;

each R a5 , R b5 , R c5 , and R d5 is independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl, wherein said C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 haloalkyl, and C 1-4 haloalkoxy;

each R e5 is independently selected from H, C 1-4 alkyl, and CN;

n is 0, 1, or 2;

m is 0, 1, or 2; and

p is 1, 2, 3, or 4;

wherein any aforementioned heterocycloalkyl group, including the heterocycloalkyl group of Ring B, is optionally substituted by 1 or 2 oxo groups.

2. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

represents a single or double bond;

A1 is CR 3 or N;

A2 is C or N;

A3 is C or N;

A4 is CR 4 or N;

wherein when one of A2 and A3 is N, then the other of A2 and A3 is C;

W is CR 5 ;

X is CR 6 or N;

Y is CR 7 or N;

Z is C 6-10 aryl, C 3-10 cycloalkyl, or 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 R Z ;

R 1 is H or C 1-4 alkyl;

R 2 is C 1-4 alkyl, C 1-4 haloalkyl, or C 1-4 hydroxyalkyl;

R 3 and R 4 are each independently selected from H, halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R 5 is H, halo, C 1-6 alkyl, or C 1-6 haloalkyl;

each R B is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , C(═NR e3 )R b3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 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, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 ;

each R a and R b is independently selected from H, halo, OH, methyl, and ethyl;

each R c and R d is independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, and cyclopropyl;

each R e1 , R e2 , R e3 , and R e4 is independently selected from H, C 1-4 alkyl, CN, OR a5 , SR b5 , S(O) 2 R b5 , C(O)R b5 , S(O) 2 NR c5 R d5 , and C(O)NR c5 R d5 ;

each R e5 is independently selected from H, C 1-4 alkyl, and CN;

n is 0, 1, or 2;

m is 0, 1, or 2; and

p is 1, 2, 3, or 4;

wherein any aforementioned heterocycloalkyl group, including the heterocycloalkyl group of Ring B, is optionally substituted by 1 or 2 oxo groups.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-4 alkyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is CR 6 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is CR 7 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is N.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is —(CR a R b ) n —O—(CR a R b ) m —.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is O or CH 2 O.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is O.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is C 6-10 aryl, C 3-7 cycloalkyl, or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 R Z .

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is C 6-10 aryl or 5-10 membered heteroaryl, each of which is optionally substituted by 1, 2, 3, 4, or 5 R Z .

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is phenyl optionally substituted by 1, 2, 3, 4, or 5 R Z .

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is C 3-7 cycloalkyl optionally substituted by 1, 2, 3, 4, or 5 R Z .

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is cyclobutyl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R Z is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, 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 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , C(═NR e4 )R b4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 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 .

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R Z is independently selected from F, Cl, and Br.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A1 is CR 3 .

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A2 is C.

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A3 is C.

22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A4 is CR 4 .

23. The compound of claim 1 having Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

the 5-membered ring formed by A2, A3, B1, B2, and B3 is (1) 5-membered heteroaryl wherein B1, B2, and B3 are each independently selected from CH, N, NH, O, and S, (2) C 5 -cycloalkyl wherein B1, B2, and B3 are each independently selected from CH, CH 2 , and C(O), or (3) 5-membered heterocycloalkyl wherein B1, B2, and B3 are each independently selected from CH, CH 2 , C(O), N, NH, O, S, S(O), and S(O) 2 ; and

q is 0, 1, 2 or 3.

24. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein B1, B2, and B3 are each independently selected from CH, CH 2 , C(O), N, and NH.

25. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein B1 is N or NH.

26. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein B1 is NH.

27. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein B2 is N, CH, or C(O).

28. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein B3 is N or NH.

29. The compound of claim 23 having Formula IIa:

or a pharmaceutically acceptable salt thereof.

30. The compound of claim 23 having Formula IIb:

or a pharmaceutically acceptable salt thereof.

31. The compound of claim 23 having Formula IIc:

or a pharmaceutically acceptable salt thereof, wherein r is 0, 1, 2, 3, 4, or 5.

32. The compound of claim 23 having Formula IId, IIe, IIf, or IIg:

wherein:

r is 0, 1, 2, 3, 4, or 5; and

R 8 , R 9 , and R 10 are each independently selected from H, C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered hetero aryl, and 4-10 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 .

33. The compound of claim 32 , or a pharmaceutically acceptable salt thereof, wherein R 8 , R 9 , and R 10 are each independently selected from H, C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 .

34. The compound of claim 32 , or a pharmaceutically acceptable salt thereof, wherein r is 0, 1, 2, or 3.

35. The compound of claim 23 having Formula IIh:

or a pharmaceutically acceptable salt thereof.

36. The compound of claim 23 having Formula IIi or IIj:

or a pharmaceutically acceptable salt thereof, wherein:

R 8 , R 9 , and R 10 are each independently selected from H, C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered hetero aryl, and 4-10 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 .

37. The compound of claim 1 having Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

the 6-membered ring formed by A2, A3, B4, B5, B6, and B7 is (1) phenyl, (2) 6-membered heteroaryl wherein B4, B5, B6, and B7 are each independently selected from CH and N, (3) C 6 -cycloalkyl wherein B4, B5, B6, and B7 are each independently selected from CH, CH 2 , and C(O), or (4) 6-membered heterocycloalkyl wherein B4, B5, B6, and B7 are each independently selected from CH, CH 2 , C(O), N, NH, O, S, S(O), and S(O) 2 ; and

s is 0, 1, 2, 3, or 4.

38. The compound of claim 1 selected from:

5-(2,4-difluorophenoxy)-6-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one;

6-(2,4-difluorophenoxy)-1-methyl-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one;

4-[6-(2,4-difluorophenoxy)-1-methyl-1H-benzimidazol-5-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;

4-[6-(2,4-difluorophenoxy)-1,2-dimethyl-1H-benzimidazol-5-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;

4-[5-(2,4-difluorophenoxy)-1H-benzimidazol-6-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;

4-[5-(2,4-difluorophenoxy)-2-methyl-1H-benzimidazol-6-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; and

5-(2,4-difluorophenoxy)-1,3-dimethyl-6-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one;

4-(5-(2,4-difluorophenoxy)-1H-benzo[d][1,2,3]triazol-6-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one;

4-[6-(2,4-difluorophenoxy)-1H-benzimidazol-5-yl]-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one; and

4-[6-(2,4-difluorophenoxy)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one,

or a pharmaceutically acceptable salt of any of the aforementioned.

39. The compound of claim 1 selected from:

4-[5-(cyclobutylmethoxy)-1H-benzimidazol-6-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;

4-[5-(cyclobutylmethoxy)-1-ethyl-1H-benzimidazol-6-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;

4-[6-(cyclobutylmethoxy)-1-ethyl-1H-benzimidazol-5-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;

4-[5-(cyclobutylmethoxy)-1-methyl-1H-benzimidazol-6-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;

4-[6-(cyclobutylmethoxy)-1-methyl-1H-benzimidazol-5-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;

4-[5-(cyclobutylmethoxy)-1-benzyl-1H-benzimidazol-6-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;

4-[6-(cyclobutylmethoxy)-1-benzyl-1H-benzimidazol-5-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;

4-[5-(cyclobutylmethoxy)-1-isopropyl-1H-benzimidazol-6-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;

4-[6-(cyclobutylmethoxy)-1-isopropyl-1H-benzimidazol-5-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;

4-[5-(cyclobutylmethoxy)-2-piperidin-1-yl-1H-benzimidazol-6-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one;

4-[5-(cyclobutylmethoxy)-2-cyclopentyl-1H-benzimidazol-6-yl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one; and

ammonium 3-[5-(cyclobutylmethoxy)-6-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-1H-benzimidazol-2-yl]propanoate;

or a pharmaceutically acceptable salt of any of the aforementioned.

40. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

41. A method of inhibiting a BET protein comprising contacting a compound of claim 1 , or a pharmaceutically acceptable salt thereof, with said BET protein.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 10, 2021

From: INCYTE CORPORATION

To: INCYTE CORPORATION; INCYTE HOLDINGS CORPORATION

Reel/Frame 058815/0857 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 28, 2015

From: YUE, EDDY W.; COMBS, ANDREW P.; BUESKING, ANDREW W.

To: INCYTE CORPORATION

Reel/Frame 034831/0426 →