WDR5 inhibitors and modulators
Isoquinolmone compounds and derivatives inhibit WDR5 and associated protein-protein interactions, and the compounds and their pharmaceutical compositions are useful for treating disorders and conditions in a subject, such as cancer cell proliferation.
1 . A compound of formula (I-b)
or a pharmaceutically acceptable salt thereof, wherein:
G 1 is an optionally substituted 10-membered fused bicyclic ring system of formula
each represents a double bond;
X 12 is N;
X 13 is CR 10d ;
X 14 is CR 10e or N;
R 10a is hydrogen;
R 10b is hydrogen or C 1-4 alkyl;
R 10d is —C(O)N(R 1a ) 2 or -OR 1a ;
R 10e is hydrogen;
R 10f is C 1-4 alkyl or OC 1-4 alkyl;
R 1a , at each occurrence, is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 2-4 alkylene-OR 1e , —C 2-4 alkylene-N(R 1e ) 2 , -C 2-4 alkylene-N(R 1e )C(O)R 1e , G 1a , or -C 1-6 alkylene-G 1a ;
G 1a is C 3-8 cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl, wherein G 1a is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, oxo, -L 2 -X 2 , and -L 2 -G 1b ;
L 2 , at each occurrence, is independently a bond or C 1-3 alkylene;
X 2 , at each occurrence, is independently -OR 1c , -N(R 1c ) 2 , -SR 1c , cyano, —C(O)OR 1c , —C(O)N(R 1c ) 2 , —C(O)R 1c , -SOR 1d , —SO 2 R 1d , -SO 2 N(R 1c ) 2 , —NR 1c C(O)R 1c , —NR 1c C(O)OR 1c , —NR 1c C(O)N(R 1c ) 2 —NR 1c S(O) 2 R 1d , or —NR 1c S(O) 2 N(R 1c ) 2 ;
R 1c , at each occurrence, is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, G 1b , or -C 1-3 alkylene-G 1b , wherein alternatively two R 1c , together with a common nitrogen atom to which the R 1c attach form a 4- to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, oxo, —OH, and -OC 1-4 alkyl;
R 1d , at each occurrence, is independently C 1-6 alkyl, C 1-6 haloalkyl, G 1b , or —C 1-3 alkylene-G 1b ;
R 1e , at each occurrence, is independently hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, G 1b , or -C 1-3 alkylene-G 1b , wherein alternatively two R 1e , together with a common nitrogen atom to which the R 1e attach form a 4- to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, oxo, —OH, and -OC 1-4 alkyl;
G 1b is a C 3-6 cycloalkyl, a 4- to 6-membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N, and S, a 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, or a phenyl, wherein G 1b is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, oxo, —OH, and -OC 1-4 alkyl;
G 2 is a 5- to 12-membered heteroaryl, a C 3-10 carbocyclyl, a 6- to 12-membered aryl, or a 4- to 12-membered heterocyclyl, wherein G 2 is optionally substituted with 1-5 substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, halogen, oxo, —OR 4c , —N(R 4c ) 2 , —SR 4c , cyano, —C(O)OR 4c , —C(O)N(R 4c ) 2 , —C(O)R 4c , —SOR 4d , —SO 2 R 4d , —SO 2 N(R 4c ) 2 , —NR 4c C(O)R 4c , —NR 4c C(O)OR 4c , —NR 4c C(O)N(R 4c ) 2 , —NR 4c S(O) 2 R 4d , —NR 4c S(O) 2 N(R 4c ) 2 , C 3-8 cycloalkyl, and -C 1-3 alkylene-C 3-8 cycloalkyl, wherein each C 3-8 cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl and halogen;
R 4c , at each occurrence, is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, or -C 1-6 alkylene-C 3-8 cycloalkyl, wherein each C 3-8 cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl and halogen, wherein alternatively two R 4c , together with a common nitrogen atom to which the R 4c attach form a 4- to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, oxo, —OH, and -OC 1-4 alkyl;
R 4d , at each occurrence, are independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, or -C 1-6 alkylene-C 3-8 cycloalkyl, wherein each C 3-8 cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl and halogen;
R 5 and R 6 are each independently hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, or -OC 1-4 alkyl; and
R 8 is an imidazolyl unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, NO 2 , NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , C 3-8 cycloalkyl, and -C 1-3 alkylene-C 3-8 cycloalkyl, wherein each C 3-8 cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, OH, and -OC 1-4 alkyl.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 8 is
R 20a is hydrogen, C 1-4 alkyl, NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , or C 3-8 cycloalkyl; and
R 20b , R 20c , R 20d , R 20e , R 20f , R 20g , R 20h , and R 20i are each independently hydrogen, C 1-4 alkyl, or C 3-8 cycloalkyl.
3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 8 is
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 1 is
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 10d is
OCH 3 , OCF 3 ,
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G 2 is a 5- to 6-membered heteroaryl, and optionally substituted as defined in claim 1 .
7 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein G 2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
8 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein, G 2 is
9 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein, G 2 is
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.
11 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.
12 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13 . A method of treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is leukemia, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, gastric cancer, stomach cancer, lung cancer, cervical cancer, uterine cancer, or a cancer of the lymphatic system.
14 . A method of inhibiting cancer cell proliferation, comprising administering to a subject in need thereof, the compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is leukemia, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, gastric cancer, stomach cancer, lung cancer, cervical cancer, uterine B cancer, or a cancer of the lymphatic system.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 14 is N.
16 . The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 10b is hydrogen or methyl.
17 . The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 10f is ethyl or OCH 3 .
18 . The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein G 1 is
19 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein G 1 is
20 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
21 . A method of treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is a cancer of the blood.
22 . A method of inhibiting cancer cell proliferation, comprising administering to a subject in need thereof, the compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is a cancer of the blood.
23 . The method of claim 13 , wherein the compound is
24 . The method of claim 23 , wherein the cancer is leukemia.
25 . The method of claim 23 , wherein the cancer is a cancer of the lymphatic system.
26 . The method of claim 23 , wherein the cancer is breast cancer.
27 . The method of claim 23 , wherein the cancer is ovarian cancer.
28 . The method of claim 23 , wherein the cancer is bladder cancer.
29 . The method of claim 23 , wherein the cancer is pancreatic cancer.