HETEROCYCLIC COMPOUNDS AND USES THEREOF
Heterocyclic compounds as Wee1 inhibitors are provided. The compounds may find use as therapeutic agents for the treatment of diseases and may find particular use in oncology.
1 . A compound of Formula (I):
or a salt thereof, wherein:
Y is hydrogen or R 4 ;
m is 0, 1, 2, or 3;
n is 0, 1, 2, 3, or 4;
R 1 is independently F, Cl, or methyl;
R 2 is independently C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or —(C 1 -C 3 alkylene)CF 3 ;
R 3 is
wherein:
ring C is a 5- or 6-membered heteroaryl or phenyl,
each R 3a is independently halogen, C 3 -C 6 cycloalkyl, or —(C 1 -C 6 alkylene)R′, wherein the C 1 -C 6 alkylene is optionally substituted by oxo and wherein R′ is hydrogen, —CN, —NR 19 R 20 , C 1 -C 6 alkoxy, or —OH,
q is 0, 1, 2, 3, or 4;
each R 4 is independently oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —C(O)R 7 , —C(O)OR 17 , —C(O)NR 17 R 18 , —CN, —Si(C 1 -C 6 alkyl) 3 , —OR 17 , —NR 17 R 18 , —OC(O)NR 17 R 18 , —NR 17 C(O)R 18 , —S(O) 2 R 17 , —NR 17 S(O) 2 R 18 , —S(O) 2 NR 17 R 18 , C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, —(C 1 -C 3 alkylene)CN, —(C 1 -C 3 alkylene)OR 17 , —(C 1 -C 3 alkylene)NR 17 R 18 , —(C 1 -C 3 alkylene)CF 3 , —(C 1 -C 3 alkylene)C(O)R 17 , —(C 1 -C 3 alkylene)C(O)NR 17 R 18 , —(C 1 -C 3 alkylene)NR 17 C(O)R 18 , —(C 1 -C 3 alkylene)S(O) 2 R 17 , —(C 1 -C 3 alkylene)NR 17 S(O) 2 R 8 , —(C 1 -C 3 alkylene)S(O) 2 NR 17 R 18 , —(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl) or —(C 1 -C 3 alkylene)(3- to 6-membered heterocyclyl), wherein each R 4 is independently optionally substituted by halogen, oxo, —OR 19 , —NR 19 R 20 , or —C(O)R 19 ,
or two R 4 , when bound to the same carbon, are taken together with the carbon to which they are attached to form a C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, each is optionally substituted by R 19 ; and
each R 17 , R 18 , R 19 , and R 20 is independently hydrogen, C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl or C 1 -C 6 alkyl, each of which is optionally substituted by halogen, oxo or —OH,
or R 17 and R 18 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or —OH.
2 . The compound of claim 1 , or a salt thereof, wherein the compound is of Formula (II):
3 . The compound of claim 1 , or a salt thereof, wherein the compound is of Formula (III):
4 . The compound of any one of claims 1 - 3 , or a salt thereof, wherein R 2 is C 1 -C 6 alkyl.
5 . The compound of claim 4 , or a salt thereof, wherein R 2 is isopropyl or ethyl.
6 . The compound of any one of claims 1 - 3 , or a salt thereof, wherein R 2 is C 3 -C 6 cycloalkyl.
7 . The compound of claim 6 , or a salt thereof, wherein R 2 is cyclopropyl.
8 . The compound of any one of claims 1 - 3 , or a salt thereof, wherein R 2 is —(C 1 -C 3 alkylene)CF 3 .
9 . The compound of claim 8 , or a salt thereof, wherein R 2 is —CH 2 CF 3 .
10 . The compound of any one of claims 1 - 9 , or a salt thereof, wherein ring C is selected from the group consisting of:
11 . The compound of any one of claims 1 - 10 , or a salt thereof, wherein R 3a is C 3 -C 6 cycloalkyl.
12 . The compound of any one of claims 1 - 10 , or a salt thereof, wherein R 3a is —(C 1 -C 6 alkylene)R′, wherein the C 1 -C 6 alkylene is optionally substituted by oxo and wherein R′ is hydrogen, —CN, —NR 19 R 20 , C 1 -C 6 alkoxy, or —OH.
13 . The compound of claim 12 , or a salt thereof, wherein R′ is hydrogen.
14 . The compound of claim 12 , or a salt thereof, wherein R′ is —CN.
15 . The compound of claim 12 , or a salt thereof, wherein R′ is —NR 19 R 20 .
16 . The compound of claim 12 , or a salt thereof, wherein R′ is C 1 -C 6 alkoxy.
17 . The compound of claim 12 , or a salt thereof, wherein R′ is —OH.
18 . The compound of any one of claims 1 - 10 , or a salt thereof, wherein R 3a is selected from the group consisting of:
fluoro, and cyclopropyl.
19 . The compound of any one of claims 1 - 18 , or a salt thereof, wherein q is 1.
20 . The compound of any one of claims 1 - 9 , or a salt thereof, wherein R 3 is selected from the group consisting of:
21 . The compound of any one of claims 1 - 20 , or a salt thereof, wherein m is 0.
22 . The compound of any one of claims 1 - 20 , or a salt thereof, wherein m is 1 and Rn is F.
23 . The compound of any one of claims 1 - 22 , or a salt thereof, wherein Y is hydrogen.
24 . The compound of any one of claims 1 - 23 , or a salt thereof, wherein Y is C 1 -C 6 alkyl.
25 . The compound of any one of claims 1 - 24 , or a salt thereof, wherein n is 0.
26 . The compound of any one of claims 1 - 24 , or a salt thereof, wherein n is 1.
27 . The compound of any one of claims 1 - 24 , or a salt thereof, wherein n is 2.
28 . The compound of any one of claims 1 - 27 , or a salt thereof, wherein each R 4 is independently C 1 -C 6 alkyl, or two R 4 , when bound to the same carbon are taken together with the carbon or carbons to which they are attached to form a C 3 -C 6 cycloalkyl.
29 . The compound of any one of claims 1 - 20 , or a salt thereof, wherein ring A, ring B, R 1 , and R 4 are taken together to form a moiety selected from the group consisting of:
30 . A compound or a salt thereof, wherein the compound is selected from the group consisting of compounds in Table 1.
31 . The compound of claim 30 , wherein the compound is a pharmaceutically acceptable salt of a compound in Table 1.
32 . A pharmaceutical composition comprising a compound of any one of claims 1 - 30 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
33 . A method of treating a cancer in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1 - 30 , or a salt thereof.
34 . The method of claim 33 , further comprising administering a radiation therapy to the individual.
35 . The method of claim 33 or 34 , further comprising administering to the individual a therapeutically effective amount of an additional therapeutic agent.
36 . The method of claim 35 , wherein the additional therapeutic agent is a cancer immunotherapy agent or a chemotherapeutic agent.
37 . The method of claim 35 or 36 , wherein the additional therapeutic agent is a DNA alkylating agent, a platinum-based chemotherapeutic agent, a kinase inhibitor or a DNA damage repair (DDR) pathway inhibitor.
38 . The method of any one of claims 33 - 37 , wherein the cancer comprises a mutant TP53 gene.
39 . The method of any one of claims 33 - 38 , comprising selecting the individual for treatment based on (i) the presence of one or more mutations in the TP53 gene in the cancer, or (ii) expression of mutant p53 in the cancer.
40 . A method of suppressing a G 2 -M checkpoint in a cell, comprising administering a compound of any one of claims 1 - 30 , or a salt thereof, to the cell.
41 . A method of inducing premature mitosis in a cell, comprising administering a compound of any one of claims 1 - 30 , or a salt thereof, to the cell.
42 . A method of inducing apoptosis in a cell, comprising administering a compound of any one of claims 1 - 30 , or a salt thereof, to the cell.
43 . A method of inhibiting Wee1 in a cell, comprising administering a compound of any one of claims 1 - 30 , or a salt thereof, to the cell.
44 . A method of inhibiting Wee1, comprising contacting Wee1 with a compound of any one of claims 1 - 30 , or a salt thereof.
45 . The method of claim 44 , wherein the inhibitor binds to Wee1 with an IC 50 of less than 1 μM according to a kinase assay.
46 . Use of a compound of any one of claims 1 - 30 , or a salt thereof, in the manufacture of a medicament for treatment of cancer.
47 . A kit comprising a compound of any one of claims 1 - 30 , or a salt thereof.