HETEROCYCLIC COMPOUNDS AND USES THEREOF
Heterocyclic compounds as Weel 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:
U is O or S;
W is A or AB, wherein A and B are fused together;
A is phenyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with R 17a , wherein A and R 17a together are
and n is 0, 1, 2, 3, or 4;
B is C 3 -C 6 cycloalkyl, 3- to 7-membered heterocyclyl, 5- to 7-membered heteroaryl, or C 6 aryl, each of which is optionally substituted with R 17b , wherein A, B, R 17a , and R 17b together are
and m and n are independently 0, 1, 2, 3, or 4;
X is hydrogen or C 1 -C 6 alkyl;
Y is N or CR 1 ;
Z is N or CR 2 ;
R 1 and R 2 are independently hydrogen or R 17a ;
R 3a and R 3b are independently hydrogen or R 17a , or R 3a and R 3b are taken together with the carbon to which they are attached to form a C 3 -C 6 cycloalkyl;
each R 17b is independently oxo or R 17a , or
any two R 17b groups, when bound to the same carbon atom or two different carbon atoms, are taken together with the carbon or carbons to which they are attached to form a C 3 -C 6 cycloalkyl or 3- to 7-membered heterocyclyl, each is optionally substituted by R 10 ;
each R 17a is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 10 , —SR 10 , —NR 11 R 12 , —C(O)R 10 , —C(O)OR 10 , —Si(C 1 -C 6 alkyl) 3 , —C(O)NR 11 R 12 , —OC(O)NR 11 R 12 , —NR 10 C(O)R 11 , —NR 10 C(O)NR 11 R 12 , —S(O) 2 R 10 , —NR 10 S(O) 2 R 11 , —S(O) 2 NR 11 R 12 , C 3 -C 6 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14 aryl, —(C 1 -C 3 alkylene)CN, —(C 1 -C 3 alkylene)OR 10 , —(C 1 -C 3 alkylene)SR 10 , —(C 1 -C 3 alkylene)NR 11 R 12 , —(C 1 -C 3 alkylene)CF 3 , —(C 1 -C 3 alkylene)C(O)R 10 , —(C 1 -C 3 alkylene)C(O)NR 11 R 12 , —(C 1 -C 3 alkylene)NR 10 C(O)R 11 , —(C 1 -C 3 alkylene)NR 10 C(O)NR 11 R 12 , —(C 1 -C 3 alkylene)S(O) 2 R 10 , —(C 1 -C 3 alkylene)NR 10 S(O) 2 R 11 , —(C 1 -C 3 alkylene)S(O) 2 NR 11 R 12 , —(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)(3- to 12-membered heterocyclyl), —(C 1 -C 3 alkylene)(5- to 10-membered heteroaryl) or —(C 1 -C 3 alkylene)(C 6 -C 14 aryl), wherein each R 17a is independently optionally substituted by halogen, oxo, —CN, —OR 13 , —NR 13 R 14 , —C(O)R 13 , —C(O)NR 13 R 14 , —NR 13 C(O)R 14 , —S(O) 2 R 13 , —NR 13 S(O) 2 R 14 , —S(O) 2 NR 13 R 14 , —(C 1 -C 3 alkylene)C(O)NR 13 R 14 , —(C 1 -C 3 alkylene)NR 13 C(O)R 14 , —(C 1 -C 3 alkylene)S(O) 2 R 13 , —(C 1 -C 3 alkylene)NR 13 S(O) 2 R 14 , —(C 1 -C 3 alkylene)S(O) 2 NR 13 R 14 , —(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)(3- to 12-membered heterocyclyl), —Si(C 1 -C 6 alkyl) 3 , —CN, —(C 1 -C 3 alkylene)OR 13 , —(C 1 -C 3 alkylene)NR 13 R 14 , —(C 1 -C 3 alkylene)C(O)R 13 , C 3 -C 8 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by oxo, —OH or halogen;
R 4 is 5- to 10-membered heteroaryl or phenyl, wherein the 5- to 10-membered heteroaryl and phenyl of R 4 are each independently optionally substituted by halogen, oxo, —OR 13 , —NR 13 R 14 , —C(O)NR 13 R 14 , —C(O)R 13 , —CN, C 3 -C 8 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by oxo, —CN, —OH or halogen;
R 10 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are independently optionally substituted by halogen, oxo, —CN, —OR 15 , —NR 15 R 16 , or C 1 -C 6 alkyl optionally substituted by halogen, —OH or oxo;
R 11 and R 12 are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of R 11 and R 12 are independently optionally substituted by halogen, oxo, —CN, —OR 15 , —NR 15 R 16 or C 1 -C 6 alkyl optionally substituted by halogen, —OH, or oxo,
or R 11 and R 12 are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo, or C 1 -C 6 alkyl optionally substituted by halogen;
R 13 and R 14 are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl of R 13 and R 14 are optionally substituted by halogen, —CN, —OR 15 , —NR 15 R 16 , or oxo,
or R 13 and R 14 are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6 alkyl optionally substituted by halogen or oxo; and
R 15 and R 16 are each independently hydrogen, C 1 -C 6 alkyl optionally substituted by halogen or oxo, C 2 -C 6 alkenyl optionally substituted by halogen or oxo, or C 2 -C 6 alkynyl optionally substituted by halogen or oxo,
or R 15 and R 16 are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6 alkyl optionally substituted by oxo or halogen.
2 . The compound of claim 1 , or a salt thereof, wherein Y is N.
3 . The compound of claim 1 or 2 , or a salt thereof, wherein Y is CR 1 and R 1 is hydrogen.
4 . The compound of any one of claims 1 - 3 , or a salt thereof, wherein Z is N.
5 . The compound of any one of claims 1 - 4 , or a salt thereof, wherein Z is CR 2 and R 2 is hydrogen.
6 . The compound of any one of claims 1 - 5 , or a salt thereof, wherein at least one of Y and Z is N.
7 . The compound of claim 1 , or a salt thereof, wherein the compound is of Formula (Ia-1):
8 . The compound of claim 1 , or a salt thereof, wherein the compound is of Formula (Ib-1):
9 . The compound of any one of claims 1 - 8 , or a salt thereof, wherein X is hydrogen.
10 . The compound of any one of claims 1 - 9 , or a salt thereof, wherein R 3a and R 3b are independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, —CN, —OR 10 , —SR 10 , —NR 11 R 12 , —C(O)R 10 , or —C(O)NR 11 R 12 ; or R 3a and R 3b are taken together with the carbon to which they are attached to form a C 3 -C 6 cycloalkyl.
11 . The compound of any one of claims 1 - 10 , or a salt thereof, wherein R 3a and R 3b are independently hydrogen or C 1 -C 6 alkyl; or R 3a and R 3b are taken together with the carbon to which they are attached to form a C 3 -C 6 cycloalkyl.
12 . The compound of any one of claims 1 - 11 , or a salt thereof, wherein R 3a and R 3b are both hydrogen.
13 . The compound of any one of claims 1 - 12 , or a salt thereof, wherein R 4 is phenyl optionally substituted by halogen, —OR 13 , —NR 13 R 14 , —C(O)NR 13 R 14 , —C(O)R 13 , —CN, C 3 -C 8 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by oxo, —CN, —OH or halogen.
14 . The compound of any one of claims 1 - 13 , or a salt thereof, wherein R 4 is
15 . The compound of any one of claims 1 - 14 , or a salt thereof, wherein
W is AB wherein A and B are fused together;
A is phenyl or 6-membered heteroaryl, each of which is optionally substituted with R 17a , wherein A and R 17a together are
and n is 0, 1, 2, 3, or 4;
B is C 3 -C 6 cycloalkyl, 3- to 7-membered heterocyclyl, 5- to 7-membered heteroaryl, or C 6 aryl, each of which is optionally substituted with R 17b , wherein A, B, R 17a , and R 17b together are
and m and n are independently 0, 1, 2, 3, or 4.
16 . The compound of claim 15 , or a salt thereof, wherein A, B, R 17a and R 17b together are
17 . The compound of claim 15 or 16 , or a salt thereof, wherein B is 3- to 7-membered heterocyclyl;
each R 17a is independently —(C 1 -C 3 alkylene)OR 10 , C 1 -C 6 alkyl optionally substituted by halogen, —C(O)NR 11 R 12 , —(C 1 -C 3 alkylene)NR 11 R 12 , —CN, halogen, —NR 11 R 12 , C 3 -C 6 cycloalkyl, or —OR 10 ;
each R 17b is independently oxo, —(C 1 -C 3 alkylene)OR 10 , C 1 -C 6 alkyl optionally substituted by halogen, —C(O)NR 11 R 12 , —(C 1 -C 3 alkylene)NR 11 R 12 , —CN, halogen, —NR 11 R 12 , C 3 -C 6 cycloalkyl, or —OR 10 , or
any two groups R 17b , when bound to the same carbon atom, are taken together with the carbon to which they are attached to form a C 3 -C 6 cycloalkyl;
and m and n are independently 0, 1, 2, or 3.
18 . The compound of any one of claims 15 - 17 , or a salt thereof, wherein m is 0.
19 . The compound of any one of claims 15 - 17 , or a salt thereof, wherein m is 1.
20 . The compound of any one of claims 15 - 19 , or a salt thereof, wherein n is 0.
21 . The compound of any one of claims 15 - 19 , or a salt thereof, wherein n is 1.
22 . The compound of any one of claims 15 - 19 , or a salt thereof, wherein n is 2.
23 . The compound of any one of claims 1 - 14 , or a salt thereof, wherein W is selected from the group consisting of:
wherein the wavy lines denote attachment points to the parent molecule.
24 . The compound of any one of claims 1 - 14 , or a salt thereof, wherein W is A, A is phenyl or 5- or 6-membered heteroaryl, each of which is optionally substituted with R 17a , wherein A and R 17a together are
and n is 0, 1, 2, 3, or 4.
25 . The compound of claim 24 , wherein W is selected from the group consisting of:
wherein the wavy lines denote attachment points to the parent molecule.
26 . A compound selected from the group consisting of the compounds in Table 1, or a salt thereof.
27 . The compound of claim 26 , wherein the compound is a pharmaceutically acceptable salt of a compound in Table 1.
28 . A pharmaceutical composition comprising a compound of any one of claims 1 - 26 , or a salt thereof, and a pharmaceutically acceptable carrier.
29 . 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 - 26 , or a salt thereof.
30 . The method of claim 29 , further comprising administering a radiation therapy to the individual.
31 . The method of claim 29 or 30 , further comprising administering to the individual a therapeutically effective amount of an additional therapeutic agent.
32 . The method of claim 31 , wherein the additional therapeutic agent is a cancer immunotherapy agent or a chemotherapeutic agent.
33 . The method of claim 31 or 32 , 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.
34 . The method of any one of claims 29 - 33 , wherein the cancer comprises a mutant TP53 gene.
35 . The method of any one of claims 29 - 34 , 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.
36 . A method of suppressing a G 2 -M checkpoint in a cell, comprising administering a compound of any one of claims 1 - 26 , or a salt thereof, to the cell.
37 . A method of inducing premature mitosis in a cell, comprising administering a compound of any one of claims 1 - 26 , or a salt thereof, to the cell.
38 . A method of inducing apoptosis in a cell, comprising administering a compound of any one of claims 1 - 26 , or a salt thereof, to the cell.
39 . A method of inhibiting Wee1 in a cell, comprising administering a compound of any one of claims 1 - 26 , or a salt thereof, to the cell.
40 . A method of inhibiting Wee1, comprising contacting Wee1 with a compound of any one of claims 1 - 26 , or a salt thereof.
41 . The method of claim 40 , wherein the inhibitor binds to Wee1 with an IC 50 of less than 1 μM according to a kinase assay.
42 . Use of a compound of any one of claims 1 - 26 , or a salt thereof, in the manufacture of a medicament for treatment of cancer.
43 . A kit comprising a compound of any one of claims 1 - 26 , or a salt thereof.