US2023062022A1PendingUtilityA1
Heterocyclic compounds as kinase inhibitors
Est. expiryFeb 15, 2038(~11.6 yrs left)· nominal 20-yr term from priority
Inventors:Son Minh PhamSarvajit ChakravartyJayakanth KankanalaBrahmam PujalaAmit SheteBhawana BhattAnil Kumar AgarwalSanjeev SoniJiyun Chen
A61P 35/00A61K 31/538C07D 413/14C07D 417/14C07D 413/04C07D 471/04
60
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Claims
Abstract
Heterocyclic compounds as CDK4 or CDK6 or other CDK inhibitors are provided. The compounds may find use as therapeutic agents for the treatment of diseases and may find particular use in oncology.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula (J):
or a salt thereof, wherein:
Z is
wherein
A is C 3 -C 6 cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 7-membered heteroaryl, or C 6 aryl, each of which is optionally substituted with R 5 ;
L is a bond, —CR 11 R 12 —, —O—, —S—, —SO 2 —, —C(O)—, —NR 10 —, —SO 2 NR 10 —, or —NR 10 SO 2 —;
B is hydrogen, 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 6 ;
C is C 3 -C 6 cycloalkyl, 5- to 7-membered heterocyclyl, 5- to 7-membered heteroaryl, or C 6 aryl, each of which is optionally substituted with R 5 , wherein C is fused to D; and
D 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 6 ;
each X and Y are independently N or CH, provided that at least one of X and Y is N;
R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy, 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)(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)(3- to 12-membered heterocyclyl), —C(O)R 10 -(C 3 alkylene)(5- to 10-membered heteroaryl) or —(C 1 -C 3 alkylene)(C 6 -C 14 aryl), wherein R 1 is independently optionally substituted by halogen, oxo, —OR 13 , —NR 13 R 14 , —C(O)R 13 , —CN, C 3 -C 8 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by oxo, —OH or halogen, provided that when Z is
n is 1 and R 2 is oxo, then R 1 is C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy, 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)(C 3 -C 6 cycloalkyl), —C(O)R 10 , or —(C 1 -C 3 alkylene)(C 6 -C 14 aryl), wherein Ri is independently optionally substituted by halogen, oxo, —OR 13 , —C(O)R 13 , —CN, C 3 -C 8 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by oxo, —OH or halogen;
each R 2 is independently C 1 -C 6 alkyl, oxo, —NR 11 R 12 , —CN, —C(O)R 10 , —C(O)NR 11 R 12 or halogen, wherein any two R 2 groups are independently attached to same carbon or two different carbons;
each of R 3 and R 4 is independently C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halogen or —OH;
each R 5 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, oxo, —CN, —OR 10 , —SR 10 , —NR 11 R 12 , —C(O)R 10 , —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)R 10 , —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, —(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)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)NR 10 S(O) 2 NR 11 R 12 , —(C 1 -C 3 alkylene)S(O) 2 NR 11 R 12 , —(C1-C 3 alkylene)(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)(3- to 12-membered heterocyclyl), wherein each R 5 is independently optionally substituted by halogen, oxo, —OR 13 , —NR 13 R 14 , —C(O)R 13 , —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;
each R 6 is independently oxo or R 7 , or any two R 6 groups, 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;
R 7 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, —OR 10 , —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(O)R 10 , —C(O)NR 11 R 12 , (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), or —(C 1 -C 3 alkylene)(3- to 6-membered heterocyclyl), wherein each R 7 is independently optionally substituted by halogen, oxo, —OR 13 , —NR 13 R 14 , —C(O)R 13 , —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 10 is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), C 6 -C 14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, each of which is 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 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), C 6 -C 14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, each of which is 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 or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl of R 13 and R 14 are optionally substituted by halogen, —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;
1, m, p and q are each independently 0, 1,2 or 3, provided that at least one of m and 1 is not 0;
n is 0, 1, 2, 3 or 4.
2 . The compound of claim 1 , or a salt thereof, wherein the compound is of Formula (I):
3 . The compound of claim 1 , or a salt thereof, wherein the compound is of Formula (I-A):
4 . The compound of claim 1 , or a salt thereof, wherein the compound is of any one of Formula (I-B1) to (I-B12):
5 . The compound of claim 1 , or a salt thereof, wherein L is a bond, —CH 2 —, —NH—, —O—, —S—, —SO 2 —, —CO—, —NCH 3 —, —SO 2 NH—, or —HSO 2 —.
6 . The compound of claim 1 , or a salt thereof, wherein L is a bond.
7 . The compound of claim 1 , or a salt thereof, wherein L is —O—.
8 . The compound of claim 1 , or a salt thereof, wherein L is —NH—.
9 . The compound of claim 1 , or a salt thereof, wherein L is —S—.
10 . The compound of claim 1 , or a salt thereof, wherein L is —CH 2 —.
11 . The compound of claim 1 , or a salt thereof, wherein L is —SO 2 —.
12 . The compound of claim 1 , or a salt thereof, wherein L is —CO—.
13 . The compound of claim 1 , or a salt thereof, wherein L is —NCH 3 —.
14 . The compound of claim 1 , or a salt thereof, wherein L is —SO 2 NH—.
15 . The compound of claim 1 , or a salt thereof, wherein L is —NHSO 2 —.
16 . The compound of claim 1 , or a salt thereof, wherein A is phenyl, pyridine, pyrimidine, pyrazolyl, thiazolyl, oxazolyl, isooxazolyl, imidazolyl, piperidinyl, pyrrolidinyl, azetidinyl, pyridone, cyclohexyl, or cyclopentyl, each of which is optionally substituted with R 5 .
17 . The compound of claim 1 , or a salt thereof, wherein B is hydrogen, diazepanyl, azepanyl, piperazinyl, piperidinyl, pyrrolidinyl, azetidinyl, imidazolyl, pyrazolyl, phenyl, cyclopentyl, cyclohexyl, cyclohepy or cycloheptanyl, each of which is optionally substituted with R 6 .
18 . The compound of claim 1 , or a salt thereof, wherein the compound is of any one of Formula (I-C1) to (I-C23):
wherein t and t′ are each independently 0, 1,2, or 3.
19 . The compound of claim 18 , or a salt thereof, wherein t is 0 or 1.
20 . The compound of claim 1 , or a salt thereof, wherein t′ is 0 or 1.
21 . The compound of claim 1 , or a salt thereof, wherein the compound is of Formula (II):
22 . The compound of claim 1 , or a salt thereof, wherein C is fused with D to form a 7-12 membered bicyclic ring having at least one aromatic ring, wherein C and D are optionally substituted with R 5 and R 6 .
23 . The compound of claim 1 , or a salt thereof, wherein C is fused with D to form a 7-12 membered bicyclic ring having at least one aromatic ring and at least one nitrogen atom, wherein C and D are optionally substituted with R 5 and R 6 .
24 . The compound of claim 1 , or a salt thereof, wherein C is fused with D to form a ring selected from the group consisting of:
25 . The compound of claim 1 , or a salt thereof, wherein p is 0 or 1.
26 . The compound of claim 1 , or a salt thereof, wherein each R 5 is independently C 1 -C 6 alkyl, halogen, oxo, —CN, —OR 10 , —NR 11 R 12 , —C(O)R 10 , —C(O)NR 11 R 12 , C 3 -C 6 cycloalkyl, 3- to 12-membered heterocyclyl, —(C 1 -C 3 alkylene)OR 10 , —(C 1 -C 3 alkylene)NR 11 R 12 , —(C 1 -C 3 alkylene)C(O)R 10 , —(C 1 -C 3 alkylene)(C 3 -C 6 cycloalkyl), or —(C 1 -C 3 alkylene)(3- to 12-membered heterocyclyl), each of which is optionally substituted by halogen, oxo, —OR 13 , —NR 13 R 14 , —C(O)R 13 , —CN, —(C 1 -C 3 alkylene)OR 13 , —(C 1 -C 3 alkylene)NR 13 R 14 , —(C 1 -C 3 alkylene)C(OR 13 , C 3 -C 8 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by oxo, —OH or halogen.
27 . The compound of claim 1 , or a salt thereof, wherein each R 5 is independently —CN, halogen, methoxy, oxo, trifluoromethoxy, —NH(CH 3 ), —N(CH 3 ) 2 , —(CH 2 )NH(CH 3 ), —(CH 2 )NH 2 , —(CH 2 )N(CH 3 ) 2 , —C(O)NH 2 , —C(O)N(CH 3 ) 2 , methyl, ethyl, isopropyl, n-propyl, cyclopropyl, —CH 2 OH, —CH 2 OCH 3 , —NH(CH 2 ) 2 N(CH 2 CH 3 ) 2 , —O(CH 2 ) 2 N(CH 2 CH 3 ) 2 , trifluoromethyl,
28 . The compound of claim 1 , or a salt thereof, wherein q is 0 or 1.
29 . The compound of claim 1 , or a salt thereof, wherein each R 6 is independently C 1 -C 6 alkyl, halogen, oxo, —CN, —NR 11 R 12 , —C(O)R 10 , C 3 -C 6 cycloalkyl, 3- to 12-membered heterocyclyl, —(C 1 -C 3 alkylene)OR 10 , —(C 1 -C 3 alkylene)NR 11 R 12 , each of which is optionally substituted by halogen, oxo, —OR 13 , —NR 13 R 14 , —C(O)R 13 , —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; or two R 6 groups 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.
30 . The compound of claim 1 , or a salt thereof, wherein each R 6 is independently ethyl, methyl, isopropyl, pyrrolidinyl, cyclopropyl, methoxy, —N(CH 3 ) 2 , —NHCH 3 , —CH 2 OH, oxo, —C(O)CH 2 NHCH 3 , —CH 2 CH 2 OH, difluoroethyl, —CH 2 N(CH 3 ) 2 , —CH 2 NH 2 , —OH, —C(O)CH 2 OH, —C(O)CH 2 N(CH 3 ) 2 , —C(O)N(CH 3 ) 2 , —C(O)NHCH 3 , —C(O)NH 2 , —NHC(O)CH 3 , —C(O)CH 3 , —S(O) 2 CH 3 ,
31 . The compound of claim 1 , or a salt thereof, wherein R 7 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or —C(O)R 10 , each of which is optionally substituted by halogen, oxo, —OR 13 , —NR 13 R 14 , —C(O)R 13 , —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.
32 . The compound of claim 1 , or a salt thereof, wherein R 7 is hydrogen, methyl, ethyl, isopropyl, cycloproyl, —C(O)CH 2 NHCH 3 , or —CH 2 CH 2 OH.
33 . The compound of claim 1 , or a salt thereof, wherein Xis N and Y is N.
34 . The compound of claim 1 , or a salt thereof, wherein X is N and Y is CH; or X is CH and Y is N.
35 . The compound of claim 1 , or a salt thereof, wherein R 1 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C 6 -C 14 aryl, —C(O)R 10 , —(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), each of which is optionally substituted with halogen, oxo, —NH 2 .
36 . The compound of claim 1 , or a salt thereof, wherein R 1 is selected from the group consisting of:
37 . The compound of claim 1 , or a salt thereof, wherein R 1 is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, or cyclopropyl-methyl.
38 . The compound of claim 1 , or a salt thereof, wherein R 1 is isopropyl.
39 . The compound of claim 1 , or a salt thereof, wherein n is 0, 1,2, or 3.
40 . The compound of claim 1 , or a salt thereof, wherein each R 2 is independently C 1 -C 6 alkyl, oxo, —NR 11 R 12 , —CN, or halogen.
41 . The compound of claim 1 , or a salt thereof, wherein each R 2 is independently methyl, oxo, or fluoro.
42 . The compound of claim 1 , or a salt thereof, wherein m is 0 or 1.
43 . The compound of claim 1 , or a salt thereof, wherein each R 3 is independently C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or halogen.
44 . The compound of claim 1 , or a salt thereof, wherein each R 3 is independently fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, methoxy, or cyclopropyl.
45 . The compound of claim 1 , or a salt thereof, wherein each R 4 is independently C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or halogen.
46 . The compound of claim 1 , or a salt thereof, wherein each R 4 is independently fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, methoxy, or cyclopropyl.
47 . The compound of claim 1 , or a salt thereof, wherein l is 0 or 1.
48 . A compound or a salt thereof, wherein the compound is selected from the group consisting of compounds of Table 1.
49 . The compound of claim 48 , or a pharmaceutically acceptable salt thereof.
50 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
51 . 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 claim 1 , or a pharmaceutically acceptable salt thereof.
52 . The method of claim 51 , where the cancer is a breast cancer, brain cancer, colorectal cancer, lung cancer, gastric cancer, liver cancer, leukemia, lymphoma, mantle cell lymphoma, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, adult hematopoietic or solid tumor, or pediatric tumor.
53 . The method of claim 51 , further comprising administering a radiation therapy to the individual.
54 . The method of claim 51 , further comprising administering to the individual a therapeutically effective amount of a second therapeutic agent.
55 . The method of claim 54 , wherein the second therapeutic agent is a cancer immunotherapy agent, an endocrine therapy agent, or a chemotherapeutic agent.
56 . The method of claim 54 , wherein the second therapeutic agent is a cancer immunotherapy.
57 . The method of claim 54 , wherein the second therapeutic agent is an anti-PD-1 antibody.
58 . The method of claim 55 , wherein the endocrine therapy agent is an antiestrogen therapy, a selective estrogen receptor degrader (SERD), or an aromatase inhibitor.
59 . The method of claim 55 , wherein the chemotherapeutic agent is a DNA alkylating agent, a platinum-based chemotherapeutic agent, a taxane, a BTK inhibitor, a PI3K inhibitor, another kinase inhibitor, or a DNA damage repair (DDR) pathway inhibitor.
60 . The method of claim 51 , wherein the cancer comprises a mutated or overexpressed CDK gene.
61 . The method of claim 51 , comprising selecting the individual for treatment based on (i) the presence of one or more mutations or amplifications of the CDK4 or CDK6 or other CDK gene in the cancer, (ii) overexpression of CDK4 or CDK6 or other CDK protein in the cancer, (iii) amplification or overexpression of the genes encoding cyclins, (iv) loss of endogenous INK4 inhibitors by gene deletion, mutation, or promoter hypermethylation, (v) other genetic events leading to overactivity of CDK4 or CDK6 or other CDK, or (vi) phosphorylation of retinoblastoma (Rb) protein in the cancer.
62 . A method of arresting the G 1 -S checkpoint in a cell, comprising administering a compound of claim 1 , or a salt thereof, to the cell.
63 . A method of inducing senescence in a cell, comprising administering a compound of claim 1 , or a salt thereof, to the cell.
64 . A method of inducing apoptosis in a cell, comprising administering a compound of claim 1 , or a salt thereof, to the cell.
65 . A method of inhibiting CDK4 or CDK6 in a cell, comprising administering a compound of claim 1 , or a salt thereof, to the cell.
66 . A method of inhibiting CDK4 or CDK6, comprising contacting CDK4 or CDK6 with a compound of claim 1 , or a salt thereof.
67 . The method of claim 66 , wherein the inhibitor binds to CDK4 or CDK6 with an IC 50 of less than 1 μM according to a kinase assay.
68 . Use of a compound of claim 1 , or a salt thereof, in the manufacture of a medicament for treatment of cancer.
69 . A kit comprising a compound of claim 1 , or a salt thereof.Cited by (0)
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