ALK-5 Inhibitors and Uses Thereof
Provided herein are compounds (e.g., compounds of Formulae (I), (II), (III) and (IV), compounds listed in Table 1) and pharmaceutically acceptable salts thereof, pharmaceutical compositions of either of the foregoing, and kits comprising the same. The compounds provided herein are activin receptor-like kinase (e.g., ALK-5) inhibitors and are useful for treating and/or preventing diseases (e.g., proliferative diseases, e.g., cancer) in a subject, for inhibiting tumor growth in a subject, and/or for inhibiting the activity of an activin receptor-like kinase (e.g., ALK-5) in vitro or in vivo.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a C 1 -C 5 alkyl, C 3 -C 5 carbocycle, or halogen;
R 2 is —H, a halogen, a C 1 -C 3 alkyl optionally substituted with one or more —F, or a cyclopropyl optionally substituted with one or more —F;
R 3 is —H, a halogen, a C 1 -C 3 alkyl optionally substituted with one or more —F, or a cyclopropyl optionally substituted with one or more —F; and
Ring G is
wherein
indicates the point of attachment of Ring G to the —N(H)—; or
Ring G is a C 6 -C 10 aryl optionally substituted with:
(i) one or more halogens;
(ii) a sulfonamide;
(iii) a monocyclic, bicyclic or spirocyclic C 3 -C 10 carbocycle which is optionally substituted with one or more C 1 -C 6 alkyl or C 3 -C 6 carbocycle which are optionally substituted with hydroxy or one or more halogen, wherein said carbocycle is attached to Ring G by a single bond or a methylene or ethylene linker at a position on Ring G which is meta- or para- to the —N(H)— attached to Ring G; or
(iv) a monocyclic, bicyclic, bridged or spirocyclic C 3 -C 10 heterocycle which may contain up to 3 heteroatoms independently selected from N and O and which is optionally and independently substituted with one or more C 1 -C 6 alkyl or C 3 -C 6 carbocycle which are optionally substituted with hydroxy or one or more halogen, wherein said heterocycle is attached to Ring G by a single bond or a methylene or ethylene linker at a position on Ring G which is meta- or para- to the —N(H)— attached to Ring G.
2 . The compound of claim 1 , wherein R 1 is a C 1 -C 5 alkyl or C 3 -C 5 carbocycle.
3 . The compound of claim 1 , wherein R 1 is a halogen.
4 . The compound of claim 1 , wherein R 1 is methyl, cyclopropyl or chloro.
5 . The compound of any one of claims 1-4 , wherein R 2 is —H, a halogen, —CH 3 , —CF 3 or cyclopropyl.
6 . The compound of claim 5 , wherein R 2 is —H.
7 . The compound of any one of claims 1-6 , wherein R 3 is —H, a halogen, —CH 3 , —CF 3 or cyclopropyl.
8 . The compound of claim 7 , wherein R 3 is —H.
9 . The compound of any one of claims 1-8 , wherein Ring G is
10 . The compound of any one of claims 1-8 , wherein Ring G is a C 6 -C 10 aryl substituted with:
(i) one or more halogens;
(ii) a sulfonamide;
(iii) a monocyclic, bicyclic or spirocyclic C 3 -C 10 carbocycle which is optionally substituted with one or more C 1 -C 6 alkyl or C 3 -C 6 carbocycle which are optionally substituted with hydroxy or one or more halogen, wherein said carbocycle is attached to Ring G by a single bond or a methylene or ethylene linker at a position on Ring G which is meta- or para- to the —N(H)— attached to Ring G; or
(iv) a monocyclic, bicyclic, bridged or spirocyclic C 3 -C 10 heterocycle which may contain up to 3 heteroatoms independently selected from N and O and which is optionally and independently substituted with one or more C 1 -C 6 alkyl or C 3 -C 6 carbocycle which are optionally substituted with hydroxy or one or more halogen, wherein said heterocycle is attached to Ring G by a single bond or a methylene or ethylene linker at a position on Ring G which is meta- or para- to the —N(H)— attached to Ring G.
11 . The compound of claim 10 , wherein Ring G is substituted with:
i) one or more halogens;
ii) a sulfonamide;
iii) a monocyclic, bicyclic or spirocyclic C 3 -C 10 carbocycle which is optionally substituted with one or more C 1 -C 6 alkyl or C 3 -C 6 carbocycle which are optionally substituted with hydroxy or one or more halogen, wherein said carbocycle is attached to Ring G by a single bond or a methylene or ethylene linker at a position on Ring G which is meta- or para- to the —N(H)— attached to Ring G;
iv) a monocyclic C 3 -C 7 carbocycle which is optionally substituted with one or more C 1 -C 6 alkyl or C 3 -C 6 carbocycle which are optionally substituted with hydroxy or one or more halogen; or
v) a cyclohexyl which is optionally substituted with one or more C 1 -C 6 alkyl or C 3 -C 6 carbocycle which are optionally substituted with hydroxy or one or more halogen.
12 . The compound of claim 10 or 11 , wherein the carbocycle that is attached to Ring G is unsubstituted.
13 . The compound of claim 10 , wherein Ring G is substituted with a monocyclic, bicyclic, bridged or spirocyclic C 3 -C 10 heterocycle which may contain up to 3 heteroatoms independently selected from N and O and which is optionally and independently substituted with one or more C 1 -C 6 alkyl or C 3 -C 6 carbocycle which are optionally substituted with hydroxy or one or more halogen, wherein said heterocycle is attached to Ring G by a single bond or a methylene or ethylene linker at a position on Ring G which is meta- or para- to the —N(H)— attached to Ring G.
14 . The compound of claim 13 , wherein Ring G is substituted with a monocyclic C 5 -C 6 heterocycle which may contain up to 3 heteroatoms independently selected from N and O and which is optionally and independently substituted with one or more C 1 -C 6 alkyl or C 3 -C 6 carbocycle which are optionally substituted with hydroxy or one or more halogen.
15 . The compound of claim 14 , wherein Ring G is substituted with a piperazinyl, morpholinyl, piperidinyl or oxanyl, which is optionally and independently substituted with one or more C 1 -C 6 alkyl or C 3 -C 6 carbocycle which are optionally substituted with hydroxy or one or more halogen.
16 . The compound of any one of claims 13-15 , wherein the heterocycle that is attached to Ring G is unsubstituted or monosubstituted.
17 . The compound of claim 16 , wherein the heterocycle that is attached to Ring G is unsubstituted.
18 . The compound of any one of claims 10-17 , wherein the carbocycle or heterocycle that is attached to Ring G is optionally and independently substituted with methyl, CF 3 CH 2 — or HOCH 2 CH 2 —.
19 . The compound of any one of claims 10-18 , wherein the carbocycle or heterocycle attached to Ring G is attached to Ring G at a position on Ring G which is meta- to the —N(H)— attached to Ring G.
20 . The compound of any one of claims 10-18 , wherein the carbocycle or heterocycle attached to Ring G is attached to Ring G at a position on Ring G which is para- to the —N(H)— attached to Ring G.
21 . The compound of any one of claims 1-20 , wherein the C 6 -C 10 aryl of Ring G is phenyl.
22 . The compound of any one of claims 1-4 , having the following structure:
or a pharmaceutically acceptable salt thereof.
23 . The compound of any one of claims 1-4 , having the following structure:
or a pharmaceutically acceptable salt thereof, wherein:
Ring J is attached to the phenylene at a position which is meta- or para- to the —N(H)— attached to the phenylene;
A 1 is —N(R 4 )—, —O— or >C(H)(R 4 );
R 4 is —H, or a C 1 -C 6 alkyl or C 3 -C 6 carbocycle, each of which is optionally substituted with hydroxy or one or more halogen;
A 2 is >N— or >C(H)—;
Z is >CH 2 ; and X and Y are independently >CH 2 or >C(CH 3 ) 2 , or X and Y are both >CH— and are bonded together through a methylene or ethylene bridge; or
Y is >CH 2 or >C(CH 3 ) 2 , and X and Z are both >CH— and are bonded together through a methylene or ethylene bridge; and
n is 0, 1 or 2.
24 . The compound of claim 23 , wherein A 1 is >C(H)(R 4 ).
25 . The compound of claim 23 , wherein A 1 is —N(R 4 )— or —O—.
26 . The compound of any one of claims 23-25 , wherein R 4 is —H, or a C 1 -C 6 alkyl, which is optionally substituted with hydroxy or one or more halogen.
27 . The compound of claim 26 , wherein R 4 is —H, methyl, hydroxyethyl or trifluoroethyl.
28 . The compound of any one of claims 23-27 , wherein A 2 is >C(H)—.
29 . The compound of any one of claims 23-28 , wherein A 2 is >N—.
30 . The compound of claim 23 , wherein Ring J is:
31 . The compound of any one of claims 23-30 , wherein Ring J is attached to the phenylene at a position which is meta- to the —N(H)— attached to the phenylene.
32 . The compound of any one of claims 23-31 , wherein n is 0 or 1.
33 . The compound of claim 32 , wherein n is 0.
34 . The compound of any one of claims 1-4, 23-29 and 31 , having the following structure:
or a pharmaceutically acceptable salt thereof.
35 . The compound of claim 34 , wherein Ring J is:
36 . A compound, or a pharmaceutically acceptable salt thereof, having the structure:
37 . The compound of claim 36 , wherein the compound is of the following formula:
or a pharmaceutically acceptable salt thereof.
38 . The compound of claim 36 , wherein the compound is of the following formula:
or a pharmaceutically acceptable salt thereof.
39 . The compound of claim 36 , wherein the compound is of the following formula:
or a pharmaceutically acceptable salt thereof.
40 . The compound of claim 36 , wherein the compound is of the following formula:
or a pharmaceutically acceptable salt thereof.
41 . The compound of claim 36 , wherein the compound is of the following formula:
or a pharmaceutically acceptable salt thereof.
42 . The compound of claim 36 , wherein the compound is of the following formula:
or a pharmaceutically acceptable salt thereof.
43 . The compound of claim 36 , wherein the compound is of the following formula:
or a pharmaceutically acceptable salt thereof.
44 . The compound of claim 36 , wherein the compound is of the following formula:
or a pharmaceutically acceptable salt thereof.
45 . A pharmaceutical composition comprising a compound of any one of claims 1-44 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
46 . A pharmaceutical combination comprising a compound of any one of claims 1-44 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 45 , and one or more additional therapeutic agents.
47 . A method of treating a proliferative disease in a subject, the method comprising administering to the subject a compound of any one of claims 1-44 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 45 .
48 . The method of claim 47 , wherein the proliferative disease is cancer.
49 . The method of claim 48 , wherein the cancer is a hematological cancer.
50 . The method of claim 48 , wherein the cancer comprises a solid tumor.
51 . The method of claim 48 , wherein the cancer is lung cancer, brain cancer, thyroid cancer, anaplastic astrocytoma, liver cancer, pancreatic cancer, skin cancer, melanoma, metastatic melanoma, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, ovarian cancer, an HPV-associated cancer, multiple myeloma, myelodysplastic syndrome, a hematological cancer, or myelofibrosis.
52 . The method of claim 48 , wherein the cancer is non-small cell lung cancer (NSCLC), neuroblastoma, glioblastoma, anaplastic thyroid cancer (ATC), colon carcinoma, hepatocellular carcinoma (HCC), pancreatic carcinoma, anaplastic large cell lymphoma (ALCL), myelodysplastic syndrome, anaplastic astrocytoma or pancreatic ductal adenocarcinoma.
53 . The method of claim 48 , wherein the cancer is an adult granulosa cell tumor.
54 . The method of claim 48 , wherein the cancer is an HPV-associated cancer selected from cervical cancer, oropharyngeal cancer, anal cancer, vulvar/vaginal cancer, or penile cancer.
55 . The method of claim 47 , wherein the proliferative disease is a fibrotic condition.
56 . The method of claim 55 , wherein the fibrotic condition is idiopathic pulmonary fibrosis, cardiac fibrosis, a condition associated with cardiac fibrosis, valvular disease, arrhythmia, atrial fibrillation, myocardial remodeling, cardiomyopathy, dilated cardiomyopathy, ischemic cardiomyopathy, hypertrophic cardiomyopathy, restenosis, liver fibrosis, liver cirrhosis, nonalcoholic steatohepatitis, Peyronie's, Dupuytren's contracture, cystic fibrosis, beta thalassemia, actinic keratosis, hypertension, a general inflammatory disorder, dry eye, ulcer, corneal fibrosis, wet age-related macular degeneration, psoriasis, wound closure, chronic kidney disease, renal fibrosis, systemic sclerosis, or chronic Chagas' heart disease.
57 . A method of inhibiting tumor growth in a subject, the method comprising administering to the subject a compound of any one of claims 1-44 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 45 .
58 . A method of inhibiting ALK-5 activity in vivo or in vitro, the method comprising contacting ALK-5 with a compound of any one of claims 1-44 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 45 .
59 . A method of treating an inflammatory disease, disorder, or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-44 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 45 .
60 . The method of claim 59 , wherein the inflammatory disease, disorder, or condition is non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cholangitis (PBC), primary sclerosing cholangitis, autoimmune hepatitis, skin inflammation, or psoriasis.
61 . The method of claim 59 or 60 , wherein the inflammatory disease, disorder, or condition is an autoimmune disease, disorder, or condition.
62 . The method of claim 61 , wherein the autoimmune disease, disorder, or condition is osteoarthritis, rheumatoid arthritis, pain, inflammatory bowel disease, a respiratory disorder, or a skin disorder.
63 . A method of treating a fibrotic, inflammatory or proliferative disease or condition which is susceptible to inhibition of the TGFβ signaling pathway, the method comprising administering to a subject suffering from the fibrotic, inflammatory or proliferative disease or condition a compound of any one of claims 1-44 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 45 , in an amount effective to inhibit TGFβ signaling.
64 . The method of any one of claims 47-57 and 59-63 , wherein the subject is a human.
65 . The method of any one of claims 47-57 and 59-64 , wherein the proliferative disease, inflammatory disease, disorder or condition, tumor, cancer, or fibrotic, inflammatory or proliferative disease or condition expresses or has mutant forkhead box L2 (FOXL2) or FOXL2.
66 . The method of any one of claims 47-57 and 59-65 , further comprising administering one or more additional therapeutic agents to the subject selected from an anti-cancer agent and an immune checkpoint inhibitor.
67 . The method of any one of claims 47-57 and 59-66 , further comprising treating the subject with radiation therapy or surgery.
68 . A method of inhibiting epithelial to mesenchymal transition (EMT) in a subject suffering from a disease or condition which is promoted by EMT, comprising administering at least one compound of any one of claims 1-44 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 45 to the subject in an amount effective to sufficiently inhibit EMT to alter the course of the disease or condition.
69 . A method for enhancing the activity of one or more therapeutic agents for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1-44 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 45 .
70 . The method of claim 69 , further comprising administering to the subject one or more therapeutic agents selected from an anti-cancer agent or an immune checkpoint inhibitor.
71 . The method of claim 66, 67 or 70 , wherein the immune checkpoint inhibitor is a PD-1 or PD-L1 inhibitor.