US2023210847A1PendingUtilityA1
Substituted Alkynylene Compounds As Anticancer Agents
Est. expiryJan 17, 2038(~11.5 yrs left)· nominal 20-yr term from priority
C07B 2200/07C07C 2601/14A61P 35/02A61P 35/00C07D 261/04C07C 237/30C07C 237/24C07D 207/16C07D 211/62C07D 401/04C07D 209/52C07D 211/72C07C 275/26C07C 311/11C07D 205/04C07D 333/28C07D 211/58C07D 231/56C07D 295/215A61K 31/4468A61K 31/495A61K 31/496A61K 31/439C07D 471/08A61K 31/454A61K 45/06A61K 31/17C07D 295/28C07D 403/04C07D 303/36C07D 413/04
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Claims
Abstract
The present invention relates to substituted alkynylene compounds represented by the compounds of formula (I), pharmaceutically acceptable salts and stereoisomers thereof. The present invention further provides the therapeutic uses of the compounds of formula (I) as anti-cancer agents.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound of formula (I)
or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,
A represents aryl or heteroaryl;
X represents N—R y or absent;
Y represents O, S or NCN;
B represents aryl, cycloalkyl or heterocycloalkyl; wherein the aryl, cycloalkyl or heterocycloalkyl are optionally substituted with one or more groups selected from alkyl, halo and oxo;
R 1 represents alkyl; R 2 represents hydrogen or alkyl; or R 1 and R 2 together with the carbon atoms to which they are attached form 3- to 5-membered cycloalkyl ring;
R 3 represents —C(O)R a , —S(O) 2 R a , —NHS(O) 2 R a , —NR b C(O)R a , ═NOR a , heteroaryl, heterocycloalkyl or (heterocycloalkyl)alkyl-; wherein the heteroaryl and heterocycloalkyl are optionally substituted with one or more groups selected from alkyl, halo, oxo and —C(O)R x ;
R 4 represents alkyl, halo, haloalkyl, cyano, alkoxy, aryloxy, alkoxyaryl, hydroxyalkyl, acetylene, acyl, hydroxy, cycloalkyl or —N(R x ) 2 ; wherein the cycloalkyl is optionally substituted with alkyl;
R a represents alkyl, alkenyl, haloalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more groups selected from alkyl, halo, aryl, cycloalkyl, haloalkyl, amino, amido, alkylamino, aminoalkyl, hydroxyl, cyano, alkoxy, alkoxyaryl, aryloxy, hydroxyalkyl, carboxylic acid, ester, thioester, oxo(═O) and —C(O)R x ;
R x represents hydrogen, alkyl, alkenyl, acyl or —C(O)-cycloalkyl;
R y represents hydrogen or alkyl;
R b represents hydrogen, alkyl or alkenyl;
‘m’ represents 0, 1, 2 or 3.
2 . The compound of claim 1 , wherein B represents heterocycloalkyl.
3 . The compound of claim 1 , wherein B represents
4 . The compound of claim 1 , wherein R 1 represents alkyl; and R 2 represents hydrogen.
5 . The compound of claim 1 , wherein R 1 and R 2 together with the carbon atoms to which they are attached form cyclopropyl or cyclopentyl ring.
6 . The compound of any one of claims 1 to 5 , wherein A represents aryl.
7 . The compound of claim 1 , represented by compound of formula (IA):
or a pharmaceutically acceptable salt or stereoisomer thereof; wherein A, R 1 , R 2 , R 3 , R 4 , B, X and ‘m’ are as defined in claim 1 .
8 . The compound of claim 7 , wherein B represents 5- or 6-membered cycloalkyl.
9 . The compound of claim 7 , wherein B represents 5- or 6-membered heterocycloalkyl.
10 . The compound of any one of claims 7 to 9 , wherein A represents aryl.
11 . The compound of any one of claims 7 to 10 , wherein R 3 represents —NHS(O) 2 R a , or —NR b C(O)R a ; wherein R a , and R b are as defined in claim 1 .
12 . The compound of claim 1 , represented by compound of formula (IB):
or a pharmaceutically acceptable salt or stereoisomer thereof; wherein A, R 1 , R 2 , R 3 , R 4 , B, and ‘m’ are as defined in claim 1 .
13 . The compound of claim 12 , wherein B represents heterocycloalkyl optionally substituted with one or more groups selected from alkyl, halo or oxo.
14 . The compound of claim 12 , wherein B represents 5- or 6-membered heterocycloalkyl.
15 . The compound of claim 1 , represented by compound of formula (IC):
or a pharmaceutically acceptable salt or stereoisomer thereof; wherein A, R 1 , R 2 , R 3 , R 4 and ‘m’ are as defined in claim 1 .
16 . The compound of claim 15 , wherein R 1 represents alkyl; and R 2 represents hydrogen or alkyl.
17 . The compound of claim 15 , wherein R 1 and R 2 together with the carbon atoms to which they are attached form cyclopropyl or cyclopentyl.
18 . The compound of any one of claims 15 to 17 , wherein R 3 represents heterocycloalkyl optionally substituted with —C(O)R x .
19 . The compound of any one of claims 15 to 18 , wherein R 4 represents alkyl, halo, haloalkyl or cycloalkyl, wherein the cycloalkyl is optionally substituted with alkyl.
20 . The compound of claim 1 , represented by compound of formula (ID):
or a pharmaceutically acceptable salt or stereoisomer thereof; wherein A, R 1 , R 2 , R 4 , R a and m are as defined in claim 1 .
21 . The compound of claim 20 , wherein R a represents alkenyl, cycloalkyl or heterocycloalkyl; wherein the alkenyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more groups selected from halo, aryl, haloalkyl or carboxylic acid.
22 . The compound of claim 21 , wherein R a represents alkenyl substituted with alkyl or haloalkyl.
23 . The compound of claim 1 , represented by compound of formula (IE):
or a pharmaceutically acceptable salt or stereoisomer thereof; wherein A, R 4 , R a and ‘m’ are as defined in claim 1 .
24 . The compound of claim 1 , represented by compound of formula (IF):
or a pharmaceutically acceptable salt or stereoisomer thereof; wherein R 4 , R a and m are same as defined in claim 1 .
25 . A compound selected from:
Example
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or a pharmaceutically acceptable salt or a stereoisomer thereof.
26 . A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 , or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
27 . The pharmaceutical composition according to claim 26 , further comprising at least one additional agent selected from an anticancer agent, a chemotherapy agent, and an antiproliferative compound.
28 . The compound according to any one of claims 1 to 25 , or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament.
29 . A method of treating cancer or proliferative disorder, comprising administration of therapeutically effective amount of compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 1 to 25 .
30 . The method of claim 29 , wherein the cancer or proliferative disorder is selected from solid tumor, benign or malignant tumor, carcinoma of the brain, kidney, liver, stomach, vagina, ovaries, gastric tumors, breast, bladder colon, prostate, pancreas, lung, cervix, testis, skin, bone or thyroid; sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, a mammary carcinoma, follicular carcinoma, papillary carcinoma, seminoma, melanoma; hematological malignancies selected from leukemia, diffuse large B-cell lymphoma (DLBCL), activated B-cell-like DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, B-cell pro lymphocytic leukemia, small lymphocytic lymphoma, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulnemia (WM), splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma and multiple myeloma.
31 . The method of claim 29 , wherein the cancer or proliferative disorder is selected from lymphoma, leukemia, breast cancer, lung cancer (non-small cell lung cancer), colon cancer, colorectal cancer, brain cancer (glioma, medulloblastoma and ependymoma), familial adenomatous polyposis (FAP), and Barrett's esophagus.
32 . The compound according to any one of claims 1 to 25 , or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in the treatment of a cancer, an inflammatory disorder, an autoimmune disease, chronic graft versus host disease, metabolic disorder, a hereditary disorder, a hormone-related disease, immunodeficiency disorders, a condition associated with cell death, a destructive bone disorder, thrombin-induced platelet aggregation, liver disease, or cardiovascular disorder.
33 . The compound according to any one of claims 1 to 25 , or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in the management of cytokine release syndrome associated with T cell-engaging therapies including CAR-T therapy.
34 . Use of the compound according to any one of claims 1 to 25 , or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer, an inflammatory disorder, an autoimmune disease, chronic graft versus host disease, metabolic disorder, a hereditary disorder, a hormone-related disease, immunodeficiency disorders, a condition associated with cell death, a destructive bone disorder, thrombin-induced platelet aggregation, liver disease or cardiovascular disorder.Join the waitlist — get patent alerts
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