Substituted alkynylene compounds as anticancer agents
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.
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 unsubstituted alkyl; R 2 represents hydrogen or unsubstituted 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, hydroxyalkyl, acetylene, acyl, hydroxy, cycloalkyl or —N(R x ) 2 ; wherein the alkoxy is unsubstituted or substituted with unsubstituted phenyl, and 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 unsubstituted 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 claim 1 , 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 claim 7 , wherein A represents aryl.
11. The compound of claim 7 , wherein R 3 represents —NHS(O) 2 R a , or —NR b C(O)R a .
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 unsubstituted alkyl; and R 2 represents hydrogen or unsubstituted 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 claim 15 , wherein R 3 represents heterocycloalkyl optionally substituted with —C(O)R x .
19. The compound of claim 15 , 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
Structure
1
1a
1b
2
2a
2b
3
4
5
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42
42a
42b
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47
48a
48b
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77
or a pharmaceutically acceptable salt or a stereoisomer thereof.
26. A pharmaceutical composition comprising a compound according to claim 1 , 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 of claim 1 , having the formula:
or a pharmaceutically acceptable salt thereof.
29. The compound of claim 1 , having the formula:
or a pharmaceutically acceptable salt thereof.
30. The compound of claim 1 , having the formula:
or a pharmaceutically acceptable salt thereof.