Thiolactams and uses thereof
View Patent ↗This invention provides compounds of formula I: wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as described in the specification. The compounds are inhibitors of PLK and are thus useful for treating proliferative, inflammatory, or cardiovascular disorders.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from hydrogen, —CN, halogen, optionally substituted C 1-6 aliphatic, or —YR 1a ,
wherein Y is —O—, —S—, or —NR 1a , and each occurrence of R 1a is independently hydrogen, or optionally substituted C 1-6 aliphatic;
R 2 is selected from hydrogen, halogen, —ZR 2a , or —OR 2b ,
wherein Z is an optionally substituted C 1-6 alkylene chain, and R 2a is —OR 2b , —N(R 2b ) 2 , —SR 2b , —C(O)N(R 2b ) 2 , —N(R 2b )C(O)R 2b , —SO 2 N(R 2b ) 2 , —NR 2b SO 2 R 2b , —NR 2b C(O)N(R 2b ) 2 , or —NR 2b SO 2 N(R 2b ) 2 , wherein each occurrence of R 2b is independently hydrogen or optionally substituted C 1-6 alkyl, or two occurrences of R 2b , taken together with a nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
R 3 is selected from hydrogen, halogen, optionally substituted C 1-4 alkyl, or optionally substituted C 1-4 alkoxy;
R 4 is selected from hydrogen, optionally substituted C 1-6 aliphatic, an optionally substituted 3-7-membered heterocyclyl ring, —(CH 2 ) x NR 4a R 4b , —(CH 2 ) x NR 4a C(O)R 4b , —(CH 2 ) x NR 4a S(O) 2 R 4b , —(CH 2 ) x C(O)R 4b , —(CH 2 ) x C(O)NR 4a R 4b , —(CH 2 ) x S(O) 2 NR 4a R 4b , or —(CH 2 ) x OR 4b ,
wherein
each occurrence of x is independently 0-6;
wherein R 4a is hydrogen or optionally substituted C 1-6 aliphatic, and
R 4b is hydrogen, optionally substituted C 1-6 aliphatic, optionally substituted C 3-7 -heterocyclyl or C 3-7 carbocyclyl ring, or is W—R 4c , wherein W is an optionally substituted C 2-6 alkylene chain, and R 4c is an optionally substituted C 3-7 -heterocyclyl ring, —OR 4d , —N(R 4d ) 2 , —SR 4d , —C(O)N(R 4d ) 2 , —N(R 4d )C(O)R 4d , —SO 2 N(R 4d ) 2 , —NR 4d SO 2 R 4d , —NR 4d C(O)N(R 4d ) 2 , or —NR 4d SO 2 N(R 4d ) 2 , wherein each occurrence of R 4d is independently hydrogen or optionally substituted C 1-6 aliphatic, or two occurrences of R 4d , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
or wherein R 4a and R 4b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
R 5 is hydrogen, optionally substituted C 1-6 aliphatic, an optionally substituted C 3-7 -heterocyclyl ring, or is X—R 5a , wherein X is an optionally substituted C 2-6 alkylene chain or —NR 5c ,
wherein when X is an optionally substituted C 2-6 alkylene chain R 5a is —OR 5b , —N(R 5b ) 2 , —SR 5b , —C(O)N(R 5b ) 2 , —N(R 5b )C(O)R 5b , —SO 2 N(R 5b ) 2 , —NR 5b SO 2 R 5b , —NR 5b C(O)N(R 5b ) 2 , or —NR 5b SO 2 N(R 5b ) 2 ; and
when X is —NR 5c , R 5a is hydrogen or optionally substituted C 1-6 aliphatic, or R 5a and R 5C , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
wherein each occurrence of R 5b and R 5c is independently hydrogen or optionally substituted C 1-6 aliphatic, or two occurrences of R 5b , or R 5a and R 5c , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring; or
wherein R 4 and R 5 , taken together, form an optionally substituted 5-7-membered cycloaliphatic or heterocyclyl ring; and
R 6 is selected from hydrogen, halogen, optionally substituted C 1-4 alkyl, or optionally substituted C 1-4 aikoxy.
2. The compound of claim 1 , wherein R 2 , R 4 , and R 6 are each hydrogen.
3. The compound of claim 1 , wherein R 2 , R 5 , and R 6 are each hydrogen.
4. The compound of claim 1 , wherein R 1 is optionally substituted C 1-4 aliphatic, halogen, —CN, or —OMe.
5. The compound of claim 1 , wherein R 1 is methyl, ethyl, —CF 3 , Cl, —CN, —OMe, or cyclopropyl.
6. The compound of claim 1 , wherein R 2 is hydrogen or —Z—R 2a , wherein Z is —(CH 2 ) 2-4 and R 2a is N(R 2b ) 2 , wherein each occurrence of R 2b is selected from hydrogen or C 1-4 alkyl, or two occurrences of R 2b , taken together with the nitrogen atom to which they are bound, form an optionally substituted C 3-7 -heterocyclyl ring.
7. The compound of claim 1 , wherein R 3 is methyl or CF 3 .
8. The compound of claim 1 , wherein R 4 is methyl, or —NR 4a R 4b , wherein R 4a and R 4b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring, or wherein R 4a is hydrogen or C 1-4 alkyl, and R 4b is an optionally substituted C 3-7 -heterocyclyl ring or is W—R 4c , wherein W is an optionally substituted C 2-6 alkylene chain, and R 4c is an optionally substituted C 3-7 -heterocyclyl ring.
9. The compound of claim 1 , wherein R 5 is an optionally substituted C 3-7 -heterocyclyl ring or is X—R 5a , wherein X is an optionally substituted C 2-6 alkylene chain, and R 5a is —N(R 5b ) 2 , wherein each occurrence of R 5b is independently hydrogen or C 1-6 alkyl, or two occurrences of R 5b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring.
10. The compound of claim 1 , wherein R 4 and R 5 are taken together to form a ring selected from:
wherein
G 1 is —NH—, —O—or —N(CH 3 )—
R 7 is selected from hydrogen or optionally substituted C 1-6 aliphatic,
R 8 is selected from fluoro, optionally substituted C 1-6 aliphatic, or —YR 1a , wherein Y is —O—, —S—, or —NR 1a , and each occurrence of R 1a is independently hydrogen, or optionally substituted C 1-6 aliphatic; and
y is 0-4.
11. The compound of claim 1 having the structure of formula I-A:
12. The compound of claim 11 , wherein R 1 is optionally substituted C 1-4 aliphatic, halogen, —CN, or —OMe.
13. The compound of claim 11 , wherein R 1 is methyl, ethyl, —CF 3 , Cl, —CN, —OMe, or cyclopropyl.
14. The compound of claim 11 , wherein R 3 is methyl or CF 3 .
15. The compound of claim 11 , wherein R 5 is an optionally substituted C 3-7 -heterocyclyl ring or is X—R 5a , wherein X is an optionally substituted C 2-6 alkylene chain, and R 5a is —N(R 5b ) 2 , wherein each occurrence of R 5b is independently hydrogen or C 1-6 alkyl, or two occurrences of R 5b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring.
16. The compound of claim 15 , wherein R 5 is an optionally substituted pyrrolidinyl, morpholinyl, piperidinyl, or piperazinyl group, or is X—R 5a , wherein X is a C 2-4 alkylene chain, and R 5a is —N(R 5b ) 2 , wherein each occurrence of R 5b is independently hydrogen or C 1-6 alkyl, or two occurrences of R 5b , taken together with the nitrogen atom to which they are bound, form an optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl group.
17. The compound of claim 16 , wherein the pyrrolidinyl, morpholinyl, piperidinyl, or piperazinyl group is optionally substituted with 1-4 occurrences of C 1-4 alkyl or C 1-4 haloalkyl.
18. The compound of claim 11 , wherein:
a) R 1 is methyl, ethyl, propyl, —CF 3 , Cl, —CN, —OMe, or cyclopropyl;
b) R 3 is methyl or CF 3 ; and
c) R 5 is an optionally substituted pyrrolidinyl, morpholinyl, piperidinyl, or piperazinyl group, or is X—R 5a , wherein X is a C 2-4 alkylene chain, and R 5a is —N(R 5b ) 2 , wherein each occurrence of R 5b is independently hydrogen or C 1-6 alkyl, or two occurrences of R 5b , taken together with the nitrogen atom to which they are bound, form an optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl group.
19. The compound of claim 18 , wherein R 1 is Cl or CF 3 , and R 3 is methyl.
20. The compound of claim 1 having the structure of formula I—B:
21. The compound of claim 20 , wherein R 1 is optionally substituted C 1-4 aliphatic, halogen, —CN, or —OMe.
22. The compound of claim 21 , wherein R 1 is methyl, ethyl, —CF 3 , Cl, —CN, —OMe, or cyclopropyl.
23. The compound of claim 20 , wherein R 3 is methyl or CF 3 .
24. The compound of claim 20 , wherein R 4 is —NR 4a R 4b , wherein R 4a and R 4b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring, or wherein R 4a is hydrogen or C 1-4 alkyl, and R 4b is an optionally substituted C 3-7 -heterocyclyl ring or is W—R 4c , wherein W is an optionally substituted C 2-4 alkylene chain, and R 4c is an optionally substituted C 3-7 -heterocyclyl ring, or —N(R 4d ) 2 , wherein each occurrence of R 4d is independently hydrogen or C 1-6 alkyl, or two occurrences of R 4d , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring.
25. The compound of claim 24 , wherein R 4 is —NR 4a R 4b , wherein R 4a and R 4b , taken together with the nitrogen atom to which they are bound, form an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl ring, or wherein R 4a is hydrogen or C 1-4 alkyl, and R 4b is an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl ring, or is W—R 4c , wherein W is an optionally substituted C 2-4 alkylene chain, and R 4c is an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl ring, or —N(R 4d ) 2 , wherein each occurrence of R 4d is independently hydrogen or C 1-6 alkyl, or two occurrences of R 4d , taken together with the nitrogen atom to which they are bound, form an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl ring.
26. The compound of claim 20 , wherein:
a) R 1 is methyl, ethyl, propyl, —CF 3 , Cl, —CN, —OMe, or cyclopropyl;
b) R 3 is methyl or CF 3 ; and
c) R 4 is —NR 4a R 4b , wherein R 4a and R 4b , taken together with the nitrogen atom to which they are bound, form an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl ring, or wherein R 4a is hydrogen or C 1-4 alkyl, and R 4b is an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl ring, or is W—R 4c , wherein W is an optionally substituted C 2-4 alkylene chain, and R 4c is an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl ring, or —N(R 4d ) 2 , wherein each occurrence of R 4d is independently hydrogen or C 1-6 alkyl, or two occurrences of R 4d , taken together with the nitrogen atom to which they are bound, form an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl ring.
27. The compound of claim 26 , wherein R 1 is Cl or CF 3 , and R 3 is methyl.
28. The compound of claim 1 , wherein the compound is selected from:
29. A pharmaceutical composition comprising a compound of claim 1 , 11 , 20 or 28 and a pharmaceutically acceptable carrier.