CDK2 inhibitors
This invention relates to compounds of Formula (I) and enantiomers thereof, and to pharmaceutically acceptable salts of Formula (I) and said enantiomers, wherein R 1 , R 2 and R 3 are as defined herein. The invention further relates to pharmaceutical compositions comprising such compounds and salts, and to methods and uses of such compounds, salts and compositions for the treatment of abnormal cell growth, including cancer, in a subject in need thereof.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 1 is -L 1 -(5-10 membered heteroaryl) or -L 1 -(C 6 -C 12 aryl), where said 5-10 membered heteroaryl or C 6 -C 12 aryl is optionally substituted by one or more R 4 ;
R 2 and R 3 are independently H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, -L 2 -(C 3 -C 7 cycloalkyl) or -L 2 -(4-7 membered heterocyclyl), where each said C 1 -C 6 alkyl and C 1 -C 6 fluoroalkyl is optionally substituted by one or more R 5 and each said C 3 -C 7 cycloalkyl and 4-7 membered heterocyclyl is optionally substituted by one or more R 6 ; or
R 2 and R 3 are taken together with the N-atom to which they are attached to form a 4-6 membered heterocyclyl optionally containing an additional heteroatom selected from O, N(R 7 ) and S(O) q as a ring member, where said 4-6 membered heterocyclyl is optionally substituted by one or more R 8 ;
each L 1 and L 2 is independently a bond or a C 1 -C 2 alkylene optionally substituted by one or more R 9 ;
each R 4 is independently F, Cl, OH, CN, NR 10 R 11 , C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, C 3 -C 8 cycloalkyl, C(O)NR 10 R 11 , SO 2 R 12 , SO(═NH)R 12 or SO 2 NR 10 R 11 ; where each C 1 -C 4 alkyl and C 1 -C 4 fluoroalkyl is optionally substituted by one or more R 13 ;
each R 5 is independently OH, C 1 -C 4 alkoxy or NR 10 R 11 ;
each R 6 is independently F, OH, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy or NR 10 R 11 where each C 1 -C 4 alkyl and C 1 -C 4 fluoroalkyl is optionally substituted by one or more R 13 ;
R 7 is H, C 1 -C 4 alkyl or C(O)-C 1 -C 4 alkyl;
each R 8 is independently F, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or CN;
each R 9 is independently F, OH or C 1 -C 2 alkyl;
each R 10 and R 11 is independently H or C 1 -C 4 alkyl;
each R 12 is C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl;
each R 13 is independently OH, C 1 -C 4 alkoxy or NR 14 R 15 ;
each R 14 and R 15 is independently H or C 1 -C 4 alkyl; and
q is 0, 1 or 2.
2. A compound of Formula (II):
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 1 is -L 1 -(5-10 membered heteroaryl) or -L 1 -(C 6 -C 12 aryl), where said 5-10 membered heteroaryl or C 6 -C 12 aryl is optionally substituted by one or more R 4 ;
R 2 and R 3 are independently H, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, -L 2 -(C 3 -C 7 cycloalkyl) or -L 2 -(4-7 membered heterocyclyl), where each said C 1 -C 6 alkyl and C 1 -C 6 fluoroalkyl is optionally substituted by one or more R 5 and each said C 3 -C 7 cycloalkyl and 4-7 membered heterocyclyl is optionally substituted by one or more R 6 ; or
R 2 and R 3 are taken together with the N-atom to which they are attached to form a 4-6 membered heterocyclyl optionally containing an additional heteroatom selected from O, N(R 7 ) and S(O) q as a ring member, where said 4-6 membered heterocyclyl is optionally substituted by one or more R 8 ;
each L 1 and L 2 is independently a bond or a C 1 -C 2 alkylene optionally substituted by one or more R 9 ;
each R 4 is independently F, Cl, OH, CN, NR 10 R 11 , C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy, C 3 -C 8 cycloalkyl, C(O)NR 10 R 11 , SO 2 R 12 , SO(═NH)R 12 or SO 2 NR 10 R 11 , where each C 1 -C 4 alkyl and C 1 -C 4 fluoroalkyl is optionally substituted by one or more R 13 ;
each R 5 is independently OH, C 1 -C 4 alkoxy or NR 10 R 11 ;
each R 6 is independently F, OH, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy, C 1 -C 4 fluoroalkoxy or NR 10 R 11 where each C 1 -C 4 alkyl and C 1 -C 4 fluoroalkyl is optionally substituted by one or more R 13 ;
R 7 is H, C 1 -C 4 alkyl or C(O)-C 1 -C 4 alkyl;
each R 8 is independently F, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or CN;
each R 9 is independently F, OH or C 1 -C 2 alkyl;
each R 10 and R 11 is independently H or C 1 -C 4 alkyl;
each R 12 is C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl;
each R 13 is independently OH, C 1 -C 4 alkoxy or NR 14 R 15 ;
each R 14 and R 15 is independently H or C 1 -C 4 alkyl; and
q is 0, 1 or 2.
3. The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is —L 1 -(5-10 membered heteroaryl), where said 5-10 membered heteroaryl is optionally substituted by one or more R 4 .
4. The compound of claim 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein said 5-10 membered heteroaryl is pyrazolyl or isoxazolyl, optionally substituted by one or more R 4 .
5. The compound of claim 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 1 is a bond or methylene.
6. The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is independently C 1 -C 4 alkyl or C 1 -C 4 alkoxy, where each C 1 -C 4 alkyl is optionally substituted by one or more R 13 .
7. The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is H and R 3 is C 1 -C 6 alkyl.
8. The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is H and R 3 is -L 2 -(C 3 -C 7 cycloalkyl), where said C 3 -C 7 cycloalkyl is optionally substituted by one or more R 6 .
9. The compound of claim 8 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 2 is a bond or methylene.
10. A compound selected from the group consisting of:
(1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}-amino)-1H-pyrazol-5-yl]cyclopentyl propan-2-ylcarbamate; and
(1R,3S)-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H-pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate.
11. A compound having the structure:
12. A pharmaceutically acceptable solvate of a compound having the structure:
13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
14. A pharmaceutical composition comprising a compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.
15. A pharmaceutical composition comprising a compound of claim 11 , and a pharmaceutically acceptable carrier or excipient.
16. A pharmaceutical composition comprising a pharmaceutically acceptable solvate of a compound of claim 12 , and a pharmaceutically acceptable carrier or excipient.
17. The solvate of claim 12 , wherein the solvate is a hydrate.
18. The solvate of claim 12 , wherein the solvate is a hydrate of:
19. The solvate of claim 12 , wherein the solvate is:
monohydrate.
20. A pharmaceutical composition comprising the solvate of claim 18 , and a pharmaceutically acceptable carrier or excipient.
21. A pharmaceutical composition comprising the solvate of claim 19 , and a pharmaceutically acceptable carrier or excipient.