Cyclin dependent kinase inhibitors
This invention relates to compounds of Formula (I) or a pharmaceutically acceptable salt thereof, in which R-groups R 1 to R 23 , A, Q, U, V, W, X, Y, Z, n, p and q are as defined herein, to pharmaceutical compositions comprising such compounds and salts, and to methods of using such compounds, salts and compositions for the treatment of abnormal cell growth, including cancer, in a subject.
1. A compound of Formula (XI):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, F, Cl, CN, C 1 -C 2 alkyl or C 1 -C 2 fluoroalkyl, where each said C 1 -C 2 alkyl and C 1 -C 2 fluoroalkyl is optionally substituted by R 20 ;
R 2 is H, C 1 -C 5 alkyl, C 1 -C 5 fluoroalkyl, C 3 -C 8 cycloalkyl or 3-6 membered heterocyclyl, where each said C 1 -C 5 alkyl and C 1 -C 5 fluoroalkyl is optionally substituted by R 20 and each said C 3 -C 8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R 21 ;
R 4 is H, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy or C 1 -C 4 fluoroalkoxy, where each said C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy and C 1 -C 4 fluoroalkoxy is optionally substituted by R 20 ; or
R 2 can be taken together with R 4 to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR 24 , O and S(O) m as a ring member, which ring is optionally substituted by R 21 ;
R 6 is H, F, Cl, CN, CH 3 , CH 2 F, CHF 2 or CF 3 ;
R 7 and R 8 are independently H, F, Cl, CN, C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy or C 1 -C 2 fluoroalkoxy, where each said C 1 -C 2 alkyl, C 1 -C 2 fluoroalkyl, C 1 -C 2 alkoxy and C 1 -C 2 fluoroalkoxy is optionally substituted by R 20 ;
R 9 is H, OH, NH 2 , NHCH 3 or N(CH 3 ) 2 ;
each R 10 is independently F, CN, C 1 -C 2 alkyl or C 1 -C 2 fluoroalkyl, where each said C 1 -C 2 alkyl and C 1 -C 2 fluoroalkyl is optionally substituted by R 20 ;
each R 20 is independently OH, C 1 -C 2 alkoxy, C 1 -C 2 fluoroalkoxy, CN or NR 22 R 23 ;
each R 21 is independently F, OH, CN, NR 22 R 23 , C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy or C 1 -C 4 fluoroalkoxy, where each said C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkoxy and C 1 -C 4 fluoroalkoxy is optionally further substituted by OH, NH 2 , NHCH 3 or N(CH 3 ) 2 ;
each R 22 and R 23 is independently H, C 1 -C 2 alkyl or C 1 -C 2 fluoroalkyl; or
R 22 and R 23 may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;
R 24 is H, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, SO 2 R 25 , SO 2 NR 26 R 27 , COR 28 , COOR 28 or CONR 29 R 30 ;
R 25 is C 1 -C 4 alkyl or C 1 -C 4 fluoroalkyl;
each R 26 and R 27 is independently H or CH 3 ;
R 28 is C 1 -C 4 alkyl or C 1 -C 4 fluoroalkyl, where each said C 1 -C 4 alkyl and C 1 -C 4 fluoroalkyl is optionally substituted by OH, C 1 -C 2 alkoxy, C 1 -C 2 fluoroalkoxy, CN, NH 2 , NHCH 3 or N(CH 3 ) 2 ;
each R 29 and R 30 is independently H, C 1 -C 4 alkyl or C 1 -C 4 fluoroalkyl, where each said C 1 -C 4 alkyl and C 1 -C 4 fluoroalkyl is optionally substituted by OH, C 1 -C 2 alkoxy, C 1 -C 2 fluoroalkoxy, CN, NH 2 , NHCH 3 or N(CH 3 ) 2 ;
m is 0, 1 or 2; and
n is 0, 1, 2, 3 or 4.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is OH.
3. 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol, or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
5. A pharmaceutical composition comprising the compound of claim 3 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
6. A method for the treatment of cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
7. A method for the treatment of cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 3 , or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is Cl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 5 alkyl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1 -C 4 alkyl optionally substituted by R 20 , where R 20 is OH.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is F, R 7 is H, and R 8 is H.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0 and R 10 is absent.
13. The compound of claim 1 , having the Formula (XI-A):
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 9 is OH, n is 0 and R 10 is absent.
15. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 1 is Cl.
16. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 2 is i-C 3 H 7 .
17. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1 -C 4 alkyl substituted by R 20 , where R 20 is OH.
18. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 6 is F, R 7 is H, and R 8 is H.
19. 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol.
20. A pharmaceutically acceptable salt of 1,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1-(propan-2-yl)-1H-benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-threo-pentitol.