Small molecule inhibitors of CDK12/CDK13
The invention provides compounds and methods of inhibiting a cyclin-dependent kinase, comprising contacting the cyclin-dependent kinase and an effective amount or concentration of a compound of formula (I) wherein variables are as defined herein. Compounds of formula (I) can be highly selective inhibitors of cyclin-dependent kinases such as CDK12/13, relative to other kinases such as casein kinases, such as CK1δ/ε. Compounds can be used in treatment of cancers, such as breast cancer, brain cancer and ovarian cancer.
1. A method of inhibiting a cyclin-dependent kinase, comprising contacting the cyclin-dependent kinase and an effective amount or concentration of a compound of formula (I)
wherein
wherein a wavy line indicates a position of bonding;
R 2 is NR 3 R 4 , wherein R 3 and R 4 are each independently H or (C1-C6)alkyl, the alkyl being optionally substituted with hydroxyl or with N(R 6 ) 2 on any carbon atom thereof other than a carbon atom bonded directed to the nitrogen atom of NR 3 R 4 , or R 3 and R 4 together with the nitrogen atom to which they are bonded form a 5- to 7-membered heterocyclyl ring optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and NR 5 , wherein R 5 is H or (C1-C6)alkyl, the alkyl being optionally substituted with hydroxyl or with N(R 6 ) 2 on any carbon atom thereof other than a carbon atom bonded directed to the nitrogen atom of NR 5 , wherein the heterocyclyl ring is further optionally mono- or independently multi-substituted with (C1-C6)alkyl, the alkyl being optionally substituted with hydroxyl or with N(R 6 ) 2 , wherein each R 6 is independently H or (C1-C6)alkyl;
X, Y and Z are independently hydrogen, fluoro, chloro, methoxy, CN, NO 2 , CF 3 , NHCOR, lower alkyl, C(R′) 2 NR 2 , C(R′) 2 OH, C(R′) 2 OR, CO 2 R, CONR 2 ;
R is independently at each occurrence selected from the group consisting of hydrogen, deuterium, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C 3-8 )heterocyclyl optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O) and S(O) 2 ;
R′ is H or (C1-C4)alkyl;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein R 2 is a group of formula
wherein W is H or (C1-C6)alkyl, wherein the alkyl is optionally further substituted with hydroxyl or N(R 7 ) 2 , wherein each R 7 is independently H or (C1-C6)alkyl or where N(R 7 ) 2 is a 5-, 6-, or 7-membered heterocyclyl ring, wherein a wavy line indicates a position of bonding.
3. The method of claim 1 , wherein the compound of formula (I) is any one of the following compounds:
4. The method of claim 1 , wherein the cyclin-dependent kinase is cyclin-dependent kinase12 or 13 (CDK12 or CDK13).
5. The method of claim 1 , wherein the compound of formula (I) is not an effective inhibitor of casein kinase 1δ or 1ε (CK1δ/ε).
6. The method of claim 1 , wherein the cyclin-dependent kinase is disposed within the body tissue of a patient afflicted with cancer.
7. A method of treating a cancer in a patient afflicted therewith, comprising administering to the patient an effective dose of a compound of formula (I)
wherein
wherein a wavy line indicates a position of bonding;
R 2 is NR 3 R 4 , wherein R 3 and R 4 are each independently H or (C1-C6)alkyl, the alkyl being optionally substituted with hydroxyl or with N(R 6 ) 2 on any carbon atom thereof other than a carbon atom bonded directed to the nitrogen atom of NR 3 R 4 , or R 3 and R 4 together with the nitrogen atom to which they are bonded form a 5- to 7-membered heterocyclyl ring optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and NR 5 , wherein R 5 is H or (C1-C6)alkyl, the alkyl being optionally substituted with hydroxyl or with N(R 6 ) 2 on any carbon atom thereof other than a carbon atom bonded directed to the nitrogen atom of NR 5 , wherein the heterocyclyl ring is further optionally mono- or independently multi-substituted with (C1-C6)alkyl, the alkyl being optionally substituted with hydroxyl or with N(R 6 ) 2 , wherein each R 6 is independently H or (C1-C6)alkyl;
X, Y and Z are independently hydrogen, fluoro, chloro, methoxy, CN, NO 2 , CF 3 , NHCOR, lower alkyl, C(R′) 2 NR 2 , C(R′) 2 OH, C(R′) 2 OR, CO 2 R, CONR 2 ;
R is independently at each occurrence selected from the group consisting of hydrogen, deuterium, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C 3-8 )heterocyclyl optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O) and S(O) 2 ;
R′ is H or (C1-C4)alkyl;
or a pharmaceutically acceptable salt thereof.
8. The method of claim 7 , wherein R 2 is a group of formula
wherein W is H or (C1-C6)alkyl, wherein the alkyl is optionally further substituted with hydroxyl or N(R 7 ) 2 , wherein each R 7 is independently H or (C1-C6)alkyl or where N(R 7 ) 2 is a 5-, 6-, or 7-membered heterocyclyl ring, wherein a wavy line indicates a position of bonding.
9. The method of claim 7 , wherein the compound of formula (I) is any one of the following compounds:
10. The method of claim 7 , wherein the compound of formula (I) is not an effective inhibitor of casein kinase 1δ or 1ε (CK1δ/ε).
11. The method of claim 7 wherein the cancer is breast cancer, brain cancer or ovarian cancer.
12. A compound of formula (I)
wherein
wherein a wavy line indicates a position of bonding;
R 2 is NR 3 R 4 , wherein R 3 and R 4 are each independently H or (C1-C6)alkyl, the alkyl being optionally substituted with hydroxyl or with N(R 6 ) 2 on any carbon atom thereof other than a carbon atom bonded directed to the nitrogen atom of NR 3 R 4 , or R 3 and R 4 together with the nitrogen atom to which they are bonded form a 5- to 7-membered heterocyclyl ring optionally comprising 1 or 2 additional heteroatoms selected from the group consisting of O, S, and NR 5 , wherein R 5 is H or (C1-C6)alkyl, the alkyl being optionally substituted with hydroxyl or with N(R 6 ) 2 on any carbon atom thereof other than a carbon atom bonded directed to the nitrogen atom of NR 5 , wherein the heterocyclyl ring is further optionally mono- or independently multi-substituted with (C1-C6)alkyl, the alkyl being optionally substituted with hydroxyl or with N(R 6 ) 2 , wherein each R 6 is independently H or (C1-C6)alkyl;
X, Y and Z are independently hydrogen, fluoro, chloro, methoxy, CN, NO 2 , CF 3 , NHCOR, lower alkyl, C(R′) 2 NR 2 , C(R′) 2 OH, C(R′) 2 OR, CO 2 R, CONR 2 ;
R is independently at each occurrence selected from the group consisting of hydrogen, deuterium, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C 3-8 )heterocyclyl optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O) and S(O) 2 ;
R′ is H or (C1-C4)alkyl;
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 12 , wherein R 2 is a group of formula
wherein W is H or (C1-C6)alkyl, wherein the alkyl is optionally further substituted with hydroxyl or N(R 7 ) 2 , wherein each R 7 is independently H or (C1-C6)alkyl or where N(R 7 ) 2 is a 5-, 6-, or 7-membered heterocyclyl ring, wherein a wavy line indicates a position of bonding.
14. The compound of claim 12 , wherein the compound of formula (I) is any one of the following compounds: