Pyrazolo-pyrimidinone compounds for use in methods of inhibiting wee1 a kinase

Abstract

Pyrazolo-pyrimidinone compounds of formula I: for use in methods of inhibiting Wee1A kinase or both Wee1A kinase and Myt1 kinase.

Description

Pyrazolopyrimidinone compounds of formula I: (I), for methods of inhibiting Wee1A kinase or both Wee1A kinase and Myt1 kinase. Abstract

Claims

CLAIMS 1. A compound having structural formula AA:or a solvate, enantiomer, tautomer, or diastereomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: each of X, Y and Z is independently CH or N; R1is -O-, -NH-, or -N(C1-C3alkyl)-; each R2is independently fluoro, -CN, unsubstituted C1-C5 alkyl, fluoro-substituted C1-C5 alkyl, or cyano-substituted C1-C5 alkyl, wherein two R2bound to the same carbon atom are optionally taken together to form a spiro-fused C3-C7 cycloalkyl ring, or two R2bound to different carbon atoms are optionally taken together to form a bridged or fused C3-C5 cycloalkyl ring, or one R2and R8are optionally taken together to form a bridged or fused 3-5 membered ring; R3is -C1-C3alkyl or -CH2-CH=CH2;Rrepresents a point of attachment of R4to the compound; each R5and each R6is independently hydrogen, halo, -CN, -C1-C4alkyl optionally substituted with halo, -O-(C1-C4 alkyl) optionally substituted with halo, -O-(C1-C4alkyl) substituted with C3-C6cycloalkyl, an N-linked saturated 3-7 membered heterocyclyl, a 5-6 membered heteroaryl, or phenyl, wherein no more than two R6are other than hydrogen; wherein R5and an R6on an adjacent ring atom are optionally taken together to form a 4-7 membered saturated heterocyclic or cycloalkyl ring that is fused to R4; R7is hydrogen, -C1-C4 alkyl, -C1-C4 alkylene-O-C1-C4 alkyl, -C(O)- C1-C4 alkyl, or a C3-C6cycloalkyl, wherein any C1-C4alkyl or C1-C4alkylene portion of R7is optionally substituted with one or more substituents independently selected from halo and -CN; R8is hydrogen, -C1-C4alkyl, or a 4-6 membered saturated heterocycle; R9is hydrogen, halo, -CN, -C1-C4 alkyl optionally substituted with halo, -O-C1-C4 alkyl optionally substituted with halo, or an optionally substituted phenyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2 or 3; and m + n is 1, 2, 3, or 4, wherein any hydrogen atom is optionally replaced with deuterium.

2. The compound of claim 1, wherein: each of X, Y and Z is independently CH or N; R1is -O-, -NH-, or -N(C1-C3 alkyl)-; each R2is independently fluoro, -CN, unsubstituted C1-C5alkyl, fluoro-substituted C1-C5 alkyl, or cyano-substituted C1-C5 alkyl, wherein two R2bound to the same carbon atom are optionally taken together to form a spiro-fused C3-C7cycloalkyl ring, or two R2bound to different carbon atoms are optionally taken together to form a bridged C3-C5 cycloalkyl ring, or one R2and R8are optionally taken together to form a bridged or fused 3-5 membered ring;,of attachment of R4to the compound; each R5and each R6is independently hydrogen, halo, -CN, -C1-C4 alkyl optionally substituted with halo, or -O-(C1-C4alkyl) optionally substituted with halo, wherein no more than two R6are other than hydrogen; wherein R5and an R6on an adjacent ring atom are taken together to form a 4-7 membered saturated heterocyclic or cycloalkyl ring that is fused tR7is hydrogen, -C1-C4alkyl, or -C1-C4alkylene-O-C1-C4alkyl, wherein any C1-C4alkyl or C1-C4alkylene portion of R7is optionally substituted with one or more substituents independently selected from halo and -CN; R8is hydrogen or -C1-C4alkyl; R9is hydrogen, halo, -CN, -C1-C4 alkyl optionally substituted with halo, -O-C1-C4 alkyl optionally substituted with halo, or an optionally substituted phenyl; m is 0 or 1; n is 0, 1, 2 or 3; and m and n are not simultaneously 0.

3. The compound of claim 1 or 2, wherein: each of X, Y and Z is CH.

4. The compound of claim 1 or 2, wherein: X is N and each of Y and Z is CH.

5. The compound of claim 2, wherein: each of X and Y is N and Z is CH.

6. The compound of any one of claims 1-5, wherein R4is:or .

7. The compound of claim 6, wherein: R4R5is hydrogen, halo, -CN, C1-C4 alkyl optionally substituted with halo or --O-(C1-C4 alkyl) optionally substituted with halo; and each R6is independently hydrogen, halo, -CN, -C1-C4 alkyl optionally substituted with halo, -O-(C1-C4alkyl) optionally substituted with halo, -O-(C1-C4alkyl) substituted with C3-C6 cycloalkyl, an N-linked saturated 3-7 membered heterocyclyl, a 5-6 membered heteroaryl, or phenyl; or R5and R6bound to an adjacent ring atom are taken together to form methylenedioxy.

8. The compound of any one of claims 1-7, wherein: each R6is independently hydrogen, fluoro, bromo, chloro, -CN, -CF3, -CH3, -OCH3, - OCF3, -OCH2CF3, -OCH2CH3, -OCH2CH2F, -OCH2CH(CH3)CH3, cyclopropylmethoxy, morpholin-4-yl, thiomorpholin-4-yl, 1-methyl-1H-pyrazolyl, or phenyl optionally substituted with halo; andeach R5is hydrogen, fluoro, chloro, -CN, -CF3, -CH3, or -OCH3.

9. The compound of any one of claims 1-8, wherein no more than one R6is other than hydrogen.

10. The compound of claim 6, wherein:R6is hydrogen, or chloro; and R7is hydrogen, -CH3, -CH2CH3, -CH2C(CH3)2F, -CH2CH2CF3, -CH2CH2CH3, - CH(CH3)2, -CH2CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -CH2CH2CH2F, -OCH2CF3, or cyclopropyl.

11. The compound of claim 6, wherein:each R6is hydrogen or -CH3; and R9is optionally substituted phenyl.

12. The compound of claim 6, wherein: R4, n each R6is hydrogen.

13. The compound of claim 6, wherein R4is , , or, wherein each R6is hydrogen or methyl.

14. The compound of claim 6, wherein R4iswherein each R6is hydr7ogen; and R , when present, is isopropyl.

15. The compound of claim 6, wherein R4isR7is methyl or -C(O)CH3 and each R6is hydrogen.

16. The compound of claim 6, wherein: o17. The compound of claim 6, wherein R4is phenyl, 3-methylphenyl, 3-chloro-5- bromophenyl, 3,4-dichlorophenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-(1- methylpiperidin-4-yl)-5-methylphenyl, 4-trifluoromethoxyphenyl, 3-methyl-4- trifluoromethoxyphenyl, 4-(2,2,2-trifluoroethan-1-yl)oxyphenyl, 3-methyl-4-(2,2,2- trifluoroethan-1-yl)oxyphenyl, 4-trifluoromethylphenyl, 3-methyl-4-chlorophenyl, 3-methyl- 4-fluorophenyl, 3-methyl-5-fluorophenyl, 3-methyl-4-cyanophenyl, 3-methyl-4- methoxyphenyl, 3-methyl-4-(2,2,2-trifluoroethan-1-yloxy)phenyl, 3,4-methylenedioxyphenyl 4-(cyclopropylmethyloxy)phenyl, 4-(morpholin-4-yl)phenyl, 4-(thiomorpholin-4-yl)phenyl, 4-(2-methylpropan-1-yloxy)phenyl, 3-(1-methyl-1H-pyrazol-4-yl)phenyl, 4-(1-methyl-1H- pyrazol-4-yl)phenyl, 3-methyl-4-(morpholin-4-yl)phenyl, 4-(phenyl)phenyl, 3-bromophenyl, 3-cyanophenyl, 4-(2-fluoroethan-1-yloxy)phenyl, 4-cyanophenyl, , 4-(1,1-dioxothiazinan-4- yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3-(1H-imidazol-1-yl)phenyl, 3- (1H-pyrazol-1-yl)phenyl, 3-(d3-methyl)phenyl, 4-(3-fluoropropan-1-yloxy)phenyl, 4- ethoxyphenyl, 2-methylpyridin-4-yl, 6-methylpyridin-3-yl, 2,6-dimethylpyridin-4-yl, 2- trifluoromethyl-6-methylpyridin-4-yl, 2-trifluoromethylpyridin-4-yl, pyridin-3-yl, 2- methylpyridin-5-yl, 2-methoxypyridin-4-yl, 2-methoxypyridin-5-yl, 3-chloropyridin-5-yl, 3- fluoropyridin-5-yl, 3-cyanopyridin-5-yl, 3-methylpyridin-5-yl, 3-methoxypyridin-5-yl, 1- methyl-1H-pyrazol-4-yl, 1-propyl-1H-pyrazol-4yl, 1-isopropyl-1H-pyrazol-4-yl, 1-(2,2- dimethylethan-1-yl)pyrazol-4-yl, 1-(2-fluoro-2,2-dimethylethan-1-yl)-1H-pyrazol-4-yl, 1- (3,3,3-trifluoropropan-1-yl)-1H-pyrazol-4-yl, 1H-indazol-5-yl, 1-methyl-1H-indazol-5-yl, 1- ethyl-1H-indazol-5-yl, 1-propyl-1H-indazol-5-yl, 1-(3-fluoropropan-1-yl)-1H-indazol-5-yl, 1- isopropyl-1H-indazol-5-yl, 1-isobutyl-1H-indazol-5-yl, 1-cyclopropyl-1H-indazol-5-yl, 3- chloro-1H-indazol-5-yl, 3-methyl-1H-indazol-5-yl, 1,3-dimethyl-1H-indazol-5-yl, 1H- indazol-4-yl, 2-methyl-2H-indazol-5-yl, 2-ethyl-2H-indazol-5-yl, 3-phenylisothiazol-5-yl,benzofuran-6-yl, benzofuran-5-yl, 1-methyl-1H-indol-5-yl, 1-acetyl-1H-indol-5-yl, 1,2,4- triazolo[1,5-a]pyridin-6-yl, quinoxalin-6-yl, quinolin-6-yl, quinolin-7-yl, isoquinolin-6-yl, isoquinolin-7-yl, 2-methylbenzo[d]oxazol-5-yl, 2-methylbenzo[d]oxazol-6-yl, benzo[d]isoxazol-6-yl, benzo[d]thiazol-6-yl, 2-methylbenzo[d]thiazol-6-yl, 1-methyl-1H- benzo[d]imidazol-5-yl, benzo[d]thiazol-5-yl, 1-methyl-1H-indazol-6-yl, 2-methyl-2H- indazol-6-yl, imidazo[1,2-a]pyridin-6-yl, 2-(2-fluoroethoxy)pyridin-5-yl, 2-(t-butyl)-2H- indazol-5-yl, 1-isopropyl-1H-benzo[d]imidazol-5-yl, 1-isopropyl-1H-pyrazolo[3,4-b]pyridin- 5-yl, or 1-isopropyl-1H-benzo[d][1,2,3]triazol-5-yl.

18. The compound of any one of claims 1-17, wherein the ring represented by the structure:lected from pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, 1- ethylpyrrolidin-3-yl, 1-isopropylpyrrolidin-3-yl, piperidin-4-yl, piperidin-3-yl, 1- methylpiperidin-4-yl, 1-methylpiperidin-3-yl, quinuclidin-3-yl, 8-methyl-8- azabicyclo[3.2.1]octan-3-yl, and 9-methyl-9-azabicyclo[3.3.1]nonan-3-yl.

19. The compound of any one of claims 1-17, wherein the ring represented by the structure: is selected from pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, 1- ethylpyrrolidin-3-yl, 1-isopropylpyrrolidin-3-yl, piperidin-4-yl, piperidin-3-yl, 1- methylpiperidin-4-yl, 1-methylpiperidin-3-yl, 1-(methyl-d3)piperidin-4-yl, azepan-4-yl, quinuclidin-3-yl, 8-methyl-8-azabicyclo[3.2.1]octan-3-yl, and 9-methyl-9- azabicyclo[3.3.1]nonan-3-yl.

20. The compound of any one of claims 1-19, wherein R3is methyl, ethyl, n-propyl, or - CH2-CH=CH2.

21. The compound of claim 20, wherein R3is -CH2-CH=CH2.

22. The compound of any one of claims 1-21, wherein R1is -O-, -N(CH3)-, - N(CH2CH2CH3)- or -NH-.

23. The compound of claim 22, wherein R1is -O-.

24. The compound of claim 1, wherein the compound is any one of the following compounds: 6 7 8 9 0925. The compound of claim 1, wherein the compound is any one of the following compounds:

26. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-25; and a pharmaceutically acceptable carrier.

27. A method of inhibiting Wee1A kinase activity in a subject comprising the step of administering to the subject an effective amount of a compound of any one of claims 1-25, or a composition of claim 26.

28. A method of treating a subject suffering from a cancer or other disordered cell growth characterized by aberrant Wee1A kinase activity comprising the step of administering to the subject an effective amount of a compound of any one of claims 1-25, or a composition ofclaim 26.

29. The method of claim 28, wherein the subject is suffering from a cancer associated with inactivation of p53.

30. A method of inhibiting both Wee1A kinase and Myt1 kinase activity in a subject comprising the step of administering to the subject an effective amount of a compound of any one of claims 1-25 that is a dual inhibitor, or a composition of claim 26 comprising a dual inhibitor.

31. A method of treating a subject suffering from a cancer or other disordered cell growth characterized by both aberrant Wee1A kinase activity and aberrant Myt1 kinase activity comprising the step of administering to the subject an effective amount of a compound of any one of claims 1-25, or a composition of claim 26.

32. The method of any one of claims 28, 29, or 31, wherein the cancer is selected from a brain cancer, a cervicocerebral cancer, a cardiac cancer, a gastrointestinal cancer, an esophageal cancer, a thyroid cancer, a small cell cancer, a non-small cell cancer, a breast cancer, a lung cancer, a stomach cancer, a gallbladder / bile duct cancer, a liver cancer, a pancreatic cancer, a colon cancer, a rectal cancer, an ovarian cancer, a choriocarcinoma, an uterus body cancer, an uterocervical cancer, a renal pelvis / ureter cancer, a bladder cancer, a prostate cancer, a penis cancer, a testicular cancer, a fetal cancer, Wilms' cancer, a skin cancer, malignant melanoma, a neuroblastoma, an osteosarcoma, an Ewing's tumor, a soft part sarcoma, an acute leukemia, a chronic lymphatic leukemia, a chronic myelocytic leukemia, polycythemia vera, a malignant lymphoma, multiple myeloma, a Hodgkin's lymphoma, and a non-Hodgkin’s lymphoma.

33. The method of claim 32, wherein the subject is suffering from a cancer selected from uterine serous carcinoma or a renal cancer.