Substituted pyrimidinyl-pyrazoles as CDK2 inhibitors
The present disclosure provides a compound represented by structural formula (I): (I), or a pharmaceutically acceptable salt thereof useful for treating a cancer.
1 . A compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein
each R 1 is independently selected from the group consisting of halo, OH, CN, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 3 halo;
each R 2 is independently selected from the group consisting of halo, OH, CN, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 3 halo;
R 3 is C 1 -C 6 alkyl optionally substituted with 1 or 2 groups each independently selected from the group consisting of halo, OH, C 3 -C 6 cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C 3 -C 6 cycloalkyl is optionally substituted with OH, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR a and then is optionally substituted on a ring carbon with OH; or
R 3 is C 3 -C 6 cycloalkyl or 3 to 6-membered heterocyclyl, wherein the C 3 -C 6 cycloalkyl is optionally substituted with OH or —CH 2 OH, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR a and then is optionally substituted on a ring carbon with OH or —CH 2 OH;
each R a is independently H or C 1 -C 6 alkyl;
m is selected from the group consisting of 0, 1, 2, 3, and 4, and
n is selected from the group consisting of 0, 1, and 2.
2 . The compound of claim 1 , wherein the compound is of Formula IIA, Formula IIB, Formula IIC, or Formula IID
or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 , wherein each R 1 is independently selected from the group consisting of halo, methyl, and methoxy.
4 . The compound of claim 1 , wherein each R 2 is independently selected from the group consisting of halo, CN, methyl, and ethyl, wherein the methyl and ethyl are each optionally substituted with 1 to 3 halo.
5 . The compound of claim 1 , wherein R 3 is C 1 -C 5 alkyl optionally substituted with 1 or 2 groups each independently selected from the group consisting of halo, OH, cyclopropyl and oxetanyl, wherein the cyclopropyl and oxetanyl are each optionally substituted with OH.
6 . The compound of claim 1 , wherein R 3 is C 1 -C 5 alkyl substituted with OH.
7 . The compound of claim 1 , wherein each R 1 is methyl, each R 2 is independently selected from the group consisting of halo, methyl, and CF 3 , and R 3 is C 1 -C 6 alkyl substituted with OH.
8 . The compound of claim 1 , wherein each R 1 is halo, each R 2 is independently selected from the group consisting of halo, CN, methyl, ethyl, and CF 3 , and R 3 is C 1 -C 6 alkyl substituted with OH.
9 . A compound selected from the group consisting of:
10 . A pharmaceutically acceptable salt of a compound selected from the group consisting of:
11 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
12 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 9 , or a pharmaceutically acceptable salt thereof.
13 . A method of treating a cancer in a subject in need thereof, comprising administering to the subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
14 . The method of claim 13 , wherein the cancer is breast cancer.
15 . A method of treating a subject suffering from, or at risk of developing, a solid tumor cancer, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
16 . The method of claim 15 , wherein the solid tumor cancer is at least one of: uterine cancer, endometrial cancer, breast cancer, ovarian cancer, stomach cancer, gastric cancer, colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma, sarcoma, esophageal cancer, bladder cancer, lung cancer, cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma.
17 . A method of treating a cancer in a subject in need thereof, comprising administering to the subject an effective amount of the compound of claim 9 , or a pharmaceutically acceptable salt thereof.
18 . The method of claim 17 , wherein the cancer is breast cancer.
19 . A method of treating a subject suffering from, or at risk of developing, a solid tumor cancer, comprising administering to the subject a therapeutically effective amount of a compound of claim 9 , or a pharmaceutically acceptable salt thereof.
20 . The method of claim 19 , wherein the solid tumor cancer is at least one of: uterine cancer, endometrial cancer, breast cancer, ovarian cancer, stomach cancer, gastric cancer, colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma, sarcoma, esophageal cancer, bladder cancer, lung cancer, cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma.