CDK2 INHIBITORS AND METHODS OF MAKING AND USING SAME

1 . A compound of Formula (I-1),

or a pharmaceutically acceptable salt thereof, wherein

R 1 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4 to 6 membered heterocyclyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1 to 4 groups independently selected from halo and C 3 -C 6 cycloalkyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from halo and C 1 -C 4 alkyl optionally substituted with 1 to 4 halo, wherein the heterocyclyl includes 1 or 2 heteroatoms independently selected from O, N, or S;

R 2 is H or C 1 -C 6 alkyl, or

R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a 4 to 6 membered heterocyclyl, wherein the heterocyclyl optionally includes 1 or 2 heteroatoms independently selected from O, N, or S in addition to the nitrogen atom attached to R 1 and R 2 , and is optionally substituted with 1 to 4 groups independently selected from the group consisting of halo, CO 2 R d , 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 4 halo,

X 1 is N or CR 3 ;

X 2 is N or CR 3 ;

X 3 is N or CR 3 ;

X 4 is N or CR 2 ; wherein at least 2 of X 1 , X 2 , X 3 , and X 4 are CR 3 ;

R 3 , independently for each occurrence, is selected from the group consisting of H, halo, CN, OH, NR a R b , SO w R c , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and C 3 -C 6 cycloalkyl, wherein the alkyl or alkoxy is optionally substituted with 1 to 4 groups independently selected from halo, OR 3a , and C 3 -C 6 cycloalkyl, and the C 3 -C 6 cycloalkyl is optionally substituted with 1 to 4 groups independently selected from halo and OH;

w is 0, 1, or 2;

R a is independently for each occurrence H or C 1 -C 4 alkyl optionally substituted by one, two or three halos;

R b is independently for each occurrence H or C 1 -C 4 alkyl optionally substituted by one, two or three halos;

R c is independently for each occurrence C 1 -C 4 alkyl optionally substituted by one, two or three halos;

R d is independently for each occurrence H or C 1 -C 4 alkyl optionally substituted by one, two or three halos; and

R 3a for each occurrence is H or C 1-4 alkyl optionally substituted by one, two or three halos.

2 . A compound of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein

R 1 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4 to 6 membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with 1 to 4 groups selected from halo and C 1 -C 4 alkyl optionally substituted with 1 to 4 halo, wherein the heterocyclyl includes 1 or 2 heteroatoms selected from O, N, or S;

R 2 is H or C 1 -C 6 alkyl, or

R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a 4 to 6 membered heterocyclyl, optionally substituted with 1 to 4 groups selected from halo or C 1 -C 4 alkyl,

X 1 is N or CR 3 ;

X 2 is N or CR 3 ;

X 3 is Nor CR 3 ;

X 4 is N or CR 3 ; wherein at least 2 of X 1 , X 2 , X 3 , and X 4 are CR 3 ;

R 3 , independently for each occurrence is selected from the group consisting of H, halo, CN, OH, NR a R b , SO w R c , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and C 3 -C 6 cycloalkyl, wherein the alkyl or alkoxy is optionally substituted with 1 to 4 groups independently selected from halo, OR 3a , and C 3 -C 6 cycloalkyl, and the C 3 -C 6 cycloalkyl is optionally substituted with 1 to 4 groups independently selected from halo and OH;

w is 0, 1, or 2;

R a is independently for each occurrence H or C 1 -C 4 alkyl optionally substituted by one, two or three halos;

R b is independently for each occurrence H or C 1 -C 4 alkyl optionally substituted by one, two or three halos;

R c is independently for each occurrence C 1 -C 4 alkyl optionally substituted by one, two or three halos; and

R 3a for each occurrence is H or C 1-4 alkyl optionally substituted by one, two or three halos.

3 . The compound of claim 1 or 2 , wherein the compound is selected from the group consisting of: Formula IIA, IIB, IIC, IID, IIE, and IIF:

or a pharmaceutically acceptable salt thereof.

4 . The compound of any one of claims 1-3 , wherein R 1 is C 1 -C 6 alkyl and R 2 is H.

5 . The compound of claim 1 or 3 , wherein R 1 is C 1 -C 6 alkyl optionally substituted with 1 to 4 groups selected from halo and C 3 -C 6 cycloalkyl and R 2 is H.

6 . The compound of any one of claims 1-3 , wherein R 1 is C 3-4 cycloalkyl, optionally substituted by methyl.

7 . The compound of any one of claims 1-3 , wherein R 1 is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperdinyl optionally substituted by methyl or CF 3 .

8 . The compound of claim 6 , wherein the compound is selected from the group consisting of Formula IIIA, IIIB, IIIC, IIID, IIIE and IIIF:

or a pharmaceutically acceptable salt thereof.

9 . The compound of any one of claims 1-3 , wherein R 1 and R 2 , together with the nitrogen to which they are attached, form a 4-5 membered heterocyclyl, optionally substituted on a free carbon by one or two methyl groups.

10 . The compound of claim 1 or 3 , wherein R 1 and R 2 , together with the nitrogen to which they are attached, form a 4-6 membered heterocyclyl, wherein the heterocyclyl optionally includes 1 or 2 heteroatoms independently selected from O, N, or S in addition to the nitrogen atom attached to R 1 and R 2 , and is optionally substituted on a free carbon or nitrogen by CN, CO 2 C(CH 3 ) 3 , OCH 3 , or one or two methyl groups optionally substituted with 1 to 4 halo.

11 . The compound of claim 9 or 10 , wherein the structure is selected from the group consisting of Formula IVA, IVB, IVC, IVD, IVE and IVF:

or a pharmaceutically acceptable salt thereof.

12 . The compound of any one of claims 1 to 11 wherein

each R 3 is independently selected from the group consisting of H, —OH, halo, CN, NR a R b , SO 2 R c , C 1 -C 4 alkyl, and C 1 -C 4 alkoxyl, wherein the alkyl and alkoxy are each optionally substituted with 1 to 4 groups independently selected from halo, OR 3a , or cyclopropyl;

each R a is independently selected for each occurrence from the group consisting of H, methyl, or ethyl;

each R b is independently selected for each occurrence from methyl and ethyl;

R 3a is independently selected for each occurrence from methyl or ethyl; and

R c is selected for each occurrence from methyl or ethyl.

13 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1-12 , or a pharmaceutically acceptable salt thereof.

14 . A method of treating a cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any of claims 1-12 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 13 .

15 . The method of claim 14 , wherein the cancer is at least one of: uterine cancer (including uterine carcinosarcoma, uterine corpus endometrial carcinoma), endometrial cancer, breast cancer (including breast invasive carcinoma, TNBC (triple negative breast cancer), ER (estrogen receptor)+HER2 (human epidermal growth factor 2)− breast cancer, and HER2+ breast cancer), ovarian cancer (e.g., ovarian serous cystadenocarcinoma), stomach cancer (including stomach adenocarcinoma), gastric cancer (including gastrointestinal stromal tumor), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (including B-cell lymphoma), sarcoma, esophageal cancer (including esophageal carcinoma), bladder cancer (including bladder urothelial carcinoma), lung cancer (including lung squamous carcinoma and non-small cell lung cancer, e.g., EGFRm (epidermal growth factor receptor mutant)+ non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma.

16 . A method of inhibiting CDK2, comprising administering to a subject in need thereof an effective amount of the compound of any of claims 1-12 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 13 .

17 . A method of treating a subject having, or at risk of developing, a disease or disorder associated with CDK2, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-12 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 13 , wherein the subject has an amplification of the CCNE1 gene and/or has an expression level of CCNE1 higher than a control expression level of CCNE1.

18 . The method of claim 17 , wherein the disease or disorder associated with CDK2 is cancer.

19 . A method of treating a patient having an amplified expression level of CCNE1 and suffering from, or at risk of developing, a cancer, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-12 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 13 .

20 . The method of claim 19 , wherein the cancer is at least one of: uterine cancer (including uterine carcinosarcoma, uterine corpus endometrial carcinoma), endometrial cancer, breast cancer (including breast invasive carcinoma, TNBC (triple negative breast cancer), ER (estrogen receptor)+HER2 (human epidermal growth factor 2)− breast cancer, and HER2+ breast cancer), ovarian cancer (e.g., ovarian serous cystadenocarcinoma), stomach cancer (including stomach adenocarcinoma), gastric cancer (including gastrointestinal stromal tumor), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (including B-cell lymphoma), sarcoma, esophageal cancer (including esophageal carcinoma), bladder cancer (including bladder urothelial carcinoma), lung cancer (including lung squamous carcinoma and non-small cell lung cancer, e.g., EGFRm (epidermal growth factor receptor mutant)+ non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma.