CDK2 inhibitors

Patent metadata

Field	Value
Publication number	US-12545684-B2
Application number	US-202418605248-A
Country	US
Kind code	B2
Filing date	Mar 14, 2024
Priority date	Jun 28, 2021
Publication date	Feb 10, 2026
Grant date	Feb 10, 2026

Abstract

The present disclosure provides a compound represented by structural Formula (I): or a pharmaceutically acceptable salt thereof useful for treating a cancer.

First claim

The invention claimed is:

1 . A method of treating a cancer, comprising administering to a subject in need thereof an effective amount of a compound of Formula (Ia),

or a pharmaceutically acceptable salt thereof,
wherein
R 1 is C 1 -C 4 alkyl optionally substituted with 1 to 4 groups each independently selected from halo and D;
R 2 is C 1 -C 4 alkyl or Ring A, wherein the C 1 -C 4 alkyl is optionally substituted with 1 to 4 groups each independently selected from halo, D, CN, and OH and/or 1 group of 5 to 6 membered heteroaryl having 1 to 3 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR d ; and
R 3 is selected from the group consisting of H, D, C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl, and 4 to 12-membered heterocyclyl, wherein the C 1 -C 4 alkyl and C 3 -C 10 cycloalkyl are each optionally substituted with 1 to 4 R c , wherein the 4 to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR d and then is optionally substituted on a ring carbon with 1 to 4 R c ; or
R 2 and R 3 are taken together with the carbon atom to which they are attached to form Ring B, wherein Ring B is C 3 -C 10 cycloalkyl or 4 to 12-membered heterocyclyl, wherein the C 3 -C 10 cycloalkyl is optionally substituted with 1 to 4 R b , wherein the 4 to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of NR d , N, O, and S and then is optionally substituted on a ring carbon by 1 to 4 R b ;
Ring A is selected from the group consisting of C 3 -C 10 cycloalkyl, phenyl, naphthyl, 4 to 12-membered heterocyclyl, and 4 to 12-membered heteroaryl, wherein the C 3 -C 10 cycloalkyl, phenyl, and naphthyl are each optionally substituted with 1 to 4 R a , wherein the 4 to 12-membered heterocyclyl and 4 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR d and then are optionally substituted on a ring carbon with 1 to 4 R a ;
Each R a is independently selected from the group consisting of D, halo, OH, CN, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy, or two R a , attached to the same atom, form a ═O, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN;
Each R b is independently selected from the group consisting of D, halo, OH, CN, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy, or two R b , attached to the same atom, form a ═O, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH and CN;
Each R c is independently selected from the group consisting of D, halo, OH, CN, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy, or two R c , attached to the same atom, form a ═O, wherein the C 1 -C 4 alkyl and C 1 -C 4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH, and CN;
Each R d is independently selected from the group consisting of H, D, and C 1 -C 6 alkyl;
R 4 is selected from the group consisting of H, D, and C 1 -C 4 alkyl optionally substituted with 1 to 4 groups each independently selected from halo, D and OH;
R 5 is selected from the group consisting of H, D, halo, CN, and C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is optionally substituted with 1 to 4 groups each independently selected from halo and OH;
R 6 is H or D; and
R 7 is H or D.

2 . The method of claim 1 , wherein R 1 is methyl or ethyl, each optionally substituted with 1 to 4 halo or D.

3 . The method of claim 1 , wherein R 1 is selected from the group consisting of methyl, ethyl, CF 3 , CH 2 F, and CHF 2 .

4 . The method of claim 1 , wherein the compound is of Formula (IIa):

or a pharmaceutically acceptable salt thereof.

5 . The method of claim 4 , wherein Ring A is 4 to 10-membered heterocyclyl, optionally substituted on a ring carbon with 1 to 3 groups each independently selected from the group consisting of D, halo, OH, ═O, 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 groups each independently selected from the group consisting of halo, OH, and CN.

6 . The method of claim 4 , wherein Ring A is 4 to 10-membered heteroaryl, optionally substituted on a ring carbon with 1 to 3 groups each independently selected from the group consisting of D, halo, OH, ═O, 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 groups each independently selected from the group consisting of halo, OH, and CN.

7 . The method of claim 1 , wherein the compound is of Formula IIIa:

or a pharmaceutically acceptable salt thereof.

8 . The method of claim 7 , wherein Ring B is C 3 -C 8 cycloalkyl, optionally substituted with 1 to 3 groups each independently selected from the group consisting of D, halo, OH, ═O, 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 groups each independently selected from the group consisting of halo, OH, and CN.

9 . The method of claim 1 , wherein R 3 is selected from the group consisting of H, D, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, and 4 to 10-membered heterocyclyl, wherein the C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, and 4 to 10-membered heterocyclyl are each optionally substituted (on a ring carbon if R 3 is 4 to 10-membered heterocyclyl) with 1 to 3 groups each independently selected from the group consisting of D, halo, and OH.

10 . The method of claim 1 , wherein R 3 is selected from the group consisting of H, D, methyl, ethyl, cyclopropyl, and oxetanyl, each of which is optionally substituted (on a ring carbon if R 3 is oxetanyl) with 1 to 3 groups each independently selected from the group consisting of D, halo, and OH.

11 . The method of claim 1 , wherein R 4 is selected from the group consisting of H, D, and CH 3 .

12 . The method of claim 1 , wherein R 5 is H.

13 . The method of claim 1 , wherein the compound is of Formula IVa-1 or IVb-1:

or a pharmaceutically acceptable salt thereof.

14 . The method of claim 1 , wherein the cancer is a solid tumor cancer.

15 . The method of claim 14 , wherein the solid tumor 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 car

Assignees

• Blueprint Medicines Corp

Inventors

• Wilson Douglas
• Bifulco Jr Neil
• Brooijmans Natasja
• Kim Joseph L
• Ramsden Philip D
• Vargas Richard
• Wenglowsky Steven Mark

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/4985 Primary

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title