Cdk2 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-2024174665-A1
Application number	US-202318453163-A
Country	US
Kind code	A1
Filing date	Aug 21, 2023
Priority date	Aug 19, 2022
Publication date	May 30, 2024
Grant date	—

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

First claim

1 . A compound of formula I-a′:

or a pharmaceutically acceptable salt thereof, wherein:
Ring W and Ring X are independently fused rings selected from benzo, a 4 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
Ring Y is a ring selected from phenylenyl, a 3 to 12-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclylenyl or heterocyclylenyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
Y is a covalent bond, —S(O) 2 —, —S(O)—, —S(O)(NR)—, —P(O)R—, —P(O)OR—, or

Ring Z is an optionally substituted 3-12 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Q 5 is carbon or sulfur;
X is —NR 2 or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3 to 12-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
each R w , R x , and R y is independently selected from hydrogen, R A , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —SiR 3 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)NROR, —OC(O)R, —OC(O)NR 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)NR 2 , —OP(O)(NR 2 ) 2 , —P(O)R 2 , —P(O)(OR) 2 , —P(O)(OR)NR 2 , —P(O)(NR 2 ) 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)N(R) 2 , —NRS(O) 2 R, —NP(O)R 2 , —NRP(O)(OR) 2 , —NRP(O)(OR)NR 2 , —NRP(O)(NR 2 ) 2 , and —NRS(O) 2 R; or
two R w groups attached to the same or adjacent carbon atom are optionally taken together to form a spiro fused or 1,2-fused ring selected from a 3-12 membered saturated or partially unsaturated carbocyclyl and a 3-12 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R A is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-12 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same atom are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the atom or atoms to which they are attached, independently selected from nitrogen, oxygen, and sulfur; and

w, x, and y are independently 0, 1, 2, 3, or 4.

2 . The compound of claim 1 , wherein said compound is a compound of any of the following formulae:

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 1 , wherein Ring W is a fused ring selected from benzo, a 4 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

4 . The compound of claim 1 , wherein Ring X is a fused ring selected from benzo, a 4 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

5 . The compound of claim 1 , wherein R w is hydrogen, R A , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)NROR, —OC(O)R, —OC(O)NR 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)N(R) 2 , or —NRS(O) 2 R.

6 . The compound of claim 1 , wherein R x is hydrogen, R A , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)NROR, —OC(O)R, —OC(O)NR 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)N(R) 2 , or —NRS(O) 2 R.

7 . The compound of claim 1 , wherein R y is hydrogen, R A , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)NROR, —OC(O)R, —OC(O)NR 2 , —NRC(O)OR, —NRC(O)R, —NRC(O)N(R) 2 , or —NRS(O) 2 R.

8 . A compound of formula I-b′:

or a pharmaceutically acceptable salt thereof, wherein:
Ring W and Ring X are independently rings selected from phenyl, a 4 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
Ring Y is a ring selected from phenyl, a 3 to 12-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
Y is a covalent bond, —S(O) 2 —, —S(O)—, —S(O)(NR)—, —P(O)R—, —P(O)OR—, or

Ring Z is an optionally substituted 3-12 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Q 5 is carbon or sulfur;
X is —NR 2 or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3 to 12-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5 to 6-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
R w , R x , and R y are independently selected from hydrogen, R A , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —SiR 3 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)NROR, —OC(O)R, —OC(O)NR 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)NR 2 , —OP(O)(NR 2 ) 2 , —P(O)R 2 , —P(O)(OR) 2 , —P(O)(OR)NR 2 , —P(O)(

Assignees

• Kymera Therapeutics Inc

Inventors

• Collier Philip
• Zheng Xiaozhang
• Zhu Xiao
• Ford Melissa
• Weiss Matthew M
• Aversa Robert
• Mahasenan Kiran Vijayakumari
• Zhang Yi

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D215/227

  only one oxygen atom which is attached in position 2 · CPC title

• C07D231/40

  Acylated on said nitrogen atom · CPC title

• C07D239/42

  One nitrogen atom (nitro radicals C07D239/30) · CPC title

• C07D239/84

  Nitrogen atoms · CPC title