CDK inhibitors and their use as pharmaceuticals

Patent metadata

Field	Value
Publication number	US-12486277-B2
Application number	US-202318295394-A
Country	US
Kind code	B2
Filing date	Apr 4, 2023
Priority date	Sep 11, 2019
Publication date	Dec 2, 2025
Grant date	Dec 2, 2025

Abstract

The disclosure is directed to, in part, to CDK inhibitors, pharmaceutical compositions comprising the same, as well as methods of their use and preparation.

First claim

What is claimed:

1 . A compound of

or a pharmaceutically acceptable salt or solvate thereof,
wherein:
X 1 , X 2 , and X 3 are each independently N or CR 3 ;
A 1 is N or C—R 4 ,
B 1 is C—R 6 R 7 , N—R 5 ;
A 2 is N—R 8 , S, or O;
B 2 is C—R 9 ;
R 1 is C 3-10 cycloalkyl or 4-10 membered heterocycloalkyl optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8 independently selected Rb substituents;
R 2 is C 1-6 alkyl;
R 3 is H, D, OH, halogen, CN, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkoxyl, C 1-6 haloalkyl, or 4-14 membered heterocycloalkyl;
R 4 is H, D, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl;
R 5 is C 1-6 alkyl, C 1-6 alkoxy, —CF 3 (CH)CH 3 , C 3-6 cycloalkyl, —CH 2 -(C 3-6 cycloalkyl), or 4-6 membered heterocycloalkyl;
or R 4 and R 5 , together with the atoms to which they are attached, form a 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with 1, 2, 3, 4 or 5 independently selected Rb substituents;
R 6 is C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl;
R 7 is C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl;
or R 6 and R 7 together with the carbon atom to which they are both attached, form a C 4-7 spirocyclic ring;

R 8 is C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl; and
R 9 is C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, or 4-6 membered heterocycloalkyl;
or R 8 and R 9 , together with the atoms to which they are attached, form an 5- or 6-membered heterocycloalkyl ring optionally substituted with 1, 2, 3, 4 or 5 independently selected Rb substituents;

R b is CN, C 1-4 alkyl, 5-10 membered heteroaryl, 4-14 membered heterocycloalkyl, NR c C(═NR c )NR c R c , NR c C(═NOH)NR c R c , NR c C(═NCN)NR c R c , NR c C(O)R c , NR c C(O)OR c , NR c C(O)NR c R c , NR c S(O)R c , or NR c S(O) 2 R c , NR c S(O) 2 NR c R c ;
each R c is independently H, OH, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl, C 3-10 cycloalkyl-C 1-4 alkyl, or (4-10 membered heterocycloalkyl)-C 1-4 alkyl, or (5-10 membered heteroaryl)-C 1-4 alkyl;
wherein when R c is C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, or (5-10 membered heteroaryl)-C 1-4 alkyl, then R c is optionally substituted with 1, 2, 3, 4, or 5 independently selected R f substituents;
each R f is independently halogen, CN, C 1-4 alkyl, or OR g ; and
each R g is independently H or C 1-6 alkyl.

2 . The compound of claim 1 , wherein the compound has a formula:

or a
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
X 1 , X 2 , and X 3 are each independently N or CR 3 ;
A 1 is N or C—R 4 ;
B 1 is C—R 6 R 7 , N—R 5 ;
A 2 is N—R 8 , S, or O;
B 2 is C—R 9 ;
R 1 is C 3-10 cycloalkyl optionally substituted with 1, 2, 3, 4, 5, 6, 7 or 8 independently selected Rb substituents;
R 2 is C 1-6 alkyl;
R 3 is H, D, OH, halogen, CN, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkoxyl, or 4-14 membered heterocycloalkyl;
R 4 is H, D, C 1-6 alkyl, or C 1-6 alkoxy;
R 5 is C 1-6 alkyl or C 1-6 alkoxy;
or R 4 and R 5 , together with the atoms to which they are attached, form an 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with 1, 2, 3, 4 or 5 independently selected Rb substituents;

R 6 is C 1-6 alkyl;
R 7 is C 1-6 alkyl;
or R 6 and R 7 together with the carbon atom to which they are both attached, form a C 4-7 spirocyclic ring;

R 8 is C 1-6 alkyl; and
R 9 is C 1-6 alkyl;
or R 8 and R 9 , together with the atoms to which they are attached, form an 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted with 1, 2, 3, 4 or 5 independently selected Rb substituents;

R b is C 1-4 alkyl, NR c C(═NR c )NR c R c , NR c C(═NOH)NR c R c , NR c C(═NCN)NR c R c , NR c C(O)R c , NR c C(O)OR c , NR c C(O)NR c R c , NR c S(O)R c , NR c S(O)(═NR c )R c , NR c S(O) 2 R c , or NR c S(O) 2 NR c R c ;
each R c is independently H, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, or (5-10 membered heteroaryl)-C 1-4 alkyl;
wherein when R c is C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, or (5-10 membered heteroaryl)-C 1-4 alkyl, then R c is optionally substituted with 1, 2, 3, 4, or 5 independently selected R f substituents;
each R f is independently halogen, CN, C 1-4 alkyl, or OR g ; and
each R g is independently H or C 1-6 alkyl.

3 . The compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is CH 3 or CH 2 CH 3 .

4 . The compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein said compound is a compound of Formula (I):

5 . The compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein said compound is a compound of Formula (II):

6 . The compound of claim 1 , wherein the compound has a formula of

or a pharmaceutically acceptable salt or solvate thereof.

7 . The compound of claim 1 , wherein the compound has a formula of

or a pharmaceutically acceptable salt or solvate thereof.

8 . The compound according to claim 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein said compound is a compound of Formula (V), Formula (VI), Formula (VII), or Formula (XI):

9 . The compound according to claim 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein said compound is a compound of Formula (VIII), Formula (IX), Formula (X), or Formula (XII):

10 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is

wherein n is 0 or 1.

11 . The compound of claim 10 , or a pharmaceutically acceptable salt or solvate thereof, wherein the 1 Rb substituent on R 1 is acetamido (—NHC(O)CH 3 ), 3-hydroxybutanamido (—NHC(O)CH 2 CH(OH)CH 3 ), propionamido (—NHC(O)CH 2 CH 3 ), 2-methoxyacetamido (—NHC(O)CH 2 —OCH 3 ), 2-cyanoacetamido (—NHC(O)CH 2 —CN),

methylsulfonamido (—NHSO 2 CH 3 ), 3-methylureido (—NHC(O)NHCH 3 ), 3-methoxyureido (—NHC(O)NHOCH 3 ), 3,3-dimethylureido (—NHC(O)N(CH 3 ) 2 ), 3-ethylureido (—NHC(O)NHCH 2 CH 3 ),

12 . The compound

Assignees

• Prelude Therapeutics Inc
• Prelude Therapeutis Incorporated

Inventors

• Lu Liang
• Shetty Rupa
• Combs Andrew Paul
• Dai Chaofeng
• Leal Raul Andrew
• Bersch Klare Lazor

Classifications

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P35/00

  Antineoplastic agents · CPC title