BCL-2 inhibitors and their use as pharmaceuticals

Patent metadata

Field	Value
Publication number	US-11622970-B2
Application number	US-202117241390-A
Country	US
Kind code	B2
Filing date	Apr 27, 2021
Priority date	Apr 28, 2020
Publication date	Apr 11, 2023
Grant date	Apr 11, 2023

Abstract

The disclosure is directed to, in part, to BCL-2 inhibitors, pharmaceutical compositions comprising the same, as well as methods of their use and preparation.

First claim

What is claimed:

1. A compound having the formula of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

wherein:
L is absent, (CR 29 R 30 ) k , O, NR 15 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
E is C, N, or CR 11 , wherein when E is C, is a double bond; when E is CR 11 , is a single bond; and when E is N, is a single bond;
G is CR 16 or CR 16 R 17 , wherein when is a double bond, G is CR 16 ;
X, Y, and Z are each, independently, N or CR 20 ;
Cy 1 and Cy 2 are each, independently, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
Cy 3 is optionally substituted aryl, optionally substituted cycloalkyl, or optionally substituted heteroaryl;
R is H, D, halo, optionally substituted C 1-6 alkyl, OR 8 , SR 8 , or NR 9 R 10 ,

wherein ring A is a 4- to 14-membered heterocycle or heteroaryl containing at least one nitrogen;
Y A and Y B are each, independently, N, O, S, or CR 21 ;
R 1 is H, D, halo, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , N 3 , OR A , SR A , C(O)R B , C(O)NR C R D , C(O)OR A , OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , C(═(NR C )R B , C(═NR C )NR C R D , NR C S(O)R B , NR C S(O) 2 NR C R D , NR C C(═NR C )NR C R D , NR C C(═NOR A )NR C R D , NR C C(═NCN)NR C R D , S(O)(═NR C )R B , S(O)(═NR C )NR C R D , NR C C(O)OR A , P(O)R E R F , P(O)OR E OR F , OP(O)OR E OR F , SF 5 , S(O)R B , S(O)NR C R D , S(O) 2 R B , NR C S(O) 2 R B , S(O) 2 NR C R D , B(OR A ) 2 , Cy 4 , C 1-6 alkyl-Cy 4 , O—C 1-6 alkyl-Cy 4 , or O—C 1-6 alkyl-Cy 4 -C 0-6 alkyl-Cy 5 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, O—C 1-6 alkyl, Cy 4 , and Cy 5 are each optionally substituted;
wherein two adjacent R 1 , together with the atom or atoms to which they are attached, optionally form a fused 3- to 10-membered cycloalkyl ring or a fused 4- to 10-membered heterocycloalkyl ring, each of which is optionally substituted by 1, 2, 3, 4, 5, or 6 substituents, wherein each said substituent is independently D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , oxo, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , C(═(NR c )R b , C(═NR c )NR c R d , NR c S(O)R b , NR c S(O) 2 NR c R d , NR c C(═NR c )NR c R d , NR c C(═NOR a )NR c R d , NR c (═NCN)NR c R d , S(O)(═NR c )R b , S(O)(═NR c )NR c R d , NR c C(O)OR a , P(O)R e R f , P(O)OR e OR f , OP(O)OR e OR f , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , or S(O) 2 NR c R d , B(OR a ) 2 , aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are each optionally substituted;
each R 2 is H, D, halo, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, cycloalkyl, heterocycloalkyl, CN, NO 2 , OR A , SR A , C(O)R B C(O)NR C R D , C(O)OR A , OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , C(═(NR C )R B , C(═NR C )NR C R D , NR C S(O)R B , NR C S(O) 2 NR C R D , NR C C(═NR C )NR C R D , NR C C(═NOR A )NR C R D , NR C C(═NCN)NR C R D , S(O)(═NR C )R B , S(O)(═NR C )NR C R D , NR C C(O)OR A , P(O)R E R F , P(O)OR E OR F , OP(O)OR E OR F , SF 5 , S(O)R B , S(O)NR C R D , S(O) 2 R B , NR C S(O) 2 R B , S(O) 2 NR C R D or B(OR A ) 2 ;
wherein two R 2 , together with the atom or atoms to which they are attached form a 3- to 7-membered cycloalkyl group or 4- to 7-membered heterocycloalkyl group, each of which is optionally substituted by 1, 2, or 3 substituents, wherein each said substituent is independently H, D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkyl NR c R d , CN, NO 2 , oxo, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , C(═(NR c )R b , C(═NR)NR c R d , NR c S(O)R b , NR c S(O) 2 NR c R d , NR c C(═NR)NR c R d , NR c C(═NOR a )NR c R d , NR c (═NCN)NR c R d , S(O)(═NR c )R b , S(O)(═NR)NR c R d , NR c C(O)OR a , P(O)R e R f , P(O)OR e OR f , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , or S(O) 2 NR c R d ;
each R 3 is H, D, halo, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, Cy 4 , C 1-6 alkyl-Cy 4 , CN, NO 2 , OR A , SR A , C(O)R B , C(O)NR C R D , C(O)OR A , OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , C(═(NR C )R B , C(═NR C )NR C R D , NR C S(O)R B , NR C S(O) 2 NR C R D , NR C C(═NR C )NR C R D , NR C C(═NOR A )NR C R D , NR C C(═NCN)NR C R D , S(O)(═NR C )R B , S(O)(═NR C )NR C R D , NR C C(O)OR A , P(O)R E R F , P(O)OR E OR F , OP(O)OR E OR F , SF 5 , S(O)R B , S(O)NR C R D , S(O) 2 R B , NR C S(O) 2 R B , S(O) 2 NR C R D , B(OR A ) 2 ;
wherein two R 3 , together with the atom or atoms to which they are attached form a 3- to 7-membered cycloalkyl group or 4- to 7-membered heterocycloalkyl group, each of which is optionally substituted by 1, 2, or 3 substituents, wherein each said substituent is independently H, D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkyl NR c R d , CN, NO 2 , oxo, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , C(═(NR c )R b , C(═NR)NR c R d , NR c S(O)R b , NR c S(O) 2 NR c R d , NR c C(═NR c )NR c R d , NR c C(═NOR a )NR c R d , NR c C(═NCN)NR c R d , S(O)(═NR c )R b , S(O)(═NR)NR c R d , NR c C(O)OR a , P(O)R e R f , P(O)OR e OR f , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , or S(O) 2 NR c R d ;
each R 4 is H, D, halo, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, Cy 4 , C 1-6 alkyl-Cy 4 , CN, NO 2 , OR A , SR A , C(O)R B , C(O)NR C R D , C(O)OR A , OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R D , NR C C(O)NR C R D , C(═(NR C )R B , C(═NR C )NR C R D , NR C S(O)R B , NR C S(O) 2 NR C R D , NR C C(═NR C )NR C R D , NR C C(═NOR A )NR C R D , NR C C(═NCN)NR C R D , S(O)(═NR C )R B , S(O)(═NR C )NR C R D , NR C C(O)OR A , P(O)R E R F , P(O)OR E OR F , OP(O)OR E OR F , SF 5 , S(O)R B , S(O)NR C R D , S(O) 2 R B , NR C S(O) 2 R B , S(O) 2 NR C R D , B(OR A ) 2 ;
wherein two R 4 , together with the atom or atoms to which they are attached form a 3- to 7-membered cycloalkyl group or 4- to 7-membered heterocycloalkyl group, each of which is optionally substituted by 1, 2, or 3 substituents, wherein each said substituent is independently H, D, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkyl, NR c R d , CN, NO 2 , oxo, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , C(═(NR c )R b , C(═NR)NR c R d , NR c S(O)R b , NR c S(O) 2 NR c R d , NR c C(═NR)NR c R d , NR c C(═NOR a )NR c R d , NR c (═NCN)NR c R d , S(O)(═NR c )R b , S(O)(═NR C )NR c R d , NR c C(O)OR a , P(O)R e R f , P(O)OR e OR f , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , or S(O) 2 NR c R d ;
R 5 , R 6 , R 7 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 29 , and R 30 are each, independently, absent, H, D, halo, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, CN, NO 2 , C(O)NR C R D , C(O)OR A or B(OR A ) 2

Assignees

• Prelude Therapeutics Inc
• Prelude Therapeutics Inc

Inventors

• Zhuo Jincong
• Combs Andrew Paul
• Wei Peng
• Wang Jialiang

Classifications

• C07D295/096

  with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• 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

• C07D239/69 Primary

  Benzenesulfonamido-pyrimidines · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title