US 12,735,400 B2Granted

BCL-2 inhibitors

AssigneeEli Therapeutics, Inc.

InventorsVolodymyr Kysil, Vladislav Zenonovich Parchinsky, Alexei Pushechnikov, Alexandre Vasilievich Ivachtchenko, Ruben Abagyan, Nikolay Savchuk

Life of this patent

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Abstract

The present invention is generally directed to inhibitors of BCL-2 proteins useful in the treatment of diseases and disorders modulated by said enzyme and having the Formula (I):

Claims19

Dependent claims

A compound of Formula (I):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein:
R1 is selected from halogen, —OH, —CN, and —CONH2;
R1a is H;
or R1 and R1a, together with the atom to which they are attached, come together to form a 3- to 10-membered heteroaryl ring further comprising 1, 2, or 3 heteroatoms selected from N, O, and S;
R2 and R3 each independently selected from C1-C6 alkyl;
or R2 and R3, together with the atom to which they are attached, come together to form a 3- to 10-membered heterocyclyl ring further comprising 1, 2, or 3 heteroatoms selected from N, O, and S;
each R4 is independently selected from halogen, —OH, —CN, —NO2, —COOH, —CH2CN, CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, C1-C6 halogenalkoxy, —O—(C2-C6 alkenyl), —O—(C2-C6 alkynyl), C2-C6 alkenyl, C2-C6 alkynyl, —OH, —OP(O)(OH)2, —OC(O)(C1-C6 alkyl), —C(O)(C1-C6 alkyl), —OC(O)O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)(C1-C6 alkyl), —C(O)NH2, —C(O)NH(C1-C6 alkyl), —S(O)2(C1-C6 alkyl), —S(O)NH(C1-C6 alkyl), and S(O)N(C1-C6 alkyl)2;
R5 is selected from
each R6 is independently selected from halogen, —OH, —CN, —COOH, —CH2CN, —CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, C1-C6 halogenalkoxy, —O—(C2-C6) alkenyl, —O—(C2-C6) alkynyl, C2-C6 alkenyl, C2-C6 alkynyl, —OH, —OP(O)(OH)2, —OC(O)(C1-C6) alkyl, —C(O)(C1-C6) alkyl, —OC(O)O(C1-C6) alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)(C1-C6) alkyl, —C(O)NH(C1-C6)alkyl, —S(O)2(C1-C6) alkyl, —S(O)NH(C1-C6) alkyl, and S(O)N(C1-C6 alkyl)2;
each R7 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl;
wherein alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —COOH, —CH2CN, —CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, C1-C6 halogenalkoxy, —O—(C2-C6) alkenyl, —O—(C2-C6) alkynyl, C2-C6 alkenyl, C2-C6 alkynyl, —OH, —OP(O) (OH)2, —OC(O) (C1-C6) alkyl, —C(O) (C1-C6) alkyl, —OC(O) O(C1-C6) alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O) (C1-C6) alkyl, —C(O) NH(C1-C6) alkyl, —S(O)2(C1-C6) alkyl, —S(O)NH(C1-C6) alkyl, and S(O)N(C1-C6 alkyl)2;
or two R7 together with the nitrogen atom to which they are bound and any intervening atoms, form a heterocycle;
wherein heterocycle is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —COOH, —CH2CN, —CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, C1-C6 halogenalkoxy, —O—(C2-C6) alkenyl, —O—(C2-C6) alkynyl, C2-C6 alkenyl, C2-C6 alkynyl, —OH, —OP(O)(OH)2, —OC(O)(C1-C6) alkyl, —C(O) (C1-C6) alkyl, —OC(O)O(C1-C6) alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)(C1-C6) alkyl, —C(O)NH(C1-C6) alkyl, —S(O)2(C1-C6) alkyl, —S(O)NH(C1-C6) alkyl, and S(O)N(C1-C6 alkyl)2;
R8 is selected from H, C1-6 alkyl, C3-8 cycloalkyl, aryl, C1-6 halogenalkyl;
R9 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —(CH2)1-6OR8, C3-8 cycloalkyl, aryl, heterocycle;
wherein alkyl, cycloalkyl, aryl or heterocycle are optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —COOH, —CH2CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, C1-C6 halogenalkoxy, —O—(C2-C6) alkenyl, —O—(C2-C6) alkynyl, C2-C6 alkenyl, C2-C6 alkynyl, —OH, —OP(O)(OH)2, —OC(O)(C1-C6) alkyl, —C(O)(C1-C6) alkyl, —OC(O)O(C1-C6) alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)(C1-C6) alkyl, —C(O)NH(C1-C6) alkyl, —S(O)2(C1-C6) alkyl, —S(O)NH(C1-C6) alkyl, and S(O)N(C1-C6 alkyl)2;
wherein,
x is an integer selected from 0, 1, 2, 3;
y is an integer selected from 0, 1, 2, 3;
m is an integer selected from 0, 1, and 2;
each n is an integer independently selected from 1, 2, 3;
aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings;
heterocycle is saturated or partially unsaturated 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, and B.

20 more elements

A compound selected from:

Cmpd
#
Structure
IUPAC name
1
3-[5-chloro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- chlorophenyl)-N-[(2- cyanophenyl)methyl]- 5,6,7,8- tetrahydroindolizine-1- carboxamide
2
3-[5-chloro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- chlorophenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-5,6,7,8- tetrahydroindolizine-1- carboxamide
3
3-[5-chloro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-[(2- cyanopenyl)methyl]-N- (4-hydroxyphenyl)- 5,6,7,8- tetrahydroindolizine-1- carboxamide
4
3-[5-chloro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-5,6,7,8- tetrahydroindolizine-1- carboxamide
5
N-(4-hydroxyphenyl)-N- [(3-methoxy-2-methyl- phenyl)methyl]-3-[2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]- 5,6,7,8- tetrahydroindolizine-1- carboxamide
6
5-[5-chloro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-[(2- cyanophenyl)methyl]-N- (4-hydroxyphenyl)-1,2- dimethyl-pyrrole-3- carboxamide
7
5-[5-chloro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
8
N-(4-hydroxyphenyl)-N- [(3-methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-5-[2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2- carbonyl]phenyl]pyrrole- 3-carboxamide
9
5-[5-chloro-4-cyano-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
10
N-(4-chlorophenyl)-5-[5- (difluoromethyl)-4- methoxy-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
11
5-[5-chloro-4-methoxy-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
12
N-(4-chlorophenyl)-5-[4- (difluoromethoxy)-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
13
N-(4-chlorophenyl)-5-[5- cyano-4- (difluoromethoxy)-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
14
5-[4-cyano-5-fluoro-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
15
5-[5-chloro-4-methoxy-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- cyanophenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
16
5-[4-(difluoromethoxy)-5- fluoro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
17
5-[5-(difluoromethyl)-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
18
N-(4-chlorophenyl)-5-[4- cyano-5-fluoro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
19
5-[4-cyano-5- (difluoromethyl)-2-[(3S)- 3-(morpholinomethyl)- 3,4-dihydro-1H- isoquinoline-2- carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
20
5-[4-chloro-5- (difluoromethoxy)-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
21
5-[5-fluoro-4-methoxy-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
22
N-(4-chlorophenyl)-5-[4- cyano-5-(difluoromethyl)- 2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-[(2- cyanophenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
23
5-[5-(difluoromethyl)-4- methyl-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
24
5-[4-chloro-5- (difluoromethyl)-2-[(3S)- 3-(morpholinomethyl)- 3,4-dihydro-1H- isoquinoline-2- carbonyl]phenyl]-N-(4- cyanophenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
25
N-(4-chlorophenyl)-5-[4- (difluoromethoxy)-5- methyl-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
26
N-(4-chlorophenyl)-5-[4- (difluoromethoxy)-5- fluoro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
27
5-[5-chloro-4-fluoro-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
28
N-(4-chlorophenyl)-5-[5- (difluoromethyl)-4- methyl-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
29
5-[5-chloro-4-fluoro-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- cyanophenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
30
N-(4-cyanophenyl)-5-[5- fluoro-4-methoxy-2-[(3S)- 3-(morpholinomethyl)- 3,4-dihydro-1H- isoquinoline-2- carbonyl]phenyl]-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
31
5-[4-(difluoromethoxy)-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
32
5-[5-chloro-4- (difluoromethoxy)-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- chlorophenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
33
5-[5-chloro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- cyanophenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
34
5-[5-chloro-4-cyano-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(2- methoxyphenyl)methyl]- 1,2-dimethyl-pyrrole-3- carboxamide
35
N-(4-cyanophenyl)-5-[5- (difluoromethyl)-4-fluoro- 2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
36
5-[5-chloro-4- (difluoromethoxy)-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
37
5-[5-cyano-4-methoxy-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
38
N-(4-cyanophenyl)-5-[5- (difluoromethyl)-4- methoxy-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
39
5-[4-chloro-5- (difluoromethyl)-2-[(3S)- 3-(morpholinomethyl)- 3,4-dihydro-1H- isoquinoline-2- carbonyl]phenyl]-N-(4- chlorophenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
40
5-[5-chloro-4- (difluoromethoxy)-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- cyanophenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
41
5-[5-(difluoromethyl)-4- methoxy-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
42
N-(4-chlorophenyl)-5-[4- cyano-5-(difluoromethyl)- 2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
43
5-[4-chloro-5- (difluoromethyl)-2-[(3S)- 3-(morpholinomethyl)- 3,4-dihydro-1H- isoquinoline-2- carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
44
N-(4-cyanophenyl)-5-[4- (difluoromethoxy)-5- fluoro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
45
5-[4-cyano-5- (difluoromethoxy)-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
46
5-[5-(difluoromethoxy)-4- fluoro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
47
5-[4-(difluoromethoxy)-5- methyl-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
48
5-[5-acetamido-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
49
N-(4-hydroxyphenyl)-N- [(3-methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-5-[5- methylsulfonyl-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2- carbonyl]phenyl]pyrrole- 3-carboxamide
50
5-[4-chloro-2-methyl-6- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
51
5-[4,5-difluoro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
52
5-[5-fluoro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
53
N-[(2- cyanophenyl)methyl]-5- [4,5-difluoro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-1,2- dimethyl-pyrrole-3- carboxamide
54
5-[5-fluoro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(2- methoxyphenyl)methyl]- 1,2-dimethyl-pyrrole-3- carboxamide
55
5-[5-cyano-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(2- methoxyphenyl)methyl]- 1,2-dimethyl-pyrrole-3- carboxamide
56
N-(4-chlorophenyl)-5-[4- cyano-5-methoxy-2-[(3S)- 3-(morpholinomethyl)- 3,4-dihydro-1H- isoquinoline-2- carbonyl]phenyl]-N-[(2- methoxyphenyl)methyl]- 1,2-dimethyl-pyrrole-3- carboxamide
57
5-[5-cyano-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
58
5-[4-cyano-5-methoxy-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
59
N-(4-chlorophenyl)-5-[4- cyano-5-methoxy-2-[(3S)- 3-(morpholinomethyl)- 3,4-dihydro-1H- isoquinoline-2- carbonyl]phenyl]-N-[(2- cyanophenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
60
N-(4-chlorophenyl)-5-[4- cyano-5-methoxy-2-[(3S)- 3-(morpholinomethyl)- 3,4-dihydro-1H- isoquinoline-2- carbonyl]phenyl]-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
61
N-(4-hydroxyphenyl)-N- [(3-methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-5-[2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]-5-nitro- phenyl]pyrrole-3- carboxamide
62
N-[(2- cyanophenyl)methyl]-N- (4-hydroxyphenyl)-1,2- dimethyl-5-[2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]-5-nitro- phenyl]pyrrole-3- carboxamide
63
5-[4-carbamoyl-5- methoxy-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- chlorophenyl)-N-[(2- methoxyphenyl)methyl]- 1,2-dimethyl-pyrrole-3- carboxamide
64
5-[5-carbamoyl-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
65
N-(1H-indazol-5-yl)-N- [(3-methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-5-[2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]-5-nitro- phenyl]pyrrole-3- carboxamide
66
N-[(2- cyanophenyl)methyl]-N- (1H-indazol-6-yl)-1,2- dimethyl-5-[2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]-5-nitro- phenyl]pyrrole-3- carboxamide
67
N-(1H-indazol-6-yl)-N- [(3-methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-5-[2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]-5-nitro- phenyl]pyrrole-3- carboxamide
68
5-[5-chloro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-[(2- cyanophenyl)methyl]-N- (1H-indazol-5-yl)-1,2- dimethyl-pyrrole-3- carboxamide
69
5-[5-chloro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N- (1H-indazol-5-yl)-N-[(2- methoxyphenyl)methyl]- 1,2-dimethyl-pyrrole-3- carboxamide
70
5-[5-chloro-2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N- (1H-indazol-5-yl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
71
N-[(2- cyanophenyl)methyl]-N- (1H-indazol-5-yl)-1,2- dimethyl-5-[2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]-5-nitro- phenyl]pyrrole-3- carboxamide
72
N-(1H-indazol-6-yl)-N- [(2- methoxyphenyl)methyl]- 1,2-dimethyl-5-[2-[(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]-5-nitro- phenyl]pyrrole-3- carboxamide
73
5-[5-chloro-4-fluoro-2- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- cyanophenyl)-N-[(3- methoxy-2-methyl- phenyl)methyl]-1,2- dimethyl-pyrrole-3- carboxamide
74
5-[4-chloro-2-methyl-6- [(3S)-3- (morpholinomethyl)-3,4- dihydro-1H-isoquinoline- 2-carbonyl]phenyl]-N-(4- hydroxyphenyl)-N-[(2- methoxyphenyl)methyl]- 1,2-dimethyl-pyrrole-3- carboxamide
or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

150 more elements

Dependencies are inferred from the claim text.

Facts

Application: 18/725,057Filed 27 Dec 2022 · us provisional application
Priority: 29 Dec 2021
Published: US 2025/0115577 A110 Apr 2025
Granted: 15 Sep 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

A61P 35/00
Antineoplastic agents
C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61K 31/5377
1,4-Oxazines, e.g. morpholine: not condensed and containing further heterocyclic rings, e.g. timolol
C07D 401/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings

Family

Application63/294,646Us provisional application · filed 29 Dec 2021
Application63/415,203Us provisional application · filed 11 Oct 2022
US 2025/0115577 A1Pre-grant publication · published 10 Apr 2025
US 12,735,400 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

The present invention is generally directed to inhibitors of BCL-2 proteins useful in the treatment of diseases and disorders modulated by said enzyme and having the Formula (I):

A compound of Formula (I):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, wherein:
R1 is selected from halogen, —OH, —CN, and —CONH2;
R1a is H;
or R1 and R1a, together with the atom to which they are attached, come together to form a 3- to 10-membered heteroaryl ring further comprising 1, 2, or 3 heteroatoms selected from N, O, and S;
R2 and R3 each independently selected from C1-C6 alkyl;
or R2 and R3, together with the atom to which they are attached, come together to form a 3- to 10-membered heterocyclyl ring further comprising 1, 2, or 3 heteroatoms selected from N, O, and S;
each R4 is independently selected from halogen, —OH, —CN, —NO2, —COOH, —CH2CN, CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, C1-C6 halogenalkoxy, —O—(C2-C6 alkenyl), —O—(C2-C6 alkynyl), C2-C6 alkenyl, C2-C6 alkynyl, —OH, —OP(O)(OH)2, —OC(O)(C1-C6 alkyl), —C(O)(C1-C6 alkyl), —OC(O)O(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)(C1-C6 alkyl), —C(O)NH2, —C(O)NH(C1-C6 alkyl), —S(O)2(C1-C6 alkyl), —S(O)NH(C1-C6 alkyl), and S(O)N(C1-C6 alkyl)2;
R5 is selected from
each R6 is independently selected from halogen, —OH, —CN, —COOH, —CH2CN, —CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, C1-C6 halogenalkoxy, —O—(C2-C6) alkenyl, —O—(C2-C6) alkynyl, C2-C6 alkenyl, C2-C6 alkynyl, —OH, —OP(O)(OH)2, —OC(O)(C1-C6) alkyl, —C(O)(C1-C6) alkyl, —OC(O)O(C1-C6) alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)(C1-C6) alkyl, —C(O)NH(C1-C6)alkyl, —S(O)2(C1-C6) alkyl, —S(O)NH(C1-C6) alkyl, and S(O)N(C1-C6 alkyl)2;
each R7 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl;
wherein alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —COOH, —CH2CN, —CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, C1-C6 halogenalkoxy, —O—(C2-C6) alkenyl, —O—(C2-C6) alkynyl, C2-C6 alkenyl, C2-C6 alkynyl, —OH, —OP(O) (OH)2, —OC(O) (C1-C6) alkyl, —C(O) (C1-C6) alkyl, —OC(O) O(C1-C6) alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O) (C1-C6) alkyl, —C(O) NH(C1-C6) alkyl, —S(O)2(C1-C6) alkyl, —S(O)NH(C1-C6) alkyl, and S(O)N(C1-C6 alkyl)2;
or two R7 together with the nitrogen atom to which they are bound and any intervening atoms, form a heterocycle;
wherein heterocycle is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —COOH, —CH2CN, —CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, C1-C6 halogenalkoxy, —O—(C2-C6) alkenyl, —O—(C2-C6) alkynyl, C2-C6 alkenyl, C2-C6 alkynyl, —OH, —OP(O)(OH)2, —OC(O)(C1-C6) alkyl, —C(O) (C1-C6) alkyl, —OC(O)O(C1-C6) alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)(C1-C6) alkyl, —C(O)NH(C1-C6) alkyl, —S(O)2(C1-C6) alkyl, —S(O)NH(C1-C6) alkyl, and S(O)N(C1-C6 alkyl)2;
R8 is selected from H, C1-6 alkyl, C3-8 cycloalkyl, aryl, C1-6 halogenalkyl;
R9 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —(CH2)1-6OR8, C3-8 cycloalkyl, aryl, heterocycle;
wherein alkyl, cycloalkyl, aryl or heterocycle are optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —COOH, —CH2CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogenalkyl, C1-C6 halogenalkoxy, —O—(C2-C6) alkenyl, —O—(C2-C6) alkynyl, C2-C6 alkenyl, C2-C6 alkynyl, —OH, —OP(O)(OH)2, —OC(O)(C1-C6) alkyl, —C(O)(C1-C6) alkyl, —OC(O)O(C1-C6) alkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)(C1-C6) alkyl, —C(O)NH(C1-C6) alkyl, —S(O)2(C1-C6) alkyl, —S(O)NH(C1-C6) alkyl, and S(O)N(C1-C6 alkyl)2;
wherein,
x is an integer selected from 0, 1, 2, 3;
y is an integer selected from 0, 1, 2, 3;
m is an integer selected from 0, 1, and 2;
each n is an integer independently selected from 1, 2, 3;
aryl is cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings;
heterocycle is saturated or partially unsaturated 3-10 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms selected from O, N, S, P, Se, and B.

20 more elements

Facts

Application

18/725,057Filed 27 Dec 2022 · us provisional application

Priority

29 Dec 2021

Published

US 2025/0115577 A110 Apr 2025

Granted

15 Sep 2026

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

A61P 35/00
Antineoplastic agents
C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61K 31/5377
1,4-Oxazines, e.g. morpholine: not condensed and containing further heterocyclic rings, e.g. timolol
C07D 401/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings