Back to results
US 11,697,650 B2Granted
Compounds having tetrahydroindolizine-1-carboxamide as BCL-2 inhibitors
AssigneeEil Therapeutics, Inc.
InventorsVolodymyr Kysil, Vladislav Zenonovich Parchinsky, Alexei Pushechnikov, Alexandre Vasilievich Ivachtchenko, Ruben Abagyan, Andrew Orry, Polo Chun-Hung Lam, Nikolay Savchuk
Life of this patent
Estimating the term…
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):
Claims61
A compound of Formula (I):
- or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof,
- wherein:
- Ring A is selected from aryl or heteroaryl;
- each R1 is independently selected from halo, —OH, —CN, —NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, aryl, —C(O)OR4, and —C(O)NR5R6, wherein aryl is optionally substituted with one or more R7;
- R2 is selected from H, C1-C6 alkyl, and —C(O)R4;
- R3 is selected from 3- to 8-membered heterocyclyl, —O(CH2O)oR8, and —N(R9)2, wherein the heterocyclyl is optionally substituted with one or more R10;
- each R4 is independently selected from H and C1-C6 alkyl;
- each R5 is independently selected from H, C1-C6 alkyl, —(CH2)pOR11, —(CH2)pN(R11)2, and S(O)2R11;
- each R6 is independently selected from H and C1-C6 alkyl,
- or R5 and R6, 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, wherein the heterocyclyl is optionally substituted with one or more R11;
- each R7 is independently selected from halo, —OH, —CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;
- R8 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and 3- to 8-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more R10;
- each R9 is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl;
- each R10 is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, and —OH;
- each R11 is independently selected from H and C1-C6 alkyl;
- m is an integer selected from 0, 1, 2, 3, 4, and 5;
- and
- n is an integer selected from 0, 1, 2, 3, and 4;
- o is an integer selected from 0, 1, and 2;
- and
- p is an integer selected from 0, 1, 2, 3, 4, 5, and 6.
18 more elements
A compound selected from:
- Compound No.
- Compound Name
- 1
- (S)-N-(4-hydroxyphenyl)-N-(4-((2-methoxyethyl)carbamoyl)benzyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 2
- (S)-N-(4-hydroxyphenyl)-N-(3-((2-methoxyethyl)carbamoyl)benzyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 3
- (S)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 4
- (S)-N-(4-hydroxyphenyl)-N-(2-methylbenzyl)-3-(6-(3-(morpholinomethyl)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8- tetrahydroindolizine-1-carboxamide;
- 5
- (S)-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-N-(2- (trifluoromethyl)benzyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide;
- 6
- (S)-N-(3-((2-(dimethylamino)ethyl)carbamoyl)benzyl)-N-(4-hydroxyphenyl)- 3-(6-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 7
- (S)-N-(3-carbamoylbenzyl)-N-(4-hydroxyphenyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 8
- (S)-N-(4-((2-(dimethylamino)ethyl)carbamoyl)benzyl)-N-(4-hydroxyphenyl)- 3-(6-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 9
- (S)-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-N-(pyridin-4- ylmethyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide;
- 10
- (S)-N-(4-hydroxyphenyl)-N-(3-(4-methylpiperazine-1-carbonyl)benzyl)-3-(6- (3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 11
- (S)-N-(2-fluorobenzyl)-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8- tetrahydroindolizine-1-carboxamide;
- 12
- (S)-N-(4-hydroxyphenyl)-N-(4-(4-methylpiperazine-1-carbonyl)benzyl)-3-(6- (3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 13
- (S)-N-(4-carbamoylbenzyl)-N-(4-hydroxyphenyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 14
- (S)-N-(4-hydroxyphenyl)-N-(3-methylbenzyl)-3-(6-(3-(morpholinomethyl)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8- tetrahydroindolizine-1-carboxamide;
- 15
- (S)-N-benzyl-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8- tetrahydroindolizine-1-carboxamide;
- 16
- (S)-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-N-(3- (trifluoromethyl)benzyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide;
- 17
- (S)-N-(4-fluorobenzyl)-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8- tetrahydroindolizine-1-carboxamide;
- 18
- (S)-N-([1,1′-biphenyl]-3-ylmethyl)-N-(4-hydroxyphenyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 19
- (S)-N-(2,6-difluorobenzyl)-N-(4-hydroxyphenyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 20
- (S)-N-(4-hydroxyphenyl)-N-(4-methylbenzyl)-3-(6-(3-(morpholinomethyl)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8- tetrahydroindolizine-1-carboxamide;
- 21
- (S)-N-(3-fluorobenzyl)-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8- tetrahydroindolizine-1-carboxamide;
- 22
- (S)-N-(2-fluoro-6-(trifluoromethyl)benzyl)-N-(4-hydroxyphenyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 23
- (S)-N-(4-hydroxyphenyl)-N-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)- 3-(6-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 24
- (S)-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-N-(4- (trifluoromethyl)benzyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide;
- 25
- (S)-4-((N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8- tetrahydroindolizine-1-carboxamido)methyl)benzoic acid;
- 26
- (S)-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-N-(4- (trifluoromethoxy)benzyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide;
- 27
- (S)-N-((2-(4-ethoxyphenyl)-5-(13-methyl)oxazol-4-yl)methyl)-N-(4- hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline- 2-carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 28
- (S)-3-((N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8- tetrahydroindolizine-1-carboxamido)methyl)benzoic acid;
- 29
- tert-butyl (S)-3-((N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8- tetrahydroindolizine-1-carboxamido)methyl)benzoate;
- 30
- (S)-N-(2,6-dimethylbenzyl)-N-(4-hydroxyphenyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 31
- (S)-N-(4-hydroxyphenyl)-N-(2-methoxybenzyl)-3-(6-(3-(morpholinomethyl)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8- tetrahydroindolizine-1-carboxamide;
- 32
- (S)-N-(2-fluoro-6-methylbenzyl)-N-(4-hydroxyphenyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 33
- (S)-N-(2-chlorobenzyl)-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8- tetrahydroindolizine-1-carboxamide;
- 34
- (S)-N-(2-chloro-6-methylbenzyl)-N-(4-hydroxyphenyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 35
- (S)-N-(6-chloro-2,3-difluorobenzyl)-N-(4-hydroxyphenyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 36
- (S)-N-([1,1′-biphenyl]-2-ylmethyl)-N-(4-hydroxyphenyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 37
- (S)-N-(4-hydroxyphenyl)-N-(2-methyl-4-(trifluoromethyl)benzyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 38
- (S)-N-(4-hydroxyphenyl)-N-(2-methyl-5-(trifluoromethyl)benzyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 39
- (S)-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-N-(pyridin-3- ylmethyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide;
- 40
- (S)-N-((2-(4-ethoxyphenyl)-5-methyloxazol-4-yl)methyl)-N-(4- hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline- 2-carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 41
- (S)-4-(N-(3-carbamoylbenzyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4- tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8- tetrahydroindolizine-1-carboxamido)phenyl acetate;
- 42
- (S)-N-(3-carbamoylbenzyl)-N-(4-ethoxyphenyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 43
- (S)-N-(4-hydroxyphenyl)-N-(3-((methylsulfonyl)carbamoyl)benzyl)-3-(6-(3- (morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2- carbonyl)benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1- carboxamide;
- 44
- 4-[(4-Hydroxy-N-[3-[6-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H- isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]-5,6,7,8-tetrahydroindolizine- 1-carbonyl]anilino)methyl]benzoic acid
- 45
- 3-[(4-Hydroxy-N-[3-[6-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H- isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]-5,6,7,8-tetrahydroindolizine- 1-carbonyl]anilino)methyl]benzoic acid
- 46
- tert-Butyl 3-[(4-hydroxy-N-[3-[6-[(3S)-3-(morpholinomethyl)-3,4-dihydro- 1H-isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]-5,6,7,8- tetrahydroindolizine-1-carbonyl]anilino)methyl]benzoate
- 47
- N-[(2-Cyanophenyl)methyl]-N-(4-hydroxyphenyl)-3-[6-[(3S)-3- (morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,3- benzodioxol-5-yl]-5,6,7,8-tetrahydroindolizine-1-carboxamide
- 48
- N-(4-Hydroxyphenyl)-N-[(4-methyl-1,2,4-triazol-3-yl)methyl]-3-[6-[(3S)-3- (morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,3- benzodioxol-5-yl]-5,6,7,8-tetrahydroindolizine-1-carboxamide
- 49
- N-(4-Hydroxyphenyl)-3-[6-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H- isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]-N-[(3-nitrophenyl)methyl]- 5,6,7,8-tetrahydroindolizine-1-carboxamide
- 50
- N-(4-Hydroxyphenyl)-N-[(2-methyl-3-nitro-phenyl)methyl]-3-[6-[(3S)-3- (morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,3- benzodioxol-5-yl]-5,6,7,8-tetrahydroindolizine-1-carboxamide.
- or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.
100 more elements
A compound selected from:
- Compound No.
- Compound Name
- 1 HCl salt
- N-(4-hydroxyphenyl)-N-{4-[(2- methoxyethyl)carbamoyl]benzyl}-3-(6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-
- dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3-benzodioxol-5-yl)-5,6,7,8- tetrahydroindolizine-1-carboxamide hydrochloride;
- 7 HCl salt
- N-(3-carbamoylbenzyl)-N-(4-hydroxyphenyl)-3-(6-{[(3S)-3- (morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- benzodioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamide hydrochloride;
- and
- 13 HCl salt
- N-(4-carbamoylbenzyl)-N-(4-hydroxyphenyl)-3-(6-{[(3S)-3- (morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}-1,3- benzodioxol-5-yl)-5,6,7,8-tetrahydroindolizine-1-carboxamide hydrochloride.
7 more elements
Dependencies are inferred from the claim text.