US 12,595,248 B2Granted

PRMT5 inhibitors

AssigneeMerck Sharp & Dohme Corp.

InventorsMichelle Machacek, Michael D. Altman, Chunghui Huang, Michael H. Reutershan, David L. Sloman, Phieng Siliphaivanh, Sebastian E. Schneider, Charles S. Yeung, David J. Witter, Craig R. Gibeau, Yingchun Ye

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Abstract

The present invention provides a compound of Formula (I) and the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are PRMT5 inhibitors. Also provided are methods of making compounds of Formula I, pharmaceutical compositions comprising compounds of Formula I, and methods of using these compounds to treat cancer, sickle cell, and hereditary persistence of foetal hemoglobin (HPFH) mutations.

Claims32

Dependent claims

A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein
A is a 6 membered heterocycle containing 1 nitrogen ring atom and 5 carbon ring atoms,
wherein A is substituted with OH and optionally substituted with 0-2 R2;
z1 is
when present, W1 is H, CHF2, NHW2, or OCHF2;
when present, W2 is
when present, R1 is independently selected from hydrogen, halogen, ═O, C1-6alkyl, OC0-6alkyl, C1-6alkylOC1-6alkyl, tetrahydrofuran, cyclopropyl, triazole, thiazole or pyrazole, wherein the C1-6alkyl, OC0-6alkyl, C1-6alkylOC1-6alkyl, tetrahydrofuran, or cyclopropyl are optionally substituted with one to three substituents independently selected from halogen, CH3, CN, cyclopropyl, or ═O, or wherein the triazole, thiazole or pyrazole are optionally substituted with one to three substituents independently selected from halogen, CH3, CN, or cyclopropyl;
when present, R2 is selected from H or CH3;
each R3 is selected from hydrogen or deuterium;
when present, R6 is H, C1-6alkyl, C(O)C1-6alkyl, C(O)OC1-6alkyl, C(O)C1-6cycloalkyl, C(O)N(C1-6alkyl)2, or S(O)2C1-6alkyl;
when present, R7 is H or ═O;
when present, R9 is H, halogen or CH3;
when present, Z4 is N while Z5 is C, or Z4 is C while Z5 is N;
when present, each X1 is selected from N or CR1, provided no more than one X1 is N;
when present, X2 is independently selected from O, C═O, CHR1, C(R1)2, or NR1, where two X2 in the same ring cannot both be NR1;
when present, t is 1 or 2;
when present, p is 0 or 1;
and
when present, q is 1 or 2,
provided that the compound of formula (I) is not:

17 more elements

A compound of Formula Ii,

or a pharmaceutically acceptable salt thereof, wherein
Z1 is
when present, W1 is H, CHF2, NHW2, or OCHF2;
when present, W2 is
when present, R1 is independently selected from H, halogen, ═O, C1-6alkyl, OC0-6alkyl, C1-6alkylOC1-6alkyl, tetrahydrofuran, cyclopropyl, triazole, thiazole or pyrazole, wherein the C1-6alkyl, OC0-6alkyl, C1-6alkylOC1-6alkyl, tetrahydrofuran, or cyclopropyl are optionally substituted with one to three substituents independently selected from halogen, CH3, CN, cyclopropyl, or ═O, or wherein the triazole, thiazole or pyrazole are optionally substituted with one to three substituents independently selected from halogen, CH3, CN, or cyclopropyl,
when present, R2 is independently selected from H or CH3;
each R3 is selected from hydrogen or deuterium;
when present, R6 is H, C1-6alkyl, C(O)C1-6alkyl, C(O)C1-6cycloalkyl, C(O)OC1-6alkyl, C(O)N(C1-6alkyl)2, or S(O)2C1-6alkyl;
when present, R7 is H or ═O;
when present R9 is H, halogen, or CH3;
when present, Z4 is N while Z5 is C, or Z4 is C while Z5 is N;
when present, X1 is selected from N or CR1, provided no more than one X1 is N;
when present, X2 is independently selected from O, C═O, CHR1, C(R1)2, or NR1, where two X2 in the same ring cannot both be NR1;
when present, p is 0 or 1;
when present, t is 1 or 2;
and
when present, q is 1 or 2.

14 more elements

A compound or a pharmaceutically acceptable salt thereof, which is:

(6-Bromoimidazo [1,2-a]pyridin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(6-Bromoimidazo [1,2-a]pyridin-2-yl)((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
((3S,4S)-3-hydroxy-4-(6-methyl-3,4-dihydroisoquinolin-2 (1H)-yl)piperidin-1-yl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanone,
((3R,4R)-3-hydroxy-4-(6-methyl-3,4-dihydroisoquinolin-2 (1H)-yl)piperidin-1-yl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanone,
1-(-4-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyridin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one,
1-(-4-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyridin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one,
1-(-4-((4-((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyridin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one,
1-(-4-((4-((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyridin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one,
6-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2-ethyl-2H-benzo[b][1,4]oxazin-3 (4H)-one,
6-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2-ethyl-2H-benzo[b][1,4]oxazin-3 (4H)-one,
6-((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2-ethyl-2H-benzo[b][1,4]oxazin-3 (4H)-one,
6-((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2-ethyl-2H-benzo[b][1,4]oxazin-3 (4H)-one,
1-(-4-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-3-fluoropyridin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one,
1-(-4-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-3-fluoropyridin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one,
1-(-4-((4-((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-3-fluoropyridin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one,
1-(-4-((4-((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-3-fluoropyridin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one,
1-(4-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-3-fluoropyridin-2-yl)amino)piperidin-1-yl)ethan-1-one,
1-(4-((4-((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-3-fluoropyridin-2-yl)amino)piperidin-1-yl)ethan-1-one,
1-(4-((4-(4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxy-2-methylpiperidine-1-carbonyl)pyridin-2-yl)amino)piperidin-1-yl)ethan-1-one,
1-(4-((4-(4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxy-2-methylpiperidine-1-carbonyl)pyridin-2-yl)amino)piperidin-1-yl)ethan-1-one,
1-(4-((4-(4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxy-2,2-dimethylpiperidine-1-carbonyl)pyridin-2-yl)amino)piperidin-1-yl)ethan-1-one,
1-(4-((4-(4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxy-2,2-dimethylpiperidine-1-carbonyl)pyridin-2-yl)amino)piperidin-1-yl)ethan-1-one,
1-(4-((4-(-4-(4,4-difluoro-3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-fluoropyridin-2-yl)amino)piperidin-1-yl)ethan-1-one,
1-(4-((5-chloro-4-(-4-(4,4-difluoro-3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyridin-2-yl)amino)piperidin-1-yl)ethan-1-one,
(-4-(4,4-difluoro-3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanone,
1-(4-((5-fluoro-4-(-4-(4,4-difluoro-3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyridin-2-yl)amino)piperidin-1-yl)ethan-1-one,
1-(4-((5-chloro-4-(-4-(4,4-difluoro-3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)pyridin-2-yl)amino)piperidin-1-yl)ethan-1-one,
(-4-(4,4-difluoro-3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanone,
1-{4-[(4-{[(1R,4R)-5-(3,4-dihydroisoquinolin-2 (1H)-yl)-6-hydroxy-2-azabicyclo[2.2.1]hept-2-yl]carbonyl}-5-fluoropyridin-2-yl)amino]piperidin-1-yl}ethenone,
4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one,
4-((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one,
(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxyphenyl)((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxyphenyl)((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)phenyl)((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)phenyl)((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)phenyl)((3S,4S)-4-(5-fluoro-3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)phenyl)((3R,4R)-4-(5-fluoro-3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)phenyl)((3S,4S)-4-(6-fluoro-3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)phenyl)((3R,4R)-4-(6-fluoro-3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)phenyl)((3S,4S)-4-(7-fluoro-3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)phenyl)((3R,4R)-4-(7-fluoro-3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanone,
((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanone,
((3R,4R or 3S,4S)-3-hydroxy-4-(7-methyl-3,4-dihydroisoquinolin-2 (1H)-yl)piperidin-1-yl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanone,
((3S,4S or 3R,4R)-3-hydroxy-4-(7-methyl-3,4-dihydroisoquinolin-2 (1H)-yl)piperidin-1-yl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanone,
1-{4-[(5-chloro-4-{[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]carbonyl}pyridin-2-yl)amino]piperidin-1-yl}ethenone,
((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)(5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanone,
(6-bromo-8-ethoxyimidazo [1,2-a]pyrazin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(2-(difluoromethyl)pyridin-4-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(2-(difluoromethoxy)pyridin-4-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl][6-(2,4-dimethyl-1,3-thiazol-5-yl)imidazo [1,2-a]pyrimidin-2-yl]methanone,
[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl][6-(1-methyl-1H-pyrazol-5-yl)imidazo [1,2-a]pyrimidin-2-yl]methanone,
[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]{8-[(1R)-1-methoxyethyl]-6-(propan-2-yl)imidazo [1,2-a]pyridin-2-yl}methanone,
[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]{8-[(1R)-1-methoxyethyl]-6-methylimidazo [1,2-a]pyridin-2-yl}methanone,
(4-(1-cyclopropyl-1H-1,2,4-triazol-5-yl)phenyl)((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(4-(1-cyclopropyl-1H-1,2,4-triazol-5-yl)phenyl)((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
8-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-4-isopropyl-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazepin-5-one,
(3-cyclopropyl-4-hydroxyquinolin-7-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
8-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-4-ethyl-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazepin-5-one,
8-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-4-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazepin-5-one,
(6-bromo-5-methylimidazo [1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(6-bromo-7-methylimidazo [1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(6-bromo-8-((R or S)-1-methoxyethyl)imidazo [1,2-a]pyridin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(6-bromo-7-methoxyimidazo [1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(6-bromo-7-hydroxyimidazo [1,2-a]pyrimidin-2-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
(6-bromoimidazo [1,2-a]pyrimidin-2-yl)[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone,
[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl](6-methylimidazo [1,2-a]pyrimidin-2-yl)methanone,
(6-bromo-7-methylimidazo [1,2-a]pyrimidin-3-yl)[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone,
(6-bromo-5-methylimidazo [1,2-a]pyrimidin-3-yl)[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone,
2-{2-[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl]imidazo [1,2-a]pyrimidin-6-yl}propanenitrile,
(6-bromo-7-cyclopropylimidazo [1,2-a]pyrimidin-2-yl)[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone,
[6-bromo-7-(propan-2-yl)imidazo [1,2-a]pyrimidin-2-yl][(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone,
2-cyclopropyl-6-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2H-benzo[b][1,4]oxazin-3 (4H)-one,
2-cyclopropyl-6-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2H-benzo[b][1,4]oxazin-3 (4H)-one,
((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl) (-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo [1,2-a]pyridin-2-yl)methanone,
((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl) (-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo [1,2-a]pyridin-2-yl)methanone,
6-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2-(-5,5-dimethyltetrahydrofuran-3-yl)-2H-benzo[b][1,4]oxazin-3 (4H)-one,
6-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2-(-5,5-dimethyltetrahydrofuran-3-yl)-2H-benzo[b][1,4]oxazin-3 (4H)-one,
1-(4-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-fluoropyridin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one,
1-(4-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-fluoropyridin-2-yl)amino)-3,3-difluoropiperidin-1-yl)ethan-1-one,
1-(4-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-methoxypyridin-2-yl)amino)piperidin-1-yl)ethan-1-one,
2-(5-{[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]carbonyl}pyridin-2-yl)-2-methylpropanenitrile,
2-(5-{[(3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]carbonyl}pyridin-2-yl)-2-methylpropanenitrile,
7-((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-4-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one,
7-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-4-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one,
7-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-4-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one,
7-((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-4-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one,
7-((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-4,4-dimethyl-3,4-dihydroquinolin-2 (1H)-one,
7-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-4,4-dimethyl-3,4-dihydroquinolin-2 (1H)-one,
7-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-4,4-dimethyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one,
7-((3R,4R)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-4,4-dimethyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one,
7-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-6-fluoro-4-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one,
7-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-6-fluoro-4-methyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one,
6-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3 (4H)-one,
8-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-4-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazepin-5-one,
tert-butyl-3-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-fluoropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate,
((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)(5-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyridin-4-yl)methanone,
ethyl 4-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-fluoropyridin-2-yl)amino)piperidine-1-carboxylate,
1-(4-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-ethoxypyridin-2-yl)amino)piperidin-1-yl)ethan-1-one,
(2-((1-(cyclopropanecarbonyl)piperidin-4-yl)amino)-5-fluoropyridin-4-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
methyl 4-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-fluoropyridin-2-yl)amino)piperidine-1-carboxylate,
4-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-fluoropyridin-2-yl)amino)-N,N-dimethylpiperidine-1-carboxamide,
1-(4-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-fluoropyridin-2-yl)amino)piperidin-1-yl) propan-1-one,
4-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-fluoropyridin-2-yl)amino)-1-methylpiperidin-2-one,
1-(-3-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-fluoropyridin-2-yl)amino) pyrrolidin-1-yl)ethan-1-one,
1-(-3-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-fluoropyridin-2-yl)amino) pyrrolidin-1-yl)ethan-1-one,
7-[(4-{[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]carbonyl}-5-fluoropyridin-2-yl)amino]hexahydroindolizin-3 (2H)-one,
7-[(4-{[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]carbonyl}-5-fluoropyridin-2-yl)amino]hexahydroindolizin-3 (2H)-one,
7-[(4-{[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]carbonyl}-5-fluoropyridin-2-yl)amino]hexahydroindolizin-3 (2H)-one,
7-[(4-{[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]carbonyl}-5-fluoropyridin-2-yl)amino]hexahydroindolizin-3 (2H)-one,
1-(5-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-fluoropyridin-2-yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)ethan-1-one,
1-(5-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-fluoropyridin-2-yl)amino)-2-azabicyclo[2.2.1]heptan-2-yl)ethan-1-one,
(2-((8-azabicyclo[3.2.1]octan-3-yl)amino)-5-fluoropyridin-4-yl)((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)methanone,
1-(3-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-fluoropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)ethan-1-one,
1-((S)-3-(((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-fluoropyridin-2-yl)amino)methyl) pyrrolidin-1-yl)ethan-1-one,
1-((1R,5S)-8-((4-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)-5-fluoropyridin-2-yl)amino)-3-azabicyclo[3.2.1]octan-3-yl)ethan-1-one,
1-(2-((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidine-1-carbonyl)imidazo [1,2-a]pyridin-6-yl) cyclopropane-1-carbonitrile,
((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)(4-hydroxy-3-(2,2,2-trifluoroethyl) quinolin-7-yl)methanone,
1-(2-{[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]carbonyl}imidazo [1,2-a]pyrimidin-6-yl)-2,2-dimethylcyclopropanecarbonitrile,
1-(2-{[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]carbonyl}imidazo [1,2-a]pyrimidin-6-yl)-2,2-dimethylcyclopropanecarbonitrile,
((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)(6-(2-methylcyclopropyl)imidazo [1,2-a]pyrimidin-2-yl)methanone,
((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)(6-(2-methylcyclopropyl)imidazo [1,2-a]pyrimidin-2-yl)methanone,
((3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl)(6-(2-methylcyclopropyl)imidazo [1,2-a]pyrimidin-2-yl)methanone,
(6-chloroimidazo [1,2-a]pyridin-2-yl)[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone,
(6-bromo-3-chloropyrazolo[1,5-a]pyrimidin-2-yl)[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone,
(8-bromo-6-methylimidazo [1,2-a]pyridin-2-yl)[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone,
(6-bromo-8-methylimidazo [1,2-a]pyridin-2-yl)[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone,
(8-chloro-6-methylimidazo [1,2-a]pyridin-2-yl)[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone,
[8-chloro-6-(trifluoromethyl)imidazo [1,2-a]pyridin-2-yl][(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone,
(8-bromo-6-chloroimidazo [1,2-a]pyridin-2-yl)[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone,
(6-bromo-8-iodoimidazo [1,2-a]pyridin-2-yl)[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone,
(6,8-dichloroimidazo [1,2-a]pyridin-2-yl)[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone,
(6-bromo-8-fluoroimidazo [1,2-a]pyridin-2-yl)[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone,
(6,8-dibromoimidazo [1,2-a]pyridin-2-yl)[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone, or
(6-bromopyrazolo[1,5-a]pyrimidin-2-yl)[(3S,4S)-4-(3,4-dihydroisoquinolin-2 (1H)-yl)-3-hydroxypiperidin-1-yl]methanone.

132 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/783,975Filed 14 Dec 2020 · us provisional application
Priority: 17 Dec 2019
Published: US 2023/0108114 A16 Apr 2023
Granted: 7 Apr 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

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…:…
A61P 35/00
Antineoplastic agents
C07D 405/14
Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having…:…
C07D 413/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms:…

Family

Application62/949,245Us provisional application · filed 17 Dec 2019
Application63/025,561Us provisional application · filed 15 May 2020
US 2023/0108114 A1Pre-grant publication · published 6 Apr 2023
US 12,595,248 B2This patent

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

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