US 11,629,135 B2Granted

Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation

AssigneeJubilant Prodell LLC

InventorsChandregowda Venkateshappa, Athisayamani Jeyaraj Duraiswamy, Rama Kishore V P Putta, Sridharan Rajagopal

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Abstract

The compounds of Formula Ib, Formula Ia, and Formula I are described herein along with their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof. The process of preparation of the compounds of Formula Ib, Formula Ia, and Formula I is also described. The compounds described herein, their polymorphs, stereoisomers, tautomers, prodrugs, solvates, and pharmaceutically acceptable salts thereof are 2-(benzyloxy)pyrimidine derivatives that are inhibitors of PD-1/PD-L1 activation.

Claims16

Dependent claims

A compound of Formula I

their stereoisomers and pharmaceutically acceptable salts thereof,
wherein
R1 is selected from hydrogen, C1-10 alkyl, C1-6 haloalkyl, C5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O,
wherein, C1-10 alkyl, C5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl, are optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl and cyano,
R2 is selected from hydrogen, C1-10 alkyl, C1-10 alkoxy, C5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O,
wherein, C1-10 alkyl, C5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl, are optionally substituted with one or more of the groups selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy and C1-6 heterocyclyl,
wherein, C1-6 alkyl, C1-6 alkoxy and C1-6 heterocyclyl are optionally substituted with one or more of the groups selected from C1-6 alkyl or C1-6 heterocyclyl,
wherein, C1-6 heterocyclyl is optionally substituted with one or more halogen;
R3 and R4 are independently selected from hydrogen, C1-10 alkyl and C1-10 alkoxy;
O is absent or is oxygen;
R5 is —NR7R8, wherein, R7 and R8 are selected from the group consisting of hydrogen, C3-10 cycloalkyl, C1-6 alkyl, 5-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, wherein, C3-10 cycloalkyl, C1-6 alkyl and the 5-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring are optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH2, C(O)CH2CN, NHR6, COOH, COOR6, NHC(O)R6, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C5-6 aryl, SR6 or 5-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, wherein, C1-6 alkyl and the 5-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring are independently substituted with one or more substituents selected from hydroxyl and R6;
or R7 and R8 can be taken together to form a 4-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, wherein, the 4-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, C1-6 alkyl, COOH, R6, NHR6, C(O)NHR6, C(O)NHSO2R6, C(O)(CH2)nNHC(O)CH3 and combinations thereof, wherein, C1-6 alkyl is further substituted with groups selected from oxo, hydroxyl, COOH, COOR6 or NHR6;
n is 1-6;
and R6 is selected from the group consisting of hydrogen, C1-6 alkyl, C(O)C1-6 alkyl and combinations thereof, wherein, C1-6 alkyl and C(O)C1-6 alkyl are optionally substituted with substituents selected from the group consisting of hydroxyl, COOH, NHR6, NHC(O)NHR6 and combinations thereof.

11 more elements

A compound or its stereoisomers and pharmaceutically acceptable salts thereof, which is selected from a group consisting of:

N-(2-(((2-((4′-fluoro-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound-1),
N-((4-ethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-N-methyl glycine (Compound-2),
N-((4-ethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-N-methyl glycine (Compound-3),
(1R,6R)-2-((4,6-dimethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (Compound-4),
(1S,6R)-2-((4,6-dimethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (Compound-5),
N-(2-(((4,6-diethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound-6),
(S)-1-((4-methoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound-7),
(S)-1-((4-((3-cyano-4-fluorobenzyl)oxy)-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound-8),
(S)-1-((2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound-9),
(S)-1-((4-(4-hydroxybutoxy)-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound-10),
(2S,4R)-1-((2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidin-5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound-11),
(S)-1-((4-((5-cyanopyridin-3-yl)methoxy)-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound-12),
(S)-1-((2-((3′-(3-(3,3-difluoropyrrolidin-1-yl)propoxy)-2,2′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound-13),
N-(2-(((4-methoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound-14),
(R)-1-((4-methoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 15),
(S)-1-((2-((4′-fluoro-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound-16),
(S)-1-((2-((3′-fluoro-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 17),
N-(2-(((2-((3′-fluoro-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound-18),
(S)-1-((2-((2′-fluoro-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 19),
N-(2-(((2-((2′-fluoro-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-4-methoxypyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 20),
N-(2-(((4-ethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 21),
(S)-1-((4-ethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl) piperidine-2-carboxylic acid (Compound 22),
1-(((4-ethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)cyclopropane-1-carboxylic acid (Compound 23),
(3-(((4-ethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)propanoic acid (Compound 24),
2-(((4-ethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)-2-(hydroxymethyl)propane-1,3-diol (Compound 25),
(2-(((4-ethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)(methyl)amino)-2-(hydroxymethyl)propane-1,3-diol (Compound 26),
(S)-3-(((4-ethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)butanoic acid (Compound 27),
((4-ethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-D-alanine (Compound 28),
((4-ethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)asparagine (Compound 29),
(2R,4R)-1-((4-ethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 30),
1-((4-ethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)azetidine-2-carboxylic acid (Compound 31),
N-(2-(((4-(benzyloxy)-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 32),
1-((4-(benzyloxy)-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 33),
(2S,4R)-1-((4,6-dimethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 34),
2-(((4,6-dimethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)-2-(hydroxymethyl)propane-1,3-diol (Compound 35),
((4,6-dimethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-L-proline (Compound 36),
Methyl 4-((4,6-dimethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl) morpholine-3-carboxylate (Compound 37),
4-((4,6-dimethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)morpholine-3-carboxylic acid (Compound 38),
(2S,4R)-1-((4,6-diethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 39),
((S)-1-((4,6-diethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 40),
2-(((4,6-diethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)-2-(hydroxymethyl)propane-1,3-diol (Compound 41),
2-(((4,6-dimethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)-2-(hydroxymethyl)propane-1,3-diol (Compound 42),
(S)-4-((4,6-dimethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)morpholine-3-carboxylic acid (Compound 43),
2-(4-((4,6-dimethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)morpholin-3-yl)acetic acid (Compound 44),
(S)-1-((4,6-dimethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 45),
(S)-5-((4,6-dimethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (Compound 46),
7-((4,6-dimethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2,7-diazaspiro[4.5]decan-1-one (Compound 47),
rac-(1R,6S)-2-((4,6-dimethoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2-azabicyclo[4.1.0]heptane-1-carboxylic acid (Compound 48),
(S)-4-acetyl-1-((4-methoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperazine-2-carboxylic acid (Compound 49),
(S)-1-((4-methoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperazine-2-carboxylic acid (Compound 50),
(S)-5-((4-methoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (Compound 51),
7-((4-methoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-2,7-diazaspiro[4.5]decan-1-one (Compound 52),
N-(2-(((4-((3-cyano-4-fluorobenzyl)oxy)-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 53),
(2S,4R)-1-((4-((3-cyano-4-fluorobenzyl)oxy)-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylicacid (Compound 54),
(S)-1-((2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 55),
N-(2-(((2-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-4,6-dimethoxypyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 56),
N-(2-(((2-((3′,4′-dimethoxy-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-4,6-dimethoxypyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 57),
((2S,4R)-1-((2-((3′,4′-dimethoxy-2-methyl-[1,1′-biphenyl]-3-yl)methoxy)-4,6-dimethoxypyrimidin-5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 58),
(2S,4R)-1-((4-((5-cyanopyridin-3-yl)methoxy)-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)-4-hydroxypyrrolidine-2-carboxylic acid (Compound 59),
(S)-2-(1-((4-methoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidin-2-yl) acetic acid (Compound 60),
(R)-2-(1-((4-methoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidin-2-yl) acetic acid (Compound 61),
(S)-4-(6-acetamidohexanoyl)-1-((4-methoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperazine-2-carboxylic acid (Compound 62),
(S)-4,4-difluoro-1-((4-methoxy-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 63),
(S)-1-((4-methyl-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)piperidine-2-carboxylic acid (Compound 64), and
N-(2-(((4-methyl-2-((2-methyl-[1,1′-biphenyl]-3-yl)methoxy)pyrimidin-5-yl)methyl)amino)ethyl)acetamide (Compound 65).

62 more elements

A process of preparation of compounds of Formula I

their stereoisomers and pharmaceutically acceptable salts thereof,
wherein
R1 is selected from hydrogen, C1-10 alkyl, C1-6 haloalkyl, C5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O,
wherein, C1-10 alkyl, C5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl, are optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl and cyano,
R2 is selected from hydrogen, C1-10 alkyl, C1-10 alkoxy, C5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O,
wherein, C1-10 alkyl, C5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl, are optionally substituted with one or more of the groups selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy and C1-6 heterocyclyl,
wherein, C1-6 alkyl, C1-6 alkoxy and C1-6 heterocyclyl are optionally substituted with one or more of the groups selected from C1-6 alkyl or C1-6 heterocyclyl,
wherein, C1-6 heterocyclyl is optionally substituted with one or more halogen;
R3 and R4 are independently selected from hydrogen, C1-10 alkyl and C1-10 alkoxy;
O is absent or is oxygen;
R5 is —NR7R8, wherein, R7 and R8 are selected from the group consisting of hydrogen, C3-10 cycloalkyl, C1-6 alkyl, 5-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, wherein, C3-10 cycloalkyl, C1-6 alkyl and the 5-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring are optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH2, C(O)CH2CN, NHR6, COOH, COOR6, NHC(O)R6, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C5-6 aryl, SR6 or 5-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, wherein, C1-6 alkyl and the 5-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring are independently substituted with one or more substituents selected from hydroxyl and R6;
or R7 and R8 can be taken together to form a 4-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, wherein, the 4-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, C1-6 alkyl, COOH, R6, NHR6, C(O)NHR6, C(O)NHSO2R6, C(O)(CH2)nNHC(O)CH3 and combinations thereof, wherein, C1-6 alkyl is further substituted with groups selected from oxo, hydroxyl, COOH, COOR6 or NHR6;
n is 1-6;
and R6 is selected from the group consisting of hydrogen, C1-6 alkyl, C(O)C1-6 alkyl and combinations thereof, wherein, C1-6 alkyl and C(O)C1-6 alkyl are optionally substituted with substituents selected from the group consisting of hydroxyl, COOH, NHR6, NHC(O)NHR6 and combinations thereof, the process comprising (a) reacting compounds of Formula IV and Formula B3 in presence of a base, a solvent, and optionally a coupling reagent to obtain compounds of Formula V or Formula XIII;
(b) processing the compounds of Formula V and Formula XIII to obtain compounds of Formula VI and Formula VII;
and (c) reacting compounds of Formula VII with substituted amines in presence of a reducing agent and a third solvent to obtain compounds of Formula I
wherein, R1 of Formula I, Formula IV, Formula V, Formula VI, Formula VII, and Formula XIII are independently selected from hydrogen, C1-10 alkyl, C1-6 haloalkyl, C5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O,
wherein, C1-10 alkyl, C5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl, are optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl and cyano;
R2 of Formula I, Formula V, Formula VI, Formula VII, Formula XIII and Formula B3 are independently selected from hydrogen, C1-10 alkyl, C1-10 alkoxy, C5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O,
wherein, C1-10 alkyl, C5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl, are optionally substituted with one or more of the groups selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy and C1-6 heterocyclyl,
wherein, C1-6 alkyl, C1-6 alkoxy and C1-6 heterocyclyl are optionally substituted with one or more of the groups selected from C1-6 alkyl or C1-6 heterocyclyl,
wherein, C1-6 heterocyclyl is optionally substituted with one or more halogen;
R3, and R4 of Formula I, Formula IV, Formula V, Formula VI, Formula VII, Formula XIII and Formula B3 independently selected from hydrogen, C1-10 alkyl and C1-10 alkoxy;
X of Formula I, Formula V, Formula VI, Formula VII, and Formula XIII is —CH2O where O is absent or is oxygen;
R5 of Formula I is —NR7R8, wherein, R7 and R8 are independently selected from the group consisting of hydrogen, C3-10 cycloalkyl, C1-6 alkyl, 5-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, wherein, C3-10 cycloalkyl, C1-6 alkyl, and the 5-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring are optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH2, C(O)CH2CN, NHR6, COOH, COOR6, NHC(O)R6, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C5-6 aryl, SR6 or 5-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, wherein, C1-6 alkyl and the 5-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring are independently substituted with one or more substituents selected from hydroxyl and R6;
or R7 and R8 can be taken together to form a 4-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, wherein, the 4-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, C1-6 alkyl, COOH, R6, NHR6, C(O)NHR6, C(O)NHSO2R6, C(O)(CH2)nNHC(O)CH3 and combinations thereof, wherein, C1-6 alkyl is further substituted with groups selected from hydroxyl, COOH or NHR6;
n is 1-6;
and R6 is selected from the group consisting of hydrogen, C1-6 alkyl, C(O)C1-6 alkyl and combinations thereof, wherein, C1-6 alkyl and C(O)C1-6 alkyl are optionally substituted with substituents selected from the group consisting of hydroxyl, COOH, NHR6, NHC(O)NHR6 and combinations thereof.

25 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/761,792Filed 6 Nov 2018
Priority: IN 2017410395356 Nov 2017
Published: US 2021/0179580 A117 Jun 2021
Granted: 18 Apr 2023
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 35/00
Antineoplastic agents
A61P 35/04
Antineoplastic agents: specific for metastasis

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Abstract

A compound of Formula I

their stereoisomers and pharmaceutically acceptable salts thereof,
wherein
R1 is selected from hydrogen, C1-10 alkyl, C1-6 haloalkyl, C5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O,
wherein, C1-10 alkyl, C5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl, are optionally substituted with one or more of the groups selected from hydrogen, halogen, hydroxyl and cyano,
R2 is selected from hydrogen, C1-10 alkyl, C1-10 alkoxy, C5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl with 1-5 heteroatoms selected from N, S or O,
wherein, C1-10 alkyl, C5-10 aryl and 5-10 membered monocyclic or bicyclic heteroaryl, are optionally substituted with one or more of the groups selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy and C1-6 heterocyclyl,
wherein, C1-6 alkyl, C1-6 alkoxy and C1-6 heterocyclyl are optionally substituted with one or more of the groups selected from C1-6 alkyl or C1-6 heterocyclyl,
wherein, C1-6 heterocyclyl is optionally substituted with one or more halogen;
R3 and R4 are independently selected from hydrogen, C1-10 alkyl and C1-10 alkoxy;
O is absent or is oxygen;
R5 is —NR7R8, wherein, R7 and R8 are selected from the group consisting of hydrogen, C3-10 cycloalkyl, C1-6 alkyl, 5-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, and combinations thereof, wherein, C3-10 cycloalkyl, C1-6 alkyl and the 5-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring are optionally substituted with one or more substituents selected from oxo, cyano, halogen, hydroxyl, morpholino, C(O)NH2, C(O)CH2CN, NHR6, COOH, COOR6, NHC(O)R6, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C5-6 aryl, SR6 or 5-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, wherein, C1-6 alkyl and the 5-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring are independently substituted with one or more substituents selected from hydroxyl and R6;
or R7 and R8 can be taken together to form a 4-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring with 1-3 heteroatoms selected from N, S or O, wherein, the 4-10 membered monocyclic or bicyclic, saturated or unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, C1-6 alkyl, COOH, R6, NHR6, C(O)NHR6, C(O)NHSO2R6, C(O)(CH2)nNHC(O)CH3 and combinations thereof, wherein, C1-6 alkyl is further substituted with groups selected from oxo, hydroxyl, COOH, COOR6 or NHR6;
n is 1-6;
and R6 is selected from the group consisting of hydrogen, C1-6 alkyl, C(O)C1-6 alkyl and combinations thereof, wherein, C1-6 alkyl and C(O)C1-6 alkyl are optionally substituted with substituents selected from the group consisting of hydroxyl, COOH, NHR6, NHC(O)NHR6 and combinations thereof.

11 more elements

Facts

Application

16/761,792Filed 6 Nov 2018

Priority

IN 2017410395356 Nov 2017

Published

US 2021/0179580 A117 Jun 2021

Granted

18 Apr 2023

Term ends

Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 35/00
Antineoplastic agents
A61P 35/04
Antineoplastic agents: specific for metastasis