US 10,647,680 B2Granted

Urea compound, preparation method therefor and medical use thereof

AssigneeAncureall Pharmaceutical (Shanghai) Co., Ltd.

InventorsJutong Si, Meifeng Jiang

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Abstract

Provided are a urea compound represented by general formula (I), a pharmaceutically acceptable salt thereof, a preparation method therefor, and use thereof as an FLT3 tyrosine protein kinase inhibitor, particularly in the prevention and/or treating of cancer.

Claims26

Dependent claims

A compound of general formula (I) or the pharmaceutically acceptable salts, solvates or prodrugs thereof,

wherein:
the group
is
W and Z are each independently selected from C—BR1;
R51 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkoxy, alkenyl, alkynyl, —N(Ry)(Rz), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, —N(Ry)(Rz), cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally further substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, ester groups;
in the absence of R1, B is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally further substituted by one or more of Q groups;
in the presence of R1, B is identical or different and each is independently selected from the group consisting of —O— and —NR4—;
and R1 is identical or different and each is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —RuORx, —RuC(O)ORx, —RuN(Ry)(Rz), —C(O)N(Ry)(Rz), —RuS(O)nN(Ry)(Rz), —RuS(O)uRx;
the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl groups are optionally further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxy, alkyl, alkoxy, hydroxyalkyl, hydroxyalkoxy, amido, cycloalkyl, heterocyclyl, aryl, haloaryl, heteroaryl, cycloalkyl-heteroaryl;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl, or R4 and R1 together with the nitrogen atom attached them form a heterocyclyl group, and the heterocyclyl group is optionally further substituted by one or more groups selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy;
when R2 is hydrogen, G is selected from 5-membered heteroaryl, and the 5-membered heteroaryl is optionally further substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, amino, acyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, acyl, cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally further substituted by one or more groups selected from the group consisting of halogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, hydroxy, alkoxy, halo alkoxy, cycloalkyl, ester, and cyano;
or,
when R2 is not hydrogen, G and R2 together with the nitrogen atom attached them form a 5-membered heteroaryl group, the heteroaryl group is optionally further substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted by one or more groups selected from the group consisting of halogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, ester, and cyano;
R3 is selected from the hydrogen, halogen, hydroxy, amino, alkyl, alkoxy, cycloalkyl, cyano, heterocyclyl;
Ru is selected from a bond, alkylene, alkenylene, or alkynylene;
Rx is selected from hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkenyl, or alkynyl;
or
the oxygen in —RuORx— together with Ru and Rx attached to them form an oxygen-containing 3-7 membered heterocyclic ring, which is optionally substituted by one or more of Q groups;
Ry and Rz are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and haloalkyl;
or,
Ry and Rz together with the nitrogen atom attached to them form a heterocyclyl or heteroaryl group, and the heterocyclyl or heteroaryl group is optionally further substituted by one or more groups selected from the group consisting of halogen, haloalkyl, alkyl, alkenyl and alkynyl groups;
Q is selected from the group consisting of hydrogen, halogen, hydroxy, amino, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, cyano, aryl, heterocyclyl and heteroaryl, and the amino, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, or heteroaryl is optionally further substituted by one or more groups selected from the group consisting of hydroxy, halogen and alkyl;
n is an integer from 0 to 2.

20 more elements

A compound selected from the group consisting of:

1-(4-benzimidazol-1-yl-phenyl)3-isoxazol-3-yl-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-(5-tert-butyl-isoxazol-3-yl)-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(5-hydroxy-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(5-methoxyl-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(5-ethoxyl-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(5-hexyloxyl-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(5-isopropoxy-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[5-(3-methyl-oxetan-3-ylmethoxy)-benzimidazol-1-yl]-phenyl}-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[5-(tetrahydrofuran-2-ylmethoxy)-benzimidazol-1-yl]-phenyl}-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[5-(2-hydroxy-ethoxyl)-benzimidazol-1-yl]-phenyl] urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[5-(2-methoxyl-ethoxyl)-benzimidazol-1-yl]-phenyl] urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[5-(2-ethoxyl-ethoxyl)-benzimidazol-1-yl]-phenyl] urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-(4-{5-[2-(2-hydroxy-ethoxyl)-ethoxyl]-benzimidazol-1-yl}-phenyl)-urea;
1-{4-[3-(5-tert-butyl-isoxazol-3-yl)-carbamido]-phenyl}-1H-benzimidazol-5-yl morpholine-4-carboxylicate;
1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[5-(2-morpholin-4-yl-ethoxyl)-benzimidazol-1-yl]-phenyl}-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[5-(2-piperidine-1-yl-ethoxyl)-benzimidazol-1-yl]-phenyl}-urea;
1-{4-[5-(2-azacycloheptan-1-yl-ethoxyl)-benzimidazol-1-yl]-phenyl}-3-(5-tert-butyl-isoxazol-3-yl)-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-(4-{5-[3-(4-methyl-piperazin-1-yl)-propoxyl]-benzimidazol-1-yl}-phenyl)-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[5-(2-dimethylamino-ethoxyl)-benzimidazol-1-yl]-phenyl}-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(5-trifluoromethoxy-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(5-fluor-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(5-trifluoromethyl-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(5-methyl-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(6-methoxyl-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[6-(2-methoxyl-ethoxyl)-benzimidazol-1-yl]-phenyl]urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[6-(2-morpholin-4-yl-ethoxyl)-benzimidazol-1-yl]-phenyl}-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-(4-{6-[(2-dimethylamino-ethyl)-methyl-amino]-benzimidazol-1-yl}-phenyl)-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[6-(4-methyl-piperazin-1-yl)-benzimidazol-1-yl]-phenyl}-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(2-morpholin-4-yl-ethoxyl)-benzimidazol-1-yl]-phenyl}-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(5,6-dimethoxyl-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(5,6-dimethyl-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(5-fluoro-7-methyl-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(4-fluor-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(2-methyl-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(2-chlorobenzimidazole-1-yl)-phenyl]-urea;
1-(4-benzimidazol-1-yl-3-methyl-phenyl)-3-(5-tert-butyl-isoxazol-3-yl)-urea;
1-(4-benzimidazol-1-yl-3-chloro-phenyl)-3-(5-tert-butyl-isoxazol-3-yl)-urea;
1-(4-benzimidazol-1-yl-3-fluoro-phenyl)-3-(5-tert-butyl-isoxazol-3-yl)-urea;
1-(4-benzimidazol-1-yl-3, 5-difluoro-phenyl)-3-(5-tert-butyl-isoxazol-3-yl)-urea;
1-(4-benzimidazol-1-yl-2-chloro-phenyl)-3-(5-tert-butyl-isoxazol-3-yl)-urea;
1-(6-benzimidazol-1-yl-pyridin-3-yl)-3-(5-tert-butyl-isoxazol-3-yl)-urea;
1-(2-benzimidazol-1-yl-pyrimidin-5-yl)-3-(5-tert-butyl-isoxazol-3-yl)-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-thiazol-2-yl-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-(4-methyl-thiazole-2-yl)-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-[1,3,4]thiadiazole-2-yl-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-tert-butyl-[1,3,4]thiadiazole-2-yl)-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-(5-methyl-1H-pyrazol-3-yl)-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-(5-phenyl-1H-pyrazol-3-yl)-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-(5-cyclopropyl-2H-pyrazol-3-yl)-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-trifluoro methyl-2H-pyrazole-3-yl)-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-tert-butyl-2H-pyrazole-3-yl)-urea;
1-(5-tert-butyl-2H-pyrazole-3-yl)-3-[4-(5-fluor-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-2H-pyrazole-3-yl)-3-[4-(5-trifluoromethyl-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-2H-pyrazole-3-yl)-3-[4-(5-methoxyl-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-2H-pyrazole-3-yl)-3-[4-(5-ethoxyl-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-2H-pyrazole-3-yl)-3-[4-(5-hexyloxyl-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-2H-pyrazole-3-yl)-3-[4-(5-isopropoxy-benzimidazol-1-yl)-phenyl]-urea;
1-[4-(5-sec-butoxyl-benzimidazol-1-yl)-phenyl]-3-(5-tert-butyl-2H-pyrazol-3-yl)-urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-[4-(5-isobutoxy-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-{4-[5-(2-methoxyl-ethoxyl)-benzimidazol-1-yl]-phenyl}-urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-{4-[5-(2-ethoxyl-ethoxyl)-benzimidazol-1-yl]-phenyl}-urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-{4-[5-(2-hydroxy-ethoxyl)-benzimidazol-1-yl]-phenyl]urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-{4-[5-(2-hydroxy-3-methoxyl-propoxyl)-benzimidazol-1-yl]-phenyl]urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-{4-[5-(3-dimethylamino-propoxyl)-benzimidazol-1-yl]-phenyl}-urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-{4-[5-(3-dibutylaminopropyloxyl)-benzimidazol-1-yl]-phenyl}-urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-[4-(5-cyanomethoxy-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-[4-(5-trifluoromethoxy-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-{4-[5-(3-methyl-oxetan-3-ylmethoxy)-benzimidazole-1-yl]-phenyl]urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-{4-[5-(tetrahydrofuran-2-ylmethoxyl)-benzimidazol-1-yl]-phenyl}-urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-{4-[5-(tetrahydrofuran-2-ylmethoxyl)-benzimidazol-1-yl]-phenyl}-urea;
Ethyl (1-{4-[3-(5-tert-butyl-2H-pyrazole-3-yl)-carbamido]-phenyl}-1H-benzimidazol-5-yloxy)-acetate;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-{4-[5-(2-morpholin-4-yl-ethoxyl)-benzimidazol-1-yl]-phenyl}-urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-{4-[5-(2-piperidine-1-yl-ethoxyl)-benzimidazol-1-yl]-phenyl}-urea;
1-{4-[5-(2-azacycloheptan-1-yl-ethoxyl)-benzimidazol-1-yl]-phenyl}-3-(5-tert-butyl-2H-pyrazol-3-yl)-urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-{4-[5-(4-morpholin-4-yl-[1,2,5]thiadiazol-3-yloxdazol-1-yl}-phenyl)-urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-{4-[5-(3-fluoro-benzyloxy)-benzimidazol-1-yl]-phenyl]urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-(4-{5-[4-(1-cyclohexyl-1H-tetrazol-5-yl)-butoxy]-benzimidazol-1-yl}-phenyl)-urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-{4-[5-(4-morpholin-4-yl-[1,2,5]thiadiazol-3-yloxy)-benzimidazol-1-yl]-phenyl]urea;
4-(1-{4-[3-(5-tert-butyl-2H-pyrazol-3-yl)-carbamido]-phenyl}-1H-benzimidazol-5-yloxy)-pyridin-2-carboxylic acid methylamine;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-[4-(5-fluoro-7-methyl-benzimidazol-1-yl)-phenyl]-urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-{4-[6-(2-methoxyl-ethoxyl)-benzimidazol-1-yl]-phenyl}-urea;
1-(5-tert-butyl-2H-pyrazol-3-yl)-3-[4-(5,6-dimethoxyl-benzimidazol-1-yl)-phenyl]-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-urea;
1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[5-(2-methoxyl-ethoxyl)-benzimidazol-1-yl]-phenyl]urea;
1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[5-(2-morpholin-4-yl-methoxyl)-benzimidazol-1-yl]-phenyl}-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-[5-tert-butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-(5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-[5-tert-butyl-2-(4-methoxyl-phenyl)-2H-pyrazole-3-yl]-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-[5-tert-butyl-2-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-[5-tert-butyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-[5-tert-butyl-2-(2-fluoro-phenyl)-2H-pyrazol-3-yl]-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-(5-tert-butyl-2-pyrazol-3-yl)-urea;
4-{5-[3-(4-benzimidazol-1-yl-phenyl)-carbamido]-3-tert-butyl-pyrazol-1-yl}-benzoate;
3-amino-5-methylpyrazol-1-carboxylic acid (4-benzimidazol-1-yl-phenyl)-amide;
5-amino-3-cyclopropylpyrazol-1-carboxylic acid (4-benzimidazol-1-yl-phenyl)-amide;
5-amino-3-trifluoromethylpyrazol-1-carboxylic acid (4-benzimidazol-1-yl-phenyl)-amide;
5-amino-3-tert-butyl-pyrazol-1-carboxylic acid (4-benzimidazol-1-yl-phenyl)-amide;
5-amino-3-tert-butyl-pyrazol-1-carboxylic acid [4-(5-hexyloxyl-benzimidazol-1-yl)-phenyl]-amide;
5-amino-3-tert-butyl-pyrazol-1-carboxylic acid (4-{5-[3-(4-methyl-piperazin-1-yl)-propoxyl]-benzimidazol-1-yl}phenyl)-amide;
5-amino-3-tert-butyl-pyrazol-1-carboxylic acid {4-[5-(2-morpholin-4-yl-ethoxyl)-benzimidazol-1-yl]-phenyl}-amide;
5-amino-3-tert-butyl-pyrazol-1-carboxylic acid {4-[5-(2-methoxyl-ethoxyl)-benzimidazol-1-yl]-phenyl}-amide;
5-amino-3-tert-butyl-pyrazol-1-carboxylic acid {4-[5-(2-hydroxy-ethoxyl)-benzimidazol-1-yl]-phenyl}-amide;
5-amino-3-tert-butyl-pyrazol-1-carboxylic acid {4-[5-(tetrahydrofuran-2-ylmethoxyl)-benzimidazol-1-yl]-phenyl}-amide;
5-amino-3-tert-butyl-pyrazol-1-carboxylic acid {4-[5-(tetrahydrofuran-2-ylmethoxy)-benzimidazol-1-yl]-phenyl}-amide;
(1-{4-[(5-amino-3-tert-butyl-pyrazol-1-carbonyl)-amino]-phenyl}-1H-benzimidazol-5-yloxyl)-acetic acid;
5-amino-3-tert-butyl-pyrazol-1-carboxylic acid [4-(5-fluoro-benzimidazol-1-yl)-phenyl]-amide;
5-amino-3-tert-butyl-pyrazol-1-carboxylic acid [4-(5-trifluoro methyl-benzimidazol-1-yl)-phenyl]-amide;
4-(1-{4-[(5-amino-3-tert-butyl-pyrazol-1-carbonyl)-amino]-phenyl}-1H-benzimidazol-5-yloxyl)-pyridin-2-carboxylate acid methylamide;
5-amino-3-tert-butyl-pyrazol-1-carboxylic acid {4-[6-(2-methoxyl-ethoxyl)-benzimidazol-1-yl]-phenyl}-amide;
5-amino-3-tert-butyl-pyrazol-1-carboxylic acid [4-(5,6-dimethoxyl-benzimidazol-1-yl)-phenyl]-amide;
3-tert-butyl-pyrazol-1-carboxylic acid (4-benzimidazol-1-yl-phenyl)-amide;
1-(4-benzimidazol-1-yl-phenyl)-3-(3,4 oxazol-5-yl)-urea;
1-(4-benzimidazol-1-yl-phenyl)-3-(3-isopropyl-isoxazol-5-yl)-urea;
and
1-(4-benzimidazol-1-yl-phenyl)-3-(3-tert-butyl-isoxazol-5-yl)-urea.

114 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/078,054Filed 10 Mar 2017
Priority: CN 2016 1 014204911 Mar 2016
Published: US 2019/0047964 A114 Feb 2019
Granted: 12 May 2020
Term ends: Not estimatedThe source records don’t support an estimate.

Classification21 codes

C07D 235/06
Benzimidazoles; Hydrogenated benzimidazoles: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in…
A61K 31/4184
1,3-Diazoles: condensed with carbocyclic rings, e.g. benzimidazoles
A61K 31/422
Oxazoles: not condensed and containing further heterocyclic rings
A61K 31/427
Thiazoles: not condensed and containing further heterocyclic rings

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US 2019/0047964 A1Pre-grant publication · published 14 Feb 2019
US 10,647,680 B2This patent

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Abstract

A compound of general formula (I) or the pharmaceutically acceptable salts, solvates or prodrugs thereof,

wherein:
the group
is
W and Z are each independently selected from C—BR1;
R51 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkoxy, alkenyl, alkynyl, —N(Ry)(Rz), cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, —N(Ry)(Rz), cycloalkyl, heterocyclyl, aryl or heteroaryl are optionally further substituted by one or more groups selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, ester groups;
in the absence of R1, B is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cyano, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally further substituted by one or more of Q groups;
in the presence of R1, B is identical or different and each is independently selected from the group consisting of —O— and —NR4—;
and R1 is identical or different and each is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —RuORx, —RuC(O)ORx, —RuN(Ry)(Rz), —C(O)N(Ry)(Rz), —RuS(O)nN(Ry)(Rz), —RuS(O)uRx;
the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl groups are optionally further substituted by one or more groups selected from the group consisting of halogen, cyano, hydroxy, alkyl, alkoxy, hydroxyalkyl, hydroxyalkoxy, amido, cycloalkyl, heterocyclyl, aryl, haloaryl, heteroaryl, cycloalkyl-heteroaryl;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl, or R4 and R1 together with the nitrogen atom attached them form a heterocyclyl group, and the heterocyclyl group is optionally further substituted by one or more groups selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy;
when R2 is hydrogen, G is selected from 5-membered heteroaryl, and the 5-membered heteroaryl is optionally further substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, amino, acyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, acyl, cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally further substituted by one or more groups selected from the group consisting of halogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, hydroxy, alkoxy, halo alkoxy, cycloalkyl, ester, and cyano;
or,
when R2 is not hydrogen, G and R2 together with the nitrogen atom attached them form a 5-membered heteroaryl group, the heteroaryl group is optionally further substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted by one or more groups selected from the group consisting of halogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, ester, and cyano;
R3 is selected from the hydrogen, halogen, hydroxy, amino, alkyl, alkoxy, cycloalkyl, cyano, heterocyclyl;
Ru is selected from a bond, alkylene, alkenylene, or alkynylene;
Rx is selected from hydrogen, alkyl, hydroxyalkyl, haloalkyl, alkenyl, or alkynyl;
or
the oxygen in —RuORx— together with Ru and Rx attached to them form an oxygen-containing 3-7 membered heterocyclic ring, which is optionally substituted by one or more of Q groups;
Ry and Rz are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, and haloalkyl;
or,
Ry and Rz together with the nitrogen atom attached to them form a heterocyclyl or heteroaryl group, and the heterocyclyl or heteroaryl group is optionally further substituted by one or more groups selected from the group consisting of halogen, haloalkyl, alkyl, alkenyl and alkynyl groups;
Q is selected from the group consisting of hydrogen, halogen, hydroxy, amino, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, cyano, aryl, heterocyclyl and heteroaryl, and the amino, alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, or heteroaryl is optionally further substituted by one or more groups selected from the group consisting of hydroxy, halogen and alkyl;
n is an integer from 0 to 2.

20 more elements

Facts

Application

16/078,054Filed 10 Mar 2017

Priority

CN 2016 1 014204911 Mar 2016

Published

US 2019/0047964 A114 Feb 2019

Granted

12 May 2020

Term ends

Not estimatedThe source records don’t support an estimate.

Classification21 codes

C07D 235/06
Benzimidazoles; Hydrogenated benzimidazoles: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in…
A61K 31/4184
1,3-Diazoles: condensed with carbocyclic rings, e.g. benzimidazoles
A61K 31/422
Oxazoles: not condensed and containing further heterocyclic rings
A61K 31/427
Thiazoles: not condensed and containing further heterocyclic rings