US 10,370,360 B2Granted

Small-molecule inhibitors targeting discoidin domain receptor 1 and uses thereof

AssigneesBoard of Regents, The University of Texas System, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences

InventorsRolf A. Brekken, Ke Ding, Xiaomei Ren, Zhengchao Tu, Zhen Wang, Kristina Y. Aguilera

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Abstract

Compounds of formula (I), their pharmaceutically acceptable salts and stereoisomers thereof, as well as application in effectively inhibiting the enzymatic activity of discoidin domain receptor 1 and can be used as new therapeutic agents for preventing and treating e.g. inflammation, liver fibrosis, kidney fibrosis, lung fibrosis, skin scar, atherosclerosis, and cancer. The compound of formula I is: wherein the variables are as defined herein.

Claims19

Dependent claims

A compound of the formula:

wherein:
A is —NR8C(O)— or —C(O)NR8—;
wherein:
R8 is hydrogen, alkyl(C≤6), or substituted alkyl(C≤6);
R1 is aryl(C≤12 ), heteroaryl(C≤12), or a substituted version of either of these groups;
R2, R3, and R3′ are each independently hydrogen, alkyl(C≤12), cycloalkyl(C≤12), substituted alkyl(C≤12), or substituted cycloalkyl(C≤12);
R4 is hydrogen, alkyl(C≤12), cycloalkyl(C≤12), aryl(C≤12), substituted alkyl(C≤12), substituted cycloalkyl(C≤12), or substituted aryl(C≤12),
R5 is
—X—R9, wherein:
X is a covalent bond, alkanediyl(C≤8), or substituted alkanediyl(C≤8);
R9 is amino or heterocycloalkyl(C≤12), heteroaryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), or a substituted version of any of these groups;
or a group of the formula:
wherein:
R10 is hydrogen, alkyl(C≤12), cycloalkyl(C≤12), substituted alkyl(C≤12), or substituted cycloalkyl(C≤12);
and
p and q are each 0, 1, or 2;
R6 and R7 are each independently amino, cyano, halo, hydroxy, hydroxysulfonyl, nitro, sulfonamide;
or
substituted or unsubstituted alkyl(C≤8), acyl(C≤8), alkoxy(C≤8), amido(C≤8), acyloxy(C≤8), alkylamino(C≤8), or dialkylamino(C≤8);
and
m and n are each independently 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.

19 more elements

A compound of the formula:

4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide;
N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(quinolin-3-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4,4-dimethyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(4-chloro-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(4-methyl-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(3-(2-(4-methylpiperazin-1-yl)ethyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-2-(pyrimidin-5-yl)-N-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(3-((4-methyl-1,4-diazepan-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-ethyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-isopropyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(3-(piperidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-2-(pyrimidin-5-yl)-N-(3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-cyclohexyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-(((R)-3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-tert-butyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-N-(5-((4-methylpiperazin-1-yl)methyl)biphenyl-3-yl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
3-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-cyclopropyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-cyclopentyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
N-(3-((4-cyclohexylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-ethyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
4-methyl-2-(pyrimidin-5-yl)-N-(3-(thiomorpholinomethyl)-5-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
3-((4-methylpiperazin-1-yl)methyl)-N-(2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-(trifluoromethyl)benzamide;
(S)-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
(R)-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide;
(S)—N-(4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide;
(R)—N-(4-methyl-2-(pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide;
or a pharmaceutically acceptable salt thereof.

38 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/521,107Filed 21 Oct 2015 · us provisional application
Priority: 22 Oct 2014
Published: US 2018/0022730 A125 Jan 2018
Granted: 6 Aug 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification19 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…:…
A61K 31/337
Having oxygen as the only ring hetero atom, e.g. fungichromin: having four-membered rings, e.g. taxol
A61K 31/4725
Non-condensed isoquinolines, e.g. papaverine: containing further heterocyclic rings
A61K 31/7068
Containing condensed or non-condensed pyrimidines: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid

Family

Application62/067,070Us provisional application · filed 22 Oct 2014
Application62/204,176Us provisional application · filed 12 Aug 2015
US 2018/0022730 A1Pre-grant publication · published 25 Jan 2018
US 10,370,360 B2This patent

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

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