# US 10,370,360 B2 · Small-molecule inhibitors targeting discoidin domain receptor 1 and uses thereof

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- Number: US 10,370,360 B2
- Document ID: US10370360B2
- Status: Granted
- Kind: B2
- Application number: 15/521,107
- Filed: 2015-10-21
- Published: 2018-01-25
- Granted: 2019-08-06
- Earliest claimed: 2014-10-22
- Assignees: Board of Regents, The University of Texas System; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
- Applicants: The Board of Regents of the University of Texas System; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
- Inventors: Rolf A. Brekken; Ke Ding; Xiaomei Ren; Zhengchao Tu; Zhen Wang; Kristina Y. Aguilera
- Web page: https://patentgrep.com/patent/US10370360B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/4725: containing further heterocyclic rings
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is further defined as:
wherein: A, R1, R3, R3′, R4, R5, R6, and n are as defined above;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the compound is further defined as:
wherein: A, R1, R3, R3′, R4, R5, R6, and n are as defined above;
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R1 is heteroaryl(C≤12).

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R3 is alkyl(C≤12).

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R3 is hydrogen.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R3′ is hydrogen.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein R4 is alkyl(C≤12) or substituted alkyl(C≤12).

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R4 is cycloalkyl(C≤12) or substituted cycloalkyl(C≤12).

### Claim 10 (depends on 1)

The compound according to claim 1, wherein R4 is aryl(C≤12 ).

### Claim 11 (depends on 1)

The compound according to claim 1, wherein m is 0.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein m is 1.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein R7 is alkyl(C≤8) or substituted alkyl(C≤8).

### Claim 14 (depends on 1)

The compound according to claim 1, wherein R7 is halo.

### Claim 15

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.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising:
(a) a compound according to claim 1; and
(b) a pharmaceutically acceptable carrier.

### Claim 17 (depends on 1)

A method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound according to claim 1, wherein said disease or disorder is mediated by DDAR activation.

### Claim 18 (depends on 1)

A method of inhibiting discoidin domain receptor (DDR) protein comprising contacting the protein with a compound according to claim 1 in an amount sufficient to inhibit the protein.

### Claim 19 (depends on 1)

A method of treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of:
(a) a compound according to claim 1; and
(b) a second chemotherapeutic compound.