# US 11,992,489 B2 · Substituted tetrahydroquinoline compounds as indoleamine 2,3-dioxygenase inhibitors

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- Number: US 11,992,489 B2
- Document ID: US11992489B2
- Status: Granted
- Kind: B2
- Application number: 17/267,866
- Filed: 2019-08-12
- Published: 2021-06-03
- Granted: 2024-05-28
- Earliest claimed: 2018-08-17
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme LLC
- Inventors: Dane Clausen; Xavier Fradera; Yongxin Han; Alexander Pasternak; Li Xiao; Hongjun Zhang
- Web page: https://patentgrep.com/patent/US11992489B2

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 35/00: Antineoplastic agents
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D 215/14: Radicals substituted by oxygen atoms
- C07D 215/20: Oxygen atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed herein are compounds of formula (I) which are inhibitors of an IDO enzyme (I). Also disclosed herein are uses of the compounds in the potential treatment or prevention of an IDO-associated disease or disorder. Also disclosed herein are compositions comprising these compounds. Further disclosed herein are uses of the compositions in the potential treatment or prevention of an IDO-associated disease or disorder.

## Claims

### Claim 1

A compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from (1) a bond, (2) —O—, (3) —S— and (4) —NH—;
each occurrence of R1 is independently selected from: (1) hydrogen, (2) halogen and (3) C1-6 alkyl;
each of R2 and R3 is independently selected from: (1) hydrogen and (2) C1-6 alkyl;
or alternatively, R2 and R3 together with the carbon to which they are attached form a C3-5 cycloalkyl; and
R is selected from:
(1) aryl,
(2) heteroaryl and
(3) C1-6 alkyl, optionally substituted with a C3-5 cycloalkyl;
wherein each of the aryl of (1) and the heteroaryl of (2) is optionally substituted with one to four substituents independently selected from:
(a) halogen,
(b) —OH,
(c) —CN,
(d) C1-6 alkyl, optionally substituted with one to four substituents independently selected from (i) halogen and (ii) C3-6 cycloalkyl, and
(e) —NRaRa, wherein each occurrence of Ra is independently selected from (i) hydrogen and (ii) C1-6 alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
X is selected from (1) a bond, (2) —O— and (3) —NH—;
each occurrence of R1 is independently selected from: (1) hydrogen and (2) halogen;
R2 is hydrogen and R3 is C1-4 alkyl;
or alternatively, R2 and R3 together with the carbon to which they are attached form a cyclopropyl; and
R is selected from:
(1) phenyl,
(2) heteroaryl, and
(3) C1-4 alkyl, optionally substituted with a C3-4 cycloalkyl;
wherein each of the phenyl of (1) and the heteroaryl of (2) is optionally substituted with one to four substituents independently selected from:
(a) halogen,
(b) —CN,
(c) C1-6 alkyl, optionally substituted with one to four halogens, and
(d) —NRaRa, wherein each occurrence of Ra is independently selected from (i) hydrogen and (ii) C1-4 alkyl.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is phenyl, optionally substituted with one to four substituents independently selected from:
(a) halogen,
(b) —CN,
(c) C1-4 alkyl, optionally substituted with one to three halogens, and
(d) —NRaRa, wherein each occurrence of Ra is independently selected from (i) hydrogen and (ii) C1-4 alkyl.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is a heteroaryl selected from pyridinyl and pyrimidinyl, each of which is optionally substituted with one to four substituents independently selected from:
(a) halogen,
(b) —CN,
(c) C1-4 alkyl, optionally substituted with one to three halogens, and
(d) —NRaRa, wherein each occurrence of Ra is independently selected from (i) hydrogen and (ii) C1-4 alkyl.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is selected from (1) methyl, (2) ethyl and (3) propyl, each of which is optionally substituted with a C3-4 cycloalkyl.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen and R3 is selected from (1) methyl, (2) ethyl and (3) propyl.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together with the carbon to which they are attached form a cyclopropyl or cyclobutyl.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein one R1 group is halogen and each of the three remaining R1 groups is hydrogen.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, of formula (Ia):
wherein:
X is selected from (1) a bond, (2) —O— and (3) —NH—;
R1 is a halogen;
R2 is hydrogen;
R3 is C1-4 alkyl; and
R is selected from (1) phenyl and (2) a heteroaryl, each of which is optionally substituted with one to three substituents independently selected from:
(a) halogen, and
(b) C1-4 alkyl, optionally substituted with one to three halogens.

### Claim 10 (depends on 9)

The compound of claim 9, or a pharmaceutically acceptable salt thereof,
wherein:
X is selected from (1) a bond and (2) —O—;
R1 is a fluoro;
R2 is hydrogen;
R3 is selected from (1) methyl, (2) ethyl and (3) propyl; and
R is a heteroaryl selected from (1) pyridinyl and (2) pyrimidinyl, each of which is optionally substituted with one to three substituents independently selected from:
(a) halogen, and
(b) C1-4 alkyl, optionally substituted with one to three halogens.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, of formula (Ib):
wherein:
n is 1 or 2;
X is selected from (1) a bond, (2) —O— and (3) —NH—;
each occurrence of R1 is independently selected from: (1) hydrogen, (2) halogen and (3) C1-6 alkyl; and
R is selected from:
(1) aryl,
(2) heteroaryl and
(3) C1-6 alkyl, optionally substituted with a C3-4 cycloalkyl;
wherein each of the aryl of (1) and the heteroaryl of (2) is optionally substituted with one to four substituents independently selected from:
(a) halogen,
(b) —CN,
(c) C1-6 alkyl, optionally substituted with one to four halogens, and
(d) —NRaRa, wherein each occurrence of Ra is independently selected from (i) hydrogen and (ii) C1-6 alkyl.

### Claim 12 (depends on 11)

The compound of claim 11, or a pharmaceutically acceptable salt thereof, of formula (IC):
wherein:
X is selected from (1) a bond, (2) —O— and (3) —NH—;
R1 is a halogen; and
R is selected from:
(1) phenyl,
(2) heteroaryl and
(3) C1-4 alkyl; optionally substituted with a C3-4 cycloalkyl;
wherein each of the phenyl of (1) and the heteroaryl of (2) is optionally substituted with one to three substituents independently selected from:
(a) halogen,
(b) —CN,
(c) C1-4 alkyl, optionally substituted with one to three substituents independently selected from (i) halogen and (ii) C3-4cycloalkyl, and
(d) —NRaRa, wherein each occurrence of Ra is independently selected from (i) hydrogen, (ii) methyl and (iii) ethyl.

### Claim 13 (depends on 12)

The compound of claim 12, or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from (1) a bond, (2) —O— and (3) —NH—;
R1 is a fluoro; and
R is selected from:
(1) phenyl,
(2) a heteroaryl selected from (1) pyridinyl and (2) pyrimidinyl,
(3) methyl, optionally substituted with a cyclopropyl and
(4) ethyl, optionally substituted with a cyclopropyl;
wherein each of the phenyl of (1) and heteroaryl of (2) is optionally substituted with one tothree substituents independently selected from:
(a) halogen,
(b) —CN,
(c) C1-4 alkyl, optionally substituted with one to three halogens, and
(d) —N(CH3)2.

### Claim 14 (depends on 1)

The compound of claim 1 selected from the group consisting of:
N-(1-(5-(3-chlorophenoxy)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)-4-fluorobenzamide,
N-(1-(5-((2-(dimethylamino)pyrimidin-5-yl)oxy)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)-4-fluorobenzamide,
4-fluoro-N-(1-(5-(6-fluoropyridin-3-yl)oxy)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)benzamide,
N-(1-(5-((5-chloropyridin-3-yl)oxy)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)-4-fluorobenzamide,
N-(1-(5-(3-cyanophenoxy)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)-4-fluorobenzamide,
4-fluoro-N-(1-(5-(6-fluoropyridin-3-yl)oxy)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)benzamide,
4-fluoro-N-(1-(5-((4-methylpyridin-3-yl)oxy)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)benzamide,
N-(1-(5-((5-chloropyridin-3-yl)oxy)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)-4-fluorobenzamide,
N-(1-(5-(3-cyanophenoxy)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)-4-fluorobenzamide,
4-fluoro-N-(1-(5-((2-methylpyrimidin-5-yl)oxy)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)benzamide,
N-(1-(5-((2-(dimethylamino)pyrimidin-5-yl)oxy)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)-4-fluorobenzamide,
4-fluoro-N-(1-(5-((2-methylpyrimidin-5-yl)oxy)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)benzamide,
N-(1-(5-((3-chlorophenyl)amino)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)-4-fluorobenzamide,
N-(1-(5-(cyclopropylmethoxy)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)-4-fluorobenzamide,
4-fluoro-N-(1-(5-(2-methylpyrimidin-4-yl)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)benzamide,
4-fluoro-N-(1-(5-(5-fluoropyridin-3-yl)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)benzamide,
4-fluoro-N-(1-(5-(5-fluoropyridin-3-yl)-5,6,7,8-tetrahydroquinolin-2-yl)propyl)benzamide,
4-fluoro-N-(1-(5-(5-methylpyridin-3-yl)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)benzamide,
4-fluoro-N-(1-(5-(5-methylpyridin-3-yl)-5,6,7,8-tetrahydroquinolin-2-yl)propyl)benzamide,
4-fluoro-N-(1-(5-(5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)benzamide,
4-fluoro-N-(1-(5-(5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydroquinolin-2-yl)propyl)benzamide, and
4-fluoro-N-(1-(5-(2-methylpyrimidin-5-yl)-5,6,7,8-tetrahydroquinolin-2-yl)cyclopropyl)benzamide;
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

A composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

A method for treating an IDO-associated disease or disorder in a mammalian subject having an IDO-associated disease or disorder, which comprises administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

A method for treating an IDO-associated disease or disorder in a mammalian subject having an IDO-associated disease or disorder, which comprises administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof in combination with another anti-cancer agent.

### Claim 18 (depends on 1)

A method for treating an IDO-associated disease or disorder in a mammalian subject having an IDO-associated disease or disorder, which comprises administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof in combination with two additional anti-cancer agents.

### Claim 19 (depends on 16)

The method of claim 16, wherein the IDO-associated disease or disorder is a cancer, viral infection, HCV infection, depression, neurodegenerative disorders, trauma, age-related cataracts, organ transplantation, and autoimmune diseases.

### Claim 20 (depends on 19)

The method of claim 19, wherein the cancer is selected from colon cancer, pancreas cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testes cancer, renal cancer, head and neck cancer, lymphoma, leukemia and melanoma.