# US 8,569,282 B2 · Carboxamide compounds and their use

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- Number: US 8,569,282 B2
- Document ID: US8569282B2
- Status: Granted
- Kind: B2
- Application number: 12/747,109
- Filed: 2008-12-11
- Published: 2010-12-23
- Granted: 2013-10-29
- Earliest claimed: 2007-12-11
- Assignees: Cytopathfinder, Inc.
- Applicants: Efrat Ben-Zeev; Dongli Chen; Merav Fichman; Shomir Ghosh; Steffi Koerner; Jian Lin; Yael Marantz; Rosa E. Melendez; Pradyumna Mohanty; Sharon Shacham; Zhaoda Zhang
- Inventors: Efrat Ben-Zeev; Dongli Chen; Merav Fichman; Shomir Ghosh; Steffi Koerner; Jian Lin; Yael Marantz; Rosa E. Melendez; Pradyumna Mohanty; Sharon Shacham; Zhaoda Zhang
- Web page: https://patentgrep.com/patent/US8569282B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- 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 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Chemokine receptor antagonists, in particular, compounds of Formula (I-A) that act as antagonists of the chemokine CCR2 receptor, including pharmaceutical compositions and uses thereof to treat or prevent diseases associated with monocyte accumulation, lymphocyte accumulation or leukocyte accumulation are described herein.

## Claims

### Claim 1

A compound of formula I-A:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen; alkyl, alkoxyalkyl, alkoxyphenyl, alkylthioalkyl, alkylamino, —SO2(alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which is optionally substituted with 1, 2, or 3 R5 substituents; or R1 is optionally substituted (C1-C6alkylene)-R1a, wherein R1a is C3-6 cycloalkyl, C3-6 heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, or 3 R5 substituents;
Y is a direct bond or is CO, SO2, —N(H)CO, —N(H)SO2, C(═NH), C1-4 alkylene, C2-4 alkenylene, C2-4 alkynylene, C3-6 cycloalkylene, arylene, heterocycloalkylene, heteroarylene, —C(O)alkylene, —N(H)C(O)alkylene, or —O-alkylene; each of which may be optionally substituted with 1, 2, or 3 R5 substituents;
R3 is
wherein R11 is hydrogen or is C1-6 alkyl, (C1-C6alkylene)cycloalkyl, aralkyl, or heteroaralkyl, any of which may be optionally substituted with halo, hydroxy, alkyl, alkenyl, cycloalkyl, C1-3alkoxy, —CO2H, —CO2C1-3alkyl, cyano, aryl, heteroaryl, —CF3, —O—CF3, —O—CH2F, or —O—CHF2;
R4 is hydrogen; halo; C1-8 alkyl, alkenyl, or alkynyl optionally interrupted by oxygen or sulfur; cycloalkyl; alkoxy; arylalkoxy; or heteroarylalkoxy;
R5, when present, represents independently for each occurrence hydrogen, halo, hydroxy, alkyl, alkenyl, cycloalkyl, alkoxy, —CO2H, —CO2C1-3alkyl, cyano, aryl, heteroaryl, aralkyl, heteroaralkyl, oxo, —CF3, —O—CF3, —O—CHF2, —O—CH2F, —O-aryl, —N(H)alkyl, —N(H)SO2-alkyl, —N(H)C(O)alkyl, —SO2N(H)alkyl, —SO2N(alkyl)C(O)alkyl, or —C(O)N(H)SO2alkyl;
n is 0 or 1;
p is 1;
A1, A2, A3, and A4 are independently N or C—R5, provided that at least two of A1, A2, A3, or A4 are C—R5; and
optionally substituted with 1 or 2 halo, methyl, or ethyl groups, or is geminally substituted to form a cyclopropyl ring.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is hydrogen; alkyl, alkoxyalkyl, alkoxy-CHF2, alkoxy-CH2F, alkoxy-CF3, C3-6 cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, or (C1-C6alkylene)-R1a; wherein R1a is C3-6 cycloalkyl, C3-6 heterocycloalkyl, aryl, or heteroaryl, each of which may be independently optionally substituted with 1, 2, or 3 R5 substituents.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R1 is
wherein
z is 1, 2, or 3;
y is 1, 2, 3, or 4; and
x is O, NH, CH2, CF2, or N(C1-8alkyl).

### Claim 4 (depends on 1)

The compound of claim 1, wherein R1 is —CH2—O—CH3, CH2—O—CF3, CH2—O—CHF2, CH2—O—CH2F, —CH2—O—CH2—CH3, —CH2O—CH—(CH3)2, or —CH2—CN.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R1 is methyl;
R6 is alkyl;
R7 represents independently for each occurrence hydrogen or C1-3 alkyl; and
R8 is an alkyl group.

### Claim 6 (depends on 1)

The compound of claim 1, wherein Y is CH2,
wherein n is 0, 1 or 2.

### Claim 7 (depends on 1)

The compound of claim 1, wherein
R11 is hydrogen or C1-6 alkyl.

### Claim 8

A compound represented by the following formula:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen; alkyl, alkoxyalkyl, alkoxyphenyl, alkylthioalkyl, alkylamino, —SO2(alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which is optionally substituted with 1, 2, or 3 R5 substituents; or R1 is optionally substituted (C1-C6alkylene)-R1a, wherein R1a is C3-6 cycloalkyl, C3-6 heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, or 3 R5 substituents;
Y is a direct bond or is CO, SO2, —N(H)CO, —N(H)SO2, C(═NH), C1-4 alkylene, C2-4 alkenylene, C2-4 alkynylene, C3-6 cycloalkylene, arylene, heterocycloalkylene, heteroarylene, —C(O)alkylene, —N(H)C(O)alkylene, or —O-alkylene; each of which may be optionally substituted with 1, 2, or 3 R5 substituents;
R3 is
wherein R11 is hydrogen or is C1-6 alkyl, (C1-C6alkylene)cycloalkyl, aralkyl, or heteroaralkyl, any of which may be optionally substituted with halo, hydroxy, alkyl, alkenyl, cycloalkyl, C1-3alkoxy, —CO2H, —CO2C1-3alkyl, cyano, aryl, heteroaryl, —CF3, —O—CF3, —O—CH2F, or —O—CHF2;
R4 is hydrogen; halo; C1-8 alkyl, alkenyl, or alkynyl optionally interrupted by oxygen or sulfur; cycloalkyl; alkoxy; arylalkoxy; or heteroarylalkoxy;
R5, when present, represents independently for each occurrence hydrogen, halo, hydroxy, alkyl, alkenyl, cycloalkyl, alkoxy, —CO2H, —CO2C1-3alkyl, cyano, aryl, heteroaryl, aralkyl, heteroaralkyl, oxo, —CF3, —O—CF3, —O—CHF2, —O—CH2F, —O-aryl, —N(H)alkyl, —N(H)SO2-alkyl, —N(H)C(O)alkyl, —SO2N(H)alkyl, —SO2N(alkyl)C(O)alkyl, or —C(O)N(H)SO2alkyl;
n is 0 or 1;
p is 1;
wherein R12 is, independently for each occurrence, hydrogen, halo, alkyl, haloalkyl, haloalkoxy, alkoxy, or cyano; and
R13a and R13b are each independently hydrogen, halo, alkyl, haloalkyl, alkoxy, or haloalkoxy.

### Claim 9 (depends on 1)

The compound of claim 1, which is a compound of formula I-A3:

### Claim 10 (depends on 1)

The compound of claim 1, which is a compound of formula I-B1:
or pharmaceutically acceptable salts thereof; and Y is C1-4 alkylene.

### Claim 11 (depends on 1)

The compound of claim 1, wherein A1 is N or C—R5; and A2, A3, and A4 are C—R5.

### Claim 12 (depends on 1)

The compound of claim 1, which is:
5-((3-(cyclopropylmethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one; 5-((3-isobutyl-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one; 5-(1-(3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)ethyl)-3-methylbenzo[d]oxazol-2(3H)-one; 5-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one; (R)-6-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one; (S)-6-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one; 3-ethyl-6-((3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)benzo[d]oxazol-2(3H)-one; 5-((3-(ethoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one; 5-((3-(methoxymethyl)-3-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one; 5-((3-isopropyl-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one; 2-(1-((3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)methyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-3-yl)acetonitrile; 5-((3-(hydroxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one; 6-((4-isobutyl-4-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)piperidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one; 2-(3-(methoxymethyl)-1-((3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carbonyl)-7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-5-carbonitrile; 5-((3-(methoxymethyl)-3-(7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one; 6-(3-(methoxymethyl)-1-((3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile; 5-((3-(methoxymethyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)methyl)-3-methylbenzo[d]oxazol-2(3H)-one; 5-(2-(3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)propan-2-yl)-3-methylbenzo[d]oxazol-2(3H)-one; 5-(1-(3-(methoxymethyl)-3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)pyrrolidin-1-yl)cyclopropyl)-3-methylbenzo[d]oxazol-2(3H)-one; or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 14 (depends on 1)

A method of treating organ transplant rejection, rheumatoid arthritis, chronic contact dermatitis, inflammatory bowel disease, lupus, systemic lupus erythematosus, multiple sclerosis, atherosclerosis, psoriasis, sarcoidosis, idiopathic pulmonary fibrosis, dermatomyositis, skin pemphigoid, glomerulonephritides, vasculitides, hepatitis, allograft rejection, graft-versus-host disease, metabolic syndrome, or obesity, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

### Claim 15 (depends on 1)

A method of treating pain, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

### Claim 16 (depends on 1)

The compound of claim 1, wherein the compound is represented by
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

The compound of claim 1, wherein the compound is represented by

### Claim 18 (depends on 1)

The compound of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

The compound of claim 1, wherein the compound is

### Claim 20 (depends on 1)

The compound of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 1)

The compound of claim 1, wherein the compound is

### Claim 22 (depends on 1)

The compound of claim 1, wherein R1 is alkoxyalkyl, and R11 is hydrogen or alkyl.

### Claim 23 (depends on 22)

The compound of claim 22, wherein Y is C1-4 alkylene, and R4 is hydrogen or C1-8 alkyl, and R5 represents independently for each occurrence hydrogen, halo, hydroxy, alkyl, alkoxy, or —CF3.

### Claim 24 (depends on 23)

The compound of claim 23, wherein n is 1.

### Claim 25 (depends on 8)

The compound of claim 8, wherein R1 is alkoxyalkyl, and R11 is hydrogen or alkyl.

### Claim 26 (depends on 25)

The compound of claim 25, wherein Y is C1-4 alkylene, and R4 is hydrogen or C1-8 alkyl.

### Claim 27 (depends on 26)

The compound of claim 26, wherein R5 represents independently for each occurrence hydrogen, halo, hydroxy, alkyl, alkoxy, or —CF3; R12 is halo, alkyl, or haloalkyl; and R13a and R13b are each independently hydrogen, halo, alkyl, or haloalkyl.

### Claim 28 (depends on 27)

The compound of claim 27, wherein

### Claim 29 (depends on 27)

The compound of claim 27, wherein n is 1.

### Claim 30 (depends on 9)

The compound of claim 9, wherein R1 is alkoxyalkyl, and R11 is hydrogen or alkyl.

### Claim 31 (depends on 30)

The compound of claim 30, wherein R4 is hydrogen or C1-8 alkyl, and R5 represents independently for each occurrence hydrogen, halo, hydroxy, alkyl, alkoxy, or —CF3.

### Claim 32 (depends on 31)

The compound of claim 31, wherein n is 1.

### Claim 33 (depends on 8)

A pharmaceutical composition, comprising a compound of claim 8 and a pharmaceutically acceptable carrier.

### Claim 34 (depends on 9)

A pharmaceutical composition, comprising a compound of claim 9 and a pharmaceutically acceptable carrier.

### Claim 35 (depends on 28)

A pharmaceutical composition, comprising a compound of claim 28 and a pharmaceutically acceptable carrier.