# US 9,040,526 B2 · Benzylpyrrolidinone derivatives as modulators of chemokine receptor activity

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- Number: US 9,040,526 B2
- Document ID: US9040526B2
- Status: Granted
- Kind: B2
- Application number: 13/576,706
- Filed: 2011-02-08
- Published: 2012-11-22
- Granted: 2015-05-26
- Earliest claimed: 2010-02-09
- Assignees: Bristol-Myers Squibb Company
- Applicants: Ian K. Mangion; Percy H. Carter; Jingwu Duan; Andrew J. Tebben
- Inventors: Ian K. Mangion; Percy H. Carter; Jingwu Duan; Andrew J. Tebben
- Web page: https://patentgrep.com/patent/US9040526B2

## CPC

- C07D 498/04: Ortho-condensed systems
- A61P 19/00: Drugs for skeletal disorders
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07D 207/27: with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present application describes modulators of MCP-1 or CCR-2 of formula or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein m, n, W, X, R1 and R6, are defined herein. In addition, methods of treating and preventing inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and transplant rejection using modulators of formula (I) are disclosed.

## Claims

### Claim 1

A compound of formula (I):
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
X is O;
W is a —NR2R3 or a 3- to 20-membered nitrogen containing ring, wherein the ring is
(i) attached through the nitrogen atom, (ii) may optionally contain 1-4 heteroatoms selected from N, O, and S and (iii) be optionally substituted with one or more R10a's;
m is 1-4;
n is 0-2;
R1 is H or alkyl;
R2 is H, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein the cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with may be optionally substituted with be optionally substituted with one or more R9a's;
R3 is H, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein the cycloalkyl, aryl, heteroaryl or heterocyclyl may be optionally substituted with may be optionally substituted with be optionally substituted with one or more R9a's;
R6, at each occurrence, is independently selected from halo, alkyl, haloalkyl, haloalkoxy, and aryl optionally substituted with halo;
R9a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —CN, —NO2, —C(═O)OR14, —OCF3, —OR14, ═O, —NR14R14 or arylalkyl;
R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —CN, —NO2, —C(═O)OR14, —OCF3, —OR14, ═O, —NR14R14 or arylalkyl, wherein the aryl, cycloalkyl, heteroaryl, and heterocyclyl may be optionally substituted with on or more R14a'S;
R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may be optionally substituted with be optionally substituted with 0-3 R14a;
R14a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —CN, —NO2, —C(═O)OR24, —OCF3, —OR24, ═O, —NR24R24 or arylalkyl; and
R24, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is a compound of formula (Ia):

### Claim 3 (depends on 1)

The compound, enantiomer, diastereomer, or salt thereof, of claim 1, wherein:
X is O;
W is a —NR2R3 or a 3- to 15-membered nitrogen containing ring, wherein the ring is (i) attached through the nitrogen atom, (ii) may optionally contain 1-4 heteroatoms selected from N, O, and S and (iii) be optionally substituted with one or more R10a's;
m is 1-3;
n is 0-2;
R1 is H or alkyl;
R2 is H, alkyl, cycloalkyl, aryl or heterocyclyl, wherein the cycloalkyl, aryl or heterocyclyl may be optionally substituted with may be optionally substituted with be optionally substituted with one or more R9a's;
R3 is H, alkyl, cycloalkyl, aryl or heterocyclyl, wherein the cycloalkyl, aryl or heterocyclyl may be optionally substituted with may be optionally substituted with be optionally substituted with one or more R9a's;
R6, at each occurrence, is independently selected from halo, alkyl, haloalkyl, haloalkoxy, and aryl optionally substituted with halo;
R9a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —CN, —NO2, —C(═O)OR14, —OCF3, —OR14, ═O, or arylalkyl;
R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo,—CN, —NO2, —C(═O)OR14, —OCF3, —OR14, ═O, or arylalkyl, wherein the aryl, cycloalkyl, heteroaryl, and heterocyclyl may be optionally substituted with on or more R14a'S;
R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may be optionally substituted with be optionally substituted with 0-3 R14a;
R14a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —CN, —NO2, —C(═O)OR24, —OCF3, —OR24, ═O, or arylalkyl; and
R24, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl.

### Claim 4 (depends on 1)

The compound, enantiomer, diastereomer, or salt thereof, of claim 1, wherein:
X is O;
W is a —NR2R3 or a 3- to 12-membered nitrogen containing ring, wherein the ring is (i) attached through the nitrogen atom, (ii) may optionally contain 1-4 heteroatoms selected from N, O, and S and (iii) be optionally substituted with one or more R10a's;
m is 1-2;
n is 1-2;
R1 is H or alkyl;
R2 is H, alkyl or cycloalkyl, wherein the cycloalkyl may be optionally substituted with may be optionally substituted with be optionally substituted with one or more R9a'S;
R3 is H, alkyl or cycloalkyl, wherein the cycloalkyl may be optionally substituted with may be optionally substituted with be optionally substituted with one or more R9a 's;
R6, at each occurrence, is independently selected from halo, alkyl, haloalkyl, haloalkoxy, and aryl optionally substituted with halo;
R9a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —CN, —NO2, —C(═O)OR14, —OCF3, —OR14, or arylalkyl;
R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —CN, —NO2, —C(═O)OR14, —OCF3, —OR14, or arylalkyl, wherein the aryl, cycloalkyl, heteroaryl, and heterocyclyl may be optionally substituted with on or more R14a's;
R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl may be optionally substituted with be optionally substituted with 0-3 R14a;
R14a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —CN, —NO2, —C(═O)OR24, —OCF3, —OR24 or arylalkyl; and
R24, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl.

### Claim 5 (depends on 1)

The compound, enantiomer, diastereomer, or salt thereof, of claim 1, wherein:
X is O;
W is a —NR2R3 or a 3- to 12-membered nitrogen containing ring, wherein the ring is (i) attached through the nitrogen atom, (ii) may optionally contain 1-4 heteroatoms selected from N, O, and S and (iii) be optionally substituted with one or more R10a's;
m is 1-2;
n is 1-2;
R1 is H or alkyl;
R2 is H, alkyl or cycloalkyl, wherein the cycloalkyl may be optionally substituted with may be optionally substituted with be optionally substituted with one or more R9a's;
R3 is H, alkyl or cycloalkyl, wherein the cycloalkyl may be optionally substituted with may be optionally substituted with be optionally substituted with one or more R9a's;
R6, at each occurrence, is independently selected from halo, alkyl, haloalkyl, haloalkoxy, and aryl optionally substituted with halo;
R9a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —CN, —NO2, —C(═O)OR14, —OCF3, —OR14, or arylalkyl;
R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —CN, —NO2, —C(═O)OR14, —OCF3, —OR14, or arylalkyl, wherein the aryl, cycloalkyl, heteroaryl, and heterocyclyl may be optionally substituted with on or more R14a'S;
R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl may be optionally substituted with be optionally substituted with 0-3 R14a;
R14a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —CN, —NO2, —C(═O)OR24, —OCF3, —OR24 or arylalkyl; and
R24, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl.

### Claim 6 (depends on 1)

The compound, enantiomer, diastereomer, or salt thereof, of claim 1, wherein:
X is O;
W is a 3- to 12-membered nitrogen containing ring, wherein the ring is (i) attached through the nitrogen atom, (ii) may optionally contain 1-4 heteroatoms selected from N, O, and S and (iii) be optionally substituted with one or more R10a's;
m is 1-2;
n is 1-2;
R1 is H or alkyl;
R6, at each occurrence, is independently selected from halo, alkyl, haloalkyl, haloalkoxy, and aryl optionally substituted with halo;
R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —CN, —NO2, —C(═O)OR14, —OCF3, —OR14, or arylalkyl, wherein the aryl, cycloalkyl, heteroaryl, heterocyclyl may be optionally substituted with on or more R14a'S;
R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl may be optionally substituted with be optionally substituted with 0-3 R14a;
R14a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, halo, —CN, —NO2, —C(═O)OR24, —OCF3, —OR24 or arylalkyl; and
R24, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl.

### Claim 7 (depends on 1)

The compound, enantiomer, diastereomer, or salt thereof, of claim 1, wherein:
X is O;
W is a 5- to 12-membered nitrogen containing ring, wherein the ring is (i) attached through the nitrogen atom, (ii) may optionally contain 1-4 heteroatoms selected from N, O, and S and (iii) be optionally substituted with one or more R10a's;
m is 1-2;
n is 1-2;
R1 is H or alkyl;
R6, at each occurrence, is independently selected from halo, alkyl, haloalkyl, haloalkoxy, and aryl optionally substituted with halo;
R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, halo, —CN, —NO2, —C(═O)OR14, —OCF3, —OR14, or arylalkyl, wherein the aryl, cycloalkyl and heteroaryl may be optionally substituted with on or more R14a′s;
R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl may be optionally substituted with be optionally substituted with 0-3 R14a;
R14a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, halo, —CN, —NO2, —C(═O)OR24, —OCF3, —OR24 or arylalkyl; and
R24, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, aryl or heteroaryl.

### Claim 8 (depends on 1)

The compound, enantiomer, diastereomer, or salt thereof, of claim 1, wherein:
X is O;
W is a 5- or 6-membered nitrogen containing ring, wherein the ring is (i) attached through the nitrogen atom, (ii) may optionally contain 1-3 heteroatoms selected from N, O, and S and (iii) be optionally substituted with one or more R10a's;
m is 2;
n is 1-2;
R1 is H or alkyl;
R6, at each occurrence, is independently selected from halo, alkyl, haloalkyl, haloalkoxy, and aryl optionally substituted with halo;
R10a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, halo, —C(═O)OR14, —OCF3, —OR14, or arylalkyl, wherein the aryl, cycloalkyl and heteroaryl may be optionally substituted with on or more R14a's;
R14, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl or aryl, wherein the alkyl, cycloalkyl and aryl may be optionally substituted with be optionally substituted with 0-3 R14a;
R14a, at each occurrence, is independently selected from alkyl, haloalkyl, aryl, cycloalkyl, heteroaryl, halo, —C(═O)OR24, —OCF3, —OR24 or arylalkyl; and
R24, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, or aryl.

### Claim 9 (depends on 1)

The compound, enantiomer, diastereomer, or salt thereof, of claim 1, wherein:
X is O;
W is pyrrolidinyl, piperazinyl or piperidinyl, wherein the ring is (i) attached through a nitrogen atom and may be optionally substituted with one or more R10a's;
m is 2;
n is 1-2;
R1 is H or isopropyl;
R6, at each occurrence, is independently selected from Cl, Br, F, t-butyl, —CF3, —CF2CF3, —OCF3, and phenyl optionally substituted with Cl, Br, F or I;
R10a, at each occurrence, is independently selected from methyl, —CF3, —CF2CF3, aryl, Cl, F, Br, —C(═O)OH, —OCF3, —OH or benzyl.

### Claim 10

A compound, enantiomer, diastereomer, or salt thereof, selected from the group consisting of:

### Claim 11 (depends on 1)

A pharmaceutical composition comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 1.

### Claim 12 (depends on 10)

A pharmaceutical composition comprised of a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 10.