# US 2014/0155404 A1 · Piperazinylpiperidine derivatives as chemokine receptor antagonists

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- Number: US 2014/0155404 A1
- Document ID: US20140155404A1
- Status: Published application
- Kind: A1
- Application number: 14/176,781
- Filed: 2014-02-10
- Published: 2014-06-05
- Earliest claimed: 2004-04-13
- Assignees: Incyte Corporation
- Inventors: Chu-Biao Xue; Genfeng Cao; Taisheng Huang; Lihua Chen; Ke Zhang; Anlai Wang; David J. Meloni; Rajan Anand; Joseph Glenn; Brian W. Metcalf
- Web page: https://patentgrep.com/patent/US20140155404A1

## CPC

- C07D 401/14: containing three or more hetero rings
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/502: ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 31/18: for HIV
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- 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 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- 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

The present invention relates to compounds of Formula I: wherein variable substituents are defined herein, that modulate the activity of or bind to chemokine receptors such as CCR5. In some embodiments, the compounds of the invention are selective for CCR5. The compounds can be used, for example, to treat diseases associated with chemokine receptor expression or activity such as inflammatory diseases, immune diseases and viral infections.

## Claims

### Claim 1

A compound of Formula I:
or pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is heteroaryl optionally substituted by one or more R6;
R2 is H, halo, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, SOR7, SO2R7, COR8, OR9, SR9, COOR9, NR10R11 or NR10COR8;
R3 is F, Cl, Br, I, C1-C4 haloalkyl, C1-C4 haloalkoxy or heteroaryl;
R4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl;
R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl;
R6 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, (C1-C6 alkyl)amino or di(C1-C6 alkyl)amino;
R7 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C3-C7 cycloalkyl)alkyl, heterocycloalkylalkyl, or NR12R13;
R8 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C3-C7 cycloalkyl)alkyl, heterocycloalkylalkyl, or NR12R13;
R9 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, cycloalkyloxyalkyl, heterocycloalkyloxyalkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl; (C3-C7 cycloalkyl)alkyl or heterocycloalkylalkyl;
R10 and R11 are each, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl; (C3-C7 cycloalkyl)alkyl or heterocycloalkylalkyl;
or R10 and R11 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group;
R12 and R13 are each, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, aryl, heteroaryl, C3-C2 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl; (C3-C7 cycloalkyl)alkyl or heterocycloalkylalkyl;
or R12 and R13 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group;
r is 1, 2 or 3.

### Claim 2 (depends on 1)

The compound of claim 1 wherein R1 is a 5-, 6-, 9- or 10-membered heteroaryl group containing at least one ring-forming N atom, wherein said 5-, 6-, 9- or 10-membered heteroaryl group is optionally substituted by 1, 2, 3 or 4 R6 groups.

### Claim 3 (depends on 1)

The compound of claim 1 wherein R1 is:

### Claim 4 (depends on 1)

The compound of claim 1 wherein R1 is:

### Claim 5 (depends on 1)

The compound of claim 1 wherein R1 is:

### Claim 6 (depends on 1)

The compound of claim 1 wherein R2 is H, C1-C6 alkyl, C1-C6 haloalkyl, OR9, SR9 or NR10R11.

### Claim 7 (depends on 1)

The compound of claim 1 wherein R2 is H or OR9.

### Claim 8 (depends on 1)

The compound of claim 1 wherein R3 is F, Br, CF3, or 6- or 5-membered heteroaryl.

### Claim 9 (depends on 1)

The compound of claim 1 wherein R4 is C1-C6 alkyl.

### Claim 10 (depends on 1)

The compound of claim 1 wherein R4 is methyl.

### Claim 11 (depends on 1)

The compound of claim 1 wherein R5 is C1-C6 alkyl.

### Claim 12 (depends on 1)

The compound of claim 1 wherein R5 is methyl.

### Claim 13 (depends on 1)

The compound of claim 1 having Formula IIa:
or pharmaceutically acceptable salt form or prodrug thereof.

### Claim 14 (depends on 13)

The compound of claim 13 wherein R1 is:

### Claim 15 (depends on 13)

The compound of claim 13 wherein R1 is:

### Claim 16 (depends on 1)

The compound of claim 1 characterized as a selective binder or inhibitor of CCR5.

### Claim 17 (depends on 1)

The compound of claim 1 selected from:
5-({4-[(3S)-4-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine;
5-({4-[(3S)-4-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine;
5-({4-[(3S)-4-(6-bromo-2,3-dihydro-1H-inden-1-yl)-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine;
5-({4-[(3S)-4-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine;
5-({4-[(3S)-4-(6-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine;
5-({4-[(3S)-4-(7-bromo-1,2,3,4-tetrahydronaphthalen-1-yl)-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine;
4,6-dimethyl-5-[(4-methyl-4-{(3S)-3-methyl-4-[6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl}piperidin-1-yl)carbonyl]pyrimidine;
4,6-dimethyl-5-[(4-methyl-4-{(3S)-3-methyl-4-[5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl}piperidin-1-yl)carbonyl]pyrimidine;
1-((2S)-4-{1-[(4,6-dimethylpyrimidin-5-yl)carbonyl]-4-methylpiperidin-4-yl}-2-methylpiperazin-1-yl)-5-(trifluoromethyl)indan-2-ol;
5-[(4-{(3S)-4-[2-methoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine;
5-[(4-(3S)-4-[(1R,2R)-2-Ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine dihydrochloride;
5-[(4-{(3S)-4-[(1R,2R)-2-(2-Methoxyethoxy)-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine;
4-[(4-{(3S)-4-[(1S,2R)-2-Ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]cinnoline;
4-[(4-{(3S)-4-[(1R,2R)-2-Ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]quinoline;
5-[(4-{(3S)-4-[(1R,2R)-2-Ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]quinoline;
4-[(4-{(3S)-4-[(1R,2R)-2-Ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-1,8-naphthyridine;
5-[(4-{(3S)-4-[(1R,2R)-2-Ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]isoquinoline;
5-[(4-{(3S)-4-[(1R,2R)-5-Bromo-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine;
4-[(4-{(3S)-4-[(1R,2R)-5-bromo-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]cinnoline;
4-[(4-{(3S)-4-[(1R,2R)-5-Bromo-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-1,8-naphthyridine;
5-[(4-{(3S)-4-[(1R,2R)-5-Bromo-2-(pyridin-2-yloxy)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine;
5-[(4-{(3S)-4-[(1R,2R)-2-Ethoxy-5-(1,3-thiazol-2-yl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine;
5-[(4-{(3S)-4-[(1R,2R)-2-Ethoxy-5-pyridin-2-yl-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine;
5-[(4-{(3S)-4-[3-Methoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidin-1-yl)carbonyl]-4,6-dimethylpyrimidine.

### Claim 18 (depends on 1)

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

### Claim 19 (depends on 1)

A method of modulating activity of a chemokine receptor comprising contacting said chemokine receptor with a compound of claim 1.

### Claim 20 (depends on 19)

The method of claim 19 wherein said chemokine receptor is CCR5.

### Claim 21 (depends on 19)

The method of claim 19 wherein said modulating corresponds to inhibiting.

### Claim 22 (depends on 19)

The method of claim 19 wherein said compound is a selective inhibitor of CCR5.

### Claim 23 (depends on 19)

The method of claim 19 wherein said compound is a selective binder of CCR5.

### Claim 24 (depends on 1)

A method of treating a disease associated with expression or activity of a chemokine receptor in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1.

### Claim 25 (depends on 24)

The method of claim 24 wherein said chemokine receptor is CCR5.

### Claim 26 (depends on 25)

The method of claim 25 wherein said compound is a selective inhibitor or binder of CCR5.

### Claim 27 (depends on 1)

A method of treating a disease or condition selected from an inflammatory disease, immune disorder, and viral infection in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1.

### Claim 28 (depends on 27)

The method of claim 27 wherein said disease or condition is an inflammatory disease.

### Claim 29 (depends on 28)

The method of claim 28 wherein said disease or condition is an immune disorder.

### Claim 30 (depends on 28)

The method of claim 28 wherein said disease or condition is a viral infection.

### Claim 31 (depends on 30)

The method of claim 30 wherein said viral infection is HIV infection.

### Claim 32 (depends on 1)

A method of treating HIV infection in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1.

### Claim 33 (depends on 32)

The method of claim 32 further comprising simultaneously or sequentially administering at least one anti-viral agent.