# US 2014/0154179 A1 · Cxcr7 antagonists

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- Number: US 2014/0154179 A1
- Document ID: US20140154179A1
- Status: Published application
- Kind: A1
- Application number: 14/091,641
- Filed: 2013-11-27
- Published: 2014-06-05
- Earliest claimed: 2012-11-29
- Assignees: ChemoCentryx, Inc.
- Applicants: ChemoCentryx, Inc.
- Inventors: Junfa Fan; Antoni Krasinski; Christopher W. Lange; Rebecca M. Lui; Jeffrey P. McMahon; Jay P. Powers; Yibin Zeng; Penglie Zhang
- Web page: https://patentgrep.com/patent/US20140154179A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 51/0459: {having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine}
- A61P 25/00: Drugs for disorders of the nervous system
- 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 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- G01N 33/5759: {involving compounds localised on the membrane of tumour or cancer cells}
- G01N 2333/7158: for chemokines
- 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
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Compounds having formula I, or pharmaceutically acceptable salts, hydrates or N-oxides thereof are provided and are useful for binding to CXCR7, and treating diseases that are dependent, at least in part, on CXCR7 activity. Accordingly, the present invention provides in further aspects, compositions containing one or more of the above-noted compounds in admixture with a pharmaceutically acceptable excipient.

## Claims

### Claim 1

A compound having formula I
or a pharmaceutically acceptable salt, hydrate, N-oxide, isotopically enriched or enantiomerically enriched version or a rotamer thereof, wherein
each of ring vertices Xa, Xb and Xc is independently selected from the group consisting of N, NH, N(R2), O, CH and C(R2);
the subscript n is 0, 1 or 2;
Z is selected from the group consisting of
(i) monocyclic or fused-bicyclic aryl and heteroaryl, wherein the heteroaryl group has from 1-4 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 5 R5 substituents;
(ii) monocyclic four-, five-, six- or seven-membered ring selected from the group consisting of cycloalkane, and heterocycloalkane, wherein the heterocycloalkane rings have from 1-3 heteroatoms as ring members selected from N, O and S; and wherein each of said monocyclic Z rings are optionally substituted with from 1 to 3 R5 substituents;
R1 is a member selected from the group consisting of H and C1-8 alkyl, wherein the alkyl portion is optionally substituted with halogen, —NRaRb, —ORa, —CO2Ra, and —CONRaRb;
each R2 is independently selected from the group consisting of H, halogen, CN, C1-8 alkyl, C1-8 haloalkyl, C1-8 hydroxyalkyl, —ORa, —CO2Ra, —X—CO2Ra, —NRaRb, —CONRaRb and —X—CONRaRb;
R3 is a member selected from the group consisting of H, C1-8 alkyl, C1-8 haloalkyl, C1-8 hydroxyalkyl, —CO2Ra, —X—CO2Ra, —CONRaRb and —X—CONRaRb;
each R4, when present, is a member independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C1-8 hydroxyalkyl, —CO2Ra, —X—CO2Ra, —NRaRb, —CONRaRb and —X—CONRaRb;
each R5 is a member independently selected from the group consisting of halogen, CN, —X—CN, C1-8 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C3-5 spirocycloalkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 haloalkyl, C1-8
hydroxyalkyl, —ORa, —CO2Ra, —X—CO2Ra, —NRaRb, —CONRaRb, —X—CONRaRb, aryl, 5- or 6-membered heteroaryl, and 3-, 4-, 5- or 6-membered heterocyclic wherein the heteroatoms present as ring vertices of the heteroaryl and heterocyclic rings are selected from N, O and S, and wherein the aryl, heteroaryl and hetereocyclic portions of R5 are optionally further substituted with 1-3 Ra;
each Ra and Rb is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C1-8 alkyl, C1-8 alkoxy, C1-8 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkylalkyl, amino, C1-8 alkylamino, di C1-8 alkylamino, carboxamide, carboxy C1-4 alkyl ester, carboxylic acid, and —SO2—C1-8 alkyl;
each X is a C1-4 alkylene linking group or a linking group having the formula —(CH2)mO(CH2)p—, wherein the subscripts m and p are integer of from 0 to 5, and m+p is from 0 to 6, wherein any of the methylene portions of X are optionally substituted with one or two methyl groups.

### Claim 2 (depends on 1)

The compound of claim 1, wherein Z is monocyclic or fused-bicyclic heteroaryl, having 1-3 heteroatoms as ring members selected from N, O and S; and wherein said heteroaryl group is optionally substituted with from 1 to 5 R5 substituents.

### Claim 3 (depends on 1)

The compound of claim 1, wherein Z is monocyclic or fused-bicyclic heteroaryl selected from the group consisting of imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiazole, oxazole, oxadiazole, pyrimidine, pyrazine, pyridazine, and quinazoline, each of which is optionally substituted with from 1-2 R5 substituents.

### Claim 4 (depends on 2)

The compound of claim 2, wherein n is 0.

### Claim 5 (depends on 4)

The compound of claim 4, wherein R1 is H.

### Claim 6 (depends on 1)

The compound of claim 1, wherein each R2 is independently selected from the group consisting of H and C1-4 alkyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R3 is selected from the group consisting of H, CH2OH and C(O)NH2.

### Claim 8 (depends on 1)

The compound of claim 1, having the structure:

### Claim 9 (depends on 8)

The compound of claim 8, wherein the bicyclic portion having Xa, Xb and Xc as ring vertices is selected from the group consisting of:

### Claim 10 (depends on 8)

A compound of claim 8, wherein Z is a 5-membered heteroaryl group substituted with one R5 group selected from an optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl ring, and optionally with up to two additional R5 groups which are selected from halogen, C1-4 alkyl, C1-4 haloalkyl and CH2CN.

### Claim 11 (depends on 10)

A compound of claim 10, wherein Z is selected from the group consisting of:

### Claim 12 (depends on 8)

The compound of claim 8, wherein Z has the formula:
wherein each Q is independently selected from the group consisting of N, CH, and C(R5).

### Claim 13 (depends on 1)

The compound of claim 1, having the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 13)

The compound of claim 13, wherein Ra is selected from the group consisting of selected from the group consisting of hydrogen, halogen, cyano, C1-8 alkyl and —SO2— C1-8 alkyl.

### Claim 15 (depends on 13)

The compound of claim 13, wherein R2 is selected from the group consisting of H and C1-4 alkyl.

### Claim 16 (depends on 13)

The compound of claim 13, wherein Ra is selected from the group consisting of hydrogen, halogen, cyano, C1-8 alkyl and —SO2— C1-8 alkyl; and R2 is selected from the group consisting of H and C1-4 alkyl.

### Claim 17 (depends on 1)

The compound of claim 1, selected from the compounds of the Examples.

### Claim 18 (depends on 1)

The compound of claim 1, selected from those in Table 1.

### Claim 19 (depends on 1)

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

### Claim 20 (depends on 19)

The pharmaceutical composition of claim 19, wherein the compound is a compound of Table 1.

### Claim 21 (depends on 1)

A method of treating a disease or disorder in a mammal, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1, for a period of time sufficient to treat said disease or disorder.

### Claim 22 (depends on 21)

The method of claim 21, wherein the compound is a compound of Table 1.

### Claim 23 (depends on 21)

The method of claim 21, wherein said disease or disorder is selected from the group consisting of cancer, inflammation and neural or progenitor/stem cell disorders.

### Claim 24 (depends on 1)

A method of inhibiting the binding of chemokines I-TAC or SDF-1 to a CXCR7 receptor, comprising contacting a compound of claim 1 with a cell that expresses the CXCR7 receptor for a time sufficient to inhibit the binding of the chemokines to the CXCR7 receptor.

### Claim 25 (depends on 24)

The method of claim 24, wherein the compound is a compound of Table 1.

### Claim 26 (depends on 1)

A method for imaging a tumor, organ, or tissue, said method comprising:
(a) administering to a subject in need of such imaging, a radiolabeled or detectable form of a compound of any of claim 1; and
(b) detecting said compound to determine where said compound is concentrated in said subject.

### Claim 27 (depends on 26)

A method in accordance with claim 26, wherein said compound is radiolabeled.

### Claim 28 (depends on 1)

A method for detecting elevated levels of CXCR7 in a sample, said method comprising:
(a) contacting a sample suspected of having elevated levels of CXCR7 with a radiolabeled or detectable form of a compound of any of claim 1;
(b) determining a level of compound that is bound to CXCR7 present in said sample to determine the level of CXCR7 present in said sample; and
(c) comparing the level determined in step (b) with a control sample to determine if elevated levels of CXCR7 are present in said sample.

### Claim 29 (depends on 28)

A method in accordance with claim 28, wherein said compound is radiolabeled.