CXCR7 antagonists

Patent metadata

Field	Value
Publication number	US-9783544-B2
Application number	US-201514836172-A
Country	US
Kind code	B2
Filing date	Aug 26, 2015
Priority date	Nov 29, 2012
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

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.

First claim

What is claimed is:

1. A method of treating a disease or disorder in a subject, wherein said disease or disorder is selected from the group consisting of a cancer, an inflammatory disease, a demyelinating disease, and a hypertensive disorder, said method comprising administering to said subject a therapeutically effective amount of a compound of 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 X a , X b and X c is independently selected from the group consisting of N, NH, N(R 2 ), O, CH and C(R 2 );
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 R 5 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 R 5 substituents;
R 1 is a member selected from the group consisting of H and C 1-8 alkyl, wherein the alkyl portion is optionally substituted with halogen, —NR a R b , —OR a , —CO 2 R a , and —CONR a R b ;
each R 2 is independently selected from the group consisting of H, halogen, CN, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —OR a , —CO 2 R a , —X—CO 2 R a , —NR a R b , —CONR a R b and —X—CONR a R b ;
R 3 is a member selected from the group consisting of H, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —CO 2 R a , —X—CO 2 R a , —CONR a R b and —X—CONR a R b ;
each R 4 , when present, is a member independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 ; hydroxyalkyl, —OR a , —CO 2 R a —X—CO 2 R a , —NR a R b , —CONR a R b and —X—CONR a R b ;
each R 5 is a member independently selected from the group consisting of halogen, CN, —X—CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 3-5 spirocycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —OR a , —CO 2 R a , —X—CO 2 R a , —NR a R b , —CONR a R b , —X—CONR a R b , aryl, 5- or 6-memembered heteroaryl, and 3-, 4-, 5- or 6-membered herocyclic wherein the heteroataoms 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 R 5 are optionally further substituted with 1-3 R a ;
each R a and R b is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylalkyl, amino, C 1-8 alkylamino, di C 1-8 alkylamino, carboxamide, carboxy C 1-4 alkyl ester, carboxylic acid, and —SO 2 —C 1-8 alkyl;
each X is a C 1-4 alkylene linking group or a linking group having the formula —(CH 2 ) m O(CH 2 ) 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 methy groups, for a period of time sufficient to treat said disease or disorder wherein said cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, glioblastoma, leukemia, lymphoma, prostate cancer, Burkitt's lymphoma, head and neck cancer, colon cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, cancer of the esophagus, stomach cancer, pancreatic cancer, hepatobiliary cancer, cancer of the gallbladder, cancer of the small intestine, rectal cancer, kidney cancer, renal cancer, bladder cancer, prostate cancer, penile cancer, urethral cancer, testicular cancer, cervical cancer, vaginal cancer, uterine cancer, ovarian cancer, thyroid cancer, parathyroid cancer, adrenal cancer, pancreatic endocrine cancer, carcinoid cancer, bone cancer, skin cancer, retinoblastomas, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

2. The method of claim 1 , wherein the compound is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

3. The method 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 R 5 substituents.

4. The method of claim 3 , wherein n is 0.

5. The method of claim 4 , wherein R 1 is H.

6. The method of claim 1 , wherein Z is monocyclic or fused-bicyclic heteroaryl selected from the group consisting

Assignees

• Chemocentryx Inc

Inventors

• Fan Junfa
• Krasinski Antoni
• Lange Christopher W
• Lui Rebecca M
• Mcmahon Jeffrey P
• Powers Jay P
• Zeng Yibin
• Zhang Penglie

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• G01N33/5759

  involving compounds localised on the membrane of tumour or cancer cells · CPC title