Anti-alphavbeta1 integrin inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-10214522-B2
Application number	US-201615067124-A
Country	US
Kind code	B2
Filing date	Mar 10, 2016
Priority date	Mar 10, 2015
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

Provided herein, inter alia, are methods and compositions for inhibiting αvβ1 integrin and for treating fibrosis.

First claim

What is claimed is:

1. A method for treating fibrosis, said method comprising administering to a subject in need thereof an effective amount of a compound, or a salt thereof, having the formula:

wherein,
Ring A is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Ring C is aryl or heteroaryl;
L 2 is independently a bond or substituted, unsubstituted C 1 -C 10 alkylene, or unsubstituted 2 to 10 membered heteroalkylene;
L 3 is a bond, substituted or unsubstituted C 1 -C 10 alkylene, substituted or unsubstituted 2 to 10 membered heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted alkylarylene;
Y is —C(O)N(R 4 )—, —O—, —C(O)O—, —S—, —N(SO 2 R 4 )—, —N(C(O)R 4 )—, —N(C(O)OR 4 )—, —N(R 4 )C(O)—, —N(R 4 )—, —N(R 4 )C(O)NH—, —NHC(O)N(R 4 )—, —N(R 4 )C(O)O—, —C(O)—, —N(R 4 )CH 2 —, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or substituted or unsubstituted arylene;
R 1 is independently halogen, —N 3 , —CX 3 , —CHX 2 , —CH 2 X, —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 CH 3 —SO 3 H, —OSO 3 H, —SO 2 NH 2 , —SO 2 Ph, —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —OPO 3 H, —PO 3 H 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety;
R 2 is —NR 3A R 3B , —C(NH)NH 2 , —C(NH)R 3B , —C(NR 3A )NH 2 , —C(NR 3A )R 3B , —C(NCN)NH 2 , —NH 2 , —C(NH)NHR 3B , —C(NR 3A )NHR 3B , —C(NCN)NHR 3B , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted fused ring cycloalkyl, substituted or unsubstituted fused ring heterocycloalkyl, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted fused ring heteroaryl;
R 3A and R 3B are independently hydrogen, —C(NH)NH 2 , —C(NH)R 3D , —C(NR 3C )NH 2 , —C(NR 3C )R 3D , —C(NCN)NH 2 , —NH 2 , —C(NH)NHR 3D , —C(NR 3C )NHR 3D , —C(NCN)NHR 3D , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein R 3A and R 3B are optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R 3C is hydrogen, halogen, —N 3 , —CX 1C 3 , —CHX 1C 2 , —CH 2 X 1C , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 CH 3 —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3D is hydrogen, halogen, —N 3 , —CX 1D 3 , —CHX 1D 2 , —CH 2 X 1D , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 CH 3 —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 4 is hydrogen or unsubstituted C 1 -C 5 alkyl;
R 12 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a prodrug moiety;
each X, X 1C and X 1D is independently —F, —Cl, —Br, or —I; and
z1 is an integer from 0 to 5.

2. The method of claim 1 , wherein said fibrosis is pulmonary fibrosis, liver fibrosis, skin fibrosis, cardiac fibrosis, or kidney fibrosis.

3. The method of claim 1 , wherein R 12 is a substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

4. The method of claim 1 , wherein Ring C is phenyl or Ring C is 5 to 6 membered heteroaryl and z1 is an integer between 0 to 3.

5. The method of claim 1 , wherein Ring A is unsubstituted phenyl or unsubstituted 5 to 6 membered heteroaryl.

6. The method of claim 1 , wherein R 2 is —NR 3A R 3B or substituted or unsubstituted heteroaryl.

7. The method of claim 1 , wherein R 2 is a substituted pyridyl, substituted imidazolyl, substituted oxazolyl, substituted thiazolyl, substituted oxadiazolyl, substituted triazolyl or substituted thiadiazolyl.

8. The method of claim 1 , wherein R 2 is a substituted heterocycloalkyl.

9. The method of claim 1 , wherein R 2 is —C(NH)NH 2 , —C(NH)R 3B , —C(NR 3A )NH 2 , —C(NR 3A )R 3B , —C(NCN)NH 2 , —NH 2 , —C(NH)NHR 3B , —C(NR 3A )NHR 3B , or —C(NCN)NHR 3B .

10. The method of claim 1 , wherein L 2 is unsubstituted C 1 -C 5 alkylene or unsubstituted 2 to 5 membered heteroalkylene.

11. The method of claim 1 , wherein L 3 is substituted or unsubstituted C 1 -C 8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, unsubstituted phenylene, unsubstituted 5 to 6 membered heteroarylene, or unsubstituted alkylarylene.

12. The method of claim 1 , wherein
L 3 is R 6 -substituted C 1 -C 3 alkylene;
R 6 is —NHC(O)R 6A ;
R 6A is —C(NCN)R 6C , —C(NH)R 6C , R 6C -substituted or unsubstituted alkyl, or R 6C -substituted or unsubstituted heteroalkyl;
R 6C is hydrogen, halogen, oxo, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —COR 6D , —OR 6D , —NR 6D R 6E , —COOR 6E , —CONR 6D R 6E , —NHC(O)R 6D , —NO 2 , —SR 6D , —SO n6 R 6D , —NHNR 6D R 6E , —ONR 6D R 6E , —NHC(O)NHNR 6D R 6E , —C(NCN)R 6D , —C(NH)R 6D , R 6E -substituted or unsubstituted alkyl, R 6E -substituted or unsubstituted heteroalkyl, R 6E -substituted or unsubstituted cycloalkyl, R 6E -substituted or unsubstituted heterocycloalkyl, R 6E -substituted or unsubstituted aryl, or R 6E -substituted or unsubstituted heteroaryl;
n6 is 2, 3, or 4; and
R 6D , R 6E and R 6F are independently hydrogen, halogen, oxo, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 , —SO 2 Cl, —SO 2 CH 3 —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a detectable moiety.

13. The method of claim 1 , wherein R 6C or R 6D is a detectable moiety.

14. The method of claim 1 , wherein Y is —O—, —N(R 4 )C(O)—, —N(R 4 )C(O)NH—, —NHC(O)N(R 4 )—, —N(R 4 )C(O)O—, —C(O)—, or —N(R 4 )CH 2 .

15. The method of claim 1 , wherein R 1 is independently hydrogen, halogen, —OMe, —SMe, —SO 2 Me, —SO 2 Ph, —COOH, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted 2 to 5 membered heteroalkyl, or substituted or unsubstituted C 6 -C 10 aryl.

16. The method of claim 1 , wherein the compound, or salt thereof, has the formula:

Assignees

• Univ California

Inventors

• Degrado William F
• Sheppard Dean
• Jo Hyunil
• Reed Nilgun Isik
• Tang Youzhi
• Mcintosh Joel

Classifications

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D233/50

  with carbocyclic radicals directly attached to said nitrogen atoms · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title