Anti-alphavbeta1 integrin compounds and methods

Patent metadata

Field	Value
Publication number	US-2016376266-A1
Application number	US-201615083836-A
Country	US
Kind code	A1
Filing date	Mar 29, 2016
Priority date	Sep 30, 2013
Publication date	Dec 29, 2016
Grant date	—

Abstract

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

First claim

1 . A compound having the formula:

wherein,
Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
L 1 and L 2 are independently a bond or substituted or unsubstituted C 1 -C 10 alkylene;
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, or substituted or unsubstituted alkylarylene;
X is a bond, —C—, —C—C—, —C═C—, —C—C—C—, —C═C—C—, —C—C═C—, —O—C—, —C—O—, —C—O—C, —S—C—, —C—S—, —C—S—C—;
Y is a bond, —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 )—, —(NR 4 )C(O)—, —N(R 4 )—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R 1 is independently 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, —OSO 3 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;
R 2 is independently halogen, —N 3 , —CF 3 , —CCl 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, —OSO 3 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, or wherein if z2 an integer of 2 to 5, two R 2 substituents attached to adjacent ring carbons are optionally joined to form a substituted or unsubstituted aryl or substituted or unsubstituted 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, 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, or R 3A and R 3B are optionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R 3C and R 3D are independently hydrogen, halogen, oxo, —N 3 , —CF 3 , —CCl 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, or substituted or unsubstituted heteroaryl;
R 4 is independently hydrogen or unsubstituted C 1 -C 5 alkyl;
z1 is an integer from 1 to 9; and
z2 is an integer from 1 to 5.

2 . The compound of claim 1 , wherein L 1 is a bond.

3 . The compound of claim 1 or claim 2 , wherein L 2 is unsubstituted methylene.

4 . The compound of claim 1 , wherein L 3 is substituted or unsubstituted C 1 -C 5 alkylene, substituted, unsubstituted 2 to 6 membered heteroalkylene, or substituted or unsubstituted alkylarylene.

5 . The compound 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 3C -substituted or unsubstituted alkyl, or R 6C -substituted or unsubstituted heteroalkyl; R 6C 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 6F -substituted or unsubstituted alkyl, R 6F -substituted or unsubstituted heteroalkyl, R 6F -substituted or unsubstituted cycloalkyl, R 6F -substituted or unsubstituted heterocycloalkyl, R 6F -substituted or unsubstituted aryl, or R 6F -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.

6 . (canceled)

7 . (canceled)

8 . The compound of claim 1 , wherein Y is —NHC(O)—, —NCH 3 —, —NC(O)CH 3 —, —NC(O)OCH 3 —, —N(SO 2 CH 3 )—, —S—, —O—, C(O)O—, substituted or unsubstituted 3 to 6 membered heterocycloalkylene, 4 to 6 membered unsubstituted heteroarylene, or unsubstituted 5 or 6 membered arylene.

9 . (canceled)

10 . The compound of claim 1 , wherein R 2 is independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —NH 2 , —NO 2 , —SO 2 CH 3 , substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted 2 to 5 membered heteroalkyl, substituted or unsubstituted 5 or 6 membered aryl, or a detectable moiety.

11 . The compound of claim 1 , wherein R 3A and R 3B are independently hydrogen, —C(NH)NH 2 , —C(NCN)NH 2 , substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, or joined to form a substituted or unsubstituted 5 or 6 membered heterocycloalkyl or substituted or unsubstituted 5 or 6 membered heteroaryl.

12 . The compound of claim 1 having the formula:

13 . The compound of claim 12 having the formula:

14 . (canceled)

15 . (canceled)

16 . The compound of claim 12 , wherein R 2 is hydrogen, halogen, —SO 2 CH 3 , —NO 2 , —NH 2 , substituted or unsubstituted C 1 -C 3 alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl.

17 . The compound of claim 12 , wherein R 3A and R 3B are independently hydrogen, —C(NH)NH 2 , —C(NCN)NH 2 , or substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.

18 . The compound of claim 12 having the formula:

Assignees

• Univ California

Inventors

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

Classifications

• C07D417/12

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

• C07D413/12

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

• C07D409/12

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

• C07D403/12

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

• C07D401/12

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