Heterocyclic compounds and use thereof

Patent metadata

Field	Value
Publication number	US-9862703-B2
Application number	US-201514860033-A
Country	US
Kind code	B2
Filing date	Sep 21, 2015
Priority date	Sep 22, 2014
Publication date	Jan 9, 2018
Grant date	Jan 9, 2018

Abstract

Heterocyclic compounds of Formula (I) shown herein. Also disclosed are pharmaceutical compositions containing the heterocyclic compounds and methods of using the heterocyclic compounds to mobilize hematopoietic stem cells and endothelial progenitor cells into the peripheral circulation. Further provided are methods for treating tissue injury, cancer, inflammatory disease, and autoimmune disease with the heterocyclic compounds.

First claim

What is claimed is:

1. A compound of formula (I):

wherein
R 1 and R 2 , together with the two carbon atoms to which they are bonded, are phenyl, optionally substituted with halo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxyl, aryl, heteroaryl, or C(O)OR a , in which R a is H, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, aryl, or heteroaryl; and
each of R 3 and R 4 , independently, is NR b R c ,

at least one of R 3 and R 4 being

in which
each of R b and R c , independently, is H or C 1-6 alkyl;
R 5 is H, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl alkyl, heteroaryl alkyl, aryl, or heteroaryl, each of C 1-6 alkyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl alkyl, heteroaryl alkyl, aryl, and heteroaryl being optionally substituted with halo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, or heteroaryl;
R 6 is H, C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, or heteroaryl;
L 1 is heteroaryl, C 1-10 heterocycloalkyl, NH, or NR d , in which R d is C(O)(CH 2 ) 2 CHNH 2 CO 2 R e , R e being H, C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, aryl, or heteroaryl;
R 7 is H, C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, or heteroaryl, each of C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, and heteroaryl being optionally substituted with hydroxy, hydroxy C 1-6 alkyl, halo, nitro, cyano, amino, amino C 1-6 alkyl, amino C 3-10 cycloalkyl, amino C 1-10 heterocycloalkyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, or heteroaryl;
m is 1-6;
n is 1-6;
each of R 8 and R 9 , independently, is H, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, or heteroaryl, each of C 1-6 alkyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, and heteroaryl being optionally substituted with C(O)OR f , in which R f is H, C 1-10 alkyl, C 3-20 cycloalkyl, C 3-20 heterocycloalkyl, aryl, or heteroaryl; or R 8 and R 9 , together with the nitrogen atoms to which they are bonded, are C 3-10 heterocycloalkyl;
L 2 is C 1-6 alkyl; or L 2 , together with R 8 or R 9 and the nitrogen atom to which they are bonded, is C 4-10 heterocycloalkyl or heteroaryl; and
R 10 is H, C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, C(O)OR g , C(S)NR h R i , C(O)NR j R k , or C(O)R p , each of C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, heteroaryl, aryl alkyl, and heteroaryl alkyl being optionally substituted with hydroxy, halo, nitro, cyano, amino, C(O)OR 11 , or P(O)(OR 12 ) 2 , in which each of R 11 and R 12 , independently, is H or C 1-6 alkyl; or R 10 , together with R 9 and the nitrogen atom to which they are bonded, is C 4-10 heterocycloalkyl or heteroaryl; each of R g , R h , R i , R j , and R k , independently, being H, C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 alkyl, aryl alkyl, heteroaryl alkyl, aryl, or heteroaryl; and R p being H, C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, or

in which each of C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl is optionally substituted with halo, P(O)(OH) 2 , or P(O)(O—C 1-6 alkyl) 2 ; o is 0-2; D 1 is OH or NR 14 R 15 , each of R 14 and R 15 , independently, being H, C(O)CH(NH 2 )CH 2 OH, or C(NH)NH 2 ; D 2 is O or NR 16 , R 16 being H, C 1-6 alkyl, S(O) 2 R q , NHR r , or CH 2 CO 2 R s , in which each of R q and R r , independently, is aryl optionally substituted with halo or alkoxyl, and R s is H, C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 alkyl, aryl alkyl, heteroaryl alkyl, aryl, or heteroaryl; R 13 is H, C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, aryl alkyl, heteroaryl alkyl, aryl, or heteroaryl, each of C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, aryl alkyl, heteroaryl alkyl, aryl, and heteroaryl being optionally substituted with hydroxy, C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, aryl alkyl, heteroaryl alkyl, aryl, heteroaryl, P(O)(OH) 2 , P(O)(O—C 1-6 alkyl) 2 , hydroxy, or C(O)OR t , in which R t is H, C 1-6 alkyl, C 1-6 alkoxyl, C 1-6 alkyl, aryl alkyl, heteroaryl alkyl, aryl, or heteroaryl; and X is ═O or -aryl.

2. The compound of claim 1 , wherein each of R 3 and R 4 , independently, is

3. The compound of claim 2 , wherein R 5 is H, aryl alkyl, or heteroaryl alkyl, each of aryl alkyl and heteroaryl alkyl being optionally substituted with cyano.

4. The compound of claim 3 , wherein R 5 is H,

5. The compound of claim 2 , wherein R 6 is H, aryl, or heteroaryl.

6. The compound of claim 5 , wherein R 6 is H, phenyl, or pyridinyl.

7. The compound of claim 2 , wherein L 1 is NH,

or —NC(O)(CH 2 ) 2 CHNH 2 CO 2 H.

8. The compound of claim 2 , wherein R 7 is H, CH 2 OH,

9. The compound of claim 2 , wherein each of R 8 and R 9 , independently, is H or C 1-6 alkyl being optionally substituted with C(O)OR f , in which R f is H or C 1-10 alkyl.

10. The compound of claim 2 , wherein R 8 and R 9 , together with the nitrogen atoms to which they are bonded, are

11. The compound of claim 2 , wherein L 2 , together with R 8 or R 9 and the nitrogen atom to which they are bonded, is C 4-10 heterocycloalkyl.

12. The compound of claim 11 , wherein L 2 , together with R 9 and the nitrogen atom to which they are bonded, is

13. The compound of claim 2 , wherein R 10 is H, C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, C(O)OR g , C(S)NR h R i , or C(O)NR j R k , each of C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, heteroaryl, aryl alkyl, and heteroaryl alkyl being optionally substituted with hydroxy, halo, C(O)OR 11 , or P(O)(OR 12 ) 2 ; or R 10 , together with R 9 and the nitrogen atom to which they are bonded, is C 4-10 heterocycloalkyl or heteroaryl.

14. The compound of claim 2 , wherein R 10 is C(O)R p , R p being C 1-6 alkyl, C 3-10 cycloalkyl, aryl, heteroaryl, or

in which each of C 1-6 alkyl, C 3-10 cycloalkyl, aryl, and heteroaryl is optionally substituted with halo or P(O)(OH) 2 .

15. The compound of claim 14 , wherein X is ═O.

Assignees

• National Health Res Inst

Inventors

• Shia Kak-Shan
• Jan Jiing-Jyh
• Tsou Lun Kelvin
• Chen Chiung-Tong
• Chao Yu-Sheng

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title