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NZ730195B2 - Heterocyclic compounds and use thereof - Google Patents

Heterocyclic compounds and use thereof

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Publication number
NZ730195B2
NZ730195B2 NZ730195A NZ73019515A NZ730195B2 NZ 730195 B2 NZ730195 B2 NZ 730195B2 NZ 730195 A NZ730195 A NZ 730195A NZ 73019515 A NZ73019515 A NZ 73019515A NZ 730195 B2 NZ730195 B2 NZ 730195B2
Authority
NZ
New Zealand
Prior art keywords
alkyl
heteroaryl
aryl
heterocycloalkyl
cycloalkyl
Prior art date
Application number
NZ730195A
Other versions
NZ730195A (en
Inventor
Yu Sheng Chao
Chiung Tong Chen
Jiing Jyh Jan
Kak Shan Shia
Lun Kelvin Tsou
Original Assignee
National Health Research Institutes
Filing date
Publication date
Application filed by National Health Research Institutes filed Critical National Health Research Institutes
Priority claimed from PCT/US2015/051143 external-priority patent/WO2016048861A2/en
Publication of NZ730195A publication Critical patent/NZ730195A/en
Publication of NZ730195B2 publication Critical patent/NZ730195B2/en

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

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.

Claims (37)

WHAT IS CLAIMED IS:
1. A compound of formula (I): wherein each of R and R , independently, is H, halo, nitro, cyano, amino, C alkyl, 1 2 1-6 C alkoxyl, C cycloalkyl, C heterocycloalkyl, aryl, or heteroaryl; or R and R , 1-6 3-10 1-10 1 2 together with the two carbon atoms to which they are bonded, are C cycloalkyl, C 5-10 3-10 heterocycloalkyl, aryl, or heteroaryl, each of C alkyl, C alkoxyl, C cycloalkyl, C 1-6 1-6 3-10 1-10 heterocycloalkyl, C cycloalkyl, C heterocycloalkyl, aryl, and heteroaryl being 5-10 3-10 optionally substituted with halo, nitro, cyano, amino, C alkyl, C alkoxyl, aryl, heteroaryl, 1-6 1-6 or C(O)OR , in which R is H, C alkyl, C cycloalkyl, C heterocycloalkyl, aryl, or a a 1-10 3-10 3-10 heteroaryl; and each of R and R , independently, is NR R , , or 3 4 b c , provided that at least one of R and R being , in which each of R and R , independently, is H or C alkyl; b c 1-6 21626763 R is H, C alkyl, C cycloalkyl, C heterocycloalkyl, aryl alkyl, 5 1-6 3-10 1-10 heteroaryl alkyl, aryl, or heteroaryl, each of C alkyl, C cycloalkyl, C 1-6 3-10 1-10 heterocycloalkyl, aryl alkyl, heteroaryl alkyl, aryl, and heteroaryl being optionally substituted with halo, nitro, cyano, amino, C alkyl, C alkoxyl, C cycloalkyl, 1-6 1-6 3-10 C heterocycloalkyl, aryl, or heteroaryl; R is H, C alkyl, C alkoxyl, C cycloalkyl, C heterocycloalkyl, aryl, 6 1-6 1-6 3-10 1-10 or heteroaryl; L is heteroaryl, C heterocycloalkyl, NH, or NR , in which R is 1 1-10 d d C(O)(CH ) CHNH CO R , R being H, C alkyl, C cycloalkyl, 2 2 2 2 e e 1-6 3-10 C heterocycloalkyl, aryl, or heteroaryl; R is H, C alkyl, C alkoxyl, C cycloalkyl, C heterocycloalkyl, aryl, 7 1-6 1-6 3-10 1-10 or heteroaryl, each of C alkyl, C alkoxyl, C cycloalkyl, C heterocycloalkyl, 1-6 1-6 3-10 1-10 aryl, and heteroaryl being optionally substituted with hydroxy, hydroxy C alkyl, halo, nitro, cyano, amino, amino C alkyl, amino C cycloalkyl, amino C 1-6 3-10 1-10 heterocycloalkyl, C cycloalkyl, C heterocycloalkyl, aryl, or heteroaryl; 3-10 1-10 m is 1-6; n is 1-6; each of R and R independently, is H, C alkyl, C cycloalkyl, 8 9, 1-6 3-10 C heterocycloalkyl, aryl, or heteroaryl, each of C alkyl, C cycloalkyl, 1-10 1-6 3-10 C heterocycloalkyl, aryl, and heteroaryl being optionally substituted with C(O)OR , in which R is H, C alkyl, C cycloalkyl, C heterocycloalkyl, aryl, f f 1-10 3-20 3-20 or heteroaryl; or R and R together with the nitrogen atoms to which they are bonded, are C heterocycloalkyl; L is C alkyl; or L , together with R or R and the nitrogen atom to which 2 1-6 2 8 9 they are bonded, is C heterocycloalkyl or heteroaryl; and 21626763 R is H, C alkyl, C alkoxyl, C cycloalkyl, C heterocycloalkyl, aryl, 10 1-6 1-6 3-10 1-10 heteroaryl, aryl alkyl, heteroaryl alkyl, C(O)OR , C(S)NR R , C(O)NR R , or C(O)R , g h i j k p each of C alkyl, C alkoxyl, C cycloalkyl, C heterocycloalkyl, aryl, 1-6 1-6 3-10 1-10 heteroaryl, aryl alkyl, and heteroaryl alkyl being optionally substituted with hydroxy, halo, nitro, cyano, amino, C(O)OR , or P(O)(OR ) , in which each of R and R , 11 12 2 11 12 independently, is H or C alkyl; or R , together with R and the nitrogen atom to 1-6 10 9 which they are bonded, is C heterocycloalkyl or heteroaryl; each of R , R , R , R , 4-10 g h i j and R , independently, being H, C alkyl, C alkoxyl, C alkyl, aryl alkyl, k 1-6 1-6 1-6 heteroaryl alkyl, aryl, or heteroaryl; and R being H, C alkyl, C alkoxyl, C p 1-6 1-6 3-10 cycloalkyl, C heterocycloalkyl, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, or , in which each of C alkyl, C alkoxyl, C cycloalkyl, C 1-6 1-6 3-10 1-10 heterocycloalkyl, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl is optionally substituted with halo, P(O)(OH) or P(O)(O-C alkyl) ; o is 0-2; D is OH or NR R , each of 2, 1-6 2 1 14 15 R and R , independently, being H, C(O)CH(NH )CH OH, or C(NH)NH ; D is O 14 15 2 2 2 2 or NR , R being H, C alkyl, S(O) R , NHR , or CH CO R , in which each of R 16 16 1-6 2 q r 2 2 s q and R , independently, is aryl optionally substituted with halo or alkoxyl, and R is H, C alkyl, C alkoxyl, C alkyl, aryl alkyl, heteroaryl alkyl, aryl, or heteroaryl; R 1-6 1-6 1-6 13 is H, C alkyl, C cycloalkyl, C heterocycloalkyl, aryl alkyl, heteroaryl alkyl, 1-6 3-10 3-10 aryl, or heteroaryl, each of C alkyl, C cycloalkyl, C heterocycloalkyl, aryl 1-6 3-10 3-10 alkyl, heteroaryl alkyl, aryl, and heteroaryl being optionally substituted with hydroxy, C alkyl, C cycloalkyl, C heterocycloalkyl, aryl alkyl, heteroaryl alkyl, aryl, 1-6 3-10 3-10 heteroaryl, P(O)(OH) P(O)(O-C alkyl) hydroxy, or C(O)OR , in which R is H, 2, 1-6 2, t t C alkyl, C alkoxyl, C alkyl, aryl alkyl, heteroaryl alkyl, aryl, or heteroaryl; and 1-6 1-6 1-6 X is O or aryl. 21626763
2. The compound of claim 1, wherein each of R and R , independently, is H, NH , or C heterocycloalkyl optionally substituted with C alkyl or C(O)OR , in 2 1-10 1-6 a which R is H or C alkyl. a 1-10
3. The compound of claim 2, wherein each of R and R , independently, is H, NH , morpholine, piperidine, or piperazine substituted with C alkyl or C(O)OR . 2 1-6 a
4. The compound of claim 1, wherein R and R , together with the two carbon atoms to which they are bonded, are C cycloalkyl, C heterocycloalkyl, aryl, or 5-10 3-10 heteroaryl.
5. The compound of claim 4, wherein R and R , together with the two carbon atoms to which they are bonded, are , , , , or , each of R , R , R , R , and R , independently, being H, halo, i ii iii iv v C alkyl, C alkoxyl, C cycloalkyl, C heterocycloalkyl, aryl, or heteroaryl. 1-10 1-6 3-10 3-10
6. The compound of claim 1, wherein each of R and R , independently, is
7. The compound of claim 6, wherein R is H, aryl alkyl, or heteroaryl alkyl, each of aryl alkyl and heteroaryl alkyl being optionally substituted with cyano. 21626763
8. The compound of claim 7, wherein R is H, , or .
9. The compound of claim 6, wherein R is H, aryl, or heteroaryl.
10. The compound of claim 9, wherein R is H, phenyl, or pyridinyl.
11. The compound of claim 6, wherein L is NH, , , , or -NC(O)(CH ) CHNH CO H. 2 2 2 2
12. The compound of claim 6, wherein R is H, CH OH, , , , , , , , , , , or .
13. The compound of claim 6, wherein each of R and R independently, is H or C alkyl being optionally substituted with C(O)OR , in which R is H or C alkyl. 1-6 f f 1-10 21626763
14. The compound of claim 6, wherein R and R together with the nitrogen atoms to which they are bonded, are .
15. The compound of claim 6, wherein L , together with R or R and the nitrogen 2 8 9 atom to which they are bonded, is C heterocycloalkyl.
16. The compound of claim 15, wherein L , together with R and the nitrogen atom to which they are bonded, is or .
17. The compound of claim 6, wherein R is H, C alkyl, C alkoxyl, C 10 1-6 1-6 3-10 cycloalkyl, C heterocycloalkyl, aryl, heteroaryl, aryl alkyl, heteroaryl alkyl, C(O)OR , 1-10 g C(S)NR R , or C(O)NR R , each of C alkyl, C alkoxyl, C cycloalkyl, C h i j k 1-6 1-6 3-10 1-10 heterocycloalkyl, aryl, heteroaryl, aryl alkyl, and heteroaryl alkyl being optionally substituted with hydroxy, halo, C(O)OR , or P(O)(OR ) ; or R , together with R and 11 12 2 10 9 the nitrogen atom to which they are bonded, is C heterocycloalkyl or heteroaryl.
18. The compound of claim 6, wherein R is C(O)R , R being C alkyl, C 10 p p 1-6 3-10 cycloalkyl, aryl, heteroaryl, or , in which each of C alkyl, C 1-6 3-10 cycloalkyl, aryl, and heteroaryl is optionally substituted with halo or P(O)(OH) .
19. The compound of claim 18, wherein X is O. 21626763
20. The compound of claim 17, wherein each of R and R , independently, is H, amino, C heterocycloalkyl optionally substituted with C alkyl or C(O)OR , in which 1-10 1-6 a R is H, C - alkyl; R is H, aryl alkyl, heteroaryl alkyl, each of aryl alkyl and heteroaryl a 1 10 5 alkyl being optionally substituted with cyano; R is H, aryl, or heteroaryl; L is NH, , , , or -NC(O)(CH ) CHNH CO H; R is H, CH OH, , 2 2 2 2 7 2 , , , , , , , , , or ; each of R and R independently, is H or C alkyl being optionally 8 9, 1-6 substituted with C(O)OR , in which R is H or C alkyl, or R and R together with the f f 1-10 8 9, nitrogen atoms to which they are bonded, are ; or L , together with R or R and the 2 8 9 nitrogen atom to which they are bonded, is C heterocycloalkyl.
21. The compound of claim 19, wherein each of R and R , independently, is H, amino, C heterocycloalkyl optionally substituted with C alkyl or C(O)OR , in which 1-10 1-6 a R is H, C alkyl; R is H, aryl alkyl, heteroaryl alkyl, each of aryl alkyl and heteroaryl a 1-10 5 alkyl being optionally substituted with cyano; R is H, aryl, or heteroaryl; L is NH, 21626763 , , , or -NC(O)(CH ) CHNH CO H; R is H, CH OH, , 2 2 2 2 7 2 , , , , , , , , , or ; each of R and R independently, is H or C alkyl being optionally substituted with 8 9, 1-6 C(O)OR , in which R is H or C alkyl, or R and R together with the nitrogen atoms to f f 1-10 8 9, which they are bonded, are ; or L , together with R or R and the nitrogen atom to 2 8 9 which they are bonded, is C heterocycloalkyl.
22. The compound of claim 17, wherein R and R , together with the two carbon atoms to which they are bonded, are C cycloalkyl, C heterocycloalkyl, aryl, or 5-10 3-10 heteroaryl; R is H, aryl alkyl, heteroaryl alkyl, each of aryl alkyl and heteroaryl alkyl being optionally substituted with cyano; R is H, aryl, or heteroaryl; L is NH, , , , or -NC(O)(CH ) CHNH CO H; R is H, CH OH, , 2 2 2 2 7 2 , , , , , , , , , or ; each of R and R independently, is H or C alkyl being optionally substituted with 8 9, 1-6 21626763 C(O)OR , in which R is H or C alkyl, or R and R together with the nitrogen atoms to f f 1-10 8 9, which they are bonded, are ; or L , together with R or R and the nitrogen atom to 2 8 9 which they are bonded, is C heterocycloalkyl.
23. The compound of claim 19, wherein R and R , together with the two carbon atoms to which they are bonded, are C cycloalkyl, C heterocycloalkyl, aryl, or 5-10 3-10 heteroaryl; R is H, aryl alkyl, heteroaryl alkyl, each of aryl alkyl and heteroaryl alkyl being optionally substituted with cyano; R is H, aryl, or heteroaryl; L is NH, , , , or -NC(O)(CH ) CHNH CO H; R is H, CH OH, , 2 2 2 2 7 2 , , , , , , , , , or ; each of R and R independently, is H or C alkyl being optionally substituted with 8 9, 1-6 C(O)OR , in which R is H or C alkyl, or R and R together with the nitrogen atoms to f f 1-10 8 9, which they are bonded, are ; or L , together with R or R and the nitrogen atom to 2 8 9 which they are bonded, is C heterocycloalkyl.
24. A compound having one of the following structures: 21626763 N N N N N H N N N Me O N N MeO N N MeO N N N H N Me O Me O N Me O N N 21626763 Cl N N N NN N H H H N N N N NN N NN N H H H H NN N NN N H H H H N N N N N H H HN N HN N N N N N NN N NN N H H H H 21 22 HN HN N NN N NN N H H H H 23 24 21626763 NN N N N H H H N N N 25 26 NN N N N N N H H NH NH N N N N N N N NN OH 21626763 NH NH HN HN N N N N NN N NN N H N H H N NN N H H H N N H H NCO Me N N N N NN N NN N H H N H H 45 46 N H H N N H H 47 48 N N H H 21626763 N N N N N H H N H H N N O N N N N NN N NN N N H H N H H 53 54 H NN N N H H 21626763 CO Bn CO Bn 2 HN HN N N NN N H H H H N N N NN N N H H H H H N N N N OBn N MeO N NN N N NN N H H H H N N N 65 66 O O O O N O N OB n NH NH HN HN N N Cl N N NN N NN N H H H H N N N N N H H N H H N N H H 21626763 N N N N H H N 75 76 H H N N H H N H H NH NH N N N N NN N NN N H H N 21626763 CO O E t HN HN NN N NN N N N H H 83 84 HN HN OH N N N N NN N NN N H H H H O H O NH NH H H N N H H 21626763 HN NH N N H N H H N 91 92 H H N N H N NN N N N N H H Me O O C NN N N N N H H H NN N N N N H H 21626763 HN HN N N N N N H H N 10 1 102 CO O E t N OB n H H N N H H 10 3 10 4 HN N OH N H H 10 5 1 0 6 NN N NN N H H H H N N N N NN N NN N H H H H 21626763 O O O O N O N OH N H H N H H NH NH HN HN N N N N NN N NN N N H H H H N OH NH N N N NN NN N H H N H H 11 5 1 1 6 OH HN N P NH OH NH N 2 N H H H H N 11 7 1 1 8 HN HN N H H 119 1 2 0 21626763 NN N N N N H H H N H H 12 1 12 2 N N N N N N H H H H N N N N N N N N S N H H N N N N N N N N N N N N H N N 21626763 H H N H H N N H H H NN N NN N H H H H O O O CO Bn N OB n N N N N NN N H H H N N N 13 9 14 0 N N H N N N NN N 2 NN N H H H H 14 1 142 N N NN H N N 21626763 N N N N N N N HN N H N O N 14 5 14 6 N N N N N N O N N O 14 8 CO Bn N N N H N N 2 NN N H N N 14 9 150 HN NN N NN N HN N N N N N NH N OBn 21626763 Me O N N Me O N Me O N N Me O N N N N N H H N N N N N N N NH NN N N N N H H 21626763 H N N N H N N H N N N H N N N NN NN 16 9 17 0 NH OH O N P O H N N N N H H 21626763 H N N N H N N N N H H N N OH N H H H H N 18 1 18 2 21626763 H N N N H N N N N N H H H N N N H H N H H P ( O)(O H ) NH P(O) ( O H) H N N N H H N H H 21626763 H N N N H N N N N H H H H N NN N NN N N H H H H N N N N OBn NN N N N H H H 21626763 N N N H H H N H H 20 3 20 4 NN N N N H H H N H H N N OH N N P OO OH N N N N H H N NN N NN N H H N H H 21626763 N P 2 N OEt H N H H H N N N NN N NN N H H H H N N N 21626763 H N N N N N N N N H H O O O N N OH N HN HN N H H N CO H HN HO N N NN N H H H N N OH 21626763 N CO H HN O HN N O N N N NN N H H H NH N N NN N NN N H H H H N N N N N NN N NN N H N H H HN N 2 21626763 N OM e N N N NN N NN N H H H N N P N H H N CO H N CO Me HN HN N N NN N N N H H H N N N N N NN N H H H H N N OH N N NN N H H H H H N 21626763 NN N N N H H H N N N NN N N N N H H H H O O O N O N N N N NN N H H H H N N N NN N NN N N H H H H N N NN N H H H H N N N N N N 21626763 H N N N NN N H N H H N OH NH HN HN N N NN N H H H HN HN N N N N H H H H ?e? N N Cl N N N H H O O ? NH N N N N 21626763 N H H N H H
25. The compound of claim 24, wherein the compound is one of the following compounds: 21626763 NCO H Me N N NN N H H H 21626763 N N CO HN N OH OH NH NN N Me N N H H H
26. Use of a compound of claim 1 in the manufacture of a medicament for mobilizing hematopoietic stem cells (HSC) and endothelial progenitor cells (EPC) into the peripheral circulation.
27. Use of a compound of claim 1 in the manufacture of a medicament for treating a disease mediated by the interaction between type 4 CXC chemokine receptor and stromal-derived factor-1 in a subject in need thereof, wherein the disease is tissue injury, cancer, inflammatory disease, or autoimmune disease.
28. The use of claim 27, wherein the disease is tissue injury, the tissue injury being neurodegenerative disease, retinal pigment epithelium dysfunction, heart and myocardial infarction, ischemic disease, wound, bone fracture, pancreatic injury, kidney injury, intestinal injury, or lung injury.
29. The use of claim 27, wherein the disease is cancer, the cancer being acute myeloid leukemia, non-small cell lung cancer, multiple myeloma, or pancreatic cancer.
30. The use of claim 27, wherein the disease is inflammatory disease, the inflammatory disease being inflammatory bowel disease, allergic asthma, or ocular uveitis. 21626763
31. The use of claim 27, wherein the disease is autoimmune disease, the autoimmune disease being rheumatoid arthritis.
32. The use of claim 28, wherein the tissue injury is kidney injury.
33. The use of claim 28, wherein the tissue injury is an ischemic disease, the ischemic disease being ischemic stroke or limb ischemia.
34. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier thereof.
35. A compound according to claim 1, substantially as herein described with reference to any example thereof.
36. A use according to claim 26 or claim 27, substantially as herein described with reference to any example thereof.
37. A pharmaceutical composition according to claim 34, substantially as herein described with reference to any example thereof.
NZ730195A 2015-09-21 Heterocyclic compounds and use thereof NZ730195B2 (en)

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US201462053389P 2014-09-22 2014-09-22
PCT/US2015/051143 WO2016048861A2 (en) 2014-09-22 2015-09-21 Heterocyclic compounds and use thereof

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NZ730195B2 true NZ730195B2 (en) 2024-03-26

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