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Publication numberCN1342150 A
Publication typeApplication
Application numberCN 99815788
PCT numberPCT/US1999/027825
Publication date27 Mar 2002
Filing date23 Nov 1999
Priority date24 Nov 1998
Also published asCA2352261A1, CN100390154C, EP1133480A1, US6180632, US6528526, US6696434, US6821962, US6852712, US20030130285, US20030139399, US20030139400, WO2000031051A1, WO2000031051B1
Publication number99815788.0, CN 1342150 A, CN 1342150A, CN 99815788, CN-A-1342150, CN1342150 A, CN1342150A, CN99815788, CN99815788.0, PCT/1999/27825, PCT/US/1999/027825, PCT/US/1999/27825, PCT/US/99/027825, PCT/US/99/27825, PCT/US1999/027825, PCT/US1999/27825, PCT/US1999027825, PCT/US199927825, PCT/US99/027825, PCT/US99/27825, PCT/US99027825, PCT/US9927825
InventorsMR梅耶尔斯, 何伟, AP斯巴达, MP玛古伊勒
Applicant阿温蒂斯药物制品公司
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
Quinoline and quinoxaline compounds as PDGF-receptor and/or LCK tyrosine kinase inhibitors
CN 1342150 A
Abstract  translated from Chinese
本发明涉及式(I)的喹啉/喹喔啉化合物,所述化合物能抑制血小板衍生长因子或p56 The present invention relates to formula (I) of quinoline / quinoxaline compounds which inhibit platelet-derived growth factor or p56
Claims(99)  translated from Chinese
1.式I化合物、其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐: A compound of formula I, their N- oxides, hydrates, solvates thereof, prodrugs thereof, or a pharmaceutically acceptable salt thereof: 其中X是L1H或L2Z2;L1是(CR3aR3b)r或(CR3aR3b)m-Z3-(CR3'aR3'b)n;L2是(CR3aR3b)p-Z4-(CR3'aR3'b)q或乙烯基;Z1是CH或N;Z2是任选取代的环烷基、任选取代的环烯基、任选取代的杂环基或任选取代的杂环烯基;Z3是O、NR4、S、SO或SO2;Z4是O、NR4、S、SO、SO2、或一个键;m是0或1;n是2或3,且n+m=2或3;p和q独立地为0、1、2、3或4,并且当Z4是一个键时,p+q=0、1、2、3或4,当Z4不是一个键时,p+q=0、1、2或3;r是2、3或4;R1a和R1b独立地为任选取代的烷基、任选取代的芳基、任选取代的杂芳基、羟基、酰氧基、任选取代的烷氧基、任选取代的环烷氧基、任选取代的杂环氧基、任选取代的杂环基羰基氧基、任选取代的芳氧基、任选取代的杂芳氧基、氰基、R5R6N-或酰基R5N-,或者R1a和R1b当中一个是氢或卤素,另一个是任选取代的烷基、任选取代的芳基、任选取代的杂芳基、羟基、酰氧基、任选取代的烷氧基、任选取代的环烷氧基、任选取代的杂环氧基、任选取代的杂环基羰基氧基、任选取代的芳氧基、任选取代的杂芳氧基、氰基、R5R6N-或酰基R5N-;R1c是氢、任选取代的烷基、任选取代的芳基、任选取代的杂芳基、羟基、酰氧基、任选取代的烷氧基、任选取代的环烷氧基、任选取代的杂环氧基、任选取代的芳氧基、任选取代的杂芳氧基、卤素、氰基、R5R6N-或酰基R5N-;R3a、R3b、R3'a和R3'b独立地为氢或烷基;R4是氢、烷基或酰基;且R5和R6独立地为氢或烷基,或者R5和R6与它们所连接的氮原子一起形成氮杂杂环基。 Wherein X is L1H or L2Z2; L1 is (CR3aR3b) r or (CR3aR3b) m-Z3- (CR3'aR3'b) n; L2 is (CR3aR3b) p-Z4- (CR3'aR3'b) q or ethenyl ; Z1 is CH or N; Z2 is an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl or optionally substituted heterocyclenyl; Z3 is O, NR4, S, SO or SO2; Z4 is O, NR4, S, SO, SO2, or a bond; m is 0 or 1; n is 2 or 3, and n + m = 2 or 3; p and q are independently 0, 1 , 2, 3 or 4, and when Z4 is a bond when, p + q = 0,1,2,3 or 4 when Z4 is not a bond, p + q = 0,1,2 or 3; r is 2, 3 or 4; R1a and R1b are independently optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted heterocyclic oxy, optionally substituted heterocyclyl carbonyl group, an optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, R5R6N- or acyl R5N-, or R1a and R1b which one is hydrogen or halogen, and the other is an optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted heterocyclic oxy, optionally substituted heterocyclyl carbonyl group, an optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, R5R6N- or acyl R5N-; R1c is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted heterocyclic oxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, halo, cyano, R5R6N- or acyl R5N-; R3a, R3b , R3'a and R3'b independently hydrogen or alkyl; R4 is hydrogen, an alkyl group or an acyl group; and R5 and R6 are independently hydrogen or alkyl, or R5 and R6 and the nitrogen atom to which they are attached form aza-heterocyclic group.
2.权利要求1的化合物、其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐,其中L1是(CR3aR3b)m-Z3-(CR3'aR3'b)n;L2是(CR3aR3b)p-Z4-(CR3'aR3'b)q;Z2是任选取代的环烷基、任选取代的环烯基、或任选取代的杂环基;Z4是O和NR4;m是0;n是2或3;p+q=0或1;R1a和R1b独立地为任选取代的烷基、任选取代的烷氧基、任选取代的环烷氧基、任选取代的杂环氧基、或R5R6N-,或者R1a和R1b当中一个是氢或卤素,另一个是任选取代的烷基、任选取代的烷氧基、任选取代的环烷氧基、任选取代的杂环氧基、或R5R6N-;R1c是氢、任选取代的烷基、或任选取代的烷氧基;R3a、R3b、R3'a和R3'b独立地为氢或低级烷基;R4是氢;且R5和R6与它们所连接的氮原子一起形成氮杂杂环基。 M-Z3- (CR3'aR3'b compound according to claim 1, N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof, wherein L1 is (CR3aR3b) ) n; L2 is (CR3aR3b) p-Z4- (CR3'aR3'b) q; Z2 is an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or optionally substituted heterocyclyl; Z4 is O and NR4; m is 0; n is 2 or 3; p + q = 0 or 1; R1a and R1b are independently optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkoxy group, optionally substituted heterocyclic oxy group, or R5R6N-, or R1a and R1b which one is hydrogen or halogen, and the other is an optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl alkoxy, optionally substituted heterocyclyloxy, or R5R6N-; R1c is hydrogen, optionally substituted alkyl, or optionally substituted alkoxy; R3a, R3b, R3'a and R3'b are independently hydrogen or lower alkyl; R4 is hydrogen; and R5 and R6 and the nitrogen atom to which they are attached form a heterocyclic aza groups.
3.权利要求1的式I化合物、其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐,其中X是L2Z2;L2是(CR3aR3b)p-Z4-(CR3'aR3'b)q;Z2是任选取代的环烷基或任选取代的环烯基;Z3是O和NR4;p是0;q是0或1;R1a和R1b独立地为任选取代的烷基、任选取代的烷氧基、任选取代的环烷氧基、或任选取代的杂环氧基,或者R1a和R1b当中-个是氢或卤素;R1c是氢;R3'a和R3'b独立地为氢;且R4是氢。 Compound of formula according to claim I 1, N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof, wherein X is L2Z2; L2 is (CR3aR3b) p-Z4- (CR3'aR3'b) q; Z2 is an optionally substituted cycloalkyl or optionally substituted cycloalkenyl; Z3 is O and NR4; p is 0; q is 0 or 1; R1a and R1b are independently either optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkoxy, or optionally substituted heterocyclic oxy group, or R1a and R1b which - are hydrogen or halogen; R1c is hydrogen; R3 'a and R3'b independently hydrogen; and R4 is hydrogen.
4.权利要求1的化合物,其中L1H为低级烷基。 4. The compound of claim 1, wherein L1H is lower alkyl.
5.权利要求1的化合物,其中Z1为CH。 5. The compound of claim 1, wherein Z1 is CH.
6.权利要求1的化合物,其中Z1为N。 6. The compound of claim 1, wherein Z1 is N.
7.权利要求1的化合物,其中Z2为任选取代的环烷基。 7. The compound of claim 1, wherein Z2 is optionally substituted cycloalkyl.
8.权利要求1的化合物,其中Z2为烷基取代的单环环烷基。 8. The compound of claim 1, wherein Z2 is alkyl substituted monocyclic cycloalkyl.
9.权利要求1的化合物,其中Z2为甲基环戊基或甲基环己基。 9. The compound of claim 1, wherein Z2 is methylcyclopentyl or methylcyclohexyl.
10.权利要求1的化合物,其中Z2为多环环烷基。 10. The compound of claim 1, wherein Z2 is multicyclic cycloalkyls.
11.权利要求1的化合物,其中Z2为[2.2.1]二环庚烷基(降冰片烷基)或[2.2.2]二环辛烷基。 11. The compound of claim 1, wherein Z2 is [2.2.1] hept-bicyclo alkyl (norbornyl) or [2.2.2] bicyclic octanyl.
12.权利要求1的化合物,其中Z2为任选取代的环烯基。 12. The compound of claim 1, wherein Z2 is optionally substituted cycloalkenyl.
13.权利要求1的化合物,其中Z2为环戊烯基和环己烯基。 13. The compound of claim 1, wherein Z2 is cyclopentenyl and cyclohexenyl.
14.权利要求1的化合物,其中Z2为[2.2.1]二环庚烯基(降冰片烯基)和[2.2.2]二环辛烯基。 14. The compound of claim 1, wherein Z2 is [2.2.1] bicyclo heptenyl (norbornenyl) and [2.2.2] bicyclo-octenyl.
15.权利要求1的化合物,其中p和q为0。 15. The compound of claim 1, wherein p and q are 0.
16.权利要求1的化合物,其中p+q=1。 16. The compound of claim 1, wherein p + q = 1.
17.权利要求1的化合物,其中Z4为O。 17. The compound of claim 1, wherein Z4 is O.
18.权利要求1的化合物,其中Z4为O,且p和q为0。 18. The compound of claim 1, wherein Z4 is O, and p and q are 0.
19.权利要求1的化合物,其中Z4为O,且p+q=1。 19. The compound of claim 1, wherein Z4 is O, and p + q = 1.
20.权利要求1的化合物,其中Z4为NR4。 20. The compound of claim 1, wherein Z4 is NR4.
21.权利要求1的化合物,其中Z4为NR4,且p和q为0。 21. The compound of claim 1, wherein Z4 is NR4, and p and q are 0.
22.权利要求1的化合物,其中Z4为NR4,且m+n=1。 22. The compound of claim 1, wherein Z4 is NR4, and m + n = 1.
23.权利要求1的化合物,其中Z4为S。 23. The compound of claim 1, wherein Z4 is S.
24.权利要求1的化合物,其中Z4为S,且p和q为0。 24. The compound of claim 1, wherein Z4 is S, and p and q are 0.
25.权利要求1的化合物,其中Z4为S,且p+q=1。 25. The compound of claim 1, wherein Z4 is S, and p + q = 1.
26.权利要求1的化合物,其中R1a和R1b独立地为任选被羟基取代的低级烷基、羟基、低级烷氧基、环烷氧基、杂环氧基,或者R1a和R1b中一个是氢或卤素。 26. The compound of claim 1, wherein R1a and R1b are independently optionally hydroxy substituted lower alkyl, hydroxy, lower alkoxy, cycloalkoxy group, a heterocyclic oxy group, or R1a and R1b is hydrogen and or halogen.
27.权利要求1的化合物,其中R1a和R1b独立地为杂环基羰基氧基或任选取代的低级烷氧基。 27. The compound of claim 1, wherein R1a and R1b are independently a carbonyl group or a heterocyclic group optionally substituted lower alkoxy.
28.权利要求1的化合物,其中所述低级烷氧基为甲氧基或乙氧基。 28. The compound of claim 1, wherein the lower alkoxy is methoxy or ethoxy.
29.权利要求1的化合物,其中R1a和R1b为低级烷基。 29. The compound of claim 1, wherein R1a and R1b is lower alkyl.
30.权利要求1的化合物,其中所述低级烷基为甲基或乙基。 30. The compound of claim 1, wherein the lower alkyl is methyl or ethyl.
31.权利要求1的化合物,其中R1a和R1b当中一个是低级烷氧基,另一个是卤素。 31. The compound of claim 1, wherein R1a and R1b which is a lower alkoxy, and the other is halogen.
32.权利要求1的化合物,其中所述低级烷氧基为甲氧基或乙氧基,且卤素为氯或溴。 32. The compound of claim 1, wherein the lower alkoxy is methoxy or ethoxy, and halogen is chlorine or bromine.
33.权利要求1的化合物,其中R1a和R1b当中一个是低级烷基,另一个是低级烷氧基。 33. The compound of claim 1, wherein R1a and R1b which one is lower alkyl, the other is a lower alkoxy.
34.权利要求1的化合物,其中所述低级烷氧基为甲氧基或乙氧基,且低级烷基为甲基或乙基。 34. The compound of claim 1, wherein the lower alkoxy is methoxy or ethoxy, and the lower alkyl group is methyl or ethyl.
35.权利要求1的化合物,其中R1a和R1b当中一个是低级烷氧基,另一个是环烷氧基。 35. The compound of claim 1, wherein R1a and R1b is lower alkoxy which one, the other is a cyclic alkoxy.
36.权利要求1的化合物,其中所述低级烷氧基为甲氧基或乙氧基,且环烷氧基为环戊氧基或环己氧基。 36. The compound of claim 1, wherein the lower alkoxy is methoxy or ethoxy, and the cycloalkyloxy group is cyclopentyloxy or cyclohexyloxy.
37.权利要求1的化合物,其中R1a和R1b当中一个是氢,另一个是低级烷氧基、环烷氧基或杂环氧基。 37. The compound of claim 1, wherein R1a and R1b which one is hydrogen and the other is a lower alkoxy group, a cycloalkyl group or a heterocyclic oxy group.
38.权利要求37的化合物,其中所述低级烷氧基为甲氧基或乙氧基。 38. The compound of claim 37, wherein the lower alkoxy is methoxy or ethoxy.
39.权利要求37的化合物,其中所述环烷氧基为环戊氧基或环己氧基。 39. The compound of claim 37, wherein the cycloalkyl group is a cyclopentyl group or a cyclohexyl group.
40.权利要求37的化合物,其中所述杂环氧基为呋喃基氧基。 40. The compound of claim 37, wherein the heterocyclic group is a furyl group.
41.权利要求1的化合物,其中R1c是氢、低级烷基或低级氧烷基。 41. The compound of claim 1, wherein R1c is hydrogen, lower alkyl or lower oxyalkyl.
42.权利要求41的化合物,所述其中低级烷氧基为甲氧基或乙氧基。 42. The compound of claim 41, wherein said lower alkoxy is methoxy or ethoxy.
43.权利要求1的化合物,其中R1a和R1b是低级烷氧基,所述低级烷氧基可任选被烷氧基、杂环基、羧基、烷氧羰基或氨基甲酰基取代。 43. The compound of claim 1, wherein R1a and R1b is lower alkoxy, the lower alkoxy group which may optionally be substituted by alkoxy, substituted heterocyclic group, a carboxyl group, an alkoxycarbonyl group or a carbamoyl group.
44.权利要求1的化合物,其中R1a和R1b当中一个是未被取代的低级烷氧基,另一个是被烷氧基、杂环基、羧基、烷氧羰基或氨基甲酰基取代的低级烷氧基。 44. The compound of claim 1, wherein one of R1a and R1b which is unsubstituted lower alkoxy, and the other is an alkoxy group, a heterocyclic group, a carboxyl group, an alkoxycarbonyl group or a carbamoyl-substituted lower alkoxy groups.
45.权利要求1的化合物,其中R1a和R1b当中一个是甲氧基,另一个是[1,4′-]-联哌啶-1′-基羰基氧基、2-(乙氧基)乙氧基、2-(4-吗啉基)乙氧基、2-(4-甲基哌嗪-1-基)乙氧基、羧基甲氧基、甲氧基羰基甲氧基、氨基羰基甲氧基、N-甲基氨基羰基甲氧基、或N,N-二甲基氨基羰基甲氧基。 45. The compound of claim 1, wherein one of R1a and R1b which are methoxy, and the other is [1,4 '-] - bipiperidinyl-1'-carbonyl group, 2- (ethoxy) ethyl group, 2- (4-morpholinyl) ethoxy, 2- (4-methyl-piperazin-1-yl) ethoxy, carboxymethoxy, methoxycarbonyl methoxy, aminocarbonyl A group, N- methyl-aminocarbonyl-methoxy, or N, N- dimethyl-aminocarbonyl methoxy.
46.权利要求1的化合物,其是:3-环己氧基-6,7-二甲氧基喹啉;2-环己基氨基-6,7-二甲氧基喹喔啉;外-二环[2.2.1]庚-2-基-(6-氯-7-甲氧基喹喔啉-2-基)胺;外-二环[2.2.1]庚-2-基-(7-氯-6-甲氧基喹喔啉-2-基)胺;二环[2.2.1]庚-2-基-(6,7-二甲基喹喔啉-2-基)胺;2-环庚基氨基-6,7-二甲氧基喹喔啉;2-环戊基氨基-6,7-二甲氧基喹喔啉;2-环己基氨基-6-甲氧基喹喔啉;3-氨基环己基-6,7-二甲氧基喹啉;(6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基环己基)胺;2-环己基氨基-6-甲氧基-7-溴喹喔啉盐酸盐;(6,7-二甲氧基喹啉-3-基)-顺式/反式-(3-(R)-甲基环己基)胺;(6,7-二甲氧基喹啉-3-基)-反式-(3-(R)-甲基-环己基)胺;(6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基-环己基)胺;(6.7-二甲氧基喹啉-3-基)-(3-甲基环戊基)胺;环己-3-烯基-(6,7-二甲氧基喹喔啉-2-基)胺;2,7-二环己氧基-6-甲氧基喹喔啉;环己基-(6,7-二甲氧基喹喔啉-2-基甲基)胺;(6,7-二甲氧基喹啉-3-基)异丁基胺;环己基-(6-甲氧基-7-吗啉-4-基喹喔啉-2-基)胺;()-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;外-二环[2.2.1]庚-5-烯-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;环己基-(6,8-二甲基喹喔啉-2-基)胺;内-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;(6,7-二甲氧基喹喔啉-2-基)-(4-甲氧基环己基)胺;外-二环[2.2.1]庚-2-基-(6-甲氧基喹喔啉-2-基)胺;外-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉;(二环[2.2.2]辛-2-基氧基)-6,7-二甲氧基喹喔啉;内-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉;外-2-(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉;(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉;2-环己氧基-6,7-二甲氧基喹喔啉;2-环戊硫基-6,7-二甲氧基喹喔啉;6,7-二甲氧基-2-环戊氧基喹喔啉;2-环戊基甲氧基-6,7-二甲氧基喹喔啉;6,7-二甲氧基-2-四氢吡喃-4-氧基喹喔啉;外,外-6,7-二甲氧基-2-(5,6-环氧二环[2.2.1]庚烷-2-基氧基)喹喔啉;顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己烷甲酸;6,7-二甲氧基-2-(4-甲氧基环己氧基)喹喔啉;(1R,2R,4S)-(+)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;(1S,2S,4R)-(-)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;(6,7-二甲氧基喹喔啉-2-基)-2-氮杂二环[2.2.2]辛烷-3-酮;顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸;顺式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;(6,7-二甲氧基喹喔啉-2-基)-顺式/反式-(3-(R)-甲基环己基)胺;(6,7-二甲氧基喹喔啉-2-基)-反式-(3-(R)-甲基环己基)胺;(6,7-二甲氧基喹喔啉-2-基)-顺式-(3-(R)-甲基环己基)胺;或顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己烷甲酸甲酯;或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 46. The compound of claim 1, which is: 3-cyclohexyl-6,7-dimethoxy-quinoline; 2-cyclohexyl-6,7-dimethoxy-quinoxaline; outside - two bicyclo [2.2.1] hept-2-yl - (6-chloro-7-methoxy-quinoxalin-2-yl) amine; outer - bicyclo [2.2.1] hept-2-yl - (7- chloro-6-methoxy-quinoxalin-2-yl) amine; bicyclo [2.2.1] hept-2-yl - (6,7-dimethyl-quinoxalin-2-yl) amine; 2- cycloheptyl-amino-6,7-dimethoxy-quinoxaline; 2- cyclopentyl-6,7-dimethoxy-quinoxaline; 2-cyclohexyl-amino-6-methoxy-quinoxaline ; 3-amino-cyclohexyl-6,7-dimethoxy-quinoline; (6,7-dimethoxy-quinolin-3-yl) - cis - (3- (R) - methyl-cyclohexyl) amine; 2-cyclohexyl-amino-6-methoxy-7-bromo-quinoxaline hydrochloride; (6,7-dimethoxy-quinolin-3-yl) - cis / trans - (3- (R) - methyl-cyclohexyl) amine; (6,7-dimethoxy-quinolin-3-yl) - trans - (3- (R) - methyl - cyclohexyl) amine; (6,7 - dimethoxy-quinoline-3-yl) - cis - (3- (R) - methyl - cyclohexyl) amine; (6,7-dimethoxy-quinolin-3-yl) - (3- cyclopentyl) amine; cyclohex-3-enyl - (6,7-dimethoxy-quinoxalin-2-yl) amine; 2,7-dicyclohexyl-6-methoxy-quinoline quinoxaline; cyclohexyl - (6,7-dimethoxy-quinoxalin-2-yl-methyl) amine; (6,7-dimethoxy-quinolin-3-yl) isobutylamine; cyclohexyl - (6-methoxy-7-morpholin-4-quinoxalin-2-yl) amine; () - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy oxy quinoxalin-2-yl) amine; outer - bicyclo [2.2.1] hept-5-en-2-yl - (6,7-dimethoxy-quinoxalin-2-yl) amine; cyclohexyl - (6,8-dimethyl-quinoxalin-2-yl) amine; the - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-quinoxalin-2 - yl) amine; (6,7-dimethoxy-quinoxalin-2-yl) - (4-methoxy-cyclohexyl) amine; outer - bicyclo [2.2.1] hept-2-yl - ( 6-methoxy-quinoxalin-2-yl) amine; outer -2- (bicyclo [2.2.1] hept-2-yloxy) -6,7-dimethoxy-quinoxaline; (two bicyclo [2.2.2] oct-2-yloxy) -6,7-dimethoxy-quinoxaline; the 2- (bicyclo [2.2.1] hept-2-yloxy) -6, 7- dimethoxy-quinoxaline; outer -2- (bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxy-quinoxaline; (bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxy-quinoxaline; 2-cyclohexyl-6,7-dimethoxy-quinoxaline; 2 - cyclopentylthio-6,7-dimethoxy-quinoxaline; 6,7-dimethoxy-2-cyclopentyloxy-quinoxaline; 2-cyclopentyl-methoxy-6,7- dimethoxy-quinoxaline; 6,7-dimethoxy-2-tetrahydropyran-4-yloxy quinoxaline; outer, outer-6,7-dimethoxy-2- (5, 6- epoxy bicyclo [2.2.1] heptane-2-yloxy) quinoxaline; cis / trans-4- (6,7-quinoxaline-2-yloxy ) cyclohexanecarboxylic acid; 6,7-dimethoxy-2- (4-methoxy-cyclohexyloxy) quinoxaline; (1R, 2R, 4S) - (+) - bicyclo [2.2.1 ] hept-2-yl - (6,7-dimethoxy-quinoxalin-2-yl) amine; (1S, 2S, 4R) - (-) - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-quinoxalin-2-yl) amine; (6,7-dimethoxy-quinoxalin-2-yl) -2-aza-bicyclo [2.2.2] oct- -3-one; cis / trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid methyl ester; cis / trans-4- (6, 7- dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid; cis-4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid methyl ester; trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid methyl ester; (6,7-dimethoxy-quinoxalin-2-yl) - cis / trans - (3- (R) - methyl-cyclohexyl) amine; (6,7-dimethoxy-quinoxalin-2-yl) - trans - (3- (R) - methyl-cyclohexyl ) amine; (6,7-dimethoxy-quinoxalin-2-yl) - cis - (3- (R) - methyl-cyclohexyl) amine; or cis / trans-4- (6, 7- dimethoxy-quinoxalin-2-yloxy) cyclohexane carboxylate; or a N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
47.权利要求1的化合物,其是2-环己基氨基-6,7-二甲氧基喹喔啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 47. The compound of claim 1, which is 2-cyclohexyl-6,7-dimethoxy-quinoxaline, or an N- oxide thereof, a hydrate thereof, a solvate, a prodrug thereof, or pharmaceutically acceptable salt thereof.
48.权利要求1的化合物,其是外-二环[2.2.1]庚-2-基-(6-氯-7-甲氧基喹喔啉-2-基)胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 48. The compound of claim 1, which is external - bicyclo [2.2.1] hept-2-yl - (6-chloro-7-methoxy-quinoxalin-2-yl) amine, or a N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
49.权利要求1的化合物,其是外-二环[2.2.1]庚-2-基-(7-氯-6-甲氧基喹喔啉-2-基)胺。 (7-chloro-6-methoxy-quinoxalin-2-yl) amine - 49. The compound of claim 1, which is external - bicyclo [2.2.1] hept-2-yl.
50.权利要求1的化合物,其是二环[2.2.1]庚-2-基-(6,7-二甲基喹喔啉-2-基)胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 50. The compound of claim 1, which is a bicyclo [2.2.1] hept-2-yl - (6,7-dimethyl-quinoxalin-2-yl) amine, or a N- oxide, hydrated thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
51.权利要求1的化合物,其是2-环庚基氨基-6,7-二甲氧基喹喔啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 51. The compound of claim 1, which is 2-cycloheptylamino-6,7-dimethoxy-quinoxaline, or an N- oxide thereof, a hydrate thereof, a solvate, a prodrug thereof, or pharmaceutically acceptable salts thereof.
52.权利要求1的化合物,其是2-环戊基氨基-6,7-二甲氧基喹喔啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 52. The compound of claim 1, which is 2-cyclopentyl-6,7-dimethoxy-quinoxaline, or an N- oxide thereof, a hydrate thereof, a solvate, a prodrug thereof, or pharmaceutically acceptable salts thereof.
53.权利要求1的化合物,其是3-氨基环己基-6,7-二甲氧基喹啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 53. The compound of claim 1 which is 3-amino-cyclohexyl-6,7-dimethoxy-quinoline, or an N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
54.权利要求1的化合物,其是(6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基环己基)胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 54. The compound of claim 1, which is (6,7-dimethoxy-quinolin-3-yl) - cis - (3- (R) - methyl-cyclohexyl) amine, or a N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
55.权利要求1的化合物,其是(6,7-二甲氧基喹啉-3-基)-顺式/反式-(3-(R)-甲基环己基)胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 55. The compound of claim 1, which is (6,7-dimethoxy-quinolin-3-yl) - cis / trans - (3- (R) - methyl-cyclohexyl) amine, or N - oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
56.权利要求1的化合物,其是(6,7-二甲氧基喹啉-3-基)-反式-(3-(R)-甲基环己基)胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 56. The compound of claim 1, which is (6,7-dimethoxy-quinolin-3-yl) - trans - (3- (R) - methyl-cyclohexyl) amine, or a N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
57.权利要求1的化合物,其是(6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基环己基)胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 57. The compound of claim 1, which is (6,7-dimethoxy-quinolin-3-yl) - cis - (3- (R) - methyl-cyclohexyl) amine, or a N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
58.权利要求1的化合物,其是环己-3-烯基-(6,7-二甲氧基喹喔啉-2-基)胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 58. The compound of claim 1, which is a cyclohex-3-enyl - (6,7-dimethoxy-quinoxalin-2-yl) amine, N- oxide thereof, a hydrate thereof, a solvent compound, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
59.权利要求1的化合物,其是2,7-二环己氧基-6-甲氧基喹喔啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 59. The compound of claim 1, which is 2,7-dicyclohexyl-6-methoxy-quinoxaline, or an N- oxide thereof, a hydrate thereof, a solvate, a prodrug thereof, or pharmaceutically acceptable salts thereof.
60.权利要求1的化合物,其是(6,7-二甲氧基喹啉-3-基)异丁基胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 60. The compound of claim 1, which is (6,7-dimethoxy-quinolin-3-yl) iso-butylamine, or N- oxide thereof, a hydrate thereof, a solvate, a prodrug thereof , or a pharmaceutically acceptable salt thereof.
61.权利要求1的化合物,其是()-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 61. The compound of claim 1 which is () - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-quinoxalin-2-yl) amine, or N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
62.权利要求1的化合物,其是外-二环[2.2.1]庚-5-烯-2-基-(6,7-二甲氧基喹喔啉-2-基)胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 62. The compound of claim 1, which is external - bicyclo [2.2.1] hept-5-en-2-yl - (6,7-dimethoxy-quinoxalin-2-yl) amine, or N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
63.权利要求1的化合物,其是内-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 63. The compound of claim 1, which is within - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-quinoxalin-2-yl) amine, N- oxides thereof thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
64.权利要求1的化合物,其是外-二环[2.2.1]庚-2-基-(6-甲氧基喹喔啉-2-基)胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 64. The compound of claim 1, which is external - bicyclo [2.2.1] hept-2-yl - amine, or a N- oxide (6-methoxy-quinoxalin-2-yl), which hydrated thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
65.权利要求1的化合物,其是外-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 65. The compound of claim 1, which is exo-2 (bicyclo [2.2.1] hept-2-yloxy) -6,7-dimethoxy-quinoxaline, or an N- oxide, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
66.权利要求1的化合物,其是2-(二环[2.2.2]辛-2-基氧基)-6,7-二甲氧基喹喔啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 66. The compound of claim 1, which is 2- (bicyclo [2.2.2] oct-2-yloxy) -6,7-dimethoxy-quinoxaline, or an N- oxide, hydrated thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
67.权利要求1的化合物,其是内-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 67. The compound of claim 1, which is the 2- (bicyclo [2.2.1] hept-2-yloxy) -6,7-dimethoxy-quinoxaline, or an N- oxide, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
68.权利要求1的化合物,其是外-2-(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 68. The compound of claim 1, which is exo-2 (bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxy-quinoxaline, or an N - oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
69.权利要求1的化合物,其是2-(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 69. The compound of claim N- oxide, which is 2- (bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxy-quinoxaline, or thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
70.权利要求1的化合物,其是2-环己氧基-6,7-二甲氧基喹喔啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 70. The compound of claim 1, which is 2-cyclohexyl-6,7-dimethoxy-quinoxaline, or an N- oxide thereof, a hydrate thereof, a solvate, a prodrug thereof, or pharmaceutically acceptable salts thereof.
71.权利要求1的化合物,其是2-环戊硫基-6,7-二甲氧基喹喔啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 71. The compound of claim 1, which is 2-cyclopentylthio-6,7-dimethoxy-quinoxaline, or an N- oxide thereof, a hydrate thereof, a solvate, a prodrug thereof, or pharmaceutically acceptable salts thereof.
72.权利要求1的化合物,其是6,7-二甲氧基-2-环戊氧基喹喔啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 72. The compound of claim 1, which is 6,7-dimethoxy-2-cyclopentyloxy-quinoxaline, or an N- oxide thereof, a hydrate thereof, a solvate, a prodrug thereof, or pharmaceutically acceptable salts thereof.
73.权利要求1的化合物,其是2-环戊基甲氧基-6,7-二甲氧基喹喔啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 73. The compound of claim 1, which is 2-cyclopentyl-methoxy-6,7-dimethoxy-quinoxaline, or an N- oxide thereof, a hydrate thereof, a solvate, a prodrug thereof , or a pharmaceutically acceptable salt thereof.
74.权利要求1的化合物,其是6,7-二甲氧基-2-四氢吡喃-4-氧基喹喔啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 74. The compound of claim 1, which is 6,7-dimethoxy-2-tetrahydropyran-4-yloxy quinoxaline, or an N- oxide thereof, a hydrate thereof, a solvate, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
75.权利要求1的化合物,其是外,外-6,7-二甲氧基-2-(5,6-环氧二环[2.2.1]庚烷-2-基氧基)喹喔啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 75. The compound of claim 1, which is outside the outer-6,7-dimethoxy-2- (5,6-epoxy-bicyclo [2.2.1] heptane-2-yloxy) quinoxalin morpholine, or an N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
76.权利要求1的化合物,其是6,7-二甲氧基-2-(4-甲氧基环己氧基)喹喔啉,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 76. The compound of claim 1, which is 6,7-dimethoxy-2- (4-methoxy-cyclohexyloxy) quinoxaline, or an N- oxide thereof, hydrate thereof, solvate thereof thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
77.权利要求1的化合物,其是(1R,2R,4S)-(+)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 77. The compound of claim 1 which is (1R, 2R, 4S) - (+) - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-quinoxalin-2 yl) amine, or an N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
78.权利要求1的化合物,其是(1S,2S,4R)-(-)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 78. The compound of claim 1 which is (1S, 2S, 4R) - (-) - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-quinoxalin-2 yl) amine, or an N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
79.权利要求1的化合物,其是顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 79. The compound of claim 1, which is a cis / trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid methyl ester, or N- oxide, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
80.权利要求1的化合物,其是顺式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 80. The compound of claim 1, which is cis-4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid methyl ester, or N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
81.权利要求1的化合物,其是反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 81. The compound of claim 1, which is trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid methyl ester, or N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
82.权利要求1的化合物,其是(6,7-二甲氧基喹喔啉-2-基)-顺式/反式-(3-(R)-甲基环己基)胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 82. The compound of claim 1, which is (6,7-dimethoxy-quinoxalin-2-yl) - cis / trans - (3- (R) - methyl-cyclohexyl) amine, or N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
83.权利要求1的化合物,其是(6,7-二甲氧基喹喔啉-2-基)-反式-(3-(R)-甲基环己基)胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 N- amine oxide, or a compound of claim 83. which is (6,7-dimethoxy-quinoxalin-2-yl) - (trans) - - (methyl cyclohexyl 3- (R)) thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
84.权利要求1的化合物,其是(6,7-二甲氧基喹喔啉-2-基)-顺式-(3-(R)-甲基环己基)胺,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 N- amine oxide, or a compound of claim 84. which is (6,7-dimethoxy-quinoxalin-2-yl) - cis - - (methyl cyclohexyl 3- (R)) thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
85.权利要求1的化合物,其是顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己烷甲酸甲酯,或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 85. The compound of claim N- oxide, which is a cis / trans-4- (6,7-dimethoxy-quinoxalin-2-yloxy) cyclohexane carboxylate, or thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.
86.药物组合物,其含有权利要求1的化合物或其可药用盐和可药用载体。 86. A pharmaceutical composition comprising the compound of claim or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
87.抑制PDGF酪氨酸激酶活性的方法,包括将权利要求1的化合物与含有PDGF酪氨酸激酶的组合物接触。 87. inhibiting PDGF tyrosine kinase activity comprising the compound of claim 1 with a composition containing a PDGF tyrosine kinase contact.
88.抑制Lck酪氨酸激酶活性的方法,包括将权利要求1的化合物与含有Lck酪氨酸激酶的组合物接触。 88. inhibiting Lck tyrosine kinase activity comprising the compound of claim 1 with a composition containing a Lck tyrosine kinase contact.
89.在患有特征是细胞增殖和/或分化和/或介质释放的疾病的患者中抑制细胞增殖、分化或介质释放的方法,包括给患者施用药物学有效量的权利要求1的化合物。 89. In patients characterized by cell proliferation and / or differentiation and / or diseases of mediator release inhibiting cell proliferation, differentiation or mediator release comprising administering to a patient a pharmaceutically effective amount of a compound of claim 1.
90.治疗与过度增殖性病症有关的疾病的方法,所述方法包括给需要这种治疗的患者施用药物学有效量的权利要求1的化合物。 90. Treatment of conditions associated with a hyperproliferative disease, said method comprising administering to a patient in need of such treatment is administered a pharmaceutically effective amount of a compound of claim 1.
91.权利要求90的方法,其中所述疾病是再狭窄。 91. The method of claim 90, wherein the disease is restenosis.
92.在患者中治疗再狭窄的方法,包括给需要这种治疗的患者在预定位点施用药物学有效量的权利要求1的化合物。 92. The method of treating restenosis in a patient, comprising administering to a patient in need of such treatment is administered a pharmaceutically effective amount of a compound of claim 1 at a predetermined site.
93.权利要求90的方法,其中所述过度增殖性病症是在通过血管成形术治疗动脉粥样硬化损伤时所产生的动脉壁机械损伤位点上发生的。 93. The method of claim 90, wherein said hyperproliferative disorder is the occurrence of mechanical damage to the artery wall by the angioplasty site of treatment of atherosclerosis of injury arising.
94.权利要求92的方法,其中权利要求1的化合物是通过用权利要求1的化合物饱和的亲水性膜包衣的血管成形术用囊来施用的。 94. The method of claim 92, wherein the compound of claim 1 is the compound of claim 1 with a hydrophilic film coating vessel saturated with balloon angioplasty to administration.
95.权利要求92的方法,其中权利要求1的化合物是通过包含输注室的导管来施用的,其中所述输注室含有权利要求1的化合物的溶液。 95. The method of claim 92, wherein the compound of claim 1 through the catheter containing an infusion chamber is to be administered, wherein said infusion chamber containing a solution of a compound of claim 1.
96.权利要求92的方法,其中使用在斯滕特固定模装置上的包衣来施用权利要求1的化合物,其中所述包衣含有权利要求1的化合物。 96. The method of claim 92, wherein the stent coating device to administering a compound of claim 1, wherein the coating comprises a compound of claim 1 or claim 2.
97.权利要求90的方法,其中所述与过度增殖性病症有关的疾病是可通过抑制PDGF酪氨酸激酶来治疗的癌症。 97. The method of claim 90, wherein the condition associated with hyperproliferative disease is cancer by inhibiting the tyrosine kinases PDGF treatment.
98.权利要求97的方法,其中所述癌症是脑癌、卵巢癌、结肠癌、前列腺癌、肺癌、卡波西肉瘤或恶性黑素瘤。 98. The method of claim 97, wherein said cancer is brain cancer, ovarian cancer, colon cancer, prostate cancer, lung cancer, Kaposi's sarcoma or malignant melanoma.
99.在患有炎症的患者中治疗炎症的方法,包括给所述患者施用有效量的权利要求1的化合物。 99. A method of treating inflammation in a patient suffering from inflammation, including administering to said patient an effective amount of a compound of claim 1.
Description  translated from Chinese
用作PDGF-受体和/或LCK酪氨酸激酶抑制剂的喹啉和喹喔啉化合物 Used as PDGF- receptor and / or LCK tyrosine kinase inhibitors quinoline and quinoxaline compounds

相关申请案介绍本申请是在1998年11月24日提交的第09/198,718号美国专利申请的延续,而该美国专利申请又是在1998年5月28日提交的第PCT/US98/11036号国际专利申请的延续,该国际专利申请是在1997年11月18日提交的第08/972,614号美国专利申请的延续,该美国专利申请是在1997年5月18日提交的、现在已经放弃的第08/864,455号美国专利申请的延续。 RELATED APPLICATIONS This application is a continuation of the introduction No. 09 / 198,718 US Patent Application 24 November 1998 submitted, and the US patent application is in the May 28, 1998 filed on PCT / US98 / continuation of international patent application No. 11036, which is an international patent application is No. 08 / 972,614 a continuation of US patent application 18 November 1997 filed the patent application in the United States May 18, 1997 submission, now give up No. 08 / 864,455 a continuation of US patent application.

发明背景1.发明领域本发明涉及使用可用作蛋白质酪氨酸激酶抑制剂(TKIs)的喹啉/喹喔啉化合物来抑制细胞增殖和/或细胞基质产生和/或细胞运动(趋化性)和/或T细胞活化和增殖。 BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to the use of protein tyrosine kinase inhibitors useful as (TKIs) of quinoline / quinoxaline compounds to inhibit cell proliferation and / or cell matrix production and / or cell movement (chemotaxis ) and / or T-cell activation and proliferation.

细胞信号传导是通过相互作用系统介导的,包括细胞-细胞接触或细胞-基质接触或细胞外受体-底物接触。 Cell signaling is mediated by the interaction of the system, including cell - cell contact or cell - matrix contact or extracellular receptor - substrate contact. 细胞外信号经常通过酪氨酸激酶介导的磷酸化事件传递到细胞的其它部分,该磷酸化事件影响细胞膜结合的信号传导复合物的下游底物蛋白。 Extracellular signal is often transmitted through the tyrosine kinase mediated phosphorylation event to other parts of the cell, the phosphorylation events downstream substrates cell membrane-bound protein signaling complexes. 特定的受体-酶例如胰岛素受体、表皮生长因子受体(EGF-R)或血小板衍生生长因子受体(PDGF-R)是参与细胞信号传导的酪氨酸激酶的实例。 Specific receptors - enzymes such as the insulin receptor, epidermal growth factor receptor (EGF-R) or platelet-derived growth factor receptor (PDGF-R) tyrosine kinase involved in cell signaling instances. 对于有效的酶介导的、含有酪氨酸残基的底物蛋白的磷酸化,酶的自身磷酸化是必需的。 For efficient enzyme-mediated phosphorylation of tyrosine residues containing substrate proteins, enzyme autophosphorylation is required. 已知这些底物引起很多细胞事件,包括细胞增殖、细胞基质产生、细胞迁移和细凋亡(这只是其中的一小部分事件)。 These substrates are known to cause a lot of cellular events, including cell proliferation, extracellular matrix production, cell migration and fine apoptosis (This is just a small part of the event).

众所周知,有大量疾病是由于失控的细胞增殖或细胞基质过度生成或失控的编程性细胞死亡(细胞凋亡)引起的。 As we all know, there are a number of diseases are due to uncontrolled cell proliferation or excessive production of extracellular matrix or runaway programmed cell death (apoptosis) induced. 这些疾病涉及多种细胞类型,并包括病症例如白血病、癌症、成胶质细胞瘤、牛皮癣、炎性疾病、骨疾病、纤维变性疾病、动脉粥样硬化和冠状动脉、股动脉或肾动脉的血管成形术后发生的再狭窄,或纤维增生性疾病例如关节炎,肺、肾和肝脏的纤维变性。 These diseases involve a variety of cell types, and such as leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, bone diseases, fibrotic diseases, atherosclerosis and coronary artery, femoral artery or renal artery vascular disorders including angioplasty restenosis occurs, or fibroproliferative diseases such as arthritis, lung, kidney and liver fibrosis. 此外,冠状动脉旁路手术后会发生失控的细胞增殖。 In addition, uncontrolled cell proliferation will occur after coronary artery bypass surgery. 据信抑制酪氨酸激酶活性可用于控制失控的细胞增殖或细胞基质过度生成或失控的编程性细胞死亡(细胞凋亡)。 It is believed that inhibition of tyrosine kinase activity may be used to control the uncontrolled proliferation of cells or overproduction of matrix or uncontrolled cell programmed cell death (apoptosis).

已知有一些酪氨酸激酶抑制剂可以与一类以上的酪氨酸激酶相互作用。 There are some known tyrosine kinase kinase inhibitors can interact with the more than one class of tyrosine. 而有一些酪氨酸激酶对于身体正常功能是至关重要的。 While some tyrosine kinases for the normal function of the body is essential. 例如,在大多数情况下并不希望抑制胰岛素的作用。 For example, in most cases not want to inhibit the action of insulin. 因此,能在有效地抑制胰岛素受体激酶的浓度以下的浓度抑制PDGF-R酪氨酸激酶活性的化合物可以给特征是细胞增殖和/或细胞基质产生和/或细胞运动(趋化性)的疾病例如再狭窄的选择性治疗提供有价值的治疗剂。 Therefore, the concentration can be effectively suppressed below the concentration of insulin receptor kinase inhibition PDGF-R tyrosine kinase activity can give compounds characterized by cell proliferation and / or cell matrix production and / or cell movement (chemotaxis) of diseases such as restenosis selective treatment provide valuable therapeutic agents.

本发明涉及调节和/或抑制细胞信号传导、细胞增殖、细胞外基质产生、趋化性,控制异常的细胞生长和细胞炎性反应。 The present invention relates to regulation and / or inhibition of cell signaling, cell proliferation, extracellular matrix production, chemotaxis, the control of abnormal cell growth and cell inflammatory response. 更具体来说,本发明涉及取代的喹喔啉化合物的应用,所述化合物能通过有效地抑制血小板衍生生长因子受体(PDGF-R)酪氨酸激酶活性和/或Lck酪氨酸激酶活性而选择性地抑制分化、增殖或介质释放。 More particularly, the present invention relates to substituted quinoxaline compound application, the compound can effectively inhibit platelet-derived growth factor receptor (PDGF-R) tyrosine kinase activity and / or Lck tyrosine kinase activity selectively inhibit the differentiation, proliferation or mediator release. 2.报道进展有许多文献报道描述了对于酪氨酸激酶受体酶例如EGF-R或PDGF-R或非受体胞质酪氨酸激酶例如v-abl、p561ck或c-src有选择性的酪氨酸激酶抑制剂。 2. There are a number of literature reports progress described for tyrosine kinase receptor enzymes such as EGF-R or PDGF-R or non-receptor cytosolic tyrosine kinases such as v-abl, p561ck or c-src selective tyrosine kinase inhibitors. Spada和Myers(Exp.Opin.Ther.Patents1995.,5(8).805)与Bridges(Exp.Opin.Ther.Patents 1995,5(12),1245)的近期综述分别总结了关于酪氨酸激酶抑制剂和EGF-R选择性抑制剂的文献。 Spada and Myers (Exp.Opin.Ther.Patents1995., 5 (8) .805) and Bridges (Exp.Opin.Ther.Patents 1995,5 (12), 1245) are summarized in a recent review on the tyrosine kinase literature inhibitors and EGF-R selective inhibitors. 此外,Law和Lydon总结了酪氨酸激酶抑制剂的抗癌潜力(Emerging Drugs:The Prospect ForImproved Medicines 1996,241-260)。 In addition, Law and Lydon summarizes the anticancer potential of tyrosine kinase inhibitors (Emerging Drugs: The Prospect ForImproved Medicines 1996,241-260).

已知的PDGF-R酪氨酸激酶活性抑制剂包括Maguire等人(J.Med.Chem.1994,37,2129)和Dolle等人(J.Med.Chem.1994,37,2627)报道的基于喹啉的抑制剂。 Known PDGF-R tyrosine kinase activity inhibitors include Maguire et al (J.Med.Chem.1994,37,2129) and Dolle et al (J.Med.Chem.1994,37,2627) reported on quinoline inhibitors. 最近下述作者报道了一类基于苯基氨基嘧啶的抑制剂:Traxler等人在EP564409中,和Zimmerman,J.;和Traxler,P.等人(Biorg.&Med.Chem.Lett.1996,6(11),1221-1226)和Buchdunger,E.等人(Proc.Nat.Acad.Sci.1995,92,2558)。 The following recently reported a class of phenylamino pyrimidine inhibitors: Traxler et al. In EP564409 in and Zimmerman, J .; and Traxler, P et al. (Biorg & amp; Med.Chem.Lett.1996,.. 6 (11), 1221-1226) and Buchdunger, E. et al. (Proc.Nat.Acad.Sci.1995,92,2558). 尽管在本领域内取得了这些进展,但是在这些类化合物当中,没有一种被批准用来在人中治疗增殖性疾病。 Despite these advances in the art, but among these compounds, not to be approved for treatment of proliferative diseases in humans.

在整个科学文献中,多因子再狭窄疾病与PDGF和PDGF-R之间的关系有广泛的文献报道。 Throughout the scientific literature, multifactorial disease of restenosis relationship between PDGF and PDGF-R with a wide range of literature. 然而,最近关于肺纤维变性疾病的病因(Antoniades,HN;等人.J.Clin.Invest.1990,86,1055)、肾和肝脏纤维变性疾病的病因(Peterson,TCHepatology,1993,17,486)的研究进展表明PDGF和PDGF-R可能也在这些疾病中起作用。 However, recent pulmonary fibrosis disease etiology (Antoniades, HN; et al .J.Clin.Invest.1990,86,1055), renal and liver fibrosis disease etiology (Peterson, TCHepatology, 1993,17,486) The study showed that PDGF progress and PDGF-R may also play a role in these diseases. 例如,肾小球肾炎是肾衰竭的主要原因,据鉴定在体外对于肾小球细胞,PDGF是有力的促细胞分裂剂,Shultz等人(Am.J.Physiol.1988,255,F674)和Floege等人(Clin.Exp.Immun.1991,86,334)证实了这一点。 For example, glomerulonephritis is the main reason of kidney failure, according to the identification in vitro glomerular cells, PDGF is a potent mitogen, Shultz et al. (Am.J.Physiol.1988,255, F674) and Floege et al. (Clin.Exp.Immun.1991,86,334) confirms this. Thornton,SC等人(Clin.Exp.Immun.1991,86,79)等人报道,TNF-α和PDGF(得自类风湿性关节炎患者)是参与滑液细胞增殖的主要细胞因子。 Thornton, SC, et al. (Clin.Exp.Immun.1991,86,79), who reported, TNF-α and PDGF (obtained from rheumatoid arthritis patients) are the major cytokines participate synovial cell proliferation. 此外,已经鉴定出了过度表达PDGF蛋白或受体、并由此通过自分泌或旁分泌机制导致失控的癌细胞生长的具体肿瘤细胞类型(参见Silver,BJ,BioFactors,1992,3,217),例如成胶质细胞瘤和卡波西肉瘤。 Additionally, have been identified over-expression of PDGF protein or receptor, and thereby through autocrine or paracrine mechanisms leading to specific tumor cell types uncontrolled growth of cancer cells (see Silver, BJ, BioFactors, 1992,3,217), such as glioblastoma and Kaposi's sarcoma. 由此,预计PDGF酪氨酸激酶抑制剂可用于治疗多种表面上看来无关的、但是特征是在其病因中涉及PDGF和/或PDGF-R的人类疾病。 Thus, PDGF tyrosine kinase inhibitors are expected to be useful for treating a variety of seemingly unrelated, but is characterized by involving PDGF and / or PDGF-R in their etiology in human diseases.

Hanke等人(Inflamm.Res.1995,44,357)与Bolen和Brugge(Ann.Rev.Immunol.,1997,15,371)总结回顾了非受体酪氨酸激酶例如p56lck(下文中称为″Lck″)在涉及T细胞活化和增殖的炎症相关性病症中的作用。 Hanke et al (Inflamm.Res.1995,44,357) and Bolen and Brugge (Ann.Rev.Immunol., 1997,15,371) A review of the non-receptor tyrosine kinases such as p56lck (hereinafter " Lck ") in relation to the role of T cell activation and proliferation of inflammation-related disorders. 这些炎性病症包括变态反应、自身免疫性疾病、类风湿性关节炎和移植排斥。 These inflammatory conditions include allergy, autoimmune diseases, rheumatoid arthritis and transplant rejection. 另一篇近期综述总结了各类酪氨酸激酶抑制剂,包括具有Lck抑制活性的化合物(Groundwater等人,医用化学进展(Progress in Medicinal Chemistry),1996,33,233)。 Another recent review summarizes various types of article tyrosine kinase inhibitors including compounds having activity (Groundwater, et al., Progress in Medical Chemistry (Progress in Medicinal Chemistry), 1996,33,233) Lck inhibition. Lck酪氨酸激酶活性抑制剂包括通常是非选择性酪氨酸激酶抑制剂的几种天然产物,例如星形孢菌素、金雀异黄素、一些黄酮和制表菌素。 Lck tyrosine kinase activity inhibitors include several natural products generally non-selective tyrosine kinase inhibitors, such as staurosporine, genistein, some flavonoids and tabulation streptozotocin. 虎刺醇是最近报道的低纳摩尔Lck抑制剂(Faltynek,等人,Biochemistry,1995,34,12404)。 Damnacanthus alcohol is recently reported low nanomolar inhibitor of Lck (Faltynek, et al., Biochemistry, 1995,34,12404). Lck合成抑制剂的实例包括:据报道具有低微摩尔-亚微摩尔活性的一系列二羟基异喹啉抑制剂(Burke,等人,J.Med.Chem.1993,36,425);和Lck IC50为610微摩尔的活性差很多的喹啉衍生物。 Examples of synthetic Lck inhibitors include: reported to have low micromolar - a series of sub-micromolar activity of dihydroxy-isoquinoline inhibitors (Burke, et al., J.Med.Chem.1993,36,425); and Lck IC50 610 micromolar activity much worse quinoline derivatives. 研究人员已经公开了在微摩尔-亚微摩尔低浓度下抑制Lck的一系列4-取代的喹唑啉(Myers等人,WO95/15758和Myers等人,Bioorg.Med.Chem.Lett.1997,7,417)。 Researchers have been disclosed in the micromolar - inhibit Lck in the low micromolar concentration under sub-series of 4-substituted quinazoline (Myers et al, WO95 / 15758 and Myers, et al., Bioorg.Med.Chem.Lett.1997, 7,417). Pfizer的研究人员(Hanke等人,J.Biol.Chem.1996,271,695)公开了具有抗Lck和Fyn(另一Src家族激酶)的低毫微摩尔效力的称为PP1和PP2的两种具体吡唑并嘧啶抑制剂。 Researchers at Pfizer (Hanke et al., J.Biol.Chem.1996,271,695) disclose two with anti-Lck and Fyn (another Src family kinases) is referred to as the low nanomolar potency of PP1 and PP2 specific pyrazolopyrimidine inhibitors. 没有报道过任何关于基于喹啉或喹喔啉的化合物的Lck抑制剂。 There are no reports on any Lck inhibitor compound quinoline or quinoxaline based. 因此,预计基于喹啉或喹喔啉的Lck酪氨酸激酶活性抑制剂可用于治疗多种表面上看来无关的、但是特征是在其病因中涉及Lck酪氨酸激酶信号传导的人类病症。 Thus, based on expected quinoline or quinoxaline of Lck tyrosine kinase activity inhibitors are useful for treating a variety of seemingly unrelated, but is characterized by involving Lck tyrosine kinase signaling in their etiology of human diseases.

发明概述本发明涉及式I化合物、其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐: Summary of the Invention The present invention relates to compounds of formula I, their N- oxides, hydrates, solvates thereof, prodrugs thereof, or a pharmaceutically acceptable salt thereof: 其中X是L1H或L2Z2;L1是(CR3aR3b)r或(CR3aR3b)m-Z3-(CR3'aR3'b)n;L2是(CR3aR3b)p-Z4-(CR3'aR3'b)q或乙烯基;Z1是CH或N;Z2是任选取代的环烷基、任选取代的环烯基、任选取代的杂环基或任选取代的杂环烯基;Z3是O、NR4、S、SO或SO2;Z4是O、NR4、S、SO、SO2、或一个键;m是0或1;n是2或3,且n+m=2或3;p和q独立地为0、1、2、3或4,并且当Z4是一个键时,p+q=0、1、2、3或4,当Z4不是一个键时,p+q=0、1、2或3;r是2、3或4;R1a和R1b独立地为任选取代的烷基、任选取代的芳基、任选取代的杂芳基、羟基、酰氧基、任选取代的烷氧基、任选取代的环烷氧基、任选取代的杂环氧基、任选取代的杂环基羰基氧基、任选取代的芳氧基、任选取代的杂芳氧基、氰基、R5R6N-或酰基R5N-,或者R1a和R1b当中一个是氢或卤素,另一个是任选取代的烷基、任选取代的芳基、任选取代的杂芳基、羟基、酰氧基、任选取代的烷氧基、任选取代的环烷氧基、任选取代的杂环氧基、任选取代的杂环基羰基氧基、任选取代的芳氧基、任选取代的杂芳氧基、氰基、R5R6N-或酰基R5N-;R1c是氢、任选取代的烷基、任选取代的芳基、任选取代的杂芳基、羟基、酰氧基、任选取代的烷氧基、任选取代的环烷氧基、任选取代的杂环氧基、任选取代的芳氧基、任选取代的杂芳氧基、卤素、氰基、R5R6N-或酰基R5N-;R3a、R3b、R3'a和R3'b独立地为氢或烷基;R4是氢、烷基或酰基;且R5和R6独立地为氢或烷基,或者R5和R6与它们所连接的氮原子一起形成氮杂杂环基。 Wherein X is L1H or L2Z2; L1 is (CR3aR3b) r or (CR3aR3b) m-Z3- (CR3'aR3'b) n; L2 is (CR3aR3b) p-Z4- (CR3'aR3'b) q or ethenyl ; Z1 is CH or N; Z2 is an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl or optionally substituted heterocyclenyl; Z3 is O, NR4, S, SO or SO2; Z4 is O, NR4, S, SO, SO2, or a bond; m is 0 or 1; n is 2 or 3, and n + m = 2 or 3; p and q are independently 0, 1 , 2, 3 or 4, and when Z4 is a bond when, p + q = 0,1,2,3 or 4 when Z4 is not a bond, p + q = 0,1,2 or 3; r is 2, 3 or 4; R1a and R1b are independently optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted heterocyclic oxy, optionally substituted heterocyclyl carbonyl group, an optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, R5R6N- or acyl R5N-, or R1a and R1b which one is hydrogen or halogen, and the other is an optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted heterocyclic oxy, optionally substituted heterocyclyl carbonyl group, an optionally substituted aryloxy, optionally substituted heteroaryloxy, cyano, R5R6N- or acyl R5N-; R1c is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyloxy, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted heterocyclic oxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, halo, cyano, R5R6N- or acyl R5N-; R3a, R3b , R3'a and R3'b independently hydrogen or alkyl; R4 is hydrogen, an alkyl group or an acyl group; and R5 and R6 are independently hydrogen or alkyl, or R5 and R6 and the nitrogen atom to which they are attached form aza-heterocyclic group.

本发明另一方面涉及含有药物学有效量的式I化合物或其可药用盐和可药用载体的药物组合物。 Aspect of the invention relates to a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier A pharmaceutical composition comprising a compound of formula I or a pharmaceutically effective amount. 本发明还涉及用于制备式I化合物的中间体,制备所述中间体和式I化合物的方法,以及式I化合物在治疗患有或易患有涉及细胞分化、增殖、细胞外基质产生或介质释放和/或T细胞活化和增殖的疾病/病症的患者中的应用。 The present invention also relates to intermediates for the preparation of compounds of formula I, methods for preparing the compound I and the intermediates of formula and the compound of formula I in treating a patient suffering from or susceptible involved in cell differentiation, proliferation, extracellular matrix production or medium release and / or in a patient by T cell activation and proliferation diseases / disorders.

发明详述除非另有说明,否则在上文和整个本发明说明书中使用的下述术语具有下述含义:定义“患者”包括人和其它哺乳动物。 DETAILED DESCRIPTION OF THE INVENTION Unless otherwise stated, the following terms used in the present invention described above and throughout the specification have the following meanings: Definitions "Patient" includes both human and other mammals.

“有效量”是指能有效抑制PDGF-R酪氨酸激酶活性和/或Lck酪氨酸激酶活性、从而产生期望疗效的本发明化合物的量。 "Effective amount" refers to effectively inhibit PDGF-R tyrosine kinase activity and / or Lck tyrosine kinase activity, resulting in the desired therapeutic effect of the amount of the compounds of the present invention.

“烷基”是指具有约1-约10个碳原子的支链或直链脂族烃基。 "Alkyl" refers to a branched or straight chain aliphatic hydrocarbon group having from about 1 to about 10 carbon atoms. 优选的烷基是具有约1-约6个碳原子、更优选具有约1-约4个碳原子的“低级烷基”。 Preferred alkyl groups having from about 1 to about 6 carbon atoms, more preferably from about 1 to about 4 carbon atoms, "lower alkyl." 支链是指一个或多个低级烷基例如甲基、乙基或丙基接在直链烷基链上。 Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl connected to the linear alkyl chain. 烷基还可任选被烷氧基、卤素、羧基、羟基或R5R6N-取代。 Alkyl may optionally be substituted alkoxy, halogen, carboxy, hydroxy or R5R6N-. 烷基的实例包括甲基、氟甲基、二氟甲基、三氟甲基、乙基、正丙基、异丙基、丁基、仲丁基、叔丁基、戊基和己基。 Examples of alkyl groups include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.

“链烯基”是指含有碳-碳双键、在链中具有约2-约10个碳原子的直链或支链脂族烃基。 "Alkenyl" means a carbon - straight-chain or branched aliphatic hydrocarbon-carbon double bond, having from about 2 to about 10 carbon atoms in the chain. 优选的链烯基在链中具有2-约6个碳原子;更优选在链中具有约2-约4个碳原子。 Preferred alkenyl groups having from 2 to about 6 carbon atoms in the chain; and more preferably in the chain having from about 2 to about 4 carbon atoms. 支链是指一个或多个低级烷基例如甲基、乙基或丙基接在直链链烯基链上。 Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl connected to the straight alkenyl chain. “低级链烯基”是指在直链或支链的链中具有约2-约4个碳原子。 "Lower alkenyl" means about 2 to about 4 carbon atoms in a straight chain or branched chain. 链烯基可被烷氧羰基取代。 Alkenyl group may be substituted with an alkoxycarbonyl group. 链烯基的实例包括乙烯基、丙烯基、正丁烯基、异丁烯基、3-甲基丁-2-烯基、正戊烯基、庚烯基、辛烯基、环己基丁烯基和癸烯基。 Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexyl-butylene group and decenyl.

“1,2-亚乙烯基(ethylenyl)”是指-CH=CH-。 "Vinylene (ethylenyl)" means -CH = CH-.

“环烷基”是指具有约3-约10个碳原子的非芳族单环或多环环状系统。 "Cycloalkyl" means a non-aromatic having from about 3 to about 10 carbon atoms, monocyclic or polycyclic ring system. 作为变量R1a、R1b或R1c一部分的环烷基可任选被一个或多个、优选1-3个、更优选1-2个下述“环烷基的取代基”取代:烷基、羟基、酰氧基、烷氧基、卤素、R5R6N-、酰基R5N-、羧基或R5R6NCO-取代基,或者在邻近碳原子上被二价氧(-O-)取代以形成环氧化物,更优选的取代基是烷基、羟基、酰氧基、烷氧基、二价氧和R5R6NCO-。 As variables R1a, R1b or R1c portion cycloalkyl can be optionally substituted with one or more, preferably 1-3, more preferably 1 to 2 of the following "cycloalkyl substituents" substituted: alkyl, hydroxy, acyloxy, alkoxy, halo, R5R6N-, acyl R5N-, carboxy or R5R6NCO- substituents, or on adjacent carbon atoms are divalent oxygen (-O-) to form a substituted epoxide, more preferred substituents are alkyl, hydroxy, acyloxy, alkoxy, bivalent oxygen and R5R6NCO-. 作为变量Z2一部分的环烷基可任选被一个或多个、优选1-3个、更优选1-2个下述“环烷基的取代基”取代:烷基、烷氧基、卤素、R5R6N-、酰基R5N-、羧基或R5R6NCO-取代基,或者在邻近碳原子上被二价氧(-O-)取代以形成环氧化物,更优选的取代基是烷基、羟基、酰氧基、烷氧基、二价氧和R5R6NCO-。 As part of the variable Z2 cycloalkyl optionally substituted with one or more, preferably 1-3, more preferably 1 to 2 of the following "cycloalkyl substituents" substituted: alkyl, alkoxy, halogen, R5R6N-, acyl R5N-, carboxy or R5R6NCO- substituents, or a bivalent oxygen on the adjacent carbon atom (-O-) to form a substituted epoxide, more preferred substituents are alkyl, hydroxy, acyloxy , alkoxy, bivalent oxygen and R5R6NCO-. 此外,当环烷基被至少两个羟基取代基取代时,则至少两个羟基取代基可以与具有1-6个碳原子的醛或酮发生缩酮化或缩醛化作用,以形成相应的缩酮或缩醛。 Further, when a cycloalkyl group is substituted with at least two hydroxy substituents, then at least two hydroxyl groups may be substituted having 1 to 6 carbon atoms, an aldehyde or ketal or acetal of ketone action occurs, to form the corresponding ketal or acetal. 偕二醇的缩酮化导致形成螺稠合环系。 Kai glycol ketal leads form a spiro-fused ring system. 优选的螺环烷基环是1,4-二氧杂螺[4,5]癸-8-基。 A preferred spiro cycloalkyl ring is 1,4-dioxa-spiro [4.5] dec-8-yl. 优选的未取代或取代的单环环烷基环包括环戊基、氟环戊基、环己基和环庚基;更优选环己基和环戊基。 Preferred unsubstituted or substituted monocyclic cycloalkyl rings include cyclopentyl, fluoro cyclopentyl, cyclohexyl and cycloheptyl; more preferably cyclohexyl and cyclopentyl. 多环环烷基环的实例包括1-十氢化萘、金刚烷(1-或2-)基、[2.2.1]二环庚烷基(降冰片基)和[2.2.2]二环辛烷基;更优选[2.2.1]二环庚烷基和[2.2.2]二环辛烷基。 Examples of polycyclic cycloalkyl rings include 1-decalin, adamantane (1- or 2-) yl, [2.2.1] bicyclo heptanyl (norbornyl) and [2.2.2] oct-bicyclo alkyl; more preferably [2.2.1] heptyl group and a bicyclic [2.2.2] bicyclic octyl.

“环烯基”是指包含碳-碳双键、并具有约3-约10个碳原子的非芳族单环或多环环状系统。 "Cycloalkenyl" means containing a carbon - carbon double bond, and having from about 3 to about 10 carbon atoms, a non-aromatic monocyclic or polycyclic ring system. 作为变量R1a、R1b或R1c一部分的环烯基可任选被一个或多个、优选1-3个、更优选1-2个如上所述的环烷基的取代基取代。 As variables R1a, R1b or R1c part cycloalkenyl group can be optionally substituted with one or more, preferably 1-3, more preferably 1-2 cycloalkyl group as described above substituents. 作为变量Z2一部分的环烯基可任选被一个或多个、优选1-3个、更优选1-2个如上所述的环烷基的取代基取代。 As part of the variable Z2 cycloalkenyl group can be optionally substituted with one or more, preferably 1-3, more preferably 1-2 cycloalkyl group as described above substituents. 优选的未取代或取代的单环环烯基环包括环戊烯基、环己烯基和环庚烯基;更优选环戊烯基和环己烯基。 Preferred unsubstituted or substituted monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl and cycloheptenyl; more preferably cyclopentenyl and cyclohexenyl. 优选的多环环烯基环包括[2.2.1]二环庚烯基(降冰片烯基)和[2.2.2]二环辛烯基。 Preferred polycyclic cycloalkenyl rings include [2.2.1] bicyclo heptenyl (norbornenyl) and [2.2.2] bicyclo-octenyl.

“芳基”是指包含约6-约10个碳原子的芳族碳环基团。 "Aryl" refers to contain from about 6 to about 10 carbon atoms, an aromatic carbocyclic group. 芳基的实例包括苯基或萘基,或者被一个或多个相同或不同的芳基的取代基取代的苯基或萘基,其中“芳基的取代基”包括氢、羟基、卤素、烷基、烷氧基、羧基、烷氧羰基或Y1Y2NCO-,其中Y1和Y2独立地为氢或烷基。 Examples of aryl groups include phenyl or naphthyl, or substituted with one or more identical or different substituents of the aryl group substituted with a phenyl or naphthyl group, wherein "aryl group substituent" includes hydrogen, hydroxy, halogen, alkoxy group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group or Y1Y2NCO-, wherein Y1 and Y2 are independently hydrogen or alkyl. 优选的芳基的取代基包括氢、卤素和烷氧基。 Preferred aryl group substituents include hydrogen, halogen and alkoxy.

“杂芳基”是指约5元-约10元芳族单环或多环烃环状系统,其中环状系统中的一个或多个碳原子是非碳元素,例如氮、氧或硫。 "Heteroaryl" refers to a 5-dollar - about 10 membered aromatic monocyclic or polycyclic hydrocarbon ring system, wherein the ring system one or more carbon atoms non-carbon elements, such as nitrogen, oxygen or sulfur. 作为前缀加在杂芳基前面的氮杂、氧杂或硫杂称谓是定义分别存在至少一个氮原子、氧原子或硫原子作为环原子。 Added as a prefix in front of the heteroaryl aza, oxa or thia title is defined at least one nitrogen atom, an oxygen atom or a sulfur atom, respectively, as a ring atom. “杂芳基”也可以被一个或多个如上所述的“芳基的取代基”取代。 "Heteroaryl" may also be as described above with one or more "aryl group substituents" substituted. 杂芳基的实例包括取代的吡嗪基、呋喃基、噻吩基、吡啶基、嘧啶基、异噁唑基、异噻唑基、噁唑基、噻唑基、吡唑基、呋咱基、吡咯基、咪唑并[2,1-b]噻唑基、苯并呋咱基、吲哚基、吖吲哚基、苯并咪唑基、苯并噻吩基、喹啉基、咪唑基和异喹啉基。 Examples of heteroaryl groups include substituted pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl imidazo [2,1-b] thiazolyl, benzofurazanyl, indolyl, acridine indolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl and isoquinolinyl.

“杂环基”是指约4元-约10元单环或多环环状系统,其中环状系统中的一个或多个原子是选自氮、氧和硫的非碳元素。 "Heterocyclyl" refers to about 4 yuan - about 10-membered monocyclic or polycyclic ring system, wherein the ring system one or more atoms are selected from nitrogen, oxygen and sulfur, non-carbon elements. 作为变量R1a、R1b或R1c一部分的杂环基可任选被一个或多个、优选1-3个、更优选1-2个如上所述的环烷基的取代基取代。 As variables R1a, R1b or R1c part heterocyclyl may be optionally substituted with one or more, preferably 1-3, more preferably 1-2 cycloalkyl group as described above substituents. 作为变量Z2一部分的杂环基可任选被一个或多个、优选1-3个、更优选1-2个如上所述的环烷基的取代基取代。 As part of the variable Z2 heterocyclyl may be optionally substituted with one or more, preferably 1-3, more preferably 1-2 cycloalkyl group as described above substituents. 作为前缀加在杂环基前面的氮杂、氧杂或硫杂称谓是定义分别存在至少一个氮原子、氧原子或硫原子作为环原子。 Added as a prefix in front of the heterocyclic group aza, oxa or thia title is defined at least one nitrogen atom, an oxygen atom or a sulfur atom, respectively, as a ring atom. 单环杂环基的实例包括哌啶基、吡咯烷基、哌嗪基、吗啉基、硫代吗啉基、噻唑烷基、1,3-二氧杂环戊烷基(1,3-dioxolanyl)、1,4-二氧杂环己烷基(1,4-dioxanyl)、四氢呋喃基、四氢噻吩基、四氢噻喃基等。 Examples of monocyclic heterocyclyl groups include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl (1,3- dioxolanyl), 1,4- dioxane-yl (1,4-dioxanyl), tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl and the like. 杂环基部分的实例包括奎宁环基(quinuclidyl)、硫杂己环、四氢吡喃基、四氢噻吩基、吡咯烷基、四氢呋喃基、7-氧杂二环[2.2.1]庚烷基、或4-哌啶子基哌啶。 Examples of heterocyclyl moieties include quinuclidinyl (quinuclidyl), thiahexanoic ring, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydrofuranyl, 7-oxa-bicyclo [2.2.1] hept- alkyl group, or a 4-piperidino-piperidine.

“杂环基羰基氧基”是指杂环基-C(O)O-,其中杂环基如本文所定义。 "Heterocyclic carbonyl group" means a heterocyclic group -C (O) O-, wherein heterocyclyl is as defined herein. 杂环基羰基氧基的实例是[1,4']-联哌啶基-1'-羰基氧基(4-哌啶子基哌啶-1-基羰基氧基)。 Examples of the heterocyclic carbonyl group is [1,4 '] - bipiperidinyl-1'-carbonyl group, (4-piperidino-piperidine-1-carbonyloxy).

“杂环烯基”是指约4元-约10元部分不饱和单环或多环环系,其中环系中的一个或多个原子是选自氮、氧和硫的非碳元素。 "Heterocycloalkenyl" refers to about 4 yuan - about 10 membered partially unsaturated monocyclic or polycyclic ring system, wherein the ring system of one or more atoms are selected from nitrogen, oxygen and sulfur, non-carbon elements. 作为变量R1a、R1b或R1c一部分的杂环烯基可任选被一个或多个、优选1-3个、更优选1-2个如上所述的环烷基的取代基取代。 As variables R1a, R1b or R1c part heterocyclenyl may be optionally substituted with one or more, preferably 1-3, more preferably 1-2 cycloalkyl group as described above substituents. 作为变量Z2一部分的杂环烯基可任选被一个或多个、优选1-3个、更优选1-2个如上所述的环烷基的取代基取代。 As part of the variable Z2 heterocyclenyl may be optionally substituted with one or more, preferably 1-3, more preferably 1-2 cycloalkyl group as described above substituents. 作为前缀加在杂环烯基前面的氮杂、氧杂或硫杂称谓是定义分别存在至少一个氮原子、氧原子或硫原子作为环原子。 Added as a prefix in front of the heterocyclenyl aza, oxa or thia title is defined at least one nitrogen atom, an oxygen atom or a sulfur atom as a ring atom, respectively. 单环氮杂杂环烯基的实例包括1,2,3,4-四氢吡啶基、1,2-二氢吡啶基、1,4-二氢吡啶基、1,2,3,6-四氢吡啶基、1,4,5,6-四氢嘧啶基、2-吡咯啉基、3-吡咯啉基、2-咪唑啉基、2-吡唑啉基等。 Examples of monocyclic aza heterocycloalkenyl groups include 1,2,3,4-tetrahydropyridyl, 1,2-dihydro-pyridyl, 1,4-dihydro-pyridyl, 1,2,3,6- tetrahydro-pyridinyl, 1,4,5,6-tetrahydro-pyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2- imidazolinyl, 2-pyrazoline-yl and the like. 氧杂杂环烯基的实例包括3,4-二氢-2H-吡喃、二氢呋喃基、和氟二氢呋喃基。 Examples oxa heterocyclenyl groups include 3,4-dihydro -2H- pyran, dihydro-furyl, dihydro-furyl, and fluoro. 多环氧杂杂环烯基的实例是7-氧杂二环[2.2.1]庚烯基。 Examples of polyepoxy heteroaryl heterocyclenyl is 7- oxabicyclo [2.2.1] heptenyl. 单环硫杂杂环烯基的实例包括二氢噻吩基和二氢噻喃基。 Examples of monocyclic thia heterocycloalkenyl groups include dihydro-thienyl and dihydro-thiopyranyl.

“酰基”是指H-CO-或烷基-CO-,其中烷基如上所定义。 "Acyl" means H-CO- or alkyl -CO-, wherein alkyl is as defined above. 优选的酰基包含低级烷基。 Preferred acyls contain a lower alkyl. 酰基的实例包括甲酰基、乙酰基、丙酰基、2-甲基丙酰基、丁酰基和己酰基。 Examples of acyl groups include formyl, acetyl, propionyl, 2-methyl-propionyl, butanoyl and hexanoyl.

“芳酰基”是指芳基-CO-,其中烷基如上所定义。 "Aroyl" means an aryl--CO-, wherein alkyl is as defined above. 其实例包括苯甲酰基与1-萘甲酰基和2-萘甲酰基。 Examples thereof include benzoyl and 1-naphthoyl and 2-naphthoyl.

“烷氧基”是指烷基-O-,其中烷基如上所定义。 "Alkoxy" refers to alkyl -O-, where alkyl is as defined above. 优选的烷氧基是具有约1-约6个碳原子的“低级烷氧基”。 Preferred alkoxy groups having from about 1 to about 6 carbon atoms, "lower alkoxy." 烷氧基可任选被一个或多个氨基、烷氧基、羧基、烷氧羰基、羧基芳基、氨基甲酰基或杂环基取代。 Alkoxy optionally substituted with one or more amino, alkoxy, carboxy, alkoxycarbonyl, carboxyaryl, carbamoyl or heterocyclic group. 烷氧基的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、庚氧基、2-(吗啉-4-基)乙氧基、2-(乙氧基)乙氧基、2-(4-甲基哌嗪-1-基)乙氧基、氨基甲酰基、N-甲基氨基甲酰基、N,N-二甲基氨基甲酰基、羧基甲氧基和甲氧基羰基甲氧基。 Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, heptoxy, 2- (morpholin-4-yl) ethoxy, 2- ( ethoxy) ethoxy, 2- (4-methyl-piperazin-1-yl) ethoxy, carbamoyl, N- methylcarbamoyl, N, N- dimethylcarbamoyl group, a carboxyl group methoxy and methoxycarbonyl methoxy.

“环烷氧基”是指环烷基-O-,其中环烷基如上所定义。 "Cycloalkoxy" means a cycloalkyl -O-, wherein cycloalkyl is as defined above. 环烷氧基的实例包括环戊基氧基和环己基氧基。 Examples of cycloalkoxy groups include cyclopentyloxy and cyclohexyloxy.

“杂环氧基”是指杂环基-O-,其中杂环基如上所定义。 "Heterocyclic group" means a heterocyclic group -O-, wherein heterocyclyl is defined as above. 杂环氧基的实例包括奎宁环氧基、硫杂己环氧基、四氢吡喃基氧基、四氢噻吩基氧基、吡咯烷基氧基、四氢呋喃基氧基和7-氧杂二环[2.2.1]庚烷氧基。 Examples of the heterocyclic group include quinuclidinyloxy, thiahexanoic epoxy group, tetrahydropyranyl group, a tetrahydrothienyl group, a pyrrolidinyl group, tetrahydrofuranyl group and 7-oxa- [2.2.1] heptane group.

“芳氧基”是指芳基-O-,其中芳基如上所定义。 "Aryloxy" refers to an aryl group -O-, wherein aryl is as defined above.

“杂芳氧基”是指杂芳基-O-,其中杂芳基如上所定义。 "Heteroaryl group" refers to a heteroaryl group -O-, wherein heteroaryl is as defined above.

“酰氧基”是指酰基-O-,其中酰基如上所定义。 "Acyloxy" means an acyl group -O-, wherein the acyl group as defined above.

“羧基”是指HO(O)C-(羧酸)基。 "Carboxy" refers to HO (O) C- (carboxylic acid) group.

“R5R6N-”是指取代或未取代的氨基,其中R5和R6如上所定义。 "R5R6N-" means a substituted or unsubstituted amino group, wherein R5 and R6 are defined as above. 其实例包括氨基(H2N-)、甲基氨基、乙基甲基氨基、二甲基氨基和二乙基氨基。 Examples thereof include amino (H2N-), methylamino, ethylmethylamino, dimethylamino and diethylamino.

“R5R6NCO-”是指取代或未取代的氨基甲酰基,其中R5和R6如上所定义。 "R5R6NCO-" means a substituted or unsubstituted carbamoyl group, wherein R5 and R6 are defined as above. 其实例是氨基甲酰基(H2NCO-)、N-甲基氨基甲酰基(MeNHCO-)、和N,N-二甲基氨基甲酰基(Me2NCO-)。 Examples thereof are carbamoyl (H2NCO -), N- methylcarbamoyl (MeNHCO-), and N, N- dimethyl-carbamoyl (Me2NCO-).

“酰基R5N-”是指酰基氨基,其中R5和酰基如上所定义。 "Acyl R5N-" refers to an acyl group, wherein R5 and acyl are as defined above.

“卤素”是指氟、氯、溴或碘。 "Halogen" refers to fluoro, chloro, bromo or iodo. 优选氟、氯或溴,更优选氟或氯。 Preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

“前药”是指式I化合物这样的形式,它们适于给患者施用,不引起不适的毒性、刺激、过敏反应等,并能有效地实现其预期应用,包括缩酮、酯和两性离子形式。 "Prodrug" refers to the form of such a compound of formula I, which are adapted to be administered to a patient without causing discomfort toxicity, irritation, allergic response, and can be effective for their intended use, including ketal, ester and zwitterionic forms . 前药在体内转化成式I母体化合物,例如通过在血液中水解转化成母化合物。 Prodrug converted in vivo to the parent compound of formula I, for example by hydrolysis in blood is converted to the parent compound. T.Higuchi和V.Stella,“作为新的递送系统的前药”(Pro-drues as Novel DeliverySvstems),the ACSSymposium Series第14卷,和Edward B.Roche,编,“药物设计中生物可逆转的载体”(Bioreversible Carriers in Drug Design),AmericanPharmaceutical Association and Pergamon Press,1987中对前药作了充分论述,二者引入本发明以作参考。 T.Higuchi and V.Stella, "as the new prodrug delivery system" (Pro-drues as Novel DeliverySvstems), the ACSSymposium Series Vol. 14, and Edward B.Roche, ed., "Drug Design biological reversible vector "(Bioreversible Carriers in Drug Design), AmericanPharmaceutical Association and Pergamon Press, 1987 has been fully in discussion of prodrugs, both incorporated herein by reference.

“溶剂合物”是指本发明化合物与一个或多个溶剂分子形成的物理结合体。 "Solvate" refers to the physical compound with one or more solvent molecules of the present invention to form a joint body. 该物理结合体涉及不同程度的离子键和共价键,包括氢键。 This physical association involves varying degrees of ionic body and covalent bonding, including hydrogen bonding. 在某些情况下,例如当一个或多个溶剂分子掺入到结晶固体的晶格中时,溶剂合物能被分离出来。 In some cases, for example when one or more solvent molecules are incorporated into the crystalline lattice of the solid, solvate can be isolated. “溶剂合物”包括溶液相和可分离溶剂合物。 "Solvate" encompasses both solution-phase and isolatable solvates. 溶剂合物的实例包括乙醇合物、甲醇合物等。 Examples of solvates include ethanolate, methanolate and the like. “水合物”是溶剂分子是H2O的溶剂合物。 "Hydrate" is a solvent molecule is H2O solvate.

另外优选的本发明化合物是定义如下的式I化合物、其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐,其中X是L2Z2;L2是(CR3aR3b)p-Z4-(CR3'aR3'b)q;Z2是任选取代的环烷基或任选取代的环烯基;Z3是O和NR4;p是0;q是0或1;R1a和R1b独立地为任选取代的烷基、任选取代的烷氧基、任选取代的环烷氧基、或任选取代的杂环氧基,或者R1a和R1b当中一个是氢或卤素;R1c是氢;R3'a和R3'b独立地为氢;且R4是氢。 Further preferred compounds of the present invention is a compound of formula I as defined below, its N- oxide, hydrate, solvate thereof, prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein X is L2Z2; L2 is (CR3aR3b) p-Z4- (CR3'aR3'b) q; Z2 is an optionally substituted cycloalkyl or optionally substituted cycloalkenyl; Z3 is O and NR4; p is 0; q is 0 or 1; R1a and R1b is independently an optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkoxy, or optionally substituted heterocyclic oxy group, or R1a and R1b is hydrogen or halo among; R1c is hydrogen; R3'a and R3'b independently hydrogen; and R4 is hydrogen.

另外优选的本发明化合物是L1H为低级烷基的式I化合物。 Further preferred compounds of the present invention is a compound of formula I L1H is lower alkyl.

另外优选的本发明化合物是Z1为CH的式I化合物。 Further preferred compounds of the present invention is a compound of formula I CH Z1 is.

另外优选的本发明化合物是Z1为N的式I化合物。 Further preferred compounds of the present invention is a compound of formula I N Z1 is.

另外优选的本发明化合物是Z2为任选取代的环烷基的式I化合物。 Further preferred compounds of the present invention is a compound of formula I Z2 is an optionally substituted cycloalkyl group.

另外优选的本发明化合物是Z2为烷基取代的单环环烷基、更优选为甲基环戊基或甲基环己基的式I化合物。 Further preferred compounds of the present invention, Z2 is alkyl substituted monocyclic cycloalkyl, compounds of formula I and more preferably methyl cyclopentyl or cyclohexyl methyl group.

另外优选的本发明化合物是Z2为多环环烷基、更优选为[2.2.1]二环庚烷基(降冰片烷基)和[2.2.2]二环辛烷基的式I化合物。 Further preferred compounds of the present invention is Z2 is a polycyclic cycloalkyl group, more preferably a [2.2.1] bicyclo heptanyl (norbornyl) and [2.2.2] bicyclic compounds of formula I octyl group.

另外优选的本发明化合物是Z2为任选取代的环烯基、更优选为环戊烯基和环己烯基的式I化合物。 Further preferred compounds of the present invention is to Z2 is an optionally substituted cycloalkenyl, more preferably cyclopentenyl and cyclohexenyl compound of formula I. 优选的多环环烯基包括[2.2.1]二环庚烯基(降冰片烯基)和[2.2.2]二环辛烯基。 Preferred polycyclic cycloalkenyl groups include [2.2.1] bicyclo heptenyl (norbornenyl) and [2.2.2] bicyclo-octenyl.

另外优选的本发明化合物是Z2为环戊烯基和环己烯基的式I化合物。 Further preferred compounds of the present invention is a compound of formula Z2 I cyclopentenyl and cyclohexenyl as.

另外优选的本发明化合物是Z2为多环环烯基、更优选为[2.2.1]二环庚烯基(降冰片烯基)和[2.2.2]二环辛烯基的式I化合物。 Further preferred compounds of formula I compounds of the present invention is Z2 is a polycyclic cycloalkenyl group, more preferably a [2.2.1] bicyclo hept-enyl (norbornenyl) and [2.2.2] bicyclo octene groups.

另外优选的本发明化合物是p和q为0的式I化合物。 Further preferred compounds of the present invention is a compound of formula I 0 of p and q.

另外优选的本发明化合物是p+q=1的式I化合物。 Further preferred compounds of the present invention is p + q = a compound of formula I 1.

另外优选的本发明化合物是Z4为0的式I化合物。 Further preferred compounds of the present invention is a compound of formula I 0 Z4 is.

另外优选的本发明化合物是Z4为O、且p和q为O的式I化合物。 Further preferred compounds of the present invention is to Z4 is O, and p and q are the compounds of formula I O.

另外优选的本发明化合物是Z4为O、且p+q=1的式I化合物。 Further preferred compounds of the present invention is to Z4 is O, and p + q = a compound of formula I 1.

另外优选的本发明化合物是Z4为NR4的式I化合物。 Further preferred compounds of the present invention is a compound of formula I NR4 Z4 is.

另外优选的本发明化合物是Z4为NR4、且p和q为0的式I化合物。 Further preferred compounds of the present invention is to Z4 is NR4, and the compound of formula I 0 of p and q.

另外优选的本发明化合物是Z4为NR4、且m+n=1的式I化合物。 Further preferred compounds of the present invention is to Z4 is NR4, and m + n = a compound of formula I 1.

另外优选的本发明化合物是Z4为S的式I化合物。 Further preferred compounds of the present invention is a compound of formula I S Z4 is.

另外优选的本发明化合物是Z4为S、且p和q为0的式I化合物。 Further preferred compounds of the present invention is to Z4 is S, and the compound of formula I 0 of p and q.

另外优选的本发明化合物是Z4为S、且p+q=1的式I化合物。 Further preferred compounds of the present invention is to Z4 is S, and p + q = a compound of formula I 1.

另外优选的本发明化合物是R1a和R1b独立地为任选被羟基取代的低级烷基、羟基、低级烷氧基、环烷氧基、杂环氧基,或者R1a和R1b中一个是氢或卤素的式I化合物。 Further preferred compounds of the present invention is to R1a and R1b are independently optionally hydroxy substituted lower alkyl, hydroxy, lower alkoxy, cycloalkoxy group, a heterocyclic oxy group, or R1a and R1b is hydrogen or a halogen the compound of formula I.

另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b独立地为杂环基羰基氧基或任选取代的低级烷氧基;更优选低级烷氧基为甲氧基或乙氧基。 Further preferred compounds of the present invention are compounds of formula I, wherein R1a and R1b are independently a carbonyl group or a heterocyclic group optionally substituted lower alkoxy; more preferably lower alkoxy is methoxy or ethoxy .

另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b为低级烷基;更优选低级烷基为甲基或乙基。 Further preferred compounds of the present invention are compounds of formula I, wherein R1a and R1b is lower alkyl; more preferably lower alkyl is methyl or ethyl.

另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b当中一个是低级烷氧基,另一个是卤素;更优选低级烷氧基为甲氧基或乙氧基,卤素为氯或溴。 Further preferred compounds of the present invention are compounds of formula I, wherein R1a and R1b which is a lower alkoxy, and the other is halogen; more preferably lower alkoxy is methoxy or ethoxy, halogen is chlorine or bromine .

另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b当中一个是低级烷基,另一个是低级烷氧基;更优选低级烷氧基为甲氧基或乙氧基,低级烷基为甲基或乙基。 Further preferred compounds of the present invention are compounds of formula I, wherein R1a and R1b which is a lower alkyl group, the other is a lower alkoxy group; more preferably lower alkoxy is methoxy or ethoxy, a lower alkyl group is methyl or ethyl.

另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b当中一个是低级烷氧基,另一个是环烷氧基;更优选低级烷氧基为甲氧基或乙氧基,环烷氧基为环戊氧基或环己氧基。 Further preferred compounds of the present invention are compounds of formula I, wherein R1a and R1b is lower alkoxy which one, the other is a cyclic alkoxy group; more preferably lower alkoxy is methoxy or ethoxy, cycloalkyl group is cyclopentyloxy or cyclohexyloxy.

另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b当中一个是氢,另一个是低级烷氧基、环烷氧基或杂环氧基;更优选低级烷氧基为甲氧基或乙氧基,环烷氧基为环戊氧基或环己氧基,且杂环氧基更优选为呋喃基氧基。 Further preferred compounds of the present invention are compounds of formula I, wherein R1a and R1b which one is hydrogen and the other is a lower alkoxy group, a cycloalkyl group or a heterocyclic group; more preferably lower alkoxy is methoxy or ethoxy group, a cycloalkyl group is cyclopentyloxy or cyclohexyloxy group, and a heterocyclic group and more preferably furyl group.

另外优选的本发明化合物是这样的式I化合物,其中R1c是氢、低级烷基或低级氧烷基;更优选低级烷氧基为甲氧基或乙氧基。 Further preferred compounds of the present invention are compounds of formula I, wherein R1c is hydrogen, lower alkyl or lower oxyalkyl; more preferably lower alkoxy is methoxy or ethoxy.

另外优选的本发明化合物是Z2为(羟基或烷基)取代的羟基环烷基、更优选为(低级烷基)羟基环烷基的式I化合物。 Further preferred compounds of the present invention is Z2 is (hydroxy or alkyl) substituted cycloalkyl, hydroxy, more preferably (lower alkyl) hydroxyl cycloalkyl group of compounds of formula I.

另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b是低级烷氧基,其中所述低级烷氧基可任选被烷氧基、杂环基、羧基、烷氧羰基或氨基甲酰基取代。 Further preferred compounds of the present invention are compounds of formula I, wherein R1a and R1b is lower alkoxy, wherein the lower alkoxy group which may optionally be substituted by alkoxy, a heterocyclic group, a carboxyl group, an alkoxycarbonyl group or a carbamoyl acyl substitution.

另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b当中一个是未取代的低级烷氧基,另一个是被烷氧基、杂环基、羧基、烷氧羰基或氨基甲酰基取代的低级烷氧基。 Further preferred compounds of the present invention are compounds of formula I, wherein one of R1a and R1b which is unsubstituted lower alkoxy, the other is a substituted alkoxy group, a heterocyclic group, a carboxyl group, an alkoxycarbonyl group or a carbamoyl group lower alkoxy.

另外优选的本发明化合物是这样的式I化合物,其中R1a和R1b当中一个是甲氧基,另一个是[1,4′-]-联哌啶-1′-基羰基氧基、2-(乙氧基)乙氧基、2-(4-吗啉基)乙氧基、2-(4-甲基哌嗪-1-基)乙氧基、羧基甲氧基、甲氧基羰基甲氧基、氨基羰基甲氧基、N-甲基氨基羰基甲氧基、或N,N-二甲基氨基羰基甲氧基。 Further preferred compounds of the present invention are compounds of formula I, wherein R1a and R1b which one is methoxy and the other is [1,4 '-] - bipiperidinyl-1'-carbonyl group, 2- ( ethoxy) ethoxy, 2- (4-morpholinyl) ethoxy, 2- (4-methyl-piperazin-1-yl) ethoxy, carboxy, methoxy, methoxycarbonyl-methoxy group, aminocarbonyl methoxy, N- methylaminocarbonyl, methoxy, or N, N- dimethyl-aminocarbonyl methoxy.

优选的本发明化合物选自:3-环己氧基-6,7-二甲氧基喹啉;2-环己基氨基-6,7-二甲氧基喹喔啉;外-二环[2.2.1]庚-2-基-(6-氯-7-甲氧基喹喔啉-2-基)胺;外-二环[2.2.1]庚-2-基-(7-氯-6-甲氧基喹喔啉-2-基)胺;二环[2.2.1]庚-2-基-(6,7-二甲基喹喔啉-2-基)胺;2-环庚基氨基-6,7-二甲氧基喹喔啉;2-环戊基氨基-6,7-二甲氧基喹喔啉;2-环己基氨基-6-甲氧基喹喔啉;3-氨基环己基-6,7-二甲氧基喹啉;(6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基环己基)胺;2-环己基氨基-6-甲氧基-7-溴喹喔啉盐酸盐;(6,7-二甲氧基喹啉-3-基)-顺式/反式-(3-(R)-甲基环己基)胺;(6,7-二甲氧基喹啉-3-基)-反式-(3-(R)-甲基-环己基)胺;(6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基-环己基)胺;(6.7-二甲氧基喹啉-3-基)-(3-甲基环戊基)胺;环己-3-烯基-(6,7-二甲氧基喹喔啉-2-基)胺;2,7-二环己氧基-6-甲氧基喹喔啉;环己基-(6,7-二甲氧基喹喔啉-2-基甲基)胺;(6,7-二甲氧基喹啉-3-基)异丁基胺;环己基-(6-甲氧基-7-吗啉-4-基喹喔啉-2-基)胺;()-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;外-二环[2.2.1]庚-5-烯-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;环己基-(6,8-二甲基喹喔啉-2-基)胺;内-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;(6,7-二甲氧基喹喔啉-2-基)-(4-甲氧基环己基)胺;外-二环[2.2.1]庚-2-基-(6-甲氧基喹喔啉-2-基)胺;外-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉;2-(二环[2.2.2]辛-2-基氧基)-6,7-二甲氧基喹喔啉;内-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉;外-2-(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉;2-(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉;2-环己氧基-6,7-二甲氧基喹喔啉;2-环戊硫基-6,7-二甲氧基喹喔啉;6,7-二甲氧基-2-环戊氧基喹喔啉;2-环戊基甲基氧基-6,7-二甲氧基喹喔啉;6,7-二甲氧基-2-四氢吡喃-4-氧基喹喔啉;外,外-6,7-二甲氧基-2-(5,6-环氧二环[2.2.1]庚烷-2-基氧基)喹喔啉;顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己烷甲酸;6,7-二甲氧基-2-(4-甲氧基-环己氧基)喹喔啉;3-环己氧基-6,7-二甲氧基喹喔啉1-氧化物;(1R,2R,4S)-(+)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;(1S,2S,4R)-(-)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;2-(6,7-二甲氧基喹喔啉-2-基)-2-氮杂-二环[2.2.2]辛烷-3-酮;顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸;顺式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;(6,7-二甲氧基喹喔啉-2-基)-顺式/反式-(3-(R)-甲基环己基)胺;(6,7-二甲氧基喹喔啉-2-基)-反式-(3-(R)-甲基环己基)胺;(6,7-二甲氧基喹喔啉-2-基)-顺式-(3-(R)-甲基环己基)胺;和顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己烷甲酸甲酯;或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 Preferred compounds of the present invention is selected from: 3-cyclohexyl-6,7-dimethoxy-quinoline; 2-cyclohexyl-6,7-dimethoxy-quinoxaline; outer - bicyclo [2.2 .1] hept-2-yl - (6-chloro-7-methoxy-quinoxalin-2-yl) amine; outer - bicyclo [2.2.1] hept-2-yl - (7-chloro-6 - methoxy-quinoxalin-2-yl) amine; bicyclo [2.2.1] hept-2-yl - (6,7-dimethyl-quinoxalin-2-yl) amine; 2- cycloheptyl amino-6,7-dimethoxy-quinoxaline; 2- cyclopentyl-6,7-dimethoxy-quinoxaline; 2-cyclohexyl-amino-6-methoxy-quinoxaline; 3- Amino-cyclohexyl-6,7-dimethoxy-quinoline; (6,7-dimethoxy-quinolin-3-yl) - cis - (3- (R) - methyl-cyclohexyl) amine; 2 - cyclohexyl-amino-6-methoxy-7-bromo-quinoxaline hydrochloride; (6,7-dimethoxy-quinolin-3-yl) - cis / trans - (3- (R) - methyl-cyclohexyl) amine; (6,7-dimethoxy-quinolin-3-yl) - trans - (3- (R) - methyl - cyclohexyl) amine; (6,7-dimethoxy oxy-quinolin-3-yl) - cis - (3- (R) - methyl - cyclohexyl) amine; (6,7-dimethoxy-quinolin-3-yl) - (3-methyl-cyclopentyl yl) amine; cyclohex-3-enyl - (6,7-dimethoxy-quinoxalin-2-yl) amine; 2,7-dicyclohexyl-6-methoxy-quinoxaline; cyclohexyl - (6,7-dimethoxy-quinoxalin-2-yl-methyl) amine; (6,7-dimethoxy-quinolin-3-yl) isobutylamine; cyclohexyl - (6 - methoxy-7-morpholin-4-quinoxalin-2-yl) amine; () - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-quinoline 2- yl) amine; outer - bicyclo [2.2.1] hept-5-en-2-yl - (6,7-dimethoxy-quinoxalin-2-yl) amine; cyclohexyl - (6,8-dimethyl-quinoxalin-2-yl) amine; the - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-quinoxalin-2-yl) amine; (6,7-dimethoxy-quinoxalin-2-yl) - (4-methoxy-cyclohexyl) amine; outer - bicyclo [2.2.1] hept-2-yl - (6- oxy quinoxalin-2-yl) amine; outer -2- (bicyclo [2.2.1] hept-2-yloxy) -6,7-dimethoxy-quinoxaline; 2- (bicyclo [2.2.2] oct-2-yloxy) -6,7-dimethoxy-quinoxaline; the 2- (bicyclo [2.2.1] hept-2-yloxy) -6,7 - dimethoxy-quinoxaline; outer -2- (bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxy-quinoxaline; 2- (di bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxy-quinoxaline; 2-cyclohexyl-6,7-dimethoxy-quinoxaline; 2- cyclopentylthio-6,7-dimethoxy quinoxaline; 6,7-dimethoxy-2-cyclopentyloxy-quinoxaline; 2- cyclopentylmethyl group -6, 7- dimethoxy-quinoxaline; 6,7-dimethoxy-2-tetrahydropyran-4-yloxy quinoxaline; outer, outer-6,7-dimethoxy-2- ( 5,6-epoxy-bicyclo [2.2.1] heptane-2-yloxy) quinoxaline; cis / trans-4- (6,7-quinoxaline-2-yl oxy) cyclohexanecarboxylic acid; 6,7-dimethoxy-2- (4-methoxy - cyclohexyloxy) quinoxaline; 3-cyclohexyl-6,7-dimethoxy quinoxaline-1-oxide; (1R, 2R, 4S) - (+) - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-quinoxalin-2-yl) amine; (1S, 2S, 4R) - (-) - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-quinoxalin-2-yl) amine; 2- (6 , 7-dimethoxy-quinoxalin-2-yl) -2-aza - bicyclo [2.2.2] octan-3-one; cis / trans-4- (6,7-dimethoxy oxy quinoxalin-2-ylamino) cyclohexane carboxylate; cis / trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid; cis -4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid methyl ester; trans-4- (6,7-dimethoxy-quinoxalin-2-yl amino) cyclohexanecarboxylic acid methyl ester; (6,7-dimethoxy-quinoxalin-2-yl) - cis / trans - (3- (R) - methyl-cyclohexyl) amine; (6, 7- dimethoxy-quinoxalin-2-yl) - trans - (3- (R) - methyl-cyclohexyl) amine; (6,7-dimethoxy-quinoxalin-2-yl) - cis - (3- (R) - methyl-cyclohexyl) amine; cis / trans-4- (6,7-dimethoxy-quinoxalin-2-yloxy) cyclohexane carboxylate ; or a N- oxide thereof, a hydrate thereof, a solvate, a prodrug, or a pharmaceutically acceptable salt thereof.

更优选的化合物是:2-环己基氨基-6,7-二甲氧基喹喔啉;外-二环[2.2.1]庚-2-基-(6-氯-7-甲氧基喹喔啉-2-基)胺;外-二环[2.2.1]庚-2-基-(7-氯-6-甲氧基喹喔啉-2-基)胺;二环[2.2.1]庚-2-基-(6,7-二甲基-喹喔啉-2-基)胺;2-环庚基氨基-6,7-二甲氧基喹喔啉;2-环戊基氨基-6,7-二甲氧基喹喔啉;3-氨基环己基-6,7-二甲氧基喹啉;(6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基-环己基)胺;(6,7-二甲氧基喹啉-3-基)-顺式/反式-(3-(R)-甲基-环己基)胺;(6,7-二甲氧基喹啉-3-基)-反式-(3-(R)-甲基环己基)胺;(6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基环己基)胺;环己-3-烯基-(6,7-二甲氧基喹喔啉-2-基)胺;2,7-二环己氧基-6-甲氧基喹喔啉;(6,7-二甲氧基喹啉-3-基)异丁基胺;()-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;外-二环[2.2.1]庚-5-烯-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;内-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;外-二环[2.2.1]庚-2-基-(6-甲氧基喹喔啉-2-基)胺;外-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉;2-(二环[2.2.2]辛-2-基氧基)-6,7-二甲氧基喹喔啉;内-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉;外-2-(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉;2-(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉;2-环己氧基-6,7-二甲氧基喹喔啉;2-环戊硫基-6.7-二甲氧基喹喔啉;6,7-二甲氧基-2-环戊氧基喹喔啉;2-环戊基甲氧基-6,7-二甲氧基喹喔啉;6,7-二甲氧基-2-四氢吡喃-4-氧基喹喔啉;外,外-6,7-二甲氧基-2-(5,6-环氧二环[2.2.1]庚烷-2-基氧基)喹喔啉;6,7-二甲氧基-2-(4-甲氧基-环己氧基)喹喔啉;(1R,2R,4S)-(+)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;(1S,2S,4R)-(-)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺;顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;顺式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯;(6,7-二甲氧基喹喔啉-2-基)-顺式/反式-(3-(R)-甲基环己基)胺;(6,7-二甲氧基喹喔啉-2-基)-反式-(3-(R)-甲基环己基)胺;(6,7-二甲氧基喹喔啉-2-基)-顺式-(3-(R)-甲基环己基)胺;顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己烷甲酸甲酯;或其N-氧化物、其水合物、其溶剂合物、其前药、或其可药用盐。 More preferred compounds are: 2-cyclohexyl-6,7-dimethoxy-quinoxaline; outer - bicyclo [2.2.1] hept-2-yl - (6-chloro-7-methoxy-quinoline 2- yl) amine; outer - bicyclo [2.2.1] hept-2-yl - (7-chloro-6-methoxy-quinoxalin-2-yl) amine; bicyclo [2.2.1 ] hept-2-yl - (6,7-dimethyl - quinoxalin-2-yl) amine; 2-heptyl-6,7-dimethoxy-quinoxaline; 2-cyclopentyl- amino-6,7-dimethoxy-quinoxaline; 3-amino-cyclohexyl-6,7-dimethoxy-quinoline; (6,7-dimethoxy-quinolin-3-yl) - cis - (3- (R) - methyl - cyclohexyl) amine; (6,7-dimethoxy-quinolin-3-yl) - cis / trans - (3- (R) - methyl - ring hexyl) amine; (6,7-dimethoxy-quinolin-3-yl) - trans - (3- (R) - methyl-cyclohexyl) amine; (6,7-dimethoxy-quinoline - 3- yl) - cis - (3- (R) - methyl-cyclohexyl) amine; cyclohex-3-enyl - (6,7-dimethoxy-quinoxalin-2-yl) amine; 2 , 7-dicyclohexyl-6-methoxy-quinoxaline; (6,7-dimethoxy-quinolin-3-yl) isobutylamine; () - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-quinoxalin-2-yl) amine; outer - bicyclo [2.2.1] hept-5-en-2-yl - (6,7-bis methoxy-quinoxalin-2-yl) amine; the - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-quinoxalin-2-yl) amine; outside - two bicyclo [2.2.1] hept-2-yl - (6-methoxy-quinoxalin-2-yl) amine; outer -2- (bicyclo [2.2.1] hept-2-yloxy) -6 , 7-dimethoxy-quinoxaline; 2- (bicyclo [2.2.2] oct-2-yloxy) -6,7-dimethoxy-quinoxaline; the 2- (bicyclo [ 2.2.1] hept-2-yloxy) -6,7-dimethoxy-quinoxaline; outer -2- (bicyclo [2.2.1] hept-5-en-2-yloxy) - 6,7-dimethoxy-quinoxaline; 2- (bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxy-quinoxaline; 2- hexyloxy-6,7-dimethoxy-quinoxaline; 2- cyclopentylthio-6,7-dimethoxy-quinoxaline; 6,7-dimethoxy-2-cyclopentyloxy-quinoxaline morpholine; 2- cyclopentyl-methoxy-6,7-dimethoxy-quinoxaline; 6,7-dimethoxy-2-tetrahydropyran-4-yloxy quinoxaline; outer, outer 6,7-dimethoxy-2- (5,6-epoxy-bicyclo [2.2.1] heptane-2-yloxy) quinoxaline; 6,7-dimethoxy-2- (4-methoxy - cyclohexyloxy) quinoxaline; (1R, 2R, 4S) - (+) - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy- quinoxalin-2-yl) amine; (1S, 2S, 4R) - (-) - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-quinoxalin-2 yl) amine; cis / trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid methyl ester; cis-4- (6,7-dimethoxy- yl quinoxalin-2-yl-amino) cyclohexane carboxylate; trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid methyl ester; (6, 7- dimethoxy-quinoxalin-2-yl) - cis / trans - (3- (R) - methyl-cyclohexyl) amine; (6,7-dimethoxy-quinoxalin-2 yl) - trans - (3- (R) - methyl-cyclohexyl) amine; (6,7-dimethoxy-quinoxalin-2-yl) - cis - (3- (R) - methyl cyclohexyl) amine; cis / trans-4- (6,7-dimethoxy-quinoxalin-2-yloxy) cyclohexane carboxylate; or a N- oxide thereof, a hydrate, solvate thereof, prodrug thereof, or a pharmaceutically acceptable salt thereof.

应当理解,本发明包括本文特定和优选组的所有适当组合。 It should be understood that the invention herein includes all appropriate combinations of particular and preferred groups.

本发明化合物可通过使用文献中已知的方法由已知化合物或易于制得的中间体制得。 The compounds of this invention may be prepared from known compounds or readily prepared by using an intermediate system known in the literature method. 一般方法的实例如下。 Examples of the general method is as follows.

此外,式I化合物是依据下述反应方案I-VIII制得的,其中各变量如上文所述,但是本领域技术人员可理解的与所述方法不相容的变量除外。 Furthermore, compounds of formula I is according to the following reaction schemes I-VIII prepared, wherein the variables are as described above, except with the method incompatible variable skilled in the art appreciated. 反应方案I Reaction scheme I 反应方案II Reaction scheme II 反应方案III Reaction scheme III 反应方案IV Reaction scheme IV 反应方案V Reaction scheme V 反应方案VI Reaction scheme VI 其中R1a、R1b和R1c当中至 其中R1a、R1b和R1c当中至少有一个是低级烷氧基, 少有一个如本文所定义,且X是L1OP'或L2Z2,其 且X是L1OP',然后除去保中P'是适于在碱和烷化剂 护基P'以生成相应的OH存在下保护羟基部分的保 部分护基在反应方案VI、VII和VIII中,R代表如本文所定义的R1a、R1b或R1c的前体基团,这样在反应方案VI、VII和VIII中所描述的条件下,RBr、ROH、或RCOCl与芳羟基的反应导致形成R1a、R1b或R1c。 Wherein R1a, R1b and R1c thereto among R1a, R1b and R1c which at least one is a lower alkoxy group, a rare as defined herein, and X is L1OP 'or L2Z2, thereof and X is L1OP', then removed Bulgaria P 'is a base and an alkylating agent suitable protecting group P' to form the corresponding protected hydroxy moiety presence of OH retaining portion protecting group in Reaction Scheme VI, VII and VIII, R represents R1a as defined herein, , R1b or R1c is a precursor group, so that in Reaction Scheme VI, VII and VIII in the conditions described, RBr, ROH, or RCOCl with the aromatic hydroxy group reaction results in the formation R1a, R1b or R1c. 代表性的RBr包括溴乙酸和溴乙酸甲酯与溴乙酸乙酯。 Representative RBr include bromoacetic acid and methyl bromoacetate and ethyl bromoacetate. 代表性的ROH包括2-乙氧基乙醇、2-(4-吗啉基)乙醇和3-(4-甲基哌嗪基)丙醇。 Representative ROH include 2-ethoxyethanol, 2- (4-morpholinyl) ethanol and 3- (4-methyl-piperazin-yl) propanol. 代表性的RCOCl是[1,4']-联哌啶-1'-基羰基氯。 Representative RCOCl is [1,4 '] - bipiperidinyl-1'-yl-carbonyl chloride. 反应方案VIII Reaction scheme VIII 反应方案VIII Reaction scheme VIII 反应方案IX Reaction scheme IX 反应方案X Reaction scheme X I.一般方法:1.将2-氯取代的喹喔啉与胺或苯胺偶联将2-氯-6,7-二甲氧基喹喔啉(1当量)与胺(约1-约5当量)的混合物在约160-约180℃加热约3小时至过夜。 I. General procedure: 1 mixture of 2-chloro substituted quinoxaline and amines or aniline was coupled to 2-chloro-6,7-dimethoxy quinoxaline (1 eq.) With an amine (about 1 to about 5 equiv.) was heated for about 3 hours at about 160 to about 180 ℃ to overnight. 将该深棕色残余物溶于甲醇/二氯甲烷(0%-10%)中,并通过硅胶色谱纯化,用己烷/乙酸乙酯或甲醇/二氯甲烷(0%-100%)洗脱,获得所需产物。 The dark brown residue was dissolved in methanol / methylene chloride (0% -10%), and purified by chromatography on silica gel with hexane / ethyl acetate or methanol / methylene chloride (0% -100%) to afford to give the desired product. 可通过在甲醇、二氯甲烷或甲醇/水中重结晶来将所需产物进一步纯化。 Can be prepared by methanol, dichloromethane, or methanol / water recrystallization The desired product was further purified. 2.将2-氯取代的喹喔啉与醇或苯酚偶联将醇或硫醇(1当量)与氢化钠(约1-约3当量)在无水DMF/THF(0%-50%)中的悬浮液回流1小时,然后加入2-氯-6,7-二甲氧基喹喔啉(1当量)。 2. 2-chloro substituted quinoxaline and alcohols or phenols coupling an alcohol or mercaptan (1 eq.) And sodium hydride (about 1 to about 3 equivalents) in anhydrous DMF / THF (0% -50%) The suspension was refluxed for 1 hour, then 2-chloro-6,7-dimethoxy-quinoxaline (1 eq.). 将所得混合物回流约1-约4小时。 The resulting mixture was refluxed for about 1 to about 4 hours. 将该悬浮液中和至约pH5-8,并在二氯甲烷与盐水之间分配。 The suspension was neutralized to about pH5-8, and partitioned between methylene chloride and brine. 将二氯甲烷浓缩后,通过硅胶色谱纯化残余物,用己烷/乙酸乙酯或甲醇/二氯甲烷(0%-100%)洗脱,获得所需产物。 After the dichloromethane was concentrated, the residue was purified by chromatography on silica gel with hexane / ethyl acetate or methanol / methylene chloride (0% -100%) to afford the desired product. 3.将氨基喹啉与醛或酮进行还原胺化反应将适当取代的3-氨基喹啉(1当量)与1当量合适的醛或酮在甲醇(或另一合适的溶剂混合物)中搅拌直至TLC表明亚胺形成已完全。 3. The amino-quinoline aldehyde or ketone with a reductive amination reaction to an appropriately substituted 3-amino quinoline (1 eq.) With an equivalent of an appropriate aldehyde or ketone was stirred in methanol (or another suitable solvent mixture) until TLC indicated that the imine formation was complete. 加入过量NaCNBH4或NaBH4、或另一种合适的还原剂,将该混合物搅拌直至TLC表明亚胺中间体已完全反应。 Addition of excess NaCNBH4 or NaBH4, or another suitable reducing agent, and the mixture was stirred until TLC indicated complete reaction intermediate imine. 将该混合物浓缩,通过硅胶色谱纯化残余物,用己烷/乙酸乙酯(0-100%)或氯仿/甲醇(0-20%)洗脱,获得所需产物。 The mixture was concentrated, the residue was purified by silica gel chromatography, or chloroform / methanol (0-20%) eluting with hexane / ethyl acetate (0-100%), to obtain the desired product. 4.将3-氨基取代的喹啉与溴苯基化合物偶联在惰性气氛例如氩气氛下,将适当取代的3-氨基喹啉(1当量)与~1.4当量强碱例如叔丁醇钠、1当量合适的溴苯基化合物、和催化量的2,2'-二(二苯基膦基)-1,1'-联萘(S-BINAP)与二(二亚苄基丙酮)钯(Pd(dba)2)搅拌混合在惰性有机溶剂例如甲苯中,并在约80℃加热过夜。 4. 3-amino substituted quinolines and bromophenyl compounds coupling under an inert atmosphere such as argon atmosphere, a suitably substituted 3-amino quinoline (1 eq.) And to 1.4 equivalents of a strong base such as sodium tert-butoxide, 1 equivalent of an appropriate bromophenyl compound, and catalytic amount of 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (S-BINAP) and bis (dibenzylidene acetone) palladium ( Pd (dba) 2) mixed with stirring in an inert organic solvent such as toluene and heated overnight at about 80 ℃. 将该混合物冷却,用溶剂例如乙醚稀释,过滤,浓缩并通过色谱法纯化,用50%EtOAc/己烷洗脱,获得所需产物。 The mixture was cooled, diluted with a solvent such as diethyl ether, filtered, concentrated and purified by chromatography eluting with 50% EtOAc / hexane to afford the desired product. 5.通过Mitsunobu条件由3-羟基取代的喹啉形成醚用各1当量的所需醇、三苯膦和最后的偶氮二甲酸二乙酯(DEAD)或适当的等同物处理适当取代的羟基喹喔啉的THF溶液(在约0-约25℃)。 5. The formation of ether and 1 equivalent of the desired alcohol by Mitsunobu conditions from 3-hydroxy substituted quinolines, triphenylphosphine and finally diethylazodicarboxylate (DEAD) or a suitable equivalent thereof treated appropriately substituted hydroxy quinoxaline in THF (about 0 to about 25 ℃). 通过TLC监测反应进程,反应完全后(约1-约24小时),将该混合物浓缩,通过硅胶色谱纯化残余物,获得所需产物。 The reaction progress was monitored by TLC, the reaction was complete (about 1 to about 24 hours), the mixture was concentrated, the residue was purified by silica gel chromatography to give the desired product. 6.低级烷氧基取代的喹啉或喹喔啉的脱烷基化、和随后的烷基化用过量乙硫醇钠(通常约2或更多当量)处理在DMF中的适当低级烷氧基取代的喹啉或喹喔啉(1当量),在搅拌下将该反应混合物加热约1-约24小时。 6. The lower alkoxy substituted quinoline or quinoxaline dealkylation, and subsequent alkylation with an excess of sodium ethyl mercaptan (usually about 2 or more eq.) And the appropriate lower alkoxy in DMF substituted quinoline or quinoxaline (1 eq.), stirring the reaction mixture was heated for about 1 to about 24 hours. 将该混合物在水与乙酸乙酯之间分配。 The mixture was partitioned between water and ethyl acetate. 萃取,如果需要的话然后进行色谱纯化,获得了相应的羟基取代的所需喹啉或喹喔啉产物。 Extract, if desired, then purified by chromatography, to obtain the corresponding desired hydroxy substituted quinoline or quinoxaline product.

可用如上所详述的Mitsunobu反应条件将所得羟基取代的喹啉或喹喔啉产物烷基化。 Available Mitsunobu reaction conditions as detailed above and the resulting hydroxy substituted quinoline or quinoxaline product of alkylation. 或者,采用本领域众所周知的方法,在合适的溶剂中使用NaH或另一适当碱,用活性烷基卤或苄基卤进行简单烷基化,以生成所需烷基化产物。 Alternatively, using methods well known in the art, in a suitable solvent using NaH or another appropriate base, simple alkylation with an active alkyl halide or benzyl halide to produce the desired alkylate product. 7.将喹啉或喹喔啉中的氮氧化成相应的N-氧化物。 7. quinoline or quinoxaline nitrogen oxidized to the corresponding N- oxide.

式(I)喹啉或喹喔啉化合物中的亚胺(=N-)部分可转化成该亚胺部分被氧化成N-氧化物的相应化合物,优选通过与过酸例如在乙酸中的过乙酸或在惰性溶剂例如二氯甲烷中的间氯过苯甲酸于约室温-回流温度、优选提高的温度下反应来进行氧化。 Of formula (I) quinoline or quinoxaline compound of imine (= N-) moiety may be converted to the imine moiety is oxidized to the corresponding N- oxide compound, preferably with a peracid such as peracetic in acetic acid acetic acid or in an inert solvent such as dichloromethane m-chloroperbenzoic acid at about room temperature - reflux temperature, preferably at an elevated temperature to an oxidation reaction.

游离碱或游离酸或可药用盐形式的本发明化合物都是有用的。 The free acid or free base or pharmaceutically acceptable salt form of compounds of the invention are useful. 所有这些形式都在本发明范围内。 All of these forms are within the scope of the present invention.

当本发明化合物被碱性部分取代时,可形成酸加成盐,并且其只是更便于使用的形式;实际上,使用该盐形式本质上相当于使用游离碱形式。 When the compounds of the present invention is substituted basic moiety, acid addition salts may be formed, and which is more convenient form for use; in practice, use of the salt form inherently amounts to use of the free base form. 可用于制备酸加成盐的酸优选包括当与游离碱合并时能生成可药用盐的酸,可药用盐是表示在该盐的药用剂量下其阴离子对患者没有毒性,这样该游离碱所固有的对PDGF的有益抑制作用就不被阴离子的副作用所失效。 Acid preferably can be used to prepare the acid addition salts include, when combined with the free base can form pharmaceutically acceptable salts of the acid, pharmaceutically acceptable salts are represented in pharmaceutical doses of the salts whose anions are not toxic to the patient, so that the free alkali inherent beneficial inhibitory effects on PDGF failure was not a side effect of the anion. 虽然所述碱性化合物的可药用盐是优选的,但是所有酸加成盐都可用作游离碱形式的来源,即使特定的盐自身仅作为中间产物而需要,例如形成该盐仅是为了纯化和鉴定,或者该盐用作通过离子交换方法制备可药用盐的中间体。 Although only the basic compound may be pharmaceutically acceptable salts are preferred, but all acid-addition salts can be used as sources of the free base form, even if the particular salt itself is required only as an intermediate product, for example in order to form the salt purification and identification, or the salt thereof used as intermediates in the preparation of pharmaceutically acceptable salts by ion exchange method. 在本发明范围内的可药用盐是用下述酸形成的盐:无机酸例如盐酸、硫酸、磷酸、和氨基磺酸;和有机酸例如乙酸、柠檬酸、乳酸、酒石酸、丙二酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环己基氨基磺酸、奎尼酸等。 Within the scope of the present invention, pharmaceutically acceptable salts are salts with the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexyl sulfamic acid, quinic acid and the like. 相应的酸加成盐分别包含下述盐:氢卤酸盐例如盐酸盐和氢溴酸盐,硫酸盐、磷酸盐、硝酸盐、氨基磺酸盐、乙酸盐、柠檬酸盐、乳酸盐、酒石酸盐、丙二酸盐、草酸盐、水杨酸盐、丙酸盐、琥珀酸盐、富马酸盐、马来酸盐、亚甲基二-β-羟基萘甲酸盐、2,5-二羟基苯甲酸盐、甲磺酸盐、羟乙基磺酸盐和二对甲苯甲酰基酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、环己基氨基磺酸盐和奎尼酸盐。 Corresponding acid addition salts comprise the following salts, respectively: hydrohalogenic acid salts such as hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate , tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene bis -β- hydroxy naphthoate, 2,5-dihydroxy benzoate, methanesulfonate, isethionate and di-p-toluoyl tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonic acid salts, cyclohexyl sulfamate and quinate.

依据本发明另一方面,本发明化合物的酸加成盐可通过使用已知方法或对已知方法作改动将游离碱与合适的酸反应而制得。 According to the present invention, on the other hand, the acid addition salts of the compounds of the present invention, the free base can be reacted with the appropriate acid prepared by using known methods or methods known to make changes. 例如,本发明化合物的酸加成盐可这样制得:将游离碱溶于含有适当酸的水溶液或含水醇溶液或其它合适溶剂中,并通过蒸发该溶液分离出所生成的盐;或者将游离碱与酸在有机溶剂中反应,在这种情况下,盐直接分离出来,或者可通过将溶液浓缩来获得盐。 For example, acid addition salts of the present compounds may be prepared: The free base was dissolved in an aqueous solution containing the appropriate acid or aqueous alcohol solution or other suitable solvent and evaporating the solution by the salt produced is separated; or the free base an acid in an organic solvent and, in this case the salt separates directly out, or may be obtained by the solution was concentrated salt.

通过使用已知方法或对已知方法作改动,可从酸加成盐再生出本发明化合物。 By using known methods or methods known to make changes, the compounds of the present invention can be regenerated from the acid addition salt thereof. 例如,本发明母体化合物可通过用碱例如碳酸氢钠水溶液或氨水溶液处理而从其酸加成盐再生出来。 For example, parent compounds of the invention may be, for example aqueous sodium bicarbonate solution or aqueous ammonia solution regenerated by treatment with a base from its acid addition salt.

当本发明化合物被酸性部分取代时,可形成碱加成盐,并且其只是更便于使用的形式;实际上,使用该盐形式本质上相当于使用游离酸形式。 When the compounds of the present invention is substituted acidic moiety, base addition salts may be formed, and it is more convenient form for use; in practice, use of the salt form inherently amounts to use of the free acid form. 可用于制备碱加成盐的碱优选包括当与游离酸合并时能生成可药用盐的碱,可药用盐是表示在该盐的药用剂量下其阳离子对动物机体没有毒性,这样该游离酸所固有的对PDGF的有益抑制作用就不被阳离子的副作用所失效。 Can be used to prepare the base addition salts preferably include alkali when combined with the free acid may be capable of forming pharmaceutically acceptable base salts, pharmaceutically acceptable salts are represented in pharmaceutical doses of the salts whose cations are not toxic to the animal organism, so that the inherent in the free acid on the inhibition of PDGF beneficial side effect not being invalid cations. 在本发明范围内的可药用盐,包括例如碱金属盐和碱土金属盐,是用下述碱形成的盐:氢化钠、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化铝、氢氧化锂、氢氧化镁、氢氧化锌、氨、三甲胺、三乙胺、乙二胺、N-甲基葡糖胺、赖氨酸、精氨酸、鸟氨酸、胆碱、N,N'-二苄基乙二胺、氯普鲁卡因、二乙醇胺、普鲁卡因、N-苄基苯乙胺、二乙胺、哌嗪、三(羟基甲基)氨基甲烷、氢氧化四甲基铵等。 Within the scope of the present invention can be pharmaceutically acceptable salts, including for example alkali and alkaline earth metal salts are the salts formed by the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium oxide, magnesium hydroxide, zinc hydroxide, ammonia, trimethylamine, triethylamine, ethylenediamine, N- methylglucamine, lysine, arginine, ornithine, choline, N, N '- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, tetrakis methyl ammonium.

本发明化合物的金属盐可通过将游离酸形式的本发明化合物与所选金属的氢化物、氢氧化物、碳酸盐或类似活性化合物在含水溶剂或有机溶剂中接触来制得。 Metal salts of the compounds of the present invention can be prepared by hydride free acid form of the present invention is a compound of the selected metal, hydroxide, carbonate or similar reactive compound in contact with an aqueous solvent or an organic solvent system. 所用的含水溶剂可以是水,或者可以是水与有机溶剂的混合物,所述有机溶剂优选为醇例如甲醇或乙醇,酮例如丙酮,脂族醚例如四氢呋喃,或酯例如乙酸乙酯。 The aqueous solvent used may be water, or may be a mixture of water and an organic solvent, the organic solvent is preferably an alcohol such as methanol or ethanol, ketones such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate. 这样的反应通常是在室温进行的,但是如果需要的话,可以在加热条件下进行。 This reaction is usually carried out at room temperature, but if desired, can be carried out under heating.

本发明化合物的胺盐可通过将游离酸形式的本发明化合物与胺在含水溶剂或有机溶剂中接触来制得。 Amine salts of compounds of the invention may be prepared by the free acid form of the compound of the present invention is contacted with an amine in an aqueous solvent or an organic solvent system. 合适的含水溶剂可以是水以及水与下述有机溶剂的混合物:醇例如甲醇或乙醇,醚例如四氢呋喃,腈例如乙腈,或酮例如丙酮。 Suitable aqueous solvent may be a mixture of water and an organic solvent of water and the following: alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile, or ketones such as acetone. 氨基酸盐可通过类似方法制得。 Amino acid salts may be prepared by analogous methods.

通过使用已知方法或对已知方法作改动,可从碱加成盐再生出本发明化合物。 By using known methods or methods known to make changes, the compounds of the present invention can be regenerated from the base addition salts. 例如,本发明母体化合物可通过用酸例如盐酸处理其碱加成盐而从中再生出来。 For example, parent compounds of the invention may be treated with an acid such as hydrochloric acid and base addition salts thereof regenerated therefrom.

除了用作活性化合物以外,本发明化合物的盐还可用于纯化本发明化合物,例如,通过采用本领域技术人员众所周知的技术,利用该盐与母体化合物、副产物和/或原料之间的溶解度差异来进行纯化。 In addition to use as active compounds, salts of compounds of the invention may also be used for purification of the compounds of the present invention, for example, by employing well known to those skilled in the art, utilizing the solubility difference between the salts and the parent compounds, by-products and / or materials between be purified.

本发明化合物可含有不对称中心。 The compounds of the invention may contain asymmetric centers. 这些不对称中心可独立地呈R或S构型。 These asymmetric centers may independently be in the R or S configuration. 某些式I化合物还可能表现出几何异构现象,这对于本领域技术人员来说也是显而易见的。 Certain compounds of formula I may exhibit geometrical isomerism, that the skilled artisan is obvious. 几何异构体包括顺式和反式形式的本发明化合物,即在环系上有链烯基部分或取代基的化合物。 Geometric isomers include compounds of cis and trans forms of the present invention, i.e., in the ring system compound having alkenyl moieties or substituents. 此外,二环环系包括内型和外型异构体。 Additionally, bicyclic ring system comprising endo and exo isomers. 本发明包含单独的几何异构体、立体异构体、对映体和它们的混合物。 The present invention includes individual geometrical isomers, stereoisomers, enantiomers and mixture thereof.

通过使用已知方法或对已知方法作改动,例如使用色谱技术和重结晶技术,可从其混合物中分离出这样的异构体,或者可用其中间体的适当异构体分开地制备它们,例如通过使用或改变本文所述方法来进行制备。 By using known methods or methods known to make changes, for example, using chromatographic techniques and recrystallization techniques, can be isolated from a mixture of such isomers, or may be their appropriate isomers of their intermediates prepared separately, for example by using or changing be prepared by methods described herein.

原料和中间体是通过使用已知方法或对已知方法作改动,例如使用在参考实施例中描述的方法或其明显的化学同等方法,或者通过依据本发明描述的方法制得的。 Starting materials and intermediates are known methods or by the use of known methods to make changes, for example using the method described in Reference Example Example obvious chemical equivalent or a method, or manufactured by the method according to the present invention was described.

描述本发明化合物制备的下述示例性实施例进一步举例说明了本发明,但不是对本发明的限制。 The following description of exemplary embodiments of the preparation of compounds of the present invention further illustrate the present invention but not limitative of the present invention.

此外,下述实施例是用于合成本发明化合物的代表性方法。 In addition, the following examples are representative methods for the synthesis of compounds of the present invention. 实施例1 3-环己氧基-6,7-二甲氧基喹啉在0℃,向THF溶液(30mL)中加入3-羟基-6,7-二甲氧基喹啉(0.237g,1.15mmol)、环己醇(0.347g,3.46mmol)、Ph3P(0.908g,3.46mmol)。 Example 1 3-cyclohexyl-6,7-dimethoxy-quinoline at 0 ℃, the THF solution (30mL) was added 3-hydroxy-6,7-dimethoxy-quinoline (0.237g, 1.15mmol), cyclohexanol (0.347g, 3.46mmol), Ph3P (0.908g, 3.46mmol). 分批加入偶氮二甲酸二乙酯直至该溶液保持深红色为止(0.663g,3.81mmol)。 Diethyl azodicarboxylate was added in portions until the deep red solution was maintained until (0.663g, 3.81mmol). 4小时后,将该溶液浓缩,通过色谱法纯化残余物(50%EtOAc的己烷溶液)。 After 4 hours, the solution was concentrated, the residue was purified by chromatography (50% EtOAc in hexanes). 用异丙醇/己烷将该产物重结晶,获得了其盐酸盐,为白色固体(mp229-232℃,分解温度)。 With isopropanol / hexane the product was recrystallized to give the hydrochloride salt as a white solid (mp229-232 ℃, decomposition temperature). 实施例2 2-苯氨基-6-异丙氧基喹喔啉盐酸盐在氩气氛下,向NaH(0.033g,0.84mmol)加入1mL DMF。 Example 2 2-phenylamino-6-isopropoxy-quinoxaline hydrochloride Under an argon atmosphere, NaH (0.033g, 0.84mmol) was added 1mL DMF. 分批加入在1.5mL DMF中的2-苯氨基-6-喹喔啉醇(0.1g,0.42mmol)。 In 1.5mL DMF was added in portions of 2-phenyl-amino-6-quinoxalinol (0.1g, 0.42mmol). 30分钟后,滴加2-溴丙烷,将该溶液在50℃加热1.5小时。 After 30 minutes, a solution of 2-bromopropane, the solution was heated at 50 ℃ 1.5 hours. 用水处理该冷却的反应混合物,在EtOAc与水之间分配,依次用H2O(3)、盐水洗涤,干燥(MgSO4),并浓缩。 The cooled reaction mixture was treated with water and partitioned between EtOAc and water, and washed sequentially with H2O (3 ), washed with brine, dried (MgSO4), and concentrated. 通过色谱法纯化残余物(30%EtOAc/己烷),获得了0.05g二烷基化产物和0.1g本标题化合物。 The residue was purified by chromatography (30% EtOAc / hexanes) gave 0.05g dialkylated product and 0.1g of the title compound. 将IPA(异丙醇)/HCl加到该游离碱的Et2O/IPA溶液中以制得盐酸盐(mp205-210℃,分解温度),将其用作盐酸盐分析样本。 The IPA (isopropanol) / HCl was added to the free base Et2O / IPA solution to obtain a hydrochloride (mp205-210 ℃, decomposition temperature), which was used as the hydrochloride salt to analyze samples. 元素分析C17H17N3OHCl计算值:C,64.65;H,5.74;N,13.31;实测值:C,64.51;H,5.90;N,13.09。 Elemental analysis for C17H17N3O HCl Calcd: C, 64.65; H, 5.74; N, 13.31; Found: C, 64.51; H, 5.90; N, 13.09. 实施例3 2-环己基氨基-6,7-二甲氧基喹喔啉向0.3g(1.34mmol)2-氯-6,7-二甲氧基喹喔啉中加入约1mL环己基胺。 Quinoxaline to 0.3g (1.34mmol) 2- chloro-6,7-dimethoxy-quinoxaline is added about 1mL cyclohexylamine Example 32- cyclohexyl-6,7-dimethoxy-quinoline embodiment. 将该混合物在105℃加热过夜,然后在135℃加热10小时。 The mixture was heated overnight at 105 ℃, and then heated at 135 ℃ 10 hours. 将该混合物在二氯甲烷和饱和NaHCO3之间分配。 The mixture was partitioned between dichloromethane and saturated NaHCO3. 将有机层干燥(MgSO4)并浓缩。 The organic layer was dried (MgSO4) and concentrated. 通过色谱法纯化所得浆状物(1∶1 EtOAc∶CH2Cl2),以69%的产率获得了0.265g产物,为浅棕色固体(mp188-189.5℃)。 Through the resulting slurry was chromatographed (1:1 EtOAc:CH2Cl2), 69% yield obtained 0.265g of product as a light brown solid (mp188-189.5 ℃). 元素分析C16H21N3O2计算值:C,66.88;H,7.37;N,14.62实测值:C,66.82;H,7.28;N,14.45。 Elemental analysis for C16H21N3O2 Calcd: C, 66.88; H, 7.37; N, 14.62 Found: C, 66.82; H, 7.28; N, 14.45.

采用上述标准偶联方法,用适当原料制得了下述化合物:外-二环[2.2.1]庚-2-基-(6-氯-7-甲氧基喹喔啉-2-基)胺(mp171-173℃)元素分析C16H18N3OCl计算值:C,63.26;H,5.97;N,13.83实测值:C,63.37;H,5.91;N,13.83。 Using standard coupling methods described above, using the appropriate starting materials the following compounds were prepared: External - bicyclo [2.2.1] hept-2-yl - (6-chloro-7-methoxy-quinoxalin-2-yl) amine (mp171-173 ℃) Elemental analysis for C16H18N3OCl Calcd: C, 63.26; H, 5.97; N, 13.83 Found: C, 63.37; H, 5.91; N, 13.83. 外-二环[2.2.1]庚-2-基-(7-氯-6-甲氧基喹喔啉-2-基)胺(mp146-147.5℃)元素分析C16H18N3OCl计算值:C,63.26;H,5.97;N,13.83实测值:C,63.34;H,5.93;N,13.77。 Outer - bicyclo [2.2.1] hept-2-yl - (7-chloro-6-methoxy-quinoxalin-2-yl) amine (mp146-147.5 ℃) Elemental analysis for C16H18N3OCl Calcd: C, 63.26; H, 5.97; N, 13.83 Found: C, 63.34; H, 5.93; N, 13.77. 二环[2.2.1]庚-2-基-(6,7-二甲基喹喔啉-2-基)胺(mp155-157℃)元素分析C17H21N3计算值:C,76.37;H,7.92;N,15.72实测值:C,75.58;H,7.55;N,15.38。2-环庚基氨基-6,7-二甲氧基喹喔啉(mp134-136℃)元素分析C17H23N3O2计算值:C,67.75;H,7.69;N,13.94实测值:C,67.80;H,7.61;N,13.77。2-环戊基氨基-6,7-二甲氧基喹喔啉(mp149-151℃)元素分析C15H19N3O2计算值:C,65.91;H,7.01;N,15.37实测值:C,66.04;H,6.96;N,15.47。2-环己基氨基-6-甲氧基喹喔啉(mp242-248℃)实施例4 3-氨基环己基-6,7-二甲氧基喹啉在氩气氛下,向4分子筛粉末(0.11g)的MeOH(3mL)溶液中加入3-氨基-6,7-二甲氧基喹啉盐酸盐(0.17g,0.68mmol)和NaOMe(0.039g,0.71mmol)。 Bicyclo [2.2.1] hept-2-yl - (6,7-dimethyl-quinoxalin-2-yl) amine (mp155-157 ℃) Elemental analysis for C17H21N3 Calcd: C, 76.37; H, 7.92; N, 15.72 Found: C, 75.58; H, 7.55; N, 15.38.2- cycloheptyl-amino-6,7-dimethoxy quinoxaline (mp134-136 ℃) Elemental analysis for C17H23N3O2 Calcd: C, 67.75; H, 7.69; N, 13.94 Found: C, 67.80; H, 7.61; N, 13.77.2- cyclopentyl-6,7-dimethoxy quinoxaline (mp149-151 ℃) Elemental analysis C15H19N3O2 Calcd: C, 65.91; H, 7.01; N, 15.37 Found: C, 66.04; H, 6.96; N, 15.47.2- cyclohexyl amino-6-methoxy-quinoxaline (mp242-248 ℃) EXAMPLE 4 3-Amino-cyclohexyl-6,7-dimethoxy-quinoline Under argon atmosphere, 4 molecular sieve powder (0.11g) in MeOH (3mL) was added 3-amino-6,7- methoxy-quinoline hydrochloride (0.17g, 0.68mmol) and NaOMe (0.039g, 0.71mmol). 将该反应混合物在室温搅拌30分钟,依次滴加环己酮(0.074mL,0.71mmol)和吡啶硼烷(0.072mL,0.071mmol)。 The reaction mixture was stirred at room temperature for 30 minutes, followed by dropwise addition of cyclohexanone (0.074mL, 0.71mmol) and pyridine borane (0.072mL, 0.071mmol). 将该混合物搅拌4.5小时,然后滴加5N HCl(1.4mL,6.8mmol)。 The mixture was stirred for 4.5 hours, then a solution of 5N HCl (1.4mL, 6.8mmol). 将该反应混合物搅拌45分钟,然后用5N NaOH将其碱化至呈强碱性。 The reaction mixture was stirred for 45 minutes, then basified with 5N NaOH to strongly alkaline. 将该混合物在EtOAc和水之间分配,用EtOAc(2)洗涤水层。 The mixture was partitioned between EtOAc and water, with EtOAc (2 ) the aqueous layer was washed. 用盐水(1)洗涤合并的有机层,干燥(MgSO4),通过色谱法纯化(50%EtOAc/己烷),并用EtOAc/己烷重结晶,以57%的产率获得了0.112g浅黄色固体(mp164-165℃)。 Washed with brine (1 ) The combined organic layer was washed, dried (MgSO4), purified by chromatography (50% EtOAc / hexanes), and by using EtOAc / hexane to yield 57% of the obtained pale yellow 0.112g solid (mp164-165 ℃). 元素分析C17H22N2O2计算值:C,71.30;H,7.74;N,9.78实测值:C,71.45;H,7.49;N,9.80。 Elemental analysis for C17H22N2O2 Calcd: C, 71.30; H, 7.74; N, 9.78 Found: C, 71.45; H, 7.49; N, 9.80. 实施例5 2-环己基氨基-6-甲氧基-7-溴喹喔啉盐酸盐在密封管中,向0.75g(2.7mmol)7∶17-溴-6-甲氧基喹喔啉-2-醇:6-溴-7-甲氧基喹喔啉-2-醇中加入5mL环己基胺。 Example 5 2-cyclohexyl-amino-6-methoxy-7-bromo-quinoxaline embodiment morpholine hydrochloride in a sealed tube, to 0.75g (2.7mmol) 7:17--bromo-6-methoxy-quinoxaline 2-ol: 6-bromo-7-methoxy-quinoxalin-2-ol was added 5mL cyclohexylamine. 将该反应混合物在120℃加热2小时。 The reaction mixture was heated at 120 ℃ 2 hours. 将环己基胺减压除去,把残余物在EtOAc/H2O之间分配。 The cyclohexylamine was removed under reduced pressure, to between EtOAc / H2O and the residue partitioned. 将有机层依次用H2O(2)、盐水(1)洗涤,并干燥(MgSO4)。 The organic layer was washed with H2O (2 ), brine (1 ) and dried (MgSO4). 通过色谱法纯化所得残余物(20%然后是30%EtOAc/己烷),以88%的产率获得了0.81g主产物。 By purifying the resulting residue was chromatographed (20% then 30% EtOAc / hexanes) to yield 88% of the main product was obtained 0.81g. 通过将约0.13g该游离碱转化成其盐酸盐(mp280℃,分解温度)来获得分析样本。 By adding approximately 0.13g of the free base was converted into its hydrochloride salt (mp280 ℃, decomposition temperature) to obtain the analysis samples. 元素分析C15H18N3OBrHCl计算值:C,48.34;H,5.14;N,11.27实测值:C,48.51;H,4.98;N,11.09。 Elementary analysis C15H18N3OBr HCl Calcd: C, 48.34; H, 5.14; N, 11.27 Found: C, 48.51; H, 4.98; N, 11.09. 实施例6 (6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基环己基)胺二盐酸盐和(6,7-二甲氧基喹啉-3-基)-反式-(3-(R)-甲基环己基)胺二盐酸盐将通过3-氨基-6,7-二甲氧基喹啉和3-(R)-甲基环己酮的还原胺化制得的(6,7-二甲氧基喹啉-3-基)-(3-(R)-甲基环己基)胺的顺式/反式混合物通过RP-HPLC分离。 6 (6,7-dimethoxy-quinolin-3-yl) Example - cis - (3- (R) - methyl-cyclohexyl) amine dihydrochloride and (6,7-dimethoxy- quinolin-3-yl) - trans - (3- (R) - methyl-cyclohexyl) amine dihydrochloride by reaction of 3-amino-6,7-dimethoxy-quinoline and 3- (R) cis / trans mixture of amines - methyl cyclohexanone prepared by reductive amination of (6,7-dimethoxy-quinolin-3-yl) - - (methyl cyclohexyl 3- (R)) separated by RP-HPLC. 将所得两个样本都再次进行色谱处理(70%EtOAc/己烷)以获得纯游离碱。 The obtained two samples were chromatographed (70% EtOAc / hexanes) again to obtain pure free base. 通过将游离碱分别单独转化成无定形且有几分吸湿的二盐酸盐来获得各异构体的分析样本。 Separately by reacting the free base is converted to amorphous and somewhat hygroscopic dihydrochloride were analyzed to obtain a sample of each isomer. 产物的500Mhz1H NMR是一致的,并且LC/MS和FAB证实了各异构体的M+H=301。 Product 500Mhz1H NMR is consistent, and the LC / MS and FAB confirmed isomers of M + H = 301. 实施例7环己-3-烯基-(6,7-二甲氧基喹喔啉-2-基)胺在-78℃,向反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己醇(303mg,1mmol)在10mL THF内的溶液中加入三苯基膦(524mg,2mmol)和偶氮二甲酸二乙酯(1mL)。 7-cyclohexyl-3-enyl Example - (6,7-dimethoxy-quinoxalin-2-yl) amine at -78 ℃, the trans-4- (6,7-dimethoxy-quinoline quinoxaline-2-ylamino) cyclohexanol (303mg, 1mmol) was added to a solution of 10mL THF within triphenylphosphine (524mg, 2mmol) and diethyl azodicarboxylate (1mL). 将该混合物在-78℃搅拌1小时,然后加入4-硝基苯甲酸(334mg,2mmol)。 The mixture was stirred for 1 hour at -78 ℃, followed by addition of 4-nitrobenzoic acid (334mg, 2mmol). 在-78℃搅拌1小时后,将该混合物再在室温继续搅拌1小时,然后浓缩。 After -78 ℃ stirred for 1 hour, the mixture was further stirred for 1 hour at room temperature and then concentrated. 通过硅胶色谱纯化残余物(乙醚),获得了250mg(87.7%)环己-3-烯基-(6,7-二甲氧基喹喔啉-2-基)胺。 The residue was purified by silica gel chromatography (diethyl ether) to give 250mg (87.7%) cyclohex-3-enyl - (6,7-dimethoxy-quinoxalin-2-yl) amine. 实施例8 2-苯氨基-6-喹喔啉醇按照Feutrill,GI;Mirrington,RNTet.Lett.1970,1327的方法,将芳基甲基醚转化成苯酚衍生物。 Example 8 2-amino-6-phenyl quinoline embodiment quinoxalinols accordance Feutrill, GI; Mirrington, methods RNTet.Lett.1970,1327 of the aryl methyl ether is converted to the phenol derivative. 在氩气氛下,向DMF中的2-苯氨基-6-甲氧基喹喔啉(0.27g,1.07mmol)中加入乙硫醇钠(0.19g,2mmol)。 Under an argon atmosphere, DMF, 2-anilino-6-methoxy-quinoxaline (0.27g, 1.07mmol) was added to sodium ethanethiolate (0.19g, 2mmol). 将该反应混合物在110℃加热过夜。 The reaction mixture was heated overnight at 110 ℃. 将该混合物浓缩,并在乙酸乙酯与水/5%酒石酸之间分配,使得水层的pH大约为4。 The mixture was concentrated, and partitioned between ethyl acetate and water / 5% tartaric acid distribution, so that the water layer pH of about 4. 依次用水(4)、2.5%氢氧化钠(4)洗涤有机层。 Washed with water (4 ), 2.5% sodium hydroxide (4 ) and the organic layer was washed. 将碱性层合并,用乙酸乙酯(2)洗涤,用5%酒石酸再酸化,并用EtOAc乙酸乙酯洗涤多次。 The basic layers combined, washed with ethyl acetate (2 ), dried and then acidified with 5% tartaric acid, and washed with EtOAc several times with ethyl acetate. 将有机层合并,用盐水洗涤,干燥(硫酸钠)并浓缩。 The organic layers were combined, washed with brine, dried (sodium sulfate) and concentrated. 通过色谱法纯化残余物(50%EtOAc/己烷)。 The residue was purified by chromatography (50% EtOAc / hexanes). 用Et2O将产物研制,获得了黄色粉末(mp211-213℃),将其用作分析样本。 The product was developed with Et2O to give a yellow powder (mp211-213 ℃), which is used to analyze samples. 元素分析C14H11N3O计算值:C,70.88;H,4.67;N,17.71;实测值:C,70.64;H,4.85;N,17.58。 Elemental analysis for C14H11N3O Calcd: C, 70.88; H, 4.67; N, 17.71; Found: C, 70.64; H, 4.85; N, 17.58. 实施例9苯基-[6-(四氢呋喃-3-(R)-基氧基)喹喔啉-2-基]胺在0℃、氩气氛下,向THF溶液中加入2-苯氨基-6-喹喔啉醇(0.23g,0.97mmol)、(S)-(+)-3-羟基四氢呋喃(0.086mL,1.3mmol)和三苯基膦(0.31g,1.2mmol)。 Example 9-phenyl - [6- (tetrahydrofuran -3- (R) - yl oxy) quinoxalin-2-yl] amine at 0 ℃, an argon atmosphere, THF was added 2-phenylamino -6 - quinoxaline-ol (0.23g, 0.97mmol), (S) - (+) - 3- hydroxy-tetrahydrofuran (0.086mL, 1.3mmol) and triphenylphosphine (0.31g, 1.2mmol). 滴加DEAD(0.18mL,1.2mmol)。 Was added dropwise DEAD (0.18mL, 1.2mmol). 将该反应混合物升至室温,并搅拌1.5小时。 The reaction mixture was warmed to room temperature, and stirred for 1.5 hours. 将该混合物浓缩,并在乙酸乙酯和水之间分配。 The mixture was concentrated, and partitioned between ethyl acetate and water. 依次用水和盐水洗涤有机层,干燥(MgSO4),并浓缩。 Washed with water and brine, the organic layer was dried (MgSO4), and concentrated. 通过色谱法纯化所得黄色油状物(50%EtOAc/己烷),并置于Et2O/IPA。 The resultant was purified by chromatography on a yellow oil (50% EtOAc / hexanes), and placed in Et2O / IPA. 滴加HCl/Et2O溶液,将所得红橙色粉末真空干燥。 Dropwise addition of HCl / Et2O solution and the resulting red-orange powder is dried in vacuo. 通过在含有洗涤过的(3H2O、5MeOH)碱离子交换树脂的甲醇中搅拌来除去所得粉末中的碱。 The resulting powder was removed by stirring in a base containing washed (3 H2O, 5 MeOH) basic ion exchange resin in methanol. 将该混合物搅拌30分钟,过滤,浓缩,并用EtOAc/己烷重结晶,分两批获得了产物(mp173-175℃)。 The mixture was stirred for 30 minutes, filtered, concentrated, and treated with EtOAc / hexane to obtain two batches of the product (mp173-175 ℃). 元素分析C18H17N3O2计算值:C,70.35;H,5.57;N,13.67;实测值:C,70.19;H,5.60;N,13.66。 Elemental analysis for C18H17N3O2 Calcd: C, 70.35; H, 5.57; N, 13.67; Found: C, 70.19; H, 5.60; N, 13.66. 实施例10 2,7-二环己氧基-6-甲氧基喹喔啉在氩气氛下,向NaH(0.32g,8mmol)的DMF溶液(5mL)中滴加环己醇(0.7mL,6.7mmol)。 Example 10 2,7-dicyclohexyl-6-methoxy quinoline embodiment quinoxaline Under an argon atmosphere, NaH (0.32g, 8mmol) in DMF (5mL) was added dropwise cyclohexanol (0.7mL, 6.7mmol). 将该混合物在室温搅拌25分钟,然后滴加2-氯-6,7二甲氧基喹喔啉。 The mixture was stirred for 25 minutes at room temperature, then a solution of 2-chloro-6,7-dimethoxy-quinoxaline. 将该反应在室温搅拌15分钟,在90℃搅拌2小时,在110℃搅拌1小时。 The reaction was stirred at room temperature for 15 minutes, followed by stirring at 90 ℃ 2 hours, and stirred at 110 ℃ 1 hour. 将该混合物冷却,用水处理,并在EtOAc/H2O之间分配。 The mixture was cooled, treated with water and partitioned between EtOAc / H2O. 用水和盐水洗涤有机层,干燥(MgSO4),并通过色谱法纯化(10%EtOAc/己烷),获得了蜡状白色固体(mp75-78℃)。 The organic layer was washed with water and brine, dried (MgSO4), and purified by chromatography (10% EtOAc / hexanes) gave a waxy white solid (mp75-78 ℃). 元素分析C21H28N2O3计算值:C,70.76;H,7.92;N,7.86;实测值:C,70.81;H,7.79;N,7.70。 Elemental analysis for C21H28N2O3 Calcd: C, 70.76; H, 7.92; N, 7.86; Found: C, 70.81; H, 7.79; N, 7.70. 实施例11环己基-(6,7-二甲氧基喹喔啉-2-基甲基)胺向0.067M 6,7-二甲氧基-2-喹喔啉甲醛在2∶1 MeOH/1,2-二氯乙烷(7.5mL,0.5mmol)内的溶液中加入环己基胺(0.11mL,0.9mmol)。 Cyclohexyl Example 11 - (6,7-dimethoxy-quinoxalin-2-yl-methyl) amine to 0.067M 6,7- dimethoxy-2-quinoxaline-carbaldehyde 2:1 MeOH / 1,2-dichloroethane was added a solution of cyclohexylamine (7.5mL, 0.5mmol) within the (0.11mL, 0.9mmol). 将该反应在室温搅拌过夜,然后加入NaBH4(0.038g,1mmol),并将该反应混合物搅拌过夜。 The reaction was stirred overnight at room temperature, followed by addition of NaBH4 (0.038g, 1mmol), and the reaction mixture was stirred overnight. 然后将该混合物浓缩,并通过色谱法纯化(50%EtOAc/己烷-约5%MeOH在50%EtOAc/己烷中的溶液)。 The mixture was then concentrated and purified by chromatography (50% EtOAc / hexanes - approximately 5% MeOH solution in 50% EtOAc / hexanes) by. 将所得油状物溶于EtOAc/己烷,并用HCl的EtOH溶液处理。 The resulting oil was dissolved in EtOAc / hexanes and treated with a solution of HCl in EtOH. 将所得溶液浓缩,异丙醇研制所得固体,在60℃真空干燥,获得了白色固体(mp185-190℃,分解温度)。 The resulting solution was concentrated, the resulting solid was developed isopropanol, and dried in vacuo at 60 ℃, obtained as white solid (mp185-190 ℃, decomposition temperature). 元素分析C17H23N3O2HCl计算值:C,60.44;H,7.16;N,12.44;实测值:C,60.48;H,6.88;N,12.07。 Elemental analysis for C17H23N3O2 HCl Calcd: C, 60.44; H, 7.16; N, 12.44; Found: C, 60.48; H, 6.88; N, 12.07. 实施例12(6,7-二甲氧基喹啉-3-基)-反式-(3-(R)-甲基环己基)胺和(6,7-二甲氧基喹啉-3-基)-顺式-(3-(R)-甲基环己基)胺按照与上述制备类似的方式,用3-氨基-6,7-二甲氧基喹啉的游离碱(0.32g,1.6mmol)与(R)-(+)-3-甲基环己酮(0.23mL,1.9mmol)进行反应。 Example 12 (6,7-dimethoxy-quinolin-3-yl) - trans - (3- (R) - methyl-cyclohexyl) -amine and (6,7-dimethoxy-quinoline -3 - yl) - cis - (3- (R) - methyl-cyclohexyl) amine was prepared according to a similar manner to the above, using 3-amino-6,7-dimethoxy-quinoline free base (0.32g, 1.6mmol) and (R) - (+) - 3- methyl cyclohexanone (0.23mL, 1.9mmol) was reacted. 通过色谱法纯化所得产物混合物(70%EtOAc/己烷),并用EtOAc/己烷重结晶,获得了白色固体(1∶1的顺式和反式异构体混合物)(mp153-160℃)。 The product was purified by chromatography on a mixture of (70% EtOAc / hexanes) and treated with EtOAc / hexane to obtain a white solid (1:1 cis and trans isomer mixture) (mp153-160 ℃). 元素分析C18H24N2O2计算值:C,71.97;H,8.05;N,9.33;实测值:C,72.12;H,7.85;N,9.29。 Elemental analysis for C18H24N2O2 Calcd: C, 71.97; H, 8.05; N, 9.33; Found: C, 72.12; H, 7.85; N, 9.29.

采用上述标准偶联方法,用适当原料制得了下述化合物:(6,7-二甲氧基喹啉-3-基)-(3-甲基环戊基)胺(mp106-109℃)元素分析C17H22N2O2计算值:C,71.30;H,7.74;N,9.78实测值:C,71.24;H,7.56;N,9.61。 Using standard coupling methods described above, using the appropriate starting materials the following compounds were prepared: (6,7-dimethoxy-quinolin-3-yl) - (3-methyl-cyclopentyl) amine (mp106-109 ℃) element Analysis C17H22N2O2 Calcd: C, 71.30; H, 7.74; N, 9.78 Found: C, 71.24; H, 7.56; N, 9.61. 实施例13 3-(6,7-二甲氧基喹啉-3-基氨基)-2,2-二甲基丙-1-醇按照与实施例11中的制备相类似的方式进行反应。 Example 13 3- (6,7-dimethoxy-quinolin-3-ylamino) -2,2-dimethyl-propan-1-ol was prepared in accordance with the similar manner as in Example 11 was reacted. 在氩气氛下,向4分子筛粉末(0.35g)的MeOH溶液中加入3-氨基-6,7-二甲氧基喹啉(0.32g,1.6mmol)和2,2-二甲基-3-羟基丙醛(0.19g,1.9mmol)。 Under an argon atmosphere, 4 zeolite powder (0.35g) in MeOH was added 3-amino-6,7-dimethoxy-quinoline (0.32g, 1.6mmol) and 2,2-dimethyl-3 - hydroxy propionaldehyde (0.19g, 1.9mmol). 通过色谱法纯化该产物混合物(3%MeOH/CHCl3),获得了0.10g物质,将其在CH2Cl2/10%NaOH之间分配。 The product was purified by chromatography on a mixture of (3% MeOH / CHCl3), to obtain 0.10g of material which was partitioned between CH2Cl2 / 10% NaOH. 依次用10%NaOH、H2O和盐水洗涤有机层,然后干燥(MgSO4),并用EtOAc/己烷重结晶,获得了浅橙色固体(mp170-173.5℃)元素分析C16H22N2O3计算值:C,66.18;H,7.64;N,9.65;实测值:C,66.11;H,7.49;N,9.33。 Washed successively with 10% NaOH, the organic layer was washed with H2O and brine, then dried (MgSO4), and treated with EtOAc / hexane to obtain a pale orange solid (mp170-173.5 ℃) Elemental analysis for C16H22N2O3 Calcd: C, 66.18; H, 7.64; N, 9.65; Found: C, 66.11; H, 7.49; N, 9.33.

采用上述标准偶联方法,用适当原料制得了下述化合物:(6,7-二甲氧基喹啉-3-基)异丁基胺(mp158-162℃)元素分析C15H20N2O2计算值:C,69.20;H,7.74;N,10.76实测值:C,69.06;H,7.82;N,11.01。 Using standard coupling methods described above, using the appropriate starting materials the following compounds were prepared: (6,7-dimethoxy-quinolin-3-yl) isobutylamine (mp158-162 ℃) Elemental analysis for C15H20N2O2 Calcd: C, 69.20; H, 7.74; N, 10.76 Found: C, 69.06; H, 7.82; N, 11.01. 实施例14环己基-(6-甲氧基-7-吗啉-4-基-喹喔啉-2-基)胺该制备是通过将Buchwald,等人在J.Am.Chem.Soc.,1996,118,7215中描述的方法作适当改动而进行的。 EXAMPLE 14 Cyclohexyl-- (6-methoxy-7-morpholin-4-yl - quinoxalin-2-yl) amine which is prepared by Buchwald, et al, J.Am.Chem.Soc,. 1996,118,7215 method described be suitably adapted and performed. 在氩气氛下,向2-环己基氨基-6-甲氧基-7-溴喹喔啉(0.1g,0.3mmol)的甲苯溶液中加入吗啉(0.1g,0.3mmol)、叔丁醇钠(0.04g,0.42mmol)、S-(-)-BINAP(催化剂,0.001g)、和二(二亚苄基丙酮)钯(催化剂,0.001g)。 Under an argon atmosphere, 2-cyclohexyl-amino-6-methoxy-7-bromo-quinoxaline (0.1g, 0.3mmol) in toluene was added morpholine (0.1g, 0.3mmol), sodium tert-butoxide (0.04g, 0.42mmol), S - (-) - BINAP (catalyst, 0.001g), and bis (dibenzylidene acetone) palladium (catalyst, 0.001g). 将该反应混合物在80℃加热过夜。 The reaction mixture was heated at 80 ℃ overnight. 将该混合物冷却,用乙醚稀释,过滤,浓缩,并通过色谱法纯化(50%EtOAc/己烷)。 The mixture was cooled, diluted with ether, filtered, concentrated, and purified by chromatography (50% EtOAc / hexanes). 用EtOAc/己烷将产物重结晶,分两批获得了黄色固体(mp194-196℃)。 With EtOAc / hexane and the product was recrystallized in two batches to obtain a yellow solid (mp194-196 ℃). 元素分析C19H26N4O2计算值:C,66.64;H,7.65;N,16.36;实测值:C,66.60;H,7.60;N,16.51。 Elemental analysis for C19H26N4O2 Calcd: C, 66.64; H, 7.65; N, 16.36; Found: C, 66.60; H, 7.60; N, 16.51. 实施例15反式-4-(7-氯-6-甲氧基喹喔啉-2-氨基)环己醇和反式-4-(6-氯-7-甲氧基喹喔啉-2-基-氨基)环己醇在氩气氛下,向装配有迪安-斯达克分水器和冷凝器的反应烧瓶中加入6∶1 2,7-二氯-6-甲氧基喹喔啉:2,6-二氯-7-甲氧基喹喔啉(0.30g,1.3mmol)和反式-4-氨基环己醇(0.35g,3mmol)。 Cyclohexanol and trans-4- (6-chloro-7-methoxy-quinoxalin-2 Example 15 trans-4- (7-chloro-6-methoxy-quinoxalin-2-ylamino) yl - amino) cyclohexanol under an argon atmosphere, equipped with a Dean - Stark trap and condenser, the reaction flask was added 6:1 2,7-dichloro-6-methoxy-quinoxaline : 2,6-dichloro-7-methoxy-quinoxaline (0.30g, 1.3mmol) and trans-4-aminocyclohexanol (0.35g, 3mmol). 将该反应混合物在170℃加热约10小时,然后浓缩,进行2次色谱分离(7%MeOH/CHCl3,然后是5%MeOH/CHCl3)。 The reaction mixture was heated for about 10 hours at 170 ℃, then concentrated, twice chromatographed (7% MeOH / CHCl3, then 5% MeOH / CHCl3). 用EtOAc/己烷将产物重结晶,获得了浅黄色固体(mp144-147℃)。 With EtOAc / hexane and the product was recrystallized to give a pale yellow solid (mp144-147 ℃). 元素分析C19H26N4O20.4H2O计算值:C,57.20;H,6.02;N,13.34;实测值:C,57.21;H,5.97;N,13.08。1H NMR分析表明产物是2∶1的反式-4-(7-氯-6-甲氧基喹喔啉-2-氨基)环己醇:反式-4-(6-氯-7-甲氧基喹喔啉-2-基-氨基)环己醇混合物。 Elemental analysis for C19H26N4O2 0.4H2O Calcd: C, 57.20; H, 6.02; N, 13.34; Found: C, 57.21; H, 5.97; N, 13.08.1H NMR analysis showed the product was 2:1 trans -4 - (7-chloro-6-methoxy-quinoxalin-2-ylamino) cyclohexanol: trans-4- (6-chloro-7-methoxy-quinoxalin-2-yl - amino) cyclohexyl alcohol mixture. 实施例16反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己醇将反式-4-氨基环己醇(0.11g,2当量)与2-氯-6,7-二甲氧基喹喔啉(0.1g,1当量)混合,并在160-180℃加热4-8小时。 Cyclohexanol and trans-4- aminocyclohexanol (0.11g, 2 equiv.) Example 16 trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) with 2-chloro -6,7-dimethoxy-quinoxaline (0.1g, 1 eq) were mixed and heated at 160-180 ℃ 4-8 hours. 将该深棕色悬浮液过滤并浓缩。 The dark brown suspension was filtered and concentrated. 通过快速柱色谱法纯化残余物,用3%甲醇/二氯甲烷洗脱,获得了产物,为黄色粉末,熔点为119-123℃。 Purification by flash column chromatography on the residue, using 3% methanol / dichloromethane, gave the product as a yellow powder, mp 119-123 ℃. 元素分析C16H21N3O3计算值:C,62.33;H,7.05;N,13.63;实测值:C,62.35;H,7.09;N,13.18。 Elemental analysis for C16H21N3O3 Calcd: C, 62.33; H, 7.05; N, 13.63; Found: C, 62.35; H, 7.09; N, 13.18.

可通过下述方法将该化合物重结晶。 The compound can be recrystallized by the following method. 将0.2g黄色粉末在2.5mL水与1.25mL甲醇的混合物中回流以获得澄清的橙色溶液。 0.2g of yellow powder was refluxed in a mixture of 2.5mL of water and 1.25mL of methanol to obtain a clear orange solution. 将该热溶液静止,并逐渐冷却。 The hot solution is stationary, and gradually cooled. 通过过滤收集橙色针状结晶,并在高度真空下干燥,获得了黄色固体(mp119-120℃)。 Orange needle crystals were collected by filtration, and dried under high vacuum to give a yellow solid (mp119-120 ℃).

或者,按如下所述制备本标题化合物的盐酸盐:在0℃,向反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己醇的异丙醇溶液中加入HCl溶液。 Alternatively, the title compound was prepared according to the hydrochloride salt as follows: at 0 ℃, the trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanol isopropanol HCl solution was added. 将该混合物搅拌15分钟,然后过滤。 The mixture was stirred for 15 minutes, then filtered. 将所收集的固体在高度真空下干燥,获得了反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己醇盐酸盐。 The collected solid was dried under high vacuum to give trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanol hydrochloride. 元素分析C16H22ClN3O31.2H2O计算值:C,53.19;H,6.80;N,11.63;Cl,9.81;实测值:C,53.14;H,6.85;N,11.24;Cl,10.28。 Elemental analysis for C16H22ClN3O3 1.2H2O Calcd: C, 53.19; H, 6.80; N, 11.63; Cl, 9.81; Found: C, 53.14; H, 6.85; N, 11.24; Cl, 10.28.

或者,按如下所述制备本标题化合物的硫酸盐:按照常规操作,将反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己醇溶于丙酮或另一适当有机溶剂中,并按照需要温热至45℃。 Alternatively, the title compound according sulfate prepared as follows: In accordance with conventional operation, the trans-4- (6,7-dimethoxy-quinoxalin-2-yl-amino) cyclohexyl dissolved in acetone or another a suitable organic solvent, and, if necessary warmed to 45 ℃. 在快速搅拌下向所得溶液中小心地加入硫酸水溶液(1当量,1M溶液)。 Under rapid stirring to the resulting solution was carefully added aqueous sulfuric acid (1 equiv., 1M solution). 收集由此形成的盐并干燥,以>80%的产率获得了硫酸盐。 Salt thus formed was collected and dried to> 80% yield obtained sulfate. 实施例17 ()-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺方法A:将2-氯-6,7-二甲氧基喹喔啉(5g,22.3mmol)与()-外-降冰片烷基-2-胺(10g,90mmol)的混合物在160-180℃加热过夜。 Example 17 () - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-2-yl quinoxalin) amine Method A: A mixture of 2-chloro-6,7 dimethoxy quinoxaline (5g, 22.3mmol) and () - outside - a mixture of norbornyl-2-amine (10g, 90mmol) was heated at 160-180 ℃ overnight. 将该深棕色残余物溶于200mL二氯甲烷中,并用1N NaOH(50mL)洗涤。 The dark brown residue was dissolved in 200mL methylene chloride and 1N NaOH (50mL) and washed with. 用硫酸镁将有机层干燥,然后过滤。 The organic layer was dried with magnesium sulfate, and then filtered. 浓缩后,通过硅胶色谱纯化残余物,用己烷/乙酸乙酯(80%)洗脱,获得了所需产物,为黄色固体,可将其在甲醇中重结晶。 After concentration, the residue was purified by chromatography on silica gel with hexane / ethyl acetate (80%) to afford the desired product as a yellow solid, which can be recrystallized in methanol.

方法B:将2-氯-6,7-二甲氧基喹喔啉(9g,40.1mmol)与()-外降冰片烷-2-胺(5.77g,52mmol)、叔丁醇钠(4.22g,44mmol)、2,2'-二(二苯基膦基)-1,1'-联萘(BINAP,120mg)以及二(二亚苄基丙酮)钯(Pd(dba)2,40mg)在80mL甲苯中的混合物在80℃加热8小时。 Method B: A mixture of 2-chloro-6,7-dimethoxy quinoxaline (9g, 40.1mmol) and () - outer norbornane-2-amine (5.77g, 52mmol), sodium tert-butoxide ( 4.22g, 44mmol), 2,2'- bis (diphenylphosphino) -1,1'-binaphthyl (BINAP, 120mg) and bis (dibenzylideneacetone) palladium (Pd (dba) 2,40mg ) mixture in 80mL of toluene was heated at 80 ℃ 8 hours. 加入另一部分BINAP(60mg)和Pd(dba)2(20mg),将该混合物在100℃加热过夜。 Another portion of BINAP (60mg) and Pd (dba) 2 (20mg), and the mixture was heated at 100 ℃ overnight. 用200mL二氯甲烷稀释后,用1NNaOH(100mL)洗涤该反应混合物。 After dilution with 200mL dichloromethane, washed with 1NNaOH (100mL) and the reaction mixture was washed. 用硫酸镁将有机层干燥并过滤。 The organic layer was dried with magnesium sulfate and filtered. 浓缩后,通过硅胶色谱法纯化残余物,用己烷/乙酸乙酯(80%)洗脱,获得了所需产物,为浅黄色固体(mp188-189℃)。 After concentration, the residue was purified by chromatography on silica gel was eluted with hexane / ethyl acetate (80%) to give the desired product as a pale yellow solid (mp188-189 ℃). 元素分析C17H21N3O3计算值:C,68.20;H,7.07;N,14.04;实测值:C,68.18;H.7.03;N,14.03。 Elemental analysis for C17H21N3O3 Calcd: C, 68.20; H, 7.07; N, 14.04; Found: C, 68.18; H.7.03; N, 14.03.

用适当原料以类似方法(方法A)制备下述化合物:外-二环[2.2.1]庚-5-烯-2-基-(6,7-二甲氧基喹喔啉-2-基)胺(mp175-177℃)元素分析C17H19N3O20.4H2O计算值:C,60.94;H,6.56;N,13.78;实测值:C,66.98;H,6.62;N,12.73。 In a similar manner using the appropriate starting material (Method A) Preparation of the following compounds: - bicyclo [2.2.1] hept-5-en-2-yl - (6,7-dimethoxy-quinoxalin-2-yl ) amine (mp175-177 ℃) Elemental analysis for C17H19N3O2 0.4H2O Calcd: C, 60.94; H, 6.56; N, 13.78; Found: C, 66.98; H, 6.62; N, 12.73. 环己基-(6,8-二甲基喹喔啉-2-基)胺[MS m/z:255(M+)]元素分析C16H21N3计算值:C,75.26;H,8.29;N,16.46;实测值:C,75.08;H,8.28;N,15.86。 Cyclohexyl - (6,8-dimethyl-quinoxalin-2-yl) amine [MS m / z: 255 (M +)] Elemental analysis for C16H21N3 Calcd: C, 75.26; H, 8.29; N, 16.46; Found Value: C, 75.08; H, 8.28; N, 15.86. 内-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺(mp79-82℃)。 The - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-quinoxalin-2-yl) amine (mp79-82 ℃). (6,7-二甲氧基喹喔啉-2-基)-(4-甲氧基环己基)胺(mp58-68℃)。 (6,7-dimethoxy-quinoxalin-2-yl) - (4-methoxy-cyclohexyl) amine (mp58-68 ℃). 元素分析C17H23N3O30.5H2O计算值:C,62.56;H,7.41;N,12.87;实测值:C,62.53;H,7.22;N,12.22。 Elemental analysis for C17H23N3O3 0.5H2O Calcd: C, 62.56; H, 7.41; N, 12.87; Found: C, 62.53; H, 7.22; N, 12.22. 外-二环[2.2.1]庚-2-基-(6-甲氧基喹喔啉-2-基)胺(mp98-100℃)元素分析C16H19N3O计算值:C,71.35;H,7.11;N,15.60;实测值:C,70.38;H,7.03;N,15.05。 Outer - bicyclo [2.2.1] hept-2-yl - (6-methoxy-quinoxalin-2-yl) amine (mp98-100 ℃) Elemental analysis for C16H19N3O Calcd: C, 71.35; H, 7.11; N, 15.60; Found: C, 70.38; H, 7.03; N, 15.05. 实施例18外-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉将外-2-降冰片(223mg,2 mmol)和NaH(60%,100mg,2.5mmol)在10mL无水THF中的混合物回流0.5小时,然后加入2-氯-6,7-二甲氧基喹喔啉(336mg,1.5mmol)。 Example 18 exo-2 (bicyclo [2.2.1] hept-2-yloxy) -6,7-dimethoxy-quinoxaline exo-2-norbornyl (223mg, 2 mmol) and NaH (60%, 100mg, 2.5mmol) in 10mL of anhydrous THF mixture was refluxed for 0.5 hours, then 2-chloro-6,7-dimethoxy quinoxaline (336mg, 1.5mmol). 将所得混合物继续回流2小时。 The resulting mixture was refluxed for 2 hours. 过滤并浓缩后,通过硅胶色谱纯化残余物(50%乙醚/己烷),获得了所需产物,为白色固体(mp135-137C)。 After filtration and concentration, the residue was purified by silica gel chromatography (50% ether / hexane) to give the desired product as a white solid (mp135-137C). 元素分析C17H20N2O3计算值:C,67.98;H,6.71;N,9.33;实测值:C,67.96;H,6.762;N,9.19。 Elemental analysis for C17H20N2O3 Calcd: C, 67.98; H, 6.71; N, 9.33; Found: C, 67.96; H, 6.762; N, 9.19.

用适当原料以标准偶联方法制备下述化合物:2-(二环[2.2.2]辛-2-基氧基)-6,7-二甲氧基喹喔啉(mp147-148℃)。 Using standard coupling methods with appropriate starting materials following compounds were prepared: 2- (bicyclo [2.2.2] oct-2-yloxy) -6,7-dimethoxy-quinoxaline (mp147-148 ℃). 内-2-(二环[2.2.1]庚-2-基氧基)-6,7-二甲氧基喹喔啉(mp110-111℃)。 The 2- (bicyclo [2.2.1] hept-2-yloxy) -6,7-dimethoxy-quinoxaline (mp110-111 ℃). 外-2-(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉(mp108-110℃).元素分析C17H18N2O3计算值:C,68.44;H,6.08;N,9.39;实测值:C,68.54;H,6.23;N,9.27。2-(二环[2.2.1]庚-5-烯-2-基氧基)-6,7-二甲氧基喹喔啉(mp93-95℃).元素分析C17H18N2O3计算值:C,68.44;H,6.08;N,9.39;实测值:C,68.32;H,5.98;N,9.25。2-环己氧基-6,7-二甲氧基喹喔啉(mp104-106℃)。 The outer -2- (bicyclo [2.2.1] hept-5-en-2-yloxy) -6,7-dimethoxy-quinoxaline (mp108-110 ℃) Elemental analysis for C17H18N2O3 Calcd: C , 68.44; H, 6.08; N, 9.39; Found: C, 68.54; H, 6.23; N, 9.27.2- (bicyclo [2.2.1] hept-5-en-2-yloxy) -6 , 7-dimethoxy quinoxaline (mp93-95 ℃) Elemental analysis for C17H18N2O3 Calcd: C, 68.44; H, 6.08; N, 9.39; Found:. C, 68.32; H, 5.98; N, 9.25. 2-cyclohexyl-6,7-dimethoxy quinoxaline (mp104-106 ℃). 2-环戊硫基-6,7-二甲氧基喹喔啉(mp123-124℃)。 2- cyclopentylthio-6,7-dimethoxy quinoxaline (mp123-124 ℃). 元素分析C15H18N2O2S计算值:C,62.04;H,6.25;N,9.65实测值:C,61.90;H,6.02;N,9.48。6,7-二甲氧基-2-环戊氧基喹喔啉(mp87-89℃)元素分析C15H18N2O3计算值:C,65.68;H,6.61;N,10.21实测值:C,65.63;H,6.52;N,10.13。2-环戊基甲氧基-6,7-二甲氧基喹喔啉(mp99-102℃)元素分析C16H20N2O3计算值:C,66.65;H,6.99;N,9.72实测值:C,66.66;H,7.03;N,9.70。6,7-二甲氧基-2-四氢吡喃-4-氧基喹喔啉(mp155-158℃)元素分析C15H18N2O4计算值:C,62.06;H,6.25;N,9.65实测值:C,62.26;H,6.27;N,9.67。 Elemental analysis for C15H18N2O2S Calcd: C, 62.04; H, 6.25; N, 9.65 Found: C, 61.90; H, 6.02; N, 9.48.6,7--dimethoxy-2-cyclopentyloxy-quinoxaline (mp87-89 ℃) Elemental analysis for C15H18N2O3 Calcd: C, 65.68; H, 6.61; N, 10.21 Found: C, 65.63; H, 6.52; N, 10.13.2- cyclopentyl-methoxy-6,7 - dimethoxy quinoxaline (mp99-102 ℃) Elemental analysis for C16H20N2O3 Calcd: C, 66.65; H, 6.99; N, 9.72 Found: C, 66.66; H, 7.03; N, 9.70.6,7- dimethoxy-2-tetrahydropyran-4-yloxy quinoxaline (mp155-158 ℃) Elemental analysis for C15H18N2O4 Calcd: C, 62.06; H, 6.25; N, 9.65 Found: C, 62.26; H , 6.27; N, 9.67. 外,外-6,7-二甲氧基-2-(5,6-环氧二环[2.2.1]庚烷-2-基氧基)喹喔啉(mp173-175℃)。 In addition, the outer-6,7-dimethoxy-2- (5,6-epoxy-bicyclo [2.2.1] heptane-2-yloxy) quinoxaline (mp173-175 ℃). 实施例19顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己烷甲酸将顺式/反式-4-羟基-环己烷甲酸(144mg,1mmol)和NaH(60%,160mg,4mmol)在无水THF/DMF(10mL/2mL)中的混合物回流1小时,然后加入2-氯-6,7-二甲氧基喹喔啉(225mg,1mmol)。 Cyclohexanecarboxylic acid (- Example 19 cis / trans-4- (6,7-dimethoxy-quinoxalin-2-yloxy) cyclohexanecarboxylic acid cis / trans-4-hydroxy 144mg, 1mmol) and NaH (60%, 160mg, 4mmol) in anhydrous THF / DMF (10mL / 2mL) was refluxed for 1 hour, then 2-chloro-6,7-dimethoxy quinoxaline ( 225mg, 1mmol). 将所得混合物继续回流4小时。 The resulting mixture was refluxed for 4 hours. 将所得混合物中和至pH5,并用乙酸乙酯萃取(250mL)。 The resulting mixture was neutralized to pH5, and extracted with ethyl acetate (2 50mL). 用硫酸镁干燥合并的有机溶液,并过滤。 The combined organic solution was dried over magnesium sulfate, and filtered. 浓缩后,通过硅胶色谱纯化残余物(乙酸乙酯,然后甲醇),获得了所需产物,为白色固体(mp90-93℃)。 After concentration, the residue was purified by chromatography on silica gel (ethyl acetate then methanol) to give the desired product as a white solid (mp90-93 ℃). 元素分析C17H20N2O50.5H2O计算值:C,59.89;H,6.19;N,8.22;实测值:C,59.91;H,6.62;N,7.90。 Elemental analysis for C17H20N2O5 0.5H2O Calcd: C, 59.89; H, 6.19; N, 8.22; Found: C, 59.91; H, 6.62; N, 7.90. 实施例20 6,7-二甲氧基-2-(4-甲氧基环己氧基)喹喔啉将顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己醇(170mg,0.56mmol)和NaH(60%,22.4mg,0.56mmol)在无水THF/DMF(10mL/2mL)中的混合物在0℃搅拌10分钟,然后加入甲基碘(50μl,0.56mmol)。 EXAMPLE 20 6,7-dimethoxy-2- (4-methoxy-cyclohexyloxy) quinoxaline A solution of cis / trans-4- (6,7-dimethoxy-quinoxaline - 2- yloxy) cyclohexanol (170mg, 0.56mmol) and NaH (60%, 22.4mg, 0.56mmol) in anhydrous THF / DMF (10mL / 2mL) was stirred for 10 minutes at 0 ℃, followed by addition of Methyl iodide (50μl, 0.56mmol). 在室温搅拌4小时后,用水(0.5mL)中止该反应,然后浓缩。 After stirring for 4 hours at room temperature, washed with water (0.5mL) to suspend the reaction, and then concentrated. 用二氯甲烷(220mL)萃取水层,用盐水(5mL)洗涤合并的有机溶液。 (2 20mL) and the aqueous layer was extracted with dichloromethane, the organic solution was washed with brine (5mL) and washed combined. 浓缩后,通过硅胶色谱纯化残余物(30%乙酸乙酯/己烷),获得了80mg(45%)所需产物(mp85-90℃)。 After concentration, the residue was purified by silica gel chromatography (30% ethyl acetate / hexanes) to give 80mg (45%) of the desired product (mp85-90 ℃). 实施例21 3-环己氧基-6,7-二甲氧基喹喔啉1-氧化物将2-环己氧基-6,7-二甲氧基喹喔啉(110mg,0.38mmol)和间氯过苯甲酸(70%,113mg,0.46mmol)在10mL二氯甲烷中的混合物于室温搅拌一天。 Example 21 3-cyclohexyl-6,7-dimethoxy-quinoxaline-1-oxide A mixture of 2-cyclohexyl-6,7-dimethoxy quinoxaline (110mg, 0.38mmol) and m-chloroperbenzoic acid (70%, 113mg, 0.46mmol) in 10mL of dichloromethane the mixture was stirred at room temperature one day. 过滤后,将该溶液浓缩,通过硅胶色谱纯化残余物(20%乙酸乙酯/己烷),获得了所需产物(mp167-169℃)。 After filtration, the solution was concentrated, the residue was purified by silica gel chromatography (20% ethyl acetate / hexanes) to give the desired product (mp167-169 ℃). 以类似方法制备反式-4-(6,7-二甲氧基-4-氧基喹喔啉-2-基氨基)环己醇(mp220-222℃)。 In a similar process for the preparation of trans-4- (6,7-dimethoxy-4-yloxy quinoxalin-2-ylamino) cyclohexanol (mp220-222 ℃). 元素分析C16H21N3O40.2H2O计算值:C,59.42;H,6.69;N,12.99;实测值:C,59.43;H,6.64;N,12.95。 Elemental analysis for C16H21N3O4 0.2H2O Calcd: C, 59.42; H, 6.69; N, 12.99; Found: C, 59.43; H, 6.64; N, 12.95. 实施例22 (1R,2R,4S)-(+)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺将实施例17的()-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺在手性HPLC柱(Chiralpac AD,252cm,含有10mM(1S)-(+)-樟脑磺酸的60%庚烷/40%乙醇,12mL/分钟)上拆分,获得了作为首批洗脱物的上述标题产物。 Example 22 (1R, 2R, 4S) - (+) - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-quinoxalin-2-yl) amine Example 17 of () - bicyclo [2.2.1] hept-2-yl - (6,7-dimethoxy-quinoxalin-2-yl) amine in a chiral HPLC column (Chiralpac AD, 25 2cm, comprising 10mM (1S) - (+) - camphorsulfonic acid, 60% heptane / 40% ethanol, 12mL / min) on the split, the first eluate obtained as the above-titled product. 合并所收集的级分,用50mL1N NaOH洗涤,然后干燥(MgSO4)。 The collected fractions were combined, 50mL1N NaOH and washed, then dried (MgSO4). 过滤后,将该溶液在旋转蒸发仪上蒸发,然后在高度真空下干燥。 After filtration, the solution was evaporated on a rotary evaporator, then dried under high vacuum. 获得了黄色固体。 Received a yellow solid. [α]d20+19.5(c=0.20,CH2Cl2)mp184-186℃。 [Α] d20 + 19.5 (c = 0.20, CH2Cl2) mp184-186 ℃. 元素分析C17H21N3O2x0.3H2O计算值:C,66.90;H,7.15;N,13.77实测值:C,66.86;H,7.01;N,13.86。 Elemental analysis C17H21N3O2x0.3H2O Calcd: C, 66.90; H, 7.15; N, 13.77 Found: C, 66.86; H, 7.01; N, 13.86. 实施例23 (1S,2S,4R)-(-)-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺(i)将实施例17的()-二环[2.2.1]庚-2-基-(6,7-二甲氧基喹喔啉-2-基)胺在手性HPLC柱(Chiralpac AD,252cm,含有10mM(1S)-(+)-樟脑磺酸的60%庚烷/40%乙醇,12mL/分钟)上拆分,获得了作为第二批洗脱物的上述标题产物。 Hept-2-yl bicyclo [2.2.1] - - Example 23 (1S, 2S, 4R) - (-) (6,7- dimethoxy-quinoxalin-2-yl) amine (i) the hept-2-yl bicyclo [2.2.1] - - Example 17 () (6,7- dimethoxy-quinoxalin-2-yl) amine in a chiral HPLC column (Chiralpac AD, 25 2cm, containing 10mM (1S) - (+) - camphorsulfonic acid, 60% heptane / 40% ethanol, 12mL / min) on the resolution, obtained as the eluate of the second batch of the above-titled product. 合并所收集的级分,用50mL 1N NaOH洗涤,然后用硫酸镁干燥。 The collected fractions were combined, 50mL 1N NaOH and washed, and then dried over magnesium sulfate. 过滤后,将该溶液在旋转蒸发仪上蒸发,然后在高度真空下干燥。 After filtration, the solution was evaporated on a rotary evaporator, then dried under high vacuum. 获得了黄色固体。 Received a yellow solid. [α]d20-19.5(c=0.22,CH2Cl2)mp185-187℃。 [Α] d20-19.5 (c = 0.22, CH2Cl2) mp185-187 ℃. (ii)将2-氯-6,7-二甲氧基喹喔啉(462mg,2.06mmol)与(1S,2S,4R)降冰片烷基-2-胺(300mg,2.7mmol)、叔丁醇钠(220mg,2.3mmol)、BINAP(9mg)和Pd(dba)2(3mg)在10mL甲苯中的混合物在80-100℃加热过夜。 (Ii) 2-Chloro-6,7-dimethoxy quinoxaline (462mg, 2.06mmol) and (1S, 2S, 4R) norbornyl-2-amine (300mg, 2.7mmol), tert-butyl sodium methoxide (220mg, 2.3mmol), BINAP (9mg) and Pd (dba) 2 (3mg) in a mixture of 10mL of toluene was heated overnight at 80-100 ℃. 通过硅胶色谱纯化该悬浮液,用己烷/乙酸乙酯(60%)洗脱,获得了370mg(60%)所需产物,为黄色固体,在上述手性HPLC条件下,该产物的保留时间与首批洗脱物相同。 Purification by silica gel chromatography of the suspension, eluting with hexane / ethyl acetate (60%) to give 370mg (60%) of the desired product as a yellow solid, chiral HPLC under the above conditions, the retention time of the product The first eluted with the same thing. [α]d20-19(c=0.19,CH2Cl2)。 [Α] d20-19 (c = 0.19, CH2Cl2). 实施例24 2-(6,7-二甲氧基喹喔啉-2-基)-2-氮杂二环[2.2.2]辛烷-3-酮将2-氮杂二环[2.2.2]辛烷-3-酮(228mg,2.3mmol)溶于THF/DMF(5mL/3mL)混合物中,并用NaH(60%,184mg,4.6mmol)处理。 Example 24 2- (6,7-dimethoxy-quinoxalin-2-yl) -2-aza-bicyclo [2.2.2] octan-3-one A mixture of 2-aza-bicyclo [2.2. 2] octan-3-one (228mg, 2.3mmol) was dissolved in THF / DMF (5mL / 3mL) mixture and treated with NaH (60%, 184mg, 4.6mmol) processing. 将所得混合物在60℃加热0.5小时,然后加入2-氯-6,7-二甲氧基喹喔啉(344mg,1.5mmol)。 The resulting mixture was heated 0.5 hours at 60 ℃, then 2-chloro-6,7-dimethoxy quinoxaline (344mg, 1.5mmol). 在80℃加热过夜后,将该反应混合物浓缩。 After 80 ℃ heated overnight, the reaction mixture was concentrated. 通过硅胶色谱纯化残余物(50%乙酸乙酯/己烷),获得了164mg(23%)黄色固体(mp158-159℃)。 The residue was purified by silica gel chromatography (50% ethyl acetate / hexane) to give 164mg (23%) as a yellow solid (mp158-159 ℃). 实施例25 顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯向2-(6,7-二甲氧基喹喔啉-2-基)-2-氮杂二环[2.2.2]辛烷-3-酮(100mg,0.32mmol)在10mL甲醇内的溶液中加入新制备的NaOMe/甲醇溶液(54mg,1mmol),将该混合物在室温搅拌0.5小时,然后浓缩。 Example 25 cis / trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid methyl ester 2- (6,7-dimethoxy-quinoxaline embodiment 2-yl) -2-aza-bicyclo [2.2.2] octan-3-one (100mg, 0.32mmol) was added / methanol solution of freshly prepared NaOMe (54mg, 1mmol) in 10mL of methanol inside, The mixture was stirred for 0.5 hours at room temperature and then concentrated. 使用二氯甲烷进行萃取,然后用硫酸镁干燥。 Extracted with dichloromethane, and then dried over magnesium sulfate. 过滤并浓缩后,通过硅胶色谱纯化残余物(40%乙酸乙酯),获得了85mg(77%)顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯,为浅黄色固体(mp68-80℃)。 After filtration and concentration, the residue was purified by silica gel chromatography (40% ethyl acetate) to give 85mg (77%) of cis / trans-4- (6,7-dimethoxy-quinoxalin-2-yl amino) cyclohexane-carboxylate as a pale yellow solid (mp68-80 ℃). 实施例26顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸当在上述方法中用NaOH替换NaOMe时,则2-(6,7-二甲氧基喹喔啉-2-基)-2-氮杂二环[2.2.2]辛烷-3-酮被转化成顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸。 When Example 26 cis / trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid with NaOH in the above method when replacing NaOMe, the 2- (6, 7- dimethoxy-quinoxalin-2-yl) -2-aza-bicyclo [2.2.2] octan-3-one is converted into cis / trans-4- (6,7-dimethoxy oxy quinoxalin-2-ylamino) cyclohexanecarboxylic acid. 实施例27 顺式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯和反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯通过制备性TLC,由顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸酯分离顺式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯[MS m/z:345(M+)]和反式-4-(6,7-二甲氧基喹喔啉-2-基氨基)环己烷甲酸甲酯[MS m/z:345(M+)],用65%乙酸乙酯/己烷洗脱,二者分别作为首批和第二批洗脱物被分离出来。 Example 27 cis-4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid methyl ester and trans-4- (6,7-dimethoxy quinoxaline 2-ylamino) cyclohexane carboxylic acid methyl ester by preparative TLC, the cis / trans-4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid ester separation of cis-4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid methyl ester [MS m / z: 345 (M +)] and trans-4- (6, 7- dimethoxy-quinoxalin-2-ylamino) cyclohexanecarboxylic acid methyl ester [MS m / z: 345 (M +)], with 65% ethyl acetate / hexane, respectively, as the first two batch and the second batch elution was isolated. 实施例28反式-4-[7-甲氧基-6-(2-吗啉-4-基乙氧基)喹喔啉-2-基氨基]环己醇和反式-4-[6-甲氧基-7-(2-吗啉-4-基-乙氧基)喹喔啉-2-基氨基]环己醇本标题化合物是这样制得的:使用实施例1的方法,将6-羟基-7-甲氧基-2-氯喹喔啉:7-(2-吗啉-4-基乙氧基)-6-甲氧基-2-氯喹喔啉与2-(吗啉-4-基)乙醇反应进行Mitsunobu偶联,并使用实施例11的方法将所得6-(2-吗啉-4-基乙氧基)-7-甲氧基-2-氯喹喔啉:7-(2-吗啉-4-基乙氧基)-6-甲氧基-2-氯喹喔啉与反式-4-氨基-环己醇反应。 Example 28 trans-4- [7-methoxy-6- (2-morpholin-4-yl-ethoxy) quinoxalin-2-ylamino] cyclohexanol and trans-4- [6- methoxy-7- (2- morpholin-4-yl - ethoxy) quinoxalin-2-ylamino] cyclohexanol The title compound is thus obtained: the method of Example 1, the 6 - hydroxy-7-methoxy-2-chloroquinoxaline: 7- (2-morpholin-4-yl-ethoxy) -6-methoxy-2-chloroquinoxaline and 2- (morpholin -4 - yl) ethanol Mitsunobu coupling reaction is carried out, using the method of Example 11 and the resulting 6- (2-morpholin-4-yl-ethoxy) -7-methoxy-2-chloroquinoxaline: 7- ( 2- morpholin-4-yl-ethoxy) -6-methoxy-2-chloroquinoxaline and trans-4-amino - cyclohexanol reaction. 实施例29 2-[2-(反式-4-羟基环己基氨基)-7-甲氧基喹喔啉-6-基氧基]-1-乙酸和2-[2-(反式-4-羟基-环己基氨基)-6-甲氧基喹喔啉-7-基氧基]-1-乙酸本标题化合物是这样制得的:按照实施例8的方法,用乙硫醇的钠盐在DMF中将4-(6,7-二甲氧基喹喔啉-2-基氨基)环己醇脱烷基化,然后如一般方法6中所述,在碱存在下用溴乙酸烷基化。 Example 29 2- [2- (trans-4-hydroxy-cyclohexylamino) -7-methoxy-quinoxalin-6-yloxy] -1-acetic acid and 2- [2- (trans-4 - hydroxy - cyclohexylamino) -6-methoxy-quinoxalin-7-yloxy] -1-acetic acid The title compound is thus obtained: According to Example 8, with the sodium salt of ethanethiol in DMF, 4- (6,7-dimethoxy-quinoxalin-2-ylamino) cyclohexanol dealkylation, and then as described in general procedure 6, the presence of a base with an alkyl bromoacetate technology. 实施例30 2-[2-(反式-4-羟基环己基氨基)-7-甲氧基喹喔啉-6-基氧基]-N,N-二甲基乙酰胺和2-[2-(反式-4-羟基环己基氨基)-6-甲氧基喹喔啉-7-基氧基]-N,N-二甲基乙酰胺本标题化合物是用二甲基胺将实施例29的化合物氨解而制得的。 Example 30 2- [2- (trans-4-hydroxy-cyclohexylamino) -7-methoxy-quinoxalin-6-yloxy] -N, N- dimethyl acetamide and 2- [2 - (trans-4-hydroxy-cyclohexylamino) -6-methoxy-quinoxalin-7-yloxy] -N, N- dimethyl-acetamide The title compound is dimethyl amine Example ammonia solution of Compound 29 was prepared. 实施例31 (6,7-二甲氧基喹喔啉-2-基)-(3-(R)-甲基环己基)胺及其顺式和反式异构体该化合物首先是作为顺式和反式异构体的混合物制得的。 Example 31 (6,7-dimethoxy-quinoxalin-2-yl) - (3- (R) - methyl-cyclohexyl) amine compound and the cis and trans isomers first as cis mixtures and trans isomers obtained. 它们是这样制得的:将3-(R)-甲基环己酮的肟还原成环己基胺,然后在标准条件下将该胺与2-氯-6,7-二甲氧基喹喔啉偶联。 They are thus obtained: the 3- (R) - methyl cyclohexanone oxime is reduced to cyclohexyl amine, then the amine under standard conditions with 2-chloro-6,7-dimethoxy quinoxaline morpholino coupling. 通过制备性RP-HPLC获得了各异构体的分析样本。 By preparative RP-HPLC analysis of the samples obtained each isomer. 300Mhz1H NMR和MS与这两种异构体的结构都一致,虽然不能确定携带氮的环己基碳的相对立体化学。 300Mhz1H NMR and MS were consistent with the structure of these two isomers, although it can not determine the relative stereochemistry carrying nitrogen cyclohexyl carbons. 实施例32顺式/反式-4-(6,7-二甲氧基喹喔啉-2-基氧基)环己烷甲酸甲酯通过用标准技术将实施例19的产物酯化制得了本标题化合物。 Example 32 cis / trans-4- (6,7-dimethoxy-quinoxalin-2-yloxy) cyclohexane carboxylate by standard techniques of the product of Example 19 had esterification of the title compound. Mp130-132℃.元素分析C18H22N2O5计算值:C,62.42;H,6.40;N,8.09实测值:C,62.60;H,6.55;N,7.89。 Mp130-132 ℃ Elemental analysis for C18H22N2O5 Calcd: C, 62.42; H, 6.40; N, 8.09 Found:. C, 62.60; H, 6.55; N, 7.89. 中间体实施例1 4-溴-5-甲氧基-苯-1,2-二胺二盐酸盐在氩气氛下,向EtOAc(50mL)与5-溴-4-甲氧基-2-硝基-苯基胺(2.5g,10mmol)的溶液中加入5%Pd/C(0.5g)。 Intermediate Example 1 4-Bromo-5-methoxy - benzene-1,2-diamine dihydrochloride Under an argon atmosphere, EtOAc (50mL) and 5-bromo-4-methoxy-2- nitro - phenyl-amine (2.5g, 10mmol) was added 5% Pd / C (0.5g). 将该反应混合物在50psi氢化1小时。 The reaction mixture was hydrogenated at 50psi for 1 hour. 将该反应混合物经由硅藻土过滤到HCl/IPA/EtOAc溶液中,用EtOAc洗涤滤垫。 The reaction mixture was filtered through celite to HCl / IPA / EtOAc solution, and the filter pad was washed with EtOAc. 滤出所得沉淀,获得了白色固体。 The resulting precipitate was filtered off to give a white solid. 中间体实施例2 7-溴-6-甲氧基喹喔啉-2-醇和6-溴-7-甲氧基喹喔啉-2-醇在氨气氛下,向MeOH(15mL)中加入粉碎的NaOH颗粒(0.86g,21mmol)和4-溴-5-甲氧基-苯-1,2-二胺二盐酸盐(2.7g,9.3mmol)。 Example 2 7-Bromo-6-methoxy-quinoline intermediates embodiment quinoxaline-2-ol 6-bromo-7-methoxy-quinoxalin-2-ol in ammonia atmosphere, MeOH (15mL) was added pulverized of NaOH pellets (0.86g, 21mmol) and 4-bromo-5-methoxy - benzene-1,2-diamine dihydrochloride (2.7g, 9.3mmol). 将该混合物搅拌10分钟,然后滴加45%乙醛酸乙酯的甲苯溶液(2.7g,12mmol)。 The mixture was stirred for 10 minutes, then a solution of 45% toluene solution of ethyl glyoxylate (2.7g, 12mmol). 将该反应混合物回流1小时,然后冷却,加入水,之后将该悬浮液过滤。 The reaction mixture was refluxed for 1 hour, then cooled, water was added, after which the suspension was filtered. 依次用水、MeOH、IPA、和Et2O洗涤所得固体,获得了黄色粉末。 Washed successively with water, MeOH, IPA, and the resulting solid was washed with Et2O to give a yellow powder. 中间体实施例3 7-溴-2-氯-6-甲氧基喹喔啉和6-溴-2-氯-7-甲氧基喹喔啉向7-溴-6-甲氧基喹喔啉-2-醇和6-溴-7-甲氧基喹喔啉-2-醇的混合物(1g,3.9mmol)中加入POCl3(5mL)。 Example 3 7-Bromo-2-chloro-6-methoxy-quinoxaline and 6-bromo-2-chloro-7-methoxy-quinoline intermediates embodiment quinoxaline 7-bromo-6-methoxy-quinoxalin 6-bromo-2-ol 7-methoxy-quinoxaline-2-ol mixture (1g, 3.9mmol) was added POCl3 (5mL). 将该反应混合物回流1小时,倒入冰水中,过滤,然后用水洗涤,获得了浅褐色固体。 The reaction mixture was refluxed for 1 hour, poured into ice water, filtered, then washed with water to give a light brown solid. 1HNMR证实7-溴-2-氯-6-甲氧基喹喔啉:6-溴-2-氯-7-甲氧基喹喔啉比例约为7∶1。 1HNMR confirmed that 7-bromo-2-chloro-6-methoxy-quinoxaline: 6-bromo-2-chloro-7-methoxy-quinoxaline ratio is about 7:1. 中间体实施例4 5-氯-4-甲氧基-2-硝基苯胺向N-(5-氯-4-甲氧基-2-硝基苯基)乙酰胺(2g,8.2mmol)在5NHCL(20mL)内的溶液中加入1,4-二氧杂环己烷(10mL),将该混合物在60℃搅拌1.5小时。 Intermediate Example 4 5-Chloro-4-methoxy-2-nitroaniline to N- (5- chloro-4-methoxy-2-nitrophenyl) acetamide (2g, 8.2mmol) in 5NHCL (20mL) was added a solution within the 1,4-dioxane (10mL), the mixture was stirred at 60 ℃ 1.5 hours. 将该反应混合物浓缩,并在EtOAc/2 N NaOH之间分配。 The reaction mixture was concentrated and partitioned between EtOAc / 2 N NaOH. 将水层用EtOAc(3)、盐水洗涤,干燥(MgSO4),吸附在硅胶上,并通过色谱法纯化(70%EtOAc/己烷),获得了橙色粉末。 The aqueous layer was washed with EtOAc (3 ), washed with brine, dried (MgSO4), adsorbed on silica gel, and purified by chromatography (70% EtOAc / hexane) to give an orange powder. 中间体实施例5 4-氯-5-甲氧基-苯-1,2-二胺二盐酸盐在氩气氛下,向EtOAc(50mL)与5-氯-4-甲氧基-2-硝基苯基胺(1.6g,7.9mmol)的溶液中加入5%Pd/C(0.5g)。 Intermediate Example 5 4-Chloro-5-methoxy - benzene-1,2-diamine dihydrochloride Under an argon atmosphere, EtOAc (50mL) and 5-chloro-4-methoxy-2- nitrophenyl amine (1.6g, 7.9mmol) was added 5% Pd / C (0.5g). 将该反应混合物在50psi氢化1小时。 The reaction mixture was hydrogenated at 50psi for 1 hour. 在N2气氛中将该反应混合物经由硅藻土过滤到1N HCl/Et2O的EtOAc溶液中,用EtOAc洗涤滤垫。 In an N2 atmosphere and the reaction mixture was filtered through celite into EtOAc solution was 1N HCl / Et2O, the filter pad was washed with EtOAc. 滤出所得沉淀,获得了白色固体。 The resulting precipitate was filtered off to give a white solid. 中间体实施例6 7-氯-6-甲氧基-喹喔啉-2-醇和6-氯-7-甲氧基-喹喔啉-2-醇在0℃、氩气氛下,向4-氯-5-甲氧基-苯-1,2-二胺二盐酸盐(1.8g,7.2mmol)在EtOH(15mL)内的溶液中加入TEA(2.5mL,18mmol)。 Intermediate Example 6 7-Chloro-6-methoxy - quinoxalin-2-ol and 6-chloro-7-methoxy - quinoxaline-2-ol at 0 ℃, under an argon atmosphere, 4- chloro-5-methoxy - benzene-1,2-diamine dihydrochloride (1.8g, 7.2mmol) was added to a solution (15mL) inside of EtOH TEA (2.5mL, 18mmol). 将该混合物搅拌20分钟,然后滴加45%乙醛酸乙酯的甲苯溶液(2.1g,9.3mmol)。 The mixture was stirred for 20 minutes, then a solution of 45% ethyl glyoxylate in toluene (2.1g, 9.3mmol). 将该反应混合物升至室温,回流1.5小时,然后冷却,加入水,然后将该悬浮液过滤,并依次用水、IPA、和Et2O洗涤,获得了浅黄色粉末。 The reaction mixture was warmed to room temperature, refluxed for 1.5 hours, then cooled, water was added, then the suspension was filtered and washed successively with water, IPA, and washed with Et2O, to obtain a pale yellow powder. 用甲苯将该产物共沸数次,并在使用前真空干燥。 The product was azeotroped several times with toluene, and dried under vacuum prior to use. 中间体实施例7 2,7-二氯-6-甲氧基喹喔啉和2,6-二氯-7-甲氧基喹喔啉在用CaCl2干燥的试管内,向7-氯-6-甲氧基喹喔啉-2-醇和6-氯-7-甲氧基喹喔啉-2-醇(1g,4.7mmol)的混合物中加入POCl3(5mL)。 Example 7 2,7-Dichloro-6-methoxy-quinoxaline and 2,6-dichloro-7-methoxy-quinoline intermediates used in the embodiment quinoxaline CaCl2 drying tube, a solution of 7- chloro-6 - methoxy-quinoxalin-2-ol and 6-chloro-7-ol (1g, 4.7mmol) in a mixture of methoxy-quinoxalin-2 was added POCl3 (5mL). 将该反应混合物回流30分钟,倒入冷的饱和碳酸氢钠溶液中,过滤,然后用水洗涤,获得了固体。 The reaction mixture was refluxed for 30 minutes, poured into cold saturated sodium bicarbonate solution, filtered, then washed with water to give a solid. 1H NMR证实2,7-二氯-6-甲氧基喹喔啉:2,6-二氯-7-甲氧基喹喔啉的比例约为6∶1。 1H NMR confirmed that 2,7-dichloro-6-methoxy-quinoxaline: 2,6-dichloro-7-methoxy-quinoxaline ratio of about 6:1. 中间体实施例8 (1S,2S,4R)-降冰片烷基-2-胺(3a):在-78℃,向R-(+)-内-降冰片(2.24g,20mmol)在20mLTHF内的溶液中加入三苯基膦(6.55g,25mmol)、邻苯二甲酰亚胺(3.68g,25mmol)和偶氮二甲酸二乙酯(4.4mL,28mmol)。 Intermediate Example 8 (1S, 2S, 4R) - norbornyl-2-amine (3a): at -78 ℃, the R - (+) - endo - norbornyl (2.24g, 20mmol) in 20mLTHF was added triphenylphosphine (6.55g, 25mmol), phthalimide (3.68g, 25mmol) and diethyl azodicarboxylate (4.4mL, 28mmol). 将该混合物在室温搅拌过夜,然后浓缩。 The mixture was stirred at room temperature overnight, then concentrated. 通过硅胶色谱纯化残余物(20%乙酸乙酯/己烷),获得了4.6g(95%)(1S,2S,4R)-2-二环[2.2.1]庚-2-基异吲哚-1,3-二酮。 The residue was purified by silica gel chromatography (20% ethyl acetate / hexanes) to give 4.6g (95%) (1S, 2S, 4R) -2- bicyclo [2.2.1] hept-2-yl isoindole 1,3-dione. (3b):将(1S,2S,4R)-2-二环[2.2.1]庚-2-基异吲哚-1,3-二酮(1.2g,5mmol)和H2NNH2一水合物(300mg,6mmol)在10mL甲醇中的混合物回流4小时,然后浓缩至干。 (3b): the (1S, 2S, 4R) -2- bicyclo [2.2.1] hept-2-yl isoindole-1,3-dione (1.2g, 5mmol) and H2NNH2 monohydrate (300mg , 6mmol) in a mixture of 10mL of methanol was refluxed for 4 hours, then concentrated to dryness. 用二氯甲烷(2100mL)萃取,通过过滤滤出固体。 (2 100mL) and extracted with dichloromethane, the solid was filtered off by filtration. 将二氯甲烷蒸发,获得了300mg(54%)(1S,2S,4R)-降冰片烷基-2-胺。 The dichloromethane was evaporated to give 300mg (54%) (1S, 2S, 4R) - norbornyl-2-amine. 中间体实施例9外-二环[2.2.1]庚-5-烯-2-胺外-二环[2.2.1]庚-5-烯-2-胺按照与中间体实施例12相同的方法由5-降冰片烯-2-醇经由通用中间体外-2-二环[2.2.1]庚-5-烯-2-基异吲哚-1,3二酮制得的。 Intermediate Example 9 - Relationship bicyclo [2.2.1] hept-5-en-2-amine outer - bicyclo [2.2.1] hept-5-en-2-amine Following the same Intermediate Example 12 Methods by 5-norbornene-2-ol via a universal intermediate exo-2-bicyclo [2.2.1] hept-5-en-2-yl isoindole-1,3-dione obtained. 中间体实施例10 2-甲基-6,7-二甲氧基喹喔啉本标题化合物是通过将Tamao等人在Tetrahedron,1982,38,3347-3354中公开的方法作改进而制得的。 Intermediate Example 10 2-Methyl-6,7-dimethoxy quinoline Example quinoxaline The title compound is prepared by Tamao et al., Tetrahedron, 1982,38,3347-3354 make improvements in the method disclosed in the prepared . 在氩气氛下向THF溶液中加入2-氯-6,7-二甲氧基喹喔啉(5g,26mmol)和NiCl2(dppp)(0.14g,0.26mmol)。 Was added to the THF solution of 2-chloro-6,7-dimethoxy quinoxaline (5g, 26mmol) under an argon atmosphere and NiCl2 (dppp) (0.14g, 0.26mmol). 将该反应混合物冷却至0℃,向其中滴加3MMeMgBr的乙醚溶液(13mL,39mmol)。 The reaction mixture was cooled to 0 ℃, to which was added dropwise 3MMeMgBr ether solution (13mL, 39mmol). 将该反应混合物升至室温,搅拌1小时,然后回流1.5小时。 The reaction mixture was warmed to room temperature, stirred for 1 hour, then refluxed for 1.5 hours. 将该混合物冷却,用10%HCl中止反应,搅拌10分钟,然后用5%NaOH碱化。 The mixture was cooled, the reaction was quenched with 10% HCl, stirred for 10 minutes, then basified with 5% NaOH. 向该反应混合物中加入CH2Cl2和H2O,将该反应混合物搅拌过夜,然后加入CH2Cl2、H2O、和NaCl,过滤该混合物。 To the reaction mixture was added CH2Cl2 and H2O, the reaction mixture was stirred overnight, then added CH2Cl2, H2O, and NaCl, the mixture was filtered. 将所得溶液倒入分液漏斗中,用二氯甲烷将水层洗涤3次。 The resulting solution was poured into a separatory funnel, the aqueous layer was washed with dichloromethane three times. 合并有机层,用盐水洗涤,干燥(MgSO2),浓缩到硅胶上,并通过色谱法处理(50%-80%EtOAc/己烷),获得了橙色固体(产率为49%)。 The combined organic layers were washed with brine, dried (MgSO2), and concentrated onto silica gel, and by chromatography (50% -80% EtOAc / hexanes) to give an orange solid (49% yield). 中间体实施例11 6,7-二甲氧基-2-喹喔啉甲醛在氩气氛下,向反应烧瓶中加入1,4-二氧杂环己烷(20mL)、2-甲基-6,7-二甲氧基喹喔啉(1.09g,5.3mmol)和SeO2(1.8g,16mmol)。 Intermediate Example 11 6,7-Dimethoxy-2-quinoxaline-carbaldehyde Under an argon atmosphere, the reaction flask was added 1,4-dioxane (20mL), 2- methyl-6 , 7-dimethoxy-quinoxaline (1.09g, 5.3mmol) and SeO2 (1.8g, 16mmol). 将该混合物在100℃加热2小时45分钟,冷却,并经由硅藻土过滤。 The mixture was heated at 100 ℃ 2 hours and 45 minutes, cooled, and filtered through celite. 用EtOAc和CH2Cl2将滤垫洗涤数次。 With EtOAc and the filter pad was washed with CH2Cl2 several times. 将所得溶液浓缩,置于MeOH/CH2Cl2中,施加到硅胶柱上,进行色谱处理(30%EtOAc/CH2Cl2),获得了黄白色固体(产率为73%)。 The resulting solution was concentrated, placed in MeOH / CH2Cl2, and applied to a silica gel column and chromatographed (30% EtOAc / CH2Cl2), to obtain a white solid (73% yield). 中间体实施例12 (2外,5外)-5-氨基二环[2.2.1]庚烷-2-乙酸酯依据R.Gagnon(J.Chem.Soc.,Perkin trans.1,15051995)的方法、并作较小改进,由二环[2.2.1]庚-2,5-二烯制备外-5-乙酰氧基二环[2.2.1]庚烷-2-酮和外-6-乙酰氧基二环[2.2.1]庚烷-2-酮。 Intermediate Example 12 (2, the outer 5) -5-amino-bicyclo [2.2.1] heptane-2-acetate according to R.Gagnon (J.Chem.Soc., Perkin trans.1,15051995) methods, and make minor improvement, from the outside bicyclo [2.2.1] hepta-2,5-diene -5-acetoxy-bicyclo [2.2.1] heptane-2-one and an outer -6 - acetoxy-bicyclo [2.2.1] heptane-2-one.

在室温,向外-5-乙酰氧基二环[2.2.1]庚烷-2-酮(350mg,2.08mmol)在10mL THF内的溶液中加入1M硼烷/THF溶液(1.2mL,1.2mmol)。 At room temperature, outwardly -5-acetoxy-bicyclo [2.2.1] heptane-2-one (350mg, 2.08mmol) in 10mL THF was added 1M borane / THF solution (1.2mL, 1.2mmol ). 将该混合物搅拌0.5小时,然后在0℃用甲醇(3mL)和1NHCl(1.5mL)中止反应。 The mixture was stirred for 0.5 hours, then at 0 ℃ with methanol (3mL) and 1NHCl (1.5mL) stop the reaction. 用乙酸乙酯(330mL)萃取,并用硫酸镁干燥。 With ethyl acetate (3 30mL) was extracted, and dried over magnesium sulfate. 过滤并浓缩后,通过硅胶色谱纯化,获得了(2内,5外)-5-乙酰氧基二环[2.2.1]庚烷-2-醇。 After filtration and concentration, was purified by chromatography on silica gel to give the (2, 5 outside) -5-acetoxy-bicyclo [2.2.1] heptane-2-ol.

在0℃,向(2内,5外)-5-乙酰氧基二环[2.2.1]庚烷-2-醇(350mg,2.06mmol)在THF(10mL)内的溶液中加入邻苯二甲酰亚胺(454mg,3.09mmol)、三苯基膦(810mg,3.09mmol)和偶氮二甲酸二乙酯(0.49mL.3.09mmol)。 At 0 ℃, the (2, 5 outside) -5-acetoxy-bicyclo [2.2.1] heptane-2-ol (350mg, 2.06mmol) was added phthaloyl solution (10mL) of THF within A imide (454mg, 3.09mmol), triphenylphosphine (810mg, 3.09mmol) and diethyl azodicarboxylate (0.49mL.3.09mmol). 将该反应混合物搅拌过夜,然后用旋转蒸发仪浓缩,通过色谱柱纯化残余物(20%乙酸乙酯/己烷),获得了所需产物,为黄色固体。 The reaction mixture was stirred overnight and then concentrated using a rotary evaporator, the residue was purified by column chromatography (20% ethyl acetate / hexanes) to give the desired product as a yellow solid.

将上述固体(300mg,1mmol)和肼(0.126mL,2.2mmol)在5mL甲醇中的混合物加热回流6小时。 The above solid (300mg, 1mmol) and hydrazine (0.126mL, 2.2mmol) in a mixture of 5mL of methanol was heated at reflux for 6 hours. 除去甲醇后,用二氯甲烷(330mL)萃取残余物。 After removal of the methanol, treated with dichloromethane (3 30mL) and the residue extracted. 将溶剂浓缩,获得了(外,外)-5-氨基二环[2.2.1]庚烷-2-乙酸酯(127mg,75%),不用进一步纯化直接用于偶联反应。 The solvent was concentrated to obtain the (outer, outer) -5-amino-bicyclo [2.2.1] heptane-2-acetate (127mg, 75%), without further purification was used directly in the coupling reaction.

同样,由适当原料制备(2内,5外)-5-氨基二环[2.2.1]庚烷-2-乙酸酯、(2内,6外)-6-氨基二环[2.2.1]庚烷-2-乙酸酯和(2外,6外)-6-氨基二环[2.2.1]庚烷-2-乙酸酯。 Similarly prepared from the appropriate starting material (2, 5 outside) -5-amino-bicyclo [2.2.1] heptane-2-acetate, (2, 6 external) -6-amino-bicyclo [2.2.1 ] heptane-2-acetate and (2, the outer 6) -6-amino-bicyclo [2.2.1] heptane-2-acetate. 中间体实施例13 2-甲氧基-4,5-二氨基苯酚二盐酸盐本标题化合物是依据Ehrlich等人,J.Org.Chem.,1947,12,522的方法,通过将2-甲氧基-4,5-二硝基苯酚氢化而制得的。 4,5-di-aminophenol dihydrochloride salt of the title compound of Example 13 2-Methoxy Intermediate embodiment is based on Ehrlich et al., J.Org.Chem., Method 1947,12,522 by 2- methoxy-4,5-dinitro-phenol hydrogenation obtained. 中间体实施例14 7-羟基-6-甲氧基喹喔啉-2-醇和6-羟基-7-甲氧基喹喔啉-2-醇按照中间体实施例2的方法,通过将4-甲氧基-5-羟基苯-1,2-二胺二盐酸盐与NaOH和乙醛酸乙酯反应制得了本标题化合物。 Example 14 7-Hydroxy-6-methoxy-quinoline intermediates embodiment quinoxaline-2-ol 6-hydroxy-7-methoxy-quinoxalin-2-ol according to the method of Intermediate Example 2, by replacing 4 methoxy-5-hydroxy-1,2-diamine dihydrochloride with NaOH and glyoxylic acid ethyl ester The title compound was prepared. 中间体实施例15 7-羟基-6-甲氧基-2-氯喹喔啉和6-羟基-7-甲氧基-2-氯喹喔啉。 Intermediate Example 15 7-Hydroxy-6-methoxy-2-chloroquinoxaline and 6-hydroxy-7-methoxy-2-chloro-quinoxaline.

按照中间体实施例3的方法,通过将7-羟基-6-甲氧基喹喔啉-2-醇和6-羟基-7-甲氧基喹喔啉-2-醇与POCl3反应制得了本标题化合物。 Following the procedure of Intermediate Example 3 by 7-hydroxy-6-methoxy-quinoxalin-2-ol and 6-hydroxy-7-methoxy-quinoxalin-2-ol and POCl3 to give the title reaction compounds.

本发明式I化合物通过抑制PDGF-R酪氨酸激酶活性而抑制细胞增殖和/或细胞基质产生和/或细胞运动(趋化性)。 The compounds of the invention of formula I by inhibiting PDGF-R tyrosine kinase activity and inhibit cell proliferation and / or cell matrix production and / or cell movement (chemotaxis). 有大量疾病是由于失控的细胞增殖或细胞基质过度生成或失控的编程性细胞死亡(细胞凋亡)引起的。 There are a number of diseases are due to uncontrolled cell proliferation or excessive production of extracellular matrix or runaway programmed cell death (apoptosis) induced. 这些疾病涉及多种细胞类型,并包括病症例如白血病、癌症、成胶质细胞瘤、牛皮癣、炎性疾病、骨疾病、纤维变性疾病、动脉粥样硬化和冠状动脉、股动脉或肾动脉的血管成形术后发生的再狭窄,或纤维增生性疾病例如关节炎,肺、肾和肝脏的纤维变性。 These diseases involve a variety of cell types, and such as leukemia, cancer, glioblastoma, psoriasis, inflammatory diseases, bone diseases, fibrotic diseases, atherosclerosis and coronary artery, femoral artery or renal artery vascular disorders including angioplasty restenosis occurs, or fibroproliferative diseases such as arthritis, lung, kidney and liver fibrosis. 具体地,据报道,PDGF和PDGF-R参与多种特定类型的癌症和肿瘤,例如脑癌、卵巢癌、结肠癌、前列腺癌、肺癌、卡波西肉瘤和恶性黑素瘤。 Specifically, it was reported, PDGF and PDGF-R participation in more specific types of cancer and tumors, such as brain cancer, ovarian cancer, colon cancer, prostate cancer, lung cancer, Kaposi's sarcoma and malignant melanoma. 此外,冠状动脉旁路手术后会发生失控的细胞增殖。 In addition, uncontrolled cell proliferation will occur after coronary artery bypass surgery. 据信抑制酪氨酸激酶活性可用于控制失控的细胞增殖或细胞基质过度生成或失控的编程性细胞死亡(细胞凋亡)。 It is believed that inhibition of tyrosine kinase activity may be used to control the uncontrolled proliferation of cells or overproduction of matrix or uncontrolled cell programmed cell death (apoptosis).

本发明涉及调节和/或抑制细胞信号传导、细胞增殖和/或细胞基质产生和/或细胞运动(趋化性),控制异常的细胞生长和细胞炎性反应。 The present invention relates to regulation and / or inhibition of cell signaling, cell proliferation and / or cell matrix production and / or cell movement (chemotaxis), the control of abnormal cell growth and cell inflammatory response. 更具体来说,本发明涉及取代的喹啉和喹喔啉化合物的应用,所述化合物能通过有效地抑制血小板衍生生长因子受体(PDGF-R)酪氨酸激酶活性而选择性地抑制分化、增殖、基质产生、趋化性或介质释放。 More particularly, the present invention relates to substituted quinoline and quinoxaline compounds application, the compound can effectively inhibit platelet-derived growth factor receptor (PDGF-R) tyrosine kinase activity and selective inhibition of differentiation proliferation, matrix production, chemotaxis or mediator release.

抑制自身磷酸化,即生长因子受体自身的磷酸化,和细胞内底物的受体的磷酸化是在细胞信号传导、细胞增殖、基质产生、趋化性和介质释放过程中涉及的一些生物事件。 Inhibit autophosphorylation, i.e., growth factor receptor phosphorylation itself, and intracellular substrates receptor phosphorylation in cell signaling, cell proliferation, matrix production, chemotaxis and a number of biological processes involved in mediator release events.

通过有效地抑制Lck酪氨酸激酶活性,本发明化合物还可用于治疗移植抵抗和自身免疫性疾病例如类风湿性关节炎、多发性硬化和全身性红斑狼疮,移植物排斥,移植物对宿主疾病,过度增殖性(hyperproliferative)疾病例如肿瘤和牛皮癣,和其中细胞接受促炎性信号的疾病例如哮喘、炎性肠病和胰腺炎。 By effectively inhibiting Lck tyrosine kinase activity, the compounds of the present invention is also useful for treating autoimmune diseases and transplant resistance such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus, graft rejection, graft versus host disease , hyperproliferative (hyperproliferative) diseases such as tumors and psoriasis, and in which cells receive pro-inflammatory signals diseases such as asthma, inflammatory bowel disease and pancreatitis. 在治疗移植物排斥时,本发明化合物可用于预防人体对移植的器官或组织的不良反应,或者在发生这样的反应后对其进行治疗。 In the treatment of graft rejection, the compounds of the present invention are useful for preventing adverse effects on the human body organ or tissue transplantation, or in the event of such a reaction after its treatment. 当预防性地使用时,在进行移植手术前将本发明化合物施用给患者或欲进行移植的组织或器官。 When used prophylactically, before proceeding to transplant the administration of the compounds of the present invention to the patient or the desire of the tissue or organ transplant. 预防性治疗还包括在移植手术后、但是在观察到任何移植不良反应征兆之前进行给药治疗。 Prophylactic treatment also included in the post transplant, but before transplantation observed any signs of adverse reactions administered treatment. 当发生不良反应后再给药时,在表现出外在抵抗症状之后,将本发明化合物直接对患者给药以治疗对移植物的抵抗性。 When the occurrence of adverse reactions after administration, in the performance of resistance to go out after the symptoms, the compounds of the present invention is directly administered to a patient to treat graft resistance.

依据本发明另一个方面,本发明提供了抑制PDGF酪氨酸激酶活性的方法,包括将权利要求1的化合物与含有PDGF酪氨酸激酶的组合物接触。 According to another aspect of the present invention, the present invention provides a method for inhibiting the activity of PDGF tyrosine kinase, comprising a compound of Claim 1 will be in contact with a composition containing a PDGF tyrosine kinase.

依据本发明另一个方面,本发明提供了抑制Lck酪氨酸激酶活性的方法,包括将权利要求1的化合物与含有Lck酪氨酸激酶的组合物接触。 According to another aspect of the present invention, the present invention provides a method of Lck tyrosine kinase activity inhibition, comprising contacting a compound with a composition containing a Lck tyrosine kinase of claim 1.

依据本发明另一个方面,本发明提供了治疗患有或易患可通过施用PDGF-R酪氨酸激酶活性和/或Lck酪氨酸激酶活性抑制剂而得到改善或阻止的疾病例如上述疾病之患者的方法,包括给所述患者施用有效量的式I化合物或含有式I化合物的组合物,或其可药用盐。 According to another aspect of the present invention, the present invention provides a method of treating may be suffering from or susceptible by administering PDGF-R tyrosine kinase activity and / or Lck tyrosine kinase activity inhibitor improve or prevent diseases such as the above-mentioned diseases patient, comprising administering to said patient an effective amount of a compound of formula I or a composition containing a compound of Formula I, or a pharmaceutically acceptable salt thereof.

本文所提及的治疗包括预防性治疗和治疗已发疾病。 Mentioned herein include treatment and prophylaxis and treatment of diseases have been issued.

本发明范围还包括含有可药用量的至少一种式I化合物与可药用载体例如辅药、稀释剂、包衣和赋形剂的药物组合物。 Scope of the present invention also include those containing a pharmaceutically acceptable amount of at least one compound of formula I with a pharmaceutically acceptable carrier such as an adjuvant, diluent, coating and excipient composition.

在实践中,本发明化合物或组合物可以以任意合适的形式给药,例如吸入给药、局部给药、肠胃外给药、直肠给药或口服给药,更优选口服给药。 In practice, the compounds or compositions of the invention may be administered in any suitable form, e.g., inhalation, topically, parenterally, rectally or orally, more preferably administered orally. 更具体的给药途径包括静脉内给药、肌内给药、皮下给药、眼内给药、滑膜内给药、结肠给药、腹膜给药、经上皮给药包括经皮给药、眼(ophthalmic)给药、舌下给药、颊给药、皮肤给药、眼(ocular)给药、通过吹入法的鼻吸入给药、和喷雾给药。 More specific routes of administration include intravenous administration, intramuscular administration, subcutaneous administration, intraocular administration, intrasynovial administration, colonic administration, intraperitoneal administration, transdermal administration epithelial administration includes, ocular (ophthalmic), sublingual, buccal administration, transdermal administration, eye (ocular) administration, by nasal inhalation insufflation, and aerosol delivery.

式I化合物可在能容许以大多数合适途径给药的剂型中施用,并且本发明还涉及含有至少一种适于用作治疗患者的药物的本发明化合物的药物组合物。 The compounds of formula I may be able to tolerate most suitable route of administration in the dosage form is administered, and the present invention also relates to pharmaceutical compositions containing at least one suitable for use as a medicament treating a patient the compounds of the present invention. 这些组合物可依据常规方法,用一种或多种可药用辅料或赋形剂制得。 These compositions can be based on conventional methods, using one or more pharmaceutically acceptable adjuvant or excipient prepared. 辅料尤其包括稀释剂、无菌含水介质和各种无毒有机溶剂。 Excipients particularly include diluents, sterile aqueous media and various non-toxic organic solvents. 本发明组合物可呈片剂、丸剂、粒剂、粉剂、水溶液或悬浮剂、注射液、酏剂或糖浆剂的形式,并且为了获得可药用制剂,本发明组合物可含有一种或多种选自下述物质的辅助剂:甜料例如蔗糖、乳糖、果糖、糖精或Nutrasweet,矫味剂例如薄荷油、冬绿油、或樱桃或橙子调味剂,着色剂,或稳定剂例如对羟基苯甲酸甲酯和对羟基苯甲酸丙酯。 The compositions of the invention may be in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or in the form of syrups, and in order to obtain pharmaceutically acceptable preparations, compositions of the invention may contain one or more kinds of substances selected from the following adjuvants: sweeteners such as sucrose, lactose, fructose, saccharin or Nutrasweet, flavoring agents such as peppermint, oil of winter green, or cherry or orange flavoring agents, coloring agents, or stabilizers such as methylparaben and propylparaben.

载体的选择和活性物质在载体中的含量通常是由产物的溶解性和化学性质、特定给药方式和药物实践中所遵守的原则决定的。 The choice of carrier and content of the active substance in the carrier is usually caused by the solubility and chemical properties of the product, the particular mode of administration and the principle as to comply with pharmaceutical practice determined. 例如,赋形剂如乳糖、柠檬酸钠、碳酸钙、磷酸二钙和崩解剂例如淀粉、藻酸和一些复合硅胶以及润滑剂例如硬脂酸镁、十二烷基硫酸钠和滑石粉可用于制备片剂、锭剂、丸剂、胶囊等。 For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acid and certain complex silica and lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used the manufacture of tablets, troches, pills, capsules and the like. 为了制备胶囊,使用乳糖和液体载体例如高分子量聚乙二醇是有利的。 To prepare a capsule, a liquid carrier such as lactose and high molecular weight polyethylene glycols is advantageous. 可使用各种其它物质以用作包衣或修饰剂量单位的物理形态。 Physical form can be used in various other materials for use as a coating or a modified dosage unit. 例如,可用虫胶、糖或虫胶和糖将片剂、丸剂或胶囊包衣。 For example, shellac, sugar or shellac and sugar tablets, pills, or capsules coated. 当使用水悬浮剂时,其可含有乳化剂或促进悬浮的物质。 When water suspensions, which may contain emulsifying agents or suspending promoting substances. 还可以使用稀释剂例如蔗糖、乙醇、多元醇例如聚乙二醇、丙二醇和甘油、和氯仿或它们的混合物。 May also be used a diluent such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerol, and chloroform or mixtures thereof. 此外,可将活性化合物配制成缓释制剂。 In addition, the active compound may be formulated into sustained release formulations.

为了口服给药,可将活性化合物与例如惰性稀释剂或可同化的可食用载体一起给药,或者可将其包封在硬或软明胶胶囊壳中,或者可将其压制成片,或者直接与食品混合,或者与赋形剂混合,并以吞服片、口腔片、锭剂、胶囊、酏剂、悬浮剂、糖浆剂、糯米纸囊剂(wafer)等形式使用。 For oral administration, the active compound such as an inert diluent or with an assimilable edible carrier administered together, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or directly mixed with food, or mixed with excipients, and to swallow tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers (wafer), etc. used in the form.

为了非胃肠道给药,可使用本发明化合物在植物油例如芝麻油、花生油或橄榄油,或含水有机溶液例如水和丙二醇,可注射有机酯例如油酸乙酯,以及可药用盐的无菌水溶液等中的乳剂、悬浮剂或溶液剂。 For parenteral administration, the compounds of the present invention may be used in a vegetable oil such as sesame oil, peanut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as pharmaceutically acceptable salts of sterile The aqueous solution emulsions, suspensions or solutions. 注射剂型的流动性必须达到易于注射的程度,并且可通过例如使用包衣如卵磷脂,通过维持所需粒剂大小(对于分散体)和通过使用表面活性剂来维持适当流动性。 Injectable dosage forms must be fluid to the extent that easy syringability exists, and for example, by use of a coating such as lecithin, and to maintain proper fluidity by the use of surfactants maintenance of the required granule size (for dispersion) through. 可通过使用延迟吸收的物质例如一硬脂酸铝和明胶来延长注射组合物的吸收。 May, for example, aluminum monostearate and gelatin Prolonged absorption of the injectable compositions by using delaying absorption material. 本发明产物的盐的溶液尤其适用于通过肌内或皮下注射进行给药。 Solution of the product of the present invention is particularly suitable salt is administered by intramuscular or subcutaneous injection. 作为游离碱或可药用盐的活性化合物的溶液可在适当与表面活性剂例如羟丙基纤维素混合的水中制备。 As the base solutions of the active compound or pharmaceutically acceptable salt of the free water can be prepared with a surfactant in an appropriate such as hydroxypropyl cellulose mixed. 还可以在甘油、液体聚乙二醇、和它们的混合物以及油中制备分散体。 Polyethylene glycol may also be prepared in glycerol, liquid, and mixtures thereof and in oils dispersion. 包含所述盐在纯蒸馏水中的溶液的水溶液可用于静脉内给药,条件是适当地调节其pH,将其适当地缓冲和用足量葡萄糖或氯化钠使其等渗,并通过加热、辐射、微量过滤、和/或通过各种抗菌剂和杀真菌剂例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等将其灭菌。 An aqueous solution containing the salt solution in pure distilled water can be used for intravenous administration, the condition is suitably adjusted pH, and be suitably buffered with a sufficient amount of glucose or sodium chloride to make it isotonic, and by heating, irradiation, microfiltration, and / or by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like is sterilized.

无菌注射液是通过将必需量的活性化合物与各种其它上述组分(按照需要)混合在适当溶剂中、然后过滤灭菌制得的。 Sterile injectable solutions by mixing the active compound with a variety of other ingredients necessary amount of the above-mentioned (as required) were mixed in a suitable solvent, followed by filtered sterilization obtained. 分散体一般是通过将各种灭菌的活性组分加到含有分散基质和必需的其它上述组分的无菌载体中制得的。 Dispersions typically by the various sterilized active ingredient is added to a sterile vehicle containing a dispersion matrix and the required other ingredients in the above-described obtained. 对于制备无菌注射液的无菌粉末,优选的制备方法是真空干燥和冷冻干燥技术,通过使用这样的技术可由其无菌过滤溶液制得活性组分与任意其它所需组分的粉末。 For the preparation of sterile injectable solutions, sterile powders, preferred methods of preparation are vacuum drying and freeze-drying techniques, may be prepared by sterile-filtered solution of the active ingredient and any other desired components of the powder by using such techniques.

对于局部给药,可使用含有本发明化合物的凝胶剂(以水或醇为基质)、霜剂或软膏剂。 For topical administration, gels containing the compounds of the present invention (water or alcohol as a substrate), creams or ointments. 还可将本发明化合物掺入到用于在贴剂中施用的凝胶或基质中,其中贴剂能经由经皮屏障控制化合物释放。 Compounds of the invention may also be incorporated in a patch for administration to a gel or matrix, wherein the compound capable of controlling the release of the patch via transdermal barrier.

对于吸入给药,可将本发明化合物溶解或悬浮在用于喷雾器或悬浮液或溶液气雾剂的适当载体中,或者可将本发明化合物吸收或吸附在用于干粉吸入器的适当固体载体上。 For administration by inhalation may be dissolved or suspended in a suitable carrier for aerosol nebulizer or a suspension or solution of the compound of the present invention, or may be absorbed or adsorbed compound of the present invention in a suitable solid carrier for the dry powder inhaler .

直肠给药固体组合物包括依据已知方法配制的并含有至少一种式I化合物的栓剂。 Solid compositions for rectal administration include formulated according to known methods and containing at least one compound of formula I suppositories of.

还可以将本发明组合物配制成这样的制剂,它们抵抗通过对流和/或扩散从血管(动脉和静脉)壁中的快速清除,因此延长了药物在所需作用位点的停留时间。 Compositions of this invention may be formulated into such formulations, they resist by convection and / or diffusion from the vascular (arterial and venous) wall rapid clearance, thus prolonging the drug at the desired site of action of the residence time. 可使用含有本发明化合物的外膜周围贮药库来进行持续释放。 Storage depots may be used around the compound of the present invention comprises the outer membrane to be sustained release. 一种适用于施用本发明化合物的这样的贮药库可以是被硅化橡胶壳环绕的共聚物基质,例如乙烯-乙酸乙烯酯共聚物或聚乙烯醇凝胶。 Such storage depots, one for administration of the compounds of this invention may be a copolymer matrix surrounded by a shell siliconized rubber, such as ethylene - vinyl acetate copolymer or polyvinyl alcohol gel. 或者,可从植入在外膜中的硅氧烷聚合物中局部释放本发明化合物。 Alternatively, in the outer membrane from the implantable silicone polymer in the local release of the compounds of this invention.

将在经皮、经血管递送期间本发明化合物的冲失程度降至最小的方法包括使用不可扩散的药物洗脱(drug-eluting)微颗粒。 The degree of washout period in transdermal, vascular delivery of compounds of the invention comprises a method for minimizing the use of non-diffusion of the drug-eluting (drug-eluting) microparticles. 微颗粒可以由多种合成聚合物例如聚交酯(polyactide)或天然物包括蛋白质或多糖构成。 Microparticles may be composed of a variety of synthetic polymers such as polylactide (polyactide) or a natural product comprising a protein or polysaccharide composition. 这样的微颗粒能以预定方式控制包括药物总剂量及其释放动力学在内的可变参数。 Such micro-particles can be controlled variable parameters including total dose of drug and its release kinetics, including a predetermined manner. 可通过多孔囊式导管或固定在斯滕特固定模上的囊有效地将微颗粒注射到动脉或静脉壁内,并且在血管壁和外膜周组织中保持至少2周。 Effectively microparticles injected through a porous balloon catheter or stent is fixed to the capsule into the arterial or venous wall, and held in the vessel wall and the periadventitial tissue for at least 2 weeks. Reissen等人的(J.Am.Coll.Cardiol.1994;23:1234-1244)中描述了用于局部血管内定点递送治疗剂的制剂和方法,该文献全文引入本发明以作参考。 Reissen et al. (J.Am.Coll.Cardiol.1994; 23: 1234-1244) described a method for the preparation and delivery of local intravascular site-directed therapeutic agent, which is hereby incorporated herein by reference.

本发明组合物还可包含水凝胶,这样的水凝胶是由可用作药物吸收海绵的任何生物相容或无毒(均聚或或杂聚)聚合物例如亲水性聚丙烯酸聚合物制得的。 The compositions of the invention may further comprise a hydrogel, such hydrogels are useful as drug absorption from any biocompatible sponge or a non-toxic (or homo- or hetero) polymer such as a hydrophilic polyacrylic acid polymer obtained. 这样的聚合物描述在例如WO93/08845中,该文献全文引入本发明以作参考。 Such polymers are described in e.g., WO93 / 08845, and which is hereby incorporated herein by reference. 其中一些聚合物,例如得自乙烯和/或氧化丙烯的聚合物可商业获得。 Some polymers, e.g., obtained from ethylene and / or propylene oxide polymers are commercially available.

在使用本发明化合物来治疗与过度增殖性病症有关的疾病时,可以以不同方法施用本发明化合物。 When using the compounds of the invention for treating conditions associated with hyperproliferative diseases, may be administered in different ways the compounds of this invention. 为了治疗再狭窄,通过血管成形术囊将本发明化合物直接施加到血管中,所述囊包衣着用本发明化合物饱和的亲水性膜(例如水凝胶),或通过含有化合物输注室(infusion chamber)的任何其它导管施用本发明化合物,其中能以精确方式将这样的导管施用到预治疗位点,并使得化合物在所治疗的细胞位置局部且高效地释放。 For the treatment of restenosis by angioplasty balloon compound of the present invention is applied directly to the blood vessel, the bladder bag clothing saturated with the compound of the present invention is hydrophilic film (e.g. hydrogel), or by infusion chamber containing the compound ( infusion chamber) of any other catheter administration of the compounds of the present invention, can be precise manner in which such a catheter to a pre-treatment site, and such that the compound is released locally and efficiently at the location of the treated cells. 该给药方法能有利地使化合物与需要治疗的细胞迅速接触。 This method of administration advantageously makes contact with the need to quickly compound treated cells.

本发明治疗方法优选包括将本发明化合物导入到治疗位点。 Therapeutic methods of the invention preferably comprises introducing a compound of the invention to the treatment site. 例如,可将含有组合物的水凝胶直接放置在欲治疗组织的表面,例如在手术期间放置。 For example, the hydrogel-containing composition is placed directly on the surface of tissue to be treated, for example during surgery to place. 有利起见,通过下述方式将水凝胶引入到目的血管内位点上:包衣导管例如囊导管,并递送到血管壁,优选在血管成形术期间递送。 Advantageously sake, in the following manner the hydrogel is introduced into the object of the intravascular site of: coating a catheter, for example a balloon catheter, and delivery to the vessel wall, preferably during angioplasty delivery. 在一种特别有利的方式中,通过囊导管将饱和水凝胶引入到治疗位点。 In a particularly advantageous manner, the balloon catheter through the saturated hydrogel is introduced into the treatment site. 在将导管放置到靶血管中时,可用保护鞘保护囊,以使得在导管引入到血流内后药物冲失降至最小。 When the catheter is placed into the target vessel, the available protective sheath to protect the capsule so that the catheter is introduced to minimize after drug washout within the bloodstream.

在本发明另一实施方案中,通过灌注囊施用本发明化合物。 In another embodiment of the invention, the compounds of the present invention by infusion bag is administered. 这些灌注囊能够通过囊的膨胀维持血流,并因此降低心肌缺血的危险性,还能使得化合物在常压下释放20分钟以上的较长时间,这可能是实现其最佳作用所必需的。 These perfusion balloon to maintain blood flow through the balloon expansion, and thus reduce the risk of myocardial ischemia, such compounds can release a long time of 20 minutes or more at atmospheric pressure, which may be the best action to achieve its required . 或者,可使用具有通道的囊式导管(“具有通道的囊式血管成形术用导管”,Mansfield Medical,BostonScientific Corp.,Watertown,MA)。 Alternatively, using a channel of bladder catheter ("bladder vascular channels have angioplasty catheters", Mansfield Medical, BostonScientific Corp., Watertown, MA). 后者由包衣着一层24个有孔通道的常规囊构成,这些有孔通道通过另外的输注口经由独立的腔灌注。 The latter consists of a layer of clothing, bag 24 has a conventional bag cell passages, these passages have holes through another infusion port perfused via a separate lumen. 可用于实施本发明的各种类型囊式导管,例如双重囊、多孔囊、微孔囊、通道囊、固定在斯滕特固定模上的囊、和水凝胶导管公开在Reissen等人.(1994)的文献中,该文献全文引入本发明以作参考。 Can be used in the practice of this invention, various types of balloon catheters, such as double balloon, porous balloon, microporous balloon, channel balloon, is fixed to the stent balloon, and hydrogel catheters are disclosed in Reissen et al. ( 1994) in the literature, which is hereby incorporated herein by reference.

使用灌注囊式导管是特别有利的,因为能同时获得将囊维持膨胀较长时间(通过保持促进的滑行性)和维持水凝胶的位点特异性这两个效果。 Using perfusion balloon catheter is especially advantageous, because they can be obtained simultaneously inflate the balloon to maintain a long time (by sliding Keeping promoted), and to maintain the hydrogel both site-specific effects.

本发明另一方面涉及含有本发明化合物和泊咯沙姆的药物组合物,例如Poloxamer407是市售的无毒的生物相容多元醇(BASF,Parsippany,NJ)。 Aspect of the invention relates to pharmaceutical compositions containing the compound of the present invention, poloxamer, e.g. Poloxamer407 are commercially available non-toxic, biocompatible polyol (BASF, Parsippany, NJ).

可将浸渗有本发明化合物的泊咯沙姆直接放在治疗组织的表面,例如在手术期间放置。 May be impregnated with the compounds of this invention poloxamers directly on the surface treatment of tissue, such as during surgery is placed. 泊咯沙姆具有与水凝胶基本上相同的优点,同时具有较低粘度。 Poloxamers having substantially the same advantages as hydrogel while having a lower viscosity.

使用含有浸渗着本发明化合物的泊咯沙姆的通道囊式导管是特别有利的。 Containing poloxamer impregnated with a compound of the invention channel bladder catheter is particularly advantageous. 在这种情况下,优点是能在保持促进的滑行性的情况下同时获得将囊维持膨胀较长时间和维持泊咯沙姆的位点特异性这两个效果。 In this case, the advantage is obtained simultaneously inflate the balloon to maintain a long time and maintain poloxamers two site-specific effects in the coasting of maintaining promoted.

活性组分在本发明组合物中的百分比可以变化,其必须占一定比例以获得合适的剂量。 The percentage of active ingredient in the compositions of the present invention may vary, it must be certain proportion to obtain a suitable dosage. 很明显,可大约同时施用几个单位剂型。 Obviously, several units can be administered at about the same dosage form. 所用剂量可由医师或有资格的医疗执业人员确定,并取决于所期望的治疗效果、给药途径和治疗持续时间、以及患者的身体状况。 The dose by a physician or a qualified health care practitioner to determine, and depending on the desired therapeutic effect, route of administration and duration of treatment, and the physical condition of the patient. 对于成人,当吸入给药时,剂量一般为约0.001-约50、优选约0.001-约5mg/kg体重/天,当口服给药时,剂量一般为约0.01-约100、优选0.1-70、更优选0.5-10mg/kg体重/天,当静脉内给药时,剂量一般为约0.001-约10、优选0.01-10mg/kg体重/天。 For an adult, when inhaled, the dosage is typically from about 0.001 to about 50, preferably from about 0.001 to about 5mg / kg body weight / day, when administered orally, the dose is generally about 0.01 to about 100, preferably from 0.1 to 70, more preferably 0.5-10mg / kg body weight / day, when administered intravenously, the dose is generally about 0.001 to about 10, preferably 0.01-10mg / kg body weight / day. 在每一特定情况下,剂量是依据欲治疗患者的特定因素,例如年龄、体重、一般健康状况和可影响本发明化合物效力的其它因素确定的。 In each particular case, the dose is based on factors specific to the patient to be treated, such as age, body weight, general health, and other factors of the compounds of this invention may affect the effectiveness determined.

本发明化合物/组合物可以按照需要频繁给药以获得所需疗效。 The compounds of the invention / compositions may be administered as needed to achieve the desired therapeutic effect frequently. 某些患者可能会对较高或较低剂量迅速起反应,并且可能很低的维持剂量就足够了。 Some patients may be higher or lower doses react quickly, and very low maintenance dose may be sufficient. 对于其它患者,可能需要依据每一特定患者的生理需要以1-4次给药/天的速度进行长期治疗。 For other patients, it may take in accordance with the physiological needs of each particular patient to be administered / day 1-4 times the speed of long-term treatment. 本发明活性产物通常每天口服给药1-4次。 Active product of the present invention is generally administered orally 1-4 times per day. 当然,对于其它患者,必须每天给药不超过1次或2次。 Of course, for other patients, must be administered no more than once per day or twice.

还可以将本发明化合物配制成与其它治疗剂例如活性剂联合使用或者与治疗技术联合使用的形式,以治疗可通过施用式I化合物得以改善的病症,例如:本发明化合物可用于治疗使用任何方法例如气囊扩张术、消融术(ablation)或激光技术的血管成形术后的再狭窄。 Also compounds of this invention may be formulated with other therapeutic agents such as an active agent in combination or in combination with therapeutic techniques in the form, for the treatment by administering a compound of formula I can be ameliorated, e.g.: The compounds of this invention are useful in treating any of the methods used such as balloon angioplasty, angioplasty catheter ablation (ablation) or laser technology shaping restenosis after surgery. 本发明化合物可用于在将斯滕特固定模(stent)置于血管系统中之后在下述两种情况下治疗再狭窄,1)初次治疗血管阻塞,或者2)在使用装置的血管成形术未能给患者提供动脉的情况。 The compounds of the invention can be used in the after stent (stent) is placed in the vascular system in the following two cases the treatment of restenosis, a) the initial treatment of vascular blockage, or 2) the use of the device failed angioplasty provide information to the patient's artery. 本发明化合物可通过口服、肠胃外给药来使用,或者本发明化合物可通过放置在特定装置中或者适当地配制成在斯滕特固定模装置上的包衣来局部施用。 The compounds of this invention may be administered by oral, parenteral use, or compounds of the present invention may be placed in a particular device or suitably formulated as a coating on a stent device according to topical administration.

在一个方面,斯滕特固定模上的包衣是通过将掺合着本发明化合物的聚合材料涂敷在斯滕特固定模装置的至少一个表面上而形成的。 In one aspect, the coating on the stent is obtained by blending a polymeric material compound of the present invention is applied on at least one surface of the stent device is formed.

适于掺合本发明化合物的聚合材料包括具有低加工温度的聚合物,例如聚己内酯、聚(乙烯共聚乙酸乙烯酯)或聚乙酸乙烯酯或硅氧烷树胶橡胶以及具有类似较低加工温度的聚合物。 Compounds of the invention suitable for blending polymeric materials include polymers having a low processing temperatures, e.g., polycaprolactone, poly (ethylene-vinyl acetate copolymer), or polyvinyl acetate or silicone gum rubber and the like having a lower processing temperature of the polymer. 其它合适的聚合物包括能携带和递送治疗药物的不可降解聚合物,例如胶乳、尿烷、聚硅氧烷、苯乙烯-乙烯/丁烯-苯乙烯嵌段共聚物(SEBS),和能携带与递送治疗药物的生物可降解、生物可吸附的聚合物,例如聚-DL-乳酸(DL-PLA)、和聚-L-乳酸(L-PLA)、聚原酸酯、聚亚氨基碳酸酯、脂族聚碳酸酯、和聚磷腈。 Other suitable polymers include non-degradable can carry and deliver the therapeutic agent in the polymer, such as latex, urethane, silicone, styrene - ethylene / butylene - styrene block copolymer (SEBS), and can carry with the delivery of therapeutic drugs biodegradable, bio-adsorbable polymer, such as poly -DL- acid (DL-PLA), and poly -L- lactic acid (L-PLA), polyorthoesters, poly iminocarbonates aliphatic polycarbonates, and polyphosphazenes.

还可以通过将porosigen与治疗药物一起加到聚合物中来把porosigen掺入到负载药物的聚合物中,以形成多孔负载药物的聚合膜。 Can also be added to the porosigen polymer and the therapeutic agent together to load the porosigen drugs incorporated into the polymer in order to form a polymeric film having a porous drug-loaded. “Porosigen”是指当浸在体液中时能溶解或降解以在聚合材料中留下多孔网络的任何部分,例如氯化钠、乳糖或肝素钠的微粒。 "Porosigen" means that when immersed in body fluids can dissolve or degrade to leave any part of the porous network of the polymeric material, such as sodium chloride, lactose, or sodium heparin microparticles. 这样的porosigen留下的孔一般可大至10微米。 Such porosigen leaving large holes generally to 10 microns. 通过porosigen例如聚乙二醇(PEG)、聚氧化乙烯/聚氧化丙烯(PEO/PPO)共聚物形成的孔可例如小于1微米,当然从连续的药物负载聚合基质中形成相分离、并且随后可被体液浸滤出的类似材料也可用于形成小于1微米的孔。 Such as polyethylene glycol (PEG), polyethylene oxide through porosigen ethylene / polypropylene oxide (PEO / PPO) copolymers hole may be formed, for example less than 1 micron, of course, formed from the continuous phase separation of the drug load in the polymeric matrix, and then can be leaching out of the bodily fluid like materials may also be used to form the hole less than 1 micron. 可将聚合材料涂敷在斯滕特固定模上,同时治疗药物和porosigen材料包含在聚合材料中,这样当把斯滕特固定模置于血管中时porosigen溶解或降解,或者可将porosigen溶解并从聚合材料中除去以在聚合材料中形成孔,然后将与斯滕特固定模结合的聚合材料放置在血管中。 The polymeric material may be coated on a stent, and a therapeutic agent and porosigen material contained in the polymeric material, so that when the stent is placed porosigen dissolve or degrade when a blood vessel, or may be dissolved porosigen and removed from the polymeric material to form pores in the polymeric material, and then combined with the stent polymeric material is placed in the vessel.

如果需要的话,还可在药物负载聚合物上涂敷控速膜以限制本发明化合物的释放速度。 If desired, also on the drug loading rate controlling membrane coating polymer compound of the present invention to limit the rate of release. 可通过从溶液中涂敷上包衣或直接涂敷上分层包衣来加上控速膜。 The coating can be applied from a solution or layered coating applied directly to plus speed control film. 涂敷在聚合材料上的控速膜可包含porosigen在控速膜中的均匀分散体,在控速膜中的porosigen可溶解并在控速膜中形成通常大至10微米或小至1微米的孔,但是所形成的孔也可以小于1微米。 Coated on the polymerization rate-controlling membrane material may comprise porosigen in the rate-controlling membrane in a uniform dispersion, porosigen in the rate-controlling membrane can be dissolved and formed generally as large as 10 microns or as small as 1 micron in the rate-controlling membrane hole, but the hole is formed to be less than 1 micron. 在控速膜中的porosigen可以是例如氯化钠、乳糖、肝素钠、聚乙二醇、聚氧化乙烯/聚氧化丙烯共聚物以及它们的混合物。 Porosigen in the rate-controlling membrane may be, for example sodium chloride, lactose, sodium heparin, polyethylene glycol, polyoxyethylene / polyoxypropylene copolymers and mixtures thereof.

另一方面,斯滕特固定模装置上的包衣可这样形成:将本发明化合物施加在斯滕特固定模装置的至少一个表面上以形成生物活性层,然后在生物活性层上施加一层或多层具有足够厚度以提供化合物缓释效果的多孔聚合材料包衣。 On the other hand, the coating on the stent device can be formed by: applying the compound of the present invention on at least one surface of the stent device to form a bioactive layer and then applying a layer of the biologically active layer The porous polymeric material or multi-layer having a sufficient thickness to provide sustained release of the compound coating.

多孔聚合材料可由通过不使用催化剂的蒸气沉积由聚酰胺、聚对亚苯基二甲基或聚对亚苯基二甲基衍生物组成。 The porous polymeric material may be deposited from a polyamide, by not using catalyst vapor-dimethyl-p-phenylene or a poly-p-phenylene di-methyl derivatives thereof. “聚对亚苯基二甲基”是指基于对苯二甲基的聚合物,并且是按照在US5824049中描述的汽相聚合法制得的,该文献引入本发明以作参考。 "Poly-p-phenylene-dimethyl" refers to p-xylylene-based polymers, and in accordance with the vapor phase polymerization as described in US5824049 are prepared, which is herein incorporated by reference.

或者,通过等离子体沉积涂敷多孔聚合材料。 Alternatively, the porous polymeric coating by plasma deposition material. 适用于等离子体沉积的代表性聚合物包括聚(氧化乙烯)、聚(乙二醇)、聚(氧化丙烯),和甲烷、硅氧烷、四氟乙烯四甲基二硅氧烷的聚合物等。 Representative suitable plasma deposited polymer comprises poly (ethylene oxide), poly (ethylene glycol), poly (propylene oxide), and methane, silicone, tetrafluoroethylene tetramethyldisiloxane polymers and so on.

其它合适的聚合物系统包括源自可光聚合的单体例如液体单体的聚合物,所述单体优选具有至少两个交联CC(碳碳)双键,并且是可非气相加成聚合的烯不饱和化合物,在常压下的沸点大于100℃,分子量约为100-1500,并且能易于形成高分子量加聚物。 Other suitable polymer systems include those derived from photopolymerizable monomers such as liquid monomers of the polymer, the monomer preferably has at least two crosslinking CC (carbon-carbon) double bonds, and is a non-gaseous addition polymerizable The ethylenically unsaturated compound, having a boiling point at atmospheric pressure of greater than 100 ℃, molecular weight of about 100-1500, and the high molecular weight addition polymers can be formed easily. 更优选地,单体优选为含有2个或更多个丙烯酸酯或异丁烯酸酯基团/分子的可加成光聚合的多烯不饱和丙烯酸酯或异丁烯酸酯或它们的混合物。 More preferably, the monomer is preferably containing two or more acrylate or methacrylate groups / molecule of an addition photopolymerizable polyethylenically unsaturated acrylic or methacrylic acid ester or mixtures thereof. 这样的多官能团丙烯酸酯的代表性实例是乙二醇二丙烯酸酯、乙二醇二异丁烯酸酯、三羟甲基丙烷三丙烯酸酯、三羟甲基丙烷三异丁烯酸酯、季戊四醇四丙烯酸酯、或季戊四醇四异丁烯酸酯、1,6-己二醇二异丁烯酸酯、和二甘醇二异丁烯酸酯。 Representative examples of such polyfunctional acrylates are ethylene glycol diacrylate, ethylene glycol dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, pentaerythritol tetraacrylate, or pentaerythritol tetra methacrylate, 1,6-hexanediol dimethacrylate, and diethylene glycol dimethacrylate.

在某些特别情况中,也可使用一丙烯酸酯例如丙烯酸正丁酯、异丁烯酸正丁酯、丙烯酸2-乙基己酯、丙烯酸月桂酯、和丙烯酸2-羟基丙酯。 In some special cases, also be used an acrylic ester such as n-butyl acrylate, n-butyl methacrylate, 2-ethylhexyl acrylate, lauryl acrylate, and 2-hydroxypropyl acrylate. 少量(甲基)丙烯酸的酰胺例如N-羟甲基异丁烯酰胺丁基醚也是合适的,N-乙烯基化合物例如N-乙烯吡咯烷酮、脂族一元羧酸的乙烯基酯例如油酸乙烯酯、二醇的乙烯基醚例如丁二醇-1,4-二乙烯基醚和烯丙基醚以及烯丙基酯也是合适的。 A small amount of (meth) acrylic acid amides such as N- methylol methacrylamide butyl ether are also suitable, N- vinyl compounds such as N- vinyl pyrrolidone, aliphatic monocarboxylic acids such as oleic acid vinyl esters, vinyl two vinyl ethers of alcohols such as butanediol-1,4-divinyl ether and allyl ether and allyl ester are also suitable. 还包括其它单体例如二环氧化物或多环氧化物例如丁二醇-1,4-一缩二甘油醚或双酚A一缩二甘油醚与(甲基)丙烯酸的反应产物。 Also included are other monomers such as diepoxide or polyepoxide such as the reaction product of 1,4-butanediol diglycidyl ether or dipropylene bisphenol A diglycidyl ether and diethylene (meth) acrylic acid. 对于具体应用,可合适地选择单体或其混合物来改变光聚合液体分散介质的特征。 For specific applications, may be suitably selected monomer or mixture thereof to change the photopolymerizable liquid dispersing medium characteristics.

其它有用的聚合物系统包括生物相容的、并且当植入斯滕特固定模时将对血管的刺激降至最小的聚合物。 Other useful polymer systems include a biocompatible, and when the stent implanted Rusitengte will minimize vascular irritation when the polymer. 根据所需的释放速度或者所需的聚合物稳定性程度,聚合物可以是生物稳定或可生物吸收的聚合物。 According to the degree of stability of the polymer or the desired release rate desired, the polymer may be biostable or bioabsorbable polymer. 可使用的可生物吸收的聚合物包括聚(L-乳酸)、聚己内酯、聚(丙交酯-共聚-乙交酯)、聚(羟基丁酸酯)、聚(羟基丁酸酯-共聚-戊酸酯)、聚二氧杂环己酮、聚原酸酯、聚酐、聚(乙醇酸)、聚(D,L-乳酸)、聚(乙醇酸-共聚-碳酸亚丙基酯)、聚磷酸酯、聚磷酸酯尿烷、聚(氨基酸)、氰基丙烯酸酯、聚(碳酸亚丙基酯)、聚(亚氨碳酸酯)、共聚(醚-酯)(例如PEO/PLA)、聚亚烷基草酸酯、聚磷腈,和生物分子例如纤维蛋白、纤维蛋白原、纤维素、淀粉、胶原和透明质酸。 Bioabsorbable polymers can be used include poly (L- lactic acid), polycaprolactone, poly (lactide - copolymerization - glycolide), poly (hydroxybutyrate), poly (hydroxybutyrate - copolymerization - valerate), poly dioxanone, polyorthoesters, polyanhydrides, poly (glycolic acid), poly (D, L- lactic acid), poly (glycolic acid - copolymers - propylene carbonate ), polyphosphoester, polyphosphoester urethane, poly (amino acids), cyanoacrylates, poly (propylene carbonate), poly (imino carbonate), copoly (ether - esters) (e.g. PEO / PLA ), polyalkylene oxalates, polyphosphazenes, and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid. 还可以使用具有较低慢性组织反应的生物稳定聚合物,例如聚氨酯、硅氧烷和聚酯,也可以使用能溶解并固化或聚合在斯滕特固定模上的其它聚合物,例如聚烯烃、聚异丁烯和乙烯-α烯烃共聚物;丙烯酸聚合物和共聚物、乙烯基卤聚合物和共聚物例如聚氯乙烯;聚乙烯基醚,例如聚乙烯基甲基醚;聚偏二卤代乙烯,例如聚偏二氟乙烯和聚偏二氯乙烯;聚丙烯腈,聚乙烯基酮,聚乙烯基芳族化合物例如聚苯乙烯,聚乙烯基酯例如聚乙酸乙烯酯;乙烯基单体彼此间的共聚物和乙烯基单体与烯烃的共聚物,例如乙烯-异丁烯酸甲酯共聚物、丙烯腈-苯乙烯共聚物、ABS树脂、和乙烯-乙酸乙烯酯共聚物;聚酰胺,例如Nylone66和聚己内酰胺;烷基树脂,聚碳酸酯;聚甲醛;聚酰亚胺、聚醚;环氧树脂、聚氨酯;人造纤维;三乙酸人造纤维;纤维素、乙酸纤维素、丁酸纤维素;乙酸丁酸纤维素;玻璃纸、硝酸纤维素;丙酸纤维素;纤维素醚;和羧甲基纤维素。 You can also use a biostable polymer having a relatively low chronic tissue response, such as polyurethanes, silicones, and polyesters, can also be used other dissolved and cured or polymerized on the stent in a polymer, e.g. a polyolefin, polyisobutylene and ethylene -α-olefin copolymers; acrylic polymers and copolymers, vinyl halide polymers and copolymers such as polyvinyl chloride; polyvinyl ethers such as polyvinyl methyl ether; polyvinylidene vinyl halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics such as polystyrene, polyvinyl esters such as polyvinyl acetate; vinyl monomers with each other of and copolymers of vinyl monomers with olefins, e.g., ethylene - methyl methacrylate copolymers, acrylonitrile - styrene copolymers, ABS resins, and ethylene - vinyl acetate copolymer; polyamides, such as poly Nylone66 and caprolactam; alkyl resins, polycarbonates; polyoxymethylene; polyimides, polyethers; epoxy resins, polyurethane; rayon; triacetate rayon; cellulose, cellulose acetate, cellulose butyrate; acetate butyrate cellulose; cellophane, cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethyl cellulose.

除了等离子体沉积和气相沉积以外,可采用在斯滕特固定模表面上涂敷各种包衣的其它技术。 In addition to plasma deposition and vapor phase deposition, other techniques may be employed in coating the surface of a variety of stent coating. 例如,可将聚合物溶液涂敷在斯滕特固定模上,并让溶剂蒸发,由此在斯滕特固定模表明上留下了聚合物和治疗物质的包衣。 For example, the polymer solution may be coated on the stent and the solvent allowed to evaporate, thereby leaving on the stent showed that the coating polymer and the therapeutic substance. 在斯滕特固定模上涂敷溶液一般可通过将溶液喷雾到斯滕特固定模上或者将斯滕特固定模浸泡在聚合物溶液中来进行。 In the stent coating solution can be prepared by the general solution is sprayed onto the stent or the stent is immersed in the polymer solution is performed.

本发明化合物可用于与任何抗凝血剂、抗血小板剂、抗血栓形成剂或血纤维蛋白原溶解剂(profibrinolytic agent)联合使用来治疗再狭窄。 The compounds of the invention may be used with any anticoagulant, antiplatelet agents, anti-thrombotic agent or fibrinogen solubilizer (profibrinolytic agent) used in combination to treat restenosis. 通常在手术前、手术期间或手术后用这些类治疗剂对患者进行并行治疗,以使手术能安全地进行或者防止血栓形成的有害作用。 Usually before surgery, during surgery or after surgery with these classes of therapeutic agents for the treatment of patients in parallel, so that the operation can be performed safely or to prevent deleterious effects of thrombus formation. 作为已知抗凝血剂、抗血小板剂、抗血栓形成剂或血纤维蛋白原溶解剂的治疗剂的一些实例包括肝素、低分子量肝素、戊糖、血纤蛋白原受体拮抗剂、凝血酶抑制剂、Xa因子抑制剂或VIIa因子抑制剂的所有制剂。 As known anticoagulants, antiplatelet agents, anti-thrombotic agent or a solubilizer fibrinogen Some examples of therapeutic agents include heparin, low molecular weight heparin, pentose, fibrinogen receptor antagonists, thrombin inhibitors, Xa factor inhibitors or factor VIIa inhibitor of all preparations.

本发明化合物可用于与抗高血压剂或胆固醇或脂质调节剂联合使用来实施与高血压或动脉粥样硬化治疗并行进行的再狭窄或动脉粥样硬化的治疗。 The compounds of this invention can be used with an anti-hypertensive agent or cholesterol or lipid regulating agent used in combination to implement restenosis or atherosclerosis and hypertension treatment or treatment of atherosclerosis in parallel. 可用于治疗高血压的治疗剂的一些实例包括下述种类的化合物:β-阻滞剂、ACE抑制剂、钙通道拮抗剂和α-受体拮抗剂。 Some examples can be used in the treatment of hypertension therapeutic agents include the following classes of compounds: β- blockers, ACE inhibitors, calcium channel antagonists and α- receptor antagonists. 可用于治疗高胆固醇水平或失调的脂质水平的治疗剂的一些实例包括作为已知HMGCoA还原酶抑制剂的化合物、fibrate类化合物。 Some examples can be used to treat high cholesterol levels or lipid levels disorder therapeutic agents include compounds known as HMGCoA reductase inhibitors, fibrate compounds.

本发明化合物还可单独使用或者与可用于治疗癌症的已知化合物联合使用来治疗各种类型癌症。 The compounds of the invention may also be used alone or in combination with known compounds for treating cancer in combination to treat various types of cancer.

应当理解,本发明包括本发明化合物与一种或多种上述类型治疗剂的组合。 It should be understood that the present invention comprises a combination of a compound with one or more of the above types of therapeutic agents of the present invention.

在依据文献描述进行的试验中,在本发明范围内的化合物表现出显著的药理活性,我们相信这些试验结果与在人和其它哺乳动物中的药理活性相关。 In tests carried out according to the literature described, the compounds within the scope of the present invention exhibit significant pharmacological activity, we believe these results associated with pharmacological activity in humans and other mammals. 下述体外和体内药理试验结果是本发明化合物的典型特征。 The following pharmacological in vitro and in vivo test results are typical characteristics of compounds of the invention.

药物组合物制备和药理试验部分在本发明范围内的化合物表现出显著的蛋白酪氨酸激酶抑制剂活性,并具有下述治疗价值:作为抗细胞增殖剂用于治疗一些病症包括牛皮癣、动脉粥样硬化和再狭窄损伤。 Preparation and pharmacological testing portion of the drug composition comprising a compound within the scope of this invention exhibit significant activity of protein tyrosine kinase inhibitor, and having the following therapeutic value: as anti-cell proliferative agents useful in the treatment of disorders including psoriasis, atherosclerosis atherosclerosis and restenosis injuries. 在本发明范围内的化合物表现出调节和/或抑制细胞信号传导和/或细胞增殖和/或基质产生和/或趋化性和/或细胞炎性反应的活性,并且可用于预防或延迟这样的病症的发作或复发或治疗这样的病症。 Within the scope of the present invention exhibit compounds that modulate and / or inhibition of cell signaling and / or cell proliferation and / or matrix production and / or chemotaxis and / or cell inflammatory response activity, and may be used to prevent or delay such onset or recurrence of a disorder or the treatment of such disorders.

为了确定本发明化合物的有效性,使用在本领域内接受的、并且被公认与在哺乳动物中的药理活性相关的下述药理试验。 In order to determine the effectiveness of compounds of the invention, using accepted in the art, and are recognized with pharmacological activity in mammals associated with the following pharmacological tests. 已在这些不同试验中测试了在本发明范围内的化合物,并且认为所得结果与有用的细胞分化介质活性相关。 Compounds have been tested within the scope of the invention in these various tests, and the results obtained were considered useful activity related to cell differentiation medium. 相信这些试验结果能给药理和药物化学领域的技术人员提供足够的信息,以确定出在一个或多个其中所述的治疗中使用所研究化合物的参数。 Believe that these results will give pharmacological and medicinal chemistry arts in the art to provide sufficient information to determine the parameters used in the treatment of the studied compound wherein said one or more of the. 1. PDGF-R酪氨酸激酶自身磷酸化ELISA测定本标题测定是按照Dolle等人(J.Med.Chem 1994,37,2627)的方法进行的(该文献引入本发明以作参考),但是不同之处在于使用如下所述的来自人主动脉平滑肌细胞(HAMSC)的细胞溶解产物。 1. PDGF-R tyrosine kinase autophosphorylation ELISA assay is measured in accordance with the present title Dolle et al. (J.Med.Chem 1994,37,2627) method (which is herein incorporated by reference), but except that cells used as described below from human aortic smooth muscle cells (HAMSC) lysate. 2.有丝分裂测定一般方法a.细胞培养将人主动脉平滑肌细胞(第4-9代)以6000个细胞/孔的浓度铺在含有生长支持培养基的96孔平板中,并生长2-3天。 2. Determination of mitosis general approach a. Cell culture human aortic smooth muscle cells (4-9 generation) at a concentration of 6000 cells / well spread support growth medium containing 96-well plates and grown for 2-3 days . 在达到大约85%融合时,用不含血清的培养基(SFM)中止细胞生长。 Upon reaching about 85% confluence, serum-free medium (SFM) suspension cell growth. b.有丝分裂测定剥夺血清24小时后,除去培养基,并代之以在SFM中的测试化合物/载体(200μl/孔)。 b. postmitotic measured serum deprivation for 24 hours, the medium was removed, and replaced in SFM test compound / vehicle (200μl / well). 化合物是以10mM的浓度溶解在细胞培养物DMSO中,并在SFM中进一步稀释。 Compound is the concentration of 10mM dissolved in cell culture DMSO and further diluted in the SFM.

与化合物预孵育30分钟后,用PDGF以10ng/mL的浓度刺激细胞。 After pre-incubation with the compound for 30 minutes with PDGF at a concentration of 10ng / mL of the stimulator cells. 对于每一化合物浓度,用刺激和未刺激的孔以一式两份的方式进行测定。 For each compound concentration, with stimulation and unstimulated wells in a manner determined in duplicate.

4小时后,加入1μCi3H胸腺嘧啶核苷/孔。 After 4 hours, added 1μCi3H thymidine / well.

加入生长因子24小时后,中止培养物的生长。 24 hours after the growth factor was added, the suspension culture growth thereof. 用胰蛋白酶解离细胞,并用自动细胞收获器(Wallac MachII96)将细胞收获到滤器垫上。 Cells were dissociated with trypsin, and with an automatic cell harvester (Wallac MachII96) The cells were harvested into a filter mat. 将该滤器垫在闪烁计数器(Wallac Betaplate)中计数,以测定掺入DNA的标记。 The filter pads in a scintillation counter (Wallac Betaplate) counted to determine incorporation of DNA markers. 3.趋化性测定从ATCC获得早代人主动脉平滑肌细胞(HASMC)。 3. chemotaxis assay get early generation of human aortic smooth muscle cells (HASMC) from ATCC. 将细胞在Clonetics SmGM 2 SingleQuots(培养基)中生长,使用第4-10代细胞。 The cells Clonetics SmGM 2 SingleQuots (medium) growth, using 4-10 cells. 当细胞达到80%汇合时,向培养基中加入荧光探针—钙黄绿素AM(5mM,Molecular Probe),将细胞培养30分钟。 When the cells reached 80% confluence, the medium was added to the fluorescent probe - calcein AM (5mM, Molecular Probe), the cells were incubated for 30 minutes. 用HEPES缓冲盐水洗涤后,用胰蛋白酶解离细胞,并用含有0.1%BSA、10mM谷氨酰胺和10%胎牛血清的MCDB131缓冲液(Gibco)中和。 After washing with HEPES buffered saline, cells were dissociated with trypsin, and containing 0.1% BSA, 10mM glutamine and 10% fetal bovine serum MCDB131 buffer (Gibco) neutralization. 离心后,将细胞再洗涤一次,并以30000个细胞/50mL的浓度重悬在不含胎牛血清的相同缓冲液中。 After centrifugation, the cells were washed once, and the concentration of 30,000 cells / 50mL resuspended in the same buffer without fetal bovine serum. 将细胞与不同浓度的式I化合物(终DMSO浓度=1%)在37℃培养30分钟。 The compounds of formula I with different concentrations of cells (final DMSO concentration = 1%) were cultured at 37 ℃ 30 minutes. 为了测定趋化性,使用96孔改进的Boyden室(Neuroprobe,Inc.)和具有8mm孔的聚碳酸酯膜(Poretics,CA)。 For the determination of chemotaxis, using a 96-well modified Boyden chambers (Neuroprobe, Inc.) And a polycarbonate film having 8mm hole (Poretics, CA). 用胶原(Sigma C3657,0.1mg/mL)包被该膜。 The film was coated collagen (Sigma C3657,0.1mg / mL). 将含有和不含有式I化合物的在缓冲液中的PDGF-ββ(3ng/mL)加到下面的室中。 Containing and not containing the buffer PDGF-ββ (3ng / mL) the compounds of formula I is added to the following chamber. 将含有和不含有抑制剂的细胞(30000)加到上部的室中。 Containing cells with and without inhibitor (30,000) was added to the upper portion of the chamber. 将细胞培养4小时。 The cells were cultured for 4 hours. 取出滤膜,并除去在膜上侧的细胞。 Remove the membrane, and removing the membrane side of the cell. 干燥后,使用CytofluorII(Millipore)在485/530nm的激发/发射波长测定在膜上的荧光。 After drying, use CytofluorII (Millipore) at excitation 485 / 530nm / emission wavelength in fluorescence film. 在每一实验中,从6个平行测定中获得平均细胞迁移。 In each experiment, an average cell migration from six parallel assays. 由使用DMSO处理的对照值确定抑制百分比。 By the use of DMSO-treated control value determining percent inhibition. 从5个点的浓度-依赖性抑制计算IC50值。 5 points from the concentration - dependent inhibition IC50 values were calculated. 所得结果以从5个这样实验获得的平均值SEM表示。 The obtained results obtained from five such experiments represent mean SEM. 4.EGF-受体纯化按照Yarden和Schlessinger的方法纯化EGF-受体。 4.EGF- receptor purified receptor purified according to Yarden and Schlessinger EGF- approach. 将A431细胞在80cm2瓶中生长至汇合(2107个细胞/瓶)。 The A431 cells were grown to confluence in 80cm2 flasks (2 107 cells / bottle). 用PBS将细胞洗涤2次,并用含有11.0mmol EDTA的PBS收获细胞(在37℃1小时,并以600g离心10分钟)。 The cells were washed with PBS twice, and the cells were harvested with PBS containing 11.0mmol EDTA (in the 37 ℃ 1 h and centrifuged for 10 minutes to 600g). 将细胞以2107个细胞/mL的浓度溶解在冷的溶解缓冲液(50mmol Hepes缓冲液,pH7.6,1%Triton X-100,150mmol NaCl,5mmol EGTA,1mmol PMSF,50mg/mL抑酶肽,25mmol苄脒,5mg/mL亮抑蛋白酶肽,和10mg/mL大豆胰蛋白酶抑制剂)中,在4℃保持20分钟。 The cells at a concentration of 2 107 cells / mL dissolved in cold lysis buffer (50mmol Hepes buffer, pH7.6,1% Triton X-100,150mmol NaCl, 5mmol EGTA, 1mmol PMSF, 50mg / mL aprotinin peptide, 25mmol benzamidine, 5mg / mL leupeptin, and 10mg / mL soybean trypsin inhibitor), and kept at 4 ℃ 20 minutes. 以100000g离心30分钟后,将上清液施加到WGA-琼脂糖柱上(100mL填充树脂/2107细胞),并在4℃摇动2小时。 In 100000g rpm for 30 minutes, the supernatant was applied to WGA- Sepharose column (100mL filler resin / 2 107 cells) and shaken at 4 ℃ 2 hours. 除去未吸收的材料,将树脂依次用HTN缓冲液(50mmol Hepes,pH7.6,0.1%Triton X-100,150mmol NaCl)洗涤2次、用含有1MNaCl的HTN缓冲液洗涤2次、和用HTNG缓冲液(50mmol Hepes,pH7.6,0.1%Triton X-100,150mmol NaCl,和10%乙二醇)洗涤2次。 Removal of non-absorbable material, the resin washed sequentially with HTN buffer (50mmol Hepes, pH7.6,0.1% Triton X-100,150mmol NaCl) was washed twice with HTN buffer containing 1MNaCl washed with 2 times, and with HTNG buffer solution (50mmol Hepes, pH7.6,0.1% Triton X-100,150mmol NaCl, and 10% ethylene glycol) twice. 用含有0.5M N-乙酰基-D-葡萄糖胺的HTNG缓冲液分批洗脱EGF受体(200mL/2107细胞)。 With HTNG buffer containing 0.5M N- acetyl -D- glucosamine batch elution of the EGF receptor (200mL / 2 107 cells). 将洗脱物以等分试样的形式在-70℃贮存,在使用前用TMTNG缓冲液(50mmol Tris-Mes缓冲液,pH7.6,0.1%Triton X-100,150mmol NaCl,10%乙二醇)稀释。 The eluate was stored as aliquots at -70 ℃, before use with TMTNG buffer (50mmol Tris-Mes buffer, pH7.6,0.1% Triton X-100,150mmol NaCl, 10% ethylene alcohol) dilution. 5.抑制EGF-R自身磷酸化将A431细胞在包被着人纤连蛋白的组织培养皿中生长至汇合。 5. The inhibition of EGF-R autophosphorylation in A431 cells will be coated with human fibronectin were grown to confluence in tissue culture dishes. 用冰冷的PBS洗涤2次后,加入500mL/培养皿裂解缓冲液(50mmolHepes,pH7.5,150mmol NaCl,1.5mmol MgCl2,1mmol EGTA,10%甘油,1%tritonX-100,1mmol PMSF,1mg/mL抑酶肽,1mg/mL亮抑蛋白酶肽)将细胞裂解,在4℃培养5分钟。 Washed 2 times with ice-cold PBS, add 500mL / dish of lysis buffer (50mmolHepes, pH7.5,150mmol NaCl, 1.5mmol MgCl2,1mmol EGTA, 10% glycerol, 1% tritonX-100,1mmol PMSF, 1mg / mL Aprotinin, 1mg / mL leupeptin) to the cell lysate, incubated at 4 ℃ 5 minutes. 用EGF刺激(500mg/mL 10分钟,37℃)后,用抗EGF-R(Ab108)进行免疫沉淀,将自身磷酸化反应(50mL等分试样,3mCi[g-32P]ATP)样品在2或10mM本发明化合物存在下于4℃反应2分钟。 After stimulation with EGF (500mg / mL 10 分钟, 37 ℃), with anti-EGF-R (Ab108) for immunoprecipitation, the autophosphorylation reaction (50mL aliquot, 3mCi [g-32P] ATP) sample 2 or compounds of the present invention in the presence of 10mM at 4 ℃ for 2 minutes. 通过加入电泳样品缓冲液中止该反应。 By the addition of electrophoresis sample buffer The reaction was quenched. 进行SDA-PAGE分析(7.5%els),然后进行放射自显影分析,通过X-射线胶片测光密度扫描定量测定该反应。 Conduct SDA-PAGE analysis (7.5% els), followed by autoradiographic analysis, the reaction is measured by X- ray film quantitative scanning densitometry. a.细胞培养如下所述制备称为HER14和K721A的细胞:用野生型EGF-受体或缺乏酪氨酸激酶活性的EGF-受体突变体(在ATP-结合位点的Lys721被Ala残基替代)的cDNA结构转染缺乏内源性EGF-受体的NIH3T3细胞(克隆2.2)(得自C.Fryling,NCI,NIH)。 Preparation of a cell culture as described below and K721A called HER14 cells: with wild-type EGF- receptor lacking tyrosine kinase activity or EGF- receptor mutant (in the ATP- binding site Lys721 is Ala residue substitution) of cDNA transfection structure devoid of endogenous receptors EGF- NIH3T3 cells (clone 2.2) (obtained from C.Fryling, NCI, NIH). 将所有细胞在含有10%胎牛血清的DMEM中(Hyclone,Logan,Utah)生长。 All cells containing 10% fetal calf serum in DMEM (Hyclone, Logan, Utah) growth. 6.使用市售试剂盒测定对PKA知PKC的选择性a.Pierce Colorimetric PKA测定试剂盒,Spinzyme Format方案简述:PKA酶(牛心脏)1U/分析管Kemptide肽(染料标记的)底物45分钟于30℃在570nm的吸光度b. Pierce Colorimetric PKC测定试剂盒,Spinzyme Format方案简述:PKC酶(大鼠脑)0.025U/分析管Neurogranin肽(染料标记的)底物30分钟于30℃在570nm的吸光度7. p56lck酪氨酸激酶抑制活性测定依据在US5714493中公开的方法测定p56lck酪氨酸激酶抑制活性,该文献引入本发明以作参考。 6. Use a commercially available kit known selective determination of PKA a.Pierce PKC of Colorimetric PKA assay kit, Spinzyme Format Programme Description: PKA enzyme (bovine heart) 1U / analyzer tube Kemptide peptide (dye-labeled) substrate 45 . at 30 ℃ absorbance at 570nm was measured minutes b Pierce Colorimetric PKC kit, Spinzyme Format Programme Description: PKC enzyme (rat brain) 0.025U / analyzer tube Neurogranin peptide (dye labeled) substrate 30 minutes at 30 ℃ in 7. p56lck 570nm absorbance tyrosine kinase activity assay according to the method disclosed in US5714493 measuring inhibition of p56lck tyrosine kinase inhibitory activity, which is hereby incorporated herein by reference.

或者依据下述方法测定酪氨酸激酶抑制活性。 Or inhibit the tyrosine kinase activity was measured according to the following method. 首先如下所述将底物(含有酪氨酸的底物,p56lck识别的Biot-(βAla)3-Lys-Val-Glu-Lys-Ile-Gly-Glu-Gly-Thr-Tyr-Glu-Val-Val-Tyr-Lys-(NH2),1μM)磷酸化:在有或没有给定浓度的测试化合物存在下,给予一定量的从克隆酵母中纯化(该酶的纯化是通过标准方法进行的)的酶(通过在酵母结构中表达p56lck基因而制得的酶),在ATP(10μM),MgCl2(2.5mM),MnCl2(2.5mM),NaCl(25mM),DTT(0.4mM)存在下,在Hepes 50mM,pH7.5中于室温磷酸化10分钟。 First, as described below the substrate (substrate containing tyrosine, p56lck identified Biot- (βAla) 3-Lys-Val-Glu-Lys-Ile-Gly-Glu-Gly-Thr-Tyr-Glu-Val- Val-Tyr-Lys- (NH2), 1μM) phosphorylation: with or without the presence of a given concentration of the test compound, to give a certain amount of purified from clone yeast (purification of the enzyme is carried out by standard methods) enzyme (gene in yeast by expression p56lck structure prepared enzyme), in ATP (10μM), MgCl2 (2.5mM), MnCl2 (2.5mM), NaCl (25mM), DTT (0.4mM) in the presence, in Hepes 50mM, pH7.5 at room temperature for 10 minutes phosphorylation. 总的反应体积是50μl,在黑色96-孔氟平板中进行反应。 The total reaction volume is 50μl, the reaction in black 96-well plates fluorine. 通过加入150μl终止缓冲液(100mM Hepes pH7.5,KF 400mM,EDTA 133mM,BSA 1g/l)来终止反应,该终止缓冲液含有0.8μg/ml用Europium穴合物(PY20-K)标记的抗酪氨酸抗体和4μg/ml用别藻蓝蛋白标记的链霉抗生物素蛋白(XL665)。 Terminated by the addition of 150μl of anti-buffer (100mM Hepes pH7.5, KF 400mM, EDTA 133mM, BSA 1g / l) to terminate the reaction, the termination buffer containing 0.8μg / ml labeled with Europium cryptate (PY20-K) of tyrosine streptavidin antibody and 4μg / ml with allophycocyanin-labeled avidin (XL665). 链霉抗生物素蛋白和抗酪氨酸抗体的标记是通过Cis-Bio Intemational(法国)进行的。 Streptavidin and anti-tyrosine antibodies labeled by Cis-Bio Intemational (France) performed. 用能测定时间分辨均匀荧光转移(在337nm激发,在620nm和665nm读取)的PackardDiscovery计数器将该混合物计数。 Can be measured by time-resolved fluorescence uniform transfer (excitation at 337nm, 620nm and 665nm in read) PackardDiscovery counter counts the mixture. 磷酸化酪氨酸的浓度以665nm信号/620nm信号比例表示。 Concentration of tyrosine phosphorylation signal represented by 665nm / 620nm signal ratio. 通过用缓冲液替换酶来获得空白。 Blank obtained by replacing enzyme by buffer. 特异信号是不用抑制剂获得的该比例与使用空白所获得的比例的差异。 The specific signal is proportional to the blank without using inhibitors of the obtained ratio obtained difference. 计算特异信号的百分比。 Percentage of specific signal is calculated. IC50是使用Xlfit软件由一式两份的10个抑制剂浓度计算的。 IC50 is Xlfit software by using a duplicate 10 inhibitor concentration calculations. 参照化合物是staurosporine(Sigma),其IC50为306nM(n=20)。 Reference compound is staurosporine (Sigma), with an IC50 of 30 6nM (n = 20). 8.测定体外肿瘤抑制按如下所述测定本发明化合物在体外抑制肿瘤的生长:将C6大鼠神经胶质瘤细胞系(得自ATCC)以单层形式在含有2mML-谷氨酰胺、200U/ml青霉素、200μg/ml链霉素、并补充有10%(v/v)热失活的胎牛血清的Dubelcco's Modified Eagle Medium中生长。 8. Determination of in vitro determination of tumor suppression as described below in the compounds of the invention inhibit tumor growth in vitro: the C6 rat glioma cell line (obtained from ATCC) in a single layer containing 2mML- glutamine, 200U / ml penicillin, 200μg / ml streptomycin, and supplemented with 10% (v / v) heat-inactivated fetal bovine serum Dubelcco's Modified Eagle Medium grown. 用胰蛋白酶处理指数生长期的细胞,用PBS洗涤,并在完全培养基中稀释至终浓度为6500个细胞/ml。 Trypsinized cells in exponential growth phase, washed with PBS, and diluted in complete medium to a final concentration of 6500 cells / ml. 向该细胞悬浮液(2.5ml)中加入50μl测试药物或对照溶剂,加入保持在45℃的0.4ml 2.4%Noble Difco琼脂,并混合。 To the cell suspension (2.5ml) was added in 50μl test drug or control solvent was maintained at 45 ℃ of 0.4ml 2.4% Noble Difco agar, and mixed. 将该混合物立即倒入培养皿中,在4℃放置5分钟。 The mixture was immediately poured into a Petri dish, placed in 4 ℃ 5 minutes. 在5%CO2气氛下于37℃培养12天后,测定细胞克隆(>60个细胞)的数目。 Cultured for 12 days at 37 ℃ in an atmosphere of 5% CO2, cells clone number (> 60 cells). 每一药物都是以一式两份的方式以10、1、0.1和0.01μg/ml(在琼脂中的终浓度)的浓度测试的。 Each drug is to duplicate the way to 10,1,0.1 and 0.01μg / ml (final concentration in the agar) concentrations tested. 结果以相对于未处理对照组的克隆发生抑制百分比表示。 The results relative to the untreated control clone percent inhibition occurs. IC50是从对于每一药物浓度所测定的平均值的半对数图中以图解方式确定的。 IC50 for each drug concentration is the mean value of the measured semi-logarithmic diagram graphically determined. 9.测定体内肿瘤抑制使用如US5700823和US5760066中所描述的皮下异种移植模型测定本发明化合物在体内对肿瘤生长的抑制,在所述模型中,给小鼠移植C6神经胶质瘤细胞,并用游标卡尺测定肿瘤生长。 9. Determination of in vivo tumor suppression using e.g. subcutaneous xenograft model US5700823 and US5760066 described compounds of the present invention is determined in vivo inhibition of tumor growth, in the model, mice were transplanted C6 glioma cells, and with a vernier caliper Determination of tumor growth.

通过上述实验方法获得的结果表明,在本发明范围内的化合物具有有用的PDGF受体蛋白酪氨酸激酶抑制特性或p56lck酪氨酸激酶抑制特性,因此具有治疗价值。 Results obtained by the above experimental methods indicate that the compounds within the scope of the present invention possess useful PDGF receptor protein tyrosine kinase inhibition properties or p56lck tyrosine kinase inhibition properties, and therefore have therapeutic value. 对于特定治疗目标,上述药理试验结果可用于确定剂量和给药方式。 For particular therapeutic target, the above pharmacological test results may be used to determine the dosage and mode of administration.

本发明可以以不背离其精神或必要技术特征的其它具体形式实施。 The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics of the implementation of technology.

Classifications
International ClassificationA61P9/00, C07D241/52, A61P19/08, A61K31/5377, A61P17/06, A61K31/498, C07D241/54, A61K31/495, C07D405/10, A61K31/47, C07D403/04, A61P35/02, A61P43/00, A61M25/00, C07D471/08, A61F2/84, C07D215/38, C07D405/12, A61P9/10, C07D453/06, C07D241/44, C07D241/42, A61P35/00, C07D215/20, A61P29/00
Cooperative ClassificationC07D241/44, C07D215/20, C07D453/06, C07D215/38, C07D241/54, C07D241/42, C07D405/12, C07D403/04, C07D241/52
European ClassificationC07D241/54, C07D241/52, C07D403/04, C07D241/42, C07D453/06, C07D241/44, C07D215/20, C07D215/38, C07D405/12
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