CN1917880A

CN1917880A - Pyrimidines with tie2 (tek) activity

Info

Publication number: CN1917880A
Application number: CN 200480041936
Authority: CN
Inventors: C·D·琼斯; R·W·A·卢克; W·麦库尔
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2003-12-24
Filing date: 2004-12-20
Publication date: 2007-02-21
Also published as: GB0330001D0

Abstract

The invention relates to a compound of the Formula (I); or salt thereof, wherein R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, A, B, L, n and m are as defined in the description. The invention also relates to pharmaceutical compositions of said compounds, the use of said compounds as medicaments and in the production of an anti-angiogenic effect in a warm blooded animal. The invention also relates to processes for the preparation of said compounds.

Description

Has the active pyrimidines of TIE2 (TEK)

The present invention relates to have chemical compound or its pharmaceutically acceptable salt of anti-angiogenesis activity, can be used for treating the morbid state relevant in animal or human's body thus with angiogenesis.The invention still further relates to the described chemical compound of preparation method, contain Pharmaceutical composition as the described chemical compound of active component, and use described compound to be used for method at the medicine of homoiothermic animal (as the people) generation blood vessel formation against function.

Tie-2 receptor tyrosine kinase (being also referred to as TEK) mainly is expressed in endotheliocyte and the hematopoietic cell, be vascularization and the key kept (Jones, N. etc., Nature ReviewsMolecular Cell Biology, 2001:2,257-67).

Angiogenesis is to generate the defined a kind of basic process of neovascularity from the blood vessel that exists.This is the formation of in fact all organ and the extremely important and complicated biological process that physiologic function all requires.Under the normal condition, its character is immobilized, and be subjected to generating and the local equilibrium of the static factor of blood vessel controls at the rapid process medium vessels of multistep, described various procedures relate to blood vessel rudiment through endotheliocyte, branch and tubule form (relate to that activation, the loss of stability of blood vessel, the synthetic and release of digestive enzyme, EC such as endotheliocyte (ECs) moves, EC breeds, EC tissue and processes such as differentiation and mature blood vessel).

Normal angiogenesis plays an important role in various processes, and is subjected to strict control.In the adult, physiological angiogenesis major part is confined to the healing of wound and several female reproductive function tissue and embryo's growth.In undesirable or pathologic angiogenesis, local equilibrium's imbalance of the static factor of angiogenesis and blood vessel causes the formation of unsuitable and/or structural abnormal vascular.Pathologic angiogenesis always with comprise diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, sebaceous cyst, the relevant (Fan etc. of Kaposi sarcoma with the hemangioma morbid state, 1995, Trends Pharmacology.Science.16:57-66; Folkman, 1995, Nature Medicine 1:27-31).In cancer, surpass 1-2mm ³Initial stage and the second stage of growth of tumor need angiogenesis (Folkman, J.New England Journal of Medicine 1995,33,1757-1763).

Disease progression depends in the disease (as cancer) that abnormal vascular generates therein, blocks this process and can cause blocking advancing of disease (Folkman, J.1995, Nature Medicine 1:27-31).Many factors that play important pivotal role in the adjusting of angiogenesis of thinking are described in scientific and technical literature.Two primary categories of angiogenesis factor are VEGF (VEGF) and angiogenesis hormone.These polypeptide portions and its each acceptor interaction (mainly endotheliocyte being had the specific film tyrosine kinase of striding) also pass through ligand-mediated signal conduction trigger cell response.Infer VEGF and angiogenesis hormone combined effect, the various aspects of in normal and pathological angiogenesis generating process, regulating the blood vessel generating process by its each autoreceptor is passed through in the signal conduction.

Receptor tyrosine kinase (RTKs) plays a significant role in the conduction of the cytoplasma membrane of biochemical signals leap cell.These transmembrane molecules are characterised in that by the domain of extracellular binding partner to be formed, and this zone is connected in the intracellular tyrosine kinase domain by the segment in the cytoplasma membrane.The part bind receptor causes stimulating the receptor relevant with tyrosine kinase activity, makes the tyrosine residue phosphorylation on the molecule in receptor and other cell.In the tyrosine phosphorylation these change the priming signal cascade, thereby cause various cellular response.Up to now, at least 19 kinds of different RTK subfamilies determining by amino acid sequence homology have been identified.At present one of these subfamilies comprise fms-sample tyrosine kinase receptor, and Flt or Flt1 contain the receptor in kinases interpolation zone, KDR (being also referred to as Flt-1), and another kind of fms-sample tyrosine kinase receptor Flt4.Among these relevant RTKs two, Flt and KDR have demonstrated to high affinity (De Vries etc., 1992, Science 255:989-991 in conjunction with VEGF; Terman etc., 1992, Biochem.Biophys.Res.Comm.1992,187:1579-1586).VEGF is relevant with the variation of the tyrosine phosphorylation state of cell protein and calcium current amount always in conjunction with these receptors of expressing in the different cells.

Identified second family of scalable blood vessel loss of stability and sophisticated main endothelial cell specific receptor recently.VEGF hand-in-glove in these Tie receptors and part thereof, angiogenesis hormone and normal and the pathologic vessels generative process.Transmembrane receptor Tie1 and Tie2 constitute gang and relate to the family that keeps vascular integrity and relate to the endothelial cell specific tyrosine kinase receptor of angiogenic consequence and Revascula rization.Tie1 and Tie2 structurally have some common features (for example the cell intracellular domain of these receptors all contains the tyrosine kinase domain that is inserted the zone interruption by kinases separately), and constitute different RTK subfamilies thus.On amino acid levels, the homogeneity of the sufficient sequence between Tie1 and the Tie2 receptor is 44%, and its cellularity territory presents 76% homology.The targeting of Tie1 gene destroys to cause being characterized as and bleeds profusely and the mortality phenotype (Puri, M. etc., 1995 EMBO Journal:14:5884-5891) of very poor blood capillary integrity.The transgenic mice that Tie2 lacks presents defective in the rudiment of blood vessel with in building again, and the mortality phenotype that major defect caused during (E9.5-10.5) presented by embryonic blood vessel in the pregnancy in mid-term (Sato, T. etc., 1995 Nature 370:70-74).

Up to now, do not identify the part of Tie1 as yet, the ability of relevant its signal is also understood very few.But, now think Tie1 by with Tie2 receptor xenogenesis dimerization function influence Tie2 signal, potentiality is regulated the ability (Marron of Tie2 autophosphorylation thus, M. etc., 2000Journal of Biological Chemistry:275,39741-39746), recently the chimeric Tie1 receptor of reorganization studies show that Tie-1 can pass through PI3 kinases/Akt signal transduction path and suppress apoptosis (Kontos, C.D. etc., 2002 Molecular and Cellular Biology:22,1704-1713).On the contrary, multiple part indicates angiogenesis hormone and is confirmed as its angiogenesis hormone-1 (Ang1) always and is the Tie2 of best features.The tyrosine phosphorylation of Tie2 receptor through autophosphorylation brought out in the combination of Ang1, with activating its signal pathway after signal conducts.These effects in the existing report Ang2 antagonism endotheliocyte (Maisonpierre, P. etc., 1997 Science:277,55-60).The rejecting of Tie2 and part thereof and transgeneic procedure show that the control of room and time of the strictness of Tie2 signal is necessary to the correct development of neovascularity.Have between their described angiogenesis hormone parts to the activity (agonism/antagonism) of associated receptor of possibility change, also there is the probability of other two kinds of parts (Ang3 and Ang4) and assorted dimerization at least in report.The activated Tie2 receptor of Ang1 suppresses apoptosis (Papapetropoulos, A., Deng, 2000 Journal of Biological Chemistry:2759102-9105), promote the rudiment (Witzenbicher of vascular endothelial cell, B., Deng, 1998 Journal of BiologicalChemistry:27318514-18521) and promote the maturation of the blood vessel during the angiogenesis in vivo, and reduction microvascular permeability of adult and consequential leakage (Thurston, G. etc., 2000 Nature Medicine:6,460-463).Therefore it is reported activated Tie2 receptor and neovascularity branch, rudiment and grow relevant, keep vascular integrity with comprehensive in have importance periphery endothelium sustenticular cell replenish and reciprocal action as and if the promotion blood capillary stable consistent.The inhibition of active shortage of Tie2 and Tie2 autophosphorylation can cause (the Thurston that loses of blood vessel structure and substrate/cells contacting, G., Cell Tissue Res (2003), 314:61-69), and can trigger endotheliocyte death successively, especially under surviving or growth stimulant lack.Based on the effect of the Tie2 kinase activity of above report, suppressing the Tie2 kinases can provide blood vessel formation against function, therefore can be applicable to treat with pathologic vessels generate relevant morbid state.Shown Tie2 express can to the neovascularity of the various tumors of adjusted (as Peters, K.G. etc., British Journal of Cancer 1998; 77,51-56), prompting suppresses the Tie2 kinase activity will produce anti-angiogenesis activity.For supporting this hypothesis, research (Pengnian with the Tie2 receptor (ectodomain) of solubility, L. etc., 1997, Journal of ClinicalInvestigation 1997:100,2072-2078 and Pengnian, L. etc., 1998, Proceedingsof the National Academy of Sciences 1998:95 8829-8834) shows in vivo and presents anti-tumor activity in the tumor model.In addition, the destruction that these experiments are further illustrated in Tie2 signal pathway in the normal health individuality can tolerate well, and reason is not observe bad toxicity in these researchs.

Inspection (Stratmann to the breast cancer cell line of people's primary breast cancer sample and people and Mus, A. etc., 2001, International Journal of Cancer:91,273-282) the Tie2 dependent pathway that shows tumor-blood-vessel growth can exist side by side with the KDR dependent pathway, in fact, both can play a role independently of one another (Siemeister G., etc., 1999 CancerResearch:59,3185-3191) also (for example can play a role together each other, report VEGF A and Ang1 bring out angiogenesis jointly and produce the ripe blood vessel Thurston of non-leaks, G, etc., 1999 Science:286,2511-2514).The mixing of these angiogenesis even be present in probably in the single tumor.

Tie2 in the aberrant angiogenesis that is called venous malformation (VM), also play a role (Mulliken, J.B.﹠amp have been shown; Young, A.E.1998, Vascular Birthmarks:W.B.Saunders, Philadelphia).These defectives or may be genetic or may be occurrent.VM ' s generally is found in skin and the mucosa, but can influence any organ.That damage is rendered as generally that the expansible blood vessel access arranged by a large amount of endotheliocytes forms is spongy, indigo plant is to purple blood vessel block.In the genetic form of this disease, modal defective is Tie2 kinase mutant C2545T (Calvert, J.T. in the Tie2 coded sequence, Deng, 1999 Human Molecular genetics:8,1279-1289), it produces the R849W aminoacid replacement at this kinase domain.To the analysis showed that of this Tie2 mutant: even under no part, it also can be activated basically, and (Vikkula, M. is etc., 1996 Cell:87,1181-1190).

Also found the up adjusting that Tie2 expresses in the blood vessel synovial membrane pannus in the scorching joint of person joint, its effect with unaccommodated neovascularization is consistent.

These examples provide further indication: the inhibition of Tie2 phosphorylation and signal conduction subsequently can be used for the treatment of disease and other symptom of unaccommodated neovascularization.Up to now, several Tie2 inhibitor are only understood in this area.For example, international application no WO 04/013141 discloses one group of condensed pyridine and pyrimidines, and international application no WO 04/058776 discloses one group of pyridine and pyrimidines.Therefore at present to differentiating that there is a kind of demand in the another kind of Tie2 inhibitor that can be developed as the complete therapeutic efficacy of inhibition/adjusting Tie2 signal pathway.

We find that some chemical compound has the inhibition activity to the Tie2 receptor tyrosine kinase, therefore generate in the diseases associated with pathologic vessels to have value in treatment, and be unwanted disease as cancer, rheumatoid arthritis and other active angiogenesis.

According to a first aspect of the invention, provide a kind of formula I chemical compound and salt thereof, especially its pharmaceutically acceptable salt:

Formula I

Wherein:

R ¹And R ²Independently be selected from hydrogen, (1-6C) alkyl sulphonyl, phenyl (CH ₂) _u-(wherein u is 0,1,2,3,4,5 or 6), (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl, (3-6C) cycloalkyl (CH ₂) _x-(wherein x is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings, perhaps R ¹And R ²Coupled nitrogen-atoms is represented the 3-7 unit heterocycle of saturated or fractional saturation together, and this heterocycle is chosen wantonly and contained the hetero atom that another is selected from N or O;

Wherein said (1-6C) alkyl; (1-6C) alkanoyl and (3-6C) cycloalkyl independently be selected from the optional replacement of following group by one or more: fluoro; hydroxyl; (1-6C) alkyl; (1-6C) alkoxyl; (1-6C) alkoxyl (1-6C) alkoxyl; (1-6C) alkoxyl (1-6C) alkoxyl (1-6C) alkoxyl; amino; single (1-6C) alkyl amino; two [(1-6C) alkyl] amino; carbamoyl; single (1-6C) alkyl-carbamoyl; two [(1-6C) alkyl] carbamoyls or-N (R ^d) C (O) (1-6C) alkyl, wherein R ^dBe hydrogen or (1-6C) alkyl, the 3-7 unit heterocycle of perhaps saturated or fractional saturation, perhaps 5 or 6 yuan of heteroaryl rings,

Wherein (1-6C) alkoxyl, (1-6C) alkoxyl (1-6C) alkoxyl and (1-6C) alkoxyl (1-6C) alkoxyl (1-6C) alkoxyl and amino, single (1-6C) alkyl-carbamoyl, two [(1-6C) alkyl] carbamoyl of single (1-6C) alkyl amino, two [(1-6C) alkyl] and/or-N (R ^d) C (O) (1-6C) (1-6C) alkyl of alkyl replaced by one or more hydroxyl is optional,

Wherein said phenyl is selected from independently by one or more that following group is optional to be replaced: halo, (1-6C) alkyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] amino, wherein said (1-6C) alkyl and (1-6C) alkoxyl independently be selected from following group by one or more and choose replacement wantonly: hydroxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] amino;

And R wherein ¹And/or R ²In any heterocycle and heteroaryl ring be selected from by one or more that following group is optional to be replaced independently: (1-4C) alkyl, (1-4C) alkoxyl, (1-4C) alkoxyl (1-4C) alkyl, hydroxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] is amino or the first heterocycle of the 3-7 of saturated or fractional saturation, perhaps-C (O) (CH ₂) _zY, wherein z is 0,1,2 or 3, Y is selected from hydrogen, hydroxyl, (1-4C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] are amino or the 3-7 of saturated or fractional saturation unit heterocycle;

Prerequisite is to work as R ¹And/or R ²When being (1C) alkanoyl, then should do not replaced by (1C) alkanoyl by fluoro or hydroxyl;

R ³Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl, wherein said (1-6C) alkyl and (1-6C) alkoxyl independently be selected from the optional replacement of following group by one or more: fluoro, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl, amino, single (1-6C) alkyl amino, two [(1-6C) alkyl] amino, carbamoyl, single (1-6C) alkyl-carbamoyl or two [(1-6C) alkyl] carbamoyl, 3-7 unit's heterocycle or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle and heteroaryl ring are replaced independently by one or more following groups is optional: (1-4C) alkyl, (1-4C) alkoxyl, hydroxyl, amino, the first heterocycle of single (1-6C) alkyl amino or two [(1-6C) alkyl] 3-7 amino or saturated or fractional saturation;

Perhaps R ³Represent group-NR as defined above ¹R ²

R ⁴Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl;

A represents aryl or is selected from 5 or 6 yuan of following heteroaryl rings: furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl or 1,3, the 5-triazine radical;

R ⁵Be selected from cyclopropyl, cyano group, halo, (1-6C) alkoxyl or (1-6C) alkyl, wherein said (1-6C) alkyl and (1-6C) alkoxyl is optional replaces by cyano group or by one or more fluoro;

N is 0,1,2 or 3;

L is connected with respect to position or para-position between acetenyl junction point among the ring A, and representative-C (R ^aR ^b) C (O) N (R ⁹)-,-N (R ⁸) C (O) C (R ^aR ^b)-,-N (R ⁸) C (O) N (R ⁹)-,-N (R ⁸) C (O) O-or-OC (O)-N (R ⁹)-, be R wherein ⁸And R ⁹Independent represent hydrogen or (1-6C) alkyl, and R wherein ^aAnd R ^bIndependent hydrogen or (1-6C) alkyl, the perhaps R of representing ^aAnd R ^bConnected carbon atom is represented (3-6C) cycloalkyl together;

B represents (3-7C) cycloalkyl ring, 3-7 saturated or fractional saturation first heterocycle, aryl, is selected from 5 or 6 yuan of following heteroaryl rings: furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl or 1,3, the 5-triazine radical, perhaps 8,9 or 10 yuan of saturated, fractional saturations or aromatics dicyclo, it is optional to contain 1,2,3 or 4 hetero atom that independently is selected from N, O and S;

R ⁶Be selected from halo, cyano group, oxo, (3-7C) cycloalkyl ring, saturated or fractional saturation 3-7 unit heterocycle ,-S (O) _p-(1-6C) alkyl (wherein p is 0,1 or 2) ,-N (R ^a) C (O) (1-6C) alkyl, wherein R ^aBe hydrogen or (1-6C) alkyl; Perhaps

R ⁶Be selected from (1-6C) alkyl or (1-6C) alkoxyl, wherein said (1-6C) alkyl ,-S (O) _p-(1-6C) alkyl and (1-6C) alkoxyl be selected from independently by one or more that following group is optional to be replaced: the first heterocycle of 3-7 of cyano group, fluoro, hydroxyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] amino, (3-7C) cycloalkyl ring or saturated or fractional saturation; The 3-7 unit heterocycle of wherein said (3-7C) cycloalkyl ring and saturated or fractional saturation is selected from the optional replacement independently of group of (1-6C) alkyl by one or more; And

M is 0,1,2 or 3;

And when B is 8,9 or 10 yuan of bicyclic radicals of the 3-7 unit heterocycle of (3-7C) cycloalkyl ring or saturated or fractional saturation or saturated or fractional saturation, optional 1 or 2 oxo or the sulfo-substituent group of having of described ring and bicyclic radicals.

According to a second aspect of the invention, provide a kind of formula I chemical compound and salt thereof, its pharmaceutically acceptable salt especially, wherein:

R ¹And R ²Independently be selected from hydrogen, (1-6C) alkyl sulphonyl, phenyl (CH ₂) _u-(wherein u is 0,1,2,3,4,5 or 6), (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl or (3-6C) cycloalkyl (CH ₂) _x-(wherein x is 0,1,2,3,4,5 or 6), perhaps R ¹And R ²Coupled nitrogen-atoms is represented the 3-7 unit heterocycle of saturated or fractional saturation together, and this heterocycle is chosen wantonly and contained the hetero atom that another is selected from N or O;

Wherein said alkyl and cycloalkyl are selected from by one or more that following group is optional to be replaced: fluoro, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] is amino, saturated or the 3-7 of fractional saturation unit's heterocycle or 5 or 6 yuan of heteroaryl rings, and wherein said heterocycle and heteroaryl ring are by the optional replacement independently of one or more following groups: (1-4C) alkyl, hydroxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] is amino or the first heterocycle of the 3-7 of saturated or fractional saturation;

And wherein said phenyl is selected from by one or more, and following group is optional to be replaced: halo, (1-6C) alkyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] amino, wherein said (1-6C) alkyl and (1-6C) alkoxyl be selected from the optional replacement of following group: hydroxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] amino;

R ³Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl, wherein said alkyl and alkoxyl are selected from the optional replacement of following group by one or more: fluoro, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl, amino, single (1-6C) alkyl amino or two [(1-6C) alkyl] amino, 3-7 unit's heterocycle or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle and heteroaryl ring are replaced independently by one or more following groups is optional: (1-4C) alkyl, hydroxyl, amino, the first heterocycle of single (1-6C) alkyl amino or two [(1-6C) alkyl] 3-7 amino or saturated or fractional saturation;

Perhaps R ³Represent group-NR as defined above ¹R ²

R ⁴Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl;

R ⁵Be selected from cyano group, halo, (1-6C) alkoxyl or (1-6C) alkyl, wherein said (1-6C) alkoxyl or (1-6C) alkyl is optional replaces by cyano group or by one or more fluoro;

N is 0,1,2 or 3;

B representative (3-7C) cycloalkyl ring, aryl, or be selected from 5 or 6 yuan of following heteroaryl rings: furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl or 1,3, the 5-triazine radical;

R ⁶Be selected from halo, cyano group, the first heterocycle of 3-7 saturated or fractional saturation or alkanoylamino-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl; Perhaps R ⁶Be selected from (1-6C) alkyl or (1-6C) alkoxyl, wherein said alkyl and alkoxyl are selected from by one or more that following group is optional to be replaced: cyano group, fluoro, hydroxyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] are amino or the first heterocycle of the 3-7 of saturated or fractional saturation;

M is 0,1,2 or 3;

And when m was at least 2, then two substituent groups on the adjacent carbon atom can be represented methylene dioxy base together in the B ring.

According to a third aspect of the invention we, provide a kind of formula I chemical compound and salt thereof, its pharmaceutically acceptable salt especially, wherein:

Wherein said (1-6C) alkyl; (1-6C) alkanoyl and (3-6C) cycloalkyl independently be selected from the optional replacement of following group by one or more: fluoro; hydroxyl; (1-6C) alkyl; (1-6C) alkoxyl; (1-6C) alkoxyl (1-6C) alkoxyl; (1-6C) alkoxyl (1-6C) alkoxyl (1-6C) alkoxyl; amino; single (1-6C) alkyl amino; two [(1-6C) alkyl] amino; carbamoyl; single (1-6C) alkyl-carbamoyl; two [(1-6C) alkyl] carbamoyl or alkanoylamino-N (R ^d) C (O) (1-6C) alkyl, wherein R ^dBe hydrogen or (1-6C) alkyl; the first heterocycle of 3-7 perhaps saturated or fractional saturation; perhaps 5 or 6 yuan of heteroaryl rings; wherein said (1-6C) alkoxyl; (1-6C) alkoxyl (1-6C) alkoxyl and (1-6C) alkoxyl (1-6C) alkoxyl (1-6C) alkoxyl and single (1-6C) alkyl amino; two [(1-6C) alkyl] amino; single (1-6C) alkyl-carbamoyl; (1-6C) alkyl of two [(1-6C) alkyl] carbamoyls and/or alkanoylamino is by the optional replacement of one or more hydroxyl

R ³Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl, wherein said (1-6C) alkyl and (1-6C) alkoxyl independently be selected from the optional replacement of following group by one or more: fluoro, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl, amino, single (1-6C) alkyl amino or two [(1-6C) alkyl] amino, carbamoyl, single (1-6C) alkyl-carbamoyl or two [(1-6C) alkyl] carbamoyl, 3-7 unit's heterocycle or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle and heteroaryl ring are replaced independently by one or more following groups is optional: (1-4C) alkyl, (1-4C) alkoxyl, hydroxyl, amino, the first heterocycle of single (1-6C) alkyl amino or two [(1-6C) alkyl] 3-7 amino or saturated or fractional saturation;

Perhaps R ³Represent group-NR as defined above ¹R ²

R ⁴Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl;

R ⁵Be selected from cyclopropyl, cyano group, halo, (1-6C) alkoxyl or (1-6C) alkyl, wherein said (1-6C) alkoxyl or (1-6C) alkyl is optional replaces by cyano group or by one or more fluoro;

N is 0,1,2 or 3;

L is connected with respect to position or para-position between acetenyl junction point among the ring A, and representative-C (R ^aR ^b) C (O) N (R ⁹)-,-N (R ⁸) C (O) C (R ^aR ^b)-,-N (R ⁸) C (O) N (R ⁹)-,-N (R ⁸) C (O) O-or-OC (O) N (R ⁹)-, be R wherein ⁸And R ⁹Independent represent hydrogen or (1-6C) alkyl, and R wherein ^aAnd R ^bIndependent hydrogen or (1-6C) alkyl, the perhaps R of representing ^aAnd R ^bConnected carbon atom is represented (3-6C) cycloalkyl together;

R ⁶Be selected from halo, cyano group, (3-7C) cycloalkyl ring, the first heterocycle of 3-7 saturated or fractional saturation or alkanoylamino-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl; Perhaps

R ⁶Be selected from (1-6C) alkyl or (1-6C) alkoxyl, wherein said (1-6C) alkyl and (1-6C) alkoxyl be selected from independently by one or more that following group is optional to be replaced: the first heterocycle of 3-7 of cyano group, fluoro, hydroxyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] amino, (3-7C) cycloalkyl ring or saturated or fractional saturation;

M is 0,1,2 or 3;

According to a further aspect in the invention, it provides a kind of formula I chemical compound and salt thereof, its pharmaceutically acceptable salt especially, wherein:

R ⁴Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl;

N is 0,1,2 or 3;

R ⁶Be selected from one of following two groups of groups:

(i) R ⁶Be selected from halo, cyano group, (3-7C) cycloalkyl ring, the first heterocycle of 3-7 saturated or fractional saturation or alkanoylamino-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl; Or

R ⁶Be selected from (1-6C) alkyl or (1-6C) alkoxyl, wherein said (1-6C) alkyl and (1-6C) alkoxyl be selected from independently by one or more that following group is optional to be replaced: the first heterocycle of 3-7 of cyano group, fluoro, hydroxyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] amino, (3-7C) cycloalkyl ring or saturated or fractional saturation; Perhaps

(ii) R ⁶Be selected from halo, cyano group, oxo, (3-7C) cycloalkyl ring, the first heterocycle of 3-7 saturated or fractional saturation or alkanoylamino-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl; Or

R ⁶Be selected from (1-6C) alkyl ,-S (O) _p-(1-6C) alkyl (wherein p is 0,1 or 2) or (1-6C) alkoxyl,

Wherein said (1-6C) alkyl ,-S (O) _p-(1-6C) alkyl and (1-6C) alkoxyl be selected from independently by one or more that following group is optional to be replaced: the first heterocycle of the 3-7 of cyano group, fluoro, hydroxyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino, two (1-6C) alkyl amino, (3-7C) cycloalkyl ring or saturated or fractional saturation; And the 3-7 of wherein said (3-7C) cycloalkyl ring and saturated or fractional saturation unit heterocycle is selected from the optional replacement independently of group of (1-6C) alkyl by one or more;

M is 0,1,2 or 3;

One specific embodiments of formula I chemical compound is formula Ia chemical compound and salt thereof, its pharmaceutically acceptable salt especially,

Formula Ia

Wherein:

Wherein said (1-6C) alkyl; (1-6C) alkanoyl and (3-6C) cycloalkyl independently be selected from the optional replacement of following group by one or more: fluoro; hydroxyl; (1-6C) alkyl; (1-6C) alkoxyl; (1-6C) alkoxyl (1-6C) alkoxyl; (1-6C) alkoxyl (1-6C) alkoxyl (1-6C) alkoxyl; amino; single (1-6C) alkyl amino; two [(1-6C) alkyl] amino; carbamoyl; single (1-6C) alkyl-carbamoyl; two [(1-6C) alkyl] carbamoyl or alkanoylamino-N (R ^d) C (O) (1-6C) alkyl, wherein R ^dBe hydrogen or (1-6C) alkyl, the 3-7 unit heterocycle of perhaps saturated or fractional saturation, perhaps 5 or 6 yuan of heteroaryl rings,

Wherein said (1-6C) alkoxyl, (1-6C) alkoxyl (1-6C) alkoxyl and (1-6C) (1-6C) alkyl of alkoxyl (1-6C) alkoxyl (1-6C) alkoxyl and amino, single (1-6C) alkyl-carbamoyl, two [(1-6C) alkyl] carbamoyl of single (1-6C) alkyl amino, two [(1-6C) alkyl] and/or alkanoylamino replaced by one or more hydroxyl is optional

R ⁴Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl;

N is 0,1,2 or 3;

R ⁶Be selected from one of following two groups of groups:

Wherein said (1-6C) alkyl ,-S (O) _p-(1-6C) alkyl and (1-6C) alkoxyl be selected from independently by one or more that following group is optional to be replaced: the first heterocycle of 3-7 of cyano group, fluoro, hydroxyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] amino, (3-7C) cycloalkyl ring or saturated or fractional saturation; And the 3-7 of wherein said (3-7C) cycloalkyl ring and saturated or fractional saturation unit heterocycle is selected from optional replacement of group of (1-6C) alkyl by one or more;

M is 0,1,2 or 3;

And when B is 8,9 or 10 yuan of bicyclic radicals of the 3-7 unit heterocycle of (3-7C) cycloalkyl ring or saturated or fractional saturation or saturated or fractional saturation, optional 1 or 2 oxo or the sulfo-substituent group of having of described ring and bicyclic radicals; And

R ¹⁰And R ¹¹Independently be selected from hydrogen or (1-6C) alkyl.

Another specific embodiments of formula I chemical compound is formula Ia chemical compound and salt thereof, its pharmaceutically acceptable salt especially, wherein:

R ¹And R ²Independently be selected from hydrogen, (1-6C) alkyl sulphonyl, phenyl (CH ₂) _u-(wherein u is 0,1,2,3,4,5 or 6), (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl, or (3-6C) cycloalkyl (CH ₂) _x-(wherein x is 0,1,2,3,4,5 or 6), perhaps R ¹And R ²Coupled nitrogen-atoms is represented the 3-7 unit heterocycle of saturated or fractional saturation together, and this heterocycle is chosen wantonly and contained the hetero atom that another is selected from N or O;

Wherein said alkyl and cycloalkyl are selected from by one or more that following group is optional to be replaced: fluoro, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] is amino, saturated or the 3-7 of fractional saturation unit's heterocycle or 5 or 6 yuan of heteroaryl rings, and wherein said heterocycle and heteroaryl ring are selected from the optional replacement independently of following group by one or more: (1-4C) alkyl, hydroxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] is amino or the first heterocycle of the 3-7 of saturated or fractional saturation;

And wherein said phenyl is selected from by one or more, and following group is optional to be replaced: halo, (1-6C) alkyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] amino, wherein said (1-6C) alkyl or (1-6C) alkoxyl be selected from the optional replacement of following group: hydroxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] amino;

R ⁴Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl;

R ⁵Be selected from cyano group, halo, (1-6C) alkoxyl or (1-6C) alkyl, wherein said (1-6C) alkyl or (1-6C) alkoxyl is optional replaces by cyano group or by one or more fluoro;

N is 0,1,2 or 3;

B represents (3-7C) cycloalkyl ring, aryl or is selected from 5 or 6 yuan of following heteroaryl rings: furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl or 1,3, the 5-triazine radical;

R ⁶Be selected from halo, cyano group, the first heterocycle of 3-7 saturated or fractional saturation or alkanoylamino-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl; Or R ⁶Be selected from (1-6C) alkyl or (1-6C) alkoxyl, wherein said alkyl and alkoxyl are selected from by one or more that following group is optional to be replaced: cyano group, fluoro, hydroxyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] are amino or the first heterocycle of the 3-7 of saturated or fractional saturation; With

M is 0,1,2 or 3;

And when m was at least 2, then two substituent groups on the adjacent carbon atom can be represented methylene dioxy base together in the B ring; With

R ¹⁰And R ¹¹Independently be selected from hydrogen or (1-6C) alkyl.

Another specific embodiments is one group of formula Ia chemical compound and salt thereof, especially its pharmaceutically acceptable salt, wherein:

R ¹And R ²Independently be selected from hydrogen or (1-6C) alkyl;

R ⁴Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl;

R ⁵Be selected from halo, (1-6C) alkyl or (1-6C) alkoxyl;

N is 0,1,2 or 3;

L is connected with respect to position or para-position between acetenyl junction point among the ring A, and representative-CH ₂C (O) N (R ⁸)-,-N (R ⁹) C (O) CH ₂-,-N (R ⁸) C (O) N (R ⁹)-,-N (R ⁸) C (O) O-or-OC (O)-N (R ⁹)-, be R wherein ⁸And R ⁹Independent hydrogen or (1-6C) alkyl represented;

M is 0,1,2 or 3;

R ¹⁰And R ¹¹Independently be selected from hydrogen or (1-6C) alkyl.

R ¹And R ²Independently be selected from hydrogen, (1-6C) alkyl or 5 or 6 yuan of heteroaryl rings;

Wherein said (1-6C) alkyl independently is selected from the optional replacement of following group by one or more: fluoro, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl, (1-6C) alkoxyl (1-6C) alkoxyl, (1-6C) alkoxyl (1-6C) alkoxyl (1-6C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] amino, carbamoyl, list (1-6C) alkyl-carbamoyl, two [(1-6C) alkyl] carbamoyl or alkanoylamino-N (R ^d) C (O) (1-6C) alkyl, wherein R ^dBe hydrogen or (1-6C) alkyl, 3-7 unit's heterocycle or 5 or 6 yuan of heteroaryl rings of perhaps saturated or fractional saturation, wherein said (1-6C) alkoxyl, (1-6C) alkoxyl (1-6C) alkoxyl and (1-6C) (1-6C) alkyl of alkoxyl (1-6C) alkoxyl (1-6C) alkoxyl and amino, single (1-6C) alkyl-carbamoyl, two [(1-6C) alkyl] carbamoyl of single (1-6C) alkyl amino, two [(1-6C) alkyl] and/or alkanoylamino replaced by one or more hydroxyl is optional;

R ⁴Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl;

R ⁵Be selected from cyclopropyl, halo, (1-6C) alkyl or (1-6C) alkoxyl;

N is 0,1,2 or 3;

B represents (3-7C) cycloalkyl ring, aryl, is selected from 5 or 6 yuan of following heteroaryl rings: furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl or 1,3, the 5-triazine radical, perhaps 8,9 or 10 yuan of saturated, fractional saturations or aromatics dicyclo, it is optional to contain 1,2,3 or 4 hetero atom that independently is selected from N, O and S;

R ⁶Be selected from halo, cyano group, (3-7C) cycloalkyl ring, the first heterocycle of 3-7 saturated or fractional saturation or alkanoylamino-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl; Or R ⁶Be selected from (1-6C) alkyl or (1-6C) alkoxyl, wherein said (1-6C) alkyl and (1-6C) alkoxyl be selected from independently by one or more that following group is optional to be replaced: the first heterocycle of 3-7 of cyano group, fluoro, hydroxyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] amino, (3-7C) cycloalkyl ring or saturated or fractional saturation; With

M is 0,1,2 or 3;

And when B is 8,9 or 10 yuan of dicyclos of 3-7 unit's heterocycle of (3-7C) cycloalkyl ring, saturated or fractional saturation or saturated or fractional saturation, optional 1 or 2 oxo or the sulfo-substituent group of having of described ring and dicyclo; And

R ¹⁰And R ¹¹Independently be selected from hydrogen or (1-6C) alkyl.

In this manual, generic term " alkyl " comprises straight chain and branched alkyl, as propyl group, isopropyl and the tert-butyl group.But, when relating to concrete alkyl,, only refer in particular to straight chain group as " propyl group ", when relating to concrete branched alkyl,, only refer in particular to branched group as " isopropyl ".Similarly regulation is applicable to other generic term, for example (1-6C) alkoxyl comprises methoxyl group, ethyoxyl and isopropoxy, (1-6C) alkyl amino comprises methylamino, isopropylamino and ethylamino, and two [(1-6C) alkyl] amino comprises dimethylamino, lignocaine and N-methyl-N-isopropyl propyl group amino.The generic term aryl refers to phenyl or naphthyl, especially phenyl.

Should be appreciated that, some formula I chemical compound in above definition can exist under the situation of optical activity or racemic form owing to have one or more asymmetric carbon atom, and the present invention comprises having above-mentioned active any of these optical activity or racemic form in its definition.The synthetic of optical activity form can be undertaken by standard technique of organic chemistry well known in the art, for example by synthesized or passed through the fractionation of racemic modification form by the optical activity raw material.Similarly, can adopt the above-mentioned activity of hereinafter mentioning of standard laboratory technology evaluation.

The suitable implication of above-mentioned general group comprises following those that mention.5 or 6 yuan of heteroaryl rings that are fit to comprise, for example furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, 1,3,5-triazine radical or pyrazinyl.Special 5 or 6 yuan of heteroaryl rings comprise imidazole radicals, pyridine radicals, thiazolyl, thiadiazolyl group, pyrimidine radicals, different  azoles base, pyrazolyl and isothiazolyl.

The 3-7 unit heterocycle of the saturated or fractional saturation that is fit to comprises; Oxyranyle for example; oxetanyl; tetrahydrofuran base; THP trtrahydropyranyl; 2; 3-dihydro-1; the 3-thiazolyl; 1; the 3-thiazolidinyl; 1; 3- oxazolidinyl; oxa-cyclic group in heptan (oxepanyl); pyrrolinyl; pyrrolidinyl; morpholinyl; tetrahydro-1,4-thiazine base (perhydro-1; the 4-thiazinyl); (8-oxa--3-azabicyclo [3.2.1] octyl); (7-oxa--3-azabicyclo [3.1.1] heptane base); perhydro azepine  base; perhydro oxygen azepine  base (perhydrooxazepinyl); tetrahydrochysene-1; the 4-thiazinyl; 1-oxo tetrahydro-thienyl; 1; 1-dioxo tetrahydrochysene-1; the 4-thiazinyl; piperidyl; homopiperidinyl; piperazinyl; high piperazinyl; the dihydropyridine base; tetrahydro pyridyl; dihydro-pyrimidin base or tetrahydro-pyrimidine base; preferred tetrahydrofuran base; THP trtrahydropyranyl; pyrrolidinyl; morpholinyl; 1; 1-dioxo tetrahydrochysene-4H-1; the 4-thiazinyl; piperidyl or piperazinyl; more preferably oxolane-3-base; tetrahydropyran-4-base; pyrrolidine-3-base; morpholino; 1; 1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-base; piperidino; piperidin-4-yl or piperazine-1-base.These groups have 1 or 2 oxo or the substituent suitable implication of sulfo-is, for example 2-oxo-pyrrolidine base, 2-sulfo-pyrrolidinyl, 2-oxo-imidazole alkyl, 2-thiocarbamoyl imidazole alkyl, 2-oxo-piperidine base, 2,5-dioxo pyrrolidinyl, 2,5-dioxo alkyl imidazole base or 2,6-dioxopiperidine base.Described 3-7 unit heterocycle saturated or fractional saturation is optional to be replaced by one or more (1-6C) alkyl and/or by one or more hydroxyl.

Be fit to 8,9 or 10 yuan of bicyclic radicals comprise thieno [2,3-b] furyl, imidazo [2,1-b] thiazolyl, dihydro cyclopentano thiazolyl (cyclopentathiazolyl), tetrahydro cyclopentyl is [c] pyrazolyl also, furo [3,2-b] furyl, pyrrolopyrrole, the thieno pyrazolyl, thieno [2,3-b] thienyl, the indolizine base, indyl, isoindolyl, the 3H-indyl, indolinyl, benzo [b] furyl, benzo [b] thienyl, the 1H-indazolyl, benzimidazolyl, benzothiazolyl, purine radicals, the 4H-quinolizinyl, quinolyl, isoquinolyl, cinnolinyl, 2, the 3-phthalazinyl, quinazolyl, quinoxalinyl, 1, the 8-naphthyridinyl, pteridine radicals, chromanyl, the isochroman base, indenyl, naphthyl, 2,3-dihydro-1,4-benzo dioxine base, 1,3-benzo dioxole-5-base, naphthalane base and norbornane.Special 8,9 or 10 yuan of bicyclic radicals comprise thieno [2,3-b] furyl, the indolizine base, indyl, isoindolyl, the 3H-indyl, indolinyl, benzo [b] furyl, benzo [b] thienyl, the 1H-indazolyl, benzimidazolyl, benzothiazolyl, purine radicals, the 4H-quinolizinyl, quinolyl, isoquinolyl, cinnolinyl, 2, the 3-phthalazinyl, quinazolyl, quinoxalinyl, 1, the 8-naphthyridinyl, pteridine radicals, chromanyl, the isochroman base, indenyl, naphthyl, 2,3-dihydro-1,4-benzo dioxine base and 1,3-benzo dioxole-5-base.

This bicyclic group is optional by one or more R as defined above ⁶Group replaces.

Group A especially can connect on the acetenyl by the carbon atom in described aryl or the described 5 or 6 yuan of heteroaryl rings.Group B especially can be connected on the group L by carbon atom.

Any substituent group herein is (as ' R ' group (R ¹-R ¹¹)) or A, B or L group in the suitable implication of various groups comprise:

Halo: fluoro, chloro, bromo and iodo;

(1-6C) alkyl: methyl, ethyl, propyl group, isopropyl and the tert-butyl group;

(1-6C) alkoxyl: methoxyl group, ethyoxyl, propoxyl group, different oxygen propyl group

And butoxy;

(1-6C) alkyl sulphonyl: mesyl and ethylsulfonyl;

(1-6C) alkyl amino: methylamino, ethylamino, third amino, isopropylamino

With fourth amino;

Two-[(1-6C) alkyl] amino: dimethylamino, lignocaine, N-ethyl-N-first

Amino and diisopropylaminoethyl;

(1-6C) alkoxy carbonyl: methoxycarbonyl, ethoxy carbonyl, propoxyl group carbonyl

Base and tert-butoxycarbonyl;

(2-6C) alkanoyl: acetyl group and propiono;

(1-6C) alkanoylamino: acetylamino and propionamido;

Amino-(1-6C) alkyl: amino methyl, 2-amino-ethyl, 1-amino-ethyl

With the 3-aminopropyl;

(1-6C) alkyl of alkyl amino-(1-6C): methylamino methyl, ethylamino methyl, 1-methylamino

Ethyl, 2-methylamino ethyl, 2-ethylamino ethyl

With 3-ethylamino propyl group;

Two-[(1-6C) alkyl] amino-(1-6C) alkane dimethylamino methyl, lignocaine methyl, 1-

Base: dimethylaminoethyl, 2-dimethylaminoethyl and

The 3-dimethylamino-propyl;

The alkyl of halo-(1-6C): chloromethyl, 2-chloroethyl, 1-chloroethyl and 3-chlorine

Propyl group;

The alkyl of hydroxyl-(1-6C): methylol, 2-hydroxyethyl, 1-hydroxyethyl and

The 3-hydroxypropyl;

(1-6C) alkyl of alkoxyl-(1-6C): methoxy, ethoxyl methyl, 1-methoxyl group

Ethyl, 2-methoxy ethyl, 2-ethoxyethyl group

With the 3-methoxy-propyl;

The alkyl of cyano group-(1-6C): cyano methyl, 2-cyano ethyl, 1-cyano ethyl

With 3-cyano group propyl group;

(3-7C) cycloalkyl: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and

Suberyl;

(1-6C) alkoxyl of alkoxyl-(1-6C): methoxymethoxy, methoxy ethoxy, methoxy

Base propoxyl group, methoxyl group butoxy, methoxyl group oneself

Oxygen base, ethoxy ethoxy, ethyoxyl propoxyl group,

Ethyoxyl butoxy, propoxyl group propoxyl group and third oxygen

The base butoxy;

(1-6C) alkoxyl (1-6C) alkoxyl (1-6C) alkoxyl: the methoxymethoxy methoxyl group,

Methoxy ethoxy ethyoxyl, methoxy propoxy

Methoxyl group, methoxyl group butoxy ethyoxyl, methoxy

Base hexyloxy methoxyl group, ethoxy ethoxy ethoxy

Base, ethoxy-c oxygen base oxethyl, ethyoxyl fourth

Oxymethoxy, propoxyl group propoxyl group methoxyl group and

Propoxyl group butoxy methoxyl group;

Single (1-6C) alkyl-carbamoyl: N-methylamino formoxyl, N-ethylamino formyl

Base and N-propyl group carbamoyl; With

Two-[(1-6C) alkyl] carbamoyl: N, N-formyl-dimethylamino, N-ethyl-N-

Methylamino formoxyl and N, the N-diethylacbamazine

Acyl group.

When mentioning (1-4C) alkyl in this manual, should be appreciated that these groups refer to contain the alkyl of 4 carbon atoms at the most.The representative example that it will be appreciated by those skilled in the art that these groups is above those listed under (1-4C) alkyl groups, and it contains 4 carbon atoms at the most, as methyl, ethyl, propyl group, isopropyl, butyl and the tert-butyl group.Similarly, (1-3C) alkyl refers to contain the alkyl of 3 carbon atoms at the most, as methyl, ethyl, propyl group and isopropyl.Similarly regulation is applicable to above listed other group, as (1-4C) alkoxyl, (2-4C) alkenyl, (2-4C) alkynyl and (2-4C) alkanoyl.

Should be appreciated that some formula I chemical compound may exist solvate and non-solvent compound form, as hydrate forms.Should understand the present invention includes the Tie2 receptor tyrosine kinase is presented inhibiting all these solvate form thereof.

Should also be appreciated that may there be polycrystalline form in some formula I chemical compound, presents inhibiting all these forms and the present invention includes to the Tie2 receptor tyrosine kinase.

Should also be appreciated that all tautomeric forms that the present invention relates to the Tie2 receptor tyrosine kinase is presented the chemical compound of inhibiting formula I form.

Though the pharmaceutically acceptable salt of preferred The compounds of this invention also can use the pharmaceutically unacceptable salt of The compounds of this invention, for example in the preparation of the pharmaceutically acceptable salt of The compounds of this invention.

The pharmaceutically acceptable salt that formula I chemical compound is fit to is, the acid-addition salts of formula I chemical compound for example is as inorganic or organic acid acid-addition salts, example hydrochloric acid, hydrobromic acid, sulphuric acid, trifluoroacetic acid, citric acid or maleic acid; Perhaps, for example have the salt of enough tart formula I chemical compound, as alkali metal or alkali salt, as calcium or magnesium salt, perhaps ammonium salt, the perhaps salt of organic base is as methylamine, dimethylamine, trimethylamine, piperidines, morpholine or three-(2-hydroxyethyl) amine.

The present invention also provides the prodrug of the defined The compounds of this invention of context on the other hand.Can be with The compounds of this invention with the prodrug form administration, this prodrug decomposes the formula that obtains (I) chemical compound in human or animal body.The example of prodrug comprises the interior hydrolyzable ester of the body of formula (I) chemical compound.

The various forms of prodrug is known in this area.The example of these prodrug derivants, referring to:

A) H.Bundgaard, editors' such as (Elsevier, 1985) editor's Design of Prodmgs and K.Widder Methods in Enzymology, Vol.42, p.309-396 (Academic Press, 1985);

B) the A Textbook of DrugDesign and Development that edits of Krogsgaard-Larsen and H.Bundgaard, in the 5th chapter H.Bundgaard " Design andApplication of Prodrugs ", p.113-191 (1991);

c)H.Bundgaard，Advanced Drug Delivery Reviews， 8，1-38(1992)；

D) H.Bundgaard etc., Journal of Pharmaceutical Sciences, 77, 285 (1988);

E) N.Kakeya etc., Chem Pharm Bull, 32, 692 (1984).

The interior hydrolyzable ester of body that contains formula (I) chemical compound of hydroxyl is for example pharmaceutically acceptable ester, and the hydrolysis in the humans and animals body of this ester produces parent acid or alcohol.The suitable pharmaceutically acceptable ester of carboxyl comprises C _1-6Alkoxy methyl ester (for example methoxy), C _1-6Alkanoyloxymethyl ester (for example oxy acid methyl neopentyl), phthalidyl ester, C _3-8Cyclo alkoxy carbonyl oxygen base C _1-6Arrcostab (for example 1-cyclohexyl-carbonyl oxygen base ethyl); 1,3-dioxole-2-ketone group (dioxolen-2-onyl) methyl ester, 5-methyl isophthalic acid for example, 3-dioxole-2-ketone group methyl; And C _1-6The alkoxy-carbonyl oxy ethyl ester.

Contain that hydrolyzable ester comprises inorganic ester in the body of formula (I) chemical compound of hydroxyl, as phosphate ester (comprising the phosphoramidic acid cyclic ester) and alpha-acyloxy alkyl ether and this ester in vivo hydrolysis decompose the related compound of generation parent hydroxy.The example of alpha-acyloxy alkyl ether comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy-methoxyl group.The group of hydrolyzable ester formation hydroxyl comprises benzoyl and phenylacetyl group, alkoxy carbonyl (obtaining alkyl carbonate), dialkyl amido formoxyl and N-(dialkyl amido ethyl)-N-alkyl-carbamoyl (obtaining carbamate), dialkyl amido acetyl group and the carboxyl acetyl group of alkanoyl, benzoyl, phenylacetyl group and replacement in the body of selecting.

The present invention is special, and noval chemical compound comprises, for example formula I compound or its salt, especially its pharmaceutically acceptable salt, wherein unless otherwise indicated, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, A, B, L, m and n have any implication of definition in the above or following paragraph (a)-(dddd):

(a) when n is 2 or 3, R ⁵Can be identical or different;

(a ') when m is 2 or 3, R ⁶Can be identical or different;

(a ") L is-CH ₂C (O) N (R ⁹)-, be R wherein ⁹Be hydrogen or (1-6C) alkyl (R particularly ⁹Be hydrogen);

(b) L is-N (R ⁸) C (O) CH ₂-, R wherein ⁸Be hydrogen or (1-6C) alkyl (R particularly ⁸Be hydrogen);

(c) L is-N (R ⁸) C (O) N (R ⁹)-, be R wherein ⁸And R ⁹Independently be selected from hydrogen or (1-6C) alkyl (R particularly ⁸And R ⁹All be hydrogen, perhaps in another embodiment, R ⁸And R ⁹One of be hydrogen, another is a methyl);

(d) L is-N (R ⁸) C (O) O-, wherein R ⁸Be hydrogen or (1-6C) alkyl (R particularly ⁸Be hydrogen, perhaps in another embodiment, R ⁸Be methyl);

(e) L is-OC (O) N (R ⁹)-, be R wherein ⁹Be hydrogen or (1-6C) alkyl (R particularly ⁹Be hydrogen, perhaps in another embodiment, R ⁹Be methyl);

(e ') L is-N (R ⁸) C (O) N (R ⁹)-,-N (R ⁸) C (O) O-or-N (R ⁸) C (O) CH ₂-, R wherein ⁸And R ⁹Independent hydrogen or (1-6C) alkyl represented.

(f) ring B-R ⁶Wherein m is 1 or 2, be selected from the 5-tert-butyl group-1,3,4-thiadiazoles-2-base, the different  azoles of 3-methyl-5-base, 3-methoxyphenyl, 4-(trifluoromethyl) pyridine-2-base, 2-(trifluoromethyl) phenyl, 3-(trifluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, 2-fluoro-4-(trifluoromethyl) phenyl, the different  azoles of the 5-tert-butyl group-3-base, phenyl and 3-acetyl-amino phenyl;

(f ') ring B-R ⁶Wherein m is 1 or 2, be selected from 3-acetyl-amino phenyl, 2-(trifluoromethyl) phenyl, 3-(trifluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, the 2-methoxyphenyl, the 3-methoxyphenyl, 2-fluoro-5-(trifluoromethyl) phenyl, 3, the 4-Dichlorobenzene base, 2-morpholine-4-base phenyl, the 5-tert-butyl group-1,3,4-thiadiazoles-2-base, 3-methyl isothiazole-5-base, the different  azoles of 3-methyl-5-base, the different  azoles of the 5-tert-butyl group-3-base, 1-methyl-3-the tert-butyl group-pyrazoles-5-base, 1-methyl piperidine-4-base, 1-propyl group piperidin-4-yl, 4-(trifluoromethyl) pyridin-3-yl and 4-(trifluoromethyl) pyridine-2-base;

(f ") ring B-R ⁶Wherein m is 1 or 2, be selected from 2-oxo-piperidines-3-base, 1-methyl piperidine-4-base, 1-propyl group piperidin-4-yl, 2,2-dimethyl tetrahydro pyrans-4-base, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 3, the 4-Dichlorobenzene base, 2, the 5-difluorophenyl, 3, the 4-difluorophenyl, 4, the 5-difluorophenyl, the 3-chlorphenyl, the 2-methoxyphenyl, the 3-methoxyphenyl, the 4-methoxyphenyl, 3-cyano group-phenyl, 2-(trifluoromethyl) phenyl, 3-(trifluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, 2-fluoro-5-(trifluoromethyl) phenyl, 3-acetyl-amino phenyl, 2-morpholine-4-base phenyl, the 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base, the 5-tert-butyl group-1,3,4-thiadiazoles-2-base, the 5-Trifluoromethyl-1,3,4-thiadiazoles-2-base, 5-cyclopropyl-1,3,4-thiadiazoles-2-base, 5-ethyl-1,3,4-thiadiazoles-2-base, 5-isopropyl-1,3,4-thiadiazoles-2-base, 5-ethylmercapto group-1,3,4-thiadiazoles-2-base, the different  azoles of 3-methyl-5-base, the different  azoles of 5-methyl-3-base, the different  azoles of the 5-tert-butyl group-3-base, 4-tertiary butyl thiazole-2-base, 3-methyl isothiazole-5-base, 1-methyl-3-the tert-butyl group-pyrazoles-5-base, 1-methyl-3-cyclopropyl-pyrazoles-5-base, 1-methyl-3-isopropyl-pyrazoles-5-base, 1-tert-butyl group pyrazoles-4-base, the 1-tert-butyl group-3-cyclopropyl pyrazoles-5-base, 1-ethyl pyrazole-3-yl, 1-isopropyl pyrazole-3-yl, 5-isopropyl-1,3,4- diazole-2-base, 4-three fluoro-pyridine-2-base, 3-fluoro-5-(4-methyl piperazine-1-yl) phenyl, 4-(trifluoromethyl) pyridin-3-yl and 4-(trifluoromethyl) pyridine-2-base;

(f ) R ¹And R ²All be hydrogen, R ³And R ⁴All be hydrogen, n is 0, and L is-NHC (O) NH-, and ring B-R ⁶Wherein m is 1 or 2, be selected from 3-acetyl-amino phenyl, 2-(trifluoromethyl) phenyl, 3-(trifluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, the 2-methoxyphenyl, the 3-methoxyphenyl, 2-fluoro-5-(trifluoromethyl) phenyl, 3, the 4-Dichlorobenzene base, 2-morpholine-4-base phenyl, the 5-tert-butyl group-1,3,4-thiadiazoles-2-base, 3-methyl isothiazole-5-base, the different  azoles of 3-methyl-5-base, the different  azoles of the 5-tert-butyl group-3-base, 1-methyl-3-the tert-butyl group-pyrazoles-5-base, 1-methyl piperidine-4-base, 1-propyl group piperidin-4-yl, 4-(trifluoromethyl) pyridin-3-yl and 4-(trifluoromethyl) pyridine-2-base; (g) R ¹And R ²Independently be selected from hydrogen, phenyl (CH ₂) _u-(wherein u is 0,1,2,3,4,5 or 6), (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl, (3-6C) cycloalkyl (CH ₂) _x-(wherein x is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings;

(1-6C) alkyl wherein; (1-6C) alkanoyl and (3-6C) cycloalkyl optional by one or more (as 1 or 2) can be identical or different the following group that is selected from replace: fluoro; hydroxyl; (1-6C) alkyl; (1-6C) alkoxyl; (1-6C) alkoxyl (1-6C) alkoxyl; (1-6C) alkoxyl (1-6C) alkoxyl (1-6C) alkoxyl; amino; single (1-6C) alkyl amino; two [(1-6C) alkyl] amino; carbamoyl; single (1-6C) alkyl-carbamoyl; two [(1-6C) alkyl] carbamoyls or-N (R ^d) C (O) (1-6C) alkyl, wherein R ^dBe hydrogen or (1-6C) alkyl; the first heterocycle of 3-7 perhaps saturated or fractional saturation; perhaps 5 or 6 yuan of heteroaryl rings, wherein said (1-6C) alkoxyl, (1-6C) alkoxyl (1-6C) alkoxyl and (1-6C) alkoxyl (1-6C) alkoxyl (1-6C) alkoxyl and amino, single (1-6C) alkyl-carbamoyl, two [(1-6C) alkyl] carbamoyl of single (1-6C) alkyl amino, two [(1-6C) alkyl] and/or-N (R ^d) C (O) (1-6C) (1-6C) alkyl of alkyl replaced by one or more (as 1 or 2) hydroxyl is optional;

Wherein said phenyl by one or more (as 1 or 2) can be identical or different be selected from that following group is optional to be replaced: halo, (1-6C) alkyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] amino, wherein said (1-6C) alkyl or (1-6C) alkoxyl by one or more (as 1 or 2) can be identical or different be selected from the optional replacement of following group: hydroxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] amino;

And R wherein ¹And/or R ²In any heterocycle and heteroaryl ring by one or more (as 1 or 2) can be identical or different be selected from that following group is optional to be replaced independently: (1-4C) alkyl, (1-4C) alkoxyl, (1-4C) alkoxyl (1-4C) alkyl, hydroxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] is amino or the first heterocycle of the 3-7 of saturated or fractional saturation, perhaps-C (O) (CH ₂) _zY, wherein z is 0,1,2 or 3, Y is selected from hydrogen, hydroxyl, (1-4C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] are amino or the 3-7 of saturated or fractional saturation unit heterocycle;

(h) R ¹And R ²Independently be selected from hydrogen, (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl or (3-6C) cycloalkyl (CH ₂) _x-(wherein x is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings;

Wherein said (1-6C) alkyl, (1-6C) alkanoyl and (3-6C) cycloalkyl optional by one or more (as 1 or 2) can be identical or different as above in (g) defined group replace;

And R wherein ¹And/or R ²In any heterocycle and heteroaryl ring by one or more (as 1 or 2) can be identical or different defined group is optional in (g) replaces independently as above;

(i) R ¹And R ²Independently be selected from hydrogen, (1-6C) alkanoyl, (1-6C) alkyl or 5 or 6 yuan of heteroaryl rings;

Wherein said (1-6C) alkyl and (1-6C) alkanoyl optional by one or more (as 1 or 2) can be identical or different as above in (g) defined group replace;

And R wherein ¹And/or R ²In any heterocycle and heteroaryl ring by one or more (as 1 or 2) can be identical or different as above in (g) defined group replace;

(j) R ¹Be hydrogen, R ²Be selected from hydrogen, (1-6C) alkyl sulphonyl, phenyl (CH ₂) _u-(wherein u is 0,1,2,3,4,5 or 6), (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl, (3-6C) cycloalkyl (CH ₂) _x-(wherein x is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings;

Wherein said phenyl by one or more (as 1 or 2) can be identical or different above (g) in defined group is optional replaces;

And R wherein ²In any heterocycle and heteroaryl ring optional independently by one or more (as 1 or 2) can be identical or different as above in (g) defined group replace;

(k) R ¹Be hydrogen, R ²Be selected from hydrogen, (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl or (3-6C) cycloalkyl (CH ₂) _x-(wherein x is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings;

(l) R ¹Be hydrogen, R ²Be selected from hydrogen, (1-6C) alkanoyl, (1-6C) alkyl or 5 or 6 yuan of heteroaryl rings;

(m) R ¹And R ²Independently be selected from hydrogen, (1-6C) alkyl sulphonyl, phenyl (CH ₂) _u-(wherein u is 0,1,2,3,4,5 or 6), (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl, (3-6C) cycloalkyl (CH ₂) _x-(wherein x is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings;

Wherein said (1-6C) alkyl, (1-6C) alkanoyl and (3-6C) cycloalkyl optional by one or more (as 1 or 2) can be identical or different the following group that is selected from replace: hydroxyl, (1-6C) alkoxyl, (1-6C) alkoxyl (1-6C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] amino, carbamoyl, list (1-6C) alkyl-carbamoyl, two [(1-6C) alkyl] carbamoyls or-N (R ^d) C (O) (1-6C) alkyl, wherein R ^dBe hydrogen or (1-6C) alkyl; the first heterocycle of 3-7 perhaps saturated or fractional saturation; perhaps 5 or 6 yuan of heteroaryl rings, wherein said (1-6C) alkoxyl and (1-6C) alkoxyl (1-6C) alkoxyl and amino, single (1-6C) alkyl-carbamoyl, two [(1-6C) alkyl] carbamoyl of single (1-6C) alkyl amino, two [(1-6C) alkyl] and/or-N (R ^d) C (O) (1-6C) (1-6C) alkyl of alkyl replaced by one or more (as 1 or 2) hydroxyl is optional;

Wherein said phenyl by one or more (as 1 or 2) can be identical or different be selected from that following group is optional to be replaced: halo, (1-6C) alkyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] amino, wherein said (1-6C) alkyl and (1-6C) alkoxyl by one or more (as 1 or 2) can be identical or different be selected from the optional replacement of following group: hydroxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] amino;

And prerequisite is to work as R ¹And/or R ²When being (1C) alkanoyl, then should do not replaced by (1C) alkanoyl by fluoro or hydroxyl;

(n) R ¹And R ²Independently be selected from hydrogen, (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl or (3-6C) cycloalkyl (CH ₂) _x-(wherein x is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings;

Wherein said (1-6C) alkyl, (1-6C) alkanoyl and (3-6C) cycloalkyl optional by one or more (as 1 or 2) can be identical or different as above in (m) defined group replace;

And R wherein ¹And/or R ²In any heterocycle and heteroaryl ring optional independently by one or more (as 1 or 2) can be identical or different as above in (m) defined group replace;

(o) R ¹And R ²Independently be selected from hydrogen, (1-6C) alkanoyl, (1-6C) alkyl or 5 or 6 yuan of heteroaryl rings;

Wherein said (1-6C) alkyl and (1-6C) alkanoyl optional by one or more (as 1 or 2) can be identical or different as above in (m) defined group replace;

(p) R ¹Be hydrogen, R ²Be selected from hydrogen, (1-6C) alkyl sulphonyl, phenyl (CH ₂) _u-(wherein u is 0,1,2,3,4,5 or 6), (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl, (3-6C) cycloalkyl (CH ₂) _x-(wherein x is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings;

Wherein said phenyl by one or more (as 1 or 2) can be identical or different above (m) in defined group is optional replaces;

And R wherein ²In any heterocycle and heteroaryl ring optional independently by one or more (as 1 or 2) can be identical or different as above in (m) defined group replace;

(q) R ¹Be hydrogen, R ²Be selected from hydrogen, (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl, (3-6C) cycloalkyl (CH ₂) _x-(wherein x is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings;

And R wherein ²In any heterocycle and heteroaryl ring optional independently by one or more (as 1 or 2) can be identical or different as above in (m) defined group replace; (r) R ¹Be hydrogen, R ²Be selected from hydrogen, (1-6C) alkanoyl, (1-6C) alkyl or 5 or 6 yuan of heteroaryl rings;

(s) R ¹Be hydrogen, R ²Be selected from hydrogen, (1-6C) alkanoyl or (1-6C) alkyl;

(t) R ¹Be hydrogen, R ²Be selected from hydrogen, (1-6C) alkanoyl or (1-6C) alkyl;

Wherein said (1-6C) alkyl and (1-6C) alkanoyl optional by one or more (as 1 or 2) can be identical or different the following group that is selected from replace: hydroxyl, (1-4C) alkoxyl, (1-4C) alkoxyl (1-4C) alkoxyl, amino, list (1-3C) alkyl amino, two (1-3C) alkyl amino, carbamoyl or-N (R ^d) C (O) (1-3C) alkyl, wherein R ^dBe hydrogen or (1-3C) alkyl, perhaps saturated 5 or 6 yuan of heterocycles, perhaps 5 or 6 yuan of heteroaryl rings, wherein said (1-4C) alkoxyl and (1-4C) alkoxyl (1-4C) alkoxyl and single (1-3C) alkyl amino, two [(1-3C) alkyl] is amino and/or-N (R ^d) C (O) (1-6C) (1-3C) alkyl of alkyl replaced by one or more (as 1 or 2) hydroxyl is optional;

And R wherein ²In any heterocycle and heteroaryl ring by one or more (as 1 or 2) can be identical or different be selected from independently that following group is optional to be replaced: (1-4C) alkyl, (1-4C) alkoxyl, (1-4C) alkoxyl (1-4C) alkyl, hydroxyl, amino, list (1-3C) alkyl amino or two [(1-3C) alkyl] is amino or the first heterocycle of the 3-7 of saturated or fractional saturation, perhaps-C (O) (CH ₂) _zY, wherein z is 0,1,2 or 3, Y is selected from hydrogen, hydroxyl, (1-4C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] are amino or the 3-7 of saturated or fractional saturation unit heterocycle;

(u) R ¹Be hydrogen, R ²Be selected from hydrogen, (1-3C) alkanoyl or (1-3C) alkyl;

Wherein said (1-3C) alkyl and (1-3C) alkanoyl optional by one or more (as 1 or 2) can be identical or different as above in (t) defined group replace;

And R wherein ²In any heterocycle and heteroaryl ring optional independently by one or more (as 1 or 2) can be identical or different as above in (t) defined group replace;

(v) R ¹Be hydrogen, R ²Be selected from hydrogen and (1-6C) alkyl (especially (1-3C) alkyl);

Wherein said (1-6C) alkyl (especially (1-3C) alkyl) optional by one or more (as 1 or 2) can be identical or different as above in (t) defined group replace;

(w) R ¹Be hydrogen, R ²Be (1-6C) alkyl (especially (1-3C) alkyl),

(w ') R ¹And R ²All be hydrogen, perhaps R ¹Be hydrogen or (1-6C) alkyl, and R ²Be (1-6C) alkyl,

Wherein said (1-6C) alkyl is optional to be replaced by following group: hydroxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] amino, carbamoyl, (1-6C) alkoxyl, (1-6C) alkoxyl (1-6C) alkoxyl ,-N (R ^d) C (O) (1-6C) alkyl, wherein R ^dBe hydrogen or (1-6C) alkyl, 3-7 unit's heterocycle or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation;

Wherein said (1-6C) alkoxyl, list (1-6C) alkyl amino and-N (R ^d) (1-6C) alkyl is optional is replaced by hydroxyl for C (O);

The 3-7 unit heterocycle of wherein saturated or fractional saturation optional by (1-4C) alkyl or-C (O) CH ₂Y (wherein Y is selected from hydroxyl or two (1-6C) alkyl amino) replaces;

(w ") R ¹And R ²All be hydrogen, perhaps R ¹Be hydrogen or (1-6C) alkyl, and R ²Be (1-6C) alkyl,

Wherein (1-6C) is optional is replaced by following group: 3-7 unit's heterocycle or 5 or 6 yuan of heteroaryl rings of hydroxyl, amino, list (1-6C) alkyl amino or two (1-6C) alkyl amino, aryl (particularly phenyl) or saturated or fractional saturation;

Wherein said aryl rings, the first heterocycle of 3-7 saturated or fractional saturation or 5 or 6 yuan of heteroaryl rings are chosen wantonly by 1 or 2 and independently are selected from (1-4C) alkyl and (1-4C) the group replacement of alkoxyl;

(w ) R ¹And R ²All be hydrogen, perhaps R ¹Be hydrogen or (1-6C) alkyl, and R ²Be (1-6C) alkyl,

Wherein said (1-6C) is optional to be replaced by following group: hydroxyl, amino, list (1-6C) alkyl amino or two (1-6C) alkyl amino, carbamoyl, (1-6C) alkoxyl, (1-6C) alkoxyl (1-6C) alkoxyl ,-N (R ^d) C (O) (1-6C) alkyl, wherein R ^dBe hydrogen or (1-6C) 3-7 unit's heterocycle or 5 or 6 yuan of heteroaryl rings of alkyl, aryl (especially phenyl), saturated or fractional saturation;

3-7 unit's heterocycle of wherein said aryl rings, saturated or fractional saturation or 5 or 6 yuan of heteroaryl rings optional by (1-4C) alkyl, (1-4C) alkoxyl or-C (O) CH ₂Y (wherein Y is selected from hydroxyl or two (1-6C) alkyl amino) replaces.

(w " ) R ¹And R ²All be hydrogen, R ³Be amino, and R ⁴Be hydrogen;

(x) R ¹And R ²Independently be selected from hydrogen, methyl, ethyl, propyl group, the 2-hydroxyethyl, the 3-hydroxypropyl, the 2-methoxy ethyl, the 3-methoxy-propyl, the 2-amino-ethyl, the 3-aminopropyl, 2-(isopropyl amino) ethyl, 3-(isopropyl amino) propyl group, 2-(dimethylamino) ethyl, 3-(dimethylamino) propyl group, the carbamyl ylmethyl, 2-carbamoyl ethyl, 3-carbamoyl propyl group, 2-(2-methoxy ethoxy) acetyl group, 2-morpholine-4-base ethyl, 3-morpholine-4-base propyl group, 2-pyrrolidine-1-base ethyl, 3-pyrrolidine-1-base propyl group, 3-(4-methyl piperazine-1-yl) propyl group, 3-piperidines-1-base propyl group, 2-piperidines-1-base ethyl, 2-(1H-imidazol-4 yl) ethyl, 2-pyridine-2-base ethyl, 3-(1H-imidazoles-1-yl) propyl group, 2-pyridin-4-yl ethyl, 2, the different  azoles of the 4-dimethoxy-benzyl and the 5-tert-butyl group-3-base;

(y) R ¹Be hydrogen, R ²Be selected from hydrogen, methyl, ethyl, propyl group, the 2-hydroxyethyl, the 3-hydroxypropyl, the 2-methoxy ethyl, the 3-methoxy-propyl, the 2-amino-ethyl, the 3-aminopropyl, 2-(isopropyl amino) ethyl, 3-(isopropyl amino) propyl group, 2-(dimethylamino) ethyl, 3-(dimethylamino) propyl group, the carbamyl ylmethyl, 2-carbamoyl ethyl, 3-carbamoyl propyl group, 2-(2-methoxy ethoxy) acetyl group, 2-morpholine-4-base ethyl, 3-morpholine-4-base propyl group, 2-pyrrolidine-1-base ethyl, 3-pyrrolidine-1-base propyl group, 3-(4-methyl piperazine-1-yl) propyl group, 3-piperidines-1-base propyl group, 2-piperidines-1-base ethyl, 2-(1H-imidazol-4 yl) ethyl, 2-pyridine-2-base ethyl, 3-(1H-imidazoles-1-yl) propyl group, 2-pyridin-4-yl ethyl, 2, the different  azoles of the 4-dimethoxy-benzyl and the 5-tert-butyl group-3-base;

(z) R ¹Be hydrogen, R ²Be selected from hydrogen, methyl, ethyl, propyl group, 3-(isopropyl amino) propyl group, 2-pyrrolidine-1-base ethyl, the different  azoles of the 5-tert-butyl group-3-base, 3-piperidines-1-base propyl group, 2-morpholine-4-base ethyl, 2-pyrrolidine-1-base ethyl, 3-(dimethylamino) propyl group, 2-hydroxyethyl and 2-piperidines-1-base ethyl;

(z ') R ¹Be hydrogen or methyl, R ²Be selected from hydrogen, methyl, 2-hydroxyethyl, 2-amino-ethyl, the amino butyl of 4-, 3-(N-isopropyl amino) propyl group, 2-(dimethylamino) ethyl, 4-(dimethylamino) butyl, 2-pyrrolidine-1-base ethyl, 3-pyrrolidine-1-base propyl group, the different  azoles of the 5-tert-butyl group-3-base, 2-morpholine-4-base ethyl, 3-morpholine-4-base propyl group, 2-piperidines-1-base ethyl, 3-piperidines-1-base propyl group, 3-(4-methyl piperazine-1-yl) propyl group and 2, the 4-dimethoxy-benzyl;

(y ") R ¹Be hydrogen or methyl, R ²Be selected from hydrogen, methyl, the 2-hydroxyethyl, the 2-methoxy ethyl, the 3-methoxy-propyl, 2-(2-hydroxyl-oxethyl) ethyl, the 2-amino-ethyl, the 3-aminopropyl, the amino butyl of 4-, 2-(isopropyl amino) ethyl, 3-(isopropyl amino) propyl group, 2-(dimethylamino) ethyl, 3-(dimethylamino) propyl group, 4-(dimethylamino) butyl, 2-(dimethylamino)-1-Methylethyl, the carbamyl ylmethyl, 2-carbamoyl ethyl, 2-(2-methoxy ethoxy) acetyl group, 2-(2-glycoloyl amino) ethyl, 3-[N-(2-hydroxyethyl) amino] propyl group, 2-morpholine-4-base ethyl, 3-morpholine-4-base propyl group, 2-[(1-methyl-2-morpholine-4-base ethyl)], 2-pyrrolidine-1-base ethyl, 3-pyrrolidine-1-base propyl group, 1-glycolyl pyrrolidine-2-yl) methyl, 1-(N, N-dimethyl glycyl) pyrrolidine-2-base, 2-piperazine-1-base ethyl, 3-piperazine-1-base propyl group, 3-(4-methyl piperazine-1-yl) propyl group, 3-piperidines-1-base propyl group, 2-(1H-imidazol-4 yl) ethyl, 2-pyridine-2-base ethyl, 3-(1H-imidazoles-1-yl) propyl group, the different  azoles of the 5-tert-butyl group-3-base, 2-pyridin-4-yl ethyl and 2, the 4-dimethoxy-benzyl;

(z ") R ¹Be hydrogen, R ²Be selected from 2-morpholine-4-base ethyl, 3-morpholine-4-base propyl group, 3-piperidines-1-base propyl group, 2-piperidines-1-base ethyl, 2-pyrrolidine-1-base ethyl, 4-methyl-piperazine-1-base propyl group and 3-pyrrolidine-1-base propyl group;

(z ) R ¹Be hydrogen, R ²Be selected from 2-morpholine-4-base ethyl, 3-morpholine-4-base propyl group, 3-piperidines-1-base propyl group, 2-piperidines-1-base ethyl, 2-pyrrolidine-1-base ethyl, 3-pyrrolidine-1-base propyl group and 4-methyl-piperazine-1-base;

(aa) R ¹And R ²All be hydrogen;

(bb) R ¹And R ²All be (1-6C) alkyl (especially (1-3C) alkyl);

(cc) R ¹Be hydrogen, R ²It is methyl;

(dd) R ³Be selected from hydrogen, (1-3C) alkyl or (1-3C) alkoxyl,

Wherein said (1-3C) alkyl and (1-3C) alkoxyl optional by one or more (as 1 or 2) can be identical or different the following group that is selected from replace: fluoro, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl, amino, single (1-6C) alkyl amino, two [(1-6C) alkyl] amino, carbamoyl, single (1-6C) alkyl-carbamoyl or two [(1-6C) alkyl] carbamoyl, 3-7 unit's heterocycle or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle or heteroaryl ring optional by one or more (as 1 or 2) can be identical or different the following group that independently is selected from replace: (1-4C) alkyl, (1-4C) alkoxyl, hydroxyl, amino, the first heterocycle of single (1-6C) alkyl amino or two [(1-6C) alkyl] 3-7 amino or saturated or fractional saturation; Perhaps R ³Represent group-NR as defined above ¹R ²

(ee) R ³Be selected from hydrogen or (1-6C) alkyl,

Wherein said (1-6C) alkyl optional by one or more (as 1 or 2) can be identical or different the following group that is selected from replace: fluoro, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl, amino, single (1-6C) alkyl amino, two [(1-6C) alkyl] amino, carbamoyl, single (1-6C) alkyl-carbamoyl or two [(1-6C) alkyl] carbamoyl, 3-7 unit's heterocycle or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle or heteroaryl ring optional by one or more (as 1 or 2) can be identical or different the following group that is selected from replace independently: (1-4C) alkyl, (1-4C) alkoxyl, hydroxyl, amino, the first heterocycle of single (1-6C) alkyl amino or two [(1-6C) alkyl] 3-7 amino or saturated or fractional saturation;

Perhaps R ³The above definition of representative-NR ¹R ²

(ff) R ³Be selected from the group-NR of hydrogen and above definition ¹R ²(especially-NH ₂);

(gg) R ³Be hydrogen;

(hh) R ³Be the group-NR of above definition ¹R ²(especially-NH ₂);

(ii) R ⁴Independently be selected from hydrogen and (1-6C) alkyl (especially (1-3C) alkyl);

(jj) R ⁴Be hydrogen;

(kk) R ³And R ⁴All be hydrogen;

(ll) R ³Be as defined above-NR ¹R ²(especially-NH ₂), and R ⁴Be hydrogen;

(mm) A is selected from phenyl, furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl and 1,3, the 5-triazine radical;

(mm ') A is selected from phenyl,  azoles base, imidazole radicals, pyrrole radicals, pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyridine radicals, pyridazinyl, pyrazinyl and pyrimidine radicals;

(nn) A is selected from phenyl, thiazolyl, thiadiazolyl group, pyridine radicals and pyrimidine radicals;

(oo) A is a phenyl;

(oo ') A is phenyl or pyridine radicals;

(oo ") A is phenyl or pyridine radicals, and wherein the pyridine radicals nuclear nitrogen is positioned on the 3-position with respect to acetylene bond.

(pp) A is a phenyl, and n is 0;

(pp ') A is phenyl or pyridine radicals, and n is 0;

(qq) n is 0,1 or 2 (especially 0 or 1, more especially 0);

(rr) n is 1 or 2, R ⁵Independently be selected from halo, (1-6C) alkoxyl and (1-6C) alkyl, wherein said (1-6C) alkyl and (1-6C) alkoxyl is optional is replaced by cyano group or one or more fluorine;

(rr) n is 1 or 2, R ⁵Independently be selected from cyano group, halo, (1-6C) alkoxyl and (1-6C) alkyl,

Wherein said (1-6C) alkyl is replaced by cyano group or one or more fluorine with (1-6C) alkoxyl is optional;

(rr ') n is 0 or 1, when n is 1, and R ⁵Be (1-4C) alkyl (especially methyl);

(ss) n is 1 or 2, R ⁵Independently be selected from cyclopropyl and (1-6C) alkyl, wherein said (1-6C) alkyl is optional to be replaced by cyano group or one or more fluorine;

(tt) L is connected on the A ring with respect on the position between the acetenyl junction point;

(uu) L is connected on the A ring with respect on the position between the acetenyl junction point, representative-N (R ⁸) C (O) C (R ^aR ^b)-,-N (R ⁸) C (O) N (R ⁹)-or-N (R ⁸) C (O) O-, wherein R ⁸And R ⁹Independent represent hydrogen or (1-6C) alkyl, and R wherein ^aAnd R ^bIndependent hydrogen or (1-6C) alkyl, the perhaps R of representing ^aAnd R ^bConnected carbon atom is represented (3-6C) cycloalkyl together;

(vv) L is connected on the A ring with respect on the position between the acetenyl junction point, and representative-N (R ⁸) C (O) C (R ^aR ^b)-,-N (R ⁸) C (O) N (R ⁹)-or-N (R ⁸) C (O) O-, wherein R ⁸And R ⁹Independent hydrogen or (1-3C) alkyl, the wherein R of representing ^aAnd R ^bIndependent hydrogen or (1-3C) alkyl represented;

(vv ') L is connected on the A ring in the para-position with respect to the acetenyl junction point;

(ww) L is connected on the A ring in the para-position with respect to the acetenyl junction point, representative-N (R ⁸) C (O) O-or-N (R ⁸) C (O) N (R ⁹)-, be R wherein ⁸And R ⁹Independent hydrogen or (1-6C) alkyl represented;

(xx) A is selected from phenyl, furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl or 1,3,5-triazine radical (especially phenyl, thiazolyl, thiadiazolyl group, pyridine radicals and pyrimidine radicals);

N is 0; And

L is connected on the A ring with respect on the position between the acetenyl junction point, and representative-N (R ⁸) C (O) C (R ^aR ^b)-,-N (R ⁸) C (O) N (R ⁹)-or-N (R ⁸) C (O) O-, wherein R ⁸And R ⁹Independent represent hydrogen or (1-6C) alkyl, and R wherein ^aAnd R ^bIndependent hydrogen or (1-6C) alkyl, the perhaps R of representing ^aAnd R ^bConnected carbon atom is represented (3-6C) cycloalkyl together;

(yy) A is selected from phenyl, furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl or 1,3,5-triazine radical (especially phenyl, thiazolyl, thiadiazolyl group, pyridine radicals and pyrimidine radicals);

N is 0; And

L is connected on the A ring with respect on the position between the acetenyl junction point, and representative

-N (R ⁸) C (O) C (R ^aR ^b)-,-N (R ⁸) C (O) N (R ⁹)-or-N (R ⁸) C (O) O-, wherein R ⁸And R ⁹Independent represent hydrogen or (1-3C) alkyl, and R wherein ^aAnd R ^bIndependent hydrogen or (1-3C) alkyl represented;

(zz) when B was (3-7C) cycloalkyl ring, then B was selected from cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl;

(zz ') when B be saturated or during the 3-7 of fractional saturation unit heterocycle, then B is selected from oxetanyl, azetidinyl, Thietane base (thietanyl), pyrrolidinyl, morpholinyl, 1,3-dioxolanyl, tetrahydrofuran base, piperidyl, piperazinyl, tetrahydro-1,4-thiazine base, THP trtrahydropyranyl, high piperazinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyranose, tetrahydro pyridyl, 1,2,4- di azoly and dihydro thiapyran base;

(zz ") optionally contains 1 as B; 2; 3 or 4 independently are selected from N; the hetero atom of O and S; and be saturated; 8 of fractional saturation or aromatics, during 9 or 10 yuan of bicyclic radicals, then B is selected from 2,3-dihydro-1H-indenyl, benzo dioxine base, 1,2,3, the 4-tetrahydro naphthyl, 1,2,3,4-tetrahydrochysene pentalene (tetrahydropentalene), benzofuranyl, 2, the 3-dihydro benzo furyl, benzimidazolyl, benzothienyl, benzothiazolyl, the benzisothiazole base, the benzoxazol base, benzisoxa  azoles base, the pyridine-imidazole base, the pyrimido imidazole radicals, quinolyl, isoquinolyl, quinoxalinyl, quinazolyl, 2, the 3-phthalazinyl, cinnolinyl, indyl and naphthyridinyl

Perhaps B is the following formula group:

Wherein W is 5-7 unit's ring (comprising bridge atom), and this W ring comprises carbon atom or the other optional hetero atom that independently is selected from oxygen, nitrogen and sulfur, and wherein this dicyclo contains no more than altogether 4 hetero atoms.The example of these rings comprises: pyrrolo-[1,5-a] pyridine radicals, pyrrolo-[1,5-c] pyrimidine radicals, pyrrolo-[1,5-a] [1,3,5] triazine radical, 4,5-dihydro-pyrazolo [1,5-a] pyridine radicals, 4H-pyrazolo [5,1-c] [1,4] thiazinyl, 4H-pyrazolo [5,1-c] [1,4]  piperazine base, 1,2-benzisoxa  azoles base, different  azoles also [5,4-b] pyridine radicals, different  azoles also [5,4-d] pyrimidine radicals, the 4H-thiapyran is [3,4-d] different  azoles base also, the 4H-pyrans is [3,4-d] different  azoles base also, 7aH-draws the diindyl base, 7aH-pyrrolo-[2,3-b] pyridine radicals, 7aH-pyrrolo-[2,3-b] pyrimidine radicals, 4,7a-dihydro thiapyran is [4,3-b] pyrrole radicals and 4 also, the 7a-dihydropyran is [4,3-b] pyrrole radicals also.

(zz ) B be selected from saturated or fractional saturation 4-6 unit heterocycle, aryl, be selected from 5 or 6 yuan of following heteroaryl rings: furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl or 1,3, the 5-triazine radical, perhaps optionally contain 1,2,3 or 4 hetero atom that independently is selected from N, O and S, and be 8,9 or 10 yuan of bicyclic radicals of saturated, fractional saturation or aromatics;

(aaa) B is selected from 4-6 unit heterocycle, the aryl of saturated or fractional saturation, or 5 or 6 yuan be selected from following heteroaryl ring: furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl or 1,3, the 5-triazine radical;

(aaa ') B is selected from 4-6 unit heterocycle, the aryl of saturated or fractional saturation, or 5 or 6 yuan be selected from following heteroaryl ring: furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl or 1,3, the 5-triazine radical;

(aaa ") B is selected from the 4-6 unit heterocycle of saturated or fractional saturation; or 5 or 6 yuan be selected from following heteroaryl ring: furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl or 1; 3,5-triazine radical;

(bbb) B is selected from cyclopenta, cyclohexyl, piperidyl, THP trtrahydropyranyl, phenyl, furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, 1,3,5-triazine radical, 2,3-dihydro-1,4-benzo dioxine base and 1,3-benzo dioxole-5-base;

(ccc) B is selected from piperidyl, phenyl, furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, 1,3,5-triazine radical, 2,3-dihydro-1,4-benzo dioxine base and 1,3-benzo dioxole-5-base;

(ccc ') B is selected from phenyl, 2,3-dihydro-indenyl, piperidyl, pyridine radicals, pyrazolyl, isothiazolyl, thiadiazolyl group, different  azoles base or benzo dioxine base;

(ccc ") B is selected from phenyl, piperidyl, pyridine radicals, pyrazolyl, isothiazolyl, thiadiazolyl group, different  azoles base, benzo dioxolyl or THP trtrahydropyranyl;

(ccc ) B is selected from phenyl, 2,3-dihydro-indenyl, piperidyl, pyridine radicals, pyrazolyl, isothiazolyl, thiadiazolyl group, different  azoles base, benzo dioxine base, benzo dioxolyl or THP trtrahydropyranyl.

(ddd) B is selected from piperidyl, phenyl, different  azoles base, isothiazolyl, thiadiazolyl group, pyrazolyl and pyridine radicals;

(eee) B is selected from phenyl, pyrazolyl, thiadiazolyl group and different  azoles base;

(eee ') B is selected from different  azoles base, thiadiazolyl group and pyrazolyl;

(eee ") B is selected from different  azoles base and pyrazolyl;

(fff) B is a phenyl;

(ggg) B is different  azoles base;

(hhh) B is a pyrazolyl;

(iii) B is saturated or the first heterocycle of the 3-7 of fractional saturation (especially 4-6), and it contains the hetero atom that 1 or 2 (especially 1 hetero atom) is selected from oxygen and nitrogen;

(jjj) B is 8,9 or 10 yuan of dicyclos of saturated, fractional saturation or aromatics, and it is optional to contain the hetero atom that 1,2 or 3 (especially 1 or 2) is selected from N and O;

(kkk) A is a phenyl;

N is 0; With

4-6 unit heterocycle, aryl, 5 or 6 yuan that B is selected from saturated or fractional saturation are selected from following heteroaryl ring: furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl or 1,3, the 5-triazine radical perhaps optionally contains 1,2,3 or 4 and independently is selected from the hetero atom of N, O and S and is 8,9 or 10 yuan of bicyclic radicals of saturated, fractional saturation or aromatics;

(lll) A is a phenyl;

N is 0; With

B is selected from phenyl, pyrazolyl, thiadiazolyl group and different  azoles base;

(mmm) A is selected from phenyl, furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl and 1,3,5-triazine radical (especially phenyl, thiazolyl, thiadiazolyl group, pyridine radicals and pyrimidine radicals);

N is 0;

L is connected on the A ring with respect on the position between the acetenyl junction point, representative-N (R ⁸) C (O) C (R ^aR ^b)-,-N (R ⁸) C (O) N (R ⁹)-or-N (R ⁸) C (O) O-, wherein R ⁸And R ⁹Independent represent hydrogen or (1-6C) alkyl, and R wherein ^aAnd R ^bIndependent hydrogen or (1-6C) alkyl, the perhaps R of representing ^aAnd R ^bConnected carbon atom is represented (3-6C) cycloalkyl together; With

(nnn) A is selected from phenyl, furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl or 1,3,5-triazine radical (especially phenyl, thiazolyl, thiadiazolyl group, pyridine radicals and pyrimidine radicals);

N is 0;

L is connected on the A ring with respect on the position between the acetenyl junction point, representative-N (R ⁸) C (O) C (R ^aR ^b)-,-N (R ⁸) C (O) N (R ⁹)-or-N (R ⁸) C (O) O-, wherein R ⁸And R ⁹Independent represent hydrogen or (1-3C) alkyl, and R wherein ^aAnd R ^bIndependent hydrogen or (1-3C) alkyl represented; With

(ooo) m is 0,1 or 2 (especially 1 or 2);

(ppp) R ⁶Be selected from halo, cyano group, (3-4C) cycloalkyl ring, the first heterocycle of 3-7 saturated or fractional saturation or N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl; Perhaps R ⁶Be selected from (1-6C) alkyl or (1-6C) alkoxyl, wherein said (1-6C) alkyl and (1-6C) alkoxyl by one or more (for example 1 or 2) can be identical or different be selected from that following group is optional to be replaced: cyano group, fluoro, hydroxyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] are amino, the first heterocycle of 3-7 of (3-7C) cycloalkyl ring or saturated or fractional saturation;

(qqq) R ⁶Be selected from halo, cyano group, the first heterocycle of 3-7 saturated or fractional saturation or N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl; Perhaps R ⁶Be selected from (1-6C) alkyl or (1-6C) alkoxyl, wherein said (1-6C) alkyl and (1-6C) alkoxyl by one or more (for example 1 or 2) can be identical or different be selected from that following group is optional to be replaced: cyano group, fluoro, hydroxyl and amino (especially fluoro);

(rrr) R ⁶Be selected from halo, cyano group, saturated or fractional saturation 3-7 unit's heterocycle or-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-3C) alkyl; Perhaps R ⁶Be selected from (1-4C) alkyl or (1-4C) alkoxyl, wherein said (1-4C) alkyl and (1-4C) alkoxyl by one or more (for example 1 or 2) can be identical or different be selected from that following group is optional to be replaced: cyano group, fluoro, hydroxyl and amino (especially fluoro);

(sss) R ⁶Be selected from fluoro, chloro, cyano group, acetyl-amino, methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, trifluoromethyl, cyclopropyl, cyclopropyl methyl, methoxyl group, ethyoxyl, propoxyl group, butoxy and morpholine-4-base;

(ttt) R ⁶Be selected from fluoro, chloro, acetyl-amino, methyl, propyl group, the tert-butyl group, trifluoromethyl, cyclopropyl, cyclopropyl methyl, methoxyl group and morpholine-4-base;

(ttt ') R ⁶Independently be selected from halo, (1-6C) alkyl (optional by 3 groups that independently are selected from halo (especially fluoro) replace) at the most, (1-6C) alkoxyl ,-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl (especially (1-4C) alkyl), perhaps saturated 3-7 unit heterocycle (especially morpholino);

(ttt ") R ⁶Independently be selected from halo, trifluoromethyl, methyl, the tert-butyl group, methoxyl group, acetyl-amino or morpholino;

(ttt ) R ⁶Independently be selected from halo, cyano group, oxo, (3-7C) cycloalkyl, saturated 3-7 unit heterocycle (its optional replaced) by (1-4C) alkyl ,-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl (especially (1-4C) alkyl), (1-6C) alkyl (optional by 3 groups that independently are selected from halo (especially fluoro) replace) at the most or (1-6C) alkoxyl.

(ttt " ") R ⁶Independently be selected from halo, trifluoromethyl, cyano group, methyl, isopropyl, the tert-butyl group, methoxyl group, acetyl-amino, oxo, cyclopropyl or 4-methyl-piperazine-1-base;

(ttt " ) R ⁶Independently be selected from (1-6C) alkyl or (3-7C) cycloalkyl, especially independently be selected from (1-4C) alkyl or (3-5C) cycloalkyl ring, more especially independently be selected from methyl, ethyl, propyl group, isopropyl, sec-butyl, the tert-butyl group, cyclopropyl or cyclobutyl.

(uuu) B is selected from cyclopenta, cyclohexyl, piperidyl, THP trtrahydropyranyl, phenyl, furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, 1,3,5-triazine radical, 2,3-dihydro-1,4-benzo dioxine base and 1,3-benzo dioxole-5-base;

M is 1 or 2; With

R ⁶Independently be selected from fluoro, chloro, cyano group, acetyl-amino, methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, trifluoromethyl, cyclopropyl, cyclopropyl methyl, methoxyl group, ethyoxyl, propoxyl group, butoxy and morpholine-4-base;

(vvv) B is selected from phenyl, different  azoles base, isothiazolyl, thiadiazolyl group, pyrazolyl and pyridine radicals;

M is 1 or 2; With

R ⁶Independently be selected from halo, cyano group, (3-4C) cycloalkyl ring, saturated or fractional saturation 3-7 unit's heterocycle or-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl; Perhaps R ⁶Be selected from (1-6C) alkyl or (1-6C) alkoxyl, wherein said (1-6C) alkyl and (1-6C) alkoxyl by one or more (for example 1 or 2) can be identical or different be selected from that following group is optional to be replaced: cyano group, fluoro, hydroxyl and amino (especially fluoro);

(www) B is selected from phenyl, different  azoles base, isothiazolyl, thiadiazolyl group, pyrazolyl and pyridine radicals;

M is 1 or 2; With

(xxx) B is a phenyl;

M is 1 or 2; With

R ⁶Independently be selected from fluoro, chloro, cyano group, acetyl-amino, trifluoromethyl, cyclopropyl, cyclopropyl methyl, methoxyl group, ethyoxyl, propoxyl group, butoxy and morpholine-4-base;

(yyy) B is a phenyl;

M is 1 or 2; With

R ⁶Independently be selected from fluoro and trifluoromethyl;

(zzz) B is different  azoles base;

M is 1 or 2; With

R ⁶Independently be selected from fluoro, chloro, cyano group, acetyl-amino, methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, trifluoromethyl, cyclopropyl, cyclopropyl methyl, methoxyl group, ethyoxyl, propoxyl group and butoxy;

(aaaa) B is different  azoles base;

M is 1 or 2; With

R ⁶Independently be selected from methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group (the especially methyl and the tert-butyl group, the more especially tert-butyl group);

(bbbb) B is a pyrazolyl;

M is 1 or 2; With

(bbbb ') B is a pyrazolyl;

M is 1 or 2; With

(bbbb ") B is a thiadiazolyl group;

M is 1 or 2; With

R ⁶Independently be selected from fluoro, chloro, cyano group, acetyl-amino, methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, trifluoromethyl, cyclopropyl, methoxyl group, ethyoxyl, propoxyl group and butoxy;

(bbbb ) B is a thiadiazolyl group;

M is 1 or 2; With

(cccc) ring B-R ⁶Wherein m is 0,1 or 2, be selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2, the 5-difluorophenyl, 3, the 4-difluorophenyl, 3, the 5-difluorophenyl, 2-(trifluoromethyl) phenyl, 3-(trifluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, 2-fluoro-5-(trifluoromethyl) phenyl, the 2-chlorphenyl, the 3-chlorphenyl, the 4-chlorphenyl, 2, the 5-Dichlorobenzene base, 3, the 4-Dichlorobenzene base, 3, the 5-Dichlorobenzene base, the 2-methoxyphenyl, the 3-methoxyphenyl, the 4-methoxyphenyl, 2-cyano group-phenyl, 3-cyano group-phenyl, 4-cyano group-phenyl, 2-acetyl-amino phenyl, 3-acetyl-amino phenyl, 4-acetyl-amino phenyl, the 5-tert-butyl group-1,3,4-thiadiazoles-2-base, the 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base, 5-cyclopropyl-1,3,4-thiadiazoles-2-base, 1-methyl-3-cyclopropyl-pyrazoles-5-base, the 1-tert-butyl group-3-cyclopropyl pyrazoles-5-base, 3-methyl isothiazole-5-base, the different  azoles of 3-methyl-5-base, the different  azoles of 5-methyl-3-base, the different  azoles of the 5-tert-butyl group-3-base, 4-(trifluoromethyl) pyridine-2-base, 2-oxo-piperidines-3-base, 2,2-dimethyl tetrahydro-2H-pyrans-4-base, 2,3-dihydro-1,4-benzo dioxine base, 1,3-benzo dioxole-5-base, 2-morpholine-4-base phenyl, 3-morpholine-4-base phenyl, 4-morpholine-4-base phenyl, 1-methyl piperidine-4-base, 1-ethyl piperidine-4-base and 1-propyl group piperidin-4-yl; With

(dddd) ring B-R ⁶Wherein m is 1 or 2; be selected from 2-fluoro-phenyl; 3-fluoro-phenyl; 4-fluoro-phenyl; 2; the 5-difluorophenyl; 3; the 4-difluorophenyl; 3; the 5-difluorophenyl; 2-(trifluoromethyl) phenyl; 3-(trifluoromethyl) phenyl; 4-(trifluoromethyl) phenyl; 2-fluoro-5-(trifluoromethyl) phenyl; the 2-chlorphenyl; the 3-chlorphenyl; the 4-chlorphenyl; 2; the 5-Dichlorobenzene base; 3; the 4-Dichlorobenzene base; 3; the 5-Dichlorobenzene base; the 2-methoxyphenyl; the 3-methoxyphenyl; the 4-methoxyphenyl; 2-cyano group-phenyl; 3-cyano group-phenyl; 4-cyano group-phenyl; 2-acetyl-amino phenyl; 3-acetyl-amino phenyl; 4-acetyl-amino phenyl; the 5-tert-butyl group-1; 3; 4-thiadiazoles-2-base; the 5-methyl isophthalic acid; 3; 4-thiadiazoles-2-base; 5-cyclopropyl-1; 3; 4-thiadiazoles-2-base; 3-cyclopropyl-pyrazoles-5-base; the 1-tert-butyl group-3-cyclopropyl pyrazoles-5-base; 3-methyl isothiazole-5-base; the different  azoles of 3-methyl-5-base; the different  azoles of 5-methyl-3-base; the different  azoles of the 5-tert-butyl group-3-base; 4-(trifluoromethyl) pyridine-2-base; 2-oxo-piperidines-3-base; 2,2-dimethyl tetrahydro-2H-pyrans-4-base; 2-morpholine-4-base phenyl; 3-morpholine-4-base phenyl; 4-morpholine-4-base phenyl; 1-methyl piperidine-4-base; 1-ethyl piperidine-4-base and 1-propyl group piperidin-4-yl.

One specific embodiments of formula I chemical compound is formula Ib chemical compound and salt thereof, especially its pharmaceutically acceptable salt:

Formula Ib

Wherein:

Wherein said (1-6C) alkyl; (1-6C) alkanoyl and (3-6C) cycloalkyl independently be selected from the optional replacement of following group by one or more: fluoro; hydroxyl; (1-6C) alkyl; (1-6C) alkoxyl; (1-6C) alkoxyl (1-6C) alkoxyl; (1-6C) alkoxyl (1-6C) alkoxyl (1-6C) alkoxyl; amino; single (1-6C) alkyl amino; two [(1-6C) alkyl] amino; carbamoyl; single (1-6C) alkyl-carbamoyl; two [(1-6C) alkyl] carbamoyls or-N (R ^d) C (O) (1-6C) alkyl, wherein R ^dBe hydrogen or (1-6C) alkyl; the first heterocycle of 3-7 perhaps saturated or fractional saturation; perhaps 5 or 6 yuan of heteroaryl rings, wherein said (1-6C) alkoxyl, (1-6C) alkoxyl (1-6C) alkoxyl and (1-6C) alkoxyl (1-6C) alkoxyl (1-6C) alkoxyl and amino, single (1-6C) alkyl-carbamoyl, two [(1-6C) alkyl] carbamoyl of single (1-6C) alkyl amino, two [(1-6C) alkyl] and/or-N (R ^d) C (O) (1-6C) (1-6C) alkyl of alkyl replaced by one or more hydroxyl is optional,

R ³Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl, wherein said (1-6C) alkyl or (1-6C) alkoxyl be selected from independently by one or more that following group is optional to be replaced: fluoro, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl, amino, single (1-6C) alkyl amino, two [(1-6C) alkyl] amino, carbamoyl, single (1-6C) alkyl-carbamoyl or two [(1-6C) alkyl] carbamoyl, 3-7 unit's heterocycle or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle and heteroaryl ring are replaced independently by one or more following groups is optional: (1-4C) alkyl, (1-4C) alkoxyl, hydroxyl, amino, the first heterocycle of single (1-6C) alkyl amino or two [(1-6C) alkyl] 3-7 amino or saturated or fractional saturation;

Perhaps R ³Represent group-NR as defined above ¹R ²

R ⁴Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl;

N is 0,1,2 or 3;

L representative-C (R ^aR ^b) C (O) N (R ⁹)-,-N (R ⁸) C (O) C (R ^aR ^b)-,-N (R ⁸) C (O) N (R ⁹)-,-N (R ⁸) C (O) O-or-OC (O)-N (R ⁹)-, be R wherein ⁸And R ⁹Independent represent hydrogen or (1-6C) alkyl, and R wherein ^aAnd R ^bIndependent hydrogen or (1-6C) alkyl, the perhaps R of representing ^aAnd R ^bConnected carbon atom is represented (3-6C) cycloalkyl together;

The 3-7 unit heterocycle of B representative (3-7C) cycloalkyl ring, saturated or fractional saturation, aryl, 5 or 6 yuan are selected from following heteroaryl ring: furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl or 1,3, the 5-triazine radical, perhaps 8,9 or 10 yuan of saturated, fractional saturations or aromatics dicyclo, it is optional to contain 1,2,3 or 4 hetero atom that independently is selected from N, O and S;

R ⁶Be selected from one of following two groups of groups:

(i) R ⁶Be selected from halo, cyano group, oxo, (3-7C) cycloalkyl ring, saturated or fractional saturation 3-7 unit's heterocycle or-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl;

Perhaps R ⁶Be selected from (1-6C) alkyl ,-S (O) _p-(1-6C) alkyl (wherein p is 0,1 or 2) or (1-6C) alkoxyl,

Wherein said (1-6C) alkyl ,-S (O) _p-(1-6C) alkyl and (1-6C) alkoxyl be selected from independently by one or more that following group is optional to be replaced: the first heterocycle of 3-7 of cyano group, fluoro, hydroxyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] amino, (3-7C) cycloalkyl ring or saturated or fractional saturation; And the 3-7 of wherein said (3-7C) cycloalkyl ring and saturated or fractional saturation unit heterocycle is selected from the optional replacement independently of group of (1-6C) alkyl by one or more:

(ii) R ⁶Be selected from halo, cyano group, (3-7C) cycloalkyl ring, saturated or fractional saturation 3-7 unit's heterocycle or-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl;

M is 0,1,2 or 3;

Another specific embodiments of formula I chemical compound is formula Ic chemical compound and salt thereof, especially its pharmaceutically acceptable salt:

Formula Ic

Wherein:

R ³Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl, wherein said (1-6C) alkyl and (1-6C) alkoxyl be selected from by one or more that following group is optional to be replaced: fluoro, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl, amino, single (1-6C) alkyl amino, two [(1-6C) alkyl] amino, carbamoyl, single (1-6C) alkyl-carbamoyl or two [(1-6C) alkyl] carbamoyl, 3-7 unit's heterocycle or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle and heteroaryl ring are replaced independently by one or more following groups is optional: (1-4C) alkyl, (1-4C) alkoxyl, hydroxyl, amino, the first heterocycle of single (1-6C) alkyl amino or two [(1-6C) alkyl] 3-7 amino or saturated or fractional saturation;

Perhaps R ³Represent group-NR as defined above ¹R ²

R ⁴Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl;

N is 0,1 or 2;

R ⁶Be selected from one of following two groups of groups:

Wherein said (1-6C) alkyl ,-S (O) _p-(1-6C) alkyl and (1-6C) alkoxyl be selected from independently by one or more that following group is optional to be replaced: the first heterocycle of 3-7 of cyano group, fluoro, hydroxyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] amino, (3-7C) cycloalkyl ring or saturated or fractional saturation; And the 3-7 of wherein said (3-7C) cycloalkyl ring and saturated or fractional saturation unit heterocycle is selected from the optional replacement independently of group of (1-6C) alkyl by one or more;

(ii) R ⁶Be selected from halo, cyano group, (3-7C) cycloalkyl ring, saturated or fractional saturation 3-7 unit's heterocycle or-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl; Or

M is 0,1,2 or 3;

Another specific embodiments of formula I chemical compound is formula Id chemical compound and salt thereof, especially its pharmaceutically acceptable salt:

Formula Id

Wherein:

Perhaps R ³Represent group-NR as defined above ¹R ²

R ⁴Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl;

N is 0,1,2 or 3;

R ⁶Be selected from one of following two groups of groups:

M is 0,1,2 or 3;

Another specific embodiments of formula I chemical compound is formula Ie chemical compound and salt thereof, especially its pharmaceutically acceptable salt:

Formula Ie

Wherein:

Perhaps R ³Represent group-NR as defined above ¹R ²

R ⁴Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl;

R ⁶Be selected from one of following two groups of groups:

Wherein said (1-6C) alkyl ,-S (O) _p-(1-6C) alkyl and (1-6C) alkoxyl be selected from independently by one or more that following group is optional to be replaced: the first heterocycle of the 3-7 of cyano group, fluoro, hydroxyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino, two (1-6C) alkyl amino, (3-7C) cycloalkyl ring or saturated or fractional saturation; And the 3-7 of wherein said (3-7C) cycloalkyl ring and saturated or fractional saturation unit heterocycle is selected from optional replacement of group of (1-6C) alkyl by one or more;

M is 0,1,2 or 3;

And when B is 8,9 or the 1O unit bicyclic radicals of the 3-7 unit heterocycle of (3-7C) cycloalkyl ring or saturated or fractional saturation or saturated or fractional saturation, optional 1 or 2 oxo or the sulfo-substituent group of having of described ring and bicyclic radicals.

The specific chemical compound of the present invention is following one or more chemical compound and salt thereof, especially its pharmaceutically acceptable salt:

1 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-phenylurea

2 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-[2-fluoro-5-(trifluoromethyl) phenyl] urea

3 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(3, the 4-Dichlorobenzene base) urea

4 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-[2-(trifluoromethyl) phenyl] urea

5 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-[3-(trifluoromethyl) phenyl] urea

6 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-[4-(trifluoromethyl) phenyl] urea

7 N-{4-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-[2-fluoro-5-(trifluoromethyl) phenyl] urea

8 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(3-methoxyphenyl) urea

9 4-[(4,6-di-amino-pyrimidine-5-yl) and acetenyl] phenyl } the carbamic acid phenylester

10 3-[(4,6-di-amino-pyrimidine-5-yl) and acetenyl] phenyl } the carbamic acid phenylester

11 N-(the 5-tert-butyl group-1,3,4-thiadiazoles-2-yl)-N '-and 4-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl } urea

12 N-{4-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(3-methyl isothiazole-5-yl) urea

13 N-{4-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(the different  azoles of 3-methyl-5-yl) urea

14 N-{4-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-[4-(trifluoromethyl) pyridine-2-yl] urea

15 N-(3-{[({4-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl } amino) carbonyl] amino } phenyl) acetamide

16 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(3-methyl isothiazole-5-yl) urea

17 N-(3-{[({3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl } amino) carbonyl] amino } phenyl) acetamide

18 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl 1 phenyl }-N '-[4-(trifluoromethyl) pyridine-2-yl] urea

19 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(the different  azoles of 3-methyl-5-yl) urea

20 N-(the 5-tert-butyl group-1,3,4-thiadiazoles-2-yl)-N '-and 3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl } urea

21 N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-and 3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl } urea

22 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(2,3-dihydro-1,4-benzo dioxine-6-yl) urea

23 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(2-morpholine-4-base phenyl) urea

24 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(1-methyl piperidine-4-yl) urea

25 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(1-propyl group piperidin-4-yl) urea

26 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-the 2-phenyl-acetamides

27 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-2-(2-methoxyphenyl) acetamide

28 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-2-[3-(trifluoromethyl) phenyl] acetamide

29 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-2-[4-(trifluoromethyl) phenyl] acetamide

30 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-2-(3-methoxyphenyl) acetamide

31 N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-and 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea

32 N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-(3-{[4-(methylamino) pyrimidine-5-yl] acetenyl } phenyl) urea

33 N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-and 3-[(4-{[3-(isopropyl amino) propyl group] amino } pyrimidine-5-yl) acetenyl] phenyl } urea

34 N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-(4-[(2-pyrrolidine-1-base ethyl) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea

35 N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-(the different  azoles of the 4-[(5-tert-butyl group-3-yl) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea.

The present invention more particularly chemical compound is following one or more chemical compound and salt thereof, especially its pharmaceutically acceptable salt:

1 N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-and 3-[(4-{[3-(dimethylamino) propyl group] amino } pyrimidine-5-yl) acetenyl] phenyl } urea

2 N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-(the 4-[(2-hydroxyethyl) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea

3 N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-(4-[(2-morpholine-4-base ethyl) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea

4 N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-(4-[(3-pyrrolidine-1-base propyl group) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea

5 N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-(4-[(2,4-dimethoxy-benzyl) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea

6 N-{3-[(4-aminopyrimidine-5-yl) acetenyl] phenyl }-N '-(the different  azoles of the 5-tert-butyl group-3-yl) urea

7 N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-2-[4-(trifluoromethyl) phenyl] acetamide

8 N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-(4-[(2-morpholine-4-base ethyl) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea.

Formula I chemical compound or its pharmaceutically acceptable salt can be by any known method preparations that is applicable to the chemical compound that preparation chemically is correlated with.When being used for preparation I compound, these methods constitute another feature of the present invention, by the explanation of following representational method variant.Necessary raw material can obtain by vitochemical standard method.The preparation of these raw materials is in following relevant representational method variant and illustrate in the appended examples thereafter.In addition, Bi Yao raw material obtains by those cited in the ordinary skill that is similar to organic chemist methods.

Another aspect of the present invention provides a kind of preparation I compound or its pharmaceutically acceptable salt (wherein to remove and indicate R in addition ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, L, ring A and ring B, n and m be suc as formula defining among the I) method, method is as shown below.

L is method (a) in order to prepare wherein-N (R ⁸) C (O) N (H)-formula I chemical compound, make formula II chemical compound:

R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁸, n and ring A have any implication of above definition, except that if necessary protecting any functional group, and the isocyanate reaction of formula IV:

R wherein ⁶, m and ring B have any implication of above definition, except that if necessary protecting any functional group; Perhaps

L is method (b) in order to prepare wherein-N (R ⁸) C (O) N (H)-formula I chemical compound, make the aryl carbamate reaction of formula II chemical compound and formula III as defined above:

Wherein Ar is the aryl that is fit to, phenyl for example, and R ⁶, m and ring B have any implication of above definition, except that if necessary protecting any functional group; Perhaps

L is N (R to method (c) in order to prepare wherein ⁸) the formula I chemical compound of C (O)-O-, make the chemical compound reaction of formula II chemical compound and formula XI as defined above:

Lg wherein ¹Be the replaceable group that is fit to, halogeno-group (as fluoro, chloro or bromo) for example, and R ⁶, m and ring B have any implication of above definition, except that if necessary protecting any functional group; Perhaps

L is N (R to method (d) in order to prepare wherein ⁸) C (O) C (R ^aR ^b)-formula I chemical compound, make the chemical compound reaction of formula II chemical compound and formula IX as defined above:

Lg wherein ²Be the replaceable group that is fit to, for example hydroxyl, halogeno-group (as fluoro, chloro or bromo), R ^x-C (O)-O-or R ^x-O-(R wherein ^xBe the alkyl or aryl that is fit to), and R ⁶, R ^a, R ^b, m and B have any implication of above definition, except that if necessary protecting any functional group; Perhaps

(e) L is in order to prepare wherein-N (R ⁸) C (O)-N (H)-formula I chemical compound, make the tribromo-acetyl base amine reaction of formula II chemical compound and formula XIII as defined above:

R wherein ⁶, m and B have any implication of above definition, except that if necessary protecting any functional group; Perhaps

L is method (f) in order to prepare wherein-C (R ^aR ^b) C (O) N (R ⁹)-formula I chemical compound, make formula XIV chemical compound:

Lg wherein ²Be the replaceable group that is fit to as defined above, and R ¹, R ², R ³, R ⁴, R ⁵, R ^a, R ^b, n and A have any implication of above definition, except that if necessary protecting any functional group, and the amine reaction of formula XV:

R wherein ⁶, R ⁹, m and B have any implication of above definition, except that if necessary protecting any functional group; Perhaps

Method (g) makes formula XVI chemical compound:

Lg wherein ³Be the replaceable group that is fit to, for example halogeno-group (as fluoro, chloro, bromo or iodo), mesyl, methyl mercapto or aryloxy group (as phenoxy group), and R ³, R ⁴, R ⁵, R ⁶, n, m, A, B and L have any implication of above definition, except that if necessary protecting any functional group, with formula HNR ¹R ²Amine reaction, R wherein ¹And R ²Any implication with above definition is except that if necessary protecting any functional group; Perhaps

Method (h) makes formula XVII chemical compound:

Lg wherein ⁴Be the replaceable group that is fit to, for example halogeno-group (as chloro, bromo or iodo) or sulfonyloxy (as the trifluoromethyl sulfonyloxy), and R ⁵, R ⁶, n, m, A, B and L have any implication of above definition, except that if necessary protecting any functional group, and the alkyne reaction of formula XVIII:

R wherein ¹, R ², R ³And R ⁴Any implication with above definition is except that if necessary protecting any functional group; Perhaps

L is method (i) in order to prepare wherein-N (H) C (O) N (R ⁹)-formula I chemical compound, make the isocyanates of formula XIX:

R wherein ¹, R ², R ³, R ⁴, R ⁵, n and A have any implication of above definition, except that if necessary protecting any functional group, with the amine reaction of formula XV as defined above; Perhaps

L is method (j) in order to prepare wherein-N (H) C (O) N (R ⁹)-formula I chemical compound, make the chemical compound of formula XX:

Wherein Ar is the aryl that is fit to, phenyl for example, and R ¹, R ², R ³, R ⁴, R ⁵, n and A have any implication of above definition, except that if necessary protecting any functional group, with the amine reaction of formula XV as defined above.

Then, if necessary:

I) formula (I) chemical compound is converted into another kind of formula (I) chemical compound;

Ii) remove any protecting group;

Iii) form salt.

The reaction condition of method (a)

The reaction of method (a) is carried out in suitable atent solvent or diluent easily, halogenated solvent for example is as dichloromethane, chloroform or carbon tetrachloride, ether, as oxolane or 1, the 4-dioxane, amine is as pyridine, perhaps dipolar aprotic solvent, as N, dinethylformamide, N,N-dimethylacetamide.This reaction is carried out under the temperature to about 60 ℃ of scopes of ambient temperature for example easily, preferably or near carrying out under the ambient temperature.

The reaction condition of method (b)

The reaction of method (b) is carried out in the presence of suitable alkali easily.Suitable alkali is organic amine alkali for example, as pyridine or trialkylamine (as triethylamine or diisopropylethylamine).

The reaction of method (b) is carried out in the presence of suitable atent solvent or diluent easily, and ether for example is as oxolane or 1, the 4-dioxane, perhaps dipolar aprotic solvent is as N, dinethylformamide, N,N-dimethylacetamide, N-picoline alkane-2-ketone or dimethyl sulfoxine.This reaction is carried out under the temperature to about 120 ℃ of scopes of ambient temperature for example easily, preferably carries out under about 80 ℃-Yue 100 ℃.

This reaction also can be carried out at sealed container internal heating reactant by adopting suitable heater (as microwave applicator) usually.

The reaction condition of method (c)

The reaction of method (c) is carried out in the presence of suitable alkali easily.Suitable alkali is organic amine alkali for example, and as pyridine or trialkylamine (as triethylamine or diisopropylethylamine), the perhaps carbonate of alkali metal or alkaline-earth metal for example is as sodium carbonate or potassium carbonate.

The reaction of method (c) is carried out in suitable atent solvent or diluent easily, halogenated solvent for example, and as dichloromethane, chloroform or carbon tetrachloride, ether, as oxolane or 1, the 4-dioxane.This reaction is for example being carried out under about-10 ℃ of temperature to about 30 ℃ of scopes easily, preferably or near 0 ℃ under carry out.

The reaction condition of method (d)

Work as Lg ²When being hydroxyl, the reaction of method (d) is carried out in the presence of suitable coupling agent easily.Suitable coupling agent is for example suitable peptide coupling agent, as O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethylurea hexafluorophosphate (HATU), perhaps the carbodiimide of Shi Heing as dicyclohexylcarbodiimide (DCC) or carbonyl dimidazoles (CDI), is chosen wantonly in the presence of such as catalyst such as dimethylamino naphthyridine or hydroxybenzotriazoles and is carried out.

Work as Lg ²When being any as defined above suitable replaceable group, the reaction of method (d) can be carried out in the presence of suitable alkali usually.Suitable alkali is organic amine alkali for example, as pyridine, 2, and 6-lutidines, collidine, 4-dimethylamino naphthyridine, triethylamine, diisopropylethylamine, N-methylmorpholine or diazabicyclo [5.4.0] hendecane-7-alkene.Other alkali that is fit to is the carbonate of alkali metal or alkaline-earth metal for example, as sodium carbonate, potassium carbonate, cesium carbonate or calcium carbonate.

The reaction of method (d) is carried out in suitable atent solvent or diluent easily, and ester for example is as ethyl acetate, halogenated solvent is as dichloromethane, chloroform or carbon tetrachloride, ether, as oxolane or 1, the 4-dioxane, arsol is as toluene, perhaps dipolar aprotic solvent, as N, dinethylformamide, N,N-dimethylacetamide, N-picoline alkane-2-ketone or dimethyl sulfoxine.This reaction is for example being carried out under about 0 ℃ of temperature to about 120 ℃ of scopes easily, preferably or approach to carry out under the ambient temperature.

The reaction condition of method (e)

The reaction of method (e) is carried out in the presence of suitable alkali easily.Suitable alkali is organic amine alkali for example, and as pyridine or trialkylamine (as triethylamine or diisopropylethylamine), the perhaps carbonate of alkali metal or alkaline-earth metal for example is as sodium carbonate, potassium carbonate, cesium carbonate or calcium carbonate.

The reaction of method (e) is carried out in the presence of suitable atent solvent or diluent easily, and ether for example is as oxolane or 1, the 4-dioxane, perhaps dipolar aprotic solvent is as N, dinethylformamide, N,N-dimethylacetamide, N-picoline alkane-2-ketone or dimethyl sulfoxine.This reaction is carried out under the temperature to about 120 ℃ of scopes of ambient temperature for example easily, preferably carries out under about 100 ℃-Yue 120 ℃.

The reaction condition of method (f)

The reaction of method (f) is carried out under by the described condition of above method (d) easily.

The reaction condition of method (g)

The reaction of method (g) is carried out in the presence of the suitable acid of catalytic amount easily.Suitable acid is hydrogen chloride for example.

The reaction of method (g) can have or not have in the presence of suitable atent solvent or the diluent and carry out easily.Suitable atent solvent or diluent (when using) they are alcohol for example, as ethanol, isopropyl alcohol or butanols, and perhaps dipolar aprotic solvent, as acetonitrile, N, dinethylformamide, N,N-dimethylacetamide, N-picoline alkane-2-ketone or dimethyl sulfoxine.This reaction is carried out under the temperature to about 120 ℃ of scopes of ambient temperature for example easily, preferably carries out under about 80 ℃-90 ℃.

The reaction condition of method (h)

The reaction of method (h) is carried out at suitable palladium catalyst and in the presence of choosing wantonly in conjunction with suitable copper catalyst easily.Suitable palladium catalyst is for example two (triphenyl phasphine) palladium chloride, [1,1 '-two (diphenyl phosphine) ferrocene] palladium chloride or four (triphenyl phasphine) palladium (0).Suitable copper catalyst is a Hydro-Giene (Water Science). (I) for example.

The reaction of method (h) is carried out in the presence of suitable alkali easily.Suitable alkali is organic amine alkali for example, as trialkylamine (as triethylamine) or tetramethyl guanidine.

The reaction of method (h) is having or is not having in the presence of suitable atent solvent or the diluent and carry out easily, ester for example, as ethyl acetate, ether, as oxolane or 1, the 4-dioxane, perhaps dipolar aprotic solvent, as N, dinethylformamide, N,N-dimethylacetamide, N-picoline alkane-2-ketone or dimethyl sulfoxine.This reaction is for example being carried out under about-20 ℃ of temperature to about 100 ℃ of scopes easily.

The reaction condition of method (i)

The reaction of method (i) is being carried out as under the described condition of above method (a) easily.

The reaction condition of method (j)

The reaction of method (j) is being carried out as under the described condition of above method (b) easily.

The raw material of method (a)

Formula II chemical compound can obtain by conventional method.For example, pyrimidine that formula II chemical compound can be by making formula VI and the alkyne reaction of formula VII obtain, as shown in reaction process I:

Reaction process I

Lg wherein ⁴Be the replaceable group that is fit to as defined above, and R ¹, R ², R ³, R ⁴, R ⁵, R ⁸, n and A have any implication of above definition, except that if necessary protecting any functional group.

The reaction of reaction process I is carried out under the condition of aforesaid method (h) easily.

In addition, pyrimidine that formula II chemical compound can be by making formula VI and the alkyne reaction of protected formula VIa, the amine reaction with formula VIb obtains then, as shown in reaction process 2:

Reaction process 2

Lg in the chemical compound of its Chinese style VI and VIb ⁴The replaceable group that each is fit to naturally as defined above, Pg is the protecting group that is fit to, for example trialkylsilanyl (as TMS or tert-butyl group dimethylsilyl) or Me ₂(OH) C-, and R ¹, R ², R ³, R ⁴, R ⁵, R ⁸, n and A have any implication of above definition, except that if necessary protecting any functional group.

The step of reaction process 2 (i) is to make the alkynes coupling of protected formula VIa obtain the pyrimidine of formula VI.Step (i) is to carry out under the described condition of above method (h).The step of reaction process 2 (ii) is to make described alkynes deprotection under alkalescence or acid condition, obtains unsubstituted alkynes.Those skilled in the art can be easy to select the deprotection condition of proper step in (ii).The step of reaction process 2 (iii) is the amine coupling that makes described alkynes and formula VIb.The step of reaction process 2 (iii) is to carry out under the described condition of above method (h).

In addition, formula II chemical compound can make formula VIc, wherein Lg by using the reaction condition of aforesaid method (g) ³Be the replaceable group that is fit to as defined above, and R ³, R ⁴, R ⁵, R ⁸, n and A have any implication of above definition, except that if necessary protecting any functional group, with formula HNR ¹R ²Amine reaction and obtain.

The raw material of formula VI, VII, VIa, VIb and VIc and formula HNR ¹R ²Amine be commercially available or document in compound known, perhaps can be by standard method as known in the art preparation.

The isocyanates of formula IV be commercially available or document in compound known, perhaps can be by standard method as known in the art preparation.For example, those skilled in the art are clear, and described isocyanates can be by carrying out Curtis reaction preparation easily by the acid of correspondence or acyl chlorides and such as azide or diphenyl phosphoryl azide.In addition, described isocyanates can pass through corresponding amine and phosgene or phosgene equivalent (as triphosgene, two phosgene or N, N '-carbonyl dimidazoles) reaction preparation (March J. easily, Adv.Org.Chem., the 4th edition, 1992, the 1290th page, Wiley Interscience).

The raw material of method (b)

Formula II chemical compound can obtain by aforesaid conventional method.

The aryl carbamate of formula III be commercially available or document in compound known, perhaps can be by standard method as known in the art preparation.For example, described aryl carbamate can obtain by amine and the reaction of chloro-carbonic acid aryl ester that makes formula V, as shown in reaction process 3:

Reaction process 3

R wherein ⁶, m, B and Ar have any implication of above definition, except that if necessary protecting any functional group.

The reaction of reaction process 3 is carried out in the presence of suitable alkali easily.Suitable alkali is organic amine alkali for example, as pyridine or trialkylamine (as triethylamine).

This reaction is carried out in the presence of suitable atent solvent or diluent easily, ether for example, and as oxolane or 1, the 4-dioxane.This reaction easily under about-20 ℃ of temperature to about 100 ℃ of scopes for example, preferably or near 0 ℃ under carry out.

The raw material of formula V and chloro-carbonic acid aryl ester be commercially available or document in compound known, perhaps can be by standard method as known in the art preparation.

The raw material of method (c)

Formula II chemical compound can obtain by aforesaid conventional method.

Formula XI chemical compound be commercially available or document in compound known, perhaps can be by standard method as known in the art preparation.

The raw material of method (d)

Formula II chemical compound can obtain by aforesaid conventional method.

Formula IX chemical compound be commercially available or document in compound known, perhaps can be by standard method as known in the art preparation.

The raw material of method (e)

Formula II chemical compound can obtain by aforesaid conventional method.

The tribromo-acetyl base amine of formula XIII be commercially available or document in compound known, perhaps can be by standard method as known in the art preparation.

The raw material of method (f)

Formula XIV chemical compound can obtain by aforesaid conventional method.

The amine of formula XV be commercially available or document in compound known, perhaps can be by standard method as known in the art preparation.

The raw material of method (g)

It will be apparent to those skilled in the art that formula XVI chemical compound can adopt above-mentioned similar method, utilize suitable feedstock production, for example, wherein raw material can have optional protected group L g ³Replacement-NR ¹R ²Group.

Formula HNR ¹R ²Amine be commercially available or document in compound known, perhaps can be by standard method as known in the art preparation.

The raw material of method (h)

Formula XVII chemical compound be commercially available or document in compound known, perhaps can by the person skilled in the art understood like that, by adopting above-mentioned similar method, use suitable feedstock production.For example, wherein L is-N (R ⁸) C (O) N (H)-formula XVII chemical compound can be by making formula XVIIa amine and the aryl carbamate reaction of formula XVIIb obtain, as reaction

Shown in the flow process 4:

Reaction process 4

Lg wherein ⁴Be aforesaid suitable replaceable group, L is-N (R ⁸) C (O) N (H)-, and R ⁵, R ⁶, R ⁸, n, m, A and B have any implication of above definition, except that if necessary protecting any functional group.

The reaction of reaction process 4 is carried out under the condition of aforesaid method (b) easily.

The raw material of formula XVIIa and XVIIb be commercially available or document in compound known, perhaps can be by standard method as known in the art preparation.

The alkynes of formula XVIII is commercially available or can by adopting above-mentioned similar method, uses suitable feedstock production as the person skilled in the art understands.For example, formula XVIII chemical compound can make the pyrimidine of formula XVIIIa easily by under the condition of aforesaid method (h):

Lg wherein ⁴Be aforesaid suitable replaceable group, R ¹, R ², R ³And R ⁴Any implication with above definition except that if necessary protecting any functional group, with trimethyl silane ethyl-acetylene or 2-methyl-3-butyne-2-alcohol reaction, then uses standard step known in the art to remove protecting group and obtain.

The raw material of method (i)

Understand as those skilled in the art, the isocyanates of formula XIX can be by carrying out Curtis reaction preparation easily by the acid of correspondence or acyl chlorides and such as azide or diphenyl phosphoryl azide.In addition, described isocyanates can pass through corresponding amine and phosgene or phosgene equivalent (as triphosgene, two phosgene or N, N '-carbonyl dimidazoles) reaction preparation (March J. easily, Adv.Org.Chem., the 4th edition, 1992, the 1290th page, WileyInterscience).

The raw material of method (j)

Formula XX chemical compound be commercially available or document in compound known, perhaps by the person skilled in the art understood like that, by adopting above-mentioned similar method, use suitable feedstock production.

Adopt standard method conventional in this area, formula I chemical compound can be converted into another formula I chemical compound.

The example of the type of spendable conversion reaction comprises the oxidation reaction of introducing substituent group, substituent reduction reaction, substituent alkylated reaction and substituting agent by aromatics substitution reaction or nucleophilic substitution.The reagent of these methods and reaction condition are that chemical field is known.

The instantiation of aromatics substitution reaction is included under the Friedel Crafts condition, uses alkyl halide and lewis acid (as aluminum chloride) to introduce alkyl; Introduce halogeno-group.The instantiation of nucleophilic substitution comprises use standard conditions introducing alkoxyl or alkyl monosubstituted amino, dialkyl amido or contains the N heterocycle.The instantiation of reduction reaction comprises that be hydroxyl with sodium borohydride with carbonyl reduction, perhaps by being amino with the Raney nickel catalytic hydrogenation with nitroreduction, is amino with the ferrum heat treated with nitroreduction in the presence of hydrochloric acid perhaps.

An example of suitable conversion reaction is the carbamate compounds with a kind of formula I, wherein R ¹, R ², R ³, R ⁴, R ⁵, n and A as defined in claim 1, L is N (H) C (O)-O-, B is the optional phenyl that replaces, and is converted into another kind of formula I chemical compound, wherein L is N (H) C (O) NH and R ¹, R ², R ³, R ⁴, R ⁵, n, A and B as defined in claim 1.This conversion can use standard method to reach, and for example by under the condition described in for example said method (b), makes carbamate and suitable amine reaction.

Another example of suitable conversion reaction is the chemical compound with a kind of formula I, wherein R ², R ³, R ⁴, R ⁵, R ⁶, n, m, A, B and L as defined in claim 1, and R ¹And/or R ²Be hydrogen, be converted into another kind of formula I chemical compound, wherein R ¹And/or R ²It is for example optional (1-6C) alkoxy carbonyl that replaces.This conversion can use standard method to reach, for example with R ¹And/or R ²One or two hydrogen atom replace with optional (1-6C) alkoxy carbonyl that replaces on request.

Can there be stereoisomer form in some formula I chemical compound.Should be appreciated that, the present invention contain formula I chemical compound all how much and optical isomer and composition thereof, comprise racemic modification.Its tautomer and composition thereof also forms one aspect of the present invention.

Isomer can split or separation by routine techniques, as chromatography or fractional crystallization.Enantiomer can separate racemic modification or other mixture of each chemical compound by using routine techniques (as chiral high performance liquid chromatography (HPLC)).In addition, desired optical isomer can be by making suitable optical activity raw material reaction preparation under the condition that can not cause racemization, perhaps pass through derivatization, for example use same chiral acid, then pass through conventional method (as HPLC, through silica gel column chromatography) separate this non-enantiomer derivative preparation, perhaps available chiral raw material and chiral reagent prepare.All stereoisomers all are included within the scope of the invention.

The compounds of this invention can use routine techniques to separate from reactant mixture.

Should be appreciated that, during some reacts referred in this, any sensitive group in possible necessary/claimed chemical compound.For those skilled in the art, when need or claimed and suitable guard method all is known.Protecting group that can be conventional according to the standard method use (for example, referring to T.W.Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991).Therefore, if reactant comprises such as groups such as amino, carboxyl or hydroxyls claimed this group of possibility during some reacts referred in this.Protecting group can be removed by the known method that is fit to remove described protecting group of any conventional method described in the document or person skilled in the art, and selected these methods should be able to be removed described protecting group, disturb minimum to other group in the molecule simultaneously.

Be convenient opinion, below provide the particular instance of protecting group, wherein " rudimentary ", for example low alkyl group refers to used this group that preferably has 1-4 carbon atom.Should be appreciated that these examples are not whole.When providing the example of the method for removing protecting group, these methods are not all method simply yet when following.Certainly, the method that does not have the usage of the specific protecting group of mentioning and a deprotection all within the scope of the present invention.

Should also be appreciated that, the ring substituents that in the The compounds of this invention some is different can be before or after above-mentioned method, introduce by the substitution reaction of standard aromatics immediately, perhaps produce by conventional modified with functional group, these are also included within the method for the present invention.These reactions and modification comprise, for example introduce the oxidation reaction of substituent group, substituent reduction reaction, substituent alkylated reaction and substituting agent by the aromatics substitution reaction.The reagent of these methods and reaction condition are that chemical field is known.The instantiation of aromatics substitution reaction comprises use concentrated nitric acid introducing nitro, uses for example acyl halide and lewis acid (as aluminum chloride) introducing acyl group under Friedel Crafts condition; Under Friedel Crafts condition, use for example alkyl halide and lewis acid (as aluminum chloride) introducing alkyl; And introducing halogeno-group.The instantiation of modifying comprises by being amino with the Raney nickel catalytic hydrogenation with nitroreduction for example, perhaps by being amino with the ferrum heat treated with nitroreduction in the presence of hydrochloric acid; Alkylthio group is oxidized to alkyl sulphinyl or alkyl sulphonyl.

Think that now some intermediate formula II, XIV, XVI, XIX, XX and VIc chemical compound are noval chemical compounds, also on the other hand claimed at this as the present invention.

Biological test

Below test can be used for measuring the effect of The compounds of this invention as Tie2 autophosphorylation inhibitor in external Tie2 inhibitor and the full cell of conduct.

A. extracorporeal receptor tyrosine kinase inhibition test

Inhibitory action for test Tie2 receptor tyrosine kinase, in the test of acellular protein tyrosine kinase, by measuring the ability that chemical compound is suppressed at the protein kinase phosphorylation of the tyrosine that contains peptide substrate in the test of ELISA microtitration plate, assess each chemical compound.Under this concrete test situation, measure the IC of three kinds of different recombined human tyrosine kinase Tie2, KDR and Flt ₅₀Value.

For promoting the generation of tyrosine kinase, use standard molecular biology clone and induced-mutation technique to produce the recombinant receptor gene.Only form in the recombiant protein segment of these intragenic these codings, and found kinase domain therein by the C-end portion of the intracellular portion of each receptor.Each segment clone who contains kinase domain with these coding recombinations is expressed in standard baculovirus/Sf21 system (or other equivalent system) then.

By with ice-cooled molten born of the same parents' buffer (20mM N-2-hydroxyethyl piperazine-N '-2-ethanesulfonic acid (HEPES) pH7.5,150mM NaCl, 10% glycerol, 1%Triton X-100,1.5mMMgCl ₂, 1mM ethylene glycol-two (beta-amino ether) N ', N ', N ', N '-tetraacethyl (EGTA)) and protease inhibitor handle carry out protein expression after, preparation molten cytosol, centrifugal clarification then from the host insect cell.

Divide equal portions to store Tie2, KDR and the molten cytosol of Flt1 in-80C.

The composition kinase activity of these recombiant proteins can be measured by the ability (is the randomcopolymer formation of 6: 3: 1 glutamic acid, alanine and tyrosine by ratio) of the synthetic peptide of its phosphorylation.Specifically, with Nunc Maxisorb ^TM96-hole immunity titer plate with the synthetic peptide Sigma P3899 bag of 100 microlitres by (before carrying out plate bag quilt), then 4 ℃ of following overnight incubation with the 1mg/ml storing solution of PBS to be diluted among the PBS at 1: 500.Under the room temperature, each plate is washed with 50mMHEPES pH 7.4, to remove any excessive unconjugated synthetic peptide.

By at room temperature, at 100mM HEPES pH 7.4,5 μ mol (or Km concentration of each enzyme) adenosine triphosphate (ATP), 10mM MnCl ₂, 0.1mM Na ₃VO ₄, 0.2mM DL-dithiothreitol, DTT (DTT), 0.1%Triton X-100 and the final concentration scope that is dissolved among the DMSO (final concentration 2.5%) be in the test compound of 0.05 μ mol-100 μ mol, to hatch 60 minutes (Tie2), 20 minutes (KDR at the molten cytosol (being respectively 1: 200,1: 400 and 1: 1000) of the dilution of the suitable new system in the titer plate of peptide bag quilt, Flt), assess the activity of Tie2, KDR or Flt1.By removing the liquid component cessation reaction of this test, then wash each plate with PBS-T (phosphate buffered saline (PBS) that has 0.5% polysorbas20) or other lavation buffer solution that is equal to.

Be somebody's turn to do the immobilization phosphono-peptide prod of reaction by determination of immunological methods.At first, at room temperature, the antibody (4G10, Upstate Biotechnology UBI 16-105) that each plate and Mus monoclonal anti-phosphorylated tyrosine-HRP (horseradish peroxidase) yoke close was hatched 4 hours.Use the PBS-T thorough washing then, colorific 22 '-azine group-two-[3-ethyl benzo thiazole phenanthroline sulfonate (6)] di-ammonium salts crystal ABTS with hatching 30-45 minute (Sigma P4922-is according to each product description preparation) is as substrate, HRP activity in the colorimetric method for determining plate in each hole adds 100ul 1M H then ₂SO ₄Cessation reaction.

Read on the plate device at Molecular Devices ThermoMax microtitration plate,, will develop the color quantitatively and quantitative thus enzymatic activity by measure trap at the 405nm place.The kinase inhibitory activity of given chemical compound is expressed as IC ₅₀Value.It can obtain the required compound concentrations of 50% phosphorylation inhibitory action by calculating and determine in this test.From just (medium adds ATP) and negative (medium subtracts ATP) control value, calculate the scope of phosphorylation.

B. cell Tie2 autophosphorylation test

This test is to measure the ability that chemical compound suppresses the autophosphorylation of Tie2 receptor, and the autophosphorylation of Tie2 receptor generally causes the generation of " activation " receptor, begins the concrete signal conduction relevant with this receptor function then.

Autophosphorylation can be finished by number of ways.The expression of reorganization kinase domain can cause the generation of phosphorylation and activated receptor in the known rhabdovirus system.The overexpression itself of reporting receptor in the recombinant cell lines in addition can cause not having receptor autophosphorylation (Heldin C-H.1995 Cell:80, the 213-223 of part under existing; Blume-J.P, Hunter T.2001Nature:411,355-65).In addition, existing lot of documents example has wherein made up a lot of Chimerical receptors.In these examples, natural, the exogenous structure of cell surface territory of this receptor by known by adding suitable part (TrkA-Tie2/NGF part (Marron for example, M.B. etc., 2000 Journal of Biological Chemistry:275:39741-39746) or C-fms-Tie-1/CSF-1 part (Kontos, C.D. etc., 2002 Molecular and CellularBiology:22 1704-1713) are easy to two polymeric zones and replace.Therefore when Chimerical receptor was expressed in separately part of host cell system and adding, it brought out the autophosphorylation of Chimerical receptor kinase domain.The part that this approach has common usefulness known (and usually easily obtain) replaces must identifying and separates each advantage about the native ligand of receptor.

Certainly, if part is getable, can utilizes the known receptor that can express select and can stimulate to obtain the natural cell line or the primary cell of the phosphorylation that part brings out with part is simple.Can measure the ability that chemical compound suppresses Tie2 receptor autophosphorylation by this test, described expression of receptor at EA.hy926/B3 cell for example (by J.McLean/B.Tuchi, Univ.of N.Carolina at Chapel Hill, CB-4100,300 Bynum Hall, ChapelHill, N.C.27599-41000, USA provides) or former generation HUVEC (human umbilical vein's epithelial cell-obtain by various commercial source).

Natural A ng1 part can adopt the standard purification technology to separate from the tumor cell supernatant, perhaps can adopt standard molecular biological technique and expression system with Ang1 gene clone and recombinant expressed.In this case, perhaps can prepare the part of native state, perhaps make the part of recombiant protein form, for example the design of recombiant protein genetic engineering can be contained other purification labelling (for example polyhistidyl peptide, antibody Fc domain) and be beneficial to this method.

For example use the ligand stimulation of EA.hy926/B3 or HUVEC cell Tie2 receptor, can set up the cell receptor phosphorylation test of Ang1 ligand stimulation, to be used for the usefulness that the assay determination chemical compound suppresses this process.For example, with the EA.hy926/B3 cell with 5 * 10 ⁵Suitable tissue culture medium (TCM) in the density of cells/well is inoculated in 6 orifice plates adds in 10% hyclone (FCS), makes its growth 2 days then.The 3rd,, described cell was hatched 2 hours under shortage serum by above culture medium is replaced with the culture medium that only contains 1%FCS.Behind the serum-free following 1 hour 40 minutes, remove culture medium, with diluent (prepare diluted chemical compound liquid with serum-free medium, keep DMSO concentration the to be lower than 0.8%) replacement of 1ml test compound.Behind following 1.5 hours of the serum-free, add positive vanadate, make that its final concentration is 0.1mM under last 10 minutes serum-frees.

Serum-free amounted to down after 2 hours, added the autophosphorylation (part can or with the pure product form of the dilution in the serum-free medium or with the cell conditioned medium liquid of the non-purification that contains part (for example when for recombinant expressed mammalian cell) form adding) of part and positive vanadate irritation cell Tie2 receptor.

After hatching 10 minutes with part under 37 ℃, with cell in cooled on ice, the cold PBS washing that contains the positive vanadate of 1mM with about 5ml, ((20mM Tris pH 7.6,150mM NaCl, 50mM NaF, 0.1%SDS, 1%NP40,0.5%DOC, the positive vanadate of 1mM, 1mM EDTA, 1mM PMSF, 30 μ l/ml aprotiniies, 10 μ g/ml Pepstatins, 10 μ g/ml leupeptins) were placed on ice 10-20 minute to add the ice-cold molten born of the same parents' buffer of 1ml then in cell.Shift out molten cytosol, be transferred in the 1.5ml Eppendorf pipe, under 4 ℃, 13000rpm centrifugal 3 minutes.Each molten cytosol of 800 μ l is transferred in the new 2ml Eppendorf pipe carries out immunoprecipitation.The anti-phosphorylated tyrosine antibody (Santa Cruz PY99-sc-7020) that adds 3mg=15 μ l in molten cytosol was cultivated 2 hours down at 4 ℃.In molten cytosol, add the MagnaBind pearl (goat-anti-mice IgG, Pierce 21354) that 600 μ l have washed, under 4 ℃, each pipe rotation is spent the night.

Sample was handled in magnetic field 1 minute, carefully removed molten born of the same parents' supernatant then.Then the molten cytosol of 1ml is joined in the beadlet, repeat more than this step 2 time.94 ℃ of hot down 2X Laemmli loading buffer liquid that this beadlet are suspended in 25 μ l add in the beta-mercaptoethanol, place 15 minutes under the room temperature.

Beadlet is shifted out by be exposed in the pipe 1 minute in magnetic field, from being loaded in polyacrylamide/SDS protein gel (precast type 4-12%BisTris NuPAGE/MOPS 12 hole gels, derive from Novex) on each immunoprecipitation in beadlet in, isolate all liquid.Carry out protein gel under 200V, then under 50V/250mA, trace was in 30 minutes last 1 hours of NC film.Under the room temperature, all traces were handled 1 hour with 5%Marvel/PBS-tween liquid, to reduce the non-specific binding of described detection antibody.Add the rabbit that PBS-tween liquid with 0.5%Marvel carries out dilution in 1: 500 and resist-Tie2 (Santa Cruz sc-324), then 4 ℃ of following overnight incubation.Trace with PBS-tween thorough washing, is added then with the goat antirabbit-POD conjugates (DakoP0448) of 0.5%Marvel/PBS-tween with dilution in 1: 5000.To place 1 hour under the antibody room temperature, then then with PBS-tween washing trace.The Western blotting of various immunoprecipitation samples is shown trace with LumiGLO (NEB 7003).Be transferred to then in the X-x ray chamber x, with 15 seconds/30 seconds and 60 seconds exposure photograph.Use FluorS BioRad imaging analysis system, assess the relative intensity of the albumen band of the Tie2 receptor that belongs to phosphorylation.Phosphorylation percentage rate IC with each experimental compound dilution series ₅₀Value is determined, IC ₅₀Value is by adopting suitable check sample as obtaining with reference to calculating through standard method.

Though as was expected, the pharmacological properties of formula I chemical compound changes with structural change, in general, the activity that formula I chemical compound is had can be by above one or more experiment (a) and following concentration or dosage (b) prove:

1 (a) :-IC ₅₀Scope, μ M for example＜100;

Experiment (b) :-IC ₅₀Scope, μ M for example＜50;

By example, the activity of Table A explanation representative compounds of the present invention.The secondary series of Table A shows the IC of the vitro inhibition effect of experiment (a) Tie2 receptor tyrosine kinase ₅₀Data, the 3rd row show the inhibiting IC of experiment (b) Tie2 receptor tyrosine kinase autophosphorylation ₅₀Data.

Table A:

Embodiment number	IC ₅₀(μ M) tests (a): the vitro inhibition effect of Tie2 receptor tyrosine kinase	IC ₅₀(μ M) tests (b): the inhibitory action of Tie2 receptor tyrosine kinase autophosphorylation
Embodiment number			11	0.879	5.557
12	2.849	0.3513	11	0.879	5.557
12	2.849	0.3513	19	2.141	3.539

Another aspect of the present invention provides a kind of Pharmaceutical composition, and said composition contains formula I chemical compound or its pharmaceutically acceptable salt and pharmaceutically acceptable diluent or carrier as defined above.

Compositions of the present invention can be the form that is suitable for an oral application (tablet for example, lozenge, hard or soft capsule, aqueous or oiliness suspensoid, Emulsion, dispersibility powder agent or granule, syrup or elixir), the form of topical application (cream for example, ointment, gel or aqueous or oily solution agent or suspensoid), the form of inhalation (for example finely divided powder agent or liquid aerosol), be blown into the form (for example finely divided powder agent) of administration or the form of parenteral and (for example supply vein, subcutaneous, the suppository of the sterile aqueous of intramuscular or intramuscular dosed administration or oily solution agent or confession rectally).

Compositions of the present invention can be passed through conventional pharmaceutical excipient well known in the art, obtains through conventional method.Therefore, being used for oral compositions can contain such as one or more coloring agent, sweeting agent, correctives and/or antiseptic.

The amount that produces the active component of single dose form with one or more excipient composition must change according to the concrete approach of host who is treated and administration.For example, the oral Preparation that is used for human body generally contains the 0.5mg-0.5g active component and (is more suitable for being 0.5-100mg, 1-30mg for example), it mixes mutually with excipient suitable and convention amount, and the amount of excipient can account for about 5-98% weight of said composition total amount.

Be used for the treatment of or prevent the dosage size of formula I chemical compound of purpose general, change according to the character of disease and seriousness, animal or patient's age or sex and route of administration according to the medicine principle of knowing.

Using that formula I chemical compound is treated or when preventing, usually with the daily dose scope such as for the amount of every kg body weight 0.1mg-75mg gives, if desired, this daily dose can be given with divided dose.Usually, when using parenteral route, give lower dosage.Therefore, for example, for intravenously administrable, normally used dosage range is for example every kg body weight 0.1mg-30mg.Similarly, for inhalation, the dosage range of use is for example every kg body weight 0.05mg-25mg.But the preferred oral administration is especially with tablet form.Unit dosage form generally contains the 0.5mg-0.5g that has an appointment chemical compound of the present invention.

The most important character of The compounds of this invention defined herein is its blood vessel formation against function.The expectation The compounds of this invention can be used for treating or prevents wide range and disease undesirable or pathologic associated angiogenesis, comprise cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi sarcoma, hemangioma, lymphoma, acute and chronic nephropathy, sebaceous cyst, arterial restenosis, autoimmune disease, acute inflammation, excessively scar formation and adhesion, endometriosis, dysfunction temper palace is hemorrhage with the relevant oculopathy of retinal vessel propagation.Cancer can influence any tissue, and it comprises leukemia, multiple myeloma and lymphoma.Particularly expect effectively the slow down growth of constitutional and recurrent entity tumor of The compounds of this invention, described entity tumor is just like colon, breast, prostate, lung and skin.

We think that the angiogenesis inhibitor character of The compounds of this invention comes from its Tie2 receptor tyrosine kinase inhibition activity.Therefore, the expectation The compounds of this invention is used for producing the Tie2 inhibitory action at the homoiothermic animal of this kind of needs treatment.Therefore The compounds of this invention can be used for producing by suppressing the blood vessel formation against function that the Tie2 receptor tyrosine kinase is independent or part mediates.

More particularly, the expectation The compounds of this invention suppresses any cancer relevant with Tie2.For example, the growth of initial stage relevant with Tie2 and recidivity solid tumor, particularly its growth and diffusion obviously depend on those tumors of Tie2 receptor tyrosine kinase.

Another aspect of the present invention provides a kind of I chemical compound of formula as defined above or its pharmaceutically acceptable salt purposes as medicine.

Another aspect of the present invention provides a kind of I chemical compound of formula as defined above or its pharmaceutically acceptable salt to be used for being used as purposes in the medicine of Tie2 receptor tyrosine kinase inhibitors at homoiothermic animal (as the people) in preparation.

Another aspect of the present invention provides a kind of I chemical compound of formula as defined above or its pharmaceutically acceptable salt to be used for producing purposes in the medicine of blood vessel formation against function at homoiothermic animal (as the people) in preparation.

Another aspect of the present invention provides a kind of I chemical compound of formula as defined above or its pharmaceutically acceptable salt to be used for purposes in the medicine of homoiothermic animal (as the people) treatment cancer in preparation.

Another aspect of the present invention provides a kind of I chemical compound of formula as defined above or its pharmaceutically acceptable salt to be used for being selected from purposes in the medicine of following cancer in homoiothermic animal (as the people) treatment in preparation: leukemia, breast carcinoma, pulmonary carcinoma, colon cancer, rectal cancer, gastric cancer, carcinoma of prostate, bladder cancer, cancer of pancreas, ovarian cancer, lymphatic cancer, carcinoma of testis, neuroma, hepatocarcinoma, cancer of biliary duct, renal cell carcinoma, uterus carcinoma, thyroid carcinoma and skin carcinoma.

Another aspect of the present invention provides the method that suppresses the Tie2 receptor tyrosine kinase in a kind of homoiothermic animal in the treatment of this kind of needs (as the people), and this method comprises the I chemical compound of formula as defined above or its pharmaceutically acceptable salt that gives this animal effective dose.

Another aspect of the present invention provides the method that produces blood vessel formation against function in a kind of homoiothermic animal in the treatment of this kind of needs (as the people), and this method comprises the I chemical compound of formula as defined above or its pharmaceutically acceptable salt that gives this animal effective dose.

Another aspect of the present invention provides treatment method for cancer in a kind of homoiothermic animal in the treatment of this kind of needs (as the people), and this method comprises the I chemical compound of formula as defined above or its pharmaceutically acceptable salt that gives this animal effective dose.

Another aspect of the present invention provides to treat in a kind of homoiothermic animal in the treatment of this kind of needs (as the people) and is selected from following method for cancer, this method comprises the I chemical compound of formula as defined above or its pharmaceutically acceptable salt that gives this animal effective dose, and described cancer is selected from: leukemia, breast carcinoma, pulmonary carcinoma, colon cancer, rectal cancer, gastric cancer, carcinoma of prostate, bladder cancer, cancer of pancreas, ovarian cancer, lymphatic cancer, carcinoma of testis, neuroma, hepatocarcinoma, cancer of biliary duct, renal cell carcinoma, uterus carcinoma, thyroid carcinoma and skin carcinoma.

Another aspect of the present invention provides a kind of I chemical compound of formula as defined above or its pharmaceutically acceptable salt that is used to suppress the Tie2 receptor tyrosine kinase in homoiothermic animal (as the people).

Another aspect of the present invention provides a kind of I chemical compound of formula as defined above or its pharmaceutically acceptable salt that is used to produce blood vessel formation against function in homoiothermic animal (as the people).

Another aspect of the present invention provides a kind of I chemical compound of formula as defined above or its pharmaceutically acceptable salt that is used for the treatment of cancer.

Another aspect of the present invention provides a kind of I chemical compound of formula as defined above or its pharmaceutically acceptable salt that is selected from following cancer that be used for the treatment of: leukemia, breast carcinoma, pulmonary carcinoma, colon cancer, rectal cancer, gastric cancer, carcinoma of prostate, bladder cancer, cancer of pancreas, ovarian cancer, lymphatic cancer, carcinoma of testis, neuroma, hepatocarcinoma, cancer of biliary duct, renal cell carcinoma, uterus carcinoma, thyroid carcinoma and skin carcinoma.

As above carry, expect that also The compounds of this invention has the activity of antagonism by inductive other disease of undesirable or pathologic angiogenesis, described other disease comprise psoriasis, rheumatoid arthritis, Kaposi sarcoma, hemangioma, lymphoma, acute and chronic nephropathy, sebaceous cyst, arterial restenosis, autoimmune disease, acute inflammation, excessively scar formation and adhesion, endometriosis, dysfunction temper palace is hemorrhage with the relevant oculopathy of retinal vessel propagation.

Anti-angiogenesis activity in this definition can be used as monotherapy, perhaps can with one or more other medicines and/or the therapy use in conjunction except that The compounds of this invention.This conjoint therapy can by with each therapeutic component simultaneously, in turn or the approach of administration respectively reach.In medical oncology, use the conjoint therapy treatment cancer patient of different form of therapy usually.In medical oncology, except that the cell cycle inhibition therapy of above definition, other component of these therapeutic alliances can comprise: operation, radiation therapy or chemotherapy.This chemotherapy can comprise the antineoplastic agent in one or more following catalogue:

(i) anti-erosion agent (for example inhibitor of inhibitors of metalloproteinase (as Marimastat) and urokinase plasminogen activator function of receptors);

Antiproliferative/antineoplastic agent and the combination thereof used during (ii) medical antitumor is learned are as alkylating agent (for example cisplatin, carboplatin, cyclophosphamide, nitrogen are situated between, melphalan, chlorambucil, busulfan and nitrosoureas); Anti-metabolism is (as antifol, as the fluorine miazines, as 5-fluorouracil and tegafur (tegafur), Raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea, perhaps one of disclosed preferred antimetabolite among the european patent application No.562734 for example, for example (2S)-2-{ neighbour-fluoro-right-[N-{2,7-dimethyl-4-oxo-3,4-dihydroquinazoline-6-ylmethyl }-N-(Propargyl) amino] benzamido }-4-(tetrazolium-5-yl) butanoic acid); Antitumor antibiotics (anthracene nucleus class for example, as amycin, bleomycin, doxorubicin, daunorubicin, Epirubicin, idarubicin, Mitomycin-C, D actinomycin D and plicamycin); Antimitotic agent (for example vinca alkaloids medicine, as vincristine, vinblastine, vindesine and vincaleucoblastine (vinorelbine) and taxanes medicine, as paclitaxel and docetaxel); And topoisomerase enzyme inhibitor (as epipodophyllotoxin, as etoposide and teniposide, amsacrine, topotecan and camptothecine);

(iii) cytostatic agent, as antiestrogen (as tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogen (as must mucositis amine, flutamide, nilutamide and cyproterone acetate), lhrh antagonist or LHRH agonist (as goserelin, leuprorelin and buserelin), progestogens medicine (as megestrol acetate), aromatase inhibitor (for example Arimidex, letrozole, vorazole and exemestane) and 5 inhibitor, as Finasteride;

(iv) somatomedin depressant of functions, for example this type of inhibitor comprises growth factor antibodies, growth factor receptor antibody, farnesyl transferase inhibitor, tyrosine kinase inhibitor and serine/threonine kinase inhibitor, epidermal growth factor family inhibitor (EGFR tyrosine kinase inhibitor for example for example, as N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxyl group) quinazoline-4-amine (ZD 1839), N-(3-ethynyl phenyl)-6,7-(2-methoxy ethoxy) quinazoline-4-amine (CP 358774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxyl group) quinazoline-4-amine (CI1033)), the inhibitor of for example platelet-derived growth factor family and for example inhibitor of hepatocyte growth factor family;

(v) different anti-angiogenic agent with the above mechanism of action, as suppress the anti-angiogenic agent of VEGF, as disclosed chemical compound among International Patent Application WO 97/22596, WO97/30035, WO 97/32856 and the WO 98/13354, and the anti-angiogenic agent (for example linomide, beta 2 integrin alpha v β 33 depressant of functions and angiostatin (angiostatin)) that acts on other mechanism;

(vi) the Biotherapeutics approach for example uses or the peptide of isolated receptors ligand, block ligand bind receptor or reduction receptor signal (as owing to strengthen the receptor degraded or reduce expression) and the approach of albumen (as antibody or solubility external receptors domain structure);

(vii) antisense therapy agent, as relate to those therapeutic agents of above-mentioned target, as ISIS 2503, anti--agent of ras antisense therapy;

(viii) gene therapy approach, comprise and for example replace aberrant gene (as unusual p53 or unusual BRCA1 or BRCA2) approach, GDEPT (the enzyme prodrug therapy that relates to gene), use the approach of cytosine deaminase, breast (gland pyrimi piperidine deoxidating nucleus) glycosides or antibacterial nitroreductases and the approach (as multiple drug resistance gene therapy) that increases chemotherapy of patients or X-ray therapy toleration such as those; And

(ix) immunization therapy approach, comprise the immunogenicity that increases the parent tumor cell in for example external and body, as use such as cytokine transfections such as interleukin II, interleukin-4 or granulocyte-macrophage colony stimulating factor, the approach of tumor cell line that reduces the anergic approach of T-cell, the approach of using the immunocyte (as the arborescent cell of cytokine transfection) of transfection, the transfection of the application cell factor and the approach that uses anti-id AB.

This conjoint therapy can by with each therapeutic component simultaneously, in turn or the approach of administration respectively reach.This drug combination product is used the The compounds of this invention of above-mentioned dosage range and is respectively ratified other interior forms of pharmacologically active agents of dosage range.

Of the present invention this provides a kind of drug products on the one hand, and this product comprises in order to the I chemical compound of formula as defined above of therapeutic alliance cancer and another kind cancer therapy drug as defined above.

Except they purposes pharmaceutically, formula I chemical compound and pharmaceutically acceptable salt thereof also can be used as the pharmacological tool as the part of seeking new medicine, in vitro and in vivo in the research and standardization of experimental system, in order to the effect of the active inhibitor of cell cycle in the assessment laboratory animal (as cat, Canis familiaris L., rabbit, monkey, rat and mice).

Example by following indefiniteness illustrates the present invention now, wherein, and unless otherwise indicated, otherwise:

(i) temperature with degree centigrade (℃) provide; Operate under room temperature or the ambient temperature and carry out, be i.e. 18-25 ℃ temperature range;

(ii) organic solution is through anhydrous magnesium sulfate drying; Rotary Evaporators is adopted in the evaporation of solvent, decompression (600-4000 Pascal; 4.5-30mmHg), the bath relaxing the bowels with purgatives of warm nature that is up to 60 ℃ carries out;

(iii) chromatography refers to flash chromatography on silica gel; Thin layer chromatography (TLC) carries out on silica gel plate;

(iv) course of reaction is monitored by TLC and/or analysis LC-MS usually, and the response time that provides only supplies the usefulness of explanation;

(v) end-product has satisfied proton magnetic resonance (PMR) (NMR) spectrum and/or mass spectrometric data;

(vi) productive rate only is the usefulness of explanation, might not be by making great efforts the yield that research obtains; More if desired product can repeat preparation;

(vii) unless otherwise indicated, the NMR data that provide are the δZhi of principal character proton, provide with a few millionths (ppm) with respect to internal standard substance tetramethylsilane (TMS), adopt full deuterated dimethyl sulfoxide (DMSO-d ₆) as solvent, under 300MHz, measure; Use following abbreviation: s, unimodal; D, bimodal; T, triplet; Q, quartet; M, multiplet; B, broad peak;

(viii) chemical symbol has its common implication; Use SI units and symbol;

(ix) the solvent ratio is with volume: volume (v/v) provides;

(x) mass spectrum (MS) adopts and directly exposes probe, and chemi-ionization mode (CI) is carried out under 70 electron-volts of voltages; Wherein indicated ionizing is undertaken by electronic impact (EI), fast atom bombardment (FAB) or electronic spraying (ESP); Provide the value of m/z; Usually, only report the ion that shows the parent quality; Unless otherwise indicated, the mass ion that provides is MH+;

(xi) unless otherwise indicated, containing the carbon of asymmetric replacement and/or the chemical compound of sulphur atom is not split;

(xii) when describe in a kind of synthetic and the foregoing description of describing synthetic similar the time, ratio used in the mM ratio of used amount and the foregoing description is equal to;

(xvi) use following abbreviation:

AcOH acetic acid

AIBN 2,2 '-azodiisobutyronitrile

The DCM dichloromethane

The DIPEA diisopropylethylamine

The DMA N,N-dimethylacetamide

DMF N, dinethylformamide

The DMSO dimethyl sulfoxine

DMTMM 4-(4,6-dimethoxy-1,3,5-triazines-2-yl)-4-methyl morpholine-4-chlorination

The dppf thing

1,1 '-two (diphenyl phosphine) ferrocene

The EtOAc ethyl acetate

HATU O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethylurea hexafluoro phosphorus

Hydrochlorate

The iPrMgCl isopropyl-magnesium chloride

LDA diisopropyl lithamide

LHMDS two (TMS) lithamide

The m-CPBA metachloroperbenzoic acid

MeOH methanol

The MeCN acetonitrile

MCX mixed-cation exchanger resin

The MTBE methyl tertiary butyl ether(MTBE)

The LCMS liquid chromatography-mass spectrography

The NMP 1-Methyl-2-Pyrrolidone

PhTosMIC α-p-toluenesulfonyl benzyl isocyanide

POCl ₃Phosphoryl chloride phosphorus oxychloride

The RPHPLC reversed-phase high-performance liquid chromatography

The TFA trifluoroacetic acid

The THF oxolane

(xvii) though described synthetic generation acid-addition salts (as HCI salt) stoichiometry of this salt is not marked.Unless otherwise indicated, all NMR data all with the free base material report, are converted into free alkali form with isolating salt before evaluation.

Embodiment 1

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-phenylurea

With the 5-[(3-aminophenyl) acetenyl] pyrimidine-4,6-diamidogen (M875810) (45.0mg) stirs in THF, drips Carbimide. phenylester (33.4mg).After 30 minutes, add methyl ethylenediamine-polystyrene (400mg), continue to stir 30 minutes.Reactant mixture is filtered, concentrate and obtain yellow solid, grind, obtain title compound (38mg, 56%) into beige solid with DCM (7mL);

¹H NMR(DMSO-d ₆)6.61(bs，4H)，7.01-7.06(m，2H)，7.31-7.40(m，4H)，7.46-7.54(m，3H)，7.77-7.79(m，1H)，7.90(s，1H)，8.72-8.76(m，2H)；MS m/e MH ⁺345。

The preparation of intermediate

The 5-[(3-aminophenyl) acetenyl] pyrimidine-4, the 6-diamidogen

With 4,6-diaminourea-5-iodine pyrimidine (J.Med.Chem., 2001,44,3133-2138) (2.36g), two (triphenyl phasphine) palladium chloride (350mg) and Copper diiodide (I) (40mg) stir in DMF (100mL)-triethylamine (20mL) and outgased 1O minute with nitrogen.Add 3-acetenyl aniline (1.29g), with 95 ℃ of mixture heated 20 hours.Evaporating solvent, residue are through the flash chromatography on silica gel purification, and the DCM solution of using 1-10% (the MeOH liquid of 7M ammonia) is as eluant.Be further purified through grinding, obtain title compound (970mg, 43%) into brown solid with DCM (20mL);

¹H NMR(DMSO-d ₆)3.72(bs，2H)，5.17(bs，4H)，6.67-6.71(m，1H)，6.80-6.82(m，1H)，6.88-6.92(m，1H)，7.11-7.17(m，1H)，8.08(s，1H)；

MS m/e MH ⁺226.

Embodiment 2

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-the 2-phenyl-acetamides

Phenyllacetyl chloride (55.7mg) and pyridine (47.5mg) are joined the 5-[(3-aminophenyl) acetenyl] pyrimidine-4, in the agitating solution of 6-diamidogen (67.6mg) in THF.After 60 minutes, with the concentrated yellow solid that obtains of reactant mixture.Residue is through the flash chromatography on silica gel purification, and the DCM solution of using 1-5% (the MeOH liquid of 7M ammonia) obtains the title compound (23.2mg, 23%) into yellow solid as eluant;

¹H NMR(DMSO-d ₆)3.66(8，2H)，6.55(bs，4H)，7.26-7.42(m，8H)，7.52-7.55(m，1H)，7.86(s，1H)，10.20(bs，1H)；

MS m/e MH ⁺ 344.

Embodiment 3

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(3, the 4-Dichlorobenzene base) urea

Raw material: intermediate 1 and 3,4-dichlorophenyl isocyanate.

¹H NMR(DMSO-d ₆)6.57(bs，2H)，7.31-7.45(m，6H)，7.36-8.84(m，4H)，9.50-9.60(m，1H)，12.74(bs，1H)；

MS m/e MH ⁺414.

Embodiment 4

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-[2-(trifluoromethyl) phenyl] urea

Raw material: intermediate 1 and 2-trifluoromethylbenzene based isocyanate.

¹H NMR(DMSO-d ₆)6.54(s，4H)，7.26-7.72(m，6H)，7.83(s，1H)，7.93-7.95(m，1H)，8.10(s，1H)，9.37(bs，1H)，11.65(bs，1H)；

MS m/e MH ⁺413.

Embodiment 5

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-[3-(trifluoromethyl) phenyl] urea

Raw material: intermediate 1,3-trifluoromethylbenzene based isocyanate.

¹H NMR(DMSO-d ₆)6.55(s，4H)，7.28-7.55(m，5H)，7.75(8，1H)，7.83(s，1H)，8.03(s，1H)，8.77(s，1H)，9.07(s，1H)，11.65(bs，1H)；

MS m/e MH ⁺413.

Embodiment 6

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-[4-(trifluoromethyl) phenyl] urea

Raw material: intermediate 1 and 4-trifluoromethylbenzene based isocyanate.

¹H NMR(DMSO-d ₆)6.55(s，4H)，7.268-7.84(m，8H)，8.80(s，1H)，9.14(s，1H)，11.65(bs，1H)；

MS m/e MH ⁺413.

Embodiment 7

N-{4-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-[2-fluoro-5-(trifluoromethyl) phenyl] urea

According to embodiment 1 similar method, replace intermediate 1 with intermediate 2, and replace phenyl isocyanate, preparation embodiment 7 with 2-fluoro-5-trifluoromethylbenzene based isocyanate.

¹H NMR(DMSO-d ₆)6.54(s，4H)，7.38-7.57(m，4H)，7.66-7.69(m，2H)，7.85(s，1H)，8.62-8.65(m，1H)，8.95(bs，1H)，9.32(bs，1H)；

MS m/e MH ⁺431.

Embodiment 8

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(3-methoxyphenyl) urea

Under 60 ℃, with phosgene (20% toluene solution) (2.3mL) drips of solution be added to the 5-[(3-aminophenyl) acetenyl] pyrimidine-4,6-diamidogen (intermediate 1) is (50mg) in the stirred suspension in EtOAc (1.2mL).After 1 hour, temperature is increased under the reflux temperature spends the night.With the reactant mixture vacuum concentration, with methylbenzene azeotropic.Solution in THF (1mL) joins in the suspension of described isocyanates in THF (1mL) with m-anisidine (27mg) and DIPEA (O.08mL).After 10 minutes, add entry (10mL), (2 * 5mL) extract, with the Organic substance drying (MgSO that merges with EtOAc with reactant mixture ₄), filter vacuum concentration.Through the flash chromatography on silica gel purification, the DCM solution of using 1-10%MeOH obtains the title compound (32mg, 39%) into white solid as eluant

¹H NMR(DMSO-d ₆)3.72(s，3H)，6.48-6.61(m，5H)，6.89-6.95(m，1H)，7.13-7.21(m，2H)，7.23-7.34(m，2H)，7.38-7.43(m，1H)，7.70(s，1H)，7.83(s，1H)，8.63(s，1H)，8.70(s，1H)；

MS m/e MH ⁺375.

Embodiment 9

4-[(4,6-di-amino-pyrimidine-5-yl) and acetenyl] phenyl } the carbamic acid phenylester

Under 0 ℃, (0.84mL) is added drop-wise to the 5-[(4-aminophenyl with the chloro-carbonic acid phenylester) acetenyl] pyrimidine-4,6-diamidogen (intermediate 2) is (1.0g) and in the agitating solution of pyridine (0.72mL) in THF (75mL).After 2 hours, add entry (10ml), reactant mixture was stirred 10 minutes, then vacuum concentration.The solid and the water that obtain are ground, then grind,, obtain title compound (1.21g, 79%) into brown solid at 60 ℃ of following vacuum dryings with ether

¹H NMR(DMSO-d ₆)6.47-6.61(bs，4H)，7.18-7.29(m，3H)，7.38-7.54(m，4H)，7.62-7.69(d，2H)，7.83(s，1H)，10.35(s，1H)；

MS m/e MH ⁺346.

Embodiment 10

3-[(4,6-di-amino-pyrimidine-5-yl) and acetenyl] phenyl } the carbamic acid phenylester

Prepare embodiment 10 according to embodiment 9 similar methods, then by grinding with ether, then with the DCM solution of 1-10%MeOH as eluant through flash chromatography on silica gel, grind with methanol then and carry out purification.

Raw material: intermediate 1 and chloro-carbonic acid phenylester.

¹H NMR(DMSO-d ₆)6.53(s，4H)，7.17-7.46(m，8H)，7.77(s，1H)，7.83(s，1H)，10.24(bs，1H)；

MS m/e MH ⁺346.

Embodiment 11

N-(the 5-tert-butyl group-1,3,4-thiadiazoles-2-yl)-N '-and 4-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl } urea

(CEM detector under microwave condition, 80 ℃, 50W), with the 5-[(4-aminophenyl) acetenyl] pyrimidine-4,6-diamidogen (intermediate 2) (30.0mg), triethylamine (0.022mL) and (the 5-tert-butyl group-1,3,4-thiadiazoles-2-yl) (44.0mg) irradiation 20 minutes in THF (2mL) of carbamic acid phenylester (intermediate 3).With the reactant mixture vacuum concentration, the DCM solution of usefulness 1-10%MeOH through the flash chromatography on silica gel purification, obtains the title compound (11mg, 21%) into yellow solid as eluant.

¹H NMR(DMSO-d ₆)1.38(s，9H)，6.52(bs，4H)，7.49-7.52(d，2H)，7.63-7.66(d，2H)，7.82(s，1H)，9.18(bs，1H)；

MS m/e MH ⁺409.

Intermediate 3

(the 5-tert-butyl group-1,3,4-thiadiazoles-2-yl) carbamic acid phenylester

Under 0 ℃, chloro-carbonic acid phenylester (0.6mL) is added drop-wise to 2-amino-5-tert-butyl group-1,3, in 4-thiadiazoles (0.5g) and the solution of pyridine (0.51mL) in THF (40mL).After 2 hours, with reactant mixture water (10mL) quencher, (3 * 10mL) extract with EtOAc.With the Organic substance drying (MgSO that merges ₄), filter vacuum concentration.Through the flash chromatography on silica gel purification, the isohexane solution of using the 20-50% ethyl acetate obtains the title compound (0.819mg, 93%) into yellow solid as eluant;

¹H NMR(DMSO-d ₆)1.38(s，9H)，7.22-7.28(m，3H)，7.41-7.44(m，2H)；MS m/e MH ⁺278.

According to intermediate 3 similar methods, by adopting suitable amino-heterocycles, preparation intermediate 4-8.

Intermediate 4

(the different  azoles of 3-methyl-5-yl) carbamic acid phenylester

Raw material: chloro-carbonic acid phenylester and the different  azoles of 5-amino-3-methyl.

¹H NMR(DMSO-d ₆)2.17(s，3H)，5.93(s，1H)，7.21-7.30(m，3H)，7.41-7.46(m，2H)，11.79(bs，1H)；

MS m/e MH ⁺219.

Intermediate 5

(the different  azoles of the 5-tert-butyl group-3-yl) carbamic acid phenylester

Raw material: chloro-carbonic acid phenylester and the different  azoles of 3-amino-5-tert-butyl group.

¹H NMR(DMSO-d ₆)1.28(s，9H)，6.42(s，1H)，7.18-7.26(m，3H)，7.39-7.45(m，2H)，11.13(bs，1H)；

MS m/e MH ⁺261.

Intermediate 6

[4-(trifluoromethyl) pyridine-2-yl] carbamic acid phenylester

Raw material: chloro-carbonic acid phenylester and 2-amino-4-5-flumethiazine.

¹H NMR(DMSO-d ₆)7.22-7.30(m，3H)，7.41-7.46.(m，3H)，8.11(s，1H)，8.59-8.61(d，1H)，11.23(bs，1H)；

MS m/e MH ⁺283.

Intermediate 7

[3-(acetyl-amino) phenyl] carbamic acid phenylester

Raw material: chloro-carbonic acid phenylester and 3-amino-acetyl group aniline.

¹H NMR(DMSO-d ₆)2.01(s，3H)，7.17-7.30(m，6H)，7.38-7.44(m，2H)，7.77(s，1H)，9.90(bs，1H)，10.16(bs，1H)；

MS m/e MH ⁺271.

Intermediate 8

(3-methyl isothiazole-5-yl) carbamic acid phenylester

Raw material: chloro-carbonic acid phenylester and 5-amino-3-methyl isothiazole.

¹H NMR(DMSO-d ₆)2.30(s，3H)，6.68(s，1H)，7.25-7.31(m，3H)，7.41-7.46(m，2H)，11.90(bs，1H)；

MS m/e MH ⁺235.

According to method similar to Example 11, by making intermediate 2 and suitable carbamic acid phenylester reaction, preparation intermediate 12-15.

Embodiment 12

N-{4-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(3-methyl isothiazole-5-yl) urea raw material: intermediate 2 and intermediate 8.

¹H NMR(DMSO-d ₆)2.28(s，3H)，6.65(s，1H)，6.68(bs，4H)，7.46-7.49(d，2H)，7.64-7.66(d，2H)，7.86(s，1H)，9.28(s，1H)，10.44(bs，1H)；

MS m/e MH ⁺366.

Embodiment 13

N-{4-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(the different  azoles of 3-methyl-5-yl) urea raw material: intermediate 2 and intermediate 4.

¹H NMR(DMSO-d ₆)2.16(s，3H)，5.95(s，1H)，6.66(bs，4H)，7.44-7.47(d，2H)，7.62-7.65(d，2H)，7.85(s，1H)，9.12(s，1H)，10.20(bs，1H)；

MS m/e MH ⁺350.

Embodiment 14

N-{4-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-[4-(trifluoromethyl) pyridine-2-yl] urea

Raw material: intermediate 2 and intermediate 6.

¹H NMR(DMSO-d ₆)7.37(d，1H)，7.54-7.57(d，2H)，7.70-7.73(d，2H)，7.88(bs，4H)，8.06(s，1H)，8.16(s，1H)，8.53-8.55(d，1H)，9.77(s，1H)，9.91(8，1H)；

MS m/e MH ⁺414.

Embodiment 15

N-(3-{[({4-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl } amino) carbonyl] amino } phenyl) acetamide

Raw material: intermediate 2 and intermediate 7.

¹H NMR(DMSO-d ₆)2.05(s，3H)，6.85-7.05(m，1H)，7.08-7.10(m，1H)，7.15(bs，4H)，7.48-7.50(d，2H)，7.64-7.68(d，2H)，7.79(s，1H)，8.18(s，1H)，8.78-8.82(d，1H)，9.88(s，1H)；

MS m/e MH ⁺402.

According to method similar to Example 11, but replace intermediate 2 and suitable carbamic acid phenylester reaction, preparation intermediate 16-18 with intermediate 1.

Embodiment 16

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(3-methyl isothiazole-5-yl) urea

Raw material: intermediate 1 and intermediate 8.

¹H NMR(DMSO-d ₆)2.27(s，3H)，6.56(bs，4H)，6.65(s，1H)，7.27-7.33(m，1H)，7.36-7.44(m，2H)，7.74(m，1H)，7.83(s，1H)，9.08(s，1H)，10.35(bs，1H)；

MS m/e MH ⁺366.

Embodiment 17

N-(3-{[({3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl } amino) carbonyl] amino } phenyl) acetamide

Raw material: intermediate 1 and intermediate 7.

¹H NMR(DMSO-d ₆)2.03(s，3H)，6.54(bs，4H)，7.14-7.19(m，3H)，7.23-7.34(m，2H)，7.39-7.44(m，1H)，7.69(s，1H)，7.77(s，1H)，7.83(s，1H)，8.57(s，1H)，8.74(s，1H)，9.88(s，1H)；

MS m/e MH ⁺402.

Embodiment 18

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-[4-(trifluoromethyl) pyridine-2-yl] urea

Raw material: intermediate 1 and intermediate 6.

¹H NMR(DMSO-d ₆)6.57(bs，4H)，7.28-7.41(m，3H)，7.47-7.52(m，1H)，7.79(s，1H)，7.84(s，1H)，8.04(s，1H)，8.52-8.55(d，1H)，9.76(s，1H)，9.78(s，1H)；

MS m/e MH ⁺414.

According to method similar to Example 16, but purification carries out preparation embodiment 19-20 by grinding with ether.

Embodiment 19

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(the different  azoles of 3-methyl-5-yl) urea raw material: intermediate 1 and intermediate 4.

¹H NMR(DMSO-d ₆)2.16(s，3H)，5.95(s，1H)，6.56(bs，4H)，7.27-7.33(m，1H)，7.37-7.45(m，2H)，7.71(s，1H)，7.83(s，1H)，8.80(s，1H)，10.11(bs，1H)；

MS m/e MH ⁺350.

Embodiment 20

N-(the 5-tert-butyl group-1,3,4-thiadiazoles-2-yl)-N '-and 3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl } urea

Raw material: intermediate 1 and intermediate 3.

¹H NMR(DMSO-d ₆)1.38(s，9H)，6.56(bs，4H)，7.27-7.33(m，1H)，7.36-7.41(m，1H)，7.43-7.49(m，1H)，7.78(s，1H)，7.83(s，1H)，9.06(s，1H)；

MS m/e MH ⁺409.

Embodiment 21

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-and 3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl } urea

With the 5-[(3-aminophenyl) acetenyl] pyrimidine-4,6-diamidogen (intermediate 1) is (0.494g), triethylamine (0.4mL) and (the different  azoles of the 5-tert-butyl group-3-yl) carbamic acid phenylester (intermediate 5) (0.69g) refluxed 4 hours in THF (20mL).With the reactant mixture vacuum concentration, the DCM solution of usefulness 1-10%MeOH through the flash chromatography on silica gel purification, obtains the title compound (558mg, 65%) into beige solid as eluant.

¹H NMR(DMSO-d ₆)1.29(s，9H)，6.49(s，1H)，6.57(bs，4H)，7.25-7.32(m，1H)，7.34-7.39(m，1H)，7.40-7.45(m，1H)，7.72(s，1H)，7.83(s，1H)，8.79(s，1H)，9.56(s，1H)；

MS m/e MH ⁺409.

Embodiment 22

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(2,3-dihydro-1,4-benzo dioxine-6-yl) urea

Under 100 ℃, with the 5-[(3-aminophenyl) acetenyl] pyrimidine-4,6-diamidogen (intermediate 1) (50mg), sodium carbonate (141mg) and N-(tribromo-acetyl base)-3, (79mg) heating 5 days in DMF (2mL) of 4-ethylidene dioxy base aniline (intermediate 9).Through RPHPLC (H ₂O: purification MeCN 0-70%) obtains the title compound (8mg, 9%) into beige solid;

¹H NMR(DMSO-d ₆)4.14-4.24(m，4H)，6.75-6.79(m，2H)，7.07-7.10(d，1H)，7.26-7.39(m，3H)，7.82(s，1H)，7.86(bs，4H)，8.16(s，1H)，8.56(s，1H)，8.66(s，1H)；

MS m/e MH ⁺403.

Intermediate 9

2,2,2-three chloro-N-(2,3-dihydro-1,4-benzo dioxine-6-yl) acetamide

Under inert gas atmosphere, with 10 minutes, 3 under trichloro-acetic chloride (12.3mL) is added drop-wise in refrigerative (ice bath), stirs was in the solution of 4-ethylidene dioxy base aniline (15.12g) in EtOAc (150mL).Observe the purple precipitation, continue to stir the dissolving again of this precipitation under the room temperature.After 4 hours, with the reactant mixture vacuum concentration, recrystallization from ethanol obtains solid title compound (25.79g, 87%);

¹H NMR(DMSO-d ₆)4.22(s，4H)，6.83-6.87(m，1H)，7.07-7.13(m，1H)，7.19(s，1H)，10.59(bs，1H)；

MS m/e MH ⁺296.

Intermediate 10

2,2,2-three chloro-N-(2-morpholine-4-base phenyl) acetamide

According to intermediate 9 similar methods, adopt N-(2-aminophenyl) morpholino for 3,4-ethylidene dioxy base aniline, preparation intermediate 10:

¹H NMR(DMSO-d ₆)2.81-2.89(m，4H)，3.70-3.78(m，4H)，7.18-7.25(m，2H)，7.27-7.40(m，1H)，7.85-7.92(m，1H)，10.21(bs，1H)；

MS m/e MH ⁺323.

Embodiment 23

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(2-morpholine-4-base phenyl) urea

According to embodiment 22 similar methods, but replace intermediate 9 with intermediate 10, preparation embodiment 23.

¹H NMR(DMSO-d ₆)2.76-2.83(m，4H)，3.80-3.88(m，4H)，6.95-7.02(m.1H)，7.03-7.10(m，1H)，7.16-7.21(m，1H)，7.31-7.49(m，3H)，7.87-7.90(s，1H)，7.99-8.10(m，4H)，8.17(s，1H)，8.20(s.1H)，9.59(s，1H)；

MS m/e MH ⁺430.

Embodiment 24

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(1-methyl piperidine-4-yl) urea

Under inert atmosphere, will { 3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl } carbamic acid phenylester (embodiment 10) (50mg), 1-methyl piperidine-4-amine (34mg) and triethylamine (44mg) be heated to backflow 18 hours in THF (2mL).Evaporating solvent dilutes residue with ether (10mL).Product is filtered, and vacuum drying obtains the title compound (41mg, 77%) into beige solid;

¹H NMR(DMSO-d ₆)1.36-1.46(m，2H)，1.79-1.83(m，2H)，1.98-2.06(m，2H)，2.17(s，3H)，2.63-2.67(m，2H)，3.44-3.48(m，1H)，6.18(m，1H)，6.53(s，4H)，7.20-7.27(m，2H)，7.34-7.38(m，1H)，7.63(s，1H)，7.86(s，1H)，8.32(s，1H)；

MS m/e MH ⁺366.

Embodiment 25

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(1-propyl group piperidin-4-yl) urea

According to embodiment 24 similar methods, but replace 1-methyl piperidine-4-amine with 1-propyl group piperidines-4-amine, preparation embodiment 25.

¹H NMR(DMSO-d ₆)0.87(t，3H)，1.37-1.48(m，4H)，1.76-1.83(m，2H)，1.99-2.06(m，2H)，2.23(t，2H)，2.71-2.75(m，2H)，3.41-3.52(m，1H)，6.17(d，1H)，6.52(s，4H)，7.19-7.26(m，2H)，7.34-7.38(m，1H)，7.63(s，1H)，7.85(s，1H)，8.34(s，1H)；

MS m/e MH ⁺394.

Embodiment 26

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-the 2-phenyl-acetamides

Phenyl chloroacetic chloride (55.7mg) and pyridine (47.5mg) are joined the 5-[(3-aminophenyl) acetenyl] pyrimidine-4,6-diamidogen (intermediate 1) is (67.6mg) in the solution of the stirring of THF.After 60 minutes, reactant mixture is concentrated into yellow solid.Through the flash chromatography on silica gel purification, as eluant, obtain title compound (23mg, 23%) into yellow solid with the solution of 1-5% (the MeOH solution of 7M ammonia) in DCM;

¹H NMR(DMSO-d ₆)3.66(s，2H)，6.55(bs，4H)，7.26-7.42(m，8H)，7.52-7.55(m，1H)，7.86(s，1H)，10.20(bs，1H)；

MS m/e MH ⁺344.

Embodiment 27

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-2-(2-methoxyphenyl) acetamide

DMF (1mL) solution of 2-methoxybenzene guanidine-acetic acid (50mg) is joined HATU (120mg) and polymer supported minus DIPEA (Argonaut Technologies, 3.9mmolg ^-1, 300mg) in.With mixture jolting 5 minutes.Add the 5-[(3-aminophenyl) acetenyl] pyrimidine-4,6-diamidogen (intermediate 1) is the solution in DMF (1mL) (68mg), stirs then and spend the night.Remove by filter resin, with DCM (15mL) washing.With the filtrate evaporation, residue is distributed between ethyl acetate (15mL) and water (10mL).With Organic substance again water (10mL) and saline (4 * 10mL) washings are through anhydrous MgSO ₄Drying, vacuum evaporation.Grind with DCM, obtain being solid title compound (63mg, 56%);

¹H NMR(DMSO-d ₆)3.63(s，2H)，3.77(s，3H)，6.51(bs，4H)6.89(t，1H)，6.97(d，2H)，7.21(d，2H)，7.28(t，1H)，7.37(d，1H)，7.51(s，1H)，7.81-7.86(m，2H)，10.04，s，1H)；

MS m/e MH ⁺374.

According to embodiment 27 similar methods, but with suitable acid substitution 2-methoxyphenylacetic acid, preparation embodiment 28-30.

Embodiment 28

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-2-[3-(trifluoromethyl) phenyl] acetamide

Raw material: intermediate 1 and 3-trifluoromethyl phenylacetic acid.

¹H NMR(DMSO-d ₆)3.78(s，2H)，6.52(bs，4H)，7.29(t，1H)，7.40(d，1H)，7.49(d，1H)，7.53-7.66(m，4H)，7.69(s，1H)，7.81-7.87(m，2H)，10.25(s，1H)；

MS m/e MH ⁺412.

Embodiment 29

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-2-[4-(trifluoromethyl) phenyl] acetamide

Raw material: intermediate 1 and 4-trifluoromethyl phenylacetic acid.

¹H NMR(DMSO-d ₆)3.77(s，2H)，6.44-6.63(bs，4H)，7.29(t，1H)，7.39(d，1H)，7.50(d，1H)，7.55(d，2H)，7.70(d，2H)，7.83(s，2H)，10.25(s，1H)；

MS m/e MH ⁺412.

Embodiment 30

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-2-(3-methoxyphenyl) acetamide

Raw material: intermediate 1 and 3-methoxyphenylacetic acid.

¹H NMR(DMSO-d ₆)3.61(s，2H)，3.73(s，3H)，6.78-6.95(m，6H)，7.19-7.33(m，2H)，7.38(d，1H)，7.87(s，1H)，7.90(s，1H)，10.30(s，1H)；

MS m/e MH ⁺374.

Embodiment 31

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-and 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea

Under microwave condition (130 ℃, 600W), with N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-{ 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea (intermediate 12) (195mg), the diethyl ether solution of HC1 (1.0M, 0.1mL), the solution irradiation of liquefied ammonia (3mL) and THF (10mL) 4 hours.With the reactant mixture vacuum concentration, through RPHPLC purification (H ₂O: MeCN 10-90%), obtains the title compound (11mg) into colorless solid;

¹H NMR(DMSO-d ₆)9.61(s，1H)，8.95(s，1H)，8.57(s，1H)，8.50(s，1H)，7.86(s，1H)，7.26-7.44(m，3H)，6.48(s，1H)，1.29(s，9H)；

MS m/e MH ⁺377.

Intermediate 11

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-(3-ethynyl phenyl) urea

Under 80 ℃, with (2.56g) heating of the solution in MeCN (30mL) 4 hours of the inferior acylamino-carbonic esters of the different  azoles of the 5-tert-butyl group-3-amine (1.4g) and two succinyls (succinimidyl carbonate).This solution is cooled to room temperature, adds 3-acetenyl aniline (1.17g), under 80 ℃, mixture restir 16 hours.Reactant mixture is cooled to room temperature, vacuum concentration.Residue is distributed between ether and water, organic facies is washed with water, then vacuum concentration.Grind with isohexane, obtain title compound (1.57g) into colorless solid;

¹H NMR(DMSO-d ₆)9.53(s，1H)，8.87(s，1H)，7.65(d，1H)，7.29(t，1H)，7.11(d，1H)，6.49(s，1H)，4.14(s，1H)，1.28(s，9H)；

MS m/e MH ⁺284.

Intermediate 12

Will two (triphenyl phasphine) palladium chlorides (170mg), Hydro-Giene (Water Science). (I) (12.5mg) and triethylamine (10mL) join 4-chloro-5-iodine pyrimidine (Chem.Pharm.Bull.1986,34 (7), 2719-2724) (2.40g) and N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-(3-ethynyl phenyl) urea (intermediate 11) (3.1g) in the de gassed solution of DMF (50mL), heated 1.5 hours down at 50 ℃ then.Reactant mixture is concentrated, add entry, be extracted among the DCM then.Organic layer water and saline are washed in turn, and vacuum concentration obtains the title compound (4.50g) into brown foam, without being further purified direct use.

MS m/e MH ⁺396( ³⁵Cl)，398( ³⁷Cl)。

Embodiment 32

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-(3-{[4-(methylamino) pyrimidine-5-yl] acetenyl } phenyl) urea

Adopt and embodiment 31 similar methods, replace ammonia, preparation embodiment 32 with methylamine.

¹H NMR(DMSO-d ₆)9.61(s，1H)，8.97(s，1H)，8.66(s，1H)，8.47(s，1H)，8.25(s，br，1H)，7.86(s，1H)，7.31-7.61(m，3H)，6.48(s，1H)，2.98(d，3H)，1.28(s，9H)；

MS m/e MH ⁺391.

Embodiment 33

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-and 3-[(4-{[3-(isopropyl amino) propyl group] amino } pyrimidine-5-yl) acetenyl] phenyl } urea

With N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-{ 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea (intermediate 12) (200mg), HCl (1.0M ether solution) (0.1mL) and N-isopropyl propane-1, the solution of 3-diamidogen (0.14mL) in MeCN (5.0mL) be heated to 50 ℃ 3 hours.With the reactant mixture vacuum concentration, add NaHCO ₃(50% saturated aqueous solution) is extracted into mixture among the DCM, washes vacuum concentration with water.Through flash chromatography on silica gel (0-10% (7N NH ₃MeOH solution), obtain title compound (72mg) into yellow solid;

¹H NMR(DMSO-d ₆)9.41(s，br，1H)，8.52(s，1H)，8.29(s，1H)，7.79(s，1H)，7.50(d，1H)，7.31(t，1H)，7.23(d，1H)，6.38(t，1H)，5.89(s，1H)，3.63(q，1H)，2.71-2.81(m，3H)，1.82(p，2H)，1.35(s，9H)，1.00(d，6H)；

MS m/e MH ⁺476.

Adopt and embodiment 33 similar methods, replace N-isopropyl propane-1 with the amine that is fit to, the 3-diamidogen, and be further purified through RPHPLC, prepare embodiment 34 and 35.

Embodiment 34

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-(4-[(2-pyrrolidine-1-base ethyl) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea

Raw material: intermediate 12 and 1-(2-amino-ethyl) pyrrolidine.

¹H NMR(DMSO-d ₆)9.68(s，1H)，9.51(s，br，1H)，9.06(s，1H)，8.62(s，1H)，8.58(s，1H)，7.87(s，1H)，7.71(s.br，1H)，7.28-7.40(m，3H)，6.47(s，1H)，3.80(q，1H)，3.60-3.70(m，2H)，3.39(dd，2H)，3.00-3.15(m，2H)，1.94-2.06(m，2H)，1.80-1.92(m，2H)，1.28(s，9H)；

MS m/e MH ⁺474.

Embodiment 35

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-(the different  azoles of the 4-[(5-tert-butyl group-3-yl) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea

Raw material: intermediate 12 and the different  azoles of 3-amino-5-tert-butyl group.

¹H NMR(DMSO-d ₆)10.01(s，1H)，9.57(s，1H)，8.91(s，1H)，8.69(s，1H)，8.64(s，1H)，7.86(s，1H)，7.33-7.45(m，3H)，6.73(s，1H)，6.50(s，1H)，1.32(s，9H)，1.29(s，9H)；

MS m/e MH ⁺500.

According to embodiment 31 similar modes, replace ammonia with suitable amine, preparation the following example.

Embodiment 36

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-and 3-[(4-{[3-(dimethylamino) propyl group] amino } pyrimidine-5-yl) acetenyl] phenyl } urea

Raw material: N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-{ 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea (intermediate 12), N, the N-dimethyl propylamine.Through the silica gel column chromatography purification, the DCM solution of using 0-10% (solution of 10% ammonia in methanol) is as eluent, then through RPHPLC purification (H ₂O: MeCN, 0-70%).

¹H NMR(DMSO-d ₆)1.28(s，9H)，1.88-2.03(m，2H)，2.49(s，6H)，3.02-3.18(m，2H)，3.48-3.62(m，2H)，6.47(s，1H)，7.27-7.46(m，3H)，7.89(s，1H)，8.23(t，1H)，8.50(s，1H)，8.64(s，1H)，9.30(s，1H)，9.62(br，1H)，9.89(s，1H)；

MS m/e MH ⁺462.

Embodiment 37

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-(the 4-[(2-hydroxyethyl) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea

Raw material: N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-{ 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea (intermediate 12), ethanolamine.Through the silica gel column chromatography purification, the DCM solution of using 0-10% (solution of 10% ammonia in methanol) is as eluent, then through RPHPLC purification (H ₂O: MeCN, 0-70%).

¹H NMR(DMSO-d ₆)1.29(s，9H)，3.55-3.61(m，4H)，6.48(s，1H)，7.29-7.48(m，3H)，7.85(s，1H)，8.19(s，br，1H)，8.45(s，1H)，8.64(s，1H)，8.98(s，1H)，9.61(s，1H)；

MS m/e MH ⁺421.

Embodiment 38

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-(4-[(2-morpholine-4-base ethyl) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea

Raw material: N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-{ 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea (intermediate 12), 2-morpholine-4-base ethamine.Through the silica gel column chromatography purification, the DCM solution of using 0-10% (solution of 10% ammonia in methanol) is as eluent.

¹H NMR(DMSO-d ₆)1.29(s，9H)，2.40-2.57(m，6H)，3.50-3.59(m，6H)，6.50(s，1H)，7.08(t，1H)，7.24-7.42(m，3H)，7.83(s，1H)，8.32(s，1H)，8.46(s，1H)，8.90(s，1H)，9.56(s，1H)；

MS m/e MH ⁺490.

Embodiment 39

N-[3-(the amino butyl of 4-[(4-) and amino] pyrimidine-5-yl } acetenyl) phenyl]-N '-(the different  azoles of the 5-tert-butyl group-3-yl) urea

Raw material: N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-and 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea (intermediate 12), 1, the 4-butanediamine.Through the silica gel column chromatography purification, the DCM solution of using 0-10% (solution of 10% ammonia in methanol) is as eluent.

¹H NMR(CDCl ₃)1.29(s，9H)，1.33-1.45(m，2H)，1.53-1.66(m，2H)，2.57(t，2H)，3.37-3.49(m，2H)，6.49(s，1H)，7.30(d，1H)，7.35(d，1H)，7.38-7.46(m，2H)，7.78(s，1H)，8.29(s，1H)，8.43(s，1H)；

MS m/e MH ⁺448.

Embodiment 40

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-(4-[(3-pyrrolidine-1-base propyl group) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea

Raw material: N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-{ 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea (intermediate 12), 3-pyrrolidine-1-base third-1-amine.Through the silica gel column chromatography purification, use the DCM solution of 0-10% (1% ammonia, the solution of 10% methanol in DCM) and 20% alcoholic acid ethyl acetate solution in turn as eluent.

¹H NMR(DMSO-d ₆)1.29(s，9H)，1.57-1.64(m，4H)，1.68-1.79(m，2H)，2.37-2.57(m，6H)，3.49(q，2H)，6.49(s，1H)，7.25-7.44(m，4H)，7.78(s，1H)，8.29(s，1H)，8.44(s，1H)，8.90(s，1H)，9.56(s，1H)；

MS m/e MH ⁺ 488.

Embodiment 41

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-(4-[(2,4-dimethoxy-benzyl) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea

Raw material: N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-and 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea (intermediate 12), 2, the 4-dimethoxybenzylamine.Through the silica gel column chromatography purification, the isohexane solution of using the DCM solution of 0-10% (methanol solution of 10% ammonia) and 20% ethyl acetate in turn is as eluent.

¹H NMR(DMSO-d ₆)1.29(s，9H)，3.71(s，3H)，3.81(s，3H)，4.57(d，2H)，6.45(d，1H)，6.49(s，1H)，6.57(d，1H)，7.00(d，1H)，7.30(d，1H)，7.36(t，1H)，7.41(d，1H)，7.54(t，1H)，7.60(s，1H)，8.35(s，1H)，8.41(s，1H)，8.90(s，1H)，9.56(s，1H)；

MS m/e MH ⁺527.

Embodiment 42

N-[3-(the 4-[(2-amino-ethyl) and amino] pyrimidine-5-yl } acetenyl) phenyl]-N '-(the different  azoles of the 5-tert-butyl group-3-yl) urea

Raw material: N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-{ 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea (intermediate 12), 1.Through the silica gel column chromatography purification, the DCM solution of using 0-10% (solution of 10% ammonia in methanol) then grinds purification with ether and DCM as eluent.

¹H NMR(DMSO-d ₆)1.29(s，9H)，2.75(t，2H)，3.36-3.49(m，2H)，6.49(d，1H)，6.49(s，1H)，7.21-7.46(m，3H)，7.77(s，1H)，8.30(s，1H)，8.43(s，1H)，8.94(s，1H)，9.56(s，1H)；

MS m/e MH ⁺420.

Embodiment 43

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-and 3-[(4-{[2-(dimethylamino) ethyl] amino } pyrimidine-5-yl) acetenyl] phenyl } urea

Raw material: N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-{ 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea (intermediate 12), N, N-dimethyl-1.Purification is by embodiment 42 described carrying out.

¹H NMR(DMSO-d ₆)1.29(s，9H)，2.12-2.37(m，8H)，3.41-3.57(m，2H)，6.48(s，1H)，7.17(t，1H)，7.26-7.46(m，3H)，7.79(s，1H)，8.31(s，1H)，8.45(s，1H)，8.91(s，1H)，9.57(s，1H)；

MS m/e MH ⁺448.

Embodiment 44

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-and 3-[(4-{[4-(dimethylamino) butyl [amino } pyrimidine-5-yl) acetenyl] phenyl } urea

Raw material: N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-{ 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea (intermediate 12), N, N-dimethyl-1,2-diaminobutane.Purification is by embodiment 42 described carrying out.

¹H NMR(DMSO-d ₆)1.29(s，9H)，1.44-1.64(m，4H)，2.38(s，6H)，2.50-2.61(m，2H)，3.36-3.54(m，2H)，6.48(s，1H)，7.24-7.42(m，4H)，7.80(s，1H)，8.30(s，1H)，8.44(s，1H)，8.92(s，1H)，9.58(s，1H)；

MS m/e MH ⁺476.

Embodiment 45

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-({ 4-[N-{2-(dimethylamino) ethyl }-N-methyl-amino] pyrimidine-5-yl } acetenyl) phenyl] urea

Raw material: N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-and 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea (intermediate 12), 1,1,2-trimethyl-1.Purification is by embodiment 42 described carrying out.

¹H NMR(DMSO-d ₆)1.29(s，9H)，2.48(s，6H)，2.57-2.70(m，2H)，3.28(s，3H)，4.00(t，2H)，6.48(s，1H)，7.18(d，1H)，7.33-7.42(m，2H)，7.73(s，1H)，8.44(s，1H)，8.50(s，1H)，9.04(s，1H)，9.59(s，1H)；

MS m/e MH ⁺462.

Embodiment 46

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-(4-[(2-piperidines-1-base ethyl) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea

Raw material: N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-{ 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea (intermediate 12), 2-piperidines-1-base ethamine.Purification is by embodiment 42 described carrying out.

¹H NMR(DMSO-d ₆)1.29(s，9H)，1.30-1.80(m，6H)，2.39-2.60(m，2H)，2.82-3.03(m，2H)，3.46-3.85(m，4H)，6.47(s，1H)，7.25-7.51(m，4H)，7.85(s，1H)，8.39(s，1H)，8.51(s，1H)，8.92(s，1H)，9.58(8，1H)；

MS m/e MH ⁺488.

Embodiment 47

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-(4-[(3-morpholine-4-base propyl group) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea

Raw material: N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-{ 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea (intermediate 12), 3-morpholine-4-base third-1-amine.Purification is by embodiment 42 described carrying out.

¹H NMR(DMSO-d ₆)1.29(s，9H)，1.85-2.04(m，2H)，2.45-2.52(m，4H)，3.00-3.15(m，2H)，3.22-3.70(m，6H)，6.47(s，1H)，7.27-7.51(m，4H)，7.63(s，1H)，8.35(s，1H)，8.47(s，1H)，8.92(s，1H)，9.57(s，1H)；

MS m/e MH ⁺504.

Embodiment 48

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-[3-(4-[(3-piperidines-1-base propyl group) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea

Raw material: N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-{ 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea (intermediate 12), 3-piperidines-1-base third-1-amine.Purification is by embodiment 42 described carrying out.

¹H NMR(DMSO-d ₆)1.29(s，9H)，1.48-2.05(m，8H)，2.67-3.62(m，8H)，6.47(s，1H)，7.25-7.48(m，4H)，7.83(s，1H)，8.35(s，1H)，8.47(s，1H)，8.92(s，1H)，9.57(s，1H)；

MS m/e MH ⁺502.

Embodiment 49

N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-and 3-[(4-{[3-(4-methyl piperazine-1-yl) propyl group] amino } pyrimidine-5-yl) acetenyl] phenyl } urea

Raw material: N-(the different  azoles of the 5-tert-butyl group-3-yl)-N '-{ 3-[(4-chloropyrimide-5-yl) acetenyl] phenyl } urea (intermediate 12), 3-(4-methyl piperazine-1-yl) third-1-amine.Purification is by embodiment 42 described carrying out.

¹H NMR(DMSO-d ₆)1.29(s，9H)，1.68-1.84(m，2H)，2.22-2.78(m，13H)，3.41-3.56(m，2H)，6.49(s，1H)，7.26-7.46(m，4H)，7.79(s，1H)，8.31(s，1H)，8.44(s，1H)，8.94(s，1H)，9.58(s，1H)；

MS m/e MH ⁺516

Embodiment 50

N-(the 3-tert-butyl group-1-methyl isophthalic acid H-pyrazoles-5-yl)-N '-[3-(4-[(2-morpholine-4-base ethyl) and amino] pyrimidine-5-yl } acetenyl) phenyl] urea

With N-(the 3-tert-butyl group-1-methyl isophthalic acid H-pyrazoles-5-yl)-N '-[3-({ 4-[(2-morpholine-4-base ethyl) amino] pyrimidine-5-yl } acetenyl) phenyl] and the ether solution (1) of solution, 2-morpholine-4-base ethamine (0.18mL) and the 2.0M HCl of urea (intermediate 15) in THF (6mL) be heated to together 45 ℃ 16 hours.After being cooled to room temperature, add silica gel, solvent removed in vacuo.Through the silica gel column chromatography purification, with 0-10% (10%NH ₃The MeOH solution of aqueous solution) DCM solution is as eluant, then through RPHPLC purification (H ₂O: MeCN 0-70%), grinds with aqueous sodium carbonate, filters and collects the title compound (35mg) that obtains to colorless solid;

¹H NMR(DMSO-d ₆)1.20(s，9H)，2.42(t，4H)，2.53(t，2H)，3.50-3.58(m，6H)，3.59(s，3H)，6.05(s，1H)，7.08(t，1H)，7.25(d，1H)，7.31-7.40(m，2H)，7.84(s，1H)，8.31(s，1H)，8.45(s，1H)，8.53(s，1H)，8.98(s，1H)；

MS m/e MH ⁺503.

Intermediate 13

3-acetylenylbenzene aminocarbamic acid phenylester

The chloro-carbonic acid phenylester is added drop-wise in THF (300mL) solution of 3-acetenyl aniline (20.0mL) under 0 ℃ and pyridine (24.1mL).Then under 0 ℃, with the solution stirring that obtains 3.5 hours.Add pyridine (7.5mL), then be added dropwise to other chloro-carbonic acid phenylester (6mL).Add entry (50mL), vacuum is removed THF.The waterborne suspension that obtains is extracted in the ether, and with 1M HCl, water and salt water washing, vacuum concentration obtains being the solid title compound of light brown (27.5g).

¹H NMR(CDCl ₃)3.06(s，1H)，7.00(s，br，1H)，7.14-7.31(m，5H)，7.35-7.51(m，3H)，7.56(s，1H)；

MS m/e(M-H) ^-236.

Intermediate 14

N-(the 3-tert-butyl group-1-methyl isophthalic acid H-pyrazoles-5-yl)-N '-(3-ethynyl phenyl) urea

With the 3-tert-butyl group-1-methyl isophthalic acid H-pyrazoles-5-amine (792mg), 3-acetylenylbenzene aminocarbamic acid phenylester (intermediate 13) (1.19g) and the solution of triethylamine (1.4mL) in THF (30mL) be heated to 60 ℃ 24 hours.Add the triethylamine (0.5mL) and the 3-tert-butyl group-1-methyl isophthalic acid H-pyrazoles-5-amine (200mg) again, with mixture reheat 4 hours, vacuum concentration.Residue is distributed between DCM and 50% saturated aqueous sodium carbonate.Water layer is extracted with DCM, with the Organic substance that merges with 50% saturated aqueous sodium carbonate, water and salt water washing, vacuum concentration.Through the flash chromatography on silica gel purification, the DCM solution of using 0-5%MeOH is as eluant, and then the DCM solution of using 20-50%EtOAc obtains the title compound (725mg, 49%) into white solid as eluant.

¹H NMR(CDCl ₃)1.30(s，9H)，3.08(s，1H)，3.75(s，3H)，6.11(s，1H)，6.63(s，1H)，6.84(s，1H)，7.19-7.30(m，2H)，7.40(dt，1H)，7.46(s，1H)；

MS m/e MH ⁺297

Intermediate 15

N-(the 3-tert-butyl group-1-methyl isophthalic acid H-pyrazoles-5-yl)-N '-[3-({ 4-chloropyrimide-5-yl } acetenyl) phenyl] urea

Triethylamine (5.0mL) is joined 4-chloro-5-iodine pyrimidine (Chem.Pharm.Bull.1986,34 (7), 2719-2724) (590mg), N-(the 3-tert-butyl group-1-methyl isophthalic acid H-pyrazoles-5-yl)-N '-(3-third-1-alkynyl phenyl) urea (intermediate 14) (725mg), PdCl ₂(PPh ₃) ₂(40mg) and Copper diiodide (I) (3mg) in the de gassed solution of DMF (12.5mL).Under 60 ℃, with mixture heated 6.5 hours, vacuum concentration.Residue is dissolved among the THF (18mL), without being further purified direct use.

MS m/e MH ⁺409，411。

Press embodiment 21 similar modes, preparation the following example.

Embodiment 51

N-{3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl }-N '-(2,3-dihydro-1H-indenes-1-yl) urea

Raw material: { 3-[(4,6-di-amino-pyrimidine-5-yl) acetenyl] phenyl } carbamic acid phenylester (embodiment 10), 1-indane amine (indanamine).

¹H NMR(DMSO-d ₆)1.74-1.86(m，1H)，2.43-2.53(m，1H)，2.75-3.01(m，2H)，5.19(q，1H)，6.54(s，4H)，6.59(d，1H)，7.22-7.32(m，6H)，7.40-7.44(m，1H)，7.69(s，1H)，7.86(s，1H)，8.40(s，1H)；

MS m/e MH ⁺385.

Claims

1. formula (I) chemical compound and salt thereof:

Formula I

Wherein:

R ¹And R ²Independently be selected from hydrogen, (1-6C) alkyl sulphonyl, phenyl (CH ₂) _u-wherein u be 0,1,2,3,4,5 or 6, (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl, (3-6C) cycloalkyl (CH ₂) _x-, wherein x is 0,1,2,3,4,5 or 6, perhaps 5 or 6 yuan of heteroaryl rings, perhaps R ¹And R ²Coupled nitrogen-atoms is represented the 3-7 unit heterocycle of saturated or fractional saturation together, and described heterocycle is chosen wantonly and contained the hetero atom that another is selected from N or O;

Wherein said (1-6C) alkoxyl, (1-6C) alkoxyl (1-6C) alkoxyl and (1-6C) alkoxyl (1-6C) alkoxyl (1-6C) alkoxyl and amino, single (1-6C) alkyl-carbamoyl, two [(1-6C) alkyl] carbamoyl of single (1-6C) alkyl amino, two [(1-6C) alkyl] and/or-N (R ^d) C (O) (1-6C) (1-6C) alkyl of alkyl replaced by one or more hydroxyl is optional,

And R wherein ¹And/or R ²In any heterocycle and heteroaryl ring replaced independently by the group below one or more is optional: (1-4C) alkyl, (1-4C) alkoxyl, (1-4C) alkoxyl (1-4C) alkyl, hydroxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] is amino or the first heterocycle of the 3-7 of saturated or fractional saturation, perhaps-C (O) (CH ₂) _ZY, wherein z is 0,1,2 or 3, and Y is selected from hydrogen, hydroxyl, (1-4C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] are amino or the 3-7 of saturated or fractional saturation unit heterocycle;

And prerequisite is to work as R ¹And/or R ²When being (1C) alkanoyl, then described (1C) alkanoyl is not replaced by fluoro or hydroxyl;

R ³Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl, (1-6C) alkoxyl, wherein said alkyl and alkoxyl are selected from the optional replacement of following group by one or more: fluoro, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl, carbamoyl, single (1-6C) alkyl-carbamoyl or two [(1-6C) alkyl] carbamoyl, amino, single (1-6C) alkyl amino or two [(1-6C) alkyl] amino, 3-7 unit's heterocycle or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle and heteroaryl ring are replaced independently by one or more following groups is optional: (1-4C) alkyl, (1-4C) alkoxyl, hydroxyl, amino, the first heterocycle of single (1-6C) alkyl amino or two [(1-6C) alkyl] 3-7 amino or saturated or fractional saturation;

Perhaps R ³Represent group-NR as defined above ¹R ²

R ⁴Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl;

N is 0,1,2 or 3;

B represents (3-7C) cycloalkyl ring, 3-7 saturated or fractional saturation first heterocycle, aryl, is selected from 5 or 6 yuan of following heteroaryl rings: furyl, pyrrole radicals, thienyl,  azoles base, different  azoles base, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazole radical, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl or 1,3, the 5-triazine radical, perhaps 8,9 or 10 yuan optional contain 1,2,3 or 4 heteroatomic saturated, fractional saturation or aromatics bicyclic radicals that independently is selected from N, O and S;

R ⁶Be selected from halo, cyano group, oxo, (3-7C) cycloalkyl ring, saturated or fractional saturation 3-7 unit heterocycle ,-S (O) _p-(1-6C) alkyl, wherein p is 0,1 or 2;-N (R ^a) C (O) (1-6C) alkyl, wherein R ^aBe hydrogen or (1-6C) alkyl; Perhaps

M is 0,1,2 or 3;

2. according to the formula I chemical compound and the salt thereof of claim 1, wherein:

R ⁶Be selected from (1-6C) alkyl or (1-6C) alkoxyl, wherein said (1-6C) alkyl and (1-6C) alkoxyl be selected from independently by one or more that following group is optional to be replaced: the first heterocycle of 3-7 of cyano group, fluoro, hydroxyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] amino, (3-7C) cycloalkyl ring or saturated or fractional saturation.

3. according to the formula I chemical compound and the salt thereof of claim 1, wherein:

R ¹And R ²Independently be selected from hydrogen, (1-6C) alkyl sulphonyl, phenyl (CH ₂) _u-wherein u be 0,1,2,3,4,5 or 6, (1-6C) alkanoyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl or (3-6C) cycloalkyl (CH ₂) _x-, wherein x is 0,1,2,3,4,5 or 6, perhaps R ¹And R ²Coupled nitrogen-atoms is represented the optional 3-7 unit heterocycle that contains another heteroatomic saturated or fractional saturation that is selected from N or O together;

Wherein said phenyl is selected from by one or more that following group is optional to be replaced: halo, (1-6C) alkyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] amino, wherein said (1-6C) alkyl or (1-6C) alkoxyl be selected from the optional replacement of following group: hydroxyl, amino, list (1-6C) alkyl amino or two [(1-6C) alkyl] amino;

Perhaps R ³Represent group-NR as defined above ¹R ²

R ⁴Be selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl;

N is 0,1,2 or 3;

R ⁶Be selected from halo, cyano group, the first heterocycle of 3-7 saturated or fractional saturation or alkanoylamino-N (R ^a) C (O) (1-6C) alkyl, wherein R ^aBe hydrogen or (1-6C) alkyl; Perhaps R ⁶Be selected from (1-6C) alkyl or (1-6C) alkoxyl, wherein said alkyl and alkoxyl are selected from by one or more that following group is optional to be replaced: cyano group, fluoro, hydroxyl, (1-6C) alkoxyl, amino, list (1-6C) alkyl amino, two [(1-6C) alkyl] are amino, saturated or the first heterocycle of the 3-7 of fractional saturation; And

M is 0,1,2 or 3;

And when m was 2 at least, then two substituent groups on the adjacent carbon atom can be represented methylene dioxy base together in the B ring.

4. according to each chemical compound in the claim 1,2 and 3, wherein A is selected from phenyl, pyridine radicals, thiazolyl, thiadiazolyl group or pyrimidine radicals.

5. according to each chemical compound in the aforementioned claim, wherein B is selected from phenyl, 2,3-dihydro-indenyl, piperidyl, pyridine radicals, pyrazolyl, isothiazolyl, thiadiazolyl group, different  azoles base, benzo dioxine base, benzo dioxolyl or THP trtrahydropyranyl.

6. according to each chemical compound in the aforementioned claim, wherein L representative-N (R ⁸) C (O) N (R ⁹)-,-N (R ⁸) C (O) O-or-N (R ⁸) C (O) CH ₂-, R wherein ⁸And R ⁹Independent hydrogen or (1-6C) alkyl represented.

7. according to each chemical compound in the aforementioned claim, wherein R ¹And R ²All be hydrogen, perhaps R ¹Be hydrogen or (1-6C) alkyl, and R ²Be (1-6C) alkyl, wherein (1-6C) alkyl is replaced by following groups is optional: hydroxyl, amino, list (1-6C) alkyl amino or two (1-6C) alkyl amino, carbamoyl, (1-6C) alkoxyl, (1-6C) alkoxyl (1-6C) alkoxyl, R wherein ^dBe hydrogen or (1-6C) alkyl-N (R ^d) C (O) (1-6C) 3-7 unit's heterocycle or 5 or 6 yuan of heteroaryl rings of alkyl, aryl (especially phenyl), saturated or fractional saturation,

Wherein (1-6C) alkoxyl, list (1-6C) alkyl amino and-N (R ^d) C (O) (1-6C) alkyl replaced by hydroxyl is optional; And wherein the 3-7 of aryl, saturated or fractional saturation unit's heterocycle or 5 or 6 yuan of heteroaryls by (1-4C) alkyl, (1-4C) alkoxyl or-C (O) CH ₂Y is optional to be replaced, and wherein Y is selected from hydroxyl or two (1-6C) alkyl amino.

8. according to each chemical compound in the aforementioned claim, wherein R ³And R ⁴All be hydrogen.

9. according to each chemical compound in the aforementioned claim, wherein R ⁶Independently be selected from halo, cyano group, oxo, (3-7C) cycloalkyl, the optional saturated 3-7 unit heterocycle that is replaced by (1-4C) alkyl, R wherein ^cBe hydrogen or (1-6C) alkyl (especially (1-4C) alkyl)-N (R ^c) C (O) (1-6C) alkyl, optional (1-6C) alkyl that is replaced by halogeno-group, or (1-6C) alkoxyl, and m is selected from 1 or 2.

10. according to the chemical compound of claim 1, it is any one or more of compound or its salt of embodiment 1-51.

11. a Pharmaceutical composition, it comprises according to the formula I chemical compound of each definition among the claim 1-10 or its pharmaceutically acceptable salt and pharmaceutically acceptable diluent or carrier.

12. formula I chemical compound or its pharmaceutically acceptable salt according to each definition among the claim 1-10 as medicine.

13. formula I chemical compound or the purposes of its pharmaceutically acceptable salt in preparing the medicine that in homoiothermic animal such as people, is used as the Tie2 receptor tyrosine kinase inhibitors according to each definition among the claim 1-10.

14. be used for producing purposes in the medicine of blood vessel formation against function in preparation homoiothermic animal such as people according to the formula I chemical compound of each definition among the claim 1-10 or its pharmaceutically acceptable salt.

15. one kind prepare as defined in claim 1 formula I chemical compound or the method for its pharmaceutically acceptable salt, wherein remove and indicate R in addition ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, L, ring A and ring B, n and m such as in claim 1 definition, described method comprises:

(a) for L wherein be-N (R ⁸) C (O) N (H)-formula I chemical compound, make formula II chemical compound:

R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁸, n and A have any implication of above definition, except that if necessary protecting any functional group, and the isocyanate reaction of formula IV:

(b) for L wherein be-N (R ⁸) C (O) N (H)-formula I chemical compound, make the aryl carbamate reaction of formula II chemical compound and formula III as defined above:

Wherein Ar is the aryl that is fit to, phenyl for example, and R ⁶, m and B have any implication of above definition, except that if necessary protecting any functional group; Perhaps

(c) be N (R for L wherein ⁸) the formula I chemical compound of C (O)-O-, make the chemical compound reaction of formula II chemical compound and formula XI as defined above:

Lg wherein ¹Be the replaceable group that is fit to, for example halogeno-group such as fluoro, chloro or bromo, and R ⁶, m and ring B have any implication of above definition, except that if necessary protecting any functional group; Perhaps

(d) be N (R for L wherein ⁸) C (O) C (R ^aR ^b) formula I chemical compound, make the chemical compound reaction of formula II chemical compound and formula IX as defined above:

Lg wherein ²Be the replaceable group that is fit to, for example hydroxyl, halogeno-group such as fluoro, chloro or bromo, R ^x-C (O)-O-or R ^x-O-, wherein R ^xBe the alkyl or aryl that is fit to, and R ⁶, R ^a, R ^b, m and B have any implication of above definition, except that if necessary protecting any functional group; Perhaps

(e) for L wherein be-N (R ⁸) C (O) N (H)-formula I chemical compound, make the tribromo-acetyl base amine reaction of formula II chemical compound and formula XIII as defined above:

(f) for L wherein be-C (R ^aR ^b) C (O) N (R ⁹)-formula I chemical compound, make formula XIV chemical compound:

(g) make formula XVI chemical compound:

Lg wherein ³Be the replaceable group that is fit to, for example halogeno-group such as fluoro, chloro, bromo or iodo, methyl sulphonyl, methyl mercapto or aryloxy group such as phenoxy group, and R ³, R ⁴, R ⁵, R ⁶, n, m, A, B and L have any implication of above definition, except that if necessary protecting any functional group, with formula HNR ¹R ²Amine reaction, R wherein ¹And R ²Any implication with above definition is except that if necessary protecting any functional group; Perhaps

(h) make formula XVII chemical compound:

Lg wherein ⁴Be the replaceable group that is fit to, for example halogeno-group such as chloro, bromo or iodo or sulfonyloxy such as trifluoromethyl sulfonyloxy, and R ⁵, R ⁶, n, m, A, B and L have any implication of above definition, except that if necessary protecting any functional group, and the alkyne reaction of formula XVIII:

(i) for L wherein be-N (H) C (O) N (R ⁹)-formula I chemical compound, make the isocyanates of formula XIX:

(j) for L wherein be-N (H) C (O) N (R ⁹)-formula I chemical compound, make the chemical compound of formula XX:

Wherein Ar is the aryl that is fit to, phenyl for example, and R ¹, R ², R ³, R ⁴, R ⁵, n and A have any implication of above definition, except that if necessary protecting any functional group, with the amine reaction of formula XV as defined above;

Then, if necessary:

Ii) remove any protecting group;

Iii) form salt.

16. one kind is selected from defined formula II, XIV in the claim 15, XVI, XIX and XX chemical compound or formula VIc compound or its salt:

Lg wherein ³, R ³, R ⁴, R ⁵With n as defined in claim 15.