CN102316738A

CN102316738A - Amides as kinase inhibitors

Info

Publication number: CN102316738A
Application number: CN2010800081899A
Authority: CN
Inventors: 陈永胜
Original assignee: SYNTECH SOLUTION LLC
Current assignee: SYNTECH SOLUTION LLC
Priority date: 2009-02-18
Filing date: 2010-02-17
Publication date: 2012-01-11
Also published as: WO2010096395A1

Abstract

The present invention is directed to amides, and pharmaceutical compositions thereof, which are inhibitors of kinases such as BCR AbI, FLT3, c-Kit, KDR, LCK, Epha2 and PDGFR subfamily and are useful in the treatment of cancer and other diseases related to the dysregulation of kinase pathways.

Description

Amide-type as inhibitors of kinases

Invention field

The present invention relates to amide-type and pharmaceutical composition thereof, its for such as but be not limited to the inhibitors of kinases of BCR Ab1, FLT3, c-Kit, KDR, LCK, Epha2 and PDGFR subfamily and be used to treat cancer and other disease relevant with kinases pathway dysregulation.

Background of invention

Protein kinase (PKs) comprises that for regulating cell growth, survival and differentiation, organ form and one group of enzyme of the multiple important bioprocess of form formation, neovascularization, organization restoration and regeneration etc.Protein kinase through catalysis γ-phosphate from ATP to protein and the transfer of the hydroxyl on Ser/Thr the polypeptide or the Tyr side chain bring into play their physiologic function; And possibly participate in the control of multiple important cells function the most closely: signal transduction, differentiation and propagation.The function in normal structure/organ, many protein kinases are also to the more effect of specialization of host's performance of the human diseases that comprises cancer.When imbalance, the subgroup of protein kinase (also being called the carcinogenic protein kinases) can cause tumour to form and growth, and further helps tumour to keep and increase.

Protein kinase can be categorized as receptor type and non-receptor type.Receptor tyrosine kinase (RTKs) has the extracellular part, strides diaphragm area and intracellular portion, and nonreceptor tyrosine kinase is intracellular for fully.Usually the RTK Mediated Signal Transduction interacts through the extracellular with concrete growth factor (part) and begins, and next is receptor dimerization effect, the stimulation of intrinsic protein tyrosine kinase activity and acceptor transphosphorylation usually.Produce the binding site that is used for the intracellular signal transduction molecule thus and caused comprising the formation of the compound of a series of cytoplasmic signal molecules that promote suitable cell effect, the variation of for example cell division of said cell effect, differentiation, metabolic effect and extracellular microenvironment.

A large amount of EGFR-TK (acceptor and non-acceptor the two) and related to cancer (referring to Jianming Zhang, Priscilla L Yang and Nathanael S Gray; Targeting Cancer with small molecules kinase inhibitors (with little molecule inhibitors of kinases target on cancer), Nature Review Cancer, 2009,9 (1): 28-39.).The kinases of sudden change mark has promoted to investigate concentrated trial (Futreal, the people A census of human Cancer genes (generaI investigation of human cancer gene) such as P.A. of the kinases group of passing the tumor type that is widely used in sudden change as the success of drug target; Nature Rev.Cancer 4,177-183 (2004)).The sudden change of c-Kit EGFR-TK is relevant with the decrease in survival rate of gastrointestinal stromal tumor.In acute myelocytic leukemia, the short DFS rate of Flt-3 sudden change indication.Tumor vessel is generated important VEGFR expresses relevant with the low survival rate of lung cancer.It is the sign of poor prognosis in the important dopester of chronic myelocytic leukemia reaction and all stages that the Src EGFR-TK is colorectal cancer that BCR-Ab1 expresses.

Summary of the invention

The present invention especially provide have a general formula I be the compound of inhibitors of kinases or the acceptable salt of its medicine or its prodrug; Said kinases comprises receptor tyrosine kinase, and said receptor tyrosine kinase is such as but not limited to BCR Ab1, FLT3, c-Kit, KDR, LCK, Epha2 and PDGFR subfamily:

Wherein this paper has defined the formation element of said compound or the acceptable salt of its medicine or its prodrug.

The present invention also provides the composition that comprises compound of Formula I or acceptable salt of its medicine and at least a medicine acceptable carrier.

The present invention also provides the method that suppresses the activity of acceptor or nonreceptor tyrosine kinase, and it comprises makes said kinases contact with compound of Formula I or the acceptable salt of its medicine.

The present invention also provides the method that suppresses BCR Ab1 kinase signal pathway in the cell, and it comprises makes said cell contact with compound of Formula I or the acceptable salt of its medicine.

The present invention also provides the method that suppresses flt3 kinase signal pathway in the cell, and it comprises makes said cell contact with compound of Formula I or the acceptable salt of its medicine.

The present invention also provides the method that suppresses C-KIT kinase signal pathway in the cell, and it comprises makes said cell contact with compound of Formula I or the acceptable salt of its medicine.

The present invention also provides the method that suppresses the proliferation activity of cell, and it comprises makes said cell contact with compound of Formula I or the acceptable salt of its medicine.

The present invention also provides the method that suppresses the patient tumors growth, and it comprises compound of Formula I or the acceptable salt of its medicine that gives said patient treatment effective dose.

The present invention also provides and has suppressed the method that patient tumors shifts, and it comprises compound of Formula I or the acceptable salt of its medicine that gives said patient treatment effective dose.

The present invention also provides the method for treatment patient disease, and wherein said disease is relevant with the dysregulation of BCR Ab1 signal transduction path, and said method comprises compound of Formula I or the acceptable salt of its medicine that gives said patient treatment effective dose.

The present invention also provides the treatment patient method for cancer, and it comprises compound of Formula I or the acceptable salt of its medicine that gives said patient treatment effective dose.

The present invention also provides and has been used for the compound of Formula I used in treatment.

The present invention also provides the compound of Formula I that is used for being prepared in the medicine that treatment uses.

Detail

Wherein:

X is N or CR ²

R ¹For H or separately randomly by substituted aryl of 1,2,3,4 or 5-W-X-Y-Z or heteroaryl;

R2, R3 and R7 are H, cyclic hydrocarbon radical, aryl, heterocycle alkyl, heteroaryl, halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Haloalkyl, CN, NO ₂, OR ^A, SR ^A, C (O) R ^B, C (O) NR ^CR ^D, C (O) OR ^A, OC (O) R ^B, OC (O) NR ^CR ^D, NR ^CR ^D, NR ^CC (O) R ^B, NR ^CC (O) NR ^CR ^D, NR ^CC (O) OR ^A, S (O) R ^B, S (O) NR ^CR ^D, S (O) ₂R ^B, NR ^CS (O) ₂R ^BAnd S (O) ₂NR ^CR ^DWherein said cyclic hydrocarbon radical, aryl, heterocycle alkyl, heteroaryl or C _1-6Alkyl is randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Haloalkyl, halogenosulfanes base, CN, OR ^A1, SR ^A1, C (O) R ^B1, C (O) NR ^C1R ^D1, C (O) OR ^A1, OC (O) R ^B1, OC (O) NR ^C1R ^D1, NR ^C1R ^D1, NR ^C1C (O) R ^B1, NR ^C1C (O) NR ^C1R ^D1, NR ^C1C (O) OR ^A1, C (=NR ^g) NR ^C1R ^D1, NR ^C1C (=NR ^g) NR ^C1R ^D1, S (O) R ^B1, S (O) NR ^C1R ^D1, S (O) ₂R ^B1, NR ^C1S (O) ₂R ^B1And S (O) ₂NR ^C1R ^D1

The B ring is heteroaryl;

L is (CR ⁴R ⁵) _m, (CR ⁴R ⁵) _p-(inferior cyclic hydrocarbon radical)-(CR ⁴R ⁵) _q, (CR ⁴R ⁵) _p-(inferior heterocycle alkyl)-(CR ⁴R ⁵) _q, wherein said inferior cyclic hydrocarbon radical, inferior heterocycle alkyl are randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Haloalkyl, halogenosulfanes base, CN, OR ^a, SR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, C (=NR ^g) NR ^cR ^d, NR ^cC (=NR ^g) NR ^cR ^d, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^bAnd S (O) ₂NR ^cR ^d

C _yFor separately randomly by substituted heterocycle alkyl of 1,2,3,4 or 5-W '-X '-Y '-Z ' or cyclic hydrocarbon radical;

R ⁴And R ⁵Be independently selected from H, halogen, OH, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Alkoxyl, alkoxyalkyl, cyanoalkyl, heterocycle alkyl, cyclic hydrocarbon radical, C _1-6Haloalkyl, CN and NO ₂

Or R ⁴And R ⁵Form 3,4,5,6 or 7 yuan of cyclic hydrocarbon radical or heterocyclic hydrocarbon basic ring with the atom that links to each other with them, said cyclic hydrocarbon radical or heterocyclic hydrocarbon basic ring are randomly replaced by 1,2 or 3 substituting group separately, and said substituting group is independently selected from halogen, OH, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Alkoxyl, alkoxyalkyl, cyanoalkyl, heterocycle alkyl, cyclic hydrocarbon radical, C _1-6Haloalkyl, CN and NO ₂

R ⁸Be H, C _1-6Alkyl, C _2-6Thiazolinyl or C _2-6Alkynyl, wherein said C _1-6Alkyl, C _2-6Thiazolinyl and C _2-6Alkynyl is randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from halogen, (CR ⁴R ⁵) _p-(inferior cyclic hydrocarbon radical)-(CR ⁴R ⁵) _q, (CR ⁴R ⁵) _p-(arlydene)-(CR ⁴R ⁵) _q, CN, OR ^a, SR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a

W and W ' do not exist independently or are independently selected from C _1-6Alkylidene, C _2-6Alkenylene, C _2-6Alkynylene, O, S, NR ^h, CO, COO, CONR ^h, SO, SO ₂, SONR ^hAnd NR ^hCONR ⁱ, C wherein _1-6Alkylidene, C _2-6Alkenylene and C _2-6Alkynylene is randomly replaced by 1,2 or 3 substituting group separately, and said substituting group is independently selected from halogen, C _1-6Alkyl, C _1-6Haloalkyl, OH, C _1-6Alkoxyl, C _1-6Halogenated alkoxy, amino, C _1-6Alkyl amino and C _2-8Dialkyl amido;

X and X ' do not exist independently or are independently selected from C _1-6Alkylidene, C _2-6Alkenylene, C _2-6Alkynylene, arlydene, inferior cyclic hydrocarbon radical, inferior heteroaryl and inferior heterocycle alkyl, wherein C _1-6Alkylidene, C _2-6Alkenylene, C _2-6Alkynylene, arlydene, inferior cyclic hydrocarbon radical, inferior heteroaryl and inferior heterocycle alkyl are randomly replaced by 1,2 or 3 substituting group separately, and said substituting group is independently selected from halogen, CN, NO ₂, OH, C _1-6Alkyl, C _1-6Haloalkyl, C _2-8Alkoxyalkyl, C _1-6Alkoxyl, C _1-6Halogenated alkoxy, C _2-8Alkoxyl alkoxyl, cyclic hydrocarbon radical, heterocycle alkyl, C (O) OR ^j, C (O) NR ^hR ⁱ, amino, C _1-6Alkyl amino and C _2-8Dialkyl amido;

Y and Y ' do not exist independently or are independently selected from C _1-6Alkylidene, C _2-6Alkenylene, C _2-6Alkynylene, O, S, NR ^h, CO, COO, CONR ^h, SO, SO ₂, SONR ^hAnd NR ^hCONR ⁱ, C wherein _1-6Alkylidene, C _2-6Alkenylene and C _2-6Alkynylene is randomly replaced by 1,2 or 3 substituting group separately, and said substituting group is independently selected from halogen, C _1-6Alkyl, C _1-6Haloalkyl, OH, C _1-6Alkoxyl, C _1-6Halogenated alkoxy, amino, C _1-6Alkyl amino and C _2-8Dialkyl amido;

Z and Z ' are independently selected from H, halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Haloalkyl, halogenosulfanes base, CN, NO ₂, N ₃, OR ^A2, SR ^A2, C (O) R ^B2, C (O) NR ^C2R ^D2, C (O) OR ^A2, OC (O) R ^B2, OC (O) NR ^C2R ^D2, NR ^C2R ^D2, NR ^C2C (O) R ^B2, NR ^C2C (O) NR ^C2R ^D2, NR ^C2C (O) OR ^A2, C (=NR ^g) NR ^C2R ^D2, NR ^C2C (=NR ^g) NR ^C2R ^D2, S (O) R ^B2, S (O) NR ^C2R ^D2, S (O) ₂R ^B2, NR ^C2S (O) ₂R ^B2, S (O) ₂NR ^C2R ^D2, aryl, cyclic hydrocarbon radical, heteroaryl and heterocycle alkyl, wherein said C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cyclic hydrocarbon radical, heteroaryl and heterocycle alkyl are randomly replaced by 1,2,3,4 or 5 substituting group, and said substituting group is independently selected from halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Haloalkyl, halogenosulfanes base, CN, NO ₂, N ₃, OR ^A2, SR ^A2, C (O) R ^B2, C (O) NR ^C2R ^D2, C (O) OR ^A2, OC (O) R ^B2, OC (O) NR ^C2R ^D2, NR ^C2R ^D2, NR ^C2C (O) R ^B2, NR ^C2C (O) NR ^C2R ^D2, NR ^C2C (O) OR ^A2, C (=NR ^g) NR ^C2R ^D2, NR ^C2C (=NR ^g) NR ^C2R ^D2, S (O) R ^B2, S (O) NR ^C2R ^D2, S (O) ₂R ^B2, NR ^C2S (O) ₂R ^B2And S (O) ₂NR ^C2R ^D2

Two 4-20 unit heterocyclic hydrocarbon basic rings that adjacent-W-X-Y-Z randomly forms the 4-20 unit's cyclic hydrocarbon basic ring that condenses or condenses with the atom that links to each other with them wherein; Said cyclic hydrocarbon basic ring or heterocyclic hydrocarbon basic ring are randomly replaced by 1,2 or 3 substituting group separately, and said substituting group is independently selected from halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Haloalkyl, halogenosulfanes base, CN, NO ₂, OR ^A3, SR ^A3, C (O) R ^B3, C (O) NR ^C3R ^D3, C (O) OR ^A3, OC (O) R ^B3, OC (O) NR ^C3R ^D3, NR ^C3R ^D3, NR ^C3C (O) R ^B3, NR ^C3C (O) NR ^C3R ^D3, NR ^C3C (O) OR ^A3, C (=NR ^g) NR ^C3R ^D3, NR ^C3C (=NR ^g) NR ^C3R ^D3, S (O) R ^B3, S (O) NR ^C3R ^D3, S (O) ₂R ^B3, NR ^C3S (O) ₂R ^B3, S (O) ₂NR ^C3R ^D3, aryl, cyclic hydrocarbon radical, heteroaryl and heterocycle alkyl;

Two 4-20 unit heterocyclic hydrocarbon basic rings that adjacent-W '-X '-Y '-Z ' randomly forms the 4-20 unit's cyclic hydrocarbon basic ring that condenses or condenses with the atom that links to each other with them wherein; Said cyclic hydrocarbon basic ring or heterocyclic hydrocarbon basic ring are randomly replaced by 1,2 or 3 substituting group separately, and said substituting group is independently selected from halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Haloalkyl, halogenosulfanes base, CN, NO ₂, OR ^A3, SR ^A3, C (O) R ^B3, C (O) NR ^C3R ^D3, C (O) OR ^A3, OC (O) R ^B3, OC (O) NR ^C3R ^D3, NR ^C3R ^D3, NR ^C3C (O) R ^B3, NR ^C3C (O) NR ^C3R ^D3, NR ^C3C (O) OR ^A3, C (=NR ^g) NR ^C3R ^D3, NR ^C3C (=NR ^g) NR ^C3R ^D3, S (O) R ^B3, S (O) NR ^C3R ^D3, S (O) ₂R ^B3, NR ^C3S (O) ₂R ^B3, S (O) ₂NR ^C3R ^D3, aryl, cyclic hydrocarbon radical, heteroaryl and heterocycle alkyl;

R ^ABe H, C _1-4Alkyl, C _2-4Thiazolinyl, C _2-4Alkynyl, cyclic hydrocarbon radical, heterocycle alkyl, aryl or heteroaryl, wherein said C _1-4Alkyl, C _2-4Thiazolinyl, C _2-4Alkynyl, cyclic hydrocarbon radical, heterocycle alkyl, aryl or heteroaryl are randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from OH, CN, amino, halogen and C _1-4Alkyl;

R ^BBe H, C _1-4Alkyl, C _2-4Thiazolinyl, C _2-4Alkynyl, cyclic hydrocarbon radical, heterocycle alkyl, aryl or heteroaryl, wherein said C _1-4Alkyl, C _2-4Thiazolinyl or C _2-4Alkynyl, cyclic hydrocarbon radical, heterocycle alkyl, aryl or heteroaryl are randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from OH, CN, amino, halogen and C _1-4Alkyl;

R ^CAnd R ^DBe independently selected from H, C _1-4Alkyl, C _2-4Thiazolinyl or C _2-4Alkynyl, wherein said C _1-4Alkyl, C _2-4Thiazolinyl or C _2-4Alkynyl is randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from OH, CN, amino, halogen and C _1-4Alkyl;

Or R ^CAnd R ^DForm randomly by 1,2 or 3 substituted 4-of substituting group, 5-, 6-or 7 yuan of heterocycle alkyl with the N atom that links to each other with them, said substituting group is independently selected from OH, CN, amino, halogen and C _1-4Alkyl;

R ^a, R ^A1, R ^A2And R ^A3Be independently selected from H, C _1-6Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cyclic hydrocarbon radical, heteroaryl, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl and heterocycle alkyl alkyl, wherein said C _1-6Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cyclic hydrocarbon radical, heteroaryl, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl are randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl and C _1-6Halogenated alkoxy;

R ^b, R ^B1, R ^B2And R ^B3Be independently selected from H, C _1-6Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cyclic hydrocarbon radical, heteroaryl, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl and heterocycle alkyl alkyl, wherein said C _1-6Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cyclic hydrocarbon radical, heteroaryl, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl are randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl and C _1-6Halogenated alkoxy;

R ^cAnd R ^dBe independently selected from H, C _1-10Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, heteroaryl, cyclic hydrocarbon radical, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl, wherein said C _1-10Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, heteroaryl, cyclic hydrocarbon radical, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl are randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl and C _1-6Halogenated alkoxy;

Or R ^cAnd R ^dForm randomly by 1,2 or 3 substituted 4-of substituting group, 5-, 6-or 7 yuan of heterocycle alkyl with the N atom that links to each other with them, said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl and C _1-6Halogenated alkoxy;

R ^C1And R ^D1Be independently selected from H, C _1-10Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, heteroaryl, cyclic hydrocarbon radical, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl, wherein said C _1-10Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, heteroaryl, cyclic hydrocarbon radical, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl are randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl and C _1-6Halogenated alkoxy;

Or R ^C1And R ^D1Form randomly by 1,2 or 3 substituted 4-of substituting group, 5-, 6-or 7 yuan of heterocycle alkyl with the N atom that links to each other with them, said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl and C _1-6Halogenated alkoxy;

R ^C2And R ^D2Be independently selected from H, C _1-10Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, heteroaryl, cyclic hydrocarbon radical, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl, heterocycle alkyl alkyl, aryl rings alkyl, aryl-heterocyclic alkyl, aryl heteroaryl, biaryl, heteroaryl ring alkyl, heteroaryl heterocycle alkyl, heteroaryl aryl and couplet heteroaryl, wherein said C _1-10Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, heteroaryl, cyclic hydrocarbon radical, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl, heterocycle alkyl alkyl, aryl rings alkyl, aryl-heterocyclic alkyl, aryl heteroaryl, biaryl, heteroaryl ring alkyl, heteroaryl heterocycle alkyl, heteroaryl aryl and couplet heteroaryl are randomly replaced by 1,2 or 3 substituting group separately, and said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, hydroxy alkyl, cyanoalkyl, aryl, heteroaryl, alkoxyalkyl and alkoxyl alkoxyl;

Or R ^C2And R ^D2Form randomly by 1,2 or 3 substituted 4-of substituting group, 5-, 6-or 7 yuan of heterocycle alkyl with the N atom that links to each other with them, said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, hydroxy alkyl, cyanoalkyl, aryl, heteroaryl, alkoxyalkyl and alkoxyl alkoxyl;

R ^C3And R ^D3Be independently selected from H, C _1-10Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, heteroaryl, cyclic hydrocarbon radical, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl, wherein said C _1-10Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, heteroaryl, cyclic hydrocarbon radical, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl are randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl and C _1-6Halogenated alkoxy;

Or R ^C3And R ^D3Form randomly by 1,2 or 3 substituted 4-of substituting group, 5-, 6-or 7 yuan of heterocycle alkyl with the N atom that links to each other with them, said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl and C _1-6Halogenated alkoxy;

R ^gBe H, CN and NO ₂

R ^hAnd R ⁱBe independently selected from H and C _1-6Alkyl;

R ^jBe H, C _1-6Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cyclic hydrocarbon radical, heteroaryl, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl;

M is 0,1,2,3,4,5 or 6;

P is 0,1,2,3 or 4;

Q is 0,1,2,3 or 4.

In certain embodiments, when X was CH, R1 was H;

In certain embodiments, when X was CH, then R1, R2 and R3 were H, and R7 is an alkyl;

In certain embodiments, compound of the present invention has general formula I I:

In certain embodiments, compound of the present invention has general formula III, and wherein Cy is for randomly by the substituted cyclic hydrocarbon radical of 1,2,3,4 or 5-W-X-Y-Z:

In certain embodiments, compound of the present invention has general formula I V:

In certain embodiments, compound of the present invention has general formula III and general formula I V, and wherein L does not exist or is C _1-6Alkyl; Cy is for randomly by the substituted cyclic hydrocarbon radical of 1,2,3,4 or 5-W '-X '-Y '-Z ';

In certain embodiments, compound of the present invention has general formula III and general formula I V, and wherein L does not exist or is C _1-6Alkyl; Cy is for randomly by the substituted heterocycle alkyl of 1,2,3,4 or 5-W-X '-Y '-Z ';

In certain embodiments, compound of the present invention has general formula I V, and wherein L does not exist or is C _1-6Alkyl; And Cy is for randomly by halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, CN, OR ^a, SR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, C (=NR ^g) NR ^cR ^d, NR ^cC (=NR ^g) NR ^cR ^d, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^bAnd S (O) ₂NR ^cR ^dSubstituted cyclic hydrocarbon radical; Wherein said alkyl can be randomly by halogen, heterocycle alkyl, CN, OR ^a, SR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^aReplace.

A plurality of positions in this manual are with the substituting group of group or the open The compounds of this invention of the form of scope.It specifically means each independent son combination of the member who the present invention includes such group and scope.For example, term " C _1-6Alkyl " specifically mean separately openly methyl, ethyl, C ₃Alkyl, C ₄Alkyl, C ₅Alkyl and C ₆Alkyl.

It also means compound of the present invention is stable." stable " as used herein is meant that compound is enough stable in from reactant mixture, being separated to the purity process of significant degree, keeping existing, and preferably can prepare and become the efficacious therapy agent.

Should also be understood that for clear, can also be provided at some characteristic of the present invention of describing in the context of separate embodiments with the form that makes up in one embodiment.On the contrary, for succinctly, can also be provided at of the present invention a plurality of characteristics of describing in the context of an embodiment individually or with any suitable sub-combining form.

As used herein, the meaning of term " alkyl " is meant the saturated hydrocarbyl of straight or branched.Exemplary alkyl comprises methyl (Me), ethyl (Et), propyl group (for example n-pro-pyl and isopropyl), butyl (for example normal-butyl, isobutyl group, the tert-butyl group), amyl group (for example n-pentyl, isopentyl, neopentyl) etc.Alkyl can comprise 1 to about 20,2 to about 20,1 to about 10,1 to about 8,1 to about 6,1 to about 4 or 1 to about 3 carbon atoms.

As used herein, term " alkylidene " is meant the alkyl of connection.

As used herein, " thiazolinyl " is meant the alkyl with one or more carbon-to-carbon double bonds.Exemplary thiazolinyl comprises vinyl, acrylic etc.

As used herein, " alkenylene " is meant the thiazolinyl of connection.

As used herein, " alkynyl " is meant the alkyl with one or more carbon-to-carbon triple bonds.Exemplary alkynyl comprises acetenyl, propinyl etc.

As used herein, " alkynylene " is meant the alkynyl of connection.

As used herein, " haloalkyl " is meant the alkyl with one or more halogenic substituents.Exemplary haloalkyl comprises CF ₃, C ₂F ₅, CHF ₂, CCl ₃, CHCl ₂, C ₂Cl ₅Deng.

As used herein, " aryl " is meant the aromatic hydrocarbon of monocycle or many rings (for example having 2,3 or 4 condensed ring), for example phenyl, naphthyl, anthryl, phenanthryl, indanyl, indenyl etc.In some embodiments, aryl has 6 to about 20 carbon atoms.

As used herein, " arlydene " is meant the aryl of connection.

As used herein, " cyclic hydrocarbon radical " is meant non-aromaticity carbocyclic ring, it comprises alkyl, thiazolinyl and the alkynyl of cyclisation.Cyclic hydrocarbon radical comprises monocycle or encircles member ring systems (for example having 2,3 or 4 condensed ring) more that it comprises volution.In certain embodiments, cyclic hydrocarbon radical can have 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms or 3 to 7 carbon atoms.Cyclic hydrocarbon radical can also have 0,1,2 or 3 two key and/or 0,1 or 2 triple bond.Also comprise the part that has with the cyclic hydrocarbon basic ring the one or more aromatic rings that condense (promptly having common key) in the definition of cyclic hydrocarbon radical, for example the benzo derivative of pentane, amylene, hexane etc.Can connect through fragrance or non-aromatic portion and have the cyclic hydrocarbon radical of one or more aromatic rings that condense.For example, one or more one-tenth ring carbon atoms of ability oxidation cyclic hydrocarbon radical make it have oxo or sulfo-substituting group.Exemplary cyclic hydrocarbon radical comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclopentenyl, cyclohexenyl group, cyclohexadienyl, cycloheptatriene base, norborny, norpinane base (norpinyl), norcarnyl, adamantyl etc.

Use like this paper, " inferior cyclic hydrocarbon radical " is meant the cyclic hydrocarbon radical of connection.

Use like this paper, " heteroaryl " group is meant to have at least one aromatic heterocycle such as the heteroatomic ring member of sulphur, oxygen or nitrogen.Heteroaryl comprises monocycle and polycyclic system (for example having 2,3 or 4 condensed ring).Any one-tenth ring N atom in can also the oxidation heteroaryl is to form N-oxo part.The instance of heteroaryl includes but not limited to pyridine radicals, N-oxy picolinate base, pyrimidine radicals, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazole radicals, thiazolyl, indyl, pyrrole radicals 、 oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl 、 isoxazolyl, pyrazolyl, triazolyl, tetrazole radical, indazolyl, 1; 2,4-thiadiazolyl group, isothiazolyl, benzothienyl, purine radicals, carbazyl, benzimidazolyl, indolinyl etc.In certain embodiments, heteroaryl has 1 to about 20 carbon atoms, and in other embodiment, has about 3 to about 20 carbon atoms.In certain embodiments, heteroaryl comprises 3 to about 14,3 to about 7 or 5 to 6 one-tenth annular atomses.In certain embodiments, heteroaryl has 1 to about 4,1 to about 3 or 1 to 2 hetero atom.

Use like this paper, " inferior heteroaryl " is meant the heteroaryl of connection.

As used herein, " heterocycle alkyl " is meant the heterocycle of non-fragrance, wherein one or more become annular atoms is the hetero atom such as O, N or S atom.The heterocycle alkyl can comprise monocycle or encircle member ring systems (for example having 2,3 or 4 condensed ring) and volution more.Exemplary " heterocycle alkyl " base comprises morpholinyl, thio-morpholinyl, piperazinyl, tetrahydrofuran base, tetrahydro-thienyl, 2; 3-dihydro benzo furyl, 1; 3-benzo dioxole, phendioxin, 4-diox, piperidyl, pyrrolidinyl, isoxazole alkyl, isothiazole alkyl, pyrazolidinyl, oxazole alkyl, thiazolidinyl, imidazolidinyl etc.Also comprise the part that has with nonaromatic heterocycles the one or more aromatic rings that condense (promptly having common key) in the definition of heterocycle alkyl, for example the benzo derivative of phthalimidyl, phthalimido (naphthalimidyl) and heterocycle.Can connect heterocycle alkyl through the part of fragrance or non-fragrance with one or more aromatic rings that condense.Comprise also in the definition of heterocycle alkyl that wherein one or more become annular atoms by 1 or 2 oxygen base or the substituted part of sulfenyl.In certain embodiments, the heterocycle alkyl has 1 to about 20 carbon atoms, and in other embodiment, has about 3 to about 20 carbon atoms.In certain embodiments, the heterocycle alkyl comprises 3 to about 20,3 to about 14,3 to about 7 or 5 to 6 one-tenth annular atomses.In certain embodiments, the heterocycle alkyl has 1 to about 4,1 to about 3 or 1 to 2 hetero atom.In certain embodiments, the heterocycle alkyl comprises 0 to 3 two key.In certain embodiments, the heterocycle alkyl comprises 0 to 2 triple bond.

As used herein, " inferior heterocycle alkyl " is meant the heterocycle alkyl of connection.

As used herein, " aryl rings alkyl " is meant by the substituted cyclic hydrocarbon radical of aryl.

As used herein, " aryl-heterocyclic alkyl " is meant by the substituted heterocycle alkyl of aryl.

As used herein, " aryl heteroaryl " is meant by the substituted heteroaryl of aryl.

As used herein, " biaryl " is meant by the substituted aryl of another aryl.

As used herein, " heteroaryl ring alkyl " is meant by the substituted cyclic hydrocarbon radical of heteroaryl.

As used herein, " heteroaryl heterocycle alkyl " is meant by the substituted heterocycle alkyl of heteroaryl.

As used herein, " heteroaryl aryl " is meant by the substituted aryl of heteroaryl.

As used herein, " couplet heteroaryl " is meant by the substituted heteroaryl of another heteroaryl.

As used herein, " halogen (halo) " or " halogen (halogen) " comprises fluorine, chlorine, bromine and iodine.

As used herein, " halogenosulfanes base " is meant the methylthio group with one or more halogenic substituents.Exemplary halogenosulfanes base comprises such as SF ₅Five halogenosulfanes bases.

As used herein, " alkoxyl " is meant-the O-alkyl.Exemplary alkoxyl comprises methoxyl group, ethyoxyl, propoxyl group (for example positive propoxy and isopropoxy), tert-butoxy etc.

As used herein, " hydroxy alkyl " is meant the substituted alkyl by OH.

As used herein, " cyanoalkyl " is meant the substituted alkyl by CN.

As used herein, " alkoxyalkyl " is meant the substituted alkyl of alkoxy.

As used herein, " alkoxyl alkoxyl " is meant the substituted alkoxyl of alkoxy.

As used herein, " halogenated alkoxy " is meant-O-(haloalkyl) group.

As used herein, " aryl alkyl " is meant by the substituted alkyl of aryl and " cyclic hydrocarbon radical alkyl " and is meant by the substituted alkyl of cyclic hydrocarbon radical.Exemplary aryl alkyl is a benzyl.

As used herein, " heteroaryl alkyl " is meant by the substituted alkyl of heteroaryl and " heterocycle alkyl alkyl " and is meant by the substituted alkyl of heterocycle alkyl.

As used herein, " amino " is meant NH ₂

As used herein, " alkyl amino " is meant by the substituted amino of alkyl.

As used herein, " dialkyl amido " is meant by two substituted amino of alkyl.

Compound described herein can be asymmetrical (for example having one or more three-dimensional centers).Unless otherwise indicated, intention comprises all stereoisomers such as enantiomter and diastereoisomer.The compound of the present invention that can comprise asymmetric substituted carbon atom with optical activity or racemization isolated in form.How prepare that the method for optical activity form is known in the art, for example the fractionation through racemic mixture or synthetic through stereoselectivity from optically active starting material.In compound described herein, can also there be the multiple geometric isomer of alkene, the two keys of C=N etc., and the present invention includes the stable isomer of all these types.Described The compounds of this invention cis and trans geometric isomer and can mixture of isomers form or said cis of individual isomers isolated in form and trans geometric isomer.

Compound of the present invention also comprises tautomeric form.Tautomeric form is produced by the exchange of singly-bound and adjacent two keys and the protolysis of following.Tautomeric form comprises the proton translocation dynamic isomer, and it is the isomery protonation state with identical empirical formula and total electrical charge.Exemplary proton translocation dynamic isomer comprise keto-enol to, acid amides-imidic acid to, lactam-lactim to, acid amides-imidic acid to, enamine-imines to occupying the annular form of two or more positions of heterocyclic system with proton wherein; For example 1H-and 3H-imidazoles; 1H-, 2H-and 4H-1; 2,4-triazole, 1H-and 2H-iso-indoles and 1H-and 2H-pyrazoles.Tautomeric form can be in balance or locked a kind of form through suitable replacement by the space.

Compound of the present invention can also be included in all isotopes of the atom that exists in intermediate or the final compound.Isotope comprises having the same atoms quality and those different atoms of mass number.For example, the isotope of hydrogen comprises tritium and deuterium.

In certain embodiments, separate compound of the present invention and salt thereof basically." basic separate " was meant compound part or basic separation at least from its formation or the environment that is detected.Part is separated and is comprised the composition that for example is rich in The compounds of this invention.Comprise basic the separation, by weight, comprise at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97% or at least about 99% the The compounds of this invention or the composition of its salt.The method that is used for separating compound and salt thereof is the conventional method of this area.

The present invention also comprises the acceptable salt of the medicine of compound described herein.As used herein, " the acceptable salt of medicine " is meant the derivative of disclosed compound, wherein partly is converted into its salt form through the acid that will exist or alkali and modifies parent compound.The instance of the acceptable salt of medicine includes but not limited to such as the mineral salt of the alkaline residue of amine or organic acid salt; Such as the alkali salt of the acidic residues of carboxylic acid or organic salt etc.For example, the acceptable salt of medicine of the present invention comprises the conventional non-toxic salts of the parent compound that is formed by avirulence inorganic acid or organic acid.Can synthesize the acceptable salt of medicine of the present invention from the parent compound that comprises alkalescence or acidic moiety through the conventional chemical method.Usually, can prepare such salt through free acid or alkali form with chemical suitable alkali or the acid reaction of measuring in water or organic solvent or in the mixture of the two with these compounds; Usually, preferably like the non-aqueous media of ether, ethyl acetate, ethanol, isopropyl alcohol or acetonitrile.At Remington ' pharmaceutical Sciences (the Lei Shi pharmacy is complete works of), the 17th edition, Mack Publishing Company; Easton, Pa., 1985; P.1418 with Journal of pharmaceutical Science; Find the inventory of suitable salt in 66,2 (1977), said document is incorporated herein with the form of quoting with its integral body separately.

The phrase " medicine is acceptable " that this paper uses is meant those compounds, material, composition and/or the formulation in rational medical judgment scope; It is applicable to and contacts with human and animal's tissue and do not have excessive toxicity, excitant, allergy or other problem or complication to have rational benefit/risk ratio.

The present invention also comprises the prodrug of compound described herein.Use like this paper, " prodrug " be meant any covalently bound carrier of release active parent drug when to the mammalian subject administration.Can or in vivo modification be split into the such mode of parent compound with routine operation and prepare prodrug through the functional group that exists in the modified compound.Prodrug comprises that when to the mammalian subject administration hydroxyl that wherein combines with any group, amino, sulfydryl or carboxyl fracture form free hydroxyl, amino, sulfydryl or carboxyl respectively.The instance of prodrug includes but not limited to acetate, formates and the benzoate derivative of the alkohol and amine functional group of The compounds of this invention.The 14th volume and Bioreversible Carriers in Drug Design (the biological reversible carrier in the drug design) at T.Higuchi and V.Stella " Prodrugs as Novel Delivery Systems (as the prodrug of novel delivery system) " A.C.S.Symposium Series; Ed.Edward B.Roche; American Pharmaceutical Association and Pergamon Press; The preparation and the use of prodrug have been discussed in 1987, and the two all is incorporated herein with the form of quoting with its integral body.

Synthetic

Can be with the known prepared in various methods of the technical staff in organic synthesis field new compound of the present invention.The modification of the said method that can use the known synthetic method in method that hereinafter describes and synthetic organic chemistry field or it will be apparent to those skilled in the art that is synthesized compound of the present invention.

Can use following conventional method and step to prepare compound of the present invention from the starting material of easy acquisition.Only if should be appreciated that in addition regulation, under the situation that provides standard or method for optimizing condition (being the mol ratio, solvent, pressure etc. of reaction temperature, time, reactant), can also use other method condition.Optimum reaction condition can change with the special reaction thing or the solvent that use, but such condition can be confirmed through conventional optimization step by those skilled in the art.

Can monitor method described herein according to any suitable method known in the art.For example, can be through the formation of spectrum means monitoring product, for example nuclear magnetic resonance spectrometry is (for example ¹H or ¹³C), infra-red sepectrometry, AAS (for example UV-is visible) or mass spectrum, or through formation such as the chromatography monitoring product of high performance liquid chromatography (HPLC) or thin-layer chromatography.

The preparation of compound comprises the protection and the deprotection of various chemical groups.In order to protect the needs with deprotection, those skilled in the art confirm the selection of suitable protection base easily.For example at people Protective Groups in Organic Synthesis (the protection base in the organic synthesis) such as Greene, the 2nd edition, Wiley&Sons can find the chemistry of protection base in 1991, and it is incorporated herein with the form of quoting with its integral body.

Can in suitable solvent, carry out the reaction of method described herein, the technical staff in organic synthesis field selects to select easily said solvent.Under the temperature of reacting, promptly from the temperature of the boiling temperature of freezing point temperature to the solvent of solvent, suitable solvent and starting material (reactant), intermediate or product do not react basically.Can carry out given reaction at a kind of solvent or in more than a kind of mixture of solvent.According to specific reactions step, can select to be used for the suitable solvent of specific reactions step.

Can carry out the fractionation of the racemic mixture of compound through any several different methods known in the art.Exemplary method comprises the substep recrystallization of use " chiral resolution acid ", and said " chiral resolution acid " is optical activity, the organic acid that forms salt.The suitable resolution reagent that is used for the substep recrystallization method is for example optically active acid, like tartaric D and L shaped formula, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acid.Can also carry out the fractionation of racemic mixture through wash-out on the post of filling with optical activity resolution reagent (for example dinitrobenzoyl phenylglycine).Those skilled in the art can confirm suitable eluting solvent composition.

The reaction path and technology preparation compound of the present invention that for example can use hereinafter to describe.

The amide derivatives that can prepare a series of general formulas 8 through the method that scheme 1 is summarized.2,4-dichloro pyrimidine 2 has prepared corresponding chlorinated pyrimidine 3 with the Suzuki coupling of suitable boric acid 1, can be through with 4 reactions of 3-Aminobenzoate said chlorinated pyrimidines 3 being converted into compound 5 under heating condition.Compound 5 produces acid 6 with hydrolysis such as the alkali of LiOH, NaOH or KOH, can acid 6 and suitable amine 7 couplings come easily acid 6 to be converted into corresponding amide 8 through using the acid-amine coupling reagent such as BOP, ByBOP, EDCI, HATU, HBTU or diethyl cyanic acid phosphate etc.

Reaction scheme 1

The pyrimidine ester that can prepare a series of general formulas 5 through the method that scheme 2 is summarized.Thermal response through pyridine enamine ketone 10 and guanidine 9 can prepare compound 5 easily, can obtain said guanidine 9 through using cyanamide to handle aniline 4.Can compound 5 be converted into acid amides 8 as stated then.

Reaction scheme 2

Perhaps, can prepare compound 5 through the method that scheme 3 is summarized.Enamine ketone 10 produces pyrilamine 11 with the thermal response of guanidine carbonate.Such as CS ₂CO ₃, K ₂CO ₃, KOBu-t or NaOBu-t the existence of alkali under, under palladium catalyst and suitable ligand such as xantphos or BINAP etc., can through 11 with the amination acquisition compound 5 of the substituted benzoic ether 12 of halogen (X=Br, I).

Reaction scheme 3

The imdazole derivatives that can prepare a series of general formulas 7 through the method that scheme 4 is summarized.At CuI with such as N, N '-dimethyl-ethylenediamine, (±)-trans-cyclohexanediamine, 1 under the existence of the amine of 10-phenanthroline or oxine, can be accomplished imidazoles 14 and react to produce compound 7 with the N-arylation of the copper catalysis of bromination aniline 13 under heat condition.

Reaction scheme 4

Perhaps, can prepare compound 7 according to the method that scheme 5 is summarized.Imidazoles 14 can produce nitroimidazole 16 with the reaction of compound 15 (X=F, Cl), under the hydrogenation of palladium catalysis or chemical method, can be corresponding amine with nitroreduction wherein.

Reaction scheme 5

Can also prepare compound 7 according to the method that scheme 6 is summarized.Imidazoles 14 can produce cyanic acid-imidazoles 18 with the reaction of compound 17.The hydrolysis of cyanic acid can produce corresponding acid 19 in 18 under alkali condition, in the tert-butyl alcohol, refluxes then and can be converted into N-Boc aniline 20 with said sour 19 through using diphenyl phosphate azide to handle.The N-Boc protection base that the acid of use such as HCl and TFA removes in 20 can produce compound 7.

Reaction scheme 6

The imdazole derivatives that can prepare a series of general formulas 14 through the method that scheme 7 is summarized.Can obtain compound 14 easily through the α-bromo-ketone 22 and the reaction of carbonamidine acetate (formimidamide acetate).

Reaction scheme 7

With similar methods, can obtain compound 14 through the reaction of carbonamidine acetate and alpha-chloro-ketone 25, can prepare said alpha-chloro-ketone 25 from corresponding sour 23 through the method that scheme 8 is summarized.

Reaction scheme 8

Perhaps, can prepare imdazole derivatives 14 with ammonia treatment from suitable aldehyde 26 then with tolysulfonyl methyl isonitrile according to the method that scheme 9 is summarized.

Reaction scheme 9

The imdazole derivatives that can prepare a series of general formulas 33 through the method that scheme 10 is summarized.Can be converted into corresponding ketone 31 from the acid amides 28 that acid 27 obtains through using reagent 30 to handle, said reagent 30 can generate from iodide 29 original positions through the reaction with EtMgBr or i-PrMgBr.Ketone 31 can produce imidazoles 33 with the reaction of hydrazine.

Reaction scheme 10

The anil and final compound 36 that can prepare a series of general formulas 35 through the method that scheme 11 is summarized.Bromination aniline 13 can generate corresponding aniline 35 with the Suzuki coupling of suitable heteroaryl boric acid 34, and the condition of use front description is converted into final compound 36 with aniline 35.

Reaction scheme 11

The anil and final compound 38 that can prepare a series of general formulas 37 through the method that scheme 12 is summarized.Bromination aniline 13 can generate corresponding aniline 37 with the coupling of the Cu catalysis of suitable heteroaryl compound 39, and the condition of use front description is converted into final compound 38 with aniline 37.

Reaction scheme 12

Method for using

Compound of the present invention can be regulated the activity of protein kinase.The exemplary protein kinase of regulating through compound of the present invention comprises RTKs, the FLK subfamily (RTKs of kinases insertion zone-acceptor tire liver kinases-1 (KDR/FLK-1) for example of PDGF subfamily (for example PDGF α and beta receptor, CSFIR, c-kit and FLK-II); Tire liver kinases 4 (FLK-4) and fms appearance EGFR-TK 1 and 3 (fit-1 and flt-3)) RTKs, the RTKs and the Src of FGF receptor family (for example FGFR1, FGFR2, FGFR3 and FGFR4), the RTKs of Ab1 subfamily.

Term " adjusting " means the ability that increases or reduce enzyme or receptor active.Adjusting can be in external or generation in vivo.Adjusting can also take place in cell.Therefore, can be through enzyme (or cell or comprise the sample of enzyme) is contacted with any or multiple compound described herein or composition in the method for regulating, use compound of the present invention such as the protein kinase of RTK.

In certain embodiments, compound of the present invention be applicable to treatment such as cancer, arteriosclerosis, pulmonary fibrosis, kidney fibrosis and regeneration, liver diseases, irritated illness, inflammatory disease, autoimmune disorder, cranial vascular disease, angiocardiopathy or with the disease of organ transplant disease states associated.In other embodiment, compound of the present invention can be used for suppressing the method for patient's tumor growth or metastases.

The exemplary cancer that can treat through method described herein comprises carcinoma of urinary bladder; Breast cancer; Cervical carcinoma; Cholangiocarcinoma; Colorectal cancer; Cancer of the esophagus; Cancer of the stomach; Head and neck cancer; Kidney; Liver cancer; Lung cancer; Nasopharyngeal carcinoma; Oophoroma; Cancer of pancreas; Prostate cancer; Thyroid cancer; Osteosarcoma; Synovial sarcoma; Rhabdomyosarcoma; The MFH/ fibrosarcoma; Leiomyosarcoma; Kaposi; Huppert's disease; Lymphoma; The adult T-cell leukemia; Acute myelocytic leukemia; Chronic myelocytic leukemia; Glioblastoma; Astrocytoma; Melanoma; The celiothelioma or the nephroblastoma etc.

As used herein, that the meaning of term " cell " is meant is external, in vitro or the cell in the body.In certain embodiments, in vitro cell can be a part of tissue samples from cutting off such as mammiferous organism.In certain embodiments, cell in vitro can be the cell in the cell culture medium.In certain embodiments, the cell of cells in vivo in such as mammiferous organism, surviving.

As used herein, term " contact " is meant that the part that in vitro system or body, will point out in the system links together.Compound of the present invention and protein kinase " are contacted " comprise to give compound of the present invention, and for example compound of the present invention is introduced in the sample of the preparation protein kinase that comprises cell or purifying to individuality or patient such as the people.

As used herein; Commutative used term " individuality " or " patient " are meant any animal that comprises mammal, are preferably mouse, rat, other rodent, rabbit, dog, cat, pig, ox, sheep, horse or primate and most preferably are the people.

As used herein; Phrase " treatment effective dose " is meant through what researcher, animal doctor, doctor or other clinician sought and causes the amount of the reactive compound or the medicament of biology or drug response at tissue, system, animal, individuality or philtrum, and it comprises following one or more:

(1) prevent disease is for example prevented susceptible disease, morbid state or illness but is not experienced or show disease, morbid state or the illness in the individuality of pathology or symptom of disease;

(2) suppress disease, for example suppress experience or show disease, morbid state or the illness of individuality of pathology or the symptom of disease, morbid state or illness; And

(3) palliate a disease, for example alleviate experience or show disease, morbid state or the illness (promptly reversing pathology and/or symptom) of individuality of pathology or the symptom of disease, morbid state or illness, for example reduce the order of severity of disease.

Therapeutic alliance

Can use one or more other medicaments or methods of treatment and compound therapeutic alliance of the present invention disease described herein, illness or morbid state such as chemotherapeutant, anticancerogenics, cytotoxic agent or anti-cancer therapies (for example radiation, hormone etc.).Can give (for example being mixed into a kind of formulation) said medicament or therapy or simultaneously or give said medicament or therapy in succession with compound of the present invention through independent method of administration.

Suitable anticancerogenics comprises inhibitors of kinases, and said inhibitors of kinases is included in for example WO 2005/004808, and WO 2005/004607; WO 2005/005378, and WO 2004/076412, and WO 2005/121125; WO 2005/039586, and WO 2005/028475, and WO 2005/040345; WO 2005/039586, and WO 2003/097641, and WO 2003/087026; WO 2005/040154; WO 2005/030140, and WO 2006/014325, and WO 2005/070891; WO 2005/073224, WO 2005/113494 and No. 2005/0085473, No. 2006/0046991 and No. 2005/0075340 open middle Herceptin (Trastuzumab), Imatinib (Ge Lieweike), Gefitinib (Yi Ruisha), Erlotinib hydrochloride (Te Luokai), Cetuximab (Erbitux), bevacizumab (A Wasiting), Sorafenib (Nexavar), Sutent (Suo Tan) and the RTK inhibitor of describing of U.S. Patent application.

Suitable chemotherapeutant or other anticancerogenics also comprise for example alkylating agent (including but not limited to mustargen, aziridine derivative, alkylsulfonate, nitroso ureas and triazenes), for example uracil mastard, chlorine mustard, cyclophosphamide (Cytoxan ^TM), ifosfamide, melphalan, Chlorambucil, pipobroman, triethylene melamine, triethylene thiophosphoramide, busulfan, BCNU, lomustine, chain assistant star, Dacarbazine and Temozolomide.

Suitable chemotherapeutant or other anticancerogenics also comprise for example antimetabolite (including but not limited to antifol, pyrimidine analogue, purine analogue and adenosine deaminase inhibitors), for example methotrexate (MTX), 5 FU 5 fluorouracil, floxuridine, cytarabine, Ismipur, 6-thioguanine, fludarabine phosphate, Pentostatin and gemcitabine.

Suitable chemotherapeutant or other anticancerogenics also comprise for example some natural products and derivative (for example vinca alkaloids, antitumor antibiotics, enzyme, lymphokine and epipodophyllotoxin), for example vincaleukoblastinum, vincristine, eldisine, bleomycin, dactinomycin D, daunorubicin, adriamycin, epirubicin, idarubicin, cytarabine, taxol (Taxol ^TM), mithramycin, deoxycoformycin, Mitomycin-C, L-Asnase, interferon (especially IFN-a), Etoposide and Teniposide.

Other cytotoxic agent comprises NVB, CPT-11, Anastrozole, Letrozole, capecitabine, reloxafine, cyclophosphamide, ifosfamide and droloxafine.

Also suitable is the cytotoxic agent such as Teniposide (epidophyllotoxin), antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, the platinum coordination complex such as cis-platinum and carboplatin, BRM, growth inhibitor, hormone antagonist therapeutic agent, folinic acid, tegafur and hemopoieticgrowth factor.

Other anticancerogenics comprises the Antybody therapy agent such as Herceptin (Trastuzumab), to such as the antibody of the costimulatory molecules of CTLA-4,4-1BB and PD-1 or the antibody of the pair cell factor (IL-10, TGF-etc.).The additional antibody therapeutic agent comprises the antibody to EGFR-TK and/or their part, for example anti-HGF antibody and/or anti-c-Met antibody.Term " antibody " be meant comprise complete antibody (for example monoclone antibody, polyclonal antibody, chimeric antibody, anthropomorphic antibody, people's antibody etc.) with and Fab.

Other anticancerogenics also comprises those medicines of enhance immunity system or the adoptive transfer of T cell, for example adjuvant.

Other anticancerogenics comprises anti-cancer vaccine, for example BMDC, synthetic polypeptide, dna vaccination and recombinant virus.

The safety of most of said medicine is known with effective medication to those skilled in the art.Their administration has been described in normative document in addition.For example, " Physicians ' Desk Reference (handbook on doctor's table) " (PDR, for example 1996 editions; Medical Economics Company; Montvale has described the administration of number of chemical therapeutic agent in NJ), and its content is incorporated this paper with its integral body into the form of quoting.

Pharmaceutical preparation and formulation

When using with the form of medicine, can form with pharmaceutical composition and give compound of the present invention, said pharmaceutical composition comprises compound of the present invention and medicine acceptable carrier.Can prepare these compositions and ability administered by various routes with the method that drug world is known, this depends on expectation local or whole body therapeutic and subject zone.Administration can be the part and (comprises that eyes are sent and the mucosal delivery in comprising nose; Vagina and rectum are sent) administration, lung (the for example suction through powder agent or aerosol or be blown into administration, it comprises through administration in sprayer administration, the tracheae, intranasal administration, epidermis administration and percutaneous dosing) administration, ophthalmic administration, oral administration or parenteral.Being used for the method that eyes send comprises under topical (eye drops), the conjunctiva, near the eyes or intravitreal injection or introduce or place eye implantation agent (ophthalmic insert) at conjunctival sac through operation through balloon catheter.Parenteral comprises in intravenous, intra-arterial, subcutaneous, the peritonaeum or intramuscular injection or injection; Or the encephalic administration, for example sheath is interior or the interior administration of ventricle.Parenteral can or can for example carry out parenteral through continuous charge pump for the form of single bolus.The pharmaceutical composition and the preparation that are used for topical can comprise through skin patch, ointment, lotion, cream, gel, drops, suppository, spray, liquid agent and powder agent.Conventional pharmaceutical carrier, the aqueous solution, powder or oleaginous base, thickeners etc. can be necessary or expectation.

The present invention also comprises pharmaceutical composition, and it comprises the compound as one or more the invention described above of active component that combines with one or more medicine acceptable carriers.In the process of the preparation present composition, usually with active component and mixed with excipients, through excipient dilution or pack into in such carrier that for example capsule, pouch, paper or other vessel form exist.When the thinner of the media, carrier or the medium that are used for active component was served as in the excipient conduct, it can be solid, semisolid or fluent material.Therefore; Composition can be the form of tablet, pill, powder agent, lozenge, sachet agent, cachet, elixir, suspending agent, emulsion, solution, syrup, aerosol (as solid or in liquid medium), for example comprises the form up to the powder agent of ointment, soft capsule and hard shell capsules, suppository, aseptic injectable solution agent and the aseptic packaging of 10% reactive compound by weight.

In the preparation preparation,, reactive compound can mill reactive compound before mixing with other composition so that suitable particle diameter to be provided.If reactive compound does not dissolve basically, then can it be milled to less than 200 purpose particle diameters.If reactive compound is water-soluble then can regulate particle diameter through milling and distribute for example about 40 orders uniformly in preparation, to provide basically for basically.

Some instances of suitable excipient comprise lactose, glucose, sucrose, sorbierite, mannitol, starch, gum Arabic, calcium phosphate, alginates, bassora gum, gelatin, calcium silicates, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose.Preparation can comprise in addition: such as the lubricant of talcum, dolomol and mineral oil; Wetting agent; Emulsifier and suspending agent; Preservative such as methyl hydroxybenzoate and nipasol; Sweetener and flavor enhancement.Can be through using the step preparation present composition known in the art the quick, lasting of active component to be provided after giving the patient or to postpone to discharge.

Can be with the form compositions formulated of unit dosage forms, each dosage comprises about 5mg to about 100mg, is more typically the active component of about 10mg to about 30mg.Term " unit dosage forms " is meant the unit that is suitable as the physical separation that is used for individual human and other mammiferous single dose, and per unit comprises the active material that calculates the scheduled volume that produces the expectation result of treatment that combines with suitable drug excipient.

Reactive compound is effectively and usually with the form administration of medicine effective quantity on dosage range widely.Yet; Be to be understood that; The amount of common actual administered compound confirms that according to relevant situation this comprises age, body weight and the reaction of the morbid state that will treat, the method for administration of selection, actual administered compound, individual patient, the seriousness of patient's symptom etc. by the doctor.

Solid composite for preparation such as tablet mixes the solid preformulation composite that comprises the homogeneous mixture of The compounds of this invention with formation with main active with drug excipient.When mentioning that these pre-preparation compositions are uniform, usually active component is evenly disperseed in composition so that can composition easily be further divided into the unit dosage forms of equivalence, for example tablet, pill and capsule.Then, this solid preformulation is further divided into the unit dosage forms of the above-mentioned type, said unit dosage forms for example comprises 0.1mg to the active component of the present invention of about 500mg.

Can be with tablet of the present invention or coating of pill or additional mixing so that the formulation that produces long-acting advantage to be provided.For example, dosage and external dose component in tablet or pill can comprise, the latter exists with the form of sealing the former.Can be through separating two components as the complete enteric layer that is sent to duodenum or postpones to discharge of component in disintegration and the permission in the opposing stomach.Multiple material can be used for such enteric layer or dressing, and such material comprises the acid and mixtures of material such as shellac, hexadecanol and cellulose acetate of acid and the polymerization of some polymerizations.

Be used for the liquid form that has wherein comprised compound of the present invention and composition oral or through drug administration by injection comprise aqueous pharmaceutical, suitably taste syrup, water or oil-suspending agent and use such as the emulsion of the edible oil seasoning of cottonseed oil, sesame oil, cocoa butter or peanut oil and elixir and similar drug media.

The composition that is used to suck or be blown into comprises that medicine can accept solution and suspension, water or organic solvent or its mixture and the powder of form.The liquid or solid composition can comprise above-mentioned suitable pharmaceutically-acceptable excipients.In some embodiments, through port or nasal respiration approach give composition and are used for part or whole body effect.Can be used for spray composition through making of inert gas.Can directly breathe the solution that sprays, maybe can spray appliance be connected with mouth mask or intermittent positive pressure breathing machine from spray appliance.Can be oral or from giving solution, suspension or powder composition with intranasal the equipment of suitable manner delivery formulation.

Change to the variation of the amount of patient's administered compound or composition, for example prevention or treatment, patient's state, administering mode etc. according to the purpose of the compound that is given or composition, administration.In treatment was used, the amount of composition that gives to suffer from the patient of disease was enough to cure or the symptom of part control disease and complication thereof at least.Effectively dosage depends on subject morbid state and by curing mainly the clinician according to the judgement such as factors such as severity of disease, patient's age, body weight and comprehensive states.

The composition that gives to the patient can be the form of aforementioned pharmaceutical compositions.Can filter with these composition sterilizations or with these composition steriles through the conventional sterilization technology.In order to use aqueous solution packing or freeze-drying according to present appearance, lyophilized formulations mixes with sterile aqueous carrier before administration.The pH of compound formulation is generally 3 to 11, and more preferably 5 to 9 and most preferably be 7 to 8.The use that should be appreciated that some aforementioned excipients, carrier or stabilizing agent will cause the formation of drug salts.

The variation of the specific use that the therapeutic dose ability basis of The compounds of this invention is for example treated, the mode of compound administration, patient's health and morbid state and prescriber's judgement changes.The ratio of the The compounds of this invention in the pharmaceutical composition or concentration can change according to the variation of the some factors that comprise dosage, chemical property (for example hydrophobicity) and method of administration.For example, for parenteral, can compound of the present invention be provided to the form of the water-based physiological buffer solution of the compound of about 10%w/v to comprise about 0.1%w/v.Some typical dosage ranges are about

extremely about 1g/kg body weight every day.In certain embodiments, dosage range is the extremely about 100mg/kg body weight of about 0.01mg/kg every day.The variation of the formulation of the overall health of the type of dosage possibility basis such as disease or illness and development degree, particular patient, the relative biological effect of selected compounds, excipient and the variable factor of method of administration thereof changes.Can infer effective dosage from the dose-effect curve that is derived from external or animal model test system.

Can also combine one or more other active components to prepare compound of the present invention, said active component comprises any medicament such as anti-virus formulation, vaccine, antibody, immunopotentiator, immunodepressant, antiinflammatory etc.

The labeled compound and the method for inspection

The present invention relates to fluorescent dye, spin labeling, heavy metal or radiolabeled compound of the present invention on the other hand, and said labeled compound not only is used for forming images but also being used to locate the check in the external and body of discerning kinase ligands with the protein kinase target spot of the tissue samples that quantitatively comprises the people with through the combination that suppresses labeled compound.Therefore, the present invention includes the kinases check that comprises such labeled compound.

The present invention also comprises the compound of isotope-labeled The compounds of this invention.The compound of " isotope " or " radiolabeled " is a The compounds of this invention, atomic mass that wherein one or more atoms are had or mass number and the atomic mass of finding (being that nature exists) usually naturally or different atom replacement or the replacements of mass number.The suitable radionuclide that can in compound of the present invention, comprise includes but not limited to ²H (deuterium is also write D), ³H (tritium is also write T), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I with ¹³¹I.The radionuclide that in instant radiolabeled compound, comprises relies on the special applications with radiolabeled compound.For example, for external IDO enzyme labeling and competition assays, comprise usually ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵The compound of S is the most useful.Use for radiophotography, ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br is the most useful usually.

Should be appreciated that " radiolabeled " or " compound of mark " is for comprising the compound of at least a radionuclide.In certain embodiments, radionuclide is selected from ³H, ¹⁴C, ¹²⁵I, ³⁵S with ⁸²Br.

Be used for the synthetic method that radioisotope is sneaked into organic compound is applicable to compound of the present invention and for well known.

Radiolabeled compound of the present invention can be used for the screening test for identification/assessing compound.In general, can estimate new compound (being test compound) synthetic or identification and reduce the ability that radiolabeled compound of the present invention combines with enzyme.Therefore, test compound is directly relevant with its binding affinity with the ability that radiolabeled compound competition combines with enzyme.

Kit

The present invention also comprises the pharmaceutical kit of the disease of other disease that for example is used to treat or prevents to relate to such as cancer and this paper; It comprises one or more containers that comprise pharmaceutical composition, and said pharmaceutical composition comprises the compound of the present invention or the acceptable salt of its medicine of treating effective dose.One of ordinary skill in the art will readily recognize that kit such when needing can also comprise one or more various conventional medicine kit assemblies, for example comprises the container of one or more medicine acceptable carriers, other container etc.Can also comprise in the kit as inset or label point out wait to give component amount specification, administration guide and/or be used for the guide of blending ingredients.

Through specific embodiment the present invention is described in more detail.The purpose that is used for example provides the following example, and is not intended to limit by any way the present invention.Those skilled in the art discern easily and can be changed or revise to produce the multiple nonessential parameter of identical result in essence.One or more checks according to this paper provides find that the compound of embodiment is the inhibitor of BCR Ab1, FLT3, c-Kit, KDR, LCK, Epha2 and PDGFR subfamily.

Embodiment

Embodiment 1

N-(3-(4-cyclopropyl-1H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl)-4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2--amino) benzamide (compound 1)

Step 1.2-bromo-1-cyclopropyl ketenes

To the cooling (ice-water bath) 1-cyclopropyl ketenes (4.20g, dripping bromine in methyl alcohol 50.0mmol) (35mL) solution (7.99g, 2.58mL, 50mmoL).At 0 ℃ mixture is stirred 2h, and at room temperature stirred 30 minutes.Add water (10mL).At room temperature stirred the mixture in addition 15 minutes, and water (50mL) dilution.(3 * 60mL) extraction mixtures are used saturated NaHCO with ether ₃And brine wash.At MgSO ₄The organic layer of last dry mixed filters and concentrates to produce crude product 8.05g (98.8%), and it does not need other purifying and directly is used for step reaction down.

Step 2.4-cyclopropyl-1H-imidazoles

Under 135 ℃, (1.63g is 10.0mmol) with carbonamidine acetate (5.24g, ethylene glycol 50.0mmol) (50mL) mixture heated overnight with 2-bromo-1-cyclopropyl ketenes.After the cooling, water (50mL) diluted mixture thing also extracts several times with ether.At MgSO ₄The organic layer of last dry mixed filters, and concentrates to produce crude product, and it does not need other purifying and directly is used for step reaction down.LCMS：(M+H) ⁺＝109.3。

Step 3.3-(4-cyclopropyl-1H-imidazoles-1-yl)-5-(trifluoromethyl) aniline

In microwave tube, with 3-bromo-5-(trifluoromethyl) aniline (0.48g, 2.0mmol), 4-cyclopropyl-1H-imidazoles (0.26g, 2.4mmol), K ₂CO ₃(0.35g, 2.5mmol), CuI (57mg, 0.30mmol) and oxine (44mg, dry DMSO (2mL) mixture 0.30mmol) are cooled to-78 ℃ and vacuum outgas and use N ₂Replace three times.Under 120 ℃ with the mixture heated overnight.Mixture is cooled to 40 ℃-50 ℃ and add 14% NH ₄The OH aqueous solution.Under 40 ℃-50 ℃, mixture is stirred 1h.After the cooling, the dilute with water mixture is also with ethyl acetate (3 * 15mL) extractions.At MgSO ₄The organic layer of last dry mixed filters and concentrating under reduced pressure.Through the flash chromatography purifying residue (CH of 5%MeOH on silicagel column ₂Cl ₂) to produce crude product (0.41g).LCMS：(M+H) ⁺＝268.3。

Step 4.3-iodo-4-methyl benzoyl chloride

Under refluxing with 3-iodo-4-methyl benzoic acid (1.31g, SOCl 5.0mmol) ₂(5mL) heating 1h.Remove volatile matter under the decompression.Use toluene coevaporation residue and vacuum drying to produce the target chloride, it does not need other purifying and directly is used for step reaction down.

Step 5.N-(3-(4-cyclopropyl-1H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl)-3-iodo-4-methyl benzamide

To 3-(4-cyclopropyl-1H-imidazoles-1-yl)-5-(trifluoromethyl) aniline (26.8mg, 0.10mmol), add 3-iodo-4-methyl benzoyl chloride (28.5mg) in THF (2mL) mixture of diisopropylethylamine (25 μ L), DMAP (3mg).At room temperature mixture is stirred 2h and uses shrend to go out.With ethyl acetate (3 * 2mL) extraction mixtures.At MgSO ₄The organic layer of last dry mixed filters and concentrates to produce crude product, and it does not need other purifying and directly is used for step reaction down.LCMS：(M+H) ⁺＝512.0。

Step 6.4-(pyridin-3-yl) pyrimidine-2-amine

(0.78g, (3.52g is 20.0mmol) and in n-butanol (20mL) mixture of guanidine carbonate (1.80g) 19.5mmol) to be added into 3-(dimethylamino)-1-(pyridin-3-yl) third-2-alkene-1-ketone with NaOH.At 120 ℃ mixture is heated 2h.After the cooling, through the sediment that filter to collect forms and vacuum drying to produce target product (2.3g, 66%).LCMS：(M+H) ⁺＝173.2。

Step 7.N-(3-(4-cyclopropyl-1H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl)-4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2--amino) benzamide

With N-(3-(4-cyclopropyl-1H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl)-3-iodo-4-methyl benzamide (50.0mg), 4-(pyridin-3-yl) pyrimidine-2-amine (34.4.mg), Cs ₂CO ₃(81.5mg), Pd ₂(dba) ₃(5.0mg) and Xantphos (6.0mg) 1,4-diox (0.80mL) and the tert-butyl alcohol (0.40mL) mixture are cooled to-78 ℃ and vacuum outgas and use N ₂Replace repeatedly 3 times.Stir 7h down with the mixture heating that produces and at 110 ℃.After the cooling, with methyl alcohol diluted mixture thing and filtration.Filtrate to produce target product (26mg) through the RP-HPLC purifying.LCMS：(M+H) ⁺＝556.4。 ¹H?NMR(400MHz，CD ₃OD，ppm)：9.19(d，1H)，8.52-8.54(dd，1H)，8.46(m，1H)，8.41(d，1H)，8.36(d，1H)，8.15(s，1H)，8.00(d，2H)，7.63(dd，1H)，7.52(s，1H)，7.44(m，1)，7.35(d，1H)，7.31(d，1H)，7.29(d，1H)，2.33(s，3H)，1.81(m，1H)，0.79(m，2H)，0.67(m，2H)。

Embodiment 2

N-(3-(4-cyclobutyl-1H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl)-4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2--amino) benzamide, compound 9.

10

Use with embodiment 1 described those the similar steps that are used for compound 1 and prepare compound 9 from compound 10,1-cyclobutyl ketenes.Compound 10:LCMS: (M+H) ⁺=570.6. ¹H?NMR(400MHz，CDCl ₃，ppm)：9.34(s，1H)，8.91(s，1H)，8.70(d，1H)，8.66(b，1H)，8.54(d，1H)，8.35(m，2H)，8.07(b，1H)，7.92(s，1H)，7.60(m，1H)，7.40(m，1H)，7.36(m，2H)，7.20(d，1H)，7.13(s，1H)，3.53(m，1H)，2.37(m，2H)，2.28(m，2H)，2.04(m，1H)，1.94(m，1H)。

Embodiment A

Usually use the following method of inspection or use the method for inspection known in the art to check compound of the present invention to suppress ability such as the protein kinase of c-kit, PDGFR β, Ab1, BCR-Ab1, FGFR3, FLT3, Lck, KDR and Epha2 kinases or its mutant form to detect them.

The kinases check

According at " SelectScreen ^TMKinase Profiling Service " revision the 14-SEP-2007 version (Invitrogen Corporation, 501 Charmany Drive, Madison, WI 53719; Www.invitrogen.com/drugdiscovery/) in " SELECTSCREEN of the Invitrogen that describes ^TMASSAY CONDITIONS " described in condition carry out kinases check.

Think IC ₅₀Be that 10 M or lower compound have activity.

Embodiment B

Cell BCR-Ab1 dependence inhibition of proliferation

The mouse cell line that uses for what use BCR-Ab1 cDNA (32D-p210) conversion with the 32D HPC is.In the RPMI/10% hyclone (RPMI/FCS) that is supplemented with penicillin 50 μ g/mL, streptomycin 50 μ g/mL and L-glutaminate 200mM, keep these cells.Keep unconverted 32D cell with similar approach, and add 15% WEHI conditioned medium as the IL3 source.With the density of 15000 cells in every hole 32D or the 32D-p210 cell suspending liquid of 50 μ l placed Greiner384 hole microwell plate.The test compound (the DMSO stoste of 1mM) of the twice serial dilution of 50 μ L is added into each hole (comprising that STI571 is as positive control).At 37 ℃, 5%CO ₂Following incubated cell 72 hours.The MTT (Promega) of 15 μ L is added into each hole and cell was hatched other 5 hours.Optical density under the spectrophotometric standard measure 570nm, and confirm IC from dose-effect curve ₅₀Value.

The influence of pair cell BCR-Ab1 autophosphorylation

With reference to (La Rosse P.Corbin AS, Stoffregen EP, Deininger MW; Druker BJ; Cancer Res 2002,62, description 7149-53) produces, selects and keeps Ba/F3 transfectant (using the point mutation of kinases territory to express total length wild type Bcr-Ab1 or BCR-Ab1).Use the antibody of the special seizure of c-ab1 and the quantitative BCR-Ab1 autophosphorylation of Elisa that anti-phosphotyrosine antibody utilization is caught.In 50 μ L medium, with 2 * 10 ⁵The form in the every hole of cell places 96 hole TC plates with the 32D-p210 cell.Test compound (C with 50 μ L twice serial dilutions _MaximumBe 10 μ M) be added into each hole.At 37 ℃, 5% CO ₂Down cell was hatched 90 minutes.Then, the lysis buffer (Tris-HCl of 50mM, pH are 7.4, the NaCl of 150mM, the EDTA of 5mM, the EGTA of 1mM and 1% NP-40) that uses 150 μ L to comprise protease and inhibitors of phosphatases was handled cell 1 hour on ice.The cell pyrolysis liquid of 50 μ L is added among the 96-hole optiplates that applies and seal with anti--ab1 specific antibody in advance.Under 4 ℃, plate was hatched 4 hours.Use after the washing of TBS-polysorbas20 buffer solution, add anti-phosphotyrosine antibody that the alkaline phosphatase of 50 μ L combines and under 4 ℃ with the further incubated overnight of plate.Use after the washing of TBS-polysorbas20 buffer solution, add the luminous substrate of 90 μ L and use Acquest ^TM(Molecular Devices) is quantitatively luminous in system.The test compound of the present invention that suppresses BCR-Ab1 express cell propagation suppresses cell BCR-Ab1 autophosphorylation with the dose dependent mode.

Ba/F3FL FLT3 breeds check

The Ba/F3 mouse pro-B cell-line that the mouse cell line that uses makes up as high expressed total length FLT3.Be supplemented with penicillin 50 μ g/mL, streptomycin 50 μ g/mL and L-glutaminate 200mM and adding these cells of maintenance in RPMI 1640/10% hyclone (RPMI/FBS) of mouse reorganization IL3.16 hours IL3 is hungry for Ba/F3 total length FLT3 cell experience, in 25 μ l medium, with the mode of every hole 5,000 cells it is inserted in the TC plate of 384-hole then, and adds the test compound of 0.06nM to 10 μ M.After adding compound, add FLT3 part or the IL3 that is used for the cytotoxicity contrast with the form of every hole 25 μ l culture fluids with suitable concentration.Then, at 37 ℃, 5% CO ₂Down cell was hatched 48 hours.After incubated cell, the BRIGHT GLO

of 25 μ L (Promega) is added into each hole and use the Analyst GT-light-emitting mode-50000 of RLU form to read plate the time of integration according to the specification of manufacturer.

FGFR3 (cellular assay)

Test the ability of the Ba/F3-TEL-FGFR3 cell proliferation of compound inhibition conversion of the present invention, it is active that this depends on the FGFR3 cell kinase.Contain 800,000 cells/mL in the cultivation Ba/F3-TEL-FGFR3 as many as suspension, use the RPMI 1640 that is supplemented with 10% hyclone as medium.In 50 μ L medium, cell is distributed the plate that gets into the 384-well format with 5000 cells/well.In dimethyl sulfoxide (DMSO) (DMSO), dissolve and dilute compound of the present invention.In DMSO, process ten two serial dilutions in 1: 3 are generally 10mM to 0.05JUM with generation concentration gradient.The compound that uses 50nL to dilute adds cell and in the cell culture couveuse, hatched 48 hours.The AlamarBlue

(TREK Diagnostic Systems) that ultimate density with 10% will be used to monitor the reducing environment that is produced by proliferative cell is added into cell.After in 37 ℃ cell culture couveuse, hatching other four hours; On Analyst GT (Molecular Devices Corp.), quantitatively come the fluorescence signal (530nm excites, and 580nm excites) of the AlamarBlue

of autoreduction.IC is calculated in the linear regression analysis of the inhibition percentage through each compound under 12 concentration ₅₀Value.

FLT3 and PDGFR β (cellular assay)

Except that using Ba/F3-FLT3-ITD to replace the employed Ba/F3-TEL-FGFR3, use the method identical to carry out the influence of The compounds of this invention to the FLT3 cytoactive with the above-mentioned FGFR3 of being used for cytoactive.

The check of C-kit propagation

With in triplicate in the 96-orifice plate with the every hole making sheet of 5 * 104 cells before, twice of cell washing and use or do not use hemopoieticgrowth factor (HGF) to stimulate in PBS.After cultivating 2 days, interpolation 37Bq (1.78Tbq/mmol) [ ³H] (Amersham Life Science, UK), the time is 6 hours to thymidine.Harvesting and through glass fiber filter filter and in scintillation counter, detect [ ³H] the thymidine adding.

For propagation check, in DMSO with all medicines of prepare of 20mM stoste and-80 ℃ of following preservations.Before each experiment, carry out the fresh dilution among the PBS.Begin to add the DMSO dissolved drug what cultivate.Use corresponding D MSO dilution to carry out contrast culture.Be regarded as 100% form ecbatic through the propagation that will not contain inhibitor with percentage.Obtain cell Ba/F3 mouse kit and people's kit, Ba/F3mkit Δ 27 (nearly film disappearance (juxtamembrane deletion)) and hkitD816V from mouse IL-3 dependence Ba/F3proB lymphocyte.FMA3 and P815 cell-line are the mast cell oncocyte of the endogenous mutant form of expression kit, the i.e. disappearance of frame (frame) in the nearly film of the mouse code area of acceptor-codon 573 to 579.Human leukemia MC is that HMC-I has expressed two point mutant (being mutant JM-V560G and kinases territory mutant kitD816V), yet HMCl subclone α 155 has only expressed mutant JM-V560G.

Immune precipitation check and western blot analysis

For each check, remove to use the rmKL irritation cell of 250ng/ml, have according to description cracking such as (Beslu people, 1996) multiple c-kit mutant 5.106Ba/F3 cell and Ba/F3-source cell and carry out immunoprecipitation.The rabbit immune serum that uses target to have the kit cytoplasm zone of anti-mouse kit people such as (, 1991) Rottapel or anti-human kit (Santa Cruz) comes the immunoprecipitation cell pyrolysis liquid.With the anti-phosphotyrosine antibody of 4G10 (UBI) or with the suitable anti-kit of rabbit immune serum or with different antibody (describing in the antibody paragraph) the hybridization immunity marking.The goat anti-rabbit igg antibody (Immunotech) that uses the goat anti-mouse IgG antibody of HRP-combination then or use HRP-to combine is hatched said film, then through with hatching of ECL reagent (Amersham) protein of interest matter being manifested.

Know that from aforementioned description those the multiple modification of the present invention except that this paper describes will be apparent to those skilled in the art.Such modification also is intended to fall in the scope of additional claim.Each list of references of quoting in this application comprises that all patents, patent application and publication all are incorporated herein with the form of using with its integral body.

List the biologically active of embodiment below:

Embodiment 1:

Enzyme suppresses IC50:nM.

BCR?Able：＜12nM

cKit：＜12nM

EPHA2：＜12nM

LCK：709nM

PDGFRβ：66nM

Embodiment 2:

BCR?Able：＜12nM

cKit：＜12nM

EPHA2：＜12nM

LCK：1882nM

PDGFRβ：25nM

Claims

The present invention especially provide have a general formula I be the compound of inhibitors of kinases or the acceptable salt of its medicine or its prodrug, said kinases is such as but not limited to BCR Ab1, FLT3, c-Kit, KDR, LCK, Epha2 and PDGFR subfamily:

Wherein:

X is N or CR ²

R ¹For H or separately randomly by substituted aryl of 1,2,3,4 or 5-W-X-Y-Z or heteroaryl;

R2, R3 and R7 are H, cyclic hydrocarbon radical, aryl, heterocycle alkyl, heteroaryl, halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Haloalkyl, CN, NO ₂, OR ^A, SR ^A, C (O) R ^B, C (O) NR ^CR ^D, C (O) OR ^A, OC (O) R ^B, OC (O) NR ^CR ^D, NR ^CR ^D, NR ^CC (O) R ^B, NR ^CC (O) NR ^CR ^D, NR ^CC (O) OR ^A, S (O) R ^B, S (O) NR ^CR ^D, S (O) ₂R ^B, NR ^CS (O) ₂R ^BAnd S (O) ₂NR ^CR ^DWherein said cyclic hydrocarbon radical, aryl, heterocycle alkyl, heteroaryl or C _1-6Alkyl is optional to be replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Haloalkyl, halogenosulfanes base, CN, OR ^A1, SR ^A1, C (O) R ^B1, C (O) NR ^C1R ^D1, C (O) OR ^A1, OC (O) R ^B1, OC (O) NR ^C1R ^D1, NR ^C1R ^D1, NR ^C1C (O) R ^B1, NR ^C1C (O) NR ^C1R ^D1, NR ^C1C (O) OR ^A1, C (=NR ^g) NR ^C1R ^D1, NR ^C1C (=NR ^g) NR ^C1R ^D1, S (O) R ^B1, S (O) NR ^C1R ^D1, S (O) ₂R ^B1, NR ^C1S (O) ₂R ^B1And S (O) ₂NR ^C1R ^D1

The B ring is heteroaryl;

L is (CR ⁴R ⁵) _m, (CR ⁴R ⁵) _p-(inferior cyclic hydrocarbon radical)-(CR ⁴R ⁵) _q, (CR ⁴R ⁵) _p-(inferior heterocycle alkyl)-(CR ⁴R ⁵) _q, wherein said inferior cyclic hydrocarbon radical, inferior heterocycle alkyl are chosen wantonly by 1,2 or 3 substituting group and are replaced, and said substituting group is independently selected from halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Haloalkyl, halogenosulfanes base, CN, OR ^a, SR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, C (=NR ^g) NR ^cR ^d, NR ^cC (=NR ^g) NR ^cR ^d, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^bAnd S (O) ₂NR ^cR ^d

C _yFor separately randomly by substituted heterocycle alkyl of 1,2,3,4 or 5-W '-X '-Y '-Z ' or cyclic hydrocarbon radical;

R ⁴And R ⁵Be independently selected from H, halogen, OH, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Alkoxyl, alkoxyalkyl, cyanoalkyl, heterocycle alkyl, cyclic hydrocarbon radical, C _1-6Haloalkyl, CN and NO ₂

Or R ⁴And R ⁵Form 3,4,5,6 or 7 yuan of cyclic hydrocarbon radical or heterocyclic hydrocarbon basic ring with the atom that links to each other with them, said cyclic hydrocarbon radical or said heterocyclic hydrocarbon basic ring are randomly replaced by 1,2 or 3 substituting group separately, and said substituting group is independently selected from halogen, OH, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Alkoxyl, alkoxyalkyl, cyanoalkyl, heterocycle alkyl, cyclic hydrocarbon radical, C _1-6Haloalkyl, CN and NO ₂

R ⁸Be H, C _1-6Alkyl, C _2-6Thiazolinyl or C _2-6Alkynyl, wherein said C _1-6Alkyl, C _2-6Thiazolinyl and C _2-6Alkynyl is optional to be replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from halogen, (CR ⁴R ⁵) _p-(inferior cyclic hydrocarbon radical)-(CR ⁴R ⁵) _q, (CR ⁴R ⁵) _p-(arlydene)-(CR ⁴R ⁵) _q, CN, OR ^a, SR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a

W and W ' do not exist independently or are independently selected from C _1-6Alkylidene, C _2-6Alkenylene, C _2-6Alkynylene, O, S, NR ^h, CO, COO, CONR ^h, SO, SO ₂, SONR ^hAnd NR ^hCONR ⁱ, C wherein _1-6Alkylidene, C _2-6Alkenylene and C _2-6Alkynylene is randomly replaced by 1,2 or 3 substituting group separately, and said substituting group is independently selected from halogen, C _1-6Alkyl, C _1-6Haloalkyl, OH, C _1-6Alkoxyl, C _1-6Halogenated alkoxy, amino, C _1-6Alkyl amino and C _2-8Dialkyl amido;

X and X ' do not exist independently or are independently selected from C _1-6Alkylidene, C _2-6Alkenylene, C _2-6Alkynylene, arlydene, inferior cyclic hydrocarbon radical, inferior heteroaryl and inferior heterocycle alkyl, wherein C _1-6Alkylidene, C _2-6Alkenylene, C _2-6Alkynylene, arlydene, inferior cyclic hydrocarbon radical, inferior heteroaryl and inferior heterocycle alkyl are randomly replaced by 1,2 or 3 substituting group separately, and said substituting group is independently selected from halogen, CN, NO ₂, OH, C _1-6Alkyl, C _1-6Haloalkyl, C _2-8Alkoxyalkyl, C _1-6Alkoxyl, C _1-6Halogenated alkoxy, C _2-8Alkoxyl alkoxyl, cyclic hydrocarbon radical, heterocycle alkyl, C (O) OR ^j, C (O) NR ^hR ⁱ, amino, C _1-6Alkyl amino and C _2-8Dialkyl amido;

Y and Y ' do not exist independently or are independently selected from C _1-6Alkylidene, C _2-6Alkenylene, C _2-6Alkynylene, O, S, NR ^h, CO, COO, CONR ^h, SO, SO ₂, SONR ^hAnd NR ^hCONR ⁱ, C wherein _1-6Alkylidene, C _2-6Alkenylene and C _2-6Alkynylene is randomly replaced by 1,2 or 3 substituting group separately, and said substituting group is independently selected from halogen, C _1-6Alkyl, C _1-6Haloalkyl, OH, C _1-6Alkoxyl, C _1-6Halogenated alkoxy, amino, C _1-6Alkyl amino and C _2-8Dialkyl amido;

Z and Z ' are independently selected from H, halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Haloalkyl, halogenosulfanes base, CN, NO ₂, N ₃, OR ^A2, SR ^A2, C (O) R ^B2, C (O) NR ^C2R ^D2, C (O) OR ^A2, OC (O) R ^B2, OC (O) NR ^C2R ^D2, NR ^C2R ^D2, NR ^C2C (O) R ^B2, NR ^C2C (O) NR ^C2R ^D2, NR ^C2C (O) OR ^A2, C (=NR ^g) NR ^C2R ^D2, NR ^C2C (=NR ^g) NR ^C2R ^D2, S (O) R ^B2, S (O) NR ^C2R ^D2, S (O) ₂R ^B2, NR ^C2S (O) ₂R ^B2, S (O) ₂NR ^C2R ^D2, aryl, cyclic hydrocarbon radical, heteroaryl and heterocycle alkyl, wherein said C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cyclic hydrocarbon radical, heteroaryl and heterocycle alkyl are randomly replaced by 1,2,3,4 or 5 substituting group, and said substituting group is independently selected from halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Haloalkyl, halogenosulfanes base, CN, NO ₂, N ₃, OR ^A2, SR ^A2, C (O) R ^B2, C (O) NR ^C2R ^D2, C (O) OR ^A2, OC (O) R ^B2, OC (O) NR ^C2R ^D2, NR ^C2R ^D2, NR ^C2C (O) R ^B2, NR ^C2C (O) NR ^C2R ^D2, NR ^C2C (O) OR ^A2, C (=NR ^g) NR ^C2R ^D2, NR ^C2C (=NR ^g) NR ^C2R ^D2, S (O) R ^B2, S (O) NR ^C2R ^D2, S (O) ₂R ^B2, NR ^C2S (O) ₂R ^B2And S (O) ₂NR ^C2R ^D2

Wherein two adjacent-W-X-Y-Z and the optional 4-20 unit heterocyclic hydrocarbon basic ring that forms the 4-20 unit's cyclic hydrocarbon basic ring that condenses or condense of the atom that links to each other with them; Said cyclic hydrocarbon basic ring and said heterocyclic hydrocarbon basic ring are randomly replaced by 1,2 or 3 substituting group separately, and said substituting group is independently selected from halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Haloalkyl, halogenosulfanes base, CN, NO ₂, OR ^A3, SR ^A3, C (O) R ^B3, C (O) NR ^C3R ^D3, C (O) OR ^A3, OC (O) R ^B3, OC (O) NR ^C3R ^D3, NR ^C3R ^D3, NR ^C3C (O) R ^B3, NR ^C3C (O) NR ^C3R ^D3, NR ^C3C (O) OR ^A3, C (=NR ^g) NR ^C3R ^D3, NR ^C3C (=NR ^g) NR ^C3R ^D3, S (O) R ^B3, S (O) NR ^C3R ^D3, S (O) ₂R ^B3, NR ^C3S (O) ₂R ^B3, S (O) ₂NR ^C3R ^D3, aryl, cyclic hydrocarbon radical, heteroaryl and heterocycle alkyl;

Two 4-20 unit heterocyclic hydrocarbon basic rings that adjacent-W '-X '-Y '-Z ' randomly forms the 4-20 unit's cyclic hydrocarbon basic ring that condenses or condenses with the atom that links to each other with them wherein; Said cyclic hydrocarbon basic ring and said heterocyclic hydrocarbon basic ring are randomly replaced by 1,2 or 3 substituting group separately, and said substituting group is independently selected from halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Haloalkyl, halogenosulfanes base, CN, NO ₂, OR ^A3, SR ^A3, C (O) R ^B3, C (O) NR ^C3R ^D3, C (O) OR ^A3, OC (O) R ^B3, OC (O) NR ^C3R ^D3, NR ^C3R ^D3, NR ^C3C (O) R ^B3, NR ^C3C (O) NR ^C3R ^D3, NR ^C3C (O) OR ^A3, C (=NR ^g) NR ^C3R ^D3, NR ^C3C (=NR ^g) NR ^C3R ^D3, S (O) R ^B3, S (O) NR ^C3R ^D3, S (O) ₂R ^B3, NR ^C3S (O) ₂R ^B3, S (O) ₂NR ^C3R ^D3, aryl, cyclic hydrocarbon radical, heteroaryl and heterocycle alkyl;

R ^ABe H, C _1-4Alkyl, C _2-4Thiazolinyl, C _2-4Alkynyl, cyclic hydrocarbon radical, heterocycle alkyl, aryl or heteroaryl, wherein said C _1-4Alkyl, C _2-4Thiazolinyl, C _2-4Alkynyl, cyclic hydrocarbon radical, heterocycle alkyl, aryl or heteroaryl are randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from OH, CN, amino, halogen and C _1-4Alkyl;

R ^BBe H, C _1-4Alkyl, C _2-4Thiazolinyl, C _2-4Alkynyl, cyclic hydrocarbon radical, heterocycle alkyl, aryl or heteroaryl, wherein said C _1-4Alkyl, C _2-4Thiazolinyl or C _2-4Alkynyl, cyclic hydrocarbon radical, heterocycle alkyl, aryl or heteroaryl are randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from OH, CN, amino, halogen and C _1-4Alkyl;

R ^CAnd R ^DBe independently selected from H, C _1-4Alkyl, C _2-4Thiazolinyl or C _2-4Alkynyl, wherein said C _1-4Alkyl, C _2-4Thiazolinyl or C _2-4Alkynyl is randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from OH, CN, amino, halogen and C _1-4Alkyl;

Or R ^CAnd R ^DForm randomly by 1,2 or 3 substituted 4-of substituting group, 5-, 6-or 7 yuan of heterocycle alkyl with the N atom that links to each other with them, said substituting group is independently selected from OH, CN, amino, halogen and C _1-4Alkyl;

R ^a, R ^A1, R ^A2And R ^A3Be independently selected from H, C _1-6Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cyclic hydrocarbon radical, heteroaryl, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl and heterocycle alkyl alkyl, wherein said C _1-6Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cyclic hydrocarbon radical, heteroaryl, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl are randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl and C _1-6Halogenated alkoxy;

R ^b, R ^B1, R ^B2And R ^B3Be independently selected from H, C _1-6Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cyclic hydrocarbon radical, heteroaryl, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl and heterocycle alkyl alkyl, wherein said C _1-6Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cyclic hydrocarbon radical, heteroaryl, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl are randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl and C _1-6Halogenated alkoxy;

R ^cAnd R ^dBe independently selected from H, C _1-10Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, heteroaryl, cyclic hydrocarbon radical, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl, wherein said C _1-10Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, heteroaryl, cyclic hydrocarbon radical, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl are randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl and C _1-6Halogenated alkoxy;

Or R ^cAnd R ^dForm randomly by 1,2 or 3 substituted 4-of substituting group, 5-, 6-or 7 yuan of heterocycle alkyl with the N atom that links to each other with them, said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl and C _1-6Halogenated alkoxy;

R ^C1And R ^D1Be independently selected from H, C _1-10Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, heteroaryl, cyclic hydrocarbon radical, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl, wherein said C _1-10Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, heteroaryl, cyclic hydrocarbon radical, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl are randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl and C _1-6Halogenated alkoxy;

Or R ^C1And R ^D1Form randomly by 1,2 or 3 substituted 4-of substituting group, 5-, 6-or 7 yuan of heterocycle alkyl with the N atom that links to each other with them, said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl and C _1-6Halogenated alkoxy;

R ^C2And R ^D2Be independently selected from H, C _1-10Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, heteroaryl, cyclic hydrocarbon radical, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl, heterocycle alkyl alkyl, aryl rings alkyl, aryl-heterocyclic alkyl, aryl heteroaryl, biaryl, heteroaryl ring alkyl, heteroaryl heterocycle alkyl, heteroaryl aryl and couplet heteroaryl, wherein said C _1-10Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, heteroaryl, cyclic hydrocarbon radical, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl, heterocycle alkyl alkyl, aryl rings alkyl, aryl-heterocyclic alkyl, aryl heteroaryl, biaryl, heteroaryl ring alkyl, heteroaryl heterocycle alkyl, heteroaryl aryl and couplet heteroaryl are randomly replaced by 1,2 or 3 substituting group separately, and said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, hydroxy alkyl, cyanoalkyl, aryl, heteroaryl, alkoxyalkyl and alkoxyl alkoxyl;

Or R ^C2And R ^D2Form randomly by 1,2 or 3 substituted 4-of substituting group, 5-, 6-or 7 yuan of heterocycle alkyl with the N atom that links to each other with them, said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, hydroxy alkyl, cyanoalkyl, aryl, heteroaryl, alkoxyalkyl and alkoxyl alkoxyl;

R ^C3And R ^D3Be independently selected from H, C _1-10Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, heteroaryl, cyclic hydrocarbon radical, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl, wherein said C _1-10Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, heteroaryl, cyclic hydrocarbon radical, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl are randomly replaced by 1,2 or 3 substituting group, and said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl and C _1-6Halogenated alkoxy;

Or R ^C3And R ^D3Form randomly by 1,2 or 3 substituted 4-of substituting group, 5-, 6-or 7 yuan of heterocycle alkyl with the N atom that links to each other with them, said substituting group is independently selected from OH, CN, amino, halogen, C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Haloalkyl and C _1-6Halogenated alkoxy;

R ^gBe H, CN and NO ₂

R ^hAnd R ⁱBe independently selected from H and C _1-6Alkyl;

R ^jBe H, C _1-6Alkyl, C _1-6Haloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cyclic hydrocarbon radical, heteroaryl, heterocycle alkyl, aryl alkyl, heteroaryl alkyl, cyclic hydrocarbon radical alkyl or heterocycle alkyl alkyl;

M is 0,1,2,3,4,5 or 6;

P is 0,1,2,3 or 4;

Q is 0,1,2,3 or 4.
2. compound as claimed in claim 1 or the acceptable salt of its medicine, wherein X is N.
3. compound as claimed in claim 1 or the acceptable salt of its medicine, wherein X is CR ²
4. compound as claimed in claim 1 or the acceptable salt of its medicine, wherein X is CH.
5. compound as claimed in claim 1 or the acceptable salt of its medicine, wherein Cy is for randomly by the substituted cyclic hydrocarbon radical of 1,2,3,4 or 5-W-X-Y-Z.
6. compound as claimed in claim 1 or the acceptable salt of its medicine, wherein R1, R2, R3 are that H and R7 are alkyl, B ring is heteroaryl, and Cy is for randomly by the substituted cyclic hydrocarbon radical of 1,2,3,4 or 5-W-X-Y-Z.
7. compound as claimed in claim 1 or the acceptable salt of its medicine, wherein R1, R2, R3 are that H and R7 are alkyl, L does not exist, B ring for heteroaryl and Cy for randomly by the substituted cyclic hydrocarbon radical of 1,2,3,4 or 5-W-X-Y-Z.
8. compound as claimed in claim 1 or the acceptable salt of its medicine, it has general formula I I:

Wherein Cy is for randomly by the substituted cyclic hydrocarbon radical of 1,2,3,4 or 5-W-X-Y-Z.
9. compound as claimed in claim 1 or the acceptable salt of its medicine, it has general formula III:

Wherein Cy is for randomly by the substituted cyclic hydrocarbon radical of 1,2,3,4 or 5-W-X-Y-Z.
10. compound as claimed in claim 1 or the acceptable salt of its medicine, it has general formula I V:

Wherein Cy is for randomly by halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, CN, OR ^a, SR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^a, C (=NR ^g) NR ^cR ^d, NR ^cC (=NR ^g) NR ^cR ^d, S (O) R ^b, S (O) NR ^cR ^d, S (O) ₂R ^b, NR ^cS (O) ₂R ^bAnd S (O) ₂NR ^cR ^dSubstituted cyclic hydrocarbon radical; Wherein said alkyl can be randomly by halogen, heterocycle alkyl, CN, OR ^a, SR ^a, C (O) R ^b, C (O) NR ^cR ^d, C (O) OR ^a, OC (O) R ^b, OC (O) NR ^cR ^d, NR ^cR ^d, NR ^cC (O) R ^b, NR ^cC (O) NR ^cR ^d, NR ^cC (O) OR ^aReplace.
11. compound as claimed in claim 1, it is selected from:

N-(3-(4-cyclopropyl-1H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl)-4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2--amino) benzamide; Or the acceptable salt of its medicine,

N-(3-(4-cyclobutyl-1H-imidazoles-1-yl)-5-(trifluoromethyl) phenyl)-4-methyl-3-(4-(pyridin-3-yl) pyrimidine-2--amino) benzamide; Or the acceptable salt of its medicine.
12. composition, it comprises the described compound of arbitrary claim or acceptable salt of its medicine and at least a medicine acceptable carrier in the claim 1 to 11.
13. suppress the active method of acceptor or nonreceptor tyrosine kinase, it comprises makes in said kinases and the claim 1 to 11 described compound of arbitrary claim or the acceptable salt of its medicine contact.
14. method as claimed in claim 13, wherein said kinases belong to BCR Ab1, FLT3, c-Kit, KDR, LCK, Epha2 and PDGFR subfamily.
15. method as claimed in claim 13, wherein said kinases are BCR Ab1.
16. the method for BCR Ab1 kinase signal pathway in the inhibition cell, it comprises makes in said cell and the claim 1 to 11 described compound of arbitrary claim or the acceptable salt of its medicine contact.
17. suppress the method for patient tumors growth, it comprises described compound of arbitrary claim or the acceptable salt of its medicine in the claim 1 to 11 that gives said patient treatment effective dose.
18. suppress the method that patient tumors shifts, it comprises described compound of arbitrary claim or the acceptable salt of its medicine in the claim 1 to 11 that gives said patient treatment effective dose.
19. treatment patient method for cancer, it comprises described compound of arbitrary claim or the acceptable salt of its medicine in the claim 1 to 11 that gives said patient treatment effective dose.
20. method as claimed in claim 19, wherein said cancer are carcinoma of urinary bladder, breast cancer, cervical carcinoma, cholangiocarcinoma, colorectal cancer, cancer of the esophagus, cancer of the stomach, head and neck cancer, kidney, liver cancer, lung cancer, nasopharyngeal carcinoma, oophoroma, cancer of pancreas, prostate cancer, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, MFH/ fibrosarcoma, leiomyosarcoma, Kaposi, Huppert's disease, lymphoma, adult T-cell leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, glioblastoma, astrocytoma, melanoma, celiothelioma or the nephroblastoma.