CN104447701B

CN104447701B - Pyrazole derivatives and application thereof

Info

Publication number: CN104447701B
Application number: CN201410471458.5A
Authority: CN
Inventors: 张健存; 刘兵; 张英俊; 聂凛凛; 杨学绮
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2013-09-17
Filing date: 2014-09-16
Publication date: 2019-03-22
Anticipated expiration: 2034-09-16
Also published as: CN104447701A

Abstract

The present invention relates to the substituted pyrazole derivatives and its stereoisomer for inhibiting protein kinase to be overexpressed, geometric isomer, tautomers, nitrogen oxides, solvate, hydrate, metabolite, ester, pharmaceutically acceptable salt or its prodrug, and contain these compounds as the pharmaceutical composition of active constituent and the compound and its pharmaceutical composition to prepare for protecting, the purposes of the drug of processing, treatment or mitigation Patient cells' growth failure disease.

Description

Pyrazole derivatives and application thereof

Invention field

The present invention relates to inhibition or the novel pyrazoles compounds of regulatory protein kinase activity；Such compound is that one kind is controlled The noval chemical compound of the purposes for the treatment of, alleviation or prevention disease related with enzymatic activity or illness or one or more symptom；This hair It is bright that the preparation method of Pharmaceutical composition and new chemical intermediate and such compound containing such compound is also provided.

Background of invention

Protein kinase (PKs) is the di of tyrosine on catalytic proteins, serine and threonine group Enzyme is responsible for controlling a variety of signal transduction processes in the cell.PKs can be divided into two classes: tyrosine protein kinase (PTKs) and Serine-threonine protein kinase enzyme (STKs).The example of kinases in protein kinase family includes Abl1 (v- without limitation Abl Abelson murine leukemia virus oncogene autoploid 1), Akt, Bcr-Abl1, Blk, Brk, Btk, c-Kit, c-Met, c-Src、c-Fms、CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK8、CDK9、CDK10、cRaf1、CSF1R、 CSK、EGFR、EebB2、EebB3、EebB4、Erk、FGFR1、FGFR2、FGFR3、FGFR4、FGFR5、FLT-3、Abl、Flt-5、 Fps、Frk、Jak、KDR、MEK、PDGFR、PIK、PKC、PYK2、Ros、Raf、Ret、Aurora-A、Aurora-B、Aurora- C, Tie, Tie2, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Lck, Lyn, p38, Ros, TRK, Yes and Zap70。

It is reported that many diseases are related with the abnormal cell response that the event that protein kinase mediates causes.These diseases Including autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological disease and neurodegenerative disease, cancer is cardiovascular Disease, allergy and asthma, Alzheimer disease and hormone related condition.

Tyrosine protein kinase (PTKs)

Receptor tyrosine kinases (RTK) are the group iii Asia receptor kinases in tyrosine kinase (PTKs) family, packet Include platelet derived growth factor receptor (pdgf receptor α and β), colony stimulating factor (CSF-1) receptor (CSF-1R, c-Fms), FLT-3, Janus kinases (JAK), Abl (c-Abl) and stem cell factor receptor (c-kit) etc., with various kinds of cell hyperplasia and inflammation Etc. diseases it is related.

Patient with neurotic glue tumor or sarcoma raises with gene magnification or PDGFR level.Suffering from chronic grain list The activation of PDGFR- α is found in the patient of chronic myeloid leukemia (CMML).In the patient with gastroenteric tumor and suffer from primary It has also been found that PDGFR- α gene mutation and small fragment missing in the patient of eosnophilia leukocytosis syndrome.In tumor vessel Middle discovery has PDGFR- β expression, research shows that PDGFR- β is inhibited anti-angiogenic can to regenerate.Research finds most of solid tumor There is PDGFR- β expression in tumor stroma, so that this receptor becomes the potential target spot of antineoplaston.

Tyrosine kinase -3 (FLT-3) is also referred to as human stem cell kinases -1 (STK-1), is platelet growth factor receptor (PDGFR) second member of family, plays an important role in the proliferation and differentiation of candidate stem cell.

In addition, Flt-3 inhibits related with inflammation and autoimmune response.There is item research shows that Flt-3 inhibitor C EP-701 The myelin loss of experimental autoimmune encephalomyelitis (EAE) in multiple sclerosis disease mouse model can be effectively reduced (referring to PNAS, 2005,102,16741-16746, Whartenby etc.).Flt-3 ligand is in langerhans cells hyperblastosis disease disease It is in high level in the serum of people and lupus erythematosus patient, further demonstrates that Flt-3 is functioned in autoimmune disease (referring to J Immunol., 2005,174,3067-3071, Rolland etc.).

The change of Abl gene activity (performance) is relevant with a variety of deficiency disorders, disease and other deleterious conditions.Through what is changed Gene performance may cause disease, deficiency disorder and symptom, the disease comprising inflammation, proliferative, hyper-proliferative and immunity regulatin remedy. Bcr-Abl protein is in the 90% of chronic myelogenous leukemia (CML) all patients and Acute Lymphoblastic Leukemia (ALL) the cytoplasmic tyrosine kinase of constitutive activity present in the 15-30% of adult patient.Many researchs have shown that The activation of bcr-Abl is required for the mosaic type protein carciongenic potency.

Janus kinases (JAK)

Janus kinases (JAK) is cytoplasmic tyrosine kinase, and transducer cell factor signal transduction is from membrane receptor to STAT Transcription factor.Four kinds of JAK family members are described, JAK1, JAK2, JAK3 and TYK2.When cell factor is in conjunction with its receptor, JAK family member autophosphorylation and/or turn phosphorylation each other, subsequent STAT phosphorylation, then migrate in nucleus to adjust Transcription.JAK-STAT intracellular signal transduction is suitable for interferon, most of interleukins and cytokine profiles and interior Secretion factor, such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF, PRL etc..

TYK2 is the potential target spot of Immunoinflammatory Disorders, has passed through people's science of heredity and mouse rejects research confirmation.

JAK family member is related to other illnesss, including bone marrow proliferation sexual dysfunction (referring to MolImmunol., 2007,44 (10), 2497-506, O ' Sullivan etc.), wherein identifying the mutation in JAK2.This shows the inhibition of JAK, particularly JAK2 Agent can be used for treatment bone marrow proliferation sexual dysfunction.In addition, JAK family, particularly JAK1, JAK2 and JAK3, with cancer, particularly Leukaemia such as acute myeloid leukaemia (referring to Mol Immunol., 2007,44 (10), 2497-506, O ' Sullivan etc.) With acute lymphoblastic leukemia or solid tumor such as leiomyosarcoma of uterus (referring to Trends in Biochemical Sciences, 2007,33 (3), 122-131, Constantinescu etc.), prostate cancer is (referring to BritishJournal of Cancer, 2007,97,378-383, Tam etc.) it is related.These the result shows that JAK, particularly JAK1 and/or JAK2 inhibitor It can be also used for treating cancer (leukaemia and solid tumor, such as leiomyosarcoma of uterus, prostate cancer).

In addition, Castleman is sick, Huppert's disease, Pathology of Mesangial Proliferative Glomerulonephritis, psoriasis and Kaposi sarcoma It may be attributed to the hypersecretion of cell factor IL-6, the biological effect of IL-6 is by intracellular JAK-STAT signal transduction (the Arthritis Res, 2002,4 (suppl3), S233-S242, Tetsuji Naka, Norihiro Nishimoto mediated With Tadamitsu Kishimoto).This is the result shows that the inhibitor of discovery JAK can be also used for treating the disease.

Have determined being associated with for JAK3 and Tyk2 and autoimmune disease.JAK3 and stream signal conductive components γ-c by Body chain and being mutated for IL7 receptor add up to the people's severe combined immunodeficiency example for accounting for~70%.Notice JAK1 cooperate with JAK3 from γ-c receptor chain transduction signal.In the systemic loupus erythematosus (SLE) discovery Tyk2 polymorphism (referring to MolImmunol., 2007,44 (10), 2497-506, O ' Sullivan etc.).Therefore, targeting JAK family can provide in immuno-inflammatory field and control Treat chance.

Serine-threonine protein kinase enzyme (CSF-1R)

Serine-threonine protein kinase enzyme (CSF-1R) is macrophage colony irritation factor acceptor (M-CSF, CSF- 1 or fms) it is expressed in many breast cancer, prostate, human epithelium's cancer, ovary, endometrium and leukaemia, this proves CSF- 1R may be the therapy target of leukemia and solid tumor (referring to Blood, 1997,89,2537-2545, Haran-Ghera).

Aurora A

Existing research is it has been verified that handle expression and the function that human tumor cell line eliminates Ou Ruola-A by antisense oligonucleotides Energy (WO1997022702 and WO1999037788) causes the cell cycle to be suppressed, generates antiproliferative in these tumour cells Effect.Furthermore, it has already been proven that the micromolecular inhibitor of Ou Ruola-A and Ou Ruola-B in human tumor cells there is antiproliferative to make With only siRNA processing is alternative eliminates Ou Ruola-B expression.This illustrates to inhibit the function of Ou Ruola-A and Ou Ruola-B will produce Raw antiproliferative effect, this can be used for treating human tumour and other hyperproliferative diseases.In addition, with for cell cycle upstream Signal transduction path is compared, and Ou Ruola (Aurora) kinases is inhibited to have apparent advantage as the treatment method of these diseases. Since the cell cycle conducts movable most downstream in all these unlike signals, so the therapy for the cell cycle will be to all Proliferating tumor cell is effective, and for signal specific transduction molecule such as EGF-R ELISA method will only to express this The tumour cell of a little receptors is effective.

Many kinases inhibitor disclose, and adjust or more particularly inhibit kinase activity, for treating kinases correlation Illness or other obstacles.For example, US6596746 and WO2005096784 disclose the phentriazine as kinase inhibitor； WO200181311 discloses substituted benzoic amide for inhibiting angiogenesis；US6440965 discloses substituted pyrimidine derivatives For treating in neurodegeneration or neurological disorder；WO2002008205 reports that pyrimidine derivatives have neurotrophic activity； WO2003014111 discloses aryl piperazines and Arylpiperidine and their purposes as metal protease inhibitors； WO2003024448 describes inhibitor of the compound as histone deacetylase enzymatic activity；WO2004058776 discloses tool There is the compound of anti-angiogenesis activity.WO2001094341 and WO2002016352 discloses quinazoline derivatives as kinase inhibition Agent.WO2003026666 and WO2003018021 discloses the pyrimidinyl derivatives as kinase inhibitor.US6498165 report is phonetic The kinase inhibitor compounds of acridine compound class.

Abstract of invention

The present invention provides a series of pyrazole compounds and its pharmaceutically acceptable salt as kinases inhibitor Application in the drug of preparation treatment and protein kinase activity related disease.Experimental study proves: pyrazole compound and its Pharmaceutical salts therapeutic treatment and the Aurora A for the protein kinase family for adjusting primary type and/or mutant form, Aurora B, It plays an important role in the kinase activities such as JAK, Abl, FLT-3.

The invention proposes a new class of pyrazole derivatives, it can effectively inhibit or adjust related enzyme activity, and pre- Counting them can be used for preventing or treating the purposes of certain kinase mediated diseases or illness.

The present invention proposes the vertical of pyrazole derivatives shown in one kind pyrazole derivatives as shown in formula (I) or formula (I) Body isomers, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, ester pharmaceutically may be used The salt of receiving or its prodrug,

Wherein:

Each R¹And R^1aIt independently is H or C_1-4Alkyl；

R²For alkyl amino, bridge bicyclic group, the miscellaneous bicyclic group of bridge, condensed-bicyclic base condenses miscellaneous bicyclic group, spiral shell bicyclic group, spiral shell Miscellaneous bicyclic group, aryl, heteroaryl, heterocycle ,-Y¹-R^2aGroup or carbocylic radical；

Wherein, Y¹For a key ,-(CH₂)_n-N(R⁸)-,-N (R⁸)-,-O- ,-O- (CH₂)_nOr-(CH₂)_n-；

R^2aFor H, alkyl-S (=O)₂Alkyl, alkyl, cycloalkyl-alkyl, aryl alkyl, heterocyclylalkyl group, alkyl amino, Bridge bicyclic group, the miscellaneous bicyclic group of bridge, condensed-bicyclic base condense miscellaneous bicyclic group, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, aryl, heteroaryl, Heterocycle or carbocylic radical；

X¹It is CR^4aR⁴Or NR⁶；

X²It is CR^4aOr N；

R³For hydrogen, F, Cl, Br, I, C_1-4Alkoxy, halogenated C_1-4Alkyl or C_1-4Alkyl；

Each R^4aAnd R⁴It independently is H or C_1-4Alkyl；

R⁶For H or C_1-4Alkyl；

Each R⁵It independently is H, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkyl, or-Y²-R⁷Group；

Wherein, each Y²It independently is a key ,-O- ,-C (=S)-,-C (=O)-,-C (=O) O- ,-S (=O)_t,- (CH₂)_n-N(R^8a)-,-N (R^8a)-,-S (=O)_tN(R^8a)-,-N (R^8a) C (=O)-, or-(CH₂)_n-；

Each R⁷It independently is hydrogen, alkyl, alkyl amino, carbocylic radical, condensed-bicyclic base condenses miscellaneous bicyclic group, aryl, heteroaryl Base, alkenyl, alkynyl, halogenated alkyl, bridge bicyclic group, the miscellaneous bicyclic group of bridge, condensed-bicyclic base alkyl condense miscellaneous bicyclic group alkyl, spiral shell Bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell bicyclic group alkyl, the miscellaneous bicyclic group alkyl of spiral shell, naphthenic base, heterocyclylalkyl group, cycloalkyl-alkyl, virtue Base alkyl, heteroaryl alkyl, hydroxy alkyl, alkoxy, (HO- (CH₂)_n)-N(R^8a)-or heterocycle；

Each R^8aAnd R⁸It independently is H or C_1-6Alkyl；

Each t independently is 0,1 or 2；

Each p independently is 1,2,3 or 4；

Each n independently 0,1,2,3 or 4；

Wherein, the alkyl, carbocylic radical, alkenyl, alkynyl, alkyl-S (=O)₂Alkyl, halogenated alkyl, bridge bicyclic group, The miscellaneous bicyclic group of bridge ,-(CH₂)_n,-(CH₂)_n-N(R⁸)-,-(CH₂)_n-N(R^8a)-, heterocycle, alkyl amino, condensed-bicyclic base are thick Close miscellaneous bicyclic group, aryl, heteroaryl, condensed-bicyclic base alkyl condenses miscellaneous bicyclic group alkyl, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell Bicyclic group alkyl, the miscellaneous bicyclic group alkyl of spiral shell, naphthenic base, heterocyclylalkyl group, cycloalkyl-alkyl, aryl alkyl, heteroaryl alkyl, hydroxyl Base alkyl, alkoxy, and (HO- (CH₂)_n)-N(R^8a)-, can be independently by oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyanogen Base, hydroxy alkyl, sulfydryl, nitro, carboxyl, C_1-4Alkoxy, C_1-4Alkyl amino, C_1-4Alkylthio group, C_1-4Alkyl-S (=O)₂, Halogenated C_1-4Alkyl, C_1-4Alkyl, C_2-4Alkenyl or C_2-4Monosubstituted or identical or different polysubstituted of alkynyl.

In some embodiments, R²For C_1-6Alkyl amino, C_5-12Condensed-bicyclic base, C_5-12Condense miscellaneous bicyclic group, C_5-12 Bridge bicyclic group, C_5-12The miscellaneous bicyclic group of bridge, C_5-12Spiral shell bicyclic group, C_5-12The miscellaneous bicyclic group of spiral shell, C_6-10Aryl, C_1-9Heteroaryl, C_2-10Heterocycle Base ,-Y¹-R^2aGroup or C_3-10Carbocylic radical；

Y¹For a key ,-(CH₂)_n-N(R⁸)-,-N (R⁸)-,-O- ,-O- (CH₂)_nOr-(CH₂)_n-；

R^2aFor H, C_1-6Alkyl-S (=O)₂-C_1-6Alkyl, C_1-6Alkyl, C_3-10Naphthenic base C_1-4Alkyl, C_6-10Aryl C_1-6Alkane Base, C_1-6Alkyl amino, C_5-12Condensed-bicyclic base, C_5-12Condense miscellaneous bicyclic group, C_5-12Bridge bicyclic group, C_5-12The miscellaneous bicyclic group of bridge, C_5-12 Spiral shell bicyclic group, C_5-12The miscellaneous bicyclic group of spiral shell, C_6-10Aryl, C_1-9Heteroaryl, C_2-10Heterocycle, C_2-10Heterocycle C_1-6Alkyl or C_3-10 Carbocylic radical；

Each R⁸It independently is H or C_1-6Alkyl；

Wherein, the alkyl, alkyl-S (=O)₂Alkyl, carbocylic radical, heterocycle, alkyl amino, aryl, heteroaryl, Heterocyclylalkyl group, cycloalkyl-alkyl, aryl alkyl, bridge bicyclic group, the miscellaneous bicyclic group of bridge, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell condense double Ring group, and condense miscellaneous bicyclic group, can be independently by oxo (=O), F, Cl, Br, I, cyano, hydroxy alkyl, sulfydryl, nitro, Carboxyl, C_1-4Alkoxy, C_1-4Alkyl amino, C_1-4Alkylthio group, C_1-4Alkyl-S (=O)₂, C_1-4Alkyl, C_2-4Alkenyl or C_2-4Alkynes Monosubstituted or identical or different polysubstituted of base.

Other embodiment is:

R²For C_1-6Alkyl amino, C_5-12Condensed-bicyclic base, C_5-12Condense miscellaneous bicyclic group, C_5-12Bridge bicyclic group, C_5-12Bridge is miscellaneous double Ring group, C_5-12Spiral shell bicyclic group, C_5-12The miscellaneous bicyclic group of spiral shell, C_6-10Aryl, C_1-9Heteroaryl, C_2-10Heterocycle ,-Y¹-R^2aGroup or C_3-10Carbocylic radical；

R^2aFor H, C_1-6Alkyl-S (=O)₂-C_1-6Alkyl, C_1-6Alkyl, C_1-6Alkyl amino, C_3-10Carbocylic radical, or following son Structural formula:

Wherein, each Z¹It independently is N or CH；

Each Z²It independently is N or CH；

Each Z³It independently is-N (R⁸)-, or-CH₂-；

Each E¹It independently is a key ,-O- ,-N (R⁸)-,-SO₂Or-S-；

Each V¹It independently is a key, or-(CH₂)_n-；

Each T independently is-CH₂-(CH₂)_n, or-CH=CH-；

Each T¹And T²It independently is-N (R⁸)-, or-CH₂-；

Each J¹It independently is-O-, or-S-；

Each R⁹It independently is oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, hydroxy alkyl, sulfydryl, nitro, carboxylic Base, C_1-4Alkoxy, C_1-4Alkyl amino, C_1-4Alkylthio group, C_1-4Alkyl-S (=O)₂, C_1-4Alkyl, C_2-4Alkenyl or C_2-4Alkynes Base；

Each j independently is 0,1,2,3 or 4；

Each n independently is 0,1,2,3 or 4.

In other embodiment, R²For following subformula,

According to the present invention, pyrazole derivatives or its stereoisomer shown in formula (I), geometric isomer, tautomerism Body, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug, in which:

Each R⁵It independently is H, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6Alkoxy, halogenated C_1-6Alkyl, or-Y²-R⁷ Group；

Each R⁷It independently is hydrogen, C_1-4Alkyl, C_1-4Alkyl amino, C_3-10Carbocylic radical, C_5-12Condensed-bicyclic base, C_5-12It is condensed Miscellaneous bicyclic group, C_6-10Aryl, C_1-9Heteroaryl, C_2-4Alkenyl, C_2-4Alkynyl, C_5-12Bridge bicyclic group, C_5-12The miscellaneous bicyclic group of bridge, it is halogenated C_1-4Alkyl, C_5-12Condensed-bicyclic base C_1-4Alkyl, C_5-12Condense miscellaneous bicyclic group C_1-4Alkyl, C_5-12Spiral shell bicyclic group, C_5-12Spiral shell is miscellaneous double Ring group, C_5-12Spiral shell bicyclic group C_1-4Alkyl, C_5-12The miscellaneous bicyclic group C of spiral shell_1-4Alkyl, C_3-10Naphthenic base, C_2-10Heterocycle C_1-4Alkyl, C_3-10Naphthenic base C_1-4Alkyl, C_5-12Aryl C_1-4Alkyl, C_5-12Heteroaryl C_1-4Alkyl, hydroxyl C_1-6Alkyl, C_1-4Alkoxy, (HO- (CH₂)_n)-N(R^8a)-or C_2-10Heterocycle；

Each R^8aIt independently is H or C_1-4Alkyl；

Wherein, the alkyl, alkyl amino, carbocylic radical, alkenyl, alkynyl, halogenated alkyl, bridge bicyclic group, bridge are miscellaneous bicyclic Base ,-(CH₂)_n, heterocycle, condensed-bicyclic base condenses miscellaneous bicyclic group, aryl, heteroaryl, and condensed-bicyclic base alkyl condenses miscellaneous double Cyclylalkyl, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell bicyclic group alkyl, the miscellaneous bicyclic group alkyl of spiral shell, naphthenic base, heterocyclylalkyl group, ring Alkyl-alkyl, aryl alkyl, heteroaryl alkyl, hydroxy alkyl, alkoxy, (HO- (CH₂)_n)-N(R^8a)-, and-(CH₂)_n-N (R^8a)-, can be independently by oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, hydroxy alkyl, sulfydryl, nitro, carboxyl, C_1-4Alkoxy, C_1-4Alkyl amino, C_1-4Alkylthio group, C_1-4Alkyl-S (=O)₂, C_1-4Alkyl, C_2-4Alkenyl or C_2-4Alkynyl list Replace or identical or different polysubstituted.

In some embodiments, each R⁵It independently is-Y²-R⁷Group；

Wherein, each Y²It independently is a key ,-O- ,-(CH₂)_n-N(R^8a)-, or-(CH₂)_n-；

Each R⁷It independently is hydrogen, C_1-4Alkyl, C_1-4Alkyl amino, hydroxyl C_1-4Alkyl, C_1-4Alkoxy, C_3-10Carbocylic radical, C_6-12Aryl, C_1-9Heteroaryl, C_3-10Naphthenic base, (HO- (CH₂)_n)-N(R^8a)-or C_2-10Heterocycle；Or following subformula:

Wherein, each Q, Q¹, Q²And Q³It independently is N or CH；

Each W and W¹It independently is-CH₂,-O- ,-N (R^8a)-or-S-；

Each R^8aIt independently is H, methyl or ethyl；

Each q independently is 0,1,2,3 or 4；

Each n independently is 0,1,2,3 or 4；

Each m independently is 0,1,2,3 or 4.

In other embodiments, each R⁷It independently is following subformula:

According to pyrazole derivatives of the present invention, have as described in structural formula or the formula (II) as described in formula (II) The stereoisomer of compound, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, Ester, pharmaceutically acceptable salt or its prodrug,

Wherein:

Y¹For a key ,-(CH₂)_n-N(R⁸)-,-N (R⁸)-,-O- ,-O- (CH₂)_nOr-(CH₂)_n-；

R^2aFor H, C_1-6Alkyl, C_1-4Alkyl-S (=O)₂-C_1-4Alkyl, C_5-12Condensed-bicyclic base, C_5-12Miscellaneous bicyclic group is condensed, C_5-12Bridge bicyclic group, C_5-12The miscellaneous bicyclic group of bridge, C_5-12Spiral shell bicyclic group, C_5-12The miscellaneous bicyclic group of spiral shell, C_6-10Aryl, C_1-4Alkyl amino, C_1-9Heteroaryl, C_3-10Naphthenic base C_1-4Alkyl, C_6-10Aryl C_1-6Alkyl, C_2-10Heterocycle C_1-6Alkyl, C_2-10Heterocycle, or C_3-10Carbocylic radical；

Wherein, Y²For a key ,-O- ,-(CH₂)_n-N(R^8a)-, or-(CH₂)_n-；

R⁷For hydrogen, C_1-4Alkyl, C_1-4Alkyl amino, hydroxyl C_1-4Alkyl, C_1-4Alkoxy, C_3-10Carbocylic radical, C_5-12It is condensed double Ring group, C_5-12Condense miscellaneous bicyclic group, C_5-10Aryl, C_1-9Heteroaryl, C_5-12Bridge bicyclic group, C_5-12The miscellaneous bicyclic group of bridge, C_5-12Spiral shell is bicyclic Base, C_5-12The miscellaneous bicyclic group of spiral shell, C_3-10Naphthenic base, (HO- (CH₂)_n)-N(R^8a)-or C_2-10Heterocycle；

Each R⁸It independently is hydrogen or C_1-6Alkyl；

Each R^8aIt independently is hydrogen or C_1-4Alkyl；

Each n independently is 0,1,2,3 or 4；

Wherein, the alkyl, carbocylic radical, alkenyl, alkynyl, halogenated alkyl, alkyl-S (=O)₂Alkyl, bridge bicyclic group, The miscellaneous bicyclic group of bridge ,-(CH₂)_n,-(CH₂)_n-N(R⁸)-,-(CH₂)_n-N(R^8a)-, heterocycle, alkyl amino, condensed-bicyclic base are thick Close miscellaneous bicyclic group, aryl, heteroaryl, condensed-bicyclic base alkyl condenses miscellaneous bicyclic group alkyl, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell Bicyclic group alkyl, the miscellaneous bicyclic group alkyl of spiral shell, naphthenic base, heterocyclylalkyl group, cycloalkyl-alkyl, aryl alkyl, heteroaryl alkyl, hydroxyl Base alkyl, alkoxy, and (HO- (CH₂)_n)-N(R^8a)-, can be independently by oxo (=O), hydroxyl, amino, F, Cl, Br, I, Cyano, hydroxy alkyl, sulfydryl, nitro, carboxyl, C_1-4Alkoxy, C_1-4Alkyl amino, C_1-4Alkylthio group, C_1-4Alkyl-S (=O)₂, C_1-4Alkyl, C_2-4Alkenyl or C_2-4Monosubstituted or identical or different polysubstituted of alkynyl.

In other embodiment, R²For C_1-6Alkyl amino, C_5-12Condensed-bicyclic base, C_5-12Miscellaneous bicyclic group is condensed, C_6-10Aryl, C_1-9Heteroaryl, C_2-10Heterocycle ,-Y¹-R^2aGroup or C_3-10Carbocylic radical；

Wherein, each Z¹It independently is N or CH；

Each Z²It independently is N or CH；

Each Z³It independently is-N (R⁸)-, or-CH₂-；

Each E¹It independently is a key ,-O- ,-N (R⁸)-,-SO₂Or-S-；

Each V¹It independently is a key, or-(CH₂)_n-；

Each T independently is-CH₂-(CH₂)_n, or-CH=CH-；

Each T¹And T²It independently is-N (R⁸)-, or-CH₂-；

Each J¹It independently is-O-, or-S-；

Each R⁹It independently is oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, hydroxy alkyl, sulfydryl, nitro, carboxylic Base, C_1-4Alkane

Oxygroup, C_1-4Alkyl amino, C_1-4Alkylthio group, C_1-4Alkyl-S (=O)₂, C_1-4Alkyl, C_2-4Alkenyl or C_2-4Alkynes Base；

Each j independently is 0,1,2,3 or 4；

Each n independently is 0,1,2,3 or 4.

In other embodiment, R²For following subformula,

Compound according to the present invention, in some embodiments, R⁷For hydrogen, C_1-4Alkyl, C_1-4Alkylamino, C_1-4 Alkenyl, C_1-4Alkynyl, halogenated C_1-4Alkyl, hydroxyl C_1-4Alkyl, C_1-4Alkoxy, C_3-10Carbocylic radical, C_3-10Naphthenic base, C_2-10Heterocycle Base, C_6-10Aryl, C_1-9Heteroaryl, (HO- (CH₂)_n)-N(R^8a)-or following subformula:

Wherein, each Q, Q¹, Q²And Q³It independently is N or CH；

Each W and W¹It independently is-CH₂,-O- ,-N (R^8a)-or-S-；

Each R^8aIt independently is hydrogen or C_1-4Alkyl；

Each q independently is 0,1,2,3 or 4；

Each n independently is 0,1,2,3 or 4；

Each m independently is 0,1,2,3 or 4.

In other embodiments, R⁷For following subformula:

On the one hand, the present invention contains simultaneously comprising a kind of pharmaceutical composition, includes a kind of pyrazoles as shown in formula (I) or (II) Analog derivative or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, solvate, hydrate, metabolism produce Object, ester, pharmaceutically acceptable salt or its prodrug.

In some embodiments, pharmaceutical composition of the present invention further includes pharmaceutically acceptable carrier, assigns Shape agent, diluent, at least one of adjuvant and medium.

In some embodiments, present invention simultaneously provides one kind pyrazole derivatives as shown in formula (I) or (II) or Its stereoisomer, geometric isomer, tautomer, nitrogen oxides, solvate, hydrate, metabolite, ester, pharmacy Upper acceptable salt or its prodrug, and the pharmaceutical composition comprising the above compound, wherein further being controlled comprising additional Agent is treated, these additional therapeutic agents are chemotherapeutic agent, antiproliferative, immunosuppressor, immunostimulant, for treating artery The drug of atherosis, for treating the drug or their combination of pulmonary fibrosis.

In some embodiments, the additional therapeutic agent referred in pharmaceutical composition of the present invention is Chlorambucil (chlorambucil), melphalan (melphalan), cyclophosphamide (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busulfan), Carmustine (carmustine), lomustine (lomustine), chain urea assistant Rhzomorph (streptozocin), cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin) reach Carbazine (dacarbazine), Temozolomide (temozolomide), procarbazine (procarbazine), methotrexate (MTX) (methotrexate), fluorouracil (fluorouracil), cytarabine (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vincaleukoblastinum (vinblastine), vincristine (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), topotecan (topotecan), Irinotecan (irinotecan), Etoposide (etoposide), tributidine (trabectedin), dactinomycin D (dactinomycin), Doxorubicin (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), mitomycin C (mitomycin), Ipsapirone (ixabepilone), tamoxifen (tamoxifen), Flutamide (flutamide), Gonadorelin analog (gonadorelin analogues), megestrol acetate (megestrol), prednisone (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Thalidomide (thalidomide), interferon-' alpha ' (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Afatinib (afatinib), alisertib, amuvatinib, A Pa replaces Buddhist nun (apatinib), Axitinib (axitinib), bortezomib (bortezomib), posupini (bosutinib), brivanib, cabozantinib, Si Dinibu (cediranib), crenolanib, gram Zhuo replace Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib angstrom gram are replaced Buddhist nun (icotinib), Imatinib (imatinib), iniparib, Lapatinib (lapatinib), lenvatinib, Linifanib, linsitinib, Masitinib (masitinib), momelotinib come that not for husky Buddhist nun (motesanib) For Buddhist nun (neratinib), nilotinib (nilotinib), niraparib, oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, Rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Sorafenib (sorafenib) relax Buddhist nun replaces Buddhist nun (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, Trametinib, Vande Thani (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, Volasertib, alemtuzumab (alemtuzumab), bevacizumab (bevacizumab), brentuximab vedotin, card Appropriate rope monoclonal antibody (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), difficult to understand (ofatumumab), Victibix (panitumumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab) or their combination.

On the other hand, the present invention provides a kind of pyrazole derivatives as shown in formula (I) or (II) or its stereoisomer, Geometric isomer, tautomer, nitrogen oxides, solvate, hydrate, metabolite, ester, pharmaceutically acceptable salt or Its prodrug, and the pharmaceutical composition comprising the above compound can be used as cell caused by inhibiting protein kinase to be overexpressed The purposes of the drug of growth failure disease.

In some embodiments, the present invention provides a kind of pyrazole derivatives as shown in formula (I) or (II) or its solid Isomers, geometric isomer, tautomer, nitrogen oxides, solvate, hydrate, metabolite, ester can pharmaceutically connect The salt or its prodrug received, and the pharmaceutical composition comprising the above compound can be used as and protein kinase overexpression inhibited to draw The purposes of the drug of the cell growth abnormity disease risen.Wherein the protein kinase be Abl, FLT-3, Jak, Aurora-A, Or Aurora-B.

In some embodiments, the present invention provides a kind of pyrazole derivatives as shown in formula (I) or (II) or its solid Isomers, geometric isomer, tautomer, nitrogen oxides, solvate, hydrate, metabolite, ester can pharmaceutically connect The salt or its prodrug received, and the pharmaceutical composition comprising the above compound can be used as and protein kinase overexpression inhibited to draw The purposes of the drug of the cell growth abnormity disease risen.Wherein the cell growth abnormity disease is mainly proliferative diseases.

Wherein, compound provided by the present invention and pharmaceutical composition can be used as protection, processing, treatment or mitigate patient's increasing The purposes of the drug of value property disease, the proliferative diseases refer to acute myelocytic leukemia (AML), the chronic marrow of mutation Property leukaemia (CML), acute lymphoblastic leukemia (ALL), colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate Cancer, cancer of pancreas, thyroid cancer, kidney, brain tumor, neck cancer, the cancer of CNS (central nervous system), glioblastoma, myelosis Disease, atherosclerosis, pulmonary fibrosis, leukaemia, lymph cancer, rheumatic disease, chronic inflammation, cryoglobulinemia, non-leaching Bar network tumour, papular mucinosis, familial splenic anemia, Huppert's disease, amyloidosis, isolatism Plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinaemia, half point Sub- disease, monocytic leukemia, primary macroglobulinaemia purpura, secondary benign monoclonal gammopathy, bone resorption Venereal disease becomes, lymphoblastoma, non-Hodgkin lymphoma, Sezary syndrome, infectious mononucleosis, acute organ Cytosis, Hodgkin lymphoma, hairy cell leukemia, colon cancer, the carcinoma of the rectum, polyposis intestinalis, diverticulitis, colitis, pancreas Adenositis, hepatitis, Small Cell Lung Cancer, neuroblastoma, neuroendocrine cell tumour, islet-cell tumour, medullary carcinoma of thyroid gland, Melanoma, retinoblastoma, uterine cancer, chronic hepatitis, cirrhosis, oophoroma, cholecystitis, G. cephalantha, digestion Road malignant tumour, non-small cell lung cancer, cervical carcinoma, orchioncus, bladder cancer or myeloma.

On the one hand, the present invention provides a kind of pyrazole derivatives as shown in formula (I) or (II) or its stereoisomer, several What isomers, tautomer, nitrogen oxides, solvate, hydrate, metabolite, ester, pharmaceutically acceptable salt or it Prodrug, and the pharmaceutical composition comprising the above compound, to prepare for inhibiting in biological sample or regulatory protein swashs The purposes of the drug of enzymatic activity, wherein the purposes include use pyrazole derivatives as shown in formula (I) or (II) or its Stereoisomer, geometric isomer, tautomer, nitrogen oxides, solvate, hydrate, metabolite, ester, pharmaceutically Acceptable salt or its prodrug, and the pharmaceutical composition comprising the above compound, contact with the biological sample.

In some of embodiments, these compounds can be used as the inhibitor of protein kinase, and the protein kinase referred to is Tyrosine protein kinase or serine-threonine protein kinase enzyme.

In some embodiments, these compounds can be used as the inhibitor of tyrosine protein kinase, the tyrosine egg referred to White kinases is FLT-3, Abl, Jak or their combination.

In some embodiments, these compounds can be used as the inhibitor of serine-threonine protein kinase enzyme, the silk referred to Propylhomoserin-Serineprotein kinase is Aurora-A, Aurora-B or their combination.

On the other hand, the present invention provides a kind of pyrazole derivatives as shown in formula (I) or (II) or its stereoisomer, Geometric isomer, tautomer, nitrogen oxides, solvate, hydrate, metabolite, ester, pharmaceutically acceptable salt or Its prodrug, and the pharmaceutical composition comprising the above compound increase to prepare for protecting, handling, treat or mitigating patient The purposes of the drug of growing property disease.

Drug containing the compounds of this invention has the purposes for treating proliferative diseases, especially acute myelocytic Leukaemia (AML), mutation chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), colorectal cancer, gastric cancer, Breast cancer, lung cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid cancer, kidney, brain tumor, neck cancer, CNS (central nervous system) It is cancer, glioblastoma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukaemia, lymph cancer, rheumatic disease, slow It is property inflammation, cryoglobulinemia, non-lymphoreticular system tumour, papular mucinosis, familial splenic anemia, multiple Property myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, It is primary macroglobulinaemia, half molecule disease, monocytic leukemia, primary macroglobulinaemia purpura, secondary benign Monoclonal gamma globulin disease, osteolytic lesion, lymphoblastoma, non-Hodgkin lymphoma, Sezary syndrome, infectiousness Monocytosis,mononucleosis, acute histocytic increase disease, Hodgkin lymphoma, hairy cell leukemia, colon and rectum carcinoma, intestines Road polyp, diverticulitis, colitis, pancreatitis, hepatitis, Small Cell Lung Cancer, neuroblastoma, neuroendocrine cell tumour, Islet-cell tumour, medullary carcinoma of thyroid gland, melanoma, retinoblastoma, uterine cancer, chronic hepatitis, cirrhosis, ovary Cancer, cholecystitis, G. cephalantha, malignant tumor of digestive tract, non-small cell lung cancer, cervical carcinoma, orchioncus, bladder cancer or marrow Tumor.

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects and other aspect Content will make more specific complete description below.

Detailed description of the invention book

Definition and general terms

The present invention will list in detail document corresponding to the content determining materialization, and embodiment is all accompanied by structure The diagram of formula and chemical formula.The present invention, which has, expectedly covers all choices, variant and coordinate, these may be as right Existing invention field is included in defined in it is required that like that.Those skilled in the art will identify it is many similar or equivalent to This described method and substance, these can be applied to the practice of the present invention.The present invention is limited to absolutely not method and substance Description.There are many documents and similar substance to distinguish or contradict with the present patent application including but not limited to term Definition, the usage of term, the technology of description, or the range controlled as the present patent application.

The present invention will be using defined below unless other aspects show.Purpose according to the present invention, chemical element is according to member Plain periodic table, CAS version and chemicals handbook, 75,^thEd, 1994 define.In addition, organic chemistry General Principle is shown in " Organic Chemistry,"Thomas Sorrell,University Science Books,Sausalito:1999, and"March's Advanced Organic Chemistry,"by Michael B.Smith and Jerry March, John Wiley&Sons, New York:2007, therefore all contents have all merged bibliography.

As described in the invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can be used interchangeably " optionally replacing " this term with " substituted or non-substituted ".In general, art Language " optionally " whether it is before the term " replaced ", indicates that one or more hydrogen atoms in given structure are specific Replaced substituent group.Unless otherwise indicated, an optional substituent group can have a substituent group group is each can Substituted position is replaced.When more than one position can be selected from the one or more of specific group in given structural formula Replaced substituent group, then substituent group can replace at various locations identical or differently.Wherein the substituent group can be, But it is not limited to: hydrogen, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxyl, alkyl, alkyl-S (=O)₂, alkyl halide Base, hydroxy alkyl, alkoxy, alkylamino, alkylthio group, halogenated alkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocycle Base, sulfydryl, nitro, aryloxy group, hydroxy alkoxy base or alkoxyalkyl etc..

Terminology used in the present invention " halogen ", " halogen atom " or " halogen atom " include fluorine, chlorine, bromine, iodine.

Terminology used in the present invention " alkyl " includes the univalence hydrocarbyl of 1-20 carbon atom saturated straight chain or branch, wherein alkane Base can be individually optionally replaced one or more substituent groups described in the invention.Some of embodiments are alkyl Group contains 1-10 carbon atom, and other embodiment is that alkyl group contains 1-8 carbon atom, other embodiment It is that alkyl group contains 1-6 carbon atom, other embodiment is that alkyl group contains 1-4 carbon atom.Alkyl group Further example includes, but is not limited to, methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), n-propyl (n-Pr ,- CH₂CH₂CH₃), isopropyl (i-Pr ,-CH (CH₃)₂), normal-butyl (n-Bu ,-CH₂CH₂CH₂CH₃), isobutyl group (i-Bu ,-CH₂CH (CH₃)₂), sec-butyl (s-Bu ,-CH (CH₃)CH₂CH₃), tert-butyl (t-Bu ,-C (CH₃)₃) etc..Term " alkyl " He Qiqian Sew " alkane " to use here, all includes the saturated carbon chains of straight chain and branch.

Term used in the present invention " alkoxy ", is related to alkyl, as defined in the present invention, is connected by oxygen atom It is connected in main carbochain.

Term " halogenated alkyl " or " halogenated alkoxy " indicate that alkyl or alkoxy can be by one or more identical or not With situation replaced halogen atom.Wherein alkyl and alkoxy base have meaning as described in the present invention, such example Include, but is not limited to trifluoromethyl, trifluoromethoxy etc..

Term " hydroxy alkyl ", " hydroxyl substituted alkyl group " or " hydroxy alkoxy base " indicate that alkyl or alkoxy can be by one Or situation replaced multiple hydroxyls.Wherein alkyl and alkoxy base have meaning as described in the present invention, such example Include, but is not limited to methylol, 1- ethoxy, hydroxypropyl, 1,2- dihydroxypropyl, hydroxyl methoxyl group, 1- hydroxy ethoxy etc..

Term " aryl " can be used alone or as " aralkyl ", a big portion of " aralkoxy " or " aryloxy alkyl " Point, indicate the monocycle altogether containing 6-14 member ring, bicyclic and tricyclic carbocyclic ring system, wherein at least one ring system is aromatic series , wherein each ring system includes 3-7 member ring, and only one attachment point is connected with the rest part of molecule.Term " virtue Base " can be used interchangeably with term " aromatic rings ", if aromatic rings may include phenyl, naphthalene and anthracene.And the aryl can be with Be it is substituted or non-substituted, wherein substituent group can be, but be not limited to, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyanogen Base, hydroxy alkyl, sulfydryl, nitro, carboxyl, alkoxy, alkyl amino, alkylthio group, alkyl-S (=O)₂, alkyl, alkenyl, or Alkynyl etc..

Term " heteroaryl " can be used alone or as " heteroaryl alkyl " or " heteroarylalkoxy " a part, table Show the monocycle altogether containing 5-14 member ring, bicyclic and three-ring system, wherein at least one ring system is aromatic, and at least one A ring system includes one or more hetero atoms, and wherein each ring system includes 3-7 member ring, and only one attachment point with point Sub- rest part is connected.Term " heteroaryl " can be used interchangeably with term " heteroaromatic " or " heteroaromatics ".Depending on structure Depending on, heteroaryl can be monoradical or bivalent group (that is, inferior heteroaryl).And the heteroaryl can be substitution or non-take Generation, wherein substituent group can be, but be not limited to, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, hydroxy alkyl, Sulfydryl, nitro, carboxyl, alkoxy, alkyl amino, alkylthio group, alkyl-S (=O)₂, alkyl, alkenyl or alkynyl etc..

Other embodiment is that hetero-aromatic ring includes monocycle below, but is not limited to these monocycles: 2- furyl, 3- Furyl, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazolyl, 4- methylisoxazole -5- base, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyrrole Piperidinyl, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine radicals, 4- pyrimidine radicals, pyrimidine -5- base, pyridazinyl (such as 3- pyridazinyl), 2- thiazole Base, 4- thiazolyl, 5- thiazolyl, tetrazole radical (such as 5- tetrazole radical), triazolyl (such as 2- triazolyl and 5- triazolyl), 2- thiophene Base, 3- thienyl, pyrazolyl (such as 2- pyrazolyl), isothiazolyl, 1,2,3-oxadiazoles base, 1,2,5- oxadiazoles base, 1,2,4- Oxadiazoles base, 1,2,3-triazoles base, 1,2,3- thio biphosphole base, 1,3,4- thio biphosphole base, 1,2,5- thio biphosphole base, 1,3, 4- thiadiazoles -2- base, pyrazinyl, pyrazine -2- base, 1,3,5-triazines base, benzo [d] thiazol-2-yl, imidazo [1,5-a] pyrrole Pyridine -6- base；It also include below bicyclic, but it is bicyclic to be not limited to these: benzimidazolyl, benzofuranyl, benzothienyl, Benzothiazolyl, indyl (such as 2- indyl), isoindolyl, isoindoline base, purine radicals, quinolyl (such as 2- quinolyl, 3- Quinolyl, 4- quinolyl), isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl), tetralyl, benzo Pyrazolyl etc..

Term " carbocylic radical " or " annular aliphatic ", " carbocyclic ring ", " naphthenic base " refer to monovalence or multivalence, and non-aromatic is satisfied And/or part unsaturated ring, and do not include hetero atom, two of monocycle or 7-12 carbon atom including 3-12 carbon atom Ring or tricyclic.Bicyclic carbocyclic ring with 7-12 atom can be two rings [4,5], [5,5], and [5,6] or [6,6] system has simultaneously There is the bicyclic carbocyclic ring of 9 or 10 atoms to can be two rings [5,6] or [6,6] system.The example of cyclic aliphatic group is further wrapped It includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyl, 1- cyclopenta -2- alkenyl, 1- cyclopenta - 3- alkenyl, cyclohexyl, 1- cyclohexyl -1- alkenyl, 1- cyclohexyl -2- alkenyl, 1- cyclohexyl -3- alkenyl, cyclohexadienyl, cycloheptyl Base, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, adamantyl etc..And " carbocylic radical " or " annular aliphatic ", " carbocyclic ring ", " naphthenic base " can be substituted or non-substituted, and wherein substituent group can be, but be not limited to, Oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, hydroxy alkyl, sulfydryl, nitro, carboxyl, alkoxy, alkyl amino, alkane Sulfenyl, alkyl-S (=O)₂, alkyl, alkenyl or alkynyl etc..

Term " heterocycle ", " heterocycle ", " heteroalicyclic " or " heterocycle " are used interchangeably here, all refer to monocycle, Bicyclic or three-ring system, individually optionally replaced hetero atom, ring can be completely full one or more atoms in middle ring Sum or comprising one or more degrees of unsaturation, but definitely not aromatic, only one tie point are connected on other molecules It goes.Hydrogen atom on one or more rings is individually optionally replaced one or more substituent groups described in the invention.Its In some embodiments be " heterocycle ", " heterocycle ", " heteroalicyclic " or " heterocycle " group is the monocycle (1-6 of 3-7 member ring Carbon atom and it is selected from N, O, P, the 1-3 hetero atom of S optionally obtain picture replaced one or more oxygen atoms in this S or P SO, SO₂, PO, PO₂Group, when the ring is a three-membered ring, only one of them hetero atom) or 7-10 member bicyclic (4- 9 carbon atoms and be selected from N, O, P, the 1-3 hetero atom of S, this S or P optionally replaced one or more oxygen atoms must To as SO, SO₂, PO, PO₂Group).Depending on structure, heterocycle can be monoradical or bivalent group (that is, sub- heterocycle).

" heterocycle " can be carbon-based or heteroatom group." heterocycle " equally also include heterocyclic group and saturation or part not Saturated rings or heterocycle and close be formed by group.The example of heterocycle includes, but is not limited to, pyrrolidinyl, tetrahydrofuran base, and two Hydrogen furyl, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, thiophene oxane base, azetidin Base, oxetanylmethoxy, thietanyl, piperidyl, homopiperidinyl, glycidyl, azacycloheptyl, oxetane, thia Suberyl, N- morpholinyl, 2- morpholinyl, morpholinyl, thio-morpholinyl, N- piperazinyl, 2- piperazinyl, 3- piperazinyl, high piperazine Piperazine base, 4- Methoxy-piperidin -1- base, 1,2,3,6- tetrahydropyridine -1- base, oxygen azatropylidene base, diazepine base, sulphur azatropylidene Base, pyrrolin -1- base, 2- pyrrolinyl, 3- pyrrolinyl, indolinyl, 2- indoline base, 2H- pyranose, 4H- pyrans Base, dioxacyclohexyl, 1,3- dioxymyl, pyrazolinyl, dithianyl, dithienyl group, dihydrothiophene, pyrazolidinyl Imidazolinyl, imidazolidinyl, 1,2,3,4- tetrahydro isoquinolyl, 1,2,6- thiadiazine alkane 1,1- dioxy -2- base, hexahydro -2H- [Isosorbide-5-Nitrae] dioxin [2,3-c] pyrrole radicals, quinazinyl, thiomorpholine 1,1- dioxide base, the different Yin of 2,3,3a, 7a- tetrahydro -1H- Diindyl base, 1,2,3,4- tetrahydroquinoline, isoindoline and N- pyridyl urea.And the heterocycle can be substitution or non-take Generation, wherein substituent group can be, but be not limited to, hydrogen, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, hydroxyl alkane Base, sulfydryl, nitro, carboxyl, alkoxy, alkyl amino, alkylthio group, alkyl-S (=O)₂, alkyl, alkenyl or alkynyl etc..Example Such as 1- picoline -2 (1H) -one, 6- methyl cyclohexane -2,4- dienone, (2S, 6R) -2,6- dimethylated morpholinyl etc..

Term " condensed-bicyclic ", " condensed ring ", " condensed-bicyclic base " or " condensed ring radical " indicate saturated or unsaturated condensed ring body System, is related to the bicyclic system of non-aromatic, at least one ring is nonaromatic.Such system may include independent Or the undersaturated condition of conjugation, but its nuclear structure does not include aromatic rings or heteroaromatic (but aromatic series can be used as thereon Substituent group).Each of condensed-bicyclic ring is either carbocyclic ring or is heteroalicyclic, and such example includes, but and unlimited In, hexahydro-furo [3,2-b] furyl, 2,3,3a, 4,7,7a- hexahydro -1H- indenyls, 7- azabicyclo [2.2.1] heptane base, Condensed-bicyclic [3.3.0] octyl, condensed-bicyclic [3.1.0] hexyl, 1,2,3,4,4a, 5,8,8a- octahydro naphthalenes, these are all Within the system of condensed-bicyclic.And the condensed-bicyclic base can be substituted or non-substituted, and wherein substituent group can It to be, but is not limited to, hydrogen, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, hydroxy alkyl, sulfydryl, nitro, carboxylic Base, alkoxy, alkyl amino, alkylthio group, alkyl-S (=O)₂, alkyl, alkenyl or alkynyl etc..

Term " condensing miscellaneous bicyclic group " indicates saturated or unsaturated fused ring system, is related to the bicyclic body of non-aromatic System, at least one ring is nonaromatic.Such system may include independent or conjugation undersaturated condition, but its core Core structure does not include aromatic rings or heteroaromatic (but aromatic series can be used as substituent group thereon).And at least one ring system packet Containing one or more hetero atoms, wherein each ring system includes 3-7 member ring, i.e., comprising 1-6 carbon atom and selected from N, O, P, S 1-3 hetero atom, optionally obtained replaced one or more oxygen atoms in this S or P as SO, SO₂, PO, PO₂Group, Such example includes, but is not limited to hexahydro -2H- [Isosorbide-5-Nitrae] dioxin [2,3-c]) pyrrole radicals, 3- azabicyclo [3.3.0] Octyl, 3- methyl -3,7- diazabicyclo [3.3.0] octyl, 8- azabicyclo [4.3.0] nonyl, 8- azabicyclo [4.3.0] nonane 3- base, 3- azabicyclo [4.3.0] nonane -3- base, 1,5- dioxy -8- azabicyclo [4.3.0] nonyl, (1R, 6S) -2,5- dioxy -8- azabicyclo [4.3.0] nonyl, (1R, 6R) -2,5- dioxy -8- azabicyclo [4.3.0] nonyl Alkyl, isoindoline base, 1,2,3,4- tetrahydric quinoline group, (1S, 5S) -1- hydroxyl -3- azabicyclo [3.1.0] hexyl, (1R, 5S) -1- hydroxyl -3- azabicyclo [3.1.0] hexyl, (1R, 5S) -1-N, N- dimethylamino -3- azabicyclo [3.1.0] hexyl, (1S, 5R, 6R) -1- methyl -6- alcohol -3- azabicyclo [3.2.0] heptane base, 3- nitrogen -7- oxabicyclo [3.3.0] octyl, 3,7- diazabicyclos [3.3.0] octyl, 2,6- diazabicyclos [3.3.0] octyl, 2,7- bis- Azabicyclo [3.3.0] octyl, 3- ethyl -3,7- diazabicyclo [3.3.0] octyl, 2,7- diazabicyclos [3.3.0] octyl, 7- acetyl group -2,7- diazabicyclo [3.3.0] octyl, 2,8- diazabicyclos [4.3.0] nonane Base, 3,8- diazabicyclos [4.3.0] nonyl, 2- methyl -2,8- diazabicyclo [4.3.0] nonyl, 3- oxygen -8- azepine Bicyclic [4.3.0] nonyl, 2- oxygen -8- azabicyclo [4.3.0] nonyl, 2,8- phenodiazine -5- oxabicyclo [4.3.0] nonanes Base, (1S, 6R) -2- methyl -2,8- phenodiazine -5- oxabicyclo [4.3.0] nonyl, 3- ethyl -3,9- diazabicyclo [4.3.0] nonyl, 4,9- diazabicyclos [4.3.0] nonyl, 2,9- diazabicyclos [4.3.0] nonyl, 3- methyl- 3,9- diazabicyclos [4.3.0] nonyl, 3- ethyl -3,7- diazabicyclo [4.3.0] nonyl, 3- methyl -3,7- bis- Azabicyclo [4.3.0] nonyl, 2- ethyl -2,8- diazabicyclo [4.3.0] nonyl, 2- oxo -3- oxygen -8- azepine are double Ring [4.3.0] nonyl, 3- oxo -2,4, tri- azabicyclo of 8- [4.3.0] nonyl, 3- oxo -4- oxygen -2,8- diaza are double Ring [4.3.0] nonyl, 3- oxo -2,8- diazabicyclo [4.3.0] nonyl, 3,8- diazabicyclos [4.3.0] nonane Base, 8- methyl -2,8- diazabicyclo [4.3.0] nonyl, 3,7- diazabicyclos [4.3.0] nonyl, 3,9- diazas Bicyclic [4.3.0] nonyl, 3- oxygen -8- azabicyclo [4.3.0] nonyl, 3- sulphur -8- azabicyclo [4.3.0] nonyl, 9- methyl -3,9- diazabicyclo [4.3.0] nonyl, 7- methyl -3,7- diazabicyclo [4.3.0] nonyl, 9- ethyl - 3,9- diazabicyclos [4.3.0] nonyl, 7- ethyl -3,7- diazabicyclo [4.3.0] nonyl, 8- ethyl -2,8- bis- Azabicyclo [4.3.0] nonyl, 5,6- dihydro -4H- pyrrolo- [3,4-c] isoxazolyls, 3- ethyl-[1,2,4] triazole [4,3-a] and piperidyl, [1,2,4] triazole [4,3-a] and piperidyl, 3- methyl-isoxazole simultaneously [4,3-c] piperidyl, 3- Methyl -5,6- dihydro -4H- pyrrolo- [3,4-c] isoxazolyl, 2- methyl -4,5,6,7- tetrahydro -1H- imidazo [4,5-c] pyrroles Piperidinyl, 2- methyl -4,5,6,7- tetrahydro oxazoles simultaneously [4,5-c] pyridyl group, 2- methyl -4,5,6,7- tetrahydro -1H- thiazoles simultaneously [4, 5-c] pyridyl group, isoxazole simultaneously [4,3-c] piperidyl, 4,5,6,7- tetrahydro isoxazoles simultaneously [3,4-c] pyridyl group, [1,2,4] three Nitrogen azoles simultaneously [4,3-a] piperazinyl, 3- trifluoromethyl-[1,2,4] triazole simultaneously [4,3-a] piperazinyl, 3- methyl-[1,2,4] three Nitrogen azoles simultaneously [4,3-a] piperazinyl, 2- oxo -3- oxygen -8- azabicyclo [4.3.0] nonyl, 1,3- dimethyl -4,5,6,7- tetra- Hydrogen -1H- pyrazolo [4,3-c] pyridin-2-yl, 2- oxygen -7- azabicyclo [4.4.0] decyl, 1,5- dioxy -9- azabicyclo [4.4.0] decyl, 2,3- dimethyl -4,5,6,7- tetrahydro -2H- pyrazolo [4,3-c] pyridin-2-yls, 3- azabicyclo [4.4.0] decyl, 2,7- diaza decahydro naphthalenes or 2- oxygen -8- azabicyclo [4.4.0] decyl etc..And it is described thick Closing miscellaneous bicyclic group can be substituted or non-substituted, and wherein substituent group can be, but be not limited to, hydrogen, oxo (=O), hydroxyl, Amino, F, Cl, Br, I, cyano, hydroxy alkyl, sulfydryl, nitro, carboxyl, alkoxy, alkyl amino, alkylthio group, alkyl-S (= O)₂, alkyl, alkenyl or alkynyl etc..

Term " the miscellaneous bicyclic group of bridge " indicates saturated or unsaturated bridged-ring system, is related to the bicyclic system of non-aromatic. Such system may include independent or conjugation undersaturated condition, but its nuclear structure does not include aromatic rings or heteroaromatic (but aromatic series can be used as substituent group thereon).And at least one ring system includes one or more hetero atoms, wherein often One ring system includes 3-7 member ring, i.e., comprising 1-6 carbon atom and selected from N, O, P, the 1-3 hetero atom of S is appointed in this S or P Selection of land is obtained replaced one or more oxygen atoms as SO, SO₂, PO, PO₂Group, such example includes, but and unlimited In 2- oxygen -5- azabicyclo [2.2.1] heptane base, thio -5- azabicyclo [2.2.1] the heptane base of 2-, 2- oxo -5- azepine is double Ring [2.2.1] heptane base, 2,5- diazabicylos [2.2.1] heptane base, 2- methyl -2,5- diazabicylo [2.2.1] heptane Base etc..And the miscellaneous bicyclic group of bridge can be substituted or non-substituted, and wherein substituent group can be, but be not limited to, hydrogen, oxygen Generation (=O), hydroxyl, amino, F, Cl, Br, I, cyano, hydroxy alkyl, sulfydryl, nitro, carboxyl, alkoxy, alkyl amino, alkane sulphur Base, alkyl-S (=O)₂, alkyl, alkenyl or alkynyl etc..

Term " bridge bicyclic group " indicates saturated or unsaturated bridged-ring system, is related to the bicyclic system of non-aromatic.This The system of sample may include independent or conjugation undersaturated condition, but its nuclear structure does not include aromatic rings or aromatic ring (still Aromatic series can be used as substituent group thereon).Wherein each ring system includes 3-7 member ring, and such example includes, but not It is limited to bicyclic [2.2.1] heptane base, miscellaneous two ring [2.2.1] the heptane base of 2- methyl-, etc..And the bridge bicyclic group, which can be, to be taken In generation, is non-substituted, and wherein substituent group can be, but be not limited to, hydrogen, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyanogen Base, hydroxy alkyl, sulfydryl, nitro, carboxyl, alkoxy, alkyl amino, alkylthio group, alkyl-S (=O)₂, alkyl, alkenyl, or Alkynyl etc..

Term " bridge bicyclic group alkyl " indicate alkyl group replaced one or more bridge bicyclic group groups, wherein alkyl Group and bridge bicyclic group group have meaning as described in the present invention, and such example includes, but is not limited to bicyclic [2.2.1] Heptane ylmethyl, miscellaneous two ring [2.2.1] the heptane base ethyl of 2- methyl-, etc..

Term " the miscellaneous bicyclic group alkyl of bridge " indicate alkyl group replaced the miscellaneous bicyclic group group of one or more bridges, wherein Alkyl group and the miscellaneous bicyclic group group of bridge have meaning as described in the present invention, and such example includes, but is not limited to 2- oxygen- 5- azabicyclo [2.2.1] heptane base ethyl, thio -5- azabicyclo [2.2.1] the heptane base propyl of 2-, 2,5- diazabicylos [2.2.1] heptane ylmethyl, 2- methyl -2,5- diazabicylo [2.2.1] heptane base butyl etc..

Term " alkynyl " indicates the monovalent hydrocarbon of 2-12 carbon atom straight chain or branch, and wherein at least one position is insatiable hunger And state, i.e. a C-C is tri- key of sp, and wherein alkynyl group can be individually optionally by one or more described in the invention Replaced substituent group, specific example is included, but is not limited to, acetenyl (three CH of-C), propargyl (- CH₂Tri- CH of C), etc..

Term " alkenyl " indicates the monovalent hydrocarbon of 2-12 carbon atom straight chain or branch, and wherein at least one position is insatiable hunger And state, i.e. a C-C is sp²Double bond, wherein the group of alkenyl can be retouched by one or more present invention individually optionally Replaced the substituent group stated, there is the positioning of negation " just " or " E " " Z " including group, wherein specific example includes, but and unlimited In vinyl (- CH=CH₂), allyl (- CH₂CH=CH₂), etc..

Term " cycloalkyl-alkyl " indicates that alkyl group can be replaced one or more groups of naphthene base, wherein naphthenic base There is meaning as described in the present invention with groups, such example includes, but is not limited to Cvclopropvlmethvl, cyclopropyl second Base, Cyclopropylpropyl, cyclopentyl-methyl, cyclohexyl-ethyl etc..

Term " heterocyclylalkyl group " indicates that alkyl group can be replaced one or more heterocyclyl groups, wherein heterocycle There is meaning as described in the present invention with alkyl group.

Term " aryl alkyl " indicate alkyl group replaced one or more aryl groups, wherein alkyl group and virtue Base group has meaning as described in the present invention, and such example includes, but is not limited to phenethyl, benzyl, to toluene second Base, etc..

Term " heteroaryl alkyl " indicate alkyl group replaced one or more heteroaryl groups, wherein alkyl group There is meaning as described in the present invention with heteroaryl groups, such example includes, but is not limited to pyridine -2- ethyl, thiazole - 2- methyl, imidazoles -2- ethyl, pyrimidine -2- propyl etc..

Term " alkylthio group " includes C_1-10The alkyl of linear chain or branched chain is connected on the sulphur atom of divalent, wherein alkyl group With meaning as described in the present invention.Some of embodiments are that alkylthio group is the C of lower level_1-3Alkylthio group, such example Include, but is not limited to methyl mercapto (CH₃S-), ethylmercapto group etc..

Term " alkylamino " or " alkyl amino " include " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino Group is separately replaced one or two alkyl group, and wherein alkyl group has meaning as described in the present invention. Some of embodiments are that alkyl amino is one or two C_1-6Alkyl is connected to the alkyl amino of the lower level on nitrogen-atoms Group.Other embodiment is that alkyl amino is C_1-3Lower level alkylamino group.Suitable alkylamino group It can be alkyl monosubstituted amino or dialkyl amido, such example includes, but is not limited to, N- methylamino, N- ethylamino, N, N- Dimethylamino, N, N- lignocaine etc..

Term " cycloalkyl-alkyl " indicates that alkyl group can be replaced one or more groups of naphthene base, wherein cycloalkanes Base and alkyl group have meaning as described in the present invention.Such example includes, but is not limited to cyclohexyl methyl, cyclopropyl Ethyl etc..The naphthenic base can be further by halogen, alkyl, replaced alkoxy and hydroxyl.

Term " condensed-bicyclic base alkyl " indicate alkyl group replaced one or more condensed-bicyclic base groups, wherein Alkyl group and condensed-bicyclic base group have meaning as described in the present invention, and such example includes, but is not limited to 1,2, 3,4,4a, 5,8,8a- octahydro naphtylethyl groups, 1,2,3,4,4a, 5,8,8a- octahydro naphthyl methyls, 1,2,3,4,4a, 5,8,8a- Octahydro naphthylpropyl, condensed-bicyclic [3.3.0] octane ylmethyl, condensed-bicyclic [3.1.0] hexyl ethyl etc..

Term " condensing miscellaneous bicyclic group alkyl " indicates that alkyl group is condensed replaced miscellaneous bicyclic group group by one or more, Wherein alkyl group and condense miscellaneous bicyclic group group with meaning as described in the present invention, such example includes, but and unlimited In hexahydro-furo [3,2-b] furans -2- base ethyl, hexahydro-furo [3,2-b] furans -2- ylmethyl, 7- azabicyclo [2.2.1] heptane -2- ylmethyl, 7- azabicyclo [2.2.1] heptane -2- base ethyl, 7- azabicyclo [2.2.1] heptane -4- Ylmethyl etc..

Term " loop coil base ", " loop coil ", " spiral shell bicyclic group ", " spiral shell is bicyclic " indicate a ring originating from special on another ring Cyclic annular carbon.For example, the bridged-ring system (ring B and B') of a saturation is referred to as " condensed-bicyclic ", on the contrary as disclosed below A carbon atom is shared in the ring system that ring A and ring B is saturated at two, then is referred to as " loop coil ".Each ring inside loop coil It is carbocyclic ring or is heteroalicyclic.Such example includes, but is not limited to 4- azaspiro [2.4] heptane -5- base, 4- oxygen Miscellaneous spiral shell [2.4] heptane -5- base, 5- azaspiro [2.4] heptane -5- base, spiral shell [2.4] heptane base, spiral shell [4.4] nonyl, 7- hydroxyl - 5- azaspiro [2.4] heptane -5- base etc..And the spiral shell bicyclic group can be substituted or non-substituted, and wherein substituent group can be with It is, but is not limited to, hydrogen, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, hydroxy alkyl, sulfydryl, nitro, carboxyl, Alkoxy, alkyl amino, alkylthio group, alkyl-S (=O)₂, alkyl, alkenyl or alkynyl etc..

Term " the miscellaneous bicyclic group of spiral shell " indicates a ring originating from particularly ring-shaped carbon on another ring.For example, as institute above Description, the bridged-ring system (ring B and B') of a saturation is referred to as " condensed-bicyclic ", otherwise the ring that ring A and ring B is saturated at two A carbon atom is shared in system, then is referred to as " loop coil ".And at least one ring system includes one or more hetero atoms, wherein Each ring system includes 3-7 member ring, i.e., comprising 1-6 carbon atom and selected from N, O, P, the 1-3 hetero atom of S, in this S or P It is optionally obtained replaced one or more oxygen atoms as SO, SO₂, PO, PO₂Group, such example includes, but not It is limited to 4- azaspiro [2.4] heptane -5- base, 4- oxaspiro [2.4] heptane -5- base, 5- azaspiro [2.4] heptane -5- base, 7- hydroxyl Base -5- azaspiro [2.4] heptane -5- base, 2- azaspiro [4.5] decyl, 2- azepine spiroheptane base, 2- azaspiro [4.4] nonyl, 2- methyl -2,6- diaza spiro [4.5] decyl, etc..And the miscellaneous bicyclic group of spiral shell can be substitution or Non-substituted, wherein substituent group can be, but be not limited to, hydrogen, oxo (=O), hydroxyl, amino, F, Cl, Br, I, cyano, hydroxyl Base alkyl, sulfydryl, nitro, carboxyl, alkoxy, alkyl amino, alkylthio group, alkyl-S (=O)₂, alkyl, alkenyl or alkynyl etc. Deng.

Term " spiral shell bicyclic group alkyl " indicate alkyl group replaced one or more spiral shell bicyclic group groups, wherein alkyl There is meaning as described in the present invention with spiral shell bicyclic group group, such example includes, but is not limited to spiral shell [2.4] heptane Ji Jia Base, spiral shell [2.4] heptane base ethyl, spiral shell [2.4] heptane base propyl, spiral shell [4.4] nonane ylmethyl, spiral shell [4.4] nonyl ethyl, 4- Azaspiro [2.4] heptane -5- ylmethyl, 4- azaspiro [2.4] heptane -5- base ethyl, 4- oxaspiro [2.4] heptane -5- base second Base, 5- azaspiro [2.4] heptane -5- base propyl, 7- hydroxyl -5- azaspiro [2.4] heptane -5- base propyl etc..

Term " the miscellaneous bicyclic group alkyl of spiral shell " indicate alkyl group replaced the miscellaneous bicyclic group group of one or more spiral shells, wherein Alkyl group and the miscellaneous bicyclic group group of spiral shell have meaning as described in the present invention, and such example includes, but is not limited to 4- nitrogen Miscellaneous spiral shell [2.4] heptane -5- ylmethyl, 4- azaspiro [2.4] heptane -5- base ethyl, 4- oxaspiro [2.4] heptane -5- base ethyl, 5- azaspiro [2.4] heptane -5- base propyl, 7- hydroxyl -5- azaspiro [2.4] heptane -5- base propyl etc..

As described in the present invention, substituent R is keyed to the ring system formed on the ring at center by one and represents substituent R It any on ring can may replace or any reasonable position is replaced.For example, formula_aRepresent any possibility quilt on A ring or B ring Substituted position can be replaced by R, as shown in formula b, formula c, formula d, formula e, formula f, formula g and formula h.

As described in the present invention, substituent group (R)_nThe ring system formed on the ring at center, which is keyed to, by one represents n Substituent R can be replaced any substitutive position on ring.For example, formula i is represented and any on A ring or B ring may be taken The position in generation can be replaced by n R.

As described in the invention, can be connected with molecule rest part on ring C there are two tie point, for example, such as formula j institute Show, indicate either the end E be also possible to E ' end be connected with the rest part of molecule, i.e. the connection type at both ends can be interchanged.

As described in the present invention, attachment point can be connect any attachable position on ring with molecule rest part.Example Such as, formula k, which represents any possible connected position on A ring or B ring, can be used as the point of connection.

As described in the present invention, attachment point can be connect any attachable position on ring with molecule rest part, together When the both ends that connect can be interchanged.For example, formula m, which represents any possible connected position on ring, can be used as the point of connection, together When tie point both ends can be interchanged.

In addition, it is necessary to explanation, unless otherwise explicitly pointing out, describing mode as used throughout this document " each ... and ... independently be ", " ... and ... be each independently " and " ... and ... separately for " can be interchanged, and should do extensively Reason and good sense solution does not influence mutually between expressed specific option between the same symbol either referring among the different groups, It can indicate in the same group, not influenced mutually between expressed specific option between the same symbol.For example, structural formula Q and structural formula s each Z between the two¹Specific option it is unaffected from each other, meanwhile, it is multiple such as formula q in same structure formula The specific option of G is unaffected between each other；Or such as formula s, multiple R⁹Specific option it is unaffected from each other.

The definition of neutral body chemistry of the present invention and the use of convention are typically referenced to following documents: S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons, Inc., New York, 1994. the compound of the present invention may include asymmetric center or chiral centre, therefore There are different stereoisomers.All stereoisomeric forms in any ratio of the compound of the present invention, it is including but not limited to, diastereomeric Body, enantiomter, atropisomer and their mixture, such as racemic mixture constitute a part of the invention. Many organic compounds all exist with optical active forms, i.e. the plane of their capable Plane of rotation polarised lights.In description light When learning reactive compound, prefix D, L or R, S are used to indicate the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) use Come name compound linearly polarized light rotate symbol, (-) or l refer to compound be it is left-handed, prefix (+) or d refer to chemical combination Object is dextrorotation.The chemical structure of these stereoisomers is identical, but their stereochemical structure is different.It is specific vertical Body isomers can be enantiomer, and the mixture of isomers is commonly referred to as enantiomeric mixture.The enantiomer of 50:50 mixes Object is referred to as racemic mixture or racemic modification, this, which may cause in chemical reaction process, does not have stereoselectivity or three-dimensional fixed Tropism.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomters, lack light Learn activity.

Term " tautomer " or " tautomeric form " indicate that the isomer of different-energy can be by lower The mutual inversion of phases of energy barrier.Such example includes, but is not limited to, and proton tautomer (i.e. prototropic change isomers) includes Pass through the interconversion of proton transfer, such as the isomerization of keto-enol and imine-enamine.Valence tautomer packet Include the recombination interconversion of some bonding electrons.

" hydrate " of the invention refers to that solvent molecule is that water is formed by associated matter.

" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.

" ester " of the invention refers to that the formula (I) containing hydroxyl or formula (II) compound can form internal hydrolyzable ester.This The ester of sample is the pharmaceutically acceptable ester that hydrolysis generates parent alcohol for example in human or animal's body.Formula (I) containing hydroxyl or The group of hydrolyzable ester includes, but are not limited to phosphate, acetoxymethoxy, 2,2- diformazans in formula (II) compound body Base propionyloxy methoxyl group, alkanoyl, benzoyl, the first and second acyl group of benzene, alkoxy carbonyl, dialkyl carbamoyl and N- (di-alkyaminoethyl group)-N- alkyl-carbamoyl etc..

" nitrogen oxides " of the invention refer to when compound is containing several amine functional groups, can nitrogen by 1 or greater than 1 it is former Son oxidation forms N- oxide.The particular example of N- oxide is the N- oxidation of the N- oxide or nitrogen-containing heterocycle nitrogen-atoms of tertiary amine Object.The corresponding amine formation N- oxide of available oxidant such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) processing (referring to Advanced Organic Chemistry, Wiley Interscience, the 4th edition, Jerry March, pages).Especially It is that N- oxide can be prepared (Syn.Comm.1977,7,509-514) with the method for L.W.Deady, wherein for example molten in inertia In agent such as methylene chloride, react amine compounds with m- chloroperoxybenzoic acid (MCPBA).

Compound may be present a variety of different geometric isomers and tautomer, formula (I) compound include it is all this Class form.For the avoidance of doubt, when compound exists with one of several geometric isomers or tautomer and only specifically describes Or when showing a kind of, it is clear that all other form is included in formula (I).

Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.This hair Bright pro-drug compounds can be ester, and ester can be used as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, it can is acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are obtaining through the di on parent.It is completely begged for about pro-drug By following documents can be referred to: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008,51,2328-2345.

Unless otherwise indicated, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more different originals The enriched isotope of son.

" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66: 1-19,1977. documented.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, anti-with amino group The inorganic acid salt that should be formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetate, Oxalates, maleate, tartrate, citrate, succinate, malonate, or by described in the books or literature Other methods such as ion-exchanges obtains these salt.Other pharmaceutically acceptable salts include adipate, Lactic acid Alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphoric acid Salt, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, anti-butylene Diacid salt, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxyl Base-esilate, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, methanesulfonic acid Salt, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenyl third Hydrochlorate, picrate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, Etc..Salt obtained by an appropriate base includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.The present invention is also intended to structure The compound for having thought the group of any included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can pass through Quaternization obtains.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt is into one Step includes appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylation Object, hydrosulphate, phosphoric acid compound, nitric acid compound, C_1-8Sulphonic acid compound and aromatic sulphonic acid compound.

When term " blocking group " or " Pg " refer to a substituent group and other reacted with functional groups, commonly used to resistance It is disconnected or protect special functionality.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or the functionality of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group (CBZ) and 9- fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to the substitution of hydroxyl Base is used to block or protect the functionality of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl-protecting group Group " refers to that the substituent group of carboxyl is used to block or protect the functionality of carboxyl, general carboxyl-protecting group includes- CH₂CH₂SO₂Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group can refer to document: T W.Greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.

The description of the compounds of this invention

The present invention provides a series of pyrazole compounds and its pharmaceutically acceptable salt as kinases inhibitor Application in the drug of preparation treatment and protein kinase activity related disease.Experimental study proves: pyrazole compound and its Pharmaceutical salts therapeutic treatment and the Kit for the protein kinase family for adjusting primary type and/or mutant form, PDGF- α, PDGF- β, CSF1R, DDR1, Aurora A, Aurora B, CDK8, CDK11 and HIPK4 of JAK, Abl, FLT3 and/or CDK family etc. swash It plays an important role in enzymatic activity.

The present invention proposes the alloisomerism of compound shown in one kind pyrazole derivatives as shown in formula (I) or formula (I) Body, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, ester are pharmaceutically acceptable Salt or its prodrug,

Wherein:

Each R¹And R^1aIt independently is H or C_1-4Alkyl；

X¹It is CR^4aR⁴Or NR⁶；

X²It is CR^4aOr N；

Each R^4aAnd R⁴It independently is H or C_1-4Alkyl；

R⁶For H or C_1-4Alkyl；

Each R^8aAnd R⁸It independently is H or C_1-6Alkyl；

Each t independently is 0,1 or 2；

Each p independently is 1,2,3 or 4；

Each n independently 0,1,2,3 or 4；

Wherein, the alkyl, carbocylic radical, alkenyl, alkynyl, alkyl-S (=O)₂Alkyl, halogenated alkyl, bridge bicyclic group, The miscellaneous bicyclic group of bridge ,-(CH₂)_n,-(CH₂)_n-N(R⁸)-,-(CH₂)_n-N(R^8a)-, heterocycle, alkyl amino, condensed-bicyclic base are thick Close miscellaneous bicyclic group, aryl, heteroaryl, condensed-bicyclic base alkyl condenses miscellaneous bicyclic group alkyl, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell Bicyclic group alkyl, the miscellaneous bicyclic group alkyl of spiral shell, naphthenic base, heterocyclylalkyl group, cycloalkyl-alkyl, aryl alkyl, heteroaryl alkyl, hydroxyl Base alkyl, alkoxy, and (HO- (CH₂)_n)-N(R^8a)-, can be independently by oxo (=O), hydroxyl, amino, F, Cl, Br, I, Cyano, hydroxy alkyl, sulfydryl, nitro, carboxyl, C_1-4Alkoxy, C_1-4Alkyl amino, C_1-4Alkylthio group, C_1-4Alkyl-S (=O)₂, Halogenated C_1-4Alkyl, C_1-4Alkyl, C_2-4Alkenyl or C_2-4Monosubstituted or identical or different polysubstituted of alkynyl.

Y¹For a key ,-(CH₂)_n-N(R⁸)-,-N (R⁸)-,-O- ,-O- (CH₂)_nOr-(CH₂)_n-；

Each R⁸It independently is H or C_1-6Alkyl；

Some of embodiments are:

Wherein, each Z¹It independently is N or CH；

Each Z²It independently is N or CH；

Each Z³It independently is-N (R⁸)-, or-CH₂-；

Each E¹It independently is a key ,-O- ,-N (R⁸)-,-SO₂Or-S-；

Each V¹It independently is a key, or-(CH₂)_n-；

Each T independently is-CH₂-(CH₂)_n, or-CH=CH-；

Each T¹And T²It independently is-N (R⁸)-, or-CH₂-；

Each J¹It independently is-O-, or-S-；

Each j independently is 0,1,2,3 or 4；

Each n independently is 0,1,2,3 or 4.

In some embodiments, R²For following subformula,

According to the present invention, the solid of pyrazole derivatives shown in pyrazole derivatives shown in formula (I) or formula (I) is different Structure body, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, ester are pharmaceutically acceptable Salt or its prodrug, in which:

Each R^8aIt independently is H or C_1-4Alkyl；

In some embodiments, each R⁵It independently is-Y²-R⁷Group；

Wherein, each Q, Q¹, Q²And Q³It independently is N or CH；

Each W and W¹It independently is-CH₂,-O- ,-N (R^8a)-or-S-；

Each R^8aIt independently is H, methyl or ethyl；

Each q independently is 0,1,2,3 or 4；

Each n independently is 0,1,2,3 or 4；

Each m independently is 0,1,2,3 or 4.

In other embodiments, each R⁷It independently is following subformula:

According to pyrazole derivatives of the present invention, have as described in compound or the formula (II) as described in formula (II) The stereoisomer of compound, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, Ester, pharmaceutically acceptable salt or its prodrug,

Wherein:

Y¹For a key ,-(CH₂)_n-N(R⁸)-,-N (R⁸)-,-O- ,-O- (CH₂)_nOr-(CH₂)_n-；

Wherein, Y²For a key ,-O- ,-(CH₂)_n-N(R^8a)-, or-(CH₂)_n-；

Each R⁸It independently is hydrogen or C_1-6Alkyl；

Each R^8aIt independently is hydrogen or C_1-4Alkyl；

Each n independently is 0,1,2,3 or 4；

In some embodiments, R²For C_1-6Alkyl amino, C_5-12Condensed-bicyclic base, C_5-12Condense miscellaneous bicyclic group, C_6-10 Aryl, C_1-9Heteroaryl, C_2-10Heterocycle ,-Y¹-R^2aGroup or C_3-10Carbocylic radical；

Wherein, each Z¹It independently is N or CH；

Each Z²It independently is N or CH；

Each Z³It independently is-N (R⁸)-, or-CH₂-；

Each E¹It independently is a key ,-O- ,-N (R⁸)-,-SO₂Or-S-；

Each V¹It independently is a key, or-(CH₂)_n-；

Each T independently is-CH₂-(CH₂)_n, or-CH=CH-；

Each T¹And T²It independently is-N (R⁸)-, or-CH₂-；

Each J¹It independently is-O-, or-S-；

Each j independently is 0,1,2,3 or 4；

Each n independently is 0,1,2,3 or 4.

In other embodiments, R²For following subformula,

Wherein, each Q, Q¹, Q²And Q³It independently is N or CH；

Each W and W¹It independently is-CH₂,-O- ,-N (R^8a)-or-S-；

Each R^8aIt independently is hydrogen or C_1-4Alkyl；

Each q independently is 0,1,2,3 or 4；

Each n independently is 0,1,2,3 or 4；

Each m independently is 0,1,2,3 or 4.

In other embodiments, R⁷For following subformula:

According to pyrazole derivatives of the present invention, the structure comprising one of:

Or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, solvate, hydrate, metabolism produce Object, ester, pharmaceutically acceptable salt or its prodrug.

In some embodiments, pharmaceutical composition of the present invention further includes pharmaceutically acceptable load Body, excipient, diluent, at least one of adjuvant and medium.

Drug containing the compounds of this invention has the purposes for treating proliferative diseases, especially acute myelocytic Leukaemia (AML), the chronic myelogenous leukemia (CML) of mutation, acute lymphoblastic leukemia (ALL), colorectal cancer, gastric cancer, Breast cancer, lung cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid cancer, kidney, brain tumor, neck cancer, CNS's (central nervous system) Cancer, glioblastoma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukaemia, lymph cancer, rheumatic disease, slowly Property inflammation, cryoglobulinemia, non-lymphoreticular system tumour are papular mucinosis, familial splenic anemia, multiple Property myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, Primary macroglobulinaemia, half molecule disease, monocytic leukemia, primary macroglobulinaemia purpura are secondary benign Monoclonal gamma globulin disease, osteolytic lesion, lymphoblastoma, non-Hodgkin lymphoma, Sezary syndrome, infectiousness Monocytosis,mononucleosis, acute histocytic increase disease, Hodgkin lymphoma, hairy cell leukemia, colon cancer, the carcinoma of the rectum, intestines Road polyp, diverticulitis, colitis, pancreatitis, hepatitis, Small Cell Lung Cancer, neuroblastoma, neuroendocrine cell tumour, Islet-cell tumour, medullary carcinoma of thyroid gland, melanoma, retinoblastoma, uterine cancer, chronic hepatitis, cirrhosis, ovary Cancer, cholecystitis, G. cephalantha, malignant tumor of digestive tract, non-small cell lung cancer, cervical carcinoma, orchioncus, bladder cancer or marrow Tumor.

Unless otherwise indicated, the stereoisomer that the compound of the present invention is all, geometric isomer, tautomerism Body, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug belong to this hair Bright range.

Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " includes substance or composition must Must be suitble to chemistry or toxicologically, it is related with the other components of composition preparation and mammal for treatment.

The salt of the compound of the present invention further includes the intermediate for being used to prepare or purifying compound shown in formula (I) or formula (II) Or the salt of the enantiomter of the separation of compound shown in formula (I) or formula (II), but it is not necessarily pharmaceutically acceptable salt.

If the compound of the present invention be it is alkaline, conceivable salt can be by provided in the literature any suitable Method is prepared, for example, using inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid etc..Or using organic Acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid；Pyrans Saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and tartaric acid；Amino acid, such as asparatate and paddy Propylhomoserin；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, ethanesulfonic acid, etc..

If the compound of the present invention be it is acid, conceivable salt can be prepared by suitable method, e.g., Using inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxide, etc. Deng.Suitable salt includes, but is not limited to, organic salt obtained from amino acids, such as glycine and arginine, ammonia, and such as primaquine, secondary Ammonia and tertiary ammonia and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium Inorganic salts.

The composition of the compound of the present invention, preparation and administration

The characteristics of pharmaceutical composition of the invention includes the compound of formula (I) or formula (II) according to another aspect, the present invention The compound and pharmaceutically acceptable carrier of listed compound or embodiment 1-11, adjuvant or excipient.The present invention Composition in the amount of compound effectively can detectably inhibit the protein kinase of biological sample or patient's body.

There are free forms for the compound of the present invention, or it is suitable, as pharmaceutically acceptable derivates.According to this hair Bright, pharmaceutically acceptable derivates include, but is not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt or energy of esters Other any adducts or derivative being directly or indirectly administered according to the needs of patient, the present invention other aspect described in Compound, metabolite or his residue.

As described in the invention, the pharmaceutically acceptable composition of the present invention further includes pharmaceutically acceptable load Body, adjuvant or excipient, these are as applied by the present invention, including any solvent, diluent or other liquid excipients, point Powder or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., It is suitable for distinctive target formulation.As described in following documents: In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins, Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick And J.C.Boylan, 1988-1999, Marcel Dekker, New York, the content of comprehensive document herein, shows different Carrier can be applied to the preparation and their well known preparation methods of pharmaceutically acceptable composition.In addition to any conventional carrier The medium range incompatible with the compound of the present invention, for example, caused by any undesirable biological effect or with can pharmaceutically connect The interaction that any other component for the composition received generates in harmful manner, their purposes are also that the present invention is considered Range.

The substance that can be used as pharmaceutically acceptable carrier includes, but is not limited to, ion-exchanger, aluminium, aluminum stearate, ovum Phosphatide, haemocyanin, such as human albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate are saturated vegetable butter The partial glyceride mixtures of fat acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorination Sodium, zinc salt, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking polymerization Body, lanolin, sugar, such as lactose, dextrose and saccharose；Starch such as cornstarch and potato starch；The derivative of cellulose and it Such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Gum powder；Malt；Gelatin；Talcum powder；Auxiliary material such as cocoa bean Rouge and suppository wax；Oil such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil；Glycols chemical combination Object, such as propylene glycol and polyethylene glycol；Esters such as ethyl oleate and ethyl laurate；Agar；Buffer such as magnesium hydroxide and Aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge (family name) solution；Ethyl alcohol, phosphate buffer solution and other are nontoxic Suitable lubricant such as Sodium Laurylsulfate and magnesium stearate, colorant, releasing agent, coating agents, sweetener, flavoring agent and perfume (or spice) Material, preservative and antioxidant.

Composition of the invention can be oral administration, drug administration by injection, Aerosol inhalation, local administration, per rectum administration, Nose administration, buccal administration or are administered vagina administration by implantable medicine box.Term used herein " through what is injected " includes It is subcutaneous, vein, it is intramuscular, it is intra-articular, it is intrasternal in synovial membrane (chamber), in film, intraocular, in liver, lesion Interior and encephalic injection or infusion techniques.Preferred composition is oral administration, to Intraperitoneal medication or intravenous injection.This The injection system of the composition sterile of invention can be water or oil suspension.These suspension can be according to known skill Art is using suitable dispersing agent, wetting agent and suspending agent by formula manufacture.Aseptic injection can be aseptic parenteral solution or suspension Liquid is injection nontoxic acceptable diluent or solvent, such as 1,3-BDO solution.These acceptable excipient and solvent It can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, sterile non-volatile oil can be made by convention For solvent or suspension media.

With this end in view, any mild non-volatile oil can be the list or diphenylglycerol diester of synthesis.Fat Acid, if oleic acid and its glyceride ester derivatives can be used for the preparation of injectable, as natural pharmaceutically acceptable oil Rouge, such as olive oil or castor oil, especially their polyoxyethylene deriv.These oil solutions or suspension may include long-chain Alcohol diluent or dispersing agent are generally used for the drug system of pharmaceutically acceptable dosage form such as carboxymethyl cellulose or similar dispersing agents Agent includes emulsion and suspension.Other common surfactants, such as Tweens, spans and other emulsifiers or biological medicament The hardening agent of efficiency is generally used for pharmaceutically acceptable solid, liquid or other dosage forms, and can be applied to drug target The preparation of preparation.

The pharmaceutically acceptable composition of the present invention can be to be administered orally with any acceptable peroral dosage form, In include, but is not limited to, capsule, tablet, water suspension or solution.It is administered orally about tablet, carrier generally comprises cream Sugar and cornstarch.Lubricant, such as magnesium stearate, are all typically added.Capsule oral is administered, suitable diluent packet Include lactose and dry cornstarch.When oral administration is water suspension, effective component is made of emulsifier and suspending agent. If expecting these dosage forms, certain sweeteners, flavoring agent or colorant can also be added.

In addition, the pharmaceutically acceptable composition of the present invention can in the form of suppository rectally.These can pass through Reagent and suitable non-perfusing adjuvant are mixed with, this adjuvant be at room temperature solid but rectum at a temperature of then For liquid, to melt in the rectum and discharge drug.Such substance includes cocoa butter, beeswax and polyethylene glycols.This When inventing pharmaceutically acceptable composition and can be local administration, especially local application, it is related to controlling for region or organ It treats target to be easy to reach, such as the disease of eye, skin or lower intestinal tract.Suitable topical preparations can be prepared and be applied to These fields or organ.

Rectal suppository (see the above content) or suitable enema can be applied to the local application of lower intestine.Local skin Skin spot is it is also possible that medication.For local application, pharmaceutically acceptable composition can be prepared into properly by formulation method Ointment, the ointment include active constituent be suspended or dissolved in one or more carriers.Local administration of the present invention it is supported It closes object and includes, but is not limited to mineral oil, atoleine, albolene, propylene glycol, polyoxyethylene, polyoxypropylene compound, cream Change wax and water.In addition, pharmaceutically acceptable composition can be prepared into suitable lotion or emulsion, the lotion or emulsion include Active constituent is suspended in or is dissolved in one or more pharmaceutically acceptable carriers.Suitable carrier includes, but is not limited to, mine Object oil, Arlacel-60 (Arlacel-60), polysorbate60 (polysorbate 60), cetyl esters wax, palmityl alcohol, 2- Octyldodecanol, benzyl alcohol and water.

Preparation can be prepared into for ophthalmically acceptable, pharmaceutically acceptable composition, such as isotonic micronized suspension, pH The Sterile Saline of adjusting or other aqueous solutions, it is preferable that the Sterile Saline or other aqueous solutions that isotonic solution and pH are adjusted, it can be with Add disinfection preservative such as benzalkonium chloride.In addition, pharmaceutically acceptable composition can be by pharmaceutical formulation system for ophthalmically acceptable For at ointment such as vaseline oil.The pharmaceutically acceptable composition of the present invention can be carried out by the gaseous solvents or inhalant of nose to Medicine.Such composition can be prepared according to the well-known technique of pharmaceutical formulation, or can be prepared into salting liquid, use benzene first Alcohol or other suitable preservatives, sorbefacient, fluorocarbon or other conventional solubilizer or dispersing agent improve biology Availability.

The liquid dosage form of oral administration includes, but is not limited to, pharmaceutically acceptable emulsion, microemulsion, solution, suspends Liquid, syrup and elixir.In addition to the active compound, liquid dosage form may include well known general inert diluent, for example, water Or other solvents, solubilizer and emulsifier, such as ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Ergol, Propylene glycol, 1,3-BDO, dimethylformamide, grease (especially cottonseed, peanut, corn, microorganism, olive, castor-oil plant and Sesame oil), glycerol, Tetrahydrofurfuryl Alcohol, polyethylene glycol, sorbitan alcohol fatty acid ester and their mixture.Except lazy Except the diluent of property, Orally administered composition also may include adjuvant such as wetting agent, emulsifier or suspending agent, sweetener, flavoring agent And aromatic.

Injection, as aseptic parenteral solution or oil suspension can according to well-known technique using suitable dispersing agent, Wetting agent and suspending agent are prepared by pharmaceutical formulation.Aseptic injection can be nontoxic through parenterally acceptable diluent Or aseptic parenteral solution, suspension made of solvent or lotion, for example, 1,3-BDO solution.Acceptable excipient and solvent It can be water, Lin Ge (family name) solution, U.S.P. and isotonic sodium chlorrde solution.In addition, sterile non-volatile oil is by convention As solvent or suspension media.With this end in view any mild non-volatile oil may include that the list synthesized or two Portugal's bases are sweet Oily diester.In addition, fatty acid such as oleic acid can be applied to injection.

Injection can be sterile, such as defends filter by bacterium and filters, or in the form of aseptic solid composite Bactericidal agent is mixed, can be dissolved in or be scattered in disinfectant or other sterile injectable mediums using preceding bactericidal agent.In order to prolong The effect of long the compound of the present invention, it usually needs slow down the absorption of compound by subcutaneous injection or intramuscular injection.In this way It may be implemented to solve the problems, such as crystal or non-crystalline material poorly water-soluble using liquid suspension.The absorptivity of compound depends on Its dissolution rate successively depends on grain size and crystal shape.Furthermore it is possible to be dissolved in oil vehicles by compound Or dispersion absorbs to complete the delay of compound injection administration.

Injection storage form is by biodegradable polymer, and such as more lactic acid-polyglycolide forms chemical combination What the microcapsule matrix of object was completed.The controlled release ratio of compound depends on the ratio and particular polymer that compound forms polymer Property.Other biodegradable polymers include poly- (positive esters) and poly- (acid anhydrides).Injection storage form can also pass through Compound is embedded in the liposome or microemulsion compatible with bodily tissue and is prepared.

Some of embodiments are, the composition of rectum or vagina administration is suppository, and suppository can be by will be of the invention Compound mixes to be prepared with the auxiliary material of suitable non-perfusing or carrier, and such as cocoa butter, polyethylene glycol or suppository are wax-like Object, they are solid in room temperature but are under body temperature then liquid, therefore release of active conjunction is just melted in vagina or cavity of tunica vaginalis Object.

The solid dosage forms of oral administration includes capsule, tablet, pill, pulvis and granula.In these dosage forms, active ingredient Object is mixed at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or calcium phosphate or filler or a) Filler such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) adhesive such as carboxymethyl cellulose, alginates are bright Glue, polyvinyl pyrrolidone, sucrose and Arabic gum, c) moisturizer such as glycerol, d) disintegrating agent such as agar, calcium carbonate, potato starch Or tapioca, alginic acid, certain silicates and sodium carbonate, e) retardance agent solution such as paraffin, f) sorbefacient such as quaternary ammonium Compound, g) wetting agent such as hexadecanol and glycerin monostearate, h) absorbent such as white bole and bentonite, i) lubricant such as talcum Powder, calcium stearate, magnesium stearate, solid polyethylene glycol, Sodium Laurylsulfate and their mixture.As for capsule, tablet and ball Agent, these dosage forms may include buffer.

The solid composite of similar type can be filler and riddle soft or hard capsule, and used auxiliary material has cream Sugared and high molecular polyethylene glycol etc..Solid dosage forms photo agent, pastille, capsule, pill and granula can pass through coating, shell adding As well known coating method is prepared on enteric coating and other drugs preparation.They can optionally include opacifier, or Preferably, in certain a part of enteron aisle, arbitrarily, with the sole active agent in the method release composition of delay.Such as implantation Composition may include multimeric species and wax.

Reactive compound can be formed together microcapsule formulations with one or more excipient described in the invention.Solid The agent of dosage form photo, pastille, capsule, pill and granula can be by coating or shell addings, such as enteric coating, controlled release coat and other public affairs The drug formulation process known.In these solid dosage forms, reactive compound can be mixed at least one inert diluent, such as sugarcane Sugar, lactose or starch.Such dosage form also may include additive besides inert diluents as general application, such as Tableting lubricant and other compression aids such as magnesium stearate and microcrystalline cellulose.As for capsule, tablet and pill, these dosage forms can To include buffer.They can optionally include sedative, or preferably, in certain a part of enteron aisle, with what is arbitrarily postponed Method discharges the sole active agent in composition.Applicable implant compositions may include, but be not limited to, polymer and Wax.

The compound of the present invention by part or dosage form through percutaneous drug delivery include ointment, paste, emulsion, lotion coagulates Jelly, pulvis, solution, spray, inhalant, patch.Active constituent under sterile conditions with pharmaceutically acceptable carrier It is mixed with any required preservative or required buffer.The pharmaceutical preparation of ophthalmology, auristilla and eye drops are all this hairs The range of bright consideration.In addition, present invention further contemplates that the application of transdermal patch, it, which is transmitted to aspect in vivo in control compound, has More advantages, such dosage form can be prepared by dissolving or dispersing compound into suitable medium.It absorbs and promotees Into agent can increase compound pass through skin flow, through-rate control film or by compound be scattered in polymer matrix or Gelatin controls its rate.

The compound of the present invention is preferably prepared into dosage unit form by pharmaceutical formulation to mitigate the equal of dosage and dosage Even property.Term " dosage " unit type " obtains the physical dispersion unit of drug needed for suitably treating referred to herein as patient.However, answering Understand the daily total usage of the compound of the present invention or composition will by attending physician according to reliable medicine range judge come It determines.It includes being controlled that specific effective dose level, which will depend on many factors for any one special patient or organism, The illness for the treatment of and the seriousness of illness, the activity of particular compound, concrete composition used, the age of patient, weight, health Situation, gender and eating habit, administration time, the discharge rate of administration route and particular compound used, treatment it is lasting when Between, medicinal application in drug combination or with specific compound combination and some other factor well-known in the field of pharmacy.

The change that the dosage of the compound of the present invention of single dosage form composition can be generated in conjunction with carrier mass depends on It cures mainly and special mode of administration.Some of embodiments are that composition can be prepared into dosage in 0.01- by formulation method The inhibitor of 200mg/kg body weight/day receives the amount of composition by patient to be administered.

The compound of the present invention can be with only pharmaceutical agents or other one or more additional treatment (pharmacy of combination ) agent is administered, wherein drug combination causes acceptable adverse reaction, this has the treatment of high proliferative disease such as cancer There is special meaning.In this case, the compound of the present invention can be in conjunction with known cytotoxic agent, and single transduction inhibits Agent or other antitumor and anticancer agents and their mixture and combination.As used in the present invention, additional therapeutic agent is normally administered and controls Special disease is treated, exactly known " suitably treating disease "." additional therapeutic agent " used in the present invention includes Chemo-Therapy It treats drug or other antiproliferative drugs can be in conjunction with the compound of the present invention treatment proliferative diseases or cancer.

Chemotherapeutic agent or other anti-proliferative drugs include histon deacetylase (HDAC) (HDAC) inhibitor, including but simultaneously It is not limited to, SAHA, MS-275, compound described in MGO103 and those following patents: WO 2006/010264, WO 03/024448,WO 2004/069823,US 2006/0058298,US 2005/0288282,WO 00/71703,WO 01/ 38322, WO 01/70675, WO 03/006652, WO 2004/035525, WO2005/030705, WO 2005/092899, and Demethylating agent includes, but is not limited to, miscellaneous -2 '-deoxycytidine of nitrogen (5-aza-dC) of 5-, azacitidine (Vidaza), Compound described in his shore (Decitabine) of west and following documents: US 6,268137, US 5,578,716, US5,919, 772, US 6,054,439, US 6,184,211, US 6,020,318, US 6,066,625, US 6,506,735, US 6, 221,849,US 6,953,783,US 11/393,380。

Other embodiment is that chemotherapeutic agent or other anti-proliferative drugs can be controlled in conjunction with the compound of the present invention Treat proliferative diseases and cancer.Known chemotherapeutic agent includes, but is not limited to, other therapies or anticancer agent can combine Anticancer agent of the invention is with including surgery, and (a little example such as γ is radiated radiotherapy, neutron beam radiotherapy, electron beam evaporation Therapy, proton therapy, brachytherapy and system isotope therapy), endocrinotherapy, taxanes (Japanese yew Alcohol, Docetaxel etc.), the derivative of platinum, biological response modifiers (interferon, interleukin, tumor necrosis factor (TNF), the effect of TRAIL receptor target and medium), overheat and cold therapy dilute reagent (such as antiemetic of any adverse reaction Medicine) and other approve chemotherapeutic agent, including but not limited to, alkylating drug (mustargen, Chlorambucil, ring phosphinylidyne Amine, melphalan, ifosfamide), antimetabolite (methotrexate (MTX), pemetrexed (Pemetrexed) etc.), purine Antagonist and Pyrimidine antagonists (6-MP (6-Mercaptopurine), 5 FU 5 fluorouracil, Cytarabile, gemcitabine (Gemcitabine)), spindle poison (vincaleukoblastinum, vincristine, vinorelbine, taxol), podophyllotoxin (rely on pool Glycosides, Irinotecan (Irinotecan), Hycamtin (Topotecan)), antibiotic (win by Doxorubicin (Doxorubicin) Lay mycin (Bleomycin), mitomycin (Mitomycin)), nitroso ureas (Carmustine (Carmustine), lomustine (Lomustine)), inorganic ions (cis-platinum, carboplatin), (KSP is pressed down cell division cycle inhibitor by mitotic kinesins Preparation, CENP-E and CDK inhibitor), ferment (asparaginase), (tamoxifen (Tamoxifen), bright third is auspicious for hormone Woods (Leuprolide), Flutamide (Flutamide), megestrol acetate (Megestrol)), Gleevec (Gleevec), adriamycin (Adriamycin), dexamethasone (Dexamethasone) and cyclophosphamide.Anti-angiogenesis (Avastin (Avastin) and other), kinase inhibitor (Imatinib (Imatinib), Sutent (Sutent), Sorafenib (Nexavar), Cetuximab (Erbitux), Trastuzumab (Herceptin), Tarceva (Tarceva), Iressa (Iressa) and other).Drug inhibition or activate cancer approach such as mTOR, HIF (hypoxia inducible factor) approach and other.Cancer Disease is treated wide forum and is seenhttp://www.nci.nih.gov/, FAD approve oncologic inventory seehttp:// www.fda.gov/cder/cancer/druglist-rame.htmAnd Merck Manual, the 18th edition .2006, all contents All it is combined with bibliography.

Other embodiment is that the compound of the present invention can be with combination cell toxin anticancer agent.Such anticancer agent can To find the 13rd edition Merck index (2001) is inner.These anticancer agents include, but are not limited to, L-Asparaginasum (Asparaginase), bleomycin (Bleomycin), carboplatin, Carmustine (Carmustine), Chlorambucil (Chlorambucil), cis-platinum, L-ASP (Colaspase), cyclophosphamide, cytarabine (Cytarabine) reach Carbazine (Dacarbazine), actinomycin D (Dactinomycin), daunorubicin (Daunorubicin), adriamycin is (more It is soft than star), epirubicin (Epirubicin), Etoposide (Etoposide), 5-fluor-uracil, hexamethyl melamine, hydroxyl Base urea, ifosfamide, Irinotecan, folinic acid, lomustine, mustargen, Ismipur, mesna (Mesna), first ammonia Pterin (Methotrexate), mitomycin C (Mitomycin C), mitoxantrone (Mitoxantrone), prednisolone (Prednisolone), prednisone (Prednisone), procarbazine (Procarbazine), Raloxifene (Raloxifen), Streptozocin (Streptozocin), tamoxifen (Tamoxifen), thioguanine (Thioguanine), Hycamtin are long Spring alkali, vincristine, eldisine.

It is included, but is not limited to other suitable cytotoxic drugs of the compound of the present invention drug combination, these Admittedly it is applied to the compound of tumor disease treatment, as described in following documents: Goodman and Gilman's The Pharmacological Basis of Therapeutics(Ninth Edition,1996,McGraw-Hill.)；This A little anticancer agents include, but are not limited to, aminoglutethimide (Aminoglutethimide), l-Asparaginase, imuran, 5- Azacytidine, Cladribine (Cladribine), busulfan (Busulfan), diethylstilbestrol, 2', 2'- difluoro dCDP Choline, Docetaxel, red hydroxyl nonyl adenine (Erythrohydroxynonyladenine), ethinylestradiol, 5- Fluorodeoxyuridine, floxuridine monophosphate, fludarabine phosphate (Fludarabine phosphate), fluorine first Testosterone (Fluoxymesterone), Flutamide (Flutamide), hydroxyprogesterone caproate, idarubicin (Idarubicin), interference Element, medroxyprogesterone acetate, megestrol acetate, melphalan (Melphalan), mitotane (Mitotane), taxol, spray department he Fourth (Pentostatin), N- phosphate base-L-Aspartic acid (PALA), plicamycin (Plicamycin), methyl cyclohexane are sub- Nitre urea (Semustine), Teniposide (Teniposide), testosterone propionate, phosphinothioylidynetrisaziridine (Thiotepa), trimethyl melamine Amine urinates nucleosides and vinorelbine.

Other include suitably newfound cell with the cytotoxin class anticancer agent of the compound of the present invention use in conjunction Toxic substance, including, but be not limited to, oxaliplatin (Oxaliplatin), gemcitabine (Gemcitabine), card training His shore (Capecitabine), macrolides antineoplastic and its natural or synthetic derivative, Temozolomide (Temozolomide) (Quinn et al., J.Clin.Oncology, 2003,21 (4), 646-651), tositumomab (Bexxar), Trabedectin (Vidal et al., Proceedings of the American Society for Clinical Oncology, 2004,23, abstract3181), and driving albumen spindle protein inhibitor Eg5 (Wood et al.,Curr.Opin.Pharmacol.2001,1,370-377)。

Other embodiment is that the compound of the present invention can combine other signal transduction inhibitors.What is interesting is letters Number transduction inhibitor using EGFR family as target, such as EGFR, HER-2 and HER-4 (Raymond et al., Drugs, 2000, 60(Suppl.l),15-23；Harari et al., Oncogene, 2000,19 (53), 6102-6114) and their own match Body.Such reagent includes, but is not limited to, antibody therapy such as Trastuzumab (trastuzumab), Cetuximab (Erbitux), With handkerchief trastuzumab (Pertuzumab).Such therapy also includes, but is not limited to, small molecule kinase inhibitors such as Iressa (Gefitinib), Tarceva (Erlotinib), Tykerb (Lapatinib), CANERTINIB (CI1033), AEE788 (Traxler et al.,Cancer Research,2004,64,4931-4941)。

Other embodiment is that the compound of the present invention combines other signal transduction inhibitor targetings to swash in division Enzyme field family receptor kinase (VEGFR, FGFR, PDGFR, flt-3, c-kit, c-fins, Abl, Jak, Aurora-A, or Aurora-B etc.) and their own ligand.Such reagent includes, but is not limited to, antibody such as bevacizumab (Avastin).Such reagent includes, but is not limited to, micromolecular inhibitor such as Gleevec/Imanitib, Sprycel (Dasatinib), Tasigna/Nilotinib, Nexavar (Vandetanib), Vatalanib (PTK787/ZK222584) (Wood et al.,Cancer Res.2000,60(8),2178-2189),Telatinib/BAY-57-9352,BMS- 690514,BMS-540215,Axitinib/AG-013736,Motesanib/AMG706,Sutent/Sunitinib/SU- 11248,ZD-6474(Hennequin et al.,92nd AACR Meeting,New Orleans,Mar.24-28,2001, abstract 3152),KRN-951(Taguchi et al.,95th AACR Meeting,Orlando,FIa,2004, abstract2575),CP-547,632(Beebe et al.,Cancer Res.2003,63,7301-7309),CP-673, 451(Roberts et al.,Proceedings of the American Association of Cancer Research,2004,45,abstract3989),CHIR-258(Lee et al.,Proceedings of the American Association of Cancer Research,2004,45,abstract2130),MLN-518(Shen et al.,Blood,2003,102,11,abstract476)。

Other embodiment is that the compound of the present invention can be with bonding histone deacetylase inhibitors.It is such Reagent includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824 (Ottmann et al., Proceedings of the American Society for Clinical Oncology,2004,23,abstract3024),LBH-589 (Beck et al.,Proceedings of the American Society for Clinical Oncology,2004, 23,abstract3025),MS-275(Ryan et al.,Proceedings of the American Association of Cancer Research,2004,45,abstract2452),FR-901228(Piekarz et al.,Proceedings Of the American Society for Clinical Oncology, 2004,23, abstract3028) and MGCDOI03 (US6,897,220)。

Other embodiment is that the compound of the present invention can combine other anticancer agents such as proteasome inhibitor and m- TOR inhibitor.These include, but are not limited to, bortezomib (Bortezomib) (Mackay et al., Proceedings Of the American Society for Clinical Oncology, 2004,23, Abstract3109), and CCI-779 (Wu et al.,Proceedings of the American Association of Cancer Research,2004, 45,abstract3849).The compound of the present invention can be combined with other anticancer agents such as topoisomerase enzyme inhibitor, including but It is not limited to camptothecine.

Those additional therapeutic agents can separately be administered with the composition comprising the compound of the present invention, as more dosage regimens A part.Alternatively, those therapeutic agents can be a part of one-pack type, mix to form list with the compound of the present invention A composition.If a part as more dosage regimens is administered, two activating agents can be simultaneously continuously or in a period of time Interior mutual transmitting, to obtain destination agent activity.

(those include one additional to the compound and the dosage of additional therapeutic agent that one-pack type can be generated in conjunction with carrier mass The composition of therapeutic agent is as described in the invention) change depend on cure mainly and special mode of administration.Normally, of the invention It includes therapeutic agent as the normal amount administered of unique activating agent that the amount of composition additional therapeutic agent, which will be no more than composition,.Separately On the one hand, the range of the amount of existing disclosed composition additional therapeutic agent is about the 50%-100% of existing composition normal amount, The reagent for including is as sole active therapeutic agent.In the composition that those include additional therapeutic agent, additional therapeutic agent will be with this The compound of invention plays synergistic effect.

The purposes of the compound of the present invention and composition

The feature of pharmaceutical composition of the invention includes listed by formula (I) or formula (II) compound represented or the present invention Compound and pharmaceutically acceptable carrier, adjuvant or excipient.The amount of compound can be effective in composition of the invention Ground detectably inhibits protein kinase such as Abl, FLT-3, Jak, the activity of Aurora-A or Aurora-B.Chemical combination of the invention Object will be applied to the treatment as anti-tumor drug or reduce harmful work of Abl, FLT-3, Jak, Aurora-A or Aurora-B With.

The compound of the present invention will be applied to, but be not limited to, and use the compound of the present invention or the effective quantity of composition It administers to a patient to prevent or treat patient's proliferative diseases.Such disease includes cancer, and especially acute myelocytic is white Blood disease (AML), the chronic myelogenous leukemia (CML) of mutation, acute lymphoblastic leukemia (ALL), metastatic carcinoma, Atherosclerosis Change and pulmonary fibrosis.

The compound of the present invention includes proliferative diseases by the treatment of tumor is applied to, and further comprises, but be not limited to acute Myelocytic leukemia (AML), the chronic myelogenous leukemia (CML) of mutation, acute lymphoblastic leukemia (ALL), Colon and rectum Cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, cancer of pancreas, thyroid cancer, kidney, brain tumor, neck cancer, CNS (nervous centralis System) cancer, glioblastoma, myeloproliferative disease, atherosclerosis, pulmonary fibrosis, leukaemia, lymph cancer, rheumatic Disease, chronic inflammation, cryoglobulinemia, non-lymphoreticular system tumour, papular mucinosis, familial splenic are poor Blood, Huppert's disease, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic It is leukaemia, primary macroglobulinaemia, half molecule disease, monocytic leukemia, primary macroglobulinaemia purpura, secondary Property benign monoclonal gammopathy, osteolytic lesion, lymphoblastoma, non-Hodgkin lymphoma, Sezary syndrome, Infectious mononucleosis, acute histocytic increase disease, Hodgkin lymphoma, hairy cell leukemia, colon cancer, rectum Cancer, polyposis intestinalis, diverticulitis, colitis, pancreatitis, hepatitis, Small Cell Lung Cancer, neuroblastoma, neuroendocrine cell Tumour, islet-cell tumour, medullary carcinoma of thyroid gland, melanoma, retinoblastoma, uterine cancer, chronic hepatitis, cirrhosis, Oophoroma, cholecystitis, G. cephalantha, malignant tumor of digestive tract, non-small cell lung cancer, cervical carcinoma, orchioncus, bladder cancer or Myeloma.

The compound of the present invention can also be used to treat eye disease such as corneal graft rejection, and the new vessels of eye are formed, Retinal neovascularazation includes that damage or metainfective new vessels are formed；Diabetic retinopathy；It is fine after crystalline lens Tie up hyperblastosis disease and neovascular glaucoma；Treat retinal ischemic；Vitreous hemorrhage；Ulcer disease such as gastric ulcer；Pathology The blood vessel of situation such as hemangioma learn but non-malignant, including baby's hemangioendothelioma, nasopharynx and no vascular osteonecrosis is fine Tie up tumor；Female repro ductive system disorder such as mullerianosis.These compounds are equally also used for treatment oedema and vascular permeability Excessively high situation.

The compound of the present invention can be used for handling the situation such as diabetic retinopathy and micro- blood related to diabetes Pipe disease.The compound of the present invention is equally used for the case where cancer patient's blood flow is reduced.The compound of the present invention is to patient tumors Transfer, which is reduced, also beneficial effect.

The compound of the present invention is in addition to beneficial to other than, applying also for veterinary treatment pet, introduced variety to human treatment Animal and farm animal, including mammal, rodent etc..The example of other animal include horse, dog and Cat.Here, the compound of the present invention includes its pharmaceutically acceptable derivates.

In the case where plural form is applied to compound salt etc., also mean single compound, salt etc..

It further comprise to patient's additional therapeutic agent comprising the treatment method that the compound of the present invention or composition are administered The administration of (combination therapy), wherein additional therapeutic agent is selected from: chemotherapy, immunosuppressor, immunostimulant, antiproliferative or Anti-inflammatory agent, wherein additional therapeutic agent is suitable for treated disease, and additional therapeutic agent can be with the compound of the present invention or group Object administering drug combinations, the compound of the present invention or composition are closed as single dosage form or separated compound or composition as more A part of dosage form.Additional therapeutic agent can be administered simultaneously with the compound of the present invention or not be administered simultaneously.The case where the latter, is given Medicine can be staggered progress such as 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months and carry out.

Additional therapeutic agent of the present invention refers to Chlorambucil (chlorambucil), melphalan (melphalan), Cyclophosphamide (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busulfan), Carmustine (carmustine), lomustine (lomustine), streptozotocin (streptozocin), cis-platinum (cisplatin), card Platinum (carboplatin), oxaliplatin (oxaliplatin), Dacarbazine (dacarbazine), Temozolomide (temozolomide), procarbazine (procarbazine), methotrexate (MTX) (methotrexate), fluorouracil (fluorouracil), cytarabine (cytarabine), gemcitabine (gemcitabine), purinethol (mercaptopurine), fludarabine (fludarabine), vincaleukoblastinum (vinblastine), vincristine (vincristine), vinorelbine (vinorelbine), taxol (paclitaxel), Docetaxel (docetaxel), Topotecan (topotecan), Irinotecan (irinotecan), Etoposide (etoposide), tributidine (trabectedin), dactinomycin D (dactinomycin), Doxorubicin (doxorubicin), epirubicin (epirubicin), daunomycin (daunorubicin), mitoxantrone (mitoxantrone), bleomycin (bleomycin), mitomycin C (mitomycin), Ipsapirone (ixabepilone), tamoxifen (tamoxifen), fluorine His amine (flutamide), Gonadorelin analog (gonadorelin analogues), megestrol acetate (megestrol), by force Pine (prednidone), dexamethasone (dexamethasone), methylprednisolone (methylprednisolone), Sha Lidu Amine (thalidomide), interferon-' alpha ' (interferon alfa), Calciumlevofolinate (leucovorin), sirolimus (sirolimus), temsirolimus (temsirolimus), everolimus (everolimus), Afatinib (afatinib), alisertib, amuvatinib, Ah pa replace Buddhist nun (apatinib), and Axitinib (axitinib), boron is for assistant Rice (bortezomib), posupini (bosutinib), brivanib, cabozantinib, Si Dinibu (cediranib), Crenolanib, gram Zhuo replace Buddhist nun (crizotinib), dabrafenib, dacomitinib, danusertib, Dasatinib (dasatinib), dovitinib, Tarceva (erlotinib), foretinib, ganetespib, Gefitinib (gefitinib), ibrutinib, Conmana (icotinib), Imatinib (imatinib), iniparib, Lapatinib (lapatinib), lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, For husky Buddhist nun (motesanib), linatinib (neratinib), nilotinib (nilotinib), niraparib, Oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, Regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Sorafenib (sorafenib), Sutent (sunitinib), tasocitinib, telatinib, tivantinib, Tivozanib, tofacitinib, trametinib, Vande Thani (vandetanib), veliparib, Wei Luofeini (vemurafenib), vismodegib, volasertib, alemtuzumab (alemtuzumab), bevacizumab (bevacizumab), brentuximabvedotin, catumaxomab (catumaxomab), Cetuximab (cetuximab), ground promise monoclonal antibody (denosumab), lucky trastuzumab (gemtuzumab), her monoclonal antibody (ipilimumab), Buddhist nun's trastuzumab (nimotuzumab), difficult to understand (ofatumumab), Victibix (panitumumab), rituximab list Anti- (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab) or their combination.

The present invention equally includes the cell growth inhibition to expression Abl, FLT-3, Jak, Aurora-A or Aurora-B Method, the method includes that the compound of the present invention or composition are contacted with cell, so that cell be inhibited to grow.Growth can be suppressed Cell include: breast cancer cell, colorectal cancer cell, lung carcinoma cell, papillary carcinoma cell, prostate gland cancer cell, lymph Oncocyte, colon cancer cell, pancreatic cancer cell, ovarian cancer cell, cervical cancer cell, central nervous system cancer cell, skeletonization Sarcoma cell, kidney cancer cell, hepatocellular carcinoma cells, bladder cancer cell, stomach cancer cell, head or carcinoma of neck cell, melanoma are thin Born of the same parents and leukaemia cell.

The present invention provides inhibit Abl, FLT-3, Jak, Aurora-A or Aurora-B kinase activity in biological sample Method, the method includes contacting the compound of the present invention or composition with biological sample.Term used in the present invention is " raw Object sample " refers to the sample of vitro, including but not limited to, cell culture or cell extraction；From mammal or its mention The biopsy substance for taking object to obtain；Blood, saliva, urine, excrement, sperm, tears or other living tissue liquid substances and Its extract.Inhibit kinase activity, especially Abl in biological sample, FLT-3, Jak, Aurora-A or Aurora-B kinases is lived Property, it can be used for multiple use well known to one of ordinary skill in the art.Such purposes includes, but is not limited to, hematometachysis, organ Transplanting, biological sample storage and bioassay.

" effective quantity " or " effective dose " of the compound of the present invention or pharmaceutically acceptable composition refer to processing or Mitigate the effective quantity that one or more present invention are previously mentioned the severity of illness.According to the method for the present invention, compound and combination Object can be any dosage and any administration route to be efficiently used for handling or mitigate the severity of disease.Required standard True amount will change according to the case where patient, this is depending on ethnic, the age, the general condition of patient, the severity of infection, Special factor, administration mode, etc..Compound or composition can be administered in combination with one or more other therapeutic agents, such as What the present invention was discussed.

The compound of the present invention or its pharmaceutical composition can be applied to the coating of implantable medical device, such as prosthese, Artificial valve, artificial blood vessel, stem and catheter.For example, vascular stem, have been used for overcoming restenosis (vessel wall after injury It shrinks again).However, patient will have the risk of clot formation or platelet activation using stem or other implantable devices.These Unfavorable effect can be hindered by using the pharmaceutically acceptable composition precoating device comprising the compound of the present invention Only or mitigate.

The general preparation method of suitable coating and the coating of implantable device is in document US 6,099,562；US 5, 886,026；It is described in US 5,304,121, coating is typically biocompatible polymeric material such as hydrogel Condensate, poly- two silicon ether of methyl, polycaprolactone, polyethylene glycol, polylactic acid, ethane-acetic acid ethyenyl ester and its mixture.Packet Clothing can be covered optionally further by suitably coating, such as fluoro dimeticone, polysaccharase, polyethylene glycol, phosphatide Class or their combination carry out the feature of performing combination object control release.Another aspect of the present invention includes using change of the invention Close the implantable device of object coating.The compound of the present invention can also be coated in can plant on intracorporal medical instruments, such as pearl Object, or " medicine storage institute " is provided with polymer or other molecular mixings, therefore compared with pharmaceutical aqueous solution administration mode, permit Perhaps drug release has longer time limit.

General synthetic method

Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I) or formula (II).Following reaction scheme and embodiment is for further lifting Example illustrates the contents of the present invention.

Those skilled in the art will realize that: chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.

The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Imperial chemistry examination is risen in factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Qingdao Agent Co., Ltd and Haiyang Chemical Plant, Qingdao are commercially available.

Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride It with chloroform is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.

Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.

Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDC1₃,d⁶-DMSO,CD₃OD or d⁶Acetone is solvent (report is as unit of ppm), with TMS (0ppm) or chloroform (7.25ppm) As reference standard.When there is multiplet, following abbreviation will be used: s (singlet, unimodal), d (doublet, it is double Peak), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant is indicated with hertz (Hz).

By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to low resolution mass spectrometry (MS) data DEG C) the spectrometer of Agilent6320 series LC-MS measure, G1329A automatic sampler and G1315B DAD detector Applied to analysis, the source ESI is applied to LC-MS spectrometer.

Low resolution mass spectrometry (MS) data are by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C) 6120 series LC-MS of Agilent spectrometer come what is measured, G1329A automatic sampler and G1315D DAD detector are answered For analyzing, the source ESI is applied to LC-MS spectrometer.

Both the above spectrometer is provided with Agilent Zorbax SB-C18 column, and specification is 2.1 × 30mm, and 5 μm.Note Beam product is determined by sample concentration；Flow velocity is 0.6mL/min；The peak value of HPLC is by 210nm and 254nm UV-Vis wavelength records reading.Mobile phase is that 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid are ultrapure water-soluble Liquid (phase B).Condition of gradient elution is as shown in table 1:

Table 1

Compound purifying is by Agilent1100 series of high efficiency liquid chromatogram (HPLC) come what is evaluated, and wherein UV is detected At 210nm and 254nm, Zorbax SB-C18 column, specification be 2.1 × 30mm, 4 μm, 10 minutes, flow velocity 0.6mL/min, (0.1% aqueous formic acid) of (0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.

The use of logogram word below is through the present invention:

Intermediate synthetic schemes 1

After compound 1 aoxidizes cyclization, by BrCH₂CH₂OH replaces open loop to generate compound 2, and cyclization occurs under alkaline condition Reaction generates 3, is further reduced and generates 4a.

Reaction scheme 1

Generation 6 is reacted with compound 4 after compound 5 is acylated, is reacted generation compound 9,9 by reduction generation 7,7 and 8 and is passed through After crossing reduction, generation 10 is reacted with TCDI, further generates product 11 with the salt substitution reaction of corresponding alkali or alkali.

Reaction scheme 2

Compound 9 by reduction after, react with compound 13 generate 12, further with the salt substitution reaction of corresponding alkali or alkali Generate product 11.

Wherein, R^2’For condensed-bicyclic base, miscellaneous bicyclic group, aryl, heteroaryl, heterocycle or carbocylic radical are condensed；R^2a, Y², And R⁷With definition as described herein.

The following examples can be with the present invention will be further described, however, these embodiments should not be used as to this hair The limitation of bright range.

Embodiment

Embodiment 1

(4aR, 7aR)-hexahydro -2H- [1,4] dioxin [2,3-c] pyrroles

Step 1:6- oxygen -3- azabicyclo [3.1.0] hexane -3- benzyl carboxylate

2,5- pyrrolin alkane -1- benzyl formate (10g, 49.24mmol) is dissolved in methylene chloride (30mL), is slowly added dropwise Into methylene chloride (70mL) mixed liquor of metachloroperbenzoic acid (10.55g, 61.14mmol), it is small that reaction 16 is stirred at room temperature When.Filtering, filtrate saturated sodium thiosulfate (100mL) and saturated sodium bicarbonate (100mL) are respectively washed once, anhydrous Na₂SO₄It is dry It is dry.Decompression boils off solvent, and the direct column chromatography for separation of residue (EA/PE (V/V)=1/3) obtains product (7.39g, 68.49%).

LC-MS:220(M+1).

Step 2:(4aR, 7aR)-tetrahydro -2H- [1,4] dioxin [2,3-c] pyrroles -6 (3H)-benzyl carboxylate

6- oxygen -3- azabicyclo [3.1.0] hexane -3- benzyl carboxylate (6.0g, 27.37mmol) is dissolved in dry methylene chloride It in (100mL), is added ethylene bromohyrin (3.73g, 30.13mmol), the ether for being then slowly added to boron trifluoride at room temperature is molten Liquid (0.39g, 2.74mmol), is stirred overnight at room temperature.Pressurization boils off solvent, obtains crude product, is directly used in the next step.

(3R, 4R) -3- (2- bromine oxethyl) -4- hydroxyl pyrrolidine -1- benzyl carboxylate (above walking crude product) is dissolved in dehydrated alcohol In (80mL), the aqueous solution (10mL) of potassium hydroxide (1.54g, 27.39mmol) is added, is then heated to reflux 6 hours.Filtering, Filter cake is eluted with ethyl acetate (50mL), merging filtrate, evaporated under reduced pressure, residue column chromatography for separation (EA/PE (V/V)=1/1) Obtain product (0.60g, 8.40%).

LC-MS:264(M+1)；

¹H NMR(400MHz,CDCl₃):δ7.30-7.36(m,5H),5.17(s,2H),3.81-3.87(m,5H),3.59- 3.77(m,2H),3.12-3.18(m,2H),1.24-1.27(m,1H).

Step 3:(4aR, 7aR)-hexahydro -2H- [1,4] dioxin [2,3-c] pyrroles

(4aR, 7aR)-tetrahydro -2H- [1,4] dioxin [2,3-c] pyrroles -6 (3H)-benzyl carboxylate (0.60g, It 2.28mmol) is dissolved in dry THF (10mL), is added 10%Pd/C (0.30g), hydrogen is replaced twice, is then heated to 50 DEG C Hydrogenolysis 6 hours.Filtering, filtrate are evaporated to obtain product, are directly used in the next step.

Embodiment 2

1- cyclopropyl -3- (3- (5- (((4aR, 7aR)-tetrahydro -2H- [1,4] dioxin [2,3-c] pyrroles -6 (3H)-yl) Methyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- base) thiocarbamide

Step 1:(3,4- dinitrophenyl) (4aR, 7aR)-tetrahydro -2H- [1,4] dioxin [2,3-c] pyrroles -6 (3H) - Base) ketone

3,4- dinitrobenzoic acids (0.58g, 2.74mmol) are dissolved in THF (20mL), and 2 drop DMF, SOCl are added₂ (0.24mL, 3.62mmol) is heated to reflux 2 hours.Then mixed liquor is cooled to 0 DEG C, be added triethylamine (0.59mL, 4.14mmol), THF (5mL) solution of (4aR, 7aR)-hexahydro -2H- [Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles, mixing is then added Liquid, which is warmed to room temperature, continues stirring 24 hours.It after solvent is removed under reduced pressure, is added water (20mL), methylene chloride extracts (150mL), anhydrous Sodium sulphate (25g) dry organic layer, concentration, column chromatography for separation (EA/PE (V/V)=1/1) obtain faint yellow solid (365mg, 41.29%).

LC-MS:324[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ8.10(d,1H),7.99(d,1H),7.89-7.91(m,1H),4.00- 4.03(m,1H),3.87-3.98(m,5H),3.85-3.86(m,1H),3.73-3.79(m,2H),3.38-3.44(m,2H).

Step 2:(4aR, 7aR) -6- (3,4- dinitrobenzyl) hexahydro -2H- [1,4] dioxin [2,3-c] pyrroles

Sodium borohydride (0.23g, 6.13mmol) is suspended in dry THF (20mL), and mixed liquor is cooled to 0 DEG C, is added dropwise three It is fluorinated borate ether (0.77mL, 6.13mmol), (3,4- dinitrophenyl) (4aR, 7aR)-tetrahydro -2H- [Isosorbide-5-Nitrae] two is then added Oxygen glutinous rehmannia [2,3-c] pyrroles -6 (3H)-yl) ketone (0.90g, 2.79mmol), it is slowly increased to be stirred overnight at room temperature.Mixed liquor is again It is cooled to 0 DEG C, is slowly added to be heated to reflux 1 hour after methanol (5mL) is generated to no gas.Solvent is removed under reduced pressure, in residue Ethyl acetate (50mL) is added to extract, is washed with water (30mL), dry (20g) organic layer of anhydrous sodium sulfate, concentration obtains Weak yellow liquid (0.60g, 71.69%).

LC-MS:333[M+23]⁺.

Step 3:4- (((4aR, 7aR)-tetrahydro -2H- [1,4] dioxin [2,3-c] pyrroles -6 (3H)-yl) methyl) benzene - 1,2- diamines

(4aR, 7aR) -6- (3,4- dinitrobenzyl) hexahydro -2H- [1,4] dioxin [2,3-c] pyrroles (1.40g, It 4.53mmol) is dissolved in DMF (20mL), 10%Pd/C (0.3g) is added and is stirred overnight at room temperature under conditions of hydrogen.Filtering Pd/C is removed, filtrate is directly used in the next step.

LC-MS:250[M+1]⁺.

Step 4:(4aR, 7aR) -6- ((2- (4- nitro -1H- pyrazole-3-yl) -1H- benzo [d] imidazoles -5- base) methyl) Hexahydro -2H- [1,4] dioxin [2,3-c] pyrroles

4- nitro -1H- pyrroles -3- carboxylic acid (0.65g, 4.12mmol) is added in step reaction solution upwards, EDCI (0.87g, 4.53mmol) with HOBt (0.61g, 4,53mmol), it is stirred overnight at room temperature.Solvent is removed under reduced pressure, acetic acid is added into residue (20mL) is heated to reflux 3 hours.Solvent is removed under reduced pressure, crosses column and is purified, obtain product (1.10g, 54%).

LC-MS:371[M+1]⁺.

Step 5:3- (6- (((4aR, 7aR)-tetrahydro -2H- [1,4] dioxin [2,3-c] pyrroles -6 (3H)-yl) methyl) - 1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- amine

(4aR, 7aR) -6- ((2- (4- nitro -1H- pyrazole-3-yl) -1H- benzo [d] imidazoles -5- base) methyl) hexahydro - 2H- [Isosorbide-5-Nitrae] dioxin [2,3-c] pyrroles (2.10g, 5.7mmol) is dissolved in DMF (20mL), is added 10%Pd/C (0.5g) It is stirred overnight at room temperature under conditions of hydrogen.It is filtered to remove Pd/C, filtrate, column chromatography for separation (CH is concentrated under reduced pressure₂Cl₂/CH₃OH (V/V)=20/1 product (0.37g, 19.17%)) is obtained.

LC-MS:341[M+1]⁺.

Step 6:8- (((4aR, 7aR)-tetrahydro -2H- [1,4] dioxin [2,3-c] pyrroles -6 (3H)-yl) methyl) -2H- Benzo [4,5] imidazoles [1,2-c] pyrroles [3,4-e] pyrimidine -5 (4H)-thioketones

3- (6- (((4aR, 7aR)-tetrahydro -2H- [1,4] dioxin [2,3-c] pyrroles -6 (3H)-yl) methyl) -1H- benzene And [d] imidazoles -2- base) -1H- pyrazoles -4- amine (0.34g, 0.98mmol) and thio-carbonyldiimidazole (0.35g, 1.97mmol) It is dissolved in DMAC (10mL) and is heated to 80 DEG C of stirrings 24 hours, LC-MS shows raw material fully reacting, directly carries out anti-in next step It answers.

LC-MS:383[M+1]⁺.

Embodiment 3

N- (3- (5- (morpholinomethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- base) -1H- imidazoles -1- sulphur For formamide

Step 1:(3,4- dinitrophenyl)-(morpholinyl)-ketone synthesis

3,4- dinitrobenzoic acids (10.0g, 47.2mmol) and DMF (0.1mL) are dissolved in THF (100mL), then SOCl₂It is added drop-wise in mixed liquor and is heated to reflux 2.5 hours.Mixed liquor is cooled to 0 DEG C, is added dropwise triethylamine (10mL, 71.2mmol) Temperature is kept to be longer than 20 minutes lower than 5 DEG C of times, being then added dropwise morpholine (7.2mL.82.1mmol) time is longer than 15 minutes, at this time A large amount of solid occurs, and mixed liquor slowly restores to be stirred overnight at room temperature.Ice water (250mL) is added in mixed liquor, is cooled to 0 DEG C so After filter, obtain yellow solid, washed with ice water, it is dry, obtain yellow solid (11.95g, 90%).

The synthesis of step 2:4- (3,4- dinitrobenzyl)-morpholine

The NaBH under the protection of nitrogen₄(3.36g, 89.78mmol) is dispersed in THF (360mL), after being cooled to 0 DEG C, is added Enter boron trifluoride ether (11.3mL, 89.78mmol), pay attention to there is hydrogen releasing at this time, (3,4- dinitrobenzenes are then once added Base)-(morpholinyl)-ketone (11.91g, 42.35mmol), it removes cryostat, and slowly restores to be stirred at room temperature 2 hours.It is carefully added into Methanol (100mL), heating mixed liquor flow back 1 hour.Concentrated liquid is dissolved with ethyl acetate (100mL), is saturated NaHCO₃It is water-soluble Liquid (100mL) washes organic phase, and ethyl acetate (3 × 50mL) aqueous phase extracted merges organic phase, and saturated common salt washes (50mL), does It is dry, it is concentrated to give solid, is recrystallized with methanol (50mL), product (10g, 89.3%) is obtained.

The synthesis of step 3:4- (morpholinyl methyl)-phenyl -1,2- diamines

Under the protection of nitrogen 10%Pd/C (0.525g) and 4- (3,4- dinitrobenzyl)-morpholine (10.5g, 42.35mmol) in ethanol, mixed liquor is cooled to 0 DEG C, and nitrogen is replaced into hydrogen, restores to be stirred overnight at room temperature for dissolution.Filtering Filtrate is concentrated in mixed liquor, crosses column and is purified (CH₂Cl₂/CH₃OH (V/V)=20/1), obtain product (6.34g, 61%).

¹H NMR(400MHz,d₆- DMSO): δ 6.47 (d, J=2.0Hz, 1H), 6.40-6.42 (d, J=7.6Hz, 1H), 6.27-6.29 (m, 1H), 4.32-4.38 (d, J=21.2Hz, 4H), 3.52-3.54 (t, J=4.8Hz, 4H), 3.18 (d, J= 2.0Hz,2H),2.28(s,4H).

The synthesis of step 4:4- ((2- (4- nitro -1H- pyrazole-3-yl) -1H- benzo [d] imidazoles -5- base) methyl) morpholine

4- (morpholinyl methyl)-phenyl -1,2- diamines (2.3g, 11.1mmol), 4- nitro -1H- pyrazoles -3- formic acid (1.57g, 10mmol), EDCHCl (2.13g, 11.1mmol) and HOBt (1.5g, 11.1mmol) are dissolved in anhydrous DMF In (25mL), it is stirred overnight at room temperature.Solvent is removed under reduced pressure, is added glacial acetic acid (40mL), is heated to reflux 3 hours, is removed in decompression Solvent is removed, column is crossed and is purified (CH₂Cl₂/CH₃OH (V/V)=20/1), then wash (30mL) with methanol, obtain solid (0.9g, 27%).

LC-MS:329[M+1]⁺,327[M-1]^-.

Step 5:3- (5- (morpholinyl methyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- amine

4- ((2- (4- nitro -1H- pyrazole-3-yl) -1H- benzo [d] imidazoles -5- base) methyl) morpholine under nitrogen protection (0.9g, 2.7mmol) is dissolved in DMF (30mL), is added 10%Pd/C (88mg), hydrogen is replaced, and is stirred at room temperature 5 hours Afterwards, it is filtered to remove solid, washes solid with methanol, concentration filtrate obtains brownish black solid, directly progress next step reaction.It is produced Object (0.84g, > 100%).

Step 6:N- (3- (5- (morpholinomethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- base) -1H- miaow Azoles -1- thioformamide

3- (5- (morpholinomethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- amine (0.596g, 2.0mmol) and N, N'- thiocarbonyldiimidazole (699mg, 3.92mmol) are dissolved in heated overnight at reflux in THF (8mL).Solid is obtained by filtration, into Row is dried under reduced pressure, directly progress next step reaction.

LC-MS:341.1[M+1]⁺.

Embodiment 4

8- (((4aR, 7aR)-tetrahydro -2H- [1,4] dioxin [2,3-c] pyrroles -6 (3H)-yl) methyl) -2H- benzo [4,5] imidazoles [1,2-c] pyrroles [3,4-e] pyrimidine -5 (4H)-thioketones is dissolved in DMAC (10mL), addition cyclopropylamine (2mL, 28.91mmol), 80 DEG C are heated to react 24 hours.After solvent is removed under reduced pressure, residue is dissolved in methylene chloride/methanol ((V/V) =50mL/2mL), twice, saturated sodium-chloride water solution is washed primary (20mL) for washing, and anhydrous sodium sulfate (10g) is dry.Decompression is steamed Remove solvent, column chromatographic purifying (CH₂Cl_2/CH₃OH (V/V)=10/1), crude product is obtained, chromatogram purification is prepared and obtains sterling (107mg, 24.88%).

LC-MS:440[M+1]⁺.

¹H NMR(400MHz,DMSO):δ13.16(s,1H),12.97(s,2H),11.33(brs,1H),8.96(s, 1H),8.63(s,1H),7.49-7.53(m,1H),7.42-7.44(m,1H),7.13-7.21(m,1H),3.88(s,1H), 3.75-3.77(m,3H),3.54-3.57(m,3H),3.16-3.18(d,1H),2.79-3.90(m,2H),2.58-2.59(m, 1H),2.50(s,2H),1.06(s,2H),0.72(s,2H).

Embodiment 5

1,1- diethyl -3- (3- (5- (((4aR, 7aR)-tetrahydro -2H- [1,4] dioxin [2,3-c] pyrroles -6 (3H) - Base) methyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- base) thiocarbamide

To N- (3- (5- (morpholinomethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- base) -1H- imidazoles -1- Diethylamine (2mL, 19.41mmol) is added in thioformamide reaction solution, is heated to 100 DEG C and reacts 24 hours.It is removed under reduced pressure molten After agent, residue is dissolved in methylene chloride/methanol ((V/V)=50mL/2mL), is washed twice (2 × 20mL), saturated sodium chloride water Solution is washed primary (30mL), and anhydrous sodium sulfate (10g) is dry.Decompression boils off solvent, column chromatographic purifying (CH₂Cl₂/CH₃OH(V/V) =10/1) crude product, is obtained, chromatogram purification is prepared and obtains sterling (72mg, 16.17%), purity 99.21%.

LC-MS:456[M+1]⁺.

¹H NMR(400MHz,DMSO):δ13.13(s,1H),13.02(s,2H),11.14(s,1H),8.92(s,1H), 8.03(s,1H),7.50-7.55(m,1H),7.42-7.45(m,1H),7.15-7.22(m,1H),3.83-3.91(m,6H), 3.75-3.79(m,2H),3.63-3.65(m,2H),3.16-3.18(m,1H),2.89(s,2H),2.57-2.61(m,2H), 1.31-1.34(m,6H).

Embodiment 6

1- cyclopropyl -3- (3- (5- (morpholinomethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- base) thiocarbamide

N- (3- (5- (morpholinomethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- base) -1H- imidazoles -1- sulphur It is dissolved in DMF (5mL) for formamide (0.316g, 0.93mmol) and cyclopropylamine (0.52mL, 7.4mmol), is heated to 100 degree It is stirred overnight, column purification (CH is crossed in mixed liquor concentration₂Cl₂/CH₃OH (V/V)=10/1), obtain white solid (0.06g, 16%).

LC-MS:398.1[M+1]⁺.

¹H NMR(400MHz,DMSO):δ13.17(s,1H),12.97(s,1H),11.30(s,1H),8.95(s,1H), 8.63 (s, 1H), 7.50-7.54 (t, J=8.0Hz, 1H), 7.43-7.45 (d, J=8.4Hz, 1H), 7.14-7.22 (m, 1H), 3.56-3.57 (d, J=4.8Hz, 6H), 2.78 (s, 1H), 2.37 (s, 4H), 1.05 (s, 2H), 0.71 (s, 2H)

Embodiment 7

1,1- diethyl -3- (3- (5- (morpholinomethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- base) sulphur Urea

N- (3- (5- (morpholinomethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- base) -1H- imidazoles -1- sulphur It is dissolved in DMF (5mL) for formamide (316mg, 0.93mmol) and diethylamine (0.6mL, 7.4mmol), is heated to 100 degree and stirs It mixes overnight, column purification (CH is crossed in mixed liquor concentration₂Cl₂/CH₃OH (V/V)=10/1), obtain white solid (0.16g, 42%).

LC-MS:414.1[M+1]⁺.

¹H NMR(400MHz,d₆- DMSO): δ 13.13 (s, 1H), 13.03 (s, 1H), 11.13-11.14 (d, J= 5.2Hz, 1H), 8.92 (s, 1H), 7.52-7.56 (t, J=8.4Hz, 1H), 7.43-7.46 (d, J=8.4Hz, 1H), 7.17- 7.23 (m, 1H), 3.87-3.88 (d, J=6.0Hz, 4H), 3.57 (s, 6H), 2.38 (s, 4H), 1.33 (s, 6H)

Embodiment 8

N- (3- (5- (morpholinomethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- base) pyrrolidines -1- is thio Formamide

N- (3- (5- (morpholinomethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- base) -1H- imidazoles -1- sulphur It is dissolved in DMAC (5mL) for formamide (100mg, 0.29mmol) and pyrrolidines (0.24mL, 2.90mmol), is heated to 100 It DEG C is stirred overnight, column purification (CH is crossed in mixed liquor concentration₂Cl₂/CH₃OH (V/V)=10/1), obtain light yellow solid (60mg, 50.10%).

LC-MS:[M+1]⁺=412.3

¹H NMR(400MHz,d₆- DMSO): δ 13.16 (s, 1H), 13.02 (s, 1H), 10.91-10.97 (d, J= 21.6Hz, 1H), 8.88 (s, 1H), 7.56-7.60 (t, J=8.0Hz, 1H), 7.44-7.46 (d, J=8.4Hz, 1H), 7.16- 7.23 (m, 1H), 3.77 (s, 4H), 3.57 (s, 6H), 2.38 (s, 4H), 1.99-2.03 (d, J=14.8Hz, 4H)

Embodiment 9

1- (3- (5- (morpholinomethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- base) -3- isopropylthiourea

¹H NMR(400MHz,d₆- DMSO): δ 13.18 (s, 1H), 13.06 (s, 1H), 10.96-11.01 (d, J= 21.6Hz, 1H), 10.27 ((brs, 1H), 8.89 (s, 1H), 7.57-7.61 (t, J=8.0Hz, 1H), 7.44-7.46 (d, J= 8.4Hz,1H),7.16-7.23(m,1H),4.35(s,1H),3.59(s,6H),2.38(s,4H),1.26(s,6H)

LC-MS:[M+1]⁺=400.3

Embodiment 10

1- (3- (5- (morpholinomethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- base) -3- (pentane -3- base) Thiocarbamide

N- (3- (5- (morpholinomethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- base) -1H- imidazoles -1- sulphur It is dissolved in DMAC (5mL), is heated to for formamide (100mg, 0.29mmol) and 3- aminopentane (0.34mL, 2.90mmol) 100 DEG C are stirred overnight, and column purification (CH is crossed in mixed liquor concentration₂Cl₂/CH₃OH (V/V)=10/1), obtain light yellow solid (20mg, 16.00%).

LC-MS:[M+1]⁺=428.4

¹H NMR(400MHz,d₆- DMSO): δ 13.13 (s, 1H), 13.03 (s, 1H), 11.13-11.14 (d, J= 5.2Hz, 1H), 8.92 (s, 1H), 7.52-7.56 (t, J=8.4Hz, 1H), 7.43-7.46 (d, J=8.4Hz, 1H), 7.17- 7.23 (m, 1H), 6.96-6.98 (m, 1H), 4.35-4.37 (m, 1H), 3.87-3.88 (d, J=6.0Hz, 4H), 3.57 (s, 6H),2.38(s,4H),1.33(s,6H).

Embodiment 11

1- cyclopropyl -3- (3- (5- (octahydro pentamethylene [c] pyrroles is for methyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrrole Azoles -4- base) thiocarbamide

Step 1:(3,4- dinitrophenyl)-(octahydro pentamethylene [c] pyrrole radicals)-ketone

DMF (0.1mL) solution of 3,4- dinitrobenzoic acids (15.0g, 70.75mmol) is added in THF (100mL), Then 6.5ml SOCl₂It is added drop-wise in mixed liquor and is heated to reflux 2.5h, TLC tracking, raw material disappears.Mixed liquor is cooled to 0 DEG C, drop Add triethylamine (13mL, 106.13mmol) that temperature is kept to be longer than 20min lower than 5 DEG C of times, octahydro pentamethylene [c] pyrrole is then added dropwise Coughing up hydrochloride (15.5g, the 84.90mmol) time is longer than 15min, and solid is precipitated in system at this time, and mixed liquor slowly restores room temperature and stirs It mixes overnight.250mL ice water is added in mixed liquor, is cooled to 0 DEG C, is extracted with EA, is concentrated, obtains yellow solid, it is dry, obtain Huang Color solid.(20.1g, 93.00%).

LC-MS:[M+1]⁺=306.2

Step 2:4- (3,4- dinitrobenzyl)-octahydro pentamethylene [c] pyrroles

The NaBH under the protection of nitrogen₄(3.36g, 88.42mmol) is dispersed in THF (360mL), after being cooled to 0 DEG C, is added Enter boron trifluoride ether (11.3mL, 88.42mmol), (3,4- dinitrophenyl)-(octahydro pentamethylene [c] is then once added Pyrrole radicals)-ketone (11.91g, 42.11mmol), it removes cryostat, and slowly restores that 2h is stirred at room temperature.It is carefully added into methanol (100mL), heating mixed liquor reflux 0.5h.Concentrated liquid is dissolved with ethyl acetate (100mL), is saturated NaHCO₃Solution (100mL) washes organic phase, and ethyl acetate aqueous phase extracted merges organic phase, and saturated common salt washing is dry, is concentrated to give solid, uses first Alcohol is recrystallized, and yellow solid (10.0g, 66.30%) is obtained.

LC-MS:[M+1]⁺=292.2

The synthesis of step 3:4- (octahydro pentamethylene [c] pyrrol ylmethyl)-phenyl -1,2- diamines

By 10%Pd/C (0.35g) and 4- (3,4- dinitrobenzyl)-octahydro pentamethylene [c] pyrroles (3.5g, 11.47mmol) in ethanol, mixed liquor is cooled to 0 DEG C for dissolution, is hydrogen by air displacement, restores to be stirred overnight at room temperature.Filtering Filtrate is concentrated in mixed liquor, crosses column and is purified (CH₂Cl₂/CH₃OH (V/V)=10/1), obtain black solid (859mg, 31.00%).

LC-MS:[M+1]⁺=232.2

Step 4:4- ((2- (4- nitro -1H- pyrazole-3-yl) -1H- benzo [d] imidazoles -5- base) methyl) octahydro pentamethylene [c] pyrroles

4- (octahydro pentamethylene [c] pyrrol ylmethyl)-phenyl -1,2- diamines (4.0g, 17.32mmol), 4- nitro -1H- Pyrazoles -3- formic acid (2.47g, 17.32mmol), EDCHCl (4.98g, 19.05mmol) and HOBt (3.4g, 19.05mmol) It is dissolved in anhydrous DMF (25mL), is stirred overnight at room temperature.Solvent is removed under reduced pressure, is added glacial acetic acid (40mL), is heated to flowing back Solvent is being removed under reduced pressure in 3h, crosses column and is purified, is then washed with methanol, the yellow solid insoluble in methanol is product, is obtained Yellow solid (0.90g, 23.94%).

LC-MS:[M+1]⁺=353.5

Step 4:3- (5- (octahydro pentamethylene [c] pyrrol ylmethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- Amine

4- ((2- (4- nitro -1H- pyrazole-3-yl) -1H- benzo [d] imidazoles -5- base) methyl) octahydro under nitrogen protection Pentamethylene [c] pyrroles (1g, 28.41mmol) is dissolved in dehydrated alcohol (20mL), is added 10%Pd/C (0.1g), and hydrogen carries out Displacement, after 5h is stirred at room temperature, is filtered to remove solid, washes solid with methanol, concentration filtrate obtain brownish black solid (0.84g, 91.80%).

LC-MS:[M+1]⁺=323.2

Step 6:N- (3- (5- (octahydro pentamethylene [c] pyrrol ylmethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles - 4- yl) -1H- imidazoles -1- thioformamide

3- (5- (octahydro pentamethylene [c] pyrrol ylmethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- amine (0.5g, 1.55mmol) and thio carbon-based diimidazole (0.53g, 1.64mmol) are dissolved in THF (10mL), are heated to reflux 16h. Mixed liquor is cooled to room temperature, and filtering is collected filter cake, washed with THF, dry, directly progress next step reaction.Obtain pale solid (0.23g, 38.53%).

LC-MS:[M+1]⁺=365.2

Step 7:1- cyclopropyl -3- (3- (5- (octahydro pentamethylene [c] pyrroles is for methyl) -1H- benzo [d] imidazoles -2- Base) -1H- pyrazoles -4- base) thiocarbamide

N- (3- (5- (octahydro pentamethylene [c] pyrrol ylmethyl) -1H- benzo [d] imidazoles -2- base) -1H- pyrazoles -4- base) - 1H- imidazoles -1- thioformamide (0.23g, 0.63mmol) and cyclopropylamine (252mg, 4.42mmol) are dissolved in DMF, heating To 100 DEG C of reaction 16h.Mixed liquor is concentrated after being cooled to room temperature, and crosses column purification, obtains faint yellow solid (0.23g, 86.47%).

LC-MS:[M+1]⁺=422.5

¹H NMR(400MHz,d₆-DMSO):δ13.12(s,1H),12.86(s,1H),11.28(s,1H),8.87(s, 1H), 8.61 (s, 1H), 7.48-7.50 (t, J=8.0Hz, 1H), 7.41-7.44 (d, J=8.4Hz, 1H), 7.15-7.24 (m, 1H), 3.58-3.59 (d, J=4.8Hz, 6H), 2.78 (s, 1H), 2.37 (td, J=8.0Hz, J=8.6Hz, 2H), 2.37 (d, J=8.0Hz 4H), 2.37 (td, J=8.8Hz, J=8.0Hz, 4H), 1.05 (s, 2H)

Embodiment 12-40

The chemical combination of embodiment 12-40 is prepared according to the synthetic method of embodiment 11 by the suitable starting material of selection Object.

Embodiment 1

External Aurora-A and Aurora-B kinase inhibition test

Test-compound is formulated as to 50 × concentration of highest response concentration with 100% dimethyl sulfoxide (DMSO), draws 100 μ L is into 96 orifice plate, one hole.Then the concentration gradient dilution that 4 times are hole-specifically carried out with 100%DMSO, prepares 10 concentration.Then will Each concentration is diluted with water 10 times.Then, 5 μ L compounds are added into each hole of detection plate." complete " and " blank " control wells are used The 10%DMSO of 10 μ L is replaced.Wherein, " complete " control wells are no compound group, and " blank " control wells are no kinases group.Then, By 10 μ L2.5 × kinase solution (by kinases be added 1.25 × kinases basis buffer (62.5mM HEPES pH7.5, 0.001875%Brij-35,12.5mM MgCl₂, 2.5mM DTT) be formulated) be added into each hole of detection plate.Incubation at room temperature 10 minutes.By 10 μ L2.5 × peptide solution (by FAM-labeled peptide and ATP be added 1.25 × kinases basis buffer It is formulated) it is added in each hole of detection plate.28 DEG C are incubated for 1 hour.Be added 25 μ L terminate liquids (100mM HEPES, pH7.5, 0.015%Brij-35,0.2%Coating Reagent#3,50mM EDTA) terminate reaction.Then Caliper read plate carries out Detection finally calculates IC according to Conversion value and inhibition concentration mapping₅₀Value.

Test result is shown in Table 2:

2 data of table illustrate that in this test, the compounds of this invention, which has, inhibits Aurora-A kinases, and Aurora-B kinases is living Property ability, be a kind of novel pyrazoles compound for having and preferably inhibiting protein kinase activity.

Claims

1. compound, for such as flowering structure:

Or its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable Salt.

2. pharmaceutical composition includes compound as described in claim 1.

3. pharmaceutical composition according to claim 2 further includes pharmaceutically acceptable carrier, excipient, adjuvant With at least one of medium.

4. pharmaceutical composition according to claim 2, wherein further including additional therapeutic agent, these additional treatments Agent is chemotherapeutic agent, antiproliferative, immunosuppressor, immunostimulant, for treating the drug of atherosclerosis, is used In the drug or their combination for the treatment of pulmonary fibrosis.

5. compound described in claim 1 or any pharmaceutical composition of claim 2-4, inhibit as being used to prepare Purposes in the drug of cell growth abnormity disease caused by protein kinase is overexpressed.

6. purposes according to claim 5, wherein the protein kinase be Abl, FLT-3, Jak, Aurora-A or Aurora-B。

7. purposes according to claim 5, wherein the cell growth abnormity disease refers to proliferative diseases.

8. purposes according to claim 5 is dashed forward wherein the proliferative diseases refer to acute cell leukaemia (AML) The chronic myelogenous leukemia (CML) of change, acute lymphoblastic leukemia (ALL), gastric cancer, breast cancer, liver cancer, prostate cancer, pancreas Gland cancer, thyroid cancer, kidney, brain tumor, neck cancer, CNS cancer, glioblastoma, myeloproliferative disease, atherosclerosis, lung are fine Dimensionization, rheumatic disease, chronic inflammation, cryoglobulinemia, non-lymphoreticular system tumour, papular mucinosis, Familial splenic anemia, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, chronic lymphocytic leukemia are primary Property macroglobulinemia, half molecule disease, monocytic leukemia, primary macroglobulinaemia purpura, secondary benign Dan Ke Grand gammopathy, osteolytic lesion, lymphoblastoma, non-Hodgkin lymphoma, Sezary syndrome, infectiousness monokaryon Cytosis, acute histocytic increase disease, Hodgkin lymphoma, hairy cell leukemia, colon cancer, the carcinoma of the rectum, enteron aisle breath Meat, Small Cell Lung Cancer, neuroblastoma, neuroendocrine cell tumour, islet-cell tumour, melanoma, retina are female thin Born of the same parents' tumor, uterine cancer, oophoroma, G. cephalantha, non-small cell lung cancer, cervical carcinoma, orchioncus or bladder cancer.