CN106749268A - Heteroaryl compound and its application in medicine - Google Patents

Abstract

Application the invention discloses heteroaryl compound and its in medicine, specifically, the present invention provides a class heteroaryl compound or its stereoisomer, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug, and the pharmaceutical composition comprising the compound；The invention also discloses the purposes of the compound or its pharmaceutical composition in medicine is prepared, and its application in terms for the treatment of autoimmune disease or proliferative diseases.

Description

Heteroaryl compound and its application in medicine

Invention field

The invention belongs to pharmaceutical technology field, and in particular to a class has the heteroaryl compound of protein kinase inhibiting activity, Pharmaceutical composition comprising the compound, and compound of the invention or pharmaceutically comprising the compounds of this invention medicine group Application of the compound in medicine.

Background of invention

Janus kinases (JAK) belongs to family tyrosine kinase, by JAK1, JAK2, JAK3 and TYK2 composition.JAK is in cell Played an important role in factor signal transduction.JAK1, JAK2 and TYK2 can suppress several genes expression, but JAK3 only exists Played a role in granulocyte.The exemplary functions of cytokine receptor are present as heterodimer form, therefore not usually one Jak kinase is planted to be acted on cytokine receptor.

Every kind of JAK preferentially partly associates with the kytoplasm of discrete cytokine receptor (Annu.Rev.Immunol.1998,16,pp.293-322).JAK is activated after ligand binding, and by by cell because Sub- receptor phosphorylation and commencing signal conduct, and the cytokine receptor lacks inherent kinase activity in itself.This phosphorylation is being received The stop position of other molecules for referred to as stat protein (signal transducer and the activator of transcription), and phosphorus are produced on body The JAK of acidifying combines various stat proteins.Stat protein, or STAT is the DNA knots activated by tyrosine residue phosphorylation Hop protein, while playing a part of signal transduction molecule and transcription factor, and is eventually combined into cell factor-response On specific DNA sequences present in the promoter of group (J.Allergy Clin.Immunol., Leonard, et al, 2000,105:877-888)。

Genetic biology research shows, JAK1 by with IFNalpha, the cell factor receptor such as IFNgamma, IL-2, IL-6 Body is acted on and played a role, and JAK1 knock-out mices are dead because LIF receptor signals are lacked.Observe the feature of JAK1 knock-out mices Tissue, finds JAK1 in IFN, is played an important role in the cell pathway such as IL-10, IL-2/IL-4 and IL-6.

Genetic biology research show, JAK2 with it is single-stranded, exist between IL-3 and interferon gamma cytokine receptor family Contact.Corresponding, JAK2 knock-out mices die from anaemia.Kinase mediated JAK2 variations and human bone marrow's proliferative disorder phase Close, including polycythemia vera, hemorrhagic thrombocythemia, chronic idiopathic myelofibrosis, with myelofibrosis Myeloide metaplasia, chronic special myelomatosis, chronic myelomonocytic leukemia etc..

JAK3 is specific to act on gamma cells factor acceptor chain, and it is in IL-2, IL-4, IL-7, IL-9, IL-15, IL- Exist in 21 grade cytokine receptors.JAK3 plays an important role in lymphocyte growth, hyperplasia in mutation process, occurs different Serious immune deficiency can often be caused.Verify that the JAK3 protein levels for suffering from XSCID colonies are seriously reduced or it is total γ chains gene defect, display immunosuppressive action be due to having blocked the signal transmission by JAK3 paths.Zooscopy Show that JAK3 not only plays key effect to the maturation of B and T lymphocytes, and be also required to JAK3 to maintain T from composition The function of cell.The effect of lymphocyte is adjusted based on it, the path of JAK3 and JAK3 mediations is used to adjust immunosuppressant Indication.JAK3 implications in the mediation of many abnormal immune responses, such as allergy, asthma, autoimmune disease is as pressed down Graft rejection processed, rheumatoid arthritis, muscle contracting lateral sclerosis and multiple sclerosis and entity and hematologic malignancies Such as leukaemia, lymthoma.

JAK3 inhibitor is useful therapeutic agent as following immunodepressant：Organ transplant, heterograft, wolf Sore, multiple sclerosis, rheumatoid arthritis, psoriasis, type i diabetes and the complication from diabetes, cancer, asthma, Atopic dermatitis, autoimmune thyroid disorder, ulcerative colitis, Crohn disease, alzheimer's disease, leukaemia and immune suppression The suitable other symptoms of system.

It is also reported that JAK3 non-hematopoietic expression, although this meaning functionally it is not clear (J.Immunol., 2002,168:2475-2482).Because the bone-marrow transplantation for SCID is medicable (Blood, 2004,103:2009- 2018), it appears that JAK3 unlikely has necessary non-redundant function in its hetero-organization or organ.Therefore, with immune suppression Other targets of pharmacy thing are conversely, the limitation distribution of JAK3 is attracting.Act on to have and be limited to dividing for the expression of immune system The activating agent of sub- target may cause optimal drug effect：Toxicity ratio.Therefore, in theory, targeting JAK3 will need its situation Under (i.e. to being actively engaged in the cell of immune response) immunosupress is provided, without causing any effect outside these cell colonys Really.Although in various STAT^-/-Defective immune response (J.Investig.Med., 1996,44 have been described in bacterial strain: 304-311；Curr.Opin.Cell Biol.,1997,9:233-239), but the generally distribution of STAT and these molecules lack The fact that the enzymatic activity that can be targetted with micromolecular inhibitor, has facilitated them as the non-of immunosuppressant crucial target Selectivity.

TYK2 acts on the cytokine receptor complex such as interferon type Ⅰ, IL-6, IL-10, IL-12, IL-23.Phase therewith It is consistent, the primary cell of the people of TYK2 missings is derived from, in interferon type Ⅰ, the letter of IL-6, IL-10, IL-12, IL-23 Number conduction in there is obstacle.

Bruton's tyrosine kinase (Bruton ' s tyrosine kinase, BTK), a kind of nonreceptor tyrosine kinase The member of Tec families, is the pass expressed in all hematopoetic cell types in addition to T lymphocytes and NK Key signals enzyme.BTK stimulates to response in downstream cellular in connection cell surface B-cell receptor (B-cell receptor, BCR) B cell signal transduction path in play the part of vital role.

B- cells are signaled by B- cell receptors (BCR), can produce biology department's output of wide scope, and these depend on In the stage of development of B- cells.The value of BCR signals and duration must be exactly adjusted.Fan walks the signal of BCR- mediations Can cause imbalance B- cell-stimulatings and/or formed cause a disease from antibody, cause multiple autoimmune disease and/or inflammatory disease Disease.Mutation of the BTK in human body causes to produce X- chains without globulinemia (XLA).This disease and B- cell damages it is ripe, subtract The generation of few immunoglobulin, the impaired immune response for not relying on T- cells and the Ca2+ oscillations lasting when BCR stimulates Substantially decay is related.

Effects of the BTK to allergic disorder and/or autoimmune disease and/or inflammatory disease lacks small in BTK- It is confirmed in mouse model.For example, before the standard murine of Systemic Lupus Eryhamatosus (SLE) clinical (preclinical) In model, show that BTK missings can substantially change disease process.

A large amount of evidences demonstrate B- cells and human immune system in autoimmune disease and/or inflammatory disease pathogenesis In effect.Allergic disorder and/or autoimmunity and/or inflammatory disease, such as SLE, wind can be treated using BTK activity is suppressed Wet arthritis, multiple vasculitis (multiple vasculitides), ITP (ITP), weight Disease gravis, compliance rhinitis and asthma.Additionally, reported that BTK plays a role in Apoptosis, therefore, suppress BTK and live Property method can be used for treating cancer, and treatment B- cell lymphomas and aleukemic leukemia.

EGF-R ELISA (epidermal growth factor receptor, EGFR) is a kind of receptor type junket Histidine kinase, is distributed widely in the multi-functional glycoprotein on each cell membranes in tissue of human body, is birds EBL virus (avian erythroblastic leukemia viral, v-erb-b) oncogene autoploid.Human epidermal growth factor receptor/HER1/ErbB- 1 and HER-2 (human epidermal growth factorreceptor-2)/ErbB-2/Teu/p185, HER3/ErbB- 3, HER4/ErbB-4 etc. are attributed to HER/ErbB families, belong to protein tyrosine kinase (PTKs).They are single polypeptide Chain, respectively by the coded by said gene on coloured differently body.EGFR etc. epithelial origin tumour, such as incidence squamous cell There is overexpression in the kinds of tumors such as cancer, breast cancer, the carcinoma of the rectum, oophoroma, prostate cancer, non-small cell lung cancer, their table Up to related to the phenomenon such as cancer cell multiplication, transfer.

Acquired resistance turns into world-famous puzzle during tumor pharmacother at present, while being also invalid treatment tumour Reason.EGFR-TKI medicines (Tarceva or Gefitinib) are very important targeting medicines in treatment of advanced non-small cell lung cancer Thing, but the appearance of its acquired resistance limits clinical application, it is therefore desirable to try to explore the Forming Mechanism of acquired resistance. The mechanism of EGFR-TKI medicine acquired resistances is not completely clear and definite yet at present.Existing research display, EGFR-TKI is acquired resistance to The generation of medicine may be mainly relevant with following two mechanism：Secondary cases extron T790M is mutated and the amplification of MET Secondary cases.

T790M mutation are a point mutation in the outer aobvious factors of EGFR 20, be the resistance mechanism more approved at present it One.T790M is located at the entrance of EGFR and ATP binding pockets, and the size of its side chain directly affects the binding ability of EGFR and ATP. T790M mutation spatially hinder the effect of EGFR inhibitor and ATP-binding site, increase affinity of the EGFR to ATP, so that Cell is set to produce resistance to EGFR inhibitor.Initially, T790M is only found in NSCLC patient's sample of Endodontic failure, but with Also it is found in the sample without any treatment afterwards, therefore it is now recognized that the mutation exists in the tumor group without TKI treatments In knitting, but a small number of clone cells are detected in, because these clone cells are selected after the treatment to the repellence of TKI.

Therefore it provides the suppression protein kinase for the treatment of disease (such as autoimmune disease, inflammatory disease and cancer) Compound exist need.

Abstract of invention

Heteroaryl compound of the invention can effectively suppress the activity of protein kinase, and these protein kinases include, but do not limit In：Ab1、Akt1、Akt2、Akt3、ALK、Alk5、A-Raf、B-Raf、Brk、BLK、BTK、BMX、Cdk2、CDK4、CDK5、 CDK6、CHK1、C-Raf-1、Csk、EGFR、EphA1、EphA2、EphB2、EphB4、EGFR T790M、Erk2、Fak、FGFR1、 FGFR2、FGFR3、FGFR4、Flt1、Flt3、Flt4、Fms、Frk、Fyn、Gsk3.alpha.、Gsk3.beta、HCK、Her2/ Erbb2、Her4/Erbb4、IGF1R、IKK.beta、Irak4、Itk、JAK1、JAK2、JAK3、Jnk1、Jnk2、Jnk3、Kdr、 Kit、LCK、MAP2K1、MAP2K2、MAP4K4、MAPKAPK2、Met、Mnk1、MLK1、p38、PDGFRA、PDGFRB、PDPK1、 Pim1、Pim2、Pim3、PKC.alpha、PKC.beta、PKC.theta、Plk1、Pyk2、Ret、ROCK1、ROCK2、Ron、 Src, Stk6, Syk, TEC, TXK, Tie2, TrkA, TrkB, Yes and/or Zap70, and their variant.In particular, originally Invention compound is to BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4, EGFR or EGFR T790M With stronger inhibitory action.This kind of compound will be played in treatment autoimmune disease and/or inflammatory disease and/or cancer Potential effect.

Compound for protein kinase activity of the invention has inhibitory action.It is more satisfactory, compound of the invention There is multiple suppression function, BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4 can be suppressed, EGFR or EGFR T790M.Especially, compound of the present invention and pharmaceutically acceptable pharmaceutical composition, can have Effect ground suppresses as BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4, EGFR or EGFR T790M Agent.

On the one hand, the present invention relates to a kind of compound, it is the compound or formula (III) shownization as shown in formula (III) The stereoisomer of compound, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvate, metabolism is produced Thing and pharmaceutically acceptable salt or prodrug：

Wherein each L¹, Cy, L², R², R³, R⁴, W¹, W², R^5xAnd R^5aWith implication as described in the present invention.

Some of them embodiment is, L¹It is-O- ,-N (R^1a)-,-S (=O)_p- ,-C (=O)-,-C (=O)-N (R^1a)-,-S (=O)_p-N(R^1a)-,-(CR^mR^w)_g- or-(CR^mR^w)_n-CR^1a=CR^1a-(CR^mR^w)_n-；

Wherein each R^1a, R^m, R^w, p, g and n have implication as described in the present invention.

Some of them embodiment is, L²It is a key ,-O- ,-N (R^1a)-,-CH₂-N(R^1a)-,-CH (CH₃)-N (R^1a)-,-C (CH₃)₂-N(R^1a)-,-C (=O)-N (R^1a)-or-S (=O)_p-N(R^1a)-；

Wherein each R^1aThere is implication as described in the present invention with p.

Some of them embodiment is, each R^1aIt independently is hydrogen, deuterium, C_1-3Alkyl, C_2-4Alkenyl or C_2-4Alkynyl.

Some of them embodiment is that Cy is C_3-8Cycloalkyl, C_3-8Cycloalkenyl group, C_2-10Heterocyclic radical, C_6-10Aryl or C_1-9It is miscellaneous Aryl；Cy is individually optionally by one or more R^yReplaced；

Wherein each R^yWith implication as described in the present invention.

Some of them embodiment is, each R^yIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkylamino, C_1-6Alkylamino C_1-6Alkylamino or halo C_1-6Alkyl.

Some of them embodiment is, R²It is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, C_1-6Alkyl, C_2-6Alkenyl or C_2-6Alkynes Base.

Some of them embodiment is, each R³And R⁴It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, carboxyl ,- (CR^mR^w)_n-NR^m1R^w1, C_1-6Alkyl, halo C_1-6Alkyl or C_2-10Heterocyclic radical C_1-6Alkyl；

Wherein each n, R^m, R^m1, R^wAnd R^w1With implication as described in the present invention.

Some of them embodiment is, each R^mAnd R^wIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C_1-6Alkyl, cyano group substitution C_1-6Alkyl, halo C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_3-8Cycloalkyl, C_6-10Aryl, C_1-9Heteroaryl, C_2-10Heterocyclic radical Or C_2-10Heterocyclic radical C_1-6Alkyl.

Some of them embodiment is, each R^m1And R^w1It independently is hydrogen, C_1-6Alkyl, the C of cyano group substitution_1-6Alkyl, halo C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, C_3-8Cycloalkyl, C_6-10Aryl, C_1-9Heteroaryl, C_2-10Heterocyclic radical or C_2-10Heterocyclic radical C_1-6Alkyl.

Some of them embodiment is, R^m1、R^w1Form former molecular by 3-12 together with the N atoms being attached thereto Heterocycle.

Some of them embodiment is, each W¹And W²It independently is N or CR^5y；

Wherein each R^5yWith implication as described in the present invention.

Some of them embodiment is, each R^5xIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, C_1-6Alkyl, C_2-8Alkenyl, C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkylamino, C_1-6Alkylamino, C_1-6Alkylamino C_1-6Alkyl, C_1-6Alkylamino C_1-6Alkylamino, C_1-6Alkylthio group, halo C_1-6Alkane Base, halo C_1-6Alkoxy, the C of hydroxyl substitution_1-6Alkyl, the C of hydroxyl substitution_1-6Alkylamino, the C of cyano group substitution_1-6Alkyl, cyano group Substituted C_1-6Alkoxy, the C of cyano group substitution_1-6Alkylamino or the C of amino substitution_1-6Alkyl；Each R^5xIndividually optionally by one or Multiple R¹³Replaced；

Wherein each R¹³With implication as described in the present invention.

Some of them embodiment is, each R^5yIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, C_1-6Alkyl, C_2-8Alkenyl, C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkylamino, C_1-6Alkylamino, C_1-6Alkylamino C_1-6Alkyl, C_1-6Alkylamino C_1-6Alkylamino, C_1-6Alkylthio group, halo C_1-6Alkane Base, halo C_1-6Alkoxy, the C of hydroxyl substitution_1-6Alkyl, the C of hydroxyl substitution_1-6Alkylamino, the C of cyano group substitution_1-6Alkyl, cyano group Substituted C_1-6Alkoxy, the C of cyano group substitution_1-6Alkylamino or the C of amino substitution_1-6Alkyl；Each R^5yIndividually optionally by one or Multiple R¹³Replaced；

Wherein each R¹³With implication as described in the present invention.

Some of them embodiment is, R^5aIt is heteroaryl alkyl or Heteroarylcycloalkyl；R^5aIndividually optionally by one or Multiple R¹⁴, R^14xOr R^14yReplaced；

Wherein each R¹⁴, R^14xAnd R^14yWith implication as described in the present invention.

Some of them embodiment is that each n independently is 0,1,2,3 or 4.

Some of them embodiment is that g is 1,2,3 or 4.

Some of them embodiment is that each p independently is 0,1 or 2.

Some of them embodiment is, each R¹³It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl-C (=O)-, cyano group substitution C_1-6Alkyl-C (=O)-, C_1-6Alkylamino, halo C_1-6Alkyl, the C of hydroxyl substitution_1-6Alkyl or the C of cyano group substitution_1-6Alkyl.

Some of them embodiment is, each R¹⁴It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl-C (=O)-, cyano group substitution C_1-6Alkyl-C (=O)-, C_1-6Alkylamino, halo C_1-6Alkyl, the C of hydroxyl substitution_1-6Alkyl or the C of cyano group substitution_1-6Alkyl.

Some of them embodiment is, each R^14xIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, ammonia Base, carboxyl, oxo (=O), C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl-C (=O)-, cyano group substitution C_1-6Alkyl-C (=O)-, C_1-6Alkylamino, halo C_1-6Alkyl, the C of hydroxyl substitution_1-6Alkyl or the C of cyano group substitution_1-6Alkyl.

Some of them embodiment is, each R^14yIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, ammonia Base, carboxyl, oxo (=O), C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl-C (=O)-, cyano group substitution C_1-6Alkyl-C (=O)-, C_1-6Alkylamino, halo C_1-6Alkyl, the C of hydroxyl substitution_1-6Alkyl or the C of cyano group substitution_1-6Alkyl.

Some of them embodiment is to work as R^14xAnd R^14yIt is connected to when on same carbon atom, R^14xAnd R^14yIt is former together with carbon Son is optionally formed 3-8 former molecular ring together.

Other embodiment is that Cy is C_3-6Cycloalkyl, C_3-6Cycloalkenyl group, C_2-6Heterocyclic radical, C_6-10Aryl or C_1-6It is miscellaneous Aryl；Cy is individually optionally by one or more R^yReplaced；

Wherein each R^yWith implication as described in the present invention.

Other embodiment is that Cy is cyclobutyl, cyclobutane base, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexene Base, phenyl, indenyl, naphthyl, furyl, pyrrole radicals, thienyl, imidazole radicals, pyrazolyl, triazolyl, tetrazole radical, pentazolyl, thiophene Oxazolyl, isothiazolyl, oxazolyl, isoxazolyl, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl Or triazine radical；Or each Cy independently is following subformula：

Cy is individually optionally by one or more R^yReplaced；

Wherein each R^yWith implication as described in the present invention.

Other embodiment is, each R^yIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, C_1-3Alkyl, C_1-3Alkoxy, C_1-3Alkylamino, C_1-3Alkylamino C_1-4Alkylamino or halo C_1-3Alkyl.

Other embodiment is, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (V) (V) stereoisomer of compound shown in, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvation Thing, metabolite and pharmaceutically acceptable salt or prodrug：

Wherein each L¹, R², R³, R⁴, R^5x, R^5yAnd R^5aWith implication as described in the present invention.

Other embodiment is, L¹It is-O- ,-S- or-(CH₂)-。

Other embodiment is, R²It is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, C_1-3Alkyl, C_2-4Alkenyl or C_2-4Alkynes Base.

Other embodiment is, each R³And R⁴It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, carboxyl ,- (CR^mR^w)_n-NR^m1R^w1, C_1-3Alkyl, halo C_1-3Alkyl or C_2-10Heterocyclic radical C_1-3Alkyl；

Wherein each n, R^m, R^m1, R^wAnd R^w1With implication as described in the present invention.

Other embodiment is, each R^mAnd R^wIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C_1-4Alkyl, cyano group substitution C_1-4Alkyl, halo C_1-3Alkyl, C_1-3Alkoxy C_1-4Alkyl, C_3-6Cycloalkyl, C_2-10Heterocyclic radical or C_2-10Heterocyclic radical C_1-3Alkane Base.

Other embodiment is, each R^m1And R^w1It independently is hydrogen, C_1-4Alkyl, the C of cyano group substitution_1-4Alkyl, halo C_1-3Alkyl, C_1-3Alkoxy C_1-4Alkyl, C_3-6Cycloalkyl, C_2-10Heterocyclic radical or C_2-10Heterocyclic radical C_1-3Alkyl.

Other embodiment is, R^m1、R^w1Form former molecular by 3-12 together with the N atoms being attached thereto Heterocycle.

Other embodiment is, R^5aIt is C_1-9Heteroaryl C_1-6Alkyl or C_1-9Heteroaryl C_3-8Cycloalkyl；Each R^5aIt is independent Optionally by one or more R¹⁴, R^14xOr R^14yReplaced；

Wherein each R¹⁴, R^14xAnd R^14yWith implication as described in the present invention.

Other embodiment is, R^5aIt is C_1-6Heteroaryl C_1-4Alkyl or C_1-6Heteroaryl C_3-6Cycloalkyl；Each R^5aIt is independent Optionally by one or more R¹⁴, R^14xOr R^14yReplaced；

Wherein each R¹⁴, R^14xAnd R^14yWith implication as described in the present invention.

Other embodiment is, R^5aIt is pyridylmethyl, pyridyl-ethyl group, Pyrimidylmethyl, pyrimidinylethyl, pyrrole Piperazine ylmethyl, pyrazinyl ethyl, pyridazinylmethyl, pyridazinyl ethyl, triazine ylmethyl, triazine radical ethyl, imidazolyl methyl, miaow Oxazolyl ethyl, pyrazolmethyl, pyrazolylethyl, pyridyl ring propyl group, pyrimidine-ring propyl group, benzothiazolylmethyl, thiazolyl second Base or thiazolyl propyl group；Each R^5aIndividually optionally by one or more R¹⁴, R^14xAnd R^14yReplaced；

Wherein each R¹⁴, R^14xAnd R^14yWith implication as described in the present invention.

Other embodiment is, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (V-a) (V-a) stereoisomer of compound shown in, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvent Compound, metabolite and pharmaceutically acceptable salt or prodrug：

Wherein：

Y is CH or N；

S is 0,1,2,3 or 4；

Each R^5x, R^5y, R¹⁴, R^14xAnd R^14yWith implication as described in the present invention.

Other embodiment is, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (V-b) (V-b) stereoisomer of compound shown in, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvent Compound, metabolite and pharmaceutically acceptable salt or prodrug：

Wherein：

Y is CH or N；

S is 0,1,2,3 or 4；

Each R^5x, R^5y, R¹⁴, R^14xAnd R^14yWith implication as described in the present invention.

Other embodiment is, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (V-c) (V-c) stereoisomer of compound shown in, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvent Compound, metabolite and pharmaceutically acceptable salt or prodrug：

Wherein：

Each Y independently is CH or N；

S is 0,1,2,3 or 4；

Each R^5x, R^5y, R¹⁴, R^14xAnd R^14yWith implication as described in the present invention.

Other embodiment is, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (V-d) (V-d) stereoisomer of compound shown in, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvent Compound, metabolite and pharmaceutically acceptable salt or prodrug：

Wherein：

Each T²And T³It independently is CH or N；

T¹It is-O- ,-S- or-NH-；

S is 0,1,2,3 or 4；

Each R^5x, R^5y, R¹⁴, R^14xAnd R^14yWith implication as described in the present invention.

Other embodiment is, each R^5xIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, C_1-5Alkyl, C_2-6Alkenyl, C_1-4Alkoxy, C_1-4Alkoxy C_1-4Alkyl, C_1-4Alkoxy C_1-4Alkoxy, C_1-3Alkoxy C_1-4Alkylamino, C_1-4Alkylamino, C_1-3Alkylamino C_1-3Alkyl, C_1-4Alkylamino C_1-4Alkylamino, C_1-4Alkylthio group, halo C_1-4Alkane Base, halo C_1-4Alkoxy, the C of hydroxyl substitution_1-4Alkyl, the C of hydroxyl substitution_1-4Alkylamino, the C of cyano group substitution_1-4Alkyl, cyano group Substituted C_1-4Alkoxy, the C of cyano group substitution_1-4Alkylamino or the C of amino substitution_1-4Alkyl；Each R^5xIndividually optionally by one or Multiple R¹³Replaced；

Wherein each R¹³With implication as described in the present invention.

Other embodiment is, each R^5yIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, C_1-5Alkyl, C_2-6Alkenyl, C_1-4Alkoxy, C_1-4Alkoxy C_1-4Alkyl, C_1-4Alkoxy C_1-4Alkoxy, C_1-3Alkoxy C_1-4Alkylamino, C_1-4Alkylamino, C_1-3Alkylamino C_1-3Alkyl, C_1-4Alkylamino C_1-4Alkylamino, C_1-4Alkylthio group, halo C_1-4Alkane Base, halo C_1-4Alkoxy, the C of hydroxyl substitution_1-4Alkyl, the C of hydroxyl substitution_1-4Alkylamino, the C of cyano group substitution_1-4Alkyl, cyano group Substituted C_1-4Alkoxy, the C of cyano group substitution_1-4Alkylamino or the C of amino substitution_1-4Alkyl；Each R^5yIndividually optionally by one or Multiple R¹³Replaced；

Wherein each R¹³With implication as described in the present invention.

Other embodiment is, each R¹³It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), C_1-4Alkyl, C_1-3Alkoxy, C_1-3Alkoxy C_1-4Alkyl, C_1-3Alkyl-C (=O)-, cyano group substitution C_1-3Alkyl-C (=O)-, C_1-3Alkylamino, halo C_1-3Alkyl, the C of hydroxyl substitution_1-3Alkyl or the C of cyano group substitution_1-3Alkyl.

Other embodiment is, each R¹⁴It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), C_1-4Alkyl, C_1-3Alkoxy, C_1-3Alkoxy C_1-4Alkyl, C_1-3Alkyl-C (=O)-, cyano group substitution C_1-3Alkyl-C (=O)-, C_1-3Alkylamino, halo C_1-3Alkyl, the C of hydroxyl substitution_1-3Alkyl or the C of cyano group substitution_1-3Alkyl.

Other embodiment is, each R^14xIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, ammonia Base, carboxyl, oxo (=O), C_1-4Alkyl, C_1-3Alkoxy, C_1-3Alkoxy C_1-4Alkyl, C_1-3Alkyl-C (=O)-, cyano group substitution C_1-3Alkyl-C (=O)-, C_1-3Alkylamino, halo C_1-3Alkyl, the C of hydroxyl substitution_1-3Alkyl or the C of cyano group substitution_1-3Alkyl.

Other embodiment is, each R^14yIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, ammonia Base, carboxyl, oxo (=O), C_1-4Alkyl, C_1-3Alkoxy, C_1-3Alkoxy C_1-4Alkyl, C_1-3Alkyl-C (=O)-, cyano group substitution C_1-3Alkyl-C (=O)-, C_1-3Alkylamino, halo C_1-3Alkyl, the C of hydroxyl substitution_1-3Alkyl or the C of cyano group substitution_1-3Alkyl.

Other embodiment is to work as R^14xAnd R^14yIt is connected to when on same carbon atom, R^14xAnd R^14yIt is former together with carbon Son is optionally formed 3-6 former molecular ring together.

On the other hand, the present invention includes but is not limited to the compound with one of following structure or is tied with one of following The stereoisomer of structure compound, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, Pharmaceutically acceptable salt or prodrug：

One aspect of the present invention is related to a kind of pharmaceutical composition, and comprising compound of the present invention, or theirs is three-dimensional different Structure body, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvate, metabolite pharmaceutically may be used The salt of receiving or their prodrug.

Some of them embodiment is that pharmaceutical composition of the present invention further includes pharmaceutically acceptable load At least one in body, excipient, diluent, assistant agent or medium.

Some of them embodiment is that pharmaceutical composition of the present invention further includes additional therapeutic agent, its choosing From chemotherapeutics or antiproliferative, anti-inflammatory agent, immunomodulator or immunodepressant, neurotrophic factor, for treating angiocarpy The activating agent of disease, activating agent and activating agent for treating autoimmune disease for treating diabetes.

Another aspect of the present invention is directed to use with a kind of compound of the present invention or pharmaceutical composition of the present invention Purposes in medicine is prepared, wherein the medicine is used to preventing, process, treat or mitigating autologous patient immunological diseases or propagation Property disease.

Some of them embodiment is that autoimmune disease of the present invention is lupus, multiple sclerosis, muscle contracting Lateral sclerosis, rheumatoid arthritis, psoriasis, type i diabetes, because of complication caused by organ transplant, foreign matter transplanting, glycosuria Disease, cancer, asthma, atopic dermatitis, AITD, ulcerative colitis, Crohn disease, Alzheimer Disease, leukaemia or lymthoma.

Some of them embodiment is that proliferative diseases of the present invention are metastatic carcinoma, colon cancer, sdenocarcinoma of stomach, bladder Cancer, breast cancer, kidney, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostate cancer, cancer of pancreas, CNS's (central nervous system) Cancer, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.

On the other hand, compound of the present invention or pharmaceutical composition of the present invention are used the present invention relates to one kind To prepare the purposes for the medicine of suppression or regulatory protein kinase activity in biological sample.

Some of them embodiment is, protein kinase is BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4, EGFR or EGFR T790M.

One aspect of the present invention is related to pharmaceutical composition, comprising compound of the invention, or their stereoisomer, geometry Isomers, dynamic isomer, raceme, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or Their prodrug.

Some of them embodiment is that pharmaceutical composition of the present invention further includes pharmaceutically acceptable load At least one in body, excipient, diluent, assistant agent or medium.

Some of them embodiment is that pharmaceutical composition of the present invention further includes additional therapeutic agent, its choosing From chemotherapeutics or antiproliferative, anti-inflammatory agent, immunomodulator or immunodepressant, neurotrophic factor, for treating angiocarpy The activating agent of disease, activating agent and activating agent for treating autoimmune disease for treating diabetes.

Another aspect of the present invention is directed to use with a kind of compound of the invention or the medicine group comprising compound of the invention Compound is prepared for preventing, processing or treat autologous patient immunological diseases or proliferative diseases, and mitigates its order of severity The purposes of medicine.

Some of them embodiment is that autoimmune disease of the present invention is lupus, multiple sclerosis, muscle contracting Lateral sclerosis, rheumatoid arthritis, psoriasis, type i diabetes, because of complication caused by organ transplant, foreign matter transplanting, glycosuria Disease, cancer, asthma, atopic dermatitis, AITD, ulcerative colitis, Crohn disease, Alzheimer Disease, leukaemia or lymthoma.

Some of them embodiment is that proliferative diseases of the present invention are metastatic carcinoma, colon cancer, sdenocarcinoma of stomach, bladder Cancer, breast cancer, kidney, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostate cancer, cancer of pancreas, CNS's (central nervous system) Cancer, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.

On the other hand, pharmaceutical composition the present invention relates to the compounds of this invention or comprising the compounds of this invention prepares use In the purposes of the medicine of suppression or regulatory protein kinase activity in biological sample.

Some of them embodiment is, protein kinase is BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4, EGFR or EGFR T790M.

On the one hand, the present invention relates to prepare the intermediate of the compound that formula (III) or (V) are included.

Another aspect of the present invention is related to the preparation of the compound that formula (III) or (V) included, separate and purifying method.

Content noted earlier only outlines certain aspects of the invention, but be not limited to these aspects and it is otherwise in Appearance will below make more specific complete description.

Detailed description of the invention book

Definition and general terms

Certain embodiments of the present invention will now be described in more detail, the example is by the structural formula enclosed and chemical formula explanation.This Invention intention covers all of replacement, modification and equivalent technical solutions, and they are included in the present invention defined such as claim In the range of.Those skilled in the art will appreciate that many can be used in similar or equivalent method of the present invention and material The practice present invention.The present invention is not limited to method of the present invention and material.In the document, patent and similar material that are combined One or more or contradict in the case of (including but not limited to defined term, term application, institutes different from the application Technology of description, etc.), it is defined by the application.

It will further be appreciated that some features of the invention, are clearly visible, carried out in multiple independent embodiments Description, but it is also possible to provide in combination in single embodiment.Conversely, various features of the invention, for brevity, It is described in single embodiment, but it is also possible to individually or with any suitable sub-portfolio provide.

Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.

Unless otherwise indicated, following definition used in the present invention should be applied.For purposes of the present invention, chemical element With periodic table of elements CAS editions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can With reference to " 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:Description in 2007, entire contents are incorporated by reference into the present invention.

There are obvious conflict, article " " used herein, " one (kind) " unless otherwise indicated or in context " described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more than one Component be taken into account in the implementation method of the embodiment and use or use.

Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.It is tested right As for example also referring to primate (such as the mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described to receive Examination pair as if people.

Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.

Term "comprising" is open language, i.e., including the content specified by the present invention, but be not precluded from otherwise Content.

" stereoisomer " refers to but atom or the group spatially different change of arrangement mode with identical chemical constitution Compound.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..

" chirality " be have with its mirror image can not overlap property molecule；And " achirality " refer to can be overlap with its mirror image Molecule.

" enantiomter " refers to the two of compound isomers that can not be overlapped but be mutually mirror.

" diastereoisomer " refers to have two or more chiral centres and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral quality and reactivity.Diastereoisomer is mixed Compound can be operated such as electrophoresis and chromatogram by high resolution analysis, and such as HPLC is separated.

Stereochemical definitions used in the present invention and rule typically follow 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。

Many organic compounds exist with optical active forms, i.e., they have rotates the plane of linearly polarized light Ability.When optically active compound is described, represent molecule on one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols for the rotation of linearly polarized light caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix is dextrorotation for the compound of (+) or d.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter:50 mixtures Referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereoselectivity or stereospecificity when, May occur in which such case.

Any asymmetric atom (for example, carbon etc.) that the present invention discloses compound can be enriched with racemic or enantiomer Form exist, for example (R)-, (S)-or (R, S)-configuration be present.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration aspect have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least at least 80% enantiomeric excess, at least 90% enantiomeric excess, 95% enantiomeric excess, or at least 99% enantiomer It is excessive.

According to the selection of starting material and method, the compounds of this invention can with possible isomers or they Mixture, the form of such as racemic modification and the non-corresponding isomer mixture quantity of asymmetric carbon atom (this depend on) deposits .Optically active (R)-or (S)-isomers can be used chiral synthon or chiral reagent to prepare, or be torn open using routine techniques Point.If compound contains a double bond, substitution base may be E or Z configurations；If containing dibasic cycloalkanes in compound Base, the substitution base of cycloalkyl may have cis or trans configuration.

The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.

The racemic modification of any gained end-product or intermediate can be passed through into those skilled in the art with known method Familiar method splits into optical antipode, e.g., is separated by its diastereoisomeric salt for obtaining.Racemic product Thing can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can be prepared by asymmetric syntheses, for example, Jacques is referred to, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2^ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。

Term " dynamic isomer " or " tautomeric form " refer to that can build (low by low energy with different-energy Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of dynamic isomer.Unless otherwise noted, all tautomeric forms of the compounds of this invention are all in the present invention Within the scope of.

As described in the invention, compound of the invention optionally can be replaced by one or more substitution bases, such as General formula compound above, or as the special example in embodiment the inside, subclass, and the class compound that the present invention is included. Should be appreciated that " optionally substituted " this term can be exchanged with " substituted or non-substituted " this term to use.In general, art Language it is " substituted " represent institute to one or more hydrogen atoms in structure by specifically replaced base replace.Unless other aspect tables Bright, an optional substituted radical can be replaced each commutable position in group.When in given structural formula not Only position can be selected from one or more substitution bases of specific group and be replaced, then replace the base can be with identical or different In the substitution of each position.Wherein described substitution base can be, but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitre Base, amino, carboxyl, alkyl, alkoxy, alkoxyalkyl, alkyloxy-alkoxy, alkoxy alkylamino, aryloxy group, heteroaryl oxygen Base, heterocyclic radical epoxide, alkoxy aryl, heteroarylalkoxy, heterocyclylalkoxy, cycloalkyl alkoxy, alkylamino, alkylamino Alkyl, alkylamino alkylamino, cycloalkyl amino, amino-n-cycloalkyl, alkylthio group, haloalkyl, halogenated alkoxy, hydroxyl substitution Alkyl, hydroxyl substitution alkylamino, cyano group substitution alkyl, cyano group substitution alkoxy, cyano group substitution alkylamino, amino Substituted alkyl, alkyl acyl, miscellaneous alkyl, cycloalkyl, cycloalkenyl group, cycloalkyl-alkyl, heterocyclic radical, cycloheteroalkylalkyl, heterocyclic radical Acyl group, aryl, aryl alkyl, fragrant amino, heteroaryl, heteroaryl alkyl, heteroaryl amino, amide groups, sulfonyl, aminosulfonyl Base etc..

In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode for being used in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, and it both may be used Referring in different groups, not influenceed mutually between expressed specific option between same-sign, it is also possible to represent in phase In same group, do not influenceed mutually between expressed specific option between same-sign.

In each several part of this specification, the substitution base that the present invention discloses compound is disclosed according to radical species or scope.It is special Do not point out, each independent sub-combinations thereof of each member of the present invention including these radical species and scope.For example, term “C₁-C₆Alkyl " or " C_1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

In each several part of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.Unless other aspects show, the side of writing of linker structural formula Formula does not have any hint for the direction of linker.If for example, the structure needs linking group and for the horse of the variable The assorted group definition in storehouse lists " alkyl " or " aryl ", then it should be understood that being somebody's turn to do the Asia that " alkyl " or " aryl " represents connection respectively Alkyl group or arylene group.For example, structural formula Cy, respectively by L¹And L²It is connected with the remainder of molecule, when enumerating Cy During for aryl or heteroaryl, it is thus understood that " aryl " or " heteroaryl " represents the arylene group or inferior heteroaryl base of connection respectively Group.

Terminology used in the present invention " alkyl " or " alkyl group ", represent contain 1 to 20 carbon atom, the straight chain of saturation or Side chain univalent hydrocarbyl group, wherein, the alkyl group can optionally by the substitution base institute of one or more present invention descriptions Substitution.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1- 12 carbon atoms；In one embodiment, alkyl group contains 1-8 carbon atom；In another embodiment, alkyl group contains There is 1-6 carbon atom；In yet another embodiment, alkyl group contains 1-4 carbon atom；Also in one embodiment, alkyl Group contains 1-3 carbon atom.

The example of alkyl group is included, 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), the tert-butyl group (t-Bu ,-C (CH₃)₃), n-pentyl (- CH₂CH₂CH₂CH₂CH₃), 2- amyl groups (- CH (CH₃)CH₂CH₂CH₃), 3- amyl groups (- CH (CH₂CH₃)₂), 2- methyl -2- butyl (- C (CH₃)₂CH₂CH₃), 3- methyl -2- butyl (- CH (CH₃)CH(CH₃)₂), 3- methyl isophthalic acids-butyl (- CH₂CH₂CH(CH₃)₂), 2- first Base -1- butyl (- CH₂CH(CH₃)CH₂CH₃), etc..

Term " alkenyl " is represented and contains the 2-12 straight or branched monovalent hydrocarbon of carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp²Double bond, wherein, the alkenyl group can be retouched optionally by one or more present invention The substitution base stated is replaced, its positioning for including " cis " and " tans ", or " E " and " Z " positioning.In one embodiment, Alkenyl group includes 2-8 carbon atom；In another embodiment, alkenyl group includes 2-6 carbon atom；In another embodiment party In case, alkenyl group includes 2-4 carbon atom.The example of alkenyl group is included, but is not limited to, vinyl (- CH=CH₂), Pi-allyl (- CH₂CH=CH₂), acrylic (CH₃- CH=CH-), the cyclobutenyl (CH of oxo₃- C (=O)-CH=CH-) etc..

Term " alkynyl " represented containing the 2-12 straight or branched monovalent hydrocarbon of carbon atom, wherein at least one carbon- The keys of carbon sp tri-.

Term " alkoxy " represents that alkyl group is connected by oxygen atom with molecule remainder, and wherein alkyl group has Implication as described in the present invention.The example of alkoxy base is included, but is not limited to, methoxyl group (MeO ,-OCH₃), ethyoxyl (EtO、-OCH₂CH₃), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH₂CH₂CH₃), 2- propoxyl group (i-PrO, i- propoxyl group ,- OCH(CH₃)₂) etc..

Term " alkoxyalkyl " represents that alkyl group is replaced by one or more alkoxy bases, wherein alkyl and alkane Epoxide group has implication as described in the present invention, and such example includes, but is not limited to methoxy, methoxyl group second Base, ethoxyl methyl, ethoxyethyl group etc..

Term " alkyloxy-alkoxy " represents that alkoxy base is replaced by one or more alkoxy bases, wherein alcoxyl Base group has implication as described in the present invention.

Term " haloalkyl " or " halogenated alkoxy " represent alkyl or alkoxy base by one or more halogen atoms Replaced, such example is included, but is not limited to ,-CH₂F ,-CHF₂,-CF₃,-CH₂Cl ,-CH₂CF₃,-CH₂CH₂CF₃,- OCH₂F ,-OCF₃Deng.

Term " alkyl of cyano group substitution ", " alkoxy of cyano group substitution " or " alkylamino of cyano group substitution " represents alkyl base Group, alkoxy base or alkylamino radicals are replaced by one or more cyano group.

Term " alkyl of hydroxyl substitution " or " alkylamino of hydroxyl substitution " represent alkyl group or alkylamino radicals by one Individual or multiple hydroxyls are replaced, and such example is included, but is not limited to ,-CH₂OH ,-CH₂CH₂OH ,-CH₂CH₂CH₂OH ,- CH₂C(CH₃)₂OH ,-NHCH₂CH₂OH ,-NHCH (OH) CH₂OH etc..

Term " alkylthio group " refers to C_1-10The alkyl of straight or branched is connected on the sulphur atom of divalence, and alkyl group has such as Implication of the present invention.

Term " cycloalkyl " represents that, containing 3-12 carbon atom, the saturation of univalent or multivalence is monocyclic, bicyclic or three ring bodies System.In one embodiment, cycloalkyl includes 3-12 carbon atom；In another embodiment, cycloalkyl is former comprising 3-8 carbon Son；In yet another embodiment, cycloalkyl includes 3-6 carbon atom.The group of naphthene base can it is independently unsubstituted or Replaced by one or more substitution bases described in the invention.Such example is included, but is not limited to, cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..

Term " cycloalkenyl group " represented containing 3-12 carbon atom, 3-8 carbon atom or 3-6 carbon atom, univalent Or multivalence, monocyclic, the bicyclic or three-ring system of non-aromatic, including at least a carbon-carbon double bond.

Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to the saturation comprising 3-12 annular atom or portion Divide undersaturated monocyclic, bicyclic or tricyclic, wherein do not include aromatic rings in monocyclic, bicyclic or tricyclic, and at least one annular atom Selected from nitrogen, sulphur and oxygen atom.Unless otherwise indicated, heterocyclic radical can be carbon-based or nitrogen base, and-CH₂- group can be optionally By-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can optionally by oxygen Chemical conversion N- oxygen compounds.The example of heterocyclic radical includes, but are not limited to：Oxyranyle, azelidinyl, oxetanylmethoxy, sulphur Heterocycle butyl, pyrrolidinyl (such as 2- pyrrolidinyls), 2- pyrrolinyls, 3- pyrrolinyls, pyrazolidinyl, imidazolinyl, imidazoles Alkyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3- dioxy cyclopenta, two sulphur cyclopenta, four Hydrogen pyranose, dihydro pyranyl, 2H- pyranoses, 4H- pyranoses, tetrahydro thiapyran base, piperidyl (2- piperidyls, 3- piperidyls, 4- piperidyls), morpholinyl, thio-morpholinyl, (1- oxos)-thio-morpholinyl, (1,1- dioxo)-thio-morpholinyl, piperazine Base, alkyl dioxin, dithiane base, thioxane base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia cycloheptyl alkyl, 2- Oxa- -5- azabicyclo [2.2.1] hept- 5- bases, tetrahydro pyridyl.- CH in heterocyclic radical₂- group is by the reality of-C (=O)-substitution Example includes, but not limited to 2- oxo-pyrrolidine bases, oxo -1,3-thiazoles alkyl, 2- piperidone bases, 3,5- dioxy piperazine piperidinyls. The oxidized example of sulphur atom includes, but not limited to sulfolane base, 1,1- dioxothiomorpholinyl in heterocyclic radical.Described Heterocyclyl groups optionally can be replaced by one or more substitution bases described in the invention.When the structure clearly needs During linking group, linking group is interpreted as the Markush variable cited by the group.If for example, the structure needs to connect Connect group and the Markush group definition for the variable lists " heterocyclic radical ", then it should be understood that should " heterocyclic radical " representative The sub- heterocyclyl groups of connection.

Term " cycloheteroalkylalkyl " refers to the alkyl of heterocyclic radical substitution；Wherein heterocyclic radical and alkyl group have such as the present invention Described implication.

Term " n former molecular ", wherein n is integer, the number of ring member nitrogen atoms in molecule is typically described, described The number of ring member nitrogen atoms is n in molecule.For example, piperidyl is 6 molecular Heterocyclylalkyls of original.

Contain one or more degrees of unsaturation in " undersaturated " the expression group of term for being used in the present invention.

Term " hetero atom " refers to O, S, N, P and Si, including any oxidation state of N, S and P form；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, for example, N is (as in 3,4- dihydro-2 h-pyrrole bases N), NH (as the NH in pyrrolidinyl) or NR (as the NR in the pyrrolidinyl that N- replaces).

Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Term " aryl " represents and contains 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom is monocyclic, double The carbocyclic ring system of ring and three rings, wherein, at least one member ring systems are aromatic, and each of which member ring systems are former comprising 3-7 Molecular ring, and there are one or more attachment points to be connected with the remainder of molecule.Term " aryl " can be with term " fragrance Ring " is exchanged and used.The example of aromatic yl group can include phenyl, indenyl, naphthyl and anthracene.The aromatic yl group can be with individually optional Ground is replaced by one or more substitution bases described in the invention.

Term " heteroaryl " represents and contains 5-12 annular atom, or 5-10 annular atom, or 5-6 annular atom it is monocyclic, Bicyclic and three-ring system, wherein at least one member ring systems are aromatic, and at least one member ring systems are miscellaneous comprising one or more Atom, each of which member ring systems include 5-7 former molecular ring, and have one or more attachment points and molecule remainder It is connected.Term " heteroaryl " can be exchanged and used with term " hetero-aromatic ring " or " heteroaromatics ".The heteroaryl groups are appointed Selection of land is replaced by one or more substitution bases described in the invention.In one embodiment, 5-10 original is molecular miscellaneous Aryl includes 1,2,3 or 4 hetero atom for being independently selected from O, S and N.

The example of heteroaryl groups is included, but is not limited to, 2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyls, 2- oxazolyls, 4- oxazolyls, 5- oxazoles Base, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- Pyrimidine radicals, pyridazinyl (such as 3- pyridazinyls), 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, tetrazole radical (such as 5- tetrazole radicals), triazole Base (such as 2- triazolyls and 5- triazolyls), 2- thienyls, 3- thienyls, pyrazolyl, isothiazolyl, 1,2,3- oxadiazolyl, 1, 2,5- oxadiazolyls, 1,2,4- oxadiazolyl, 1,2,3-triazoles base, 1,2,3- thio biphosphole base, 1,3,4- thio biphosphole base, 1, 2,5- thio biphosphole bases, pyrazinyl, 1,3,5-triazines base, pyrimidine ketone group, pyriconyl；Also include it is following bicyclic, but never It is limited to these bicyclic：Benzimidazolyl, benzofuranyl, benzo tetrahydrofuran base, benzothienyl, indyl (such as 2- indoles Base), etc..

Term " pyrazolyl " refers to 1H- pyrazol-1-yls, 1H- pyrazole-3-yls, 1H- pyrazoles -4- bases or 1H- pyrazoles -5- bases.

Term " heteroaryl alkyl " represents that alkyl group is replaced by one or more heteroaryl groups, wherein alkyl group There is implication as described in the present invention with heteroaryl groups, such example includes, but is not limited to pyridine -2- ylmethyls, pyrrole Pyridine -2- base ethyls, pyridin-3-yl methyl, pyridin-4-yl methyl, pyrimidine -2-base methyl, pyrimidine -2-base ethyl, pyrimidine -2-base Propyl group, pyrimidine-4-yl methyl, pyrimidine -5- ylmethyls, thiazol-2-yl methyl, thiazole-4-yl methyl, thiazole -5- ylmethyls, miaow Azoles -2- ylmethyls, imidazoles -2- base ethyls, pyrazine -2- ylmethyls, etc..

Term " Heteroarylcycloalkyl " represents that group of naphthene base is replaced by one or more heteroaryl groups, wherein cycloalkanes Base group and heteroaryl groups have implication as described in the present invention, and such example is included, but is not limited to (pyridine -2- bases) Cyclopropyl, (pyridin-3-yl) cyclopropyl, (pyridin-4-yl) cyclopropyl, (pyrimidine -2-base) cyclopropyl, (pyrimidine-4-yl) ring third Base, (pyrimidine -5- bases) cyclopropyl, etc..

No matter term " carboxyl ", be single use or be used in conjunction with other terms, such as " carboxyalkyl ", expression-CO₂H。

Term " alkyl amino " or " alkylamino " include " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced by one or two alkyl group.Some of them embodiment is that alkyl amino is one or two C_1-6Alkyl is connected to the alkylamino group of the lower level on nitrogen-atoms.Other embodiment is that alkyl amino is C_1-3's The alkylamino group of lower level.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, such reality Example is included, but is not limited to, N- methylaminos, N- ethylaminos, N, N- dimethylamino, N, N- lignocaine etc..

Term " alkoxy alkylamino " refers to that alkylamino is replaced by one or more alkoxies, wherein alkoxy and alkane ammonia Base group has implication as described in the present invention.

Term " alkylamino alkylamino " refers to that alkylamino is replaced by one or more alkylaminos, wherein alkylamino radicals tool There is implication as described in the present invention.Such example includes, but are not limited to-NHCH₂NHCH₃,-NHCH₂NHCH₂CH₃,- NHCH₂CH₂N(CH₃)₂,-N (CH₃)CH₂CH₂NHCH₂CH₃Deng.

Term " alkyl amino alkyl " represents that alkyl group is replaced by one or more alkylamino radicals, wherein alkyl group There is implication as described in the present invention with alkylamino radicals.

Term " aminoalkyl " or " alkyl of amino substitution " include the C replaced by one or more amino_1-10Straight chain Or branched alkyl group.Some of them embodiment is that aminoalkyl is the C replaced by one or more amino groups_1-6" compared with Rudimentary aminoalkyl ".

Term " prodrug " used in the present invention, represents a compound and is converted into vivo shown in formula (III) or (V) Compound.It is such conversion by pro-drug hydrolyze in blood or in blood or tissue through enzymatic conversion for precursor structure shadow Ring.Pro-drug compounds of the present invention can be ester, and ester can have phenyl ester class as pro-drug in existing invention, Aliphatic (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.For example in the present invention A compound include hydroxyl, you can the compound of prodrug form is obtained to be acylated.Other pro-drug shapes Formula includes phosphate, and such as these phosphate compounds are obtained through the di on parent.It is complete on pro-drug Whole discussion may be referred to documents below：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 Phosphatesand Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。

" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology known to art Adopted as stating and experimentally characterized.Such product can, by aoxidizing, be reduced, water by drug compound Solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc. method are obtained.Correspondingly, the present invention includes compound Metabolite, including compound of the invention and mammal are fully contacted the metabolite produced by a period of time.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of compound of the invention.Medicine Acceptable salt is known to us in art on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail inJ.Pharmaceutical Sciences,1977, 66:Described in 1-19..The salt that pharmaceutically acceptable nontoxic acid is formed is included, but is not limited to, and is reacted with amino group The inorganic acid salt of formation has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetate, grass Hydrochlorate, maleate, tartrate, citrate, succinate, malonate, or by described its on books document His method such as ion-exchange obtains these salt.Other pharmaceutically acceptable salts include adipate, alginates, Vitamin C Hydrochlorate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camsilate, Cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, glucoheptose Hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonate salts, breast Glycuronate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulfonates, Nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, Pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..By appropriate The salt that obtains of alkali include alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.The present invention is also intended to contemplate any bag The quaternary ammonium salt that the compound of the group containing N is formed.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization Arrive.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt is further included suitably , nontoxic ammonium, such as amine cation that quaternary ammonium salt and gegenions are formed, halide, hydroxide, carboxylate, sulphation Thing, phosphoric acid compound, nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

" solvate " of the invention refers to the association that one or more solvent molecules are formed with compound of the invention Thing.The solvent for forming solvate is included, but is not limited to, water, isopropanol, ethanol, methyl alcohol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is associated matter that water is formed.

Term " treatment " any disease as used in the present invention or illness, in some of these embodiments, " treatment " Referring to improves disease or illness (slow down or prevent or mitigate disease or the development of its at least one clinical symptoms).In other realities Apply in scheme, " treatment " refers to mitigation or improve at least one body parameter, including the body parameter that may not be discovered by patient. In other embodiments, " treatment " refer to from body (for example stablize perceptible symptom) or physiologically (for example stablize The parameter of body) or above-mentioned two aspects regulation disease or illness.In other embodiments, " treatment " refer to prevention or postpone disease Breaking-out, generation or the deterioration of disease or illness.

" inflammatory disease " used in the present invention refers to the excessive inflammation caused by excessive or out of control inflammatory responses Property symptom, host tissue infringement or function of organization any disease for losing, disorderly or symptom." inflammatory disease " also refers to by leucocyte Inflow and/or the pathologic state of Neutrophil chemotaxis mediation.

" inflammation " used in the present invention refers to that the topical protective caused by tissue damaged or destruction is responded, and it is used to break Tissue that is bad, diluting or separate (isolation) harmful material and be damaged.Inflammation is flowed into leucocyte and/or neutrophil cell becomes The property changed has significant contact.Inflammation can result from infection and the non-infectious mode of pathogenic organism and virus, such as heart Wound or Reperfu- sion after muscle infarction or apoplexy, to the immune response and autoimmune response of exotic antigen.Therefore, it can with this The inflammatory disease of disclosure of the invention compounds for treating includes：Reacted with the reaction of specific system of defense and non-specific defense system Related disease.

" autoimmune disease " used in the present invention or " autoimmune disease " refer to and body fluid or cell-mediated The set of any disease of the tissue damage related to the response of body itself component.The example of autoimmune disease includes lupus, Multiple sclerosis, muscle contracting lateral sclerosis, rheumatoid arthritis, psoriasis, type i diabetes, caused by organ transplant Complication, foreign matter transplanting, diabetes, cancer, asthma, atopic dermatitis, AITD, ulcerative colitis, Crohn disease, Alzheimer disease, leukaemia and lymthoma.

" arthritis disease " refers to be to be attributable to various etiologic etiological arthritis damages as used in the present invention Any disease of feature." dermatitis " refers to be characterized with being attributable to various etiologic etiological scytitises as used in the present invention Disease of skin extended familys in any one." graft rejection " refers to transplanting or surrounding tissue as used in the present invention Function forfeiture, such as the confrontation transplanting tissue that is characterized of pain, swelling, leukocytosis and decrease of platelet, organ or cell Any immune response of (such as marrow).Treatment method of the invention is included for treating the disease related to inflammatory cell activation Method.

Term " cancer " and " cancer " refer to or description patient in the usual physiology that is characterized with cell growth out of control Illness." tumour " includes one or more cancer cell.The example of cancer includes but is not limited to cancer (carcinoma), lymthoma, embryo Cytoma, sarcoma and leukaemia, or malignant lymph proliferative disease (lymphoid malignancies).Such cancer is more Specific example includes squamous cell carcinoma (such as epithelium squamous cell carcinoma), lung cancer (including ED-SCLC, non-small cell lung cancer (NSCLC), adenocarcinoma of lung and lung carcinoma squamosum), peritoneal cancer, hepatocellular carcinoma (hepatocellularcancer), stomach cancer (gastric Or stomach cancer) (including human primary gastrointestinal cancers), cancer of pancreas, glioblastoma, cervical carcinoma, oophoroma, liver cancer (livercancer), carcinoma of urinary bladder, hepatoma (hepatoma), breast cancer, colon and rectum carcinoma, colorectal cancer, intrauterine Film cancer or the cancer of the uterus, salivary-gland carcinoma, kidney or renal cancer (kidney or renal cancer), prostate cancer, carcinoma of vulva, first Shape gland cancer, liver cancer (hepatic carcinoma), cancer of anus, carcinoma of penis and head and neck cancer.

Term " biological sample " used in the present invention refers to the sample of vitro, including but not limited to, cell training Support or cell extraction；From the biopsy material that mammal or its extract are obtained；Blood, saliva, urine, excrement, essence Liquid, tears, or other living tissue liquid substances and its extract.Suppress or adjust kinase activity in biological sample, particularly BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4, EGFR or EGFR T790M kinase activities, can For multiple use known to one of ordinary skill in the art.Such purposes includes, but is not limited to, hematometachysis, organ transplant, Biological sample is stored and bioassay.

The description of the compounds of this invention

The treatment of compound of the invention and its pharmaceutical composition to autoimmune disease or cancer has potential effect.

On the one hand, the present invention relates to a kind of heteroaryl compound or its stereoisomer, geometric isomer, dynamic isomer, Raceme, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug.

Some of them embodiment is, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (I) (I) stereoisomer of compound shown in, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvation Thing, metabolite and pharmaceutically acceptable salt or prodrug：

Wherein each X, X¹, X², X³And R¹With implication as described in the present invention.

Some of them embodiment is, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (II) (II) stereoisomer of compound shown in, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvent Compound, metabolite and pharmaceutically acceptable salt or prodrug：

Wherein each X, X³, R⁰, R¹, L¹, Cy, L², L³, R², R³And R⁴With implication as described in the present invention.

Some of them embodiment is, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (IIa) (IIa) stereoisomer of compound shown in, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvent Compound, metabolite and pharmaceutically acceptable salt or prodrug：

Wherein：

Each Z¹、Z²And Z³It independently is N or CR^y；

Each R^yIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, C_1-6Alkyl, C_1-6Alkane Epoxide, C_1-6Alkylamino, C_1-6Alkylamino C_1-6Alkylamino or halo C_1-6Alkyl；

Wherein each X, X³, R⁰, R¹, L¹, L², L³, R², R³And R⁴With implication as described in the present invention.

Some of them embodiment is, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (IIb) (IIb) stereoisomer of compound shown in, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvent Compound, metabolite and pharmaceutically acceptable salt or prodrug：

Wherein：

M is 0,1 or 2；

Q is 0,1,2 or 3；

Wherein each X, X³, R¹, L¹, L³, R², R³And R⁴With implication as described in the present invention.

Some of them embodiment is, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (III) (III) stereoisomer of compound shown in, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvent Compound, metabolite and pharmaceutically acceptable salt or prodrug：

Wherein：

Each W¹And W²It independently is N or CR^5y；

Wherein each L¹, Cy, L², R², R³, R⁴, R^5x, R^5yAnd R^5aWith implication as described in the present invention.

Some of them embodiment is, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (IV) (IV) stereoisomer of compound shown in, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvent Compound, metabolite and pharmaceutically acceptable salt or prodrug：

Wherein：

Each V, Z²And Z³It independently is N or CR^y；

Each R^yIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, C_1-6Alkyl, C_1-6Alkane Epoxide, C_1-6Alkylamino, C_1-6Alkylamino C_1-6Alkylamino or halo C_1-6Alkyl.

Wherein each L¹, R², R³, R⁴, R^5x, R^5yAnd R^5aWith implication as described in the present invention.

Some of them embodiment is, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (V) (V) stereoisomer of compound shown in, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvation Thing, metabolite and pharmaceutically acceptable salt or prodrug：

Wherein each L¹, R², R³, R⁴, R^5x, R^5yAnd R^5aWith implication as described in the present invention.

Some of them embodiment is, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (V-a) (V-a) stereoisomer of compound shown in, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvent Compound, metabolite and pharmaceutically acceptable salt or prodrug：

Wherein：

Y is CH or N；

S is 0,1,2,3 or 4；

Each R^5x, R^5y, R¹⁴, R^14xAnd R^14yWith implication as described in the present invention.

Some of them embodiment is, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (V-b) (V-b) stereoisomer of compound shown in, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvent Compound, metabolite and pharmaceutically acceptable salt or prodrug：

Wherein：

Y is CH or N；

S is 0,1,2,3 or 4；

Each R^5x, R^5y, R¹⁴, R^14xAnd R^14yWith implication as described in the present invention.

Some of them embodiment is, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (V-c) (V-c) stereoisomer of compound shown in, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvent Compound, metabolite and pharmaceutically acceptable salt or prodrug：

Wherein：

Each Y independently is CH or N；

S is 0,1,2,3 or 4；

Each R^5x, R^5y, R¹⁴, R^14xAnd R^14yWith implication as described in the present invention.

Some of them embodiment is, the present invention relates to a kind of compound, it is the compound or formula as shown in formula (V-d) (V-d) stereoisomer of compound shown in, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvent Compound, metabolite and pharmaceutically acceptable salt or prodrug：

Wherein：

Each T²And T³It independently is CH or N；

T¹It is-O- ,-S- or-NH-；

S is 0,1,2,3 or 4；

Each R^5x, R^5y, R¹⁴, R^14xAnd R^14yWith implication as described in the present invention.

Some of them embodiment is that X is N or CR^x；

Wherein R^xWith implication as described in the present invention.

Some of them embodiment is, each X¹And X²It independently is N, CR⁰Or CR^x1；Condition is X¹And X²In at least one be CR^x1；

Wherein each R⁰And R^x1With implication as described in the present invention.

Some of them embodiment is, each R^x1It independently is following subformula： Each R^x1Individually optionally by one or more R⁵Substitution；

Wherein each R⁵With implication as described in the present invention；

Wherein each L¹, Cy, L², L³, R², R³And R⁴With implication as described in the present invention.

Some of them embodiment is, X³It is CR or N；

Wherein R has implication as described in the present invention.

Some of them embodiment is that R is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, carboxyl, alkyl, alcoxyl Base, alkenyl or alkynyl；R is optionally by one or more R⁵Substitution；

Wherein each R⁵With implication as described in the present invention.

Some of them embodiment is, each R^xIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl；Each R^xIndividually optionally by one or Multiple R⁵Substitution；

Wherein each R⁵With implication as described in the present invention.

Some of them embodiment is, each R⁰It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl；Each R⁰Individually optionally by one or Multiple R⁵Substitution；

Wherein each R⁵With implication as described in the present invention.

Some of them embodiment is, R¹It is cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, heteroaryl, condensed-bicyclic base is thick Close miscellaneous bicyclic group, spiral shell bicyclic group or the miscellaneous bicyclic group of spiral shell；R¹Further by one or more R^5aReplaced；R¹Optionally by one or Multiple R⁵、R^5xOr R^5yReplaced；

Wherein each R⁵、R^5x、R^5yAnd R^5aWith implication as described in the present invention.

Some of them embodiment is, each L¹It independently is-O- ,-N (R^1a)-,-S (=O)_p- ,-C (=O)-,-C (= O)-N(R^1a)-,-S (=O)_p-N(R^1a)-,-(CR^mR^w)_g- or-(CR^mR^w)_n-CR^1a=CR^1a-(CR^mR^w)_n-；Each L¹It is individually optional Ground is by one or more R⁵Substitution；

Wherein each R^1a, R^m, R^w, R⁵, p, g and n have implication as described in the present invention.

Some of them embodiment is, each L²It independently is a key ,-O- ,-N (R^1a)-,-CH₂-N(R^1a)-,-CH (CH₃)-N(R^1a)-,-C (CH₃)₂-N(R^1a)-,-C (=O)-N (R^1a)-or-S (=O)_p-N(R^1a)-；Each L²Individually optional ground quilt One or more R⁵Substitution；

Wherein each R^1a, R⁵There is implication as described in the present invention with p.

Some of them embodiment is, each L³It independently is-C (=O)-or-S (=O)₂-。

Some of them embodiment is that each Cy independently is cycloalkyl, and cycloalkenyl group, heterocyclic radical, aryl, heteroaryl is condensed Bicyclic group, condenses miscellaneous bicyclic group, spiral shell bicyclic group or the miscellaneous bicyclic group of spiral shell；Each Cy is individually optionally by one or more R⁵Substitution；

Wherein each R⁵With implication as described in the present invention.

Some of them embodiment is, each R²It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, alkyl, alkenyl or alkynes Base；Each R²Individually optionally by one or more R⁵Substitution；

Wherein each R⁵With implication as described in the present invention.

Some of them embodiment is, each R³And R⁴It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, carboxyl ,- (CR^mR^w)_n-NR^m1R^w1, alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl, alkyl amino alkyl, alkylthio alkyl, cycloalkanes Base, cycloalkyl-alkyl, heterocyclic radical, cycloheteroalkylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, condensed-bicyclic base is thick Close bicyclic group alkyl, condense miscellaneous bicyclic group, condense miscellaneous bicyclic group alkyl, spiral shell bicyclic group, spiral shell bicyclic group alkyl, the miscellaneous bicyclic group of spiral shell or The miscellaneous bicyclic group alkyl of spiral shell；Each R³And R⁴Individually optionally by one or more R⁵Substitution；

Wherein each n, R⁵, R^m, R^m1, R^wAnd R^w1With implication as described in the present invention.

Some of them embodiment is that each n independently is 0,1,2,3 or 4.

Some of them embodiment is that g is 1,2,3 or 4.

Some of them embodiment is that each p independently is 0,1 or 2.

Some of them embodiment is, each R^1aIt independently is hydrogen, deuterium, alkyl, alkenyl or alkynyl；Each R^1aIndividually optionally By one or more R⁵Substitution；

Wherein each R⁵With implication as described in the present invention.

Some of them embodiment is, each R^mAnd R^wIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, alkyl, the alkane of cyano group substitution Base, haloalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic radical or cycloheteroalkylalkyl；Each R^mAnd R^wIt is individually optional Ground is by one or more R⁵Substitution；

Wherein each R⁵With implication as described in the present invention.

Some of them embodiment is, each R^m1And R^w1It independently is hydrogen, alkyl, the alkyl of cyano group substitution, haloalkyl, Alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic radical or cycloheteroalkylalkyl；Each R^m1And R^w1Individually optionally by one or Multiple R⁵Substitution；

Wherein each R⁵With implication as described in the present invention.

Some of them embodiment is, R^m1、R^w1Form former molecular by 3-12 together with the N atoms being attached thereto Heterocycle.

Some of them embodiment is, each R⁵It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkyloxy-alkoxy, alkoxy alkylamino, aryloxy group, heteroaryl epoxide, Heterocyclic radical epoxide, alkoxy aryl, heteroarylalkoxy, heterocyclylalkoxy, alkylamino, alkyl amino alkyl, alkylamino alkane ammonia Base, cycloalkyl amino, alkylthio group, haloalkyl, halogenated alkoxy, the alkyl of hydroxyl substitution, the alkylamino of hydroxyl substitution, cyano group Substituted alkyl, the alkoxy of cyano group substitution, the alkylamino of cyano group substitution, the alkyl of amino substitution, alkyl acyl, miscellaneous alkyl, Cycloalkyl, cycloalkenyl group, cycloalkyl-alkyl, heterocyclic radical, cycloheteroalkylalkyl, heterocyclic radical alkylamino, heterocyclylacyl, aryl, aryl Alkyl, fragrant amino, heteroaryl, heteroaryl alkyl, heteroaryl amino, NH₂- C (=O)-, alkyl-N (R⁶)-C (=O)-, NH₂-S (=O)₂-, alkyl-N (R⁶)-S (=O)₂-, NH₂- S (=O)₂- alkyl-, alkyl-N (R⁶)-S (=O)₂- alkyl-, alkyl-S (=O)₂-N(R⁶)-alkyl-, aryl-alkyl-N (R⁶)-C (=O)-, alkyl-C (=O)-N (R⁶)-, alkyl-N (R⁶)-C (= O)-alkyl-N (R⁶)-, alkyl-S (=O)₂-, alkyl-S (=O)₂- alkyl-,-(CH₂)_n-N(R⁶)-(CH₂)_n- S (=O)_p- R⁷,-(CH₂)_n-N(R⁶)-(CH₂)_n-N(R⁶)-S (=O)_p-R⁷,-(CR⁸R⁹)_n-COOR¹⁰Or R¹¹R¹²N-C (=O)-alkyl-；Respectively R⁵Individually optionally by one or more R¹³Replaced；

Wherein each R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²And R¹³With implication as described in the present invention.

Some of them embodiment is, each R^5xIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkyloxy-alkoxy, alkoxy alkylamino, aryloxy group, heteroaryl epoxide, Heterocyclic radical epoxide, alkoxy aryl, heteroarylalkoxy, heterocyclylalkoxy, alkylamino, alkyl amino alkyl, alkylamino alkane ammonia Base, cycloalkyl amino, alkylthio group, haloalkyl, halogenated alkoxy, the alkyl of hydroxyl substitution, the alkylamino of hydroxyl substitution, cyano group Substituted alkyl, the alkoxy of cyano group substitution, the alkylamino of cyano group substitution, the alkyl of amino substitution, alkyl acyl, miscellaneous alkyl, Cycloalkyl, cycloalkenyl group, cycloalkyl-alkyl, heterocyclic radical, cycloheteroalkylalkyl, heterocyclic radical alkylamino, heterocyclylacyl, aryl, aryl Alkyl, fragrant amino, heteroaryl, heteroaryl alkyl, heteroaryl amino, NH₂- C (=O)-, alkyl-N (R⁶)-C (=O)-, NH₂-S (=O)₂-, alkyl-N (R⁶)-S (=O)₂-, NH₂- S (=O)₂- alkyl-, alkyl-N (R⁶)-S (=O)₂- alkyl-, alkyl-S (=O)₂-N(R⁶)-alkyl-, aryl-alkyl-N (R⁶)-C (=O)-, alkyl-C (=O)-N (R⁶)-, alkyl-N (R⁶)-C (= O)-alkyl-N (R⁶)-, alkyl-S (=O)₂-, alkyl-S (=O)₂- alkyl-,-(CH₂)_n-N(R⁶)-(CH₂)_n- S (=O)_p- R⁷,-(CH₂)_n-N(R⁶)-(CH₂)_n-N(R⁶)-S (=O)_p-R⁷,-(CR⁸R⁹)_n-COOR¹⁰Or R¹¹R¹²N-C (=O)-alkyl-；Respectively R^5xIndividually optionally by one or more R¹³Replaced；

Wherein each R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²And R¹³With implication as described in the present invention.

Some of them embodiment is, each R^5yIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, alkyl, alkenyl, alkoxy, alkoxyalkyl, alkyloxy-alkoxy, alkoxy alkylamino, aryloxy group, heteroaryl epoxide, Heterocyclic radical epoxide, alkoxy aryl, heteroarylalkoxy, heterocyclylalkoxy, alkylamino, alkyl amino alkyl, alkylamino alkane ammonia Base, cycloalkyl amino, alkylthio group, haloalkyl, halogenated alkoxy, the alkyl of hydroxyl substitution, the alkylamino of hydroxyl substitution, cyano group Substituted alkyl, the alkoxy of cyano group substitution, the alkylamino of cyano group substitution, the alkyl of amino substitution, alkyl acyl, miscellaneous alkyl, Cycloalkyl, cycloalkenyl group, cycloalkyl-alkyl, heterocyclic radical, cycloheteroalkylalkyl, heterocyclic radical alkylamino, heterocyclylacyl, aryl, aryl Alkyl, fragrant amino, heteroaryl, heteroaryl alkyl, heteroaryl amino, NH₂- C (=O)-, alkyl-N (R⁶)-C (=O)-, NH₂-S (=O)₂-, alkyl-N (R⁶)-S (=O)₂-, NH₂- S (=O)₂- alkyl-, alkyl-N (R⁶)-S (=O)₂- alkyl-, alkyl-S (=O)₂-N(R⁶)-alkyl-, aryl-alkyl-N (R⁶)-C (=O)-, alkyl-C (=O)-N (R⁶)-, alkyl-N (R⁶)-C (= O)-alkyl-N (R⁶)-, alkyl-S (=O)₂-, alkyl-S (=O)₂- alkyl-,-(CH₂)_n-N(R⁶)-(CH₂)_n- S (=O)_p- R⁷,-(CH₂)_n-N(R⁶)-(CH₂)_n-N(R⁶)-S (=O)_p-R⁷,-(CR⁸R⁹)_n-COOR¹⁰Or R¹¹R¹²N-C (=O)-alkyl-；Respectively R^5yIndividually optionally by one or more R¹³Replaced；

Wherein each R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²And R¹³With implication as described in the present invention.

Some of them embodiment is, each R^5aIt independently is heteroaryl alkyl or Heteroarylcycloalkyl；Each R^5aIt is individually optional Ground is by one or more R¹⁴, R^14xOr R^14yReplaced；

Wherein each R¹⁴, R^14xAnd R^14yWith implication as described in the present invention.

Some of them embodiment is, each R⁶, R⁷, R⁸, R⁹And R¹⁰It independently is hydrogen, deuterium, alkyl, alkenyl or alkynyl.

Some of them embodiment is, each R¹¹And R¹²It independently is hydrogen, deuterium, alkyl, the alkyl of cyano group substitution, alkyl halide Base, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclic radical or cycloheteroalkylalkyl.

Some of them embodiment is, R¹¹、R¹²Form former molecular by 3-12 together with the N atoms being attached thereto Heterocycle.

Some of them embodiment is, each R¹³It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), alkyl, alkoxy, alkoxyalkyl, alkyl-C (=O)-, the alkyl-C (=O) that cyano group replaces-, alkane Amino, NH₂- S (=O)₂-, alkyl-N (R^13a)-S (=O)₂-, NH₂- S (=O)₂- alkyl-, alkyl-N (R^13a)-S (=O)₂- alkane Base-, alkyl-S (=O)₂-N(R^13a)-alkyl-, haloalkyl, the alkyl of hydroxyl substitution, the alkyl of cyano group substitution, cycloalkyl, Heterocyclic radical, aryl, aryloxy group, alkoxy aryl or heteroaryl；

Wherein each R^13aWith implication as described in the present invention.

Some of them embodiment is, each R¹⁴It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, Carboxyl, oxo (=O), alkyl, alkoxy, alkoxyalkyl, alkyl-C (=O)-, the alkyl-C (=O) that cyano group replaces-, alkane Amino, NH₂- S (=O)₂-, alkyl-N (R^13a)-S (=O)₂-, NH₂- S (=O)₂- alkyl-, alkyl-N (R^13a)-S (=O)₂- alkane Base-, alkyl-S (=O)₂-N(R^13a)-alkyl-, haloalkyl, the alkyl of hydroxyl substitution, the alkyl of cyano group substitution, cycloalkyl, Heterocyclic radical, aryl, aryloxy group, alkoxy aryl or heteroaryl；

Wherein each R^13aWith implication as described in the present invention.

Some of them embodiment is, each R^14xIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, ammonia Base, carboxyl, oxo (=O), alkyl, alkoxy, alkoxyalkyl, alkyl-C (=O)-, the alkyl-C (=O) that cyano group replaces-, Alkylamino, NH₂- S (=O)₂-, alkyl-N (R^13a)-S (=O)₂-, NH₂- S (=O)₂- alkyl-, alkyl-N (R^13a)-S (=O)₂- Alkyl-, alkyl-S (=O)₂-N(R^13a)-alkyl-, haloalkyl, the alkyl of hydroxyl substitution, the alkyl of cyano group substitution, cycloalkanes Base, heterocyclic radical, aryl, aryloxy group, alkoxy aryl or heteroaryl；

Wherein each R^13aWith implication as described in the present invention.

Some of them embodiment is, each R^14yIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, ammonia Base, carboxyl, oxo (=O), alkyl, alkoxy, alkoxyalkyl, alkyl-C (=O)-, the alkyl-C (=O) that cyano group replaces-, Alkylamino, NH₂- S (=O)₂-, alkyl-N (R^13a)-S (=O)₂-, NH₂- S (=O)₂- alkyl-, alkyl-N (R^13a)-S (=O)₂- Alkyl-, alkyl-S (=O)₂-N(R^13a)-alkyl-, haloalkyl, the alkyl of hydroxyl substitution, the alkyl of cyano group substitution, cycloalkanes Base, heterocyclic radical, aryl, aryloxy group, alkoxy aryl or heteroaryl；

Wherein each R^13aWith implication as described in the present invention.

Some of them embodiment is to work as R^14xAnd R^14yIt is connected to when on same carbon atom, R^14xAnd R^14yIt is former together with carbon Son is optionally formed 3-12 former molecular ring together.

Some of them embodiment is, each R^13aIt independently is hydrogen, deuterium, alkyl, alkenyl or alkynyl.

Application of the present invention also comprising compound of the invention and its pharmaceutically acceptable salt, for producing medical product Treatment autoimmune disease or proliferative diseases, including those are described in the invention.Compound of the invention is equally used for life A kind of pharmaceuticals are produced for mitigating, are prevented, controlled or treat by BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, The illness that HER2, HER4, EGFR or EGFR T790M are mediated.

The present invention includes pharmaceutical composition, and the pharmaceutical composition includes formula (I), formula (II), formula (IIa), formula (IIb), formula (III), the compound and at least one medicine representated by formula (IV), formula (V), formula (V-a), formula (V-b), formula (V-c) or formula (V-d) Effective treatment consumption needed for the combination of acceptable carrier on, assistant agent or diluent.

It is of the invention same comprising treatment autologous patient immunological diseases or proliferative diseases, or the method sensitive to this illness, The method includes the formula of use (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IV), formula (V), formula (V-a), formula (V- B), formula (V-c) or the therapeutically effective amount of compound is treated to patient representated by formula (V-d).

Unless other aspects show, all of stereoisomer of compound of the invention, geometric isomer, tautomerism Body, raceme, nitrogen oxides, hydrate, solvate, metabolite, metabolic precursor thereof, salt and pharmaceutically acceptable prodrug are all Belong to the scope of the present invention.

Specifically, salt is pharmaceutically acceptable salt.Term is " pharmaceutically acceptable " to include that material or composition must Must be adapted to chemistry or toxicologically, with composition preparation other components and for treat mammal it is relevant.

The salt of compound of the invention, also including for prepare or purify formula (I), formula (II), formula (IIa), formula (IIb), The intermediate or formula of formula (III), formula (IV), formula (V), formula (V-a), formula (V-b), formula (V-c) or compound shown in formula (V-d) (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IV), formula (V), formula (V-a), formula (V-b), formula (V-c) or formula (V-d) salt of the enantiomter that compound shown in is separate, but it is not necessarily pharmaceutically acceptable salt.

Pharmaceutically useful acid-addition salts can be formed with inorganic acid and organic acid, for example acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Thing/hydrochloride, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, apple Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.

The inorganic acid that salt can be obtained by its derivative is including such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc..

The organic acid that salt can be obtained by its derivative includes such as acetic acid, propionic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, butanedioic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, sulfo group water Poplar acid etc..

Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.

The inorganic base of salt can be obtained by its derivative includes, the metal of I races to the XII races of such as ammonium salt and periodic table. In some embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.

The organic base that salt can be obtained by its derivative includes primary amine, secondary amine and tertiary amine, and substituted amine includes naturally occurring Substituted amine, cyclic amine, deacidite etc..Some organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.

Officinal salt of the invention can be synthesized with conventional chemical processes by parent compound, alkalescence or acidic moiety. In general, such salt can by make the free acid form of these compounds and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or by making the free alkali form of these compounds and chemistry The suitable acid reaction of metered amount is prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, it is necessary to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile in the case of appropriate. Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,1985；" pharmaceutical salts handbook：Property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) in can find the list of the suitable salt of other.

In addition, compound disclosed by the invention, the salt including them, it is also possible to their hydrate forms or comprising it The form of solvent (such as ethanol, DMSO, etc.) is obtained, for their crystallization.The present invention discloses compound can be with pharmacy Upper acceptable solvent (including water) inherently or by design forms solvate；Therefore, it is contemplated that including solvation And unsolvated form.

Any structural formula that the present invention is given is also intended to expression these compounds not by the form of isotope enrichment and same The form of position element enrichment.The compound of isotope enrichment has the structure that the formula that the present invention is provided is described, except one or many Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes in the compounds of this invention can be introduced into Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as²H,³H,¹¹C,¹³C,¹⁴C,¹⁵N,¹⁷O,¹⁸O,¹⁸F,³¹P,³²P,³⁵S,³⁶Cl and¹²⁵I。

On the other hand, compound of the present invention includes the defined compound of the present invention of isotope enrichment, for example, its In there is radio isotope, such as³H,¹⁴C and¹⁸Those compounds of F, or wherein there is non radioactive isotope, such as²H and¹³C.The compound of such isotope enrichment can be used for metabolism research and (use¹⁴C), Reaction kinetics research are (using for example²H or³H), detection or imaging technique, such as positron emission tomography (PET) or including medicine or substrate tissue measure of spread SPECT (SPECT), or can be used in the radiotherapy of patient.¹⁸The compound of F enrichments to PET or It is especially desirable for SPECT researchs.The formula (I) of isotope enrichment, formula (II), formula (IIa), formula (IIb), formula (III), formula (IV), formula (V), formula (V-a), formula (V-b), formula (V-c) or compound shown in formula (V-d) can be ripe by those skilled in the art Embodiment and preparation process in the routine techniques or the present invention known is described former using suitable isotope labeling reagent replacement Carry out used unmarked reagent to prepare.

Additionally, higher isotope particularly deuterium is (i.e.,²H or D) substitution some treatment advantages can be provided, these advantages are Brought by metabolic stability is higher.For example, Half-life in vivo increases or volume requirements are reduced or therapeutic index obtains improving band Come.It should be appreciated that the deuterium in the present invention be counted as formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IV), The substitution base of formula (V), formula (V-a), formula (V-b), formula (V-c) or compound shown in formula (V-d).Isotope enrichment factor can be used To define the concentration of such higher isotope particularly deuterium.Term " isotope enrichment factor " used in the present invention refers to meaning Determine the ratio between the isotope abundance of isotope and natural abundance.If the substitution base of the compounds of this invention is designated as deuterium, The compound has at least 3500 (at each specified D-atoms 52.5% deuterium mix), at least for each D-atom specified 4000 (60% deuterium is mixed), at least 4500 (67.5% deuterium is mixed), at least 5000 (75% deuterium is mixed), at least 5500 (82.5% deuterium is mixed), at least 6000 (90% deuterium is mixed), at least 6333.3 (95% deuterium is mixed), at least 6466.7 The isotope enrichment of (97% deuterium is mixed), at least 6600 (99% deuterium is mixed) or at least 6633.3 (99.5% deuterium is mixed) The factor.The pharmaceutically useful solvate of the present invention can be such as D of isotope substitution including wherein recrystallisation solvent₂O, acetone-d₆、 DMSO-d₆Those solvates.

The pharmaceutical composition of the compounds of this invention, preparation and administration

The present invention provides a kind of pharmaceutical composition, and it includes the present invention and discloses compound and pharmaceutically acceptable figuration Agent, carrier, adjuvant, solvent or combinations thereof.The amount of compound refers to effectively to examine in pharmaceutical composition disclosed by the invention Measure the amount for suppressing biological specimen or patient's vivo protein kinases.

It will also be appreciated that some compounds of the invention can exist in a free form to be used to treat, or it is if appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some nonrestrictive implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when be administered to patient in need can it is direct or Any other adduct or derivative of compound of the present invention or its metabolite or residue is provided indirectly.

Drug pharmaceutical compositions disclosed by the invention can be prepared and be packaged as (bulk) form in bulk, wherein extractable safety The formula (I) of effective dose, formula (II), formula (IIa), formula (IIb), formula (III), formula (IV), formula (V), formula (V-a), formula (V-b), formula (V-c) compound or shown in formula (V-d), then gives patient with powder or syrup form.Or, medicine disclosed by the invention Composition can be prepared and be packaged as unit dosage forms, and wherein each physically discrete unit contains formula (I), the formula of safe and effective amount (II), formula (IIa), formula (IIb), formula (III), formula (IV), formula (V), formula (V-a), formula (V-b), formula (V-c) or formula (V-d) institute The compound for showing.When being prepared with unit dosage forms, pharmaceutical composition disclosed by the invention can generally contain, for example, 0.5mg to 1g, Or the compound disclosed by the invention of 1mg to 700mg or 5mg to 100mg.

" pharmaceutically acceptable excipient " means related to form of administration or pharmaceutical composition uniformity used by the present invention Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with other of pharmaceutical composition into Split-phase is held, and the interaction of effect for disclosing compound of the invention can be substantially reduced during avoiding that patient is administered and can be caused not It is the interaction of pharmaceutically acceptable pharmaceutical composition.Additionally, every kind of excipient must be pharmaceutically acceptable, example Such as, with sufficiently high purity.

Suitable pharmaceutically acceptable excipient can be different according to selected specific formulation.Additionally, can be according to them in group Specific function in compound selects pharmaceutically acceptable excipient.For example, may be selected to can help to produce equal one dosage type low temperature Some pharmaceutically acceptable excipient.Some the pharmaceutically acceptable figurations that can help to produce stabilizer type may be selected Agent.May be selected to contribute to when patient be administered to carry or transport it is of the invention compound is disclosed from an organ of body or partly to Another organ of body or the pharmaceutically acceptable excipient of some partial.Some medicines of enhancing patient compliance may be selected Acceptable excipient on.

Suitable pharmaceutically acceptable excipient includes following kind of excipient：Diluent, filler, adhesive, Disintegrant, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweetener, rectify Taste agent, odor mask, colouring agent, anticaking agent, NMF, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilization Agent, surfactant and buffer.Technical staff can be appreciated that some pharmaceutically acceptable excipient can provide more than one Function, and provide alternative function, this depends on existing in preparation in how much excipient and preparation in the presence of which other Excipient.

Technical staff grasps the knowledge and skills of this area, so that they can be selected for the suitable of appropriate amount of the invention Pharmaceutically acceptable excipient.Additionally, there are resource obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),TheHandbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of PharmaceuticalExcipients(the American Pharmaceutical Association and the Pharmaceutical Press)。

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 Disclosed in Dekker, New York for configuring the various carriers of pharmaceutically acceptable composition, and prepared for it Known technology, the respective content of these documents is incorporated by reference into the present invention.Except any such as because producing any undesirable life Thing is acted on, or so that any other composition in harmful way and pharmaceutically acceptable composition occurs to interact with the present invention Outside the incompatible any commonly employed carrier of open compound, pay close attention to its application and belong to the scope of the present invention.

Pharmaceutical composition disclosed by the invention is prepared using technology well known by persons skilled in the art and method.This area The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。

Therefore, on the other hand, the technique the present invention relates to prepare pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, assistant agent, solvent or combinations thereof, the technique include that mixing is each Plant composition.The pharmaceutical composition of compound is disclosed comprising the present invention, can mix to make under such as environment temperature and atmospheric pressure It is standby.

Compound disclosed by the invention is usually formulated as the formulation for being suitable for that patient is administered by required approach.Example Such as, formulation is suitable for the formulation of following method of administration including those：(1) it is administered orally, such as tablet, capsule, caplet agent, ball Agent, containing tablet, pulvis, syrup, elixir, supensoid agent, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, supensoid agent and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) suck, such as aerosol, solution and dry powder doses；(6) it is local administration, such as cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gel.

In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention can be with It is configured to nose administration formulation.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. Also in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.

The pharmaceutical composition that the present invention is provided can with compressed tablets, develop piece, chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets are provided.Enteric coatel tablets are to use to be resistant to the material bag that hydrochloric acid in gastric juice acts on but dissolved in intestines or be disintegrated The compressed tablets of clothing, so as to prevent the sour environment of active ingredient contacts stomach.Enteric coating includes, but not limited to aliphatic acid, fat Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.

Sugar coated tablet is the compressed tablets that sugar-coat is surrounded, and it can be beneficial to cover taste beastly or smell and can prevent Tablet is aoxidized.Thin membrane coated tablet is the compressed tablets covered with the thin layer or film of water-soluble substances.Film coating includes, but does not limit In hydroxyethyl cellulose, sodium carboxymethylcellulose, Macrogol 4000 and cellulose acetate phthalate ester.Film coating Possess and sweet tablet identical general characteristic.Multiple compressed tablet is the compressed tablets by being prepared more than press cycles, including multilayer Piece and pressed coated or dry coating tablet.

Tabules can be by the one kind in powder, crystallization or granular active component individually or with present invention description Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrant, controlled release polymer, profit Lubrication prescription, diluent and/or colouring agent.Fumet and sweetener are particularly useful when chewable tablets and lozenge is formed.

Exemplary pharmaceutically acceptable carrier or its component are carbohydrates, such as lactose, dextrose and saccharose；Starch, example Such as cornstarch and farina；Cellulose and its derivates, such as sodium carboxymethylcellulose, ethyl cellulose and Methyl cellulose Element；Powdered tragacanth；Malt；Gelatin；Talcum；Kollag, such as stearic acid and magnesium stearate；Calcium sulfate；Artificial oil；Plant Thing oil, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil；Polyalcohol, such as propane diols, glycerine, sorbierite, sweet dew Alcohol and polyethylene glycol；Alginic acid；PBS；Emulsifying agent, such as Tweens；Wetting agent, such as lauryl sodium sulfate； Colouring agent；Flavor enhancement；Tablet agent；Stabilizer；Antioxidant；Preservative；Apirogen water；Isotonic saline solution；It is molten with phosphate-buffered Liquid.

The pharmaceutical composition that the present invention is provided can be provided with soft capsule or hard shell capsules, and it can be fine by gelatin, methyl Element, starch or calcium alginate is tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is constituted by two sections, one section Fill in another section, therefore enclose active component completely.SEC (SEC) is soft, spherical shell, such as gelatin shell, It passes through to add glycerine, sorbierite or similar polyalcohol to plastify.Soft gelatin shell can be comprising the pre- preventing microorganism life of preservative It is long.Suitable preservative for as described in the present invention those, including methyl hydroxybenzoate and nipalgin and refer to, and sorbic acid.This Inventing liquid, semisolid and the solid dosage forms for providing can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution and supensoid agent in propene carbonate, vegetable oil or triglycerides.Capsule comprising such solution can such as in the U.S. Patent U.S.Pat.Nos.4,328,245；Preparing described in 4,409,239 and 4,410,545.The capsule can also be adopted Coating as is known to persons skilled in the art is used, so as to improve or maintain the dissolution of active component.

The pharmaceutical composition that the present invention is provided can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of which liquid is thoroughly dispersed in another liquid in pellet form, It can be oil-in-water type or water-in-oil type.Emulsion can include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifying agent and Preservative.Supensoid agent can include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions can include pharmaceutically may be used Two (low alkyl group) acetals of the acetal of receiving, such as low alkyl group aldehyde, such as acetaldehyde diethyl acetal；With with one or many The water-soluble solvent of individual hydroxyl, such as propane diols and ethanol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and also preservative can be included.For liquid dosage form, for example, the solution in polyethylene glycol Can be diluted with enough pharmaceutically acceptable liquid-carriers such as water, to be accurately, conveniently administered.

Other useful liquid and semisolid dosage form include, but are not limited to the active component provided comprising the present invention and two grades Change those formulations of list-or poly- alkylene glycol, the list-or poly- alkylene glycol include：1,2- dimethoxymethane, diethylene glycol (DEG) Dimethyl ether, triglyme, tetraethylene glycol dimethyl ether, polyethylene glycol -350- dimethyl ether, polyethylene glycol -550- dimethyl ether, poly- second Glycol -750- dimethyl ether (wherein 350,550,750 refer to the approximate mean molecule quantity of polyethylene glycol).These preparations can be further Including one or more antioxidant, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propylgallate, vitamin E, hydrogen Quinone, Hydroxycoumarin, monoethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbierite, phosphoric acid, bisulfites, Jiao Sodium sulfite, thio-2 acid and its ester and dithiocarbamate.

Where appropriate, the dosage unit preparations microencapsulation that will can be administered orally.Can also be prepared into extending or tieing up The composition of release is held, for example, is coated or is embedded in polymer, wax or the like by by microparticle material.

The combination of oral medication that the present invention is provided can also be carried in the form of liposome, micella, microballoon or nanometer system For.Micella formulation can be prepared with the method for U.S.Pat.No.6,350,458 descriptions.

The pharmaceutical composition that the present invention is provided can be provided with the granule and pulvis of non-effervesce or effervesce, to be reconstructed into Liquid dosage form.The pharmaceutically acceptable carrier and excipient used in non-effervescent or pulvis can include dilution Agent, sweetener and wetting agent.The pharmaceutically acceptable carrier and excipient used in effervescent or pulvis can be wrapped Include organic acid and carbon dioxide source.

Colouring agent and flavor enhancement can be used in all above-mentioned formulations.

Compound disclosed in this invention can also be combined with the soluble polymer as target medicine carrier.It is such Polymer includes polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl asparagus fern acyl Amine phenol or the oxide polylysine of palmitoyl residues substitution.Additionally, compound disclosed in this invention can with reality The class Biodegradable polymeric used in the control release of existing medicine is combined, for example, PLA, poly-epsilon-caprolactone, poly- The crosslinking of hydroxybutyric acid, poe, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and hydrogel or amphiphilic block are common Polymers.

The pharmaceutical composition that the present invention is provided can be configured to immediately or Modified release dosage forms, including postpone-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.

The pharmaceutical composition that the present invention is provided can be common with other active components that will not damage expected therapeutic action Prepare, or the material co-formulation with the expected effect of supplement.

The pharmaceutical composition that the present invention is provided can be by injection, infusion or implantation parenteral, for local or complete Body is administered.The parenteral used such as the present invention is included in intravenous, intra-arterial, intraperitoneal, intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical composition that the present invention is provided can be configured to be suitable to any formulation of parenteral, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and being suitable to is made consolidating for solution or suspension in a liquid before the injection Body form.Such formulation can according to known to the technical staff in pharmaceutical science field conventional method preparing (referring to Remington:The Science and Practice of Pharmacy, ibid).

Be intended for the pharmaceutical composition of parenteral can include one or more pharmaceutically acceptable carrier and Excipient, includes, but not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and dispersion that thing grows Agent, wetting agent or emulsifying agent, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent And inert gas.

Suitably include, but are not limited to containing transporter：Water, salt solution, physiological saline or phosphate buffered saline (PBS) (PBS), Sodium chloride injection, Ringers parenteral solutions, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers parenteral solutions.Non- transporter includes, but not limited to fixed oil, castor oil, corn oil, the cottonseed of plant origin The middle chain of oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soya-bean oil, hydrogenated vegetable oil, hydrogenated soybean oil and coconut oil Triglycerides and palm seed oil.Water miscibility carrier includes, but not limited to the poly- second two of ethanol, 1,3-BDO, liquid Alcohol (such as Liquid Macrogol and PEG400), propane diols, glycerine, METHYLPYRROLIDONE, N, N- dimethylacetamides Amine and dimethyl sulfoxide.

Suitable antimicrobial or preservative include, but not limited to phenol, cresols, mercurial, phenmethylol, chlorobutanol, Methyl p-hydroxybenzoate and propylparaben, thimerosal, benzalkonium chloride (such as benzethonium chloride), methyl hydroxybenzoate and Propylben and sorbic acid.Suitable isotonic agent includes, but not limited to sodium chloride, glycerine and glucose.Suitable buffer Include, but not limited to phosphate and citrate.Suitable antioxidant is including the sulfurous acid such as present invention description Hydrogen salt and sodium metabisulfite.Suitable local anesthetic includes, but are not limited to procaine hydrochloride.Suitable suspending agent and point Powder is including sodium carboxymethylcellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone such as present invention description. Suitable emulsifying agent includes those of present invention description, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene takes off Water sorbitol monooleate 80 and triethanolamine oleate ester.Suitable sequestering agent or chelating agent include, but are not limited to EDTA. Suitable pH adjusting agent includes, but are not limited to NaOH, hydrochloric acid, citric acid and lactic acid.Suitable complexing agent includes, but does not limit In cyclodextrin, including alpha-cyclodextrin, beta-schardinger dextrin, HP-β-CD, Sulfobutylether-beta-schardinger dextrin and sulfobutyl group Ether 7- beta-schardinger dextrins (CyDex,Lenexa,KS)。

The pharmaceutical composition that the present invention is provided can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multiple dose parenteral administration must include antibacterial or fungistatic concentrations anti-micro- Biological agent.All of parenteral administration all must be aseptic, as known in the art with practice.

In one embodiment, pharmaceutical composition is provided with instant sterile solution.In another embodiment, medicine Composition is provided with aseptic dried soluble product, including freeze-dried powder and hypodermic tablet, and it is using preceding using carrier Reconstruct.In yet another embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In yet another embodiment, medicine Compositions dry insolubility product before being formulated into use with the aseptic of carrier reconstruct.Also in one embodiment, Pharmaceutical composition is formulated into instant without bacterial emulsion.

Pharmaceutical composition can be configured to supensoid agent, solid, semisolid or thixotropic liquid, the reservoir administration as implantation. In one embodiment, pharmaceutical composition disclosed in this invention is dispersed in solid interior matrix, its be insoluble to body fluid but The outside polymeric membrane for allowing the active component in pharmaceutical composition to diffuse through is surrounded.

Suitable internal matrix include polymethyl methacrylate, poly- butyl methacrylate, plasticising or it is unplasticizied Polyvinyl chloride, plasticising nylon, plasticising PET, plasticising polyethylene terephthalate, natural rubber, Polyisoprene, polyisobutene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, poly- diformazan silica Alkane, silicone carbonate copolymer, hydrogel, collagen, the crosslinking of the ester of hydrophilic polymer such as acrylic acid and methacrylic acid The polyvinyl acetate of the partial hydrolysis of polyvinyl alcohol and coach.

Suitable outside polymeric membrane includes polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate copolymerization Thing, ethylene/vinyl acetate copolymer, silicone rubber, dimethyl silicone polymer, neoprene, haloflex, polychlorostyrene second The copolymer of alkene, ethlyene dichloride and vinyl acetate, vinylidene chloride, ethene and propylene, ionomer are poly- to benzene two Formic acid second diester, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol trimer and Ethylene/vinyl ethoxy-ethanol copolymer.

On the other hand, pharmaceutical composition disclosed in this invention can be configured to be suitable to any dose to patient's inhalation Type, such as dry powder doses, aerosol, supensoid agent or liquid composite.In one embodiment, drug regimen disclosed in this invention Thing can be configured to be suitable to the formulation with dry powder doses to patient's inhalation.In yet another embodiment, it is disclosed in this invention Pharmaceutical composition can be configured to be suitable to the formulation by sprayer to patient's inhalation.By the dry powder of inhalation delivery to lung Composition generally comprise fine powdered compound disclosed in this invention and one or more it is fine powdered pharmaceutically Acceptable excipient.The pharmaceutically acceptable excipient for being especially suitable for use as dry powder doses is known to those skilled in the art Dawn, it includes lactose, starch, mannitol and single-, two- and polysaccharide.Fine powder can be prepared for example, by being micronized and grinding Obtain.In general, compound can be by about 1 to 10 micron of D for (such as the micronizing) that size reduces₅₀Value (for example, with swash The measurement of optical diffraction method) define.

Can be by the way that be suspended or dissolved in compound disclosed in this invention to prepare in liquefied propellant by aerosol.It is adapted to Propellant include chlorohydrocarbon, hydro carbons and other liquid gas.Representational propellant includes：Arcton 11 (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), HFC-134a (HFA-134a), 1,1- difluoros Ethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, Perfluorinated butane, perflenapent, butane, iso-butane and pentane.Aerosol comprising compound disclosed in this invention generally passes through Metered dose inhaler (MDI) is administered to patient.Such device dawn known to those skilled in the art.

Aerosol can include pharmaceutically acceptable excipient that is extra, being used by MDIs, such as surface-active Agent, lubricant, cosolvent and other excipient, with improve preparation physical stability, improve valve characteristic, improve dissolubility, Or improve taste.

Being suitable for the pharmaceutical composition of cutaneous penetration can be prepared into discontinuous paster agent, it is intended that the epidermis with patient keeps It is in close contact the time of an elongated segment.For example, the delivering active ingredients from paster agent can be permeated by ion, such as Pharmaceutical Research, 1986,3 (6), the general description in 318.

Be suitable for the pharmaceutical composition of local administration can be formulated into ointment, cream, supensoid agent, lotion, pulvis, Solution, paste, gel, spray, aerosol or finish.For example, ointment, cream and gel can use water or oil Matrix, and suitable thickener and/or gel and/or solvent are configured.Such matrix can include, water, and/or oily example Such as liquid-liquid paraffin and vegetable oil (such as peanut oil or castor oil), or solvent such as polyethylene glycol.Made according to medium property Thickener and gel include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, poly- carboxylic second Alkene and cellulose derivative, and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.

Lotion can be prepared with water or oil matrix, and generally also contain one or more emulsifying agent, stabilizer, dispersion Agent, suspending agent or thickener.

Externally-applied powder can be molded in the presence of any suitable powder matrix such as talcum powder, lactose or starch.Drops Can be formulated with water or non-aqueous matrix comprising one or more dispersant, solubilizer, suspending agent or preservative.

Topical formulations can be administered using one or many daily by affected part；The impermeable plastic wound dressing for covering skin is preferential Used.Adhesiveness store system can realize continuous or extension administration.

Treatment eyes, or when other organs such as face and skin, can apply as the combination of topical ointment or cream Thing.When ointment is formulated as, compound disclosed in this invention can be used together with paraffin or water-soluble ointment matrix.Or Person, compound disclosed in this invention can be configured to cream together with Oil-in-water emulsifiable paste agent matrix or oil-in-water base.

The purposes of the compounds of this invention and composition

The present invention is provided and swashed by JAK using compound disclosed in this invention and medicine composite for curing, prevention or improvement Enzyme is swashed including JAK1, JAK2, JAK3 or TYK2 kinases behavior mediation or the disease for otherwise influenceing or disorder or by JAK Enzyme includes the disease or one kind of disorder or many that the behavior of JAK1, JAK2, JAK3 or TYK2 kinases is mediated or otherwise influenceed The method for planting symptom.

Jak kinase can be wild type and/or the mutation of JAK1, JAK2, JAK3 or TYK2 kinases.

In one embodiment, the present invention provides class compound disclosed in this invention or comprising presently disclosedization The pharmaceutical composition of compound, is mediated or otherwise shadow for treating, preventing or improve by unsuitable JAK1 kinases behavior Loud disease or disease or the one of disorder that is disorderly or being mediated by unsuitable JAK1 kinases behavior or otherwise influenceed Plant or various symptoms.

In another embodiment, the disease, disorder or disease or one or more symptom of disorder with it is inappropriate The behavior of JAK2 kinases it is related.

Also in one embodiment, the disease, disorder or disease or one or more symptom of disorder with it is inappropriate The behavior of JAK3 kinases it is related.

" unsuitable jak kinase behavior " refer to occur deviate with particular patient normal jak kinase behavior JAK swash Enzyme behavior.Unsuitable jak kinase behavior can show as example active abnormal growth or jak kinase time of the act point With the form of the deviation in control.This unsuitable kinases behavior comes from, for example, the overexpression or mutation of protein kinase and Caused inappropriate or uncontrolled behavior.Therefore, the present invention provides the method for treating these diseases and disorder.

Consistent with above description, such disease or disorder are included but is not limited to：Bone marrow proliferative diseases, for example very Property polycythemia (PCV), essential thrombocythemia, idiopathic myelofibrosis (IMF)；Leukaemia, such as medullary system Leukaemia includes chronic myelogenous leukemia (CML), the CML forms of resistance to Imatinib, acute myeloid leukemia (AML) and AML's Hypotype, acute megakaryoblastic leukemia (AMKL)；Lymphoproliferative disease, such as myeloma；Cancer includes incidence cancer, preceding Row gland cancer breast cancer, oophoroma, melanoma, lung cancer, brain tumor, cancer of pancreas and kidney；And with immunologic function disorder, immune deficiency, The relevant diseases associated with inflammation of immunological regulation or disorder, autoimmune disease, tissue transplantation rejection, graft versus host disease(GVH disease), wound Mouth healing, ephrosis, multiple sclerosis, thyroiditis, type i diabetes, sarcoidosis, psoriasis, allergic rhinitis, IBD Closed including Crohn disease and ulcerative colitis (UC), systemic loupus erythematosus (SLE), arthritis, osteoarthritis, rheumatoid Section inflammation, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD) and dry eye syndrome (or keratoconjunctivitis sicca (KCS))。

On the one hand, the present invention provides class compound disclosed in this invention or the medicine comprising presently disclosed compound Compositions, proliferative diseases, autoimmune disease, anaphylaxis for preventing and/or treating mammal (including mankind) Disease, inflammatory disease or graft rejection.

On the other hand, the present invention provides a kind for the treatment of and suffers from or the risky mammal for suffering from disease disclosed herein Method, methods described include give effectively treatment illness amount or effectively prevention illness amount one or more medicine disclosed herein Compositions or compound.On the other hand, suffered from provided herein is one kind treatment or risky suffer from proliferative diseases, autologous exempt from The method of the mammal of epidemic disease, anaphylactia, inflammatory disease or graft rejection.

In a kind of method in terms for the treatment of, the present invention provides treatment and/or prevention is susceptible or suffering from proliferative diseases The method of mammal, methods described includes giving one or more medicine disclosed herein of effective therapeutic dose or effective preventive dose Compositions or compound.In particular instances, proliferative diseases are selected from cancer (for example, solid tumor such as uterine leio muscle Knurl or prostate cancer), polycythemia vera, primary thrombocytosis, myelofibrosis, leukaemia (for example, AML, CML, ALL or CLL) and Huppert's disease.

On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing proliferative diseases. In specific embodiment, proliferative diseases be selected from cancer (for example, solid tumor such as leiomyosarcoma of uterus or prostate cancer), Polycythemia vera, primary thrombocytosis, myelofibrosis, leukaemia (for example, AML, CML, ALL or CLL) And Huppert's disease.

On the other hand, provided herein is class compound disclosed herein, or the drug regimen comprising compound disclosed herein Thing, the medicine for preparing treatment or prevention proliferative diseases.In particular instances, proliferative diseases are selected from cancer (for example, real Body knurl such as leiomyosarcoma of uterus or prostate cancer), polycythemia vera, primary thrombocytosis, marrow it is fine Dimensionization, leukaemia (for example, AML, CML, ALL or CLL) and Huppert's disease.

On the other hand, the side of the mammal of autoimmune disease is susceptible or suffering from provided herein is treatment and/or prevention Method, methods described includes giving one or more pharmaceutical composition disclosed herein or the change of effective therapeutic dose or effective preventive dose Compound.In particular instances, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, skin lupus erythematosus, wolf Sore ephritis, dermatomyositis, Sjogren syndrome, psoriasis, type i diabetes and inflammatory bowel disease.

On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing autoimmune disease. In certain embodiments, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, skin lupus erythematosus, wolf Sore ephritis, dermatomyositis, Sjogren syndrome, psoriasis, type i diabetes and inflammatory bowel disease.

On the other hand, provided herein is class compound disclosed herein, or the drug regimen comprising compound disclosed herein Thing, the medicine for preparing treatment or prevention autoimmune disease.In certain embodiments, autoimmune disease is selected from COPD, asthma, systemic loupus erythematosus, skin lupus erythematosus, LN, dermatomyositis, Sjogren syndrome, psoriasis, I Patients with type Ⅰ DM and inflammatory bowel disease.

On the other hand, the method for the mammal of anaphylactia is susceptible or suffering from provided herein is treatment and/or prevention, Methods described includes giving one or more pharmaceutical composition disclosed herein or chemical combination of effective therapeutic dose or effective preventive dose Thing.In certain embodiments, anaphylactia is selected from respiratory anaphylactic disease, nasosinusitis, eczema and measles, food mistake Quick and insect venom allergies.

On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing anaphylactia. In specific embodiment, anaphylactia be selected from respiratory anaphylactic disease, nasosinusitis, eczema and measles, food hypersenstivity and Insect venom allergies.

On the other hand, provided herein is class compound disclosed herein, or the drug regimen comprising compound disclosed herein Thing, the medicine for preparing treatment or prevention anaphylactia.In certain embodiments, anaphylactia is selected from respiratory tract Anaphylactia, nasosinusitis, eczema and measles, food hypersenstivity and insect venom allergies.

On the other hand, the method for the mammal of inflammatory disease, institute are susceptible or suffering from provided herein is treatment and/or prevention Stating method includes giving one or more pharmaceutical composition disclosed herein or compound of effective therapeutic dose or effective preventive dose. In certain embodiments, inflammatory disease is selected from inflammatory bowel disease, Crohn disease, rheumatoid arthritis, juvenile arthritis And psoriasis arthropathica.

On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing inflammatory disease.In spy In fixed embodiment, inflammatory disease is selected from inflammatory bowel disease, Crohn disease, rheumatoid arthritis, juvenile arthritis and silver Bits disease arthritis.

On the other hand, provided herein is class compound disclosed herein, or the drug regimen comprising compound disclosed herein Thing, the medicine for preparing treatment or prevention inflammatory disease.In certain embodiments, inflammatory disease be selected from inflammatory bowel disease, Crohn disease, rheumatoid arthritis, juvenile arthritis and psoriasis arthropathica.

On the other hand, the method for the mammal of graft rejection, institute are susceptible or suffering from provided herein is treatment and/or prevention Stating method includes giving one or more pharmaceutical composition disclosed herein or compound of effective therapeutic dose or effective preventive dose. In particular instances, graft rejection is organ-graft refection, tissue transplantation rejection and cell transplant rejection.

On the other hand, provided herein is class compound disclosed herein, for treating and/or preventing graft rejection.In spy In fixed embodiment, graft rejection is organ-graft refection, tissue transplantation rejection and cell transplant rejection.

On the other hand, provided herein is class compound disclosed herein, or the drug regimen comprising compound disclosed herein Thing, the medicine for preparing treatment or prevention graft rejection.In particular instances, graft rejection is organ-graft refection, tissue Graft rejection and cell transplant rejection.

On the other hand, it is especially used as treating and/or preventing disease medicament noted earlier as medicine provided herein is a class Compound disclosed herein.It is also provided with that compound manufacture treatment is disclosed herein and/or prevents the medicine of disease noted earlier Thing.

One special projects of this method include that the present invention for giving the study subject effective dose with inflammation discloses chemical combination For a period of time, the time is enough to reduce the level of inflammation of study subject to thing, and preferably terminates the process of the inflammation.The party The special embodiment of method includes giving with or being susceptible to suffer from that the present invention of tested patients' effective dose of bone rheumatoid arthritis is public Compound become civilized for a period of time, the time is enough to reduce respectively or prevent the arthritis of the patient, and preferably terminates institute State the process of inflammation.

Another special projects of this method include giving the present invention of the study subject effective dose with proliferative diseases For a period of time, the time is enough to reduce the hyperplasia level of study subject to open compound, and preferably terminates the increasing The process of growing property disease.The special embodiment of the method includes giving being disclosed herein for the tested patients' effective dose with cancer For a period of time, the time is enough to reduce respectively or prevent the cancer symptom of the patient to compound, and preferably terminates described The process of cancer.

The present invention is also provided using compound disclosed in this invention and medicine composite for curing, prevention or improved by BTK The kinase mediated or disease that otherwise influences or disorderly or kinase mediated by the BTK or disease that otherwise influences or The method of one or more disorderly symptom.

The present invention provides the side for the treatment of rheumatoid arthritis, systemic loupus erythematosus, multiple sclerosis and/or asthma Method, the compounds of this invention and its pharmaceutically acceptable salt, solvate and mixture are the sole actives for giving patient, and The method for also including treatment rheumatoid arthritis, systemic loupus erythematosus, multiple sclerosis and/or asthma, wherein incite somebody to action this Invention compound and its pharmaceutically acceptable salt, solvate and mixture and one or more other activating agent are given in combination trouble Person.

Compound disclosed in this invention and pharmaceutical composition are kinase inhibitors, comprising Btk inhibitor.These inhibitor One or more disease of response kinase inhibition that can be used for treating in mammal, including response Btk suppresses and/or B- is thin The disease of born of the same parents' Proliferation Ability.It is not intended to be bound by any specific theory, it is believed that the compounds of this invention is led with the interaction of Btk The suppression of Btk activity is caused, and therefore obtains the pharmaceutical applications of these compounds.Therefore, the present invention includes having for treatment and rings The suppression for answering Btk activity and/or the mammal of the disease for suppressing B- cells propagation, the method for such as people, the method include：To The chemical entities of the offer at least one herein of the mammal effective dosage with such disease.Can be in experiment On for example by determining the haemoconcentration of compound, or determine valid density by calculating bioavilability in theory.Except Outside Btk, it is also possible to which affected other kinases are included but is not limited to, other EGFR-TKs and serine/threonine kinase Enzyme.

In the Btk scopes relevant with disease, the mitigation of disease and disease symptomses, preventive treatment and prophylactic treatment are all at this In the range of invention.

Can be treated with the compounds of this invention or the immune of prevention, autoimmunity and inflammatory disease include rheumatic disease (example Such as rheumatoid arthritis, psoriasis arthropathica, infectional arthritis, progressive chornic arthritis, deforming arthritis, bone Arthritis, traumatic arthritis, urarthritis, Reiter syndromes, polychondritis, acute synovitis and spondylitis), Glomerulonephritis (is with or without nephrotic syndrome), autoimmune hematological system condition (such as hemolytic anemia, aregeneratory Property anaemia, idiopathic thrombocytopenia and neutropenia), autoimmune gastritis and autoimmune inflammatory Enteropathy (such as ulcerative colitis and CrohnShi diseases), host vs. graft disease, allograft rejection, chronic first shape Adenositis, Graves' disease (Graves ' disease), chorionitis, diabetes (I types and II types), active hepatitis (it is acute and It is chronic), pancreatitis, PBC, myasthenia gravis, multiple sclerosis, systemic loupus erythematosus, silver bits Disease, atopic dermatitis, contact dermatitis, eczema, skin sunburn, vasculitis (such as BehcetShi disease), chronic renal insufficiency, Stevens-Johnson syndromes, inflammatory pain, idiopathic steatorrhea (idiopathic sprue), cachexia, sarcoidosis, Guillain-Barr é syndromes, uveitis, conjunctivitis, keratoconjunctivitis, tympanitis, periodontosis, interstitial lung fibrosis, Asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary insufficiency syndrome, pulmonary emphysema, pulmonary fibrosis, silicosis, chronic inflammatory Other inflammatories or occlusive disease of tuberculosis (such as chronic obstructive pulmonary disease) and respiratory tract.

In some embodiments, the illness of response Btk activity and/or B cell and/or myeloid cell activity suppression is cancer Disease, osteopathy, allergic disease and/or autoimmunity and/or inflammatory disease and/or acute inflammatory reaction.

The present invention includes that treatment suffers from cancer, osteopathy, allergic disease and/or autoimmunity and/or inflammatory disease And/or the method for the patient of acute inflammatory reaction, its compounds of this invention for passing through effective dosage and its pharmaceutically acceptable Salt, solvate and mixture.

In some embodiments, the illness and disease that can be influenceed using the compounds of this invention are included but is not limited to：

Allergic disease, including but not limited to eczema, allergic rhinitis or rhinitis, pollinosis, bronchial astehma, nettle Measles (urticaria) and food hypersenstivity and other idiocrasy illnesss；

Autoimmunity and/or inflammatory disease, including but not limited to psoriasis, Crohn disease, intestinal irritable syndrome, drying are comprehensive Simulator sickness, tissue transplantation rejection reaction and the hyperacute rejection of transplant organ, asthma, systemic loupus erythematosus are (and related Glomerulonephritis), dermatomyositis, multiple sclerosis, chorionitis, vasculitis (ANCA related and other vasculitises), autoimmunity It is ABO-HD and thrombocytopenic state, Goodpasture's syndrome (and glomerulonephritis and empsyxis of correlation), dynamic Pulse atherosclerosis, rheumatoid arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura (ITP), Addison disease, handkerchief The gloomy disease of gold, Alzheimer disease, diabetes (1 type), infectious shock, myasthenia gravis, ulcerative colitis, aplastic Anaemia, Coeliac diseases, wegener granulomatosis and wherein cell and antibody are caused and facedown by individual autologous tissue The Other diseases of the autologous tissue of body；

Acute inflammatory reaction, including but not limited to skin sunburn, inflammatory pelvic disease, inflammatory bowel disease, urethritis, grape Film inflammation, nasosinusitis, pneumonia, encephalitis, meningitis, myocarditis, ephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gum Inflammation, appendicitis, pancreatitis and cholecystitis；

Cancer, including but not limited to malignant hematologic disease such as B cell lymphoma and acute lymphoblastic leukemia, urgency Property myelogenous leukemia, chronic myelogenous leukemia, chronic and ALL, hairy cell leukemia, Hodgkin's disease, NHL, Huppert's disease and other diseases being characterized with the cancer of blood or lymphatic system；With

Osteopathy, including but not limited to osteoporosis.

Btk is the inhibitor of known lymthoma B cell apoptosis.Defect apoptosis contributes to the hair of human leukemia and lymthoma Disease and the resistance to the action of a drug.Therefore, the method for also providing the Apoptosis of promotion or induced expression Btk, it includes making the cell and this Invention compound and its contact of pharmaceutically acceptable salt, solvate and mixture.

Therapeutic alliance

The compounds of this invention can be administered as single active agent, or can be administered with other therapeutic agents, Including being defined as safe and efficient other compounds with same or similar therapeutic activity and for such administering drug combinations.

On the one hand, the present invention provides treatment, prevention or improves the method for disease or illness, including gives safe and effective amount The combination medicine of compound and one or more therapeutically active agent is disclosed comprising the present invention.In one embodiment, combination medicine Comprising one or two other therapeutic agents.

The example of other therapeutic agents is included but is not limited to：Anticancer, including chemotherapeutics and antiproliferative；Antiinflammatory；With exempt from Epidemic disease conditioning agent or immunodepressant.

On the other hand, the present invention is provided includes the product of the compounds of this invention and at least one other therapeutic agents, can prepare Into the combination simultaneously, separately or sequentially applied in the treatment.In one embodiment, treatment is directed to and is situated between by jak kinase activity The treatment of the disease or symptom led.In one embodiment, treatment is directed to the disease that is mediated by BTK kinase activities or symptom Treatment.Joint prepares the product for providing and compound and other treatment is disclosed herein including being present in be included in same pharmaceutical composition The composition of agent, or the compound disclosed herein that exists in different forms and other therapeutic agents, for example, medicine box.

On the other hand, the present invention provides a kind of medicine comprising compound disclosed herein and another or various therapeutic agents Composition.In one embodiment, pharmaceutical composition can comprising pharmaceutically acceptable excipient as described above, carrier, Adjuvant or solvent.

On the other hand, the present invention provides the medicine box comprising two kinds or more of drug alone composition, wherein at least one Pharmaceutical composition discloses compound comprising the present invention.In one embodiment, medicine box includes individually keeping the work of the composition Tool, such as container, separate bottle or separate paper tinsel box.The example of this kind of medicine box is blister package, be commonly used for package troche, Capsule etc..

Present invention also offers the compounds of this invention in the disease or symptom for the treatment of JAK or BTK kinase activity mediations Previously (such as in 24 hours) is treated with other therapeutic agents for purposes, wherein patient.Present invention also offers it The purposes of his therapeutic agent in the disease and symptom for the treatment of JAK or BTK kinase activity mediations, wherein patient is previously (such as 24 In hour) treated with the compounds of this invention.

Compound disclosed herein can be applied as single-activity component or as such as adjuvant, applied jointly with other medicines With.The other medicines include that immunodepressant, immunomodulator, other antiinflammatories are for example of the same race different for treating or preventing Body or xenograft acute or chronic rejection, inflammatory, the medicine of autoimmune disease；Or chemotherapeutics, such as malignant cell Antiproliferative.For example, the present invention discloses compound and can combine with following active component：Calcium nerve element inhibitor, such as ring spore Rhzomorph A or FK506；MTOR inhibitors, such as rapamycin, 40-O- (2- hydroxyethyls)-rapamycin, CCI779, ABT578, AP23573, TAFA-93, biolimus-7 or biolimus-9；Ascosin with immunosuppressive properties, for example ABT-281, ASM981 etc.；Corticosteroid；Endoxan；Imuran；Methotrexate (MTX)；Leflunomide；Mizoribine；Wheat Examine phenolic acid or salt；Mycophenolate mofetil；15- deoxyspergualins or its immunosupress homologue, analog or derivative； Described in pkc inhibitor, such as WO 02/38561 or WO 03/82859, such as compound of embodiment 56 or 70；It is immune Suppression monoclonal antibody, the monoclonal antibody of such as leukocyte receptors, for example, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or its part；Other immunomodulatory compounds, such as with CTLA4's The restructuring binding molecule or its mutant of at least part of extracellular domain, the CTLA4 being for example connected with non-CTLA4 protein sequences is extremely Few extracellular portion or its mutant, such as CTLA4Ig (being for example named as ATCC 68629) or its mutant, such as LEA29Y； Adhesion molecule inhibitor, such as LFA-1 antagonists, the antagonists of ICAM-1 or -3, VCAM-4 antagonists or VLA-4 antagonists；Or Chemotherapeutics, such as taxol, gemcitabine, cis-platinum, Doxorubicin or 5 FU 5 fluorouracil；Or anti-infective.

Compound is disclosed with other immunotherapeutic agent/immunomodulators, antiinflammatory, chemotherapy or anti-infective in the present invention In the case for the treatment of administering drug combinations, the immunodepressant of administering drug combinations, immunomodulator, antiinflammatory, chemotherapeutant or anti-sense The dosage for contaminating compound certainly can be according to used by combination medicine type, for example whether it is that steroidal or calcineurin suppress Agent, specific medicine used, illness to be treated etc. and change.

On the one hand, the present invention provides a kind of present invention that includes and discloses compound and β₂The connection of-adrenoceptor agonists Close.β₂The example of-adrenoceptor agonists includes salmeterol, salbutamol, Formoterol, salmefamol, Fei Nuote Sieve, carmoterol, Yi Tanteluo, naminterol, Clenbuterol, pirbuterol, Flerobuterol, reproterol, special sieve of promulgation, indenes Da Teluo, Terbutaline, and their salt, the xinafoate (1- hydroxy-2-naphthoic acids salt) of such as salmeterol, husky butylamine The sulfate or free alkali or the fumarate of Formoterol of alcohol.In one embodiment, long-acting beta₂- adrenocepter swashs Dynamic agent, for example, provide effective bronchiectasis up to 12 hours or the compound of longer time, is preferred.

β₂- adrenoceptor agonists can be with the form of pharmaceutically acceptable sour forming salt.It is described pharmaceutically The acid of receiving is selected from sulfuric acid, hydrochloric acid, fumaric acid, carbonaphthoic acid (such as 1- or 3- hydroxy-2-naphthoic acids), cinnamic acid, the meat of substitution Cinnamic acid, triphenylacetic acid, sulfamic acid, p-aminobenzene sulfonic acid, 3- (1- naphthyls) acrylic acid, benzoic acid, 4- methoxy benzoic acids, 2- or 4-HBA, 4- chlorobenzoic acids and 4- Phenylbenzoic acids.

On the other hand, the present invention provides a kind of joint that compound and corticosteroid are disclosed comprising the present invention.Suitably Corticosteroid refers to those oral and suction corticosteroids, and its has the prodrug of anti-inflammatory activity.Example sprinkles including methyl Ni Songlong, prednisolone (prednisolone), dexamethasone (dexamethasone), fluticasone propionate (fluticasone propionate), the α of-16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-17-[(4- methyl-1,3-thiazoles- 5- carbonyls) epoxide] -17 β of -3- oxo-androst -1,4- diene-thiocarboxylic acid S- fluorine methyl esters, 6 α, fluoro- 17 α of 9 α-two-[(2- furans Mutter carbonyl) epoxide]-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of-11 beta-hydroxy-16-thiocarboxylic acid S- fluorine methyl esters (furancarboxylic acids Fluticasone) ,-17 α of Alpha-Methyl-3- oxos of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-16-β of propionyloxy-androsta-1,4- diene-17- Thiocarboxylic acid S- (2- oXo-tetrahydro furans-3S- bases) ester, the α of-16 Alpha-Methyl-3- oxos of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-17- (2,2,3,3- tetramethyls cyclopropyl carbonyl) epoxide--17 β of androstane -1,4- diene-thiocarboxylic acid S- cyano methyl esters and 6 α, 9 α-two The fluoro- α of-16 Alpha-Methyl of 11 beta-hydroxy-17-β of (1- ethyls cyclopropyl carbonyl) epoxide-3- oxo-androst-1,4- diene-17-thio Carboxylic acid S- methyl fluorides ester, beclomethasone ester (such as 17- propionic esters or 17,21- dipropionic acids fat), budesonide (budesonide), Flunisolide (flunisolide), Mometasone ester (such as momestasone furoate), Triamcinolone acetonide (triamcinolone Acetonide), ([[(R)-cyclohexyl is sub- for 16 α, 17- for sieve fluoronaphthalene moral (rofleponide), ciclesonide (ciclesonide) Methyl] double (epoxides)] -11 β, 21- dihydroxy-pregnant steroid -1,4- diene -3,20- diketone), butixocort propionate (butixocortpropionate), RPR-106541 and ST-126.Preferred corticosteroid includes fluticasone propionate (fluticasone propionate), the α of-16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-17-[(4- methyl-1,3-thiazoles- 5- carbonyls) epoxide] -17 β of -3- oxo-androst -1,4- diene-thiocarboxylic acid S- methyl fluorides ester, 6 α, the fluoro- 17 α-[(2- of 9 α-two Furanylcarbonyl) epoxide]-17 β of Alpha-Methyl-3- oxo-androst-1,4- diene of-11 beta-hydroxy-16-thiocarboxylic acid S- methyl fluorides ester, The α of-16 Alpha-Methyl-3- oxos of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-17-(2,2,3,3- tetramethyls cyclopropyl carbonyl) epoxide-androstane- - 17 β of 1,4- diene-thiocarboxylic acid S- cyano methyl esters and the α of-16 Alpha-Methyl of 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-17-(1- methyl ring third Base carbonyl) -17 β of epoxide -3- oxo-androst -1,4- diene-thiocarboxylic acid S- fluorine methyl esters.In some embodiments, cortex class Sterol is 6 α, fluoro- 17 α of the 9 α-two-Alpha-Methyl -3- oxo-androsts -1,4- two of [(2- furanylcarbonyls) epoxide] -11 beta-hydroxy -16 The β of alkene-17-thiocarboxylic acid S- methyl fluoride esters.

On the other hand, the present invention provides a kind of joint that compound and nonsteroidal GR activators are disclosed comprising the present invention. Have to Transcription inhibition selectivity (compared with transcriptional activation), can be used for therapeutic alliance with glucocorticoid agonist activity Nonsteroidal compound covered in the compound in following patent including those：WO 03/082827、WO 98/54159、WO 04/005229、WO 04/009017、WO 04/018429、WO 03/104195、WO 03/082787、WO 03/082280、WO 03/059899、WO 03/101932、WO 02/02565、WO 01/16128、WO 00/66590、WO 03/086294、WO 04/026248th, WO 03/061651 and WO 03/08277.More nonsteroidal compounds are in WO 2006/000401, WO It is included in 2006/000398 and WO 2006/015870.

On the other hand, the present invention provides a kind of present invention that includes and discloses compound and nonsteroidal anti-inflammatory drug (NSAID's) Joint.The example of NSAID's includes nasmil, sodium nedocromil (nedocromil sodium), phosphodiesterase (PDE) inhibitor (such as theophylline, PDE4 inhibitor or mixed type PDE3/PDE4 inhibitor), leukotriene antagonist, leukotriene are closed Into inhibitor (such as montelukast), iNOS inhibitor, trypsase and elastatinal, Beta 2 integrin antagonist With adenosine receptor agonist or antagonist (e.g., adenosine 2a receptor stimulating agents), (such as chemokine receptors is short of money for cytokine antagonist Anti-agent, including CCR3 antagonists), cytokine synthesis inhibitor or 5-LO inhibitor.Wherein, iNOS (inductivities one Nitric oxide synthase) inhibitor is preferably administered orally.The example of iNOS inhibitor includes those in WO93/13055, WO 98/ 30537th, the compound disclosed in WO 02/50021, WO 95/34534 and WO 99/62875.CCR3 inhibitor include those Compound disclosed in WO 02/26722.

In one embodiment, the present invention relates to the present invention disclose compound with phosphodiesterase 4 (PDE4) inhibitor Joint in application, the especially application in inhalant dosage form.PDE4 specific inhibitors for this aspect of the present invention can To be known suppression PDE4 enzymes or be found to be used as any compound of PDE4 inhibitor, they are only PDE4 inhibitor, It is not to suppress other members, the compound of such as PDE3 and PDE5 in PDE families.Compound includes cis -4- cyano group -4- (3- rings Amyl group epoxide -4- methoxyphenyls) hexamethylene -1- carboxylic acids, 2- carbomethoxy -4- cyano group -4- (3- cyclo propyl methoxy -4- difluoros Methoxyphenyl) hexamethylene -1- ketone and cis-[4- cyano group -4- (3- cyclo propyl methoxy -4- difluoro-methoxies phenyl) hexamethylene Alkane -1- alcohol]；Also include that cis -4- cyano group -4- [3- (ring propoxyl group) -4- methoxyphenyls] hexamethylene -1- carboxylic acids are (also referred to as western Lip river department) and its salt, ester, prodrug or physical form, its in 09 month 1996 No. 03 United States Patent (USP) US 5 for authorizing, in 552,438 Open, this patent and its disclosed compound are incorporated herein by reference in their entirety.

On the other hand, the present invention provides a kind of joint that compound and anticholinergic are disclosed comprising the present invention.Cholinolytic Can agent example be those be used as muscarinic receptor antagonist compounds, particularly those as M1 or M3 receptor antagonists, M₁/M₃Or M₂/M₃Receptor dual antagonist or M₁/M₂/M₃The compound of the general antagonist of acceptor.The example compound bag of inhalation Include ipratropium (for example, as bromide, CAS22254-24-6,For trade name is sold), Oxygen support ammonium (for example, as bromide, CAS 30286-75-0) and tiotropium are (for example, as bromide, CAS 136310-93- 5,For trade name is sold)；Be also interested in also have Revatropate (for example, as hydrobromate, CAS 262586-79-8) and LAS-34273 disclosed in WO01/04118.The example compound of oral administration includes piperazine logical sequence Xiping (CAS 28797-61-7), darifenacin (CAS 133099-04-4, or its hydrobromate CAS133099-07-7, withFor trade name is sold), oxybutynin (CAS 5633-20-5,For trade name is sold Sell), terodiline (CAS 15793-40-5), Tolterodine (CAS 124937-51-5, or its tartrate CAS 124937- 52-6,For trade name is sold), Austria for ammonium (for example, as bromide, CAS 26095-59-0, withFor trade name is sold), trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1, Or its succinate CAS 242478-38-2, i.e. compound YM-905,For trade name is sold).

On the other hand, the present invention provides a kind of joint that compound and H1 antagonists are disclosed comprising the present invention.H1 antagonists Example include, but not limited to Amlexanox (amelexanox), western this imidazoles (astemizole), azatadine (azatadine), azelastine (azelastine), Acrivastine (acrivastine), Brompheniramine (brompheniramine), cetirizine (cetirizine), levocetirizine (levocetirizine), Efletirizine (efletirizine), chloropheniramine (chlorpheniramine), clemastine (clemastine), marezine (cyclizine), Carebastine (carebastine), cyproheptadine (cyproheptadine), carbinoxamine (carbinoxamine), descarboethoxyloratadine (descarboethoxyloratadine), doxylamine (doxylamine), diformazan indenes (dimethindene), Ebastine (ebastine), epinastine (epinastine), second Fluorine profit piperazine (efletirizine), fexofenadine (fexofenadine), hydroxyzine (hydroxyzine), Ketotifen (ketotifen), Loratadine (loratadine), levocabastine (levocabastine), Mizolastine (mizolastine), mequitazine (mequitazine), Mianserin (mianserin), the primary STING of promise (noberastine), meclizine (meclizine), Tecastemizole (norastemizole), olopatadine (olopatadine), piperacetazine (picumast), than Lamine (pyrilamine), phenergan (promethazine), special Fei Nading (terfenadine), Tripelennamine (tripelennamine), temelastine (temelastine), nedeltran (trimeprazine) and triprolidine (triprolidine), preferably cetirizine (cetirizine), levocetirizine (levocetirizine), Efletirizine (efletirizine) and fexofenadine (fexofenadine).In another implementation In scheme, the present invention provides a kind of joint that compound and H3 antagonists (and/or inverse agonist) are disclosed comprising the present invention.H3 is short of money The example of anti-agent includes those compounds disclosed in WO 2004/035556 and WO2006/045416.Can be used for and this hair Bright united other histamine receptor antagonists of open compound include H4 receptor antagonists (and/or inverse agonist), for example, exist Jablonowski et al.,J.Med.Chem.,2003,46:Compound disclosed in 3957-3960.

Another aspect, the present invention provides a kind of present invention that includes and discloses compound, with PDE4 inhibitor and β₂- adrenaline The joint of receptor stimulating agent.

Also on the one hand, the present invention provides a kind of present invention that includes and discloses compound, suppresses with anticholinergic drug and PDE-4 The joint of agent.

Above-described joint easily can be prepared into pharmaceutical composition to use, therefore, including defined above group Conjunction represents another aspect of the present invention with the pharmaceutical composition of pharmaceutically acceptable excipient or carrier.

These united each compounds with alone or in combination pharmaceutical dosage forms order of administration or can be administered simultaneously. In one embodiment, each compound component is administered simultaneously with the pharmaceutical dosage forms for combining.Known treatment agent be adapted to Dosage is easy to be understood by the person skilled in the art.

Therefore, on the other hand, the present invention provides a kind of pharmaceutical composition, is controlled with other comprising compound disclosed by the invention Treat the joint of activating agent.

In one embodiment, the pharmaceutical composition that the present invention is provided discloses compound and phosphodiesterase comprising the present invention The joint of 4 (PDE4) inhibitor.

In another embodiment, the pharmaceutical composition that the present invention is provided is disclosed on compound and β 2- kidneys comprising the present invention The joint of adrenoceptor activator.

In another embodiment, the pharmaceutical composition that the present invention is provided discloses compound and consolidates with cortex class comprising the present invention The joint of alcohol.

In another embodiment, the pharmaceutical composition that the present invention is provided discloses compound and nonsteroidal comprising the present invention The joint of GR activators.

In another embodiment, the pharmaceutical composition that the present invention is provided discloses compound and anticholinergic comprising the present invention The joint of medicine.

In yet another embodiment, the pharmaceutical composition that the present invention is provided discloses compound and antihistamine comprising the present invention Joint.

In medical oncology field, combine that to carry out treating cancer patient be conventional means using different form of therapy.Including In section's oncology, being added to one or more of the present composition other co-therapies form can be, for example, performing the operation, putting Treatment, chemotherapy, single transduction inhibitor or conditioning agent (for example, kinase inhibitor or conditioning agent) and/or monoclonal antibody.

The present invention discloses compound and can also be advantageously utilised in combination with other compounds, or and other therapeutic agents, especially During it is the combination of antiproliferative.Such antiproliferative includes, but not limited to aromatase inhibitor；Antiestrogenic；Topology is different Structure enzyme I inhibitor；Topoisomerase II inhibitors；Microtubule active agent；Alkylating agent；Histon deacetylase (HDAC) inhibitor；Induction The compound of cell differentiation procedure；Cyclooxygenase-2 inhibitors；MMP inhibitor；MTOR inhibitors；Antitumor antimetabolite；Platinum Compound；The compound and the compound of other anti-angiogenesis of targeting/reduction albumen or lipid kinase activity；Targeting, reduce or Suppress the compound of albumen or lipid phosphate esterase active；Gonadorelin excitomotor；Antiandrogen；Methionine aminopeptidase suppresses Agent；Diphosphonate；BRM；Antiproliferation antibodies；Heparanase inhibitors；The carcinogenic hypotype inhibitor of Ras；Telomere Enzyme inhibitor；Proteasome inhibitor；Treat the medicament of neoplastic hematologic disorder；Targeting, the compound for reducing or suppressing Flt-3 activity； Hsp90 inhibitor；TemozolomideAnd Calciumlevofolinate.

Term used herein " aromatase inhibitor ", refers to suppress the compound that estrogen is produced, that is, suppress substrate male Alkene diketone and testosterone change into the compound of oestrone and estradiol respectively.The term includes, but are not limited to：Steroid, especially It is atamestane (atamestane),

Exemestane (exemestane) and formestane (formestane)；And, particularly non-steroids, especially It is aminoglutethimide (aminoglutethimide), Rogletimide (roglethimide), Pyridoglutethimide (pyridoglutethimide), Trilostane (trilostane),

Testolactone (testolactone), ketoconazole (ketoconazole), fluorine chlorazol (vorozole), Fadrozole (fadrozole), Anastrozole (anastrozole) and Letrozole (letrozole).Exemestane can be with commercially available, such as Trade mark isForm administration.Formestane (formestane) can be with commercially available, as trade mark isForm administration.Fadrozole (fadrozole) can be with commercially available, as trade mark is Form administration.Anastrozole (anastrozole) can be with commercially available, as trade mark is Form Administration.Letrozole (letrozole) can be with commercially available, as trade mark isOrForm give Medicine.Aminoglutethimide (aminoglutethimide) can be with commercially available, as trade mark isForm Administration.Combination of the present invention including aromatase inhibitor chemotherapeutic is particularly useful for the treatment of the tumour that hormone receptor is positive, such as breast Adenoncus knurl.

Term used herein " antiestrogenic ", refers to the compound in Estrogen Receptor antagonising oestrogen effectiveness. The term includes, but not limited to TAM (tamoxifen), fulvestrant (fulvestrant), Raloxifene And raloxifene hydrochloride (raloxifenehydrochloride) (raloxifene).TAM (tamoxifen) can be with With commercially available, as trade mark isForm administration.

Raloxifene hydrochloride (raloxifene hydrochloride) can be with commercially available, as trade mark isForm administration.

Fulvestrant (fulvestrant) can be with United States Patent (USP) US 4, the formulation disclosed in 659,516 or commercially available , such as trade mark isForm administration.Combination of the present invention including antiestrogenic chemotherapeutic is particularly useful for the treatment of female The tumour that hormone receptor is positive, such as tumor of breast.

Term used herein " antiandrogen " refers to any material that can suppress male sex hormone biological action, and it is wrapped Include, but be not limited to, Bicalutamide (bicalutamide, trade name), its formulation can be according to United States Patent (USP) US 4,636,505 prepare.

Term used herein " Gonadorelin excitomotor " includes, but not limited to abarelix (abarelix), Ge She Rayleigh (goserelin) and goserelin acetate.Goserelin is disclosed in United States Patent (USP) US 4 in 100,274, can be with city Sell, such as trade mark is Form administration.Abarelix (abarelix) can be according to United States Patent (USP) Method disclosed in US 5,843,901 prepares formulation.

Term used herein " topoisomerase I inhibitor ", includes, but are not limited to TPT (topotecan), Ji Horse is for health (gimatecan), Irinotecan (irinotecan), camptothecine (camptothecian) and the like, 9- nitros Camptothecine (9-nitrocamptothecin) and macromolecular camptothecin conjugated compound PNU-166148 are (in WO 99/17804 Compound A1).Irinotecan can be with commercially available, as trade mark isForm administration.Topology is replaced Health can be with commercially available, as trade mark isForm administration.

Term used herein " Topoisomerase II inhibitors " includes, but are not limited to anthracycline compound, such as how soft ratio Star (doxorubicin), its Lipidosome, trade nameDaunomycin (daunorubicin)；Epirubicin (epirubicin)；Idarubicin (idarubicin)；The not soft pyrrole star of naphthalene (nemorubicin)；Anthraquinones mitoxantrone (mitoxantrone) and Losoxantrone (losoxantrone)；Podophillotoxines Etoposide (etoposide) and Teniposide (teniposide).Etoposide can be with commercially available, as trade mark isForm administration.Teniposide can be with commercially available, as trade mark is's Form is administered.Doxorubicin can be with commercially available, as trade mark isOrForm administration.Epirubicin can be with commercially available, as trade mark isForm administration.Idarubicin can be with commercially available, as trade mark isForm administration.Mitoxantrone can be with commercially available, as trade mark is Form administration.

Term " microtubule active agent " refers to microtubule stabilizer, microwave destabiliser and microtubule polymerization inhibitor.It includes, but not It is limited to taxanes, such as taxol (paclitaxel) and Docetaxel (docetaxel)；Vinca alkaloids, such as Changchun Alkali (vinblastine), especially vinblastine sulfate, especially vincristine, vincristine sulphate and vinorelbine (vinorelbine)；discodermolides；Colchicin；And Epothilones and its derivative, such as epothilone B or D Or derivatives thereof.Taxol can be with commercially available, as trade mark isForm administration.Docetaxel can be with With commercially available, as trade mark isForm administration.Vinblastine sulfate can be with commercially available, such as trade mark ForForm administration.Vincristine sulphate can be with commercially available, as trade mark isShape Formula is administered.Discodermolide can be obtained according to the method disclosed in United States Patent (USP) US 5,010,099.It is additionally included in WO 98/10121st, United States Patent (USP) 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, the and of WO 98/22461 Epothilones analog derivative disclosed in WO 00/31247, particularly preferred ebomycin A and/or B.

Term used herein " alkylating agent " includes, but not limited to endoxan (cyclophosphamide), different ring phosphorus Acid amides (ifosfamide), melphalan (melphalan) or Nitrosourea (nitrosourea, such as BCNU or carmustine).Ring phosphinylidyne Amine can be with commercially available, as trade mark is Form administration.Ifosfamide can with commercially available, As trade mark isForm administration.

Term " histon deacetylase (HDAC) inhibitor " or " hdac inhibitor " they refer to inhibition of histone deacetylase, and Compound with antiproliferative activity.It is included in the compound disclosed in WO 02/22577, especially N- hydroxyls -3- [4- [[(2- ethoxys) [2- (1H- indol-3-yls) ethyl]-amino] methyl] phenyl] -2E-2- acrylamides, N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- bases)-ethyl]-amino] methyl] phenyl] -2E-2- acrylamides and its can pharmaceutically connect The salt received.Especially include Vorinostat (SAHA).

Term " antineoplastic antimetabolite " includes, but not limited to 5-fluor-uracil (5-fluorouracil) or 5-FU； Capecitabine (capecitabine)；Gemcitabine (gemcitabine)；DNA demethylation reagents, such as U-18496 (5- ) and Decitabine (decitabine) azacytidine；Methotrexate (MTX) (methotrexate) and Edatrexate (edatrexate)；And antifol, such as pemetrexed (pemetrexed).Capecitabine can be with commercially available, such as trade mark ForForm administration.Gemcitabine can be with commercially available, as trade mark is 's Form is administered.This term also includes monoclonal antibody Herceptin (trastuzumab), can be with commercially available, as trade mark isForm administration.

Term used herein " platinum compounds " includes, but are not limited to carboplatin (carboplatin), cDDP (cis- Platin), cis-platinum (cisplatinum) and oxaliplatin (oxaliplatin).Carboplatin can be with commercially available, as trade mark isForm administration.Oxaliplatin can be with commercially available, as trade mark isForm Administration.

Term used herein " targeting/reduce albumen or lipid kinase activity or albumen or the active change of lipid phosphatase Compound, or other anti-angiogenesis compound " include, but not limited to protein tyrosine kinase and/or serine and/or Threonine inhibitor, or lipid kinase inhibitors, for example

A) target, reduce or suppress the compound of platelet derived growth factor receptor (PDGFR) activity；Targeting, reduction Or suppress the active compounds of PDGFR, the compound for especially suppressing pdgf receptor includes N- phenyl-2-pyrimidine-amine derivatives, Such as Imatinib (imatinib), SU101, SU6668, GFB-111 etc.；

B) target, reduce or suppress the active compound of fibroblast growth factor acceptor (FGFR)；

C) target, reduce or suppress the active compound of IGF-1-1 (IGF-1R)；Targeting, reduction Or suppress the active compounds of IGF-1R, especially suppressing the compound of IGF-1 receptor actives includes those in patent WO 02/ Compound disclosed in 092599；

D) compound of targeting, reduction or suppression Trk receptor tyrosine kinase family actives；

E) compound of targeting, reduction or suppression Axl family active；

F) compound of targeting, reduction or suppression c-Met receptor actives；

G) compound of targeting, reduction or suppression Kit/SCFR receptor tyrosine kinase activities；

H) target, reduce or suppress the active chemical combination of C-kit receptor tyrosine kinases (part in PDGFR families) Thing；Targeting, the compound for reducing or suppressing C-kit receptor tyrosine kinase family actives, especially suppress the change of c-Kit acceptors Compound, including Imatinib (imatinib) etc.；

I) target, reduce or suppress c-Abl families and their gene fusion products, such as change of BCR-Abl kinase activities Compound；Targeting, the compound for reducing or suppressing c-Abl family members and their Gene Fusion things include N- phenyl -2- pyrimidines - Amine derivative, such as Imatinib, PD180970, AG957, NSC 680410, the PD173955 from ParkeDavis；

J) Raf family members in targeting, reduction or suppression protein kinase C (PKC) and serine/threonine kinases, MEK, SRC, JAK, FAK, PDK and Ras/MAPK family member, Pl (3) kinase families member, or Pl (3) kinases associated kinase family into Member, and/or cell cycle protein dependent kinase family (CDK) member activity compound；Particularly those are in United States Patent (USP) US 5,093, the staurosporine derivatives disclosed in 330, such as midostaurin (midostaurin)；More examples of compounds Also include, UCN-01；Safingol (safingol)；BAY 43-9006；Bryostatin 1；Piperazine Li Fuxin (Perifosine)；She Mo Fuxin (llmofosine)；RO 318220 and RO 320432；GO 6976；Isis 3521；LY333531/LY379196； Isoquinoline compound, such as in WO 00/09495 those disclosed；FTIs；PD184352；Or a kind of QAN697 (P13K suppressions Preparation)；

K) target, reduce or suppress the active compound of protein tyrosine kinase inhibitor；Targeting, reduction suppress The compound of protein tyrosine kinase inhibitor activity includes GleevecOr tyrosine phosphorylation Inhibitor；Preferred low-molecular-weight (the Mr of tyrphostin<1500) compound, or its pharmaceutically acceptable salt, especially Its compound for being selected from the eyeball class of the eyeball class of benzyl allyl two or S- aryl sheet the third two or Double bottom thing quinolines, further selected from tyrosine Phosphorylation inhibitor A23/RG-50810, AG 99, tyrphostin AG213, tyrphostin AG 1748, tyrphostin AG 490, tyrphostin B44, tyrphostin B44 (+) Enantiomer, tyrphostin AG 555, AG 494, tyrphostin AG 556, AG957 and Adaphostin (4- { [(2,5- dihydroxy phenyls) methyl] amino }-benzoic acid Buddha's warrior attendant alkyl ester, NSC 680410, adaphostin)；With

I) target, reduce or suppress receptor tyrosine kinase epidermal growth factor receptor family (EGFR, ErbB2, The equal or heterodimer of ErbB3, ErbB4) activity compound；Targeting, reduction suppress Epidermal Growth Factor Receptor Family Compound refer in particular to suppress EGF receptor family member (such as EGF receptor, ErbB2, ErbB3, ErbB4, or can with EGF or The material that EGF associated ligands are combined) compound, albumen or antibody, is particularly summarized in the following documents or it is specific openly Compound, albumen or monoclonal antibody：WO 97/02266 (such as embodiment 39), EP 0 564 409, WO 99/03854, EP 0520722、EP 0 566 226、EP 0 787 722、EP 0 837 063、US 5,747,498、WO 98/10767、WO 97/30034th, WO 97/49688 and WO 97/38983, WO 96/30347 (such as CP 358774), WO96/33980 (such as chemical combination Thing ZD 1839), WO 95/03283 (such as compound ZM105180), Herceptin (Trastuzumab), Cetuximab, Yi Rui Sand, Erlotinib, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, E7.6.3, and the 7H- pyrrolo-es being disclosed in WO 03/013541-[2,3-d] pyrimidine derivatives.

Additionally, anti-angiogenic compounds include having other active mechanisms (for example, suppressing not with albumen or lipid kinase It is related) compound, such as ThalidomideAnd TNP-470.

The compound of targeting, reduction or suppression albumen or lipid kinase activity is the inhibitor of phosphatase -1, phosphatase 2A suppressions Preparation, PTEN inhibitor or CDC25 inhibitor, such as okadaic acid or derivatives thereof.

The compound of Cell differentiation inducing activity process is vitamin A acid, α-, γ-or Delta-Tocopherol, α-, γ-or δ-fertility triolefin Phenol.

Term used herein " cyclooxygenase-2 inhibitors " includes, but not limited to Cox-2 inhibitor, and 5- is alkyl-substituted 2- fragrant aminos phenylacetic acid and its derivative, such as celecoxibRofecoxibEtoricoxib, cut down Examine former times, or 5- alkyl -2- fragrant amino phenylacetic acids, such as 5- methyl -2- (the chloro- 6'- fluoroanilinos of 2'-) phenylacetic acids or reed rice Examine former times.

Term used herein " diphosphonate " includes, but not limited to Etidronic Acid, Clodronate, Tiludronic Acid, handkerchief rice phosphine Acid, alendronic acid, ibandronic acid, Risedronic Acid and zoledronic acid.Etidronic Acid can be with commercially available, such as trade nameForm administration.Clodronate can be with commercially available, such as trade name's Form is administered.Tiludronic Acid can be with commercially available, such as trade nameForm administration；Pamidronic acid (Pamidronic acid) can be with commercially available, such as trade name Aredia^TM(AREDIA^TM) form administration；Alendronic acid Can be with commercially available, such as trade nameForm administration；Ibandronic acid can be with commercially available, such as business The name of an article isForm administration；Risedronic Acid can be with commercially available, such as trade name Form administration；Zoledronic acid can be with commercially available, such as trade nameForm Administration.

Term " mTOR inhibitors " refers to suppress mammal rapamycin (mTOR) target protein, with antiproliferative activity Compound, such as sirolimus (sirolimus,), everolimus (CERTICAN^TM), CCI-779 and ABT578。

Term used herein " heparanase inhibitors " refers to target, reduce or suppress acetylsulfuric acid depolymerized heparin Compound.This term includes, but does not limit PI-88.

Term used herein " BRM " refers to lymphokine or interferon, such as interferon gamma.

Term used herein " the carcinogenic hypotypes of Ras (such as H-Ras, K-Ras or N-Ras) inhibitor " refers to targeting, reduces Or suppress Ras carcinogenic activities compound, such as " farnesyl transferase inhibitor ", such as L-744832, DK8G557 or R115777(Zarnestra)。

Term used herein " telomerase inhibitor " refers to targeting, the compound for reducing or suppressing telomerase activation.Target To, reduce or suppress telomerase activation compound refer in particular to suppress telornerase receptor compound, such as telomere mycin.

Term used herein " methionine aminopeptidase inhibitor " refers to targeting, reduces or suppress methionine aminopeptidase activity Compound.The compound of targeting, reduction or suppression methionine aminopeptidase activity includes bengamide or derivatives thereof.

Term used herein " proteasome inhibitor " refers to targeting, reduces or the active chemical combination of protease inhibition body Thing.The compound of targeting, reduction or protease inhibition body activity includes PS-341 and MLN 341.

Term used herein " NMPI " or " MMP inhibitor " include, but not limited to glue Former albumen peptides and non-peptide inhibitor, such as tetracycline derivant, hydroxamic acid peptide inhibitor Batimastat (batimastat) With the equivalent homologue Marimastat (marimastat, BB-2516) of its oral bio, Pu Masita (prinomastat, AG3340), Mei Tasita (metastat, NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996。

Term used herein " being used for treating the reagent of neoplastic hematologic disorder " includes, but not limited to FMS- sample EGFR-TKs Inhibitor.Targeting, the compound for reducing or suppressing FMS- samples tyrosine kinase receptor (Flt-3R) activity；Interferon, 1-b-D- Arabinofuranosyl adenin cytimidine (ara-c) and bisulfan；With ALK inhibitor, such as targeting, reduction or suppression anaplastic lymphoma kinase Compound.

The compound of targeting, reduction or suppression FMS- samples tyrosine kinase receptor (Flt-3R) especially suppresses Flt-3 and receives The compound of body kinase families member, albumen or antibody, such as PKC412, midostaurin (midostaurin), staurosporin Derivative, SU11248 and MLN518.

Term used herein " HSP90 inhibitor " includes, but are not limited to target, reduce or suppress the endogenous of HSP90 The compound of atpase activity；The chemical combination for degraded by ubiquitin protein body enzymatic pathway, targetting, reduce or suppress HSP90 client proteins Thing.Targeting, the compound of the Endogenous ATP enzymatic activity for reducing or suppressing HSP90 refer in particular to suppress the Endogenous ATP of HSP90 The compound of enzymatic activity, albumen or antibody, for example, 17- allyl aminos, 17-AAG (17AAG), its The compound of his geldanamycin correlation, red shell rhzomorph and hdac inhibitor.

Term used herein " antiproliferation antibodies " includes, but not limited to Herceptin (HERCEPTIN^TM), toltrazuril Monoclonal antibody-DM1, Tarceva (TARCEVA^TM), bevacizumab (AVASTIN^TM), RituximabPR064553 And 2C4 antibody (anti-CD40).Antibody means complete monoclonal antibody, polyclonal antibody, by least 2 complete antibody The multi-specificity antibody and antibody fragment (as long as they have desired bioactivity) of formation.For the white blood of acute myeloid sample For the treatment of sick (AML), the present invention can be disclosed compound and be used in combination with the leukemia therapy of standard, especially with It is used in combination in the therapy of AML treatments.Specifically, the present invention can be disclosed into compound to suppress with such as farnesyl tranfering enzyme Agent and/or other be used for AML treatment medicine for example daunorubicin, adriamycin, Ara-C, VP-16, Teniposide, mitoxantrone, Idarubicin, carboplatin and PKC412 administering drug combinations.

Compound disclosed by the invention can also be advantageously utilised in the combination of other compounds or with other therapeutic agents In combination, especially other anti-malarial agents.Such anti-malarial agents include, but are not limited to chloroguanide (proguanil), Chlorproguanil (chlorproguanil), TMP (trimethoprim), chloroquine (chloroquine), Mefloquine (mefloquine), Lumefantrine (lumefantrine), Atovaquone (atovaquone), pyrimethamine-sulfanilamide (SN) (pyrimethamine- Sulfadoxine), pyrimethamine-chlorobenzene (pyrimethamine-dapsone), halofantrine (halofantrine), quinine (quinine), quinindium (quinidine), amodiaquine (amodiaquine), amopyroquine (amopyroquine), sulfanilamide (SN) Class medicine, qinghaosu, Arteflene (arteflene), Artemether, Artesunate, primaquine, suction NO, L-arginine, dipropyl Alkene triamine NONO esters (NO donor), Rosiglitazone (PPARy activators), activated carbon, hematopoietin, levamisol, And Malaridine.

Compound disclosed by the invention can also be advantageously used in the group of the combination or other therapeutic agents with other compounds In conjunction, for example, treat the other therapeutic agents of leishmaniasis, trypanosomiasis, toxoplasmosis and cerebral cysticercosis.Such medicament includes, but It is not limited to nivaquin, atovaquone-proguanil, Artemether-lumenfantrine, quinine sulfate, Artesunate, quinine, fortimicin (doxycycline), clindamycin (clindamycin), meglumine antimony (meglumine antimoniate), gluconic acid Antimony sodium (sodium stibogluconate), Miltefosine (miltefosine), ketoconazole (ketoconazole), pentamidine (pentamidine), amphotericin B (AmB), AmB liposomes, paromomycin (paromomycine), Eflornithine (eflornithine), nifurtimox (nifurtimox), suramin (suramin), melarsoprol (melarsoprol), sprinkle Ni Songlong (prednisolone), benzimidazole, sulphadiazine, pyrimethamine, synergistic sulfonamide methylisoxazole, radonil, Ah Miramycin (azitromycin), Atovaquone, dexamethasone, praziquantel, albendazole (albendazole), beta-lactam, FQNS medicine, macrolides medicine, aminoglycoside medicine, sulphadiazine and pyrimethamine.

Can be from classic " The as code name, the structure of common name or active component determined by trade name and its preparation Merck Index (Merck index) " current edition (such as M.J.O ' Neil et al. compile ' The MerckIndex ', the 13rd edition, Merck Research Laboratories, 2001) or (such as Patents International are (for example from database IMS World Publications)) in know.

It is above-described, can with the present invention compound that compound is applied in combination be disclosed, can be by people in the art Member, prepares and is administered according to the method described in above-mentioned document.

Compound disclosed by the invention can also combine with therapeutic process, improve curative effect.For example, give hormone therapy or Special radiotherapy.Compound disclosed by the invention is used especially as radiosensitizer, it is especially useful in those radiotherapies The oncotherapy of sensitiveness weak ground.

" joint " represents the medicine box of the fixing joint in single dose unit form or the part for administering drug combinations, its In compound disclosed by the invention and joint companion can be in same time individual application or can be in certain time interval Inside apply respectively, joint companion shown cooperation, for example acted synergistically.As the term is employed herein " co-administered " Or " administering drug combinations " etc. are intended to include selected joint companion is applied to the single individuality (such as patient) for needing it, and anticipate It is intended to include that wherein material is without going through identical method of administration or the therapeutic scheme being administered simultaneously." medicine as the term is employed herein Joint " is represented and mixes or the resulting product of joint more than one active components, and both fixed connection including active component Close and also combine including on-fixed.Term " fixing joint " represents active component compound for example disclosed by the invention, and joint companion It is administered simultaneously in patient in the form of single entities or dosage.Term " on-fixed joint " represents that active component is disclosed such as the present invention Compound, and joint companion as corpus separatum simultaneously, it is common or without special time limitation ground successively to patient's administration, its In the administering mode treatment levels of significance of two kinds of compounds are provided in patient's body.The latter applies also for HAART, For example apply three or more active component.

Treatment method

In one embodiment, treatment method disclosed by the invention includes giving safe and effective amount to patient in need The compounds of this invention or the pharmaceutical composition comprising the compounds of this invention.Each embodiment disclosed by the invention is included by having The present invention that the patient of needs gives safe and effective amount discloses compound or the pharmaceutical composition of compound is disclosed comprising the present invention, Method to treat disease mentioned above.

In one embodiment, the present invention disclose compound or can be with comprising the of the invention pharmaceutical composition for disclosing compound It is administered by any suitable method of administration, including Formulations for systemic administration and local administration.Formulations for systemic administration includes oral administration, stomach and intestine External administration, cutaneous penetration and rectally.Typical parenteral refer to it is by injection or administered by infusion including intravenous, Intramuscular and hypodermic injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, suction and intranasal Administration.In one embodiment, the present invention disclose compound or can be with comprising the of the invention pharmaceutical composition for disclosing compound It is to be administered orally.In another embodiment, the present invention discloses compound or the drug regimen of compound is disclosed comprising the present invention Thing can be inhalation.In a further embodiment, the present invention discloses compound or discloses compound comprising the present invention can be Intranasal administration.

In one embodiment, the present invention disclose compound or can be with comprising the of the invention pharmaceutical composition for disclosing compound Once daily, or according to dosage regimen, at the appointed time in section, in different time interval administrations several times.For example, every It is administered once, twice, three times or four times.In one embodiment, it is administered once a day.In yet another embodiment, daily It is administered twice.Can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.It is of the invention public Become civilized compound or comprising the present invention disclose compound pharmaceutical composition appropriate dosage regimen depending on the compound medicine generation Kinetic property, for example, dilute, be distributed and half-life period, and these can be by determination of technical staff.Additionally, the present invention discloses compound Or the appropriate dosage regimen of the pharmaceutical composition of compound is disclosed comprising the present invention, including implement the duration of the program, take Certainly in treated disease, the order of severity of disease being treated, the age of patient under consideration and health, patient under consideration Medical history, while the factor in the range of technical staff's knowledge and experience such as the property of therapy, desired therapeutic effect.It is such Technical staff should also be understood that the reaction to dosage regimen for individual patient, or passage individual patient needs to become over time During change, in order to be sufficiently accurate it may be desired to adjust the dosage regimen of matters.

The present invention discloses compound other therapeutic agents can simultaneously, or before it or be afterwards administered with one or more. The compounds of this invention can be respectively administered with other therapeutic agents by identical or different method of administration, or therewith with same medicine group Solvate form is administered.

For the individuality of about 50-70kg, the present invention pharmaceutical composition disclosed and combination can be containing about 1-1000mg, Or the unit dose of about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg active components Amount form.The therapeutically effective amount of compound, pharmaceutical composition or its combination be depend on individual species, body weight, the age and Individual instances, treated disease (disorder) or disease (disease) or its order of severity.Possesses the doctor of conventional technical ability Teacher, clinician or animal doctor can easily determine to prevent, treat or suppress disease (disorder) or disease (disease) development During required each active component effective dose.

Dose Characteristics cited above using favourable mammal (such as mouse, rat, dog, monkey) or its from Confirmed in the external and in vivo studies of body organ, tissue and sample.The present invention discloses compound with solution, such as aqueous solution form Use in vitro, it is also possible to such as suspension or the aqueous solution form enteral in vivo, it is parenteral, it is especially intravenous to use.

In one embodiment, it is about 0.1mg daily to about 2 that the present invention disclose the treatment effective dose of compound, 000mg.Its pharmaceutical composition should provide about 0.1mg to about 2,000mg compounds of dosage.In a particular In, the pharmaceutical dosage unit forms of preparation can provide about 1mg to about 2,000mg, about 10mg to about 1,000mg, and about 20mg is to about The combination of each main component in 500mg, or the main active or every dosage unit form of about 25mg to about 250mg.One In particular, the pharmaceutical dosage unit forms of preparation can provide about 10mg, 20mg, 25mg, 50mg, 100mg, 250mg, 500mg, 1000mg or 2000mg main active.

Additionally, compound disclosed by the invention can be administered with prodrug forms.In the present invention, the present invention discloses compound " prodrug " be that finally can in vivo discharge the functional derivatives that the present invention discloses compound when being administered to patient.In the past When medicine form gives compound disclosed by the invention, those skilled in the art can implement one kind in following manner and more than：(a) Change the internal onset time of compound；B () changes the internal acting duration of compound；C () changes the internal of compound Conveying is distributed；D () changes the internal solubility of compound；And (e) overcomes the side effect or other difficult points that compound faced. Typical functional derivatives for preparing prodrug, comprising in vivo chemically or enzyme the mode compound that cracks Variant.Comprising preparing these variants of phosphate, acid amides, ester, monothioester, carbonate and carbaminate to people in the art It is well-known for member.

General building-up process

Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein substitution base definition such as formula (I), formula (II), formula (IIa), formula (IIb), formula (III), formula (IV), formula (V), formula (V-a), shown in formula (V-b), formula (V-c) or formula (V-d).Following reaction scheme and embodiment are used to that this to be further illustrated The content of invention.

Those skilled in the art will realize that：Chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds more of the invention, and be considered as in model of the invention for preparing other methods of compound of the invention Within enclosing.For example, the synthesis of the compound according to those non-illustrations of the invention can successfully by those skilled in the art Completed by method of modifying, such as appropriate protection interference group, by using other known reagents except 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 applied to the preparation of other compounds of the invention.

The embodiments described below, unless other aspects show that all of temperature is set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all not by being further purified when using, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Rise imperial chemistry examination in factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Qingdao Agent Co., Ltd and Haiyang Chemical Plant, Qingdao are commercially available.

Anhydrous tetrahydro furan, dioxane, toluene, ether is dried to obtain by metallic sodium backflow.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride backflow.Ethyl acetate, petroleum ether, n-hexane, DMA and N, N- Dimethylformamide is that drying is used in advance through anhydrous sodium sulfate.

Below reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb all suitable rubber stoppers beyond the Great Wall, substrate is squeezed into by syringe.Glassware is all dried.

Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.The survey of proton nmr spectra Strip part is：Under room temperature condition, the nuclear magnetic resonance spectrometer of Brooker (Bruker) 400MHz or 600MHz, with CDC1₃, d₆- DMSO, CD₃OD Or d₆- acetone is solvent (report is in units of ppm), with TMS (0ppm) or chloroform (7.26ppm) as reference standard.When going out When existing multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, bimodal), t (triplet, three Weight peak), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, double doublet), ddd (doublet of doublet of doublets, double two times of doublets), dt (doublet of triplets, double triplets).Coupling constant, is represented with hertz (Hz).

The condition of Algorithm (MS) data determination is：Agilent 6120Quadrupole HPLC-MS (pillars Model：Zorbax SB-C18,2.1x 30mm, 3.5 μm, 6min, flow velocity is 0.6mL/min, mobile phase：5%-95% (contains The CH of 0.1% formic acid₃CN) in (H containing 0.1% formic acid₂O the ratio in))), detected with UV in 210/254nm, with electron spray electricity From pattern (ESI).

The characteristic manner of compound purity is：The preparative high performance liquid chromatographies of Agilent 1260 (Pre-HPLC) or Calesep Pump 250 preparative high performance liquid chromatography (Pre-HPLC) (pillar model：NOVASEP, 50/80mm, DAC), 210nm/254nm is detected with UV.

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

HPLC high performance liquid chromatography；H₂O water；MeOH,CH₃OH methyl alcohol；CD₃OD deuterated methanols；EtOH, ethanol ethanol； HCOOH formic acid；CH₃CN, MeCN acetonitrile；DCM,CH₂Cl₂Dichloromethane；CHCl₃Chloroform, chloroform；CDCl₃Deuterochloroform； Cyclohexane hexamethylenes；CDI N, N'- carbonyl dimidazoles；Cs₂CO₃Cesium carbonate；DAST diethylin sulfur trifluorides；DCC bis- Carbodicyclo hexylimide；DMSO dimethyl sulfoxide (DMSO)s；DIEA, DIPEA N, N- diisopropylethylamine；DMF N, N- dimethyl formyls Amine；DME dimethyl ether；Et₃N,TEA,NEt₃Triethylamine；EtOAc ethyl acetate；PE petroleum ethers；EDCI 1- (3- dimethylaminos third Base) -3- ethyl-carbodiimide hydrochlorides；HOBT I-hydroxybenzotriazoles；HATU 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester；LiOH lithium hydroxides；NaH sodium hydrides；NaOH NaOH；NaHCO₃Sodium acid carbonate； Na₂SO₄Sodium sulphate；KOH potassium hydroxide；KI KIs；K₂CO₃Potassium carbonate；KOAc potassium acetates；HCl hydrogen chloride；H₂SO₄Sulfuric acid； TFA trifluoroacetic acids；THF tetrahydrofurans；Pd/C palladium carbons；SEMCl2- (TMS) ethoxymethyl chlorine；TsCl is to toluene sulphur Acyl chlorides；Pd(dppf)Cl₂[double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride；The double diphenylphosphines of Xantphos 4,5-- 9,9- dimethyl xanthenes；X-Phos 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyls；DBU 1,8- diazabicyclos [5.4.0] 11 carbon -7- alkene；G grams；Mg milligrams；Mol moles；Mmol mMs；H hours；Min minutes；L liters；ML, ml milliliter； R.t, RT room temperature；Rt retention times；HEPES hydroxyethyl piperazine second thiosulfonic acids；Brij-35 Brij-35s；DTT bis- Sulphur threitol；EDTA ethylenediamine tetra-acetic acids；EGFR EGF-R ELISAs；BTK bruton's tyrosine kinases；EGFR T790M EGF-R ELISA T790M mutant；Peptide FAM-P22 FAM-labeled peptides 22；ATP atriphos；96- The orifice plates of well plate 96；The orifice plates of 384-well plate 384；Staurosporine staurosporines；Coating Reagent#3#3 fruit glaze agents.

Synthetic method one

Compound 1 can be prepared by synthetic method one, wherein X¹, X³, X, Z¹, Z², Z³And R¹With such as present invention Described implication.Compound 1-1 in alkali (such as：Sodium hydride, potassium tert-butoxide etc.) effect is lower and SEMCl reactions obtain compound 1-2； Compound 1-2 and compound 1-3 passes through metal (such as：Copper (0), copper (I), copper (II), palladium (0), Ni (0) etc.) catalysis, in alkali (such as：Potassium carbonate, cesium carbonate, potassium phosphate etc.) catalysis, reacting generating compound 1-4；Compound 1-4 in polar solvent (such as： DMSO, DMF, acetone etc.) in, obtain compound 1-5 with iodination reagent reaction；Compound 1-5 and compound R¹-B(OH)₂In mistake Generation Suzuki cross-coupling reactions under metal catalytic are crossed, compound 1-6 is obtained；Compound 1-6 is by catalytic hydrogenation Compound 1-7；Compound 1-7 in alkali (such as：Triethylamine, diisopropylethylamine, potassium carbonate etc.) act on lower and acyl chloride reaction generationization Compound 1-8；Compound 1-8 is in acid condition (such as：Trifluoroacetic acid, hydrogen chloride etc.) after reaction, concentrated solvent, then in alkaline bar Under part (such as：Ethylenediamine, triethylamine, NaOH, sodium acid carbonate etc.) reaction, obtain target compound 1.

Synthetic method two

Compound 2 can be prepared by synthetic method two, wherein X¹, X³, X, L¹, Z¹, Z², Z³, R¹, R², R³And R⁴Tool There is implication as described in the present invention.Compound 1-2 and compound 2-1 passes through metal (such as：Copper (0), copper (I), copper (II), palladium (0), Ni (0) etc.) catalysis, in alkali (such as：Potassium carbonate, cesium carbonate, potassium phosphate etc.) in the presence of reacting generating compound 2-2；Change Compound 2-2 in polar solvent (such as：DMSO, DMF, acetone etc.) in, obtain compound 2-3 with iodination reagent reaction；Compound 2-3 Amino benzenes compounds are obtained by catalytic hydrogenation, then in alkali (such as：Triethylamine, diisopropylethylamine, potassium carbonate etc.) effect under With acyl chloride reaction generation compound 2-4；Compound 2-4 and compound R¹-B(OH)₂Handed in transition metal-catalyzed lower generation Suzuki Fork coupling reaction obtains compound 2-5；Compound 2-5 is in acid condition (such as：Trifluoroacetic acid, hydrogen chloride etc.) reaction after, it is dense Contracting solvent, then in the basic conditions (such as：Ethylenediamine, triethylamine, NaOH, sodium acid carbonate etc.) reaction, obtain target chemical combination Thing 2.

Synthetic method three

Compound 3 can be prepared by synthetic method three, wherein X, X³, R⁵And R^5aWith containing as described in the present invention Justice.Compound 3-1 in alkali (such as：Sodium hydride, potassium tert-butoxide etc.) effect is lower and SEMCl reactions obtain compound 3-2；Compound 3- 2 in polar solvent (such as：DMSO, DMF, acetone etc.) in, obtain compound 3-3 with bromide reagent reaction；Compound 3-3 and chemical combination The reaction of thing N- (3- hydroxy phenyls) acrylamide obtains compound 3-4；1H- pyrazoles -4- pinacol borate derivative 3-5 and change Compound 3-6 reactions obtain compound 3-7；Compound 3-4 and compound 3-7 reactions obtain compound 3-8；Compound 3-8 is in acid Under the conditions of property (such as：Trifluoroacetic acid, hydrogen chloride etc.) after reaction, concentrated solvent, then in the basic conditions (such as：Ethylenediamine, three second Amine, NaOH, sodium acid carbonate etc.) reaction, obtain target compound 3.

Embodiment

Embodiment 1

N- (3- ((7- (1- (pyridine -2- methylene) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) Epoxide) phenyl) acrylamide

Step 1：Compound 2- ((4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrazoles -1- Base) methyl) pyridine synthesis

Under ice bath, to the DMF of 1H- pyrazoles -4- pinacol borates (100mg, 0.52mmol) Sodium hydride (60%, 51mg, 1.28mmol) is added in (6mL) solution, after being stirred at room temperature 30 minutes, 2- (bromomethyl) pyridine is added Hydrobromate (160mg, 0.63mmol), continues to be stirred at room temperature 20 hours, plus saturated ammonium chloride solution (15mL) is quenched, dichloromethane Alkane (20mL × 3) is extracted, anhydrous sodium sulfate drying, removes solvent, and concentrate carries out column chromatography for separation (eluent：PE/EtOAc (v/v) 76mg pale yellow oils, yield=2/1), are obtained：51.70%.MS(ESI,pos.ion)m/z:286.20[M+1 ]⁺。

Step 2：The bromo- 5- of compound 2- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine Synthesis

Bromo- 5H- pyrrolo-es [2,3-b] pyrazines (300mg, 1.52mmol) of 2- are dissolved in N,N-dimethylformamide (8mL) In, sodium hydride (60%, 91.3mg, 2.28mmol) is added under ice bath, continuation is stirred at this temperature, after 30min, adds 2- (trimethyl silicon substrate) ethoxyl methyl chlorine (404 μ L, 2.26mmol), is stirred at room temperature 12h.Add water (20mL) be quenched, dichloromethane (30mL × 2) extract, and concentration carries out column chromatography for separation (eluent：PE/EtOAc (v/v)=5/1), obtain 270mg yellow oilies Thing, yield：54.3%.

MS(ESI,pos.ion)m/z:330.10[M+1]⁺。

Step 3：The bromo- 5- of compound 2,7- bis- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] The synthesis of pyrazine

At room temperature, to the bromo- 5- of 2- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine N-bromosuccinimide (0.29g, 1.59mmol), room are added in dichloromethane (26mL) solution of (0.51g, 1.53mmol) Temperature stirring 30h.Solvent concentration, residue carries out column chromatography for separation (eluent：Petrol ether/ethyl acetate (v/v)=5/1), obtain To 560mg white solids, yield：89.4%.

MS(ESI,pos.ion)m/z:408.0[M+1]⁺。

Step 4：Compound N-(3- ((the bromo- 5- of 7- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5H- pyrrolo-es [2,3- B] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

To the bromo- 5- of 2,7- bis- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine (0.30g, 0.73mmol), N- (3- hydroxy phenyls) acrylamide (0.15g, 0.92mmol), cesium carbonate (0.36g, 1.10mmol), iodate 1,4- dioxies are added in the mixture of cuprous (0.16g, 0.84mmol) and N, N- dimethylglycine (0.08g, 0.81mmol) Six rings (5mL), nitrogen protection, 115 DEG C are reacted 5 hours, are cooled to room temperature, diatomite filtering, eluent methylene chloride, concentration, post Chromatography (eluent：Petrol ether/ethyl acetate (v/v)=2/1), obtain 260mg pale yellow oils, yield： 72.59%.

MS(ESI,pos.ion)m/z:491.1[M+1]⁺。

Step 5：Compound N-(3- ((7- (1- (pyridine -2- methylene) -1H- pyrazoles -4- bases) -5- ((2- (trimethyl silicanes Base) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

To N- (3- ((the bromo- 5- of 7- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- Base) epoxide) phenyl) and acrylamide (30mg, 0.06mmol) 1,4- dioxane (3mL) solution in sequentially add 2- ((4- (4,4,5,5- tetramethyl -1, the ring -2- bases of 3,2- dioxy boron penta) -1H- pyrazol-1-yls) methyl) pyridine (22mg, 0.07mmol), Potassium carbonate (13mg, 0.09mmol), Pd (dppf) Cl₂(6mg, 0.01mmol) and water (0.75mL), in N₂Under protection, backflow is anti- Answer 6 hours, stop reaction, be cooled to room temperature, add saturated aqueous common salt (8mL) to be quenched, dichloromethane (10mL × 3) extraction is used Anhydrous Na₂SO₄Dry, remove solvent, concentrate carries out column chromatography for separation (eluent：PE/EtOAc (v/v)=1/1), obtain 21mg brown solids, yield：60.22%.

MS(ESI,pos.ion)m/z:568.30[M+1]⁺。

Step 6：Compound N-(3- ((7- (1- (pyridine -2- methylene) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3- B] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

To N- (3- ((7- (1- (pyridine -2- methylene) -1H- pyrazoles -4- bases) -5- ((2- (trimethyl silicon substrate) ethyoxyl) Methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (250mg, 0.44mmol) dichloromethane Trifluoroacetic acid (2mL) is added in (6mL) solution, is stirred at room temperature 5 hours, directly concentrated, add tetrahydrofuran (6mL) dissolving, satisfied PH is adjusted to sodium bicarbonate solution>7, it is stirred at room temperature 12 hours.Add saturated aqueous common salt (20mL), dichloromethane (20mL × 3) Extraction, uses anhydrous Na₂SO₄Dry, remove solvent, concentrate carries out column chromatography for separation (eluent：PE/EtOAc (v/v)=1/ 1) 66mg white solids, yield, are obtained：34.26%.

MS(ESI,pos.ion)m/z:438.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.12 (s, 1H), 10.22 (s, 1H), 8.51 (d, J=4.6Hz, 1H),8.20(s,1H),8.14(s,1H),8.13(s,1H),7.91(s,1H),7.74(td,J₁=7.7Hz, J₂=1.4Hz, 1H), 7.63 (s, 1H), 7.43 (d, J=8.2Hz, 1H), 7.36 (t, J=8.1Hz, 1H), 7.29 (dd, J₁=7.2Hz, J₂= 5.1Hz, 1H), 7.05 (d, J=7.8Hz, 1H), 6.90 (dt, J₁=16.2Hz, J₂=8.1Hz, 1H), 6.39 (dd, J₁= 17.0Hz,J₂=10.2Hz, 1H), 6.21 (m, 1H), 5.73 (m, 1H), 5.40 (s, 2H).

Embodiment 2

N- (3- ((7- (3- methyl isophthalic acids-(pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrroles Piperazine -2- bases) epoxide) phenyl) acrylamide

Step 1：Compound 2- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrroles Azoles -1- bases) methyl) pyridine synthesis

2- (bromines are added in DMF (40mL) solution of 3- methylpyrazoles -4- boric acid pinacols ester (1.40g, 6.73mmol) Methyl) pyridine hydrobromide salt (2.5g, 9.9mmol), Cs₂CO₃(3.91g, 12.0mmol) and KI (0.41g, 2.4mmol), then 10h is reacted at 70 DEG C.Reaction solution is concentrated under reduced pressure to remove DMF, adds water (40mL), and dichloromethane (50mL × 3) extraction is organic Mutually use anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v)=1/ 1) 1.3g yellow oils, yield, are obtained：65%.

MS(ESI,pos.ion)m/z:300.1[M+1]⁺。

Step 2：Compound N-(3- ((7- (3- methyl isophthalic acids-(pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide synthesis

By N- (3- ((the bromo- 5- of 7- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- Base) epoxide) phenyl) acrylamide (0.51g, 1.0mmol), 2- ((3- methyl -4- (4,4,5,5- tetramethyl -1,3,2- dioxies Ring -2- the bases of boron penta) -1H- pyrazol-1-yls) methyl) pyridine (0.5g, 2mmol), Pd (dppf) Cl₂(0.05g, 0.07mmol) and K₂CO₃(0.21g, 1.5mmol) mixes, and adds Isosorbide-5-Nitrae-dioxane (20mL) and water (5mL), then replaces nitrogen, is heated to Reacted overnight at 120 DEG C.Add water (20mL) after reaction solution cooling, dichloromethane (30mL × 3) extraction, organic phase is with anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：DCM/MeOH (v/v)=40/1), obtain 0.25g yellow oils, yield：42%.

MS-ESI:(ESI,pos.ion)m/z:582.1[M+1]⁺。

Step 3：Compound N-(3- ((7- (3- methyl isophthalic acids-(pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrroles And [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

By N- (3- ((7- (3- methyl isophthalic acids-(pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (trimethyl silicon substrate) Ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.25g, 0.43mmol) is dissolved in In dichloromethane (15mL), TFA (5mL) is subsequently adding, at room temperature stirring reaction 8h.Reaction solution is concentrated under reduced pressure, and adds THF (15mL) and TEA (2mL), is then stirred at room temperature reaction overnight again.Reaction solution is concentrated under reduced pressure, after removing solvent, is added Saturated sodium bicarbonate aqueous solution (20mL), dichloromethane (30mL × 3) extraction, saturated aqueous common salt (20mL) is washed, anhydrous sodium sulfate Dry, concentration, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：DCM/MeOH (v/v)=30/1), obtain 0.05g yellow solids, yield：30%.

MS-ESI:(ESI,pos.ion)m/z:452.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.19 (s, 1H), 10.23 (s, 1H), 8.50 (d, J=4.1Hz, 1H), 8.14 (d, J=17.7Hz, 2H), 7.93 (d, J=2.8Hz, 1H), 7.73 (d, J=1.6Hz, 1H), 7.63 (s, 1H), 7.40 (d, J=8.2Hz, 1H), 7.34 (d, J=8.1Hz, 1H), 7.28 (d, J=2.0Hz, 1H), 7.03 (d, J=7.8Hz, 1H),6.88(dd,J₁=8.0Hz, J₂=1.6Hz, 1H), 6.36 (d, J=10.2Hz, 1H), 6.20 (dd, J₁=17.0Hz, J₂ =1.7Hz, 1H), 5.71 (dd, J₁=10.2Hz, J₂=1.7Hz, 1H), 5.29 (s, 2H), 2.29 (s, 3H).

Embodiment 3

N- (3- ((7- (3- (difluoromethyl) -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3- B] pyrazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of the bromo- 1- of compound 4- (pyridine -2- ylmethyls) -1H- pyrazoles -3- formaldehyde

To addition 2- (bromomethyl) in DMF (40mL) solution of the bromo- 1H- pyrazoles -3- formaldehyde (1.01g, 5.77mmol) of 4- Pyridine hydrobromide salt (2g, 7.91mmol), Cs₂CO₃(6.6g, 20mmol) and KI (1g, 5.96mmol) is then anti-at 70 DEG C Answer 10h.Reaction solution is concentrated under reduced pressure to remove DMF, adds water (30mL), dichloromethane (50mL × 3) extraction, and organic phase is with anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v)=1/1), obtain 0.7g yellow oils, yield：50%.

MS(ESI,pos.ion)m/z:266.1[M+1]⁺。

Step 2：The synthesis of compound 2- ((4- bromo- 3- (difluoromethyl) -1H- pyrazol-1-yls) methyl) pyridine

At -20 DEG C, by DCM (1mL) solution of DAST (0.7g, 0.6mL, 5mmol) be slowly added into the bromo- 1- of 4- (pyridine - 2- ylmethyls) -1H- pyrazoles -3- formaldehyde (0.51g, 1.9mmol) DCM (20mL) solution in, reaction is then stirred at room temperature Overnight.Reaction solution is added in frozen water (20mL), dichloromethane (30mL × 3) extraction, organic phase anhydrous Na₂SO₄Dry, concentration Crude on silica gel column chromatographic isolation and purification (eluent afterwards：PE/EtOAc (v/v)=10/1), obtain 0.3g yellow oilies Thing, yield：50%.

MS(ESI,pos.ion)m/z:288.1[M+1]⁺。

Step 3：Compound 2- ((3- (difluoromethyl) -4- (ring -2- of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta Base) -1H- pyrazol-1-yls) methyl) and pyridine synthesis

By 2- ((4- bromo- 3- (difluoromethyl) -1H- pyrazol-1-yls) methyl) pyridine (0.31g, 1.1mmol), connection boric acid Pinacol ester (0.5g, 2mmol), KOAc (0.31g, 3.2mmol) and Pd (dppf) Cl₂(0.08g, 0.1mmol) mixes, and adds DMSO (10mL), then reacts overnight at 80 DEG C.Water (20mL), dichloromethane (30mL × 3) extraction are added after reaction solution cooling Take, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v) 0.12g yellow oils, yield=1/3), are obtained：33%.MS(ESI,pos.ion)m/z:336.3[M+1]⁺。

Step 4：Compound N-(3- ((7- (3- (difluoromethyl) -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide conjunction Into

To N- (3- ((the bromo- 5- of 7- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- Base) epoxide) phenyl) and acrylamide (0.15g, 0.31mmol) 1,4- dioxane (20mL) solution in add 2- ((3- (two Methyl fluoride) -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrazol-1-yls) methyl) pyridine (0.12g,0.36mmol)、Pd(dppf)Cl₂(0.03g, 0.04mmol) and K₂CO₃(0.07g, 0.5mmol), adds H₂O (5mL), after displacement nitrogen, reacts overnight at 120 DEG C.Water (20mL), dichloromethane (30mL × 3) extraction are added after reaction solution cooling Take, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：DCM/MeOH (v/v) 0.06g yellow oils, yield=50/1), are obtained：32%.

MS-ESI:(ESI,pos.ion)m/z:618.5[M+1]⁺。

Step 5：Compound N-(3- ((7- (3- (difluoromethyl) -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) - 5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide synthesis

By N- (3- ((7- (3- (difluoromethyl) -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (front threes Base silicon substrate) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.06g, 0.1mmol) it is dissolved in dichloromethane (15mL), TFA (3mL, 38.7mmol) is added at 0 DEG C, at room temperature stirring reaction 8h.Reaction Liquid is concentrated under reduced pressure, and adds THF (15mL) and TEA (3mL), and reaction is then stirred at room temperature again overnight.Reaction solution is depressurized dense Contracting, after removing solvent, adds saturated sodium bicarbonate aqueous solution (20mL), dichloromethane (30mL × 3) extraction, saturated aqueous common salt (20mL) is washed, anhydrous sodium sulfate drying, concentration, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：DCM/ MeOH (v/v)=30/1), obtain 0.01g yellow solids, yield：20%.

MS-ESI:(ESI,pos.ion)m/z:488.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.33 (s, 1H), 10.24 (s, 1H), 8.51 (d, J=4.7Hz, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 7.95 (d, J=2.8Hz, 1H), 7.81-7.75 (m, 1H), 7.66 (s, 1H), 7.41 (d, J=8.1Hz, 1H), 7.35 (t, J=8.1Hz, 1H), 7.33-7.29 (m, 1H), 7.16 (s, 1H), 7.15 (s, 1H), 6.91(dd,J₁=8.1Hz, J₂=1.4Hz, 1H), 6.38 (dd, J₁=17.0Hz, J₂=10.2Hz, 1H), 6.20 (dd, J₁= 17.0Hz,J₂=1.7Hz, 1H), 5.72 (dd, J₁=10.2Hz, J₂=1.6Hz, 1H), 5.44 (s, 2H).

Embodiment 4

N- (3- ((7- (1- (pyridine -2- ylmethyls) -3- (trifluoromethyl) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3- B] pyrazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of compound 2- ((4- bromo- 3- (trifluoromethyl) -1H- pyrazol-1-yls) methyl) pyridine

2- (bromines are added in DMF (40mL) solution of 4- bromo- 3- (trifluoromethyl) -1H- pyrazoles (1.01g, 4.7mmol) Methyl) pyridine hydrobromide salt (1.76g, 6.96mmol), Cs₂CO₃(5.3g, 16mmol) and KI (0.4g, 2mmol), Ran Hou 10h is reacted at 100 DEG C.Reaction solution is concentrated under reduced pressure to remove DMF, adds water (40mL), and dichloromethane (50mL × 3) extraction is organic Mutually use anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v)=1/ 1) 1.2g yellow oils, yield, are obtained：83%.MS(ESI,pos.ion)m/z:308.1[M+1]⁺。

Step 2：Compound 2- ((4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -3- (fluoroforms Base) -1H- pyrazol-1-yls) methyl) and pyridine synthesis

By 2- ((4- bromo- 3- (trifluoromethyl) -1H- pyrazol-1-yls) methyl) pyridine (0.51g, 1.7mmol), connection boric acid Pinacol ester (0.75g, 3.0mmol), KOAc (0.50g, 5.1mmol) and Pd (dppf) Cl₂(0.12g, 0.16mmol) mixes, DMSO (10mL) is added, is then reacted overnight at 80 DEG C.Addition water (20mL) after reaction solution cooling, dichloromethane (30mL × 3) extract, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/ EtOAc (v/v)=3/1), obtain 0.4g yellow oils, yield：70%.

MS-ESI:(ESI,pos.ion)m/z:354.4[M+1]⁺。

Step 3：Compound N-(3- ((7- (1- (pyridine -2- ylmethyls) -3- (trifluoromethyl) -1H- pyrazoles -4- bases) -5- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide conjunction Into

By N- (3- ((the bromo- 5- of 7- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- Base) epoxide) phenyl) acrylamide (0.4g, 0.82mmol), 2- ((4- (ring of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta - 2- yls) -3- (trifluoromethyl) -1H- pyrazol-1-yls) methyl) pyridine (0.42g, 1.2mmol), Pd (dppf) Cl₂(0.08g, 0.1mmol) and K₂CO₃(0.17g, 1.2mmol) mixes, and adds Isosorbide-5-Nitrae-dioxane (20mL) and water (5mL), then replaces nitrogen Gas, reacts overnight at being heated to 120 DEG C.Water (20mL) is added after reaction solution cooling, dichloromethane (30mL × 3) extraction is organic Mutually use anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：DCM/MeOH (v/v)= 40/1) 0.19g yellow oils, yield, are obtained：37%.

MS-ESI:(ESI,pos.ion)m/z:636.5[M+1]⁺。

Step 4：Compound N-(3- ((7- (1- (pyridine -2- ylmethyls) -3- (trifluoromethyl) -1H- pyrazoles -4- bases) - 5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide synthesis

By N- (3- ((7- (1- (pyridine -2- ylmethyls) -3- (trifluoromethyl) -1H- pyrazoles -4- bases) -5- ((2- (front threes Base silicon substrate) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.25g, 0.43mmol) it is dissolved in dichloromethane (15mL), is subsequently adding TFA (5mL), at room temperature stirring reaction 8h.Reaction solution decompression is dense Contracting, adds THF (15mL) and TEA (2mL), and reaction is then stirred at room temperature again overnight.Reaction solution is concentrated under reduced pressure, is removed molten After agent, saturated sodium bicarbonate aqueous solution (20mL), dichloromethane (30mL × 3) extraction, saturated aqueous common salt (20mL) is added to wash, nothing Aqueous sodium persulfate is dried, concentration, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：DCM/MeOH (v/v)= 30/1) 0.05g yellow solids, yield, are obtained：30%.

MS-ESI:(ESI,pos.ion)m/z:506.4[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.41 (s, 1H), 10.26 (s, 1H), 8.51 (d, J=4.2Hz, 1H), 8.46 (s, 1H), 8.21 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 7.39 (d, J=7.9Hz, 1H),7.33(dd,J₁=13.4Hz, J₂=5.5Hz, 2H), 7.19 (d, J=7.8Hz, 1H), 6.90 (d, J=7.7Hz, 1H), 6.37 (d, J=10.2Hz, 1H), 6.20 (d, J=16.8Hz, 1H), 5.71 (d, J=10.5Hz, 1H), 5.48 (s, 2H).

Embodiment 5

N- (3- ((7- (1- (pyridin-3-yl methyl) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) Epoxide) phenyl) acrylamide

Step 1：The synthesis of compound 1- (3- picolyls) -1H- pyrazoles -4- pinacol borates

By 3- (bromomethyl) pyridine (2.67g, 15.5mmol) and 4- pyrazoles pinacol borate (3.01g, 15.5mmol) It is dissolved in DMF (20mL), potassium carbonate (2.2g, 16mmol) is added in system, is warming up to 80 DEG C of reaction 8h.Reaction solution is poured into In water (50mL), ethyl acetate (50mL × 3) extraction, saturated common salt washing (20mL), anhydrous sodium sulfate drying removes solvent, Residue carries out pillar layer separation (eluent：PE/EtOAc (v/v)=1/1.5), obtain 280mg pale yellow oils, yield： 6.33%.

MS-ESI:(ESI,pos.ion)m/z:286.30[M+1]⁺。

Step 2：Compound N-(3- ((7- (1- (pyridin-3-yl methyl) -1H- pyrazoles -4- bases) -5- ((2- (trimethyl first Silylation) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

By 1- (3- picolyls) -1H- pyrazoles -4- pinacol borates (351mg, 1.23mmol), (((7- is bromo- for 3- for N- 5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (602mg, 1.23mmol) is dissolved in the mixed solvent of dioxane and water (15mL, (v/v)=4/1), and carbon is added in system Sour potassium (510mg, 3.7mmol) and [1,1'- double (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (100mg, 0.12mmol), nitrogen is replaced, 110 DEG C of reaction 8h are warming up to.Reaction solution is poured into water (20mL), ethyl acetate (20mL × 3) Extraction, saturated common salt washing (20mL), anhydrous sodium sulfate drying removes solvent, and residue carries out pillar layer separation (eluent： PE/EtOAc (v/v)=1/8), obtain 142mg dark brown oils, yield：20.32%.

MS-ESI:(ESI,pos.ion)m/z:569.10[M+1]⁺。

Step 3：Compound N-(3- ((7- (1- (pyridin-3-yl methyl) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3- B] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

By compound N-(3- ((7- (1- (pyridin-3-yl methyl) -1H- pyrazoles -4- bases) -5- ((2- (trimethyl silyls Base) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (170mg, 0.30mmol) It is dissolved in dichloromethane (15mL) with trifluoroacetic acid (3.1mL), room temperature reaction 6h.Reaction solution is directly spin-dried for, residual solution is dissolved in In tetrahydrofuran (5mL), saturated sodium bicarbonate solution (10mL) is added, 8h is stirred at room temperature.Reaction solution is poured into water (20mL), Ethyl acetate (20mL × 3) is extracted, saturated common salt washing (20mL), anhydrous sodium sulfate drying, the crude product silicagel column after concentration Chromatography purifies (eluent：CH₂Cl₂/ MeOH (v/v)=10/1), obtain 40mg faint yellow solids, yield：30.54%.

MS-ESI:(ESI,pos.ion)m/z:438.40[M+1]⁺；

¹H NMR(400MHz,MeOD):δ (ppm) 8.59 (d, J=20.6Hz, 2H), 8.23 (s, 1H), 8.06 (s, 1H), 8.01 (d, J=8.6Hz, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.72-7.65 (m, 2H), 7.36 (dd, J₁=14.3Hz, J₂=6.5Hz, 2H), 6.93 (d, J=8.1Hz, 1H), 6.36-6.31 (m, 1H), 5.73 (d, J=11.8Hz, 1H), 5.46 (s,2H),5.33(s,1H)。

Embodiment 6

N- (3- ((7- (1- (pyridin-4-yl methyl) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) Epoxide) phenyl) acrylamide

Step 1：Compound 4- ((4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrazoles -1- Base) methyl) pyridine synthesis

By 4- (bromomethyl) pyridine hydrochloride (3.3g, 16mmol) and 4- pyrazoles pinacol borate (3.01g, 15.6mmol) it is dissolved in DMF (20mL), potassium carbonate (2.25g, 16.3mmol) is added in system, is warming up to 80 DEG C of reaction 8h. Reaction solution is poured into water (50mL), ethyl acetate (50mL × 3) extraction, saturated common salt washing (20mL), anhydrous sodium sulfate is done It is dry, solvent is removed, residue carries out pillar layer separation (eluent：PE/EtOAc (v/v)=1/1), obtain the faint yellow oil of 267mg Shape thing, yield：6%.

MS-ESI:(ESI,pos.ion)m/z:286.25[M+1]⁺。

Step 2：Compound N-(3- ((7- (1- (pyridin-4-yl methyl) -1H- pyrazoles -4- bases) -5- ((2- (trimethyl first Silylation) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

By compound 4- ((4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrazol-1-yls) first Base) pyridine (190mg, 0.67mmol) and compound N-(3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl)- 5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (370mg, 0.76mmol) is dissolved in dioxane and water In the mixed solvent of (15mL, (v/v)=4/1), potassium carbonate (290mg, 2.10mmol) and [1,1'- double (two are added in system Phenylphosphine) ferrocene] palladium chloride dichloromethane complex (60mg, 0.07mmol), nitrogen is replaced, it is warming up to 110 DEG C of reactions 4h.Reaction solution is poured into water (20mL), ethyl acetate (20mL × 3) extraction, saturated common salt washing (20mL), anhydrous sodium sulfate Dry, remove solvent, residue carries out pillar layer separation (eluent：PE/EtOAc (v/v)=1/5), obtain 110mg brown oils Shape thing, yield：29.09%.

MS-ESI:(ESI,pos.ion)m/z:568.15[M+1]⁺。

Step 3：Compound N-(3- ((7- (1- (pyridin-4-yl methyl) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3- B] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

By N- (3- ((7- (1- (pyridin-4-yl methyl) -1H- pyrazoles -4- bases) -5- ((2- (trimethyl silyl) second Epoxide) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (123mg, 0.22mmol) and trifluoro Acetic acid (3.1mL) is dissolved in dichloromethane (15mL), room temperature reaction 6h.Reaction solution is directly spin-dried for, residual solution is dissolved in tetrahydrochysene furan Mutter in (5mL), add saturated sodium bicarbonate solution (10mL), 8h is stirred at room temperature.Reaction solution is poured into water (20mL), acetic acid second Ester (20mL × 3) is extracted, saturated common salt washing (20mL), anhydrous sodium sulfate drying, the crude product silica gel column chromatography point after concentration From purifying (eluent：CH₂Cl₂/ MeOH (v/v)=10/1), obtain 7mg yellow solids, yield：7.38%.

MS-ESI:(ESI,pos.ion)m/z:438.20[M+1]⁺；

¹H NMR(400MHz,MeOD):δ (ppm) 8.27 (s, 1H), 8.05 (d, J=9.4Hz, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.67 (s, 1H), 7.61 (s, 2H), 7.37-7.30 (m, 2H), 7.23-7.06 (m, 2H), 6.92 (d, J= 7.0Hz, 1H), 6.37-6.29 (m, 1H), 5.72 (d, J=9.9Hz, 1H), 5.57 (s, 2H), 5.32 (t, J=4.8Hz, 1H).

Embodiment 7

N- (3- ((7- (3- (methylol) -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] Pyrazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of compound (the bromo- 1H- pyrazole-3-yls of 4-) methyl alcohol

At 0 DEG C, NaBH is added in EtOH (100mL) solution to the bromo- 1H- pyrazoles -3- formaldehyde (6g, 34.3mmol) of 4-₄ (1.9g, 39mmol), then reacts overnight at room temperature.Use NH₄After Cl is quenched, it is concentrated under reduced pressure, removes solvent, crude product is through silicon Plastic column chromatography isolates and purifies (eluent：EtOAc), 3.3g white solids, yield are obtained：50%.

MS(ESI,pos.ion)m/z:179.1[M+2]⁺。

Step 2：The synthesis of compound (the bromo- 1- of 4- (pyridine -2- ylmethyls) -1H- pyrazole-3-yls) methyl alcohol

Added in DMF (100mL) solution of compound (the bromo- 1H- pyrazole-3-yls of 4-) methyl alcohol (3.34g, 18.9mmol) 2- (bromomethyl) pyridine hydrobromides salt (7.1g, 28mmol), Cs₂CO₃(21.3g, 65.4mmol) and KI (1.6g, 9.5mmol), Then reacted overnight at 70 DEG C.Reaction solution is concentrated under reduced pressure to remove DMF, adds water (30mL), dichloromethane (50mL × 3) extraction Take, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v) 2.0g yellow oil products, yield=7/3), are obtained：40%.

MS(ESI,pos.ion)m/z:270.1[M+2]⁺。

Step 3：Compound (1- (pyridine -2- ylmethyls) -4- (ring -2- of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta Base) -1H- pyrazole-3-yls) methyl alcohol synthesis

By compound (the bromo- 1- of 4- (pyridine -2- ylmethyls) -1H- pyrazole-3-yls) methyl alcohol (0.51g, 1.9mmol), connection boron Sour pinacol ester (0.85g, 3.3mmol), KOAc (0.55g, 5.6mmol) and Pd (dppf) Cl₂(0.14g, 0.19mmol) is mixed DMSO (15mL) is added after conjunction, is then reacted overnight at 90 DEG C.Water (20mL), dichloromethane are added after reaction solution cooling (30mL × 3) extract, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (drip washing after concentration Agent：PE/EtOAc (v/v)=7/3), obtain 0.3g yellow oil products, yield：50%.

MS(ESI,pos.ion)m/z:316.1[M+1]⁺。

Step 4：Compound N-(3- ((7- (3- (methylol) -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide Synthesis

To compound N-(3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] Pyrazine -2- bases) epoxide) phenyl) and acrylamide (0.31g, 0.63mmol) 1,4- dioxane (20mL) solution in add (1- (pyridine -2- ylmethyls) -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrazole-3-yls) methyl alcohol (0.28g,0.89mmol)、Pd(dppf)Cl₂(0.05g, 0.07mmol) and K₂CO₃(0.13g, 0.94mmol), adds H₂O (5mL), reacts overnight after displacement nitrogen at 115 DEG C.Water (20mL), dichloromethane (30mL × 3) extraction are added after reaction solution cooling Take, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)=40/1), obtain 0.13g yellow oil products, yield：34%.

MS-ESI:(ESI,pos.ion)m/z:598.1[M+1]⁺。

Step 5：Compound N-(3- ((7- (3- (methylol) -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5H- Pyrrolo- [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide synthesis

By compound N-(3- ((7- (3- (methylol) -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.13g, 0.22mmol) is dissolved in dichloromethane (15mL), and TFA (3mL, 38.7mmol) is added at 0 DEG C, stirs anti-at room temperature Answer 8h.THF (15mL) and TEA (3mL) is added after reaction solution is concentrated under reduced pressure, reaction is then stirred at room temperature again overnight.Will be anti- Answer liquid to be concentrated under reduced pressure, add saturated sodium bicarbonate aqueous solution (20mL), dichloromethane extraction (30mL × 3) to satisfy after removing solvent With salt washing (20mL), anhydrous sodium sulfate drying, concentration, the crude on silica gel column chromatographic isolation and purification (drip washing after concentration Agent：CH₂Cl₂/ MeOH (v/v)=30/1), then through HPLC preparative separations, obtain 0.01g yellow solids, yield：9.8%.MS- ESI:(ESI,pos.ion)m/z:468.0[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ (ppm) 12.24 (s, 1H), 10.23 (s, 1H), 8.50 (d, J=4.4Hz, 1H), 8.17 (s, 1H), 7.98 (d, J=2.4Hz, 1H), 7.79-7.70 (m, 2H), 7.57 (s, 1H), 7.42 (d, J= 8.2Hz, 1H), 7.35 (t, J=8.1Hz, 1H), 7.32-7.26 (m, 1H), 7.04 (d, J=7.9Hz, 1H), 6.90 (d, J= 6.8Hz, 1H), 6.37 (d, J=10.1Hz, 1H), 6.22 (d, J=15.2Hz, 1H), 5.74 (d, J=11.6Hz, 1H), 5.49 (s, 2H), 5.35 (t, J=5.6Hz, 1H), 4.63 (d, J=5.5Hz, 2H).

Embodiment 8

N- (3- ((7- (3- (methoxy) -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2, 3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of compound 2- ((4- bromo- 3- (methoxy) -1H- pyrazol-1-yls) methyl) pyridine

NaH (0.2g, 5mmol) is slowly added into (the bromo- 1- of 4- (pyridine -2- ylmethyls) -1H- pyrazole-3-yls) at 0 DEG C In THF (30mL) solution of methyl alcohol (0.51g, 1.9mmol), CH is added after stirring 10min₃I (0.5g, 3mmol), then in room The lower stirring reaction of temperature.Reaction solution adds water (30mL), dichloromethane (50mL × 3) extraction, organic phase anhydrous Na₂SO₄Dry, Crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v)=3/2), obtain 0.5g yellow oils Shape product, yield：94%.

MS(ESI,pos.ion)m/z:284.1[M+2]⁺。

Step 2：Compound 2- ((3- (methoxy) -4- (ring -2- of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta Base) -1H- pyrazol-1-yls) methyl) and pyridine synthesis

By 2- ((4- bromo- 3- (methoxy) -1H- pyrazol-1-yls) methyl) pyridine (0.5g, 1.8mmol), connection boric acid Pinacol ester (0.85g, 3.3mmol), KOAc (0.55g, 5.6mmol) and Pd (dppf) Cl₂(0.14g, 0.19mmol) mixes DMSO (10mL) is added afterwards, is then reacted overnight at 80 DEG C.Water (20mL), dichloromethane (30mL are added after reaction solution cooling × 3) extract, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/ EtOAc (v/v)=7/3), obtain 0.4g yellow oils, yield：70%.

MS(ESI,pos.ion)m/z:330.4[M+1]⁺。

Step 3：Compound N-(3- ((7- (3- (methoxy) -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) - 5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide Synthesis

To N- (3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine - 2- yls) epoxide) phenyl) and acrylamide (0.33g, 0.67mmol) 1,4- dioxane (16mL) solution in add 2- ((3- (methoxy) -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrazol-1-yls) methyl) pyridine (0.33g,1.0mmol)、Pd(dppf)Cl₂(0.05g, 0.07mmol) and K₂CO₃(0.14g, 1.0mmol), adds H₂O (4mL), reacts overnight after displacement nitrogen at 115 DEG C.Water (20mL), dichloromethane (30mL × 3) extraction are added after reaction solution cooling Take, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)=30/1), obtain 0.33g yellow oil products, yield：80%.

MS-ESI:(ESI,pos.ion)m/z:612.6[M+1]⁺。

Step 4：Compound N-(3- ((7- (3- (methoxy) -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) - 5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide synthesis

By compound N-(3- ((7- (3- (methoxy) -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.33g, 0.54mmol) is dissolved in dichloromethane (15mL), and TFA (3mL, 38.7mmol) is added at 0 DEG C, stirs anti-at room temperature Answer 8h.THF (15mL) and TEA (3mL) is added after reaction solution is concentrated under reduced pressure, reaction is then stirred at room temperature again overnight.Will be anti- Answer liquid to be concentrated under reduced pressure, saturated sodium bicarbonate aqueous solution (20mL) is added after removing solvent, dichloromethane (30mL × 3) extraction is satisfied With salt washing (20mL), anhydrous sodium sulfate drying, concentration, the crude on silica gel column chromatographic isolation and purification (drip washing after concentration Agent：CH₂Cl₂/ MeOH (v/v)=30/1), obtain 0.07g yellow solids, yield：27%.

MS-ESI:(ESI,pos.ion)m/z:482.5[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.25 (s, 1H), 10.24 (s, 1H), 8.50 (d, J=4.2Hz, 1H), 8.19 (s, 1H), 7.94 (d, J=2.5Hz, 1H), 7.79 (s, 1H), 7.72 (dd, J₁=9.2Hz, J₂=7.7Hz, 1H), 7.58 (s, 1H), 7.41 (d, J=8.1Hz, 1H), 7.35 (t, J=8.1Hz, 1H), 7.28 (dd, J₁=6.9Hz, J₂= 5.2Hz, 1H), 6.96 (d, J=7.8Hz, 1H), 6.90 (dd, J₁=8.0Hz, J₂=1.6Hz, 1H), 6.39 (dd, J₁= 17.0Hz,J₂=10.2Hz, 1H), 6.22 (dd, J₁=17.0Hz, J₂=1.7Hz, 1H), 5.74 (dd, J₁=10.2Hz, J₂= 1.6Hz,1H),5.45(s,2H),4.57(s,2H),3.09(s,3H)。

Embodiment 9

N- (3- ((7- (3- methyl isophthalic acids-(pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrroles Piperazine -2- bases) sulfenyl) phenyl) acrylamide

Step 1：Compound 3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3- B] pyrazine -2- bases) sulfenyl) and aniline synthesis

By the bromo- 5- of compound 2,7- bis- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrrole Piperazine (1.51g, 3.71mmol), 3- aminothiophenols (1g, 0.9mL, 8mmol), Pd (PPh₃)₄(0.34g, 0.29mmol) and EtOH (40mL) is added after KOBu-t (0.88g, 7.4mmol) mixing, heating reflux reaction is overnight after putting nitrogen.Reaction solution is cooled down Filtered with diatomite afterwards, dichloromethane washing filter cake collects filtrate, the crude on silica gel column chromatographic isolation and purification after concentration (eluent：PE/EtOAc (v/v)=4/1), obtain 1g yellow oils, yield：60%.

MS(ESI,pos.ion)m/z:452.4[M+1]⁺。

Step 2：Compound N-(3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2, 3-b] pyrazine -2- bases) sulfenyl) phenyl) acrylamide synthesis

At 0 DEG C, to 3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrroles Piperazine -2- bases) sulfenyl) aniline (0.21g, 0.47mmol) DCM (20mL) solution in add TEA (0.087g, 0.12mL) and third DCM (1mL) solution of alkene acyl chlorides (0.6g, 6mmol), then slowly returns to and reacts at room temperature overnight.Reaction solution is concentrated under reduced pressure, Crude on silica gel column chromatographic isolation and purification (eluent：PE/EtOAc (v/v)=4/1), 0.19g faint yellow solids are obtained, produce Rate：81%.

MS(ESI,pos.ion)m/z:506.1[M+1]⁺。

Step 3：Compound N-(3- ((7- (3- methyl isophthalic acids-(pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) sulfenyl) phenyl) and acrylamide synthesis

To compound N-(3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] Pyrazine -2- bases) sulfenyl) phenyl) and acrylamide (0.51g, 1.0mmol) 1,4- dioxane (20mL) solution in add 2- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrazol-1-yls) methyl) pyridine (0.5g,2mmol)、Pd(dppf)Cl₂(0.08g, 0.1mmol) and K₂CO₃(0.21g, 1.5mmol), adds H₂O (5mL), Reacted overnight at 115 DEG C after displacement nitrogen.Water (20mL) is added after reaction solution cooling, dichloromethane (30mL × 3) extraction is organic Mutually use anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：DCM/MeOH (v/v)= 40/1) 0.18g yellow oils, yield, are obtained：30%.

MS-ESI:(ESI,pos.ion)m/z:598.3[M+1]⁺。

Step 4：Compound N-(3- ((7- (3- methyl isophthalic acids-(pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrroles And [2,3-b] pyrazine -2- bases) sulfenyl) phenyl) acrylamide synthesis

By compound N-(3- ((7- (3- methyl isophthalic acids-(pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (front threes Base silane base) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) sulfenyl) phenyl) acrylamide (0.15g, 0.25mmol) it is dissolved in dichloromethane (15mL), is subsequently adding TFA (5mL), at room temperature stirring reaction 8h.Reaction solution decompression is dense THF (15mL) and TEA (2mL) is added after contracting, reaction is then stirred at room temperature again overnight.Reaction solution is concentrated under reduced pressure, is removed Saturated sodium bicarbonate aqueous solution (20mL), dichloromethane (30mL × 3) extraction, saturated common salt is added to wash (20mL) after solvent, Anhydrous sodium sulfate drying, concentration, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：DCM/MeOH (v/v)= 30/1), then through HPLC preparative separations, 0.06g yellow solids, yield are obtained：30%.

MS-ESI:(ESI,pos.ion)m/z:468.4[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.23 (s, 1H), 10.24 (s, 1H), 8.53 (d, J=4.6Hz, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.95 (d, J=2.7Hz, 1H), 7.87 (s, 1H), 7.74 (d, J=1.6Hz, 1H), 7.62 (d, J=8.1Hz, 1H), 7.33 (t, J=8.0Hz, 1H), 7.31-7.27 (m, 1H), 7.21 (d, J=7.7Hz, 1H), 7.02 (d, J=7.8Hz, 1H), 6.35 (dd, J₁=17.0Hz, J₂=10.2Hz, 1H), 6.20 (dd, J₁=17.0Hz, J₂= 1.7Hz,1H),5.75-5.70(m,1H),5.33(s,2H),2.31(s,3H)。

Embodiment 10

N- (3- ((7- (3- methyl isophthalic acids-((6- (trifluoromethyl) pyridine -2- bases) methyl) -1H- pyrazoles -4- bases) -5H- pyrroles Cough up simultaneously [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of compound (6- (trifluoromethyl) pyridine -2- bases) methylmethanesulfonate ester

At 0 DEG C by TEA (1.4g, 1.9mL, 14mmol) be added drop-wise to (6- trifluoromethylpyridin -2- bases)-methyl alcohol (1.61g, In DCM (20mL) solution 9.09mmol), nitrogen protection is lower to add MsCl (1.2g, 11mmol), then continues anti-at 0 DEG C Should.Reaction solution is concentrated under reduced pressure, and is subsequently adding saturated sodium bicarbonate aqueous solution (40mL), and dichloromethane (50mL × 3) extraction is organic Mutually use anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v)=7/ 3) 2.2g yellow solids, yield, are obtained：95%.MS(ESI,pos.ion)m/z:256.1[M+1]⁺。

Step 2：Compound 2- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrroles Azoles -1- bases) methyl) -6- (trifluoromethyl) pyridine synthesis

(6- is added in DMF (40mL) solution of 3- methylpyrazoles -4- boric acid pinacols ester (1.00g, 4.81mmol) (trifluoromethyl) pyridine -2- bases) methylmethanesulfonate ester (1.9g, 7.4mmol) and K₂CO₃(2.5g, 7.7mmol), then 100 Reacted overnight at DEG C.Reaction solution is concentrated under reduced pressure to remove DMF, adds water (40mL), dichloromethane (50mL × 3) extraction, organic phase Use anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v)=4/ 1) the faint yellow oil products of 0.7g, yield, are obtained：40%.

MS(ESI,pos.ion)m/z:368.4[M+1]⁺。

Step 3：Compound N-(3- ((7- (3- methyl isophthalic acids-((6- (trifluoromethyl) pyridine -2- bases) methyl) -1H- pyrazoles - 4- yls) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) third The synthesis of acrylamide

To compound N-(3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] Pyrazine -2- bases) epoxide) phenyl) and acrylamide (0.41g, 0.84mmol) 1,4- dioxane (20mL) solution in add 2- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrazol-1-yls) methyl) -6- (trifluoros Methyl) pyridine (0.5g, 1mmol), Pd (dppf) Cl₂(0.09g, 0.1mmol) and K₂CO₃(0.17g, 1.2mmol), adds H₂O (5mL), reacts overnight after displacement nitrogen at 115 DEG C.Water (20mL), dichloromethane (30mL × 3) are added after reaction solution cooling Extraction, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)=40/1), obtain 0.4g yellow oils, yield：70%.

MS-ESI:(ESI,pos.ion)m/z:650.6[M+1]⁺。

Step 4：Compound N-(3- ((7- (3- methyl isophthalic acids-((6- (trifluoromethyl) pyridine -2- bases) methyl) -1H- pyrazoles - 4- yls) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

By compound N-(3- ((7- (3- methyl isophthalic acids-((6- (trifluoromethyl) pyridine -2- bases) methyl) -1H- pyrazoles -4- Base) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) propylene Acid amides (0.41g, 0.63mmol) is dissolved in dichloromethane (15mL), is subsequently adding TFA (5mL), at room temperature stirring reaction 8h.Instead Answer liquid to be concentrated under reduced pressure, add THF (15mL) and TEA (2mL), reaction is then stirred at room temperature again overnight.Reaction solution is depressurized Concentration, saturated sodium bicarbonate aqueous solution (20mL), dichloromethane extraction (30mL × 3), saturated aqueous common salt are added after removing solvent Wash (20mL), anhydrous sodium sulfate drying, concentrate, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)=20/1), then through HPLC preparative separations, obtain 0.06g yellow solids, yield：22%.

MS-ESI:(ESI,pos.ion)m/z:520.5[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ (ppm) 12.19 (s, 1H), 10.19 (s, 1H), 8.18 (d, J=18.9Hz, 2H), 8.03 (t, J=7.9Hz, 1H), 7.95 (s, 1H), 7.81 (d, J=7.7Hz, 1H), 7.63 (s, 1H), 7.34 (dt, J₁ =16.1Hz, J₂=7.9Hz, 2H), 7.21 (d, J=8.0Hz, 1H), 6.88 (d, J=8.0Hz, 1H), 6.41-6.29 (m, 1H), 6.17 (d, J=16.6Hz, 1H), 5.69 (d, J=9.9Hz, 1H), 5.42 (s, 2H), 2.31 (s, 3H).

Embodiment 11

N- (3- ((7- (3- methyl isophthalic acids-(pyrimidine -2-base methyl) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrroles Piperazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of compound pyrimidine -2-base methylmethanesulfonate ester

TEA (2.1g, 21mmol) is added drop-wise to the DCM (20mL) of pyrimidine -2-base methyl alcohol (1.50g, 13.6mmol) at 0 DEG C In solution, nitrogen protection is lower to add MsCl (1.9g, 17mmol), then continues to react 1h at 0 DEG C.Reaction solution is concentrated under reduced pressure, It is subsequently adding saturated sodium bicarbonate aqueous solution (40mL), dichloromethane (50mL × 3) extraction, organic phase anhydrous Na₂SO₄Dry, Crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v)=7/3), obtain 1.3g yellow oils Shape thing, yield：51%.

Step 2：Compound 2- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrroles Azoles -1- bases) methyl) pyrimidine synthesis

To in DMF (25mL) solution of 3- methylpyrazoles -4- boric acid pinacols ester (0.91g, 4.4mmol) add pyrimidine - 2- ylmethyls methanesulfonates (1.2g, 6.4mmol) and Cs₂CO₃(2.3g, 7.1mmol), then reacts overnight at 100 DEG C.Instead Liquid removing DMF concentrated under reduced pressure is answered, water (40mL), dichloromethane (50mL × 3) extraction, organic phase anhydrous Na is added₂SO₄Dry, Crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v)=3/2), obtain 1.1g yellow oils Shape thing, yield：84%.

MS(ESI,pos.ion)m/z:301.4[M+1]⁺。

Step 3：Compound N-(3- ((7- (3- methyl isophthalic acids-(pyrimidine -2-base methyl) -1H- pyrazoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide synthesis

By compound N-(3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] Pyrazine -2- bases) epoxide) phenyl) acrylamide (0.41g, 0.84mmol), 2- ((3- methyl -4- (4,4,5,5- tetramethyl -1, Ring -2- the bases of 3,2- dioxies boron penta) -1H- pyrazol-1-yls) methyl) pyrimidine (0.5g, 1mmol), Pd (dppf) Cl₂(0.06g, 0.08mmol) and K₂CO₃Isosorbide-5-Nitrae-dioxane (20mL) and water (5mL) are added after (0.17g, 1.2mmol) mixing, is then replaced Nitrogen, reacts overnight at being heated to 115 DEG C.Water (20mL) is added after reaction solution cooling, dichloromethane (30mL × 3) extraction has Machine mutually uses anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/MeOH(v/ V)=40/1), obtain 0.35g yellow oils, yield：72%.

MS-ESI:(ESI,pos.ion)m/z:583.7[M+1]⁺。

Step 4：Compound N-(3- ((7- (3- methyl isophthalic acids-(pyrimidine -2-base methyl) -1H- pyrazoles -4- bases) -5H- pyrroles And [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

By compound N-(3- ((7- (3- methyl isophthalic acids-(pyrimidine -2-base methyl) -1H- pyrazoles -4- bases) -5- ((2- (front threes Base silane base) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.36g, 0.62mmol) it is dissolved in dichloromethane (15mL), is subsequently adding TFA (5mL), at room temperature stirring reaction 8h.Reaction solution decompression is dense After contracting, THF (15mL) and TEA (2mL) is added, reaction is then stirred at room temperature again overnight.Reaction solution is concentrated under reduced pressure, is removed Saturated sodium bicarbonate aqueous solution (20mL), dichloromethane (30mL × 3) extraction, saturated common salt is added to wash (20mL) after solvent, Anhydrous sodium sulfate drying, concentration, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/MeOH(v/v) =20/1), obtain 0.03g yellow solids, yield：14%.

MS-ESI:(ESI,pos.ion)m/z:453.5[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ (ppm) 12.16 (s, 1H), 10.18 (s, 1H), 8.74 (d, J=4.9Hz, 2H), 8.14 (d, J=8.5Hz, 2H), 7.93 (d, J=2.7Hz, 1H), 7.60 (s, 1H), 7.41 (dd, J₁=10.7Hz, J₂= 5.9Hz, 2H), 7.32 (t, J=8.1Hz, 1H), 6.88 (d, J=7.8Hz, 1H), 6.36 (dd, J₁=17.0Hz, J₂= 10.1Hz,1H),6.19(dd,J₁=17.0Hz, J₂=1.8Hz, 1H), 5.76-5.68 (m, 1H), 5.41 (s, 2H), 2.27 (s, 3H)。

Embodiment 12

N- (3- ((7- (1- ((4- fluorine pyridine -2- bases) methyl) -3- methyl isophthalic acid H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3- B] pyrazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of compound 2- (bromomethyl) -4- fluorine pyridines

By the fluoro- 2- picolines (4.32g, 4.01mL, 38.9mmol) of 4-, NBS (6g, 33.7mmol) and AIBN CCl is added after (0.56g, 3.4mmol) mixing₄(50mL), is then heated to 80 DEG C of reaction 3h.Diatomite is used after reaction solution cooling Filtering, the crude on silica gel column chromatographic isolation and purification (eluent after filtrate decompression concentration：PE/EtOAc (v/v)=9/1), obtain To 1.3g brown oil products, yield：16%.

MS(ESI,pos.ion)m/z:191.1[M+1]⁺。

Step 2：The fluoro- 2- of compound 4- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) - 1H- pyrazol-1-yls) methyl) pyridine synthesis

To addition 2- (bromines in DMF (40mL) solution of 3- methylpyrazoles -4- boric acid pinacols ester (1.01g, 4.85mmol) Methyl) -4- fluorine pyridine (1.2g, 6.3mmol), Cs₂CO₃(5.5g, 17mmol) and KI (0.4g, 2mmol), then at 70 DEG C Reaction is overnight.Reaction solution is concentrated under reduced pressure to remove DMF, adds water (40mL), dichloromethane (50mL × 3) extraction, organic phase nothing Water Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v)=1/1), obtain To 1g yellow oils, yield：65%.

MS(ESI,pos.ion)m/z:318.3[M+1]⁺。

Step 3：Compound N-(3- ((7- (1- ((4- fluorine pyridine -2- bases) methyl) -3- methyl isophthalic acid H- pyrazoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide Synthesis

By compound N-(3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] Pyrazine -2- bases) epoxide) phenyl) acrylamide (0.35g, 0.72mmol), the fluoro- 2- of 4- ((3- methyl -4- (4,4,5,5- tetramethyls Ring -2- the bases of base -1,3,2- dioxies boron penta) -1H- pyrazol-1-yls) methyl) pyridine (0.35g, 1.1mmol), Pd (dppf) Cl₂ (0.06g, 0.08mmol) and K₂CO₃Isosorbide-5-Nitrae-dioxane (20mL) and water (5mL) are added after (0.15g, 1.1mmol) mixing, so Rear substitution nitrogen, reacts overnight at being heated to 115 DEG C.Water (20mL), dichloromethane (30mL × 3) extraction are added after reaction solution cooling Take, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v) 0.21g yellow oils, yield=3/2), are obtained：49%.

MS-ESI:(ESI,pos.ion)m/z:600.3[M+1]⁺。

Step 4：Compound N-(3- ((7- (1- ((4- fluorine pyridine -2- bases) methyl) -3- methyl isophthalic acid H- pyrazoles -4- bases) - 5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide synthesis

By compound N-(3- ((7- (1- ((4- fluorine pyridine -2- bases) methyl) -3- methyl isophthalic acid H- pyrazoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.21g, 0.35mmol) is dissolved in dichloromethane (15mL), is subsequently adding TFA (5mL), at room temperature stirring reaction 8h.Reaction solution THF (15mL) and TEA (2mL) is added after concentrated under reduced pressure, reaction is then stirred at room temperature again overnight.Reaction solution is depressurized dense Contracting, saturated sodium bicarbonate aqueous solution (20mL), dichloromethane (30mL × 3) extraction, saturated common salt washing are added after removing solvent (20mL), anhydrous sodium sulfate drying, concentration, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)=20/1), obtain 0.03g yellow solids, yield：16%.

MS-ESI:(ESI,pos.ion)m/z:470.2[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)12.18(s,1H),10.20(s,1H),8.54(dd,J₁= 8.8Hz,J₂=5.7Hz, 1H), 8.15 (d, J=2.8Hz, 2H), 7.94 (s, 1H), 7.63 (s, 1H), 7.38 (d, J= 8.2Hz, 1H), 7.33 (t, J=8.0Hz, 1H), 7.27-7.16 (m, 1H), 6.90 (dd, J₁=9.8Hz, J₂=2.5Hz, 2H), 6.36(dd,J₁=16.9Hz, J₂=10.1Hz, 1H), 6.19 (dd, J₁=17.0Hz, J₂=1.7Hz, 1H), 5.74-5.65 (m,1H),5.33(s,2H),2.30(s,3H)。

Embodiment 13

N- (3- ((7- (1- ((6- fluorine pyridine -2- bases) methyl) -3- methyl isophthalic acid H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3- B] pyrazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of compound 2- (bromomethyl) -6- fluorine pyridines

By the fluoro- 6- picolines (4.32g, 38.9mmol) of 2-, NBS (6g, 33.7mmol) and AIBN (0.56g, CCl is added after 3.4mmol) mixing₄(50mL), is then heated to 80 DEG C of reaction 3h.Filtered with diatomite after reaction solution cooling, filter Crude on silica gel column chromatographic isolation and purification (eluent after liquid concentration：PE/EtOAc (v/v)=9/1), obtain 4g yellow oils Shape thing, yield：54%.

MS(ESI,pos.ion)m/z:191.1[M+1]⁺。

Step 2：The fluoro- 6- of compound 2- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) - 1H- pyrazol-1-yls) methyl) pyridine synthesis

To addition 2- (bromines in DMF (40mL) solution of 3- methylpyrazoles -4- boric acid pinacols ester (1.51g, 7.26mmol) Methyl) -6- fluorine pyridine (2.1g, 11mmol), Cs₂CO₃(8.3g, 25mmol) and KI (0.6g, 4mmol) is then anti-at 70 DEG C Should overnight.Reaction solution is concentrated under reduced pressure to remove DMF, adds water (40mL), dichloromethane (50mL × 3) extraction, and organic phase is with anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v)=4/1), obtain 1.5g yellow oils, yield：65%.

MS(ESI,pos.ion)m/z:318.3[M+1]⁺。

Step 3：Compound N-(3- ((7- (1- ((6- fluorine pyridine -2- bases) methyl) -3- methyl isophthalic acid H- pyrazoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide Synthesis

By compound N-(3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] Pyrazine -2- bases) epoxide) phenyl) acrylamide (0.41g, 0.84mmol), the fluoro- 6- of 2- ((3- methyl -4- (4,4,5,5- tetramethyls Ring -2- the bases of base -1,3,2- dioxies boron penta) -1H- pyrazol-1-yls) methyl) pyridine (0.4g, 1mmol), Pd (dppf) Cl₂ (0.09g, 0.1mmol) and K₂CO₃Isosorbide-5-Nitrae-dioxane (20mL) and water (5mL) are added after (0.17g, 1.2mmol) mixing, so Rear substitution nitrogen, reacts overnight at being heated to 115 DEG C.Water (20mL), dichloromethane (30mL × 3) extraction are added after reaction solution cooling Take, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v) 0.31g yellow oils, yield=3/2), are obtained：62%.

MS-ESI:(ESI,pos.ion)m/z:600.3[M+1]⁺。

Step 4：Compound N-(3- ((7- (1- ((6- fluorine pyridine -2- bases) methyl) -3- methyl isophthalic acid H- pyrazoles -4- bases) - 5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide synthesis

By compound N-(3- ((7- (1- ((6- fluorine pyridine -2- bases) methyl) -3- methyl isophthalic acid H- pyrazoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.3g, 0.52mmol) it is dissolved in dichloromethane (15mL), is subsequently adding TFA (5mL), at room temperature stirring reaction 8h.Reaction solution decompression is dense THF (15mL) and TEA (2mL) is added after contracting, reaction is then stirred at room temperature again overnight.Reaction solution is concentrated under reduced pressure, is removed Saturated sodium bicarbonate aqueous solution (20mL), dichloromethane (30mL × 3) extraction, saturated common salt is added to wash (20mL) after solvent, Anhydrous sodium sulfate drying, concentration, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/MeOH(v/v) =20/1), then through HPLC preparative separations, obtain 0.04g yellow solids, yield：16%.

MS-ESI:(ESI,pos.ion)m/z:470.2[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)12.19(s,1H),10.21(s,1H),8.23-8.09(m,2H), 7.93 (d, J=9.0Hz, 2H), 7.60 (d, J=24.0Hz, 1H), 7.46-7.28 (m, 2H), 7.07 (d, J=8.0Hz, 1H), 6.97 (d, J=7.3Hz, 1H), 6.88 (d, J=4.8Hz, 1H), 6.44-6.34 (m, 1H), 6.20 (t, J=15.3Hz, 1H), 5.71 (d, J=10.3Hz, 1H), 5.36 (s, 1H), 5.27 (s, 1H), 2.31 (d, J=8.2Hz, 3H).

Embodiment 14

N- (3- ((7- (3- ethyls -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrroles Piperazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of the bromo- 1- of compound 4- (pyridine -2- ylmethyls) -1H- pyrazoles -3- formaldehyde

To addition 2- (bromomethyl) pyrrole in DMF (150mL) solution of the bromo- 1H- pyrazoles -3- formaldehyde (5g, 28.6mmol) of 4- Pyridine hydrobromate (11g, 43.49mmol), Cs₂CO₃(33g, 101.28mmol) and KI (2.4g, 14mmol), then at 70 DEG C Reaction is overnight.Reaction solution cooled and filtered, the crude on silica gel column chromatographic isolation and purification (eluent after filtrate concentration：PE/ EtOAc (v/v)=7/3), obtain 2g yellow oil products, yield：26.3%.

MS(ESI,pos.ion)m/z:268.1[M+2]⁺。

Step 2：The synthesis of compound 2- ((the bromo- 3- vinyl -1H- pyrazol-1-yls of 4-) methyl) pyridine

At 0 DEG C by MeLi (3.5mL, 5.6mmol) (1.6M diethyl ether solutions) be added drop-wise to methyltriphenylphospbromide bromide phosphorus (2.27g, In THF (35mL) solution 6.35mmol), after stirring reaction 1h, then the bromo- 1- of 4- (pyridine -2- ylmethyls) -1H- is slowly added dropwise THF (5mL) solution of pyrazoles -3- formaldehyde (1.21g, 4.55mmol), 1h is reacted at 0 DEG C, is returned to room temperature and is continued to react 1h.Instead Liquid is answered to be added in saturated aqueous ammonium chloride (30mL), EtOAc (50mL × 3) extractions, organic phase anhydrous Na₂SO₄Dry, Crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v)=4/1), obtain 0.26g yellow oils Shape thing, yield：22%.

MS(ESI,pos.ion)m/z:265.1[M+1]⁺。

Step 3：Compound 2- ((4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -3- vinyl -1H- Pyrazol-1-yl) methyl) pyridine synthesis

By compound 2- ((the bromo- 3- vinyl -1H- pyrazol-1-yls of 4-) methyl) pyridine (0.26g, 0.98mmol), connection boron Sour pinacol ester (0.5g, 2mmol), KOAc (0.3g, 3mmol) and Pd (dppf) Cl₂Added after (0.08g, 0.1mmol) mixing DMSO (15mL), then reacts overnight at 90 DEG C.Water (20mL), dichloromethane (30mL × 3) extraction are added after reaction solution cooling Take, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v) 0.18g yellow oils, yield=1/1), are obtained：59%.

MS(ESI,pos.ion)m/z:312.3[M+1]⁺。

Step 4：Compound 2- ((3- ethyls -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrroles Azoles -1- bases) methyl) pyridine synthesis

To compound 2- ((4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -3- vinyl -1H- pyrroles Azoles -1- bases) methyl) pyridine (0.29g, 0.93mmol) EtOH (20mL) solution in add Pd/C (10%, 0.03g), displacement H₂Stirring reaction is overnight at room temperature afterwards.Reaction solution is filtered with diatomite, the crude on silica gel column chromatography for separation after filtrate concentration Purifying (eluent：PE/EtOAc (v/v)=4/1), obtain 0.24g yellow oil products, yield：82%.

MS-ESI:(ESI,pos.ion)m/z:314.3[M+1]⁺。

Step 5：Compound N-(3- ((7- (3- ethyls -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide synthesis

To compound N-(3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] Pyrazine -2- bases) epoxide) phenyl) and acrylamide (0.21g, 0.43mmol) 1,4- dioxane (20mL) solution in add 2- ((3- ethyls -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrazol-1-yls) methyl) pyridine (0.18g,0.57mmol)、Pd(dppf)Cl₂(0.03g, 0.04mmol) and K₂CO₃(0.09g, 0.7mmol), adds H₂O (5mL), reacts overnight after displacement nitrogen at 115 DEG C.Water (20mL), dichloromethane (30mL × 3) extraction are added after reaction solution cooling Take, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v) 0.08g yellow oil products, yield=3/2), are obtained：30%.

MS-ESI:(ESI,pos.ion)m/z:596.3[M+1]⁺。

Step 6：Compound N-(3- ((7- (3- ethyls -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrroles And [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

By compound N-(3- ((7- (3- ethyls -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (front threes Base silane base) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.08g, 0.14mmol) it is dissolved in dichloromethane (15mL), TFA (3mL, 38.7mmol) is added at 0 DEG C, at room temperature stirring reaction 8h.Instead THF (15mL) and TEA (3mL) is added after answering liquid concentrated under reduced pressure, reaction is then stirred at room temperature again overnight.Reaction solution is depressurized Concentration, saturated sodium bicarbonate aqueous solution (20mL), dichloromethane extraction (30mL × 3), saturated aqueous common salt are added after removing solvent Wash (20mL), anhydrous sodium sulfate drying, concentrate, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)=20/1), then through HPLC preparative separations, obtain 0.01g yellow solids, yield：18%.MS-ESI:(ESI, pos.ion)m/z:466.3[M+1]⁺；

1H NMR(400MHz,DMSO-d₆):δ (ppm) 12.17 (s, 1H), 10.21 (s, 1H), 8.50 (d, J=4.2Hz, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.89 (d, J=2.8Hz, 1H), 7.72 (td, J₁=7.7Hz, J₂=1.7Hz, 1H), 7.62(s,1H),7.37(dd,J₁=23.7Hz, J₂=8.2Hz, 2H), 7.31-7.25 (m, 1H), 7.01 (d, J=7.8Hz, 1H),6.88(dd,J₁=7.9Hz, J₂=1.5Hz, 1H), 6.38 (dd, J₁=16.9Hz, J₂=10.1Hz, 1H), 6.19 (dd, J₁=17.0Hz, J₂=1.8Hz, 1H), 5.71 (dd, J₁=10.1Hz, J₂=1.8Hz, 1H), 5.30 (s, 2H), 3.49 (q, J =10.4,5.0Hz, 2H), 1.10 (t, J=7.5Hz, 3H).

Embodiment 15

N- (3- ((7- (3- methyl isophthalic acids-(thiazole -5- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrroles Piperazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of compound 5- (chloromethyl) thiazole

At room temperature, thiazole -5- bases methyl alcohol (503mg, 4.37mmol) and thionyl chloride (2.59g, 21.8mmol) are dissolved in In dichloromethane (15mL), 3h is reacted.Reaction solution is poured into water (30mL), ethyl acetate (30mL × 3) extraction, saturated common salt Washing (15mL), anhydrous sodium sulfate drying removes solvent, and residue carries out pillar layer separation (eluent：PE/EtOAc(v/v) =10/1), obtain 512mg pale yellow oils, yield：87.73%.

MS-ESI:(ESI,pos.ion)m/z:134.0[M+1]⁺。

Step 2：Compound 5- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrroles Azoles -1- bases) methyl) thiazole synthesis

By 5- (chloromethyl) thiazole (502mg, 3.76mmol) and 3- methylpyrazole -4- boric acid pinacols ester (820mg, 3.94mmol) it is dissolved in acetone (10mL), Cs is added in system₂CO₃(402mg, 1.23mmol), is warming up to 60 DEG C of reaction 8h. Reacting liquid filtering, the crude product silica gel column chromatography separating purification (PE/EtOAc (v/v)=1/1) after concentration are obtained into isomers Mixture is 652mg yellow oils, yield：56.85%.

MS-ESI:(ESI,pos.ion)m/z:306.30[M+1]⁺。

Step 3：Compound N-(3- ((7- (3- methyl isophthalic acids-(thiazole -5- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (trimethyl silyl) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide conjunction Into

By compound 5- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrazoles - 1- yls) methyl) thiazole (301mg, 0.99mmol) and N- (3- ((the bromo- 5- of 7- ((2- (trimethyl silicon substrate) ethyoxyl) methyl)- 5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (482mg, 0.98mmol) is dissolved in dioxane and water In the mixed solvent of (15mL, (v/v)=4/1), potassium carbonate (342mg, 2.48mmol) and [1,1'- double (two are added in system Phenylphosphine) ferrocene] palladium chloride dichloromethane complex (70mg, 0.095mmol), nitrogen is replaced, it is warming up to 110 DEG C of reactions 6h.Reaction solution is poured into water (30mL), ethyl acetate (30mL × 3) extraction, saturated common salt washing (20mL), anhydrous sodium sulfate Dry, remove solvent, residue carries out pillar layer separation (eluent：PE/EtOAc (v/v)=1/5), obtain 220mg yellow oils Shape thing, yield：37.85%.

MS-ESI:(ESI,pos.ion)m/z:588.10[M+1]⁺。

Step 4：Compound N-(3- ((7- (3- methyl isophthalic acids-(thiazole -5- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrroles And [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

By compound N-(3- ((7- (3- methyl isophthalic acids-(thiazole -5- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (front threes Base silicyl) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (221mg, 0.38mmol) it is dissolved in dichloromethane (15mL) with trifluoroacetic acid (5mL), room temperature reaction 8h.Reaction solution is directly spin-dried for, it is remaining Liquid is dissolved in tetrahydrofuran (5mL), adds saturated sodium bicarbonate solution (10mL), and 20h is stirred at room temperature.Reaction solution is poured into water In (20mL), ethyl acetate (20mL × 3) extraction, saturated common salt washing (20mL), anhydrous sodium sulfate drying, the thick product after concentration Thing silica gel column chromatography separating purification (eluent：CH₂Cl₂/ MeOH (v/v)=10/1), obtain 25mg yellow solids, yield： 20.18%.

MS-ESI:(ESI,pos.ion)m/z:458.20[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.20(s,1H),10.23(s,1H),9.00(s,1H),8.16 (s, 1H), 7.92 (d, J=2.7Hz, 1H), 7.88 (s, 1H), 7.70 (s, 1H), 7.55 (s, 1H), 7.45 (d, J=8.1Hz, 1H), 7.36 (t, J=8.1Hz, 1H), 6.89 (dd, J₁=8.1Hz, J₂=1.8Hz, 1H), 6.42-6.37 (m, 1H), 6.23 (dd,J₁=17.0Hz, J₂=1.7Hz, 1H), 5.75 (dd, J₁=10.2Hz, J₂=1.7Hz, 1H), 5.56 (s, 2H), 2.35 (s,3H)。

Embodiment 16

N- (3- ((7- (3- methyl isophthalic acids-(pyrazine -2- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrroles Piperazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of compound 2- (chloromethyl) pyrazine

At room temperature, pyrazine -2- bases methyl alcohol (103mg, 0.094mmol) and thionyl chloride (546mg, 4.59mmol) are dissolved in In dichloromethane (15mL), 3h is reacted.Reaction solution is poured into water (30mL), ethyl acetate (30mL × 3) extraction, saturated common salt Washing (15mL), anhydrous sodium sulfate drying removes solvent, and residue carries out pillar layer separation (eluent：PE/EtOAc(v/v) =10/1), obtain 87mg pale yellow oils, yield：72.34%.

¹H NMR(400MHz,CDCl₃):δ (ppm) 8.78 (s, 1H), 8.58 (d, J=1.5Hz, 2H), 4.72 (s, 2H).

Step 2：Compound 2- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrroles Azoles -1- bases) methyl) pyrazine synthesis

By 2- (chloromethyl) pyrazine (107mg, 0.83mmol) and 3- methylpyrazole -4- boric acid pinacols ester (180mg, 0.87mmol) it is dissolved in acetone (10mL), Cs is added in system₂CO₃(402mg, 1.23mmol), is warming up to 60 DEG C of reaction 8h. Reacting liquid filtering, the crude product silica gel column chromatography separating purification (PE/EtOAc (v/v)=1/1) after concentration are obtained into isomers Mixture is 189mg yellow oils, yield：75.64%.

MS-ESI:(ESI,pos.ion)m/z:301.1[M+1]⁺。

Step 3：Compound N-(3- ((7- (3- methyl isophthalic acids-(pyrazine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (trimethyl silyl) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide conjunction Into

By compound 2- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrazoles - 1- yls) methyl) pyrazine (198mg, 0.66mmol), N- (3- ((the bromo- 5- of 7- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5H- Pyrrolo- [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (327mg, 0.67mmol) is dissolved in dioxane and water In the mixed solvent of (15mL, (v/v)=4/1), potassium carbonate (233mg, 1.69mmol) and [1,1'- double (two are added in system Phenylphosphine) ferrocene] palladium chloride dichloromethane complex (51mg, 0.069mmol), nitrogen is replaced, it is warming up to 105 DEG C of reactions 6h.Reaction solution is poured into water (30mL), ethyl acetate (30mL × 3) extraction, saturated common salt washing (20mL), anhydrous sodium sulfate Dry, remove solvent, residue carries out pillar layer separation (eluent：PE/EtOAc (v/v)=5/1), obtain 208mg faint yellow Grease, yield：54.12%.

MS-ESI:(ESI,pos.ion)m/z:583.60[M+1]⁺。

Step 4：Compound N-(3- ((7- (3- methyl isophthalic acids-(pyrazine -2- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrroles And [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

By compound N-(3- ((7- (3- methyl isophthalic acids-(pyrazine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (front threes Base silicyl) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (182mg, 0.31mmol) it is dissolved in dichloromethane (15mL) with trifluoroacetic acid (10mL), room temperature reaction 8h.Reaction solution is directly spin-dried for, it is residual Extraction raffinate is dissolved in tetrahydrofuran (5mL), adds saturated sodium bicarbonate solution (10mL), and 8h is stirred at room temperature.Reaction solution is poured into water In (20mL), ethyl acetate (20mL × 3) extraction, saturated common salt washing (20mL), anhydrous sodium sulfate drying, the thick product after concentration Thing silica gel column chromatography separating purification (eluent：CH₂Cl₂/ MeOH (v/v)=10/1), obtain 14mg yellow solids, yield： 11.74%.

MS-ESI:(ESI,pos.ion)m/z:453.20[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.20(s,1H),10.21(s,1H),8.60-8.58(m,1H), 8.57 (d, J=2.5Hz, 1H), 8.42 (s, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.71 (s, 1H), 7.56 (s, 1H), 7.42 (d, J=8.0Hz, 1H), 7.34 (s, 1H), 6.90-6.88 (m, 1H), 6.38 (s, 1H), 6.22 (d, J=15.2Hz, 1H), 5.74 (d, J=10.0Hz, 1H), 5.48 (s, 2H), 2.36 (s, 3H).

Embodiment 17

N- (3- ((7- (3- methyl isophthalic acids-(thiazol-2-yl methyl) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrroles Piperazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of compound thiazol-2-yl methyl alcohol

At 0 DEG C, thiazole -2- formaldehyde (301mg, 2.66mmol) is dissolved in methyl alcohol (15mL), boron hydrogen is added toward system Change sodium (151mg, 3.99mmol), react 2h.Reaction solution is poured into water (10mL), solvent, ethyl acetate (15mL × 3) is spin-dried for Extraction, saturated common salt washing (15mL), anhydrous sodium sulfate drying removes solvent, and residue carries out pillar layer separation (eluent： PE/EtOAc (v/v)=5/1), obtain 285mg pale yellow oils, yield：93%.

MS-ESI:(ESI,pos.ion)m/z:116.10[M+1]⁺。

Step 2：The synthesis of compound 2- (chloromethyl) thiazole

At room temperature, thiazol-2-yl methyl alcohol (287mg, 2.49mmol) and thionyl chloride (0.9mL, 10mmol) are dissolved in two In chloromethanes (15mL), 4h is reacted.Reaction solution is poured into water (30mL), ethyl acetate (30mL × 3) extraction, saturated aqueous common salt Wash (15mL), anhydrous sodium sulfate drying, remove solvent, residue carries out pillar layer separation (eluent：PE/EtOAc (v/v)= 10/1) 289mg pale yellow oils, yield, are obtained：86.79%.

Step 3：Compound 2- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrroles Azoles -1- bases) methyl) thiazole synthesis

By 2- (chloromethyl) thiazole (302mg, 2.26mmol) and 3- methylpyrazole -4- boric acid pinacols ester (463mg, 2.23mmol) it is dissolved in acetone (10mL), Cs is added in system₂CO₃(1.12g, 3.44mmol), is warming up to 60 DEG C of reaction 6h. By reacting liquid filtering, the crude product silica gel column chromatography separating purification (eluent after concentration：PE/EtOAc (v/v)=5/1), obtain 483mg yellow oils, yield：70.01%.MS-ESI:(ESI,pos.ion)m/z:306.35[M+1]⁺。

Step 4：Compound N-(3- ((7- (3- methyl isophthalic acids-(thiazol-2-yl methyl) -1H- pyrazoles -4- bases) -5- ((2- (trimethyl silyl) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide conjunction Into

By compound 2- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrazoles - 1- yls) methyl) thiazole (305mg, 1mmol), N- (3- ((the bromo- 5- of 7- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5H- pyrroles Cough up simultaneously [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (486mg, 1mmol) is dissolved in dioxane and water (15mL, (v/ V) in=mixed solvent 4/1), potassium carbonate (345mg, 2.5mmol) and [1,1'- pair of (diphenylphosphine) two are added in system Luxuriant iron] palladium chloride dichloromethane complex (75mg, 0.1mmol), nitrogen is replaced, it is warming up to 105 DEG C of reaction 6h.By reaction solution Pour into water (30mL), ethyl acetate (30mL × 3) extraction, saturated common salt washing (20mL), anhydrous sodium sulfate drying is removed molten Agent, residue carries out pillar layer separation (eluent：PE/EtOAc (v/v)=1/9), obtain 207mg brown oils, yield： 35.24%.

MS-ESI:(ESI,pos.ion)m/z:588.20[M+1]⁺。

Step 5：Compound N-(3- ((7- (3- methyl isophthalic acids-(thiazol-2-yl methyl) -1H- pyrazoles -4- bases) -5H- pyrroles And [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

By compound N-(3- ((7- (3- methyl isophthalic acids-(thiazol-2-yl methyl) -1H- pyrazoles -4- bases) -5- ((2- (front threes Base silicyl) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (204mg, 0.35mmol) it is dissolved in dichloromethane (6mL) with trifluoroacetic acid (5mL), room temperature reaction 6h.Reaction solution is directly spin-dried for, it is remaining Liquid is dissolved in tetrahydrofuran (5mL), adds saturated sodium bicarbonate solution (10mL), and 8h is stirred at room temperature.Reaction solution is poured into water In (20mL), ethyl acetate (20mL × 3) extraction, saturated common salt washing (20mL), anhydrous sodium sulfate drying, the thick product after concentration Thing silica gel column chromatography separating purification (eluent：CH₂Cl₂/ MeOH (v/v)=10/1), obtain 29mg yellow solids, yield： 16.35%.

MS-ESI:(ESI,pos.ion)m/z:458.20[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ (ppm) 12.19 (s, 1H), 10.22 (s, 1H), 8.15 (d, J=3.6Hz, 2H), 7.93 (s, 1H), 7.74 (d, J=2.9Hz, 1H), 7.67-7.59 (m, 2H), 7.40 (d, J=8.4Hz, 1H), 7.34 (t, J=8.0Hz, 1H), 6.88 (d, J=7.7Hz, 1H), 6.38 (dd, J₁=16.7Hz, J₂=10.0Hz, 1H), 6.21 (d, J =17.3Hz, 1H), 5.73 (d, J=9.7Hz, 1H), 5.56 (s, 2H), 2.30 (s, 3H).

Embodiment 18

N- (3- ((7- (3- methyl isophthalic acids-((2- methylthiazol -5- bases) methyl) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2, 3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of compound 5- (chloromethyl) -2- methylthiazols

At room temperature, by (2- methylthiazol -5- bases) methyl alcohol (304mg, 2.35mmol) and thionyl chloride (0.9mL, 10mmol) it is dissolved in dichloromethane (15mL), reacts 4h.Reaction solution is poured into water (30mL), ethyl acetate (30mL × 3) extraction Take, saturated common salt washing (15mL), anhydrous sodium sulfate drying removes solvent, and residue carries out pillar layer separation (eluent：PE/ EtOAc (v/v)=10/1), obtain 286mg pale yellow oils, yield：82.32%.

Step 2：Compound 2- methyl-the 5- ((3- methyl -4- (ring -2- of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta Base) -1H- pyrazol-1-yls) methyl) and thiazole synthesis

By compound 5- (chloromethyl) -2- methylthiazols (241mg, 1.63mmol) and 3- methylpyrazole -4- boric acid frequency that Alcohol ester (340mg, 1.63mmol) is dissolved in acetone (10mL), and Cs is added in system₂CO₃(1.3g, 4.0mmol), is warming up to 60 DEG C reaction 6h.By reacting liquid filtering, the crude product silica gel column chromatography separating purification (eluent after concentration：PE/EtOAc (v/v)= 3/1) 312mg yellow oils, yield, are obtained：59.88%.

MS-ESI:(ESI,pos.ion)m/z:320.10[M+1]⁺。

Step 3：Compound N-(3- ((7- (3- methyl isophthalic acids-((2- methylthiazol -5- bases) methyl) -1H- pyrazoles -4- bases) - 5- ((2- (trimethyl silyl) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acryloyl The synthesis of amine

By compound 2- methyl -5- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) - 1H- pyrazol-1-yls) methyl) thiazole (376mg, 1.18mmol) and N- (3- ((the bromo- 5- of 7- ((2- (trimethyl silicon substrate) ethyoxyl) Methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (570mg, 1.17mmol) is dissolved in dioxy six In the mixed solvent of ring and water (15mL, (v/v)=4/1), potassium carbonate (400mg, 2.9mmol) and [1,1'- are added in system Double (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex (86mg, 0.012mmol), nitrogen is replaced, it is warming up to 105 DEG C reaction 6h.Reaction solution is poured into water (30mL), ethyl acetate (30mL × 3) extraction, saturated common salt washing (20mL) is anhydrous Sodium sulphate is dried, and removes solvent, and residue carries out pillar layer separation (eluent：PE/EtOAc (v/v)=1/10), obtain 236mg brown oils, yield：33.29%.

MS-ESI:(ESI,pos.ion)m/z:602.55[M+1]⁺。

Step 4：Compound N-(3- ((7- (3- methyl isophthalic acids-((2- methylthiazol -5- bases) methyl) -1H- pyrazoles -4- bases) - 5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide synthesis

By compound N-(3- ((7- (3- methyl isophthalic acids-((2- methylthiazol -5- bases) methyl) -1H- pyrazoles -4- bases) -5- ((2- (trimethyl silyl) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (182mg, 0.30mmol) and trifluoroacetic acid (5mL) are dissolved in dichloromethane (5mL), room temperature reaction 6h.Reaction solution is directly revolved Dry, residual solution is dissolved in tetrahydrofuran (10mL), adds saturated sodium bicarbonate solution (15mL), and 8h is stirred at room temperature.By reaction solution Pour into water (20mL), ethyl acetate (20mL × 3) extraction, saturated common salt washing (20mL), anhydrous sodium sulfate drying, after concentration Crude product silica gel column chromatography separating purification (eluent：CH₂Cl₂/ MeOH (v/v)=10/1), 48mg yellow solids are obtained, produce Rate：24.67%.

MS-ESI:(ESI,pos.ion)m/z:472.20[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ(ppm)12.16(s,1H),10.26(s,1H),8.15(s,1H),8.04 (s, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 7.54 (s, 1H), 7.43 (d, J=8.3Hz, 1H), 7.37 (t, J=8.1Hz, 1H), 6.89 (d, J=8.1Hz, 1H), 6.44-6.36 (m, 1H), 6.23 (dd, J₁=17.0Hz, J₂=1.8Hz, 1H), 5.75 (dd,J₁=10.0Hz, J₂=1.8Hz, 1H), 5.37 (s, 2H), 2.56 (s, 3H), 2.28 (s, 3H).

Embodiment 19

N- (3- ((7- (3- methyl isophthalic acids-((4- picoline -2- bases) methyl) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2, 3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of compound 2,4- lutidines 1- oxides

It is stirred continuously down, to being slowly added to HOAc (30mL) in 2,4- lutidines (11.1g, 104mmol), then slowly H is added dropwise₂O₂(16mL), then reacts 24h at 70 DEG C.A small amount of Na is added after reaction solution cooling₂SO₃It is quenched, is stirred at room temperature After 10min, pH to 12 is adjusted with the NaOH aqueous solution (20%), then extracted with dichloromethane (50mL × 3), organic phase is with anhydrous Na₂SO₄Dry, concentration obtains 12g colourless oil liquids, yield：93.9%.

MS(ESI,pos.ion)m/z:124.3[M+1]⁺。

Step 2：The synthesis of compound (4- picoline -2- bases) methyl alcohol

To being slowly added dropwise in DCM (200mL) solution of 2,4- lutidines 1- oxides (10.11g, 82.10mmol) DCM (50mL) solution of TFAH (51.37g, 244.6mmol), is then stirred at room temperature reaction 3.5 days.It is concentrated under reduced pressure to remove Solvent, adds MeOH (200mL) and saturation K₂CO₃Solution (250mL), after 3h is stirred at room temperature, is concentrated under reduced pressure and removes MeOH, dichloro Methane (200mL × 3) is extracted, organic phase anhydrous Na₂SO₄Dry, 4g brown oil products, yield are obtained after concentration： 39.6%.

MS(ESI,pos.ion)m/z:124.3[M+1]⁺。

Step 3：The synthesis of compound (4- picoline -2- bases) methylmethanesulfonate ester

TEA (1.9g, 19mmol) is added drop-wise to (4- picoline -2- bases) methyl alcohol (1.50g, 12.2mmol) at 0 DEG C In dichloromethane (20mL) solution, nitrogen protection is lower to add MsCl (1.6g, 14mmol), then continues to react at 0 DEG C.Reaction Liquid is concentrated under reduced pressure, and is subsequently adding saturated sodium bicarbonate aqueous solution (50mL), dichloromethane (60mL × 3) extraction, organic phase nothing Water Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v)=1/1), obtain To 0.7g bronzing oil products, yield：30%.

MS(ESI,pos.ion)m/z:202.1[M+1]⁺。

Step 4：Compound 4- methyl-the 2- ((3- methyl -4- (ring -2- of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta Base) -1H- pyrazol-1-yls) methyl) and pyridine synthesis

(4- first is added in DMF (25mL) solution of 3- methylpyrazoles -4- boric acid pinacols ester (0.50g, 2.4mmol) Yl pyridines -2- bases) methylmethanesulfonate ester (0.62g, 3.1mmol) and K₂CO₃(1.3g, 4.0mmol), then reacts at 100 DEG C Overnight.Reaction solution is concentrated under reduced pressure to remove DMF, adds water (40mL), dichloromethane (50mL × 3) extraction, and organic phase is with anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v)=7/3), obtain 0.18g pale yellow oils, yield：24%.

MS(ESI,pos.ion)m/z:314.3[M+1]⁺。

Step 5：Compound N-(3- ((7- (3- methyl isophthalic acids-((4- picoline -2- bases) methyl) -1H- pyrazoles -4- bases) - 5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide Synthesis

By 4- methyl -2- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrazoles - 1- yls) methyl) pyridine (0.21g, 0.43mmol), N- (3- ((the bromo- 5- of 7- ((2- (trimethyl silicon substrate) ethyoxyl) methyl) -5H- Pyrrolo- [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.28g, 0.57mmol), Pd (dppf) Cl₂(0.03g, 0.04mmol) and K₂CO₃Isosorbide-5-Nitrae-dioxane (16mL) and water (4mL) are added after (0.09g, 0.7mmol) mixing, is then replaced Nitrogen, reacts overnight at being heated to 120 DEG C.Water (20mL) is added after reaction solution cooling, dichloromethane (30mL × 3) extraction has Machine mutually uses anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/MeOH(v/ V)=40/1), obtain 0.15g yellow oils, yield：59%.

MS-ESI:(ESI,pos.ion)m/z:596.3[M+1]⁺。

Step 6：Compound N-(3- ((7- (3- methyl isophthalic acids-((4- picoline -2- bases) methyl) -1H- pyrazoles -4- bases) - 5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide synthesis

By compound N-(3- ((7- (3- methyl isophthalic acids-((4- picoline -2- bases) methyl) -1H- pyrazoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.11g, 0.18mmol) is dissolved in dichloromethane (15mL), is subsequently adding TFA (5mL), at room temperature stirring reaction 8h.Reaction solution THF (15mL) and TEA (2mL) is added after concentrated under reduced pressure, reaction is then stirred at room temperature again overnight.Reaction solution is depressurized dense Contracting, saturated sodium bicarbonate aqueous solution (20mL), dichloromethane extraction (30mL × 3), saturated common salt washing are added after removing solvent (20mL), anhydrous sodium sulfate drying, concentration, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)=20/1), obtain 0.04g yellow solids, yield：27%.

MS-ESI:(ESI,pos.ion)m/z:466.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.21(s,1H),10.21(s,1H),9.11(s,1H),8.72 (d, J=5.2Hz, 1H), 8.18 (d, J=19.3Hz, 2H), 7.96 (d, J=2.8Hz, 1H), 7.64 (s, 1H), 7.35 (dd, J₁=16.5Hz, J₂=8.1Hz, 2H), 7.02 (d, J=5.0Hz, 1H), 6.88 (d, J=7.8Hz, 1H), 6.34 (d, J= 10.2Hz,1H),6.21-6.15(m,1H),5.71(dd,J₁=10.2Hz, J₂=1.7Hz, 1H), 5.35 (s, 2H), 2.31 (s, 3H)。

Embodiment 20

N- (3- ((7- (3- isopropyls -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrroles Piperazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of compound 2- ((the bromo- 3- isopropyls -1H- pyrazol-1-yls of 4-) methyl) pyridine

At room temperature, by the bromo- 3- isopropyls -1H- pyrazoles (310mg, 1.64mmol) of 4-, 2- (bromomethyl) pyridine (812mg, 1.96mmol) and Cs₂CO₃(1.29g, 3.97mmol) is dissolved in acetone (15mL), is warming up to 60 DEG C of reaction 8h.Diatomite is filtered, Residue carries out pillar layer separation (eluent：PE/EtOAc (v/v)=4/1), obtain 367mg weak yellow liquids, yield： 79.89%.

MS-ESI:(ESI,pos.ion)m/z:281.15[M+1]⁺。

Step 2：Compound 2- ((3- isopropyls -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- Pyrazol-1-yl) methyl) pyridine synthesis

At room temperature, by 2- ((the bromo- 3- isopropyls -1H- pyrazol-1-yls of 4-) methyl) pyridine (681mg, 2.43mmol), second Sour potassium (721mg, 7.36mmol), connection boric acid pinacol ester (780mg, 3.06mmol) and [1,1'- double (diphenylphosphines) two cyclopentadienyl Iron] palladium chloride dichloromethane complex (130mg, 0.18mmol) are dissolved in dioxane (20mL), are warming up to 100 DEG C of reactions 8h.Reaction solution is poured into water (50mL), ethyl acetate (50mL × 3) extraction, saturated aqueous common salt (15mL) is washed, anhydrous sodium sulfate Dry, remove solvent, residue carries out pillar layer separation (eluent：PE/EtOAc (v/v)=1/1), obtain 198mg yellow oils Shape thing, yield：24.89%.

MS-ESI:(ESI,pos.ion)m/z:328.25[M+1]⁺。

Step 3：Compound N-(3- ((7- (3- isopropyls -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (trimethyl silyl) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide conjunction Into

At room temperature, by compound 2- ((3- isopropyls -4- (4,4,5,5- tetramethyl -1, the ring -2- bases of 3,2- dioxy boron penta) - 1H- pyrazol-1-yls) methyl) pyridine (263mg, 0.80mmol), N- (3- ((the bromo- 5- of 7- ((2- (trimethyl silicon substrate) ethyoxyl) Methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (402mg, 0.82mmol), potassium carbonate (271g, 1.96mmol) and [double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex (45mg, 0.061mmol) it is dissolved in the mixed solvent of dioxane and water (15mL, (v/v)=4/1), is warming up to 100 DEG C of reaction 8h.Will Reaction solution is poured into water (30mL), and ethyl acetate (30mL × 3) extraction, saturated aqueous common salt (15mL) is washed, anhydrous sodium sulfate drying, Solvent is removed, residue carries out pillar layer separation (eluent：PE/EtOAc (v/v)=1/10), obtain 192mg brown oils Thing, yield：39.17%.MS-ESI:(ESI,pos.ion)m/z:610.30[M+1]⁺。

Step 4：Compound N-(3- ((7- (3- isopropyls -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrroles Cough up simultaneously [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide synthesis

At room temperature, by compound N-(3- ((7- (3- isopropyls -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (trimethyl silyl) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (192mg, 0.31mmol) and trifluoroacetic acid (5.3mL) are dissolved in dichloromethane (5mL), room temperature reaction 10h.Reaction solution is direct It is spin-dried for, residual solution is dissolved in tetrahydrofuran (5mL), adds saturated sodium bicarbonate solution (5mL), 8h is stirred at room temperature.By reaction solution Pour into water (20mL), dichloromethane (20mL × 3) extraction, saturated aqueous common salt (15mL) is washed, anhydrous sodium sulfate drying, after concentration Crude product silica gel column chromatography separating purification (eluent：CH₂Cl₂/ MeOH (v/v)=10/1), 12mg faint yellow solids are obtained, Yield：29.66%.

MS-ESI:(ESI,pos.ion)m/z:480.50[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ (ppm) 12.15 (s, 1H), 10.18 (s, 1H), 8.51 (d, J=3.9Hz, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.87 (s, 1H), 7.73 (s, 1H), 7.61 (s, 1H), 7.39 (d, J=8.4Hz, 1H), 7.34-7.26 (m, 2H), 6.98 (d, J=7.8Hz, 1H), 6.87 (d, J=8.0Hz, 1H), 6.41-6.33 (m, 1H), 6.23-6.15 (m, 1H), 5.71 (d, J=11.9Hz, 1H), 5.31 (s, 2H), 3.25 (d, J=6.0Hz, 1H), 1.11 (d, J =6.8Hz, 6H).

Embodiment 21

(E)-N- (3- ((7- (3- (3- oxo but-1-ene -1- bases) -1- (pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) - 5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide

Step 1：Compound (E) -4- (the bromo- 1- of 4- (pyridine -2- ylmethyls) -1H- pyrazole-3-yls) butyl- 3- alkene -2- ketone Synthesis

To addition 2- (bromomethyl) pyrrole in acetone (100mL) solution of the bromo- 1H- pyrazoles -3- formaldehyde (5g, 28.6mmol) of 4- Pyridine hydrobromate (11g, 43.5mmol), Cs₂CO₃(33g, 101.3mmol) and KI (1g, 5.6mmol) is then anti-at 100 DEG C Should overnight.Reaction solution cooled and filtered, filtrate decompression concentration, crude on silica gel column chromatographic isolation and purification (eluent：PE/ EtOAc (v/v)=3/2), obtain 4g faint yellow solids, yield：45.6%.

MS(ESI,pos.ion)m/z:306.3[M+1]⁺。

Step 2：Compound (E) -4- (1- (pyridine -2- ylmethyls) -4- (4,4,5,5- tetramethyl -1,3,2- dioxies boron penta Ring -2- bases) -1H- pyrazole-3-yls) butyl- 3- alkene -2- ketone synthesis

By compound (E) -4- (the bromo- 1- of 4- (pyridine -2- ylmethyls) -1H- pyrazole-3-yls) butyl- 3- alkene -2- ketone (0.49g, 1.6mmol), connection boric acid pinacol ester (0.75g, 3.0mmol), KOAc (0.50g, 5.1mmol) and Pd (dppf) Cl₂DMSO (10mL) is added after (0.12g, 0.16mmol) mixing, is then reacted overnight at 90 DEG C.Added after reaction solution cooling Water (20mL), dichloromethane (30mL × 3) extraction, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel post layer after concentration Analysis isolates and purifies (eluent：PE/EtOAc (v/v)=1/1), obtain 0.22g faint yellow solids, yield：37%.

MS-ESI:(ESI,pos.ion)m/z:354.1[M+1]⁺。

Step 3：Compound (E)-N- (3- ((7- (3- (3- oxo but-1-ene -1- bases) -1- (pyridine -2- ylmethyls) - 1H- pyrazoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) oxygen Base) phenyl) acrylamide synthesis

By compound N-(3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] Pyrazine -2- bases) epoxide) phenyl) acrylamide (0.21g, 0.43mmol), (E) -4- (1- (pyridine -2- ylmethyls) -4- (4,4, Ring -2- the bases of 5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrazole-3-yls) butyl- 3- alkene -2- ketone (0.28g, 0.79mmol), Pd(dppf)Cl₂(0.03g, 0.04mmo) and K₂CO₃(0.09g, 0.7mmol) mixing after add 1,4- dioxane (20mL) and Water (5mL), then replaces nitrogen, is reacted overnight at being heated to 115 DEG C.Water (20mL), dichloromethane are added after reaction solution cooling (30mL × 3) extract, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (drip washing after concentration Agent：CH₂Cl₂/ MeOH (v/v)=40/1), obtain 0.14g pale yellow oils, yield：51%.

MS-ESI:(ESI,pos.ion)m/z:636.7[M+1]⁺。

Step 4：Compound (E)-N- (3- ((7- (3- (3- oxo but-1-ene -1- bases) -1- (pyridine -2- ylmethyls) - 1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

By compound (E)-N- (3- ((7- (3- (3- oxo but-1-ene -1- bases) -1- (pyridine -2- ylmethyls) -1H- pyrroles Azoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) benzene Base) acrylamide (0.14g, 0.22mmol) is dissolved in dichloromethane (15mL), is subsequently adding TFA (5mL), stirs anti-at room temperature Answer 8h.THF (15mL) and TEA (2mL) is added after reaction solution is concentrated under reduced pressure, reaction is then stirred at room temperature again overnight.Will be anti- Answer liquid to be concentrated under reduced pressure, add saturated sodium bicarbonate aqueous solution (20mL), dichloromethane extraction (30mL × 3) to satisfy after removing solvent With salt washing (20mL), anhydrous sodium sulfate drying, concentration, the crude on silica gel column chromatographic isolation and purification (drip washing after concentration Agent：CH₂Cl₂/ MeOH (v/v)=30/1), obtain 0.04g brown solids, yield：40%.

MS-ESI:(ESI,pos.ion)m/z:506.1[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ (ppm) 12.39 (s, 1H), 10.19 (s, 1H), 8.53 (d, J=3.9Hz, 1H), 8.20 (d, J=8.5Hz, 2H), 8.08 (s, 1H), 7.77 (t, J=7.1Hz, 1H), 7.68 (d, J=16.1Hz, 1H), 7.59 (s, 1H), 7.47-7.24 (m, 3H), 7.18 (d, J=7.5Hz, 1H), 6.86 (d, J=7.1Hz, 1H), 6.66 (d, J= 16.0Hz, 1H), 6.36 (d, J=10.0Hz, 1H), 6.20 (d, J=17.0Hz, 1H), 5.72 (d, J=10.1Hz, 1H), 5.46(s,2H),2.23(s,3H)。

Embodiment 22

N- (3- ((7- (3- methyl isophthalic acids-((6- picoline -2- bases) methyl) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2, 3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide

Step 1：Compound 2- methyl-the 6- ((3- methyl -4- (ring -2- of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta Base) -1H- pyrazol-1-yls) methyl) and pyridine synthesis

To addition 2- (bromines in acetone (40mL) solution of 3- methylpyrazoles -4- boric acid pinacols ester (1.50g, 7.2mmol) Methyl) -6- picolines (2g, 10.8mmol), Cs₂CO₃(5.9g, 18.0mmol) and KI (0.6g, 4mmol), then at 60 DEG C Lower reaction is overnight.Reaction solution cooled and filtered, the crude on silica gel column chromatographic isolation and purification (drip washing after filtrate decompression concentration Agent：PE/EtOAc (v/v)=3/2), obtain 1.5g yellow solids, yield：66%.

MS(ESI,pos.ion)m/z:314.4[M+1]⁺。

Step 2：Compound N-(3- ((7- (3- methyl isophthalic acids-((6- picoline -2- bases) methyl) -1H- pyrazoles -4- bases) - 5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide Synthesis

By compound N-(3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] Pyrazine -2- bases) epoxide) phenyl) acrylamide (0.51g, 1.0mmol), 2- methyl -6- ((3- methyl -4- (4,4,5,5- tetramethyls Ring -2- the bases of base -1,3,2- dioxies boron penta) -1H- pyrazol-1-yls) methyl) pyridine (0.54g, 1.7mmol), Pd (dppf) Cl₂ (0.05g, 0.07mmo) and K₂CO₃Isosorbide-5-Nitrae-dioxane (20mL) and water (5mL) are added after (0.21g, 1.5mmol) mixing, so Rear substitution nitrogen, reacts overnight at being heated to 120 DEG C.Water (20mL), dichloromethane (30mL × 3) extraction are added after reaction solution cooling Take, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)=25/1), obtain the faint yellow oil products of 0.48g, yield：77%.

MS-ESI:(ESI,pos.ion)m/z:596.6[M+1]⁺。

Step 3：Compound N-(3- ((7- (3- methyl isophthalic acids-((6- picoline -2- bases) methyl) -1H- pyrazoles -4- bases) - 5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide synthesis

By compound N-(3- ((7- (3- methyl isophthalic acids-((6- picoline -2- bases) methyl) -1H- pyrazoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.48g, 0.81mmol) is dissolved in dichloromethane (15mL), is subsequently adding TFA (5mL), at room temperature stirring reaction 8h.Reaction solution THF (15mL) and TEA (2mL) is added after concentrated under reduced pressure, reaction is then stirred at room temperature again overnight.Reaction solution is depressurized dense Contracting, saturated sodium bicarbonate aqueous solution (20mL), dichloromethane extraction (30mL × 3), saturated common salt washing are added after removing solvent (20mL), anhydrous sodium sulfate drying, concentration, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)=20/1), then through HPLC preparative separations, obtain 0.07g yellow solids, yield：19%.MS-ESI:(ESI, pos.ion)m/z:466.3[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ (ppm) 12.17 (s, 1H), 10.21 (s, 1H), 8.14 (d, J=15.0Hz, 2H),7.93(s,1H),7.60(dd,J₁=14.5Hz, J₂=6.6Hz, 2H), 7.41 (d, J=7.8Hz, 1H), 7.34 (d, J= 8.0Hz, 1H), 7.13 (d, J=7.6Hz, 1H), 6.88 (d, J=7.2Hz, 1H), 6.78 (d, J=7.6Hz, 1H), 6.36 (d, J=10.1Hz, 1H), 6.20 (d, J=16.8Hz, 1H), 5.71 (d, J=10.2Hz, 1H), 5.24 (s, 2H), 2.43 (s, 3H),2.30(s,3H)。

Embodiment 23

N- (3- ((7- (3- methyl isophthalic acids-(pyrimidine-4-yl methyl) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrroles Piperazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of compound 4- (bromomethyl) pyrimidine

To in THF (150mL) solution of compound 4- methylpyrimidines (2.07g, 22.0mmol) add AIBN (0.36g, 2.2mmol), THF (20mL) solution of NBS (4.7g, 26mmol) is then added at 0 DEG C, 70 DEG C is then heated to and was reacted Night.Filtered with diatomite after reaction solution cooling, filtrate decompression concentration, crude on silica gel column chromatographic isolation and purification (eluent： PE/EtOAc (v/v)=3/2), obtain 1.5g brown-red oils, yield：39%.

MS(ESI,pos.ion)m/z:175.1[M+2]⁺。

Step 2：Compound 4- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrroles Azoles -1- bases) methyl) pyrimidine synthesis

4- (bromines are added in DMF (40mL) solution of 3- methylpyrazoles -4- boric acid pinacols ester (1.01g, 4.85mmol) Methyl) pyrimidine (1.2g, 6.9mmol), Cs₂CO₃(3.9g, 12mmol) and KI (0.4g, 2mmol), then reacted at 70 DEG C Night.Reaction solution is concentrated under reduced pressure to remove DMF, adds water (40mL), dichloromethane (50mL × 3) extraction, organic phase anhydrous Na₂SO₄ Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)=20/1), obtain 0.8g yellow oils, yield：50%.

MS(ESI,pos.ion)m/z:301.2[M+1]⁺。

Step 3：Compound N-(3- ((7- (3- methyl isophthalic acids-(pyrimidine-4-yl methyl) -1H- pyrazoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide synthesis

By compound N-(3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] Pyrazine -2- bases) epoxide) phenyl) acrylamide (0.51g, 1.0mmol), 4- ((3- methyl -4- (4,4,5,5- tetramethyl -1,3, Ring -2- the bases of 2- dioxies boron penta) -1H- pyrazol-1-yls) methyl) pyrimidine (0.8g, 2mmol), Pd (dppf) Cl₂(0.05g, 0.07mmol) and K₂CO₃Isosorbide-5-Nitrae-dioxane (20mL) and water (5mL) are added after (0.21g, 1.5mmol) mixing, is then replaced Nitrogen, reacts overnight at being heated to 115 DEG C.Water (20mL) is added after reaction solution cooling, dichloromethane (30mL × 3) extraction has Machine mutually uses anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/MeOH(v/ V)=20/1), obtain 0.29g yellow oil products, yield：48%.

MS-ESI:(ESI,pos.ion)m/z:583.3[M+1]⁺。

Step 4：Compound N-(3- ((7- (3- methyl isophthalic acids-(pyrimidine-4-yl methyl) -1H- pyrazoles -4- bases) -5H- pyrroles And [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

By compound N-(3- ((7- (3- methyl isophthalic acids-(pyrimidine-4-yl methyl) -1H- pyrazoles -4- bases) -5- ((2- (front threes Base silane base) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.29g, 0.5mmol) it is dissolved in dichloromethane (15mL), is subsequently adding TFA (5mL), at room temperature stirring reaction 8h.Reaction solution is concentrated under reduced pressure THF (15mL) and TEA (2mL) is added afterwards, and reaction is then stirred at room temperature again overnight.Reaction solution is concentrated under reduced pressure, is removed molten Saturated sodium bicarbonate aqueous solution (20mL), dichloromethane extraction (30mL × 3), saturated common salt washing (20mL), nothing are added after agent Aqueous sodium persulfate is dried, concentration, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)= 20/1), then through HPLC preparative separations, 0.02g yellow solids, yield are obtained：8.7%.

MS-ESI:(ESI,pos.ion)m/z:453.3[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.21(s,1H),10.21(s,1H),9.11(s,1H),8.72 (d, J=5.2Hz, 1H), 8.18 (d, J=19.3Hz, 2H), 7.96 (d, J=2.8Hz, 1H), 7.64 (s, 1H), 7.35 (dd, J₁=16.5Hz, J₂=8.1Hz, 2H), 7.02 (d, J=5.0Hz, 1H), 6.88 (d, J=7.8Hz, 1H), 6.34 (d, J= 10.2Hz,1H),6.21-6.15(m,1H),5.71(dd,J₁=10.2Hz, J₂=1.7Hz, 1H), 5.35 (s, 2H), 2.31 (s, 3H)。

Embodiment 24

N- (2- ((7- (3- methyl isophthalic acids-(pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrroles Piperazine -2- bases) epoxide) pyridin-4-yl) acrylamide

Step 1：Compound 2- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3- B] pyrazine -2- bases) epoxide) and pyridine -4- amine synthesis

By the bromo- 5- of 2,7- bis- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine (2.01g, 4.94mmol), 4- amino -2 hydroxy pyrimidine (0.65g, 5.9mmol), DMG (0.52g, 4.9mmol), Cs₂CO₃ Add Isosorbide-5-Nitrae-dioxane (40mL) after (2.41g, 7.39mmol) and CuI (0.94g, 4.9mmol) mixing, put after nitrogen Reacted overnight at 110 DEG C.Filtered with diatomite after reaction solution cooling, the crude on silica gel column chromatography for separation of filtrate decompression concentration Purifying (eluent：CH₂Cl₂/ MeOH (v/v)=15/1), obtain 0.92g yellow solids, yield：43%.

MS(ESI,pos.ion)m/z:437.0[M+1]⁺。

Step 2：Compound N-(2- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2, 3-b] pyrazine -2- bases) epoxide) pyridin-4-yl) acrylamide synthesis

At -10 DEG C, to 2- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] Pyrazine -2- bases) epoxide) pyridine -4- amine (0.71g, 1.6mmol) DCM (40mL) solution in add DIEA (0.43g, 3.3mmol) with DCM (1mL) solution of acryloyl chloride (0.13g, 1.5mmol), after continuing to react 2h, then 0 DEG C is slowly returned to Lower reaction 1h.Reaction solution is poured into water after being quenched with water, DCM (50mL × 3) extractions, organic phase saturated common salt water washing, Anhydrous Na is used again₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/MeOH(v/v) =20/1), obtain 0.53g solid products, yield：66%.

MS(ESI,pos.ion)m/z:492.1[M+2]⁺。

Step 3：Compound N-(2- ((7- (3- methyl isophthalic acids-(pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) pyridin-4-yl) acrylamide Synthesis

N- (2- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- Base) epoxide) pyridin-4-yl) acrylamide (0.53g, 1.1mmol), 2- ((3- methyl -4- (4,4,5,5- tetramethyls -1,3,2- Ring -2- the bases of dioxy boron penta) -1H- pyrazol-1-yls) methyl) pyridine (0.5g, 2mmol), Pd (dppf) Cl₂(0.08g, 0.1mmol) and K₂CO₃Isosorbide-5-Nitrae-dioxane (20mL) and water (5mL) are added after (0.22g, 1.6mmol) mixing, nitrogen is then replaced Gas, reacts overnight at being heated to 120 DEG C.Water (20mL) is added after reaction solution cooling, dichloromethane (30mL × 3) extraction is organic Mutually use anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/MeOH(v/v) =20/1), obtain 0.19g yellow oils, yield：30%.

MS-ESI:(ESI,pos.ion)m/z:583.2[M+1]⁺。

Step 4：Compound N-(2- ((7- (3- methyl isophthalic acids-(pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5H- pyrroles And [2,3-b] pyrazine -2- bases) epoxide) pyridin-4-yl) acrylamide synthesis

By compound N-(2- ((7- (3- methyl isophthalic acids-(pyridine -2- ylmethyls) -1H- pyrazoles -4- bases) -5- ((2- (front threes Base silane base) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) pyridin-4-yl) acrylamide (0.19g, 0.33mmol) is dissolved in dichloromethane (15mL), is subsequently adding TFA (5mL), at room temperature stirring reaction 8h.Reaction solution THF (15mL) and TEA (2mL) is added after concentrated under reduced pressure, reaction is then stirred at room temperature again overnight.Reaction solution is depressurized dense Contracting, saturated sodium bicarbonate aqueous solution (20mL), dichloromethane extraction (30mL × 3), saturated common salt washing are added after removing solvent (20mL), anhydrous sodium sulfate drying, concentration, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)=30/1), then through HPLC preparative separations, obtain 0.02g yellow solids, yield：13.3%.

MS-ESI:(ESI,pos.ion)m/z:453.2[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.41(s,1H),10.46(s,1H),8.58(s,1H),8.53 (s, 1H), 8.36 (s, 1H), 8.06 (d, J=2.6Hz, 1H), 7.93 (d, J=7.6Hz, 1H), 7.78 (s, 1H), 7.31 (s, 2H), 7.04 (d, J=2.0Hz, 1H), 6.60 (dd, J₁=7.6Hz, J₂=2.1Hz, 1H), 6.45 (dd, J₁=17.0Hz, J₂ =10.1Hz, 1H), 6.35 (dd, J₁=17.0Hz, J₂=1.5Hz, 1H), 5.92-5.85 (m, 1H), 5.42 (s, 2H), 2.38 (s,3H)。

Embodiment 25

N- (3- ((7- (3- methyl isophthalic acids-((1- methyl isophthalic acid H- imidazoles -2- bases) methyl) -1H- pyrazoles -4- bases) -5H- pyrroles And [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide

Step 1：The synthesis of the bromo- 3- methyl isophthalic acids of compound 4--((1- methyl isophthalic acid H- imidazoles -2- bases) methyl) -1H- pyrazoles

The bromo- 3- methyl isophthalic acids H- pyrazoles (1.50g, 9.3mmol) of 4- are dissolved in tetrahydrofuran (25mL), under the conditions of 0 DEG C, slowly Sodium hydride (0.47g, 12.0mmol, 60%) is added, continuation is warmed to room temperature and is reacted 1h.By 1- methyl -2- chloromethyl imidazoles (1.80g, 14.1mmol) is slowly added into above-mentioned mixed solution, replaces nitrogen, is heated to 70 DEG C of reaction 12h.Stop heating, Room temperature is cooled to, diatomite filtering concentrates filtrate.Add water (30mL), dichloromethane (30mL × 3) extraction, organic phase nothing Water Na₂SO₄Dry, the crude product after concentration is purified through preparative separation, obtains the faint yellow oil products of 0.6g, yield：25.0%.

MS(ESI,pos.ion)m/z:256.0[M+1]⁺。

Step 2：Compound 3- methyl isophthalic acids-((1- methyl isophthalic acid H- imidazoles -2- bases) methyl) -4- (4,4,5,5- tetramethyl -1, Ring -2- the bases of 3,2- dioxies boron penta) -1H- pyrazoles synthesis

By the bromo- 3- methyl isophthalic acids of 4--((1- methyl isophthalic acid H- imidazoles -2- bases) methyl) -1H- pyrazoles (0.33g, 1.3mmol), connection Boric acid pinacol ester (0.49g, 1.95mmol), Pd (dppf) Cl₂(0.09g, 0.12mmol) and KOAc (0.38g, 3.9mmol) Isosorbide-5-Nitrae-dioxane (25mL) is added after mixing, nitrogen is replaced, 80 DEG C of reaction 13h are heated to.Stop heating, be cooled to room temperature, Diatomite is filtered, and concentrates filtrate.Add water (30mL), dichloromethane (30mL × 3) extraction, organic phase anhydrous Na₂SO₄Dry, Crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)=30/1), obtain 0.22g palm fibres Color grease, yield：56%.

MS(ESI,pos.ion)m/z:303.1[M+1]⁺。

Step 3：Compound N-(3- ((7- (3- methyl isophthalic acids-((1- methyl isophthalic acid H- imidazoles -2- bases) methyl) -1H- pyrazoles -4- Base) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) propylene The synthesis of acid amides

By 3- methyl isophthalic acids-((1- methyl isophthalic acid H- imidazoles -2- bases) methyl) -4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron Penta ring -2- bases) -1H- pyrazoles (0.20g, 0.66mmol), N- (3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) first Base) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.20g, 0.41mmol), Pd (dppf) Cl₂ (0.03g, 0.04mmol) and K₂CO₃Isosorbide-5-Nitrae-dioxane (25mL) and water (5mL) are added after (0.085g, 0.61mmol) mixing, Then nitrogen is replaced, is reacted overnight at being heated to 105 DEG C.Water (30mL), dichloromethane (30mL × 3) are added after reaction solution cooling Extraction, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)=25/1), obtain 0.1g viscous brown things, yield：41.8%.

MS-ESI:(ESI,pos.ion)m/z:585.2[M+1]⁺。

Step 4：Compound N-(3- ((7- (3- methyl isophthalic acids-((1- methyl isophthalic acid H- imidazoles -2- bases) methyl) -1H- pyrazoles -4- Base) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide synthesis

By N- (3- ((7- (3- methyl isophthalic acids-((1- methyl isophthalic acid H- imidazoles -2- bases) methyl) -1H- pyrazoles -4- bases) -5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.1g, 0.17mmol) it is dissolved in dichloromethane (10mL), is subsequently adding TFA (5mL), at room temperature stirring reaction 12h.Reaction solution decompression is dense THF (10mL) and TEA (5mL) is added after contracting, reaction 12h is then stirred at room temperature again.Reaction solution is concentrated under reduced pressure, is removed molten Saturated sodium bicarbonate aqueous solution (20mL), dichloromethane extraction (30mL × 3), saturated common salt washing (20mL), nothing are added after agent Aqueous sodium persulfate is dried, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)=12/ 1) the faint yellow dopes of 0.03g, yield, are obtained：41.1%.

MS-ESI:(ESI,pos.ion)m/z:455.1[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ (ppm) 12.27 (d, J=1.9Hz, 1H), 10.37 (s, 1H), 8.17 (s, 1H), 7.94 (d, J=2.7Hz, 1H), 7.72 (s, 1H), 7.58 (s, 1H), 7.46 (d, J=7.6Hz, 2H), 7.35 (t, J= 8.1Hz,1H),7.31(s,1H),6.88(dd,J₁=8.1Hz, J₂=1.7Hz, 1H), 6.45 (dd, J₁=17.0Hz, J₂= 10.2Hz,1H),6.23(dd,J₁=17.0Hz, J₂=1.7Hz, 1H), 5.74 (dd, J₁=10.2Hz, J₂=1.7Hz, 1H), 5.56(s,2H),3.75(s,3H),2.43(s,3H)。

Embodiment 26

N- (3- ((7- (1- ((4- aminopyrimidine -2- bases) methyl) -3- methyl isophthalic acid H- pyrazoles -4- bases) -5H- pyrrolo-es [2, 3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide

Step 1：Compound 2- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) -1H- pyrroles Azoles -1- bases) methyl) pyrimidine -4- amine synthesis

2- chlorine is added in DMF (40mL) solution of 3- methylpyrazoles -4- boric acid pinacols ester (1.01g, 4.85mmol) Methyl -4- amidino-pyridines (1.1g, 7.7mmol), Cs₂CO₃(5.5g, 17mmol) and KI (0.4g, 2mmol), then at 70 DEG C Lower reaction is overnight.Reaction solution is concentrated under reduced pressure to remove DMF, adds water (40mL), and dichloromethane (50mL × 3) extraction, organic phase is used Anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)=20/ 1) 0.48g yellow solids, yield, are obtained：31%.MS(ESI,pos.ion)m/z:316.2[M+1]⁺。

Step 2：Compound N-(3- ((7- (1- ((4- aminopyrimidine -2- bases) methyl) -3- methyl isophthalic acid H- pyrazoles -4- bases) - 5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide Synthesis

By N- (3- ((the bromo- 5- of 7- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine - 2- yls) epoxide) phenyl) acrylamide (0.36g, 0.74mmol), 2- ((3- methyl -4- (4,4,5,5- tetramethyls -1,3,2- two Ring -2- the bases of oxygen boron penta) -1H- pyrazol-1-yls) methyl) pyrimidine -4- amine (0.35g, 1.1mmol), Pd (dppf) Cl₂(0.06g, 0.08mmol) and K₂CO₃Isosorbide-5-Nitrae-dioxane (20mL) and water (5mL) are added after (.15g, 1.1mmol) mixing, nitrogen is then replaced Gas, reacts overnight at being heated to 115 DEG C.Water (20mL) is added after reaction solution cooling, dichloromethane (30mL × 3) extraction is organic Mutually use anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/MeOH(v/v) =20/1), obtain 0.39g yellow oils, yield：89%.

MS-ESI:(ESI,pos.ion)m/z:598.5[M+1]⁺。

Step 3：Compound N-(3- ((7- (1- ((4- aminopyrimidine -2- bases) methyl) -3- methyl isophthalic acid H- pyrazoles -4- bases) - 5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide synthesis

By N- (3- ((7- (1- ((4- aminopyrimidine -2- bases) methyl) -3- methyl isophthalic acid H- pyrazoles -4- bases) -5- ((2- (three Methyl-monosilane base) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.39g, 0.65mmol) it is dissolved in dichloromethane (15mL), is subsequently adding TFA (5mL), at room temperature stirring reaction 8h.Reaction solution decompression is dense THF (15mL) and TEA (3mL) is added after contracting, reaction is then stirred at room temperature again overnight.Reaction solution is concentrated under reduced pressure, is removed Saturated sodium bicarbonate aqueous solution (20mL), dichloromethane extraction (30mL × 3), saturated common salt is added to wash (20mL) after solvent, Anhydrous sodium sulfate drying, concentration, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/MeOH(v/v) =20/1), then through HPLC preparative separations, obtain 0.01g yellow solids, yield：3.2%.

MS-ESI:(ESI,pos.ion)m/z:468.3[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.17(s,1H),10.22(s,1H),8.17(s,1H),7.96 (d, J=5.9Hz, 1H), 7.92 (d, J=2.7Hz, 1H), 7.64 (s, 1H), 7.57 (s, 1H), 7.42 (d, J=8.1Hz, 1H), 7.35 (t, J=8.1Hz, 1H), 6.90 (dd, J₁=8.1Hz, J₂=1.6Hz, 2H), 6.87 (s, 1H), 6.42-6.36 (m, 1H), 6.29 (d, J=5.8Hz, 1H), 6.22 (dd, J₁=17.0Hz, J₂=1.7Hz, 1H), 5.74 (dd, J₁= 10.2Hz,J₂=1.6Hz, 1H), 5.15 (s, 2H), 2.31 (s, 3H).

Embodiment 27

N- (3- ((7- (3- methyl isophthalic acids-((5- methylpyrimidine -2- bases) methyl) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2, 3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide

Step 1：Compound 5- methyl-the 2- ((3- methyl -4- (ring -2- of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta Base) -1H- pyrazol-1-yls) methyl) and pyrimidine synthesis

3- methyl -4- pyrazoles pinacol borate (1.50g, 7.2mmol) is dissolved in DMF (15mL), is then added successively Enter 2- (chloromethyl) -5- methylpyrimidines (1.5g, 11mmol), Cs₂CO₃(8.2g, 25mmol) and KI (0.6g, 3.6mmol).Then nitrogen is replaced, under nitrogen protection, 70 DEG C is heated to, 15h is reacted.Stop heating, reaction solution is cooled to room Temperature.Diatomite is filtered, and is concentrated under reduced pressure, and filtrate removes DMF, adds water (60mL), dichloromethane (30mL × 3) extraction, organic phase Use anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：PE/EtOAc (v/v)=1/ 1) 943mg pale yellow oils product (containing isomer), are obtained, is purified through preparative separation, obtain the faint yellow oil of 645mg Shape thing, yield：28%.

MS(ESI,pos.ion)m/z:315.1[M+1]⁺。

Step 2：Compound N-(3- ((7- (3- methyl isophthalic acids-((5- methylpyrimidine -2- bases) methyl) -1H- pyrazoles -4- bases) - 5- ((2- (TMS) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide Synthesis

By compound 5- methyl -2- ((3- methyl -4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) - 1H- pyrazol-1-yls) methyl) pyrimidine (0.385g, 1.2mmol), N- (3- ((the bromo- 5- of 7- ((2- (TMS) ethoxies Base) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.40g, 0.82mmol), Pd (dppf)Cl₂(0.06g, 0.08mmol) and K₂CO₃(0.17g, 1.23mmol) mixing after add 1,4- dioxane (16mL) and Water (4mL), then replaces nitrogen, and 12h is reacted at being heated to 105 DEG C.Water (30mL), dichloromethane are added after reaction solution cooling (30mL × 3) extract, organic phase anhydrous Na₂SO₄Dry, the crude on silica gel column chromatographic isolation and purification (drip washing after concentration Agent：CH₂Cl₂/ MeOH (v/v)=40/1), obtain 0.32g crocus dopes, yield：65.6%.

MS-ESI:(ESI,pos.ion)m/z:597.2[M+1]⁺。

Step 3：Compound N-(3- ((7- (3- methyl isophthalic acids-((5- methylpyrimidine -2- bases) methyl) -1H- pyrazoles -4- bases) - 5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) and acrylamide synthesis

N- (3- ((7- (3- methyl isophthalic acids-((5- methylpyrimidine -2- bases) methyl) -1H- pyrazoles -4- bases) -5- ((2- (front threes Base silane base) ethyoxyl) methyl) -5H- pyrrolo-es [2,3-b] pyrazine -2- bases) epoxide) phenyl) acrylamide (0.30g, 0.50mmol) it is dissolved in dichloromethane (10mL), is subsequently adding TFA (5mL), at room temperature stirring reaction 12h.Reaction solution decompression is dense THF (10mL) and TEA (5mL) is added after contracting, reaction 12h is then stirred at room temperature again.Reaction solution is concentrated under reduced pressure, is removed molten Saturated sodium bicarbonate aqueous solution (30mL), dichloromethane extraction (30mL × 3), saturated common salt washing (30mL), nothing are added after agent Aqueous sodium persulfate is dried, the crude on silica gel column chromatographic isolation and purification (eluent after concentration：CH₂Cl₂/ MeOH (v/v)=10/ 1) 0.04g faint yellow solids, yield, are obtained：17.6%.

MS-ESI:(ESI,pos.ion)m/z:467.1[M+1]⁺；

¹H NMR(600MHz,DMSO-d₆):δ(ppm)12.17(s,1H),10.21(s,1H),8.57(s,2H),8.15 (s, 1H), 8.12 (s, 1H), 7.92 (d, J=2.7Hz, 1H), 7.60 (s, 1H), 7.40 (d, J=8.1Hz, 1H), 7.33 (t, J =8.1Hz, 1H), 6.88 (dd, J₁=8.0Hz, J₂=1.6Hz, 1H), 6.36 (dd, J₁=16.9Hz, J₂=10.2Hz, 1H), 6.19(dd,J₁=17.0Hz, J₂=1.6Hz, 1H), 5.71 (dd, J₁=10.2Hz, J₂=1.6Hz, 1H), 5.35 (s, 2H), 2.25 (d, J=10.3Hz, 6H).

By the similar synthetic method of the embodiment of the present invention, and the synthetic method described in the present invention, suitably may be used Initiation material is selected, the compound shown in table 1 is prepared：

The title and characterize data of the compound of table 1

BA

Biological Examples 1JAK1/2/3 external activity test methods

1. using Caliper Mobility Shift Assay detection compounds to JAK1/2/3 enzyme inhibitions.

2. 1 times of kinase reaction liquid is prepared：JAK1：25mM HEPES,pH 7.5；0.001%Brij-35；0.01% Triton；0.5mM EGTA；10mM MgCl₂；JAK2/3：50mM HEPES,pH 7.5；0.0015%Brij-35；10mM MgCl₂；2mM DTT.

3. reaction terminating liquid is prepared：100mM HEPES,pH 7.5；0.0015%Brij-35；0.2%Coating Reagent#3 (Caliper, article No. 760050)；50mM EDTA.

4. enzyme prepares (JAK1/2/3)：Enzyme solutions are prepared with 1 times of kinase reaction liquid, enzyme prepares final concentration of JAK1 (30nM), JAK2 (2nM), JAK 3 (4nM).

5. substrate is prepared：Substrate solution is prepared with 1 times of kinase reaction liquid, substrate prepares final concentration and is shown in Table 2.

The substrate of table 2 prepares final concentration

According to experimental technique optimum results, experiment using 384 orifice plates (Corning, Cat.No.3573, Lot.No.12608008) detected, JAK1/2/3 enzyme concentrations are formulated as JAK1 (75nM), JAK2 (5nM), JAK 3 (10nM), reacts final concentration of JAK1 (30nM), JAK2 (2nM), JAK3 (4nM)；Substrate Peptide FAM-P22 concentration is prepared It is 7.5 μM, reacts final concentration of 3 μM；ATP compound concentrations are JAK1 (225 μM), JAK2 (50 μM), JAK3 (15.5 μM), reaction Final concentration of JAK1 (90 μM), JAK2 (20 μM), JAK3 (6.2 μM)；Peptide D (sequence 5-FAM-C6- KKHTDDGYMPMSPGVA-NH2) concentration is formulated as 7.5 μM, reacts final concentration of 3 μM；Enzyme and substrate are anti-using 1 times of kinases Liquid is answered to prepare.Reaction system is as shown in table 3.

The compounds of this invention of table 3 is to JAK1/2/3 enzymes IC₅₀Detection architecture

Detected using 384 orifice plates, Setup Experiments test sample sample wells, Positive control wells, negative control hole, each sample Compound is detected under 8 concentration to the inhibitory action of JAK1/2/3 enzymes using duplicate hole, by the use of enzyme and substrate reactions hole as sun Property control, without enzyme hole (kinase reaction liquid) as negative control.After the order addition of table 3 respective sample, buffer solution and enzyme are pressed in each hole, 25 DEG C of (RT) insulating boxs are incubated 10min, configured good Peptide solution are then added per hole, and incubate in 28 DEG C of constant temperature Educate 60min, after adding reaction terminating liquid, excited in FP485nM using Caliper EZ Reader/525nM transmitted wave strong points enter Row detection, reading data are conversion ratio.Using the softwares of Graph Pad Prism 5 under compound various concentrations to JAK1/2/3 Enzyme inhibition is mapped, and calculates IC₅₀, experimental result is shown in Table 4.

Suppression data of the compound of 4 embodiment of the present invention of table 1 to JAK1/2/3 enzymes

The data display of table 4, the embodiment of the present invention 1 has stronger inhibitory action to JAK3 kinases, embodies good to JAK3 Good selectivity.Embodiment 1 is the Typical Representative of the compounds of this invention, and other compounds of the invention also have good to JAK3 Selectivity.

Biological Examples 2BTK and EGFR^T790MExternal activity test method

1.1 × kinase buffer liquid and termination test buffer are prepared

(1) 1 × kinase buffer liquid (50mM HEPES, pH 7.5,0.01%Brij-35,10mM MgCl₂,2mM DTT)； (2) terminate test buffer (100mM HEPES, pH 7.5,0.015%Brij-35,0.2%Coating Reagent#3, 50mM EDTA)。

2. the compound of test kinase prepares：Compound serial dilution

(1) using 100%DMSO by 50 times of diluted chemical compound to highest final concentration, by the compound of the 100 μ L concentration Solution is transferred to a hole of 96 orifice plates；If compound starts test in 10000nM, 500 μM of compounds are prepared in this step DMSO solution；(2) by 4 times of compound serial dilution, totally 10 concentration gradients；(3) 100 μ L 100%DMSO solution are added To in two emptying apertures, compareed as without compound control and without enzyme, it is source plate to mark this plate；(4) intermediate plate is prepared：Respectively Each concentration compounds of 10 μ L are transferred to intermediate plate from source plate, and add 90 μ 1 × kinase buffer liquids of L, vibration is mixed 10min。

3. preparing experiment plate

Corresponding aperture transferase 45 μ L compound solutions are in corresponding 384 orifice plate from the intermediate plate of 96 orifice plates；For example, 96 holes A1 in plate is transferred to the A1 and A2 of 384 orifice plates, and the A2 in 96 orifice plates is transferred to the A3 and A4 of 384 orifice plates, by that analogy.

4. kinase reaction

(1) 2.5 × enzyme solutions are prepared：By in enzyme 1 × kinase buffer liquid of addition；(2) 2.5 × peptide solution is prepared：By fluorescence Element mark peptide and ATP are added in 1 × kinase buffer liquid；Contain the change that 5 μ L DMSO contents are 10% in (3) 384 hole brassboards Polymer solution；(4) 10 μ 2.5 × enzyme solutions of L are added to 384 holes containing the compound solution that 5 μ L DMSO contents are 10% In brassboard；(5) it is incubated at room temperature 10min；(6) by 10 μ L2.5 × peptide solution 384 hole brassboards of addition；(7) kinase reaction and Terminate：28 DEG C are incubated 1 hour, add 25 μ L stop buffer terminating reactions.5. DATA REASONING

Read data and collect.

6. curve matching

(1) data of copy and converted measurement；

(2) inhibiting rate is converted to：

Inhibiting rate=(maximum-sample value)/(maximum-minimum value) * 100；

Wherein " maximum " is DMSO control values；" minimum value " is without kinase control hole count value.

(3) enter data into corresponding analysis software Xlfit and draw IC₅₀Value, experimental result is shown in Table 5 and table 6.

Suppression data of the section Example compound of the present invention of table 5 to BTK enzymes

Embodiment	BTK IC50(nM)	Embodiment	BTK IC50(nM)	Embodiment	BTK IC50(nM)
						Embodiment 1	37.54	Embodiment 11	52.29	Embodiment 16	36.41
Embodiment 2	14.63	Embodiment 12	5.77	Embodiment 17	14.77
						Embodiment 3	13.63	Embodiment 13	13.80	Embodiment 18	60.23
Embodiment 4	11.53	Embodiment 14	2.78	Embodiment 19	10.97
						Embodiment 9	42.35	Embodiment 15	20.78	Embodiment 22	14.37

The data display of table 5, section Example compound of the present invention has stronger inhibitory action to BTK.Embodiment in table 5 Compound is the Typical Representative of the compounds of this invention, and other compounds of the invention also have stronger inhibitory action to BTK.

The compound of 6 embodiment of the present invention of table 1 is to EGFR^T790MSuppression data

Embodiment	EGFRT790M IC50(nM)
		Embodiment 1	10

The data display of table 6, the embodiment of the present invention 1 is to EGFR^T790MKinases has stronger inhibitory action.Embodiment 1 is this The Typical Representative of invention compound, other compounds of the invention are to EGFR^T790MKinases also has stronger inhibitory action.

PK researchs in the test compound rat body of biological Examples 3

Gavage gives 5mg/kg to male SD rat or hind leg peduncular veins injects the test compound of 1mg/kg by oral administration.Administration Temporally point (0.083,0.25,0.5,1,2,5,7 and 24h) tail vein blood afterwards, blood sampling volume was 200~400 μ L/ time points, It is collected in plus K₂In the anticoagulant tube of EDTA.In 60min, 12000rpm, is centrifuged 2min, separated plasma, and store to sample by 4 DEG C It is to be measured in -80 DEG C.After plasma sample is through liquid-liquid extraction, on triple quadrupole bar tandem mass spectrometer, with multiple reaction ion monitoring (MRM) mode carries out quantitative analysis.Using WinNonlin6.3 softwares, non-compartment model method calculates pharmacokinetic parameters.

PK parameter of the compound of 7 embodiment of the present invention of table 2 in rat body

Conclusion：As shown in Table 7, removing speed of the compound of the embodiment of the present invention 2 in rat body is slower, intravenous and oral The long half time of administration, bioavilability is high.

Claims (10)

1. a kind of compound, it is the stereoisomer of the compound as shown in formula (III) or compound shown in formula (III), several What isomers, dynamic isomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and pharmaceutically acceptable Salt or prodrug：

Wherein：

L¹It is-O- ,-N (R^1a)-,-S (=O)_p- ,-C (=O)-,-C (=O)-N (R^1a)-,-S (=O)_p-N(R^1a)-,- (CR^mR^w)_g- or-(CR^mR^w)_n-CR^1a=CR^1a-(CR^mR^w)_n-；

L²It is a key ,-O- ,-N (R^1a)-,-CH₂-N(R^1a)-,-CH (CH₃)-N(R^1a)-,-C (CH₃)₂-N(R^1a)-,-C (= O)-N(R^1a)-or-S (=O)_p-N(R^1a)-；

Each R^1aIt independently is hydrogen, deuterium, C_1-3Alkyl, C_2-4Alkenyl or C_2-4Alkynyl；

Cy is C_3-6Cycloalkyl, C_3-6Cycloalkenyl group, C_2-6Heterocyclic radical, C_6-10Aryl or C_1-6Heteroaryl；Cy individually optionally by one or Multiple R^yReplaced；

Each R^yIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkylamino, C_1-6Alkylamino C_1-6Alkylamino or halo C_1-6Alkyl；

R²It is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, C_1-3Alkyl, C_2-4Alkenyl or C_2-4Alkynyl；

Each R³And R⁴It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, carboxyl ,-(CR^mR^w)_n-NR^m1R^w1, C_1-3Alkyl, halo C_1-3Alkyl or C_2-10Heterocyclic radical C_1-3Alkyl；

Each R^mAnd R^wIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C_1-4Alkyl, the C of cyano group substitution_1-4Alkyl, halo C_1-3Alkyl, C_1-3Alkoxy C_1-4Alkyl, C_3-6Cycloalkyl, C_2-10Heterocyclic radical or C_2-10Heterocyclic radical C_1-3Alkyl；

Each R^m1And R^w1It independently is hydrogen, C_1-4Alkyl, the C of cyano group substitution_1-4Alkyl, halo C_1-3Alkyl, C_1-3Alkoxy C_1-4Alkane Base, C_3-6Cycloalkyl, C_2-10Heterocyclic radical or C_2-10Heterocyclic radical C_1-3Alkyl；Or R^m1、R^w1With the N atoms being attached thereto formed together by 3-12 former molecular heterocycle；

Each W¹And W²It independently is N or CR^5y；

Each R^5xAnd R^5yIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, C_1-6Alkyl, C_2-8Alkene Base, C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkylamino, C_1-6Alkane ammonia Base, C_1-6Alkylamino C_1-6Alkyl, C_1-6Alkylamino C_1-6Alkylamino, C_1-6Alkylthio group, halo C_1-6Alkyl, halo C_1-6Alkoxy, hydroxyl The C of base substitution_1-6Alkyl, the C of hydroxyl substitution_1-6Alkylamino, the C of cyano group substitution_1-6Alkyl, the C of cyano group substitution_1-6Alkoxy, cyanogen The C of base substitution_1-6Alkylamino or the C of amino substitution_1-6Alkyl；Each R^5xAnd R^5yIndividually optionally by one or more R¹³Replaced；

R^5aIt is heteroaryl alkyl or Heteroarylcycloalkyl；R^5aIndividually optionally by one or more R¹⁴, R^14xOr R^14yReplaced；

Each n independently is 0,1,2,3 or 4；

G is 1,2,3 or 4；

Each p independently is 0,1 or 2；

Each R¹³, R¹⁴, R^14xAnd R^14yIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), C_1-6Alkyl, C_1-6Alkoxy, C_1-6Alkoxy C_1-6Alkyl, C_1-6Alkyl-C (=O)-, the C of cyano group substitution_1-6Alkyl-C (=O)-, C_1-6Alkylamino, halo C_1-6Alkyl, the C of hydroxyl substitution_1-6Alkyl or the C of cyano group substitution_1-6Alkyl；

Work as R^14xAnd R^14yIt is connected to when on same carbon atom, R^14xAnd R^14y3-8 original is optionally formed together with carbon atom Molecular ring.

2. compound according to claim 1, wherein Cy is cyclobutyl, cyclobutane base, cyclopenta, cyclopentenyl, hexamethylene Base, cyclohexenyl group, phenyl, indenyl, naphthyl, furyl, pyrrole radicals, thienyl, imidazole radicals, pyrazolyl, triazolyl, tetrazole radical, Pentazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, pyrimidine radicals, pyrazine Base, pyridazinyl or triazine radical；Or each Cy independently is following subformula：

Cy is individually optionally by one or more R^yReplaced；

Each R^yIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, C_1-3Alkyl, C_1-3Alkoxy, C_1-3Alkylamino, C_1-3Alkylamino C_1-4Alkylamino or halo C_1-3Alkyl.

3. compound according to claim 1, it is the vertical of the compound as shown in formula (V) or compound shown in formula (V) Body isomers, geometric isomer, dynamic isomer, raceme, nitrogen oxides, hydrate, solvate, metabolite and medicine Acceptable salt or prodrug on：

Wherein：

L¹It is-O- ,-S- or-(CH₂)-。

4. the compound according to claim 1 or 3, wherein R^5aIt is C_1-9Heteroaryl C_1-6Alkyl or C_1-9Heteroaryl C_3-8Cycloalkanes Base；Each R^5aIndividually optionally by one or more R¹⁴, R^14xOr R^14yReplaced.

5. compound according to claim 4, wherein R^5aIt is pyridylmethyl, pyridyl-ethyl group, Pyrimidylmethyl, pyrimidine Base ethyl, pyrazinyl-methyl, pyrazinyl ethyl, pyridazinylmethyl, pyridazinyl ethyl, triazine ylmethyl, triazine radical ethyl, imidazoles Ylmethyl, imidazolylethyl, pyrazolmethyl, pyrazolylethyl, pyridyl ring propyl group, pyrimidine-ring propyl group, benzothiazolylmethyl, Thiazolylethyl or thiazolyl propyl group；Each R^5aIndividually optionally by one or more R¹⁴, R^14xOr R^14yReplaced.

6. the compound according to claim 1 or 3, wherein each R^5xAnd R^5yIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyanogen Base, hydroxyl, nitro, amino, carboxyl, C_1-5Alkyl, C_2-6Alkenyl, C_1-4Alkoxy, C_1-4Alkoxy C_1-4Alkyl, C_1-4Alkoxy C_1-4Alkoxy, C_1-3Alkoxy C_1-4Alkylamino, C_1-4Alkylamino, C_1-3Alkylamino C_1-3Alkyl, C_1-4Alkylamino C_1-4Alkylamino, C_1-4Alkylthio group, halo C_1-4Alkyl, halo C_1-4Alkoxy, the C of hydroxyl substitution_1-4Alkyl, the C of hydroxyl substitution_1-4Alkylamino, cyanogen The C of base substitution_1-4Alkyl, the C of cyano group substitution_1-4Alkoxy, the C of cyano group substitution_1-4Alkylamino or the C of amino substitution_1-4Alkyl；Respectively R^5xAnd R^5yIndividually optionally by one or more R¹³Replaced；

Each R¹³, R¹⁴, R^14xAnd R^14yIt independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, oxo (=O), C_1-4Alkyl, C_1-3Alkoxy, C_1-3Alkoxy C_1-4Alkyl, C_1-3Alkyl-C (=O)-, the C of cyano group substitution_1-3Alkyl-C (=O)-, C_1-3Alkylamino, halo C_1-3Alkyl, the C of hydroxyl substitution_1-3Alkyl or the C of cyano group substitution_1-3Alkyl；

Work as R^14xAnd R^14yIt is connected to when on same carbon atom, R^14xAnd R^14y3-6 original is optionally formed together with carbon atom Molecular ring.

7. compound according to claim 1, it is compound with one of following structure or with one of following knot The stereoisomer of structure compound, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, Pharmaceutically acceptable salt or prodrug：

8. a kind of pharmaceutical composition, comprising the compound described in claim 1-7 any one, it is further comprising pharmaceutically may be used At least one in the carrier of receiving, excipient, diluent, assistant agent or medium；Or/and

Its further include additional therapeutic agent, wherein, the additional therapeutic agent be selected from chemotherapeutics or antiproliferative, anti-inflammatory agent, Immunomodulator or immunodepressant, neurotrophic factor, the activating agent for treating angiocardiopathy, for treating diabetes Activating agent and the activating agent for treating autoimmune disease.

9. the pharmaceutical composition described in the compound or claim 8 described in claim 1-7 any one is in medicine is prepared Purposes, wherein the medicine be used for prevent, treat or mitigate autologous patient immunological diseases or proliferative diseases；

Wherein, the autoimmune disease is lupus, multiple sclerosis, muscle contracting lateral sclerosis, rheumatoid arthritis, silver Bits disease, type i diabetes, because of complication caused by organ transplant, foreign matter is transplanted, diabetes, cancer, asthma, atopic dermatitis, from Body autoimmune thyroid disease, ulcerative colitis, Crohn disease, Alzheimer disease, leukaemia or lymthoma；

The proliferative diseases are metastatic carcinoma, colon cancer, sdenocarcinoma of stomach, carcinoma of urinary bladder, breast cancer, kidney, liver cancer, lung cancer, thyroid gland Cancer, head and neck cancer, prostate cancer, cancer of pancreas, the cancer of central nervous system, glioblastoma, myeloproliferative disease, Atherosclerosis Change or pulmonary fibrosis.

10. the pharmaceutical composition described in the compound or claim 8 described in claim 1-7 any one is being prepared for pressing down Purposes in the medicine of system or regulatory protein kinase activity；Wherein, the protein kinase be BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4, EGFR or EGFR T790M.