CN110256446A - Cyclopenta [4,5] Pyrrolopyrazine -1- ketone derivatives and its application that benzheterocycle replaces - Google Patents

Abstract

Cyclopenta [4,5] Pyrrolopyrazine -1- ketone derivatives, its preparation method and the purposes pharmaceutically replaced the present invention relates to benzheterocycle.Specifically, the invention discloses formula (I) compound or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, and its preparation method and application, the definition of each group is detailed in specification and claims in formula.

Description

Benzheterocycle replace cyclopenta [4,5] Pyrrolopyrazine -1- ketone derivatives and It is applied

Technical field

The invention belongs to pharmaceutical technology fields.Specifically, the present invention is more particularly directed to the rings penta 2 that a kind of benzheterocycle replaces Alkene simultaneously [4,5] Pyrrolopyrazine -1- ketone derivatives and preparation method thereof and the application as BTK inhibitor, and by its preparation Pharmaceutical composition.

Background technique

BTK kinases is the non-receptor tyrosine kinases of one of TEC kinase families, is the key that BCR signal path is adjusted The factor, proliferation mature for B cell, survival play an important role.BTK has excessive table in a variety of B cell lymphomas It reaches, is the unique target spot of the effective drug development Jing Guo clinical verification in current TEC kinase families.BTK is inhibited to be able to suppress A series of proliferation of B cell lymphomas.

The activation of B cell antigen receptor (BCR) signal path is to induction and maintains B cell malignant tumour and auto-immune disease It plays an important role.Bruton's tyrosine kinase (Btk) plays key effect in hematopoietic cell BCR signal path, is lymph Very good target spot in the research of tumor new treatment.BTK inhibitor acts on BCR access, inhibits Btk autophosphorylation, Btk's physiology The phosphorylation of substrate PLC γ phosphorylation and downstream kinase ERK.

BTK inhibitor acts on chronic lymphocytic leukemia (CLL) cell, and inducing cytotoxic inhibits CLL cell to increase Grow ability.Inhibit the primary B cell proliferation of BCR activation, and inhibits TNF α in primary monocyte, the secretion such as IL-1 β and IL-6. BTK inhibitor acts on Collagen-Induced Arthritis model, by inhibiting B cell activity, significantly reduces foot swelling and joint hair The clinical arthritis symptom such as inflammation.

Only having the granted listing of unique BTK inhibitor ibrutinib at present, it is therefore necessary to the more activity of exploitation are more preferable, More safely and effectively BTK inhibitor.

Summary of the invention

The object of the present invention is to provide the compounds that can be used as Btk inhibitor of a kind of structure novel.

First aspect present invention provides a kind of formula (I) compound represented or its pharmaceutically acceptable salt, solid are different Structure body, solvate or prodrug:

In formula,

A ring is C_6-10The unsaturated single heterocycle of aryl rings (preferably phenyl), 5 to 6 unit monocycle heteroaryl rings or 4 to 6 yuan；

R₀For hydrogen, halogen (preferably fluorine, chlorine, bromine), C_1-8Alkyl (preferably C_1-6Alkyl, more preferably C_1-3Alkyl), it is halogenated C_1-8Alkyl (preferably halogenated C_1-6Alkyl, more preferably halogenated C_1-3Alkyl), C_1-8Alkoxy (preferably C_1-6Alkoxy, it is more excellent It is selected as C_1-3Alkoxy), halogenated C_1-8Alkoxy (preferably halogenated C_1-6Alkoxy, more preferably halogenated C_1-3Alkoxy), optionally Substituted C_3-8Naphthenic base (preferably C_3-6Naphthenic base), C_3-8Cycloalkyloxy (preferably C_3-6Cycloalkyloxy), 5 to 6 unit monocycles it is miscellaneous Aryl or-Y-L；Wherein Y is a key ,-(CH₂)_m-、-O-(CH₂)_mOr C (O)；L is the C of hydroxyl, cyano substitution_1-3Alkyl, The C optionally replaced_6-10Aryl, 5 to the 6 unit monocycle heteroaryls optionally replaced, 4 to the 6 yuan of saturations optionally replaced single heterocycle, C_1-8 Alkoxy (preferably C_1-6Alkoxy, more preferably C_1-3Alkoxy) or NR_a0R_b0；It is described it is optional substitution refer to it is unsubstituted or By 1,2 or 3 hydroxyl, halogen, C_1-10Alkyl (preferably C_1-6Alkyl, more preferably C_1-3Alkyl), hydroxyl replace C_1-10Alkyl (the preferably C of hydroxyl substitution_1-6The C that alkyl, more preferably hydroxyl replace_1-3Alkyl), halogenated C_1-8Alkyl (preferably halogenated C_1-6 Alkyl, more preferably halogenated C_1-3Alkyl, most preferably fluoro C_1-3Alkyl), replaced the single heterocycles of 4 to 6 yuan of saturations；

N, m is each independently 1,2 or 3；It should be noted that n and m are the numbers of substituent group on finger ring A, it will be appreciated that , work as R₀Being for hydrogen can be without containing substituent group on finger ring A, and the number of hydrogen atom is not suitable for the definition of n and m at this time, such as: When ring A is phenyl ring, R₀For hydrogen, it is thus understood that contain 5 hydrogen on phenyl ring.

Z is O or NR_a；

R₁For halogen, C_1-10Alkyl (preferably C_1-6Alkyl, more preferably C_1-3Alkyl) or NR_a0R_b0；

R_a、R_a0、R_b0It is each independently hydrogen or C_1-8Alkyl (preferably C_1-6Alkyl, more preferably C_1-3Alkyl)；

R₂、R₃、R₄、R₅It is each independently hydrogen, halogen (preferably fluorine, chlorine, bromine), C_1-8Alkyl (preferably C_1-6Alkyl, more Preferably C_1-3Alkyl), halogenated C_1-8Alkyl (preferably halogenated C_1-6Alkyl, more preferably halogenated C_1-3Alkyl), C_1-8Alkoxy (preferably C_1-6Alkoxy, more preferably C_1-3Alkoxy) or C_3-8Naphthenic base (preferably C_3-6Naphthenic base)；

R₆、R₇It is each independently hydrogen or C_1-8Alkyl (preferably C_1-6Alkyl, more preferably C_1-3Alkyl).

In another preferred example, in formula (I), the single heterocycle of 4 to 6 yuan of saturations is selected from: azetidine, oxa- ring fourth It is alkane, tetrahydrofuran, thiophane, nafoxidine, piperidines, oxazolidine, piperazine, dioxolanes, dioxane, morpholine, thio Quinoline, thiomorpholine -1,1- dioxide or oxinane.

In another preferred example, in formula (I), 5 to the 6 unit monocycle heteroaryl ring is selected from: thiphene ring, N- alkane cyclopyrrole Ring, furan nucleus, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3- triazole ring, 1,2,4- triazole Ring, 1,2,5- triazole ring, 1,3,4- triazole ring, tetrazole ring, isozole ring, oxadiazoles ring, 1,2,3- oxadiazoles ring, 1,2,4- are disliked Diazole ring, 1,2,5- oxadiazoles ring, 1,3,4- oxadiazoles ring, Thiadiazole, pyridine ring, pyridazine ring, pyrimidine ring, pyridine ring.

In another preferred example, in formula (I), described 4 to 6 yuan unsaturated single heterocycles are selected from: 2,3- dihydro -1H- pyrroles, 2, 5- dihydro -1H- pyrroles, 2,5- dihydrofuran, 1,2,3,6- tetrahydropyridine, 1,2,3,4- tetrahydropyridine, 3,6- dihydro -2H- pyrrole It mutters or 3,4- dihydro -2H- pyrans.

In another preferred example, in formula (I), A ring is phenyl ring, pyrazole ring, pyrimidine ring, pyridine ring or 1,2,3,6- tetrahydro pyrroles Phenazine ring.

In another preferred example, in formula (I), n is 1 or 2.

In another preferred example, in formula (I), R₀For hydrogen, C_1-8Alkyl (preferably C_1-6Alkyl, more preferably C_1-3Alkyl) Or-Y-L；Wherein Y is a key or-(CH₂)_m-；L is the single heterocycle of 4 to 6 yuan of saturations optionally replaced；The optional substitution refers to It is unsubstituted or by 1,2 or 3 C_1-10Alkyl (preferably C_1-6Alkyl, more preferably C_1-3Alkyl) it is replaced；M is 1.

In another preferred example, in formula (I), structureFor structure selected from the group below:

In another preferred example, 5 to the 6 unit monocycle heteroaryl ring is selected from:

Above-mentioned 5 to 6 unit monocycle heteroaryl Ring is optionally by 1 or 2 R₀Replace.

In another preferred example, structureFor structure selected from the group below:

In another preferred example, in formula (I), formula (I) compound is compound selected from the group below:

Second aspect of the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes first aspect present invention institute The compound stated or its pharmaceutically acceptable salt, solvate, stereoisomer or prodrug；And pharmaceutically acceptable load Body or excipient.

Third aspect present invention provide compound described in first aspect present invention or its pharmaceutically acceptable salt, Solvate, stereoisomer or prodrug or second aspect of the present invention described pharmaceutical composition are in preparing kinase inhibitor drug Application.

In another preferred example, the kinase inhibitor is BTK inhibitor.

Fourth aspect present invention provide compound described in first aspect present invention or its pharmaceutically acceptable salt, The disease that solvate, stereoisomer or prodrug or second aspect of the present invention described pharmaceutical composition are mediated in preparation by B cell Application in the drug of disease.

Fifth aspect present invention provides a kind of method of disease treated and mediated by B cell, including gives required patient Compound described in the first aspect present invention of therapeutically effective amount or its pharmaceutically acceptable salt, solvate, alloisomerism Body or prodrug or second aspect of the present invention described pharmaceutical composition.

Sixth aspect present invention provides a kind of method of disease treated and mediated by B cell, including gives required patient Compound described in the first aspect present invention of therapeutically effective amount or its pharmaceutically acceptable salt, solvate, alloisomerism Body or prodrug, and another therapeutic active agents.

In another preferred example, it is selected from by the disease that B cell mediates: tumor disease, proliferative diseases, allergy disease Disease, autoimmune disease or diseases associated with inflammation.

In another preferred example, it is selected from by the disease that B cell mediates: solid tumor, acute lymphoblastic leukemia, chronic leaching Bar chronic myeloid leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, rheumatoid arthritis, psoriatic arthritis, bone Arthritis, systemic loupus erythematosus, psoriasis, rheumatoid and urarthritis.

It in another preferred example, is solid tumor by the disease that B cell mediates.

In another preferred example, the solid tumor is selected from lymthoma, soft tissue sarcoma, lymphocytic lymphoma, set At least one of cell lymphoma, melanoma, Huppert's disease.

It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist This no longer tires out one by one states.

Specific embodiment

The present inventor is after extensive and in-depth study, it has unexpectedly been found that the cyclopenta that this kind of benzheterocycle replaces [4,5] Pyrrolopyrazine -1- ketone derivatives are to the cells such as the enzymes such as BTK WT and pBTK Y223 inhibitory activity with higher. Therefore the series compound is expected to be developed into the drug for treating tumour.On this basis, inventor completes the present invention.

Term definition

As used herein, " alkyl " refers to the aliphatic hydrocarbyl of the saturation of straight chain and branch, C_1-8Alkyl is to include 1 to 8 carbon original The alkyl of son, is preferably C_1-6Alkyl or C_1-3Alkyl defines similar；The unrestricted example of alkyl include: methyl, ethyl, N-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propylene Base, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2,3- dimethylbutyl, n-heptyl, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- methylhexyl, 2,3- dimethyl amyl group, 2,4- dimethyl amyl group, 2,2- dimethyl-penten Base, 3,3- dimethyl amyl group, 2- ethylpentyl, 3- ethylpentyl, n-octyl, 2,3- dimethylhexanyl, 2,4- dimethylhexanyl, 2,5- dimethylhexanyl, 2,2- dimethylhexanyl, 3,3- dimethylhexanyl, 4,4- dimethylhexanyl, 2- ethylhexyl, 3- ethyl Hexyl, 4- ethylhexyl, 2- methyl -2- ethylpentyl, 2- methyl -3- ethylpentyl, n-nonyl, 2- methyl -2- ethylhexyl, 2- methyl -3- ethylhexyl, 2,2- diethyl amyl group, positive decyl, 3,3- diethylhexyl, 2,2- diethylhexyl, and its it is each Kind branched isomer etc..

As used herein, " naphthenic base " refers to the unsaturated monocycle cyclic hydrocarbon group of saturation or part, " C_3-8Naphthenic base ", which refers to, includes The cyclic hydrocarbon radical of 3 to 8 carbon atoms is preferably C_3-6Naphthenic base defines similar；The non-limiting embodiment of naphthenic base includes ring Propyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, ring are pungent Base etc., preferably cyclopropyl, cyclopenta, cyclohexenyl group.

As used herein, " C_1-8Alkoxy " refers to-O- (C_1-8Alkyl), wherein alkyl is as defined above.It is preferred that C_1-6Alkane Oxygroup, more preferable C_1-3Alkoxy.Non-limiting embodiment include methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, Tert-butoxy, isobutoxy, amoxy etc..

As used herein, " C_3-8Cycloalkyloxy " refers to-O- (C_3-8Naphthenic base), wherein naphthenic base is as defined above.It is excellent Select C_3-6Cycloalkyloxy.Non-limiting embodiment includes cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..

As used herein, " C_6-10The full carbon monocycle or fused polycycle that aryl " refers to the pi-electron system with conjugation are (namely The ring of shared adjacent carbon atoms pair) group, refer to the aryl containing 6 to 10 carbon atoms；It is preferred that phenyl and naphthalene, most preferably benzene Base.

As used herein, " key ", which refers to, is covalently keyed by two groups of its connection by one.

As used herein, " halogen " refers to fluorine, chlorine, bromine or iodine.

As used herein, " halogenated " refers to that one or more (such as 1,2,3,4 or 5) hydrogen are replaced halogen in group.

For example, " halogenated C_1-8Alkyl " refers to that alkyl is replaced by one or more (such as 1,2,3,4 or 5) halogens, wherein alkyl It is as defined above.It is selected as halogenated C_1-6Alkyl, more preferably halogenated C_1-3Alkyl.Halogenated C_1-8The example of alkyl includes (but not It is limited to) chloromethyl, dichloromethyl, trichloromethyl, a chloroethyl, 1,2- Dichloroethyl, trichloroethyl, a bromoethyl, a fluorine Methyl, difluoromethyl, trifluoromethyl, a fluoro ethyl, bis-fluoro ethyls, trifluoroethyl etc..

In another example " halogenated C_1-8Alkoxy " refers to that alkoxy is replaced by one or more (such as 1,2,3,4 or 5) halogens, Middle alkoxy is as defined above.Preferably halogenated C_1-6Alkoxy, more preferably halogenated C_1-3Alkoxy.Halogenated C_1-8Alcoxyl The example of base include but is not limited to trifluoromethoxy, trifluoro ethoxy, a fluorine methoxyl group, a fluorine ethyoxyl, difluoro-methoxy, Difluoroethoxy etc..

In another example " halogenated C_3-8Naphthenic base " finger ring alkyl is replaced by one or more (such as 1,2,3,4 or 5) halogens, Middle naphthenic base is as defined above.Preferably halogenated C_3-6Naphthenic base.Halogenated C_3-8The example of naphthenic base includes but is not limited to Trifluoro cyclopropyl, a fluorine cyclopropyl, a fluorine cyclohexyl, difluorocyclopropyl, difiuorocyclohexyl etc..

As used herein, " amino " refers to NH₂, " cyano " refers to CN, and " nitro " refers to NO₂, " benzyl " refers to-CH₂Phenyl, " oxo Base " refers to=O, and " carboxyl " refers to that-C (O) OH, " acetyl group " refer to-C (O) CH₃, " methylol " refers to-CH₂OH, " ethoxy " refer to- CH₂CH₂OH or-CHOHCH₃, " hydroxyl " refers to-OH, and " mercaptan " refers to SH.

As used herein, " heteroaryl ring " is used interchangeably with " heteroaryl ", is referred to 5 to 10 annular atoms, preferably 5 Or 6 unit monocycle heteroaryl or 8 to 10 membered bicyclic heteroaryls；6,10 or 14 pi-electrons are shared in ring array；And outside carbon atom also With 1 to 5 heteroatomic groups." hetero atom " refers to nitrogen, oxygen or sulphur.

As used herein, " the single heterocycle of 4 to 6 yuan of saturations " refers to that 1,2 or 3 carbon atom in 4 to 6 unit monocycles is selected from Nitrogen, oxygen or S (O)_tIt replaced the hetero atom of (wherein t is integer 0 to 2), but does not include the ring portion of-O-O- ,-O-S- or-S-S- Point, remaining annular atom is carbon；It is preferred that 5 to 6 yuan.4 to 6 yuan of examples for being saturated single heterocycle include but is not limited to propylene oxide, nitrogen Azetidine, oxetanes, tetrahydrofuran, thiophane, nafoxidine, piperidines, pyrrolin, oxazolidine, piperazine, dioxy penta Ring, dioxane, morpholine, thiomorpholine, thiomorpholine -1,1- dioxide, oxinane etc..

As used herein, " unsaturation " refers to containing one or more unsaturated bonds but does not have the pi-electron of total conjugated System.

As used herein, " 4 to 6 yuan of unsaturated single heterocycles " includes but is not limited to: 2,3- dihydro -1H- pyrroles, 2,5- bis- Hydrogen -1H- pyrroles, 2,5- dihydrofuran, 1,2,3,6- tetrahydropyridine, 1,2,3,4- tetrahydropyridine, 3,6- dihydro -2H- pyrans, 3, 4- dihydro -2H- pyrans etc..

As used herein, " 5 to 6 unit monocycle heteroaryl ring " refers to single heteroaryl ring containing 5 to 6 annular atoms, such as wraps It includes (but being not limited to): thiphene ring, N- alkane cyclopyrrole ring, furan nucleus, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, three Azoles ring, 1,2,4- triazole ring, 1,2,5- triazole ring, 1,3,4- triazole ring, tetrazole ring, isozole ring, dislikes two at 1,2,3- triazole ring Azoles ring, 1,2,3- oxadiazoles ring, 1,2,4- oxadiazoles ring, 1,2,5- oxadiazoles ring, 1,3,4- oxadiazoles ring, Thiadiazole, pyrrole Phenazine ring, pyridazine ring, pyrimidine ring, pyridine ring etc..

As used herein, " the C that hydroxyl replaces_1-10Alkyl " refers to that one or more hydrogen on alkyl are optionally substituted by a hydroxyl group, packet Include the C of monohydroxy substitution_1-10The C that alkyl, dihydroxy replace_1-10The C that alkyl, trihydroxy replace_1-10Alkyl etc., example include but It is not limited to methylol, ethoxy, 2- hydroxy-2-methyl butyl, 2- hydroxy-butyl etc..

As used herein, " the C that cyano replaces_1-3Alkyl " refers to that one or more hydrogen on alkyl are replaced by cyano, including The C that one cyano replaces_1-3The C that alkyl, dicyano replace_1-3Alkyl etc., example include but is not limited to cyano methyl, cyano ethyl Deng.

As used herein, " substituted " refers to one or more hydrogen atoms in group, preferably 1~5 hydrogen atom each other Independently replaced by the substituent group of respective number, more preferably 1~3 hydrogen atom is independently of one another by the substituent group of respective number Replace.Self-evident, substituent group is only in their possible chemical position, and those skilled in the art can not pay excessively Possible or impossible substitution (by experiment or theory) is determined in the case where effort.For example, amino or hydroxyl with free hydrogen It may be unstable when base is in conjunction with the carbon atom with unsaturated (such as olefinic) key.

As used herein, any of the above-described group can be substituted or unsubstituted.Above-mentioned group is substituent group when replacing Preferably 1 to 5 (more preferable 1 to 3) following group, independently selected from halogen ,-O (CH₂)_pOC_1-8Alkyl ,-O (CH₂)_pOH、-(CH₂)_pOC_1-8Alkyl, 4 to 6 yuan of saturations single heterocycle, C_1-8Alkyl (preferably C_1-6Alkyl, more preferably C_1-3Alkyl), C_3-8Naphthenic base (preferably C_3-6Naphthenic base), halogenated C_1-8Alkyl (preferably halogenated C_1-6Alkyl, more preferably halogenated C_1-3Alkane Base), halogenated C_3-8Naphthenic base (preferably halogenated C_3-6Naphthenic base), hydroxyl replace C_1-8Alkyl (the preferably C of hydroxyl substitution_1-6 The C that alkyl, more preferably hydroxyl replace_1-3Alkyl), methylol, ethoxy, hydroxyl, carboxyl, NR_a0R_b0、-C(O)OC_1-6Alkyl, Acetyl group, C_1-8Alkoxy (preferably C_1-6Alkoxy, more preferably C_1-3Alkoxy), C_1-8The C that alkoxy replaces_1-8Alkyl is (excellent It is selected as C_1-6The C that alkoxy replaces_1-6Alkyl, more preferably C_1-3The C that alkoxy replaces_1-3Alkyl), halogenated C_1-8Alkoxy is (preferably For halogenated C_1-6Alkoxy, more preferably halogenated C_1-3Alkoxy) ,-SO₂C_1-8Alkyl (preferably-SO₂C_1-6Alkyl, more preferably- SO₂C_1-3Alkyl), C_6-10Aryl (preferably phenyl), 5 to 6 unit monocycle heteroaryls or-Y-L；Wherein Y is (CH₂)_qOr C (O)；L is The single heterocycle of 4 to 6 yuan of saturations or 5 to 6 unit monocycle heteroaryl rings；P, q is each independently 1,2 or 3；R_a0、R_b0It is each independently Hydrogen, acetyl group, C_1-8Alkyl (preferably C_1-6Alkyl, more preferably C_1-3Alkyl), C_1-8The C that alkoxy replaces_1-8Alkyl is (preferably For C_1-6The C that alkoxy replaces_1-6Alkyl, more preferably C_1-3The C that alkoxy replaces_1-3Alkyl).

All kinds of substituent groups discussed herein above its own be also that can be replaced by group described herein.

When the single heterocycle of 4 to 6 yuan of saturations as described herein is substituted, the position of substituent group can be in their possible chemical potentials It sets, the representative substitution situation of illustrative list heterocycle is as follows:

Wherein " Sub " is indicated herein All kinds of substituent groups；Indicate the connection with other atoms.

When the single heterocycle of 4 to 6 yuan of saturations of the present invention is substituent group, its own may be to replace or by 1,2 or 3 Replaced a substituent group selected from the group below: halogen, hydroxyl, C_1-3Alkyl, O=, NR_a0R_b0, methylol, ethoxy, carboxyl ,-C (O)OC_1-3Alkyl, acetyl group, halogenated C_1-3Alkyl, C_1-3Alkoxy, C_3-6Naphthenic base, azetidine, oxetanes, tetrahydro It is furans, thiophane, nafoxidine, piperidines, oxazolidine, piperazine, dioxolanes, dioxane, morpholine, thiomorpholine, thio Morpholine -1,1- dioxide, oxinane, thiphene ring, N- alkyl pyrrole ring, furan nucleus, thiazole ring, imidazole ring, oxazole ring, pyrrole Cough up ring, pyrazole ring, triazole ring, tetrazole ring, isozole ring, oxadiazoles ring, Thiadiazole, pyridine ring, pyridazine ring, pyrimidine ring, pyrrole Piperazine ring；Wherein R_a0、R_b0It is each independently hydrogen or C_1-3Alkyl.

As used herein, " therapeutically effective amount " refers to the biology or medicinal response that will cause individual, such as reduces or press down Enzyme or protein active processed or the present inventionization for improving symptom, alleviating illness, slowing or delaying the progression of a disease or prevent disease etc. Close the amount of object.

As used herein, " pharmaceutically acceptable carrier " refers to that nontoxic, inertia, solid-state, the substance of semisolid or liquid fill Installation, diluent, encapsulating material or auxiliary agent or any type auxiliary material, preferably mammal mutually compatible with patient, more It is preferred that being people, it is suitble to for active agent to be transported to activity of the target without terminating reagent.

As used herein, " patient " refers to a kind of animal, preferably mammal, is preferably people." lactation is dynamic for term Object " refers to homoiothermy vertebra class mammal, including such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and the mankind.

As used herein, " treatment " refers to mitigation, delay of progression, decaying, prevention, or maintains present illness or illness (example Such as cancer).Treatment further includes curing one or more symptoms of disease or illness, preventing its development or be relieved to certain journey Degree.

Preparation method

Formula (I) compound of the invention can be according to the difference of particular compound structure, referring to the example in the following example Property preparation method is easy to carry out preparation by a variety of synthetic operations, these operations are that one of ordinary skill in the art skillfully grasp 's.Reagent used in preparation process and raw material compound are commercially available to be obtained or those skilled in the art are according to designed Different compound structures be prepared with reference to known method.

Compared with prior art, main advantages of the present invention are:

Cyclopenta [4,5] Pyrrolopyrazine -1- ketone for providing a series of benzheterocycle substitution of structure novels spreads out Biology can be used as the drug for treating tumour to the cells such as the enzymes such as BTK WT and pBTK Y223 inhibitory activity with higher.

Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.Unless separately Definition, the term as used herein have the same meanings as commonly understood by one of ordinary skill in the art.In addition, any similar to described content Or same method and material all can be applied in the present invention.

As used herein, 2 DMB, 4- dimethoxy-benzyl, THF are tetrahydrofuran, and EA is ethyl acetate, and PE is petroleum Ether, Ac₂O is acetic anhydride, and NBS is N-bromosuccinimide, and DCM is methylene chloride, and AIBN is azodiisobutyronitrile, Pd (dppf)Cl₂For bis- (diphenylphosphine) ferrocene of 1,1'-] palladium chloride, TFA is trifluoroacetic acid, and TBSCl is fert-butyidimethylsilyl Chlorosilane, NCS are N- chlorosuccinimide, and DHP is dihydro oxinane, LiAlH₄For lithium aluminium hydride reduction, PMB is to methoxyl group Benzyl, LiHMDS are two (trimethyl silicon substrate) lithium amides, Pd₂(dba)₃For tris(dibenzylideneacetone) dipalladium, RuPhos is 2- bis- Cyclohexyl phosphorus -2', 6'- diisopropoxy -1,1'- biphenyl, DMAP are 4-dimethylaminopyridine, and THP is tetrahydro oxinane, n- BuLi is n-BuLi, and TMsOTf is Trimethylsilyl trifluoromethanesulfonate, and TEBAC is triethyl benzyl ammonia chloride, HATU 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, DMF is dimethylformamide, and DMSO is diformazan Base sulfoxide, DIEA are n,N-diisopropylethylamine, and BINAP is bis- diphenyl phosphine -1, the 1'- dinaphthalenes of (2R, 3S) -2,2'-.

As used herein, room temperature refers to about 20-25 DEG C.

The preparation of intermediate a

Step 1: compound a -1 (5 grams, 14.6 mMs) is dissolved in the methylene chloride of 100ml and the mixed solvent of methanol In (volume ratio 1/1), under ice baths, sodium borohydride (1.11 grams, 29.2 mMs) are added portionwise, after adding, remove ice bath, in room Under the conditions of temperature, stir 3 hours.LCMS detection, raw material convert completely.Reaction solution concentration, remaining grease ethyl acetate are dilute It releases, twice, saturated common salt washing is primary, and then anhydrous sodium sulfate dries, filters concentration, obtains colorless oil a-2 (5 for washing Gram, yield: 100%).

Step 2: compound a -2 (5 grams, 14.5 mMs) is dissolved in 100ml methylene chloride, triethylamine (4.39 grams, 43.5 mMs) it is added, then, under ice bath is cooling, the dichloromethane solution (2.26 grams, 29 mMs) of chloroacetic chloride is added dropwise, drips Add complete, reaction solution warms naturally to room temperature, is stirred overnight.Reaction solution is directly washed, and anhydrous sodium sulfate dries, filters, concentration, Remaining grease column chromatographic purifying (methylene chloride/methanol=30/1), obtain light yellow oil a-3 (5 grams, yield 89.3%).

Step 3: compound a -3 (1 gram, 2.58 mMs), duplex pinacol borate being added into 100ml round-bottomed flask (1.31 grams, 5.16 mMs), Pd (dppf) Cl₂(94 milligrams, 0.13 mM), and X-Phos (124 milligrams, 0.26 mmoles You), potassium acetate (0.76 gram, 7.74 mMs) and dioxane (35ml), under nitrogen protection, be warming up to 100 degree, it is stirred Night is cooled to room temperature, filtering and concentrating, and remaining grease is diluted with 150ml ethyl acetate, washing, saturated common salt washing, anhydrous sulphur Sour sodium is concentrated after drying, filtering, and obtains dark oil object a (yield > 100%, crude product are used directly in next step).

1 2- of embodiment (4- (3- amino -7- (5- (4- methylpiperazine-1-yl) pyridine -2- base) -1H- indazole -5- base) - 3- (hydroxymethyl) pyridine -2- base) -7,7- dimethyl -2,3,4,6,7,8- hexahydro -1H- cyclopenta [4,5] pyrrolo- The preparation of [1,2-a] pyrazine -1- ketone (Z-1)

Step 1: by Pd₂(dba)₃(229mg, 0.25mmol), Xantphos (290mg, 0.5mmol) and sodium tert-butoxide (2.88g, 30mmol) is added to the first of 2- bromo- 5- iodine pyridine (3.41g, 12mmol) and 1- methyl piperazine (1.0g, 10mmol) In benzene (50ml) solution, it is heated to 60 degrees Celsius under protection of argon gas, is stirred to react 24 hours.After reaction solution is cooled to room temperature, Filter off solid, filter cake washs with ethyl acetate, obtain crude product after filtrate decompression concentration, through Combi-flash column chromatography [DCM: MeOH=100:0~90:10] compound 1- (6- bromopyridine -3- base) -4- methyl piperazine (2.68g, 79.3%) is obtained after purification.M⁺=256.0 [M+1]⁺；

Step 2: under argon gas protection, tetrahydrofuran (20ml) solution of compound B (1.3g, 5.08mmol) is cooled to -78 Degree Celsius, n-BuLi (2.5M, 3ml, 7.62mmol) is slowly added dropwise.It is added dropwise, continues stirring and three fourths are added after ten minutes Base stannic chloride (2.48g, 7.62mmol).Reaction solution is slowly warming up to room temperature, adds potassium fluoride quenching reaction, slightly produces after reduced pressure Product obtain compound Z-1-1 (1.03g, 45%) after purification through Combi-flash column chromatography [DCM:MeOH=100:0~95:5].M⁺=468.2 [M+1]⁺；

Step 3: by the iodo- 1H- indazole -3- amine of compound Z-1-1 (348mg, 0.75mmol) and the bromo- 7- of 5- (252mg, 0.75mmol) be dissolved in 5 milliliters of dioxane, be added four triphenyl phosphorus palladiums (87mg, 0.75mmol) and potassium fluoride (130mg, 2.24mmol), under argon gas protection, it is heated to 140 degrees Celsius in microwave reactor, reacts 60 minutes.After being cooled to room temperature, instead Liquid is answered to be poured into water, ethyl acetate extracts (3*20ml), merges organic phase, is washed with 30 milliliters of saturated common salts, anhydrous sodium sulfate Dry, filter, after reduced pressure crude product, through Combi-flash column chromatography [DCM:MeOH=100:0~90:10,0.1% Et₃N] obtain compound Z-1-2 (140mg, 40.6%) after purification.M⁺=389.0 [M+1]⁺；

Step 4: compound Z-1-2 (100mg, 0.26mmol) and compound a (103mg, 0.26mmol) are dissolved in 4 millis The in the mixed solvent of acetonitrile and 2 milliliters of water is risen, PdCl is added₂(dppf) (19mg, 0.026mmol), potassium phosphate (110mg, 0.52mmol) with sodium acetate (71mg, 0.52mmol), under argon gas protection, 110 degrees Celsius of reactions are heated in microwave reactor 20 minutes.After reaction solution is cooled to room temperature, after being diluted with 30 milliliters of ethyl acetate, successively with 10 milliliters of water and 10 milliliters of saturation foods Salt washing, anhydrous sodium sulfate dry, filter, and crude product is obtained after reduced pressure, chromatograph [DCM:MeOH=through Combi-flash column 100:0~90:10,0.1%Et₃N] obtain compound Z-1-3 (140mg, 58.6%) after purification.M⁺=660.3 [M+1]⁺；

Step 5: by LiOH.H₂O (30mg, 0.71mmol) is added to compound Z-1-3 (120mg, 0.182mmol) Yu Si In the mixed solution of hydrogen furans (4ml), water (2ml) and isopropanol (2ml), stir two hours at room temperature.Reaction solution is with 30 milliliters Ethyl acetate dilution, 20 milliliters of washings, 20 milliliters of saturated common salt washings, anhydrous sodium sulfate dry, filter, are concentrated under reduced pressure slightly to produce Product obtain compound Z-1 (35mg, 26.7%) after purification through preparation liquid phase.M⁺=618.2 [M+1]⁺；¹H NMR(DMSO-d₆, 400MHz) :=11.65 (s, 1H), 8.47 (d, J=4.9Hz, 1H), 8.41 (d, J=2.9Hz, 1H), 8.06 (d, J= 1.2Hz, 1H), 7.94 (d, J=9.0Hz, 1H), 7.85 (d, J=1.2Hz, 1H), 7.45 (dd, J=9.0,2.9Hz, 1H), 7.40 (d, J=5.1Hz, 1H), 6.53 (s, 1H), 5.50 (br.s., 2H), 4.96-5.03 (m, 1H), 4.31-4.47 (m, 2H), 4.10-4.30 (m, 3H), 3.83 (d, J=7.6Hz, 1H), 3.27 (br.s., 4H), 2.51-2.60 (m, 2H), 2.49 (br.s.,4H),2.39(s,2H),2.22(s,3H),1.18ppm(br.s.,6H).

2 2- of embodiment (3- (methylol) -4- (7- (1- methyl-1 H- pyrazoles -4- base) -3- (methylamino) -1H- Yin Azoles -5- base) pyridine -2- base) -7-, 7- dimethyl 2,3,4,6,7,8- hexahydro -1H- cyclopenta [4,5] pyrrolo- [1,2- A] pyrazine -1- ketone (Z-2) preparation

The bromo- 2- fluobenzoic acid of step 1:5- (8.68 grams, 40 mMs) is dissolved in the 70ml concentrated sulfuric acid, under ice bath is cooling, Iodine (10.16 grams, 40 mMs) are added portionwise, reaction solution is stirred at room temperature 5 hours, and reaction solution is slowly poured on trash ice, Red solid is gradually precipitated, and filters, and vacuum drying obtains red solid Z-2-1 (11 grams, yield 79.7%).

Step 2: in round-bottomed flask, compound Z-2-1 (3.45 grams, 10 mMs), 25% methylamine water solution are added (4ml), EDCI (3.84 grams, 20 mMs), HOBT (2.7 grams, 20 mMs), DIPEA (3.87 grams, 30 mMs) and DMF (30ml), reaction solution is stirred overnight at room temperature, and ethyl acetate dilution, three times, saturated sodium-chloride is washed for washing, is concentrated after dry, remaining Grease column chromatographic purifying (petrol ether/ethyl acetate=4/1-2/1), obtain yellow solid Z-2-2 (2.68 grams, 7.6 mmoles You).

Step 3: compound Z-2-2 (0.5 gram, 1.4 mMs) is dissolved in toluene (15ml), and lawesson reagent is added (0.62 gram, 1.54 mMs), reaction solution are warming up to 105 degree, stir 4 hours, are cooled to room temperature, and are concentrated, residue column chromatography Purify (petrol ether/ethyl acetate=3/1), obtain yellow solid Z-2-3 (0.45 gram, yield: 86%).

Step 4: compound Z-2-3 (0.3 gram, 0.8 mM) is dissolved in DMSO (6ml), and hydrazine hydrate is added (0.5ml), reaction solution are warming up to 120 degree, stir 2 hours, are cooled to room temperature, and ethyl acetate dilution, washing three times, is saturated chlorination Sodium is washed, and is concentrated after dry, remaining grease column chromatographic purifying (petrol ether/ethyl acetate=4/1-2/1) obtains yellow solid Z- 2-4 (0.15 gram, yield 53.6%).

Step 5: compound Z-2-4 (0.15 gram, 0.43 mM), 1- methyl -4- (4,4,5,5- tetramethyls -1,3,2- Dioxaborolane -2- base) -1H- pyrazoles (104 milligrams, 0.5 mM), Pd (pddf) Cl₂(16 milligrams, 0.0215 mmoles You), potassium carbonate (115 milligrams, 0.86 mM) is blended in dioxane (15ml), under nitrogen protection, is warming up to 70 and is spent Night is cooled to room temperature, filtering, ethyl acetate dilution, washing, and saturated sodium-chloride is washed, is concentrated after dry, remaining grease column chromatography Purify (petrol ether/ethyl acetate=2/1-1/2), obtain yellow oil Z-2-5 (90 milligrams, yield: 68.7%).

Step 6: compound Z-2-5 (104 milligrams, 0.34 mM), compound a (135 milligrams, 0.34 mM), Pd (dppf) Cl2 (12 milligrams, 17 mMs), sodium acetate (56 milligrams, 0.68 mM), three water potassium phosphates (181 milligrams, 0.68 MM) and dioxane (15ml) be blended in microwave tube, under microwave condition (100 degree), stir 20 minutes, be cooled to room Temperature, ethyl acetate dilution, washing, saturated common salt washing are concentrated after dry, remaining grease with column chromatographic purifying (methylene chloride/ Methanol=30/1), obtain yellow oil Z-2-6 (146 milligrams, yield 60%).

Step 7: compound Z-2-6 (197 milligrams, 0.34 mM) is dissolved in iPA/THF/H2O=8ml/4ml/4ml In, (65 milligrams, 1.7 mMs) of Lithium hydroxide monohydrate additions are stirred at room temperature 1.5 hours, are diluted with ethyl acetate, washed, satisfied It washes, is concentrated after dry, residue is purified with HPLC, obtains light yellow solid Z-2 (8.5 milligrams) with salt.¹H NMR (400MHz,DMSO-d₆) δ 11.52 (s, 1H), 8.45 (dd, J=5.0,1.2Hz, 1H), 8.29 (d, J=5.5Hz, 1H), 7.98 (d, J=0.9Hz, 1H), 7.74-7.65 (m, 2H), 7.35 (dd, J=5.1,2.5Hz, 1H), 6.52 (s, 1H), 6.06 (d, J=5.4Hz, 1H), 4.92 (dt, J=6.0,3.4Hz, 1H), 4.38 (t, J=5.1Hz, 2H), 4.19 (m, 3H), 3.91- 3.79 (m, 4H), 2.87 (d, J=5.0Hz, 3H), 2.54 (d, J=8.2Hz, 2H), 2.39 (s, 2H), 1.19 (s, 6H)

3 2- of embodiment (4- (3- amino -7- (1- methyl-1 H- pyrazoles -4- base) benzo [d] isoxazole -5- base) -3- (hydroxyl Methyl) pyridine -2- base) -7,7- dimethyl 2,3,4,6,7,8- hexahydro -1H- cyclopenta [4,5] pyrrolo- [1,2-a] pyrrole The preparation of piperazine -1- ketone (Z-3)

Step 1: raw material acetyl group azanol (222 milligrams, 2.95 mMs) is dissolved in DMF, and t-BuOK (330 millis are added Gram, 2.95 mMs), 30 degree are warming up to, is stirred 1 hour, the fluoro- 3- iodobenzene formonitrile HCN of the bromo- 2- of 5- (800 milligrams, 2.46 mMs) It is added, reaction solution is stirred overnight, is diluted with ethyl acetate, and three times, saturated sodium-chloride is washed for washing, is concentrated after dry, and residue is used Column chromatographic purifying (petrol ether/ethyl acetate=2/1-1/1), obtain light yellow solid Z-3-1 (390 milligrams, yield: 47%).

Step 2: step 5 of the operation with reference to final product Z-2 operation in detail.

Step 3: step 6 of the operation with reference to final product Z-2 operation in detail.

Step 4: step 7 of the operation with reference to final product Z-2 operation in detail.¹H NMR(400MHz,DMSO-d₆)δ8.53(d,J =5.0Hz, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 7.98 (d, J=1.7Hz, 1H), 7.79 (d, J=1.6Hz, 1H), 7.40 (d, J=5.0Hz, 1H), 6.57-6.52 (m, 3H), 4.94 (t, J=5.2Hz, 1H), 4.39 (d, J=5.2Hz, 2H), 4.30-4.20 (m, 3H), 3.94 (s, 3H), 3.87 (d, J=10.4Hz, 1H), 2.58 (d, J=8.3Hz, 2H), 2.43 (s, 2H),1.22(s,6H).

4 2- of embodiment (3- (methylol) -4- (3- methyl -7- (1- methyl-1 H- pyrazoles -4- base) -1H- indazole -5- base) Pyridine -2- base) -7,7-- dimethyl -2,3,4,6,7,8- hexahydro -1H- cyclopenta [4,5] pyrrolo- [1,2-a] pyrazine - The preparation of 1- ketone (Z-4)

Step 1: iodine (2.54g, 10.0mmol) and silver sulfate (3.12g, 10.0mmol) are added to the bromo- 2- ethylo benzene of 4- In ethyl alcohol (30ml) solution of amine (2.0g, 10.0mmol), stir 3 hours at room temperature.It is filtered to remove solid, after filtrate concentration It is dissolved in 50 milliliters of methylene chloride, is successively washed with sodium hydrate aqueous solution (1N, 30ml), saturated common salt washes (30ml), anhydrous Sodium sulphate dries, filters, filtrate concentration, obtains crude product after filtrate decompression concentration, chromatographs [PE:EA=through Combi-flash column 100:0~95:5] the bromo- 2- ethyl -6- Iodoaniline of compound 4- (1.97g, 60.4%) is obtained after purification.M⁺=328.0 [M+1]⁺；¹H NMR (400MHz, DMSO-d6) 7.53 (d, J=2.4Hz, 1H), 7.08 (d, J=2.4Hz, 1H), 5.02 (S, 2H), 2.45-2.51 (m, 2H), 1.07 (t, J=7.6Hz, 3H)

Step 2: by sodium nitrite (54mg, 0.78mmol) be added to the bromo- 2- ethyl -6- Iodoaniline of 4- (230mg, It in acetic acid (5ml) solution 0.71mmol), is stirred to react at room temperature 3 hours, reactant obtains crude product, warp after being concentrated under reduced pressure Combi-flash column chromatographs [DCM:MeOH=99:1] and obtains compound Z-4-1 (156mg, 65.5%) after purification.M⁺=328.0 [M+1]⁺；¹H NMR (400MHz, DMSO-d6) 12.98 (s, 1H), 7.96 (d, J=1.6Hz, 1H), 7.80 (d, J=1.6Hz, 1H),2.42(s,3H)

Step 3: by PdCl₂(dppf) (92mg, 0.125mmol) and potassium carbonate (345mg, 2.5mmol) are added to chemical combination Object Z-4-1 (420mg, 1.25mmol) and 1- methyl -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- base) - In 8 milliliters of dioxane of 1H- pyrazoles (260mg, 1.25mmol) and the mixed solution of 2 milliliters of water.Under 65 degrees Celsius, in nitrogen It is vigorously stirred in atmosphere 7 hours.After reaction, it filters, crude product is obtained after filtrate decompression concentration, through Combi-flash column layer It analyses [DCM:MeOH=100:0~95:5] and obtains compound Z-4-2 (250mg, 68.7%) after purification.M⁺=291.0 [M+1]⁺；

Step 4: by PdCl₂(dppf) (50mg, 0.069mmol), potassium phosphate (291mg, 1.37mmol) and sodium acetate (187mg, 1.37mmol) is added to the 5 of compound Z-4-2 (200mg, 0.68mmol) and compound a (273mg, 0.68mmol) In the mixed solution of milliliter acetonitrile and 2 milliliters of water.Under 110 degrees Celsius, 15 points are reacted in microwave reactor under nitrogen atmosphere Clock.After reaction, it filters, obtains crude product after filtrate decompression concentration, chromatograph [DCM:MeOH=100:0 through Combi-flash column ~95:5] obtain compound Z-4-3 (117mg, 30.2%) after purification.

Step 5: by LiOH.H₂O (30mg, 0.71mmol) is added to Z-4-3 (100mg, 0.177mmol) in tetrahydrofuran In the mixed solution of (4ml), water (2ml) and isopropanol (2ml), stir two hours at room temperature.30 milliliters of acetic acid second of reaction solution Ester dilution, 20 milliliters of washings, 20 milliliters of saturated common salt washings, anhydrous sodium sulfate dry, filter, crude product are concentrated under reduced pressure to obtain, passes through It prepares liquid phase and obtains compound Z-4 (50mg, 54.3%) after purification.M⁺=522.2 [M+1]⁺；¹H NMR(DMSO-d₆, 400MHz): =12.72 (br.s., 1H), 8.47 (d, J=4.9Hz, 1H), 8.35 (s, 1H), 8.03 (s, 1H), 7.76 (d, J=1.5Hz, 1H), 7.71 (d, J=1.5Hz, 1H), 7.42 (d, J=5.1Hz, 1H), 6.52 (s, 1H), 4.99 (t, J=5.0Hz, 1H), 4.35 (d, J=4.9Hz, 2H), 4.10-4.29 (m, 3H), 3.90 (s, 3H), 3.79-3.87 (m, 1H), 2.50-2.59 (m, 5H),2.40(s,2H),1.19ppm(s,6H).

5 2- of embodiment (4- (3- amino -7- (4- (morpholinomethyl) phenyl) -1H- indazole -5- base) -3- (methylol) Pyridine -2- base) -7,7- dimethyl -2,1,3,4,6,7,8- hexahydro -1H- cyclopenta [4,5] pyrrolo- [1,2-a] pyrazines - The preparation of 1- ketone (Z-5)

The fluoro- 3- iodobenzene formonitrile HCN of the bromo- 2- of step 1:5- (2 grams, 6.1 mMs) is dissolved in THF (40ml), and 85% water is added It closes hydrazine (1.5ml), is warming up to 30 degree, is stirred overnight, diluted with ethyl acetate, three times, saturated sodium-chloride is washed for washing, dense after dry Contracting, residue is with column chromatographic purifying (petrol ether/ethyl acetate=2/1-1/1), and obtaining light yellow solid Z-5-1, (1.9 grams, receive Rate: 91.8%).

Step 2: step 5 of the operation with reference to final product Z-2 operation in detail.

Step 3: step 6 of the operation with reference to final product Z-2 operation in detail.

Step 4: step 7 of the operation with reference to final product Z-2 operation in detail.¹H NMR(400MHz,DMSO-d₆)δ11.66(s, 1H), 8.46 (d, J=5.0Hz, 1H), 7.83 (d, J=1.6Hz, 1H), 7.69-7.65 (m, 2H), 7.57 (d, J=1.6Hz, 1H), 7.44-7.35 (m, 3H), 5.48 (s, 2H), 4.92 (t, J=5.1Hz, 1H), 4.39-4.41 (m, 2H), 4.20-4.16 (m, 3H), 3.85-3.87 (m, 1H), 3.59-3.54 (m, 4H), 3.50 (s, 2H), 2.62-2.47 (m, 3H), 2.38 (d, J= 8.7Hz,6H),1.19(s,6H).

6 2- of embodiment (4- (3- amino -7- (4- (morpholinomethyl) phenyl) benzo [d] isoxazole -5- base) -3- (hydroxyl Methyl) pyridine -2- base) -7,7- dimethyl -3--1,4,7,8- tetrahydro -2H- cyclopenta [4,5] pyrrolo- [1,2-a] pyrrole The preparation of piperazine -1 (6H) -one (Z-6)

Step 1: the fluoro- 3- iodobenzene formonitrile HCN (920mg, 12.3mmol) of the bromo- 2- of 5- being dissolved in DMF (30mL), and to reaction Potassium tert-butoxide (1.38g, 12.3mmol) is added in liquid, resulting reaction solution stirring at normal temperature under helium protection is stayed overnight.Then to N- hydroxyl acetamide (4g, 12.3mmol) is added in reaction solution, and is warming up to 50 DEG C of reaction 2h.Reaction solution by ethyl acetate and After water extraction, concentration of organic layers obtains crude product, which obtains the bromo- 7- iodobenzene of 5- simultaneously [d] through silica gel column chromatography separating purification The sterling (2.2g, yield 53%) of isoxazole -3- amine.

Step 2: mixing the bromo- 7- iodobenzene of 5- simultaneously [d] isoxazole -3- amine (500mg, 1.5mmol), 4- (morpholinomethyl) benzene Ylboronic acid (326mg, 1.5mmol), Pd (dppf) Cl₂(110mg, 0.15mmol) and K₂CO₃(622mg, 4.5mmol) Yu Weibo In pipe, and dioxane (10mL) and water (5 drop) is added, reacts reaction mixture at 80 DEG C using microwave synthesizer 40min.Reaction solution is after ethyl acetate and water extraction, and concentration of organic layers obtains crude product, and the crude product is through silica gel column chromatography point From purify compound Z-6-1 sterling (220mg, yield 38.4%).

Step 3: compound Z-6-1 (220mg, 0.57mmol) being dissolved in methylene chloride (20mL), and into reaction solution It is separately added into (Boc)₂O (247mg, 1.13mmol) and DMAP (7mg, 0.057mmol).By resulting reaction mixture in room temperature Under be stirred overnight.Reaction solution is after methylene chloride and water extraction, and concentration of organic layers obtains crude product, and the crude product is through silica gel column layer Analysis isolates and purifies to obtain the sterling (280mg, yield 84%) of compound Z-6-2

Step 4: mixed compound a (135mg, 0.34mmol), compound Z-6-2 (200mg, 0.34mmol), Pd (dppf)Cl₂(25mg, 0.034mmol) and K₂CO₃Dioxane is added in microwave tube in (141mg, 1.02mmol) (10mL) and water (5 drop), make reaction mixture react 30min at 110 DEG C using microwave synthesizer.Reaction solution is through peracetic acid second After ester and water extraction, concentration of organic layers obtains crude product, which obtains the pure of compound Z-6-3 through silica gel column chromatography separating purification Product (180mg, yield 61.6%).

Step 5: compound Z-6-3 (170mg, 0.197mmol) being dissolved in TFA (10mL), reaction solution stirs at normal temperature Mix 30min.After removing major part TFA under reduced pressure, using saturated sodium bicarbonate solution neutralization reaction liquid, reaction solution is through peracetic acid After ethyl ester and water extraction, concentration of organic layers obtains the crude product of compound Z-6-4, is directly used in next step.

Step 6: compound Z-6-4 (30mg, 0.045mmol) is dissolved in THF (5mL), and be added to LiOH (300mg, In aqueous solution (5mL) 12.5mmol).Reaction mixture stirs 1 hour at normal temperature.After removing major part THF under reduced pressure, Reaction solution is extracted using ethyl acetate and water, and organic layer is depressurized the mixture obtained after concentration by preparation liquid phase color Spectrum, which isolates and purifies, obtains final product Z-6 (8.1mg, yield 29%).¹H NMR(400MHz,DMSO-d₆) δ 8.50 (d, J= 5.0Hz,1H),7.98-7.96(m,2H),7.88-7.85(m,2H),7.45-7.42(m,3H),6.55-6.52(m,3H), 4.96 (t, J=5.2Hz, 1H), 4.36 (d, J=5.2Hz, 2H), 4.20-4.17 (m, 3H), 3.86-3.84 (m, 1H), 3.55 (t, J=4.7Hz, 4H), 3.49 (s, 2H), 2.62-2.51 (m, 3H), 2.39-2.35 (m, 5H), 1.18 (s, 6H)

7 2- of embodiment (4- (3- amino -7- (1- methyl-1,2,3,6- tetrahydropyridine -4- bases) -1H- indazole -5- base) -3 (methylol) pyridine -2- base) -7,7- dimethyl -3,4,7,8- tetrahydro -2H- ring penta [4,5] pyrrolo- [1,2-a] pyrazines -1 The preparation of (6H) -one (Z-7)

Step 1: 1- methyl -4- (4,4,5,5- tetramethyl -1,3,2- dioxo bora ring being added into 100ml round-bottomed flask Pentane -2- base) -1,2,3,6- tetrahydropyridines (446 milligrams, 2.00 mMs), the iodo- 1H- indazole -3- amine of the bromo- 7- of 5- (676 millis Gram, 2.00 mMs), Pd (dppf) Cl₂(73 milligrams, 0.1 mM), sodium carbonate (630 milligrams, 6 mMs), water (5mL) With dioxane (35ml), under nitrogen protection, 100 degree is warming up to, is stirred overnight, is cooled to room temperature, filtering and concentrating, remaining oily Object is diluted with 150ml ethyl acetate, washing, and saturated common salt washing, anhydrous sodium sulfate is concentrated after drying, filtering, silica gel column chromatography Obtain white solid Z-7-1 (618 milligrams, yield: 100%).

Step 2: above compound Z-7-1 (618 milligrams, 2.00 mMs), compound being added into 100ml round-bottomed flask A (800 milligrams, 2.00 mMs), Pd (dppf) Cl₂(73 milligrams, 0.1 mM), potassium carbonate (830 milligrams, 6 mMs), Water (5mL) and dioxane (35ml), under nitrogen protection, heating is stirred at reflux overnight, is cooled to room temperature, filtering and concentrating, remaining Grease is diluted with 150ml ethyl acetate, washing, and saturated common salt washing, anhydrous sodium sulfate is concentrated after drying, filtering, silicagel column Chromatography then HPLC be prepared compound Z-7 (200 milligrams, yield: 19%).¹H NMR(400MHz,DMSO-d6)δ8.44 (d, J=5.0Hz, 1H), 8.12 (s, 1H), 7.73 (s, 1H), 7.40 (s, 1H), 7.32 (d, J=5.1Hz, 1H), 6.51 (s, 1H),6.24(s,2H),5.44(s,2H),4.89(s,1H),4.35(s,2H),4.22–4.08(m,3H),3.81(s,1H), 3.12(s,2H),2.81–2.49(m,6H),2.39(s,2H),2.32(s,3H),1.18(s,6H).

8 2- of embodiment (4- (3- amino -7- (1- (1- methyl piperidine -4- base) -1H- pyrazoles -4- base) -1H- indazole -5- Base] -3- (methylol) pyridine -2- base) -7,7- dimethyl -3,4,7,8- tetrahydro -2H- ring penta [4,5] pyrrolo- [1,2-a] pyrroles The preparation of piperazine -1 (6H) -one (Z-8)

Step 1: compound Z-8-1 (752 milligrams, 2.00 mMs), trifluoracetic acid being added into 100ml round-bottomed flask (5mL) and methylene chloride (5ml) under nitrogen protection, is stirred overnight at room temperature, and the dry grease Z-8-2 that obtains is concentrated and is directly entered down One step (yield: 100%).

Step 2: compound Z-8-2 (750 milligrams, 2.00 mMs), formalin being added into 100ml round-bottomed flask (1ml), methylene chloride (20ml), tetrahydrofuran (20ml), be added portionwise acetic acid sodium borohydride (1266 milligrams, 6.00 mmoles You), it is stirred overnight, saturated ammonium chloride solution quenching reaction under ice bath, add methylene chloride extraction, and organic phase anhydrous sodium sulfate is dry It is dry, be concentrated after filtering, silica gel column chromatography obtain white solid Z-8-3 (500 milligrams, yield: 86%).

Step 3: into 100ml round-bottomed flask, addition compound Z-8-3 (500 milligrams, 1.72 mMs), the bromo- 7- of 5- are iodo- 1H- indazole -3- amine (580 milligrams, 1.72 mMs), Pd (dppf) Cl₂(73 milligrams, 0.1 mM), sodium carbonate (630 millis Gram, 6 mMs), water (5mL) and dioxane (35ml) under nitrogen protection, are warming up to 100 degree, are stirred overnight, be cooled to room Temperature, filtering and concentrating, remaining grease are diluted with 150ml ethyl acetate, washing, and saturated common salt washing, anhydrous sodium sulfate is dry, mistake Be concentrated after filter, silica gel column chromatography obtain white solid Z-8-4 (375 milligrams, yield: 58%).

Step 4: above compound Z-8-4 (125 milligrams, 0.33 mM), compound being added into 100ml round-bottomed flask A (132 milligrams, 0.33 mM), Pd (dppf) Cl₂(15 milligrams, 0.2 mM), potassium carbonate (830 milligrams, 6 mMs), Water (5mL) and dioxane (35ml), under nitrogen protection, heating is stirred at reflux overnight, is cooled to room temperature, filtering and concentrating, remaining Grease is diluted with 150ml ethyl acetate, washing, and saturated common salt washing, anhydrous sodium sulfate is concentrated after drying, filtering, silicagel column Chromatography then HPLC be prepared compound Z-8 (100 milligrams, yield: 50%).¹H NMR(400MHz,DMSO-d6)δ11.50 (s, 1H), 8.45 (d, J=5.0Hz, 1H), 8.39 (s, 1H), 8.00 (s, 1H), 7.71 (s, 2H), 7.36 (d, J=5.1Hz, 1H), 6.51 (d, J=5.2Hz, 1H), 5.46 (s, 2H), 4.96-4.85 (m, 1H), 4.37 (d, J=6.2Hz, 2H), 4.27- 4.07 (m, 4H), 3.85 (d, J=22.2Hz, 1H), 2.85 (d, J=6.0Hz, 2H), 2.56 (t, J=11.9Hz, 2H), 2.39 (s,2H),2.19(s,3H),2.06–1.96(m,5H),1.19(s,6H).

Embodiment 9

Compound Z-9 is prepared referring to the method for embodiment 1.¹H NMR(400MHz,DMSO-d6)δ11.70(s, 1H), 8.61-8.38 (m, 2H), 8.11 (s, 1H), 8.00 (d, J=9.0Hz, 1H), 7.89 (s, 1H), 7.47 (dd, J= 22.2,5.6Hz, 2H), 6.57 (s, 1H), 5.54 (s, 2H), 5.03 (s, 1H), 4.43 (s, 2H), 4.24 (d, J=10.6Hz, 2H), 3.83 (d, J=28.8Hz, 4H), 3.38 (s, 1H), 3.26 (s, 4H), 2.61 (t, J=19.8Hz, 2H), 2.38 (d, J =40.8Hz, 2H), 1.22 (s, 6H)

Embodiment 10-14

It is prepared by the method that compound Z-10 to Z-14 can refer to embodiment 2.

Embodiment 15-16

It is prepared by the method that compound Z-15 to Z-16 can refer to embodiment 3.

Embodiment 17

It is prepared by the method that compound Z-17 can refer to embodiment 5.¹H NMR(400MHz,DMSO-d₆)δ11.80(s, 1H), 8.65 (d, J=2.2Hz, 1H), 8.48 (d, J=5.0Hz, 1H), 8.20 (d, J=1.5Hz, 1H), 8.07 (d, J= 8.3Hz, 1H), 7.95 (d, J=1.4Hz, 1H), 7.80 (dd, J=8.2,2.2Hz, 1H), 7.63-7.47 (m, 2H), 7.41 (d, J=5.0Hz, 1H), 6.53 (s, 1H), 5.53 (s, 2H), 5.03-4.95 (m, 1H), 4.39 (t, J=4.7Hz, 2H), 4.31-4.04 (m, 3H), 3.86-3.84 (m, 1H), 3.57-3.53 (m, 6H), 2.55 (d, J=8.3Hz, 2H), 2.39-2.36 (m, 4H), 1.19 (d, J=2.7Hz, 6H)

Embodiment 18

It is prepared by the method that compound Z-18 can refer to embodiment 8.¹H NMR(400MHz,DMSO-d6)δ11.52(s, 1H), 8.54-8.32 (m, 2H), 8.01 (s, 1H), 7.71 (s, 2H), 7.36 (d, J=5.0Hz, 1H), 6.52 (s, 1H), 5.49 (s, 2H), 4.99-4.86 (m, 1H), 4.40 (d, J=12.6Hz, 3H), 4.30-4.06 (m, 3H), 3.96 (d, J=11.2Hz, 2H), 3.82 (s, 1H), 3.47 (t, J=9.8Hz, 2H), 2.54 (d, J=8.4Hz, 2H), 2.39 (s, 2H), 2.00 (d, J= 18.4Hz,4H),1.19(s,6H).

Biological test

One Lantha screening kinase reaction experimental method of test case

Compound is first dissolved in 100%DMSO in advance.The drug storing liquid of room-temperature dissolution 10mM, through 8vol%DMSO solution Gradient dilution is to 10-0.005 μM of final concentration.Be added in the every hole 384 orifice plates (Corning 3676) the determinand solution of 2.5 μ l with And the diluted kinases of the reacted buffer of 2.5 μ l (Invitrogen PV3363), add the reaction buffer dilution of 5 μ l The mixture of Fluososcei-PolyGT (Invitrogen PV3610) substrate and ATP (Invitrogen PV3227) start Reaction.Wherein blank well (Blank) replaces kinases with reaction buffer, and kinases hole (Enzyme) is added without any drug.25 DEG C shaking table is protected from light after sixty minutes.Be added 10 μ l Detection Solution (Invitrogen PV3528's and EDTA Mixed liquor is diluted with TR-FRET dilution buffer, and EDTA working concentration is 5mM, Lanthascreening Tb PY20antibody working concentration is 0.2nM), it is reacted 30 minutes in room temperature shaker.In VictorX5 fluorescence microplate reader (PerkinElmer) read plate on, measurement excitation wavelength is 340nm, launch wavelength is 500nm and the light absorption of 520nm.

Inhibiting rate calculation method (referring to Invitrogen, the specification of PV3363) is as follows:

1.Emission rate (ER): Coumarin Emission (520nm)/Fluorescein Emission (500nm)

2. inhibiting rate (IR): (ER_kinase-ER_{test compound})/(ER_kinase-ER_blank) × 100%.It is soft with XLFIT 5.0 Part (IDBS company, Britain) the Fitting Calculation half-inhibitory concentration IC50.The results are shown in Table 1:

Inhibitory activity of 1 compound of table to BTK WT

The intracellular β BTK Y223 phosphorylation of test case two detects HTRF experimental method

Compound is first dissolved in 100%DMSO in advance.The drug storing liquid of room-temperature dissolution 10mM, through 5vol%DMSO solution Gradient dilution is to 3-0.0014 μM of final concentration.By Ramos cell with 4 × 10⁵The density kind in/hole is into 96 orifice plates, every 45 μ l of hole The determinand solution of 5 μ l diluted, 37 DEG C, 5% (V/V) CO are added in every hole for 1640 culture mediums containing 10% (V/V) FBS₂ Culture 1 hour.10 μ l pervanadic acid sodium dilutions (1640 dilutions of serum-free) are added, the training of 10 μ l serum-frees is added in negative control hole Base is supported, 25 DEG C of shaking tables are incubated for 30 minutes.20 μ l lysates (4x lysate: closing mother liquor 25:1) is added in every hole, and 25 DEG C of shaking tables are incubated It educates 30 minutes.Oscillator 800rpm shakes 1 minute, and 16 μ l cell pyrolysis liquids is taken to be added in 384 orifice plates (Greiner784075), The antibody-solutions that 4 μ l are pre-mixed are added, and (Phospho-BTK d2 antibody and Phospho-BTK Cryptate antibody use inspection Survey liquid and dilute 20 times), 25 DEG C of shaking tables are incubated overnight.The read plate on VictorX5 fluorescence microplate reader (PerkinElmer), measurement swash Hair wavelength is 317nm, launch wavelength is 500nm and the light absorption of 520nm (referring to Cisbio, the specification of 63ADK017PEH). With 5.0 software of XLFIT (IDBS company, Britain) the Fitting Calculation half-inhibitory concentration IC50.The results are shown in Table 2:

Inhibitory activity of 2 compound of table to β BTK Y223 cell

As can be seen from Table 1 and Table 2, representative compound of the present invention is to enzyme and cell inhibitory activity with higher.

Test case three tests the activity suppression of Wild type EGFR kinases

Agents useful for same is purchased from Invitrogen in following z-lyte test method.

It is living using inhibition of the z-lyte method measurement determinand to Wild type EGFR kinases (Invitrogen, PV3872) Property.

The working concentration of each component in 10uL Wild type EGFR kinase reaction system are as follows: 10 μM of ATP, 0.8ng/ μ L are wild Type EGFR kinases (Invitrogen, PV3872), 2 μM of Tyr04 substrates (Invitrogen, PV3193).After determinand is added Final concentration of the 2% of DMSO.

Water gradient dilution of the drug storing liquid of room-temperature dissolution 10mM through 4%DMSO is to 10-0.005 μM of final concentration.Every hole The determinand solution and the 5 diluted Wild type EGFR kinases of the reacted buffer of μ L of 2.5 μ L of middle addition and mixing for Tyr04 substrate Object is closed, the ATP starting reaction of 2.5 μ L is added.Wherein the hole C1 replaces ATP with reaction buffer, and the hole C2 is added without any drug, The substrate of phosphorylation is added in by specification description in the hole C3.It is protected from light after sixty minutes in 25 degree of shaking tables.5 μ are added LDevelopment Reagent B (Invitrogen is diluted with TR-FRET dilution buffer) is reacted in room temperature shaker 60 minutes.The read plate on VictorX5 fluorescence microplate reader (PerkinElmer), measurement excitation wavelength is 405nm, launch wavelength is The light absorption of 450nm and 520nm is (for example, C3_520nmIndicate the hole C3 in the readings of 520nm).

Inhibiting rate calculation method (referring to Invitrogen, the specification of PV3193) is as follows:

1, ER=Coumarin Emission (450nm)/Fluorescein Emission (520nm)

2, phosphoric acid rate=(1- ((ER × C3_520nm-C3_450nm)/((C1_450nm-C3_450nm)+ER×(C3_520nm- C1_520nm)))) × 100%

3, inhibiting rate (IR)=(1- (the phosphoric acid rate of test compound)/(the phosphoric acid rate of C2)) × 100%

With 5.0 software of XLFIT (IDBS company, Britain) the Fitting Calculation half-inhibitory concentration IC₅₀。

Inhibitory activity of 3 compound of table to EGFR WT

From table 3 it can be seen that representative compound of the present invention has lower inhibitory activity to Wild type EGFR kinases.Cause This example compound of the present invention has selection inhibitory activity to BTK WT kinases.

All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (15)

1. a kind of formula (I) compound represented or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug:

In formula,

A ring is C_6-10The unsaturated single heterocycle of aryl rings, 5 to 6 unit monocycle heteroaryl rings or 4 to 6 yuan；

R₀For hydrogen, halogen, C_1-8Alkyl, halogenated C_1-8Alkyl, C_1-8Alkoxy, halogenated C_1-8Alkoxy, the C optionally replaced_3-8Cycloalkanes Base, C_3-8Cycloalkyloxy, 5 to 6 unit monocycle heteroaryl rings or-Y-L；Wherein Y is a key ,-(CH₂)_m-、-O-(CH₂)_mOr C (O)；L is the C of hydroxyl, cyano substitution_1-3Alkyl, the C optionally replaced_6-10Aryl, 5 to the 6 unit monocycle heteroaryls optionally replaced Ring, 4 to 6 yuan optionally replaced saturation single heterocycle, C_1-8Alkoxy or NR_a0R_b0；It is described it is optional substitution refer to it is unsubstituted or by 1,2 or 3 hydroxyls, halogens, C_1-10The C that alkyl, hydroxyl replace_1-10Alkyl, halogenated C_1-8Alkyl, the single heterocycle of 4 to 6 yuan of saturations are taken Generation；

N, m is each independently 1,2 or 3；

Z is O or NR_a；

R₁For halogen, C_1-10Alkyl or NR_a0R_b0；

R_a、R_a0、R_b0It is each independently hydrogen or C_1-8Alkyl；

R₂、R₃、R₄、R₅It is each independently hydrogen, halogen, C_1-8Alkyl, halogenated C_1-8Alkyl, C_1-8Alkoxy or C_3-8Naphthenic base；

R₆、R₇It is each independently hydrogen or C_1-8Alkyl.

2. compound as described in claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, It is characterized in that, the single heterocycle of 4 to 6 yuan of saturations is selected from: azetidine, oxetanes, tetrahydrofuran, four in formula (I) Hydrogen thiophene, nafoxidine, piperidines, oxazolidine, piperazine, dioxolanes, dioxane, morpholine, thiomorpholine, thiomorpholine -1, 1- dioxide or oxinane.

3. compound as described in claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, It is characterized in that, 5 to the 6 unit monocycle heteroaryl ring is selected from formula (I): thiphene ring, N- alkane cyclopyrrole ring, furan nucleus, thiazole Ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3- triazole ring, 1,2,4- triazole ring, 1,2,5- triazole ring, 1,3,4- triazole ring, tetrazole ring, isozole ring, oxadiazoles ring, 1,2,3- oxadiazoles ring, 1,2,4- oxadiazoles ring, 1,2,5- are disliked Diazole ring, 1,3,4- oxadiazoles ring, Thiadiazole, pyridine ring, pyridazine ring, pyrimidine ring or pyridine ring.

4. compound as described in claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, It is characterized in that, described 4 to 6 yuan unsaturated single heterocycles are selected from: 2,3- dihydro -1H- pyrroles, 2,5- dihydro -1H- pyrrole in formula (I) It coughs up, 2,5- dihydrofuran, 1,2,3,6- tetrahydropyridine, 1,2,3,4- tetrahydropyridine, 3,6- dihydro -2H- pyrans or 3,4- dihydro - 2H- pyrans.

5. compound as described in claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, It is characterized in that, A ring is phenyl ring, pyrazole ring, pyrimidine ring, pyridine ring or 1,2,3,6- tetrahydro pyridine rings in formula (I).

6. compound as described in claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, It is characterized in that, n is 1 or 2 in formula (I).

7. compound as described in claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, It is characterized in that, in formula (I), R₀For hydrogen, C_1-8Alkyl or-Y-L；Wherein Y is a key or-(CH₂)_m-；L is 4 optionally replaced To the single heterocycle of 6 yuan of saturations；The optional substitution refers to unsubstituted or by 1,2 or 3 C_1-10Replaced alkyl；M is 1.

8. compound as described in claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, It is characterized in that, in formula (I), structureTo be selected from the group any structure:

9. compound as described in claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, It is characterized in that, 5 to the 6 unit monocycle heteroaryl ring is selected from:

Above-mentioned 5 to 6 unit monocycle heteroaryl Ring is optionally by 1 or 2 R₀Replace.

10. compound as described in claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvate or preceding Medicine, which is characterized in that structureTo be selected from the group any structure:

11. compound as described in claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvate or preceding Medicine, which is characterized in that formula (I) compound represented is selected from following any compound:

12. a kind of pharmaceutical composition, including compound described in claim 1 or its pharmaceutically acceptable salt, solvation Object, stereoisomer or prodrug and pharmaceutically acceptable carrier or excipient.

13. any one of the claim 1-11 compound or its pharmaceutically acceptable salt, solvate, stereoisomer Or pharmaceutical composition described in prodrug or claim 12 is preparing the purposes in kinase inhibitor drug.

14. purposes as claimed in claim 13, which is characterized in that the kinase inhibitor drug is for treating by B cell The drug of the disease of mediation.

15. purposes as claimed in claim 13, which is characterized in that the kinase inhibitor drug is for treating tumour disease The drug of at least one of disease, proliferative diseases, allergic disease, autoimmune disease and diseases associated with inflammation disease.