CN109970717A

CN109970717A - 4- (cycloaliphatic ring and pyrimidine/pyridine replaces) amino -1H-3- pyrazole carboxamides FLT3 inhibitor and application thereof

Info

Publication number: CN109970717A
Application number: CN201711499769.2A
Authority: CN
Inventors: 王越; 卢帅; 支燕乐; 尧超; 陆涛; 李保泉; 陈璞洲; 鲍吉银
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2017-12-28
Filing date: 2017-12-28
Publication date: 2019-07-05
Anticipated expiration: 2037-12-28
Also published as: CN109970717B

Abstract

The present invention relates to a kind of 4- (saturated fat ring and pyrimidine/pyridine replaces) amino -1H-3- pyrazole carboxamides FLT3 inhibitor and application thereof or its pharmaceutically acceptable salt, solvate, isomers, ester, acid, metabolin or prodrugs, their preparation method, including Pharmaceutical composition and their medical application containing such compound.

Description

4- (cycloaliphatic ring and pyrimidine/pyridine replaces) amino -1H-3- pyrazole carboxamides FLT3 Inhibitor and application thereof

Technical field

The present invention relates to a kind of novel FLT3 kinase inhibitor compounds, the pharmaceutical composition including the compound and Reduce or inhibit FLT3 kinases and/or the saltant type FLT3 kinases of cell or subject living using these compounds and composition Property and prevent or treat the purposes and method of cell proliferative disorders and/or FLT3 associated disease in subject.

Background technique

Cell signalling plays key effect during the growth of regulating cell, proliferation, differentiation, apoptosis etc..Carefully Born of the same parents' proliferation and the imbalance of apoptosis lead to the generation of the major diseases such as cancer, and the essence of cell carcinogenesis is the mistake of cell signalling It adjusts.When the intracellular signal transduction pathway of regulating cell normal physiological activity in cell changes under the action of carcinogen Afterwards, the natural biological effect of regulating cell growth, division and differentiation is abnormal, and then causes cell growth, abnormal division And the change of cellular morphology, lead to the generation of cancer.Due to playing key effect in intracellular signal transduction pathway, and cancer is thin It is often accompanied by the overexpression of protein kinase in born of the same parents, antineoplastic is developed as target spot using protein kinase and is had broad prospects.

In recent years, kinases inhibitor always is the hot fields of anti-tumor drug research and development, and there are many small molecules to swash Enzyme inhibitor such as Imatinib, Sorafenib and Sutent have listed, and in addition there are a large amount of small molecule kinase inhibitors In clinical investigation phase.FMS sample tyrosine kinase 3 (FMS-like tyrosine kinase 3, FLT3) is a kind of type III Receptor tyrosine kinase plays key effect in the proliferation of hematopoietic cell and lymphocyte, differentiation, apoptotic process.Mutation FLT3 typically exhibits higher activity, and autophosphorylation activation downstream letter can occur in the case where not with ligand binding Number pathway.These pathways include the accesses such as RAS/MEK, PI3K/AKT/mTOR and JAK/STAT5.FLT3 receptor is wide It is general to be distributed in the Various Tissues such as hematopoietic progenitor, thymus gland, lymph, placenta, brain, gonad.The exception of FLT3 is sharp Generation living with a series of malignant hematologic diseases especially acute myeloid leukaemia (acute myeloid leukemia, AML) Develop closely related.Therefore, become the research hotspot of malignant hematologic disease treatment using FLT3 as target developing inhibitor.

Haematological malignancies are that the blood of body is formed and immune system, the cancer of marrow and lymphoid tissue.Although In normal marrow, FLT3 expression is only limited to early progenitor cell, but in haematological malignancies, FLT3 is expressed at high levels Or FLT3 is mutated the work for causing uncontrolled FLT3 receptor and downstream molecules channel to induce possible RAS, JAK, PI3K etc. Change.Haematological malignancies include leukaemia, lymthoma (non-Hodgkin lymphoma), Hodgkin's disease (also referred to as Huo Qijin lymph Tumor) and myeloma for example, acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia or acute myeloid leukaemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), chronic neutrophilic chronic myeloid leukemia (CNL), acute undifferentiated cell leukemia (AUL), operation developmental character macrocytic Lymthoma (ALCL), human adult T cell ALL, with the AML (AML/ of the blue family of languages (trilineage) myelodysplasia TMDS), mixed type family of languages leukaemia (MLL), myelodysplastic syndrome (MDSs), myeloproliferative disorder (MPD), multiple Myeloma (MM) and spinal cord sarcoma.

FLT3 plays key effect in hemoposieis and lymphopoiesis, and the abnormal activation and kinds of tumors of FLT3 is special Be not acute myeloid leukaemia (Acute Myeloid Leukemia, AML) occurrence and development it is closely related.FLT3 is highly expressed AML patient, even if after bone-marrow transplantation, still there is very high recurrence rate, so that the prognosis of tumour is very poor.At present to FLT3 and mutation The targeted inhibition of type FLT3 become research hotspot, predominantly exploitation the cruel histidine kinase inhibitor of small molecule, by with the cruel ammonia of FLT3 Acid kinase competes its activity of the beautiful inhibition of ATP-binding site.The kinase inhibitor for coming into clinical inhibition FLT3 at present has PKC412, AC220 etc..So far, FLT3 micromolecular inhibitor has carried out many explorations in terms for the treatment of AML patient, although There are some small molecule FLT3 inhibitor to be in clinical investigation phase at present, but therapeutic effect is still extremely limited.This is because A variety of tyrosine kinase receptor structures have the homology of height, cause inhibitor selectivity not strong, thus in drug resistance amount In the range of, it is difficult to reach the effective dose for inhibiting FLT3 in AML patient.On the other hand, resistant mutation is also shadow An important factor for ringing FLT3 inhibitor for treating.In the research to tool height heterogeneity AML, FLT3 mutation is the 1st and is found Mutation.FLT3 and other kinases homologys are high, and existing FLT3 inhibitor also has inhibiting effect, thus activity to other kinases The FLT3 inhibitor high, selectivity is good has great significance for the treatment of the relationship and related disease of research FLT3 and disease.

Up to now, three phases clinic is entered by the selective FLT3 inhibitor AC220 of Daiichi Sankyo company exploitation Research, not yet selective FLT3 inhibitor listing.Currently, many FLT3 inhibitor are in clinical investigation phase, there are also more More FLT3 inhibitor is in the preclinical drug discovery stage.

Summary of the invention

The compounds of this invention has excellent FLT3 selectivity and inhibitory activity, shows stronger anti-tumor activity.Its Compound or its pharmaceutically acceptable salt, solvate, isomers, ester, acid, metabolin or prodrug including formula (I):

Technical scheme is as follows:

The compound or its pharmaceutically acceptable salt of logical formula (I):

Wherein R¹Indicate hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, heterocycle alkane Base, alkylamino, alkoxyalkyl, alkoxy formoxyl, alkylcarbamoyl, aralkyl, alkyl diaryl, heteroaromatic alkyl, Aryl or heteroaromatic；

X, Y each independently represents N atom or CH atomic group；Wherein CH atomic group can be optionally by R²Replace, R²It can be Hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl, aralkyl, diaryl alkane Base, aryl or heteroaromatic；

A¹Indicate NH, O, S or alkylene radical；Wherein NH atomic group or alkylene radical each independently can be optional By R³Replace, R³It can be hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxy alkane Base, aralkyl, alkyl diaryl, aryl or heteroaromatic；

A²Each independently represent key, alkylidene, C (O) NH, C (O), NHC (O), alkylidene-C (O), C (O)-alkylene Base, alkylidene-C (O)-alkylidene or NHC (O) NH；Wherein, alkylidene, C (O) NH, NHC (O), alkylidene-C (O), C (O)- Alkylidene, alkylidene-C (O)-alkylidene or NHC (O) NH each independently can be optionally by R⁴Replace, R⁴It can be hydrogen, alkyl, cyanogen Base, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl, aralkyl, alkyl diaryl, aryl or Heteroaromatic；

Q¹It is selected from aryl or heteroaromatic, wherein aryl or heteroaromatic each independently can be optionally by one or more R⁵It takes Generation, R⁵It can be hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl, aralkyl Base, alkyl diaryl, aryl or heteroaromatic；

Q²It is selected from aryl, heteroaromatic, C₃-C₈Aliphatic carbocyclic ring, Heterocyclylalkyl ,-NH₂Or-OH, wherein aryl, virtue are miscellaneous Ring, C₃-C₈Aliphatic carbocyclic ring, Heterocyclylalkyl each independently can be optionally by one or more R⁶Replace, R⁶It can be hydrogen, alkane Base, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl, aralkyl, alkyl diaryl, virtue Base or heteroaromatic；-NH₂Or-OH each independently can be optionally by one or more R⁷Replace, R⁷It can be hydrogen, alkyl, alkyl halide Base, alkoxyalkyl, aralkyl, alkyl diaryl, aryl or heteroaromatic；

The value range of n is 1~4；

Alkyl is linear chain or branched chain saturation or part unsaturated alkyl with 1-8 carbon atom；Or for 3-8 The cyclic annular saturation or part unsaturated alkyl of carbon atom；Or to connect the linear chain or branched chain saturation with 1-8 carbon atom or portion Divide the cyclic annular saturation or part unsaturated alkyl with 3-8 carbon atom of unsaturated alkyl；

Alkylidene is the linear chain or branched chain saturated hydrocarbyl with 1-8 carbon atom；It or is the ring-type with 3-8 carbon atom Saturated hydrocarbyl；Or it is full to connect the ring-type with 3-8 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1- carbon atom The group of hydrogen atom formation is lost with alkyl；

Heterocyclylalkyl is the unsaturated monocycle of saturation or part or polycyclic cyclic annular alkane substituent group comprising 3 to 12 annular atoms, Wherein one or more annular atoms be selected from nitrogen, oxygen or S (O) m (wherein m be 0 to 2 integer) hetero atom, remaining annular atom is Carbon, each monocycle or it is bicyclic optionally replaced by 1,2 or 3 substituent group, each substituent group is independently selected from halogen, halogenated alkyl, hydroxyl, alkane Base or alkoxy；Halogen be selected from fluorine, chlorine, bromine or iodine substituent group；

Alkoxy is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is the ring-type with 3-6 carbon atom Saturated hydrocarbyl；Or to connect the ring-type with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom Saturated hydrocarbyl；Wherein each carbon atom is optionally substituted with an oxygen；

Alkylthio group is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is the ring-type with 3-6 carbon atom Saturated hydrocarbyl；Or to connect the ring-type with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom Saturated hydrocarbyl；Wherein each carbon atom is optionally replaced by sulphur；

Alkylamino is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is the ring-type with 3-6 carbon atom Saturated hydrocarbyl；Or to connect the ring-type with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom Saturated hydrocarbyl；Wherein each carbon atom is optionally replaced by NH atomic group；

Alkoxyalkyl is that alkoxy as defined above is connect with alkyl；

Aryl is the carbocyclic ring selected from phenyl, naphthalene, acenaphthenyl or tetralyl, respectively optionally by 1,2 or 3 substituent group Replace, each substituent group is independently selected from hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkane Oxygroup alkyl, aralkyl, alkyl diaryl, aryl or heteroaromatic；

Heteroaromatic is selected from pyrrole radicals, pyrazolyl, imidazole radicals, furyl, thienyl, oxazolyl, isoxazolyl, thiazole Base, isothiazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl monocyclic heterocycles；Or it is selected from quinolyl, quinoxalinyl, indoles Base, benzimidazolyl, benzoxazolyl, benzo isoxazolyl, benzothiazolyl, benzisothia oxazolyl, benzofuranyl, benzo Thienyl, 2,3- dihydrobenzo [Isosorbide-5-Nitrae] dioxine base, benzo [1,3] dioxa cyclopentenyl bicyclic heterocycle；

Aralkyl, alkyl diaryl, heteroaromatic alkyl are that aryl as defined above or heteroaromatic are connect with alkyl；

Aryloxy group, fragrant amino, arylthio, aralkyl oxy, aryl alkyl amino, aromatic alkyl sulfurio are aryl as defined above It is linked respectively with O, S, NH, alkoxy, alkylamino, alkylthio group；

Halogenated alkyl is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom, or is the ring with 3-6 carbon atom Shape saturated hydrocarbyl, or to connect the ring with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom Shape saturated hydrocarbyl；Wherein one or more carbon atoms are optionally substituted with one or more halogen atoms.

Preferred embodiment of the invention is:

R¹Indicate hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkylamino, heterocycle Alkyl, alkoxyalkyl, alkoxy formoxyl or alkylcarbamoyl；

X, Y, Z each independently represent N atom or CH atomic group；Wherein CH atomic group can be optionally by R²Replace, R²It can be with It is hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group or alkoxyalkyl；

A¹Each independently represent NH, O, S or alkylene radical；Wherein NH atomic group or alkylene radical are respectively only It on the spot can be optionally by R³Replace, R³It can be hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group Or alkoxyalkyl；

A²Each independently represent key, alkylidene, C (O) NH, C (O), NHC (O), alkylidene-C (O), C (O)-alkylene Base, alkylidene-C (O)-alkylidene or NHC (O) NH；Wherein, alkylidene, C (O) NH, NHC (O), alkylidene-C (O), C (O)- Alkylidene, alkylidene-C (O)-alkylidene or NHC (O) NH each independently can be optionally by R⁴Replace, R⁴It can be hydrogen, alkyl, cyanogen Base, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group or alkoxyalkyl；

Q¹It is selected from aryl or heteroaromatic, wherein aryl or heteroaromatic each independently can be optionally by one or more R⁵It takes Generation, R⁵It can be hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group or alkoxyalkyl；

The value range of n is 1~4.

It is of the invention another preference is that:

Wherein R¹Indicate hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group or alkylamino；

X, Y each independently represents N atom or CH atomic group；

A¹Each independently represent NH, O, S or alkylene radical；

A²Each independently represent key, alkylidene, C (O) NH, C (O), NHC (O), alkylidene-C (O), C (O)-alkylene Base, alkylidene-C (O)-alkylidene or NHC (O) NH；

Q¹It is selected from aryl or heteroaromatic, wherein aryl or heteroaromatic each independently can be optionally by one or more R⁶It takes Generation, R⁶It can be hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group or alkoxyalkyl；

Q²It is selected from aryl, heteroaromatic, C₃-C₈Aliphatic carbocyclic ring, Heterocyclylalkyl ,-NH₂Or-OH, wherein aryl, virtue are miscellaneous Ring, C₃-C₈Aliphatic carbocyclic ring, Heterocyclylalkyl each independently can be optionally by one or more R⁷Replace, R⁷It can be hydrogen, alkane Base, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl, aralkyl, alkyl diaryl, virtue Base or heteroaromatic；-NH₂Or-OH each independently can be optionally by one or more R⁸Replace, R⁸It can be hydrogen, alkyl, alkyl halide Base, alkoxyalkyl, aralkyl, alkyl diaryl, aryl or heteroaromatic；

The value range of n is 1~4.

It is of the invention another preference is that:

Wherein R¹Selected from hydrogen；Or selected from following alkyl: methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, ring fourth Base, cyclohexyl, cyclopenta, suberyl, cyclooctyl, cyclopentenyl, cyclohexenyl group, cycloheptenyl, cyclo-octene base；Or it is following miscellaneous Naphthenic base: oxetanylmethoxy, oxocyclopentyl, oxacyclohexyl, nafoxidine base, piperidyl, N- methyl piperidine -4- base, Quinoline base, N methyl piperazine base, 3- methyl piperidine -1- base, piperazinyl；Or following alkoxy and alkylamino: cyclopropyl oxygen Base, cyclobutyl oxygroup, cyclopentyloxy, cyclohexyl oxygroup, suberyl oxygroup, cyclopentylmethoxy, cyclopenta ethyoxyl, cyclopropyl Base amino, Cyclobutylamino, clopentylamino, Cyclohexylamino, cyclo-heptylamino；Or following aryl and heteroaromatic: Phenyl, naphthalene, acenaphthenyl, tetralyl, pyrrole radicals, furyl, thienyl, pyridyl group, pyrimidine radicals；Or following aryloxy group with And fragrant amino: phenoxy group, naphthoxy, anilino-, naphthylamine base；Or following aralkoxy and arylalkylamino: benzyloxy, benzyl ammonia Base；

X, Y each independently represents N atom or CH atomic group, and at least one in X, Y is CH atomic group；

A¹Indicate NH；

A²Each independently represent key, alkylidene or C (O)；

Q¹It is selected from following aromatic rings or substituted aromatic rings: phenyl, naphthalene, pyrrole radicals, furyl, thienyl, pyrrole Piperidinyl, pyrazinyl, pyrimidine radicals, substituent group can be 1~2 halogen, methyl, methoxyl group or trifluoromethyl；

Q²It is selected from following aliphatic heterocycle: nafoxidine base, piperidyl, morpholinyl, piperazinyl, high piperazine base, sulphur For morpholinyl, pyranose, tetrahydrofuran base, aziridinyl, azete piperidinyl, N- methyl piperidine -4- base, N methyl piperazine base, 3- Methyl piperidine -1- base, piperazinyl；Or selected from following substituted-amino, substituted oxy: N, N- dipropylamino, N, N- diethyl Amino, N, N- dimethylamino, n-butylamino, 2- methoxy ethoxy, 2- Hydroxy-ethylamino, N, (the 2- methoxyl group of N- bis- Ethyl) amino；

The value range of n is 1~4.

It is of the invention another preference is that:

Wherein R¹Indicate hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclohexyl or cyclopenta；

X, Y, Z each independently represent N atom or CH atomic group, and at least one in X, Y, Z is CH atomic group；

A¹Indicate NH；

A²Each independently represent key or CH₂；

Q¹Indicate phenyl；

Q²It is to be selected from: nafoxidine base, morpholinyl, N methyl piperazine base, piperazinyl；

The value range of n is 1~4.

According to the present invention, pharmaceutically acceptable salt includes compound of Formula I and the acid-addition salts that following acid is formed: salt Acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, naphthalene sulfonic acids, citric acid, tartaric acid, lactic acid, acetone Acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, tussol.It additionally include the acid of inorganic base Salt, such as: containing alkali metal cations, alkaline earth metal cation, ammonium cation salt.

The preferably following structural compounds of compounds of formula I:

4- ((6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- (piperazine -1- base) phenyl) - 1H- pyrazole-3-formamide (I-1)

N- (4- (piperazine -1- base) phenyl) -4- ((5,6,7,8- tetrahydro quinazoline -4- base) amino) -1H- pyrazoles -3- first Amide (I-2)

4- ((6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- (morpholinomethyl) phenyl) - 1H- pyrazole-3-formamide (I-3)

N- (4- (morpholinomethyl) phenyl) -4- ((5,6,7,8- tetrahydro quinazoline -4- base) amino) -1H- pyrazoles -3- first Amide (I-4)

4- ((2- methyl -6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- (morpholinomethyl) Phenyl) -1H- pyrazole-3-formamide (I-5)

4- ((2- methyl -5,6,7,8- tetrahydro quinazoline -4- bases) amino)-N- (4- (morpholinomethyl) phenyl) -1H- pyrrole Azoles -3- formamide (I-6)

4- ((2- methyl -6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- (piperazine -1- base) Phenyl) -1H- pyrazole-3-formamide (I-7)

4- ((2- methyl -5,6,7,8- tetrahydro quinazoline -4- bases) amino)-N- (4- (piperazine -1- base) phenyl) -1H- pyrrole Azoles -3- formamide (I-8)

4- ((2- methyl -6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- ((4- methyl piperazine Piperazine -1- base) methyl) phenyl) -1H- pyrazole-3-formamide (I-9)

4- ((2- methyl -5,6,7,8- tetrahydro quinazoline -4- bases) amino)-N- (4- ((4- methylpiperazine-1-yl) methyl) Phenyl) -1H- pyrazoles -3-- formamide (I-10)

N- (4- (piperazine -1- base) phenyl) -4- ((2- (trifluoromethyl) -6,7- dihydro -5H- cyclopenta [d] pyrimidine - 4- yl) amino) -1H- pyrazole-3-formamide (I-11)

N- (4- (piperazine -1- base) phenyl) -4- ((2- (trifluoromethyl) -5,6,7,8- tetrahydro quinazoline -4- bases) amino) - 1H- pyrazole-3-formamide (I-12)

4- ((2- isopropyl -6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- (piperazine -1- Base) phenyl) -1H- pyrazole-3-formamide (I-13)

4- ((2- isopropyl -5,6,7,8- tetrahydro quinazoline -4- bases) amino)-N- (4- (piperazine -1- base) phenyl) -1H- Pyrazole-3-formamide (I-14)

4- ((2- ethyl -6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- (piperazine -1- base) Phenyl) -1H- pyrazole-3-formamide (I-15)

4- ((2- ethyl -5,6,7,8- tetrahydro quinazoline -4- bases) amino)-N- (4- (piperazine -1- base) phenyl) -1H- pyrrole Azoles -3- formamide (I-16)

4- ((chloro- 6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl of 2-) amino)-N- (4- (piperazine -1- base) benzene Base) -1H- pyrazole-3-formamide (I-17)

4- ((chloro- 5,6,7,8- tetrahydro quinazoline -4- base of 2-) amino)-N- (4- (piperazine -1- base) phenyl) -1H- pyrazoles - 3- formamide (I-18)

4- ((2- cyclopropyl -6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- (piperazine -1- Base) phenyl) -1H- pyrazole-3-formamide (I-19)

4- ((2- cyclopropyl -5,6,7,8- tetrahydro quinazoline -4- bases) amino)-N- (4- (piperazine -1- base) phenyl) -1H- Pyrazole-3-formamide (I-20)

4- ((2- methyl -6,7,8,9- tetrahydro -5H- cycloheptyls simultaneously [d] pyrimidine-4-yl) amino)-N- (4- (piperazine -1- base) Phenyl) -1H- pyrazole-3-formamide (I-21)

4- ((2- methyl -6,7,8,9- tetrahydro -5H- cycloheptyls simultaneously [d] pyrimidine-4-yl) amino)-N- (4- morphlinophenyl) - 1H- pyrazole-3-formamide (I-22).

Part of compounds of the invention the preparation method is as follows:

Method one:

Method two:

Method three:

The compounds of this invention can be prepared with above-mentioned or similar above-mentioned preparation method, according to the difference of substituent group Corresponding raw material is selected with the difference of substituting group position.

Pharmacology test result shows that compounds of formula I and its pharmaceutically acceptable salt have excellent suppression to FLT3 System activity, therefore, compound of Formula I and its pharmaceutically acceptable salt can be used for treating clinical disease related with above-mentioned kinases Disease.Disease related with above-mentioned kinases may be, but not limited to: lung cancer, melanoma, liver cancer, kidney, leukaemia, non-small thin Born of the same parents' lung cancer, prostate cancer, thyroid cancer, cutaneum carcinoma, cancer of pancreas, oophoroma, carcinoma of testis, breast cancer, bladder cancer, gallbladder cancer, bone Marrow hyperplasia abnormal syndrome, lymthoma, the cancer of the esophagus, the tumour of thyroid follcular carcinoma, gastrointestinal cancer, central or peripheral nervous system (such as astrocytoma, neuroblastoma, glioma or neurinoma), celiothelioma, II type or non-insulin rely on Patients with type Ⅰ DM, autoimmune disease.(1) the kinase inhibiting activity measurement of target compound

Synthesized compound measures the suppression to FLT3, CDK2,4,6 with fluorescence resonance energy transfer (FRET) method respectively System activity, and compared with positive control drug, filter out the preferable compound of activity.Above-mentioned kinases passes through purifying or directly purchase examination Agent box obtains.By taking the test of the inhibitory activity of FLT3 as an example, the specific method is as follows:

FLT3 is used after being diluted to suitable concentration with kinase dilution liquid.Contain FLT3, peptide in kinase reaction mixture substrate、HEPES(pH 7.5)、BRIJ-35、MgCl₂And EDTA.CDK2 phospho-peptide substrate is used Make the control of 100% phosphorylation, ATP is not added and is compareed as 0% phosphorylation.After reacting 1h at room temperature, it is added into reaction system suitable Spend diluted Development Reagent A.The reaction was continued at room temperature 1h, addition Stop Reagent stopped reaction.Excitation Wavelength 400m, while Detection wavelength is the fluorescence intensity of 445nm (coumarin) and 520nm (fluorescein).Based on formula Calculate test-compound inhibiting rate.

(2) compound to the inhibitory activity of part kinases (inhibiting rate %, 1 × 10^-6mol/L)

(3) in vitro antitumor activity assay of target compound

It is measured with mtt assay to Gastric cancer line, malignant myeloid cell lines K562, breast carcinoma cell strain MCF7, white blood The inhibiting effect of the tumor cell lines such as disease cell line MV4-11, lung cancer cell types, colon cancer cell line HCT116.

Mtt assay can make exogenous MTT be reduced into difficulty using in living cells mitochondria in the presence of dehydrogenase relevant to NADP The bluish violet crystal (Formazan) of dissolubility, and be deposited in cell, and dead cell is without this function.Dimethyl sulfoxide is used again (DMSO) or the purple crystal thing in three liquid (10%SDS-5% isobutanol -0.01mol/L HCL) dissolution cell, use are enzyme-linked Immune detector measures its OD value, its amount of viable cell of indirect reaction at 570nm wavelength.

Specific method: the tumour cell to test in cell log growth period is inoculated with by certain cell concentration In in 96 well culture plates, sieved sample (can directly add after suspension cell fishplate bar) is added in culture afterwards for 24 hours, and cell is in 37 DEG C, 5% CO₂Under the conditions of continue culture 48 hours after, be added MTT continue culture 4 hours, it is dissolving crystallized with DMSO, carried out under microplate reader Detection.

It is following to the anti tumor activity in vitro result of above-mentioned tumor cell line under 10 μM of concentration of target compound (to inhibit Rate %):

Pharmacology test result shows that the compounds of this invention has stronger inhibitory activity to FLT3, to other kinase exhibits Certain selectivity out can be used for preventing or treating clinical disease related with FLT3, CDK2, CDK4 or CDK6, these diseases May is that leukaemia, lymph (non-Hodgkin lymphoma), Hodgkin's disease (also referred to as Hodgkin lymphoma) and myeloma for example, Acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia or acute myeloid leukaemia (AML), acute progranulocyte Leukaemia (APL), chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), the white blood of chronic neutrophilic cell Sick (CNL), acute undifferentiated cell leukemia (AUL), operation developmental character macrocytic lymthoma (ALCL), human adult T cell ALL, with the AML (AML/TMDS) of the blue family of languages (trilineage) myelodysplasia, mixed type family of languages leukaemia (MLL), Myelodysplastic syndrome (MDSs), myeloproliferative disorder (MPD), Huppert's disease (MM) and spinal cord sarcoma, lung cancer, Melanoma, liver cancer, kidney, leukaemia, non-small cell lung cancer, prostate cancer, thyroid cancer, cutaneum carcinoma, cancer of pancreas, ovary Cancer, carcinoma of testis, breast cancer, bladder cancer, gallbladder cancer, myelodysplastic syndrome, lymthoma, the cancer of the esophagus, thyroid follcular carcinoma, Tumour (such as astrocytoma, neuroblastoma, glioma or the mind of gastrointestinal cancer, central or peripheral nervous system Through sheath tumor), celiothelioma, II type or Non-Insulin Dependent Diabetes Mellitus, autoimmune disease.

Specific embodiment

Fusing point is measured with b shape melting point tube, and medium is methyl-silicone oil, and thermometer does not correct；¹HNMR is with JEOL FX90Q type Fu Vertical leaf transformation Nuclear Magnetic Resonance, BRUKERACF-300 type Nuclear Magnetic Resonance (TMS internal standard)；MS 2000 type Fourier of Nicolet Leaf transformation mass spectrograph and the measurement of MAT-212 type mass spectrograph；Microwave reaction CEM Discover single mold microwave instrument.

Embodiment 1

1- methyl -4- (4- nitrobenzyl) piperazine (I-a)

It is added to nitro bromobenzyl 10g (46.3mmol) and methylene chloride 100mL, under ice-water bath in the mono- neck bottle of 500mL The methylene chloride 20mL of N methyl piperazine 4.7g (47.0mmol) and triethylamine 7.1g (70.3 mmol) is slowly added dropwise in (0-5 DEG C) Mixed liquor finishes and is heated to reflux 1h, and TLC detects raw material disappearance (ethyl acetate: petroleum ether=1: 2).By chloroform 150mL and saturation Sodium bicarbonate solution 100mL is added in reaction solution, is vigorously stirred 30min in room temperature.Reaction solution extracts (100mL × 3) with chloroform, Merge organic layer, respectively washes primary (100mL × 1) with water and saturated sodium-chloride respectively.Anhydrous magnesium sulfate dries, filters, and decompression is steamed Except solvent obtains faint yellow solid 8.5g, yield 78.1%, product is direct plungeed into and is reacted in next step without being further purified.¹H NMR (300MHz, DMSO) δ 8.1 (d, J=8.6Hz, 2H, ArH), 7.5 (d, J=8.6Hz, 2H, ArH), 3.5 (s, 2H ,- CH₂), 2.3-2.5 (br, 8H ,-CH₂× 4), 2.15 (s, 3H ,-CH₃).

Embodiment 2

4- ((4- methylpiperazine-1-yl) methyl) aniline (I-b)

I-a crude product 8.5g (36.2mmol), FeO (OH)/C catalyst 2.0g and 95% second are added in the mono- neck bottle of 500mL Alcohol 100mL, is heated to reflux, and the mixed liquor of hydrazine hydrate 25mL and 95% ethyl alcohol 20mL is slowly added dropwise, and TLC detects raw material disappearance (first Alcohol: chloroform=1: 15).It filtering while hot, the ethyl alcohol of filter cake heat washes (30mL × 2) twice, and evaporating solvent under reduced pressure obtains white solid, It is dried in vacuo (I-b) 6.7g, yield 90.3%.Product is direct plungeed into and is reacted in next step without being further purified.¹H NMR (300MHz, DMSO) δ 8.1 (d, J=8.5Hz, 2H, ArH), 7.5 (d, J=8.5Hz, 2H, ArH), 4.0 (s, 2H ,-NH₂), 3.5 (s, 2H ,-CH₂), 2.3-2.5 (br, 8H ,-CH₂× 4), 2.1 (s, 3H ,-CH₃)

Embodiment 3

N- (4- ((4- methylpiperazine-1-yl) methyl) phenyl -4- nitro -1H- pyrazole-3-formamide (I-c)

I-a ' crude product 7.5g (36.6mmol), 4- nitro -1H- pyrazoles -3- formic acid are added in 250mL round-bottomed flask 6.3g (40.1mmol), EDCHCl 8.4g (44.0mmol), HOBt 6.0g (44.4mmol) and anhydrous DMF 100mL, room Temperature stirring is for 24 hours.TLC detects raw material disappearance (methanol: chloroform=1: 10).By reaction solution to entering in ice water 200mL, it is precipitated a large amount of light Yellow solid stands, filters to obtain yellow solid, gained crude product ethyl acetate and methanol mixed solvent recrystallize (I-e) 11.1g, yield 88.2%.MS[M+H]⁺345.3。¹H NMR (300MHz, DMSO) δ 14.2 (s, 1H ,-NH-, Pyrazole), 10.6 (s, 1H ,-NHCO-), 8.8 (s, 1H, ArH), 7.6 (d, J=8.7Hz, 2H, ArH), 7.3 (d, J=8.7Hz, 2H, ArH), 3.4 (s, 2H ,-CH₂), 2.3-2.4 (br, 8H ,-CH₂× 4), 2.2 (s, 3H ,-CH₃).

Embodiment 4

N- (4- ((4- methylpiperazine-1-yl) methyl) phenyl -4- amino -1H- pyrazole-3-formamide (I-d)

I-c 6.0g (17.4mmol), FeO (OH)/C catalyst 2g and 95% ethyl alcohol are added in the mono- neck bottle of 250mL 100mL is heated to reflux, and the mixed liquor of hydrazine hydrate 25mL and 95% ethyl alcohol 20mL is slowly added dropwise, and TLC detects raw material disappearance (methanol : chloroform=1: 10).It filtering while hot, the ethyl alcohol of filter cake heat washes (30mL × 2) twice, and evaporating solvent under reduced pressure obtains off-white powder, Gained crude product ethyl acetate and methanol mixed solvent recrystallize (I- m ') 3.5g, yield 64%, MS [M+H]⁺315.8。¹H NMR (300MHz, DMSO) δ 12.7 (s, 1H, Pyrazole), 9.7 (s, 1H ,-NHCO-), 7.7 (d, J=8.6Hz, 2H, ArH), 7.1-7.2 (m, 3H, ArH), 4.7 (s, 2H ,-NH₂), 3.3 (s, 2H ,-CH₂), 2.3-2.5 (m, 8H ,-CH₂× 4), 2.1 (s, 3H ,-CH₃).

Embodiment 5

4- (4- nitrobenzyl) morpholine (I-e)

It is added to nitro bromobenzyl 10g (46.3mmol) and methylene chloride 100mL, under ice-water bath in the mono- neck bottle of 500mL The methylene chloride 20mL mixing of morpholine 4.1g (47.0mmol) and triethylamine 7.1g (70.3mmol) is slowly added dropwise in (0-5 DEG C) Liquid finishes and is heated to reflux 1h, and TLC detects raw material disappearance (ethyl acetate: petroleum ether=1: 2).By chloroform 150mL and unsaturated carbonate Hydrogen sodium solution 100mL is added in reaction solution, is vigorously stirred 30min in room temperature.Reaction solution extracts (100mL × 3) with chloroform, merges Organic layer respectively washes primary (100mL × 1) with water and saturated sodium-chloride respectively.Anhydrous magnesium sulfate dries, filters, and removes under reduced pressure molten Agent obtains faint yellow solid 8.5g, yield 78.1%, and product is direct plungeed into and reacted in next step without being further purified.¹H NMR (300MHz, DMSO) δ 7.6 (2H, d, J=8.7Hz, ArH), 6.9 (2H, d, J=8.7Hz, ArH), 3.5 (2H, s ,-CH₂), 3.2 (4H, m ,-OCH₂× 2), 2.3 (4H, m ,-NCH₂-×2).

Embodiment 6

4- (morpholinomethyl) aniline (I-f)

I-e crude product 8.5g (36.2mmol), FeO (OH)/C catalyst 2.0g and 95% second are added in the mono- neck bottle of 500mL Alcohol 100mL, is heated to reflux, and the mixed liquor of hydrazine hydrate 25mL and 95% ethyl alcohol 20mL is slowly added dropwise, and TLC detects raw material disappearance (first Alcohol: chloroform=1: 15).It filtering while hot, the ethyl alcohol of filter cake heat washes (30mL × 2) twice, and evaporating solvent under reduced pressure obtains white solid, It is dried in vacuo to obtain I-f6.5g, yield 93.5%.Product is direct plungeed into and is reacted in next step without being further purified.¹H NMR (300MHz, DMSO) δ 7.6 (2H, d, J=8.5Hz, ArH), 6.9 (2H, d, J=8.5Hz, ArH), 4.9 (2H, s ,-NH₂), 3.5 (2H, s ,-CH₂), 3.2 (4H, m ,-OCH₂× 2), 2.3 (4H, m ,-NCH₂-×2).

Embodiment 7

N- (4- (morpholinomethyl) phenyl) -4- nitro -1H- pyrazole-3-formamide (I-g)

I-f crude product 7.0g (36.6mmol), 4- nitro -1H- pyrazoles -3- formic acid 6.3g are added in 250mL round-bottomed flask (40.1mmol), EDCHCl 8.4g (44.0mmol), HOBt 6.0g (44.4mmol) and anhydrous DMF 100mL, room temperature are stirred It mixes for 24 hours.TLC detects raw material disappearance (methanol: chloroform=1: 10).By reaction solution to entering in ice water 200mL, it is precipitated a large amount of faint yellow Solid stands, filters to obtain yellow solid, and gained crude product ethyl acetate and methanol mixed solvent recrystallize (I-g) 8.6g, receives Rate 71.0%.MS[M+H]⁺ 332.3。¹H NMR (300MHz, DMSO) δ 14.2 (1H, s ,-NH-, Pyrazole), 10.7 (1H, S ,-NHCO-), 8.8 (1H, s, ArH), 7.6 (2H, d, J=8.5Hz, ArH), 7.3 (2H, d, J=8.5Hz, ArH), 3.6 (4H, m ,-OCH₂× 2), 3.4 (2H, s ,-CH₂), 2.4 (4H, m ,-NCH₂-×2).

Embodiment 8

4- amino-N- (4- (morpholinomethyl) phenyl) -1H- pyrazole-3-formamide (I-h)

I-g 5.8g (17.4mmol), FeO (OH)/C catalyst 2g and 95% ethyl alcohol are added in the mono- neck bottle of 250mL 100mL is heated to reflux, and the mixed liquor of hydrazine hydrate 25mL and 95% ethyl alcohol 20mL is slowly added dropwise, and TLC detects raw material disappearance (methanol : chloroform=1: 10).It filtering while hot, the ethyl alcohol of filter cake heat washes (30mL × 2) twice, and evaporating solvent under reduced pressure obtains off-white powder, Gained crude product ethyl acetate and methanol mixed solvent recrystallize (I- h) 4.0g, yield 76.0%, MS [M+H]⁺302.3。¹H NMR (300MHz, DMSO) δ 12.7 (1H, s ,-NH-, Pyrazole), 9.7 (1H, s ,-NHCO-), 8.8 (1H, s, ArH), 7.6 (2H, d, J=8.5Hz, ArH), 7.3 (2H, d, J=8.5Hz, ArH), 4.7 (2H, s ,-NH₂), 3.6 (4H, m ,-OCH₂-× 2), 3.3 (2H, s ,-CH₂), 2.4 (4H, m ,-NCH₂-×2).

Embodiment 9

4- (4- nitrobenzophenone) piperazine -1- carboxylic acid tert-butyl ester (I-i)

P-fluoronitrobenzene 10g (70.9mmol) and potassium carbonate 14.6g (106.4 mmol) are added in the mono- neck bottle of 500mL, With 100mL DMSO dissolve, under ice-water bath (0-5 DEG C) be slowly added dropwise N-Boc- piperazine 10.6g (106.4mmol) DMSO it is molten Liquid finishes and is heated to reflux 6h, and TLC detects raw material disappearance (ethyl acetate: petroleum ether=1: 2).1000ml water is added, yellow is precipitated Solid, filtering are dried under reduced pressure to obtain 15.2 g of faint yellow solid, yield 70.1%, and product direct plunges into down without being further purified Single step reaction.¹H NMR (300MHz, DMSO) δ 8.14 (d, J=8.7Hz, 2H, ArH), 7.85 (d, J=8.7Hz, 2H, ArH), 3.45 (s, 4H ,-CH₂× 2), 3.39 (s, 4H ,-CH₂× 2), 1.35 (s, 9H ,-CH₃×3)。

Embodiment 10

4- (4- aminophenyl) piperazine -1- carboxylic acid tert-butyl ester (I-j)

I-i crude product 10g (32.6mmol), FeO (OH)/C catalyst 1.0g and 95% second are added in the mono- neck bottle of 500mL Alcohol 100mL, is heated to reflux, and the mixed liquor of hydrazine hydrate 10mL and 95% ethyl alcohol 20mL is slowly added dropwise, and TLC detects raw material disappearance (first Alcohol: chloroform=1: 15).It filtering while hot, the ethyl alcohol of filter cake heat washes (30mL × 2) twice, and evaporating solvent under reduced pressure obtains white solid, It is dried in vacuo (I-j) 7.86g, yield 87.1%.Product is direct plungeed into and is reacted in next step without being further purified.¹H NMR (300MHz, DMSO) δ 6.94 (d, J=8.7Hz, 2H, ArH), 6.22 (s, 2H ,-NH₂), 6.15 (d, 2H, J=8.7Hz, ArH), 3.45 (t, 4H ,-CH₂× 2), 3.39 (t, 4H ,-CH₂× 2), 1.35 (s, 9H ,-CH₃× 3),

Embodiment 11

4- (4- (4- nitro -1H- pyrazole-3-formamide base) phenyl) piperazine -1- t-butyl formate (I-k)

I-j crude product 5g (18.1mmol), 3.1 g of 4- nitro -1H- pyrazoles -3- formic acid are added in 250mL round-bottomed flask (19.9mmol), 50 mL of EDCHCl 4.1g (21.7mmol), HOBt 2.9g (21.7mmol) and anhydrous DMF, is stirred at room temperature 24h.TLC detects raw material disappearance (methanol: chloroform=1: 10).By reaction solution to entering in ice water 200mL, it is precipitated a large amount of faint yellow Solid stands, filters to obtain yellow solid, and gained crude product ethyl acetate and methanol mixed solvent recrystallize (I-k) 4.7g, receives Rate 62.4%.MS[M+H]⁺417.2.¹H NMR (300MHz, DMSO) δ 11.46 (s, 1H ,-NH-, Pyrazole), 9.53 (s, 1H ,-NHCO-), 7.88 (s, 1H, ArH), 7.84 (d, J=8.7Hz, 2H, ArH), 7.45 (d, J=8.7Hz, 2H, ArH), 3.45 (t, 4H ,-CH₂× 2), 3.39 (t, 4H ,-CH₂× 2), 1.45 (s, 9H ,-CH₃×3)。

Embodiment 12

4- (4- (4- amino -1H- pyrazole-3-formamide base) phenyl) piperazine -1- t-butyl formate (I-l)

I-k 5.0g (12.0mmol), FeO (OH)/C catalyst 0.5g and 95% ethyl alcohol are added in the mono- neck bottle of 250mL 60mL is heated to reflux, and hydrazine hydrate 5mL is slowly added dropwise, and TLC detects raw material disappearance (methanol: chloroform=1: 10).It filters, filters while hot The ethyl alcohol of cake heat is washed (30mL × 2) twice, and evaporating solvent under reduced pressure obtains off-white powder, gained crude product ethyl acetate and methanol Mixed solvent recrystallizes (I-1) 3.9g, yield 85.3%, MS [M+H]⁺386.2.¹H NMR (300MHz, DMSO) δ 11.56 (s, 1H ,-NH-, Pyrazole), 9.53 (s, 1H ,-NHCO-), 7.88 (s, 1H, ArH), 7.84 (d, 2H, J=8.7Hz, ArH), 7.44 (s, 2H ,-NH₂), 6.45 (d, J=8.7Hz, 2H, ArH), 3.55 (t, 4H ,-CH2- × 2), 3.49 (t, 4H ,- CH₂× 2), 1.45 (s, 9H ,-CH₃×3)。

Embodiment 13

Morpholino (4- nitrobenzophenone) ketone (I-m)

Paranitrobenzoic acid 10g (46.3mmol) is added in the mono- neck bottle of 500mL, morpholine 4.1g (50.6 mmol), EDCI (50.6mmol) and HOBT (69mmol), is added 100mL methylene chloride, and stirring at normal temperature 5h, TLC detect raw material disappearance (second Acetoacetic ester: petroleum ether=1: 2).Decompression is spin-dried for DCM, and water is added, and extracts (100mL × 3) with chloroform, merges organic layer, use respectively Water and saturated sodium-chloride respectively wash primary (100mL × 1).Anhydrous magnesium sulfate dries, filters, and evaporating solvent under reduced pressure obtains faint yellow solid 8.5g, yield 88.1%, product are direct plungeed into and are reacted in next step without being further purified.¹H NMR (300MHz, DMSO) δ 7.7 (2H, d, J=8.7Hz, ArH), 7.0 (2H, d, J=8.7Hz, ArH), 3.7 (4H, m ,-OCH₂× 2), 3.1 (4H, m ,- NCH₂-×2).

Embodiment 14

(4- aminophenyl) (morpholino) ketone (I-n)

I-m crude product 8.5g (36.2mmol), FeO (OH)/C catalyst 2.0g and 95% second are added in the mono- neck bottle of 500mL Alcohol 100mL, is heated to reflux, and the mixed liquor of hydrazine hydrate 25mL and 95% ethyl alcohol 20mL is slowly added dropwise, and TLC detects raw material disappearance (first Alcohol: chloroform=1: 15).It filtering while hot, the ethyl alcohol of filter cake heat washes (30mL × 2) twice, and evaporating solvent under reduced pressure obtains white solid, It is dried in vacuo to obtain I-n 6.5g, yield 93.5%.Product is direct plungeed into and is reacted in next step without being further purified.¹H NMR (300MHz, DMSO) δ 7.5 (2H, d, J=8.5Hz, ArH), 6.8 (2H, d, J=8.5Hz, ArH), 5.2 (2H, s ,-NH₂), 3.6 (4H, m ,-OCH₂× 2), 3.0 (4H, m ,-NCH₂-×2).

Embodiment 15

N- (4- (morpholine -4- carbonyl) phenyl) -4- nitro -1H- pyrazole-3-formamide (I-o)

I-n crude product 7.0g (36.6mmol), 4- nitro -1H- pyrazoles -3- formic acid 6.3g are added in 250mL round-bottomed flask (40.1mmol), EDCHCl 8.4g (44.0mmol), HOBt 6.0g (44.4mmol) and anhydrous DMF 100mL, room temperature are stirred It mixes for 24 hours.TLC detects raw material disappearance (methanol: chloroform=1: 10).By reaction solution to entering in ice water 200mL, it is precipitated a large amount of faint yellow Solid stands, filters to obtain yellow solid, and gained crude product ethyl acetate and methanol mixed solvent recrystallize (I-o) 8.6g, receives Rate 72.0%.MS[M+H]⁺346.1。¹H NMR (300MHz, DMSO) δ 12.7 (1H, s ,-NH-, Pyrazole), 9.6 (1H, s ,- NHCO-), 8.4 (1H, s, ArH), 7.7 (2H, d, J=8.5Hz, ArH), 7.1 (2H, d, J=8.5Hz, ArH), 3.5 (4H, m, -OCH₂× 2), 2.6 (4H, m ,-NCH₂-×2).

Embodiment 16

4- amino-N- (4- (morpholine -4- carbonyl) phenyl) -1H- pyrazole-3-formamide (I-p)

I-05.8g (17.4mmol), FeO (OH)/C catalyst 2g and 95% ethyl alcohol are added in the mono- neck bottle of 250mL 100mL is heated to reflux, and the mixed liquor of hydrazine hydrate 25mL and 95% ethyl alcohol 20mL is slowly added dropwise, and TLC detects raw material disappearance (methanol : chloroform=1: 10).It filtering while hot, the ethyl alcohol of filter cake heat washes (30mL × 2) twice, and evaporating solvent under reduced pressure obtains off-white powder, Gained crude product ethyl acetate and methanol mixed solvent recrystallize (I- P) 4.0g, yield 76.0%, MS [M+H]⁺316.3。¹H NMR (300MHz, DMSO) δ 12.6 (1H, s ,-NH-, Pyrazole), 9.4 (1H, s ,-NHCO-), 8.3 (1H, s, ArH), 7.5 (2H, d, J=8.5Hz, ArH), 7.2 (2H, d, J=8.5Hz, ArH), 4.8 (2H, s ,-NH₂), 3.7 (4H, m ,-OCH₂-× 2), 2.9 (4H, m ,-NCH₂-×2).

Embodiment 17

Addition I-1150mg (0.39mmol), chloro- 6, the 7- dihydro -5H- cyclopenta [d] of 4- are phonetic in the mono- neck bottle of 50mL Pyridine 72.4mg (0.47mmol) and 50% acetic acid aqueous solution 5mL, is heated to reflux, the disappearance of TLC detection raw material (methanol: chloroform=1: 10), reaction solution is cooled to room temperature, and adjusts pH to 8-9 with saturated sodium bicarbonate aqueous solution, solid is precipitated, filter, filtrate acetic acid Ethyl ester extracts 3 times (50ml × 3), and combining extraction liquid, anhydrous magnesium sulfate is dry, and evaporating solvent under reduced pressure after suction filtration merges with filter cake It is dissolved afterwards with methylene chloride, is added isometric trifluoroacetic acid, stirring at normal temperature 3 hours.Evaporated under reduced pressure methylene chloride adds water tune PH To 8-9, solid is filtered to obtain, crude product, which is chromatographed through column, (methanol: chloroform=1: 15), obtains (I-1) 138mg, yield 87%, [M+H]⁺ 405.2. ¹H NMR (300MHz, DMSO) δ 13.40 (s, 1H, pyrazole), 10.10 (s, 1H ,-NH-), 9.11 (s, 1H ,- NHCO-), 8.49 (s, 1H, ArH), 7.67 (d, J=7.3Hz, 2H, ArH), 6.94 (d, J=7.3Hz, 2H, ArH), 7.52 (d, J=3.5Hz, 3H, ArH), 3.14 (m, 4H), 2.75-2.81 (m, 4H), 2.06-2.09 (s, 2H ,-CH₂-).

Embodiment 18

To be similar to the method for preparing I-1, obtains white solid (I-2), yield 53%, obtain white solid, yield 71%. MS[M+H]⁺460.3.¹H NMR (300MHz, DMSO) δ 13.49 (s, 1H, pyrazole), 10.11 (s, 1H ,-NH-), 9.27 (s, 1H ,-NHCO-), 8.63 (s, 1H, ArH), 7.71 (d, J=8.2Hz, 2H, ArH), 6.97 (d, J=8.2Hz, 2H, ArH), 3.33 (s, 4H ,-CH₂× 2), 3.26 (s, 4H ,-CH₂× 2), 2.60 (m, 2H ,-CH₂), 2.52 (s, 2H ,- CH₂), 1.83 (m, 2H ,-CH₂), 1.77 (m, 2H ,-CH₂-).

Embodiment 19

I-h 117mg (0.39mmol), chloro- 6, the 7- dihydro -5H- cyclopenta [d] of 4- are added in the mono- neck bottle of 50mL Pyrimidine 72.4mg (0.47mmol) and 50% acetic acid aqueous solution 5mL, is heated to reflux, and TLC detects raw material disappearance (methanol: chloroform=1 : 10), reaction solution is cooled to room temperature, and adjusts pH to 8-9 with saturated sodium bicarbonate aqueous solution, solid is precipitated, filter, filtrate second Acetoacetic ester extracts 3 times (50ml × 3), and combining extraction liquid, anhydrous magnesium sulfate is dry, and evaporating solvent under reduced pressure after suction filtration is closed with filter cake And crude product chromatographs through column and (methanol: chloroform=1: 15), obtains (I-3) 92mg, yield 0.56%, [M+H]⁺420.2.¹H NMR (300MHz, DMSO) δ 13.45 (s, 1H, pyrazole), 10.19 (s, 1H ,-NH-), 9.23 (s, 1H ,-NHCO-), 8.55 (s, 1H, ArH), 8.44 (s, 1H, ArH), 7.73 (d, J=8.6Hz, 2H, ArH), 6.96 (d, J=8.6Hz, 2H, ArH), 3.41 (s, 2H ,-CH₂), 3.33 (s, 4H ,-CH₂× 2), 3.11 (s, 4H ,-CH₂× 2), 2.75-2.81 (m, 4H ,-CH₂- × 2), 2.01-2.03 (s, 2H ,-CH₂-).

Embodiment 20

To be similar to the method for preparing I-3, obtain white solid (I-4), yield 47%, MS [M+H]⁺434.2.¹H NMR (300MHz, DMSO) δ 13.41 (s, 1H, pyrazole), 10.04 (s, 1H ,-NH-), 9.33 (s, 1H ,-NHCO-), 9.12 (s, 1H, ArH), 8.44 (s, 1H, ArH), 7.73 (d, J=8.8Hz, 2H, ArH), 6.97 (d, J=8.8Hz, 2H, ArH), 3.42 (s, 2H ,-CH₂), 3.23 (s, 4H ,-CH₂× 2), 3.02 (s, 4H ,-CH₂× 2), 2.61 (m, 2H ,-CH₂), 2.43 (m, 2H ,-CH₂), 1.82 (m, 2H ,-CH₂), 1.75 (m, 2H ,-CH₂-).

Embodiment 21

To be similar to the method for preparing I-3, obtain white solid (I-5), yield 54%, MS [M+H]⁺434.2.¹H NMR (300MHz, DMSO) 13.44 (s, 1H, pyrazole), 10.12 (s, 1H ,-NH-), 9.21 (s, 1H ,-NHCO-), 8.42 (s, 1H, ArH), 7.76 (d, J=8.2Hz, 2H, ArH), 6.99 (d, J=8.2Hz, 2H, ArH), 3.40 (s, 2H ,-CH₂), 3.27 (s, 4H ,-CH₂× 2), 3.01 (s, 4H ,-CH₂× 2), 2.75-2.81 (m, 4H ,-CH₂× 2), 2.61 (s, 3H ,- CH₃), 2.00-2.04 (s, 2H ,-CH₂-).

Embodiment 22

To be similar to the method for preparing I-3, obtain faint yellow solid (I-6), yield 49%, MS [M+H]⁺448.2. ¹H NMR (300MHz, DMSO) δ 13.44 (s, 1H, pyrazole), 10.12 (s, 1H ,-NH-), 9.29 (s, 1H ,-NHCO-), 9.11 (s, 1H, ArH), 7.77 (d, J=8.6Hz, 2H, ArH), 6.99 (d, J=8.6Hz, 2H, ArH), 3.42 (s, 2H ,-CH₂), 3.21 (s, 4H ,-CH₂× 2), 3.07 (s, 4H ,-CH₂× 2), 2.62 (m, 3H ,-CH₃), 2.56 (m, 4H ,-CH₂), 1.88 (m, 2H ,-CH₂), 1.74 (m, 2H ,-CH₂-).

Embodiment 23

To be similar to the method for preparing I-1, obtain faint yellow solid (I-7), yield 53%, MS [M+H]⁺419.2. ¹H NMR (300MHz, DMSO) δ 13.40 (s, 1H, pyrazole), 10.10 (s, 1H ,-NH-), 9.11 (s, 1H ,-NHCO-), 8.49 (s, 1H, ArH), 7.67 (d, J=8.4Hz, 2H, ArH), 6.95 (d, J=8.4Hz, 2H, ArH), 3.52 (m, 4H ,-CH₂-× 2), 3.01 (s, 4H ,-CH₂× 2), 2.75-2.81 (m, 4H ,-CH₂× 2), 2.51 (s, 3H ,-CH₃), 2.06-2.07 (m, 2H ,-CH₂-).

Embodiment 24

To be similar to the method for preparing I-1, obtain faint yellow solid (I-8), yield 51%, MS [M+H]⁺433.2. ¹H NMR (300MHz, DMSO) δ 13.48 (s, 1H, pyrazole), 10.16 (s, 1H ,-NH-), 9.36 (s, 1H ,-NHCO-), 8.50 (s, 1H, ArH), 7.71 (d, J=8.6Hz, 2H, ArH), 6.99 (d, J=8.6Hz, 2H, ArH), 3.33-3.35 (m, 4H ,-CH₂- × 2), 3.21-3.23 (s, 2H ,-CH₂× 2), 2.59-2.61 (m, 2H ,-CH₂), 2.46 (s, 5H ,-CH₃,-CH₂), 1.76-1.84 (m, 4H ,-CH₂-×2).

Embodiment 25

I-d 123mg (0.39mmol), 4- chloro-2-methyl -6,7- dihydro -5H- ring penta 2 are added in the mono- neck bottle of 50mL Alkene simultaneously [d] pyrimidine 79.0mg (0.47mmol) and 50% acetic acid aqueous solution 5mL, is heated to reflux, and TLC detects raw material and disappears (methanol : chloroform=1: 10), reaction solution is cooled to room temperature, and adjusts pH to 8-9 with saturated sodium bicarbonate aqueous solution, solid is precipitated, filter, Filtrate is extracted with ethyl acetate 3 times (50ml × 3), combining extraction liquid, and anhydrous magnesium sulfate is dry, evaporating solvent under reduced pressure after suction filtration, Merge with filter cake, crude product chromatographs through column and (methanol: chloroform=1: 15), obtains (I-9) 91mg, yield 52%, [M+H]⁺447.2.¹H NMR (300 MHz, DMSO) δ 13.44 (s, 1H, pyrazole), 10.11 (s, 1H), 9.42 (s, 1H), 8.61 (s, 1H, ArH), 7.72 (d, J=8.2Hz, 2H, ArH), 6.96 (d, J=8.2Hz, 2H, ArH), 3.42 (s, 2H ,-CH₂), 2.62 (s, 3H ,- CH₃), 2.35 (s, 8H ,-CH₂× 4), 2.76-2.88 (m, 4H ,-CH₂× 2), 2.12 (s, 3H ,-CH₃), 2.02-2.05 (m, 2H ,-CH₂-).

Embodiment 26

To be similar to the method for preparing I-9, obtain faint yellow solid (I-10), yield 66%, MS [M+H]⁺461.2. ¹H NMR (300MHz, DMSO) δ 13.43 (s, 1H, pyrazole), 10.11 (s, 1H ,-NH-), 9.40 (s, 1H ,-NHCO-), 8.46 (s, 1H, ArH), 7.69 (d, J=8.4Hz, 2H, ArH), 6.97 (d, J=8.4Hz, 2H, ArH), 3.42 (s, 2H ,- CH₂), 2.60 (s, 3H ,-CH₃), 2.56-2.59 (m, 2H ,-CH₂), 2.38 (s, 10H ,-CH₂× 5), 2.11 (s, 3H ,- CH₃), 1.76-1.84 (m, 4H ,-CH₂-×2).

Embodiment 27

To be similar to the method for preparing I-1, obtain faint yellow solid (I-11), yield 64%, MS [M+H]⁺473.2. ¹H NMR (300MHz, DMSO) δ 13.42 (s, 1H, pyrazole), 10.09 (s, 1H ,-NH-), 9.21 (s, 1H ,-NHCO-), 8.54 (s, 1H, ArH), 7.73 (d, J=8.4Hz, 2H, ArH), 6.99 (d, J=8.4Hz, 2H, ArH), 3.45 (m, 4H ,- CH₂× 2), 3.01 (s, 4H ,-CH₂× 2), 2.75-2.81 (m, 4H ,-CH₂× 2), 2.06-2.07 (m, 2H ,-CH₂-).

Embodiment 28

To be similar to the method for preparing I-1, obtain faint yellow solid (I-12), yield 49%, MS [M+H]⁺487.2. ¹H NMR (300MHz, DMSO) δ 13.42 (s, 1H, pyrazole), 10.14 (s, 1H ,-NH-), 9.33 (s, 1H ,-NHCO-), 8.56 (s, 1H, ArH), 7.66 (d, J=8.2Hz, 2H, ArH), 6.94 (d, J=8.2Hz, 2H, ArH), 3.34-3.37 (m, 4H ,-CH₂× 2), 3.20-3.23 (s, 4H ,-CH₂× 2), 2.59-2.61 (m, 2H ,-CH₂), 2.44 (s, 2H ,-CH₂), (1.74-1.81 m, 4H)

Embodiment 29

To be similar to the method for preparing I-1, obtain faint yellow solid (I-13), yield 67%, MS [M+H]⁺447.3. ¹H NMR (300MHz, DMSO) δ 13.41 (s, 1H, pyrazole), 10.11 (s, 1H ,-NH-), 9.22 (s, 1H ,-NHCO-), 8.51 (s, 1H, ArH), 7.72 (d, J=8.4Hz, 2H, ArH), 6.98 (d, J=8.4Hz, 2H, ArH), 3.44 (m, 4H ,- CH₂× 2), 3.31 (m, 1H), 3.04 (s, 4H ,-CH₂× 2), 2.77-2.84 (m, 4H ,-CH₂× 2), 2.04-2.06 (m, 2H ,-CH₂), 1.34 (d, J=6.8Hz, 6H)

Embodiment 30

To be similar to the method for preparing I-1, obtain faint yellow solid (I-14), yield 76%, MS [M+H]⁺461.3. ¹H NMR (300MHz, DMSO) δ 13.49 (s, 1H, pyrazole), 10.11 (s, 1H ,-NH-), 9.30 (s, 1H ,-NHCO-), 8.48 (s, 1H, ArH), 7.69 (d, J=8.4Hz, 2H, ArH), 6.98 (d, J=8.4Hz, 2H, ArH), 3.35-3.38 (m, 4H ,-CH₂× 2), 3.31 (m, 1H), 3.18-3.23 (s, 4H ,-CH₂× 2), 2.56-2.58 (m, 2H ,-CH₂), 2.41 (s, 2H ,-CH₂), 1.70-1.84 (m, 4H ,-CH₂× 2), 1.32 (d, J=6.6Hz, 6H)

Embodiment 31

To be similar to the method for preparing I-1, obtain faint yellow solid (I-15), yield 57%, MS [M+H]⁺433.2. ¹H NMR (300MHz, DMSO) δ 13.49 (s, 1H, pyrazole), 10.41 (s, 1H ,-NH-), 9.23 (s, 1H ,-NHCO-), 8.55 (s, 1H, ArH), 7.77 (d, J=8.4Hz, 2H, ArH), 6.97 (d, J=8.4Hz, 2H, ArH), 3.41-3.46 (m, 4H ,- CH₂× 2), 3.01-3.06 (m, 4H ,-CH₂× 2), 2.90 (m, 2H ,-CH₂), 2.76-2.82 (m, 4H ,-CH₂× 2), 2.02-2.04 (m, 2H ,-CH₂), 1.37 (t, J=7.4Hz, 3H)

Embodiment 32

To be similar to the method for preparing I-1, obtain faint yellow solid (I-16), yield 47%, MS [M+H]⁺447.2 ¹H NMR (300MHz, DMSO) δ 13.39 (s, 1H, pyrazole), 10.08 (s, 1H ,-NH-), 9.32 (s, 1H ,-NHCO-), 8.45 (s, 1H, ArH), 7.71 (d, J=8.4Hz, 2H, ArH), 6.96 (d, J=8.4Hz, 2H, ArH), 3.33-3.35 (m, 4H ,-CH₂- × 2), 3.11-3.15 (s, 4H ,-CH₂× 2), 2.91 (m, 2H ,-CH₂), 2.54-2.56 (m, 2H ,-CH₂), 2.44 (s, 2H ,-CH₂), 1.68-1.78 (m, 4H ,-CH₂× 2), 1.36 (t, J=7.2Hz, 3H)

Embodiment 33

To be similar to the method for preparing I-1, obtain faint yellow solid (I-17), yield 45%, MS [M+H]⁺439.2. ¹H NMR (300MHz, DMSO) δ 13.49 (s, 1H, pyrazole), 10.04 (s, 1H ,-NH-), 9.27 (s, 1H ,-NHCO-), 8.50 (s, 1H, ArH), 7.68 (d, J=8.4Hz, 2H, ArH), 6.96 (d, J=8.4Hz, 2H, ArH), 3.42 (m, 4H ,- CH₂× 2), 3.08 (m, 4H ,-CH₂× 2), 2.71-2.78 (m, 4H ,-CH₂× 2), 2.00-2.04 (m, 2H ,-CH₂-).

Embodiment 34

To be similar to the method for preparing I-1, obtain faint yellow solid (I-18), yield 29%, MS [M+H]+453.2.¹H NMR (300MHz, DMSO) δ 13.43 (s, 1H, pyrazole), 10.05 (s, 1H ,-NH-), 9.26 (s, 1H ,-NHCO-), 8.43 (s, 1H, ArH), 7.70 (d, J=8.4Hz, 2H, ArH), 6.98 (d, J=8.4Hz, 2H, ArH), 3.33-3.36 (m, 4H ,-CH₂× 2), 3.18-3.22 (s, 4H ,-CH₂× 2), 2.58-2.61 (m, 2H ,-CH₂), 2.42 (s, 2H ,-CH₂), (1.70-1.78 m, 4H)

Embodiment 35

To be similar to the method for preparing I-1, obtain faint yellow solid (I-19), yield 37%, MS [M+H]+445.2.¹H NMR (300MHz, DMSO) δ 13.41 (s, 1H, pyrazole), 10.02 (s, 1H ,-NH-), 9.21 (s, 1H ,-NHCO-), 8.42 (s, 1H, ArH), 7.68 (d, J=8.4Hz, 2H, ArH), 6.96 (d, J=8.4Hz, 2H, ArH), 3.32-3.34 (m, 4H ,-CH₂× 2), 3.16-3.23 (s, 4H ,-CH₂× 2), 2.56-2.60 (m, 2H ,-CH₂), 2.42 (s, 2H ,-CH₂), 2.21 (m, 1H), 1.68-1.74 (m, 4H), 1.07 (m, 4H)

Embodiment 36

To be similar to the method for preparing I-1, obtain faint yellow solid (I-20), yield 34%, MS [M+H]⁺459.3. ¹H NMR (300MHz, DMSO) δ 13.49 (s, 1H, pyrazole), 10.12 (s, 1H ,-NH-), 9.19 (s, 1H ,-NHCO-), 8.48 (s, 1H, ArH), 7.71 (d, J=8.4Hz, 2H, ArH), 6.94 (d, J=8.4Hz, 2H, ArH), 3.35-3.39 (m, 4H ,-CH₂× 2), 3.18-3.22 (s, 4H ,-CH₂× 2), 2.58-2.61 (m, 2H ,-CH₂), 2.42 (s, 2H ,-CH₂), 2.24 (m, 1H), 1.74-1.82 (m, 4H), 1.11 (m, 4H)

Embodiment 37

To be similar to the method for preparing I-1, obtain faint yellow solid (I-21), yield 42%, MS [M+H]⁺446.5. ¹H NMR (300MHz, DMSO) δ 13.47 (s, 1H, pyrazole), 10.06 (s, 1H ,-NH-), 9.12 (s, 1H ,-NHCO-), 8.52 (s, 1H, ArH), 7.74 (d, J=8.4Hz, 2H, ArH), 6.98 (d, J=8.4Hz, 2H, ArH), 3.53 (m, 4H ,- CH₂× 2), 3.01 (s, 4H ,-CH₂× 2), 2.74-2.82 (m, 4H ,-CH₂× 2), 2.49 (s, 3H ,-CH₃), 2.06- 2.15 (m, 6H ,-CH₂-×3).

Embodiment 38

4- ((6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- (morpholine -4- carbonyl) phenyl) - 1H- pyrazole-3-formamide (I-22)

I-q 117mg (0.39mmol), chloro- 6, the 7- dihydro -5H- cyclopenta [d] of 4- are added in the mono- neck bottle of 50mL Pyrimidine 72.4mg (0.47mmol) and 50% acetic acid aqueous solution 5mL, is heated to reflux, and TLC detects raw material disappearance (methanol: chloroform=1 : 10), reaction solution is cooled to room temperature, and adjusts pH to 8-9 with saturated sodium bicarbonate aqueous solution, solid is precipitated, filter, filtrate second Acetoacetic ester extracts 3 times (50ml × 3), and combining extraction liquid, anhydrous magnesium sulfate is dry, and evaporating solvent under reduced pressure after suction filtration is closed with filter cake And crude product chromatographs through column and (methanol: chloroform=1: 15), obtains (I-22) 84mg, yield 48%, [M+H]⁺434.2.¹H NMR (300MHz, DMSO) δ 13.44 (s, 1H, pyrazole), 10.10 (s, 1H ,-NH-), 9.24 (s, 1H ,-NHCO-), 8.53 (s, 1H, ArH), 8.41 (s, 1H, ArH), 7.70 (d, J=8.6Hz, 2H, ArH), 6.98 (d, J=8.6Hz, 2H, ArH), 3.39 (s, 4H ,-CH₂× 2), 3.10 (s, 4H ,-CH₂× 2), 2.76-2.89 (m, 4H ,-CH₂× 2), 1.99-2.02 (s, 2H ,-CH₂-).

Detailed description of the invention

Fig. 1 is logical formula (I) figure.

Claims

1. the compound of logical formula (I) or its pharmaceutically acceptable salt:

Wherein R¹Indicate hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, Heterocyclylalkyl, alkane ammonia Base, alkoxyalkyl, alkoxy formoxyl, alkylcarbamoyl, aralkyl, alkyl diaryl, heteroaromatic alkyl, aryl or virtue Heterocycle；

X, Y each independently represents N atom or CH atomic group；Wherein CH atomic group can be optionally by R²Replace, R²It can be hydrogen, alkane Base, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl, aralkyl, alkyl diaryl, virtue Base or heteroaromatic；

A¹Each independently represent NH, O, S or alkylene radical；Wherein NH atomic group or alkylene radical be each independently It can be optionally by R³Replace, R³It can be hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alcoxyl Base alkyl, aralkyl, alkyl diaryl, aryl or heteroaromatic；

A²Each independently represent key, alkylidene, C (O) NH, C (O), NHC (O), alkylidene-C (O), C (O)-alkylidene, alkylene Base-C (O)-alkylidene or NHC (O) NH；Wherein, alkylidene, C (O) NH, NHC (O), alkylidene-C (O), C (O)-alkylidene, Asia Alkyl-C (O)-alkylidene or NHC (O) NH each independently can be optionally by R⁴Replace, R⁴Can be hydrogen, alkyl, cyano, halogen, Halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl, aralkyl, alkyl diaryl, aryl or heteroaromatic；

Q¹It is selected from aryl or heteroaromatic, wherein aryl or heteroaromatic each independently can be optionally by one or more R⁵Replace, R⁵ It can be hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl, aralkyl, two Aryl alkyl, aryl or heteroaromatic；

Q²It is selected from aryl, heteroaromatic, C₃-C₈Aliphatic carbocyclic ring, Heterocyclylalkyl ,-NH₂Or-OH, wherein aryl, heteroaromatic, C₃-C₈Aliphatic carbocyclic ring, Heterocyclylalkyl each independently can be optionally by one or more R⁶Replace, R⁶Can be hydrogen, alkyl, Cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl, aralkyl, alkyl diaryl, aryl Or heteroaromatic；-NH₂Or-OH each independently can be optionally by one or more R⁷Replace, R⁷Can be hydrogen, alkyl, halogenated alkyl, Alkoxyalkyl, aralkyl, alkyl diaryl, aryl or heteroaromatic；

The value range of n is 1~4；

Alkyl is linear chain or branched chain saturation or part unsaturated alkyl with 1-8 carbon atom；Or for 3-8 carbon atom Cyclic annular saturation or part unsaturated alkyl；Or to connect the linear chain or branched chain saturation or part insatiable hunger with 1-8 carbon atom With the cyclic annular saturation or part unsaturated alkyl with 3-8 carbon atom of alkyl；

Alkylidene is the linear chain or branched chain saturated hydrocarbyl with 1-8 carbon atom；It or is the cyclic annular saturation with 3-8 carbon atom Alkyl；Or to connect the cyclic saturated hydrocarbon with 3-8 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1- carbon atom Base loses the group of hydrogen atom formation；

Heterocyclylalkyl is the unsaturated monocycle of saturation or part or polycyclic cyclic annular alkane substituent group comprising 3 to 12 annular atoms, wherein One or more annular atoms be selected from nitrogen, oxygen or S (O) m (wherein m be 0 to 2 integer) hetero atom, remaining annular atom is carbon, respectively Monocycle or it is bicyclic optionally replaced by 1,2 or 3 substituent group, each substituent group be independently selected from halogen, halogenated alkyl, hydroxyl, alkyl or Alkoxy；Halogen be selected from fluorine, chlorine, bromine or iodine substituent group；

Alkoxy is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is the cyclic annular saturation with 3-6 carbon atom Alkyl；Or to connect the cyclic saturated hydrocarbon with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom Base；Wherein each carbon atom is optionally substituted with an oxygen；

Alkylthio group is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is the cyclic annular saturation with 3-6 carbon atom Alkyl；Or to connect the cyclic saturated hydrocarbon with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom Base；Wherein each carbon atom is optionally replaced by sulphur；

Alkylamino is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom；It or is the cyclic annular saturation with 3-6 carbon atom Alkyl；Or to connect the cyclic saturated hydrocarbon with 3-6 carbon atom of the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom Base；Wherein each carbon atom is optionally replaced by NH atomic group；

Alkoxyalkyl is that alkoxy as defined above is connect with alkyl；

Aryl is the carbocyclic ring selected from phenyl, naphthalene, acenaphthenyl or tetralyl, is respectively optionally replaced by 1,2 or 3 substituent group, Each substituent group is independently selected from hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxy alkane Base, aralkyl, alkyl diaryl, aryl or heteroaromatic；

Heteroaromatic is selected from pyrrole radicals, pyrazolyl, imidazole radicals, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, different Thiazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl monocyclic heterocycles；Or it is selected from quinolyl, quinoxalinyl, indyl, benzene And imidazole radicals, benzoxazolyl, benzo isoxazolyl, benzothiazolyl, benzisothia oxazolyl, benzofuranyl, benzothiophene Base, 2,3- dihydrobenzo [Isosorbide-5-Nitrae] dioxine base, benzo [1,3] dioxa cyclopentenyl bicyclic heterocycle；

Aryloxy group, fragrant amino, arylthio, aralkyl oxy, aryl alkyl amino, aromatic alkyl sulfurio are aryl as defined above difference It is linked with O, S, NH, alkoxy, alkylamino, alkylthio group；

Halogenated alkyl is the linear chain or branched chain saturated hydrocarbyl with 1-6 carbon atom, or is full with the ring-type of 3-6 carbon atom And alkyl, or the cyclic annular saturation with 3-6 carbon atom for linear chain or branched chain saturated hydrocarbyl of the connection with 1-6 carbon atom Alkyl；Wherein one or more carbon atoms are optionally substituted with one or more halogen atoms.

2. the compound of claim 1, it is characterised in that:

Wherein R¹Indicate hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkylamino, heterocycle alkane Base, alkoxyalkyl, alkoxy formoxyl or alkylcarbamoyl；

X, Y, Z each independently represent N atom or CH atomic group；Wherein CH atomic group can be optionally by R²Replace, R²Can be hydrogen, Alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group or alkoxyalkyl；

A¹Each independently represent NH, O, S or alkylene radical；Wherein NH atomic group or alkylene radical be each independently It can be optionally by R³Replace, R³It can be hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group or alkane Oxygroup alkyl；

A²Each independently represent key, alkylidene, C (O) NH, C (O), NHC (O), alkylidene-C (O), C (O)-alkylidene, alkylene Base-C (O)-alkylidene or NHC (O) NH；Wherein, alkylidene, C (O) NH, NHC (O), alkylidene-C (O), C (O)-alkylidene, Asia Alkyl-C (O)-alkylidene or NHC (O) NH each independently can be optionally by R⁴Replace, R⁴Can be hydrogen, alkyl, cyano, halogen, Halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group or alkoxyalkyl；

Q¹It is selected from aryl or heteroaromatic, wherein aryl or heteroaromatic each independently can be optionally by one or more R⁵Replace, R⁵ It can be hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group or alkoxyalkyl；

The value range of n is 1~4.

3. the compound of claim 2, it is characterised in that:

X, Y each independently represents N atom or CH atomic group；

A¹Each independently represent NH, O, S or alkylene radical；

A²Each independently represent key, alkylidene, C (O) NH, C (O), NHC (O), alkylidene-C (O), C (O)-alkylidene, alkylene Base-C (O)-alkylidene or NHC (O) NH；

Q¹It is selected from aryl or heteroaromatic, wherein aryl or heteroaromatic each independently can be optionally by one or more R⁶Replace, R⁶ It can be hydrogen, alkyl, cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group or alkoxyalkyl；

Q²It is selected from aryl, heteroaromatic, C₃-C₈Aliphatic carbocyclic ring, Heterocyclylalkyl ,-NH₂Or-OH, wherein aryl, heteroaromatic, C₃-C₈Aliphatic carbocyclic ring, Heterocyclylalkyl each independently can be optionally by one or more R⁷Replace, R⁷Can be hydrogen, alkyl, Cyano, halogen, halogenated alkyl, hydroxyl, sulfydryl, alkoxy, alkylthio group, alkoxyalkyl, aralkyl, alkyl diaryl, aryl Or heteroaromatic；-NH₂Or-OH each independently can be optionally by one or more R⁸Replace, R⁸Can be hydrogen, alkyl, halogenated alkyl, Alkoxyalkyl, aralkyl, alkyl diaryl, aryl or heteroaromatic；

The value range of n is 1~4.

4. the compound of claim 3, it is characterised in that:

Wherein R¹Selected from following alkyl: methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopenta, Suberyl, cyclooctyl, cyclopentenyl, cyclohexenyl group, cycloheptenyl, cyclo-octene base or following Heterocyclylalkyl: oxa- ring fourth Base, oxocyclopentyl, oxacyclohexyl, nafoxidine base, piperidyl, N- methyl piperidine -4- base, morpholinyl, N methyl piperazine Base, 3- methyl piperidine -1- base, piperazinyl or following alkoxy and alkylamino: cyclopropyl oxygroup, cyclobutyl oxygroup, ring Amyl oxygroup, cyclohexyl oxygroup, suberyl oxygroup, cyclopentylmethoxy, cyclopenta ethyoxyl, cyclopropylamino, cyclobutyl ammonia Base, clopentylamino, Cyclohexylamino, cyclo-heptylamino or following aryl and heteroaromatic: phenyl, naphthalene, acenaphthenyl, Tetralyl, pyrrole radicals, furyl, thienyl, pyridyl group, pyrimidine radicals or following aryloxy group and fragrant amino: benzene oxygen Base, naphthoxy, anilino-, naphthylamine base or following aralkoxy and arylalkylamino: benzyloxy, benzyl amino；

A¹Indicate NH；

A²Each independently represent key, alkylidene or C (O)；

Q¹Selected from following aromatic rings or substituted aromatic rings: phenyl, naphthalene, pyrrole radicals, furyl, thienyl, pyridyl group, Pyrazinyl, pyrimidine radicals, substituent group can be 1~2 halogen, methyl, methoxyl group, trifluoromethyl；

Q²It is selected from following aliphatic heterocycle: nafoxidine base, piperidyl, morpholinyl, piperazinyl, high piperazine base, thiomorpholine Base, pyranose, tetrahydrofuran base, aziridinyl, azete piperidinyl, N- methyl piperidine -4- base, N methyl piperazine base, 3- methyl piperazine Pyridine -1- base, piperazinyl, or selected from following substituted-amino, substituted oxy: N, N- dipropylamino, N, N- diethylamino, N, N- dimethylamino, n-butylamino, 2- methoxy ethoxy, 2- Hydroxy-ethylamino, N, N- bis- (2- methoxy ethyl) ammonia Base；

The value range of n is 1~4.

5. the compound of claim 4, it is characterised in that:

Wherein R¹Indicate methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopenta；

A¹Indicate NH；

A²Each independently represent key, CO or CH₂；

Q¹Indicate phenyl；

Q²It is selected from following aliphatic heterocycle: nafoxidine base, morpholinyl, N methyl piperazine base, piperazinyl；

The value range of n is 1~4.

6. the compound of claim 1, it is characterised in that be following compound:

4- ((6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- (piperazine -1- base) phenyl) -1H- pyrrole Azoles -3- formamide (I-1)

N- (4- (piperazine -1- base) phenyl) -4- ((5,6,7,8- tetrahydro quinazoline -4- base) amino) -1H- pyrazole-3-formamide (I-2)

4- ((6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- (morpholinomethyl) phenyl) -1H- pyrrole Azoles -3- formamide (I-3)

N- (4- (morpholinomethyl) phenyl) -4- ((5,6,7,8- tetrahydro quinazoline -4- base) amino) -1H- pyrazole-3-formamide (I-4)

4- ((2- methyl -6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- (morpholinomethyl) benzene Base) -1H- pyrazole-3-formamide (I-5)

4- ((2- methyl -5,6,7,8- tetrahydro quinazoline -4- bases) amino)-N- (4- (morpholinomethyl) phenyl) -1H- pyrazoles - 3- formamide (I-6)

4- ((2- methyl -6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- (piperazine -1- base) benzene Base) -1H- pyrazole-3-formamide (I-7)

4- ((2- methyl -5,6,7,8- tetrahydro quinazoline -4- bases) amino)-N- (4- (piperazine -1- base) phenyl) -1H- pyrazoles -3- Formamide (I-8)

4- ((2- methyl -6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- ((4- methyl piperazine -1- Base) methyl) phenyl) -1H- pyrazole-3-formamide (I-9)

4- ((2- methyl -5,6,7,8- tetrahydro quinazoline -4- bases) amino)-N- (4- ((4- methylpiperazine-1-yl) methyl) benzene Base) -1H- pyrazoles -3-- formamide (I-10)

N- (4- (piperazine -1- base) phenyl) -4- ((2- (trifluoromethyl) -6,7- dihydro -5H- cyclopenta [d] pyrimidine -4- Base) amino) -1H- pyrazole-3-formamide (I-11)

N- (4- (piperazine -1- base) phenyl) -4- ((2- (trifluoromethyl) -5,6,7,8- tetrahydro quinazoline -4- bases) amino) -1H- Pyrazole-3-formamide (I-12)

4- ((2- isopropyl -6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- (piperazine -1- base) benzene Base) -1H- pyrazole-3-formamide (I-13)

4- ((2- isopropyl -5,6,7,8- tetrahydro quinazoline -4- bases) amino)-N- (4- (piperazine -1- base) phenyl) -1H- pyrazoles - 3- formamide (I-14)

4- ((2- ethyl -6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- (piperazine -1- base) benzene Base) -1H- pyrazole-3-formamide (I-15)

4- ((2- ethyl -5,6,7,8- tetrahydro quinazoline -4- bases) amino)-N- (4- (piperazine -1- base) phenyl) -1H- pyrazoles -3- Formamide (I-16)

4- ((chloro- 6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl of 2-) amino)-N- (4- (piperazine -1- base) phenyl) - 1H- pyrazole-3-formamide (I-17)

4- ((chloro- 5,6,7,8- tetrahydro quinazoline -4- base of 2-) amino)-N- (4- (piperazine -1- base) phenyl) -1H- pyrazoles -3- first Amide (I-18)

4- ((2- cyclopropyl -6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- (piperazine -1- base) benzene Base) -1H- pyrazole-3-formamide (I-19)

4- ((2- cyclopropyl -5,6,7,8- tetrahydro quinazoline -4- bases) amino)-N- (4- (piperazine -1- base) phenyl) -1H- pyrazoles - 3- formamide (I-20)

4- ((2- methyl -6,7,8,9- tetrahydro -5H- cycloheptyls simultaneously [d] pyrimidine-4-yl) amino)-N- (4- (piperazine -1- base) benzene Base) -1H- pyrazole-3-formamide (I-21)

4- ((6,7- dihydro -5H- cyclopenta [d] pyrimidine-4-yl) amino)-N- (4- (morpholine -4- carbonyl) phenyl) -1H- Pyrazole-3-formamide (I-22).

7. the compound of any one of claim 1-6 or its pharmaceutically acceptable salt, wherein pharmaceutically acceptable salt includes The acid-addition salts that logical formula (I) compound and following acid are formed: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene sulfonic acid, to first Benzene sulfonic acid, naphthalene sulfonic acids, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, benzene Guanidine-acetic acid, tussol；Additionally include inorganic base acid salt, such as: containing alkali metal cations, alkaline earth metal cation, Ammonium cation salt.

8. a kind of pharmaceutical composition, wherein containing compound as claimed in claim 7 or its pharmaceutically acceptable salt and pharmacy Upper acceptable carrier.

9. the described in any item compounds of claim 1-7 or its pharmaceutically acceptable salt preparation for prevent or treat with Purposes in the drug of the related clinical disease of FLT3.

10. the purposes of claim 9, wherein disease related with FLT3 can be lung cancer, melanoma, liver cancer, kidney, white blood Disease, prostate cancer, thyroid cancer, cutaneum carcinoma, cancer of pancreas, oophoroma, carcinoma of testis, breast cancer, bladder cancer, gallbladder cancer, marrow increase Raw abnormal syndrome, lymthoma, the cancer of the esophagus, gastrointestinal cancer, astrocytoma, neuroblastoma, glioma, neurolemma Tumor, celiothelioma, Non-Insulin Dependent Diabetes Mellitus, autoimmune disease.