CN109705191A - IAP inhibitor and its application in drug - Google Patents

Abstract

The invention belongs to drug fields, are related to a kind of noval chemical compound and application thereof for inhibiting IAP.Specifically, the present invention relates to a kind of compound that can be used as IAP inhibitor or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrugs.The invention further relates to the compounds and purposes of its pharmaceutical composition as drug, are especially preparing the purposes in the drug for treating or preventing proliferative diseases.

Description

IAP inhibitor and its application in drug

Technical field

The present invention relates to a kind of inhibition IAP (apoptosis inhibitory protein, inhibitors of apoptosis proteins) Noval chemical compound and its salt, its pharmaceutical composition, preparation method.The present invention additionally relate to these compounds and its salt, its Pharmaceutical composition is preparing the purposes in the drug for treating proliferative diseases, and the medicine for the treatment of cancer is especially used in preparation Purposes in object.

Background technique

Apoptosis (apoptosis) plays in the development and dynamic equilibrium in all multi-cell organisms Important function.The variation of the apoptosis pathway involved in the human pathological of many types, such lesion include developmental disorder, cancer, from Body immunity disease and neurodegenerative disorders.A kind of mode of action of chemotherapeutics is to cause cell dead by Apoptosis It dies.

Apoptosis is conservative between different plant species, and is mainly held by the Caspase (caspase) activated Row, Caspase are the cysteine proteinase families in its matrix with aspartic acid specific.Once activation, effect Factor Caspase leads to the proteolytic cleavage of wide spectrum cell target spot, eventually leads to cell death.It withers in no receiving It dies in the normal viable cells of stimulation, most of Caspase keeps disactivation.If Caspase is abnormal activation, Their proteolytic activity can be pressed down by the evolution conservative protein family of referred to as IAPs (inhibitor of apoptosis protein) System.

By preventing the activation of precursor Caspase and inhibiting the enzymatic activity of mature Caspase, IAP family protein Inhibit Apoptosis.IAPs has been described in organism (from drosophila to people), and has known them in many mankind There is overexpression in cancer.IAP prevents Apoptosis by directly interacting with caspase and neutralizing caspase. There are three types of functional domain, the structural domains of respectively referred to as BIR1,2 and 3 for prototype IAP-XIAP and cIAP tool.Think by inhibiting Guang Its protease, the domain BIR lead to anti-apoptotic effect, thus inhibit Apoptosis.Overexpression of the XIAP in tumour cell has been said It is bright, protection is provided for various preceding apoptotic stimulus, and improve the tolerance for chemotherapy.For with acute myelogenous white The patient of blood disease, it has been demonstrated that there are strong correlations between XIAP protein level and survival.

It is reported that Smac can be by neutralizing XIAP in conjunction with the peptide binding pocket on the surface BIR3, wherein XIAP is eliminated to the inhibitory effect of Apoptosis.Smac substantially interacts with all IAPs examined so far, Including XIAP, c-IAP1, c-IAP2, ML-IAP and survivin.As a result, in mammals, Smac seemingly Apoptosis Essential mediator.It has been shown that the proteolytic activations of precursor Caspase not only can be improved in Smac, and can mention The enzymatic activity of high maturation Caspase, both of them depend on the ability of itself and the Physical interaction of IAPs.

Therefore, there is demand for simulation Smac compound, for use as treatment proliferative diseases, the especially therapeutic agent of cancer. WO2005097791 and WO2008016893, which discloses a series of IAP inhibitor compounds, can be used for treating cancer, including Following structural compounds:

The present invention relates to a kind of noval chemical compounds for inhibiting IAP.The compound can be used for treating proliferative diseases, including cancer Disease.

Summary of the invention

The good characteristic of the certain parameters of the compounds of this invention, such as half-life period, clearance rate, selectivity, bioavilability, chemistry The good characteristic of stability, metabolic stability, permeability of the membrane, dissolubility etc. can promote reduction, the therapeutic index of side effect Expansion or the improvement of tolerance etc..

On the one hand, the present invention provides a kind of compounds, have the structure as shown in formula (I), (II), (III) or (IV), Or stereoisomer, geometric isomer, tautomer, the nitrogen oxygen of structural compounds shown in formula (I), (II), (III) or (IV) Compound, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

Wherein,

N1 is 1,2,3,4,5,6 or 7；

Each n2 independently is 0,1,2,3,4,5,6 or 7；

Each n3 independently is 0,1,2,3,4,5,6,7,8 or 9；

Each m independently is 0,1,2,3,4 or 5；

Q is 1,2,3 or 4；

U is 1 or 2；

Q²For covalent bond or-CH₂-；

Cy is following subformula:

Wherein, each t₁It independently is 1,2,3 or 4；

Each t₂It independently is 1 or 2；

Each t₃It independently is 0,1,2 or 3；

Wherein each subformula (Cy-i), (Cy-ii), (Cy-iii), (Cy-iv), (Cy-v) and (Cy-vi) is individually optional Ground is taken by 1,2,3 or 4 substituent group selected from D, F, Cl, Br, hydroxyl, alkyl, naphthenic base, heterocycle, alkoxy and amino Generation；

Each R¹、R²、R³、R^3aAnd R⁵It independently is H, D, alkyl, alkenyl, alkynyl or carbocylic radical, wherein the alkyl, alkene Base, alkynyl and carbocylic radical it is respectively individually optional by 1,2,3 or 4 be selected from D, F, Cl, Br, hydroxyl, alkyl, naphthenic base, heterocycle Base, alkoxy, phenyl and amino substituent group replaced；

Each R⁴It independently is H, D or alkyl；

Each R⁰It independently is D, F, Cl, Br, oxo (=O), cyano, hydroxyl, halogenated alkyl, hydroxy alkyl, haloalkoxy Base, alkoxyalkyl ,-NR⁸R⁹, aryloxy group, heterocycle ,-S (=O)-R¹⁰,-S (=O)₂-R¹⁰、-COOR⁸, aryl, alkoxy or Alkyl；Or, two R⁰3-7 member carbocyclic ring or 3-7 circle heterocyclic ring are formed together with the carbon atom being connected with them；It is halogenated described in wherein Alkyl, hydroxy alkyl, halogenated alkoxy, alkoxyalkyl, aryloxy group, heterocycle, aryl, alkoxy, alkyl, 3-7 member carbocyclic ring With 3-7 circle heterocyclic ring it is respectively individually optional by 1,2,3 or 4 be selected from D, F, Cl, Br, hydroxyl, alkyl, naphthenic base, heterocycle, alkane Replaced the substituent group of oxygroup, aryl and amino；

Each R⁶It independently is H, D, F, Cl, Br, alkyl, hydroxyl, amino, cyano or alkoxy, wherein the alkyl, ammonia Base and alkoxy it is respectively individually optional by 1,2,3 or 4 be selected from D, F, Cl, Br, hydroxyl, alkyl, naphthenic base, heterocycle, alkane Replaced the substituent group of oxygroup and amino；

Each R⁷It independently is H, D, alkyl, F, Cl, Br or amino；

Each R⁸、R⁹It independently is H, D, alkyl, naphthenic base, heterocycle, aryl or heteroaryl；The wherein alkyl, cycloalkanes Base, heterocycle, aryl and heteroaryl it is respectively individually optional by 1,2,3 or 4 be selected from D, F, Cl, Br, hydroxyl, alkyl, cycloalkanes Base, heterocycle, alkoxy, aryl and amino substituent group replaced；With

Each R¹⁰It independently is amino, alkyl, naphthenic base, heterocycle, aryl or heteroaryl；Wherein the amino, alkyl, Naphthenic base, heterocycle, aryl and heteroaryl it is respectively individually optional by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, alkyl, Naphthenic base, heterocycle, alkoxy, aryl and amino substituent group replaced.

In some embodiments, each R¹、R²、R³、R^3aAnd R⁵It independently is H, D, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl Or 3-10 member carbocylic radical, wherein the C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl and 3-10 member carbocylic radical are respectively individually optional D, F, Cl, Br, hydroxyl, C are selected from by 1,2,3 or 4_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Alkoxy, phenyl and Replaced the substituent group of amino；

Each R⁴It independently is H, D or C_1-6Alkyl；With

Each R⁷It independently is H, D, C_1-6Alkyl, F, Cl, Br or amino.

In some embodiments, each R¹、R²、R³、R^3aAnd R⁵Independently be H, D, methyl, ethyl, n-propyl, isopropyl, Normal-butyl, isobutyl group, tert-butyl ,-CH=CH₂,-CH=CH-CH₃、-CH₂- CH=CH₂,-CH=CH-CH₂CH₃-、-CH₂-CH =CH₂-CH₃、-(CH₂)₂- CH=CH₂、-C(CH₃)=CH₂-CH₃, propinyl, propargyl, cyclopropyl, cyclobutyl, cyclopenta, ring Hexyl, cyclopentenyl, cyclopentadienyl group, cyclohexenyl group or cyclohexadienyl, wherein the methyl, ethyl, n-propyl, isopropyl Base, normal-butyl, isobutyl group, tert-butyl ,-CH=CH₂,-CH=CH-CH₃、-CH₂- CH=CH₂,-CH=CH-CH₂CH₃-、-CH₂- CH=CH₂-CH₃、-(CH₂)₂- CH=CH₂、-C(CH₃)=CH₂-CH₃, propinyl, propargyl, cyclopropyl, cyclobutyl, cyclopenta, Cyclohexyl, cyclopentenyl, cyclopentadienyl group, cyclohexenyl group and cyclohexadienyl it is respectively individually optional be selected from by 1,2,3 or 4 D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, ring Amyl, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-pyrimidine base, two Six ring group of oxygen, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl and ammonia Replaced the substituent group of base；

Each R⁴It independently is H, D, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tert-butyl；With

Each R⁷It independently is H, D, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, F, Cl, Br Or amino.

In some embodiments, each R⁰It independently is D, F, Cl, Br, oxo (=O), cyano, hydroxyl, C_1-6Alkyl halide Base, C_1-6Hydroxy alkyl, C_1-6Halogenated alkoxy, C_1-6Alkoxy C_1-6Alkyl ,-NR⁸R⁹、C_6-10Aryloxy group, 3-7 circle heterocyclic ring base ,-S (=O)-R¹⁰,-S (=O)₂-R¹⁰、-COOR⁸、C_6-10Aryl, C_1-6Alkoxy or C_1-6Alkyl；Or, two R⁰It is connected with them Carbon atom be formed together 3-7 member carbocyclic ring or 3-7 circle heterocyclic ring；The wherein C_1-6Halogenated alkyl, C_1-6Hydroxy alkyl, C_1-6Halogen For alkoxy, C_1-6Alkoxy C_1-6Alkyl, C_6-10Aryloxy group, 3-7 circle heterocyclic ring base, C_6-10Aryl, C_1-6Alkoxy, C_1-6Alkyl, 3- 7 yuan of carbocyclic rings and 3-7 circle heterocyclic ring it is respectively individually optional by 1,2,3 or 4 be selected from D, F, Cl, Br, hydroxyl, C_1-4Alkyl, C_3-6Ring Alkyl, 3-6 circle heterocyclic ring base, C_1-4Alkoxy, C_6-10Replaced the substituent group of aryl and amino；

Each R⁸、R⁹It independently is H, D, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_6-10Aryl or 5-6 member heteroaryl Base；The wherein C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_6-10Aryl and 5-6 unit's heteroaryl are respectively individually optional Ground is selected from D, F, Cl, Br, hydroxyl, C by 1,2,3 or 4_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Alkoxy, C_6-10 Replaced the substituent group of aryl and amino；With

Each R¹⁰It independently is amino, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_6-10Aryl or 5-6 unit's heteroaryl； The wherein amino, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_6-10Aryl and 5-6 unit's heteroaryl are respectively independently appointed Selection of land is selected from D, F, Cl, Br, hydroxyl, C by 1,2,3 or 4_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Alkoxy, C_6-10Replaced the substituent group of aryl and amino.

In some embodiments, each R⁰It independently is D, F, Cl, Br, oxo (=O), cyano, hydroxyl, amino, trifluoro Methyl, trifluoromethoxy, hydroxymethyl, hydroxyethyl, methoxy, methoxy ethyl, ethoxyl methyl, ethyoxyl second Base ,-NR⁸R⁹,-S (=O)-R¹⁰,-S (=O)₂-R¹⁰、-COOR⁸, phenoxy group, pyrrolidinyl, piperidyl, tetrahydrofuran base, morpholine Base, piperazinyl, imidazolidinyl, phenyl, carboxyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutyl oxygen Base, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tert-butyl；Or, two R⁰With with them it Between be connected carbon atom be formed together cyclopropane, cyclobutane, pentamethylene, hexamethylene, cycloheptane, cyclopentene, cyclohexene, epoxy second Alkane, oxetanes, aziridine, 1,3- dioxolane, pyrrolidines, piperidines, piperazine, morpholine, tetrahydropyridine, tetrahydro Pyrans or tetrahydrofuran；Wherein the hydroxymethyl, hydroxyethyl, methoxy, methoxy ethyl, ethoxyl methyl, Ethoxyethyl group, phenoxy group, pyrrolidinyl, piperidyl, tetrahydrofuran base, morpholinyl, piperazinyl, imidazolidinyl, phenyl, methoxy Base, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl Base, normal-butyl, isobutyl group, tert-butyl, cyclopropane, cyclobutane, pentamethylene, hexamethylene, cycloheptane, cyclopentene, cyclohexene, epoxy Ethane, oxetanes, aziridine, 1,3- dioxolane, pyrrolidines, piperidines, piperazine, morpholine, tetrahydropyridine, four Hydrogen pyrans and tetrahydrofuran it is respectively individually optional by 1,2,3 or 4 be selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, positive third Base, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidines Base, tetrahydro-thienyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-pyrimidine base, dioxane, methoxyl group, ethyoxyl, positive third oxygen Base, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl and amino substituent group replaced；

Each R⁸And R⁹It independently is H, D, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopenta, piperidyl or phenyl； Wherein the methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopenta, piperidyl and phenyl it is respectively individually optional by 1, 2,3 or 4 are selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclopropyl Base, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, morpholinyl, Tetrahydro-pyrimidine base, dioxane, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tertiary fourth Replaced the substituent group of oxygroup, phenyl and amino；With

Each R¹⁰It independently is amino, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopenta, piperidyl or phenyl；Its Described in amino, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopenta, piperidyl or phenyl quilt respectively individually optionally 1,2,3 or 4 are selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, ring Propyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, morpholine Base, tetrahydro-pyrimidine base, dioxane, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, uncle Replaced the substituent group of butoxy, phenyl and amino.

In some embodiments, each R⁶It independently is H, D, F, Cl, Br, C_1-6Alkyl, hydroxyl, amino, cyano or C_1-6 Alkoxy, wherein the C_1-6Alkyl, amino and C_1-6Alkoxy respectively individually optionally by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, C_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Replaced the substituent group of alkoxy and amino.

In some embodiments, each R⁶It independently is H, D, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, positive fourth Base, isobutyl group, tert-butyl, hydroxyl, amino, cyano, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutyl Oxygroup or tert-butoxy, wherein the methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, amino, first Oxygroup, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy it is respectively individually optional by 1,2, 3 or 4 selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclopropyl, Cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, morpholinyl, tetrahydro Pyrimidine radicals, dioxane, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy Replaced substituent group with amino.

In some embodiments, Cy is following subformula:

Wherein each subformula (Cy-1), (Cy-2), (Cy-3), (Cy-4), (Cy-5), Cy-6), (Cy-7), (Cy-8), (Cy-9), Cy-10) D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl are selected from by 1,2,3 or 4 individually optionally Base, normal-butyl, isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro Thienyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-pyrimidine base, dioxane, methoxyl group, ethyoxyl, positive propoxy, isopropyl Oxygroup, n-butoxy, isobutoxy, tert-butoxy and amino substituent group replaced.

On the other hand, the present invention provides a kind of compound, there is knot shown in structure described in formula (VII) or formula (VII) The stereoisomer of structure compound, geometric isomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically Acceptable salt or prodrug,

Wherein,

Each R¹、R²、R³、R^3aAnd R⁵It independently is H, D, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl or 3-10 member carbocylic radical, Described in C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl and 3-10 member carbocylic radical it is respectively individually optional by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, C_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4The substituent group of alkoxy, phenyl and amino is taken Generation；

Each R⁴It independently is H, D or C_1-6Alkyl；

Each R⁷It independently is H, D, alkyl, F, Cl, Br or amino；

Wherein, each T¹And T²Stand alone as a key ,-CR¹²R¹³-、-CR¹²R¹³-O-、-O-CR¹²R¹³-、-NR¹¹-CR¹²R¹³-、- CR¹²R¹³-NR¹¹、-CR¹²R¹³)₂-、-(CR¹²R¹³)₃-、-NR¹¹,-O- or-S-；

T³For-CR¹²R¹³-、-NR¹¹,-O- or-S-；

Each R¹¹It independently is H, D, C_1-6Alkyl, hydroxyl, amino, cyano, C_1-6Alkoxy, C_3-6Naphthenic base, 3-6 circle heterocyclic ring Base or C_6-10Aryl；

Each R¹²、R¹³It independently is H, D, F, Cl, Br, hydroxyl, oxo, amino, cyano, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 Circle heterocyclic ring base or C_1-6Alkoxy；

Each R⁶It independently is H, D, F, Cl, Br, C_1-6Alkyl, hydroxyl, amino, cyano or C_1-6Alkoxy, wherein described C_1-6Alkyl, amino and C_1-6Alkoxy is selected from D, F, Cl, Br, hydroxyl, C by 1,2,3 or 4 respectively individually optionally_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Replaced the substituent group of alkoxy and amino；

Wherein each subformula Y-1a, Y-2a, Y-3a, Y-4a and Y-5a can individually optionally by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, oxo, amino, cyano, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base and C_1-6The substituent group of alkoxy It is replaced.

In some embodiments, each R¹、R²、R³、R^3aAnd R⁵Independently be H, D, methyl, ethyl, n-propyl, isopropyl, Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclopentenyl, cyclohexenyl group or phenyl, wherein the methyl, ethyl, positive third Base, isopropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclopentenyl, cyclohexenyl group and the respectively individually optional ground quilt of phenyl 1,2,3 or 4 are selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, ring Propyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, morpholine Base, tetrahydro-pyrimidine base, dioxane, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, uncle Replaced the substituent group of butoxy, phenyl and amino；

Each R⁴It independently is H, D, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tert-butyl；

Each R⁷It independently is H, D, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, F, Cl, Br Or amino；

Wherein, each R¹¹It independently is H, D, methyl, ethyl, n-propyl, isopropyl, hydroxyl, amino, cyano, methoxyl group, second Oxygroup, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, pyrrole radicals, piperazinyl, morpholinyl, tetrahydrofuran base, Piperidyl or phenyl；

Each R¹²、R¹³It independently is H, D, F, Cl, Br, hydroxyl, oxo, amino, cyano, methyl, ethyl, n-propyl, isopropyl Base, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, pyrrole radicals, piperazinyl, morpholinyl, tetrahydrofuran base, piperidyl, first Oxygroup, ethyoxyl, positive propoxy or isopropoxy；

Each R⁶Independently be H, D, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, Hydroxyl, amino, cyano, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy；

Wherein each subformula Y1a, Y2a, Y3a, Y4a, Y5a, Y6a, Y7a, Y8a, Y9a, Y10a, Y11a, Y12a, Y13a, Y14a, Y15a, Y16a, Y17a, Y18a, Y19a and Y20a can individually optionally by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, oxo, amino, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, ring Oxirane group, pyrrole radicals, piperazinyl, morpholinyl, tetrahydrofuran base, piperidyl, methoxyl group, ethyoxyl, positive propoxy or isopropyl Replaced the substituent group of oxygroup.

On the other hand, the present invention provides a kind of pharmaceutical compositions, comprising compound of the present invention and its pharmaceutically Acceptable adjuvant.

On the other hand, the present invention provides compounds of the present invention or pharmaceutical composition of the present invention to prepare The purposes in drug for preventing or treating proliferative diseases.

Unless otherwise indicated, the stereoisomer that the compound of the present invention is all, geometric isomer, tautomerism Body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug belong to model of the invention It encloses.

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

The salt of the compound of the present invention further includes being used to prepare or purifying chemical combination shown in formula (I), (II), (III) or (IV) The salt of the enantiomter of the separation of compound shown in the intermediate or formula (I), (II), (III) or (IV) of object, but it is not necessarily medicine Acceptable salt on.

Detailed description of the invention book

Definition and general terms

It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method and material described herein Trample the present invention.The present invention is not limited to method described herein and material.The one of the document, patent and the similar material that are combined Or more it is different from the application or in the case where contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be subject to the application.

It will further be appreciated that certain features of the invention, be it is clearly visible, carry out in a number of independent embodiments Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.

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

Unless otherwise stated, following definition should be obtained using used herein.For purposes of the present invention, chemical element with The periodic table of elements CAS editions, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can join It examines " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, New York:2007, entire contents are incorporated herein by reference.

Term " study subject " used in the present invention refers to animal.The typically described animal is mammal.It is tested right As, such as also refer to primate (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by Trying object is people.

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

Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise Content.

Stereochemical definitions used in the present invention and rule generally follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons, Inc.,New York,1994。

Many organic compounds exist with optical active forms, i.e., they, which have, rotates the plane of linearly polarized light Ability.When describing optically active compound, indicate molecule about one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols for the rotation of linearly polarized light caused by appointed compound, Wherein (-) or l indicate that compound is left-handed.Prefix is (+) or the compound of d is dextrorotation.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50:50 mixture of enantiomter Referred to as racemic mixture or racemic modification, when chemical reaction or in the process without stereoselectivity or stereospecificity when, It may occur in which such case.

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

According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Chiral synthon or chiral reagent preparation can be used in optically active (R)-or (S)-isomers, or is torn open using routine techniques Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing disubstituted cycloalkanes in compound The substituent group of base, naphthenic base may have cis or trans configuration.

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

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

One or more degrees of unsaturation are contained in term " unsaturation " or " unsaturated " expression part.

Except non-present invention is defined otherwise, for any substituent group or compound that are described in the present invention or any general formula structure In occur more than primary aleatory variable, definition when it occurs every time and it in other definition Anywhere occurred be mutual It is independent, it is independent of each other.In addition, the combination of substituent group and/or variable is only to allow when such combination forms stable compound 's.Stable compound is the compound with certain useful purity that can be isolated from reaction mixture.

As described in the invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound above, or a kind of compound for being included as example, subclass and the present invention special inside embodiment.It answers Understanding " optionally replacing " this term, this term can be used interchangeably with " substituted or unsubstituted ".In general, term " substitution " or " substituted " the one or more hydrogen atoms indicated in given structure are replaced specific substituent group.In some implementations In example, " being optionally substituted " indicates that group can be substituted or unsubstituted.Unless otherwise indicated, an optional substitution Group can be replaced at various substitutable position of that group.When more than one position can be selected from given structural formula Replaced one or more substituent groups of specific group, then substituent group can replace at various locations identical or differently.Its Described in substituent group can be, but be not limited to, D, F, Cl, Br, hydroxyl, alkyl, naphthenic base, heterocycle, alkoxy, aryl And amino, etc..

In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode " each ... independently be " and " ... independently respectively be " and " ... independently be " can be interchanged, and shall be understood in a broad sense, both can be with Refer among the different groups, does not influence mutually, can also indicate identical between expressed specific option between the same symbol Group in, do not influenced mutually between expressed specific option between the same symbol.For example, structural formula "-(R⁰)_n1”、“- (R⁰)_n2" and structural formula "-(R⁰)_n3" R between three⁰Specific option it is unaffected from each other；Structure "-(R⁰)_n1" in, each R⁰ Specific option it is unaffected from each other.

It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term “C_1-6Alkyl " refers in particular to the methyl being individually disclosed, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

In each section of the invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then respectively represents it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.

Term " the C used separately as prefix_m-n" group refers to any group with m to n carbon atom.

Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1 to 20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention Replace.In some embodiments, alkyl group contains 1-10 carbon atom；In some embodiments, alkyl group contains 1-6 carbon atom；In yet another embodiment, alkyl group contains 1-4 carbon atom；In yet another embodiment, alkyl base 1-3 carbon atom is contained in group.In some specific structures, when alkyl group clearly shows that as linking group, then the alkane Base group represents the alkylidene group of connection, for example, structural formula (C_6-10Aryl)-(C_1-6Alkyl)-in C_1-6Alkyl should be managed Solution is C_1-6Alkylidene.

The example of alkyl group includes, but is not limited to, methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), n-propyl (n- Pr、-CH₂CH₂CH₃), isopropyl (i-Pr ,-CH (CH₃)₂), normal-butyl (n-Bu ,-CH₂CH₂CH₂CH₃), isobutyl group (i-Bu ,- CH₂CH(CH₃)₂), sec-butyl (s-Bu ,-CH (CH₃)CH₂CH₃), tert-butyl (t-Bu ,-C (CH₃)₃), n-pentyl (- CH₂CH₂CH₂CH₂CH₃), 2- amyl (- CH (CH₃)CH₂CH₂CH₃), 3- amyl (- CH (CH₂CH₃)₂), 2- methyl -2- butyl (- C (CH₃)₂CH₂CH₃), 3- methyl -2- butyl (- CH (CH₃)CH(CH₃)₂), 3- methyl-1-butyl (- CH₂CH₂CH(CH₃)₂), 2- first Base -1- butyl (- CH₂CH(CH₃)CH₂CH₃), 2- ethyl -1- butyl (- CH₂CH(CH₂CH₃)CH₂CH₃), n-hexyl (- CH₂CH₂CH₂CH₂CH₂CH₃), 2- hexyl (- CH (CH₃)CH₂CH₂CH₂CH₃), 3- hexyl (- CH (CH₂CH₃)(CH₂CH₂CH₃))、2- Methyl -2- amyl (- C (CH₃)₂CH₂CH₂CH₃), 3- methyl -2- amyl (- CH (CH₃)CH(CH₃)CH₂CH₃), 4- methyl -2- penta Base (- CH (CH₃)CH₂CH(CH₃)₂), 3- methyl -3- amyl (- C (CH₃)(CH₂CH₃)₂), 2- methyl -3- amyl (- CH (CH₂CH₃)CH(CH₃)₂), 2,3- dimethyl -2- butyl (- C (CH₃)₂CH(CH₃)₂), 3,3- dimethyl -2- butyl (- CH (CH₃) C(CH₃)₃), n-heptyl, n-octyl, etc..

Term " amino " refers to "-NH₂”。

Term " hydroxyl " refers to "-OH ".

Term " cyano " refers to "-CN " or "-C ≡ N ".

Term " halogen " refers to F, Cl, Br or I.

Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is a carbon-to-carbon sp²Double bond, wherein the alkenyl group can be retouched optionally by one or more present invention Replaced the substituent group stated comprising the positioning of " cis " and " tans ", or the positioning of " E " and " Z ".In one embodiment, Alkenyl group includes 2-10 carbon atom；In one embodiment, alkenyl group includes 2-6 carbon atom；In another embodiment party In case, alkenyl group includes 2-4 carbon atom.The example of alkenyl group includes, but is not limited to, vinyl (- CH=CH₂)、 Allyl (- CH₂CH=CH₂), acrylic (- C=CHCH₃), isopropenyl (- C (CH₃)=CH₂) etc..

Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, that is, there is tri- key of carbon-to-carbon sp, wherein the alkynyl group can be retouched optionally by one or more present invention Replaced the substituent group stated.In one embodiment, alkynyl group includes 2-6 carbon atom；In yet another embodiment, one In embodiment, alkynyl group includes 2-10 carbon atom；Alkynyl group includes 2-4 carbon atom.The example packet of alkynyl group It includes, but is not limited to, acetenyl (- C ≡ CH), propargyl (- CH₂C ≡ CH), 1- propinyl (- C ≡ C-CH₃) etc..

Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.In one embodiment, alkoxy base contains 1-6 carbon atom；In another embodiment, Alkoxy base contains 1-4 carbon atom；In yet another embodiment, alkoxy base contains 1-3 carbon atom.The alcoxyl Replaced the substituent group that base group can be described optionally by one or more present invention.

The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH₃), ethyoxyl (EtO ,- OCH₂CH₃), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH₂CH₂CH₃), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH₃)₂), 1- butoxy (n-BuO, n- butoxy ,-OCH₂CH₂CH₂CH₃), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH₂CH(CH₃)₂), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH₃)CH₂CH₃), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH₃)₃), 1- amoxy (n- amoxy ,-OCH₂CH₂CH₂CH₂CH₃), 2- amoxy (- OCH (CH₃) CH₂CH₂CH₃), 3- amoxy (- OCH (CH₂CH₃)₂), 2- methyl -2- butoxy (- OC (CH₃)₂CH₂CH₃), 3- methyl -2- fourth Oxygroup (- OCH (CH₃)CH(CH₃)₂), 3- methyl-l- butoxy (- OCH₂CH₂CH(CH₃)₂), 2- methyl-l- butoxy (- OCH₂CH(CH₃)CH₂CH₃), etc..

Term " heterocycle " and " heterocycle " are used interchangeably here, all refer to comprising 3-12 annular atom, unit price or The monocyclic, bicyclic or tricyclic of multivalence, wherein at least one annular atom are selected from nitrogen, sulphur and oxygen atom, and ring can be fully saturated Or comprising one or more degrees of unsaturation, but an armaticity ring cannot all have.Unless otherwise stated, heterocycle can be carbon-based Or nitrogen base, and-CH₂Group can be substituted optionally by-C (=O)-.The sulphur atom of ring can optionally be oxidized to S- oxidation Object.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compound.In some embodiments, heterocycle is the miscellaneous of 3-7 member Ring group；In other embodiments, heterocycle is the heterocycle of 4-7 member；In other embodiments, heterocycle is The heterocycle of 3-6 member；In other embodiments, heterocycle is the heterocycle of 4-6 member；In other embodiment In, heterocycle is the heterocycle of 5-6 member；In other embodiments, the heterocycle that heterocycle is 5 yuan；In other In embodiment, heterocycle is 6 yuan of heterocycle；In other embodiments, the heterocycle that heterocycle is 7 yuan.Heterocycle The example of base includes, but are not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- Pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran Base, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, 1,3- dioxol base, two sulphur cyclopenta, oxinane Base, dihydro pyranyl, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, tetrahydro-pyrimidine base, dioxane, piperidyl, Quinoline base, thio-morpholinyl, piperazinyl, dioxanes base, dithianyl, thiophene oxane base, high piperazine base, homopiperidinyl, oxepane Alkyl, Isosorbide-5-Nitrae-oxaza heptane base, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulphur azepineBase, indoline Base, 1,2,3,4- tetrahydro isoquinolyl, 1,3- benzo two dislike cyclopentadienyl, 2- oxa- -5- azabicyclo [2.2.1] hept- 5- base.Heterocycle - CH in base₂Group includes, but are not limited to 2- oxo-pyrrolidine base, oxo -1,3-thiazoles alkane by-C (=the O)-example replaced Base, 2- oxo-azepan base, 2- piperidone base, 3,5- dioxy piperazine piperidinyl and hybar X base.Sulphur atom in heterocycle The example being oxidized includes, but are not limited to sulfolane base, 1,1- dioxothiomorpholinyl, etc..The heterocyclyl groups It can be optionally replaced one or more substituent groups described in the invention.

Term " carbocylic radical " or " carbocyclic ring " indicate containing 3-12 carbon atom, monovalent or multivalence nonaromatic saturation Or part unsaturated monocycle, bicyclic or three-ring system.Carbon bicyclic group includes spiral shell carbon bicyclic group and condensed carbon bicyclic group, suitably Carbocylic radical group includes, but is not limited to, naphthenic base, cycloalkenyl and cycloalkynyl radical.In some embodiments, " carbocylic radical " or " carbocyclic ring " is C_3-10Carbocylic radical or 3-10 member carbocyclic ring；In other embodiments, " carbocylic radical " or " carbocyclic ring " is C_3-7Carbocylic radical Or 3-7 member carbocyclic ring；In other embodiments, " carbocylic radical " or " carbocyclic ring " is C_4-7Carbocylic radical or 4-7 member carbocyclic ring；Another In a little embodiments, " carbocylic radical " or " carbocyclic ring " is C_4-6Carbocylic radical or 4-6 member carbocyclic ring are in other embodiment, " carbocyclic ring Base " or " carbocyclic ring " are C_3-6Carbocylic radical or 3-6 member carbocyclic ring.Such example further comprises, cyclopropyl, cyclobutyl, cyclopenta, Cyclopentenyl (1- cyclopenta -1- alkenyl, 1- cyclopenta -2- alkenyl, 1- cyclopenta -3- alkenyl), cyclopentadienyl group (2,4- ring penta Dialkylene, 1,3- cyclopentadienyl group), cyclohexyl, cyclohexenyl group (1- cyclohexyl -1- alkenyl, 1- cyclohexyl -2- alkenyl, 1- hexamethylene Base -3- alkenyl), cyclohexadienyl (1,3- cyclohexadienyl, 1,4- cyclohexadienyl), suberyl, cyclooctyl, cyclononyl, ring Decyl, ring undecyl, cyclo-dodecyl, etc..The carbocylic radical group can be optionally by one or more present invention Replaced described substituent group.

Term " naphthenic base " indicates containing 3-12 carbon atom, monovalent or multivalence saturation monocycle, bicyclic or three ring bodies System.In some embodiments, naphthenic base includes 3-6 carbon atom, i.e. C_3-6Naphthenic base.The specific example of naphthenic base includes, but Be not limited to, cyclopropyl agent, cyclopenta, cyclohexyl, suberyl, etc..The group of naphthene base can be independently unsubstituted or by one Replaced a or multiple substituent groups described in the invention.

Term " aryl " indicates the monocycle containing 6-14 annular atom or 6-12 annular atom or 6-10 annular atom, double The carbocyclic ring system of ring and tricyclic, wherein at least one ring system be it is aromatic, wherein each ring system include 3-7 original Molecular ring, and there are one or more attachment points to be connected with the rest part of molecule.In some embodiments, aryl includes 6-10 carbon atom, i.e. C_6-10Aryl.The example of aryl group may include phenyl, naphthalene and anthracene.The aryl group can be with Individually optionally replaced one or more substituent groups described in the invention.

Monocycle of term " heteroaryl " expression containing 5-12 annular atom or 5-10 annular atom or 5-6 annular atom, Bicyclic and three-ring system, wherein at least one ring system are aromatic, and at least one ring system includes one or more miscellaneous Atom (hetero atom include nitrogen, phosphorus, oxygen or sulphur), wherein each ring system includes the 5-7 molecular ring of original, and have one or Multiple attachment points are connected with molecule rest part.Term " heteroaryl " can be handed over term " hetero-aromatic ring " or " heteroaromatics " Change use.In some embodiments, heteroaryl groups are the heteroaryl of 5-6 member；In other embodiments, heteroaryl base The heteroaryl that group is 5 yuan；In other embodiments, the heteroaryl that heteroaryl groups are 6 yuan.The example packet of heteroaryl groups It includes, but is not limited to, 2- furyl, 3- furyl, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazole Base, 4- isoxazolyl, 5- isoxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazolyl, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrroles Base, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, pyridazinyl (such as 3- pyridazinyl), 2- thiazolyl, 4- thiazolyl, 5- thiazolyl, tetrazole radical (such as 5- tetrazole radical), triazolyl (such as 2- triazolyl and 5- triazolyl), 2- Thienyl, 3- thienyl, pyrazolyl (such as 2- pyrazolyl), isothiazolyl, 1,2,3- oxadiazoles base, 1,2,5- oxadiazoles base, 1, 2,4- oxadiazoles base, 1,2,3- triazolyl, 1,2,3- thio biphosphole base, 1,3,4- thio biphosphole base, 1,2,5- thio biphosphole base, Pyrazinyl, cyanuro 1,3,5；It also include below bicyclic, but it is bicyclic to be not limited to these: benzimidazolyl, benzofuran Base, benzothienyl, indyl (such as 2- indyl), purine radicals, quinolyl (such as 2- quinolyl, 3- quinolyl, 4- quinolyl), Isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl), imidazo [1,2-a] pyridyl group, pyrazolo [1,5- A] pyridyl group, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1,2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1,5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridyl group, etc..

Term " aryloxy group " indicates that aryl group is connected by oxygen atom with the rest part of molecule.Wherein aryl group has There is meaning as described in the present invention.In one embodiment, aryloxy group contains 6-10 carbon atom, i.e. C_6-10Aryloxy group. The example of aryloxy group includes, but are not limited to: phenoxy group, naphthoxy, etc..The aryloxy group can be optionally by one Or replaced the substituent group that describes of multiple present invention.

Term " halogenated alkyl " indicates the alkyl replaced by one or more halogens.In some embodiments, halogenated alkyl Group indicates the halogenated alkyl containing 1-6 carbon atom, i.e. C_1-6Halogenated alkyl；In other embodiments, halogenated alkyl base Group indicates the halogenated alkyl containing 1-4 carbon atom, i.e. C_1-4Halogenated alkyl；In other embodiments, halogenated alkyl group Indicate the halogenated alkyl containing 1-3 carbon atom, i.e. C_1-3Halogenated alkyl.Such example include, but are not limited to trifluoromethyl, Difluoromethyl, a methyl fluoride, 1,2- Dichloroethyl, 1,2- bis-fluoro ethyls, etc..

Term " hydroxy alkyl " indicates the alkyl replaced by one or more hydroxyls.In some embodiments, hydroxy alkyl Group indicates the hydroxy alkyl containing 1-6 carbon atom, i.e. C_1-6Hydroxy alkyl；In other embodiments, hydroxy alkyl base Group indicates the halogenated alkyl containing 1-4 carbon atom, i.e. C_1-4Hydroxy alkyl；In other embodiments, hydroxyalkyl groups Indicate the hydroxy alkyl containing 1-3 carbon atom, i.e. C_1-3Hydroxy alkyl.Such example includes, but are not limited to methylol, hydroxyl Ethyl, 1,2- dihydroxy ethyl, 1- hydroxypropyl, 2- hydroxypropyl, -2 methyl-propyl of 2- hydroxyl, hydroxyl butyl, etc..

Term " alkoxyalkyl " indicates the alkyl replaced by one or more alkoxies.In some embodiments, alcoxyl Base alkyl group is indicated by a C_1-6The C that alkoxy replaces_1-6Alkyl, i.e. C_1-6Alkoxy C_1-6Alkyl；Implement in other In example, alkoxy-alkyl group is indicated by a C_1-4The C that alkoxy replaces_1-4Alkyl, i.e. C_1-4Alkoxy C_1-4Alkyl；In addition In some embodiments, alkoxy-alkyl group is indicated by a C_1-3The C that alkoxy replaces_1-3Alkyl, i.e. C_1-3Alkoxy C_1-3Alkane Base；In other embodiment, alkoxy-alkyl group is indicated by a C_1-3The C that alkoxy replaces_1-4Alkyl, i.e. C_1-3Alcoxyl Base C_1-4Alkyl.Such example includes, but are not limited to methoxy, methoxy ethyl, ethoxyl methyl, ethyoxyl second Base, ethoxycarbonyl propyl, methoxy-propyl, etc..

Term " halogenated alkoxy " indicates the alkoxy replaced by one or more halogens.In some embodiments, halogenated Alkoxy base indicates the halogenated alkyl containing 1-6 carbon atom, i.e. C_1-6Halogenated alkyl；In other embodiments, halogenated Alkyl group indicates the halogenated alkyl containing 1-4 carbon atom, i.e. C_1-4Halogenated alkyl；In other embodiments, alkyl halide Base group indicates the halogenated alkyl containing 1-3 carbon atom, i.e. C_1-3Halogenated alkyl.Such example includes, but are not limited to three Fluorine methoxyl group, difluoro-methoxy, single fluorine-substituted methoxyl group, 1,2- difluoroethoxy, etc..

As described in the present invention, substituent group (R⁰)_n1The ring system formed on the ring at center is keyed to (such as formula f by one It is shown) represent n1 substituent R⁰It any on ring can may replace or any reasonable position is replaced.For example, formula f generation Any possible substituted position can be by n1 substituent R on table ring⁰Replace.

As described in the present invention, unless otherwise detailed instructions, ring substituents can be by any attachable on ring Position is connected with molecule rest part.For example, piperidyl includes piperidin-1-yl, piperidin-2-yl, piperidines -3- base and piperidines -4- Base.

Unless otherwise indicated, structural formula described in the invention includes that (such as mapping is different for all isomeric forms Structure, diastereo-isomerism and geometrical isomerism (or conformational isomerism)): such as R, S configuration containing asymmetric center, (Z) of double bond, (E) isomers, and the conformer of (Z), (E).Therefore, the single three-dimensional chemical isomer of the compound of the present invention or its is right Reflect isomers, the mixture of diastereoisomer or geometric isomer (or conformer) belongs to the scope of the present invention.

Unless otherwise indicated, structural formula described in the invention and the compound include all isomerisms Form (such as enantiomerism, diastereo-isomerism, geometrical isomerism or conformational isomerism), nitrogen oxides, hydrate, solvate, metabolism Product, pharmaceutically acceptable salt and prodrug.Therefore, the single three-dimensional chemical isomer, enantiomerism of the compound of the present invention Body, diastereoisomer, geometric isomer, conformer, nitrogen oxides, hydrate, solvate, metabolite, pharmacy The compound of upper acceptable salt and prodrug also belongs to the scope of the present invention.In addition, unless otherwise indicated, the present invention is retouched The structural formula for the compound stated includes the enriched isotope of one or more different atoms.

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

Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.

Following documents: T.Higuchi and V.Stella, Pro- can be referred to by completely discussing about pro-drug drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。

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

The definition of neutral body chemistry of the present invention and the use of convention are typically referenced to following documents: S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.

The compound of the present invention may include asymmetric center or chiral centre, therefore there are different stereoisomers. All stereoisomeric forms in any ratio of the compound of the present invention, including but not limited to, diastereomer, enantiomter hinder and turn isomery Body and their mixture, such as racemic mixture constitute a part of the invention.Many organic compounds are all with optics Active form exists, i.e. the plane of their capable Plane of rotation polarised lights.When describing optically active compound, prefix D, L Or R, S are used to indicate the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used to name compound linearly polarized light The symbol of rotation, (-) or l refer to compound be it is left-handed, prefix (+) or d refer to that compound is dextrorotation.These alloisomerisms The chemical structure of body is identical, but their stereochemical structure is different.Specific stereoisomer can be enantiomer, different The mixture of structure body is commonly referred to as enantiomeric mixture.The mixture of enantiomers of 50:50 be referred to as racemic mixture or Racemic modification, this, which may cause in chemical reaction process, does not have stereoselectivity or stereoselectivity.Term " racemic mixing Object " and " racemic modification " refer to the mixture of equimolar two enantiomters, lack optical activity.

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

Term " tautomer " or " tautomeric form " refer to that the isomer of the structure of different-energy can be with Pass through the mutual inversion of phases of low energy barrier.Such as proton tautomer (i.e. prototropic tautomer) includes passing through proton transfer Interconversion, such as the isomerization of keto-enol and imine-enamine.Valence (chemical valence) tautomer includes Recombinate the interconversion of bonding electrons.

" chirality " be with its mirror image cannot be overlapped property molecule；And " achirality " refer to can be overlapped with its mirror image Molecule.

" enantiomter " refers to two isomers that cannot be overlapped but be mutually mirror of a compound.

" diastereoisomer " refer to there are two or multiple chiral centers and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral property and reactivity.Diastereoisomer is mixed Such as electrophoresis and chromatography, such as HPLC can be operated by high resolution analysis to separate by closing object.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. documented.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphur Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that alkali appropriate obtains includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.The present invention is also intended to contemplate any The compound of the group of included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C_1-8Sulphonic acid compound and aromatic sulphonic acid compound.

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

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

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

Any disease of term " treatment " or illness as used in the present invention, refer to improvement disease in some of these embodiments Disease or illness (development for slowing down or prevent or mitigate disease or its at least one clinical symptoms).In other embodiments In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In a little embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (such as stable body Parameter) or above-mentioned two aspect adjust disease or illness.In other embodiments, " treatment ", which refers to, prevents or delays disease or disease Breaking-out, generation or the deterioration of disease.

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

On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, for example, its In there are radioactive isotopes, such as³H,¹⁴C and¹⁸Those of F compound, or wherein there is non radioactive isotope, such as²H and¹³C.The compound of such isotope enrichment can be used for being metabolized research and (use¹⁴C), Reaction kinetics research are (using for example²H or³H), detection or imaging technique, such as positron emission tomography (PET) or including drug or substrate tissue measure of spread Single photon emission computed tomography (SPECT), or can be used in the radiotherapy of patient.¹⁸The compound of F enrichment to PET or It is especially desirable for SPECT research.Compound shown in the formula (I) of isotope enrichment can be ripe by those skilled in the art It is substituted described by the embodiment and preparation process in routine techniques or the present invention known using suitable isotope labeling reagent former Carry out used unmarked reagent to prepare.

On the other hand, the present invention relates to the intermediates of preparation formula (I), (II), (III) or (IV) compound for being included.

On the other hand, the preparation of the compound for being included the present invention relates to formula (I), (II), (III) or (IV), separation and The method of purifying.

On the other hand, the present invention provides a kind of pharmaceutical composition, described pharmaceutical composition include the compounds of this invention and its Pharmaceutically acceptable adjuvant.In some embodiments, adjuvant of the present invention includes but is not limited to carrier, excipient, Diluent, solvent or their combination.In some embodiments, pharmaceutical composition can be liquid, solid, and semisolid coagulates Glue or spray-type.

In addition, higher isotope especially deuterium (that is,²H or D) substitution can provide certain treatment advantages, these advantages are By the higher bring of metabolic stability.For example, Half-life in vivo increase or reduction of volume requirements or therapeutic index obtain improving band Come.It should be appreciated that the deuterium in the present invention is seen as the substituent group of formula (I), (II), (III) or (IV) compound.It can be with together The plain enrichment factor in position defines the concentration of such higher isotope especially deuterium.Term " isotope enrichment used in the present invention The factor " refers to the ratio between the isotope abundance and natural abundance of specified isotope.If the substitution of the compounds of this invention Base is designated as deuterium, and the compound is for each specified D-atom at least 3500 (52.5% at each specified D-atom Deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% deuterium is mixed Enter), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporations), At least 6466.7 (97% deuterium incorporations), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuterium incorporations) Isotope enrichment factor.The pharmaceutical solvate of the present invention include wherein recrystallisation solvent can be isotope and replace for example D₂O, acetone-d₆、DMSO-d₆Those of solvate.

The description of the compounds of this invention

The compounds of this invention can effectively inhibit tumor cell proliferation as IAP inhibitor, can be used for preparing prevention and control Treat the drug of cancer.

On the one hand, the present invention provides a kind of compound, has the structure as shown in formula (I), (II), (III) or (IV), or Stereoisomer, geometric isomer, the tautomer, nitrogen oxidation of structural compounds shown in formula (I), (II), (III) or (IV) Object, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

Wherein,

N1 is 1,2,3,4,5,6 or 7；

Each n2 independently is 0,1,2,3,4,5,6 or 7；

Each n3 independently is 0,1,2,3,4,5,6,7,8 or 9；

Each m independently is 0,1,2,3,4 or 5；

Q is 1,2,3 or 4；

U is 1 or 2；

Q²For covalent bond or-CH₂-；

Cy is following subformula:

Wherein, each t₁It independently is 1,2,3 or 4；

Each t₂It independently is 1 or 2；

Each t₃It independently is 0,1,2 or 3；

Wherein each subformula (Cy-i), (Cy-ii), (Cy-iii), (Cy-iv), (Cy-v) and (Cy-vi) is individually optional Ground is taken by 1,2,3 or 4 substituent group selected from D, F, Cl, Br, hydroxyl, alkyl, naphthenic base, heterocycle, alkoxy and amino Generation；

Each R¹、R²、R³、R^3aAnd R⁵It independently is H, D, alkyl, alkenyl, alkynyl or carbocylic radical, wherein the alkyl, alkene Base, alkynyl and carbocylic radical it is respectively individually optional by 1,2,3 or 4 be selected from D, F, Cl, Br, hydroxyl, alkyl, naphthenic base, heterocycle Base, alkoxy, phenyl and amino substituent group replaced；

Each R⁴It independently is H, D or alkyl；

Each R⁰It independently is D, F, Cl, Br, oxo (=O), cyano, hydroxyl, halogenated alkyl, hydroxy alkyl, haloalkoxy Base, alkoxyalkyl ,-NR⁸R⁹, aryloxy group, heterocycle ,-S (=O)-R¹⁰,-S (=O)₂-R¹⁰、-COOR⁸, aryl, alkoxy or Alkyl；Or, two R⁰3-7 member carbocyclic ring or 3-7 circle heterocyclic ring are formed together with the carbon atom being connected with them；It is halogenated described in wherein Alkyl, hydroxy alkyl, halogenated alkoxy, alkoxyalkyl, aryloxy group, heterocycle, aryl, alkoxy, alkyl, 3-7 member carbocyclic ring With 3-7 circle heterocyclic ring it is respectively individually optional by 1,2,3 or 4 be selected from D, F, Cl, Br, hydroxyl, alkyl, naphthenic base, heterocycle, alkane Replaced the substituent group of oxygroup, aryl and amino；

Each R⁶It independently is H, D, F, Cl, Br, alkyl, hydroxyl, amino, cyano or alkoxy, wherein the alkyl, ammonia Base and alkoxy it is respectively individually optional by 1,2,3 or 4 be selected from D, F, Cl, Br, hydroxyl, alkyl, naphthenic base, heterocycle, alkane Replaced the substituent group of oxygroup and amino；

Each R⁷It independently is H, D, alkyl, F, Cl, Br or amino；

Each R⁸、R⁹It independently is H, D, alkyl, naphthenic base, heterocycle, aryl or heteroaryl；The wherein alkyl, cycloalkanes Base, heterocycle, aryl and heteroaryl it is respectively individually optional by 1,2,3 or 4 be selected from D, F, Cl, Br, hydroxyl, alkyl, cycloalkanes Base, heterocycle, alkoxy, aryl and amino substituent group replaced；With

Each R¹⁰It independently is amino, alkyl, naphthenic base, heterocycle, aryl or heteroaryl；Wherein the amino, alkyl, Naphthenic base, heterocycle, aryl and heteroaryl it is respectively individually optional by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, alkyl, Naphthenic base, heterocycle, alkoxy, aryl and amino substituent group replaced.

In some embodiments, each subformula (Cy-i), (Cy-ii), (Cy-iii), (Cy-iv), (Cy-v) and (Cy-vi) D, F, Cl, Br, hydroxyl, C respectively are selected from by 1,2,3 or 4 individually optionally_1-4Alkyl, C_3-6Naphthenic base, 3-6 member are miscellaneous Ring group, C_1-4Replaced the substituent group of alkoxy and amino.

In some embodiments, each R¹、R²、R³、R^3aAnd R⁵It independently is H, D, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl Or 3-10 member carbocylic radical, wherein the C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl and 3-10 member carbocylic radical are respectively individually optional D, F, Cl, Br, hydroxyl, C are selected from by 1,2,3 or 4_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Alkoxy, phenyl and Replaced the substituent group of amino；

Each R⁴It independently is H, D or C_1-6Alkyl；

Each R⁰It independently is D, F, Cl, Br, oxo (=O), cyano, hydroxyl, C_1-6Halogenated alkyl, C_1-6Hydroxy alkyl, C_1-6 Halogenated alkoxy, C_1-6Alkoxy C_1-6Alkyl ,-NR⁸R⁹、C_6-10Aryloxy group, 3-7 circle heterocyclic ring base ,-S (=O)-R¹⁰,-S (=O)₂- R¹⁰、-COOR⁸、C_6-10Aryl, C_1-6Alkoxy or C_1-6Alkyl；Or, two R⁰And the shape together with the carbon atom being connected between them At 3-7 member carbocyclic ring or 3-7 circle heterocyclic ring；The wherein C_1-6Halogenated alkyl, C_1-6Hydroxy alkyl, C_1-6Halogenated alkoxy, C_1-6Alkane Oxygroup C_1-6Alkyl, C_6-10Aryloxy group, 3-7 circle heterocyclic ring base, C_6-10Aryl, C_1-6Alkoxy, C_1-6Alkyl, 3-7 member carbocyclic ring and 3-7 member Heterocycle is selected from D, F, Cl, Br, hydroxyl, C by 1,2,3 or 4 respectively individually optionally_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring Base, C_1-4Alkoxy, C_6-10Replaced the substituent group of aryl and amino；

Each R⁶It independently is H, D, F, Cl, Br, C_1-6Alkyl, hydroxyl, amino, cyano or C_1-6Alkoxy, wherein described C_1-6Alkyl, amino and C_1-6Alkoxy is selected from D, F, Cl, Br, hydroxyl, C by 1,2,3 or 4 respectively individually optionally_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Replaced the substituent group of alkoxy and amino；

Each R⁷It independently is H, D, C_1-6Alkyl, F, Cl, Br or amino；

Each R⁸、R⁹It independently is H, D, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_6-10Aryl or 5-6 member heteroaryl Base；The wherein C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_6-10Aryl and 5-6 unit's heteroaryl are respectively individually optional Ground is selected from D, F, Cl, Br, hydroxyl, C by 1,2,3 or 4_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Alkoxy, C_6-10Replaced the substituent group of aryl and amino；With

Each R¹⁰It independently is amino, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_6-10Aryl or 5-6 unit's heteroaryl； The wherein amino, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_6-10Aryl and 5-6 unit's heteroaryl are respectively independently appointed Selection of land is selected from D, F, Cl, Br, hydroxyl, C by 1,2,3 or 4_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Alkoxy, C_6-10Replaced the substituent group of aryl and amino.

In some embodiments, each R¹、R²、R³、R^3aAnd R⁵It independently is H, D, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl Or 3-10 member carbocylic radical, wherein the C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl and each individually optional ground quilt of 3-10 member carbocylic radical 1,2,3 or 4 are selected from D, F, Cl, Br, hydroxyl, C_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Alkoxy, phenyl and ammonia Replaced the substituent group of base；

Each R⁴It independently is H, D or C_1-6Alkyl；With

Each R⁷It independently is H, D, C_1-6Alkyl, F, Cl, Br or amino.

In some embodiments, each R¹、R²、R³、R^3aIt independently is H, D, C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl or 3-6 First carbocylic radical, wherein the C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl and 3-6 member carbocylic radical it is respectively individually optional by 1,2,3 Or 4 be selected from D, F, Cl, Br, hydroxyl, C_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Alkoxy, phenyl and amino Replaced substituent group.

In some embodiments, each R⁴It independently is H, D or C_1-4Alkyl.

In some embodiments, each R⁵It independently is H, D, C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl or 3-6 member carbocyclic ring Base, wherein the C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl and 3-6 member carbocylic radical it is respectively individually optional by 1,2,3 or 4 select From D, F, Cl, Br, hydroxyl, C_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4The substituent group institute of alkoxy, phenyl and amino Replace.

In some embodiments, each R¹、R²、R³、R^3aIt independently is H, D, methyl, ethyl, n-propyl, isopropyl, positive fourth Base, isobutyl group, tert-butyl ,-CH=CH₂,-CH=CH-CH₃、-CH₂- CH=CH₂,-CH=CH-CH₂CH₃-、-CH₂- CH=CH₂- CH₃、-(CH₂)₂- CH=CH₂、-C(CH₃)=CH₂-CH₃, propinyl, propargyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Cyclopentenyl, cyclopentadienyl group, cyclohexenyl group or cyclohexadienyl, wherein the methyl, ethyl, n-propyl, isopropyl, just Butyl, isobutyl group, tert-butyl ,-CH=CH₂,-CH=CH-CH₃、-CH₂- CH=CH₂,-CH=CH-CH₂CH₃-、-CH₂- CH= CH₂-CH₃、-(CH₂)₂- CH=CH₂、-C(CH₃)=CH₂-CH₃, propinyl, propargyl, cyclopropyl, cyclobutyl, cyclopenta, hexamethylene Base, cyclopentenyl, cyclopentadienyl group, cyclohexenyl group and cyclohexadienyl it is respectively individually optional by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, Cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-pyrimidine base, dioxy six Ring group, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl and amino Replaced substituent group.

In some embodiments, each R⁴It independently is H, D, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl Base or tert-butyl.

In some embodiments, each R⁵It independently is H, D, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl Base, tert-butyl ,-CH=CH₂,-CH=CH-CH₃、-CH₂- CH=CH₂,-CH=CH-CH₂CH₃-、-CH₂- CH=CH₂-CH₃、- (CH₂)₂- CH=CH₂、-C(CH₃)=CH₂-CH₃, propargyl, propinyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, ring penta Alkenyl, cyclopentadienyl group, cyclohexenyl group or cyclohexadienyl, wherein the methyl, ethyl, n-propyl, isopropyl, positive fourth Base, isobutyl group, tert-butyl ,-CH=CH₂,-CH=CH-CH₃、-CH₂- CH=CH₂,-CH=CH-CH₂CH₃-、-CH₂- CH=CH₂- CH₃、-(CH₂)₂- CH=CH₂、-C(CH₃)=CH₂-CH₃, propargyl, propinyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Cyclopentenyl, cyclopentadienyl group, cyclohexenyl group and cyclohexadienyl it is respectively individually optional by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, ring Hexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-pyrimidine base, dioxane Base, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl and amino take Replaced Dai Ji.

In some embodiments, each R⁷It independently is H, D, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl Base, tert-butyl, F, Cl, Br or amino.

In some embodiments, each R⁰It independently is D, F, Cl, Br, oxo (=O), cyano, hydroxyl, C_1-6Alkyl halide Base, C_1-6Hydroxy alkyl, C_1-6Halogenated alkoxy, C_1-6Alkoxy C_1-6Alkyl ,-NR⁸R⁹、C_6-10Aryloxy group, 3-7 circle heterocyclic ring base ,-S (=O)-R¹⁰,-S (=O)₂-R¹⁰、-COOR⁸、C_6-10Aryl, C_1-6Alkoxy or C_1-6Alkyl；Or, two R⁰It is connected with them Carbon atom be formed together 3-7 member carbocyclic ring or 3-7 circle heterocyclic ring；The wherein C_1-6Halogenated alkyl, C_1-6Hydroxy alkyl, C_1-6Halogen For alkoxy, C_1-6Alkoxy C_1-6Alkyl, C_6-10Aryloxy group, 3-7 circle heterocyclic ring base, C_6-10Aryl, C_1-6Alkoxy, C_1-6Alkyl, 3- 7 yuan of carbocyclic rings and 3-7 circle heterocyclic ring it is respectively individually optional by 1,2,3 or 4 be selected from D, F, Cl, Br, hydroxyl, C_1-4Alkyl, C_3-6Ring Alkyl, 3-6 circle heterocyclic ring base, C_1-4Alkoxy, C_6-10Replaced the substituent group of aryl and amino.

In some embodiments, each R⁸、R⁹It independently is H, D, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_6-10 Aryl or 5-6 unit's heteroaryl；The wherein C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_6-10Aryl and 5-6 member heteroaryl Base is selected from D, F, Cl, Br, hydroxyl, C by 1,2,3 or 4 respectively individually optionally_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Alkoxy, C_6-10Replaced the substituent group of aryl and amino；With

Each R¹⁰It independently is amino, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_6-10Aryl or 5-6 unit's heteroaryl； The wherein amino, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_6-10Aryl and 5-6 unit's heteroaryl are respectively independently appointed Selection of land is selected from D, F, Cl, Br, hydroxyl, C by 1,2,3 or 4_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Alkoxy, C_6-10Replaced the substituent group of aryl and amino.

In some embodiments, each R⁰It independently is D, F, Cl, Br, oxo (=O), cyano, hydroxyl, C_1-4Alkyl halide Base, C_1-4Hydroxy alkyl, C_1-4Halogenated alkoxy, C_1-4Alkoxy C_1-4Alkyl ,-NR⁸R⁹、C_6-10Aryloxy group, 3-7 circle heterocyclic ring base ,-S (=O)-R¹⁰,-S (=O)₂-R¹⁰、-COOR⁸、C_6-10Aryl, C_1-4Alkoxy or C_1-4Alkyl；Or, two R⁰And between them Connected carbon atom is formed together 3-7 member carbocyclic ring or 3-7 circle heterocyclic ring；The wherein C_1-4Halogenated alkyl, C_1-4Hydroxy alkyl, C_1-4Halogenated alkoxy, C_1-4Alkoxy C_1-4Alkyl, C_6-10Aryloxy group, 3-7 circle heterocyclic ring base, C_6-10Aryl, C_1-4Alkoxy, C_1-4Alkane Base, 3-7 member carbocyclic ring and 3-7 circle heterocyclic ring it is respectively individually optional by 1,2,3 or 4 be selected from D, F, Cl, Br, hydroxyl, C_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Replaced the substituent group of alkoxy, phenyl and amino.

In some embodiments, each R⁰It independently is D, F, Cl, Br, oxo (=O), cyano, hydroxyl, amino, trifluoro Methyl, trifluoromethoxy, hydroxymethyl, hydroxyethyl, methoxy, methoxy ethyl, ethoxyl methyl, ethyoxyl second Base ,-NR⁸R⁹,-S (=O)-R¹⁰,-S (=O)₂-R¹⁰、-COOR⁸, phenoxy group, pyrrolidinyl, piperidyl, tetrahydrofuran base, morpholine Base, piperazinyl, imidazolidinyl, phenyl, carboxyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutyl oxygen Base, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tert-butyl；Or, two R⁰With with them it Between be connected carbon atom be formed together cyclopropane, cyclobutane, pentamethylene, hexamethylene, cycloheptane, cyclopentene, cyclohexene, epoxy second Alkane, oxetanes, aziridine, 1,3- dioxolane, pyrrolidines, piperidines, piperazine, morpholine, tetrahydropyridine, tetrahydro Pyrans or tetrahydrofuran；Wherein the hydroxymethyl, hydroxyethyl, methoxy, methoxy ethyl, ethoxyl methyl, Ethoxyethyl group, phenoxy group, pyrrolidinyl, piperidyl, tetrahydrofuran base, morpholinyl, piperazinyl, imidazolidinyl, phenyl, methoxy Base, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl Base, normal-butyl, isobutyl group, tert-butyl, cyclopropane, cyclobutane, pentamethylene, hexamethylene, cycloheptane, cyclopentene, cyclohexene, epoxy Ethane, oxetanes, aziridine, 1,3- dioxolane, pyrrolidines, piperidines, piperazine, morpholine, tetrahydropyridine, four Hydrogen pyrans and tetrahydrofuran it is respectively individually optional by 1,2,3 or 4 be selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, positive third Base, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidines Base, tetrahydro-thienyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-pyrimidine base, dioxane, methoxyl group, ethyoxyl, positive third oxygen Base, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl and amino substituent group replaced.

In some embodiments, each R⁸、R⁹It independently is H, D, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, ring penta Base, piperidyl or phenyl；Wherein the methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopenta, piperidyl and phenyl are each From individually optionally by by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, Isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidines Base, piperazinyl, morpholinyl, tetrahydro-pyrimidine base, dioxane, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, positive fourth oxygen Base, isobutoxy, tert-butoxy, phenyl and amino substituent group replaced.

In some embodiments, each R¹⁰It independently is amino, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, ring penta Base, piperidyl or phenyl；Wherein amino, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopenta, piperidyl or the benzene Base is selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, positive fourth by 1,2,3 or 4 respectively individually optionally Base, isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, Piperidyl, piperazinyl, morpholinyl, tetrahydro-pyrimidine base, dioxane, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, just Butoxy, isobutoxy, tert-butoxy, phenyl and amino substituent group replaced.

In some embodiments, each R⁶It independently is H, D, F, Cl, Br, C_-6Alkyl, hydroxyl, amino, cyano or C_1-6Alkane Oxygroup, wherein the C_1-6Alkyl, amino and C_1-6Alkoxy respectively individually optionally by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, C_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Replaced the substituent group of alkoxy and amino.

In some embodiments, each R⁶It independently is H, D, F, Cl, Br, C_1-4Alkyl, hydroxyl, amino, cyano or C_1-4 Alkoxy, wherein the C_1-4Alkyl, amino and C_1-4Alkoxy respectively individually optionally by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, C_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Replaced the substituent group of alkoxy and amino.

In some embodiments, each R⁶It independently is H, D, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, positive fourth Base, isobutyl group, tert-butyl, hydroxyl, amino, cyano, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutyl Oxygroup or tert-butoxy, wherein the methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, amino, first Oxygroup, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy it is respectively individually optional by 1,2, 3 or 4 selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclopropyl, Cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, morpholinyl, tetrahydro Pyrimidine radicals, dioxane, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy Replaced substituent group with amino.

In some embodiments, Cy is following subformula:

Wherein each subformula (Cy-1), (Cy-2), (Cy-3), (Cy-4), (Cy-5), Cy-6), (Cy-7), (Cy-8), (Cy-9), Cy-10) D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl are selected from by 1,2,3 or 4 individually optionally Base, normal-butyl, isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro Thienyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-pyrimidine base, dioxane, methoxyl group, ethyoxyl, positive propoxy, isopropyl Oxygroup, n-butoxy, isobutoxy, tert-butoxy and amino substituent group replaced.

In some embodiments, the present invention provides structurings shown in the compound of structure shown in formula (V) or formula (V) It closes the stereoisomer of object, geometric isomer, tautomer, nitrogen oxides, solvate, metabolite, can pharmaceutically connect The salt or prodrug received,

Wherein, R⁰、R⁶、R⁷, m and n1 there is definition as described in the present invention.

In some embodiments, the present invention provides structures shown in the compound of structure shown in formula (VI) or formula (VI) The stereoisomer of compound, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically may be used at geometric isomer The salt or prodrug of receiving,

Wherein, R⁰There is definition as described in the present invention with n1.

On the other hand, the present invention provides a kind of compound, there is knot shown in structure described in formula (VII) or formula (VII) The stereoisomer of structure compound, geometric isomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically Acceptable salt or prodrug,

Wherein,

Each R¹、R²、R³、R^3aAnd R⁵It independently is H, D, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl or 3-10 member carbocylic radical, Described in C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl and 3-10 member carbocylic radical it is respectively individually optional by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, C_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4The substituent group of alkoxy, phenyl and amino is taken Generation；

Each R⁴It independently is H, D or C_1-6Alkyl；

Each R⁷It independently is H, D, alkyl, F, Cl, Br or amino；

Wherein, each T¹And T²Stand alone as a key ,-CR¹²R¹³-、-CR¹²R¹³-O-、-O-CR¹²R¹³-、-NR¹¹-CR¹²R¹³-、- CR¹²R¹³-NR¹¹、-CR¹²R¹³)₂-、-(CR¹²R¹³)₃-、-NR¹¹,-O- or-S-；

T³For-CR¹²R¹³-、-NR¹¹,-O- or-S-；

Each R¹¹It independently is H, D, C_1-6Alkyl, hydroxyl, amino, cyano, C_1-6Alkoxy, C_3-6Naphthenic base, 3-6 circle heterocyclic ring Base or C_6-10Aryl；

Each R¹²、R¹³It independently is H, D, F, Cl, Br, hydroxyl, oxo, amino, cyano, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 Circle heterocyclic ring base or C_1-6Alkoxy；

Each R⁶It independently is H, D, F, Cl, Br, C_1-6Alkyl, hydroxyl, amino, cyano or C_1-6Alkoxy, wherein described C_1-6Alkyl, amino and C_1-6Alkoxy is selected from D, F, Cl, Br, hydroxyl, C by 1,2,3 or 4 respectively individually optionally_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Replaced the substituent group of alkoxy and amino；

Wherein each subformula Y-1a, Y-2a, Y-3a, Y-4a and Y-5a can individually optionally by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, oxo, amino, cyano, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base and C_1-6The substituent group of alkoxy It is replaced.

In some embodiments, each R¹、R²、R³、R^3aAnd R⁵Independently be H, D, methyl, ethyl, n-propyl, isopropyl, Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclopentenyl, cyclohexenyl group or phenyl, wherein the methyl, ethyl, positive third Base, isopropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclopentenyl, cyclohexenyl group and the respectively individually optional ground quilt of phenyl 1,2,3 or 4 are selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, ring Propyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, morpholine Base, tetrahydro-pyrimidine base, dioxane, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, uncle Replaced the substituent group of butoxy, phenyl and amino；

Each R⁴It independently is H, D, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tert-butyl；

Each R⁷It independently is H, D, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, F, Cl, Br Or amino；

Wherein, each R¹¹It independently is H, D, methyl, ethyl, n-propyl, isopropyl, hydroxyl, amino, cyano, methoxyl group, second Oxygroup, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, pyrrole radicals, piperazinyl, morpholinyl, tetrahydrofuran base, Piperidyl or phenyl；

Each R¹²、R¹³It independently is H, D, F, Cl, Br, hydroxyl, oxo, amino, cyano, methyl, ethyl, n-propyl, isopropyl Base, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, pyrrole radicals, piperazinyl, morpholinyl, tetrahydrofuran base, piperidyl, first Oxygroup, ethyoxyl, positive propoxy or isopropoxy；

Each R⁶Independently be H, D, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, Hydroxyl, amino, cyano, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy；

Wherein each subformula Y1a, Y2a, Y3a, Y4a, Y5a, Y6a, Y7a, Y8a, Y9a, Y10a, Y11a, Y12a, Y13a, Y14a, Y15a, Y16a, Y17a, Y18a, Y19a and Y20a can individually optionally by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, oxo, amino, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, ring Oxirane group, pyrrole radicals, piperazinyl, morpholinyl, tetrahydrofuran base, piperidyl, methoxyl group, ethyoxyl, positive propoxy or isopropyl Replaced the substituent group of oxygroup.

In some embodiments, the present invention provides structurings shown in structure described in formula (VIII) or formula (VIII) It closes the stereoisomer of object, geometric isomer, tautomer, nitrogen oxides, solvate, metabolite, can pharmaceutically connect The salt or prodrug received,

Wherein,With definition as described in the present invention.

On the other hand, compound provided by the invention has the structure or its stereoisomer, geometry of one of Isomers, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

On the other hand, the present invention provides a kind of pharmaceutical composition, comprising compound of the present invention and its pharmaceutically may be used The adjuvant of receiving.

On the other hand, the present invention provides compound of the present invention or pharmaceutical composition of the present invention and uses in preparation Purposes in the drug for preventing or treating proliferative diseases.On the other hand, the present invention provide compound of the present invention or Pharmaceutical composition of the present invention, for preventing or treating proliferative diseases.

Clever on the one hand the present invention provides a kind of method for being used for or treating proliferative diseases disease, and method includes to have given The compound of the present invention or medicine of the present invention of the pharmaceutically acceptable therapeutically effective amount of the patient of proliferative diseases Compositions.

In some embodiments, proliferative diseases of the present invention are cancers.

In some embodiments, cancer of the present invention includes, but are not limited to the carcinoma of the rectum, kidney, oophoroma, pancreas Cancer, prostate cancer, breast cancer, melanoma, glioblastoma, acute myeloid leukemia, Small Cell Lung Cancer, non-small cell lung Cancer, rhabdomyosarcoma and basal-cell carcinoma, etc..

In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure All stereoisomers all consider within the present invention, and be included in the invention as disclosed compound of present invention.When Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure Body is with regard to this clear and definition.

The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.It can be by an elevated temperature using normal Corresponding nitrogen-containing basic substance is aoxidized, or pass through in the presence of the acid of such as acetic acid with oxidant (such as hydrogen peroxide) It reacts in suitable solvent with peracid, such as is reacted in methylene chloride, ethyl acetate or methyl acetate with peracetic acid, or It is reacted in chloroform or methylene chloride with 3- chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.

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

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

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

According to another aspect, the characteristics of pharmaceutical composition of the invention include formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) compound represented, the present invention listed by compound or embodiment compound.Of the invention The amount of compound can effectively treat or mitigate the proliferative diseases of patient, including cancer in composition.

As described in the invention, the pharmaceutically acceptable composition of the present invention further includes pharmaceutically acceptable auxiliary Agent, these are as applied by the present invention, including any solvent, diluent or other liquid excipients, dispersing agent or suspending agent, Surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc. are suitable for distinctive mesh Mark dosage form.As described in following documents: In Remington:The Science and Practice of Pharmacy, 21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, the content of comprehensive document herein, show that different adjuvants can be applied to medicine The preparation of acceptable composition and their well known preparation methods on.In addition to any conventional adjuvant and chemical combination of the invention The incompatible range of object, for example, caused by any undesirable biological effect or with pharmaceutically acceptable composition it is any its The interaction that his component generates in harmful manner, their purposes are also the range that the present invention is considered.

When available for treatment, the compounds of this invention of therapeutically effective amount, especially formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) compound and its pharmaceutically acceptable salt can be used as unprocessed chemicals and give, also The active constituent that can be used as pharmaceutical composition provides.Therefore, the content of present invention also provides pharmaceutical composition, the pharmaceutical composition packet Include this compounds of this invention of therapeutically effective amount, especially formula (I), (II), (III), (IV), (V) or (VI) compound or its Pharmaceutically acceptable salt and one or more pharmaceutically acceptable adjuvants, adjuvant include but is not limited to carrier, diluent or Excipient, etc..Term as used herein " therapeutically effective amount ", which refers to, to be enough to show significant patient benefit (such as cancer is thin Born of the same parents reduce) each active component total amount.When using separate active ingredients for separate administration, which only refers to the ingredient.When When combined application, no matter the term then refers to combination, when being sequentially or simultaneously administered, all cause the group of the active constituent of therapeutic effect Resultant.The compounds of this invention, especially formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) compound and Its pharmaceutically acceptable salt is as described above.From it is compatible with preparation other compositions and to its recipient it is harmless in the sense that come It says, carrier, diluent or excipient must be acceptable.The another aspect of content according to the present invention is also provided and is used to prepare The method of pharmaceutical preparation, this method include by the compounds of this invention, especially formula (I), (II), (III), (IV), (V) or (VI) Compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers, diluent or excipient mix. Term " pharmaceutically acceptable " used in the present invention refers to such compound, raw material, composition and/or dosage form, they Within the scope of reasonable medical judgment, be suitable for contacted with patient tissue and without excessive toxicity, irritation, allergy or with conjunction Interests/Hazard ratio of reason symmetrical other problems and complication, and effective for given application.

In conjunction with one or more adjuvants with prepare one-pack type active constituent amount by must according to the host for the treatment of and Specific administration routes and change.Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) compound and carrier Material mixing with prepare single formulation active constituent amount will according to disease to be treated, the severity of disease, administration when Between, the discharge rate of administration route, compound used therefor, treatment time and patient age, gender, weight and situation and change.It is excellent The unit dosage forms of choosing are the daily dose containing hereinbefore active constituent or divided dose or the unit dosage forms of its appropriate fraction.It can use The low dose of already clearly below compound optimal dose starts to treat.Hereafter, escalated dose is come until this with lesser increment In the case of reach optimum efficiency.In general, the concentration level for most desirably giving compound is usually can be in anti-tumor aspect Effective result is provided without regard to causing any harmful or toxic side effect.

Pharmaceutical composition includes the active constituent of about 1%- about 95%, preferably from about 20%- about 90%.Medicine group of the invention Closing object can be such as unit dosage form, such as form of ampoule, bottle, suppository, dragee, tablet or capsule.

It delivers medicine to patient's for example, about dosage of the compound of formula I of the people of 70kg weight or its officinal salt and is preferably about 3mg- About 1000mg/ person/days of about 10g, more preferably from about 10mg- about 1.5g, most preferably from about 100mg-, being preferably divided into 1-3 for example can be with It is the single dose of same size.The dosage of child is the half of adult human dose.

Pharmaceutical composition provided by the invention include therapeutically effective amount one or more formulas (I) provided by the invention, (II), (III), (IV), (V), (VI), (VII) or (VIII) compound, is used to prevent, treat or improve excess proliferative One or more symptoms of disease or the related illness of -9 activity of living with Caspase Activity, including caspase.These Disease or illness include but is not limited to excess proliferative disease, autoimmune disease, psoriasis, hyperplasia and restenosis.

Pharmaceutical composition is suitable for being administered by any suitable approach, for example, by oral (including oral cavity or sublingual), directly Intestines, nose, part (including oral cavity, sublingual or percutaneous), vagina or parenteral (including subcutaneous, intradermal, intramuscular, intra-articular, synovial membrane It is interior, breastbone is interior, intrathecal, intralesional, intravenous or intradermal injection or infusion) approach.Can by art of pharmacy it is any Perception method prepares this kind of preparation, such as by mixing active constituent with carrier or excipient.It is preferred that being administered orally or being administered to Medicine.

When furthermore needing or is required, suitable adhesive, lubricant, disintegrating agent and colorant can also be mixed mixture In.Suitable adhesive includes starch, gelatin, natural sugar (such as glucose or beta lactose), corn sweetener, natural and synthesis Gummy (such as gum arabic, tragacanth or mosanom), carboxymethyl cellulose, polyethylene glycol etc..For these dosage forms Lubricant includes enuatrol, sodium chloride etc..Disintegrating agent includes but is not limited to starch, methylcellulose, agar, bentonite, xanthan Glue etc..For example, lubricant and disintegrating agent is added by the way that pulverulent mixture, granulation or pre- tabletting is made, and it is tabletted, to make At tablet.By the compound suitably crushed and diluent as described above or base-material, optionally with adhesive, (such as carboxymethyl is fine Tie up element, alginates, gelatin or polyvinylpyrrolidone), dissolve inhibitor (such as paraffin), absorbsion accelerator (quaternary salt) and/or Absorbent (such as bentonite, kaolin or Dicalcium Phosphate) mixing, to prepare pulverulent mixture.Useful binders (such as syrup, shallow lake Slurry, mucialga of arabic gummy (acadiamucilage) or cellulosic material or polymeric material solution) wetting after pressurize sieving, by powder Shape granulating mixture.One alternative of granulation is pulverulent mixture can be passed through tablet press machine, the result is that bad by being formed Agglomerate smashes particle is made again.Can be by the way that stearic acid, stearate be added, talcum powder or mineral oil make particle lubrication to prevent from gluing Onto the punch die of tablet press machine.Then the mixture through lubricating is tabletted.The compound of the content of present invention can also be with free flow Dynamic inert carrier mixing, can be tabletted without passing through granulation or pre- tableting step.Can provide it is transparent or opaque by The protectiveness packet of shellac seal coat, sugar-coat or polymeric material clothing and wax polishing clothing (polish coating of wax) composition Clothing material.Dyestuff can be added in these coating materials and distinguish different unit doses.

It will be appreciated that preparation further includes related with the preparation type other than the ingredient being particularly mentioned above Other ingredients commonly used in the art, be for example suitable for oral administration this kind of preparation may include corrigent.

The purposes of the compounds of this invention and pharmaceutical composition

The characteristics of pharmaceutical composition of the invention include formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) compound, compound or embodiment compound and pharmaceutically acceptable adjuvant listed by the present invention, adjuvant For example, carrier, adjuvant or excipient, etc..Compound is suitable for the prevention and treatment of proliferative diseases in composition of the invention.

Proliferative diseases are mainly tumor disease (or cancer) (and/or any metastatic tumor).The compound of the present invention or its Pharmaceutical composition can be used for preparing treatment especially suitable for treating cancer, including tumour, such as cutaneum carcinoma, breast cancer, the cancer of the brain, neck Cancer, carcinoma of testis etc..Shifted it is especially suitable for treatment or malignant tumour.It more particularly, can composition and side through the invention Method treatment cancer include, but are not limited to following tumor type: for example astrocyte cancer, breast cancer, neck cancer, colorectal cancer, Carcinoma of endometrium, the cancer of the esophagus, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngocarcinoma, lung cancer, carcinoma of mouth, oophoroma, prostate cancer and first shape Gland cancer and sarcoma.More particularly, these compounds can be used for treating: cardia cancer: sarcoma (angiosarcoma, fiber meat Tumor, rhabdomyosarcoma, embryonal-cell lipoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma；Lung cancer: branch gas Pipe cancer (pinacocyte, undifferentiated cellule, undifferentiated maxicell, gland cancer), alveolar (bronchiole) cancer, bronchial gland Tumor, sarcoma, lymthoma, cartilage hamartoma, celiothelioma；Gastrointestinal tract site cancer: cancer of the esophagus (squamous cell carcinoma, gland cancer, smooth muscle Sarcoma, lymthoma), gastric cancer (cancer, lymthoma, leiomyosarcoma), cancer of pancreas (duct adenocarcinoma, insulinoma, glucagonoma, Gastrinoma, carcinoid tumor, vasopressin), carcinoma of small intestine (gland cancer, lymthoma, carcinoid tumor, Kaposi sarcoma, liomyoma, Hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer it is (gland cancer, tubular adenoma, villous adenoma, hamartoma, smooth Myomata)；Genitourinary tract cancer: kidney (gland cancer, WilmShi tumour (nephroblastoma), lymthoma, leukaemia), bladder and urethra Cancer (squamous cell carcinoma, transitional cell carcinoma, gland cancer), prostate cancer (gland cancer, sarcoma), carcinoma of testis (seminoma, teratoma, Embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell cancer, fibroma, adenofibroma, adenomatoid tumor, lipoma)；Liver Dirty position cancer: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, adenoma, hemangioma；Bony site Associated cancer: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, pernicious Lymthoma (reticulosarcoma), Huppert's disease, malignant giant born of the same parents chordoma, osteochondrofibroma (osteochronfroma) (osteocartilaginous exostosis), benign chondromas, chondroblastoma, chondromyxoid fibroma (chondromyxofibroma), osteoidosteoma and giant-cell tumor；Nervous system cancer: skull cancer (osteoma, hemangioma, granulation Swollen, xanthoma, osteitis deformans), meninx cancer (meningoma, meningeal sarcoma (meningiosarcoma), glioma), The cancer of the brain (astrocytoma, neuroblastoma, glioma, ependymoma, gonioma (pinealoma), spongioblast Tumor, oligodendroglioma, neurinoma, retinoblastoma, congenital tumor), intraspinal cord neurinomas, meninges Tumor, glioma, sarcoma)；Gynecological cancer: uterine cancer (carcinoma of endometrium), cervical carcinoma (neck cancer, preneoplastic uterine neck SARS Type hyperplasia (pre-tumor cervicaldysplasia)), oophoroma (oophoroma (serous cystoma gland cancer, mucocele Gland cancer, non-classified cancer), granulosa egg capsule thecoma (granulosa-thecal cell tumors), Sai-Lay cell Tumor, dysgerminoma, malignant teratoma), carcinoma of vulva (squamous cell carcinoma, intraepithelial carcinoma, gland cancer, fibrosarcoma, melanoma), yin Road cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), salpingioma (cancer)；Blood cancer Disease: leukemia (myelocytic leukemia (acute and chronic), acute lymphoblastic leukemia, the white blood of chronic lymphocytic Disease, myeloproliferative disease, Huppert's disease, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma)；Skin cancer: chromoma, basal-cell carcinoma, squamous cell carcinoma, Kaposi sarcoma, dysplastic nevus, Lipoma, hemangioma, histiocytoma, cheloid, psoriasis；And adrenal gland cancer, neuroblastoma.Therefore, herein The term " cancer cell " of offer includes the cell with any or relevant illness determined above.

Inventionbroadly proliferative diseases can also be excess proliferative situation from of the invention, such as leukaemia, hyperplasia, Fibrosis (especially fibrosis of the pulmonary fibrosis but it is also possible to be other types of fibrosis such as kidney), angiogenesis, ox-hide The narrow or restenosis of tinea, atherosclerosis and endovascular proliferation of smooth muscle such as postangioplasty.

When mentioning tumour, tumor disease, cancer or cancer, also in addition or extraly imply in former organ or tissue and/or The metastatic tumor at any other position, the position regardless of tumour and/or metastatic tumor.

The compounds of this invention can be administered alone or be administered with other anti-cancer agent in conjunction, such as can inhibit Tumor Angiongesis Compound, such as protease inhibitors, epidermal growth factor receptor kinase inhibitor, vascular endothelial growth factor receptor kinases Inhibitor etc.；Cytotoxic drug, such as antimetabolite, such as purine and pyrimidine simulate antimetabolite；Antimitotic agent is such as Microtubule stabilization drug and antimitotic alkaloid；The complex compound of platinum coordination；Antitumor antibiotic；Alkylating agent is such as Mustargen and nitroso ureas；Endocrine agents such as adrenocorticotro, androgen, antiandrogen, estrogen, resist it is female swash It element, aromatase inhibitor, GuRH-A and SMS 201-995 and targets in tumour cell The compound of the enzyme or receptor that over-express and/or be related in the middle specific metabolic pathway raised, such as ATP and GTP phosphoric acid Diester enzyme inhibitor, histone deacetylase inhibitor, kinases inhibitor such as serine, threonine and tyrosine kinase Inhibitor, such as Abelson protein tyrosine kinase and various growth factors, their receptor and kinase inhibitor, such as table Skin growth factor receptor kinase inhibitor, vascular endothelial growth factor receptor kinase inhibitor, fibroblast growth factor suppression Preparation, insulin-like growth factor acceptor inhibitor and growth factor receptor kinase inhibitor from blood platelet etc.；Methionine Aminopeptidase inhibitor, proteasome inhibitor and cyclooxygenase-2 inhibitor, for example, cyclooxygenase-1 or -2 inhibitor.

In some embodiments, when administering drug combinations, there are two types of modes: 1) by compound of the present invention or medicine group Close object with can associated with other active medicines individual preparation is respectively prepared, two kinds of dosage forms can be identical or different, and when use can Successively to use, can also use simultaneously；Successively in use, the first drug does not lose it also in body when giving second of drug Interior useful effect；2) by the compounds of this invention or pharmaceutical composition and can associated with other active medicines single formulation is made, It is administered simultaneously.

The invention further relates to the method for the cell undergoes apoptosis for promoting fast breeding, this method includes will be quick The cell of proliferation is the same as promotion a effective amount of sheet that can be combined with the Smac binding site of XIAP and/or cIAP albumen of Apoptosis Invention formula (I), (II), (III), (IV), (V), (VI), (VII) or the contact of (VIII) compound.

In another embodiment of the present invention, the compound of the present invention or composition can with chemotherapeutant and/or With radiotherapy, immunotherapy and/or photodynamic therapy are applied together, are promoted Apoptosis and are enhanced the chemotherapy, The validity of radiotherapy, immunotherapy and/or photodynamic therapy.

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

The general synthetic method of the compounds of this invention

Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII).Under The reaction scheme and embodiment in face are for being further illustrated the contents of the present invention.

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

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

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

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

Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDC1₃Or DMSO-d₆For solvent (report is as unit of ppm), use TMS (0ppm) or chloroform (7.25ppm) as reference standard. When there is multiplet, following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t will be used (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant is indicated with hertz (Hz).

By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to low resolution mass spectrometry (MS) data DEG C) the spectrometer of Agilent 6320 series LC-MS measure, G1329A automatic sampler and G1315B DAD detector Applied to analysis, the source ESI is applied to LC-MS spectrometer.

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

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

Compound purifying is by 1100 series of high efficiency liquid chromatogram (HPLC) of Agilent come what is evaluated, and wherein UV is detected At 210nm and 254nm, Zorbax SB-C18 column, specification be 2.1 × 30mm, 4 μm, 10 minutes, flow velocity 0.6mL/min, (0.1% aqueous formic acid) of (0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.

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

The ethyl acetate solution of HCl/EA hydrochloric acid

PE petroleum ether

EA, EtOAc ethyl acetate

HCl hydrochloric acid

MeOH methanol

EtOH ethyl alcohol

DCM methylene chloride

NH₄Cl ammonium chloride

TFAA trifluoroacetic anhydride

LiOH.H₂Mono- hydronium(ion) lithia of O

NaOH sodium hydroxide

I₂Iodine

NH₄F ammonium fluoride

KHCO₃Saleratus

CuBr₂Copper bromide

(Boc)₂O di-tert-butyl dicarbonate

The chloro- 4,6- dimethoxy -1,3,5- triazine of CDMT 2-

ACN acetonitrile

BOC-L-Proline N- tertbutyloxycarbonyl-L-PROLINE

TFA trifluoroacetic acid

H₂O water

DMT-MM 4- (4,6- dimethoxy-triazine) -4- methylmorpholinium chloride

SOCl₂Thionyl chloride

EDC.HCl 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate

HBTU benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphate

DMF N,N-dimethylformamide

DIPEA N, N- diisopropylethylamine

THF tetrahydrofuran

NaCl sodium chloride

AlCl₃Alchlor

DEG C degree Celsius

Min minutes

H hours

ML, ml milliliters

Mmol mMs

G grams

Mg milligrams

N mol/L

Rt room temperature

N₂Nitrogen

TLC thin-layer chromatography

HPLC high performance liquid chromatography

Following synthetic schemes describes the step of preparation disclosed compound of present invention.Unless otherwise stated, Cy, R¹、R³、 R^3a、R⁴、R⁵、R⁶、R⁷、R⁰、m、u、q、n3、n2、n1、Q²With definition as described in the present invention.

Synthetic schemes 1

Formula (II-A) compound can be prepared by the method that synthetic schemes 1 describes, wherein R^AFor C_1-4Alkyl, it is excellent Select methyl, ethyl；R^BFor alkali metal, preferably potassium, sodium.Formula (II-1) compound is closing under acid condition (for example, HCl, etc.) It is reacted to obtain formula (II-2) compound in suitable solvent (such as ethyl acetate)；Formula (II-2) compound and R^AOH compound Esterification is carried out in suitable solvent (for example, thionyl chloride, etc.) obtains formula (II-3) compound；Formula (II-3) compound Condensation reaction, which is carried out, with formula (1) compound obtains formula (II-4) compound；Formula (II-4) compound is in alkaline condition (such as hydrogen-oxygen Change lithium) under obtain formula (II-5) compound；Formula (II-5) compound and formula (II-b) are at condensation reagent (for example, DMT-MM, etc.) In the presence of, condensation reaction occurs under alkaline condition (such as N-methylmorpholine) and obtains formula (II-a) compound；Formula (II-a) is changed Object deamination under acid condition (for example, HCl/EA solution, etc.) is closed to protect to obtain formula (II-A) compound.

Synthetic schemes 2

Formula (IV-A) compound can be prepared by the method that synthetic schemes 2 describes.Formula (IV-1) compound and formula (IV-2) in the presence of condensation reagent (for example, DMT-MM, etc.), it is anti-that condensation occurs under alkaline condition (such as N-methylmorpholine) It should obtain formula (IV-a) compound；Formula (IV-a) compound deamination under acid condition (for example, trifluoroacetic acid, etc.) is protected To formula (IV-A) compound.

Synthetic schemes 3

Formula (I-A) compound can be prepared by the method that synthetic schemes 3 describes.Formula (IV-2) compound and formula (I-b) compound occurs under alkaline condition (such as N-methylmorpholine) in the presence of condensation reagent (for example, DMT-MM, etc.) Condensation reaction obtains formula (II-a) compound；Formula (II-a) compound deamination under acid condition (for example, HCl/EA solution, etc.) Base is protected to obtain formula (I-A) compound.

Synthetic schemes 4

Compound can be prepared by the method that synthetic schemes 4 describes.Formula (IV-2) compound and formula (III-b) change Object is closed in the presence of condensation reagent (for example, DMT-MM, etc.), condensation reaction occurs under alkaline condition (such as N-methylmorpholine) Obtain formula (II-a) compound；Formula (II-a) compound deamination under acid condition (for example, HCl/EA solution, etc.) is protected To formula (III-A) compound.

Synthetic schemes 5

Formula (VII) compound can be prepared by the method that synthetic schemes 5 describes.Formula (I-V2) compound and formula (I-b1) compound occurs under alkaline condition (such as N-methylmorpholine) in the presence of condensation reagent (for example, DMT-MM, etc.) Condensation reaction obtains formula (I-a1) compound；Formula (I-a1) compound deamination under acid condition (for example, HCl/EA solution, etc.) Base is protected to obtain formula (VII) compound.

Intermediate synthetic schemes 1

Formula (I-b) compound can be prepared by the method that intermediate synthetic schemes 1 describes, wherein R^AFor C_1-4Alkane Base, preferably methyl, ethyl；X is halogen, preferably chlorine, bromine.Formula (I-b-1) compound is in lawesson reagent (lawesson's Reagent under the action of), formula (I-b-2) compound is obtained in suitable solvent (glycol dimethyl ether)；Formula (I-b-2) is changed It closes object and formula (I-b-3) compound cyclization obtains formula (I-b-4) compound；Formula (I-b-4) compound carries out in acid condition Reduction elimination reaction obtains formula (I-b-5) compound；Formula (I-b-5) compound hydrolyzes under alkaline condition (e.g., lithium hydroxide) Obtain formula (I-b-6) compound；Formula (I-b-6) compound and compound N H (OCH₃)CH₃Formula is obtained under HBTU, DIPEA effect (I-b-7) compound；Formula (I-b-7) compound reacts to obtain formula (I-b-9) compound with Grignard Reagent (I-b-8) compound； Formula (I-b-9) compound in acid condition protect to obtain formula (I-b) compound by deamination.

Embodiment

Embodiment 1:(R) -1- ((R) -6- ((R) -2- (4- (4- fluoro benzoyl) thiazol-2-yl) pyrrolidines -1- carbonyl Base) -5- azaspiro [2.4] heptane -5- base) -2- (methylamino) propane -1- ketone

Step 1:(S) -5- azaspiro [2.4] heptane -6- formic acid

(S) HCl/ is added in -5- (tertbutyloxycarbonyl) -5- azaspiro [2.4] heptane -6- potassium formate (1.60g, 5.73mmol) In EA (4N) (9.5mL), rt stirring.TLC monitors raw material fully reacting.Reaction solution is spin-dried for obtaining 0.9g white solid.

MS(ESI,pos.ion)m/z:142.1(M+H)⁺。

Step 2:(S) -5- azaspiro [2.4] heptane -6- methyl formate hydrochloride

(S) -5- azaspiro [2.4] heptane -6- formic acid (5.73mmol) is added in MeOH (10mL), -8 DEG C of low temperature, SOCl₂ (0.7mL, 10mmol) is slowly added into, and 10min is added, and after -1 DEG C of setting reaction 1.5h, rt 20min, is warming up to 50 DEG C of reactions. TLC monitors raw material fully reacting.It drains to obtain white solid 1.2g, directly casts single step reaction.

MS(ESI,pos.ion)m/z:156.1(M+H)⁺。

Step 3:(S) -5- ((S) -2- ((tertbutyloxycarbonyl) (methyl) amino) propiono) -5- azaspiro [2.4] heptane - 6- methyl formate

(S) -5- azaspiro [2.4] heptane -6- methyl formate hydrochloride (195mg, 1.0174mmol), (S) -2- ((tertiary fourth Oxygen carbonyl) (methyl) amino) propionic acid (230mg, 1.1317mmol), 2- oxime ethyl cyanoacetate (98mg, 0.68961mmol), DCM (5mL) is sequentially added in reaction flask.- 5 DEG C of low temperature, EDC.HCl (683mg, 3.563mmol) points of 4 additions, 20min are added, After 5min, DIPEA (0.95mL, 5.7mmol) is slowly added into, and about 15min is added, after 10-15min, rt stirring.TLC monitoring is former Expect fully reacting.NH₄Quenching reaction is added in Cl solution, and DCM is extracted 3 times, merges organic phase, dry, and column, PE/EA=are crossed in concentration 8:1 is eluant, eluent, obtains white solid 205mg, yield 59%.

MS(ESI,pos.ion)m/z:341.2(M+H)⁺。

Step 4:(S) -5- ((S) -2- ((tertbutyloxycarbonyl) (methyl) amino) propiono) -5- azaspiro [2.4] heptane - 6- formic acid

(S) -5- ((S) -2- ((tertbutyloxycarbonyl) (methyl) amino) propiono) -5- azaspiro [2.4] heptane -6- formic acid Methyl esters (205mg, 0.6022mmol), dioxane (2mL), LiOH.H₂O (78mg, 1.859mmol) is dissolved in H₂In O (2mL), rt Stirring.TLC monitors raw material fully reacting.Acetic acid, which is added, adjusts PH=3-4, and EA is extracted 3 times, merges organic phase, dry, is spin-dried for obtaining Transparent oil 180mg, yield 91%.

MS(ESI,pos.ion)m/z:327.2(M+H)⁺。

Step 5:((S) -1- ((S) -6- ((S) -2- (4- (4- fluoro benzoyl) thiazol-2-yl) pyrrolidines -1- carbonyl) - 5- azaspiro [2.4] heptane -5- base) -1- oxa- propane -2- base) (methyl) t-butyl carbamate

(S)-(4- fluorophenyl) (2- (pyrrolidin-2-yl) thiazole-4-yl) ketone (169mg, 0.5403mmol), DMT-MM (186mg, 0.67216mmol), (S-5- ((S) -2- ((tertbutyloxycarbonyl) (methyl) amino) propiono) -5- azaspiro [2.4] Heptane -6- formic acid (130mg, 0.3983mmol) is added in EA (6mL), -1 DEG C of low temperature bath.After 5min, N-methylmorpholine (0.21mL, 1.9mmol) is slowly added into, and 40-45min is added.After 30min, rt stirring, TLC monitors raw material fully reacting. NH₄Quenching reaction is added in Cl, and EA is extracted 3 times, merges organic phase, dry, and column is crossed in concentration, and PE/EA=3:1 is eluant, eluent, is obtained White solid 168mg, yield 60%.

MS(ESI,pos.ion)m/z:585.2(M+H)⁺。

Step 6:(S) -1- ((S) -6- ((S) -2- (4- (4- fluoro benzoyl) thiazol-2-yl) pyrrolidines -1- carbonyl) - 5- azaspiro [2.4] heptane -5- base) -2- (methylamino) propane -1- ketone

((S) -1- ((S) -6- ((S) -2- (4- (4- fluoro benzoyl) thiazol-2-yl) pyrrolidines -1- carbonyl) -5- azepine Spiral shell [2.4] heptane -5- base) -1- oxa- propane -2- base) (methyl) t-butyl carbamate (260mg, 0.4447mmol) addition In HCl/EA (4N) (9mL), rt stirring, TLC monitor raw material fully reacting.Reaction solution concentration, crosses column, and DCM/MeOH=10:1 is Eluant, eluent obtains white solid 90mg, yield 41%.

¹H NMR(400MHz,CDCl₃) δ 8.28 (dd, J=8.7,5.6Hz, 2H), 8.14 (s, 1H), 7.14 (t, J= 8.7Hz, 2H), 5.61 (dd, J=7.7,2.0Hz, 1H), 4.91 (dd, J=8.4,5.1Hz, 1H), 3.93 (dd, J=17.2, 8.8Hz, 1H), 3.69 (m, 1H), 3.59 (d, J=9.4Hz, 1H), 3.51 (d, J=9.5Hz, 1H), 3.37 (q, J=6.7Hz, 1H),2.36(s,3H),2.27(m,7H),1.28(m,3H),0.71–0.55(m,4H)。

¹³C NMR(151MHz,CDCl₃)δ185.41,173.23,172.76,170.78,166.60,164.91, (154.04,133.50 d, J=9.2Hz), 131.02,128.92,128.26,115.47,115.32,68.29,58.71, 58.42,56.62,54.79,47.25,36.76,31.56,24.75,21.42,18.05,14.17,11.63,10.89。

MS(ESI,pos.ion)m/z:485.5(M+H)⁺。

HPLC 97.2%.

Embodiment 2:(S)-N- ((S) -1- suberyl -2- (2- (4,5- dihydro -1H- naphtho- [1,2-d] imidazoles -2- base) pyrrole Cough up alkane -1- base) -2- oxoethyl) -2- (methylamino) propionyl amine isomer 1；(S)-N- ((R) -1- suberyl -2- (2- (4,5- Dihydro -1H- naphtho- [1,2-d] imidazoles -2- base) pyrrolidin-1-yl) -2- oxoethyl) -2- (methylamino) propionyl amine isomer 2

Step 1:(S) -2- ((tertbutyloxycarbonyl) (methyl) amino) propionic acid

(2S) -2- (methylamino) propionic acid (8.25g, 80.0mmol) is added in the NaOH (1N) (100mL) of -4 DEG C of low temperature Stirring and dissolving, acetone (50mL) are added, (Boc)₂O (23mL, 100mmol) is slowly added into, and 30-40min is added.After 1-1.5h, Rt stirring.TLC monitors raw material fully reacting.Acetic acid adjusts PH=4-5, and EA is extracted 3 times, and dry, concentration is spin-dried for, clear oil Object.Fraction solids, PE/EA recrystallization is precipitated.It drains to obtain white solid 10.1g.Yield 62%.

MS(ESI,neg.ion)m/z:202.1(M-H)^-。

Step 2:(S) -2- amino -2- cyclohexyl-acetic acid methyl ester hydrochloride

Cyclohexylglycine (11.2g, 71.2mmol), MeOH (40mL) are sequentially added in reaction flask.- 12 DEG C of low temperature, SOCl₂(8.2mL, 110mmol) is slowly added into, and 15-20min is added, and turbid solution becomes clarification.1.5h, rt are reacted in 0 DEG C of setting After 20min, it is warming up to 50 DEG C of reactions.TLC monitors raw material fully reacting.It drains to obtain white solid 15.5g, quantitative yield.

MS(ESI,pos.ion)m/z:172.2(M+H)⁺。

Step 3:(S) -2- ((S) -2- ((tertbutyloxycarbonyl) (methyl) amino) propionamido-) -2- cyclohexyl-acetic acid methyl esters

(S) -2- ((tertbutyloxycarbonyl) (methyl) amino) propionic acid (1.02g, 5.02mmol), (S) -2- amino -2- hexamethylene Acetic acid methyl ester hydrochloride (1.25g, 6.02mmol), EA (26mL), CDMT (0.98g, 5.6mmol) sequentially add reaction flask In.- 3 DEG C of low temperature are slowly added into N-methylmorpholine (1.9mL, 17mmol), and about 5min is added.Rt is stirred after 5min.TLC monitoring Raw material fully reacting.Reaction solution filtering, EA wash 5 filtrates, then saturated sodium bicarbonate, 10% acetic acid, sodium chloride solution according to Secondary washing.Concentration, it is eluant, eluent that column, which chromatographs PE/EA=10:1, obtains colorless oil 1.6g, yield 90%.

MS(ESI,pos.ion)m/z:379.3(M+Na)⁺。

¹H NMR(400MHz,d₆- DMSO) δ 7.93 (d, J=38.8Hz, 1H), 4.53 (d, J=45.1Hz, 1H), 4.15 (s, 1H), 3.62 (s, 3H), 2.75 (s, 3H), 1.66 (d, J=12.4Hz, 3H), 1.59 (d, J=10.4Hz, 2H), 1.52 (d, J=12.2Hz, 1H), 1.37 (s, 9H), 1.28-1.11 (m, 6H), 1.10-1.00 (m, 2H).

Step 4:(S) -2- ((S) -2- ((tertbutyloxycarbonyl) (methyl) amino) propionamide) -2- cyclohexyl-acetic acid

(S) -2- ((S) -2- ((tertbutyloxycarbonyl) (methyl) amino) propionamido-) -2- cyclohexyl-acetic acid methyl esters (1580mg, 4.432mmol) is added in acetone (15mL).0 DEG C of setting, LiOH.H₂The water of O (1250mg, 29.79mmol) (15mL) solution is added, and 5-10min is added.TLC monitors raw material fully reacting.Reaction solution concentration, water are added, and EA is extracted 3 times, do It is dry, concentration, PE/EA, low temperature recrystallization.It drains to obtain white solid 1.95g.Quantitative yield.

MS(ESI,pos.ion)m/z:297.1(M+H)⁺。

¹H NMR(400MHz,d₆- DMSO) δ 7.69 (d, J=67.9Hz, 1H), 4.58 (s, 1H), 4.11 (d, J= 6.5Hz, 1H), 2.75 (s, 3H), 1.62 (dd, J=37.4,10.7Hz, 6H), 1.38 (s, 9H), 1.20 (m, 5H), 1.09- 0.92(m,3H)。

Bromo- 3,4- dihydronaphthalene -1 (2H) -one of step 5:2-

3,4- dihydro -1 (2H)-naphthalenone (2.22g, 15.2mmol), EtOH (50mL), CuBr₂(6.22g,27.8mmol) It is added in reaction flask.40 DEG C of oil bath heating reactions, TLC monitor raw material fully reacting.Stop heating.Diatomite filtering, concentration, mistake Column, PE/EA=100:1-40:1 obtain white solid 3.3g.Yield 97%.

MS(ESI,pos.ion)m/z:225.0,227.0(M+H)⁺。

¹H NMR(400MHz,CDCl₃) δ 8.09 (d, J=7.8Hz, 1H), 7.52 (td, J=7.6,1.1Hz, 1H), 7.34 (t, J=7.6Hz, 1H), 7.31-7.24 (m, 1H), 4.75 (m, 1H), 3.31 (m, 1H), 2.92 (dt, J=17.1,4.4Hz, 1H),2.59–2.40(m,2H)。

Step 6:(2S) two carbonic acid 1- tert-butyl ester of -2- (1- oxo -1,2,3,4- naphthane -2- base) pyrrolidines -1,2-

Bromo- 3,4- dihydronaphthalene -1 (2H) -one (648mg, 2.8790mmol) of 2-, ACN (12mL), DIPEA (0.73mL, 4.4mmol), BOC-L-Proline (795mg, 3.6934mmol) is sequentially added in reaction flask, 50 DEG C of oil bath heating stirrings.TLC Monitor raw material fully reacting.NH₄Cl solution is added, and DCM is extracted 3 times, merges organic phase, dry, concentration.Cross column, PE/EA= 10:1 is eluant, eluent, obtains transparent oil 755mg, yield 73%.

MS(ESI,pos.ion)m/z:382.1(M+Na)⁺。

¹H NMR(400MHz,CDCl₃) δ 7.99 (t, J=8.4Hz, 1H), 7.50 (dd, J=12.2,6.8Hz, 1H), 7.32 (dd, J=13.1,7.0Hz, 1H), 7.26 (s, 1H), 5.66-5.49 (m, 1H), 4.50-4.33 (m, 1H), 3.51 (m, 2H),3.28–3.03(m,2H),2.32(m,4H),2.09(m,1H),1.92(m,1H),1.45(m,9H)。

Step 7:2- (4,5- dihydro -1H- naphtho- [1,2-d] imidazoles -2- base) pyrrolidines -1- t-butyl formate

The bis- carbonic acid 1- tert-butyl ester of (2S) -2- (1- oxo -1,2,3,4- naphthane -2- bases) pyrrolidines -1,2- (3340mg, 9.293mmol), ammonium acetate (4200mg, 54.487mmol), toluene (50mL) sequentially add in reaction flask.115 DEG C of oil bath heatings It is stirred at reflux reaction.TLC monitors raw material fully reacting.Water is added in reaction solution, and EA is extracted 3 times, merges organic phase, dry, concentration, Column is crossed, PE/EA=4:1 is eluant, eluent, obtains non-corresponding isomer mixture, pale solid 2.7g, yield 88%.

MS(ESI,pos.ion)m/z:340.1(M+H)⁺。

¹H NMR(400MHz,CDCl₃) δ 7.30 (s, 1H), 7.16 (dd, J=16.6,7.8Hz, 2H), 7.05 (t, J= 7.0Hz, 1H), 4.99 (d, J=5.1Hz, 1H), 3.42 (s, 2H), 2.97 (d, J=5.2Hz, 2H), 2.81 (m, 2H), 2.17 (m, 2H), 1.91 (d, J=26.2Hz, 2H), 1.54-1.43 (m, 9H).

Step 8:2- (pyrrolidin-2-yl) -4,5- dihydro -1H- naphtho- [1,2-d] imidazoles

2- (4,5- dihydro -1H- naphtho- [1,2-d] imidazoles -2- base) pyrrolidines -1- t-butyl formate (980mg, 2.887mmol) it is added in DCM (10mL).Mixed liquor is cooled to -4 DEG C, and TFA (3.1mL, 42mmol) is slowly added into, and 10min adds It is complete.Rt stirring.TLC monitors raw material fully reacting.Reaction solution concentration, drains 800mg white solid, quantitative yield.Positive HPLC Analysis non-corresponding isomers content ratio is 63:36.

MS(ESI,pos.ion)m/z:240.1(M+H)⁺。

Step 9:((S) -1- (((S) -1- cyclohexyl -2- (2- (4,5- dihydro -1H- naphtho- [1,2-d] imidazoles -2- base) pyrrole Cough up alkane -1- base) -2- oxoethyl) amino) -1- oxopropan -2- base) isomers 1 of (methyl) t-butyl carbamate and different Structure body 2

2- (pyrrolidin-2-yl) -4,5- dihydro -1H- naphtho- [1,2-d] imidazoles (354mg, 0.8136mmol), (S) -2- ((S) -2- ((tertbutyloxycarbonyl) (methyl) amino) propionamide) -2- cyclohexyl-acetic acid (517mg, 1.057mmol), DMT-MM (294mg, 1.0624mmol), EA (8mL) set -1 DEG C, and N-methylmorpholine (0.25mL, 2.3mmol) is slowly added into, 60min It adds.After 20min, it is warming up to 19 DEG C of stirrings.TLC monitors raw material fully reacting.NH₄Quenching reaction is added in Cl solution.EA extraction 3 It is secondary, merge organic phase, dry, column is crossed in concentration, and PE/EA=1:1 is eluant, eluent.It obtains: target compound isomers 1,233mg, White solid foam, yield 28%；Target compound isomers 2,187mg, transparent oil, yield 22%.

Isomers 1:MS (ESI, pos.ion) m/z:564.3 (M+H)⁺。

Isomers 2:MS (ESI, pos.ion) m/z:564.3 (M+H)⁺。

Step 10:(S)-N- ((S) -1- cyclohexyl -2- (2- (4,5- dihydro -1H- naphtho- [1,2-d] imidazoles -2- base) pyrrole Cough up alkane -1- base) -2- oxoethyl) -2- (methylamino) propionamide isomers 1

((S) -1- (((S) -1- cyclohexyl -2- (2- (4,5- dihydro -1H- naphtho- [1,2-d] imidazoles -2- base) pyrrolidines - 1- yl) -2- oxoethyl) amino) -1- oxopropan -2- base) (methyl) t-butyl carbamate isomers 1 (562mg, It 0.9970mmol) is added in DCM (20mL).Mixeding liquid temperature is cooled to -2 DEG C, and TFA (4mL) is added, and 5-10min is added, about Rt is stirred after 5min.TLC monitors raw material fully reacting.It is spin-dried for, preparation HPLC is sent to obtain 190mg white solid, yield 41%.

¹H NMR(400MHz,CDCl₃) δ 7.86 (d, J=5.0Hz, 1H), 7.73 (d, J=8.6Hz, 1H), 7.23-7.08 (m, 2H), 7.04 (m, 1H), 5.22 (dd, J=7.9,4.2Hz, 1H), 4.57 (t, J=8.0Hz, 0.5H), 4.24 (t, J= 6.9Hz, 0.5H), 3.92 (dd, J=17.0,7.5Hz, 0.5H), 3.73-3.62 (m, 1H), 3.49 (dd, J=14.4, 5.7Hz, 0.5H), 3.08 (ddd, J=28.7,23.7,16.4Hz, 2H), 2.98-2.82 (m, 3H), 2.77 (d, J=6.7Hz, 1H), 2.50 (s, 1H), 2.41 (s, 2H), 2.31 (dd, J=11.6,7.2Hz, 1H), 2.16 (dd, J=12.3,7.7Hz, 1H),2.12–2.04(m,1H),2.01–1.85(m,3H),1.84–1.50(m,8H),1.25(s,3H)。

¹³C NMR(151MHz,CDCl₃)δ177.00,175.02,172.39,169.87,128.00,126.77, (125.60,120.58,60.53,56.23,54.81 d, J=2.8Hz), 48.05,45.98,40.88,35.24 (d, J= 8.9Hz), 32.03,29.80,28.47,26.34,26.05 (dd, J=27.1,11.9Hz), 25.47,22.80,22.32, 19.81。

MS(ESI,pos.ion)m/z:464.2(M+H)⁺。

HPLC 97.6%.

Step 11:(S)-N- ((S) -1- cyclohexyl -2- (2- (4,5- dihydro -1H- naphtho- [1,2-d] imidazoles -2- base) pyrrole Cough up alkane -1- base) -2- oxoethyl) -2- (methylamino) propionamide isomers 2

((S) -1- (((S) -1- cyclohexyl -2- (2- (4,5- dihydro -1H- naphtho- [1,2-d] imidazoles -2- base) pyrrolidines - 1- yl) -2- oxoethyl) amino) -1- oxopropan -2- base) (methyl) t-butyl carbamate isomers 2 (410mg, It 0.7273mmol) is added in DCM (15mL).Mixed liquor is cooled to -2 DEG C, and TFA (3mL) is added, and 5-10min is added, about 5min Rt is stirred afterwards.TLC monitors raw material fully reacting.It is spin-dried for, preparation HPLC is sent to obtain 200mg white solid, yield 59%.

¹H NMR(400MHz,CDCl₃) δ 7.78 (d, J=6.2Hz, 1H), 7.51 (s, 1H), 7.19-7.11 (m, 2H), 7.03 (t, J=7.4Hz, 1H), 5.37 (d, J=6.6Hz, 1H), 4.29 (t, J=7.7Hz, 1H), 4.06 (t, J=7.4Hz, 1H), 3.61 (dd, J=16.8,8.9Hz, 1H), 3.06 (q, J=6.9Hz, 1H), 2.99 (t, J=7.8Hz, 2H), 2.81 (t, J=7.8Hz, 2H), 2.69 (d, J=7.4Hz, 1H), 2.31 (s, 3H), 2.21-2.07 (m, 3H), 1.90 (d, J=13.1Hz, 2H),1.85–1.64(m,7H),1.40(m,2H),1.33(s,3H)。

¹³C NMR(151MHz,CDCl₃)δ176.66,171.58,147.62,134.02,128.07,126.61, 125.43,119.98,60.32,56.63,55.66,47.54,39.84,35.10,32.06,30.52,29.93,29.75, 29.29,26.27,25.99 (d, J=11.9Hz), 24.49,22.82,19.36,14.25.

MS(ESI,pos.ion)m/z:464.2(M+H)⁺。

HPLC 93.6%.

Embodiment 3 (S)-N- ((S) -1- cyclohexyl -2- (the fluoro- 2- of (2S, 4R) -4- (4- (this formoxyl of 4- fluorine) thiazole -2- Base) pyrrolidinyl -1- base) -2- oxoethyl) -2- (methylamino) propionamide

Step 1:(2S, 4R) -1- tert-butyl 2- methyl 4- fluoropyrrolidine base -1,2- dicarboxylic acid esters

(2S, 4S) -1- tert-butyl 2- methyl 4- hydroxyl pyrrolidine -1,2- dicarboxylic acid esters (14.7g, 59.9mmol), DCM (90mL) is sequentially added in reaction flask.N₂Under protection, -62 DEG C of low temperature stirrings, diethylin sulfur trifluoride (20.5mL, It 155mmol) is slowly added into, 15-20min is added.After 90-100min, rt stirring.TLC monitors raw material fully reacting.Under low temperature, NaCl solution is added, and acutely deflates, stratification, collects organic phase, and EA is extracted 3 times, concentration.Column is crossed, PE/EA=10:1 is to wash De- agent, obtains grease 12g, yield 80%.

Step 2:(2S, 4R) -1- (tertbutyloxycarbonyl) -4- fluoropyrrolidine -2- formic acid

(2S, 4R) -1- tert-butyl 2- methyl 4- fluoropyrrolidine base -1,2- dicarboxylic acid esters (5400mg, 21.839mmol), THF (30mL) is sequentially added in reaction flask.- 8 DEG C of low temperature, LiOH.H₂The H of O (4360mg, 103.9mmol)₂O (30mL) solution adds Enter, rt stirring.TLC monitors raw material fully reacting.It is concentrated, under low temperature, concentrated hydrochloric acid is added, and PH=3-4, EA are extracted 4 times, is associated with Machine phase, it is dry, it is concentrated to get grease 3.28g, yield 64%.

MS(ESI,pos.ion)m/z:256.1(M+Na)⁺。

Step 3:(2S, 4R) -2- carbamoyl -4- fluoropyrrolidine -1- t-butyl formate

(2S, 4R) -1- (tertbutyloxycarbonyl) -4- fluoropyrrolidine -2- formic acid (800mg, 3.4299mmol), N-methylmorpholine (0.59mL, 5.4mmol), THF (10mL) are sequentially added in reaction flask.At -15 DEG C, isobutyl chlorocarbonate (1mL, It 7.915mmol) is slowly added into reaction solution, 10min is added.There is a muddiness, after 80-90min, NH₃.H₂O (25-28%) (1.6mL) It is slowly added into, 1h is added.After 15min, rt stirring.TLC monitors raw material fully reacting.Concentration, saturated sodium bicarbonate solution are added, EA is extracted 3 times, dry, concentration, and PE/EA recrystallization obtains pale yellow transparent grease 800mg, quantitative yield.

MS(ESI,pos.ion)m/z:255.1(M+Na)⁺。

¹H NMR(400MHz,CDCl₃)δ6.91(s,0.5H),6.33–5.85(m,1H),5.29–5.06(m,1H),4.94 (s, 0.5H), 4.38 (d, J=56.3Hz, 1H), 3.89 (d, J=6.7Hz, 1H), 3.63-3.35 (m, 1H), 2.50 (m, 2H), 2.21(m,1H),1.44(s,9H)。

Step 4:(2S, 4R) -2- thiocarbamoyl -4- fluoropyrrolidine -1- t-butyl formate

(2S, 4R) -2- carbamoyl -4- fluoropyrrolidine -1- t-butyl formate (850mg, 3.6598mmol), Lao Senshi Agent (1.3g, 3.2mmol) is added in glycol dimethyl ether (8mL), rt stirring.TLC monitors raw material fully reacting.Unsaturated carbonate Hydrogen sodium solution is added, and EA is extracted 3 times, dry, and column is crossed in concentration, and PE/EA=4:1 is eluant, eluent, obtains 620mg faint yellow solid, Yield 68%.

MS(ESI,pos.ion)m/z:271.0(M+Na)⁺。

¹H NMR(400MHz,CDCl₃) δ 8.45 (s, 0.5H), 8.12-7.64 (m, 1.5H), 5.19 (d, J=52.9Hz, 1H), 4.82 (t, J=8.2Hz, 1H), 4.04-3.80 (m, 1H), 3.58 (ddd, J=36.6,13.1,2.7Hz, 1H), 2.60 (d, J=36.9Hz, 1.5H), 1.96 (m, 0.5H), 1.44 (s, 9H).

Step 5:2- ((2S, 4R) -1- (tertbutyloxycarbonyl) -4- fluoropyrrolidine base -2- base) -4- hydroxyl -4,5- dihydro thiophene Azoles -4- Ethyl formate

KHCO₃(2.04g, 20.4mmol), the tertiary fourth of (2S, 4R) -2- thiocarbamoyl -4- fluoropyrrolidine -1- formic acid Ester (620mg, 2.4968mmol) is added in glycol dimethyl ether (15mL), N₂Protection, rt stir 5min.Under -1 DEG C of low temperature, The bromo- 2- oxygen of ethyl -3--propionic ester (1.3mL, 8.1mmol) is slowly added into, and 20min is added, rt stirring.TLC monitors raw material reaction Completely.Reaction solution concentration, NH₄Cl solution is added, and EA is extracted 3 times, merges, dry, is spin-dried for obtaining brown oil 1g, quantitative to receive Rate directly casts single step reaction.

MS(ESI,pos.ion)m/z:363.0(M+H)⁺。

Step 6:2- ((2S, 4R) -1- (tertbutyloxycarbonyl) -4- fluoropyrrolidine -2- base) 4-thiazolecarboxylic acid ethyl ester

2- ((2S, 4R) -1- (tertbutyloxycarbonyl) -4- fluoropyrrolidine base -2- base) -4- hydroxyl -4,5- thiazoline -4- first Acetoacetic ester (2.5mmol), DME (15mL) are sequentially added in reaction flask, N₂Protection, -1 DEG C of low temperature, pyridine (1.8mL, 22mmol) It is slowly added into, 2-3min is added.After 5-10min, TFAA (1.55mL, 11.2mmol) is slowly added into, and 25-30min is added.Three second Amine (0.69mL, 5.0mmol) is slowly added into, and about 30min is added.Reaction is overnight.TLC monitors raw material fully reacting.Concentration, mistake Column, PE/EA=5:1 are eluant, eluent.Obtain faint yellow solid 535mg, yield 62%.

MS(ESI,pos.ion)m/z:345.2(M+H)⁺。

¹H NMR(400MHz,CDCl₃) δ 8.09 (s, 1H), 5.35 (s, 1H), 5.24 (d, J=52.4Hz, 1H), 4.40 (d, J=6.8Hz, 2H), 3.88 (m, 0.5H), 3.76-3.54 (m, 1.5H), 2.84 (s, 1H), 2.40 (dd, J=95.5, 38.1Hz, 1H), 1.45 (s, 3H), 1.38 (t, J=7.0Hz, 4H), 1.29 (s, 6H).

Step 7:2- ((2S, 4R) -1- (tertbutyloxycarbonyl) -4- fluorine pyridine -2- base) 4-thiazolecarboxylic acid

2- ((2S, 4R) -1- (tertbutyloxycarbonyl) -4- fluoropyrrolidine -2- base) 4-thiazolecarboxylic acid ethyl ester (535mg, 1.553mmol)、THF(5mL)、LiOH.H₂The H of O (346mg, 8.246mmol)₂O (5mL) solution sequentially adds in reaction flask, rt Stirring.TLC monitors raw material fully reacting.Reaction solution concentration, -3 DEG C of low temperature, 1N HCl are adjusted to PH=3-4, solid are precipitated gradually, Filtering, drying obtain faint yellow solid 356mg, yield 72%.MS(ESI,pos.ion)m/z:339.0(M+Na)⁺。

Step 8:(2S, 4R) the fluoro- 2- of -4- (4- (methoxyl group (methyl) carbamyl) thiazol-2-yl) pyrrolidines -1- formic acid The tert-butyl ester

2- ((2S, 4R) -1- (tertbutyloxycarbonyl) -4- fluorine pyridine -2- base) 4-thiazolecarboxylic acid (356mg, 1.125mmol), HBTU (657mg, 1.7324mmol), DMF (8mL) are sequentially added in reaction flask.Mixed liquor is cooled to -1 DEG C of low temperature, DIPEA (0.95mL, 5.7mmol) and methoxy amine hydrochlorate (193mg, 1.98mmol) are added.Rt stirring.It is anti-that TLC monitors raw material It should be complete.NH₄Quenching reaction is added in Cl solution.EA is extracted 3 times, merges organic phase, and NaCl solution is washed 2 times, dry, concentration, PE/EA=2.5:1 is eluant, eluent, obtains white solid 350mg, yield 86%.

MS(ESI,pos.ion)m/z:382.2(M+Na)⁺。

¹H NMR(400MHz,CDCl₃) δ 7.93 (s, 1H), 5.25 (d, J=52.7Hz, 2H), 4.16-3.90 (m, 1H), 3.76 (s, 3H), 3.64 (dd, J=36.9,14.3Hz, 1H), 3.40 (s, 3H), 2.78 (s, 3H), 2.62-2.24 (m, 1H), 1.45(s,3.5H),1.30(s,6.5H)。

Step 9:(2S, 4R) the fluoro- 2- of -4- (4- (4- fluoro benzoyl) thiazol-2-yl) pyrrolidines -1- t-butyl formate

The fluoro- 2- of (2S, 4R) -4- (4- (methoxyl group (methyl) carbamyl) thiazol-2-yl) pyrrolidines -1- t-butyl formate (430mg, 0.9572mmol) is dissolved in THF (12mL).N₂Protection, is cooled to -22 DEG C of low temperature, the tetrahydro of 4- flourophenyl magnesium bromide Tetrahydrofuran solution (1N, 7mL) is slowly added into, and 1h is added, heating, maintains -11 DEG C of low temperature stirrings.TLC monitors raw material fully reacting.It is full And NH₄Reaction solution is added in Cl solution 18mL, and EA is extracted 3 times, merges organic phase, and dry, concentration, crossing column PE/EA=10:1 is to wash De- agent.Obtain grease 220mg, yield 60%.

MS(ESI,pos.ion)m/z:417.0(M+Na)⁺。

¹H NMR(400MHz,CDCl₃) δ 8.27 (s, 2H), 8.18 (s, 1H), 7.14 (t, J=7.8Hz, 2H), 5.33 (m, 2H), 4.14-3.89 (m, 1H), 3.67 (dd, J=35.8,14.0Hz, 1H), 2.83 (d, J=11.9Hz, 1H), 2.41 (dd, J =55.8,45.2Hz, 1H), 1.47 (s, 4H), 1.31 (s, 5H).

Step 10:(4- fluorophenyl) (2- ((2S, 4R) -4- fluoropyrrolidine -2- base) thiazole-4-yl) ketone

The fluoro- 2- of (2S, 4R) -4- (4- (4- fluoro benzoyl) thiazol-2-yl) pyrrolidines -1- t-butyl formate (290mg, 0.7353mmol), HCl/EA (4N) (5mL) is sequentially added, and rt stirring, TLC monitors raw material fully reacting.Reaction solution is spin-dried for obtaining 230mg white solid.Quantitative yield.

MS(ESI,pos.ion)m/z:295.1(M+H)⁺。

Step 11:((S) -1- (((S) -1- cyclohexyl -2- (the fluoro- 2- of (2S, 4R) -4- (4- (this formoxyl of 4-) thiazole -2- Base) pyrrolidinyl -1- base) -2- oxoethyl) amino) -1- oxopropan -2- base) (methyl) t-butyl carbamate

(4- fluorophenyl) (2- ((2S, 4R) -4- fluoropyrrolidine -2- base) thiazole-4-yl) ketone (78mg, 0.2650mmol), (2S) -2- [[(2S) -2- [tertbutyloxycarbonyl (methyl) amino] propiono] amino] -2- cyclohexyl-acetic acid (158mg, 0.4614mmol), DMT-MM (103mg, 0.37222mmol), EA (3mL) are added in reaction flask, -1 DEG C of low temperature bath, N-methylmorpholine (0.095mL, 0.86mmol) is slowly added into, and 10min is added.Rt stirring, TLC monitor raw material fully reacting. NH₄Quenching reaction is added in Cl.EA is extracted 3 times, merges organic phase, dry, and column is crossed in concentration.EA/ETOH=5:1 is eluant, eluent.? It is the mixture of isomers 1 and 2, ratio 1:2, total recovery 60% to white solid 98mg.

MS(ESI,pos.ion)m/z:619.2(M+H)⁺。

Step 12:(S)-N- ((S) -1- cyclohexyl -2- (the fluoro- 2- of (2S, 4R) -4- (4- (this formoxyl of 4- fluorine) thiazole -2- Base) pyrrolidinyl -1- base) -2- oxoethyl) -2- (methylamino) propionamide

((S) -1- (((S) -1- cyclohexyl -2- (the fluoro- 2- of (2S, 4R) -4- (4- (this formoxyl of 4-) thiazol-2-yl) pyrroles Alkyl -1- base) -2- oxoethyl) amino) -1- oxopropan -2- base) (methyl) t-butyl carbamate (180mg, 0.2909mmol) (isomer mixture), HCl/EA (4N) (4mL), rt stirring.TLC monitors raw material fully reacting.It is spin-dried for, 150mg crude product.Preparation HPLC obtains primary product white solid 80mg, yield 53%.MS(ESI,pos.ion)m/z: 519.2(M+H)⁺。

¹H NMR(400MHz,CDCl₃) δ 8.27 (dd, J=8.8,5.5Hz, 2H), 8.20 (s, 1H), 7.68 (d, J= 9.3Hz, 1H), 7.15 (t, J=8.7Hz, 2H), 5.66 (t, J=8.1Hz, 1H), 5.44 (s, 1H), 5.34-5.11 (m, 1H), 4.63-4.55 (m, 1H), 4.42 (dd, J=19.8,12.5Hz, 1H), 3.92-3.76 (m, 1H), 3.08 (q, J=6.9Hz, 1H),2.86–2.64(m,2H),2.37(s,3H),1.66(m 7H),1.31(s,3H),0.88(m,4H)。

¹³C NMR(101MHz,CDCl₃) δ 175.03,171.76,170.48,153.69,133.39 (d, J=9.2Hz), 129.03,115.58,115.36,92.39,90.59,60.50,56.98,54.88,54.05 53.75 (d, J=12.2Hz), 40.96,38.66,38.45,35.24,32.07,29.86 (t, J=7.8Hz), 29.49,28.41 (d, J=12.9Hz), 26.23,25.92 (d, J=7.0Hz), 22.83,19.82,14.23.

HPLC 96.6%.

The synthesis of embodiment 17-19

Suitable raw material is selected, embodiment 17-19 is synthesized referring to the synthetic schemes of embodiment 2, and characterize data is as follows:

The synthesis of embodiment 10,14

Suitable raw material is selected, embodiment 10 is synthesized referring to the synthetic schemes of embodiment 4, and characterize data is as follows:

The synthesis of embodiment 4-9, embodiment 11-13, embodiment 15-16, embodiment 20-38

Select suitable raw material, embodiment 4-9, embodiment 11-13, embodiment 15-16, embodiment 20-38 reference implementation Example 1 or synthetic schemes 3 synthesize.

Embodiment 39:(S)-N- ((S) -1- cyclohexyl -2- ((S) -2- (4- (the fluoro- 2,3- dihydro -1H- indenes -4- carbonyl of 7-) Thiazol-2-yl) pyrrolidinyl -1- base) -2- oxoethyl) -2- (methylamino) propionamide

Step 1:3- (the bromo- 2- fluorophenyl of 5-) propionic acid

Triethylamine (8.3mL, 60mmol) is slowly added into -5 DEG C of formic acid (5.9mL, 160mmol), and 10-15min is added. After 15min, the fluoro- benzaldehyde of the bromo- 2- of 5- (4.1g, 20mmol), 2,2- dimethyl-1,3-dioxane -4,6- diketone (3.2g, 22mmol) sequentially add.100 DEG C of oil bath heating reaction solutions.TLC monitors raw material fully reacting.Reaction solution stops heating, and ice water adds Enter, 1N HCl is acidified to pH=3, and white solid is precipitated, drains 4.17g, yield 84%.

MS(ESI,pos.ion)m/z:247.0,249.0(M)⁺。

¹H NMR(400MHz,CDCl₃) δ 7.40-7.28 (m, 2H), 6.91 (t, J=9.1Hz, 1H), 2.95 (t, J= 7.7Hz, 2H), 2.68 (t, J=7.7Hz, 2H)

Step 2:3- (the bromo- 2- fluorophenyl of 5-) propionyl chloride

3- (the bromo- 2- fluorophenyl of 5-) propionic acid (4.17g, 16.9mmol), DMF (0.75mL), DCM (25mL) are sequentially added instead It answers in bottle, under 0 DEG C of low temperature, is slowly added into oxalyl chloride (3.7mL, 44mmol), 30min is added, and rt stirs 1h, is spin-dried for obtaining oily Object 4.5g, directly casts single step reaction.

The fluoro- 2,3- dihydro -1H- 1-Indanone of the bromo- 4- of step 3:7-

AlCl₃(3.07g, 23.0mmol), DCM (25mL) are sequentially added in reaction flask.- 15 DEG C of low temperature, 3- (the bromo- 2- of 5- Fluorophenyl) DCM (25mL) solution of propionyl chloride (16.9mmol) is slowly added into, and 25min is added.After 5min, 40 DEG C of oil bath reactions. TLC monitors raw material fully reacting.Reaction solution quenching reaction is added in ice water, collects organic phase, and water phase DCM is extracted 2 times, dry, dense Column is crossed in contracting, and PE/EA=10:1 is eluant, eluent, obtains white solid 3.68g.Yield 95%.

MS(ESI,pos.ion)m/z:229.0,230.9(M)⁺。

¹H NMR(400MHz,CDCl₃) δ 7.49 (dd, J=8.5,4.1Hz, 1H), 7.13 (t, J=8.2Hz, 1H), 3.12–3.07(m,2H),2.80–2.75(m,2H).

The fluoro- 2,3- dihydro -1H- indenes of the bromo- 7- of step 4:4-

The fluoro- 2,3- dihydro -1H- 1-Indanone (3.68g, 16.1mmol) of the bromo- 4- of 7-, NH₄F (3.62g, 97.7mmol), TFA (25mL, 336.6mmol) is sequentially added in reaction flask.- 5 DEG C, triethylsilane (15.5mL, 97.0mmol) is slowly added into, 25min is added.After rt 5min, enter 50 DEG C of oil baths, overnight.TLC monitors raw material fully reacting.Reaction solution concentration, sodium bicarbonate are molten Liquid is added, and EA is extracted 3 times, merges organic phase, dry, and column is crossed in concentration, and PE/EA=30:1 is eluant, eluent, obtains transparency liquid 1.7g, yield 50%.

¹H NMR(400MHz,CDCl₃) δ 7.26-7.21 (m, 1H), 6.75 (dd, J=15.1,6.6Hz, 1H), 3.04 (t, J=7.5Hz, 2H), 2.95 (t, J=7.5Hz, 2H), 2.13 (p, J=7.6Hz, 2H)

The fluoro- 2,3- dihydro -1H- indenes -4- base of step 5:(7-) magnesium bromide

N₂Under, magnesium chips (310mg, 12.755mmol), I₂(38mg, 0.1497mmol), THF (10mL) sequentially add reaction In bottle.30 DEG C of oil bath heatings, the THF (4mL) of fluoro- 2, the 3- dihydro -1H- indenes (1700mg, 7.9048mmol) of the bromo- 7- of 4- slowly add Enter, 40min is added.Grignard Reagent is made after 1h with spare.

Step 6:(S) -2- (4- (methoxyl group (methyl) carbamyl) thiazol-2-yl) pyrrolidines -1- t-butyl formate

(S) -2- (1- (tertbutyloxycarbonyl) pyrrolidin-2-yl) 4-thiazolecarboxylic acid 180mg, 0.6032mmol), HBTU (343mg, 0.904mmol), DMF (5mL) are sequentially added in reaction flask.Mixture is cooled to -1 DEG C of low temperature, DIPEA (0.51mL, 3.1mmol), methoxy amine hydrochlorate (130mg, 1.33mmol) sequentially adds, rt stirring.TLC monitoring raw material has reacted Entirely.Reaction solution concentration, NH₄Cl solution is added, and EA is extracted 3 times, merges organic phase, dry, concentration.Column is crossed, PE/EA=3:1 is Eluant, eluent obtains grease 190mg, yield 92%.

MS(ESI,pos.ion)m/z:342.2(M+H)⁺。

¹H NMR(600MHz,CDCl₃) δ 7.94 (s, 1H), 5.26-5.09 (m, 1H), 3.75 (s, 3H), 3.57 (d, J= 18.6Hz, 1H), 3.50 (d, J=8.5Hz, 1H), 3.41 (s, 3H), 2.26 (m, 2H), 1.92 (t, J=7.1Hz, 2H), 1.46 (s,3H),1.30(s,6H).

Step 7:(S) -2- (4- (the fluoro- 2,3- dihydro -1H- indenes -4- carbonyl of 7-) thiazol-2-yl) pyrrolidinyl -1- formic acid The tert-butyl ester

N₂Under protection, (S) -2- (4- (methoxyl group (methyl) carbamyl) thiazol-2-yl) pyrrolidines -1- t-butyl formate (550mg, 1.611mmol) is added in THF (10mL).Mixture is cooled to -22 DEG C, (fluoro- 2, the 3- dihydro -1H- indenes -4- of 7- Base) magnesium bromide (self-control) (7.5mmol, 13mL) is slowly added into, and about 70min is added.TLC monitors raw material fully reacting.It is saturated chlorine Change ammonium salt solution to be added, EA is extracted 3 times, merges organic phase, and dry, concentration, crossing column PE/EA=10:1 is eluant, eluent, is obtained yellowish Color grease 535mg, yield 79%.

MS(ESI,pos.ion)m/z:417.2(M+H)⁺。

¹H NMR(400MHz,CDCl₃) δ 8.01 (s, 1H), 7.79 (s, 1H), 6.90 (t, J=8.4Hz, 1H), 5.21 (d, J=28.4Hz, 1H), 3.69-3.38 (m, 2H), 3.18 (t, J=7.4Hz, 2H), 2.95 (t, J=7.4Hz, 2H), 2.28 (d, J=21.3Hz, 2H), 2.11 (p, J=7.5Hz, 2H), 1.94 (dd, J=13.1,6.8Hz, 2H), 1.48 (s, 4H), 1.35 (s,5H).

Step 8:(S)-(the fluoro- 2,3- dihydro -1H- indenes -4- base of 7-) (2- (pyrrolidin-2-yl) thiazole-4-yl) ketone

(S) -2- (4- (the fluoro- 2,3- dihydro -1H- indenes -4- carbonyl of 7-) thiazol-2-yl) pyrrolidinyl -1- t-butyl formate (475mg, 1.140mmol), HCl/EA (4N, 8.5mL) are added in reaction flask, rt stirring.TLC monitors raw material fully reacting.Instead It answers liquid to be spin-dried for, obtains faint yellow solid 400mg, quantitative yield.

MS(ESI,pos.ion)m/z:317.1(M+H)⁺。

Step 9:((S) -1- (((S) -1- cyclohexyl -2- ((S) -2- (4- (the fluoro- 2,3- dihydro -1H- indenes -4- carbonyl of 7-) Thiazol-2-yl) pyrrolidin-1-yl) -2- oxoethyl) amino) -1- oxopropan -2- base) (methyl) t-butyl carbamate

(S)-(the fluoro- 2,3- dihydro -1H- indenes -4- base of 7-) (2- (pyrrolidin-2-yl) thiazole-4-yl) ketone (446mg, 1.410mmol), DMT-MM (512mg, 1.8502mmol), (2R) -2- [[(2S) -2- [tertbutyloxycarbonyl (methyl) amino] third Acyl group] amino] -2- cyclohexyl-acetic acid (622mg, 1.817mmol), EA (18mL) sequentially add in reaction flask.- 1 DEG C of low temperature It bathes, after 5min, N-methylmorpholine (0.55mL, 5.0mmol) is slowly added into, and about 60min is added, heating rt stirring, and TLC monitoring is former Expect fully reacting.NH₄Quenching reaction is added in Cl solution, and EA is extracted 3 times, merges organic phase, dry, and column, PE/EA=are crossed in concentration 4:1 is eluant, eluent, obtains white solid 690mg, yield 76%.

MS(ESI,pos.ion)m/z:641.3(M+H)⁺。

¹H NMR(600MHz,CDCl₃) δ 8.02 (s, 1H), 7.82 (dd, J=8.4,5.1Hz, 1H), 6.90 (t, J= 8.4Hz, 1H), 6.74 (m, 1H), 5.51 (dd, J=8.0,2.2Hz, 1H), 4.65-4.58 (m, 1H), 3.88-3.82 (m, 1H), 3.79-3.73 (m, 1H), 3.18 (m, 2H), 2.95 (t, J=7.5Hz, 2H), 2.78 (s, 3H), 2.44-2.37 (m, 1H), 2.31-2.22 (m, 1H), 2.12 (m, 4H), 1.75-1.57 (m, 7H), 1.46 (s, 9H), 1.32 (d, J=7.1Hz, 3H),1.20–1.01(m,5H)。

Step 10:(S)-N- ((S) -1- cyclohexyl -2- ((S) -2- (4- (the fluoro- 2,3- dihydro -1H- indenes -4- carbonyl of 7-) thiophene Azoles -2- base) pyrrolidin-1-yl) -2- oxoethyl) -2- (methylamino) propionamide

((S) -1- (((S) -1- cyclohexyl -2- ((S) -2- (4- (the fluoro- 2,3- dihydro -1H- indenes -4- carbonyl of 7-) thiazole -2- Base) pyrrolidin-1-yl) -2- oxoethyl) amino) -1- oxopropan -2- base) (methyl) t-butyl carbamate (630mg, 0.9831mmol), HCl/EA (4N) (11mL) is added in reaction flask, rt stirring.Gradually white solid is precipitated.Reaction solution is spin-dried for, Preparation HPLC is sent, white solid 430mg is obtained.Yield 81%.

¹H NMR(400MHz,CDCl₃) δ 8.03 (s, 1H), 7.84 (dd, J=8.4,5.1Hz, 1H), 7.69 (d, J= 9.2Hz, 1H), 6.91 (t, J=8.5Hz, 1H), 5.52 (dd, J=7.8,2.3Hz, 1H), 4.62 (dd, J=9.1,6.3Hz, 1H), 3.92 (dd, J=16.9,8.7Hz, 1H), 3.83-3.74 (m, 1H), 3.27-3.13 (m, 2H), 3.06 (q, J= 6.9Hz 1H), 2.96 (t, J=7.5Hz, 2H), 2.39 (s, 4H), 2.32-2.22 (m, 1H), 2.19-2.05 (m, 4H), 1.67 (m,7H),1.31(m,3H),1.11(m,5H)。

¹³C NMR(151MHz,CDCl₃)δ187.53,175.11,172.42,171.56,162.53,160.85, 154.71,151.08 (d, J=7.3Hz), 131.89 (dd, J=32.2,13.4Hz), 130.22 (d, J=3.1Hz), 128.01,112.69,112.54,60.52,58.78,54.63,47.69,40.94,35.29,33.91,31.65,30.19, 29.82,28.45,28.19,26.23,26.11,25.93,25.38,24.71,19.84。

MS(ESI,pos.ion)m/z:541.3(M+H)⁺。

HPLC 97.7%.

The synthesis of embodiment 40-57

Suitable raw material is selected, embodiment 41-57 is synthesized referring to the synthetic schemes of embodiment 39, and characterize data is as follows:

Biological activity test embodiment

Embodiment A: detection compound external activity

One, experiment reagent and test sample used are as follows:

McCoy ' s 5a culture medium, DMEM culture medium, dual anti-(Pen .- Strep) are purchased from Hyclone；

Fetal calf serum (FBS) is purchased from Gibco；

Dimethyl sulfoxide (DMSO) is purchased from Sigma；

CCK8 kit is purchased from Japanese colleague's chemistry；

Cell strain MDA-MB-231 and SKOV3 are purchased from ATCC.

Two, experimental procedure is as follows:

1. plating cells

A. complete medium is prepared, is mixed well.

Cultivate the complete medium of cell MDA-MB-231 are as follows: the dual anti-+ 89%DMEM of 10%FBS+1%；

Cultivate the complete medium of cell SKOV3 are as follows: dual anti-+ 89%McCoy ' the s 5a of 10%FBS+1%；

B. recovery cell passes or so two generations selection good cell strain of growth conditions.

C. Tissue Culture Flask is taken out from incubator, checks the Cell Name marked on bottle, type of culture medium and cell Number.

D. cell suspension is moved into centrifuge tube with pipette, the revolving speed of 800-1000rpm is centrifuged 3-5 minutes.

E. the cell supernatant abandoned in centrifuge tube is inhaled.

F. add the culture medium of proper volume into centrifuge tube, it is uniform that cell is resuspended in soft piping and druming.

G. it is counted using Vi-Cell XR cell counter.

H. cell suspension is adjusted to suitable concentration.

I. cell suspension is added in 96 white orifice plates of bottom transmural, 100 holes μ l/.Cell Name is marked, plate density, day are planted Culture plate is placed in CO by the details such as phase₂In incubator overnight.

2. test sample prepares and addition:

A., compound is configured to the stock storing liquid of 10mM with DMSO

B.2mM it the preparation of compound: respectively takes the compound of 20 μ l 10mM to be added in 80 μ l DMSO and is diluted to 2mM.

C. using 2mM as maximum concentration, with DMSO gradually 3 times of dilutions, the compound of 10 concentration gradients is obtained.

3. the addition of test sample:

A. it is added in the tissue culture plate that is incubated overnight from pipetting 0.5 μ l in corresponding compound plate.

B. it is incubated for 72 hours in 37 DEG C of incubators.

4. detection and analysis

After being incubated for 72 hours, former culture medium is discarded, 100 complete mediums of the μ l containing 10%CCK-8 are added and are placed in 37 DEG C of trainings It supports and is incubated for 1-2 hours in case, absorbance (A) value in each hole is detected at microplate reader 450nm.

5. data analysing method

Drug is calculated as follows to the inhibiting rate of growth of tumour cell:

Growth of tumour cell inhibiting rate %=[(Ac-As)/(Ac-Ab)] × 100

As: the absorbance (cell+CCK-8+ untested compound) of sample

Ac: the absorbance (cell+CCK-8+DMSO) of negative control

Ab: the absorbance (culture medium+CCK-8+DMSO) of blank control

And use 5 software analysis data of Graph Pad Prism and mapping.

Data processing software calculates separately IC50 value of each compound at 72 hours.

Three, experimental result is as follows:

Table 1

Compound	MDA-MB-231,IC50(nM)	Compound	MDA-MB-231,IC50(nM)
				Embodiment 3	41.00	Embodiment 15	55.00
Embodiment 4	10.00	Embodiment 16	20.00
				Embodiment 5	7.00	Embodiment 20	70.00
Embodiment 6	45.00	Embodiment 25	36.00
				Embodiment 7	10.00	Embodiment 29	15.00
Embodiment 10	90.00	Embodiment 35	6.00
				Embodiment 11	100.00	Embodiment 37	121.00
Embodiment 12	30.00	Embodiment 39	41.00

Four, experiment conclusion:

The compounds of this invention has good inhibitory effect to MDA-MB-231 cell.

Embodiment B: the pharmacokinetics of detection compound

One, experiment reagent and test sample used are as follows:

Propranolol (Propranolol (internal standard)), methanol, ammonium acetate, K2EDTA, formic acid, acetonitrile, MTBE (methyl- tert Butyl ether),

KolliphorHS15 (12 hydroxy stearic acid ester of polyethylene glycol), DMSO (dimethyl sulfoxide) are commercially available.

SD rat: male, 180-220g, 7-8 week old are purchased from Hunan Si Laike experimental animal Co., Ltd.

Two, experimental procedure is as follows:

1, test sample is prepared

Test solution is configured by 5%DMSO+5%KolliphorHS15+90% physiological saline, with specific reference to eachization The dissolution situation for closing object is adjusted, and compound is enable to be completely dissolved.

2, zoopery design is as shown in table 2

Table 2

3, animal dosage is as shown in table 3

Table 3

Group	Gender	Size of animal	Dosage	Administration concentration	Administered volume
						IV	Male	3	1mg/kg	0.5mg/mL	2mL/kg
IG	Male	3	5mg/kg	0.5mg/mL	10mL/kg

4, solution is prepared

(1) configuration of test sample stock solution: precision weighs appropriate test sample, is dissolved with DMSO, with dilution in acetonitrile to 1mg/ ML shakes up to obtain the final product.It is saved under the conditions of being placed in -20 DEG C stand-by.

(2) internal standard substance solution is prepared: precision draws a certain amount of 1mg/mL Propranolol stock solution, is diluted with water to 100ng/mL。

5, sample analysis

Sample is handled using liquid-liquid extraction method, carries out chromatographic isolation, on triple quadrupole bar tandem mass spectrometer, with multiple anti- It answers ion monitoring (MRM) mode to carry out quantitative analysis, concentration calculation is carried out to result with instrument quantitative software.

6, plasma sample pre-processes

Precision draws the plasma sample of 30 μ L, and 250 μ L internal standards are added, and vortex mixed is uniform.One is extracted with the MTBE of 1mL Secondary, 13000rpm is centrifuged 2min at 4 DEG C, and 800 μ L of Aspirate supernatant is volatilized in 96 hole nitrogen evaporators, 150 μ L first of residue Alcohol: water=50:50 redissolves, vortex mixed, sample introduction, and sample volume is 8 μ L.

7, the preparation of standard sample

Suitable compound stock solution is accurately drawn, dilution in acetonitrile is added, standard serial solution is made.It accurately draws above-mentioned 180 μ L of blank plasma is added in each 20 μ L of standard serial solution, is vortexed and mixes, be configured to be equivalent to plasma concentration be 3,5,10, 30, the plasma sample of 100,300,1000,3000,5000 and 10000ng/mL is grasped by 3.5.1. " plasma sample pretreatment " Make, each concentration carries out two-sample analysis, establishes standard curve.

8, analysis method

The untested compound content after different compounds are administered in rat plasma is measured using LC/MS/MS method.

9, data processing

Using 6.1 software of WinNonlin, non-compartment model method calculates pharmacokinetic parameters.

Three, experimental result is as follows:

The PK parameter of 4 the compounds of this invention of table

Four, experiment conclusion

Table 4 the experimental results showed that, the compounds of this invention compared to control compounds 1 have good bioavilability.It is (standby Note: the chemical name of control compounds 1 is to show (S)-N- ((S) -1- cyclohexyl -2- ((S) -2- (4- (4- fluoro benzoyl) thiophene Azoles -2- base) pyrrolidin-1-yl) -2- oxoethyl) -2- (methylamino) propionamide)

In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means particular features, structures, materials, or characteristics described in conjunction with this embodiment or example It is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are different Surely identical embodiment or example is referred to.Moreover, particular features, structures, materials, or characteristics described can be any It can be combined in any suitable manner in one or more embodiment or examples.

Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art are not departing from the principle of the present invention and objective In the case where can make changes, modifications, alterations, and variations to the above described embodiments within the scope of the invention, the scope of the present invention It is defined by the claims and their equivalents.

Claims (13)

1. a kind of compound, have the structure as shown in formula (I), (II), (III) or (IV) or formula (I), (II), (III) or (IV) stereoisomer of structural compounds shown in, geometric isomer, tautomer, nitrogen oxides, solvate, metabolism produce Object, pharmaceutically acceptable salt or prodrug,

Wherein,

N1 is 1,2,3,4,5,6 or 7；

Each n2 independently is 0,1,2,3,4,5,6 or 7；

Each n3 independently is 0,1,2,3,4,5,6,7,8 or 9；

Each m independently is 0,1,2,3,4 or 5；

Q is 1,2,3 or 4；

U is 1 or 2；

Q²For covalent bond or-CH₂-；

Cy is following subformula:

Wherein, each t₁It independently is 1,2,3 or 4；

Each t₂It independently is 1 or 2；

Each t₃It independently is 0,1,2 or 3；

Wherein each subformula (Cy-i), (Cy-ii), (Cy-iii), (Cy-iv), (Cy-v) and (Cy-vi) individually optional ground quilt 1, replaced 2,3 or 4 substituent groups selected from D, F, Cl, Br, hydroxyl, alkyl, naphthenic base, heterocycle, alkoxy and amino；

Each R¹、R²、R³、R^3aAnd R⁵It independently is H, D, alkyl, alkenyl, alkynyl or carbocylic radical, wherein the alkyl, alkenyl, alkynes Base and carbocylic radical it is respectively individually optional by 1,2,3 or 4 be selected from D, F, Cl, Br, hydroxyl, alkyl, naphthenic base, heterocycle, alkane Replaced the substituent group of oxygroup, phenyl and amino；

Each R⁴It independently is H, D or alkyl；

Each R⁰It independently is D, F, Cl, Br, oxo (=O), cyano, hydroxyl, halogenated alkyl, hydroxy alkyl, halogenated alkoxy, alkane Oxygroup alkyl ,-NR⁸R⁹, aryloxy group, heterocycle ,-S (=O)-R¹⁰,-S (=O)₂-R¹⁰、-COOR⁸, aryl, alkoxy or alkyl； Or, two R⁰3-7 member carbocyclic ring or 3-7 circle heterocyclic ring are formed together with the carbon atom being connected with them；Wherein the halogenated alkyl, Hydroxy alkyl, halogenated alkoxy, alkoxyalkyl, aryloxy group, heterocycle, aryl, alkoxy, alkyl, 3-7 member carbocyclic ring and 3-7 Circle heterocyclic ring respectively individually optionally by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, alkyl, naphthenic base, heterocycle, alkoxy, Replaced the substituent group of aryl and amino；

Each R⁶Independently be H, D, F, Cl, Br, alkyl, hydroxyl, amino, cyano or alkoxy, wherein the alkyl, amino and Alkoxy is selected from D, F, Cl, Br, hydroxyl, alkyl, naphthenic base, heterocycle, alkoxy by 1,2,3 or 4 respectively individually optionally Replaced substituent group with amino；

Each R⁷It independently is H, D, alkyl, F, Cl, Br or amino；

Each R⁸、R⁹It independently is H, D, alkyl, naphthenic base, heterocycle, aryl or heteroaryl；Wherein the alkyl, naphthenic base, Heterocycle, aryl and heteroaryl it is respectively individually optional by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, alkyl, naphthenic base, Heterocycle, alkoxy, aryl and amino substituent group replaced；With

Each R¹⁰It independently is amino, alkyl, naphthenic base, heterocycle, aryl or heteroaryl；The wherein amino, alkyl, cycloalkanes Base, heterocycle, aryl and heteroaryl it is respectively individually optional by 1,2,3 or 4 be selected from D, F, Cl, Br, hydroxyl, alkyl, cycloalkanes Base, heterocycle, alkoxy, aryl and amino substituent group replaced.

2. compound according to claim 1, wherein each R¹、R²、R³、R^3aAnd R⁵It independently is H, D, C_1-6Alkyl, C_2-6 Alkenyl, C_2-6Alkynyl or 3-10 member carbocylic radical, wherein the C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl and 3-10 member carbocylic radical are each From individually optionally by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, C_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4 Replaced the substituent group of alkoxy, phenyl and amino；

Each R⁴It independently is H, D or C_1-6Alkyl；With

Each R⁷It independently is H, D, C_1-6Alkyl, F, Cl, Br or amino.

3. compound according to claim 1, wherein each R¹、R²、R³、R^3aAnd R⁵It independently is H, D, methyl, ethyl, just Propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl ,-CH=CH₂,-CH=CH-CH₃、-CH₂- CH=CH₂,-CH=CH- CH₂CH₃、-CH₂- CH=CH₂-CH₃、-(CH₂)₂- CH=CH₂、-C(CH₃)=CH₂-CH₃, propinyl, propargyl, cyclopropyl, ring Butyl, cyclopenta, cyclohexyl, cyclopentenyl, cyclopentadienyl group, cyclohexenyl group or cyclohexadienyl, wherein the methyl, second Base, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl ,-CH=CH₂,-CH=CH-CH₃、-CH₂- CH=CH₂,-CH= CH-CH₂CH₃-、-CH₂- CH=CH₂-CH₃、-(CH₂)₂- CH=CH₂、-C(CH₃)=CH₂-CH₃, propinyl, propargyl, cyclopropyl Base, cyclobutyl, cyclopenta, cyclohexyl, cyclopentenyl, cyclopentadienyl group, cyclohexenyl group and cyclohexadienyl are respectively individually optional Ground is selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary fourth by 1,2,3 or 4 Base, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, Morpholinyl, tetrahydro-pyrimidine base, dioxane, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutyl oxygen Base, tert-butoxy, phenyl and amino substituent group replaced；

Each R⁴It independently is H, D, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tert-butyl；With

Each R⁷It independently is H, D, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, F, Cl, Br or ammonia Base.

4. compound according to claim 1, wherein

Each R⁰It independently is D, F, Cl, Br, oxo (=O), cyano, hydroxyl, C_1-6Halogenated alkyl, C_1-6Hydroxy alkyl, C_1-6It is halogenated Alkoxy, C_1-6Alkoxy C_1-6Alkyl ,-NR⁸R⁹、C_6-10Aryloxy group, 3-7 circle heterocyclic ring base ,-S (=O)-R¹⁰,-S (=O)₂-R¹⁰、- COOR⁸、C_6-10Aryl, C_1-6Alkoxy or C_1-6Alkyl；Or, two R⁰3-7 member carbon is formed together with the carbon atom being connected with them Ring or 3-7 circle heterocyclic ring；The wherein C_1-6Halogenated alkyl, C_1-6Hydroxy alkyl, C_1-6Halogenated alkoxy, C_1-6Alkoxy C_1-6Alkane Base, C_6-10Aryloxy group, 3-7 circle heterocyclic ring base, C_6-10Aryl, C_1-6Alkoxy, C_1-6Alkyl, 3-7 member carbocyclic ring and 3-7 circle heterocyclic ring are respectively D, F, Cl, Br, hydroxyl, C are selected from by 1,2,3 or 4 individually optionally_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Alkane Oxygroup, C_6-10Replaced the substituent group of aryl and amino；

Each R⁸、R⁹It independently is H, D, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_6-10Aryl or 5-6 unit's heteroaryl；Its Described in C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_6-10Aryl and 5-6 unit's heteroaryl it is respectively individually optional by 1, 2,3 or 4 are selected from D, F, Cl, Br, hydroxyl, C_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Alkoxy, C_6-10Aryl and Replaced the substituent group of amino；With

Each R¹⁰It independently is amino, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_6-10Aryl or 5-6 unit's heteroaryl；Wherein The amino, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_6-10Aryl and 5-6 unit's heteroaryl are respectively individually optional D, F, Cl, Br, hydroxyl, C are selected from by 1,2,3 or 4_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Alkoxy, C_6-10Virtue Replaced the substituent group of base and amino.

5. compound according to claim 1, wherein

Each R⁰It independently is D, F, Cl, Br, oxo (=O), cyano, hydroxyl, amino, trifluoromethyl, trifluoromethoxy, hydroxyl first Base, hydroxyethyl, methoxy, methoxy ethyl, ethoxyl methyl, ethoxyethyl group ,-NR⁸R⁹,-S (=O)-R¹⁰、-S (=O)₂-R¹⁰、-COOR⁸, phenoxy group, pyrrolidinyl, piperidyl, tetrahydrofuran base, morpholinyl, piperazinyl, imidazolidinyl, benzene Base, carboxyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, methyl, ethyl, N-propyl, isopropyl, normal-butyl, isobutyl group or tert-butyl；Or, two R⁰And the carbon atom being connected between them is formed together Cyclopropane, cyclobutane, pentamethylene, hexamethylene, cycloheptane, cyclopentene, cyclohexene, ethylene oxide, oxetanes, azacyclo- third Alkane, 1,3- dioxolane, pyrrolidines, piperidines, piperazine, morpholine, tetrahydropyridine, oxinane or tetrahydrofuran；Wherein institute Hydroxymethyl, hydroxyethyl, methoxy, methoxy ethyl, ethoxyl methyl, ethoxyethyl group, the phenoxy group, pyrroles stated It is alkyl, piperidyl, tetrahydrofuran base, morpholinyl, piperazinyl, imidazolidinyl, phenyl, methoxyl group, ethyoxyl, positive propoxy, different Propoxyl group, n-butoxy, isobutoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary fourth Base, cyclopropane, cyclobutane, pentamethylene, hexamethylene, cycloheptane, cyclopentene, cyclohexene, ethylene oxide, oxetanes, azepine Cyclopropane, 1,3- dioxolane, pyrrolidines, piperidines, piperazine, morpholine, tetrahydropyridine, oxinane and tetrahydrofuran are respectively D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl are selected from by 1,2,3 or 4 individually optionally Base, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, Piperazinyl, morpholinyl, tetrahydro-pyrimidine base, dioxane, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, Isobutoxy, tert-butoxy, phenyl and amino substituent group replaced；

Each R⁸And R⁹It independently is H, D, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopenta, piperidyl or phenyl；Wherein The methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopenta, piperidyl and phenyl it is respectively individually optional by 1,2,3 or 4 are selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclopropyl, ring Butyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, morpholinyl, tetrahydro are phonetic Piperidinyl, dioxane, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, benzene Replaced the substituent group of base and amino；With

Each R¹⁰It independently is amino, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopenta, piperidyl or phenyl；Wherein institute Amino, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopenta, piperidyl or the phenyl stated respectively individually optionally by 1,2, 3 or 4 selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclopropyl, Cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, morpholinyl, tetrahydro Pyrimidine radicals, dioxane, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, Replaced the substituent group of phenyl and amino.

6. compound according to claim 1, wherein

Each R⁶It independently is H, D, F, Cl, Br, C_1-6Alkyl, hydroxyl, amino, cyano or C_1-6Alkoxy, wherein the C_1-6Alkane Base, amino and C_1-6Alkoxy is selected from D, F, Cl, Br, hydroxyl, C by 1,2,3 or 4 respectively individually optionally_1-4Alkyl, C_3-6Ring Alkyl, 3-6 circle heterocyclic ring base, C_1-4Replaced the substituent group of alkoxy and amino.

7. compound according to claim 1, wherein

Each R⁶Independently be H, D, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, hydroxyl, Amino, cyano, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, wherein institute The methyl stated, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, amino, methoxyl group, ethyoxyl, positive propoxy, Isopropoxy, n-butoxy, isobutoxy and tert-butoxy it is respectively individually optional by 1,2,3 or 4 selected from D, F, Cl, Br, Hydroxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, hexamethylene Base, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-pyrimidine base, dioxane, Methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and amino substituent group taken Generation.

8. compound according to claim 1, wherein Cy is following subformula:

Wherein each subformula (Cy-1), (Cy-2), (Cy-3), (Cy-4), (Cy-5), Cy-6), (Cy-7), (Cy-8), (Cy- 9), Cy-10) individually optionally by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, just Butyl, isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydrofuran base, pyrrolidinyl, thiophane Base, piperidyl, piperazinyl, morpholinyl, tetrahydro-pyrimidine base, dioxane, methoxyl group, ethyoxyl, positive propoxy, isopropyl oxygen Base, n-butoxy, isobutoxy, tert-butoxy and amino substituent group replaced.

It is stereoisomer with structural compounds shown in structure or formula (VII) described in formula (VII), several 9. a kind of compound What isomers, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

Wherein,

Each R¹、R²、R³、R^3aAnd R⁵It independently is H, D, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl or 3-10 member carbocylic radical, wherein institute The C stated_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl and 3-10 member carbocylic radical it is respectively individually optional by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, C_1-4Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base, C_1-4Replaced the substituent group of alkoxy, phenyl and amino；

Each R⁴It independently is H, D or C_1-6Alkyl；

Each R⁷It independently is H, D, alkyl, F, Cl, Br or amino；

For

Wherein, each T¹And T²Stand alone as a key ,-CR¹²R¹³-、-CR¹²R¹³-O-、-O-CR¹²R¹³-、-NR¹¹-CR¹²R¹³-、- CR¹²R¹³-NR¹¹、-CR¹²R¹³)₂-、-(CR¹²R¹³)₃-、-NR¹¹,-O- or-S-；

T³For-CR¹²R¹³-、-NR¹¹,-O- or-S-；

Each R¹¹It independently is H, D, C_1-6Alkyl, hydroxyl, amino, cyano, C_1-6Alkoxy, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base or C_6-10Aryl；

Each R¹²、R¹³It independently is H, D, F, Cl, Br, hydroxyl, oxo, amino, cyano, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 member are miscellaneous Ring group or C_1-6Alkoxy；

Each R⁶It independently is H, D, F, Cl, Br, C_1-6Alkyl, hydroxyl, amino, cyano or C_1-6Alkoxy, wherein the C_1-6Alkane Base, amino and C_1-6Alkoxy is selected from D, F, Cl, Br, hydroxyl, C by 1,2,3 or 4 respectively individually optionally_1-4Alkyl, C_3-6Ring Alkyl, 3-6 circle heterocyclic ring base, C_1-4Replaced the substituent group of alkoxy and amino；

Wherein each subformula Y-1a, Y-2a, Y-3a, Y-4a and Y-5a can individually optionally by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, oxo, amino, cyano, C_1-6Alkyl, C_3-6Naphthenic base, 3-6 circle heterocyclic ring base and C_1-6The substituent group institute of alkoxy Replace.

10. compound according to claim 9, wherein

Each R¹、R²、R³、R^3aAnd R⁵Independently be H, D, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopenta, Cyclohexyl, cyclopentenyl, cyclohexenyl group or phenyl, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, cyclopentenyl, cyclohexenyl group and phenyl it is respectively individually optional by 1,2,3 or 4 selected from D, F, Cl, Br, hydroxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, ring Hexyl, tetrahydrofuran base, pyrrolidinyl, tetrahydro-thienyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-pyrimidine base, dioxane Base, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl and amino take Replaced Dai Ji；

Each R⁴It independently is H, D, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tert-butyl；

Each R⁷It independently is H, D, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, F, Cl, Br or ammonia Base；

For

Wherein, each R¹¹It independently is H, D, methyl, ethyl, n-propyl, isopropyl, hydroxyl, amino, cyano, methoxyl group, ethoxy Base, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, pyrrole radicals, piperazinyl, morpholinyl, tetrahydrofuran base, piperazine Piperidinyl or phenyl；

Each R¹²、R¹³It independently is H, D, F, Cl, Br, hydroxyl, oxo, amino, cyano, methyl, ethyl, n-propyl, isopropyl, ring Butyl, cyclopenta, cyclohexyl, Oxyranyle, pyrrole radicals, piperazinyl, morpholinyl, tetrahydrofuran base, piperidyl, methoxyl group, Ethyoxyl, positive propoxy or isopropoxy；

Each R⁶Independently be H, D, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, hydroxyl, Amino, cyano, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy；

Wherein each subformula Y1a, Y2a, Y3a, Y4a, Y5a, Y6a, Y7a, Y8a, Y9a, Y10a, Y11a, Y12a, Y13a, Y14a, Y15a, Y16a, Y17a, Y18a, Y19a and Y20a can be selected from D, F, Cl, Br, hydroxyl by 1,2,3 or 4 individually optionally Base, oxo, amino, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, epoxy second Alkyl, pyrrole radicals, piperazinyl, morpholinyl, tetrahydrofuran base, piperidyl, methoxyl group, ethyoxyl, positive propoxy or isopropoxy Substituent group replaced.

11. structure or its stereoisomer, geometric isomer, tautomer, nitrogen oxygen that compound has one of Compound, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

12. a kind of pharmaceutical composition includes the described in any item compounds of claim 1-11 and its pharmaceutically acceptable auxiliary Agent.

13. pharmaceutical composition described in the described in any item compounds of claim 1-11 or claim 12 is in preparation for pre- Purposes in anti-or treatment proliferative diseases drugs.