CN110143949A - It can be used as the new type heterocycle derivative of SHP2 inhibitor - Google Patents

It can be used as the new type heterocycle derivative of SHP2 inhibitor Download PDF

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CN110143949A
CN110143949A CN201810440520.2A CN201810440520A CN110143949A CN 110143949 A CN110143949 A CN 110143949A CN 201810440520 A CN201810440520 A CN 201810440520A CN 110143949 A CN110143949 A CN 110143949A
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alkyl
base
methyl
carboxyl
yuan
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马存波
高攀亮
胡邵京
徐子龙
韩慧峰
吴新平
康迪
龙伟
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Beijing Jia Ke Si New Drug Research And Development Co Ltd
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Beijing Jia Ke Si New Drug Research And Development Co Ltd
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Priority to CN201810440520.2A priority Critical patent/CN110143949A/en
Priority to CN202211429905.1A priority patent/CN116003321A/en
Priority to CN202211429954.5A priority patent/CN115721648A/en
Priority to CN202011087825.3A priority patent/CN112174935B/en
Priority to CN202211420369.9A priority patent/CN115969853A/en
Priority to CN202011087795.6A priority patent/CN112409334B/en
Publication of CN110143949A publication Critical patent/CN110143949A/en
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Abstract

The present invention relates to the new type heterocycle derivatives that can be used as SHP2 inhibitor, more particularly to structural formula I compound represented or its pharmaceutically acceptable salt, purposes further to the purposes of structural formula I compound represented or its pharmaceutically acceptable salt and its pharmaceutical composition in medicine preparation, especially in the drug for preparing the disease or discomfort for treating, preventing or prevent to be mediated by SHP2 activity.

Description

It can be used as the new type heterocycle derivative of SHP2 inhibitor
Technical field
The present invention relates to can be used as certain novel pyrazines derivatives of SHP2 inhibitor (such as structural formula I, II, III or IV institute Show) and they synthesis and its for treat SHP2 mediation illness purposes.It is more particularly related to available The condensed heterocyclic derivates for making SHP2 inhibitor, the side for the disease that the method and treatment SHP2 for preparing such compound mediate Method.
Background technique
SHP2 (- 2 protein tyrosine phosphatase of Src homologous region, The Src Homolgy-2phosphatease) is one A non-Receptor Protein Tyrosine phosphatase encoded by ptpn11 gene, comprising a conservative tyrosine phosphatase enzyme domains, Two end N- Src homologous region 2 (SH2) structural domains, the end a C- tail.Two SH2 structural domains determine that the subcellular of SHP2 is fixed Position and function point analysis.Under non-activated state, the end N- SH2 structural domain can close the combination of PTP fabric domain, and be allowed to inactivate.Work as SH2 When structural domain is in conjunction with the specific tyrosine residue on receptor or adaptor protein relevant with receptor, PTP structural domain can be released It releases, autoinhibition releases.The activation of SHP2, for example, causing to be catalyzed by the stimulation of cell factor and growth factor The exposure in site leads to the enzyme activation of SHP2.
SHP2 expression extensively, and participates in a plurality of cell signaling processes, such as Ras-Erk, PI3K-Akt, Jak- Stat、 MeT, FGFR, EGFR and insulin receptor and NF-kB access, in cell Proliferation, differentiation, cell cycle and migration In play an important role.
The catalytic activity superactivation of the SHP2 as caused by germline or somatic mutation is comprehensive in Noonan syndrome, leopard's spots Simulator sickness, juvenile myelomonocyte leukemia, myelodysplastic syndrome, B precursor acute lymphoblastic leukemia and acute It is found in myelogenous leukemia.In addition, the Activating mutations of PTPN11 are also found in solid tumor, such as lung cancer, colon cancer, melanin Tumor, neuroblastoma and liver cancer.Therefore, the SHP2 activated or the SHP2 egg of up-regulation in human tumor or in Other diseases It is white to become new therapy target.Compound in the present invention meets the demand to SHP2 micromolecular inhibitor.
Summary of the invention
The present invention relates to heterocycle pyrazine compound, it is used to treat the disease mediated by SHP2 as SHP2 inhibitor.This Invention provides firstly the general formula compound as shown in structural formula I and its pharmaceutically acceptable salt:
Wherein:
Each R1Independently selected from-H, halogen ,-NH2,-CN, substituted or unsubstituted-C1-6Alkoxy or replace or not - the C replaced1-6Alkyl；
R2Selected from-H, halogen ,-NH2、-CN、-OH、-NHC1-6Alkyl ,-N (C1-6Alkyl)2, substituted or unsubstituted-C1-6 Alkoxy, substituted or unsubstituted-C1-6Alkyl or-C5-10Heterocycle；Or
R2With adjacent R1Connection and their carbon atoms for being separately connected be formed together 6-10 member aromatic ring, 5-6 member hetero-aromatic ring or 5-6 circle heterocyclic ring, and each ring system can not replace optionally independently or by 1,2 or 3 halogen ,-NH2、-CN、-C1-6Alkyl Or-CO-C1-6Alkyl replaces；
Each Y1Independently selected from N or CH；
R3Selected from-H or-NH2；
Each R4aAnd R4bIndependently selected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl or-C1-6Alkyl；Or
R4aAnd R4bCO, C=NH or C=N-OH are formed together with the carbon atom that they connect jointly；
P is 0,1,2 or 3；
Each R5aAnd R5bIndependently selected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl or-C1-6Alkyl；Or
R5aAnd Rsb3-5 circle heterocyclic ring base or C=NH are formed together with the carbon atom that they connect jointly；
Q is 0,1,2,3 or 4；
W be not present, O, S or NRw；And RwIt is-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-6Alkyl-O-C1-6 Alkoxy, substituted or unsubstituted-C1-6Alkoxy or substituted or unsubstituted-C1-6Alkyl；
Ring A is not present or 3-10 member ring；
Indicate singly-bound or double bond；
In the absence of ring A, Y2It is CR2aR2b、NR2aOr O, and Y3It is CR3aR3b、NR3aOr O；
When ring A is 3-10 member ring:
Iii) whenWhen indicating singly-bound, Y2It is CR2aOr N, and Y3It is CH or N；Or
Iv) whenWhen indicating double bond, Y2It is C, and Y3It is C；
Each R2a、R2b、R3aAnd R3bIndependently selected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl, substitution or not - the C replaced1-6Alkoxy or substituted or unsubstituted-C1-6Alkyl；
Each R6Independently selected from-H, halogen ,-NR6aR6b、-CN、-OH、-NO2, oxo base ,=O, carboxyl ,-C1-6Alcoxyl Base ,-C1-6Alkyl ,-C1-6Alkenyl-NR6aR6b、-C1-6Alkenyl-O-C1-6Alkyl ,-C1-6Alkenyl ,-CO-OR6a、-C1-6Alkenyl-C3-10 Heterocycle ,-C1-6Alkenyl-C5-10Heteroaryl ,-C1-6Alkenyl-CO-NR6aR6b、-C1-6Alkenyl-NR6a-CO-NR6aR6b、-C1-6Alkene Base-NR6a-CO-C1-6Alkyl ,-CO-NR6aR6b、-CO-CO-NR6aR6b、-C3-10Carbocylic radical ,-C3-10Heterocycle ,-CO-C1-6Alkane Base ,-CO-C1-6Alkenyl-NR6aR6b、-CO-NR6a-C3-10Heterocycle ,-CO-NR6a-C3-10Heterocycle ,-CO-C3-10Heterocycle ,- O-C1-6Alkenyl-CO-OR6a、-O-C1-6Alkenyl-CO-NR6aR6b、 -O-C1-6Alkenyl-NR6aR6b、-O-C3-10Carbocylic radical ,-O-C3-10 Heterocycle ,-NR6a-CO-C1-6Alkyl ,-NR6a-CO-NR6aR6b、-NR6a-CO-C5-10Heteroaryl ,-NR6a-C1-6Alkene- NR6aR6b、-NR6a-C1-6Alkene-C3-10Heterocycle ,-NR6a-C1-6Alkene-C5-10Heteroaryl ,-NR6a-SO2C1-6Alkyl ,-S-C1-6 Alkyl ,-SONR6aR6b、 -SO2NR6aR6b、-5O-C1-6Alkyl ,-SO2C1-6Alkyl ,-PO (C1-6Alkyl)2、-PO(C1-6Alcoxyl Base)2、-C3-10Heterocycle or-C5-10Heteroaryl；Each R6Independently optionally replaced by 1,2 or 3 substituent group or not Replace；And n is 0,1,2,3,4,5 or 6；Or
Two adjacent R6It links together and the carbon atom being separately connected with them is formed together 6 yuan of aryl, 5 yuan of heteroaryls Base, 6 unit's heteroaryls, C3-6Heterocycle or C3-6Carbocylic radical, and each ring system is independently optionally taken by one or more substituent groups In generation, does not replace；
Each R6aAnd R6bIndependently selected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl, it is substituted or unsubstituted- C1-6Alkoxy or substituted or unsubstituted-C1-6Alkyl.
Invention further provides some optimal technical schemes about structural formula I compound represented.
General formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, 2. each R1Independently selected from-H；- F； -Cl；-Br；-NH2；-CN；-OH；-NO2；Carboxyl；-C1-6Alkyl；-C1-6Alkoxy；By 1,2 or 3 halogen ,-NH2、- CN、-OH、-NO2, carboxyl ,-C1-3Alkyl or-C1-3- the C that alkoxy replaces1-6Alkyl；Or by 1,2 or 3 halogen ,-NH2、- CN、-OH、-NO2, carboxyl ,-C1-3Alkyl or-C1-3- the C that alkoxy replaces1-6Alkoxy.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, each R1 Independently selected from-H；-F；-Cl；-Br；-NH2；-CN；-OH；-NO2；Carboxyl；Methyl；Ethyl；Propyl；Isopropyl；Methoxyl group；Second Oxygroup；Propoxyl group；Isopropoxy；By 1,2 or 3-F ,-Cl ,-Br ,-NH2、-CN、-OH、 -NO2, carboxyl, methyl, ethyl, third - the C that base, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy replace1-3Alkyl；Or by 1,2 or 3-F ,-Cl ,- Br、-NH2、-CN、-OH、-NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy Substituted C1-3Alkoxy.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, each R1 Independently selected from-H；-F；-Cl；-Br；-NH2；-CN；-OH；Methyl；Ethyl；Propyl；Isopropyl；Methoxyl group；Ethyoxyl；Third oxygen Base；Isopropoxy；Or the methyl replaced by 1,2 or 3 substituent group, and each substituent group independently selected from-F ,-Cl ,-Br ,- NH2、-CN、-OH、-NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, R2Choosing From-H； -F；-Cl；-Br；-NH2；-CN；-OH；-NO2；-N3；Carboxyl；-C1-3Alkyl；-C1-3Alkoxy；-NHC1-3Alkyl；-N (C1-3Alkyl)2；-CONH2；-CONHC1-3Alkyl；-CON(C1-3Alkyl)2；-COC1-3Alkyl；-NHCOC1-3Alkyl；-N(C1-3Alkane Base)-CO-C1-3Alkyl；-C5-10Heterocycle；- F ,-Cl ,-Br ,-I ,-NH are selected from by 1,2 or 32,-CN or-OH substituent group - the C replaced1-3Alkyl；Or-F ,-Cl ,-Br ,-I ,-NH are selected from by 1,2 or 32,-CN or-OH the-C that replaces of substituent group1-3 Alkoxy.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, R2Choosing From-H； -F；-Cl；-Br；-NH2；-CN；-OH；-NO2；-N3；Carboxyl；Methyl；Ethyl；Propyl；Isopropyl；Methoxyl group；Ethoxy Base；Propoxyl group；Isopropoxy；-NHCH3；-N(CH3)2；-CONH2；-CONHCH3；-CON(CH3)2； -COCH3；-NH- COCH3；-N(CH3)-COCH3；Or first is replaced by 1,2 or 3 substituent group Base or ethyl, the substituent group are selected from-F ,-Cl ,-Br ,-NH2,-CN or-OH.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, R2With it Adjacent R1Connect and and their carbon atoms for being separately connected be formed together 5 unit's heteroaryls, 6 unit's heteroaryls, 6 yuan of aryl, 5 yuan Heterocycle or 6 circle heterocyclic ring bases,；And each heteroaryl or heterocycle include 1 or 2 hetero atom for being selected from N or O；And it is described Each ring system independently optionally by-F ,-Cl ,-Br ,-I ,-NH2、-CN、-OH、-NO2, carboxyl, oxo base ,=O ,- CONH2, substituted or unsubstituted C1-3Alkoxy, substituted or unsubstituted C1-3Alkyl ,-C1-3Alkenyl-O-C1-3Alkyl ,-C1-3Alkene Base-COOH ,-C1-3Alkenyl-NHCONH2、-CO-N(C1-3Alkyl)2、-C1-3Alkenyl-NHCO-C1-3Alkyl ,-CO-CO-N (C1-3Alkane Base)2、-CO-C1-3Alkyl ,-SONH2、-SO2NH2、-SOCH3Or-SO2CH3Replace or does not replace.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, R2With it Adjacent R1It connects and is separately connected carbon atom with them and be formed together 5 unit's heteroaryls, 6 unit's heteroaryls, 6 yuan of aryl, 5 circle heterocyclic rings Base or 6 circle heterocyclic ring bases；And each heteroaryl or heterocycle includes 1 hetero atom for being selected from N or O；And it is each of described Ring system can be independently optionally by-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2, carboxyl, oxo base ,=O ,-CONH2, first Base, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy ,-CH2OCH3、-CH2COOH、- CH2NHCONH2、-CON(CH3)2、-CH2NHCOCH3、-CO-CON(CH3)2Or-COCH3Replace or does not replace.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, R2With it Adjacent R1It connects and the carbon atom being separately connected with them is formed together
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, each R4a And R4bIndependently selected from-H ,-F ,-Cl ,-Br ,-I ,-NH2、-CN、-OH、-NO2, carboxyl or-C1-3Alkyl；Or
R4aAnd R4bC=O, C=NH or C=N-OH are formed together with the carbon atom that they connect jointly.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, each R4a And R4bIndependently selected from-H ,-NH2,-OH, methyl, ethyl, methoxy or ethoxy；Or
R4aAnd R4bC=O is formed together with the carbon atom that they connect jointly.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, each R5a And R5bIndependently selected from-H；-F；-Cl；-Br；-I；-NH2；-CN；-OH；-NO2；Carboxyl；-C1-3Alkyl； -C1-3Alkoxy； By-F ,-Cl ,-Br ,-I ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkyl or-C1-3- the C that alkoxy replaces1-6Alkyl；Or By-F ,-Cl ,-Br ,-I ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkyl or-C1-3- the C that alkoxy replaces1-6Alkoxy； Or
R5aAnd R5bIt is miscellaneous that C=NH, 3 circle heterocyclic ring bases, 4 circle heterocyclic ring bases or 5 yuan are formed together with the carbon atom that they connect jointly Ring group；And each heterocycle independently optionally includes 1 or 2 hetero atom for being selected from N or O；And it is each of described Ring system can be independently optionally by-H ,-F ,-Cl ,-Br ,-I ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkoxy or-C1-3Alkane Base replaces or does not replace.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, each R5a Or R5bIndependently selected from-H ,-NH2,-OH, methyl, ethyl, methoxy or ethoxy；Or
R5aAnd R5bIt is miscellaneous that C=NH, 3 circle heterocyclic ring bases, 4 circle heterocyclic ring bases or 5 yuan are formed together with the carbon atom that they are connected jointly Ring group；And each heterocycle includes 1 hetero atom for being selected from N or O.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, W are NRw, and RwSelected from-H ,-F ,-Cl ,-Br ,-I ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkyl-O-C1-3Alkyl ,-C1-3Alkane Oxygroup or-C1-3Alkyl.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, W are NRw, and RwSelected from-H ,-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxyl group, Ethyoxyl, propoxyl group, isopropoxy, methyl-CO- methyl or methyl-CO- methoxyl group.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, ring A choosing From 6 yuan of aryl, 10 yuan of aryl, 5 unit's heteroaryls, 6 unit's heteroaryls, 7 unit's heteroaryls, 8 unit's heteroaryls, 9 unit's heteroaryls, 10 yuan it is miscellaneous Aryl, 3 circle heterocyclic ring bases, 4 circle heterocyclic ring bases, 5 circle heterocyclic ring bases, 6 circle heterocyclic ring bases, 7 circle heterocyclic ring bases, 8 circle heterocyclic ring bases, 9 circle heterocyclic ring bases, 10 circle heterocyclic ring bases, 3 yuan of carbocylic radicals, 4 yuan of carbocylic radicals, 5 yuan of carbocylic radicals, 6 yuan of carbocylic radicals, 7 yuan of carbocylic radicals, 8 yuan of carbocylic radicals, 9 yuan of carbon Ring group or 10 yuan of carbocylic radicals；And each heteroaryl or each heterocycle are independently optionally selected from comprising 1,2 or 3 N, the hetero atom of O or S.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, ring A choosing From 6 yuan of aryl, 5 unit's heteroaryls, 6 unit's heteroaryls, 7 unit's heteroaryls, 8 unit's heteroaryls, 3 circle heterocyclic ring bases, 4 circle heterocyclic ring bases, 5 yuan it is miscellaneous Ring group, 6 circle heterocyclic ring bases, 7 circle heterocyclic ring bases, 8 circle heterocyclic ring bases；3 yuan of carbocylic radicals, 4 yuan of carbocylic radicals, 5 yuan of carbocylic radicals, 6 yuan of carbocylic radicals, 7 First carbocylic radical or 8 yuan of carbocylic radicals；And each heteroaryl and each heterocycle are independently optionally comprising 1 or 2 choosing From the hetero atom of N, O or S.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, ring A choosing From
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, each R2a、 R2b、R3aAnd R3bIndependently selected from-H ,-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkyl or-C1-3 Alkoxy.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, each R2a、 R2b、R3aAnd R3bIndependently selected from-H ,-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2, carboxyl, methyl, ethyl, third Base, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, R2aWith R2bIt is separately-H or methyl, and R3aAnd R3bIt is separately-H.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, each R6 Independently selected from-H ,-F ,-Cl ,-Br ,-NR6aR6b,-CN ,-OH, oxo base ,=O, carboxyl ,-C1-3Alkoxy ,-C1-4Alkane Base ,-C1-3Alkenyl-NR6aR6b、-C1-3Alkenyl-O-C1-3Alkyl ,-C1-3Alkenyl-CO-OR6a、-C1-3Alkenyl-C5-6Heterocycle ,-C1-3 Alkenyl-C5-6Heteroaryl ,-C1-3Alkenyl-CO-NR6aR6b、-C1-3Alkenyl ,-NR6a-CO-NR6aR6b、 -CO-NR6aR6b、-CO-CO- NR6aR6b、-CO-C1-3Alkyl ,-CO-NR6a-C5-6Heterocycle ,-CO-C5-6Heterocycle ,-O-C5-6Carbocylic radical ,-O-C5-6Heterocycle Base ,-NR6a-CO-C1-3Alkyl ,-NR6a-CO-NR6aR6b、-NR6a-C1-3Alkenyl-NR6aR6b、-NR6a-C1-6Alkenyl-C3-6Heterocycle Base ,-NR6a-SO2C1-3Alkyl ,-S-C1-3Alkyl ,-SO-C1-3Alkyl ,-SO2NR6aR6b、-SO2C1-3Alkyl ,-PO (C1-3Alkyl )2、-PO(C1-3Alkoxy)2, 5 circle heterocyclic ring bases, 6 circle heterocyclic ring bases, 5 unit's heteroaryls or 6 unit's heteroaryls, and each R6Independently appoint Selection of land is replaced or do not replaced by 1,2 or 3 substituent group, and the substituent group is selected from-F ,-Cl, Br ,-NH2,-OH, carboxyl, oxo Base ,=O, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy；Each R6aAnd R6b Independently selected from-H；-F；-Cl；Br；I；-NH2；-CN；-OH；-NO2；Carboxyl；-C1-3Alkoxy；-C1-3Alkyl or by 1,2 or 3-H, halogens ,-NH2,-the C that replaces of-CN or-OH1-3Alkyl；Or
Two adjacent R6 link together and the carbon atom being separately connected with them is formed together 6 yuan of aryl, 5 yuan of carbocyclic rings Base, 5 unit's heteroaryls or 5 circle heterocyclic ring bases；And each heteroaryl or heterocycle includes 1 or 2 miscellaneous original for being selected from N, O or S Son；And each ring system is independently optionally replaced by 1,2 or 3 substituent group or does not replace, each substituent group Independently selected from-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2,=O, oxo base, carboxyl ,-CONH2、 -PO(CH3)2, first Base, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, each R6 Independently selected from-H；-F；-Cl；-Br；-NR6aR6b；-CN；-OH；Oxo base；=O；Carboxyl；Methoxyl group；Ethyoxyl；Third oxygen Base；Isopropoxy；Methyl；Ethyl；Propyl；Isopropyl；Tert-butyl；-C1-3Alkenyl-NR6aR6b； -NR6a-CO-NR6aR6b；-CO- NR6aR6b；-CO-CO-NR6aR6b；- CO- methyl；- CO- ethyl；-CO-NR6a-C5-6Heterocycle；-CO-C5-6Heterocycle；-O-C5-6 Carbocylic radical；-O-C5-6Heterocycle；-NR6a- CO- methyl；-NR6a-CO-NR6aR6b； -NR6a-C1-3Alkenyl-NR6aR6b；-NR6a- C1-6Alkenyl-C3-6Heterocycle；-NR6a-SO2Methyl；-NR6a-SO2Ethyl；- S- methyl；- S- ethyl；- SO- methyl；-SO- Ethyl；-SO2NR6aR6b；-SO2Methyl；-SO2Ethyl；- PO (methyl)2；- PO (ethyl)2；- PO (methoxyl group)2；- PO (ethoxy Base)2；Contain 1,2 or 3 heteroatomic 5 circle heterocyclic ring base；Contain 1,2 or 3 heteroatomic 6 circle heterocyclic ring base；Contain 1,2 or 3 A heteroatomic 5 unit's heteroaryl；Or containing 1,2 or 3 heteroatomic 6 unit's heteroaryl, the hetero atom is selected from N, O or S；Its In each R6Independently optionally replaced by 1,2 or 3 substituent group or do not replace, the substituent group be selected from-F ,-Cl, Br ,- NH2,-OH, carboxyl, oxo base ,=O, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy； Each R6aAnd R6bIndependently selected from-H；-F；-Cl；Br；I；-NH2；-CN；-OH；-NO2；Carboxyl；Methyl；Ethyl；Methoxyl group； Ethyoxyl；By 1,2 or 3-H, F, Cl, Br ,-NH2, the methyl that replaces of-CN or-OH；Or by 1,2 or 3-H, F, Cl, Br ,- NH2, the ethyl that replaces of-CN or-OH；Or
Two adjacent R6Link together and the carbon atom that is separately connected with them be formed together phenyl, 5 yuan of carbocylic radicals, 5 unit's heteroaryls containing 1 or 2 N or O or the 5 circle heterocyclic ring bases containing 1 or 2 N or O；And each ring system is independently Optionally replaced by 1,2 or 3 substituent group or do not replace, each substituent group independently selected from-F ,-C1 ,-Br ,- NH2、-CN、-OH、-NO2,=O, oxo base, carboxyl ,-CONH2、-PO(CH3)2, methyl, ethyl, propyl, isopropyl, methoxyl group, Ethyoxyl, propoxyl group or isopropoxy.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, each R6 Independently selected from-F ,-Cl ,-Br ,=O ,-OH ,-CN ,-NH2,-SCH3、-SOCH3、 - SO2CH3、-PO(CH3)2、-PO(OC2H5)2、-NHSO2CH3、-C(O)NH2, methyl, ethyl, isopropyl, methoxyl group, ethyoxyl, =O, oxo base ,-OH ,-CN ,-NH2、-Cl、-Br、-CF3、-OCF3、-SO2NH2、-SO2CH3、 -CH2NH2、-SCH3、 -NHCOCH3、-NHCONHCH3、 Or
Two adjacent R6It links together and the carbon atom being separately connected with them is formed together
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, describedization Closing object is formula II compound represented:
It is wherein:
R3Selected from-H or-NH2；
Each R4aOr R4bIndependently selected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl or substituted or unsubstituted- C1-3Alkyl；Or
R4aAnd R4bC=O, C=NH or C=N-OH are formed together with the carbon atom that they connect jointly；
P is 0,1,2 or 3；
Each R5aOr R5bIndependently selected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl or substituted or unsubstituted- C1-3Alkyl；Or
R5aAnd R5b3-5 circle heterocyclic ring base is formed together with the carbon atom that they connect jointly；And each heterocycle is only On the spot optionally replaced by 1,2 or 3 substituent group or do not replace, the substituent group is selected from-H, halogen ,-NH2,-CN or-OH；
Q is 0,1,2,3 or 4；
Ring A is 3-6 member carbocylic radical, 3-6 circle heterocyclic ring base, phenyl or 5-6 unit's heteroaryl；
Indicate singly-bound or double bond；Wherein,
Iii) whenWhen indicating singly-bound, Y2It is CR2aOr N, and Y3It is CH or N；Or
Iv) whenWhen indicating double bond, Y2It is C, and Y3It is C；
R2aSelected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl or substituted or unsubstituted-C1-3Alkyl；
Each R6Independently selected from-H, halogen ,-NR6aR6b、-CN、-OH、-NO2, oxo base ,=O, carboxyl ,-C1-3Alcoxyl Base ,-C1-4Alkyl ,-CO-NR6aR6b、-CO-CO-NR6aR6b、-CO-C1-3Alkyl ,-CO-NR6a-C3-10Heterocycle ,-CO-NR6a- C3-10Heterocycle ,-CO-C4-6Heterocycle ,-O-C3-6Carbocylic radical ,-O-C3-6Heterocycle ,-NR6a-CO-C1-3Alkyl ,-NR6a-CO- NR6aR6b、-NR6a-CO-C5-6Heteroaryl ,-NR6a-SO2C1-3Alkyl ,-S-C1-3Alkyl,
-SONR6aR6b、-SO2NR6aR6b、-SO-C1-3Alkyl ,-SO2-C1-3Alkyl ,-PO (C1-3Alkyl)2、-PO(C1-3Alcoxyl Base)2、-C3-6Heterocycle or-C5-6Heteroaryl, wherein each R6Independently optionally replaced by 1,2 or 3 substituent group or does not take Generation；And n is 0,1,2 or 3；Or
Two adjacent R6The carbon atom being separately connected with it that links together is formed together 6 yuan of aryl, 5 unit's heteroaryls, 6 Unit's heteroaryl, C3-6Heterocycle or C3-6Carbocylic radical, each ring system are independently optionally replaced by 1,2 or 3 substituent group Or do not replace；
Each R6aAnd R6bIndependently selected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl or substituted or unsubstituted-Alkyl.
In some technical solutions, general formula compound shown in structure formula (II) or its pharmaceutically acceptable salt, each R5aOr R5bIndependently selected from-H ,-Cl ,-Br ,-NH2,-OH, carboxyl, methyl, ethyl, methoxy or ethoxy；Or
R5aAnd R5bIt is formed together with the carbon atom that they connect jointlyAnd * C indicates the carbon atom and R5aAnd R5bEven It connects.
In some technical solutions, general formula compound shown in structure formula (II) or its pharmaceutically acceptable salt, ring A is 6 yuan of phenyl, 3 circle heterocyclic ring bases, 4 circle heterocyclic ring bases, 5 circle heterocyclic ring bases, 6 circle heterocyclic ring bases, 5 unit's heteroaryls, 6 unit's heteroaryls, 9 yuan of heteroaryls Base, 3 yuan of carbocylic radicals, 4 yuan of carbocylic radicals, 5 yuan of carbocylic radicals or 6 yuan of carbocylic radicals；And each heteroaryl independently includes 1 or 2 A hetero atom selected from N, O or S；Each heterocycle independently includes 1 or 2 hetero atom for being selected from N or O.
In some technical solutions, general formula compound shown in structure formula (II) or its pharmaceutically acceptable salt, ring A choosing From
In some technical solutions, general formula compound shown in structure formula (II) or its pharmaceutically acceptable salt, R2aChoosing From-H；-F；-Cl；-Br；-NH2；-CN；-OH；-NO2；Carboxyl；Methyl；Ethyl；Propyl；Isopropyl；Methoxyl group；Ethyoxyl；Third Oxygroup；Isopropoxy；By-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy - the C that base, ethyoxyl, propoxyl group or isopropoxy replace1-3Alkyl；Or by-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2, carboxylic - the C that base, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy replace1-3Alkoxy.
In some technical solutions, general formula compound shown in structure formula (II) or its pharmaceutically acceptable salt, Y2It is CH or N, and Y3It is CH or N.
In some technical solutions, general formula compound shown in structure formula (II) or its pharmaceutically acceptable salt, Y2It is C, and Y3It is C.
In some technical solutions, general formula compound shown in structure formula (II) or its pharmaceutically acceptable salt, each R6Independently selected from-H ,-F ,-Cl ,-Br ,-NH2、-N(CH3)2,-CN ,-OH, oxo base ,=O, carboxyl, methoxyl group, ethoxy Base, methyl, ethyl, isopropyl, tert-butyl ,-CH2NH2、-CH2CH2OCH3、-CH2-COOH、 -CH2NH-CONHCH3、- CONH2、-CON(CH3)2、-CONHOH、-CONHCH2CH2OH、 -CO-CON(CH3)2、-COCH3、-SO2NH2、-SO2CH3、- SCH3、-SOCH3、-PO(CH3)2-PO(OC2H5)2 -NHSO2CH3、-NH-COCH3、-NH-CONHCH3、 Wherein Each R6Independently optionally by 1,2 or 3-F ,-Cl ,-NH2,-OH, oxo base ,=O, methyl, ethyl or propyl replace or not Replace.
In some technical solutions, general formula compound shown in structure formula (II) or its pharmaceutically acceptable salt, each R6aAnd R6bIndependently selected from-H ,-Cl ,-Br ,-NH2, it is-OH, carboxyl, methyl, ethyl, methoxyl group, ethyoxyl, propoxyl group, different The methyl that propoxyl group, quilt-OH replace or the ethyl replaced by-OH.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, describedization Conjunction object is structure formula (III) compound represented:
It is wherein:
Each R1And R2Independently selected from-H ,-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkoxy Or-C1-3Alkyl；Or
R1R adjacent thereto2Connect and the carbon atom that is separately connected with them be formed together comprising 1,2 or 3 selected from N or Heteroatomic 5 circle heterocyclic ring of O, and 5 circle heterocyclic ring is optionally by 1,2 or 3 halogen ,-NH2、-CN、-OH、-NO2, carboxyl, oxo Base ,=O ,-CONH2Or-CO-C1-3Alkyl replaces or does not replace；
Y1Selected from N or CH；
R3Selected from-H or-NH2；
Ring B is selected from phenyl ring, 5 yuan of hetero-aromatic rings, 6 yuan of hetero-aromatic rings, 3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 5 yuan Heterocycle or 6 circle heterocyclic rings, and each heteroaryl ring group or heterocycle is independently optionally miscellaneous selected from N or O comprising 1 or 2 Atom；
Iii) whenWhen indicating singly-bound, Y3It is CH or N；Or
Iv) whenWhen indicating double bond, Y3It is C；
R7 is selected from halogen ,-NH2、-CN、-OH、-NO2, carboxyl, oxo base ,=O ,-CONH2、-NH-COCH3, replace or not - the C replaced1-6Alkoxy or substituted or unsubstituted-C1-6Alkyl；And m is 0,1 or 2.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, R1With it Adjacent R2It connects and the carbon atom being separately connected with them is formed togetherAnd the ring system is independently optionally by 1 Or 2-F or-COCH3Replace or does not replace.
In some technical solutions, general formula compound shown in structure formula (III) or its pharmaceutically acceptable salt, ring B It is selected from
In some technical solutions, general formula compound shown in structure formula (III) or its pharmaceutically acceptable salt, R7Choosing From-NH2,-CN, oxo base ,=O ,-CONH2、-NH-COCH3, methyl or methoxy.
In some technical solutions, general formula compound shown in structure formula (I) or its pharmaceutically acceptable salt, describedization Closing object is structure formula (IV) compound represented:
Wherein:
Each R1And R2Independently selected from-H；-F；-Cl；-Br；-NH2；-CN；-OH；-NO2；Carboxyl；-NHC1-3Alkane Base；-N(C1-3Alkyl)2；-C1-3Alkoxy；-C1-3- the C that alkyl or 1,2 or 3 halogen replace1-3Alkyl；Or
R1R adjacent thereto2It connects and the carbon atom being separately connected with them is formed together 6 yuan of carbocyclic rings, 6 yuan of aryl, includes 1 or 2 is selected from heteroatomic 6 circle heterocyclic ring of N or O selected from heteroatomic 5 circle heterocyclic ring of N or O or comprising 1 or 2, and each of described Ring system is independently optionally by 1,2 or 3 halogen ,-NH2、-CN、-OH、-NO2, carboxyl, oxo base ,=O ,-CONH2、-C1-3 Alkoxy ,-C1-3Alkyl or-CO-C1-3Alkyl replaces or does not replace；
Y1It is N or CH；
R3It is-H or-NH2；
Ring D is selected from 6 yuan of aryl, 5 unit's heteroaryls, 6 unit's heteroaryls, 3 yuan of carbocylic radicals, 4 yuan of carbocylic radicals, 5 yuan of carbocylic radicals, 6 yuan Carbocylic radical, 3 circle heterocyclic ring bases, 4 circle heterocyclic ring bases, 5 circle heterocyclic ring bases or 6 circle heterocyclic ring bases, each heteroaryl or heterocycle are only The hetero atom of N, O or S are on the spot optionally selected from comprising 1 or 2；
Indicate singly-bound or double bond；And
Iii) whenWhen indicating singly-bound, Y2It is CR2aOr N, and Y3It is CR3aOr N；Or
Iv) whenWhen indicating double bond, Y2And Y3It is C；
Each R2aAnd R3aIndependently selected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkoxy or-C1-3 Alkyl；
R8Selected from halogen ,-NH2、-CN、-OH、-NO2, carboxyl, oxo base ,=O, C1-4Alkyl, C1-3Alkoxy ,- SO2NR8aR8b、-S-C1-3Alkyl ,-SO-C1-3Alkyl ,-SO2-C1-3Alkyl ,-CO-NR8aR8b、-PO(C1-3Alkyl)2、-PO(C1-3 Alkoxy)2、-NR8a-CO-C1-3Alkyl ,-NR8a-CO-NR8aR8b,-O-5 member carbocylic radical ,-O-5 circle heterocyclic ring base ,-O-6 circle heterocyclic ring Base, 5 circle heterocyclic ring bases, 6 circle heterocyclic ring bases, 5 unit's heteroaryls or 6 unit's heteroaryls；And each R8Independently optionally by 1,2 or 3 Selected from halogen, methyl, ethyl, methoxyl group, oxo base ,-NH2,-CN or-OH substituent group replace or do not replace；And t is 0,1,2 Or 3；Or
Two adjacent R8The carbon atom being separately connected with it that links together is formed together 6 yuan of aryl or 5 unit's heteroaryls, And each ring system is independently optionally substituted or does not replace；
Each R8aAnd R8bIndependently selected from H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkoxy or-C1-3 Alkyl.
In some technical solutions, general formula compound shown in structure formula (IV) or its pharmaceutically acceptable salt, each R1And R2Independently selected from-H ,-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2、-CF3, carboxyl ,-NHCH3、 -N(CH3)2, first Oxygroup, ethyoxyl, methyl or ethyl；Or
R1R adjacent thereto2It connects and the carbon atom being separately connected with them is formed together 6 yuan of carbocyclic rings, 6 yuan of aryl, includes 1 is selected from the heteroatomic 5 yuan of hetero-aromatic rings of N or O selected from the heteroatomic 5 circle heterocyclic ring base of N or O or including 1；And each ring System is independently optionally selected from-F ,-Cl ,-Br ,-NH by 1,2 or 32、-CN、-OH、-NO2, carboxyl, oxo base ,=O ,- CONH2, methoxyl group, ethyoxyl, methyl, ethyl ,-CO- methyl or-CO- ethyl substituent group replace or do not replace.
In some technical solutions, general formula compound shown in structure formula (IV) or its pharmaceutically acceptable salt, each R1And R2Independently selected from-H ,-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2、-CF3, carboxyl ,-NHCH3、 -N(CH3)2, first Oxygroup, ethyoxyl, methyl or ethyl；Or
R1R adjacent thereto2It connects and the carbon atom being separately connected with them is formed togetherAnd the ring system is independently optionally selected from-F or-COCH by 1,2 or 33Substitution Base replaces or does not replace.
In some technical solutions, general formula compound shown in structure formula (IV) or its pharmaceutically acceptable salt, ring D choosing From
In some technical solutions, general formula compound shown in structure formula (IV) or its pharmaceutically acceptable salt, each R2aAnd R3aIndependently selected from-H, methyl or methoxy.
In some technical solutions, general formula compound shown in structure formula (IV) or its pharmaceutically acceptable salt, R8Choosing From-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2, carboxyl, oxo base ,=O, methyl, ethyl, propyl, isopropyl, tert-butyl, Methoxyl group, ethyoxyl, propoxyl group, isopropoxy ,-CO- methyl ,-SO2NR8aR8b,-S- methyl ,-S- ethyl ,-SO- methyl ,- SO- ethyl ,-SO2Methyl ,-SO2Ethyl ,-CO-C3-6Heterocycle ,-CO-NR8aR8b,-PO (methyl)2,-PO (ethyl)2、-PO (methoxyl group)2,-PO (ethyoxyl)2、-NR8a- CO- methyl ,-NR8a- CO- ethyl ,-NR8a-CO-NR8aR8b、-NR8a-SO2First Base ,-O-5 member carbocylic radical ,-O-5 circle heterocyclic ring base ,-O-6 circle heterocyclic ring base, 5 circle heterocyclic ring bases, 6 circle heterocyclic ring bases, 5 unit's heteroaryls or 6 yuan Heteroaryl, each heterocycle or heteroaryl contain 1 or 2 hetero atom for being selected from O, N or S；Each R8Independently optionally Ground is selected from-F ,-Cl ,-Br ,-NH by 1,2 or 32,-CN ,-OH, oxo base ,=O, methoxyl group, ethyoxyl, methyl or ethyl Substituent group replace or do not replace.
In some technical solutions, general formula compound shown in structure formula (IV) or its pharmaceutically acceptable salt, R8Choosing From-F ,-Cl ,-Br ,-NH2,-CN ,-OH, carboxyl, oxo base ,=O, methyl, ethyl, isopropyl, tert-butyl, CF3, methoxy Base ,-SOCH3、-5O2CH3、-SCH3、P(O)(CH3)2P(O)(OC2H5)2NHS(O)2CH3、-CONH2、 -NH-COCH3、-NH- CONHCH3、-NH-COCH3、
In some technical solutions, structure formula (I), (II), general formula compound shown in (III) (IV) or its pharmaceutically may be used The salt of receiving, the compound is:
On the other hand, the present invention also provides a kind of pharmaceutical composition, comprising at least one structure of the invention formula (I), (II), (III) or general formula compound shown in (IV) or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable auxiliary Material.
Further, in the pharmaceutical composition, structure formula (I), (II), described shown in (III) or (IV) The weight ratio of compound or its pharmaceutically acceptable salt and the auxiliary material is 0.0001~10.
On the other hand, the present invention also provides the purposes that the pharmaceutical composition is used to prepare drug.
In some technical solutions, the drug is used to treat, prevent or prevent the disease that is mediated by SHP2 activity or not It is suitable.
In some technical solutions, the disease mediated by SHP2 activity or discomfort are cancer, metastasis of cancer, cardiovascular disease Disease, immunologic derangement, fibrosis or visual disorders.
In some technical solutions, the disease mediated by SHP2 activity or uncomfortable selected from one or more lower epidemies Disease: Noonan syndrome, leopard syndrome, juvenile myelomonocyte leukaemia, neuroblastoma, melanoma, incidence Squamous cell carcinoma, acute myelogenous leukemia, breast cancer, esophageal tumor, lung cancer, colon cancer, head cancer, gastric cancer, lymthoma, plastic Cell plastid tumor, gastric cancer, cancer of pancreas and combinations thereof.
Unless otherwise indicated, refer to fluorine, chlorine, bromine or iodine in term " halogen " present invention.Preferably, halogen include fluorine, Chlorine and bromine.Term " halogenated C1-6Alkyl ", " halogenated C2-6Alkenyl ", " halogenated C2-6Alkynyl " and " halogenated C1-6Alkoxy " refers to wherein One or more (especially 1,2 or 3) hydrogen atoms are substituted with halogen atoms, especially fluorine or chlorine atom.In some implementations In scheme, preferably fluoro C1-6Alkyl, fluoro C2-6Alkenyl, fluoro C2-6Alkynyl and fluoro C1-6Alkoxy, especially fluoro C1-3 Alkyl, such as CF3、CHF2、CH2F、CH2CH2F、CH2CHF2、 CH2CF3；Fluoro C1-3Alkoxy, such as OCF3、OCHF2、 OCH2F、OCH2CH2F、OCH2CHF2Or OCH2CF3；Particularly relate to CF3、OCF3And OCHF2。
Unless otherwise indicated, the alkyl in the present invention includes the saturation monovalent hydrocarbon with straight chain, branch or annulus.
For example, alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, normal-butyl, isobutyl group, sec-butyl, tertiary fourth Base, cyclobutyl, n-pentyl, 3- (2- methyl) butyl, 2- amyl, 2- methyl butyl, neopentyl, cyclopenta, n-hexyl, 2- oneself Base, 2- methyl amyl and cyclohexyl.Similarly, C in the present invention1-8The definition of alkyl be arrange with linear chain or branched chain with 1, 2, the group of 3,4,5,6,7 or 8 carbon atoms.
Alkylidene refers to the double functional group obtained and removing hydrogen atom from alkyl defined above.For example, sub- Methyl (i.e.-CH2-), ethylidene (i.e.-CH2-CH2- or-CH (CH3) -) and propylidene (i.e.-CH2-CH2-CH2- ,-CH (- CH2-CH3)-or-CH2-CH(CH3)-)。
Alkoxy is the oxygen ether formed by the straight chain, branch or cyclic alkyl of foregoing description.
Unless otherwise indicated, the term as used herein " aryl " itself or a part as another substituent group refer to list Ring or polycyclic aromatic hydrocarbon.Phenyl and naphthalene are preferred aryl.Most preferred aryl is phenyl.
Unless otherwise stated, the term as used herein " heterocycle " itself or a part as another substituent group are Refer to containing one or more heteroatomic unsubstituted and substituted monocycles or polycyclic non-aromatic, part insatiable hunger and/or fully saturated Ring system.Preferred hetero atom includes N, O and S, including N- oxide, oxysulfide and dioxide.It is preferred that the ring be three to Eight yuan and fully saturated or there are one or more degrees of unsaturation.In this definition include multiple degree of substitution, preferably one, two Or three degree of substitution.
The example of such heterocycle includes but is not limited to azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, oxygen For piperazinyl, oxo-piperidine base, nitrogen heterocyclic heptyl, tetrahydrofuran base, dioxolanyl, imidazolidine base, tetrahydro-thiazoles Base, tetrahydro oxazolyl, THP trtrahydropyranyl, morpholinyl, thio-morpholinyl, thiomorpholino sulfoxide, oxadiazoles or oxazerine.
Unless otherwise stated, the term as used herein " heteroaryl " itself or a part as another substituent group Refer to containing carbon and at least one heteroatomic aromatics ring system.Heteroaryl can be monocycle or polycyclic, substituted or unsubstituted. Bicyclic heteroaryl can have 1 to 4 hetero atom in ring, and polyheteroaromatic can contain 1 to 10 hetero atom.It is polycyclic miscellaneous Aryl rings can be containing condensed loop coil or bridged ring, for example, ring heteroaryl is polyheteroaromatic.Bicyclic heteroaryl ring can contain 8 To 12 member atoms.Bicyclic heteroaryl ring can contain 5 to 8 member atoms' (carbon number and hetero atom).The example packet of heteroaryl Include but be not limited to thienyl, furyl, imidazole radicals, isoxazolyl, oxazolyl, pyrazolyl, pyrrole radicals, thiazolyl, thiadiazolyl group, Triazolyl, pyridyl group, pyridazinyl, indyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothiophene Base, benzothiazolyl, diazosulfide base, benzotriazole base adenyl, quinolyl or isoquinolyl.
Unless otherwise indicated, the term as used herein " naphthenic base " itself or a part as another substituent group refer to Substituted or unsubstituted monocycle, two rings or polycyclic non-aromatic saturation or the unsubstituted alkyl in part, optionally include alkylidene Linker can be connected by its naphthenic base.Illustratively " naphthenic base " group includes but is not limited to cyclopropyl, cyclobutyl, Cyclopenta, cyclohexyl etc..
Term " carbonyl ", "-C=O ", " C=O ", "-CO ", "-C (O) " and " CO " refer to group
Term " oxo " refers to group=O.
Term " oxo " or "=O " refer to that its coupled carbon atom is formed together C=O.
Whenever term " alkyl " or any of " aryl " or its prefix root appear in substituent group (such as aralkyl or Dialkyl amido) title in when, unless otherwise indicated, itself or as another substituent group a part, should be interpreted that packet Include the limitation of " alkyl " and " aryl " given above.Specified carbon atom number (for example, Cl-6) should independently refer to alkyl portion Carbon atom number or in which alkyl in point is as the carbon atom number in the moieties of the relatively large-substituent of its prefix root.
Two " R in general formula I, II, III or IV1" substituent group can be identical or different.Similar to " R1", and general formula I, Two " Y of II, III or IV1" can be identical or different.
Compound as described herein, such as certain compounds of general formula I, II, III or IV can be containing R or S configurations not The carbon atom (or chiral centre) symmetrically replaced.The present invention includes racemic mixture, opposite and absolute stereo isomers, and Opposite and absolute stereo isomers mixture.
Compound as described herein, when being specially designated as R- or S- isomers with chemical name, should understand respectively based on It is configured as R- isomers or S- isomers.For example, in any embodiment as described herein, this R- or specified different of S- Structure body can be substantially free of chirality each (such as by chirality HPLC determination less than 5%, less than 1% or undetectable) Another isomers at center.R- or S- isomers can be prepared by the method enumerated in the application, such as by synthesizing Chiral auxiliary such as R- or S- t-butyl sulfonamide is used in the process.Its other party of Preferred conformations R- or S- isomers is prepared herein Method includes but is not limited to the chiral HPLC purifying of stereoisomer mixture (such as racemic mixture).It is separated using HPLC vertical The conventional method of body isomers (such as enantiomter and/or diastereoisomer) is known in the art.
Compound as described herein can exist in the form of isotope labelling or enrichment, contain one or more atoms Quality or mass number are different from the atom of atomic mass or mass number the most abundant in nature.Isotope can be radioactivity Or non radioactive isotope.Such as hydrogen, carbon, phosphorus, sulphur, fluorine, chlorine and the equiatomic isotope of iodine include but is not limited to 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36C1 and 125I.The change of other isotopes containing these and or other atoms Close object within the scope of the invention.In some embodiments, one or more hydrogen atoms of any compound as described herein It can be replaced by deuterium to provide accordingly by label or the compound of enrichment.
As used herein, term " subject " (being alternatively referred to as " patient " in the present invention), which refers to, has become treatment, The animal of observation or experiment object, preferably mammal, it is optimal to choose.
It (may also be referred to as " loop system ") unless otherwise stated, terms used herein " ring system " and include but is unlimited In carbocyclic ring, heterocycle, hetero-aromatic ring etc. can also only include heterocycle and/or hetero-aromatic ring, and based on context need with specifically including Which ring determined, nevertheless, " ring system " does not include based on C1-6Alkyl or C1-3The naphthenic base of alkyl group, and do not include Based on C1-6Alkoxy or C1-3Alkoxy.
The compound of general formula I, II, III or IV can have different isomeric forms.For example, any asymmetric carbon atom can To be present in (R)-, in (S)-or (R, S)-configuration, preferably exist with (R)-or (S)-configuration.Taking on double bond or especially ring Can exist in the form of cis- (=Z-) or trans- (=E-) for base.Therefore these compounds can be used as the mixture of isomers Or preferably exist with pure isomer, preferably exist with pure diastereoisomer or pure enantiomter.
When using plural form (such as compound, salt) comprising singular (such as single compound, mono-salt)." chemical combination Object " is not excluded for (such as in pharmaceutical preparation) there are more than one general formula I, II, III or IV compound (or its salt), " a " only generation Table indefinite article.Therefore " A " can be preferably understood as " one or more ", be understood not to "one"
" SHP2 " refers to " -2 protein tyrosine phosphatase of homologous region containing Src ", also referred to as SH-PTP2, SH-PTP3, Syp, PTP1D, PTP2C, SAP-2 or PTPN11.
The cancer for carrying " PTPNll mutation " includes but is not limited to: N58Y；D61Y,V；E69K；A72V,T, D；E76G,Q, K(ALL)；G60A；D61Y；E69V；F71K；A72V；T73I；E76G,K； R289G；G503V(AML)；G60R；D61Y,V,N； Y62D；E69K；A72T,V；T73I；E76K, V,G,A,Q；E139D；G503A,R；Q506P(JMML)；G60V；D61V；E69K； F71L； A72V；E76A(MDS)；Y63C(CMML)；Y62C；E69K；T507K (neuroblastoma)；V46L； N58S；E76V (lung cancer)；R138Q (melanoma)；E76G (colon cancer).
In the present invention, term " composition " refers to the product including the special component containing specific quantity, also includes any straight It connects or indirectly by any product of the special component of specific quantity being composed.Therefore, using the compounds of this invention as activity at The pharmaceutical composition divided and the method for preparing the compounds of this invention are also a part of the invention.In addition, the compounds of this invention Some crystal forms can exist in the form of polymorph, and be included in the invention.In addition, some compounds can be with Solvate is formed with water (i.e. hydrate) or ordinary organic solvents, and such solvate is also included within model of the invention In enclosing.
The compound of the present invention can also exist as a pharmaceutically acceptable salt form.In order to be used for drug, the present invention The salt of compound refers to nontoxic " pharmaceutically acceptable salt ".Pharmaceutically acceptable salt include it is pharmaceutically acceptable it is acid/ Anion or basic/cationic salts.Pharmaceutically acceptable acidity/anion salt be usually taken wherein basic nitrogen by inorganic acid or The form of organic acid protonation, representative organic acid or inorganic acid include but is not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, high chlorine Acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, lemon Lemon acid, benzoic acid, mandelic acid, methanesulfonic acid, ethylenehydrinsulfonic acid, oxalic acid, pamoic acid, 2- naphthalene sulfonic acids, p-methyl benzenesulfonic acid, hexamethylene Alkylamino sulfonic acid, salicylic acid, saccharin or trifluoroacetic acid.Pharmaceutically acceptable basic/cationic salts include but is not limited to aluminium, Calcium, chloroprocanine, choline, diethanol amine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.
The pro-drug of the compounds of this invention is also included in protection scope of the present invention.Under normal conditions, before such Body drug is the functional derivatives of the compounds of this invention, is easy to be converted to required compound in vivo.Therefore, in this hair In bright treatment method, term " administration " (administering) will include with specifically disclosed compound of the present invention, It also include using possible not specifically disclosed compound, but these compounds can be converted into specifically in vivo after giving patient Compound, various illnesss or discomfort for treatment.The conventional method for selecting and preparing suitable pro-drug is described more, example Such as 1985 " Prodrug formed designs " write by H.Bundgaard and Elsevier published.
In the present invention, the definition of any substituent group or variable of specific position and the substituent group of other positions in the molecule Or the definition of variable is unrelated.It should be appreciated that the substituent group and substitution form on the compounds of this invention can be by the common skills in this field Art personnel selection, with provide it is chemically stable and can by techniques known in the art and set forth herein those of method hold The compound being easily-synthesized.
The compound by the invention can be containing one or more asymmetric centers and therefore issuable non- Enantiomter and optical isomer.The present invention includes that the possible diastereoisomer of all that and their racemic are mixed Close object, their substantially pure detachable enantiomter, all possible geometric isomer and its pharmaceutically acceptable Salt.
Above formula I, II, III or IV do not represent spatial chemistry determining on location.The present invention include Formulas I, All stereoisomers and its pharmaceutically acceptable salt of II, III or IV.In addition, further including the mixture of stereoisomer And the specific stereoisomer of separation.During being used to prepare the synthetic method of these compounds, or using ability During racemization known to field technique personnel or epimereation process, the product of these methods can be alloisomerism The mixture of body.
Outer unless stated otherwise, when Formulas I, II, III or IV compound are there are when tautomer, the present invention includes any Possible tautomer and its pharmaceutically acceptable salt and their mixture.
When there are the form of solvate or polycrystalline for Formulas I, the compound of II, III or IV and its pharmaceutically acceptable salt When the form of type, the present invention includes any possible solvate and polymorphic forms.Form the type of the solvent of solvate It is not particularly limited, as long as solvent is pharmacologically being subjected to.It is, for example, possible to use water, ethyl alcohol, propyl alcohol, acetone etc..
Term " pharmaceutically acceptable salt " refers to the salt by pharmaceutically acceptable nontoxic alkali or acid preparation.When this hair When bright compound is acid, corresponding salt can be convenient by pharmaceutically acceptable nontoxic alkali (including inorganic base and Organic base) preparation.When the compounds of this invention be alkalinity when, corresponding salt can be convenient by pharmaceutically acceptable nontoxic Acid (including inorganic acid and organic acid) preparation.Since the compound of Formulas I, II, III or IV are used for pharmacy, they are excellent Choosing provides in a substantially pure form, and for example, at least 60% is pure, be more suitable for it is at least 75% pure, it is especially at least 98% pure (% with On the basis of weight).
Pharmaceutical composition of the invention includes that by Formulas I, II, III or IV, (or its is pharmaceutically acceptable as active constituent Salt) compound that indicates, pharmaceutically acceptable carrier and optional other therapeutic components or adjuvant.Although any given In the case of most suitable approach depend on specific main body and its illness (active constituent is applied to the illness) property and Severity, but the composition include be suitable for taking orally, rectum, topical and parenteral (including subcutaneous, intramuscular and intravenous) to The composition of medicine.Pharmaceutical composition exists in a unit and can be by well known in pharmaceutical field in which can be convenient Any method preparation.
In practice, according to conventional pharmaceutical hybrid technology, the present invention is indicated as the Formulas I of active constituent, II, III or IV Compound or its prodrug or metabolin or its pharmaceutically acceptable salt closely can mix (intimate with pharmaceutical carrier Admixture it is combined in).Depending on the dosage form needed for being administered, such as oral or extra-parenteral (including intravenous), carrier can To take many forms.Therefore, pharmaceutical composition of the invention can be used as the independent unit offer for being suitable for oral administration, Such as the respectively capsule containing predetermined amounts of active ingredients, cachet (cachets) or tablet.In addition, the composition can be with The form of powder, particle, solution, the suspension in waterborne liquid, non-aqueous liquid, oil-in-water emulsion or water-in-oil liquid emulsion In the presence of.Other than above-mentioned common formulations, the compound or its pharmaceutically acceptable salt that Formulas I, II, III or IV are indicated can be with It is administered by controlled-release device and/or delivery apparatus.The composition can be prepared by any method of pharmacy.In general, these methods Including making active constituent and comprising the carrier-bound step of one or more essential components.
In general, the composition by by active constituent and liquid-carrier or solid carrier fine crushing or both uniformly And mix (uniformly and intimately admixing) closely to prepare.Then product can easily be moulded Cause required form.
Therefore, pharmaceutical composition of the invention may include the change of pharmaceutically acceptable carrier and Formulas I, II, III or IV Close object or pharmaceutically acceptable salt.Formulas I, the compound of II, III or IV or its pharmaceutically acceptable salt can also be with one kind Or various other therapeutical active compound joints are included in pharmaceutical composition.
Pharmaceutical carrier used for example can be solid, liquid or gas.The example of solid carrier includes lactose, land plaster (terra alba), sucrose, talcum, gelatin, agar, pectin, Arabic gum, magnesium stearate and stearic acid.The reality of liquid-carrier Example is syrup, peanut oil, olive oil and water.The example of carrier gas includes carbon dioxide and nitrogen.Oral agents are used in preparation When the composition of type, any convenient drug media can be used.It is, for example, possible to use water, ethylene glycol, oil, alcohol, flavoring agent, Preservative, colorant etc. form oral liquid (such as suspension, elixir (elixirs) and solution)；And carrier is as formed sediment Powder, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, adhesive, disintegrating agent etc. can be used to form oral solid formulation (such as pulvis, capsule and tablet).Due to being easy to be administered, so tablets and capsules are preferred oral dosage units, thus Use solid pharmaceutical carriers.Optionally, tablet can be coated by standard aqueous or nonaqueous techniques.
Tablet containing the present composition can be prepared by suppressing or molding, optionally with one or more auxiliary Ingredient or auxiliary agent are prepared together.Compressed tablets can be by suppressing the free-flowing shape such as powder or particle in suitable machine Prepared by the active constituent of formula, optionally come with adhesive, lubricant, inert diluent, surfactant or dispersant Preparation.Molded tablets can pass through the mixing for the powder compound that molding inert liquid diluent soaks in suitable machine It is prepared by object.Every preferably comprises from about the active constituent of 0.05mg to about 5g, and each cachet or capsule preferably comprise from about The active constituent of 0.05mg to about 5g.For example, being intended for that about 0.5mg can be contained extremely to the preparation of oral administration in human The activating agent of about 5g is mixed with the suitable carrier material with the amount of convenience, the carrier material can total composition about 5 to Change between about 95%.Unit dosage forms usually contain about 1mg to the active constituent between about 2g, typically 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000mg.
Pharmaceutical composition of the present invention suitable for parenteral administration can be prepared into reactive compound solution in water or Suspension.Suitable surfactant may include such as hydroxypropyl cellulose.Dispersion can also be in glycerol, the poly- second two of liquid It is prepared in alcohol and its mixture in the oil.Furthermore, it is possible to prevent the obnoxious growth of microorganism comprising preservative.
It include aseptic aqueous solution or dispersion liquid suitable for injecting the pharmaceutical composition of the present invention used.In addition, the composition It can be the aseptic powdery form for this sterile injectable solution of extemporaneous preparation or dispersion.In all cases, finally Injection must be sterile, and must be effective liquid, in order to inject.Described pharmaceutical composition is being manufactured and is being stored up It must stablize under the conditions of depositing；Therefore the contamination of the microorganism such as bacterium and fungi should preferably be prevented.Carrier, which can be, to be contained There is the molten of such as water, ethyl alcohol, polyalcohol (such as glycerol, propylene glycol and liquid macrogol), vegetable oil and its suitable mixture Agent or decentralized medium.
Pharmaceutical composition of the invention can be suitable for the form of local use, such as aerosol, cream, ointment Agent, lotion, face powder (dustingpowder) etc..In addition, the composition, which can be, is suitable for the shape used in transdermal device Formula.The compound or its pharmaceutically acceptable salt indicated using Formulas I of the invention, II, III or IV, these preparations can lead to Conventional treatment method is crossed to prepare.For example, passing through the institute of mixing hydrophilic material and water and about 5 weight % to about 10 weight % Compound is stated to prepare emulsifiable paste or ointment, to generate the emulsifiable paste or ointment with required consistency.
It is solid that pharmaceutical composition of the invention, which can be suitable for the form of rectally and the carrier,.Preferably, institute It states mixture and forms unit dose suppositories.Suitable carrier includes cocoa butter and other materials commonly used in the art.Suppository can be with By first mixing the composition with the carrier of softening or fusing, then cools down in a mold and form and facilitate landform At.
Other than above-mentioned carrier components, said medicine preparation can optionally include one or more other carriers at Point, such as diluent, buffer, flavoring agent, adhesive, surfactant, thickener, lubricant, preservative be (including anti-oxidant Agent) etc..Furthermore, it is possible to comprising other adjuvants so that preparation and the blood of target recipient are isotonic.It is retouched containing Formulas I, II, III or IV The composition of the compound stated or its pharmaceutically acceptable salt can also be prepared into powder or liquid concentrate form.
In general, daily about 0.01mg/kg weight can be used to the dosage level of about 150mg/kg weight or optional The above-mentioned illness of dosage level treatment ground about 0.5mg daily to every patient of about 7g.For example, per kg body weight per day by application About 0.01 to the compound of 50mg or every patient about 0.5mg to about 3.5g daily compound, inflammation, cancer, ox-hide Tinea, allergy/asthma, the disease of immune system and illness, the disease of central nervous system (CNS) and illness can be effective Treatment.
However, it should be understood that various factors will be depended on for the specific dosage level of any particular patient, including It is age, weight, general health, gender, diet, administration time, administration route, discharge rate, medication combined and The severity for the specified disease treated.
From following in written description of the invention, these and other aspects will be apparent from.
Embodiment
Following intermediate and embodiment are provided for illustrating the present invention.Unless expressly stated otherwise, all numbers and percentage Than being by weight, all temperature are degree Celsius.Following abbreviation has been used in example:
Intermediate A 1
In a nitrogen environment, to the DMF of 6- methoxyl group -2,3- dihydro -1H- 1-Indanone (1.50g, 9.25mmol) Sodium hydride (60% dispersion oil, 1.11g, 27.75mmol) is added portionwise in (10mL) solution.It heats the mixture to It 60 DEG C, stirs 20 minutes at this temperature.Be added dropwise bis- (2- chloroethyl) t-butyl carbamates (2.46g, 10.17mmol), and by the mixture 85min is stirred.After being cooled to RT, reaction system is diluted with EA (200mL), uses salt water (3 × 200mL) washing, organic phase anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Residue (is used by silica gel chromatography EA: Hex=1: 12, v/v elution) purifying, obtain 6- methoxyl group -1- oxo -1,3- dihydro spiral shell [indenes -2,4 '-of yellow solid Piperidines] -1 '-carboxylic acid tert-butyl ester (557mg).MS:m/z 332 (M+H)+.
Following compounds are synthesized using above-mentioned steps and corresponding starting material.
Table 1
Intermediate A 2
Step a: by diethanol amine (198.15g, 1.88mol), K2CO3(520.95g, 3.77mol), cylite The mixture of (386.79g, 2.26mol) and acetonitrile (2000mL) stirs 2.5h at 90 DEG C.After being cooled to RT, filtering, filter cake It is eluted with EA (2 × 100mL).Filtrate decompression is concentrated.Residue (uses MeOH: DCM=1: 10, v/v by silica gel chromatography Elution) purifying, obtain the N- benzyl diethanol amine (89.44g) of colorless oil.MS:m/z 196 (M+H)+.
Step b: three are added dropwise into toluene (300mL) solution of 0 DEG C of N- benzyl diethanol amine (30.66g, 0.16mol) Phosphonium bromide (69.13g, 0.26mol).System is warming up to 105 DEG C of stirring 16h.After being cooled to RT, it is concentrated under reduced pressure and removes volatile matter. Residue is diluted with water (300mL), and pH value is adjusted to 9 with NaOH.System is extracted with EA (3 × 150 mL), merges organic phase, Through anhydrous Na2SO4It dries and filters.Filtrate decompression is concentrated, N- benzyl -2- bromo- N- (2- bromoethyl) ethane -1- amine is obtained (41.58g) is directly used in next step without any further purification.MS:m/z 320 (M+H)+.
Step c: in a nitrogen environment, to 0 DEG C of 6,7- dihydro -5H- cyclopenta [b] pyridine -5- ketone (1.70g, 12.77 mmol) DMF (20mL) solution in be added in three batches sodium hydride (60% dispersion oil, 982mg, 24.55 Mmol), 60 DEG C are then heated the mixture to, stirs 1h at this temperature.Then the bromo- N- of N- benzyl -2- (2- bromine second is added Base) ethane -1- amine (4.54g, 14.14mmol), and 1h is stirred at 60 DEG C.After being cooled to RT, by reaction system water (80mL) is quenched, and is extracted with EA (3 × 80mL).Combined organic phase is washed with water (3 × 80mL), uses anhydrous Na2SO4It is dry, It filters and is concentrated under reduced pressure.Residue is purified by silica gel chromatograph (being eluted with EA), obtains 1 '-benzyl spiral shell [cyclopenta [b] pyrrole Pyridine -6,4 '-piperidines] -5 (7H) -one (1.14g).MS:m/z 293 (M+H)+.
Step d: to 0 DEG C of 1 '-benzyl spiral shell [cyclopenta [b] pyridine -6,4 '-piperidines] -5 (7H) -one (1.05g, Chloroformate -1-chloro-ethyl ester (903mg, 6.32mmol) is added dropwise in DCE (10mL) solution 3.59mmol).System is stirred at RT 1.5h.It is concentrated under reduced pressure and removes volatile matter, residue is dissolved in MeOH (20mL), stirs 4h at 80 DEG C.It is concentrated under reduced pressure and removes Volatile matter, residue are dissolved in DCM (20mL).It is added DIEA (1.33g, 10.32mmol) and (Boc)2O (1.38g, 6.32mmol).Acquired solution stirs 16h at RT.Reaction solution is concentrated under reduced pressure.Residue by silica gel chromatography (use EA: Hex=1: 1, v/v elution) purifying, obtain 5- oxo -5,7- dihydro spiral shell [cyclopenta [b] pyridine -6,4 '-piperidines] -1 ' - Carboxylic acid tert-butyl ester (438mg).MS:m/z 303 (M+H)+.
Intermediate A 3
Step a: in a nitrogen environment, to -70 DEG C of piperidines-Isosorbide-5-Nitraes-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (8.14g, LDA (the THF/Hex solution of 2M, 24mL, 48.00mmol) is added dropwise in THF (80mL) solution 31.64mmol).Acquired solution After stirring 70min at this temperature, 1- bromo- 4- (bromomethyl) benzene (7.91g, 31.64mmol) is added portionwise.Acquired solution- 3h is stirred at 70 DEG C, and (50mL) carefully then is quenched with saturated ammonium chloride solution.The water phase isolated is with EA (1 × 80mL) Extraction merges organic phase, uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 4- (4- bromobenzyl) piperazine of brown oil Pyridine-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (14.55g) is directly used in next step without any further purification.MS:m/z 426(M+H)+.
Step b: by 4- (4- bromobenzyl) piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (14.55g, 34.13mmol), The mixture of NaOH (8.12g, 203.00mmol), MeOH (80mL) and water (80mL) stirs 16.5h at 75 DEG C.It is cooled to After RT, it is concentrated under reduced pressure and removes volatile matter.System is extracted with EA (3 × 80mL).Combined organic phase anhydrous Na2SO4It is dry, mistake It filters and is concentrated under reduced pressure, 4- (4- bromobenzyl) -1- (tertbutyloxycarbonyl) piperidines -4- carboxylic acid (16.87g) is obtained, without any into one Step purifying is directly used in next step.MS:m/z 398 (M+H)+.
Step c: by 4- (4- bromobenzyl) -1- (tertbutyloxycarbonyl) piperidines -4- carboxylic acid (16.87g, 42.36mmol) and PPA The mixture of (60 mL) stirs 30min at 120 DEG C.Reaction solution is poured into mixture of ice and water (300mL), with NaOH by pH Value is adjusted to 10.Then (Boc) is added2O (13.86g, 63.53mmol) simultaneously stirs 18h at RT.Reaction system with EA (3 × 150mL) extract.By combined organic phase with no Na2SO4It dries, filters and is concentrated under reduced pressure, obtain the bromo- 1- oxo -1,3- bis- of 6- Hydrogen spiral shell [indenes -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (16.87g) is directly used in next step without any further purification.MS: m/z 380(M+H)+.
Using the step of above-mentioned steps or modification and corresponding starting material synthesize following compounds.
Table 2
Intermediate A 4
In a nitrogen environment, by bromo- 1- oxo -1, the 3- dihydro spiral shell of 6- [indenes -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (2.06g, 5.42 mm0l), Pd (PPh3)4(626mg, 0.54mmol), DBU (252mg, 1.66mmol), t-BuOH (15mL), The mixture of water (15mL) and potassium ferrocyanide trihydrate (1.16g, 2.75mmol) is in 90 DEG C of stirring 22.5h.It is cooled to RT Afterwards, mixture is diluted with EA (30mL), and filtering, filter cake is eluted with EA (15mL).Filtrate is washed with salt water (1 × 30mL), with nothing Water Na2SO4It dries, filters and is concentrated under reduced pressure.Residue (elutes) purifying by silica gel chromatography with EA: Hex=1: 10, v/v, Obtain 6- cyano -1- oxo -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (1.86 g).327 (M of MS:m/z +H)+.
Following compounds are synthesized using above-mentioned steps and corresponding starting material.
Table 3
Intermediate A 5
By 4- cyano -1- oxo -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (0.93g, 2.85mmol), the mixture of KOH (1.60g, 28.50mmol), MeOH (15mL) and water (15mL) stirs 2h at 100 DEG C. After being cooled to RT, reaction solution is diluted with water (30mL), is extracted with EA (60mL, 30mL).By combined organic phase salt water (1 × 80mL) washing, use anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 4- carbamoyl -1- oxo -1,3- dihydro Spiral shell [indenes -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (1.04g) is directly used in next step without any further purification.MS:m/z 345(M+H)+.
Following compounds are synthesized using above-mentioned steps and corresponding starting material.
Table 4
Intermediate A 6
To 6- carbamoyl -1- oxo -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (1.57g, Sodium hydride (60% dispersion oil, 0.91g, 22.79mmol) is added in DMF (15mL) solution 4.56mmol), then CH is added3I (1mL, 16.06mmol).System is stirred into 17h at RT.Reaction solution is quenched with salt water (50mL), with EA (2 × 50mL) extract.Combined organic phase is washed with salt water (1 × 100mL), uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure. Residue (elutes) purifying by silica gel chromatography with EA: Hex=1: 3, v/v, obtains 6- (formyl-dimethylamino) -1- Oxo -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (0.82g).MS:m/z373 (M+H)+.
Intermediate A 7
Step a-c: the step of using intermediate A 3 (a-c) obtains 1 '-(tertbutyloxycarbonyl) -1- oxo -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -6- carboxylic acid.MS:m/z 346 (M+H)+.
Intermediate A 8
Bromo- 1- oxo -1, the 3- dihydro spiral shell of 6- [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester is added into 50mL tube sealing (998mg, 2.62 mmol), DMSO (8mL), water (4mL), CuI (217mg, 1.14mmol) and ammonium hydroxide (25%, 4mL). System stirs 5 days at 100 DEG C.After being cooled to RT, reaction solution salt water (20mL) and EA (30mL) are diluted.By organic phase point From using anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 6- amino -1- oxo -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] - 1 '-carboxylic acid tert-butyl ester (750mg).MS:m/z 317 (M+H)+.
Intermediate A 9
In a nitrogen environment, by bromo- 1- oxo -1, the 3- dihydro spiral shell of 6- [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester (531mg, 1.40 mmol), Methanesulfomide (371mg, 3.90mmol), K2CO3(1.10g, 7.95mmol), N, N '-dimethyl- The mixture of 1,2- ethylenediamine (85mg, 0.96mmol), CuI (72mg, 0.38mmol) and Isosorbide-5-Nitrae-dioxane (20mL) exists 23h is stirred at 110 DEG C.It adds Methanesulfomide (370mg, 3.89mmol), N, N '-dimethyl -1,2- ethylenediamine (85 mg, 0.96mmol) with CuI (75mg, 0.39mmol), it is stirred for 7h at that same temperature.After being cooled to RT, reaction solution water (30mL) is quenched, and is extracted with EA (3 × 50mL).By combined organic phase through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.It is residual Excess (elutes) purifying by silica gel chromatography with EA: Hex=2: 3, v/v, obtains 6- (methanesulfonamido) -1- oxo -1,3- Dihydro spiral shell [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester (562mg).MS:m/z 395 (M+H)+.
Following compounds are synthesized using above-mentioned steps and corresponding starting material.
Table 5
Intermediate A 10
To 6- amino -1- oxo -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester (0.66g, The water of Zassol (0.28g, 4.31mmol) 2.09mmol) is added dropwise in the solution in AcOH (5mL) and water (10mL) (2mL) solution.System stirs 4h at 50 DEG C.After being cooled to RT, the pH value of reaction system is adjusted to ammonium hydroxide (25%) 12, then extracted with DCM (60mL, 30mL).Combined organic phase is washed with salt water (1 × 60mL), uses anhydrous Na2SO4It is dry It is dry, it filters and is concentrated under reduced pressure.Residue (elutes) purifying by silica gel chromatography with EA: Hex=2: 1, v/v, obtains 1- oxo- 6- urea groups -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester (0.39g).MS:m/z360 (M+H)+.
Intermediate A 11
To 0 DEG C of 6- (methyl mercapto) -1- oxo -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester Be added in the MeOH (20mL) of (336mg, 0.97 mmol) and the solution of water (20mL) permonosulphuric acid potassium (296mg, 1.76mmol).System stirs 1h at 0 DEG C.Reaction solution saturation Na2S2O3(10mL) is quenched, and is concentrated under reduced pressure and removes volatile matter. System is extracted with EA (3 × 40mL), combined organic phase is through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Residue passes through Silica gel chromatography (elutes) purifying with EA: Hex=4: 1, v/v, obtains 6- (methylsulfinyl) -1- oxo -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester (285mg).MS:m/z 364 (M+H)+.
Following compounds are synthesized using above-mentioned steps and corresponding starting material.
Table 6
Intermediate A 12
In a nitrogen environment, by bromo- 1- oxo -1, the 3- dihydro spiral shell of 6- [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester (1.51g, 3.97 mmol), dimethyl phosphorus (503mg, 6.44mmol), Pd (OAc)2(92mg, 0.41mmol), Xantphos (457mg, 0.79mmol), K3PO4The mixture of (1.57g, 7.40mmol) and DMF (30mL) are stirred at 130 DEG C 16.5h.After being cooled to RT, reaction solution is quenched with water (120mL), is extracted with EA (3 × 80mL).By combined organic phase salt Water (1 × 120mL) washing, uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Residue (is used into MeOH by silica gel chromatography : DCM=1: 30, v/v elution) purifying, obtain white solid 6- (solutions of dimethyl phosphoryl base) -1- oxo -1,3- dihydro spiral shell [indenes - 2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (0.81g).MS:m/z 378 (M+H)+.
Following compounds are synthesized using above-mentioned steps and corresponding starting material.
Table 7
Intermediate A 13
In a nitrogen environment, by bromo- 1- oxo -1, the 3- dihydro spiral shell of 6- [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester (1.09g, 2.87 mmol), 1H- imidazoles (180mg, 2.64mmol), CuBr (34mg, 0.24mmol), Cs2CO3(851mg, 2.61mmol), 1, the mixture of 2,3,4- tetrahydros -8-hydroxyquinoline (74mg, 0.49mmol) and DMSO (10mL) are at 110 DEG C Stir 23h.After being cooled to RT, reaction system is quenched with water (30mL), is extracted with EA (1 × 40mL).Organic phase is through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Residue is purified by silica gel chromatography (being eluted with EA), obtains yellow solid 6- (1H- imidazoles -1- base) -1- oxo -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester (142mg).MS:m/z 368(M+H)+.
Following compounds are synthesized using above-mentioned steps and corresponding starting material.
Table 8
Intermediate A 14
By 1 '-(tertbutyloxycarbonyl) -1- oxo -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -6- carboxylic acid (345mg, 1.00mmol), piperidines (129mg, 1.51mmol) and HATU (422mg, 1.11mmol) stir 1h in DMF.With water (30mL) With EA (30mL) dilute reaction solution.Organic phase is separated, is washed with salt water (1 × 30mL), uses anhydrous Na2SO4It dries, filters simultaneously It is concentrated under reduced pressure, obtains 1- oxo -6- (piperidines -1- carbonyl) -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (380mg).MS:m/z413 (M+H)+.
Intermediate A 15
In a nitrogen environment, by bromo- 1- oxo -1, the 3- dihydro spiral shell of 6- [indenes -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (1.02g, 2.68 mmol), morpholine (0.67g, 7.69mmol), Cu (OAc)2(0.51g, 2.81mmol), DBU (1.03g, 6.77mmol) and the mixture of DMSO (10mL) is in 130 DEG C of stirring 23h.It is after being cooled to RT, reaction solution is dilute with water (70mL) It releases, is extracted with EA (3 × 50mL).By combined organic phase through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Residue passes through Silica gel chromatography (with EA: Hex=1: 1, v/v elute) purifying, obtain 6- morpholino -1- oxo -1,3- dihydro spiral shell [indenes -2, 4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (467mg).MS:m/z387 (M+H)+.
Intermediate A 16
In a nitrogen environment, by bromo- 1- oxo -1, the 3- dihydro spiral shell of 6- [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester (500mg, 1.31 mmol), 1- methyl piperazine (270mg, 2.70mmol), Cs2CO3(1306mg, 4.01mmol), Pd2 (dba)3 The mixture of (66mg, 0.07mmol), XantPhos (75mg, 0.13mmol) and Isosorbide-5-Nitrae-dioxane (18mL) is stirred at 100 DEG C Mix 0.5h.After being cooled to RT, reaction solution is quenched with water, and is extracted with EA (2 × 100mL).By combined organic phase with salt water (1 × It 100mL) washs, uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 6- (4- methylpiperazine-1-yl) oxo-1-1-, 3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester (0.87g, crude product), is directly used in down without any further purification One step.MS:m/z400 (M+H)+.
Intermediate A 17
Step a: in a nitrogen environment, to -60 DEG C of piperidines-Isosorbide-5-Nitraes-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (15.52g, 60.31 mmol) THF (100ml) solution in LDA (the THF/Hex solution of 2M, 45.00mL, 90.00 mmol) are added dropwise. System warms naturally to -20 DEG C and stirs 50min, is cooled to -50 DEG C, and CH is added dropwise3I's (8.56g, 60.31 mmol) THF (20mL) solution.Then 50min is stirred at this temperature.Carefully (80mL) is quenched with saturated ammonium chloride in reaction solution, uses EA (100mL, 50mL) extraction.By combined organic phase anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 4- methyl piperidine- Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (17.70g) is directly used in next step without any further purification.MS:m/z 216 (M+H-56)+.
Step b: to 0 DEG C of 4- methyl piperidine-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (17.70g, 65.23mmol) LiBH is added in THF (150mL) solution4(THF solution of 2M, 98.00mL, 196.00mmol).System stirs at 70 DEG C 18h.After being cooled to RT, water (100mL) is added dropwise and is quenched.System is extracted with EA (200mL, 100mL), by combined organic phase It is washed with salt water (1 × 200mL), uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 4- (methylol) -4- methyl piperazine Pyridine -1- carboxylic acid tert-butyl ester (12.90g) is directly used in next step without any further purification.MS:m/z 174 (M+H-56)+.
Step c: DMSO is added dropwise into DCM (150mL) solution of -78 DEG C of oxalyl chlorides (10.71g, 84.38mmol) DCM (30mL) solution of (10.99g, 140.63mmol), stirs 30min at such a temperature.4- (methylol) -4- is added dropwise DCM (30mL) solution of methyl piperidine -1- carboxylic acid tert-butyl ester (12.90g, 56.25mmol), stirs 30min at -78 DEG C.Drop Add triethylamine (22.77g, 225.02mmol), then warms naturally to -20 DEG C, and stir 40min.Reaction solution is with water (80mL) It is quenched.Organic phase is collected, water phase is extracted with DCM (1 × 80mL).Combined organic phase is washed with salt water (1 × 200mL), is used Anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Residue is pure by silica gel chromatography (being eluted with EA: Hex=1: 20, v/v) Change, obtains 4- formoxyl -4- methyl piperidine -1- carboxylic acid tert-butyl ester (11.82 g) .MS:m/z172 (M+H-56)+.
Step d: LDA (2M is added dropwise into THF (50mL) solution of -70 DEG C of 3- chloropyridines (2.25g, 17.64mmol) THF/Hex solution, 11.00mL, 22.00mmol).System is warming up to -60 DEG C and stirs 1.5h.In -70 DEG C of dropwise addition 4- formyls THF (10mL) solution of base -4- methyl piperidine -1- carboxylic acid tert-butyl ester (3.95g, 17.37mmol).After stirring 1h, mixture is used Water (50mL) is quenched.Organic phase is collected, aqueous phase separation water phase is extracted with EA (60mL, 30mL).By combined organic phase salt water (1 × 80mL) washing, uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 4- ((3- chloropyridine -4- base) (hydroxyl) first Base) -4- methyl piperidine -1- carboxylic acid tert-butyl ester (8.10g), next step is used for without any purifying.MS:m/z341 (M+H )+.
Step e: to 4- ((3- chloropyridine -4- base) (hydroxyl) methyl) -4- methyl piperidine -1- carboxylic acid tert-butyl ester (8.10g, 23.76 mmol) DCM (50ml) solution in be added Dai Si-Martin's oxidant (20.12g, 47.44mmol).By system in RT Lower stirring 16h.Reaction solution is diluted with DCM (100mL), with saturation Na2S2O3(25%, 1 × 80mL) is saturated NaHCO3(1× 80mL) washed with salt water (1 × 100mL).Organic phase is through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Residue passes through silica gel Chromatography (elutes) purifying with EA: Hex=1: 3, v/v, obtains the tertiary fourth of 4- (the different nicotinoyl base of 3- chlorine) -4- methyl piperidine -1- carboxylic acid Ester (4.81g).MS:m/z339 (M+H)+.
Step f: in a nitrogen environment, by 4- (the different nicotinoyl base of 3- chlorine) -4- methyl piperidine -1- carboxylic acid tert-butyl ester (6.31g, 18.62 mmol), Cs2CO3 (6.72g, 21.90mmol), pivalic acid (571mg, 5.60mmol), Pd (OAc)2(0.22g, 0.98mmol), the mixture of Cy3PHBF4 (0.70g, 1.90mmol) and 1,3,5- trimethylbenzenes (40mL) are stirred at 140 DEG C 72h.After being cooled to RT, filtering, then EA (3 × 40mL) is eluted.Filtrate decompression is concentrated.Residue passes through silica gel chromatography (being eluted with EA: Hex=1: 1, v/v) purifying, obtains 5- oxo -5,7- dihydro spiral shell [6,4 '-piperazine of cyclopenta [c] pyridine - Pyridine] -1 '-carboxylic acid tert-butyl ester (2.82g).MS:m/z303 (M+H)+.
Following compounds are synthesized using above-mentioned steps and corresponding starting material.
Table 9
Intermediate A 18
Step a: dropwise into MeOH (100mL) solution of the bromo- 6- chloropyridine -2- carboxylic acid (9.98g, 42.21mmol) of 3- H is added2SO4(98%, 10.00mL).3h is stirred at 70 DEG C.After being cooled to RT, ammonium hydroxide (25%) is added by the pH of reaction solution Value is adjusted to 9.It is concentrated under reduced pressure and removes volatile matter.With water (60mL) diluted mixture, extracted with EA (1 × 100mL).It will be organic It is mutually washed with salt water (1 × 60mL), uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, it is bromo- to obtain grayish white solid 3- 6- chloropyridine -2- carboxylate methyl ester (10.14g).MS:m/z250 (M+H)+.
Step b: to the MeOH (150mL) of the bromo- 6- chloropyridine -2- carboxylate methyl ester (10.14g, 40.48mmol) of 0 DEG C of 3- NaBH is added portionwise in solution4(4.62g, 122.13mmol).It warms naturally to RT and stirs 16h.By reaction solution salt water (110mL) dilution, and be concentrated under reduced pressure and remove MeOH.It is extracted with EA (100mL, 80mL), organic phase anhydrous Na2SO4It is dry, mistake It filters and is concentrated under reduced pressure, obtain (the bromo- 6- chloropyridine -2- base of 3-) methanol (8.31g).MS:m/z222 (M+H)+.
Step c: to -15 DEG C of (the bromo- 6- chloropyridine -2- base of 3-) methanol (8.31g, 37.35mmol) and triethylamine MsC1 (4.71g, 41.12mmol) is added dropwise in DCM (100mL) solution of (7.63g, 75.40mmol).It warms naturally to RT simultaneously stirs 2h.Reaction solution is quenched with water (50mL) and separates water phase.Organic phase is washed with salt water (1 × 50mL), with nothing Water Na2SO4It dries, filters and is concentrated under reduced pressure, obtain methanesulfonic acid (the bromo- 6- chloropyridine -2- base of 3-) methyl esters (8.54 g).MS:m/z 300(M+H)+.
Step d: in a nitrogen environment, to -50 DEG C of piperidines-Isosorbide-5-Nitraes-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (9.66g, LDA (the THF/Hex solution of 2M, 23.00mL, 46.00mmol) is added dropwise in THF (30mL) solution 37.54mmol).? 1 h is stirred at a temperature of this.The THF of methanesulfonic acid (the bromo- 6- chloropyridine -2- base of 3-) methyl esters (8.54g, 28.41mmol) is added dropwise (15mL) solution, warms naturally to RT and stirs 1h.Reaction system is quenched with salt water (60mL) and is extracted with EA (1 × 30mL) It takes.Organic phase is through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 4- ((the bromo- 6- chloropyridine -2- base of 3-) methyl) piperidines - Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (17.73g), without being further purified i.e. in next step.MS:m/z461 (M+H)+.
Step e: by 4- ((the bromo- 6- chloropyridine -2- base of 3-) methyl) piperidines-Isosorbide-5-Nitrae-dioctyl phthalate 1- tert-butyl ester 4- ethyl ester The mixture of (17.73g, 38.39 mmol), NaOH (8.03g, 200.75mmol), MeOH (100mL) and water (20mL) is 65 16h is stirred at DEG C.It after being cooled to RT, is concentrated under reduced pressure and removes volatile matter, system is diluted with water (150mL).It is molten with saturated lemon PH value is adjusted to 6 by liquid.It is extracted with EA (2 × 100mL), combined organic phase is washed with salt water (1 × 100mL), and use is anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Residue (elutes) purifying by silica gel chromatography with EA: Hex=1: 10, v/v, obtains To 4- ((the bromo- 6- chloropyridine -2- base of 3-) methyl) -1- (tertbutyloxycarbonyl) piperidines -4- carboxylic acid and 4- ((the bromo- 6- methoxyl group of 3- Pyridine -2- base) methyl) -1- (tertbutyloxycarbonyl) piperidines -4- carboxylic acid mixture (18.24g).MS:m/z 433 (M+H)+, MS:m/z 429 (M+H)+.
Step f: in a nitrogen environment, to -15 DEG C of 4- ((the bromo- 6- chloropyridine -2- base of 3-) methyl) -1- (tertiary butyloxycarbonyl Base) piperidines -4- carboxylic acid and 4- ((the bromo- 6- methoxypyridine -2- base of 3-) methyl) -1- (tertbutyloxycarbonyl) piperidines -4- carboxylic acid Sodium hydride is added portionwise in THF (20mL) solution of the mixture of (3.80g, 8.76mmol), and (60% dispersion is in mineral oil In, 0.42g, 10.50 mmol).After stirring 1h at this temperature, mixture is cooled to -60 DEG C.It is added dropwise into the mixture N-BuLi (the Hex solution of 2.5M, 5mL, 12.50mmol), then stirs 1h.Reaction solution is quenched with water (20mL), with EA (1 × 40mL) extraction.Organic phase is washed with salt water (1 × 30mL), anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Residue passes through Silica gel chromatography (EA: Hex=1: 10, v/v) purifying, obtains chloro- 5- oxo -5, the 7- dihydro spiral shell of 2- [cyclopenta [b] pyrrole Pyridine -6,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester and 2- methoxyl group -5- oxo -5,7- dihydro spiral shell [cyclopenta [b] pyridine -6, 4 '-piperidines] -1 '-carboxylic acid tert-butyl ester mixture (1.48g).MS:m/z 337 (M+H)+.MS:m/z 333 (M+H)+.
Following compounds are synthesized using above-mentioned steps and corresponding starting material.
Table 10
Intermediate A 19
Step a: in a nitrogen environment, to -78 DEG C of piperidines-Isosorbide-5-Nitraes-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (2.83g, LDA (the THF/Hex solution of 2M, 6.00mL, 12.00mmol) is added dropwise in THF (50mL) solution 11.00mmol).? 1h is stirred at a temperature of this.2- chloro- 5- (chloromethyl) thiazole (being dissolved in 3mLTHF, 1.69g, 10.06mmol) is added dropwise, and stirs Mix 1h.Reaction solution is quenched with salt water (50mL), is extracted with EA (2 × 30mL).By combined organic phase through anhydrous Na2SO4It is dry It is dry, it filters and is concentrated under reduced pressure.Residue (elutes) purifying by silica gel chromatography with EA: Hex=1: 20, v/v, obtains 4- ((2- diuril azoles -5- base) methyl) piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (1.15g).MS:m/z 389 (M+H)+.
Step b: in a nitrogen environment, to -78 DEG C of 4- ((2- diuril azoles -5- base) methyl) piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- Be added dropwise in THF (50mL) solution of tert-butyl ester 4- ethyl ester (900mg, 2.31mmol) LDA (the THF/Hex solution of 2M, 3.00mL, 6.00mmol).It is quenched after stirring 30min with salt water (30mL).It is extracted with EA (2 × 30mL), merges organic phase, used Anhydrous Na2SO4Dry, filter and be concentrated under reduced pressure, obtain chloro- 4- oxo -4, the 6- dihydro spiral shell of 2- [cyclopenta [d] thiazole -5, 4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (832mg).MS:m/z 343 (M+H)+.
Intermediate A 20
Step a: LAH is added into THF (50mL) solution of 0 DEG C of 2- methylnicotinic acid (4.56g, 33.25mmol) (1.51g, 39.90mmol).It warms naturally to RT and stirs 4h.Reaction solution is carefully diluted with saturated ammonium chloride (50mL).Filtering, Filtrate liquid separation, organic phase anhydrous Na2SO4It is dry, it filters again, filtrate decompression concentration obtains (the 2- methyl pyrrole of yellow oily Pyridine -3- base) methanol (1.42g).MS:m/z 124 (M+H)+.
Step b: into DCM (20mL) solution of 0 DEG C (2- picoline -3- base) methanol (1.41 g, 11.45mmol) PBr is added dropwise3(1.86g, 6.87mmol).System is warming up to RT and stirs 1.5h.It is added NaOH aqueous solution (5M, 10mL) The pH for adjusting reaction solution is 8.Water phase is separated, organic phase is washed with salt water (1 × 20mL), with anhydrous Na 2SO4 drying and is depressurized dense Contracting, obtains the 3- bromomethyl -2- picoline (3.52g) of yellow oily, can be used in next step without being further purified.MS: m/z 186(M+H)+.
Step c: to -50 DEG C of piperidines-Isosorbide-5-Nitraes-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (4.63g, 18.00mmol) THF (30 ML LDA (the THF/Hex solution of 2M, 12.00mL, 24.00mmol)) is added dropwise in solution, stirs 1h at this temperature.It is added 3- bromomethyl -2- picoline (3.25g, 18.00mmol), warms naturally to RT and stirs 16h.Reaction solution saturation NH4Cl (50mL) carefully dilutes.Water phase is separated, organic phase is washed with salt water (1 × 50mL), anhydrous Na2SO4It dries, filters and depressurizes dense Contracting, obtains 4- ((2- picoline -3- base) methyl) piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester of Red oil (4.87g), without being further purified i.e. for next step.MS:m/z363 (M+H)+.
Step d: to -20 DEG C of 4- ((2- picoline -3- base) methyl) piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester In THF (40mL) solution of (4.23g, 11.67mmol) be added dropwise LDA (the THF/Hex solution of 2M, 12.00mL, 24.00 Mmol), it is warming up to RT and stirs 2h.Carefully use salt water (50mL) dilute reaction solution.Water phase is separated, organic phase is with anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Residue (elutes) purifying by silica gel chromatography with EA: Hex=1: 1, v/v, obtains To yellow oily 7 '-oxos -7 ', -5 ' H- spiral shell of 8 '-dihydro [piperidines -4,6 '-quinoline] -1- carboxylic acid tert-butyl ester (1.23 g). MS:m/z317 (M+H)+.
Intermediate A 21
Step a: with the mixing of 1, the 2- dimethoxy-ethane (50mL) of -60 DEG C of t-BuOK (5.92g, 52.76mmol) 1,2- dimethoxy-ethane (20mL) solution of 2- tosyl acetonitrile (5.08g, 26.02mmol) is added dropwise in object.To 1,2- dimethoxy-ethane (20mL) solution of 2- bromine nicotine aldehyde (4.81g, 25.86mmol) is added dropwise in system.At this temperature It after stirring 1h, is added MeOH (50mL), warms naturally to RT, stir 1h and be warming up to 85 DEG C, be stirred for 1h.After being cooled to RT, It is concentrated under reduced pressure and removes volatile matter, diluted with salt water (200mL) and extracted with EA (3 × 150 mL).By combined organic phase through nothing Water Na2SO4It dries, filters and is concentrated under reduced pressure.Residue (elutes) purifying by silica gel chromatography with EA: Hex=1: 10, v/v, Obtain 2- (2- bromopyridine -3- base) acetonitrile (2.21g).MS:m/z 197 (M+H)+.
Step b: into DMF (20mL) solution of 0 DEG C of 2- (2- bromopyridine -3- base) acetonitrile (2.21g, 11.21mmol) Sodium hydride (60% dispersion oil, 1.12g, 28.03mmol) is added portionwise.Reaction system is warming up to 60 DEG C and stirs 1.5h.Will be bis- (2- chloroethyl) t-butyl carbamate (3.26g, 13.46mmol) be added in mixture and stirred at 60 DEG C Mix 2h.After being cooled to RT, reaction system is quenched with salt water (50mL), is extracted with EA (3 × 100mL).By combined organic phase It is washed with salt water (3 × 80mL), through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.(EA: Hex=1 is used by silica gel chromatography : 3, v/v elutions) purifying residue, obtain 4- (2- bromopyridine -3- base) -4- cyano piperidine -1- carboxylic acid tert-butyl ester (1.56g). MS:m/z 366 (M+H)+.
Step c: in a nitrogen environment, by 4- (2- bromopyridine -3- base) -4- cyano piperidine -1- carboxylic acid tert-butyl ester (1.56g, 4.26 mmol), K2CO3 (2.35g, 17.04mmol), three boroxane of front three basic ring (1.07g, 8.52mmol), Pd (PPh3)4 The mixture of (47mg, 0.041mmol), Isosorbide-5-Nitrae-dioxane (40mL) and water (8mL) stirs 2h at 110 DEG C.Add front three Three boroxane of basic ring (2.15g, 17.13mmol) and Pd (PPh3)4(45mg, 0.039mmol) is simultaneously stirred for 3h.It is cooled to RT Afterwards, reaction system is diluted with salt water (100mL), is extracted with EA (3 × 100mL), merge organic phase, through anhydrous Na2SO4It is dry, It filters and is concentrated under reduced pressure.Purifying residue (is eluted) with EA: Hex=2: 1, v/v by silica gel chromatography, obtains 4- cyano -4- (2- picoline -3- base) piperidines -1- carboxylic acid tert-butyl ester (1.08g).MS:m/z302 (M+H)+.
Step d: to 0 DEG C of 4- cyano -4- (2- picoline -3- base) piperidines -1- carboxylic acid tert-butyl ester (1.08g, H is added dropwise in MeOH (50mL) solution 3.58mmol)2SO4(98%, 45mL).System stirs 18h at a reflux temperature. After being cooled to room temperature, reaction system is poured into ice/water mixture (200mL), pH value is adjusted to 9 with NaOH.To the mixing (Boc) is added in object2Simultaneously 2h is stirred at room temperature in O (11.00g, 50.40mmol).It is extracted, is associated with EA (3 × 100mL) Machine phase, through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Residue is purified by silica gel chromatography (being eluted with EA), is obtained 4- (2- picoline -3- base) piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- methyl esters (467mg).MS:m/z 335 (M+H)+.
Step e: in a nitrogen environment, to 0 DEG C of 4- (2- picoline -3- base) piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester - Bis- (trimethylsilyl) potassamides are added dropwise in THF (10.50mL) solution of 4- methyl esters (467mg, 1.40mmol), and (THF of 1M is molten Liquid, 7.00mL, 7.00mmol).It warms naturally to RT and stirs 3.5h, be then quenched with saturated ammonium chloride (10mL) and use EA (3 × 40mL) extraction.By combined organic phase through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Residue passes through silica gel chromatograph Method (being eluted with EA) purifying, obtains 6- oxo -6,7- dihydro spiral shell [5,4 '-piperidines of cyclopenta [b] pyridine -] -1 '-carboxylic acid The tert-butyl ester (170mg).MS:m/z303 (M+H)+.
Intermediate A 22
Step a: to the DMF (60mL) of 0 DEG C of 4- formyl piperidine -1- carboxylic acid tert-butyl ester (15.00g, 70.33mmol) Tert-butyl alcohol lithium (6.75g, 84.44mmol) is added portionwise in solution.System is stirred 30 minutes at 0 DEG C.At 0 DEG C to the mixing Object is added dropwise 3- bromopropene (9.73g, 80.44mmol) and stirs 1h at such a temperature.Reaction system is dilute with salt water (100mL) It releases, is extracted with EA (3 × 200mL).Organic phase merges, and uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Residue passes through silicon Glue chromatography (elutes) purifying with EA: Hex=1: 20, v/v, obtains 4- allyl -4- formyl piperidine -1- carboxylic acid tert-butyl ester (7.01g).MS:m/z254 (M+H)+.
Step b: to -78 DEG C of 4- allyl -4- formyl piperidine -1- carboxylic acid tert-butyl esters (7.01g, 27.63mmol) Allylic bromination magnesium (THF solution of 1M, 63.55mL, 63.55mmol) is added dropwise in THF (30mL) solution.It is warming up to RT and stirs Mix 1.5h.Reaction system is quenched with saturated ammonium chloride.It is extracted with EA (3 × 200mL).By combined organic phase with salt water (1 × It 200mL) washs, uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 4- allyl -4- (1- hydroxyl allyl) piperidines - 1- carboxylic acid tert-butyl ester (7.01g).MS:m/z 282 (M+H)+.
Step c: to 4- allyl -4- (1- hydroxyl allyl) piperidines -1- carboxylic acid tert-butyl ester (7.00g, 24.88mmol) Dai Si-Martin's oxidant (12.66g, 29.85mmol) is added portionwise in DCM (50mL) solution.After stirring 1.5h at RT, Reaction system is diluted with salt water (150mL) and is extracted with EA (3 × 200mL).By combined organic phase through anhydrous Na2SO4It is dry It is dry, it filters and is concentrated under reduced pressure.Residue is purified by silica gel chromatography (EA: Hex=1: 30, v/v), obtains 4- acryloyl group- 4- allylpiperidin -1- carboxylic acid tert-butyl ester (5.63g).MS:m/z280 (M+H)+.
Step d: in a nitrogen environment, by 4- acryloyl group -4- allylpiperidin -1- carboxylic acid tert-butyl ester (5.63g, 20.15 Mmol), the mixture of GrubbsII (428mg, 0.50mmol) and toluene (30mL) is in 85 DEG C of stirring 3.5h.It is being cooled to RT Afterwards, mixture is concentrated under reduced pressure.Purifying residue (is eluted) with EA: Hex=1: 5, v/v by silica gel chromatography, obtains 1- oxygen Generation -8- azaspiro [4.5] decyl- 2- alkene -8- carboxylic acid tert-butyl ester (3.61g).MS:m/z252 (M+H)+.
Step e: hydrogenation is added portionwise into DMSO (50mL) solution of Trimethylsulfoxonium Iodide (3.79g, 17.22mmol) After stirring 30min, 1- oxo -8- azaspiro [4.5] decyl- is added dropwise in sodium (60% dispersion oil, 730mg, 18.25mmol) 2- alkene -8- carboxylic acid tert-butyl ester (DMSO solution, 3.61g, 14.36mmol).System is stirred into 1.5h at RT.Reaction system is used Salt water (200mL) dilution, is extracted with EA (3 × 200mL).Combined organic phase is washed with salt water (3 × 200mL), use is anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 2- oxo spiral shell [two rings [3.1.0] hexane -, 3,4 '-piperidines] tertiary fourth of -1 '-carboxylic acid Ester (3.60g).MS:m/z 266 (M+H)+.
Intermediate A 23
Step a: to -10 DEG C of tetrahydro -2H- pyrans -4- alcohol (3.54g, 34.66mmol), triethylamine (4.65g, MsCl (4.61g, 40.24mmol) is added in DCM (100mL) solution 45.95mmol).After stirring 30min, by reaction system It is diluted with water (100mL), is extracted with DCM (100mL, 50mL).Combined organic phase is washed with salt water (1 × 50mL), with nothing Water Na2SO4It dries, filters and is concentrated under reduced pressure, obtain methanesulfonic acid tetrahydro -2H- pyrans -4- base ester (6.74g).181 (M of MS:m/z +H)+.
Step b: to 1 '-benzyl -6- methoxyl group spiral shell [2,4 '-piperidines of indenes -] -1 (3H) -one (4.35g, 13.53mmol) (the DCM solution of 1M, 15.00mL, 15.00mmol) is added in DCM (200mL) solution, stirs 13h at 45 DEG C.Add BBr3 (the DCM solution of 1M, 5.00mL, 5.00mmol) is simultaneously stirred for 24 hours at 45 DEG C.After being cooled to RT, by reaction system water (150mL) dilution, is added portionwise NaHCO3(20.00g).Obtained mixture is extracted with DCM (2 × 100mL), is associated with Machine phase, uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 1 '-benzyl -6- hydroxyl spiral shell [2,4 '-piperidines of indenes -] -1 (3H) -one (2.80g), without further purification i.e. in next step.MS:m/z308 (M+H)+.
Step c: by 1 '-benzyl -6- hydroxyl spiral shell [2,4 '-piperidines of indenes -] -1 (3H) -one (2.80g, 9.11mmol), tetrahydro - 2H- pyrans -4- base methanesulfonates (3.40g, 18.87mmol) and K2CO3(8.23g, 59.55mmol) and DMF's (60mL) is mixed It closes liquid and stirs 5.5h at 110 DEG C.Add tetrahydro -2H- pyrans -4- base methanesulfonates (1.10g, 6.10mmol) and K2CO3 (4.55g, 32.92mmol), and 1.5h is stirred at 110 DEG C.After being cooled to RT, by mixture water (300 mL) and EA (600mL) dilution.Separate water phase simultaneously to be extracted with EA (1 × 200mL), merging organic phase, with water (2 × 300mL) and salt water (1 × It 300mL) washs, uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.(MeOH: DCM=1: 40, v/v is used by silica gel chromatography Elution) purifying residue, obtain 1 '-benzyl -6- ((tetrahydro -2H- pyrans -4- base) oxygroup) spiral shell [indenes -2,4 '-piperidines] -1 (3H) -one (1.70g).MS:m/z392 (M+H)+.
Step d: under hydrogen environment, by 1 '-benzyl -6- ((tetrahydro -2H- pyrans -4- base) oxygroup) spiral shell [indenes -2,4 '-piperazine Pyridine] -1 (3H) -one (1.70g, 4.34mmol) and Pd (OH)2The MeOH solution of (10%, 1.21g) stirs 3h at RT.Filtering Reaction system.(Boc) is added into filtrate2Simultaneously 40h is stirred at room temperature in O (1.10g, 5.04mmol).Reaction system is depressurized Concentration.Purifying residue (is eluted) with EA: Hex=1: 5, v/v by silica gel chromatography, obtains 1- oxo -6- ((tetrahydro -2H- Pyrans -4- base) oxygroup) -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (1.45g).MS:m/z402 (M+H) Intermediate A 24
In a nitrogen environment, by bromo- 1- oxo -1, the 3- dihydro spiral shell of 6- [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester (1017mg, 2.67 mmol), diethyl phosphonate (564mg, 4.08mmol), potassium phosphate (1156mg, 5.45mmol), Pd (OAc)2The mixture of (63 mg, 0.28mmol), XantPhos (307mg, 0.53mmol) and DMF (10mL) stir at 130 DEG C Mix 21h.After being cooled to RT, reaction system is quenched with water (60mL), is filtered, filter cake is eluted with EA (2 × 30mL).Filtrate point Layer, water layer are extracted with EA (2 × 60mL).By combined organic phase through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Pass through silicon Glue chromatography (being eluted with EA) purify residue, obtain 6- (diethoxy phosphoryl) -1- oxo -1,3- dihydro spiral shell [indenes -2, 4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (134mg), without further purification i.e. in next step.MS:m/z438 (M+H)+.
Intermediate A 25
The step of according to Y.Uto etal./Bioorg.Med.Chem.Lett.20 (2010) 746-754, synthetic intermediate A25.
Following compounds are synthesized using above-mentioned steps and corresponding starting material.
Table 11
Intermediate A 26
Step a: to -65 DEG C of piperidines-Isosorbide-5-Nitraes-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (5.23g, 20.32mmol) THF (30 Ml LDA (the THF/Hex solution of 2M, 12.00mL, 24.00mmol)) is added dropwise in solution.The mixture that will be obtained at this temperature Stir 1.0h.2- bromobenzaldehyde (3.44g, 18.59mmol) is added dropwise at -70 DEG C.After stirring 1h, by mixture salt water (40mL) is quenched.Organic phase is separated, anhydrous Na is used2SO4It dries, filters and is concentrated under reduced pressure, obtain 4- ((2- bromophenyl) (hydroxyl Base) methyl) piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (9.15g), it is used without further purification in next step.MS:m/ z442(M+H)+.
Step b: to -5 DEG C of 4- ((2- bromophenyl) (hydroxyl) methyl) piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester Dai Si-Martin's oxidant (18.02g, 42.49mmol) is added in DCM (70ml) solution of (9.15g, 20.68mmol).By body It ties up under RT and stirs 2.5h.Use Na2S2O3Aqueous solution (25%, 1 × 80mL), saturation NaHCO3 (1 × 80mL) and salt water (1 × 100mL) wash.Organic phase is through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.By silica gel chromatography (use EA: Hex=1: 5, V/v elution) purifying residue, obtain 4- (2- benzoyl bromide) piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (7.16g). MS:m/z440 (M+H)+.
Step c: to -80 DEG C of 4- (2- benzoyl bromide) piperidines-Isosorbide-5-Nitraes-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (2.00g, 1.8mL n-BuLi (the THF/Hex solution of 2.5M) is added in THF (20mL) solution 4.54mmol), nitrogen protection.System Spontaneous recovery room temperature continues to stir 1h.System is added 30mL saturated salt solution and is quenched, and collects organic phase.20mL EA is added in water phase Extraction.Merge organic phase, anhydrous Na2SO4It dries, filters, is concentrated under reduced pressure.(EA: Hex=1: 10, v/ is used by silica gel chromatography V elution) purifying residue, obtain 1,3- dioxo -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (500mg), MS:m/z316 (M+H)+.
Intermediate A 27
According to J.Org.Chem.1999, the step of 64,5504-5510, synthetic intermediate A27.
Intermediate A 28
Step a: to MeOH (250mL) solution of 0 DEG C of 2- chlorine thiazole -4-carboxylic acid ethyl ester (24.95g, 130.19mmol) In NaBH is added portionwise4(17.29g, 456.97mmol).It warms naturally to RT and stirs 2h.By reaction system with water (200mL) It dilutes and removes volatile matter being concentrated under reduced pressure.With EA (2 × 200mL) extraction system, merging is washed with salt water (1 × 400mL) Organic phase uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain (2- chlorine thiazole-4-yl) methanol (18.88g).MS:m/ z150(M+H)+.
Step b: to (2- chlorine thiazole-4-yl) methanol (18.88g, 130.19mmol) and triethylamine (25.56g, It is added dropwise MsCl (15.96g, 139.30mmol) in DCM (200mL) solution 252.57mmol), 15min is added dropwise.By body Tie up to RT stirring 25min.Reaction system is quenched with salt water (200mL), separates water phase.Organic phase anhydrous Na2SO4It is dry, mistake It filters and is concentrated under reduced pressure, obtain methanesulfonic acid (2- chlorine thiazole-4-yl) methyl esters, without further purification i.e. in next step.MS:m/ z228(M+H)+.
Step c: in a nitrogen environment, to -60 DEG C of piperidines-Isosorbide-5-Nitraes-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (35.67g, 138.62 mmol) THF (200mL) solution in be added dropwise LDA (the THF/Hex solution of 2M, 75.00mL, 150.00mmol), drop Add 30min.Then THF (50mL) solution of methanesulfonic acid (2- chlorine thiazole-4-yl) methyl esters is added dropwise, warms naturally to RT and stirs 2h.Reaction system is quenched with salt water (300mL).Organic phase is separated, anhydrous Na is used2SO4It dries, filters and is concentrated under reduced pressure.It is logical It crosses silica gel chromatography and (elutes) purifying residue with EA: Hex=1: 10, v/v, obtain 4- ((2- chlorine thiazole-4-yl) methyl) piperazine Pyridine-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl 4- ethyl ester (38.12g).MS:m/z389 (M+H)+.
Step d: in a nitrogen environment, to -60 DEG C of 4- ((2- chlorine thiazole-4-yl) methyl) piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- In THF (80mL) solution of tert-butyl 4- ethyl ester (8.51g, 21.88mmol) be added dropwise LDA (the THF/Hex solution of 2M, 11.00mL 22.00mmol).After dripping off, reaction solution is quenched with salt water (50mL).Organic phase is separated, anhydrous Na is used2SO4It is dry It is dry, it filters and is concentrated under reduced pressure.Purifying residue (is eluted) with EA: Hex=1: 10, v/v by silica gel chromatography, and it is chloro- to obtain 2- 6- oxo -4,6- dihydro spiral shell [5,4 '-piperidines of cyclopenta [d] thiazole -] -1 '-carboxylic acid tert-butyl ester (1.93g).MS:m/z 343(M+H)+.
Intermediate A 29
Step (a-c): (b-c) and (b) synthesis 1- (tertiary butyloxycarbonyl the step of intermediate A 3 the step of referring to intermediate A 28 Base) -4- (thiophene -2- ylmethyl) piperidines -4- carboxylic acid
Step d: by 1- (tertbutyloxycarbonyl) -4- (thiophene -2- ylmethyl) piperidines -4- carboxylic acid (4.92g, 15.12mmol) 5h is stirred at 110 DEG C with the mixture of PPA (30.12g).Reaction system is poured into ice/water mixture (100mL), is used PH value is adjusted to 10 by NaOH.Then (Boc) is added2Simultaneously 18h is stirred at room temperature in O (5.05g, 23.14mmol).With EA (2 × 50mL) extract.Combined organic phase is washed with salt water (1 × 50mL), through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain To 2- tert-butyl -4- oxo -4,6- dihydro spiral shell [5,4 '-piperidines of cyclopenta [b] thiophene -] -1 '-carboxylic acid tert-butyl ester (1.70g).MS:m/z 364 (M+H)+.
Step e: by 1- (tertbutyloxycarbonyl) -4- (thiophene -2- ylmethyl) piperidines -4- carboxylic acid (4.88g, 15.12mmol), HCl (Isosorbide-5-Nitrae-dioxane solution of 4M, 8mL) and the mixture of DCM (50mL) stir 1h at RT.Reaction system is depressurized Concentration.It is added PPA (21.15g), and system is stirred into 1.5h at 110 DEG C.Reaction solution is poured into ice/water mixture (100mL) In, pH value is adjusted to 10 with NaOH.Then (Boc) is added2Simultaneously 18h is stirred at room temperature in O (5.12g, 23.46mmol).With EA (2 × 50mL) extraction.Combined organic phase is washed with salt water (1 × 100mL), uses anhydrous Na2SO4It dries, filters and depressurizes Concentration.Purifying residue (is eluted) with EA: Hex=1: 10, v/v by silica gel chromatography, obtains -4 spiral shell of 4- oxo -4,6- dihydro [5,4 '-piperidines of cyclopenta [b] thiophene -] -1 '-carboxylic acid tert-butyl ester (2.71g).MS:m/z 308 (M+H)+.
Intermediate A 30
Step a: sodium hydride (60% mine is added portionwise into DMF (50mL) solution of benzyl alcohol (5.15g, 47.62mmol) Object oil dispersion liquid, 3.01g, 75.25mmol), stir 20min.4- chloropyridine -2- formic acid (2.68g, 17.01mmol) is added simultaneously 3.5h is stirred at 85 DEG C.After being cooled to RT, it is added HCl (Isosorbide-5-Nitrae-dioxane solution of 4M, 10mL).System is directly used in down One step.MS:m/z 230 (M+H)+.
Step b: by step a reaction system and NaHCO3(7.51g, 89.39mmol), CH3I (1.5mL) and DMF (10mL) Mixing.After stirring 0.5h, CH is added3I (1.5mL) simultaneously stirs 16h.Reaction system is diluted with EA (250 mL), filtering, filtrate It is washed with salt water (2 × 150mL).Organic phase is through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.(EA is used by silica gel chromatography : Hex=1: 1, v/v elution) purifying residue, obtain 4- (benzyloxy) pyridine -2- methyl formate (1.50g).MS:m/z 244 (M+H)+.
Step c: by 4- (benzyloxy) pyridine -2- methyl formate (1.50g, 6.17mmol), LiBH4(THF solution of 2M, 9.00mL, 18.00mmol) and the mixture of THF (40mL) stir 1h at 50 DEG C.By reaction system with MeOH (15mL) and Water (150mL) dilution, is extracted with EA (200mL, 50mL).Combined organic phase is washed with salt water (2 × 100mL), use is anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Residue is purified by silica gel chromatography (being eluted with EA), obtains (4- (benzyloxy) Pyridine -2- base) methanol (0.50g).MS:m/z216 (M+H)+.
Step d: by (4- (benzyloxy) pyridine -2- base) methanol (0.50g, 2.32mmol), Dai Si-Martin's oxidant (1.25 g, 2.95mmol) and DCM (20mL) mixture stir 1.5h.By reaction solution saturation NaHSO3Aqueous solution, saturation NaHCO3Aqueous solution and DCM (50mL) dilution.It is extracted by aqueous phase separation and with DCM (50mL).By combined organic phase with anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Residue obtains 4- (benzyloxy) pyridine-2-formaldehyde through Silica gel chromatography (0.40g).MS:m/z 214 (M+H)+.
Step e: to 0 DEG C of piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (0.52g, 2.02mmol) THF (15 ML LDA (the THF/Hex solution of 2M, 1.30mL, 2.60mmol)) is added dropwise in solution.System is cooled to -70 DEG C, 4- (benzyl is added Oxygroup) pyridine-2-formaldehyde (0.40g, 1.88mmol) THF (5mL) solution.It warms naturally to -15 DEG C and stirs 30min, so It is quenched with saturated ammonium chloride (10mL), is diluted with water (50mL) and is extracted with EA (1 × 100mL) afterwards.By organic phase salt water (2 × 50mL) washing, use anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.Pass through silica gel chromatography (with EA: Hex=1: 1 elution) Residue is purified, 4- ((4- (benzyloxy) pyridine -2- base) (hydroxyl) methyl) piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- second is obtained Ester (0.25g).MS:m/z471 (M+H)+.
Step f: by 4- ((4- (benzyloxy) pyridine -2- base) (hydroxyl) methyl) piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- Ethyl ester (0.25 g, 0.53mmol), LiBH4THF (10mL) solution of (THF solution of 2M, 1.00mL, 2.00mmol) is 55 40min is stirred at DEG C.Reaction system is quenched with MeOH (10mL), is concentrated under reduced pressure and removes volatile matter.By residue water (150mL) dilution, is extracted with EA (1 × 50mL).Organic phase is washed with salt water (1 × 30mL), uses anhydrous Na2SO4It is dry, mistake It filters and is concentrated under reduced pressure, obtain 4- ((4- (benzyloxy) pyridine -2- base) (hydroxyl) methyl) -4- (hydroxymethyl) piperidines -1- carboxylic acid The tert-butyl ester (0.22g).MS:m/z 429 (M+H)+.
Step g: by 4- ((4- (benzyloxy) pyridine -2- base) (hydroxyl) methyl) -4- (hydroxymethyl) piperidines -1- carboxylic acid uncle The mixture of butyl ester (0.22 g, 0.51mmol), Pd/C (10%, 0.12g) and MeOH (20mL) stir 1.5 under hydrogen environment h.Filtering reacting liquid, filter cake are eluted with MeOH, and filtrate decompression concentration obtains 4- (hydroxyl (4- pyridone -2- base) methyl) -4- (hydroxymethyl) piperidines -1- carboxylic acid tert-butyl ester (154mg).MS:m/z339 (M+H)+.
Step h: to 4- (hydroxyl (4- pyridone -2- base) methyl) -4- (hydroxymethyl) piperidines -1- carboxylic acid tert-butyl ester N, N, N ', N '-tetramethyl is added in THF (10mL) solution of (120mg, 0.36mmol) and triphenyl phasphine (175mg, 0.67mmol) Base azodicarbonamide (158mg, 0.68mmol).Mixture is stirred into 30min at RT.(MeOH is used by silica gel chromatography : DCM=1: 7, v/v elution) purifying, obtain 1- hydroxyl -7- oxo -1,7- dihydro -3H- spiral shell [indolizine -2,4 '-piperidines] - 1 '-carboxylic acid tert-butyl ester (100mg).MS:m/z 321 (M+H)+.
Step i: by 1- hydroxyl -7- oxo -1,7- dihydro -3H- spiral shell [indolizine -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester The mixture of (0.35g, 1.09 mmol), Dai Si-Martin's oxidant (0.72g, 1.70mmol) and DCM (35mL) are stirred at RT Mix 2h.System saturation Na2SO3(1 × 20mL) and saturation NaHCO3Aqueous solution (1 × 20mL) washing.Organic phase is with anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 1,7- dioxo -1,7- dihydro -3H- spiral shell [indolizine -2,4 '-piperidines] -1 ' - Carboxylic acid tert-butyl ester (0.33g).MS:m/z 319 (M+H)+.
Following compounds are synthesized using above-mentioned steps and corresponding starting material.
Table 12
Intermediate B 1
The step of according to WO2017211303 A1 is raw material through three step synthetic intermediate B1 using 4- iodine isatin.
Intermediate B 2
The step of according to WO2017211303 A1 is raw material through 2 step synthetic intermediates using the bromo- 6- chloropyrazine of 2- amino -3- B2。
Following compounds are synthesized using above-mentioned steps and corresponding starting material.
Table 13
Intermediate B 3
The fluoro- 3- chlorine-4-iodine pyridine (10.10g, 39.23mmol) of 2- and DMSO (50mL) are added in tube sealing, ammonia is added dropwise Water (25%, 50mL).System stirs 16h at 80 DEG C.After cooling to rt, reaction system is poured into water (250mL), mistake Filter obtains sediment, is dissolved in DCM (280mL), is washed with salt water (1 × 100mL), use anhydrous Na2SO4It dries, filters and depressurizes Concentration, obtains 3- chlorine-4-iodine pyridine -2- amine (7.01g).MS:m/z255 (M+H)
Following compounds are synthesized using above-mentioned steps and corresponding starting material.
Table 14
Intermediate B 4
In a nitrogen environment, by 3- chlorine-4-iodine pyridine -2- amine (25.53g, 100.33mmol), 3- amino -5- chloropyrazine - 2- sodium mercaptides (20.18g, 109.92mmol), Pd2(dba)3(4.47g, 4.88mmol), and XantPhos (5.81g, 10.04 Mmol) and the mixture of Isosorbide-5-Nitrae-dioxane (100mL) of DIEA (26.12g, 202.10mmol) is in 70 DEG C of stirring 1.5h.It is cold But to room temperature, then the filtering of reaction system diatomite is washed with Isosorbide-5-Nitrae-dioxane (30mL) and filtrate decompression is concentrated.It is remaining DCM (100mL) and EA (100mL) is added in object, stirs 40min.Sediment is collected, it is dry in vacuum drying oven, obtain 3- ((2- Amino -3- chloropyridine -4- base) sulfenyl) -6- chloropyrazine -2- amine (13.86g).MS:m/z 288 (M+H)+.
Following compounds are synthesized using above-mentioned steps and corresponding starting material.
Table 15
Embodiment 1
(R) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -2,3- dihydro spiral shell [indenes-Isosorbide-5-Nitrae '-piperidines] -2- amine
Step a: by compound 1H- indenes (11.62g, 0.10mol) and LiHMDS (the THF solution of 220mL, 1mol/L) Mixture in THF (120mL) stirs 1h at -50 DEG C.Will be bis- (2- chloroethyl) t-butyl carbamate (24.21g, It 0.10mol) is added in reaction solution and stirs 1h at -50 DEG C.Salt water (300mL) is added to be quenched.By organic phase with anhydrous Na2S04 is dried, filtered and is concentrated under reduced pressure.It is purified by silica gel chromatography residue, obtains the compound spiral shell in yellow solid [indenes-Isosorbide-5-Nitrae '-piperidines] -1 '-carboxylic acid tert-butyl ester (10.36g, 36%).MS:286 (M+H)+.
Step b: by compound spiral shell [indenes-Isosorbide-5-Nitrae '-piperidines] -1 '-carboxylic acid tert-butyl ester (117.02g, 0.41mol) and borine two THF (800mL) solution of dimethylsulfide complex (10mol/L, 220mL) stirs 3h at 0 DEG C.Addition NaOH (2 mol/L, 1.2L) and H2O2(300mL) and 1h is stirred at 0 DEG C.Organic phase is collected, anhydrous Na is used2SO4It dries, filters and is concentrated under reduced pressure, Obtain 2- hydroxyl -2,3- dihydro spiral shell [indenes-Isosorbide-5-Nitrae '-piperidines] -1 '-carboxylic acid tert-butyl ester and 3- hydroxyl -2,3- dihydro spiral shell [indenes-Isosorbide-5-Nitrae ' - Piperidines] -1 '-carboxylic acid tert-butyl ester, yellow oil (130.33g, crude product).MS:304 (M+H)+.
Step c: by 2- hydroxyl -2,3- dihydro spiral shell [indenes-Isosorbide-5-Nitrae '-piperidines] -1 '-carboxylic acid tert-butyl ester and 3- hydroxyl -2,3- bis- Hydrogen spiral shell [indenes-Isosorbide-5-Nitrae '-piperidines] -1 '-carboxylic acid tert-butyl ester (130.02g, 0.43mol), Dai Si-Martin's oxidant (364.76g, 0.86mol) and the mixture of DCM (2L) stirs 12h at 25 DEG C.Filtering reacting liquid, filtrate saturated sodium bicarbonate solution The washing of (1L) and salt water (1L), uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.By column chromatography eluting residue, obtain To compound as white solid 3- oxo -2,3- dihydro spiral shell [indenes-Isosorbide-5-Nitrae '-piperidines] -1 '-carboxylic acid tert-butyl ester (41.75g, 34%, two Walk yield).MS:302 (M+H)+.
Step d: to compound 3- oxo -2,3- dihydro spiral shell [indenes-Isosorbide-5-Nitrae '-piperidines] -1 '-carboxylic acid tert-butyl ester (41.01g, R- (+)-t-butyl sulfonamide (49.46g, 0.41mol) is added in tetraethyl titanate (80mL) solution 0.14mol).System 2h is stirred at 85 DEG C.EA (0.5L) and water (0.5L) are added in reaction system.Filtering reaction system simultaneously collects organic phase. Water phase is extracted with EA (200mL × 2).Combined organic phase is washed with salt water (500mL), uses anhydrous Na2SO4It dries, filters simultaneously It is concentrated under reduced pressure, obtains compound (R, E) -2- ((terf-butylsulfinyl) imino group) -2,3- dihydro spiral shell [indenes-Isosorbide-5-Nitrae '-piperazine Pyridine] -1 '-carboxylic acid tert-butyl ester (132.05g, crude product).MS:405 (M+H)+It does not purify and is directly used in next step..
Step e: by compound (R, E) -2- ((terf-butylsulfinyl) imino group) -2,3- dihydro spiral shell [indenes-Isosorbide-5-Nitrae '-piperazine Pyridine] THF (200mL) solution of -1 '-carboxylic acid tert-butyl ester (132.02g, 0.33mol) is cooled to -50 DEG C of stirrings.NaBH is added4 (7.71g, 0.51mol), warms naturally to RT.It is quenched with saturated ammonium chloride solution (100mL).Organic phase is collected, use is anhydrous Na2S04It dries, filters and is concentrated under reduced pressure.Residue is purified by column chromatography, obtains (R) -2- (((R)-terf-butylsulfinyl) Amino) -2,3- dihydro spiral shell [indenes-Isosorbide-5-Nitrae '-piperidines] -1 '-carboxylic acid tert-butyl ester be white solid (27.25g, 49%, two step yield). MS:407 (M+H)+.
Step f:(R) -2- (((R)-terf-butylsulfinyl) amino) -2,3- dihydro spiral shell [indenes-Isosorbide-5-Nitrae '-piperidines] -1 '-carboxylic Tert-butyl acrylate (1.16 g, 3.98mmol), CF3DCM (20mL) solution of COOH (3.6mL) stirs 1.5h at 25 DEG C.It will be anti- It answers liquid to be concentrated under reduced pressure, residue is dissolved in NMP (15mL), 3- ((2- amino -3- chloropyridine -4- base) sulfenyl)-then is added 6- chloropyrazine -2- amine (1.03g, 3.59mmol) and K2CO3(6.60g, 47.76mmol) stirs 16h at 90 DEG C.To reaction H is added in liquid2O (30mL) is simultaneously filtered.Filter cake is dissolved in DCM (40mL) and is washed with salt water (40mL).Organic phase anhydrous Na2SO4 It dries, filters and is concentrated under reduced pressure, obtain compound (R)-N- ((R) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -3- Base) pyrimidine-4-yl) sulfenyl) pyrazine -2- base) -2,3- dihydro spiral shell [indenes-Isosorbide-5-Nitrae '-piperidines] -2- base) Asia -2- methylpropane -2- sulphur Amide (1.55g, 70%) is yellow solid.
Step g: to compound (R)-N- ((R) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrrole Piperazine -2- base) -2,3- dihydro spiral shell [indenes-Isosorbide-5-Nitrae '-piperidines] -2- base) -2- methylpropane -2- sulfenamide (1.52g, HCl/1,4- dioxane (2mL, 4mol/L) is added in DCM (20mL) solution 2.72mmol).System is stirred at 25 DEG C 1h is mixed, precipitating is collected by filtration.Filter cake is dispersed in DCM (30mL), and ammonium hydroxide (5mL) is added to adjust pH > 10.It will mixing Object is washed with salt water (40mL), uses anhydrous Na2SO4It dries and is concentrated under reduced pressure.Residue is purified by column chromatography, obtains compound (R) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -2,3- dihydro spiral shell [indenes-Isosorbide-5-Nitrae '-piperazine Pyridine] -2- amine, be yellow solid (530mg, 42%).MS:454 (M+H)+.1HNMR (400MHz, DMSO-d6) δ 7.64-7.66 (m, 2H), 7.30 (d, 1H), 7.20 (d, 1H), 7.13-7.15 (m, 2H), 6.78 (d, 1H), 4.05-4.09 (m, 1H), 3.91- 3.95 (m, 1H), 3.54-3.60 (m, 3H), 3.12-3.18 (m, 1H), 2.57-2.63 (m, 1H), 1.91-2.09 (m, 2H), 1.66-1.76 (m, 1H), 1.49-1.58 (m, 1H)
Embodiment 2
(S) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1- amine
Step a: sodium hydride (60%) (3.63g, 90.80mmol) is added to compound 2,3- dihydro -1H- 1-Indanone In DMF (80mL) solution of (4.00 g, 30.27mmol).Mixture stirs 30min at 16 DEG C.Bis- (2- chlorine are added dropwise Ethyl) t-butyl carbamate (8.06g, 33.29mmol).Then mixture is stirred into 16h at 60 DEG C.Use salt water Mixture is quenched in (200mL), is extracted with EA (100mL × 2).Organic phase is merged, and is washed with salt water (100mL × 2), is used Anhydrous Na2SO4It is dry.After concentration, by column chromatography eluting residue, compound 1- oxo -1,3- dihydro spiral shell [indenes-is obtained 2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (1.21g, 13%), kermesinus oil.MS:302 (M+H)+.
Step b: after tetraethyl titanate (12.00g) is heated to 90 DEG C, by compound 1- oxo -1,3- dihydro spiral shell [indenes -2, 4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (1.21g, 4.01mmol) and (R) -2- methylpropane -2- sulfenamide (1.22g, 12.04mmol) be added.After stirring 19h at 90 DEG C.It pours the mixture into EA (200mL), and salt water (200mL) is added. After stirring 15 minutes, filtering.Filtrate layered.Organic phase is washed with salt water (200mL × 2), through anhydrous Na2SO4It is dry.It filters out Filtrate is concentrated under reduced pressure in solid.By column chromatography eluting residue, (R, Z) -1- ((terf-butylsulfinyl) imido is obtained Base) -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester (1.01g, 62%) is black solid.MS:405 (M+ H)+.
Step c: by (R, Z) -1- ((terf-butylsulfinyl) imino group) -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -1 ' - THF (10mL) solution of carboxylic acid tert-butyl ester (1.01g, 2.50mmol) is cooled to -50 DEG C.NaBH is added portionwise4(142mg, 3.74 mmol).Room temperature is warmed naturally to, 15.5h is stirred, is subsequently poured into EA (100mL).It is washed with salt water (100mL × 3) Mixture.Organic phase is dried, filtered and is concentrated under reduced pressure through anhydrous Na 2S04.Residue is purified by column chromatography, obtains compound (S) -1- (((R)-terf-butylsulfinyl) amino) -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -1- carboxylic acid tert-butyl ester (580 Mg, 57%), it is yellow oil.MS:407 (M+H)+.
Step d: by compound (S) -1- (((R)-terf-butylsulfinyl) amino) -1,3- dihydro spiral shell [indenes -2,4 '-piperazine Pyridine] -1 '-t-butyl formate (580mg, 1.43mmol) and TFA (1mL) DCM (5mL) solution in 20 DEG C of stirring 40min.It will be molten Liquid concentration, obtains compound (R)-N- ((S) -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1- base) Asia -2- methylpropane -2- sulphur Amide (520mg, 90%) is yellow oil.MS:307 (M+H)+.
Step e: by compound (R)-N- ((S) -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1- base) -2- methylpropane -2- Sulfenamide (260 mg, 0.62mmol), 3- ((2- amino -3- chloropyridine -4- base) sulfenyl) -6- chloropyrazine -2- amine (196mg, 0.68mmol), K2CO3(427mg, 3.09mmol) and NMP (8mL) are in 100 DEG C of stirring 16h.Pour the mixture into EA (200 ML it is washed in) and with salt water (200mL × 3).Organic phase is dried, filtered and is concentrated under reduced pressure through anhydrous Na 2SO4.Pass through column chromatography Method purifies residue, obtains compound (R)-N- ((S) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) Indenes -2- base) -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1- base) -2- methylpropane -2- sulfenamide (260mg, 65%), be Yellow solid.MS:558 (M+H)+.
Step f: by compound (R)-N- ((S) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrrole Piperazine -2- base) -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1- base) -2- methylpropane -2- sulfenamide (260mg, It 0.47mmol) is dissolved in DCM (5mL), HCl/1,4- dioxane (4mol/L, 5mL) is added dropwise.Mixture is at 20 DEG C Stirring 30 minutes.Mixture is concentrated and residue is dissolved in methanol (2mL).And EA (5mL) is added.Solid is collected by filtration, Obtain compound (S) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1- amine (123mg, 54%) is pale solid.MS:454 (M+H)+.1HNMR (400MHz, DMSO- D6) δ 7.81 (d, 1H), 7.72 (s, 1H), 7.62 (d, 1H), 7.27-7.36 (m, 3H), 6.12 (d, 1H), 4.21-4.35 (m, 3H), 2.97- 3.24 (m, 4H), 1.77-1.91 (m, 2H), 1.49-1.59 (m, 2H)
Embodiment 3
(R) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -3,4- dihydro -2H- Spiral shell [naphthalene-Isosorbide-5-Nitrae '-piperidines] -2- amine
Step a: by the HCl/1,4- of bis- (2- chloroethyl) t-butyl carbamates (11.00g, 45.43mmol) of compound Dioxane (4mol/L, 200mL) solution stirs 1h at 20 DEG C.Solution is concentrated and residue is dissolved in DCE (200 mL) In.Triethylamine (22.95g, 227.14mmol) and benzaldehyde (7.23g, 68.14mmol) is added.Then NaBH is added portionwise (OAc)3(24.07g, 113.57mmol).Mixture is stirred into 54h at 20 DEG C, EA (300mL) and salt water is then added (200mL).Organic phase is separated, is concentrated under reduced pressure.Residue is dissolved in HCl solution (2mol/ L, 200mL) and with EA (100mL) Washing.With saturation Na2CO3The pH value of water phase is adjusted to 9 by solution.Mixture is extracted with EA (200mL).Organic phase is with anhydrous Na2SO4 is dried, filtered and is concentrated under reduced pressure, and obtains the colorless oil compound N-chloro- N- of benzyl -2- (2- chloroethyl) ethane -1- amine (8.52g, 81%).
Step b: to the compound N-chloro- N- of benzyl -2- (2- chloroethyl) ethane -1- amine (8.52g, 36.70mmol) and 3, Uncle is added in the mixed solution of the THF (80mL) and DMSO (50mL) of 4- dihydronaphthalene -2 (1H) -one (4.88g, 33.36mmol) Butanol potassium (9.36g, 83.14mmol).20h is stirred at 20 DEG C.Mixture is concentrated and EA (200 mL) is used to dilute.Then it uses Salt water (200mL × 3) washing.Organic phase is dried, filtered and is concentrated under reduced pressure through anhydrous Na 2SO4.It is purified by column chromatography remaining Object obtains 1 '-benzyl -3,4- dihydro -2H- spiral shell [naphthalene-Isosorbide-5-Nitrae '-piperidines] -2- ketone (2.32g, 21%) of dark oil.MS: 306(M+H)+.
Step c: compound 1 '-benzyl -3,4- dihydro -2H- spiral shell [naphthalene-Isosorbide-5-Nitrae '-piperidines] -2- ketone is added into tetraethyl titanate (2.32g, 7.60mmol) and (R) -2- methylpropane -2- sulfenamide (2.76g, 22.79mmol).It is stirred at 100 DEG C 19h.EA (200mL) and water (200mL) is added.By filtrate layered after filtering, organic phase is collected.By organic phase salt water (100 ML × 5) washing, it is dried, filtered and is concentrated under reduced pressure with anhydrous Na 2SO4.By column chromatography purify residue, obtain compound (R, E)-N- (1 '-benzyl -3,4- dihydro -2H- spiral shell [naphthalene-Isosorbide-5-Nitrae '-piperidines] -2- subunit) -2- methylpropane -2- sulfenamide (660 Mg, 21%), it is yellow oil.MS:409 (M+H)+.
Step d: by compound (R, E)-N- (1 '-benzyl -3,4- dihydro -2H- spiral shell [naphthalene-Isosorbide-5-Nitrae '-piperidines] -2- subunit) - THF (10mL) solution of 2- methylpropane -2- sulfenamide (660mg, 1.62mmol) is cooled to -50 DEG C.Then it is added portionwise NaBH4(122mg, 3.23mmol).The mixture is stirred into 18h and warms naturally to RT.It is quenched with water (50mL), uses EA (50mL × 2) extraction.Organic phase is merged, and is washed with salt water (50mL × 2), is dried, filtered and is depressurized with anhydrous Na 2SO4 Concentration.By column chromatography purify residue, obtain compound (R)-N- ((R) -1 '-benzyl -3,4- dihydro -2H- spiral shell [naphthalene -1, 4 '-piperidines] -2- base) -2- methylpropane -2- sulfenamide (195mg, 29%) is yellow oil.MS:411 (M+H)+.
Step e: to compound (R)-N- ((R) -1 '-benzyl -3,4- dihydro -2H- spiral shell [naphthalene-Isosorbide-5-Nitrae '-piperidines] -2- base) - In methanol (5mL) solution of 2- methylpropane -2- sulfenamide (195mg, 0.47mmol) be added palladium dydroxide (20%, 120mg).In 40 DEG C of stirring 18h under hydrogen environment.It filters and is concentrated under reduced pressure, obtain compound (R)-N- ((R) -3,4- bis- Hydrogen -2H- spiral shell [naphthalene-Isosorbide-5-Nitrae '-piperidines] -2- base) -2- methylpropane -2- sulfenamide (92mg, 60%).MS:321 (M+H)+.
Step f: by compound (R)-N- ((R) -3,4- dihydro -2H- spiral shell [naphthalene-Isosorbide-5-Nitrae '-piperidines] -2- base) -2- methyl-prop Alkane -2- sulfenamide (92mg, 0.29mmol) is dissolved in NMP (3mL).3- ((2- amino -3- chloropyridine -4- base) sulphur is added Base) -6- chloropyrazine -2- amine (91mg, 0.32mmol) and K2CO3(198mg, 1.44mmol).In 100 DEG C of stirring 3h, EA is used (30mL) dilution, is washed with salt water (30mL × 3).Organic phase anhydrous Na2SO4It is dry.Residue is purified by Pre-TLC To (R)-N- ((R) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -3,4- dihydro -2H- Spiral shell [naphthalene-Isosorbide-5-Nitrae '-piperidines] -2- base) -2- methylpropane -2- sulfenamide (18mg, 11%) is pale solid.
Step g: to compound (R)-N- ((R) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrrole Piperazine -2- base) -3,4- dihydro -2H- spiral shell [naphthalene-Isosorbide-5-Nitrae '-piperidines] -2- base) -2- methylpropane -2- sulfenamide (18mg, HCl/1,4- dioxane (4mol/L, 2mL) is added in Isosorbide-5-Nitrae-dioxane (2mL) solution 0.03mmol).Stir 30min It is concentrated and is washed twice with EA afterwards.By solid high vacuum dry, compound (R) -1 '-(6- amino -5- ((2- amino -3- is obtained Chloropyridine -4- base) sulfenyl) pyrazine -2- base) 4- dihydro -2H- spiral shell [naphthalene-Isosorbide-5-Nitrae '-piperidines] -2- amine (14mg, 88%) is greyish white Color solid.MS:468 (M+H)+.
Embodiment 4
(R) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -5,6- dihydro spiral shell [ring Pentadiene simultaneously 7,4 '-piperidines of [b] pyridine -] -6- amine
Step a: at 0 DEG C, NaHMDS (THF solution of 38ml, 2mol/L) is added to the fluoro- 3- methyl pyrrole of compound 2- Pyridine (5.56g, 50.00mmol) and the piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester 14.15g, 55.00mmol) toluene In (50mL) solution, warms naturally to 20 DEG C and stir for 24 hours.Reaction system is quenched with salt water (100mL).By organic phase nothing Water Na2SO4 is dried, filtered and is concentrated under reduced pressure.By column chromatography eluting residue, the compound 4- in yellow oily is obtained (3- picoline -2- base) piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (6.32g, 36%).MS:349 (M+H)+.
Step b: by compound 4- (3- picoline -2- base) piperidines-Isosorbide-5-Nitrae-dicarboxylic acids 1- tert-butyl ester 4- ethyl ester (4.80g, 13.78 mmol) and THF (48mL) solution of LDA (2mol/L, 17mL) stir 0.5h at 0 DEG C.It is concentrated under reduced pressure and removes volatilization Object.Residue is purified by column chromatography with 6- oxo -5,6- dihydro spiral shell [cyclopenta [b] pyrrole for the oily that obtains taking on a red color 7,4 '-piperidines of pyridine -] -1 '-carboxylic acid tert-butyl ester (0.95g, 23%).MS:303 (M+H)+.
Step c: to 6- oxo -5,6- dihydro spiral shell [7,4 '-piperidines of cyclopenta [b] pyridine -] -1 '-carboxylic acid tert-butyl ester In tetraethyl titanate (5mL) solution of (0.94g, 3.11 mol) be added (R) -2- methylpropane -2- sulfenamide (1.13g, 9.33mmol).1h is stirred at 80 DEG C.EA (30mL) and water (20mL) are added in reaction solution.Filtering is collected in filtrate Organic phase.With EA (10mL × 2) aqueous phase extracted.Combined organic phase is washed with salt water (50mL), it is dry with anhydrous Na 2SO4, It filters and is concentrated under reduced pressure, obtain (R, Z) -6- ((terf-butylsulfinyl) imino group) -5,6- dihydro spiral shell [cyclopenta [b] Pyridine -7,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (2.51g, crude product).It is not further purified and directly throws in next step.MS:406 (M+H)+.
Step d: by compound (R, Z) -6- ((terf-butylsulfinyl) imino group) -5,6- dihydro spiral shell [cyclopenta 7,4 '-piperidines of [b] pyridine -] THF (20mL) solution of -1 '-carboxylic acid tert-butyl ester (2.12g, crude product) stirs at -50 DEG C.It will NaBH4(176mg, 4.66mmol) is added in reaction system and warms naturally to RT.With saturated ammonium chloride solution (30mL) Quenching reaction.Organic phase is collected, anhydrous Na 2SO4 is dried, filtered and is concentrated under reduced pressure.By column chromatography eluting residue, obtain Yellow solid (R) -6- (((S)-terf-butylsulfinyl) amino) -5,6- dihydro spiral shell [cyclopenta [b] pyridine -7, 4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (0.21g, 17%, two step yield).MS:408 (M+H)+.
Step e: by compound (R) -6- (((S)-terf-butylsulfinyl) amino) -5,6- dihydro spiral shell [cyclopenta 7,4 '-piperidines of [b] pyridine -] -1 '-carboxylic acid tert-butyl ester (204mg, 0.50mmol) and CF3The DCM (10mL) of COOH (1mL) is mixed It closes liquid and stirs 1.5h at 25 DEG C.Reaction system is concentrated under reduced pressure.Residue is dissolved in NMP (10mL), 3- ((2- ammonia is added Base -3- chloropyridine -4- base) sulfenyl) -6- chloropyrazine -2- amine (144mg, 0.50mmol) and K2CO3(0.82g, 6.00mmol), 16h is stirred at 95 DEG C.H is added2O (50mL) is extracted with EA (30mL × 2).Combined organic phase is washed with salt water (50mL), Through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain compound (S)-N- ((R) -1 '-(6- amino -5- ((2- amino -3- Chloropyridine -4- base) sulfenyl) pyrazine -2- base) -5,6- dihydro spiral shell [7,4 '-piperidines of cyclopenta [b] pyridine -] -6- base) -2- Methylpropane -2- sulfenamide (302mg, crude product).It is not further purified and directly throws in next step.MS:559 (M+H)+.
Step f: to compound (S)-N- ((R) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrrole Piperazine -2- base) 7,4 '-piperidines of pyridine -] -6- base) and -2- methylpropane -2- sulfenamide (302mg, 0.54mmol) DCM HCl/1,4-dixoane (4mol/L, 1mL) are added in (10mL) solution.System is stirred into 1h at 25 DEG C, is filtered.Filter cake is molten In MeOH (2mL), DCM (15mL) then is added, stirs 0.5h, filtering, obtain the compound (R) -1 of yellow solid ' - (6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -5,6- dihydro spiral shell [cyclopenta [b] pyrrole 7,4 '-piperidines of pyridine -] -6- amine (163mg, 71%, two step yield).MS:455 (M+H)+.1HNMR (600MHz, MeOH-d4) δ 8.69 (d, 1H), 8.54 (d, 1H), 7.92-7.96 (m, 1H), 7.88 (s, 1H), 7.75 (d, 1H), 6.58 (d, 1H), 4.54- 4.67 (m, 3H), 3.89-3.95 (m, 1H), 3.37-3.61 (m, 3H), 2.79-2.86 (m, 1H), 1.93-2.20 (m, 3H)
Embodiment 5
(S) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -6- methoxyl group -1,3- Dihydro spiral shell [2,4 '-piperidines of indenes -] -1- amine
Step a: by 6- methoxyl group -1- oxo -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (557mg, 1.68 mmol) and (R) -2- methylpropane -2- sulfenamide (610mg, 5.04mmol) Ti (OEt)4(5mL) solution is 100 16h is stirred at DEG C.After being cooled to RT, reaction system is diluted with EA (20mL) and water (30mL).It is filtered, is used by Celite pad EA elution.Filtrate is washed with salt water (1 × 50mL), through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain (R, Z) -1- ((terf-butylsulfinyl) imino group) -6- methoxyl group -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (0.98g), without being further purified i.e. in next step.MS:m/z 435 (M+H)+.
Step b: to (R, Z) -1- ((terf-butylsulfinyl) imino group) -6- methoxyl group -1,3- dihydro spiral shell [indenes -2,4 ' - Piperidines] -1 '-carboxylic acid tert-butyl ester (0.98g, 2.25mmol) THF (10mL) solution in NaBH is added4(0.17g, 4.51mmol).It warms naturally to RT and stirs for 24 hours.With EA (50mL) and water (50mL) diluting reaction system, organic phase is separated, It is washed with salt water (1 × 50mL), anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.By silica gel chromatography (use EA: Hex=1: 5, v/v elutions) purifying residue, obtain (S) -1- (((R)-terf-butylsulfinyl) amino) -6- methoxyl group -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester (380mg).MS:m/z437 (M+H)+.
Step c: to (S) -1- (((R)-terf-butylsulfinyl) amino) -6- methoxyl group -1,3- dihydro spiral shell [indenes -2,4 ' - Piperidines] -1 '-carboxylic acid tert-butyl ester (380mg, 0.87mmol) DCM (10mL) solution in TFA (2mL) is added, stir 1.5 under RT h.System is concentrated under reduced pressure.Residue is dissolved in NMP (10mL), and 3- ((2- amino -3- chloropyridine -4- base) sulfenyl) -6- chlorine pyrrole is added Piperazine -2- amine (301mg, 1.04mmol) and K2CO3(601mg, 4.35mmol).System stirs 16h at 100 DEG C.It is cooled to RT Afterwards, reaction system water (50mL) and EA (50mL) are diluted.Water phase is separated, organic phase is washed with salt water (2 × 50mL), through nothing Water Na2SO4It dries, filters and is concentrated under reduced pressure.It is remaining that purifying (is eluted) with MeOH: DCM=1: 20, v/v by silica gel chromatography Object obtains (R)-N- ((S) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -5- methoxy Base -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -3- base) -2- methylpropane -2- sulfenamide (254mg).MS:m/z588 (M+ H)+.
Step d: to (R)-N- ((S) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- Base) -5- methoxyl group -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -3- base) -2- methylpropane -2- sulfenamide (254mg, HCl (Isosorbide-5-Nitrae-dioxane solution of 4M, 3mL) is added dropwise in Isosorbide-5-Nitrae-dioxane (3mL) solution 0.43mmol), is stirred at RT Mix 30min.It filters and the sediment of collection is dry in vacuum drying oven, obtains (S) -1 '-(6- amino -5- ((2- amino -3- Chloropyridine -4- base) sulfenyl) pyrazine -2- base) -6- methoxyl group -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1- amine (221mg, hydrochloric acid Salt).MS:m/z484 (M+ H)+.1H NMR (600MHz, MeOH-d4) δ 7.90 (s, 1H), 7.76 (d, 1H), 7.28 (d, 1H), 7.12 (d, 1H), 6.95-6.89 (m, 1H), 6.58 (d, 1H), 4.35-4.50 (m, 3H), 3.82 (s, 3H), 3.40-3.49 (m, 2H), 3.08-3.16 (m, 2H), 1.66-2.01 (m, 4H)
Following embodiment is synthesized referring to the corresponding intermediate A of the above method and intermediate B.
Following embodiment is free alkali form or the form of its pharmaceutically acceptable salt.
Embodiment 82
(S) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -5,7- dihydro spiral shell [ring Pentadiene simultaneously 6,4 '-piperidines of [b] pyridine -] -7- amine
Step a: by 7- oxo -5,7- dihydro spiral shell [6,4 '-piperidines of cyclopenta [b] pyridine -] -1 '-carboxylic acid tert-butyl ester The tetraethyl titanate (8mL) of (936mg, 3.10mmol) and (R) -2- methylpropane -2- sulfenamide (1045mg, 8.62mmol) is molten Liquid stirs 2h at 100 DEG C.After being cooled to RT, reaction system is diluted with EA (50mL) and water (50mL).Pass through Celite pad Filtering, filter cake are eluted with EA.Organic phase in filtrate is separated, anhydrous Na is used2SO4It dries, filters and is concentrated under reduced pressure, obtain (R, Z) -7- ((terf-butylsulfinyl) imino group) -5,7- dihydro spiral shell [6,4 '-piperidines of cyclopenta [b] pyridine -] -1 '-carboxylic Tert-butyl acrylate (1.41g).MS:m/z 406 (M+H)+.
Step b: to -40 DEG C (R, Z) -7- ((terf-butylsulfinyl) imino group) -5,7- dihydro spiral shell [cyclopenta [b] pyridine -6,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (1.41g, 3.48mmol) THF (50mL) solution in BH is added3(1M THF solution, 10.00mL, 10.00mmol).It warms naturally to RT and stirs 1h.Reaction system is quenched with salt water (100mL) It goes out.Organic phase is collected, water phase is extracted with EA (1 × 60mL), is merged organic phase, is used anhydrous Na2SO4It dries, filters and depressurizes dense Contracting.Residue is dissolved in MeOH (100mL) and stirs 15h at 80 DEG C.After being cooled to RT, reaction system is concentrated under reduced pressure. Purifying residue (is eluted) with MeOH: DCM=1: 60, v/v by silica gel chromatography, obtains (S) -7- (((R)-tert-butyl Asia sulphur Acyl group) amino) -5,7- dihydro spiral shell [cyclopenta [b] pyridine -6,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (309mg).MS:m/ z 408(M+H)+.
Step c: to (S) -7- (((R)-terf-butylsulfinyl) amino) -5,7- dihydro spiral shell [cyclopenta [b] pyrrole 6,4 '-piperidines of pyridine -] -1 '-carboxylic acid tert-butyl ester (309mg, 0.76mmol) DCM (20mL) solution in be added HCl (EA of 4M is molten Liquid, 2mL, 8.00mmol), 1.5h is stirred at RT.It is concentrated under reduced pressure to give (S) -5,7- dihydro spiral shell [cyclopenta [b] pyridine - 6,4 '-piperidines] -7- amine (227mg).MS:m/z204 (M+H)+.
Step d: by (S) -5,7- dihydro spiral shell [6,4 '-piperidines of cyclopenta [b] pyridine -] -7- amine (HCl salt, 227mg, 0.73 mmol), 3- ((2- amino -3- chloropyridine -4- base) sulfenyl) -6- chloropyrazine -2- amine (249mg, 0.86mmol), K2CO3 The mixture return stirring 44h of (1149 mg, 8.31mmol) and acetonitrile (15mL).After being cooled to RT, by reaction system salt water (100mL) dilution, is extracted with EA (2 × 50mL).Organic phase is merged, anhydrous Na is used2SO4It dries, filters and is concentrated under reduced pressure.It is logical It crosses silica gel chromatography and (elutes) purifying residue with MeOH: DCM=1: 6, v/v, obtain (S) -1 '-(6- amino -5- ((2- ammonia Base -3- chloropyridine -4- base) pyrimidine -5- base) sulfenyl) pyrazine -2- base) -5,7- dihydro spiral shell [cyclopenta [b] pyridine -6,4 ' - Piperidines] -7- amine (77mg).MS:m/z 455 (M+H)+.1H NMR (400MHz, MeOH-d4) δ 8.51 (s, 1H), 7.81 (d, 1H), 7.63 (s, 1H), 7.38 (s, 1H), 5.94 (d, 1H), 4.49-4.30 (m, 3H), 3.37-3.09 (m, 4H), 2.05- 1.95 (m, 1H), 1.85-1.70 (m, 2H), 1.60-1.50 (m, 1H)
Following embodiment is synthesized referring to the corresponding intermediate A of the above method and intermediate B.
In the step a of embodiment 82, (R) -2- methylpropane -2- sulfenamide is replaced with t-butyl sulfonamide, is obtained To corresponding racemic product.
Following embodiment is free alkali form or the form of its pharmaceutically acceptable salt.
Embodiment 133
(S) -4- ((5- (1- amino -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -1 '-yl) pyrazine -2- base) sulfenyl) -3- chlorine Pyridine -2- alcohol
Step a-c: (R)-N- ((S) -1 '-(5- ((chloro- 2- methoxyl group pyrrole of 3- is obtained by (a-c) the step of embodiment 5 Pyridine -4- base) sulfenyl) pyrazine -2- base) -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1- base) -2- methylpropane -2- sulfenyl Amine .MS:m/z 558 (M+H)+.
Step d: by (R)-N- ((S) -1 '-(5- ((the chloro- 2- methoxypyridine -4- base of 3-) sulfenyl) pyrazine -2- base) -1, 3- dihydro spiral shell [indenes -2,4 '-piperidines] -1- base) -2- methylpropane -2- sulfenamide (112mg, 0.20mmol), DCM (5mL) 17h is stirred at RT with the mixture of HCl (Isosorbide-5-Nitrae-dioxane solution of 4M, 10mL).Mixture is concentrated under reduced pressure, it is remaining Object is dissolved in MeOH (10mL), and is stirred for 23h at 60 DEG C.After being cooled to RT, reaction system is concentrated under reduced pressure.By residue point It is dispersed in MeOH (2mL) and EA (20mL), precipitating is collected by filtration, is dried under reduced pressure, obtain (S) -4- ((5- (1- amino -1,3- bis- Hydrogen spiral shell [2,4 '-piperidines of indenes -] -1 '-yl) pyrazine -2- base) sulfenyl) -3- chloropyridine -2- alcohol (73mg).440 (M+H of MS:m/z )+.1H NMR (400MHz, DMSO-d6) δ 8.51 (s, 1H), 8.34 (s, 1H), 7.59 (d, 1H), 7.28-7.37 (m, 3H), 7.23 (d, 1H), 5.52 (d, 1H), 4.28-4.40 (m, 3H), 3.21-3.38 (m, 3H), 3.02-2.99 (d, 1H), 1.75- 1.82 (m, 2H), 1.52-1.60 (m, 2H)
The following example is synthesized with corresponding starting material by the above method..
Following embodiment is the form of its free alkali form or pharmaceutically acceptable salt.
Table 18
Embodiment 137
(S) -1 ' of -1- amino-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -1,3- bis- Hydrogen spiral shell [2,4 '-piperidines of indenes -] -6- alcohol
(S) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -6- methoxyl group -1,3- BBr is added in DCM (2mL) solution of dihydro loop coil [2,4 '-piperidines of indenes -] -1- amine (74mg, 0.14mmol)3(DCM of 1M is molten Liquid, 0.71mL).System is stirred into 6h at RT.It is concentrated under reduced pressure and removes volatile matter, residue is dispersed in water, solid is filtered out, With saturation NaHCO3The pH value of filtrate is adjusted to 7 by aqueous solution.The precipitating being collected by filtration, and it is dry in vacuum drying oven, Obtain (S) -1- amino -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -6- alcohol (7mg).MS:m/z 470 (M+H)+.
The following example is synthesized with corresponding starting material by the above method.
Table 19
Embodiment 139
1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -5- methyl -5,7- dihydro spiral shell [6,4 '-piperidines of cyclopenta [b] pyridine -] -5- amine
Step a: (R, Z) -5- ((terf-butylsulfinyl) imino group) -5,7- dihydro is synthesized referring to the step a of embodiment 5 Spiral shell [cyclopenta [b] pyridine -6,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester.MS:m/z406 (M+H)+.
Step b: to (R, Z) -5- ((terf-butylsulfinyl) imino group) -5,7- dihydro spiral shell [cyclopenta of -60aC [b] pyridine -6,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (1.49g, 3.67mmol) THF (15mL) solution in lithium methide is added dropwise (diethyl ether solution of 1.3M, 14mL, 18.20mmol).It warms naturally to RT and stirs 20h.With water (10mL) and EA (20mL) dilution.Water phase is separated, is added NaOH (1.00g, 25.00mmol) and (Boc)2O(0.50mL).By mixture at RT Stir 1.5h.It is extracted with EA (2 × 50mL), merges organic phase, washed with salt water (1 × 30mL), use anhydrous Na2SO4It is dry, mistake It filters and is concentrated under reduced pressure.Purifying residue (is eluted) with EA: Hex=1: 1, v/v by silica gel chromatography, obtains 5- (((R)-uncle Butylsulfinyl) amino) -5- methyl -5,7- dihydro spiral shell [cyclopenta [b] pyridine -6,4 '-piperidines] -1 '-carboxylic acid uncle Butyl ester (823mg).MS:m/z 422 (M+H)+.
Step (c-d): (c-d) synthesizes 1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- referring to the step of embodiment 5 Base) sulfenyl) pyrazine -2- base) -5- methyl -5,7- dihydro spiral shell [6,4 '-piperidines of cyclopenta [b] pyridine -] -5- amine (71mg) .MS:m/z469 (M+H)+. 1H NMR (400MHz, MeOH-d4) δ 8.50-8.44 (m, 1H), 7.93-7.87 (m, 1H), 7.67- 7.61 (m, 2H), 7.41-7.35 (m, 1H), 5.97 (d, 1H), 4.54 (m, 2H), 3.35 (d, 1H), 3.23-3.08 (m, 3H), 1.92-1.78 (m, 2H), 1.57-1.48 (m, 2H), 1.44 (s, 3H)
Embodiment 140
1- amino -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -3H- spiral shell [middle nitrogen Indenes -2,4 '-piperidines] -7 (1H) -one
Step a: to -10 DEG C 1- hydroxyl -7- oxo -1,7- dihydro -3H- spiral shell [indolizine -2,4 '-piperidines] -1 '-carboxylic acid The tert-butyl ester (100mg, 0.31mmol), in the THF (10mL) and DCM (2mL) solution of triethylamine (157mg, 1.55mmol) plus Enter MsCl (66mg, 0.58mmol).Resulting solution is stirred into 1h at RT.Reaction solution is diluted with water (50 mL), uses DCM (3 × 50mL) extraction.By combined organic phase through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 1- ((mesyl) Oxygroup) -7- oxo -1,7- dihydro -3H- spiral shell [indolizine -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (155mg).MS:m/z399 (M+H)+.
Step b: by 1- ((mesyl) oxygroup) -7- oxo -1,7- dihydro -3H- spiral shell [indolizine -2,4 '-piperidines] - The mixture of 1 '-carboxylic acid tert-butyl ester (155mg, 0.39mmol), sodium azide (136mg, 2.09mmol) and DMF (5mL) are 75 1h is stirred at DEG C, and stirs 4h at 85 DEG C.After being cooled to RT, reaction system is diluted with EA (30mL), is filtered and by filtrate It is concentrated under reduced pressure.Residue (is eluted into) purifying by silica gel chromatography with MeOH: DCM=1: 10, v/v, is obtained 1- azido- 7- oxo -1,7- dihydro -3H- spiral shell [indolizine -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (32mg).MS:m/z346 (M+H)+.
Step c: by the tertiary fourth of 1- azido -7- oxo -1,7- dihydro -3H- spiral shell [indolizine -2,4 '-piperidines] -1 '-carboxylic acid EtOH (6mL) solution of ester (32mg, 0.093mmol), Pd/C (10%, 15mg) stirs 3h under hydrogen environment.Filtering reaction System, filter cake are eluted with EtOH, be concentrated under reduced pressure filtrate, obtain 1- amino -7- oxo -1,7- dihydro -3H- spiral shell [indolizine -2, 4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (26mg).MS:m/z 320 (M+H)+.
Step d: to 1- amino -7- oxo -1,7- dihydro -3H- spiral shell [indolizine -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester TFA (2mL) is added in solution in the DCM (2mL) of (26mg, 0.081 mmol), and 30min is stirred at room temperature.System subtracts Pressure concentration.Residue is dissolved in NMP (2.5mL), 3- ((2- amino -3- chloropyridine -4- base) sulfenyl) -6- chloropyrazine-is added 2- amine (46mg, 0.16mmol) and K2CO3(395mg, 2.86mmol) stirs 16h at 95 DEG C.After being cooled to RT, DCM is used (30mL) dilution, filters and is concentrated under reduced pressure.Residue (being eluted with MeOH: DCM=1: 3, v/v) is purified by Pre-TLC, is obtained To 1- amino -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -3H- spiral shell [indolizine -2, 4 '-piperidines] -7 (1H) -one (2mg).MS:m/z 471 (M+H)+.
The following example is synthesized with corresponding starting material by the above method.
Table 20
Embodiment 142
3- ((2- amino -3- chloropyridine -4- base) sulfenyl) -6- (1- imino group -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] - 1 '-yl) pyrazine -2- amine
Step a: (R, Z) -1- ((terf-butylsulfinyl) imino group) -1,3- dihydro is synthesized by the step a of embodiment 5 Spiral shell [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester .MS:m/z 405 (M+H)+.
Step b: to (R, Z) -1- ((terf-butylsulfinyl) imino group) -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1 ' - TFA (1mL) is added in DCM (10mL) solution of carboxylic acid tert-butyl ester (405mg, 1.00mmol), and stirs 1.5h at RT.Body System is concentrated under reduced pressure.Residue is dissolved in NMP (10mL), 3- ((2- amino -3- chloropyridine -4- base) sulfenyl) -6- chlorine pyrrole is added Piperazine -2- amine (288mg, 1.00mmol) and K2CO3(1.38g, 10.00mmol).System stirs 18h at 100 DEG C.It is cooled to RT Afterwards, it is diluted with water (50mL) and is extracted with EA (3 × 30mL).Combined organic phase is washed with salt water (1 × 100mL), with nothing Water Na2SO4It dries, filters and is concentrated under reduced pressure.It is remaining that purifying (is eluted) with MeOH: DCM=1: 5, v/v by silica gel chromatography Object obtains 3- ((2- amino -3- chloropyridine -4- base) sulfenyl) -6- (1- imino group -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] - 1 '-yl) pyrazine -2- amine (50mg).MS:m/z452 (M+H)+.1H NMR (400 MHz, MeOH-d4) δ 7.83 (d, 1H), 7.37- 7.74 (m, 5H), 5.96 (d, 1H), 4.43-4.58 (m, 2H), 3.12-3.28 (m, 4H), 2.01-2.06 (m, 2H), 1.56- 1.60 (m, 2H)
The following example is synthesized with corresponding starting material referring to the above method.
Table 21
Embodiment 148
1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -7- methoxyl group -1,3- dihydro Spiral shell [indenes -2,4 '-piperidines] -1- amine
Step a: to 7- methoxyl group -1- oxo -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester (552mg, 1.07 mmol) MeOH (10mL) solution in, be added hydroxylamine hydrochloride (348mg, 5.01mmol) and AcONa (822 mg, 10.02mmol).System is stirred into 4h at RT.Reaction system is concentrated under reduced pressure.Residue is dissolved in EA (15 mL) and water In (15mL), organic phase is separated, is washed with salt water (1 × 15mL), uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain Huang (Z) -1- (oxyimino) -7- methoxyl group -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester of color solid-like (520mg).MS:m/z347 (M+H)+.
Step b: by (Z) -1- (oxyimino) -7- methoxyl group -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1 '-carboxylic acid The tert-butyl ester (510 mg, 1.47mmol), PtO2The mixture of (30mg) and AcOH (10mL) stir under hydrogen environment in 60 DEG C 17h.After being cooled to RT, reaction system is diluted with EA (45mL) and water (45mL), is separated water phase, is used K2CO3PH value is adjusted to by solid 10.System is extracted with DCM (2 × 30mL), combined organic phase is washed with salt water (1 × 50 mL), uses anhydrous Na2SO4It is dry It is dry, filter and be concentrated under reduced pressure, obtain 1- amino -7- methoxyl group -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1 of colorless oil ' - Carboxylic acid tert-butyl ester (202mg).MS:m/z333 (M+H)+.
Step c: to 1- amino -7- methoxyl group -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester (199mg, 0.60 mmol) DCM (10mL) solution in TFA (1mL) is added, and stir 1.5h at RT.System is concentrated under reduced pressure.It will be remaining Object is dissolved in NMP (5mL), addition 3- ((2- amino -3- chloropyridine -4- base) sulfenyl) -6- chloropyrazine -2- amine (144mg, 0.50mmol) and K2CO3(691mg, 5.90mmol).System stirs 3h at 95 DEG C.After being cooled to RT, by reaction system water (50mL) dilution is simultaneously extracted with EA (1 × 50mL).Organic phase is washed with salt water (1 × 50mL), uses anhydrous Na2SO4It is dry, mistake It filters and is concentrated under reduced pressure.Residue (being eluted with MeOH: DCM=1: 5, v/v) is purified by Pre-TLC, obtains 1 '-(6- amino- 5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -7- methoxyl group -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] - 1- amine (20mg).MS:m/z484 (M+H)+.1H NMR (400MHz, DMSO-d6) 6 7.66 (s, 1H), 7.64 (d, 1H), 7.36- 7.28 (m, 1H), 6.90 (d, 1H), 6.88 (d, 1H), 5.75 (d, 1H), 4.29 (s, 1H), 4.20 (d, 1H), 4.09 (d, 1H), 3.83 (s, 3H), 3.30-3.15 (m, 2H), 3.10 (d, 1H), 2.96 (d, 1H), 1.87-1.76 (m, 1H), 1.70- 1.54 (m, 2H), 1.41 (d, 1H)
The following example is synthesized with corresponding starting material referring to the above method.
Table 22
Embodiment 150
(S) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -2- methoxyl group -4,6- Dihydro spiral shell [5,4 '-piperidines of cyclopenta [d] thiazole -] -4- amine
Step (a-b): (a-b) synthesis (S) -4- (((R)-terf-butylsulfinyl) amino)-referring to the step of embodiment 5 Chloro- 4, the 6- dihydro spiral shell of 2- [5,4 '-piperidines of cyclopenta [d] thiazole -] -1 '-carboxylic acid tert-butyl ester.MS:m/z 448 (M+H)+.
Step c:(S) -4- (((R)-terf-butylsulfinyl) amino) -2- chloro- 4,6- dihydro spiral shell [cyclopenta [d] 5,4 '-piperidines of thiazole -] -1 '-carboxylic acid tert-butyl ester (403mg, 0.90mmol), NaOH (358mg, 8.95mmol) and MeOH The mixture of (15mL) stirs 5h at 65 DEG C.After being cooled to RT, it is concentrated under reduced pressure and removes volatile matter.Residue is soluble in water, It adds saturated lemon aqueous solution and pH value is adjusted to 7.System is extracted with EA (3 × 30mL), by combined organic phase through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain (S) -4- (((R)-terf-butylsulfinyl) amino) -2- first of brown oil Oxygroup -4,6- dihydro spiral shell [5,4 '-piperidines of cyclopenta [d] thiazole -] -1 '-carboxylic acid tert-butyl ester (360mg).MS:m/z 444 (M+H)+.
Step (d-e): (c-d) synthesizes (S) -1 '-(6- amino -5- ((2- amino -3- chlorine pyrrole referring to the step of embodiment 5 Pyridine -4- base) sulfenyl) pyrazine -2- base) -2- methoxyl group -4,6- dihydro spiral shell [5,4 '-piperidines of cyclopenta [d] thiazole -] -4- Amine.MS:m/z 491 (M+H)+.
Embodiment 151
(S) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -4,6- dihydro spiral shell [ring Pentadiene simultaneously [d] thiazole -5-, 4 '-piperidines] -4- amine
Step (a-b): (a-b) synthesis (S) -4- (((R)-terf-butylsulfinyl) amino)-referring to the step of embodiment 5 Chloro- 4, the 6- dihydro spiral shell of 2- [5,4 '-piperidines of cyclopenta [d] thiazole -] -1 '-carboxylic acid tert-butyl ester.MS:m/z448 (M+H)+.
Step c:(S) -4- (((R)-terf-butylsulfinyl) amino) -2- chloro- 4,6- dihydro spiral shell [cyclopenta [d] 5,4 '-piperidines of thiazole -] -1 '-carboxylic acid tert-butyl ester (2.50g, 5.58mmol), TEA (2mL), Pd/C (10%, 690mg) and MeOH The mixture of (50mL) stirs for 24 hours under hydrogen environment at 40 DEG C.Filtering, Pd/C is added into filtrate, and (10%, 1.32 g).? Under hydrogen environment, 16h is stirred at 50 DEG C.Filtering, filtrate decompression concentration.By silica gel chromatography (use EA: Hex=1: 1, V/v elution) purifying residue, obtain (S) -4- (((R)-terf-butylsulfinyl) amino) -4,6- dihydro spiral shell [cyclopentadiene And [d] thiazole -5,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (1.28g).MS:m/z 414 (M+H)+.
Step (d-e): (c-d) synthesizes (S) -1 '-(6- amino -5- ((2- amino -3- chlorine pyrrole referring to the step of embodiment 5 Pyridine -4- base) sulfenyl) pyrazine -2- base) -4,6- dihydro spiral shell [cyclopenta [d] thiazole -5,4 '-piperidines] -4- amine.MS:m/z 461(M+H)+.1H NMR (400MHz, DMSO-d6) δ 8.94 (s, 1H), 7.63-7.66 (m, 2H), 5.76 (d, 1H), 3.99- 4.07 (m, 2H), 3.87 (s, 1H), 3.28-3.38 (m, 2H), 2.78-2.93 (m, 2H), 1.47-1.87 (m, 4H)
In the step a of embodiment 5, (R) -2- methylpropane -2-2 sulfonamide is replaced with t-butyl sulfonamide, is obtained Corresponding racemic product.
The following example is synthesized with corresponding starting material referring to the above method.
Table 23
EXAMPLE 155
(S) -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -4,6- dihydro spiral shell [ring Pentadiene simultaneously [d] thiazole -5,4 '-piperidines] -6- amine
Step a: synthesizing (R, Z) -6- ((terf-butylsulfinyl) imino group) -2- chloro- 4 referring to the step a of embodiment 5, 6- dihydro spiral shell [cyclopenta [d] thiazole -5,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester.MS:m/z 446 (M+H)+.
Step b: to chloro- 4, the 6- dihydro spiral shell [cyclopenta of (R, Z) -6- ((terf-butylsulfinyl) imino group) -2- [d] thiazole -5,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (4.25g, 9.53mmol) THF (30mL) solution in BH is added3(1M THF solution, 30.00mL, 30.00mmol).It warms naturally to RT and stirs 18h.Reaction system is quenched with salt water (50mL) It goes out.Organic phase is separated, anhydrous Na is used2SO4It dries, filters and is concentrated under reduced pressure.It is purified by silica gel chromatography residue, with (EA : Hex=1: 2, v/v) elution, obtain (S) -6- (((R)-terf-butylsulfinyl) amino) -4,6- dihydro spiral shell [cyclopenta [d] thiazole -5,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (1.12g).MS:m/z414 (M+H)+.
Step (c-d): (c-d) synthesizes (S) -1 '-(6- amino -5- ((2- amino -3- chlorine pyrrole referring to the step of embodiment 5 Pyridine -4- base) sulfenyl) pyrazine -2- base) -4,6- dihydro spiral shell [cyclopenta [d] thiazole -5,4 '-piperidines] -6- amine.1H NMR (400MHz, DMSO-d6) δ 9.01 (s, 1H), 7.63-7.66 (m, 2H) 5.76 (d, 1H), 4.19-4.23 (m, 2H), 4.09 (s, 1H), 3.15-3.32 (m, 2H), 2.80-2.93 (m, 2H), 1.60-1.87 (m, 4H) .MS:m/z 461 (M+H)+.
The following example is synthesized with corresponding starting material referring to the above method.
Table 24
Embodiment 157
(S) -1 '-(6- amino -5- ((the fluoro- 1H- indoles -4- base of 3-) sulfenyl) pyrazine -2- base) -1,3- dihydro spiral shell [indenes -2, 4 '-piperidines] -1- amine
(S) -1- (4- ((3- amino -5- (1- amino -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -1 '-yl) pyrazine -2- base) Sulfenyl) bis- fluoro indole quinoline -1- base of -3,3-) ethane -1- ketone (86mg, 0.16mmol) is dissolved in MeOH (8mL) and NaOH is added (17mg, 0.43mmol).System is stirred for 21h at 65 DEG C.After being cooled to RT, reaction system is concentrated under reduced pressure.Residue is used Water (10mL) and EA (20mL) dilution.The organic phase separated is washed with salt water (10mL), uses anhydrous Na2SO4It dries, filters simultaneously It is concentrated under reduced pressure.EA (5mL) and Hex (3mL) mashing is added, precipitating is collected by filtration, is dried under reduced pressure, obtains (S) -1 '-(6- amino - 5- ((the fluoro- 1H- of 3-WDraw diindyl -4- base) sulfenyl) pyrazine -2- base) -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -1- amine (14mg).1H NMR (400MHz, DMSO-d6) δ 7.59 (s, 1H), 7.37-7.21 (m, 5H), 7.13 (d, 1H), 7.00-6.93 (m, 1H), 6.40 (d, 1H), 4.18 (d, 2H), 3.97 (s, 1H), 3.09 (m, 3H), 2.72 (m, 1H), 1.77-1.62 (m, 2H), 1.50- 1.47 (m, 1H), 1.20-1.16 (m, 1H) MS:461 (M+H)+.
Embodiment 158
(S) -1- (1- amino -1 '-(6- amino -5- ((2- amino -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -1, 3- dihydro spiral shell [indenes -2,4 '-piperidines] -6- base) ethane -1- ketone
Step a-b: (a-b) synthesizes (S) -1- (((R)-terf-butylsulfinyl) amino) -6- referring to the step of embodiment 5 Cyano -1,3- dihydro spiral shell [indenes -2,4 '-piperidines] -1 '-carboxylic acid tert-butyl ester.MS:m/z 432 (M+H)+.
Step c: to -50 DEG C of (S) -1- (((R)-terf-butylsulfinyl) amino) -6- cyano -1,3- dihydro spiral shells [indenes -2, 4 '-piperidines] -1 '-carboxylic acid tert-butyl ester (430mg, 1.00mmol) THF (10mL) solution in be added dropwise methyl-magnesium-bromide (3M's THF/ Hex solution, 0.50mL, 1.50mmol).It warms naturally to room temperature and stirs for 24 hours.By reaction system with salt water (10mL) It is quenched.Organic phase is separated, anhydrous Na is used2SO4It dries, filters and is concentrated under reduced pressure, obtain (S) -6- acetyl group -1- (((R)-uncle Butylsulfinyl) amino) -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -1 '-carboxylic acid tert-butyl ester (0.72g), without further pure Change i.e. in next step.MS:m/z 449 (M+H)+.
Step d-e: (c-d) synthesizes (S) -1- (1- amino -1 '-(6- amino -5- ((2- ammonia referring to the step of embodiment 5 Base -3- chloropyridine -4- base) sulfenyl) pyrazine -2- base) -1,3- dihydro spiral shell [2,4 '-piperidines of indenes -] -6- base) ethane -1- ketone.MS: 496(M+H)+.
The following example is synthesized with corresponding starting material referring to the above method.
Table 25
The above method and the synthesis of suitable starting material can be used in following embodiment:
Table 26
Pharmacology test
Embodiment A phosphatase activity detects (single dose):
Single dose inhibitory activity detection, using the fluoro- 4-methyl umbelliferone phosphate (DiFMUP) of 6,8- bis- as reaction bottom Object, SHP2 enzyme solutions (being diluted to 0.5nM in reaction solution) and dPEG8 peptide are in reaction solution (60mM 3,3- dimethyl glutarate (PH7.2), 75mM NaCl, 75mM KCl, 1mM EDTA, 0.05%Tween 20,2mM dithiothreitol (DTT) (DTT)) in it is common 30 minutes are incubated for activate PTP.(0.5% (V/V) or compound (100nM) are added in mixed liquor DMSO, and continuation is incubated at room temperature Educate 30min.DiFMUP (12 μM, reaction solution total volume is 100 μ L) are added, starts to react, uses 2104- after being incubated for 30min Fluorescence intensity (the exciting light of 0020EnVisionXcite Multilabel Reader (PerkinElmer) detection reaction solution 340nm emits light 450nm).Each dosage sets three multiple holes.The fluorescent value of control wells (DMSO) is set as 100%, at compound Reason hole indicates its inhibitory activity with the percentage relative to control wells.Compound is shown in Table the inhibitory activity of SHP2 in the present invention A。
Table A
Phosphatase activity detects (IC50 measurement):
IC50Value detection is used as reaction substrate, SHP2 enzyme using the fluoro- 4-methyl umbelliferone phosphate (DiFMUP) of 6,8- bis- Solution (being diluted to 0.5nM in reaction solution) and dPEG8 peptide are in reaction solution (60mM3,3- dimethyl glutarate (PH7.2), 75mM NaCl, 75mM KCl, 1mM EDTA, 0.05%Tween 20,2mM dithiothreitol (DTT) (DTT)) in be incubated for 30 minutes jointly to live Change PTP.(0.5% (V/V) or compound (concentration: 0.3nM~1 μM) are added in mixed liquor DMSO, continue to be incubated at room temperature 30min.DiFMUP (12 μM, reaction solution total volume is 100 μ L) are added, starts to react, uses 2104- after being incubated for 30min Fluorescence intensity (the exciting light of 0020EnVision Xcite Multilabel Reader (PerkinElmer) detection reaction solution 340nm emits light 450nm).Compound inhibits the IC of SHP2 enzymatic activity in the present invention50It is shown in Table B.
Table B
The detection of embodiment C cell Proliferation:
MV-4-11 cell (4000 cells/every hole) is inoculated in 96 well culture plates, culture medium is that 100 holes μ L/ (contain The IMDM of 3% fetal calf serum (FBS) comes from Gibco company).After culture 24 hours, the present invention is added and is configured to various concentration Compound.8th day, 30 μ L MTS/PMS reagents (being purchased from Promega, Sigma respectively) was added in every hole, according to reagent specification (Promega) light absorption value is detected.The IC of compound in the present invention50Value is shown in Table C.
Table C
Embodiment D p-ERK cell-based assay
By the method for immunoblotting, the activation levels of ERK1/2 are detected using the antibody of an anti-p-ERK1/2.Letter A series of compounds (concentration is from 0.3nM to 100nM) are added in Yan Zhi, MV-4-11 human leukemia cell, are incubated for 2 hours together. With the RIPA buffer of the protease inhibitor cocktail containing Halt (Thermo Fisher Scientific, Rockford, IL, USA) lytic cell and total protein of cell is collected.10 μ L total proteins are separated with SDS-PAGE under the reducing conditions, and are shifted To on PVDF film (Bio-Rad).After the Tris buffered saline solution closing containing 5%BSA, film and primary antibody are incubated at 4 DEG C Overnight, the secondary antibody then with horseradish peroxidase (HRP) label is incubated for 1 hour.The secondary antibody combined using chemiluminescence detection.
Embodiment E MV-4-11 xenograft tumor models
MV-4-11 cell culture expands, and collects and be subcutaneously injected into the female NOD/SCID mouse (5 × 10 of 5-8 week old6 A cell/every mouse, n=6~10/ group) in vivo.As mean tumour volume about 100-200mm3When, start oral administration gavage It is administered (0.1-10mpk/ dosage).(once or twice a day, continue 2-4 weeks) during treatment, it is swollen using vernier caliper measurement Knurl product.The difference of gross tumor volume between statistics each group is analyzed using single factor test ANOVA.Solvent is negative control.
Compound provided by the invention is preferably formulated to the pharmaceutical composition being administered by all means.Most preferably, should Pharmaceutical composition for being administered orally, this pharmaceutical composition and preparation method thereof be in the art it is well known, can join See such as Remington: pharmaceutical science and practicing (Ah Zhan Naluo et al. compile, the 19th edition, Mike publishing company, 1995) [REMINGTON:THE SCIENCE AND PRACTICE OF PHARMACY (A.Gennaro, et al, eds., 19th Ed., Mack Publishing Co., 1995)], compound shown in structural formula I, II, III or IV is usually in very wide dosage model It encloses interior effective.
In short, the majority of compounds listed in the present invention is highly effective and has selectivity, IC50 is lower than 10nM.They Good antitumor action is also showed that in model in vivo.For example, daily dosage generally falls in about 0.2mg to 100mg dosage In the range of, preferably 0.2mg to 50mg dosage, more preferable 0.2mg to 20mg dosage.In some cases, it is lower than above range The dosage level of lower limit may be sufficient, and in other cases, bigger dosage can be used.Above-mentioned dosage range is not It limits the scope of the invention in any way.It should be understood that the practical dosage of compound will be by doctor according to mutually concerning feeling Condition determine, including illness to be treated, the administration route of selection, it is actual to drug compound, the age of individual patient, weight and The severity of reaction and patient condition.

Claims (51)

1. structural formula I compound represented or its pharmaceutically acceptable salt:
It is characterized by:
Each R1Independently selected from-H, halogen ,-NH2,-CN, substituted or unsubstituted-C1-6Alkoxy is substituted or unsubstituted - C1-6Alkyl；
R2Selected from-H, halogen ,-NH2、-CN、-OH、-NHC1-6Alkyl ,-N (C1-6Alkyl)2, substituted or unsubstituted-C1-6Alcoxyl Base, substituted or unsubstituted-C1-6Alkyl or-C5-10Heterocycle；Or
R2With adjacent R1Connection and the carbon atom that they are separately connected are formed together 6-10 member aromatic ring, 5-6 member hetero-aromatic ring or 5-6 Circle heterocyclic ring, and each ring system can not replace optionally independently or by 1,2 or 3 halogen ,-NH2、-CN、-C1-6Alkyl or- CO-C1-6Alkyl replaces；
Each Y1Independently selected from N or CH；
R3Selected from-H or-NH2；
Each R4aAnd R4bIndependently selected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl or-C1-6Alkyl；
Or
R4aAnd R4bCO, C=NH or C=N-OH are formed together with the carbon atom that they connect jointly；
P is 0,1,2 or 3；
Each R5aAnd R5bIndependently selected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl or-C1-6Alkyl；Or
R5aAnd R5b3-5 circle heterocyclic ring base or C=NH are formed together with the carbon atom that they connect jointly；
Q is 0,1,2,3 or 4；
W be not present, O, S or NRw；And RwIt is-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-6Alkyl-O-C1-6Alcoxyl Base, substituted or unsubstituted-C1-6Alkoxy or substituted or unsubstituted-C1-6Alkyl；
Ring A is not present or 3-10 member ring；
Indicate singly-bound or double bond；
In the absence of ring A, Y2It is CR2aR2b、NR2aOr O, and Y3It is CR3aR3b、NR3aOr O；
When ring A is 3-10 member ring:
I) whenWhen indicating singly-bound, Y2It is CR2aOr N, and Y3It is CH or N；Or
Ii) whenWhen indicating double bond, Y2It is C, and Y3It is C；
Each R2a、R2b、R3aAnd R3bIndependently selected from-H, halogen ,-NH2、-CN、-OH、-NO2, it is carboxyl, substituted or unsubstituted - C1-6Alkoxy or substituted or unsubstituted-C1-6Alkyl；
Each R6Independently selected from-H, halogen ,-NR6aR6b、-CN、-OH、-NO2, oxo base ,=O, carboxyl ,-C1-6Alkoxy ,- C1-6Alkyl ,-C1-6Alkenyl-NR6aR6b、-C1-6Alkenyl-O-C1-6Alkyl ,-C1-6Alkenyl ,-CO-OR6a、-C1-6Alkenyl-C3-10Heterocycle Base ,-C1-6Alkenyl-C5-10Heteroaryl ,-C1-6Alkenyl-CO-NR6aR6b、-C1-6Alkenyl-NR6a-CO-NR6aR6b、-C1-6Alkenyl- NR6a-CO-C1-6Alkyl ,-CO-NR6aR6b、-CO-CO-NR6aR6b、-C3-10Carbocylic radical ,-C3-10Heterocycle ,-CO-C1-6Alkyl ,- CO-C1-6Alkenyl-NR6aR6b、-CO-NR6a-C3-10Heterocycle ,-CO-NR6a-C3-10Heterocycle ,-CO-C3-10Heterocycle ,-O-C1-6 Alkenyl-CO-OR6a、-O-C1-6Alkenyl-CO-NR6aR6b、-O-C1-6Alkenyl-NR6aR6b、-O-C3-10Carbocylic radical ,-O-C3-10Heterocycle Base ,-NR6a-CO-C1-6Alkyl ,-NR6a-CO-NR6aR6b、-NR6a-CO-C5-10Heteroaryl ,-NR6a-C1-6Alkene-NR6aR6b、- NR6a-C1-6Alkene-C3-10Heterocycle ,-NR6a-C1-6Alkene-C5-10Heteroaryl ,-NR6a-SO2C1-6Alkyl ,-S-C1-6Alkyl ,- SONR6aR6b、-SO2NR6aR6b、-SO-C1-6Alkyl ,-SO2C1-6Alkyl ,-PO (C1-6Alkyl)2、-PO(C1-6Alkoxy)2、-C3-10 Heterocycle or-C5-10Heteroaryl；Each R6Independently optionally replaced by 1,2 or 3 substituent group or does not replace；And n is 0,1,2,3,4,5 or 6；Or
Two adjacent R6It links together and the carbon atom being separately connected with them is formed together 6 yuan of aryl, 5 unit's heteroaryls, 6 Unit's heteroaryl ,-C3-6Heterocycle or-C3-6Carbocylic radical, and each ring system is independently optionally substituted by one or more substituents Or do not replace；
Each R6aAnd R6bIndependently selected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl, substituted or unsubstituted-C1-6Alkane Oxygroup or substituted or unsubstituted-C1-6Alkyl.
2. the compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that: each R1It is independent Ground is selected from-H；-F；-Cl；-Br；-NH2；-CN；-OH；-NO2；Carboxyl；-C1-6Alkyl；-C1-6Alkoxy；By 1,2 or 3 halogen Element ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkyl or-C1-3- the C that alkoxy replaces1-6Alkyl；Or by 1,2 or 3 halogen Element ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkyl or-C1-3- the C that alkoxy replaces1-6Alkoxy.
3. compound according to claim 1 or 2 or its pharmaceutically acceptable salt, it is characterised in that: each R1Independently Selected from-H；-F；-Cl；-Br；-NH2；-CN；-OH；-NO2；Carboxyl；Methyl；Ethyl；Propyl；Isopropyl；Methoxyl group；Ethyoxyl； Propoxyl group；Isopropoxy；By 1,2 or 3-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2, it is carboxyl, methyl, ethyl, propyl, different - the C that propyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy replace1-3Alkyl；Or by 1,2 or 3-F ,-Cl ,-Br ,- NH2、-CN、-OH、-NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy replace C1-3Alkoxy.
4. compound according to any one of claim 1-3 or its pharmaceutically acceptable salt, it is characterised in that: each R1Independently selected from-H；-F；-Cl；-Br；-NH2；-CN；-OH；Methyl；Ethyl；Propyl；Isopropyl；Methoxyl group；Ethyoxyl；Third Oxygroup；Isopropoxy；Or the methyl replaced by 1,2 or 3 substituent group, and each substituent group independently selected from-F ,-Cl ,- Br、-NH2、-CN、-OH、-NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropyl oxygen Base.
5. compound described in any one of -4 or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: R2Choosing From-H；-F；-Cl；-Br；-NH2；-CN；-OH；-NO2；-N3；Carboxyl；-C1-3Alkyl；-C1-3Alkoxy；-NHC1-3Alkyl；-N (C1-3Alkyl)2；-CONH2；-CONHC1-3Alkyl；-CON(C1-3Alkyl)2；-COC1-3Alkyl；-NHCOC1-3Alkyl；-N(C1-3Alkane Base)-CO-C1-3Alkyl；-C5-10Heterocycle；- F ,-Cl ,-Br ,-I ,-NH are selected from by 1,2 or 32,-CN or-OH substituent group take - the C in generation1-3Alkyl；Or-F ,-Cl ,-Br ,-I ,-NH are selected from by 1,2 or 32,-CN or-OH the-C that replaces of substituent group1-3Alkane Oxygroup.
6. compound according to any one of claims 1-5 or its pharmaceutically acceptable salt, it is characterised in that: R2Choosing From-H；-F；-Cl；-Br；-NH2；-CN；-OH；-NO2；-N3；Carboxyl；Methyl；Ethyl；Propyl；Isopropyl；Methoxyl group；Ethoxy Base；Propoxyl group；Isopropoxy；-NHCH3；-N(CH3)2；-CONH2；-CONHCH3；-CON(CH3)2；-COCH3；-NH-COCH3；- N(CH3)-COCH3；Or by 1,2 or 3 substituent group substituent methyl or ethyl, The substituent group is selected from-F ,-Cl ,-Br ,-NH2,-CN or-OH.
7. compound described in any one of -4 or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: R2With Its adjacent R1Connect and and their carbon atoms for being separately connected be formed together 5 unit's heteroaryls, 6 unit's heteroaryls, 6 yuan of aryl, 5 yuan Heterocycle or 6 circle heterocyclic ring bases,；And each heteroaryl or heterocycle include 1 or 2 hetero atom for being selected from N or O；And it is described Each ring system independently optionally by-F ,-Cl ,-Br ,-I ,-NH2、-CN、-OH、-NO2, carboxyl, oxo base ,=O ,- CONH2, substituted or unsubstituted C1-3Alkoxy, substituted or unsubstituted C1-3Alkyl ,-C1-3Alkenyl-O-C1-3Alkyl ,-C1-3Alkene Base-COOH ,-C1-3Alkenyl-NHCONH2、-CO-N(C1-3Alkyl)2、-C1-3Alkenyl-NHCO-C1-3Alkyl ,-CO-CO-N (C1-3Alkane Base)2、-CO-C1-3Alkyl ,-SONH2、-SO2NH2、-SOCH3Or-SO2CH3Replace or does not replace.
8. compound described in any one of -4 or 7 or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: R2 R adjacent thereto1It connects and is separately connected carbon atom with them and be formed together 5 unit's heteroaryls, 6 unit's heteroaryls, 6 yuan of aryl, 5 yuan Heterocycle or 6 circle heterocyclic ring bases；And each heteroaryl or heterocycle includes 1 hetero atom for being selected from N or O；And it is described Each ring system can be independently optionally by-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2, carboxyl, oxo base ,=O ,-CONH2、 Methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy ,-CH2OCH3、-CH2COOH、- CH2NHCONH2、-CON(CH3)2、-CH2NHCOCH3、-CO-CON(CH3)2Or-COCH3Replace or does not replace.
9. compound described in any one of -4 or 7-8 or its pharmaceutically acceptable salt according to claim 1, R2It is adjacent thereto R1It connects and the carbon atom being separately connected with them is formed together
10. -9 described in any item compounds or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: each R4aAnd R4bIndependently selected from-H ,-F ,-Cl ,-Br ,-I ,-NH2、-CN、-OH、-NO2, carboxyl or-C1-3Alkyl；Or
R4aAnd R4bC=O, C=NH or C=N-OH are formed together with the carbon atom that they connect jointly.
11. compound according to claim 1 to 10 or its pharmaceutically acceptable salt, it is characterised in that: every A R4aAnd R4bIndependently selected from-H ,-NH2,-OH, methyl, ethyl, methoxy or ethoxy；Or
R4aAnd R4bC=O is formed together with the carbon atom that they connect jointly.
12. compound described in any one of -11 or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: every A R5aAnd R5bIndependently selected from-H；-F；-Cl；-Br；-I；-NH2；-CN；-OH；-NO2；Carboxyl；-C1-3Alkyl；-C1-3Alcoxyl Base；By-F ,-Cl ,-Br ,-I ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkyl or-C1-3- the C that alkoxy replaces1-6Alkyl； Or by-F ,-Cl ,-Br ,-I ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkyl or-C1-3- the C that alkoxy replaces1-6Alkoxy； Or
R5aAnd R5bC=NH, 3 circle heterocyclic ring bases, 4 circle heterocyclic ring bases or 5 circle heterocyclic ring bases are formed together with the carbon atom that they connect jointly； And each heterocycle independently optionally includes 1 or 2 hetero atom for being selected from N or O；And each ring system can Independently optionally by-H ,-F ,-Cl ,-Br ,-I ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkoxy or-C1-3Alkyl replaces Or do not replace.
13. compound described in any one of -12 or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: every A R5aOr R5bIndependently selected from-H ,-NH2,-OH, methyl, ethyl, methoxy or ethoxy；Or
R5aAnd R5bC=NH, 3 circle heterocyclic ring bases, 4 circle heterocyclic ring bases or 5 circle heterocyclic ring bases are formed together with the carbon atom that they are connected jointly； And each heterocycle includes 1 hetero atom for being selected from N or O.
14. compound according to claim 1 to 13 or its pharmaceutically acceptable salt, it is characterised in that: W It is NRw, and RwSelected from-H ,-F ,-Cl ,-Br ,-I ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkyl-O-C1-3Alkyl ,-C1-3 Alkoxy or-C1-3Alkyl.
15. compound described in any one of -14 or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: W It is NRw, and RwSelected from-H ,-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy Base, ethyoxyl, propoxyl group, isopropoxy, methyl-CO- methyl or methyl-CO- methoxyl group.
16. compound described in any one of -15 or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: ring A is selected from 6 yuan of aryl, 10 yuan of aryl, 5 unit's heteroaryls, 6 unit's heteroaryls, 7 unit's heteroaryls, 8 unit's heteroaryls, 9 unit's heteroaryls, 10 yuan Heteroaryl, 3 circle heterocyclic ring bases, 4 circle heterocyclic ring bases, 5 circle heterocyclic ring bases, 6 circle heterocyclic ring bases, 7 circle heterocyclic ring bases, 8 circle heterocyclic ring bases, 9 circle heterocyclic ring bases, 10 circle heterocyclic ring bases, 3 yuan of carbocylic radicals, 4 yuan of carbocylic radicals, 5 yuan of carbocylic radicals, 6 yuan of carbocylic radicals, 7 yuan of carbocylic radicals, 8 yuan of carbocylic radicals, 9 yuan of carbon Ring group or 10 yuan of carbocylic radicals；And each heteroaryl or each heterocycle are independently optionally selected from comprising 1,2 or 3 N, the hetero atom of O or S.
17. compound described in any one of -16 or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: ring A is selected from 6 yuan of aryl, 5 unit's heteroaryls, 6 unit's heteroaryls, 7 unit's heteroaryls, 8 unit's heteroaryls, 3 circle heterocyclic ring bases, 4 circle heterocyclic ring bases, 5 yuan Heterocycle, 6 circle heterocyclic ring bases, 7 circle heterocyclic ring bases, 8 circle heterocyclic ring bases；3 yuan of carbocylic radicals, 4 yuan of carbocylic radicals, 5 yuan of carbocylic radicals, 6 yuan of carbocylic radicals, 7 yuan of carbocylic radicals or 8 yuan of carbocylic radicals；And each heteroaryl and each heterocycle are independently optionally comprising 1 or 2 choosing From the hetero atom of N, O or S.
18. compound described in any one of -17 or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: ring A is selected from
19. compound described in any one of -18 or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: every A R2a、R2b、R3aAnd R3bIndependently selected from-H ,-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkyl or- C1-3Alkoxy.
20. compound according to claim 19 or its pharmaceutically acceptable salt, it is characterised in that: each R2a、R2b、 R3aAnd R3bIndependently selected from-H ,-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2, carboxyl, methyl, ethyl, propyl, isopropyl, Methoxyl group, ethyoxyl, propoxyl group, isopropoxy.
21. compound described in 9 or 20 or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: R2aAnd R2bPoint It is not independently-H or methyl, and R3aAnd R3bIt is separately-H.
22. compound described in any one of -21 or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: every A R6Independently selected from-H ,-F ,-Cl ,-Br ,-NR6aR6b,-CN ,-OH, oxo base ,=O, carboxyl ,-C1-3Alkoxy ,-C1-4 Alkyl ,-C1-3Alkenyl-NR6aR6b、-C1-3Alkenyl-O-C1-3Alkyl ,-C1-3Alkenyl-CO-OR6a、-C1-3Alkenyl-C5-6Heterocycle ,- C1-3Alkenyl-C5-6Heteroaryl ,-C1-3Alkenyl-CO-NR6aR6b、-C1-3Alkenyl ,-NR6a-CO-NR6aR6b、-CO-NR6aR6b、-CO- CO-NR6aR6b、-CO-C1-3Alkyl ,-CO-NR6a-C5-6Heterocycle ,-CO-C5-6Heterocycle ,-O-C5-6Carbocylic radical ,-O-C5-6Heterocycle Base ,-NR6a-CO-C1-3Alkyl ,-NR6a-CO-NR6aR6b、-NR6a-C1-3Alkenyl-NR6aR6b、-NR6a-C1-6Alkenyl-C3-6Heterocycle Base ,-NR6a-SO2C1-3Alkyl ,-S-C1-3Alkyl ,-SO-C1-3Alkyl ,-SO2NR6aR6b、-SO2C1-3Alkyl ,-PO (C1-3Alkyl )2、-PO(C1-3Alkoxy)2, 5 circle heterocyclic ring bases, 6 circle heterocyclic ring bases, 5 unit's heteroaryls or 6 unit's heteroaryls, and each R6Independently optionally Ground is replaced or do not replaced by 1,2 or 3 substituent group, and the substituent group is selected from-F ,-Cl, Br ,-NH2,-OH, carboxyl, oxo base, =O, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy；Each R6aAnd R6b? Independently selected from-H；-F；-Cl；Br；I；-NH2；-CN；-OH；-NO2；Carboxyl；-C1-3Alkoxy；-C1-3Alkyl or by 1,2 or 3 A-H, halogen ,-NH2,-the C that replaces of-CN or-OH1-3Alkyl；Or
Two adjacent R6It links together and the carbon atom being separately connected with them is formed together 6 yuan of aryl, 5 yuan of carbocylic radicals, 5 Unit's heteroaryl or 5 circle heterocyclic ring bases；And each heteroaryl or heterocycle includes 1 or 2 hetero atom for being selected from N, O or S；And Each ring system is independently optionally replaced by 1,2 or 3 substituent group or does not replace, and each substituent group is independent Ground is selected from-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2,=O, oxo base, carboxyl ,-CONH2、-PO(CH3)2, methyl, ethyl, Propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy.
23. compound described in any one of -19 or 22 or its pharmaceutically acceptable salt, feature exist according to claim 1 In: each R6Independently selected from-H；-F；-Cl；-Br；-NR6aR6b；-CN；-OH；Oxo base；=O；Carboxyl；Methoxyl group；Ethoxy Base；Propoxyl group；Isopropoxy；Methyl；Ethyl；Propyl；Isopropyl；Tert-butyl；-C1-3Alkenyl-NR6aR6b；-NR6a-CO- NR6aR6b；-CO-NR6aR6b；-CO-CO-NR6aR6b；- CO- methyl；- CO- ethyl；-CO-NR6a-C5-6Heterocycle；-CO-C5-6It is miscellaneous Ring group；-O-C5-6Carbocylic radical；-O-C5-6Heterocycle；-NR6a- CO- methyl；-NR6a-CO-NR6aR6b；-NR6a-C1-3Alkenyl- NR6aR6b；-NR6a-C1-6Alkenyl-C3-6Heterocycle；-NR6a-SO2Methyl；-NR6a-SO2Ethyl；- S- methyl；- S- ethyl；- SO- methyl；- SO- ethyl；-SO2NR6aR6b；-SO2Methyl；-SO2Ethyl；- PO (methyl)2；- PO (ethyl)2；- PO (methoxy Base)2；- PO (ethyoxyl)2；Contain 1,2 or 3 heteroatomic 5 circle heterocyclic ring base；Contain 1,2 or 3 heteroatomic 6 circle heterocyclic ring base； Contain 1,2 or 3 heteroatomic 5 unit's heteroaryl；Or containing 1,2 or 3 heteroatomic 6 unit's heteroaryl, the hetero atom is selected from N, O or S；Wherein each R6Independently optionally replaced by 1,2 or 3 substituent group or do not replace, the substituent group be selected from- F、-Cl、Br、-NH2,-OH, carboxyl, oxo base ,=O, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group Or isopropoxy；Each R6aAnd R6bIndependently selected from-H；-F；-Cl；Br；I；-NH2；-CN；-OH；-NO2；Carboxyl；Methyl； Ethyl；Methoxyl group；Ethyoxyl；By 1,2 or 3-H, F, Cl, Br ,-NH2, the methyl that replaces of-CN or-OH；Or by 1,2 or 3- H、F、Cl、Br、-NH2, the ethyl that replaces of-CN or-OH；Or
Two adjacent R6It links together and the carbon atom being separately connected with them is formed together phenyl, 5 yuan of carbocylic radicals, contains 1 2 N or O 5 unit's heteroaryls or 5 circle heterocyclic ring bases containing 1 or 2 N or O；And each ring system is independently optional Ground is replaced or do not replaced by 1,2 or 3 substituent group, and each substituent group is independently selected from-F ,-Cl ,-Br ,-NH2、- CN、-OH、-NO2,=O, oxo base, carboxyl ,-CONH2、-PO(CH3)2, methyl, ethyl, propyl, isopropyl, methoxyl group, ethoxy Base, propoxyl group or isopropoxy.
24. compound described in any one of -23 or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: every A R6Independently selected from-F ,-Cl ,-Br ,=O ,-OH ,-CN ,-NH2、-SCH3、-SOCH3、- SO2CH3、-PO(CH3)2、-PO(OC2H5)2、-NHSO2CH3、-C(O)NH2, methyl, ethyl, isopropyl, methoxyl group, ethyoxyl, =O, oxo base ,-OH ,-CN ,-NH2、-Cl、-Br、-CF3、-OCF3、-SO2NH2、-SO2CH3、-CH2NH2、-SCH3、 -NHCOCH3、-NHCONHCH3、Or
Two adjacent R6It links together and the carbon atom being separately connected with them is formed together
25. compound described in any one of -24 or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: institute Stating compound is formula II compound represented:
It is characterized by:
R3Selected from-H or-NH2；
Each R4aOr R4bIndependently selected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl or substituted or unsubstituted-C1-3 Alkyl；Or
R4aAnd R4bC=O, C=NH or C=N-OH are formed together with the carbon atom that they connect jointly；
P is 0,1,2 or 3；
Each R5aOr R5bIndependently selected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl or substituted or unsubstituted-C1-3 Alkyl；Or
R5aAnd R5b3-5 circle heterocyclic ring base is formed together with the carbon atom that they connect jointly；And each heterocycle is independently Optionally replaced by 1,2 or 3 substituent group or do not replace, the substituent group is selected from-H, halogen ,-NH2,-CN or-OH；
Q is 0,1,2,3 or 4；
Ring A is 3-6 member carbocyclic ring, 3-6 circle heterocyclic ring, benzene or 5-6 member hetero-aromatic ring；
Indicate singly-bound or double bond；Wherein,
I) whenWhen indicating singly-bound, Y2It is CR2aOr N, and Y3It is CH or N；Or
Ii) whenWhen indicating double bond, Y2It is C, and Y3It is C；
R2aSelected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl or substituted or unsubstituted-C1-3Alkyl；
Each R6Independently selected from-H, halogen ,-NR6aR6b、-CN、-OH、-NO2,=O, carboxyl ,-C1-3Alkoxy ,-C1-4Alkane Base ,-CO-NR6aR6b、-CO-CO-NR6aR6b、-CO-C1-3Alkyl ,-CO-NR6a-C3-10Heterocycle ,-CO-NR6a-C3-10Heterocycle Base ,-CO-C4-6Heterocycle ,-O-C3-6Carbocylic radical ,-O-C3-6Heterocycle ,-NR6a-CO-C1-3Alkyl ,-NR6a-CO-NR6aR6b、- NR6a-CO-C5-6Heteroaryl ,-NR6a-SO2C1-3Alkyl ,-S-C1-3Alkyl ,-SONR6aR6b、-SO2NR6aR6b、-SO-C1-3Alkyl ,- SO2-C1-3Alkyl ,-PO (C1-3Alkyl)2、-PO(C1-3Alkoxy)2、-C3-6Heterocycle or-C5-6Heteroaryl, wherein each R6? Independently optionally replaced by 1,2 or 3 substituent group or does not replace；And n is 0,1,2 or 3；Or
Two adjacent R6The carbon atom being separately connected with it that links together be formed together 6 yuan of aryl, 5 unit's heteroaryls, 6 yuan it is miscellaneous Aryl, C3-6Heterocycle or C3-6Carbocylic radical, each ring system are independently optionally replaced by 1,2 or 3 substituent group or not Replace；
Each R6aAnd R6bIndependently selected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl or substituted or unsubstituted-C1-3Alkane Base.
26. compound according to claim 25 or its pharmaceutically acceptable salt, it is characterised in that: each R5aOr R5bSolely On the spot it is selected from-H ,-Cl ,-Br ,-NH2,-OH, carboxyl, methyl, ethyl, methoxy or ethoxy；Or
R5aAnd R5bIt is formed together with the carbon atom that they connect jointlyAnd * C indicates the carbon atom and R5aAnd R5bConnection.
27. the compound according to claim 25 or 26 or its pharmaceutically acceptable salt, it is characterised in that: ring A is 6 yuan Phenyl, 3 circle heterocyclic ring bases, 4 circle heterocyclic ring bases, 5 circle heterocyclic ring bases, 6 circle heterocyclic ring bases, 5 unit's heteroaryls, 6 unit's heteroaryls, 9 unit's heteroaryls, 3 First carbocylic radical, 4 yuan of carbocylic radicals, 5 yuan of carbocylic radicals or 6 yuan of carbocylic radicals；And each heteroaryl independently includes 1 or 2 choosing From the hetero atom of N, O or S；Each heterocycle independently includes 1 or 2 hetero atom for being selected from N or O.
28. the compound according to any one of claim 25-27 or its pharmaceutically acceptable salt, it is characterised in that: Ring A is selected from
29. the compound according to any one of claim 25-28 or its pharmaceutically acceptable salt, it is characterised in that: R2aSelected from-H；-F；-Cl；-Br；-NH2；-CN；-OH；-NO2；Carboxyl；Methyl；Ethyl；Propyl；Isopropyl；Methoxyl group；Ethoxy Base；Propoxyl group；Isopropoxy；By-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2, carboxyl, methyl, ethyl, propyl, isopropyl, - the C that methoxyl group, ethyoxyl, propoxyl group or isopropoxy replace1-3Alkyl；Or by-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2、 - the C that carboxyl, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group or isopropoxy replace1-3Alkoxy.
30. the compound according to any one of claim 25-29 or its pharmaceutically acceptable salt, it is characterised in that: Y2 It is CH or N, and Y3It is CH or N.
31. the compound according to any one of claim 25-29 or its pharmaceutically acceptable salt, it is characterised in that: Y2 It is C, and Y3It is C.
32. the compound according to any one of claim 25-31 or its pharmaceutically acceptable salt, it is characterised in that: Each R6Independently selected from-H ,-F ,-Cl ,-Br ,-NH2、-N(CH3)2,-CN ,-OH, oxo base ,=O, carboxyl, methoxyl group, Ethyoxyl, methyl, ethyl, isopropyl, tert-butyl ,-CH2NH2、-CH2CH2OCH3、-CH2-COOH、-CH2NH-CONHCH3、- CONH2、-CON(CH3)2、-CONHOH、-CONHCH2CH2OH、-CO-CON(CH3)2、-COCH3、-SO2NH2、-SO2CH3、- SCH3、-SOCH3、-PO(CH3)2、-PO(OC2H5)2、-NHSO2CH3、-NH-COCH3、-NH-CONHCH3、
Wherein each R6Independently optionally by 1,2 or 3-F ,-Cl ,-NH2,-OH, oxo base ,=O, methyl, ethyl or propyl Replace or does not replace.
33. the compound according to any one of claim 25-32 or its pharmaceutically acceptable salt, it is characterised in that: Each R6aAnd R6bIndependently selected from-H ,-Cl ,-Br ,-NH2,-OH, carboxyl, methyl, ethyl, methoxyl group, ethyoxyl, the third oxygen The methyl that base, isopropoxy, quilt-OH replace or the ethyl replaced by-OH.
34. compound described in any one of -24 or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: institute Stating compound is formula II I compound represented:
It is characterized by:
Each R1And R2Independently selected from-H ,-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkoxy or-C1-3 Alkyl；Or
R1R adjacent thereto2It connects and the carbon atom being separately connected with them is formed together comprising 1,2 or 3 selected from the miscellaneous original of N or O 5 circle heterocyclic rings of son, and 5 circle heterocyclic ring is optionally by 1,2 or 3 halogen ,-NH2、-CN、-OH、-NO2, carboxyl, oxo base ,= O、-CONH2Or-CO-C1-3Alkyl replaces or does not replace；
Y1Selected from N or CH；
R3Selected from-H or-NH2；
Ring B be selected from phenyl ring, 5 yuan of hetero-aromatic rings, 6 yuan of hetero-aromatic rings, 3 yuan of carbocyclic rings, 4 yuan of carbocyclic rings, 5 yuan of carbocyclic rings, 6 yuan of carbocyclic rings, 5 circle heterocyclic rings or 6 circle heterocyclic rings, and each heteroaryl ring group or heterocycle is independently optionally selected from the hetero atom of N or O comprising 1 or 2；
I) whenWhen indicating singly-bound, Y3It is CH or N；Or
Ii) whenWhen indicating double bond, Y3It is C；
R7Selected from halogen ,-NH2、-CN、-OH、-NO2, carboxyl, oxo base ,=O ,-CONH2、-NH-COCH3, it is substituted or unsubstituted - C1-6Alkoxy or substituted or unsubstituted-C1-6Alkyl；And m is 0,1 or 2.
35. compound according to claim 34 or its pharmaceutically acceptable salt, it is characterised in that: R1Adjacent thereto R2It connects and the carbon atom being separately connected with them is formed togetherAnd the ring system independently optionally by 1 or 2- F or-COCH3Replace or does not replace.
36. the compound according to claim 34 or 35 or its pharmaceutically acceptable salt, it is characterised in that: ring B is selected from
37. the compound according to any one of claim 34-36 or its pharmaceutically acceptable salt, it is characterised in that: R7 Selected from-NH2,-CN, oxo base ,=O ,-CONH2、-NH-COCH3, methyl or methoxy.
38. any one of -24 compound or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: institute Stating compound is structural formula IV compound represented:
It is characterized by:
Each R1And R2Independently selected from-H；-F；-Cl；-Br；-NH2；-CN；-OH；-NO2；Carboxyl；-NHC1-3Alkyl；-N (C1-3Alkyl)2；-C1-3Alkoxy；-C1-3- the C that alkyl or 1,2 or 3 halogen replace1-3Alkyl；Or
R1R adjacent thereto2It connects and the carbon atom being separately connected with them is formed together 6 yuan of carbocyclic rings, 6 yuan of aryl, comprising 1 or 2 It is a to be selected from heteroatomic 6 circle heterocyclic ring of N or O, and each ring system selected from heteroatomic 5 circle heterocyclic ring of N or O or comprising 1 or 2 Independently optionally by 1,2 or 3 halogen ,-NH2、-CN、-OH、-NO2, carboxyl, oxo base ,=O ,-CONH2、-C1-3Alcoxyl Base ,-C1-3Alkyl or-CO-C1-3Alkyl replaces or does not replace；
Y1It is N or CH；
R3It is-H or-NH2；
Ring D is selected from 6 yuan of aryl, 5 unit's heteroaryls, 6 unit's heteroaryls, 3 yuan of carbocylic radicals, 4 yuan of carbocylic radicals, 5 yuan of carbocylic radicals, 6 yuan of carbocyclic rings Base, 3 circle heterocyclic ring bases, 4 circle heterocyclic ring bases, 5 circle heterocyclic ring bases or 6 circle heterocyclic ring bases, each heteroaryl or heterocycle are independently The hetero atom of N, O or S are optionally selected from comprising 1 or 2；
Indicate singly-bound or double bond；And
I) whenWhen indicating singly-bound, Y2It is CR2aOr N, and Y3It is CR3aOr N；Or
Ii) whenWhen indicating double bond, Y2And Y3It is C；
Each R2aAnd R3aIndependently selected from-H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkoxy or-C1-3Alkane Base；
R8Selected from halogen ,-NH2、-CN、-OH、-NO2, carboxyl, oxo base ,=O, C1-4Alkyl, C1-3Alkoxy ,-SO2NR8aR8b、- S-C1-3Alkyl ,-SO-C1-3Alkyl ,-SO2-C1-3Alkyl ,-CO-NR8aR8b、-PO(C1-3Alkyl)2、-PO(C1-3Alkoxy)2、- NR8a-CO-C1-3Alkyl ,-NR8a-CO-NR8aR8b,-O-5 member carbocylic radical ,-O-5 circle heterocyclic ring base ,-O-6 circle heterocyclic ring base, 5 circle heterocyclic rings Base, 6 circle heterocyclic ring bases, 5 unit's heteroaryls or 6 unit's heteroaryls；And each R8Halogen, first optionally independently are selected from by 1,2 or 3 Base, ethyl, methoxyl group, oxo base ,-NH2,-CN or-OH substituent group replace or do not replace；And t is 0,1,2 or 3；Or
Two adjacent R8The carbon atom being separately connected with it that links together is formed together 6 yuan of aryl or 5 unit's heteroaryls, and every A ring system is independently optionally substituted or does not replace；
Each R8aAnd R8bIndependently selected from H, halogen ,-NH2、-CN、-OH、-NO2, carboxyl ,-C1-3Alkoxy or-C1-3Alkyl.
39. the compound according to claim 38 or its pharmaceutically acceptable salt, it is characterised in that: each R1And R2? Independently selected from-H ,-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2、-CF3, carboxyl ,-NHCH3、-N(CH3)2, methoxyl group, ethoxy Base, methyl or ethyl；Or
R1R adjacent thereto2It connects and the carbon atom being separately connected with them is formed together 6 yuan of carbocyclic rings, 6 yuan of aryl, comprising 1 The heteroatomic 5 yuan of hetero-aromatic rings of N or O are selected from selected from the heteroatomic 5 circle heterocyclic ring base of N or O or including 1；And each ring system - F ,-Cl ,-Br ,-NH optionally independently are selected from by 1,2 or 32、-CN、-OH、-NO2, carboxyl, oxo base ,=O ,- CONH2, methoxyl group, ethyoxyl, methyl, ethyl ,-CO- methyl or-CO- ethyl substituent group replace or do not replace.
40. the compound according to claim 38 or 39 or its pharmaceutically acceptable salt, it is characterised in that: each R1With R2Independently selected from-H ,-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2、-CF3, carboxyl ,-NHCH3、-N(CH3)2, methoxyl group, Ethyoxyl, methyl or ethyl；Or
R1R adjacent thereto2It connects and the carbon atom being separately connected with them is formed together And the ring system is independently optionally selected from-F or-COCH by 1,2 or 33Substituent group replace or do not replace.
41. the compound according to any one of claim 38-40 or its pharmaceutically acceptable salt, it is characterised in that: Ring D is selected from
42. the compound according to any one of claim 38-41 or its pharmaceutically acceptable salt, it is characterised in that: Each R2aAnd R3aIndependently selected from-H, methyl or methoxy.
43. the compound according to any one of claim 38-42 or its pharmaceutically acceptable salt, it is characterised in that: R8 Selected from-F ,-Cl ,-Br ,-NH2、-CN、-OH、-NO2, carboxyl, oxo base ,=O, methyl, ethyl, propyl, isopropyl, tert-butyl, Methoxyl group, ethyoxyl, propoxyl group, isopropoxy ,-CO- methyl ,-SO2NR8aR8b,-S- methyl ,-S- ethyl ,-SO- methyl ,- SO- ethyl ,-SO2Methyl ,-SO2Ethyl ,-CO-C3-6Heterocycle ,-CO-NR8aR8b,-PO (methyl)2,-PO (ethyl)2、-PO (methoxyl group)2,-PO (ethyoxyl)2、-NR8a- CO- methyl ,-NR8a- CO- ethyl ,-NR8a-CO-NR8aR8b、-NR8a-SO2First Base ,-O-5 member carbocylic radical ,-O-5 circle heterocyclic ring base ,-O-6 circle heterocyclic ring base, 5 circle heterocyclic ring bases, 6 circle heterocyclic ring bases, 5 unit's heteroaryls or 6 yuan Heteroaryl, each heterocycle or heteroaryl contain 1 or 2 hetero atom for being selected from O, N or S；Each R8Independently optionally Ground is selected from-F ,-Cl ,-Br ,-NH by 1,2 or 32,-CN ,-OH, oxo base ,=O, methoxyl group, ethyoxyl, methyl or ethyl Substituent group replaces or does not replace.
44. the compound according to any one of claim 38-43 or its pharmaceutically acceptable salt, it is characterised in that: R8 Selected from-F ,-Cl ,-Br ,-NH2,-CN ,-OH, carboxyl, oxo base ,=O, methyl, ethyl, isopropyl, tert-butyl, CF3, methoxy Base ,-SOCH3、-SO2CH3、-SCH3、P(O)(CH3)2、P(O)(OC2H5)2、NHS(O)2CH3、--CONH2、-NH-COCH3、-NH- CONHCH3、-NH-COCH3、 Or
2 R8CompositionOr phenyl ring.
45. compound described in any one of -44 or its pharmaceutically acceptable salt according to claim 1, it is characterised in that: institute Compound is stated to be selected from
46. a kind of pharmaceutical composition, comprising compound described in any one of at least one claim 1-45 or its pharmaceutically Acceptable salt, and at least one pharmaceutically acceptable auxiliary material.
47. pharmaceutical composition according to claim 46, it is characterised in that: the compound or its is pharmaceutically acceptable The weight ratio of salt and the auxiliary material is 0.0001~10.
48. compound described in any one of the pharmaceutical composition according to claim 46 or 47 or claim 1-45 is used In the purposes for preparing drug.
49. purposes according to claim 48, it is characterised in that: the drug is for treating, preventing or preventing by SHP2 The disease or discomfort that activity mediates.
50. the purposes according to claim 48 or 49, it is characterised in that: the disease or discomfort mediated by SHP2 activity It is cancer, metastasis of cancer, cardiovascular disease, immunologic derangement, fibrosis or visual disorders.
51. the purposes according to any one of claim 48-50, it is characterised in that: the disease mediated by SHP2 activity Disease uncomfortable is selected from one or more following illnesss: Noonan syndrome, leopard syndrome, juvenile myelomonocyte leukaemia, Neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute myelogenous leukemia, breast cancer, esophageal tumor, lung cancer, Colon cancer, head cancer, gastric cancer, lymthoma, spongioblastoma, gastric cancer, cancer of pancreas and combinations thereof.
CN201810440520.2A 2018-05-09 2018-05-09 It can be used as the new type heterocycle derivative of SHP2 inhibitor Pending CN110143949A (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CN201810440520.2A CN110143949A (en) 2018-05-09 2018-05-09 It can be used as the new type heterocycle derivative of SHP2 inhibitor
CN202211429905.1A CN116003321A (en) 2018-05-09 2018-05-09 Novel heterocyclic derivatives useful as SHP2 inhibitors
CN202211429954.5A CN115721648A (en) 2018-05-09 2018-05-09 Novel heterocyclic derivatives useful as SHP2 inhibitors
CN202011087825.3A CN112174935B (en) 2018-05-09 2018-05-09 Heterocyclic derivatives useful as SHP2 inhibitors
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US11840536B2 (en) 2016-05-31 2023-12-12 Board Of Regents, The University Of Texas System Heterocyclic inhibitors of PTPN11
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WO2023072191A1 (en) * 2021-10-27 2023-05-04 正大天晴药业集团股份有限公司 Pyrrolopyrazole spiro compound
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
CN115611869A (en) * 2022-05-11 2023-01-17 山东大学 Heterocyclic pyrazine derivative and application thereof in preparation of SHP2 inhibitor
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors

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