CN114230512A - Aromatic vinyl compound, preparation method thereof, intermediate, pharmaceutical composition and application thereof - Google Patents

Aromatic vinyl compound, preparation method thereof, intermediate, pharmaceutical composition and application thereof Download PDF

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CN114230512A
CN114230512A CN202110995765.3A CN202110995765A CN114230512A CN 114230512 A CN114230512 A CN 114230512A CN 202110995765 A CN202110995765 A CN 202110995765A CN 114230512 A CN114230512 A CN 114230512A
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substituted
alkyl
deuterium
alkoxy
independently
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王玉光
吴添智
蔡森林
何敏
吴新亮
张顺利
张农
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Guangzhou Maxinovel Pharmaceuticals Co Ltd
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Guangzhou Maxinovel Pharmaceuticals Co Ltd
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Priority to TW110133424A priority Critical patent/TW202214568A/en
Priority to EP21865980.3A priority patent/EP4212511A1/en
Priority to US18/042,599 priority patent/US20230331675A1/en
Priority to PCT/CN2021/117066 priority patent/WO2022052926A1/en
Priority to JP2023515809A priority patent/JP2023540612A/en
Publication of CN114230512A publication Critical patent/CN114230512A/en
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Abstract

The invention discloses an aromatic vinyl compound, a preparation method thereof, an intermediate, a pharmaceutical composition and application thereof. The aromatic vinyl compound disclosed by the invention is shown as a formula I-0. The aromatic vinyl compound has an obvious inhibiting effect on PD-1/PD-L1, has higher drug peak concentration, larger drug time curve area and better oral bioavailability, is a very effective small molecule inhibitor for PD-1/PD-L1, and can effectively relieve or treat related diseases such as cancer.

Description

Aromatic vinyl compound, preparation method thereof, intermediate, pharmaceutical composition and application thereof
Technical Field
The invention relates to an aromatic vinyl compound, a preparation method thereof, an intermediate, a pharmaceutical composition and application thereof.
Background
PD-1(programmed death 1) programmed death receptor 1, an important immunosuppressive molecule. It is a member of the CD28 superfamily, originally cloned from the apoptotic mouse T cell hybridoma 2B 4.11. The immunoregulation taking PD-1 as a target point has important significance for resisting tumor, infection, autoimmune disease, organ transplantation survival and the like. The ligand PD-L1 can also be used as a target, and the corresponding antibody can also play the same role.
PD-1/PD-L1 exerts a negative immune regulation effect. When PD-1 on the surface of the cell is coupled with PD-L1, Tyr of an Immunoreceptor Tyrosine-based switch motif (ITSM) structure domain of a T cell cytoplasmic region can be phosphorylated, and then the phosphorylated Tyr can recruit phosphatase protein tyrosinase 2 and protein tyrosinase 1, so that activation of extracellular signal-regulated kinase can be blocked, activation of phosphatidylinositol 3-kinase (PI3K) and serine-threonine protein kinase (Akt) can be blocked, and T lymphocyte proliferation and secretion of related cytokines can be finally inhibited. PD-1/PD-L1 signals inhibit T cell activation and proliferation, while the secretion of the cytokines interleukin 2(IL2), interferon gamma and IL-10 is also reduced (Eur. J. Immunol.,2002,32(3), 634-643.). In addition, the PD-1/PD-L1 signal has similar immune function to the B cell as the T cell, when PD-1 and B cell antigen receptor are cross-linked, PD-1 cytoplasm region acts with tyrosinase containing protein tyrosinase 2 binding site, finally blocking the activation of the B cell. The role of the immune negative regulator PD-1/PD-L1 in tumor immune escape is increasingly attracting attention. A large number of researches prove that the surface PD-L1 of the tumor cell in the tumor microenvironment is increased, and simultaneously, the PD-L1 is combined with the PD-1 on the activated T cell to transmit a negative regulation signal, so that the apoptosis or the immunity incapability of the tumor antigen specific T cell is caused, the immune response is inhibited, and the escape of the tumor cell is promoted.
PD-1/PD-L1 antibody inhibitors that are currently on the market are Nivolumab of BMS (2014), Lambolizumab of Merck (2014), and Atezolizumab of Roche (2016). Among the PD-1/PD-L1 antibody inhibitors in the study were Pidilizumab from Cure Tech, AMP-224 from GSK, and Alixican MEDI-4736. These are biological macromolecules, and small molecule PD-1/PD-L1 inhibitors are currently in the early development stage, small molecule PD-1/PD-L1 inhibitors of the Curis polypeptides, AC-170(WO2012168944, WO 033299, WO2015033301, WO2015036927, WO2015044900), just before entering clinical stage I, of the BMS benzyl phenyl ethers (WO2015034820, WO2015160641, WO2017066227, WO2018009505, WO2018044963, WO2018118848), and in the early clinical research stage, Incyte also makes a series of small molecule PD-1/PD-L1 inhibitors (WO2017070089, WO2017087777, WO2017106634, WO2017112730, WO 20192961, WO 20172464, WO 2017272976, WO 2012280137783789, WO 201192443, WO 20119281192814463, WO 20119281818181818163, WO 20119281810563, and WO 20172976, WO 20180223789, WO 201192811928180. Compared with biological macromolecules, the small molecular compound can penetrate through cell membranes to act on intracellular targets, so that the application range is wide. And secondly, the micromolecules are chemically modified to have good bioavailability and compliance, and decomposition and inactivation of enzymes in the digestive intestinal tract are effectively avoided. Finally, the research on small molecules is well established in various aspects such as production process, dosage form design and administration mode.
At present, reports that biphenyl compounds as small molecular PD-1/PD-L1 inhibitors are successfully listed in the prior art do not appear, and the current situation needs to be solved urgently.
Disclosure of Invention
The invention aims to provide an aromatic vinyl compound completely different from the prior art, a preparation method, an intermediate, a pharmaceutical composition and application thereof. The aromatic vinyl compound has an obvious inhibiting effect on PD-1/PD-L1, has higher drug peak concentration, larger drug time curve area and better oral bioavailability, is a very effective small molecule inhibitor for PD-1/PD-L1, and can effectively relieve or treat related diseases such as cancer.
(in the following invention, we mark the place of this change with blue font and please know.)
The invention provides an aromatic vinyl compound shown as a formula I-0, a tautomer, a stereoisomer, a racemate or an isotope derivative thereof, or pharmaceutically acceptable salts of the aromatic vinyl compound, the tautomer, the stereoisomer, the racemate or the isotope derivative thereof (which refer to the aromatic vinyl compound shown as the formula I-0, the tautomer, the stereoisomer, the racemate or the isotope derivative thereof);
Figure BDA0003234055820000021
wherein:
R1is cyano, C1-C4Alkyl, C substituted by one or more deuterium1-C4Alkyl, halogen, C substituted by one or more halogens1-C4An alkyl group;
R3、R6、R12、R13and R14Independently is H or deuterium;
R2is hydroxy, halogen, C1-C4Alkyl, by one or more RA-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RA-2Substituted C1-C6An alkoxy group;
RA-1and RA-2Independently is deuterium, hydroxy, halogen, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C4Alkoxy radical,
Figure BDA0003234055820000022
RA-1-1Is C1-C4Alkyl or C substituted by one or more deuterium1-C4An alkyl group; rA-1-2And RA-1-3Independently of one another H, deuterium, C1-C4Alkyl or by one or more RA-1-1-1Substituted C1-C4Alkyl radical, said RA -1-1-1Is deuterium, hydroxy or COORA-1-1-2；
R4And R5Independently of one another, hydroxy, halogen, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group;
RB-1and RB-2Independently is deuterium, hydroxy, halogen, cyano, C6-C10Aryl radicals, substituted by one or more RB-1-3Substituted C6-C10Aryl, 3-12 membered heteroaryl, substituted with one or more RB-1-4Substituted 3-12 membered heteroaryl, C1-C4Alkoxy, C substituted by one or more deuterium1-C4Alkoxy radical,
Figure BDA0003234055820000023
In the heteroaryl, the heteroatom is selected from one or more of N, O and S, and the number of the heteroatom is 1-4;
RB-1-3and RB-1-4Independently of one another is cyano, halogen, C1-C4Alkyl or C1-C4An alkoxy group;
RB-1-1and RB-1-2Independently of one another H, deuterium, C1-C4Alkyl or by one or more RB-1-1-1Substituted C1-C4Alkyl radical, said RB-1-1-1Is deuterium, hydroxy or COORB-1-1-5；
Or, RB-1-1、RB-1-2And the nitrogen atom to which they are attached together form a 5-to 7-membered carbocyclic heterocyclic ring or are substituted by one or more RB-1-1-2Substituted carbon heterocyclic ring, wherein in the carbon heterocyclic ring, heteroatoms are selected from one or more of N, O and S, the number of heteroatoms is 1-4, and R isB-1-1-2Is deuterium, C1-C4Alkyl, C substituted by one or more deuterium1-C4Alkyl, COORB-1-1-6Or C1-C4An amide group;
RA-1-1-2、RB-1-1-5and RB-1-1-6Independently of one another H, deuterium, C1-C4Alkyl or C substituted by one or more deuterium1-C4An alkyl group;
R7、R8、R9、R10and R11Independently is H or deuterium;
R15and R16Independently H, deuterium or halogen.
In some embodiments, in the aromatic vinyl compound of formula I-0, RB-1And RB-2Independently is deuterium, hydroxy, halogen, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C4Alkoxy radical,
Figure BDA0003234055820000031
The other variables are defined as in any aspect of the invention.
The invention provides an aromatic vinyl compound shown as a formula I, a tautomer, a stereoisomer, a racemate or an isotope derivative thereof, or pharmaceutically acceptable salts of the aromatic vinyl compound, the tautomer, the stereoisomer, the racemate or the isotope derivative thereof (which refer to the aromatic vinyl compound shown as the formula I, the tautomer, the stereoisomer, the racemate or the isotope derivative thereof);
Figure BDA0003234055820000032
wherein:
R1is cyano, C1-C4Alkyl, C substituted by one or more deuterium1-C4An alkyl group;
R3、R6、R12、R13and R14Independently is H or deuterium;
R2is hydroxy, halogen, C1-C4Alkyl, by one or more RA-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RA-2Substituted C1-C6An alkoxy group;
RA-1and RA-2Independently is deuterium, hydroxy, halogen, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C4Alkoxy radical,
Figure BDA0003234055820000033
RA-1-1Is C1-C4Alkyl or C substituted by one or more deuterium1-C4An alkyl group; rA-1-2And RA-1-3Independently of one another H, deuterium, C1-C4Alkyl or by one or more RA-1-1-1Substituted C1-C4Alkyl radical, said RA -1-1-1Is deuterium, hydroxy or COORA-1-1-2；
R4And R5Independently of one another, hydroxy, halogen, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group;
RB-1and RB-2Independently is deuterium, hydroxy, halogen, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C4Alkoxy radical,
Figure BDA0003234055820000041
RB-1-1And RB-1-2Independently of one another H, deuterium, C1-C4Alkyl or by one or more RB-1-1-1Substituted C1-C4Alkyl radical, said RB-1-1-1 is deuterium, hydroxy or COORB-1-1-5；
Or, RB-1-1、RB-1-2And the nitrogen atom to which they are attached together form a 5-to 7-membered carbocyclic heterocyclic ring or are substituted by one or more RB-1-1-2Substituted carbon heterocyclic ring, wherein in the carbon heterocyclic ring, heteroatoms are selected from one or more of N, O and S, the number of heteroatoms is 1-4, and R isB-1-1-2Is deuterium, C1-C4Alkyl, C substituted by one or more deuterium1-C4Alkyl, COORB-1-1-6Or C1-C4An amide group;
RA-1-1-2、RB-1-1-5and RB-1-1-6Independently of one another H, deuterium, C1-C4Alkyl or C substituted by one or more deuterium1-C4An alkyl group;
R7、R8、R9、R10and R11Independently is H or deuterium.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is1Is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl, and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is1Being substituted by one or more deuteriumC1-C4When alkyl, said C substituted by one or more deuterium1-C4Alkyl is C substituted by one or more deuterium1-C2Alkyl groups, such as a mono-deuterated methyl, a di-deuterated methyl, a tri-deuterated methyl, a mono-deuterated ethyl, a di-deuterated ethyl, a tri-deuterated ethyl, a tetra-deuterated ethyl, or a pentadeuterated ethyl, and, for example, a tri-deuterated methyl, the other variables being as defined in any of the schemes herein.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is1In the case of halogen, the halogen is fluorine, chlorine, bromine or iodine, for example chlorine, and the other variables are as defined in any of the embodiments of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is1Is C substituted by one or more halogens1-C4When alkyl, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine, and the other variables are as defined in any of the embodiments of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is1Is C substituted by one or more halogens1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl, and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is2In the case of halogen, the halogen is fluorine, chlorine, bromine or iodine, for example chlorine, and the other variables are as defined in any of the embodiments of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is2Is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl, and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is2Is represented by one or more RA-1Substituted C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl, and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is2Is represented by one or more RA-1Substituted C1-C4When it is alkyl, each RA-1The plurality is 2,3, 4 or 5, and the other variables are as defined in any aspect of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is2Is C1-C6At alkoxy, the C1-C6Alkoxy is C1-C4Alkoxy, for example methoxy, ethoxy, n-propoxy or n-butoxy, and further for example methoxy, the other variables being as defined in any of the schemes of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is2Is represented by one or more RA-2Substituted C1-C6At alkoxy, the C1-C6Alkoxy is C1-C4Alkoxy, for example methoxy, ethoxy, n-propoxy or n-butoxy, and the other variables are as defined in any of the schemes herein.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is2Is represented by one or more RA-2Substituted C1-C6At alkoxy, each RA-2The plurality is 2,3, 4 or 5, and the other variables are as defined in any aspect of the invention.
In some embodiments, the aryl group is of formula I-0 or IIn the styryl compounds, when R isA-1And RA-2Independently halogen, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine, and the other variables are as defined in any of the embodiments of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isA-1And RA-2Independently is C1-C4At alkoxy, the C1-C4Alkoxy is methoxy, ethoxy, n-propoxy or n-butoxy, for example methoxy, and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isA-1And RA-2Independently C substituted by one or more deuterium1-C4Alkoxy, said C substituted by one or more deuterium1-C4Alkoxy is C substituted by one or more deuterium1-C2Alkoxy, such as mono-deuterium methoxy, di-deuterium methoxy, tri-deuterium methoxy, mono-deuterium ethoxy, di-deuterium ethoxy, tri-deuterium ethoxy, tetra-deuterium ethoxy or penta-deuterium ethoxy, such as tri-deuterium methoxy, the other variables being as defined in any of the schemes herein.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isA-1-1Is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl, and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isA-1-1Is C substituted by one or more deuterium1-C4When alkyl, said C substituted by one or more deuterium1-C4Alkyl is C substituted by one or more deuterium1-C2Alkyl radicals, e.g. mono-deuteromethyl, di-deuteromethyl, tri-deuteromethyl, mono-deuteroethyl, di-deuteroethyl, tri-deuteroethyl, tetra-deuteroethyl or penta-deuteroethylDeuterated ethyl, and further, for example, trideuteromethyl, the other variables being as defined in any of the schemes of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isA-1-2And RA -1-3Independently is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl, ethyl or isopropyl, and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isA-1-2And RA -1-3Independently by one or more RA-1-1-1Substituted C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl, ethyl or isopropyl, and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isA-1-2And RA -1-3Independently by one or more RA-1-1-1Substituted C1-C4When it is alkyl, each RA-1-1-1The plurality is 2,3, 4 or 5, and the other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is4And R5Independently halogen, the halogen is fluorine, chlorine, bromine or iodine, for example chlorine, and the other variables are as defined in any of the embodiments of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is4And R5Independently is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for exampleSuch as methyl, and the other variables are as defined in any of the embodiments of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is4And R5Independently by one or more RB-1Substituted C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl, and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is4And R5Independently by one or more RB-1Substituted C1-C4When it is alkyl, each RB-1The plurality is 2,3, 4 or 5, which are the same or different, and the other variables are as defined in any aspect of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is4And R5Independently is C1-C6At alkoxy, the C1-C6Alkoxy is C1-C4Alkoxy, for example methoxy, ethoxy, n-propoxy or n-butoxy, and further for example methoxy, the other variables being as defined in any of the schemes of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is4And R5Independently by one or more RB-2Substituted C1-C6At alkoxy, the C1-C6Alkoxy is C1-C4Alkoxy, for example methoxy, ethoxy, n-propoxy or n-butoxy, and the other variables are as defined in any of the schemes herein.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R is4And R5Independently by one or more RB-2Substituted C1-C6At alkoxy, each RB-2The plurality is 2,3, 4 or 5, and the other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1And RB-2When independently halogen, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine, and the other variables are as defined in any of the embodiments of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1And RB-2Is independently C6-C10Aryl is said to C6-C10Aryl is phenyl and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1And RB-2Is independently one or more RB-1-3Substituted C6-C10Aryl is said to C6-C10Aryl is phenyl and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1And RB-2Is independently one or more RB-1-3Substituted C6-C10At aryl radical, each RB-1-3The plurality is 2,3, 4 or 5, and the other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1And RB-2When independently a 3-12 membered heteroaryl, the 3-12 membered heteroaryl is a 5-7 membered heteroaryl, and the other variables are as defined in any of the embodiments of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1And RB-2When independently is a 3-12 membered heteroaryl, the heteroatom of said 3-12 membered heteroaryl is selected fromFrom N, the number of heteroatoms is 1 and the other variables are as defined in any of the embodiments of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1And RB-2Is independently one or more RB-1-4When substituted with a 3-12 membered heteroaryl group, the 3-12 membered heteroaryl group is a 5-7 membered heteroaryl group, and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1And RB-2Is independently one or more RB-1-4In the case of a substituted 3-12 membered heteroaryl group, the heteroatom of the 3-12 membered heteroaryl group is selected from N, the number of heteroatoms is 1, and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1And RB-2Is independently one or more RB-1-4When substituted with 3-12 membered heteroaryl, each RB-1-4The plurality is 2,3, 4 or 5, and the other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1-3And RB -1-4Independently halogen, said halogen being fluorine, chlorine, bromine or iodine, for example fluorine or iodine, the other variables being as defined in any of the embodiments of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1And RB-2Is independently C1-C4Alkoxy radical, said C1-C4Alkoxy is methoxy, ethoxy, n-propoxy or n-butoxy, for example methoxy, and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1And RB-2Is independently a quiltOne or more deuterium substituted C1-C4Alkoxy, said C substituted by one or more deuterium1-C4Alkoxy is C substituted by one or more deuterium1-C2Alkoxy, such as mono-deuterium methoxy, di-deuterium methoxy, tri-deuterium methoxy, mono-deuterium ethoxy, di-deuterium ethoxy, tri-deuterium ethoxy, tetra-deuterium ethoxy or penta-deuterium ethoxy, such as tri-deuterium methoxy, the other variables being as defined in any of the schemes herein.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1-1And RB -1-2Independently is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl, ethyl or isopropyl, and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1-1And RB -1-2Independently by one or more RB-1-1-1Substituted C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl, ethyl or isopropyl, and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1-1And RB -1-2Independently by one or more RB-1-1-1Substituted C1-C4When it is alkyl, each RB-1-1-1The plurality is 2,3, 4 or 5, and the other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1-1、RB -1-2And the nitrogen atom to which they are attached, together form a 5-to 7-membered carbon heterocyclic ring in whichThe heteroatoms are N and/or O and the other variables are as defined in any of the embodiments of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1-1、RB -1-2And the nitrogen atom to which they are attached, together form a 5-7 membered carbocyclic heterocyclic ring in which the number of heteroatoms is 1 or 2 and the other variables are as defined in any of the embodiments of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1-1、RB -1-2And the nitrogen atom to which they are attached together form a group consisting of one or more RB-1-1-2In the case of substituted carbocycles, the heteroatoms in the carbocycles are N and/or O, and the other variables are as defined in any of the embodiments of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1-1、RB -1-2And the nitrogen atom to which they are attached together form a group consisting of one or more RB-1-1-2In the case of substituted carbon heterocycles, the number of heteroatoms in the carbon heterocycle is 1 or 2, and the other variables are as defined in any of the embodiments of the invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isB-1-1、RB -1-2And the nitrogen atom to which they are attached together form a group consisting of one or more RB-1-1-2When substituted by a carbocyclic ring, each RB-1-1-2The plurality is 2,3, 4 or 5, and the other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compound represented by formula I-0 or I, when R isB-1-1-2Is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl, and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compound represented by formula I-0 or I, when R isB -1-1-2Is C substituted by one or more deuterium1-C4When alkyl, said C substituted by one or more deuterium1-C4Alkyl is C substituted by one or more deuterium1-C2Alkyl groups, such as a mono-deuterated methyl, a di-deuterated methyl, a tri-deuterated methyl, a mono-deuterated ethyl, a di-deuterated ethyl, a tri-deuterated ethyl, a tetra-deuterated ethyl, or a pentadeuterated ethyl, and, for example, a tri-deuterated methyl, the other variables being as defined in any of the schemes herein.
In some embodiments, in the aromatic vinyl compound represented by formula I-0 or I, when R isB -1-1-2Is C1-C4When it is an amide group, the C1-C4Amide is
Figure BDA0003234055820000081
RB-1-1-3And RB-1-1-4Independently of one another H, deuterium, C1-C4Alkyl or C substituted by one or more deuterium1-C4Alkyl radical, said C1-C4Alkyl is for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, said C being substituted by one or more deuterium1-C4Alkyl is for example trideuteromethyl, the other variables being as defined in any of the schemes of the present invention.
In some embodiments, in the aromatic vinyl compounds of formula I-0 or I, when R isA-1-1-2、RB -1-1-5And RB-1-1-6Independently is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl, and the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, the aromatic vinyl compound of formula I-0, when R is15And R16When independently halogen, the halogen is fluorine, chlorine, bromine or iodine, e.g. fluorine or bromineAnd the other variables are defined as in any of the aspects of the invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, R3、R6、R12、R13And R14Independently H and the other variables are as defined in any aspect of the invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, R2Is halogen, C1-C4Alkyl or by one or more RA-1Substituted C1-C4Alkyl, and other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RA-1And RA-2Independently is hydroxy, halogen, cyano, C1-C4Alkoxy radical,
Figure BDA0003234055820000082
The other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RA-1Is halogen or
Figure BDA0003234055820000083
The other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RA-1For halogen, the other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RA-1-1Is C1-C4Alkyl, and other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RA-1-2And RA-1-3Independently H or quiltOne or more RA-1-1-1 substituted C1-C4Alkyl, and other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RA-1-2And RA-1-3One of which is H and the other is substituted by one or more RA-1-1-1Substituted C1-C4Alkyl, and other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RA-1-1-2、RB -1-1-5And RB-1-1-6Independently is H or C1-C4Alkyl, and other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RA-1-1-2、RB -1-1-5And RB-1-1-6Independently H and the other variables are as defined in any aspect of the invention.
In some embodiments, the aromatic vinyl compound of formula I-0 or I is substituted with one or more RA-1-1-1Substituted C1-C4Alkyl is
Figure BDA0003234055820000091
The other variables are defined as in any aspect of the invention.
In some embodiments, the aromatic vinyl compound of formula I-0 or I is substituted with one or more RA-1-1-1Substituted C1-C4Alkyl is
Figure BDA0003234055820000092
The other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, R4And R5Independently of one another, halogen, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6Alkoxy, and other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RB-1And RB-2Independently is deuterium, hydroxy, cyano, C6-C10Aryl radicals, substituted by one or more RB-1-3Substituted C6-C10Aryl, 3-12 membered heteroaryl, substituted with one or more RB-1-4Substituted 3-12 membered heteroaryl, C1-C4Alkoxy, C substituted by one or more deuterium1-C4Alkoxy radical,
Figure BDA0003234055820000093
Figure BDA0003234055820000094
The other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RB-1And RB-2Independently is deuterium, hydroxy, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy radical,
Figure BDA0003234055820000095
The other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RB-1Is hydroxy, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy, or
Figure BDA0003234055820000096
The other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RB-1Is hydroxy or
Figure BDA0003234055820000101
The other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RB-2Is deuterium, cyano, hydroxy, C6-C10Aryl radicals, substituted by one or more RB-1-3Substituted C6-C10Aryl, 3-12 membered heteroaryl, substituted with one or more RB-1-4Substituted 3-12 membered heteroaryl or C1-C4Alkoxy, and other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RB-2Is deuterium, cyano, hydroxy or C1-C4Alkoxy, and other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RB-1-3And RB-1-4Independently cyano or halogen, and the other variables are as defined in any of the embodiments of the invention.
In some embodiments, the aromatic vinyl compound of formula I-0 or I is substituted with one or more RB-1-3Substituted C6-C10Aryl is
Figure BDA0003234055820000102
The other variables are defined as in any aspect of the invention.
In some embodiments, the aromatic vinyl compound of formula I-0 or I, wherein the 3-12 membered heteroaryl is
Figure BDA0003234055820000103
The other variables are defined as in any aspect of the invention.In some embodiments, the aromatic vinyl compound of formula I-0 or I is substituted with one or more RB-1-4Substituted 3-12 membered heteroaryl is
Figure BDA0003234055820000104
Figure BDA0003234055820000105
The other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RB-1-1And RB-1-2Independently H or by one or more RB-1-1-1Substituted C1-C4An alkyl group; or, RB-1-1、RB-1-2And together with the nitrogen atom to which they are attached form a 5-to 7-membered ring substituted by one or more RB-1-1-2Substituted carbon heterocycles, the other variables being as defined in any of the schemes of the invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RB-1-1And RB-1-2One of which is H and the other is substituted by one or more RB-1-1-1Substituted C1-C4An alkyl group; or, RB-1-1、RB-1-2And together with the nitrogen atom to which they are attached form a 5-to 7-membered ring substituted by one or more RB-1-1-2Substituted carbon heterocycles, the other variables being as defined in any of the schemes of the invention.
In some embodiments, the aromatic vinyl compound of formula I-0 or I is substituted with one or more RB-1-1-1Substituted C1-C4Alkyl is
Figure BDA0003234055820000111
The other variables are defined as in any aspect of the invention.
In some embodiments, the aromatic vinyl compound of formula I-0 or I is substituted with one or more RB-1-1-1Substituted C1-C4Alkyl radicalIs composed of
Figure BDA0003234055820000112
The other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RB-1-1-2Is C1-C4Alkyl, COORB-1-1-6Or C1-C4Amide groups, and other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, RB-1-1-2Is methyl, carboxyl or-CONH2And the other variables are defined as in any of the aspects of the invention.
In some embodiments, the aromatic vinyl compound of formula I-0 or I, the carbon heterocycle is
Figure BDA0003234055820000113
Figure BDA0003234055820000114
The other variables are defined as in any aspect of the invention.
In some embodiments, the aromatic vinyl compound of formula I-0 or I is substituted with one or more RB-1-1-2Substituted carbon heterocycle is
Figure BDA0003234055820000115
The other variables are defined as in any aspect of the invention.
In some embodiments, the aromatic vinyl compound of formula I-0 or I is substituted with one or more RB-1-1-2Substituted carbon heterocycle is
Figure BDA0003234055820000116
The other variables are defined as in any aspect of the invention.
In some embodiments, the compound is represented by formula I-0 or IIn the aromatic vinyl compound of (2), R4Is composed of
Figure BDA0003234055820000117
The other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compound of formula I-0 or I, R5Is halogen, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group; rB-1And RB-2Independently is deuterium, hydroxy, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy or
Figure BDA0003234055820000121
The other variables are defined as in any aspect of the invention.
In some embodiments, the aromatic vinyl compound of formula I-0 or I,
Figure BDA0003234055820000122
is composed of
Figure BDA0003234055820000123
The other variables are defined as in any aspect of the invention.
In some embodiments, the aromatic vinyl compound of formula I-0 or I,
Figure BDA0003234055820000124
is composed of
Figure BDA0003234055820000125
The other variables are defined as in any aspect of the invention.
In some embodiments, the aromatic vinyl compound of formula I-0 or I,
Figure BDA0003234055820000126
is composed of
Figure BDA0003234055820000127
Figure BDA0003234055820000128
Figure BDA0003234055820000129
The other variables are defined as in any aspect of the invention.
In some embodiments, the aromatic vinyl compound of formula I-0 or I,
Figure BDA00032340558200001210
is composed of
Figure BDA00032340558200001211
Figure BDA0003234055820000131
In some embodiments, in the aromatic vinyl compound of formula I-0, R15And R16At least one of which is H or deuterium, the other variables being as defined in any of the schemes of the present invention.
In some embodiments, in the aromatic vinyl compound of formula I-0, R15Is H or deuterium; r16Is H, deuterium or halogen, and the other variables are as defined in any of the schemes herein.
In some embodiments, in the aromatic vinyl compound of formula I-0, R1Is halogen, C substituted by one or more halogens1-C4Alkyl, and other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compound of formula I-0, R15For deuterium or halogen, the other variables are as defined in any of the schemes of the present invention.
In some embodiments, in the aromatic vinyl compound of formula I-0, R16For deuterium or halogen, the other variables are as defined in any of the schemes of the present invention.
In some embodiments, the aromatic vinyl compound of formula I-0 or I is selected from any of the following schemes, scheme one: r2Is composed of
Figure BDA0003234055820000132
R4And R5Independently of one another, halogen, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group; rB-1And RB-2Independently is deuterium, hydroxy, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy or
Figure BDA0003234055820000133
R3、R6、R12、R13And R14Is H;
scheme II: r2Is halogen, C1-C4Alkyl or by one or more RA-1Substituted C1-C4An alkyl group; rA-1Is halogen; r4Is composed of
Figure BDA0003234055820000134
R5Is halogen, hydroxy, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group; rB-1And RB-2Independently is deuterium, hydroxy, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy or
Figure BDA0003234055820000135
R3、R6、R12、R13And R14Is H;
the third scheme is as follows: r2Is halogen, C1-C4Alkyl or by one or more RA-1Substituted C1-C4An alkyl group; rA-1Is halogen; r4Is halogen, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group; rB-1And RB-2Independently is deuterium, hydroxy, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy or
Figure BDA0003234055820000141
R5Is composed of
Figure BDA0003234055820000142
R3、R6、R12、R13And R14Is H;
and the scheme is as follows: r2Is composed of
Figure BDA0003234055820000143
R4And R5Independently of one another, halogen, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group; rB-1And RB-2Independently is deuterium, hydroxy, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy or
Figure BDA0003234055820000144
R3、R6、R12、R13And R14Is H; r15And R16At least one of which is H or deuterium;
and a fifth scheme: r2Is halogen, C1-C4Alkyl or by one or more RA-1Substituted C1-C4An alkyl group; rA-1Is halogen; r4Is composed of
Figure BDA0003234055820000145
R5Is halogen, hydroxy, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group; rB-1And RB-2Independently is deuterium, hydroxy, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy or
Figure BDA0003234055820000146
R3、R6、R12、R13And R14Is H; r15And R16At least one of which is H or deuterium;
scheme six: r2Is halogen, C1-C4Alkyl or by one or more RA-1Substituted C1-C4An alkyl group; rA-1Is halogen; r4Is halogen, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group; rB-1And RB-2Independently is deuterium, hydroxy, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy or
Figure BDA0003234055820000147
R5Is composed of
Figure BDA0003234055820000148
R3、R6、R12、R13And R14Is H; r15And R16At least one of which is H or deuterium.
In some embodiments, in the aromatic vinyl compound of formula I-0, R1Is cyano, CH3、CD3、Cl、CH2F. C substituted by one or more halogens1-C4Alkyl, and other variables are as defined in any of the embodiments of the present invention.
In some embodiments, in the aromatic vinyl compound represented by formula I-0,
Figure BDA0003234055820000149
is composed of
Figure BDA00032340558200001410
Figure BDA0003234055820000151
Figure BDA0003234055820000161
Figure BDA0003234055820000171
Figure BDA0003234055820000172
The other variables are defined as in any aspect of the invention.
In some embodiments, in the aromatic vinyl compound of formula I-0, R15And R16Independently H, deuterium, Br or F, and the other variables are as defined in any of the schemes herein.
In some embodiments, the aromatic vinyl compound of formula I-0 or I is any one of the following:
Figure BDA0003234055820000181
Figure BDA0003234055820000191
Figure BDA0003234055820000201
Figure BDA0003234055820000211
Figure BDA0003234055820000221
Figure BDA0003234055820000231
Figure BDA0003234055820000241
the invention also provides a preparation method of the aromatic vinyl compound shown in the formula I-0, and the preparation method of the aromatic vinyl compound shown in the formula I-0 comprises the following steps of 1,2, 3, 4,5 or 6:
the method 1 comprises the following steps: in a solvent, under the action of a reducing agent, carrying out reductive amination reaction on a compound shown as a formula II-a-0 and a compound shown as a formula III-a as shown in the specification to obtain an aromatic vinyl compound shown as a formula I-0;
Figure BDA0003234055820000251
in Process 1, R4Is composed of
Figure BDA0003234055820000252
R1、R2、R3、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、RB-1-1And RB-1-2As defined above;
the method 2 comprises the following steps: in a solvent, under the action of alkali, carrying out substitution reaction shown as the following on a compound shown as a formula II-b-0 and a compound shown as a formula III-a to obtain an aromatic vinyl compound shown as a formula I-0;
Figure BDA0003234055820000253
in Process 2, R4Is composed of
Figure BDA0003234055820000254
R1、R2、R3、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、RB-1-1And RB-1-2As defined above, X1Is halogen;
the method 3 comprises the following steps: in a solvent, under the action of a reducing agent, carrying out reductive amination reaction on a compound shown as a formula II-c-0 and a compound shown as a formula III-a as shown in the specification to obtain an aromatic vinyl compound shown as a formula I-0;
Figure BDA0003234055820000255
in method 3, R5Is composed of
Figure BDA0003234055820000256
R1、R2、R3、R4、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、RB-1-1And RB-1-2As defined above;
the method 4 comprises the following steps: in a solvent, under the action of alkali, carrying out substitution reaction shown as the following on a compound shown as a formula II-d-0 and a compound shown as a formula III-a to obtain an aromatic vinyl compound shown as a formula I-0;
Figure BDA0003234055820000261
in method 4, R5Is composed of
Figure BDA0003234055820000262
R1、R2、R3、R4、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、RB-1-1And RB-1-2As defined above, X2Is halogen;
the method 5 comprises the following steps: in a solvent, under the action of a reducing agent, carrying out reductive amination reaction on a compound shown as a formula II-e-0 and a compound shown as a formula III-b as shown in the specification to obtain an aromatic vinyl compound shown as a formula I-0;
Figure BDA0003234055820000263
in method 5, R2Is composed of
Figure BDA0003234055820000264
R1、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、RA -1-1And RA-1-2As defined above;
the method 6 comprises the following steps: in a solvent, under the action of alkali, carrying out substitution reaction shown as the following on a compound shown as a formula II-f-0 and a compound shown as a formula III-b to obtain an aromatic vinyl compound shown as a formula I-0;
Figure BDA0003234055820000265
in method 6, R2Is composed of
Figure BDA0003234055820000266
R1、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、RA -1-1And RA-1-2As defined above, X3Is halogen.
The invention also provides a preparation method of the aromatic vinyl compound shown in the formula I, which comprises the following steps of:
the first method comprises the following steps: in a solvent, under the action of a reducing agent, carrying out reductive amination reaction on a compound shown as a formula II-a and a compound shown as a formula III-a as shown in the specification to obtain an aromatic vinyl compound shown as a formula I;
Figure BDA0003234055820000271
in the first process, R4Is composed of
Figure BDA0003234055820000272
R1、R2、R3、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、RB-1-1And RB-1-2As defined above;
the second method comprises the following steps: in a solvent, under the action of alkali, carrying out substitution reaction shown as the following on a compound shown as a formula II-b and a compound shown as a formula III-a to obtain an aromatic vinyl compound shown as a formula I;
Figure BDA0003234055820000273
in the second process, R4Is composed of
Figure BDA0003234055820000274
R1、R2、R3、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、RB-1-1And RB-1-2As defined above, X1Is halogen;
the third method comprises the following steps: in a solvent, under the action of a reducing agent, carrying out reductive amination reaction on a compound shown as a formula II-c and a compound shown as a formula III-a as shown in the specification to obtain an aromatic vinyl compound shown as a formula I;
Figure BDA0003234055820000275
in the third process, R5Is composed of
Figure BDA0003234055820000276
R1、R2、R3、R4、R6、R7、R8、R9、R10、R11、R12、R13、R14、RB-1-1And RB-1-2As defined above;
the method IV comprises the following steps: in a solvent, under the action of alkali, carrying out substitution reaction shown as the following on a compound shown as a formula II-d and a compound shown as a formula III-a to obtain an aromatic vinyl compound shown as a formula I;
Figure BDA0003234055820000281
in the fourth process, R5Is composed of
Figure BDA0003234055820000282
R1、R2、R3、R4、R6、R7、R8、R9、R10、R11、R12、R13、R14、RB-1-1And RB-1-2As defined above, X2Is halogen;
the method five comprises the following steps: in a solvent, under the action of a reducing agent, carrying out reductive amination reaction on a compound shown as a formula II-e and a compound shown as a formula III-b as shown in the specification to obtain an aromatic vinyl compound shown as a formula I;
Figure BDA0003234055820000283
in the fifth process, R2Is composed of
Figure BDA0003234055820000284
R1、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、RA-1-1 and RA-1-2As defined above;
the method six comprises the following steps: in a solvent, under the action of alkali, carrying out substitution reaction shown as the following on a compound shown as a formula II-f and a compound shown as a formula III-b to obtain an aromatic vinyl compound shown as a formula I;
Figure BDA0003234055820000285
in the sixth process, R2Is composed of
Figure BDA0003234055820000286
R1、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、RA-1-1And RA-1-2As defined above, X3Is halogen.
Methods and conditions for the reductive amination reaction in method 1, method 3, method 5, method one, method three, or method five may be conventional in the art for such reactions.
Methods and conditions for the substitution reaction described in method 2, method 4, method 6, method two, method four, or method six may be those conventional in the art for such reactions.
The invention also provides compounds shown as II-a-0, II-b-0, II-c-0, II-d-0, II-e-0 or II-f-0,
Figure BDA0003234055820000291
in the compounds of the above formula, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15And R16As defined above, X1、X2And X3Independently a halogen.
The invention also provides compounds as shown in II-a, II-b, II-c, II-d, II-e or II-f,
Figure BDA0003234055820000292
Figure BDA0003234055820000301
in the compounds of the above formula, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13And R14As defined above, X1、X2And X3Independently a halogen.
In some embodiments, the compound of formula II-a-0 or II-a is any of the following:
Figure BDA0003234055820000302
Figure BDA0003234055820000311
Figure BDA0003234055820000321
Figure BDA0003234055820000331
in some embodiments, the compound of formula II-b is a compound of formula II:
Figure BDA0003234055820000341
in some embodiments, the compound of formula II-c is any one of the following:
Figure BDA0003234055820000342
in some embodiments, the compound of formula II-e is any one of the following:
Figure BDA0003234055820000343
the invention also provides any one of the following aromatic vinyl compounds, tautomers, stereoisomers, racemates or isotopic derivatives thereof, or pharmaceutically acceptable salts of the compounds (any one of the following aromatic vinyl compounds, tautomers, stereoisomers, racemates or isotopic derivatives thereof);
Figure BDA0003234055820000351
the invention also provides a pharmaceutical composition, which comprises the aromatic vinyl compound, the tautomer, the stereoisomer, the racemate or the isotopic derivative thereof, or the pharmaceutically acceptable salt of the aromatic vinyl compound, the tautomer, the stereoisomer, the racemate or the isotopic derivative thereof and pharmaceutical excipients.
The invention also provides a pharmaceutical composition, which comprises the aromatic vinyl compound, the tautomer, the stereoisomer, the racemate or the isotopic derivative thereof, or the pharmaceutically acceptable salt of the aromatic vinyl compound, the tautomer, the stereoisomer, the racemate or the isotopic derivative thereof and at least one other drug, wherein the other drug is a chemotherapeutic drug or a targeted drug. The targeted drug is preferably one or more of a COX-2 inhibitor, a DPP4 inhibitor, a CSF-1 alpha inhibitor and an A2a antagonist.
In the pharmaceutical composition, the amount of the aromatic vinyl compound, the tautomer, the stereoisomer, the racemate, or the isotopic derivative thereof, or the pharmaceutically acceptable salt thereof (referring to the aromatic vinyl compound, the tautomer, the stereoisomer, the racemate, or the isotopic derivative thereof) can be therapeutically effective.
The pharmaceutical excipients may be those widely used in the field of pharmaceutical production. The excipients are used primarily to provide a safe, stable and functional pharmaceutical composition and may also provide methods for dissolving the active ingredient at a desired rate or for promoting the effective absorption of the active ingredient after administration of the composition by a subject. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, antiadherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents and sweeteners.
The pharmaceutical compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention may also be in a controlled release or delayed release dosage form (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.
The invention also provides the aromatic vinyl compound, the tautomer, the stereoisomer, the racemate or the isotopic derivative thereof, or the pharmaceutically acceptable salt of the aromatic vinyl compound, the tautomer, the stereoisomer, the racemate or the isotopic derivative thereof, and the application of the pharmaceutical composition in preparing PD-1 inhibitors and/or PD-L1 inhibitors.
In the use, the PD-1 inhibitor or PD-L1 inhibitor is useful in a mammalian organism; also useful in vitro, primarily for experimental purposes, for example: the antibody can be used as a standard sample or a control sample for comparison, or can be prepared into a kit according to the conventional method in the field, so as to provide rapid detection for the inhibition effect of PD-1 or PD-L1.
The invention also provides the application of the aromatic vinyl compound, the tautomer, the stereoisomer, the racemate or the isotopic derivative thereof, or the pharmaceutically acceptable salt of the aromatic vinyl compound, the tautomer, the stereoisomer, the racemate or the isotopic derivative thereof, and the pharmaceutical composition in preparing medicaments for preventing and/or treating diseases related to the PD-1/PD-L1 signal path.
The diseases related to the PD-1/PD-L1 signal channel are selected from cancers, infectious diseases, autoimmune diseases or related diseases thereof.
The cancer is preferably one or more of lung cancer, esophageal cancer, gastric cancer, carcinoma of large intestine, blood tumor, lymphoma, head and neck cancer, hepatocarcinoma, nasopharyngeal carcinoma, brain tumor, breast cancer, cervical cancer, leukemia and bone cancer.
The infectious disease is preferably a bacterial infection and/or a viral infection.
The autoimmune disease is preferably one or more of rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, systemic vasculitis and recurrent polychondritis.
Unless otherwise defined, the terms used in the present invention have the following meanings:
the term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for use by the patient. The "patient" is preferably a mammal, more preferably a human.
The term "pharmaceutically acceptable salt" refers to salts prepared from the compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acids include organic acids including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4, 4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they may be converted to base addition salts or acid addition salts. See in particular Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19(1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P.Heinrich Stahl and Camile G.Wermuth, ed., Wiley-VCH, 2002).
The terms "compound", "tautomer", "stereoisomer", "racemate", "isotopic derivative" and "pharmaceutically acceptable salt thereof" may exist in crystalline or amorphous form. The term "crystal form" refers to a form in which ions or molecules are arranged strictly periodically in a three-dimensional space in a defined manner and have a periodic recurring pattern at a distance; due to the above described periodic arrangement, various crystal forms, i.e. polymorphism, may exist. The term "amorphous" refers to a state in which ions or molecules are distributed in a disordered manner, i.e., the ions and molecules do not have a periodic arrangement.
The term "stereoisomer" refers to either a cis-trans isomer or an optical isomer. The stereoisomers can be separated, purified and enriched by an asymmetric synthesis method or a chiral separation method (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography and the like), and can also be obtained by chiral resolution in a mode of forming bonds (chemical bonding and the like) or salifying (physical bonding and the like) with other chiral compounds and the like.
The term "isotopic derivative" means that the atoms in the "compounds", "tautomers", "stereoisomers", "racemates" and "pharmaceutically acceptable salts thereof can exist in their natural or unnatural abundance. In the case of hydrogen atoms, in its natural abundance, it is understood that about 99.985% is protium and about 0.015% is deuterium; in its unnatural abundance, it is meant that about 95% thereof is deuterium. That is, one or more atoms in the terms "compound", "tautomer", "stereoisomer", "racemate", and "pharmaceutically acceptable salt thereof, may be an atom that is present in a non-natural abundance.
When any variable (e.g. R)A-1) In the definition of a compound, the occurrence at each position of the variable is defined multiple times independently of the occurrence at the remaining positions, and their meanings are independent of each other and independent of each other. Thus, if a group is substituted by 1,2, 3, 4 or 5RA-1Substituted by radicals, i.e. the radicals may be substituted by up to 5RA-1Substituted in the position RA-1Is defined by the definition of (1) and the remaining positions RA-1The definitions of (a) and (b) are independent of each other, may be different from each other, and may be the same. In addition, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms.
The term "alkoxy" refers to the group-O-RXWherein R isXIs an alkyl group as defined above.
The term "pharmaceutical excipient" refers to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations, and is intended to include all substances in a pharmaceutical formulation, except for the active ingredient. See the pharmacopoeia of the people's republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe,2009Sixth Edition).
The term "prevention" refers to a reduced risk of acquiring or developing a disease or disorder.
The term "treatment" refers to therapeutic therapy. Where specific conditions are involved, treatment refers to: (1) relieving one or more biological manifestations of a disease or disorder, (2) interfering with (a) one or more points in a biological cascade that causes or leads to a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of one or more biological manifestations of a disorder or disorder.
The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like, with humans being most preferred.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the aromatic vinyl compound or the pharmaceutically acceptable salt thereof has obvious inhibition effect on PD-1 and PD-L1, has better drug peak concentration, drug time curve area and oral bioavailability, and can effectively relieve or treat related diseases such as cancer.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples, room temperature means 10 ℃ to 30 ℃; overnight means 8 to 24 hours, preferably 12 to 18 hours.
The structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS), wherein the NMR is obtained by a Bruker Avance-500 instrument, deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol and the like are used as solvents, and Tetramethylsilane (TMS) is used as an internal standard. Mass spectra were obtained from liquid chromatography-Mass Spectrometry (LC-MS) Agilent Technologies 6110 using an ESI ion source.
The microwave reaction is carried out in an Explorer full-automatic microwave synthesizer produced by CEM company in America, the magnetron frequency is 2450MHz, and the continuous microwave output power is 300W.
The apparatus used for the high performance liquid preparation was Waters 2767 and the preparative column used was XBrige C18, 19X 150mm X5 μm. Acid mobile phase: 1% formic acid (a) + acetonitrile (B); alkaline mobile phase: 5mmol/L ammonium bicarbonate aqueous solution. Flow rate: 15 mmL/min. Gradient: 20% -70% (initial mobile phase 80% water/20% acetonitrile, end mobile phase 30% water/70% acetonitrile, wherein% refers to volume%). Detection wavelength: 214nm and 254 nm.
Example 1
(S, E) -1- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -3-trifluoromethylbenzyl) piperidine-2-carboxylic acid (Compound 1)
Figure BDA0003234055820000381
Synthesis of Compound 1-c
Add water (4mL), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (365mg, 0.5mmol) and sodium carbonate (2.65g, 25.0mmol) to a solution of 2-bromo-6-chlorobenzonitrile (2.16g, 10.0mmol) and phenylboronic acid (1.33g, 11.0mmol) in 1, 4-dioxane (40 mL). The reaction mixture was heated to 80 ℃ and stirred under nitrogen for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 6: 1) to give compound 1-c (1.55g, yield: 72%).
Synthesis of Compound 1-b
To a solution of compound 1-c (1.50g, 7.0mmol) and vinylppinacol borate (2.13g, 8.4mmol) in 1, 4-dioxane (80mL) were added water (8mL), palladium acetate (78mg, 0.35mmol), 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl (333mg, 0.70mmol), cesium fluoride (2.10g, 14.0mmol) and potassium phosphate (2.97g, 14.0 mmol). The reaction mixture was heated to 80 ℃ and stirred under nitrogen for 6 hours. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 6: 1) to give compound 1-b (1.17g, yield: 82%).
1H NMR(400MHz,CD3Cl):δ7.67(dd，J＝1.2Hz,7.6Hz，1H),7.59(t，J＝8.0Hz，1H),7.53-7.56(m,2H),7.44-7.50(m,3H),7.37(dd，J＝1.2Hz,7.6Hz，1H),7.20(dd，J＝10.8Hz,17.6Hz，1H),5.96(d，J＝17.6Hz，1H),5.57(d，J＝10.8Hz，1H)ppm
Synthesis of Compound 1-a
Compound 1-b (100mg,0.487mmol) and 4-bromo-3-trifluoromethylbenzaldehyde (123mg, 0.487mmol) were dissolved in a toluene solution (20mL), and N, N' -diisopropylethylamine (504mg, 3.896mmol) and bis (tri-tert-butylphosphine) palladium (18mg, 0.034mmol) were added. The reaction solution was replaced with nitrogen gas three times at room temperature, heated to 80 ℃ and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100mL), and then washed with water (100mL × 3) and saturated brine (100mL) in this order, the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate: 20:1 to 5:1) to obtain compound 1-a (62mg, yield: 33.7%).
1H NMR(400MHz,CDCl3):δ10.01(s,1H),8.15(s,1H),8.05-8.00(m,2H),7.77-7.75(d,J＝8.0Hz,1H),7.67-7.60(m,3H),7.51-7.39(m,6H)ppm
Synthesis of Compound 1
Compound 1-a (62mg, 0.164mmol) was suspended in methanol (10mL), and (S) -piperidine-2-carboxylic acid (43mg, 0.329mmol) and sodium cyanoborohydride (21mg, 0.329mmol) were added. The reaction solution was heated to 70 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 1(15mg, yield: 18.8%).
LC-MS(ESI):m/z＝491.0[M+H]+.
1H NMR(400MHz,CD3OD):δ8.08-8.06(d,J＝8.0Hz,1H),8.03(s,1H),7.93-7.88(m,2H),7.81-7.77(t,J＝8.0Hz,1H),7.76-7.71(m,1H),7.66-7.59(m,3H),7.56-7.50(m,4H),4.73-4.70(d,J＝12.8Hz,1H),4.21-4.17(m,1H),3.53-3.50(m,1H),3.39-3.36(m,1H),3.02-2.97(m,1H),2.32-2.29(m,1H),1.88-1.84(m,3H),1.74-1.68(m,1H),1.62-1.56(m,1H)ppm。
Example 2
(S, E) -1- (3-chloro-4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) benzyl) piperidine-2-carboxylic acid (Compound 2)
Figure BDA0003234055820000401
Synthesis of Compound 2-a
Compound 1-b (205.0mg,1.0mmol) and 4-bromo-3-chlorobenzaldehyde (240.9mg,1.1mmol) were dissolved in toluene solution (30mL), and N, N' -diisopropylethylamine (387mg, 3.0mmol) and bis (tri-t-butylphosphine) palladium (51.1mg, 0.1mmol) were added. The reaction solution was replaced with nitrogen gas three times at room temperature, heated to 90 ℃ and stirred for 10 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100mL), and then washed with water (100mL × 3) and saturated brine (100mL) in this order, the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate: 20:1 to 5:1) to obtain compound 2-a (270mg, yield: 78%).
Synthesis of Compound 2
Compound 2-a (172mg, 0.5mmol) was suspended in methanol (30mL), and (S) -piperidine-2-carboxylic acid (43mg, 0.329mmol) and sodium cyanoborohydride (63.0mg,1.0mmol) were added. The reaction solution was heated to 60 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to prepare 2(75mg, yield: 32%) as a white solid.
LC-MS(ESI):m/z＝457.3[M+H]+.
1H NMR(400MHz,CD3OD):δ7.97(d,J＝7.2Hz,1H),7.93(t,J＝8.0Hz,1H),7.82-7.75(m,3H),7.66-7.47(m,3H),4.62(d,J＝12.8Hz,1H),4.13-4.08(m,1H),3.50-3.40(m,2H),3.00-2.94(m,1H),2.32-2.28(m,1H),1.87-1.54(m,5H)ppm。
Example 3
(S, E) -1- (3-chloro-4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) benzyl) piperidine-2-carboxylic acid (Compound 3)
Figure BDA0003234055820000402
Synthesis of Compound 3-c
Phenylboronic acid (1.626g, 13.34mmol) and 2, 6-dibromotoluene (5.0g, 20.0mmol) were dissolved in a mixed solution of 1, 4-dioxane (60mL) and water (3mL), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (1.154g, 1.334mmol) and sodium carbonate (3.535g, 33.35mmol) were added. After the reaction system was replaced with nitrogen three times, it was heated to 80 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100mL), and then washed with water (100 mL. times.3) and saturated brine (100mL) in this order, the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether) to give compound 3-c (1.9g, yield: 57.2%).
1H NMR(400MHz,CDCl3):δ7.56-7.54(m,1H),7.44-7.35(m,3H),7.28-7.25(m,2H),7.17-7.15(m,1H),7.08(t,J＝8Hz,1H),2.31(s,3H)ppm
Synthesis of Compound 3-b
Compound 3-c (1.071g, 4.33mmol) and vinyl boronic acid pinacol ester (800.9mg, 5.20mmol) were dissolved in a solution of toluene (50mL), and bis (tri-tert-butylphosphino) palladium (154.8mg, 0.303mmol) and triethylamine (3.51g, 34.64mmol) were added. After the reaction system was replaced with nitrogen three times, it was heated to 80 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50mL), and then washed with water (50 mL. times.3) and saturated brine (50mL) in this order, the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 3-b (0.89g, yield: 64.1%).
1H NMR(400MHz,CDCl3):δ7.75-7.71(d,J＝18Hz,1H),7.56-7.54(m,1H),7.41-7.39(m,2H),7.36-7.34(m,1H),7.30-7.28(m,2H),7.23-7.17(m,2H),6.12-6.07(d,J＝18Hz,1H),2.82(s,3H),1.32(s,12H)ppm
Synthesis of Compound 3-a
Compound 3-b (349mg, 1.09mmol) and 3-chloro-4-bromobenzaldehyde (200mg, 0.911mmol) were dissolved in ethylene glycol dimethyl ether (20mL), and cesium fluoride (277mg, 1.82mmol), sodium carbonate (242mg, 2.28mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (79mg, 0.091mmol) were added. The reaction solution was replaced with nitrogen gas three times at room temperature. Heated to 80 ℃ and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100mL), and washed with water (100 mL. times.3) and saturated brine (100 mL). The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 20:1 to 5:1) to obtain compound 3-a (175mg, yield: 57.8%).
1H NMR(400MHz,CDCl3):δ9.90(s,1H),7.85-7.79(m,2H),7.72-7.70(d,J＝8.0Hz,1H),7.60-7.57(m,1H),7.52-7.48(m,1H),7.38-7.34(m,3H),7.31-7.21(m,5H),2.26(s,3H)ppm
Synthesis of Compound 3
Compound 3-a (175mg, 0.526mmol) was suspended in a solution of methanol (15mL), and (S) -piperidine-2-carboxylic acid (136mg, 1.052mmol) and sodium cyanoborohydride (66mg, 1.052mmol) were added. The reaction solution was heated to 70 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 3(43mg, yield: 18.3%).
LC-MS(ESI):m/z＝446.0[M+H]+.
1H NMR(400MHz,CD3OD):δ7.82-7.80(d,J＝8.0Hz,1H),7.58(s,1H),7.52-7.48(m,2H),7.41-7.39(d,J＝7.2Hz,1H),7.34-7.25(m,4H),7.20-7.16(m,3H),7.07-7.06(d,J＝6.8Hz,1H),4.50-4.47(d,J＝12.4Hz,1H),3.99-3.94(m,1H),3.37-3.34(d,J＝10.4Hz,1H),3.28-3.25(m,1H),2.88-2.82(t,J＝12.4Hz,1H),2.19(s,3H),2.16(s,1H),1.75-1.72(m,3H),1.63-1.60(m,1H),1.48-1.41(m,1H)ppm。
Example 4
(S, E) -1- (4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -3-trifluoromethylbenzyl) piperidine-2-carboxylic acid (Compound 4)
Figure BDA0003234055820000421
Synthesis of Compound 4-a
Compound 3-b (304mg, 0.949mmol) and 3-trifluoromethyl-4-bromobenzaldehyde (200mg, 0.791mmol) were dissolved in ethylene glycol dimethyl ether (20mL), and cesium fluoride (241mg, 1.582mmol), sodium carbonate (210mg, 1.98mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (69mg, 0.079mmol) were added. The reaction solution was replaced with nitrogen gas three times at room temperature. Heated to 80 ℃ and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100mL), and washed with water (100 mL. times.3) and saturated brine (100 mL). The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 20:1 to 5:1) to obtain compound 4-a (132mg, yield: 45.7%).
1H NMR(400MHz,CDCl3):δ9.98(s,1H),8.12(s,1H),8.01-7.98(d,J＝8.4Hz,1H),7.92-7.90(d,J＝8.4Hz,1H),7.54-7.48(m,2H),7.38-7.22(m,8H),2.26(s,3H)ppm
Synthesis of Compound 4
Compound 4-a (132mg, 0.36mmol) was suspended in a solution of methanol (15mL), and (S) -piperidine-2-carboxylic acid (93mg, 0.72mmol) and sodium cyanoborohydride (46mg, 0.72mmol) were added. The reaction solution was heated to 70 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 4(39mg, yield: 22.7%).
LC-MS(ESI):m/z＝480.0[M+H]+.
1H NMR(400MHz,CD3OD):δ7.99-7.97(d,J＝8.0Hz,1H),7.88(s,1H),7.75-7.73(d,J＝8.0Hz,1H),7.56-7.52(d,J＝16.0Hz,1H),7.49-7.47(d,J＝8.0Hz,1H),7.37-7.34(t,J＝7.2Hz,2H),7.30-7.19(m,5H),7.12-7.10(d,J＝7.2Hz,1H),4.63-4.59(d,J＝12.8Hz,1H),4.10-4.07(m,1H),3.41-3.39(d,J＝10.4Hz,1H),2.93-2.87(t,J＝10.8Hz,1H),2.22(s,3H),2.20(m,1H),1.78-1.76(m,3H),1.65-1.62(m,1H),1.52-1.46(m,1H)ppm。
Example 5
(S, E) -1- (-5-chloro-2-methyl-4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) ethenyl) benzyl) piperidine-2-carboxylic acid (Compound 5)
Figure BDA0003234055820000422
Synthesis of Compound 5-c
5-chloro-2-methylphenol (2.85g, 20.0mmol) was dissolved in anhydrous dichloromethane (100mL), titanium tetrachloride (11.38g, 60.0mmol) was added, and the reaction solution was cooled to 0 ℃. Dichloromethoxymethane (6.90g, 60.0mmol) was added dropwise under nitrogen protection. After the dropwise addition, the reaction solution was warmed to room temperature and stirred for 2 hours. Then, the reaction solution was poured into crushed ice to quench the reaction, extracted with ethyl acetate (100 mL. times.2), and the organic phases were combined and washed with water (100mL) and saturated brine (100mL) in this order. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1 to 3:1) to obtain compound 5-c (1.569g, yield: 45.9%).
LC-MS(ESI):m/z＝171.0[M+H]+.
Synthesis of Compound 5-b
Compound 5-c (1.05g, 6.16mmol) was dissolved in anhydrous dichloromethane (100mL) and triethylamine (1.25g, 12.32mmol) was added. The reaction was cooled to-78 ℃ under nitrogen and trifluoromethanesulfonic anhydride (2.61g, 9.23mmol) was added dropwise. After the addition, the reaction solution was warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100mL), and washed with water (100mL) and saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 50:1 to 10:1) to obtain compound 5-b (1.50g, yield: 80.2%).
Synthesis of Compound 5-a
Compound 3-b (634.7mg, 1.982mmol) and compound 5-b (500mg, 1.652mmol) were dissolved in toluene solution (20mL) at room temperature, and potassium phosphate (701.4mg, 3.304mmol), cesium fluoride (501.9mg, 3.304mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (142.7mg, 0.165mmol) were added. The reaction solution was heated to 80 ℃ and stirred under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100mL), and washed with water (100mL) and saturated brine (100 mL). The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 50:1 to 20:1) to obtain compound 5-a (501mg, yield: 87.6%).
Synthesis of Compound 5
To a solution of compound 5-a (70mg, 0.20mmol) and L-piperidine-2-carboxylic acid (52mg, 0.40mmol) in methanol (10mL) was added dichloromethane (10 mL). After the mixture was stirred at room temperature for 1 hour, sodium cyanoborohydride (32mg, 0.50mmol) was added. After stirring the reaction at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure, and the residue was washed with water (100mL), filtered, and prepared by high performance liquid chromatography to give 5(34mg, yield: 37%) as a white solid.
LC-MS(ESI):m/z＝460[M+H]+.
1H NMR(400MHz,CD3Cl):δ7.77(s,1H),7.70(s,1H),7.62～7.63(m,1H),7.60(d,J＝18.0Hz,1H),7.43～7.47(m,2H),7.34～7.39(m,2H),7.27～7.32(m,3H),7.17～7.19(m,1H),4.88(d,J＝12.8Hz,1H),4.67(d,J＝12.8Hz,1H),4.05～4.09(m,1H),3.53～3.57(m,1H),3.01～3.06(m,1H),2.53(s,3H),2.32(s,3H),2.27～2.31(m,1H),1.82～1.89(m,3H),1.72～1.75(m,1H),1.57～1.64(m,1H)ppm。
Example 6
(S, E) -1- (2-methoxy-4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -5-trifluoromethylbenzyl) piperidine-2-carboxylic acid (Compound 6)
Figure BDA0003234055820000431
Figure BDA0003234055820000441
Synthesis of Compound 6-b
To a solution of 2-bromo-4-methoxy-1- (trifluoromethyl) benzene (1.28g, 5.0mmol) in dry dichloromethane (30mL) at 0 deg.C was added titanium tetrachloride (2.84g,15.0 mmol). The mixture was slowly dropped with stirring at 0 ℃ with 1,1' -dichloromethyl ether (1.15g, 10.0 mmol). After the addition, the reaction was continued at 0 ℃ for 3 hours. The reaction was quenched by slowly adding ice water (30 mL). The mixture was extracted with ethyl acetate (30 mL. times.3), and washed with water (30 mL. times.2) and saturated brine (30 mL. times.2) in this order. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 15: 1) to give compound 6-b (254mg, yield: 18%).
1H NMR(400MHz,CD3Cl):δ10.40(s,1H),8.14(s,1H),7.35(s,1H)，4.01(s,3H)ppm
Synthesis of Compound 6-a
To a mixture of compound 6-b (141mg, 0.50mmol), compound 3-b (200mg, 0.62mmol) and toluene (25mL) was added [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (48mg, 0.12mmol), potassium phosphate (212mg, 1.0mmol), cesium fluoride (150mg, 1.0mmol) and stirred at 80 ℃ for 16 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 6:1 to 4:1) to give compound 6-a (107mg, yield: 54%).
LC-MS(ESI):m/z＝397[M+H]+.
Synthesis of Compound 6
To a solution of compound 6-a (80mg, 0.20mmol) and L-piperidine-2-carboxylic acid (52mg, 0.40mmol) in methanol (10mL) was added dichloromethane (10 mL). After the mixture was stirred at room temperature for 1 hour, sodium cyanoborohydride (32mg, 0.50mmol) was added. The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure, and the residue was washed with water (30 mL. times.3), filtered, concentrated under reduced pressure, and then subjected to high performance liquid chromatography to give the product 6(41mg, yield: 40%) as a white solid.
LC-MS(ESI):m/z＝510[M+H]+.
1H NMR(400MHz,CD3OD):δ7.81(s,1H),7.54(d,J＝16.0Hz,1H),7.45(d,J＝16.0Hz,1H),7.44(s,1H),7.32～7.35(m,2H),7.24～7.28(m,2H),7.17～7.21(m,3H),7.09(d,J＝7.6Hz,1H),4.45(d,J＝12.8Hz,1H),4.31(d,J＝12.8Hz,1H),3.98(s,3H),3.40～3.44(m,1H),2.87～2.94(m,1H),2.21(s,3H),2.14～2.17(m,1H),1.67～1.77(m,3H),1.45～1.51(m,1H)ppm。
Example 7
(S, E) -1- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2-methoxy-5-trifluoromethylbenzyl) piperidine-2-carboxylic acid (Compound 7)
Figure BDA0003234055820000442
Synthesis of Compound 7-a
Compound 1-b (100mg,0.487mmol) and 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde (138mg,0.487mmol) were dissolved in a toluene solution (20mL), and N, N' -diisopropylethylamine (504mg, 3.896mmol) and bis (tri-tert-butylphosphine) palladium (25mg, 0.049mmol) were added. The reaction solution was replaced with nitrogen gas at room temperature for one minute, heated to 110 ℃ under microwave conditions, and stirred for 30 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100mL), and then washed with water (100mL × 3) and saturated brine (100mL) in this order, the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate ═ 20:1 to 5:1) to give compound 7-a (17mg, yield: 8.6%).
LC-MS(ESI):m/z＝408.0[M+H]+.
Synthesis of Compound 7
Compound 7-a (17mg, 0.042mmol) was suspended in methanol (5mL), and (S) -piperidine-2-carboxylic acid (11mg, 0.084mmol) and sodium cyanoborohydride (6.0mg, 0.084mmol) were added. The reaction solution was heated to 70 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 7(3.7mg, yield: 7.0%).
LC-MS(ESI):m/z＝521.0[M+H]+.
1H NMR(400MHz,CD3OD):δ7.86(s,1H),7.80(d,J＝7.6Hz,1H),7.70-7.66(t,J＝8.0Hz,1H),7.62-7.52(m,2H),7.50-7.47(m,2H),7.44-7.37(m,5H),4.46-4.43(d,J＝13.2Hz,2H),4.32-4.29(d,J＝12.8Hz,1H),3.98(s,3H),3.43-3.41(m,1H),2.93-2.87(m,1H),2.17-2.14(m,1H),1.79-1.61(m,4H),1.48-1.45(m,1H)ppm。
Example 8
(S, E) -1- (5-chloro-4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2-methylbenzyl) piperidine-2-carboxylic acid (Compound 8)
Figure BDA0003234055820000451
Synthesis of Compound 8-c
The method comprises the following steps:
biphenyl-2-carboxylic acid (5g,25.22mmol) was dissolved in anhydrous tetrahydrofuran (180mL), dried under nitrogen stirring and cooled to-78 ℃ using a glacial acetone bath, and a 1.3M solution of s-butyllithium in n-hexane (44mL,57.2mmol) was added dropwise to the mixture over 30 minutes under nitrogen. After the addition was complete, stirring was continued at-78 ℃ under nitrogen for 2.5 hours. To the resulting orange-red solution was added 1, 2-dibromotetrachloroethane (24.6g,75.6 mmol). The dry ice acetone bath was removed and the reaction allowed to return to room temperature and stirred for 16 hours. Water (30mL) was added to the reaction mixture, and the mixture was separated. The aqueous phase was washed with diethyl ether (40mL) and then adjusted to pH 1 with 4N hydrochloric acid. Extraction with ether (20 mL. times.4), combining the organic phases and washing with brine (20mL), concentration under reduced pressure, and recrystallization of the residue from petroleum ether/ethyl acetate gave compound 8-e (4.9g, yield: 71%). LC-MS (ESI) M/z 276[ M-H ═]+.
Compound 8-e (2.75g,10mmol) was dissolved in dichloromethane (50mL) and two drops of N, N' -dimethylformamide were added as a catalyst. Oxalyl chloride (5.54g,20mmol) was added dropwise with stirring, and after the addition was complete, stirring was carried out for one hour. And (4) spin-drying to obtain a crude acyl chloride product. The acid chloride was dissolved in dichloromethane (50mL) and the solution was slowly added dropwise to stirred concentrated aqueous ammonia (50 mL). After completion of the dropwise addition, stirring was carried out for one hour, followed by extraction with ethyl acetate (20 mL. times.3), and the organic phases were combined and washed with brine (20mL), and concentrated under reduced pressure to obtain compound 8-d (2.56g, yield: 93%) which was used directly in the next reaction. LC-MS (ESI) with M/z 277[ M + H ]]+.
Compound 8-d (2.50g,9.1mmol) was dissolved in dichloromethane (50mL), to which triethylamine (2.30g,23mmol) was added. Trifluoroacetic anhydride (2.5g,11.8mmol) was added dropwise at 0 ℃ and stirred for two hours. The reaction mixture was diluted with ethyl acetate (200mL), washed with brine (20 mL. times.3), and concentrated under reduced pressure to give 8-c (2.10g, yield: 92%) as a white solid, which was used in the next reaction.
Method two
Phenylboronic acid (3.06g, 10mmol) and 2-bromo-6-iodobenzonitrile (3.0g, 12mmol) were dissolved in a mixed solution of 1, 4-dioxane (40mL) and water (4mL), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (731mg, 1.0mmol) and sodium carbonate (4.08g, 30mmol) were added. After the reaction system was replaced with nitrogen three times, it was heated to 40 ℃ and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether: dichloromethane ═ 7:1) to give compound 8-c (1.65g, yield: 67.5%).
Synthesis of Compound 8-b
Compound 8-c (516mg, 2mmol) and vinyl boronic acid pinacol ester (462mg, 3mmol) were dissolved in a toluene (20mL) solution, and bis (tri-tert-butylphosphino) palladium (102mg,0.2mmol) and triethylamine (2.02g,20mmol) were added. After the reaction system was replaced with nitrogen three times, it was heated to 80 ℃ and stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to obtain compound 8-b (364mg, yield: 55%).
1H NMR(400MHz,DMSO-d6):δ8.01(d,J＝7.6Hz,1H),7.79-7.75(m,1H),7.60-7.50(m,7H),6.50(d,J＝18Hz,1H),2.28(s,3H),1.27(s,12H)ppm
Synthesis of Compound 8-a
Compound 8-b (110mg, 0.332mmol) and compound 8-f (84mg, 0.277mmol) were dissolved in toluene solution (20mL), and potassium phosphate (118mg, 0.554mmol), cesium fluoride (84mg, 0.554mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (24mg, 0.028mmol) were added. The reaction solution was replaced with nitrogen three times, then heated to 90 ℃ and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100mL), and washed with water (100mL) and saturated brine (100mL) in that order. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 20:1 to 5:1) to obtain compound 8-a (56mg, yield: 56.6%).
Synthesis of Compound 8
Compound 8-a (56mg, 0.156mmol) was suspended in methanol (10mL), and (S) -piperidine-2-carboxylic acid (41mg, 0.313mmol) and sodium cyanoborohydride (20mg, 0.313mmol) were added. The reaction solution was heated to 70 ℃ and stirred for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 8(21.9mg, yield: 29.7%).
LC-MS(ESI):m/z＝471.0[M+H]+.
1H NMR(400MHz,CD3OD):δ7.85-7.84(d,J＝7.6Hz,1H),7.67-7.61(m,4H),7.52-7.46(m,3H),7.42-7.38(m,4H),4.57-4.47(m,2H),3.99-3.96(m,1H),3.47-3.44(m,1H),2.95-2.88(m,1H),2.42(s,3H),2.20-2.15(m,1H),1.77-1.61(m,4H),1.52-1.46(m,1H)ppm。
Example 9
(S, E) -4- (5-chloro-4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2-methylbenzyl) morpholine-3-carboxylic acid (Compound 9)
Figure BDA0003234055820000471
Synthesis of Compound 9
Compound 8-a (100mg, 0.279mmol) and (S) -morpholine-3-carboxylic acid (73mg, 0.559mmol) were suspended in methanol (10mL) and sodium cyanoborohydride (36mg, 0.559mmol) was added. The reaction was heated to 70 ℃ and stirred for 16 hours. After completion of the reaction, the solution was spin-dried, and the resulting white residue was dissolved in ethyl acetate and washed once with water and saturated brine. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100mL), and washed with water (100mL) and saturated brine (100mL) in that order. The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 9(7.3mg, yield: 5.5%).
LC-MS(ESI):m/z＝473.0[M+H]+.
1H NMR(400MHz,CD3OD):δ7.81-7.79(d,J＝7.6Hz,1H),7.62-7.57(m,2H),7.53(s,1H),7.45-7.33(m,8H),4.18-4.14(d,J＝13.2Hz,1H),3.92-3.89(dd,J＝3.6Hz,J＝11.6Hz,1H),3.73-3.64(m,3H),3.60-3.55(m,1H),3.35-3.33(m,1H),2.98-2.93(m,1H),2.60-2.56(m,1H),2.33(s,3H)ppm。
Example 10
(S, E) -1- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2, 5-dimethylbenzyl) piperidine-3-carboxylic acid (Compound 10)
Figure BDA0003234055820000472
Synthesis of Compound 10-b
1, 4-dibromo-2, 5-dimethylbenzene (2.64g,10.0mmol) was dissolved in anhydrous tetrahydrofuran (60mL), and the solution was cooled to-78 ℃ and a 2.4M n-butyllithium solution (5.0mL,12.0mmol) was slowly added dropwise with stirring under a nitrogen atmosphere. After the dropwise addition, the reaction solution was slowly warmed to-20 ℃. After ten minutes, the temperature was again lowered to-78 ℃ and anhydrous NN' -dimethylformamide (876mg, 12.0mmol) was added dropwise. Stirring for 30 minutes, removing the ice-water bath, naturally heating the reaction system to room temperature, and continuing stirring for 10 hours. The reaction solution was quenched by pouring it into an ice-water mixture, and then extracted with ethyl acetate (200mL), the organic phase was washed with water (200mL) and saturated brine (200mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 100:1 to 10:1) to obtain compound 10-b (1.2g, yield: 56%).
1H NMR:(400MHz DMSO-d6):δ10.17(s,3H),7.75(s,1H),7.62(s,1H),2.56(s,3H),2.38(s,3H)ppm
Synthesis of Compound 10-a
Compound 10-b (106.5mg,0.5mmol) and compound 8-b (198.6mg,0.6mmol) were dissolved in anhydrous toluene (30mL), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (73.1mg,0.1mmol), potassium phosphate (424mg,2.0mmol) and cesium fluoride (304mg,2.0mmol) were added to the mixture. The reaction mixture was stirred at 100 ℃ for 16 hours under nitrogen, the reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 15:1 to 5:1) to give 10-a (80mg, yield: 48%) as a yellow solid.
Synthesis of Compound 10
Compound 10-a (80.0mg,0.237mmol) and (S) -piperidine-2-carboxylic acid (61.2mg,0.474mmol) were dissolved in methanol (20ml), and sodium cyanoborohydride (37.3mg,0.59mmol) was added, and the reaction was heated to 60 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 10(36.1mg, yield: 34%) as a white solid.
LC-MS(ESI):m/z＝451.3[M+H]+.
1H NMR(400MHz CD3OD):δ7.96(d,J＝8.0Hz,1H),7.74(t,J＝8.0Hz,1H),7.67(d,J＝16.0Hz,1H),7.59-7.45(m,9H),4.67(d,J＝12.8Hz,1H),4.06(d,J＝12.8Hz,1H),3.56-3.53(m,1H),3.33-3.32(m,1H),3.01-2.98(m,1H),2.50(s,3H),2.49(s,3H)，2.31-2.27(m,1H),1.88-1.60(m,5H)ppm。
Example 11
(S, E) -4- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2, 5-dimethylbenzyl) morpholine-3-carboxylic acid (Compound 11)
Figure BDA0003234055820000481
Synthesis of Compound 11
Compound 10-a (80.0mg,0.237mmol) and (S) -morpholine-3-carboxylic acid (62mg,0.474mmol) were dissolved in methanol (25ml), sodium cyanoborohydride (37.3mg,0.59mmol) was added, and the reaction was heated to 60 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 11(50mg, yield: 46%) as a white solid.
LC-MS(ESI):m/z＝453.3[M+H]+.
1H NMR(400MHz CD3OD):δ7.95(d,J＝7.6Hz,1H),7.73(t,J＝8.0Hz,1H),7.66(d,J＝16.4Hz,1H),7.59-7.47(m,7H),7.44(d,J＝7.2Hz,1H),7.38(s,1H),4.55(d,J＝12.8Hz,1H),4.16(dd,J1＝3.6Hz,J2＝12.0Hz,1H),3.94(d,J＝12.8Hz,1H),3.90-3.85(m,1H),3.79-3.61(m,3H),3.13-3.10(m,1H),3.00-2.94(m,1H),2.50(s,3H),2.48(s,3H)ppm。
Example 12
(S, E) -2- ((4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2, 5-dimethylbenzyl) amino) -3-hydroxy-2-methylpropanoic acid (Compound 12)
Figure BDA0003234055820000491
Synthesis of Compound 12
Methylserine (127mg,1.06mmol) was dissolved in methanol (10mL), and 0.53M aqueous sodium hydroxide solution (2mL,1.06mmol) was added dropwise with stirring and stirred for 10 minutes. The reaction mixture was cooled to 0 ℃ and a solution of compound 10-a (120.0mg,0.35mmol) in tetrahydrofuran (6mL) was slowly added dropwise. The reaction solution was warmed to room temperature and stirred for 16 hours. Sodium borohydride (27.0mg,0.71mmol) was added to the reaction solution and stirring was continued for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 12(12mg, yield: 7%) as a white solid.
LC-MS(ESI):m/z＝441.4[M+H]+.
1H NMR(400MHz DMSO-d6):δ8.07(d,J＝7.6Hz,1H),7.77(t,J＝8.0Hz,1H),7.68(d,J＝16.0Hz,1H),7.61-7.47(m,6H),7.43(s,2H),7.32(d,J＝16.0Hz,1H),7.32(s,1H),6.09(bs,1H),3.63(s,2H),3.44-3.38(m,2H),2.40(s,3H),2.32(s,3H),1.15(s,3H)ppm。
Example 13
(S, E) -1- (5-chloro-4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2-methylbenzyl) piperazine-2-carboxylic acid (Compound 13)
Figure BDA0003234055820000492
Synthesis of Compound 13-a
Compound 8-a (100mg, 0.279mmol) and (S) -4-Boc-piperazine-2-carboxylic acid (129mg, 0.559mmol) were dissolved in methanol (20ml), and sodium cyanoborohydride (36mg, 0.559mmol) was added, heated to 70 ℃ and stirred for reaction for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100mL) and washed with water (100mL) and saturated brine (100mL) in this order. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 13-a (28mg, yield: 17.5%).
LC-MS(ESI):m/z＝572.0[M+H]+.
Synthesis of Compound 13
Compound 13-a (28mg, 0.049mmol) was dissolved in dichloromethane solution (10mL), trifluoroacetic acid (2mL) was added, the reaction was stirred at room temperature for 2 hours, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 13(10.9mg, yield: 47.4%).
LC-MS(ESI):m/z＝472.0[M+H]+.
1H NMR(400MHz,CD3OD):δ7.93-7.91(d,J＝8.0Hz,1H),7.74-7.70(m,2H),7.61-7.55(m,4H),7.51-7.46(m,5H),4.59(s,1H),3.79(s,2H),3.41-3.37(m,1H),3.24-3.20(m,2H),3.13-3.04(m,2H),2.63-2.59(m,1H),2.41(s,3H)ppm。
Example 14
(S, E) -1- (5-chloro-4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2-methylbenzyl) -4-methylpiperazine-2-carboxylic acid (Compound 14)
Figure BDA0003234055820000501
Synthesis of Compound 14-c
(S) -1-Boc-piperazine-2-carboxylic acid methyl ester (200mg, 0.819mmol) was dissolved in methanol solution (20mL), and 37% aqueous formaldehyde (0.5mL, 4.10mmol), glacial acetic acid (99mg, 1.64mmol) and 10% Pd-C (50mg) were added. The reaction solution was stirred at room temperature for 16 hours under hydrogen gas. The reaction solution was filtered through celite, washed with methanol (30mL × 3), the filtrates were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:1) to give compound 14-c (204mg, yield: 96.7%).
LC-MS(ESI):m/z＝159.0[M-Boc+H]+.
Synthesis of Compound 14-b
Compound 14-c (204mg, 0.79mmol) was dissolved in dichloromethane (30mL) and trifluoroacetic acid (6mL) was added. The reaction solution was stirred at room temperature for 2 hours, concentrated under reduced pressure, and the residue was added with methylene chloride (30mL) and then concentrated under reduced pressure and repeated once, and the residue was then added with toluene (30mL) and then concentrated under reduced pressure and repeated once. The residue was dried in vacuo to give compound 14-b (123mg, yield: 99.0%) which was used directly in the next reaction.
LC-MS(ESI):m/z＝159.0[M+H]+.
Synthesis of Compound 14-a
Compound 8-a (136mg, 0.38mmol) and compound 14-b (195mg, 0.76mmol) were dissolved in methanol solution (20mL), and sodium cyanoborohydride (48mg, 0.76mmol) and sodium acetate (155mg, 1.14mmol) were added. The reaction solution was heated to 70 ℃ and stirred for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in methylene chloride (100mL) and washed with water (100mL) and saturated brine (100mL) in this order. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 14-a (30mg, yield: 15.8%).
LC-MS(ESI):m/z＝500.0[M+H]+.
Synthesis of Compound 14
Compound 14-a (70mg, 0.185mmol) was dissolved in a mixed solution of methanol (5mL), tetrahydrofuran (5mL) and water (1mL), and sodium hydroxide (23mg, 0.371mmol) was added. The reaction was stirred at room temperature for 16 hours. After the reaction is finished, the mixture is concentrated under reduced pressure, the residue is diluted by adding water (50mL), the pH value of the solution is adjusted to 3-5 by using dilute hydrochloric acid, and white solid is separated out. Filtration and the filtrate cake was subjected to high performance liquid chromatography to give Compound 14(11.0mg, yield: 37.9%).
LC-MS(ESI):m/z＝486.0[M+H]+.
1H NMR(400MHz,CD3OD):δ7.92-7.90(d,J＝8.0Hz,1H),7.74-7.69(m,2H),7.60-7.55(m,3H),7.54-7.52(m,1H),7.51-7.41(m,5H),3.82(s,2H),3.40(s,2H),3.22-3.20(d,J＝8.4Hz,2H),3.07-3.05(d,J＝9.2Hz,1H),2.79(s,3H),2.69-2.65(m,1H),2.40(s,3H)ppm。
Example 15
(S, E) -1- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (4-cyanobutoxy) -5-methylbenzyl) piperidine-2-carboxylic acid (Compound 15)
Figure BDA0003234055820000511
Synthesis of Compound 15-c
A mixture of 3-bromo-4-methylphenol (374mg,1.0mmol), 5-bromovaleronitrile (486mg,3.0mmol), potassium carbonate (553mg,4mmol) and N, N' -dimethylformamide (5mL) was heated to 60 ℃ and stirred for 16 h. The reaction was cooled to room temperature and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (20mL x 2). The organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1) to obtain 15-c (536mg, yield: 100%) as a white solid.
1H NMR(400MHz,CDCl3):δ7.12(d,J＝8.4Hz,1H),7.08(d,J＝2.6Hz,1H),6.74(dd,J＝8.4,2.6Hz,1H),3.96(t,J＝5.7Hz,2H),2.44(t,J＝6.8Hz,2H),2.32(s,3H),1.97–1.82(m,4H)ppm
Synthesis of Compounds 15-b-1 and 15-b-2
Compound 15-c (268mg,1mmol), 1, 2-dichloromethyl methyl ether (138mg,1.2mmol) was dissolved in dichloromethane (5 mL). Titanium tetrachloride (569mg, 3.0mmol) was added dropwise at 0 ℃ and stirred for 2 hours. The reaction solution was quenched with ice water (20mL), and the resulting mixture was extracted with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 3:1) to give 15-b-1(141mg, yield: 48%) as a white solid and 15-b-2(100mg, yield: 34%) as a pale yellow solid.
Compound 15-b-1:
1H NMR(400MHz,CDCl3):δ10.39(s,1H),7.67(s,1H),7.18(s,1H),4.11(t,J＝5.9Hz,2H)，2.47(t,J＝6.9Hz,2H),2.36(s,3H),2.03(dt,J＝8.8,5.8Hz,2H),1.96–1.84(m,2H)ppm
compound 15-b-2:
1H NMR(400MHz,CDCl3):δ10.41(s,1H),7.34(d,J＝8.5Hz,1H),6.85(d,J＝8.5Hz,1H),4.07(t,J＝5.7Hz,2H),2.48(t,J＝6.8Hz,2H),2.08–1.85(m,4H)ppm
synthesis of Compound 15-a
A mixture of compound 15-b-2(135mg,0.46mmol), compound 8-b (181mg,0.55mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (37mg,0.05mmol), potassium carbonate (126mg,0.91mmol), 1, 4-dioxane (2mL) and water (0.2mL) was stirred at 90 ℃ under nitrogen for 16 h. The reaction mixture was cooled to room temperature, and diluted with saturated brine (20 mL). The resulting mixture was extracted with dichloromethane (50 mL. times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to obtain compound 15-a (130mg, yield: 68%).
LC-MS(ESI):m/z＝421.4[M+H]+.
1H NMR(400MHz,CDCl3):δ10.45(s,1H),7.80(d,J＝7.6Hz,1H),7.70–7.63(m,2H),7.60–7.42(m,8H),7.21(s,1H),4.22(t,J＝5.9Hz,2H),2.48(t,J＝7.0Hz,2H),2.42(s,3H),2.12–2.02(m,2H),2.00–1.89(m,2H)ppm
Synthesis of Compound 15
To a mixture of compound 15-a (50mg,0.12mmol), (S) -piperidine-2-carboxylic acid (31mg, 0.24mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (15mg,0.24 mmol). The reaction solution was heated to 70 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to prepare 15(32mg, yield: 50%) as a white solid.
LC-MS(ESI):m/z＝534.5[M+H]+.
1H NMR(400MHz,CD3OD):δ7.96(d,J＝7.8Hz,1H),7.73(t,J＝7.9Hz,1H),7.67(d,J＝16.1Hz,1H),7.60–7.54(m,2H),7.54–7.44(m,5H),7.40(s,1H),7.33(s,1H),4.50(d,J＝12.9Hz,1H),4.34(d,J＝12.7Hz,1H),4.22(t,J＝6.1Hz,2H),3.53(d,J＝7.5Hz,1H),3.32(s,1H),2.99(t,J＝12.3Hz,1H),2.57(t,J＝7.0Hz,2H),2.45(s,3H),2.29–2.16(m,1H),2.09–1.99(m,2H),1.95–1.65(m,6H),1.63–1.50(m,1H)ppm。
Example 16
(E) - (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (4-cyanobutoxy) -5-methylbenzyl) glycine (Compound 16)
Figure BDA0003234055820000521
Synthesis of Compound 16
To a mixture of compound 15-a (80mg,0.19mmol), glycine (57mg, 0.76mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (60mg,0.95 mmol). The reaction solution was heated to 70 ℃ and stirred for 1 hour, then sodium cyanoborohydride (60mg,0.95mmol) was added, and stirring was continued for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 16(19.6mg, yield: 21%) as a white solid.
LC-MS(ESI):m/z＝480.5[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.05(d,J＝7.9Hz,1H),7.79(t,J＝7.9Hz,1H),7.67(d,J＝16.0Hz,1H),7.62–7.47(m,6H),7.40(d,J＝16.0Hz,1H),7.26(d,J＝5.6Hz,2H),4.12(t,J＝6.0Hz,2H),3.94(s,2H),3.13(s,2H),2.60(t,J＝7.0Hz,2H),2.38(s,3H),1.93–1.84(m,2H),1.83–1.74(m,2H)ppm。
Example 17
(S, E) -4- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (4-cyanobutoxy) -5-methylbenzyl) morpholine-3-carboxylic acid (Compound 17)
Figure BDA0003234055820000531
Synthesis of Compound 17
To a mixture of compound 15-a (63mg,0.15mmol), (S) -morpholine-3-carboxylic acid (39mg, 0.30mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (38mg,0.60 mmol). The reaction solution was heated to 65 ℃ and stirred for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 17(46.1mg, yield: 57%) as a white solid.
LC-MS(ESI):m/z＝536.4[M+H]+.
1H NMR(400MHz,CD3OD):δ7.95(d,J＝7.9Hz,1H),7.72(t,J＝7.9Hz,1H),7.66(d,J＝16.1Hz,1H),7.59–7.54(m,2H),7.54–7.43(m,5H),7.40(s,1H),7.32(s,1H),4.50(d,J＝12.8Hz,1H),4.33(d,J＝12.7Hz,1H),4.26–4.13(m,3H),3.93(d,J＝12.8Hz,1H),3.82–3.64(m,3H),3.25(d,J＝12.6Hz,1H),3.09(t,J＝9.8Hz,1H),2.57(t,J＝7.0Hz,2H),2.44(s,3H),2.09–1.98(m,2H),1.95–1.83(m,2H)ppm。
Example 18
(S, E) -1- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (4-cyanobutoxy) -5-methylbenzyl) piperazine-2-carboxylic acid (Compound 18)
Figure BDA0003234055820000532
Synthesis of Compound 18
To a mixture of compound 15-a (63mg,0.15mmol), (S) -4- (tert-butoxycarbonyl) piperazine-2-carboxylic acid (69mg, 0.30mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (38mg,0.60 mmol). The reaction mixture was warmed to 60 ℃ and stirred for 1 hour, cooled to room temperature, concentrated under reduced pressure, and the resulting residue was dissolved in methylene chloride (1mL) and trifluoroacetic acid (1mL) and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 18(36.5mg, yield: 45%) as a white solid.
LC-MS(ESI):m/z＝535.5[M+H]+.
1H NMR(400MHz,CD3OD):δ7.94(d,J＝8.0Hz,1H),7.71(t,J＝7.9Hz,1H),7.65(d,J＝16.0Hz,1H),7.59–7.39(m,7H),7.31(s,1H),7.22(s,1H),4.12(t,J＝5.8Hz,2H),3.92(s,2H),3.42(t,J＝4.9Hz,1H),3.29(s,1H),3.19–3.05(m,3H),2.69(m,1H),2.56(t,J＝6.9Hz,2H),2.42(s,3H),2.03–1.83(m,4H)ppm。
Example 19
(E) - (5-chloro-4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2-methylbenzyl) glycine (Compound 19)
Figure BDA0003234055820000541
Synthesis of Compound 19-c
Compound 8-a (260mg, 0.727mmol) was dissolved in a mixed solution of methanol (5mL) and tetrahydrofuran (5mL), and sodium borohydride (55mg, 1.454mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (50mL), washed with water (50mL) and saturated brine (50mL) in this order, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 20:1 to 3:1) to give compound 19-c (218mg, yield: 83.8%).
Synthesis of Compound 19-b
Compound 19-c (116mg, 0.322mmol) was dissolved in dichloromethane (10mL), 1 drop of N, N' -dimethylformamide was added, followed by dropwise addition of thionyl chloride (0.5mL), and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added with methylene chloride (50 mL. times.2) and concentrated under reduced pressure. The residue was dried in vacuo to give compound 19-b (122mg, yield: 99.0%) which was used directly in the next reaction.
Synthesis of Compound 19-a
Serine methyl ester hydrochloride (41mg, 0.322mmol) and compound 19-b (122mg, 0.322mmol) were dissolved in acetonitrile (20mL), and potassium carbonate (223mg, 1.61mmol) and sodium iodide (10mg, 0.065mmol) were added. The reaction solution was heated to 80 ℃ and stirred for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in methylene chloride (50mL) and washed with water (50mL) and saturated brine (50mL) in this order. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1 to 1:2) to obtain compound 19-a (63mg, yield: 45.5%).
LC-MS(ESI):m/z＝431.0[M+H]+.
Synthesis of Compound 19
Compound 19-a (63mg, 0.146mmol) was dissolved in a mixed solution of methanol (5mL), tetrahydrofuran (5mL) and water (1mL), sodium hydroxide (12mg, 0.292mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours, after which the reaction was terminated and concentrated under reduced pressure. The residue was diluted with water (50mL), the pH of the solution was adjusted to 3-5 with dilute hydrochloric acid, a white solid precipitated, filtered, and the filter cake was subjected to high performance liquid chromatography to give compound 19(10.0mg, yield: 16.4%).
LC-MS(ESI):m/z＝417.0[M+H]+.
1H NMR(400MHz,CD3OD):δ7.97-7.95(d,J＝8.0Hz,1H),7.79-7.72(m,3H),7.64-7.57(m,4H),7.52-7.47(m,4H),4.35(s,2H),4.05(s,2H),2.52(s,3H)ppm。
Example 20
(S, E) -1- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2-hydroxymethyl-5-trifluoromethylbenzyl) piperidine-2-carboxylic acid (Compound 20)
Figure BDA0003234055820000551
Synthesis of Compound 20-h
5-bromophenphthalide (6.3g,30mmol) was dissolved in trifluoromethanesulfonic acid (60mL) and cooled to 0 ℃ with stirring. N-iodosuccinimide (16.8g, 75mmol) powder was slowly added to the reaction system. Subsequently, the ice bath was removed and the solution was warmed to room temperature and stirred for 16 hours. The reaction mixture was poured into ice water (200mL) and a large amount of dark yellow solid precipitated, which was filtered and washed with water (500 mL. times.3). The solid was then dissolved in dichloromethane (500mL) and washed with saturated sodium thiosulfate solution (100 mL. times.2). The organic phase was washed again with water (200mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a dark yellow solid 20-h (9.0g, yield: 89.1%). The product was used directly in the next reaction without further purification.
Synthesis of Compound 20-g
Compound 20-h (6.7g, 20mmol), methyl fluorosulfonyl difluoroacetate (19g, 100mmol) and cuprous iodide (760mg, 2mmol) were mixed in N, N-dimethylformamide (50mL), and the reaction was stirred at 90 ℃ for 16h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, ethyl acetate (300mL) was added to the filtrate, washed with water (50mL × 3) and saturated brine (50mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to obtain 20-g (900mg, yield: 16.0%) of a white solid.
LC-MS(ESI):m/z＝282[M+H]+.
Synthesis of Compound 20-f
Compound 20-g (800mg,2.8mmol) was dissolved in a mixed solvent of tetrahydrofuran (18mL) and water (2 mL). Lithium hydroxide monohydrate (420mg, 10mmol) was added thereto, and stirred at room temperature for 16 hours. The pH was adjusted to 1 with 1N hydrochloric acid, concentrated under reduced pressure and purified by reverse phase chromatography (Biotage Flash) to give 20-f (650mg, yield: 75.6%) as a white solid.
LC-MS(ESI):m/z＝299[M-H]+.
Synthesis of Compound 20-e
Compound 20-f (600mg, 2mmol) was dissolved in N, N-dimethylformamide (10mL), to which imidazole (260mg, 4mmol) and t-butyldimethylsilyl chloride (450mg, 3mmol) were added. The reaction was stirred at room temperature for 16 hours. To the reaction mixture was added ethyl acetate (100mL), which was washed with water (20mL × 3) and saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give compound 20-e (600mg, yield: 72.6%).
1H NMR(400MHz,DMSO-d6) Synthesis of delta 8.19(s,1H),8.11(s,1H),5.10(s,2H),5.10(s,9H),0.11(s,6H) ppm of Compound 20-d
Compound 20-e (413mg, 1mmol) was dissolved in anhydrous tetrahydrofuran (10mL), and a borane tetrahydrofuran solution (5mL, 5mmol) was added dropwise thereto at 0 ℃ under nitrogen, and the mixture was refluxed for 16 hours. The reaction mixture was cooled to room temperature, and methanol (10mL) was slowly added dropwise thereto under reflux for one hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to give compound 20-d (260mg, yield: 65.0%).
LC-MS(ESI):m/z＝399[M-H]+.
Synthesis of Compound 20-c
Compound 20-d (210mg, 0.52mmol) was dissolved in dichloromethane (10mL), to which manganese dioxide (450mg, 5.2mmol) was added. The reaction was stirred at room temperature for 16 hours. Filtered and washed with dichloromethane (10 mL. times.3). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1) to give compound 20-c (150mg, yield: 71.5%). The product was not further purified.
Synthesis of Compound 20-b
A mixture of compound 20-c (120mg, 0.42mmol), compound 8-b (141mg, 0.42mmol), sodium carbonate (132mg,1.26mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (31mg,0.042mmol) in 1, 4-dioxane (5mL) and water (0.5mL) was stirred at 80 ℃ under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to give compound 20-b (65mg, yield: 29.8%).
LC-MS(ESI):m/z＝522[M+H]+.
Synthesis of Compound 20-a
A mixture of compound 20-b (50mg, 0.096mmol), L-piperidine-2-carboxylic acid (24mg, 0.19mmol), sodium cyanoborohydride (12mg,0.19mmol) and methanol (3mL) was stirred at 80 ℃ under nitrogen for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by reverse phase chromatography (Biotage Flash) to give compound 20-a (35mg, yield: 57.6%).
LC-MS(ESI):m/z＝635[M+H]+.
Synthesis of Compound 20
Compound 20-a (30mg, 0.047mmol) was dissolved in tetrahydrofuran (5mL), a 1.0M tetrabutylammonium fluoride solution (0.5mL,0.5mmol) was added thereto, the reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 20(8mg, yield: 33.3%).
LC-MS(ESI):m/z＝521[M+H]+.
1H NMR(400MHz,CD3OD):δ8.04(s,1H),7.93(s,1H),7.89(d,J＝8.0Hz,1H),7.77(t,J＝8.0Hz,1H),7.72-7.62(m,2H),7.59-7.46(m,6H),5.04(d,J＝12.4Hz,1H),4.92-4.91(m,1H),4.81-4.80(m,1H),4.21(d,J＝12.8Hz,1H),3.56-3.53(m,1H),3.21-3.18(m,1H),2.95-2.89(m,1H),2.26-2.23(m,1H),1.94-1.76(m,3H),1.63-1.58(m,2H)ppm。
Example 21
(S, E) -4- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2-hydroxymethyl-5-trifluoromethylbenzyl) morpholine-3-carboxylic acid (Compound 21)
Figure BDA0003234055820000571
Synthesis of Compound 21-a
A mixture of compound 20-b (50mg, 0.096mmol), L-morpholine-3-carboxylic acid (24mg, 0.19mmol), sodium cyanoborohydride (12mg,0.19mmol) and methanol (3mL) was stirred at 80 deg.C under nitrogen for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by reverse phase chromatography (Biotage Flash) to give compound 21-a (35mg, yield: 57.6%).
LC-MS(ESI):m/z＝635[M+H]+.
Synthesis of Compound 21
Compound 21-a (30mg, 0.047mmol) was dissolved in tetrahydrofuran (5mL), a 1.0M tetrabutylammonium fluoride solution (0.5mL,0.5mmol) was added thereto, the reaction was stirred at room temperature for 16 hours and then concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 21(8mg, yield: 33.3%).
LC-MS(ESI):m/z＝523[M+H]+.
1H NMR(400MHz,CD3OD):δ8.03(s,1H),7.87(d,J＝8.0Hz,1H),7.81(s,1H),7.75(t,J＝8.0Hz,1H),7.67-7.47(m,8H),4.98(d,J＝13.2Hz,1H),4.81-4.80(m,1H),4.51(d,J＝12.8Hz,1H),4.03-3.99(m,1H),3.88-3.74(m,3H),3.66-3.61(m,1H),3.43-3.42(m,1H),3.00-2.96(m,1H),2.63-2.59(m,1H)ppm。
Example 22
(S, E) -4- (5-chloro-2-methyl-4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) benzyl) morpholine-3-carboxylic acid (Compound 22)
Figure BDA0003234055820000581
Synthesis of Compound 22
Compound 5-a (100mg, 0.288mmol) and (S) -morpholine-3-carboxylic acid (75.7mg, 0.577mmol) were dissolved in methanol (10mL), sodium cyanoborohydride (36.3mg, 0.577mmol) was added, and the reaction solution was heated to 70 ℃ and stirred for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 22(37.2mg, yield: 27.8%) as a white solid.
LC-MS(ESI):m/z＝462.0[M+H]+.
1H NMR(400MHz,CD3OD):δ7.69(s,1H),7.60-7.52(m,3H),7.44-7.40(m,2H),7.36-7.24(m,5H),7.16-7.14(d,J＝7.6Hz,2H),4.44-4.40(d,J＝13.2Hz,2H),4.11-4.07(dd,J＝4.0Hz,J＝12.4Hz,1H),3.93-3.90(d,J＝13.2Hz,1H),3.86-3.79(m,2H),3.74-3.68(m,1H),3.61-3.58(m,1H),3.15-3.12(m,1H),2.91-2.86(m,1H),2.48(s,3H),2.29(s,3H)ppm。
Example 23
(S, E) -1- (5-chloro-2-methyl-4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) benzyl) piperazine-2-carboxylic acid (Compound 23)
Figure BDA0003234055820000582
Synthesis of Compound 23-a
Compound 5-a (100mg, 0.288mmol) and (S) -4- (tert-butoxycarbonyl) piperazine-2-carboxylic acid (133mg, 0.577mmol) were dissolved in methanol (10mL), sodium cyanoborohydride (36mg, 0.577mmol) was added, and the reaction solution was heated to 70 ℃ and stirred for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 23-a (76mg, yield: 46.9%).
LC-MS(ESI):m/z＝561.0[M+H]+.
Synthesis of Compound 23
Compound 23-a (76mg, 0.135mmol) was dissolved in dichloromethane (10mL), and trifluoroacetic acid (2mL) was added thereto and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give Compound 23(29.4mg, yield: 46.8%).
LC-MS(ESI):m/z＝461.0[M+H]+.
1H NMR(400MHz,CD3OD):δ7.63(s,1H),7.59-7.57(d,J＝7.6Hz,1H),7.51-7.47(d,J＝16.0Hz,1H),7.44-7.41(m,3H),7.37-7.24(m,5H),7.15-7.13(d,J＝7.2Hz,1H),3.96-3.85(q,J＝13.6Hz,J＝16.4Hz,2H),3.75-3.73(t,J＝4.0Hz,1H),3.59-3.55(dd,J＝4.4Hz,J＝13.2Hz,1H),3.38-3.34(dd,J＝4.0Hz,J＝12.8Hz,1H),3.25-3.19(m,2H),3.12-3.06(m,1H),2.84-2.80(m,1H),2.41(s,3H),2.29(s,3H)ppm。
Example 24
(S, E) -1- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (2-methoxyethoxy) -5-methylbenzyl) piperidine-2-carboxylic acid (Compound 24)
Figure BDA0003234055820000591
Synthesis of Compound 24-c
A mixture of 3-bromo-4-methylphenol (3.74g,20mmol), paraformaldehyde (4.41g,152mmol), magnesium chloride (2.86g,30mmol), triethylamine (7.56g,75mmol) and acetonitrile (150mL) was heated under reflux for 4 hours. The reaction was cooled to room temperature, diluted with water (500mL) and adjusted to pH 2-3 with 1M hydrochloric acid. The mixture was extracted with ethyl acetate (500 mL. times.2). The organic phases were combined, washed with saturated brine (200mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 50:1) to give 24-c (2.45g, yield: 57%) as a white solid.
Synthesis of Compound 24-b
A mixture of compound 24-c (645mg,3.0mmol), 1-bromo-2-methoxyethane (625mg,4.5mmol), potassium carbonate (829mg,6.0mmol) and N, N' -dimethylformamide (5mL) was heated to 60 ℃ and stirred for 4 hours. The reaction was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50mL), and the organic phases were washed with water (50mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 5:1) to give 24-b (624mg, yield: 76%) as a white solid.
1H NMR(400MHz,CDCl3):δ10.43(s,1H),7.67(s,1H),7.21(s,1H),4.21(t,J＝6.0,2H),3.79(t,J＝4.0,2H),3.45(s,3H),2.36(s,3H)ppm
Synthesis of Compound 24-a
A mixture of compound 24-b (273mg,1.0mmol), compound 8-b (397mg,1.2mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (73mg,0.1mmol), potassium carbonate (276mg,2.0mmol), 1, 4-dioxane (5mL) and water (0.5mL) was stirred at 90 ℃ under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, diluted with saturated brine (20mL), and the resulting mixture was extracted with ethyl acetate (40 mL. times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was washed with ethyl acetate (50mL) to give 24-a (330mg, yield: 83%) as a pale green solid.
LC-MS(ESI):m/z＝398.4[M+H]+.
Synthesis of Compound 24
To a mixture of compound 24-a (60mg,0.15mmol), (S) -piperidine-2-carboxylic acid (39mg, 0.30mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (38mg,0.60mmol), and the reaction solution was stirred at elevated temperature to 65 ℃ for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 24(35.2mg, yield: 46%) as a white solid.
LC-MS(ESI):m/z＝511.5[M+H]+.
1H NMR(400MHz,CD3OD):δ7.96(d,J＝7.9Hz,1H),7.73(t,J＝7.9Hz,1H),7.66(d,J＝16.1Hz,1H),7.60–7.54(m,2H),7.54–7.44(m,5H),7.34(s,2H),4.82–4.77(m,1H),4.60(d,J＝12.8Hz,1H),4.36–4.26(m,2H),4.22(d,J＝13.1Hz,1H),3.94–3.74(m,2H),3.57–3.48(m,1H),3.45(s,3H),2.95(t,J＝12.0Hz,1H),2.44(s,3H),2.34–2.20(m,J＝15.8Hz,1H),1.94–1.76(m,3H),1.74–1.62(m,1H),1.61–1.47(m,1H)ppm。
Example 25
(S, E) -4- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (2-methoxyethoxy) -5-methylbenzyl) morpholine-3-carboxylic acid (Compound 25)
Figure BDA0003234055820000601
Synthesis of Compound 25
To a mixture of compound 24-a (60mg,0.15mmol), (S) -morpholine-3-carboxylic acid (39mg, 0.30mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (38mg,0.60mmol), and the reaction was warmed to 65 ℃ and stirred for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 25(41.0mg, yield: 53%) as a white solid.
LC-MS(ESI):m/z＝513.5[M+H]+.
1H NMR(400MHz,CD3OD):δ7.96(d,J＝7.9Hz,1H),7.73(t,J＝7.9Hz,1H),7.66(d,J＝16.1Hz,1H),7.59–7.54(m,J＝8.0,1.6Hz,2H),7.54–7.44(m,5H),7.36(s,1H),7.34(s,1H),4.65(d,J＝12.7Hz,1H),4.36–4.20(m,4H),3.98–3.86(m,2H),3.85–3.77(m,1H),3.77–3.64(m,3H),3.46(s,3H),3.26–3.10(m,2H),2.44(s,3H)ppm。
Example 26
(S, E) -4- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (2-hydroxyethoxy) -5-methylbenzyl) piperidine-2-carboxylic acid (Compound 26)
Figure BDA0003234055820000602
Figure BDA0003234055820000611
Synthesis of Compound 26-b
A mixture of compound 24-c (645mg,3.0mmol), (2-bromoethoxy) (tert-butyl) dimethylsilane (1.08g,4.5mmol), potassium carbonate (829mg,6.0mmol) and N, N' -dimethylformamide (5mL) was heated to 60 ℃ and stirred for 16 hours. The reaction was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with water (50mL) and saturated brine (20mL), respectively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give 26-b (767mg, yield: 68%) as a white solid.
Synthesis of Compound 26-a
A mixture of compound 26-b (373mg,1.0mmol), compound 8-b (397mg,1.2mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (73mg,0.1mmol), potassium carbonate (276mg,2.0mmol), 1, 4-dioxane (5mL) and water (0.5mL) was stirred at 90 ℃ under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, and diluted with saturated brine (20 mL). The resulting mixture was extracted with dichloromethane (30 mL. times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 5:1) to give 26-a (355mg, yield: 71%) as a yellow solid.
LC-MS(ESI):m/z＝498.5[M+H]+.
Synthesis of Compound 26
To a mixture of compound 26-a (75mg,0.15mmol), (S) -piperidine-2-carboxylic acid (39mg, 0.30mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (38mg,0.60 mmol)). The reaction mixture was stirred for 1 hour at 60 ℃ and then concentrated under reduced pressure, and the obtained residue was added with tetrahydrofuran (1mL), water (one drop) and trifluoroacetic acid (0.5mL) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 26(48.3mg, yield: 53%) as a white solid.
LC-MS(ESI):m/z＝497.5[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.05(d,J＝8.0Hz,1H),7.79(t,J＝7.9Hz,1H),7.67(d,J＝16.0Hz,1H),7.63–7.47(m,6H),7.40(d,J＝16.0Hz,1H),7.27(s,2H),7.07(s,1H),4.13–3.90(m,5H),3.75(t,J＝4.6Hz,2H),3.28–3.21(m,1H),3.08–3.00(m,1H),2.38(s,3H),1.97–1.86(m,1H),1.78–1.66(m,1H),1.63–1.48(m,3H),1.45–1.31(m,1H)ppm。
Example 27
(S, E) -1- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (2-methoxyethoxy) -5-methylbenzyl) piperazine-2-carboxylic acid (Compound 27)
Figure BDA0003234055820000621
Synthesis of Compound 27
To a mixture of compound 24-a (60mg,0.15mmol), (S) -4- (tert-butoxycarbonyl) piperazine-2-carboxylic acid (69mg, 0.30mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (38mg,0.60mmol), the reaction solution was warmed to 60 ℃ and stirred for 1 hour, then cooled to room temperature, concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (1.5mL) and trifluoroacetic acid (0.5mL) and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 27(66.7mg, yield: 87%) as a white solid.
LC-MS(ESI):m/z＝512.4[M+H]+.
1H NMR(400MHz,CD3OD):δ7.95(d,J＝7.9Hz,1H),7.72(t,J＝7.8Hz,1H),7.65(d,J＝16.1Hz,1H),7.59–7.54(m,J＝8.0,1.5Hz,2H),7.53–7.41(m,5H),7.30(s,1H),7.27(s,1H),4.22(t,J＝4.4Hz,2H),4.06(d,J＝13.1Hz,1H),3.97(d,J＝13.4Hz,1H),3.85–3.75(m,2H),3.49(dd,J＝7.0,3.5Hz,1H),3.44(s,3H),3.35(dd,J＝12.9,3.5Hz,1H),3.25(dd,J＝13.1,6.9Hz,1H),3.18–3.08(m,3H),2.79–2.71(m,1H),2.42(s,3H)ppm。
Example 28
(S, E) -1- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2-hydroxymethyl-5-trifluoromethylbenzyl) piperazine-2-carboxylic acid (Compound 28)
Figure BDA0003234055820000622
Synthesis of Compound 28-a
A mixture of compound 20-b (50mg, 0.096mmol), (S) -4-tert-butoxycarbonyl-2-piperazinecarboxylic acid (44mg, 0.19mmol), sodium cyanoborohydride (12mg,0.19mmol) and methanol (3mL) was stirred at 80 ℃ for 3 hours under nitrogen. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by reverse phase chromatography (Biotage Flash) to give compound 28-a (42mg, yield: 60%).
LC-MS(ESI):m/z＝736[M+H]+.
Synthesis of Compound 28
Compound 28-a (34mg, 0.047mmol) was dissolved in dichloromethane (5mL), to which trifluoroacetic acid (1mL) was added, and the reaction was stirred at room temperature overnight. Concentration under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 28(11mg, yield: 45%).
LC-MS(ESI):m/z＝522[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.01(s,1H),7.98(d,J＝8.0Hz,1H),7.82(t,J＝8.0Hz,1H),7.77(s,1H),7.67-7.47(m,8H),4.75(dd,J＝36.8Hz,14.8Hz,2H),3.81(dd,J＝38.4Hz,13.6Hz,2H),3.16-3.12(m,2H),3.01-2.98(m,2H),2.93-2.90(m,1H),2.86-2.84(m,2H)ppm。
Example 29
(S, E) -4-carbamoyl-1- (5-chloro-4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2-methylbenzyl) piperazine-2-carboxylic acid (Compound 29)
Figure BDA0003234055820000631
Synthesis of Compound 29-c
(S) -1-Boc-piperazine-2-carboxylic acid methyl ester (733mg, 3.0mmol) and triethylamine (3.036g, 30.0mmol) were dissolved in tetrahydrofuran solution (50mL), cooled to 0 ℃ in an ice bath, and trimethylsilyl isocyanate (3.456g, 30.0mmol) was added dropwise. After the completion of the dropwise addition, the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50mL) and washed with water (50mL) and saturated brine (50mL) in this order. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 1000:3) to obtain compound 29-c (663mg, yield: 76.9%).
LC-MS(ESI):m/z＝288.0[M+H]+.
Synthesis of Compound 29-b
Compound 29-c (663mg, 2.308mmol) was dissolved in dichloromethane (15mL), trifluoroacetic acid (3mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. Concentrated under reduced pressure, and toluene (20mL) was added to the residue, concentrated under reduced pressure, and toluene (20mL) was added again to the residue, concentrated under reduced pressure, and the residue was dried under vacuum to give compound 29-b (1.132g, yield: 99%) which was used in the next reaction.
Synthesis of Compound 29-a
Compound 29-b (79mg, 0.208mmol) and compound 19-b (59mg, 0.208mmol) were dissolved in acetonitrile (20mL), and potassium carbonate (144g, 1.04mmol) and sodium iodide (7mg, 0.042mmol) were added. The reaction solution was heated to 80 ℃ and stirred for 16 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50mL) and washed with water (50mL) and saturated brine (50mL) in this order. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 29-a (56mg, yield: 50.9%).
LC-MS(ESI):m/z＝529.0[M+H]+.
Synthesis of Compound 29
Compound 29-a (56mg, 0.106mmol) was dissolved in methanol (5mL), tetrahydrofuran (5mL) and water (1mL), and sodium hydroxide (9mg, 0.212mmol) was added thereto, followed by stirring at room temperature for 3 hours. The pH was adjusted to 4-5 with 1N hydrochloric acid, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give Compound 29(14.9mg, yield: 27.3%).
LC-MS(ESI):m/z＝515.0[M+H]+.
1H NMR(400MHz,CD3OD):δ7.95-7.93(d,J＝8.0Hz,1H),7.76-7.72(m,2H),7.66(s,1H),7.59-7.46(m,8H),4.21-4.17(d,J＝13.2Hz,1H),3.83-3.76(m,2H),3.70-3.64(m,1H),3.59-3.55(m,1H),3.42-3.37(m,2H),3.13-3.06(m,1H),2.62-2.57(m,1H),2.45(s,3H)ppm。
Example 30
(S, E) -4- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (2-hydroxyethoxy) -5-methylbenzyl) morpholine-3-carboxylic acid (Compound 30)
Figure BDA0003234055820000641
Synthesis of Compound 30
To a mixture of compound 26-a (75mg,0.15mmol), (S) -morpholine-3-carboxylic acid (39mg, 0.30mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (38mg,0.60 mmol). The reaction mixture was warmed to 65 ℃ and stirred for 1 hour, then cooled to room temperature, concentrated under reduced pressure, and the resulting residue was added with tetrahydrofuran (1.0mL), water (0.5mL) and trifluoroacetic acid (0.5mL) and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 30(66mg, yield: 88%) as a white solid.
LC-MS(ESI):m/z＝499.5[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.05(d,J＝7.8Hz,1H),7.78(t,J＝7.9Hz,1H),7.66(d,J＝16.0Hz,1H),7.63–7.47(m,6H),7.37(d,J＝16.0Hz,1H),7.23(s,1H),7.20(s,1H),4.06(t,J＝5.1Hz,2H),3.85(d,J＝13.9Hz,1H),3.81–3.67(m,5H),3.59(bs,2H),3.24(t,J＝4.6Hz,1H),3.02–2.94(m,1H),2.38(s,3H),2.36–2.31(m,1H)ppm。
Example 31
(S, E) -1- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2-hydroxy-5-methylbenzyl) piperidine-2-carboxylic acid (Compound 31)
Figure BDA0003234055820000642
Synthesis of Compound 31-a
A mixture of compound 24-c (215mg,1.0mmol), compound 8-b (397mg,1.2mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (73mg,0.1mmol), potassium carbonate (276mg,2.0mmol), 1, 4-dioxane (5mL) and water (1mL) was stirred at 90 ℃ under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, diluted with saturated brine (20mL), and the pH was adjusted to about 3 with 1M dilute hydrochloric acid. The resulting mixture was extracted with dichloromethane (50 mL. times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was washed with ethyl acetate (50mL) to give 31-a (210mg, yield: 62%) as a brown solid.
LC-MS(ESI):m/z＝340.3[M+H]+.
Synthesis of Compound 31
To a mixture of compound 31-a (51mg,0.15mmol), (S) -piperidine-2-carboxylic acid (39mg, 0.30mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (38mg,0.60 mmol). The reaction mixture was warmed to 65 ℃ and stirred for 1 hour, then cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 31(21.6mg, yield: 32%) as a white solid.
LC-MS(ESI):m/z＝453.4[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.08(d,J＝8.0Hz,1H),7.78(t,J＝7.9Hz,1H),7.64(d,J＝16.0Hz,1H),7.61–7.47(m,6H),7.30(d,J＝16.0Hz,1H),7.06(s,1H),7.02(s,1H),4.01(d,J＝13.6Hz,1H),3.48(d,J＝13.5Hz,1H),3.09(d,J＝6.1Hz,1H),2.93(d,J＝11.8Hz,1H),2.33(s,3H),2.28(t,J＝9.6Hz,1H),1.96–1.85(m,1H),1.73–1.51(m,3H),1.51–1.30(m,2H)ppm。
Example 32
(S, E) -4- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2-hydroxy-5-methylbenzyl) morpholine-3-carboxylic acid (Compound 32)
Figure BDA0003234055820000651
Synthesis of Compound 32
To a mixture of compound 31-a (75mg,0.15mmol), (S) -morpholine-3-carboxylic acid (39mg, 0.30mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (38mg,0.60 mmol). The reaction mixture was warmed to 65 ℃ and stirred for 1 hour, then cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 32(19.8mg, yield: 29%) as a white solid.
LC-MS(ESI):m/z＝455.4[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.09(d,J＝8.0Hz,1H),7.77(t,J＝7.8Hz,1H),7.65(d,J＝16.0Hz,1H),7.62–7.46(m,6H),7.29(d,J＝16.0Hz,1H),7.09(s,1H),7.04(s,1H),3.93(d,J＝13.9Hz,1H),3.83(dd,J＝11.2,3.5Hz,1H),3.70(dd,J＝11.2,6.6Hz,1H),3.66–3.53(m,3H),3.29–3.27(m,1H),2.96–2.87(m,1H),2.38–2.29(m,4H)ppm。
Example 33
(S, E) -1- (5-chloro-2- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -4- (2-methoxyethoxy) benzyl) piperidine-2-carboxylic acid (Compound 33)
Figure BDA0003234055820000661
Synthesis of Compound 33-c
To a solution of 2, 4-dihydroxy-5-chlorobenzaldehyde (1.73g, 10.0mmol) in N, N-dimethylformamide (16mL) was added potassium carbonate (1.66g, 12.0 mmol). The mixture was stirred at 0 ℃ for 15 minutes. The temperature was reduced to-10 ℃ and a solution of N-phenyl (bistrifluoromethanesulfonyl) imide (3.56g, 10.0mmol) in N, N-dimethylformamide (20mL) was added dropwise to the mixture. After the addition, the reaction was carried out at-10 ℃ for 2 hours. 100mL of water was added, and extracted with ethyl acetate (30 mL. times.3). The organic phases were combined, washed successively with water (30 mL. times.1) and brine (30 mL. times.1). Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to give compound 33-c (2.51g, yield: 82%).
1H NMR(400MHz,CD3Cl):δ10.07(s,1H),7.99(s,1H),7.07(s,1H)ppm
Synthesis of Compound 33-b
To a mixture of compound 33-c (524mg, 1.73mmol) and compound 8-b (662mg, 2.00mmol) in toluene (25mL) was added [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (88mg, 0.12mmol), potassium phosphate (733mg, 3.46mmol), cesium fluoride (519mg, 3.46mmol), and the mixture was stirred at 80 ℃ for 16 hours under nitrogen atmosphere. Concentrated under reduced pressure, the residue was diluted with water, adjusted to pH less than 3 with 1M hydrochloric acid and extracted with dichloromethane (30 mL. times.3). The combined organic phases were washed with saturated brine (30 mL. times.1). Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to give compound 33-b (447mg, yield: 72%).
LC-MS(ESI):m/z＝358[M-H]-.
Synthesis of Compound 33-a
To a solution of compound 33-b (358mg, 1.00mmol) in N, N-dimethylformamide (15mL) were added potassium carbonate (276mg, 2.00mmol), 2-bromoethyl methyl ether (210mg, 1.50 mmol). The mixture was stirred at 60 ℃ for 6 hours. Cool to room temperature, dilute with water (100mL), and extract with ethyl acetate (30 mL. times.3). The organic phases were combined, washed with water (30 mL. times.2) and brine (30 mL). Concentration under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to give compound 33-a (347mg, yield: 83%).
LC-MS(ESI):m/z＝418[M+H]+.
Synthesis of Compound 33
To a solution of compound 33-a (84mg, 0.20mmol) in dichloromethane (10mL) were added (S) -piperidine-2-carboxylic acid (39mg, 0.30mmol) and methanol (10mL), and the mixture was stirred at room temperature for 1 hour, followed by addition of sodium cyanoborohydride (32mg, 0.50 mmol). After the addition, the mixture was stirred at room temperature for 16 hours. Concentration under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 33(35mg, yield: 28%).
LC-MS(ESI):m/z＝531[M+H]+.
1H NMR(400MHz,CD3Cl):δ8.30(d,J＝8.0Hz,1H),8.05(d,J＝16.0Hz,1H),7.77(t,J＝8.0Hz,1H),7.66(s,1H),7.56～7.60(m,3H),7.47～7.53(m,5H),4.32～4.34(m,2H),4.06～4.11(m,1H),3.81～3.84(m,2H),3.54～3.57(m,1H),3.44～3.46(m,2H),3.40(s,3H),2.94～3.00(m,1H),2.29～2.33(m,1H),1.80～1.87(m,3H),1.68～1.71(m,1H),1.54～1.61(m,1H)ppm。
Example 34
(S, E) -4- (5-chloro-2- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -4- (2-methoxyethoxy) benzyl) morpholine-3-carboxylic acid (Compound 34)
Figure BDA0003234055820000671
Synthesis of Compound 34
To a solution of compound 33-a (84mg, 0.20mmol) in dichloromethane (10mL) were added (S) -morpholine-3-carboxylic acid (39mg, 0.30mmol) and methanol (10 mL). The mixture was stirred at room temperature for 1 hour, then sodium cyanoborohydride (32mg, 0.50mmol) was added, and after the addition was completed, stirring was carried out at room temperature for 16 hours. Concentration under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 34(36mg, yield: 28%).
LC-MS(ESI):m/z＝533[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.09(d,J＝7.6Hz,1H),8.05(d,J＝18.0Hz,1H),7.78(t,J＝8.0Hz,1H),7.58～7.61(m,2H),7.49～7.55(m,4H),7.46(s,1H),7.43(d,J＝18.0Hz,1H),7.39(s,1H),4.29(t,J＝4.8Hz,2H),4.02(d,J＝12.6Hz,1H),3.71～3.73(m,4H),3.50～3.57(m,3H),3.35(s,3H),3.19(t,J＝4.8Hz,1H),2.73～2.80(m,1H),2.23～2.28(m,1H)ppm。
Example 35
(S, E) -2- ((5-chloro-2- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -4- (2-methoxyethoxy) benzyl) amino) -3-hydroxy-2-methylpropanoic acid (Compound 35)
Figure BDA0003234055820000672
Synthesis of Compound 35
To a suspension of (S) -methylserine (60mg, 0.50mmol) in methanol (10mL) was added a 1M aqueous solution of sodium hydroxide (1mL, 1.0mmol), and the mixture was stirred to dissolve the solid. To the mixture was added a solution of compound 33-a (63mg,0.15mmol) in tetrahydrofuran (5mL), and after the addition was completed, the mixture was stirred for 16 hours. Sodium borohydride (19mg, 0.50mmol) was added and stirring was continued for 1 hour. Concentration under reduced pressure, washing of the residue with water, extraction with ethyl acetate, and concentration under reduced pressure, the obtained residue was purified by preparative liquid chromatography to give compound 35(21mg, yield: 27%).
LC-MS(ESI):m/z＝521[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.21(d,J＝7.6Hz,1H),8.06(d,J＝16.0Hz,1H),7.79(t,J＝8.0Hz,1H),7.56～7.61(m,3H),7.52～7.55(m,3H),7.51(s,1H),7.47(d,J＝16.0Hz,1H),7.47(s,1H),4.30～4.32(m,2H),4.00(dd,J＝24.0Hz,12.6Hz,2H),3.72～3.79(m,2H),3.66(d,J＝10.8Hz,1H),3.57(d,J＝10.8Hz,1H),3.35(s,3H),1.32(s,3H)ppm。
Example 36
(S, E) -1- (5-chloro-2- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -4- (3-methylsulfonyl) propoxy) benzyl) piperidine-2-carboxylic acid (Compound 36)
Figure BDA0003234055820000681
Synthesis of Compound 36-b
To a 100mL reaction flask was added 3-methylsulfonyl-1-propanol (1.38g,10mmol), 1, 4-diazabicyclo [2.2.2] octane (1.68g,15mmol), and dry dichloromethane (40 mL). To this mixture was added p-toluenesulfonyl chloride (2.29g,12mmol) portionwise at 0 ℃. After the addition, the mixture was stirred at room temperature for 16 hours. Water (60mL) was added to the mixture, the organic phase was separated, and the aqueous phase was extracted with dichloromethane (40 mL. times.2). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give compound 36-b (2.69g, yield: 92%).
Synthesis of Compound 36-a
Compound 33-b (80.0mg,0.22mol) and compound 33-b (92.9mg,0.33mol) were dissolved in anhydrous N, N-dimethylformamide (20mL), and potassium carbonate (91.0mg,0.66mmol) was added to the solution. The reaction mixture was stirred under nitrogen at 50 ℃ for 16 hours, cooled to room temperature, water (100mL) was added to form a suspension, and 4N diluted hydrochloric acid was added dropwise to adjust the suspension to pH 7. The mixture was extracted with ethyl acetate (150mL), the organic phase was washed with water (60mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10-3:1) to give 36-a (80mg, yield: 77%) as a yellow solid.
LC-MS(ESI):m/z＝480.1[M+H]+.
Synthesis of Compound 36
Compound 36-a (80.0mg,0.17mmol) and (S) -piperidine-2-carboxylic acid (56.7mg,0.44mmol) were dissolved in methanol (20ml), and sodium cyanoborohydride (27.7mg,0.44mmol) was added, heated to 60 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 36(28.1mg, yield: 28%) as a white solid.
LC-MS(ESI):m/z＝593.2[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.17-7.81(m,2H),7.79(t,J＝8.0Hz,1H),7.62-7.50(m,6H),7.45(s,1H),7.44-7.41(m,2H),4.30(t,J＝6.4Hz,2H),4.02(d,J＝12.8Hz,1H),3.34-3.30(m,3H),3.10-3.06(bs,1H),3.05(s,3H),2.79-2.74(m,1H),2.26-2.21(m,3H),1.81-1.47(m,4H),1.38-1.36(m,2H)ppm。
Example 37
(S, E) -4- (5-chloro-2- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -4- (3-methylsulfonyl) propoxy) benzyl) morpholine-3-carboxylic acid (Compound 37)
Figure BDA0003234055820000691
Synthesis of Compound 37
Compound 36-a (150mg,0.31mmol) and (S) -morpholine-3-carboxylic acid (131mg,1.0mmol) were dissolved in methanol (20ml), sodium cyanoborohydride (63.0mg,1.0mmol) was added, the mixture was heated to 60 ℃ and stirred for reaction for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 37(15.0mg, yield: 5.0%) as a white solid.
LC-MS(ESI):m/z＝595.2[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.10(d,J＝8.0Hz,1H),8.06(d,J＝16.0Hz,1H),7.80(t,J＝8.0Hz,1H),7.62-7.51(m,6H),7.46-7.42(m,3H),4.29(t,J＝6.0Hz,2H),4.03(d,J＝12.8Hz,1H),3.75-3.72(m,2H),3.59-3.52(m,3H),3.31-3.28(m,3H),3.22-3.20(m,1H),3.05(s,3H),2.82-2.78(m,1H),2.29-2.20(m,3H)ppm。
Example 38
(S, E) -2- ((5-chloro-2- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -4- (3-methylsulfonyl) propoxy) benzyl) amino) -3-hydroxy-2-methylpropanoic acid (Compound 38)
Figure BDA0003234055820000692
Synthesis of Compound 38
(S) -Methylserine (74.5mg,0.626mmol) was dissolved in methanol (8mL), and 0.313M aqueous sodium hydroxide solution (2mL,0.626mmol) was added dropwise with stirring, after completion, the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0 ℃ and a solution of compound 36-a (120.0mg,0.35mmol) in tetrahydrofuran (6mL) was slowly added dropwise. After the addition, the temperature was raised to room temperature and stirred for 16 hours. To the reaction mixture was added sodium borohydride (27.0mg,0.71mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 38(27.0mg, yield: 22%) as a white solid.
LC-MS(ESI):m/z＝441.4[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.21(d,J＝8.0Hz,1H),8.05(d,J＝6.0Hz,1H),7.77(t,J＝8.0Hz,1H),7.60-7.44(m,9H),4.30(t,J＝6.4Hz,2H),4.05-4.00(m,2H),3.70-3.58(m,2H),3.31-3.29(m,3H),3.03(s,3H),2.25-2.20(m,2H),1.32(s,3H)ppm。
Example 39
(S, E) -1- (5- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (4-cyanobutoxy) -4-methylbenzyl) piperidine-2-carboxylic acid (Compound 39)
Figure BDA0003234055820000701
Synthesis of Compound 39-c
A mixture of 4-bromo-3-methylphenol (1.87g,10.0mmol), paraformaldehyde (2.21g,76.2mmol), magnesium chloride (1.43g,15.0mmol), triethylamine (3.78g,37.4mmol) and acetonitrile (70mL) was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (100mL) and adjusted to pH 3 with 1M hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL. times.2). The organic phases were combined, washed with water (100mL) and saturated brine (50mL), respectively, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 50:1) to give 39-c as a white solid (1.4g, yield: 66%).
Synthesis of Compound 39-b
A mixture of compound 39-c (500mg,2.33mmol), 5-bromovaleronitrile (452mg,2.79mmol), potassium carbonate (482mg,3.49mmol) and N, N-dimethylformamide (5mL) was heated at 60 ℃ for 16 hours. The reaction was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL). The organic phase was washed with water (50mL) and saturated brine (20mL), respectively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to give 39-b (550mg, yield: 80%) as a white solid.
1H NMR(400MHz,CDCl3):δ10.33(s,1H),7.95(s,1H),6.86(s,1H),4.12(t,J＝5.9Hz,2H),2.47(t,J＝6.9Hz,2H),2.44(s,3H),2.09–2.00(m,2H),1.96–1.86(m,2H)ppm
Synthesis of Compound 39-a
A mixture of compound 39-b (296mg,1.0mmol), compound 8-b (397mg,1.2mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (73mg,0.1mmol), potassium carbonate (276mg,2.0mmol), 1, 4-dioxane (5mL)) and water (0.5mL) was stirred at 90 ℃ under nitrogen for 16 hours. The reaction mixture was diluted with saturated saline (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL. times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to obtain compound 39-a (260mg, yield: 62%).
LC-MS(ESI):m/z＝421.3[M+H]+.
Synthesis of Compound 39
To a mixture of compound 39-a (50mg,0.12mmol), (S) -piperidine-2-carboxylic acid (31mg, 0.24mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (30mg,0.24 mmol). The reaction solution was stirred at 65 ℃ for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 39(37.7mg, yield: 56%) as a white solid.
LC-MS(ESI):m/z＝534.6[M+H]+.
1H NMR(400MHz,CD3OD):δ7.88(d,J＝7.9Hz,1H),7.82(s,1H),7.70(t,J＝8.0Hz,1H),7.61(d,J＝16.1Hz,1H),7.58–7.45(m,5H),7.43(d,J＝7.6Hz,1H),7.39(d,J＝16.1Hz,1H),7.00(s,1H),4.57(d,J＝12.8Hz,1H),4.37(d,J＝12.7Hz,1H),4.17(t,J＝6.1Hz,2H),3.56(d,J＝6.5Hz,1H),3.32(s,1H),3.03(t,J＝10.3Hz,1H),2.58(t,J＝7.0Hz,2H),2.50(s,3H),2.23(d,J＝13.3Hz,1H),2.09–1.98(m,2H),1.98–1.81(m,4H),1.80–1.51(m,3H)ppm。
Example 40
(S, E) -4- (5- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (4-cyanobutoxy) -4-methylbenzyl) morpholine-3-carboxylic acid (Compound 40)
Figure BDA0003234055820000711
Synthesis of Compound 40
To a mixture of compound 39-a (50mg,0.12mmol), (S) -morpholine-3-carboxylic acid (31mg, 0.24mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (30mg,0.24 mmol). The reaction solution was stirred at 65 ℃ for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 40(39mg, yield: 61%) as a white solid.
LC-MS(ESI):m/z＝536.5[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.08(d,J＝8.0Hz,1H),7.76(t,J＝7.9Hz,1H),7.71(s,1H),7.68(d,J＝16.0Hz,1H),7.63–7.48(m,5H),7.46(d,J＝7.7Hz,1H),7.28(d,J＝16.0Hz,1H),6.88(s,1H),4.05(t,J＝5.9Hz,2H),3.91–3.81(m,2H),3.77–3.62(m,3H),3.61–3.54(m,1H),3.29(t,J＝3.8Hz,1H),3.10–3.02(m 1H),2.60(t,J＝7.0Hz,2H),2.44(s,3H),2.38–2.30(m,1H),1.88–1.80(m,2H),1.79–1.70(m,2H)ppm。
EXAMPLE 41
(S, E) -1- (5- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (2-hydroxyethoxy) -4-methylbenzyl) piperidine-2-carboxylic acid (Compound 41)
Figure BDA0003234055820000712
Figure BDA0003234055820000721
Synthesis of Compound 41-b
A mixture of compound 39-c (400mg,1.86mmol), (2-bromoethoxy) (tert-butyl) dimethylsilane (534mg,2.23mmol), potassium carbonate (514mg,3.72mmol) and N, N-dimethylformamide (4mL) was heated at 60 ℃ for 16 hours. The reaction was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL. times.2). The organic phases were combined, washed with water (50mL) and saturated brine (20mL), respectively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 30:1) to give 41-b (526mg, yield: 76%) as a white solid.
Synthesis of Compound 41-a
A mixture of compound 41-b (373mg,1.0mmol), compound 8-b (397mg,1.2mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (73mg,0.1mmol), potassium carbonate (276mg,2.0mmol), 1, 4-dioxane (5mL) and water (0.5mL) was stirred at 90 ℃ under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, diluted with saturated brine (20mL), and the resulting mixture was extracted with dichloromethane (50 mL. times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was recrystallized from ethyl acetate to give 41-a (420mg, yield: 84%) as a yellow solid.
LC-MS(ESI):m/z＝498.5[M+H]+.
Synthesis of Compound 41
To a mixture of compound 41-a (75mg,0.15mmol), (S) -piperidine-2-carboxylic acid (39mg, 0.30mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (38mg,0.60 mmol). The reaction mixture was stirred at 65 ℃ for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and tetrahydrofuran (1mL), water (0.5mL) and trifluoroacetic acid (0.5mL) were added to the residue and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to high performance liquid chromatography to give white solid 41(40.2mg, yield: 54%).
LC-MS(ESI):m/z＝495.5[M-H]+.
1H NMR(400MHz,DMSO-d6):δ8.06(d,J＝7.9Hz,1H),7.76(t,J＝7.9Hz,1H),7.74(s,1H),7.66(d,J＝16.0Hz,1H),7.62–7.58(m,2H),7.57–7.48(m,3H),7.47(d,J＝7.6Hz,1H),7.27(d,J＝16.0Hz,1H),6.91(s,1H),4.10–3.97(m,4H),3.81(d,J＝13.7Hz,1H),3.73(t,J＝4.6Hz,2H),3.12(dd,J＝8.2,3.9Hz,1H),3.07–3.00(m,1H),2.45(s,3H),2.42–2.31(m,1H),1.90–1.80(m,1H),1.77–1.65(m 1H),1.61–1.45(m,3H),1.43–1.22(m,1H)ppm。
Example 42
(S, E) -4- (5- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (2-hydroxyethoxy) -4-methylbenzyl) morpholine-3-carboxylic acid (Compound 42)
Figure BDA0003234055820000731
Synthesis of Compound 42
To a mixture of compound 41-a (75mg,0.15mmol), (S) -morpholine-3-carboxylic acid (39mg, 0.30mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (38mg,0.60 mmol). The reaction mixture was stirred at 65 ℃ for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and tetrahydrofuran (1mL), water (0.5mL) and trifluoroacetic acid (0.5mL) were added to the residue and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to high performance liquid chromatography to give 42(53.3mg, yield: 58%) as a white solid.
LC-MS(ESI):m/z＝499.5[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.08(d,J＝7.9Hz,1H),7.76(t,J＝7.9Hz,1H),7.72(s,1H),7.68(d,J＝16.0Hz,1H),7.63–7.50(m,5H),7.46(d,J＝7.7Hz,1H),7.28(d,J＝16.0Hz,1H),6.88(s,1H),4.03(t,J＝4.1Hz,2H),3.92(d,J＝14.4Hz,1H),3.80–3.71(m,4H),3.67(d,J＝14.5Hz,1H),3.61(t,J＝4.7Hz,2H),3.22(t,J＝4.5Hz,1H),3.02–2.95(m,1H),2.44(s,3H),2.37–2.28(m,1H)ppm。
Example 43
(S, E) -1- (5- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (2-methoxyethoxy) -4-methylbenzyl) piperidine-2-carboxylic acid (Compound 43)
Figure BDA0003234055820000732
Synthesis of Compound 43-b
A mixture of compound 39-c (400mg,1.86mmol), 1-bromo-2-methoxyethane (310mg,2.23mmol), potassium carbonate (514mg,3.72mmol) and N, N-dimethylformamide (4mL) was heated at 60 ℃ for 20 hours. The reaction mixture was cooled to room temperature, diluted with water (50mL), and the resulting mixture was extracted with ethyl acetate (50 mL. times.2). The organic phases were combined, washed with water (50mL) and saturated brine (20mL), respectively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to obtain 43-b (433mg, yield: 85%) as a white solid.
Synthesis of Compound 43-a
A mixture of compound 43-b (273mg,1.0mmol), compound 8-b (397mg,1.2mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (73mg,0.1mmol), potassium carbonate (276mg,2.0mmol), 1, 4-dioxane (5mL) and water (0.5mL) was stirred at 90 ℃ under nitrogen for 16 hours. The reaction mixture was diluted with saturated saline (20 mL). The resulting mixture was extracted with dichloromethane (50 mL. times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was washed with ethyl acetate (20mL) to give 43-a as an off-white solid (284mg, yield: 71%).
LC-MS(ESI):m/z＝398.4[M+H]+.
Synthesis of Compound 43
To a mixture of compound 43-a (40mg,0.1mmol), (S) -piperidine-2-carboxylic acid (26mg, 0.2mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (25mg,0.4 mmol). The reaction mixture was stirred at 65 ℃ for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was subjected to high performance liquid chromatography to prepare 43(33.2mg, yield 65%) as a white solid.
LC-MS(ESI):m/z＝511.4[M+H]+.
1H NMR(400MHz,CD3OD):δ7.89(d,J＝8.0Hz,1H),7.76(s,1H),7.70(t,J＝7.8Hz,1H),7.61(d,J＝16.1Hz,1H),7.58–7.45(m,5H),7.43(d,J＝7.6Hz,1H),7.38(d,J＝16.1Hz,1H),6.99(s,1H),4.68(d,J＝12.7Hz,1H),4.35–4.16(m,3H),3.97–3.86(m,1H),3.84–3.73(m,1H),3.56(d,1H),3.45(s,3H),3.29–3.21(m,1H),3.00(t,J＝11.6Hz,1H),2.50(s,3H),2.25(s,1H),1.99–1.49(m,5H)ppm。
Example 44
(S, E) -4- (5- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (2-methoxyethoxy) -4-methylbenzyl) morpholine-3-carboxylic acid (Compound 44)
Figure BDA0003234055820000741
Synthesis of Compound 44
To a mixture of compound 43-a (40mg,0.1mmol), (S) -morpholine-3-carboxylic acid (26mg, 0.2mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (25mg,0.4 mmol). The reaction mixture was stirred at 65 ℃ for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was subjected to high performance liquid chromatography to give 44(26mg, yield: 51%) as a white solid.
LC-MS(ESI):m/z＝513.4[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.08(d,J＝8.0Hz,1H),7.76(t,J＝7.8Hz,1H),7.74(s,1H),7.68(d,J＝16.0Hz,1H),7.64–7.48(m,5H),7.46(d,J＝7.6Hz,1H),7.29(d,J＝16.1Hz,1H),6.89(s,1H),4.18–4.10(m,2H),3.90–3.81(m,2H),3.78–3.55(m,7H),3.33(s,3H),3.06(t,J＝10.8Hz,1H),2.44(s,3H),2.36(d,J＝12.0Hz,1H)ppm。
Example 45
(S, E) -1- (2- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -6- (4-cyanobutoxy) -3-methylbenzyl) piperidine-2-carboxylic acid (Compound 45)
Figure BDA0003234055820000751
Synthesis of Compound 45-a
A mixture of compound 15-b-1(250mg,0.84mmol), compound 8-b (334mg,1.01mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (58mg,0.08mmol), potassium carbonate (232mg,1.68mmol), 1, 4-dioxane (5mL) and water (0.5mL) was stirred at 90 ℃ under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, and diluted with saturated brine (20 mL). The resulting mixture was extracted with dichloromethane (50 mL. times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was washed with acetonitrile (20mL) and a mixed solution (20mL) of dioxane and water (5:1) to give off-white solid 45-a (280mg, yield: 79%).
LC-MS(ESI):m/z＝421.4[M+H]+.
Synthesis of Compound 45
To a mixture of compound 45-a (42mg,0.1mmol), (S) -piperidine-2-carboxylic acid (26mg, 0.2mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (25mg,0.4 mmol). The reaction mixture was stirred at 65 ℃ for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was subjected to high performance liquid chromatography to give 45(30.8mg, yield: 58%) as a white solid.
LC-MS(ESI):m/z＝534.5[M+H]+.
1H NMR(400MHz,CD3OD):δ8.11(d,J＝7.9Hz,1H),7.79(t,J＝7.9Hz,1H),7.62(d,J＝16.8Hz,1H),7.59–7.45(m,6H),7.39(d,J＝8.5Hz,1H),7.06(d,J＝6.8Hz,1H),7.03(d,J＝14.9Hz,1H),4.76(d,1H),4.59(d,J＝13.9Hz,1H),4.27–4.14(m,2H),3.63(s,1H),3.28–3.22(m,1H),3.18–3.04(m,1H),2.58(t,J＝7.0Hz,2H),2.39(s,3H),2.17–1.99(m,J＝9.0,5.9Hz,4H),1.94–1.85(m,2H),1.85–1.75(m,1H),1.75–1.54(m,3H)ppm。
Example 46
(S, E) -4- (2- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -6- (4-cyanobutoxy) -3-methylbenzyl) morpholine-3-carboxylic acid (Compound 46)
Figure BDA0003234055820000761
Synthesis of Compound 46
To a mixture of compound 45-a (42mg,0.1mmol), (S) -morpholine-3-carboxylic acid (26mg, 0.2mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (25mg,0.4 mmol). The reaction mixture was stirred at 65 ℃ for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was subjected to high performance liquid chromatography to give 46(25.3mg, yield: 47%) as a white solid.
LC-MS(ESI):m/z＝536.5[M+H]+.
1H NMR(400MHz,CD3OD):δ8.18(d,J＝7.9Hz,1H),7.78(t,J＝7.9Hz,1H),7.71(d,J＝16.5Hz,1H),7.60–7.54(m,2H),7.54–7.44(m,4H),7.37(d,J＝8.6Hz,1H),7.06(d,J＝16.9Hz,1H),7.02(d,J＝9.2Hz,1H),4.71(d,J＝13.0Hz,1H),4.55(d,J＝13.2Hz,1H),4.22–4.13(m,2H),4.10(dd,J＝12.6,3.8Hz,1H),3.97–3.83(m,2H),3.80–3.66(m,2H),3.29–3.22(m,1H),3.15–3.02(m,1H),2.58(t,J＝7.0Hz,2H),2.40(s,3H),2.10–1.98(m,2H),1.94–1.82(m,2H)ppm
Example 47
(S, E) -1- (5-chloro-2- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -4- (cyanomethoxy) benzyl) piperidine-2-carboxylic acid (Compound 47)
Figure BDA0003234055820000762
Synthesis of Compound 47-a
Compound 33-b (155mg,0.43mol) and bromoacetonitrile (102.7mg,0.86mol) were dissolved in anhydrous N, N-dimethylformamide (15mL), and potassium carbonate (178mg,1.29mmol) was added to the solution. The reaction mixture was stirred at 30 ℃ under nitrogen for about 5 hours and then cooled to room temperature. Water (100mL) was added to form a suspension, and the pH was adjusted to 7 with 4N hydrochloric acid. The mixture was extracted with ethyl acetate (150mL), which was then washed with water (60mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10-3:1) to give compound 47-a (70mg, yield: 41%).
LC-MS(ESI):m/z＝399.1[M+H]+.
Synthesis of Compound 47
Compound 47-a (70.0mg,0.175mmol) and the starting material (S) -piperidine-2-carboxylic acid (45.3mg,0.35mmol) were dissolved in methanol (12ml), sodium cyanoborohydride (22.1mg,0.35mmol) was added, the mixture was heated to 60 ℃ and stirred for reaction for 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 47(25.0mg, yield: 28%) as a white solid.
LC-MS(ESI):m/z＝512.3[M+H]+.
1H NMR:(400MHz DMSO-d6):δ8.14(s,1H),8.11(d,J＝9.6Hz,1H),7.79(t,J＝8.0Hz,1H),7.61-7.44(m,9H),5.40(s,2H),7.44-7.41(m,2H),3.98(d,J＝13.2Hz,1H),3.43(d,J＝13.2Hz,1H),3.08-3.05(m,1H),2.76-2.73(m,1H),2.15-2.11(m,1H),1.78-1.68(m,2H),1.54-1.36(m,4H)ppm。
Example 48
(S, E) -1- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (cyanomethoxy) -5-methylbenzyl) piperidine-2-carboxylic acid (Compound 48)
Figure BDA0003234055820000771
Synthesis of Compound 48-b
A mixture of compound 24-c (215mg,1.0mmol), bromoacetonitrile (120mg,1.2mmol), potassium carbonate (276mg,2.0mmol) and N, N-dimethylformamide (3mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL). The precipitated solid was filtered and dried to obtain 48-b (213mg, yield: 84%) as a white solid.
Synthesis of Compound 48-a
A mixture of compound 48-b (210mg,0.826mmol), compound 8-b (328mg,0.992mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (61mg,0.083mmol), potassium carbonate (228mg,1.65mmol), 1, 4-dioxane (5mL) and water (0.5mL) was stirred at 90 deg.C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, and diluted with saturated brine (20 mL). The resulting mixture was extracted with dichloromethane (50 mL. times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was washed with ethyl acetate (20 mL. times.2) to give 48-a (300mg, yield: 96%) as a pale green solid.
LC-MS(ESI):m/z＝379.3[M+H]+.
Synthesis of Compound 48
To a mixture of compound 48-a (57mg,0.15mmol), (S) -piperidine-2-carboxylic acid (39mg, 0.30mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (38mg,0.60 mmol). The reaction mixture was stirred at 65 ℃ for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 48(14.7mg, yield: 20%) as a white solid.
LC-MS(ESI):m/z＝492.4[M+H]+.
1H NMR(400MHz,CD3OD):δ7.97(d,J＝8.0Hz,1H),7.75(t,J＝7.9Hz,1H),7.69(d,J＝16.1Hz,1H),7.62–7.44(m,9H),5.20(s,2H),4.49(d,J＝12.9Hz,1H),4.34(d,J＝12.8Hz,1H),3.50(d,J＝8.4Hz,1H),3.42–3.33(m,1H),2.97(t,J＝10.5Hz,1H),2.49(s,3H),2.26(d,J＝12.2Hz,1H),1.95–1.66(m,4H),1.63–1.46(m,1H)ppm。
Example 49
(S, E) -1- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (methoxymethyl) -5-trifluoromethylbenzyl) piperidine-2-carboxylic acid (Compound 49)
Figure BDA0003234055820000781
Synthesis of Compound 49-d
Compound 20-f (600mg, 2mmol) was dissolved in anhydrous N, N-dimethylformamide (10mL), and sodium hydride (80mg, 4mmol) was added under nitrogen at 0 ℃ and then warmed to room temperature and stirred for reaction for 30 minutes. Methyl iodide (570mg, 4mmol) was added, and the reaction was stirred at room temperature for 3 hours. The reaction was quenched by addition of water (1mL), extracted with ethyl acetate (100mL), washed with water (20mL × 3) and saturated brine (50mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give compound 49-d (292mg, yield: 45.0%).
1H NMR(400MHz,DMSO-d6):δ8.22(s,1H),8.09(s,1H),4.87(s,2H),3.92(s,3H),3.46(s,3H)ppm。
Synthesis of Compound 49-c
Compound 49-d (290mg, 0.88mmol) is dissolved in dry methanol (10mL), and sodium borohydride (100mg, 2.66mmol) is added under nitrogen at 0 ℃ and then refluxed for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to obtain compound 49-c (170mg, yield: 65.0%).
LC-MS(ESI):m/z＝299[M-H]+.
Synthesis of Compound 49-b
Compound 49-c (170mg, 0.56mmol) was dissolved in dichloromethane (10mL) and manganese dioxide (493mg, 5.6mmol) was added. The reaction solution was stirred at room temperature for 16 hours. Filtration was carried out and the filter cake was washed with dichloromethane (20 mL. times.3). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1) to give compound 49-b (114mg, yield: 68%).
Synthesis of Compound 49-a
Compound 49-b (110mg, 0.36mmol), compound 8-b (141mg, 0.42mmol), sodium carbonate (132mg,1.26mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (31mg,0.042mmol) was added to a mixed solution of 1, 4-dioxane (5mL) and water (0.5mL), and the mixture was stirred at 80 ℃ under nitrogen for 16 h. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1) to give compound 49-a (65mg, yield: 43.0%).
LC-MS(ESI):m/z＝422[M+H]+.
Synthesis of Compound 49
A mixture of compound 49-a (30mg, 0.07mmol), (S) -piperidine-2-carboxylic acid (24mg, 0.19mmol), sodium cyanoborohydride (12mg,0.19mmol) and methanol (3mL) was stirred at 80 deg.C under nitrogen for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 49(10mg, yield: 26.3%).
LC-MS(ESI):m/z＝535[M+H]+.
1H NMR(400MHz,DMSO-d6):δ7.97(d,J＝8.0Hz,1H),7.93(s,1H),7.83(d,J＝8.0Hz,1H),7.80(s,1H),7.66-7.46(m,8H),4.67(s,2H),3.87(d,J＝14.4Hz,1H),3.57(d,J＝14.4Hz,1H),3.38(s,3H),3.17(t,J＝5.6Hz,1H),2.81-2.78(m,1H),2.20-2.19(m,1H),1.78-1.76(m,2H),1.45-1.37(m,4H)ppm。
Example 50
(S, E) -4- (4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2- (methoxymethyl) -5-trifluoromethylbenzyl) morpholine-3-carboxylic acid (Compound 50)
Figure BDA0003234055820000791
Synthesis of Compound 50
A mixture of compound 49-a (30mg, 0.07mmol), (S) -morpholine-3-carboxylic acid (24mg, 0.19mmol), sodium cyanoborohydride (12mg,0.19mmol) and methanol (3mL) was stirred at 80 deg.C under nitrogen for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 50(10mg, yield: 33.3%).
LC-MS(ESI):m/z＝537[M+H]+.
1H NMR(400MHz,DMSO-d6):δ7.90(d,J＝8.0Hz,1H),7.87(s,1H),7.83(t,J＝8.0Hz,1H),7.69(s,1H),7.59-7.39(m,8H),4.61(s,2H),3.91(d,J＝14.4Hz,1H),3.80-3.76(m,1H),3.69-3.64(m,2H),3.56-3.52(m,1H),3.48-3.42(m,2H),3.32(s,3H),2.87-2.83(m,1H),2.21-2.18(m,1H)ppm。
Example 51
(S, E) -1- (2-methoxy-4- (2- (2-methyl-d)3) - [1,1' -Biphenyl group]-3-yl) vinyl) -5-trifluoromethylbenzyl) piperidine-2-carboxylic acid (Compound 51)
Figure BDA0003234055820000792
Synthesis of Compound 51-c
Potassium tert-butoxide (84mg,0.75mmol) was added to a mixture of compound 3-c (618mg,2.5mmol) and deuterated dimethyl sulfoxide (3 mL). The reaction solution was stirred at room temperature for 20 hours and then diluted with water (20 mL). The mixture was extracted with petroleum ether (50 mL). The resulting organic phase was washed with water (20mL), saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 51-c (550mg, yield: 88%).
1H NMR(400MHz,DMSO-d6):δ7.67–7.59(m,1H),7.49–7.37(m,3H),7.35–7.28(m,2H),7.23–7.17(m,2H)ppm
Synthesis of Compound 51-b
A mixture of compound 51-c (500mg,2.0mmol), vinylppinacol boronate (462mg,3.0mmol), bis (tri-tert-butylphosphino) palladium (102mg,0.2mmol), triethylamine (2.02g,20mmol)) and toluene (10mL) was stirred at 80 ℃ under nitrogen for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 50:1) to obtain compound 51-b (450mg, yield: 70%).
Synthesis of Compound 51-a
A mixture of compound 6-b (113mg,0.4mmol), compound 51-b (155mg,0.48mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (29mg,0.04mmol), potassium carbonate (110mg,0.8mmol), 1, 4-dioxane (3mL) and water (0.5mL) was stirred at 90 ℃ under nitrogen for 5 hours. The reaction mixture was cooled to room temperature, and diluted with saturated brine (20 mL). The resulting mixture was extracted with dichloromethane (40 mL. times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 50:1), and the resulting product was washed with methanol (1.5mL × 2) to give 51-a (75mg, yield: 47%) as a white solid.
LC-MS(ESI):m/z＝400.4[M+H]+.
1H NMR(400MHz,CDCl3):δ10.44(s,1H),8.16(s,1H),7.59(dd,J＝7.6,1.0Hz,1H),7.51–7.28(m,10H),7.25–7.23(m,1H),4.07(s,3H)ppm
Synthesis of Compound 51
To a mixture of compound 51-a (40mg,0.1mmol), (S) -piperidine-2-carboxylic acid (26mg, 0.2mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (25mg,0.4 mmol). The reaction mixture was stirred at 65 ℃ for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 51(16.2mg, yield: 32%) as a white solid.
LC-MS(ESI):m/z＝513.5[M+H]+.
1H NMR(400MHz,CD3OD):δ7.89(s,1H),7.62(d,J＝15.8Hz,1H),7.56–7.51(m,2H),7.42(t,J＝7.3Hz,2H),7.37–7.24(m,5H),7.20–7.15(m,1H),4.53(d,J＝12.9Hz,1H),4.40(d,J＝12.9Hz,1H),4.06(s,3H),3.57–3.46(m,1H),3.31(s,1H),3.00(t,J＝10.7Hz,1H),2.24(d,J＝14.8Hz,1H),1.97–1.64(m,4H),1.63–1.48(m,1H)ppm
Example 52
(S, E) -1- (5-chloro-2- (2- (2-cyano- [1,1' -biphenyl) S]-3-yl) vinyl) -4- (methoxy-d3) Benzyl) piperidine-2-carboxylic acid (Compound 52)
Figure BDA0003234055820000801
Synthesis of Compound 52-a
Compound 33-b (140mg,0.39mol) and deuteroiodomethane (565.5mg,3.9mol) were dissolved in anhydrous N, N-dimethylformamide (15mL), followed by addition of potassium carbonate (269.1mg,1.95 mmol). The reaction mixture was stirred under nitrogen at 30 ℃ for 12 hours and then returned to room temperature. Water (100mL) was added to the suspension, and a 4N hydrochloric acid solution was added dropwise to adjust the suspension to neutrality. Ethyl acetate (150mL × 3) was extracted, the organic phase was washed with water (60mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20-10:1) to give 52-a (110mg, yield: 75%) as a white solid.
LC-MS(ESI):m/z＝377.4[M+H]+.
Synthesis of Compound 52
Compound 52-a (110.0mg,0.292mmol) and (S) -piperidine-2-carboxylic acid (75.3mg,0.58mmol) were dissolved in methanol (20ml), sodium cyanoborohydride (36.8mg,0.58mmol) was added, and the mixture was heated to 60 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 52 as a white solid (19.0mg, yield: 13%).
LC-MS(ESI):m/z＝490.4[M+H]+.
1H NMR(400MHz,DMSO-d6):δ8.17-8.13(m,2H),7.78(t,J＝8.0Hz,1H),7.62-7.41(m,9H),4.00(d,J＝12.4Hz,1H),3.41(d,J＝12.8Hz,1H),3.12-3.03(m,1H),2.78-2.74(m,1H),2.16-2.12(m,1H),1.82-1.36(m,6H)ppm。
Example 53
(S, E) -1- (4- (2- (2-cyano- [1,1' -biphenyl) S]-3-yl) vinyl) -2- ((methoxy-d3) Methyl) -5-trifluoromethylbenzyl) piperidine-2-carboxylic acid (Compound 53)
Figure BDA0003234055820000811
Synthesis of Compound 53-d
Compound 20-f (600mg, 2mmol) was dissolved in anhydrous N, N-dimethylformamide (10mL), and sodium hydride (80mg, 4mmol) was added thereto under ice-cooling and nitrogen protection, and after completion of the addition, the reaction was returned to room temperature and stirred for 30 minutes. Deuterated iodomethane (570mg, 4mmol) was added to the reaction mixture, and the reaction was stirred at room temperature for 3 hours. The reaction was quenched by addition of water (1mL), ethyl acetate (100mL) was added, washed with water (20mL × 3), washed with saturated brine (50mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give compound 53-d (292mg, yield: 45.0%).
Synthesis of Compound 53-c
Compound 53-d (290mg, 0.88mmol) was dissolved in dry methanol (10mL), sodium borohydride (100mg, 2.66mmol) was added under nitrogen at 0 deg.C, and the reaction mixture was refluxed for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to give compound 53-c (170mg, yield: 65.0%).
LC-MS(ESI):m/z＝301[M-H]+.
Synthesis of Compound 53-b
Compound 53-c (170mg, 0.56mmol) was dissolved in dichloromethane (10mL), manganese dioxide (493mg, 5.6mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. Filtered and the manganese dioxide washed with dichloromethane. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1) to give compound 53-b (114mg, yield: 68%).
1H NMR(400MHz,DMSO-d6):δ10.17(s,1H),8.31(s,1H),8.08(s,1H),4.88(s,2H)ppm
Synthesis of Compound 53-a
A mixture of compound 53-b (110mg, 0.36mmol), compound 8-b (141mg, 0.42mmol), sodium carbonate (132mg,1.26mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (31mg,0.042mmol), 1, 4-dioxane (5mL) and water (0.5mL) was stirred at 80 ℃ under nitrogen for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to give compound 53-a (65mg, yield: 43.0%).
LC-MS(ESI):m/z＝425[M+H]+.
Synthesis of Compound 53
A mixture of compound 53-a (30mg, 0.07mmol), (S) -piperidine-2-carboxylic acid (24mg, 0.19mmol), sodium cyanoborohydride (12mg,0.19mmol) and methanol (3mL) was stirred at 80 deg.C under nitrogen for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 53(10mg, yield: 26.3%).
LC-MS(ESI):m/z＝538[M+H]+.
1H NMR(400MHz,DMSO-d6):δ7.97(d,J＝8.0Hz,1H),7.94(s,1H),7.82(t,J＝8.0Hz,1H),7.80(s,1H),7.66-7.46(m,8H),4.66(s,2H),3.91(d,J＝14.0Hz,1H),3.61(d,J＝14.4Hz,1H),3.23-3.21(m,1H),2.83-2.80(m,1H),2.26-2.23(m,1H),1.81-1.78(m,2H),1.54-1.40(m,4H)ppm
Example 54
(S, E) -4- (4- (2- (2-cyano- [1,1' -biphenyl) S]-3-yl) vinyl) -2- ((methoxy-d3) Methyl) -5-trifluoroMethylbenzyl) morpholine-3-carboxylic acid (compound 54)
Figure BDA0003234055820000821
Synthesis of Compound 54
A mixture of compound 53-a (30mg, 0.07mmol), (S) -morpholine-3-carboxylic acid (24mg, 0.19mmol), sodium cyanoborohydride (12mg,0.19mmol) and methanol (3mL) was stirred at 80 deg.C under nitrogen for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 54(10mg, yield: 33.3%).
LC-MS(ESI):m/z＝540[M+H]+.
1H NMR(400MHz,DMSO-d6):δ7.97(d,J＝8.0Hz,1H),7.93(s,1H),7.82(t,J＝8.0Hz,1H),7.79(s,1H),7.61-7.49(m,8H),4.71(s,2H),4.06(d,J＝14.0Hz,1H),3.74-3.73(m,2H),3.58-3.52(m,3H),3.06(d,J＝14.4Hz,1H),2.82-2.79(m,1H),2.20-2.15(m,1H)ppm
Example 55
(S, E) -3-hydroxy-2-methyl- ((3- (2- (2-methyl-d)3) - [1,1' -Biphenyl group]-3-yl) vinyl) -4-trifluoromethylbenzyl) amino) propanoic acid (Compound 55)
Figure BDA0003234055820000831
Synthesis of Compound 55-a
A mixture of compound 51-c (125mg,0.5mmol), 4- (trifluoromethyl) -3-vinylbenzaldehyde (150mg,0.75mmol), bis (tri-tert-butylphosphino) palladium (26mg,0.05mmol), triethylamine (506mg,5.0mmol) and toluene (2mL) was stirred at 80 ℃ under nitrogen for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 0-0.04:1) to give compound 55-a (92mg, yield: 50%).
Synthesis of Compound 55
To a mixture of compound 55-a (37mg,0.1mmol), (S) -2-amino-3-hydroxy-2-methylpropanoic acid (24mg, 0.2mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (25mg,0.4 mmol). The reaction mixture was heated to 65 ℃ and stirred for 1 hour, then cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 55(18.4mg, yield: 39%) as a white solid.
LC-MS(ESI):m/z＝473.5[M+H]+.
1H NMR(400MHz,CD3OD):δ8.15(s,1H),7.80(d,J＝8.1Hz,1H),7.67–7.59(m,2H),7.55(dd,J＝7.7Hz,1H),7.46–7.39(m,2H),7.39–7.25(m,5H),7.18(dd,J＝7.6,1.2Hz,1H),4.35(q,J＝12.5Hz,2H),4.06(d,J＝12.2Hz,1H),3.86(d,J＝12.1Hz,1H),1.60(s,3H)ppm
Example 56
(S, E) -3-hydroxy-2-methyl-2- (((3- (2- (2-methyl- [1,1' -biphenylyl) oxy) phenyl)]-3-yl) vinyl) -4-trifluoromethylphenyl) methylene-d2) Amino) propionic acid (compound 56)
Figure BDA0003234055820000832
Synthesis of Compound 56-d
To 3-bromo-4-trifluoromethylbenzaldehyde (253mg, 0.79mmol) and 3-b (300mg, 0.79mmol) of 1, 4-dioxane (20mL) and water (2mL) were added [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (57.8mg, 0.079mmol) and sodium carbonate (216.2g, 2.4mmol) at room temperature, and the reaction mixture was heated to 80 ℃ and stirred under nitrogen for 16 hours. After cooling to room temperature, concentration was performed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 15: 1) to obtain compound 56-d (136mg, yield: 47%).
Synthesis of Compound 56-c
Sodium hydroxide (360.0mg,9.0mmol) was added to silver oxide (510.4mg,2.2mmol) in water (20mL) and dioxane (50mL) at room temperature, and compound 56-d (732.0mg,2.0mmol) was added portionwise. The reaction mixture was warmed to 70 ℃ and stirred for 12 h, cooled to room temperature, concentrated under reduced pressure, the residue dissolved in water (40mL) and adjusted to Ph 4-5 with 4M hydrochloric acid solution, a large amount of white solid precipitated, filtered off with suction, and the filter cake dried to give 56-c as a white solid (740mg, yield: 96%), which was not further purified.
1H NMR (400MHz, DMSO-d6): δ 13.34(s,1H),8.44(s,1H),8.03(d, J ═ 8.0Hz,1H),7.92(d, J ═ 8.4Hz,1H),7.66-7.59(m,2H),7.50-7.46(m,2H),7.42-7.25(m,5H),7.22(d, J ═ 6.8Hz,1H),2.30(s,3H) ppm synthesis of compound 56-b
Compound 56-c (740mg,1.93mol) was dissolved in anhydrous tetrahydrofuran (40mL), N-carbonyldiimidazole (333.5mg,2.03mmol) was added at room temperature, and the mixture was stirred at room temperature under nitrogen for 16 hours. A solution of sodium deuteroborohydride (203.3mg,4.84mmol) in heavy water (8mL) was slowly added dropwise to the reaction mixture, and stirring was continued at room temperature for 16 hours. Concentrated under reduced pressure, and the residue was added with water (50mL) and adjusted to neutral with 4M hydrochloric acid solution. Ethyl acetate (150mL × 3) was extracted, the organic phase was washed with water (50mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10-2:1) to obtain 56-b (630mg, yield: 88%) as a white solid.
1H NMR(400MHz,DMSO-d6):δ7.95(s,1H),7.73(d,J＝8.4Hz,1H),7.58(d,J＝2.8Hz,1H),7.56(d,J＝11.6Hz,1H),7.49-7.45(m,3H),7.40-7.24(m,5H),7.19(d,J＝7.2Hz,1H),5.40(s,1H),2.28(s,3H)ppm
Synthesis of Compound 56-a
Compound 56-b (630mg,1.70mmol) was dissolved in anhydrous dichloromethane (50ml), and thionyl chloride (2.02g,17.0mmol) and anhydrous N, N-dimethylformamide (0.5ml) were added thereto, and the mixture was heated to 70 ℃ and stirred for 6 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 30: 10-1) to give compound 56-a (600mg, yield: 90%).
1H NMR(400MHz,DMSO-d6):δ8.15(s,1H),7.80(d,J＝8.0Hz,1H),7.65-7.59(m,3H),7.50-7.23(m,7H),7.21(d,J＝7.2Hz,1H),2.31(s,3H)ppm
Synthesis of Compound 56
Compound 56-a (116.4mg,0.30mmol) and the starting material (S) -2-methylserine methyl ester hydrochloride (183.0mg,0.60mmol) were dissolved in acetonitrile (20ml), and potassium carbonate (207mg,1.5mmol) and sodium iodide (45.0mg,0.30mmol) were added, heated to 80 ℃ and stirred for 5 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 56(13.5mg, yield: 9.5%).
LC-MS(ESI):m/z＝572.5[M+H]+.
1H NMR(400MHz，DMSO-d6):δ 8.05(s，1H)，7.77(d J＝8.4Hz，1H)，7.65-7.58(m 2H)，7.52-7.46(m,3H),7.42-7.32(m,4H),7.29-7.24(m,1H),7.21(d,J＝6.8Hz,1H),5.06(t,J＝6.0Hz,1H),3.61-3.57(dd,J1＝5.6Hz,J2＝10.0Hz,1H),3.41 3.37(dd,J1＝5.2Hz,J2＝10.0Hz,1H),2.29(s,3H),1.94(bs,1H),1.20(s,3H)ppm
Example 57
(S, E) -1- (5-chloro-4- (2- (2-cyano- [1,1' -biphenyl ] -3-yl) vinyl) -2-methoxybenzyl) piperidine-2-carboxylic acid (Compound 57)
Figure BDA0003234055820000851
Synthesis of Compound 57-c
To a mixture of 3-bromo-4-chlorophenol (2.07g, 10.0mmol) and methanesulfonic acid (15mL) was slowly added urotropin (1.54g, 11.0mmol) in portions. The mixture was stirred at 105 ℃ for 1 hour. The reaction mixture was cooled to room temperature, and an ice-water mixture (100mL) was added. Extraction was performed with ethyl acetate (30 mL. times.3), and the organic phases were combined and washed successively with water (30mL) and saturated brine (30 mL). Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1) to give compound 57-c (750mg, yield: 32%).
1H NMR(400MHz,CDCl3):δ10.90(brs,1H)，9.83(s,1H)，7.62(s,1H)，7.34(s,1H)ppm
Synthesis of Compound 57-b
To a mixture of compound 57-c (200mg, 0.85mmol), cesium carbonate (552mg, 1.70mmol) and N, N-dimethylformamide (10mL) was added methyl iodide (362mg, 2.55mmol), and the mixture was stirred at room temperature for 4 hours. The mixture was diluted with water (100mL), extracted with ethyl acetate (30 mL. times.3), and the organic phases were combined and washed successively with water (30mL) and saturated brine (30 mL). Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1) to give compound 57-b (170mg, yield: 80%).
Synthesis of Compound 57-a
To a mixture of compound 57-b (150mg, 0.60mmol) and compound 8-b (260mg, 0.78mmol) in toluene (25mL) was added [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (44mg, 0.06mmol), potassium phosphate (318mg,1.5mmol), cesium fluoride (225mg, 1.5mmol), and stirred under nitrogen at 90 ℃ for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 5:1) to give compound 57-a (210mg, yield: 94%).
1H NMR(400MHz,CDCl3):δ10.41(s,1H)，7.88(d,J＝7.6Hz,1H),7.87(s,1H)，7.65～7.68(m,3H)，7.45～7.58(m,6H)，7.34(s,1H),4.03(s,3H)ppm
Synthesis of Compound 57
To a solution of 57-a (112mg, 0.30mmol) in dichloromethane (10mL) was added (S) -piperidine-2-carboxylic acid (59mg, 0.46mmol) and methanol (10 mL). The mixture was stirred at room temperature for 1 hour, then sodium cyanoborohydride (32mg, 0.50mmol) was added, and stirred at room temperature for 16 hours. Concentration under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 57(56mg, yield: 38%).
LC-MS(ESI):m/z＝487[M+H]+.
1H NMR(400MHz,CD3OD):δ 7.96(d,J＝7.6Hz,1H)，7.77(t,J＝8.0Hz,1H)，7.74(d,J＝16.0Hz,1H)，7.66(s,1H)，7.65(d,J＝16.0Hz,1H)，7.56-7.58(m,2H)，7.46-7.53(m,5H)，4.47(d,J＝12.8Hz,1H)，4.34(d,J＝12.8Hz,1H)，4.00(s,3H)，3.48-3.53(m,1H)，2.96-3.03(m,1H)，2.22-2.26(m,1H)，1.73-1.85(m,5H)，1.54-1.59(m,1H)ppm
Example 58
(S, E) -1- (5-chloro-2-methoxy-4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) benzyl) piperidine-2-carboxylic acid (Compound 58)
Figure BDA0003234055820000861
Synthesis of Compound 58-a
To a mixture of compound 57-b (250mg, 1.00mmol) and compound 3-b (400mg, 1.25mmol) in toluene (20mL) was added [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (73mg, 0.10mmol), potassium phosphate (424mg,2.0mmol), cesium fluoride (300mg, 2.0mmol), and stirred at 90 ℃ under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 5:1) to give compound 58-a (272mg, yield: 75%).
1H NMR(400MHz,CDCl3):δ10.39(s,1H),7.85(s,1H),7.63(d,J＝8.0Hz,1H),7.49(d,J＝16.0Hz,1H),7.36-7.45(m,4H),7.28-7.31(m,3H),7.23-7.25(m,2H),4.01(s,3H),2.33(s,3H)ppm
Synthesis of Compound 58
To a solution of compound 58-a (109mg, 0.30mmol) in dichloromethane (10mL) was added (S) -piperidine-2-carboxylic acid (59mg, 0.46mmol), methanol (10 mL). The mixture was stirred at room temperature for 1 hour, then sodium cyanoborohydride (32mg, 0.50mmol) was added, and stirred at room temperature for 16 hours. Concentration under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 58(66mg, yield: 46%).
LC-MS(ESI):m/z＝476[M+H]+.
1H NMR(400MHz,CD3OD):δ7.59-7.65(m,3H),7.40-7.44(m,3H),7.33-7.37(m,2H),7.25-7.30(m,3H),7.16(d,J＝7.2Hz,1H),4.46(d,J＝12.8Hz,1H),4.34(d,J＝12.8Hz,1H),4.00(s,3H),3.48-3.53(m,1H),2.96-3.03(m,1H),2.30(s,1H),2.22-2.26(m,1H),1.76-1.86(m,5H),1.54-1.59(m,1H)ppm
Example 59
(S, E) -1- (5-chloro-2- (methoxy-d)3) -4- (2- (2-methyl- [1,1' -biphenyl)]-3-yl) vinyl) benzyl) piperidine-2-carboxylic acid (compound 59)
Figure BDA0003234055820000862
Figure BDA0003234055820000871
Synthesis of Compound 59-b
To a mixture of compound 57-c (150mg, 0.60mmol), cesium carbonate (390mg, 1.20mmol) and N, N-dimethylformamide (8mL) was added deuterated iodomethane (362mg, 2.55mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (50mL), extracted with ethyl acetate (30 mL. times.3), and the organic phases were combined and washed successively with water (30mL) and saturated brine (30 mL). Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1) to give compound 59-b (136mg, yield: 85%).
1H NMR(400MHz,CDCl3):δ10.35(s,1H),7.87(s,1H),7.28(s,1H)ppm
Synthesis of Compound 59-a
To a mixture of compound 59-b (133mg, 0.50mmol) and compound 3-b (200mg, 0.62mmol) in toluene (20mL) was added [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (65mg, 0.089mmol), potassium phosphate (212mg, 1.0mmol), cesium fluoride (150mg, 1.0mmol), and stirred under nitrogen at 90 ℃ for 16 hours. The reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 7:1) to give compound 59-a (123mg, yield: 67%).
1H NMR(400MHz,CDCl3):δ10.39(s,1H),7.85(s,1H),7.63(d,J＝8.0Hz,1H),7.49(d,J＝16.0Hz,1H),7.35-7.43(m,4H),7.28-7.30(m,3H),7.23-7.25(m,2H),4.01(s,3H),2.33(s,3H)ppm
Synthesis of Compound 59
To a solution of compound 59-a (120mg, 0.33mmol) in dichloromethane (10mL) was added (S) -piperidine-2-carboxylic acid (109mg, 0.78mmol), methanol (10 mL). The mixture was stirred at room temperature for 1 hour, then sodium cyanoborohydride (100mg, 1.58mmol) was added, and stirred at room temperature for 16 hours. Concentration under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 59(62mg, yield: 43%).
LC-MS(ESI):m/z＝479[M+H]+.
1H NMR(400MHz,CD3OD):δ7.59-7.65(m,3H),7.40-7.44(m,3H),7.33-7.37(m,2H),7.25-7.30(m,3H),7.16(d,J＝7.2Hz,1H),4.46(d,J＝12.8Hz,1H),4.34(d,J＝12.8Hz,1H),3.50-3.53(m,1H),2.96-3.02(m,1H),2.30(s,1H)，2.22-2.26(m,1H),1.76-1.86(m,5H),1.54-1.60(m,1H)ppm。
Example 60
(S, E) -1- (2- (methoxy-d)3) -4- (2- (2-methyl- [1,1' -biphenyl)]-3-yl) vinyl) -5-trifluoromethylbenzyl) piperidine-2-carboxylic acid (Compound 60)
Figure BDA0003234055820000872
Figure BDA0003234055820000881
Synthesis of Compound 60-c
To a solution of 4-bromo-2-methoxy-5-trifluoromethyl-benzaldehyde (283mg, 1.0mmol) in dichloromethane (10mL) was slowly added boron tribromide (1.0M) in dichloromethane (2.5mL, 2.5mmol) dropwise at 0 ℃. After the addition, the ice bath was removed and the mixture was stirred at room temperature for 16 hours. The mixture was slowly added to 50mL of a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate (30 mL. times.3). The organic phases were combined and washed successively with water (30mL) and saturated brine (30 mL). Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1) to give compound 60-c (142mg, yield: 53%).
LC-MS(ESI):m/z＝267[M-H]-.
Synthesis of Compound 60-b
To a mixture of compound 60-c (130mg, 0.48mmol), cesium carbonate (500mg, 1.54mmol) and N, N-dimethylformamide (8mL) was added deuterated iodomethane (290mg, 2.00mmol), and the mixture was stirred at room temperature for 16 hours. Water (100mL) was added to the mixture to dilute it, and extraction was performed with ethyl acetate (30 mL. times.3). The organic phases were combined and washed successively with water (30mL) and saturated brine (30 mL). Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1) to give compound 60-b (106mg, yield: 78%).
Synthesis of Compound 60-a
To a mixture of compound 60-b (100mg, 0.35mmol) and compound 3-b (145mg, 0.45mmol) in toluene (15mL) was added [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (25mg, 0.035mmol), potassium phosphate (148mg, 0.7mmol), cesium fluoride (105mg, 0.7mmol), and the mixture was stirred at 90 ℃ for 16 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 6: 1) to give compound 60-a (95mg, yield: 68%).
MS(ESI):m/z＝400[M+H]+.
Synthesis of Compound 60
To a solution of compound 60-a (40mg, 0.10mmol) in dichloromethane (10mL) was added L-piperidine-2-carboxylic acid (39mg, 0.3mmol), methanol (10 mL). The mixture was stirred at room temperature for 1 hour, then sodium cyanoborohydride (16mg, 0.25mmol) was added, and after the addition was completed, stirring was carried out at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to give compound 60(20mg, yield: 39%).
LC-MS(ESI):m/z＝513[M+H]+.
1H NMR(400MHz,CD3OD):δ 7.90(s,1H),7.63(d,J＝16.0Hz,1H),7.54(d,J＝8.0Hz,1H),7.53(s,1H),7.41～7.44(m,2H),7.35(d,J＝8.0Hz,1H),7.26～7.33(m,4H),7.18(d,J＝7.6Hz,1H),4.53(d,J＝12.8Hz,1H),4.40(d,J＝12.8Hz,1H),3.49～3.52(m,1H),2.93～3.03(m,1H),2.30(s,3H),2.22～2.26(m,1H),1.67～1.85(m,5H),1.54～1.59(m,1H)ppm.
Example 61
(S, E) -1- (2-methoxy-4- (2- (2-methyl- [1,1' -biphenyl) S]-3-yl-2 ', 3 ', 4 ', 5 ', 6 ' -d5) Vinyl) -5-trifluoromethylbenzyl) piperidine-2-carboxylic acid (Compound 61)
Figure BDA0003234055820000891
Synthesis of Compound 61-d
To a solution of 1-bromo-3-chloro-2-methylbenzene (2.05g, 10.0mmol) and vinylboronic acid pinacol ester (2.00g, 13.0mmol) in toluene (40mL) were added bis (tri-tert-butylphosphine) palladium (400mg, 0.8mmol), and triethylamine (3.03g, 30.0mmol), and the mixture was stirred at 80 ℃ for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to obtain compound 61-d (2.36g, yield: 85%).
Synthesis of Compound 61-c
To a mixture of compound 61-d (279mg, 1.00mmol) and 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde (300mg, 1.06mmol) in toluene (15mL) was added [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (73mg, 0.10mmol), potassium phosphate (424mg,2.0mmol), cesium fluoride (300mg, 2.0mmol), and the mixture was stirred at 90 ℃ for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 8: 1) to give compound 61-c (205mg, yield: 58%).
Synthesis of Compound 61-b
To a mixture of compound 61-c (200mg, 0.56mmol) and pinacol diboron diboronate (200mg, 0.78mmol) in toluene (15mL) was added tris (dibenzylideneacetone) dipalladium (37mg, 0.04mmol), 2-cyclohexylphosphine-2 ', 4 ', 6 ' -triisopropylbiphenyl (76mg, 0.16mmol), potassium acetate (165mg, 1.68 mmol). Stirred at 90 ℃ for 16 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 7:1) to give compound 61-b (103mg, yield: 41%).
1H NMR(400MHz,CD3Cl):δ10.44(s,1H),8.15(s,1H),7.77(d,J＝7.6Hz,1H),7.62(d,J＝7.6Hz,1H),7.46(d,J＝16.0Hz,1H),7.23～7.30(m,3H),4.07(s,3H),2.64(s,3H),1.37(s,12H)ppm
Synthesis of Compound 61-a
To a solution of compound 61-b (100mg, 0.22mmol) and pentadeuterated bromobenzene (54mg, 0.33mmol) in toluene (10mL) were added [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (32mg, 0.044mmol), potassium phosphate (93mg, 0.44mmol), cesium fluoride (66mg, 0.44mmol), and the mixture was stirred at 90 ℃ for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 5:1) to give compound 61-a (60mg, yield: 68%).
1H NMR(400MHz,CD3Cl):δ10.44(s,1H),8.16(s,1H),7.59(d,J＝7.6Hz,1H),7.48(d,J＝16.0Hz,1H),7.33～7.38(m,3H),7.24～7.28(m,1H),4.07(s,3H),2.33(s,3H)ppm
Synthesis of Compound 61
To a solution of compound 61-a (60mg,0.15mmol) in dichloromethane (10mL) was added L-piperidine-2-carboxylic acid (40mg, 0.3mmol), methanol (10 mL). The mixture was stirred at room temperature for 1 hour, then sodium cyanoborohydride (28mg, 0.45mmol) was added, and after the addition was completed, stirring was carried out at room temperature for 16 hours. Concentration under reduced pressure, and purification of the residue by preparative liquid chromatography gave compound 61(21mg, yield: 27%).
LC-MS(ESI):m/z＝515[M+H]+.
1H NMR(400MHz,CD3OD):δ7.90(s,1H),7.63(d,J＝16.0Hz,1H),7.54(d,J＝8.0Hz,1H),7.53(s,1H),7.26～7.33(m,2H),7.18(d,J＝7.6Hz,1H),4.53(d,J＝12.8Hz,1H),4.40(d,J＝12.8Hz,1H),4.07(s,3H),3.49～3.52(m,1H),2.97～3.03(m,1H),2.30(s,3H),2.23～2.27(m,1H),1.67～1.85(m,5H),1.54～1.59(m,1H)ppm.
Example 62
(R, E) -1- (2-methoxy-4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -5-trifluoromethylbenzyl) piperidine-2-carboxylic acid (Compound 62)
Figure BDA0003234055820000901
Synthesis of Compound 62
To a solution of compound 6-a (198mg, 0.5mmol) and D-piperidine-2-carboxylic acid (161.2mg, 1.25mmol) in methanol (30mL) was added sodium cyanoborohydride (63mg, 1.0 mmol). The mixture was heated to 60 ℃ and stirred for 2 hours, then cooled to room temperature, concentrated under reduced pressure, and the residue was washed with water (30 mL. times.3), filtered, concentrated under reduced pressure, and then subjected to high performance liquid chromatography to give the product 62(110mg, yield: 43%) as a white solid.
LC-MS(ESI):m/z＝510.5[M+H]+.
1H NMR:(400MHz DMSO-d6):δ7.78(s,1H),7.65(d,J＝16.0Hz,1H),7.58(d,J＝7.6Hz,1H),7.50-7.46(m,3H),7.42-7.32(m,4H),7.25-7.19(m,2H),3.97(s,3H),3.82-3.67(m,2H),2.94-2.90(m,1H),2.30(s,3H),2.29-2.27(m,1H),1.85-1.78(m,2H),1.52-1.41(m,4H)ppm。
Example 63
(S, E) -1- (2, 5-dimethoxy-4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) benzyl) piperidine-2-carboxylic acid (Compound 63)
Figure BDA0003234055820000911
Synthesis of Compound 63-a
To a mixture of compound 3-b (160mg,0.5mmol) and 4-bromo-2, 5-dimethoxybenzaldehyde (122.5mg,0.5mmol) in toluene (25mL) was added [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (36.6mg,0.05mmol), potassium phosphate (318mg,1.5mmol), cesium fluoride (231mg,1.5mmol), and the mixture was stirred at 110 ℃ for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20-3: 1) to give compound 63-a (140mg, yield: 78%).
LC-MS(ESI):m/z＝359.2[M+H]+.
Synthesis of Compound 63
To a solution of compound 63-a (140.0mg,0.39mmol) in methanol (20mL) were added (S) -piperidine-2-carboxylic acid (126.1mg,0.97mmol) and sodium cyanoborohydride (49.1mg,0.78mmol), and the mixture was heated to 60 ℃ and stirred for 2 hours. After cooling to room temperature, concentration under reduced pressure was carried out, and the residue was subjected to high performance liquid chromatography to give compound 63(110mg, yield: 59%).
LC-MS(ESI):m/z＝472.3[M+H]+.
1H NMR(400MHz,CD3OD):δ7.60(d,J＝12.0Hz,1H),7.56(d,J＝2.0Hz,1H),7.43-7.40(m,2H),7.39-7.21(m,6H),7.11(d,J＝7.2Hz,1H),4.47(d,J＝12.4Hz,1H),4.36(d,J＝12.4Hz,1H),3.97(s,3H),3.91(s,3H),3.50-3.47(m,1H),3.38-3.30(m,1H),2.95-2.90(m,1H),2.27(s,3H),2.26-2.23(m,1H),1.90-1.53(m,5H)ppm
Example 64
(S, Z) -1- (4- (1-fluoro-2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) 2-methoxy-5-trifluoromethylbenzyl) piperidine-2-carboxylic acid (Compound 64)
Figure BDA0003234055820000912
Figure BDA0003234055820000921
Synthesis of Compound 64-d
The compound (2-methyl- [1,1' -biphenyl ] -3-yl) methanol (1.98g,10.0mmol) was dissolved in methylene chloride (100mL), and manganese dioxide (2.64g,30.0mmol) was added to the solution. The reaction mixture was stirred at room temperature for 16 hours, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10-5:1) to obtain 64-d (1.9g, yield: 96.9%) as colorless crystals.
LC-MS(ESI):m/z＝197.2[M+H]+.
Synthesis of Compound 64-c
Compound 64-d (3.92g,20mmol) was dissolved in N, N-dimethylformamide (39mL), triphenylphosphine (6.1g,23.28mmol) was added, and after heating to 100 deg.C, a 2.0M solution of sodium chlorodifluoroacetate (4.4g,29.1mmol) in N, N-dimethylformamide was added dropwise, and the reaction was continued for 1 hour at 100 deg.C with stirring. The mixture was poured into water (200mL), extracted with ethyl acetate (100 mL. times.2), the organic phase was washed successively with water (100mL) and saturated brine (100mL), dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to give compound 64-c (2.67g, yield: 58.1%).
Synthesis of Compound 64-b
Compound 64-c (2.3g,10mmol) was dissolved in tetrahydrofuran (30mL) and pinacol ester diboron (4.04g,15.9mmol), cuprous chloride (10.5mg,0.106mmol), tricyclohexylphosphine (59.4mg,0.212mmol) and potassium acetate (1.25g,12.72mmol) were added. The reaction was stirred at 40 ℃ for 16 hours. After cooling to room temperature, concentration was performed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 9:1) to obtain compound 64-b (3.0g, yield: 90%).
Synthesis of Compound 64-a
In a mixed solvent of compound 64-b (200mg, 0.59mmol), 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde (168mg, 0.59mmol), potassium carbonate (163mg,1.18mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (43mg,0.059mmol) and 1, 4-dioxane (5mL) and water (0.5mL), the mixture was stirred at 80 ℃ under nitrogen for 16 hours and then cooled to room temperature. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1) to give compound 64-a (154mg, yield: 63.0%).
LC-MS(ESI):m/z＝415[M+H]+.
Synthesis of Compound 64
A mixture of compound 64-a (29mg,0.07mmol), (S) -piperidine-2-carboxylic acid (24mg, 0.19mmol), sodium cyanoborohydride (12mg,0.19mmol) and methanol (3mL) was stirred at 80 ℃ under nitrogen for 3 hours and then cooled to room temperature. Concentration under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 64(15mg, yield: 40.6%).
LC-MS(ESI):m/z＝528[M+H]+.
1H NMR(400MHz,DMSO-d6):δ7.87(s,1H),7.62(d,J＝7.6Hz,1H),7.46(d,J＝7.6Hz,2H),7.39(t,J＝7.2Hz,1H),7.35-7.31(m,4H),7.18(d,J＝7.6Hz,1H),6.50(d,J＝36.8Hz,1H),3.95(s,3H),3.81-3.67(m,2H),3.24-3.22(m,1H),2.90-2.88(m,1H),2.28-2.25(m,1H),2.21(s,3H),1.88-1.73(m,2H),1.50-1.41(m,4H)ppm
Example 65
(Z) -2- ((4- (1-fluoro-2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -2-methoxy-5-trifluoromethylbenzyl) amino) -1-ethanol (Compound 65)
Figure BDA0003234055820000931
Synthesis of Compound 65
A mixture of compound 64-a (29mg,0.07mmol), ethanolamine (11mg, 0.19mmol), sodium cyanoborohydride (12mg,0.19mmol) and methanol (3mL) was stirred at 80 ℃ under nitrogen for 3 hours and then cooled to room temperature. Concentration under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 64(18mg, yield: 50.1%).
LC-MS(ESI):m/z＝460[M+H]+.
1H NMR(400MHz,DMSO-d6):δ7.83(s,1H),7.62(d,J＝7.6Hz,1H),7.46(d,J＝7.6Hz,2H),7.39(t,J＝7.2Hz,1H),7.35-7.31(m,4H),7.17(d,J＝7.6Hz,1H),6.50(d,J＝36.8Hz,1H),4.51(t,J＝5.2Hz,1H),3.96(s,3H),3.77(s,3H),3.49(q,J＝5.6Hz,2H),2.60(t,J＝5.6Hz,2H),2.20(s,3H)ppm
Example 66
(Z) -2- ((4- (1-bromo-2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -2-methoxy-5-trifluoromethylbenzyl) amino) -1-ethanol (Compound 66)
Figure BDA0003234055820000932
Figure BDA0003234055820000941
Synthesis of Compound 66-c
Compound 6-b (1.42g,5.0mmol) and the compound bis-pinacolatodiboron (1.90g,7.5mmol) were dissolved in toluene (60mL) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (366mg,0.5mmol) and potassium acetate (1.47g,15.0mmol) were added to the solution. The reaction solution was heated to 100 ℃ and stirred for 6 hours, and then cooled to room temperature. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 15-3:1) to give 66-c (1.5g, yield: 90%) as a pale yellow solid.
Synthesis of Compound 66-b
Compound 64-d (588mg,3.0mmol) was dissolved in anhydrous dichloromethane (40mL), carbon tetrabromide (1.48g,4.5mmol) was added, and then cooled to zero degrees. A solution of triphenylphosphine (1.56g,6.0mmol) in dichloromethane (10mL) was slowly added dropwise to the reaction mixture. The temperature was raised to room temperature and stirring was continued for 1 hour. The reaction mixture was filtered, and the filtrate was washed with saturated sodium bicarbonate solution (20mL) and brine (20mL), respectively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 100-20:1) to give 66-b (1.05g, yield: 99%) as a colorless oil.
1H NMR(400MHz,CDCl3):δ7.52(s,1H),7.43-7.34(m,4H),7.30-7.27(m,2H),7.23-7.21(m,2H),2.14(s,3H)ppm
Synthesis of Compound 66-a
Compound 66-b (220mg,0.625mmol) and compound 66-c (247.5mg,0.75mmol) were dissolved in a mixed solution of dioxane (30mL) and water (10mL), bis (dibenzylideneacetone) palladium (28.6mg,0.03mmol), tris (2-furyl) phosphine (43.5mg,0.187mmol) and cesium fluoride (406.2mg,1.25mmol) were added to the solution, and the reaction solution was stirred at 65 ℃ for 16 hours. Cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 66-a (80mg, yield: 27%) as a white solid.
Synthesis of Compound 66
Compound 66-a (80mg,0.169mmol) was dissolved in a mixed solution of dichloromethane (15mL) and methanol (5mL), and ethanolamine (51.5mg,0.845mmol) and one drop of glacial acetic acid were added. After the reaction was stirred at room temperature for 2 hours, sodium cyanoborohydride (21.4mg,0.34mmol) was added and stirring was continued for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 66(30.9mg, yield: 35%) as a white solid.
LC-MS(ESI):m/z＝520.1[M+H]+.
1H NMR(400MHz,CD3OD):δ7.71(s,1H),7.51(d,J＝8.0Hz,1H),7.48-7.43(m,2H),7.39-7.37(m,1H),7.34-7.30(m,3H),7.22(d,J＝6.8Hz,1H),7.17(s,1H),7.08(s,1H),4.04(s,3H),3.90(s,2H),3.71(t,J＝6.0Hz,2H),2.76(t,J＝6.0Hz,2H),2.20(s,3H)ppm
Example 67
(S, Z) -1- (4- (1-bromo-2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -2-methoxy-5-trifluoromethylbenzyl) piperidine-2-carboxylic acid (Compound 67)
Figure BDA0003234055820000951
Synthesis of Compound 67
A mixture of compound 66-a (110mg, 0.23mmol), (S) -piperidine-2-carboxylic acid (89mg, 0.69mmol), sodium cyanoborohydride (28.9mg,0.46mmol) and methanol (20mL) was stirred at 60 ℃ for 2 hours and then cooled to room temperature. Concentration under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 67(46mg, yield: 34%).
LC-MS(ESI):m/z＝588.2[M+H]+.
1H NMR(400MHz,CD3OD):δ8.00(s,1H),7.53(d,J＝7.6Hz,1H),7.48-7.43(m,2H),7.38(d,J＝7.2Hz,1H),7.34-7.30(m,4H),7.23(d,J＝7.2Hz,1H),7.12(s,1H),4.59(d,J＝13.2Hz,1H),4.45(d,J＝12.4Hz,1H),4.05(s,3H),3.57-3.53(m,1H),3.43-3.39(m,1H),3.07-3.01(m,1H),2.33-2.26(m,1H),2.20(s,3H),1.93-1.58(m,5H)ppm
Example 68
(S, Z) -1- (4- (2-bromo-2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -2-methoxy-5-methylbenzyl) piperidine-2-carboxylic acid (Compound 68)
Figure BDA0003234055820000952
Synthesis of Compound 68-f
The mixture of 3-bromo-2-methyl-1, 1 '-biphenyl (989mg, 4.0mmol), bis-pinacolato borate (1.52g, 6.0mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (293mg,0.4mmol), potassium acetate (1.18g,1.2mmol), 1, 4-dioxane (10mL) was stirred under nitrogen at 90 ℃ for 16 hours. Cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 20:1) to give 68-f (1.0g, yield: 85%) as a colorless liquid.
1H NMR(400MHz,CD3OD):δ7.76(dd,J＝7.2,1.3Hz,1H),7.43–7.36(m,2H),7.36–7.26(m,4H),7.24–7.19(m,1H),2.41(s,3H),1.36(s,12H)ppm
Synthesis of Compound 68-e
A mixture of 4-bromo-2-hydroxy-5-methylbenzaldehyde (6.45g,30.0mmol), iodomethane (5.11g,36.0mmol), potassium carbonate (8.29g,60.0mmol) and N, N' -dimethylformamide (30mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (150 mL). The precipitated solid was filtered, dried and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1) to obtain 68-e (5.59g, yield: 81%) as a white solid.
Synthesis of Compound 68-d
A mixture of compound 68-e (5.10g,22.3mmol), triethyl orthoformate (6.60g,44.5mmol), ammonium chloride (119mg,2.2mmol) and ethanol (3.08g, 66.8mmol) was refluxed for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and dried in vacuo, the resulting product, 68-d (6.75 g), was used directly in the next step.
Synthesis of Compound 68-c
Compound 68-d (1.52g,5.0mmol) was dissolved in dry tetrahydrofuran (15 mL). N-butyllithium (2.2mL, 2.5M n-hexane solution) was slowly added dropwise at-78 ℃. After completion of the dropwise addition, the mixture was stirred at-78 ℃ for 0.5 hour, and N, N' -dimethylformamide (431mg,10mmol) was added dropwise. After the addition was complete, the mixture was stirred at-78 ℃ for 2 hours. After warming to room temperature, the reaction was quenched with saturated sodium bicarbonate solution (10 mL). The resulting mixture was extracted with ethyl acetate (50 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1) to give 68-c (1.07g, yield: 85%) as a pale yellow liquid.
1H NMR(400MHz,DMSO-d6):δ10.24(s,1H),7.41(s,1H),7.36(s,1H),5.67(s,1H),3.85(s,3H),3.61–3.47(m,4H),2.56(s,3H),1.12(t,J＝7.0Hz,6H)ppm
Synthesis of Compound 68-b
To a mixture of triphenylphosphine (2.73g,10.4mmol) and dichloromethane (10mL) at 0 deg.C was added dropwise a solution of carbon tetrabromide (1.72g) in dichloromethane (5 mL). After the addition, stirring was continued at 0 ℃ for 10 minutes. Then, a solution of compound 68-c (1.01g,4.0mmol) and triethylamine (1.21g) in dichloromethane (5mL) was added dropwise. After the addition, the reaction solution was warmed to room temperature and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 20:1) to give 68-b (700mg, yield: 52%) as a white solid.
1H NMR(400MHz,DMSO-d6):δ 10.31(s,1H),7.83(s,1H),7.55(s,1H),7.21(s,1H),3.91(s,3H),2.20(s,3H)ppm
Synthesis of Compound 68-a
A mixture of compound 68-b (586mg,1.75mmol), compound 68-f (397mg, 1.35mmol), bis (dibenzylideneacetone) palladium (62mg, 0.068mmol), tris (2-furyl) phosphine (94mg, 0.40mmol), sodium carbonate solution (2.7mL, 1M), dioxane (7mL) was reacted under nitrogen at 60 ℃ for 5 hours. After cooling to room temperature, the reaction mixture was diluted with water (10mL), and the resulting mixture was extracted with dichloromethane (30 mL). The organic phase was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 68-a (88mg, yield: 10%).
LC-MS(ESI):m/z＝421.2[M+H]+.
Synthesis of Compound 68
To a mixture of compound 68-a (42mg,0.10mmol), (S) -piperidine-2-carboxylic acid (26mg, 0.20mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (25mg,0.40 mmol). The reaction mixture was stirred at 60 ℃ for 1 hour, then cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 68(21mg, yield: 39%) as a white solid.
LC-MS(ESI):m/z＝534.2[M+H]+.
1H NMR(400MHz,CD3OD):δ7.47–7.25(m,9H),7.22(dd,J＝7.5,1.4Hz,1H),7.03(s,1H),4.47(d,J＝12.7Hz,1H),4.34(d,J＝12.8Hz,1H),3.94(s,3H),3.50(d,J＝11.3Hz,1H),3.32(s,1H),2.97(t,J＝11.9Hz,1H),2.32(s,3H),2.31(s,3H),2.23(d,J＝10.5Hz,1H),1.98–1.63(m,4H),1.61–1.46(m,1H)ppm
Example 69
(Z) -2- ((4- (2-bromo-2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -2-methoxy-5-methylbenzyl) amino) -1-ethanol (Compound 69)
Figure BDA0003234055820000971
Synthesis of Compound 69
To a mixture of compound 68-a (29mg,0.07mmol), ethanolamine (9mg, 0.15mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (18mg,0.28 mmol). The reaction mixture was stirred at 60 ℃ for 1 hour, cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 69(17mg, yield: 52%) as a white solid.
LC-MS(ESI):m/z＝466.2,468.2[M+H]+.
1H NMR(400MHz,CD3OD):δ8.53(s,1H),7.47–7.20(m,10H),7.03(s,1H),4.20(s,2H),3.96(s,3H),3.84–3.77(m,2H),3.13–3.06(m,2H),2.32(s,3H),2.31(s,3H)ppm
Example 70
(S, E) -1- (2-methoxy-5-methyl-4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) benzyl) piperidine-2-carboxylic acid (Compound 70)
Figure BDA0003234055820000972
Synthesis of Compound 70-a
A mixture of 4-bromo-2-methoxy-5-methylbenzaldehyde (115mg, 0.5mmol), compound 3-b (192mg,0.6mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (37mg,0.05mmol), potassium carbonate (138mg,1.0mmol), 1, 4-dioxane (2mL) and water (0.4mL) was stirred at 90 deg.C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, diluted with saturated brine (10mL), and the resulting mixture was extracted with dichloromethane (20 mL. times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 5:1) to give 70-a (135mg, yield: 79%) as a yellow solid.
Synthesis of Compound 70
To a mixture of compound 70-a (51mg,0.15mmol), (S) -piperidine-2-carboxylic acid (38mg, 0.30mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (37mg,0.60 mmol). The reaction mixture was stirred at 60 ℃ for 1 hour, then cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 70(26mg, yield: 38%) as a white solid.
LC-MS(ESI):m/z＝456.3[M+H]+.
1H NMR(400MHz,CD3OD δ 7.60(d, J ═ 7.5Hz,1H), 7.48-7.19 (m,10H),7.14(d, J ═ 7.4Hz,1H),4.46(d, J ═ 12.7Hz,1H),4.33(d, J ═ 12.7Hz,1H),3.96(s,3H),3.48(d, J ═ 7.1Hz,1H), 3.38-3.32 (m,1H),2.96(t, J ═ 11.7Hz,1H),2.40(s,3H),2.29(s,3H),2.23(d, J ═ 13.4Hz,1H), 1.97-1.43 (m,5H) ppm example 71 ppm
(S, E) -1- (4- (2- (2-chloro- [1,1' -biphenyl ] -3-yl) vinyl) -2-methoxy-5-trifluoromethylbenzyl) piperidine-2-carboxylic acid (Compound 71)
Figure BDA0003234055820000981
Synthesis of Compound 71-c
The mixture of 3-bromo-2-chloro-benzaldehyde (878mg, 4.0mmol), phenylboronic acid (536mg, 4.4mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (146mg,0.2mmol), potassium carbonate (1.11g,8.0mmol), 1, 4-dioxane (12mL) and water (4.0mL) was stirred under nitrogen at 90 ℃ for 16 hours. The reaction was cooled to room temperature, diluted with water (20mL) and the mixture extracted with dichloromethane (40 mL). The organic phase was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 30:1) to give 71-c (764mg, yield: 88%) as a colorless liquid.
Synthesis of Compound 71-b
Potassium tert-butoxide (787mg,4.02mmol) was added to a mixture of methyltriphenylphosphonium bromide (2.51g, 7.02mmol) and tetrahydrofuran (20mL) at room temperature and stirred at room temperature for 2 hours. After the reaction solution was cooled to-78 deg.C, compound 71-c (760mg, 3.51mmol) was added, and the reaction solution was warmed to room temperature and stirred for 16 hours. The reaction was quenched with saturated ammonium chloride solution (30 mL). The resulting mixture was extracted with ethyl acetate (40 mL. times.2). The organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to give compound 71-b (360mg, yield: 48%) as a colorless liquid.
Synthesis of Compound 71-a
A mixture of compound 71-b (107mg,0.50mmol), 4-bromo-2-methoxy-5- (trifluoromethyl) benzaldehyde (212mg,0.75mmol), bis (tri-tert-butylphosphine) palladium (26mg,0.05mmol), triethylamine (506mg,5.0mmol) and toluene (2mL) was reacted under nitrogen at 80 ℃ for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 5:1) to give 71-a (60mg, yield: 29%) as a yellow solid.
LC-MS(ESI):m/z＝417.2[M+H]+.
Synthesis of Compound 71
To a mixture of compound 71-a (60mg,0.144mmol), (S) -piperidine-2-carboxylic acid (37mg, 0.288mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (36mg,0.576 mmol). The reaction mixture was stirred at 60 ℃ for 1 hour, then cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 71(19mg, yield: 25%) as a white solid.
LC-MS(ESI):m/z＝530.2[M+H]+.
1H NMR(400MHz,CD3OD):δ7.93(s,1H),7.75–7.66(m,2H),7.52–7.35(m,8H),7.33(dd,J＝7.5,1.3Hz,1H),4.45(d,J＝13.0Hz,1H),4.30(d,J＝13.1Hz,1H),4.05(s,3H),3.43(dd,J＝10.5,3.3Hz,1H),3.30–3.24(m,1H),2.88(t,J＝10.6Hz,1H),2.21(d,J＝11.9Hz,1H),1.94–1.44(m,5H)ppm
Example 72
(S, E) -1- (2-methoxy-4- (2- (2-methyl- [1,1' -biphenyl) S]-3-yl) vinyl-1, 2-d2) -5-trifluoromethylbenzyl) piperidine-2-carboxylic acid (Compound 72)
Figure BDA0003234055820000991
Synthesis of Compound 72-d
Compound 3-c (1.0g, 4.05mmol) and trimethylethynylsilicon (596.2mg, 6.07mmol) were dissolved in N, N-dimethylformamide (15mL), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (142.5mg, 0.203mmol) and triethylamine (3.279g, 32.4mmol) were added. The reaction mixture was heated to 70 ℃ under nitrogen and stirred for 16 hours, cooled to room temperature, diluted with ethyl acetate (15mL), and washed once with water (50mL) and saturated brine (50 mL). The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to give compound 72-d (551mg, yield: 51.5%).
1H NMR(400MHz,CDCl3):δ7.56-7.54(d,J＝7.6Hz,1H),7.44-7.34(m,3H),7.28-7.26(m,2H),7.17-7.15(d,J＝7.6Hz,1H),7.10-7.06(t,J＝7.6Hz,1H),2.31(s,3H)ppm
Synthesis of Compound 72-c
Compound 72-d (551mg, 2.084mmol) was dissolved in methanol (15mL), and potassium carbonate (863.9mg, 6.251mmol) was added. The reaction solution was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50mL), which was washed with water (50mL) and saturated brine (50 mL). The resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain the objective compound 72-c (361mg, yield: 90.3%).
1H NMR(400MHz,CDCl3):δ7.50-7.48(m,1H),7.43-7.35(m,3H),7.30-7.28(m,2H),7.23-7.19(m,2H),3.29(s,1H),2.37(s,3H)ppm
Synthesis of Compound 72-b
Compound 72-c (100mg, 0.52mmol) was dissolved in anhydrous tetrahydrofuran (10mL), the reaction solution was cooled to-50 ℃ in an ice salt bath, and a 1.56M n-butyllithium n-hexane solution (0.4mL, 0.624mmol) was added dropwise. After the addition, the reaction mixture was stirred at-50 ℃ for 0.5 hour.
Solid dry ice was added to the reaction solution, and the mixture was stirred for 0.5 hour, then, the reaction solution was warmed to room temperature, and stirring was continued for 1 hour. The reaction was quenched by addition of water (10mL) and the solution was then adjusted to pH 1-2 with dilute hydrochloric acid (1N). The mixture was extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was slurried with petroleum ether to give compound 72-b (83mg, yield: 67.5%).
1H NMR(400MHz,DMSO-d6):δ7.62-7.58(m,1H),7.49-7.45(m,2H),7.42-7.39(m,1H),7.37-7.33(m,4H),2.33(s,3H)ppm
Synthesis of Compound 72-a
Compound 72-b (83mg, 0.351mmol) and bis-pinacolato borate (107.2mg, 0.422mmol) were dissolved in 1, 4-dioxane (10mL), and cuprous oxide (5mg, 0.035mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (20.3mg, 0.035mmol) and heavy water (42mg, 2.106mmol) were added. Stirring was carried out overnight at room temperature under nitrogen.
To the above reaction solution were added compound 6-b (99mg, 0.351mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (30.3mg, 0.035mmol), sodium carbonate (93mg, 0.878mmol) and heavy water (0.5mL, 0.106 mmol). The reaction was heated to 80 ℃ and stirred under nitrogen overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20mL), and washed with water (20 mL. times.2) and saturated brine (20 mL. times.2) in that order. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to give compound 72-a (41mg, yield: 29.5%).
1H NMR(400MHz,CDCl3):δ10.442(s,1H),8.16(s,1H),7.60-7.58(m,1H),7.45-7.35(m,4H),7.32-7.28(m,4H),4.07(s,3H),2.33(s,3H)ppm
Synthesis of Compound 72
Compound 72-a (56mg, 0.106mmol) was dissolved in a mixed solution of methanol (5.5mL) and dichloromethane (5.5mL), glacial acetic acid (9mg, 0.212mmol) was added, and the reaction solution was stirred at room temperature for 1 hour, after which sodium cyanoborohydride (56mg, 0.106mmol) was added and stirring was continued for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20mL), which was washed with water (20mL) and saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give compound 72(11.6mg, yield: 25.4%).
LC-MS(ESI):m/z＝444[M+H]+.
1H NMR(400MHz,CD3OD delta 7.62(s,1H),7.54-7.52(d, J ═ 7.6Hz,1H),7.43-7.40(m,3H),7.36-7.25(m,4H),7.17-7.15(m,1H),4.01(s,3H),3.85(s,2H),3.69-3.67(m,2H),2.74-2.72(m,2H),2.30(s,3H) ppm example 73
(S, E) -1- (4- (2- (2-fluoromethyl- [1,1' -biphenyl ] -3-yl) vinyl) -2-methoxy-5-trifluoromethylbenzyl) piperidine-2-carboxylic acid (Compound 73)
Figure BDA0003234055820001011
Synthesis of Compound 73-c
To a solution of 2, 6-dibromo-benzyl alcohol (2.40g, 9.06mmol) in dry dichloromethane (60mL) was slowly added dropwise diethylaminosulfur trifluoride (1.90g, 11.8mmol) at-78 ℃. Stirring was continued for 30 minutes at-78 ℃ after the addition was complete. The cooling bath was removed, the temperature was naturally raised to room temperature, and stirring was continued at room temperature for 1 hour. The reaction mixture was quenched by slowly adding saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated, and the aqueous layer was extracted with methylene chloride (30 mL. times.2). The organic phases were combined, washed successively with water (30mL) and saturated brine (30mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to give compound 73-c (1.86g, yield: 78%).
Synthesis of Compound 73-b
To a mixture of compound 6-b (1.40g, 5.0mmol), vinyl boronic acid pinacol ester (1.15g, 7.5mmol), triethylamine (1.51g, 15.0mmol) and toluene (20mL) was added bis (tri-tert-butylphosphine) palladium (255mg, 0.50 mmol). The reaction mixture was stirred at 80 ℃ for 16 hours under nitrogen atmosphere. Cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 6: 1) to obtain compound 73-b (1.08g, yield: 61%).
LC-MS(ESI):m/z＝357[M+H]+.
Synthesis of Compound 73-a
To a mixture of compound 73-b (391mg, 1.1mmol) and compound 73-c (268mg, 1.0mmol) in toluene (15mL) was added phenylboronic acid (134mg, 1.1mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (146mg,0.2mmol), potassium phosphate (848mg, 4.0mmol), cesium fluoride (600mg, 4.0 mmol). The reaction mixture was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 8: 1) to give compound 73-a (150mg, yield: 36%).
LC-MS(ESI):m/z＝415[M+H]+.
Synthesis of Compound 73
To a solution of compound 73-a (41mg, 0.10mmol) in dichloromethane (10mL) were added (S) -piperidine-2-carboxylic acid (39mg, 0.3mmol) and methanol (10 mL). The mixture was stirred at room temperature for 1 hour, then sodium cyanoborohydride (16mg, 0.25mmol) was added, and after the addition was completed, stirring was carried out at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to give compound 73(22mg, yield: 42%).
LC-MS(ESI):m/z＝528[M+H]+.
1H NMR(400MHz,CD3OD):δ 7.92(s,1H),7.70～7.73(m,2H),7.50～7.55(m,2H),7.41～7.48(m,4H),7.38～7.40(m,2H),7.33～7.35(m,1H),5.50(s,1H),5.38(s,1H),4.53(d,J＝12.8Hz,1H),4.39(d,J＝12.8Hz,1H),3.49～3.51(m,1H),2.95～3.01(m,1H),2.30(s,3H),2.22～2.26(m,1H),1.70～1.89(m,5H),1.54～1.58(m,1H)ppm
Example 74
(E) -2- ((4- (2- (2-fluoromethyl- [1,1' -biphenyl ] -3-yl) vinyl) -2-methoxy-5-trifluoromethylbenzyl) amino) -1-ethanol (Compound 74)
Figure BDA0003234055820001021
Synthesis of Compound 74
To a solution of 73-a (41mg, 0.10mmol) in dichloromethane (10mL) were added ethanolamine (31mg, 0.5mmol) and methanol (10 mL). The mixture was stirred at room temperature for 1 hour, then sodium cyanoborohydride (20mg, 0.31mmol) was added, and after the addition was completed, stirring was carried out at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to give compound 74(23mg, yield: 50%).
LC-MS(ESI):m/z＝460[M+H]+.
1H NMR(400MHz,CD3OD):δ7.69(d,J＝7.6Hz,1H),7.64(s,1H),7.62～7.66(m,1H),7.51～7.53(m,1H),7.42～7.46(m,4H),7.38～7.41(m,3H),7.31(d,J＝8.0Hz,1H),5.48(s,1H),5.36(s,1H),4.01(s,3H),3.84(s,2H),3.68(t,J＝4.2Hz,2H),2.72(t,J＝4.2Hz,2H)ppm。
Example 75
(S, E) -1- (2- ((3-iodobenzyloxy) -5-methyl-4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) benzyl) piperidine-2-carboxylic acid (compound 75)
Figure BDA0003234055820001031
Synthesis of Compound 75-b
Compound 24-c (280mg,1.30mmol) and 3-b (500mg,1.56mmol) were dissolved in 1, 4-dioxane (5mL) and water (1mL), and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (48mg,0.065mmol) and potassium carbonate (359mg,2.6 mmol). The reaction solution was purged with nitrogen three times to remove oxygen in the system, followed by heating and stirring at 90 ℃ for 16 hours. The reaction was cooled to room temperature, and water (20mL) was added. The mixture was extracted with methylene chloride (40 mL. times.2), and the resulting organic phase was washed with saturated brine (20 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with ethyl acetate, washed and filtered to give 75-b (189mg, yield: 44%) as a brown solid. LC-MS (ESI) M/z 329.27(M + H)+.
Synthesis of Compound 75-a
Compound 75-b (33mg,0.10mmol), 3-iodobenzyl bromide (36mg,0.12mmol), cesium carbonate (65mg,0.20mmol) were dissolved in 1, 4-dioxane (0)5mL), the reaction mixture was heated and stirred at 50 ℃ for 16 hours. The reaction mixture was cooled to room temperature, and subjected to direct reverse phase chromatography (mobile phase: 0.1% aqueous formic acid solution: acetonitrile 0% -100%) to give 75-a (33mg, yield: 61%) as a pale yellow solid. LC-MS (ESI) M/z 545.09(M + H)+.
Synthesis of Compound 75
Compound 75-a (33mg,0.061mmol) and (S) -piperidine-2-carboxylic acid (16mg, 0.12mmol) were dissolved in methanol (1mL) and tetrahydrofuran (1mL), and sodium cyanoborohydride (15mg,0.24mmol) was added. The reaction solution was heated and stirred at 60 ℃ for 1 hour. The reaction solution was cooled to room temperature, and prepared by high performance liquid chromatography (mobile phase: 1% aqueous formic acid solution: acetonitrile 20% -70%) to obtain 75(12mg, yield: 30%) of a white solid. LC-MS (ESI) M/z 658.36(M + H)+.
1H-NMR(400MHz,MeOD)δ：7.90(s,1H),7.69(d,J＝7.9Hz,1H),7.59(d,J＝7.7Hz,1H),7.54(d,J＝7.5Hz,1H),7.46–7.39(m,2H),7.36–7.26(m,6H),7.25–7.12(m,4H),5.25(s,2H),4.47(d,J＝12.6Hz,1H),4.36(d,J＝12.8Hz,1H),3.71–3.53(m,1H),3.45–3.34(m,1H),3.05–2.90(m,1H),2.39(s,3H),2.29–2.19(m,4H),1.98–1.63(m,4H),1.6–1.47(m,1H)ppm
Example 76
(S, E) -1- (2- ((2-iodobenzyloxy) -4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid (compound 76)
Figure BDA0003234055820001041
Synthesis of Compound 76-a
Compound 4-a (38mg,0.10mmol) and 2-iodobenzyl bromide (36mg,0.12mmol) were dissolved in N, N-dimethylformamide (0.5mL), cesium carbonate (65mg,0.20mmol) was added, and the reaction solution was heated and stirred at 50 ℃ for 1 hour. The reaction solution was cooled to room temperature, and the reaction solution was directly subjected to reverse phase chromatography (mobile phase: 0.1% aqueous formic acid solution: acetonitrile 0% -100%) to give 76-a (40mg, yield: 67%) as a pale yellow solid.
Synthesis of Compound 76
Compound 76-a (40mg,0.067mmol) and (S) -piperidine-2-carboxylic acid (17mg, 0.13mmol) were dissolved in methanol (1mL) and tetrahydrofuran (1mL), and sodium cyanoborohydride (17mg,0.27mmol) was added. The reaction solution was heated and stirred at 60 ℃ for 1 hour. The reaction solution was cooled to room temperature, and directly subjected to high performance liquid chromatography (mobile phase: 0.1% aqueous formic acid solution: acetonitrile 20% -70%) to obtain 76(13mg, yield: 27%) as a white solid. LC-MS (ESI) M/z 712.4(M + H)+.
1H-NMR(400MHz,MeOD)δ：8.00-7.91(m,2H),7.61-7.49(m,4H),7.48-7.39(m,3H),7.39-7.23(m,5H),7.18(d,J＝6.8Hz,1H),7.12(td,J＝7.7,1.6Hz,1H),5.50-5.37(m,2H),4.56(d,J＝12.9Hz,1H),4.41(d,J＝13.0Hz,1H),3.61(d,J＝8.7Hz,1H),3.47-3.36(m,1H),2.98(t,J＝10.6Hz,1H),2.28(s,3H),2.26-2.16(m,1H),1.90-1.48(m,5H)ppm
Example 77
(S, E) -1- (2- ((3-iodobenzyloxy) -4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid (Compound 77)
Figure BDA0003234055820001042
Synthesis of Compound 77-a
Compound 4-a (38mg,0.10mmol) and 3-iodobenzyl bromide (36mg,0.12mmol) were dissolved in N, N-dimethylformamide (0.5mL), cesium carbonate (65mg,0.20mmol) was added, and the reaction solution was heated and stirred at 50 ℃ for 1 hour. The reaction mixture was cooled to room temperature, and subjected to direct reverse phase chromatography (mobile phase: 0.1% aqueous formic acid solution: acetonitrile 0-100%) to give 77-a (50mg, yield: 84%) as a pale yellow solid.
Synthesis of Compound 77
Compound 77-a (40mg,0.067mmol) and (S) -piperidine-2-carboxylic acid (17mg, 0.13mmol) were dissolved in methanol (1mL) and tetrahydrofuran (1mL), and sodium cyanoborohydride (17mg,0.27mmol) was added. The reaction solution was heated and stirred at 60 ℃ for 1 hour. Cooling the reaction liquid to room temperature, and directly subjecting the reaction liquid to preparative high performance liquid chromatography (mobile phase: 0.1% formic acid water solution: acetonitrile 20% -70%) White solid 377(18mg, yield: 38%). LC-MS (ESI) M/z 712.4(M + H)+.
1H-NMR(400MHz,MeOD)δ：7.94(s,2H),7.73(d,J＝7.9Hz,1H),7.60-7.33(m,7H),7.33-7.24(m,4H),7.23-7.15(m,2H),5.38(s,2H),4.55(d,J＝13.0Hz,1H),4.42(d,J＝13.0Hz,1H),3.64(d,J＝8.0Hz,1H),3.45-3.34(m,1H),3.01(t,J＝10.4Hz,1H),2.29(s,3H),2.28-2.22(m,1H),1.95-1.49(m,5H)ppm
Example 78
(S, E) -1- (2- ((4-iodobenzyloxy) -4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid (compound 78)
Figure BDA0003234055820001051
Synthesis of Compound 78-a
Compound 4-a (38mg,0.10mmol) and 4-iodobenzyl bromide (36mg,0.12mmol) were dissolved in N, N-dimethylformamide (0.5mL), cesium carbonate (65mg,0.20mmol) was added, and the reaction solution was heated and stirred at 50 ℃ for 1 hour. The reaction mixture was cooled to room temperature, and subjected to direct reverse phase chromatography (mobile phase: 0.1% aqueous formic acid solution: acetonitrile 0-100%) to give 78-a (50mg, yield: 84%) as a pale yellow solid.
Synthesis of Compound 78
To a mixture of compound 78-a (40mg,0.067mmol), (S) -piperidine-2-carboxylic acid (17mg, 0.13mmol), methanol (1mL) and tetrahydrofuran (1mL) was added sodium cyanoborohydride (17mg,0.27 mmol). The reaction mixture was stirred at 60 ℃ for 1 hour. The reaction solution was cooled to room temperature, and the resulting mixture was subjected to preparative high performance liquid chromatography (mobile phase: 0.1% aqueous formic acid solution: acetonitrile 20% -70%) to give 78(20mg, yield: 42%) as a white solid. LC-MS (ESI) M/z 712.4(M + H)+.
1H-NMR(400MHz,MeOD)δ：7.93(s,1H),7.82-7.75(m,2H),7.55(s,1H),7.53(d,J＝7.7Hz,1H),7.49-7.39(m,3H),7.39-7.23(m,7H),7.18(d,J＝7.5Hz,1H),5.38(s,2H),4.55(d,J＝13.0Hz,1H),4.42(d,J＝13.0Hz,1H),3.66(d,J＝8.3Hz,1H),3.45-3.34(m,1H),3.07-2.92(m,1H),2.26(s,3H),2.26-2.20(m,1H),1.98-1.47(m,5H)ppm
Example 79
(S, E) -1- (2- ((4-iodo-pyridin-2-yl) methoxy) -5-methyl-4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) benzyl) piperidine-2-carboxylic acid (Compound 79)
Figure BDA0003234055820001052
Synthesis of Compound 79-c
4-Iodopyridinic acid (500mg,2mmol) was dissolved in anhydrous tetrahydrofuran (10mL) and borane tetrahydrofuran solution (4mL,4mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction solution was cooled to 0 ℃, methanol (10mL) was added dropwise to the reaction solution, the reaction solution was then heated at 70 ℃ and stirred for 1 hour, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 1:1) to give 79-c (300mg, yield 63.6%). LC-MS (ESI) 236(M + H) M/z+.
Synthesis of Compound 79-b
Compound 79-c (300mg,1.2mmol) was dissolved in dichloromethane (10mL), to which was slowly added thionyl chloride (400mg,3.6 mmol). The reaction solution was stirred at room temperature for 2 hours. After concentration under reduced pressure, 79-b (355mg, yield: 96.2%) was obtained and used in the next reaction without purification. LC-MS (ESI) 254(M + H) with M/z+.
Synthesis of Compound 79-a
Compound 79-b (57mg, 0.2mmol) and compound 75-b (50mg, 0.13mmol) were dissolved in N, N-dimethylformamide (5mL), potassium carbonate (54mg,0.39mmol) and potassium iodide (214mg,1.3mmol) were added, and the reaction solution was heated at 50 ℃ and stirred for 30 minutes. The reaction mixture was cooled to room temperature and prepared directly by HPLC to give 79-a (30mg, yield 38.4%). LC-MS (ESI) M/z 546(M + H)+.
Synthesis of Compound 79
Compound 79-a (20mg, 0.037mmol) and s-piperidine-2-carboxylic acid (7mg, 0.054mmol) were dissolved in methanol (3mL), sodium cyanoborohydride (5mg,0.075mmol) was added, and the reaction mixture was placed under nitrogenThe oxygen in the system was removed three times and then heated at 60 ℃ for 30 minutes. The reaction was cooled to room temperature. Concentrated under reduced pressure, and the residue was purified by HPLC to give 79(6mg, yield 29.7%). LC-MS (ESI) M/z 659(M + H)+.
1H-NMR(400MHz,MeOD)δ:8.33(d,J＝5.2Hz,1H),7.99(s,1H),7.59-7.27(m,2H),7.43-7.31(m,5H),7.28-7.21(m,5H),7.12(d,J＝7.6Hz,1H),5.28(s,3H),4.45-4.42(m,1H),4.27-4.24(m,1H),3.42-3.41(m,1H),2.90-2.78(m,1H),2.28-2.25(m,1H),2.39(s,3H),2.24(s,3H),2.20-2.16(m,1H),1.92-1.68(m,4H),1.52-1.50(m,1H),1.32-1.28(m,1H)ppm
Example 80
(S, E) -1- (2- ((4-iodopyridin-2-yl) methoxy) -4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid (Compound 80)
Figure BDA0003234055820001061
Synthesis of Compound 80-a
Compound 79-b (57mg, 0.2mmol) and compound 4-a (50mg, 0.13mmol) were dissolved in N, N-dimethylformamide (5mL), potassium carbonate (54mg,0.39mmol) and potassium iodide (214mg,1.3mmol) were added, and the reaction solution was heated at 50 ℃ and stirred for 30 minutes. The reaction mixture was cooled to room temperature and directly subjected to high performance liquid chromatography to give 80-a (30mg, yield: 38.4%). LC-MS (ESI) 600(M + H) M/z+.
Synthesis of Compound 80
Compound 80-a (20mg, 0.037mmol) and s-piperidine-2-carboxylic acid (7mg, 0.054mmol) were dissolved in methanol (3mL), sodium cyanoborohydride (5mg,0.075mmol) was added, and the reaction solution was replaced with nitrogen three times to remove oxygen from the system, followed by heating at 60 ℃ for 30 minutes. The reaction was cooled to room temperature. Concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 80(8mg, yield: 30.7%). LC-MS (ESI) 713(M + H)+.
1H-NMR(400MHz，MeOD)δ:8.27(d J＝5.6Hz，1H)，8.09(s，1H)，7.91(s，1H)，7.81(dJ＝6.8Hz,1H),7.55-7.41(m,5H),7.37-7.25(m,5H),7.28(d,J＝7.2Hz,1H),5.48(s,2H),4.72-4.64(m,1H),4.56(s,2H),4.40-4.37(m,1H),3.61-3.57(m,1H),3.04-3.02(m,1H),2.28(s,3H),1.88-1.76(m,4H),1.59-1.57(m,1H)ppm
Example 81
(S, E) -1- (2- ((2-iodopyridin-4-yl) methoxy) -4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid (Compound 81)
Figure BDA0003234055820001071
Synthesis of Compound 81-c
2-Iodoisonicotinic acid (500mg,2mmol) was dissolved in anhydrous tetrahydrofuran (10mL), and borane tetrahydrofuran solution (4mL,4mmol) was added dropwise thereto. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was cooled to 0 ℃, methanol (10mL) was added dropwise to the reaction solution, the reaction solution was then heated at 70 ℃ and stirred for 1 hour, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 1:1) to give 81-c (280mg, yield: 53.9%). LC-MS (ESI) 236(M + H) M/z+.
Synthesis of Compound 81-b
Compound 81-c (280mg,1.1mmol) was dissolved in dichloromethane (10mL), to which was slowly added thionyl chloride (400mg,3.6 mmol). The reaction solution was stirred at room temperature for 2 hours. After concentration under reduced pressure, 81-b (342mg, yield: 97.0%) was obtained and used in the next reaction without purification. LC-MS (ESI) 254(M + H) with M/z+.
Synthesis of Compound 81-a
Compound 81-b (57mg, 0.2mmol) and compound 4-a (50mg, 0.13mmol) were dissolved in N, N-dimethylformamide (5mL), potassium carbonate (54mg,0.39mmol) and potassium iodide (214mg,1.3mmol) were added, and the reaction solution was heated at 50 ℃ and stirred for 30 minutes. The reaction mixture was cooled to room temperature and directly subjected to high performance liquid chromatography to give 81-a (30mg, yield: 38.4%). LC-MS (ESI) 600(M + H) M/z+。
Synthesis of Compound 81
Compound 81-a (20mg, 0.037mmol) and s-piperidine-2-carboxylic acid (7mg, 0.054mmol) were dissolved in methanol (3mL), sodium cyanoborohydride (5mg,0.075mmol) was added, and the reaction solution was replaced with nitrogen three times to remove oxygen from the system, followed by heating at 60 ℃ for 30 minutes. The reaction was cooled to room temperature. Concentration under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 81(9mg, yield: 34.6%). LC-MS (ESI) 713(M + H)+.
1H-NMR(400MHz,MeOD)δ:8.37(d,J＝4.8Hz,1H),8.03(s,1H),7.98(s,1H),7.61(d,J＝4.8Hz,1H),7.55-7.41(m,5H),7.37-7.25(m,5H),7.18(d,J＝7.2Hz,1H),5.43(s,2H),4.62-4.56(m,3H),4.45-4.42(m,1H),3.61-3.54(m,1H),3.01-2.97(m,1H),2.28(s,3H),1.89-1.71(m,4H),1.65-1.55(m,1H)ppm
Example 82
(S, E) -1- (2- ((5-iodopyridin-3-yl) methoxy) -4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid (Compound 82)
Figure BDA0003234055820001081
Synthesis of Compound 82-c
5-iodonicotinic acid (250mg, 1mmol) was dissolved in anhydrous tetrahydrofuran (10mL), borane tetrahydrofuran solution (3mL, 3mmol) was added dropwise, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0 ℃ and methanol (10mL) was added dropwise to the reaction mixture, which was then heated at 70 ℃ and stirred for 1 hour, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with ethyl acetate (10mL), and the organic phase was washed with water (10 mL. times.3) and saturated brine (10 mL. times.1) in succession. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 82-c (141mg, yield: 59.7%) which was used in the next reaction without purification. LC-MS (ESI) 236.0[ M + H ]]+.
Synthesis of Compound 82-b
Compound 82-c (141mg, 0.6mmol) was dissolved in dichloromethane (5mL), to which was slowly added thionyl chloride (214mg, 1.8 mmol). The reaction solution was stirred at room temperature for 2 hours. After concentration under reduced pressure, 82-b (146mg, 96.2%) was obtained and used in the next reaction without purification.
Synthesis of Compound 82-a
Compound 82-b (43mg, 0.170mmol) and compound 4-a (50mg, 0.131mmol) were dissolved in N, N-dimethylformamide (2mL), sodium carbonate (41.7mg, 0.393mmol) and potassium iodide (65.2mg, 0.393mmol) were added, and the reaction mixture was stirred at 80 ℃ for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10mL), and the organic phase was washed successively with water (10 mL. times.3) and saturated brine (10 mL. times.1). The obtained organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether ═ 100%) to obtain 82-a (48.8mg, yield: 62.2%). LC-MS (ESI) 600.0[ M + H ]]+.
Synthesis of Compound 82
Compound 82-a (48.8mg, 0.082mmol) and s-piperidine-2-carboxylic acid (21.2mg, 0.164mmol) were dissolved in a mixed solution of methanol and tetrahydrofuran (10mL, 1:1in v: v), glacial acetic acid (9.8mg, 0.164mmol) and sodium cyanoborohydride (25.8mg, 0.41mmol) were added, and the reaction solution was replaced three times with nitrogen to remove oxygen in the system, followed by heating at 60 ℃ for 30 minutes. The reaction was cooled to room temperature. Concentration under reduced pressure, and high performance liquid chromatography of the residue to give 82(16.4mg, yield: 28.2%). LC-MS (ESI) M/z 713.0[ M + H ]]+；
1H-NMR(400MHz,CD3OD)δ:8.81(s,1H),8.73(s,1H),8.44(s,1H),7.97(s,1H),7.62-7.53(m,3H),7.45-7.41(m 2H)，7.37-7.26(m 5H)，7.20(m 1H)，5.43(s，2H)，4.56-4.53(d J＝12.8Hz，1H)，4.42-4.39(dJ＝12.8Hz,1H),3.60(m,1H),3.01-2.95(m,1H),2.31(s,3H),2.27-2.19(m,1H),1.87-1.28(m,6H)ppm
Example 83
(S, E) -1- (2- (4-Fluorobutoxy) -5-methyl-4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) benzyl) piperidine 2-carboxylic acid (Compound 83)
Figure BDA0003234055820001091
Synthesis of Compound 83-a
Compound 75-b (200mg, 0.609mmol) and 1-bromo-4-fluorobutane (141.7mg, 0.914mmol) were dissolved in N, N' -dimethylformamide (5mL), and potassium carbonate (252.5mg, 1.827mmol) was added. The reaction solution was stirred at 60 ℃ for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (3mL), and washed with water (3 mL. times.3) and saturated brine (3mL) in that order. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether: ethyl acetate: 5:1) to give 83-a (180mg, yield: 73.5%). LC-MS (ESI) M/z 403.0[ M + H ]]+.
Synthesis of Compound 83
Compound 83-a (180mg, 0.447mmol) and s-piperidine-2-carboxylic acid (115.5mg, 0.894mmol) were dissolved in a mixed solution of methanol (5mL) and tetrahydrofuran (5mL), glacial acetic acid (53.7mg, 0.894mmol) was added, the reaction solution was heated at 60 ℃ for stirring for 3 hours, and then sodium cyanoborohydride (140.5mg, 2.235mmol) was added and stirred for 0.5 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 83(61.9mg, yield: 26.9%). LC-MS (ESI) M/z 516.0[ M + H ]]+；
1H-NMR(400MHz,CD3OD)δ:7.61-7.59(d,J＝7.6Hz,1H),7.46-7.40(m,3H),7.36-7.21(m,7H),7.15-7.13(d,J＝7.2Hz,1H),4.61-4.58(t,J＝5.6Hz,1H),4.49-4.46(t,J＝5.6Hz,2H),4.34-4.31(d,J＝12.4Hz,1H),4.22-4.19(t,J＝5.6Hz,2H),3.56-3.54(m,1H),3.37-3.35(m,1H),3.01-2.96(m,1H),2.40(s,3H),2.28(s,3H),2.25-2.19(m,1H),2.04-1.55(m,9H)ppm.
Example 84
(S, E) -1- (2- (3-Fluoropropoxy) -5-methyl-4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) benzyl) piperidine 2-carboxylic acid (Compound 84)
Figure BDA0003234055820001092
Synthesis of Compound 84-a
Compound 75-b (200mg, 0)609mmol) and 1-bromo-3-fluorobutane (128.9mg, 0.914mmol) were dissolved in N, N' -dimethylformamide (5mL), and potassium carbonate (252.5mg, 1.827mmol) was added. The reaction solution was heated and stirred at 60 ℃ for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (3mL), and washed with water (3 mL. times.3) and saturated brine (3mL) in that order. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether: ethyl acetate 5:1) to give 84-a (200mg, yield: 84.7%). LC-MS (ESI) M/z 389.0[ M + H ]]+；
Synthesis of Compound 84
Compound 84-a (200mg, 0.515mmol) and s-piperidine-2-carboxylic acid (133mg, 1.03mmol) were dissolved in a mixed solution of methanol (5mL) and tetrahydrofuran (5mL), glacial acetic acid (61.9mg, 1.03mmol) was added, and the mixture was heated and stirred at 60 ℃ for 3 hours, followed by addition of sodium cyanoborohydride (161.8mg, 2.575mmol) and stirring for 0.5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to give 84(60.5mg, yield: 23.4%). LC-MS (ESI) M/z 502.0[ M + H ]]+；
1H-NMR(400MHz,CD3OD)δ:7.61-7.60(d,J＝7.6Hz,1H),7.47-7.40(m,3H),7.36-7.21(m,7H),7.15-7.13(d,J＝7.2Hz,1H),4.77-4.74(t,J＝5.6Hz,1H),4.65-4.62(t,J＝5.6Hz,2H),4.52-4.49(d,J＝12.8Hz,1H),4.32-4.27(m,3H),3.54-3.52(m,1H),3.00-2.95(m,1H),2.41(s,3H),2.33-2.30(m,1H),2.28(s,3H),2.26-2.22(m,2H),1.94-1.55(m,5H)ppm.
Example 85
(S, E) -1- (2- (4-Fluorobutoxy) -4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid (Compound 85)
Figure BDA0003234055820001101
Synthesis of Compound 85-a
Tert-butyl (S, E) -1- (2-hydroxy-4- (2- (2-methyl- [1,1' -biphenyl)]-3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid salt (50mg, 0.091mmol) and 1-bromo-4-fluorobutane (2)1mg, 0.136mmol) was dissolved in N, N-dimethylformamide (3mL), potassium carbonate (37.3mg, 0.273mmol) was added, and the reaction mixture was stirred at 60 ℃ for 16 hours. The reaction was cooled to room temperature, and the reaction solution was diluted with ethyl acetate (3mL) and washed with water (3 mL. times.3) and saturated brine (3mL) in that order. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether: ethyl acetate: 5:1) to give 85-a (37mg, yield: 65.1%). LC-MS (ESI) M/z 626.0[ M + H ]]+.
Synthesis of Compound 85
Compound 85-a (37mg, 0.059mmol) was dissolved in hydrochloric acid/dioxane solution (4.0M, 10mL), the reaction was stirred at room temperature for 16 hours, concentrated under reduced pressure, and the residue was purified by prep-HPLC to give 85(17.1mg, yield: 51.5%). LC-MS (ESI) M/z 570.0[ M + H ]]+；
1H-NMR(400MHz,CD3OD)δ:7.94(s,1H),7.64-7.60(d,J＝16.0Hz,1H),7.55-7.53(m,2H),7.44-7.41(m,2H),7.37-7.26(m,5H),7.19-7.17(d,J＝7.6Hz,1H),4.62-4.59(t,J＝5.6Hz,1H),4.57-4.54(d,J＝13.2Hz,1H),4.50-4.47(t,J＝5.6Hz,1H),4.40-4.32(m,3H),3.58-3.56(m,1H),3.05-2.99(m,1H),2.30(s,3H),2.24-2.23(m,1H),2.07-1.57(m,9H)ppm.
Example 86
(S, E) -1- (2- (3-Fluoropropoxy) -4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid (Compound 86)
Figure BDA0003234055820001111
Synthesis of Compound 86-a
Tert-butyl (S, E) -1- (2-hydroxy-4- (2- (2-methyl- [1,1' -biphenyl)]-3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid salt (50mg, 0.091mmol) and 1-bromo-3-fluoropropane (19.2mg, 0.136mmol) were dissolved in N, N-dimethylformamide (3mL), potassium carbonate (37.3mg, 0.273mmol) was added, and the reaction was stirred at 60 ℃ for 16 hours. The reaction mixture was diluted with ethyl acetate (3mL), and then saturated with water (3 mL. times.3)Washed with brine (3 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether: ethyl acetate: 5:1) to give 86-a (47mg, yield: 84.7%). LC-MS (ESI) M/z 612.0[ M + H ]]+.
Synthesis of Compound 86
Compound 86-a (47mg, 0.077mmol) was dissolved in a hydrochloric acid/dioxane solution (4.0M, 10mL), the reaction mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give 86(19.2mg, yield: 45.2%). LC-MS (ESI) M/z 556.0[ M + H ]]+；
1H-NMR(400MHz,CD3OD)δ:7.92(s,1H),7.65-7.61(d,J＝16.4Hz,1H),7.56-7.53(m,2H),7.44-7.41(m,2H),7.37-7.26(m,5H),7.19-7.17(d,J＝7.6Hz,1H),4.78-4.75(t,J＝5.6Hz,1H),4.66-4.64(t,J＝5.2Hz,1H),4.60-4.57(d,J＝12.8Hz,1H),4.44-4.35(m,3H),3.56-3.52(m,1H),3.04-2.99(m,1H),2.36-2.34(m,1H),2.30(s,3H),2.28-2.24(m,2H),1.89-1.56(m,5H)ppm.
Example 87
(S, E) -1- (2- (2-Fluoroethoxy) -4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid (Compound 87)
Figure BDA0003234055820001112
Synthesis of Compound 87-a
Tert-butyl (S, E) -1- (2-hydroxy-4- (2- (2-methyl- [1,1' -biphenyl)]-3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid salt (50mg, 0.091mmol) and 1-bromo-2-fluoroethane (17.3mg, 0.136mmol) were dissolved in N, N-dimethylformamide (3mL), potassium carbonate (37.3mg, 0.273mmol) was added, and the reaction was stirred at 60 ℃ for 16 hours. The reaction mixture was diluted with ethyl acetate (3mL), and washed with water (3 mL. times.3) and saturated brine (3mL) in that order. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether: ethyl acetate: 5:1) to give 87-a (27mg, yield: 50.0%). LC-MS (ESI) M/z 598.0[ M + H ]]+.
Synthesis of Compound 87
Compound 87-a (47mg, 0.077mmol) was dissolved in a hydrochloric acid/dioxane solution (4.0M, 10mL), the reaction mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give 87(14.7mg, yield: 60.0%). LC-MS (ESI) M/z 542.0[ M + H ]]+；
1H-NMR(400MHz,DMSO-d6)δ:7.79(s,1H),7.66-7.62(d,J＝16.0Hz,1H),7.57-7.52(m,2H),7.48-7.45(m,2H),7.40-7.31(m,4H),7.23-7.18(m,2H),4.88-4.86(s,1H),4.76-4.74(s,1H),4.54-4.53(s,1H),4.47-4.46(s,1H),3.82-3.79(d,J＝14.8Hz,1H),3.71-3.67(d,J＝14.8Hz,1H),3.22-3.20(m,1H),2.93-2.91(s,1H),2.29(s,4H),1.81-1.77(m,2H),1.50-1.41(m,4H)ppm.
Example 88
(S, E) -1- (2- ((5-Fluoropyridin-3-yl) methoxy) -4- (2- (2-methyl- [1,1' -Biphenyl ] -3-yl) ethenyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid (Compound 88)
Figure BDA0003234055820001121
Synthesis of Compound 88-a
Tert-butyl (S, E) -1- (2-hydroxy-4- (2- (2-methyl- [1,1' -biphenyl)]-3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid salt (100mg, 0.181mmol) and hydrogen chloride 3- (bromomethyl) -5-fluoropyridine (34.44mg, 0.181mmol) were dissolved in N, N-dimethylformamide (3mL), potassium carbonate (75.16mg, 0.544mmol) was added, and the reaction solution was stirred at 60 ℃ for 12 hours. The reaction mixture was diluted with ethyl acetate (3mL), and washed with water (3 mL. times.3) and saturated brine (3mL) in that order. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by a silica gel column (petroleum ether: ethyl acetate: 5:1) to give 88-a (119mg, yield: 99.35%). LC-MS (ESI) M/z 661.0[ M + H ]]+.
Synthesis of Compound 88
Compound 88-a (119mg, 0.180mmol) was dissolved in hydrochloric acid/dioxane solution (4.0M, 10mL)The reaction mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give 88(43.89mg, yield: 40.31%). LC-MS (ESI) M/z 605.0[ M + H ]]+.
Example 89
(S, E) -1- (2- ((4-Fluorobenzyl) oxy) -4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -5- (trifluoromethyl)) benzyl) piperidine-2-carboxylic acid (Compound 89)
Figure BDA0003234055820001122
Synthesis of Compound 89-a
Tert-butyl (S, E) -1- (2-hydroxy-4- (2- (2-methyl- [1,1' -biphenyl)]-3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid salt (100mg, 0.181mmol) and 1- (bromomethyl) -4-fluorobenzene (34.21mg, 0.181mmol) were dissolved in N, N-dimethylformamide (3mL), potassium carbonate (75.16mg, 0.544mmol) was added, and the reaction was stirred at 60 ℃ for 12 hours. The reaction mixture was diluted with ethyl acetate (3mL), and washed with water (3 mL. times.3) and saturated brine (3mL) in that order. The obtained organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by a silica gel column (petroleum ether: ethyl acetate: 10:1) to obtain 89-a (118mg, yield: 98.81%). LC-MS (ESI) M/z 660.0[ M + H ]]+.
Synthesis of Compound 89
Compound 89-a (118mg, 0.179mmol) was dissolved in a hydrochloric acid/dioxane solution (4.0M, 10mL), the reaction mixture was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give 89(45.48mg, yield: 42.12%). LC-MS (ESI) M/z 604.0[ M + H ]]+.
Example 90
(S, E) -1- (4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -2- (pyridin-3-ylmethoxy) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid (Compound 90)
Figure BDA0003234055820001131
Synthesis of Compound 90-a
Tert-butyl (S, E) -1- (2-hydroxy-4- (2- (2-methyl- [1,1' -biphenyl)]-3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid salt (55.1mg, 0.1mmol) and 3- (chloromethyl) pyridine (25.51mg, 0.2mmol) were dissolved in N, N-dimethylformamide (3mL), potassium carbonate (69.0mg, 0.5mmol) was added, and the reaction was stirred at 50 ℃ for 5 hours. The reaction mixture was diluted with ethyl acetate (3mL), and washed with water (3 mL. times.3) and saturated brine (3mL) in that order. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column (petroleum ether: ethyl acetate 10:1) to give 90-a (50mg, yield: 77.01%). LC-MS (ESI) M/z 642.2[ M + H ]]+.
Synthesis of Compound 90
The compound tert-butyl (S, E) -1- (4- (2- (2-methyl- [1,1' -biphenyl) is reacted with]-3-yl) vinyl) -2- (pyridin-3-ylmethoxy) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylate (50mg,0.078mm0l) was dissolved in dichloromethane (10mL), trifluoroacetic acid (5.0mL) was added, the reaction was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was purified by high performance liquid phase to give 90(45.64mg, yield: 48.20%). LC-MS (ESI) M/z 587.3[ M + H ]]+.
1H-NMR(CD3OD-d4)δ：8.77(s,1H),8.59(s,1H),8.11(d,J＝8.0Hz,1H),8.00(s,1H),7.66(s,1H),7.61-7.55(m,3H),7.61-7.55(m,3H),7.47-7.44(m,2H),7.40-7.29(m,5H),7.21(d,J＝7.2Hz,1H),5.52(s,2H),4.58(d,J＝12.8Hz,1H),4.42(d,J＝12.8Hz,1H),3.58-3.55(m,1H),3.43-3.38(m,3H),3.01-2.95(m,1H),2.32(s,3H),2.30-2.24(m,1H),1.81-1.54(m,5H)ppm.
Example 91
(S, E) -1- (2- ((5-cyanopyridin-3-yl) methoxy) -4- (2- (2-methyl- [1,1' -biphenyl ] -3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid (Compound 91)
Figure BDA0003234055820001132
Synthesis of Compound 91-a
Tert-butyl (S, E) -1- (2-hydroxy-4- (2- (2-methyl- [1,1' -biphenyl)]-3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid salt (55.1mg, 0.1mmol) and hydrogen chloride 5- (chloromethyl) nicotinonitrile (37.81mg, 0.2mmol) were dissolved in N, N-dimethylformamide (3mL), potassium carbonate (69mg, 0.5mmol) was added, and the reaction solution was stirred at 50 ℃ for 12 hours. The reaction mixture was diluted with ethyl acetate (3mL), and washed with water (3 mL. times.3) and saturated brine (3mL) in that order. The obtained organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by a silica gel column (petroleum ether: ethyl acetate 10:1) to obtain 91-a (110mg, yield: 82.36%). LC-MS (ESI) M/z 667.2[ M + H ]]+.
Synthesis of Compound 91
The compound tert-butyl (S, E) -1- (2- ((5-cyanopyridin-3-yl) methoxy) -4- (2- (2-methyl- [1,1' -biphenyl)]-3-yl) vinyl) -5- (trifluoromethyl) benzyl) piperidine-2-carboxylic acid ester (110mg,0.165mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (5.0mL) was added, the reaction was stirred at room temperature for 12 hours, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give 91(58.7mg, yield: 58.26%). LC-MS (ESI) where M/z is 612.4[ M + H ]]+.
1H-NMR(CD3OD-d4)δ:9.04(s,1H),8.95(s,1H),8.48(s,1H),8.02(s,1H),7.67(s,1H),7.65-7.56(m,2H),7.47-7.44(m,2H),7.40-7.29(m,5H),7.21(d,J＝8.0Hz,1H),5.55(s,2H),4.60(d,J＝12.8Hz,1H),4.44(d,J＝12.8Hz,1H),3.58-3.55(m,1H),3.35-3.30(m,1H),3.02-2.96(m,1H),2.32(s,3H),2.28-2.24(m,1H),1.89-1.54(m,5H)ppm.
Effect example 1 homogeneous phase time-resolved fluorescence method
Homogeneous Time-Resolved Fluorescence (HTRF) binding assays were used to examine the binding capacity of compounds of the invention to PD-1/PD-L1.
The commercially available kit (CisBio, #64CUS000C-1) contains reagents required for the experiments, such as PD-1, PD-L1, Anti-tag1-Eu, Anti-tag2-XL665, Dilute Buffer, and protection Buffer.
Experimental procedure
1. Compounds were formulated with 100% DMSO at 10 concentrations with a 3-fold concentration gradient.
2. The DMSO solution of the compound was added to a dilution Buffer (Dilute Buffer), mixed uniformly, and transferred to a 96-well plate.
3. PD-L1 was diluted with a dilution Buffer (Dilute Buffer) and then added to the above 96-well plate.
4. PD-1 was diluted with a dilution Buffer solution (Dilute Buffer), then added to the above 96-well plate, and incubated at room temperature for 30 minutes.
5. One part of Anti-tag1-Eu and one part of Anti-tag2-XL665 are added to a Detection Buffer solution (Detection Buffer), mixed uniformly and transferred to the above 96-well plate.
6. The mixture in the 96-well plate was incubated at room temperature for 1 to 24 hours.
7. HTRF values were read using Envision.
Results of the experiment
The biological activity of the compounds of the present invention was determined by the above assay and the results are shown in table 1 below:
TABLE 1 IC binding of partial compounds of the invention to PD-1/PD-L150Value of
Figure BDA0003234055820001141
Figure BDA0003234055820001151
Figure BDA0003234055820001161
Effect example 2 mouse pharmacokinetic study
Reagent: acetonitrile, formic acid, methanol (HPLC grade) were purchased from Sigma-Aldrich (usa) and pure water was purchased from the group of wa haha, llc (hangzhou, china). Other chemical reagents are analytically pure.
The test instrument: a liquid chromatograph (UPLC-MS/MS, consisting of AB SCIEX TRIPLE QUAD 6500 TRIPLE quadrupole mass spectrometer, Shimadzu high performance liquid system, Analyst 1.6.2 data acquisition and processing system).
Other instruments: mettler electronic balances Mettler-ToledoXP26 and XS60025 (usa); thermo Fisher-70 ℃ ultra low temperature refrigerator (usa); thermo hereus Multifuge X3R cryocentrifuge (germany); IKA VIBRAX VXR basic oscillator (germany); IKA disperser (germany); new Ganoderma SCIENTZ-48L freezing type high flux tissue grinder (Ningbo, China), etc.
Test animals: 6 male CD1 mice, 29-30g before administration, were purchased from Shanghai Jihui laboratory animal Breeding Co., Ltd, and had an animal certificate of SCXK (SH) 2017-001220170012001403. Animals should be kept for at least 3 days to acclimate to the environment prior to the test. Throughout the experiment, animals had free access to food and water.
The experimental steps are as follows:
1) preparing a mother solution: weighing a certain amount of the tested medicine, placing the medicine in a clean sample bottle, adding dimethyl sulfoxide, fully whirling for 1 minute, and carrying out ultrasonic treatment for 5 minutes to obtain a solution of 4 mg/mL.
Preparing a medicament for intravenous administration: sucking a certain amount of the solution, placing the solution in a clean sample bottle, adding polyethylene glycol-15 hydroxystearate, fully vortexing for 1 minute, adding physiological saline, and continuously vortexing for 1 minute to obtain a solution A of 4 mg/mL.
Preparation of orally administered drugs: weighing a certain amount of tested medicine, placing the medicine in a clean sample bottle, adding a prepared solvent of 10% (w/v) polyoxyethylene 40 hydrogenated castor oil + 20% (w/v) sulfobutyl ether beta-cyclodextrin and 70% water, fully swirling for 1 minute, magnetically stirring for 20-25 minutes, and performing ultrasonic treatment for 10 minutes to obtain a solution B of 1 mg/mL.
2) Intravenous administration: 3 mice were injected with 2mg/kg (5mL/kg) of solution A via the tail vein.
Oral administration: 3 mice were given 10mg/kg (10mL/kg) of solution B by gavage.
3) Plasma sample collection and storage: blood samples were collected from the orbital venous plexus of mice according to predetermined time points (5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr and 24 hr). mu.L of blood was placed in an EDTA-K2 anticoagulation tube (on wet ice), and 20. mu.L of blood was immediately diluted with 60. mu.L of water and vortexed thoroughly until well mixed. The plasma was stored in a refrigerator at-70 ℃ for a long period until the samples were analyzed.
4) Analysis of plasma samples: 25 μ L of plasma sample, 200 μ L of acetonitrile (containing 100ng/mL internal standard), vortex for 10 minutes, and centrifuge at 5800rpm for 10 minutes. Take 70. mu.L of supernatant to 96 wells for spotting. 1 μ L of plasma samples were subjected to LC-MS/MS detection.
5) And calculating pharmacokinetic parameters according to the detection result.
Results of the experiment
Some of the compounds of the present invention and their control compounds were tested above to obtain certain pharmacokinetic parameters, and the results are shown in table 2 below:
table 2: kinetic parameters of partial Compounds of the invention and control Compounds thereof
Figure BDA0003234055820001171
As can be seen from Table 2: compared with the control compound, the compound of the invention has very obvious higher peak concentration of the drug, larger area under the curve of the drug-hour and better oral bioavailability in the in-vivo pharmacokinetic study of mice.

Claims (21)

1. An aromatic vinyl compound shown as formula I-0, its tautomer, its stereoisomer, its racemate or its isotope derivative, or their pharmaceutically acceptable salts;
Figure FDA0003234055810000011
wherein:
R1is cyano, C1-C4Alkyl, C substituted by one or more deuterium1-C4Alkyl, halogen, C substituted by one or more halogens1-C4An alkyl group;
R3、R6、R12、R13and R14Independently is H or deuterium;
R2is hydroxy, halogen, C1-C4Alkyl, by one or more RA-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RA-2Substituted C1-C6An alkoxy group;
RA-1and RA-2Independently is deuterium, hydroxy, halogen, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C4Alkoxy radical,
Figure FDA0003234055810000012
RA-1-1Is C1-C4Alkyl or C substituted by one or more deuterium1-C4An alkyl group; rA-1-2And RA-1-3Independently of one another H, deuterium, C1-C4Alkyl or by one or more RA-1-1-1Substituted C1-C4Alkyl radical, said RA-1-1-1Is deuterium, hydroxy or COORA-1-1-2；
R4And R5Independently of one another, hydroxy, halogen, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group;
RB-1and RB-2Independently is deuterium, hydroxy, halogen, cyano, C6-C10Aryl radicals, substituted by one or more RB-1-3Substituted C6-C10Aryl, 3-12 membered heteroaryl, substituted with one or more RB-1-4Substituted 3-12 membered heteroaryl, C1-C4Alkoxy, C substituted by one or more deuterium1-C4Alkoxy radical,
Figure FDA0003234055810000013
In the heteroaryl, the heteroatom is selected from one or more of N, O and S, and the number of the heteroatom is 1-4;
RB-1-3and RB-1-4Independently of one another is cyano, halogen, C1-C4Alkyl or C1-C4An alkoxy group;
RB-1-1and RB-1-2Independently of one another H, deuterium, C1-C4Alkyl or by one or more RB-1-1-1Substituted C1-C4Alkyl radical, said RB -1-1-1Is deuterium, hydroxy or COORB-1-1-5；
Or, RB-1-1、RB-1-2And the nitrogen atom to which they are attached together form a 5-to 7-membered carbocyclic heterocyclic ring or are substituted by one or more RB -1-1-2Substituted carbon heterocyclic ring, wherein in the carbon heterocyclic ring, heteroatoms are selected from one or more of N, O and S, the number of heteroatoms is 1-4, and R isB-1-1-2Is deuterium, C1-C4Alkyl, C substituted by one or more deuterium1-C4Alkyl, COORB-1-1-6Or C1-C4An amide group;
RA-1-1-2、RB-1-1-5and RB-1-1-6Independently of one another H, deuterium, C1-C4Alkyl or C substituted by one or more deuterium1-C4An alkyl group;
R7、R8、R9、R10and R11Independently is H or deuterium;
R15and R16Independently H, deuterium or halogen.
2. The aromatic vinyl compound of formula I-0, the tautomer, the stereoisomer, the racemate, the isotopic derivative thereof, or the pharmaceutically acceptable salt thereof according to claim 1, wherein R is RB-1And RB-2Independently is deuterium, hydroxy, halogen, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C4Alkoxy radical,
Figure FDA0003234055810000021
3. The aromatic vinyl compound shown in the formula I-0, the tautomer, the stereoisomer, the racemate or the isotopic derivative thereof or the pharmaceutically acceptable salt thereof according to claim 1,
the aromatic vinyl compound shown in the formula I-0 is an aromatic vinyl compound shown in the formula I:
Figure FDA0003234055810000022
wherein:
R1is cyano, C1-C4Alkyl, C substituted by one or more deuterium1-C4An alkyl group;
R3、R6、R12、R13and R14Independently is H or deuterium;
R2is hydroxy, halogen, C1-C4Alkyl, by one or more RA-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RA-2Substituted C1-C6An alkoxy group;
RA-1and RA-2Independently is deuterium, hydroxy, halogen, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C4Alkoxy radical,
Figure FDA0003234055810000023
RA-1-1Is C1-C4Alkyl or C substituted by one or more deuterium1-C4An alkyl group; rA -1-2And RA-1-3Independently of one another H, deuterium, C1-C4Alkyl or by one or more RA-1-1-1Substituted C1-C4Alkyl radical, said RA-1-1-1Is deuterium, hydroxy or COORA-1-1-2；
R4And R5Independently of one another, hydroxy, halogen, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group;
RB-1and RB-2Independently is deuterium, hydroxy, halogen, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C4Alkoxy radical,
Figure FDA0003234055810000024
RB-1-1And RB-1-2Independently of one another H, deuterium, C1-C4Alkyl or by one or more RB-1-1-1Substituted C1-C4Alkyl radical, said RB -1-1-1Is deuterium, hydroxy or COORB-1-1-5；
Or, RB-1-1、RB-1-2And the nitrogen atom to which they are attached together form a 5-to 7-membered carbocyclic heterocyclic ring or are substituted by one or more RB -1-1-2Substituted carbon heterocyclic ring, wherein in the carbon heterocyclic ring, heteroatoms are selected from one or more of N, O and S, the number of heteroatoms is 1-4, and R isB-1-1-2Is deuterium, C1-C4Alkyl, C substituted by one or more deuterium1-C4Alkyl, COORB-1-1-6Or C1-C4An amide group;
RA-1-1-2、RB-1-1-5and RB-1-1-6Independently of one another H, deuterium, C1-C4Alkyl or C substituted by one or more deuterium1-C4An alkyl group;
R7、R8、R9、R10and R11Independently is H or deuterium.
4. The aromatic vinyl compound of formula I-0, the tautomer, the stereoisomer, the racemate or the isotopic derivative thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein when R is1Is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or when R1Is C substituted by one or more deuterium1-C4When alkyl, said C substituted by one or more deuterium1-C4Alkyl is C substituted by one or more deuterium1-C2An alkyl group;
and/or when R1When halogen, the halogen is fluorine, chlorine, bromine or iodine;
and/or when R1Is C substituted by one or more halogens1-C4When alkyl, the halogen is fluorine, chlorine, bromine or iodine;
and/or when R1Is C substituted by one or more halogens1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or when R2When halogen, the halogen is fluorine, chlorine, bromine or iodine;
and/or when R2Is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or when R2Is represented by one or more RA-1Substituted C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or when R2Is represented by one or more RA-1Substituted C1-C4When it is alkyl, each RA-1The same or different, said plurality being 2,3, 4 or5, the number of the cells is 5;
and/or when R2Is C1-C6At alkoxy, the C1-C6Alkoxy is C1-C4An alkoxy group;
and/or when R2Is represented by one or more RA-2Substituted C1-C6At alkoxy, the C1-C6Alkoxy is C1-C4An alkoxy group;
and/or when R2Is represented by one or more RA-2Substituted C1-C6At alkoxy, each RA-2The same or different, said plurality is 2,3, 4 or 5;
and/or when RA-1And RA-2When independently halogen, the halogen is fluorine, chlorine, bromine or iodine;
and/or when RA-1And RA-2Independently is C1-C4At alkoxy, the C1-C4Alkoxy is methoxy, ethoxy, n-propoxy or n-butoxy;
and/or when RA-1And RA-2Independently C substituted by one or more deuterium1-C4Alkoxy, said C substituted by one or more deuterium1-C4Alkoxy is C substituted by one or more deuterium1-C2An alkoxy group;
and/or when RA-1-1Is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or when RA-1-1Is C substituted by one or more deuterium1-C4When alkyl, said C substituted by one or more deuterium1-C4Alkyl is C substituted by one or more deuterium1-C2An alkyl group;
and/or when RA-1-2And RA-1-3Independently is C1-C4When alkyl, said C1-C4The alkyl is methyl, ethyl, n-propyl,Isopropyl, n-butyl, isobutyl, or tert-butyl;
and/or when RA-1-2And RA-1-3Independently by one or more RA-1-1-1Substituted C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or when RA-1-2And RA-1-3Independently by one or more RA-1-1-1Substituted C1-C4When it is alkyl, each RA-1-1-1The same or different, said plurality is 2,3, 4 or 5;
and/or when R4And R5When independently halogen, the halogen is fluorine, chlorine, bromine or iodine;
and/or when R4And R5Independently is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or when R4And R5Independently by one or more RB-1Substituted C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or when R4And R5Independently by one or more RB-1Substituted C1-C4When it is alkyl, each RB-1Are the same or different, said plurality is 2,3, 4 or 5;
and/or when R4And R5Independently is C1-C6At alkoxy, the C1-C6Alkoxy is C1-C4An alkoxy group;
and/or when R4And R5Independently by one or more RB-2Substituted C1-C6At alkoxy, the C1-C6Alkoxy is C1-C4An alkoxy group;
and/or when R4And R5Independently by one or more RB-2Substituted C1-C6At alkoxy, each RB-2The same or different, said plurality is 2,3, 4 or 5;
and/or when RB-1And RB-2When independently halogen, the halogen is fluorine, chlorine, bromine or iodine;
and/or when RB-1And RB-2Is independently C6-C10Aryl is said to C6-C10Aryl is phenyl;
and/or when RB-1And RB-2Is independently one or more RB-1-3Substituted C6-C10Aryl is said to C6-C10Aryl is phenyl;
and/or when RB-1And RB-2Is independently one or more RB-1-3Substituted C6-C10At aryl radical, each RB-1-3The same or different, said plurality is 2,3, 4 or 5;
and/or in the aromatic vinyl compound shown as the formula I-0 or I, when R isB-1And RB-2When independently is a 3-12 membered heteroaryl, said 3-12 membered heteroaryl is a 5-7 membered heteroaryl;
and/or in the aromatic vinyl compound shown as the formula I-0 or I, when R isB-1And RB-2When independently is a 3-12 membered heteroaryl, the heteroatoms of said 3-12 membered heteroaryl are selected from N, the number of heteroatoms is 1;
and/or when RB-1And RB-2Is independently one or more RB-1-4When substituted 3-12 membered heteroaryl, said 3-12 membered heteroaryl is 5-7 membered heteroaryl;
and/or when RB-1And RB-2Is independently one or more RB-1-4(ii) when substituted 3-12 membered heteroaryl, the heteroatom of said 3-12 membered heteroaryl is selected from N, the number of heteroatoms is 1;
and/or when RB-1And RB-2Is independently asBy one or more RB-1-4When substituted with 3-12 membered heteroaryl, each RB-1-4The same or different, said plurality is 2,3, 4 or 5;
and/or when RB-1-3And RB-1-4Independently is halogen, which is fluorine, chlorine, bromine or iodine;
and/or when RB-1And RB-2Is independently C1-C4Alkoxy radical, said C1-C4Alkoxy is methoxy, ethoxy, n-propoxy or n-butoxy;
and/or when RB-1And RB-2Is independently C substituted by one or more deuterium1-C4Alkoxy, said C substituted by one or more deuterium1-C4Alkoxy is C substituted by one or more deuterium1-C2An alkoxy group;
and/or when RB-1-1And RB-1-2Independently is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or when RB-1-1And RB-1-2Independently by one or more RB-1-1-1Substituted C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or when RB-1-1And RB-1-2Independently by one or more RB-1-1-1Substituted C1-C4When it is alkyl, each RB-1-1-1The same or different, said plurality is 2,3, 4 or 5;
and/or when RB-1-1、RB-1-2And the nitrogen atom to which they are attached, together form a 5-7 membered carbocyclic heterocyclic ring in which the heteroatoms are independently N and/or O;
and/or when RB-1-1、RB-1-2And the nitrogen atom to which they are attached, together form a 5-to 7-membered carbon heterocyclic ring in which the hetero atomThe number of the son is 1 or 2;
and/or when RB-1-1、RB-1-2And the nitrogen atom to which they are attached together form a group consisting of one or more RB-1-1-2When the carbon heterocyclic ring is substituted, the heteroatom in the carbon heterocyclic ring is N and/or O;
and/or when RB-1-1、RB-1-2And the nitrogen atom to which they are attached together form a group consisting of one or more RB-1-1-2When the carbon heterocyclic ring is substituted, the number of the hetero atoms in the carbon heterocyclic ring is 1 or 2;
and/or when RB-1-1、RB-1-2And the nitrogen atom to which they are attached together form a group consisting of one or more RB-1-1-2When substituted by a carbocyclic ring, each RB-1-1-2The same or different, said plurality is 2,3, 4 or 5;
and/or, when said R isB-1-1-2Is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or, when said R isB-1-1-2Is C substituted by one or more deuterium1-C4When alkyl, said C substituted by one or more deuterium1-C4Alkyl is C substituted by one or more deuterium1-C2An alkyl group;
and/or, when said R isB-1-1-2Is C1-C4When it is an amide group, the C1-C4Amide is
Figure FDA0003234055810000051
RB-1-1-3And RB -1-1-4Independently of one another H, deuterium, C1-C4Alkyl or C substituted by one or more deuterium1-C4An alkyl group;
and/or when RA-1-1-2、RB-1-1-5And RB-1-1-6Independently is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
and/or when R15And R16Independently halogen, the halogen is fluorine, chlorine, bromine or iodine.
5. The aromatic vinyl compound, the tautomer, the stereoisomer, the racemate or the isotopic derivative thereof, or the pharmaceutically acceptable salt thereof according to claim 4, wherein when R is R, R is1Is C1-C4When alkyl, said C1-C4Alkyl is methyl;
and/or when R1Is C substituted by one or more deuterium1-C4When alkyl, said C substituted by one or more deuterium1-C4The alkyl is a deuterium methyl, dideuteromethyl, trideuteromethyl, deuteroethyl, dideuteroethyl, trideuteriomethyl, tetradeuteroethyl or pentadeuteroethyl group; such as trideuteriomethyl;
and/or when R1When halogen, the halogen is chlorine;
and/or when R1Is C substituted by one or more halogens1-C4When alkyl, the halogen is fluorine;
when R is1Is C substituted by one or more halogens1-C4When alkyl, said C1-C4Alkyl is methyl;
and/or when R2When halogen, the halogen is chlorine;
and/or when R2Is C1-C4When alkyl, said C1-C4Alkyl is methyl;
and/or when R2Is represented by one or more RA-1Substituted C1-C4When alkyl, said C1-C4Alkyl is methyl;
and/or when R2Is C1-C6At alkoxy, the C1-C6Alkoxy is methoxy, ethoxy, n-propoxy or n-butoxy; such as methoxy;
and/or when R2Is represented by one or more RA-2Substituted C1-C6At alkoxy, the C1-C6Alkoxy is methoxy, ethoxy, n-propoxy or n-butoxy;
and/or when RA-1And RA-2When independently halogen, the halogen is fluorine;
and/or when RA-1And RA-2Independently is C1-C4At alkoxy, the C1-C4Alkoxy is methoxy;
and/or when RA-1And RA-2Independently C substituted by one or more deuterium1-C4Alkoxy, said C substituted by one or more deuterium1-C4Alkoxy is mono-deuterium methoxy, di-deuterium methoxy, tri-deuterium methoxy, mono-deuterium ethoxy, di-deuterium ethoxy, tri-deuterium ethoxy, tetra-deuterium ethoxy or penta-deuterium ethoxy, such as tri-deuterium methoxy;
and/or when RA-1-1Is C1-C4When alkyl, said C1-C4Alkyl is methyl;
and/or when RA-1-1Is C substituted by one or more deuterium1-C4When alkyl, said C substituted by one or more deuterium1-C4Alkyl is mono-deuteromethyl, di-deuteromethyl, tri-deuteromethyl, mono-deuteroethyl, di-deuteroethyl, tri-deuteroethyl, tetra-deuteroethyl or pentadeuteroethyl, for example tri-deuteromethyl;
and/or when RA-1-2And RA-1-3Independently is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl or isopropyl;
and/or when RA-1-2And RA-1-3Independently by one or more RA-1-1-1Substituted C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl or isopropyl;
and/or when R4And R5When independently halogen, the halogen is chlorine;
and/or when R4And R5Independently is C1-C4When alkyl, said C1-C4Alkyl is methyl;
and/or when R4And R5Independently by one or more RB-1Substituted C1-C4When alkyl, said C1-C4Alkyl is methyl;
and/or when R4And R5Independently is C1-C6At alkoxy, the C1-C6Alkoxy is methoxy, ethoxy, n-propoxy or n-butoxy, for example methoxy;
and/or when R4And R5Independently by one or more RB-2Substituted C1-C6At alkoxy, the C1-C6Alkoxy is methoxy, ethoxy, n-propoxy or n-butoxy;
and/or when RB-1And RB-2When independently halogen, the halogen is fluorine;
and/or when RB-1-3And RB-1-4Independently is a halogen, said halogen is fluorine or iodine;
and/or when RB-1And RB-2Is independently C1-C4Alkoxy radical, said C1-C4Alkoxy is methoxy;
and/or when RB-1And RB-2Is independently C substituted by one or more deuterium1-C4Alkoxy, said C substituted by one or more deuterium1-C4Alkoxy is mono-deuterium methoxy, di-deuterium methoxy, tri-deuterium methoxy, mono-deuterium ethoxy, di-deuterium ethoxy, tri-deuterium ethoxy, tetra-deuterium ethoxy or penta-deuterium ethoxy, such as tri-deuterium methoxy;
and/or when RB-1-1And RB-1-2Independently is C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl or isopropyl;
and/or when RB-1-1And RB-1-2Independently by one or more RB-1-1-1Substituted C1-C4When alkyl, said C1-C4Alkyl is methyl, ethyl or isopropyl;
and/or, when said R isB-1-1-2Is C1-C4When alkyl, said C1-C4Alkyl is methyl;
and/or, when said R isB-1-1-2Is C substituted by one or more deuterium1-C4When alkyl, said C substituted by one or more deuterium1-C4Alkyl is mono-deuteromethyl, di-deuteromethyl, tri-deuteromethyl, mono-deuteroethyl, di-deuteroethyl, tri-deuteroethyl, tetra-deuteroethyl or pentadeuteroethyl, for example tri-deuteromethyl;
and/or, when said R isB-1-1-2Is C1-C4When it is an amide group, the C1-C4Amide is
Figure FDA0003234055810000061
RB-1-1-3And RB -1-1-4Independently of one another H, deuterium, C1-C4Alkyl or C substituted by one or more deuterium1-C4Alkyl radical, said C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, said C being substituted by one or more deuterium1-C4Alkyl is tri-deuteromethyl;
and/or when RA-1-1-2、RB-1-1-5And RB-1-1-6Independently is C1-C4When alkyl, said C1-C4Alkyl is methyl;
and/or when R15And R16When independently halogen, the halogen is fluorine or bromine.
6. The aromatic vinyl compound of formula I-0, the tautomer, the stereoisomer, the racemate or the isotopic derivative thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R is3、R6、R12、R13And R14Independently is H;
and/or, R2Is halogen, C1-C4Alkyl or by one or more RA-1Substituted C1-C4An alkyl group;
and/or in the aromatic vinyl compound shown as the formula I-0 or I, RA-1And RA-2Independently is hydroxy, halogen, cyano, C1-C4Alkoxy radical,
Figure FDA0003234055810000071
And/or, RA-1-1Is C1-C4An alkyl group;
and/or, RA-1-2And RA-1-3Independently H or by one or more RA-1-1-1Substituted C1-C4An alkyl group;
and/or, RA-1-1-2、RB-1-1-5And RB-1-1-6Independently is H or C1-C4An alkyl group;
and/or said is one or more RA-1-1-1Substituted C1-C4Alkyl is
Figure FDA0003234055810000072
Figure FDA0003234055810000073
And/or, R4And R5Independently of one another, halogen, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group;
and/or, RB-1And RB-2Independently is deuterium, hydroxy, cyano, C6-C10Aryl radicals, substituted by one or more RB-1-3Substituted C6-C10Aryl, 3-12 membered heteroaryl, substituted by one or moreR isB-1-4Substituted 3-12 membered heteroaryl, C1-C4Alkoxy, C substituted by one or more deuterium1-C4Alkoxy radical,
Figure FDA0003234055810000074
And/or, RB-1-3And RB-1-4Independently cyano or halogen;
and/or, RB-1-1And RB-1-2Independently H or by one or more RB-1-1-1Substituted C1-C4An alkyl group; or, RB-1-1、RB -1-2And together with the nitrogen atom to which they are attached form a 5-to 7-membered ring substituted by one or more RB-1-1-2A substituted carbon heterocycle;
and/or said is one or more RB-1-1-1Substituted C1-C4Alkyl is
Figure FDA0003234055810000075
Figure FDA0003234055810000076
And/or, RB-1-1-2Is C1-C4Alkyl, COORB-1-1-6Or C1-C4An amide group;
and/or the carbon heterocycle is
Figure FDA0003234055810000081
And/or, R15And R16At least one of which is H or deuterium.
7. The aromatic vinyl compound of formula I-0, the tautomer, the stereoisomer, the racemate or the isotopic derivative thereof, or the pharmaceutically acceptable salt thereof according to claim 6, wherein R is R2Is halogen or C1-C4An alkyl group;
and/or, RA-1Is halogen or
Figure FDA0003234055810000082
And/or, RA-1-2And RA-1-3One of which is H and the other is substituted by one or more RA-1-1-1Substituted C1-C4An alkyl group;
and/or, RA-1-1-2、RB-1-1-5And RB-1-1-6Independently is H;
and/or, RB-1Is hydroxy, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy, or
Figure FDA0003234055810000083
And/or, RB-2Is deuterium, cyano, hydroxy, C6-C10Aryl radicals, substituted by one or more RB-1-3Substituted C6-C10Aryl, 3-12 membered heteroaryl, substituted with one or more RB-1-4Substituted 3-12 membered heteroaryl or C1-C4An alkoxy group;
and/or said is one or more RB-1-3Substituted C6-C10Aryl is
Figure FDA0003234055810000084
And/or said is one or more RB-1-4Substituted 3-12 membered heteroaryl is
Figure FDA0003234055810000085
And/or said is one or more RB-1-4Substituted 3-12 membered heteroaryl is
Figure FDA0003234055810000086
Figure FDA0003234055810000087
And/or, RB-1-1And RB-1-2One of which is H and the other is substituted by one or more RB-1-1-1Substituted C1-C4An alkyl group; or, RB-1-1、RB-1-2And together with the nitrogen atom to which they are attached form a 5-to 7-membered ring substituted by one or more RB-1-1-2A substituted carbon heterocycle;
and/or, RB-1-1-2Is methyl, carboxyl or-CONH2；
And/or said is one or more RB-1-1-2Substituted carbon heterocycle is
Figure FDA0003234055810000088
Figure FDA0003234055810000091
And/or, R4Is composed of
Figure FDA0003234055810000092
And/or, R5Is halogen, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group; rB-1And RB-2Independently is deuterium, hydroxy, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy or
Figure FDA0003234055810000093
And/or, R15Is H or deuterium; r16Is H, deuterium or halogen.
8. The aromatic vinyl compound of formula I-0, the tautomer, the stereoisomer, the compound,Its racemate or its isotopic derivative, or their pharmaceutically acceptable salts, characterized in that RB-1Is hydroxy or
Figure FDA0003234055810000094
And/or the presence of a gas in the gas,
Figure FDA0003234055810000095
is composed of
Figure FDA0003234055810000096
And/or the presence of a gas in the gas,
Figure FDA0003234055810000097
is composed of
Figure FDA0003234055810000098
Figure FDA0003234055810000099
9. The aromatic vinyl compound of formula I-0, the tautomer, the stereoisomer, the racemate or the isotopic derivative thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R is1Is halogen, C substituted by one or more halogens1-C4An alkyl group;
and/or, R15Is deuterium or halogen;
and/or, R16Is deuterium or halogen.
10. The aromatic vinyl compound shown in the formula I-0, the tautomer, the stereoisomer, the racemate or the isotopic derivative thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the aromatic vinyl compound shown in the formula I-0 or I is selected from any one of the following schemes,
the first scheme is as follows: r2Is composed of
Figure FDA0003234055810000101
R4And R5Independently of one another, halogen, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group; rB-1And RB-2Independently is deuterium, hydroxy, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy or
Figure FDA0003234055810000102
R3、R6、R12、R13And R14Is H;
scheme II: r2Is halogen, C1-C4Alkyl or by one or more RA-1Substituted C1-C4An alkyl group; rA-1Is halogen; r4Is composed of
Figure FDA0003234055810000103
R5Is halogen, hydroxy, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group; rB-1And RB-2Independently is deuterium, hydroxy, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy or
Figure FDA0003234055810000104
R3、R6、R12、R13And R14Is H;
the third scheme is as follows: r2Is halogen, C1-C4Alkyl or by one or more RA-1Substituted C1-C4An alkyl group; rA-1Is halogen; r4Is halogen, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group; rB-1And RB-2Independently is deuterium, hydroxy, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy or
Figure FDA0003234055810000105
R5Is composed of
Figure FDA0003234055810000106
R3、R6、R12、R13And R14Is H;
and the scheme is as follows: r2Is composed of
Figure FDA0003234055810000107
R4And R5Independently of one another, halogen, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group; rB-1And RB-2Independently is deuterium, hydroxy, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy or
Figure FDA0003234055810000108
R3、R6、R12、R13And R14Is H; r15And R16At least one of which is H or deuterium;
and a fifth scheme: r2Is halogen, C1-C4Alkyl radicals or substituted by one or moreR isA-1Substituted C1-C4An alkyl group; rA-1Is halogen; r4Is composed of
Figure FDA0003234055810000109
R5Is halogen, hydroxy, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group; rB-1And RB-2Independently is deuterium, hydroxy, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy or
Figure FDA00032340558100001010
R3、R6、R12、R13And R14Is H; r15And R16At least one of which is H or deuterium;
scheme six: r2Is halogen, C1-C4Alkyl or by one or more RA-1Substituted C1-C4An alkyl group; rA-1Is halogen; r4Is halogen, C1-C4Alkyl, by one or more RB-1Substituted C1-C4Alkyl radical, C1-C6Alkoxy or by one or more RB-2Substituted C1-C6An alkoxy group; rB-1And RB-2Independently is deuterium, hydroxy, cyano, C1-C4Alkoxy, C substituted by one or more deuterium1-C2Alkoxy or
Figure FDA0003234055810000111
R5Is composed of
Figure FDA0003234055810000112
R3、R6、R12、R13And R14Is H; r15And R16At least one of which is H or deuterium.
11. The aromatic vinyl compound of formula I-0, the tautomer, the stereoisomer, the racemate or the isotopic derivative thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R is1Is cyano, CH3、CD3、Cl、CH2F. C substituted by one or more halogens1-C4An alkyl group;
and/or the presence of a gas in the gas,
Figure FDA0003234055810000113
is composed of
Figure FDA0003234055810000114
Figure FDA0003234055810000115
Figure FDA0003234055810000121
Figure FDA0003234055810000131
Figure FDA0003234055810000141
And/or, R15And R16Independently H, deuterium, Br or F.
12. Any one of the following aromatic vinyl compounds, tautomers thereof, stereoisomers thereof, racemates thereof or isotopic derivatives thereof, or pharmaceutically acceptable salts thereof,
Figure FDA0003234055810000142
Figure FDA0003234055810000151
Figure FDA0003234055810000161
Figure FDA0003234055810000171
Figure FDA0003234055810000181
Figure FDA0003234055810000191
Figure FDA0003234055810000201
Figure FDA0003234055810000211
13. the method for producing an aromatic vinyl compound according to any one of claims 1 to 12, comprising the following method 1, method 2, method 3, method 4, method 5 or method 6:
the method 1 comprises the following steps: in a solvent, under the action of a reducing agent, carrying out reductive amination reaction on a compound shown as a formula II-a-0 and a compound shown as a formula III-a as shown in the specification to obtain an aromatic vinyl compound shown as a formula I-0;
Figure FDA0003234055810000221
in Process 1, R4Is composed of
Figure FDA0003234055810000222
R1、R2、R3、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、RB-1-1And RB-1-2As defined in any one of claims 1 to 12;
the method 2 comprises the following steps: in a solvent, under the action of alkali, carrying out substitution reaction shown as the following on a compound shown as a formula II-b-0 and a compound shown as a formula III-a to obtain an aromatic vinyl compound shown as a formula I-0;
Figure FDA0003234055810000223
in Process 2, R4Is composed of
Figure FDA0003234055810000224
R1、R2、R3、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、RB-1-1And RB-1-2Is as defined in any one of claims 1 to 12, X1Is halogen;
the method 3 comprises the following steps: in a solvent, under the action of a reducing agent, carrying out reductive amination reaction on a compound shown as a formula II-c-0 and a compound shown as a formula III-a as shown in the specification to obtain an aromatic vinyl compound shown as a formula I-0;
Figure FDA0003234055810000225
in method 3, R5Is composed of
Figure FDA0003234055810000226
R1、R2、R3、R4、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、RB-1-1And RB-1-2As defined in any one of claims 1 to 12;
the method 4 comprises the following steps: in a solvent, under the action of alkali, carrying out substitution reaction shown as the following on a compound shown as a formula II-d-0 and a compound shown as a formula III-a to obtain an aromatic vinyl compound shown as a formula I-0;
Figure FDA0003234055810000231
in method 4, R5Is composed of
Figure FDA0003234055810000232
R1、R2、R3、R4、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、RB-1-1And RB-1-2Is as defined in any one of claims 1 to 12, X2Is halogen;
the method 5 comprises the following steps: in a solvent, under the action of a reducing agent, carrying out reductive amination reaction on a compound shown as a formula II-e-0 and a compound shown as a formula III-b as shown in the specification to obtain an aromatic vinyl compound shown as a formula I-0;
Figure FDA0003234055810000233
in method 5, R2Is composed of
Figure FDA0003234055810000234
R1、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、RA-1-1And RA-1-2As defined in any one of claims 1 to 12;
the method 6 comprises the following steps: in a solvent, under the action of alkali, carrying out substitution reaction shown as the following on a compound shown as a formula II-f-0 and a compound shown as a formula III-b to obtain an aromatic vinyl compound shown as a formula I-0;
Figure FDA0003234055810000235
in method 6, R2Is composed of
Figure FDA0003234055810000236
R1、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、RA-1-1And RA-1-2Is as defined in any one of claims 1 to 12, X3Is halogen.
14. Such as compounds represented by II-a-0, II-b-0, II-c-0, II-d-0, II-e-0 or II-f-0,
Figure FDA0003234055810000241
in the compounds of the above formula, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15And R16Is as defined in any one of claims 1 to 12, X1、X2And X3Independently a halogen.
15. A compound according to any one of the following, wherein,
Figure FDA0003234055810000242
Figure FDA0003234055810000251
Figure FDA0003234055810000261
Figure FDA0003234055810000271
Figure FDA0003234055810000281
Figure FDA0003234055810000291
16. a pharmaceutical composition, comprising the aromatic vinyl compound, the tautomer thereof, the stereoisomer thereof, the racemate thereof or the isotopic derivative thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, and a pharmaceutical excipient;
and/or, the pharmaceutical composition comprises the aromatic vinyl compound, the tautomer thereof, the stereoisomer thereof, the racemate thereof or the isotopic derivative thereof, or the pharmaceutically acceptable salt thereof, according to any one of claims 1 to 10, and at least one other drug; wherein the other drugs are chemotherapeutic drugs or targeted drugs.
17. The pharmaceutical composition of claim 16, wherein the targeted drug is one or more of a COX-2 inhibitor, a DPP4 inhibitor, a CSF-1 α inhibitor, and an A2a antagonist.
18. Use of the aromatic vinyl compound, the tautomer thereof, the stereoisomer thereof, the racemate thereof or the isotopic derivative thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, or the pharmaceutical composition according to claim 16 or 17, for the preparation of a PD-1 inhibitor and/or a PD-L1 inhibitor.
19. Use of the aromatic vinyl compound, the tautomer thereof, the stereoisomer thereof, the racemate thereof, or the isotopic derivative thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, or the pharmaceutical composition according to claim 16 or 17, for the preparation of a medicament for the prevention and/or treatment of diseases associated with the PD-1/PD-L1 signaling pathway.
20. The use of claim 19, wherein the disease associated with the PD-1/PD-L1 signaling pathway is cancer, an infectious disease, an autoimmune disease, or a disease related thereto.
21. The use of claim 20, wherein the cancer is one or more of lung cancer, esophageal cancer, gastric cancer, colorectal cancer, hematological tumors, lymphoma, head and neck cancer, liver cancer, nasopharyngeal cancer, brain tumor, breast cancer, cervical cancer, hematological cancer, and bone cancer;
and/or the infectious disease is a bacterial infection and/or a viral infection;
and/or, the autoimmune disease is one or more of rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, systemic vasculitis, and relapsing polychondritis.
CN202110995765.3A 2020-09-09 2021-08-27 Aromatic vinyl compound, preparation method thereof, intermediate, pharmaceutical composition and application thereof Pending CN114230512A (en)

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US18/042,599 US20230331675A1 (en) 2020-09-09 2021-09-08 Aromatic ethylene compound and preparation method therefor, and intermediate, pharmaceutical composition, and application thereof
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