CN115260165A - Benzo nitrogen-containing five-membered heterocyclic compound and synthesis and application thereof - Google Patents

Benzo nitrogen-containing five-membered heterocyclic compound and synthesis and application thereof Download PDF

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CN115260165A
CN115260165A CN202210426932.7A CN202210426932A CN115260165A CN 115260165 A CN115260165 A CN 115260165A CN 202210426932 A CN202210426932 A CN 202210426932A CN 115260165 A CN115260165 A CN 115260165A
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赵玉军
李志强
严子琴
李亚芳
吕细林
周飞龙
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Shanghai Institute of Materia Medica of CAS
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Abstract

The structure of the compound is shown as a general formula I, and the definition of each substituent is described in the specification and the claims. The compound can competitively inhibit the interaction of the nuclear transcription factor TEAD and the coactivator YAP protein thereof, and can be used for preventing and/or treating related diseases mediated by the nuclear transcription factor TEAD, especially the drug resistance of cancers and antitumor drugs.

Description

Benzo nitrogen-containing five-membered heterocyclic compound and synthesis and application thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a compound with a benzo nitrogen-containing five-membered heterocyclic structure, a stereoisomer, an enantiomer or a pharmaceutically acceptable salt thereof, a preparation method and application thereof.
Background
The functions of the Hippo signaling pathway include regulation of tissue and organ size, regulation of cell proliferation, survival and differentiation, and influencing of tissue development and regeneration processes, and their roles are of great importance. The Hippo signaling pathway is regulated by a complex kinase cascade, the core nodes of which include the nuclear transcription factor TEAD and its cofactor YAP/TAZ. In the resting state of the cell, the kinase LATS1/2 phosphorylates YAP/TAZ to promote degradation of YAP/TAZ by proteasomes or to promote its binding to 14-3-3 in the cytoplasm without entering the nucleus. When the kinase of LATS1/2 is in malfunction, the unphosphorylated YAP/TAZ is obviously increased and enters the nucleus, and is combined with the transcription factor TEAD protein in the nucleus to start the expression of downstream genes (CTGF, cyr61, axl and the like) and promote the proliferation and growth of cells.
Studies have shown that abnormally elevated YAP levels in cancer cells, and TEAD-mediated gene transcriptional overactivation, are closely related to tumor cell overgrowth compared to normal cells. In addition, cancer cells that rely on YAP overexpression exhibit resistance to traditional tumor drugs.
YAP does not bind directly to domains of DNA that regulate gene transcription through direct interaction with TEAD. The existing research clearly demonstrates that the protein interaction of TEAD/YAP in the tumor cell is blocked, and the protein interaction has the anti-tumor activity. Firstly, in cells and animal models, TEAD2-DN (dominant negative) protein without DNA binding domain but with YAP binding domain is overexpressed, which can competitively block the protein interaction of wild TEAD and YAP in cells, and can inhibit liver cancer formation induced by overexpression of YAP in mice. Second, the endogenous protein TEAD4-s is the TEAD4 protein N-terminal cleavage body. TEAD4-s, although lacking a domain that binds to DNA, had the ability to bind YAP proteins. The intracellular high-expression TEAD4-s can block the combination of YAP and full-length TEAD, inhibit the growth and metastasis of tumors, and show anti-tumor curative effect in a mouse transplanted tumor model. Third, endogenous proteins VgLL4 and YAP competitively bind to TEAD, and the interfaces at which the two bind to TEAD partially overlap. The 5-year survival rate of the gastric cancer patients with high expression of VgLL4 clinically is higher, and one of the important reasons is that intracellular VgLL4 is combined with TEAD, so that the number of TEAD/YAP dimers is reduced competitively, and the TEAD/YAP mediated gene expression level is inhibited. The biological research shows that the protein interaction of TEAD/YAP in tumor cells is competitively blocked, the number of wild TEAD/YAP dimers in the cells is reduced, TEAD-mediated gene transcription can be inhibited, the anti-tumor effect is shown, and the method is one of the hot research directions of drug development.
The compounds CPD3.1 (Smith et al, 2019, J Med Chem 62, 1291-1305), TEAD-347 (Bum-erden et al, 2019, cell Chem Biol 26, 378-389), verteporfin (Liu-Chittenden et al, 2012, gene Dev 26, 1300-1305) are reported in the literature to be capable of blocking TEAD/YAP protein interactions in cells and exhibit certain antitumor activity. WO2019232216, WO2020097389 (A1) and WO2020243415A2 in the patent also report that different structural compounds have the function of blocking TEAD/YAP protein interaction and have the potential of treating related diseases.
Disclosure of Invention
The invention aims to provide a compound for inhibiting the interaction of TEAD and YAP/TAZ.
In a first aspect of the present invention, there is provided a compound represented by the general formula (I), a stereoisomer, an enantiomer, or a pharmaceutically acceptable salt thereof:
Figure BDA0003608794920000021
in the formula, RaSelected from the group consisting of: hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy;
A1、A2、A3、A4and A5Each independently is represented as CRbOr N, wherein RbEach occurrence is independently selected from the group consisting of: hydrogen atom, halogen, cyano, nitro, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, -NR1R2、-CO2R3Substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C5-C8 cycloalkenyl, substituted or unsubstituted C5-C8 heterocycloalkyl, substituted or unsubstituted C5-C8 heterocycloalkenyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-8 membered heteroaryl; or two adjacent RbForm, with the carbon atom to which it is attached, a substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, nitro, hydroxy, carboxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, -NR4R5；
Under the condition of valence bond permission, each
Figure BDA0003608794920000027
Independently a double or single bond;
x, Y, Z are each independently CR under valency permissive conditionscOr NRdAnd forms a five-membered heteroaromatic ring with two carbon atoms of the phenyl ring;
under the condition of valence bond permission, RcEach occurrence is independently selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-to 8-membered heteroaryl group, a carboxyl group, -CONH- (C1-C6 alkylene) Re,
Figure BDA0003608794920000022
Figure BDA0003608794920000023
Substituted or unsubstituted
Figure BDA0003608794920000024
Wherein said substitution means substitution by one or more groups selected from the group consisting of: halogen, oxo radical
Figure BDA0003608794920000025
Hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, 5-to 8-membered heteroaryl, - (CH)2)m1-CO2R6、-(CH2)m2-SO3R7、-SO2NR8R9、-NR8R9-NHCOC1-C6 alkyl;
Ar1selected from the group consisting of: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, - (CH)2)m3-CO2R10、-CONR11R12、-SO2NR13R14、-(CH2)m4-SO3R15C1-C4 alkyl, C1-C4 alkoxy;
Reselected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group; wherein said substitution is by one or more groups selected from the group consisting of: halogen, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, -SO2OR15Oxo group
Figure BDA0003608794920000026
Hydroxy, methanesulfonyl, trifluoromethyl, - (CH)2)m5-CO2R16；
Ar2Selected from the group consisting of: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methylsulfonyl, trifluoromethyl, - (CH)2)m6-CO2R17、-CONR18R19、-SO2NR20R21、-(CH2)m7-SO3R22C1-C4 alkyl, C1-C4 alkoxy;
Rfselected from: substituted or unsubstituted C1-C6 alkyl, carboxyl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, nitroA group;
Ar3selected from the group consisting of: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, nitro, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy;
E1is NR33Or O; e2Is NR31R32OR OR34；
Ar4Selected from the group consisting of: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methylsulfonyl, trifluoromethyl, - (CH)2)m8-CO2R23、-CONR24R25、-SO2NR26R27、-(CH2)m9-SO3R28C1-C4 alkyl, C1-C4 alkoxy;
under the condition of valence bond permission RdEach occurrence is independently selected from the group consisting of: absent, a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group,
Figure BDA0003608794920000031
Wherein said substitution is by one or more groups selected from the group consisting of: halogen, - (CH)2)m8-CO2R23Cyano, nitro, hydroxy, oxo
Figure BDA0003608794920000032
-NH2Methanesulfonyl, sulfonic acid, aminosulfonyl, (C1-C4) alkoxy, (C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;
Ar5selected from the group consisting of: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution means substitution by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, - (CH)2)m10-CO2R29、-CONR30R31、-SO2NR32R33、-(CH2)m11-SO3R34C1-C4 alkyl, C1-C4 alkoxy;
at each occurrence, R1-R34Each independently selected from a hydrogen atom or a C1-C4 alkyl group;
n1 is 0,1, 2,3 or 4;
n2 is 0,1 or 2;
n3 is 0,1 or 2;
n4 is 1,2 or 3;
m1 to m11 are each independently 0,1 or 2.
In the present invention, R1-R6Is denoted by R1、R2、R3、R4、R5、R6And so on. m1-m5 are m1, m2, m3, m4, m5, and so on.
In the present invention, the halogen is F, cl, br or I.
In the present invention, the pharmaceutically acceptable salt of the present invention may be a salt of an anion with a positively charged group on the compound of formula I. Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methylsulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate or maleate. Similarly, salts may be formed from cations with negatively charged groups on the compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium ions, such as tetramethylammonium.
In another preferred embodiment, "pharmaceutically acceptable salt" refers to a salt of a compound of formula I with an acid selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid and the like; or a sodium, potassium, calcium, aluminum or ammonium salt of a compound of formula I with an inorganic base; or methylamine salt, ethylamine salt or ethanolamine salt formed by the compound of the general formula I and organic base
In another preferred embodiment, the C5-C8 heterocycloalkenyl structure is
Figure BDA0003608794920000033
M is an oxygen atom (O) or-NH-; j. each k is independently an integer from 1-4, and j + k =2, 3,4, or 5.
In another preferred embodiment, ra is H.
In another preferred embodiment, the compound has a structure represented by formula (I-1):
Figure BDA0003608794920000041
in the formula, Rz1Selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group,
Figure BDA0003608794920000042
Wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, carboxy, cyano, nitro, amino, (C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;
Ar6selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: nitro, halogen, hydroxy, cyano, methanesulfonyl, trifluoromethyl, - (CH)2)m12-CO2R35、-CONR36R37、-SO2NR38R39、-(CH2)m13-SO3R40C1-C3 alkyl, C1-C3 alkoxy;
Rx1selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl,
Figure BDA0003608794920000043
Figure BDA0003608794920000044
-CONH- (C1-C6 alkylene) Re,
Figure BDA0003608794920000045
Wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano;
Ar7selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 4-6 membered cycloalkyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, - (CH)2)m14-CO2R41、-CONR42R43、-SO2NR44R45、-(CH2)m15-SO3R46C1-C4 alkyl, C1-C4 alkoxy;
Rhselected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group; wherein said substitution is by one or more groups selected from the group consisting of: halogen, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, -SO2OR15Oxo group
Figure BDA0003608794920000046
Hydroxy, - (CH)2)m16-CO2R47；
Ar8Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methanesulfonyl, trifluoromethyl, - (CH)2)m17-CO2R48、-CONR49R50、-SO2NR51R52、-(CH2)m18-SO3R53C1-C4 alkyl, C1-C4 alkoxy;
Riselected from substituted or unsubstituted C1-C6 alkyl, carboxyl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, amino, carboxyl, cyano, nitro;
Ar9selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, nitro, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy;
Ar10selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methylsulfonyl, trifluoromethyl, - (CH)2)m19-CO2R54、-CONR55R56、-SO2NR57R58、-(CH2)m20-SO3R59C1-C4 alkyl, C1-C4 alkoxy;
R35-R59each independently selected from a hydrogen atom or a C1-C4 alkyl group;
n5 is 1,2 or 3; n6 is 1,2 or 3; n7 is 0,1, 2,3 or 4;
n8 is 0,1 or 2; n9 is 0,1 or 2;
m12-m20 are each independently 0,1 or 2;
Ra、Re、Ar5、n4、A1、A2、A3、A4、A5、E1、E2the definition is the same as before.
In another preferred embodiment, the compound has a structure represented by formula (I-2):
Figure BDA0003608794920000051
in the formula, Ry1Is composed of
Figure BDA0003608794920000052
Ar11Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, - (CH)2)m21-CO2R60、-CONR61R62、-SO2NR63R64、-(CH2)m22-SO3R65C1-C3 alkyl, C1-C3 alkoxy;
R60-R65each independently selected from a hydrogen atom or a C1-C4 alkyl group;
n10 is 0,1, 2 or 3;
m21 and m22 are each independently 0,1 or 2;
Ra、A1、A2、A3、A4、A5the definition of (1) is as before.
In another preferred embodiment, the compound has a structure represented by the formula (I-3):
Figure BDA0003608794920000053
wherein R isa、A1、A2、A3、A4、A5The definition of (1) is as before;
Figure BDA0003608794920000054
represents a single bond or a double bond, whereiny2The attached carbon atoms cannot participate in the formation of two double bonds at the same time;
Rx2and Rz2One of which is absent and the other is H,
Figure BDA0003608794920000055
Substituted or unsubstituted C1-C6 alkyl; ar (Ar)12Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, - (CH)2)m23-CO2R66、-CONR67R68、-SO2NR69R70、-(CH2)m24-SO3R71C1-C4 alkyl, C1-C4 alkoxy, 5-6 membered heteroaryl, 3-8 membered heterocyclyl, -NH2(C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;
Ry2selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted
Figure BDA0003608794920000061
Ar13Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: oxo radical
Figure BDA0003608794920000062
Halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, - (CH)2)m25-CO2R72、-CONR73R74、-SO2NR75R76、-(CH2)m26-SO3R77C1-C4 alkyl, C1-C4 alkoxy, 5-6 membered heteroaryl, 3-8 membered heterocyclyl, -NH2(C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino, -NHCOC1-C4 alkyl;
R66-R77each independently selected from a hydrogen atom or a C1-C4 alkyl group;
n11 is 0,1, 2 or 3; n12 is 0,1, 2 or 3; m23 to m26 are each independently 0,1 or 2.
In another preferred embodiment, A1、A2、A3、A4And A5Each independently is represented by CRbOr N, wherein RbEach occurrence is independently selected from the group consisting of: hydrogen atom, halogen, cyano, nitro, hydroxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, -NR1R2、-CO2R3Substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C5-C6 cycloalkenyl, substituted or unsubstituted C5-C8 heterocycloalkyl, substituted or unsubstituted C5-C6 heterocycloalkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; or two adjacent RbForm, with the carbon atom to which it is attached, a substituted or unsubstituted phenyl, a substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, nitro, hydroxy, carboxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, -NH2(C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;
at each occurrence, R1、R2、R3Each independently selected from a hydrogen atom or a C1-C4 alkyl group.
In another preferred embodiment, X, Y, Z are each independently CRcOr NRdAnd forms a five-membered heteroaromatic ring with two carbon atoms of the benzene ring;
under the condition of valence bond permission, RcEach occurrence is independently selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-to 6-membered heteroaryl group, a carboxyl group, -CONH- (C1-C6 alkylene) Re, a,
Figure BDA0003608794920000063
Substituted or unsubstituted
Figure BDA0003608794920000064
Wherein said substitution means substitution by one or more groups selected from the group consisting of: halogen, oxo radical
Figure BDA0003608794920000065
Hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl,5-6 membered heteroaryl, - (CH)2)m1-CO2R6、-(CH2)m2-SO3R7、-SO2NR8R9、-NR8R9-NHCOC1-C4 alkyl;
Ar1selected from the group consisting of: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, - (CH)2)m3-CO2R10、-CONR11R12、-SO2NR13R14、-(CH2)m4-SO3R15C1-C4 alkyl, C1-C4 alkoxy;
Reselected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group; wherein said substitution is by one or more groups selected from the group consisting of: halogen, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, -SO2OR15Oxo group
Figure BDA0003608794920000066
Hydroxy, methanesulfonyl, trifluoromethyl, - (CH)2)m5-CO2R16；
Ar2Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methylsulfonyl, trifluoromethyl, - (CH)2)m6-CO2R17、-CONR18R19、-SO2NR20R21、-(CH2)m7-SO3R22C1-C4 alkyl, C1-C4 alkoxy;
Rfis substituted or unsubstituted C1-C4 alkyl or carboxy; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, amino, carboxyl, cyano, nitro;
Ar3selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution by one or more groups selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, nitro, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy;
Ar4selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methylsulfonyl, trifluoromethyl, - (CH)2)m8-CO2R23、-CONR24R25、-SO2NR26R27、-(CH2)m9-SO3R28C1-C4 alkyl, C1-C4 alkoxy;
under the condition of valence bond permission RdEach occurrence is independently selected from the group consisting of: absent, a hydrogen atom, a substituted or unsubstituted C1-C4 alkyl group,
Figure BDA0003608794920000071
Wherein said substitution is by one or more groups selected from the group consisting of: halogen, - (CH)2)m8-CO2R23Cyano, nitro, hydroxy, oxo
Figure BDA0003608794920000072
-NH2Methanesulfonyl, sulfonic acid, aminosulfonyl, (C1-C4) alkoxy, (C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;
Ar5selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, - (CH)2)m10-CO2R29、-CONR30R31、-SO2NR32R33、-(CH2)m11-SO3R34C1-C4 alkyl, C1-C4 alkoxy;
R1-R34、n1-n4、m1-m11、E1、E2the definition is the same as before.
In another preferred embodiment, the compound is selected from any one of the compounds listed in the examples tables.
In a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the first aspect, a stereoisomer, enantiomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
In a third aspect of the invention, there is provided the use of a compound of the first aspect, a stereoisomer, enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the second aspect, for the preparation of an inhibitor of the interaction of TEAD with YAP; or for the preparation of a medicament for the prevention and/or treatment of a disease associated with a nuclear transcription factor TEAD mediated disease; or for non-therapeutically reversing the resistance of tumor cells to anti-tumor drugs; or used for preparing the medicine for reversing the drug resistance of the tumor cells to the antitumor medicine.
In another preferred embodiment, the inhibitor of TEAD interaction with YAP is used for the prevention and/or treatment of cancer.
In another preferred embodiment, the nuclear transcription factor TEAD-mediated related disease is cancer.
In another preferred embodiment, the cancer is selected from: multiple myeloma, squamous cell carcinoma, breast cancer, colon cancer, gastric cancer, non-small cell lung cancer, ovarian cancer.
In another preferred embodiment, said compound, its stereoisomer, enantiomer or a pharmaceutically acceptable salt thereof or said pharmaceutical composition is for use in blocking TEAD/YAP1 protein interactions.
In another preferred embodiment, said compound, its stereoisomer, enantiomer or a pharmaceutically acceptable salt thereof or said pharmaceutical composition is used for the preparation of a medicament for the treatment of cancer.
In another preferred embodiment, said compound, its stereoisomer, enantiomer or a pharmaceutically acceptable salt thereof or said pharmaceutical composition is used for preparing a medicament for treating gastric cancer.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows the inhibitory effect of compounds on CYR61, CTGF and CDX2 gene expression, wherein VP represents positive compound Verteporfin, QJ68 is the compound of example 4, and DMSO is a blank control without compound.
FIG. 2 shows the inhibitory effect of compounds on CYR61, CTGF and CDX2 gene expression, wherein VP represents positive compound Verteporfin, QJ156 is the compound of example 30, QK3 is the compound of example 31, and DMSO is a blank control without compound.
FIG. 3 shows the inhibition of CTGF gene expression by compounds wherein VP represents the positive compound Verteporfin, LYA95 is the compound of example 86, LYA102 is the compound of example 87, and DMSO is the blank without compound.
FIG. 4 shows the inhibitory effect of compounds on CYR61 and CDX2 gene expression, wherein VP represents positive compound Verteporfin, FC3-2 is the compound of example 97, and DMSO is a blank control without compound.
Detailed Description
After long-term and intensive research, the inventors of the present invention unexpectedly found that the compound of the present invention can inhibit the TEAD/YAP1 interaction and regulate the TEAD-mediated gene expression in tumor cells, and thus can be used for preventing and treating diseases related to the TEAD/YAP1 interaction, such as cancer. Based on the above findings, the inventors have completed the present invention.
Synthesis method
1. Synthesis method of compound intermediates S1 and S1a
The method comprises the following steps: a method for synthesizing a compound S1.
Figure BDA0003608794920000081
1) In a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1,4-dioxane/water, DMF/water, etc.) over a suitable palladium catalyst (e.g., pd (PPh)3)4、Pd(dppf)Cl2-CH2Cl2、Pd2(dba)3、Pd(OAc)2Pd/C, etc.) and a base (e.g., na)2CO3、K2CO3、NaOH、Et3N, etc.) and taking the compound S2 and the compound S3 as raw materials to obtain a compound S4 by utilizing a Suzuki coupling reaction;
2) Reacting the compound S4 with hydrazine hydrate in a proper solvent (such as n-butanol) at a proper reaction temperature (such as oil bath heating reflux and microwave heating reflux) to generate a compound S1;
wherein, A3= CRb；RbIs a single substituent such as F atom, chlorine atom, C1-C4 alkyl, C1-C4 alkoxy, etc.;
r represents OH, or two R together with the linking B atom represent pinacolboronic acid ester,
Figure BDA0003608794920000082
-BF3K, et al, can facilitate the Suzkuki coupling reaction of S3.
Ra, rb, A1, A2, A3, A4, A5 are as defined above.
In the general formula S1, with A3= CRbThe intermediate S1a is described as a representative. In the specific implementation process, the synthesis method of S1 and S1a is also suitable for any unit of A1/A2/A4/A5 to represent CRb。
Figure BDA0003608794920000091
The second method comprises the following steps: a method for synthesizing a compound S1a.
Figure BDA0003608794920000092
1) In a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1,4-dioxane/water, DMF/water, etc.) over a suitable palladium catalyst (e.g., pd (PPh)3)4、Pd(dppf)Cl2-CH2Cl2、Pd2(dba)3、Pd(OAc)2Pd/C, etc.) and a base (e.g., na)2CO3、K2CO3、NaOH、Et3N, etc.) to contain RbTaking a compound S5 and a compound S6 of the groups as raw materials, and obtaining a compound S7 through a Suzuki coupling reaction;
2) In a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1,4-dioxane/water, DMF/water, etc.) over a suitable palladium catalyst (e.g., pd (PPh)3)4、Pd(dppf)Cl2-CH2Cl2、Pd2(dba)3、Pd(OAc)2Pd/C, etc.) and a base (e.g., na)2CO3、K2CO3、NaOH、Et3N, etc.), reacting the compound S7 with a diboron acid pinacol ester to obtain a compound S8;
3) In a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1,4-dioxane/water, DMF/water, etc.) over a suitable palladium catalyst (e.g., pd (PPh)3)4、Pd(dppf)Cl2-CH2Cl2、Pd2(dba)3、Pd(OAc)2Pd/C, etc.) and a base (e.g., na)2CO3、K2CO3、NaOH、Et3N, etc.) and taking the compound S8 and the compound S2 as raw materials to obtain a compound S9 through a Suzuki coupling reaction;
4) Reacting compound S9 with hydrazine hydrate in a suitable solvent (such as n-butanol) to produce compound S1a;
wherein Ra, rb, A1, A2, A3, A4 and A5 are as defined above;
the definition of R is consistent with that of method one.
The third method comprises the following steps: a method for synthesizing a compound S9.
Figure BDA0003608794920000101
1) In a suitable solvent (e.g., 1,4-dioxane) over a palladium catalyst (e.g., pd (dppf) Cl)2-CH2Cl2) Under the action, reacting the compound S2 with the diboron acid pinacol ester to obtain a compound S10;
2) In a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1,4-dioxane/water, DMF/water, etc.) over a suitable palladium catalyst (e.g., pd (PPh)3)4、Pd(dppf)Cl2-CH2Cl2、Pd2(dba)3、Pd(OAc)2Pd/C, etc.) and a base (e.g., na)2CO3、K2CO3、NaOH、Et3N, etc.), compound S9 can also be prepared by Suzuki coupling reaction using compound S7 and compound S10 as starting materials;
wherein Ra, rb, A1, A2, A3, A4 and A5 are as defined above.
The method four comprises the following steps: a method for synthesizing a compound S9.
Figure BDA0003608794920000102
1) In a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1,4-dioxane/water, DMF/water, etc.) over a suitable palladium catalyst (e.g., pd (PPh)3)4、Pd(dppf)Cl2-CH2Cl2、Pd2(dba)3、Pd(OAc)2Pd/C, etc.) and a base (e.g., na)2CO3、K2CO3、NaOH、Et3N, etc.) and taking the compound S10 and the compound S11 as raw materials to obtain a compound S12 through a Suzuki coupling reaction;
2) In a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1,4-dioxane/water, DMF/water, etc) In a suitable palladium catalyst (e.g. Pd (PPh)3)4、Pd(dppf)Cl2-CH2Cl2、Pd2(dba)3、Pd(OAc)2Pd/C, etc.) and a base (e.g., na)2CO3、K2CO3、NaOH、Et3N, etc.) with the compound S12 and containing RbThe compound S5 is used as a raw material, and the compound S9 can also be prepared through a Suzuki coupling reaction;
wherein Ra, rb, A1, A2, A3, A4 and A5 are as defined above;
the definition of R is consistent with that of method one.
The method five comprises the following steps: a method for synthesizing a compound S9.
Figure BDA0003608794920000103
1) In a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1,4-dioxane/water, DMF/water, etc.) over a suitable palladium catalyst (e.g., pd (PPh)3)4、Pd(dppf)Cl2-CH2Cl2、Pd2(dba)3、Pd(OAc)2Pd/C, etc.) and a base (e.g., na)2CO3、K2CO3、NaOH、Et3N, etc.) and taking the compound S2 and the compound S13 as raw materials to obtain a compound S12 through a Suzuki coupling reaction;
2) In a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1,4-dioxane/water, DMF/water, etc.) over a suitable palladium catalyst (e.g., pd (PPh)3)4、Pd(dppf)Cl2-CH2Cl2、Pd2(dba)3、Pd(OAc)2Pd/C, etc.) and a base (e.g., na)2CO3、K2CO3、NaOH、Et3N, etc.) with a compound S12 and a compound containing RbThe compound S5 is used as a raw material, and the compound S9 can also be prepared through a Suzuki coupling reaction;
wherein Ra, rb, A1, A2, A3, A4 and A5 are as defined above;
the definition of R is consistent with that of method one.
The method six: a method for synthesizing a compound S1a.
Figure BDA0003608794920000111
1) Reacting the compound S2 with hydrazine hydrate in a proper solvent (such as n-butanol) at a proper reaction temperature (such as oil bath heating reflux and microwave heating reflux) to generate a compound S14;
2) In a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1,4-dioxane/water, DMF/water, etc.) over a suitable palladium catalyst (e.g., pd (PPh)3)4、Pd(dppf)Cl2-CH2Cl2、Pd2(dba)3、Pd(OAc)2Pd/C, etc.) and a base (e.g., na)2CO3、K2CO3、NaOH、Et3N, etc.), the compound S14 and the compound S8 are subjected to Suzuki coupling reaction to obtain a compound S1a;
wherein Ra, rb, A1, A2, A3, A4 and A5 are as defined above.
2. Methods for synthesizing the final product I-1 include, but are not limited to, methods seven, eight, nine, ten, eleven.
The method comprises the following steps:
Figure BDA0003608794920000112
1) In a suitable solvent (1,2-dichloroethane) in a suitable reducing agent (e.g., naBH (OAc)3、NaBH3CN、NaBH4、BH3) Under the action, a compound S1a and a compound S21 are used as raw materials, and a compound I-1a is obtained through reductive amination;
2) Hydrolyzing the reductive amination product I-1a in a proper solvent (tetrahydrofuran/methanol/water) by using proper alkali (LiOH, naOH or the like) to obtain a final product I-1;
wherein step 2 is carried out only when the carboxylic ester which is not hydrolyzed is contained in I-1a;
Rs1selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl,
Figure BDA0003608794920000113
Figure BDA0003608794920000121
Wherein said substitution means substitution by one or more groups selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano;
Ars1selected from the group consisting of substituted or unsubstituted: phenyl, 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, - (CH)2)q1-CO2Rt1、-CONRt2Rt3、-SO2NRt4Rt5、-(CH2)q2-SO3Rt6Trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy;
Ars2selected from the group consisting of substituted or unsubstituted: phenyl, 5-6 membered heteroaryl; wherein said substitution means substitution by one or more groups selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, nitro, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy;
Rs2selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group; wherein said substitution means substitution by one or more groups selected from the group consisting of: halogen, hydroxy, amino, carboxyl, cyano, nitro;
Ws、Vsare N or O respectively; when W issOr VsWhen the unsubstituted form is complete, the hydrogen atom is used for filling;
Rt1-Rt6each independently is a hydrogen atom or a C1-C4 alkyl group;
p1 is 0,1, 2 or 3;
q1 and q2 are each independently 0,1 or 2;
ra, rb, A1, A2, A3, A4, A5, rx1, rz1 are as defined above.
The method eight:
Figure BDA0003608794920000122
1) Carrying out metal-catalyzed C-N coupling reaction on the compound S1a and the compound S22 in a proper solvent (methanol/water) to generate a compound I-1C;
2) Hydrolyzing the compound I-1c with a suitable base (LiOH or NaOH, etc.) in a suitable solvent (tetrahydrofuran/methanol/water) to obtain a final product I-1;
wherein step 2 is performed only when the carboxylic ester is not hydrolyzed in I-1c;
Ars3selected from the group consisting of substituted or unsubstituted: phenyl, 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, nitro, trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy;
Ra、Rb、A1、A2、A3、A4、A5、Rx1、Rz1the definition of (1) is as before.
The method comprises the following steps:
Figure BDA0003608794920000131
1) In a suitable solvent (tetrahydrofuran), the compound S1a is reacted with Boc2O in alkali (e.g. DMAP, et)3N) to generate a compound S23;
2) In a suitable solvent (dichloromethane), a base (e.g. DMAP, et)3N) reacting the reaction compound S23 with an acylating agent S24 to produce a compound S25;
3) Reacting compound S25 with trifluoroacetic acid in a suitable solvent (dichloromethane) to produce compound S26;
4) Hydrolyzing the compound S26 with a suitable base (LiOH, naOH or the like) in a suitable solvent (tetrahydrofuran/methanol/water) to obtain a final product I-1;
wherein LG is1Is an atom or group which can be removed, such as chlorine atom, bromine atom, iodine atom, OTf, OSu, etc.;
Rs3is substituted or unsubstituted C1-C6 alkyl; wherein said substitution is by one or more groups selected from the group consisting of: oxo radical
Figure BDA0003608794920000132
Hydroxyl, amino, carboxyl, cyano, nitro;
Ra、Rb、A1、A2、A3、A4、A5、Rx1、Rz1the definition of (1) is as before.
The method comprises the following steps:
Figure BDA0003608794920000133
1) In a suitable solvent (N, N-dimethylformamide), in a suitable base (e.g. LiHMDS, naH, K)2CO3、Cs2CO3、Et3N), reacting the compound S1a with S27 to generate a compound S28;
2) In a suitable solvent (1,2-dichloroethane) in a suitable reducing agent (e.g., naBH (OAc)3、NaBH3CN、NaBH4、BH3) Under the action, the compound S27 and the compound S21 are subjected to reductive amination reaction to obtain a final product I-1;
wherein R iss1、Rs2Has the definition as described in method seven;
LG2is an atom or group which can be removed, such as chlorine atom, bromine atom, iodine atom, OTf, OSu, etc.;
Ra、Rb、A1、A2、A3、A4、A5、Rx1、Rz1the definition of (1) is as before;
the definition of R is consistent with that of method one.
The method eleven comprises the following steps:
Figure BDA0003608794920000141
1) In a suitable solvent (1,2-dichloroethane) in a suitable reducing agent (e.g., naBH (OAc)3、NaBH3CN、NaBH4、BH3) Under the action, the compound S1a and the compound S21 are subjected to reductive amination reaction to generate a compound S29;
2) In a suitable solvent (tetrahydrofuran), in a suitable base (e.g. DMAP, et)3N), reacting the compound S29 with the compound S30 to generate a compound S31;
3) In a proper solvent, removing a protecting group from the compound S31 to obtain a final product I-1;
wherein R isPGR substituted by a protecting groups1(ii) a When protected Rs1When the nitrogen group is contained, the protective group is an N protective group such as Boc, fmoc or Cbz; when protected Rs1When the compound contains a carboxylic ester structure, the protecting group is a carboxylic acid protecting group such as methyl, ethyl, tert-butyl, etc. for protecting a carboxylic acid;
Rs1and Rs2The definition is consistent with the definition in method seven;
ra, rb, A1, A2, A3, A4, A5, rx1, rz1 are as defined above.
3. Synthesis method of final product I-2
The method twelve:
Figure BDA0003608794920000142
1) In a suitable solvent (isopropanol) under the action of a suitable reagent (for example Bu)3P、Bu3P/orthoformate (EtO)3PO/orthoformate) with a compound S41 to produce a compound S43;
2) In a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1,4-dioxane/water, DMF/water, etc.) over a suitable palladium catalyst (e.g., pd (PPh)3)4、Pd(dppf)Cl2-CH2Cl2、Pd2(dba)3、Pd(OAc)2Pd/C, etc.) and a base(e.g., na)2CO3、K2CO3、NaOH、Et3N, etc.) and then carrying out Suzuki coupling reaction by using a compound S43 and a compound S8 as raw materials to obtain a compound S44;
3) Hydrolyzing the compound S44 with a suitable base (LiOH, naOH or the like) in a suitable solvent (tetrahydrofuran/methanol/water) to obtain a final product I-2;
wherein X is a leaving atom or group such as chlorine atom, bromine atom, iodine atom, OTf and the like;
Rs4is composed of
Figure BDA0003608794920000151
Substituted or unsubstituted C1-C6 alkyl;
Ars3is a substituted or unsubstituted group of the following group: phenyl, 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, - (CH)2)q3-CO2Rt7、-CONRt8Rt9、-SO2NRt10Rt11、-(CH2)q4-SO3Rt12Trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy;
Rt7-Rt12each independently is a hydrogen atom or a C1-C4 alkyl group;
p2 is 0,1, 2 or 3;
q3 and q4 are each independently 0,1 or 2;
r, ra, rb, A1, A2, A3, A4, A5 and Ry1 are as defined above;
the definition of R is consistent with that of method one.
4. Synthesis method of compound intermediates S54-1, S54-2 and S54-3
The method thirteen comprises the following steps:
Figure BDA0003608794920000152
1) Reacting the compound S51 with an aldehyde group-containing compound S52 in a proper solvent (such as ethanol) under the action of a proper acid or an oxidizing agent (p-toluenesulfonic acid and sodium pyrosulfate) to generate compounds S53 and S54;
wherein X is a leaving atom or group such as chlorine atom, bromine atom, iodine atom, OTf and the like;
Rs5is composed of
Figure BDA0003608794920000153
Substituted or unsubstituted C1-C6 alkyl;
Ars4selected from the group consisting of substituted or unsubstituted: phenyl, 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, - (CH)2)m23-CO2R66、-CONR67R68、-SO2NR69R70、-(CH2)m24-SO3R71C1-C4 alkyl, C1-C4 alkoxy, 5-6 membered heteroaryl, 3-8 membered heterocyclyl, -NH2Di (C1-C4 alkyl) amino, (C1-C4 alkyl) amino;
R66-R71each independently is a hydrogen atom or a C1-C4 alkyl group;
p3 is 0,1 or 2;
ra is as defined above.
The method is fourteen:
Figure BDA0003608794920000154
1) In a suitable solvent (e.g. N, N-dimethylformamide, DMSO), in a suitable base (e.g. LiHMDS, naH, K)2CO3、Cs2CO3、Et3N), reacting the compound S53 with the compound S55 to generate a compound S56;
wherein, LG3Is bromine atom, iodine atom, OMs, OTs or other easy-to-leave atom or group;
x is an atom or a group which can be separated, such as a chlorine atom, a bromine atom, an iodine atom, OTf and the like;
Rs6is composed of
Figure BDA0003608794920000161
Substituted or unsubstituted C1-C6 alkyl; (ii) a
Ars5Selected from the group consisting of substituted or unsubstituted: phenyl, 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methanesulfonyl, trifluoromethyl, - (CH)2)m25-CO2R72、-CONR73R74、-SO2NR75R76、-(CH2)m26-SO3R77C1-C4 alkyl, C1-C4 alkoxy, 5-6 membered heteroaryl, 3-8 membered heterocyclyl, -NH2(C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;
R66-R77 are each independently selected from a hydrogen atom or a C1-C4 alkyl group;
m23-m26 are each independently 0,1 or 2;
p4 is 1,2 or 3;
Rs5the definition is consistent with that of method thirteen, previously described. Ra is as defined above.
5. Synthesis method of final product I-3
Fifteen steps of the method:
Figure BDA0003608794920000162
1) In a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1,4-dioxane/water, DMF/water, etc.) over a suitable palladium catalyst (e.g., pd (PPh)3)4、Pd(dppf)Cl2-CH2Cl2、Pd2(dba)3、Pd(OAc)2Pd/C, etc.) and a base (e.g., na)2CO3、K2CO3、NaOH、Et3N, etc.), the compound S53, S54 or S56 and the compound S8 undergo a Suzuki coupling reaction to produce a compound S57;
2) Hydrolyzing the compound S57 with a suitable base (LiOH or NaOH, etc.) in a suitable solvent (tetrahydrofuran/methanol/water) to obtain a final product I-3;
wherein R iss8Is H, -CH2-RS5Or Rs6；
Ra、A1、A2、A3、A4、A5、Rx2、Ry2、Rz2The definition of (1) is as before;
the definition of R is consistent with that of method one.
General synthetic method for intermediate synthesis:
general synthetic method 1, see synthetic intermediate 1;
general synthetic method 2, see synthetic intermediate 8;
general synthetic method 3, see synthetic intermediate 19;
general synthetic method 4, see synthetic intermediate 21;
general synthetic method 5, see synthetic intermediate 22;
general synthetic method 10, see synthetic intermediate 38;
general synthetic method 11, see synthetic intermediate 42.
Examples general procedure was synthesized:
general synthetic method 6, see example 1;
general synthetic method 7, see example 26;
general synthetic procedure 8, see example 35;
general synthetic method 9, see example 89;
general synthetic method 12, see example 138;
general synthetic method 13, see example 92;
general synthetic method 14, see example 133;
general synthetic procedure 15, see example 140. The following compounds can be synthesized by using commercially available raw materials as substrates and reagents according to the above-mentioned method:
synthesis of intermediate 1:4- (4-chlorophenyl) -1H-indazol-3-amine (QJ 50)
Figure BDA0003608794920000171
The general method comprises the following steps:
the method comprises the following steps: synthesis of 4 '-chloro-3-fluoro- [1,1' -biphenyl ] -2-carbonitrile (QJ 49)
2-bromo-6-fluorobenzonitrile (200 mg) and (4-chlorophenyl) boronic acid (357 mg) were added to a round bottom flask, ethylene glycol dimethyl ether (10 mL) and aqueous sodium carbonate solution (2M, 5 mL) were added, oxygen was removed from the reaction solution, and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (80 mg) was added to the reaction solution, and oxygen was removed again, and the temperature was raised to 90 ℃ and the reaction solution was stirred overnight. After the reaction is finished, the reaction product is cooled to room temperature, water is added to quench the reaction product, the water phase is extracted for 3 times by ethyl acetate, the organic phases are combined, the mixture is washed by saturated saline solution, dried by anhydrous sodium sulfate, concentrated by a rotary evaporator and purified by a silica gel column to obtain the target compound 219mg.1H NMR(400MHz,Chloroform-d)δ7.64(td,J＝8.17,5.75Hz,1H),7.52–7.43(m,4H),7.30–7.15(m,3H),6.79–6.73(m,1H)。
Step two: synthesis of 4- (4-chlorophenyl) -1H-indazol-3-amine (QJ 50)
QJ49 (219 mg) was put in an eggplant type flask, and n-butanol (10 mL) and hydrazine hydrate (85%, 5 mL) were added to the flask, and the mixture was stirred overnight while the temperature was raised to 110 ℃. After the reaction, the reaction mixture was cooled to room temperature, concentrated by a rotary evaporator, and purified by a silica gel column to obtain 207mg of the target compound.1H NMR(400MHz,Methanol-d4)δ7.52–7.46(m,4H),7.37–7.30(m,2H),6.88(dd,J＝6.14,1.71Hz,1H)。
Synthesis of intermediate 2:4- (3-chlorophenyl) -1H-indazol-3-amine (QJ 55)
Figure BDA0003608794920000172
Using 2-bromo-6-fluorobenzonitrile (200 mg) and (4-chlorophenyl) boronic acid (357 mg) as starting materials, 243mg of the objective compound was obtained according to general procedure one.1H NMR(400MHz,Methanol-d4)δ7.47–7.27(m,6H),6.81(dd,J＝5.76,2.09Hz,1H)。
Synthesis of intermediate 3: 4-phenyl-1H-indazol-3-amine (QJ 59)
Figure BDA0003608794920000173
Using 2-bromo-6-fluorobenzonitrile (2000 mg) and phenylboronic acid (1342 mg) as starting materials, 1943mg of the objective compound was obtained according to general method one.1H NMR(500MHz,Chloroform-d)δ7.55–7.46(m,4H),7.46–7.40(m,1H),7.37(dd,J＝8.34,7.01Hz,1H),7.30(d,J＝8.40Hz,1H),6.95(d,J＝6.97Hz,1H)。
Synthesis of intermediate 4:4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (QJ 65)
Figure BDA0003608794920000181
Starting from 2-bromo-6-fluorobenzonitrile (500 mg) and (4- (tert-butyl) phenyl) boronic acid (490 mg), according to general procedure one, 644mg of the title compound was obtained.1H NMR(400MHz,Chloroform-d)δ7.51(d,J＝8.43Hz,1H),7.46(d,J＝8.41Hz,1H),7.36(dd,J＝8.41,6.97Hz,1H),7.31–7.26(m,1H),6.95(d,J＝6.95Hz,1H),1.39(s,9H)。
Synthesis of intermediate 5:4- (3- (tert-butyl) phenyl) -1H-indazol-3-amine (QJ 66)
Figure BDA0003608794920000182
Starting from 2-bromo-6-fluorobenzonitrile (500 mg) and (3- (tert-butyl) phenyl) boronic acid (490 mg), 384mg of the title compound was obtained according to general procedure one.1H NMR(400MHz,Chloroform-d)δ7.59(t,J＝1.84Hz,1H),7.51–7.41(m,2H),7.36(dd,J＝8.43,6.77Hz,2H),7.30(dd,J＝8.46,1.00Hz,1H),6.98(dd,J＝6.94,1.00Hz,1H),1.40(s,9H)。
Synthesis of intermediate 6:4- (Naphthalen-2-yl) -1H-indazol-3-amine (QJ 71)
Figure BDA0003608794920000183
By 2-bromo-6-Fluorobenzonitrile (500 mg) and naphthalen-2-ylboronic acid (473 mg) were used as starting materials to obtain 234mg of the objective compound according to general procedure one.1H NMR(500MHz,Chloroform-d)δ8.02–7.95(m,2H),7.92(dq,J＝7.36,2.52,2.11Hz,2H),7.67(dd,J＝8.40,1.76Hz,1H),7.59–7.51(m,2H),7.41(dd,J＝8.40,6.96Hz,1H),7.34(d,J＝8.39Hz,1H),7.05(d,J＝6.92Hz,1H)。
Synthesis of intermediate 7:4- (1H-indol-5-yl) -1H-indazol-3-amine (QJ 72)
Figure BDA0003608794920000191
Starting from 2-bromo-6-fluorobenzonitrile (500 mg) and (1H-indol-5-yl) boronic acid (668 mg), the expected compound (736 mg) was obtained according to general procedure one.1H NMR(400MHz,Methanol-d4)δ7.70–7.53(m,3H),7.44–7.33(m,2H),7.22(dd,J＝8.29,1.74Hz,1H),7.11(d,J＝7.10Hz,1H),6.55(d,J＝3.15Hz,1H)。
Synthesis of intermediate 8:4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QJ 99)
Figure BDA0003608794920000192
The general method II comprises the following steps:
the method comprises the following steps: synthesis of 4 '-bromo-3-fluoro- [1,1' -biphenyl ] -2-carbonitrile (QJ 92)
2-fluoro-6-iodobenzonitrile (1 g) and (4-bromophenyl) boronic acid (810 mg) were charged in a round bottom flask, ethylene glycol dimethyl ether (10 mL) and aqueous sodium carbonate solution (2M, 5 mL) were added, oxygen was removed from the reaction solution, and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (326 mg) was added to the reaction solution, and oxygen was again removed, and the reaction solution was heated to 90 ℃ and stirred overnight. After the reaction is finished, cooling to room temperature, adding water to quench the reaction, extracting the water phase for 3 times by using ethyl acetate, combining the organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, concentrating by using a rotary evaporator, and purifying by using a silica gel column to obtain 956mg of a target compound.1H NMR(500MHz,Chloroform-d)δ7.67–7.61(m,3H),7.46–7.41(m,2H),7.29(dd,J＝7.93,1.00Hz,1H),7.23(td,J＝8.47,1.01Hz,1H)。
Step two: synthesis of 3-fluoro-2 ",3",4",5" -tetrahydro- [1,1':4', 1' -Triterphenyl ] -2-carbonitrile (QJ 95)
QJ92 (485 mg) and cyclohex-1-en-1-ylboronic acid (244 mg) were charged into a round bottom flask, ethylene glycol dimethyl ether (10 mL) and aqueous sodium carbonate solution (2M, 5 mL) were added, oxygen was removed from the reaction solution, and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (163 mg) was added to the reaction solution, and oxygen was again removed, and the temperature was raised to 90 ℃ and the reaction solution was stirred overnight. After the reaction is finished, the reaction product is cooled to room temperature, water is added to quench the reaction product, the water phase is extracted for 3 times by ethyl acetate, the organic phases are combined, the mixture is washed by saturated saline solution, dried by anhydrous sodium sulfate, concentrated by a rotary evaporator and purified by a silica gel column to obtain 432mg of a target compound.1H NMR(500MHz,Chloroform-d)δ7.60(td,J＝8.16,5.87Hz,1H),7.51(d,J＝0.97Hz,4H),7.31(dd,J＝7.81,1.02Hz,1H),7.17(td,J＝8.52,1.01Hz,1H),6.24(tq,J＝4.00,1.97Hz,1H),2.45(tq,J＝6.21,2.29Hz,2H),2.25(ddt,J＝8.53,6.33,2.70Hz,2H),1.82(dtt,J＝8.85,6.14,3.39Hz,2H),1.69(dhept,J＝9.27,3.41Hz,2H)。
Step three: synthesis of 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QJ 99)
QJ95 (432 mg) was put into an eggplant type flask, and n-butanol (10 mL) and hydrazine hydrate (85%, 5 mL) were added to the flask, and the mixture was stirred overnight at 110 ℃. After the reaction, the reaction mixture was cooled to room temperature, concentrated by a rotary evaporator, and purified by a silica gel column to obtain 356mg of the objective compound.1H NMR(500MHz,Chloroform-d)δ7.53–7.48(m,2H),7.48–7.44(m,2H),7.36(dd,J＝8.40,6.99Hz,1H),7.28(dd,J＝8.41,0.91Hz,1H),6.95(dd,J＝7.02,0.88Hz,1H),6.24(tt,J＝3.92,1.73Hz,1H),2.47(tq,J＝6.42,2.32Hz,2H),2.25(ddt,J＝8.70,6.56,2.99Hz,2H),1.86–1.78(m,2H),1.73–1.65(m,2H)。
Synthesis of intermediate 9:4- ([ 1,1' -biphenyl ] -4-yl) -1H-indazole-3-amine (QJ 125)
Figure BDA0003608794920000201
4' -bromo-3-fluoro- [1,1-Biphenyl]Starting from (E) -2-carbonitrile (230 mg) and phenylboronic acid (122 mg), according to general procedure II, 183mg of the objective compound was obtained.1H NMR(500MHz,Chloroform-d)δ7.75–7.71(m,2H),7.69–7.65(m,2H),7.63–7.59(m,2H),7.48(dd,J＝8.31,7.07Hz,2H),7.42–7.36(m,2H),7.32(dd,J＝8.39,0.87Hz,1H),7.00(dd,J＝6.98,0.92Hz,1H)。
Synthesis of intermediate 10:5- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (QJ 89)
Figure BDA0003608794920000202
Starting from 5-bromo-2-fluorobenzonitrile (500 mg) and (4- (tert-butyl) phenyl) boronic acid (490 mg), the title compound (642 mg) was obtained in accordance with general procedure one.1H NMR(500MHz,Chloroform-d)δ7.74(dd,J＝1.65,0.79Hz,1H),7.62(dd,J＝8.69,1.67Hz,1H),7.58–7.52(m,2H),7.49–7.44(m,2H),7.36(dd,J＝8.60,0.82Hz,1H),1.38(s,9H)。
Synthesis of intermediate 11:5- (3- (tert-butyl) phenyl) -1H-indazol-3-amine (QJ 90)
Figure BDA0003608794920000203
Starting from 5-bromo-2-fluorobenzonitrile (500 mg) and (3- (tert-butyl) phenyl) boronic acid (490 mg), the expected compound was obtained in an amount of 641mg according to general procedure one.1H NMR(500MHz,Chloroform-d)δ7.74(dd,J＝1.64,0.84Hz,1H),7.64–7.60(m,2H),7.45–7.35(m,4H),1.40(s,9H)。
Synthesis of intermediate 12:4- (4-isopropylphenyl) -1H-indazol-3-amine (QJ 98)
Figure BDA0003608794920000211
Starting from 2-bromo-6-fluorobenzonitrile (200 mg) and (4-isopropylphenyl) boronic acid (180 mg), 216mg of the title compound was obtained according to general procedure one.1H NMR(500MHz,Chloroform-d)δ7.47–7.42(m,2H),7.38–7.33(m,3H),7.28(dd,J＝8.42,0.89Hz,1H),6.94(dd,J＝7.01,0.89Hz,1H),3.00(h,J＝6.94Hz,1H),1.32(d,J＝6.95Hz,6H)。
Synthesis of intermediate 13:4- (4- (cyclopent-1-en-1-yl) phenyl) -1H-indazol-3-amine (QJ 100)
Figure BDA0003608794920000212
With 4 '-bromo-3-fluoro- [1,1' -biphenyl]Starting from (471 mg) 2-carbonitrile and phenylboronic acid (230 mg), according to general procedure II, 423mg of the title compound was obtained.1H NMR(500MHz,Chloroform-d)δ7.58–7.54(m,2H),7.50–7.46(m,2H),7.44(d,J＝8.09Hz,1H),7.31–7.28(m,1H),6.95(ddd,J＝6.69,5.76,0.97Hz,1H),6.29(p,J＝2.14Hz,1H),2.77(ddt,J＝9.95,6.70,2.25Hz,2H),2.58(ddd,J＝7.73,6.03,2.50Hz,2H),2.10–2.02(m,2H)。
Synthesis of intermediate 14:4- (4-Cyclohexylphenyl) -1H-indazol-3-amine (QJ 102)
Figure BDA0003608794920000213
4- (4- (cyclopent-1-en-1-yl) phenyl) -1H-indazol-3-amine (174 mg) was placed in a round bottom flask, methanol was added, the reaction solution was deoxygenated, palladium on carbon (40 mg) was added, the reaction solution was deoxygenated again, and the mixture was stirred overnight under a hydrogen atmosphere. After the reaction, the reaction mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated to obtain 163mg of the objective compound.1H NMR(500MHz,Chloroform-d)δ7.46–7.42(m,2H),7.38–7.31(m,3H),7.28(dd,J＝8.40,0.89Hz,1H),6.94(dd,J＝7.01,0.90Hz,1H),2.58(ddt,J＝11.62,6.95,3.41Hz,1H),2.00–1.85(m,4H),1.78(dtt,J＝12.63,3.15,1.46Hz,1H),1.53–1.38(m,4H),1.34–1.28(m,1H)。
Synthesis of intermediate 15:4- (4-Cyclopentylphenyl) -1H-indazol-3-amine (QJ 106)
Figure BDA0003608794920000221
4- (4- (cyclopentyl-1-ene)-1-yl) phenyl) -1H-indazol-3-amine (100 mg) was placed in an eggplant-shaped flask, methanol was added, the reaction solution was deoxygenated, palladium on carbon (20 mg) was added, the reaction solution was deoxygenated again, and the mixture was stirred overnight under a hydrogen atmosphere. After the reaction, the reaction mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated to obtain 100mg of the objective compound.1H NMR(500MHz,Methanol-d4)δ7.36–7.26(m,6H),6.81(dd,J＝5.87,1.98Hz,1H),3.02(tt,J＝9.62,7.43Hz,1H),2.06(dddd,J＝13.79,10.97,5.60,2.08Hz,2H),1.81(ddt,J＝11.33,9.58,5.80Hz,2H),1.74–1.65(m,2H),1.60(tdd,J＝12.00,9.45,5.02Hz,2H)。
Synthesis of intermediate 16:4- (4- (3-amino-1H-indazol-4-yl) phenyl) -3,6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (QJ 128)
Figure BDA0003608794920000222
With 4 '-bromo-3-fluoro- [1,1' -biphenyl]-2-carbonitrile (710 mg) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (877 mg) as starting materials gave 297mg of the title compound according to general procedure II.1H NMR(500MHz,Chloroform-d)δ7.50(s,4H),7.37(dd,J＝8.42,7.00Hz,1H),7.30(dd,J＝8.51,0.91Hz,1H),6.95(dd,J＝7.01,0.91Hz,1H),6.15(s,1H),4.15–4.09(m,2H),3.68(t,J＝5.54Hz,2H),2.59(s,2H),1.51(s,9H)。
Synthesis of intermediate 17:5- (4- (3-amino-1H-indazol-4-yl) phenyl) -3,6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (QJ 136)
Figure BDA0003608794920000223
With 4 '-bromo-3-fluoro- [1,1' -biphenyl]-2-carbonitrile (550 mg) and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (680 mg) were used as starting materials to give 216mg of the title compound, according to general procedure II.1H NMR(500MHz,Chloroform-d)δ7.50(s,4H),7.37(t,J＝7.65Hz,1H),7.30(d,J＝8.43Hz,1H),6.95(d,J＝6.81Hz,1H),6.32(s,1H),4.34(s,2H),3.59(s,2H),2.36 (s, 2H), 1.52 (s, 9H). Synthesis of intermediate 18:4- (4- (pyridin-4-yl) phenyl) -1H-indazol-3-amine (QJ 135)
Figure BDA0003608794920000231
With 4 '-bromo-3-fluoro- [1,1' -biphenyl]-2-Carbonitrile (275 mg) and pyridin-4-ylboronic acid (146 mg) were used as starting materials to give 224mg of the objective compound according to general method II.1H NMR(500MHz,Chloroform-d)δ8.72–8.69(m,2H),7.78(d,J＝8.30Hz,2H),7.65(d,J＝8.15Hz,2H),7.60–7.56(m,2H),7.41(dd,J＝8.43,6.94Hz,1H),7.36–7.33(m,1H),6.99(dd,J＝7.02,0.91Hz,1H)。
Synthesis of intermediate 19:4- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QJ 160)
Figure BDA0003608794920000232
The general method is three:
the method comprises the following steps: synthesis of 4' -bromo-3 ' -methoxy-2,3,4,5-tetrahydro-1,1 ' -biphenyl (QJ 148)
Adding cyclohex-1-en-1-ylboronic acid (126 mg) and 1-bromo-4-iodo-2-methoxybenzene (343 mg) into a round bottom flask, adding ethylene glycol dimethyl ether (10 mL) and aqueous sodium carbonate solution (2M, 5 mL), removing oxygen from the reaction solution, and adding [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (80 mg) was added to the reaction solution, and oxygen was removed again, and the temperature was raised to 90 ℃ and the reaction solution was stirred overnight. After the reaction, the reaction mixture was cooled to room temperature, water was added to quench the reaction mixture, the aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by a rotary evaporator, and purified by a silica gel column to obtain 263mg of the objective compound.1H NMR(500MHz,Chloroform-d)δ7.44(d,J＝8.20Hz,1H),6.92(d,J＝2.12Hz,1H),6.84(dd,J＝8.23,2.11Hz,1H),6.13(tt,J＝3.90,1.75Hz,1H),3.90(s,3H),2.39(tq,J＝6.48,2.28Hz,2H),2.21(tq,J＝5.24,2.63Hz,2H),1.84–1.75(m,2H),1.72–1.64(m,2H)。
Step two: synthesis of 2- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborane (QJ 149)
QJ148 (263 mg), pinacol diboron (318 mg) and potassium acetate (294 mg) were charged in a round bottom flask, 1,4-dioxane (10 mL) was added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (41 mg) was added to the reaction solution, and oxygen was removed again, and the temperature was raised to 90 ℃ and the reaction solution was stirred overnight. After the reaction, the reaction mixture was cooled to room temperature, water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified with silica gel column to obtain 294mg of the target compound.1H NMR(500MHz,Chloroform-d)δ7.59(d,J＝7.63Hz,1H),6.92(dd,J＝7.64,1.49Hz,1H),6.83(d,J＝1.48Hz,1H),6.13(tt,J＝3.88,1.71Hz,1H),3.82(s,3H),2.42–2.32(m,2H),2.17(th,J＝7.28,2.93,2.49Hz,2H),1.75(pd,J＝6.16,5.40,1.78Hz,2H),1.63(dtt,J＝8.49,5.71,2.38Hz,2H),1.31(s,12H)。
Step three: synthesis of 3-fluoro-2 '-methoxy-2 ",3",4",5" -tetrahydro- [1,1':4', 1' -Tribiphenylyl ] -2-carbonitrile (QJ 146)
QJ149 (294 mg) and 2-bromo-6-fluorobenzonitrile (238 mg) were charged in a round bottom flask, ethylene glycol dimethyl ether (10 mL) and aqueous sodium carbonate solution (2M, 5 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (90 mg), the reaction solution was deoxygenated again, warmed to 90 ℃ and stirred overnight. After the reaction is finished, cooling to room temperature, adding water to quench the reaction, extracting the water phase for 3 times by using ethyl acetate, combining the organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, concentrating by using a rotary evaporator, and purifying by using a silica gel column to obtain the target compound of 137mg.1H NMR(500MHz,Chloroform-d)δ7.63–7.60(m,1H),7.52(tdd,J＝6.62,5.05,1.31Hz,1H),7.28(dd,J＝7.80,1.02Hz,1H),7.23(dd,J＝7.58,2.06Hz,1H),7.18(td,J＝8.56,0.99Hz,1H),7.14–7.06(m,2H),6.26(tt,J＝3.94,1.70Hz,1H),3.91(s,3H),2.49(tq,J＝6.15,2.05Hz,2H),2.33–2.27(m,2H),1.89–1.80(m,2H),1.77–1.69(m,2H)。
Step four: synthesis of 4- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QJ 160)
QJ146 (137 mg) was put into an eggplant-shaped flask, and n-butanol (10 mL) and hydrazine hydrate (85%, 5 mL) were added thereto, and the mixture was heated to 110 ℃ and stirred overnight. After the reaction, the reaction mixture was cooled to room temperature, concentrated by a rotary evaporator, and purified by a silica gel column to obtain 89mg of the target compound.1H NMR(500MHz,Chloroform-d)δ7.33(dd,J＝8.42,6.96Hz,1H),7.26–7.20(m,2H),7.13–7.09(m,1H),7.06(d,J＝1.61Hz,1H),6.92(t,J＝5.56Hz,1H),6.25(tt,J＝3.86,1.67Hz,1H),3.77(s,3H),2.49(tt,J＝6.23,1.75Hz,2H),2.27(tt,J＝6.12,3.01Hz,2H),1.87–1.80(m,2H),1.75–1.68(m,2H)。
Synthesis of intermediate 20:4- (2-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 13)
Figure BDA0003608794920000241
Using cyclohex-1-en-1-ylboronic acid (500 mg) and 4-bromo-1-iodo-2-methoxybenzene (1360 mg) as starting materials, 314mg of the title compound was obtained by reference to general procedure three.1H NMR(500MHz,Chloroform-d)δ7.37(dd,J＝8.40,7.00Hz,1H),7.29(dd,J＝8.04,0.78Hz,1H),7.24(d,J＝7.63Hz,1H),7.05(dd,J＝7.60,1.66Hz,1H),7.02(d,J＝1.63Hz,1H),6.98(dd,J＝7.01,0.91Hz,1H),5.87(tt,J＝3.74,1.73Hz,1H),3.86(s,3H),2.42(tt,J＝6.34,2.27Hz,2H),2.23(dtd,J＝8.65,6.00,3.21Hz,2H),1.81–1.67(m,4H)。
Synthesis of intermediate 21:4- (3-ethoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 79)
Figure BDA0003608794920000251
The general method comprises the following steps:
the method comprises the following steps: synthesis of 2-bromo-5-iodophenol (QK 51)
1-bromo-4-iodo-2-methoxybenzene (1 g) was charged into an eggplant-shaped flask, and methylene chloride (20 mL) was added thereto, and then the mixture was cooled to-78 ℃ and a solution of boron tribromide in methylene chloride (1M, 10mL) was added dropwise thereto. Stirring at-78 deg.C for 2 hr, naturally heating to room temperature, and stirringStirring overnight. After the reaction, the reaction mixture was slowly poured into ice water, the aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by a rotary evaporator, and purified with a silica gel column to obtain 948mg of the target compound.1H NMR(500MHz,Chloroform-d)δ7.37(d,J＝1.96Hz,1H),7.16(d,J＝8.37Hz,1H),7.13(dd,J＝8.36,1.95Hz,1H),5.50(s,1H)。
Step two: synthesis of 4-bromo-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -3-ol (QK 55)
QK51 (500 mg) and cyclohex-1-en-1-ylboronic acid (192 mg) were charged into a round bottom flask, ethylene glycol dimethyl ether (10 mL) and aqueous sodium carbonate solution (2M, 5 mL) were added, oxygen was removed from the reaction solution, and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (80 mg) was added to the reaction solution, and oxygen was removed again, and the temperature was raised to 90 ℃ and the reaction solution was stirred overnight. After the reaction, the reaction mixture was cooled to room temperature, water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by a rotary evaporator, and purified by a silica gel column to obtain 451mg of the target compound.1H NMR(500MHz,Chloroform-d)δ7.36(d,J＝8.37Hz,1H),7.04(d,J＝2.17Hz,1H),6.85(dd,J＝8.39,2.21Hz,1H),6.13(tq,J＝3.46,1.71Hz,1H),2.35(tq,J＝6.23,2.33Hz,2H),2.19(ddt,J＝8.47,6.30,2.72Hz,2H),1.77(dtt,J＝8.84,6.14,2.75Hz,2H),1.68–1.62(m,2H)。
Step three: synthesis of 4' -bromo-3 ' -ethoxy-2,3,4,5-tetrahydro-1,1 ' -biphenyl (QK 72)
QK55 (100 mg) was placed in an eggplant type flask, N-dimethylformamide (5 mL) was added, sodium hydride (32 mg) was added, ethyl iodide (93 mg) was added dropwise, the temperature was raised to 100 ℃ and the mixture was stirred overnight. After the reaction is finished, cooling to room temperature, adding water to quench the reaction, extracting the water phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain 106mg of the target compound.1H NMR(500MHz,Chloroform-d)δ7.43(d,J＝8.25Hz,1H),6.90(d,J＝2.11Hz,1H),6.83(dd,J＝8.23,2.10Hz,1H),6.11(tq,J＝3.89,2.08Hz,1H),4.12(q,2H),2.37(tq,J＝6.12,2.22Hz,2H),2.20(ddq,J＝6.28,4.28,2.65Hz,2H),1.78(dtt,J＝8.76,6.10,2.91Hz,2H),1.66(dtt,J＝9.29,6.19,3.01Hz,2H),1.47(t,J＝7.00Hz,3H)。
Step four: synthesis of 2 '-ethoxy-3-fluoro-2 ",3",4",5" -tetrahydro- [1,1':4', 1' -terphenyl ] -2-carbonitrile (QK 75)
QK72 (106 mg) and 2-fluoro-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) benzonitrile (148 mg) were added to a eggplant-shaped flask, ethylene glycol dimethyl ether (10 mL) and an aqueous solution of sodium carbonate (2M, 5 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (33 mg) was added to the reaction solution, and oxygen was removed again, and the temperature was raised to 90 ℃ and the reaction solution was stirred overnight. After the reaction is finished, the reaction product is cooled to room temperature, water is added to quench the reaction product, the water phase is extracted for 3 times by ethyl acetate, the organic phases are combined, the mixture is washed by saturated saline solution, dried by anhydrous sodium sulfate, concentrated by a rotary evaporator and purified by a silica gel column to obtain 71mg of a target compound.1H NMR(500MHz,Chloroform-d)δ7.60–7.55(m,1H),7.25(dd,J＝8.13,1.22Hz,1H),7.19(d,J＝7.89Hz,1H),7.15(td,J＝8.61,1.01Hz,1H),7.05(dd,J＝7.93,1.67Hz,1H),7.02(d,J＝1.64Hz,1H),6.20(tt,J＝3.97,1.72Hz,1H),4.13(q,J＝6.96Hz,2H),2.44(tp,J＝6.20,2.43Hz,2H),2.24(tq,J＝6.33,2.75Hz,2H),1.80(ddt,J＝11.81,10.40,6.03Hz,2H),1.68(dqd,J＝11.66,5.92,2.96Hz,2H),1.37(t,J＝7.02Hz,3H)。
Step five: synthesis of 4- (3-ethoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 79)
QK75 (71 mg) was placed in an eggplant-shaped flask, and n-butanol (10 mL) and hydrazine hydrate (85%, 5 mL) were added thereto, and the mixture was heated to 110 ℃ and stirred overnight. After the reaction, the reaction mixture was cooled to room temperature, concentrated by a rotary evaporator, and purified by a silica gel column to obtain 55mg of the objective compound.1H NMR(500MHz,Chloroform-d)δ7.36(dd,J＝8.40,7.03Hz,1H),7.30–7.24(m,2H),7.12(dd,J＝7.79,1.75Hz,1H),7.08(d,J＝1.69Hz,1H),6.95(dt,J＝7.15,1.50Hz,1H),6.26(tq,J＝3.94,2.04Hz,1H),4.05(q,J＝6.98Hz,2H),2.49(tq,J＝6.56,2.37Hz,2H),2.28(ddt,J＝8.60,6.34,3.17Hz,2H),1.88–1.82(m,2H),1.73(dhept,J＝9.24,3.00Hz,2H),1.22(t,J＝6.97Hz,3H)。
Synthesis of intermediate 22:4- (5- (cyclohex-1-en-1-yl) pyridin-2-yl) -1H-indazol-3-amine (QK 83)
Figure BDA0003608794920000261
The general method is as follows:
the method comprises the following steps: synthesis of 2- (5-bromopyridin-2-yl) -6-fluorobenzonitrile (QK 73)
5-bromo-2-iodopyridine (310 mg) and 2-fluoro-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl) benzonitrile (247 mg) were added to a eggplant-shaped flask, ethylene glycol dimethyl ether (10 mL) and an aqueous solution of sodium carbonate (2M, 5 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (80 mg) was added to the reaction solution, and oxygen was removed again, and the temperature was raised to 90 ℃ and the reaction solution was stirred overnight. After the reaction is finished, cooling to room temperature, adding water to quench the reaction, extracting the water phase for 3 times by using ethyl acetate, combining the organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, concentrating by using a rotary evaporator, and purifying by using a silica gel column to obtain 50mg of a target compound.1H NMR(500MHz,Chloroform-d)δ8.83(dd,J＝2.32,0.77Hz,1H),7.98(dd,J＝8.40,2.36Hz,1H),7.72–7.65(m,2H),7.62(dd,J＝7.93,1.18Hz,1H),7.29(td,J＝8.34,1.14Hz,1H)。
Step two: synthesis of 2- (5- (cyclohex-1-en-1-yl) pyridin-2-yl) -6-fluorobenzonitrile (QK 77)
QK73 (50 mg) and cyclohex-1-en-1-ylboronic acid (27 mg) were charged into a round bottom flask, ethylene glycol dimethyl ether (10 mL) and aqueous sodium carbonate solution (2M, 5 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (20 mg) was added to the reaction solution, and oxygen was removed again, and the temperature was raised to 90 ℃ and the reaction solution was stirred overnight. After the reaction is finished, the reaction product is cooled to room temperature, water is added to quench the reaction product, the water phase is extracted for 3 times by ethyl acetate, the organic phases are combined, the mixture is washed by saturated saline solution, dried by anhydrous sodium sulfate, concentrated by a rotary evaporator and purified by a silica gel column to obtain 52mg of a target compound.1H NMR(500MHz,Chloroform-d)δ8.81–8.76(m,1H),7.78(dd,J＝8.27,2.33Hz,1H),7.72(dd,J＝8.23,0.89Hz,1H),7.65(td,J＝3.89,2.59Hz,2H),7.23(ddd,J＝9.09,5.99,3.51Hz,1H),6.95–6.89(m,1H),6.29(tt,J＝3.91,1.71Hz,1H),2.43(tq,J＝6.28,2.28Hz,2H),2.26(tq,J＝6.23,2.74Hz,2H),1.85–1.78(m,2H),1.72–1.66(m,2H)。
Step three: 4- (5- (cyclohex-1-en-1-yl) pyridin-2-yl) -1H-indazol-3-amine (QK 83)
QK77 (52 mg) was put in an eggplant type flask, and n-butanol (10 mL) and hydrazine hydrate (85%, 5 mL) were added thereto, and the mixture was heated to 110 ℃ and stirred overnight. After the reaction, the reaction mixture was cooled to room temperature, concentrated by a rotary evaporator, and purified by a silica gel column to obtain 43mg of the objective compound.1H NMR(500MHz,Chloroform-d)δ8.76–8.72(m,1H),7.78(dd,J＝8.32,2.39Hz,1H),7.73–7.69(m,2H),7.39–7.28(m,2H),7.21(dd,J＝6.90,1.07Hz,1H),6.26(tt,J＝3.90,1.74Hz,1H),2.44(tq,J＝6.40,2.29Hz,2H),2.26(tq,J＝6.40,2.80Hz,2H),1.86–1.78(m,2H),1.74–1.65(m,2H)。
Synthesis of intermediate 23:4- (3-Isopropoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 84)
Figure BDA0003608794920000271
With 4-bromo-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-3-ol (200 mg) as starting material, according to general procedure four, gave 62mg of the title compound.1H NMR(500MHz,Chloroform-d)δ7.33(dd,J＝8.43,7.02Hz,1H),7.26–7.22(m,2H),7.12(dd,J＝7.86,1.75Hz,1H),7.08(d,J＝1.74Hz,1H),6.92(dd,J＝7.03,0.87Hz,1H),6.22(tt,J＝3.97,1.73Hz,1H),4.33(dt,J＝12.10,6.03Hz,1H),2.46(tq,J＝6.43,2.39Hz,2H),2.25(ddt,J＝8.38,6.32,2.77Hz,2H),1.85–1.78(m,2H),1.70(pd,J＝6.40,3.62Hz,2H),1.14(d,J＝6.10Hz,3H),1.07(d,J＝5.99Hz,3H)。
Synthesis of intermediate 24:4- (6- (cyclohex-1-en-1-yl) pyridin-3-yl) -1H-indazol-3-amine (QK 104)
Figure BDA0003608794920000272
Starting from 2-bromo-5-iodopyridine (500 mg), the title compound was obtained in an amount of 72mg, according to general procedure five.1H NMR(500MHz,Chloroform-d)δ8.71(d,J＝2.35Hz,1H),7.78(dd,J＝8.17,2.46Hz,1H),7.46(d,J＝8.21Hz,1H),7.34–7.24(m,2H),6.88(dd,J＝6.51,1.40Hz,1H),6.79(tt,J＝3.94,1.71Hz,1H),2.55(tq,J＝6.49,2.21Hz,2H),2.27(dh,J＝6.54,2.82Hz,2H),1.79(dtt,J＝11.13,7.59,4.03Hz,2H),1.71–1.65(m,2H)。
Synthesis of intermediate 25:4- (3- (dimethylamino) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 111)
Figure BDA0003608794920000281
Using cyclohex-1-en-1-ylboronic acid (158 mg) and 2-bromo-5-iodo-N, N-dimethylaniline (446 mg) as starting materials, 55mg of the title compound was obtained according to general procedure four.1H NMR(500MHz,Chloroform-d)δ7.31–7.16(m,3H),6.87(d,J＝6.97Hz,1H),6.79–6.67(m,2H),5.76–5.66(m,1H),3.05(s,6H),2.01(ddq,J＝12.33,6.18,3.12Hz,2H),1.93–1.78(m,2H),1.49–1.36(m,4H)。
Synthesis of intermediate 26:4- (2-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 128)
Figure BDA0003608794920000282
Starting from 4-bromo-1-iodo-2-methylbenzene (1292 mg) and cyclohex-1-en-1-ylboronic acid (500 mg), 412mg of the title compound was obtained according to general procedure four.1H NMR(500MHz,Chloroform-d)δ7.38–7.30(m,3H),7.30–7.26(m,1H),7.23(d,J＝7.70Hz,1H),6.99–6.94(m,1H),5.69(tt,J＝3.62,1.72Hz,1H),2.40(s,3H),2.30(dp,J＝5.75,2.18Hz,2H),2.25(dq,J＝6.13,3.50Hz,2H),1.84(dhept,J＝9.07,3.04Hz,2H),1.76(dtt,J＝8.92,6.10,2.55Hz,2H)。
Synthesis of intermediate 27:4- (3-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 129)
Figure BDA0003608794920000291
Starting from 1-bromo-4-iodo-2-methylbenzene (1292 mg) and cyclohex-1-en-1-ylboronic acid (500 mg), 389mg of the title compound was obtained according to general procedure four.1H NMR(500MHz,Chloroform-d)δ7.37–7.33(m,2H),7.31(dd,J＝7.83,1.93Hz,1H),7.28–7.26(m,1H),7.22(d,J＝7.93Hz,1H),6.86–6.80(m,1H),6.23(tt,J＝4.04,1.76Hz,1H),2.47(tq,J＝5.96,2.09Hz,2H),2.25(tt,J＝6.04,3.05Hz,2H),2.15(s,3H),1.81(qq,J＝5.34,2.91Hz,2H),1.73–1.66(m,2H)。
Synthesis of intermediate 28:4- (3-amino-1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -3-carboxylic acid methyl ester (QK 145)
Figure BDA0003608794920000292
Cyclohex-1-en-1-ylboronic acid (250 mg) and methyl 2-bromo-5-iodobenzoate (746 mg) were used as starting materials to give 365mg of the title compound, according to general procedure three.1H NMR(500MHz,Chloroform-d)δ7.90(d,J＝1.93Hz,1H),7.58(dd,J＝7.83,1.99Hz,1H),7.54(d,J＝8.07Hz,1H),7.30–7.28(m,1H),7.03(ddd,J＝7.86,6.54,1.19Hz,1H),6.94–6.89(m,1H),5.65(tt,J＝3.75,1.69Hz,1H),3.86(s,3H),2.29(ddd,J＝8.14,5.02,3.05Hz,2H),2.18(dtt,J＝6.17,4.25,2.67Hz,2H),1.79(dtt,J＝11.19,7.53,4.17Hz,2H),1.70(pd,J＝6.70,6.03,4.07Hz,2H)。
Synthesis of intermediate 29:4- (3-amino-1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -2-carboxylic acid methyl ester (QK 140)
Figure BDA0003608794920000301
Using cyclohex-1-en-1-ylboronic acid (500 mg) and methyl 5-bromo-2-iodobenzoate (1479 mg) as starting materials, 175mg of the title compound was obtained according to general procedure three.1H NMR(500MHz,Chloroform-d)δ7.90(d,J＝1.98Hz,1H),7.60(dd,J＝7.90,1.94Hz,1H),7.39–7.28(m,3H),6.98–6.92(m,1H),5.65(tt,J＝3.67,1.68Hz,1H),3.86(s,3H),2.30(tq,J＝6.14,2.24Hz,2H),2.19(dtd,J＝8.78,6.08,2.75Hz,2H),1.84–1.76(m,2H),1.74–1.66(m,2H)。
Synthesis of intermediate 30:4- (3-amino-1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -2-ol (QK 154)
Figure BDA0003608794920000302
Starting from cyclohex-1-en-1-ylboronic acid (189 mg) and 5-bromo-2-iodophenol (730 mg), 117mg of the title compound was obtained according to general procedure three.1H NMR (500mhz, chloroform-d) δ 7.46 (d, J =7.90hz, 1h), 7.24-7.08 (m, 2H), 7.01-6.91 (m, 2H), 6.86 (d, J =6.70hz, 1h), 5.98 (tt, J =3.83,1.73hz, 1h), 2.44 (td, J =5.68,2.47hz, 2h), 2.20 (H, J =3.30hz, 2h), 1.81-1.74 (m, 2H), 1.72-1.64 (m, 2H). Synthesis of intermediate 31:4- (3-amino-1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl]-3-ol (QL 1)
Figure BDA0003608794920000311
Starting from cyclohex-1-en-1-ylboronic acid (366 mg) and 5-bromo-2-iodophenol (953 mg), 151mg of the title compound was obtained according to general procedure three.1H NMR(500MHz,Chloroform-d)δ7.73–7.67(m,1H),7.52–7.47(m,2H),7.26–7.21(m,1H),7.02–6.94(m,2H),6.29–6.23(m,1H),2.49–2.42(m,2H),2.29–2.22(m,2H),1.85–1.79(m,2H),1.74–1.66(m,2H)。
Synthesis of intermediate 32: 3-amino-4- (4- (tert-butyl) phenyl) -1H-indazole-1-carboxylic acid tert-butyl ester (QL 16)
Figure BDA0003608794920000312
4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (500 mg) and 4-dimethylaminopyridine (49 mg) were charged in a round flask, acetonitrile (5 mL) and triethylamine (384 mg) were added, a solution of di-tert-butyl dicarbonate (452 mg) in methylene chloride (5 mL) was added dropwise, and the mixture was stirred at room temperature for 30min. After the reaction is finished, water is added to quench the reaction, and the aqueous phase is extracted by ethyl acetateThe organic phases were taken 3 times, combined, washed with saturated brine, dried over anhydrous sodium sulfate and purified by silica gel column to give the target compound 536mg.1H NMR(500MHz,DMSO-d6)δ8.04(d,J＝8.40Hz,1H),7.60–7.51(m,3H),7.40(dd,J＝7.71,4.72Hz,2H),7.13(d,J＝7.26Hz,1H),5.04(s,2H),1.60(d,J＝3.52Hz,9H),1.34(s,9H)。
Synthesis of intermediate 33: 3-amino-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-1-carboxylic acid tert-butyl ester (QL 27)
Figure BDA0003608794920000313
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting with (500 mg) of (E) -4-yl) -1H-indazol-3-amine according to the QL16 synthesis method, 503mg of the title compound was obtained.1H NMR(500MHz,Chloroform-d)δ7.55–7.44(m,4H),7.43–7.37(m,2H),7.11(dd,J＝7.28,0.95Hz,1H),6.24(dtt,J＝5.73,3.95,1.65Hz,1H),2.46(dddt,J＝8.42,6.14,4.31,2.42Hz,2H),2.25(dtp,J＝6.33,4.50,2.39Hz,2H),1.82(qq,J＝6.10,2.75,2.35Hz,2H),1.72–1.67(m,11H)。
Synthesis of intermediate 34:2- (3-amino-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-1-yl) ethan-1-ol (QL 103)
Figure BDA0003608794920000321
The method comprises the following steps: synthesis of 2- (3-amino-4-iodo-1H-indazol-1-yl) ethan-1-ol (QL 92)
2-fluoro-6-iodobenzonitrile (500 mg) was added to a round bottom flask, n-butanol (10 mL) and 2-hydroxyphenylalanin-1-ol (5 mL) were added, the temperature was raised to 110 ℃ and the mixture was stirred overnight. After the reaction, water was added to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified with silica gel column to obtain 242mg of the target compound.1H NMR(500MHz,Chloroform-d)δ7.41(dd,J＝7.28,0.71Hz,1H),7.21(dd,J＝8.45,0.69Hz,1H),6.97(dd,J＝8.50,7.27Hz,1H),4.21(dd,J＝5.52,4.16Hz,2H),4.03–3.99(m,2H)。
Step two: synthesis of 2- (3-amino-4- (4-bromophenyl) -1H-indazol-1-yl) ethan-1-ol (QL 99)
QL92 (242 mg) and (4-bromophenyl) boronic acid (160 mg) were charged in a eggplant type flask, ethylene glycol dimethyl ether (10 mL) and an aqueous solution of sodium carbonate (2M, 5 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (65 mg) was added to the reaction solution, and oxygen was removed again, and the temperature was raised to 90 ℃ and the reaction solution was stirred overnight. After the reaction, the reaction mixture was cooled to room temperature, water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by silica gel column to obtain 247mg of the objective compound.1H NMR(500MHz,Chloroform-d)δ7.62–7.57(m,2H),7.38–7.32(m,3H),7.25(dd,J＝8.61,0.78Hz,1H),6.86(dd,J＝7.03,0.80Hz,1H),4.28–4.24(m,2H),4.04–4.00(m,2H)。
Step three: synthesis of 2- (3-amino-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-1-yl) ethan-1-ol (QL 103)
QL99 (247 mg) and cyclohex-1-en-1-ylboronic acid (113 mg) were charged into a round bottom flask, ethylene glycol dimethyl ether (10 mL) and aqueous sodium carbonate solution (2M, 5 mL) were added, oxygen was removed from the reaction solution, and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (65 mg) was added to the reaction solution, and oxygen was removed again, and the temperature was raised to 90 ℃ and the reaction solution was stirred overnight. After the reaction, the reaction mixture was cooled to room temperature, water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified with silica gel column to obtain the target compound 193mg.1H NMR(500MHz,Chloroform-d)δ7.51–7.48(m,2H),7.44–7.40(m,2H),7.35(dd,J＝8.50,6.97Hz,1H),7.21(d,J＝8.50Hz,1H),6.90(d,J＝6.98Hz,1H),6.24(tt,J＝3.97,1.69Hz,1H),4.25(t,J＝5.08Hz,2H),4.02(t,J＝5.13Hz,2H),2.46(tq,J＝6.20,2.19Hz,2H),2.28–2.22(m,2H),1.86–1.79(m,2H),1.73–1.66(m,2H)。
Synthesis of intermediate 35:4- (4- (3,6-dihydro-2H-pyran-4-yl) phenyl) -1H-indazol-3-amine (LYA 6)
Figure BDA0003608794920000331
With 4 '-bromo-3-fluoro- [1,1' -biphenyl]Starting from (E) -2-carbonitrile (100 mg) and 2- (3,6-dihydro-2H-pyran-4-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborane (76 mg), the expected compound (43.5 mg) was obtained according to general procedure II.1H NMR(500MHz,Chloroform-d)δ7.56–7.48(m,4H),7.41–7.34(m,1H),7.31(dd,J＝8.4,0.9Hz,1H),6.96(dd,J＝6.9,0.9Hz,1H),6.24(tt,J＝3.0,1.6Hz,1H),4.37(q,J＝2.8Hz,2H),3.98(t,J＝5.4Hz,2H),2.59(dddd,J＝5.7,4.5,2.9,1.5Hz,2H)。
Synthesis of intermediate 36:4- (4- (pyridin-3-yl) phenyl) -1H-indazol-3-amine (LYA 10)
Figure BDA0003608794920000332
With 4 '-bromo-3-fluoro- [1,1' -biphenyl]-2-Carbonitrile (100 mg) and pyridin-3-ylboronic acid (44.7 mg) were used as starting materials to give 48.7mg of the objective compound according to general procedure two.1H NMR(500MHz,Methanol-d4) δ 8.89 (d, J =2.3hz, 1h), 8.54 (dd, J =4.9,1.6hz, 1h), 8.17 (ddd, J =8.0,2.4,1.6hz, 1h), 7.83-7.78 (m, 2H), 7.67-7.61 (m, 2H), 7.54 (ddd, J =7.9,4.9,0.9hz, 1h), 7.41-7.30 (m, 2H), 6.92 (dd, J =6.5,1.4hz, 1h). Synthesis of intermediate 37:4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-indazole-3-carboxylic acid (FB 55)
Figure BDA0003608794920000333
The method comprises the following steps: synthesis of 4-bromo-1H-indazole-3-carboxylic acid (FB 47)
4-bromoindole-2,3-dione (6 g) and sodium hydroxide (1176 mg) were added to an eggplant-shaped flask, water (48 mL) was added, the temperature was raised to 50 ℃ and stirring was carried out for 30min. After the reaction was completed, it was cooled to 0 ℃. A sodium nitrite solution (2028 mg) and dilute sulfuric acid (concentrated sulfuric acid: water = 4.2ml. Stannous chloride monohydrate (15 g) and concentrated hydrochloric acid (60 mL) were then added to the reaction mixtureN2Slowly heating to room temperature under protection, and stirring for 2h. After the reaction was completed, water was added to quench the reaction, and the reaction mixture was filtered under reduced pressure, and the filter cake was washed with water, dissolved in methanol, and concentrated by rotary evaporator to give the target compound (7 g) which was used in the next step without further purification.1H NMR(500MHz,Methanol-d4)δ7.60(d,J＝8.3Hz,1H),7.45(d,J＝7.3Hz,1H),7.32–7.27(m,1H)。
Step two: synthesis of 4-bromo-1H-indazole-3-carboxylic acid methyl ester (FB 49)
FB47 (7 g) was placed in an eggplant-shaped flask, methanol (80 mL) was added, concentrated sulfuric acid (0.5 mL) was added dropwise, and the mixture was heated to 65 ℃ and stirred overnight. After the reaction, the reaction mixture was cooled to room temperature, a saturated sodium bicarbonate solution was added, the aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by a rotary evaporator, and purified by a silica gel column to obtain 545mg of the objective compound.1H NMR(500MHz,Chloroform-d)δ7.59(dd,J＝8.4,0.8Hz,1H),7.54(dd,J＝7.4,0.7Hz,1H),7.28(dd,J＝8.4,7.5Hz,1H),4.06(s,3H)。
Step three: synthesis of methyl 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxylate (FB 53)
FB49 (574 mg) and 4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl were added]-4-yl) -1,3,2-dioxaborane (673 mg) was added to a eggplant-shaped flask, ethylene glycol dimethyl ether (15 mL) and an aqueous solution of sodium carbonate (2M, 10mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (179 mg) was added to the reaction solution, and after further oxygen removal, the temperature was raised to 90 ℃ and the reaction solution was stirred overnight. After the reaction is finished, cooling to room temperature, adding water to quench the reaction, extracting the water phase for 3 times by using ethyl acetate, combining the organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, concentrating by using a rotary evaporator, and purifying by using a silica gel column to obtain 500mg of a target compound.1H NMR(500MHz,Chloroform-d)δ7.68–7.59(m,1H),7.49–7.38(m,3H),7.36–7.30(m,2H),7.18(t,J＝6.6Hz,1H),6.16(tq,J＝3.9,1.9Hz,1H),3.33(d,J＝1.5Hz,3H),2.43(ddt,J＝6.6,4.8,2.3Hz,2H),2.25–2.19(m,2H),1.83–1.74(m,2H),1.72–1.61(m,2H).
Step four: synthesis of 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxylic acid (FB 55)
FB53 (500 mg) was put in an eggplant type flask, and 40mL of a mixed solvent (MeOH: H) was added2O =1: 1) Subsequently, sodium hydroxide (361 mg) was added, the temperature was raised to 80 ℃ and the mixture was stirred overnight. After the reaction is finished, cooling to room temperature, adding dilute hydrochloric acid, extracting the water phase for 3 times by using ethyl acetate, combining the organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, concentrating by using a rotary evaporator, pulping and purifying to obtain 216mg of a target compound.1H NMR(500MHz,DMSO-d6)δ7.60(d,J＝8.4Hz,1H),7.47(dd,J＝8.5,7.1Hz,1H),7.44(d,J＝8.1Hz,2H),7.33(d,J＝8.2Hz,2H),7.15(d,J＝7.1Hz,1H),6.31–6.20(m,1H),2.41(s,2H),2.27–2.17(m,2H),1.82–1.70(m,2H),1.69–1.59(m,2H)。
Synthesis of intermediate 38: methyl 3- ((4-bromo-2H-indazol-2-yl) methyl) benzoate (FB 94)
Figure BDA0003608794920000341
The general method comprises the following steps:
the method comprises the following steps: synthesis of methyl 3- ((4-bromo-2H-indazol-2-yl) methyl) benzoate (FB 94)
2-bromo-6-nitrobenzaldehyde (130 mg) and methyl 3- (aminomethyl) benzoate (125 mg) were charged in an eggplant-shaped flask, isopropanol (10 mL) was added, and the mixture was stirred at 80 ℃ for 4 hours. After the reaction, the reaction mixture was cooled to room temperature, tributylphosphine (453 mg) was added dropwise thereto, and the mixture was stirred for 16 hours while being warmed to 80 ℃. After the reaction is finished, the reaction product is cooled to room temperature, water is added to quench the reaction product, the water phase is extracted for 3 times by ethyl acetate, the organic phases are combined, the mixture is washed by saturated saline solution, dried by anhydrous sodium sulfate, concentrated by a rotary evaporator and purified by a silica gel column to obtain 95.2mg of a target compound.1H NMR(500MHz,Chloroform-d)δ8.01(dt,J＝9.1,1.9Hz,2H),7.94(d,J＝1.0Hz,1H),7.65(dd,J＝8.6,0.9Hz,1H),7.50–7.38(m,2H),7.25–7.20(m,1H),7.13(dd,J＝8.7,7.2Hz,1H),5.62(s,2H),3.90(s,3H)。
Synthesis of intermediate 39:4- ((4-bromo-2H-indazol-2-yl) methyl) benzoic acid methyl ester (FB 114)
Figure BDA0003608794920000351
Starting from 2-bromo-6-nitrobenzaldehyde (115 mg) and methyl 4- (aminomethyl) benzoate (90.7 mg), 29.4mg of the title compound was obtained according to general procedure ten.1H NMR(500MHz,Chloroform-d)δ8.06–8.00(m,2H),7.95(s,1H),7.65(d,J＝8.6Hz,1H),7.32(d,J＝8.0Hz,2H),7.24(d,J＝7.2Hz,1H),7.14(dd,J＝8.7,7.2Hz,1H),5.64(s,2H),3.90(s,3H)。
Synthesis of intermediate 40:4- (2- (4-bromo-2H-indazol-2-yl) ethyl) benzoic acid methyl ester (FB 129)
Figure BDA0003608794920000352
Starting from 2-bromo-6-nitrobenzaldehyde (230 mg) and methyl 4- (2-aminoethyl) benzoate (211 mg), 101mg of the title compound was obtained according to general procedure ten.1H NMR(500MHz,Chloroform-d)δ8.00–7.96(m,2H),7.78(s,1H),7.69(d,J＝8.6Hz,1H),7.26(d,J＝7.1Hz,1H),7.23–7.15(m,3H),4.68(t,J＝7.3Hz,2H),3.93(s,3H),3.43(t,J＝7.3Hz,2H)。
Synthesis of intermediate 41: methyl 3- (2- (4-bromo-2H-indazol-2-yl) ethyl) benzoate (FB 148)
Figure BDA0003608794920000353
Using 2-bromo-6-nitrobenzaldehyde (230 mg) and methyl 3- (2-aminoethyl) benzoate (192.3 mg) as starting materials, 57.6mg of the title compound was obtained in accordance with general procedure ten.1H NMR (500mhz, chloroform-d) δ 7.91 (d, J =7.7hz, 1h), 7.83 (s, 1H), 7.74 (s, 1H), 7.66 (d, J =8.6hz, 1h), 7.32 (t, J =7.7hz, 1h), 7.22 (d, J =7.0hz, 2h), 7.17-7.10 (m, 1H), 4.63 (t, J =7.4hz, 2h), 3.88 (s, 3H), 3.38 (t, J =7.4hz, 2h). Synthesis of intermediate 42:4- (4-bromo-1H-benzo [ d ]]Imidazol-2-yl) benzoic acid methyl ester (FB 157-1) and 4- (4-bromo-1- (4- (methoxycarbonyl) benzyl) -1H-benzo [ d]Imidazol-2-yl) benzoic acid methyl ester (FB 157-2)
Figure BDA0003608794920000354
The general method eleven:
the method comprises the following steps: synthesis of methyl 4- (4-bromo-1H-benzo [ d ] imidazol-2-yl) benzoate (FB 157-1) and methyl 4- (4-bromo-1- (4- (methoxycarbonyl) benzyl) -1H-benzo [ d ] imidazol-2-yl) benzoate (FB 157-2)
3-bromobenzene 1,2-diamine (187 mg) and methyl 4-formylbenzoate (181 mg) were added to an eggplant-shaped flask, ethanol (8 mL) was added, p-toluenesulfonic acid monohydrate was added, the temperature was raised to 80 ℃ and stirring was carried out for 24 hours. After the reaction is finished, the mixture is cooled to room temperature, water is added to quench the reaction, the water phase is extracted for 3 times by ethyl acetate, the organic phases are combined, the mixture is washed by saturated saline solution, dried by anhydrous sodium sulfate, concentrated by a rotary evaporator and purified by silica gel column to obtain 286mg of a mixture of FB157-1 and FB 157-2.1H NMR(500MHz,Methanol-d4,FB157-1)δ8.23(s,4H),7.71(dd,J＝8.2,0.8Hz,1H),7.64(dd,J＝7.8,0.8Hz,1H),7.38(t,J＝8.0Hz,1H),3.97(s,3H)。1H NMR(500MHz,Methanol-d4,FB157-2)δ8.32–8.16(m,2H),8.04–7.94(m,2H),7.95–7.83(m,2H),7.75(dd,J＝7.9,0.8Hz,1H),7.63(d,J＝8.2Hz,1H),7.42(t,J＝8.1Hz,1H),7.22(d,J＝8.2Hz,2H),5.75(s,2H),3.96(s,3H),3.88(s,3H)。
Synthesis of intermediate 43: methyl 3- (4-bromo-1H-benzo [ d ] imidazol-2-yl) benzoate (FB 160-1) and methyl 3- (4-bromo-1- (3- (methoxycarbonyl) benzyl) -1H-benzo [ d ] imidazol-2-yl) benzoate (FB 160-2)
Figure BDA0003608794920000361
A mixture of FB160-1 and FB160-2 (752 mg) was obtained using 3-bromobenzene 1,2-diamine (561 mg) and methyl 3-formylbenzoate (541.2 mg) as starting materials by the general method eleven.1H NMR(500MHz,Chloroform-d,FB160-1)δ8.65(s,1H),8.38(d,J＝7.8Hz,1H),8.14(d,J＝7.8Hz,1H),7.65(s,1H),7.59(t,J＝7.8Hz,1H),7.45(d,J＝7.8Hz,1H),7.18(t,J＝7.9Hz,1H),3.95(s,3H)。1H NMR(500MHz,Methanol-d4,FB160-2)δ8.26(t,J＝1.7Hz,1H),8.22(dt,J＝7.9,1.4Hz,1H),7.94(d,J＝7.8Hz,1H),7.93–7.90(m,1H),7.71–7.65(m,2H),7.62(dd,J＝7.8,0.9Hz,1H),7.58(dd,J＝8.3,0.8Hz,1H),7.42(t,J＝7.8Hz,1H),7.34–7.28(m,1H),5.64(s,2H),3.87(s,3H),3.83(s,3H)。
Synthesis of intermediate 44: methyl 2- (4- (4-bromo-1H-benzo [ d ] imidazol-2-yl) phenyl) acetate (FC 56-1) and methyl 2- (4- (4-bromo-1- (4- (2-methoxy-2-oxoethyl) benzyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) acetate (FC 56-2)
Figure BDA0003608794920000362
A mixture of FC56-1 and FC56-2 (169 mg) was prepared by starting from 3-bromobenzene 1,2-diamine (156.7 mg) and methyl 3-formylbenzoate (163.7 mg) by the general method eleventh.1H NMR(500MHz,Methanol-d4,FC56-1)δ8.12–8.06(m,2H),7.70(d,J＝8.1Hz,1H),7.64(d,J＝7.8Hz,1H),7.57(d,J＝8.1Hz,2H),7.38(t,J＝8.0Hz,1H),3.80(s,2H),3.72(s,3H)。1H NMR(500MHz,Chloroform-d,FC56-2)δ7.69–7.63(m,2H),7.57(dd,J＝7.2,1.5Hz,1H),7.45–7.38(m,2H),7.30–7.24(m,2H),7.23–7.15(m,2H),7.02(d,J＝8.1Hz,2H),5.46(s,2H),3.72–3.68(m,8H),3.62(s,2H)。
Synthesis of intermediate 45: methyl 2- (3- (4-bromo-1H-benzo [ d ] imidazol-2-yl) phenyl) acetate (FC 55-1) and methyl 2- (3- (4-bromo-1- (3- (2-methoxy-2-oxoethyl) benzyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) acetate (FC 55-2)
Figure BDA0003608794920000371
Starting from 3-bromobenzene 1,2-diamine (335 mg) and methyl 2- (3-formylphenyl) acetate (350 mg), 419mg of a mixture of FC55-1 and FC55-2 was obtained by reference to general method eleven.1H NMR(500MHz,Methanol-d4,FC55-1)δ8.10–8.02(m,2H),7.72(dd,J＝8.1,0.8Hz,1H),7.67(dd,J＝7.9,0.8Hz,1H),7.64–7.62(m,2H),7.44–7.39(m,1H),3.83(s,2H),3.72(s,3H)。1H NMR(500MHz,Methanol-d4,FC55-2)δ7.69(q,J＝1.6,1.1Hz,1H),7.65–7.52(m,5H),7.39–7.34(m,1H),7.24(dd,J＝7.6,2.7Hz,1H),7.19(dt,J＝7.8,1.4Hz,1H),7.04–6.97(m,2H),5.60(s,2H),3.74(s,2H),3.64(s,3H),3.60(s,3H),3.56(s,2H)。
Synthesis of intermediate 46:4- (4- (trifluoromethyl) phenyl) -1H-indazol-3-amine (QM 73)
Figure BDA0003608794920000372
Starting from 2-bromo-6-fluorobenzonitrile (521 mg) and (4- (trifluoromethyl) phenyl) boronic acid (521 mg), 577mg of the objective compound was obtained according to general method one.1H NMR(500MHz,Chloroform-d)δ7.76(d,J＝8.01Hz,2H),7.66(d,J＝7.93Hz,2H),7.42–7.32(m,2H),6.96(dd,J＝6.78,1.07Hz,1H)。
Synthesis of intermediate 47:4- (2-fluoro-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 82)
Figure BDA0003608794920000373
Starting from cyclohex-1-en-1-ylboronic acid (630 mg) and 4-bromo-2-fluoro-1-iodobenzene (1500 mg), 623mg of the title compound was obtained according to general procedure three.1H NMR(500MHz,Chloroform-d)δ7.38–7.33(m,2H),7.32–7.28(m,1H),7.25(dd,J＝7.78,1.46Hz,1H),7.20(dd,J＝11.64,1.73Hz,1H),6.94(dd,J＝6.92,0.99Hz,1H),6.05(tt,J＝3.79,1.68Hz,1H),2.47–2.39(m,2H),2.28–2.21(m,2H),1.83–1.76(m,2H),1.74–1.67(m,2H)。
Synthesis of intermediate 48:4- (3-fluoro-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 85)
Figure BDA0003608794920000381
Starting from cyclohex-1-en-1-ylboronic acid (630 mg) and 1-bromo-2-fluoro-4-iodobenzene (1500 mg), the title compound was obtained in 551mg by reference to general procedure three.
Synthesis of intermediate 49:4- (4-Cyclopropylphenyl) -1H-indazol-3-amine (QM 107)
Figure BDA0003608794920000382
With 4 '-bromo-3-fluoro- [1,1' -biphenyl]-2-Carbonitrile (500 mg) and cyclopropylboronic acid (156 mg) were used as starting materials to give 266mg of the title compound in accordance with general procedure II.1H NMR(500MHz,Chloroform-d)δ7.44(d,J＝7.68Hz,2H),7.40–7.27(m,2H),7.21(d,J＝7.83Hz,2H),6.95(d,J＝7.00Hz,1H),2.00(tt,J＝8.51,5.12Hz,1H),1.09–1.03(m,2H),0.84–0.77(m,2H)。
Synthesis of intermediate 50: methyl 3- ((4-bromo-1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (FC 25)
Figure BDA0003608794920000383
Starting with 3-bromobenzene 1,2-diamine (225 mg) and methyl 3- (2-oxoethyl) benzoate (425 mg), 125mg of the title compound was obtained according to general procedure eleven. Data for trifluoroacetate-type compound1H NMR(500MHz,Methanol-d4)δ8.09(s,1H),8.01(dt,J＝7.8,1.4Hz,1H),7.69(ddd,J＝15.8,8.2,0.8Hz,3H),7.55(d,J＝7.7Hz,1H),7.43(t,J＝8.1Hz,1H),4.61(s,2H),3.90(s,4H).13C NMR(126MHz,Methanol-d4)δ167.91,155.12,135.32,134.86,134.41,133.57,132.47,131.17,130.73,130.27,129.83,128.09,114.32,107.25,52.81,33.61。
Synthesis of intermediate 51:4- ((4-bromo-1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid methyl ester (FE 72)
Figure BDA0003608794920000391
Using 3-bromobenzene 1,2-diamine (2.3 g) and 4- (2-oxoethyl) methyl benzoate (2.2 g) as starting materials, the title compound was obtained according to general procedure eleven840.3mg. Data for trifluoroacetate type compounds1H NMR(500MHz,Methanol-d4)δ8.08–7.98(m,2H),7.70(t,J＝8.6Hz,2H),7.51(d,J＝8.1Hz,2H),7.43(t,J＝8.0Hz,1H),4.62(s,2H),3.90(s,3H).13C NMR(126MHz,Methanol-d4)δ167.92,154.74,139.94,134.31,133.47,131.43,131.20,130.37,129.88,128.15,114.34,107.22,52.75,33.66。
Synthesis of intermediate 52: 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FC 98)
Figure BDA0003608794920000392
Using 4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1,3,2-dioxaborane (1250 mg) and 4-bromo-2-methyl-1H-benzo [ d ]]Imidazole (775.3 mg) was used as a starting material, and the objective compound 764.3mg was obtained according to general method fourteen. Data for trifluoroacetate-type compound1H NMR(500MHz,Methanol-d4)δ7.63(dd,J＝8.1,1.1Hz,1H),7.61–7.55(m,4H),7.53(t,J＝7.8Hz,1H),7.47(dd,J＝7.6,1.1Hz,1H),6.25(tt,J＝3.9,1.8Hz,1H),2.77(s,3H),2.48(tq,J＝6.3,2.2Hz,2H),2.26(tq,J＝6.0,2.8Hz,2H),1.88–1.80(m,2H),1.75–1.67(m,2H).13C NMR(126MHz,Methanol-d4)δ153.29,144.15,137.44,135.99,135.02,131.90,129.83,129.39,126.70,126.52,126.36,125.79,113.64,28.41,26.93,24.19,23.27,12.72。
Synthesis of intermediate 53: 2-Ethyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FE 2)
Figure BDA0003608794920000393
The method comprises the following steps: starting with 3-bromobenzene 1,2-diamine (500 mg) and propionaldehyde (157 mg), the title compound was obtained as 201mg by the general method eleven. Data for trifluoroacetate type compounds1H NMR(500MHz,Chloroform-d)δ7.46(d,J＝8.0Hz,1H),7.38(d,J＝7.7Hz,1H),7.07(t,J＝7.9Hz,1H),3.01(q,J＝7.7Hz,2H),1.40(t,J＝7.6Hz,3H)。
Step two: using 4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1,3,2-dioxaborane (312 mg) and 4-bromo-2-ethyl-1H-benzo [ d ]]Imidazole (201 mg) was used as a starting material to obtain 211.5mg of a target compound according to general method fourteen. Data for trifluoroacetate type compounds1H NMR(500MHz,Methanol-d4)δ7.71(dd,J＝8.2,1.1Hz,1H),7.65–7.54(m,6H),6.26(tt,J＝3.9,1.7Hz,1H),3.20(q,J＝7.7Hz,2H),2.48(tq,J＝6.3,2.3Hz,2H),2.27(ddt,J＝8.4,6.1,2.7Hz,2H),1.89–1.80(m,2H),1.75–1.67(m,2H),1.50(t,J＝7.7Hz,3H).13C NMR(126MHz,Methanol-d4)δ157.67,144.41,137.41,135.52,133.65,130.80,130.08,129.44,127.23,126.79,126.60,126.52,113.46,28.40,26.93,24.18,23.25,21.25,11.80。
Synthesis of intermediate 54:2- (2- ((tert-butyldiphenylsilyl) oxy) ethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FC 76)
Figure BDA0003608794920000401
The method comprises the following steps: starting from 3-bromobenzene 1,2-diamine (617 mg) and 3- ((tert-butyldiphenylsilyl) oxy) propanal (1.0 g), the title compound 394.6mg was obtained according to general procedure eleven. Data for trifluoroacetate type compounds1H NMR(500MHz,Methanol-d4)δ7.76–7.70(m,2H),7.48(t,J＝8.1Hz,1H),7.42–7.35(m,6H),7.27–7.23(m,4H),4.18(t,J＝5.7Hz,2H),3.41(t,J＝5.7Hz,2H),0.93(s,9H).13C NMR(126MHz,Methanol-d4)δ155.26,136.39,135.93,133.67,133.63,131.15,129.90,128.83,128.24,114.21,106.94(d,J＝21.6Hz),62.51,31.48,27.14,19.79。
Step two: using 4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1,3,2-dioxaborane (458 mg) and 4-bromo-2- (2- ((tert-butyldiphenylsilyl) oxy) ethyl) -1H-benzo [ d]Imidazole (394.6 mg) was used as the starting material, and the title compound 419.7mg was obtained according to general method fourteen. Data for trifluoroacetate type compounds1H NMR(500MHz,Chloroform-d)δ7.61(d,J＝7.3Hz,5H),7.41(q,J＝7.1,6.5Hz,5H),7.33(dd,J＝9.7,5.6Hz,7H),6.14(d,J＝4.1Hz,1H),4.06(t,J＝5.6Hz,2H),3.15(t,J＝5.6Hz,2H),2.41(q,J＝5.2Hz,2H),2.24(tq,J＝6.1,2.8Hz,2H),1.81(ddt,J＝12.0,8.7,4.5Hz,2H),1.73–1.64(m,2H),1.03(s,9H)。
Synthesis of intermediate 55: methyl 4- ((2- (2-hydroxyethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoate (FD 77)
Figure BDA0003608794920000402
The method comprises the following steps: with 2- (2- ((tert-butyldiphenylsilyl) oxy) ethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (200 mg) and methyl 4- (bromomethyl) benzoate (156 mg) were used as starting materials to obtain 167.5mg of the objective compound according to general procedure twelve. Data for trifluoroacetate type compounds1H NMR(500MHz,Chloroform-d)δ7.98(d,J＝8.1Hz,2H),7.94(d,J＝8.1Hz,2H),7.53–7.48(m,6H),7.43(d,J＝7.5Hz,1H),7.38–7.33(m,2H),7.25(td,J＝7.5,7.1,3.9Hz,5H),7.08(d,J＝8.0Hz,1H),7.03(d,J＝8.1Hz,2H),6.19(td,J＝4.0,1.9Hz,1H),5.42(s,2H),4.13(t,J＝6.3Hz,2H),3.90(s,3H),3.14(t,J＝6.3Hz,2H),2.47(td,J＝5.9,5.3,2.5Hz,2H),2.24(tq,J＝6.0,2.9Hz,2H),1.81(dtt,J＝8.7,6.1,3.1Hz,2H),1.69(ddd,J＝9.2,7.4,4.6Hz,2H),1.02(s,9H)。
Step two: methyl 4- ((2- (2- ((tert-butyldiphenylsilyl) oxy) ethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl)) -1H-benzo [ d]Imidazol-1-yl) methyl) benzoate (167.5 mg) and tetrabutylammonium fluoride trihydrate (95 mg) were put in an eggplant-shaped flask, and THF (10 mL) was added thereto, followed by stirring overnight. After the reaction, the reaction mixture was concentrated by a rotary evaporator and purified by a silica gel column to obtain 99.1mg of the objective compound.1H NMR(500MHz,Chloroform-d)δ7.98(dd,J＝11.7,8.1Hz,4H),7.53(d,J＝8.2Hz,2H),7.45(d,J＝7.5Hz,1H),7.28(t,J＝7.6Hz,1H),7.14(d,J＝8.0Hz,1H),7.09(d,J＝8.1Hz,2H),6.23(td,J＝3.9,1.9Hz,1H),5.33(s,2H),4.07(t,J＝5.4Hz,2H),3.89(s,3H),2.93(t,J＝5.4Hz,2H),2.47(tt,J＝4.6,2.3Hz,2H),2.25(dh,J＝5.9,2.7Hz,2H),1.89–1.77(m,2H),1.74–1.61(m,2H)。
Synthesis of intermediate 56:3- (4-bromo-1H-benzo [ d ] imidazol-2-yl) propionic acid methyl ester (FC 120)
Figure BDA0003608794920000411
Starting with 3-bromobenzene 1,2-diamine (400 mg) and methyl 4-oxobutanoate (270 mg) the title compound was obtained in an amount of 83.5mg according to general procedure eleven. Data for trifluoroacetate type compounds1H NMR(500MHz,Methanol-d4)δ7.69(ddd,J＝9.3,8.1,0.8Hz,2H),7.42(t,J＝8.1Hz,1H),3.68(s,3H),3.43(t,J＝7.1Hz,2H),3.05(t,J＝7.1Hz,2H).13C NMR(126MHz,Methanol-d4)δ173.32,156.08,134.23,133.35,129.56,127.84,114.21,106.99,52.61,31.45,23.41。
Synthesis of intermediate 57:3- (4-bromo-1H-benzo [ d ] imidazol-2-yl) propionic acid methyl ester (FD 33)
Figure BDA0003608794920000412
192.4mg of the objective compound was obtained by starting from 3-bromobenzene 1,2-diamine (412 mg) and methyl 5-oxopentanoate (573 mg) in accordance with general procedure eleven.1H NMR(500MHz,Chloroform-d)δ7.52(d,J＝8.1Hz,1H),7.38(d,J＝7.8Hz,1H),7.11(t,J＝7.9Hz,1H),3.68(s,3H),3.02(t,J＝7.4Hz,2H),2.46(t,J＝7.0Hz,2H),2.18(p,J＝7.3Hz,2H)。
Synthesis of intermediate 58: 4-bromo-2- (3- ((tert-butyldiphenylsilyl) oxy) propyl) -1H-benzo [ d ] imidazole (FD 126)
Figure BDA0003608794920000413
Starting from 3-bromobenzene 1,2-diamine (2548 mg) and 4- ((tert-butyldiphenylsilyl) oxy) butyraldehyde (4.45 g), the title compound 667.9mg was obtained by reference to general method eleven.1H NMR(500MHz,Chloroform-d)δ7.68–7.60(m,4H),7.49–7.28(m,8H),7.06(d,J＝7.9Hz,1H),3.77(t,J＝5.8Hz,2H),3.13(t,J＝7.4Hz,2H),2.10(ddd,J＝12.8,7.2,5.6Hz,2H),1.05(s,9H)。
Synthesis of intermediate 59: methyl 4- ((1- (3- (dimethylamino) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (FC 158)
Figure BDA0003608794920000414
The method comprises the following steps: using methyl 4- ((4-bromo-1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (97.6 mg) and 3-bromo-N, N-dimethylpropan-1-amine (280 mg) as starting materials, and referring to general procedure twelve, a crude compound (56 mg) was obtained.
Step two: starting from 4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3,2-dioxaborane (127 mg) and methyl 4- ((4-bromo-1- (3- (dimethylamino) propyl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (56 mg), reference was made to general procedure fourteen to give crude compound (7.6 mg), MS =507.3.
Synthesis of intermediate 60: methyl 4- ((1- (3- ((tert-butyldiphenylsilyl) oxy) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl)) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (FD 125)
Figure BDA0003608794920000421
The method comprises the following steps: with 4- ((4-bromo-1H-benzo [ d)]Imidazol-2-yl) methyl) benzoate (388.6 mg) and tert-butyl (3-iodopropoxy) diphenylsilane (932.8 mg) were used as starting materials, and 274.8mg of the objective compound was obtained by reference to general method twelve.1H NMR(500MHz,Chloroform-d)δ7.95–7.91(m,2H),7.64–7.60(m,4H),7.47–7.42(m,3H),7.38(dd,J＝7.9,6.6Hz,4H),7.27(dd,J＝11.3,8.0Hz,3H),7.09(t,J＝7.9Hz,1H),4.45(s,2H),4.13(td,J＝7.2,2.6Hz,2H),3.88(s,3H),3.58(t,J＝5.5Hz,2H),1.78–1.56(m,2H),1.10(s,9H)。
Step two: using 4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1,3,2-dioxaborane (185 mg) and 4- ((4-bromo-1- (3- ((tert-butyl)Diphenylsilyl) oxy) propyl) -1H-benzo [ d]Imidazol-2-yl) methyl) benzoate (274.8 mg) as a starting material, with reference to the general procedure fourteen, the target compound (198.1 mg) was obtained.1H NMR(500MHz,Chloroform-d)δ8.07–8.02(m,2H),7.99–7.94(m,2H),7.69–7.65(m,4H),7.58–7.54(m,2H),7.50–7.39(m,7H),7.34–7.30(m,4H),6.23(tt,J＝3.9,1.7Hz,1H),4.47(s,2H),4.20(dd,J＝8.3,6.4Hz,2H),3.92(s,3H),3.65(t,J＝5.4Hz,2H),2.50(tq,J＝6.4,2.2Hz,2H),2.27(tt,J＝6.2,3.1Hz,2H),1.88–1.75(m,4H),1.75–1.67(m,2H),1.14(s,9H)。
Synthesis of intermediate 61: methyl 4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (FE 88)
Figure BDA0003608794920000422
The method comprises the following steps: methyl 4- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (572.7 mg) and Cs2CO3 (456 mg) were added to an eggplant-shaped flask, DMF (5 mL) was added, the temperature was raised to 90 ℃, and stirred for 20H. After the reaction, cooled to room temperature, added with water to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporator to give crude product (544.7 mg). LC-Ms:437.5.
Step two: 4- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1H-benzo [ d]Imidazole-2-carbonyl) benzoic acid methyl ester (200 mg) and HO-NH2HCl (324 mg) was added to an eggplant-shaped flask, and a mixed solvent (8 mL, ethanol: pyridine = 1:1) and KOAc (461 mg) were added thereto, and the mixture was heated to 80 ℃ and stirred overnight. After the reaction is finished, cooling to room temperature, adding water to quench the reaction, extracting the water phase for 3 times by using ethyl acetate, combining the organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, concentrating by using a rotary evaporator, and purifying by using a silica gel column to obtain a crude compound. Then, zn (366 mg) was added to the eggplant type flask, and AcOH (5 mL) was added thereto overnight at room temperature. After the reaction is finished, adjusting the pH value to be alkalescent by using saturated sodium bicarbonate, extracting the water phase by using ethyl acetate for 3 times, combining the organic phases,washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by a rotary evaporator, and purified by a silica gel column to obtain 171.2mg of the objective compound. Data for trifluoroacetate type compounds1H NMR(500MHz,Methanol-d4)δ8.10(d,J＝8.1Hz,2H),7.83(d,J＝8.0Hz,2H),7.65(d,J＝8.1Hz,2H),7.51(dd,J＝16.1,8.0Hz,3H),7.39(d,J＝7.4Hz,1H),7.33(t,J＝7.7Hz,1H),6.19(q,J＝2.8,2.1Hz,1H),5.96(s,1H),3.90(s,3H),2.45(tt,J＝4.5,2.4Hz,2H),2.23(dh,J＝6.1,2.8Hz,2H),1.86–1.77(m,2H),1.73–1.63(m,2H).13C NMR(126MHz,Methanol-d4)δ167.61,150.40,143.17,140.38,139.59,138.51,137.69,137.62,132.88,131.50,131.43,129.80,129.69,126.12,125.68,124.79,123.19,118.38,116.08,114.35,53.71,52.88,28.42,26.90,24.21,23.30。
Synthesis of intermediate 62: 2-propyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FE 10)
Figure BDA0003608794920000431
Using 4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1,3,2-dioxaborane (233 mg) and 4-bromo-2-propyl-1H-benzo [ d]Imidazole (162 mg) was used as a starting material, and according to general procedure fourteen, 195mg of the title compound was obtained. Data for trifluoroacetate type compounds1H NMR (500mhz, methanol-d 4) δ 7.71 (d, J =8.1hz, 1h), 7.65-7.52 (m, 6H), 6.26 (dq, J =4.1,1.9hz, 1h), 3.14 (t, J =7.6hz, 2h), 2.48 (ddt, J =6.2,3.9,2.2hz, 2h), 2.26 (tq, J =6.1,2.8hz, 2h), 1.94 (H, J =7.4hz, 2h), 1.84 (dtt, J =10.9,7.5,3.9hz, 2h), 1.76-1.67 (m, 2H), 1.06 (t, J =7.4hz, 3h), 13C (mthol-3763, 3763). Synthesis of intermediate 63: 2-butyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (FE 20)
Figure BDA0003608794920000432
Step (ii) ofFirstly, the method comprises the following steps: starting with 3-bromobenzene 1,2-diamine (500 mg) and pentanal (232 mg), the title compound was obtained in 208mg according to general procedure eleven.1H NMR(500MHz,Chloroform-d)δ7.46(d,J＝8.0Hz,1H),7.38(d,J＝7.8Hz,1H),7.07(t,J＝7.9Hz,1H),3.00–2.88(m,2H),1.79(p,J＝7.7Hz,2H),1.38–1.29(m,2H),0.83(t,J＝7.4Hz,3H)。
Step two: using 4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1,3,2-dioxaborane (284 mg) and 4-bromo-2-butyl-1H-benzo [ d]Imidazole (208 mg) was used as a starting material to obtain 214mg of a target compound according to general procedure fourteen. Data for trifluoroacetate type compounds1H NMR(500MHz,Methanol-d4)δ7.71(d,J＝8.1Hz,1H),7.65–7.53(m,6H),6.26(tt,J＝3.7,1.6Hz,1H),3.17(t,J＝7.8Hz,2H),2.48(tt,J＝4.5,2.3Hz,2H),2.26(tq,J＝6.0,2.8Hz,2H),1.94–1.78(m,4H),1.77–1.63(m,2H),1.47(h,J＝7.4Hz,2H),1.01(t,J＝7.4Hz,3H).13C NMR(126MHz,Methanol-d4)δ156.61,144.54,137.39,135.26,133.01,130.26,130.14,129.46,127.62,126.93,126.85,126.60,113.35,30.63,28.40,27.13,26.93,24.17,23.25,13.79。
Synthesis of intermediate 64: 2-isopropyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FE 78)
Figure BDA0003608794920000441
The method comprises the following steps: 3-bromobenzene 1,2-diamine (1000 mg) and isobutyraldehyde (385 mg) were used as raw materials, and the target compound 409.3mg was obtained by referring to general method eleven.1H NMR(500MHz,Chloroform-d)δ7.45(d,J＝8.1Hz,1H),7.37(d,J＝7.7Hz,1H),7.06(t,J＝7.9Hz,1H),3.34(p,J＝7.0Hz,1H),1.45(s,3H),1.44(s,3H)。
Step two: using 4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1,3,2-dioxaborane (568 mg) and 4-bromo-2-isopropyl-1H-benzo [ d]Imidazole (409.3 mg) was used as the starting material, and 470.2mg of the target compound was obtained according to general procedure fourteen. Data for trifluoroacetate type compounds1H NMR(500MHz,Methanol-d4)δ7.72(dd,J＝8.2,1.0Hz,1H),7.60(t,J＝7.9Hz,1H),7.58–7.54(m,4H),7.51(dd,J＝7.6,1.0Hz,1H),6.24(tt,J＝3.9,1.7Hz,1H),3.57(p,J＝7.0Hz,1H),2.46(tq,J＝6.3,2.3Hz,2H),2.24(dtt,J＝6.3,4.2,2.2Hz,2H),1.86–1.78(m,2H),1.73–1.65(m,2H),1.54(s,3H),1.52(s,3H).13C NMR(126MHz,Methanol-d4)δ144.44,137.35,135.23,132.94,130.21,130.17,129.50,127.56,127.04,126.78,126.52,28.77,28.37,26.92,24.15,23.23,20.75。
Synthesis of intermediate 65: methyl 4- ((2- (3-aminopropyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoate (FD 126)
Figure BDA0003608794920000442
The method comprises the following steps: with 2- (3- ((tert-butyldiphenylsilyl) oxy) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (300 mg) and methyl 4- (bromomethyl) benzoate (229 mg) were used as starting materials, and 338.9mg of the title compound was obtained in accordance with general procedure twelve.1H NMR(500MHz,Chloroform-d)δ8.04–8.01(m,2H),7.99–7.95(m,2H),7.63–7.60(m,4H),7.53–7.50(m,2H),7.47–7.43(m,2H),7.41–7.39(m,1H),7.33(dd,J＝7.9,6.7Hz,4H),7.28–7.24(m,1H),7.11(dd,J＝8.1,1.0Hz,1H),7.08(d,J＝8.2Hz,2H),6.21(tt,J＝4.0,1.6Hz,1H),5.40(s,2H),3.91(s,3H),3.81(t,J＝5.8Hz,2H),3.00(t,J＝7.7Hz,2H),2.48(ddq,J＝6.5,4.2,2.1Hz,2H),2.25(dt,J＝9.4,4.5Hz,2H),2.10(dq,J＝12.4,6.1Hz,2H),1.87–1.79(m,2H),1.73–1.66(m,2H),1.04(s,9H)。
Step two: methyl 4- ((2- (3- ((tert-butyldiphenylsilyl) oxy) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl)) -1H-benzo [ d]Imidazol-1-yl) methyl) benzoate (338.9 mg) and tetrabutylammonium fluoride trihydrate (296 mg) were put in an eggplant-shaped flask, and THF (20 mL) was added thereto, followed by stirring at room temperature overnight. After the reaction, the reaction mixture was concentrated by a rotary evaporator and purified by a silica gel column to obtain 195.4mg of the objective compound.1H NMR(500MHz,Chloroform-d)δ7.96(d,J＝8.1Hz,2H),7.91(d,J＝8.2Hz,2H),7.53(d,J＝8.3Hz,2H),7.41(d,J＝7.5Hz,1H),7.26(t,J＝7.7Hz,1H),7.11(d,J＝8.0Hz,1H),7.08(d,J＝8.1Hz,2H),6.21(tt,J＝3.7,1.6Hz,1H),5.34(s,2H),3.89(s,3H),3.71(t,J＝5.2Hz,2H),2.94(t,J＝6.5Hz,2H),2.45(ddt,J＝6.2,4.3,2.1Hz,2H),2.22(dq,J＝9.1,5.5,4.1Hz,2H),2.01(q,J＝5.9Hz,2H),1.82–1.76(m,2H),1.70–1.62(m,2H)。
Step three: methyl 4- ((2- (3-hydroxypropyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazol-1-yl) methyl) benzoate (195.4 mg) and isoindoline-1,3-dione (91 mg) were added to an eggplant-shaped flask, THF (10 mL) and triphenylphosphine (314 mg) were added, stirring was performed at 0 ℃ for 0.5h, followed by dropwise addition of 1,2-dicarboxylic acid diisopropyl ester (242 mg), warming to room temperature at 0 ℃ and stirring overnight. After the reaction is finished, adding water to quench the reaction, extracting the water phase for 3 times by using ethyl acetate, combining the organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, and concentrating by using a rotary evaporator to obtain a crude product. The crude product was then added to an eggplant-shaped flask and dissolved in methanol (10 mL), and N was added2H4-H2O (50 mg). After stirring overnight at room temperature, the mixture was purified by silica gel column to obtain 76.1mg of the objective compound. Data for trifluoroacetate type compounds1H NMR(500MHz,Methanol-d4)δ7.96–7.90(m,2H),7.84–7.78(m,2H),7.47(d,J＝8.3Hz,2H),7.31(dd,J＝5.6,2.9Hz,1H),7.26–7.20(m,2H),7.14(d,J＝8.2Hz,2H),6.18(tt,J＝3.9,1.7Hz,1H),5.53(s,2H),3.84(s,3H),2.93(t,J＝7.5Hz,2H),2.70(t,J＝6.9Hz,2H),2.43(tq,J＝6.5,2.2Hz,2H),2.21(tq,J＝6.2,2.7Hz,2H),1.86(p,J＝7.2Hz,2H),1.83–1.74(m,2H),1.71–1.58(m,2H)。
Synthesis of intermediate 66: methyl 2- (4- ((4-bromo-2-phenyl-1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetate (FE 128)
Figure BDA0003608794920000451
The method comprises the following steps: with 4-bromo-2-phenyl-1H-benzo [ d]Imidazole (489.6 mg) and (4- (bromomethyl) phenethyloxy) (tert-butyl) diphenylsilane (1.6 g) were used as starting materials to obtain 284.5mg of a target compound, in accordance with general procedure twelve.1H NMR(500MHz,Chloroform-d)δ7.74–7.70(m,2H),7.60–7.57(m,4H),7.51–7.46(m,3H),7.44–7.39(m,4H),7.34(d,J＝7.4Hz,3H),7.15–7.12(m,2H),7.07(d,J＝7.8Hz,1H),6.98(d,J＝7.8Hz,2H),5.41(s,2H),3.84(t,J＝6.7Hz,2H),2.84(t,J＝6.7Hz,2H),1.02(s,9H)。
Step two: reacting 4-bromo-1- (4- (2- ((tert-butyldiphenylsilyl) oxy) ethyl) benzyl) -2-phenyl-1H-benzo [ d]Imidazole (284.5 mg) and tetrabutylammonium fluoride trihydrate (277 mg) were put in an eggplant type flask, and THF (10 mL) was added thereto, followed by stirring at room temperature overnight. After the reaction was completed, concentration was performed on a rotary evaporator to obtain a crude compound (159 mg). IBX (280 mg) was then added to the eggplant-shaped flask, THF (5 mL) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, water was added to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator to give a crude compound (141.6 mg). The crude compound is then dissolved in H2O t-BuOH (0.1M, 5 mL), 2,3-dimethyl-2-butene (0.1 mL), naH were added2PO4(35.6 mg) and sodium chlorite (28 mg) were reacted at room temperature for 3 hours, after the reaction was completed, water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporator to obtain a crude compound (147 mg). Then dissolved in methanol, concentrated sulfuric acid (0.1 mL) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, concentration was performed on a rotary evaporator to obtain a crude compound (140 mg).1H NMR(500MHz,Chloroform-d)δ7.66–7.63(m,2H),7.49–7.46(m,1H),7.45–7.42(m,1H),7.40(d,J＝7.5Hz,2H),7.22(d,J＝8.0Hz,2H),7.13(dd,J＝8.4,1.0Hz,1H),7.07(t,J＝7.9Hz,1H),7.00(d,J＝7.9Hz,2H),5.38(s,2H),3.68(s,3H),3.60(s,2H)。
Synthesis of intermediate 67: methyl 2- (2- ((4-bromo-2-phenyl-1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetate (FD 157)
Figure BDA0003608794920000461
The method comprises the following steps: starting from 4-bromo-2-phenyl-1H-benzo [ d ] imidazole (400 mg) and (2- (bromomethyl) phenethyloxy) (tert-butyl) diphenylsilane (1.67 g), 1.53g of the title compound was obtained according to general procedure twelve.
Step two: reacting 4-bromo-1- (2- (2- ((tert-butyldiphenylsilyl) oxy) ethyl) benzyl) -2-phenyl-1H-benzo [ d]Imidazole (300 mg) and tetrabutylammonium fluoride trihydrate (290 mg) were put in an eggplant-shaped flask, THF (15 mL) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, concentration was performed on a rotary evaporator to obtain a crude compound (130 mg). IBX (256 mg) was then added to the eggplant-shaped flask, THF (5 mL) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, water was added to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporator to give a crude compound (135 mg). The crude compound is then dissolved in H2O t-BuOH (0.1M, 5mL), 2,3-dimethyl-2-butene (0.1 mL), naH were added2PO4(34 mg) and sodium chlorite (25 mg) were reacted at room temperature for 3 hours, after the reaction was completed, water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporator to obtain a crude compound (125 mg). Then dissolved in methanol, concentrated sulfuric acid (0.1 mL) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, concentration was performed on a rotary evaporator to obtain a crude compound (86.6 mg). Data for trifluoroacetate type compounds1H NMR(500MHz,Methanol-d4)δ7.75–7.70(m,2H),7.66(td,J＝7.6,1.1Hz,2H),7.62–7.53(m,2H),7.48(dd,J＝8.3,0.9Hz,1H),7.35–7.25(m,3H),7.18(ddd,J＝8.9,7.0,2.0Hz,1H),6.74–6.69(m,1H),5.68(s,2H),3.75(s,2H),3.56(s,3H).13C NMR(126MHz,Methanol-d4)δ173.00,155.56,138.10,136.51,135.15,133.47,133.01,132.71,130.77,130.32,129.44,129.19,128.96,127.32,127.07,126.97,112.81,111.02,52.63,38.81。
EXAMPLE 1 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (4-chlorophenyl) -1H-indazol-3-amine (QJ 54)
Figure BDA0003608794920000462
The general method is six:
4- (4-chlorophenyl) -1H-indazol-3-amine (99 mg) and 1H-imidazole-4-carbaldehyde (47 mg) were added to an eggplant-shaped flask, 1,2-dichloroethane was added, followed by sodium triacetoxyborohydride (174 mg), acetic acid (0.1 mL) was added dropwise, and stirred at room temperature overnight under nitrogen blanket. After the reaction is finished, adding a saturated sodium bicarbonate solution, extracting for 3 times by using ethyl acetate, combining organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, concentrating by using a rotary evaporator, purifying by using HPLC (high performance liquid chromatography) to obtain trifluoroacetate of a target compound, and freeze-drying to obtain a solid of 37.4mg.1H NMR(400MHz,Methanol-d4) δ 8.74 (d, J =1.48hz, 1h), 7.56-7.45 (m, 4H), 7.40-7.30 (m, 3H), 6.89 (dd, J =6.07,1.85hz, 1h), 4.49 (s, 2H). Theoretical calculation of ESI-MS C17H15 35ClN5 +[M+H]+=324.1; the experiment shows that: 324.0.
EXAMPLE 2 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (3-chlorophenyl) -1H-indazol-3-amine (QJ 60)
Figure BDA0003608794920000471
Starting from 4- (3-chlorophenyl) -1H-indazol-3-amine (73 mg) and 1H-imidazole-4-carbaldehyde (35 mg), 64.2mg of the trifluoroacetate salt of the objective compound was obtained according to general procedure six.1H NMR(400MHz,Methanol-d4) δ 8.77 (d, J =1.44hz, 1h), 7.52 (t, J =1.83hz, 1h), 7.48-7.35 (m, 6H), 6.90 (dd, J =6.27,1.62hz, 1h), 4.53 (s, 2H). ESI-MS theoretical calculation C17H15 35ClN5 +[M+H]+=324.1; the experiment shows that: 324.1.
EXAMPLE 3 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4-phenyl-1H-indazol-3-amine (QJ 64)
Figure BDA0003608794920000472
Starting from 4-phenyl-1H-indazol-3-amine (50 mg) and 1H-imidazole-4-carbaldehyde (28 mg), 52.8mg of the trifluoroacetate salt of the target compound was obtained according to general procedure six.1H NMR(400MHz,Methanol-d4) δ 8.74 (d, J =1.48hz, 1h), 7.58-7.40 (m, 5H), 7.40-7.24 (m, 3H), 6.88 (dd, J =6.49,1.41hz, 1h), 4.48 (s, 2H). ESI-MS theoretical calculation C17H16N5 +[M+H]+=290.1; the experiment shows that: 290.1.
EXAMPLE 4 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (QJ 68)
Figure BDA0003608794920000473
Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (65 mg) and 1H-imidazole-4-carbaldehyde (28 mg), 70.4mg of the trifluoroacetate salt of the title compound was obtained according to general method six.1H NMR(400MHz,Methanol-d4) δ 8.77 (d, J =1.47hz, 1h), 7.56-7.48 (m, 2H), 7.47-7.40 (m, 2H), 7.40-7.29 (m, 3H), 6.88 (dd, J =6.82,1.12hz, 1h), 4.49 (s, 2H), 1.36 (s, 9H). Theoretical calculation of ESI-MS C21H24N5 +[M+H]+=346.2; the experiment shows that: 346.3.
EXAMPLE 5 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (3- (tert-butyl) phenyl) -1H-indazol-3-amine (QJ 73)
Figure BDA0003608794920000474
Starting from 4- (3- (tert-butyl) phenyl) -1H-indazol-3-amine (96 mg) and 1H-imidazole-4-carbaldehyde (42 mg), 70.4mg of the trifluoroacetate salt of the title compound was obtained according to general method six.1H NMR(400MHz,Methanol-d4) δ 8.77 (d, J =1.45hz, 1h), 7.55-7.46 (m, 2H), 7.46-7.39 (m, 2H), 7.38-7.28 (m, 3H), 6.92 (dd, J =6.95,0.99hz, 1h), 4.52 (s, 2H), 1.32 (s, 9H). Theoretical calculation of ESI-MS C21H24N5 +[M+H]+=346.2; the test shows that: 346.2.
EXAMPLE 6 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (naphthalen-2-yl) -1H-indazol-3-amine (QJ 74)
Figure BDA0003608794920000481
Starting from 4- (naphthalen-2-yl) -1H-indazol-3-amine (80 mg) and 1H-imidazole-4-carbaldehyde (36 mg), the trifluoroacetate salt of the target compound was obtained (81.4 mg) according to general method six.1H NMR(400MHz,Methanol-d4) δ 8.69 (d, J =1.57hz, 1h), 8.04-7.97 (m, 2H), 7.96-7.88 (m, 2H), 7.66 (dd, J =8.48,1.76hz, 1h), 7.58-7.50 (m, 2H), 7.45-7.33 (m, 2H), 7.25 (d, J =1.38hz, 1h), 7.01 (dd, J =6.68,1.18hz, 1h), 4.44 (s, 2H). ESI-MS theoretical calculation C21H18N5 +[M+H]+=340.1; the test shows that: 340.1.
EXAMPLE 7 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (1H-indol-5-yl) -1H-indazol-3-amine (QJ 75)
Figure BDA0003608794920000482
Starting from 4- (1H-indol-5-yl) -1H-indazol-3-amine (263 mg) and 1H-imidazole-4-carbaldehyde (122 mg), 74.3mg of the trifluoroacetate salt of the objective compound was obtained according to general method six.1H NMR(400MHz,Methanol-d4) δ 8.72 (d, J =1.47hz, 1h), 7.63 (d, J =1.75hz, 1h), 7.51 (d, J =8.32hz, 1h), 7.46 (dd, J =8.51,7.03hz, 1h), 7.35-7.28 (m, 3H), 7.25 (d, J =1.34hz, 1h), 7.21 (dd, J =8.32,1.75hz, 1h), 6.97 (d, J =7.01hz, 1h), 4.48 (s, 2H). Theoretical calculation of ESI-MS C19H17N6 +[M+H]+=329.1; the experiment shows that: 329.0.
EXAMPLE 8 Synthesis of 4-phenyl-N- (thiazol-2-ylmethyl) -1H-indazol-3-amine (QJ 77)
Figure BDA0003608794920000483
Starting from 4-phenyl-1H-indazol-3-amine (60 mg) and thiazole-2-carbaldehyde (40 mg), the trifluoroacetate salt of the title compound was obtained according to general procedure six.2mg。1H NMR(400MHz,Methanol-d4) δ 7.83 (d, J =3.55hz, 1h), 7.63 (d, J =3.46hz, 1h), 7.56-7.45 (m, 6H), 7.38 (dd, J =8.48,0.88hz, 1h), 6.98 (dd, J =6.97,0.89hz, 1h), 4.83 (s, 2H). Theoretical calculation of ESI-MS C17H15N4S+[M+H]+=307.1; the experiment shows that: 306.6.
EXAMPLE 9 Synthesis of 4-phenyl-N- (pyridin-4-ylmethyl) -1H-indazol-3-amine (QJ 78)
Figure BDA0003608794920000491
Starting from 4-phenyl-1H-indazol-3-amine (60 mg) and isonicotinal (40 mg), 8.6mg of the trifluoroacetate salt of the target compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4) δ 8.72-8.66 (m, 2H), 8.01-7.94 (m, 2H), 7.61-7.57 (m, 2H), 7.55-7.51 (m, 2H), 7.48-7.44 (m, 1H), 7.39 (dd, J =8.44,6.94hz, 1h), 7.32 (dd, J =8.47,0.86hz, 1h), 6.92 (dd, J =7.02,0.89hz, 1h), 4.73 (s, 2H). ESI-MS theoretical calculation C19H17N4 +[M+H]+=301.1; the experiment shows that: 300.6.
EXAMPLE 10 Synthesis of 4-phenyl-N- (pyridin-3-ylmethyl) -1H-indazol-3-amine (QJ 80)
Figure BDA0003608794920000492
Starting from 4-phenyl-1H-indazol-3-amine (50 mg) and nicotinaldehyde (28 mg), 29.3mg of the trifluoroacetate salt of the target compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 8.76-8.72 (m, 1H), 8.70 (d, J =5.72hz, 1h), 8.54 (dt, J =8.17,1.72hz, 1h), 8.00 (dd, J =8.13,5.75hz, 1h), 7.58-7.50 (m, 4H), 7.48-7.43 (m, 1H), 7.40 (dd, J =8.47,6.94hz, 1h), 7.33 (dd, J =8.43,0.89hz, 1h), 6.92 (dd, J =6.99,0.92hz, 1h), 4.64 (s, 2H). Theoretical calculation of ESI-MS C19H17N4 +[M+H]+=301.1; the test shows that: 300.6.
EXAMPLE 11 Synthesis of N, 1-bis (((1H-imidazol-4-yl) methyl) -4- ([ [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QJ 91)
Figure BDA0003608794920000493
With 4- ([ 1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (35 mg) and 1H-imidazole-4-carbaldehyde (18 mg), according to general procedure six, 25.2mg of the trifluoroacetate salt of the target compound was obtained.1H NMR(500MHz,Methanol-d4) δ 8.83 (d, J =1.46hz, 1h), 8.72 (d, J =1.45hz, 1h), 7.79-7.73 (m, 2H), 7.70-7.65 (m, 2H), 7.59-7.55 (m, 2H), 7.52-7.43 (m, 5H), 7.39-7.30 (m, 2H), 6.99 (dd, J =6.95,1.02hz, 1h), 5.57 (s, 2H), 4.53 (s, 2H). Theoretical calculation of ESI-MS C27H24N7 +[M+H]+=446.2; the test shows that: 446.1.
EXAMPLE 12 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -5- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (QJ 93)
Figure BDA0003608794920000501
Starting from 5- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (92 mg) and 1H-imidazole-4-carbaldehyde (36 mg), according to general procedure six, 60.3mg of the trifluoroacetate salt of the title compound was obtained.1H NMR(500MHz,Methanol-d4) δ 8.83 (d, J =1.51hz, 1h), 8.00 (dd, J =1.73,0.84hz, 1h), 7.73 (dd, J =8.75,1.70hz, 1h), 7.58-7.53 (m, 2H), 7.51 (q, J =1.02hz, 1h), 7.48-7.44 (m, 2H), 7.41 (dd, J =8.68,0.84hz, 1h), 4.71 (s, 2H), 1.35 (s, 9H). Theoretical calculation of ESI-MS C21H24N5 +[M+H]+=346.2; the experiment shows that: 345.9.
EXAMPLE 13 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -5- (3- (tert-butyl) phenyl) -1H-indazol-3-amine (QJ 94)
Figure BDA0003608794920000502
Starting from 5- (3- (tert-butyl) phenyl) -1H-indazol-3-amine (95 mg) and 1H-imidazole-4-carbaldehyde (37 mg), 107.4mg of the trifluoroacetate salt of the title compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4) δ 8.86 (d, J =1.47hz, 1h), 8.15-8.08 (m, 1H), 7.82 (dd, J =8.82,1.69hz, 1h), 7.64 (t, J =1.87hz, 1h), 7.56 (d, J =1.33hz, 1h), 7.46 (d, J =8.80hz, 1h), 7.42-7.31 (m, 3H), 4.76 (s, 2H), 1.35 (s, 9H). Theoretical calculation of ESI-MS C21H24N5 +[M+H]+=346.2; the experiment shows that: 345.6.
EXAMPLE 14 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4-isopropylphenyl) -1H-indazol-3-amine (QJ 101)
Figure BDA0003608794920000503
Starting from 4- (4-isopropylphenyl) -1H-indazol-3-amine (80 mg) and 1H-imidazole-4-carbaldehyde (33 mg), 78.5mg of the trifluoroacetate salt of the target compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4) δ 8.75 (d, J =1.47hz, 1h), 7.43 (dd, J =8.25,2.14hz, 2h), 7.39-7.29 (m, 5H), 6.87 (dt, J =6.78,1.54hz, 1h), 4.48 (s, 2H), 2.98 (pd, J =7.13,1.87hz, 1h), 1.30 (dd, J =7.01,1.51hz, 6H). Theoretical calculation of ESI-MS C20H22N5 +[M+H]+=332.1; the experiment shows that: 332.0.
EXAMPLE 15 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QJ 103)
Figure BDA0003608794920000511
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (80 mg) and 1H-imidazole-4-carbaldehyde (32 mg), according to general procedure six, 14.5mg of the trifluoroacetate salt of the title compound was obtained.1H NMR(500MHz,Methanol-d4)δ8.75(d,J＝1.48Hz,1H),7.54–7.50(m2H), 7.46-7.43 (m, 2H), 7.38 (dd, J =8.46,6.88hz, 1h), 7.35-7.30 (m, 2H), 6.90 (dd, J =6.97,0.96hz, 1h), 6.23 (tt, J =3.85,1.70hz, 1h), 4.50 (s, 2H), 2.46 (tq, J =6.41,2.27hz, 2h), 2.26 (ddt, J =8.54,6.26,3.11hz, 2h), 1.87-1.80 (m, 2H), 1.74-1.67 (m, 2H). Theoretical calculation of ESI-MS C23H24N5 +[M+H]+=370.2; the experiment shows that: 370.3.
EXAMPLE 16 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (cyclopent-1-en-1-yl) phenyl) -1H-indazol-3-amine (QJ 104)
Figure BDA0003608794920000512
Starting from 4- (4- (cyclopent-1-en-1-yl) phenyl) -1H-indazol-3-amine (80 mg) and 1H-imidazole-4-carbaldehyde (34 mg), 47.2mg of the trifluoroacetate salt of the title compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4) δ 8.75 (d, J =1.48hz, 1h), 7.61-7.57 (m, 2H), 7.49-7.45 (m, 2H), 7.44-7.40 (m, 2H), 7.34-7.30 (m, 1H), 6.92 (dd, J =8.06,6.90hz, 1h), 6.31 (p, J =2.26hz, 1h), 4.51 (s, 2H), 2.76 (tq, J =6.92,2.24hz, 2h), 2.57 (tq, J =7.45,2.52hz, 2h), 2.07 (p, J =7.57hz, 2h). Theoretical calculation of ESI-MS C22H22N5 +[M+H]+=356.1; the experiment shows that: 356.4.
EXAMPLE 17 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4-cyclohexylphenyl) -1H-indazol-3-amine (QJ 107)
Figure BDA0003608794920000513
Starting from 4- (4-cyclohexylphenyl) -1H-indazol-3-amine (80 mg) and 1H-imidazole-4-carbaldehyde (32 mg), 31mg of the trifluoroacetate salt of the target compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4)δ8.76(d,J＝1.42Hz,1H),7.44–7.41(m,2H),7.40–7.30(m,5H),6.89(dd,J＝6.94,0.94Hz,1H),4.49(d,J＝0.99Hz,2H),2.64–2.54(m,1H),1.95–1.75(m,5H),1.56–1.41(m,4H),1.39–1.29(m,1H)。ESITheoretical calculation of MS C23H26N5 +[M+H]+=372.1; the experiment shows that: 372.3.
EXAMPLE 18 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4-cyclopentylphenyl) -1H-indazol-3-amine (QJ 109)
Figure BDA0003608794920000521
Starting from 4- (4-cyclopentylphenyl) -1H-indazol-3-amine (100 mg) and 1H-imidazole-4-carbaldehyde (32 mg), 33.2mg of the trifluoroacetate salt of the title compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 8.77 (s, 1H), 7.45-7.29 (m, 7H), 6.90 (d, J =6.82hz, 1h), 4.50 (s, 2H), 3.08 (ddd, J =17.14,9.77,7.47hz, 1h), 2.15-2.05 (m, 2H), 1.86 (tq, J =10.28,5.85,4.28hz, 2h), 1.75 (qt, J =6.12,3.67hz, 2h), 1.70-1.56 (m, 2H). Theoretical calculation of ESI-MS C22H24N5 +[M+H]+=358.2; the experiment shows that: 358.8.
EXAMPLE 19 Synthesis of 4- (4- (tert-butyl) phenyl) -N- (pyridin-4-ylmethyl) -1H-indazol-3-amine (QJ 111)
Figure BDA0003608794920000522
Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (80 mg) and isonicotinal (32 mg), 10.4mg of the trifluoroacetate salt of the target compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4) δ 8.71-8.67 (m, 2H), 8.00-7.95 (m, 2H), 7.60-7.56 (m, 2H), 7.55-7.50 (m, 2H), 7.38 (dd, J =8.47,6.94hz, 1h), 7.30 (dd, J =8.39,0.87hz, 1h), 6.91 (dd, J =7.00,0.89hz, 1h), 4.74 (s, 2H), 1.38 (s, 9H). Theoretical calculation of ESI-MS C23H25N4 +[M+H]+=357.2; the experiment shows that: 356.5.
EXAMPLE 20 Synthesis of 4- (4- (tert-butyl) phenyl) -N- (pyridin-3-ylmethyl) -1H-indazol-3-amine (QJ 112)
Figure BDA0003608794920000523
Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (80 mg) and nicotinaldehyde (32 mg), 28.4mg of the trifluoroacetate salt of the title compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4) δ 8.78-8.73 (m, 1H), 8.69 (d, J =5.69hz, 1h), 8.52 (dt, J =8.26,1.61hz, 1h), 7.98 (dd, J =8.15,5.71hz, 1h), 7.58-7.53 (m, 2H), 7.52-7.47 (m, 2H), 7.37 (dd, J =8.43,6.94hz, 1h), 7.30 (dd, J =8.56,0.89hz, 1h), 6.89 (dd, J =6.92,0.95hz, 1h), 4.64 (s, 2H), 1.37 (s, 9H). Theoretical calculation of ESI-MS C23H25N4 +[M+H]+=357.2; the experiment shows that: 357.3.
EXAMPLE 21 Synthesis of 4- (4- (tert-butyl) phenyl) -N- (pyridin-2-ylmethyl) -1H-indazol-3-amine (QJ 114)
Figure BDA0003608794920000531
Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (80 mg) and picolinic aldehyde (32 mg), 27.7mg of the trifluoroacetate salt of the title compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 8.66 (dt, J =5.76,1.23hz, 1h), 8.46 (td, J =7.92,1.58hz, 1h), 7.98 (d, J =8.10hz, 1h), 7.87 (ddd, J =7.48,5.82,1.24hz, 1h), 7.60-7.52 (m, 4H), 7.38 (dd, J =8.46,6.94hz, 1h), 7.31 (dd, J =8.41,0.89hz, 1h), 6.92 (dd, J =7.00,0.92hz, 1h), 4.80 (s, 2H), 1.38 (s, 9H). Theoretical calculation of ESI-MS C23H25N4 +[M+H]+=357.2; the experiment shows that: 357.2.
EXAMPLE 22 Synthesis of 4- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QJ 116)
Figure BDA0003608794920000532
With 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (80 mg) and4-formylbenzoic acid (45 mg) was used as a starting material to obtain 17.1mg of a trifluoroacetate salt of the objective compound according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 8.03-7.96 (m, 2H), 7.67 (dd, J =8.59,7.10hz, 1h), 7.54-7.49 (m, 2H), 7.47-7.41 (m, 3H), 7.36 (d, J =8.05hz, 2h), 7.10 (d, J =7.10hz, 1h), 4.51 (s, 2H), 1.29 (s, 9H). Theoretical calculation of ESI-MS C25H26N3O2 +[M+H]+=400.2; the experiment shows that: 399.7.
EXAMPLE 23 Synthesis of 3- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QJ 121)
Figure BDA0003608794920000533
Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (58 mg) and 3-formylbenzoic acid (31 mg), 15.3mg of the trifluoroacetate salt of the target compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4) δ 8.00 (d, J =1.85hz, 1h), 7.96 (dt, J =7.63,1.58hz, 1h), 7.62 (dd, J =8.57,7.11hz, 1h), 7.53-7.47 (m, 3H), 7.47-7.38 (m, 4H), 7.06 (d, J =6.96hz, 1h), 4.48 (s, 2H), 1.26 (s, 9H). Theoretical calculation of ESI-MS C25H26N3O2 +[M+H]+=400.2; the experiment shows that: 399.6.
EXAMPLE 24 Synthesis of 2- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QJ 122)
Figure BDA0003608794920000541
Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (60 mg) and 2-formylbenzoic acid (32 mg), 15.3mg of the trifluoroacetate salt of the title compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4)δ8.03(dd,J＝7.78,1.47Hz,1H),7.63(dd,J＝8.56,7.06Hz,1H),7.52(td,J＝7.55,1.50Hz,1H),7.46–7.38(m,5H),7.33–7.29(m,2H),7.05(dd,J＝7.14,0.80Hz,1H),4.71(s,2H),1.27(s,9H). ESI-MS theoretical calculation C25H26N3O2 +[M+H]+=400.2; the test shows that: 400.0.
EXAMPLE 25 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- ([ [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QJ 126)
Figure BDA0003608794920000542
With 4- ([ 1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (80 mg) and 1H-imidazole-4-carbaldehyde (26 mg), 28.5mg of the trifluoroacetate salt of the title compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 8.74 (s, 1H), 7.77 (d, J =7.70hz, 2h), 7.69 (d, J =7.63hz, 2h), 7.61 (d, J =7.76hz, 2h), 7.52-7.30 (m, 6H), 6.98 (d, J =6.95hz, 1h), 4.53 (s, 2H). ESI-MS theoretical calculation C23H20N5 +[M+H]+=366.1; the test shows that: 366.7.
EXAMPLE 26 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl) -1H-indazol-3-amine (QJ 131)
Figure BDA0003608794920000543
The general method is seven:
the method comprises the following steps: synthesis of 4- (4- (3- ((((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) phenyl) -3,6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (QJ 131-1)
4- (4- (3-amino-1H-indazol-4-yl) phenyl) -3,6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (80 mg) and 1H-imidazole-4-carbaldehyde (19 mg) were added to an eggplant-shaped flask, 1,2-dichloroethane was added, followed by sodium triacetoxyborohydride (85 mg), acetic acid (0.1 mL) was added dropwise, and stirred at room temperature under nitrogen overnight. After the reaction was completed, a saturated sodium bicarbonate solution was added, extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporator to be used directly in the next step.
Step two: synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl) -1H-indazol-3-amine (QJ 131)
All of QJ131 obtained in the previous step was placed in an eggplant type flask, methylene chloride (8 mL) was added, and trifluoroacetic acid (2 mL) was added dropwise and stirred at room temperature overnight. After the reaction, the reaction mixture was concentrated by a rotary evaporator and purified by HPLC to obtain 58.2mg of trifluoroacetate salt of the objective compound.1H NMR (500mhz, chloroform-d) δ 8.74 (d, J =1.40hz, 1h), 7.62-7.58 (m, 2H), 7.54-7.51 (m, 2H), 7.41 (dd, J =8.49,6.87hz, 1h), 7.37-7.33 (m, 2H), 6.92 (dd, J =6.86,0.99hz, 1h), 6.24 (tt, J =3.55,1.68hz, 1h), 4.52 (s, 2H), 3.90 (q, J =2.66hz, 2h), 3.50 (t, J =6.12hz, 2h), 2.86 (tt, J =6.82, 1.74742h). Theoretical calculation of ESI-MS C22H23N6 +[M+H]+=371.1; the test shows that: 370.7.
EXAMPLE 27 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4-bromophenyl) -1H-indazol-3-amine (QJ 132)
Figure BDA0003608794920000551
Starting from 4- (4-bromophenyl) -1H-indazol-3-amine (91 mg) and 1H-imidazole-4-carbaldehyde (29 mg), 51.4mg of the trifluoroacetate salt of the target compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4) δ 8.76 (s, 1H), 7.65 (d, J =8.17hz, 2h), 7.48-7.34 (m, 5H), 6.93 (d, J =6.92hz, 1h), 4.53 (s, 2H). ESI-MS theoretical calculation C17H15 79BrN5 +[M+H]+=368.0; the experiment shows that: 367.0.
EXAMPLE 28 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (1,2,5,6-tetrahydropyridin-3-yl) phenyl) -1H-indazol-3-amine (QJ 138)
Figure BDA0003608794920000552
With 5- (4- (3-amino-1H-indazol-4-yl) phenyl) -3,6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (80 mg) and 1H-imidazoleOxazole-4-carbaldehyde (19 mg) was used as a starting material, and 12.4mg of a trifluoroacetate salt of the objective compound was obtained according to general procedure seven.1H NMR(500MHz,Methanol-d4) δ 8.74 (d, J =1.46hz, 1h), 7.56 (s, 4H), 7.42-7.31 (m, 3H), 6.91 (d, J =6.68hz, 1h), 6.46 (td, J =4.13,2.06hz, 1h), 4.51 (s, 2H), 4.15 (q, J =2.25hz, 2h), 3.41 (t, J =6.21hz, 2h), 2.64 (dh, J =8.83,2.69hz, 2h). Theoretical calculation of ESI-MS C22H23N6 +[M+H]+=371.1; the experiment shows that: 370.1.
EXAMPLE 29 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (4- (pyridin-4-yl) phenyl) -1H-indazol-3-amine (QJ 143)
Figure BDA0003608794920000561
Starting from 4- (4- (pyridin-4-yl) phenyl) -1H-indazol-3-amine (224 mg) and 1H-imidazole-4-carbaldehyde (68 mg), 191.5mg of the trifluoroacetate salt of the target compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4) δ 8.92-8.86 (m, 2H), 8.73 (d, J =1.47hz, 1h), 8.49-8.43 (m, 2H), 8.14-8.09 (m, 2H), 7.82-7.76 (m, 2H), 7.46-7.38 (m, 2H), 7.36 (d, J =1.37hz, 1h), 6.99 (dd, J =6.16,1.70hz, 1h), 4.53 (s, 2H). ESI-MS theoretical calculation C22H19N6 +[M+H]+=367.1; the experiment shows that: 367.3.
EXAMPLE 30 Synthesis of 3- (((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QJ 156)
Figure BDA0003608794920000562
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (60 mg) and 3-formylbenzoic acid (28 mg), 2mg of the trifluoroacetate salt of the title compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4)δ8.01–7.93(m,2H),7.59(dd,J＝8.54,7.04Hz,1H),7.52–7.36(m,7H),7.05(d,J＝7.05Hz,1H),6.12(tt,J =3.85,1.68hz, 1h), 4.48 (s, 2H), 2.35 (tq, J =6.34,2.33hz, 2h), 2.23 (dh, J =8.92,2.78hz, 2h), 1.84-1.76 (m, 2H), 1.72-1.64 (m, 2H). Theoretical calculation of ESI-MS C27H26N3O2 +[M+H]+=424.2; the experiment shows that: 422.8.
EXAMPLE 31 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 3)
Figure BDA0003608794920000563
With 4- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (89 mg) of (E) -4-yl) -1H-indazol-3-amine and (26 mg) of 1H-imidazole-4-carbaldehyde, according to general procedure six, 48.4mg of the trifluoroacetate salt of the target compound was obtained.1H NMR(500MHz,Methanol-d4) δ 8.75 (d, J =1.43hz, 1h), 7.40 (dd, J =8.48,6.97hz, 1h), 7.34-7.28 (m, 2H), 7.22-7.18 (m, 1H), 7.13-7.07 (m, 2H), 6.85 (dd, J =6.97,0.87hz, 1h), 6.24 (tt, J =3.95,1.70hz, 1h), 4.49 (dd, J =2.20,0.95hz, 2h), 3.72 (s, 3H), 2.46 (tq, J =6.38, 2.38hz, 2h), 2.26 (ddt, J =8.48,6.35,2.77hz, 2h), 1.87-1.79 (m, 2H), 1.74-1.66 (m, 2H). Theoretical calculation of ESI-MS C24H26N5O+[M+H]+=400.2; the experiment shows that: 399.8.
EXAMPLE 32 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (2-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 15)
Figure BDA0003608794920000571
With 4- (2-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (105 mg) and 1H-imidazole-4-carbaldehyde (31 mg), according to general procedure six, 50.5mg of the trifluoroacetate salt of the target compound was obtained.1H NMR(500MHz,Methanol-d4)δ8.76(d,J＝1.44Hz,1H),7.39(dd,J＝8.46,6.88Hz,1H),7.36–7.31(m,2H),7.19(d,J=7.60hz, 1h), 7.06-6.99 (m, 2H), 6.93 (dd, J =6.86,1.02hz, 1h), 4.53 (s, 2H), 3.80 (s, 3H), 2.37 (tq, J =6.37,2.17hz, 2h), 2.20 (qd, J =5.65,4.75,2.63hz, 2h), 1.79-1.65 (m, 4H). Theoretical calculation of ESI-MS C24H26N5O+[M+H]+=400.2; the experiment shows that: 400.1.
EXAMPLE 33 Synthesis of 4- (4- (tert-butyl) phenyl) -N-phenethyl-1H-indazol-3-amine (QK 16)
Figure BDA0003608794920000572
Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (50 mg) and phenylacetaldehyde (23 mg), 1.3mg of the trifluoroacetate salt of the target compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4) δ 7.50 (dd, J =8.50,7.05hz, 1h), 7.43-7.39 (m, 2H), 7.35 (d, J =8.40hz, 1h), 7.28-7.18 (m, 5H), 7.06-7.01 (m, 2H), 6.92 (d, J =6.97hz, 1h), 3.52 (t, J =6.38hz, 2h), 2.82 (t, J =6.36hz, 2h), 1.36 (s, 9H). Theoretical calculation of ESI-MS C25H28N3 +[M+H]+=370.2; the experiment shows that: 368.8.
EXAMPLE 34 Synthesis of N- (3- (1H-imidazol-4-yl) propyl) -4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (QK 18)
Figure BDA0003608794920000573
The method comprises the following steps: synthesis of 4- (4- (tert-butyl) phenyl) -N- (3- (1-trityl-1H-imidazol-4-yl) propyl) -1H-indazol-3-amine
4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (48 mg) and 3- (1-trityl-1H-imidazol-4-yl) propanal (56 mg) were added to an eggplant-shaped flask, 1,2-dichloroethane was added, followed by sodium triacetoxyborohydride (64 mg), acetic acid (0.1 mL) was added dropwise, and stirred at room temperature under nitrogen overnight. After the reaction was completed, a saturated sodium bicarbonate solution was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by a rotary evaporator to be used directly in the next step.
Step two: synthesis of N- (3- (1H-imidazol-4-yl) propyl) -4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (QK 18)
Adding all the products into an eggplant-shaped flask, adding tetrahydrofuran (10 mL) and hydrochloric acid (1M, 3 mL), heating to reflux, stirring for 2h, concentrating by a rotary evaporator after the reaction is finished, and purifying by HPLC to obtain the trifluoroacetate of the target compound of 32.1mg.1H NMR(500MHz,Methanol-d4) δ 8.79 (d, J =1.46hz, 1h), 7.65-7.57 (m, 3H), 7.45 (dq, J =8.01,1.78,1.35hz, 3h), 7.41 (dd, J =8.59,0.78hz, 1h), 7.27 (t, J =1.20hz, 1h), 7.05 (dd, J =7.15,0.81hz, 1h), 3.35-3.31 (m, 2H), 2.76-2.69 (m, 2H), 1.95-1.86 (m, 2H). Theoretical calculation of ESI-MS C23H28N5 +[M+H]+=374.2; the experiment shows that: 373.4.
EXAMPLE 35 Synthesis of 4- (2- ((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) ethyl) benzoic acid (QK 23)
Figure BDA0003608794920000581
The general method comprises the following steps:
the method comprises the following steps: synthesis of methyl 4- (2- ((4- (4- (4-tert-butyl) phenyl) -1H-indazol-3-yl) amino) ethyl) benzoate (QL 23-1)
4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (118 mg) and methyl 4- (2-oxyethyl) benzoate (66 mg) were added to a eggplant-shaped flask, 1,2-dichloroethane were added, followed by sodium triacetoxyborohydride (157 mg), acetic acid (0.1 mL) was added dropwise, and the mixture was stirred at room temperature under nitrogen overnight. After the reaction was completed, a saturated sodium bicarbonate solution was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator to obtain a crude product of 72mg, which was used directly in the next step.
Step two: synthesis of 4- (2- ((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) ethyl) benzoic acid (QK 23)
Adding all the crude products into a eggplant-shaped flask, and adding 10mL of mixed solutionAgent (MeOH: THF: H)2O =1:1: 1) Lithium hydroxide monohydrate (100 mg) was added thereto, and the mixture was stirred at room temperature overnight. After the reaction, the reaction mixture was concentrated by a rotary evaporator and purified by HPLC to obtain 9.8mg of the trifluoroacetate salt of the objective compound.1H NMR(500MHz,Methanol-d4) δ 7.97-7.91 (m, 2H), 7.57 (dd, J =8.52,7.08hz, 1h), 7.41-7.34 (m, 3H), 7.23-7.20 (m, 2H), 7.19-7.15 (m, 2H), 6.97 (dd, J =7.05,0.79hz, 1h), 3.58 (dd, J =7.05,5.57hz, 2h), 2.93 (t, J =6.27hz, 2h), 1.33 (s, 10H). Theoretical calculation of ESI-MS C26H28N3O2 +[M+H]+=414.2; the experiment shows that: 414.3.
EXAMPLE 36 Synthesis of 3- ((((4- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QK 44)
Figure BDA0003608794920000582
With 4- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (4-yl) -1H-indazol-3-amine (50 mg) and 3-formylbenzoic acid (20 mg), according to general procedure six, 5.9mg of the trifluoroacetate salt of the title compound was obtained.1H NMR(500MHz,Methanol-d4) δ 7.98-7.93 (m, 1H), 7.90 (d, J =1.82Hz, 1H), 7.57 (dd, J =8.54,7.10Hz, 1H), 7.46-7.40 (m, 2H), 7.37 (d, J =8.50Hz, 1H), 7.17 (d, J =7.75Hz, 1H), 7.06-6.99 (m, 2H), 6.96 (d, J =7.05Hz, 1H), 6.09 (tt, J =3.86,1.69hz, 1h), 4.43 (q, J =14.13hz, 2h), 3.73 (s, 3H), 2.33 (tq, J =6.30,2.31hz, 2h), 2.23 (ddt, J =8.72,6.44,2.70hz, 2h), 1.83-1.75 (m, 2H), 1.72-1.65 (m, 2H). Theoretical calculation of ESI-MS C28H28N3O3 +[M+H]+=454.2; the experiment shows that: 453.9.
EXAMPLE 37 Synthesis of 3- (2- ((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) ethyl) benzoic acid (QK 60)
Figure BDA0003608794920000591
Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (100 mg) and methyl 3- (2-oxyethyl) benzoate (80 mg), 11.6mg of the trifluoroacetate salt of the title compound was obtained according to general procedure eight.1H NMR(500MHz,Methanol-d4) δ 7.93 (dt, J =7.82,1.46hz, 1h), 7.82 (t, J =1.84hz, 1h), 7.54 (dd, J =8.50,7.10hz, 1h), 7.41-7.33 (m, 4H), 7.30 (dt, J =7.60,1.49hz, 1h), 7.23-7.17 (m, 2H), 6.95 (dd, J =7.13,0.84hz, 1h), 3.57 (dd, J =6.95,5.72hz, 2h), 2.90 (t, J =6.32hz, 2h), 1.32 (s, 9H). Theoretical calculation of ESI-MS C26H28N3O2 +[M+H]+=414.2; the experiment shows that: 415.5.
EXAMPLE 38 Synthesis of 2- (2- ((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) ethyl) benzoic acid (QK 68)
Figure BDA0003608794920000592
Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (100 mg) and methyl 2- (2-oxyethyl) benzoate (80 mg), 1.5mg of the trifluoroacetate salt of the title compound was obtained according to general procedure eight.1H NMR(500MHz,Methanol-d4) δ 7.99 (dd, J =7.79,1.50hz, 1h), 7.60 (dd, J =8.50,7.07hz, 1h), 7.47-7.35 (m, 5H), 7.29-7.24 (m, 2H), 7.09 (dd, J =7.63,1.30hz, 1h), 7.01 (dd, J =7.04,0.78hz, 1h), 3.57 (t, J =6.48hz, 2h), 3.25 (t, J =6.49, 2h), 1.36 (s, 9H). Theoretical calculation of ESI-MS C26H28N3O2 +[M+H]+=414.2; the experiment shows that: 414.3.
EXAMPLE 39 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (3-ethoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 85)
Figure BDA0003608794920000593
With 4- (3-ethoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-indazol-3-amine (55 mg) and 1H-imidazole-4-carbaldehyde (22 mg) as starting materialsFollowing general procedure six, 14.6mg of the trifluoroacetate salt of the target compound was obtained.1H NMR(500MHz,Methanol-d4) δ 8.75 (d, J =1.48hz, 1h), 7.38 (dd, J =8.45,6.95hz, 1h), 7.33-7.30 (m, 2H), 7.20 (d, J =7.65hz, 1h), 7.12-7.08 (m, 2H), 6.85 (dd, J =6.88,0.90hz, 1h), 6.22 (tt, J =3.89,1.72hz, 1h), 4.48 (s, 2H), 3.98 (q, J =6.96hz, 2h), 2.45 (tq, J =6.47, 2.1hz, 2h), 2.26 (3238 zft 3238, J =8.60,6.36, 3.322hz, 2h), 1.86-1.80 (m, 2H), 1.70 (J = 62, 9, 3.1h), 3.81, 3.32H, 3.80 (m, 2H). Theoretical calculation of ESI-MS C25H28N5O+[M+H]+=414.2; the experiment shows that: 415.4.
EXAMPLE 40 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (5- (cyclohex-1-en-1-yl) pyridin-2-yl) -1H-indazol-3-amine (QK 91)
Figure BDA0003608794920000601
Starting from 4- (5- (cyclohex-1-en-1-yl) pyridin-2-yl) -1H-indazol-3-amine (43 mg) and 1H-imidazole-4-carbaldehyde (13 mg), according to general procedure six, 3.5mg of the trifluoroacetate salt of the title compound was obtained.
1H NMR(500MHz,Methanol-d4) δ 8.77 (d, J =2.28hz, 1h), 8.76 (d, J =1.47hz, 1h), 8.38 (dd, J =8.54,2.29hz, 1h), 8.08 (d, J =8.44hz, 1h), 7.56 (d, J =8.30hz, 1h), 7.50 (dd, J =8.47,7.06hz, 1h), 7.44 (d, J =1.38hz, 1h), 7.35 (d, J =6.95hz, 1h), 6.53 (tt, J =3.92,1.67hz, 1h), 4.60 (s, 2H), 2.48 (tq, J =6.44,2.22hz, 2h), 2.30 (td, J =6.15, 3.31h), 1.85 (8978, J = 11.78, 18, 84, 21.78, 21H), 1.76H, 1H, 18hz, 18H, 21H, 18hz, 1.78, 84H, 1H. Theoretical calculation of ESI-MS C22H23N6 +[M+H]+=371.2; the experiment shows that: 371.2.
EXAMPLE 41 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (tert-butyl) phenyl) -1-methyl-1H-indazol-3-amine (QK 92)
Figure BDA0003608794920000602
The method comprises the following steps: synthesis of 4- (4- (tert-butyl) phenyl) -1-methyl-1H-indazol-3-amine (QK 92-1)
4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (100 mg) was charged in an eggplant-shaped flask, acetonitrile (10 mL) was added, and methyl iodide (64 mg) and potassium carbonate (157 mg) were sequentially added. The temperature was raised to 70 ℃ and stirred overnight. After the reaction, water was added to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified with silica gel column to give 23mg of the objective compound.1H NMR(500MHz,Chloroform-d)δ7.53–7.50(m,2H),7.44–7.41(m,2H),7.37–7.33(m,1H),7.28–7.25(m,1H),6.90(d,J＝7.09,0.57Hz,1H),2.93(s,2H),1.40(s,9H)。
Step two: synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (tert-butyl) phenyl) -1-methyl-1H-indazol-3-amine (QK 92)
Starting from QK92-1 (23 mg) and 1H-imidazole-4-carbaldehyde (9 mg), with reference to general procedure I, 3.9mg of the trifluoroacetate salt of the desired compound was obtained.1H NMR(500MHz,Methanol-d4) δ 8.77 (d, J =1.47hz, 1h), 7.55-7.52 (m, 2H), 7.46-7.42 (m, 2H), 7.41-7.37 (m, 1H), 7.35 (d, J =1.31hz, 1h), 7.31 (d, J =8.42hz, 1h), 6.88 (d, J =6.92hz, 1h), 4.48 (s, 2H), 3.88 (s, 3H), 1.37 (s, 9H). Theoretical calculation of ESI-MS C22H26N5 +[M+H]+=360.2; the experiment shows that: 361.0.
EXAMPLE 42 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (3-isopropoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 93)
Figure BDA0003608794920000611
With 4- (3-isopropoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (62 mg) and 1H-imidazole-4-carbaldehyde (15 mg), 23.6mg of the trifluoroacetate salt of the title compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4)δ8.75(d,J＝1.45Hz,1H),7.40(dd,J＝8.46,6.97Hz,1H),7.34–7.30(m,2H),7.22(d,J＝7.81Hz,1H),7.14(dd,J＝7.86,1.73Hz,1H)7.11 (d, J =1.71hz, 1h), 6.86 (d, J =6.83hz, 1h), 6.21 (tq, J =4.49,2.76,2.23hz, 1h), 4.49 (s, 2H), 4.35 (hept, J =6.00hz, 1h), 2.44 (tq, J =6.41,2.27hz, 2h), 2.26 (ddt, J =8.47,6.32,3.18hz, 2h), 1.86-1.79 (m, 2H), 1.74-1.67 (m, 2H), 1.06 (d, J =6.08hz, 3h), 0.97 (d, J =6.02hz, 3h). Theoretical calculation of ESI-MS C26H30N5O+[M+H]+=428.2; the test shows that: 428.2.
EXAMPLE 43 Synthesis of N- (3- (1H-imidazol-4-yl) propyl) -4- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 101)
Figure BDA0003608794920000612
With 4- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting with (60 mg) of (e) -4-yl) -1H-indazol-3-amine and (62 mg) of 3- (1-trityl-1H-imidazol-4-yl) propanal, 26mg of the trifluoroacetate salt of the objective compound was obtained according to the synthesis method of final product 34 (QK 018).1H NMR(500MHz,Methanol-d4) δ 8.76 (d, J =1.40hz, 1h), 7.52 (dd, J =8.51,7.07hz, 1h), 7.35 (d, J =8.50hz, 1h), 7.23-7.19 (m, 2H), 7.17-7.12 (m, 2H), 6.92 (d, J =7.03hz, 1h), 6.24 (td, J =3.96,1.94hz, 1h), 3.76 (s, 3H), 2.65 (t, J =7.69h, 2h), 2.45 (tq, J =6.35,2.34hz, 2h), 2.24 (tq, J =6.18,2.81hz, 2h), 2.07-2.01 (m, 2H), 1.92-1.77 (m, 4H), 1.72-1.66 (m, 2H). Theoretical calculation of ESI-MS C26H30N5O+[M+H]+=428.2; the test shows that: 428.7.
EXAMPLE 44 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (6- (cyclohex-1-en-1-yl) pyridin-3-yl) -1H-indazol-3-amine (QK 106)
Figure BDA0003608794920000621
Starting from 4- (6- (cyclohex-1-en-1-yl) pyridin-3-yl) -1H-indazol-3-amine (72 mg) and 1H-imidazole-4-carbaldehyde (21 mg), according to general procedure six, 20.9mg of the trifluoroacetate salt of the title compound was obtained.1H NMR(500MHz,Methanol-d4) δ 8.84 (d, J =2.09hz, 1h), 8.76 (d, J =1.48hz, 1h), 8.66 (dd, J =8.55,2.17hz, 1h), 8.17 (d, J =8.54hz, 1h), 7.54-7.45 (m, 2H), 7.42 (d, J =1.39hz, 1h), 7.11 (dd, J =6.85,1.04hz, 1h), 7.01 (td, J =3.99,1.96hz, 1h), 4.54 (s, 2H), 2.61 (tq, J =6.19,2.27hz, 2h), 2.44 (tq, J =5.82,2.81hz, 2h), 1.96-1.89 (m, 2H), 1.82-1.75 (m, 2H). Theoretical calculation of ESI-MS C22H23N6 +[M+H]+=371.2; the test shows that: 371.4.
EXAMPLE 45 Synthesis of 3- (1- ((4- (6- (cyclohex-1-en-1-yl) pyridin-3-yl) -1H-indazol-3-yl) amino) ethyl) benzoic acid (QK 116)
Figure BDA0003608794920000622
4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-indazol-3-amine (60 mg) and 3-acetylbenzoic acid (31 mg) were charged in an eggplant-shaped flask, toluene (20 mL) was added, and water was removed under reflux overnight. After the reaction, the reaction mixture was concentrated by a rotary evaporator, methanol (1 mL) and sodium borohydride (100 mg) were added, and the mixture was stirred at room temperature for 2 hours, concentrated by a rotary evaporator, and purified by HPLC to obtain 0.8mg of trifluoroacetate salt of the objective compound.1H NMR(500MHz,Methanol-d4) δ 7.93 (d, J =1.83hz, 1h), 7.88 (dt, J =7.44,1.57hz, 1h), 7.58-7.52 (m, 2H), 7.47-7.40 (m, 4H), 7.37 (t, J =7.60hz, 1h), 7.31 (d, J =8.41hz, 1h), 6.94 (d, J =6.97hz, 1h), 6.22 (tt, J =4.08,1.80hz, 1h), 4.78 (q, J =6.78hz, 1h), 2.45 (tdq, J =6.49,4.33,2.33hz, 2h), 2.30-2.22 (m, 2H), 1.88-1.80 (m, 2H), 1.75-1.67 (m, 2H), 1.35 (m, 71h), 3H, 1.35H). Theoretical calculation of ESI-MS C28H28N3O2 +[M+H]+=438.2; the test shows that: 437.9.
EXAMPLE 46 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (3- (dimethylamino) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 120)
Figure BDA0003608794920000623
With 4- (3- (dimethylamino) -2',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (55 mg) and 1H-imidazole-4-carbaldehyde (19 mg), 35.7mg of the trifluoroacetate salt of the title compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 8.75 (d, J =1.53hz, 1h), 7.53 (dd, J =8.23,2.59hz, 1h), 7.50-7.45 (m, 2H), 7.35 (d, J =1.45hz, 1h), 7.34 (s, 1H), 7.30 (d, J =1.30hz, 1h), 6.79 (dd, J =4.64,3.26hz, 1h), 5.67 (tt, J =3.75,1.73hz, 1h), 4.48 (s, 2H), 3.33 (s, 6H), 2.03-1.85 (m, 2H), 1.84-1.70 (m, 2H), 1.46-1.25 (m, 4H). Theoretical calculation of ESI-MS C25H29N6 +[M+H]+=413.2; the experiment shows that: 411.9.
EXAMPLE 47 Synthesis of N, 1-bis ((1H-imidazol-4-yl) methyl) -4- (3-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 133)
Figure BDA0003608794920000631
With 4- (3-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (60 mg) and 1H-imidazole-4-carbaldehyde (28 mg), 27.8mg of the trifluoroacetate salt of the title compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 8.84 (d, J =1.40hz, 1h), 8.73 (d, J =1.45hz, 1h), 7.49-7.42 (m, 3H), 7.35 (d, J =1.94hz, 1h), 7.30 (dd, J =7.88,1.96hz, 1h), 7.25 (d, J =1.37hz, 1h), 7.13 (d, J =7.89hz, 1h), 6.82 (dd, J =6.51,1.31hz, 1h), 6.19 (tt, J =3.82,1.69hz, 1h), 5.55 (s, 2H), 4.43 (s, 2H), 2.43 (tq, J =6.37,2.29hz, 2h), 2.24 (tdq, J =6.90,5.01, 2.4886, 2.78H, 1.78H, 1.31H, 1H, 11H). Theoretical calculation of ESI-MS C28H30N7 +[M+H]+=464.2; the experiment shows that: 465.0.
EXAMPLE 48 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (2-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 136)
Figure BDA0003608794920000632
With 4- (2-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (60 mg) and 1H-imidazole-4-carbaldehyde (28 mg), 32.2mg of the trifluoroacetate salt of the target compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 8.77 (d, J =1.50hz, 1h), 7.39 (dd, J =8.47,6.92hz, 1h), 7.36-7.28 (m, 3H), 7.25 (dd, J =7.67,1.92hz, 1h), 7.15 (d, J =7.67hz, 1h), 6.89 (dd, J =6.87,0.97hz, 1h), 5.58 (dp, J =3.46,1.66hz, 1h), 4.52 (s, 2H), 2.32 (s, 3H), 2.26-2.16 (m, 4H), 1.81 (pd, J =5.95,3.58hz, 2h), 1.73 (tq, J =5.89,2.32hz, 2h). Theoretical calculation of ESI-MS C24H26N5 +[M+H]+=384.2; the experiment shows that: 384.8.
EXAMPLE 49 Synthesis of (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) glycine (QK 141)
Figure BDA0003608794920000641
The method comprises the following steps: synthesis of (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) glycine ethyl ester (QK 138)
4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-indazol-3-amine (100 mg) and ethyl 2-bromoacetate (51 mg) were added to an eggplant-shaped flask, acetonitrile (10 mL) was added, potassium carbonate (70 mg) and potassium iodide (6 mg) were added, the temperature was raised to reflux, and stirring was performed overnight. After the reaction, the reaction mixture was cooled to room temperature, water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified with silica gel column to obtain 59mg of the objective compound.1H NMR(500MHz,Chloroform-d)δ7.52–7.49(m,2H),7.47–7.41(m,3H),7.26–7.22(m,1H),6.78(dd,J＝6.84,0.79Hz,1H),6.24(tt,J＝3.99,1.72Hz,1H),5.05(s,2H),2.50–2.44(m,2H),2.25(dq,J＝7.26,2.99,2.42Hz,2H),1.85–1.79(m,2H),1.73–1.66(m,2H)。
Step two: synthesis of (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) glycine (QK 141)
QK138 (59 mg) was put in an eggplant type flask, and 10mL of a mixed solvent (MeOH: THF: H) was added2O =1:1: 1) Lithium hydroxide monohydrate (100 mg) was added thereto, and the mixture was stirred at room temperature overnight. After the reaction, the reaction mixture was concentrated by a rotary evaporator and purified by HPLC to obtain 13.4mg of trifluoroacetate salt of the objective compound.1H NMR(500MHz,Methanol-d4) δ 7.65 (dd, J =8.56,7.07hz, 1h), 7.60-7.56 (m, 2H), 7.47-7.41 (m, 3H), 7.11 (d, J =7.12hz, 1h), 6.27 (tq, J =4.42,2.20hz, 1h), 2.47 (ddp, J =7.53,5.32,2.49hz, 2h), 2.25 (tq, J =8.35,5.45,4.46hz, 2h), 1.83 (qq, J =7.69,4.91,3.96hz, 2h), 1.70 (ddd, J =9.34,7.42,4.75hz, 2h). Theoretical calculation of ESI-MS C21H22N3O2 +[M+H]+=348.1; the test shows that: 349.1.
EXAMPLE 50 Synthesis of methyl 4- (3- ((((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -2-carboxylate (QK 149)
Figure BDA0003608794920000642
With 4- (3-amino-1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl]Methyl (88 mg) 2-carboxylate and 1H-imidazole-4-carbaldehyde (25 mg) were used as starting materials to give 54.6mg of a trifluoroacetate salt of the objective compound according to general procedure VI.1H NMR(500MHz,Methanol-d4) δ 8.78 (d, J =1.43hz, 1h), 7.80 (d, J =1.96hz, 1h), 7.61 (dd, J =7.91,1.98hz, 1h), 7.41-7.31 (m, 4H), 6.90 (dd, J =6.27,1.60hz, 1h), 5.55 (tt, J =3.70,1.67hz, 1h), 4.52 (s, 2H), 3.83 (s, 3H), 2.26 (tq, J =6.48,2.31hz, 2h), 2.20-2.11 (m, 2H), 1.78 (dtt, J =10.15,6.47,3.60hz, 2h), 1.73-1.65 (m, 2H). Theoretical calculation of ESI-MS C25H26N5O2 +[M+H]+=428.2; the test shows that: 427.3.
EXAMPLE 51 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (3-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 152)
Figure BDA0003608794920000651
With 4- (3-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (60 mg) and 1H-imidazole-4-carbaldehyde (23 mg), according to general procedure six, 17.8mg of the trifluoroacetate salt of the target compound was obtained.1H NMR(500MHz,Methanol-d4) δ 8.74 (d, J =1.50hz, 1h), 7.40 (dd, J =8.51,6.87hz, 1h), 7.37-7.29 (m, 3H), 7.26 (d, J =1.33hz, 1h), 7.17 (d, J =7.87hz, 1h), 6.78 (dd, J =6.87,0.91hz, 1h), 6.19 (tt, J =3.88,1.76hz, 1h), 4.42 (s, 2H), 2.44 (tq, J =6.44,2.34hz, 2h), 2.25 (ddt, J =8.35,6.27,2.66hz, 3tt), 2.08 (s, 3H), 1.82 (dtt, J =9.00,5.54, 3.3.003, 1.73H, 2H (2-tt). ESI-MS theoretical calculation C24H26N5 +[M+H]+=384.2; the test shows that: 384.5.
EXAMPLE 52 Synthesis of 4- (3- (((((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -2-carboxylic acid (QK 153)
Figure BDA0003608794920000652
Reacting 4- (3- (((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl]Methyl (72 mg) of (E) -2-carboxylate was placed in an eggplant type flask, and 10mL of a mixed solvent (MeOH: THF: H) was added2O =1:1: 1) Lithium hydroxide monohydrate (100 mg) was added thereto, and the mixture was stirred at room temperature overnight. After the reaction, the reaction mixture was concentrated by a rotary evaporator and purified by HPLC to obtain 21.4mg of a trifluoroacetate salt of the objective compound.1H NMR(500MHz,Methanol-d4) δ 8.75 (d, J =1.47hz, 1h), 7.85 (d, J =1.98hz, 1h), 7.62 (dd, J =7.87,1.98hz, 1h), 7.44-7.31 (m, 4H), 6.94 (dd, J =6.75,1.08hz, 1h), 5.61 (tt, J =3.69,1.69hz, 1h), 4.52 (s, 2H), 2.32 (dp, J =6.38,2.29hz, 2h), 2.18 (tq, J =5.85,2.70hz, 2h), 1.79 (qq, J =5.86,3.35hz, 2h), 1.74-1.65 (m, 2H). Theoretical calculation of ESI-MS C24H24N5O2 +[M+H]+=414.2; the experiment shows that: 413.0.
EXAMPLE 53 Synthesis of methyl 4- (3- (((((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -3-carboxylate (QK 156)
Figure BDA0003608794920000653
With 4- (3-amino-1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl]Methyl (91 mg) 3-carboxylate and 1H-imidazole-4-carbaldehyde (30 mg) were used as starting materials to give 25.9mg of a trifluoroacetate salt of the objective compound according to general procedure VI.1H NMR(500MHz,Methanol-d4) δ 8.78 (d, J =1.45hz, 1h), 7.81 (d, J =1.92hz, 1h), 7.63 (dd, J =7.83,1.98hz, 1h), 7.43-7.31 (m, 4H), 6.92 (dd, J =6.56,1.31hz, 1h), 5.56 (tt, J =3.67,1.68hz, 1h), 4.52 (s, 2H), 3.84 (s, 3H), 2.27 (tq, J =6.19,2.24hz, 2h), 2.17 (dtd, J =8.66,5.99,2.66hz, 2h), 1.80 (dtt, J =10.24,6.55,3.64hz, 2h), 1.71 (pd, J = 6.736, 3.3, 2h). Theoretical calculation of ESI-MS C25H26N5O2 +[M+H]+=428.2; the experiment shows that: 427.4.
EXAMPLE 54 Synthesis of 4- (3- ((((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -2-ol (QL 2)
Figure BDA0003608794920000661
With 4- (3-amino-1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (E) -2-ol (117 mg) and 1H-imidazole-4-carbaldehyde (40 mg), 51mg of the trifluoroacetate salt of the objective compound was obtained according to general procedure VI.1H NMR (500mhz, chloroform-d) δ 8.75 (d, J =1.51hz, 1h), 7.39-7.29 (m, 3H), 7.15 (d, J =7.55hz, 1h), 6.92-6.86 (m, 3H), 5.82 (tt, J =3.76,1.77hz, 1h), 4.52 (s, 2H), 2.40 (tq, J =6.32,2.19hz, 2h), 2.20 (tq, J =5.97,2.73hz, 2h), 1.77 (qq, J =4.77,2.83,2.37hz, dd2h), 1.70 (qp, J =9.17,6.04,2.84hz, 2h). Theoretical calculation of ESI-MS C23H24N5O+[M+H]+=386.2; the experiment shows that: 385.5.
EXAMPLE 55 Synthesis of 4- (3- (((((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -3-ol (QL 5)
Figure BDA0003608794920000662
With 4- (3-amino-1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (151 mg) of (E) -3-ol and (46 mg) of 1H-imidazole-4-carbaldehyde (general procedure VI), 46.2mg of the trifluoroacetate salt of the objective compound was obtained.1H NMR(500MHz,Methanol-d4) δ 8.74 (d, J =1.46hz, 1h), 7.40 (dd, J =8.47,7.01hz, 1h), 7.34-7.27 (m, 2H), 7.14 (d, J =7.81hz, 1h), 7.02 (dd, J =7.84,1.79hz, 1h), 6.99 (d, J =1.73hz, 1h), 6.88 (d, J =6.79hz, 1h), 6.19 (tt, J =3.84,1.69hz, 1h), 4.51 (d, J =4.61hz, 2h), 2.41 (tq, J =6.37,2.26hz, 2h), 2.24 (ddt, J =8.24,6.11,3.06hz, 2h), 1.86-1.77 (m, 2H), 1.73-1.64H). Theoretical calculation of ESI-MS C23H24N5O+[M+H]+=386.2; the test shows that: 386.0.
EXAMPLE 56 Synthesis of 3- ((((1- (carboxymethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QL 8)
Figure BDA0003608794920000671
The method comprises the following steps: synthesis of methyl 3- (((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) carboxylate (QK 158)
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (500 mg) and methyl 3-formylbenzoate (340 mg), the title compound was purified on silica gel column according to general procedure six to yield 524mg.1H NMR(500MHz,Chloroform-d)δ8.00(t,J＝1.70Hz,1H),7.90(dt,J＝7.73,1.48Hz,1H),7.50–7.43(m,5H),7.38–7.32(m,2H),7.27(d,J＝0.88Hz,1H),6.93(dd,J＝7.03,0.84Hz,1H),6.17(tt,J＝3.94,1.71Hz,1H),4.54(d,J＝4.59Hz,2H),3.91(s,3H),2.40(tq,J＝5.88,1.73Hz,2H),2.24(dtt,J＝8.80,6.12,2.46Hz,2H),1.83–1.77(m,2H),1.69(ddp,J＝9.25,6.18,3.29Hz,2H)。
Step two: synthesis of methyl 3- (((1- (2-ethoxy-2-oxoethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoate (QL 7)
QK158 (150 mg) and ethyl 3-bromo-2-oxopropionate (51 mg) were placed in a round flask, acetonitrile (10 mL) was added, potassium carbonate (64 mg) and potassium iodide (6 mg) were added, the mixture was heated to reflux, and the mixture was stirred overnight. After the reaction, the reaction mixture was cooled to room temperature, water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified with silica gel column to obtain 123mg of the objective compound.1H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.91(dt,J＝7.77,1.51Hz,1H),7.48–7.42(m,5H),7.38–7.31(m,2H),7.12(d,J＝8.36Hz,1H),6.93–6.90(m,1H),6.14(tt,J＝3.94,1.68Hz,1H),4.96(s,2H),4.52(d,J＝5.24Hz,2H),4.21(q,J＝7.11Hz,2H),3.92(s,3H),2.38(tq,J＝5.82,2.08Hz,2H),2.27–2.18(m,2H),1.83–1.76(m,2H),1.72–1.64(m,2H),1.26(t,J＝7.15Hz,3H)。
Step three: synthesis of 3- ((((1- (carboxymethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QL 8)
QL7 (123 mg) was placed in an eggplant type flask, and a mixed solvent (THF: meOH: H) was added2O =1:1:1,10ml), and sodium hydroxide (50 mg) was added thereto, followed by stirring at room temperature overnight. After the reaction, the reaction mixture was concentrated by a rotary evaporator and purified by HPLC to obtain 5.7mg of the trifluoroacetate salt of the objective compound. ESI-MS theoretical calculation C29H28N3O4 +[M+H]+=482.2; the experiment shows that: 482.5.
EXAMPLE 57 Synthesis of 4- (3- ((((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -3-carboxylic acid (QL 11)
Figure BDA0003608794920000681
Reacting 4- (3- (((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl]Methyl (90 mg) of (E) -3-carboxylate was placed in an eggplant type flask, and 10mL of a mixed solvent (MeOH: THF: H) was added2O =1:1: 1) Lithium hydroxide monohydrate (100 mg) was added thereto, and the mixture was stirred at room temperature overnight. After the reaction is finished, the reaction product is concentrated by a rotary evaporator and purified by HPLC to obtain 3.3mg of trifluoroacetate of the target compound.1H NMR(500MHz,Methanol-d4) δ 8.75 (d, J =1.52hz, 1h), 7.86 (d, J =1.93hz, 1h), 7.64 (dd, J =7.81,1.98hz, 1h), 7.43-7.33 (m, 4H), 6.94 (dd, J =6.70,1.16hz, 1h), 5.62 (tt, J =3.70,1.70hz, 1h), 4.51 (d, J =0.94hz, 2h), 2.33 (tq, J =6.27,2.36hz, 2h), 2.19 (tq, J =5.65,2.75hz, 2h), 1.84-1.76 (m, 2H), 1.75-1.66 (m, 2H). ESI-MS theoretical calculation C24H24N5O2 +[M+H]+=414.2; the experiment shows that: 412.9.
example 58 Synthesis of 2- ((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) -2-oxoacetic acid (QL 25)
Figure BDA0003608794920000682
The method comprises the following steps: synthesis of tert-butyl 4- (4- (tert-butyl) phenyl) -3- (2-methoxy-2-oxoacetamido) -1H-indazole-1-carboxylate (QL 19)
Tert-butyl 3-amino-4- (4- (tert-butyl) phenyl) -1H-indazole-1-carboxylate (200 mg) was added to a eggplant-shaped flask, methylene chloride (10 mL) was added, methyl 2-chloro-2-oxoacetate (80 mg) and triethylamine (81 mg) were added dropwise, and the mixture was stirred at room temperature overnight. After the reaction, water was added to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified with silica gel column to obtain 121mg of the objective compound.1H NMR(500MHz,Chloroform-d)δ8.81(s,1H),8.21(d,J＝8.50Hz,1H),7.58(dd,J＝8.57,7.20Hz,1H),7.51(d,J＝8.01Hz,2H),7.34(d,J＝8.09Hz,2H),7.24(d,J＝7.21Hz,1H),3.79(s,3H),1.71(s,9H),1.38(s,9H)。
Step two: synthesis of methyl 2- ((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) -2-oxoacetate (QL 22)
QL19 (121 mg) was placed in an eggplant type flask, methylene chloride (8 mL) was added, and trifluoroacetic acid (2 mL) was added dropwise thereto and the mixture was stirred at room temperature overnight. After the reaction, saturated sodium bicarbonate solution was added to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified with silica gel column to obtain 94mg of the target compound.1H NMR(500MHz,Chloroform-d)δ8.97(s,1H),7.61–7.51(m,3H),7.44–7.34(m,3H),7.04(d,J＝6.96Hz,1H),3.83(s,3H),1.42(s,9H)。
Step three: synthesis of 2- ((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) -2-oxoacetic acid (QL 25)
QL22 was placed in an eggplant-shaped flask, N-dimethylformamide (6 mL) was added thereto, lithium chloride (224 mg) was added thereto, the temperature was raised to 160 ℃ and the mixture was stirred overnight. After the reaction is finished, cooling to room temperature, and purifying by HPLC to obtain the trifluoroacetate of the target compound.1H NMR(500MHz,Methanol-d4) δ 7.63-7.54 (m, 1H), 7.52-7.39 (m, 3H), 7.38-7.32 (m, 2H), 7.13-7.02 (m, 1H), 1.36 (s, 9H). Theoretical calculation of ESI-MS C19H20N3O3 +[M+H]+=338.1; the test shows that: 338.0.
EXAMPLE 59 Synthesis of 3- (((4- (4- (cyclopent-1-en-1-yl) phenyl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QL 43)
Figure BDA0003608794920000691
Starting from 4- (4- (cyclopent-1-en-1-yl) phenyl) -1H-indazol-3-amine (60 mg) and 3-formylbenzoic acid (39 mg), 2.7mg of the trifluoroacetate salt of the target compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4)δ7.99(q,J＝2.15Hz,1H),7.93(dt,J＝7.72,1.58Hz,1H),7.59–7.50(m,3H),7.50–7.46(m,1H),7.46–7.36(m,4H),7.01(d,J＝7.07Hz,1H),6.25(p,J＝2.29Hz,1H),4.47(s,2H),2.68(ddt,J＝9.91,6.93,2.23Hz,2H),2.55(tq,J＝7.64,2.58hz, 2h), 2.04 (p, J =7.56hz, 2h). Theoretical calculation of ESI-MS C26H24N3O2 +[M+H]+=410.2; the experiment shows that: 409.5.
EXAMPLE 60 Synthesis of 2-oxo-2- (((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) acetic acid (QL 53)
Figure BDA0003608794920000692
With 3-amino-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Tert-butyl (200 mg) of (E) -4-yl) -1H-indazole-1-carboxylate (prepared by the method for synthesizing QL 25), was used as a starting material to obtain 10.2mg of a trifluoroacetate salt of a target compound.1H NMR(500MHz,Methanol-d4) δ 7.52-7.44 (m, 2H), 7.40 (d, J =8.36hz, 2h), 7.36 (d, J =8.39hz, 2h), 7.10 (dd, J =6.77,1.06hz, 1h), 6.15 (tt, J =3.88,1.77hz, 1h), 2.45 (tq, J =6.44,2.33hz, 2h), 2.24 (ddt, J =8.38,6.14,3.07hz, 2h), 1.86-1.78 (m, 2H), 1.73-1.66 (m, 2H). Theoretical calculation of ESI-MS C21H20N3O3 +[M+H]+=362.1; the experiment shows that: 361.4.
EXAMPLE 61 Synthesis of 3-oxo-3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) propanoic acid (QL 56)
Figure BDA0003608794920000701
With 3-amino-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Tert-butyl (200 mg) of (E) -4-yl) -1H-indazole-1-carboxylate (prepared by the method for synthesizing QL 25) was used as a starting material to obtain 4.8mg of a trifluoroacetate salt of a target compound.1H NMR(500MHz,Methanol-d4) δ 7.60-7.31 (m, 6H), 7.07 (d, J =6.63hz, 1h), 6.24-6.14 (m, 1H), 2.52-2.41 (m, 2H), 2.29-2.17 (m, 2H), 1.88-1.76 (m, 2H), 1.76-1.62 (m, 4H). Theoretical calculation of ESI-MS C22H22N3O3 +[M+H]+=376.2; the experiment shows that: 376.8.
EXAMPLE 62 Synthesis of N- (3- (1H-imidazol-4-yl) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QL 61)
Figure BDA0003608794920000702
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting with (41 mg) of (E) -4-yl) -1H-indazol-3-amine and (48 mg) of 3- (1-trityl-1H-imidazol-4-yl) propanal, 1.3mg of the trifluoroacetate salt of the objective compound was obtained according to the synthesis method of final product 34 (QK 18).1H NMR(500MHz,Methanol-d4) δ 8.77 (d, J =1.46hz, 1h), 7.56 (d, J =8.09hz, 2h), 7.49-7.39 (m, 3H), 7.34 (d, J =8.47hz, 1h), 7.24 (s, 1H), 6.92 (d, J =7.01hz, 1h), 6.24 (td, J =4.04,2.02hz, 1h), 2.71 (t, J =7.66hz, 2h), 2.46 (dp, J =6.40,2.46hz, 2h), 2.30-2.18 (m, 2H), 1.93-1.77 (m, 4H), 1.71 (ddd, J =9.22,7.35,4.60hz, 2h), 1.32-1.23 (m, 2H). Theoretical calculation of ESI-MS C25H28N5 +[M+H]+=398.2; the experiment shows that: 396.8.
EXAMPLE 63 Synthesis of 2- (2- (((4- (6- (cyclohex-1-en-1-yl) pyridin-3-yl) -1H-indazol-3-yl) amino) methyl) phenyl) acetic acid (QL 86)
Figure BDA0003608794920000711
Starting from 4- (6- (cyclohex-1-en-1-yl) pyridin-3-yl) -1H-indazol-3-amine (40 mg) and methyl 2- (2-formylphenyl) acetate (36 mg), according to general procedure eight, 3.6mg of the trifluoroacetate salt of the title compound was obtained.1H NMR(500MHz,Methanol-d4) δ 8.72 (d, J =2.04hz, 1h), 8.58 (dd, J =8.52,2.11hz, 1h), 8.01 (d, J =8.52hz, 1h), 7.55-7.48 (m, 2H), 7.41-7.36 (m, 1H), 7.27-7.21 (m, 3H), 7.11 (dd, J =6.49,1.37hz, 1h), 6.81 (td, J =4.00,1.95hz, 1h), 4.41 (s, 2H), 3.74 (s, 2H), 2.48 (ddq, J =6.29,4.29,2.22hz, 2h), 2.41 (dtt, J =9.09,6.35,2.67hz, 2h), 1.92-1.84 (m, 2H), 1.80-1.72 (m, 2H). Theoretical calculation of ESI-MS C27H27N4O2 +[M+H]+=439.2; the experiment shows that: 439.9.
EXAMPLE 64 Synthesis of 4- (3- (((((1H-imidazol-4-yl) methyl) amino) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-1-yl) -4-oxobutanoic acid (QL 93)
Figure BDA0003608794920000712
The method comprises the following steps: synthesis of tert-butyl 4- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) -1H-imidazole-1-carboxylate (QL 83)
4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-indazol-3-amine (100 mg) and tert-butyl 4-formyl-1H-imidazole-1-carboxylate (81 mg) were added to an eggplant-shaped flask, 1,2-dichloroethane (10 mL) was added, sodium triacetoxyborohydride (222 mg) was added, acetic acid (0.1 mL) was added dropwise, and the mixture was stirred at room temperature overnight. After the reaction, a saturated sodium bicarbonate solution was added to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified with a silica gel column to obtain 87mg of the target compound.1H NMR(500MHz,Chloroform-d)δ7.96(d,J＝1.36Hz,1H),7.50(d,J＝8.37Hz,2H),7.47–7.43(m,2H),7.33(dd,J＝8.35,6.97Hz,1H),7.26(d,J＝8.29,1H),7.20(d,J＝1.29Hz,1H),6.90(dd,J＝7.01,0.92Hz,1H),6.23(tt,J＝3.92,1.68Hz,1H),4.43(s,2H),2.46(tq,J＝5.82,1.97Hz,2H),2.28–2.21(m,2H),1.85–1.78(m,2H),1.73–1.66(m,2H),1.58(s,9H)。
Step two: synthesis of 4- (3- ((((1- (tert-butoxycarbonyl) -1H-imidazol-4-yl) methyl) amino) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-1-yl) -4-oxobutanoic acid (QL 88)
QL83 (87 mg) was placed in a round bottom flask, 1,4-dioxane (10 mL) was added, dihydrofuran-2,5-dione (19 mg) was added, the temperature was raised to 80 ℃, and the mixture was stirred overnight. After the reaction, the reaction mixture was concentrated by a rotary evaporator and purified by a silica gel column to obtain 23mg of the objective compound.1H NMR(500MHz,Chloroform-d)δ8.39(dd,J＝8.50,4.39Hz,1H),8.03(s,1H),7.56–7.44(m,3H),7.42–7.34(m,2H),7.24(d,J＝21.34Hz,1H),7.12(d,J＝7.28Hz,1H),6.27–6.20(m,1H),4.43(d,J＝5.69Hz,2H),3.42(t,J＝6.90Hz,2H),2.83(t,J＝6.79Hz,2H),2.51–2.39(m,2H),2.24(tt,J＝7.48,3.59Hz,2H),1.86–1.74(m,2H),1.72–1.64(m,2H),1.59(s,9H)。
Step three: synthesis of 4- (3- ((((1H-imidazol-4-yl) methyl) amino ] amino) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-1-yl) -4-oxobutanoic acid (QL 93)
QL88 (23 mg) was placed in an eggplant type flask, and methylene chloride (8 mL) and trifluoroacetic acid (2 mL) were added thereto, followed by stirring at room temperature overnight. After the reaction, the reaction mixture was concentrated by a rotary evaporator and purified by HPLC to obtain 11mg of trifluoroacetate salt of the objective compound.1H NMR(500MHz,Methanol-d4) δ 8.73 (d, J =1.46hz, 1h), 8.33 (d, J =8.33hz, 1h), 7.60-7.53 (m, 3H), 7.47-7.38 (m, 3H), 7.19 (d, J =7.27hz, 1h), 6.26 (tt, J =3.93,1.73hz, 1h), 4.58 (s, 2H), 3.33 (t, J =6.45hz, 2h), 2.76 (t, J =6.71hz, 2h), 2.47 (tq, J =6.48,2.30hz, 2h), 2.26 (tq, J =6.26,2.68hz, 2h), 1.83 (qq, J =8.31,5.63, 4.342h), 1.71 (qq, J =8.66,5.51, 4.042h). Theoretical calculation of ESI-MS C27H28N5O3 +[M+H]+=470.2; the experiment shows that: 469.7.
EXAMPLE 65 Synthesis of 3- ((((1- (3-carboxypropionyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QL 95)
Figure BDA0003608794920000721
The method comprises the following steps: synthesis of methyl 3- (((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoate (QL 71)
4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-indazol-3-amine (289 mg) and methyl 3-formylbenzoate (196 mg) were charged in an eggplant-shaped flask, 1,2-dichloroethane (10 mL) was added, sodium triacetoxyborohydride (636 mg) was added, acetic acid (0.1 mL) was added dropwise, and the mixture was stirred at room temperature overnight. After the reaction is finished, adding saturated sodium bicarbonate solution to quench the reaction, and using ethyl acetate for the water phaseThe ester was extracted 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified with silica gel column to give 192mg of the target compound. Theoretical calculation of ESI-MS C28H28N3O2 +[M+H]+=438.2; the experiment shows that: 438.8.
step two: synthesis of 4- (3- ((3- (methoxycarbonyl) benzyl) amino) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-1-yl) -4-oxobutanoic acid (QL 81)
QL71 (192 mg) was placed in an eggplant type flask, 1,4-dioxane (10 mL) was added, dihydrofuran-2,5-dione (52 mg) was added, the temperature was raised to 80 ℃ and the mixture was stirred overnight. After the reaction, the reaction mixture was concentrated by a rotary evaporator and purified by a silica gel column to obtain 275mg of the target compound.1H NMR(500MHz,Chloroform-d)δ8.36(ddd,J＝8.39,2.93,0.89Hz,1H),7.99(dt,J＝7.79,1.83Hz,2H),7.90(ddt,J＝7.80,2.89,1.53Hz,2H),7.54–7.32(m,5H),7.12(dd,J＝7.32,0.86Hz,1H),6.16(tt,J＝3.88,1.64Hz,1H),4.70(s,2H),3.87(s,3H),3.38(t,J＝6.92Hz,2H),2.81(t,J＝6.80Hz,2H),2.37(ddt,J＝6.27,4.34,2.09Hz,2H),2.27–2.17(m,2H),1.79(dqd,J＝12.05,5.96,2.88Hz,2H),1.67(hd,J＝6.06,2.78Hz,2H)。
Step three: synthesis of 3- ((((1- (3-carboxypropionyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QL 95)
QL81 (91 mg) was placed in an eggplant type flask, ethyl acetate (10 mL) was added, lithium iodide (450 mg) was added, and the mixture was heated to reflux and stirred overnight. After the reaction, the reaction mixture was concentrated by a rotary evaporator and purified by HPLC to obtain 1.7mg of the trifluoroacetate salt of the objective compound.1H NMR(500MHz,Methanol-d4) δ 8.33 (d, J =8.27hz, 1h), 8.01 (d, J =1.77hz, 1h), 7.91 (dd, J =7.76,1.53hz, 1h), 7.58-7.54 (m, 1H), 7.52-7.47 (m, 3H), 7.42-7.37 (m, 3H), 7.18 (d, J =7.21hz, 1h), 6.14 (tt, J =3.93,1.78hz, 1h), 4.48 (s, 2H), 3.36 (t, J =6.65hz, 2h), 2.75 (t, J =6.66hz, 2h), 2.37 (ddp, J =6.78,4.53,2.18hz, 3h), 2.24 (tq, J =6.27, 2.7186, 1.86, 1.75H), 1.73H (1H, 1H), 1H, 73H, 3.73H). ESI-MS theoretical calculation C31H30N3O5 +[M+H]+=524.2; experiment ofAnd (3) measuring: 523.9.
EXAMPLE 66 Synthesis of 4- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) benzoic acid (QL 105)
Figure BDA0003608794920000731
The method comprises the following steps: synthesis of methyl 4- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) aminomethylbenzoate (QL 105-1)
Copper acetate (80 mg) was added to an eggplant-shaped flask, and methylene chloride (15 mL) and methanol (1 mL) were added and the mixture was stirred at room temperature for 5min. Subsequently, 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (100 mg), 4- (methoxycarbonyl) phenyl) boronic acid (124 mg) and N, N-diisopropylethylamine (57 mg) were added in this order, and stirred at room temperature for 20H. After the reaction, water was added to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified with silica gel column to give 105mg of the objective compound.
Step two: synthesis of 4- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) benzoic acid (QL 105)
QL105-1 (30 mg) was placed in an eggplant type flask, and a mixed solvent (MeOH: THF: H) was added2O =1:1:1,10ml), and lithium hydroxide (100 mg) was added thereto, followed by stirring at room temperature overnight. After the reaction is finished, the reaction product is concentrated by a rotary evaporator and purified by HPLC to obtain 3.7mg of trifluoroacetate of the target compound.1H NMR(500MHz,DMSO-d6) δ 8.07 (d, J =8.59hz, 2h), 7.91 (d, J =8.58hz, 1h), 7.85 (d, J =8.58hz, 2h), 7.59 (d, J =8.07hz, 2h), 7.52 (dd, J =8.59,7.13hz, 1h), 7.46 (d, J =8.09hz, 2h), 7.05 (d, J =7.13hz, 1h), 6.35-6.29 (m, 1H), 2.47-2.41 (m, 2H), 2.26-2.19 (m, 2H), 1.82-1.73 (m, 2H), 1.67-1.60 (m, 2H). Theoretical calculation of ESI-MS C26H24N3O2 +[M+H]+=410.2; the experiment shows that: 410.3.
EXAMPLE 67 Synthesis of N-benzyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QL 106)
Figure BDA0003608794920000741
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (4-yl) -1H-indazol-3-amine (50 mg) and benzaldehyde (21 mg), 20.1mg of the trifluoroacetate salt of the title compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 7.63 (dd, J =8.60,7.10hz, 1h), 7.47-7.35 (m, 5H), 7.33-7.25 (m, 3H), 7.23-7.17 (m, 2H), 7.06 (d, J =7.14hz, 1h), 6.14 (dq, J =3.99,1.94hz, 1h), 4.41 (s, 2H), 2.35 (ddq, J =6.49,4.65,2.30hz, 2h), 2.23 (tq, J =6.14,2.83hz, 2h), 1.84-1.75 (m, 2H), 1.72-1.62 (m, 2H). Theoretical calculation of ESI-MS C26H26N3 +[M+H]+=380.2; the experiment shows that: 380.5.
EXAMPLE 68 Synthesis of 3- (((1- (2-hydroxyethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QL 108)
Figure BDA0003608794920000742
With 2- (3-amino-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-1-yl) ethan-1-ol (60 mg) and 3-formylbenzoic acid (32 mg), according to general procedure six, 24.2mg of the trifluoroacetate salt of the target compound was obtained.1H NMR(500MHz,Methanol-d4) δ 8.01-7.85 (m, 2H), 7.51-7.25 (m, 9H), 6.08 (d, J =4.19hz, 1h), 4.76-4.08 (m, 4H), 3.89 (t, J =5.48hz, 2h), 2.32 (td, J =6.31,3.16hz, 2h), 2.20 (tq, J =6.20,2.90hz, 2h), 1.82-1.73 (m, 2H), 1.70-1.59 (m, 2H). Theoretical calculation of ESI-MS C29H30N3O3 +[M+H]+=468.2; the test shows that: 467.8.
EXAMPLE 69 Synthesis of 3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) benzoic acid (QL 120)
Figure BDA0003608794920000743
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (100 mg) of (4-yl) -1H-indazol-3-amine and (3- (methoxycarbonyl) phenyl) boronic acid (124 mg), 1.5mg of the trifluoroacetate salt of the objective compound was obtained according to the method for synthesizing QL 105.1H NMR(500MHz,Methanol-d4) δ 8.32 (s, 1H), 7.93 (d, J =8.32hz, 2h), 7.70 (d, J =8.47hz, 1h), 7.64 (t, J =7.93hz, 1h), 7.57 (d, J =8.00hz, 2h), 7.52-7.46 (m, 3H), 7.04 (d, J =7.06hz, 1h), 6.27 (s, 1H), 2.53-2.47 (m, 2H), 2.30-2.24 (m, 2H), 1.89-1.82 (m, 2H), 1.76-1.69 (m, 2H). ESI-MS theoretical calculation C26H24N3O2 +[M+H]+=410.2; the experiment shows that: 410.5.
EXAMPLE 70 Synthesis of 3- (((((4- (4-cyclohexylphenyl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QL 122)
Figure BDA0003608794920000751
Starting from 4- (4-cyclohexylphenyl) -1H-indazol-3-amine (60 mg) and 3-formylbenzoic acid (37 mg), 17.4mg of the trifluoroacetate salt of the target compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4) δ 8.01-7.95 (m, 2H), 7.59 (dd, J =8.56,7.03hz, 1h), 7.49 (dt, J =7.63,1.64hz, 1h), 7.46-7.38 (m, 4H), 7.33-7.29 (m, 2H), 7.03 (dd, J =6.99,0.82hz, 1h), 4.46 (s, 2H), 2.49 (tt, J =11.52,3.42hz, 1h), 1.89-1.65 (m, 4H), 1.48-1.18 (m, 6H). Theoretical calculation of ESI-MS C27H28N3O2 +[M+H]+=426.2; the experiment shows that: 425.8.
EXAMPLE 71 Synthesis of 4- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) phenol (LYA 13)
Figure BDA0003608794920000752
With 4- (4- (tert-butyl) phenyl) Starting from (e) 1H-indazol-3-amine (100 mg) and 4-hydroxybenzaldehyde (41.39 mg), 45mg of the trifluoroacetate salt of the target compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 7.67 (dd, J =8.6,7.1hz, 1h), 7.48-7.41 (m, 3H), 7.39-7.34 (m, 2H), 7.09 (d, J =7.0hz, 1h), 7.07-7.01 (m, 2H), 6.78-6.71 (m, 2H), 4.27 (s, 2H), 1.28 (s, 9H). ESI-MS theoretical calculation C24H26N3O+[M+H]+=372.2; the experiment shows that: 372.3.
EXAMPLE 72 Synthesis of 3- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) phenol (LYA 14)
Figure BDA0003608794920000753
Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (100 mg) and 3-hydroxybenzaldehyde (41.39 mg), 28.4mg of the trifluoroacetate salt of the title compound was obtained according to general procedure six.1H NMR (500mhz, chloroform-d) δ 7.60 (dd, J =8.5,7.1hz, 1h), 7.49-7.43 (m, 2H), 7.40 (d, J =8.5hz, 1h), 7.35-7.29 (m, 2H), 7.09 (t, J =7.8hz, 1h), 7.05 (s, 1H), 6.75 (d, J =8.1hz, 1h), 6.62 (s, 1H), 6.56 (d, J =7.5hz, 1h), 1.28 (s, 9H). Theoretical calculation of ESI-MS C24H26N3O+[M+H]+=372.2; the test shows that: 371.2.
EXAMPLE 73 Synthesis of 2- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) phenol (LYA 15)
Figure BDA0003608794920000761
Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (100 mg) and 2-hydroxybenzaldehyde (41.39 mg), 41.8mg of the trifluoroacetate salt of the target compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4)δ7.56(dd,J＝8.5,7.1Hz,1H),7.50–7.45(m,2H),7.40–7.34(m,3H),7.12(td,J＝7.7,1.7Hz,1H),7.08(dd,J＝7.5,1.7Hz,1H),7.00(dd,J＝7.1,0.8Hz,1H),6.80(dd,J＝8.1,1.1Hz,1H),675 (td, J =7.5,1.2hz, 1h), 4.35 (s, 2H), 1.31 (s, 9H). Theoretical calculation of ESI-MS C24H26N3O+[M+H]+=372.2; the test shows that: 372.2.
EXAMPLE 74 Synthesis of 2- (4- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) phenyl) acetic acid (LYA 42)
Figure BDA0003608794920000762
Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (43.4 mg) and methyl 2- (4-formylphenyl) acetate (25 mg), according to general procedure eight, 4.5mg of the trifluoroacetate salt of the title compound was obtained.1H NMR(500MHz,Methanol-d4) δ 7.53 (dd, J =8.5,7.1hz, 1h), 7.50-7.47 (m, 2H), 7.42-7.36 (m, 3H), 7.25 (d, J =8.0hz, 2h), 7.18 (d, J =8.1hz, 2h), 6.99 (dd, J =7.0,0.9hz, 1h), 4.38 (s, 2H), 3.58 (s, 2H), 1.31 (s, 9H). Theoretical calculation of ESI-MS C26H28N3O2 +[M+H]+=414.2; the experiment shows that: 414.3.
EXAMPLE 75 Synthesis of 2- (2- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) phenyl) acetic acid (LYA 58)
Figure BDA0003608794920000763
Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (54 mg) and methyl 2- (2-formylphenyl) acetate (25 mg), using methanol and sodium cyanoborohydride (12.6 mg), according to general procedure eight, 6mg of the trifluoroacetate salt of the title compound was obtained.1H NMR(500MHz,Methanol-d4) δ 7.55 (dd, J =8.5,7.0hz, 1h), 7.41 (d, J =2.1hz, 2h), 7.40-7.35 (m, 3H), 7.28-7.25 (m, 2H), 7.24-7.18 (m, 2H), 7.00 (dd, J =7.1,0.9hz, 1h), 4.43 (s, 2H), 3.68 (s, 2H), 1.26 (s, 9H). Theoretical calculation of ESI-MS C26H28N3O2 +[M+H]+=414.2; the experiment shows that: 414.3.
EXAMPLE 76 Synthesis of- (3- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) phenyl) acetic acid (LYA 62)
Figure BDA0003608794920000771
Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (66.3 mg) and methyl 2- (3-formylphenyl) acetate (67.9 mg), using methanol and sodium cyanoborohydride (18.9 mg), 51.1mg of the trifluoroacetate salt of the objective compound was obtained according to general procedure eight.1H NMR(500MHz,Methanol-d4) δ 7.56 (dd, J =8.5,7.1hz, 1h), 7.49-7.43 (m, 2H), 7.41-7.34 (m, 3H), 7.29-7.23 (m, 1H), 7.20 (dt, J =4.4,2.1hz, 2h), 7.09 (dt, J =7.7,1.5hz, 1h), 7.00 (dd, J =7.1,0.8hz, 1h), 4.38 (s, 2H), 3.58 (s, 2H), 1.27 (s, 9H). Theoretical calculation of ESI-MS C26H28N3O2 +[M+H]+=414.2; the experiment shows that: 414.3.
EXAMPLE 77 Synthesis of 2- (3-amino-4- (4- (tert-butyl) phenyl) -1H-indazol-1-yl) acetic acid (LYA 47)
Figure BDA0003608794920000772
The method comprises the following steps: synthesis of ethyl 2- (3-amino-4- (4- (tert-butyl) phenyl) -1H-indazol-1-yl) acetate (LYA 39)
4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (40 mg), ethyl 2-bromoacetate (28 mg) and potassium carbonate (62.2 mg) were added to a eggplant-shaped flask, acetonitrile was added, the temperature was raised to 80 ℃, and stirring was performed for 6 hours. After the reaction is finished, the reaction solution is cooled to room temperature, water is added to quench the reaction solution, the water phase is extracted for 3 times by ethyl acetate, the organic phases are combined, the mixture is washed by saturated saline solution, dried by anhydrous sodium sulfate, concentrated by a rotary evaporator and purified by a silica gel column to obtain 22.7mg of a target compound which is directly used in the next step.
Step two: synthesis of 2- (3-amino-4- (4- (tert-butyl) phenyl) -1H-indazol-1-yl) acetic acid (LYA 47)
LYA39 (22.7 mg) was placed in an eggplant type flask, and 5mL of a mixed solvent (MeOH: THF: H) was added2O =1:1: 1) Lithium hydroxide monohydrate (7.9 mg) was added, the temperature was raised to 60 ℃, and stirring was carried out overnight. After the reaction, the reaction mixture was cooled to room temperature, concentrated by a rotary evaporator, and purified by HPLC to obtain 1.5mg of the trifluoroacetate salt of the target compound.1H NMR(500MHz,Methanol-d4) δ 7.73 (dd, J =8.6,7.2hz, 1h), 7.67-7.60 (m, 2H), 7.49-7.41 (m, 3H), 7.14 (dd, J =7.2,0.8hz, 1h), 5.07 (s, 2H), 1.40 (s, 9H). Theoretical calculation of ESI-MS C19H22N3O2 +[M+H]+=324.2; the experiment shows that: 324.6.
EXAMPLE 78 Synthesis of (4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) glycine (LYA 45)
Figure BDA0003608794920000781
Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (40 mg) and ethyl 2-oxoacetate (82.8 mg), using methanol and sodium cyanoborohydride (11.3 mg), 2mg of the trifluoroacetate salt of the objective compound was obtained according to general procedure eight.1H NMR(500MHz,Methanol-d4) δ 7.65-7.55 (m, 3H), 7.51-7.43 (m, 3H), 7.34 (d, J =8.4hz, 1h), 4.00 (s, 2H), 1.40 (s, 9H). Theoretical calculation of ESI-MS C19H22N3O2 +[M+H]+=324.2; the test shows that: 324.2.
EXAMPLE 79 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (3,6-dihydro-2H-pyran-4-yl) phenyl) -1H-indazol-3-amine (LYA 53)
Figure BDA0003608794920000782
Starting from 4- (4- (3,6-dihydro-2H-pyran-4-yl) phenyl) -1H-indazol-3-amine (32.4 mg) and 1H-imidazole-4-carbaldehyde (9.6 mg), according to general procedure six, 3.2mg of the trifluoroacetate salt of the title compound was obtained.1H NMR(500MHz,Methanol-d4)δ8.74(d,J＝1.5Hz,1H),7.62–7.56(m,2H),7.54–7.48(m,2H),7.41–7.30(m,3H),6.90(dd,J＝6.8,1.1Hz,1H),6.34–6.25(m,1H),4.50(d,J＝0.9Hz, 2H), 4.34 (q, J =2.8hz, 2h), 3.96 (t, J =5.5hz, 2h), 2.58 (dt, J =4.6,2.8hz, 2h). Theoretical calculation of ESI-MS C22H22N5O+[M+H]+=372.2; the test shows that: 372.3.
EXAMPLE 80 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (pyridin-3-yl) phenyl) -1H-indazol-3-amine (LYA 12)
Figure BDA0003608794920000783
Starting from 4- (4- (pyridin-3-yl) phenyl) -1H-indazol-3-amine (48.7 mg) and 1H-imidazole-4-carbaldehyde (14.7 mg), 2mg of the trifluoroacetate salt of the target compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4) δ 9.15 (d, J =2.2hz, 1h), 8.78 (dd, J =5.4,1.4hz, 1h), 8.76-8.70 (m, 2H), 8.00 (dd, J =8.1,5.4hz, 1h), 7.97-7.91 (m, 2H), 7.79-7.74 (m, 2H), 7.46-7.37 (m, 2H), 7.36 (d, J =1.4hz, 1h), 6.98 (dd, J =6.5,1.3hz, 1h), 4.53 (d, J =1.0hz, 2h). Theoretical calculation of ESI-MS C22H19N6 +[M+H]+=367.2; the experiment shows that: 367.3.
EXAMPLE 81 Synthesis of 4- (3-amino-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-1-yl) -4-oxobutanoic acid (LYA 132)
Figure BDA0003608794920000791
4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-indazol-3-amine (70 mg) and dihydrofuran-2,5-dione (24 mg) were added to a round bottom flask, tetrahydrofuran (10 mL) was added, the temperature was raised to 60 ℃, and stirring was performed overnight. After the reaction, the reaction mixture was cooled to room temperature, quenched by addition of water, the aqueous phase was extracted 3 times with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by HPLC to obtain 64mg of trifluoroacetate salt of the target compound.1H NMR(500MHz,DMSO-d6)δ8.29(dd,J＝8.3,0.8Hz,1H),7.64–7.56(m,3H),7.46–7.41(m,2H),7.19(dd,J＝7.3,09hz, 1h), 6.31 (tt, J =4.0,1.7hz, 1h), 3.22 (dd, J =7.4,5.9hz, 2h), 2.64 (t, J =6.6hz, 2h), 2.43 (tq, J =6.5,2.3hz, 2h), 2.26-2.17 (m, 2H), 1.79-1.71 (m, 2H), 1.67-1.59 (m, 2H). Theoretical calculation of ESI-MS C23H24N3O3 +[M+H]+=390.2; the experiment shows that: 390.3.
EXAMPLE 82 Synthesis of 4- (((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) picolinic acid (LYA 83)
Figure BDA0003608794920000792
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (4-yl) -1H-indazol-3-amine (70 mg) and methyl 4-formylpicolinate (60 mg), using methanol and sodium cyanoborohydride (18 mg), the title compound was obtained as trifluoroacetate salt (9.5 mg) according to general procedure eight.1H NMR(500MHz,Methanol-d4) δ 8.52 (d, J =5.5hz, 1h), 8.17 (s, 1H), 7.55 (d, J =8.4hz, 3h), 7.50 (d, J =8.3hz, 2h), 7.39-7.34 (m, 1H), 7.31 (d, J =8.4hz, 1h), 6.90 (d, J =6.7hz, 1h), 6.21 (s, 1H), 4.16-4.06 (m, 2H), 2.45 (s, 2H), 2.25 (s, 2H), 1.87-1.78 (m, 2H), 1.71 (d, J =6.0hz, 2h). Theoretical calculation of ESI-MS C26H25N4O2 +[M+H]+=425.2; the experiment shows that: 424.5.
EXAMPLE 83 Synthesis of 2- (((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) isonicotinic acid (LYA 101)
Figure BDA0003608794920000793
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (4-yl) -1H-indazol-3-amine (70 mg) and methyl 2-formylisonicotinate (60 mg), using methanol and sodium cyanoborohydride (18 mg), 14mg of the title compound was obtained according to general procedure eight.1H NMR(500MHz,Methanol-d4)δ8.57(d,J＝5.3Hz,1H),8.01(s,1H),7.87(dd,J＝5.2,1.6Hz,1H)7.57-7.50 (m, 2H), 7.50-7.45 (m, 2H), 7.43 (dd, J =8.4,7.0hz, 1h), 7.33 (d, J =8.4hz, 1h), 6.94 (d, J =7.0hz, 1h), 6.22 (tt, J =4.0,1.7hz, 1h), 4.63 (s, 2H), 2.45 (tq, J =6.5,2.4hz, 2h), 2.25 (ddt, J =8.6,6.5,3.3hz, 2h), 1.92-1.78 (m, 2H), 1.77-1.65 (m, 2H). ESI-MS theoretical calculation C26H25N4O2 +[M+H]+=425.2; the experiment shows that: 425.6.
EXAMPLE 84 Synthesis of 6- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) picolinic acid (LYA 72)
Figure BDA0003608794920000801
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (4-yl) -1H-indazol-3-amine (70 mg) and methyl 2-formylisonicotinate (60 mg), using methanol and sodium cyanoborohydride (18 mg), 10mg of the trifluoroacetate salt of the title compound was obtained according to general procedure eight.1H NMR(500MHz,Methanol-d4) δ 8.11 (d, J =7.6hz, 1h), 8.06 (t, J =7.7hz, 1h), 7.67 (d, J =7.8hz, 1h), 7.61-7.50 (m, 3H), 7.48 (d, J =8.3hz, 2h), 7.39 (d, J =8.4hz, 1h), 7.04 (d, J =7.1hz, 1h), 6.19 (s, 1H), 4.65 (s, 2H), 2.42 (s, 2H), 2.24 (q, J =2.7hz, 2h), 1.90-1.77 (m, 2H), 1.77-1.65 (m, 2H). Theoretical calculation of ESI-MS C26H25N4O2 +[M+H]+=425.2; the experiment shows that: 425.6.
EXAMPLE 85 Synthesis of 5- (((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) nicotinic acid (LYA 129)
Figure BDA0003608794920000802
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (56 mg) and methyl 2-formylisonicotinate (60 mg), using methanol and sodium cyanoborohydride (15 mg) according to general procedure eight, 6mg of the trifluoroacetate salt of the target compound was obtained.1H NMR(500MHz,DMSO-d6) δ 8.90 (d, J =2.0hz, 1h), 8.71 (d, J =2.2hz, 1h), 8.22 (d, J =2.2hz, 1h), 7.53 (d, J =8.0hz, 2h), 7.46 (d, J =7.9hz, 2h), 7.36-7.24 (m, 2H), 6.83 (d, J =6.2hz, 1h), 6.24 (d, J =4.1hz, 1h), 4.45 (d, J =5.8hz, 2h), 2.39 (q, J =5.4hz, 2h), 2.20 (tt, J =5.6,3.1hz, 2h), 1.80-1.69 (m, 2H), 1.62 (8978 xzft 78, J =11.7,9.1, 4.0h). Theoretical calculation of ESI-MS C26H25N4O2 +[M+H]+=425.2; the experiment shows that: 424.3.
EXAMPLE 86 Synthesis of 2- (3- (((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl (LYA 95)
Figure BDA0003608794920000811
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (60 mg) of (E) -4-yl) -1H-indazol-3-amine and methyl 2- (3-formylphenyl) acetate (55 mg), using methanol and sodium cyanoborohydride (16 mg), according to general procedure eight, 14mg of the trifluoroacetate salt of the objective compound was obtained.1H NMR(500MHz,Methanol-d4) δ 7.65 (dd, J =8.6,7.1hz, 1h), 7.53-7.48 (m, 2H), 7.46-7.40 (m, 3H), 7.28 (t, J =7.6hz, 1h), 7.22 (dt, J =7.7,1.4hz, 1h), 7.18 (d, J =1.8hz, 1h), 7.12 (dt, J =7.6,1.5hz, 1h), 7.09 (d, J =7.1hz, 1h), 6.18 (tt, J =4.0,1.7hz, 1h), 4.43 (s, 2H), 3.59 (s, 2H), 2.39 (tq, J =6.3,2.3hz, 2h), 2.25 (ddt, J =8.5,6.3,3.2hz, 2h), 1.86-1.79 (m, 2H), 1.74-1.67 (m, 2H). Theoretical calculation of ESI-MS C28H28N3O2 +[M+H]+=438.2; the experiment shows that: 438.1.
EXAMPLE 87 Synthesis of 2- (2- (((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) phenyl) acetic acid (LYA 102)
Figure BDA0003608794920000812
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-indazol-3-amine (60 mg) andmethyl 2- (2-formylphenyl) acetate (55 mg) was used as a starting material, and methanol and sodium cyanoborohydride (16 mg) were used to obtain 15mg of a trifluoroacetate salt of the objective compound by referring to general method eight.1H NMR(500MHz,Methanol-d4) δ 7.67 (dd, J =8.5,7.2hz, 1h), 7.46-7.37 (m, 5H), 7.28 (dd, J =3.9,1.8hz, 2h), 7.24 (ddd, J =8.7,5.7,3.0hz, 1h), 7.21-7.17 (m, 1H), 7.11 (d, J =7.1hz, 1h), 6.11 (tt, J =4.0,1.7hz, 1h), 4.47 (s, 2H), 3.68 (s, 2H), 2.34 (tq, J =6.4, 2.4h), 2.23 (ddt, J =8.6,6.3,3.3hz, 2h), 1.84-1.77 (m, 2H), 1.73-1.64 (m, 2H). Theoretical calculation of ESI-MS C28H28N3O2 +[M+H]+=438.2; the experiment shows that: 438.4.
EXAMPLE 88 Synthesis of 2- (4- (((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) phenyl) acetic acid (LYA 84)
Figure BDA0003608794920000813
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (60 mg) of (E) -4-yl) -1H-indazol-3-amine and methyl 2- (4-formylphenyl) acetate (55 mg), 22.1mg of the trifluoroacetate salt of the objective compound was obtained using methanol and sodium cyanoborohydride (16 mg) according to general method eight.1H NMR(500MHz,Methanol-d4) δ 7.59 (ddd, J =8.4,7.1,1.4hz, 1H), 7.51-7.46 (m, 2H), 7.44-7.38 (m, 3H), 7.25 (d, J =8.2hz, 2h), 7.20-7.14 (m, 2H), 7.04 (d, J =7.1hz, 1h), 6.18 (tt, J =3.9,1.7hz, 1h), 4.41 (s, 2H), 3.59 (s, 2H), 2.40 (tq, J =6.4,2.3hz, 2h), 2.26 (ddt, J =8.6,6.4,3.3hz, 2h), 1.88-1.79 (m, 2H), 1.75-1.66 (m, 2H). ESI-MS theoretical calculation C28H28N3O2 +[M+H]+=438.2; the experiment shows that: 438.4.
EXAMPLE 89 Synthesis of 3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxamido) methyl) benzoic acid (FB 11)
Figure BDA0003608794920000821
The general method comprises the following steps:
the method comprises the following steps: synthesis of methyl 3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxamido) methylbenzoate (FB 5)
4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxylic acid (FB 55,60 mg), (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) (140 mg) and 1-hydroxybenzotriazole monohydrate (38 mg) were charged into a eggplant-shaped flask, N-dimethylformamide and N, N-diisopropylethylamine (94 mg) were added, and after stirring at room temperature for 10min, methyl 3- (aminomethyl) benzoate hydrochloride (74 mg) was added and the mixture was stirred at room temperature overnight. After the reaction, water quenching is added to quench the reaction, the water phase is extracted by ethyl acetate for 3 times, the organic phases are combined, washed by saturated saline solution, dried by anhydrous sodium sulfate, concentrated by a rotary evaporator and purified by a silica gel column to obtain 47mg of the target compound.
Step two: synthesis of 3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxamido) methyl) benzoic acid (FB 11)
All of FB5 (47 mg) was put in an eggplant type flask, and 5mL of a mixed solvent (MeOH: H) was added2O =1:1.5 Sodium hydroxide (24 mg) was added thereto, the temperature was raised to 80 ℃ and the mixture was stirred overnight. After the reaction, the reaction mixture was concentrated by a rotary evaporator and purified by HPLC to obtain 4mg of trifluoroacetate salt of the objective compound.1H NMR(500MHz,Methanol-d4) δ 8.00-7.92 (m, 2H), 7.58 (dd, J =8.4,0.9hz, 1H), 7.54-7.41 (m, 3H), 7.39 (d, J =8.3hz, 2h), 7.35-7.30 (m, 2H), 7.20 (dd, J =7.0,0.9hz, 1H), 4.32 (s, 2H), 2.42 (tq, J =6.3,2.3hz, 2h), 2.27 (ddt, J =8.3,6.3,2.7hz, 2h), 1.88-1.79 (m, 2H), 1.74-1.70 (m, 2H). Theoretical calculation of ESI-MS C28H26N3O3 +[M+H]+=452.2; the experiment shows that: 451.2.
example 90 Synthesis: 4- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxamido) methyl) benzoic acid (FB 28)
Figure BDA0003608794920000822
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (60 mg) of (e) -4-yl) -1H-indazole-3-carboxylic acid and (140 mg) of methyl 4- (aminomethyl) benzoate hydrochloride, 5mg of the trifluoroacetate salt of the objective compound was obtained according to general method nine.1H NMR(500MHz,Methanol-d4) δ 8.00-7.92 (m, 2H), 7.55 (dd, J =8.4,0.9hz, 1h), 7.48 (dd, J =8.4,7.0hz, 1h), 7.39-7.34 (m, 2H), 7.32-7.26 (m, 4H), 7.17 (dd, J =7.0,0.9hz, 1h), 6.13 (tt, J =4.0,1.7hz, 1h), 4.32 (s, 2H), 2.39 (tq, J =6.4,2.3hz, 2h), 2.24 (dp, J =8.8,3.2,2.7hz, 2h), 1.86-1.77 (m, 2H), 1.74-1.64 (m, 2H). Theoretical calculation of ESI-MS C28H26N3O3 +[M+H]+=452.2; the experiment shows that: 451.2.
example 91 Synthesis: (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) methanol (FB 85)
Figure BDA0003608794920000831
4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Methyl (50 mg) of (E) -4-yl) -1H-indazole-3-carboxylate was charged in an eggplant-shaped flask, tetrahydrofuran (10 mL) was added thereto, a solution of lithium borohydride in tetrahydrofuran (2M, 0.1 mL) was added thereto, and the mixture was stirred at room temperature for 3 hours. After the reaction is finished, water quenching is added to quench the reaction, the aqueous phase is extracted for 3 times by ethyl acetate, the organic phases are combined, the mixture is washed by saturated saline solution, dried by anhydrous sodium sulfate, concentrated by a rotary evaporator and purified by HPLC to obtain the trifluoroacetate of the target compound of 3.1mg.1H NMR(500MHz,Methanol-d4) δ 7.52-7.48 (m, 3H), 7.47-7.43 (m, 2H), 7.41 (dd, J =8.4,7.0hz, 1h), 7.01 (dd, J =6.9,0.9hz, 1h), 6.24 (tt, J =3.9,1.8hz, 1h), 4.54 (s, 2H), 2.49 (tq, J =6.2,2.2hz, 2h), 2.26 (ddp, J =8.8,6.3,3.1,2.7hz, 2h), 1.89-1.80 (m, 2H), 1.76-1.67 (m, 2H). ESI-MS theoretical calculation C20H21N2O+[M+H]+=305.2; the experiment shows that: 305.2.
EXAMPLE 92 Synthesis of 3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -2H-indazol-2-yl) methyl) benzoic acid (FB 107)
Figure BDA0003608794920000832
A general method thirteen:
the method comprises the following steps: methyl 3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -2H-indazol-2-yl) methyl) benzoate (FB 104)
Mixing (4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1,3,2-dioxaborane (88 mg) and methyl 3- ((4-bromo-2H-indazol-2-yl) methyl) benzoate (95 mg) were added to a eggplant-shaped flask, ethylene glycol dimethyl ether (6 mL) and aqueous sodium carbonate solution (2M, 3mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (23 mg), the reaction solution was again deoxygenated, then warmed to 90 ℃ and stirred overnight. After the reaction is finished, the reaction product is cooled to room temperature, water is added to quench the reaction product, the water phase is extracted for 3 times by ethyl acetate, the organic phases are combined, the mixture is washed by saturated saline solution, dried by anhydrous sodium sulfate, concentrated by a rotary evaporator and purified by a silica gel column to obtain 59.4mg of a target compound.1H NMR(500MHz,Chloroform-d)δ8.02(d,J＝1.9Hz,1H),7.99(dt,J＝7.3,1.6Hz,1H),7.71(d,J＝8.7Hz,1H),7.59(d,J＝8.0Hz,2H),7.49(d,J＝8.2Hz,2H),7.45(dt,J＝7.6,1.6Hz,1H),7.41(d,J＝7.6Hz,1H),7.40–7.34(m,1H),7.18(d,J＝6.9Hz,1H),6.21(tt,J＝3.8,1.7Hz,1H),5.64(s,2H),3.90(d,J＝2.6Hz,3H),2.46(tq,J＝6.7,2.2Hz,2H),2.24(tq,J＝6.0,2.8Hz,2H),1.81(qd,J＝7.7,6.2,4.2Hz,2H),1.74–1.62(m,2H)。
Step two: 3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -2H-indazol-2-yl) methyl) benzoic acid (FB 107)
FB107 (59.4 mg) was put in an eggplant type flask, and 6mL of a mixed solvent (THF: H) was added2O: meOH =1:1: 1) Lithium hydroxide monohydrate (58 mg) was added thereto, and the mixture was stirred at room temperature overnight. After the reaction, the reaction mixture was concentrated by a rotary evaporator and purified by HPLC to obtain 21.2mg of the trifluoroacetate salt of the objective compound.1H NMR(500MHz,DMSO-d6)δ8.77(s,1H),7.92(d,J＝1.8Hz,1H),7.87(dt,J＝7.6,1.4Hz,1H),7.71–7.64(m,2H),7.60 (dd, J =11.5,8.2hz, 2h), 7.57-7.52 (m, 2H), 7.48 (t, J =7.7hz, 1h), 7.33 (dd, J =8.7,6.9hz, 1h), 7.18 (d, J =6.9hz, 1h), 6.26 (dt, J =4.4,2.5hz, 1h), 5.74 (s, 2H), 2.43 (dt, J =6.3,3.4hz, 2h), 2.22 (dq, J =6.6,3.6hz, 2h), 1.76 (qd, J =7.6,6.1,3.9hz, 2h), 1.64 (tq, J =6.3,2.7hz, 2h). Theoretical calculation of ESI-MS C27H25N2O2 +[M+H]+=409.2; the experiment shows that: 408.7.
EXAMPLE 93 Synthesis of 4- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -2H-indazol-2-yl) methyl) benzoic acid (FB 122)
Figure BDA0003608794920000841
With (4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]Starting with (e) -4-yl) -1,3,2-dioxaborane (145 mg) and methyl 4- ((4-bromo-2H-indazol-2-yl) methyl) benzoate (193 mg), the desired compound was obtained as 4.8mg of trifluoroacetate salt according to general procedure thirteen.1H NMR(500MHz,DMSO-d6) δ 8.75 (d, J =1.0hz, 1h), 7.95-7.87 (m, 2H), 7.73-7.66 (m, 2H), 7.59 (d, J =8.7hz, 1h), 7.57-7.52 (m, 2H), 7.41 (d, J =8.3hz, 2h), 7.33 (dd, J =8.7,6.9hz, 1h), 7.23-7.12 (m, 1H), 6.31-6.23 (m, 1H), 5.75 (s, 2H), 2.43 (s, 2H), 2.22 (s, 2H), 1.80-1.70 (m, 2H), 1.68-1.60 (m, 2H). Theoretical calculation of ESI-MS C27H25N2O2 +[M+H]+=409.2; the experiment shows that: 409.7.
EXAMPLE 94 Synthesis of 4- (2- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -2H-indazol-2-yl) ethyl) benzoic acid (FB 141)
Figure BDA0003608794920000842
Is prepared from (4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting with (E) -4-yl) -1,3,2-dioxaborane (57 mg) and methyl 4- (2- (4-bromo-2H-indazol-2-yl) ethyl) benzoate (70 mg), the title compound was obtained according to general procedure thirteen3.7mg of trifluoroacetate salt.1H NMR(500MHz,DMSO-d6) δ 8.37 (s, 1H), 7.83 (d, J =7.9hz, 2h), 7.58 (dd, J =12.4,8.3hz, 3h), 7.50 (d, J =8.1hz, 2h), 7.37-7.26 (m, 3H), 7.14 (d, J =6.9hz, 1h), 6.30-6.20 (m, 1H), 4.73 (t, J =7.3hz, 2h), 2.46-2.37 (m, 2H), 2.22 (td, J =6.2, 3.hz 42h), 1.75 (qd, J =7.6,6.2,4.3hz, 2h), 1.69-1.54 (m, 2H). Theoretical calculation of ESI-MS C28H27N2O2 +[M+H]+=423.2; the experiment shows that: 423.8.
EXAMPLE 95 Synthesis of 3- (2- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -2H-indazol-2-yl) ethyl) benzoic acid (FB 152)
Figure BDA0003608794920000851
With (4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]Starting from (4) -yl) -1,3,2-dioxaborane (64 mg) and methyl 3- (2- (4-bromo-2H-indazol-2-yl) ethyl) benzoate (57.6 mg) according to general procedure thirteen, 7.5mg of the trifluoroacetate salt of the title compound was obtained.1H NMR (500mhz, chloroform-d) δ 7.99 (d, J =7.7hz, 1h), 7.91 (d, J =7.4hz, 2h), 7.76 (d, J =8.7hz, 1h), 7.57 (t, J =7.8hz, 1h), 7.48 (d, J =7.9hz, 2h), 7.38 (dd, J =24.9,7.8hz, 3h), 7.33-7.27 (m, 2H), 6.22 (d, J =4.2hz, 1h), 4.85 (t, J =6.9hz, 2h), 3.40 (t, J =7.0hz, 2h), 2.44 (dt, J =7.7,3.9hz, 2h), 2.24 (td, J =6.5, 2.80, 1.80H), 1.7, 4.73H, 1.73H, 1H, 4H, 3.73H, 2.7.7, 3.3H, 3H, 2.24 (td, 2.3, 3H). Theoretical calculation of ESI-MS C28H27N2O2 +[M+H]+=423.2; the experiment shows that: 423.5.
examples 96 and 97 Synthesis of 4- (7- (2 ',3',4',5' -tetrahydro- [1,1 '-biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) benzoic acid (FC 3-1) and 4- (1- (4-carboxybenzyl) -4- (2', 3',4',5 '-tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) benzoic acid (FC 3-2)
Figure BDA0003608794920000852
With (4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1,3,2-dioxaborane (369 mg) and 4- (4-bromo-1H-benzo [ d ]]Imidazol-2-yl) benzoic acid methyl ester and 4- (4-bromo-1- (4- (methoxycarbonyl) benzyl) -1H-benzo [ d]Using an imidazol-2-yl) benzoic acid methyl ester mixture (286 mg) as a starting material, according to general procedure thirteen, trifluoroacetate salt of target compound 96 (FC 3-1) was obtained (41.9 mg).1H NMR(500MHz,Methanol-d4) δ 8.30-8.25 (m, 2H), 8.21 (d, J =8.6hz, 2h), 7.79 (dd, J =8.2,1.0hz, 1h), 7.72-7.64 (m, 3H), 7.63-7.55 (m, 3H), 6.27 (tt, J =4.0,1.7hz, 1h), 2.49 (tq, J =6.4,2.3hz, 2h), 2.27 (tq, J =6.1,2.8hz, 2h), 1.91-1.80 (m, 2H), 1.77-1.67 (m, 2H). Theoretical calculation of ESI-MS C26H23N2O2 +[M+H]+=395.2; the experiment shows that: 395.5. thus, 6.8mg of the trifluoroacetate salt of the objective compound 97 (FC 3-2) was obtained.1H NMR(500MHz,Methanol-d4) δ 8.25 (d, J =8.2hz, 2h), 8.01 (d, J =8.1hz, 2h), 7.90 (d, J =8.1hz, 2h), 7.76-7.64 (m, 5H), 7.60 (d, J =8.1hz, 2h), 7.31 (d, J =8.1hz, 2h), 6.33-6.20 (m, 1H), 5.84 (s, 2H), 2.48 (td, J =6.2,2.7hz, 2h), 2.26 (tq, J =6.1,2.8hz, 2h), 1.83 (qd, J =7.7,6.2,4.3hz, 2h), 1.71 (ddd, J =9.2,7.5,4.6, 2h). Theoretical calculation of ESI-MS C34H29N2O4 +[M+H]+=529.2; the test shows that: 528.9.
examples 98 and 99 Synthesis of 3- (7- (2 ',3',4',5' -tetrahydro- [1,1 '-biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) benzoic acid (FC 11-1) and 3- (1- (3-carboxybenzyl) -4- (2', 3',4',5 '-tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) benzoic acid (FC 11-2)
Figure BDA0003608794920000861
With (4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1,3,2-dioxaborane (467 mg) and 3- (4-bromo-1H-benzo [ d)]Imidazol-2-yl) benzoic acid methyl ester and 3- (4-bromo-1- (3- (methoxycarbonyl) benzyl) -1H-benzo [ d]Imidazol-2-yl) benzoic acid methyl ester mixture (752 mg) referenceThirteenth general procedure, 39.3mg of the trifluoroacetate salt of the target compound 98 (FC 11-1) was obtained.1H NMR(500MHz,Methanol-d4) δ 8.81 (t, J =1.8hz, 1h), 8.35 (tt, J =8.3,1.3hz, 2h), 7.83-7.76 (m, 2H), 7.66 (dd, J =15.8,7.9hz, 3h), 7.58 (dd, J =8.5,7.4hz, 3h), 6.26 (tt, J =4.0,1.7hz, 1h), 2.48 (tq, J =6.5,2.3hz, 2h), 2.26 (dp, J =8.9,3.1,2.6hz, 2h), 1.89-1.80 (m, 2H), 1.77-1.66 (m, 2H). Theoretical calculation of ESI-MS C26H23N2O2 +[M+H]+=395.2; the test shows that: 395.3. 6.0mg of the trifluoroacetate salt of the objective compound 99 (FC 11-2) was obtained.1H NMR(500MHz,Methanol-d4) δ 8.41 (t, J =1.8hz, 1h), 8.35 (dt, J =7.9,1.4hz, 1h), 7.99 (dt, J =7.8,1.6hz, 2h), 7.82 (q, J =1.8hz, 1h), 7.79-7.73 (m, 2H), 7.72-7.64 (m, 4H), 7.61-7.56 (m, 2H), 7.47 (t, J =7.7hz, 1h), 7.42 (dt, J =7.8,1.6hz, 1h), 6.25 (tt, J =3.9,1.7hz, 1h), 5.82 (s, 2H), 2.55-2.42 (m, 2H), 2.26 (ddt, J =8.6,6.3,3.4hz, 2h), 1.90-1.76 (m, 2H), 1.71 (ddp, J =9.3,6.2,3.0hz, 2h). ESI-MS theoretical calculation C34H29N2O4 +[M+H]+=529.2; the test shows that: 529.5.
example 100 Synthesis of 3- ((((4- ([ 1,1' -biphenyl ] -4-yl ] -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 10)
Figure BDA0003608794920000862
With 4- ([ 1,1' -biphenyl]Starting from (4-yl) -1H-indazol-3-amine (50 mg) and 3-formylbenzoic acid (32 mg), according to general procedure six, 9.5mg of the trifluoroacetate salt of the title compound was obtained.1H NMR(500MHz,Methanol-d4) δ 8.04 (d, J =1.92hz, 1h), 7.94 (dt, J =7.73,1.53hz, 1h), 7.79-7.74 (m, 2H), 7.67 (dd, J =8.56,7.08hz, 1h), 7.63-7.57 (m, 4H), 7.53-7.50 (m, 1H), 7.48-7.40 (m, 4H), 7.38-7.34 (m, 1H), 7.15 (d, J =7.04hz, 1h), 4.53 (s, 2H). Theoretical calculation of ESI-MS C27H22N3O2 +[M+H]+=420.2; the experiment shows that: 419.7.
EXAMPLE 101 Synthesis of 3- ((((4- (2-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 11)
Figure BDA0003608794920000871
With 4- (2-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (50 mg) and 3-formylbenzoic acid (30 mg), the title compound was obtained as the trifluoroacetate salt (12.3 mg) according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 8.02-7.94 (m, 2H), 7.64 (t, J =7.89hz, 1h), 7.55-7.39 (m, 3H), 7.29-7.19 (m, 2H), 7.12 (d, J =7.69hz, 1h), 7.07 (d, J =7.11hz, 1h), 5.41 (s, 1H), 4.48 (s, 2H), 2.62-2.02 (m, 7H), 1.81-1.64 (m, 4H). ESI-MS theoretical calculation C28H28N3O2 +[M+H]+=438.2; the experiment shows that: 437.7.
example 102 Synthesis of 3- ((((4-phenyl-1H-indazol-3-yl) amino) methyl) benzoic acid (QM 16)
Figure BDA0003608794920000872
Starting from 4-phenyl-1H-indazol-3-amine (50 mg) and 3-formylbenzoic acid (43 mg), 22.7mg of the trifluoroacetate salt of the target compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4) δ 7.96-7.90 (m, 2H), 7.58 (dd, J =8.56,7.06hz, 1h), 7.52-7.44 (m, 5H), 7.43-7.37 (m, 3H), 7.02 (d, J =7.01hz, 1h), 4.49 (s, 2H). ESI-MS theoretical calculation C21H18N3O2 +[M+H]+=344.1; the experiment shows that: 343.8.
EXAMPLE 103 Synthesis of N-methyl-3- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzamide (QM 25)
Figure BDA0003608794920000873
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (50 mg) and 3-formyl-N-methylbenzamide (33 mg), according to general procedure six, 4.3mg of the trifluoroacetate salt of the target compound was obtained.1H NMR(500MHz,Methanol-d4) δ 7.80 (dd, J =2.05,1.00hz, 1h), 7.73 (ddd, J =5.65,3.47,1.84hz, 1h), 7.59 (dd, J =8.54,7.13hz, 1h), 7.50-7.46 (m, 2H), 7.45-7.38 (m, 5H), 6.13 (tt, J =3.89,1.70hz, 1h), 4.49 (s, 2H), 2.93 (s, 3H), 2.36 (tq, J =6.32,2.27hz, 2h), 2.23 (ddt, J =8.54,6.37,2.96hz, 2h), 1.83-1.77 (m, 2H), 1.72-1.65 (m, 2H). Theoretical calculation of ESI-MS C28H29N4O+[M+H]+=437.2; the experiment shows that: 436.7.
EXAMPLE 104 Synthesis of N-isopropyl-3- (((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzamide (QM 27)
Figure BDA0003608794920000881
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (4-yl) -1H-indazol-3-amine (50 mg) and 3-formyl-N-isopropylbenzamide (50 mg), 5.1mg of the trifluoroacetate salt of the target compound was obtained according to general method six. ESI-MS theoretical calculation C30H33N4O+[M+H]+=465.3; the experiment shows that: 464.7.
EXAMPLE 105 Synthesis of N, N-dimethyl-3- (((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzamide (QM 29)
Figure BDA0003608794920000882
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (4-yl) -1H-indazol-3-amine (50 mg) and 3-formyl-N, N-dimethylbenzamide (92 mg), 24mg of the trifluoroacetate salt of the title compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 7.60 (dd, J =8.55,7.10hz, 1h), 7.51-7.47 (m, 2H), 7.45-7.38 (m, 4H), 7.37-7.30 (m, 3H), 7.04 (d, J =7.11hz, 1h), 6.18 (tt, J =3.86,1.70hz, 1h), 4.49 (s, 2H), 3.09 (s, 3H), 2.92 (s, 3H), 2.39 (tq, J =6.35,2.26hz, 2h), 2.24 (tp, J =6.09,2.75hz, 2h), 1.80 (dtt, J =10.28,6.71, 683.683H), 1.69 (dhept, J =9.23, 3.32h). ESI-MS theoretical calculation C29H31N4O+[M+H]+=451.2; the experiment shows that: 450.7.
EXAMPLE 106 Synthesis of N-ethyl-3- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzamide (QM 31)
Figure BDA0003608794920000883
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (4-yl) -1H-indazol-3-amine (50 mg) and N-ethyl-3-formylbenzamide (153 mg), 16.3mg of the trifluoroacetate salt of the title compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 7.80 (s, 1H), 7.74 (td, J =4.71,1.90hz, 1h), 7.56 (dd, J =8.54,7.07hz, 1h), 7.50-7.46 (m, 2H), 7.46-7.42 (m, 2H), 7.42-7.37 (m, 3H), 7.02 (dd, J =7.10,0.84hz, 1h), 6.14 (td, J =3.96,2.02hz, 1h), 4.48 (s, 2H), 3.42 (q, J =7.36hz, 2h), 2.40-2.33 (m, 2H), 2.26-2.20 (m, 2H), 1.84-1.77 (m, 2H), 1.73-1.66 (m, 2H), 1.24 (t, J =7.24h, 3h, 3hz, 1.24 (m, 2H). Theoretical calculation of ESI-MS C29H31N4O+[M+H]+=451.2; the experiment shows that: 451.3.
EXAMPLE 107 Synthesis of N- (3- (1H-pyrazol-4-yl) benzyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 39)
Figure BDA0003608794920000891
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-indazol-3-amine (138 mg) and 3- (1H-pyrazol-4-yl) benzaldehyde (83 mg) as starting materials, according to the general procedureSixthly, 27.6mg of trifluoroacetate salt of the objective compound is obtained.1H NMR(500MHz,Methanol-d4) δ 8.01 (s, 2H), 7.66 (dd, J =8.58,7.13hz, 1h), 7.55 (dt, J =7.84,1.41hz, 1h), 7.48 (d, J =1.80hz, 1h), 7.44 (d, J =8.56hz, 1h), 7.42-7.36 (m, 4H), 7.33 (t, J =7.68hz, 1h), 7.09 (dd, J =7.31,2.08hz, 2h), 5.98 (tt, J =3.86,1.67hz, 1h), 4.43 (s, 2H), 2.19 (tq, J =6.17,2.16hz, 2h), 2.14 (dtt, J =8.86,6.12, 2.56h), 1.70 (J =6.17,2.16hz, 2h), 1.79 (qxft, 1.58, 1.79H). ESI-MS theoretical calculation C29H28N5 +[M+H]+=446.2; the experiment shows that: 446.6.
EXAMPLE 108 Synthesis of N- (3- (pyridin-3-yl) benzyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 41)
Figure BDA0003608794920000892
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (96 mg) and 3- (pyridin-3-yl) benzaldehyde (73 mg), 22.7mg of the trifluoroacetate salt of the target compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 9.09 (d, J =2.11hz, 1h), 8.82 (d, J =5.56hz, 1h), 8.78 (dt, J =8.20,1.77hz, 1h), 8.10 (dd, J =8.21,5.58hz, 1h), 7.72 (dt, J =7.73,1.48hz, 1h), 7.68 (d, J =1.85hz, 1h), 7.54 (t, J =7.71hz, 1h), 7.49 (dd, J =8.54,7.03hz, 1h), 7.46-7.41 (m, 5H), 7.37 (d, J =8.41hz, 1h), 6.97 (d, J =6.89hz, 1h), 6.07 (tt, J =3.86,1.69hz, 1h), 4.53 (s, 2H), 2.30 (tq, J =6.34,2.26hz, 2h), 2.18 (ddt, J =8.28,6.14,2.58hz, 2h), 1.78-1.71 (m, 2H), 1.68-1.61 (m, 2H). ESI-MS theoretical calculation C31H29N4 +[M+H]+=457.2; the experiment shows that: 456.7.
EXAMPLE 109 Synthesis of N- (3- (1H-pyrazol-5-yl) benzyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 46)
Figure BDA0003608794920000893
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (50 mg) and 3- (1H-pyrazol-5-yl) benzaldehyde (50 mg), 21.2mg of the trifluoroacetate salt of the target compound was obtained according to general method six.1H NMR(500MHz,Methanol-d4) δ 7.77-7.70 (m, 3H), 7.65 (dd, J =8.57,7.10hz, 1h), 7.45-7.35 (m, 6H), 7.20 (dt, J =7.68,1.47hz, 1h), 7.08 (d, J =7.05hz, 1h), 6.72 (d, J =2.36hz, 1h), 5.97 (tt, J =3.82,1.67hz, 1h), 4.47 (s, 2H), 2.19 (tq, J =6.03,2.18hz, 2h), 2.14 (dtt, J =8.80,6.06,2.56hz, 2h), 1.70 (qq, J =5.82,3.30hz, 2h), 1.64-1.58 (m, 2H). ESI-MS theoretical calculation C29H28N5 +[M+H]+=446.2; the test shows that: 446.8.
EXAMPLE 110 Synthesis of N- (3- (pyridin-4-yl) benzyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 50)
Figure BDA0003608794920000901
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (60 mg) and 3- (pyridin-4-yl) benzaldehyde (60 mg), 2.5mg of the trifluoroacetate salt of the title compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 8.91-8.83 (m, 2H), 8.37-8.30 (m, 2H), 7.89 (dt, J =7.75,1.57hz, 1h), 7.86 (d, J =1.81hz, 1h), 7.59 (t, J =7.65hz, 1h), 7.56-7.49 (m, 2H), 7.47-7.41 (m, 4H), 7.38 (d, J =8.43hz, 1h), 6.99 (d, J =6.93hz, 1h), 6.06 (tt, J =3.97,1.70hz, 1h), 4.55 (s, 2H), 2.29 (tq, J =6.24,2.26hz, 2h), 2.17 (dtt, J =8.81,6.01, 2.642H), 1.68, 1.79, 1.60H, 1.79, 1H, 60H, 1H). Theoretical calculation of ESI-MS C31H29N4 +[M+H]+=457.2; the experiment shows that: 457.7.
EXAMPLE 111 Synthesis of N- (3- (1H-tetrazol-5-yl) benzyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 52)
Figure BDA0003608794920000902
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (66 mg) of (E) -4-yl) -1H-indazol-3-amine and (80 mg) of 3- (1H-tetrazol-5-yl) benzaldehyde, 3.3mg of the trifluoroacetate salt of the objective compound was obtained according to general method VI.1H NMR(500MHz,Methanol-d4) δ 8.01 (d, J =1.74hz, 1h), 7.94 (dt, J =7.74,1.48hz, 1h), 7.60-7.52 (m, 2H), 7.50-7.39 (m, 6H), 7.03 (dd, J =7.07,0.83hz, 1h), 5.98 (tt, J =3.93,1.70hz, 1h), 4.52 (s, 2H), 2.21 (tq, J =6.23,2.35hz, 2h), 2.14 (tdd, J =6.24,4.07,2.60hz, 2h), 1.75-1.68 (m, 2H), 1.65-1.59 (m, 2H). ESI-MS theoretical calculation C27H26N7 +[M+H]+=448.2; the experiment shows that: 447.8.
EXAMPLE 112 Synthesis of 2- (((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 66)
Figure BDA0003608794920000911
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (4-yl) -1H-indazol-3-amine (50 mg) and 2-formylbenzoic acid (39 mg), 5.8mg of the trifluoroacetate salt of the title compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 8.03 (dd, J =7.77,1.47hz, 1h), 7.62 (dd, J =8.55,7.11hz, 1h), 7.51 (td, J =7.52,1.51hz, 1h), 7.46-7.37 (m, 5H), 7.34-7.29 (m, 2H), 7.04 (d, J =7.11hz, 1h), 6.15 (tt, J =3.88,1.70hz, 1h), 4.72 (s, 2H), 2.38 (tq, J =6.31,2.25hz, 2h), 2.24 (ddt, J =8.37,6.15,3.13hz, 2h), 1.86-1.77 (m, 2H), 1.73-1.66 (m, 2H). Theoretical calculation of ESI-MS C27H26N3O2 +[M+H]+=424.2; the experiment shows that: 424.9.
EXAMPLE 113 Synthesis of 4- (((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 69)
Figure BDA0003608794920000912
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (4-yl) -1H-indazol-3-amine (50 mg) and 4-formylbenzoic acid (39 mg), 6mg of the trifluoroacetate salt of the title compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 7.97 (d, J =7.90hz, 2h), 7.57 (t, J =7.80hz, 1h), 7.46 (d, J =7.94hz, 2h), 7.43-7.37 (m, 3H), 7.32 (d, J =7.95hz, 2h), 7.04 (d, J =7.03hz, 1h), 6.17-6.10 (m, 1H), 4.47 (s, 2H), 2.41-2.31 (m, 2H), 2.27-2.19 (m, 2H), 1.85-1.77 (m, 2H), 1.73-1.63 (m, 2H). Theoretical calculation of ESI-MS C27H26N3O2 +[M+H]+=424.2; the experiment shows that: 423.7.
EXAMPLE 114 Synthesis of 4- (((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) cyclohexane-1-carboxylic acid (QM 71)
Figure BDA0003608794920000913
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (50 mg) and 4-formylcyclohexane-1-carboxylic acid (39 mg), the title compound was obtained as the trifluoroacetate salt (26.2 mg) according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 7.67 (dd, J =8.59,7.12hz, 1h), 7.63-7.58 (m, 2H), 7.47-7.38 (m, 3H), 7.10 (d, J =7.02hz, 1h), 6.30 (tt, J =3.93,1.68hz, 1h), 3.10 (d, J =6.14hz, 2h), 2.48 (tq, J =6.65, 2.hz, 2h), 2.26 (tq, J =5.72,2.73hz, 2h), 2.19 (tt, J =12.29,3.62hz, 1h), 1.94 (dt, J =12.33,3.59hz, 2h), 1.87-1.79 (m, 2H), 1.74-1.66 (m, 2H), 1.62 (dd, J = 13.13, 3, 3560, 3.59hz, 2h), 1.87-1.79 (m, 2H), 1.74-1.66 (m, 2H), 1.62 (J =13, 3.13H), 3.3513H, 3, 3.31H, 1.13H, 3, 3.31H, 3.13H). Theoretical calculation of ESI-MS C27H32N3O2 +[M+H]+=430.2; the experiment shows that: 430.7.
example 115 Synthesis of 3- (((4- (4- (trifluoromethyl) phenyl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 74)
Figure BDA0003608794920000921
Starting from 4- (4- (trifluoromethyl) phenyl) -1H-indazol-3-amine (50 mg) and 3-formylbenzoic acid (41 mg), 8.8mg of the trifluoroacetate salt of the target compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 8.00 (d, J =1.90hz, 1h), 7.92 (dt, J =7.61,1.57hz, 1h), 7.80 (d, J =8.06hz, 2h), 7.72 (d, J =8.04hz, 2h), 7.57 (dd, J =8.55,6.97hz, 1h), 7.51-7.47 (m, 1H), 7.47-7.38 (m, 2H), 7.05 (d, J =7.01hz, 1h), 4.49 (s, 2H). Theoretical calculation of ESI-MS C22H17F3N3O2 +[M+H]+=412.1; the experiment shows that: 411.6. example 116 Synthesis of 3- (((4- (2-fluoro-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 83)
Figure BDA0003608794920000922
With 4- (2-fluoro-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (60 mg) and 3-formylbenzoic acid (58 mg), 5.5mg of the trifluoroacetate salt of the title compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 7.99 (d, J =1.79hz, 1h), 7.95 (dt, J =7.71,1.49hz, 1h), 7.57-7.50 (m, 2H), 7.46-7.39 (m, 2H), 7.35 (t, J =7.87hz, 1h), 7.25 (dd, J =7.84,1.78hz, 1h), 7.19 (dd, J =11.50,1.74hz, 1h), 7.02 (d, J =6.97hz, 1h), 5.88 (tt, J =3.73,1.73hz, 1h), 4.49 (s, 2H), 2.30 (dtt, J =5.61,3.80,1.83hz, 2h), 2.22 (dtt, J =8.85,6.06,2.66hz, 2h), 1.77 (tdd, J =8.49,5.28,2.72hz, 2h), 1.70 (dtt, J =9.24,6.03,2.84hz, 2h). Theoretical calculation of ESI-MS C27H25FN3O2 +[M+H]+=442.2; the experiment shows that: 442.7.
EXAMPLE 117 Synthesis of 3- ((((4- (3-fluoro-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 87)
Figure BDA0003608794920000923
With 4- (3-fluoro-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (50 mg) and 3-formylbenzoic acid (49 mg), the title compound was obtained as the trifluoroacetate salt (14.5 mg) according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 7.98 (d, J =1.82hz, 1h), 7.96 (dd, J =7.63,1.53hz, 1h), 7.64 (t, J =7.87hz, 1h), 7.49 (dt, J =7.65,1.66hz, 1h), 7.47-7.41 (m, 2H), 7.37 (t, J =7.88hz, 1h), 7.31 (dd, J =7.94,1.74hz, 1h), 7.25 (dd, J =11.73,1.73hz, 1h), 7.08 (d, J =7.09hz, 1h), 6.19 (tt, J =3.93,1.73hz, 1h), 4.48 (s, 2H), 2.33 (tq, J =6.41, 2.30h), 2.23 (223, 8, 86.86, dp, 1.76, 1.081H), 2.83-1.76H (d, J = 11.71H, 1H). Theoretical calculation of ESI-MS C27H25FN3O2 +[M+H]+=442.2; the experiment shows that: 442.7.
EXAMPLE 118 Synthesis of 3- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzonitrile (QM 93)
Figure BDA0003608794920000931
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (50 mg) and 3-formylbenzonitrile (45 mg), according to general method six, the desired compound was obtained as the trifluoroacetate salt in an amount of 1.2mg.1H NMR(500MHz,Methanol-d4) δ 7.63-7.59 (m, 2H), 7.56 (dt, J =8.24,1.49hz, 1h), 7.53-7.41 (m, 6H), 7.35 (d, J =8.43hz, 1h), 6.96 (d, J =6.97hz, 1h), 6.19 (tt, J =3.95,1.74hz, 1h), 4.45 (s, 2H), 2.43 (ddd, J =8.19,5.03,3.08hz, 2h), 2.25 (dh, J =8.92, 2.732h), 1.86-1.79 (m, 2H), 1.74-1.66 (m, 2H). Theoretical calculation of ESI-MS C27H25N4 +[M+H]+=405.2; the experiment shows that: 405.4.
EXAMPLE 119 Synthesis of N- (3- (3-Aminooxetan-3-yl) benzyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 108)
Figure BDA0003608794920000932
4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-indazol-3-amine (100 mg) and N- (3- (3-formylphenyl) oxetan-3-yl) -2-methylpropan-2-sulfinamide (194 mg) were added to a eggplant-shaped flask, 1,2-dichloroethane (10 mL) was added, sodium triacetoxyborohydride (212 mg) and acetic acid (0.1 mL) were added, and stirring was performed overnight at room temperature. After the reaction, a saturated sodium bicarbonate solution was added, the aqueous phase was extracted 3 times with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and purified on a silica gel column to obtain QM106 (263 mg). Theoretical calculation of ESI-MS C33H39N4O2S+[M+H]+=555.3; the experiment shows that: 556.6.
QM106 (131 mg) was placed in an eggplant-shaped flask, methanol (5 mL) was added thereto, and a methanol hydrochloric acid solution (4M, 1mL) was added dropwise thereto at 0 ℃ and the mixture was stirred for 10 minutes. After the reaction, the reaction mixture was concentrated by a rotary evaporator and purified by HPLC to obtain 14.6mg of the trifluoroacetate salt of the objective compound.1H NMR(500MHz,Methanol-d4) δ 7.55-7.42 (m, 6H), 7.41-7.33 (m, 4H), 6.99 (d, J =7.01hz, 1h), 6.19 (tt, J =3.98,1.73hz, 1h), 5.03 (d, J =7.82hz, 2h), 4.50 (s, 2H), 2.41 (tq, J =6.44,2.34hz, 2h), 2.25 (pt, J =6.24,3.24hz, 2h), 1.86-1.77 (m, 2H), 1.73-1.65 (m, 2H). Theoretical calculation of ESI-MS C29H31N4O+[M+H]+=451.2; the experiment shows that: 451.4.
EXAMPLE 120 Synthesis of 3- (3- (((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) phenyl) oxetan-3-ol (QM 110)
Figure BDA0003608794920000941
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-indazol-3-amine (50 mg) and 3-(3-hydroxyoxetan-3-yl) benzaldehyde (62 mg) was used as a starting material, and 12.9mg of a trifluoroacetate salt of the objective compound was obtained by following general method VI.1H NMR(500MHz,Methanol-d4) δ 7.62 (dd, J =8.54,7.11hz, 1h), 7.61-7.56 (m, 2H), 7.50-7.46 (m, 2H), 7.44-7.40 (m, 3H), 7.40-7.36 (m, 1H), 7.20 (dt, J =7.64,1.51hz, 1h), 7.06 (d, J =7.02hz, 1h), 6.15 (tt, J =3.89,1.71hz, 1h), 4.88 (d, J =6.77hz, 2h), 4.76 (d, J =7.01hz, 2h), 4.47 (s, 2H), 2.37 (dddt, J =8.56,6.48,4.36, 2.292h), 2.23 (tq, J =5.68, 2.7765, 1.7784H), 1.71H (1.71, 71H), 1.71H). Theoretical calculation of ESI-MS C29H30N3O2 +[M+H]+=452.2; the experiment shows that: 452.4.
EXAMPLE 121 Synthesis of 2-hydroxy-5- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 111)
Figure BDA0003608794920000942
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (60 mg) and 5-formyl-2-hydroxybenzoic acid (69 mg), according to general procedure six, 9.5mg of the trifluoroacetate salt of the title compound was obtained.1H NMR(500MHz,Methanol-d4) δ 7.79 (d, J =2.38hz, 1h), 7.61 (dd, J =8.54,7.06hz, 1h), 7.49-7.31 (m, 7H), 7.06 (d, J =7.06hz, 1h), 6.89 (d, J =8.52hz, 1h), 6.08 (tt, J =3.87,1.73hz, 1h), 4.31 (s, 2H), 2.32 (tq, J =6.41,2.34hz, 2h), 2.22 (td, J =6.12,3.36hz, 2h), 1.82-1.75 (m, 2H), 1.72-1.64 (m, 2H). Theoretical calculation of ESI-MS C27H26N3O3 +[M+H]+=440.2; the test shows that: 440.2.
EXAMPLE 122 Synthesis of 3- (((((4- (4-cyclopropylphenyl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 113)
Figure BDA0003608794920000943
With 4- (4-cyclopropyl groupPhenyl) -1H-indazol-3-amine (133 mg) and 3-formylbenzoic acid (160 mg) were used as starting materials to obtain 94.6mg of a trifluoroacetate salt of the target compound according to general method six. Theoretical calculation of ESI-MS C24H22N3O2 +[M+H]+=384.2; the test shows that: 384.3.
example 123 Synthesis of 3- (3- (((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) phenyl) azetidin-3-ol (QM 115)
Figure BDA0003608794920000951
4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-indazol-3-amine (125 mg) and tert-butyl 3- (3-formylphenyl) -3-hydroxyazetidine-1-carboxylate (240 mg) were added to a round bottom flask, 1,2-dichloroethane (10 mL) was added, sodium triacetoxyborohydride (273 mg) and acetic acid (0.1 mL) were added, and the mixture was stirred at room temperature overnight. After the reaction, a saturated sodium bicarbonate solution was added, the aqueous phase was extracted 3 times with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by a rotary evaporator, and purified by a silica gel column to obtain QM112. Theoretical calculation of ESI-MS C34H39N4O3 +[M+H]+=551.3; the test shows that: 552.0.
the entirety of QM112 was placed in an eggplant-shaped flask, methylene chloride (4 mL) was added thereto, trifluoroacetic acid (1 mL) was added dropwise thereto, and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was concentrated by a rotary evaporator and purified by HPLC to obtain 33.9mg of the trifluoroacetate salt of the objective compound.1H NMR(500MHz,Methanol-d4) δ 7.60 (dd, J =8.55,7.12hz, 1h), 7.54-7.46 (m, 4H), 7.46-7.37 (m, 4H), 7.26 (dt, J =7.64,1.49hz, 1h), 7.04 (d, J =7.03hz, 1h), 6.18 (tt, J =3.96,1.69hz, 1h), 4.50 (s, 2H), 4.48-4.42 (m, 2H), 4.19-4.12 (m, 2H), 2.39 (tq, J =6.43,2.29hz, 2h), 2.24 (tq, J =5.71,2.67hz, 2h), 1.85-1.76 (m, 2H), 1.73-1.64 (m, 2H). ESI-MS theoretical calculation C29H31N4O+[M+H]+=451.2; the test shows that: 450.4.
EXAMPLE 124 Synthesis of 3- (((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzenesulfonamide (QM 126)
Figure BDA0003608794920000952
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (57 mg) and 3-formylbenzenesulfonamide (73 mg), according to general procedure six, 7.8mg of the trifluoroacetate salt of the title compound was obtained.1H NMR(500MHz,Methanol-d4) δ 7.90 (d, J =1.92hz, 1h), 7.81 (dt, J =7.11,1.94hz, 1h), 7.57-7.42 (m, 7H), 7.38 (dd, J =8.56,0.78hz, 1h), 7.01 (dd, J =7.06,0.81hz, 1h), 6.20 (tt, J =3.92,1.67hz, 1h), 4.52 (s, 2H), 2.41 (tq, J =6.41,2.31hz, 2h), 2.23 (ddt, J =8.45,6.24,2.67hz, 2h), 1.85-1.75 (m, 2H), 1.73-1.63 (m, 2H). ESI-MS theoretical calculation C26H27N4O2S+[M+H]+=459.2; the experiment shows that: 459.3.
EXAMPLE 125 Synthesis of 2-hydroxy-3- (((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QN 2)
Figure BDA0003608794920000961
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (60 mg) and 3-formyl-2-hydroxybenzoic acid (73 mg), 30.8mg of the trifluoroacetate salt of the title compound was obtained according to general procedure six.1H NMR(500MHz,Methanol-d4) δ 7.57 (dd, J =8.52,7.05hz, 1h), 7.50-7.42 (m, 4H), 7.41-7.35 (m, 3H), 7.17 (d, J =7.76hz, 1h), 7.03 (d, J =7.02hz, 1h), 6.16 (dq, J =4.05,2.09hz, 1h), 4.41 (s, 2H), 2.43-2.35 (m, 2H), 2.25 (td, J =6.15,3.32hz, 2h), 1.86-1.78 (m, 2H), 1.74-1.65 (m, 2H). Theoretical calculation of ESI-MS C27H26N3O3 +[M+H]+=440.2; the experiment shows that: 440.3.
EXAMPLE 126 Synthesis of N- (3- (3-Aminoazetidin-3-yl) benzyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 134)
Figure BDA0003608794920000962
4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-indazol-3-amine (144 mg) and tert-butyl 3- ((tert-butylsulfinyl) amino) -3- (3-formylphenyl) azetidine-1-carboxylate (386 mg) were added to an eggplant-shaped flask, 1,2-dichloroethane (10 mL) was added, sodium triacetoxyborohydride (318 mg) and acetic acid (0.1 mL) were added, and stirring was continued overnight at room temperature. After the reaction was completed, a saturated sodium bicarbonate solution was added, the aqueous phase was extracted 3 times with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and purified by a silica gel column to obtain QM132 (231 mg). Theoretical calculation of ESI-MS C38H48N5O3S+[M+H]+=654.3; the test shows that: 651.8.
QM132 (77 mg) was placed in an eggplant type flask, methylene chloride (4 mL) was added thereto, and trifluoroacetic acid (1 mL) was added dropwise thereto and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated by a rotary evaporator, methanol (5 mL) was added, and a methanol hydrochloride solution (4M, 1mL) was added dropwise thereto at 0 ℃ and stirred for 10 minutes. After the reaction, the reaction mixture was concentrated by a rotary evaporator and purified by HPLC to obtain 21mg of trifluoroacetate salt of the objective compound.1H NMR(500MHz,Methanol-d4) δ 7.57-7.44 (m, 8H), 7.42 (dd, J =7.67,1.46hz, 1h), 7.37 (d, J =8.42hz, 1h), 6.98 (d, J =7.01hz, 1h), 6.24 (tt, J =3.98,1.75hz, 1h), 4.74 (d, J =12.52hz, 2h), 4.69 (d, J =12.79hz, 2h), 4.54 (s, 2H), 2.45 (tq, J =6.44,2.28hz, 2h), 2.25 (dp, J =8.85,3.19,2.74hz, 2h), 1.87-1.78 (m, 2H), 1.74-1.66 (m, 2H). ESI-MS theoretical calculation C29H32N5 +[M+H]+=450.2; the test shows that: 449.7.
EXAMPLE 127 Synthesis of 4-hydroxy-3- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 136)
Figure BDA0003608794920000971
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (60 mg) and 3-formyl-4-hydroxybenzoic acid (69 mg), according to general procedure six, 65.5mg of the trifluoroacetate salt of the title compound was obtained. Theoretical calculation of ESI-MS C27H26N3O3 +[M+H]+=440.2; the test shows that: 440.2.
EXAMPLE 128 Synthesis of 2-fluoro-5- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 143)
Figure BDA0003608794920000972
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (60 mg) and methyl 2-fluoro-5-formylbenzoate (76 mg), 35.3mg of the trifluoroacetate salt of the target compound was obtained according to general procedure eight.1H NMR(500MHz,DMSO-d6) δ 7.84 (dd, J =7.23,2.42hz, 1h), 7.56-7.50 (m, 3H), 7.48-7.42 (m, 2H), 7.33-7.25 (m, 2H), 7.21 (dd, J =10.81,8.48hz, 1h), 6.82 (dd, J =5.97,1.95hz, 1h), 6.24 (dq, J =3.96,1.92hz, 1h), 4.36 (s, 2H), 2.38 (ddt, J =8.81,4.65, 2.hz, 2h), 2.20 (td, J =6.08,3.19hz, 2h), 1.79-1.69 (m, 2H), 1.66-1.56 (m, 2H). Theoretical calculation of ESI-MS C27H25FN3O2 +[M+H]+=442.2; the experiment shows that: 442.3.
EXAMPLE 129 Synthesis of 3-hydroxy-5- (((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QN 18)
Figure BDA0003608794920000973
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-indoleAzol-3-amine (86 mg) and 3-formyl-4-hydroxybenzoic acid (100 mg) were used as starting materials, according to general procedure six, to give 65.5mg of trifluoroacetate salt of the target compound.1H NMR(500MHz,Methanol-d4) δ 7.62 (dd, J =8.56,7.08hz, 1h), 7.50-7.46 (m, 2H), 7.44-7.34 (m, 5H), 7.05 (d, J =7.10hz, 1h), 6.92 (t, J =2.02hz, 1h), 6.12 (tt, J =3.79,1.65hz, 1h), 4.39 (s, 2H), 2.34 (tq, J =6.39,2.20hz, 2h), 2.20 (dp, J =6.24,3.04,2.54hz, 2h), 1.78 (2, J =5.74,2.39hz, 2h), 1.67 (dtt, J =9.31,6.16,2.89hz, 2.89pdh). Theoretical calculation of ESI-MS C27H26N3O3 +[M+H]+=440.2; the experiment shows that: 439.8.
EXAMPLE 130 Synthesis of 2-fluoro-3- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 154)
Figure BDA0003608794920000981
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (60 mg) and 2-fluoro-3-formylbenzoic acid (70 mg), 34.7mg of the trifluoroacetate salt of the target compound was obtained according to general method six.1H NMR(500MHz,DMSO-d6) δ 7.70 (td, J =7.40,1.87hz, 1h), 7.57-7.49 (m, 3H), 7.48-7.41 (m, 2H), 7.35-7.26 (m, 2H), 7.18 (t, J =7.66hz, 1h), 6.83 (dd, J =6.11,1.84hz, 1h), 6.25 (t, J =3.91hz, 1h), 4.43 (s, 2H), 2.40 (dt, J =7.73, 3.812h), 2.20 (dh, J =5.92,2.75hz, 2h), 1.79-1.70 (m, 2H), 1.66-1.57 (m, 2H). Theoretical calculation of ESI-MS C27H25FN3O2 +[M+H]+=442.2; the experiment shows that: 441.8.
EXAMPLE 131 Synthesis of 3-fluoro-5- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 155)
Figure BDA0003608794920000982
With 4- (2 ',3',4',5' -tetrahydro-2)- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (60 mg) and 3-fluoro-5-formylbenzoic acid (70 mg), 49.4mg of the trifluoroacetate salt of the target compound was obtained according to general procedure six.1H NMR(500MHz,DMSO-d6) δ 7.79 (d, J =5.04hz, 1h), 7.61-7.42 (m, 5H), 7.40-7.23 (m, 3H), 6.84 (d, J =6.15hz, 1h), 6.25 (s, 1H), 4.43 (s, 2H), 2.44-2.34 (m, 2H), 2.25-2.14 (m, 2H), 1.80-1.68 (m, 2H), 1.66-1.55 (m, 2H). Theoretical calculation of ESI-MS C27H25FN3O2 +[M+H]+=442.2; the experiment shows that: 441.7.
EXAMPLE 132 Synthesis of 2-hydroxy-4- (((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QN 1)
Figure BDA0003608794920000983
With 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]Starting from (e) -4-yl) -1H-indazol-3-amine (82 mg) and methyl 2-fluoro-5-formylbenzoate (103 mg), 35.3mg of the trifluoroacetate salt of the target compound was obtained according to general procedure eight.1H NMR(500MHz,Methanol-d4) δ 7.82 (dd, J =7.96,1.76hz, 1h), 7.58 (dd, J =8.52,7.00hz, 1h), 7.43 (d, J =7.88hz, 2h), 7.41-7.36 (m, 2H), 7.33 (d, J =7.85hz, 2h), 7.01 (d, J =6.97hz, 1h), 6.83 (t, J =7.64hz, 1h), 6.14 (tt, J =3.80,1.71hz, 1h), 4.41 (s, 2H), 2.38 (tq, J =6.18,2.26hz, 2h), 2.24 (tq, J =5.83,2.76hz, 2h), 1.85-1.78 (m, 2H), 1.73-1.66 (m, 2H). Theoretical calculation of ESI-MS C27H26N3O3 +[M+H]+=440.2; the experiment shows that: 440.2.
EXAMPLE 133 Synthesis of 2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FC 50)
Figure BDA0003608794920000991
The general method is fourteen:
mixing (4,4,5,5-tetramethyl-2- (2)',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1,3,2-dioxaborane (100 mg) and 4-bromo-2-phenyl-1H-benzo [ d]Imidazole (80 mg) was added to an eggplant-shaped flask, ethylene glycol dimethyl ether (10 mL) and an aqueous solution of sodium carbonate (2M, 5 mL) were added, oxygen was removed from the reaction solution, and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (25 mg) was added to the reaction solution, and oxygen was removed again, and the temperature was raised to 90 ℃ and stirred overnight. After the reaction is finished, cooling to room temperature, adding water to quench the reaction, extracting the water phase for 3 times by using ethyl acetate, combining the organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, concentrating by using a rotary evaporator, and purifying by using HPLC (high performance liquid chromatography) to obtain 21.3mg of trifluoroacetate of the target compound.1H NMR(500MHz,Methanol-d4) δ 8.16-8.10 (m, 2H), 7.80-7.72 (m, 2H), 7.72-7.62 (m, 5H), 7.62-7.53 (m, 3H), 6.27 (tt, J =3.9,1.7hz, 1h), 2.50 (tq, J =6.4,2.3hz, 2h), 2.27 (tq, J =6.0,2.7hz, 2h), 1.94-1.79 (m, 2H), 1.77-1.64 (m, 2H). Theoretical calculation of ESI-MS C25H23N2 +[M+H]+=351.2; the experiment shows that: 350.9.
examples 134 and 135 Synthesis of 2- (4- (7- (2 ',3',4',5' -tetrahydro- [1,1 '-biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) phenyl) acetic acid (FC 63-1) and 2- (4- (1- (4- (carboxymethyl) benzyl) -4- (2', 3',4',5 '-tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) phenyl) acetic acid (FC 63-2)
Figure BDA0003608794920000992
With (4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1,3,2-dioxaborane (175 mg) and 2- (4- (4-bromo-1H-benzo [ d)]Imidazol-2-yl) phenyl) acetic acid methyl ester and 2- (4- (4-bromo-1- (4- (2-methoxy-2-oxoethyl) benzyl) -1H-benzo [ d]Imidazol-2-yl) phenyl) acetic acid methyl ester mixture (177 mg) according to general method fourteen, to give the title compound 134 (FC 63-1) as trifluoroacetic acid salt 21.7mg.1H NMR(500MHz,Methanol-d4)δ8.09(d,J＝8.2Hz,2H),7.77(d,J＝8.2Hz,1H),7.70–7.53(m,8H),6.26(tt,J＝3.9,1.7Hz,1H),3.79(s,2H),2.48(tq,J＝6.5,2.3Hz,2H),2.26(tq,J＝5.9,2.8Hz,2H),194-1.79 (m, 2H), 1.77-1.61 (m, 2H). Theoretical calculation of ESI-MS C27H25N2O2 +[M+H]+=409.2; the experiment shows that: 409.2.
6.8mg of the trifluoroacetate salt of the target compound 135 (FC 63-2) was obtained.1H NMR(500MHz,Methanol-d4) δ 7.80-7.75 (m, 2H), 7.73 (dd, J =6.9,2.5hz, 1h), 7.70-7.64 (m, 4H), 7.61 (d, J =8.0hz, 4h), 7.34-7.24 (m, 2H), 7.23-7.10 (m, 2H), 6.27 (tq, J =4.0,2.2,1.7hz, 1h), 5.75 (s, 2H), 3.80 (s, 2H), 3.61 (s, 2H), 2.48 (tq, J =6.5,2.4hz, 2h), 2.27 (ddt, J =8.4,6.1,3.3hz, 2h), 1.91-1.79 (m, 2H), 1.78-1.63 (m, 2H). Theoretical calculation of ESI-MS C36H33N2O4 +[M+H]+=557.2; the experiment shows that: 557.3. examples 136 and 137 Synthesis of 2- (3- (7- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazol-2-yl) phenyl) acetic acid (FC 59-1) and 2- (3- (1- (3- (carboxymethyl) benzyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazol-2-yl) phenyl) acetic acid (FC 59-2)
Figure BDA0003608794920001001
With (4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1,3,2-dioxaborane (415 mg) and 2- (3- (4-bromo-1H-benzo [ d)]Imidazol-2-yl) phenyl) acetic acid methyl ester and 2- (3- (4-bromo-1- (3- (2-methoxy-2-oxoethyl) benzyl) -1H-benzo [ d]Imidazol-2-yl) phenyl) acetic acid methyl ester mixture (419 mg) as a starting material was subjected to the general method fourteen to obtain 58.2mg of a trifluoroacetate salt of the objective compound 136 (FC 59-1).1H NMR(500MHz,Methanol-d4) δ 8.05 (d, J =1.8hz, 1h), 8.01 (dt, J =7.6,1.5hz, 1h), 7.76 (dd, J =8.2,0.9hz, 1h), 7.69-7.48 (m, 8H), 6.25 (tt, J =3.9,1.8hz, 1h), 3.78 (s, 2H), 2.46 (tq, J =6.4,2.2hz, 2h), 2.26 (tq, J =6.0,2.7, 2h), 1.90-1.78 (m, 2H), 1.76-1.62 (m, 2H). Theoretical calculation of ESI-MS C27H25N2O2 +[M+H]+=409.2; the experiment shows that: 408.4. to obtain the trifluoroacetate salt of the target compound 137 (FC 59-2)16.4mg。1H NMR(500MHz,Methanol-d4) δ 7.80 (dd, J =7.9,1.4hz, 1h), 7.75 (d, J =1.8hz, 1h), 7.68 (tt, J =7.5,4.8hz, 6h), 7.64-7.57 (m, 3H), 7.30 (t, J =7.6hz, 1h), 7.26 (dt, J =7.8,1.4hz, 1h), 7.14 (d, J =1.8hz, 1h), 7.10hz (dt, J =7.6,1.5, 1h), 6.26 (tt, J =4.0,1.7hz, 1h), 5.76 (s, 2H), 3.76 (s, 2H), 3.57 (s, 2H), 2.48 (tq, J =6.3,2.3hz, 2h), 2.26 (ddt, J =8.1,5.8,3.0hz, 2h), 1.84 (pd, J =5.9,2.6hz, 2h), 1.76-1.64 (m, 2H). Theoretical calculation of ESI-MS C36H33N2O4 +[M+H]+=557.2; the experiment shows that: 556.9.
EXAMPLE 138 Synthesis of 4- ((2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FC 65-14)
Figure BDA0003608794920001002
The general method is twelve:
2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (50 mg) and methyl 2- (4-bromophenyl) acetate (47 mg) were put in an eggplant type flask, DMF (5 mL) was added, and K was added2CO3(70 mg), the temperature was raised to 80 ℃ and the mixture was stirred overnight. After the reaction, the reaction mixture was cooled to room temperature, water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by silica gel column to obtain 38mg of crude compound.
Mixing the crude compound with LiOH-H2O (15 mg) was added to the eggplant-shaped flask, and a mixed solvent (4 ml2O = 1:1). After stirring overnight at room temperature, HPLC purification afforded the trifluoroacetate salt of target compound 138 (FC 65-14) which was lyophilized to give 22.3mg of solid.1H NMR(500MHz,Methanol-d4) δ 8.00 (d, J =8.2hz, 2H), 7.85-7.73 (m, 3H), 7.73-7.63 (m, 7H), 7.59 (d, J =8.2hz, 2H), 7.30 (d, J =8.2hz, 2H), 6.26 (dq, J =3.9,1.9hz, 1H), 5.84 (s, 2H), 2.47 (td, J =6.0,2.7hz, 2H), 2.25 (tq, J =5.9,2.7hz, 2H), 1.90-1.77 (m, 2H), 1.77-1.62 (m, 2H). Theoretical calculation of ESI-MS C33H29N2O2 +[M+H]+=485.2; the experiment shows that: 485.2.
EXAMPLE 139 Synthesis of 3- ((2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FC 74-15)
Figure BDA0003608794920001011
With 2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (30 mg) and methyl 3- (bromomethyl) benzoate (23 mg) were used as starting materials to give a crude compound according to general procedure twelve. Subsequently adding LiOH-H2O (10 mg) hydrolyzed methyl ester, which was purified by HPLC to give the trifluoroacetate salt of target compound 139 (FC 74-15), which was lyophilized to give 24mg of solid.1H NMR(500MHz,Methanol-d4) δ 7.99 (dt, J =7.6,1.4hz, 1H), 7.85-7.73 (m, 5H), 7.68 (qd, J =7.9,2.0hz, 6H), 7.63-7.58 (m, 2H), 7.47 (t, J =7.7hz, 1H), 7.42 (dt, J =7.8,1.5hz, 1H), 6.26 (tt, J =4.0,1.7hz, 1H), 5.83 (s, 2H), 2.48 (tq, J =6.6,2.3hz, 2H), 2.26 (tq, J =6.3,2.7hz, 2H), 1.89-1.79 (m, 2H), 1.76-1.65 (m, 2H), ESI-MS theoretical calculation C33H29N2O2 +[M+H]+=485.2; the experiment shows that: 485.3.
example 140: synthesis of 3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FC 83-9)
Figure BDA0003608794920001012
A general method fifteen:
4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1,3,2-dioxaborane (48 mg) and 3- ((4-bromo-1H-benzo [ d)]Imidazol-2-yl) methyl) benzoate (50 mg) was placed in an eggplant-shaped flask, ethylene glycol dimethyl ether (5 mL) and an aqueous solution of sodium carbonate (2M, 2mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (ii)10 mg), the reaction solution was again deoxygenated, and the temperature was raised to 90 ℃ and stirred overnight. After the reaction is finished, cooling to room temperature, adding water to quench the reaction, extracting the water phase for 3 times by using ethyl acetate, combining the organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, and concentrating by using a rotary evaporator to obtain a crude product. Followed by LiOH-H2O (10 mg) was added to an eggplant-shaped flask, and a mixed solvent (4 ml2O = 1:1). After stirring overnight at room temperature, HPLC purification afforded the trifluoroacetate salt of target compound 139 (FC 83-9), which was lyophilized to give 2.5mg of a solid.1H NMR(500MHz,DMSO-d6) δ 7.99 (d, J =1.8hz, 1h), 7.86 (d, J =7.7hz, 1h), 7.78 (d, J =7.9hz, 2h), 7.67-7.55 (m, 4H), 7.53-7.39 (m, 3H), 6.27 (td, J =3.9,1.8hz, 1h), 4.45 (s, 2H), 2.43 (tt, J =4.5,2.3hz, 2h), 2.22 (td, J =6.1,3.2hz, 2h), 1.81-1.72 (m, 2H), 1.68-1.57 (m, 2H). Theoretical calculation of ESI-MS C27H25N2O2 +[M+H]+=409.2; the experiment shows that: 408.7.
example 141: synthesis of 4- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FC 92)
Figure BDA0003608794920001021
Using 4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1,3,2-dioxaborane (197 mg) and 4- ((4-bromo-1H-benzo [ d)]Imidazol-2-yl) methyl) benzoate (199 mg) as a starting material was subjected to the general procedure fifteen to give the trifluoroacetate salt of the objective compound 141 (FC 92), which was lyophilized to give 28mg as a solid.1H NMR(500MHz,DMSO-d6) δ 8.00-7.89 (m, 2H), 7.73 (d, J =8.0hz, 2h), 7.70-7.63 (m, 1H), 7.62-7.55 (m, 2H), 7.56-7.46 (m, 4H), 6.27 (tt, J =3.9,1.7hz, 1h), 4.52 (s, 2H), 2.42 (tq, J =6.6,2.2hz, 2h), 2.21 (tq, J =5.8,2.7hz, 2h), 1.81-1.71 (m, 2H), 1.67-1.54 (m, 2H). Theoretical calculation of ESI-MS C27H25N2O2 +[M+H]+=409.2; the experiment shows that: 409.8.
example 142: synthesis of 4- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FC 88-2)
Figure BDA0003608794920001022
With 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (53 mg) and methyl 4- (bromomethyl) benzoate (51 mg) were used as starting materials to give a crude compound according to general procedure twelve. Subsequently adding LiOH-H2O (17 mg) hydrolyzed methyl ester, which was purified by HPLC to give the trifluoroacetate salt of target compound 142 (FC 88-2), which was lyophilized to give 43mg of a solid.1H NMR(500MHz,Methanol-d4) δ 8.06 (d, J =8.1hz, 2h), 7.71 (dd, J =7.6,1.8hz, 1h), 7.66-7.57 (m, 6H), 7.43 (d, J =8.1hz, 2h), 6.28 (tt, J =4.1,1.8hz, 1h), 5.86 (s, 2H), 2.91 (s, 3H), 2.49 (tq, J =6.5,2.3hz, 2h), 2.27 (dh, J =9.0,2.8hz, 2h), 1.84 (dp, J =8.7,2.8hz, 2h), 1.78-1.66 (m, 2H). Theoretical calculation of ESI-MS C28H27N2O2 +[M+H]+=423.2; the experiment shows that: 422.7.
example 143: synthesis of 3- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FC 95-2)
Figure BDA0003608794920001031
With 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (30 mg) and methyl 3- (bromomethyl) benzoate (27 mg) were used as starting materials to give a crude compound according to general procedure twelve. Subsequently adding LiOH-H2O (10 mg) hydrolyzed methyl ester, which was purified by HPLC to give the trifluoroacetate salt of target compound 143 (FC 95-2), which was lyophilized to give 22.9mg of a solid.1H NMR(500MHz,Methanol-d4) δ 8.06-8.00 (m, 1H), 7.98 (s, 1H), 7.73 (d, J =8.0hz, 1h), 7.66-7.49 (m, 8H), 6.27 (dt, J =4.9,2.5hz, 1h), 5.84 (s, 2H), 2.92 (s, 3H), 2.47 (ddt, J =6.9,4.6,2.4hz, 2h), 2.25 (dp, J =9.3,3.1hz, 2h), 1.89-1.78 (m, 2H), 1.75-1.63 (m, 2H). Calculated value of ESI-MS theoryC28H27N2O2 +[M+H]+=423.2; the experiment shows that: 422.3.
example 144: synthesis of 4- ((2-Ethyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FE 7)
Figure BDA0003608794920001032
With 2-ethyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (30 mg) and methyl 4- (bromomethyl) benzoate (35 mg) were used as starting materials to give a crude compound according to general procedure twelve. Subsequently adding LiOH-H2O (10 mg) hydrolyzed methyl ester, which was purified by HPLC to give the trifluoroacetate salt of the title compound 144 (FE 7), which was lyophilized to give 12.3mg of a solid.1H NMR (500mhz, methanol-d 4) δ 8.06 (d, J =8.2hz, 2h), 7.71-7.58 (m, 7H), 7.39 (d, J =8.1hz, 2h), 6.28 (td, J =4.0,1.9hz, 1h), 5.91 (s, 2H), 2.50 (tq, J =6.4,2.3hz, 2h), 2.30-2.22 (m, 2H), 1.91-1.80 (m, 2H), 1.77-1.65 (m, 2H), 1.35 (t, J =7.6hz, 3h). . Theoretical calculation of ESI-MS C29H29N2O2 +[M+H]+=437.2; the experiment shows that: 437.2.
example 146:4- ((2- (2-hydroxyethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FD 80)
Figure BDA0003608794920001041
Methyl 4- ((2- (2-hydroxyethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazol-1-yl) methyl) benzoate (99.1 mg) was charged in an eggplant-shaped flask, and 10mL of a mixed solvent (THF: h2O =1: 1) Lithium hydroxide monohydrate (46 mg) was added thereto, and the mixture was stirred at room temperature overnight. After the reaction was completed, HPLC purification gave trifluoroacetate salt of the target compound, which was lyophilized to give 68.4mg as a solid.1H NMR(500MHz,Methanol-d4)δ8.03(d,J＝8.1Hz,2H),7.60(d,J＝10.7hz, 7H), 7.41 (d, J =8.1hz, 2h), 6.27 (td, J =3.9,1.8hz, 1h), 5.95 (s, 2H), 3.98 (t, J =3.0hz, 2h), 3.50 (t, J =5.8hz, 2h), 2.47 (dp, J =6.3,2.4hz, 2h), 2.26 (tq, J =6.0,2.7hz, 2h), 1.89-1.78 (m, 2H), 1.71 (dp, J =8.9,2.8hz, 2h). Theoretical calculation of ESI-MS C29H29N2O3 +[M+H]+=453.2; the experiment shows that: 453.0.
example 149:3- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) propionic acid (FC 121)
Figure BDA0003608794920001042
Using 4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1,3,2-dioxaborane (101 mg) and 3- (4-bromo-1H-benzo [ d]Imidazol-2-yl) propionic acid methyl ester (83.5 mg) as a starting material according to general procedure fifteen, to give the trifluoroacetate salt of target compound 149 (FC 121), which was lyophilized to give 22.4mg as a solid.1H NMR(500MHz,Methanol-d4) δ 7.71 (dd, J =8.2,1.0hz, 1h), 7.65-7.54 (m, 6H), 6.26 (tt, J =3.9,1.7hz, 1h), 3.42 (t, J =7.0hz, 2h), 3.02 (t, J =7.0hz, 2h), 2.48 (tq, J =6.4,2.3hz, 2h), 2.26 (dp, J =8.9,3.2hz, 2h), 1.90-1.80 (m, 2H), 1.77-1.66 (m, 2H). Theoretical calculation of ESI-MS C22H23N2O2 +[M+H]+347.2; the experiment shows that: 347.0.
example 151:2- (2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) acetic acid (FC 108)
Figure BDA0003608794920001043
With 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (9 mg) and ethyl 2-chloroacetate (8 mg) were used as starting materials, and the crude compound was obtained according to general procedure twelve. Subsequently LiOH-H was added2O (7 mg) hydrolyzed methyl ester, HPLC purified to give trifluoroacetate salt of target compound 151 (FC 108), lyophilized to give a solid 2mg。1H NMR(500MHz,Methanol-d4) δ 7.79 (dd, J =8.2,1.0hz, 1h), 7.68 (t, J =7.9hz, 1h), 7.65-7.58 (m, 5H), 6.28 (tt, J =4.0,1.7hz, 1h), 5.41 (s, 2H), 2.86 (s, 3H), 2.49 (ddt, J =8.5,4.3,2.2hz, 2h), 2.28 (ddt, J =8.5,6.4,2.8hz, 2h), 1.92-1.81 (m, 2H), 1.80-1.63 (m, 2H). Theoretical calculation of ESI-MS C22H23N2O2 +[M+H]+=347.2; the experiment shows that: 346.7.
example 152:4- (2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) butanoic acid (FE 139)
Figure BDA0003608794920001051
With 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (60 mg) and methyl 4-bromobutyrate (57 mg) were used as starting materials to give a crude compound according to general procedure twelve. Subsequently adding LiOH-H2O (20 mg) hydrolyzed methyl ester, which was purified by HPLC to give the trifluoroacetate salt of the title compound 152 (FE 139), which was lyophilized to give 45.3mg of a solid.1H NMR(500MHz,Methanol-d4) δ 7.90 (d, J =8.3hz, 1h), 7.67 (t, J =8.0hz, 1h), 7.60 (dd, J =7.9,4.3hz, 5h), 6.27 (tt, J =3.8,1.6hz, 1h), 4.62-4.49 (m, 2H), 2.91 (s, 3H), 2.55 (t, J =6.6hz, 2h), 2.48 (dp, J =6.5,2.4hz, 2h), 2.29-2.18 (m, 4H), 1.84 (dtt, J =9.8,6.3, 3.3hq, 2h), 1.71 (d, J =9.2,7.4,4.6hz, 2h). ESI-MS theoretical calculation C24H27N2O2 +[M+H]+=375.2; the experiment shows that: 374.7.
example 241:4- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methylbenzonitrile (FE 133)
Figure BDA0003608794920001052
With 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (50 mg) and 4- (bromomethyl) benzonitrile (51 mg) as starting materials, in accordance with the general proceduresMethod twelve, HPLC purification gave the trifluoroacetate salt of target compound 241 (FE 133) and lyophilization afforded 29.4mg of solid.1H NMR (500mhz, methanol-d 4) δ 7.77 (d, J =8.2hz, 2H), 7.68 (dd, J =7.4,2.0hz, 1H), 7.61 (s, 6H), 7.50 (d, J =8.1hz, 2H), 6.28 (dq, J =4.1,1.9hz, 1H), 5.88 (s, 2H), 2.91 (s, 3H), 2.49 (ddq, J =6.0,4.2,2.1hz, 2H), 2.27 (s, 2H), 1.91-1.80 (m, 2H), 1.78-1.63 (m, 2H). Theoretical calculation of ESI-MS C28H26N3 +[M+H]+=404.2; the experiment shows that: 404.0.
example 242:4- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methylphenol (FG 17)
Figure BDA0003608794920001061
With 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (50 mg) and (4- (bromomethyl) phenoxy) (tert-butyl) diphenylsilane (111 mg) were used as starting materials to give a crude compound according to general procedure twelve. Tetrabutylammonium fluoride trihydrate (79 mg), THF (10 mL) was then added, stirred at room temperature overnight, deprotected, and purified by HPLC to give the trifluoroacetate salt of target compound 242 (FG 17) and lyophilized to give 5.6mg of a solid.1H NMR (500mhz, methanol-d 4) δ 7.77 (dd, J =8.2,1.1hz, 1H), 7.67-7.55 (m, 6H), 7.24-7.16 (m, 2H), 6.85-6.77 (m, 2H), 6.27 (tt, J =3.9,1.7hz, 1H), 5.62 (s, 2H), 2.90 (s, 3H), 2.48 (tt, J =6.2,3.1hz, 2H), 2.27 (td, J =6.2,3.4hz, 2h), 1.90-1.79 (m, 2H), 1.71 (dtt, J =10.1,7.1,3.2hz, 2h). Theoretical calculation of ESI-MS C27H27N2O+[M+H]+=395.2; the experiment shows that: 395.3.
example 248:2- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) ethanol (FD 28)
Figure BDA0003608794920001062
Reacting 2- (2- ((tert-butyl diphenyl silyl) oxygenYl) Ethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (80 mg) and tetrabutylammonium fluoride trihydrate (79 mg) were put in an eggplant-shaped flask, THF (10 mL) was added, and the mixture was stirred at room temperature overnight. After the reaction is finished, concentrating by a rotary evaporator to obtain a crude product. Purification by HPLC gave the trifluoroacetate salt of the target compound, which was lyophilized to give 15.6mg of solid.1H NMR(500MHz,Methanol-d4)δ7.72(d,J＝8.1Hz,1H),7.67–7.51(m,6H),6.27(td,J＝4.1,1.9Hz,1H),4.02(t,J＝5.8Hz,2H),3.34(t,J＝5.8Hz,2H),2.49(td,J＝6.1,2.6Hz,2H),2.27(tt,J＝6.1,3.2Hz,2H),1.89–1.80(m,2H),1.77–1.68(m,2H).13C NMR (126MHz, DMSO-d 6) delta 153.93,141.80,135.46,134.26,132.57,128.52,127.76,125.42,125.29,125.14,124.40,112.66,58.39,30.50,26.66,25.46,22.60,21.69. Theoretical calculation of ESI-MS C21H23N2O+[M+H]+=319.2; the test shows that: 318.8.
example 249:2- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) ethylamine (FD 57)
Figure BDA0003608794920001063
2- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1H-benzo [ d]Imidazol-2-yl) ethanol (50 mg) and isoindoline-1,3-dione (35 mg) were added to an eggplant-shaped flask, THF (5 mL) and triphenylphosphine (126 mg) were added, and stirring was performed at 0 ℃ for 0.5h, followed by dropwise addition of 1,2-dicarboxylic acid diisopropyl ester (113 mg), warming to room temperature at 0 ℃ and stirring overnight. After the reaction is finished, adding water to quench the reaction, extracting the water phase for 3 times by using ethyl acetate, combining the organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, and concentrating by using a rotary evaporator to obtain a crude product. The crude product was then added to an eggplant-shaped flask and dissolved in methanol (5 mL), and N was added2H4-H2O (21 mg). Stirring overnight at room temperature, HPLC purification afforded the trifluoroacetate salt of title compound 249 (FD 57), which was lyophilized to give 20.1mg of a solid.1H NMR(500MHz,Methanol-d4)δ7.74(d,J＝8.1Hz,1H),7.58(tt,J＝12.2,6.1Hz,6H),6.25(td,J＝3.9,1.9Hz,1H),3.64–3.52(m,4H) 2.48 (tq, J =4.4,2.1hz, 2h), 2.26 (tq, J =6.1,2.8hz, 2h), 1.91-1.78 (m, 2H), 1.77-1.59 (m, 2H). ESI-MS theoretical calculation C21H24N3 +[M+H]+=318.2; the experiment shows that: 318.2.
example 250: n, N-dimethyl-2- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) ethylamine (FD 76)
Figure BDA0003608794920001071
With 2- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1H-benzo [ d]Imidazol-2-yl) ethylamine (926.3 mg), HCHO hydrate (111 mg) and NaBH3CN (548.1 mg) as starting materials, methanol as solvent, according to general method six, HPLC purification gave the trifluoroacetate salt of target compound 250 (FD 76), which was lyophilized to give 184.8mg of a solid.1H NMR(500MHz,Methanol-d4) δ 7.75 (d, J =8.1hz, 1h), 7.69-7.55 (m, 6H), 6.26 (dq, J =3.8,2.0hz, 1h), 3.72 (q, J =4.5hz, 4h), 3.01 (s, 6H), 2.49 (td, J =6.2,3.3hz, 2h), 2.27 (td, J =6.2,3.3hz, 2h), 1.91-1.82 (m, 2H), 1.79-1.62 (m, 2H). Theoretical calculation of ESI-MS C23H28N3 +[M+H]+=346.2; the experiment shows that: 345.4.
example 251:4- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) butanoic acid (FD 34)
Figure BDA0003608794920001072
Using 4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1,3,2-dioxaborane (369 mg) and 4- (4-bromo-1H-benzo [ d ]]Imidazol-2-yl) butyric acid methyl ester (192.4 mg) as a starting material was subjected to the general procedure fifteen to give a trifluoroacetate salt of the objective compound 251 (FD 34), which was lyophilized to give 3.3mg as a solid.1H NMR(500MHz,Methanol-d4)δ7.71(d,J＝8.1Hz,1H),7.68–7.56(m,6H),6.27(dq,J＝3.8,2.1,1.6Hz,1H),3.24(t,J＝7.7Hz,2H),2.50(t,J＝6.9Hz,4H),2.27(dh,J＝6.2,2.8Hz,2H),2.20(p,J＝7.3Hz, 2H), 1.91-1.80 (m, 2H), 1.77-1.67 (m, 2H). Theoretical calculation of ESI-MS C23H25N2O2 +[M+H]+=361.2; the experiment shows that: 361.3.
example 252:3- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) propanol (FD 130)
Figure BDA0003608794920001081
Using 4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1,3,2-dioxaborane (596.4 mg) and 4-bromo-2- (3- ((tert-butyldiphenylsilyl) oxy) propyl) -1H-benzo [ d]Imidazole (667.9 mg) was used as the starting material and the general procedure fourteen was referenced to yield 530.5mg of the crude compound. The crude product (57 mg) and tetrabutylammonium fluoride trihydrate (63 mg) were then added to an eggplant-shaped flask, THF (15 mL) was added, and the mixture was stirred at room temperature overnight. After the reaction is finished, the reaction solution is concentrated by a rotary evaporator. HPLC purification gave the trifluoroacetate salt of the target compound 252 (FD 130) and lyophilization afforded 10.5mg of solid.1H NMR(500MHz,Methanol-d4) δ 7.71 (dd, J =8.1,1.0hz, 1h), 7.66-7.53 (m, 6H), 6.27 (tt, J =3.9,1.7hz, 1h), 3.70 (t, J =5.8hz, 2h), 3.28 (t, J =7.4hz, 2h), 2.49 (tq, J =6.3,2.3hz, 2h), 2.27 (tq, J =6.2,2.7hz, 2h), 2.12 (tt, J =7.4,5.8hz, 2h), 1.89-1.81 (m, 2H), 1.77-1.65 (m, 2H). Theoretical calculation of ESI-MS C22H25N2O+[M+H]+=333.2; the experiment shows that: 332.5.
example 253:4- ((1- (3- (dimethylamino) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FD 1)
Figure BDA0003608794920001082
Methyl 4- ((1- (3- (dimethylamino) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazol-2-yl) methyl) benzoate (7.6 mg) and LiOH-H2O (4.2 mg) was put in an eggplant type flask, and thenInto a mixed solvent (4ml, thf2O = 1:1). Stirring overnight at room temperature, HPLC purification afforded the trifluoroacetate salt of target compound 253 (FD 1), and lyophilization afforded 2.3mg of a solid.1H NMR (500mhz, methanol-d 4) δ 8.15-8.00 (m, 2H), 7.85 (dd, J =8.1,1.1hz, 1h), 7.75-7.59 (m, 6H), 7.51-7.40 (m, 2H), 6.27 (tt, J =3.9,1.8hz, 1h), 4.75 (s, 2H), 4.51 (t, J =7.7hz, 2h), 3.16-3.07 (m, 2H), 2.76 (s, 6H), 2.49 (tq, J =6.4,2.2hz, 2h), 2.27 (tdt, J =6.3,4.2,2.5hz, 2h), 2.04 (ddt, J =12.2,8.0,4.5h, 1.92-80H), theoretical calculated values of 1.78H, 1H, 67H, 1H, 2H, 67m, 2H, calculated values32H36N3O2 +[M+H]+=494.3; the experiment shows that: 493.9.
example 254:4- ((1- (3-hydroxypropyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FD 127-1)
Figure BDA0003608794920001091
Methyl 4- ((1- (3- ((tert-butyldiphenylsilyl) oxy) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl)) -1H-benzo [ d]Imidazol-2-yl) methyl) benzoate (198 mg) and tetrabutylammonium fluoride trihydrate (176 mg) were put in an eggplant-shaped flask, and THF (20 mL) was added thereto, followed by stirring at room temperature overnight. After the reaction is finished, concentrating by a rotary evaporator to obtain a crude compound. Subsequently taking LiOH-H2O (21 mg) was put in an eggplant-shaped flask, and a mixed solvent (10ml, thf2O = 1:1). After stirring overnight at room temperature, HPLC purification afforded the trifluoroacetate salt of target compound 254 (FD 127-1), which was lyophilized to give a solid as 5.6mg.1H NMR (500mhz, methanol-d 4) δ 8.05-8.01 (m, 2H), 7.80 (dd, J =8.1,1.1hz, 1h), 7.69-7.66 (m, 2H), 7.65-7.56 (m, 4H), 7.41 (d, J =8.3hz, 2h), 6.26 (tt, J =4.0,1.7hz, 1h), 4.72 (s, 2H), 4.48 (t, J =7.3hz, 2h), 3.57 (t, J =5.7hz, 2h), 2.49 (tq, J =6.2,2.2hz, 2h), 2.27 (ddt, J =8.2,6.0,3.1hz, 2h), 1.95-1.87 (m, 2H), 1.87-1.81 (m, 2H), 1.75-1.69 (m, 2H), ESI-MS theoretical calculation C30H31N2O3 +[M+H]+=467.2; the experiment shows that: 466.6.
example 255:4- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole-2-carbonyl) benzoic acid (FD 156)
Figure BDA0003608794920001092
Methyl 4- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole-2-carbonyl) benzoate (20 mg) and LiOH-H2O (7 mg) were added to an eggplant-shaped flask, and a mixed solvent (4 ml, thf. Stirring overnight at room temperature, HPLC purification afforded the trifluoroacetate salt of target compound 255 (FD 156), which was lyophilized to give 5.1mg of a solid. 1H NMR (500mhz, dmso-d 6) δ 8.68 (d, J =8.1hz, 2h), 8.15 (dd, J =15.0,8.1hz, 4h), 7.62-7.55 (m, 4H), 7.51 (t, J =7.7hz, 1h), 6.28 (d, J =4.2hz, 1h), 2.44 (d, J =6.6hz, 2h), 2.22 (tt, J =6.3,2.9hz, 2h), 1.76 (td, J =8.8,7.4,4.8hz, 2h), 1.69-1.54 (m, 2H).
Example 256:4- (hydroxy (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FE 6)
Figure BDA0003608794920001101
4- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1H-benzo [ d]Imidazole-2-carbonyl) benzoic acid (18 mg) and NaBH4(3.8 mg) was charged into an eggplant-shaped flask, and a mixed solvent (4 ml, thf2O = 1:1). After stirring at room temperature for 5h, HPLC purification gave the trifluoroacetate salt of the target compound 256 (FE 6), which was lyophilized to give 7.4mg of a solid.1H NMR (500mhz, methanol-d 4) δ 8.08 (d, J =8.1hz, 2h), 7.74 (d, J =8.2hz, 1h), 7.65 (d, J =7.9hz, 3h), 7.56 (q, J =4.3,3.9hz, 3h), 7.53 (d, J =8.2hz, 2h), 6.32 (s, 1H), 6.28-6.20 (m, 1H), 2.46 (tt, J =4.7,2.4hz, 2h), 2.25 (tq, J =6.2,2.9hz, 2h), 1.88-1.78 (m, 2H), 1.74-1.65 (m, 2H). ESI-MS theoretical calculation C27H25N2O3 +[M+H]+=425.2; the experiment shows that: 425.6.
example 257:4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FE 43)
Figure BDA0003608794920001102
Reacting methyl 4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1H-benzo [ d]Imidazol-2-yl) methyl) benzoate (13 mg) and LiOH — H2O (10 mg) were charged in an eggplant-shaped flask, and a mixed solvent (4 ml, thf. Stirring overnight at room temperature, HPLC purification afforded the trifluoroacetate salt of target compound 257 (FE 43), which was lyophilized to give a solid as 5.9mg.1H NMR(500MHz,Methanol-d4) δ 8.12 (d, J =8.2hz, 2h), 7.86 (d, J =8.2hz, 2h), 7.63 (d, J =8.2hz, 2h), 7.52 (dd, J =8.0,5.6hz, 3h), 7.41 (d, J =7.4hz, 1h), 7.35 (t, J =7.7hz, 1h), 6.28-6.18 (m, 1H), 5.94 (s, 1H), 2.47 (td, J =6.0,2.6hz, 2h), 2.25 (tq, J =6.1,2.8hz, 2h), 1.88-1.78 (m, 2H), 1.75-1.66 (m, 2H). Theoretical calculation of ESI-MS C27H26N3O2 +[M+H]+=424.2; the experiment shows that: 424.6.
example 258:4- ((dimethylamino) (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FE 45)
Figure BDA0003608794920001103
With methyl 4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1H-benzo [ d]Imidazol-2-yl) methyl) benzoate (23 mg), aqueous Formaldehyde (20 mg) and NaBH3CN (7 mg) was used as the starting material, methanol was used as the solvent, and according to general procedure eight, HPLC purification gave the trifluoroacetate salt of the target compound 258 (FE 45), which was lyophilized to give 5.8mg of a solid.1H NMR(500MHz,Methanol-d4) δ 8.13 (d, J =8.2hz, 2h), 7.77 (dd, J =12.6,8.1hz, 4h), 7.57 (dd, J =7.8,1.3hz, 1h), 7.52 (d, J =8.2hz, 2h), 7.44-7.34 (m, 2H), 6.21 (td, J =3.9,1.9hz, 1h), 5.82 (s, 1H), 2.93 (s, 6H), 2.47 (ddq, J =6.3,4.4,2.2hz, 2h), 2.25 (dp, J =6.2,3.0hz, 2h), 1.89-1.79 (m, 2H), 1.78-1.62 (m, 2H). ESI-MS theory meterCalculation of C29H30N3O2 +[M+H]+=452.2; the experiment shows that: 452.2.
example 259:4- ((ethylamino) (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FE 92)
Figure BDA0003608794920001111
Reacting methyl 4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1H-benzo [ d]Imidazol-2-yl) methyl) benzoate (60 mg) and acetaldehyde (13 mg) were charged in an eggplant type flask, and Ti (OEt) was added4(64 mg) and THF (5 mL) were stirred at room temperature overnight. Followed by the addition of NaBH4(11 mg) was stirred at room temperature for 5h. After the reaction is finished, adding water for quenching reaction, extracting the water phase for 3 times by using ethyl acetate, combining organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, concentrating by using a rotary evaporator, and purifying by using a silica gel column to obtain a crude compound. Followed by LiOH-H2O (8.4 mg) was added to the eggplant-shaped flask, and a mixed solvent (4 ml2O = 1:1). After stirring overnight at room temperature, HPLC purification gave the trifluoroacetate salt of the title compound 259 (FE 92) and lyophilization afforded 8.5mg of a solid.1H NMR(500MHz,Methanol-d4) δ 8.13 (d, J =8.1hz, 2h), 7.84 (d, J =8.0hz, 2h), 7.69 (d, J =8.2hz, 2h), 7.52 (t, J =7.9hz, 3h), 7.40 (d, J =7.3hz, 1h), 7.35 (d, J =7.8hz, 1h), 6.21 (tt, J =3.8,1.7hz, 1h), 5.88 (s, 1H), 3.25 (dq, J =12.2,7.3hz, 1h), 3.16-3.05 (m, 1H), 2.47 (tq, J =4.7,2.1hz, 2h), 2.25 (tq, J =6.3,2.9hz, 2h), 1.88-1.80 (m, 2H), 1.77-1.66 (m, 2H), 1.39 (t, J =7.2hz, 3h). ESI-MS theoretical calculation C29H30N3O2 +[M+H]+=452.2; the experiment shows that: 452.2.
example 260:4- ((Ethyl (methyl) amino) (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FE 96)
Figure BDA0003608794920001112
With methyl 4- ((ethylamino) (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1H-benzo [ d]Imidazol-2-yl) methyl) benzoate (29.7 mg), aqueous Formaldehyde (18 mg) and NaBH3CN (8 mg) as the starting material and methanol as the solvent were purified by HPLC according to general procedure eight to give the trifluoroacetate salt of the target compound 260 (FE 96), which was lyophilized to give 8.3mg as a solid.1H NMR(500MHz,Methanol-d4) δ 8.13 (d, J =8.2hz, 2h), 7.77 (dd, J =21.5,8.0hz, 4h), 7.54 (dd, J =13.8,7.9hz, 3h), 7.39 (dt, J =15.2,7.4hz, 2h), 6.23 (td, J =3.9,1.9hz, 1h), 5.78 (s, 1H), 3.31-3.19 (m, 2H), 2.48 (td, J =6.0,2.6hz, 2h), 2.26 (tq, J =6.1,2.8hz, 2h), 1.89-1.80 (m, 2H), 1.77-1.67 (m, 2H), 1.40 (t, J =7.2hz, 3h). Theoretical calculation of ESI-MS C30H32N3O2 +[M+H]+=466.2; the experiment shows that: 466.3.
example 261:4- ((methyl (propyl) amino) (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FG 7)
Figure BDA0003608794920001121
The method comprises the following steps: reacting methyl 4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1H-benzo [ d]Imidazol-2-yl) methyl) benzoate (50 mg) and propionaldehyde (13 mg) were put in an eggplant type flask, and Ti (OEt) was added4(58 mg) and THF (5 mL) were stirred at room temperature overnight. Followed by the addition of NaBH4(9 mg) and stirred at room temperature for 5h. After the reaction is finished, adding water to quench and react, extracting the water phase for 3 times by using ethyl acetate, combining the organic phases, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, concentrating by using a rotary evaporator, and purifying by using a silica gel column to obtain a crude compound. LC-Ms =480.3.
Step two: with methyl 4- ((propylamino) (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1H-benzo [ d]Imidazol-2-yl) methyl) benzoate (46.8 mg), aqueous Formaldehyde (30 mg) and NaBH3CN (9 mg) as starting material and methanol as solvent, according to general procedure eight, HPLC purification gave the title compound 261 (F)G7 ) was added to the reaction solution, and lyophilized to obtain 4mg of a solid.1H NMR (500mhz, methanol-d 4) δ 8.17-8.12 (m, 2H), 7.80 (d, J =7.9hz, 2h), 7.76-7.72 (m, 2H), 7.59-7.50 (m, 3H), 7.47-7.36 (m, 2H), 6.22 (tt, J =4.0,1.7hz, 1H), 5.89 (s, 1H), 3.29-3.23 (m, 1H), 3.19-3.11 (m, 1H), 2.84 (s, 3H), 2.48 (tq, J =6.5,2.4hz, 2h), 2.26 (dtd, J =8.9,7.4,6.4,4.2hz, 2h), 1.96-1.81 (m, 4H 69), 1.75-1.75 (m, 2H), 0.3h (J =0, 7.4 hz). Theoretical calculation of ESI-MS C31H34N3O2 +[M+H]+=480.2; the experiment shows that: 480.3.
example 262:4- ((diethylamino) (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FE 84)
Figure BDA0003608794920001122
With methyl 4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1H-benzo [ d]Imidazol-2-yl) methyl) benzoate (50 mg), acetaldehyde (48 mg) and NaBH3CN (10 mg) was used as the starting material and methanol was used as the solvent, and according to general procedure eight, HPLC purification gave the trifluoroacetate salt of the target compound 262 (FE 84), which was lyophilized to give 21.7mg of solid.1H NMR(500MHz,Methanol-d4)δ8.13(d,J＝8.1Hz,2H),7.82(d,J＝8.3Hz,2H),7.78(d,J＝8.1Hz,2H),7.57(dd,J＝7.7,1.3Hz,1H),7.52(d,J＝8.2Hz,2H),7.42–7.34(m,2H),6.21(tt,J＝3.8,1.7Hz,1H),5.96(s,1H),3.42(dq,J＝14.4,7.2Hz,2H),3.21(dq,J＝14.7,7.5Hz,2H),2.46(ddq,J＝6.4,4.3,2.2Hz,2H),2.25(tq,J＝6.1,2.8Hz,2H),1.89–1.79(m,2H),1.77–1.65(m,2H),1.35(t,J＝7.2Hz,6H)。
Example 263:4- ((dipropylamino) (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FE 91)
Figure BDA0003608794920001131
With methyl 4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1H-benzo[d]Imidazol-2-yl) methyl) benzoate (45.1 mg), propionaldehyde (58 mg) and NaBH3CN (9 mg) was used as the starting material and methanol was used as the solvent, and according to general procedure eight, HPLC purification gave the trifluoroacetate salt of the target compound 263 (FE 91), which was lyophilized to give 3.4mg as a solid.1H NMR(500MHz,Methanol-d4) δ 8.14 (d, J =8.0hz, 2h), 7.78 (dd, J =8.4,3.6hz, 4h), 7.55 (dd, J =19.6,7.8hz, 3h), 7.47-7.38 (m, 2H), 6.26-6.20 (m, 1H), 5.97 (s, 1H), 3.30-3.23 (m, 2H), 3.04 (d, J =14.1hz, 2h), 2.48 (td, J =6.2,2.2, 2h), 2.26 (J =6.1,2.8hz, 2h), 1.83 (ddd, J =19.6,11.2,5.9hz, 6h), 1.76-1.66 (m, 2H), 0.91 (t, J =7.6h, 3h). Theoretical calculation of ESI-MS C33H38N3O2 +[M+H]+=508.3; the experiment shows that: 508.3.
example 264:4- (acetylamino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FG 2)
Figure BDA0003608794920001132
With methyl 4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1H-benzo [ d]Imidazol-2-yl) methyl) benzoate (45.1 mg) and acetic anhydride (7 mg) were charged in an eggplant-shaped flask, followed by addition of triethylamine (21 mg) and CH2Cl2(5 mL), stirred overnight at room temperature and concentrated on a rotary evaporator to give the crude compound. Followed by LiOH-H2O (8.4 mg) was added to the eggplant-shaped flask, and a mixed solvent (4 ml2O = 1:1). Stirring overnight at room temperature, HPLC purification afforded the trifluoroacetate salt of target compound 264 (FG 2), which was lyophilized to give 10.2mg of a solid.1H NMR(500MHz,Methanol-d4) δ 8.16-8.08 (m, 2H), 7.75 (dd, J =8.3,1.0hz, 1h), 7.65 (t, J =7.9hz, 1h), 7.61-7.50 (m, 7H), 6.49 (s, 1H), 6.24 (tt, J =3.9,1.7hz, 1h), 2.46 (ddt, J =8.5,4.4,2.2hz, 2h), 2.25 (ddt, J =8.5,6.3,2.7hz, 2h), 2.12 (s, 3H), 1.87-1.79 (m, 2H), 1.75-1.63 (m, 2H). Theoretical calculation of ESI-MS C29H28N3O3 +[M+H]+=466.2; the test shows that: 466.7.
example 265:4- ((2-propyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FE 17)
Figure BDA0003608794920001141
With 2-propyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (40 mg) and methyl 4- (bromomethyl) benzoate (44 mg) were used as starting materials to give a crude compound according to general procedure twelve. Subsequently LiOH-H was added2Hydrolysis of methyl O (15 mg) and HPLC purification afforded the trifluoroacetate salt of target compound 265 (FE 17) which was lyophilized to afford 16.2mg of a solid.1H NMR(500MHz,Methanol-d4) δ 8.05 (d, J =8.2hz, 2h), 7.68-7.56 (m, 7H), 7.38 (d, J =8.1hz, 2h), 6.28 (tt, J =3.8,1.7hz, 1h), 5.92 (s, 2H), 3.29-3.21 (m, 2H), 2.49 (tq, J =6.4,2.2hz, 2h), 2.27 (dq, J =6.2,3.4hz, 2h), 1.89-1.81 (m, 2H), 1.79-1.65 (m, 4H), 1.02 (t, J = 7.hz, 3h). ESI-MS theoretical calculation C30H31N2O2 +[M+H]+=451.2; the experiment shows that: 451.4.
example 266:4- ((2-butyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FE 22)
Figure BDA0003608794920001142
With 2-butyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (40 mg) and methyl 4- (bromomethyl) benzoate (42 mg) were used as starting materials to give a crude compound according to general procedure twelve. Subsequently adding LiOH-H2O (18 mg) hydrolyzed methyl ester and purified by HPLC to give the trifluoroacetate salt of the title compound 266 (FE 22) which was lyophilized to give 4.8mg of solid.1H NMR(500MHz,Methanol-d4)δ8.09–8.03(m,2H),7.69–7.60(m,7H),7.38(d,J＝8.3Hz,2H),6.28(tt,J＝3.9,1.7Hz,1H),5.91(s,2H),3.29–3.21(m,2H),2.50(tq,J＝6.4,2.3Hz,2H),2.28(dh,J＝8.8,2.7Hz,2H),1.91–1.80(m,2H),1.76–1.69(m,2H),1.66(ddt,J＝9.6,79,3.5hz, 2h), 1.42 (h, J =7.4hz, 2h), 0.90 (t, J =7.3hz, 3h). ESI-MS theoretical calculation C31H33N2O2 +[M+H]+=465.3; the test shows that: 465.4.
example 267:4- ((2-isopropyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FE 83)
Figure BDA0003608794920001151
With 2-isopropyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (40 mg) and methyl 4- (bromomethyl) benzoate (44 mg) were used as starting materials to give a crude compound according to general procedure twelve. Subsequently adding LiOH-H2O (18 mg) hydrolyzed methyl ester and purified by HPLC to give the trifluoroacetate salt of the title compound 267 (FE 83) and lyophilized to give 27.8mg of solid.1H NMR(500MHz,Methanol-d4) δ 8.12-8.02 (m, 2H), 7.76 (d, J =8.2hz, 1h), 7.65 (t, J =7.9hz, 1h), 7.61 (s, 5H), 7.37 (d, J =8.1hz, 2h), 6.28 (tt, J =3.8,1.7hz, 1h), 5.95 (s, 2H), 3.72 (hept, J =7.1hz, 1h), 2.50 (tq, J =6.2,2.2hz, 2h), 2.28 (tq, J =6.0,2.7hz, 2h), 1.92-1.80 (m, 2H), 1.78-1.63 (m, 2H), 1.45 (s, 3H), 1.44 (s, 3H). ESI-MS theoretical calculation C30H31N2O2 +[M+H]+=451.2; the experiment shows that: 451.1.
example 268:4- ((2- (3- (dimethylamino) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FD 134)
Figure BDA0003608794920001152
With methyl 4- ((2- (3-aminopropyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl)]-4-yl) -1H-benzo [ d]Imidazol-1-yl) methyl) benzoate (76.1 mg), formaldehyde hydrate (64 mg) and NaBH3CN (15 mg) as a starting material and methanol as a solvent were purified by HPLC to give a trifluoroacetate salt of the target compound 268 (FD 134) according to general procedure eight, and the resulting product was frozenDry to give 74.4mg of a solid.1H NMR(500MHz,Methanol-d4) δ 8.05 (d, J =8.2hz, 2h), 7.67-7.63 (m, 3H), 7.62-7.57 (m, 4H), 7.38 (d, J =8.2hz, 2h), 6.27 (tt, J =3.8,1.7hz, 1h), 5.90 (s, 2H), 3.35 (dd, J =9.4,6.1hz, 2h), 3.26-3.18 (m, 2H), 2.79 (s, 6H), 2.49 (td, J =4.1,2.0hz, 2h), 2.32-2.23 (m, 2H), 2.23-2.13 (m, 2H), 1.89-1.78 (m, 2H), 1.77-1.66 (m, 2H). Theoretical calculation of ESI-MS C32H36N3O2 +[M+H]+=494.3; the test shows that: 494.8.
example 269:3- ((2-Ethyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FE 73)
Figure BDA0003608794920001161
With 2-ethyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (60 mg) and methyl 3- (bromomethyl) benzoate (70 mg) were used as starting materials to give a crude compound according to general procedure twelve. Subsequently adding LiOH-H2O (24 mg) hydrolyzed methyl ester and HPLC purified to give the trifluoroacetate salt of the title compound 269 (FE 73) which was lyophilized to give 47.8mg of solid.1H NMR (500mhz, methanol-d 4) δ 8.03 (dt, J =6.4,1.9hz, 1h), 7.95 (d, J =1.9hz, 1h), 7.70 (dd, J =7.9,1.3hz, 1h), 7.65-7.58 (m, 6H), 7.53 (d, J =6.5hz, 2h), 6.27 (dq, J =3.7,1.8hz, 1h), 5.90 (s, 2H), 2.48 (td, J =6.1,3.3hz, 2h), 2.26 (tq, J =6.1,2.8hz, 2h), 1.89-1.80 (m, 2H), 1.77-1.64 (m, 2H), 1.35 (t, J =7.6hz, 3h). Theoretical calculation of ESI-MS C29H29N2O2 +[M+H]+=437.2; the test shows that: 437.3.
example 270:2- (2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) acetic acid (FC 144)
Figure BDA0003608794920001162
With 2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-Benzo [ d ] carbonyl]Imidazole (50 mg) and methyl 3- (bromomethyl) benzoate (35 mg) were used as starting materials to give a crude compound according to general procedure twelve. Subsequently adding LiOH-H2O (16 mg) hydrolyzed methyl ester and HPLC purified to give the trifluoroacetate salt of target compound 270 (FC 144) and lyophilized to give 9.6mg of solid.1H NMR(500MHz,Methanol-d4) δ 7.86 (d, J =8.3hz, 1h), 7.84-7.78 (m, 3H), 7.78-7.65 (m, 6H), 7.60 (d, J =8.3hz, 2h), 6.26 (tt, J =3.8,1.7hz, 1h), 5.32 (s, 2H), 2.48 (tq, J =6.3,2.2hz, 2h), 2.26 (tq, J =6.0,2.8hz, 2h), 1.92-1.78 (m, 2H), 1.78-1.62 (m, 2H). Theoretical calculation of ESI-MS C27H25N2O2 +[M+H]+=409.2; the test shows that: 409.5.
example 271:2- ((2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FC 118)
Figure BDA0003608794920001163
With 2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (80 mg) and methyl 2- (bromomethyl) benzoate (79 mg) were used as starting materials to give a crude compound according to general procedure twelve. Subsequently adding LiOH-H2O (27 mg) hydrolyzed methyl ester, which was purified by HPLC to afford the trifluoroacetate salt of the title compound 271 (FC 118), which was lyophilized to afford 21.4mg as a solid.1H NMR (500mhz, methanol-d 4) δ 8.19 (dd, J =7.5,1.8hz, 1h), 7.87-7.37 (m, 14H), 7.06 (dd, J =7.5,1.4hz, 1h), 6.28 (tt, J =3.9,1.8hz, 1h), 6.16 (s, 2H), 2.50 (tq, J =6.5,2.3hz, 2h), 2.27 (tq, J =6.0,2.7hz, 2h), 1.92-1.80 (m, 2H), 1.81-1.60 (m, 2H). Theoretical calculation of ESI-MS C33H29N2O2 +[M+H]+=485.2; the experiment shows that: 484.6.
example 272:2- (3- ((2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetic acid (FC 143)
Figure BDA0003608794920001171
With 2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (80 mg) and methyl 2- (3- (bromomethyl) phenyl) acetate (111 mg) were used as starting materials to obtain a crude compound according to general procedure twelve. Subsequently adding LiOH-H2O (25 mg) hydrolyzed methyl ester and HPLC purified to give the trifluoroacetate salt of target compound 272 (FC 143) and lyophilized to give 8.3mg of solid.1H NMR(500MHz,Methanol-d4) δ 7.88-7.74 (m, 4H), 7.68 (d, J =7.9hz, 6H), 7.60 (d, J =8.1hz, 2h), 7.32 (t, J =7.6hz, 1h), 7.27 (d, J =7.6hz, 1h), 7.14 (s, 1H), 7.10 (d, J =7.6hz, 1h), 6.27 (tt, J =3.8,1.6hz, 1h), 5.75 (s, 2H), 3.58 (s, 2H), 2.48 (tq, J =6.3,2.2hz, 2h), 2.26 (tq, J =5.9,2.7hz, 2h), 1.91-1.78 (m, 2H), 1.77-1.63 (m, 2H). Theoretical calculation of ESI-MS C34H31N2O2 +[M+H]+=499.2; the experiment shows that: 499.1.
example 273:2- (4- ((2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetic acid (FE 130)
Figure BDA0003608794920001172
Using 4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1,3,2-dioxaborane (73 mg) and 2- (4- ((4-bromo-2-phenyl-1H-benzo [ d)]Imidazol-1-yl) methyl) phenyl) acetic acid methyl ester (92.9 mg) was used as a starting material, and according to general procedure fifteen, HPLC purification gave the trifluoroacetate salt of the title compound 273 (FE 130), which was lyophilized to give 30.1mg of a solid.1H NMR(500MHz,Methanol-d4) δ 7.81 (d, J =7.7hz, 2h), 7.78 (t, J =7.6hz, 1h), 7.73 (dd, J =7.3,2.1hz, 1h), 7.67 (td, J =8.0,2.3hz, 6h), 7.59 (d, J =8.1hz, 2h), 7.29 (d, J =7.9hz, 2h), 7.15 (d, J =7.9hz, 2h), 6.30-6.22 (m, 1H), 5.74 (s, 2H), 3.60 (s, 2H), 2.47 (tt, J =4.6,2.4hz, 2h), 2.25 (tq, J =6.1,2.8hz, 2h), 1.89-1.79 (m, 2H), 1.75-1.66H (m, 2H). Theoretical calculation of ESI-MS C34H31N2O2 +[M+H]+=499.2; the experiment shows that: 499.1.
example 274:2- (2- ((2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetic acid (FG 12)
Figure BDA0003608794920001181
Using 4,4,5,5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1,3,2-dioxaborane (86.4 mg) and 2- (2- ((4-bromo-2-phenyl-1H-benzo [ d)]Imidazol-1-yl) methyl) phenyl) acetic acid methyl ester (86.6 mg) was used as a starting material, and according to general procedure fifteen, HPLC purification afforded the trifluoroacetate salt of the title compound 274 (FG 12), which was lyophilized to give 17.2mg of a solid.1H NMR(500MHz,Methanol-d4) δ 7.76 (dd, J =20.3,7.6hz, 3H), 7.70 (d, J =8.1hz, 2H), 7.64 (dt, J =20.1,5.4hz, 7H), 7.35 (dt, J =14.7,7.4hz, 2H), 7.22 (t, J =7.4hz, 1H), 6.88 (d, J =7.7hz, 1H), 6.30-6.25 (m, 1H), 5.86 (s, 2H), 3.77 (s, 2H), 2.49 (td, J =6.2,2.6hz, 2H), 2.27 (tq, J =6.1,2.8hz, 2H), 1.93-1.74 (m, 2H), 1.79-1.56 (m, 2H). ESI-MS theoretical calculation C34H31N2O2 +[M+H]+=499.2; the experiment shows that: 499.2.
example 275: n, N-dimethyl-3- (2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) propan-1-amine (FE 132)
Figure BDA0003608794920001182
With 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (60 mg) and 3-bromo-N, N-dimethylpropan-1-amine hydrochloride (100 mg) were used as starting materials, and with reference to general procedure twelve, HPLC purification gave the trifluoroacetate salt of the target compound 275 (FE 132), which was lyophilized to give 35.5mg of a solid.1H NMR(500MHz,Methanol-d4)δ7.90(d,J＝8.3Hz,1H),7.70(t,J＝7.9Hz,1H),7.66–7.54(m,5H),6.27(dq,J＝3.8,1.9Hz,1H),4.60(t,J＝7.6Hz,2H),3.41–3.33(m,2H),2.92(d,J＝1.3Hz,9H),2.49(ddt,J＝6.3,4.2,2.2Hz,2H),2.45–2.34(m,2H),2.32–2.21(m,2H),1.89–1.78(m,2H),1.79–1.63 (m, 2H). Theoretical calculation of ESI-MS C25H32N3 +[M+H]+=374.3; the experiment shows that: 373.9.
example 276:3- (2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) propan-1-ol (FG 26)
Figure BDA0003608794920001191
With 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (30 mg) and tert-butyl (3-iodopropyl) diphenylsilane (85 mg) were used as starting materials to give a crude compound according to general procedure twelve. Tetrabutylammonium fluoride trihydrate (32 mg) was then added to an eggplant-shaped flask, and THF (10 mL) was added thereto, followed by stirring at room temperature overnight. HPLC purification afforded the trifluoroacetate salt of target compound 276 (FG 26), which was lyophilized to give 6.5mg of a solid.1H NMR (500mhz, methanol-d 4) δ 7.88 (dd, J =8.3,0.9hz, 1h), 7.71-7.66 (m, 1H), 7.63-7.56 (m, 5H), 6.27 (tt, J =3.7,1.8hz, 1h), 4.61 (t, J =7.0hz, 2h), 3.65 (t, J =5.6hz, 2h), 2.92 (s, 3H), 2.49 (tq, J =6.1,2.2hz, 2h), 2.27 (tq, J =6.1,2.7hz, 2h), 2.15 (H, J =6.0,5.5hz, 2h), 1.90-1.80 (m, 2H), 1.75-1.68 (m, 2H). Theoretical calculation of ESI-MS C23H27N2O+[M+H]+347.2; the test shows that: 346.6.
example 277:5- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) picolinic acid (FE 140)
Figure BDA0003608794920001192
With 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (52 mg) and methyl 5- (bromomethyl) picolinate (62 mg) were used as starting materials to give a crude compound according to general procedure twelve. Subsequently adding LiOH-H2O (18 mg) hydrolyzed methyl ester, which was purified by HPLC to give the trifluoroacetate salt of the desired compound 277 (FE 140), which was lyophilized to give 42.2mg of a solid.1H NMR(500MHz,Methanol-d4) δ 8.98 (d, J =2.1hz, 1h), 8.41 (dd, J =8.1,2.1hz, 1h), 7.76 (d, J =8.2hz, 1h), 7.70 (dd, J =8.1,1.2hz, 1h), 7.63-7.50 (m, 6H), 6.25 (tt, J =3.8,1.6hz, 1h), 5.96 (s, 2H), 2.97 (s, 3H), 2.47 (tq, J =6.4,2.1hz, 2h), 2.25 (tt, J =6.0,3.1hz, 2h), 1.88-1.78 (m, 2H), 1.75-1.64 (m, 2H). Theoretical calculation of ESI-MS C27H26N3O2 +[M+H]+=424.2; the experiment shows that: 423.6.
example 278:1- (4-methoxybenzyl) -2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FG 4)
Figure BDA0003608794920001193
With 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (50 mg) and 1- (bromomethyl) -4-methoxybenzene (68 mg) were used as starting materials and purified by HPLC according to general procedure twelve to give the trifluoroacetate salt of the title compound 278 (FG 4) which was lyophilized to give 11.7mg of a solid.1H NMR (500mhz, methanol-d 4) δ 7.77 (dd, J =8.1,1.2hz, 1H), 7.66-7.57 (m, 6H), 7.35-7.26 (m, 2H), 7.00-6.92 (m, 2H), 6.30-6.24 (m, 1H), 5.67 (s, 2H), 3.78 (s, 3H), 2.91 (s, 3H), 2.49 (tq, J =6.5,2.2hz, 2H), 2.27 (tq, J =5.8,2.7hz, 2H), 1.92-1.77 (m, 2H), 1.77-1.63 (m, 2H). Theoretical calculation of ESI-MS C28H29N2O+[M+H]+=409.2; the test shows that: 409.0.
example 279:4- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) phenol (FG 17)
Figure BDA0003608794920001201
With 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (50 mg) and (4- (bromomethyl) phenoxy) (tert-butyl) diphenylsilane (111 mg) were used as starting materials to give a crude compound according to general procedure twelve. Tetrabutylammonium fluoride trihydrate (79 mg) was then added to eggplantTHF (10 mL) was added to the flask and the mixture was stirred at room temperature overnight. HPLC purification afforded the trifluoroacetate salt of target compound 279 (FG 17), which was lyophilized to give 5.6mg of a solid.1H NMR (500mhz, methanol-d 4) δ 7.77 (dd, J =8.2,1.1hz, 1H), 7.67-7.55 (m, 6H), 7.24-7.16 (m, 2H), 6.85-6.77 (m, 2H), 6.27 (tt, J =3.9,1.7hz, 1H), 5.62 (s, 2H), 2.90 (s, 3H), 2.48 (tt, J =6.2,3.1hz, 2H), 2.27 (td, J =6.2,3.4hz, 2h), 1.90-1.79 (m, 2H), 1.71 (dtt, J =10.1,7.1,3.2hz, 2h). Theoretical calculation of ESI-MS C27H27N2O+[M+H]+=395.2; the test shows that: 395.3.
example 280: 2-methyl-1- (pyridin-4-ylmethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FG 20)
Figure BDA0003608794920001202
With 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (30 mg) and 4- (bromomethyl) pyridine (30 mg) were used as starting materials, and HPLC purification afforded the trifluoroacetate salt of title compound 280 (FG 20) according to general procedure twelve, which was lyophilized to give 4.5mg of a solid.1H NMR (500mhz, methanol-d 4) δ 8.83-8.73 (m, 2H), 7.82-7.73 (m, 2H), 7.64 (d, J =8.7hz, 7H), 6.29 (td, J =3.9,1.9hz, 1h), 6.09 (s, 2H), 2.91 (s, 3H), 2.50 (tq, J =6.2,2.2hz, 2h), 2.28 (tq, J =6.2,2.8hz, 2h), 1.91-1.82 (m, 2H), 1.78-1.59 (m, 2H). ESI-MS theoretical calculation C26H26N3 +[M+H]+=380.2; the experiment shows that: 380.3.
example 281:2- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FC 104)
Figure BDA0003608794920001211
With 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (100 mg) and methyl 2- (bromomethyl) benzoate (120 mg) as starting materials, according to general procedure twelve, to giveTo the crude compound. Subsequently adding LiOH-H2O (26 mg) hydrolyzed methyl ester, which was purified by HPLC to give the trifluoroacetate salt of the title compound 281 (FC 104), which was lyophilized to give 99.2mg as a solid.1H NMR(500MHz,Methanol-d4) δ 8.22-8.15 (m, 1H), 7.61 (s, 4H), 7.58-7.43 (m, 5H), 6.96-6.87 (m, 1H), 6.27 (tt, J =3.9,1.7hz, 1h), 6.17 (s, 2H), 2.85 (s, 3H), 2.48 (tq, J =6.2,2.2hz, 2h), 2.26 (tq, J =5.8,2.7hz, 2h), 1.90-1.79 (m, 2H), 1.77-1.64 (m, 2H). Theoretical calculation of ESI-MS C28H27N2O2 +[M+H]+=423.2; the experiment shows that: 423.4.
example 282:2- (4- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetic acid (FC 131)
Figure BDA0003608794920001212
With 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (80 mg) and methyl 2- (4- (bromomethyl) phenyl) acetate (101 mg) were used as starting materials to give a crude compound according to general procedure twelve. Subsequently adding LiOH-H2O (28 mg) hydrolyzed methyl ester, which was purified by HPLC to afford the trifluoroacetate salt of target compound 282 (FC 131), which was lyophilized to afford 18.2mg of a solid.1H NMR(500MHz,M；ethanol-d4) δ 7.76 (dd, J =7.9,1.4hz, 1h), 7.68-7.57 (m, 6H), 7.34 (d, J =8.2hz, 2h), 7.30 (d, J =8.2hz, 2h), 6.28 (tt, J =4.0,1.7hz, 1h), 5.75 (s, 2H), 3.62 (s, 2H), 2.90 (s, 3H), 2.49 (ddt, J =8.4,4.2,2.2hz, 2h), 2.27 (dh, J =8.9,2.7hz, 2h), 1.92-1.81 (m, 2H), 1.79-1.66 (m, 2H). Theoretical calculation of ESI-MS C29H29N2O2 +[M+H]+=437.2; the experiment shows that: 436.9.
example 283:2- (3- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetic acid (FC 136)
Figure BDA0003608794920001213
With 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (80 mg) and methyl 2- (3- (bromomethyl) phenyl) acetate (136 mg) were used as starting materials to give a crude compound according to general procedure twelve. Subsequently adding LiOH-H2O (21 mg) hydrolyzed methyl ester, which was purified by HPLC to give the desired compound 283 (FC 136) as the trifluoroacetate salt, which was lyophilized to give 13.6mg as a solid.1H NMR(500MHz,Methanol-d4) δ 7.76 (dd, J =8.0,1.4hz, 1h), 7.62 (d, J =10.2hz, 6h), 7.37 (t, J =8.0hz, 1h), 7.34-7.28 (m, 2H), 7.22 (d, J =7.8hz, 1h), 6.27 (tt, J =3.8,1.7hz, 1h), 5.75 (s, 2H), 3.63 (s, 2H), 2.91 (s, 3H), 2.49 (ddt, J =6.2,4.1,2.1hz, 2h), 2.27 (ddt, J =8.3,6.2,3.1hz, 2h), 1.90-1.80 (m, 2H), 1.76-1.65 (m, 2H). Theoretical calculation of ESI-MS C29H29N2O2 +[M+H]+=437.2; the experiment shows that: 437.5.
example 284:2- (2- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetic acid (FD 158)
Figure BDA0003608794920001221
With 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl]-4-yl) -1H-benzo [ d]Imidazole (60 mg) and methyl 2- (2- (bromomethyl) phenyl) acetate (102 mg) were used as starting materials to give a crude compound according to general procedure twelve. Subsequently adding LiOH-H2O (20 mg) hydrolyzed methyl ester, which was purified by HPLC to give the trifluoroacetate salt of target compound 284 (FD 158), which was lyophilized to give 10.8mg of a solid.1H NMR(500MHz,Methanol-d4) δ 7.69-7.56 (m, 7H), 7.39 (dd, J =7.7,1.4hz, 1H), 7.35 (d, J =7.3hz, 1H), 7.23 (td, J =7.5,1.4hz, 1H), 6.74 (d, J =7.7hz, 1H), 6.28 (tt, J =3.8,1.6hz, 1H), 5.87 (s, 2H), 3.90 (s, 2H), 2.82 (s, 3H), 2.50 (tq, J =6.2,2.2hz, 2h), 2.28 (tq, J =6.1,2.7hz, 2h), 1.92-1.80 (m, 2H), 1.78-1.62 (m, 2H). Theoretical calculation of ESI-MS C29H29N2O2 +[M+H]+=437.2; the experiment shows that: 437.2.
the following compounds can be prepared according to the above example method by selecting corresponding commercially available reagents, catalysts, solvents and other raw materials:
Figure BDA0003608794920001222
Figure BDA0003608794920001231
Figure BDA0003608794920001241
Figure BDA0003608794920001251
Figure BDA0003608794920001261
Figure BDA0003608794920001271
Figure BDA0003608794920001281
Figure BDA0003608794920001291
Figure BDA0003608794920001301
Figure BDA0003608794920001311
Figure BDA0003608794920001321
Figure BDA0003608794920001331
Figure BDA0003608794920001341
Figure BDA0003608794920001351
Figure BDA0003608794920001361
Figure BDA0003608794920001371
Figure BDA0003608794920001381
Figure BDA0003608794920001391
Figure BDA0003608794920001401
Figure BDA0003608794920001411
Figure BDA0003608794920001421
Figure BDA0003608794920001431
Figure BDA0003608794920001441
Figure BDA0003608794920001451
Figure BDA0003608794920001461
Figure BDA0003608794920001471
Figure BDA0003608794920001481
Figure BDA0003608794920001491
Figure BDA0003608794920001501
Figure BDA0003608794920001511
Figure BDA0003608794920001521
Figure BDA0003608794920001531
Figure BDA0003608794920001541
Figure BDA0003608794920001551
Figure BDA0003608794920001561
Figure BDA0003608794920001571
Figure BDA0003608794920001581
Figure BDA0003608794920001591
Figure BDA0003608794920001601
Figure BDA0003608794920001611
Figure BDA0003608794920001621
Figure BDA0003608794920001631
Figure BDA0003608794920001641
Figure BDA0003608794920001651
Figure BDA0003608794920001661
Figure BDA0003608794920001671
Figure BDA0003608794920001681
Figure BDA0003608794920001691
Figure BDA0003608794920001701
Figure BDA0003608794920001711
Figure BDA0003608794920001721
Figure BDA0003608794920001731
Figure BDA0003608794920001741
Figure BDA0003608794920001751
Figure BDA0003608794920001761
Figure BDA0003608794920001771
Figure BDA0003608794920001781
Figure BDA0003608794920001791
Figure BDA0003608794920001801
biological activity test method 1: data on the activity of compounds to inhibit the TEAD2/YAP1 interaction:
the YAP1 binding domain TEAD2 (217-447) of HIS-tag TEAD2 is expressed in Escherichia coli, and TEAD2 protein is purified by Ni affinity column and ion exchange chromatography column. Meanwhile, FAM-labeled YAP 1-derived polypeptide (FAM-YAP 1) is synthesized, and the sequence of the polypeptide is as follows:
(5-FAM)-H2N-(β-Ala)-(β-Ala)-DSETD-LEALF-NAVMN-PKTAN-VPQTV-P-Trp(6-Cl)-R-Ac3c-R-K-Cba-Hyp-D-S-F-(1-Nal)-K-E-P-CO2h (reference Bioorganic)&Medicinal Chemistry Letters 29 (2019) 2316-2319). Based on the TEAD2 protein and the fluorescent molecular probe FAM-YAP1 which are expressed and purified, the dissociation constant K of the FAM-YAP1 and the TEAD2 is measured by using a fluorescence polarization analysis methoddAt 1.9nM.
96-well plates were purchased from Corning Inc. (Black, # 3694). The multifunctional microplate reader is a product of TECAN company, and has the following model: SPARK 10M. Compound buffer dilution: 1 XPBS (pH 7.4), 20% DMSO (Sigma) and 0.01% Trition X-100 (Sigma), the experimental water is Millipore-Q pure water. Detection buffer solution: 1 XPBS (pH 7.4), 0.01%.
The test compounds were first dissolved in DMSO to 20mM standard stock. Subsequently, the standard stock solution of test compound was diluted with the dilute compound buffer in an EP tube to prepare a working sample solution with a concentration =10 times the highest sample concentration required on the test plate (10 × test compound solution), and the compound was diluted in a gradient 2 times in an EP tube for use.
A gradient of 5. Mu.L of the test compound A10X test compound solution was added to wells B1-D1 to B12-D12 of a 96-well plate, and a gradient of 5. Mu.L of the test compound B10X test compound solution was added to wells E1-G1 to E12-G12, respectively. To each well was added 40 μ L of 62.5nm TEAD2 protein solution. Finally, 50nM Tracer was added to each well.
A1-A3 wells served as blank control: add 50. Mu.L of assay buffer. A4-A6 wells served as negative signal reference group: add 50. Mu.L of buffer containing only 5nM of the FAM-YAP1 fluorescently labeled molecular probe. A7-A9 wells served as positive reference group: add 50. Mu.L of a mixed solution containing 5nM FAM-YAP1 fluorescently labeled molecular probe and 50nM TEAD2 protein.
The reaction plate was covered with aluminum foil paper, and after incubating the 96-well plate on a 96-well plate shaker at room temperature for 1 hour and 1.5 hours, the fluorescence polarization mP value at Ex485nm/Em530nm was read with a microplate reader. The measured mP value is plotted against the compound concentration gradient, and the concentration of the sample compound corresponding to the median of the maximum and minimum mP values is the IC of the binding of the compound and the protein50Value ([ I ]]50)。
According to this IC50Value ([ I ]]50) Calculating the binding rate of the compound and the protein by using a formulai:Ki＝[I]50/([L]50/Kd+[P]0/Kd+1)。
Wherein [ L ] is]50Represents 50% of the concentration of fluorescently labeled molecular probes in the test system; [ P ]]0Representing the TEAD2 protein concentration in the above test system, kd is the dissociation constant of the protein and the fluorescently labeled molecular probe.
Figure BDA0003608794920001811
Figure BDA0003608794920001821
Figure BDA0003608794920001831
Figure BDA0003608794920001841
****:IC50<10uM；***:IC50The range of values is 10-50uM; * IC50The range of values is 50-250uM; * : IC (integrated circuit)50The range of values is 250-1000uM
The above data indicate that at the protein level, the compounds are able to block the protein interaction of TEAD2/YAP 1.
Biological activity test method 2: data for activity of compounds to inhibit TEAD4/YAP1 interaction:
the YAP1 binding domain TEAD4 (217-434) of HIS-tag labeled TEAD4 was expressed in E.coli, and TEAD4 protein was purified by Ni affinity column and ion exchange chromatography column. Meanwhile, FAM-labeled YAP 1-derived polypeptides were synthesized (FAM-YAP 1, biological activity test method 1). Based on the expression and purification of TEAD4 protein and the fluorescent molecular probe FAM-YAP1, a fluorescence deviation analysis method is utilized to measure the dissociation constant Kd of FAM-YAP1 and TEAD2 to be 2.4nM.
96-well plates were purchased from Corning Inc. (Black, # 3694). The multifunctional microplate reader is a product of TECAN company, and has the following model: SPARK 10M. Compound buffer dilution: 1 XPBS (pH 7.4), 20% DMSO (Sigma) and 0.01% Trition X-100 (Sigma), the experimental water was Millipore-Q pure water. Detection buffer solution: 1X PBS (pH 7.4), 0.01% Trition X-100 (Sigma).
The test compounds were first dissolved in DMSO to 20mM standard stock. Subsequently, the standard stock solution of test compound was diluted with dilution compound buffer to a working sample solution in an EP tube, prepared at a concentration =10 times the highest sample concentration required on the test plate (10 × test compound solution), and the compound was diluted in a 2-fold gradient in an EP tube for use.
A gradient of 5. Mu.L of the test compound A10X test compound solution was added to wells B1-D1 to B12-D12 of a 96-well plate, and a gradient of 5. Mu.L of the test compound B10X test compound solution was added to wells E1-G1 to E12-G12, respectively. To each well was added 40uL 37.5nM TEAD4 protein solution. Finally, 50nM Tracer was added to each well.
A1-A3 wells served as blank control: add 50. Mu.L of assay buffer. A4-A6 wells served as negative signal reference group: add 50. Mu.L of buffer containing only 5nM FAM-YAP1 fluorescently labeled molecular probe. A7-A9 wells served as positive reference group: add 50. Mu.L of a mixed solution containing 5nM FAM-YAP1 fluorescently labeled molecular probe and 30nM TEAD4 protein.
The reaction plate was covered with aluminum foil paper, and after incubating the 96-well plate on a 96-well plate shaker at room temperature for 1 hour and 1.5 hours, the fluorescence polarization mP value at Ex485nm/Em530nm was read with a microplate reader. The measured mP value is plotted against the compound concentration gradient, and the concentration of the sample compound corresponding to the median of the maximum and minimum mP values is the IC of the binding of the compound and the protein50Value ([ I ]]50)。
According to this IC50Value ([ I ]]50) Calculating the binding rate of the compound and the protein by using a formulai:Ki＝[I]50/([L]50/Kd+[P]0/Kd+1)。
Wherein [ L ] is]50Represents 50% of the concentration of fluorescently labeled molecular probes in the test system; [ P ]]0Indicates the TEAD4 protein concentration, K, in the test systemdIs the dissociation constant of the protein and the fluorescently labeled molecular probe.
Figure BDA0003608794920001851
Figure BDA0003608794920001861
****:IC50<10uM；***:IC50The range of values is 10-50uM; * IC50The range of values is 50-250uM; * : IC (integrated circuit)50The range of values is 250-1000uM
The above data indicate that at the protein level, the compounds are able to block the protein interaction of TEAD4/YAP 1.
Biological activity test method 3: in human gastric cancer cell line HGC-27, the example compounds inhibit the expression levels of TEAD target genes CYR61, CTGF and CDX2
Literature research shows that three genes, namely CYR61, CTGF and CDX2, are target genes of TEAD, and blocking the protein interaction of TEAD/YAP1 can inhibit the expression of the three genes. YAP1 is over-expressed in a human gastric cancer cell strain HGC-27, the growth of the cell depends on a TEAD/YAP1 signal pathway, and the cell is sensitive to an inhibitor of TEAD/YAP1 interaction. HGC-27 cells were treated with the compound, and changes in the gene expression levels of CYR61, CTGF, and CDX2 were detected by quantitative PCR (qPCR).
After 24 hours of treatment with the compound, HGC-27 cells were collected and washed twice with PBS solution. Then, RNA extraction and reverse transcription were performed using an RNA extraction kit (cat # 9767) and an RNA reverse transcription kit (cat # RR 047) of Baojiri physician's technology Co., ltd in this order to obtain a cDNA template, and the experimental procedures were as described in the kit's instructions. The quantitative determination was carried out using a chimeric fluorescent detection reagent (cat # RR 820) of this company, and the procedure was as follows:
first, a PCR reaction solution was prepared on ice according to the following components.
Reagent Amount of use (mu L) Final concentration
TB Green Premix Ex Taq II(Tli RNase Plus)(2×) 2.5 1×
Gene upstream primer (10. Mu.M) 1 0.4μM
Gene downstream primer (10. Mu.M) 1 0.4μM
cDNA template (<100ng) 2
DEPC water 8.5
Total volume 25
Next, after mixing well, the reaction solution was added to a 384-well qPCR reaction plate at a volume of 7. Mu.l/well. Then, the mixture was centrifuged at 4000rpm for 10min at 4 ℃. The detection was performed using a CFX384 Real-Time PCR detection system and a two-step amplification procedure (preheating at 95 ℃ for 30 seconds; denaturation at 95 ℃ for 5 seconds; annealing at 60 ℃ for 30 seconds; total 40 cycles), and calculated using the 2- Δ Δ t method, the gene primer sequences used in the experiments are given in the following Table:
Figure BDA0003608794920001871
comparing the signal read by the PCR detection system with the internal reference, calculating and normalizing by adopting 2-delta t, and plotting the obtained value and the corresponding drug concentration (shown in the following figures 1-4) to obtain the change of the expression levels of the CYR61, the CTGF and the CDX2 relative to the treatment group without the compound (DMSO).
The data in FIG. 1 show that the compound of example 4 (QJ 68) dose-dependently inhibited the expression of CYR61, CTGF, CDX2 genes, as compared to the blank control (DMSO) without compound.
The data in FIG. 2 show that the compounds of examples 30 (QJ 156) and 31 (QK 3) can inhibit the expression of CYR61 and CTGF genes dose-dependently, and the compound of example 30 can inhibit the expression of CDX2 gene, compared with the blank control (DMSO) without the compound.
The data in FIG. 3 show that the compounds of examples 86 (LYA 95) and 87 (LYA 102) inhibit the expression of CTGF gene as compared to the blank control (DMSO) without the compound.
FIG. 4 shows that the compound of example 97 (FC 3-2) inhibits the expression of CYR61 and CDX2 genes compared to the blank control (DMSO) without compound.
The data show that the compounds of the listed examples can inhibit the expression levels of TEAD target genes CYR61, CTGF and CDX2 in human gastric cancer cell strains HGC-27, and the compounds can block the interaction of TEAD/YAP1 proteins in cells.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A compound of formula (I), a stereoisomer, an enantiomer, or a pharmaceutically acceptable salt thereof:
Figure FDA0003608794910000011
in the formula, RaSelected from the group consisting of: hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy;
A1、A2、A3、A4and A5Each independently is represented as CRbOr N, wherein RbEach occurrence is independently selected from the group consisting of: hydrogen atom, halogen, cyano, nitro, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, -NR1R2、-CO2R3Substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C5-C8 cycloalkenyl, substituted or unsubstituted C5-C8 heterocycloalkyl, substituted or unsubstituted C5-C8 heterocycloalkenyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-8 membered heteroaryl; or two adjacent RbForm, with the carbon atom to which it is attached, a substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, nitro, hydroxy, carboxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, -NR4R5；
Each one of
Figure FDA0003608794910000016
Independently a double or single bond;
x, Y, Z are each independently CR under valency permissive conditionscOr NRdAnd forms a five-membered heteroaromatic ring with two carbon atoms of the benzene ring;
under the condition of valence bond permission, RcEach occurrence is independently selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-8 membered heteroaryl, carboxy, -CONH- (C1-C6 alkylene) Re,
Figure FDA0003608794910000012
Figure FDA0003608794910000013
Wherein said substitution is by one or more groups selected from the group consisting of: halogen, oxo radical
Figure FDA0003608794910000014
Hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, 5-to 8-membered heteroaryl, - (CH)2)m1-CO2R6、-(CH2)m2-SO3R7、-SO2NR8R9、-NR8R9；
Ar1Selected from the group consisting of: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, - (CH)2)m3-CO2R10、-CONR11R12、-SO2NR13R14、-(CH2)m4-SO3R15C1-C4 alkyl, C1-C4 alkoxy;
Reselected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group; wherein said substitution is by one or more groups selected from the group consisting of: halogen, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, -SO2OR15Oxo group
Figure FDA0003608794910000015
Hydroxy, methanesulfonyl, trifluoromethyl, - (CH)2)m5-CO2R16；
Ar2Selected from the group consisting of: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methylsulfonyl, trifluoromethyl, - (CH)2)m6-CO2R17、-CONR18R19、-SO2NR20R21、-(CH2)m7-SO3R22C1-C4 alkyl, C1-C4 alkoxy;
Rfselected from: substituted or unsubstituted C1-C6 alkyl, carboxyl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, amino, carboxyl, cyano, nitro;
Ar3selected from the group consisting of: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, nitro, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy;
E1is NR33Or O; e2Is NR31R32OR OR34；
Ar4Selected from the group consisting of: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methylsulfonyl, trifluoromethyl, - (CH)2)m8-CO2R23、-CONR24R25、-SO2NR26R27、-(CH2)m9-SO3R28C1-C4 alkyl, C1-C4 alkoxy;
under the condition of valence bond permission RdEach occurrence is independently selected from the group consisting of: absent, a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group,
Figure FDA0003608794910000021
Wherein said substitution is by one or more groups selected from the group consisting ofAnd (3) substitution: halogen, - (CH)2)m8-CO2R23Cyano, nitro, hydroxy, oxo
Figure FDA0003608794910000022
-NH2Methanesulfonyl, sulfonic acid, aminosulfonyl, (C1-C4) alkoxy, (C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;
Ar5selected from the group consisting of: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methanesulfonyl, trifluoromethyl, - (CH)2)m10-CO2R29、-CONR30R31、-SO2NR32R33、-(CH2)m11-SO3R34C1-C4 alkyl, C1-C4 alkoxy;
at each occurrence, R1-R34Each independently selected from a hydrogen atom or a C1-C4 alkyl group;
n1 is 0,1, 2,3 or 4;
n2 is 0,1 or 2;
n3 is 0,1 or 2;
n4 is 1,2 or 3;
m1 to m11 are each independently 0,1 or 2.
2. The compound of claim 1, wherein Y is CR, under conditions permissive for a valence bondcOr NRdAnd forms a five-membered heteroaromatic ring with two carbon atoms of the benzene ring;
under the condition of valence bond permission, RcEach occurrence is independently selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-to 8-membered heteroaryl group, a carboxyl group, -CONH- (C1-C6 alkylene) Re,
Figure FDA0003608794910000023
Figure FDA0003608794910000024
Substituted or unsubstituted
Figure FDA0003608794910000025
Wherein said substitution means substitution by one or more groups selected from the group consisting of: halogen, oxo radical
Figure FDA0003608794910000026
Hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, 5-to 8-membered heteroaryl, - (CH)2)m1-CO2R6、-(CH2)m2-SO3R7、-SO2NR8R9、-NR8R9-NHCOC1-C6 alkyl.
3. The compound of claim 1, wherein the compound has the structure of formula (I-1):
Figure FDA0003608794910000031
in the formula, Rz1Selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group,
Figure FDA0003608794910000032
Wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, carboxy, cyano, nitro, amino, (C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;
Ar6selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: nitro, halogen, hydroxy, cyano, methanesulfonyl, trifluoromethyl, - (CH)2)m12-CO2R35、-CONR36R37、-SO2NR38R39、-(CH2)m13-SO3R40C1-C3 alkyl, C1-C3 alkoxy;
Rx1selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl,
Figure FDA0003608794910000033
Figure FDA0003608794910000034
-CONH- (C1-C6 alkylene) Re,
Figure FDA0003608794910000035
Wherein said substitution means substitution by one or more groups selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano;
Ar7selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 4-6 membered cycloalkyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, - (CH)2)m14-CO2R41、-CONR42R43、-SO2NR44R45、-(CH2)m15-SO3R46C1-C4 alkyl, C1-C4 alkoxy;
Rhselected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group; wherein said substitution means substitution by one or more groups selected from the group consisting of: halogen, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, -SO2OR15Oxo group
Figure FDA0003608794910000036
Hydroxy, - (CH)2)m16-CO2R47；
Ar8Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; it is composed ofWherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methylsulfonyl, trifluoromethyl, - (CH)2)m17-CO2R48、-CONR49R50、-SO2NR51R52、-(CH2)m18-SO3R53C1-C4 alkyl, C1-C4 alkoxy;
Riselected from substituted or unsubstituted C1-C6 alkyl, carboxyl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, amino, carboxyl, cyano, nitro;
Ar9selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, nitro, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy;
Ar10selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methylsulfonyl, trifluoromethyl, - (CH)2)m19-CO2R54、-CONR55R56、-SO2NR57R58、-(CH2)m20-SO3R59C1-C4 alkyl, C1-C4 alkoxy;
R35-R59each independently selected from a hydrogen atom or a C1-C4 alkyl group;
n5 is 1,2 or 3;
n6 is 1,2 or 3;
n7 is 0,1, 2,3 or 4;
n8 is 0,1 or 2;
n9 is 0,1 or 2;
m12-m20 are each independently 0,1 or 2;
Ra、Re、Ar5、n4、A1、A2、A3、A4、A5、E1、E2is defined as followsThe method according to claim 1.
4. The compound of claim 1, wherein the compound has the structure of formula (I-2):
Figure FDA0003608794910000041
in the formula, Ry1Is composed of
Figure FDA0003608794910000042
Ar11Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methanesulfonyl, trifluoromethyl, - (CH)2)m21-CO2R60、-CONR61R62、-SO2NR63R64、-(CH2)m22-SO3R65C1-C3 alkyl, C1-C3 alkoxy;
R60-R65each independently selected from a hydrogen atom or a C1-C4 alkyl group;
n10 is 0,1, 2 or 3;
m21 and m22 are each independently 0,1 or 2;
Ra、A1、A2、A3、A4、A5is as defined in claim 1.
5. The compound of claim 1, wherein the compound has the structure of formula (I-3):
Figure FDA0003608794910000043
wherein R isa、A1、A2、A3、A4、A5As defined in claim 1;
Figure FDA0003608794910000045
represents a single bond or a double bond, whereiny2The attached carbon atoms cannot participate in the formation of two double bonds at the same time;
Rx2and Rz2One of which is absent and the other is H,
Figure FDA0003608794910000044
Substituted or unsubstituted C1-C6 alkyl; ar (Ar)12Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, - (CH)2)m23-CO2R66、-CONR67R68、-SO2NR69R70、-(CH2)m24-SO3R71C1-C4 alkyl, C1-C4 alkoxy, 5-6 membered heteroaryl, 3-8 membered heterocyclyl, -NH2(C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;
Ry2selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted
Figure FDA0003608794910000051
Ar13Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: oxo radical
Figure FDA0003608794910000052
Halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, - (CH)2)m25-CO2R72、-CONR73R74、-SO2NR75R76、-(CH2)m26-SO3R77C1-C4 alkyl, C1-C4 alkoxy, 5-6 membered heteroaryl, 3-8 membered heterocyclyl, -NH2(C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino, -NHCOC1-C4 alkyl;
R66-R77each independently selected from a hydrogen atom or a C1-C4 alkyl group;
n11 is 0,1, 2 or 3;
n12 is 0,1, 2 or 3;
m23 to m26 are each independently 0,1 or 2.
6. The compound of claim 1, wherein a is1、A2、A3、A4And A5Each independently is represented by CRbOr N, wherein RbEach occurrence is independently selected from the group consisting of: hydrogen atom, halogen, cyano, nitro, hydroxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, -NR1R2、-CO2R3Substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C5-C6 cycloalkenyl, substituted or unsubstituted C5-C8 heterocycloalkyl, substituted or unsubstituted C5-C6 heterocycloalkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; or two adjacent RbForm, with the carbon atom to which it is attached, a substituted or unsubstituted phenyl, a substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, nitro, hydroxy, carboxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, -NH2(C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;
at each occurrence, R1、R2、R3Each independently selected from a hydrogen atom or a C1-C4 alkyl group.
7. The compound of claim 1, wherein X, Y, Z are each independently CRcOr NRdAnd forms a five-membered heteroaromatic ring with two carbon atoms of the phenyl ring;
under the condition of valence bond permission, RcEach occurrence is independently selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-to 6-membered heteroaryl group, a carboxyl group, -CONH- (C1-C6 alkylene) Re,
Figure FDA0003608794910000053
Substituted or unsubstituted
Figure FDA0003608794910000054
Wherein said substitution is by one or more groups selected from the group consisting of: halogen, oxo radical
Figure FDA0003608794910000055
Hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, 5-6 membered heteroaryl, - (CH)2)m1-CO2R6、-(CH2)m2-SO3R7、-SO2NR8R9、-NR8R9-nhoc 1-C4 alkyl;
Ar1selected from the group consisting of: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, - (CH)2)m3-CO2R10、-CONR11R12、-SO2NR13R14、-(CH2)m4-SO3R15C1-C4 alkyl, C1-C4 alkoxy;
Reselected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group; wherein said substitution is by one or more groups selected from the group consisting of: halogen, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, -SO2OR15Oxo, oxoRadical (I)
Figure FDA0003608794910000061
Hydroxy, methanesulfonyl, trifluoromethyl, - (CH)2)m5-CO2R16；
Ar2Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methylsulfonyl, trifluoromethyl, - (CH)2)m6-CO2R17、-CONR18R19、-SO2NR20R21、-(CH2)m7-SO3R22C1-C4 alkyl, C1-C4 alkoxy;
Rfis substituted or unsubstituted C1-C4 alkyl or carboxy; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, amino, carboxyl, cyano, nitro;
Ar3selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution is by one or more groups selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, nitro, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy;
Ar4selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methylsulfonyl, trifluoromethyl, - (CH)2)m8-CO2R23、-CONR24R25、-SO2NR26R27、-(CH2)m9-SO3R28C1-C4 alkyl, C1-C4 alkoxy;
under the condition of valence bond permission RdEach occurrence is independently selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C4 alkyl group,
Figure FDA0003608794910000062
Wherein said substitution is by one or more groups selected from the group consisting of: halogen, - (CH)2)m8-CO2R23Cyano, nitro, hydroxy, oxo
Figure FDA0003608794910000063
-NH2Methanesulfonyl, sulfonic acid, aminosulfonyl, (C1-C4) alkoxy, (C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;
Ar5selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution by one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, - (CH)2)m10-CO2R29、-CONR30R31、-SO2NR32R33、-(CH2)m11-SO3R34C1-C4 alkyl, C1-C4 alkoxy;
R1-R34、n1-n4、m1-m11、E1、E2as defined in claim 1.
8. The compound of claim 1, wherein the compound is selected from the group consisting of:
Figure FDA0003608794910000064
Figure FDA0003608794910000071
Figure FDA0003608794910000081
Figure FDA0003608794910000091
Figure FDA0003608794910000101
Figure FDA0003608794910000111
Figure FDA0003608794910000121
Figure FDA0003608794910000131
Figure FDA0003608794910000141
Figure FDA0003608794910000151
Figure FDA0003608794910000161
Figure FDA0003608794910000171
Figure FDA0003608794910000181
Figure FDA0003608794910000191
Figure FDA0003608794910000201
Figure FDA0003608794910000211
Figure FDA0003608794910000221
Figure FDA0003608794910000231
Figure FDA0003608794910000241
Figure FDA0003608794910000251
Figure FDA0003608794910000261
Figure FDA0003608794910000271
9. a pharmaceutical composition comprising a compound of any one of claims 1-8, a stereoisomer, enantiomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
10. Use of a compound of any one of claims 1-8, a stereoisomer, enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 9, for the preparation of an inhibitor of TEAD and YAP interaction (preferably, for the prevention and/or treatment of cancer); or for the preparation of a medicament for the prevention and/or treatment of a nuclear transcription factor TEAD-mediated associated disease; or for non-therapeutically reversing the resistance of tumor cells to anti-tumor drugs; or used for preparing the medicine for reversing the drug resistance of the tumor cells to the antitumor medicine.
CN202210426932.7A 2021-04-29 2022-04-21 Benzo nitrogen-containing five-membered heterocyclic compound and synthesis and application thereof Pending CN115260165A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040110956A1 (en) * 2002-09-05 2004-06-10 Dominique Lesuisse Novel aminoindazole derivatives as medicaments and pharmaceutical compositions including them
US20040132794A1 (en) * 2002-12-12 2004-07-08 Dominique Lesuisse Novel aminoindazole derivatives as medicaments and pharmaceutical compositions including them
CN101979382A (en) * 2002-12-12 2011-02-23 安万特医药股份有限公司 Aminoindazole derivatives and use thereof as kinase inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040110956A1 (en) * 2002-09-05 2004-06-10 Dominique Lesuisse Novel aminoindazole derivatives as medicaments and pharmaceutical compositions including them
CN1678589A (en) * 2002-09-05 2005-10-05 安万特医药股份有限公司 Novel aminoindazole derivatives as medicaments and pharmaceutical compositions including them
US20040132794A1 (en) * 2002-12-12 2004-07-08 Dominique Lesuisse Novel aminoindazole derivatives as medicaments and pharmaceutical compositions including them
CN101979382A (en) * 2002-12-12 2011-02-23 安万特医药股份有限公司 Aminoindazole derivatives and use thereof as kinase inhibitors

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