CN117751099A - Amide compound and application thereof - Google Patents

Amide compound and application thereof Download PDF

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Publication number
CN117751099A
CN117751099A CN202280052853.2A CN202280052853A CN117751099A CN 117751099 A CN117751099 A CN 117751099A CN 202280052853 A CN202280052853 A CN 202280052853A CN 117751099 A CN117751099 A CN 117751099A
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compound
alkyl
synthesis
pharmaceutically acceptable
stereoisomer
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焦宇
张雁
陈亚东
赵思奇
张文强
闫晓华
李红玫
唐锋
丁海敏
庄银枪
彭少平
陆涛
任晋生
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China Pharmaceutical University
Jiangsu Simcere Pharmaceutical Co Ltd
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Jiangsu Simcere Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings

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Abstract

A compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof, pharmaceutical compositions containing them and their use as Selective Androgen Receptor Degradants (SARD) and/or Androgen Receptor (AR) antagonists, particularly for the manufacture of a medicament for the treatment or prophylaxis of diseases mediated by the androgen receptor.

Description

Amide compound and application thereof
Cross Reference to Related Applications
The present application claims the benefit and priority of the following 3 chinese patent applications of inventions, which are incorporated herein by reference in their entirety:
202110896906.6 patent application No. 202110896906.6 submitted to China national intellectual property office on day 5 and 8 of 2021;
202210114403.3 patent application submitted to China national intellectual property office on 1 month 30 of 2022; and
patent application 202210724756.5 submitted to the China national intellectual property agency on 24 th month 2022.
Technical Field
The present application relates to the field of pharmaceutical chemistry, in particular to an amide compound or a stereoisomer or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same and use as a selective androgen receptor degradation agent (SARD) and/or Androgen Receptor (AR) antagonist.
Background
Androgen receptor (Androgen receptor, AR) is one of the nuclear receptor family members, the AR comprising four major regions: an N-terminal active transcription control region (NTD), a DNA binding region (DNA binding domain, DBD), a hinge region, and a C-terminal ligand binding region (Ligand binding domain, LBD). Since Huggins and Hodges discovered that androgens promote prostate cancer growth in the early 40 s of the 20 th century, AR has been an important target for prostate cancer treatment.
Prostate cancer (PCa) is one of the most common cancers worldwide. Endocrine treatment of prostate cancer is the primary treatment for advanced prostate cancer. Various Androgen Deprivation Therapies (ADT) are effective at the initial stages of endocrine therapy, but after a median time of 14-30 months almost all patient lesions will develop from androgen dependent prostate cancer (HDPC) to androgen independent prostate cancer (HIPC), also known as castration-resistant prostate cancer (CRPC). The currently available oral drugs for the treatment of castration resistant prostate cancer are mainly abiraterone and enzalutamide. Among them, abiraterone is a novel androgen biosynthesis inhibitor, which can block androgen synthesis in testis, adrenal gland or tumor cell environment. While enzalutamide is an androgen receptor inhibitor capable of competitively inhibiting androgen binding to the receptor. Once enzalutamine binds to AR, nuclear transport of AR can be further inhibited, blocking interaction of AR with DNA. However, CRPC patients currently have no effective treatment, and a number of studies have shown high AR expression in 80% of advanced CRPC. Thus, the study of the degradation activity of novel molecules on AR and/or the antagonistic activity on AR is of great importance for the further study of diseases associated with high expression of AR.
Some compounds have also been reported in the literature as Selective Androgen Receptor Degradants (SARD) (e.g. patent document WO 2017/214634). Selective Androgen Receptor Degradants (SARD) are not only capable of inhibiting the androgen receptor, blocking the process of androgen receptor signaling, but also capable of degrading the receptor itself, with the potential for further benefits. Thus, there is a need for a new class of selective androgen receptor degradants and/or Androgen Receptor (AR) antagonists.
Detailed Description
In one aspect, the present application provides compounds of formula (I) and stereoisomers or pharmaceutically acceptable salts thereof. These compounds are useful as selective androgen receptor degradants and/or Androgen Receptor (AR) antagonists for the treatment of diseases associated with high expression of AR.
A compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein,
x is CH or N;
R 1 selected from H, OH, C 1-6 Alkyl, -O-C 1-6 Alkyl, -OCOR a 、-COR a 、-CONHR a or-NHCOR a ；
R 2 Selected from C 1-6 Alkyl or C 1-6 A haloalkyl group; or alternatively
From R 1 And R is R 2 And C linked thereto together form C 3-6 Cycloalkyl or 4-6 membered heterocyclyl;
R 4 selected from halogen, CF 3 or-O-C 1-6 An alkyl group;
R 5 selected from CN, NO 2 、-COR a 、-CONHR a 、-S(O) 2 R a or-S (O) 2 N(R a ) 2 ；
R a Independently selected from H, OH, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
R 6 selected from H or-O-C 1-6 An alkyl group;
R 7 and R is 8 Independently selected from H or halogen;
w is selected fromOr a 4-10 membered fully saturated heterocyclic group, said 4-10 membered fully saturated heterocyclic group optionally being substituted with R b Substitution; r is R b Independently selected from halogen, OH, NH 2 、NO 2 、CN、C 1-6 Alkyl, C 1-6 Haloalkyl, -O-C 1-6 Alkyl or-S (=o) 2 -C 1-6 An alkyl group;
ring D is selected from 5-10 membered heteroaryl or C 6-10 An aryl group;
each R is 3 Independently selected from halogen, OH, NH 2 、NO 2 、CN、-CONH 2 、-CONHR 3A 、-O-C 1-6 Alkyl, -S (=o) 2 -C 1-6 Alkyl, C 1-6 Alkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl or C 6-10 Aryl, said C 1-6 Alkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl or C 6-10 Aryl is optionally substituted with R 3A Substitution;
R 3A independently selected from halogen, OH, NO 2 、CN、CH 2 F、CHF 2 、CF 3 、C 1-6 Alkyl, -O-C 1-6 Alkyl or-S (=o) 2 -C 1-6 An alkyl group;
n is selected from 0, 1, 2, 3 or 4;
p is selected from 0 or 1.
In some embodiments of the present application, X is CH.
In some embodiments of the present application, X is N.
In some embodiments of the present application, W is selected from 4-10 membered fully saturated heterocyclyl, said 4-10 membered fully saturated heterocyclyl optionally being substituted with R b And (3) substitution.
In some embodiments of the present application, W is selected from 4-8 membered fully saturated heterocyclyl, said 4-8 membered fully saturated heterocyclyl optionally being substituted with R b And (3) substitution.
In some embodiments of the present application, W is selected from a 4, 5, 6, 7, or 8 membered fully saturated heterocyclic group containing 1 or 2N atoms, said 4, 5, 6, 7, or 8 membered fully saturated heterocyclic group optionally being substituted with R b And (3) substitution.
In some embodiments of the present application, W is selected from 6-8 membered fully saturated heterocyclyl, said 6-8 membered fully saturated heterocyclyl optionally being substituted with R b And (3) substitution.
In some embodiments of the present application, W is selected from a 6, 7 or 8 membered fully saturated heterocyclic group containing 1 or 2N atoms, said 6, 7 or 8 membered fully saturated heterocyclic group optionally being R b And (3) substitution.
In some embodiments of the present application, W is selected from 7-8 membered fully saturated heterocyclyl, said 7-8 membered fully saturated heterocyclyl optionally being substituted with R b And (3) substitution.
In some embodiments of the present application, W is selected from the group consisting of azetidinyl, piperazinyl, 1, 4-diazepinyl, 3, 8-diazabicyclo [3.2.1 ]]Octyl, 2, 5-diazabicyclo [2.2.1]Heptyl or heptyl radicalsThe azetidinyl, piperazinyl, 1, 4-diazacycloheptyl, 3, 8-diazabicyclo [3.2.1]Octyl, 2, 5-diazabicyclo [2.2.1]Heptyl or heptyl radicalsOptionally by R b And (3) substitution.
In some embodiments of the present application, W is selected from the group consisting of azetidinyl, piperazinyl, 1, 4-diazepinyl, 3, 8-diazabicyclo [3.2.1 ]]Octyl or 2, 5-diazabicyclo [2.2.1]Heptyl, said azetidinyl, piperazinyl, 1, 4-diazacycloheptyl, 3, 8-diazabicyclo [3.2.1 ]Octyl or 2, 5-diazabicyclo [2.2.1]Heptyl is optionally substituted with R b And (3) substitution.
In some embodiments of the present application, W is selected from the group consisting of azetidinyl, piperazinyl, 3, 8-diazabicyclo [3.2.1 ]]Octyl or 2, 5-diazabicyclo [2.2.1]Heptyl, said azetidinyl, piperazinyl, 3, 8-diazabicyclo [3.2.1]Octyl or 2, 5-diazabicyclo [2.2.1]Heptyl is optionally substituted with R b And (3) substitution.
In some embodiments of the present application, ring D is selected from phenyl or 5-10 membered heteroaryl.
In some embodiments of the present application, ring D is selected from phenyl or a 5, 6, 7, 8, 9, or 10 membered heteroaryl group containing 1 or 2N atoms.
In some embodiments of the present application, ring D is selected from phenyl or a 5 or 6 membered heteroaryl group containing 1 or 2N atoms.
In some embodiments of the present application, ring D is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, pyridazinyl, benzopyrrolyl, quinolinyl, isoquinolinyl, or benzopyrazolyl.
In some embodiments of the present application, ring D is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, or pyridazinyl.
In some embodiments of the present application, R b Selected from C 1-6 An alkyl group.
In some embodiments of the present application, R b Selected from CH 3 。
In some embodiments of the present application, R 3 Selected from halogen, NO 2 、CN、-O-C 1-6 Alkyl, -S (=o) 2 -C 1-6 Alkyl, -CONHR 3A 、C 1-6 Alkyl, 5-to 10-membered heteroaryl or C 6-10 Aryl, said C 1-6 Alkyl, 5-to 10-membered heteroaryl or C 6-10 Aryl is optionally substituted with R 3A And (3) substitution.
In some embodiments of the present application, R 3 Selected from halogen, CN, NO 2 、-O-C 1-6 Alkyl, -CONHR 3A 、C 1-6 Alkyl, 5-to 10-membered heteroaryl or C 6-10 Aryl, said C 1-6 Alkyl, 5-to 10-membered heteroaryl or C 6-10 Aryl is optionally substituted with R 3A Substituted, R 3A May preferably be selected from halogen, CN, CF 3 、NO 2 Or CH (CH) 3 And R is 3A May be more preferably selected from halogen, CN, CF 3 Or CH (CH) 3 。
In some embodiments of the present application, R 3 Selected from halogen、NO 2 、CN、-O-C 1-6 Alkyl, -S (=o) 2 -C 1-6 Alkyl, C 1-6 Alkyl, 5-to 10-membered heteroaryl or C 6-10 Aryl, said C 1-6 Alkyl, 5-to 10-membered heteroaryl or C 6-10 Aryl is optionally substituted with R 3A And (3) substitution.
In some embodiments of the present application, R 3 Selected from halogen, CN, NO 2 、-O-C 1-6 Alkyl, C 1-6 Alkyl, 5-to 10-membered heteroaryl or C 6-10 Aryl, said C 1-6 Alkyl, 5-to 10-membered heteroaryl or C 6-10 Aryl is optionally substituted with R 3A Substituted, R 3A May preferably be selected from halogen, CN, CF 3 、NO 2 Or CH (CH) 3 And R is 3A May be more preferably selected from halogen, CN or CF 3 。
In some embodiments of the present application, R 3 Selected from halogen, NO 2 、CN、-O-C 1-6 Alkyl, -S (=o) 2 -CH 3 、C 1-6 Alkyl, 5-6 membered heteroaryl or phenyl, said C 1-6 Alkyl, 5-6 membered heteroaryl or phenyl optionally substituted with R 3A And (3) substitution.
In some embodiments of the present application, R 3 Selected from halogen, CN, NO 2 、-O-C 1-6 Alkyl, C 1-6 Alkyl, 5-6 membered heteroaryl or phenyl, said C 1-6 Alkyl, 5-6 membered heteroaryl or phenyl optionally substituted with R 3A Substituted, R 3A May preferably be selected from halogen, CN, CF 3 、NO 2 Or CH (CH) 3 And R is 3A May be more preferably selected from halogen, CN or CF 3 。
In some embodiments of the present application, R 3 Selected from F, cl, br, CN, NO 2 、-O-C 1-6 Alkyl, C 1-6 Alkyl group,5-6 membered heteroaryl or phenyl containing 1 or 2N atoms, said C 1-6 Alkyl, 5-6 membered heteroaryl or phenyl optionally substituted with R 3A Substituted, R 3A May preferably be selected from halogen, CN, CF 3 、NO 2 Or CH (CH) 3 And R is 3A May be more preferably selected from halogen, CN or CF 3 。
In some embodiments of the present application, R 3 Selected from F, cl, br, CN, NO 2 、-O-C 1-2 Alkyl, C 1-2 Alkyl, 5-6 membered heteroaryl containing 1 or 2N atoms, or phenyl, said C 1-6 Alkyl, 5-6 membered heteroaryl or phenyl optionally substituted with R 3A Substituted, R 3A May preferably be selected from halogen, CN, CF 3 、NO 2 Or CH (CH) 3 And R is 3A May be more preferably selected from F, CN or CF 3 。
In some embodiments of the present application, R 3 Selected from halogen, NO 2 、CN、-O-CH 3 、-CF 3 、-CH 3 、-S(＝O) 2 -CH 3 、-CONHCH 3 Pyrimidinyl, pyrazolyl, pyridinyl or phenyl, said pyrimidinyl, pyrazolyl, pyridinyl or phenyl optionally being substituted with R 3A And (3) substitution.
In some embodiments of the present application, R 3 Selected from halogen, NO 2 、CN、-O-CH 3 、-CF 3 、-CH 3 、-CONHCH 3 Pyrimidinyl, pyrazolyl, pyridinyl or phenyl, said pyrimidinyl, pyrazolyl, pyridinyl or phenyl optionally being substituted with R 3A And (3) substitution.
In some embodiments of the present application, R 3 Selected from halogen, NO 2 、CN、-O-CH 3 、-CF 3 Pyrimidinyl, pyrazolyl, pyridinyl or phenyl, said pyrimidinyl, pyrazolyl, pyridinyl or phenyl optionally being substituted with R 3A And (3) substitution. In some embodiments of the present application, R 3A Independently selected from halogen, OH, NO 2 、CN、CH 2 F、CHF 2 、CF 3 Or C 1-6 An alkyl group.
In some embodiments of the present application, R 3 Selected from F, cl, br, CN, NO 2 、-CF 3 、-O-CH 3 、-CH 3 、-CONHCH 3 Pyrimidinyl, pyrazolyl, pyridinyl or phenyl, said pyrimidinyl, pyrazolyl, pyridinyl or phenyl optionally being substituted with R 3A Substituted, R 3A May preferably be selected from halogen, CN, CF 3 Or NO 2 And R is 3A May be more preferably selected from F, CN or CF 3 。
In some embodiments of the present application, R 3A Independently selected from halogen, NO 2 、CN、CF 3 Or CH (CH) 3 。
In some embodiments of the present application, R 3A Independently selected from halogen, CN or CF 3 。
In some embodiments of the present application, R 1 Selected from H, OH, C 1-6 Alkyl or-O-C 1-6 An alkyl group.
In some embodiments of the present application, R 1 Selected from OH.
In some embodiments of the present application, R 2 Selected from C 1-6 An alkyl group.
In some embodiments of the present application, R 2 Selected from CH 3 。
In some embodiments of the present application, R 4 Selected from halogen, CF 3 or-O-CH 3 。
In some embodiments of the present application, R 4 Selected from F, cl, br, CF 3 or-O-CH 3 。
In some embodiments of the present application, R 4 Selected from F, cl, CF 3 or-O-CH 3 。
In some embodiments of the present application, R 4 Selected from Cl or CF 3 。
In some embodiments of the present application, R 4 Selected from CF 3 。
In some embodiments of the present application, R 5 Selected from CN or NO 2 。
In some embodiments of the present application, R 5 Is CN.
In some embodiments of the present application, R 6 Selected from H.
In some embodiments of the present application, R 7 ，R 8 Independently selected from H or F.
In some embodiments of the present application, R 7 ，R 8 Independently selected from H.
In some embodiments of the present application, n is selected from 0, 1, or 2.
In some embodiments of the present application, n is selected from 1 or 2.
In some embodiments of the present application, p is 0.
In some embodiments of the present application, X is CH or N; w is selected fromOr a 4-8 membered fully saturated heterocyclic group, said 4-8 membered fully saturated heterocyclic group optionally being substituted with R b Substitution; r is R b Independently C 1-6 An alkyl group; ring D is selected from phenyl or 5-10 membered heteroaryl; r is R 3 Selected from halogen, CN, NO 2 、-O-C 1-6 Alkyl, -CONHR 3A 、C 1-6 Alkyl, 5-to 10-membered heteroaryl or C 6-10 Aryl, said C 1-6 Alkyl, 5-to 10-membered heteroaryl or C 6-10 Aryl is optionally substituted with R 3A Substitution; r is R 3A Selected from halogen, CN, CF 3 、NO 2 Or CH (CH) 3 ；R 1 OH; r is R 2 Is CH 3 ；R 4 Selected from halogen, CF 3 or-O-CH 3 ；R 5 Selected from CN or NO 2 ；R 6 、R 7 And R is 8 All are H; n is selected from 0, 1 or 2; and p is 0 or 1.
In some embodiments of the present application, X is CH or N; w is a 4-8 membered fully saturated heterocyclic group, said 4-8 membered fully saturated heterocyclic group optionally being substituted by R b Substitution; r is R b Independently C 1-2 An alkyl group; ring D is selected from phenyl or 5-6 membered heteroaryl; r is R 3 Selected from halogen, CN, NO 2 、-O-C 1-2 Alkyl, -CONHR 3A 、C 1-2 Alkyl, 5-6 membered heteroaryl or phenyl, said C 1-2 Alkyl, 5-6 membered heteroaryl or phenyl optionally substituted with R 3A Substitution; r is R 3A Selected from halogen, CN, CF 3 、NO 2 Or CH (CH) 3 ；R 1 OH; r is R 2 Is CH 3 ；R 4 Selected from halogen, CF 3 or-O-CH 3 ；R 5 Selected from CN or NO 2 ；R 6 、R 7 And R is 8 All are H; n is selected from 0, 1 or 2; and p is 0 or 1.
In some embodiments of the present application, X is CH or N; w is a 4-8 membered fully saturated heterocyclic group containing 1 or 2N, said 4-8 membered fully saturated heterocyclic group optionally being R b Substitution; r is R b Independently CH 3 The method comprises the steps of carrying out a first treatment on the surface of the Ring D is selected from phenyl or a 5-6 membered heteroaryl group containing 1 or 2N; r is R 3 Selected from halogen, CN, NO 2 、-O-CH 3 、-CONHR 3A 、CH 3 A 5-6 membered heteroaryl group containing 1 or 2N or phenyl group, said CH 3 5-to 6-membered heteroaryl or benzeneThe radicals optionally being R 3A Substitution; r is R 3A Selected from halogen, CN, CF 3 、NO 2 Or CH (CH) 3 ；R 1 OH; r is R 2 Is CH 3 ；R 4 Selected from halogen, CF 3 or-O-CH 3 ；R 5 Selected from CN or NO 2 ；R 6 、R 7 And R is 8 All are H; n is selected from 0, 1 or 2; and p is 0 or 1.
In some embodiments of the present application, X is CH or N; w is a 4-8 membered fully saturated heterocyclic group containing 1 or 2N, said 4-8 membered fully saturated heterocyclic group optionally being R b Substitution; r is R b Independently CH 3 The method comprises the steps of carrying out a first treatment on the surface of the Ring D is selected from phenyl or a 5-6 membered heteroaryl group containing 1 or 2N; r is R 3 Selected from F, cl, br, CN, NO 2 、-O-CH 3 、CH 3 A 5-6 membered heteroaryl group containing 1 or 2N or phenyl group, said CH 3 Optionally R is a 5-to 6-membered heteroaryl or phenyl group 3A Substitution; r is R 3A Selected from F, CN, CF 3 Or NO 2 ；R 1 OH; r is R 2 Is CH 3 ；R 4 Selected from F, cl, CF 3 or-O-CH 3 ；R 5 Is CN; r is R 6 、R 7 And R is 8 All are H; n is selected from 0, 1 or 2; and p is 0.
In some embodiments of the present application, X is CH or N; w is selected from the group consisting of azetidinyl, piperazinyl, 1, 4-diazaheptyl, 3, 8-diazabicyclo [3.2.1]Octyl or 2, 5-diazabicyclo [2.2.1]Heptyl, said azetidinyl, piperazinyl, 1, 4-diazacycloheptyl, 3, 8-diazabicyclo [3.2.1 ]Octyl or 2, 5-diazabicyclo [2.2.1]Heptyl is optionally substituted with R b Substitution; r is R b Independently CH 3 The method comprises the steps of carrying out a first treatment on the surface of the Ring D is selected from phenyl or a 5-6 membered heteroaryl group containing 1 or 2N; r is R 3 Selected from F, cl, br, CN, NO 2 、-O-CH 3 、CH 3 A 5-6 membered heteroaryl group containing 1 or 2N or phenyl group, said CH 3 Optionally R is a 5-to 6-membered heteroaryl or phenyl group 3A Substitution; r is R 3A Selected from F, CN, CF 3 Or NO 2 ；R 1 OH; r is R 2 Is CH 3 ；R 4 Selected from F, cl, CF 3 or-O-CH 3 ；R 5 Is CN; r is R 6 、R 7 And R is 8 All are H; n is selected from 0, 1 or 2; and p is 0.
In some embodiments of the present application, the compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof is selected from the group consisting of the compound of formula (II) or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein the ring D, W, X, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 N and p are as defined above.
In some embodiments of the present application, the compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (III) or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein the ring D, W, X, R 3 、R 4 、R 5 、R 7 、R 8 N and p are as defined above.
In some embodiments of the present application, the compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (IV) or a stereoisomer or pharmaceutically acceptable salt thereof,
Wherein the ring D, W, X, R 3 、R 4 、R 5 、R 7 、R 8 And n is as defined above.
In some embodiments of the present application, the compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (V) or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein the ring D, W, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 N and p are as defined above.
In some embodiments of the present application, the compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof is selected from the group consisting of the compound of formula (VI) or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein the ring D, X, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 And n is as defined above;
a 1 、a 2 、a 3 and a 4 Each independently selected from bond or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the A) 5 Selected from CH 2 Or CH (CH) 2 CH 2 。
In some embodiments of the present application, the compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (VI-a) or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein the ring D, X, R 1 、R 2 、R 3 、R 4 、R 5 、R 7 、R 8 And n is as defined above;
a 1 、a 2 、a 3 and a 4 Each independently selected from bond or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the A) 5 Selected from CH 2 Or CH (CH) 2 CH 2 。
In some embodiments of the present application,selected from:
in some embodiments of the present application, the compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof is selected from the group consisting of:
In another aspect, the present application also provides a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), (VI) or (VI-a), or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
In yet another aspect, the present application relates to the use of a compound of formula (I), (II), (III), (IV), (V), (VI) or (VI-a), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of a disorder mediated by an androgen receptor.
In yet another aspect, the present application relates to the use of a compound of formula (I), (II), (III), (IV), (V), (VI) or (VI-a), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of a disorder mediated by an androgen receptor.
In yet another aspect, the present application relates to a compound of formula (I), (II), (III), (IV), (V), (VI) or (VI-a) or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of a disorder mediated by an androgen receptor.
In yet another aspect, the present application relates to a method of treating a disorder mediated by an androgen receptor, the method comprising administering to a patient a therapeutically effective dose of a pharmaceutical formulation comprising a compound of formula (I), (II), (III), (IV), (V), (VI) or (VI-a) or a stereoisomer or pharmaceutically acceptable salt thereof, as described herein.
Further, the androgen receptor mediated disease is selected from prostate cancer or androgenic alopecia.
Definition and description of terms
Unless otherwise indicated, the terms used in the present application have the following meanings, and the groups and term definitions recited in the present application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and combined with each other. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
Herein, a method of manufacturing a semiconductor deviceRepresenting the ligation site.
The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J.chem. Ed.1985, 62:114-120. Unless otherwise indicated, wedge keys and virtual wedge keys are usedRepresenting the absolute configuration of a solid center by using black real and virtual keysRepresenting the relative configuration of a stereocenter (e.g., the cis-trans configuration of a alicyclic compound).
The term "tautomer" refers to a functional group isomer that results from the rapid movement of an atom in a molecule at two positions. The compounds of the present application may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones such as acetaldehyde, the ketone type predominates; whereas, among phenols, the enol form is dominant. This application includes all tautomeric forms of the compounds.
The term "stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers and diastereomers.
The compounds of the present application may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, and thus the compounds of the present application may exist in specific geometric or stereoisomeric forms. Particular geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic or other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the definition of compounds of the present application. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms may be present in the substituents such as alkyl groups, and all such isomers and mixtures thereof are included within the definition of compounds of the present application. The asymmetric atom-containing compounds of the present application may be isolated in optically pure form or in racemic form, which may be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.
The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl may be unsubstituted (CH 2 CH 3 ) Monosubstituted (CH) 2 CH 2 F、CH 2 CH 2 Cl, etc.), polysubstituted (CHFCH 2 F、CH 2 CHF 2 、CHFCH 2 Cl、CH 2 CHCl 2 Etc.) or fully substituted (CF) 2 CF 3 、CF 2 CCl 3 、CCl 2 CCl 3 Etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.
When any variable (e.g. R a 、R b ) Where the composition or structure of a compound occurs more than once, its definition is independent in each case. For example, if a group is substituted with 2R b Substituted, each R b There are independent options.
When the number of one linking group is 0, such as- (CH) 2 ) 0 -, indicating that the linking group is a bond.
When a linking group referred to herein is linked if its linking direction is not indicatedThe direction of the connection is arbitrary. For example when building blocksL of (3) 1 Selected from "C 1 -C 3 alkylene-O ", in which case L 1 Either the rings Q and R can be connected in a direction from left to right 1 Form a "ring Q-C 1 -C 3 alkylene-O-R 1 ", rings Q and R may be connected in a right-to-left direction 1 Form a "ring Q-O-C 1 -C 3 Alkylene group-R 1 ”。
When the bond of a substituent is cross-linked to two atoms on a ring, the substituent may be bonded to any atom on the ring. For example, structural unitsR represents 5 Substitution may occur at any position on the phenyl ring.
C herein m - n Refers to having an integer number of carbon atoms in the m-n range. For example "C 1 - 10 By "is meant that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.
The term "alkyl" refers to a compound of the formula C n H 2n+1 The alkyl group may be linear or branched. The term "C 1 - 10 Alkyl "is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1,2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl Neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, etc.; the term "C 1 -C 6 Alkyl "is understood to mean an alkyl group having 1,2, 3, 4, 5 or 6 carbon atoms, specific examples including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like. The term "C 1 - 3 Alkyl "is understood to mean a straight-chain or branched saturated alkyl group having 1,2 or 3 carbon atoms. The "C 1 - 10 Alkyl "may contain" C 1 - 6 Alkyl "or" C 1 - 3 Alkyl "and the like, said" C 1 - 6 The alkyl group may further comprise "C 1 - 3 An alkyl group.
The term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C 1-6 Haloalkyl "means C as defined above substituted with one or more halo groups 1-6 Alkyl groups including, but not limited to, trifluoromethyl, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, and the like.
The term "cycloalkyl" refers to a fully saturated carbocycle in the form of a single ring, a parallel ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. The term "C 3 - 10 Cycloalkyl "is understood to mean a saturated monocyclic, parallel, spiro or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo [ 2.2.1)]Heptyl), bicyclo [2.2.2]Octyl and diamondAlkyl, spiro [4.5 ]]Decyl, and the like. The term "C 3 - 10 Cycloalkyl "may contain" C 3 - 6 Cycloalkyl ", the term" C 3 - 6 Cycloalkyl "is understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, or 6 carbon atoms, specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "heterocyclyl" refers to a fully saturated or partially saturated (not aromatic in nature as a whole) monocyclic, bicyclic, spiro, or bridged ring radical containing 1, 2, 3, 4, or 5 heteroatoms or groups of heteroatoms (i.e., groups of heteroatoms) in the ring atoms, including but not limited to nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), S (=o) 2 -、-S(＝O)-、-P(＝O) 2 -P (=o) -, -NH-, -S (=o) (=nh) -, -C (=o) NH-, or-NHC (=o) NH-, etc. The term "4-10 membered heterocyclic group" refers to a heterocyclic group having 4,5, 6, 7, 8, 9 or 10 ring atoms and containing 1,2, 3,4 or 5 heteroatoms or groups of heteroatoms independently selected from those described above. "4-10 membered heterocyclyl" includes "4-8 membered heterocyclyl", wherein specific examples of 4 membered heterocyclyl include, but are not limited to, azetidinyl, thietanyl or oxetanyl; specific examples of 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4, 5-dihydro-oxazolyl, or 2, 5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclyl groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, 4H- [1,3,4]Thiadiazinyl orSpecific examples of 7-membered heterocyclyl groups include, but are not limited to, diazepinyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5 membered bicyclic groups include, but are not limited to, hexahydroCyclopenta [ c ]]Pyrrol-2 (1H) -yl; specific examples of 5,6 membered bicyclo groups include, but are not limited to, hexahydropyrrolo [1,2-a ] ]Pyrazin-2 (1H) -yl, 5,6,7, 8-tetrahydro- [1,2,4]Triazolo [4,3-a ]]Pyrazinyl or 5,6,7, 8-tetrahydroimidazo [1,5-a ]]And pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group of the above 4-8 membered heterocyclic group, specific examples include, but are not limited to, dihydroisoquinolinyl and the like. "4-10 membered heterocyclic group" may include the ranges of "5-10 membered heterocyclic group", "4-8 membered heterocyclic group", "5-6 membered heterocyclic group", "6-8 membered heterocyclic group", "4-10 membered heterocycloalkyl group", "5-10 membered heterocycloalkyl group", "4-8 membered heterocycloalkyl group", "5-6 membered heterocycloalkyl group", "6-8 membered heterocycloalkyl group" and the like, and "4-8 membered heterocyclic group" may further include the ranges of "4-6 membered heterocyclic group", "5-6 membered heterocyclic group", "4-8 membered heterocycloalkyl group", "4-6 membered heterocycloalkyl group", "5-6 membered heterocycloalkyl group" and the like. Although some bicyclic heterocyclic groups in this application contain in part one benzene ring or one heteroaryl ring, the heterocyclic groups as a whole are not aromatic.
The term "aryl" refers to an all-carbon monocyclic or fused-polycyclic aromatic ring radical having a conjugated pi-electron system. The aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. The term "C 6 - 20 Aryl "is understood to mean aryl having 6 to 20 carbon atoms, in particular a ring having 6 carbon atoms (" C 6 Aryl "), such as phenyl; or a ring having 9 carbon atoms ("C) 9 Aryl "), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C) 10 Aryl "), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring having 13 carbon atoms ("C) 13 Aryl "), such as fluorenyl; or a ring having 14 carbon atoms ("C 14 Aryl "), such as anthracenyl. The term "C 6 - 10 Aryl "is understood to mean aryl having 6 to 10 carbon atoms. In particular having 6 carbon atoms ("C) 6 Aryl "), such as phenyl; or a ring having 9 carbon atoms ("C) 9 Aryl "), such as indanyl or indenyl; or having 10 carbon atomsRing (' C) 10 Aryl "), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. The term "C 6 - 20 Aryl "may contain" C 6 - 10 Aryl group).
The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being aromatic ring groups of C. The term "5-10 membered heteroaryl" is understood to include such mono-or bicyclic aromatic ring systems: it has 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it comprises 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and their benzo derivatives, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or the like, and their benzo derivatives, such as quinolinyl, quinazolinyl, or isoquinolinyl, or the like; or an axcinyl group, an indolizinyl group, a purinyl group, etc., and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and which contains 1, 2 or 3, preferably 1-2 heteroatoms independently selected from N, O and S.
The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "hydroxy" refers to an-OH group.
The term "cyano" refers to a-CN group.
The term "amino" refers to-NH 2 A group.
The term "nitro" refers to-NO 2 A group.
The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and disclosure.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable acid or base addition salts, including salts of compounds with inorganic or organic acids, and salts of compounds with inorganic or organic bases.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
The words "comprise" or "include" and variations thereof such as "comprises" or "comprising" are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to.
The application also includes and is not limited toIsotopically-labeled compounds, wherein one or more atoms are replaced by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature, are those recited herein. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as, respectively 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 123 I、 125 I and 36 cl, and the like.
Certain isotopically-labeled compounds of the present application (e.g., with 3 H is H 14 C-tag) can be used in compound and/or substrate tissue distribution analysis. Tritiation (i.e 3 H) And carbon-14 (i.e 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as 15 O、 13 N、 11 C and C 18 F can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or examples below by substituting an isotopically-labeled reagent for an non-isotopically-labeled reagent.
The pharmaceutical compositions of the present application may be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of the compounds of the present application or stereoisomers or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present application may be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulating, emulsifying, lyophilizing, and the like.
In some embodiments of the present application, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, and the like.
The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
In all methods of administration of the compounds of formula (I) described herein, the daily dose is from 0.01mg/kg to 200mg/kg body weight, either alone or in divided doses.
Drawings
FIG. 1 shows a graph of western blot results of skin samples of mice 24h after the end of the last dose of compound II-51 of the present application.
FIG. 2 shows graphs of western blot analysis results of skin samples of mice 24h after the end of the last dose of compound II-51 of the present application.
FIG. 3 shows a graph of the results of western blot analysis of skin samples of mice 24h after the end of the last dose of compound 0XX of the present application.
FIG. 4 shows a graph of the evaluation of hair growth in mice by the compound II-51 of the present application.
FIG. 5 shows a graph of compound II-51 of the present application versus mouse body weight.
FIG. 6 shows a plot of compound 0XX of the present application against mouse hair growth score.
FIG. 7 shows a graph of compound 0XX of the present application versus mouse weight change.
Examples
The following examples illustrate the technical aspects of the present application in detail, but the scope of protection of the present application includes but is not limited thereto.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is Tetramethylsilane (TMS); "IC50" refers to half the inhibitory concentration, and refers to the concentration at which half the maximum inhibitory effect is achieved.
Abbreviations:
DMF: n, N-dimethylformamide; et (Et) 3 N and TEA: triethylamine; THF: tetrahydrofuran; DMSO: dimethyl sulfoxide; TBSCl: t-butyldimethylchlorosilane; THF: tetrahydrofuran; DCM: dichloromethane; EDC: 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride; HOBT: 1-hydroxybenzotriazole; naOBu-t: sodium tert-butoxide; pd (OAc) 2: palladium acetate; p (Bu-t) 3 : tri (t-butyl) phosphorus; EA: ethyl acetate; pd (Pd) 2 (dba) 3 : tris (benzalacetone) dipalladium; BINAP:1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine; dioxane: a dioxane; xantphos:4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene; ethanol: ethanol; acetate one: acetone; naHMDS: sodium bis (trimethylsilyl) amide; IPA; isopropyl alcohol; tolutene: toluene; NMM: n-methylmorpholine; chloroform: chloroform; TFA: trifluoroacetic acid; pdCl 2 (dppf): 1,1' -bis-diphenylphosphino ferrocene palladium dichloride.
Synthesis of intermediate S2:
step 1: synthesis of S1
Thionyl chloride (0.55 mL,7.65 mmol) was slowly added dropwise to a solution of (2R) -3-bromo-2-hydroxy-2-methylpropanoic acid (1 g,5.46 mmol) in anhydrous tetrahydrofuran (20 mL) under nitrogen protection in an ice bath, and reacted for 3 hours. Then, et was added dropwise under ice bath conditions 3 N (1.06 mL,7.65 mmol), stirring for 20min, slowly dropwise adding 4-amino-2- (trifluoromethyl) benzonitrile (762.85 mg,4.10 mmol) anhydrous tetrahydrofuran solution, stirring for 5min, and heating to room temperature for reaction for 16 hr. After completion of the reaction, TLC was monitored with saturated NaHCO 3 The aqueous solution was adjusted to neutral, the aqueous phase was extracted with ethyl acetate (10 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated, and the resulting residue was separated by silica gel column chromatography (dichloromethane: triethylamine=500:1) to give 1.05g of a white solid in a yield of 73.01%. 1 H NMR(300MHz,DMSO-d 6 )δ10.54(s,1H),8.55(d,J＝2.0Hz,1H),8.31(dd,J＝8.6,2.0Hz,1H),8.11(d,J＝8.7Hz,1H),6.42(s,1H),3.83(d,J＝10.4Hz,1H),3.59(d,J＝10.4Hz,1H),1.49(s,3H).MS(ESI)m/z:352.1[M+H] + .
Step 2: synthesis of S2
Into a two-necked flask equipped with a stirrer were added S1 (1 g,2.85 mmol) and anhydrous K 2 CO 3 (787.21 mg,5.70 mmol) and acetone (15 mL) were dissolved and refluxed (60 ℃ C.) under nitrogen for 4 hours. After the reaction was complete as monitored by TLC, cooled to room temperature and filtered through a celite pad. The filtrate was concentrated directly and the resulting residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give 620mg of white solid in 80.57% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.22(s,1H),8.42(d,J＝2.0Hz,1H),8.21(dd,J＝8.6,2.1Hz,1H),8.10(d,J＝8.6Hz,1H),3.08(d,J＝5.2Hz,1H),3.02(d,J＝5.1Hz,1H),1.55(s,3H).LC-MS(ESI)m/z:269[M-H] + .
Synthesis of intermediate S4:
step 1: synthesis of S3
The preparation method was the same as S1 except that 4-amino-2- (trifluoromethyl) benzonitrile was replaced with 5-amino-3- (trifluoromethyl) -2-cyanopyridine (3.83 g,20.49 mmol), and Compound S3 was prepared as a white solid 4.10g in 56.83% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.82(s,1H),9.41(d,J＝2.2Hz,1H),8.91(d,J＝2.3Hz,1H),6.52(s,1H),3.83(d,J＝10.4Hz,1H),3.60(d,J＝10.4Hz,1H),1.50(s,3H).LC-MS(ESI)m/z:351.50[M+H] + .
Step 2: synthesis of S4
The preparation method was the same as S2 except that (R) -3-bromo-N- (4-cyano-3- (trifluoromethyl) phenyl) -2-hydroxy-2-methylpropanamide was replaced with (R) -3-bromo-N- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -2-hydroxy-2-methylpropanamide (1 g,2.85 mmol), and Compound S4 was prepared in the same manner as above to give 620mg of white solid in 80.57%. mp is 76-86 ℃. 1 H NMR(300MHz,DMSO-d 6 )δ10.22(s,1H),8.42(d,J＝2.0Hz,1H),8.21(dd,J＝8.6,2.1Hz,1H),8.10(d,J＝8.6Hz,1H),3.08(d,J＝5.2Hz,1H),3.02(d,J＝5.1Hz,1H),1.55(s,3H).LC-MS(ESI)m/z:270.80[M-H] + .
Synthesis of intermediate S5
To a two-necked flask equipped with a stirrer were added 4-bromophenylboric acid (2.13 g,10.60 mmol), nickel iodide (132.46 mg,0.42 mmol), (1R, 2R) -2-aminocyclohexanol hydrochloride (64.27 mg,0.42 mmol) and sodium bis (trimethylsilyl) amide (7.06 mL,28.26 mmol), 30mL of anhydrous isopropanol under nitrogen protection, stirred at room temperature for 10 minutes, sonicated for 1 minute, and 1-t-butoxycarbonyl-3-iodoazetidine (1.23 mL,7.06 mmol) was added, and refluxed (80 ℃) for 12 hours. After the completion of the TLC monitoring reaction, the reaction was cooled to room temperature and saturatedAnd aqueous ammonium chloride, extracted with ethyl acetate (15 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated, and the resulting residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate=100:1) to give 1.60g of a white solid in 72.54% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.59–7.51(m,2H),7.37–7.27(m,2H),4.26(d,J＝10.8Hz,2H),3.79(q,J＝5.2Hz,3H),1.40(s,9H).LC-MS(ESI)m/z:310.20[M-H] + .
Synthesis of intermediate S6
Referring to the synthesis of intermediate S5, except that the 4-bromophenylboronic acid in the step was replaced with 2-bromopyridine-5-boronic acid, compound S6 was prepared in the same manner as 0.7g of a pale yellow solid with a yield of 63.28%. 1 H NMR(300MHz,DMSO-d 6 )δ8.37(d,J＝2.6Hz,1H),7.91–7.77(m,1H),7.66(dd,J＝8.3,1.4Hz,1H),4.25(d,J＝9.0Hz,2H),3.88(q,J＝5.1,4.5Hz,3H),1.42(d,J＝1.0Hz,9H).LC-MS(ESI)m/z:313.00[M+H] + .
Synthesis of intermediate S7:
referring to the synthesis of intermediate S5, except that the 4-bromophenylboronic acid in the step was replaced with 3-bromophenylboronic acid, compound S7 was prepared in the same manner as above, to give 150mg of yellow oil in 68.01% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.54(t,J＝1.8Hz,1H),7.46(dt,J＝7.3,1.8Hz,1H),7.40–7.29(m,2H),4.22(d,J＝7.6Hz,2H),3.83(dt,J＝10.6,3.8Hz,3H),1.40(s,9H).LC-MS(ESI)m/z:312.30[M+H] + .
Synthesis of intermediate S9
Step 1: synthesis of S8
The preparation method is the same as S1, except that 4-amino-2- (trifluoromethyl) benzonitrile is replaced by 4-nitro-3-trifluoromethylaniline (4.22 g,20.49 mmol), and compound S8 is prepared as a yellow solid in an amount of 7g and a yield of 69.04%. 1 H NMR(300MHz,Chloroform-d)δ9.09(s,1H),8.20–7.99(m,3H),4.08(dd,J＝10.5,1.3Hz,1H),3.65(dd,J＝10.5,1.2Hz,1H),1.70(s,3H).LC-MS(ESI)m/z:370.85[M+H] + .
Step 2: synthesis of S9
The preparation method was the same as S2 except that (R) -3-bromo-N- (4-cyano-3- (trifluoromethyl) phenyl) -2-hydroxy-2-methylpropanamide was replaced with (R) -3-bromo-2-hydroxy-2-methyl-N- (4-nitro-3- (trifluoromethyl) phenyl) propanamide (3.5 g,9.43 mmol), and Compound S9 was obtained in the same manner as above to give 1.82g of pale yellow solid in 66.50% yield. 1 H NMR(300MHz,Chloroform-d)δ8.50(s,1H),8.03(d,J＝9.9Hz,3H),3.06(s,2H),1.73(s,3H).LC-MS(ESI)m/z:291.10[M+H] + .
Synthesis of intermediate S11
Step 1: synthesis of S10
The preparation method was the same as S1 except that 4-amino-2- (trifluoromethyl) benzonitrile was replaced with 4-amino-2-methoxybenzonitrile (546.51 mg,3.69 mmol), and compound S10 was prepared as a yellow oil, 270mg, in 17.53% yield. 1 H NMR(300MHz,Chloroform-d)δ8.91(s,1H),7.75(d,J＝1.9Hz,1H),7.52(d,J＝8.4Hz,1H),6.96(dd,J＝8.4,1.9Hz,1H),4.13(d,J＝11.2Hz,1H),3.97(s,3H),3.71(d,J＝11.2Hz,1H),3.30(t,J＝3.9Hz,1H),1.61(s,3H).LC-MS(ESI)m/z:313.00[M+H] + .
Step 2: synthesis of S11
The preparation was the same as S2 except that (R) -3-bromo-N- (4-cyano-3- (trifluoromethyl) phenyl) -2-hydroxy-2-methylpropanamide was replaced with (R) -3-bromo-N- (4-cyano-3-methoxyphenyl) -2-hydroxy-2-methylpropanamide (3.5 g,9.43 mmol), and Compound S11 was obtained as a pale yellow solid in an amount of 1.82g and a yield of 66.50%. 1 H NMR(300MHz,Chloroform-d)δ8.50(s,1H),8.03(d,J＝9.9Hz,3H),3.85(s,3H),3.06(d,J＝3.8Hz,2H),1.73(s,3H).LC-MS(ESI)m/z:233.10[M+H] + .
Synthesis of intermediate S13
Step 1: synthesis of S12
The preparation method was the same as S1 except that 4-amino-2- (trifluoromethyl) benzonitrile was replaced with 4-amino-3-fluoro-2-methoxybenzonitrile (194 mg,3.69 mmol), and Compound S12 was prepared as a pale yellow solid, 141mg, with a yield of 27.14%. 1 H NMR(300MHz,Chloroform-d)δ9.14(s,1H),8.23(dd,J＝8.8,6.7Hz,1H),7.37(dd,J＝8.7,2.0Hz,1H),4.16(d,J＝2.8Hz,3H),4.05(d,J＝10.5Hz,1H),3.62(d,J＝10.5Hz,1H),1.66(s,3H).LC-MS(ESI)m/z:331.10[M+H] + .
Step 2: synthesis of S13
The preparation method was the same as S2 except that (R) -3-bromo-N- (4-cyano-3- (trifluoromethyl) phenyl) -2-hydroxy-2-methylpropanamide was replaced with (R) -3-bromo-N- (4-cyano-2-fluoro-3-methoxyphenyl) -2-hydroxy-2-methylpropanamide (500 mg,1.51 mmol), and Compound S13 was prepared as a pale yellow solid in 200mg and a yield of 52.93%. 1 H NMR(300MHz,Chloroform-d)δ8.52(s,1H),8.17(dd,J＝8.7,6.7Hz,1H),7.34(dd,J＝8.8,2.0Hz,1H),4.13(d,J＝2.7Hz,3H),3.03(d,J＝4.8Hz,1H),3.00(d,J＝4.8Hz,1H),1.69(s,3H).LC-MS(ESI)m/z:251.10[M+H] + .
Synthesis of intermediate S15
Step 1: synthesis of S14
The preparation method was the same as S1 except that 4-amino-2- (trifluoromethyl) benzonitrile was replaced with 4-amino-2-chlorobenzonitrile (2.5 g,16.38 mmol), and Compound S14 was prepared as a pale yellow solid, 4.1g, with a yield of 78.80%. 1 H NMR(300MHz,DMSO-d6)δ10.34(s,1H),8.26(d,J＝1.9Hz,1H),8.11–7.81(m,2H),6.40(s,1H),3.82(d,J＝10.4Hz,1H),3.57(d,J＝10.4Hz,1H),1.47(s,3H).LC-MS(ESI)m/z:318.20[M+H] + .
Step 2: synthesis of S15
The preparation was the same as S2 except that (R) -3-bromo-N- (4-cyano-3- (trifluoromethyl) phenyl) -2-hydroxy-2-methylpropanamide was replaced with (R) -3-bromo-N- (3-chloro-4-cyanophenyl) -2-hydroxy-2-methylpropanamide (1.2 g,3.78 mmol), and Compound S15 was prepared as a white solid, 440mg in 49.20% yield. 1 H NMR(300MHz,DMSO-d6)δ10.05(s,1H),8.14(d,J＝1.8Hz,1H),7.97–7.79(m,2H),3.06(d,J＝5.2Hz,1H),3.01(d,J＝5.1Hz,1H),1.54(s,3H).LC-MS(ESI)m/z:237.50[M+H] + .
Synthesis of intermediate S17
Step 1: synthesis of S16
The preparation method was the same as S1 except that 4-amino-2- (trifluoromethyl) benzonitrile was replaced with 5-amino-3-chloro-2-pyridinecarbonitrile (630 mg,4.10 mmol), and Compound S16 was prepared as a pale yellow solid, 1.2g, with a yield of 91.92%. 1 H NMR(300MHz,DMSO-d6)δ10.65(s,1H),9.10(d,J＝2.1Hz,1H),8.66(d,J＝2.1Hz,1H),6.49(s,1H),3.82(d,J＝10.4Hz,1H),3.58(d,J＝10.3Hz,1H),1.49(s,3H).LC-MS(ESI)m/z:317.90[M+H] + .
Step 2: synthesis of S17
The preparation was the same as S2 except that (R) -3-bromo-N- (4-cyano-3- (trifluoromethyl) phenyl) -2-hydroxy-2-methylpropanamide was replaced with (R) -3-bromo-N- (5-chloro-6-cyanopyridin-3-yl) -2-hydroxy-2-methylpropanamide (600 mg,1.88 mmol), and compound S17 was prepared as a white solid at 160mg with a yield of 35.75%. 1 H NMR(300MHz,DMSO-d6)δ10.31 (s,1H),8.97(d,J＝2.1Hz,1H),8.54(d,J＝2.0Hz,1H),3.18–2.95(m,2H),1.55(s,3H).LC-MS(ESI)m/z:238.10[M+H] + .
Example 1
Step 1: synthesis of I-1-1
In a two-necked flask equipped with a stirrer were placed 4-fluoro-1H-pyrazole (200 mg,2.32 mmol), 1-t-butoxycarbonyl-3-iodoazetidine (484.32. Mu.L, 2.79 mmol) and anhydrous K 2 CO 3 (642.29 mg,4.65 mmol) in DMF (N, N-dimethylformamide, 6 mL) was dissolved, nitrogen protected and reacted at 60℃for 16 hours. After TLC monitored completion of the reaction, cooled to room temperature, quenched with water, extracted with DCM (5 ml×3), the combined organic phases dried over anhydrous sodium sulfate, filtered, and the concentrated organic phase was separated by column chromatography on silica gel (petroleum ether: ethyl acetate=10:1) to give 320mg of colorless oil in 57.08% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.07(dd,J＝4.5,0.8Hz,1H),7.61(dd,J＝4.3,0.8Hz,1H),5.15-5.06(m,1H),4.26(t,J＝8.5Hz,2H),4.09(t,J＝7.3Hz,2H),1.40(s,9H).LC-MS(ESI)m/z:264.10[M+Na] + .
Step 2: synthesis of I-1-2
Tert-butyl 3- (4-fluoro-1H-pyrazol-1-yl) azetidine-1-carboxylate (I-1-1) (200 mg,2.79 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of the TLC monitoring reaction for 1H at room temperature, DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 90mg of a colorless oil in 53.05% yield.
Step 3: synthesis of I-1
I-1-2 (90 mg,0.64 mmol) and S2 (172.30 mg,0.64 mmol) were dissolved in 3mL of anhydrous ethanol and refluxed for 4h, after completion of the TLC monitoring reaction, the residue was evaporated to dryness under reduced pressure and the obtained residue was separated by silica gel column chromatography (dichloromethane: methanol=100:1) to give 110mg of white solid in a yield of 41.94%. 1 H NMR(300MHz,DMSO-d 6 )δ10.47(s,1H),8.57(d,J＝2.1Hz,1H),8.34(dd,J＝8.6,2.1Hz,1H),8.12(d,J＝8.6Hz,1H),7.98(dd,J＝4.6,0.9Hz,1H),7.53(dd,J＝4.3,0.8Hz,1H),5.77(s,1H),4.85(tt,J＝7.9,5.3Hz,1H),3.82(t,J＝7.3Hz,1H),3.66(q,J＝7.3Hz,1H),3.46(t,J＝7.0Hz,2H),2.92(d,J＝12.4Hz,1H),2.63(d,J＝12.4Hz,1H),1.34(s,3H).LC-MS(ESI)m/z:412.15[M+H] + .
Example 2
Step 1: synthesis of I-2-1
Referring to the synthesis of intermediate S5, except that 4-bromophenylboronic acid in the step was replaced with 4-fluorobenzeneboronic acid, compound I-2-1 was prepared in the same manner to give 100mg of colorless oil with a yield of 37.55%. 1 H NMR(300MHz,DMSO-d 6 )δ7.46–7.34(m,2H),7.25–7.10(m,2H),4.27(q,J＝9.3,7.9Hz,2H),3.83(q,J＝4.7Hz,3H),1.43(s,9H).LC-MS(ESI)m/z:250.10[M-H] + .
Step 2: synthesis of I-2-2
I-2-1 (200 mg,0.80 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 85mg of a colorless oil with a 70.64% yield.
Step 3: synthesis of I-2
Reference example 1 the synthetic method of step 3, except that I-1-2 in step 3 was replaced with I-2-2, compound I-2 was prepared in the same manner,62mg of white solid was obtained in 39.76% yield. 1 H NMR(300MHz,DMSO-d 6 )δ10.46(s,1H),8.56(s,1H),8.32(d,J＝8.6Hz,1H),8.11(d,J＝8.7Hz,1H),7.34(t,J＝6.7Hz,2H),7.04(t,J＝8.7Hz,2H),5.70(s,1H),3.70(t,J＝7.0Hz,1H),3.57(dt,J＝13.5,7.3,6.8Hz,2H),3.15(dt,J＝19.7,6.3Hz,2H),2.84(d,J＝12.4Hz,1H),2.59(d,J＝12.4Hz,1H),1.32(s,3H).LC-MS(ESI)m/z:422[M+H] + .
Example 3
Step 1: synthesis of I-3-1
Referring to the synthesis of intermediate S5, except that 4-bromophenylboronic acid in the step was replaced with 4-cyanobenzeneboronic acid, compound I-3-1 was prepared in the same manner to give 270mg of a white solid with a yield of 59.18%. 1 H NMR(300MHz,DMSO-d 6 )δ7.83(d,J＝8.2Hz,2H),7.56(d,J＝8.3Hz,2H),4.26(t,J＝7.9Hz,2H),3.92(dt,J＝8.0,5.8Hz,1H),3.85(d,J＝7.7Hz,2H),1.40(s,9H).LC-MS(ESI)m/z:259.65[M+H] + .
Synthesis of step 2:I-3-2
I-3-1 (200 mg,0.77 mmol) was dissolved in DCM (2 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 120mg of a white solid in 65.31% yield.
Synthesis of step 3:I-3
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with I-3-2, compound I-3 was prepared in the same manner as 110mg of a white solid with a yield of 40.62%. 1 H NMR(300MHz,DMSO-d 6 )δ10.44(s,1H),8.54(s,1H),8.32(d,J＝8.4Hz,1H),8.10(d,J＝8.6Hz,1H),7.67(d,J＝7.9Hz,2H),7.51(d,J＝8.0Hz,2H),5.73(s,1H),3.83–3.68(m,1H),3.67–3.53(m,2H),3.30–3.09(m,2H),2.84(d,J＝12.4Hz,1H),2.57(d,J＝12.4Hz,1H),1.32(s,3H).LC-MS(ESI)m/z:429.10[M+H] + .
Example 4
Step 1: synthesis of II-11-1
In a round bottom flask, 2-cyano-5-fluoropyridine (200 mg,1.64 mmol), 1- (tert-butoxycarbonyl) piperazine (457 mg,2.46 mmol) and K were added sequentially 2 CO 3 (452 mg,3.28 mmol). Then 6mL of DMF was added and the reaction was carried out at 80℃for 4 hours. After the completion of the TLC monitoring reaction, the reaction was cooled to room temperature, 20mL of water was added, and the solid was precipitated by stirring, and was suction-filtered under reduced pressure to obtain 400mg of a white solid, with a yield of 84.69%. 1 H NMR(300MHz,Chloroform-d)δ8.32(d,J＝2.9Hz,1H),7.55(dd,J＝8.8,0.6Hz,1H),7.11(dd,J＝8.8,3.0Hz,1H),3.63(dd,J＝6.5,4.1Hz,4H),3.38(dd,J＝6.5,4.2Hz,4H),1.50(s,9H).LC-MS(ESI)m/z:289.10[M+H] + .
Step 2: synthesis of II-11-2
II-11-1 (250 mg,0.87 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 110mg of a yellow solid in 67.40% yield.
Step 3: synthesis of II-11
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-11-2, compound II-11 was produced in the same manner as in 140mg of pale yellow solid with a yield of 57.48%. mp 92-94℃1H NMR (300 MHz, chloroform-d) delta 9.39 (s, 1H), 8.25 (d, J=2.9 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H), 7.97 (dd, J=8.5, 2.2Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.07 (dd, J=8.8, 3.0Hz, 1H), 4.93 (s, 1H), 3.40 (s, 1H), 3.36 (t, J=5.1 Hz, 4H), 2.76 (q, J=5.4 Hz, 4H), 2.54 (d, J=13.3 Hz, 1H), 1.47 (s, 3H), LC-MS (ESI) m/z 459.10H] + .
Example 5
Step 1: synthesis of II-14-1
With reference to the synthetic method of step 1 of example 4, except that 2-cyano-5-fluoropyridine in step 1 was replaced with 4-fluoro-2- (trifluoromethyl) benzonitrile, compound II-14-1 was produced in the same manner to obtain 850mg of a white solid in 90.47% yield. 1 H NMR(300MHz,Chloroform-d)δ7.66(dd,J＝8.7,0.8Hz,1H),7.13(d,J＝2.6Hz,1H),6.98(dd,J＝8.8,2.6Hz,1H),3.63(dd,J＝6.6,4.0Hz,4H),3.41(dd,J＝6.5,4.1Hz,4H),1.51(s,9H).LC-MS(ESI)m/z:354.30[M-H] + .
Step 2 Synthesis of II-14-2
II-14-1 (300 mg,0.84 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 200mg of a pale yellow solid in 92.82% yield.
Step 2 Synthesis of II-14
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-14-2, compound II-14 was produced in the same manner as in 120mg of a white solid with a yield of 58.29%. 1 H NMR(300MHz,Chloroform-d)δ9.36(s,1H),8.15(d,J＝2.1Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.83(d,J＝8.5Hz,1H),7.63(d,J＝8.7Hz,1H),7.11(d,J＝2.6Hz,1H),6.95(dd,J＝8.8,2.6Hz,1H),4.94(s,1H),3.38(d,J＝6.2Hz,5H),2.76(s,4H),2.55(d,J＝13.2Hz,1H),1.48(s,3H).LC-MS(ESI)m/z:526.10[M+H] + .
Example 6
Step 1: synthesis of II-15-1
With reference to the synthetic method of step 1 of example 4, except that 2-cyano-5-fluoropyridine in step 1 was replaced with 2-cyano-3, 5-difluoropyridine, compound II-15-1 was produced in the same manner to obtain 320mg of a white solid in 73.17% yield. 1 H NMR(300MHz,Chloroform-d)δ8.14(dd,J＝2.5,1.5Hz,1H),6.82(dd,J＝11.8,2.5Hz,1H),3.64(dd,J＝6.6,4.0 Hz,4H),3.48–3.36(m,4H),1.51(s,9H).LC-MS(ESI)m/z:307.10[M+H] + .
Step 2: synthesis of II-15-2
II-15-1 (220 mg,0.72 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 110mg of a yellow solid in 74.27% yield.
Step 3: synthesis of II-15
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-15-2, compound II-15 was produced in the same manner as in 120mg of a white solid with a yield of 47.22%. 1 H NMR(300MHz,Chloroform-d)δ9.36(s,1H),8.17(d,J＝2.1Hz,1H),8.12(d,J＝1.9Hz,1H),7.99(dd,J＝8.5,2.1Hz,1H),7.85(d,J＝8.5Hz,1H),6.81(dd,J＝11.8,2.4Hz,1H),4.83(s,1H),3.52–3.32(m,5H),2.80(d,J＝5.9Hz,4H),2.57(d,J＝13.3Hz,1H),1.50(s,3H).MS(ESI)m/z:477.7[M+H] + .
Example 7
Step 1: synthesis of II-19-1
With reference to the synthetic method of step 1 of example 4, except that 2-cyano-5-fluoropyridine in step 1 was replaced with 5-bromo-2-nitrobenzotrifluoride, compound II-19-1 was produced in the same manner, 314mg of a white solid was obtained, and the yield was 75.68%. 1 H NMR(300MHz,Chloroform-d)δ8.05(d,J＝9.1Hz,1H),7.16(d,J＝2.8Hz,1H),6.95(dd,J＝9.2,2.8Hz,1H),3.64(dd,J＝6.6,4.0Hz,4H),3.48–3.43(m,5H),1.45(s,9H).LC-MS(ESI)m/z:376.75[M+H] + .
Step 2: synthesis of II-19-2
II-19-1 (314 mg,0.84 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 162mg of a white solid in 70.07% yield.
Step 3: synthesis of II-19
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-19-2, compound II-19 was produced in the same manner as in example 1, 132mg of a white solid was produced in a yield of 41.02%. 1 H NMR(300MHz,Chloroform-d)δ9.38(s,1H),8.17(d,J＝2.1Hz,1H),8.08–7.96(m,2H),7.86(d,J＝8.5Hz,1H),7.17(d,J＝2.7Hz,1H),6.96(dd,J＝9.2,2.8Hz,1H),3.46(d,J＝5.6Hz,4H),3.40(s,1H),2.80(d,J＝7.0Hz,4H),2.58(d,J＝13.3Hz,1H),1.51(s,3H).LC-MS(ESI)m/z:546.10[M+H] + .
Example 8
Step 1: synthesis of II-20-1
With reference to the synthetic method of step 1 of example 4, except that 2-cyano-5-fluoropyridine in step 1 was replaced with 3-cyano-6-chloropyridazine, compound II-20-1 was produced in the same manner to obtain 438mg of a white solid in 94.02% yield. 1 H NMR(300MHz,Chloroform-d)δ7.49(d,J＝9.6Hz,1H),6.87(d,J＝9.6Hz,1H),3.82(s,4H),3.66–3.57(m,4H),1.51(s,9H).LC-MS(ESI)m/z:290.10[M-H] + .
Step 2: synthesis of II-20-2
II-20-1 (303 mg,1.05 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 158mg of a white solid in 79.52% yield.
Step 3: synthesis of II-20
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-20-2, compound II-20 was prepared in the same manner as in 179mg of a white solid with a yield of 44.45%. 1 H NMR(300MHz,Chloroform-d)δ9.37(s,1H),8.14(d,J＝2.1Hz,1H),7.98(dd,J＝8.5,2.2Hz,1H),7.83(d,J＝8.5Hz,1H),7.47(d,J＝9.6Hz,1H),6.83(d,J＝9.6Hz,1H),4.92(s,1H),3.91–3.67(m,4H),3.38(d,J＝13.3Hz,1H),2.76(d,J＝6.9Hz,4H),2.55(d,J＝13.3Hz,1H),1.48(s,3H).LC-MS(ESI)m/z:458.10[M-H] + .
Example 9
Step 1: synthesis of II-22-1
With reference to the synthetic method of step 1 of example 4, except that 2-cyano-5-fluoropyridine in step 1 was replaced with p-fluorobenzenesulfone, compound II-22-1 was produced in the same manner to obtain 406mg of a white solid in 41.55% yield. 1 H NMR(300MHz,Chloroform-d)δ7.87–7.74(m,2H),7.00–6.87(m,2H),3.60(dd,J＝6.6,4.0Hz,4H),3.36(dd,J＝6.5,4.0Hz,4H),3.03(s,3H),1.50(s,9H).LC-MS(ESI)m/z:289.10[M+H] + .
Step 2: synthesis of II-22-2
II-22-1 (250 mg,0.73 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 100mg of a white solid with a yield of 56.66%.
Step 3: synthesis of II-22
Reference example 1 the synthesis of step 3 was followed except that I-1-2 in step 3 was replaced with II-22-2, and Compound II-22 was prepared in the same manner as 100mg of a white solid with a yield of 47.07％。 1 H NMR(300MHz,Chloroform-d)δ9.43(s,1H),8.16(d,J＝2.1Hz,1H),7.99(dd,J＝8.5,2.2Hz,1H),7.82(d,J＝8.5Hz,1H),7.79–7.70(m,2H),6.95–6.82(m,2H),5.06(s,1H),3.42–3.20(m,5H),3.02(s,3H),2.74(s,4H),2.54(d,J＝13.2Hz,1H),1.47(s,3H).LC-MS(ESI)m/z:459.10[M+H] + .
Example 10
Step 1: synthesis of II-23-1
Reference example 4 the synthesis of step 1 was followed, except that 2-cyano-5-fluoropyridine in step 1 was replaced with 5-bromo-3- (trifluoromethyl) -2-cyanopyridine, and compound II-23-1 was produced in the same manner to give 400mg of solid in 93.92%. 1 H NMR(300MHz,Chloroform-d)δ8.45(d,J＝2.8Hz,1H),7.32(d,J＝2.7Hz,1H),3.69(dd,J＝6.6,4.1Hz,4H),3.51(dd,J＝6.6,4.0Hz,4H),1.54(s,9H).LC-MS(ESI)m/z:357.10[M+H] + .
Step 2: synthesis of II-23-2
II-23-1 (300 mg,0.84 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to afford 185mg of a yellow solid in 85.76% yield.
Step 3: synthesis of II-23
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-23-2, compound II-23 was produced in the same manner as in 130mg of a white solid with a yield of 63.27%. 1 H NMR(300MHz,Chloroform-d)δ9.35(s,1H),8.36(d,J＝2.8Hz,1H),8.15(d,J＝2.1Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.82(d,J＝8.5Hz,1H),7.26(d,J＝2.8Hz,1H),4.79(s,1H),3.46(t,J＝5.3Hz,4H),3.38(s,1H),2.79(q,J＝5.7Hz,4H),2.56(d,J＝13.4Hz,1H),1.48(s,3H).LC-MS(ESI)m/z:527.10[M+H] + .
Example 11
Step 1: synthesis of II-24-1
In a round bottom flask, p-fluorobenzonitrile (500 mg,4.13 mmol), t-butyl 1, 4-diazacycloheptane-1-carboxylate (1.22 mL,2.46 mmol) and K were added sequentially 2 CO 3 (1.14 g,8.26 mmol). Then 6mL of DMF was added and the reaction was carried out at 80℃for 4 hours. After completion of the reaction by TLC, it was cooled to room temperature, 20mL of water was added, extracted with ethyl acetate (10 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated, and the resulting residue was separated by silica gel column chromatography (dichloromethane: triethylamine=500:1) to give 600mg of a white solid in 48.22% yield. 1 H NMR(300MHz,Chloroform-d)δ7.87–7.74(m,2H),7.00–6.87(m,2H),3.60(dd,J＝6.6,4.0Hz,4H),3.36(dd,J＝6.5,4.0Hz,4H),3.03(s,2H),1.50(s,9H).LC-MS(ESI)m/z:302.10[M+H] + .
Step 2: synthesis of II-24-2
II-24-1 (300 mg,1.00 mmol) was dissolved in DCM (3 mL), TFA 1mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of the TLC monitoring reaction for 1h at room temperature, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 160mg of a white solid with a yield of 79.86%.
Step 3: synthesis of II-24
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-24-2, compound II-24 was produced in the same manner as in 115mg of a white solid with a yield of 50.60%. 1 H NMR(300MHz,Chloroform-d)δ9.24(s,1H),8.13(d,J＝2.0Hz,1H),7.91(dd,J＝8.5,2.2Hz,1H),7.83(d,J＝8.5Hz,1H),7.54–7.42(m,2H),6.72–6.60(m,2H),4.91(s,1H),3.65(d,J＝16.5Hz,1H),3.61–3.41(m,4H),2.94(s,2H),2.79(s,2H),2.48(d,J＝13.7Hz,1H),1.91(s,2H),1.40(s,3H).MS(ESI)m/z:471.9[M+H] + .
Example 12
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with 4-piperazinylbenzonitrile, compound II-1 was prepared in the same manner as the compound II-1, 120mg of a white solid was obtained in a yield of 70.88%. 1 H NMR(300MHz,DMSO-d 6 )δ10.48(s,1H),8.53(d,J＝2.0Hz,1H),8.29(dd,J＝8.6,2.1Hz,1H),8.09(d,J＝8.6Hz,1H),7.54(d,J＝8.6Hz,2H),6.96(d,J＝8.6Hz,2H),5.79(s,1H),3.31–3.13(m,4H),2.86–2.66(m,3H),2.63–2.51(m,3H),1.34(s,3H).LC-MS(ESI)m/z:458.10[M+H] + .
Example 13
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with 1- (4-fluorophenyl) piperazine, compound II-2 was prepared in the same manner as a white solid 120mg in a yield of 48.01%. 1 H NMR(300MHz,DMSO-d 6 )δ10.48(s,1H),8.53(d,J＝2.0Hz,1H),8.28(dd,J＝8.6,2.0Hz,1H),8.09(d,J＝8.6Hz,1H),7.00(t,J＝8.9Hz,2H),6.94–6.79(m,2H),5.75(s,1H),3.04–2.89(m,4H),2.76(td,J＝11.8,10.3,6.6Hz,3H),2.63–2.52(m,3H),1.34(s,3H).LC-MS(ESI)m/z:451.10[M+H] + .
Example 14
Reference example 1 Synthesis method of step 3 except that I-1-2 in step 3 was replaced with 1- (3-cyanophenyl) piperazine, compound II-4 was prepared in the same manner as the compound II-4, 238mg as a white solid with a yield of48.62％。 1 H NMR(400MHz,Chloroform-d)δ9.40(s,1H),8.14(d,J＝2.1Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.83(d,J＝8.4Hz,1H),7.37–7.29(m,1H),7.16–7.05(m,3H),5.10(s,1H),3.37(d,J＝13.2Hz,1H),3.21(q,J＝4.4,3.2Hz,4H),2.76(tq,J＝11.8,6.7,5.6Hz,4H),2.54(d,J＝13.2Hz,1H),1.47(s,3H).LC-MS(ESI)m/z:458.20[M+H] + .
Example 15
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with 1- (2-benzonitrile) piperazine, compound II-6 was prepared in the same manner as a white solid 100mg in a yield of 40.93%. 1 H NMR(300MHz,Chloroform-d)δ9.40(s,1H),8.10(d,J＝2.1Hz,1H),8.01(dd,J＝8.5,2.2Hz,1H),7.83(d,J＝8.5Hz,1H),7.58(dd,J＝7.6,1.6Hz,1H),7.50(ddd,J＝8.3,7.5,1.7Hz,1H),7.05(td,J＝7.6,1.0Hz,1H),6.98(dd,J＝8.4,1.0Hz,1H),5.22(s,1H),3.40(d,J＝13.2Hz,1H),3.23(t,J＝4.9Hz,4H),2.81(s,4H),2.55(d,J＝13.3Hz,1H),1.47(s,3H).LC-MS(ESI)m/z:458.10[M+H] + .
Example 16
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with 1- (4-pyridyl) piperazine, compound II-9 was prepared in the same manner as a pale yellow solid 120mg, with a yield of 45.19%. 1 H NMR(300MHz,DMSO-d 6 )δ10.47(s,1H),8.53(d,J＝2.0Hz,1H),8.28(dd,J＝8.6,2.0Hz,1H),8.10(t,J＝7.8Hz,3H),6.93–6.59(m,2H),5.80(s,1H),3.20(dt,J＝6.7,3.5Hz,4H),2.78(d,J＝13.6Hz,1H),2.75–2.63(m,2H),2.55(d,J＝5.5Hz,3H),1.34(s,3H).LC-MS(ESI)m/z:434.10[M+H] + .
Example 17
Referring to the synthesis of example 1, step 3, except that I-1-2 in step 3 was replaced with 1- (4-trifluoromethylphenyl) piperazine, compound II-10 was prepared in the same manner as the compound II-10, 150mg of a white solid was obtained in a yield of 69.01%. 1 H NMR(300MHz,Chloroform-d)δ9.40(s,1H),8.14(d,J＝2.1Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.83(d,J＝8.5Hz,1H),7.49(d,J＝8.6Hz,2H),6.90(d,J＝8.7Hz,2H),5.16(s,1H),3.37(d,J＝13.2Hz,1H),3.33–3.12(m,4H),2.75(q,J＝5.4Hz,4H),2.54(d,J＝13.2Hz,1H),1.47(s,3H).LC-MS(ESI)m/z:501.10[M+H] + .
Example 18
Referring to the synthesis of example 1, step 3, except that I-1-2 in step 3 was replaced with 1- (4-nitrophenyl) piperazine, compound II-12 was prepared in the same manner as a yellow solid, 150mg, with a yield of 54.26%. 1 H NMR(300MHz,Chloroform-d)δ8.15(d,J＝2.1Hz,1H),8.14–8.07(m,2H),7.98(dd,J＝8.5,2.2Hz,1H),7.83(d,J＝8.5Hz,1H),6.86–6.76(m,2H),5.01(s,1H),3.39(d,J＝5.9Hz,4H),3.36(s,1H),2.87–2.63(m,4H),2.54(d,J＝13.3Hz,1H),1.48(s,3H).LC-MS(ESI)m/z:478.15[M+H] + .
Example 19
Reference example 1 the synthetic procedure of step 3 was followed, except that I-1-2 in step 3 was replaced with 5- (piperazin-1-yl) pyrimidine, and Compound II-13 was prepared in the same manner as the above, 80mg of a white solid was obtained in a yield of 30.24％。 1 H NMR(300MHz,Chloroform-d)δ9.38(s,1H),8.73(s,1H),8.35(s,2H),8.14(d,J＝2.1Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.83(d,J＝8.5Hz,1H),5.01(s,1H),3.39(d,J＝13.3Hz,1H),3.32–3.14(m,4H),2.77(q,J＝5.1Hz,4H),2.53(d,J＝13.3Hz,1H),1.47(s,3H).LC-MS(ESI)m/z:435.55[M+H] + .
Example 20
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with 1- (4-methoxyphenyl) piperazine, compound II-16 was produced in the same manner as a pale yellow solid 120mg, with a yield of 49.89%. 1 H NMR(300MHz,Chloroform-d)δ9.46(s,1H),8.16(d,J＝2.5Hz,1H),8.00(dd,J＝8.3,2.1Hz,1H),7.85(d,J＝8.5Hz,1H),6.98–6.81(m,4H),3.81(s,3H),3.38(d,J＝13.2Hz,1H),3.10(d,J＝5.1Hz,4H),2.87–2.69(m,4H),2.56(d,J＝13.2Hz,1H),1.49(s,3H).LC-MS(ESI)m/z:463.10[M+H] + .
Example 21
1- (4-cyanophenyl) piperazine (100 mg,0.53 mmol) and S4 (144.31 mg,0.53 mmol) were dissolved in 4mL absolute ethanol and refluxed for 4h, after completion of the TLC monitoring the reaction, the residue was evaporated to dryness under reduced pressure and the resulting residue was separated by silica gel column chromatography (dichloromethane: methanol=100:1) to give 110mg as yellow solid in 44.93% yield. 1 H NMR(300MHz,Chloroform-d)δ9.54(s,1H),8.93(d,J＝2.4Hz,1H),8.84(d,J＝2.3Hz,1H),7.53(d,J＝8.8Hz,2H),6.86(d,J＝8.7Hz,2H),3.43–3.28(m,5H),2.77(t,J＝5.1Hz,4H),2.59(d,J＝13.3Hz,1H),1.51(s,3H).LC-MS(ESI)m/z:459.10[M+H] + .
Example 22
Step 1: synthesis of II-3-1
In a two-necked flask, 4-bromobenzonitrile (187.77 mg,1.03 mmol), (S) -1-N-t-butoxycarbonyl-2-methylpiperazine (300 mg,1.50 mmol), naOBu-t (191.93 mg,2.00 mmol), pd were added sequentially 2 (dba) 3 (91.44 mg,0.1 mmol) and BINAP (124.36 mg,0.2 mmol). 4mL of redistilled toluene was added and the reaction was carried out at 80℃under nitrogen protection for 12 hours. After TLC monitored completion of the reaction, cooled to room temperature, quenched with water, extracted with ethyl acetate (5 ml×3), combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate=10:1) to give 264mg of a white solid in 85.04% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.64–7.53(m,2H),7.02–6.92(m,2H),4.16(dt,J＝6.9,3.4Hz,1H),3.74(ddd,J＝16.3,12.5,2.8Hz,3H),3.26–3.12(m,2H),2.93(ddt,J＝11.5,8.0,3.3Hz,1H),1.42(s,9H),1.11(d,J＝6.6Hz,3H).LC-MS(ESI)m/z:300.45[M-H] + .
Step 2: II-3-2 synthesis:
II-3-1 (200 mg,0.66 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 127mg of a white solid in 95.61% yield.
Step 3: II-3 synthesis:
with reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-3-2, compound II-3 was prepared in the same manner as in 122.28mg of a white solid with a yield of 41.17%. 1 H NMR(300MHz,DMSO-d 6 )δ10.49(s,1H),8.53(d,J＝2.0Hz,1H),8.28(dd,J＝8.7,2.0Hz,1H),8.10(d,J＝8.6Hz,1H),7.62–7.50(m,2H),7.07–6.92(m,2H),5.64(s,1H),3.41(dd,J＝12.8,3.2Hz,2H),3.21–3.02(m,1H),2.92(dd,J＝12.3,7.2Hz,2H),2.80–2.54(m,4H),1.35(s,3H),1.02(d,J＝6.2Hz,3H).LC-MS(ESI)m/z:472.10[M+H] + .
Example 23
Step 1: synthesis of II-5-1
Reference example 22 Synthesis method of step 1 except that (S) -1-N-t-butoxycarbonyl-2-methylpiperazine in step 1 was replaced with 3, 8-diazabicyclo [3.2.1]Compound II-5-1 was prepared from tert-butyl octane-3-carboxylate in the same manner to give 368mg of yellow solid in 74.79% yield. 1 H NMR(300MHz,DMSO-d 6) δ7.66–7.54(m,2H),7.05–6.94(m,2H),4.47(s,2H),3.63(t,J＝16.4Hz,2H),3.10(d,J＝12.9Hz,1H),2.96(d,J＝13.0Hz,1H),2.02–1.92(m,2H),1.75(t,J＝6.7Hz,2H),1.42(s,9H).LC-MS(ESI)m/z:314.05[M+H] + .
Step 2: synthesis of II-5-2
II-5-1 (268 mg,1.17 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 200mg of a yellow solid in 80.15% yield.
Step 2: synthesis of II-5
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-5-2, compound II-5 was prepared in the same manner as in 153mg of a yellow solid with a yield of 33.66%. 1 H NMR(300MHz,Chloroform-d)δ9.32(s,1H),8.12(d,J＝2.1Hz,1H),7.97(dd,J＝8.6,2.1Hz,1H),7.84(d,J＝8.5Hz,1H),7.49(d,J＝8.8Hz,2H),6.70(d,J＝8.7Hz,2H),5.02(s,1H),4.31(s,1H),4.17(s,1H),3.20(d,J＝13.3Hz,1H),2.88(d,J＝10.3Hz,1H),2.60(d,J＝11.1Hz,2H),2.39–2.27(m,2H),2.06(d,J＝13.7Hz,3H),1.91–1.80(m,1H),1.42(s,3H).LC-MS(ESI)m/z:484.10[M+H] + .
Example 24
Step 1: synthesis of II-18-1
Reference example 22 Synthesis method of step 1 except that 4-bromobenzonitrile and (S) -1-N-t-butoxycarbonyl-2-methylpiperazine in step 1 were replaced with p-bromofluorobenzene and 3, 8-diazabicyclo [3.2.1]Compound II-18-1 was obtained as a white solid 249mg in a yield of 59.32% by the same method as that of tert-butyl octane-3-carboxylate. 1 H NMR(300MHz,Chloroform-d)δ7.02–6.92(m,2H),6.81–6.71(m,2H),4.20–4.04(m,2H),3.75(d,J＝13.1Hz,1H),3.69–3.53(m,1H),3.26(dd,J＝26.8,12.7Hz,2H),2.13–1.95(m,2H),1.94–1.75(m,2H),1.47(s,9H).LC-MS(ESI)m/z:307.80[M+H] + .
Step 2: synthesis of II-18-2
II-18-1 (249 mg,0.81 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 154mg of a white solid in 92.18% yield.
Step 3: synthesis of II-18
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-18-2, compound II-18 was produced in the same manner as in the case of 135mg of a white solid with a yield of 37.78%. 1 H NMR(300MHz,Chloroform-d)δ9.36(s,1H),8.12(d,J＝2.1Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.83(d,J＝8.5Hz,1H),7.00–6.89(m,2H),6.77–6.64(m,2H),4.15(q,J＝3.7,3.2Hz,1H),4.02(s,1H),3.20(d,J＝13.2Hz,1H),2.97(dd,J＝10.8,1.7Hz,1H),2.68(dd,J＝10.8,1.7Hz,1H),2.59–2.49(m,1H),2.31(t,J＝11.5Hz,2H),2.12–1.94(m,3H),1.81(q,J＝10.0,8.5Hz,1H),1.42(s,3H).LC-MS(ESI)m/z:477.20[M+H] + .
Example 25
Step 1: synthesis of II-7-1
In a two-necked flask, 4-bromobenzonitrile (48.12. Mu.L, 0.42 mmol) and (1S, 4S) - (-) -2-t-butoxycarbonyl-2, 5-diazabicyclo [2.2.1 were sequentially added]Heptane (100 mg,0.50 mmol), naOBu-t (121.18 mg,1.26 mmol), pd (OAc) 2 (28.32 mg,0.04 mmol) and P (Bu-t) 3 (9.88. Mu.L, 0.09 mmol). 4mL of redistilled toluene was added for dissolution, and the reaction was carried out for 4 hours at 80℃under nitrogen protection. After TLC monitored completion of the reaction, cooled to room temperature, quenched with water, extracted with ethyl acetate (5 ml×3), combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate=20:1) to give 102mg of a white solid in 81.06% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.57(d,J＝8.6Hz,2H),6.74(d,J＝8.5Hz,2H),4.70(s,1H),4.50(d,J＝15.8Hz,1H),3.57(t,J＝8.5Hz,1H),3.38(d,J＝10.6Hz,1H),3.21–3.07(m,2H),2.03–1.90(m,2H),1.39(d,J＝15.6Hz,9H).MS(ESI)m/z:300.10[M+H] + .
Step 2: synthesis of II-7-2
The crude II-7-1 (102 mg,0.34 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 60mg of a yellow oil in 88.38% yield.
Step 3: synthesis of II-7
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-7-2, compound II-7 was produced in the same manner as in 60mg of a white solid with a yield of 42.44%. 1 H NMR(300MHz,Chloroform-d)δ9.37(s,1H),8.06(d,J＝2.1Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.82(d,J＝8.5Hz,1H),7.55–7.39(m,2H),6.59–6.40(m,2H),5.02(s,1H),4.31(s,1H),3.65(s,1H),3.46(dd,J＝9.6,2.1Hz,1H),3.37(d,J＝12.8Hz,1H),3.29(d,J＝9.5Hz,1H),2.97(dd,J＝9.6,2.0Hz,1H),2.69(d,J＝9.5Hz,1H),2.59(d,J＝12.8Hz,1H),2.07–1.89(m,2H),1.42(s,3H).LC-MS(ESI)m/z:470.10[M+H] + .
Example 26
Step 1: synthesis of II-8-1
Reference example 25 Synthesis method of step 1 except that 4-bromobenzonitrile in step 1, (1S, 4S) - (-) -2-t-butoxycarbonyl-2, 5-diazabicyclo [2.2.1]Substitution of heptane for p-bromofluorobenzene and (1S, 4S) - (-) -2-tert-butoxycarbonyl-2, 5-diazabicyclo [2.2.1]Heptane, compound II-8-1 was prepared in the same manner as above to obtain 220mg of a white solid, yield 89.51%. 1 H NMR(300MHz,DMSO-d 6 )δ7.07–6.93(m,2H),6.66–6.51(m,2H),4.53–4.32(m,2H),3.53(td,J＝9.3,1.9Hz,1H),3.23(ddd,J＝23.5,11.1,2.5Hz,2H),2.91(t,J＝8.2Hz,1H),1.96–1.78(m,2H),1.35(d,J＝16.7Hz,9H).LC-MS(ESI)m/z:293.20[M+H] + .
Step 2: synthesis of II-8-2
II-8-1 (220 mg,0.75 mmol) was dissolved in DCM (4 mL), TFA 1.0mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 120mg of a yellow oil in 82.95% yield.
Step 3: synthesis of II-8
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-8-2, compound II-8 was produced in the same manner as in 200mg of a yellow solid with a yield of 83.14%. 1 H NMR(300MHz,Chloroform-d)δ9.45(s,1H),8.05(d,J＝2.1Hz,1H),7.93(dd,J＝8.5,2.2Hz,1H),7.81(d,J＝8.5Hz,1H),7.00–6.90(m,2H),6.49–6.41(m,2H),4.22–4.15(m,1H),3.58(s,1H),3.49(dd,J＝9.2,2.2Hz,1H),3.32(d,J＝12.8Hz,1H),3.15(d,J＝9.2Hz,1H),2.97–2.87(m,1H),2.76(d,J＝9.5Hz,1H),2.59(d,J＝12.8Hz,1H),1.98(s,2H),1.41(s,3H).LC-MS(ESI)m/z:463.10[M+H] + .
Example 27
Step 1: synthesis of II-17-1
Reference example 25 Synthesis method of step 1 except that 4-bromobenzonitrile and (1S, 4S) - (-) -2-t-butoxycarbonyl-2, 5-diazabicyclo [2.2.1 ] in step 1]The heptane was replaced with p-bromofluorobenzene and (S) -1-N-t-butoxycarbonyl-2-methylpiperazine, and compound II-17-1 was prepared in the same manner as in the above, to obtain 300mg of a yellow oil in 59.45% yield. 1 H NMR(300MHz,Chloroform-d)δ7.06–6.93(m,2H),6.93–6.82(m,2H),4.36(s,1H),3.97(dt,J＝13.1,2.8Hz,1H),3.39(ddt,J＝11.3,3.9,2.1Hz,1H),3.32–3.17(m,2H),2.88(dd,J＝11.8,3.9Hz,1H),2.70(td,J＝11.7,3.5Hz,1H),1.51(s,9H),1.33(d,J＝6.8Hz,3H).LC-MS(ESI)m/z:295.10[M+H] + .
Step 2: synthesis of II-17-2
II-17-1 (200 mg,0.68 mmol) was dissolved in DCM (4 mL), TFA 1.0mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 100mg of a yellow oil in 75.77% yield.
Step 3: synthesis of II-17
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-17-2, compound II-17 was produced in the same manner as in the case of 90mg of pale yellow solid, the yield was 37.64%. 1 H NMR(300MHz,Chloroform-d)δ9.43(s,1H),8.14(s,1H),7.97(d,J＝8.6Hz,1H),7.81(d,J＝8.5Hz,1H),6.95(t,J＝8.5Hz,2H),6.83(dd,J＝9.0,4.6Hz,2H),5.32(d,J＝1.7Hz,1H),3.32(d,J＝11.6Hz,1H),3.23(d,J＝13.0Hz,2H),2.96–2.70(m,4H),2.70–2.43(m,2H),1.46(s,3H),1.18(d,J＝6.0Hz,3H).LC-MS(ESI)m/z:464.46[M+H] + .
Example 28
Step 1: synthesis of II-25-1
Reference example 25 Synthesis method of step 1 except that 4-bromobenzonitrile and (1S, 4S) - (-) -2-t-butoxycarbonyl-2, 5-diazabicyclo [2.2.1 ] in step 1]The heptane was replaced with 4-bromo-2-fluorobenzonitrile and 1- (t-butoxycarbonyl) piperazine, and compound II-25-1 was prepared in the same manner as described above, to obtain 1.64g of a pale yellow solid, yield 53.78%. 1 H NMR(300MHz,Chloroform-d)δ7.43(dd,J＝8.8,7.6Hz,1H),6.64(dd,J＝8.9,2.4Hz,1H),6.56(dd,J＝12.8,2.4Hz,1H),3.69–3.53(m,4H),3.35(dd,J＝6.6,4.1Hz,4H),1.50(s,9H).LC-MS(ESI)m/z:304.65[M-H] + .
Step 2: synthesis of II-25-2
II-25-1 (200 mg,0.65 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 95mg of a pale yellow solid in 70.67% yield.
Step 3: synthesis of II-25
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-25-2, compound II-25 was produced in the same manner as in example 1, 118mg of a white solid was produced in a yield of 53.62%. 1 H NMR(300MHz,Chloroform-d)δ9.36(s,1H),8.14(d,J＝2.1Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.83(d,J＝8.5Hz,1H),7.41(dd,J＝8.8,7.6Hz,1H),6.61(dd,J＝8.9,2.4Hz,1H),6.53(dd,J＝12.7,2.4Hz,1H),4.96(s,1H),3.40(s, 1H),3.34(d,J＝7.5Hz,4H),2.73(s,4H),2.53(d,J＝13.3Hz,1H),1.47(s,3H).MS(ESI)m/z:475.9[M+H] + .
Example 29
Step 1: synthesis of II-26-1
Reference example 22 Synthesis method of step 1 except that 4-bromobenzonitrile and (1S, 4S) - (-) -2-t-butoxycarbonyl-2, 5-diazabicyclo [2.2.1 ] in step 1]The heptane was replaced with 4-bromo-2-chlorobenzonitrile and 1- (t-butoxycarbonyl) piperazine to give compound II-26-1 as a pale yellow solid 213mg in 71.64% yield. 1 H NMR(300MHz,Chloroform-d)δ7.49(d,J＝8.8Hz,1H),6.89(d,J＝2.5Hz,1H),6.75(dd,J＝8.9,2.5Hz,1H),3.67–3.52(m,4H),3.35(dd,J＝6.6,4.1Hz,4H),1.50(s,9H).LC-MS(ESI)m/z:320.35[M-H] + .
Step 2: synthesis of II-26-2
II-26-1 (200 mg,0.62 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 106mg of a yellow solid in 76.94% yield.
Step 3: synthesis of II-26
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-26-2, compound II-26 was produced in the same manner as in 126mg of a white solid with a yield of 56.79%. 1 H NMR(300MHz,Chloroform-d)δ9.39(s,1H),8.17(d,J＝2.0Hz,1H),7.99(dd,J＝8.5,2.1Hz,1H),7.86(d,J＝8.5Hz,1H),7.49(d,J＝8.8Hz,1H),6.88(d,J＝2.4Hz,1H),6.75(dd,J＝8.9,2.5Hz,1H),4.99(s,1H),3.43(s,1H),3.36(s,4H),2.76(s,4H),2.56(d,J＝13.2Hz,1H),1.50(s,3H).MS(ESI)m/z:492.0[M+H] + .
Example 30
Step 1: III-1-1 Synthesis
In a two-necked flask, S5 (600 mg,1.92 mmol), 4-fluorophenylboronic acid pinacol ester (512.12 mg,2.31 mmol) and PdCl were sequentially added 2 (dppf) (70.32 mg,0.10 mmol) andCs 2 CO 3 (1.25 g,3.84 mmol). 2mL of water was added to dissolve Cs 2 CO 3 Then 12mL dioxane and water (V: v=6:1) were added and reacted for 4 hours at 100 ℃ under nitrogen protection. After TLC monitored completion of the reaction, cooled to room temperature, quenched with water, extracted with ethyl acetate (5 ml×3), combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate=50:1) to give 510mg as a pale yellow oil in 81.06% yield. 1 H NMR(300MHz,Chloroform-d)δ7.66–7.52(m,4H),7.47–7.39(m,2H),7.23–7.09(m,2H),4.41(t,J＝8.6Hz,2H),4.06(dd,J＝8.5,6.0Hz,2H),3.82(tt,J＝8.7,5.9Hz,1H),1.53(s,9H).LC-MS(ESI)m/z:350.00[M+Na] + .
Step 2: III-1-2 Synthesis
III-1-1 (510 mg,1.56 mmol) was dissolved in DCM (6 mL), TFA 1.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 300mg of a white solid with 84.74% yield.
Step 3: III-1 Synthesis
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with III-1-2, compound III-1 was prepared in the same manner as in the case of 150mg of a white solid with a yield of 40.31%.1H NMR (300 MHz, chloroform-d) δ9.66 (s, 1H), 8.12 (d, J=2.1 Hz, 1H), 7.95 (dd, J=8.5, 2.2Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.65-7.43 (m, 4H), 7.43-7.31 (m, 2H), 7.24-7.05 (m, 2H), 3.91 (td, J=6.8, 2.2Hz, 1H), 3.85-3.68 (m, 2H), 3.56-3.37 (m, 2H), 3.26 (d, J=12.5 Hz, 1H), 2.68 (d, J=12.5 Hz, 1H), 1.45 (s, 3H) LC-MS (ESI) m/z 498.10[ M+H) ] + .
Example 31
Step 1: III-2-1 Synthesis
Reference example 30 the procedure of step 1 was followed except that 4-fluorobenzeneboronic acid pinacol ester in step 1 was replaced with 4-benzonitrile boronic acid pinacol ester, and compound III-2-1 was prepared in the same manner to obtain 250mg of pale yellow oil in 77.80% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.96–7.85(m,4H),7.79–7.71(m,2H),7.52–7.44(m,2H),4.27(d,J＝8.1Hz,2H),3.87(q,J＝5.1,4.5Hz,3H),1.41(s,9H).LC-MS(ESI)m/z:335.05[M+H] + .
Step 2: synthesis of III-2-2
III-2-1 (250 mg,0.75 mmol) was dissolved in DCM (4 mL), TFA 1.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 120mg of a yellow oil in 68.51% yield.
Step 3: III-2 Synthesis
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with III-2-2, compound III-2 was prepared in the same manner as in 100mg of a white solid with a yield of 38.70%. 1 H NMR(300MHz,Chloroform-d)δ9.57(s,1H),8.10(d,J＝2.1Hz,1H),7.95(dd,J＝8.5,2.2Hz,1H),7.81(d,J＝8.5Hz,1H),7.75(d,J＝8.3Hz,2H),7.68(d,J＝8.4Hz,2H),7.57(d,J＝8.1Hz,2H),7.38(d,J＝8.0Hz,2H),3.93(m,J＝6.7,4.3Hz,1H),3.85–3.73(m,2H),3.56–3.40(m,2H),3.28(d,J＝12.5Hz,1H),2.69(d,J＝12.5Hz,1H),1.45(s,3H).LC-MS(ESI)m/z:505.30[M+H] + .
Example 32
Step 1: III-3-1 synthesis:
reference example 30 the procedure of step 1 was followed except that the 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with 3-fluorophenylboronic acid, and compound III-3-1 was prepared in the same manner to give 210mg of yellow oil in 66.75% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.74–7.65(m,2H),7.57–7.47(m,3H),7.44(dd,J＝8.3,1.6Hz,2H),7.24–7.14(m,1H),4.28(q,J＝8.0,7.1Hz,2H),3.86(q,J＝5.1Hz,3H),1.41(s,9H).LC-MS(ESI)m/z:326.65[M-H] + .
Step 2: III-3-2 synthesis:
the crude III-3-1 (210 mg,0.64 mmol) was dissolved in DCM (4 mL), TFA 1.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 110mg of a yellow oil in 75.45% yield.
Step 3: III-3 synthesis:
with reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with III-3-2, compound III-3 was produced in the same manner as in 100mg of a white solid with a yield of 41.53%. 1 H NMR(300MHz,DMSO-d 6 )δ10.46(s,1H),8.58(d,J＝2.0Hz,1H),8.34(dd,J＝8.6,2.1Hz,1H),8.12(d,J＝8.6Hz,1H),7.59–7.53(m,2H),7.52–7.43(m,3H),7.42–7.36(m,2H),7.23–7.13(m,1H),5.71(s,1H),3.75(t,J＝7.0Hz,1H),3.69–3.52(m,2H),3.22(m,J＝20.2,6.0Hz,2H),2.86(d,J＝12.4Hz,1H),2.60(d,J＝12.4Hz,1H),1.33(s,3H).LC-MS(ESI)m/z:498.10[M+H] + .
Example 33
Step 1: III-4-1 Synthesis
With reference to the synthetic method of step 1 of example 30, except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 were replaced with S7 and 4-fluorophenylboronic acid pinacol ester, compound III-4-1 was prepared in the same manner to obtain 270mg of yellow oil in 85.82% yield. 1 H NMR(300MHz,DMSO-d 6 )δ7.83–7.68(m,2H),7.60(t,J＝1.8Hz,1H),7.55(dt,J＝7.7,1.5Hz,1H),7.47(t,J＝7.6Hz,1H),7.38(t,J＝1.5Hz,1H),7.32(dd,J＝10.1,7.8Hz,2H),4.29(d,J＝7.7Hz,2H),3.92(dq,J＝13.4,7.5,6.7Hz,3H),1.43(s,9H).LC-MS(ESI)m/z:326.90[M-H] + .
Step 2: synthesis of III-4-2
III-4-1 (270 mg,0.82 mmol) was dissolved in DCM (4 mL), TFA 1mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h at room temperature, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 130mg of a yellow oil in 69.36% yield.
Step 3: III-4 Synthesis
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with III-4-2, compound III-4 was prepared in the same manner as in the case of 110mg of a white solid with a yield of 38.66%. 1 H NMR(300MHz,DMSO-d 6 )δ10.48(s, 1H),8.57(d,J＝2.0Hz,1H),8.33(dd,J＝8.6,2.1Hz,1H),8.10(d,J＝8.6Hz,1H),7.72–7.62(m,2H),7.58(s,1H),7.47(dt,J＝5.4,2.4Hz,1H),7.38–7.31(m,2H),7.31–7.20(m,2H),5.73(s,1H),3.78(t,J＝7.4Hz,1H),3.65(d,J＝8.1Hz,2H),3.28(dd,J＝14.8,8.5Hz,2H),2.90(d,J＝12.3Hz,1H),2.62(d,J＝12.4Hz,1H),1.35(s,3H).LC-MS(ESI)m/z:498.10[M+H] + .
Example 34
Step 1: III-5-1 Synthesis
Reference example 30 the procedure of step 1 was followed except that the S5 and 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with S7 and 4-pyridineboronic acid pinacol ester, to thereby prepare compound III-5-1 in the form of a yellow oil of 220mg with a yield of 73.76%. 1 H NMR(300MHz,DMSO-d6)δ8.71–8.58(m,2H),7.82–7.63(m,4H),7.57–7.41(m,2H),4.27(d,J＝7.4Hz,2H),4.04–3.97(m,3H),1.41(s,9H).LC-MS(ESI)m/z:311.10[M+H] + .
Step 2: III-5-2 Synthesis
The crude III-5-1 (220 mg,0.71 mmol) was dissolved in DCM (4 mL), TFA 1.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 110mg of a yellow oil with 73.81% yield.
Step 3: III-5 Synthesis
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with III-5-2, compound III-5 was prepared in the same manner as in the case of 100mg of a white solid with a yield of 39.79%. 1 H NMR(300MHz,DMSO-d 6 )δ10.46(s,1H),8.62–8.57(m,2H),8.55(d,J＝2.0Hz,1H),8.31(dd,J＝8.5,2.1Hz,1H),8.08(d,J＝8.6Hz,1H),7.70(d,J＝1.7Hz,1H),7.67–7.63(m,2H),7.63–7.58(m,1H),7.44(dt,J＝7.7,1.6Hz,1H),7.38(t,J＝7.5Hz,1H),5.73(s,1H),3.80–3.71(m,1H),3.64(h,J＝7.1Hz,2H),3.34–3.20(m,2H),2.88(d,J＝12.4Hz,1H),2.60(d,J＝12.4Hz,1H),1.33(s,3H).LC-MS(ESI)m/z:481.10[M-H] + .
Example 35
Step 1: III-6-1 Synthesis
With reference to the synthetic method of step 1 of example 30, except that 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with pyrimidine-5-boronic acid pinacol ester, the compound III-6-1 was prepared in the same manner to obtain 230mg of yellow oil with a yield of 73.76%. 1 H NMR(300MHz,DMSO-d 6 )δ9.19(d,J＝11.3Hz,3H),7.90–7.78(m,2H),7.60–7.49(m,2H),4.31(s,2H),3.94(d,J＝12.8Hz,1H),3.90(d,J＝4.2Hz,2H),1.44(s,9H).LC-MS(ESI)m/z:312.10[M+H] + .
Step 2: III-6-2 Synthesis
The crude III-6-1 (230 mg,0.74 mmol) was dissolved in DCM (5 mL), TFA 1mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 140mg of a yellow oil in 89.71% yield.
Step 3: III-6 Synthesis
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with III-6-2, compound III-6 was prepared in the same manner as in 180mg of a white solid with a yield of 56.42%. 1 H NMR(300MHz,Chloroform-d)δ9.55(s,1H),9.23(s,1H),8.95(s,2H),8.10(d,J＝2.1Hz,1H),7.96(dd,J＝8.5,2.2Hz,1H),7.81(d,J＝8.5Hz,1H),7.59–7.53(m,2H),7.47–7.39(m,2H),3.99–3.88(m,1H),3.88–3.74(m,2H),3.53–3.40(m,2H),3.29(d,J＝12.5Hz,1H),2.68(d,J＝12.5Hz,1H),1.44(s,3H).LC-MS(ESI)m/z:482.10[M+H] + .
Example 36
Step 1: III-7-1 Synthesis
With reference to the synthetic method of step 1 of example 30, except that 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with 3-cyano-4-fluorophenylboronic acid pinacol ester, the compound III-7-1 was prepared in the same manner to obtain 400mg of pale yellow solid with a yield of 93.48%. 1 H NMR(300MHz,DMSO-d 6 )δ8.26(dd,J＝6.2,2.4Hz,1H),8.09(td,J＝8.8,5.2,2.5Hz,1H),7.77–7.68(m,2H),7.62(t,J＝9.1Hz,1H),7.52–7.41(m,2H),4.28(s,2H),3.85(t,J＝4.0Hz,3H),1.41(s,9H).LC-MS(ESI)m/z:353.10[M+H] + .
Step 2: III-7-2 Synthesis
III-7-1 (300 mg,0.85 mmol) was dissolved in DCM (3 mL), TFA 1mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of the TLC monitoring reaction for 1h at room temperature, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 120mg of a yellow solid in 55.87% yield.
Step 3: III-7 Synthesis
Reference example 1 the synthetic method of step 3, except that the procedure was followedThe I-1-2 in step 3 was replaced with III-7-2, and Compound III-7 was obtained in the same manner as described above, and 45mg of a pale yellow solid was obtained in a yield of 23.47%. 1 H NMR(300MHz,DMSO-d 6 )δ10.49(s,1H),8.59(s,1H),8.35(d,J＝8.6Hz,1H),8.22(d,J＝6.1Hz,1H),8.13(d,J＝8.6Hz,1H),8.05(t,J＝7.1Hz,1H),7.61(d,J＝7.8Hz,3H),7.43(d,J＝7.8Hz,2H),5.73(s,1H),3.77(d,J＝6.7Hz,1H),3.63(q,J＝6.6Hz,2H),3.24(dt,J＝13.5,5.9Hz,2H),2.89(d,J＝12.4Hz,1H),2.62(d,J＝12.4Hz,1H),1.35(s,3H).LC-MS(ESI)m/z:523.15[M+H] + .
Example 37
Step 1: III-8-1 Synthesis
With reference to the synthetic method of step 1 of example 30, except that 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with 4-pyridineboronic acid pinacol ester, compound III-8-1 was prepared in the same manner to obtain 220mg of pale yellow solid with a yield of 73.76%. 1 H NMR(300MHz,DMSO-d 6 )δ8.72–8.57(m,2H),7.81(d,J＝8.1Hz,2H),7.75–7.62(m,2H),7.50(d,J＝8.1Hz,2H),4.27(d,J＝10.9Hz,2H),3.89(d,J＝9.8Hz,3H),1.51–1.32(m,9H).LC-MS(ESI)m/z:311.10[M+H] + .
Step 2: III-8-2 Synthesis
III-8-1 (200 mg,0.64 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 100mg of a yellow solid in 73.81% yield.
Step 3: III-8 Synthesis
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with III-8-2, compound III-8 was prepared in the same manner as in the case of 100mg of pale yellow solid, with a yield of 43.76%. 1 H NMR(300MHz,DMSO-d 6 )δ10.48(s, 1H),8.70–8.59(m,2H),8.58(d,J＝2.0Hz,1H),8.34(d,J＝8.5Hz,1H),8.12(d,J＝8.6Hz,1H),7.65(d,J＝6.5Hz,4H),7.45(d,J＝7.9Hz,2H),5.74(s,1H),3.75(t,J＝7.0Hz,1H),3.62(dq,J＝13.7,7.1Hz,2H),3.23(dt,J＝20.5,5.9Hz,2H),2.86(d,J＝12.4Hz,1H),2.59(d,J＝12.4Hz,1H),1.33(s,3H).LC-MS(ESI)m/z:481.25[M+H] + .
Example 38
Step 1 Synthesis of III-9-1
Reference example 30 the procedure of step 1 was followed except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with 1-t-butoxycarbonyl-pyrazole-4-boronic acid pinacol ester and p-bromofluorobenzene, to obtain compound III-9-1 in the same manner as in step 1, 200mg of a yellow solid was obtained in 44.86% yield. 1 H NMR(300MHz,DMSO-d 6 )δ12.96(s,1H),8.18(s,1H),7.91(s,1H),7.72–7.55(m,2H),7.28–7.11(m,2H).LC-MS(ESI)m/z:163.00[M+H] + .
Step 2: III-9-2 Synthesis
In a round bottom flask, III-9-1 (50 mg,0.31 mmol), 1-tert-butoxycarbonyl-3-iodoazetidine (65. Mu.L, 0.37 mmol) and K were added sequentially 2 CO 3 (86 mg,0.62 mmol). 4mL of DMF was then added and the reaction was allowed to proceed at 80℃for 4 hours. After completion of the TLC monitoring reaction, cooled to room temperature, extracted with 10mL of water, ethyl acetate (5 ml×3), combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was separated by silica gel column chromatography (dichloromethane: methanol=100:1) to give 70mg of a white solid in 71.54% yield. 1 H NMR(300MHz,Chloroform-d)δ7.81(d,J＝0.8Hz,1H),7.74(d,J＝0.8Hz,1H),7.50–7.40(m,2H),7.14–7.03(m,2H),5.09(tt,J＝7.8,5.5Hz,1H),4.43(dd,J＝9.3,7.8Hz,2H),4.36(dd,J＝9.5,5.6Hz,2H),1.49(s,9H).LC-MS(ESI)m/z:318.30[M+H] + .
Step 3 Synthesis of III-9-3
III-9-2 (200 mg,0.63 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 100mg of a pale yellow solid in 73.04% yield.
Step 4 Synthesis of III-9
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with III-9-3, compound III-9 was prepared in the same manner as in the case of 90mg of pale yellow solid with a yield of 40.11%. 1 H NMR(300MHz,DMSO-d 6 )δ10.48(s,1H),8.57(d,J＝2.0Hz,1H),8.34(dd,J＝8.6,2.1Hz,1H),8.29–8.22(m,1H),8.09(d,J＝8.6Hz, 1H),7.91(d,J＝0.7Hz,1H),7.55(ddd,J＝8.6,5.4,2.7Hz,2H),7.24–7.09(m,2H),5.79(s,1H),4.94(p,J＝6.7Hz,1H),3.85(t,J＝7.3Hz,1H),3.71(t,J＝7.2Hz,1H),3.53(q,J＝6.7Hz,2H),2.95(d,J＝12.4Hz,1H),2.65(d,J＝12.4Hz,1H),1.33(s,3H).LC-MS(ESI)m/z:488.30[M+H] + .
Example 39
Step 1: III-10-1 Synthesis
With reference to the synthetic method of step 1 of example 30, except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 were replaced with S7 and 4-cyanobenzeneboronic acid pinacol ester, compound III-10-1 was prepared in the same manner as in step 1 to obtain 400mg of yellow oil in 74.69% yield. 1 H NMR(300MHz,Chloroform-d)δ7.81–7.67(m,4H),7.57–7.46(m,3H),7.45–7.36(m,1H),4.41(t,J＝8.7Hz,2H),4.05(dd,J＝8.6,5.9Hz,2H),3.83(tt,J＝8.8,5.9Hz,1H),1.50(s,9H).LC-MS(ESI)m/z:333.60[M-H] + .
Step 2: III-10-2 Synthesis
III-10-1 (300 mg,0.82 mmol) was dissolved in DCM (4 mL), TFA 1mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h at room temperature, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to a yellow oil of 150mg in 71.36% yield.
Step 3: III-10 Synthesis
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with III-10-2, compound III-10 was prepared in the same manner as in the case of 72mg of a white solid with a yield of 33.44%. 1 H NMR(300MHz,DMSO-d 6 )δ8.53(d,J＝2.0Hz,1H),8.29(dd,J＝8.7,2.1Hz,1H),8.07(d,J＝8.6Hz,1H),7.93-7.82(m,4H),7.66(s,1H),7.56(d,J＝6.6Hz,1H),7.38(d,J＝7.3Hz,2H),3.74(d,J＝7.1Hz,1H),3.65(s,2H),3.31–3.19(m,2H),2.87(d,J＝12.3Hz,1H),2.60(d,J＝12.3Hz,1H),1.32(s,3H).LC-MS(ESI)m/z:505.20[M+H] + .
Example 40
Step 1: III-11-1 Synthesis
With reference to the synthetic method of step 1 of example 30, except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 were replaced with S6 and 4-cyanobenzeneboronic acid pinacol ester, the compound III-11-1 was prepared in the same manner to obtain 280mg of pale yellow solid with a yield of 87.15%. 1 H NMR(300MHz,Chloroform-d)δ8.66(d,J＝2.2Hz,1H),8.18–8.11(m,2H),7.89(dd,J＝8.2,2.3Hz,1H),7.85–7.79(m,2H),7.78(d,J＝1.7Hz,1H),4.44(t,J＝8.6Hz,2H),4.01(dd,J＝8.6,5.7Hz,2H),3.83(tt,J＝8.6,5.7Hz,1H),1.50(s,9H).LC-MS(ESI)m/z:336.10[M+H] + .
Step 2: synthesis of III-11-2
III-11-1 (200 mg,0.60 mmol) was dissolved in DCM (4 mL), TFA 1.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 112mg of a yellow oil in 79.83% yield.
Step 3: III-11 Synthesis
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with III-11-2, compound III-11 was prepared in the same manner as in the case of 66mg of pale yellow solid, with a yield of 30.72%. 1 H NMR(300MHz,DMSO-d 6 )δ8.63(d,J＝26.1Hz,2H),8.35(d,J＝8.6Hz,1H),8.26(d,J＝8.0Hz,2H),8.13(d,J＝8.6Hz,1H),7.97(d,J＝6.0Hz,4H),3.72(d,J＝27.2Hz,3H),3.26(s,2H),2.90(d,J＝12.4Hz,1H),2.64(d,J＝12.5Hz,1H),1.37(s,3H).LC-MS(ESI)m/z:506.20[M+H] + .
Example 41
Step 1: III-12-1 Synthesis
Reference example 30 the synthesis of step 1 was followed except that S5 in step 1 was replaced with S6 to prepare Compound III-12-1 in the same manner, 210mg of pale yellow solid was obtained, and the yield was 71.00%. 1 H NMR(300MHz,Chloroform-d)δ8.59(d,J＝2.2Hz,1H),8.10–7.92(m,2H),7.82(dd,J＝8.2,2.1Hz,1H),7.73(d,J＝8.2Hz,1H),7.18(t,J＝8.7Hz,2H),4.40(q,J＝8.5Hz,2H),4.01(dd,J＝8.6,5.7Hz,2H),3.81(m,J＝8.6,4.3Hz,1H),1.50(s,9H).LC-MS(ESI)m/z:329.10[M+H] + .
Step 2: III-12-2 Synthesis
III-12-1 (250 mg,0.75 mmol) was dissolved in DCM (4 mL), TFA 1.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 100mg of a yellow oil in 71.93% yield.
Step 3: III-12 Synthesis
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with III-12-2, compound III-12 was prepared in the same manner as in the case of 93mg of pale yellow solid, with a yield of 42.59%. 1 H NMR(300MHz,DMSO-d 6 )δ8.59(d,J＝2.1Hz,2H),8.35(dd,J＝8.7,2.1Hz,1H),8.23–8.04(m,3H),7.89(dd,J＝8.2,2.3Hz,1H),7.82(d,J＝8.2Hz,1H),7.32(t,J＝8.8Hz,2H),3.84–3.72(m,1H),3.65(p,J＝6.9Hz,2H),3.33–3.17(m,2H),2.90(d,J＝12.3Hz,1H),2.64(d,J＝12.3Hz,1H),1.36(s,3H).LC-MS(ESI)m/z:499.10[M+H] + .
Example 42
Step 1: III-13-1 Synthesis
S5 (399.01 mg,1.28 mmol), 4-fluoro-1H-pyrazole (100 mg,1.16 mmol), cu were added sequentially to a branched tube 2 O (16.63 mg,0.12 mmol) and Cs 2 CO 3 (378.55 mg,1.16 mmol). 5mL of anhydrous DMF was added and the mixture was reacted at 100℃for 16 hours under nitrogen protection. After TLC monitored completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate (5 ml×3), the combined organic phases dried over anhydrous sodium sulfate, filtered, and concentrated, and the resulting residue was separated by silica gel column chromatography (dichloromethane: triethylamine=500:1) to give 200mg of yellow oil in 54.24% yield. 1 H NMR(300MHz,Chloroform-d)δ7.82(dd,J＝4.8,0.8Hz,1H),7.65–7.60(m,2H),7.60–7.56(m,1H),7.45–7.39(m,2H),4.38(t,J＝8.6Hz,2H),3.99(dd,J＝8.7,6.0Hz,2H),3.79(td,J＝8.7,4.3Hz,1H),1.49(s,9H).LC-MS(ESI)m/z:318.20[M+H] + .
Step 2: synthesis of III-13-2
III-13-1 (200 mg,0.63 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 100mg of a yellow oil in 73.04% yield.
Step 3: III-13 Synthesis
With reference to the synthesis of step 3 of example 1, except that I-1-2 in step 3 was replaced with III-13-2, compound III-13 was prepared in the same manner as in example 1, and 50mg of a pale yellow solid was obtained in a yield of 22.28%. 1 H NMR(300MHz,Chloroform-d)δ9.56(s,1H),8.09(s,1H),7.94(d,J＝8.7Hz,1H),7.88–7.70(m,2H),7.58(d,J＝6.8Hz,3H),7.34(d,J＝8.2Hz,2H),3.88(s,1H),3.77(s,2H),3.54–3.33(m,2H),3.25(d,J＝12.4Hz,1H),2.66(d,J＝12.5Hz,1H),1.43(s,3H).LC-MS(ESI)m/z:488.10[M+H] + .
Example 43
Referring to the synthesis of example 30, step 3, except that S2 in step 3 was replaced with S4, compound III-14 was prepared in the same manner as described above, and 90mg of a white solid was obtained in a yield of 41.04%. 1 H NMR(300MHz,Chloroform-d)δ9.84(s,1H),8.82(dd,J＝25.9,2.4Hz,2H),7.73–7.43(m,4H),7.34(d,J＝7.8Hz,2H),7.14(t,J＝8.6Hz,2H),4.00–3.86(m,1H),3.79(dd,J＝9.1,4.9Hz,2H),3.48(dd,J＝11.8,5.7Hz,2H),3.25(d,J＝12.5Hz,1H),2.70(d,J＝12.5Hz,1H),1.45(s,3H).LC-MS(ESI)m/z:499.10[M+H] + .
Example 44
Step 1: synthesis of V-1-1
Reference example 30 the synthesis of step 1 was repeated except that S5 and 4-fluorobenzeneboronic acid pinacol ester in step 1 was replaced with p-bromofluorobenzene and 4- (4-t-butoxycarbonyl-1-piperazinyl) phenylboronic acid pinacol ester, and compound V-1-1 was prepared in the same manner to give 523mg of a white solid in 69.46% yield. 1 H NMR(300MHz,Chloroform-d)δ7.58–7.45(m,4H),7.16–7.07(m,2H),7.02(d,J＝8.3Hz,2H),3.64(t,J＝5.2Hz,4H),3.21(t,J＝5.2Hz,4H),1.52(s,9H).LC-MS(ESI)m/z:357.20[M+H] + .
Step 2: synthesis of V-1-2
V-1-1 (300 mg,0.84 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of TLC monitoring the reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to afford 182mg of a white solid in 84.32% yield.
Step 3: synthesis of V-1
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with V-1-2, compound V-1 was produced in the same manner as in 87mg of a white solid with a yield of 42.37%. 1 H NMR(300MHz,DMSO-d 6 )δ10.50(s,1H),8.54(d,J＝2.0Hz,1H),8.29(dd,J＝8.7,2.0Hz,1H),8.10(d,J＝8.6Hz,1H),7.66–7.55(m,2H),7.47(d,J＝8.4Hz,2H),7.28–7.15(m,2H),6.95(d,J＝8.3Hz,2H),5.77(s,1H),3.08(d,J＝5.6Hz,4H),2.86–2.71(m,3H),2.66–2.52(m,3H),1.35(s,3H).LC-MS(ESI)m/z:527.10[M+H] + .
Example 45
Step 1: synthesis of V-2-1
Reference example 30 the procedure of step 1 was followed except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with 1-t-butoxycarbonyl-4- (4-bromophenyl) piperazine and 4-cyanophenylboronic acid pinacol ester, and compound V-2-1 was produced in the same manner as in step 1 to obtain 319mg of yellow solid in 73.75% yield. 1 H NMR(300MHz,Chloroform-d)δ7.78–7.65(m,4H),7.58(d,J＝8.7Hz,2H),7.06(d,J＝8.3Hz,2H),3.66(t,J＝5.1Hz,4H),3.28(t,J＝5.1Hz,4H),1.54(s,9H).LC-MS(ESI)m/z:364.10[M+H] + .
Step 2: synthesis of V-2-2
V-2-1 (210 mg,0.58 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to afford 150mg of a yellow solid in 98.21% yield.
Step 3: synthesis of V-2
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with V-2-2, compound V-2 was prepared in the same manner as in 122mg of a yellow solid with a yield of 40.11%. 1 H NMR(300MHz,DMSO-d 6 )δ10.50(s,1H),8.54(d,J＝2.0Hz,1H),8.29(dd,J＝8.7,2.1Hz,1H),8.10(d,J＝8.5Hz,1H),7.86–7.77(m,4H),7.62(d,J＝8.6Hz,2H),6.99(d,J＝8.6Hz,2H),5.78(s,1H),3.15(d,J＝6.3Hz,4H),2.79(t,J＝11.9Hz,3H),2.64–2.54(m,3H),1.35(s,3H).LC-MS(ESI)m/z:534.20[M+H] + .
Example 46
Step 1: synthesis of V-3-1
Reference example 30 the procedure of step 1 was followed except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with 1-t-butoxycarbonyl-4- (4-bromophenyl) piperazine and 4-pyridineboronic acid pinacol ester, and compound V-3-1 was produced in the same manner as in example 30 to obtain 279.86mg of yellow solid with a yield of 56.47%. 1 H NMR(300MHz,DMSO-d 6 )δ8.58–8.52(m,2H),7.76–7.62(m,4H),7.11–7.02(m,2H),3.47(dd,J＝6.6,3.8Hz,4H),3.22(dd,J＝6.5,3.9Hz,4H),1.43(s,9H).LC-MS(ESI)m/z:340.20[M+H] + .
Step 2: synthesis of V-3-2
V-3-1 (254 mg,0.75 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 134mg of a yellow solid in 74.66% yield.
Step 3: synthesis of V-3
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with V-3-2, compound V-3 was prepared in the same manner as 89mg of a yellow solid with a yield of 31.19%. 1 H NMR(300MHz,DMSO-d 6 )δ10.50(s,1H),8.53(dd,J＝6.7,1.9Hz,3H),8.29(dd,J＝8.7,2.0Hz,1H),8.09(d,J＝8.6Hz,1H),7.70–7.59(m,4H),6.99(d,J＝8.8Hz,2H),5.78(s,1H),3.16(q,J＝5.3Hz,4H),2.78(td,J＝11.8,10.6,6.3Hz,3H),2.64–2.52(m,3H),1.35(s,3H).LC-MS(ESI)m/z:510.10[M+H] + .
Example 47
Step 1: synthesis of V-4-1
Reference example 30 the procedure of step 1 was followed except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with 1-t-butoxycarbonyl-4- (4-bromophenyl) piperazine and 3-fluoro-4-cyanobenzeneboronic acid pinacol ester, and compound V-4-1 was prepared in the same manner to obtain 145mg of yellow solid with a yield of 18.54%. 1 H NMR(300MHz,DMSO-d 6 )δ7.91(dd,J＝8.2,7.2Hz,1H),7.82(dd,J＝11.6,1.6Hz,1H),7.78–7.66(m,3H),7.16–7.01(m,2H),3.47(dd,J＝6.6,3.8Hz,4H),3.24(dd,J＝6.5,3.9Hz,4H),1.43(d,J＝2.2Hz,9H).LC-MS(ESI)m/z:380.20[M-H] + .
Step 2: synthesis of V-4-2
V-4-1 (145 mg,0.38 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of TLC monitoring, the reaction was quenched by TLC, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 100mg of a yellow solid in 97.36% yield.
Step 3: synthesis of V-4
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with V-4-2, compound V-4 was produced in the same manner as in the case of 82mg of a white solid with a yield of 40.18%. 1 H NMR(300MHz,Chloroform-d)δ9.47(s,1H),8.18(s,1H),8.01(d,J＝8.6Hz,1H),7.85(d,J＝8.5Hz,1H),7.64(t,J＝7.4Hz,1H),7.52(d,J＝8.3Hz,2H),7.42(dd,J＝18.9,9.4Hz,2H),6.97(d,J＝8.4Hz,2H),3.39(d,J＝13.3Hz,1H),3.30(t,J＝5.2Hz,4H),2.79(q,J＝5.4Hz,4H),2.56(d,J＝13.2Hz,1H),1.50(s,3H).LC-MS(ESI)m/z:552.10[M+H] + .
Example 48
Step 1: synthesis of V-5-1
Reference example 30 the procedure of step 1 was followed except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with 1-t-butoxycarbonyl-4- (4-bromophenyl) piperazine and 2-cyanophenylboronic acid pinacol ester, and compound V-5-1 was produced in the same manner as in step 1 to obtain 370mg of a yellow solid with a yield of 69.53%. 1 H NMR(300MHz,Chloroform-d)δ7.75(dd,J＝7.8,1.3Hz,1H),7.63(td,J＝7.7,1.4Hz,1H),7.56–7.48(m,3H),7.40(td,J＝7.6,1.3Hz,1H),7.08–7.00(m,2H),3.63(dd,J＝6.4,4.0Hz,4H),3.26(t,J＝5.2Hz,4H),1.52(s,9H).LC-MS(ESI)m/z:386.15[M+Na] + .
Step 2: synthesis of V-5-2
V-5-1 (370 mg,1.02 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 260mg of a yellow solid in 96.79% yield.
Step 3: synthesis of V-5
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with V-5-2, compound V-5 was produced in the same manner as in 252mg of a white solid with a yield of 47.71%.1H NMR (300 MHz, chloride-d) δ9.46 (s, 1H), 8.18 (d, J=2.1 Hz, 1H), 7.97 (dd, J=8.5, 2.2Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.74 (dd, J=7.7, 1.3Hz, 1H), 7.62 (td, J=7.7, 1.4Hz, 1H), 7.56-7.43 (m, 3H), 7.39 (td, J=7.6, 1.3Hz, 1H), 7.03-6.91 (m, 2H), 5.19 (s, 1H), 3.37 (d, J=13.2 Hz, 1H), 3.26 (t, J=5.0 Hz, 4H), 2.76 (q, J=6.7 Hz, 4H), 2.55 (d, J=7.7.4 Hz, 1H), 7.56-7.43 (m, 3H), 7.39 (td, J=7.6, 1.3Hz, 1H), 7.03-6.91 (m, 2H), 5.19 (s, 1H), 3.37 (3.34 Hz, 1H) and (ESS-3.4H) ] + .
Example 49
Step 1: synthesis of V-6-1
Reference example 30 the procedure of step 1 was followed except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with 1-t-butoxycarbonyl-4- (4-bromophenyl) piperazine and 3-cyanophenylboronic acid pinacol ester, and compound V-6-1 was produced in the same manner as in step 1 to obtain 319mg of yellow solid in 60.11% yield. 1 H NMR(300MHz,Chloroform-d)δ7.86–7.83(m,1H),7.79(dt,J＝7.6,1.7Hz,1H),7.58(dt,J＝7.7,1.5Hz,1H),7.55–7.53(m,1H),7.52–7.48(m,2H),7.06–6.99(m,2H),3.67–3.59(m,4H),3.24(dd,J＝6.2,4.2Hz,4H),1.52(s,9H).LC-MS(ESI)m/z:364.45[M+H] + .
Step 2: synthesis of V-6-2
V-6-1 (396 mg,1.50 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 280mg of a yellow solid in 70.88% yield.
Step 3: synthesis of V-6
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with V-6-2, compound V-6 was prepared in the same manner as in the case of 303mg of yellow solid with a yield of 56.79%. 1 H NMR(300MHz,Chloroform-d)δ9.45(s,1H),8.18(d,J＝2.1Hz,1H),8.01(dd,J＝8.5,2.2Hz,1H),7.92–7.83(m,2H),7.80(dt,J＝7.6,1.7Hz,1H),7.64–7.55(m,2H),7.52(dd,J＝8.3,1.9Hz,3H),7.06–6.95(m,2H),3.43(d,J＝13.2Hz,1H),3.31(s,4H),2.83(s,4H),2.61(d,J＝13.2Hz,1H),1.52(s,3H).LC-MS(ESI)m/z:534.25[M+H] + .
Example 50
Step 1: synthesis of V-7-1
Reference example 30 the procedure of step 1 was followed except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with 5-bromo-2-cyanopyridine and 4- (4-t-butoxycarbonyl-1-piperazinyl) phenylboronic acid pinacol ester, and compound V-7-1 was prepared in the same manner to give 183mg of yellow solid in 48.75% yield. 1 H NMR(300MHz,DMSO-d 6 )δ9.09(d,J＝2.2Hz,1H),8.30(dd,J＝8.2,2.4Hz,1H),8.06(d,J＝8.2Hz,1H),7.78(d,J＝8.8Hz,2H),7.11(d,J＝8.8Hz,2H),3.52–3.47(m,4H),3.28(dd,J＝6.5,4.0Hz,4H),1.46(s,9H).LC-MS(ESI)m/z:365.05[M+H] + .
Step 2: synthesis of V-7-2
V-7-1 (183 mg,0.50 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 132mg of a yellow solid in 99.87% yield.
Step 3: synthesis of V-7
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with V-7-2, compound V-7 was produced in the same manner as 80mg of a white solid with a yield of 29.93%. 1 H NMR(300MHz,Chloroform-d)δ9.42(s,1H),8.90(dd,J＝2.3,0.8Hz,1H),8.16(d,J＝2.1Hz,1H),8.03–7.90(m,2H),7.83(d,J＝8.5Hz,1H),7.72(dd,J＝8.2,0.8Hz,1H),7.63–7.43(m,2H),7.11–6.93(m,2H),3.54–3.36(m,1H),3.29(d,J＝5.5Hz,4H),2.79(s,4H),2.57(d,J＝13.1Hz,1H),1.48(s,3H).LC-MS(ESI)m/z:535.20[M+H] + .
Example 51
Step 1: synthesis of V-8-1
Reference example 30 Synthesis method of step 1 except that S5 and 4-fluorophenylboronic acid in step 1 were reactedThe pinacol ester was replaced with 1-t-butoxycarbonyl-4- (4-bromophenyl) piperazine and 6-fluoropyridine-3-boronic acid pinacol ester, which was then prepared to give compound V-8-1 as a yellow solid 353mg in 84.41% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.48(dt,J＝2.8,0.8Hz,1H),8.26–8.15(m,1H),7.65–7.56(m,2H),7.35(ddd,J＝8.8,6.8,3.1Hz,1H),7.11–7.03(m,2H),3.48(dd,J＝6.5,3.9Hz,4H),3.19(dd,J＝6.2,4.1Hz,4H),1.43(s,9H).LC-MS(ESI)m/z:358.15[M+H] + .
Step 2: synthesis of V-8-2
V-8-1 (353 mg,0.99 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 250mg of a yellow solid in 98.14% yield.
Step 3: synthesis of V-8
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with V-8-2, compound V-8 was produced in the same manner as 150mg of a white solid with a yield of 29.31%. 1 H NMR(300MHz,Chloroform-d)δ9.47(s,1H),8.40(d,J＝2.4Hz,1H),8.18(d,J＝2.1Hz,1H),8.05–7.91(m,2H),7.86(d,J＝8.5Hz,1H),7.54–7.43(m,2H),7.01(dd,J＝8.8,2.4Hz,3H),5.35(s,1H),3.62–3.37(m,1H),3.28(d,J＝5.3Hz,4H),2.82(q,J＝5.8,5.4Hz,4H),2.60(d,J＝13.2Hz,1H),1.51(s,3H).LC-MS(ESI)m/z:528.10[M+H] + .
Example 52
Synthesis of step 1:V-9-1
With reference to the synthetic method of step 1 of example 30, except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 were replaced with 1-t-butoxycarbonyl-4- (4-bromophenyl) piperazine and 3-cyano-4-fluorophenylboronic acid pinacol ester, compound V-9-1 was prepared in the same manner to obtain 400mg of a yellow solid with a yield of 71.82%. 1 H NMR(300MHz,DMSO-d 6 )δ8.17(dd,J＝6.1,2.5Hz,1H),8.02(ddd,J＝8.9,5.3,2.4Hz,1H),7.62(d,J＝8.7Hz,2H),7.55(t,J＝9.1Hz,1H),7.05(d,J＝8.8Hz,2H),3.47(t,J＝5.0Hz,4H),3.19(dd,J＝6.5,3.9Hz,4H),1.43(s,9H).LC-MS(ESI)m/z:382.15[M+H] + .
Synthesis of step 2:V-9-2
V-9-1 (400 mg,1.05 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was quenched by adding DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 292mg of yellow solid in 98.85% yield.
Synthesis of Steps 3:V-9
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with V-9-2, compound V-9 was produced in the same manner as in 120mg of a white solid with a yield of 21.12%. 1 H NMR(300MHz,Chloroform-d)δ9.43(s,1H),8.16(d,J＝2.2Hz,1H),7.98(dd,J＝8.5,2.2Hz,1H),7.83(d,J＝8.5Hz,1H),7.80–7.68(m,2H),7.43(d,J＝8.3Hz,2H),7.24(d,J＝9.2Hz,1H),6.96(d,J＝8.4Hz,2H),3.38(d,J＝13.1Hz,1H),3.25(q,J＝7.9,6.6Hz,4H),2.78(q,J＝5.8,5.4Hz,4H),2.56(d,J＝13.2Hz,1H),1.48(s,3H).LC-MS(ESI)m/z:552.10[M+H] + .
Example 53
Step 1: synthesis of V-10-1
Reference example 30 the synthesis of step 1 was carried out except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with 4-bromo-2- (trifluoromethyl) benzonitrile and 4- (4-t-butoxycarbonyl-1-piperazinyl) phenylboronic acid pinacol ester, and compound V-10-1 was prepared in the same manner to give 250mg of a yellow solid in 44.91% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.16(d,J＝2.2Hz,3H),7.85–7.72(m,2H),7.12–7.04(m,2H),3.49–3.45(m,4H),3.26(dd,J＝6.5,4.0Hz,4H),1.43(s,9H).LC-MS(ESI)m/z:432.10[M+H] + .
Step 2: synthesis of V-10-2
V-10-1 (250 mg,0.58 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of TLC monitoring, the reaction was quenched by TLC, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 192mg of yellow solid in 99.90% yield.
Step 3: synthesis of V-10
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with V-10-2, compound V-10 was prepared in the same manner as 128mg of a white solid with a yield of 36.69%. 1 H NMR(300MHz,Chloroform-d)δ9.42(s,1H),8.16(d,J＝2.1Hz,1H),7.98(dd,J＝8.5,2.2Hz,1H),7.94(d,J＝1.6Hz,1H),7.84(qt,J＝6.6,3.7Hz,3H),7.59–7.50(m,2H),7.04–6.93(m,2H),3.40(d,J＝13.2Hz,1H),3.30(d,J＝5.7Hz,4H),2.80(s,4H),2.68–2.51(m,1H),1.49(s,3H).LC-MS(ESI)m/z:602.10[M+H] + .
Example 54
Step 1: synthesis of V-20-1
Reference example 30 the synthesis of step 1 was followed except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with 1-t-butoxycarbonyl-4- (4-bromophenyl) piperazine and pyrimidine-5-boronic acid pinacol ester, and compound V-20-1 was prepared in the same manner to obtain 210mg of yellow solid with a yield of 42.25%. 1 H NMR(300MHz,Chloroform-d)δ9.18(s,1H),8.96(s,2H),7.56(d,J＝8.5Hz,2H),7.08(d,J＝8.9Hz,2H),3.66(t,J＝5.1Hz,4H),3.28(t,J＝5.2Hz,4H),1.54(s,9H).LC-MS(ESI)m/z:341.65[M+H] + .
Step 2: synthesis of V-20-2
V-20-1 (250 mg,0.73 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 140mg of a yellow solid in 79.81% yield.
Step 3: synthesis of V-20
The procedure of example 1, step 3 was referenced, except that I-1-2 in step 3 was replaced with V-20-2 to give 212mg of a yellow solid in 71.60% yield. 1 H NMR(300MHz,Chloroform-d)δ9.42(s,1H),9.15(s,1H),8.92(s,2H),8.15(d,J＝2.2Hz,1H),7.98(dd,J＝8.5,2.2Hz,1H),7.83(d,J＝8.5Hz,1H),7.54–7.46(m,2H),7.06–6.95(m,2H),5.20(s,1H),3.38(d,J＝13.2Hz,1H),3.27(d,J＝5.3Hz,4H),2.78(d,J＝5.8Hz,4H),2.55(d,J＝13.2Hz,1H),1.48(s,3H).LC-MS(ESI)m/z:511.10[M+H] + .
Example 55
Step 1: synthesis of V-11-1
Reference example 30 the procedure of step 1 was followed except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with 1-t-butoxycarbonyl-4- (4-bromophenyl) piperazine and 4-trifluoromethylphenylboronic acid pinacol ester, and compound V-11-1 was prepared in the same manner to obtain 145mg of a white solid in 40.58% yield. 1 H NMR(300MHz,Chloroform-d)δ7.70(s,4H),7.65–7.53(m,2H),7.09(d,J＝8.3Hz,2H),3.68(t,J＝5.1Hz,4H),3.27(t,J＝5.1Hz,4H),1.54(s,9H).LC-MS(ESI)m/z:407.10[M+H] + .
Step 2: synthesis of V-11-2
V-11-1 (110 mg,0.27 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 75mg of a white solid in 90.47% yield.
Step 3: synthesis of V-11
With reference to the synthetic method of step 3 of example 1,except that I-1-2 in step 3 was replaced with V-11-2, compound V-11 was produced in the same manner as 88mg of a white solid with a yield of 66.80%. 1 H NMR(300MHz,Chloroform-d)δ9.43(s,1H),8.15(d,J＝2.1Hz,1H),7.98(dd,J＝8.5,2.2Hz,1H),7.84(d,J＝8.5Hz,1H),7.66(s,4H),7.59–7.49(m,2H),7.03–6.93(m,2H),3.40(d,J＝13.1Hz,1H),3.28(s,4H),2.80(s,4H),2.58(d,J＝13.2Hz,1H),1.49(s,3H).LC-MS(ESI)m/z:577.15[M+H] + .
Example 56
Step 1: synthesis of V-12-1
Reference example 30 the synthesis of step 1 was carried out except that the S5 and 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with 4- (4-t-butoxycarbonyl-1-piperazinyl) phenylboronic acid pinacol ester and 5-bromo-3- (trifluoromethyl) -2-cyanopyridine, and compound V-12-1 was prepared in the same manner to give 290mg of a yellow solid with a yield of 84.16%. 1 H NMR(300MHz,Chloroform-d)δ9.10–9.06(m,1H),8.22–8.18(m,1H),7.64–7.57(m,2H),7.09–7.01(m,2H),3.67–3.59(m,4H),3.32(dd,J＝6.3,4.2Hz,4H),1.52(s,9H).LC-MS(ESI)m/z:433.00[M+H] + .
Step 2: synthesis of V-12-2
V-12-1 (200 mg,0.46 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 140mg of a yellow solid with 91.09% yield.
Step 3: synthesis of V-12
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with V-12-2, compound V-12 was prepared in the same manner as in 110mg of a white solid with a yield of 55.92%. 1 H NMR(300MHz,Chloroform-d)δ9.39(s,1H),9.06(d,J＝2.1Hz,1H),8.18(d,J＝2.1Hz,1H),8.15(s,1H),8.02–7.93(m,1H),7.84(d,J＝8.5Hz,1H),7.58(d,J＝8.6Hz,2H),7.01(d,J＝8.6Hz,2H),5.13(s,1H),3.41(s,1H),3.33(s,4H),2.79(s,4H),2.56(d,J＝13.3Hz,1H),1.49(s,3H).LC-MS(ESI)m/z:603.10[M+H] + .
Example 57
Step 1: synthesis of IV-4-1
P-fluoronitrobenzene (226. Mu.L, 2.13 mmol) and N, N' -dimethylethylenediamine (458. Mu.L, 4.25 mmol) were dissolved in 6ml tetrahydrofuran, and triethylamine (887. Mu.L, 6.38 mmol) was added dropwise thereto and refluxed for 6 hours. After completion of the TLC monitoring, cooled to room temperature and concentrated, the resulting residue was separated by silica gel column chromatography (dichloromethane: methanol=20:1) to give IV-4-1 as a yellow solid, 300mg, 67.43% yield. 1 H NMR(300MHz,DMSO-d 6 )δ8.10–7.96(m,2H),6.87–6.69(m,2H),3.54(t,J＝6.7Hz,2H),3.07(s,3H),2.66(t,J＝6.7Hz,2H),2.29(s,3H).LC-MS(ESI)m/z:210.10[M+H] + .
Step 2: synthesis of IV-4
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with IV-4-1, compound IV-4 was prepared in the same manner as the yellow solid, 87mg, with a yield of 37.97%. 1 H NMR(300MHz,DMSO-d 6 )δ10.39(s,1H),8.50(d,J＝2.0Hz,1H),8.24(dd,J＝8.6,2.0Hz,1H),8.05(d,J＝8.6Hz,1H),7.93–7.77(m,2H),6.73–6.57(m,2H),5.65(s,1H),3.48(t,J＝6.7Hz,2H),2.98(s,3H),2.90(d,J＝13.5Hz,1H),2.72-2.55(m,2H),2.35(s,3H),1.28(s,3H).MS(ESI)m/z:480.10[M+H] + .
Example 58
Step 1: synthesis of V-13-1
Reference example 30 the synthesis of step 1 was repeated except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with 1-t-butoxycarbonyl-4- (4-bromophenyl) piperazine and 2-fluoropyridine-4-boronic acid pinacol ester, and compound V-13-1 was prepared in the same manner to obtain 230mg of a white solid in 73.20% yield. 1 H NMR(300MHz,Chloroform-d)δ8.22(d,J＝5.3Hz,1H),7.66–7.56(m,2H),7.38(dt,J＝5.4,1.8Hz,1H),7.10(d,J＝1.4Hz,1H),7.08–6.99(m,2H),3.69–3.57(m,4H),3.33–3.21(m,4H),1.51(s,9H).LC-MS(ESI)m/z:358.10[M+H] + .
Step 2: synthesis of V-13-2
V-13-1 (180 mg,0.50 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 100mg of a yellow solid in 77.17% yield.
Step 3: synthesis of V-12
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with V-13-2, compound V-13 was prepared in the same manner as 70mg of pale yellow solid with a yield of 34.14%. 1 H NMR(300MHz,Chloroform-d)δ9.45(s,1H),8.20(d,J＝5.3Hz,1H),8.18–8.09(m,1H),8.04–7.92(m,1H),7.83(d,J＝8.5Hz,1H),7.56(d,J＝8.3Hz,2H),7.36(d,J＝5.3Hz,1H),7.07(s,1H),6.96(d,J＝8.4Hz,2H),3.37(d,J＝13.2Hz,1H),3.30-3.26(m,4H),2.83-2.71(m,4H),2.55(d,J＝13.2Hz,1H),1.47(s,3H).LC-MS(ESI)m/z:528.20[M+H] + .
Example 59
Step 1: synthesis of V-14-1
Reference example 30 Synthesis method of step 1 except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 were replaced with 4- (4-t-butoxycarbonyl-1-piperazinyl) phenylboronic acid pinacol ester and 4-bromopyridine-2-carbonitrile, which were prepared by the same method Compound V-14-1 gave 250mg of a yellow solid in 83.69% yield. 1 H NMR(300MHz,Chloroform-d)δ8.70(d,J＝5.2Hz,1H),7.91(d,J＝1.9Hz,1H),7.70(dd,J＝5.3,1.9Hz,1H),7.67–7.54(m,2H),7.05(d,J＝8.7Hz,2H),3.65(t,J＝5.1Hz,4H),3.32(t,J＝5.2Hz,4H),1.54(s,9H).LC-MS(ESI)m/z:365.10[M+H] + .
Step 2: synthesis of V-14-2
V-14-1 (200 mg,0.55 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of TLC monitoring, the reaction was quenched by TLC, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 110mg of a yellow solid in 75.83% yield.
Step 3: synthesis of V-14
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with V-14-2, compound V-14 was prepared in the same manner as 70mg of a yellow solid with a yield of 34.62%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s, 1H),8.70(d,J＝5.2Hz,1H),8.18(d,J＝2.1Hz,1H),8.01(dd,J＝8.5,2.2Hz,1H),7.89(d,J＝1.8Hz,1H),7.86(d,J＝8.4Hz,1H),7.69(dd,J＝5.3,1.9Hz,1H),7.60(d,J＝8.8Hz,2H),7.07–6.93(m,2H),3.41(d,J＝13.2Hz,1H),3.33(q,J＝5.3Hz,4H),2.80(q,J＝5.4Hz,4H),2.57(d,J＝13.2Hz,1H),1.51(s,3H).LC-MS(ESI)m/z:535.20[M+H] + .
Example 60
Step 1: synthesis of V-15-1
Reference example 30 the synthesis of step 1 was repeated except that the S5 and 4-fluorophenylboronic acid pinacol ester in step 1 was replaced with 4- (4-t-butoxycarbonyl-1-piperazinyl) phenylboronic acid pinacol ester and 5-bromo-2-nitrobenzotrifluoride to give compound V-15-1 as a yellow solid in 300mg and 75.51% yield. 1 H NMR(300MHz,Chloroform-d)δ8.05–7.99(m,2H),7.88(dd,J＝8.4,2.1Hz,1H),7.65–7.58(m,2H),7.13–7.06(m,2H),3.68(t,J＝5.2Hz,4H),3.32(t,J＝5.2Hz,4H),1.54(s,9H).LC-MS(ESI)m/z:452.15[M+H] + .
Step 2: synthesis of V-15-2
V-15-1 (300 mg,0.66 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 200mg of a yellow solid in 86.25% yield.
Step 3: synthesis of V-15
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with V-15-2, compound V-15 was produced in the same manner as 189mg of yellow solid with a yield of 53.88%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),8.18(d,J＝2.1Hz,1H),8.05–7.94(m,3H),7.87(dd,J＝8.5,1.9Hz,2H),7.58(d,J＝8.7Hz,2H),7.02(dd,J＝9.0,3.3Hz,2H),3.43(d,J＝13.2Hz,1H),3.33(d,J＝5.8Hz,4H),2.83(s,4H),2.63(d,J＝13.0Hz,1H),1.52(s,3H).LC-MS(ESI)m/z:622.20[M+H] + .
Example 61
With reference to the synthetic method of step 3 of example 1, except that I-1-2 and S2 in step 3 were replaced with V-1-2 and S4, compound V-16 was prepared in the same manner as in 243mg of white solid with a yield of 88.91%. 1 H NMR(300MHz,Chloroform-d)δ9.56(s,1H),8.91(d,J＝2.4Hz,1H),8.83(d,J＝2.4Hz,1H),7.55–7.49(m,2H),7.48(d,J＝0.7Hz,1H),7.46(d,J＝2.0Hz,1H),7.15–7.06(m,2H),6.97(d,J＝2.1Hz,1H),6.95(d,J＝2.0Hz,1H),3.38(d,J＝13.3Hz,1H),3.24(d,J＝5.2Hz,4H),2.79(s,4H),2.59(d,J＝13.3Hz,1H),1.50(s,3H).LC-MS(ESI)m/z:528.20[M+H] + .
Example 62
With reference to the synthetic method of step 3 of example 1, except that I-1-2 and S2 in step 3 were replaced with V-2-2 and S4, compound V-17 was prepared in the same manner as 125mg of yellow solid with a yield of 42.52%. 1 H NMR(300MHz,Chloroform-d)δ9.58(s,1H),8.94(d,J＝2.4Hz,1H),8.85(d,J＝2.4Hz,1H),7.69(q,J＝8.5Hz,4H),7.60–7.50(m,2H),7.05–6.91(m,2H),3.41(d,J＝13.2Hz,1H),3.31(s,4H),2.82(s,4H),2.62(d,J＝13.4Hz,1H),1.52(s,3H).LC-MS(ESI)m/z:535.25[M+H] + .
Example 63
With reference to the synthetic method of step 3 of example 1, except that I-1-2 and S2 in step 3 were replaced with V-2-2 and S9, compound V-18 was prepared in the same manner as 125mg of a yellow solid with a yield of 42.52%. 1 H NMR(300MHz,Chloroform-d)δ9.58(s,1H),8.94(d,J＝2.4Hz,1H),8.85(d,J＝2.4Hz,1H),7.69(q,J＝8.5Hz,4H),7.60–7.50(m,2H),7.05–6.91(m,2H),3.41(d,J＝13.2Hz,1H),3.31(s,4H),2.82(s,4H),2.62(d,J＝13.4Hz,1H),1.52(s,3H).LC-MS(ESI)m/z:535.25[M+H] + .
Example 64
Step 1: synthesis of V-19-1
Reference example 22 Synthesis method of step 1 except that 4-bromobenzonitrile and (S) -1-N-t-butoxycarbonyl-2-methylpiperazine in step 1 were replaced with 4-bromo-4-cyanobiphenyl and 3, 8-diazabicyclo [3.2.1]Compound V-19-1 was prepared from tert-butyl octane-3-carboxylate in the same manner to give 300mg of a yellow solid in 75.51% yield. 1 H NMR(300MHz,Chloroform-d)δ8.05–7.99(m,2H),7.88(dd,J＝8.4,2.1Hz,1H),7.65–7.58(m,2H),7.13–7.06(m,2H),3.68(t,J＝5.2Hz,4H),3.32(t,J＝5.2Hz,4H),1.54(s,9H).LC-MS(ESI)m/z:452.15[M+H] + .
Step 2: synthesis of V-19-2
V-19-1 (300 mg,0.66 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 200mg of a yellow solid in 86.25% yield.
Step 3: synthesis of V-19
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with V-19-2, compound V-19 was produced in the same manner as 189mg of yellow solid with a yield of 53.88%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),8.18(d,J＝2.1Hz,1H),8.05–7.94(m,3H),7.87(dd,J＝8.5,1.9Hz,2H),7.58(d,J＝8.7Hz,2H),7.02(dd,J＝9.0,3.3Hz,2H),3.43(d,J＝13.2Hz,1H),3.33(d,J＝5.8Hz,4H),2.83(s,4H),2.63(d,J＝13.0Hz,1H),1.52(s,3H).LC-MS(ESI)m/z:622.20[M+H] + .
Example 65
Step 1: synthesis of II-27-1
Reference example 22 Synthesis method of step 1 except that (S) -1-N-t-butoxycarbonyl-2-methylpiperazine in step 1 was replaced with 8-t-butoxycarbonyl-3, 8-diazabicyclo [3.2.1]Octane, compound II-27-1 was obtained by the same method, 320mg of a yellow solid was obtained, and the yield was 86.53%. 1 H NMR(300MHz,Chloroform-d)δ7.58–7.50(m,2H),6.88–6.79(m,2H),4.44(s,2H),3.54(d,J＝2.2Hz,1H),3.51(d,J＝2.3Hz,1H),3.14(d,J＝11.4Hz,2H),2.04(dd,J＝8.3,4.3Hz,2H),1.84(t,J＝6.7Hz,2H),1.52(s,9H).LC-MS(ESI)m/z:314.50[M+H] + .
Step 2: synthesis of II-27-2
II-27-1 (320 mg,1.02 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 200mg of a yellow solid in 92.16% yield.
Step 3: synthesis of II-27
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-27-2, compound II-27 was produced in the same manner as in 144mg of a yellow solid with a yield of 31.76%. 1 H NMR(300MHz,Chloroform-d)δ9.40(s,1H),8.17(d,J＝2.1Hz,1H),7.98(dd,J＝8.5,2.1Hz,1H),7.85(d,J＝8.5Hz,1H),7.50(d,J＝8.6Hz,2H),6.76(d,J＝8.6Hz,2H),5.34(s,1H),3.60–3.37(m,3H),3.32(s,2H),3.22(s,1H),2.99(s,1H),2.41(s,1H),2.05(s,2H),1.93–1.71(m,2H),1.49(s,3H).LC-MS(ESI)m/z:484.20[M+H] + .
Example 66
Step 1: synthesis of II-28-1
Reference example 11 Synthesis method of step 1 except that tert-butyl 1, 4-diazacycloheptane-1-carboxylate in step 1 was replaced with 6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1]Heptane, compound II-28-1 was prepared in the same manner as above to obtain 240mg of a yellow solid in 48.55% yield. 1 H NMR(300MHz,Chloroform-d)δ7.58–7.49(m,2H),6.79–6.65(m,2H), 4.32(d,J＝6.2Hz,2H),3.98(s,2H),3.33(d,J＝10.8Hz,2H),2.74–2.65(m,1H),1.64(s,1H),1.37(s,9H).LC-MS(ESI)m/z:298.20[M-H] + .
Step 2: synthesis of II-28-2
II-28-1 (200 mg,0.67 mmol) was dissolved in DCM (3 mL), TFA 1mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of the TLC monitoring reaction for 1h at room temperature, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 110mg of oil in 82.63% yield.
Step 3: synthesis of II-28
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-28-2, compound II-28 was produced in the same manner as in 110mg of a white solid with a yield of 42.44%. 1 H NMR(300MHz,Chloroform-d)δ9.41(s,1H),8.14–7.91(m,2H),7.82(d,J＝8.5Hz,1H),7.56(d,J＝8.4Hz,2H),6.77(d,J＝8.5Hz,2H),4.98(s,1H),3.98–3.70(m,2H),3.67–3.48(m,2H),3.37(dd,J＝22.5,11.6Hz,2H),3.20(d,J＝13.2Hz,1H),2.70(q,J＝7.4,6.9Hz,1H),2.30(d,J＝13.2Hz,1H),1.63(d,J＝8.9Hz,1H),1.39(s,3H).MS(ESI)m/z:470.15[M+H] + .
Example 67
Step 1: synthesis of II-29-1
In a single vial, tert-butyl 4- (4-carboxyphenyl) piperazine-1-carboxylate (200.00 mg,0.65 mmol), carbamazepine hydrochloride (52.89 mg,0.78 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (187.72 mg,0.98 mmol), 1-hydroxybenzotriazole (132.32 mg,0.98 mmol) and N-methylmorpholine (0.34 ml, 0.003mmol) were added sequentially. 1.2mL of N, N-dimethylformamide was added thereto, and the mixture was reacted at room temperature for 2 hours. After TLC monitored completion of the reaction, cooled to room temperature, quenched with water, extracted with ethyl acetate (5 ml×3), combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give 190mg of a white solid in 91.12% yield. 1 H NMR(300MHz,Chloroform-d)δ7.76–7.66(m,2H),6.96–6.84(m,2H),6.13(d,J＝5.3Hz,1H),3.60(dd,J＝6.5,4.0Hz,4H),3.26(dd,J＝6.4,4.1Hz,4H),3.01(d,J＝4.7Hz,3H),1.50(s,9H).MS(ESI)m/z:320.20[M+H] + .
Step 2: synthesis of II-29-2
II-29-1 (190 mg,0.59 mmol) was dissolved in DCM (3 mL), TFA 1mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of the TLC monitoring reaction for 4h at room temperature, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 110mg of a white solid in 84.33% yield.
Step 3: synthesis of II-29
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-29-2, compound II-29 was produced in the same manner as in 130mg of a white solid with a yield of 60.72%. 1 H NMR(300MHz,Chloroform-d)δ9.58(s,1H),8.18(s,1H),7.99(d,J＝8.5Hz,1H),7.72(dd,J＝37.6,8.5Hz,3H),6.79(d,J＝8.5Hz,2H),6.30(q,J＝4.7Hz,1H),5.13(s,1H),3.38–3.08(m,5H),2.96(d,J＝4.7Hz,3H),2.70(q,J＝4.9Hz,4H),2.51(d,J＝13.3Hz,1H),1.45(s,3H).MS(ESI)m/z:488.10[M-H] + .
Example 68
Step 1: synthesis of II-30-1
Reference example 22 Synthesis method of step 1 except that (S) -1-N-t-butoxycarbonyl-2-methylpiperazine in step 1 was replaced with 3, 6-diazabicyclo [3.1.1]Heptane-3-carboxylic acid tert-butyl ester was prepared in the same manner as compound II-30-1 to obtain 280mg of pale yellow solid, with a yield of 75.52%. 1 H NMR(300MHz,Chloroform-d)δ7.55–7.44(m,2H),6.58–6.46(m,2H),4.44-4.29(m,2H),3.94-3.80(m,2H),3.51-3.36(m,2H),2.86-2.73(m,1H),1.68(s,1H),1.41(s,9H).LC-MS(ESI)m/z:300.40[M+H] + .
Step 2: synthesis of II-30-2
II-30-1 (200 mg,0.67 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was quenched by adding DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 115mg of a yellow solid in 86.39% yield.
Step 3: synthesis of II-30
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-30-2, compound II-30 was produced in the same manner as in the case of 55mg of a white solid with a yield of 58.36%. 1 H NMR(300MHz,Chloroform-d)δ8.93(s,1H),8.20(s,1H),7.91–7.77(m,2H),7.48(d,J＝8.2Hz,2H),6.52(d,J＝8.3Hz,2H),4.29(s,2H),3.74(s,1H),3.39(d,J＝13.5Hz,1H),3.33(dd,J＝11.2,2.5Hz,1H),3.23(dd,J＝11.1,3.1Hz,1H),2.84(dd,J＝11.1,7.7Hz,2H),2.79–2.70(m,1H),2.40(d,J＝13.6Hz,1H),1.69(d,J＝8.4Hz,1H),1.29(s,3H).LC-MS(ESI)m/z:470.15[M+H] + .
Example 69
Step 1: synthesis of II-31-1
Reference example 4 the synthetic procedure of step 1 was followed except that 2-cyano-5-fluoropyridine in step 1 was replaced with 4- (bromomethyl) benzonitrile, and compound II-31-1 was prepared in the same manner to give 714mg of white solid in 92.89% yield. 1 H NMR(300MHz,Chloroform-d)δ7.67–7.59(m,2H),7.47(d,J＝8.1Hz,2H),3.57(s,2H),3.50–3.40(m,4H),2.40(t,J＝5.0Hz,4H),1.47(s,9H).LC-MS(ESI)m/z:300.55[M-H] + .
Step 2: synthesis of II-31-2
II-31-1 (250 mg,0.83 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 150mg of a yellow solid in 89.85% yield.
Step 3: synthesis of II-31
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-31-2, compound II-31 was produced in the same manner as in 250mg of a white solid with a yield of 82.09%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),8.10(d,J＝2.1Hz,1H),7.95(dd,J＝8.5,2.1Hz,1H),7.79(d,J＝8.5Hz,1H),7.64–7.54(m,2H),7.42(d,J＝8.1Hz,2H),5.16(s,1H),3.53(s,2H),3.26(d,J＝13.2Hz,1H),2.59(q,J＝5.3Hz,4H),2.51–2.32(m,5H),1.42(s,3H).LC-MS(ESI)m/z:472.15[M+H] + .
Example 70
Step 1: synthesis of II-32-1
With reference to the synthetic method of step 1 of example 4, except that 2-cyano-5-fluoropyridine in step 1 was replaced with 4-fluoro-2-methylbenzonitrile, compound II-32-1 was produced in the same manner to obtain 400mg of a white solid in 35.87% yield. 1 H NMR(300MHz,Chloroform-d)δ7.46(dd,J＝8.1,0.9Hz,1H),6.71(d,J＝8.2Hz,2H),3.65–3.51(m,4H),3.31(dd,J＝6.4,4.1Hz,4H),2.49(s,3H),1.50(s,9H).LC-MS(ESI)m/z:302.85[M+H] + .
Step 2: synthesis of II-32-2
II-32-1 (200 mg,0.66 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 100mg of a yellow solid in 74.87% yield.
Step 3: synthesis of II-32
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-32-2, compound II-32 was produced in the same manner as in 200mg of pale yellow solid with a yield of 85.38%. 1 H NMR(400MHz,Chloroform-d)δ9.39(s,1H),8.14(d,J＝2.1Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.82(d,J＝8.5Hz,1H),7.43(d,J＝8.5Hz,1H),6.72–6.63(m,2H),5.05(s,1H),3.35(d,J＝13.2Hz,1H),3.33–3.20(m,4H),2.79–2.62(m,4H),2.52(d,J＝13.3Hz,1H),2.46(s,3H),1.47(s,3H).LC-MS(ESI)m/z:472.20[M+H] + .
Example 71
Step 1: synthesis of II-33-1
Reference example 4 Synthesis method of step 1 except that 2-cyano-5-fluoropyridine and 1- (t-butoxycarbonyl) piperazine in step 1 were replaced with 4- (bromomethyl) benzonitrile and 3, 8-diazabicyclo [3.2.1]Compound II-33-1 was obtained as a white solid (240 mg, 71.85% yield) from tert-butyl octane-3-carboxylate. 1 H NMR(300MHz,Chloroform-d)δ7.68–7.58(m,2H),7.54(d,J＝8.0Hz,2H),3.76(d,J＝12.5Hz,1H),3.65(s,1H),3.59(s,2H),3.07(t,J＝18.8Hz,4H),1.99(t,J＝5.5Hz,2H),1.74(s,2H),1.47(s,9H).LC-MS(ESI)m/z:328.20[M+H] + .
Step 2: synthesis of II-33-2
II-33-1 (195 mg,0.60 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 112mg of a yellow solid in 82.73% yield.
Step 3: synthesis of II-33
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-33-2, compound II-33 was produced in the same manner as in 175mg of a white solid with a yield of 79.96%. 1 H NMR(300MHz,Chloroform-d)δ9.35(s,1H),8.09(d,J＝2.1Hz,1H),7.95(dd,J＝8.5,2.2Hz,1H),7.80(d,J＝8.5Hz,1H),7.69–7.56(m,2H),7.49(d,J＝8.0Hz,2H),5.33(s,1H),3.56(s,2H),3.26(d,J＝13.2Hz,1H),3.14(s,1H),3.02(s,1H),2.83(d,J＝10.2Hz,1H),2.58(d,J＝10.3Hz,1H),2.51(d,J＝10.5Hz,1H),2.40(d,J＝13.2Hz,1H),2.32(d,J＝10.6Hz,1H),2.13–1.94(m,2H),1.87(t,J＝9.6Hz,1H),1.67(d,J＝6.3Hz,1H),1.42(s,3H).LC-MS(ESI)m/z:498.20[M+H] + .
Example 72
Step 1: synthesis of II-34-1
With reference to the synthetic method of step 1 of example 4, except that 2-cyano-5-fluoropyridine in step 1 was replaced with 2-bromo-4-fluorobenzonitrile, compound II-34-1 was produced in the same manner, to obtain 200mg of a yellow solid, yield 72.81%. 1 H NMR(300MHz,Chloroform-d)δ7.48(d,J＝8.8Hz,1H),7.06(d,J＝2.5Hz,1H),6.79(dd,J＝8.9,2.5Hz,1H),3.65–3.55(m,4H),3.35(dd,J＝6.5,4.1Hz,4H),1.50(s,9H).LC-MS(ESI)m/z:366.35[M+H] + .
Step 2: synthesis of II-34-2
With reference to the synthetic method of step 1 of example 30, except that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 were replaced with II-34-1 and phenylboronic acid pinacol ester, the compound II-34-2 was prepared in the same manner to obtain 150mg of yellow solid in 75.58% yield. 1 H NMR(300MHz,Chloroform-d)δ7.65(d,J＝8.6Hz,1H),7.58(dt,J＝5.8,1.8Hz,2H),7.55–7.44(m,3H),6.91(d,J＝7.9Hz,2H),3.64(dd,J＝6.7,3.8Hz,4H),3.40(dd,J＝6.4,4.0Hz,4H),1.53(s,9H).LC-MS(ESI)m/z:362.20[M-H] + .
Step 3: synthesis of II-34-3
II-34-2 (150 mg,0.41 mmol) was dissolved in DCM (4 mL), TFA 1mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of the TLC monitoring reaction for 4h at room temperature, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 60mg of a yellow oil in 55.21% yield.
Step 4: synthesis of II-34
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-34-3, compound II-34 was produced in the same manner as in the case of 90mg of a white solid with a yield of 74.03%. 1 H NMR(300MHz,Chloroform-d)δ9.37(s,1H),8.14(d,J＝2.1Hz,1H),7.96(dd,J＝8.6,2.1Hz,1H),7.83(d,J＝8.5Hz,1H),7.65–7.57(m,1H),7.55–7.39(m,5H),6.85(d,J＝7.7Hz,2H),5.09(s,1H),3.51(s,1H),3.38(s,4H),2.76(s,4H),2.56(s,1H),1.48(s,3H).LC-MS(ESI)m/z:532.20[M-H] + .
Example 73
Step 1: synthesis of II-35-1
Reference example 25 Synthesis method of step 1 except that 4-bromobenzonitrile and (1S, 4S) - (-) -2-t-butoxycarbonyl-2, 5-diazabicyclo [2.2.1 ] in step 1]The heptane was replaced with 4-bromo-2-methoxybenzonitrile and 1-t-butoxycarbonyl piperazine, and compound II-35-1 was prepared in the same manner as described above, to give 342mg of a white solid, yield 91.39%. 1 H NMR(400MHz,Chloroform-d)δ7.40(d,J＝8.7Hz,1H),6.46(dd,J＝8.7,2.2Hz,1H),6.34(d,J＝2.2Hz,1H),3.92(s,3H),3.61(dd,J＝6.5,4.0Hz,4H),3.34(dd,J＝6.4,4.1Hz,4H),1.50(s,9H).LC-MS(ESI)m/z:318.30[M+H] + .
Step 2: synthesis of II-35-2
II-35-1 (349mg, 1.08 mmol) was dissolved in DCM (2 mL), TFA 0.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 130mg of a white solid in 55.40% yield.
Step 3: synthesis of II-35
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-35-2, compound II-35 was produced in the same manner as in 72mg of a white solid with a yield of 25.62%. 1 H NMR(300MHz,Chloroform-d)δ9.40(s,1H),8.18(d,J＝2.1Hz,1H),7.99(dd,J＝8.5,2.2Hz,1H),7.85(d,J＝8.5Hz,1H),7.41(d,J＝8.7Hz,1H),6.44(dd,J＝8.7,2.2Hz,1H),6.32(d,J＝2.2Hz,1H),5.08(s,1H),3.90(s,3H),3.44(s,1H),3.35(s,4H),2.77(s,4H),2.58(s,1H),1.50(s,3H).LC-MS(ESI)m/z:489.30[M+H] + .
Example 74
Step 1: synthesis of II-36-1
II-34-1 (200 mg,0.55 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 107mg of a pale yellow solid in 73.63% yield.
Step 3: synthesis of II-36
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-36-1, compound II-36 was produced in the same manner as in 152mg of a white solid with a yield of 75.42%. 1 H NMR(300MHz,Chloroform-d)δ9.37(s,1H),8.15(d,J＝2.1Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.83(d,J＝8.5Hz,1H),7.46(d,J＝8.8Hz,1H),7.04(d,J＝2.5Hz,1H),6.77(dd,J＝8.9,2.5Hz,1H),4.99(s,1H),3.41(s,1H),3.34(s,4H),2.74(s,4H),2.54(d,J＝13.1Hz,1H),1.48(s,3H).LC-MS(ESI)m/z:536.55[M+H] + .
Example 75
Step 1: synthesis of II-37-1
Reference example 4 the procedure of step 1 was followed except that 2-cyano-5-fluoropyridine in step 1 was replaced with 5-bromo-2-cyanopyrimidine, and compound II-37-1 was produced in the same manner to obtain 700mg of a yellow solid in 89.03% yield. 1 H NMR(300MHz,Chloroform-d)δ8.34(s,2H),3.73–3.55(m,4H),3.52–3.29(m,4H),1.49(s,9H).LC-MS(ESI)m/z:290.85[M+H] + .
Step 2: synthesis of II-37-2
II-37-1 (250 mg,0.86 mmol) was dissolved in DCM (3 mL), TFA 1mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of TLC monitoring for 0.5h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 130mg of a pale yellow solid in 79.51% yield.
Step 4: synthesis of II-37
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-37-2, compound II-37 was produced in the same manner as in 40mg of a white solid with a yield of 32.95%. 1 H NMR(300MHz,Chloroform-d)δ9.34(s,1H),8.31(s,2H),8.15(d,J＝2.1Hz,1H),7.96(dd,J＝8.6,2.2Hz,1H),7.83(d,J＝8.5Hz,1H),4.81(s,1H),3.42(s,5H),2.80(s,4H),2.56(d,J＝11.4Hz,1H),1.49(s,3H).LC-MS(ESI)m/z:460.20[M+H] + .
Example 76
Step 1: synthesis of II-38-1
In a round bottom flask, 6-fluoronicotinonitrile (200 mg,1.64 mmol), 3, 8-diazabicyclo [3.2.1 ] was added sequentially ]Octane-3-carboxylic acid tert-butyl ester (417.28 mg,1.97 mmol) and K 2 CO 3 (452.75 mg,3.28 mmol). Then 6mL of DMF was added and the reaction was carried out at 80℃for 4 hours. After the completion of the TLC monitoring reaction, the reaction was cooled to room temperature, 20mL of water was added, and the solid was precipitated by stirring, and suction filtration was performed under reduced pressure to obtain 480mg of a white solid, the yield was 93.21%. 1 H NMR(300MHz,Chloroform-d)δ8.45(d,J＝2.2Hz,1H),7.65(dd,J＝8.9,2.3Hz,1H),6.57(d,J＝8.9Hz,1H),4.63(s,2H),3.95(d,J＝12.9Hz,1H),3.80(d,J＝12.8Hz,1H),3.19(d,J＝12.8Hz,1H),3.09(d,J＝12.9Hz,1H),2.15–2.00(m,2H),2.00–1.84(m,2H),1.50(s,9H).LC-MS(ESI)m/z:313.55[M-H] + .
Step 2: synthesis of II-38-2
II-38-1 (280 mg,0.89 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 160mg of a white solid in 83.84% yield.
Step 3: synthesis of II-38
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-38-2, compound II-38 was produced in the same manner as in the case of 170mg of a white solid with a yield of 75.19%. 1 H NMR(300MHz,Chloroform-d)δ9.33(s,1H),8.41(dd,J＝2.3,0.8Hz,1H),8.12(d,J＝2.1Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.84(d,J＝8.5Hz,1H),7.62(dd,J＝8.9,2.3Hz,1H),6.48(d,J＝8.9Hz,1H),5.02(s,1H),4.57(d,J＝61.6Hz,2H),3.23(d,J＝13.2Hz,1H),2.89–2.62(m,2H),2.59–2.41(m,2H),2.38(d,J＝13.3Hz,1H),2.06(s,3H),1.95–1.77(m,1H),1.43(s,3H).LC-MS(ESI)m/z:485.20[M+H] + .
Example 77
Step 1: synthesis of II-39-1
With reference to the synthetic method of step 1 of example 76, except that 6-fluoronicotinonitrile in step 1 was replaced with 2-chloro-5-cyanopyrimidine, compound II-39-1 was prepared in the same manner as in example 76, to obtain 280mg of a yellow solid in 61.94% yield. 1 H NMR(300MHz,Chloroform-d)δ8.53(s,2H),4.87(d,J＝13.6Hz,2H),4.02(d,J＝13.0Hz,1H),3.86(d,J＝12.8Hz,1H),3.15(d,J＝12.8Hz,1H),3.06(d,J＝12.9Hz,1H),2.06(dd,J＝11.0,6.4Hz,2H),1.93(d,J＝16.3Hz,2H),1.51(s,9H).LC-MS(ESI)m/z:316.90[M+H] + .
Step 2: synthesis of II-39-2
II-39-1 (200 mg,0.63 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 130mg of a pale yellow solid with 95.23% yield.
Step 3: synthesis of II-39
Reference example 1 the synthetic method of step 3, except that the procedure was followedThe substitution of I-1-2 in step 3 for II-39-2 produced compound II-39 in the same way as described above gave 107mg of a white solid in 47.44% yield. 1 H NMR(300MHz,Chloroform-d)δ9.32(s,1H),8.47(q,J＝3.2Hz,2H),8.09(d,J＝2.1Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.82(d,J＝8.5Hz,1H),4.95(s,1H),4.85(d,J＝3.5Hz,1H),4.78–4.66(m,1H),3.22(d,J＝13.3Hz,1H),2.77(d,J＝2.3Hz,2H),2.49(d,J＝2.3Hz,2H),2.40(d,J＝13.3Hz,1H),2.03(tt,J＝10.1,5.8Hz,3H),1.84(dt,J＝13.0,4.9Hz,1H),1.42(s,3H).LC-MS(ESI)m/z:486.55[M+H] + .
Example 78
With reference to the synthetic method of step 3 of example 1, except that I-1-2 and S2 in step 3 were replaced with II-5-2 and S4, compound II-40 was prepared in the same manner as in 100mg of a yellow solid with a yield of 38.87%. 1 H NMR(300MHz,Chloroform-d)δ9.47(s,1H),8.91(d,J＝2.4Hz,1H),8.81(d,J＝2.4Hz,1H),7.49(d,J＝8.5Hz,2H),6.71(d,J＝8.8Hz,2H),5.06(s,1H),4.32(s,1H),4.19(d,J＝4.4Hz,1H),3.18(d,J＝13.5Hz,1H),2.89(d,J＝10.8Hz,1H),2.71–2.48(m,2H),2.34(t,J＝12.2Hz,2H),2.08(d,J＝7.8Hz,3H),1.85(d,J＝12.6Hz,1H),1.43(s,3H).LC-MS(ESI)m/z:485.15[M+H] + .
Example 79
With reference to the synthetic method of step 3 of example 1, except that I-1-2 and S2 in step 3 were replaced with II-5-2 and S15, compound II-41 was prepared in the same manner as in step 1, 172mg of pale yellow solid was obtained, and the yield was 58.24%. 1 H NMR(300MHz,Chloroform-d)δ9.23(s,1H),8.01(d,J＝2.0Hz,1H),7.64(d,J＝8.5Hz,1H),7.55(dd,J＝8.6,2.1Hz,1H),7.51–7.41(m,2H),6.74–6.64(m,2H),4.97(s,1H),4.29(d,J＝4.7Hz,1H),4.17(d,J＝5.3Hz,1H),3.17(d,J＝13.3Hz,1H),2.94–2.78(m,1H),2.68–2.50(m,2H),2.32(dd,J＝11.9,8.3Hz,2H),2.16–1.96(m,3H),1.95–1.79(m,1H),1.40(s,3H).LC-MS(ESI)m/z:450.90[M+H] + .
Example 80
Step 1: synthesis of II-42-1
With reference to the synthetic method of step 1 of example 4, except that 2-cyano-5-fluoropyridine in step 1 was replaced with 5-cyano-2-fluoropyridine, compound II-42-1 was produced in the same manner to obtain 210mg of a white solid in 88.92% yield. 1 H NMR(300MHz,Chloroform-d)δ8.46(d,J＝2.2Hz,1H),7.68(dd,J＝9.0,2.3Hz,1H),6.65(d,J＝9.0Hz,1H),3.73(dd,J＝6.8,3.8Hz,4H),3.59(dd,J＝6.7,3.7Hz,4H),1.53(s,9H).LC-MS(ESI)m/z:289.10[M+H] + .
Step 2 Synthesis of II-42-2
II-42-1 (210 mg,0.73 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched at room temperature for 4h, after completion of TLC monitoring, 1M aqueous NaOH solution was added, the reaction was quenched, DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 120mg of a yellow oil, 87.54% yield.
Step 2 Synthesis of II-42
With reference to the synthesis of example 1, step 3, except that I-1-2 in step 3 was replaced with II-42-2, compound II-42 was prepared in the same manner as 150mg of oily substance with a yield of 51.32%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),8.36(d,J＝2.4Hz,1H),8.15(d,J＝2.2Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.80(d,J＝8.5 Hz,1H),7.59(dd,J＝9.0,2.4Hz,1H),6.57(d,J＝9.0Hz,1H),5.02(s,1H),3.66(dt,J＝7.4,3.2Hz,4H),3.31(d,J＝13.3Hz,1H),2.66(q,J＝4.7Hz,4H),2.51(d,J＝13.3Hz,1H),1.45(s,3H).LC-MS(ESI)m/z:459.70[M+H] + .
Example 81
With reference to the synthetic method of step 3 of example 1, except that S2 and I-1-2 in step 3 were replaced with S11 and II-5-2, compound II-43 was prepared in the same manner as in step 3, 120mg of yellow oil was obtained in a yield of 69.50%. 1 H NMR(300MHz,Chloroform-d)δ9.19(s,1H),7.75(d,J＝1.9Hz,1H),7.52(d,J＝8.3Hz,1H),7.49–7.41(m,2H),6.97(dd,J＝8.4,1.9Hz,1H),6.79–6.59(m,2H),4.98(s,1H),4.30(s,1H),4.17(d,J＝5.3Hz,1H),3.96(s,3H),3.17(d,J＝13.2Hz,1H),2.86(dd,J＝10.9,1.7Hz,1H),2.58(ddd,J＝11.2,6.1,2.0Hz,2H),2.37(dd,J＝11.1,2.5Hz,1H),2.31(d,J＝13.2Hz,1H),2.05(p,J＝5.1,4.5Hz,3H),1.93–1.79(m,1H),1.41(s,3H).LC-MS(ESI)m/z:466.20[M+H] + .
Example 82
Referring to the synthesis of example 1, step 3, except that S2 and I-1-2 in step 3 were replaced with S9 and II-5-2, compound II-44 was prepared in the same manner as described above, 110mg of a yellow solid was obtained in 58.25% yield. 1 H NMR(300MHz,Chloroform-d)δ9.40(s,1H),8.14(d,J＝2.0Hz,1H),8.10–7.98(m,2H),7.50(d,J＝8.6Hz,2H),6.72(d,J＝8.6Hz,2H),5.03(s,1H),4.33(s,1H),4.20(s,1H),3.22(d,J＝13.3Hz,1H),2.91(d,J＝10.8Hz,1H),2.65(d,J＝3.2Hz,1H),2.61(d,J＝3.5Hz,1H),2.39(d,J＝3.4Hz,1H),2.35(d,J＝3.9Hz,1H),2.10(dt,J＝11.6,6.6Hz,3H),1.99–1.80(m,1H),1.45(s,3H).LC-MS(ESI)m/z:504.50[M+H] + .
Example 83
Step 1: synthesis of II-45-1
Reference example 22 Synthesis method of step 1 except that 4-bromobenzonitrile and (S) -1-N-t-butoxycarbonyl-2-methylpiperazine in step 1 were replaced with 4-bromo-3-methylbenzonitrile and 3, 8-diazabicyclo [3.2.1]Compound II-45-1 was obtained as a pale yellow solid (260 mg) in 77.84% yield by the same method as in tert-butyl octane-3-carboxylate. 1 H NMR(300MHz,Chloroform-d)δ7.44(d,J＝2.0Hz,1H),7.40(dd,J＝8.3,2.1Hz,1H),6.85(d,J＝8.3Hz,1H),3.94(d,J＝12.3Hz,1H),3.81(d,J＝14.1Hz,3H),3.28(d,J＝11.8Hz,1H),3.19(d,J＝12.3Hz,1H),2.37(s,3H),1.92(t,J＝6.3Hz,2H),1.83(d,J＝15.7Hz,2H),1.50(s,9H).LC-MS(ESI)m/z:328.00[M+H] + .
Step 2: synthesis of II-45-2
II-45-1 (220 mg,0.67 mmol) was dissolved in DCM (2 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 123mg of a white solid with 80.53% yield.
Step 2: synthesis of II-45
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-45-2, compound II-45 was produced in the same manner as in 200mg of a white solid with a yield of 91.38%. 1 H NMR(300MHz,Chloroform-d)δ9.36(s,1H),8.13(d,J＝2.1Hz,1H),7.98(dd,J＝8.5,2.2Hz,1H),7.83(d,J＝8.5Hz,1H),7.42(d,J＝2.1Hz,1H),7.37(dd,J＝8.3,2.1Hz,1H),6.81(d,J＝8.4Hz,1H),5.19(s,1H),3.88(s,1H),3.74(d,J＝5.8Hz,1H),3.34(d,J＝13.2Hz,1H),3.05–2.91(m,1H),2.76(dd,J＝10.6,3.0Hz,1H),2.68(dd,J＝10.6,1.7Hz,1H),2.56–2.41(m,2H),2.33(s,3H),2.06–1.94(m,2H),1.89(q,J＝7.3Hz,1H),1.83–1.69(m,1H),1.46(s,3H).MS(ESI)m/z:498.80[M+H] + .
Example 84
Step 1: synthesis of II-46-1
Reference example 22 Synthesis method of step 1 except that 4-bromobenzonitrile and (S) -1-N-t-butoxycarbonyl-2-methylpiperazine in step 1 were replaced with 3-fluoro-4-bromobenzonitrile and 3, 8-diazabicyclo [3.2.1]Compound II-46-1 was obtained as a pale yellow solid in 217mg and 43.66% yield. 1 H NMR(300MHz,Chloroform-d)δ7.34–7.24(m,2H),6.85(t,J＝8.6Hz,1H),4.36(s,2H),3.85(d,J＝13.0Hz,1H),3.72(d,J＝11.9Hz,1H),3.23(d,J＝12.8Hz,1H),3.14(d,J＝12.9Hz,1H),2.05–1.94(m,2H),1.87(d,J＝16.2Hz,2H),1.47(s,10H).LC-MS(ESI)m/z:332.35[M+H] + .
Step 2: synthesis of II-46-2
II-46-1 (200 mg,0.60 mmol) was dissolved in DCM (2 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 70mg of a white solid with a yield of 50.15%.
Step 2: synthesis of II-46
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-46-2, compound II-46 was produced in the same manner as in 112mg of a white solid with a yield of 73.79%. 1 H NMR(300MHz,Chloroform-d)δ9.33(s,1H),8.11(d,J＝2.0Hz,1H),7.96(dd,J＝8.6,2.1Hz,1H),7.82(d,J＝8.5Hz,1H),7.33–7.20(m,1H),6.77(t,J＝8.6Hz,1H),5.00(s,1H),4.39(s,1H),4.23(s,1H),3.21(d,J＝13.3Hz,1H),2.87(d,J＝11.0Hz,1H),2.70–2.52(m,2H),2.45–2.28(m,2H),2.15–1.91(m,3H),1.91–1.73(m,1H),1.41(s,3H).MS(ESI)m/z:502.70[M+H] + .
Example 85
Reference example 1 the synthetic method of step 3, except that S2 and I-1-2 in step 3 were replaced with S13 and II-5-2, compound II-47 was obtained as a pale yellow solid (117 mg) in a yield of 76.91%. 1 H NMR(300MHz,Chloroform-d)δ9.42(d,J＝3.5Hz,1H),8.18(dd,J＝8.8,6.7Hz,1H),7.46(d,J＝8.5Hz,2H),7.34(dd,J＝8.6, 1.8Hz,1H),6.67(d,J＝8.6Hz,2H),4.94(s,1H),4.28(s,1H),4.16(d,J＝2.6Hz,4H),3.16(d,J＝13.3Hz,1H),2.85(d,J＝10.8Hz,1H),2.66–2.48(m,2H),2.43–2.21(m,2H),2.17–1.95(m,3H),1.94–1.75(m,1H),1.40(s,3H).MS(ESI)m/z:464.40[M+H] + .
Example 86
1- (4-bromophenyl) piperazine hydrochloride (115 mg,0.41 mmol) was suspended in saturated aqueous sodium bicarbonate (5 mL), stirred at room temperature for 10min, extracted with EA, anhydrous Na 2 SO 4 Drying, filtering and concentrating. The solid was dissolved in absolute ethanol, S2 (111.94 mg,0.41 mmol) was added, refluxed for 4h, after completion of the tlc monitoring reaction, evaporated to dryness under reduced pressure and the residue obtained was separated by silica gel column chromatography (dichloromethane: methanol=100:1) to give 204mg of a white solid with a yield of 96.30%. 1 H NMR(300MHz,Chloroform-d)δ9.43(s,1H),8.16(d,J＝2.1Hz,1H),7.99(dd,J＝8.5,2.1Hz,1H),7.84(d,J＝8.5Hz,1H),7.42–7.32(m,2H),6.83–6.71(m,2H),5.23(s,1H),3.38(d,J＝13.2Hz,1H),3.16(d,J＝5.2Hz,4H),2.77(q,J＝5.3Hz,4H),2.56(d,J＝13.2Hz,1H),1.49(s,3H).LC-MS(ESI)m/z:511.20[M+H] + .
Example 87
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with 1- (4-chlorophenyl) piperazine, compound II-49 was prepared in the same manner as a white solid 100mg with a yield of 57.71%. 1 H NMR(300MHz,Chloroform-d)δ9.41(s,1H),8.14(d,J＝2.2Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.83(d,J＝8.5Hz,1H),7.26–7.14(m,2H),6.89–6.73(m,2H),5.25(s,1H),3.37(d,J＝12.9Hz,1H),3.14(d,J＝5.2Hz,4H),2.75(q,J＝5.4Hz,4H),2.54(d,J＝13.0Hz,1H),1.47(s,3H).LC-MS(ESI)m/z:467.40[M+H] + .
Example 88
Step 1: synthesis of II-50-1
Reference example 4 Synthesis method of step 1 except that 2-cyano-5-fluoropyridine and 1- (t-butoxycarbonyl) piperazine in step 1 were replaced with 2-cyano-3, 5-difluoropyridine and 3, 8-diazabicyclo [3.2.1]Compound II-50-1 was obtained in the same manner as in tert-butyl octane-3-carboxylate to give 300mg of a white solid in 63.22% yield. 1 H NMR(300MHz,Chloroform-d)δ8.02(t,J＝2.0Hz,1H),6.72(dd,J＝11.5,2.4Hz,1H),4.29(s,2H),3.92(d,J＝13.2Hz,1H),3.77(d,J＝13.1Hz,1H),3.21(d,J＝13.1Hz,1H),3.10(d,J＝13.2Hz,1H),2.09(d,J＝7.3Hz,2H),2.03–1.87(m,2H),1.47(s,9H).LC-MS(ESI)m/z:333.10[M+H] + .
Step 2 Synthesis of II-50-2
II-50-1 (250 mg,0.83 mmol) was dissolved in DCM (4 mL), TFA 1mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of TLC monitoring, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 150mg of a white solid in 85.86% yield.
Step 3 Synthesis of II-50
With reference to the synthesis of example 1, step 3, except that I-1-2 in step 3 was replaced with II-50-2, compound II-50 was prepared in the same manner as 230mg of oil with a yield of 70.88%. 1 H NMR(300MHz,Chloroform-d)δ9.31(s,1H),8.12(d,J＝2.2Hz,1H),8.07–7.90(m,2H),7.84(d,J＝8.5Hz,1H),6.66(dd,J＝11.4,2.4Hz,1H),4.68(s,1H),4.32(s,1H),4.19(s,1H),3.22(d,J＝13.3Hz,1H),2.84(d,J＝11.1Hz,1H),2.78–2.66(m,1H),2.57(d,J＝11.4Hz,1H),2.45(dd,J＝11.2,2.4Hz,1H),2.38(d,J＝13.4Hz,1H),2.10(q,J＝10.0,6.9Hz,3H),1.99–1.79(m,1H),1.43(s,3H).LC-MS(ESI)m/z:501.10[M-H] + .
Example 89
With reference to the synthetic method of step 3 of example 1, except that S2 and I-1-2 in step 3 were replaced with S4 and II-30-2, compound II-51 was prepared in the same manner as in 130mg of pale yellow solid with a yield of 68.83%. 1 H NMR(300MHz,Chloroform-d)δ9.12(s,1H),8.86(d,J＝2.5Hz,1H),8.77(d,J＝2.4Hz,1H),7.50(d,J＝8.2Hz,2H),6.50(d,J＝8.3Hz,2H),4.37–4.17(m,2H),3.90(s,1H),3.34(d,J＝13.9Hz,1H),3.29(d,J ＝9.8Hz,1H),3.20(d,J＝11.3Hz,1H),2.82(d,J＝11.0Hz,2H),2.79–2.65(m,1H),2.42(d,J＝13.5Hz,1H),1.72(d,J＝8.4Hz,1H),1.30(s,3H).LC-MS(ESI)m/z:471.10[M+H] + .
Example 90
With reference to the synthetic method of step 3 of example 1, except that S2 and I-1-2 in step 3 were replaced with S4 and II-46-2, compound II-52 was prepared in the same manner, 165mg of a white solid was obtained in 75.94% yield. 1 H NMR(300MHz,Chloroform-d)δ9.47(s,1H),8.90(d,J＝2.4Hz,1H),8.80(d,J＝2.5Hz,1H),7.40–7.15(m,2H),6.78(t,J＝8.6Hz,1H),5.04(s,1H),4.55–4.09(m,2H),3.20(d,J＝13.3Hz,1H),2.88(d,J＝10.9Hz,1H),2.76–2.50(m,2H),2.37(td,J＝8.5,7.7,4.8Hz,2H),2.03(qt,J＝11.7,6.0Hz,3H),1.84(p,J＝10.3,8.5Hz,1H),1.43(s,3H).LC-MS(ESI)m/z:525.25[M+Na] + .
Example 91
Step 1: synthesis of II-53-1
Reference example 22 Synthesis method of step 1 except that 4-bromobenzonitrile and (S) -1-N-t-butoxycarbonyl-2-methylpiperazine in step 1 were replaced with 4-bromo-3-fluorobenzonitrile and 3, 6-diazabicyclo [ 3.1.1.1 ]Heptane-3-carboxylic acid tert-butyl ester was obtained in the same manner as Compound II-53-1 to obtain 1.3g of pale yellow solid, yield 54.14%. 1 H NMR(300MHz,Chloroform-d)δ7.39–7.12(m,2H),6.58(t,J＝8.3Hz,1H),4.43(ddd,J＝16.7,5.9,3.0Hz,2H),3.79(t,J＝12.3Hz,2H),3.64–3.35(m,2H),2.85(q,J＝6.8Hz,1H),1.69(d,J＝8.6Hz,1H),1.41(s,9H).LC-MS(ESI)m/z:318.10[M+H] + .
Step 2: synthesis of II-53-2
II-53-1 (200 mg,0.63 mmol) was dissolved in DCM (2 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 100mg of a pale yellow solid in 73.04% yield.
Step 2: synthesis of II-53
Referring to the synthesis of example 1, step 3, except that S2 and I-1-2 in step 3 were replaced with S15 and II-53-2, compound II-53 was prepared in the same manner as in example 1, 113mg of a white solid was obtained in a yield of 54.08%. 1 H NMR(300MHz,Chloroform- d)δ9.09(s,1H),8.15(d,J＝2.0Hz,1H),8.02–7.69(m,2H),7.28(dd,J＝17.5,10.2Hz,2H),6.55(t,J＝8.4Hz,1H),4.37(d,J＝5.8Hz,2H),4.11(s,1H),3.37(d,J＝13.4Hz,1H),3.21(d,J＝11.3Hz,2H),2.85(td,J＝16.2,8.8Hz,3H),2.45(d,J＝13.4Hz,1H),1.83(d,J＝8.3Hz,1H),1.34(s,3H).LC-MS(ESI)m/z:488.15[M+H] + .
Example 92
Step 1: synthesis of II-54-1
Reference example 22 Synthesis method of step 1 except that 4-bromobenzonitrile and (S) -1-N-t-butoxycarbonyl-2-methylpiperazine in step 1 were replaced with 3-methoxy-4-bromobenzonitrile and 3, 8-diazabicyclo [3.2.1]Compound II-54-1 was prepared from tert-butyl octane-3-carboxylate in the same manner to give 340mg of a yellow solid in 83.97% yield. 1 H NMR(300MHz,Chloroform-d)δ7.19(dd,J＝8.3,1.8Hz,1H),7.03(d,J＝1.8Hz,1H),6.78(d,J＝8.4Hz,1H),4.32(s,2H),3.87(s,3H),3.83(d,J＝12.0Hz,1H),3.76–3.64(m,1H),3.20(dd,J＝26.1,12.7Hz,2H),1.94(dt,J＝13.2,6.0Hz,2H),1.87–1.69(m,2H),1.46(s,9H).LC-MS(ESI)m/z:344.25[M+H] + .
Step 2: synthesis of II-54-2
II-54-1 (200 mg,0.58 mmol) was dissolved in DCM (2 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of TLC monitoring, the reaction was extracted with DCM (5 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give 120mg of a yellow solid in 84.69% yield.
Step 3: synthesis of II-54
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-54-2, compound II-54 was produced in the same manner as in 200mg of a white solid with a yield of 78.97%. 1 H NMR(300MHz,Chloroform-d)δ9.39(s,1H),8.14(d,J＝2.1Hz,1H),7.98(dd,J＝8.5,2.2Hz,1H),7.83(d,J＝8.5Hz,1H),7.18(dd,J＝8.3,1.8Hz,1H),7.02(d,J＝1.8Hz,1H),6.74(d,J＝8.3Hz,1H),5.21(s,1H),4.54–4.10(m,2H),3.85(s,3H),3.25(d,J＝13.2Hz,1H),2.93(d,J＝10.7Hz,1H),2.65(d,J＝10.9Hz,2H),2.39(d,J＝12.5Hz,2H),2.14–1.86(m,3H),1.79(d,J＝6.0Hz,1H),1.43(s,3H).LC-MS(ESI)m/z:514.20[M+H] + .
Example 93
Step 1: synthesis of II-55-1
Reference example 22 Synthesis method of step 1 except that 4-bromobenzonitrile and (S) -1-N-t-butoxycarbonyl-2-methylpiperazine in step 1 were replaced with 5-bromo-2-cyanopyrimidine and 3, 8-diazabicyclo [3.2.1]Compound II-55-1 was prepared from tert-butyl octane-3-carboxylate in the same manner to obtain 274mg of yellow solid in 79.93% yield. 1 H NMR(300MHz,Chloroform-d)δ8.23(s,2H),4.35(d,J＝11.7Hz,2H),3.84(dd,J＝41.8,13.3Hz,2H),3.14(dd,J＝33.3,13.5Hz,2H),2.25–1.84(m,4H),1.46(s,9H).LC-MS(ESI)m/z:316.20[M+H] + .
Step 2: synthesis of II-55-2
II-55-1 (174 mg,0.55 mmol) was dissolved in DCM (2 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 104mg of a yellow solid in 87.57% yield.
Step 3: synthesis of II-55
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-55-2, compound II-55 was produced in the same manner as in example 1, with 113mg of a white solid in 54.32% yield. 1 H NMR(300MHz,Chloroform-d)δ9.19(s,1H),7.99(d,J＝2.0Hz,1H),7.64(d,J＝8.5Hz,1H),7.54(dd,J＝8.6,2.1Hz,1H),7.26(dd,J＝23.3,1.9Hz,2H),6.77(t,J＝8.6Hz,1H),4.98(s,1H),4.31(d,J＝45.4Hz,2H),3.21(d,J＝13.2Hz,1H),2.87(d,J＝11.4Hz,1H),2.73–2.46(m,2H),2.35(t,J＝12.3Hz,2H),2.03(p,J＝11.1,9.6Hz,3H),1.81(s,1H),1.40(s,3H).LC-MS(ESI)m/z:468.15[M+H] + .
Example 94
Reference example 1 the synthetic method of step 3, except that S2 and I-1-2 in step 3 were replaced with S17 and II-5-2, and Compound II-56 was prepared in the same manner 104mg of pale yellow solid was found to be 61.49% in yield. 1 H NMR(300MHz,Chloroform-d)δ9.30(s,1H),8.64(d,J＝2.2Hz,1H),8.54(d,J＝2.3Hz,1H),7.47(d,J＝8.4Hz,2H),6.68(d,J＝8.5Hz,2H),5.01(s,1H),4.22(d,J＝38.1Hz,2H),3.16(d,J＝13.3Hz,1H),2.86(d,J＝10.9Hz,1H),2.69–2.44(m,2H),2.31(t,J＝11.0Hz,2H),2.17–1.93(m,3H),1.85(q,J＝10.3,9.3Hz,1H),1.40(s,3H).LC-MS(ESI)m/z:449.10[M-H] + .
Example 95
Step 1: synthesis of II-57-1
Reference example 25 Synthesis method of step 1 except that (1S, 4S) - (-) -2-t-butoxycarbonyl-2, 5-diazabicyclo [2.2.1 ] in step 1]The heptane was replaced with (S) -3-methylpiperazine-1-carboxylic acid tert-butyl ester, and compound II-57-1 was prepared in the same manner as to obtain 251mg of brown solid in 37.90% yield. 1 H NMR(300MHz,Chloroform-d)δ7.63–7.48(m,2H),6.87(d,J＝8.6Hz,2H),4.03(d,J＝30.7Hz,3H),3.47(d,J＝11.5Hz,1H),3.38–2.95(m,3H),1.53(s,9H),1.16(d,J＝6.7Hz,3H).LC-MS(ESI)m/z:302.10[M+H] + .
Step 2: synthesis of II-57-2
II-57-1 (150 mg,0.52 mmol) was dissolved in DCM (3 mL), TFA 0.8mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 100mg of a yellow solid in 95.38% yield.
Step 3: synthesis of II-57
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-57-2, compound II-57 was produced in the same manner as in 160mg of a white solid with a yield of 68.30%. 1 H NMR(300MHz,Chloroform-d)δ9.37(s,1H),8.14(d,J＝2.2Hz,1H),7.91(dd,J＝8.5,2.2Hz,1H),7.81(d,J＝8.5Hz,1H),7.58–7.39(m,2H),6.77(d,J＝8.6Hz,2H),5.03(s,1H),4.00(s,1H),3.50(d,J＝12.3Hz,1H),3.35–3.10(m,2H),2.92(d,J＝11.3Hz,1H),2.81–2.32(m,4H),1.46(s,3H),1.05(d,J＝6.6Hz,3H).LC-MS(ESI)m/z:472.20[M+H] + .
Example 96
Referring to the synthesis of example 1, step 3, except that S2 and I-1-2 in step 3 were replaced with S15 and II-46-2, compound II-58 was prepared in the same manner as a pale yellow solid (125 mg) with a yield of 61.78%. 1 H NMR(300MHz,Chloroform-d)δ9.19(s,1H),7.99(d,J＝2.0Hz,1H),7.64(d,J＝8.5Hz,1H),7.54(dd,J＝8.6,2.1Hz,1H),7.26(dd,J＝23.3,1.9Hz,2H),6.77(t,J＝8.6Hz,1H),4.98(s,1H),4.31(d,J＝45.4Hz,2H),3.21(d,J＝13.2Hz,1H),2.87(d,J＝11.4Hz,1H),2.73–2.46(m,2H),2.35(t,J＝12.3Hz,2H),2.03(p,J＝11.1,9.6Hz,3H),1.81(s,1H),1.40(s,3H).LC-MS(ESI)m/z:468.15[M+H] + .
Example 97
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-55-2, compound II-59 was produced in the same manner as in example 1, 118mg of a white solid was produced in a yield of 52.32%. 1 H NMR(300MHz,DMSO-d 6 )δ10.48(s,1H),8.61(d,J＝2.0Hz,1H),8.43(s,2H),8.36(dd,J＝8.6,2.1Hz,1H),8.12(d,J＝8.6Hz,1H),5.78(s,1H),4.45(d,J＝16.8Hz,2H),3.09–2.95(m,1H),2.63(d,J＝13.7Hz,1H),2.48–2.32(m,4H),1.88(d,J＝7.0Hz,1H),1.64(td,J＝18.4,14.8,6.9Hz,3H),1.29(s,3H).LC-MS(ESI)m/z:486.15[M+H] + .
Example 98
With reference to the synthetic method of step 3 of example 1, except that S2 and I-1-2 in step 3 were replaced with S17 and II-46-2, compound II-60 was prepared in the same manner as in 97mg of pale yellow solid with a yield of 7.84%. 1 H NMR(300MHz,Chloroform-d)δ9.31(s,1H),8.65(d,J＝2.3Hz,1H),8.55(d,J＝2.3Hz,1H),7.33–7.19(m,2H),6.77(t,J＝8.6Hz,1H),5.00(s,1H),4.44–4.18(m,2H),3.19(d,J＝13.3Hz,1H),2.87(d,J＝10.8Hz,1H),2.71–2.49(m,2H),2.42–2.26(m,2H),2.02(q,J＝12.7,8.8Hz,3H),1.88–1.74(m,1H),1.41(s,3H).LC-MS(ESI)m/z:469.10[M+H] + .
Example 99
Step 1: synthesis of II-60
Referring to the synthesis of example 1, step 3, except that S2 and I-1-2 in step 3 were replaced with S4 and II-55-2, compound II-61 was prepared in the same manner as a pale yellow solid (95 mg) with a yield of 52.96%. 1 H NMR(300MHz,DMSO-d 6 )δ10.77(s,1H),9.46(d,J＝2.2Hz,1H),8.97(d,J＝2.3Hz,1H),8.43(s,2H),5.90(s,1H),4.45(d,J＝18.4Hz,2H),3.04(d,J＝10.9Hz,1H),2.64(d,J＝13.7Hz,1H),2.49–2.27(m,4H),1.87(q,J＝10.3Hz,1H),1.79–1.46(m,3H),1.31(s,3H).LC-MS(ESI)m/z:487.15[M+H] + .
Example 100
With reference to the synthetic method of step 3 of example 1, except that S2 and I-1-2 in step 3 were replaced with S15 and II-30-2, compound II-62 was prepared in the same manner as 165mg of a white solid with a yield of 74.65%. 1 H NMR(300MHz,Chloroform-d)δ8.79(s,1H),8.03(d,J＝2.0Hz,1H),7.66(d,J＝8.5Hz,1H),7.45(t,J＝8.7Hz,3H),6.50(d,J＝8.2Hz,2H),4.27(p,J＝5.7,5.1Hz,2H),3.67(s,1H),3.37(d,J＝13.5Hz,1H),3.34–3.25(m,1H),3.25–3.12(m,1H),2.93–2.65(m,3H),2.36(d,J＝13.5Hz,1H),1.68(s,1H),1.26(s,3H).LC-MS(ESI)m/z:436.15[M+H] + .
Example 101
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-53-2, compound II-63 was produced in the same manner as in example 1, and 108mg of a white solid was obtained in a yield of 56.63%. 1 H NMR(300MHz,Chloroform-d)δ9.09(s,1H),8.15(d,J＝2.0Hz,1H),8.02–7.69(m,2H),7.28(dd,J＝17.5,10.2Hz,2H),6.55(t,J＝8.4Hz,1H),4.37(d,J＝5.8Hz,2H),4.11(s,1H),3.37(d,J＝13.4Hz,1H),3.21(d,J＝11.3Hz,2H),2.85(td,J＝16.2,8.8Hz,3H),2.45(d,J＝13.4Hz,1H),1.83(d,J＝8.3Hz,1H),1.34(s,3H).LC-MS(ESI)m/z:488.15[M+H] + .
Example 102
With reference to the synthetic method of step 3 of example 1, except that S2 and I-1-2 in step 3 were replaced with S4 and II-53-2, compound II-64 was prepared in the same manner as a pale yellow solid 98mg, with a yield of 60.54%. 1 H NMR(300MHz,Chloroform-d)δ9.26(s,1H),8.87(d,J＝2.4Hz,1H),8.77(d,J＝2.4Hz,1H),7.52–7.09(m,2H),6.54(t,J＝8.4Hz,1H),4.37(d,J＝6.0Hz,2H),4.21(s,1H),3.34(d,J＝13.4Hz,1H),3.18(d,J＝11.3Hz,2H),3.02–2.63(m,3H),2.47(d,J＝13.4Hz,1H),1.85(d,J＝8.4Hz,1H),1.35(s,3H).LC-MS(ESI)m/z:489.15[M+H] + .
Example 103
Referring to the synthesis of example 1, step 3, except that S2 and I-1-2 in step 3 were replaced with S17 and II-53-2, compound II-65 was prepared in the same manner as described above, 84mg of a white solid was obtained in a yield of 66.86%. 1 H NMR(300MHz,DMSO-d 6 )δ10.40(s,1H),9.03(s,1H),8.59(s,1H),7.49(d,J＝12.7Hz,1H),7.32(d,J＝8.5Hz,1H),6.75(t,J＝8.5Hz,1H),5.67(s,1H),4.30(s,2H),3.24–3.03(m,3H),2.82(d,J＝12.7Hz,2H),2.55(s,2H),1.73(d,J＝7.6Hz,1H),1.20(s,3H).LC-MS(ESI)m/z:455.10[M+H] + .
Example 104
Step 1: synthesis of II-66-1
Reference example 4 Synthesis method of step 1 except that 2-cyano-5-fluoropyridine and 1- (t-butoxycarbonyl) piperazine in step 1 were replaced with 5-bromo-2-cyanopyrimidine and 3, 6-diazabicyclo [3.1.1]Heptane-3-carboxylic acid tert-butyl ester, compound II-66-1 was prepared in the same manner to obtain 420mg of a yellow solid, yield 42.51%. 1 H NMR(300MHz,Chloroform-d)δ8.06(s,2H),4.64–4.38(m,2H),3.89(dt,J＝13.1,1.7Hz,2H),3.70–3.51(m,2H),2.97(q,J＝7.0Hz,1H),1.82(d,J＝8.9Hz,1H),1.46(s,9H).LC-MS(ESI)m/z:302.10[M+H] + .
Step 2: synthesis of II-66-2
II-66-1 (250 mg,0.83 mmol) was dissolved in DCM (3 mL), TFA 1mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of TLC monitoring for 0.5h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 120mg as a pale yellow solid with 71.88% yield.
Step 4: synthesis of II-66
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-66-2, compound II-66 was produced in the same manner as in step 1, 110mg of a white solid was produced in a yield of 58.69%. 1 H NMR(300MHz,DMSO-d 6 )δ10.23(s,1H),8.45(d,J＝2.0Hz,1H),8.32–8.14(m,3H),8.07(d,J＝8.6Hz,1H),5.61(s,1H),4.41(s,2H),3.39(d,J＝2.6Hz,1H),3.25(dd,J＝11.1,1.8Hz,1H),3.03(d,J＝11.3Hz,1H),2.87(d,J＝13.9Hz,1H),2.83–2.75(m,1H),2.66–2.54(m,2H),1.66(d,J＝8.0Hz,1H),1.15(s,3H).LC-MS(ESI)m/z:472.15[M+H] + .
Example 105
Referring to the synthesis method of step 3 of example 1, except that S2 and I-1-2 in step 3 were replaced with S4 and II-66-2, compound II-67 was prepared in the same manner as 102mg of pale yellow solid with a yield of 52.98%. 1 H NMR(400MHz,DMSO-d 6 )δ10.46(s,1H),9.31(d,J＝2.2Hz,1H),8.80(d,J＝2.2Hz,1H),8.19(s,2H),5.72(s,1H),4.40(d,J＝6.0Hz,2H),3.50(d,J＝10.9Hz,1H),3.29(d,J＝11.0Hz,1H),2.96(d,J＝11.2Hz,1H),2.90(d,J＝13.9Hz,1H),2.78(d,J＝11.4Hz,1H),2.66–2.56(m,2H),1.60(d,J＝8.1Hz,1H),1.16(s,3H).LC-MS(ESI)m/z:473.10[M+H] + .
Example 106
Referring to the synthesis of example 1, step 3, except that S2 and I-1-2 in step 3 were replaced with S15 and II-66-2, compound II-68 was prepared in the same manner as in example 1, 122mg of a white solid was obtained in a yield of 46.96%. 1 H NMR(300MHz,DMSO-d 6 )δ10.06(s,1H),8.29–8.10(m,3H),7.96–7.80(m,2H),5.61(s,1H),4.44(d,J＝5.4Hz,2H),3.33(d,J＝2.4Hz,1H),3.26(dd,J＝11.3,2.4Hz,1H),3.06(dd,J＝11.5,1.6Hz,1H),2.95–2.74(m,2H),2.67–2.55(m,2H),1.70(d,J＝8.0Hz,1H),1.16(s,3H).LC-MS(ESI)m/z:436.05[M-H] + .
Example 107
Step 1: synthesis of II-69-1
Reference example 4 Synthesis method of step 1 except that 2-cyano-5-fluoropyridine and 1- (t-butoxycarbonyl) piperazine in step 1 were replaced with 3-chloro-4-fluorobenzonitrile and 3, 6-diazabicyclo [3.1.1]Heptane-3-carboxylic acid tert-butyl ester was prepared in the same manner to give Compound II-69-1 as a pale yellow solid 435mg, and yield 81.08%. 1 H NMR(300MHz,Chloroform-d)δ7.49(d,J＝1.9Hz,1H),7.37(dd,J＝8.6,1.9Hz,1H),6.57(d,J＝8.5Hz,1H),4.70(d,J＝7.1Hz,2H),3.84(t,J＝14.1Hz,2H),3.49(ddd,J＝12.7,7.2,1.6Hz,2H),2.84(q,J＝7.0Hz,1H),1.67(d,J＝8.6Hz,1H),1.41(s,9H).LC-MS(ESI)m/z:334.10[M+H] + .
Step 2: synthesis of II-69-2
II-69-1 (150 mg,0.45 mmol) was dissolved in DCM (3 mL), TFA 1mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of TLC monitoring the reaction for 0.5h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 150mg of a yellow solid in 95.23% yield.
Step 4: synthesis of II-69
Referring to the synthesis of example 1, step 3, except that S2 and I-1-2 in step 3 were replaced with S4 and II-69-2, compound II-69 was prepared in the same manner as 88mg of a white solid with a yield of 40.73%. 1 H NMR(300MHz,Chloroform-d)δ9.15(s,1H),8.85(d,J＝2.4Hz,1H),8.76(d,J＝2.4Hz,1H),7.52(d,J＝1.9Hz,1H),7.47–7.34(m,1H),6.57(d,J＝8.5Hz,1H),4.60(d,J＝29.2Hz,2H),4.01(s,1H),3.35(d,J＝13.4Hz,1H),3.29(d,J＝11.6Hz,1H),3.19(d,J＝11.2Hz,1H),2.95–2.71(m,3H),2.45(d,J＝13.4Hz,1H),1.71(d,J＝8.4Hz,1H),1.33(s,3H).LC-MS(ESI)m/z:505.10[M+H] + .
Example 108
Step 1: synthesis of II-70-1
Reference example 4 Synthesis method of step 1 except that 2-cyano-5-fluoropyridine and 1- (t-butoxycarbonyl) piperazine in step 1 were replaced with 6-chloro-3-pyridazinecarbonitrile and 3, 6-diazabicyclo [3.1.1 ]Heptane-3-carboxylic acid tert-butyl ester was prepared in the same manner to give compound II-70-1 as a pale yellow solid (512 mg) in 94.83% yield. 1 H NMR(300MHz,Chloroform-d)δ7.50(d,J＝9.2Hz,1H),6.62(d,J＝9.3Hz,1H),4.64(d,J＝20.1Hz,2H),4.07(d,J＝12.4Hz,1H),3.88(d,J＝13.0Hz,1H),3.59(dd,J＝12.9,1.6Hz,1H),3.54(dd,J＝12.7,1.6Hz,1H),2.96–2.91(m,1H),1.78(d,J＝8.8Hz,1H),1.42(s,9H).LC-MS(ESI)m/z:302.15[M+H] + .
Step 2: synthesis of II-70-2
II-70-1 (300 mg,1 mmol) was dissolved in DCM (3 mL), TFA 1mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH solution after completion of the TLC monitoring reaction for 0.5h at room temperature, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 152mg of yellow solid in 75.87% yield.
Step 4: synthesis of II-70
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-70-2, compound II-70 was produced in the same manner as 58mg of a white solid with a yield of 29.10%. 1 H NMR(300MHz,Chloroform-d)δ9.05(s,1H),8.20(d,J＝2.0Hz,1H),8.04(d,J＝9.1Hz,1H),7.97–7.77(m,3H),6.70(d,J＝9.1Hz,1H),4.64–4.38(m,2H),3.96(s,1H),3.35(d,J＝13.2Hz,3H),2.88(t,J＝12.4Hz,3H),2.44(d,J＝13.4Hz,1H),1.82(d,J＝8.4Hz,1H),1.32(s,3H).LC-MS(ESI)m/z:472.15[M+H] + .
Example 109
Step 1: synthesis of II-71-1
Reference example 4 Synthesis method of step 1 except that 2-cyano-5-fluoropyridine and 1- (t-butoxycarbonyl) piperazine in step 1 were replaced with 2-cyano-3, 5-difluoropyridine and 3, 6-diazabicyclo [3.1.1]Heptane-3-carboxylic acid tert-butyl ester was prepared in the same manner to give compound II-71-1 as a white solid in 550mg, yield 60.51%. 1 H NMR(300MHz,Chloroform-d)δ7.81–7.71(m,1H),6.52(dd,J＝10.3,2.2Hz,1H),4.53–4.34(m,2H),3.84(dt,J＝13.2,1.7Hz,2H),3.52(ddd,J＝12.9,7.2,1.6Hz,2H),2.96–2.82(m,1H),1.76(d,J＝8.8Hz,1H),1.42(s,9H).LC-MS(ESI)m/z:319.05[M+H] + .
Step 2 Synthesis of II-71-2
II-71-1 (600 mg,1.88 mmol) was dissolved in DCM (7 mL), TFA 2.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to give 350mg of a yellow solid in 85.09% yield.
Step 3 Synthesis of II-71
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-71-2, compound II-71 was produced in the same manner as 150mg of pale yellow solid with a yield of 67.02%. 1 H NMR(300MHz,Chloroform-d)δ9.06(s,1H),8.28(s,1H),7.95(dd,J＝8.5,2.1Hz,1H),7.88(d,J＝8.5Hz,1H),7.75(s,1H),6.57(dd,J＝10.3,2.2Hz,1H),4.39(d,J＝6.0Hz,2H),3.75(s,1H),3.46(d,J＝13.5Hz,1H),3.27(t,J＝10.3Hz,2H),2.91(dd,J＝23.8,9.1Hz,3H),2.48(d,J＝13.5Hz,1H),1.84(d,J＝8.7Hz,1H),1.37(s,3H).LC-MS(ESI)m/z:489.10[M+H] + .
Example 110
Step 1: synthesis of II-72-1
Reference example 4 Synthesis method of step 1 except that 2-cyano-5-fluoropyridine and 1- (t-butoxycarbonyl) piperazine in step 1 were replaced with 2-cyano-3, 5-difluoropyridine and 3, 6-diazabicyclo [3.1.1]Heptane-3-carboxylic acid tert-butyl ester was prepared in the same manner to give Compound II-72-1 as a white solid in 300mg, yield 33.00%. 1 H NMR(300MHz,Chloroform-d)δ7.96(d,J＝2.4Hz,1H),6.61(dd,J＝9.8,2.4Hz,1H),4.81(t,J＝4.7Hz,1H),4.65(d,J＝6.1Hz,1H),3.92(dt,J＝13.0,1.7Hz,2H),3.55(dd,J＝13.1,1.7Hz,2H),2.89(q,J＝7.1Hz,1H),1.73(d,J＝8.8Hz,1H),1.43(s,9H).LC-MS(ESI)m/z:319.10[M+H] + .
Step 2 Synthesis of II-72-2
II-72-1 (300 mg,0.94 mmol) was dissolved in DCM (4 mL), TFA 1.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 170mg of a yellow solid in 82.66% yield.
Step 3 Synthesis of II-72
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-72-2, compound II-72 was produced in the same manner as in 160mg of a white solid with a yield of 71.49%. 1 H NMR(300MHz,Chloroform-d)δ9.09(s,1H),8.22(d,J＝2.1Hz,1H),8.07(d,J＝2.3Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.87(d,J＝8.5Hz,1H),6.66(dd,J＝9.8,2.4Hz,1H),4.73(s,1H),4.60(s,1H),3.82(s,1H),3.46(d,J＝13.3Hz,1H),3.37(d,J＝11.6Hz,2H),3.08–2.80(m,3H),2.51(d,J＝13.4Hz,1H),1.79(d,J＝8.5Hz,1H),1.39(s,3H).LC-MS(ESI)m/z:489.10[M+H] + .
Example 111
Reference to the synthetic method of step 3 of example 1, different S2 and I-1-2 in the step 3 were replaced with S17 and II-30-2, and the compound II-73 was prepared in the same manner as the compound II-73 in a yield of 38.01% in 25mg of a white solid. 1 H NMR(300MHz,Chloroform-d)δ8.96(s,1H),8.59(d,J＝2.2Hz,1H),8.53(d,J＝2.2Hz,1H),7.49(d,J＝8.3Hz,2H),6.61–6.39(m,2H),4.37–4.16(m,2H),3.84(s,1H),3.33(d,J＝13.5Hz,1H),3.30–3.23(m,1H),3.19(dd,J＝11.4,2.8Hz,1H),2.88–2.78(m,2H),2.74(q,J＝6.7Hz,1H),2.39(d,J＝13.5Hz,1H),1.71(d,J＝8.4Hz,1H),1.28(s,3H).LC-MS(ESI)m/z:437.10[M+H] + .
Example 112
Step 1: synthesis of II-74-1
In a two-necked flask, tert-butyl 3-oxopiperazine-1-carboxylate (700 mg,3.5 mmol), 4-bromoxynil (1.27 g,6.99 mmol), cs were added sequentially 2 CO 3 (2.28g,6.99mmol),Pd(OAc) 2 (31.39 mg,0.14 mmol) and Xantphos (242.73 mg,0.42 mmol). 15mL of anhydrous dioxane was added thereto, and the reaction was carried out at 90℃under nitrogen protection for 16 hours. After completion of the reaction by TLC, it was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 ml×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated, and the resulting residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give 815mg of brown oil in 77.36% yield. 1 H NMR(300MHz,Chloroform-d)δ7.76–7.69(m,2H),7.54–7.46(m,2H),4.29(s,2H),3.89–3.75(m,4H),1.52(s,9H).LC-MS(ESI)m/z:302.15[M+H] + .
Step 2 Synthesis of II-74-2
II-74-1 (500 mg,1.66 mmol) was dissolved in DCM (7 mL), TFA 2.5mL was slowly added dropwise, the reaction was quenched by adding 1M aqueous NaOH after completion of the TLC monitoring reaction for 1h, the DCM (5 mL. Times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 275mg of a brown oil with 82.36% yield.
Step 3 Synthesis of II-74
With reference to the synthetic method of step 3 of example 1, except that I-1-2 in step 3 was replaced with II-74-2, compound II-74 was produced in the same manner as 160mg of pale yellow solid with a yield of 45.53%. 1 H NMR(300MHz,Chloroform-d)δ9.33(s,1H),8.13(d,J＝2.1Hz,1H),7.96(dd,J＝8.5,2.2Hz,1H),7.80(d,J＝8.5Hz,1H),7.74–7.61(m,2H),7.50–7.40(m,2H),4.51(s,1H),3.73(qdd,J＝11.4,6.4,4.2Hz,2H),3.60–3.35(m,3H),3.03(tdd,J＝16.7,9.2,4.3Hz,2H),2.61(d,J＝13.4Hz,1H),1.48(s,3H).LC-MS(ESI)m/z:472.15[M+H] + .
Example 113
To a solution of starting material 1-1 (5 g) in anhydrous tetrahydrofuran (30 mL) was slowly added dropwise dichlorosulfine (2.78 mL) at 0deg.C under nitrogen protection, and the reaction was continued for 3 hours. Triethylamine (5.34 mL) was added dropwise at 0deg.C and stirred for 10 min. A solution of 5-amino-3- (trifluoromethyl) -2-pyridine-carbonitrile (3.83 g) in anhydrous tetrahydrofuran (20 mL) was slowly added dropwise thereto at 0℃and the mixture was stirred for 30 minutes and then reacted at 25℃for 18 hours. LCMS monitored reaction was complete. Water (100 mL) was added, the aqueous phase extracted with ethyl acetate (100 mL. Times.2), the organic phases combined and washed with saturated sodium chloride solution (100 mL). Dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and methyl tert-butyl ether (30 mL) was added to the residue to pulp, filtered, and the cake was washed with methyl tert-butyl ether (10 mL) to give 5.3g of intermediate 1-2.LC-MS (ESI) m/z=351.9, 353.9[ M+H ]] +
Sodium hydroxide (0.9 g) was added to a solution of intermediate 1-2 (5.3 g) in acetone (80 mL) at 25℃and stirred for 2 hours at 65 ℃. TLC monitored reaction was complete. Cooled to 25 ℃, diluted with ethyl acetate (50 mL) and filtered, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate gradient elution) to give 2.9g of intermediate 1-3.LC-MS (ESI) m/z=2 72.1[M+H] +
1-4 (8.4 g), 3, 6-diazabicyclo [3.1.1 ] is added to the reaction flask]Heptane-6-carboxylic acid tert-butyl ester (11.0 g), sodium tert-butoxide (8.9 g), tris (dibenzylideneacetone) dipalladium (4.2 g), (+ -) -2,2 '-bis (diphenylphosphine) -1,1' -binaphthyl (5.8 g) and dried toluene (130 mL). The reaction was carried out at 80℃for 18 hours under nitrogen protection. LCMS monitored reaction was complete. The reaction was cooled to 25℃and quenched with water (50 mL), filtered through celite, the filter cake washed with ethyl acetate (50 mL), the solution separated and the organic phase washed with saturated aqueous sodium chloride (100 mL) and water (100 mL). Drying over anhydrous sodium sulfate, evaporating the solvent under reduced pressure to obtain 18.3g of intermediate 1-5, and directly carrying out the next reaction. LC-MS (ESI) m/z=300.1 [ M+H ]] +
18.3g of intermediate 1-5 was dissolved in dry toluene (75 mL), trifluoroacetic acid (20.4 mL) was added dropwise at 20℃and the reaction was continued for 18 hours. LCMS monitored reaction was complete. The mixture was allowed to stand and layer, the resulting lower phase was dropped into methyl t-butyl ether (100 mL), stirred at 20℃for 2 hours, a solid was precipitated, filtered, and the cake was washed with methyl t-butyl ether (30 mL). The filter cake was dissolved in 5% aqueous sodium carbonate (100 mL), extracted with dichloromethane (100 mL), separated and the organic phase was washed with saturated aqueous sodium chloride (80 mL). Dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was slurried with methyl tert-butyl ether (30 mL) and filtered to give 2.8g of intermediate 1-6.LC-MS (ESI) m/z=200.1 [ M+H ] ] +
Intermediate 1-3 (2.9 g) and intermediate 1-6 (2.1 g) were dissolved in absolute ethanol (30 mL), and reacted for 4h at 80 ℃. LCMS monitored reaction was complete. The solvent was distilled off under reduced pressure, and the residue was purified by reverse phase high performance liquid chromatography (column: spheral-C18; mobile phase: A is water; B is acetonitrile, B% is 0% -40%,80 mL/min) to give 1.8g of compound 0XX. LC-MS (ESI) m/z=471.1 [ m+h ];
1 H NMR(400MHz,Chloroform-d)δ9.52(s,1H),8.88(d,1H),8.72(d,1H),7.58-7.53(m,2H),6.80-6.71(m,2H),5.15-4.92(m,1H),3.92-3.72(m,2H),3.65-3.48(m,2H),3.46-3.29(m,2H),3.23-3.10(m,1H),2.76-2.65(m,1H),2.38-2.24(m,1H),1.66-1.59(m,1H),1.39(s,3H).
experimental example 1:
1. inhibitory Effect of Compounds of the present application on 22Rv1 cell proliferation
The test method comprises the following steps: the effect of the compounds of the present application on 22Rv1 cell proliferation was assessed by CellTiter-Glo luminescence cell viability assay kit (CTG).
22Rv1 cells (ATCC, cat# CRL-2505) were inoculated into 384-well cell culture plates (Corning, CLS3764-100 EA) and then placed at 37℃with 5% CO 2 The incubator was incubated overnight (note: 1% carbon adsorption of serum), and the next day diluted compounds of the present application were added to the plates using a nanoliter pipetting system (LABCYTE, P-0200). Finally, after 7 days of incubation of the compounds and cells, the compounds are addedThe luminescence value (the optical signal is proportional to the amount of ATP in the system, and the content of ATP directly characterizes the number of living cells in the system) is read by using an Envision multifunctional microplate reader (Promega, G7573). Finally, using XLFIT software to obtain IC of compound by using nonlinear fitting formula 50 (half inhibition concentration). The corresponding activity test results of the test compounds are shown in Table 1.
2. Inhibition of LNCap cell proliferation by Compounds of the present application
The test method comprises the following steps: the effect of the compounds of the present application on LNCap cell proliferation was assessed by CellTiter-Glo luminescence cell viability assay kit (CTG).
LNCap cells (ATCC CRL-1740) were inoculated into 384-well cell culture plates (Corning, CLS3764-100 EA) and placed at 37℃with 5% CO 2 The incubator was incubated overnight (note: 1% carbon to adsorb serum), and the diluted test compound was added to the plate for 1 hour using a nanoliter pipetting system (LABCYTE, P-0200) and then R1881 (Sitaka new technology Co., ltd., product No. K-ZJ-25741) was added the next day. Finally, after the test compound and the cells are incubated for 7 days, the test compound is addedThe luminescence value (the optical signal is proportional to the amount of ATP in the system, and the content of ATP directly characterizes the number of living cells in the system) is read by using an Envision multifunctional microplate reader (Promega, G7573). Finally, using XLFIT software to obtain IC of compound by using nonlinear fitting formula 50 (half inhibition concentration). The corresponding activity test results of the test compounds are shown in Table 1.
3. Effect of the compounds of the present application on AR antagonistic Activity
(1) Materials and reagents:
product name Suppliers (suppliers) Goods number
LNCaP cells ATCC CRL-1740
Phenol red-free 1640 culture medium Gibco 11835-030
Dialysis serum Biological Industries 04-011-1A
Glutamine Invitrogen 35050061
Phosphate buffer Corning 21-031-CVR
Pancreatin Gibco 25200072
96-well plate Grenier 655098
Lipofectamine 3000 Invitrogen L3000-001
Opti-MEM medium Gibco 11058021
pGL4.36 vector Promega E1360
Steady-Glo Promega E2550
(2) Instrument:
product name Suppliers (suppliers) Model number
Cell counter BECKMAN Vi-Cell XR
ECHO2 Labcyte ECHO 555
Enzyme label instrument PerkinElmer Envision
(3) The experimental method comprises the following steps:
the first day: floor board
1) Plating medium: 89%1640 medium, 10% dialysis serum, 1% glutamine;
2) The culture medium, pancreatin and phosphate buffer are placed in a water bath at 37 ℃ for preheating;
3) Sucking the culture medium in the cell culture flask, adding phosphate buffer solution to rinse the cells once, and sucking;
4) Adding pancreatin, gently shaking to make pancreatin fully contact with cells, and sucking;
5) The flask was placed in 5% CO at 37 ℃C 2 Culturing the incubator for about 2min;
6) Beating the flask, after observing under a microscope that >90% of the cells fall off the bottom of the flask, adding plating medium to resuspend the cells, and transferring the cell suspension to a 50mL centrifuge tube;
7) Blowing uniformly, and taking out about 0.6mL of cell suspension for counting;
8) Diluting the cell suspension with a medium to a desired cell density for plating;
9) Add 80. Mu.L of cell suspension to cell plate and place at 37℃in 5% CO 2 The incubator cultures for 24 hours.
The following day: transfection
1) Preparing a solution A containing pGL4.36 and P3000 and a solution B containing Lipofectamine by using Opti-MEM, and standing at room temperature for 5min;
2) Adding solution B into solution A, gently mixing, adding 10uL transfection reagent into each well of cell plate, and placing at 37deg.C 5% CO 2 The incubator cultures for 24 hours.
Third day: dosing
1) The compounds of the present application were subjected to 3-fold gradient dilution with plating medium to give 8 concentration spots, 10uL of the compounds were transferred to cell plates and placed at 37℃in 5% CO 2 The incubator was incubated for 30min.
2) Testone was diluted to 10000 XEC 80 concentration with plating medium, 10nL per well was added to 96-well plates with TECEN and placed at 37℃in 5% CO 2 The incubator cultures for 24 hours.
Fourth day: detection and data analysis
1) To each well of the cell plate, 100uL of Steady-Glo was added, centrifuged at 1000rpm for 10s, and the plate was read on Envision with shaking at 300rpm for 15min at room temperature.
2) The Inhibition ratio was obtained according to the formula (% Inhibition) = (Sample value-HC)/(LC-HC) ×100%. The data analysis used XL-fit Software (Supplier: ID Business Solutions Ltd., software version: XL fit 5.0)
Sample value: a sample test value; HC: highest test value control; LC (liquid crystal): lowest test value comparison; the corresponding activity test results of the test compounds are shown in Table 1.
TABLE 1 results of corresponding Activity tests for the compounds of the present application
"-" means not tested
Experimental example 2: determination of metabolic stability in Compound liver microsomes of the present application
The metabolic stability of the compounds of the present application in liver microsomes was determined using the following assay.
1. Test material and instrument
1. Liver microsome source: human liver microsomes (Corning 452117), CD-1 mouse liver microsomes (Corning 452701)
2.Na 2 HPO 4 (Tianjin city light complex fine chemical engineering institute 20180130)
3.KH 2 PO 4 (Tianjin city light complex fine chemical engineering institute 20180920)
4.MgCl 2 (Tianjin city light complex fine chemical engineering institute 20191216)
5.NADPH(Solarbio 1216C022)
6. Positive control compound verapamil (Sigma MKBV 4993V)
7.AB Sciex Triple Quad 4000 liquid chromatography-mass spectrometer
2. Test procedure
Preparation of 1.100 mM Phosphate Buffer (PBS): 7.098g of Na is weighed 2 HPO 4 500mL of pure water was added for ultrasonic dissolution as solution A. 3.400g KH was weighed out 2 PO 4 250mL of pure water was added for ultrasonic dissolution as solution B. Solution A was placed on a stirrer and solution B was slowly added until the pH reached 7.4 to prepare 100mM PBS buffer.
2. Preparation of the reaction System
The reaction system was prepared according to the following table
3. The reaction was pre-incubated in a 37℃water bath for 10 minutes. To the reaction system, 40. Mu.L of 10mM NADPH solution (NADPH was dissolved in 100mM phosphate buffer) was added, and the final concentration of NADPH was 1mM. As a negative control, 40. Mu.L of phosphate buffer was used instead of NADPH solution. The effect of the negative control is to exclude the effect of the chemical stability of the compound itself.
4. The reaction was initiated by adding 4. Mu.L of 100. Mu.M of the compound of the present application and verapamil as a positive control compound to the reaction system, with a final concentration of 1. Mu.M.
5. After 0.5, 15, 30, 45 and 60 minutes, the vortex shaker was thoroughly mixed, 50 μl of each incubation sample was removed and the reaction was quenched with 4 times glacial acetonitrile containing an internal standard. The sample was centrifuged at 3,220g for 45 minutes. After centrifugation, 90. Mu.L of the supernatant was transferred to a sample plate, and 90. Mu.L of ultrapure water was added and mixed for LC-MS/MS analysis.
All data were calculated by Microsoft Excel software. The peak area was detected by extracting the ion spectrum. The in vitro half-life (T 1/2 )。
In vitro half-life (in vitro T) 1/2 ) Calculated by slope k:
in vitro T 1/2 ＝0.693/k
intrinsic clearance in vitro (in vitro CL int Units: μL/min/mg protein) was calculated using the following formula:
in vitro CL int =k×incubation volume/enzyme protein content;
t calculated by the above formula 1/2 And CL int The values are shown in Table 2.
TABLE 2 half-life and intrinsic clearance values in liver microsomes of compounds of the present application
Experimental example 3: degradation of AR in mouse skin tissue by the Compounds of the present application
1. Sample of
1.1 Experimental reagent
A solvent: propylene glycol/ethanol (30:70, v/v)
1.2 Experimental methods
Animal information: c57BL/6 mice, male, 5-6 weeks, weight about 18-20 g, animals purchased from Shanghai Ling Biotechnology Co., ltd, were kept in SPF-grade environment with each cage individually ventilated and all animals were free to obtain standard certified commercial laboratory diet and free drinking water.
Skin preparation: after 1 week of adaptive feeding, the hair was removed from the 2cm x 3cm area of the back of the mice with a razor, and it was confirmed that the hair of the mice was in resting stage (pink skin) and the skin was not damaged.
Administration: group A: group dosing was performed on day 3 post-shave. Compound II-51 of example 89 herein was applied to shaved areas twice a day in the morning and evening at a concentration of 0.5wt% for 42 days with control solvent applied to the control group. 3 mice per group.
Group B: group dosing was performed on day 3 post-shave. Compound 0XX of the present application was applied to shaved areas twice a day, in the morning and evening, at a concentration of 0.5wt% for 28 days with control groups being applied with control solvent. Each group had 4 mice.
Skin tissue was collected 24h after the end of the last dose, weighed and flash frozen in liquid nitrogen, and then transferred to a-80 ℃ refrigerator for storage. For further Western Blot analysis.
2. Material
2.1 reagent consumable
2.2 antibody information table
2.3 Secondary antibody information Table
Antibodies to Suppliers (suppliers) Goods number
Anti-rabbit IgG abcam ab6721
2.4 Equipment Instrument
Vibrating refiner
Analytical balance (Sartorius, ID: BI-DE-074)
Shaking table (SCILOGEX, ID: BI-DE-047)
Electrophoresis apparatus (Bio-Rad, ID: BI-DE-050)
Numerical control dry bath pan (Labnet, ID: BI-DE-052)
Centrifuge (Eppendorf, ID:5428IH 027954)
ChemiDoc TM XRS+ imager (BIO-RAD, ID: SIC-DI-518)
3. Method of
3.1. Preparation of lysate
1) Preparing lysis buffer (mixing, placing on ice)
a) RIPA buffer
b)0.5M EDTA
c)0.5M EGTA
d) HALT protease and phosphatase inhibitors
e) Glycerol
f) Protease inhibitors (EDTA-free)
g) Phosphatase inhibitor Cocktail a (Bimake)
h) Phosphatase inhibitor Cocktail B (Bimake)
i) 100 mM PMSF
The proportions are set forth in the following table (per 10 ml):
2) A piece of skin tissue sample frozen in a refrigerator at-80℃was transferred to a 2mL polypropylene tube containing 5 volumes of lysis buffer A. A sample of tissue was taken in an actual 180mg amount, and 900uL of lysate was added.
3) The skin tissue samples were placed in an oscillating homogenizer at 4 ℃,60HZ, and oscillated for 120s until completely homogenized.
4) Rest on ice for 15 minutes.
5) Centrifugation was performed at 12700rpm for 15 minutes at 4℃to remove tissue fragments.
6) The supernatant was aspirated into a clean 1.5mL centrifuge tube.
7) Repeating step 5).
8) Repeating step 6).
9) Subpackaging into 3 parts, and storing at-80deg.C for use.
3.2. Protein concentration detection of lysate samples
This section refers to "Pierce 23227 BCA protein assay kit Specification" page 2: preparation of "standard and working reagents" section and page 3 "microplate procedure (sample to reagent ratio=1:8)" section
1) BCA standards (31.25. Mu.g/mL, 62.5. Mu.g/mL, 125. Mu.g/mL, 250. Mu.g/mL, 500. Mu.g/mL, 1000. Mu.g/mL, 2000. Mu.g/mL) were prepared according to the instructions for use.
2) In a 96-well plate, 25 μl of 20-fold diluted samples were added to the corresponding wells.
3) 25 μl of each standard was pipetted into the corresponding well and repeated.
4) 200. Mu.L of working reagent (50:1 of reagent A: B) was added to each well and the plate was thoroughly stirred on a plate shaker for 30 seconds.
5) Cover plate, incubate for 30 min at 37 ℃.
6) The tray was cooled to room temperature. Absorbance at or near 562nm was measured on Envision. The total protein amount of each sample was calculated.
7) Each sample was leveled to a uniform concentration using loading buffer. Heated at 100℃for 15 minutes. Cooling on ice briefly, centrifuging and packaging. A3 ug/uL protein concentration, 60uL volume of sample was prepared.
3.3. Western blotting
1) To 4-12% of the pre-gel 8uL protein Marker and 10uL samples were added.
2) The gel was run at constant pressure 80V for 15 minutes and then at 110V for 60 minutes as the dye approached the lower edge.
3) The PVDF membrane was pre-activated in methanol for 1min, then the membrane and filter paper were pre-wet in the transfer solution. Filter paper "sandwich" was assembled-for wet transfer, conditions: constant current 300mA,70min.
4) After the transfer is completed, the molecular weight of the target protein and the corresponding marker bands are used.
5) PVDF membranes were immersed in 5% nonfat dry milk formulated in TBST and blocked by shaking at room temperature for 60 minutes. Shaking speed was 25rpm/min.
6) After membrane cutting, the primary antibody was dissolved in 5% skim milk-TBST at the appropriate dilution and incubated overnight at 4 ℃. Anti-concentration AR 1:1000, shaking speed 25rpm/min.
7) The membrane was washed with TBST for 3 times for 10 minutes and shaken at 50rpm/min.
8) 5% skim milk-TBST solution was diluted 1:2000 with anti-rabbit secondary antibody, incubated for 60 minutes at room temperature, and shaken at 25rpm/min.
9) The membrane was washed with TBST for 3 times for 10 minutes and shaken at 60rpm/min.
10 Preparing chemiluminescent liquid according to the specification. And uniformly dripping luminous liquid on the surface of the membrane, and incubating for 1min in a dark place.
11 Using ChemiDoc) TM Xrs+ imager chemiluminescent image analysis systems detect target protein bands.
12 Quantification of each protein band and normalization of each target protein to its load protein. The normalized values for each treatment group were averaged and the inhibition rate was then calculated for each marker for the treatment group versus the vehicle group.
3.4. Statistical analysis results
Each band gray value was calculated using ImageJ software. All data are expressed as mean ± standard deviation, and a one-factor variance test is used to analyze whether there is a statistical difference in optical density values between groups, thereby semi-quantitatively analyzing the inhibition rate of each administration group on the target protein. Target protein inhibition was treated with Excel. Data are expressed as Mean ± standard deviation (Mean ± SEM), and the significance of control and dosing groups was analyzed using a one-way variance test, p +.0.05, +.0.01, +.0.001. The specific results are shown in FIGS. 1 and 2. Experimental results: as can be seen from fig. 1 and 2, the AR protein expression in the skin tissue of mice was significantly reduced 24 hours after administration of the compound II-51 of example 89 of the present application, compared to the control group, with a statistical difference. As can be seen from fig. 3, the AR protein expression in the skin tissue of mice was significantly reduced 24 hours after administration of the compound 0XX of the present application, compared to the control group, with a statistical difference.
Experimental example 4 in vivo efficacy study
4.1 Experimental reagents
A solvent: propylene glycol/ethanol (30:70, v/v)
4.2 Experimental methods
Animal information: c57BL/6 mice, male, 4-6 weeks, weight about 18-20 g, animals purchased from Shanghai Ling Biotechnology Co., ltd, were kept in SPF-grade environment with each cage individually ventilated and all animals were free to obtain standard certified commercial laboratory diet and free drinking water.
Skin preparation: after the mice were kept for 1-2 weeks, hair was removed from the back of the mice in a region of 2cm x 3cm by a shaver, and it was confirmed that the hair of the mice was in resting stage (pink skin) and the skin was not damaged.
Administration: group A: group dosing was performed on day 3 post-shave. Compound II-51 of the present application was applied to shaved areas twice a day, in the morning and evening, at a concentration of 0.5wt% for 42 days, with control solvent applied to control groups of 11 mice each. Group B: compound 0XX of the present application was applied to shaved areas twice a day, in the morning and evening, at a concentration of 0.5wt% for 28 days, and control solvent was applied to control groups of 18 mice each.
4.3 mice State observations and Hair growth scoring
Observing the states of mice in each group during the experiment, and judging whether the skin has the phenomena of erythema, cracking, dandruff and the like;
Group A: mice were weighed on days 7, 14, 18, 21, 24, 28, 32, 35, 39, 42, respectively, scored for hair growth and photographed;
group B: mice were scored for hair growth and photographs taken on days 7, 14, 18, 21, 24, 28, respectively; mice were weighed at 14, 18, 21, 28 days, respectively;
the scoring criteria are as follows:
0 minutes, hair does not grow in the dehairing area;
1 min, hair growth in the dehairing area is less than 20%;
2, the hair in the dehairing area grows by 20 to 40 percent;
3, the hair in the dehairing area grows 40% -60%;
4, the hair in the dehairing area grows by 60 to 80 percent;
5 minutes, the hair in the dehairing area grows 80% -100%.
4.4 experimental results
The results of the compounds of the present application on hair growth and weight change in mice are shown in tables 3-4, figures 4-7.
Table 3 compounds of the present application score for mouse hair growth
Table 4 compounds of the present application score for mouse hair growth
4.5 conclusion of experiments
In mice with telogen, compound II-51 and Compound 0XX of the present application were at a concentration of 0.5%, 20uL/cm 2 The skin application has remarkable promoting effect on hair growth according to BID administration mode (P<0.0001). The compound II-51 and the compound 0XX have no significant effect on the body weight of mice at the attempted dose, and do not cause any skin rash, cracking, dandruff and the like.

Claims (25)

  1. A compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof,
    wherein,
    x is CH or N;
    R 1 selected from H, OH, C 1-6 Alkyl, -O-C 1-6 Alkyl, -OCOR a 、-COR a 、-CONHR a or-NHCOR a ；
    R 2 Selected from C 1-6 Alkyl or C 1-6 A haloalkyl group;
    or by R 1 And R is R 2 And C linked thereto together form C 3-6 Cycloalkyl or 4-6 membered heterocyclyl;
    R 4 selected from halogen, CF 3 or-O-C 1-6 An alkyl group;
    R 5 selected from CN, NO 2 、-COR a 、-CONHR a 、-S(O) 2 R a or-S (O) 2 N(R a ) 2 ；
    R a Independently selected from H, OH, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
    R 6 selected from H or-O-C 1-6 An alkyl group;
    R 7 ，R 8 independently selected from H or halogen;
    w is selected fromOr a 4-10 membered fully saturated heterocyclic group, said 4-10 membered fully saturated heterocyclic group optionally being substituted with R b Substitution; r is R b Selected from halogen, OH, NH 2 、NO 2 、CN、C 1-6 Alkyl, C 1-6 Haloalkyl, -O-C 1-6 Alkyl or-S (=o) 2 -C 1- 6 An alkyl group;
    ring D is selected from 5-10 membered heteroaryl or C 6-10 An aryl group;
    each R is 3 Independently selected from halogen, OH, NH 2 、NO 2 、CN、-CONH 2 、-CONHR 3A 、-O-C 1-6 Alkyl, -S (=o) 2 -C 1-6 Alkyl, C 1-6 Alkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl or C 6-10 Aryl, said C 1-6 Alkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl or C 6-10 Aryl is optionally substituted with R 3A Substitution;
    R 3A independently selected from halogen, OH, NO 2 、CN、CH 2 F、CHF 2 、CF 3 、C 1-6 Alkyl, -O-C 1-6 Alkyl or-S (=o) 2 -C 1-6 An alkyl group;
    n is selected from 0, 1, 2, 3 or 4;
    p is selected from 0 or 1.
  2. A compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 wherein W is 4-10 membered fully saturated heterocyclyl, optionally substituted with R b Substitution; or,
    w is a 4-8 membered fully saturated heterocyclic group, said 4-8 membered fully saturated heterocyclic group optionally being substituted by R b Substitution; or,
    w is a 4, 5, 6, 7 or 8 membered fully saturated heterocyclic group containing 1 or 2N atoms, said 4, 5, 6, 7 or 8 membered fully saturated heterocyclic group optionally being substituted by R b Substitution; or,
    w is selected from the group consisting of azetidinyl, piperazinyl, 1, 4-diazaheptyl, 3, 8-diazabicyclo [3.2.1]Octyl, 2, 5-diazabicyclo [2.2.1]Heptyl or heptyl radicalsThe azetidinyl, piperazinyl, 1, 4-diazacycloheptyl, 3, 8-diazabicyclo [3.2.1]Octyl, 2, 5-diazabicyclo [2.2.1]Heptyl or heptyl radicalsOptionally by R b Substitution; or,
    w is selected from the group consisting of azetidinyl, piperazinyl, 3, 8-diazabicyclo [3.2.1 ]]Octyl or 2, 5-diazabicyclo [2.2.1]Heptyl, said azetidinyl, piperazinyl, 3, 8-diazabicyclo [3.2.1]Octyl or 2, 5-diazabicyclo [2.2.1]Heptyl is optionally substituted with R b And (3) substitution.
  3. A compound of formula (I) according to claim 1 or 2, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the ring D is selected from phenyl or 5-10 membered heteroaryl; alternatively, the ring D is selected from phenyl or a 5, 6, 7, 8, 9 or 10 membered heteroaryl group containing 1 or 2N atoms; alternatively, the ring D is selected from phenyl or a 5 or 6 membered heteroaryl group containing 1 or 2N atoms; alternatively, the ring D is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl or pyridazinyl.
  4. A compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof as claimed in any one of claims 1-3, wherein R b Is C 1-6 An alkyl group; alternatively, R b Is CH 3 。
  5. A compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 3 Selected from halogen, NO 2 、CN、-O-C 1-6 Alkyl, -S (=o) 2 -C 1-6 Alkyl, C 1-6 Alkyl, 5-to 10-membered heteroaryl or C 6-10 Aryl, said C 1-6 Alkyl, 5-to 10-membered heteroaryl or C 6-10 Aryl is optionally substituted with R 3A Substitution; or,
    R 3 selected from halogen, NO 2 、CN、-O-CH 3 、-CF 3 、-S(＝O) 2 -CH 3 PyrimidineA group, pyrazolyl, pyridinyl or phenyl, said pyrimidinyl, pyrazolyl, pyridinyl or phenyl optionally being substituted with R 3A Substitution; or,
    R 3 selected from halogen, CN, NO 2 、-O-C 1-6 Alkyl, -CONHR 3A 、C 1-6 Alkyl, 5-to 10-membered heteroaryl or C 6-10 Aryl, said C 1-6 Alkyl, 5-to 10-membered heteroaryl or C 6-10 Aryl is optionally substituted with R 3A Substitution; or,
    R 3 selected from halogen, CN, NO 2 、-O-C 1-6 Alkyl, C 1-6 Alkyl, 5-to 10-membered heteroaryl or C 6-10 Aryl, said C 1-6 Alkyl, 5-to 10-membered heteroaryl or C 6-10 Aryl is optionally substituted with R 3A Substitution; or,
    R 3 selected from halogen, CN, NO 2 、-O-C 1-6 Alkyl, C 1-6 Alkyl, 5-6 membered heteroaryl or phenyl, said C 1-6 Alkyl, 5-6 membered heteroaryl or phenyl optionally substituted with R 3A Substitution; or,
    R 3 Selected from F, cl, br, CN, NO 2 、-O-C 1-6 Alkyl, C 1-6 Alkyl, 5-6 membered heteroaryl containing 1 or 2N atoms, or phenyl, said C 1-6 Alkyl, 5-6 membered heteroaryl or phenyl optionally substituted with R 3A Substitution; or,
    R 3 selected from F, cl, br, CN, NO 2 、-O-C 1-2 Alkyl, C 1-2 Alkyl, 5-6 membered heteroaryl containing 1 or 2N atoms, or phenyl, said C 1-6 Alkyl, 5-6 membered heteroaryl or phenyl optionally substituted with R 3A Substitution; or,
    R 3 selected from F, cl, br, CN, NO 2 、-CF 3 、-O-CH 3 、-CH 3 、-CONHCH 3 Pyrimidinyl, pyrazolyl, pyridinyl or phenyl, said pyrimidinyl, pyrazolyl, pyridinyl or phenyl optionally being substituted with R 3A And (3) substitution.
  6. A compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 3A Independently selected from halogen, OH, NO 2 、CN、CH 2 F、CHF 2 、CF 3 Or C 1-6 An alkyl group; alternatively, R 3A Independently selected from halogen, CN, CF 3 、NO 2 Or CH (CH) 3 The method comprises the steps of carrying out a first treatment on the surface of the Alternatively, R 3A Independently selected from halogen, CN, CF 3 Or NO 2 The method comprises the steps of carrying out a first treatment on the surface of the Alternatively, R 3A Independently selected from halogen, CN or CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Alternatively, R 3A Independently selected from F, CN or CF 3 。
  7. A compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 1 Selected from H, OH, C 1-6 Alkyl or-O-C 1-6 An alkyl group; alternatively, R 1 Is OH.
  8. A compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 2 Is C 1-6 An alkyl group; alternatively, R 2 Is CH 3 。
  9. A compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 4 Selected from halogen, CF 3 or-O-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the Alternatively, R 4 Selected from F, cl,Br、CF 3 or-O-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the Alternatively, R 4 Selected from F, cl, CF 3 or-O-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the Alternatively, R 4 Selected from Cl or CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Alternatively, R 4 Is CF (CF) 3 。
  10. A compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 5 Selected from CN or NO 2 The method comprises the steps of carrying out a first treatment on the surface of the Alternatively, R 5 Is CN.
  11. A compound of formula (I) according to any one of claims 1 to 10, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is selected from 0, 1 or 2; alternatively, n is selected from 1 or 2.
  12. A compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 6 、R 7 And R is 8 All are H.
  13. A compound of formula (I) according to any one of claims 1 to 12, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein p is 0.
  14. The compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof is a compound of formula (II) or a stereoisomer or a pharmaceutically acceptable salt thereof,
    wherein the ring D, W, X, R 3 、R 4 、R 5 、R 6 、R 7 、R 8 N and p are as defined in claim 1.
  15. The compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof is a compound of formula (III) or a stereoisomer or a pharmaceutically acceptable salt thereof,
    wherein the ring D, W, X, R 3 、R 4 、R 5 、R 7 、R 8 N and p are as defined in claim 1.
  16. The compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof is a compound of formula (IV) or a stereoisomer or a pharmaceutically acceptable salt thereof,
    wherein the ring D, W, X, R 3 、R 4 、R 5 、R 7 、R 8 And n is as defined in claim 1.
  17. The compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof is a compound of formula (V) or a stereoisomer or a pharmaceutically acceptable salt thereof,
    Wherein the ring D, W, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 N and p are as defined in claim 1.
  18. The compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof is a compound of formula (VI) or a stereoisomer or a pharmaceutically acceptable salt thereof,
    wherein the ring D, X, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 And n is as defined in claim 1;
    a 1 、a 2 、a 3 and a 4 Independently selected from bond or CH 2 The method comprises the steps of carrying out a first treatment on the surface of the A) 5 Selected from CH 2 Or CH (CH) 2 CH 2 。
  19. The compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  20. a pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 19 or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
  21. Use of a compound of formula (I) as defined in any one of claims 1 to 19 or a stereoisomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in claim 20 in the manufacture of a medicament for the prophylaxis or treatment of a disorder mediated by androgen receptor.
  22. A method for treating a disorder mediated by an androgen receptor, comprising administering to a subject in need thereof a compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 20, as defined in any one of claims 1-19.
  23. A compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 20 for use in the prevention or treatment of a disorder mediated by an androgen receptor.
  24. Use of a compound of formula (I) as defined in any one of claims 1 to 19 or a stereoisomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in claim 20 for the prevention or treatment of a disorder mediated by an androgen receptor.
  25. The use according to claim 21 or 24 or the method according to claim 22 or the compound of formula (I) according to claim 23 or a stereoisomer or a pharmaceutically acceptable salt or pharmaceutical composition thereof, wherein the disorder mediated by androgen receptor is selected from prostate cancer or androgenic alopecia.
CN202280052853.2A 2021-08-05 2022-08-04 Amide compound and application thereof Pending CN117751099A (en)

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US6472415B1 (en) * 1998-12-18 2002-10-29 Biophysica, Inc. Androgen receptor suppressors in the therapy and diagnosis of prostate cancer, alopecia and other hyper-androgenic syndromes
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JP2005503339A (en) * 2001-04-11 2005-02-03 アボット・ラボラトリーズ Convenient adjustment of health-related quality of life and health-related quality adaptation time to disease progression in prostate patients
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US20090170886A1 (en) * 2005-08-08 2009-07-02 Pfizer Inc Androgen modulators
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