WO2023011596A1 - Amide compound and use thereof - Google Patents

Amide compound and use thereof Download PDF

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Publication number
WO2023011596A1
WO2023011596A1 PCT/CN2022/110325 CN2022110325W WO2023011596A1 WO 2023011596 A1 WO2023011596 A1 WO 2023011596A1 CN 2022110325 W CN2022110325 W CN 2022110325W WO 2023011596 A1 WO2023011596 A1 WO 2023011596A1
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WIPO (PCT)
Prior art keywords
alkyl
pharmaceutically acceptable
synthesis
stereoisomer
formula
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PCT/CN2022/110325
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French (fr)
Chinese (zh)
Inventor
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
Original Assignee
中国药科大学
江苏先声药业有限公司
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Application filed by 中国药科大学, 江苏先声药业有限公司 filed Critical 中国药科大学
Priority to CN202280052853.2A priority Critical patent/CN117751099A/en
Publication of WO2023011596A1 publication Critical patent/WO2023011596A1/en

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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

Definitions

  • Patent application No. 202110896906.6 submitted to the State Intellectual Property Office of China on August 5, 2021;
  • Patent Application No. 202210114403.3 filed with the State Intellectual Property Office of China on January 30, 2022;
  • Patent application No. 202210724756.5 submitted to the State Intellectual Property Office of China on June 24, 2022.
  • the application relates to the field of medicinal chemistry, in particular to a class of amide compounds or their stereoisomers or pharmaceutically acceptable salts, pharmaceutical compositions containing them and as selective androgen receptor degraders (SARD) and/or Use of androgen receptor (AR) antagonists.
  • SARD selective androgen receptor degraders
  • AR androgen receptor
  • AR Androgen receptor
  • NTD N-terminal active transcription control region
  • DBD DNA binding domain
  • LBD C-terminal ligand binding domain
  • AR has been an important target for prostate cancer therapy since Huggins and Hodges discovered in the early 1940s that androgens promote prostate cancer growth.
  • Prostate cancer is one of the most common cancers worldwide.
  • Prostate cancer endocrine therapy is the main treatment for advanced prostate cancer.
  • various androgen deprivation therapy ADT
  • ADT androgen deprivation therapy
  • HDPC high-density prostate cancer
  • HIPC Androgen-independent prostate cancer
  • CRPC castration-resistant prostate cancer
  • approved oral drugs for the treatment of castration-resistant prostate cancer mainly include abiraterone and enzalutamide.
  • abiraterone is a new type of androgen biosynthesis inhibitor, which can block the synthesis of androgen in the testis, adrenal gland or tumor cell environment.
  • Enzalutamide is an androgen receptor inhibitor that competitively inhibits the binding of androgen to the receptor. When enzalutamide is combined with AR, it can further inhibit the nuclear translocation of AR, thereby blocking the interaction between AR and DNA.
  • SARDs selective androgen receptor degraders
  • SARDs can not only inhibit the androgen receptor and block the process of androgen receptor signal transduction, but also degrade the receptor itself, which is expected to bring more benefits. Therefore, there is an urgent need for a new class of selective androgen receptor degraders and/or androgen receptor (AR) antagonists.
  • the present application provides the compound represented by formula (I) and its stereoisomer or pharmaceutically acceptable salt. These compounds can be used as selective androgen receptor degraders and/or androgen receptor (AR) antagonists for treating diseases related to high expression of AR.
  • AR androgen receptor
  • X is CH or N
  • R 1 is selected from H, OH, C 1-6 alkyl, -OC 1-6 alkyl, -OCOR a , -COR a , -CONHR a or -NHCOR a ;
  • R 2 is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • a C 3-6 cycloalkyl group or a 4-6 membered heterocyclic group is formed by R 1 and R 2 and the connected C together;
  • R 4 is selected from halogen, CF 3 or -OC 1-6 alkyl
  • R 5 is selected from CN, NO 2 , -COR a , -CONHR a , -S(O) 2 R a or -S(O) 2 N(R a ) 2 ;
  • R is independently selected from H, OH, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 6 is selected from H or -OC 1-6 alkyl
  • R and R are independently selected from H or halogen
  • W selected from Or a 4-10 membered fully saturated heterocyclic group, the 4-10 membered fully saturated heterocyclic group is optionally substituted by R b ;
  • Ring D is selected from 5-10 membered heteroaryl or C 6-10 aryl
  • n is selected from 0, 1, 2, 3 or 4;
  • p is selected from 0 or 1.
  • X is CH.
  • X is N.
  • W is selected from 4-10 membered fully saturated heterocyclic groups optionally substituted by R b .
  • W is selected from 4-8 membered fully saturated heterocyclic groups optionally substituted by R b .
  • W is selected from 4, 5, 6, 7 or 8 membered fully saturated heterocyclic groups containing 1 or 2 N atoms, and the 4, 5, 6, 7 or 8 membered fully saturated heterocyclic groups are Heterocyclyl is optionally substituted with Rb .
  • W is selected from 6-8 membered fully saturated heterocyclic groups optionally substituted by R b .
  • W is selected from 6, 7 or 8 membered fully saturated heterocyclic groups containing 1 or 2 N atoms, and the 6, 7 or 8 membered fully saturated heterocyclic groups are optionally replaced by R b replaces.
  • W is selected from 7-8 membered fully saturated heterocyclic groups, and the 7-8 membered fully saturated heterocyclic groups are optionally substituted by R b .
  • W is selected from azetidinyl, piperazinyl, 1,4-diazepanyl, 3,8-diazabicyclo[3.2.1]octyl , 2,5-diazabicyclo[2.2.1]heptanyl or The azetidinyl, piperazinyl, 1,4-diazepanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[ 2.2.1] Heptyl or is optionally substituted by Rb .
  • W is selected from azetidinyl, piperazinyl, 1,4-diazepanyl, 3,8-diazabicyclo[3.2.1]octyl Or 2,5-diazabicyclo[2.2.1]heptyl, the azetidinyl, piperazinyl, 1,4-diazepanyl, 3,8-diazabicyclo [3.2.1]octyl or 2,5-diazabicyclo[2.2.1]heptyl is optionally substituted by R b .
  • W is selected from azetidinyl, piperazinyl, 3,8-diazabicyclo[3.2.1]octyl or 2,5-diazabicyclo[2.2.1 ]heptyl, the azetidinyl, piperazinyl, 3,8-diazabicyclo[3.2.1]octyl or 2,5-diazabicyclo[2.2.1]heptyl is optionally substituted by Rb .
  • ring D is selected from phenyl or 5-10 membered heteroaryl.
  • Ring D is selected from phenyl or 5, 6, 7, 8, 9 or 10 membered heteroaryl containing 1 or 2 N atoms.
  • ring D is selected from phenyl or 5- or 6-membered heteroaryl containing 1 or 2 N atoms.
  • ring D is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, pyridazinyl, benzopyrrolyl, quinolinyl, isoquinolinyl or benzopyrazolyl.
  • Ring D is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl or pyridazinyl.
  • R b is selected from C 1-6 alkyl.
  • R b is selected from CH 3 .
  • R 3 is selected from halogen, CN, NO 2 , -OC 1-6 alkyl, -CONHR 3A , C 1-6 alkyl, 5-10 membered heteroaryl or C 6- 10 aryl, the C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl is optionally substituted by R 3A , R 3A can be preferably selected from halogen, CN, CF 3 , NO 2 or CH 3 , and R 3A may more preferably be selected from halogen, CN, CF 3 or CH 3 .
  • R 3 is selected from halogen, CN, NO 2 , -OC 1-6 alkyl, C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl,
  • the C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl is optionally substituted by R 3A
  • R 3A can be preferably selected from halogen, CN, CF 3 , NO 2 or CH 3
  • R 3A may more preferably be selected from halogen, CN or CF 3 .
  • R 3 is selected from halogen, CN, NO 2 , -OC 1-6 alkyl, C 1-6 alkyl, 5-6 membered heteroaryl or phenyl, and the C 1 -6 alkyl, 5-6 membered heteroaryl or phenyl is optionally substituted by R 3A , R 3A may preferably be selected from halogen, CN, CF 3 , NO 2 or CH 3 , and R 3A may be more preferably is selected from halogen, CN or CF3 .
  • R 3 is selected from F, Cl, Br, CN, NO 2 , -OC 1-6 alkyl, C 1-6 alkyl, 5- 6-membered heteroaryl or phenyl, the C 1-6 alkyl, 5-6-membered heteroaryl or phenyl is optionally substituted by R 3A , R 3A can be preferably selected from halogen, CN, CF 3 , NO 2 or CH 3 , and R 3A may more preferably be selected from halogen, CN or CF 3 .
  • R 3 is selected from F, Cl, Br, CN, NO 2 , -OC 1-2 alkyl, C 1-2 alkyl, 5- 6-membered heteroaryl or phenyl, the C 1-6 alkyl, 5-6-membered heteroaryl or phenyl is optionally substituted by R 3A , R 3A can be preferably selected from halogen, CN, CF 3 , NO 2 or CH 3 , and R 3A may more preferably be selected from F, CN or CF 3 .
  • R 3 is selected from halogen, NO 2 , CN, -O-CH 3 , -CF 3 , -CH 3 , -CONHCH 3 , pyrimidinyl, pyrazolyl, pyridyl or phenyl , the pyrimidinyl, pyrazolyl, pyridyl or phenyl is optionally substituted by R 3A .
  • R 3 is selected from halogen, NO 2 , CN, -O-CH 3 , -CF 3 , pyrimidinyl, pyrazolyl, pyridyl or phenyl, and the pyrimidinyl, pyrazole Base, pyridyl or phenyl is optionally substituted by R 3A .
  • R 3A is independently selected from halogen, OH, NO 2 , CN, CH 2 F, CHF 2 , CF 3 or C 1-6 alkyl.
  • R 3 is selected from F, Cl, Br, CN, NO 2 , -CF 3 , -O-CH 3 , -CH 3 , -CONHCH 3 , pyrimidinyl, pyrazolyl, pyridine or phenyl, said pyrimidinyl, pyrazolyl, pyridyl or phenyl is optionally substituted by R 3A , R 3A may preferably be selected from halogen, CN, CF 3 or NO 2 , and R 3A may be more preferably is selected from F, CN or CF 3 .
  • R 3A is independently selected from halogen, NO 2 , CN, CF 3 or CH 3 .
  • R 3A is independently selected from halogen, CN or CF 3 .
  • R 1 is selected from H, OH, C 1-6 alkyl or -OC 1-6 alkyl.
  • R 1 is selected from OH.
  • R 2 is selected from C 1-6 alkyl.
  • R 2 is selected from CH 3 .
  • R 4 is selected from halogen, CF 3 or -O-CH 3 .
  • R 4 is selected from F, Cl, Br, CF 3 or —O—CH 3 .
  • R 4 is selected from F, Cl, CF 3 or -O-CH 3 .
  • R 4 is selected from Cl or CF 3 .
  • R 4 is selected from CF 3 .
  • R 5 is selected from CN or NO 2 .
  • R 5 is CN
  • R is selected from H.
  • R 7 and R 8 are independently selected from H or F.
  • R 7 and R 8 are independently selected from H.
  • n is selected from 0, 1 or 2.
  • n is selected from 1 or 2.
  • p 0.
  • X is CH or N; W is selected from Or a 4-8 membered fully saturated heterocyclic group, the 4-8 membered fully saturated heterocyclic group is optionally substituted by R b ; R b is independently C 1-6 alkyl; Ring D is selected from phenyl or 5 -10 membered heteroaryl; R 3 is selected from halogen, CN, NO 2 , -OC 1-6 alkyl, -CONHR 3A , C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl Base, the C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl is optionally substituted by R 3A ; R 3A is selected from halogen, CN, CF 3 , NO 2 or CH 3 ; R 1 is OH; R 2 is CH 3 ; R 4 is selected from halogen, CF 3 or -O-CH 3 ; R 5 is selected from CN or NO 2 ; R 6
  • X is CH or N; W is a 4-8 membered fully saturated heterocyclic group, and the 4-8 membered fully saturated heterocyclic group is optionally substituted by R b ;
  • R b is independently is C 1-2 alkyl;
  • ring D is selected from phenyl or 5-6 membered heteroaryl;
  • R 3 is selected from halogen, CN, NO 2 , -OC 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 are optionally substituted by R 3A ;
  • R 3A is selected from halogen, CN, CF 3.
  • R 1 is OH;
  • R 2 is CH 3 ;
  • R 4 is selected from halogen, CF 3 or -O-CH 3 ;
  • R 5 is selected from CN or NO 2 ;
  • R 6 , R 7 and R 8 are all H;
  • n is selected from 0, 1 or 2; and
  • p is 0 or 1.
  • X is CH or N; W is a 4-8 membered fully saturated heterocyclic group containing 1 or 2 N, and the 4-8 membered fully saturated heterocyclic group is optionally replaced by R b is substituted; R b is independently CH 3 ; ring D is selected from phenyl or 5-6 membered heteroaryl containing 1 or 2 N; R 3 is selected from halogen, CN, NO 2 , -O-CH 3.
  • R 3A is selected from halogen, CN, CF 3 , NO 2 or CH 3 ;
  • R 1 is OH;
  • R 2 is CH 3 ;
  • R 4 is selected from halogen, CF 3 or -O-CH 3 ;
  • R 5 is selected from CN or NO 2 ;
  • R 6 , R 7 and R 8 are all H;
  • n is selected from 0, 1 or 2; and
  • p is 0 or 1.
  • X is CH or N; W is a 4-8 membered fully saturated heterocyclic group containing 1 or 2 N, and the 4-8 membered fully saturated heterocyclic group is optionally replaced by R b is substituted; R b is independently CH 3 ; ring D is selected from phenyl or 5-6 membered heteroaryl containing 1 or 2 N; R 3 is selected from F, Cl, Br, CN, NO 2 , -O-CH 3 , CH 3 , 5-6 membered heteroaryl or phenyl containing 1 or 2 N, said CH 3 , 5-6 membered heteroaryl or phenyl is optionally substituted by R 3A ; R 3A is selected from F, CN, CF 3 or NO 2 ; R 1 is OH; R 2 is CH 3 ; R 4 is selected from F, Cl, CF 3 or -O-CH 3 ; R 5 is CN; R 6 , R 7 and R 8 are all H; n is selected from 0,
  • X is CH or N;
  • W is selected from azetidinyl, piperazinyl, 1,4-diazepanyl, 3,8-diazabicyclo[3.2 .1] octanyl or 2,5-diazabicyclo[2.2.1]heptyl, the azetidinyl, piperazinyl, 1,4-diazepanyl, 3, 8-diazabicyclo[3.2.1]octyl or 2,5-diazabicyclo[2.2.1]heptyl is optionally substituted by R b ;
  • R b is independently CH 3 ;
  • ring D is selected from Phenyl or a 5-6 membered heteroaryl group containing 1 or 2 Ns;
  • R 3 is selected from F, Cl, Br, CN, NO 2 , -O-CH 3 , CH 3 , containing 1 or 2 Ns 5-6 membered heteroaryl or phenyl, said CH 3 ,
  • the compound shown in formula (I) or its stereoisomer or pharmaceutically acceptable salt is selected from the compound shown in formula (II) or its stereoisomer or pharmaceutically acceptable salt Salt,
  • rings D, W, X, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , n and p are as defined above.
  • the compound shown in formula (I) or its stereoisomer or pharmaceutically acceptable salt is selected from the compound shown in formula (III) or its stereoisomer or pharmaceutically acceptable salt Salt,
  • rings D, W, X, R 3 , R 4 , R 5 , R 7 , R 8 , n and p are as defined above.
  • the compound shown in formula (I) or its stereoisomer or pharmaceutically acceptable salt is selected from the compound shown in formula (IV) or its stereoisomer or pharmaceutically acceptable salt Salt,
  • ring D, W, X, R 3 , R 4 , R 5 , R 7 , R 8 and n are as defined above.
  • the compound shown in formula (I) or its stereoisomer or pharmaceutically acceptable salt is selected from the compound shown in formula (V) or its stereoisomer or pharmaceutically acceptable salt Salt,
  • rings 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.
  • the compound shown in formula (I) or its stereoisomer or pharmaceutically acceptable salt is selected from the compound shown in formula (VI) or its stereoisomer or pharmaceutically acceptable salt Salt,
  • ring D, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and n are as defined above;
  • a 1 , a 2 , a 3 and a 4 are each independently selected from a bond or CH 2 ; and a 5 is selected from CH 2 or CH 2 CH 2 .
  • the compound shown in formula (I) or its stereoisomer or pharmaceutically acceptable salt is selected from the compound shown in formula (VI-a) or its stereoisomer or pharmaceutically acceptable salt accepted salt,
  • ring D, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and n are as defined above;
  • a 1 , a 2 , a 3 and a 4 are each independently selected from a bond or CH 2 ; and a 5 is selected from CH 2 or CH 2 CH 2 .
  • the compound shown in formula (I) or its stereoisomer or pharmaceutically acceptable salt is selected from the following compounds or its stereoisomer or pharmaceutically acceptable salt:
  • the present application also provides a pharmaceutical composition, which comprises formula (I), (II), (III), (IV), (V), (VI) or (VI-a) Compounds or their stereoisomers or pharmaceutically acceptable salts, and pharmaceutically acceptable auxiliary materials.
  • the present application relates to compounds represented by formula (I), (II), (III), (IV), (V), (VI) or (VI-a) or their stereoisomers or pharmaceutically acceptable Use of the accepted salt or its pharmaceutical composition in the preparation of medicaments for preventing or treating diseases mediated by androgen receptors.
  • the present application relates to compounds represented by formula (I), (II), (III), (IV), (V), (VI) or (VI-a) or their stereoisomers or pharmaceutically acceptable Use of the accepted salt or its pharmaceutical composition in preventing or treating diseases mediated by androgen receptor.
  • the present application relates to the formula (I), (II), (III), (IV), (V), (VI) or (VI-a) for the prevention or treatment of diseases mediated by androgen receptors
  • the compound or its stereoisomer or pharmaceutically acceptable salt or its pharmaceutical composition The compound or its stereoisomer or pharmaceutically acceptable salt or its pharmaceutical composition.
  • the present application relates to a method for treating a disease mediated by the androgen receptor, the method comprising administering to the patient a therapeutically effective dose comprising formula (I), (II), (III), ( Pharmaceutical preparations of compounds IV), (V), (VI) or (VI-a) or stereoisomers or pharmaceutically acceptable salts thereof.
  • the disease mediated by androgen receptor is selected from prostate cancer or androgenetic alopecia.
  • tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions. Compounds of the present application may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. This application includes all tautomeric forms of the compounds.
  • stereoisomer refers to isomers produced by different arrangements of atoms in a molecule in space, including 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, so the compounds of the present application may exist in specific geometric or stereoisomer forms.
  • Specific 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 enantiomers or diastereomers Enriched mixtures, all of the above isomers and mixtures thereof fall within the definition of the compounds of the present application.
  • asymmetric carbon atoms there may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups, and these isomers and their mixtures involved in all substituents are also included in Within the definition of the compounds of the present application.
  • the compounds containing asymmetric atoms of the present application can be isolated in optically pure form or racemic form, optically active form can be resolved from racemic mixture, or synthesized by using chiral raw materials or chiral reagents .
  • substituted means that any one or more hydrogen atoms on the specified atom are replaced by a substituent, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • ethyl is “optionally” substituted with halogen , meaning that the ethyl group can be unsubstituted ( CH2CH3 ), monosubstituted ( CH2CH2F , CH2CH2Cl , etc.), polysubstituted ( CHFCH2F , CH2CHF2 , CHFCH2Cl , CH2CHCl2 , etc. ) or fully substituted ( CF2CF3 , CF2CCl3 , CCl2CCl3 , etc.) . It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
  • any variable eg R a , R b
  • its definition is independent at each occurrence. For example, if a group is substituted by 2 R b , each R b has independent options.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
  • linking group mentioned herein does not indicate its linking direction
  • its linking direction is arbitrary.
  • L 1 in is selected from “C 1 -C 3 alkylene-O”
  • L 1 can connect ring Q and R 1 in the direction from left to right to form “ring QC 1 -C 3 alkylene Group -OR 1 "
  • ring Q and R 1 can also be connected from right to left to form “ring QOC 1 -C 3 alkylene-R 1 ".
  • the substituent When a bond of a substituent cross-links two atoms in a ring, the substituent may be bonded to any atom on the ring.
  • the structural unit Indicates that R 5 can be substituted at any position on the benzene ring.
  • C m - n herein means having an integer number of carbon atoms in the range of mn.
  • C 1 - 10 means that the group can 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.
  • alkyl refers to a hydrocarbon group having the general formula C n H 2n+1 , and the alkyl group may be straight or branched.
  • C 1-10 alkyl is understood to mean a linear or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7 , 8, 9 or 10 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 6 alkyl" can be understood as meaning
  • C 1-3 alkyl is understood to mean a linear or branched saturated alkyl group having 1, 2 or 3 carbon atoms.
  • the "C 1-10 alkyl” may include “C 1-6 alkyl “ or “C 1-3 alkyl”, and the “C 1-6 alkyl “ may further include “C 1-3 alkyl”.
  • haloalkyl is intended to include monohaloalkyl and polyhaloalkyl.
  • C 1-6 haloalkyl means a C 1-6 alkyl group as defined above substituted with one or more halogens, including but not limited to trifluoromethyl, 2,2,2-trifluoroethyl group, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl and pentachloroethyl, etc.
  • cycloalkyl refers to a fully saturated carbocyclic ring in the form of a monocyclic ring, a double ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring.
  • C 3 -10 cycloalkyl is understood to mean a saturated monocyclic, fused, spiro or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • cycloalkyl examples 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, adamantyl, spiro [4.5] decanyl, etc.
  • C 3 - 10 cycloalkyl may include “C 3 - 6 cycloalkyl”, and the term “C 3 - 6 cycloalkyl” can be understood as representing a saturated monocyclic or bicyclic hydrocarbon ring, which has 3, 4 , 5 or 6 carbon atoms, specific examples include but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.
  • 4-10 membered heterocyclic group refers to a heterocyclic group with 4, 5, 6, 7, 8, 9 or 10 ring atoms, and its ring atoms contain 1, 2, 3, 4 or 5 independent selected from the heteroatoms or heteroatom groups described above.
  • 4--10 membered heterocyclic group includes “4-8 membered heterocyclic group", wherein, specific examples of 4-membered heterocyclic group include but are not limited to azetidinyl, thietanyl or oxa Cyclobutanyl; specific examples of 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-di Hydroxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thio Morpholinyl, piperazinyl, trithianyl, tetrahydropyridyl, 4H-[1,3,4]thiadiazinyl or
  • the heterocyclic group can also be a bicyclic group, wherein, specific examples of the 5,5-membered bicyclic group include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; 5,6-membered bicyclic group Specific examples 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]pyrazinyl.
  • the heterocyclic group may be a benzofused cyclic group of the above-mentioned 4-8 membered heterocyclic group, specific examples include but not limited to dihydroisoquinolyl and the like.
  • “4-10 membered heterocyclic group” may include “5-10 membered heterocyclic group”, “4-8 membered heterocyclic group”, “5-6 membered heterocyclic group”, “6-8 membered heterocyclic group” , “4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-8 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered "Heterocycloalkyl” and other ranges, "4-8 membered heterocyclyl” may further include "4-6 membered heterocyclyl", “5-6 membered heterocyclyl”, “4-8 membered heterocyclyl” , “4-6 membered heterocycloalkyl”, "5-6 membered
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • Aryl groups can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • C 6 - 20 aryl can be understood as an aryl group having 6 to 20 carbon atoms, especially a ring having 6 carbon atoms (“C 6 aryl”), such as phenyl; or a ring having 9 carbon atoms 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.
  • C 6 aryl a ring having 6 carbon atoms
  • C 9 aryl such as indanyl or indenyl
  • C 10 aryl such as tetrahydronaphthyl, dihydronaphth
  • C 6 -10 aryl can be understood as an aryl group having 6 to 10 carbon atoms. Especially rings with 6 carbon atoms (“C aryl ”), such as phenyl; or rings with 9 carbon atoms (“C aryl”), such as indanyl or indenyl; or rings with 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • C 6-20 aryl may include “C 6-10 aryl”.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, and S, and an aromatic ring group whose ring atoms are C.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, and S, and an aromatic ring group whose ring atoms are C.
  • 5-10 membered heteroaryl is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S.
  • heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiazolyl Diazolyl, etc.
  • benzo derivatives such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazole Linyl or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc.
  • 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 .
  • halo or halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxyl refers to a -OH group.
  • cyano refers to a -CN group.
  • amino refers to a -NH2 group.
  • nitro refers to a -NO2 group.
  • terapéuticaally effective amount means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying the The amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder.
  • 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 a person skilled in the art according to its own knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable acid addition or base addition salts, including salts formed between compounds and inorganic or organic acids, and salts formed between compounds and inorganic or organic bases.
  • composition refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable auxiliary materials.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those 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 present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 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, etc.
  • Certain isotopically labeled compounds of the present application are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (ie3H ) and carbon-14 (ie14C ) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 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 similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes for administering a compound of the present application, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, ophthalmic Intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, emulsifying methods, freeze-drying methods and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets Or the core of the sugar coating.
  • Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
  • the pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
  • dosages of 0.01 mg/kg to 200 mg/kg body weight are administered per day, in single or divided doses.
  • Figure 1 shows the western blot results of mouse skin samples 24 hours after the last administration of Compound II-51 of the present application.
  • Figure 2 shows the results of western blot statistical analysis of mouse skin samples 24 hours after the last administration of Compound II-51 of the present application.
  • Figure 3 shows the results of western blot statistical analysis of mouse skin samples 24 hours after the last administration of the compound OXX of the present application.
  • Fig. 4 shows the scoring chart of compound II-51 of the present application on mouse hair growth.
  • Fig. 5 is a graph showing the change of compound II-51 of the present application on the body weight of mice.
  • Figure 6 shows the scoring chart of compound OXX of the present application on mouse hair growth.
  • Figure 7 shows the curve of the compound OXX of the present application on the body weight change of mice.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • DMF N,N-dimethylformamide
  • Et3N and TEA triethylamine
  • THF tetrahydrofuran
  • DMSO dimethylsulfoxide
  • TBSCl tert-butyldimethylsilyl chloride
  • 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 tris(tert-butyl)phosphorus
  • EA ethyl acetate
  • Pd2 (dba) 3 tris(benzylideneacetone)dipalladium
  • BINAP 1,1'-binaphthyl-2,2'-bisdiphenylpho
  • the preparation method is the same as S1, except that 4-amino-2-(trifluoromethyl)benzonitrile is replaced by 5-amino-3-(trifluoromethyl)-2-cyanopyridine (3.83g, 20.49mmol ), compound S3 was obtained by the same method, and 4.10 g of white solid was obtained, and the yield was 56.83%.
  • the preparation method is the same as S2, and the difference is that (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxyl-2-methylpropionamide is replaced by ( R)-3-bromo-N-(6-cyano-5-(trifluoromethyl)pyridin-3 base)-2-hydroxyl-2-methylpropionamide (1g, 2.85mmol), the compound was prepared in the same way S4, 620 mg of white solid was obtained, and the yield was 80.57%. mp: 76-86°C.
  • the preparation method is the same as S1, except that 4-amino-2-(trifluoromethyl)benzonitrile is replaced by 4-nitro-3-trifluoromethylaniline (4.22g, 20.49mmol), and the compound is obtained in the same way S8, 7 g of yellow solid was obtained, and the yield was 69.04%.
  • the preparation method is the same as S2, and the difference is that (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxyl-2-methylpropionamide is replaced by ( R)-3-bromo-2-hydroxyl-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide (3.5g, 9.43mmol), the same method to obtain compound S9 , 1.82 g of a light yellow solid was obtained, and the yield was 66.50%.
  • the preparation method is the same as S1, the difference is that 4-amino-2-(trifluoromethyl)benzonitrile is replaced by 4-amino-2-methoxybenzonitrile (546.51mg, 3.69mmol), and the compound is obtained in the same way S10, 270mg of yellow oil was obtained, the yield was 17.53%.
  • the preparation method is the same as S2, and the difference is that (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxyl-2-methylpropionamide is replaced by ( R)-3-bromo-N-(4-cyano-3-methoxyphenyl)-2-hydroxy-2-methylpropionamide (3.5g, 9.43mmol), the compound S11 was obtained in the same way as Yellow solid 1.82g, yield 66.50%.
  • the preparation method is the same as S1, except that 4-amino-2-(trifluoromethyl)benzonitrile is replaced by 4-amino-3-fluoro-2-methoxybenzonitrile (194mg, 3.69mmol).
  • Compound S12 was prepared by the above method to obtain 141 mg of a light yellow solid with a yield of 27.14%.
  • the preparation method is the same as S2, and the difference is that (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxyl-2-methylpropionamide is replaced by ( R)-3-bromo-N-(4-cyano-2-fluoro-3-methoxyphenyl)-2-hydroxy-2-methylpropionamide (500mg, 1.51mmol), the same method to obtain compound S13 , to obtain 200mg of light yellow solid, the yield was 52.93%.
  • the preparation method is the same as S2, and the difference is that (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxyl-2-methylpropionamide is replaced by ( R)-3-Bromo-N-(3-chloro-4-cyanophenyl)-2-hydroxy-2-methylpropionamide (1.2g, 3.78mmol), compound S15 was prepared in the same way to obtain 440mg of white solid , the yield was 49.20%.
  • the preparation method is the same as S1, the difference is that 4-amino-2-(trifluoromethyl)benzonitrile is replaced by 5-amino-3-chloro-2-pyridinecarbonitrile (630mg, 4.10mmol), and the compound is obtained in the same way S16, 1.2 g of a light yellow solid was obtained, and the yield was 91.92%.
  • the preparation method is the same as S2, and the difference is that (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxyl-2-methylpropionamide is replaced by ( R)-3-Bromo-N-(5-chloro-6-cyanopyridin-3-yl)-2-hydroxy-2-methylpropionamide (600mg, 1.88mmol), the compound S17 was obtained in the same way as white The solid is 160mg, and the yield is 35.75%.
  • 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) , slowly drop TFA 0.5mL, react at room temperature for 1h, after TLC monitors the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, extract with DCM (5mL ⁇ 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 90 mg of colorless oil, yield 53.05%.
  • Dissolve II-11-1 (250mg, 0.87mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 110 mg of yellow solid with a yield of 67.40%.
  • step 1 of Example 4 the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 4-fluoro-2-(trifluoromethyl)benzonitrile, and compound II- 14-1, 850 mg of white solid was obtained, and the yield was 90.47%.
  • Dissolve II-14-1 (300mg, 0.84mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 200 mg of light yellow solid with a yield of 92.82%.
  • step 1 of Example 4 the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 2-cyano-3,5-difluoropyridine, and compound II-15-1 is obtained in the same way , to obtain 320 mg of white solid, yield 73.17%.
  • 1 H NMR 300MHz, Chloroform-d
  • 3.48–3.36(m,4H) 1.51(s,9H).
  • Dissolve II-15-1 (220mg, 0.72mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 110 mg of yellow solid with a yield of 74.27%.
  • step 1 of Example 4 the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 5-bromo-2-nitrobenzotrifluoride, and compound II-19-1 is prepared in the same way, 314 mg of white solid was obtained with a yield of 75.68%.
  • Dissolve II-19-1 (314mg, 0.84mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 162 mg of white solid with a yield of 70.07%.
  • Dissolve II-20-1 (303mg, 1.05mmol) in DCM (3mL), slowly add TFA 0.8mL dropwise, react at room temperature for 1h, after TLC monitors the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 158 mg of white solid with a yield of 79.52%.
  • Dissolve II-22-1 (250mg, 0.73mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of white solid with a yield of 56.66%.
  • step 1 of Example 4 the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 5-bromo-3-(trifluoromethyl)-2-cyanopyridine, and prepared in the same way Compound II-23-1, 400 mg of solid was obtained, and the yield was 93.92%.
  • 1 H NMR 300MHz, Chloroform-d
  • 3.51(dd,J 6.6,4.0Hz,4H)
  • 1.54(s,9H LC-MS(ESI)m/z:357.10[M+H] + .
  • Dissolve II-23-1 (300mg, 0.84mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 185 mg of yellow solid with a yield of 85.76%.
  • Dissolve II-24-1 (300mg, 1.00mmol) in DCM (3mL), slowly add 1mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3 ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 160 mg of a white solid with a yield of 79.86%.
  • step 3 of Example 1 Referring to the synthesis method of step 3 of Example 1, the difference is that I-1-2 in step 3 is replaced by 4-piperazinylbenzonitrile, and compound II-1 is obtained in the same way to obtain 120 mg of white solid, and the yield is 70.88%.
  • step 3 of Example 1 Referring to the synthesis method of step 3 of Example 1, the difference is that I-1-2 in step 3 is replaced by 1-(4-trifluoromethylphenyl)piperazine, and compound II-10 is obtained in the same way as white
  • the solid was 150mg, and the yield was 69.01%.
  • Dissolve II-3-1 (200mg, 0.66mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 127 mg of white solid with a yield of 95.61%.
  • step 1 of Example 22 Referring to the synthesis method of step 1 of Example 22, the difference is that (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 is replaced by 3,8-diazabicyclo[3.2.1 ] Octane-3-carboxylic acid tert-butyl ester, the compound II-5-1 was prepared in the same way to obtain 368 mg of yellow solid, and the yield was 74.79%.
  • Dissolve II-5-1 (368mg, 1.17mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 200 mg of yellow solid with a yield of 80.15%.
  • step 1 of Example 22 the difference is that 4-bromobenzonitrile and (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 are replaced by p-bromofluorobenzene and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate was prepared in the same way as compound II-18-1, and 249 mg of white solid was obtained with a yield of 59.32%.
  • Dissolve II-18-1 (249mg, 0.81mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 154 mg of white solid with a yield of 92.18%.
  • step 1 4-bromobenzonitrile, (1S,4S)-(-)-2-tert-butoxycarbonyl-2,5-diazabicyclo[2.2 .1] heptane was replaced by p-bromofluorobenzene and (1S, 4S)-(-)-2-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]heptane, and compound II- 8-1, 220 mg of white solid was obtained, and the yield was 89.51%.
  • Dissolve II-8-1 (220mg, 0.75mmol) in DCM (4mL), slowly add TFA 1.0mL dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 120 mg of yellow oil with a yield of 82.95%.
  • step 1 of Example 25 the difference is that 4-bromobenzonitrile and (1S,4S)-(-)-2-tert-butoxycarbonyl-2,5-diazabicyclo[2.2 .1] Heptane was replaced by p-bromofluorobenzene and (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine, and compound II-17-1 was obtained in the same way to obtain 300 mg of yellow oil, with a yield of 59.45%.
  • Dissolve II-17-1 (200mg, 0.68mmol) in DCM (4mL), slowly add 1.0mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of yellow oil with a yield of 75.77%.
  • step 1 of Example 25 the difference is that 4-bromobenzonitrile and (1S,4S)-(-)-2-tert-butoxycarbonyl-2,5-diazabicyclo[2.2 .1] Heptane was replaced by 4-bromo-2-fluorobenzonitrile and 1-(tert-butoxycarbonyl)piperazine, and compound II-25-1 was obtained in the same way to obtain 1.64g of a light yellow solid, with a yield of 53.78% .
  • Dissolve II-25-1 (200mg, 0.65mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 95 mg of light yellow solid with a yield of 70.67%.
  • step 1 of Example 22 the difference is that 4-bromobenzonitrile and (1S,4S)-(-)-2-tert-butoxycarbonyl-2,5-diazabicyclo[2.2 .1] Heptane was replaced by 4-bromo-2-chlorobenzonitrile and 1-(tert-butoxycarbonyl)piperazine, and compound II-26-1 was obtained in the same way to obtain 213 mg of a light yellow solid with a yield of 71.64%.
  • Dissolve II-26-1 (200mg, 0.62mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 106 mg of a yellow solid with a yield of 76.94%.
  • Dissolve III-1-1 (510mg, 1.56mmol) in DCM (6mL), slowly add 1.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 300 mg of white solid with a yield of 84.74%.
  • Step 1 of Example 30 the difference is that in Step 1, 4-fluorophenylboronic acid pinacol ester was replaced by 4-benzonitrile boric acid pinacol ester, and compound III-2-1 was obtained in the same way as 250 mg of yellow oil, yield 77.80%.
  • Dissolve III-2-1 (250mg, 0.75mmol) in DCM (4mL), slowly add 1.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 120 mg of yellow oil with a yield of 68.51%.
  • Step 1 of Example 30 the difference is that in Step 1, 4-fluorophenylboronic acid pinacol ester was replaced by 3-fluorophenylboronic acid, and compound III-3-1 was obtained in the same way to obtain 210 mg of yellow oil , yield 66.75%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by S7 and 4-fluorophenylboronic acid pinacol ester, and compound III-4- 1. Obtain 270mg of yellow oily substance, yield 85.82%.
  • Dissolve III-4-1 (270mg, 0.82mmol) in DCM (4mL), slowly add 1mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3 ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 130 mg of a yellow oil, with a yield of 69.36%.
  • step 1 of Example 30 the difference is that in step 1, S5 and 4-fluorophenylboronic acid pinacol ester are replaced by S7 and 4-pyridineboronic acid pinacol ester, and compound III-5-1 is prepared in the same way , 220 mg of yellow oil, yield 73.76%.
  • Step 1 the difference is that in Step 1, 4-fluorophenylboronic acid pinacol ester was replaced by pyrimidine-5-boronic acid pinacol ester, and compound III-6-1 was obtained in the same way as yellow 230 mg of oily substance, yield 73.76%.
  • LC-MS(ESI) m/z: 312.10[M+H] + .
  • step 1 of Example 30 the difference is that 4-fluorophenylboronic acid pinacol ester in step 1 is replaced by 3-cyano-4-fluorophenylboronic acid pinacol ester, and compound III-7 is prepared in the same way -1, 400 mg of a light yellow solid was obtained, and the yield was 93.48%.
  • Dissolve III-7-1 (300mg, 0.85mmol) in DCM (3mL), slowly add 1mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3 ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 120 mg of a yellow solid with a yield of 55.87%.
  • Step 1 of Example 30 the difference is that in Step 1, 4-fluorophenylboronic acid pinacol ester was replaced by 4-pyridineboronic acid pinacol ester, and compound III-8-1 was obtained in the same way as light yellow Solid 220mg, yield 73.76%.
  • Dissolve III-8-1 (200mg, 0.64mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of yellow solid with a yield of 73.81%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-pyrazole-4-boronic acid pinacol ester and p-bromo Fluorobenzene, compound III-9-1 was prepared in the same way to obtain 200 mg of yellow solid, and the yield was 44.86%.
  • Dissolve III-9-2 (200mg, 0.63mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 100 mg of light yellow solid with a yield of 73.04%.
  • step 1 of Example 30 the difference is that in step 1, S5 and 4-fluorophenylboronic acid pinacol ester are replaced by S7 and 4-cyanophenylboronic acid pinacol ester, and compound III-10 is prepared in the same way -1, 400mg of yellow oil was obtained, yield 74.69%.
  • Dissolve III-10-1 (300mg, 0.82mmol) in DCM (4mL), slowly add 1mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3 ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 150 mg of a yellow oil with a yield of 71.36%.
  • step 1 of Example 30 the difference is that in step 1, S5 and 4-fluorophenylboronic acid pinacol ester are replaced by S6 and 4-cyanophenylboronic acid pinacol ester, and compound III-11 is prepared in the same way -1, 280 mg of a light yellow solid was obtained, and the yield was 87.15%.
  • Dissolve III-12-1 (250mg, 0.75mmol) in DCM (4mL), slowly add 1.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of yellow oil with a yield of 71.93%.
  • Dissolve III-13-1 (200mg, 0.63mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of yellow oil with a yield of 73.04%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by p-bromofluorobenzene and 4-(4-tert-butoxycarbonyl-1-piperazinyl ) phenylboronic acid pinacol ester, compound V-1-1 was obtained by the same method, and 523 mg of white solid was obtained, and the yield was 69.46%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 4 -Pinacol cyanophenylboronic acid ester, compound V-2-1 was prepared in the same way to obtain 319 mg of yellow solid, and the yield was 73.75%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 4 - Pyridineboronic acid pinacol ester, compound V-3-1 was obtained by the same method, and 279.86 mg of yellow solid was obtained, with a yield of 56.47%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 3 -Fluoro-4-cyanophenylboronic acid pinacol ester, compound V-4-1 was obtained by the same method, and 145 mg of yellow solid was obtained, with a yield of 18.54%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 2 -Pinacol cyanophenylboronic acid ester, compound V-5-1 was obtained by the same method, and 370 mg of yellow solid was obtained, and the yield was 69.53%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 3 -Pinacol cyanophenylboronic acid ester, compound V-6-1 was obtained by the same method, and 319 mg of yellow solid was obtained, with a yield of 60.11%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 5-bromo-2-cyanopyridine and 4-(4-tert-butoxycarbonyl- 1-Piperazinyl) phenylboronic acid pinacol ester was prepared in the same way as compound V-7-1 to obtain 183 mg of yellow solid with a yield of 48.75%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 6 - Fluoropyridine-3-boronic acid pinacol ester, compound V-8-1 was prepared in the same way to obtain 353 mg of yellow solid, with a yield of 84.41%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 3 -Cyano-4-fluorophenylboronic acid pinacol ester, the compound V-9-1 was obtained by the same method, and 400 mg of yellow solid was obtained, and the yield was 71.82%.
  • Example 30 step 1 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 4-bromo-2-(trifluoromethyl)benzonitrile and 4-(4 - tert-butoxycarbonyl-1-piperazinyl) phenylboronic acid pinacol ester, compound V-10-1 was prepared in the same way to obtain 250 mg of a yellow solid, with a yield of 44.91%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and pyrimidine - 5-Nacol boronic acid ester, compound V-20-1 was obtained by the same method, and 210 mg of yellow solid was obtained, and the yield was 42.25%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 4 -Nacol trifluoromethyl phenyl borate, the compound V-11-1 was prepared in the same way to obtain 145 mg of white solid with a yield of 40.58%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 4-(4-tert-butoxycarbonyl-1-piperazinyl)phenylboronic acid pinacol ester Alcohol ester and 5-bromo-3-(trifluoromethyl)-2-cyanopyridine were prepared in the same way as compound V-12-1, and 290 mg of yellow solid was obtained with a yield of 84.16%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 2 -Fluoropyridine-4-boronic acid pinacol ester, compound V-13-1 was prepared in the same way, and 230 mg of white solid was obtained, with a yield of 73.20%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 4-(4-tert-butoxycarbonyl-1-piperazinyl)phenylboronic acid pinacol ester Alcohol ester and 4-bromopyridine-2-carbonitrile were used to obtain compound V-14-1 in the same way to obtain 250 mg of yellow solid with a yield of 83.69%.
  • step 1 of Example 30 the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 4-(4-tert-butoxycarbonyl-1-piperazinyl)phenylboronic acid pinacol ester Alcohol ester and 5-bromo-2-nitrobenzotrifluoride were used to obtain compound V-15-1 in the same way to obtain 300 mg of yellow solid with a yield of 75.51%.
  • step 3 of Example 1 Referring to the synthesis method in step 3 of Example 1, the difference is that I-1-2 and S2 in step 3 were replaced by V-1-2 and S4, and compound V-16 was obtained in the same way to obtain 243 mg of a white solid with a yield of was 88.91%.
  • step 3 of Example 1 Referring to the synthesis method in step 3 of Example 1, the difference is that I-1-2 and S2 in step 3 were replaced by V-2-2 and S9, and compound V-18 was obtained in the same way to obtain 125 mg of a yellow solid with a yield of was 42.52%.
  • step 1 of Example 22 Referring to the synthesis method of step 1 of Example 22, the difference is that 4-bromobenzonitrile and (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 are replaced by 4-bromo-4 -Cyanobiphenyl and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate were prepared in the same way as compound V-19-1 to obtain 300 mg of a yellow solid with a yield of 75.51%.
  • step 1 of Example 22 Referring to the synthesis method of step 1 of Example 22, the difference is that (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 is replaced by 8-tert-butoxycarbonyl-3,8-di Azabicyclo[3.2.1]octane, compound II-27-1 was obtained by the same method to obtain 320 mg of a yellow solid with a yield of 86.53%.
  • Dissolve II-27-1 (320mg, 1.02mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 200 mg of yellow solid with a yield of 92.16%.
  • step 1 of Example 11 Referring to the synthesis method of step 1 of Example 11, the difference is that tert-butyl 1,4-diazepane-1-carboxylate in step 1 is replaced by 6-(tert-butoxycarbonyl)-3,6-di Azabicyclo[3.1.1]heptane, compound II-28-1 was obtained by the same method, and 240 mg of a yellow solid was obtained, with a yield of 48.55%.
  • Dissolve II-28-1 (200mg, 0.67mmol) in DCM (3mL), slowly add 1mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3 ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 110 mg of oil, with a yield of 82.63%.
  • Dissolve II-29-1 (190mg, 0.59mmol) in DCM (3mL), slowly add 1mL of TFA dropwise, react at room temperature for 4h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3 ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 110 mg of a white solid with a yield of 84.33%.
  • step 1 of Example 22 Referring to the synthesis method of step 1 of Example 22, the difference is that (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 is replaced by 3,6-diazabicyclo[3.1.1 ] Heptane-3-carboxylic acid tert-butyl ester, the compound II-30-1 was obtained by the same method, and 280 mg of light yellow solid was obtained, and the yield was 75.52%.
  • Dissolve II-30-1 (200mg, 0.67mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 115 mg of yellow solid with a yield of 86.39%.
  • step 1 of Example 4 the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 4-(bromomethyl)benzonitrile, and compound II-31-1 is obtained in the same way as White solid 714mg, yield 92.89%.
  • Dissolve II-31-1 (250mg, 0.83mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 150 mg of yellow solid with a yield of 89.85%.
  • Dissolve II-32-1 (200mg, 0.66mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 100 mg of a yellow solid with a yield of 74.87%.
  • Dissolve II-33-1 (195mg, 0.60mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 112 mg of yellow solid with a yield of 82.73%.
  • step 1 of Example 4 the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 2-bromo-4-fluorobenzonitrile, and compound II-34-1 is obtained in the same way as Yellow solid 200 mg, yield 72.81%.
  • 1 H NMR 300MHz, Chloroform-d
  • step 1 of Example 30 the difference is that in step 1, S5 and 4-fluorophenylboronic acid pinacol ester are replaced by II-34-1 and phenylboronic acid pinacol ester, and compound II-34 is prepared in the same way -2, 150 mg of a yellow solid was obtained, and the yield was 75.58%.
  • Dissolve II-34-2 (150mg, 0.41mmol) in DCM (4mL), slowly add 1mL of TFA dropwise, react at room temperature for 4h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3 ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 60 mg of a yellow oil with a yield of 55.21%.
  • step 1 of Example 25 the difference is that 4-bromobenzonitrile and (1S,4S)-(-)-2-tert-butoxycarbonyl-2,5-diazabicyclo[2.2 .1] Heptane was replaced by 4-bromo-2-methoxybenzonitrile and 1-tert-butoxycarbonylpiperazine, and compound II-35-1 was obtained in the same way to obtain 342 mg of white solid with a yield of 91.39%.
  • Dissolve II-35-1 (342mg, 1.08mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 130 mg of white solid with a yield of 55.40%.
  • Dissolve II-34-1 (200mg, 0.55mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 107 mg of light yellow solid with a yield of 73.63%.
  • Dissolve II-37-1 (250mg, 0.86mmol) in DCM (3mL), slowly add 1mL of TFA dropwise, react at room temperature for 0.5h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 130 mg of light yellow solid with a yield of 79.51%.
  • Dissolve II-38-1 (280mg, 0.89mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 160 mg of white solid with a yield of 83.84%.
  • Step 1 of Example 76 the difference is that 6-fluoronicotinonitrile in Step 1 was replaced by 2-chloro-5-cyanopyrimidine, and compound II-39-1 was obtained in the same way to obtain 280 mg of a yellow solid.
  • the rate is 61.94%.
  • Dissolve II-39-1 (200mg, 0.63mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 130 mg of light yellow solid with a yield of 95.23%.
  • Step 3 of Example 1 Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 and S2 in Step 3 were replaced with II-5-2 and S15, and compound II-41 was obtained in the same way to obtain 172 mg of a light yellow solid, producing The rate is 58.24%.
  • step 1 of Example 4 the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 5-cyano-2-fluoropyridine, and compound II-42-1 is obtained in the same way as white Solid 210 mg, yield 88.92%.
  • Dissolve II-42-1 (210mg, 0.73mmol) in DCM (3mL), slowly add TFA 0.8mL, react at room temperature for 4h, after TLC monitors the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 120 mg of yellow oil with a yield of 87.54%.
  • step 1 of Example 22 Referring to the synthesis method of step 1 of Example 22, the difference is that 4-bromobenzonitrile and (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 are replaced by 4-bromo-3 -Methylbenzonitrile and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate, the compound II-45-1 was prepared in the same way to obtain 260 mg of light yellow solid, yield 77.84% .
  • Dissolve II-45-1 (220mg, 0.67mmol) in DCM (2mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 123 mg of white solid with a yield of 80.53%.
  • step 1 of Example 22 Referring to the synthesis method of step 1 of Example 22, the difference is that 4-bromobenzonitrile and (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 are replaced by 3-fluoro-4 -Bromobenzonitrile and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate were prepared in the same way as compound II-46-1 to obtain 217 mg of a light yellow solid with a yield of 43.66%.
  • Dissolve II-46-1 (200mg, 0.60mmol) in DCM (2mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 70 mg of white solid with a yield of 50.15%.
  • step 1 of Example 4 the difference is that 2-cyano-5-fluoropyridine and 1-(tert-butoxycarbonyl)piperazine in step 1 are replaced by 2-cyano-3,5-difluoro Pyridine and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate were prepared in the same way as compound II-50-1, and 300 mg of a white solid was obtained with a yield of 63.22%.
  • step 1 of Example 22 Referring to the synthesis method of step 1 of Example 22, the difference is that 4-bromobenzonitrile and (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 are replaced by 4-bromo-3 -Fluorobenzonitrile and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate, the compound II-53-1 was prepared in the same way to obtain 1.3 g of light yellow solid, yield 54.14 %.
  • Dissolve II-53-1 (200mg, 0.63mmol) in DCM (2mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 100 mg of light yellow solid with a yield of 73.04%.
  • step 1 of Example 22 Referring to the synthesis method of step 1 of Example 22, the difference is that 4-bromobenzonitrile and (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 are replaced by 3-methoxy -4-Bromobenzonitrile and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate, the compound II-54-1 was prepared in the same way to obtain 340mg of yellow solid, yield 83.97% .
  • Dissolve II-54-1 (200mg, 0.58mmol) in DCM (2mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 120 mg of yellow solid with a yield of 84.69%.
  • step 1 of Example 22 Referring to the synthesis method of step 1 of Example 22, the difference is that 4-bromobenzonitrile and (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 are replaced by 5-bromo-2 -Cyanopyrimidine and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate were prepared in the same way as compound II-55-1 to obtain 274 mg of a yellow solid with a yield of 79.93%.
  • Dissolve II-55-1 (174mg, 0.55mmol) in DCM (2mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 104 mg of yellow solid with a yield of 87.57%.
  • step 1 of Example 25 Referring to the synthesis method of step 1 of Example 25, the difference is that (1S,4S)-(-)-2-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]heptane in step 1 is replaced by (S)-tert-butyl 3-methylpiperazine-1-carboxylate was prepared in the same way as compound II-57-1 to obtain 251 mg of a brown solid with a yield of 37.90%.
  • Step 3 of Example 1 the difference is that S2 and I-1-2 in Step 3 were replaced by S15 and II-46-2, and compound II-58 was prepared in the same way to obtain 125 mg of a light yellow solid, producing The rate is 61.78%.
  • Step 3 of Example 1 the difference is that S2 and I-1-2 in Step 3 were replaced by S17 and II-53-2, and compound II-65 was prepared in the same way to obtain 84 mg of a white solid with a yield of is 66.86%.
  • step 1 of Example 4 the difference is that 2-cyano-5-fluoropyridine and 1-(tert-butoxycarbonyl) piperazine in step 1 are replaced by 5-bromo-2-cyanopyrimidine and 3 , tert-butyl 6-diazabicyclo[3.1.1]heptane-3-carboxylate was prepared in the same way as compound II-66-1 to obtain 420 mg of a yellow solid with a yield of 42.51%.
  • Dissolve II-66-1 (250mg, 0.83mmol) in DCM (3mL), slowly add 1mL of TFA dropwise, react at room temperature for 0.5h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ⁇ 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 120 mg of light yellow solid with a yield of 71.88%.

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Abstract

A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing them, and their use as a selective androgen receptor degradation (SARD) agent and/or androgen receptor (AR) antagonist, particularly suited for preparing medications for the treatment or prevention of diseases brought about by androgen receptors.

Description

酰胺类化合物及其应用Amide compounds and their applications
相关申请的交叉引用Cross References to Related Applications
本申请要求以下3件中国发明专利申请的权益和优先权，在此将它们的全部内容以援引的方式整体并入本文中：This application claims the benefit and priority of the following 3 Chinese invention patent applications, the entire contents of which are hereby incorporated by reference in their entirety:
2021年8月5日向中国国家知识产权局提交的第202110896906.6号专利申请；Patent application No. 202110896906.6 submitted to the State Intellectual Property Office of China on August 5, 2021;
2022年1月30日向中国国家知识产权局提交的第202210114403.3号专利申请；以及Patent Application No. 202210114403.3 filed with the State Intellectual Property Office of China on January 30, 2022; and
2022年6月24日向中国国家知识产权局提交的第202210724756.5号专利申请。Patent application No. 202210724756.5 submitted to the State Intellectual Property Office of China on June 24, 2022.
技术领域technical field
本申请涉及药物化学领域，具体涉及一类酰胺类化合物或其立体异构体或药学上可接受的盐，含有它们的药物组合物以及作为选择性雄激素受体降解剂(SARD)和/或雄激素受体(AR)拮抗剂的用途。The application relates to the field of medicinal chemistry, in particular to a class of amide compounds or their stereoisomers or pharmaceutically acceptable salts, pharmaceutical compositions containing them and as selective androgen receptor degraders (SARD) and/or Use of androgen receptor (AR) antagonists.
背景技术Background technique
雄激素受体(Androgen receptor，AR)是核受体家族成员之一，AR包含四个主要区域：N端活性转录控制区域(N-terminal domain，NTD)、DNA结合区域(DNA binding domain，DBD)、铰链区以及C末端的配体结合区(Ligand binding domain，LBD)。自从Huggins和Hodges在20世纪40年代早期发现雄激素促进***癌生长以来，AR一直是***癌治疗的重要靶点。Androgen receptor (AR) is a member of the nuclear receptor family. AR contains four main regions: N-terminal active transcription control region (N-terminal domain, NTD), DNA binding domain (DNA binding domain, DBD ), the hinge region and the C-terminal ligand binding domain (Ligand binding domain, LBD). AR has been an important target for prostate cancer therapy since Huggins and Hodges discovered in the early 1940s that androgens promote prostate cancer growth.
***癌(PCa)是全球最常见癌症之一。***癌内分泌治疗是晚期***癌主要治疗方法。内分泌治疗的初始阶段，各种雄激素剥夺疗法(ADT)是有效的，但经过中位时间14-30个月后，几乎所有的患者病变都将由雄激素依赖性***癌(HDPC)逐渐发展成为雄激素非依赖性***癌(HIPC)，也称去势抵抗性***癌(castration-resistant prostate cancer，CRPC)。目前获批的用于治疗去势抵抗***癌的口服药物，主要有阿比特龙和恩扎鲁胺。其中，阿比特龙为新型的雄激素生物合成抑制剂，它能够阻断睾丸、肾上腺或者肿瘤细胞内环境中雄激素的合成。而恩扎鲁胺是一种雄激素受体抑制剂，能够竞争性地抑制雄激素与受体的结合。当恩扎鲁胺与AR结合后，也可以进一步抑制AR的细胞核转运，从而阻断AR与DNA的相互作用。但是CRPC患者目前尚无有效的治疗方法，大量的研究显示在80％的晚期CRPC中AR存在高表达。因此，研究新型分子对AR的降解活性和/或对AR的拮抗活性，对进一步研究与AR高表达有关的疾病具有重要意义。Prostate cancer (PCa) is one of the most common cancers worldwide. Prostate cancer endocrine therapy is the main treatment for advanced prostate cancer. In the initial stage of endocrine therapy, various androgen deprivation therapy (ADT) is effective, but after a median time of 14-30 months, almost all patients' lesions will gradually develop from androgen-dependent prostate cancer (HDPC) to Androgen-independent prostate cancer (HIPC), also known as castration-resistant prostate cancer (CRPC). Currently approved oral drugs for the treatment of castration-resistant prostate cancer mainly include abiraterone and enzalutamide. Among them, abiraterone is a new type of androgen biosynthesis inhibitor, which can block the synthesis of androgen in the testis, adrenal gland or tumor cell environment. Enzalutamide is an androgen receptor inhibitor that competitively inhibits the binding of androgen to the receptor. When enzalutamide is combined with AR, it can further inhibit the nuclear translocation of AR, thereby blocking the interaction between AR and DNA. However, there is no effective treatment for CRPC patients. A large number of studies have shown that AR is highly expressed in 80% of advanced CRPC. Therefore, it is of great significance to study the degradation activity of new molecules on AR and/or the antagonistic activity on AR for further research on diseases related to high expression of AR.
现有文献中也报道了一些作为选择性雄激素受体降解剂(SARD)的化合物(如专利文献WO2017/214634)。选择性雄激素受体降解剂(SARD)不仅能够抑制雄激素受体，阻断雄激素受体信号传导的过程，同时也能够降解受体本身，有望带来更多的益处。因此，亟需一类新的选择性雄激素受体降解剂和/或雄激素受体(AR)拮抗剂。Some compounds as selective androgen receptor degraders (SARDs) have also been reported in the existing literature (such as patent document WO2017/214634). Selective androgen receptor degraders (SARD) can not only inhibit the androgen receptor and block the process of androgen receptor signal transduction, but also degrade the receptor itself, which is expected to bring more benefits. Therefore, there is an urgent need for a new class of selective androgen receptor degraders and/or androgen receptor (AR) antagonists.
发明详述Detailed description of the invention
一方面，本申请提供式(I)所示化合物及其立体异构体或药学上可接受的盐。这些化合物可以作为选择性雄激素受体降解剂和/或雄激素受体(AR)拮抗剂，用于治疗与AR高表达有关的疾病。In one aspect, the present application provides the compound represented by formula (I) and its stereoisomer or pharmaceutically acceptable salt. These compounds can be used as selective androgen receptor degraders and/or androgen receptor (AR) antagonists for treating diseases related to high expression of AR.
一种式(I)所示化合物或其立体异构体或药学上可接受的盐，A compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt,
Figure PCTCN2022110325-appb-000001
Figure PCTCN2022110325-appb-000001
其中，in,
X是CH或N；X is CH or N;
R 1选自H、OH、C 1-6烷基、-O-C 1-6烷基、-OCOR a、-COR a、-CONHR a或-NHCOR a； R 1 is selected from H, OH, C 1-6 alkyl, -OC 1-6 alkyl, -OCOR a , -COR a , -CONHR a or -NHCOR a ;
R 2选自C 1-6烷基或C 1-6卤代烷基；或者 R 2 is selected from C 1-6 alkyl or C 1-6 haloalkyl; or
由R 1与R 2及其连接的C共同形成C 3-6环烷基或4-6元杂环基； A C 3-6 cycloalkyl group or a 4-6 membered heterocyclic group is formed by R 1 and R 2 and the connected C together;
R 4选自卤素、CF 3或-O-C 1-6烷基； R 4 is selected from halogen, CF 3 or -OC 1-6 alkyl;
R 5选自CN、NO 2、-COR a、-CONHR a、-S(O) 2R a或-S(O) 2N(R a) 2； R 5 is selected from CN, NO 2 , -COR a , -CONHR a , -S(O) 2 R a or -S(O) 2 N(R a ) 2 ;
R a独立地选自H、OH、卤素、C 1-6烷基或C 1-6卤代烷基； R is independently selected from H, OH, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R 6选自H或-O-C 1-6烷基； R 6 is selected from H or -OC 1-6 alkyl;
R 7和R 8独立地选自H或卤素； R and R are independently selected from H or halogen;
W选自
Figure PCTCN2022110325-appb-000002
或4-10元完全饱和杂环基，所述4-10元完全饱和杂环基任选地被R b取代；R b独立地选自卤素、OH、NH 2、NO 2、CN、C 1-6烷基、C 1-6卤代烷基、-O-C 1-6烷基或-S(＝O) 2-C 1-6烷基； W selected from
Figure PCTCN2022110325-appb-000002
Or a 4-10 membered fully saturated heterocyclic group, the 4-10 membered fully saturated heterocyclic group is optionally substituted by R b ; R b is independently selected from halogen, OH, NH 2 , NO 2 , CN, C 1 -6 alkyl, C 1-6 haloalkyl, -OC 1-6 alkyl or -S(=O) 2 -C 1-6 alkyl;
环D选自5-10元杂芳基或C 6-10芳基； Ring D is selected from 5-10 membered heteroaryl or C 6-10 aryl;
每一个R 3独立地选自卤素、OH、NH 2、NO 2、CN、-CONH 2、-CONHR 3A、-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、C 1-6烷基、4-10元杂环基、5-10元杂芳基或C 6-10芳基，所述C 1-6烷基、4-10元杂环基、5-10元杂芳基或C 6-10芳基任选地被R 3A取代； Each R 3 is independently selected from halogen, OH, NH 2 , NO 2 , CN, -CONH 2 , -CONHR 3A , -OC 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl , C 1-6 alkyl, 4-10 membered heterocyclic group, 5-10 membered heteroaryl or C 6-10 aryl, the C 1-6 alkyl, 4-10 membered heterocyclic group, 5- 10-membered heteroaryl or C 6-10 aryl is optionally substituted by R 3A ;
R 3A独立地选自卤素、OH、NO 2、CN、CH 2F、CHF 2、CF 3、C 1-6烷基、-O-C 1-6烷基或-S(＝O) 2-C 1-6烷基； R 3A is independently selected from halogen, OH, NO 2 , CN, CH 2 F, CHF 2 , CF 3 , C 1-6 alkyl, -OC 1-6 alkyl or -S(=O) 2 -C 1 -6 alkyl;
n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;
p选自0或1。p is selected from 0 or 1.
在本申请的一些实施方案中，X是CH。In some embodiments of the present application, X is CH.
在本申请的一些实施方案中，X是N。In some embodiments of the present application, X is N.
在本申请的一些实施方案中，W选自4-10元完全饱和杂环基，所述4-10元完全饱和杂环基任选地被R b取代。 In some embodiments of the present application, W is selected from 4-10 membered fully saturated heterocyclic groups optionally substituted by R b .
在本申请的一些实施方案中，W选自4-8元完全饱和杂环基，所述4-8元完全饱和杂环基任选地被R b取代。 In some embodiments of the present application, W is selected from 4-8 membered fully saturated heterocyclic groups optionally substituted by R b .
在本申请的一些实施方案中，W选自含有1或2个N原子的4、5、6、7或8元完全饱和杂环基，所述4、5、6、7或8元完全饱和杂环基任选地被R b取代。 In some embodiments of the present application, W is selected from 4, 5, 6, 7 or 8 membered fully saturated heterocyclic groups containing 1 or 2 N atoms, and the 4, 5, 6, 7 or 8 membered fully saturated heterocyclic groups are Heterocyclyl is optionally substituted with Rb .
在本申请的一些实施方案中，W选自6-8元完全饱和杂环基，所述6-8元完全饱和杂环基任选地被R b取代。 In some embodiments of the present application, W is selected from 6-8 membered fully saturated heterocyclic groups optionally substituted by R b .
在本申请的一些实施方案中，W选自含有1或2个N原子的6、7或8元完全饱和杂环基，所述6、7或8元完全饱和杂环基任选地被R b取代。 In some embodiments of the present application, W is selected from 6, 7 or 8 membered fully saturated heterocyclic groups containing 1 or 2 N atoms, and the 6, 7 or 8 membered fully saturated heterocyclic groups are optionally replaced by R b replaces.
在本申请的一些实施方案中，W选自7-8元完全饱和杂环基，所述7-8元完全饱和杂环基任选地被R b取代。 In some embodiments of the present application, W is selected from 7-8 membered fully saturated heterocyclic groups, and the 7-8 membered fully saturated heterocyclic groups are optionally substituted by R b .
在本申请的一些实施方案中，W选自氮杂环丁基、哌嗪基、1,4-二氮杂环庚烷基、3,8-二氮杂双环[3.2.1]辛烷基、2,5-二氮双环[2.2.1]庚烷基或
Figure PCTCN2022110325-appb-000003
所述的氮杂环丁基、哌嗪基、1,4-二氮杂环庚烷基、3,8-二氮杂双环[3.2.1]辛烷基、2,5-二氮双环[2.2.1]庚烷基或
Figure PCTCN2022110325-appb-000004
任选地被R b取代。 In some embodiments of the present application, W is selected from azetidinyl, piperazinyl, 1,4-diazepanyl, 3,8-diazabicyclo[3.2.1]octyl , 2,5-diazabicyclo[2.2.1]heptanyl or
Figure PCTCN2022110325-appb-000003
The azetidinyl, piperazinyl, 1,4-diazepanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[ 2.2.1] Heptyl or
Figure PCTCN2022110325-appb-000004
is optionally substituted by Rb .
在本申请的一些实施方案中，W选自氮杂环丁基、哌嗪基、1,4-二氮杂环庚烷基、3,8-二氮杂双环[3.2.1]辛烷基或2,5-二氮双环[2.2.1]庚烷基，所述的氮杂环丁基、哌嗪基、1,4-二氮杂环庚烷基、3,8-二氮杂双环[3.2.1]辛烷基或2,5-二氮双环[2.2.1]庚烷基任选地被R b取代。 In some embodiments of the present application, W is selected from azetidinyl, piperazinyl, 1,4-diazepanyl, 3,8-diazabicyclo[3.2.1]octyl Or 2,5-diazabicyclo[2.2.1]heptyl, the azetidinyl, piperazinyl, 1,4-diazepanyl, 3,8-diazabicyclo [3.2.1]octyl or 2,5-diazabicyclo[2.2.1]heptyl is optionally substituted by R b .
在本申请的一些实施方案中，W选自氮杂环丁基、哌嗪基、3,8-二氮杂双环[3.2.1]辛烷基或2,5-二氮双环[2.2.1]庚烷基，所述的氮杂环丁基、哌嗪基、3,8-二氮杂双环[3.2.1]辛烷基或2,5-二氮双环[2.2.1]庚烷基任选地被R b取代。 In some embodiments of the present application, W is selected from azetidinyl, piperazinyl, 3,8-diazabicyclo[3.2.1]octyl or 2,5-diazabicyclo[2.2.1 ]heptyl, the azetidinyl, piperazinyl, 3,8-diazabicyclo[3.2.1]octyl or 2,5-diazabicyclo[2.2.1]heptyl is optionally substituted by Rb .
在本申请的一些实施方案中，环D选自苯基或5-10元杂芳基。In some embodiments of the present application, ring D is selected from phenyl or 5-10 membered heteroaryl.
在本申请的一些实施方案中，环D选自苯基或含有1个或2个N原子的5、6、7、8、9或10元杂芳基。In some embodiments of the present application, Ring D is selected from phenyl or 5, 6, 7, 8, 9 or 10 membered heteroaryl containing 1 or 2 N atoms.
在本申请的一些实施方案中，环D选自苯基或含有1个或2个N原子的5或6元杂芳基。In some embodiments of the present application, ring D is selected from phenyl or 5- or 6-membered heteroaryl containing 1 or 2 N atoms.
在本申请的一些实施方案中，环D选自苯基、吡啶基、吡唑基、嘧啶基、哒嗪基、苯并吡咯基、喹啉基、异喹啉基或苯并吡唑基。In some embodiments of the present application, ring D is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, pyridazinyl, benzopyrrolyl, quinolinyl, isoquinolinyl or benzopyrazolyl.
在本申请的一些实施方案中，环D选自苯基、吡啶基、吡唑基、嘧啶基或哒嗪基。In some embodiments of the present application, Ring D is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl or pyridazinyl.
在本申请的一些实施方案中，R b选自C 1-6烷基。 In some embodiments of the present application, R b is selected from C 1-6 alkyl.
在本申请的一些实施方案中，R b选自CH 3。 In some embodiments of the present application, R b is selected from CH 3 .
在本申请的一些实施方案中，R 3选自卤素、NO 2、CN、-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、-CONHR 3A、C 1-6烷基、5-10元杂芳基或C 6-10芳基，所述C 1-6烷基、5-10元杂芳基或C 6-10芳基任选地被R 3A取代。 In some embodiments of the present application, R 3 is selected from halogen, NO 2 , CN, -OC 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, -CONHR 3A , C 1- 6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl, said C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl is optionally substituted by R 3A .
在本申请的一些实施方案中，R 3选自卤素、CN、NO 2、-O-C 1-6烷基、-CONHR 3A、C 1-6烷基、5-10元杂芳基或C 6-10芳基，所述C 1-6烷基、5-10元杂芳基或C 6-10芳基任选地被R 3A取代，R 3A可以优选地选自卤素、CN、CF 3、NO 2或CH 3，以及R 3A可以更优选地选自卤素、CN、CF 3或CH 3。 In some embodiments of the present application, R 3 is selected from halogen, CN, NO 2 , -OC 1-6 alkyl, -CONHR 3A , C 1-6 alkyl, 5-10 membered heteroaryl or C 6- 10 aryl, the C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl is optionally substituted by R 3A , R 3A can be preferably selected from halogen, CN, CF 3 , NO 2 or CH 3 , and R 3A may more preferably be selected from halogen, CN, CF 3 or CH 3 .
在本申请的一些实施方案中，R 3选自卤素、NO 2、CN、-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、C 1-6烷基、5-10元杂芳基或C 6-10芳基，所述C 1-6烷基、5-10元杂芳基或C 6-10芳基任选地被R 3A取代。 In some embodiments of the present application, R 3 is selected from halogen, NO 2 , CN, -OC 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl, C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl, said C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl is optionally substituted by R 3A .
在本申请的一些实施方案中，R 3选自卤素、CN、NO 2、-O-C 1-6烷基、C 1-6烷基、5-10元杂芳基或C 6-10芳基，所述C 1-6烷基、5-10元杂芳基或C 6-10芳基任选地被R 3A取代，R 3A可以优选地选自卤素、CN、CF 3、NO 2或CH 3，以及R 3A可以更优选地选自卤素、CN或CF 3。 In some embodiments of the present application, R 3 is selected from halogen, CN, NO 2 , -OC 1-6 alkyl, C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl, The C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl is optionally substituted by R 3A , R 3A can be preferably selected from halogen, CN, CF 3 , NO 2 or CH 3 , and R 3A may more preferably be selected from halogen, CN or CF 3 .
在本申请的一些实施方案中，R 3选自卤素、NO 2、CN、-O-C 1-6烷基、-S(＝O) 2-CH 3、C 1-6烷基、5-6元杂芳基或苯基，所述C 1-6烷基、5-6元杂芳基或苯基任选地被R 3A取代。 In some embodiments of the present application, R 3 is selected from halogen, NO 2 , CN, -OC 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 is optionally substituted by R 3A .
在本申请的一些实施方案中，R 3选自卤素、CN、NO 2、-O-C 1-6烷基、C 1-6烷基、5-6元杂芳基或苯基，所述C 1-6烷基、5-6元杂芳基或苯基任选地被R 3A取代，R 3A可以优选地选自卤素、CN、CF 3、NO 2或CH 3，以及R 3A可以更优选地选自卤素、CN或CF 3。 In some embodiments of the present application, R 3 is selected from halogen, CN, NO 2 , -OC 1-6 alkyl, C 1-6 alkyl, 5-6 membered heteroaryl or phenyl, and the C 1 -6 alkyl, 5-6 membered heteroaryl or phenyl is optionally substituted by R 3A , R 3A may preferably be selected from halogen, CN, CF 3 , NO 2 or CH 3 , and R 3A may be more preferably is selected from halogen, CN or CF3 .
在本申请的一些实施方案中，R 3选自F、Cl、Br、CN、NO 2、-O-C 1-6烷基、C 1-6烷基、含有1个或2个N原子的5-6元杂芳基或苯基，所述C 1-6烷基、5-6元杂芳基或苯基任选地被R 3A取代，R 3A可以优选地选自卤素、CN、CF 3、NO 2或CH 3，以及R 3A可以更优选地选自卤素、CN或CF 3。 In some embodiments of the present application, R 3 is selected from F, Cl, Br, CN, NO 2 , -OC 1-6 alkyl, C 1-6 alkyl, 5- 6-membered heteroaryl or phenyl, the C 1-6 alkyl, 5-6-membered heteroaryl or phenyl is optionally substituted by R 3A , R 3A can be preferably selected from halogen, CN, CF 3 , NO 2 or CH 3 , and R 3A may more preferably be selected from halogen, CN or CF 3 .
在本申请的一些实施方案中，R 3选自F、Cl、Br、CN、NO 2、-O-C 1-2烷基、C 1-2烷基、含有1个或2个N原子的5-6元杂芳基或苯基，所述C 1-6烷基、5-6元杂芳基或苯基任选地被R 3A取代，R 3A可以优选地选自卤素、CN、CF 3、NO 2或CH 3，以及R 3A可以更优选地选自F、CN或CF 3。 In some embodiments of the present application, R 3 is selected from F, Cl, Br, CN, NO 2 , -OC 1-2 alkyl, C 1-2 alkyl, 5- 6-membered heteroaryl or phenyl, the C 1-6 alkyl, 5-6-membered heteroaryl or phenyl is optionally substituted by R 3A , R 3A can be preferably selected from halogen, CN, CF 3 , NO 2 or CH 3 , and R 3A may more preferably be selected from F, CN or CF 3 .
在本申请的一些实施方案中，R 3选自卤素、NO 2、CN、-O-CH 3、-CF 3、-CH 3、-S(＝O) 2-CH 3、-CONHCH 3、嘧啶基、吡唑基、吡啶基或苯基，所述嘧啶基、吡唑基、吡啶基或苯基任选地被R 3A取代。 In some embodiments of the present application, R 3 is selected from halogen, NO 2 , CN, -O-CH 3 , -CF 3 , -CH 3 , -S(=O) 2 -CH 3 , -CONHCH 3 , pyrimidine Base, pyrazolyl, pyridyl or phenyl, said pyrimidinyl, pyrazolyl, pyridyl or phenyl optionally substituted by R 3A .
在本申请的一些实施方案中，R 3选自卤素、NO 2、CN、-O-CH 3、-CF 3、-CH 3、-CONHCH 3、嘧啶基、吡唑基、吡啶基或苯基，所述嘧啶基、吡唑基、吡啶基或苯基任选地被R 3A取代。 In some embodiments of the present application, R 3 is selected from halogen, NO 2 , CN, -O-CH 3 , -CF 3 , -CH 3 , -CONHCH 3 , pyrimidinyl, pyrazolyl, pyridyl or phenyl , the pyrimidinyl, pyrazolyl, pyridyl or phenyl is optionally substituted by R 3A .
在本申请的一些实施方案中，R 3选自卤素、NO 2、CN、-O-CH 3、-CF 3、嘧啶基、吡唑基、吡啶基或苯基，所述嘧啶基、吡唑基、吡啶基或苯基任选地被R 3A取代。在本申请的一些实施方案中，R 3A独立地选自卤素、OH、NO 2、CN、CH 2F、CHF 2、CF 3或C 1-6烷基。 In some embodiments of the present application, R 3 is selected from halogen, NO 2 , CN, -O-CH 3 , -CF 3 , pyrimidinyl, pyrazolyl, pyridyl or phenyl, and the pyrimidinyl, pyrazole Base, pyridyl or phenyl is optionally substituted by R 3A . In some embodiments of the present application, R 3A is independently selected from halogen, OH, NO 2 , CN, CH 2 F, CHF 2 , CF 3 or C 1-6 alkyl.
在本申请的一些实施方案中，R 3选自F、Cl、Br、CN、NO 2、-CF 3、-O-CH 3、-CH 3、-CONHCH 3、嘧啶基、吡唑基、吡啶基或苯基，所述嘧啶基、吡唑基、吡啶基或苯基任选地被R 3A取代，R 3A可以优选地选自卤素、CN、CF 3或NO 2，以及R 3A可以更优选地选自F、CN或CF 3。 In some embodiments of the present application, R 3 is selected from F, Cl, Br, CN, NO 2 , -CF 3 , -O-CH 3 , -CH 3 , -CONHCH 3 , pyrimidinyl, pyrazolyl, pyridine or phenyl, said pyrimidinyl, pyrazolyl, pyridyl or phenyl is optionally substituted by R 3A , R 3A may preferably be selected from halogen, CN, CF 3 or NO 2 , and R 3A may be more preferably is selected from F, CN or CF 3 .
在本申请的一些实施方案中，R 3A独立地选自卤素、NO 2、CN、CF 3或CH 3。 In some embodiments of the present application, R 3A is independently selected from halogen, NO 2 , CN, CF 3 or CH 3 .
在本申请的一些实施方案中，R 3A独立地选自卤素、CN或CF 3。 In some embodiments of the present application, R 3A is independently selected from halogen, CN or CF 3 .
在本申请的一些实施方案中，R 1选自H、OH、C 1-6烷基或-O-C 1-6烷基。 In some embodiments of the present application, R 1 is selected from H, OH, C 1-6 alkyl or -OC 1-6 alkyl.
在本申请的一些实施方案中，R 1选自OH。 In some embodiments of the present application, R 1 is selected from OH.
在本申请的一些实施方案中，R 2选自C 1-6烷基。 In some embodiments of the present application, R 2 is selected from C 1-6 alkyl.
在本申请的一些实施方案中，R 2选自CH 3。 In some embodiments of the present application, R 2 is selected from CH 3 .
在本申请的一些实施方案中，R 4选自卤素、CF 3或-O-CH 3。 In some embodiments of the present application, R 4 is selected from halogen, CF 3 or -O-CH 3 .
在本申请的一些实施方案中，R 4选自F、Cl、Br、CF 3或-O-CH 3。 In some embodiments of the present application, R 4 is selected from F, Cl, Br, CF 3 or —O—CH 3 .
在本申请的一些实施方案中，R 4选自F、Cl、CF 3或-O-CH 3。 In some embodiments of the present application, R 4 is selected from F, Cl, CF 3 or -O-CH 3 .
在本申请的一些实施方案中，R 4选自Cl或CF 3。 In some embodiments of the present application, R 4 is selected from Cl or CF 3 .
在本申请的一些实施方案中，R 4选自CF 3。 In some embodiments of the present application, R 4 is selected from CF 3 .
在本申请的一些实施方案中，R 5选自CN或NO 2。 In some embodiments of the present application, R 5 is selected from CN or NO 2 .
在本申请的一些实施方案中，R 5为CN。 In some embodiments of the present application, R 5 is CN.
在本申请的一些实施方案中，R 6选自H。 In some embodiments of the present application, R is selected from H.
在本申请的一些实施方案中，R 7，R 8独立地选自H或F。 In some embodiments of the present application, R 7 and R 8 are independently selected from H or F.
在本申请的一些实施方案中，R 7，R 8独立地选自H。 In some embodiments of the present application, R 7 and R 8 are independently selected from H.
在本申请的一些实施方案中，n选自0、1或2。In some embodiments of the present application, n is selected from 0, 1 or 2.
在本申请的一些实施方案中，n选自1或2。In some embodiments of the present application, n is selected from 1 or 2.
在本申请的一些实施方案中，p为0。In some embodiments of the present application, p is 0.
在本申请的一些实施方案中，X是CH或N；W选自
Figure PCTCN2022110325-appb-000005
或4-8元完全饱和杂环基，所述4-8元完全饱和杂环基任选地被R b取代；R b独立地为C 1-6烷基；环D选自苯基或5-10元杂芳基；R 3选自卤素、CN、NO 2、-O-C 1-6烷基、-CONHR 3A、C 1-6烷基、5-10元杂芳基或C 6-10芳基，所述C 1-6烷基、5-10元杂芳基或C 6-10芳基任选地被R 3A取代；R 3A选自卤素、CN、CF 3、NO 2或CH 3；R 1为OH；R 2为CH 3；R 4选自卤素、CF 3或-O-CH 3；R 5选自CN或NO 2；R 6、R 7和R 8均为H；n选自0、1或2；以及p为0或1。 In some embodiments of the present application, X is CH or N; W is selected from
Figure PCTCN2022110325-appb-000005
Or a 4-8 membered fully saturated heterocyclic group, the 4-8 membered fully saturated heterocyclic group is optionally substituted by R b ; R b is independently C 1-6 alkyl; Ring D is selected from phenyl or 5 -10 membered heteroaryl; R 3 is selected from halogen, CN, NO 2 , -OC 1-6 alkyl, -CONHR 3A , C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl Base, the C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl is optionally substituted by R 3A ; R 3A is selected from halogen, CN, CF 3 , NO 2 or CH 3 ; R 1 is OH; R 2 is CH 3 ; R 4 is selected from halogen, CF 3 or -O-CH 3 ; R 5 is selected from CN or NO 2 ; R 6 , R 7 and R 8 are all H; n is selected from 0, 1 or 2; and p is 0 or 1.
在本申请的一些实施方案中，X是CH或N；W为4-8元完全饱和杂环基，所述4-8元完全饱和杂环基任选地被R b取代；R b独立地为C 1-2烷基；环D选自苯基或5-6元杂芳基；R 3选自卤素、CN、NO 2、-O-C 1-2烷基、-CONHR 3A、C 1-2烷基、5-6元杂芳基或苯基，所述C 1-2烷基、5-6元杂芳基或苯基任选地被R 3A取代；R 3A选自卤素、CN、CF 3、NO 2或CH 3；R 1为OH；R 2为CH 3；R 4选自卤素、CF 3或-O-CH 3；R 5选自CN或NO 2；R 6、R 7和R 8均为H；n选自0、1或2；以及p为0或1。 In some embodiments of the present application, X is CH or N; W is a 4-8 membered fully saturated heterocyclic group, and the 4-8 membered fully saturated heterocyclic group is optionally substituted by R b ; R b is independently is C 1-2 alkyl; ring D is selected from phenyl or 5-6 membered heteroaryl; R 3 is selected from halogen, CN, NO 2 , -OC 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 are optionally substituted by R 3A ; R 3A is selected from halogen, CN, CF 3. NO 2 or CH 3 ; R 1 is OH; R 2 is CH 3 ; R 4 is selected from halogen, CF 3 or -O-CH 3 ; R 5 is selected from CN or NO 2 ; R 6 , R 7 and R 8 are all H; n is selected from 0, 1 or 2; and p is 0 or 1.
在本申请的一些实施方案中，X是CH或N；W为含1个或2个N的4-8元完全饱和杂环基，所述4-8元完全饱和杂环基任选地被R b取代；R b独立地为CH 3；环D选自苯基或含1个或2个N的5-6元杂芳基；R 3选自卤素、CN、NO 2、-O-CH 3、-CONHR 3A、CH 3、含1个或 2个N的5-6元杂芳基或苯基，所述CH 3、5-6元杂芳基或苯基任选地被R 3A取代；R 3A选自卤素、CN、CF 3、NO 2或CH 3；R 1为OH；R 2为CH 3；R 4选自卤素、CF 3或-O-CH 3；R 5选自CN或NO 2；R 6、R 7和R 8均为H；n选自0、1或2；以及p为0或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 2 N, and the 4-8 membered fully saturated heterocyclic group is optionally replaced by R b is substituted; R b is independently CH 3 ; ring D is selected from phenyl or 5-6 membered heteroaryl containing 1 or 2 N; R 3 is selected from halogen, CN, NO 2 , -O-CH 3. -CONHR 3A , CH 3 , 5-6-membered heteroaryl or phenyl containing 1 or 2 N, said CH 3 , 5-6-membered heteroaryl or phenyl is optionally substituted by R 3A ; R 3A is selected from halogen, CN, CF 3 , NO 2 or CH 3 ; R 1 is OH; R 2 is CH 3 ; R 4 is selected from halogen, CF 3 or -O-CH 3 ; R 5 is selected from CN or NO 2 ; R 6 , R 7 and R 8 are all H; n is selected from 0, 1 or 2; and p is 0 or 1.
在本申请的一些实施方案中，X是CH或N；W为含1个或2个N的4-8元完全饱和杂环基，所述4-8元完全饱和杂环基任选地被R b取代；R b独立地为CH 3；环D选自苯基或含1个或2个N的5-6元杂芳基；R 3选自F、Cl、Br、CN、NO 2、-O-CH 3、CH 3、含1个或2个N的5-6元杂芳基或苯基，所述CH 3、5-6元杂芳基或苯基任选地被R 3A取代；R 3A选自F、CN、CF 3或NO 2；R 1为OH；R 2为CH 3；R 4选自F、Cl、CF 3或-O-CH 3；R 5为CN；R 6、R 7和R 8均为H；n选自0、1或2；以及p为0。 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 2 N, and the 4-8 membered fully saturated heterocyclic group is optionally replaced by R b is substituted; R b is independently CH 3 ; ring D is selected from phenyl or 5-6 membered heteroaryl containing 1 or 2 N; R 3 is selected from F, Cl, Br, CN, NO 2 , -O-CH 3 , CH 3 , 5-6 membered heteroaryl or phenyl containing 1 or 2 N, said CH 3 , 5-6 membered heteroaryl or phenyl is optionally substituted by R 3A ; R 3A is selected from F, CN, CF 3 or NO 2 ; R 1 is OH; R 2 is CH 3 ; R 4 is selected from F, Cl, CF 3 or -O-CH 3 ; R 5 is CN; R 6 , R 7 and R 8 are all H; n is selected from 0, 1 or 2; and p is 0.
在本申请的一些实施方案中，X是CH或N；W选自氮杂环丁基、哌嗪基、1,4-二氮杂环庚烷基、3,8-二氮杂双环[3.2.1]辛烷基或2,5-二氮双环[2.2.1]庚烷基，所述的氮杂环丁基、哌嗪基、1,4-二氮杂环庚烷基、3,8-二氮杂双环[3.2.1]辛烷基或2,5-二氮双环[2.2.1]庚烷基任选地被R b取代；R b独立地为CH 3；环D选自苯基或含1个或2个N的5-6元杂芳基；R 3选自F、Cl、Br、CN、NO 2、-O-CH 3、CH 3、含1个或2个N的5-6元杂芳基或苯基，所述CH 3、5-6元杂芳基或苯基任选地被R 3A取代；R 3A选自F、CN、CF 3或NO 2；R 1为OH；R 2为CH 3；R 4选自F、Cl、CF 3或-O-CH 3；R 5为CN；R 6、R 7和R 8均为H；n选自0、1或2；以及p为0。 In some embodiments of the present application, X is CH or N; W is selected from azetidinyl, piperazinyl, 1,4-diazepanyl, 3,8-diazabicyclo[3.2 .1] octanyl or 2,5-diazabicyclo[2.2.1]heptyl, the azetidinyl, piperazinyl, 1,4-diazepanyl, 3, 8-diazabicyclo[3.2.1]octyl or 2,5-diazabicyclo[2.2.1]heptyl is optionally substituted by R b ; R b is independently CH 3 ; ring D is selected from Phenyl or a 5-6 membered heteroaryl group containing 1 or 2 Ns; R 3 is selected from F, Cl, Br, CN, NO 2 , -O-CH 3 , CH 3 , containing 1 or 2 Ns 5-6 membered heteroaryl or phenyl, said CH 3 , 5-6 membered heteroaryl or phenyl are optionally substituted by R 3A ; R 3A is selected from F, CN, CF 3 or NO 2 ; R 1 is OH; R 2 is CH 3 ; R 4 is selected from F, Cl, CF 3 or -O-CH 3 ; R 5 is CN; R 6 , R 7 and R 8 are all H; n is selected from 0, 1 or 2; and p is 0.
在本申请的一些实施方案中，式(I)所示化合物或其立体异构体或药学上可接受的盐选自式(II)所示化合物或其立体异构体或药学上可接受的盐，In some embodiments of the present application, the compound shown in formula (I) or its stereoisomer or pharmaceutically acceptable salt is selected from the compound shown in formula (II) or its stereoisomer or pharmaceutically acceptable salt Salt,
Figure PCTCN2022110325-appb-000006
Figure PCTCN2022110325-appb-000006
其中，环D、W、X、R 3、R 4、R 5、R 6、R 7、R 8、n和p如上文所定义。 Wherein, rings D, W, X, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , n and p are as defined above.
在本申请的一些实施方案中，式(I)所示化合物或其立体异构体或药学上可接受的盐选自式(III)所示化合物或其立体异构体或药学上可接受的盐，In some embodiments of the present application, the compound shown in formula (I) or its stereoisomer or pharmaceutically acceptable salt is selected from the compound shown in formula (III) or its stereoisomer or pharmaceutically acceptable salt Salt,
Figure PCTCN2022110325-appb-000007
Figure PCTCN2022110325-appb-000007
其中，环D、W、X、R 3、R 4、R 5、R 7、R 8、n和p如上文所定义。 Wherein, rings D, W, X, R 3 , R 4 , R 5 , R 7 , R 8 , n and p are as defined above.
在本申请的一些实施方案中，式(I)所示化合物或其立体异构体或药学上可接受的盐选自式(IV)所示化合物或其立体异构体或药学上可接受的盐，In some embodiments of the present application, the compound shown in formula (I) or its stereoisomer or pharmaceutically acceptable salt is selected from the compound shown in formula (IV) or its stereoisomer or pharmaceutically acceptable salt Salt,
Figure PCTCN2022110325-appb-000008
Figure PCTCN2022110325-appb-000008
其中，环D、W、X、R 3、R 4、R 5、R 7、R 8和n如上文所定义。 Wherein, ring D, W, X, R 3 , R 4 , R 5 , R 7 , R 8 and n are as defined above.
在本申请的一些实施方案中，式(I)所示化合物或其立体异构体或药学上可接受的盐选自式(V)所示化合物或其立体异构体或药学上可接受的盐，In some embodiments of the present application, the compound shown in formula (I) or its stereoisomer or pharmaceutically acceptable salt is selected from the compound shown in formula (V) or its stereoisomer or pharmaceutically acceptable salt Salt,
Figure PCTCN2022110325-appb-000009
Figure PCTCN2022110325-appb-000009
其中，环D、W、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、n和p如上文所定义。 Wherein, rings 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.
在本申请的一些实施方案中，式(I)所示化合物或其立体异构体或药学上可接受的盐选自式(VI)所示化合物或其立体异构体或药学上可接受的盐，In some embodiments of the present application, the compound shown in formula (I) or its stereoisomer or pharmaceutically acceptable salt is selected from the compound shown in formula (VI) or its stereoisomer or pharmaceutically acceptable salt Salt,
Figure PCTCN2022110325-appb-000010
Figure PCTCN2022110325-appb-000010
其中，环D、X、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和n如上文所定义； Wherein, ring D, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and n are as defined above;
a 1、a 2、a 3和a 4各自独立地选自键或CH 2；以及a 5选自CH 2或CH 2CH 2。 a 1 , a 2 , a 3 and a 4 are each independently selected from a bond or CH 2 ; and a 5 is selected from CH 2 or CH 2 CH 2 .
在本申请的一些实施方案中，式(I)所示化合物或其立体异构体或药学上可接受的盐选自式(VI-a)所示化合物或其立体异构体或药学上可接受的盐，In some embodiments of the present application, the compound shown in formula (I) or its stereoisomer or pharmaceutically acceptable salt is selected from the compound shown in formula (VI-a) or its stereoisomer or pharmaceutically acceptable salt accepted salt,
Figure PCTCN2022110325-appb-000011
Figure PCTCN2022110325-appb-000011
其中，环D、X、R 1、R 2、R 3、R 4、R 5、R 7、R 8和n如上文所定义； Wherein, ring D, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and n are as defined above;
a 1、a 2、a 3和a 4各自独立地选自键或CH 2；以及a 5选自CH 2或CH 2CH 2。 a 1 , a 2 , a 3 and a 4 are each independently selected from a bond or CH 2 ; and a 5 is selected from CH 2 or CH 2 CH 2 .
在本申请的一些实施方案中，
Figure PCTCN2022110325-appb-000012
选自：
Figure PCTCN2022110325-appb-000013
In some embodiments of the present application,
Figure PCTCN2022110325-appb-000012
selected from:
Figure PCTCN2022110325-appb-000013
在本申请的一些实施方案中，式(I)所示化合物或其立体异构体或药学上可接受的盐选自以下化合物或其立体异构体或药学上可接受的盐:In some embodiments of the present application, the compound shown in formula (I) or its stereoisomer or pharmaceutically acceptable salt is selected from the following compounds or its stereoisomer or pharmaceutically acceptable salt:
Figure PCTCN2022110325-appb-000014
Figure PCTCN2022110325-appb-000014
Figure PCTCN2022110325-appb-000015
Figure PCTCN2022110325-appb-000015
Figure PCTCN2022110325-appb-000016
Figure PCTCN2022110325-appb-000016
Figure PCTCN2022110325-appb-000017
Figure PCTCN2022110325-appb-000017
Figure PCTCN2022110325-appb-000018
Figure PCTCN2022110325-appb-000018
Figure PCTCN2022110325-appb-000019
Figure PCTCN2022110325-appb-000019
Figure PCTCN2022110325-appb-000020
Figure PCTCN2022110325-appb-000020
另一方面，本申请还提供了药物组合物，所述药物组合物包含式(I)、(II)、(III)、(IV)、(V)、(VI)或(VI-a)所示化合物或其立体异构体或药学上可接受的盐，以及药学上可接受的辅料。On the other hand, the present application also provides a pharmaceutical composition, which comprises formula (I), (II), (III), (IV), (V), (VI) or (VI-a) Compounds or their stereoisomers or pharmaceutically acceptable salts, and pharmaceutically acceptable auxiliary materials.
再一方面，本申请涉及式(I)、(II)、(III)、(IV)、(V)、(VI)或(VI-a)所示化合物或其立体异构体或药学上可接受的盐或其药物组合物在制备预防或者治疗由雄激素受体介导的疾病的药物中的用途。In another aspect, the present application relates to compounds represented by formula (I), (II), (III), (IV), (V), (VI) or (VI-a) or their stereoisomers or pharmaceutically acceptable Use of the accepted salt or its pharmaceutical composition in the preparation of medicaments for preventing or treating diseases mediated by androgen receptors.
再一方面，本申请涉及式(I)、(II)、(III)、(IV)、(V)、(VI)或(VI-a)所示化合物或其立体异构体或药学上可接受的盐或其药物组合物在预防或者治疗由雄激素受体介导的疾病中的用途。In another aspect, the present application relates to compounds represented by formula (I), (II), (III), (IV), (V), (VI) or (VI-a) or their stereoisomers or pharmaceutically acceptable Use of the accepted salt or its pharmaceutical composition in preventing or treating diseases mediated by androgen receptor.
再一方面，本申请涉及预防或者治疗由雄激素受体介导的疾病的式(I)、(II)、(III)、(IV)、(V)、(VI)或(VI-a)所示化合物或其立体异构体或药学上可接受的盐或其药物组合物。In another aspect, the present application relates to the formula (I), (II), (III), (IV), (V), (VI) or (VI-a) for the prevention or treatment of diseases mediated by androgen receptors The compound or its stereoisomer or pharmaceutically acceptable salt or its pharmaceutical composition.
还一方面，本申请涉及治疗由雄激素受体介导的疾病的方法，该方法包括给以患者治疗上有效剂量的包含本申请所述的式(I)、(II)、(III)、(IV)、(V)、(VI)或(VI-a)化合物或其立体异构体或药学上可接受的盐的药物制剂。In another aspect, the present application relates to a method for treating a disease mediated by the androgen receptor, the method comprising administering to the patient a therapeutically effective dose comprising formula (I), (II), (III), ( Pharmaceutical preparations of compounds IV), (V), (VI) or (VI-a) or stereoisomers or pharmaceutically acceptable salts thereof.
进一步地，所述由雄激素受体介导的疾病选自***癌或雄激素脱发。Further, the disease mediated by androgen receptor is selected from prostate cancer or androgenetic alopecia.
术语定义和说明Definitions and Explanations of Terms
除非另有说明，本申请中所用的术语具有下列含义，本申请中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the terms used in this application have the following meanings, definitions of groups and terms recorded in this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, examples The definitions of specific compounds in and etc. may be combined and combined with each other arbitrarily. A specific term should not be regarded as indeterminate or unclear if there is no special definition, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
本文中
Figure PCTCN2022110325-appb-000021
表示连接位点。 In this article
Figure PCTCN2022110325-appb-000021
Indicates the junction site.
本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚楔键
Figure PCTCN2022110325-appb-000022
表示一个立体中心的绝对构型，用黑实键和虚键
Figure PCTCN2022110325-appb-000023
表示一个立体中心的相对构型(如脂环化合物的顺反构型)。 Graphical representations of racemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise specified, with wedge and dotted keys
Figure PCTCN2022110325-appb-000022
Indicates the absolute configuration of a stereocenter with black real and virtual bonds
Figure PCTCN2022110325-appb-000023
Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本申请化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本申请包括化合物的所有互变异构形式。The term "tautomer" refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions. Compounds of the present application may exhibit tautomerism. Tautomeric compounds can exist in two or more interconvertible species. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. This application includes all tautomeric forms of the compounds.
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异 构体、对映异构体和非对映异构体。The term "stereoisomer" refers to isomers produced by different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and diastereomers.
本申请的化合物可以具有不对称原子如碳原子、硫原子、氮原子、磷原子或不对称双键，因此本申请的化合物可以存在特定的几何或立体异构体形式。特定的几何或立体异构体形式可以是顺式和反式异构体、E型和Z型几何异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，以及其外消旋混合物或其它混合物，例如对映异构体或非对映体富集的混合物，以上所有这些异构体以及它们的混合物都属于本申请化合物的定义范围之内。烷基等取代基中可存在另外的不对称碳原子、不对称硫原子、不对称氮原子或不对称磷原子，所有取代基中涉及到的这些异构体以及它们的混合物，也均包括在本申请化合物的定义范围之内。本申请的含有不对称原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来，光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。The compounds of the present application may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present application may exist in specific geometric or stereoisomer forms. Specific 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 enantiomers or diastereomers Enriched mixtures, all of the above isomers and mixtures thereof fall within the definition of the compounds of the present application. There may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups, and these isomers and their mixtures involved in all substituents are also included in Within the definition of the compounds of the present application. The compounds containing asymmetric atoms of the present application can be isolated in optically pure form or racemic form, optically active form can be resolved from racemic mixture, or synthesized by using chiral raw materials or chiral reagents .
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。The term "substituted" means that any one or more hydrogen atoms on the specified atom are replaced by a substituent, as long as the valence of the specified atom is normal and the substituted compound is stable. When a substituent is oxo (ie, =0), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，是指乙基可以是未被取代的(CH 2CH 3)、单取代的(CH 2CH 2F、CH 2CH 2Cl等)、多取代的(CHFCH 2F、CH 2CHF 2、CHFCH 2Cl、CH 2CHCl 2等)或完全被取代的(CF 2CF 3、CF 2CCl 3、CCl 2CCl 3等)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。 The term "optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that description includes that said event or circumstance occurs and that it does not. For example, ethyl is "optionally" substituted with halogen , meaning that the ethyl group can be unsubstituted ( CH2CH3 ), monosubstituted ( CH2CH2F , CH2CH2Cl , etc.), polysubstituted ( CHFCH2F , CH2CHF2 , CHFCH2Cl , CH2CHCl2 , etc. ) or fully substituted ( CF2CF3 , CF2CCl3 , CCl2CCl3 , etc.) . It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
当任何变量(例如R a、R b)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。例如，如果一个基团被2个R b所取代，则每个R b都有独立的选项。 When any variable (eg R a , R b ) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. For example, if a group is substituted by 2 R b , each R b has independent options.
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为键。 When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
当本文中涉及到的连接基团若没有指明其连接方向，则其连接方向是任意的。例如当结构单元
Figure PCTCN2022110325-appb-000024
中的L 1选自“C 1-C 3亚烷基-O”时，此时L 1既可以按照与从左到右的方向连接环Q和R 1构成“环Q-C 1-C 3亚烷基-O-R 1”，也可以按照从右到左的方向连接环Q和R 1构成“环Q-O-C 1-C 3亚烷基-R 1”。 When the linking group mentioned herein does not indicate its linking direction, its linking direction is arbitrary. For example when the structural unit
Figure PCTCN2022110325-appb-000024
When L 1 in is selected from "C 1 -C 3 alkylene-O", at this time L 1 can connect ring Q and R 1 in the direction from left to right to form "ring QC 1 -C 3 alkylene Group -OR 1 ", and ring Q and R 1 can also be connected from right to left to form "ring QOC 1 -C 3 alkylene-R 1 ".
当一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元
Figure PCTCN2022110325-appb-000025
表示R 5可在苯环上的任意一个位置发生取代。 When a bond of a substituent cross-links two atoms in a ring, the substituent may be bonded to any atom on the ring. For example, the structural unit
Figure PCTCN2022110325-appb-000025
Indicates that R 5 can be substituted at any position on the benzene ring.
本文中的C m- n是指具有m-n范围中的整数个碳原子。例如“C 1- 10”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。 C m - n herein means having an integer number of carbon atoms in the range of mn. For example, "C 1 - 10 " means that the group can 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.
术语“烷基”是指通式为C nH 2n+1的烃基，该烷基可以是直链或支链的。术语“C 1- 10烷基”可理解为表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和烃基。所述烷基的具体实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等；术语“C 1-C 6烷基”可理解为表示具有1、2、3、4、5或6个碳原子的烷基，具体实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等。术语“C 1- 3烷基”可理解为表示具有1、2或3个碳原子的直链或支链饱和烷基。所述“C 1- 10烷基”可以包含“C 1- 6烷基”或 “C 1- 3烷基”等范围，所述“C 1- 6烷基”可以进一步包含“C 1- 3烷基”。 The term "alkyl" refers to a hydrocarbon group having the general formula C n H 2n+1 , and the alkyl group may be straight or branched. The term "C 1-10 alkyl" is understood to mean a linear or branched saturated hydrocarbon group 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-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 6 alkyl" can be understood as meaning an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, specific examples include but are 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-methyl Pentyl etc. The term "C 1-3 alkyl" is understood to mean a linear or branched saturated alkyl group having 1, 2 or 3 carbon atoms. The "C 1-10 alkyl" may include "C 1-6 alkyl " or "C 1-3 alkyl", and the "C 1-6 alkyl " may further include "C 1-3 alkyl".
术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“C 1-6卤代烷基”意指被一个或多个卤素取代的如上所定义的C 1-6烷基，包括但不仅限于三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基、三氯甲基、五氟乙基和五氯乙基等等。 The term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C 1-6 haloalkyl" means a C 1-6 alkyl group as defined above substituted with one or more halogens, including but not limited to trifluoromethyl, 2,2,2-trifluoroethyl group, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl and pentachloroethyl, etc.
术语“环烷基”是指完全饱和的且以单环、并环、桥环或螺环等形式存在的碳环。除非另有指示，该碳环通常为3至10元环。术语“C 3- 10环烷基”可理解为表示饱和的单环、并环、螺环或桥环，其具有3、4、5、6、7、8、9或10个碳原子。所述环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基，降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、螺[4.5]癸烷基等。术语“C 3- 10环烷基”可以包含“C 3- 6环烷基”，术语“C 3- 6环烷基”可理解为表示饱和的单环或双环烃环，其具有3、4、5或6个碳原子，具体实例包括但不限于环丙基、环丁基、环戊基或环己基等。 The term "cycloalkyl" refers to a fully saturated carbocyclic ring in the form of a monocyclic ring, a double 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, fused, spiro or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of said cycloalkyl 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, adamantyl, spiro [4.5] decanyl, etc. The term "C 3 - 10 cycloalkyl" may include "C 3 - 6 cycloalkyl", and the term "C 3 - 6 cycloalkyl" can be understood as representing a saturated monocyclic or bicyclic hydrocarbon ring, which has 3, 4 , 5 or 6 carbon atoms, specific examples include but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.
术语“杂环基”是指完全饱和的或部分饱和的(整体上不是具有芳香性的杂芳族)单环、并环、螺环或桥环基团，其环原子中含有1、2、3、4或5个杂原子或杂原子团(即含有杂原子的原子团)，所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(＝O) 2-、-S(＝O)-、-P(＝O) 2-、-P(＝O)-、-NH-、-S(＝O)(＝NH)-、-C(＝O)NH-或-NHC(＝O)NH-等。术语“4-10元杂环基”是指环原子数目为4、5、6、7、8、9或10的杂环基，且其环原子中含有1、2、3、4或5个独立选自上文所述的杂原子或杂原子团。“4-10元杂环基”包括“4-8元杂环基”，其中，4元杂环基的具体实例包括但不限于氮杂环丁烷基、硫杂环丁烷基或氧杂环丁烷基；5元杂环基的具体实例包括但不限于四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、4,5-二氢噁唑基或2,5-二氢-1H-吡咯基；6元杂环基的具体实例包括但不限于四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、三噻烷基、四氢吡啶基、4H-[1,3,4]噻二嗪基或
Figure PCTCN2022110325-appb-000026
7元杂环基的具体实例包括但不限于二氮杂环庚烷基。所述杂环基还可以是双环基，其中，5,5元双环基的具体实例包括但不限于六氢环戊并[c]吡咯-2(1H)-基；5,6元双环基的具体实例包括但不限于六氢吡咯并[1,2-a]吡嗪-2(1H)-基、5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡嗪基或5,6,7,8-四氢咪唑并[1,5-a]吡嗪基。任选地，所述杂环基可以是上述4-8元杂环基的苯并稠合环基，具体实例包括但不限于二氢异喹啉基等。“4-10元杂环基”可以包含“5-10元杂环基”、“4-8元杂环基”、“5-6元杂环基”、“6-8元杂环基”、“4-10元杂环烷基”、“5-10元杂环烷基”、“4-8元杂环烷基”、“5-6元杂环烷基”、“6-8元杂环烷基”等范围，“4-8元杂环基”进一步可以包含“4-6元杂环基”、“5-6元杂环基”、“4-8元杂环烷基”、“4-6元杂环烷基”、“5-6元杂环烷基”等范围。本申请中尽管有些双环类杂环基部分地含有一个苯环或一个杂芳环，但所述杂环基整体上仍是无芳香性的。 The term "heterocyclic group" refers to a fully saturated or partially saturated (heteroaromatic which is not aromatic as a whole) monocyclic, cyclic, spiro or bridged ring group, which contains 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups (that is, atomic groups containing heteroatoms), the "heteroatoms or heteroatom groups" include but are not limited to nitrogen atoms (N), oxygen atoms (O), sulfur atoms (S) , phosphorus atom (P), boron atom (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 with 4, 5, 6, 7, 8, 9 or 10 ring atoms, and its ring atoms contain 1, 2, 3, 4 or 5 independent selected from the heteroatoms or heteroatom groups described above. "4-10 membered heterocyclic group" includes "4-8 membered heterocyclic group", wherein, specific examples of 4-membered heterocyclic group include but are not limited to azetidinyl, thietanyl or oxa Cyclobutanyl; specific examples of 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-di Hydroxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thio Morpholinyl, piperazinyl, trithianyl, tetrahydropyridyl, 4H-[1,3,4]thiadiazinyl or
Figure PCTCN2022110325-appb-000026
Specific examples of 7-membered heterocyclyl groups include, but are not limited to, diazepanyl. The heterocyclic group can also be a bicyclic group, wherein, specific examples of the 5,5-membered bicyclic group include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; 5,6-membered bicyclic group Specific examples 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]pyrazinyl. Optionally, the heterocyclic group may be a benzofused cyclic group of the above-mentioned 4-8 membered heterocyclic group, specific examples include but not limited to dihydroisoquinolyl and the like. "4-10 membered heterocyclic group" may include "5-10 membered heterocyclic group", "4-8 membered heterocyclic group", "5-6 membered heterocyclic group", "6-8 membered heterocyclic group" , "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "4-8 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered "Heterocycloalkyl" and other ranges, "4-8 membered heterocyclyl" may further include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-8 membered heterocyclyl" , "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl" and other ranges. In the present application, although some bicyclic heterocyclic groups partially contain a benzene ring or a heteroaromatic ring, the heterocyclic groups as a whole are still non-aromatic.
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。芳基可以具有6-20个碳原子、6-14个碳原子或6-12个碳原子。术语“C 6- 20芳基”可理解为具有6～20个碳原子的芳基，特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或者具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基；或者具有13个碳原子的环(“C 13芳基”)，例如芴基；或者是具有14个碳原子的环(“C 14芳基”)，例如蒽基。术语“C 6- 10芳基”可理解为具有6～10个碳原子的芳基。特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或者具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基。术语“C 6- 20芳基”可以包含“C 6- 10芳基”。 The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. Aryl groups can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C 6 - 20 aryl" can be understood as an aryl group having 6 to 20 carbon atoms, especially a ring having 6 carbon atoms ("C 6 aryl"), such as phenyl; or a ring having 9 carbon atoms 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" can be understood as an aryl group having 6 to 10 carbon atoms. Especially rings with 6 carbon atoms (“C aryl ”), such as phenyl; or rings with 9 carbon atoms (“C aryl”), such as indanyl or indenyl; or rings with 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. The term "C 6-20 aryl " may include "C 6-10 aryl".
术语“杂芳基”是指具有芳香性的单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C的芳香环基。术语“5-10元杂芳基”可理解为包括这样的单环或双环 芳族环系：其具有5、6、7、8、9或10个环原子，特别是5或6或9或10个环原子，且其包含1、2、3、4或5个，优选1、2或3个独立选自N、O和S的杂原子。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基或噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并***基、吲唑基、吲哚基或异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基或三嗪基等以及它们的苯并衍生物，例如喹啉基、喹唑啉基或异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基或吩噁嗪基等。术语“5-6元杂芳基”指具有5或6个环原子的芳族环系，且其包含1、2或3个，优选1-2个独立选自N、O和S的杂原子。The term "heteroaryl" refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, and S, and an aromatic ring group whose ring atoms are C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiazolyl Diazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinazole Linyl or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthalene Pyridyl, pteridyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, etc. 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 .
术语“卤”或“卤素”是指氟、氯、溴或碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“羟基”是指-OH基团。The term "hydroxyl" refers to a -OH group.
术语“氰基”是指-CN基团。The term "cyano" refers to a -CN group.
术语“氨基”是指-NH 2基团。 The term "amino" refers to a -NH2 group.
术语“硝基”是指-NO 2基团。 The term "nitro" refers to a -NO2 group.
术语“治疗有效量”意指(i)治疗特定疾病、病况或病症，(ii)减轻、改善或消除特定疾病、病况或病症的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病况或病症的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "therapeutically effective amount" means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying the The amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder. 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 a person skilled in the art according to its own knowledge and this disclosure.
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指药学上可接受的酸加成或碱加成盐，包括化合物与无机酸或有机酸形成的盐，以及化合物与无机碱或有机碱形成的盐。The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable acid addition or base addition salts, including salts formed between compounds and inorganic or organic acids, and salts formed between compounds and inorganic or organic bases.
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable auxiliary materials. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those 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.
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising可理解为开放的、非排他性的意义，即“包括但不限于”。The word "comprise" or "comprise" and its English variants such as comprises or comprising can be interpreted in an open and non-exclusive sense, ie "including but not limited to".
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。 The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 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, etc.
某些同位素标记的本申请化合物(例如用 3H及 14C标记)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。 Certain isotopically labeled compounds of the present application (eg, labeled with3H and14C ) are useful in compound and/or substrate tissue distribution assays. Tritiated ( ie3H ) and carbon-14 ( ie14C ) isotopes are especially preferred for their ease of preparation and detectability. Positron-emitting isotopes, such as 15 O, 13 N, 11 C, and 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 similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
给予本申请化合物或其立体异构体或药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Typical routes for administering a compound of the present application, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, ophthalmic Intraperitoneal, intramuscular, subcutaneous, intravenous administration.
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、乳化法、冷冻干燥法等。The pharmaceutical composition of the present application can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, emulsifying methods, freeze-drying methods and the like.
在本申请的一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments of the present application, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂或矫味剂等。Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets Or the core of the sugar coating. Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。The pharmaceutical composition may also be adapted for parenteral administration as a suitable unit dosage form of sterile solutions, suspensions or lyophilized products.
本文所述的式(I)化合物的所有施用方法中，每天给药的剂量为0.01mg/kg到200mg/kg体重，以单独或分开剂量的形式。In all methods of administration of the compounds of formula (I) described herein, dosages of 0.01 mg/kg to 200 mg/kg body weight are administered per day, in single or divided doses.
附图说明Description of drawings
图1显示本申请化合物II-51末次给药结束24h后小鼠皮肤样本的western印迹结果图。Figure 1 shows the western blot results of mouse skin samples 24 hours after the last administration of Compound II-51 of the present application.
图2显示本申请化合物II-51末次给药结束24h后小鼠皮肤样本的western印迹统计分析结果图。Figure 2 shows the results of western blot statistical analysis of mouse skin samples 24 hours after the last administration of Compound II-51 of the present application.
图3显示本申请化合物0XX末次给药结束24h后小鼠皮肤样本的western印迹统计分析结果图。Figure 3 shows the results of western blot statistical analysis of mouse skin samples 24 hours after the last administration of the compound OXX of the present application.
图4显示本申请化合物II-51对小鼠毛发生长评分图。Fig. 4 shows the scoring chart of compound II-51 of the present application on mouse hair growth.
图5显示本申请化合物II-51对小鼠体重变化曲线图。Fig. 5 is a graph showing the change of compound II-51 of the present application on the body weight of mice.
图6显示本申请化合物0XX对小鼠毛发生长评分图。Figure 6 shows the scoring chart of compound OXX of the present application on mouse hair growth.
图7显示本申请化合物0XX对小鼠体重变化曲线图。Figure 7 shows the curve of the compound OXX of the present application on the body weight change of mice.
实施例Example
以下实施例详细说明本申请的技术方案，但本申请的保护范围包括但不限于此。The following examples illustrate the technical solutions of the present application in detail, but the protection scope of the present application includes but is not limited thereto.
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10 -6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)；“IC50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。 Compound structures were determined by nuclear magnetic resonance (NMR) and/or mass spectroscopy (MS). The unit of NMR shift is 10 -6 (ppm). The solvents measured by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC50" refers to the half inhibitory concentration, which refers to the concentration when half of the maximum inhibitory effect is reached .
缩略词：Acronyms:
DMF：N,N-二甲基甲酰胺；Et 3N和TEA：三乙胺；THF：四氢呋喃；DMSO：二甲基亚砜；TBSCl：叔丁基二甲基氯硅烷；THF：四氢呋喃；DCM：二氯甲烷；EDC：1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐；HOBT：1-羟基苯并***；NaOBu-t：叔丁醇钠；Pd(OAc)2：乙酸钯；P(Bu-t) 3：三(叔丁基)磷；EA：乙酸乙酯；Pd 2(dba) 3：三(亚苄基丙酮)二钯；BINAP：1,1'-联萘-2,2'-双二苯膦；dioxane：二氧六环；Xantphos：4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽；Ethanol：乙醇；acetone：丙酮；NaHMDS：双(三甲基硅基)氨基钠；IPA；异丙醇；Toluene：甲苯；NMM：N-甲基吗啉；Chloroform：氯仿；TFA：三氟乙酸；PdCl 2(dppf)：1,1'-双二苯基膦二茂铁二氯化钯。 DMF: N,N-dimethylformamide; Et3N and TEA: triethylamine; THF: tetrahydrofuran; DMSO: dimethylsulfoxide; TBSCl: tert-butyldimethylsilyl chloride; 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 : tris(tert-butyl)phosphorus; EA: ethyl acetate; Pd2 (dba) 3 : tris(benzylideneacetone)dipalladium; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; dioxane: dioxane; Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene ; Ethanol: ethanol; acetone: acetone; NaHMDS: sodium bis(trimethylsilyl)amide; IPA; isopropanol; Toluene: toluene; NMM: N-methylmorpholine; Chloroform: chloroform; TFA: trifluoroacetic acid ; PdCl 2 (dppf): 1,1′-bisdiphenylphosphinoferrocenepalladium dichloride.
中间体S2的合成：Synthesis of intermediate S2:
Figure PCTCN2022110325-appb-000027
Figure PCTCN2022110325-appb-000027
步骤1：S1的合成Step 1: Synthesis of S1
在冰浴，氮气保护下，向(2R)-3-溴-2-羟基-2-甲基丙酸(1g,5.46mmol)的无水四氢呋喃(20mL)溶液中缓慢滴加二氯亚砜(0.55mL,7.65mmol)，反应3小时。然后，在冰浴条件下滴加Et 3N(1.06mL,7.65mmol)，搅拌20min，缓慢滴加4-氨基-2-(三氟甲基)苯甲腈(762.85mg,4.10mmol)的无水四氢呋喃溶液，搅拌5min后升至室温反应16小时。TLC监测反应完全后，用饱和NaHCO 3水溶液调节pH至中性，用乙酸乙酯(10mL×3)萃取水相，合并有机相，无水硫酸钠干燥，过滤，浓缩有机相，所得残余物通过硅胶柱色谱法(二氯甲烷：三乙胺＝500:1)分离，得白色固体1.05g，收率为73.01％。 1H 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] +. In an ice bath, under the protection of nitrogen, slowly add thionyl chloride ( 0.55mL, 7.65mmol), reacted for 3 hours. Then, Et 3 N (1.06mL, 7.65mmol) was added dropwise under ice-bath conditions, stirred for 20min, and 4-amino-2-(trifluoromethyl)benzonitrile (762.85mg, 4.10mmol) was added dropwise slowly. Water tetrahydrofuran solution, stirred for 5 minutes, then warmed to room temperature for 16 hours. After the completion of the reaction monitored by TLC, the pH was adjusted to neutral with saturated NaHCO 3 aqueous solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated, and the obtained residue was passed through Silica gel column chromatography (dichloromethane:triethylamine=500:1) separated to obtain 1.05 g of white solid with 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] + .
步骤2：S2的合成Step 2: Synthesis of S2
在装有搅拌子的两口瓶中加入S1(1g,2.85mmol)和无水K 2CO 3(787.21mg,5.70mmol)，丙酮(15mL)溶解，氮气保护下回流(60℃)4小时。TLC监测反应完全后，冷却至室温，硅藻土垫过滤。滤液直接浓缩，所得残余物通过硅胶柱色谱法(石油醚：乙酸乙酯＝3:1)分离，得白色固体620mg，收率为80.57％。 1H 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] +. Add S1 (1g, 2.85mmol) and anhydrous K 2 CO 3 (787.21mg, 5.70mmol) into a two-neck flask equipped with a stirring bar, dissolve in acetone (15mL), and reflux (60°C) for 4 hours under nitrogen protection. After the completion of the reaction was monitored by TLC, it was cooled to room temperature and filtered through a celite pad. The filtrate was directly concentrated, and the resulting residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 620 mg of a white solid with a yield of 80.57%. 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 [MH] + .
中间体S4的合成：Synthesis of intermediate S4:
Figure PCTCN2022110325-appb-000028
Figure PCTCN2022110325-appb-000028
步骤1：S3的合成Step 1: Synthesis of S3
制备方法同S1，不同的是将4-氨基-2-(三氟甲基)苯甲腈替换为5-氨基-3-(三氟甲基)-2-氰基吡啶(3.83g,20.49mmol)，同法制得化合物S3，得白色固体4.10g，收率为56.83％。 1H 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] +. The preparation method is the same as S1, except that 4-amino-2-(trifluoromethyl)benzonitrile is replaced by 5-amino-3-(trifluoromethyl)-2-cyanopyridine (3.83g, 20.49mmol ), compound S3 was obtained by the same method, and 4.10 g of white solid was obtained, and the yield was 56.83%. 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] + .
步骤2：S4的合成Step 2: Synthesis of S4
制备方法同S2，不同的是将(R)-3-溴-N-(4-氰基-3-(三氟甲基)苯基)-2-羟基-2-甲基丙酰胺替换为(R)-3-溴-N-(6-氰基-5-(三氟甲基)吡啶-3基)-2-羟基-2-甲基丙酰胺(1g,2.85mmol)，同法制得化合物S4，得白色固体620mg，收率为80.57％。mp:76-86℃. 1H 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] +. The preparation method is the same as S2, and the difference is that (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxyl-2-methylpropionamide is replaced by ( R)-3-bromo-N-(6-cyano-5-(trifluoromethyl)pyridin-3 base)-2-hydroxyl-2-methylpropionamide (1g, 2.85mmol), the compound was prepared in the same way S4, 620 mg of white solid was obtained, and the yield was 80.57%. mp: 76-86°C. 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[MH] + .
中间体S5的合成Synthesis of intermediate S5
Figure PCTCN2022110325-appb-000029
Figure PCTCN2022110325-appb-000029
在装有搅拌子的两口瓶中加入4-溴苯硼酸(2.13g,10.60mmol)，碘化镍(132.46mg,0.42mmol)，(1R,2R)-2-氨基环己醇盐酸盐(64.27mg,0.42mmol)和双(三甲基硅基)氨基钠(7.06mL,28.26mmol)，氮气保护下加入无水异丙醇30mL，室温下搅拌10分钟，超声1分钟，加入1-叔丁氧羰基-3-碘氮杂环丁烷(1.23mL,7.06mmol)，回流(80℃)12小时。TLC监测反应完全后，冷却至室温，饱和氯化铵水溶液淬灭，用乙酸乙酯(15mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩有机相，所得残余物通过硅胶柱色谱法(石油醚：乙酸乙酯＝100:1)分离，得白色固体1.60g，收率为72.54％。 1H 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] +. Add 4-bromophenylboronic acid (2.13g, 10.60mmol), nickel iodide (132.46mg, 0.42mmol), (1R, 2R)-2-aminocyclohexanol hydrochloride ( 64.27mg, 0.42mmol) and sodium bis(trimethylsilyl)amide (7.06mL, 28.26mmol), add anhydrous isopropanol 30mL under nitrogen protection, stir at room temperature for 10 minutes, sonicate for 1 minute, add 1-tert Butoxycarbonyl-3-iodoazetidine (1.23 mL, 7.06 mmol), reflux (80° C.) for 12 hours. After TLC monitors that the reaction is complete, cool to room temperature, quench with saturated ammonium chloride aqueous solution, extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase, and pass the residue through silica gel Column chromatography (petroleum ether: ethyl acetate = 100:1) separated to obtain 1.60 g of white solid with a yield of 72.54%. 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=5.2 Hz,3H),1.40(s,9H).LC-MS(ESI)m/z:310.20[MH] + .
中间体S6的合成Synthesis of intermediate S6
Figure PCTCN2022110325-appb-000030
Figure PCTCN2022110325-appb-000030
参考中间体S5的合成方法，不同的是将步骤中4-溴苯硼酸替换为2-溴吡啶-5-硼酸，同法制得化合物S6，得淡黄色固体0.7g，产率为63.28％。 1H 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] +. Referring to the synthesis method of intermediate S5, except that 4-bromophenylboronic acid was replaced by 2-bromopyridine-5-boronic acid in the step, compound S6 was obtained in the same way to obtain 0.7 g of light 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] + .
中间体S7的合成:Synthesis of intermediate S7:
Figure PCTCN2022110325-appb-000031
Figure PCTCN2022110325-appb-000031
参考中间体S5的合成方法，不同的是将步骤中4-溴苯硼酸替换为3-溴苯硼酸，同法制得化合物S7，得黄色油状物150mg，产率为68.01％。 1H 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] +. Referring to the synthesis method of intermediate S5, except that 4-bromophenylboronic acid was replaced by 3-bromophenylboronic acid in the step, compound S7 was prepared in the same way to obtain 150 mg of yellow oil with a yield of 68.01%. 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] + .
中间体S9的合成Synthesis of intermediate S9
Figure PCTCN2022110325-appb-000032
Figure PCTCN2022110325-appb-000032
步骤1：S8的合成Step 1: Synthesis of S8
制备方法同S1，不同的是将4-氨基-2-(三氟甲基)苯甲腈替换为4-硝基-3-三氟甲基苯胺(4.22g,20.49mmol)，同法制得化合物S8，得黄色固体7g，收率为69.04％。 1H 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] +. The preparation method is the same as S1, except that 4-amino-2-(trifluoromethyl)benzonitrile is replaced by 4-nitro-3-trifluoromethylaniline (4.22g, 20.49mmol), and the compound is obtained in the same way S8, 7 g of yellow solid was obtained, and the yield was 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] + .
步骤2：S9的合成Step 2: Synthesis of S9
制备方法同S2，不同的是将(R)-3-溴-N-(4-氰基-3-(三氟甲基)苯基)-2-羟基-2-甲基丙酰胺替换为(R)-3-溴-2-羟基-2-甲基-N-(4-硝基-3-(三氟甲基)苯基)丙酰胺(3.5g,9.43mmol)，同法制得化合物S9，得浅黄色固体1.82g，收率为66.50％。 1H 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] +. The preparation method is the same as S2, and the difference is that (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxyl-2-methylpropionamide is replaced by ( R)-3-bromo-2-hydroxyl-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide (3.5g, 9.43mmol), the same method to obtain compound S9 , 1.82 g of a light yellow solid was obtained, and the yield was 66.50%. 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] + .
中间体S11的合成Synthesis of Intermediate S11
Figure PCTCN2022110325-appb-000033
Figure PCTCN2022110325-appb-000033
步骤1：S10的合成Step 1: Synthesis of S10
制备方法同S1，不同的是将4-氨基-2-(三氟甲基)苯甲腈替换为4-氨基-2-甲氧基苯甲腈(546.51mg,3.69mmol)，同法制得化合物S10，得黄色油状物270mg，收率为17.53％。 1H 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] +. The preparation method is the same as S1, the difference is that 4-amino-2-(trifluoromethyl)benzonitrile is replaced by 4-amino-2-methoxybenzonitrile (546.51mg, 3.69mmol), and the compound is obtained in the same way S10, 270mg of yellow oil was obtained, the yield was 17.53%. 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] + .
步骤2：S11的合成Step 2: Synthesis of S11
制备方法同S2，不同的是将(R)-3-溴-N-(4-氰基-3-(三氟甲基)苯基)-2-羟基-2-甲基丙酰胺替换为(R)-3-溴-N-(4-氰基-3-甲氧基苯基)-2-羟基-2-甲基丙酰胺(3.5g,9.43mmol)，同法制得化合物S11，得浅黄色固体1.82g，收率为66.50％。 1H 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] +. The preparation method is the same as S2, and the difference is that (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxyl-2-methylpropionamide is replaced by ( R)-3-bromo-N-(4-cyano-3-methoxyphenyl)-2-hydroxy-2-methylpropionamide (3.5g, 9.43mmol), the compound S11 was obtained in the same way as Yellow solid 1.82g, yield 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] + .
中间体S13的合成Synthesis of intermediate S13
Figure PCTCN2022110325-appb-000034
Figure PCTCN2022110325-appb-000034
步骤1：S12的合成Step 1: Synthesis of S12
制备方法同S1，不同的是将4-氨基-2-(三氟甲基)苯甲腈替换为4-氨基-3-氟-2-甲氧基苯甲 腈(194mg,3.69mmol)，同法制得化合物S12，得淡黄色固体141mg，收率为27.14％。 1H 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] +. The preparation method is the same as S1, except that 4-amino-2-(trifluoromethyl)benzonitrile is replaced by 4-amino-3-fluoro-2-methoxybenzonitrile (194mg, 3.69mmol). Compound S12 was prepared by the above method to obtain 141 mg of a light yellow solid 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] + .
步骤2：S13的合成Step 2: Synthesis of S13
制备方法同S2，不同的是将(R)-3-溴-N-(4-氰基-3-(三氟甲基)苯基)-2-羟基-2-甲基丙酰胺替换为(R)-3-溴-N-(4-氰基-2-氟-3-甲氧基苯基)-2-羟基-2-甲基丙酰胺(500mg,1.51mmol)，同法制得化合物S13，得淡黄色固体200mg，收率为52.93％。 1H 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] +. The preparation method is the same as S2, and the difference is that (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxyl-2-methylpropionamide is replaced by ( R)-3-bromo-N-(4-cyano-2-fluoro-3-methoxyphenyl)-2-hydroxy-2-methylpropionamide (500mg, 1.51mmol), the same method to obtain compound S13 , to obtain 200mg of light yellow solid, the yield was 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] + .
中间体S15的合成Synthesis of Intermediate S15
Figure PCTCN2022110325-appb-000035
Figure PCTCN2022110325-appb-000035
步骤1：S14的合成Step 1: Synthesis of S14
制备方法同S1，不同的是将4-氨基-2-(三氟甲基)苯甲腈替换为4-氨基-2-氯苯甲腈(2.5g,16.38mmol)，同法制得化合物S14，得淡黄色固体4.1g，收率为78.80％。 1H 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] +. The preparation method is the same as S1, except that 4-amino-2-(trifluoromethyl)benzonitrile is replaced by 4-amino-2-chlorobenzonitrile (2.5g, 16.38mmol), and compound S14 is prepared in the same way. 4.1 g of a light yellow solid was obtained 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] + .
步骤2：S15的合成Step 2: Synthesis of S15
制备方法同S2，不同的是将(R)-3-溴-N-(4-氰基-3-(三氟甲基)苯基)-2-羟基-2-甲基丙酰胺替换为(R)-3-溴-N-(3-氯-4-氰基苯基)-2-羟基-2-甲基丙酰胺(1.2g,3.78mmol)，同法制得化合物S15，得白色固体440mg，收率为49.20％。 1H 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] +. The preparation method is the same as S2, and the difference is that (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxyl-2-methylpropionamide is replaced by ( R)-3-Bromo-N-(3-chloro-4-cyanophenyl)-2-hydroxy-2-methylpropionamide (1.2g, 3.78mmol), compound S15 was prepared in the same way to obtain 440mg of white solid , the yield was 49.20%. 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] + .
中间体S17的合成Synthesis of intermediate S17
Figure PCTCN2022110325-appb-000036
Figure PCTCN2022110325-appb-000036
步骤1：S16的合成Step 1: Synthesis of S16
制备方法同S1，不同的是将4-氨基-2-(三氟甲基)苯甲腈替换为5-氨基-3-氯-2-吡啶甲腈(630mg,4.10mmol)，同法制得化合物S16，得淡黄色固体1.2g，收率为91.92％。 1H 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] +. The preparation method is the same as S1, the difference is that 4-amino-2-(trifluoromethyl)benzonitrile is replaced by 5-amino-3-chloro-2-pyridinecarbonitrile (630mg, 4.10mmol), and the compound is obtained in the same way S16, 1.2 g of a light yellow solid was obtained, and the yield was 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] + .
步骤2：S17的合成Step 2: Synthesis of S17
制备方法同S2，不同的是将(R)-3-溴-N-(4-氰基-3-(三氟甲基)苯基)-2-羟基-2-甲基丙酰胺替换为(R)-3-溴-N-(5-氯-6-氰基吡啶-3-基)-2-羟基-2-甲基丙酰胺(600mg,1.88mmol)，同法制得化合物S17，得白色固体160mg，收率为35.75％。 1H 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] +. The preparation method is the same as S2, and the difference is that (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxyl-2-methylpropionamide is replaced by ( R)-3-Bromo-N-(5-chloro-6-cyanopyridin-3-yl)-2-hydroxy-2-methylpropionamide (600mg, 1.88mmol), the compound S17 was obtained in the same way as white The solid is 160mg, and the yield is 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] + .
实施例1Example 1
Figure PCTCN2022110325-appb-000037
Figure PCTCN2022110325-appb-000037
步骤1：I-1-1的合成Step 1: Synthesis of I-1-1
在装有搅拌子的两口瓶中加入4-氟-1H-吡唑(200mg,2.32mmol)，1-叔丁氧羰基-3-碘氮杂环丁烷(484.32μL,2.79mmol)和无水K 2CO 3(642.29mg,4.65mmol)，DMF(N,N-二甲基甲酰胺,6mL)溶解，氮气保护，60℃下反应16小时。TLC监测反应完全后，冷却至室温，加水淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩有机相，所得残余物通过硅胶柱色谱法(石油醚：乙酸乙酯＝10:1)分离，得无色油状物320mg，收率为57.08％。 1H 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] +. Add 4-fluoro-1H-pyrazole (200 mg, 2.32 mmol), 1-tert-butoxycarbonyl-3-iodoazetidine (484.32 μL, 2.79 mmol) and anhydrous K 2 CO 3 (642.29mg, 4.65mmol) was dissolved in DMF (N,N-dimethylformamide, 6mL), protected by nitrogen, and reacted at 60°C for 16 hours. After TLC monitors that the reaction is complete, cool to room temperature, add water to quench the reaction, extract with DCM (5mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase, and the resulting residue is purified by silica gel column chromatography (petroleum ether : ethyl acetate=10:1) to obtain 320 mg of a colorless oily substance with a yield of 57.08%. 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] + .
步骤2：I-1-2的合成Step 2: Synthesis of I-1-2
将3-(4-氟-1H-吡唑-1-基)氮杂环丁烷-1-羧酸叔丁酯(I-1-1)(200mg,2.79mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得无色油状物90mg，产率53.05％。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) , slowly drop TFA 0.5mL, react at room temperature for 1h, after TLC monitors the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, extract with DCM (5mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 90 mg of colorless oil, yield 53.05%.
步骤3：I-1的合成Step 3: Synthesis of I-1
将I-1-2(90mg,0.64mmol)和S2(172.30mg,0.64mmol)溶于3mL无水乙醇中，回流4h，TLC监测反应完全后，减压蒸干，所得残余物通过硅胶柱色谱法(二氯甲烷：甲醇＝100：1)分离，得白色固体110mg，收率为41.94％。 1H 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] +. I-1-2 (90mg, 0.64mmol) and S2 (172.30mg, 0.64mmol) were dissolved in 3mL of absolute ethanol, refluxed for 4h, after TLC monitored the reaction was complete, evaporated to dryness under reduced pressure, and the obtained residue was subjected to silica gel column chromatography method (dichloromethane:methanol=100:1) to obtain 110mg of white solid with 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=12.4 Hz, 1H), 2.63(d, J=12.4Hz, 1H), 1.34(s, 3H). LC-MS(ESI) m/z: 412.15[M+H] + .
实施例2Example 2
Figure PCTCN2022110325-appb-000038
Figure PCTCN2022110325-appb-000038
步骤1：I-2-1的合成Step 1: Synthesis of I-2-1
参考中间体S5的合成方法，不同的是将步骤中4-溴苯硼酸替换为4-氟苯硼酸，同法制得化合物I-2-1，得无色油状物100mg，产率为37.55％。 1H 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] +. Referring to the synthesis method of intermediate S5, except that 4-bromophenylboronic acid was replaced by 4-fluorophenylboronic acid in the step, compound I-2-1 was obtained in the same way to obtain 100 mg of a 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[MH] + .
步骤2：I-2-2的合成Step 2: Synthesis of I-2-2
将I-2-1(200mg,0.80mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得无色油状物85mg，产率70.64％。Dissolve I-2-1 (200mg, 0.80mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 85 mg of a colorless oil with a yield of 70.64%.
步骤3：I-2的合成Step 3: Synthesis of I-2
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为I-2-2，同法制得化合物I-2，得白色固体62mg，产率为39.76％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by I-2-2, compound I-2 was obtained in the same way to obtain 62 mg of white solid with a yield of 39.76%. 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] + .
实施例3Example 3
Figure PCTCN2022110325-appb-000039
Figure PCTCN2022110325-appb-000039
步骤1：I-3-1的合成Step 1: Synthesis of I-3-1
参考中间体S5的合成方法，不同的是将步骤中4-溴苯硼酸替换为4-氰基苯硼酸，同法制得化合物I-3-1，得白色固体270mg，产率为59.18％。 1H 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] +. Referring to the synthesis method of intermediate S5, except that 4-bromophenylboronic acid was replaced by 4-cyanophenylboronic acid in the step, compound I-3-1 was obtained in the same way to obtain 270 mg of 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] + .
步骤2:I-3-2的合成Step 2: Synthesis of I-3-2
将I-3-1(200mg,0.77mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得白色固体120mg，产率65.31％。Dissolve I-3-1 (200mg, 0.77mmol) in DCM (2mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 120 mg of white solid with a yield of 65.31%.
步骤3:I-3的合成Step 3: Synthesis of I-3
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为I-3-2，同法制得化合物I-3，得白色固体110mg，产率为40.62％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by I-3-2, compound I-3 was obtained in the same way to obtain 110 mg of 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] + .
实施例4Example 4
Figure PCTCN2022110325-appb-000040
Figure PCTCN2022110325-appb-000040
步骤1：II-11-1的合成Step 1: Synthesis of II-11-1
在一个圆底烧瓶中，依次加入2-氰基-5-氟吡啶(200mg,1.64mmol)，1-(叔丁氧羰基)哌嗪(457mg,2.46mmol)和K 2CO 3(452mg,3.28mmol)。然后加入6mL DMF，80℃下反应4小时。TLC监测反应完全后，冷却至室温，加入20mL水，搅拌析出固体，减压抽滤，得白色固体400mg，产率84.69％。 1H 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] +. 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 2 CO 3 (452 mg, 3.28 mmol). Then 6 mL of DMF was added and reacted at 80° C. for 4 hours. After the completion of the reaction as monitored by TLC, cool to room temperature, add 20 mL of water, stir to precipitate a solid, and filter under reduced pressure to obtain 400 mg 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] + .
步骤2：II-11-2的合成Step 2: Synthesis of II-11-2
将II-11-1(250mg,0.87mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体110mg，产率67.40％。Dissolve II-11-1 (250mg, 0.87mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 110 mg of yellow solid with a yield of 67.40%.
步骤3：II-11的合成Step 3: Synthesis of II-11
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-11-2，同法制得化合物II-11，得淡黄色固体140mg，产率为57.48％。mp:92-94℃.1H NMR(300MHz,Chloroform-d)δ9.39(s,1H),8.25(d,J＝2.9Hz,1H),8.15(d,J＝2.1Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.82(d,J＝8.5Hz,1H),7.50(d,J＝8.8Hz,1H),7.07(dd,J＝8.8,3.0Hz,1H),4.93(s,1H), 3.40(s,1H),3.36(t,J＝5.1Hz,4H),2.76(q,J＝5.4Hz,4H),2.54(d,J＝13.3Hz,1H),1.47(s,3H).LC-MS(ESI)m/z:459.10[M+H] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced by II-11-2, and compound II-11 was obtained in the same way to obtain 140 mg of a light yellow solid with a yield of 57.48% . mp:92-94℃.1H NMR(300MHz,Chloroform-d)δ9.39(s,1H),8.25(d,J＝2.9Hz,1H),8.15(d,J＝2.1Hz,1H),7.97 (dd, J=8.5,2.2Hz,1H),7.82(d,J=8.5Hz,1H),7.50(d,J=8.8Hz,1H),7.07(dd,J=8.8,3.0Hz,1H) ,4.93(s,1H), 3.40(s,1H),3.36(t,J=5.1Hz,4H),2.76(q,J=5.4Hz,4H),2.54(d,J=13.3Hz,1H) ,1.47(s,3H).LC-MS(ESI)m/z:459.10[M+H] + .
实施例5Example 5
Figure PCTCN2022110325-appb-000041
Figure PCTCN2022110325-appb-000041
步骤1：II-14-1的合成Step 1: Synthesis of II-14-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶替换为4-氟-2-(三氟甲基)苯甲腈，同法制得化合物II-14-1，得白色固体850mg，产率90.47％。 1H 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] +. Referring to the synthetic method of step 1 of Example 4, the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 4-fluoro-2-(trifluoromethyl)benzonitrile, and compound II- 14-1, 850 mg of white solid was obtained, and the yield was 90.47%. 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[MH ] + .
步骤2:II-14-2的合成Step 2: Synthesis of II-14-2
将II-14-1(300mg,0.84mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得淡黄色固体200mg，产率92.82％。Dissolve II-14-1 (300mg, 0.84mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 200 mg of light yellow solid with a yield of 92.82%.
步骤2:II-14的合成Step 2: Synthesis of II-14
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-14-2，同法制得化合物II-14，得白色固体120mg，产率为58.29％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-14-2, compound II-14 was obtained in the same way to obtain 120 mg of 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] + .
实施例6Example 6
Figure PCTCN2022110325-appb-000042
Figure PCTCN2022110325-appb-000042
步骤1：II-15-1的合成Step 1: Synthesis of II-15-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶替换为2-氰基-3,5-二氟吡啶，同法制得化合物II-15-1，得白色固体320mg，产率73.17％。 1H 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] +. Referring to the synthesis method of step 1 of Example 4, the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 2-cyano-3,5-difluoropyridine, and compound II-15-1 is obtained in the same way , to obtain 320 mg of white solid, yield 73.17%. 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] + .
步骤2：II-15-2的合成Step 2: Synthesis of II-15-2
将II-15-1(220mg,0.72mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体110mg，产率74.27％。Dissolve II-15-1 (220mg, 0.72mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 110 mg of yellow solid with a yield of 74.27%.
步骤3：II-15的合成Step 3: Synthesis of II-15
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-15-2，同法制得化合物II-15，得白色固体120mg，产率为47.22％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-15-2, compound II-15 was obtained in the same way to obtain 120 mg of 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] + .
实施例7Example 7
Figure PCTCN2022110325-appb-000043
Figure PCTCN2022110325-appb-000043
步骤1：II-19-1的合成Step 1: Synthesis of II-19-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶替换为5-溴-2-硝基三氟甲苯，同法制得化合物II-19-1，得白色固体314mg，产率75.68％。 1H 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] +. Referring to the synthesis method in step 1 of Example 4, the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 5-bromo-2-nitrobenzotrifluoride, and compound II-19-1 is prepared in the same way, 314 mg of white solid was obtained with a yield of 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] + .
步骤2：II-19-2的合成Step 2: Synthesis of II-19-2
将II-19-1(314mg,0.84mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得白色固体162mg，产率70.07％。Dissolve II-19-1 (314mg, 0.84mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 162 mg of white solid with a yield of 70.07%.
步骤3：II-19的合成Step 3: Synthesis of II-19
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-19-2，同法制得化合物II-19，得白色固体132mg，产率为41.02％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-19-2, compound II-19 was obtained in the same way to obtain 132 mg of white solid with 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] + .
实施例8Example 8
Figure PCTCN2022110325-appb-000044
Figure PCTCN2022110325-appb-000044
步骤1：II-20-1的合成Step 1: Synthesis of II-20-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶替换为3-氰基-6-氯哒嗪，同法制得化合物II-20-1，得白色固体438mg，产率94.02％。 1H 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] +. Referring to the synthesis method in step 1 of Example 4, the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 3-cyano-6-chloropyridazine, and compound II-20-1 is obtained in the same way as White solid 438mg, yield 94.02%. 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[MH] + .
步骤2：II-20-2的合成Step 2: Synthesis of II-20-2
将II-20-1(303mg,1.05mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得白色固体158mg，产率79.52％。Dissolve II-20-1 (303mg, 1.05mmol) in DCM (3mL), slowly add TFA 0.8mL dropwise, react at room temperature for 1h, after TLC monitors the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 158 mg of white solid with a yield of 79.52%.
步骤3：II-20的合成Step 3: Synthesis of II-20
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-20-2，同法制得化合物II-20，得白色固体179mg，产率为44.45％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-20-2, compound II-20 was obtained in the same way to obtain 179 mg of 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[MH] + .
实施例9Example 9
Figure PCTCN2022110325-appb-000045
Figure PCTCN2022110325-appb-000045
步骤1：II-22-1的合成Step 1: Synthesis of II-22-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶替换为对氟苯甲砜，同法制得化合物II-22-1，得白色固体406mg，产率41.55％。 1H 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] +. Referring to the synthesis method in Step 1 of Example 4, the difference is that 2-cyano-5-fluoropyridine in Step 1 was replaced by p-fluorophenylsulfone, and compound II-22-1 was obtained in the same way to obtain 406 mg of a white solid. Rate 41.55%. 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] + .
步骤2：II-22-2的合成Step 2: Synthesis of II-22-2
将II-22-1(250mg,0.73mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得白色固体100mg，产率56.66％。Dissolve II-22-1 (250mg, 0.73mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of white solid with a yield of 56.66%.
步骤3：II-22的合成Step 3: Synthesis of II-22
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-22-2，同法制得化合物II-22，得白色固体100mg，产率为47.07％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-22-2, compound II-22 was obtained in the same way to obtain 100 mg of 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] + .
实施例10Example 10
Figure PCTCN2022110325-appb-000046
Figure PCTCN2022110325-appb-000046
步骤1：II-23-1的合成Step 1: Synthesis of II-23-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶替换为5-溴-3-(三氟甲基)-2-氰基吡啶，同法制得化合物II-23-1，得固体400mg，产率93.92％。 1H 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] +. Referring to the synthesis method of step 1 of Example 4, the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 5-bromo-3-(trifluoromethyl)-2-cyanopyridine, and prepared in the same way Compound II-23-1, 400 mg of solid was obtained, and the yield was 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] + .
步骤2：II-23-2的合成Step 2: Synthesis of II-23-2
将II-23-1(300mg,0.84mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体185mg，产率85.76％。Dissolve II-23-1 (300mg, 0.84mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 185 mg of yellow solid with a yield of 85.76%.
步骤3：II-23的合成Step 3: Synthesis of II-23
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-23-2，同法制得化合物II-23，得白色固体130mg，产率为63.27％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-23-2, compound II-23 was obtained in the same way to obtain 130 mg of 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] + .
实施例11Example 11
Figure PCTCN2022110325-appb-000047
Figure PCTCN2022110325-appb-000047
步骤1：II-24-1的合成Step 1: Synthesis of II-24-1
在一个圆底烧瓶中，依次加入对氟苯甲腈(500mg,4.13mmol)，1,4-二氮杂环庚烷-1-甲酸叔丁酯(1.22mL,2.46mmol)和K 2CO 3(1.14g,8.26mmol)。然后加入6mL DMF，80℃下反应4小时。TLC监测反应完全后，冷却至室温，加入20mL水，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩有机相，所得残余物通过硅胶柱色谱法(二氯甲烷：三乙胺＝500：1)分离，得白色固体600mg，产率48.22％。 1H 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] +. In a round bottom flask, add p-fluorobenzonitrile (500 mg, 4.13 mmol), tert-butyl 1,4-diazepane-1-carboxylate (1.22 mL, 2.46 mmol) and K 2 CO 3 (1.14g, 8.26mmol). Then 6 mL of DMF was added and reacted at 80° C. for 4 hours. After TLC monitors that the reaction is complete, cool to room temperature, add 20 mL of water, extract with ethyl acetate (10 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phases, and the resulting residue is passed through silica gel column chromatography ( Dichloromethane: triethylamine = 500: 1) separated to obtain 600 mg of white solid with a yield of 48.22%. 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] + .
步骤2：II-24-2的合成Step 2: Synthesis of II-24-2
将II-24-1(300mg,1.00mmol)溶于DCM(3mL)中，缓慢滴加TFA 1mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得白色固体160mg，产率79.86％。Dissolve II-24-1 (300mg, 1.00mmol) in DCM (3mL), slowly add 1mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL×3 ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 160 mg of a white solid with a yield of 79.86%.
步骤3：II-24的合成Step 3: Synthesis of II-24
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-24-2，同法制得化合物II-24，得白色固体115mg，产率为50.60％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-24-2, compound II-24 was obtained in the same way to obtain 115 mg of 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] + .
实施例12Example 12
Figure PCTCN2022110325-appb-000048
Figure PCTCN2022110325-appb-000048
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为4-哌嗪基苯甲腈，同法制得化合物II-1，得白色固体120mg，产率为70.88％。 1H 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] +. Referring to the synthesis method of step 3 of Example 1, the difference is that I-1-2 in step 3 is replaced by 4-piperazinylbenzonitrile, and compound II-1 is obtained in the same way to obtain 120 mg of white solid, and the yield is 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] + .
实施例13Example 13
Figure PCTCN2022110325-appb-000049
Figure PCTCN2022110325-appb-000049
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为1-(4-氟苯基)哌嗪，同法制得化合物II-2，得白色固体120mg，产率为48.01％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced with 1-(4-fluorophenyl)piperazine, and compound II-2 was obtained in the same way to obtain 120 mg of a white solid. The yield was 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] + .
实施例14Example 14
Figure PCTCN2022110325-appb-000050
Figure PCTCN2022110325-appb-000050
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为1-(3-氰基苯基)哌嗪，同法制得化合物II-4，得白色固体238mg，产率为48.62％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 is replaced by 1-(3-cyanophenyl)piperazine, and compound II-4 is obtained in the same way to obtain 238 mg of white solid , and the yield was 48.62%. 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] + .
实施例15Example 15
Figure PCTCN2022110325-appb-000051
Figure PCTCN2022110325-appb-000051
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为1-(2-苯甲腈)哌嗪，同法制得化合物II-6，得白色固体100mg，产率为40.93％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced by 1-(2-benzonitrile)piperazine, and compound II-6 was obtained in the same way to obtain 100 mg of a white solid. The yield was 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] + .
实施例16Example 16
Figure PCTCN2022110325-appb-000052
Figure PCTCN2022110325-appb-000052
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为1-(4-吡啶基)哌嗪，同法制得化合物II-9，得淡黄色固体120mg，产率为45.19％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced with 1-(4-pyridyl)piperazine, and compound II-9 was obtained in the same way to obtain 120 mg of a light yellow solid. The yield is 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] + .
实施例17Example 17
Figure PCTCN2022110325-appb-000053
Figure PCTCN2022110325-appb-000053
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为1-(4-三氟甲基苯基)哌嗪，同法制得化合物II-10，得白色固体150mg，产率为69.01％。 1H 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] +. Referring to the synthesis method of step 3 of Example 1, the difference is that I-1-2 in step 3 is replaced by 1-(4-trifluoromethylphenyl)piperazine, and compound II-10 is obtained in the same way as white The solid was 150mg, and the yield was 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] + .
实施例18Example 18
Figure PCTCN2022110325-appb-000054
Figure PCTCN2022110325-appb-000054
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为1-(4-硝基苯基)哌嗪，同法制得化合物II-12，得黄色固体150mg，产率为54.26％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 is replaced by 1-(4-nitrophenyl)piperazine, and compound II-12 is obtained in the same way to obtain 150 mg of yellow solid , and the yield was 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] + .
实施例19Example 19
Figure PCTCN2022110325-appb-000055
Figure PCTCN2022110325-appb-000055
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为5-(哌嗪-1-基)嘧啶，同法制得化合物II-13，得白色固体80mg，产率为30.24％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced with 5-(piperazin-1-yl)pyrimidine, and compound II-13 was obtained in the same way to obtain 80 mg of a white solid. The yield was 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] + .
实施例20Example 20
Figure PCTCN2022110325-appb-000056
Figure PCTCN2022110325-appb-000056
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为1-(4-甲氧基苯基)哌嗪，同法制得化合物II-16，得淡黄色固体120mg，产率为49.89％。 1H 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] +. Referring to the synthetic method of Step 3 of Example 1, the difference is that I-1-2 in Step 3 is replaced by 1-(4-methoxyphenyl)piperazine, and compound II-16 is obtained in the same way as light yellow The solid was 120mg, and the yield was 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] + .
实施例21Example 21
Figure PCTCN2022110325-appb-000057
Figure PCTCN2022110325-appb-000057
将1-(4-氰基苯基)哌嗪(100mg,0.53mmol)和S4(144.31mg,0.53mmol)溶于4mL无水乙醇中，回流4h，TLC监测反应完全后，减压蒸干，所得残余物通过硅胶柱色谱法(二氯甲烷:甲醇＝100:1)分离，得黄色固体110mg，产率为44.93％。 1H 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] +. 1-(4-cyanophenyl)piperazine (100mg, 0.53mmol) and S4 (144.31mg, 0.53mmol) were dissolved in 4mL of absolute ethanol, refluxed for 4h, after the completion of the reaction monitored by TLC, evaporated to dryness under reduced pressure, The resulting residue was separated by silica gel column chromatography (dichloromethane:methanol=100:1) to obtain 110 mg of a yellow solid with a yield of 44.93%. 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=8.8 Hz, 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] + .
实施例22Example 22
Figure PCTCN2022110325-appb-000058
Figure PCTCN2022110325-appb-000058
步骤1：II-3-1的合成Step 1: Synthesis of II-3-1
在一个两口瓶中，依次加入4-溴苯甲腈(187.77mg,1.03mmol)，(S)-1-N-叔丁氧羰基-2-甲基哌嗪(300mg,1.50mmol)，NaOBu-t(191.93mg，2.00mmol)，Pd 2(dba) 3(91.44mg,0.1mmol)和BINAP(124.36mg,0.2mmol)。加入4mL重蒸甲苯，80℃，氮气保护下反应12小时。TLC监测反应完全后，冷却至室温，加水淬灭反应，乙酸乙酯(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得残余物通过硅胶柱色谱法(石油醚：乙酸乙酯＝10:1)分离，得白色固体264mg，产率85.04％。 1H 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] +. In a two-neck flask, add 4-bromobenzonitrile (187.77mg, 1.03mmol), (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine (300mg, 1.50mmol), NaOBu- t (191.93 mg, 2.00 mmol), Pd 2 (dba) 3 (91.44 mg, 0.1 mmol) and BINAP (124.36 mg, 0.2 mmol). Add 4 mL of redistilled toluene and react at 80°C for 12 hours under nitrogen protection. After TLC monitors that the reaction is complete, cool to room temperature, add water to quench the reaction, extract with ethyl acetate (5mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and the resulting residue is purified by silica gel column chromatography (petroleum ether : ethyl acetate=10:1) separation to obtain 264 mg of white solid, yield 85.04%. 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=6.6 Hz,3H).LC-MS(ESI)m/z:300.45[MH] + .
步骤2：II-3-2的合成：Step 2: Synthesis of II-3-2:
将II-3-1(200mg,0.66mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得白色固体127mg，产率95.61％。Dissolve II-3-1 (200mg, 0.66mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 127 mg of white solid with a yield of 95.61%.
步骤3：II-3的合成：Step 3: Synthesis of II-3:
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-3-2，同法制得化合物II-3，得白色固体122.28mg，产率为41.17％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced by II-3-2, and compound II-3 was obtained in the same way to obtain 122.28 mg 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] + .
实施例23Example 23
Figure PCTCN2022110325-appb-000059
Figure PCTCN2022110325-appb-000059
步骤1：II-5-1的合成Step 1: Synthesis of II-5-1
参考实施例22步骤1的合成方法，不同的是将步骤1中(S)-1-N-叔丁氧羰基-2-甲基哌嗪替换为3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯，同法制得化合物II-5-1，得黄色固体368mg，产率74.79％。 1H 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] +. Referring to the synthesis method of step 1 of Example 22, the difference is that (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 is replaced by 3,8-diazabicyclo[3.2.1 ] Octane-3-carboxylic acid tert-butyl ester, the compound II-5-1 was prepared in the same way to obtain 368 mg of yellow solid, and the yield was 74.79%. 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] + .
步骤2：II-5-2的合成Step 2: Synthesis of II-5-2
将II-5-1(368mg,1.17mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体200mg，产率80.15％。Dissolve II-5-1 (368mg, 1.17mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 200 mg of yellow solid with a yield of 80.15%.
步骤2：II-5的合成Step 2: Synthesis of II-5
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-5-2，同法制得化合物II-5，得黄色固体153mg，产率为33.66％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-5-2, Compound II-5 was obtained in the same way to obtain 153 mg 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] + .
实施例24Example 24
Figure PCTCN2022110325-appb-000060
Figure PCTCN2022110325-appb-000060
步骤1：II-18-1的合成Step 1: Synthesis of II-18-1
参考实施例22步骤1的合成方法，不同的是将步骤1中4-溴苯甲腈和(S)-1-N-叔丁氧羰基-2-甲基哌嗪替换为对溴氟苯和3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯，同法制得化合物II-18-1，得白色固体249mg，产率59.32％。 1H 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] +. Referring to the synthetic method of step 1 of Example 22, the difference is that 4-bromobenzonitrile and (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 are replaced by p-bromofluorobenzene and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate was prepared in the same way as compound II-18-1, and 249 mg of white solid was obtained with a yield of 59.32%. 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] + .
步骤2：II-18-2的合成Step 2: Synthesis of II-18-2
将II-18-1(249mg,0.81mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得白色固体154mg，产率92.18％。Dissolve II-18-1 (249mg, 0.81mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 154 mg of white solid with a yield of 92.18%.
步骤3：II-18的合成Step 3: Synthesis of II-18
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-18-2，同法制得化合物II-18，得白色固体135mg，产率为37.78％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-18-2, Compound II-18 was obtained in the same way to obtain 135 mg of 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] + .
实施例25Example 25
Figure PCTCN2022110325-appb-000061
Figure PCTCN2022110325-appb-000061
步骤1：II-7-1的合成Step 1: Synthesis of II-7-1
在一个两口瓶中，依次加入4-溴苯甲腈(48.12μL,0.42mmol)，(1S,4S)-(-)-2-叔丁氧羰基-2,5-二氮双环[2.2.1]庚烷(100mg,0.50mmol)，NaOBu-t(121.18mg，1.26mmol)，Pd(OAc) 2(28.32mg,0.04mmol)和P(Bu-t) 3(9.88μL,0.09mmol)。加入4mL重蒸甲苯溶解，80℃，氮气保护下，反应4小时。TLC监测反应完全后，冷却至室温，加水淬灭反应，乙酸乙酯(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得残余物通过硅胶柱色谱法(石油醚：乙酸乙酯＝20:1)分离，得白色固体102mg，产率81.06％. 1H 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] +. In a two-neck flask, add 4-bromobenzonitrile (48.12μL, 0.42mmol), (1S,4S)-(-)-2-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1 ] 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 μL, 0.09 mmol). Add 4 mL of redistilled toluene to dissolve, and react at 80°C for 4 hours under the protection of nitrogen. After TLC monitors that the reaction is complete, cool to room temperature, add water to quench the reaction, extract with ethyl acetate (5mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and the resulting residue is purified by silica gel column chromatography (petroleum ether : Ethyl acetate=20:1) to obtain white solid 102mg, yield 81.06%. 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] + .
步骤2：II-7-2的合成Step 2: Synthesis of II-7-2
将II-7-1粗品(102mg,0.34mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色油状物60mg，产率88.38％。Dissolve the crude product II-7-1 (102mg, 0.34mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ×3) extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 60 mg of yellow oil with a yield of 88.38%.
步骤3：II-7的合成Step 3: Synthesis of II-7
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-7-2，同法制得化合物II-7，得白色固体60mg，产率为42.44％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-7-2, Compound II-7 was obtained in the same way to obtain 60 mg of 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] + .
实施例26Example 26
Figure PCTCN2022110325-appb-000062
Figure PCTCN2022110325-appb-000062
步骤1：II-8-1的合成Step 1: Synthesis of II-8-1
参考实施例25步骤1的合成方法，不同的是将步骤1中4-溴苯甲腈，(1S,4S)-(-)-2-叔丁氧羰基-2,5-二氮双环[2.2.1]庚烷替换为对溴氟苯和(1S,4S)-(-)-2-叔丁氧羰基-2,5-二氮双环[2.2.1]庚烷，同法制得化合物II-8-1，得白色固体220mg，产率89.51％。 1H 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] +. Referring to the synthesis method of step 1 of Example 25, the difference is that in step 1, 4-bromobenzonitrile, (1S,4S)-(-)-2-tert-butoxycarbonyl-2,5-diazabicyclo[2.2 .1] heptane was replaced by p-bromofluorobenzene and (1S, 4S)-(-)-2-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]heptane, and compound II- 8-1, 220 mg of white solid was obtained, and the yield was 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] + .
步骤2：II-8-2的合成Step 2: Synthesis of II-8-2
将II-8-1(220mg,0.75mmol)溶于DCM(4mL)中，缓慢滴加TFA 1.0mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色油状物120mg，产率82.95％。Dissolve II-8-1 (220mg, 0.75mmol) in DCM (4mL), slowly add TFA 1.0mL dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 120 mg of yellow oil with a yield of 82.95%.
步骤3：II-8的合成Step 3: Synthesis of II-8
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-8-2，同法制得化合物II-8，得黄色固体200mg，产率为83.14％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-8-2, compound II-8 was obtained in the same way to obtain 200 mg 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=9.2,2.2 Hz,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] + .
实施例27Example 27
Figure PCTCN2022110325-appb-000063
Figure PCTCN2022110325-appb-000063
步骤1：II-17-1的合成Step 1: Synthesis of II-17-1
参考实施例25步骤1的合成方法，不同的是将步骤1中4-溴苯甲腈和(1S,4S)-(-)-2-叔丁氧羰基-2,5-二氮双环[2.2.1]庚烷替换为对溴氟苯和(S)-1-N-叔丁氧羰基-2-甲基哌嗪，同法制得 化合物II-17-1，得黄色油状物300mg，产率59.45％。 1H 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] +. Referring to the synthesis method of step 1 of Example 25, the difference is that 4-bromobenzonitrile and (1S,4S)-(-)-2-tert-butoxycarbonyl-2,5-diazabicyclo[2.2 .1] Heptane was replaced by p-bromofluorobenzene and (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine, and compound II-17-1 was obtained in the same way to obtain 300 mg of yellow oil, with a yield of 59.45%. 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] + .
步骤2：II-17-2的合成Step 2: Synthesis of II-17-2
将II-17-1(200mg,0.68mmol)溶于DCM(4mL)中，缓慢滴加TFA 1.0mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色油状物100mg，产率75.77％。Dissolve II-17-1 (200mg, 0.68mmol) in DCM (4mL), slowly add 1.0mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of yellow oil with a yield of 75.77%.
步骤3：II-17的合成Step 3: Synthesis of II-17
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-17-2，同法制得化合物II-17，得淡黄色固体90mg，产率为37.64％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced by II-17-2, and compound II-17 was obtained in the same way to obtain 90 mg of light yellow solid with a yield of 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] + .
实施例28Example 28
Figure PCTCN2022110325-appb-000064
Figure PCTCN2022110325-appb-000064
步骤1：II-25-1的合成Step 1: Synthesis of II-25-1
参考实施例25步骤1的合成方法，不同的是将步骤1中4-溴苯甲腈和(1S,4S)-(-)-2-叔丁氧羰基-2,5-二氮双环[2.2.1]庚烷替换为4-溴-2-氟苯甲腈和1-(叔丁氧羰基)哌嗪，同法制得化合物II-25-1，得淡黄色固体1.64g，产率53.78％。 1H 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] +. Referring to the synthesis method of step 1 of Example 25, the difference is that 4-bromobenzonitrile and (1S,4S)-(-)-2-tert-butoxycarbonyl-2,5-diazabicyclo[2.2 .1] Heptane was replaced by 4-bromo-2-fluorobenzonitrile and 1-(tert-butoxycarbonyl)piperazine, and compound II-25-1 was obtained in the same way to obtain 1.64g of a light yellow solid, with a yield of 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[MH] + .
步骤2：II-25-2的合成Step 2: Synthesis of II-25-2
将II-25-1(200mg,0.65mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得淡黄色固体95mg，产率70.67％。Dissolve II-25-1 (200mg, 0.65mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 95 mg of light yellow solid with a yield of 70.67%.
步骤3：II-25的合成Step 3: Synthesis of II-25
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-25-2，同法制得化合物II-25，得白色固体118mg，产率为53.62％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-25-2, compound II-25 was obtained in the same way to obtain 118 mg of white solid with 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] + .
实施例29Example 29
Figure PCTCN2022110325-appb-000065
Figure PCTCN2022110325-appb-000065
步骤1：II-26-1的合成Step 1: Synthesis of II-26-1
参考实施例22步骤1的合成方法，不同的是将步骤1中4-溴苯甲腈和(1S,4S)-(-)-2-叔丁氧羰基-2,5-二氮双环[2.2.1]庚烷替换为4-溴-2-氯苯甲腈和1-(叔丁氧羰基)哌嗪，同法制得化合物II-26-1，得淡黄色固体213mg，产率71.64％。 1H 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] +. Referring to the synthesis method of step 1 of Example 22, the difference is that 4-bromobenzonitrile and (1S,4S)-(-)-2-tert-butoxycarbonyl-2,5-diazabicyclo[2.2 .1] Heptane was replaced by 4-bromo-2-chlorobenzonitrile and 1-(tert-butoxycarbonyl)piperazine, and compound II-26-1 was obtained in the same way to obtain 213 mg of a light yellow solid with a yield of 71.64%. 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[MH] + .
步骤2：II-26-2的合成Step 2: Synthesis of II-26-2
将II-26-1(200mg,0.62mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体106mg，产率76.94％。Dissolve II-26-1 (200mg, 0.62mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 106 mg of a yellow solid with a yield of 76.94%.
步骤3：II-26的合成Step 3: Synthesis of II-26
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-26-2，同法制得化合物II-26，得白色固体126mg，产率为56.79％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-26-2, compound II-26 was obtained in the same way to obtain 126 mg of 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] + .
实施例30Example 30
Figure PCTCN2022110325-appb-000066
Figure PCTCN2022110325-appb-000066
步骤1：III-1-1的合成Step 1: Synthesis of III-1-1
在一个两口瓶中，依次加入S5(600mg,1.92mmol)，4-氟苯硼酸频哪醇酯(512.12mg,2.31mmol)，PdCl 2(dppf)(70.32mg,0.10mmol)和Cs 2CO 3(1.25g,3.84mmol)。加入2mL水溶解Cs 2CO 3，然后加入12mL二氧六环和水(V:V＝6:1)，100℃，氮气保护下反应4小时。TLC监测反应完全后，冷却至室温，加水淬灭反应，乙酸乙酯(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得残余物通过硅胶柱色谱法(石油醚：乙酸乙酯＝50:1)分离，得淡黄色油状物510mg，产率81.06％。 1H 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] +. In a two-neck flask, add S5 (600mg, 1.92mmol), 4-fluorophenylboronic acid pinacol ester (512.12mg, 2.31mmol), PdCl 2 (dppf) (70.32mg, 0.10mmol) and Cs 2 CO 3 (1.25g, 3.84mmol). Add 2 mL of water to dissolve Cs 2 CO 3 , then add 12 mL of dioxane and water (V:V=6:1), and react at 100°C for 4 hours under nitrogen protection. After TLC monitors that the reaction is complete, cool to room temperature, add water to quench the reaction, extract with ethyl acetate (5mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and the resulting residue is purified by silica gel column chromatography (petroleum ether : Ethyl acetate=50:1) separation to obtain 510 mg of light yellow oil, yield 81.06%. 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] + .
步骤2：III-1-2的合成Step 2: Synthesis of III-1-2
将III-1-1(510mg,1.56mmol)溶于DCM(6mL)中，缓慢滴加TFA 1.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得白色固体300mg，产率84.74％。Dissolve III-1-1 (510mg, 1.56mmol) in DCM (6mL), slowly add 1.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 300 mg of white solid with a yield of 84.74%.
步骤3：III-1的合成Step 3: Synthesis of III-1
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为III-1-2，同法制得化合物III-1，得白色固体150mg，产率为40.31％。1H NMR(300MHz,Chloroform-d)δ9.66(s,1H),8.12(d,J＝2.1Hz,1H),7.95(dd,J＝8.5,2.2Hz,1H),7.80(d,J＝8.5Hz,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＝12.5Hz,1H),2.68(d,J＝12.5Hz,1H),1.45(s,3H).LC-MS(ESI)m/z:498.10[M+H] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by III-1-2, compound III-1 was obtained in the same way to obtain 150 mg of white solid with a yield of 40.31%. 1H NMR (300MHz, Chloroform-d) δ9.66(s, 1H), 8.12(d, J=2.1Hz, 1H), 7.95(dd, J=8.5, 2.2Hz, 1H), 7.80(d, J= 8.5Hz, 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=12.5Hz,1H),2.68(d,J=12.5Hz,1H),1.45(s,3H).LC-MS( ESI)m/z:498.10[M+H] + .
实施例31Example 31
Figure PCTCN2022110325-appb-000067
Figure PCTCN2022110325-appb-000067
步骤1：III-2-1的合成Step 1: Synthesis of III-2-1
参考实施例30步骤1的合成方法，不同的是将步骤1中4-氟苯硼酸频哪醇酯替换为4-苯甲腈硼酸频哪酯，同法制得化合物III-2-1，得浅黄色油状物250mg，产率77.80％。 1H 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] +. Referring to the synthesis method in Step 1 of Example 30, the difference is that in Step 1, 4-fluorophenylboronic acid pinacol ester was replaced by 4-benzonitrile boric acid pinacol ester, and compound III-2-1 was obtained in the same way as 250 mg of yellow oil, yield 77.80%. 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] + .
步骤2：Ⅲ-2-2的合成Step 2: Synthesis of Ⅲ-2-2
将III-2-1(250mg,0.75mmol)溶于DCM(4mL)中，缓慢滴加TFA 1.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色油状物120mg，产率68.51％。Dissolve III-2-1 (250mg, 0.75mmol) in DCM (4mL), slowly add 1.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 120 mg of yellow oil with a yield of 68.51%.
步骤3：III-2的合成Step 3: Synthesis of III-2
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为III-2-2，同法制得化合物III-2，得白色固体100mg，产率为38.70％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by III-2-2, compound III-2 was obtained in the same way to obtain 100 mg of 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=8.0 Hz,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] + .
实施例32Example 32
Figure PCTCN2022110325-appb-000068
Figure PCTCN2022110325-appb-000068
步骤1：III-3-1的合成：Step 1: Synthesis of III-3-1:
参考实施例30步骤1的合成方法，不同的是将步骤1中4-氟苯硼酸频哪醇酯替换为3-氟苯基硼酸，同法制得化合物III-3-1，得黄色油状物210mg，产率66.75％。 1H 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] +. Referring to the synthesis method in Step 1 of Example 30, the difference is that in Step 1, 4-fluorophenylboronic acid pinacol ester was replaced by 3-fluorophenylboronic acid, and compound III-3-1 was obtained in the same way to obtain 210 mg of yellow oil , yield 66.75%. 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[MH ] + .
步骤2：III-3-2的合成：Step 2: Synthesis of III-3-2:
将III-3-1粗品(210mg,0.64mmol)溶于DCM(4mL)中，缓慢滴加TFA 1.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色油状物110mg，产率75.45％。Dissolve the crude product III-3-1 (210mg, 0.64mmol) in DCM (4mL), slowly add 1.5mL of TFA dropwise, and react at room temperature for 1h. ×3) extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 110 mg of yellow oil with a yield of 75.45%.
步骤3：III-3的合成：Step 3: Synthesis of III-3:
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为III-3-2，同法制得化合物III-3，得白色固体100mg，产率为41.53％。 1H 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] +. Referring to the synthesis method in step 3 of Example 1, except that I-1-2 in step 3 was replaced by III-3-2, compound III-3 was obtained in the same way to obtain 100 mg of 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] + .
实施例33Example 33
Figure PCTCN2022110325-appb-000069
Figure PCTCN2022110325-appb-000069
步骤1：III-4-1的合成Step 1: Synthesis of III-4-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为S7和4-氟苯硼酸频哪醇酯，同法制得化合物III-4-1，得黄色油状物270mg，产率85.82％。 1H 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] +. Referring to the synthesis method in step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by S7 and 4-fluorophenylboronic acid pinacol ester, and compound III-4- 1. Obtain 270mg of yellow oily substance, yield 85.82%. 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[MH] + .
步骤2：Ⅲ-4-2的合成Step 2: Synthesis of Ⅲ-4-2
将III-4-1(270mg,0.82mmol)溶于DCM(4mL)中，缓慢滴加TFA 1mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色油状物130mg，产率69.36％。Dissolve III-4-1 (270mg, 0.82mmol) in DCM (4mL), slowly add 1mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL×3 ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 130 mg of a yellow oil, with a yield of 69.36%.
步骤3：III-4的合成Step 3: Synthesis of III-4
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为III-4-2，同法制得化合物III-4，得白色固体110mg，产率为38.66％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by III-4-2, Compound III-4 was obtained in the same way to obtain 110 mg of 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] + .
实施例34Example 34
Figure PCTCN2022110325-appb-000070
Figure PCTCN2022110325-appb-000070
步骤1：III-5-1的合成Step 1: Synthesis of III-5-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为S7和4-吡啶硼酸频哪醇酯，同法制得化合物III-5-1，黄色油状物220mg，产率73.76％。 1H 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] +. Referring to the synthesis method in step 1 of Example 30, the difference is that in step 1, S5 and 4-fluorophenylboronic acid pinacol ester are replaced by S7 and 4-pyridineboronic acid pinacol ester, and compound III-5-1 is prepared in the same way , 220 mg of yellow oil, yield 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] + .
步骤2：III-5-2的合成Step 2: Synthesis of III-5-2
将III-5-1粗品(220mg,0.71mmol)溶于DCM(4mL)中，缓慢滴加TFA 1.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色油状物110mg，产率73.81％。Dissolve the crude product III-5-1 (220mg, 0.71mmol) in DCM (4mL), slowly add 1.5mL of TFA dropwise, and react at room temperature for 1h. ×3) extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 110 mg of yellow oil with a yield of 73.81%.
步骤3：III-5的合成Step 3: Synthesis of III-5
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为III-5-2，同法制得化合物III-5，得白色固体100mg，产率为39.79％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by III-5-2, compound III-5 was obtained in the same way to obtain 100 mg of 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, 2.1 Hz,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[MH] + .
实施例35Example 35
Figure PCTCN2022110325-appb-000071
Figure PCTCN2022110325-appb-000071
步骤1：III-6-1的合成Step 1: Synthesis of III-6-1
参考实施例30步骤1的合成方法，不同的是将步骤1中4-氟苯硼酸频哪醇酯替换为嘧啶-5-硼酸频哪醇酯，同法制得化合物III-6-1，得黄色油状物230mg，产率73.76％。 1H 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] +. Referring to the synthesis method in Step 1 of Example 30, the difference is that in Step 1, 4-fluorophenylboronic acid pinacol ester was replaced by pyrimidine-5-boronic acid pinacol ester, and compound III-6-1 was obtained in the same way as yellow 230 mg of oily substance, yield 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] + .
步骤2：III-6-2的合成Step 2: Synthesis of III-6-2
将III-6-1粗品(230mg,0.74mmol)溶于DCM(5mL)中，缓慢滴加TFA 1mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色油状物140mg，产率89.71％。Dissolve the crude product III-6-1 (230mg, 0.74mmol) in DCM (5mL), slowly add 1mL of TFA dropwise, react at room temperature for 1h, after TLC monitors the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 140 mg of yellow oil with a yield of 89.71%.
步骤3：III-6的合成Step 3: Synthesis of III-6
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为III-6-2，同法制得化合物III-6，得白色固体180mg，产率为56.42％。 1H 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] +. Referring to the synthesis method in step 3 of Example 1, except that I-1-2 in step 3 was replaced by III-6-2, compound III-6 was obtained in the same way to obtain 180 mg of 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] + .
实施例36Example 36
Figure PCTCN2022110325-appb-000072
Figure PCTCN2022110325-appb-000072
步骤1：III-7-1的合成Step 1: Synthesis of III-7-1
参考实施例30步骤1的合成方法，不同的是将步骤1中4-氟苯硼酸频哪醇酯替换为3-氰 基-4-氟苯硼酸频哪醇酯，同法制得化合物III-7-1，得淡黄色固体400mg，产率93.48％。 1H 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] +. Referring to the synthesis method in step 1 of Example 30, the difference is that 4-fluorophenylboronic acid pinacol ester in step 1 is replaced by 3-cyano-4-fluorophenylboronic acid pinacol ester, and compound III-7 is prepared in the same way -1, 400 mg of a light yellow solid was obtained, and the yield was 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] + .
步骤2：III-7-2的合成Step 2: Synthesis of III-7-2
将III-7-1(300mg,0.85mmol)溶于DCM(3mL)中，缓慢滴加TFA 1mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体120mg，产率55.87％。Dissolve III-7-1 (300mg, 0.85mmol) in DCM (3mL), slowly add 1mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL×3 ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 120 mg of a yellow solid with a yield of 55.87%.
步骤3：III-7的合成Step 3: Synthesis of III-7
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为III-7-2，同法制得化合物III-7，得淡黄色固体45mg，产率为23.47％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced by III-7-2, and compound III-7 was obtained in the same way to obtain 45 mg of a light yellow solid with 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] + .
实施例37Example 37
Figure PCTCN2022110325-appb-000073
Figure PCTCN2022110325-appb-000073
步骤1：III-8-1的合成Step 1: Synthesis of III-8-1
参考实施例30步骤1的合成方法，不同的是将步骤1中4-氟苯硼酸频哪醇酯替换为4-吡啶硼酸频哪醇酯，同法制得化合物III-8-1，得淡黄色固体220mg，产率73.76％。 1H 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] +. Referring to the synthesis method in Step 1 of Example 30, the difference is that in Step 1, 4-fluorophenylboronic acid pinacol ester was replaced by 4-pyridineboronic acid pinacol ester, and compound III-8-1 was obtained in the same way as light yellow Solid 220mg, yield 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=8.1 Hz, 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] + .
步骤2：III-8-2的合成Step 2: Synthesis of III-8-2
将III-8-1(200mg,0.64mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体100mg，产率73.81％。Dissolve III-8-1 (200mg, 0.64mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of yellow solid with a yield of 73.81%.
步骤3：III-8的合成Step 3: Synthesis of III-8
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为III-8-2，同法制得化合物III-8，得淡黄色固体100mg，产率为43.76％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced by III-8-2, and compound III-8 was obtained in the same way to obtain 100 mg of a light 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] + .
实施例38Example 38
Figure PCTCN2022110325-appb-000074
Figure PCTCN2022110325-appb-000074
步骤1:III-9-1的合成Step 1: Synthesis of III-9-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为1-叔丁氧羰基-吡唑-4-硼酸频哪醇酯和对溴氟苯，同法制得化合物Ⅲ-9-1，得黄色固体200mg，、产率44.86％。 1H 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] +. Referring to the synthesis method of step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-pyrazole-4-boronic acid pinacol ester and p-bromo Fluorobenzene, compound III-9-1 was prepared in the same way to obtain 200 mg of yellow solid, and the yield was 44.86%. 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] + .
步骤2：III-9-2的合成Step 2: Synthesis of III-9-2
在一个圆底烧瓶中，依次加入III-9-1(50mg,0.31mmol)，1-叔丁氧羰基-3-碘氮杂环丁烷(65μL,0.37mmol)和K 2CO 3(86mg,0.62mmol)。然后加入4mL DMF，80℃下反应4小时。TLC监测反应完全后，冷却至室温，加入10mL水，乙酸乙酯(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得残余物通过硅胶柱色谱法(二氯甲烷：甲醇＝100:1)分离，得白色固体70mg，产率71.54％。 1H 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] +. In a round bottom flask, add III-9-1 (50 mg, 0.31 mmol), 1-tert-butoxycarbonyl-3-iodoazetidine (65 μL, 0.37 mmol) and K 2 CO 3 (86 mg, 0.62 mmol). Then 4 mL of DMF was added and reacted at 80° C. for 4 hours. After TLC monitors that the reaction is complete, cool to room temperature, add 10mL of water, extract with ethyl acetate (5mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and the resulting residue is purified by silica gel column chromatography (dichloromethane : Methanol=100:1) separation to obtain 70mg of white solid, yield 71.54%. 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] + .
步骤3:III-9-3的合成Step 3: Synthesis of III-9-3
将III-9-2(200mg,0.63mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得淡黄色固体100mg，产率73.04％。Dissolve III-9-2 (200mg, 0.63mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 100 mg of light yellow solid with a yield of 73.04%.
步骤4:III-9的合成Step 4: Synthesis of III-9
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为III-9-3，同法制得化合物III-9，得淡黄色固体90mg，产率为40.11％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced by III-9-3, and compound III-9 was obtained in the same way to obtain 90 mg of a light 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] + .
实施例39Example 39
Figure PCTCN2022110325-appb-000075
Figure PCTCN2022110325-appb-000075
步骤1：III-10-1的合成Step 1: Synthesis of III-10-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为S7和4-氰基苯硼酸频哪醇酯，同法制得化合物III-10-1，得黄色油状物400mg，产率74.69％。 1H 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] +. Referring to the synthesis method in step 1 of Example 30, the difference is that in step 1, S5 and 4-fluorophenylboronic acid pinacol ester are replaced by S7 and 4-cyanophenylboronic acid pinacol ester, and compound III-10 is prepared in the same way -1, 400mg of yellow oil was obtained, yield 74.69%. 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[MH] + .
步骤2：III-10-2的合成Step 2: Synthesis of III-10-2
将III-10-1(300mg,0.82mmol)溶于DCM(4mL)中，缓慢滴加TFA 1mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色油状物150mg，产率71.36％。Dissolve III-10-1 (300mg, 0.82mmol) in DCM (4mL), slowly add 1mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL×3 ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 150 mg of a yellow oil with a yield of 71.36%.
步骤3：III-10的合成Step 3: Synthesis of III-10
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为III-10-2，同法制得化合物III-10，得白色固体72mg，产率为33.44％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by III-10-2, compound III-10 was obtained in the same way to obtain 72 mg of 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] + .
实施例40Example 40
Figure PCTCN2022110325-appb-000076
Figure PCTCN2022110325-appb-000076
步骤1：III-11-1的合成Step 1: Synthesis of III-11-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为S6和4-氰基苯硼酸频哪醇酯，同法制得化合物III-11-1，得浅黄色固体280mg，产率87.15％。 1H 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] +. Referring to the synthesis method in step 1 of Example 30, the difference is that in step 1, S5 and 4-fluorophenylboronic acid pinacol ester are replaced by S6 and 4-cyanophenylboronic acid pinacol ester, and compound III-11 is prepared in the same way -1, 280 mg of a light yellow solid was obtained, and the yield was 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] + .
步骤2：Ⅲ-11-2的合成Step 2: Synthesis of Ⅲ-11-2
将III-11-1(200mg,0.60mmol)溶于DCM(4mL)中，缓慢滴加TFA 1.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色油状物112mg，产率79.83％。Dissolve III-11-1 (200mg, 0.60mmol) in DCM (4mL), slowly add 1.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 112 mg of yellow oil with a yield of 79.83%.
步骤3：III-11的合成Step 3: Synthesis of III-11
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为III-11-2，同法制得化合物III-11，得淡黄色固体66mg，产率为30.72％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced by III-11-2, and compound III-11 was obtained in the same way to obtain 66 mg of light 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] + .
实施例41Example 41
Figure PCTCN2022110325-appb-000077
Figure PCTCN2022110325-appb-000077
步骤1：III-12-1的合成Step 1: Synthesis of III-12-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5替换为S6同法制得化合物III-12-1，得淡黄色固体210mg，产率71.00％。 1H 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] +. Referring to the synthesis method in Step 1 of Example 30, except that S5 in Step 1 was replaced by S6, Compound III-12-1 was obtained in the same way to obtain 210 mg of light yellow solid with a yield of 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] + .
步骤2：III-12-2的合成Step 2: Synthesis of III-12-2
将III-12-1(250mg,0.75mmol)溶于DCM(4mL)中，缓慢滴加TFA 1.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色油状物100mg，产率71.93％。Dissolve III-12-1 (250mg, 0.75mmol) in DCM (4mL), slowly add 1.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of yellow oil with a yield of 71.93%.
步骤3：III-12的合成Step 3: Synthesis of III-12
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为III-12-2，同法制得化合物III-12，得淡黄色固体93mg，产率为42.59％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced by III-12-2, and compound III-12 was obtained in the same way to obtain 93 mg of a light 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] + .
实施例42Example 42
Figure PCTCN2022110325-appb-000078
Figure PCTCN2022110325-appb-000078
步骤1：III-13-1的合成Step 1: Synthesis of III-13-1
在一个带支口的封管中，依次加入S5(399.01mg,1.28mmol)，4-氟-1H-吡唑(100mg,1.16mmol)，Cu 2O(16.63mg,0.12mmol)和Cs 2CO 3(378.55mg,1.16mmol)。加入5mL无水DMF，氮气保护，100℃下反应16小时。TLC监测反应完全后，加水淬灭反应，乙酸乙酯(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得残余物通过硅胶柱色谱法(二氯甲烷：三乙胺＝500:1)分离，得黄色油状物200mg，产率54.24％。 1H 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] +. In a branched sealed tube, add S5 (399.01 mg, 1.28 mmol), 4-fluoro-1H-pyrazole (100 mg, 1.16 mmol), Cu 2 O (16.63 mg, 0.12 mmol) and Cs 2 CO 3 (378.55 mg, 1.16 mmol). Add 5 mL of anhydrous DMF, under nitrogen protection, and react at 100°C for 16 hours. After TLC monitors that the reaction is complete, add water to quench the reaction, extract with ethyl acetate (5mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate, and the resulting residue is subjected to silica gel column chromatography (dichloromethane: triethyl ether). Amine=500:1) separation to obtain 200 mg of yellow oil, yield 54.24%. 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] + .
步骤2：Ⅲ-13-2的合成Step 2: Synthesis of Ⅲ-13-2
将III-13-1(200mg,0.63mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色油状物100mg，产率73.04％。Dissolve III-13-1 (200mg, 0.63mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of yellow oil with a yield of 73.04%.
步骤3：III-13的合成Step 3: Synthesis of III-13
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为III-13-2，同法制得化合物Ⅲ-13，得淡黄色固体50mg，产率为22.28％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced by III-13-2, and compound III-13 was obtained in the same way to obtain 50 mg of a light yellow solid with 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] + .
实施例43Example 43
Figure PCTCN2022110325-appb-000079
Figure PCTCN2022110325-appb-000079
参考实施例30步骤3的合成方法，不同的是将步骤3中的S2替换S4，同法制得化合物III-14，得白色固体90mg，产率为41.04％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 30, except that S2 in Step 3 was replaced by S4, Compound III-14 was obtained in the same way to obtain 90 mg of white solid with 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] + .
实施例44Example 44
Figure PCTCN2022110325-appb-000080
Figure PCTCN2022110325-appb-000080
步骤1：V-1-1的合成Step 1: Synthesis of V-1-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为对溴氟苯和4-(4-叔丁氧羰基-1-哌嗪基)苯硼酸频哪醇酯，同法制得化合物V-1-1，得白色固体523mg，产率69.46％。 1H 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] +. Referring to the synthetic method of step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by p-bromofluorobenzene and 4-(4-tert-butoxycarbonyl-1-piperazinyl ) phenylboronic acid pinacol ester, compound V-1-1 was obtained by the same method, and 523 mg of white solid was obtained, and the yield was 69.46%. 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] + .
步骤2：Ⅴ-1-2的合成Step 2: Synthesis of Ⅴ-1-2
将V-1-1(300mg,0.84mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1 h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得白色固体182mg，产率84.32％。Dissolve V-1-1 (300mg, 0.84mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1 h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL ×3) extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 182 mg of white solid with a yield of 84.32%.
步骤3：V-1的合成Step 3: Synthesis of V-1
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-1-2，同法制得化合物V-1，得白色固体87mg，产率为42.37％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by V-1-2, compound V-1 was obtained in the same way to obtain 87 mg of 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] + .
实施例45Example 45
Figure PCTCN2022110325-appb-000081
Figure PCTCN2022110325-appb-000081
步骤1：V-2-1的合成Step 1: Synthesis of V-2-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为1-叔丁氧羰基-4-(4-溴苯基)哌嗪和4-氰基苯硼酸频哪醇酯，同法制得化合物V-2-1，得黄色固体319mg，产率73.75％。 1H 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] +. Referring to the synthetic method of step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 4 -Pinacol cyanophenylboronic acid ester, compound V-2-1 was prepared in the same way to obtain 319 mg of yellow solid, and the yield was 73.75%. 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] + .
步骤2：V-2-2的合成Step 2: Synthesis of V-2-2
将V-2-1(210mg,0.58mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体150mg，产率98.21％。Dissolve V-2-1 (210mg, 0.58mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 150 mg of yellow solid with a yield of 98.21%.
步骤3：V-2的合成Step 3: Synthesis of V-2
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-2-2，同法制得化合物V-2，得黄色固体122mg，产率为40.11％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by V-2-2, compound V-2 was obtained in the same way to obtain 122 mg 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] + .
实施例46Example 46
Figure PCTCN2022110325-appb-000082
Figure PCTCN2022110325-appb-000082
步骤1：V-3-1的合成Step 1: Synthesis of V-3-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为1-叔丁氧羰基-4-(4-溴苯基)哌嗪和4-吡啶硼酸频哪醇酯，同法制得化合物V-3-1，得黄色固体279.86mg，产率56.47％。 1H 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] +. Referring to the synthetic method of step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 4 - Pyridineboronic acid pinacol ester, compound V-3-1 was obtained by the same method, and 279.86 mg of yellow solid was obtained, 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] + .
步骤2：V-3-2的合成Step 2: Synthesis of V-3-2
将V-3-1(254mg,0.75mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体134mg，产率74.66％。Dissolve V-3-1 (254mg, 0.75mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 134 mg of yellow solid with a yield of 74.66%.
步骤3：V-3的合成Step 3: Synthesis of V-3
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-3-2，同法制得化合物V-3，得黄色固体89mg，产率为31.19％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by V-3-2, compound V-3 was obtained in the same way to obtain 89 mg 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] + .
实施例47Example 47
Figure PCTCN2022110325-appb-000083
Figure PCTCN2022110325-appb-000083
步骤1：V-4-1的合成Step 1: Synthesis of V-4-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为1-叔丁氧羰基-4-(4-溴苯基)哌嗪和3-氟-4-氰基苯硼酸频哪醇酯，同法制得化合物V-4-1，得黄色固体145mg，产率18.54％。 1H 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] +. Referring to the synthetic method of step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 3 -Fluoro-4-cyanophenylboronic acid pinacol ester, compound V-4-1 was obtained by the same method, and 145 mg of yellow solid was obtained, 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[MH] + .
步骤2：V-4-2的合成Step 2: Synthesis of V-4-2
将V-4-1(145mg,0.38mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体100mg，产率97.36％。Dissolve V-4-1 (145mg, 0.38mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of yellow solid with a yield of 97.36%.
步骤3：V-4的合成Step 3: Synthesis of V-4
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-4-2，同法制得化合物V-4，得白色固体82mg，产率为40.18％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by V-4-2, compound V-4 was obtained in the same way to obtain 82 mg of 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] + .
实施例48Example 48
Figure PCTCN2022110325-appb-000084
Figure PCTCN2022110325-appb-000084
步骤1：V-5-1的合成Step 1: Synthesis of V-5-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为1-叔丁氧羰基-4-(4-溴苯基)哌嗪和2-氰基苯硼酸频哪醇酯，同法制得化合物V-5-1，得黄色固体370mg，产率69.53％。 1H 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] +. Referring to the synthetic method of step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 2 -Pinacol cyanophenylboronic acid ester, compound V-5-1 was obtained by the same method, and 370 mg of yellow solid was obtained, and the yield was 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] + .
步骤2：V-5-2的合成Step 2: Synthesis of V-5-2
将V-5-1(370mg,1.02mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体260mg，产率96.79％。Dissolve V-5-1 (370mg, 1.02mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 260 mg of yellow solid with a yield of 96.79%.
步骤3：V-5的合成Step 3: Synthesis of V-5
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-5-2，同法制得化合物Ⅴ-5，得白色固体252mg，产率为47.71％。1H NMR(300MHz,Chloroform-d)δ9.46(s,1H),8.18(d,J＝2.1Hz,1H),7.97(dd,J＝8.5,2.2Hz,1H),7.82(d,J＝8.5Hz,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＝13.2Hz,1H),3.26(t,J＝5.0Hz,4H),2.76(q,J＝6.7Hz,4H),2.55(d,J＝13.2Hz,1H),1.48(s,3H).LC-MS(ESI)m/z:534[M+H] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by V-5-2, Compound V-5 was obtained in the same way to obtain 252 mg of white solid with a yield of 47.71%. 1H NMR (300MHz, Chloroform-d) δ9.46(s, 1H), 8.18(d, J=2.1Hz, 1H), 7.97(dd, J=8.5, 2.2Hz, 1H), 7.82(d, J= 8.5Hz, 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＝13.2Hz,1H),3.26(t,J＝5.0Hz,4H),2.76(q , J=6.7Hz, 4H), 2.55(d, J=13.2Hz, 1H), 1.48(s, 3H). LC-MS (ESI) m/z: 534[M+H] + .
实施例49Example 49
Figure PCTCN2022110325-appb-000085
Figure PCTCN2022110325-appb-000085
步骤1：V-6-1的合成Step 1: Synthesis of V-6-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为1-叔丁氧羰基-4-(4-溴苯基)哌嗪和3-氰基苯硼酸频哪醇酯，同法制得化合物V-6-1，得黄色固体319mg，产率60.11％。 1H 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] +. Referring to the synthetic method of step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 3 -Pinacol cyanophenylboronic acid ester, compound V-6-1 was obtained by the same method, and 319 mg of yellow solid was obtained, with a yield of 60.11%. 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] + .
步骤2：V-6-2的合成Step 2: Synthesis of V-6-2
将V-6-1(396mg,1.50mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体280mg，产率70.88％。Dissolve V-6-1 (396mg, 1.50mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 280 mg of yellow solid with a yield of 70.88%.
步骤3：V-6的合成Step 3: Synthesis of V-6
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-6-2，同法制得化合物V-6，得黄色固体303mg，产率为56.79％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by V-6-2, compound V-6 was obtained in the same way to obtain 303 mg of a 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] + .
实施例50Example 50
Figure PCTCN2022110325-appb-000086
Figure PCTCN2022110325-appb-000086
步骤1：V-7-1的合成Step 1: Synthesis of V-7-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为5-溴-2-氰基吡啶和4-(4-叔丁氧羰基-1-哌嗪基)苯硼酸频哪醇酯，同法制得化合物V-7-1，得黄色固体183mg，产率48.75％。 1H 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] +. Referring to the synthetic method of step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 5-bromo-2-cyanopyridine and 4-(4-tert-butoxycarbonyl- 1-Piperazinyl) phenylboronic acid pinacol ester was prepared in the same way as compound V-7-1 to obtain 183 mg of yellow solid with a yield of 48.75%. 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] + .
步骤2：V-7-2的合成Step 2: Synthesis of V-7-2
将V-7-1(183mg,0.50mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体132mg，产率99.87％。Dissolve V-7-1 (183mg, 0.50mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 132 mg of yellow solid with a yield of 99.87%.
步骤3：V-7的合成Step 3: Synthesis of V-7
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-7-2，同法制得化合物V-7，得白色固体80mg，产率为29.93％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by V-7-2, compound V-7 was obtained in the same way to obtain 80 mg of 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] + .
实施例51Example 51
Figure PCTCN2022110325-appb-000087
Figure PCTCN2022110325-appb-000087
步骤1：V-8-1的合成Step 1: Synthesis of V-8-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为1-叔丁氧羰基-4-(4-溴苯基)哌嗪和6-氟吡啶-3-硼酸频哪醇酯，同法制得化合物V-8-1，得黄色固体353mg，产率84.41％。 1H 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] +. Referring to the synthetic method of step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 6 - Fluoropyridine-3-boronic acid pinacol ester, compound V-8-1 was prepared in the same way to obtain 353 mg of yellow solid, with a yield of 84.41%. 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] + .
步骤2：V-8-2的合成Step 2: Synthesis of V-8-2
将V-8-1(353mg,0.99mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体250mg，产率98.14％。Dissolve V-8-1 (353mg, 0.99mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 250 mg of yellow solid with a yield of 98.14%.
步骤3：V-8的合成Step 3: Synthesis of the V-8
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-8-2，同法制得化合物V-8，得白色固体150mg，产率为29.31％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by V-8-2, compound V-8 was obtained in the same way to obtain 150 mg of 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] + .
实施例52Example 52
Figure PCTCN2022110325-appb-000088
Figure PCTCN2022110325-appb-000088
步骤1:V-9-1的合成Step 1: Synthesis of V-9-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为1-叔丁氧羰基-4-(4-溴苯基)哌嗪和3-氰基-4氟苯硼酸频哪醇酯，同法制得化合物V-9-1，得黄色固体400mg，产率71.82％。 1H 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] +. Referring to the synthetic method of step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 3 -Cyano-4-fluorophenylboronic acid pinacol ester, the compound V-9-1 was obtained by the same method, and 400 mg of yellow solid was obtained, and the yield was 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=8.7 Hz, 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, 3.9 Hz,4H),1.43(s,9H).LC-MS(ESI)m/z:382.15[M+H] + .
步骤2:V-9-2的合成Step 2: Synthesis of V-9-2
将V-9-1(400mg,1.05mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体292mg，产率98.85％。Dissolve V-9-1 (400mg, 1.05mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 292 mg of a yellow solid with a yield of 98.85%.
步骤3:V-9的合成Step 3: Synthesis of V-9
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-9-2，同法制得化合物V-9，得白色固体120mg，产率为21.12％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by V-9-2, compound V-9 was obtained in the same way to obtain 120 mg of 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] + .
实施例53Example 53
Figure PCTCN2022110325-appb-000089
Figure PCTCN2022110325-appb-000089
步骤1：V-10-1的合成Step 1: Synthesis of V-10-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为4-溴-2-(三氟甲基)苯甲腈和4-(4-叔丁氧羰基-1-哌嗪基)苯硼酸频哪醇酯，同法制得化合物V-10-1，得黄色固体250mg，产率44.91％。 1H 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] +. Referring to the synthetic method of Example 30 step 1, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 4-bromo-2-(trifluoromethyl)benzonitrile and 4-(4 - tert-butoxycarbonyl-1-piperazinyl) phenylboronic acid pinacol ester, compound V-10-1 was prepared in the same way to obtain 250 mg of a yellow solid, with a yield of 44.91%. 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] + .
步骤2：V-10-2的合成Step 2: Synthesis of V-10-2
将V-10-1(250mg,0.58mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体192mg，产率99.90％。Dissolve V-10-1 (250mg, 0.58mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 192 mg of yellow solid with a yield of 99.90%.
步骤3：V-10的合成Step 3: Synthesis of V-10
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-10-2，同法制得化合物V-10，得白色固体128mg，产率为36.69％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by V-10-2, compound V-10 was obtained in the same way to obtain 128 mg of 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] + .
实施例54Example 54
Figure PCTCN2022110325-appb-000090
Figure PCTCN2022110325-appb-000090
步骤1：V-20-1的合成Step 1: Synthesis of V-20-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为1-叔丁氧羰基-4-(4-溴苯基)哌嗪和嘧啶-5-硼酸嚬哪醇酯，同法制得化合物V-20-1，得黄色固体210mg，产率42.25％。 1H 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] +. Referring to the synthesis method of step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and pyrimidine - 5-Nacol boronic acid ester, compound V-20-1 was obtained by the same method, and 210 mg of yellow solid was obtained, and the yield was 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] + .
步骤2：V-20-2的合成Step 2: Synthesis of V-20-2
将V-20-1(250mg,0.73mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体140mg，产率79.81％。Dissolve V-20-1 (250mg, 0.73mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 140 mg of yellow solid with a yield of 79.81%.
步骤3：V-20的合成Step 3: Synthesis of V-20
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-20-2，得黄色固体212mg，产率为71.60％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by V-20-2, 212 mg of a yellow solid was obtained with a yield of 71.60%. 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] + .
实施例55Example 55
Figure PCTCN2022110325-appb-000091
Figure PCTCN2022110325-appb-000091
步骤1：V-11-1的合成Step 1: Synthesis of V-11-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为1-叔丁氧羰基-4-(4-溴苯基)哌嗪和4-三氟甲基苯硼酸嚬哪醇酯，同法制得化合物V-11-1，得白色固体145mg，产率40.58％。 1H 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] +. Referring to the synthetic method of step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 4 -Nacol trifluoromethyl phenyl borate, the compound V-11-1 was prepared in the same way to obtain 145 mg of white solid with a yield of 40.58%. 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] + .
步骤2：V-11-2的合成Step 2: Synthesis of V-11-2
将V-11-1(110mg,0.27mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得白色固体75mg，产率90.47％。Dissolve V-11-1 (110mg, 0.27mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 75 mg of white solid with a yield of 90.47%.
步骤3：V-11的合成Step 3: Synthesis of V-11
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-11-2，同法制得化合物V-11，得白色固体88mg，产率为66.80％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by V-11-2, compound V-11 was obtained in the same way to obtain 88 mg of 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] + .
实施例56Example 56
Figure PCTCN2022110325-appb-000092
Figure PCTCN2022110325-appb-000092
步骤1：V-12-1的合成Step 1: Synthesis of V-12-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为4-(4-叔丁氧羰基-1-哌嗪基)苯硼酸频哪醇酯和5-溴-3-(三氟甲基)-2-氰基吡啶，同法制得化合物V-12-1，得黄色固体290mg，产率84.16％。 1H 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] +. Referring to the synthesis method of step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 4-(4-tert-butoxycarbonyl-1-piperazinyl)phenylboronic acid pinacol ester Alcohol ester and 5-bromo-3-(trifluoromethyl)-2-cyanopyridine were prepared in the same way as compound V-12-1, and 290 mg of yellow solid was obtained 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] + .
步骤2：V-12-2的合成Step 2: Synthesis of V-12-2
将V-12-1(200mg,0.46mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体140mg，产率91.09％。Dissolve V-12-1 (200mg, 0.46mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 140 mg of yellow solid with a yield of 91.09%.
步骤3：V-12的合成Step 3: Synthesis of V-12
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-12-2，同法制得化合物V-12，得白色固体110mg，产率为55.92％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by V-12-2, compound V-12 was obtained in the same way to obtain 110 mg of 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] + .
实施例57Example 57
Figure PCTCN2022110325-appb-000093
Figure PCTCN2022110325-appb-000093
步骤1：IV-4-1的合成Step 1: Synthesis of IV-4-1
将对氟硝基苯(226μL,2.13mmol)和N,N’-二甲基乙二胺(458μL,4.25mmol)溶于6ml四氢呋喃中，滴加三乙胺(887μL,6.38mmol)，回流6小时。TLC监测反应完全后，冷却至室温，浓缩，所得残余物通过硅胶柱色谱法(二氯甲烷：甲醇＝20:1)分离，得IV-4-1，黄色固体300mg，产率为67.43％。 1H 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] +. Dissolve p-fluoronitrobenzene (226 μL, 2.13 mmol) and N,N’-dimethylethylenediamine (458 μL, 4.25 mmol) in 6 ml of tetrahydrofuran, add triethylamine (887 μL, 6.38 mmol) dropwise, and reflux for 6 Hour. After the completion of the reaction as monitored by TLC, it was cooled to room temperature and concentrated. The resulting residue was separated by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain IV-4-1, 300 mg of yellow solid, with a yield of 67.43%. 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] + .
步骤2：IV-4的合成Step 2: Synthesis of IV-4
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为IV-4-1，同法制得化合物IV-4，得黄色固体87mg，产率为37.97％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by IV-4-1, compound IV-4 was obtained in the same way to obtain 87 mg of a yellow solid 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 ] + .
实施例58Example 58
Figure PCTCN2022110325-appb-000094
Figure PCTCN2022110325-appb-000094
步骤1：V-13-1的合成Step 1: Synthesis of V-13-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换 为1-叔丁氧羰基-4-(4-溴苯基)哌嗪和2-氟吡啶-4-硼酸频哪醇酯，同法制得化合物V-13-1，得白色固体230mg，产率73.20％。 1H 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] +. Referring to the synthetic method of step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 1-tert-butoxycarbonyl-4-(4-bromophenyl)piperazine and 2 -Fluoropyridine-4-boronic acid pinacol ester, compound V-13-1 was prepared in the same way, and 230 mg of white solid was obtained, with a yield of 73.20%. 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] + .
步骤2：V-13-2的合成Step 2: Synthesis of V-13-2
将V-13-1(180mg,0.50mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体100mg，产率77.17％。Dissolve V-13-1 (180mg, 0.50mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of yellow solid with a yield of 77.17%.
步骤3：V-12的合成Step 3: Synthesis of V-12
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-13-2，同法制得化合物V-13，得淡黄色固体70mg，产率为34.14％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced by V-13-2, and compound V-13 was obtained in the same way to obtain 70 mg of a light 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] + .
实施例59Example 59
Figure PCTCN2022110325-appb-000095
Figure PCTCN2022110325-appb-000095
步骤1：V-14-1的合成Step 1: Synthesis of V-14-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为4-(4-叔丁氧羰基-1-哌嗪基)苯硼酸频哪醇酯和4-溴吡啶-2-甲腈，同法制得化合物V-14-1，得黄色固体250mg，产率83.69％。 1H 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] +. Referring to the synthesis method of step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 4-(4-tert-butoxycarbonyl-1-piperazinyl)phenylboronic acid pinacol ester Alcohol ester and 4-bromopyridine-2-carbonitrile were used to obtain compound V-14-1 in the same way to obtain 250 mg of yellow solid with a yield of 83.69%. 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] + .
步骤2：V-14-2的合成Step 2: Synthesis of V-14-2
将V-14-1(200mg,0.55mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体110mg，产率75.83％。Dissolve V-14-1 (200mg, 0.55mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 110 mg of yellow solid with a yield of 75.83%.
步骤3：V-14的合成Step 3: Synthesis of V-14
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-14-2，同法制得化合物V-14，得黄色固体70mg，产率为34.62％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by V-14-2, compound V-14 was obtained in the same way to obtain 70 mg 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] + .
实施例60Example 60
Figure PCTCN2022110325-appb-000096
Figure PCTCN2022110325-appb-000096
步骤1：V-15-1的合成Step 1: Synthesis of V-15-1
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为4-(4-叔丁氧羰基-1-哌嗪基)苯硼酸频哪醇酯和5-溴-2-硝基三氟甲苯，同法制得化合物V-15-1，得黄色固体300mg，产率75.51％。 1H 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] +. Referring to the synthesis method of step 1 of Example 30, the difference is that S5 and 4-fluorophenylboronic acid pinacol ester in step 1 are replaced by 4-(4-tert-butoxycarbonyl-1-piperazinyl)phenylboronic acid pinacol ester Alcohol ester and 5-bromo-2-nitrobenzotrifluoride were used to obtain compound V-15-1 in the same way to obtain 300 mg of yellow solid with a yield of 75.51%. 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] + .
步骤2：V-15-2的合成Step 2: Synthesis of V-15-2
将V-15-1(300mg,0.66mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体200mg，产率86.25％。Dissolve V-15-1 (300mg, 0.66mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 200 mg of yellow solid with a yield of 86.25%.
步骤3：V-15的合成Step 3: Synthesis of V-15
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-15-2，同法制得化合物V-15，得黄色固体189mg，产率为53.88％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by V-15-2, compound V-15 was obtained in the same way to obtain 189 mg of a 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] + .
实施例61Example 61
Figure PCTCN2022110325-appb-000097
Figure PCTCN2022110325-appb-000097
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2和S2替换为V-1-2和S4，同法制得化合物V-16，得白色固体243mg，产率为88.91％。 1H 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] +. Referring to the synthesis method in step 3 of Example 1, the difference is that I-1-2 and S2 in step 3 were replaced by V-1-2 and S4, and compound V-16 was obtained in the same way to obtain 243 mg of a white solid with a yield of was 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] + .
实施例62Example 62
Figure PCTCN2022110325-appb-000098
Figure PCTCN2022110325-appb-000098
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2和S2替换为V-2-2和S4，同法制得化合物V-17，得黄色固体125mg，产率为42.52％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 and S2 in Step 3 were replaced by V-2-2 and S4, and compound V-17 was obtained in the same way to obtain 125 mg of a yellow solid with a yield of was 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=8.5 Hz,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] + .
实施例63Example 63
Figure PCTCN2022110325-appb-000099
Figure PCTCN2022110325-appb-000099
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2和S2替换为V-2-2和S9，同法制得化合物V-18，得黄色固体125mg，产率为42.52％。 1H 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] +. Referring to the synthesis method in step 3 of Example 1, the difference is that I-1-2 and S2 in step 3 were replaced by V-2-2 and S9, and compound V-18 was obtained in the same way to obtain 125 mg of a yellow solid with a yield of was 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=8.5 Hz,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] + .
实施例64Example 64
Figure PCTCN2022110325-appb-000100
Figure PCTCN2022110325-appb-000100
步骤1：V-19-1的合成Step 1: Synthesis of V-19-1
参考实施例22步骤1的合成方法，不同的是将步骤1中4-溴苯甲腈和(S)-1-N-叔丁氧羰基-2-甲基哌嗪替换为4-溴-4-氰基联苯和3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯，同法制得化合物V-19-1，得黄色固体300mg，产率75.51％。 1H 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] +. Referring to the synthesis method of step 1 of Example 22, the difference is that 4-bromobenzonitrile and (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 are replaced by 4-bromo-4 -Cyanobiphenyl and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate were prepared in the same way as compound V-19-1 to obtain 300 mg of a yellow solid with a yield of 75.51%. 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] + .
步骤2：V-19-2的合成Step 2: Synthesis of V-19-2
将V-19-1(300mg,0.66mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体200mg，产率86.25％。Dissolve V-19-1 (300mg, 0.66mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 200 mg of yellow solid with a yield of 86.25%.
步骤3：V-19的合成Step 3: Synthesis of V-19
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为V-19-2，同法制得化合物V-19，得黄色固体189mg，产率为53.88％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by V-19-2, compound V-19 was obtained in the same way to obtain 189 mg of a 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] + .
实施例65Example 65
Figure PCTCN2022110325-appb-000101
Figure PCTCN2022110325-appb-000101
步骤1：II-27-1的合成Step 1: Synthesis of II-27-1
参考实施例22步骤1的合成方法，不同的是将步骤1中(S)-1-N-叔丁氧羰基-2-甲基哌嗪替换为8-叔丁氧羰基-3,8-二氮杂双环[3.2.1]辛烷，同法制得化合物II-27-1，得黄色固体320mg，产率86.53％。 1H 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] +. Referring to the synthesis method of step 1 of Example 22, the difference is that (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 is replaced by 8-tert-butoxycarbonyl-3,8-di Azabicyclo[3.2.1]octane, compound II-27-1 was obtained by the same method to obtain 320 mg of a yellow solid with a yield of 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] + .
步骤2：II-27-2的合成Step 2: Synthesis of II-27-2
将II-27-1(320mg,1.02mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体200mg，产率92.16％。Dissolve II-27-1 (320mg, 1.02mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 200 mg of yellow solid with a yield of 92.16%.
步骤3：II-27的合成Step 3: Synthesis of II-27
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-27-2，同法制得化合物II-27，得黄色固体144mg，产率为31.76％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-27-2, compound II-27 was obtained in the same way to obtain 144 mg 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] + .
实施例66Example 66
Figure PCTCN2022110325-appb-000102
Figure PCTCN2022110325-appb-000102
步骤1：II-28-1的合成Step 1: Synthesis of II-28-1
参考实施例11步骤1的合成方法，不同的是将步骤1中1,4-二氮杂环庚烷-1-甲酸叔丁酯替换为6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷，同法制得化合物II-28-1，得黄色固体240mg，产率48.55％。 1H 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] +. Referring to the synthesis method of step 1 of Example 11, the difference is that tert-butyl 1,4-diazepane-1-carboxylate in step 1 is replaced by 6-(tert-butoxycarbonyl)-3,6-di Azabicyclo[3.1.1]heptane, compound II-28-1 was obtained by the same method, and 240 mg of a yellow solid was obtained, with a yield of 48.55%. 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[MH] + .
步骤2：II-28-2的合成Step 2: Synthesis of II-28-2
将II-28-1(200mg,0.67mmol)溶于DCM(3mL)中，缓慢滴加TFA 1mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得油状物110mg，产率82.63％。Dissolve II-28-1 (200mg, 0.67mmol) in DCM (3mL), slowly add 1mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL×3 ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 110 mg of oil, with a yield of 82.63%.
步骤3：II-28的合成Step 3: Synthesis of II-28
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-28-2，同法制得化合物II-28，得白色固体110mg，产率为42.44％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-28-2, compound II-28 was obtained in the same way to obtain 110 mg of 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] + .
实施例67Example 67
Figure PCTCN2022110325-appb-000103
Figure PCTCN2022110325-appb-000103
步骤1：II-29-1的合成Step 1: Synthesis of II-29-1
在一个单口瓶中，依次加入4-(4-羧基苯基)哌嗪-1-羧酸叔丁酯(200.00mg,0.65mmol)，甲氨盐酸盐(52.89mg,0.78mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(187.72mg，0.98mmol)，1-羟基苯并***(132.32mg,0.98mmol)和N-甲基吗啉(0.34ml,0.003mmol)。加入1.2mL N,N-二甲基甲酰胺，室温反应2小时。TLC监测反应完全后，冷却至室温，加水淬灭反应，乙酸乙酯(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得残余物通过硅胶柱色谱法(石油醚：乙酸乙酯＝1:1)分离，得白色固体190mg，产率91.12％。 1H 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] +. In a single-necked bottle, add tert-butyl 4-(4-carboxyphenyl)piperazine-1-carboxylate (200.00mg, 0.65mmol), methylamine hydrochloride (52.89mg, 0.78mmol), 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (187.72mg, 0.98mmol), 1-hydroxybenzotriazole (132.32mg, 0.98mmol) and N-methylmorpholine (0.34ml, 0.003mmol). Add 1.2mL N,N-dimethylformamide and react at room temperature for 2 hours. After TLC monitors that the reaction is complete, cool to room temperature, add water to quench the reaction, extract with ethyl acetate (5mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and the resulting residue is purified by silica gel column chromatography (petroleum ether : ethyl acetate=1:1) separation to obtain 190 mg of white solid, yield 91.12%. 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] + .
步骤2：II-29-2的合成Step 2: Synthesis of II-29-2
将II-29-1(190mg,0.59mmol)溶于DCM(3mL)中，缓慢滴加TFA 1mL，室温下反应4h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得白色固体110mg，产率84.33％。Dissolve II-29-1 (190mg, 0.59mmol) in DCM (3mL), slowly add 1mL of TFA dropwise, react at room temperature for 4h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL×3 ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 110 mg of a white solid with a yield of 84.33%.
步骤3：II-29的合成Step 3: Synthesis of II-29
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-29-2，同法制得化合物II-29，得白色固体130mg，产率为60.72％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-29-2, Compound II-29 was obtained in the same way to obtain 130 mg of 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[MH] + .
实施例68Example 68
Figure PCTCN2022110325-appb-000104
Figure PCTCN2022110325-appb-000104
步骤1：II-30-1的合成Step 1: Synthesis of II-30-1
参考实施例22步骤1的合成方法，不同的是将步骤1中(S)-1-N-叔丁氧羰基-2-甲基哌嗪替换为3,6-二氮杂双环[3.1.1]庚烷-3-羧酸叔丁酯，同法制得化合物II-30-1，得淡黄色固体280mg，产率75.52％。 1H 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] +. Referring to the synthesis method of step 1 of Example 22, the difference is that (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 is replaced by 3,6-diazabicyclo[3.1.1 ] Heptane-3-carboxylic acid tert-butyl ester, the compound II-30-1 was obtained by the same method, and 280 mg of light yellow solid was obtained, and the yield was 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] + .
步骤2：II-30-2的合成Step 2: Synthesis of II-30-2
将II-30-1(200mg,0.67mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体115mg，产率86.39％。Dissolve II-30-1 (200mg, 0.67mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 115 mg of yellow solid with a yield of 86.39%.
步骤3：II-30的合成Step 3: Synthesis of II-30
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-30-2，同法制得化合物II-30，得白色固体55mg，产率为58.36％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-30-2, compound II-30 was obtained in the same way to obtain 55 mg of 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] + .
实施例69Example 69
Figure PCTCN2022110325-appb-000105
Figure PCTCN2022110325-appb-000105
步骤1：II-31-1的合成Step 1: Synthesis of II-31-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶替换为4-(溴甲基)苯甲腈，同法制得化合物II-31-1，得白色固体714mg，产率92.89％。 1H 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] +. Referring to the synthesis method of step 1 of Example 4, the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 4-(bromomethyl)benzonitrile, and compound II-31-1 is obtained in the same way as White solid 714mg, yield 92.89%. 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[MH] + .
步骤2：II-31-2的合成Step 2: Synthesis of II-31-2
将II-31-1(250mg,0.83mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体150mg，产率89.85％。Dissolve II-31-1 (250mg, 0.83mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 150 mg of yellow solid with a yield of 89.85%.
步骤3：II-31的合成Step 3: Synthesis of II-31
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-31-2，同法制得化合物II-31，得白色固体250mg，产率为82.09％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-31-2, compound II-31 was obtained in the same way to obtain 250 mg of 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] + .
实施例70Example 70
Figure PCTCN2022110325-appb-000106
Figure PCTCN2022110325-appb-000106
步骤1：II-32-1的合成Step 1: Synthesis of II-32-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶替换为4-氟-2-甲基苯甲腈，同法制得化合物II-32-1，得白色固体400mg，产率35.87％。 1H 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] +. Referring to the synthesis method in step 1 of Example 4, the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 4-fluoro-2-methylbenzonitrile, and compound II-32-1 is prepared in the same way, 400 mg of white solid was obtained with a yield of 35.87%. 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] + .
步骤2：II-32-2的合成Step 2: Synthesis of II-32-2
将II-32-1(200mg,0.66mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体100mg，产率74.87％。Dissolve II-32-1 (200mg, 0.66mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 100 mg of a yellow solid with a yield of 74.87%.
步骤3：II-32的合成Step 3: Synthesis of II-32
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-32-2，同法制得化合物II-32，得淡黄色固体200mg，产率为85.38％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced by II-32-2, and compound II-32 was obtained in the same way to obtain 200 mg of a light 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] + .
实施例71Example 71
Figure PCTCN2022110325-appb-000107
Figure PCTCN2022110325-appb-000107
步骤1：II-33-1的合成Step 1: Synthesis of II-33-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶和1-(叔丁氧羰基)哌嗪替换为4-(溴甲基)苯甲腈和3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯，同法制得化合物II-33-1，得白色固体240mg，产率71.85％。 1H 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] +. Referring to the synthetic method of Example 4 step 1, the difference is that 2-cyano-5-fluoropyridine and 1-(tert-butoxycarbonyl) piperazine in step 1 are replaced by 4-(bromomethyl) benzonitrile and 3,8-Diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester was prepared in the same way as compound II-33-1 to obtain 240 mg of white solid with a yield of 71.85%. 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] + .
步骤2：II-33-2的合成Step 2: Synthesis of II-33-2
将II-33-1(195mg,0.60mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体112mg，产率82.73％。Dissolve II-33-1 (195mg, 0.60mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 112 mg of yellow solid with a yield of 82.73%.
步骤3：II-33的合成Step 3: Synthesis of II-33
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-33-2，同法制得化合物II-33，得白色固体175mg，产率为79.96％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-33-2, compound II-33 was obtained in the same way to obtain 175 mg of 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] + .
实施例72Example 72
Figure PCTCN2022110325-appb-000108
Figure PCTCN2022110325-appb-000108
步骤1：II-34-1的合成Step 1: Synthesis of II-34-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶替换为2-溴-4-氟苯甲腈，同法制得化合物II-34-1，得黄色固体200mg，产率72.81％。 1H 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] +. Referring to the synthesis method of step 1 of Example 4, the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 2-bromo-4-fluorobenzonitrile, and compound II-34-1 is obtained in the same way as Yellow solid 200 mg, 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] + .
步骤2：II-34-2的合成Step 2: Synthesis of II-34-2
参考实施例30步骤1的合成方法，不同的是将步骤1中S5和4-氟苯硼酸频哪醇酯替换为II-34-1和苯硼酸频哪醇酯，同法制得化合物II-34-2，得黄色固体150mg，产率75.58％。 1H 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] +. Referring to the synthesis method of step 1 of Example 30, the difference is that in step 1, S5 and 4-fluorophenylboronic acid pinacol ester are replaced by II-34-1 and phenylboronic acid pinacol ester, and compound II-34 is prepared in the same way -2, 150 mg of a yellow solid was obtained, and the yield was 75.58%. 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[MH] + .
步骤3：II-34-3的合成Step 3: Synthesis of II-34-3
将II-34-2(150mg,0.41mmol)溶于DCM(4mL)中，缓慢滴加TFA 1mL，室温下反应4h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色油状物60mg，产率55.21％。Dissolve II-34-2 (150mg, 0.41mmol) in DCM (4mL), slowly add 1mL of TFA dropwise, react at room temperature for 4h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL×3 ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 60 mg of a yellow oil with a yield of 55.21%.
步骤4：II-34的合成Step 4: Synthesis of II-34
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-34-3，同法制得化合物II-34，得白色固体90mg，产率为74.03％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-34-3, compound II-34 was obtained in the same way to obtain 90 mg of 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[MH] + .
实施例73Example 73
Figure PCTCN2022110325-appb-000109
Figure PCTCN2022110325-appb-000109
步骤1：II-35-1的合成Step 1: Synthesis of II-35-1
参考实施例25步骤1的合成方法，不同的是将步骤1中4-溴苯甲腈和(1S,4S)-(-)-2-叔丁氧羰基-2,5-二氮双环[2.2.1]庚烷替换为4-溴-2-甲氧基苯甲腈和1-叔丁氧羰基哌嗪，同法制得化合物II-35-1，得白色固体342mg，产率91.39％。 1H 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] +. Referring to the synthesis method of step 1 of Example 25, the difference is that 4-bromobenzonitrile and (1S,4S)-(-)-2-tert-butoxycarbonyl-2,5-diazabicyclo[2.2 .1] Heptane was replaced by 4-bromo-2-methoxybenzonitrile and 1-tert-butoxycarbonylpiperazine, and compound II-35-1 was obtained in the same way to obtain 342 mg of white solid with a yield of 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] + .
步骤2：II-35-2的合成Step 2: Synthesis of II-35-2
将II-35-1(342mg,1.08mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有 机相，无水硫酸钠干燥，过滤，浓缩，得白色固体130mg，产率55.40％。Dissolve II-35-1 (342mg, 1.08mmol) in DCM (2mL), slowly add 0.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 130 mg of white solid with a yield of 55.40%.
步骤3：II-35的合成Step 3: Synthesis of II-35
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-35-2，同法制得化合物II-35，得白色固体72mg，产率为25.62％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-35-2, compound II-35 was obtained in the same way to obtain 72 mg 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] + .
实施例74Example 74
Figure PCTCN2022110325-appb-000110
Figure PCTCN2022110325-appb-000110
步骤1：II-36-1的合成Step 1: Synthesis of II-36-1
将II-34-1(200mg,0.55mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得淡黄色固体107mg，产率73.63％。Dissolve II-34-1 (200mg, 0.55mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 107 mg of light yellow solid with a yield of 73.63%.
步骤3：II-36的合成Step 3: Synthesis of II-36
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-36-1，同法制得化合物II-36，得白色固体152mg，产率为75.42％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-36-1, compound II-36 was obtained in the same way to obtain 152 mg of 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] + .
实施例75Example 75
Figure PCTCN2022110325-appb-000111
Figure PCTCN2022110325-appb-000111
步骤1：II-37-1的合成Step 1: Synthesis of II-37-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶替换为5-溴-2-氰基嘧啶，同法制得化合物II-37-1，得黄色固体700mg，产率89.03％。 1H 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] +. Referring to the synthesis method in step 1 of Example 4, the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 5-bromo-2-cyanopyrimidine, and compound II-37-1 is obtained in the same way as yellow Solid 700 mg, yield 89.03%. 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] + .
步骤2：II-37-2的合成Step 2: Synthesis of II-37-2
将II-37-1(250mg,0.86mmol)溶于DCM(3mL)中，缓慢滴加TFA 1mL，室温下反应 0.5h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得淡黄色固体130mg，产率79.51％。Dissolve II-37-1 (250mg, 0.86mmol) in DCM (3mL), slowly add 1mL of TFA dropwise, react at room temperature for 0.5h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 130 mg of light yellow solid with a yield of 79.51%.
步骤4：II-37的合成Step 4: Synthesis of II-37
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-37-2，同法制得化合物II-37，得白色固体40mg，产率为32.95％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-37-2, compound II-37 was obtained in the same way to obtain 40 mg of 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] + .
实施例76Example 76
Figure PCTCN2022110325-appb-000112
Figure PCTCN2022110325-appb-000112
步骤1：II-38-1的合成Step 1: Synthesis of II-38-1
在一个圆底烧瓶中，依次加入6-氟烟腈(200mg,1.64mmol)，3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯(417.28mg,1.97mmol)和K 2CO 3(452.75mg,3.28mmol)。然后加入6mL DMF，80℃下反应4小时。TLC监测反应完全后，冷却至室温，加入20mL水，搅拌析出固体，减压抽滤，得白色固体480mg，产率93.21％。 1H 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] +. In a round bottom flask, add 6-fluoronicotinonitrile (200mg, 1.64mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (417.28mg, 1.97mmol) and K 2 CO 3 (452.75 mg, 3.28 mmol). Then 6 mL of DMF was added and reacted at 80° C. for 4 hours. After the completion of the reaction as monitored by TLC, cool to room temperature, add 20 mL of water, stir to precipitate a solid, and filter under reduced pressure to obtain 480 mg of a white solid with a yield of 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=12.9 Hz,1H),2.15–2.00(m,2H),2.00–1.84(m,2H),1.50(s,9H).LC-MS(ESI)m/z:313.55[MH] + .
步骤2：II-38-2的合成Step 2: Synthesis of II-38-2
将II-38-1(280mg,0.89mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得白色固体160mg，产率83.84％。Dissolve II-38-1 (280mg, 0.89mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 160 mg of white solid with a yield of 83.84%.
步骤3：II-38的合成Step 3: Synthesis of II-38
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-38-2，同法制得化合物II-38，得白色固体170mg，产率为75.19％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-38-2, compound II-38 was obtained in the same way to obtain 170 mg of 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] + .
实施例77Example 77
Figure PCTCN2022110325-appb-000113
Figure PCTCN2022110325-appb-000113
步骤1：II-39-1的合成Step 1: Synthesis of II-39-1
参考实施例76步骤1的合成方法，不同的是将步骤1中6-氟烟腈替换为2-氯-5-氰基嘧啶，同法制得化合物II-39-1，得黄色固体280mg，产率61.94％。 1H 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] +. Referring to the synthesis method in Step 1 of Example 76, the difference is that 6-fluoronicotinonitrile in Step 1 was replaced by 2-chloro-5-cyanopyrimidine, and compound II-39-1 was obtained in the same way to obtain 280 mg of a yellow solid. The rate is 61.94%. 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=12.8 Hz, 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=16.3 Hz,2H),1.51(s,9H).LC-MS(ESI)m/z:316.90[M+H] + .
步骤2：II-39-2的合成Step 2: Synthesis of II-39-2
将II-39-1(200mg,0.63mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得淡黄色固体130mg，产率95.23％。Dissolve II-39-1 (200mg, 0.63mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 130 mg of light yellow solid with a yield of 95.23%.
步骤3：II-39的合成Step 3: Synthesis of II-39
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-39-2，同法制得化合物II-39，得白色固体107mg，产率为47.44％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-39-2, compound II-39 was obtained in the same way to obtain 107 mg of white solid with a yield of 47.44%. 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] + .
实施例78Example 78
Figure PCTCN2022110325-appb-000114
Figure PCTCN2022110325-appb-000114
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2和S2替换为II-5-2和S4，同法制得化合物II-40，得黄色固体100mg，产率为38.87％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 and S2 in Step 3 were replaced by II-5-2 and S4, and compound II-40 was obtained in the same way to obtain 100 mg of a yellow solid with a yield of was 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=8.5 Hz, 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=13.5 Hz, 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] + .
实施例79Example 79
Figure PCTCN2022110325-appb-000115
Figure PCTCN2022110325-appb-000115
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2和S2替换为II-5-2和S15，同法制得化合物II-41，得淡黄色固体172mg，产率为58.24％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 and S2 in Step 3 were replaced with II-5-2 and S15, and compound II-41 was obtained in the same way to obtain 172 mg of a light yellow solid, producing The rate is 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] + .
实施例80Example 80
Figure PCTCN2022110325-appb-000116
Figure PCTCN2022110325-appb-000116
步骤1：II-42-1的合成Step 1: Synthesis of II-42-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶替换为5-氰基-2-氟吡啶，同法制得化合物II-42-1，得白色固体210mg，产率88.92％。 1H 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] +. Referring to the synthesis method in step 1 of Example 4, the difference is that 2-cyano-5-fluoropyridine in step 1 is replaced by 5-cyano-2-fluoropyridine, and compound II-42-1 is obtained in the same way as white Solid 210 mg, yield 88.92%. 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 ] + .
步骤2:II-42-2的合成Step 2: Synthesis of II-42-2
将II-42-1(210mg,0.73mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应4h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色油状物120mg，产率87.54％。Dissolve II-42-1 (210mg, 0.73mmol) in DCM (3mL), slowly add TFA 0.8mL, react at room temperature for 4h, after TLC monitors the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 120 mg of yellow oil with a yield of 87.54%.
步骤2:II-42的合成Step 2: Synthesis of II-42
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-42-2，同法制得化合物II-42，得油状物150mg，产率为51.32％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-42-2, Compound II-42 was obtained in the same way to obtain 150 mg 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=8.5Hz,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] + .
实施例81Example 81
Figure PCTCN2022110325-appb-000117
Figure PCTCN2022110325-appb-000117
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为S11和II-5-2，同法制得化合物II-43，得黄色油状物120mg，产率为69.50％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced by S11 and II-5-2, and compound II-43 was obtained in the same way to obtain 120 mg of a yellow oily product. The rate is 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] + .
实施例82Example 82
Figure PCTCN2022110325-appb-000118
Figure PCTCN2022110325-appb-000118
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为S9和II-5-2，同法制得化合物II-44，得黄色固体110mg，产率为58.25％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced by S9 and II-5-2, and compound II-44 was obtained in the same way to obtain 110 mg of a yellow solid with a yield of was 58.25%. 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] + .
实施例83Example 83
Figure PCTCN2022110325-appb-000119
Figure PCTCN2022110325-appb-000119
步骤1：II-45-1的合成Step 1: Synthesis of II-45-1
参考实施例22步骤1的合成方法，不同的是将步骤1中4-溴苯甲腈和(S)-1-N-叔丁氧羰基-2-甲基哌嗪替换为4-溴-3-甲基苯甲腈和3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯，同法制得化合物II-45-1，得淡黄色固体260mg，产率77.84％。 1H 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] +. Referring to the synthesis method of step 1 of Example 22, the difference is that 4-bromobenzonitrile and (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 are replaced by 4-bromo-3 -Methylbenzonitrile and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate, the compound II-45-1 was prepared in the same way to obtain 260 mg of light yellow solid, yield 77.84% . 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] + .
步骤2：II-45-2的合成Step 2: Synthesis of II-45-2
将II-45-1(220mg,0.67mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得白色固体123mg，产率80.53％。Dissolve II-45-1 (220mg, 0.67mmol) in DCM (2mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 123 mg of white solid with a yield of 80.53%.
步骤2：II-45的合成Step 2: Synthesis of II-45
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-45-2，同法制得化合物II-45，得白色固体200mg，产率为91.38％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-45-2, compound II-45 was obtained in the same way to obtain 200 mg of 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] + .
实施例84Example 84
Figure PCTCN2022110325-appb-000120
Figure PCTCN2022110325-appb-000120
步骤1：II-46-1的合成Step 1: Synthesis of II-46-1
参考实施例22步骤1的合成方法，不同的是将步骤1中4-溴苯甲腈和(S)-1-N-叔丁氧羰基-2-甲基哌嗪替换为3-氟-4-溴苯甲腈和3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯，同法制得化合物II-46-1，得淡黄色固体217mg，产率43.66％。 1H 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] +. Referring to the synthesis method of step 1 of Example 22, the difference is that 4-bromobenzonitrile and (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 are replaced by 3-fluoro-4 -Bromobenzonitrile and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate were prepared in the same way as compound II-46-1 to obtain 217 mg of a light yellow solid with a yield of 43.66%. 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] + .
步骤2：II-46-2的合成Step 2: Synthesis of II-46-2
将II-46-1(200mg,0.60mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得白色固体70mg，产率50.15％。Dissolve II-46-1 (200mg, 0.60mmol) in DCM (2mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 70 mg of white solid with a yield of 50.15%.
步骤2：II-46的合成Step 2: Synthesis of II-46
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-46-2，同法制得化合物II-46，得白色固体112mg，产率为73.79％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-46-2, compound II-46 was obtained in the same way to obtain 112 mg of 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] + .
实施例85Example 85
Figure PCTCN2022110325-appb-000121
Figure PCTCN2022110325-appb-000121
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为S13和II-5-2，同法制得化合物II-47，得淡黄色固体117mg，产率为76.91％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced by S13 and II-5-2, and compound II-47 was obtained in the same way to obtain 117 mg of a light yellow solid, producing The rate is 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] + .
实施例86Example 86
Figure PCTCN2022110325-appb-000122
Figure PCTCN2022110325-appb-000122
将1-(4-溴苯基)哌嗪盐酸盐(115mg,0.41mmol)悬浮于饱和碳酸氢钠水溶液(5mL)中,室温搅拌10min，EA萃取，无水Na 2SO 4干燥，过滤，浓缩。固体用无水乙醇溶解，加入S2(111.94mg,0.41mmol),回流4h，TLC监测反应完全后，减压蒸干，所得残余物通过硅胶柱色谱法(二氯甲烷：甲醇＝100：1)分离，得白色固体204mg，产率为96.30％。 1H 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] +. Suspend 1-(4-bromophenyl)piperazine hydrochloride (115 mg, 0.41 mmol) in saturated aqueous sodium bicarbonate (5 mL), stir at room temperature for 10 min, extract with EA, dry over anhydrous Na 2 SO 4 , filter, concentrate. Dissolve the solid in absolute ethanol, add S2 (111.94mg, 0.41mmol), reflux for 4h, monitor the completion of the reaction by TLC, evaporate to dryness under reduced pressure, and pass the obtained residue through silica gel column chromatography (dichloromethane:methanol=100:1) After separation, 204 mg of white solid was obtained 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] + .
实施例87Example 87
Figure PCTCN2022110325-appb-000123
Figure PCTCN2022110325-appb-000123
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为1-(4-氯苯基)哌嗪，同法制得化合物II-49，得白色固体100mg，产率为57.71％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced by 1-(4-chlorophenyl)piperazine, and compound II-49 was obtained in the same way to obtain 100 mg of a white solid. The yield was 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] + .
实施例88Example 88
Figure PCTCN2022110325-appb-000124
Figure PCTCN2022110325-appb-000124
步骤1：II-50-1的合成Step 1: Synthesis of II-50-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶和1-(叔丁氧羰基)哌嗪替换为2-氰基-3,5-二氟吡啶和3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯，同法制得化合物II-50-1，得白色固体300mg，产率63.22％。 1H 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] +. Referring to the synthetic method of step 1 of Example 4, the difference is that 2-cyano-5-fluoropyridine and 1-(tert-butoxycarbonyl)piperazine in step 1 are replaced by 2-cyano-3,5-difluoro Pyridine and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate were prepared in the same way as compound II-50-1, and 300 mg of a white solid was obtained with a yield of 63.22%. 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=7.3 Hz,2H),2.03–1.87(m,2H),1.47(s,9H).LC-MS(ESI)m/z:333.10[M+H] + .
步骤2:II-50-2的合成Step 2: Synthesis of II-50-2
将II-50-1(250mg,0.83mmol)溶于DCM(4mL)中，缓慢滴加TFA 1mL，室温下反应4h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得白色固体150mg，产率85.86％。Dissolve II-50-1 (250mg, 0.83mmol) in DCM (4mL), slowly add 1mL of TFA dropwise, react at room temperature for 4h, after TLC monitors the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL×3 ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 150 mg of a white solid with a yield of 85.86%.
步骤3:II-50的合成Step 3: Synthesis of II-50
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-50-2，同法制得化合物II-50，得油状物230mg，产率为70.88％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-50-2, Compound II-50 was prepared in the same way to obtain 230 mg of oily substance 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[ MH] + .
实施例89Example 89
Figure PCTCN2022110325-appb-000125
Figure PCTCN2022110325-appb-000125
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为S4和II-30-2，同法制得化合物II-51，得淡黄色固体130mg，产率为68.83％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced by S4 and II-30-2, and compound II-51 was obtained in the same way to obtain 130 mg of a light yellow solid, producing The rate is 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=8.2 Hz,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] + .
实施例90Example 90
Figure PCTCN2022110325-appb-000126
Figure PCTCN2022110325-appb-000126
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为和S4和II-46-2，同法制得化合物II-52，得白色固体165mg，产率为75.94％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced with S4 and II-46-2, and compound II-52 was obtained in the same way to obtain 165 mg of a white solid. The rate is 75.94%. 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] + .
实施例91Example 91
Figure PCTCN2022110325-appb-000127
Figure PCTCN2022110325-appb-000127
步骤1：II-53-1的合成Step 1: Synthesis of II-53-1
参考实施例22步骤1的合成方法，不同的是将步骤1中4-溴苯甲腈和(S)-1-N-叔丁氧羰基-2-甲基哌嗪替换为4-溴-3-氟苯甲腈和3,6-二氮杂双环[3.1.1]庚烷-3-羧酸叔丁酯，同法制得化合物II-53-1，得淡黄色固体1.3g，产率54.14％。 1H 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] +. Referring to the synthesis method of step 1 of Example 22, the difference is that 4-bromobenzonitrile and (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 are replaced by 4-bromo-3 -Fluorobenzonitrile and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate, the compound II-53-1 was prepared in the same way to obtain 1.3 g of light 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] + .
步骤2：II-53-2的合成Step 2: Synthesis of II-53-2
将II-53-1(200mg,0.63mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得淡黄色固体100mg，产率73.04％。Dissolve II-53-1 (200mg, 0.63mmol) in DCM (2mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 100 mg of light yellow solid with a yield of 73.04%.
步骤2：II-53的合成Step 2: Synthesis of II-53
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为S15和II-53-2，同法制得化合物II-53，得白色固体113mg，产率为54.08％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced by S15 and II-53-2, and compound II-53 was obtained in the same way to obtain 113 mg of a white solid with a yield of was 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] + .
实施例92Example 92
Figure PCTCN2022110325-appb-000128
Figure PCTCN2022110325-appb-000128
步骤1：II-54-1的合成Step 1: Synthesis of II-54-1
参考实施例22步骤1的合成方法，不同的是将步骤1中4-溴苯甲腈和(S)-1-N-叔丁氧羰基-2-甲基哌嗪替换为3-甲氧基-4-溴苯甲腈和3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯，同法制得化合物II-54-1，得黄色固体340mg，产率83.97％。 1H 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] +. Referring to the synthesis method of step 1 of Example 22, the difference is that 4-bromobenzonitrile and (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 are replaced by 3-methoxy -4-Bromobenzonitrile and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate, the compound II-54-1 was prepared in the same way to obtain 340mg of yellow solid, yield 83.97% . 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] + .
步骤2：II-54-2的合成Step 2: Synthesis of II-54-2
将II-54-1(200mg,0.58mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体120mg，产率84.69％。Dissolve II-54-1 (200mg, 0.58mmol) in DCM (2mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 120 mg of yellow solid with a yield of 84.69%.
步骤3：II-54的合成Step 3: Synthesis of II-54
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-54-2，同法制得化合物II-54，得白色固体200mg，产率为78.97％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-54-2, compound II-54 was obtained in the same way to obtain 200 mg of 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] + .
实施例93Example 93
Figure PCTCN2022110325-appb-000129
Figure PCTCN2022110325-appb-000129
步骤1：II-55-1的合成Step 1: Synthesis of II-55-1
参考实施例22步骤1的合成方法，不同的是将步骤1中4-溴苯甲腈和(S)-1-N-叔丁氧羰基-2-甲基哌嗪替换为5-溴-2-氰基嘧啶和3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯，同法制得化合物II-55-1，得黄色固体274mg，产率79.93％。 1H 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] +. Referring to the synthesis method of step 1 of Example 22, the difference is that 4-bromobenzonitrile and (S)-1-N-tert-butoxycarbonyl-2-methylpiperazine in step 1 are replaced by 5-bromo-2 -Cyanopyrimidine and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate were prepared in the same way as compound II-55-1 to obtain 274 mg of a yellow solid with a yield of 79.93%. 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] + .
步骤2：II-55-2的合成Step 2: Synthesis of II-55-2
将II-55-1(174mg,0.55mmol)溶于DCM(2mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体104mg，产率87.57％。Dissolve II-55-1 (174mg, 0.55mmol) in DCM (2mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 104 mg of yellow solid with a yield of 87.57%.
步骤3：II-55的合成Step 3: Synthesis of II-55
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-55-2，同法制得化合物II-55，得白色固体113mg，产率为54.32％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-55-2, compound II-55 was obtained in the same way to obtain 113 mg of white solid with a yield of 54.32%. 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] + .
实施例94Example 94
Figure PCTCN2022110325-appb-000130
Figure PCTCN2022110325-appb-000130
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为S17和II-5-2，同法制得化合物II-56，得淡黄色固体104mg，产率为61.49％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced by S17 and II-5-2, and compound II-56 was obtained in the same way to obtain 104 mg of a light yellow solid, producing The rate is 61.49%. 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=8.4 Hz, 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[MH] + .
实施例95Example 95
Figure PCTCN2022110325-appb-000131
Figure PCTCN2022110325-appb-000131
步骤1：II-57-1的合成Step 1: Synthesis of II-57-1
参考实施例25步骤1的合成方法，不同的是将步骤1中(1S,4S)-(-)-2-叔丁氧羰基-2,5-二氮双环[2.2.1]庚烷替换为(S)-3-甲基哌嗪-1-羧酸叔丁酯，同法制得化合物II-57-1，得褐固体251mg，产率37.90％。 1H 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] +. Referring to the synthesis method of step 1 of Example 25, the difference is that (1S,4S)-(-)-2-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]heptane in step 1 is replaced by (S)-tert-butyl 3-methylpiperazine-1-carboxylate was prepared in the same way as compound II-57-1 to obtain 251 mg of a brown solid with a yield of 37.90%. 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 ] + .
步骤2：II-57-2的合成Step 2: Synthesis of II-57-2
将II-57-1(150mg,0.52mmol)溶于DCM(3mL)中，缓慢滴加TFA 0.8mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体100mg，产率95.38％。Dissolve II-57-1 (150mg, 0.52mmol) in DCM (3mL), slowly add 0.8mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 mg of yellow solid with a yield of 95.38%.
步骤3：II-57的合成Step 3: Synthesis of II-57
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-57-2，同法制得化合物II-57，得白色固体160mg，产率为68.30％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-57-2, compound II-57 was obtained in the same way to obtain 160 mg of 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] + .
实施例96Example 96
Figure PCTCN2022110325-appb-000132
Figure PCTCN2022110325-appb-000132
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为S15和II-46-2，同法制得化合物II-58，得淡黄色固体125mg，产率为61.78％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced by S15 and II-46-2, and compound II-58 was prepared in the same way to obtain 125 mg of a light yellow solid, producing The rate is 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] + .
实施例97Example 97
Figure PCTCN2022110325-appb-000133
Figure PCTCN2022110325-appb-000133
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-55-2，同法制得化合物II-59，得白色固体118mg，产率为52.32％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-55-2, compound II-59 was obtained in the same way to obtain 118 mg of white solid with 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=13.7 Hz,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] + .
实施例98Example 98
Figure PCTCN2022110325-appb-000134
Figure PCTCN2022110325-appb-000134
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为S17和II-46-2，同法制得化合物II-60，得淡黄色固体97mg，产率为7.84％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced with S17 and II-46-2, and compound II-60 was obtained in the same way to obtain 97 mg of a light yellow solid, producing The rate is 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] + .
实施例99Example 99
Figure PCTCN2022110325-appb-000135
Figure PCTCN2022110325-appb-000135
步骤1：II-60的合成Step 1: Synthesis of II-60
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为S4和II-55-2，同法制得化合物II-61，得淡黄色固体95mg，产率为52.96％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced by S4 and II-55-2, and compound II-61 was obtained in the same way to obtain 95 mg of a light yellow solid, producing The rate is 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] + .
实施例100Example 100
Figure PCTCN2022110325-appb-000136
Figure PCTCN2022110325-appb-000136
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为S15和II-30-2，同法制得化合物II-62，得白色固体165mg，产率为74.65％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced by S15 and II-30-2, and compound II-62 was obtained in the same way to obtain 165 mg of a white solid with a yield of was 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=8.7 Hz,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] + .
实施例101Example 101
Figure PCTCN2022110325-appb-000137
Figure PCTCN2022110325-appb-000137
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-53-2，同法制得化合物II-63，得白色固体108mg，产率为56.63％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-53-2, compound II-63 was obtained in the same way to obtain 108 mg of white solid with 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] + .
实施例102Example 102
Figure PCTCN2022110325-appb-000138
Figure PCTCN2022110325-appb-000138
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为S4和II-53-2，同法制得化合物II-64，得淡黄色固体98mg，产率为60.54％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced by S4 and II-53-2, and compound II-64 was obtained in the same way to obtain 98 mg of a light yellow solid, producing The rate is 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] + .
实施例103Example 103
Figure PCTCN2022110325-appb-000139
Figure PCTCN2022110325-appb-000139
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为S17和II-53-2，同法制得化合物II-65，得白色固体84mg，产率为66.86％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced by S17 and II-53-2, and compound II-65 was prepared in the same way to obtain 84 mg of a white solid with a yield of is 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＝12.7 Hz, 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] + .
实施例104Example 104
Figure PCTCN2022110325-appb-000140
Figure PCTCN2022110325-appb-000140
步骤1：II-66-1的合成Step 1: Synthesis of II-66-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶和1-(叔丁氧羰基)哌嗪替换为5-溴-2-氰基嘧啶和3,6-二氮杂双环[3.1.1]庚烷-3-羧酸叔丁酯，同法制得化合物II-66-1，得黄色固体420mg，产率42.51％。 1H 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] +. Referring to the synthetic method of step 1 of Example 4, the difference is that 2-cyano-5-fluoropyridine and 1-(tert-butoxycarbonyl) piperazine in step 1 are replaced by 5-bromo-2-cyanopyrimidine and 3 , tert-butyl 6-diazabicyclo[3.1.1]heptane-3-carboxylate was prepared in the same way as compound II-66-1 to obtain 420 mg of a yellow solid with a yield of 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] + .
步骤2：II-66-2的合成Step 2: Synthesis of II-66-2
将II-66-1(250mg,0.83mmol)溶于DCM(3mL)中，缓慢滴加TFA 1mL，室温下反应0.5h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得淡黄色固体120mg，产率71.88％。Dissolve II-66-1 (250mg, 0.83mmol) in DCM (3mL), slowly add 1mL of TFA dropwise, react at room temperature for 0.5h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 120 mg of light yellow solid with a yield of 71.88%.
步骤4：II-66的合成Step 4: Synthesis of II-66
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-66-2，同法制得化合物II-66，得白色固体110mg，产率为58.69％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-66-2, compound II-66 was obtained in the same way to obtain 110 mg of white solid with 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=11.3 Hz,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] + .
实施例105Example 105
Figure PCTCN2022110325-appb-000141
Figure PCTCN2022110325-appb-000141
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为S4和II-66-2，同法制得化合物II-67，得淡黄色固体102mg，产率为52.98％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced by S4 and II-66-2, and compound II-67 was obtained in the same way to obtain 102 mg of a light yellow solid, producing The rate is 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] + .
实施例106Example 106
Figure PCTCN2022110325-appb-000142
Figure PCTCN2022110325-appb-000142
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为S15和II-66-2，同法制得化合物II-68，得白色固体122mg，产率为46.96％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced by S15 and II-66-2, and compound II-68 was obtained in the same way to obtain 122 mg of a white solid with a yield of was 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[MH] + .
实施例107Example 107
Figure PCTCN2022110325-appb-000143
Figure PCTCN2022110325-appb-000143
步骤1：II-69-1的合成Step 1: Synthesis of II-69-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶和1-(叔丁氧羰基)哌嗪替换为3-氯-4-氟苯甲腈和3,6-二氮杂双环[3.1.1]庚烷-3-羧酸叔丁酯，同法制得化合物II-69-1，得淡黄色固体435mg，产率81.08％。 1H 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] +. Referring to the synthetic method of Example 4 step 1, the difference is that 2-cyano-5-fluoropyridine and 1-(tert-butoxycarbonyl) piperazine in step 1 are replaced by 3-chloro-4-fluorobenzonitrile and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate was prepared in the same way as compound II-69-1 to obtain 435 mg of light yellow solid with a yield of 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] + .
步骤2：II-69-2的合成Step 2: Synthesis of II-69-2
将II-69-1(150mg,0.45mmol)溶于DCM(3mL)中，缓慢滴加TFA 1mL，室温下反应 0.5h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体150mg，产率95.23％。Dissolve II-69-1 (150mg, 0.45mmol) in DCM (3mL), slowly add 1mL of TFA dropwise, react at room temperature for 0.5h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 150 mg of yellow solid with a yield of 95.23%.
步骤4：II-69的合成Step 4: Synthesis of II-69
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为S4和II-69-2，同法制得化合物II-69，得白色固体88mg，产率为40.73％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced by S4 and II-69-2, and compound II-69 was obtained in the same way to obtain 88 mg of a white solid with a yield of was 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=1.9 Hz,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] + .
实施例108Example 108
Figure PCTCN2022110325-appb-000144
Figure PCTCN2022110325-appb-000144
步骤1：II-70-1的合成Step 1: Synthesis of II-70-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶和1-(叔丁氧羰基)哌嗪替换为6-氯-3-哒嗪甲腈和3,6-二氮杂双环[3.1.1]庚烷-3-羧酸叔丁酯，同法制得化合物II-70-1，得淡黄色固体512mg，产率94.83％。 1H 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] +. Referring to the synthetic method of step 1 of Example 4, the difference is that 2-cyano-5-fluoropyridine and 1-(tert-butoxycarbonyl) piperazine in step 1 are replaced by 6-chloro-3-pyridazine carbonitrile and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate was prepared in the same way as compound II-70-1 to obtain 512 mg of light yellow solid with a yield of 94.83%. 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] + .
步骤2：II-70-2的合成Step 2: Synthesis of II-70-2
将II-70-1(300mg,1mmol)溶于DCM(3mL)中，缓慢滴加TFA 1mL，室温下反应0.5h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体152mg，产率75.87％。Dissolve II-70-1 (300mg, 1mmol) in DCM (3mL), slowly add 1mL of TFA dropwise, and react at room temperature for 0.5h. ) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 152 mg of a yellow solid with a yield of 75.87%.
步骤4：II-70的合成Step 4: Synthesis of II-70
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-70-2，同法制得化合物II-70，得白色固体58mg，产率为29.10％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-70-2, compound II-70 was obtained in the same way to obtain 58 mg of 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 ] + .
实施例109Example 109
Figure PCTCN2022110325-appb-000145
Figure PCTCN2022110325-appb-000145
步骤1：II-71-1的合成Step 1: Synthesis of II-71-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶和1-(叔丁氧羰基)哌嗪替换为2-氰基-3,5-二氟吡啶和3,6-二氮杂双环[3.1.1]庚烷-3-羧酸叔丁酯，同法制得化合物II-71-1，得白色固体550mg，产率60.51％。 1H 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] +. Referring to the synthetic method of step 1 of Example 4, the difference is that 2-cyano-5-fluoropyridine and 1-(tert-butoxycarbonyl)piperazine in step 1 are replaced by 2-cyano-3,5-difluoro Pyridine and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate were prepared in the same way as compound II-71-1 to obtain 550 mg of white solid with a yield of 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] + .
步骤2:II-71-2的合成Step 2: Synthesis of II-71-2
将II-71-1(600mg,1.88mmol)溶于DCM(7mL)中，缓慢滴加TFA 2.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体350mg，产率85.09％。Dissolve II-71-1 (600mg, 1.88mmol) in DCM (7mL), slowly add TFA 2.5mL dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 350 mg of yellow solid with a yield of 85.09%.
步骤3:II-71的合成Step 3: Synthesis of II-71
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-71-2，同法制得化合物II-71，得淡黄色固体150mg，产率为67.02％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced by II-71-2, and compound II-71 was obtained in the same way to obtain 150 mg of a light 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] + .
实施例110Example 110
Figure PCTCN2022110325-appb-000146
Figure PCTCN2022110325-appb-000146
步骤1：II-72-1的合成Step 1: Synthesis of II-72-1
参考实施例4步骤1的合成方法，不同的是将步骤1中2-氰基-5-氟吡啶和1-(叔丁氧羰基)哌嗪替换为2-氰基-3,5-二氟吡啶和3,6-二氮杂双环[3.1.1]庚烷-3-羧酸叔丁酯，同法制得化合物II-72-1，得白色固体300mg，产率33.00％。 1H 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] +. Referring to the synthetic method of step 1 of Example 4, the difference is that 2-cyano-5-fluoropyridine and 1-(tert-butoxycarbonyl)piperazine in step 1 are replaced by 2-cyano-3,5-difluoro Pyridine and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate were prepared in the same way as compound II-72-1 to obtain 300 mg of a white solid with a yield of 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] + .
步骤2:II-72-2的合成Step 2: Synthesis of II-72-2
将II-72-1(300mg,0.94mmol)溶于DCM(4mL)中，缓慢滴加TFA 1.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得黄色固体170mg，产率82.66％。Dissolve II-72-1 (300mg, 0.94mmol) in DCM (4mL), slowly add 1.5mL of TFA dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 170 mg of yellow solid with a yield of 82.66%.
步骤3:II-72的合成Step 3: Synthesis of II-72
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-72-2，同法制得化合物II-72，得白色固体160mg，产率为71.49％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, except that I-1-2 in Step 3 was replaced by II-72-2, compound II-72 was obtained in the same way to obtain 160 mg of 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] + .
实施例111Example 111
Figure PCTCN2022110325-appb-000147
Figure PCTCN2022110325-appb-000147
参考实施例1步骤3的合成方法，不同的是将步骤3中的S2和I-1-2替换为S17和II-30-2，同法制得化合物II-73，得白色固体25mg，产率为38.01％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that S2 and I-1-2 in Step 3 were replaced by S17 and II-30-2, and compound II-73 was obtained in the same way to obtain 25 mg of a white solid with a yield of was 38.01%. 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=8.3 Hz,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] + .
实施例112Example 112
Figure PCTCN2022110325-appb-000148
Figure PCTCN2022110325-appb-000148
步骤1：II-74-1的合成Step 1: Synthesis of II-74-1
在一个两口瓶中，依次加入3-氧代哌嗪-1-羧酸叔丁酯(700mg,3.5mmol)，4-溴苯甲腈(1.27g,6.99mmol)，Cs 2CO 3(2.28g,6.99mmol),Pd(OAc) 2(31.39mg,0.14mmol)和Xantphos(242.73mg,0.42mmol)。加入15mL无水二氧六环，90℃，氮气保护下反应16小时。TLC监测反应完全后，冷却至室温，加水(10mL)稀释，乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得残余物通过硅胶柱色谱法(石油醚：乙酸乙酯＝5:1)分离，得棕色油状物815mg，产率77.36％。 1H 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] +. In a two-neck flask, tert-butyl 3-oxopiperazine-1-carboxylate (700mg, 3.5mmol), 4-bromobenzonitrile (1.27g, 6.99mmol), Cs 2 CO 3 (2.28g , 6.99 mmol), Pd(OAc) 2 (31.39 mg, 0.14 mmol) and Xantphos (242.73 mg, 0.42 mmol). Add 15 mL of anhydrous dioxane, and react at 90°C for 16 hours under nitrogen protection. After TLC monitors that the reaction is complete, cool to room temperature, dilute with water (10mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and the resulting residue is purified by silica gel column chromatography (petroleum Ether: ethyl acetate = 5:1) separation to obtain 815 mg of brown oil, yield 77.36%. 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] + .
步骤2:II-74-2的合成Step 2: Synthesis of II-74-2
将II-74-1(500mg,1.66mmol)溶于DCM(7mL)中，缓慢滴加TFA 2.5mL，室温下反应1h，TLC监测反应完全后，加入1M NaOH水溶液淬灭反应，DCM(5mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得棕色油状物275mg，产率82.36％。Dissolve II-74-1 (500mg, 1.66mmol) in DCM (7mL), slowly add TFA 2.5mL dropwise, react at room temperature for 1h, after TLC monitors that the reaction is complete, add 1M NaOH aqueous solution to quench the reaction, DCM (5mL× 3) Extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 275 mg of brown oil with a yield of 82.36%.
步骤3:II-74的合成Step 3: Synthesis of II-74
参考实施例1步骤3的合成方法，不同的是将步骤3中的I-1-2替换为II-74-2，同法制得化合物II-74，得淡黄色固体160mg，产率为45.53％。 1H 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] +. Referring to the synthesis method in Step 3 of Example 1, the difference is that I-1-2 in Step 3 was replaced by II-74-2, and compound II-74 was obtained in the same way to obtain 160 mg of a light 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] + .
实施例113Example 113
Figure PCTCN2022110325-appb-000149
Figure PCTCN2022110325-appb-000149
在0℃和氮气保护下，向起始物料1-1(5g)的无水四氢呋喃(30mL)溶液中缓慢滴加二氯亚 砜(2.78mL)，保温反应3小时。在0℃下滴加三乙胺(5.34mL)，搅拌10分钟。在0℃下缓慢滴加5-氨基-3-(三氟甲基)-2-吡啶-甲腈(3.83g)的无水四氢呋喃(20mL)溶液，搅拌30分钟后升至25℃反应18小时。LCMS监测反应完全。加入水(100mL)，乙酸乙酯(100mL*2)萃取水相，合并有机相，用饱和氯化钠溶液(100mL)洗涤。无水硫酸钠干燥，过滤，有机相减压蒸出溶剂，残留物加入甲基叔丁基醚(30mL)打浆，过滤，滤饼用甲基叔丁基醚(10mL)洗涤，得到5.3g中间体1-2。LC-MS(ESI):m/z＝351.9,353.9[M+H] + Under nitrogen protection at 0°C, thionyl chloride (2.78 mL) was slowly added dropwise to a solution of starting material 1-1 (5 g) in anhydrous tetrahydrofuran (30 mL), and the reaction was incubated for 3 hours. Triethylamine (5.34 mL) was added dropwise at 0°C, followed by stirring for 10 minutes. Slowly add a solution of 5-amino-3-(trifluoromethyl)-2-pyridine-carbonitrile (3.83g) in anhydrous tetrahydrofuran (20mL) dropwise at 0°C, stir for 30 minutes and raise to 25°C for 18 hours . LCMS monitored the reaction to be complete. Water (100 mL) was added, the aqueous phase was extracted with ethyl acetate (100 mL*2), and the organic phases were combined and washed with saturated sodium chloride solution (100 mL). Dry over anhydrous sodium sulfate, filter, evaporate the solvent from the organic phase under reduced pressure, add methyl tert-butyl ether (30mL) to the residue to make a slurry, filter, wash the filter cake with methyl tert-butyl ether (10mL) to obtain 5.3g intermediate Body 1-2. LC-MS(ESI): m/z=351.9,353.9[M+H] +
在25℃下将氢氧化钠(0.9g)加入中间体1-2(5.3g)的丙酮(80mL)溶液中，升温至65℃搅拌2小时。TLC监测反应完全。冷却至25℃，加入乙酸乙酯(50mL)稀释后过滤，滤饼用乙酸乙酯(20mL)洗涤。滤液用无水硫酸钠干燥，减压蒸出溶剂，残留物经硅胶柱色谱法(石油醚/乙酸乙酯梯度洗脱)分离，得到2.9g中间体1-3。LC-MS(ESI):m/z＝272.1[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° C., and the temperature was raised to 65° C. and stirred for 2 hours. TLC monitored the completion of the reaction. Cool to 25°C, add ethyl acetate (50 mL) to dilute and filter, and the filter cake is 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 obtain 2.9 g of intermediate 1-3. LC-MS(ESI): m/z=272.1[M+H] +
向反应瓶中加入1-4(8.4g)，3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯(11.0g)，叔丁醇钠(8.9g)，三(二亚苄基丙酮)二钯(4.2g)，(±)-2,2′-双(二苯基膦)-1,1′-联萘(5.8g)和干燥甲苯(130mL)。氮气保护，80℃反应18小时。LCMS监测反应完全。冷却至25℃，加水(50mL)淬灭反应，通过硅藻土过滤，滤饼用乙酸乙酯(50mL)洗涤，分液，有机相用饱和氯化钠水溶液(100mL)，水(100mL)洗涤。无水硫酸钠干燥，减压蒸出溶剂，得到18.3g中间体1-5，直接进行下一步反应。LC-MS(ESI):m/z＝300.1[M+H] + Add 1-4 (8.4g), 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (11.0g), sodium tert-butoxide (8.9g) to the reaction flask, Tris(dibenzylideneacetone)dipalladium (4.2 g), (±)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (5.8 g) and dry toluene (130 mL). Under nitrogen protection, react at 80°C for 18 hours. LCMS monitored the reaction to be complete. Cool to 25°C, add water (50 mL) to quench the reaction, filter through diatomaceous earth, wash the filter cake with ethyl acetate (50 mL), separate the layers, and wash the organic phase with saturated aqueous sodium chloride (100 mL), water (100 mL) . After drying with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain 18.3 g of intermediate 1-5, which was directly carried out to the next reaction. LC-MS(ESI): m/z=300.1[M+H] +
将18.3g中间体1-5用干燥甲苯(75mL)溶解，在20℃滴加三氟乙酸(20.4mL)，保温反应18小时。LCMS监测反应完全。静置分层，将所得下层相滴入甲基叔丁基醚(100mL)中，20℃搅拌2小时，析出固体，过滤，滤饼用甲基叔丁基醚(30mL)洗涤。滤饼溶解于5％碳酸钠水溶液(100mL)中，二氯甲烷(100mL)萃取，分液，有机相用饱和氯化钠水溶液(80mL)洗涤。无水硫酸钠干燥，减压蒸出溶剂，残留物用甲基叔丁基醚(30mL)打浆，过滤后得到2.8g中间体1-6。LC-MS(ESI):m/z＝200.1[M+H] + 18.3 g of Intermediate 1-5 was dissolved in dry toluene (75 mL), and trifluoroacetic acid (20.4 mL) was added dropwise at 20° C., and the reaction was incubated for 18 hours. LCMS monitored the reaction to be complete. After static separation, the resulting lower phase was dropped into methyl tert-butyl ether (100 mL), stirred at 20°C for 2 hours, a solid precipitated, filtered, and the filter cake was washed with methyl tert-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). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was slurried with methyl tert-butyl ether (30 mL), and 2.8 g of intermediate 1-6 were obtained after filtration. LC-MS(ESI): m/z=200.1[M+H] +
将中间体1-3(2.9g)和中间体1-6(2.1g)溶于无水乙醇(30mL)中,升温至80℃反应4h。LCMS监测反应完全。减压蒸出溶剂，残留物通过反相高效液相色谱法(色谱柱:spherical-C18；流动相:A为水；B为乙腈，B％:0％-40％,80mL/min)纯化，得到1.8g化合物0XX。LC-MS(ESI):m/z＝471.1[M+H]；Intermediate 1-3 (2.9g) and Intermediate 1-6 (2.1g) were dissolved in absolute ethanol (30mL), heated to 80°C for 4h. LCMS monitored the reaction to be complete. The solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase high-performance liquid chromatography (chromatographic column: spherical-C18; mobile phase: A is water; B is acetonitrile, B%: 0%-40%, 80mL/min), 1.8 g of compound OXX were obtained. LC-MS (ESI): m/z=471.1 [M+H];
1H 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). 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).
实验例1：Experimental example 1:
1.本申请化合物对22Rv1细胞增殖的抑制效果1. The inhibitory effect of the compound of the present application on the proliferation of 22Rv1 cells
试验方法：通过CellTiter-Glo发光法细胞活力检测试剂盒(CTG)评估本申请的化合物对22Rv1细胞增殖的影响。Test method: CellTiter-Glo Luminescent Cell Viability Assay Kit (CTG) was used to evaluate the effect of the compound of the present application on the proliferation of 22Rv1 cells.
将22Rv1细胞(ATCC,货号：CRL-2505)接种至384孔细胞培养板(Corning,CLS3764-100EA)中后，放置于37℃，5％CO 2恒温培养箱过夜培养(注意：使用1％碳吸附血清)，第二天将稀释好的本申请化合物利用纳升移液***(LABCYTE，P-0200)加入培养板中。最后本申请化合物与细胞共孵育7天后，加入
Figure PCTCN2022110325-appb-000150
2D试剂(Promega,G7573)，用Envision多功能酶标仪读取发光值(光信号和体系中ATP量成正比，而ATP的含量直接表征体系中的活细胞数)。最后使用XLFIT软件用非线性拟合公式得到化合物的IC 50(半数抑制浓度)。测试化合物相应的活性测试结果具体见表1。 22Rv1 cells (ATCC, product number: CRL-2505) were inoculated into 384-well cell culture plates (Corning, CLS3764-100EA), and placed in a 37°C, 5% CO2 constant temperature incubator for overnight culture (note: use 1% carbon Adsorption of serum), and the diluted compound of the present application was added to the culture plate the next day using a nanoliter pipetting system (LABCYTE, P-0200). Finally, after the compound of the application was co-incubated with cells for 7 days, add
Figure PCTCN2022110325-appb-000150
2D reagent (Promega, G7573), read the luminescence value with Envision multifunctional microplate reader (the light signal is directly proportional to the amount of ATP in the system, and the content of ATP directly represents the number of living cells in the system). Finally, XLFIT software was used to obtain the IC 50 (half inhibitory concentration) of the compound with a nonlinear fitting formula. The corresponding activity test results of the test compounds are shown in Table 1.
2.本申请化合物对LNCap细胞增殖的抑制效果2. The compound of the application inhibits the proliferation of LNCap cells
试验方法：通过CellTiter-Glo发光法细胞活力检测试剂盒(CTG)评估本申请的化合物对LNCap细胞增殖的影响。Test method: CellTiter-Glo Luminescent Cell Viability Assay Kit (CTG) was used to evaluate the effect of the compound of the present application on the proliferation of LNCap cells.
将LNCap细胞(ATCC CRL-1740)接种至384孔细胞培养板(Corning,CLS3764-100EA)中后，放置于37℃，5％CO 2恒温培养箱过夜培养(注意：使用1％碳吸附血清)，第二天将稀释好的待测化合物利用纳升移液***(LABCYTE,P-0200)加入培养板中孵育1小时后再加入R1881(西安凯新生物科技有限公司，货号是K-ZJ-25741)。最后待测化合物与细胞共孵育7天后，加入
Figure PCTCN2022110325-appb-000151
2D试剂(Promega,G7573)，用Envision多功能酶标仪读取发光值(光信号和体系中ATP量成正比，而ATP的含量直接表征体系中的活细胞数)。最后使用XLFIT软件用非线性拟合公式得到化合物的IC 50(半数抑制浓度)。测试化合物相应的活性测试结果具体见表1。 After inoculating LNCap cells (ATCC CRL-1740) into 384-well cell culture plates (Corning, CLS3764-100EA), place them in a 37°C, 5% CO2 constant temperature incubator for overnight culture (note: use 1% carbon-absorbed serum) On the next day, add the diluted compound to be tested into the culture plate using the nanoliter pipetting system (LABCYTE, P-0200) and incubate for 1 hour before adding R1881 (Xi’an Kaixin Biotechnology Co., Ltd., the product number is K-ZJ- 25741). After the last test compound was co-incubated with cells for 7 days, add
Figure PCTCN2022110325-appb-000151
2D reagent (Promega, G7573), read the luminescence value with Envision multifunctional microplate reader (the light signal is directly proportional to the amount of ATP in the system, and the content of ATP directly represents the number of living cells in the system). Finally, XLFIT software was used to obtain the IC 50 (half inhibitory concentration) of the compound with a nonlinear fitting formula. The corresponding activity test results of the test compounds are shown in Table 1.
3.本申请化合物对AR拮抗活性的作用效果3. The effect of the compound of the application on AR antagonistic activity
(1).材料与试剂：(1). Materials and reagents:
产品名称product name 供应商supplier 货号Item No.
LNCaP细胞LNCaP cells ATCCATCC CRL-1740CRL-1740
无酚红1640培养基Phenol red-free 1640 medium GibcoGibco 11835-03011835-030
透析血清Dialyzed serum Biological IndustriesBiological Industries 04-011-1A04-011-1A
谷氨酰胺Glutamine InvitrogenInvitrogen 3505006135050061
磷酸盐缓冲液Phosphate buffer CorningCorning 21-031-CVR21-031-CVR
胰酶trypsin GibcoGibco 2520007225200072
96孔板96-well plates GrenierGrenier 655098655098
Lipofectamine 3000Lipofectamine 3000 InvitrogenInvitrogen L3000-001L3000-001
Opti-MEM培养基Opti-MEM Medium GibcoGibco 1105802111058021
pGL4.36载体pGL4.36 vector PromegaPromega E1360E1360
Steady-GloSteady-Glo PromegaPromega E2550E2550
(2).仪器:(2). Instrument:
产品名称product name 供应商supplier 型号model
细胞计数仪cell counter BECKMANBECKMAN Vi-Cell XRVi-Cell XR
ECHO2ECHO2 LabcyteLabcyte ECHO 555ECHO 555
酶标仪Microplate reader PerkinElmerPerkinElmer EnvisionEnvision
(3).实验方法：(3). Experimental method:
第一天：铺板Day 1: Planking
1)铺板培养基：89％1640培养基，10％透析血清，1％谷氨酰胺；1) Plating medium: 89% 1640 medium, 10% dialyzed serum, 1% glutamine;
2)培养基，胰酶和磷酸盐缓冲液置于37℃水浴预热；2) Culture medium, trypsin and phosphate buffer were preheated in a 37°C water bath;
3)吸去细胞培养瓶中的培养基，加入磷酸盐缓冲液漂洗一次细胞后吸去；3) Aspirate the medium in the cell culture flask, add phosphate buffer to rinse the cells once and then aspirate;
4)加入胰酶，轻轻晃动，使胰酶与细胞充分接触后吸去；4) Add trypsin and shake gently to make the trypsin fully contact with the cells and absorb it;
5)培养瓶置于37℃5％CO 2培养箱约2min； 5) Place the culture bottle in a 5% CO 2 incubator at 37°C for about 2 minutes;
6)拍打培养瓶，在显微镜下观察到>90％的细胞从培养瓶底脱落后，加入铺板培养基重悬细胞，并将细胞悬液转移至50mL离心管中；6) Tap the culture flask, and after observing >90% of the cells fall off from the bottom of the culture flask under the microscope, add the plating medium to resuspend the cells, and transfer the cell suspension to a 50mL centrifuge tube;
7)吹打均匀，取出约0.6mL细胞悬液计数；7) Pipette evenly, take out about 0.6mL cell suspension and count;
8)用培养基将细胞悬液稀释到铺板所需的细胞密度；8) Dilute the cell suspension to the required cell density for plating with medium;
9)加入80μL细胞悬液到细胞板中，置于37℃5％CO 2培养箱培养24h。 9) Add 80 μL of cell suspension to the cell plate, and place it in a 5% CO 2 incubator at 37° C. for 24 hours.
第二天：转染Day 2: Transfection
1)用Opti-MEM配置包含pGL4.36和P3000的溶液A，以及包含Lipofectamine的溶液B，室温静置5min；1) Use Opti-MEM to configure solution A containing pGL4.36 and P3000, and solution B containing Lipofectamine, and let stand at room temperature for 5 minutes;
2)将溶液B加到A中，轻轻混匀，分别向细胞板每孔中加入10uL转染试剂置于37℃5％CO 2培养箱培养24h。 2) Add solution B to A, mix gently, add 10 uL of transfection reagent to each well of the cell plate, and place in a 5% CO 2 incubator at 37°C for 24 hours.
第三天：加药Day 3: Dosing
1)用铺板培养基对本申请化合物进行3倍梯度稀释，得到8个浓度点，向细胞板中转入10uL化合物，置于37℃5％CO 2培养箱培养30min。 1) The compound of the present application was serially diluted 3 times with the plating medium to obtain 8 concentration points, and 10 uL of the compound was transferred to the cell plate, and placed in a 5% CO 2 incubator at 37° C. for 30 min.
2)用铺板培养基将testosterone稀释到10000x EC80浓度，用TECEN向96孔板中每孔加入10nL，置于37℃5％CO 2培养箱培养24h。 2) Dilute testosterone to 10000x EC80 concentration with plating medium, add 10 nL to each well of a 96-well plate with TECEN, and culture in a 5% CO 2 incubator at 37° C. for 24 hours.
第四天：检测与数据分析Day 4: Detection and Data Analysis
1)向细胞板每孔中加入100uL Steady-Glo，1000rpm离心10s，室温300rpm震荡15min，在Envision上读板。1) Add 100uL Steady-Glo to each well of the cell plate, centrifuge at 1000rpm for 10s, shake at room temperature at 300rpm for 15min, and read the plate on Envision.
2)根据公式抑制率(％Inhibition)＝(Sample value-HC)/(LC-HC)×100％，得到抑制率。数据分析采用XL-fit software(Supplier:ID Business Solutions Ltd.,Software version:XL fit 5.0)2) According to the formula inhibition rate (%Inhibition)=(Sample value-HC)/(LC-HC)×100%, the inhibition rate is obtained. Data analysis using XL-fit software (Supplier: ID Business Solutions Ltd., Software version: XL fit 5.0)
Sample value：样品测试数值；HC：最高测试数值对照；LC：最低测试数值对照；测试化合物相应的活性测试结果具体见表1。Sample value: sample test value; HC: the highest test value control; LC: the lowest test value control; the corresponding activity test results of the test compounds are shown in Table 1.
表1本申请化合物相应的活性测试结果Table 1 The corresponding active test results of the compounds of the present application
Figure PCTCN2022110325-appb-000152
Figure PCTCN2022110325-appb-000152
Figure PCTCN2022110325-appb-000153
Figure PCTCN2022110325-appb-000153
Figure PCTCN2022110325-appb-000154
Figure PCTCN2022110325-appb-000154
Figure PCTCN2022110325-appb-000155
Figure PCTCN2022110325-appb-000155
“-”表示未测试"-" means not tested
实验例2：本申请的化合物肝微粒体中的代谢稳定性测定Experimental example 2: Determination of the metabolic stability of the compound of the present application in liver microsomes
本申请化合物在肝微粒体中的代谢稳定性采用如下试验方法测定。The metabolic stability of the compound of the present application in liver microsomes is determined by the following test method.
一、试验材料及仪器1. Test materials and instruments
1.肝微粒体来源：人肝微粒体(Corning 452117)，CD-1小鼠肝微粒体(Corning 452701)1. Source of liver microsomes: human liver microsomes (Corning 452117), CD-1 mouse liver microsomes (Corning 452701)
2.Na 2HPO 4(天津市光复精细化工研究所20180130) 2. Na 2 HPO 4 (Tianjin Guangfu Fine Chemical Research Institute 20180130)
3.KH 2PO 4(天津市光复精细化工研究所20180920) 3. KH 2 PO 4 (Tianjin Guangfu Fine Chemical Research Institute 20180920)
4.MgCl 2(天津市光复精细化工研究所20191216) 4. MgCl 2 (Tianjin Guangfu Fine Chemical Research Institute 20191216)
5.NADPH(Solarbio 1216C022)5. NADPH (Solarbio 1216C022)
6.阳性对照化合物维拉帕米(Sigma MKBV4993V)6. Positive control compound verapamil (Sigma MKBV4993V)
7.AB Sciex Triple Quad 4000液质联用仪7.AB Sciex Triple Quad 4000 liquid mass spectrometer
二、试验步骤2. Test steps
1. 100mM磷酸缓冲液(PBS)的配制：称取7.098g Na 2HPO 4，加入500mL纯水超声溶解，作为溶液A。称取3.400g KH 2PO 4，加入250mL纯水超声溶解，作为溶液B。将A溶液放置在搅拌器上缓慢加入B溶液直到pH值达到7.4配制成100mM的PBS缓冲液。 1. Preparation of 100mM phosphate buffer solution (PBS): Weigh 7.098g Na 2 HPO 4 , add 500mL pure water to ultrasonically dissolve, and make solution A. Weigh 3.400g of KH 2 PO 4 , add 250mL of pure water to ultrasonically dissolve, and make solution B. Place A solution on a stirrer and slowly add B solution until the pH value reaches 7.4 to prepare 100mM PBS buffer.
2.反应体系的配制2. Preparation of reaction system
按下表配制反应体系Prepare the reaction system according to the table
Figure PCTCN2022110325-appb-000156
Figure PCTCN2022110325-appb-000156
3.将反应体系置于37℃水浴中预孵育10分钟。向反应体系中加入40μL 10mM NADPH溶液(NADPH由100mM的磷酸缓冲液溶解)，NADPH的最终浓度为1mM。用40μL磷酸缓冲液代替NADPH溶液作为阴性对照。阴性对照的作用是排除化合物自身化学稳定性的影响。3. Pre-incubate the reaction system in a 37°C water bath for 10 minutes. Add 40 μL of 10 mM NADPH solution (NADPH is dissolved in 100 mM phosphate buffer) to the reaction system, and the final concentration of NADPH is 1 mM. Replace the NADPH solution with 40 μL of phosphate buffer as a negative control. The role of the negative control is to exclude the influence of the chemical stability of the compound itself.
4.在反应体系中加入4μL 100μM的本申请化合物和阳性对照化合物维拉帕米启动反应，化合物的最终浓度为1μM。4. Add 4 μL 100 μM of the compound of the present application and the positive control compound verapamil to the reaction system to start the reaction, and the final concentration of the compound is 1 μM.
5.在0.5、15、30、45和60分钟，涡旋振荡器充分混匀后，分别取出50μL孵育样品，用4倍的含有内标的冰乙腈终止反应。样品在3,220g转速下离心45分钟。离心结束后转移90μL上清液到进样板，加入90μL超纯水混匀，用于LC-MS/MS分析。5. At 0.5, 15, 30, 45 and 60 minutes, after the vortex shaker is fully mixed, take out 50 μL of incubation samples respectively, and stop the reaction with 4 times of glacial acetonitrile containing the internal standard. Samples were centrifuged at 3,220g for 45 minutes. After centrifugation, transfer 90 μL of the supernatant to the sample plate, add 90 μL of ultrapure water and mix well for LC-MS/MS analysis.
所有的数据均通过Microsoft Excel软件进行计算。通过提取离子图谱检测峰面积。通过对母药消除百分比的自然对数与时间进行线性拟合，检测母药的体外半衰期(T 1/2)。 All data were calculated by Microsoft Excel software. Peak areas were detected by extracted ion spectra. The in vitro half-life (T 1/2 ) of the parent drug was determined by linear fitting the natural logarithm of the percent elimination of the parent drug with time.
体外半衰期(in vitro T 1/2)通过斜率k计算： The in vitro half-life (in vitro T 1/2 ) is calculated by the slope k:
in vitro T 1/2＝0.693/k in vitro T 1/2 ＝0.693/k
体外固有清除率(in vitro CL int，单位：μL/min/mg protein)用下列公式计算： Intrinsic clearance in vitro (in vitro CL int , unit: μL/min/mg protein) is calculated with the following formula:
in vitro CL int＝k×孵育液体积/酶蛋白的含量； in vitro CL int = k × incubation solution volume/enzyme protein content;
经上述公式计算得到的T 1/2和CL int值见表2。 The T 1/2 and CL int values calculated by the above formula are shown in Table 2.
表2本申请化合物肝微粒体中的半衰期值和固有清除率值Table 2 Half-life values and intrinsic clearance values in the compound liver microsomes of the present application
Figure PCTCN2022110325-appb-000157
Figure PCTCN2022110325-appb-000157
实验例3：本申请化合物对小鼠皮肤组织中AR的降解作用Experimental Example 3: Degradation Effect of Compounds of the Application on AR in Mouse Skin Tissue
1.样本1. Sample
1.1实验试剂1.1 Experimental reagents
溶媒：丙二醇/乙醇(30:70,v/v)Vehicle: propylene glycol/ethanol (30:70, v/v)
1.2实验方法1.2 Experimental method
动物信息：C57BL/6小鼠，雄性，5-6周，体重约18-20克，动物购自上海灵畅生物科技有限公司，将小鼠饲养在SPF级的环境中，每个笼位单独送排风，所有动物都可以自由获取标准认证的商业实验室饮食和自由饮水。Animal information: C57BL/6 mice, male, 5-6 weeks old, weighing about 18-20 grams, were purchased from Shanghai Lingchang Biotechnology Co., Ltd., and the mice were raised in an SPF-grade environment, and each cage was individually All animals had free access to a standard certified commercial laboratory diet and water ad libitum.
备皮：小鼠适应性饲养1周后，用剃毛器除去小鼠背部2cm*3cm区域毛发，确认小鼠毛发处于休止期(皮肤为粉红色)且皮肤无破损。Skin preparation: After the mice were adaptively fed for 1 week, the hair in the 2cm*3cm area on the back of the mice was removed with a shaver, and the hair of the mice was confirmed to be in the telogen phase (the skin was pink) and the skin was not damaged.
给药：A组：剃毛后第3天进行分组给药。本申请实施例89化合物II-51按照0.5wt％浓度每天早晚两次涂抹于剃毛区域，持续给药42天，对照组涂抹对照溶剂。每组3只小鼠。Administration: Group A: administered in groups on the 3rd day after shaving. Compound II-51 of Example 89 of the present application was applied to the shaved area at a concentration of 0.5 wt% twice a day in the morning and evening for 42 days, and the control group was applied with a control solvent. 3 mice per group.
B组：剃毛后第3天进行分组给药。本申请化合物0XX按照0.5wt％浓度每天早晚两次涂抹于剃毛区域，持续给药28天，对照组涂抹对照溶剂。每组4只小鼠。Group B: administered in groups on the 3rd day after shaving. The compound OXX of the present application was applied to the shaved area twice a day in the morning and evening according to the concentration of 0.5wt%, and the administration continued for 28 days, and the control group was applied with a control solvent. 4 mice per group.
在末次给药结束24h后采集皮肤组织，称重并在液氮中快速冷冻，然后转移到-80℃冰箱保存。以进行进一步的Western Blot分析。The skin tissue was collected 24 hours after the last administration, weighed and quickly frozen in liquid nitrogen, and then transferred to a -80°C refrigerator for storage. For further Western Blot analysis.
2.材料2. Materials
2.1试剂耗材2.1 Reagent consumables
Figure PCTCN2022110325-appb-000158
Figure PCTCN2022110325-appb-000158
Figure PCTCN2022110325-appb-000159
Figure PCTCN2022110325-appb-000159
2.2抗体信息表2.2 Antibody Information Sheet
Figure PCTCN2022110325-appb-000160
Figure PCTCN2022110325-appb-000160
2.3二抗信息表2.3 Secondary Antibody Information Sheet
抗体Antibody 供应商supplier 货号Item No.
Anti-rabbit IgGAnti-rabbit IgG abcamabcam ab6721ab6721
2.4设备仪器2.4 Equipment and instruments
震荡匀浆机Vibration Homogenizer
分析天平(Sartorius，ID:BI-DE-074)Analytical balance (Sartorius, ID: BI-DE-074)
摇床(SCILOGEX,ID:BI-DE-047)Shaker (SCILOGEX, ID: BI-DE-047)
电泳仪(Bio-Rad,ID:BI-DE-050)Electrophoresis instrument (Bio-Rad, ID: BI-DE-050)
数控干浴锅(Labnet，ID:BI-DE-052)CNC dry bath (Labnet, ID: BI-DE-052)
离心机(Eppendorf,ID:5428IH027954)Centrifuge (Eppendorf, ID: 5428IH027954)
ChemiDoc TM XRS+成像仪(BIO-RAD，ID:SIC-DI-518) ChemiDoc TM XRS+ Imager (BIO-RAD, ID: SIC-DI-518)
3.方法3. Method
3.1.裂解液的制备3.1. Preparation of lysate
1)配制裂解缓冲液(混匀，置冰上)1) Prepare lysis buffer (mix well, put on ice)
a)RIPA缓冲液a) RIPA buffer
b)0.5M EDTAb) 0.5M EDTA
c)0.5M EGTAc) 0.5M EGTA
d)HALT蛋白酶和磷酸酶抑制剂d) HALT protease and phosphatase inhibitors
e)甘油e) Glycerin
f)蛋白酶抑制剂(不含EDTA)f) Protease inhibitors (EDTA-free)
g)磷酸酶抑制剂Cocktail A(Bimake)g) Phosphatase inhibitor Cocktail A (Bimake)
h)磷酸酶抑制剂Cocktail B(Bimake)h) Phosphatase inhibitor Cocktail B (Bimake)
i)100毫摩PMSFi) 100mM PMSF
配置比例如下表(每10ml)：The configuration ratio is as follows (per 10ml):
Figure PCTCN2022110325-appb-000161
Figure PCTCN2022110325-appb-000161
Figure PCTCN2022110325-appb-000162
Figure PCTCN2022110325-appb-000162
2)将一块在-80℃冰箱中冷冻的皮肤组织样本转移到含有5倍体积裂解缓冲液A的2mL聚丙烯管中。实际取组织样品180mg，加入900uL裂解液。2) Transfer a piece of skin tissue sample frozen in a -80°C refrigerator to a 2 mL polypropylene tube containing 5 times the volume of lysis buffer A. 180 mg of tissue samples were actually taken, and 900 uL of lysate was added.
3)将皮肤组织样本放入震荡匀浆机中，4℃，60HZ，震荡120s，直到完全均匀化。3) Put the skin tissue sample into a vibrating homogenizer, 4°C, 60HZ, vibrate for 120s until completely homogenized.
4)在冰上静置15分钟。4) Let stand on ice for 15 minutes.
5)在4℃下12700rpm离心15分钟以清除组织碎片。5) Centrifuge at 12700 rpm for 15 minutes at 4°C to remove tissue debris.
6)吸取上清液至干净的1.5mL离心管中。6) Pipette the supernatant into a clean 1.5mL centrifuge tube.
7)重复步骤5)。7) Repeat step 5).
8)重复步骤6)。8) Repeat step 6).
9)分装成3份储藏于-80℃备用。9) Divide into 3 parts and store at -80°C for later use.
3.2.裂解物样品的蛋白质浓度检测3.2. Detection of protein concentration in lysate samples
本部分参考“Pierce 23227 BCA蛋白质测定试剂盒说明书”第2页：“标准品和工作试剂的制备”部分和第3页“微孔板程序(样品与试剂的比率＝1:8)”部分This part refers to "Pierce 23227 BCA Protein Assay Kit Instructions" page 2: "Preparation of Standards and Working Reagents" and page 3 "Microplate Procedure (ratio of sample to reagent = 1:8)"
1)按使用说明书制备BCA标准品(31.25μg/mL、62.5μg/mL、125μg/mL、250μg/mL、500μg/mL、1000μg/mL、2000μg/mL)。1) Prepare BCA standards (31.25 μg/mL, 62.5 μg/mL, 125 μg/mL, 250 μg/mL, 500 μg/mL, 1000 μg/mL, 2000 μg/mL) according to the instruction manual.
2)在96孔板中，在相应的孔中加入25μL 20倍稀释样品。2) In a 96-well plate, add 25 μL of 20-fold diluted sample to the corresponding well.
3)用移液管将每个标准品25μL移到相应的孔中，重复。3) Transfer 25 μL of each standard to the corresponding well with a pipette, and repeat.
4)向各孔中加入200μL工作试剂(A:B试剂的50:1)，并在摇板机上充分搅拌平板30秒。4) Add 200 μL of working reagent (50:1 of A:B reagent) to each well, and fully stir the plate on a shaker for 30 seconds.
5)盖板，37℃孵育30分钟。5) Cover the plate and incubate at 37°C for 30 minutes.
6)将盘子冷却至室温。在Envision上测量562nm处或附近的吸光度。计算每个样品的总蛋白量。6) Allow the plate to cool to room temperature. Absorbance was measured at or near 562 nm on the Envision. Calculate the total protein amount for each sample.
7)利用上样缓冲液将每个样本调平至统一浓度。在100℃下加热15分钟。冰上短暂冷却后离心分装。制备3ug/uL蛋白浓度，60uL体积样品。7) Level each sample to a uniform concentration using loading buffer. Heat at 100°C for 15 minutes. Cool briefly on ice and aliquot by centrifugation. Prepare 3ug/uL protein concentration, 60uL volume samples.
3.3.蛋白印迹法3.3. Western blotting
1)向4-12％预制凝胶中加入8uL蛋白Marker和10uL样品。1) Add 8uL protein marker and 10uL sample to 4-12% precast gel.
2)用恒压80V运行凝胶15分钟，然后在染料接近下边缘时用110V运行60分钟。2) Run the gel at a constant voltage of 80V for 15 minutes, then 110V for 60 minutes as the dye approaches the lower edge.
3)在甲醇中预活化PVDF膜1分钟，然后在转膜液中预湿膜和滤纸。组装滤纸“三明治”-用于湿转，条件：恒流300mA，70min。3) Pre-activate the PVDF membrane in methanol for 1 minute, then pre-wet the membrane and filter paper in the transfer solution. Assemble filter paper "sandwich" - for wet transfer, condition: constant current 300mA, 70min.
4)转移完成后，根据目标蛋白的分子量和相应的标记带。4) After the transfer is completed, according to the molecular weight of the target protein and the corresponding label band.
5)将PVDF膜浸入TBST配制的5％脱脂奶粉中，并在室温下摇动60分钟进行封闭。摇速25rpm/min。5) Immerse the PVDF membrane in 5% skimmed milk powder prepared by TBST, and shake it at room temperature for 60 minutes for blocking. Shaking speed 25rpm/min.
6)剪膜后用相应稀释度的一抗溶解在5％脱脂牛奶-TBST中，4℃孵育过夜。一抗浓度AR 1：1000，摇速25rpm/min。6) After cutting the membrane, dissolve the corresponding dilution of the primary antibody in 5% skimmed milk-TBST, and incubate overnight at 4°C. Primary antibody concentration AR 1:1000, shaking speed 25rpm/min.
7)用TBST清洗膜，10分钟3次，摇速50rpm/min。7) Wash the membrane with TBST, three times in 10 minutes, at a shaking speed of 50 rpm/min.
8)用抗兔二抗1:2000稀释5％脱脂牛奶-TBST溶液中，室温下孵育60分钟，摇速25rpm/min。8) Dilute with anti-rabbit secondary antibody 1:2000 in 5% skim milk-TBST solution, incubate at room temperature for 60 minutes, shaking speed 25rpm/min.
9)用TBST清洗膜，10分钟3次，摇速60rpm/min。9) Wash the membrane with TBST, three times in 10 minutes, with a shaking speed of 60 rpm/min.
10)依据说明书配制化学发光液。在膜表面均匀滴落发光液，避光孵育1min。10) Prepare the chemiluminescent solution according to the instructions. Evenly drop the luminescence solution on the surface of the membrane and incubate for 1 min in the dark.
11)用ChemiDoc TM XRS+成像仪化学发光图像分析***检测靶蛋白条带。 11) Use the ChemiDoc TM XRS+ imager chemiluminescence image analysis system to detect the target protein band.
12)量化每个蛋白质条带，并将每个靶蛋白与其负载蛋白标准化。将每个治疗组的标准化值取平均值，然后计算治疗组与载体组的每个标记物的抑制率。12) Quantify each protein band and normalize each target protein to its load protein. The normalized values of each treatment group were averaged, and then the inhibition rate of each marker was calculated for the treatment group and the vehicle group.
3.4.统计分析结果3.4. Statistical analysis results
使用ImageJ软件计算各条带灰度值。所有数据均用均值±标准差表示，并使用单因素方差检验分析各组间光密度值是否存在统计学差异，以此半定量分析各给药组对靶蛋白的抑制率强弱。靶蛋白抑制率用Excel处理。数据以均数±标准差(Mean±SEM)表示，采用单因素方差检验检验分析对照组与加药组的显著性，*p≤0.05，**p≤0.01，***p≤0.001。具体结果详见图1和图2。实验结果：由图1和图2可以看出，与对照组相比，采用本申请实施例89化合物II-51给药后24小时，小鼠皮肤组织中的AR蛋白表达显著下降，具有统计学差异。由图3可以看出，与对照组相比，采用本申请实化合物0XX给药后24小时，小鼠皮肤组织中的AR蛋白表达显著下降，具有统计学差异。The gray value of each band was calculated using ImageJ software. All the data are expressed as mean ± standard deviation, and the one-way variance test is used to analyze whether there is a statistical difference in the optical density values among the groups, so as to semi-quantitatively analyze the inhibition rate of each drug administration group on the target protein. Target protein inhibition rate was processed by Excel. The data are expressed as mean ± standard deviation (Mean ± SEM), and the significance of the control group and the drug-dosed group was analyzed by one-way ANOVA test, *p≤0.05, **p≤0.01, ***p≤0.001. The specific results are shown in Figure 1 and Figure 2. Experimental results: It can be seen from Figure 1 and Figure 2 that, compared with the control group, 24 hours after the administration of Compound II-51 of Example 89 of the present application, the expression of AR protein in the mouse skin tissue was significantly reduced, with statistical significance difference. It can be seen from Figure 3 that, compared with the control group, 24 hours after administration of the compound OXX of the present application, the expression of AR protein in mouse skin tissue was significantly decreased, with a statistical difference.
实验例4体内药效研究Experimental example 4 in vivo drug effect research
4.1实验试剂4.1 Experimental reagents
溶媒：丙二醇/乙醇(30:70,v/v)Vehicle: propylene glycol/ethanol (30:70, v/v)
4.2实验方法4.2 Experimental method
动物信息：C57BL/6小鼠，雄性，4-6周，体重约18-20克，动物购自上海灵畅生物科技有限公司，将小鼠饲养在SPF级的环境中，每个笼位单独送排风，所有动物都可以自由获取标准认证的商业实验室饮食和自由饮水。Animal information: C57BL/6 mice, male, 4-6 weeks old, weighing about 18-20 grams, were purchased from Shanghai Lingchang Biotechnology Co., Ltd., and the mice were raised in an SPF-grade environment, and each cage was individually All animals had free access to a standard certified commercial laboratory diet and water ad libitum.
备皮：小鼠适应性饲养1-2周后，用剃毛器除去小鼠背部2cm*3cm区域毛发，确认小鼠毛发处于休止期(皮肤为粉红色)且皮肤无破损。Skin preparation: After the mice were adaptively fed for 1-2 weeks, the hair in the area of 2cm*3cm on the back of the mouse was removed with a shaver, and the hair of the mouse was confirmed to be in the telogen phase (the skin was pink) and the skin was not damaged.
给药：A组：剃毛后第3天进行分组给药。本申请化合物II-51按照0.5wt％浓度每天早晚两次涂抹于剃毛区域，持续42天，对照组涂抹对照溶剂，每组11只小鼠。B组：本申请化合物0XX按照0.5wt％浓度每天早晚两次涂抹于剃毛区域，持续28天，对照组涂抹对照溶剂，每组18只小鼠。Administration: Group A: administered in groups on the 3rd day after shaving. Compound II-51 of the present application was applied to the shaved area twice a day in the morning and evening at a concentration of 0.5wt% for 42 days, and a control solvent was applied to the control group, with 11 mice in each group. Group B: The compound OXX of the present application was applied to the shaved area twice a day in the morning and evening at a concentration of 0.5 wt%, for 28 days, and a control solvent was applied to the control group, with 18 mice in each group.
4.3小鼠状态观察及毛发生长评分4.3 Mouse state observation and hair growth score
实验期间观察各组小鼠状态，皮肤是否有红疹、开裂、起皮屑等现象；During the experiment, observe the state of the mice in each group, whether there are rashes, cracks, and dandruff on the skin;
A组：分别于第7、14、18、21、24、28、32、35、39、42天对小鼠进行称重，进行毛发生长评分并拍摄照片；Group A: mice were weighed on the 7th, 14th, 18th, 21st, 24th, 28th, 32nd, 35th, 39th, and 42nd days, and hair growth scores were scored and photos were taken;
B组：分别于第7、14、18、21、24、28天对小鼠进行毛发生长评分并拍摄照片；分别于14、18、21、28天对小鼠进行称重；Group B: Score the hair growth of the mice on days 7, 14, 18, 21, 24, and 28 and take photos; weigh the mice on days 14, 18, 21, and 28;
评分标准如下：The scoring criteria are as follows:
0分:脱毛区毛发未生长；0 points: no hair growth in the depilatory area;
1分:脱毛区毛发小于20％区域增长；1 point: less than 20% hair growth in the depilatory area;
2分:脱毛区毛发20％～40％区域增长；2 points: 20% to 40% hair growth in the depilatory area;
3分:脱毛区毛发40％～60％区域增长；3 points: 40% to 60% hair growth in the depilatory area;
4分:脱毛区毛发60％～80％区域增长；4 points: 60% to 80% of the hair in the depilatory area grows;
5分:脱毛区毛发80％～100％区域增长。5 points: 80% to 100% hair growth in the depilatory area.
4.4实验结果4.4 Experimental results
本申请化合物对小鼠毛发生长和体重变化情况的结果见表3-4，图4-图7。The results of the compounds of the present application on the hair growth and body weight changes of mice are shown in Table 3-4, Figure 4-Figure 7.
表3本申请化合物对小鼠毛发生长评分Table 3 The compound of the application scores the growth of mouse hair
Figure PCTCN2022110325-appb-000163
Figure PCTCN2022110325-appb-000163
表4本申请化合物对小鼠毛发生长评分Table 4 The compound of the application is scored on mouse hair growth
Figure PCTCN2022110325-appb-000164
Figure PCTCN2022110325-appb-000164
4.5实验结论4.5 Experimental conclusion
在毛发生长处于休止期的小鼠中，本申请化合物II-51和化合物0XX在0.5％的浓度，20uL/cm 2，按BID给药方式，皮肤涂抹给药对毛发生长具有显著促进作用(P<0.0001)。本申请化合物II-51和化合物0XX在所尝试剂量下未显著影响小鼠体重，也未引起任何皮肤红疹、开裂、起皮屑等现象。 In mice whose hair growth is in the telogen phase, compound II-51 and compound OXX of the present application have a significant promoting effect on hair growth (P <0.0001). Compound II-51 and compound OXX of the present application did not significantly affect the body weight of mice at the doses tried, nor did they cause any skin rashes, cracks, and dandruff.

Claims (25)

  1. 一种式(I)所示化合物或其立体异构体或药学上可接受的盐，A compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt,
    Figure PCTCN2022110325-appb-100001
    Figure PCTCN2022110325-appb-100001
    其中，in,
    X是CH或N；X is CH or N;
    R 1选自H、OH、C 1-6烷基、-O-C 1-6烷基、-OCOR a、-COR a、-CONHR a或-NHCOR a； R 1 is selected from H, OH, C 1-6 alkyl, -OC 1-6 alkyl, -OCOR a , -COR a , -CONHR a or -NHCOR a ;
    R 2选自C 1-6烷基或C 1-6卤代烷基； R 2 is selected from C 1-6 alkyl or C 1-6 haloalkyl;
    或者由R 1与R 2及其连接的C共同形成C 3-6环烷基或4-6元杂环基； Or, R 1 and R 2 and the C they are connected to together form a C 3-6 cycloalkyl group or a 4-6 membered heterocyclic group;
    R 4选自卤素、CF 3或-O-C 1-6烷基； R 4 is selected from halogen, CF 3 or -OC 1-6 alkyl;
    R 5选自CN、NO 2、-COR a、-CONHR a、-S(O) 2R a或-S(O) 2N(R a) 2； R 5 is selected from CN, NO 2 , -COR a , -CONHR a , -S(O) 2 R a or -S(O) 2 N(R a ) 2 ;
    R a独立地选自H、OH、卤素、C 1-6烷基或C 1-6卤代烷基； R is independently selected from H, OH, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R 6选自H或-O-C 1-6烷基； R 6 is selected from H or -OC 1-6 alkyl;
    R 7，R 8独立地选自H或卤素； R 7 , R 8 are independently selected from H or halogen;
    W选自
    Figure PCTCN2022110325-appb-100002
    或4-10元完全饱和杂环基，所述4-10元完全饱和杂环基任选地被R b取代；R b选自卤素、OH、NH 2、NO 2、CN、C 1-6烷基、C 1-6卤代烷基、-O-C 1-6烷基或-S(＝O) 2-C 1- 6烷基；     W selected from
    Figure PCTCN2022110325-appb-100002
    Or a 4-10 membered fully saturated heterocyclic group, the 4-10 membered fully saturated heterocyclic group is optionally substituted by R b ; R b is selected from halogen, OH, NH 2 , NO 2 , CN, C 1-6 Alkyl, C 1-6 haloalkyl, -OC 1-6 alkyl or -S(=O) 2 -C 1- 6 alkyl;
    环D选自5-10元杂芳基或C 6-10芳基； Ring D is selected from 5-10 membered heteroaryl or C 6-10 aryl;
    每一个R 3独立地选自卤素、OH、NH 2、NO 2、CN、-CONH 2、-CONHR 3A、-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、C 1-6烷基、4-10元杂环基、5-10元杂芳基或C 6-10芳基，所述C 1-6烷基、4-10元杂环基、5-10元杂芳基或C 6-10芳基任选地被R 3A取代； Each R 3 is independently selected from halogen, OH, NH 2 , NO 2 , CN, -CONH 2 , -CONHR 3A , -OC 1-6 alkyl, -S(=O) 2 -C 1-6 alkyl , C 1-6 alkyl, 4-10 membered heterocyclic group, 5-10 membered heteroaryl or C 6-10 aryl, the C 1-6 alkyl, 4-10 membered heterocyclic group, 5- 10-membered heteroaryl or C 6-10 aryl is optionally substituted by R 3A ;
    R 3A独立地选自卤素、OH、NO 2、CN、CH 2F、CHF 2、CF 3、C 1-6烷基、-O-C 1-6烷基或-S(＝O) 2-C 1-6烷基； R 3A is independently selected from halogen, OH, NO 2 , CN, CH 2 F, CHF 2 , CF 3 , C 1-6 alkyl, -OC 1-6 alkyl or -S(=O) 2 -C 1 -6 alkyl;
    n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;
    p选自0或1。p is selected from 0 or 1.
  2. 根据权利要求1所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中W为4-10元完全饱和杂环基，所述4-10元完全饱和杂环基任选地被R b取代；或者， The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to claim 1, wherein W is a 4-10 membered fully saturated heterocyclic group, and the 4-10 membered fully saturated heterocyclic group is Cyclic is optionally substituted by R; or,
    W为4-8元完全饱和杂环基，所述4-8元完全饱和杂环基任选地被R b取代；或者， W is a 4-8 membered fully saturated heterocyclic group, the 4-8 membered fully saturated heterocyclic group is optionally substituted by R b ; or,
    W为含有1个或2个N原子的4、5、6、7或8元完全饱和杂环基，所述4、5、6、7或8元完全饱和杂环基任选地被R b取代；或者， W is a 4, 5, 6, 7 or 8-membered fully saturated heterocyclic group containing 1 or 2 N atoms, and the 4, 5, 6, 7 or 8-membered fully saturated heterocyclic group is optionally replaced by R b replace; or,
    W选自氮杂环丁基、哌嗪基、1,4-二氮杂环庚烷基、3,8-二氮杂双环[3.2.1]辛烷基、2,5-二氮双环[2.2.1]庚烷基或
    Figure PCTCN2022110325-appb-100003
    所述的氮杂环丁基、哌嗪基、1,4-二氮杂环庚烷基、3,8-二氮杂双环[3.2.1]辛烷基、2,5-二氮双环[2.2.1]庚烷基或
    Figure PCTCN2022110325-appb-100004
    任选地被R b取代；或者，     W is selected from azetidinyl, piperazinyl, 1,4-diazepanyl, 3,8-diazabicyclo[3.2.1]octyl, 2,5-diazabicyclo[ 2.2.1] Heptyl or
    Figure PCTCN2022110325-appb-100003
    The azetidinyl, piperazinyl, 1,4-diazepanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[ 2.2.1] Heptyl or
    Figure PCTCN2022110325-appb-100004
    optionally substituted by R b ; or,
    W选自氮杂环丁基、哌嗪基、3,8-二氮杂双环[3.2.1]辛烷基或2,5-二氮双环[2.2.1]庚烷基，所述的氮杂环丁基、哌嗪基、3,8-二氮杂双环[3.2.1]辛烷基或2,5-二氮双环[2.2.1]庚烷基任选地被R b取代。 W is selected from azetidinyl, piperazinyl, 3,8-diazabicyclo[3.2.1]octyl or 2,5-diazabicyclo[2.2.1]heptyl, the nitrogen Heterocyclobutyl, piperazinyl, 3,8-diazabicyclo[3.2.1]octanyl or 2,5-diazabicyclo[2.2.1]heptanyl is optionally substituted by R b .
  3. 根据权利要求1或2所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中所述环D选自苯基或5-10元杂芳基；或者，所述环D选自苯基或含有1个或2个N原子的5、6、7、8、9或10元杂芳基；或者，所述环D选自苯基或含有1个或2个N原子的5或6元杂芳基；或者，所述环D选自苯基、吡啶基、吡唑基、嘧啶基或哒嗪基。The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to claim 1 or 2, wherein the ring D is selected from phenyl or 5-10 membered heteroaryl; or, The ring D is selected from phenyl or a 5, 6, 7, 8, 9 or 10-membered heteroaryl group containing 1 or 2 N atoms; or, the ring D is selected from a phenyl group or contains 1 or 2 N atoms A 5- or 6-membered heteroaryl group with N atoms; or, the ring D is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl or pyridazinyl.
  4. 根据权利要求1-3中任一项所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中R b为C 1-6烷基；或者，R b为CH 3。 According to the compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1-3, wherein R b is C 1-6 alkyl; or, R b is CH3 .
  5. 根据权利要求1-4中任一项所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中R 3选自卤素、NO 2、CN、-O-C 1-6烷基、-S(＝O) 2-C 1-6烷基、C 1-6烷基、5-10元杂芳基或C 6-10芳基，所述C 1-6烷基、5-10元杂芳基或C 6-10芳基任选地被R 3A取代；或者， The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1-4, wherein R 3 is selected from halogen, NO 2 , CN, -OC 1- 6 alkyl, -S(=O) 2 -C 1-6 alkyl, C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl, said C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl is optionally substituted by R 3A ; or,
    R 3选自卤素、NO 2、CN、-O-CH 3、-CF 3、-S(＝O) 2-CH 3、嘧啶基、吡唑基、吡啶基或苯基，所述嘧啶基、吡唑基、吡啶基或苯基任选地被R 3A取代；或者， R 3 is selected from halogen, NO 2 , CN, -O-CH 3 , -CF 3 , -S(=O) 2 -CH 3 , pyrimidinyl, pyrazolyl, pyridyl or phenyl, said pyrimidinyl, Pyrazolyl, pyridyl or phenyl is optionally substituted by R 3A ; or,
    R 3选自卤素、CN、NO 2、-O-C 1-6烷基、-CONHR 3A、C 1-6烷基、5-10元杂芳基或C 6-10芳基，所述C 1-6烷基、5-10元杂芳基或C 6-10芳基任选地被R 3A取代；或者， R 3 is selected from halogen, CN, NO 2 , -OC 1-6 alkyl, -CONHR 3A , C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl, the C 1- 6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl are optionally substituted by R 3A ; or,
    R 3选自卤素、CN、NO 2、-O-C 1-6烷基、C 1-6烷基、5-10元杂芳基或C 6-10芳基，所述C 1-6烷基、5-10元杂芳基或C 6-10芳基任选地被R 3A取代；或者， R 3 is selected from halogen, CN, NO 2 , -OC 1-6 alkyl, C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl, the C 1-6 alkyl, 5-10 membered heteroaryl or C 6-10 aryl is optionally substituted by R 3A ; or,
    R 3选自卤素、CN、NO 2、-O-C 1-6烷基、C 1-6烷基、5-6元杂芳基或苯基，所述C 1-6烷基、5-6元杂芳基或苯基任选地被R 3A取代；或者， R 3 is selected from halogen, CN, NO 2 , -OC 1-6 alkyl, C 1-6 alkyl, 5-6 membered heteroaryl or phenyl, the C 1-6 alkyl, 5-6 membered Heteroaryl or phenyl is optionally substituted by R 3A ; or,
    R 3选自F、Cl、Br、CN、NO 2、-O-C 1-6烷基、C 1-6烷基、含有1个或2个N原子的5-6元杂芳基或苯基，所述C 1-6烷基、5-6元杂芳基或苯基任选地被R 3A取代；或者， R 3 is selected from F, Cl, Br, CN, NO 2 , -OC 1-6 alkyl, C 1-6 alkyl, 5-6 membered heteroaryl or phenyl containing 1 or 2 N atoms, The C 1-6 alkyl, 5-6 membered heteroaryl or phenyl is optionally substituted by R 3A ; or,
    R 3选自F、Cl、Br、CN、NO 2、-O-C 1-2烷基、C 1-2烷基、含有1个或2个N原子的5-6元杂芳基或苯基，所述C 1-6烷基、5-6元杂芳基或苯基任选地被R 3A取代；或者， R 3 is selected from F, Cl, Br, CN, NO 2 , -OC 1-2 alkyl, C 1-2 alkyl, 5-6 membered heteroaryl or phenyl containing 1 or 2 N atoms, The C 1-6 alkyl, 5-6 membered heteroaryl or phenyl is optionally substituted by R 3A ; or,
    R 3选自F、Cl、Br、CN、NO 2、-CF 3、-O-CH 3、-CH 3、-CONHCH 3、嘧啶基、吡唑基、吡啶基或苯基，所述嘧啶基、吡唑基、吡啶基或苯基任选地被R 3A取代。 R 3 is selected from F, Cl, Br, CN, NO 2 , -CF 3 , -O-CH 3 , -CH 3 , -CONHCH 3 , pyrimidyl, pyrazolyl, pyridyl or phenyl, and the pyrimidyl , pyrazolyl, pyridyl or phenyl is optionally substituted by R 3A .
  6. 根据权利要求1-5中任一项所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中R 3A独立地选自卤素、OH、NO 2、CN、CH 2F、CHF 2、CF 3或C 1-6烷基；或者，R 3A独立地选自卤素、CN、CF 3、NO 2或CH 3；或者，R 3A独立地选自卤素、CN、CF 3或NO 2；或者，R 3A独立地选自卤素、CN或CF 3；或者，R 3A独立地选自F、CN或CF 3。 The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1-5, wherein R 3A is independently selected from halogen, OH, NO 2 , CN, CH 2 F, CHF 2 , CF 3 or C 1-6 alkyl; or, R 3A is independently selected from halogen, CN, CF 3 , NO 2 or CH 3 ; or, R 3A is independently selected from halogen, CN, CF 3 or NO 2 ; or, R 3A is independently selected from halogen, CN or CF 3 ; alternatively, R 3A is independently selected from F, CN or CF 3 .
  7. 根据权利要求1-6中任一项所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中R 1选自H、OH、C 1-6烷基或-O-C 1-6烷基；或者，R 1为OH。 According to the compound represented by formula (I) described in any one of claims 1-6, or its stereoisomer or pharmaceutically acceptable salt, wherein R is selected from H, OH, C 1-6 alkyl or -OC 1-6 alkyl; or, R 1 is OH.
  8. 根据权利要求1-7中任一项所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中R 2为C 1-6烷基；或者，R 2为CH 3。 According to the compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1-7, wherein R 2 is C 1-6 alkyl; or, R 2 is CH3 .
  9. 根据权利要求1-8中任一项所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中R 4选自卤素、CF 3或-O-CH 3；或者，R 4选自F、Cl、Br、CF 3或-O-CH 3；或者，R 4选自F、Cl、CF 3或-O-CH 3；或者，R 4选自Cl或CF 3；或者，R 4为CF 3。 The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1-8, wherein R 4 is selected from halogen, CF 3 or -O-CH 3 ; Alternatively, R 4 is selected from F, Cl, Br, CF 3 or -O-CH 3 ; alternatively, R 4 is selected from F, Cl, CF 3 or -O-CH 3 ; alternatively, R 4 is selected from Cl or CF 3 ; or, R 4 is CF 3 .
  10. 根据权利要求1-9中任一项所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中R 5选自CN或NO 2；或者，R 5为CN。 According to the compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1-9, wherein R 5 is selected from CN or NO 2 ; or, R 5 is CN .
  11. 根据权利要求1-10中任一项所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中n选自0、1或2；或者，n选自1或2。The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1-10, wherein n is selected from 0, 1 or 2; or, n is selected from 1 or 2.
  12. 根据权利要求1-11中任一项所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中R 6、R 7和R 8均为H。 The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1-11, wherein R 6 , R 7 and R 8 are all H.
  13. 根据权利要求1-12中任一项所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中p为0。The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1-12, wherein p is 0.
  14. 根据权利要求1所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中所述式(I)所示化合物或其立体异构体或药学上可接受的盐为式(II)所示化合物或其立体异构体或药学上可接受的盐，The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to claim 1, wherein the compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt The salt is a compound represented by formula (II) or its stereoisomer or pharmaceutically acceptable salt,
    Figure PCTCN2022110325-appb-100005
    Figure PCTCN2022110325-appb-100005
    其中，环D、W、X、R 3、R 4、R 5、R 6、R 7、R 8、n和p如权利要求1中所定义。 Wherein, rings 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. 根据权利要求1所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中所述式(I)所示化合物或其立体异构体或药学上可接受的盐为式(III)所示化合物或其立体异构体或药学上可接受的盐，The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to claim 1, wherein the compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt The salt is a compound represented by formula (III) or its stereoisomer or pharmaceutically acceptable salt,
    Figure PCTCN2022110325-appb-100006
    Figure PCTCN2022110325-appb-100006
    其中，环D、W、X、R 3、R 4、R 5、R 7、R 8、n和p如权利要求1中所定义。 Wherein, rings D, W, X, R 3 , R 4 , R 5 , R 7 , R 8 , n and p are as defined in claim 1 .
  16. 根据权利要求1所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中所述式(I)所示化合物或其立体异构体或药学上可接受的盐为式(IV)所示化合物或其立体异构体或药学上可接受的盐，The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to claim 1, wherein the compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt The salt is a compound represented by formula (IV) or a stereoisomer or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022110325-appb-100007
    Figure PCTCN2022110325-appb-100007
    其中，环D、W、X、R 3、R 4、R 5、R 7、R 8和n如权利要求1中所定义。 Wherein, rings D, W, X, R 3 , R 4 , R 5 , R 7 , R 8 and n are as defined in claim 1.
  17. 根据权利要求1所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中 所述式(I)所示化合物或其立体异构体或药学上可接受的盐为式(V)所示化合物或其立体异构体或药学上可接受的盐，The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to claim 1, wherein the compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt The salt is a compound represented by formula (V) or a stereoisomer or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022110325-appb-100008
    Figure PCTCN2022110325-appb-100008
    其中，环D、W、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、n和p如权利要求1中所定义。 Wherein, rings 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. 根据权利要求1所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中所述式(I)所示化合物或其立体异构体或药学上可接受的盐为式(VI)所示化合物或其立体异构体或药学上可接受的盐，The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to claim 1, wherein the compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt The salt is a compound represented by formula (VI) or its stereoisomer or pharmaceutically acceptable salt,
    Figure PCTCN2022110325-appb-100009
    Figure PCTCN2022110325-appb-100009
    其中，环D、X、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和n如权利要求1中所定义； Wherein, ring D, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and n are as defined in claim 1;
    a 1、a 2、a 3和a 4独立地选自键或CH 2；以及a 5选自CH 2或CH 2CH 2。 a 1 , a 2 , a 3 and a 4 are independently selected from a bond or CH 2 ; and a 5 is selected from CH 2 or CH 2 CH 2 .
  19. 根据权利要求1所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，其中所述式(I)所示化合物或其立体异构体或药学上可接受的盐选自以下化合物或其立体异构体或药学上可接受的盐：The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to claim 1, wherein the compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt The salt is selected from the following compounds or stereoisomers or pharmaceutically acceptable salts thereof:
    Figure PCTCN2022110325-appb-100010
    Figure PCTCN2022110325-appb-100010
    Figure PCTCN2022110325-appb-100011
    Figure PCTCN2022110325-appb-100011
    Figure PCTCN2022110325-appb-100012
    Figure PCTCN2022110325-appb-100012
    Figure PCTCN2022110325-appb-100013
    Figure PCTCN2022110325-appb-100013
    Figure PCTCN2022110325-appb-100014
    Figure PCTCN2022110325-appb-100014
    Figure PCTCN2022110325-appb-100015
    Figure PCTCN2022110325-appb-100015
  20. 药物组合物，所述药物组合物包含权利要求1-19中任一项所述的式(I)所示化合物或其立体异构体或药学上可接受的盐，以及药学上可接受的辅料。A pharmaceutical composition comprising the compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1-19, and pharmaceutically acceptable auxiliary materials .
  21. 权利要求1-19中任一项所述的式(I)所示化合物或其立体异构体或药学上可接受的盐或者权利要求20所述的药物组合物在制备用于预防或者治疗由雄激素受体介导的疾病的药物中的用途。The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1-19 or the pharmaceutical composition described in claim 20 is used for preventing or treating Use in medicine for hormone receptor mediated diseases.
  22. 用于治疗由雄激素受体介导的疾病的方法，其包括向有需要的个体施用权利要求1-19中任一项所述的式(I)所示化合物或其立体异构体或药学上可接受的盐或者权利要求20所述的药物组合物。A method for treating diseases mediated by androgen receptors, comprising administering the compound represented by formula (I) or a stereoisomer thereof according to any one of claims 1-19 to an individual in need, or pharmaceutically Acceptable salt or the pharmaceutical composition described in claim 20.
  23. 用于预防或者治疗由雄激素受体介导的疾病的权利要求1-19中任一项所述的式(I)所示化合物或其立体异构体或药学上可接受的盐或者权利要求20所述的药物组合物。The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1-19 for preventing or treating diseases mediated by androgen receptor, or claim 20 The pharmaceutical composition.
  24. 权利要求1-19中任一项所述的式(I)所示化合物或其立体异构体或药学上可接受的盐或者权利要求20所述的药物组合物在预防或者治疗由雄激素受体介导的疾病中的用途。The compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1-19 or the pharmaceutical composition described in claim 20 is effective in the prevention or treatment of androgen receptor Uses in mediated diseases.
  25. 根据权利要求21或24所述的用途或者权利要求22所述的方法或者权利要求23所述的式(I)所示化合物或其立体异构体或药学上可接受的盐或药物组合物，其中所述由雄激素受体介导的疾病选自***癌或雄激素脱发。The use according to claim 21 or 24 or the method according to claim 22 or the compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt or pharmaceutical composition according to claim 23, Wherein said androgen receptor-mediated disease is selected from prostate cancer or androgenetic alopecia.
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