WO2023284860A1 - 3-phenylpropionic acid compound, preparation method therefor and medical application thereof - Google Patents

3-phenylpropionic acid compound, preparation method therefor and medical application thereof Download PDF

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Publication number
WO2023284860A1
WO2023284860A1 PCT/CN2022/105987 CN2022105987W WO2023284860A1 WO 2023284860 A1 WO2023284860 A1 WO 2023284860A1 CN 2022105987 W CN2022105987 W CN 2022105987W WO 2023284860 A1 WO2023284860 A1 WO 2023284860A1
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Prior art keywords
general formula
alkyl
compound represented
pharmaceutically acceptable
alkoxy
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PCT/CN2022/105987
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French (fr)
Chinese (zh)
Inventor
杨方龙
郑亮亮
杨倩
贺峰
陶维康
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN202280041339.9A priority Critical patent/CN117460713A/en
Publication of WO2023284860A1 publication Critical patent/WO2023284860A1/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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring

Definitions

  • the disclosure belongs to the field of medicine, and relates to a 3-phenylpropionic acid compound, its preparation method and its application in medicine.
  • the present disclosure relates to 3-phenylpropionic acid compounds represented by general formula (M), their preparation methods, pharmaceutical compositions containing such compounds and their use as therapeutic agents, especially in the preparation of soluble guanosine Use of an acid cyclase (sGC) agonist and/or activator and in the manufacture of a medicament for the treatment and/or prevention of a disease, condition or disorder mediated through sGC.
  • M 3-phenylpropionic acid compounds represented by general formula (M)
  • M pharmaceutical compositions containing such compounds and their use as therapeutic agents, especially in the preparation of soluble guanosine
  • sGC acid cyclase
  • Heart failure is a syndrome of cardiac circulatory disturbance due to dysfunction of the systolic or diastolic function of the heart. Heart failure is not an independent disease, but the terminal stage of various cardiovascular diseases, and almost all cardiovascular diseases will eventually lead to heart failure. Patients with heart failure are facing the threat of high mortality, which seriously affects the quality of life of patients. The huge patient population and relatively high mortality pose a huge challenge to the treatment of heart failure.
  • nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway can be observed, leading to decreased myocardial and vascular function , causing left ventricular remodeling, fibrosis and inflammation, and ultimately lead to the occurrence and development of heart failure.
  • NO nitric oxide
  • sGC sGC-soluble guanylate cyclase
  • cGMP guanosine monophosphate
  • NO is an important signaling molecule in various systems such as cardiovascular, nervous, digestive, metabolic, and immune systems, especially the cardiovascular system and nervous system.
  • sGC is a key metalloenzyme in the NO signal transduction pathway. After NO activates sGC, it catalyzes the conversion of guanosine triphosphate (GTP) into cGMP.
  • GTP guanosine triphosphate
  • cGMP is an important secondary messenger molecule, which can activate various effector molecules downstream of it, such as cyclic nucleotide-gated ion channel (CNG), phosphodiesterase (PDE) and cGMP-dependent protein kinase (PKG), etc.
  • CNG cyclic nucleotide-gated ion channel
  • PDE phosphodiesterase
  • PKG cGMP-dependent protein kinase
  • NO nitric oxide synthase
  • sGC receptor protein
  • sGC is distributed throughout the cytosol of mammals and is a heterodimer containing a heme prosthetic group consisting of an ⁇ subunit and a ⁇ subunit, each of which contains an amino-terminal HNOX binding domain (Heme NO/ Oxygen binding domain), the ⁇ -helical coiled-coil domain and the catalytic domain at the carboxy-terminus, the expression of a single subunit does not have catalytic activity, and the ⁇ heterodimer is necessary for the catalytic activity of sGC.
  • sGC has two isoforms, ⁇ 1 ⁇ 1 and ⁇ 2 ⁇ 1. ⁇ 2 ⁇ 1 only exists in limited tissues, while ⁇ 1 ⁇ 1 is widely expressed in tissues.
  • the activity of sGC in blood vessels is mainly due to the high abundance expression of ⁇ 1 ⁇ 1.
  • sGC Compounds found to act directly on sGC can be divided into two categories: agonists and activators.
  • the activation of sGC is due to the combination of NO and heme in the HNOX binding domain on the ⁇ 1 subunit, which changes the conformation of sGC and activates the catalytic domain, thereby converting GTP into cGMP.
  • the sGC agonist is dependent on the heme in the HNOX binding domain and activates sGC synergistically with NO gas. It can enhance the sensitivity of sGC to NO and plays an important role in the development of cardiovascular drugs.
  • oxidative stress in the human body can promote the conversion of sGC hemoglobin from a reduced state to an oxidized state, and the content of oxidized hemoglobin in humans with cardiovascular diseases such as hypertension and hyperlipidemia and type II diabetes will also increase, or genetically
  • the mutation of sGC will lead to desensitization of sGC to NO.
  • sGC activators are a class of compounds that can act on oxidized or deheme sGC.
  • R 0 is a hydrogen atom or Preferably, R 0 is a hydrogen atom or
  • Z is N or CR4 ;
  • G is N or CR 4a ;
  • R 1 and R 2 and the connected carbon atoms form ring A', or R 2 and R 3 and the connected carbon atoms form ring A, and the ring A' and ring A are each independently selected from cycloalkyl, heterocyclyl , aryl, and heteroaryl; wherein, the cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently selected from deuterium atom, halogen, hydroxyl, alkyl, haloalkyl, deuterated alkyl Alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, cyano, oxo, alkenyl, alkynyl, -NR 12a R 12b , -NHC(O)R 13 , -C( One or more identical or different substituents in O) R 13 and -C(O)OR 13 are substituted;
  • R3 is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano , amino and nitro;
  • R1 is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino and nitro;
  • R 4 and R 4a are the same or different, and each independently selected from a hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino and nitro;
  • R 5 and R 6 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein The above-mentioned alkyl, alkoxy, hydroxyalkyl, cycloalkyl and heterocyclic groups are each independently optionally selected from one or more of alkenyl, alkynyl , cyano, amino, nitro and R The same or different substituents are substituted; or R 5 and R 6 and the connected carbon atoms form a cycloalkyl or heterocyclic group;
  • R b is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclic; wherein said alkyl, alkoxy, hydroxyalkyl, ring Alkyl and heterocyclyl are each independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, cyano, amino and nitro The same or different substituents are substituted;
  • each R is the same or different, and each independently selected from halogen, hydroxy, carboxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino, and nitro;
  • R is selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cycloalkyl;
  • R9 is selected from a hydrogen atom, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; or R8 and R9 form a ring with a connected carbon atom Alkyl or heterocyclyl;
  • R 10 and R 11 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl and haloalkyl;
  • R 12a and R 12b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; or R 12a and R 12b form a heterocyclic group together with a connected nitrogen atom;
  • R 13 is selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;
  • n 0, 1, 2, 3 or 4.
  • the compound represented by general formula (M) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
  • G is N or CR 4a ;
  • R 1 and R 2 and the connected carbon atoms form ring A', or R 2 and R 3 and the connected carbon atoms form ring A, and the ring A' and ring A are each independently selected from cycloalkyl, heterocyclyl , aryl and heteroaryl; wherein, the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy Among the group, hydroxyalkyl group, cyano group, oxo group, alkenyl group, alkynyl group, -NR 12a R 12b , -NHC(O)R 13 , -C(O)R 13 and -C(O)OR 13 Substitution by one or more identical or different substituents;
  • R3 is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano , amino and nitro;
  • R1 is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino and nitro;
  • R 4 and R 4a are the same or different, and each independently selected from a hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino and nitro;
  • R 5 and R 6 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein The above-mentioned alkyl, alkoxy, hydroxyalkyl, cycloalkyl and heterocyclic groups are each independently optionally selected from one or more of alkenyl, alkynyl , cyano, amino, nitro and R The same or different substituents are substituted; or R 5 and R 6 and the connected carbon atoms form a cycloalkyl or heterocyclic group;
  • R b is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclic; wherein said alkyl, alkoxy, hydroxyalkyl, ring Alkyl and heterocyclyl are each independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, cyano, amino and nitro The same or different substituents are substituted;
  • each R is the same or different, and each independently selected from halogen, hydroxy, carboxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino, and nitro;
  • R is selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cycloalkyl;
  • R9 is selected from a hydrogen atom, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; or R8 and R9 form a ring with a connected carbon atom Alkyl or heterocyclyl;
  • R 10 and R 11 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl and haloalkyl;
  • R 12a and R 12b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; or R 12a and R 12b form a heterocyclic group together with a connected nitrogen atom;
  • R 13 is selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;
  • n 0, 1, 2, 3 or 4.
  • the compound represented by the general formula (M), the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof Salt to use:
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 2a is the same or different, and each independently selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, oxo, alkenyl, alkynyl, -NR 12a R 12b , -NHC(O)R 13 , -C(O)R 13 and -C(O)OR 13 ;
  • n 0, 1, 2, 3 or 4;
  • R 1 , R 4 to R 11 , R 12a , R 12b , R 13 and n are as defined in general formula (M) or general formula (I).
  • the compound represented by general formula (M), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is represented by general formula (III) A compound or a pharmaceutically acceptable salt thereof:
  • G is CR 4a ;
  • Ring A, R 2a , R 4a , R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in the general formula (II).
  • the compound represented by general formula (M), general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof wherein: R 10 is selected from a hydrogen atom, a halogen and a C 1-6 alkyl group; preferably, R 10 is a hydrogen atom.
  • the compound represented by general formula (M) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (G) or a pharmaceutically acceptable salt thereof:
  • R 0 is a hydrogen atom or Preferably, R 0 is a hydrogen atom or
  • Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 2a is the same or different, and each independently selected from deuterium atom, halogen, hydroxyl, alkyl, haloalkyl, deuterated alkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, oxo, alkenyl, alkynyl, -NR 12a R 12b , -NHC(O)R 13 , -C(O)R 13 and -C(O)OR 13 ;
  • R 5a and R 5b are different, and are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein said alkyl, Alkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxy, cyano, One or more of the same or different substituents in amino and nitro;
  • n 0, 1, 2, 3 or 4;
  • Z, G, R 1 , R 7 , R 8 , R 12a , R 12b , R 13 and n are as defined in the general formula (M).
  • the compound represented by general formula (M) or general formula (G) or a pharmaceutically acceptable salt thereof is general formula (G-1) or general formula (G- 2)
  • Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G).
  • the compound represented by general formula (M), general formula (G), general formula (I), general formula (II) or general formula (III) or its pharmaceutically acceptable A salt which is a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof:
  • R 5a and R 5b are different, and are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein said alkyl, Alkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxy, cyano, One or more of the same or different substituents in amino and nitro;
  • G is CR 4a ;
  • Ring A, R 2a , R 4a , R 1 , R 4 , R 7 , R 8 , m and n are as defined in general formula (II) or general formula (III).
  • the general formula (M), general formula (G), general formula (I), general formula (II), general formula (III) or general formula (IV) A compound or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof:
  • R 5a and R 5b are different, and are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein said alkyl, Alkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxy, cyano, One or more of the same or different substituents in amino and nitro;
  • G is CR 4a ;
  • Ring A, R 2a , R 4a , R 1 , R 4 , R 7 , R 8 , m and n are as defined in general formula (II), general formula (III) or general formula (IV).
  • the compound represented by general formula (M), general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof wherein: R 5 is halogenated C 1-6 alkyl; preferably, R 5 is More preferably, R is
  • the compound represented by (IV-2) or a pharmaceutically acceptable salt thereof wherein: R 5a and R 5b are different, and are each independently selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group; wherein said C 1-6 Alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl are each independently optionally selected from halogen, C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxyl, cyano,
  • each R 2a is the same or different, and each independently selected from a deuterium atom, a halogen, and a C 1-6 alkyl group; preferably, each R 2a is the same or different, and each independently selected from a deuterium atom, a fluorine atom, a chlorine atom, and a methyl group.
  • the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II ), the general formula (III), the general formula (IV), the general formula (IV-1) or the compound shown in the general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein the ring A is selected from 6 to 10 members Aryl, 5 to 10 membered heteroaryl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl; preferably, ring A is selected from phenyl, 5 or 6 membered heteroaryl and 5 or 6 membered ring alkyl.
  • the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II ), the general formula (III), the general formula (IV), the general formula (IV-1) or the compound shown in the general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein the ring A is selected from 6 to 10 members Aryl, 5 to 10 membered heteroaryl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl; preferably, ring A is selected from phenyl, 5 or 6 membered heteroaryl, 5 or 6 membered ring Alkyl and 5 or 6 membered heterocyclyl; more preferably, Ring A is selected from phenyl, 5 or 6 membered cycloalkyl and 5 or 6 membered heterocyclyl.
  • each R 7 is the same or different, And each independently is a halogen or C 1-6 alkyl; preferably, each R 7 is the same or different, and each independently is a halogen; more preferably, each R 7 is independently a chlorine atom.
  • each R 7 is the same or different, and each independently selected from a chlorine atom, a bromine atom and a methyl group.
  • the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II ), general formula (III), general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein: each R 7 is the same or different, And each independently is halogen or C 1-6 alkyl, and n is 1, 2, 3 or 4; or n is 0;
  • R 7 is halogen or C 1-6 alkyl, and n is 1;
  • R 7 is halogen and n is 1.
  • the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II ), general formula (III), general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein: R 1 , R 4 and R 4a are the same or different, and are independently selected from hydrogen atom, halogen and C 1-6 alkyl; preferably, R 1 , R 4 and R 4a are all hydrogen atoms.
  • Ring A is selected from phenyl, 5 or 6-membered heteroaryl, 5 or 6-membered Cycloalkyl and 5- or 6-membered heterocyclyl; G is N or CR 4a ; each R 2a is the same or different, and is independently halogen or C 1-6 alkyl; m is 0, 1 or 2; R 1 , R 4 and R 4a are all hydrogen atoms; R 5 is halogenated C 1-6 alkyl; R 6 , R 9 and R 11 are all hydrogen atoms; R 10 is hydrogen atom; R 7 is halogen or C 1- 6 alkyl; n is 1; R 8 is 3 to 8 membered cycloalkyl.
  • Ring A is selected from phenyl, 5 or 6-membered heteroaryl, 5 or 6-membered Cycloalkyl and 5 or 6-membered heterocyclyl; G is CR 4a ; each R 2a is the same or different, and each independently is halogen or C 1-6 alkyl; m is 0, 1 or 2; R 1 , R 4 and R 4a are both hydrogen atoms; R 5 is a halogenated C 1-6 alkyl group; R 10 is a hydrogen atom; R 7 is a halogen or a C 1-6 alkyl group; n is 1; R 8 is a cyclopropyl group.
  • the compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein: R 5a and R 5b are different, and each independently selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclic group; wherein said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, 3 to 8-membered cycloalkyl and 3
  • the 8-membered heterocyclic group is independently optionally selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, One or more of the same or different substituents in hydroxyl, cyano, amino and nitro are substituted;
  • G is
  • the compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein: R 5a and R 5b are different, and each independently C 1-6 alkyl or halogenated C 1-6 alkyl; G is CR 4a ; R 1 , R 4 and R 4a are the same or different, and each independently selected from hydrogen atom, halogen and C 1- 6 alkyl; ring A is selected from phenyl, 5 or 6 membered heterocyclic group and 5 or 6 membered cycloalkyl; each R 2a is the same or different, and each independently is halogen or C 1-6 alkyl, m is 1, 2, 3 or 4; or m is 0; R 7 is halogen, n is 1; R 8 is C 1-6 alkyl or 3 to 8 membered cycloalkyl.
  • the compound represented by general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein: R 5a is C 1-6 alkyl, R 5b is halogenated C 1-6 alkyl; G is CR 4a ; R 1 , R 4 and R 4a are all hydrogen atoms; ring A is selected from phenyl, 5 or 6 membered heteroaryl Group, 5 or 6 membered cycloalkyl and 5 or 6 membered heterocyclic group; each R 2a is the same or different, and each independently is halogen or C 1-6 alkyl; m is 0, 1 or 2; R 7 is Halogen or C 1-6 alkyl; n is 0 or 1; R 8 is C 1-6 alkyl or 3 to 8 membered cycloalkyl.
  • Typical compounds of the present disclosure include, but are not limited to:
  • R is alkyl or Preferably, R is alkyl or
  • R w is alkyl or allyl; preferably, R w is allyl;
  • Z, G, R 1 to R 3 , R 5 to R 11 and n are as defined in the general formula (M).
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • G, R 1 to R 11 and n are as defined in the general formula (I).
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 to R 11 , m and n are as defined in the general formula (II).
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to compounds represented by general formula (GA) or salts thereof:
  • R is alkyl or Preferably, R is alkyl or
  • R w is alkyl or allyl; preferably, R w is allyl;
  • Rings A, Z, G, R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G).
  • Another aspect of the present disclosure relates to a compound or a salt thereof represented by general formula (G-1A) or general formula (G-2A):
  • R is alkyl or Preferably, R is alkyl or
  • R w is alkyl or allyl; preferably, R w is allyl;
  • Rings A, Z, G, R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (G-1) or general formula (G-2).
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (IV).
  • Another aspect of the present disclosure relates to a compound or a salt thereof represented by general formula (IV-1A) or general formula (IV-2A):
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (IV-1) or general formula (IV-2).
  • Another aspect of the present disclosure relates to a compound or a salt thereof represented by general formula (Ga-A), general formula (Ga-A1) or general formula (Ga-A2):
  • R 5a and R 5b are different, and are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein said alkyl, alkoxy
  • the radical, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, cyano, amino and One or more identical or different substituents in the nitro group are substituted; wherein when one of R 5a and R 5b is methyl, the other is not ethyl or propyl;
  • Rings A, Z, G, R 2a , m and R 1 are as defined in general formula (G), general formula (G-1) or general formula (G-2).
  • Another aspect of the present disclosure relates to a compound or a salt thereof represented by general formula (IVa-A), general formula (IVa-A1) or general formula (IVa-A2):
  • R 5a and R 5b are different, and are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein said alkyl, alkoxy
  • the radical, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, cyano, amino and One or more identical or different substituents in the nitro group are substituted; wherein when one of R 5a and R 5b is methyl, the other is not ethyl or propyl;
  • G is CR 4a ;
  • Ring A, R 2a , m, R 4a , R 1 and R 4 are as defined in general formula (IV), general formula (IV-1) or general formula (IV-2).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (M) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • a compound represented by the general formula (MA) or a salt thereof is reacted to obtain a compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof;
  • R is alkyl or Preferably, R is alkyl or
  • R w is alkyl or allyl; preferably, R w is allyl;
  • Z, G, R 0 , R 1 to R 3 , R 5 to R 11 and n are as defined in the general formula (M).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (MA) or a salt thereof, the method comprising the following steps:
  • Z, G, R, R 1 to R 3 , R 5 to R 11 and n are as defined in the general formula (MA).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • the compound represented by the general formula (IA) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • G, R 1 to R 11 and n are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IA) or a salt thereof, the method comprising the following steps:
  • the compound represented by the general formula (Ia-A) or its salt undergoes a condensation acylation reaction with the compound represented by the general formula (Ib-A) or its salt to obtain the compound represented by the general formula (IA) or its salt;
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • G, R 1 to R 11 and n are as defined in general formula (IA).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • the compound represented by the general formula (IIA) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof with the following steps;
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 to R 11 , m and n are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIA) or a salt thereof, the method comprising the following steps:
  • the compound represented by the general formula (IIa-A) or its salt undergoes a condensation acylation reaction with the compound represented by the general formula (Ib-A) or its salt to obtain the compound represented by the general formula (IIA) or its salt;
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 to R 11 , m and n are as defined in the general formula (IIA).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIA) or a salt thereof, the method comprising the following steps:
  • the compound represented by the general formula (IIIa-A) or its salt undergoes a condensation acylation reaction with the compound represented by the general formula (IIIb-A) or its salt to obtain the compound represented by the general formula (IIIA) or its salt;
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in general formula (IIIA).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • a compound represented by the general formula (GA) or a salt thereof is reacted to obtain a compound represented by the general formula (G) or a pharmaceutically acceptable salt thereof;
  • R is alkyl or Preferably, R is alkyl or
  • R w is alkyl or allyl; preferably, R w is allyl;
  • Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • R is alkyl or Preferably, R is alkyl or
  • R w is alkyl or allyl; preferably, R w is allyl;
  • Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • a compound represented by general formula (G-2A) or a salt thereof is reacted to obtain a compound represented by general formula (G-2) or a pharmaceutically acceptable salt thereof;
  • R is alkyl or Preferably, R is alkyl or
  • R w is alkyl or allyl; preferably, R w is allyl;
  • Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G-2).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G-1A) or general formula (G-2A) or a salt thereof, the method comprising the following steps:
  • Rings A, Z, G, R, R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (G-1A) or general formula (G-2A).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • the compound represented by the general formula (IVA) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (IV).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • the compound represented by the general formula (IV-1A) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (IV-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • the compound represented by the general formula (IV-2A) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (IV-2).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-1A) or general formula (IV-2A) or a salt thereof, the method comprising the following steps:
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (IV-1A) or general formula (IV-2A).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (M) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • the compound represented by the general formula (Ma-A) or its salt and the compound represented by the general formula (MB) or its salt undergo condensation acylation reaction to obtain the compound represented by the general formula (M) or its pharmaceutically acceptable salt ;
  • Z, G, R 0 , R 1 to R 3 , R 5 to R 11 and n are as defined in the general formula (M).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • G, R 1 to R 11 and n are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • Ring A, R 2a , G, R 1 , R 4 to R 11 , m and n are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • the compound represented by the general formula (IIIa-A) or its salt and the compound represented by the general formula (IIIB) or its salt undergo a condensation acylation reaction to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof ;
  • Ring A, R 2a , G, R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in the general formula (III).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G-1) or general formula (G-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • the compound represented by the general formula (Ga-A) or its salt and the compound represented by the general formula (GB) or its salt undergo a condensation acylation reaction to obtain the compound represented by the general formula (G-1) or the general formula (G-2).
  • Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G-1) or (G-2).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (IV-1) or general formula (IV-2).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G-1) and general formula (G-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • the compound represented by general formula (G) or its pharmaceutically acceptable salt is prepared and separated to obtain the compound represented by general formula (G-1) and general formula (G-2) or its pharmaceutically acceptable salt;
  • Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-1) and general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
  • Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (IV-1) or general formula (IV-2).
  • Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a therapeutically effective amount of the general formula (M), general formula (G), general formula (G-1), general formula (G- 2), the compound shown in general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2) and table A or Its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III),
  • the compound shown in general formula (IV), general formula (IV-1), general formula (IV-2) and table A or its pharmaceutically acceptable salt or the pharmaceutical composition comprising it are in the preparation of sGC agonist and/or Use in activators.
  • the present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III),
  • a disease, condition or disorder alleviated by agonizing and/or activating sGC selected from cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, Osteoporosis, fibrotic disease, neurological disease, urinary system disease, and sexual dysfunction; preferably, said disease, condition or disorder is selected from cardiovascular disease, pulmonary hypertension, and renal disease; more preferably, said renal disease is chronic Kidney failure or chronic renal insufficiency.
  • the present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III),
  • a disease, condition or disorder alleviated by agonizing and/or activating sGC selected from cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, Osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; wherein the cardiovascular disease is selected from hypertension, atherosclerosis, coronary heart disease, lumbar spinal stenosis, peripheral arterial disease, intermittent Claudication, critical lower extremity ischemia, stable or unstable angina, myocardial infarction, heart failure, hypogonadism, stroke, coronary artery spasm, cerebral vas
  • the present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III),
  • a disease, condition or disorder alleviated by agonizing and/or activating sGC selected from cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, Osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; wherein said fibrotic disease is selected from the group consisting of fibrosis of the skin, liver, kidney and lung; said urinary system disease is selected from overactive bladder , benign prostatic hyperplasia and erectile dysfunction; said neurological disease is selected from Alzheimer's disease, Parkinson's disease and neuropathic pain; said inflammatory disease is selected from
  • the present disclosure further relates to a method for agonizing and/or activating sGC, which comprises administering a therapeutically effective amount of general formula (M), general formula (G), general formula (G-1), general formula (G- 2), the compound shown in general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2) and table A or A pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it.
  • the present disclosure further relates to a method of treating and/or preventing a disease, condition or disorder alleviated by agonizing and/or activating sGC comprising administering to a patient in need thereof a therapeutically effective amount of Formula (M), Formula (G) , general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general
  • said disease, condition or disease are selected from cardiovascular disease, nephropathy, pulmonary hypertension, inflammatory disease Disease, diabetes, glaucoma, obesity, osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction.
  • said disease, condition or disorder is selected from cardiovascular disease, pulmonary hypertension and renal disease; more preferably
  • the renal disease is chronic renal failure or chronic renal insufficiency.
  • the present disclosure further relates to a method of treating and/or preventing a disease, condition or disorder alleviated by agonizing and/or activating sGC comprising administering to a patient in need thereof a therapeutically effective amount of Formula (M), Formula (G) , general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general Formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, described disease, condition or disease is that described disease, condition or disease are selected from cardiovascular disease, kidney disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction wherein said cardiovascular disease is selected from hypertension, atherosclerosis coronary artery disease, lumbar spinal stenosis, peripheral artery disease, intermittent claudication, critical lower extremity ischemia, stable or unstable angina, my
  • the present disclosure further relates to a method of treating and/or preventing a disease, condition or disorder alleviated by agonizing and/or activating sGC comprising administering to a patient in need thereof a therapeutically effective amount of Formula (M), Formula (G) , general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general
  • the present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) ), general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, which is used as a drug .
  • the present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III),
  • the present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III),
  • the present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) ), general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, which is used for the treatment of and/or prevent a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein said disease, condition or disorder is selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, Obesity, osteoporosis, fibrotic disease, neurological disease, urinary system disease, and sexual dysfunction; preferably, said disease, condition or disorder is selected from cardiovascular disease, pulmonary hypertension, and renal disease; more preferably, said renal disease For chronic renal failure or chronic renal insufficiency.
  • a disease, condition or disorder is selected from the group consisting of cardiovascular disease,
  • the present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) ), general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, which is used for the treatment of and/or preventing a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein said disease, condition or disorder is selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, Osteoporosis, fibrotic disease, neurological disease, urinary system disease, and sexual dysfunction; preferably, said disease, condition or disorder is selected from cardiovascular disease, pulmonary hypertension, and renal disease; more preferably, said renal disease is chronic Kidney failure or chronic renal insufficiency.
  • a disease, condition or disorder is selected from the group consisting of cardiovascular disease
  • the present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) ), general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, which is used for the treatment of and/or prevent a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein said disease, condition or disorder is selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, Obesity, osteoporosis, fibrosis, neurological disease, urinary system disease and sexual dysfunction; wherein the cardiovascular disease is selected from hypertension, atherosclerosis, coronary heart disease, lumbar spinal stenosis, peripheral arterial disease, Intermittent claudication, critical lower extremity ischemia, stable or unstable angina, myocardial infarction,
  • the present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) ), general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, which is used for the treatment of and/or preventing a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein said disease, condition or disorder is selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, Osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; wherein the cardiovascular disease is selected from hypertension, atherosclerosis, coronary heart disease, lumbar spinal stenosis, peripheral arterial disease, intermittent Claudication, critical lower extremity ischemia, stable or unstable angina, myocardial infarction, heart failure,
  • the present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) ), general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, which is used for the treatment of and/or prevent a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein said disease, condition or disorder is selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, Obesity, osteoporosis, fibrosis, neurological disease, urinary system disease and sexual dysfunction; wherein said fibrosis is selected from fibrosis of skin, liver, kidney and lung; said urinary system disease is selected from bladder ADHD, benign prostatic hyperplasia and erectile dysfunction; said neurological disease is selected from Alzheimer's disease, Parkinson's disease and
  • the present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) ), general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, which is used for the treatment of and/or preventing a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein said disease, condition or disorder is selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, Osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; wherein said fibrotic disease is selected from the group consisting of fibrosis of the skin, liver, kidney and lung; said urinary system disease is selected from overactive bladder , benign prostatic hyperplasia and erectile dysfunction; said neurological disease is selected from Alzheimer's
  • the active compounds are prepared in a form suitable for administration by any suitable route, and the compositions of the present disclosure are formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular or subcutaneous), administration by inhalation or insufflation.
  • the disclosed compounds can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.
  • the active compound is preferably presented in unit dose form, or in such a form that the patient can self-administer it as a single dose.
  • a unit dosage form of a compound or composition of the present disclosure may be presented as a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstituted powder or liquid.
  • a suitable unit dosage may be from 0.1 to 1000 mg.
  • the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • auxiliary materials selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the compositions may contain from 0.1 to 99% by weight of active compound.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants.
  • These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.
  • Oral formulations can also be provided in soft gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, or where the active ingredient is mixed with a water-soluble carrier or an oil vehicle.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • Oily suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil.
  • the oily suspensions may contain a thickening agent.
  • Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • compositions of the present disclosure may also be in the form of oil-in-water emulsions.
  • the oily phase may be vegetable oil, or mineral oil or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
  • Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase.
  • the injection or microemulsion may be injected into the patient's bloodstream by local bulk injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the DeltecCADD-PLUS.TM. Model 5400 intravenous pump.
  • compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blended and fixed oil may be used.
  • fatty acids are also used in the preparation of injectables.
  • the disclosed compounds may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
  • Aqueous suspensions of dispersible powders and granules can be prepared by the addition of water to administer the disclosed compounds.
  • These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
  • the dosage of the drug to be administered depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the state of health of the patient, the behavior of the patient , patient's diet, administration time, administration method, rate of excretion, combination of drugs, severity of disease, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dosage of the compound or the content of the pharmaceutically acceptable saltkinds can be validated against traditional treatment regimens.
  • alkyl refers to a saturated aliphatic hydrocarbon group comprising 1 to 20 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19 or 20) carbon atoms straight or branched (i.e. C 1-20 alkyl), preferably an alkyl group containing 1 to 12 carbon atoms (i.e. C 1-12 alk group), more preferably an alkyl group containing 1 to 6 carbon atoms (i.e. C 1-6 alkyl group).
  • 1 to 20 e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19 or 20
  • C 1-20 alkyl preferably an alkyl group containing 1 to 12 carbon atoms (i.e. C 1-12 alk group), more preferably an alkyl group containing 1 to 6 carbon atoms (i.e. C 1-6 alkyl group).
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • Alkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents being preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkenyl refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as above, preferably having 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11 and 12) carbon atoms (ie C 2-12 alkenyl), more preferably alkenyl containing 2 to 6 carbon atoms (ie C 2-6 alkenyl).
  • Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is selected from the group consisting of alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl , cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms alkynyl (ie C 2-12 alkynyl).
  • the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkynyl group).
  • Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Alkynyl may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from the group consisting of alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl
  • substituent is preferably selected from the group consisting of alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl
  • radical, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl are examples of radical, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, and butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring having 3 to 20 (for example 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie 3 to 20 membered cycloalkyl), preferably with 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e. 3 to 12 membered cycloalkyl), preferably containing 3 to 8 carbon atoms, more preferably having 3 to 6 carbon atoms (i.e.
  • cycloalkyl 3 to 6 membered cycloalkyl groups) cycloalkyl), most preferably having 5 or 6 carbon atoms (ie 5 or 6 membered cycloalkyl).
  • monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 members, sharing one carbon atom (called a spiro atom) between monocyclic rings, which may contain one or more double bonds (that is, 5 to 20 membered spirocycloalkane base). It is preferably 6 to 14 membered (ie 6 to 14 membered spirocycloalkyl), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 7 to 10 membered spirocycloalkyl).
  • spirocycloalkyl groups can be divided into multiple spirocycloalkyl groups such as single spirocycloalkyl and double spirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds (ie, 5 to 20 membered fused cycloalkyl).
  • fused cycloalkyl Preferably it is 6 to 14 membered (ie 6 to 14 membered fused cycloalkyl), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 7 to 10 membered fused cycloalkyl).
  • bicyclic, tricyclic, tetracyclic and other polycyclic condensed cycloalkyl groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan Bicycloalkyl group of 1/4, 6/5, 6/6, 6/7, 7/5 or 7/6.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5 to 20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds (i.e., 5 to 20 membered bridge Cycloalkyl). It is preferably 6 to 14 membered (ie, 6 to 14 membered bridged cycloalkyl group), more preferably 7 to 10 membered (eg, 7, 8, 9 or 10 membered) (ie, 7 to 10 membered bridged cycloalkyl group).
  • bridged cycloalkyl groups preferably bicyclic, tricyclic and other tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl) fused to an aryl, heteroaryl or heterocycloalkane
  • a radical ring where the ring attached to the parent structure is a cycloalkyl, non-limiting examples include etc.; preferred
  • Cycloalkyl may be substituted or unsubstituted and when substituted it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic ring substituent comprising 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, Said sulfur can be optionally oxoated (i.e. to form a sulfoxide or sulfone), but excluding the -O-O-, -O-S- or -S-S- ring portion, the remaining ring atoms are carbon (i.e. 3 to 20 membered heterocycle base).
  • 1, 2, 3 and 4) are hetero atom (ie 3 to 12 membered heterocyclyl); more preferably contains 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8), of which 1-3 (eg 1, 2 and 3 ) is a heteroatom (ie 3 to 12 membered heterocyclyl); more preferably contains 3 to 6 ring atoms, of which 1-3 are heteroatoms (ie 3 to 6 membered heterocyclyl); most preferably contains 5 or 6 ring atoms, of which 1-3 are heteroatoms (ie 5 or 6 membered heterocyclyl).
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperidine Zinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.
  • Polycyclic heterocyclyls include spiroheterocyclyls, fused heterocyclyls and bridged heterocyclyls.
  • spiroheterocyclyl refers to 5 to 20 membered polycyclic heterocyclic groups sharing one atom (called spiro atom) between monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur atoms, said sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds (ie 5 to 20 membered spiroheterocyclyl).
  • the spiroheterocyclyl can be divided into multiple spiroheterocyclyls such as single spiroheterocyclyl and double spiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl.
  • spiroheterocyclyls include:
  • fused heterocyclyl refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, said sulfur optionally being oxo (i.e. forming sulfoxide or sulfone), and the remaining ring atoms being carbon (i.e. 5 to 20-membered fused heterocyclyl). It is preferably 6 to 14 membered, more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 6 to 14 membered condensed heterocyclic group).
  • bicyclic, tricyclic, tetracyclic and other polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan Yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan bicyclic condensed heterocyclic group.
  • fused/4-membered 3-membered/5-membered
  • bridged heterocyclyl refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly connected, which may contain one or more double bonds, in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, said sulfur being optionally substituted with oxo (ie to form a sulfoxide or sulfone), with the remaining ring atoms being carbon (ie, a 5 to 14 membered bridged heterocyclyl).
  • it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring includes a heterocyclyl as described above (including monocyclic heterocyclyl, spiro heterocyclyl, fused heterocyclyl and bridged heterocyclyl) fused to an aryl, heteroaryl or cycloalkyl On the ring, where the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • the heterocyclyl group may be substituted or unsubstituted and when substituted it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated ⁇ -electron system, preferably 6 to 10 membered , such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include :
  • Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents being preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms (eg 1, 2, 3 and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered (e.g. 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered heteroaryl (5 or 6 membered heteroaryl), e.g.
  • the heteroaryl ring includes a heteroaryl as described above fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include :
  • Heteroaryl may be substituted or unsubstituted and when substituted it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • the above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from a parent ring atom, or by removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent
  • the residues from which the atoms are derived are "divalent cycloalkyl", "divalent heterocyclyl", “arylene” and "heteroarylene".
  • the bond Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or both Two configurations.
  • cycloalkyloxy refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
  • deuteroalkyl refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • deuterated alkoxy refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy group is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxyl refers to -OH.
  • mercapto refers to -SH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.
  • Compounds of the present disclosure include isotopic derivatives thereof.
  • isotopically derivative refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms.
  • hydrogen is replaced by "deuterium” or “tritium”
  • fluorine is replaced by 18 F-fluorine label ( 18 F isotope), or 11 C-, 13 C-, or 14 C-enriched
  • carbon 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes
  • Such compounds are useful, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.
  • deuterated forms of the compounds of the present disclosure mean that each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound.
  • Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including but not limited to deuterated borane, trideuterioborane in tetrahydrofuran , deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • Deuterated compounds generally retain comparable activity to non-deuterated compounds, and can achieve better metabolic stability when deuterated at certain sites, thereby gaining certain therapeutic advantages.
  • deuterium D When a position is specifically designated as deuterium D, the position is understood to have an abundance of deuterium (ie at least 15% deuterium incorporation) that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%).
  • Exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium (i.e. at least 15% deuterium incorporation), at least 2000 times more abundant deuterium (i.e. at least 30% deuterium incorporation) , at least 3000 times the abundance of deuterium (i.e. at least 45% deuterium incorporation), at least 3340 times the abundance of deuterium (i.e. at least 50.1% deuterium incorporation), at least 3500 times the abundance of deuterium (i.e.
  • deuterium incorporation at least 52.5% deuterium incorporation
  • at least 4000-fold more abundant deuterium i.e. at least 60% deuterium incorporation
  • at least 4500-fold more abundant deuterium i.e. at least 67.5% deuterium incorporation
  • at least 5000-fold Deuterium in abundance i.e. at least 75% deuterium incorporation
  • deuterium in at least 5500 times abundance i.e. at least 82.5% deuterium incorporation
  • deuterium in at least 6000 times abundance i.e. at least 90% deuterium incorporation deuterium incorporation
  • at least 6333.3 times the abundance of deuterium i.e. at least 95% deuterium incorporation
  • at least 6466.7 times the abundance of deuterium i.e.
  • deuterium incorporation at least 97% deuterium incorporation
  • at least 6600 times the abundance of deuterium That is, at least 99% deuterium incorporation
  • at least 6633.3 times the abundance of deuterium ie, at least 99.5% deuterium incorporation
  • or higher abundance of deuterium at least 97% deuterium incorporation
  • Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • lactam-lactim isomerization
  • An example of a lactam-lactim equilibrium is between A and B as shown below.
  • C 1-6 alkyl optionally substituted by halogen or cyano means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen And the case of cyano substitution.
  • Substituted means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by a corresponding number of substituents. Possible or impossible substitutions can be determined (by experiment or theory) by those skilled in the art without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have proper biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • the term "therapeutically effective amount” refers to the amount of the drug or agent that is sufficient to achieve or partially achieve the desired effect.
  • the determination of the therapeutically effective dose varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate therapeutically effective dose in individual cases can be determined by those skilled in the art according to routine tests.
  • the term "pharmaceutically acceptable” means those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with patient tissues without undue toxicity, irritation, allergic reaction or Other problems or complications that have a reasonable benefit/risk ratio and are valid for the intended use.
  • the preparation method of the compound represented by the general formula (M) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound represented by the general formula (MA) or a salt thereof is reacted to obtain a compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof;
  • R is alkyl or Preferably, R is alkyl or
  • R w is alkyl or allyl; preferably, R w is allyl;
  • R0 is A compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof; preferably, when R is When, the compound represented by the general formula (MA) or its salt is removed under the action of a metal catalyst (preferably tetrakis(triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) R w , to obtain R0 is A compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof; preferably, when R is When, the compound represented by the general formula (MA) or its salt is removed under the action of a metal catalyst (preferably tetrakis(triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) R w , to obtain R0 is A compound represented by general formula (M) or a pharmaceutically acceptable salt thereof;
  • Z, G, R 0 , R 1 to R 3 , R 5 to R 11 and n are as defined in the general formula (M).
  • the preparation method of the compound represented by the general formula (MA) or its salt of the present disclosure comprises the following steps:
  • Z, G, R, R 1 to R 3 , R 5 to R 11 and n are as defined in the general formula (MA).
  • the preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • G, R 1 to R 11 and n are as defined in the general formula (I).
  • the preparation method of the compound represented by the general formula (IA) or its salt of the present disclosure comprises the following steps:
  • the compound represented by the general formula (Ia-A) or its salt and the compound represented by the general formula (Ib-A) or its salt undergo a condensation acylation reaction under alkaline conditions to obtain the compound represented by the general formula (IA) or its salts;
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • G, R 1 to R 11 and n are as defined in general formula (IA).
  • the preparation method of the compound represented by the general formula (II) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 to R 11 , m and n are as defined in the general formula (II).
  • the preparation method of the compound represented by the general formula (IIA) or its salt of the present disclosure comprises the following steps:
  • the compound represented by the general formula (IIa-A) or its salt and the compound represented by the general formula (Ib-A) or its salt undergo a condensation acylation reaction under alkaline conditions to obtain the compound represented by the general formula (IIA) or its salts;
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 to R 11 , m and n are as defined in the general formula (IIA).
  • the preparation method of the compound represented by the general formula (III) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound represented by the general formula (IIIA) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in the general formula (III).
  • the preparation method of the compound represented by the general formula (IIIA) of the present disclosure or a salt thereof comprises the following steps:
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in general formula (IIIA).
  • the preparation method of the compound represented by the general formula (G) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound represented by the general formula (GA) or a salt thereof is reacted to obtain a compound represented by the general formula (G) or a pharmaceutically acceptable salt thereof;
  • R is alkyl or Preferably, R is alkyl or
  • R w is alkyl or allyl; preferably, R w is allyl;
  • R0 is A compound represented by general formula (G) or a pharmaceutically acceptable salt thereof; preferably, when R is When, the compound represented by the general formula (GA) or its salt is removed under the action of a metal catalyst (preferably tetrakis(triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) R w , to obtain R0 is A compound represented by general formula (G) or a pharmaceutically acceptable salt thereof; preferably, when R is When, the compound represented by the general formula (GA) or its salt is removed under the action of a metal catalyst (preferably tetrakis(triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) R w , to obtain R0 is A compound represented by general formula (G) or a pharmaceutically acceptable salt thereof;
  • Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G).
  • the preparation method of the compound represented by the general formula (G-1) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R is alkyl or Preferably, R is alkyl or
  • R w is alkyl or allyl; preferably, R w is allyl;
  • R is an alkyl group
  • the compound represented by the general formula (G-1A) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain R as represented by the general formula (G-1 ) of a hydrogen atom.
  • the compound represented by the general formula (G-1A) or its salt will remove R under the action of a metal catalyst (preferably tetrakis (triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) , get R 0 as A compound represented by the general formula (G-1) or a pharmaceutically acceptable salt thereof; preferably, when R is , the compound represented by the general formula (G-1A) or its salt will remove R under the action of a metal catalyst (preferably tetrakis (triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) , get R 0 as A compound represented by general formula (G-1) or a pharmaceutically acceptable salt thereof;
  • a metal catalyst preferably tetrakis (triphenylphosphine) palladium
  • a nucleophile preferably diethylamine or tetra
  • Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G-1).
  • the preparation method of the compound represented by the general formula (G-2) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R is alkyl or Preferably, R is alkyl or
  • R w is alkyl or allyl; preferably, R w is allyl;
  • R is an alkyl group
  • the compound represented by the general formula (G-2A) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain R 0 as represented by the general formula (G-2) of a hydrogen atom.
  • the compound represented by the general formula (G-2A) or its salt will remove R under the action of a metal catalyst (preferably tetrakis (triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) , get R 0 as A compound represented by the general formula (G-2) or a pharmaceutically acceptable salt thereof; preferably, when R is , the compound represented by the general formula (G-2A) or its salt will remove R under the action of a metal catalyst (preferably tetrakis (triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) , get R 0 as A compound represented by general formula (G-2) or a pharmaceutically acceptable salt thereof;
  • a metal catalyst preferably tetrakis (triphenylphosphine) palladium
  • a nucleophile preferably diethylamine or tetra
  • Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G-2).
  • the preparation method of the compound or its salt represented by general formula (G-1A) or general formula (G-2A) of the present disclosure comprises the following steps:
  • Rings A, Z, G, R, R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (G-1A) or general formula (G-2A).
  • the preparation method of the compound represented by the general formula (IV) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a compound represented by the general formula (IVA) or a salt thereof undergoes an ester hydrolysis reaction in the presence of an acid to obtain a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (IV).
  • the preparation method of the compound represented by the general formula (IV-1) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound represented by the general formula (IV-1A) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (IV-1).
  • the preparation method of the compound represented by the general formula (IV-2) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound represented by the general formula (IV-2A) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (IV-2).
  • the preparation method of the compound represented by general formula (IV-1A) or general formula (IV-2A) or its salt of the present disclosure comprises the following steps:
  • the compound represented by the general formula (IVa-A) or its salt and the compound represented by the general formula (IVb-A) or its salt undergo a condensation acylation reaction under alkaline conditions to obtain the general formula (IV-1A) or the A compound represented by formula (IV-2A) or a salt thereof;
  • R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
  • Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (IV-1A) or general formula (IV-2A).
  • the preparation method of the compound represented by the general formula (M) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • Z, G, R 0 , R 1 to R 3 , R 5 to R 11 and n are as defined in the general formula (M).
  • the preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound represented by the general formula (Ia-A) or its salt and the compound represented by the general formula (IB) or its salt undergo a condensation acylation reaction under alkaline conditions to obtain the compound represented by the general formula (I) or its salt pharmaceutically acceptable salts;
  • G, R 1 to R 11 and n are as defined in the general formula (I).
  • the preparation method of the compound represented by the general formula (II) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • Ring A, R 2a , G, R 1 , R 4 to R 11 , m and n are as defined in the general formula (II).
  • the preparation method of the compound represented by the general formula (III) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • Ring A, R 2a , G, R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in the general formula (III).
  • the preparation method of the compound represented by general formula (G-1) or general formula (G-2) or a pharmaceutically acceptable salt thereof of the present disclosure comprises the following steps:
  • Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G-1) or (G-2).
  • the preparation method of the compound represented by general formula (IV-1) or general formula (IV-2) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (IV-1) or general formula (IV-2).
  • the preparation method of the compound represented by the general formula (G-1) and the general formula (G-2) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound represented by general formula (G) or its pharmaceutically acceptable salt is prepared and separated to obtain the compound represented by general formula (G-1) and general formula (G-2) or its pharmaceutically acceptable salt;
  • Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G).
  • the preparation method of the compound represented by general formula (IV-1) and general formula (IV-2) or a pharmaceutically acceptable salt thereof of the present disclosure comprises the following steps:
  • Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (IV-1) or general formula (IV-2).
  • the reagents that provide basic conditions in the above synthesis scheme include organic bases and inorganic bases.
  • the organic bases include but are not limited to triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, Lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene
  • the inorganic bases include but not limited to Sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, cadmium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably, the reagent providing basic conditions is pyridine.
  • the acid described in the above synthesis scheme includes but not limited to mellitic acid, thiosulfuric acid, trichloroacetic acid, trinitrobenzenesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid; preferably, the acid is Trifluoroacetic acid.
  • the condensation acylation reaction involved in the above synthesis scheme is preferably carried out in the presence of a condensation reagent, and the condensation reagent is preferably 1-chloro-N,N,2-trimethylacrylamine.
  • the reaction of the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, isopropanol, acetone, acetonitrile, n-butanol, toluene, tetrahydrofuran, di Chloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, toluene, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylethane Amides, 1,2-dibromoethane and mixtures thereof.
  • the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, isopropanol, acetone, acetonitrile, n-butanol, toluene,
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined with Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High performance liquid chromatography
  • Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
  • High performance liquid phase preparative chromatography uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.
  • Chiral preparative chromatography uses a Shimadzu LC-20AP preparative chromatograph.
  • the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals, Adamas Reagent Co., Ltd., Sigma-Aldrich (Shanghai) Trading Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd., Shanghai Haohong Biomedical Technology Co., Ltd., Thermo Fisher Scientific (China) Technology Co., Ltd. Waiting for the company.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developer used for reaction, the eluent system of the column chromatography that purifies compound adopts and the developer system of thin-layer chromatography comprise: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • TLC thin-layer chromatography
  • Solution A Compound 1b (80mg, 0.324mmol) was dissolved in toluene (5mL), cooled to -20°C with a dry-ice acetone bath, added a tetrahydrofuran solution of lithium bistrimethylsilylamide (1M, 974.14 ⁇ L), at -10 °C and stirred for 15 minutes.
  • Solution B Compound 5-bromo-2,3-dihydro-1H-indene 1c (64mg, 0.324mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) was dissolved in toluene (5mL), and palladium acetate (8mg, 0.324 mmol), 2-(2-dicyclohexylphosphinephenyl)-N,N-dimethylaniline (25mg, 0.063mmol), stirred at room temperature for 10 minutes. Remove the dry ice acetone bath of solution A, add solution B to solution A, raise to room temperature and stir for 1 hour, heat to 85°C and stir for 3 hours, cool to room temperature and stir for 16 hours. The residue after concentration was purified by silica gel column chromatography with eluent system C to give the title product 1d (mixture of diastereomers, 50 mg, yield: 42%).
  • Solution A Compound 1b (86mg, 0.349mmol), dissolved in toluene (5mL), cooled to -20°C with a dry ice acetone bath, added tetrahydrofuran solution of lithium bistrimethylsilylamide (1M, 1mL), at -10 °C and stirred for 15 minutes.
  • Solution B Compound 2-bromonaphthalene 2a (71mg, 0.342mmol, Shanghai Pide Pharmaceutical Technology Co., Ltd.) was dissolved in toluene (5mL), and palladium acetate (8mg, 0.324mmol) and 2-(2-bicyclo Hexylphosphinephenyl)-N,N-dimethylaniline (27mg, 0.068mmol), stirred at room temperature for 10 minutes. Remove the dry ice acetone bath of solution A, add solution B to solution A, stir at room temperature for 1 hour, stir at 85 °C for 3 hours, and stir at room temperature for 16 hours. The residue after concentration was purified by silica gel column chromatography with eluent system C to give the title product 2b (mixture of diastereomers, 50 mg, yield: 38%).
  • Solution A Compound 1b (3.50 g, 14.21 mmol) was dissolved in toluene (100 mL). Cool to -20°C with a dry-ice acetone bath, add 1M tetrahydrofuran solution (21.3 mL) of lithium bistrimethylsilylamide, and stir at -10°C for 15 minutes.
  • Solution B Compound 5-bromo-2,2-difluorobenzo[d][1,3]dioxolane 3a (3.68 g, 15.53 mmol) was dissolved in toluene (20 mL), and acetic acid was added under nitrogen atmosphere Palladium (319 mg, 1.42 mmol), 2-(2-dicyclohexylphosphinephenyl)-N,N-dimethylaniline (1.12 g, 2.85 mmol), stirred at room temperature for 20 minutes. Remove the dry ice acetone bath of solution A, add solution B to solution A, raise to room temperature and stir for 1 hour, heat to 80°C and stir for 3 hours, cool to room temperature and stir for 2 hours. The residue after concentration was purified by silica gel column chromatography with eluent system B to obtain the title product 3b (mixture of diastereomers, 2.3 g, yield: 40.2%).
  • Compound 3-1 or 3-2 (30mg, 0.056mmol), trimethylboroxine (3M, 189 ⁇ L, 0.565mmol), 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride ( 8mg, 0.012mmol), potassium phosphate (36mg, 0.169mmol) were mixed in a reaction flask, and xylene (2mL) and water (0.7mL) were added. Under nitrogen atmosphere, microwave heating to 150° C., stirring for 0.5 hours.
  • trimethylboroxine (3M, 189 ⁇ L, 0.565mmol
  • 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride 8mg, 0.012mmol
  • potassium phosphate 36mg, 0.169mmol
  • sodium hydride (309mg, 8.06mmol, purity 60%) was dispersed in dry tetrahydrofuran (6mL), cooled to 0°C, and then tert-butyl diethylphosphonoacetate (1.82g, 7.22 mmol) in tetrahydrofuran (10 mL), stirred at room temperature for 1 hour.
  • the raw material 3a of the first step is replaced by compound 5-bromobenzo[d][1,3]dioxolane-2,2-d 2 (can be obtained from compound 4-bromo-1 , 2-methylenedioxybenzene and deuterated dibromomethane hydrogen deuterium replacement) to obtain the title compound 8-1 or 8-2 (35 mg, yield: 67%).
  • the raw material 3a of the first step was replaced by the compound 6-bromo-1-methyl-1H-indazole to obtain the title compound 12-1 or 12-2 (25 mg, yield: 36 %).
  • the raw material 3a of the first step was replaced by the compound 5-bromo-1-methyl-1H-indazole to obtain the title compound 13-1 or 13-2 (40mg, yield: 27 %).
  • the raw material 3a of the first step was replaced by the compound 2-bromo-5-chloropyrimidine to obtain the title compound 15-1 or 15-2 (19 mg, yield: 26%).
  • the raw material 3a of the first step was replaced by the compound 4-bromo-1,1'-biphenyl to obtain the title compound 16-1 or 16-2 (59 mg, yield: 46%) .
  • the raw material 3a of the first step was replaced by the compound 2-(4-bromophenyl)-2H-1,2,3-triazole to obtain the title compound 17-1 or 17-2 (39mg, Yield: 42%).
  • the raw material 3a of the first step was replaced by the compound 7-bromo-1-chloronaphthalene to obtain the title compound 18-1 or 18-2 (50 mg, yield: 43%).
  • the raw material 3a of the first step was replaced by the compound 2-bromo-6-chloronaphthalene to obtain the title compound 20-1 or 20-2 (45 mg, yield: 35%).
  • the raw material 3a of the first step is replaced by 7-bromo-4-methyl-3,4-dihydro-2H-1,4-benzo[b][1,4]oxa oxazine to obtain the title compound 27-1 or 27-2 (30 mg, yield: 27%).

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Abstract

A 3-phenylpropionic acid compound, a preparation method therefor and a medical application thereof are involved. Specifically, a 3-phenylpropionic acid compound as represented by general formula (M), a preparation method therefor, a pharmaceutical composition containing the compound, and a use of the composition as a therapeutic agent, in particular a use in the preparation of a soluble guanylate cyclase (sGC) agonist and a use in the preparation of a drug for treating and/preventing diseases, conditions, or disorders mediated by sGC are involved.

Description

3-苯基丙酸类化合物、其制备方法及其在医药上的应用3-phenylpropionic acid compound, its preparation method and its application in medicine 技术领域technical field
本公开属于医药领域，涉及一种3-苯基丙酸类化合物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(M)所示的3-苯基丙酸类化合物、其制备方法、含有该类化合物的药物组合物以及其作为治疗剂的用途，特别是在制备可溶性鸟苷酸环化酶(sGC)激动剂和/或激活剂中的用途和在制备用于治疗和/或预防通过sGC介导的疾病、病况或病症的药物中的用途。The disclosure belongs to the field of medicine, and relates to a 3-phenylpropionic acid compound, its preparation method and its application in medicine. In particular, the present disclosure relates to 3-phenylpropionic acid compounds represented by general formula (M), their preparation methods, pharmaceutical compositions containing such compounds and their use as therapeutic agents, especially in the preparation of soluble guanosine Use of an acid cyclase (sGC) agonist and/or activator and in the manufacture of a medicament for the treatment and/or prevention of a disease, condition or disorder mediated through sGC.
背景技术Background technique
随着人口老龄化进程的加快和高血压、冠心病、动脉粥样硬化等心血管疾病发病率的上升，心肌梗死和心力衰竭的患病率也正在逐渐升高。心肌梗死是在冠状动脉病变时，冠状动脉的血流急剧减少或中断，导致心肌出现严重且持久的缺血而坏死。心力衰竭简称心衰，是由于心脏的收缩功能或者舒张功能发生障碍，而引起心脏循环障碍症候群。心力衰竭不是一个独立的疾病，而是多种心血管疾病的终末阶段，几乎所有的心血管疾病最终都会导致心衰的发生。心衰患者面临着高死亡率的威胁，且严重影响了患者的生活质量，庞大的患者群体和相当高的死亡率给心衰治疗提出了巨大的挑战。With the acceleration of the aging population and the rising incidence of cardiovascular diseases such as hypertension, coronary heart disease, and atherosclerosis, the prevalence of myocardial infarction and heart failure is gradually increasing. Myocardial infarction is when the blood flow of the coronary artery is sharply reduced or interrupted during coronary artery disease, resulting in severe and persistent ischemia and necrosis of the myocardium. Heart failure, referred to as heart failure, is a syndrome of cardiac circulatory disturbance due to dysfunction of the systolic or diastolic function of the heart. Heart failure is not an independent disease, but the terminal stage of various cardiovascular diseases, and almost all cardiovascular diseases will eventually lead to heart failure. Patients with heart failure are facing the threat of high mortality, which seriously affects the quality of life of patients. The huge patient population and relatively high mortality pose a huge challenge to the treatment of heart failure.
多年以来，心衰的药物治疗领域不断取得进展，其中包括利尿药物、减慢心率的β受体阻滞剂和血管紧张素受体阻滞药物等。在心衰患者中，可以观察到一氧化氮(NO)-可溶性鸟苷酸环化酶(sGC)-环磷鸟苷(cGMP)通路的受损，该通路受损可导致心肌和血管功能下降，引起左室重构、纤维化和炎症，并最终导致心衰的发生和发展。Over the years, advances have been made in the field of drug therapy for heart failure, including diuretics, beta-blockers to slow the heart rate, and angiotensin receptor blockers, among others. In heart failure patients, impairment of the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway can be observed, leading to decreased myocardial and vascular function , causing left ventricular remodeling, fibrosis and inflammation, and ultimately lead to the occurrence and development of heart failure.
NO在心血管、神经、消化、代谢、免疫等多种***都是重要的信号分子，特别是心血管***和神经***。sGC作为NO的受体，是NO信号转导通路中的一个关键核心金属酶，NO活化sGC后，催化三磷酸鸟苷酸(GTP)转化为cGMP。cGMP是一种重要的二级信使分子，可以激活其下游多种效应分子，如环核苷酸门控离子通道(CNG)、磷酸二酯酶(PDE)和cGMP依赖蛋白激酶(PKG)等，进而引发一系列级联反应，在血液循环***和神经***中发挥重要的生理功能，例如可以促进血管和平滑肌舒张，抑制血小板凝聚、血管重塑和炎症发生等。在哺乳动物体内，NO由一氧化氮合酶(NOS)合成，然后通过脂质双分子层扩散到细胞并与其受体蛋白sGC结合，从而产生大量的cGMP。然而当NO-sGC-cGMP信号通路发生异常就会引发血管内皮细胞功能紊乱，进而引发一系列的心血管疾病，如肺动脉高压和心衰等。而sGC作为NO信号通路中的关键酶，作为多种疾病的药物靶标受到越来越多的重视。NO is an important signaling molecule in various systems such as cardiovascular, nervous, digestive, metabolic, and immune systems, especially the cardiovascular system and nervous system. As the receptor of NO, sGC is a key metalloenzyme in the NO signal transduction pathway. After NO activates sGC, it catalyzes the conversion of guanosine triphosphate (GTP) into cGMP. cGMP is an important secondary messenger molecule, which can activate various effector molecules downstream of it, such as cyclic nucleotide-gated ion channel (CNG), phosphodiesterase (PDE) and cGMP-dependent protein kinase (PKG), etc. In turn, it triggers a series of cascade reactions and plays important physiological functions in the blood circulation system and nervous system, such as promoting the relaxation of blood vessels and smooth muscles, inhibiting platelet aggregation, vascular remodeling and inflammation. In mammals, NO is synthesized by nitric oxide synthase (NOS), and then diffuses into cells through lipid bilayers and binds to its receptor protein sGC, thereby producing a large amount of cGMP. However, when the NO-sGC-cGMP signaling pathway is abnormal, it will lead to the dysfunction of vascular endothelial cells, and then lead to a series of cardiovascular diseases, such as pulmonary hypertension and heart failure. As a key enzyme in the NO signaling pathway, sGC has received more and more attention as a drug target for various diseases.
sGC遍布于哺乳动物的细胞溶质中，是由一个α亚基和一个β亚基组成的含 有血红素辅基的异源二聚体，每个亚基都包含氨基端的HNOX结合域(Heme NO/Oxygen binding domain)、α-螺旋卷曲螺旋结构域和羧基端的催化域，单个亚基的表达并不具有催化活性，αβ异源二聚体是sGC行使催化活性所必需的。sGC有α1β1和α2β1两种异构体，α2β1只存在于有限的组织当中，而α1β1则在组织中表达广泛，在血管中sGC活性主要是由于α1β1的高丰度表达。sGC is distributed throughout the cytosol of mammals and is a heterodimer containing a heme prosthetic group consisting of an α subunit and a β subunit, each of which contains an amino-terminal HNOX binding domain (Heme NO/ Oxygen binding domain), the α-helical coiled-coil domain and the catalytic domain at the carboxy-terminus, the expression of a single subunit does not have catalytic activity, and the αβ heterodimer is necessary for the catalytic activity of sGC. sGC has two isoforms, α1β1 and α2β1. α2β1 only exists in limited tissues, while α1β1 is widely expressed in tissues. The activity of sGC in blood vessels is mainly due to the high abundance expression of α1β1.
目前发现可直接作用于sGC的化合物可分为两大类：激动剂和激活剂。sGC的激活是由于NO与β1亚基上HNOX结合域的亚铁血红素相结合，使sGC构象变化、催化域激活，从而将GTP转化为cGMP。sGC激动剂是依赖于HNOX结合域的亚铁血红素并与NO气体协同激活sGC的，它可以增强sGC对NO的敏感性，在心血管药物的开发上有着重要的作用。但是人体内氧化压力可以促使sGC血红素从还原态转化为氧化态，而在高血压和高血脂等心血管疾病和II型糖尿病的人体中氧化态血红素的含量也会增加，再或者因基因的突变，都会导致sGC对NO脱敏，此时sGC激动剂就不能协同NO对sGC进行激活，而sGC激活剂就应运而生。sGC激活剂是一类可作用于氧化态或脱血红素态sGC的化合物，它不依赖与还原态血红素而主要通过结合到sGC血红素腔内激活sGC，进而催化GTP转化为cGMP，从而改善心肌和血管功能，降低心室重构、心肌肥厚、炎症和纤维化，延缓心衰进展。Compounds found to act directly on sGC can be divided into two categories: agonists and activators. The activation of sGC is due to the combination of NO and heme in the HNOX binding domain on the β1 subunit, which changes the conformation of sGC and activates the catalytic domain, thereby converting GTP into cGMP. The sGC agonist is dependent on the heme in the HNOX binding domain and activates sGC synergistically with NO gas. It can enhance the sensitivity of sGC to NO and plays an important role in the development of cardiovascular drugs. However, oxidative stress in the human body can promote the conversion of sGC hemoglobin from a reduced state to an oxidized state, and the content of oxidized hemoglobin in humans with cardiovascular diseases such as hypertension and hyperlipidemia and type II diabetes will also increase, or genetically The mutation of sGC will lead to desensitization of sGC to NO. At this time, sGC agonists cannot cooperate with NO to activate sGC, and sGC activators come into being. sGC activators are a class of compounds that can act on oxidized or deheme sGC. It does not rely on reduced heme, but activates sGC mainly by binding to the sGC heme cavity, and then catalyzes the conversion of GTP into cGMP, thereby improving Myocardium and blood vessel function, reduce ventricular remodeling, myocardial hypertrophy, inflammation and fibrosis, and delay the progression of heart failure.
公开的sGC相关的专利申请包括WO2012139888A1、US20140309307A1、US20160264515A1、WO2019105881A1、WO2020020790A1、WO2020020789A1、WO2020148379A1、CN112794848A、CN112384214A、CN111712247A和CN106459017B。公开的sGC相关的专利申请包括WO2012139888A1、US20140309307A1、US20160264515A1、WO2019105881A1、WO2020020790A1、WO2020020789A1、WO2020148379A1、CN112794848A、CN112384214A、CN111712247A和CN106459017B。
发明内容Contents of the invention
本公开的目的在于提供一种通式(M)所示的化合物或其可药用的盐：The purpose of this disclosure is to provide a compound represented by general formula (M) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022105987-appb-000001
Figure PCTCN2022105987-appb-000001
其中：in:
R 0为氢原子或
Figure PCTCN2022105987-appb-000002
优选地，R 0为氢原子或
Figure PCTCN2022105987-appb-000003
R 0 is a hydrogen atom or
Figure PCTCN2022105987-appb-000002
Preferably, R 0 is a hydrogen atom or
Figure PCTCN2022105987-appb-000003
Z为N或CR 4； Z is N or CR4 ;
G为N或CR 4a； G is N or CR 4a ;
R 1与R 2和相连的碳原子形成环A’，或者R 2与R 3和相连的碳原子形成环A， 所述环A’和环A各自独立地选自环烷基、杂环基、芳基和杂芳基；其中，所述环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、羟基、烷基、卤代烷基、氘代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、氰基、氧代基、烯基、炔基、-NR 12aR 12b、-NHC(O)R 13、-C(O)R 13和-C(O)OR 13中的一个或多个相同或不同的取代基取代； R 1 and R 2 and the connected carbon atoms form ring A', or R 2 and R 3 and the connected carbon atoms form ring A, and the ring A' and ring A are each independently selected from cycloalkyl, heterocyclyl , aryl, and heteroaryl; wherein, the cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently selected from deuterium atom, halogen, hydroxyl, alkyl, haloalkyl, deuterated alkyl Alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, cyano, oxo, alkenyl, alkynyl, -NR 12a R 12b , -NHC(O)R 13 , -C( One or more identical or different substituents in O) R 13 and -C(O)OR 13 are substituted;
当R 1与R 2和相连的碳原子形成环A’时，R 3选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氨基和硝基； When R1 and R2 and the attached carbon atom form ring A ', R3 is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano , amino and nitro;
当R 2与R 3和相连的碳原子形成环A时，R 1选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氨基和硝基； When R2 and R3 and the carbon atom connected form ring A , R1 is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino and nitro;
R 4和R 4a相同或不同，且各自独立地选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氨基和硝基； R 4 and R 4a are the same or different, and each independently selected from a hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino and nitro;
R 5和R 6相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、环烷基和杂环基；其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自烯基、炔基、氰基、氨基、硝基和R b中的一个或多个相同或不同的取代基取代；或者R 5和R 6和相连的碳原子形成环烷基或杂环基； R 5 and R 6 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein The above-mentioned alkyl, alkoxy, hydroxyalkyl, cycloalkyl and heterocyclic groups are each independently optionally selected from one or more of alkenyl, alkynyl , cyano, amino, nitro and R The same or different substituents are substituted; or R 5 and R 6 and the connected carbon atoms form a cycloalkyl or heterocyclic group;
R b选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、环烷基和杂环基；其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、羟基、氰基、氨基和硝基中的一个或多个相同或不同的取代基取代； R b is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclic; wherein said alkyl, alkoxy, hydroxyalkyl, ring Alkyl and heterocyclyl are each independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, cyano, amino and nitro The same or different substituents are substituted;
各个R 7相同或不同，且各自独立地选自卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氨基和硝基； each R is the same or different, and each independently selected from halogen, hydroxy, carboxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino, and nitro;
R 8选自卤素、羟基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基和环烷基； R is selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cycloalkyl;
R 9选自氢原子、卤素、羟基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基和杂环基；或者R 8和R 9和相连的碳原子形成环烷基或杂环基； R9 is selected from a hydrogen atom, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; or R8 and R9 form a ring with a connected carbon atom Alkyl or heterocyclyl;
R 10和R 11相同或不同，且各自独立地选自氢原子、卤素、烷基和卤代烷基； R 10 and R 11 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl and haloalkyl;
R 12a和R 12b相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基和杂环基；或者R 12a和R 12b与相连的氮原子一起形成杂环基； R 12a and R 12b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; or R 12a and R 12b form a heterocyclic group together with a connected nitrogen atom;
R 13选自氢原子、烷基、羟烷基、环烷基和杂环基； R 13 is selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;
n为0、1、2、3或4。n is 0, 1, 2, 3 or 4.
在本公开的一些实施方案中，所述的通式(M)所示的化合物或其可药用的盐，其为通式(I)所示的化合物或其可药用的盐：In some embodiments of the present disclosure, the compound represented by general formula (M) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022105987-appb-000004
Figure PCTCN2022105987-appb-000004
其中：in:
G为N或CR 4a； G is N or CR 4a ;
R 1与R 2和相连的碳原子形成环A’，或者R 2与R 3和相连的碳原子形成环A，所述环A’和环A各自独立地选自环烷基、杂环基、芳基和杂芳基；其中，所述环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、羟基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氧代基、烯基、炔基、-NR 12aR 12b、-NHC(O)R 13、-C(O)R 13和-C(O)OR 13中的一个或多个相同或不同的取代基取代； R 1 and R 2 and the connected carbon atoms form ring A', or R 2 and R 3 and the connected carbon atoms form ring A, and the ring A' and ring A are each independently selected from cycloalkyl, heterocyclyl , aryl and heteroaryl; wherein, the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy Among the group, hydroxyalkyl group, cyano group, oxo group, alkenyl group, alkynyl group, -NR 12a R 12b , -NHC(O)R 13 , -C(O)R 13 and -C(O)OR 13 Substitution by one or more identical or different substituents;
当R 1与R 2和相连的碳原子形成环A’时，R 3选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氨基和硝基； When R1 and R2 and the attached carbon atom form ring A ', R3 is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano , amino and nitro;
当R 2与R 3和相连的碳原子形成环A时，R 1选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氨基和硝基； When R2 and R3 and the carbon atom connected form ring A , R1 is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino and nitro;
R 4和R 4a相同或不同，且各自独立地选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氨基和硝基； R 4 and R 4a are the same or different, and each independently selected from a hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino and nitro;
R 5和R 6相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、环烷基和杂环基；其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自烯基、炔基、氰基、氨基、硝基和R b中的一个或多个相同或不同的取代基取代；或者R 5和R 6和相连的碳原子形成环烷基或杂环基； R 5 and R 6 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein The above-mentioned alkyl, alkoxy, hydroxyalkyl, cycloalkyl and heterocyclic groups are each independently optionally selected from one or more of alkenyl, alkynyl , cyano, amino, nitro and R The same or different substituents are substituted; or R 5 and R 6 and the connected carbon atoms form a cycloalkyl or heterocyclic group;
R b选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、环烷基和杂环基；其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、羟基、氰基、氨基和硝基中的一个或多个相同或不同的取代基取代； R b is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclic; wherein said alkyl, alkoxy, hydroxyalkyl, ring Alkyl and heterocyclyl are each independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, cyano, amino and nitro The same or different substituents are substituted;
各个R 7相同或不同，且各自独立地选自卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氨基和硝基； each R is the same or different, and each independently selected from halogen, hydroxy, carboxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino, and nitro;
R 8选自卤素、羟基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基和环烷基； R is selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cycloalkyl;
R 9选自氢原子、卤素、羟基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基和杂环基；或者R 8和R 9和相连的碳原子形成环烷基或杂环基； R9 is selected from a hydrogen atom, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; or R8 and R9 form a ring with a connected carbon atom Alkyl or heterocyclyl;
R 10和R 11相同或不同，且各自独立地选自氢原子、卤素、烷基和卤代烷基； R 10 and R 11 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl and haloalkyl;
R 12a和R 12b相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基和杂环基；或者R 12a和R 12b与相连的氮原子一起形成杂环基； R 12a and R 12b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; or R 12a and R 12b form a heterocyclic group together with a connected nitrogen atom;
R 13选自氢原子、烷基、羟烷基、环烷基和杂环基； R 13 is selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;
n为0、1、2、3或4。n is 0, 1, 2, 3 or 4.
在本公开的一些实施方案中，所述的通式(M)、通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：In some embodiments of the present disclosure, the compound represented by the general formula (M), the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof Salt to use:
Figure PCTCN2022105987-appb-000005
Figure PCTCN2022105987-appb-000005
其中：in:
环A选自环烷基、杂环基、芳基和杂芳基；Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
各个R 2a相同或不同，且各自独立地选自卤素、羟基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氧代基、烯基、炔基、-NR 12aR 12b、-NHC(O)R 13、-C(O)R 13和-C(O)OR 13； Each R 2a is the same or different, and each independently selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, oxo, alkenyl, alkynyl, -NR 12a R 12b , -NHC(O)R 13 , -C(O)R 13 and -C(O)OR 13 ;
m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
G、R 1、R 4至R 11、R 12a、R 12b、R 13和n如通式(M)或通式(I)中所定义。 G, R 1 , R 4 to R 11 , R 12a , R 12b , R 13 and n are as defined in general formula (M) or general formula (I).
在本公开的一些实施方案中，所述的通式(M)、通式(I)或通式(II)所示的化合物或其可药用的盐，其中：R 6、R 9和R 11相同或不同，且各自独立地为氢原子或C 1-6烷基；优选地，R 6、R 9和R 11均为氢原子。 In some embodiments of the present disclosure, the compound represented by general formula (M), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein: R 6 , R 9 and R 11 are the same or different, and are each independently a hydrogen atom or a C 1-6 alkyl group; preferably, R 6 , R 9 and R 11 are all hydrogen atoms.
在本公开的一些实施方案中，所述的通式(M)、通式(I)或通式(II)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：In some embodiments of the present disclosure, the compound represented by general formula (M), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is represented by general formula (III) A compound or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022105987-appb-000006
Figure PCTCN2022105987-appb-000006
其中：in:
G为CR 4a； G is CR 4a ;
环A、R 2a、R 4a、R 1、R 4、R 5、R 7、R 8、R 10、m和n如通式(II)中所定义。 Ring A, R 2a , R 4a , R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in the general formula (II).
在本公开的一些实施方案中，所述的通式(M)、通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中：R 10选自氢原子、卤素和C 1-6烷基；优选地，R 10为氢原子。 In some embodiments of the present disclosure, the compound represented by general formula (M), general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein: R 10 is selected from a hydrogen atom, a halogen and a C 1-6 alkyl group; preferably, R 10 is a hydrogen atom.
在本公开的一些实施方案中，所述的通式(M)所示的化合物或其可药用的盐，其为通式(G)所示的化合物或其可药用的盐：In some embodiments of the present disclosure, the compound represented by general formula (M) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (G) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022105987-appb-000007
Figure PCTCN2022105987-appb-000007
其中：in:
R 0为氢原子或
Figure PCTCN2022105987-appb-000008
优选地，R 0为氢原子或
Figure PCTCN2022105987-appb-000009
R 0 is a hydrogen atom or
Figure PCTCN2022105987-appb-000008
Preferably, R 0 is a hydrogen atom or
Figure PCTCN2022105987-appb-000009
环A选自环烷基、杂环基、芳基和杂芳基；Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
各个R 2a相同或不同，且各自独立地选自氘原子、卤素、羟基、烷基、卤代烷基、氘代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氧代基、烯基、炔基、-NR 12aR 12b、-NHC(O)R 13、-C(O)R 13和-C(O)OR 13； Each R 2a is the same or different, and each independently selected from deuterium atom, halogen, hydroxyl, alkyl, haloalkyl, deuterated alkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, oxo, alkenyl, alkynyl, -NR 12a R 12b , -NHC(O)R 13 , -C(O)R 13 and -C(O)OR 13 ;
R 5a和R 5b不同，且各自独立地选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、环烷基和杂环基；其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、羟基、氰基、氨基和硝基中的一个或多个相同或不同的取代基取代； R 5a and R 5b are different, and are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein said alkyl, Alkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxy, cyano, One or more of the same or different substituents in amino and nitro;
m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
Z、G、R 1、R 7、R 8、R 12a、R 12b、R 13和n如通式(M)中所定义。 Z, G, R 1 , R 7 , R 8 , R 12a , R 12b , R 13 and n are as defined in the general formula (M).
在本公开的一些实施方案中，所述的通式(M)或通式(G)所示的化合物或其可药用的盐，其为通式(G-1)或通式(G-2)所示的化合物或其可药用的盐：In some embodiments of the present disclosure, the compound represented by general formula (M) or general formula (G) or a pharmaceutically acceptable salt thereof is general formula (G-1) or general formula (G- 2) The indicated compound or its pharmaceutically acceptable salt:
Figure PCTCN2022105987-appb-000010
Figure PCTCN2022105987-appb-000010
其中：in:
环A、Z、G、R 0、R 1、R 2a、R 5a、R 5b、R 7、R 8、m和n如通式(G)中所定义。 Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G).
在本公开的一些实施方案中，所述的通式(M)、通式(G)、通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其为通式(IV)所示的化合物或其可药用的盐：In some embodiments of the present disclosure, the compound represented by general formula (M), general formula (G), general formula (I), general formula (II) or general formula (III) or its pharmaceutically acceptable A salt, which is a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022105987-appb-000011
Figure PCTCN2022105987-appb-000011
其中：in:
R 5a和R 5b不同，且各自独立地选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、环烷基和杂环基；其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、羟基、氰基、氨基和硝基中的一个或多个相同或不同的取代基取代； R 5a and R 5b are different, and are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein said alkyl, Alkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxy, cyano, One or more of the same or different substituents in amino and nitro;
G为CR 4a； G is CR 4a ;
环A、R 2a、R 4a、R 1、R 4、R 7、R 8、m和n如通式(II)或通式(III)中所定义。 Ring A, R 2a , R 4a , R 1 , R 4 , R 7 , R 8 , m and n are as defined in general formula (II) or general formula (III).
在本公开的一些实施方案中，所述的通式(M)、通式(G)、通式(I)、通式(II)、通式(III)或通式(IV)所示的化合物或其可药用的盐，其为通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐：In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (I), general formula (II), general formula (III) or general formula (IV) A compound or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022105987-appb-000012
Figure PCTCN2022105987-appb-000012
其中：in:
R 5a和R 5b不同，且各自独立地选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、环烷基和杂环基；其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、羟基、氰基、氨基和硝基中的一个或多个相同或不同的取代基取代； R 5a and R 5b are different, and are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein said alkyl, Alkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxy, cyano, One or more of the same or different substituents in amino and nitro;
G为CR 4a； G is CR 4a ;
环A、R 2a、R 4a、R 1、R 4、R 7、R 8、m和n如通式(II)、通式(III)或通式(IV)中所定义。 Ring A, R 2a , R 4a , R 1 , R 4 , R 7 , R 8 , m and n are as defined in general formula (II), general formula (III) or general formula (IV).
在本公开的一些实施方案中，所述的通式(M)、通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中：R 5为卤代C 1-6烷基；优选地，R 5为
Figure PCTCN2022105987-appb-000013
更优选地，R 5为
Figure PCTCN2022105987-appb-000014
In some embodiments of the present disclosure, the compound represented by general formula (M), general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof, wherein: R 5 is halogenated C 1-6 alkyl; preferably, R 5 is
Figure PCTCN2022105987-appb-000013
More preferably, R is
Figure PCTCN2022105987-appb-000014
在本公开的一些实施方案中，所述的通式(G)、通式(G-1)、通式(G-2)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：R 5a和R 5b不同，且各自独立地选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、3至8元环烷基和3至8元杂环基；其中所述的C 1-6烷基、C 1-6烷氧基、C 1-6羟烷基、3至8元环烷基和3至8元杂环基各自独立地任选被选自卤素、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基、氰基、氨基和硝基中的一个或多个相同或不同的取代基取代；优选地，R 5a和R 5b不同，且各自独立地为C 1-6烷基或卤代C 1-6烷基；进一步优选地，R 5a为C 1-6烷基，R 5b为卤代C 1-6烷基；更优选地，R 5a为甲基，R 5b为三氟甲基。 In some embodiments of the present disclosure, the general formula (G), general formula (G-1), general formula (G-2), general formula (IV), general formula (IV-1) or general formula The compound represented by (IV-2) or a pharmaceutically acceptable salt thereof, wherein: R 5a and R 5b are different, and are each independently selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group; wherein said C 1-6 Alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl are each independently optionally selected from halogen, C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxyl, cyano, amino and nitro are substituted by one or more of the same or different substituents ; Preferably, R 5a and R 5b are different, and each independently is C 1-6 alkyl or halogenated C 1-6 alkyl; more preferably, R 5a is C 1-6 alkyl, R 5b is halogen Substitute C 1-6 alkyl; more preferably, R 5a is methyl, R 5b is trifluoromethyl.
在本公开的一些实施方案中，所述的通式(G)、通式(G-1)、通式(G-2)、通式(II)、通式(III)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中m为0、1或2。In some embodiments of the present disclosure, the general formula (G), general formula (G-1), general formula (G-2), general formula (II), general formula (III), general formula (IV ), a compound represented by general formula (IV-1) or general formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2.
在本公开的一些实施方案中，所述的通式(G)、通式(G-1)或通式(G-2)所示的化合物或其可药用的盐，其中各个R 2a相同或不同，且各自独立地选自氘原子、卤素和C 1-6烷基；优选地，各个R 2a相同或不同，且各自独立地选自氘原子、氟原子、氯原子和甲基。 In some embodiments of the present disclosure, the compound represented by general formula (G), general formula (G-1) or general formula (G-2) or a pharmaceutically acceptable salt thereof, wherein each R 2a is the same or different, and each independently selected from a deuterium atom, a halogen, and a C 1-6 alkyl group; preferably, each R 2a is the same or different, and each independently selected from a deuterium atom, a fluorine atom, a chlorine atom, and a methyl group.
在本公开的一些实施方案中，所述的通式(G)、通式(G-1)、通式(G-2)、通式(II)、通式(III)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中各个R 2a相同或不同，且各自独立地为卤素或C 1-6烷基；优选地，各个R 2a相同或不同，且各自独立地选自氟原子、氯原子和甲基。 In some embodiments of the present disclosure, the general formula (G), general formula (G-1), general formula (G-2), general formula (II), general formula (III), general formula (IV ), a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein each R 2a is the same or different, and each independently is halogen or C 1-6 alkyl ; Preferably, each R 2a is the same or different, and each independently selected from a fluorine atom, a chlorine atom and a methyl group.
在本公开的一些实施方案中，所述的通式(G)、通式(G-1)、通式(G-2)、通式(II)、通式(III)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：各个R 2a相同或不同，且各自独立地为卤素或C 1-6烷基，且m为1、2、3或4；或者m为0；优选地，m为0。 In some embodiments of the present disclosure, the general formula (G), general formula (G-1), general formula (G-2), general formula (II), general formula (III), general formula (IV ), a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: each R 2a is the same or different, and is independently halogen or C 1-6 alkane group, and m is 1, 2, 3 or 4; or m is 0; preferably, m is 0.
在本公开的一些实施方案中，所述的通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中环A选自6至10元芳基、5至10元杂芳基、3至8元环烷基和3至8元杂环基；优选地，环A选自苯基、5或6元杂芳基和5或6元环烷基。In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II ), the general formula (III), the general formula (IV), the general formula (IV-1) or the compound shown in the general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from 6 to 10 members Aryl, 5 to 10 membered heteroaryl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl; preferably, ring A is selected from phenyl, 5 or 6 membered heteroaryl and 5 or 6 membered ring alkyl.
在本公开的一些实施方案中，所述的通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中环A选自6至10元芳基、5至10元杂芳基、3至8元环烷基和3至8元杂环基；优选地，环A选自苯基、5或6元杂芳基、5或6元环烷基和5或6元杂环基；更优选地，环A选自苯基、5或6元环烷基和5或6元杂环基。In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II ), the general formula (III), the general formula (IV), the general formula (IV-1) or the compound shown in the general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from 6 to 10 members Aryl, 5 to 10 membered heteroaryl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl; preferably, ring A is selected from phenyl, 5 or 6 membered heteroaryl, 5 or 6 membered ring Alkyl and 5 or 6 membered heterocyclyl; more preferably, Ring A is selected from phenyl, 5 or 6 membered cycloalkyl and 5 or 6 membered heterocyclyl.
在本公开的一些实施方案中，所述的通式(G)、通式(G-1)、通式(G-2)、通式(II)、通式(III)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：环A选自6至10元芳基、5至10元杂芳基、3至8元环烷基和3至8元杂环基；各个R 2a相同或不同，且各自独立地为卤素或C 1-6烷基，m为1、2、3或4；或者m为0；优选地，环A选自苯基、5或6元杂芳基、5或6元环烷基和5或6元杂环基；各个R 2a相同或不同，且各自独立地为卤素或C 1-6烷基，m为1、2、3或4；或者m为0；更优选地，环A选自苯基、5或6元环烷基和5或6元杂环基；各个R 2a相同或不同，且各自独立地为卤素或C 1-6烷基，m为1、2、3或4；或者m为0。 In some embodiments of the present disclosure, the general formula (G), general formula (G-1), general formula (G-2), general formula (II), general formula (III), general formula (IV ), a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: ring A is selected from 6 to 10 membered aryl, 5 to 10 membered heteroaryl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl; each R 2a is the same or different, and each independently is halogen or C 1-6 alkyl, m is 1, 2, 3 or 4; or m is O; preferably, ring A is selected from phenyl, 5 or 6 membered heteroaryl, 5 or 6 membered cycloalkyl and 5 or 6 membered heterocyclyl; each R 2a is the same or different, and each independently is halogen or C 1-6 alkyl, m is 1, 2, 3 or 4; or m is 0; more preferably, ring A is selected from phenyl, 5 or 6 membered cycloalkyl and 5 or 6 membered heterocyclic group; each R 2a are the same or different, and are independently halogen or C 1-6 alkyl, m is 1, 2, 3 or 4; or m is 0.
在本公开的一些实施方案中，所述的通式(M)所示的化合物或其可药用的盐，其中
Figure PCTCN2022105987-appb-000015
选自
Figure PCTCN2022105987-appb-000016
Figure PCTCN2022105987-appb-000017
In some embodiments of the present disclosure, the compound represented by general formula (M) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022105987-appb-000015
selected from
Figure PCTCN2022105987-appb-000016
Figure PCTCN2022105987-appb-000017
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中
Figure PCTCN2022105987-appb-000018
选自
Figure PCTCN2022105987-appb-000019
Figure PCTCN2022105987-appb-000020
Figure PCTCN2022105987-appb-000021
In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022105987-appb-000018
selected from
Figure PCTCN2022105987-appb-000019
Figure PCTCN2022105987-appb-000020
Figure PCTCN2022105987-appb-000021
在本公开的一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中
Figure PCTCN2022105987-appb-000022
选自
Figure PCTCN2022105987-appb-000023
Figure PCTCN2022105987-appb-000024
In some embodiments of the present disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022105987-appb-000022
selected from
Figure PCTCN2022105987-appb-000023
Figure PCTCN2022105987-appb-000024
在本公开的一些实施方案中，所述的通式(III)或通式(IV)所示的化合物或其可药用的盐，其中
Figure PCTCN2022105987-appb-000025
选自
Figure PCTCN2022105987-appb-000026
Figure PCTCN2022105987-appb-000027
In some embodiments of the present disclosure, the compound represented by general formula (III) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022105987-appb-000025
selected from
Figure PCTCN2022105987-appb-000026
Figure PCTCN2022105987-appb-000027
在本公开的一些实施方案中，所述的通式(II)、通式(III)或通式(IV)所示的化合 物或其可药用的盐，其中
Figure PCTCN2022105987-appb-000028
选自
Figure PCTCN2022105987-appb-000029
Figure PCTCN2022105987-appb-000030
In some embodiments of the present disclosure, the compound represented by general formula (II), general formula (III) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022105987-appb-000028
selected from
Figure PCTCN2022105987-appb-000029
Figure PCTCN2022105987-appb-000030
在本公开的一些实施方案中，所述的通式(II)、通式(III)或通式(IV)所示的化合物或其可药用的盐，其中
Figure PCTCN2022105987-appb-000031
选自
Figure PCTCN2022105987-appb-000032
Figure PCTCN2022105987-appb-000033
In some embodiments of the present disclosure, the compound represented by general formula (II), general formula (III) or general formula (IV) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022105987-appb-000031
selected from
Figure PCTCN2022105987-appb-000032
Figure PCTCN2022105987-appb-000033
在本公开的一些实施方案中，所述的通式(G)所示的化合物或其可药用的盐，其中
Figure PCTCN2022105987-appb-000034
选自
Figure PCTCN2022105987-appb-000035
Figure PCTCN2022105987-appb-000036
Figure PCTCN2022105987-appb-000037
In some embodiments of the present disclosure, the compound represented by general formula (G) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022105987-appb-000034
selected from
Figure PCTCN2022105987-appb-000035
Figure PCTCN2022105987-appb-000036
Figure PCTCN2022105987-appb-000037
本公开的一些实施方案中，所述的通式(G-1)所示的化合物或其可药用的盐，其中
Figure PCTCN2022105987-appb-000038
选自
Figure PCTCN2022105987-appb-000039
Figure PCTCN2022105987-appb-000040
In some embodiments of the present disclosure, the compound represented by the general formula (G-1) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022105987-appb-000038
selected from
Figure PCTCN2022105987-appb-000039
Figure PCTCN2022105987-appb-000040
本公开的一些实施方案中，所述的通式(G-2)所示的化合物或其可药用的盐，其中
Figure PCTCN2022105987-appb-000041
选自
Figure PCTCN2022105987-appb-000042
Figure PCTCN2022105987-appb-000043
In some embodiments of the present disclosure, the compound represented by the general formula (G-2) or a pharmaceutically acceptable salt thereof, wherein
Figure PCTCN2022105987-appb-000041
selected from
Figure PCTCN2022105987-appb-000042
Figure PCTCN2022105987-appb-000043
在本公开的一些实施方案中，所述的通式(IV-1)所示的化合物或其可药用的 盐，其中：
Figure PCTCN2022105987-appb-000044
选自
Figure PCTCN2022105987-appb-000045
In some embodiments of the present disclosure, the compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, wherein:
Figure PCTCN2022105987-appb-000044
selected from
Figure PCTCN2022105987-appb-000045
在本公开的一些实施方案中，所述的通式(IV-1)所示的化合物或其可药用的盐，其中：
Figure PCTCN2022105987-appb-000046
选自
Figure PCTCN2022105987-appb-000047
Figure PCTCN2022105987-appb-000048
In some embodiments of the present disclosure, the compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, wherein:
Figure PCTCN2022105987-appb-000046
selected from
Figure PCTCN2022105987-appb-000047
Figure PCTCN2022105987-appb-000048
在本公开的一些实施方案中，所述的通式(IV-1)所示的化合物或其可药用的盐，其中：
Figure PCTCN2022105987-appb-000049
选自
Figure PCTCN2022105987-appb-000050
Figure PCTCN2022105987-appb-000051
In some embodiments of the present disclosure, the compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, wherein:
Figure PCTCN2022105987-appb-000049
selected from
Figure PCTCN2022105987-appb-000050
Figure PCTCN2022105987-appb-000051
在本公开的一些实施方案中，所述的通式(IV-2)所示的化合物或其可药用的 盐，其中：
Figure PCTCN2022105987-appb-000052
选自
Figure PCTCN2022105987-appb-000053
In some embodiments of the present disclosure, the compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein:
Figure PCTCN2022105987-appb-000052
selected from
Figure PCTCN2022105987-appb-000053
在本公开的一些实施方案中，所述的通式(IV-2)所示的化合物或其可药用的盐，其中：
Figure PCTCN2022105987-appb-000054
选自
Figure PCTCN2022105987-appb-000055
Figure PCTCN2022105987-appb-000056
In some embodiments of the present disclosure, the compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein:
Figure PCTCN2022105987-appb-000054
selected from
Figure PCTCN2022105987-appb-000055
Figure PCTCN2022105987-appb-000056
在本公开的一些实施方案中，所述的通式(IV-2)所示的化合物或其可药用的盐，其中：
Figure PCTCN2022105987-appb-000057
选自
Figure PCTCN2022105987-appb-000058
Figure PCTCN2022105987-appb-000059
In some embodiments of the present disclosure, the compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein:
Figure PCTCN2022105987-appb-000057
selected from
Figure PCTCN2022105987-appb-000058
Figure PCTCN2022105987-appb-000059
在本公开的一些实施方案中，所述的通式(M)、通式(G)、通式(G-1)、通式(G-2)、 通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：各个R 7相同或不同，且各自独立地为卤素或C 1-6烷基；优选地，各个R 7相同或不同，且各自独立地为卤素；更优选地，R 7各自独立地为氯原子。 In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II ), general formula (III), general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: each R 7 is the same or different, And each independently is a halogen or C 1-6 alkyl; preferably, each R 7 is the same or different, and each independently is a halogen; more preferably, each R 7 is independently a chlorine atom.
在本公开的一些实施方案中，所述的通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：各个R 7相同或不同，且各自独立地选自氯原子、溴原子和甲基。 In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II ), general formula (III), general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: each R 7 is the same or different, and each independently selected from a chlorine atom, a bromine atom and a methyl group.
在本公开的一些实施方案中，所述的通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：n为0或1；优选地，n为1。In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II ), general formula (III), general formula (IV), general formula (IV-1) or a compound or pharmaceutically acceptable salt thereof shown in general formula (IV-2), wherein: n is 0 or 1; preferably Ground, n is 1.
在本公开的一些实施方案中，所述的通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：各个R 7相同或不同，且各自独立地为卤素或C 1-6烷基，且n为1、2、3或4；或者n为0； In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II ), general formula (III), general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: each R 7 is the same or different, And each independently is halogen or C 1-6 alkyl, and n is 1, 2, 3 or 4; or n is 0;
优选地，R 7为卤素或C 1-6烷基，且n为1； Preferably, R 7 is halogen or C 1-6 alkyl, and n is 1;
更优选地，R 7为卤素，且n为1。 More preferably, R 7 is halogen and n is 1.
在本公开的一些实施方案中，所述的通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：R 8选自C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基和3至8元环烷基；优选地；R 8为C 1-6烷基或3至8元环烷基；更优选地；R 8为3至8元环烷基；最优选地，R 8为环丙基。 In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II ), general formula (III), general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: R 8 is selected from C 1- 6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl; preferably; R 8 is C 1-6 alkyl or 3 to 8 membered cycloalkyl; more preferably; R 8 is 3 to 8 membered cycloalkyl; most preferably, R 8 is cyclopropyl.
在本公开的一些实施方案中，所述的通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：R 1、R 4和R 4a相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；优选地，R 1、R 4和R 4a均为氢原子。 In some embodiments of the present disclosure, the general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II ), general formula (III), general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 4 and R 4a are the same or different, and are independently selected from hydrogen atom, halogen and C 1-6 alkyl; preferably, R 1 , R 4 and R 4a are all hydrogen atoms.
在本公开的一些实施方案中，所述的通式(II)所示的化合物或其可药用的盐，其中：环A选自苯基、5或6元杂芳基、5或6元环烷基和5或6元杂环基；G为N或CR 4a；各个R 2a相同或不同，且各自独立地为卤素或C 1-6烷基；m为0、1或2；R 1、R 4和R 4a均为氢原子；R 5为卤代C 1-6烷基；R 6、R 9和R 11均为氢原子；R 10为氢原子；R 7为卤素或C 1-6烷基；n为1；R 8为3至8元环烷基。 In some embodiments of the present disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from phenyl, 5 or 6-membered heteroaryl, 5 or 6-membered Cycloalkyl and 5- or 6-membered heterocyclyl; G is N or CR 4a ; each R 2a is the same or different, and is independently halogen or C 1-6 alkyl; m is 0, 1 or 2; R 1 , R 4 and R 4a are all hydrogen atoms; R 5 is halogenated C 1-6 alkyl; R 6 , R 9 and R 11 are all hydrogen atoms; R 10 is hydrogen atom; R 7 is halogen or C 1- 6 alkyl; n is 1; R 8 is 3 to 8 membered cycloalkyl.
在本公开的一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中：环A选自苯基、5或6元杂芳基、5或6元环烷基和5或6元杂环基；G为CR 4a；各个R 2a相同或不同，且各自独立地为卤素或C 1-6烷基；m为0、1或2；R 1、R 4和R 4a均为氢原子；R 5为卤代C 1-6烷基；R 10为氢原子；R 7为卤素或C 1-6烷基；n为1；R 8为环丙基。 In some embodiments of the present disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from phenyl, 5 or 6-membered heteroaryl, 5 or 6-membered Cycloalkyl and 5 or 6-membered heterocyclyl; G is CR 4a ; each R 2a is the same or different, and each independently is halogen or C 1-6 alkyl; m is 0, 1 or 2; R 1 , R 4 and R 4a are both hydrogen atoms; R 5 is a halogenated C 1-6 alkyl group; R 10 is a hydrogen atom; R 7 is a halogen or a C 1-6 alkyl group; n is 1; R 8 is a cyclopropyl group.
在本公开的一些实施方案中，所述的通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：R 5a和R 5b不同，且各自独立地选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、3至8元环烷基和3至8元杂环基；其中所述的C 1-6烷基、C 1-6烷氧基、C 1-6羟烷基、3至8元环烷基和3至8元杂环基各自独立地任选被选自卤素、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基、氰基、氨基和硝基中的一个或多个相同或不同的取代基取代；G为CR 4a；R 1、R 4和R 4a相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；环A选自6至10元芳基、5至10元杂芳基、3至8元环烷基和3至8元杂环基；各个R 2a相同或不同，且各自独立地为卤素或C 1-6烷基，m为1、2、3或4；或者m为0；各个R 7相同或不同，且各自独立地为卤素或C 1-6烷基，n为1、2、3或4；或者n为0；R 8选自C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基和3至8元环烷基。 In some embodiments of the present disclosure, the compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: R 5a and R 5b are different, and each independently selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclic group; wherein said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, 3 to 8-membered cycloalkyl and 3 The 8-membered heterocyclic group is independently optionally selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, One or more of the same or different substituents in hydroxyl, cyano, amino and nitro are substituted; G is CR 4a ; R 1 , R 4 and R 4a are the same or different, and each independently selected from hydrogen atom, halogen and C 1-6 alkyl; Ring A is selected from 6 to 10 membered aryl, 5 to 10 membered heteroaryl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl; each R 2a is the same or different, And each independently is halogen or C 1-6 alkyl, m is 1, 2, 3 or 4; or m is 0; each R 7 is the same or different, and each independently is halogen or C 1-6 alkyl, n is 1, 2, 3 or 4; or n is 0 ; R is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Oxygen, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl.
在本公开的一些实施方案中，所述的通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：R 5a和R 5b不同，且各自独立地为C 1-6烷基或卤代C 1-6烷基；G为CR 4a；R 1、R 4和R 4a相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基；环A选自苯基、5或6元杂环基和5或6元环烷基；各个R 2a相同或不同，且各自独立地为卤素或C 1-6烷基，m为1、2、3或4；或者m为0；R 7为卤素，n为1；R 8为C 1-6烷基或3至8元环烷基。 In some embodiments of the present disclosure, the compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: R 5a and R 5b are different, and each independently C 1-6 alkyl or halogenated C 1-6 alkyl; G is CR 4a ; R 1 , R 4 and R 4a are the same or different, and each independently selected from hydrogen atom, halogen and C 1- 6 alkyl; ring A is selected from phenyl, 5 or 6 membered heterocyclic group and 5 or 6 membered cycloalkyl; each R 2a is the same or different, and each independently is halogen or C 1-6 alkyl, m is 1, 2, 3 or 4; or m is 0; R 7 is halogen, n is 1; R 8 is C 1-6 alkyl or 3 to 8 membered cycloalkyl.
在本公开的一些实施方案中，所述的通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：R 5a为C 1-6烷基，R 5b为卤代C 1-6烷基；G为CR 4a；R 1、R 4和R 4a均为氢原子；环A选自苯基、5或6元杂芳基、5或6元环烷基和5或6元杂环基；各个R 2a相同或不同，且各自独立地为卤素或C 1-6烷基；m为0、1或2；R 7为卤素或C 1-6烷基；n为0或1；R 8为C 1-6烷基或3至8元环烷基。 In some embodiments of the present disclosure, the compound represented by general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein: R 5a is C 1-6 alkyl, R 5b is halogenated C 1-6 alkyl; G is CR 4a ; R 1 , R 4 and R 4a are all hydrogen atoms; ring A is selected from phenyl, 5 or 6 membered heteroaryl Group, 5 or 6 membered cycloalkyl and 5 or 6 membered heterocyclic group; each R 2a is the same or different, and each independently is halogen or C 1-6 alkyl; m is 0, 1 or 2; R 7 is Halogen or C 1-6 alkyl; n is 0 or 1; R 8 is C 1-6 alkyl or 3 to 8 membered cycloalkyl.
在本公开的一些实施方案中，所述的通式(G)、通式(G-1)或通式(G-2)所示的化合物或其可药用的盐，其中：R 5a为C 1-6烷基，R 5b为卤代C 1-6烷基；环A选自苯基、5或6元杂芳基、5或6元环烷基和5或6元杂环基；Z为N或CR 4；G为N或CR 4a；R 1、R 4和R 4a均为氢原子；R 0为氢原子或
Figure PCTCN2022105987-appb-000060
各个R 2a相同或不同，且各自独立地选自氘原子、卤素和C 1-6烷基；m为0、1或2；R 7为卤素或C 1-6烷基；n为1；R 8为3至8元环烷基。 In some embodiments of the present disclosure, the compound represented by general formula (G), general formula (G-1) or general formula (G-2) or a pharmaceutically acceptable salt thereof, wherein: R 5a is C 1-6 alkyl, R 5b is halogenated C 1-6 alkyl; Ring A is selected from phenyl, 5 or 6 membered heteroaryl, 5 or 6 membered cycloalkyl and 5 or 6 membered heterocyclic group; Z is N or CR 4 ; G is N or CR 4a ; R 1 , R 4 and R 4a are all hydrogen atoms; R 0 is hydrogen atom or
Figure PCTCN2022105987-appb-000060
Each R 2a is the same or different, and is independently selected from deuterium atom, halogen and C 1-6 alkyl; m is 0, 1 or 2; R 7 is halogen or C 1-6 alkyl; n is 1; R 8 is a 3- to 8-membered cycloalkyl group.
表A本公开的典型化合物包括但不限于：Table A Typical compounds of the present disclosure include, but are not limited to:
Figure PCTCN2022105987-appb-000061
Figure PCTCN2022105987-appb-000061
Figure PCTCN2022105987-appb-000062
Figure PCTCN2022105987-appb-000062
Figure PCTCN2022105987-appb-000063
Figure PCTCN2022105987-appb-000063
Figure PCTCN2022105987-appb-000064
Figure PCTCN2022105987-appb-000064
Figure PCTCN2022105987-appb-000065
Figure PCTCN2022105987-appb-000065
Figure PCTCN2022105987-appb-000066
Figure PCTCN2022105987-appb-000066
Figure PCTCN2022105987-appb-000067
Figure PCTCN2022105987-appb-000067
Figure PCTCN2022105987-appb-000068
Figure PCTCN2022105987-appb-000068
Figure PCTCN2022105987-appb-000069
Figure PCTCN2022105987-appb-000069
Figure PCTCN2022105987-appb-000070
Figure PCTCN2022105987-appb-000070
Figure PCTCN2022105987-appb-000071
Figure PCTCN2022105987-appb-000071
Figure PCTCN2022105987-appb-000072
Figure PCTCN2022105987-appb-000072
Figure PCTCN2022105987-appb-000073
Figure PCTCN2022105987-appb-000073
Figure PCTCN2022105987-appb-000074
Figure PCTCN2022105987-appb-000074
Figure PCTCN2022105987-appb-000075
Figure PCTCN2022105987-appb-000075
Figure PCTCN2022105987-appb-000076
Figure PCTCN2022105987-appb-000076
Figure PCTCN2022105987-appb-000077
Figure PCTCN2022105987-appb-000077
Figure PCTCN2022105987-appb-000078
Figure PCTCN2022105987-appb-000078
Figure PCTCN2022105987-appb-000079
Figure PCTCN2022105987-appb-000079
Figure PCTCN2022105987-appb-000080
Figure PCTCN2022105987-appb-000080
Figure PCTCN2022105987-appb-000081
Figure PCTCN2022105987-appb-000081
本公开的另一方面涉及通式(MA)所示的化合物或其盐：Another aspect of the present disclosure relates to compounds represented by general formula (MA) or salts thereof:
Figure PCTCN2022105987-appb-000082
Figure PCTCN2022105987-appb-000082
其中：in:
R为烷基或
Figure PCTCN2022105987-appb-000083
优选地，R为烷基或
Figure PCTCN2022105987-appb-000084
R is alkyl or
Figure PCTCN2022105987-appb-000083
Preferably, R is alkyl or
Figure PCTCN2022105987-appb-000084
R w为烷基或烯丙基；优选地，R w为烯丙基； R w is alkyl or allyl; preferably, R w is allyl;
Z、G、R 1至R 3、R 5至R 11和n如通式(M)中所定义。 Z, G, R 1 to R 3 , R 5 to R 11 and n are as defined in the general formula (M).
本公开的另一方面涉及通式(IA)所示的化合物或其盐：Another aspect of the present disclosure relates to compounds represented by general formula (IA) or salts thereof:
Figure PCTCN2022105987-appb-000085
Figure PCTCN2022105987-appb-000085
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
G、R 1至R 11和n如通式(I)中所定义。 G, R 1 to R 11 and n are as defined in the general formula (I).
本公开的另一方面涉及通式(IIA)所示的化合物或其盐：Another aspect of the present disclosure relates to compounds represented by general formula (IIA) or salts thereof:
Figure PCTCN2022105987-appb-000086
Figure PCTCN2022105987-appb-000086
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4至R 11、m和n如通式(II)中所定义。 Ring A, R 2a , G, R 1 , R 4 to R 11 , m and n are as defined in the general formula (II).
本公开的另一方面涉及通式(IIIA)所示的化合物或其盐：Another aspect of the present disclosure relates to compounds represented by general formula (IIIA) or salts thereof:
Figure PCTCN2022105987-appb-000087
Figure PCTCN2022105987-appb-000087
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4、R 5、R 7、R 8、R 10、m和n如通式(III)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in the general formula (III).
本公开的另一方面涉及通式(GA)所示的化合物或其盐：Another aspect of the present disclosure relates to compounds represented by general formula (GA) or salts thereof:
Figure PCTCN2022105987-appb-000088
Figure PCTCN2022105987-appb-000088
其中：in:
R为烷基或
Figure PCTCN2022105987-appb-000089
优选地，R为烷基或
Figure PCTCN2022105987-appb-000090
R is alkyl or
Figure PCTCN2022105987-appb-000089
Preferably, R is alkyl or
Figure PCTCN2022105987-appb-000090
R w为烷基或烯丙基；优选地，R w为烯丙基； R w is alkyl or allyl; preferably, R w is allyl;
环A、Z、G、R 1、R 2a、R 5a、R 5b、R 7、R 8、m和n如通式(G)中所定义。 Rings A, Z, G, R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G).
本公开的另一方面涉及通式(G-1A)或通式(G-2A)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound or a salt thereof represented by general formula (G-1A) or general formula (G-2A):
Figure PCTCN2022105987-appb-000091
Figure PCTCN2022105987-appb-000091
其中：in:
R为烷基或
Figure PCTCN2022105987-appb-000092
优选地，R为烷基或
Figure PCTCN2022105987-appb-000093
R is alkyl or
Figure PCTCN2022105987-appb-000092
Preferably, R is alkyl or
Figure PCTCN2022105987-appb-000093
R w为烷基或烯丙基；优选地，R w为烯丙基； R w is alkyl or allyl; preferably, R w is allyl;
环A、Z、G、R 1、R 2a、R 5a、R 5b、R 7、R 8、m和n如通式(G-1)或通式(G-2)中所定义。 Rings A, Z, G, R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (G-1) or general formula (G-2).
本公开的另一方面涉及通式(IVA)所示的化合物或其盐：Another aspect of the present disclosure relates to compounds represented by general formula (IVA) or salts thereof:
Figure PCTCN2022105987-appb-000094
Figure PCTCN2022105987-appb-000094
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4、R 5a、R 5b、R 7、R 8、m和n如通式(IV)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (IV).
本公开的另一方面涉及通式(IV-1A)或通式(IV-2A)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound or a salt thereof represented by general formula (IV-1A) or general formula (IV-2A):
Figure PCTCN2022105987-appb-000095
Figure PCTCN2022105987-appb-000095
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4、R 5a、R 5b、R 7、R 8、m和n如通式(IV-1)或通式(IV-2) 中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (IV-1) or general formula (IV-2).
表B本公开的典型中间体化合物或其盐，包括但不限于：Table B Typical intermediate compounds of the present disclosure or salts thereof, including but not limited to:
Figure PCTCN2022105987-appb-000096
Figure PCTCN2022105987-appb-000096
Figure PCTCN2022105987-appb-000097
Figure PCTCN2022105987-appb-000097
Figure PCTCN2022105987-appb-000098
Figure PCTCN2022105987-appb-000098
Figure PCTCN2022105987-appb-000099
Figure PCTCN2022105987-appb-000099
Figure PCTCN2022105987-appb-000100
Figure PCTCN2022105987-appb-000100
Figure PCTCN2022105987-appb-000101
Figure PCTCN2022105987-appb-000101
Figure PCTCN2022105987-appb-000102
Figure PCTCN2022105987-appb-000102
Figure PCTCN2022105987-appb-000103
Figure PCTCN2022105987-appb-000103
Figure PCTCN2022105987-appb-000104
Figure PCTCN2022105987-appb-000104
Figure PCTCN2022105987-appb-000105
Figure PCTCN2022105987-appb-000105
Figure PCTCN2022105987-appb-000106
Figure PCTCN2022105987-appb-000106
Figure PCTCN2022105987-appb-000107
Figure PCTCN2022105987-appb-000107
Figure PCTCN2022105987-appb-000108
Figure PCTCN2022105987-appb-000108
Figure PCTCN2022105987-appb-000109
Figure PCTCN2022105987-appb-000109
Figure PCTCN2022105987-appb-000110
Figure PCTCN2022105987-appb-000110
Figure PCTCN2022105987-appb-000111
Figure PCTCN2022105987-appb-000111
Figure PCTCN2022105987-appb-000112
Figure PCTCN2022105987-appb-000112
Figure PCTCN2022105987-appb-000113
Figure PCTCN2022105987-appb-000113
Figure PCTCN2022105987-appb-000114
Figure PCTCN2022105987-appb-000114
本公开的另一方面涉及一种通式(Ga-A)、通式(Ga-A1)或通式(Ga-A2)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound or a salt thereof represented by general formula (Ga-A), general formula (Ga-A1) or general formula (Ga-A2):
Figure PCTCN2022105987-appb-000115
Figure PCTCN2022105987-appb-000115
其中：in:
R 5a和R 5b不同，且各自独立地选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基和杂环基；其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、羟基、氰基、氨基和硝基中的一个或多个相同或不同的取代基取代；其中当R 5a和R 5b之一为甲基时，另一个不为乙基或丙基； R 5a and R 5b are different, and are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein said alkyl, alkoxy The radical, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, cyano, amino and One or more identical or different substituents in the nitro group are substituted; wherein when one of R 5a and R 5b is methyl, the other is not ethyl or propyl;
环A、Z、G、R 2a、m和R 1如通式(G)、通式(G-1)或通式(G-2)中所定义。 Rings A, Z, G, R 2a , m and R 1 are as defined in general formula (G), general formula (G-1) or general formula (G-2).
本公开的另一方面涉及一种通式(IVa-A)、通式(IVa-A1)或通式(IVa-A2)所示的化合物或其盐：Another aspect of the present disclosure relates to a compound or a salt thereof represented by general formula (IVa-A), general formula (IVa-A1) or general formula (IVa-A2):
Figure PCTCN2022105987-appb-000116
Figure PCTCN2022105987-appb-000116
其中：in:
R 5a和R 5b不同，且各自独立地选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基和杂环基；其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、羟基、氰基、氨基和硝基中的一个或多个相同或不同的取代基取代；其中当R 5a和R 5b之一为甲基时，另一个不为乙基或丙基； R 5a and R 5b are different, and are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein said alkyl, alkoxy The radical, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, cyano, amino and One or more identical or different substituents in the nitro group are substituted; wherein when one of R 5a and R 5b is methyl, the other is not ethyl or propyl;
G为CR 4a； G is CR 4a ;
环A、R 2a、m、R 4a、R 1和R 4如通式(IV)、通式(IV-1)或通式(IV-2)中所定义。 Ring A, R 2a , m, R 4a , R 1 and R 4 are as defined in general formula (IV), general formula (IV-1) or general formula (IV-2).
表C本公开的典型中间体化合物或其盐，包括但不限于：Table C Typical intermediate compounds of the present disclosure or salts thereof, including but not limited to:
Figure PCTCN2022105987-appb-000117
Figure PCTCN2022105987-appb-000117
Figure PCTCN2022105987-appb-000118
Figure PCTCN2022105987-appb-000118
Figure PCTCN2022105987-appb-000119
Figure PCTCN2022105987-appb-000119
Figure PCTCN2022105987-appb-000120
Figure PCTCN2022105987-appb-000120
Figure PCTCN2022105987-appb-000121
Figure PCTCN2022105987-appb-000121
Figure PCTCN2022105987-appb-000122
Figure PCTCN2022105987-appb-000122
Figure PCTCN2022105987-appb-000123
Figure PCTCN2022105987-appb-000123
Figure PCTCN2022105987-appb-000124
Figure PCTCN2022105987-appb-000124
Figure PCTCN2022105987-appb-000125
Figure PCTCN2022105987-appb-000125
Figure PCTCN2022105987-appb-000126
Figure PCTCN2022105987-appb-000126
Figure PCTCN2022105987-appb-000127
Figure PCTCN2022105987-appb-000127
Figure PCTCN2022105987-appb-000128
Figure PCTCN2022105987-appb-000128
Figure PCTCN2022105987-appb-000129
Figure PCTCN2022105987-appb-000129
Figure PCTCN2022105987-appb-000130
Figure PCTCN2022105987-appb-000130
Figure PCTCN2022105987-appb-000131
Figure PCTCN2022105987-appb-000131
Figure PCTCN2022105987-appb-000132
Figure PCTCN2022105987-appb-000132
Figure PCTCN2022105987-appb-000133
Figure PCTCN2022105987-appb-000133
本公开的另一方面涉及一种制备通式(M)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (M) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000134
Figure PCTCN2022105987-appb-000134
通式(MA)所示的化合物或其盐发生反应，得到通式(M)所示的化合物或其可药用的盐；A compound represented by the general formula (MA) or a salt thereof is reacted to obtain a compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof;
其中：in:
R为烷基或
Figure PCTCN2022105987-appb-000135
优选地，R为烷基或
Figure PCTCN2022105987-appb-000136
R is alkyl or
Figure PCTCN2022105987-appb-000135
Preferably, R is alkyl or
Figure PCTCN2022105987-appb-000136
R w为烷基或烯丙基；优选地，R w为烯丙基； R w is alkyl or allyl; preferably, R w is allyl;
条件为，当R选自烷基时，通式(MA)所示的化合物或其盐发生酯水解反应，得到R 0为氢原子的通式(M)所示的化合物或其可药用的盐； The condition is that when R is selected from an alkyl group, the compound represented by the general formula (MA) or its salt undergoes an ester hydrolysis reaction to obtain a compound represented by the general formula (M ) whose R is a hydrogen atom or its pharmaceutically acceptable Salt;
当R为
Figure PCTCN2022105987-appb-000137
时，通式(MA)所示的化合物或其盐脱去R w，得到R 0为
Figure PCTCN2022105987-appb-000138
的通式(M)所示的化合物或其可药用的盐；优选地，当R为
Figure PCTCN2022105987-appb-000139
时，通式(MA)所示的化合物或其盐脱去R w，得到R 0为
Figure PCTCN2022105987-appb-000140
的通式(M)所示的化合物或其可药用的盐； when R is
Figure PCTCN2022105987-appb-000137
When , the compound represented by the general formula (MA) or its salt removes R w , and R 0 is obtained as
Figure PCTCN2022105987-appb-000138
A compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof; preferably, when R is
Figure PCTCN2022105987-appb-000139
When , the compound represented by the general formula (MA) or its salt removes R w , and R 0 is obtained as
Figure PCTCN2022105987-appb-000140
A compound represented by general formula (M) or a pharmaceutically acceptable salt thereof;
Z、G、R 0、R 1至R 3、R 5至R 11和n如通式(M)中所定义。 Z, G, R 0 , R 1 to R 3 , R 5 to R 11 and n are as defined in the general formula (M).
本公开的另一方面涉及一种制备通式(MA)所示的化合物或其盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (MA) or a salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000141
Figure PCTCN2022105987-appb-000141
通式(Ma-A)所示的化合物或其盐与通式(Ib-A)所示的化合物或其盐发生缩合酰化反应，得到通式(MA)所示的化合物或其盐；The compound represented by the general formula (Ma-A) or its salt and the compound represented by the general formula (Ib-A) or its salt undergo a condensation acylation reaction to obtain the compound represented by the general formula (MA) or its salt;
其中：in:
Z、G、R、R 1至R 3、R 5至R 11和n如通式(MA)中所定义。 Z, G, R, R 1 to R 3 , R 5 to R 11 and n are as defined in the general formula (MA).
本公开的另一方面涉及一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000142
Figure PCTCN2022105987-appb-000142
通式(IA)所示的化合物或其盐发生酯水解反应，得到通式(I)所示的化合物或其可药用的盐；The compound represented by the general formula (IA) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
G、R 1至R 11和n如通式(I)中所定义。 G, R 1 to R 11 and n are as defined in the general formula (I).
本公开的另一方面涉及一种制备通式(IA)所示的化合物或其盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IA) or a salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000143
Figure PCTCN2022105987-appb-000143
通式(Ia-A)所示的化合物或其盐与通式(Ib-A)所示的化合物或其盐发生缩合酰化反应，得到通式(IA)所示的化合物或其盐；The compound represented by the general formula (Ia-A) or its salt undergoes a condensation acylation reaction with the compound represented by the general formula (Ib-A) or its salt to obtain the compound represented by the general formula (IA) or its salt;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
G、R 1至R 11和n如通式(IA)中所定义。 G, R 1 to R 11 and n are as defined in general formula (IA).
本公开的另一方面涉及一种制备通式(II)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000144
Figure PCTCN2022105987-appb-000144
通式(IIA)所示的化合物或其盐发生酯水解反应，得到通式(II)所示的化合物或其可药用的盐以下步骤；The compound represented by the general formula (IIA) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof with the following steps;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4至R 11、m和n如通式(II)中所定义。 Ring A, R 2a , G, R 1 , R 4 to R 11 , m and n are as defined in the general formula (II).
本公开的另一方面涉及一种制备通式(IIA)所示的化合物或其盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIA) or a salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000145
Figure PCTCN2022105987-appb-000145
通式(IIa-A)所示的化合物或其盐与通式(Ib-A)所示的化合物或其盐发生缩合酰化反应，得到通式(IIA)所示的化合物或其盐；The compound represented by the general formula (IIa-A) or its salt undergoes a condensation acylation reaction with the compound represented by the general formula (Ib-A) or its salt to obtain the compound represented by the general formula (IIA) or its salt;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4至R 11、m和n如通式(IIA)中所定义。 Ring A, R 2a , G, R 1 , R 4 to R 11 , m and n are as defined in the general formula (IIA).
本公开的另一方面涉及一种制备通式(III)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000146
Figure PCTCN2022105987-appb-000146
通式(IIIA)所示的化合物或其盐发生酯水解反应，得到通式(III)所示的化合物或其可药用的盐；The compound represented by general formula (IIIA) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4、R 5、R 7、R 8、R 10、m和n如通式(III)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in the general formula (III).
本公开的另一方面涉及一种制备通式(IIIA)所示的化合物或其盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIA) or a salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000147
Figure PCTCN2022105987-appb-000147
通式(IIIa-A)所示的化合物或其盐与通式(IIIb-A)所示的化合物或其盐发生缩合酰化反应，得到通式(IIIA)所示的化合物或其盐；The compound represented by the general formula (IIIa-A) or its salt undergoes a condensation acylation reaction with the compound represented by the general formula (IIIb-A) or its salt to obtain the compound represented by the general formula (IIIA) or its salt;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4、R 5、R 7、R 8、R 10、m和n如通式(IIIA)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in general formula (IIIA).
本公开的另一方面涉及一种制备通式(G)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000148
Figure PCTCN2022105987-appb-000148
通式(GA)所示的化合物或其盐发生反应，得到通式(G)所示的化合物或其可药用的盐；A compound represented by the general formula (GA) or a salt thereof is reacted to obtain a compound represented by the general formula (G) or a pharmaceutically acceptable salt thereof;
其中：in:
R为烷基或
Figure PCTCN2022105987-appb-000149
优选地，R为烷基或
Figure PCTCN2022105987-appb-000150
R is alkyl or
Figure PCTCN2022105987-appb-000149
Preferably, R is alkyl or
Figure PCTCN2022105987-appb-000150
R w为烷基或烯丙基；优选地，R w为烯丙基； R w is alkyl or allyl; preferably, R w is allyl;
条件为，当R为烷基时，通式(GA)所示的化合物或其盐发生酯水解反应，得到R 0为氢原子的通式(G)所示的化合物或其可药用的盐； The condition is that when R is an alkyl group, the compound represented by the general formula (GA) or its salt undergoes an ester hydrolysis reaction to obtain a compound represented by the general formula (G ) whose R is a hydrogen atom or a pharmaceutically acceptable salt thereof ;
当R为
Figure PCTCN2022105987-appb-000151
时，通式(GA)所示的化合物或其盐脱去R w，得到R 0为
Figure PCTCN2022105987-appb-000152
的通式(G)所示的化合物或其可药用的盐；优选地，当R为
Figure PCTCN2022105987-appb-000153
时，通式(GA)所示的化合物或其盐脱去R w，得到R 0为
Figure PCTCN2022105987-appb-000154
的通式(G)所示的化合物或其可药用的盐； when R is
Figure PCTCN2022105987-appb-000151
When, the compound represented by the general formula (GA) or its salt removes R w , and R 0 is obtained as
Figure PCTCN2022105987-appb-000152
A compound represented by general formula (G) or a pharmaceutically acceptable salt thereof; preferably, when R is
Figure PCTCN2022105987-appb-000153
When, the compound represented by the general formula (GA) or its salt removes R w , and R 0 is obtained as
Figure PCTCN2022105987-appb-000154
A compound represented by general formula (G) or a pharmaceutically acceptable salt thereof;
环A、Z、G、R 0、R 1、R 2a、R 5a、R 5b、R 7、R 8、m和n如通式(G)中所定义。 Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G).
本公开的另一方面涉及一种制备通式(G-1)所示的化合物或其可药用的盐的方 法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000155
Figure PCTCN2022105987-appb-000155
通式(G-1A)所示的化合物或其盐发生反应，得到通式(G-1)所示的化合物或其可药用的盐；The compound represented by the general formula (G-1A) or its salt is reacted to obtain the compound represented by the general formula (G-1) or a pharmaceutically acceptable salt thereof;
其中：in:
R为烷基或
Figure PCTCN2022105987-appb-000156
优选地，R为烷基或
Figure PCTCN2022105987-appb-000157
R is alkyl or
Figure PCTCN2022105987-appb-000156
Preferably, R is alkyl or
Figure PCTCN2022105987-appb-000157
R w为烷基或烯丙基；优选地，R w为烯丙基； R w is alkyl or allyl; preferably, R w is allyl;
条件为，当R为烷基时，通式(G-1A)所示的化合物或其盐发生酯水解反应，得到R 0为氢原子的通式(G-1)所示的化合物或其可药用的盐； The condition is that when R is an alkyl group, the compound represented by the general formula (G-1A) or its salt undergoes an ester hydrolysis reaction to obtain a compound represented by the general formula (G-1 ) whose R is a hydrogen atom or its alternative medicinal salts;
当R为
Figure PCTCN2022105987-appb-000158
时，通式(G-1A)所示的化合物或其盐脱去R w，得到R 0为
Figure PCTCN2022105987-appb-000159
的通式(G-1)所示的化合物或其可药用的盐；优选地，当R为
Figure PCTCN2022105987-appb-000160
时，通式(G-1A)所示的化合物或其盐脱去R w，得到R 0为
Figure PCTCN2022105987-appb-000161
的通式(G-1)所示的化合物或其可药用的盐； when R is
Figure PCTCN2022105987-appb-000158
When, the compound represented by the general formula (G-1A) or its salt removes R w , and obtains R 0 as
Figure PCTCN2022105987-appb-000159
A compound represented by the general formula (G-1) or a pharmaceutically acceptable salt thereof; preferably, when R is
Figure PCTCN2022105987-appb-000160
When, the compound represented by the general formula (G-1A) or its salt removes R w , and obtains R 0 as
Figure PCTCN2022105987-appb-000161
A compound represented by general formula (G-1) or a pharmaceutically acceptable salt thereof;
环A、Z、G、R 0、R 1、R 2a、R 5a、R 5b、R 7、R 8、m和n如通式(G-1)中所定义。 Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G-1).
本公开的另一方面涉及一种制备通式(G-2)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000162
Figure PCTCN2022105987-appb-000162
通式(G-2A)所示的化合物或其盐发生反应，得到通式(G-2)所示的化合物或其可药用的盐；A compound represented by general formula (G-2A) or a salt thereof is reacted to obtain a compound represented by general formula (G-2) or a pharmaceutically acceptable salt thereof;
其中：in:
R为烷基或
Figure PCTCN2022105987-appb-000163
优选地，R为烷基或
Figure PCTCN2022105987-appb-000164
R is alkyl or
Figure PCTCN2022105987-appb-000163
Preferably, R is alkyl or
Figure PCTCN2022105987-appb-000164
R w为烷基或烯丙基；优选地，R w为烯丙基； R w is alkyl or allyl; preferably, R w is allyl;
条件为，当R为烷基时，通式(G-2A)所示的化合物或其盐发生酯水解反应，得到R 0为氢原子的通式(G-2)所示的化合物或其可药用的盐； The condition is that when R is an alkyl group, the compound represented by the general formula (G-2A) or its salt undergoes an ester hydrolysis reaction to obtain a compound represented by the general formula (G- 2 ) whose R is a hydrogen atom or its alternative medicinal salts;
当R为
Figure PCTCN2022105987-appb-000165
时，通式(G-2A)所示的化合物或其盐脱去R w，得到R 0为
Figure PCTCN2022105987-appb-000166
的通式(G-2)所示的化合物或其可药用的盐；优选地，当R为
Figure PCTCN2022105987-appb-000167
时，通式(G-2A)所示的化合物或其盐脱去R w，得到R 0为
Figure PCTCN2022105987-appb-000168
的通式(G-2)所示的化合物或其可药用的盐； when R is
Figure PCTCN2022105987-appb-000165
When, the compound represented by the general formula (G-2A) or its salt removes R w , and obtains R 0 as
Figure PCTCN2022105987-appb-000166
A compound represented by the general formula (G-2) or a pharmaceutically acceptable salt thereof; preferably, when R is
Figure PCTCN2022105987-appb-000167
When, the compound represented by the general formula (G-2A) or its salt removes R w , and obtains R 0 as
Figure PCTCN2022105987-appb-000168
A compound represented by general formula (G-2) or a pharmaceutically acceptable salt thereof;
环A、Z、G、R 0、R 1、R 2a、R 5a、R 5b、R 7、R 8、m和n如通式(G-2)中所定义。 Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G-2).
本公开的另一方面涉及一种制备通式(G-1A)或通式(G-2A)所示的化合物或其盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G-1A) or general formula (G-2A) or a salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000169
Figure PCTCN2022105987-appb-000169
通式(Ga-A)所示的化合物或其盐与通式(IVb-A)所示的化合物或其盐发生缩合酰化反应，得到通式(G-1A)或通式(G-2A)所示的化合物或其盐；Compound represented by general formula (Ga-A) or its salt and compound represented by general formula (IVb-A) or its salt generation condensation acylation reaction, obtain general formula (G-1A) or general formula (G-2A ) or a salt thereof;
其中：in:
环A、Z、G、R、R 1、R 2a、R 5a、R 5b、R 7、R 8、m和n如通式(G-1A)或通式(G-2A)中所定义。 Rings A, Z, G, R, R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (G-1A) or general formula (G-2A).
本公开的另一方面涉及一种制备通式(IV)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000170
Figure PCTCN2022105987-appb-000170
通式(IVA)所示的化合物或其盐发生酯水解反应，得到通式(IV)所示的化合物或其可药用的盐；The compound represented by the general formula (IVA) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4、R 5a、R 5b、R 7、R 8、m和n如通式(IV)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (IV).
本公开的另一方面涉及一种制备通式(IV-1)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000171
Figure PCTCN2022105987-appb-000171
通式(IV-1A)所示的化合物或其盐发生酯水解反应得到通式(IV-1)所示的化合物或其可药用的盐；The compound represented by the general formula (IV-1A) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4、R 5a、R 5b、R 7、R 8、m和n如通式(IV-1)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (IV-1).
本公开的另一方面涉及一种制备通式(IV-2)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000172
Figure PCTCN2022105987-appb-000172
通式(IV-2A)所示的化合物或其盐发生酯水解反应得到通式(IV-2)所示的化合物或其可药用的盐；The compound represented by the general formula (IV-2A) or its salt undergoes an ester hydrolysis reaction to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4、R 5a、R 5b、R 7、R 8、m和n如通式(IV-2)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (IV-2).
本公开的另一方面涉及一种制备通式(IV-1A)或通式(IV-2A)所示的化合物或其盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-1A) or general formula (IV-2A) or a salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000173
Figure PCTCN2022105987-appb-000173
通式(IVa-A)所示的化合物或其盐与通式(IVb-A)所示的化合物或其盐发生缩合酰化反应，得到通式(IV-1A)或通式(IV-2A)所示的化合物或其盐；The compound represented by general formula (IVa-A) or its salt and the compound represented by general formula (IVb-A) or its salt occur condensation acylation reaction, obtain general formula (IV-1A) or general formula (IV-2A ) or a salt thereof;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4、R 5a、R 5b、R 7、R 8、m和n如通式(IV-1A)或通式(IV-2A)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (IV-1A) or general formula (IV-2A).
本公开的另一方面涉及一种制备通式(M)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (M) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000174
Figure PCTCN2022105987-appb-000174
通式(Ma-A)所示的化合物或其盐与通式(MB)所示的化合物或其盐发生缩合酰化反应，得到通式(M)所示的化合物或其可药用的盐；The compound represented by the general formula (Ma-A) or its salt and the compound represented by the general formula (MB) or its salt undergo condensation acylation reaction to obtain the compound represented by the general formula (M) or its pharmaceutically acceptable salt ;
其中：in:
Z、G、R 0、R 1至R 3、R 5至R 11和n如通式(M)中所定义。 Z, G, R 0 , R 1 to R 3 , R 5 to R 11 and n are as defined in the general formula (M).
本公开的另一方面涉及一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000175
Figure PCTCN2022105987-appb-000175
通式(Ia-A)所示的化合物或其盐与通式(IB)所示的化合物或其盐发生缩合酰化反应，得到通式(I)所示的化合物或其可药用的盐；The compound represented by general formula (Ia-A) or its salt and the compound represented by general formula (IB) or its salt occur condensation acylation reaction, obtain the compound represented by general formula (I) or its pharmaceutically acceptable salt ;
其中：in:
G、R 1至R 11和n如通式(I)中所定义。 G, R 1 to R 11 and n are as defined in the general formula (I).
本公开的另一方面涉及一种制备通式(II)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000176
Figure PCTCN2022105987-appb-000176
通式(IIa-A)所示的化合物或其盐与通式(IB)所示的化合物或其盐发生缩合酰化反应，得到通式(II)所示的化合物或其可药用的盐；The compound represented by general formula (IIa-A) or its salt and the compound represented by general formula (IB) or its salt occur condensation acylation reaction, obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt ;
其中：in:
环A、R 2a、G、R 1、R 4至R 11、m和n如通式(II)中所定义。 Ring A, R 2a , G, R 1 , R 4 to R 11 , m and n are as defined in the general formula (II).
本公开的另一方面涉及一种制备通式(III)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000177
Figure PCTCN2022105987-appb-000177
通式(IIIa-A)所示的化合物或其盐与通式(IIIB)所示的化合物或其盐发生缩合酰化反应，得到通式(III)所示的化合物或其可药用的盐；The compound represented by the general formula (IIIa-A) or its salt and the compound represented by the general formula (IIIB) or its salt undergo a condensation acylation reaction to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof ;
其中：in:
环A、R 2a、G、R 1、R 4、R 5、R 7、R 8、R 10、m和n如通式(III)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in the general formula (III).
本公开的另一方面涉及一种制备通式(G-1)或通式(G-2)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G-1) or general formula (G-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000178
Figure PCTCN2022105987-appb-000178
通式(Ga-A)所示的化合物或其盐与通式(GB)所示的化合物或其盐发生缩合酰化反应，得到通式(G-1)或通式(G-2)所示的化合物或其可药用的盐；The compound represented by the general formula (Ga-A) or its salt and the compound represented by the general formula (GB) or its salt undergo a condensation acylation reaction to obtain the compound represented by the general formula (G-1) or the general formula (G-2). The indicated compound or its pharmaceutically acceptable salt;
其中：in:
环A、Z、G、R 0、R 1、R 2a、R 5a、R 5b、R 7、R 8、m和n如通式(G-1)或(G-2)中所定义。 Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G-1) or (G-2).
本公开的另一方面涉及一种制备通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000179
Figure PCTCN2022105987-appb-000179
通式(IVa-A)所示的化合物或其盐与通式(IVB)所示的化合物或其盐发生缩合酰化反应，得到通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐；The compound represented by the general formula (IVa-A) or its salt and the compound represented by the general formula (IVB) or its salt undergo a condensation acylation reaction to obtain the compound represented by the general formula (IV-1) or the general formula (IV-2). The indicated compound or its pharmaceutically acceptable salt;
其中：in:
环A、R 2a、G、R 1、R 4、R 5a、R 5b、R 7、R 8、m和n如通式(IV-1)或通式(IV-2) 中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (IV-1) or general formula (IV-2).
本公开的另一方面涉及一种制备通式(G-1)和通式(G-2)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (G-1) and general formula (G-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000180
Figure PCTCN2022105987-appb-000180
通式(G)所示的化合物或其可药用的盐进行制备分离，得到通式(G-1)和通式(G-2)所示的化合物或其可药用的盐；The compound represented by general formula (G) or its pharmaceutically acceptable salt is prepared and separated to obtain the compound represented by general formula (G-1) and general formula (G-2) or its pharmaceutically acceptable salt;
其中：in:
环A、Z、G、R 0、R 1、R 2a、R 5a、R 5b、R 7、R 8、m和n如通式(G)中所定义。 Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G).
本公开的另一方面涉及一种制备通式(IV-1)和通式(IV-2)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV-1) and general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
Figure PCTCN2022105987-appb-000181
Figure PCTCN2022105987-appb-000181
通式(IV)所示的化合物或其可药用的盐进行制备分离，得到通式(IV-1)和通式(IV-2)所示的化合物或其可药用的盐；The compound represented by general formula (IV) or its pharmaceutically acceptable salt is prepared and separated to obtain the compound represented by general formula (IV-1) and general formula (IV-2) or its pharmaceutically acceptable salt;
其中：in:
环A、R 2a、G、R 1、R 4、R 5a、R 5b、R 7、R 8、m和n如通式(IV-1)或通式(IV-2)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (IV-1) or general formula (IV-2).
本公开的另一方面涉及一种药物组合物，所述药物组合物含有治疗有效量的本公开通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a therapeutically effective amount of the general formula (M), general formula (G), general formula (G-1), general formula (G- 2), the compound shown in general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2) and table A or Its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.
本公开进一步涉及通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用的盐或者包含其的药物组合物在制备sGC激动剂和/或激活剂中的用途。The present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), The compound shown in general formula (IV), general formula (IV-1), general formula (IV-2) and table A or its pharmaceutically acceptable salt or the pharmaceutical composition comprising it are in the preparation of sGC agonist and/or Use in activators.
本公开进一步涉及通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用盐或者包含其的药物组合物在制备用于治疗和/或预防通过激动和/或激活sGC来减轻的疾病、病况或病症的药物中的用途，所述的疾病、病况或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、肥胖、骨质疏松、纤 维变性病、神经疾病、泌尿***疾病和性功能障碍；优选地，所述的疾病、病况或病症选自心血管疾病、肺动脉高压和肾病；更优选地，所述肾病为慢性肾功能衰竭或慢性肾功能不全。The present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), The compound shown in general formula (IV), general formula (IV-1), general formula (IV-2) and table A or its pharmaceutically acceptable salt or the pharmaceutical composition comprising it are used in the preparation for treatment and/or prevention Use in medicine for a disease, condition or disorder alleviated by agonizing and/or activating sGC selected from cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, Osteoporosis, fibrotic disease, neurological disease, urinary system disease, and sexual dysfunction; preferably, said disease, condition or disorder is selected from cardiovascular disease, pulmonary hypertension, and renal disease; more preferably, said renal disease is chronic Kidney failure or chronic renal insufficiency.
本公开进一步涉及通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用盐或者包含其的药物组合物在制备用于治疗和/或预防通过激动和/或激活sGC来减轻的疾病、病况或病症的药物中的用途，所述的疾病、病况或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；其中所述心血管疾病选自高血压、动脉粥样硬化症、冠心病、腰椎管狭窄症、外周动脉疾病、间歇性跛行、重症下肢缺血、稳定或者不稳定心绞痛、心肌梗死、心力衰竭、性腺机能减退、中风、冠状动脉痉挛、大脑血管痉挛、缺血/再灌注损伤和血栓栓塞性病症；优选地，所述心血管疾病选自高血压、心肌梗死和心力衰竭。The present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), The compound shown in general formula (IV), general formula (IV-1), general formula (IV-2) and table A or its pharmaceutically acceptable salt or the pharmaceutical composition comprising it are used in the preparation for treatment and/or prevention Use in medicine for a disease, condition or disorder alleviated by agonizing and/or activating sGC selected from cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, Osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; wherein the cardiovascular disease is selected from hypertension, atherosclerosis, coronary heart disease, lumbar spinal stenosis, peripheral arterial disease, intermittent Claudication, critical lower extremity ischemia, stable or unstable angina, myocardial infarction, heart failure, hypogonadism, stroke, coronary artery spasm, cerebral vasospasm, ischemia/reperfusion injury and thromboembolic disorders; preferably, said Cardiovascular disease is selected from hypertension, myocardial infarction and heart failure.
本公开进一步涉及通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用盐或者包含其的药物组合物在制备用于治疗和/或预防通过激动和/或激活sGC来减轻的疾病、病况或病症的药物中的用途，所述的疾病、病况或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；其中所述纤维变性病选自皮肤、肝、肾及肺的纤维变性病；所述泌尿***疾病选自膀胱过动症、良性***增生和***功能障碍；所述神经疾病选自阿尔茨海默氏病、帕金森氏病和神经病性疼痛；所述炎性疾病选自牛皮癣、多发性硬化、关节炎、哮喘、溃疡性结肠炎、克罗恩氏病和慢性阻塞性肺病。The present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), The compound shown in general formula (IV), general formula (IV-1), general formula (IV-2) and table A or its pharmaceutically acceptable salt or the pharmaceutical composition comprising it are used in the preparation for treatment and/or prevention Use in medicine for a disease, condition or disorder alleviated by agonizing and/or activating sGC selected from cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, Osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; wherein said fibrotic disease is selected from the group consisting of fibrosis of the skin, liver, kidney and lung; said urinary system disease is selected from overactive bladder , benign prostatic hyperplasia and erectile dysfunction; said neurological disease is selected from Alzheimer's disease, Parkinson's disease and neuropathic pain; said inflammatory disease is selected from psoriasis, multiple sclerosis, arthritis, asthma, ulcer colitis, Crohn's disease, and chronic obstructive pulmonary disease.
本公开进一步涉及一种激动和/或激活sGC的方法，其包括给予所需患者治疗有效量的通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物。The present disclosure further relates to a method for agonizing and/or activating sGC, which comprises administering a therapeutically effective amount of general formula (M), general formula (G), general formula (G-1), general formula (G- 2), the compound shown in general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2) and table A or A pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it.
本公开进一步涉及一种治疗和/或预防通过激动和/或激活sGC来减轻的疾病、病况或病症的方法，其包括给予所需患者治疗有效量的通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用的盐或者包括其的药物组合物，其中所述的疾病、病况或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍优选地，所述的疾病、病况或病症选自心血管疾病、肺动脉高压和肾病；更优选地，所述肾病为慢性肾功能衰竭或慢性肾功能不全。The present disclosure further relates to a method of treating and/or preventing a disease, condition or disorder alleviated by agonizing and/or activating sGC comprising administering to a patient in need thereof a therapeutically effective amount of Formula (M), Formula (G) , general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general The compound shown in formula (IV-2) and table A or its pharmaceutically acceptable salt or the pharmaceutical composition comprising it, wherein said disease, condition or disease are selected from cardiovascular disease, nephropathy, pulmonary hypertension, inflammatory disease Disease, diabetes, glaucoma, obesity, osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction. Preferably, said disease, condition or disorder is selected from cardiovascular disease, pulmonary hypertension and renal disease; more preferably Preferably, the renal disease is chronic renal failure or chronic renal insufficiency.
本公开进一步涉及一种治疗和/或预防通过激动和/或激活sGC来减轻的疾病、 病况或病症的方法，其包括给予所需患者治疗有效量的通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，所述的疾病、病况或病症为所述的疾病、病况或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍其中所述心血管疾病选自高血压、动脉粥样硬化症、冠心病、腰椎管狭窄症、外周动脉疾病、间歇性跛行、重症下肢缺血、稳定或者不稳定心绞痛、心肌梗死、心力衰竭、性腺机能减退、中风、冠状动脉痉挛、大脑血管痉挛、缺血/再灌注损伤和血栓栓塞性病症；优选地，所述心血管疾病选自高血压、心肌梗死和心力衰竭。The present disclosure further relates to a method of treating and/or preventing a disease, condition or disorder alleviated by agonizing and/or activating sGC comprising administering to a patient in need thereof a therapeutically effective amount of Formula (M), Formula (G) , general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general Formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, described disease, condition or disease is that described disease, condition or disease are selected from cardiovascular disease, kidney disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction wherein said cardiovascular disease is selected from hypertension, atherosclerosis coronary artery disease, lumbar spinal stenosis, peripheral artery disease, intermittent claudication, critical lower extremity ischemia, stable or unstable angina, myocardial infarction, heart failure, hypogonadism, stroke, coronary artery spasm, cerebral vasospasm, Blood/reperfusion injury and thromboembolic disorders; preferably, said cardiovascular disease is selected from hypertension, myocardial infarction and heart failure.
本公开进一步涉及一种治疗和/或预防通过激动和/或激活sGC来减轻的疾病、病况或病症的方法，其包括给予所需患者治疗有效量的通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其中所述的疾病、病况或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；其中所述纤维变性病选自皮肤、肝、肾及肺的纤维变性病；所述泌尿***疾病选自膀胱过动症、良性***增生和***功能障碍；所述神经疾病选自阿尔茨海默氏病、帕金森氏病和神经病性疼痛；所述炎性疾病选自牛皮癣、多发性硬化、关节炎、哮喘、溃疡性结肠炎、克罗恩氏病和慢性阻塞性肺病。The present disclosure further relates to a method of treating and/or preventing a disease, condition or disorder alleviated by agonizing and/or activating sGC comprising administering to a patient in need thereof a therapeutically effective amount of Formula (M), Formula (G) , general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general The compound shown in formula (IV-2) and table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, wherein said disease, condition or disease are selected from cardiovascular disease, nephropathy, pulmonary hypertension, inflammatory disease disease, diabetes, glaucoma, obesity, osteoporosis, fibrosis, neurological disease, urinary system disease and sexual dysfunction; wherein said fibrosis is selected from fibrosis of skin, liver, kidney and lung; said The urinary system disease is selected from overactive bladder, benign prostatic hyperplasia and erectile dysfunction; the neurological disease is selected from Alzheimer's disease, Parkinson's disease and neuropathic pain; the inflammatory disease is selected from psoriasis, multiple Sexual sclerosis, arthritis, asthma, ulcerative colitis, Crohn's disease, and chronic obstructive pulmonary disease.
本公开进一步涉及一种通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作药物。The present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) ), general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, which is used as a drug .
本公开进一步涉及通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作激动和/或激活sGC的药物。The present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), The compound shown in general formula (IV), general formula (IV-1), general formula (IV-2) and table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, it is used as agonist and/or Or drugs that activate sGC.
本公开进一步涉及通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于激动和/或激活sGC。The present disclosure further relates to general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III), The compound shown in general formula (IV), general formula (IV-1), general formula (IV-2) and table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, it is used for stimulating and/or Or activate sGC.
本公开进一步涉及一种通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作治疗和/或预防通过激动和/或激活sGC来减轻的疾病、病况或病症的药物，其中所述的疾病、病况或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；优选地，所述的疾病、病况或病症选自心血管疾病、肺动脉高压和肾病；更优选地，所述肾病为慢性肾功能 衰竭或慢性肾功能不全。The present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) ), general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, which is used for the treatment of and/or prevent a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein said disease, condition or disorder is selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, Obesity, osteoporosis, fibrotic disease, neurological disease, urinary system disease, and sexual dysfunction; preferably, said disease, condition or disorder is selected from cardiovascular disease, pulmonary hypertension, and renal disease; more preferably, said renal disease For chronic renal failure or chronic renal insufficiency.
本公开进一步涉及一种通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防通过激动和/或激活sGC来减轻的疾病、病况或病症，其中所述的疾病、病况或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；优选地，所述的疾病、病况或病症选自心血管疾病、肺动脉高压和肾病；更优选地，所述肾病为慢性肾功能衰竭或慢性肾功能不全。The present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) ), general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, which is used for the treatment of and/or preventing a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein said disease, condition or disorder is selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, Osteoporosis, fibrotic disease, neurological disease, urinary system disease, and sexual dysfunction; preferably, said disease, condition or disorder is selected from cardiovascular disease, pulmonary hypertension, and renal disease; more preferably, said renal disease is chronic Kidney failure or chronic renal insufficiency.
本公开进一步涉及一种通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作治疗和/或预防通过激动和/或激活sGC来减轻的疾病、病况或病症的药物，其中所述的疾病、病况或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；其中所述心血管疾病选自高血压、动脉粥样硬化症、冠心病、腰椎管狭窄症、外周动脉疾病、间歇性跛行、重症下肢缺血、稳定或者不稳定心绞痛、心肌梗死、心力衰竭、性腺机能减退、中风、冠状动脉痉挛、大脑血管痉挛、缺血/再灌注损伤和血栓栓塞性病症；优选地，所述心血管疾病选自高血压、心肌梗死和心力衰竭。The present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) ), general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, which is used for the treatment of and/or prevent a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein said disease, condition or disorder is selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, Obesity, osteoporosis, fibrosis, neurological disease, urinary system disease and sexual dysfunction; wherein the cardiovascular disease is selected from hypertension, atherosclerosis, coronary heart disease, lumbar spinal stenosis, peripheral arterial disease, Intermittent claudication, critical lower extremity ischemia, stable or unstable angina, myocardial infarction, heart failure, hypogonadism, stroke, coronary artery spasm, cerebral vasospasm, ischemia/reperfusion injury and thromboembolic disorders; preferably, The cardiovascular disease is selected from hypertension, myocardial infarction and heart failure.
本公开进一步涉及一种通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防通过激动和/或激活sGC来减轻的疾病、病况或病症，其中所述的疾病、病况或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；其中所述心血管疾病选自高血压、动脉粥样硬化症、冠心病、腰椎管狭窄症、外周动脉疾病、间歇性跛行、重症下肢缺血、稳定或者不稳定心绞痛、心肌梗死、心力衰竭、性腺机能减退、中风、冠状动脉痉挛、大脑血管痉挛、缺血/再灌注损伤和血栓栓塞性病症；优选地，所述心血管疾病选自高血压、心肌梗死和心力衰竭。The present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) ), general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, which is used for the treatment of and/or preventing a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein said disease, condition or disorder is selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, Osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; wherein the cardiovascular disease is selected from hypertension, atherosclerosis, coronary heart disease, lumbar spinal stenosis, peripheral arterial disease, intermittent Claudication, critical lower extremity ischemia, stable or unstable angina, myocardial infarction, heart failure, hypogonadism, stroke, coronary artery spasm, cerebral vasospasm, ischemia/reperfusion injury and thromboembolic disorders; preferably, said Cardiovascular disease is selected from hypertension, myocardial infarction and heart failure.
本公开进一步涉及一种通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作治疗和/或预防通过激动和/或激活sGC来减轻的疾病、病况或病症的药物，其中所述的疾病、病况或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；其中所述纤维变性病选自皮肤、肝、肾及肺的纤维变性病；所述泌尿***疾病选自膀胱过动症、良性*** 增生和***功能障碍；所述神经疾病选自阿尔茨海默氏病、帕金森氏病和神经病性疼痛；所述炎性疾病选自牛皮癣、多发性硬化、关节炎、哮喘、溃疡性结肠炎、克罗恩氏病和慢性阻塞性肺病。The present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) ), general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, which is used for the treatment of and/or prevent a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein said disease, condition or disorder is selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, Obesity, osteoporosis, fibrosis, neurological disease, urinary system disease and sexual dysfunction; wherein said fibrosis is selected from fibrosis of skin, liver, kidney and lung; said urinary system disease is selected from bladder ADHD, benign prostatic hyperplasia and erectile dysfunction; said neurological disease is selected from Alzheimer's disease, Parkinson's disease and neuropathic pain; said inflammatory disease is selected from psoriasis, multiple sclerosis, arthritis, asthma , ulcerative colitis, Crohn's disease and chronic obstructive pulmonary disease.
本公开进一步涉及一种通式(M)、通式(G)、通式(G-1)、通式(G-2)、通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防通过激动和/或激活sGC来减轻的疾病、病况或病症，其中所述的疾病、病况或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；其中所述纤维变性病选自皮肤、肝、肾及肺的纤维变性病；所述泌尿***疾病选自膀胱过动症、良性***增生和***功能障碍；所述神经疾病选自阿尔茨海默氏病、帕金森氏病和神经病性疼痛；所述炎性疾病选自牛皮癣、多发性硬化、关节炎、哮喘、溃疡性结肠炎、克罗恩氏病和慢性阻塞性肺病。优选地，本公开所述的外周动脉疾病选自血栓闭塞性脉管炎、外周动脉闭塞症和雷诺氏病或雷诺氏综合症。The present disclosure further relates to a general formula (M), general formula (G), general formula (G-1), general formula (G-2), general formula (I), general formula (II), general formula (III) ), general formula (IV), general formula (IV-1), general formula (IV-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising it, which is used for the treatment of and/or preventing a disease, condition or disorder alleviated by agonizing and/or activating sGC, wherein said disease, condition or disorder is selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, Osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; wherein said fibrotic disease is selected from the group consisting of fibrosis of the skin, liver, kidney and lung; said urinary system disease is selected from overactive bladder , benign prostatic hyperplasia and erectile dysfunction; said neurological disease is selected from Alzheimer's disease, Parkinson's disease and neuropathic pain; said inflammatory disease is selected from psoriasis, multiple sclerosis, arthritis, asthma, ulcer colitis, Crohn's disease, and chronic obstructive pulmonary disease. Preferably, the peripheral arterial disease described in the present disclosure is selected from thromboangiitis obliterans, peripheral arterial occlusive disease and Raynaud's disease or Raynaud's syndrome.
可将活性化合物制成适合于通过任何适当途径给药的形式，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药，吸入或吹入给药的各种剂型。本公开的化合物也可以配制成例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆等剂型。The active compounds are prepared in a form suitable for administration by any suitable route, and the compositions of the present disclosure are formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular or subcutaneous), administration by inhalation or insufflation. The disclosed compounds can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.
作为一般性指导，活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。As a general guide, the active compound is preferably presented in unit dose form, or in such a form that the patient can self-administer it as a single dose. A unit dosage form of a compound or composition of the present disclosure may be presented as a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstituted powder or liquid. A suitable unit dosage may be from 0.1 to 1000 mg.
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.
片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。Oral formulations can also be provided in soft gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, or where the active ingredient is mixed with a water-soluble carrier or an oil vehicle.
水混悬液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。Oily suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil. The oily suspensions may contain a thickening agent. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油，或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be vegetable oil, or mineral oil or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是DeltecCADD-PLUS.TM.5400型静脉注射泵。The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. The injection or microemulsion may be injected into the patient's bloodstream by local bulk injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the DeltecCADD-PLUS.TM. Model 5400 intravenous pump.
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blended and fixed oil may be used. In addition, fatty acids are also used in the preparation of injectables.
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.
可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。Aqueous suspensions of dispersible powders and granules can be prepared by the addition of water to administer the disclosed compounds. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、***的速率、药物的组合、疾病的严重性等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。As is well known to those skilled in the art, the dosage of the drug to be administered depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the state of health of the patient, the behavior of the patient , patient's diet, administration time, administration method, rate of excretion, combination of drugs, severity of disease, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dosage of the compound or the content of the pharmaceutically acceptable salt Kinds can be validated against traditional treatment regimens.
术语说明Glossary
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子的直链或支链基团(即C 1-20烷基)，优选含有1至12个碳原子的烷基(即C 1-12烷基)，更优选为含有1至6个碳原子的烷基(即C 1-6烷基)。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正 己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。 The term "alkyl" refers to a saturated aliphatic hydrocarbon group comprising 1 to 20 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19 or 20) carbon atoms straight or branched (i.e. C 1-20 alkyl), preferably an alkyl group containing 1 to 12 carbon atoms (i.e. C 1-12 alk group), more preferably an alkyl group containing 1 to 6 carbon atoms (i.e. C 1-6 alkyl group). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl ylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl 2,2-diethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers. Alkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents being preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“烯基”指分子中含有至少一个碳碳双键的烷基化合物，其中烷基的定义如上所述，优选具有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子的烯基(即C 2-12烯基)，更优选含有2至6个碳原子的烯基(即C 2-6烯基)。烯基可以是取代的或非取代的，当被取代时，取代基选自烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。 The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as above, preferably having 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11 and 12) carbon atoms (ie C 2-12 alkenyl), more preferably alkenyl containing 2 to 6 carbon atoms (ie C 2-6 alkenyl). Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is selected from the group consisting of alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl , cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11和12个)碳原子的炔基(即C 2-12炔基)。所述炔基优选具有2至6个碳原子的炔基(即C 2-6炔基)。非限制性的实例包括：乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选选自烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。 The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms alkynyl (ie C 2-12 alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkynyl group). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from the group consisting of alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl One or more of radical, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。非限制性的实例包括：甲氧基、乙氧基、丙氧基和丁氧基等。烷氧基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, and butoxy, and the like. Alkoxy may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即3至20元环烷基)，优选具有3至12个(例如3、4、5、6、7、8、9、10、11和12个)碳原子(即3至12元环烷基)，优选包含3至8个碳原子，更优选具有3至6个碳原子(即3至6元环烷基)，最优选具有5或6个碳原子(即5或6元环烷基)。单环环烷基的非限制性实例包括环丙基、环丁 基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环烷基、稠环烷基和桥环烷基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring having 3 to 20 (for example 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie 3 to 20 membered cycloalkyl), preferably with 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e. 3 to 12 membered cycloalkyl), preferably containing 3 to 8 carbon atoms, more preferably having 3 to 6 carbon atoms (i.e. 3 to 6 membered cycloalkyl groups) cycloalkyl), most preferably having 5 or 6 carbon atoms (ie 5 or 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl.
术语“螺环烷基”指5至20元，单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键(即5至20元螺环烷基)。优选为6至14元(即6至14元螺环烷基)，更优选为7至10元(例如7、8、9或10元)(即7至10元螺环烷基)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基等多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元、5元/6元、6元/6元、6元/4元或6元/5元单螺环烷基。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 members, sharing one carbon atom (called a spiro atom) between monocyclic rings, which may contain one or more double bonds (that is, 5 to 20 membered spirocycloalkane base). It is preferably 6 to 14 membered (ie 6 to 14 membered spirocycloalkyl), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 7 to 10 membered spirocycloalkyl). According to the number of spiro atoms shared between rings, spirocycloalkyl groups can be divided into multiple spirocycloalkyl groups such as single spirocycloalkyl and double spirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl. More preferably 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/6 yuan , 6-membered/4-membered or 6-membered/5-membered monospiro cycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:
Figure PCTCN2022105987-appb-000182
Figure PCTCN2022105987-appb-000182
术语“稠环烷基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键(即5至20元稠环烷基)。优选为6至14元(即6至14元稠环烷基)，更优选为7至10元(例如7、8、9或10元)(即7至10元稠环烷基)。根据组成环的数目可以分为双环、三环、四环等多环稠环烷基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元的双环烷基。稠环烷基的非限制性实例包括：The term "fused cycloalkyl" refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds (ie, 5 to 20 membered fused cycloalkyl). Preferably it is 6 to 14 membered (ie 6 to 14 membered fused cycloalkyl), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 7 to 10 membered fused cycloalkyl). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan Bicycloalkyl group of 1/4, 6/5, 6/6, 6/7, 7/5 or 7/6. Non-limiting examples of fused cycloalkyl groups include:
Figure PCTCN2022105987-appb-000183
Figure PCTCN2022105987-appb-000183
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键(即5至20元桥环烷基)。优选为6至14元(即6至14元桥环烷基)，更优选为7至10元(例如7、8、9或10元)(即7至10元桥环烷基)。根据组成环的数目可以分为双环、三环、四环等多环桥环烷基，优选为双环、三环等四环，更优选为双环或三环。桥环烷基的非限制性实例包括：The term "bridged cycloalkyl" refers to a 5 to 20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds (i.e., 5 to 20 membered bridge Cycloalkyl). It is preferably 6 to 14 membered (ie, 6 to 14 membered bridged cycloalkyl group), more preferably 7 to 10 membered (eg, 7, 8, 9 or 10 membered) (ie, 7 to 10 membered bridged cycloalkyl group). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic and other polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic and other tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
Figure PCTCN2022105987-appb-000184
Figure PCTCN2022105987-appb-000184
所述环烷基环包括如上所述的环烷基(包括单环环烷基、螺环烷基、稠环烷基和桥环烷基)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括
Figure PCTCN2022105987-appb-000185
等；优选
Figure PCTCN2022105987-appb-000186
The cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic cycloalkyl, spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl) fused to an aryl, heteroaryl or heterocycloalkane On a radical ring where the ring attached to the parent structure is a cycloalkyl, non-limiting examples include
Figure PCTCN2022105987-appb-000185
etc.; preferred
Figure PCTCN2022105987-appb-000186
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。Cycloalkyl may be substituted or unsubstituted and when substituted it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
术语“杂环基”指饱和或部分不饱和单环或多环环状取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳(即3至20元杂环基)。优选包含3至12个(例如3、4、5、6、7、8、9、10、11和12个)环原子，其中1～4个(例如1、2、3和4个)是杂原子(即3至12元杂环基)；更优选包含3至8个环原子(例如3、4、5、6、7和8个)，其中1-3个(例如1、2和3个)是杂原子(即3至12元杂环基)；更优选包含3至6个环原子，其中1-3个是杂原子(即3至6元杂环基)；最优选包含5或6个环原子，其中1-3个是杂原子(即5或6元杂环基)。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,3-二氧杂戊环基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺杂环环、稠杂环基和桥杂环基。The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring substituent comprising 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, Said sulfur can be optionally oxoated (i.e. to form a sulfoxide or sulfone), but excluding the -O-O-, -O-S- or -S-S- ring portion, the remaining ring atoms are carbon (i.e. 3 to 20 membered heterocycle base). Preferably comprising 3 to 12 (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g. 1, 2, 3 and 4) are hetero atom (ie 3 to 12 membered heterocyclyl); more preferably contains 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8), of which 1-3 (eg 1, 2 and 3 ) is a heteroatom (ie 3 to 12 membered heterocyclyl); more preferably contains 3 to 6 ring atoms, of which 1-3 are heteroatoms (ie 3 to 6 membered heterocyclyl); most preferably contains 5 or 6 ring atoms, of which 1-3 are heteroatoms (ie 5 or 6 membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperidine Zinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiroheterocyclyls, fused heterocyclyls and bridged heterocyclyls.
术语“螺杂环基”指5至20元，单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。其可以含有一个或多个双键(即5至20元螺杂环基)。优选为6至14元(即6至14元螺杂环基)，更优选为7至10元(例如7、8、9或10元)(即7至10元螺杂环基)。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基等多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元、5元/6元或6元/6元单螺杂环基。螺杂环基的非限制性实例包括：The term "spiroheterocyclyl" refers to 5 to 20 membered polycyclic heterocyclic groups sharing one atom (called spiro atom) between monocyclic rings, wherein one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur atoms, said sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds (ie 5 to 20 membered spiroheterocyclyl). It is preferably 6 to 14 membered (ie 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 7 to 10 membered spiroheterocyclyl). According to the number of spiro atoms shared between the rings, the spiroheterocyclyl can be divided into multiple spiroheterocyclyls such as single spiroheterocyclyl and double spiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered monospiroheterocyclic group. Non-limiting examples of spiroheterocyclyls include:
Figure PCTCN2022105987-appb-000187
Figure PCTCN2022105987-appb-000187
术语“稠杂环基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳(即5至20元稠杂环基)。优选为6至14元，更优选为7至10元(例如7、8、9或10元)(即6至14元稠杂环基)。根据组成环的数目可以分为双环、三环、四环等多环稠杂环基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环基。稠杂环基的非限制性实例包括：The term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, said sulfur optionally being oxo (i.e. forming sulfoxide or sulfone), and the remaining ring atoms being carbon (i.e. 5 to 20-membered fused heterocyclyl). It is preferably 6 to 14 membered, more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 6 to 14 membered condensed heterocyclic group). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan Yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan bicyclic condensed heterocyclic group. Non-limiting examples of fused heterocyclic groups include:
Figure PCTCN2022105987-appb-000188
Figure PCTCN2022105987-appb-000188
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳(即5至14元桥杂环基)。优选为6至14元(即6至14元桥杂环基)，更优选为7至10元(例如7、8、9或10元)(即7至10元桥杂环基)。根据组成环的数目可以分为双环、三环、四环等多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：The term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly connected, which may contain one or more double bonds, in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, said sulfur being optionally substituted with oxo (ie to form a sulfoxide or sulfone), with the remaining ring atoms being carbon (ie, a 5 to 14 membered bridged heterocyclyl). It is preferably 6 to 14 membered (ie 6 to 14 membered bridged heterocyclic group), more preferably 7 to 10 membered (eg 7, 8, 9 or 10 membered) (ie 7 to 10 membered bridged heterocyclic group). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:
Figure PCTCN2022105987-appb-000189
Figure PCTCN2022105987-appb-000189
所述杂环基环包括如上所述的杂环基(包括单环杂环基、螺杂环基、稠杂环基和桥杂环基)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：The heterocyclyl ring includes a heterocyclyl as described above (including monocyclic heterocyclyl, spiro heterocyclyl, fused heterocyclyl and bridged heterocyclyl) fused to an aryl, heteroaryl or cycloalkyl On the ring, where the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
Figure PCTCN2022105987-appb-000190
等。
Figure PCTCN2022105987-appb-000190
Wait.
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。The heterocyclyl group may be substituted or unsubstituted and when substituted it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6 to 10 membered , such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include :
Figure PCTCN2022105987-appb-000191
Figure PCTCN2022105987-appb-000191
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents being preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
术语“杂芳基”指包含1至4个杂原子(例如1、2、3和4个)、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元(例如5、6、7、8、9或10元)，更优选为5元或6元杂芳基(5或6元杂芳基)，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、***基、四唑基等。所述杂芳基环包括如上述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms (eg 1, 2, 3 and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g. 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered heteroaryl (5 or 6 membered heteroaryl), e.g. furyl, Thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl as described above fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include :
Figure PCTCN2022105987-appb-000192
Figure PCTCN2022105987-appb-000192
Figure PCTCN2022105987-appb-000193
Figure PCTCN2022105987-appb-000193
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基优选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。Heteroaryl may be substituted or unsubstituted and when substituted it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy , cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
上述环烷基、杂环基、芳基和杂芳基包括从母体环原子上除去一个氢原子所衍生的残基，或从母体的相同环原子或两个不同的环原子上除去两个氢原子所衍生的残基即“二价环烷基”、“二价杂环基”、“亚芳基”和“亚杂芳基”。The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from a parent ring atom, or by removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent The residues from which the atoms are derived are "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".
本公开所述化合物的化学结构中，键
Figure PCTCN2022105987-appb-000194
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022105987-appb-000195
可以为
Figure PCTCN2022105987-appb-000196
或者同时包含
Figure PCTCN2022105987-appb-000197
Figure PCTCN2022105987-appb-000198
两种构型。 In the chemical structures of the compounds described in this disclosure, the bond
Figure PCTCN2022105987-appb-000194
Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond
Figure PCTCN2022105987-appb-000195
can be
Figure PCTCN2022105987-appb-000196
or both
Figure PCTCN2022105987-appb-000197
Figure PCTCN2022105987-appb-000198
Two configurations.
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。The term "deuteroalkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
术语“氘代烷氧基”指烷氧基被一个或多个氘原子取代，其中烷氧基如上所定义。The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy group is as defined above.
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“羟基”指-OH。The term "hydroxyl" refers to -OH.
术语“巯基”指-SH。The term "mercapto" refers to -SH.
术语“氨基”指-NH 2。 The term "amino" refers to -NH2 .
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO 2。 The term "nitro" refers to -NO2 .
术语“氧代基”或“氧代”指“＝O”。The term "oxo" or "oxo" refers to "=O".
术语“羰基”指C＝O。The term "carbonyl" refers to C=O.
术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基和环烷基如上所定义。The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined above.
本公开的化合物包含其同位素衍生物。术语“同位素衍生物”指结构不同仅 在于存在一种或多种同位素富集原子的化合物。例如，具有本公开的结构，用“氘”或“氚”代替氢，或者用 18F-氟标记( 18F同位素)代替氟，或者用 11C-， 13C-，或者 14C-富集的碳( 11C-， 13C-，或者 14C-碳标记； 11C-， 13C-，或者 14C-同位素)代替碳原子的化合物处于本公开的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针，或者可以用作疾病的体内诊断成像示踪剂，或者作为药效学、药动学或受体研究的示踪剂。 Compounds of the present disclosure include isotopic derivatives thereof. The term "isotopically derivative" refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, with the structure of the present disclosure, hydrogen is replaced by "deuterium" or "tritium", or fluorine is replaced by 18 F-fluorine label ( 18 F isotope), or 11 C-, 13 C-, or 14 C-enriched Compounds in which carbon ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) replace carbon atoms are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.
本公开的各种氘化形式的化合物是指与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的化合物。在制备氘代形式的化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。氘代物通常可以保留与未氘代的化合物相当的活性，并且当氘代在某些特定位点时可以取得更好的代谢稳定性，从而获得某些治疗优势。The various deuterated forms of the compounds of the present disclosure mean that each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including but not limited to deuterated borane, trideuterioborane in tetrahydrofuran , deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc. Deuterated compounds generally retain comparable activity to non-deuterated compounds, and can achieve better metabolic stability when deuterated at certain sites, thereby gaining certain therapeutic advantages.
当一个位置被特别地指定为氘D时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即至少15％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘(即至少15％的氘掺入)、至少2000倍的丰度的氘(即至少30％的氘掺入)、至少3000倍的丰度的氘(即至少45％的氘掺入)、至少3340倍的丰度的氘(即至少50.1％的氘掺入)、至少3500倍的丰度的氘(即至少52.5％的氘掺入)、至少4000倍的丰度的氘(即至少60％的氘掺入)、至少4500倍的丰度的氘(即至少67.5％的氘掺入)、至少5000倍的丰度的氘(即至少75％的氘掺入)、至少5500倍的丰度的氘(即至少82.5％的氘掺入)、至少6000倍的丰度的氘(即至少90％的氘掺入)、至少6333.3倍的丰度的氘(即至少95％的氘掺入)、至少6466.7倍的丰度的氘(即至少97％的氘掺入)、至少6600倍的丰度的氘(即至少99％的氘掺入)、至少6633.3倍的丰度的氘(即至少99.5％的氘掺入)或更高丰度的氘。When a position is specifically designated as deuterium D, the position is understood to have an abundance of deuterium (ie at least 15% deuterium incorporation) that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). Exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium (i.e. at least 15% deuterium incorporation), at least 2000 times more abundant deuterium (i.e. at least 30% deuterium incorporation) , at least 3000 times the abundance of deuterium (i.e. at least 45% deuterium incorporation), at least 3340 times the abundance of deuterium (i.e. at least 50.1% deuterium incorporation), at least 3500 times the abundance of deuterium (i.e. at least 52.5% deuterium incorporation), at least 4000-fold more abundant deuterium (i.e. at least 60% deuterium incorporation), at least 4500-fold more abundant deuterium (i.e. at least 67.5% deuterium incorporation), at least 5000-fold Deuterium in abundance (i.e. at least 75% deuterium incorporation), deuterium in at least 5500 times abundance (i.e. at least 82.5% deuterium incorporation), deuterium in at least 6000 times abundance (i.e. at least 90% deuterium incorporation deuterium incorporation), at least 6333.3 times the abundance of deuterium (i.e. at least 95% deuterium incorporation), at least 6466.7 times the abundance of deuterium (i.e. at least 97% deuterium incorporation), at least 6600 times the abundance of deuterium ( That is, at least 99% deuterium incorporation), at least 6633.3 times the abundance of deuterium (ie, at least 99.5% deuterium incorporation), or higher abundance of deuterium.
本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本公开的范围之内。本公开的含有不对称碳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。Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为 质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。The compounds and intermediates of the present disclosure may also exist in different tautomeric forms and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine, lactam-lactim isomerization . An example of a lactam-lactim equilibrium is between A and B as shown below.
Figure PCTCN2022105987-appb-000199
Figure PCTCN2022105987-appb-000199
所有的互变异构形式在本公开的范围内。化合物的命名不排除任何互变异构体。All tautomeric forms are within the scope of the present disclosure. The naming of compounds does not exclude any tautomers.
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必然发生，该说明包括该事件或环境发生或不发生的情形。例如“任选的被卤素或者氰基取代的C 1-6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。 "Optionally" or "optionally" means that the subsequently described event or circumstance may but not necessarily occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "C 1-6 alkyl optionally substituted by halogen or cyano" means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen And the case of cyano substitution.
“取代的”指基团中的一个或多个氢原子，优选为1～5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by a corresponding number of substituents. Possible or impossible substitutions can be determined (by experiment or theory) by those skilled in the art without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
“可药用的盐”是指本公开化合物的盐，可选自无机盐或有机盐。这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备盐。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。"Pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have proper biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
针对药物或药理学活性剂而言，术语“治疗有效量”是指足以达到或部分达到预期效果的药物或药剂的用量。治疗有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的治疗有效量可以由本领域技术人员根据常规试验确定。For a drug or a pharmacologically active agent, the term "therapeutically effective amount" refers to the amount of the drug or agent that is sufficient to achieve or partially achieve the desired effect. The determination of the therapeutically effective dose varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate therapeutically effective dose in individual cases can be determined by those skilled in the art according to routine tests.
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。As used herein, the term "pharmaceutically acceptable" means those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with patient tissues without undue toxicity, irritation, allergic reaction or Other problems or complications that have a reasonable benefit/risk ratio and are valid for the intended use.
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.
当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变 化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键时，通常仅出于说明目的给出数字，而不是限制。When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it means that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be understood by those skilled in the art, when a parameter is not critical, the numbers are generally given for illustrative purposes only, and not for limitation.
本公开化合物的合成方法Synthetic Methods of the Disclosed Compounds
为了完成本公开的目的，本公开采用如下技术方案：In order to accomplish the purpose of this disclosure, this disclosure adopts the following technical solutions:
方案一Option One
本公开通式(M)所示的化合物或其可药用的盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (M) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000200
Figure PCTCN2022105987-appb-000200
通式(MA)所示的化合物或其盐发生反应，得到通式(M)所示的化合物或其可药用的盐；A compound represented by the general formula (MA) or a salt thereof is reacted to obtain a compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof;
其中：in:
R为烷基或
Figure PCTCN2022105987-appb-000201
优选地，R为烷基或
Figure PCTCN2022105987-appb-000202
R is alkyl or
Figure PCTCN2022105987-appb-000201
Preferably, R is alkyl or
Figure PCTCN2022105987-appb-000202
R w为烷基或烯丙基；优选地，R w为烯丙基； R w is alkyl or allyl; preferably, R w is allyl;
条件为，当R选自烷基时，通式(MA)所示的化合物或其盐在酸存在下发生酯水解反应，得到R 0为氢原子的通式(M)所示的化合物或其可药用的盐； The condition is that when R is selected from an alkyl group, the compound represented by the general formula (MA) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain a compound represented by the general formula (M ) whose R is a hydrogen atom or its pharmaceutically acceptable salts;
当R为
Figure PCTCN2022105987-appb-000203
时，通式(MA)所示的化合物或其盐在金属催化剂(优选四(三苯基膦)钯)和亲核试剂(优选二乙胺或四氢吡咯)的作用下脱去R w，得到R 0为
Figure PCTCN2022105987-appb-000204
的通式(M)所示的化合物或其可药用的盐；优选地，当R为
Figure PCTCN2022105987-appb-000205
时，通式(MA)所示的化合物或其盐在金属催化剂(优选四(三苯基膦)钯)和亲核试剂(优选二乙胺或四氢吡咯)的作用下脱去R w，得到R 0为
Figure PCTCN2022105987-appb-000206
的通式(M)所示的化合物或其可药用的盐； when R is
Figure PCTCN2022105987-appb-000203
When, the compound represented by the general formula (MA) or its salt is removed under the action of a metal catalyst (preferably tetrakis(triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) R w , to obtain R0 is
Figure PCTCN2022105987-appb-000204
A compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof; preferably, when R is
Figure PCTCN2022105987-appb-000205
When, the compound represented by the general formula (MA) or its salt is removed under the action of a metal catalyst (preferably tetrakis(triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) R w , to obtain R0 is
Figure PCTCN2022105987-appb-000206
A compound represented by general formula (M) or a pharmaceutically acceptable salt thereof;
Z、G、R 0、R 1至R 3、R 5至R 11和n如通式(M)中所定义。 Z, G, R 0 , R 1 to R 3 , R 5 to R 11 and n are as defined in the general formula (M).
方案二Option II
本公开通式(MA)所示的化合物或其盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (MA) or its salt of the present disclosure comprises the following steps:
Figure PCTCN2022105987-appb-000207
Figure PCTCN2022105987-appb-000207
通式(Ma-A)所示的化合物或其盐与通式(Ib-A)所示的化合物或其盐在碱性条件下发生缩合酰化反应，得到通式(MA)所示的化合物或其盐；The compound represented by the general formula (Ma-A) or its salt and the compound represented by the general formula (Ib-A) or its salt under alkaline conditions undergo a condensation acylation reaction to obtain the compound represented by the general formula (MA) or its salts;
其中：in:
Z、G、R、R 1至R 3、R 5至R 11和n如通式(MA)中所定义。 Z, G, R, R 1 to R 3 , R 5 to R 11 and n are as defined in the general formula (MA).
方案三third solution
本公开通式(I)所示的化合物或其可药用的盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000208
Figure PCTCN2022105987-appb-000208
通式(IA)所示的化合物或其盐在酸存在下发生酯水解反应得到通式(I)所示的化合物或其可药用的盐；其中：The compound represented by the general formula (IA) or a salt thereof undergoes an ester hydrolysis reaction in the presence of an acid to obtain a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof; wherein:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
G、R 1至R 11和n如通式(I)中所定义。 G, R 1 to R 11 and n are as defined in the general formula (I).
方案四Option four
本公开通式(IA)所示的化合物或其盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (IA) or its salt of the present disclosure comprises the following steps:
Figure PCTCN2022105987-appb-000209
Figure PCTCN2022105987-appb-000209
通式(Ia-A)所示的化合物或其盐与通式(Ib-A)所示的化合物或其盐在碱性条件下发生缩合酰化反应，得到通式(IA)所示的化合物或其盐；The compound represented by the general formula (Ia-A) or its salt and the compound represented by the general formula (Ib-A) or its salt undergo a condensation acylation reaction under alkaline conditions to obtain the compound represented by the general formula (IA) or its salts;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
G、R 1至R 11和n如通式(IA)中所定义。 G, R 1 to R 11 and n are as defined in general formula (IA).
方案五Option five
本公开通式(II)所示的化合物或其可药用的盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (II) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000210
Figure PCTCN2022105987-appb-000210
通式(IIA)所示的化合物或其盐在酸存在下发生酯水解反应得到通式(II)所示的化合物或其可药用的盐；其中：The compound represented by the general formula (IIA) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof; wherein:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4至R 11、m和n如通式(II)中所定义。 Ring A, R 2a , G, R 1 , R 4 to R 11 , m and n are as defined in the general formula (II).
方案六Option six
本公开通式(IIA)所示的化合物或其盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (IIA) or its salt of the present disclosure comprises the following steps:
Figure PCTCN2022105987-appb-000211
Figure PCTCN2022105987-appb-000211
通式(IIa-A)所示的化合物或其盐与通式(Ib-A)所示的化合物或其盐在碱性条件下发生缩合酰化反应，得到通式(IIA)所示的化合物或其盐；The compound represented by the general formula (IIa-A) or its salt and the compound represented by the general formula (Ib-A) or its salt undergo a condensation acylation reaction under alkaline conditions to obtain the compound represented by the general formula (IIA) or its salts;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4至R 11、m和n如通式(IIA)中所定义。 Ring A, R 2a , G, R 1 , R 4 to R 11 , m and n are as defined in the general formula (IIA).
方案七Option seven
本公开通式(III)所示的化合物或其可药用的盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (III) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000212
Figure PCTCN2022105987-appb-000212
通式(IIIA)所示的化合物或其盐在酸存在下发生酯水解反应得到通式(III)所示的化合物或其可药用的盐；The compound represented by the general formula (IIIA) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4、R 5、R 7、R 8、R 10、m和n如通式(III)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in the general formula (III).
方案八Option eight
本公开通式(IIIA)所示的化合物或其盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (IIIA) of the present disclosure or a salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000213
Figure PCTCN2022105987-appb-000213
通式(IIIa-A)所示的化合物或其盐与通式(IIIb-A)所示的化合物或其盐在碱性条件下发生缩合酰化反应，得到通式(IIIA)所示的化合物或其盐；The compound represented by the general formula (IIIa-A) or its salt and the compound represented by the general formula (IIIb-A) or its salt undergo a condensation acylation reaction under alkaline conditions to obtain the compound represented by the general formula (IIIA) or its salts;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4、R 5、R 7、R 8、R 10、m和n如通式(IIIA)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in general formula (IIIA).
方案九Option nine
本公开通式(G)所示的化合物或其可药用的盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (G) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000214
Figure PCTCN2022105987-appb-000214
通式(GA)所示的化合物或其盐发生反应，得到通式(G)所示的化合物或其可药用的盐；A compound represented by the general formula (GA) or a salt thereof is reacted to obtain a compound represented by the general formula (G) or a pharmaceutically acceptable salt thereof;
其中：in:
R为烷基或
Figure PCTCN2022105987-appb-000215
优选地，R为烷基或
Figure PCTCN2022105987-appb-000216
R is alkyl or
Figure PCTCN2022105987-appb-000215
Preferably, R is alkyl or
Figure PCTCN2022105987-appb-000216
R w为烷基或烯丙基；优选地，R w为烯丙基； R w is alkyl or allyl; preferably, R w is allyl;
条件为，当R为烷基时，通式(GA)所示的化合物或其盐在酸存在下发生酯水解反应，得到R 0为氢原子的通式(G)所示的化合物或其可药用的盐； The condition is that when R is an alkyl group, the compound represented by the general formula (GA) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain a compound represented by the general formula (G ) whose R is a hydrogen atom or its alternative medicinal salts;
当R为
Figure PCTCN2022105987-appb-000217
时，通式(GA)所示的化合物或其盐在金属催化剂(优选四(三苯基膦)钯)和亲核试剂(优选二乙胺或四氢吡咯)的作用下脱去R w，得到R 0为
Figure PCTCN2022105987-appb-000218
的通式(G)所示的化合物或其可药用的盐；优选地，当R为
Figure PCTCN2022105987-appb-000219
时，通式(GA)所示的化合物或其盐在金属催化剂(优选四(三苯基膦)钯)和亲核试剂(优选二乙胺或四氢吡咯)的作用下脱去R w，得到R 0为
Figure PCTCN2022105987-appb-000220
的通式(G)所示的化合物或其可药用的盐； when R is
Figure PCTCN2022105987-appb-000217
When, the compound represented by the general formula (GA) or its salt is removed under the action of a metal catalyst (preferably tetrakis(triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) R w , to obtain R0 is
Figure PCTCN2022105987-appb-000218
A compound represented by general formula (G) or a pharmaceutically acceptable salt thereof; preferably, when R is
Figure PCTCN2022105987-appb-000219
When, the compound represented by the general formula (GA) or its salt is removed under the action of a metal catalyst (preferably tetrakis(triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) R w , to obtain R0 is
Figure PCTCN2022105987-appb-000220
A compound represented by general formula (G) or a pharmaceutically acceptable salt thereof;
环A、Z、G、R 0、R 1、R 2a、R 5a、R 5b、R 7、R 8、m和n如通式(G)中所定义。 Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G).
方案十Plan ten
本公开通式(G-1)所示的化合物或其可药用的盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (G-1) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000221
Figure PCTCN2022105987-appb-000221
通式(G-1A)所示的化合物或其盐发生反应，得到通式(G-1)所示的化合物或其可药用的盐；The compound represented by the general formula (G-1A) or its salt is reacted to obtain the compound represented by the general formula (G-1) or a pharmaceutically acceptable salt thereof;
其中：in:
R为烷基或
Figure PCTCN2022105987-appb-000222
优选地，R为烷基或
Figure PCTCN2022105987-appb-000223
R is alkyl or
Figure PCTCN2022105987-appb-000222
Preferably, R is alkyl or
Figure PCTCN2022105987-appb-000223
R w为烷基或烯丙基；优选地，R w为烯丙基； R w is alkyl or allyl; preferably, R w is allyl;
条件为，当R为烷基时，通式(G-1A)所示的化合物或其盐在酸存在下发生酯水解反应，得到R 0为氢原子的通式(G-1)所示的化合物或其可药用的盐； The condition is that when R is an alkyl group, the compound represented by the general formula (G-1A) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain R as represented by the general formula (G-1 ) of a hydrogen atom. A compound or a pharmaceutically acceptable salt thereof;
当R为
Figure PCTCN2022105987-appb-000224
时，通式(G-1A)所示的化合物或其盐在金属催化剂(优选四(三苯基膦)钯)和亲核试剂(优选二乙胺或四氢吡咯)的作用下脱去R w，得到R 0为
Figure PCTCN2022105987-appb-000225
的通式(G-1)所示的化合物或其可药用的盐；优选地，当R为
Figure PCTCN2022105987-appb-000226
时，通式(G-1A)所示的化合物或其盐在金属催化剂(优选四(三苯基膦)钯)和亲核试剂(优选二乙胺或四氢吡咯)的作用下脱去R w，得到R 0为
Figure PCTCN2022105987-appb-000227
的通式(G-1)所示的化合物或其可药用的盐； when R is
Figure PCTCN2022105987-appb-000224
, the compound represented by the general formula (G-1A) or its salt will remove R under the action of a metal catalyst (preferably tetrakis (triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) , get R 0 as
Figure PCTCN2022105987-appb-000225
A compound represented by the general formula (G-1) or a pharmaceutically acceptable salt thereof; preferably, when R is
Figure PCTCN2022105987-appb-000226
, the compound represented by the general formula (G-1A) or its salt will remove R under the action of a metal catalyst (preferably tetrakis (triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) , get R 0 as
Figure PCTCN2022105987-appb-000227
A compound represented by general formula (G-1) or a pharmaceutically acceptable salt thereof;
环A、Z、G、R 0、R 1、R 2a、R 5a、R 5b、R 7、R 8、m和n如通式(G-1)中所定义。 Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G-1).
方案十一Plan Eleven
本公开通式(G-2)所示的化合物或其可药用的盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (G-2) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000228
Figure PCTCN2022105987-appb-000228
通式(G-2A)所示的化合物或其盐发生反应，得到通式(G-2)所示的化合物或其 可药用的盐；The compound represented by general formula (G-2A) or its salt reacts to obtain the compound represented by general formula (G-2) or its pharmaceutically acceptable salt;
其中：in:
R为烷基或
Figure PCTCN2022105987-appb-000229
优选地，R为烷基或
Figure PCTCN2022105987-appb-000230
R is alkyl or
Figure PCTCN2022105987-appb-000229
Preferably, R is alkyl or
Figure PCTCN2022105987-appb-000230
R w为烷基或烯丙基；优选地，R w为烯丙基； R w is alkyl or allyl; preferably, R w is allyl;
条件为，当R为烷基时，通式(G-2A)所示的化合物或其盐在酸存在下发生酯水解反应，得到R 0为氢原子的通式(G-2)所示的化合物或其可药用的盐； The condition is that when R is an alkyl group, the compound represented by the general formula (G-2A) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain R 0 as represented by the general formula (G-2) of a hydrogen atom. A compound or a pharmaceutically acceptable salt thereof;
当R为
Figure PCTCN2022105987-appb-000231
时，通式(G-2A)所示的化合物或其盐在金属催化剂(优选四(三苯基膦)钯)和亲核试剂(优选二乙胺或四氢吡咯)的作用下脱去R w，得到R 0为
Figure PCTCN2022105987-appb-000232
的通式(G-2)所示的化合物或其可药用的盐；优选地，当R为
Figure PCTCN2022105987-appb-000233
时，通式(G-2A)所示的化合物或其盐在金属催化剂(优选四(三苯基膦)钯)和亲核试剂(优选二乙胺或四氢吡咯)的作用下脱去R w，得到R 0为
Figure PCTCN2022105987-appb-000234
的通式(G-2)所示的化合物或其可药用的盐； when R is
Figure PCTCN2022105987-appb-000231
, the compound represented by the general formula (G-2A) or its salt will remove R under the action of a metal catalyst (preferably tetrakis (triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) , get R 0 as
Figure PCTCN2022105987-appb-000232
A compound represented by the general formula (G-2) or a pharmaceutically acceptable salt thereof; preferably, when R is
Figure PCTCN2022105987-appb-000233
, the compound represented by the general formula (G-2A) or its salt will remove R under the action of a metal catalyst (preferably tetrakis (triphenylphosphine) palladium) and a nucleophile (preferably diethylamine or tetrahydropyrrole) , get R 0 as
Figure PCTCN2022105987-appb-000234
A compound represented by general formula (G-2) or a pharmaceutically acceptable salt thereof;
环A、Z、G、R 0、R 1、R 2a、R 5a、R 5b、R 7、R 8、m和n如通式(G-2)中所定义。 Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G-2).
方案十二Plan twelve
本公开通式(G-1A)或通式(G-2A)所示的化合物或其盐的制备方法，包括以下步骤：The preparation method of the compound or its salt represented by general formula (G-1A) or general formula (G-2A) of the present disclosure comprises the following steps:
Figure PCTCN2022105987-appb-000235
Figure PCTCN2022105987-appb-000235
通式(Ga-A)所示的化合物或其盐与通式(IVb-A)所示的化合物或其盐在碱性条件下发生缩合酰化反应，得到通式(G-1A)或通式(G-2A)所示的化合物或其盐；The compound represented by the general formula (Ga-A) or its salt and the compound represented by the general formula (IVb-A) or its salt undergo condensation acylation reaction under alkaline conditions to obtain the general formula (G-1A) or the general formula A compound represented by formula (G-2A) or a salt thereof;
其中：in:
环A、Z、G、R、R 1、R 2a、R 5a、R 5b、R 7、R 8、m和n如通式(G-1A)或通式(G-2A)中所定义。 Rings A, Z, G, R, R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (G-1A) or general formula (G-2A).
方案十三Plan Thirteen
本公开通式(IV)所示的化合物或其可药用的盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (IV) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000236
Figure PCTCN2022105987-appb-000236
通式(IVA)所示的化合物或其盐在酸存在下发生酯水解反应，得到通式(IV)所示的化合物或其可药用的盐；A compound represented by the general formula (IVA) or a salt thereof undergoes an ester hydrolysis reaction in the presence of an acid to obtain a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4、R 5a、R 5b、R 7、R 8、m和n如通式(IV)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (IV).
方案十四Plan Fourteen
本公开通式(IV-1)所示的化合物或其可药用的盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (IV-1) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000237
Figure PCTCN2022105987-appb-000237
通式(IV-1A)所示的化合物或其盐在酸存在下发生酯水解反应得到通式(IV-1)所示的化合物或其可药用的盐；The compound represented by the general formula (IV-1A) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4、R 5a、R 5b、R 7、R 8、m和n如通式(IV-1)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (IV-1).
方案十五Plan fifteen
本公开通式(IV-2)所示的化合物或其可药用的盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (IV-2) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000238
Figure PCTCN2022105987-appb-000238
通式(IV-2A)所示的化合物或其盐在酸存在下发生酯水解反应得到通式(IV-2)所示的化合物或其可药用的盐；The compound represented by the general formula (IV-2A) or its salt undergoes an ester hydrolysis reaction in the presence of an acid to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4、R 5a、R 5b、R 7、R 8、m和n如通式(IV-2)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (IV-2).
方案十六Plan sixteen
本公开通式(IV-1A)或通式(IV-2A)所示的化合物或其盐的制备方法，包括以下步骤：The preparation method of the compound represented by general formula (IV-1A) or general formula (IV-2A) or its salt of the present disclosure comprises the following steps:
Figure PCTCN2022105987-appb-000239
Figure PCTCN2022105987-appb-000239
通式(IVa-A)所示的化合物或其盐与通式(IVb-A)所示的化合物或其盐在碱性条件下发生缩合酰化反应，得到通式(IV-1A)或通式(IV-2A)所示的化合物或其盐；The compound represented by the general formula (IVa-A) or its salt and the compound represented by the general formula (IVb-A) or its salt undergo a condensation acylation reaction under alkaline conditions to obtain the general formula (IV-1A) or the A compound represented by formula (IV-2A) or a salt thereof;
其中：in:
R为烷基；优选地，R为C 1-6烷基；更优选地，R为叔丁基； R is an alkyl group; preferably, R is a C 1-6 alkyl group; more preferably, R is a tert-butyl group;
环A、R 2a、G、R 1、R 4、R 5a、R 5b、R 7、R 8、m和n如通式(IV-1A)或通式(IV-2A)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (IV-1A) or general formula (IV-2A).
方案十七Plan seventeen
本公开通式(M)所示的化合物或其可药用盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (M) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000240
Figure PCTCN2022105987-appb-000240
通式(Ma-A)所示的化合物或其盐与通式(MB)所示的化合物或其盐在碱性条件 下发生缩合酰化反应，得到通式(M)所示的化合物或其可药用的盐；The compound represented by the general formula (Ma-A) or its salt and the compound represented by the general formula (MB) or its salt undergo a condensation acylation reaction under alkaline conditions to obtain the compound represented by the general formula (M) or its salt. pharmaceutically acceptable salts;
其中：in:
Z、G、R 0、R 1至R 3、R 5至R 11和n如通式(M)中所定义。 Z, G, R 0 , R 1 to R 3 , R 5 to R 11 and n are as defined in the general formula (M).
方案十八Plan eighteen
本公开通式(I)所示的化合物或其可药用盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000241
Figure PCTCN2022105987-appb-000241
通式(Ia-A)所示的化合物或其盐与通式(IB)所示的化合物或其盐在碱性条件下发生缩合酰化反应，得到通式(I)所示的化合物或其可药用的盐；The compound represented by the general formula (Ia-A) or its salt and the compound represented by the general formula (IB) or its salt undergo a condensation acylation reaction under alkaline conditions to obtain the compound represented by the general formula (I) or its salt pharmaceutically acceptable salts;
其中：in:
G、R 1至R 11和n如通式(I)中所定义。 G, R 1 to R 11 and n are as defined in the general formula (I).
方案十九Plan nineteen
本公开通式(II)所示的化合物或其可药用的盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (II) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000242
Figure PCTCN2022105987-appb-000242
通式(IIa-A)所示的化合物或其盐与通式(IB)所示的化合物或其盐在碱性条件下发生缩合酰化反应，得到通式(II)的化合物或其可药用的盐；The compound represented by the general formula (IIa-A) or its salt and the compound represented by the general formula (IB) or its salt undergo a condensation acylation reaction under alkaline conditions to obtain the compound of the general formula (II) or its pharmaceutical the salt used;
其中：in:
环A、R 2a、G、R 1、R 4至R 11、m和n如通式(II)中所定义。 Ring A, R 2a , G, R 1 , R 4 to R 11 , m and n are as defined in the general formula (II).
方案二十Program twenty
本公开通式(III)所示的化合物或其可药用的盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (III) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000243
Figure PCTCN2022105987-appb-000243
通式(IIIa-A)所示的化合物或其盐与通式(IIIB)所示的化合物或其盐在碱性条 件下发生缩合酰化反应，得到通式(III)所示的化合物或其可药用的盐；The compound represented by the general formula (IIIa-A) or its salt and the compound represented by the general formula (IIIB) or its salt undergo a condensation acylation reaction under alkaline conditions to obtain the compound represented by the general formula (III) or its salt pharmaceutically acceptable salts;
其中：in:
环A、R 2a、G、R 1、R 4、R 5、R 7、R 8、R 10、m和n如通式(III)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in the general formula (III).
方案二十一Program 21
本公开通式(G-1)或通式(G-2)所示的化合物或其可药用的盐的制备方法，包括以下步骤：The preparation method of the compound represented by general formula (G-1) or general formula (G-2) or a pharmaceutically acceptable salt thereof of the present disclosure comprises the following steps:
Figure PCTCN2022105987-appb-000244
Figure PCTCN2022105987-appb-000244
通式(Ga-A)所示的化合物或其盐与通式(GB)所示的化合物或其盐在碱性条件下发生缩合酰化反应，得到通式(G-1)或通式(G-2)所示的化合物或其可药用的盐；The compound represented by general formula (Ga-A) or its salt and the compound represented by general formula (GB) or its salt occur condensation acylation reaction under basic condition, obtain general formula (G-1) or general formula ( G-2) compound or pharmaceutically acceptable salt thereof;
其中：in:
环A、Z、G、R 0、R 1、R 2a、R 5a、R 5b、R 7、R 8、m和n如通式(G-1)或(G-2)中所定义。 Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G-1) or (G-2).
方案二十二Program twenty-two
本公开通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐的制备方法，包括以下步骤：The preparation method of the compound represented by general formula (IV-1) or general formula (IV-2) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000245
Figure PCTCN2022105987-appb-000245
通式(IVa-A)所示的化合物或其盐与通式(IVB)所示的化合物或其盐在碱性条件下发生缩合酰化反应，得到通式(IV-1)或通式(IV-2)的化合物或其可药用的盐；The compound represented by general formula (IVa-A) or its salt and the compound represented by general formula (IVB) or its salt take place condensation acylation reaction under alkaline condition, obtain general formula (IV-1) or general formula ( IV-2) compound or a pharmaceutically acceptable salt thereof;
其中：in:
环A、R 2a、G、R 1、R 4、R 5a、R 5b、R 7、R 8、m和n如通式(IV-1)或通式(IV-2)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (IV-1) or general formula (IV-2).
方案二十三Program twenty-three
本公开通式(G-1)和通式(G-2)所示的化合物或其可药用的盐的制备方法，包括以下步骤：The preparation method of the compound represented by the general formula (G-1) and the general formula (G-2) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
Figure PCTCN2022105987-appb-000246
Figure PCTCN2022105987-appb-000246
通式(G)所示的化合物或其可药用的盐进行制备分离，得到通式(G-1)和通式(G-2)所示的化合物或其可药用的盐；The compound represented by general formula (G) or its pharmaceutically acceptable salt is prepared and separated to obtain the compound represented by general formula (G-1) and general formula (G-2) or its pharmaceutically acceptable salt;
其中：in:
环A、Z、G、R 0、R 1、R 2a、R 5a、R 5b、R 7、R 8、m和n如通式(G)中所定义。 Rings A, Z, G, R 0 , R 1 , R 2a , R 5a , R 5b , R 7 , R 8 , m and n are as defined in the general formula (G).
方案二十四Program twenty-four
本公开通式(IV-1)和通式(IV-2)所示的化合物或其可药用的盐的制备方法，包括以下步骤：The preparation method of the compound represented by general formula (IV-1) and general formula (IV-2) or a pharmaceutically acceptable salt thereof of the present disclosure comprises the following steps:
Figure PCTCN2022105987-appb-000247
Figure PCTCN2022105987-appb-000247
通式(IV)所示的化合物或其可药用的盐进行制备分离，得到通式(IV-1)和通式(IV-2)所示的化合物或其可药用的盐；The compound represented by general formula (IV) or its pharmaceutically acceptable salt is prepared and separated to obtain the compound represented by general formula (IV-1) and general formula (IV-2) or its pharmaceutically acceptable salt;
其中：in:
环A、R 2a、G、R 1、R 4、R 5a、R 5b、R 7、R 8、m和n如通式(IV-1)或通式(IV-2)中所定义。 Ring A, R 2a , G, R 1 , R 4 , R 5a , R 5b , R 7 , R 8 , m and n are as defined in general formula (IV-1) or general formula (IV-2).
以上合成方案中提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、吡啶、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钠、醋酸钾、叔丁醇钠、叔丁醇钾或1,8-二氮杂二环十一碳-7-烯，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、碳酸铯、碳酸镉、氢氧化钠、一水合氢氧化锂、氢氧化锂和氢氧化钾；优选地，所述提供碱性条件的试剂为吡啶。The reagents that provide basic conditions in the above synthesis scheme include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, pyridine, N,N-diisopropylethylamine, n-butyllithium, Lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene, the inorganic bases include but not limited to Sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, cadmium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably, the reagent providing basic conditions is pyridine.
以上合成方案中所述的酸包括但不限于苯六甲酸、氮硫方酸、三氯乙酸，三硝基苯磺酸、三氟甲磺酸和三氟醋酸；优选地，所述的酸为三氟醋酸。The acid described in the above synthesis scheme includes but not limited to mellitic acid, thiosulfuric acid, trichloroacetic acid, trinitrobenzenesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid; preferably, the acid is Trifluoroacetic acid.
以上合成方案中所涉及的缩合酰化反应优选在缩合试剂存在下进行，所述的缩合试剂优选为1-氯-N,N,2-三甲基丙烯胺。The condensation acylation reaction involved in the above synthesis scheme is preferably carried out in the presence of a condensation reagent, and the condensation reagent is preferably 1-chloro-N,N,2-trimethylacrylamine.
上述步骤的反应优选在溶剂中进行，所用的溶剂包括但不限于：吡啶、乙二醇二甲醚、醋酸、甲醇、乙醇、异丙醇、丙酮、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、甲苯、1,4-二氧六环、水、 N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,2-二溴乙烷及其混合物。The reaction of the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, isopropanol, acetone, acetonitrile, n-butanol, toluene, tetrahydrofuran, di Chloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, toluene, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylethane Amides, 1,2-dibromoethane and mixtures thereof.
具体实施方式detailed description
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的范围。The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.
实施例Example
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). The determination of NMR is carried out with Bruker AVANCE-400 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is four Methylsilane (TMS).
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。MS was determined with Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。High performance liquid chromatography (HPLC) was analyzed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatography.
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.
高效液相制备色谱法使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。High performance liquid phase preparative chromatography uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.
手性制备色谱法使用Shimadzu LC-20AP制备型色谱仪。Chiral preparative chromatography uses a Shimadzu LC-20AP preparative chromatograph.
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ~0.5mm.
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。 Kinase average inhibition rate and IC 50 value were measured with NovoStar microplate reader (BMG Company, Germany).
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品、阿达玛斯试剂有限公司、西格玛奥德里奇(上海)贸易有限公司、上海毕得医药科技有限公司、上海皓鸿生物医药科技有限公司、赛默飞世尔科技(中国)科技有限公司等公司。The known starting materials of the present disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals, Adamas Reagent Co., Ltd., Sigma-Aldrich (Shanghai) Trading Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd., Shanghai Haohong Biomedical Technology Co., Ltd., Thermo Fisher Scientific (China) Technology Co., Ltd. Waiting for the company.
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。Unless otherwise specified in the examples, the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。The argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或 HC2-SS型氢化仪。The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
微波反应使用CEM Discover-S 908860型微波反应器。For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.
实施例中无特殊说明，溶液是指水溶液。Unless otherwise specified in the examples, the solution refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。The monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developer used for reaction, the eluent system of the column chromatography that purifies compound adopts and the developer system of thin-layer chromatography comprise: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
实施例1Example 1
(S)-3-(4-氯-3-((2S,3R)-2-(2,3-二氢-1H-茚-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸1-1(S)-3-(4-chloro-3-((2S,3R)-2-(2,3-dihydro-1H-inden-5-yl)-4,4,4-trifluoro-3- Methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 1-1
或or
(S)-3-(4-氯-3-((2R,3R)-2-(2,3-二氢-1H-茚-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸1-2(S)-3-(4-chloro-3-((2R,3R)-2-(2,3-dihydro-1H-inden-5-yl)-4,4,4-trifluoro-3- Methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 1-2
Figure PCTCN2022105987-appb-000248
Figure PCTCN2022105987-appb-000248
Figure PCTCN2022105987-appb-000249
Figure PCTCN2022105987-appb-000249
第一步first step
(R)-4,4,4-三氟-3-甲基丁酸苄酯1b(R)-Benzyl 4,4,4-trifluoro-3-methylbutyrate 1b
将化合物(R)-4,4,4-三氟-3-甲基丁酸1a(11.5g，73.7mmol，采用专利申请“US2012115863A1”中说明书实施例18A公开的方法制备而得)和苄醇(8g,73.9mmol)溶于二氯甲烷(300mL)，加入二异丙基乙基胺(29g,224.4mmol)，冷却至0℃，依次分批加入2-肟氰乙酸乙酯(13.6g,95.7mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(18.4g，96.0mmol)，随后自然升至室温搅拌反应10小时。浓缩后残余物用硅胶柱色谱法以洗脱剂体系B纯化得标题化合物1b(11g，产率：61％)。Compound (R)-4,4,4-trifluoro-3-methylbutanoic acid 1a (11.5g, 73.7mmol, prepared by the method disclosed in Example 18A of the patent application "US2012115863A1") and benzyl alcohol (8g, 73.9mmol) was dissolved in dichloromethane (300mL), diisopropylethylamine (29g, 224.4mmol) was added, cooled to 0°C, ethyl 2-oxime cyanoacetate (13.6g, 95.7mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (18.4g, 96.0mmol), then naturally warmed to room temperature and stirred for 10 hours. The residue after concentration was purified by silica gel column chromatography with eluent system B to obtain the title compound 1b (11 g, yield: 61%).
第二步second step
(3R)-2-(2,3-二氢-1H-茚-5-基)-4,4,4-三氟-3-甲基丁酸苄酯1d(非对映异构体混合物)(3R)-2-(2,3-Dihydro-1H-inden-5-yl)-4,4,4-trifluoro-3-methylbutyric acid benzyl ester 1d (mixture of diastereoisomers)
溶液A：化合物1b(80mg，0.324mmol)溶于甲苯(5mL)，用干冰丙酮浴冷却至-20℃，加入双三甲基硅基氨基锂的四氢呋喃溶液(1M，974.14μL)，在-10℃搅拌15分钟。溶液B：化合物5-溴-2,3-二氢-1H-茚1c(64mg，0.324mmol，上海毕得医药科技有限公司)溶于甲苯(5mL)，氮气氛下加入醋酸钯(8mg，0.324mmol)、2-(2-二环己基膦苯基)-N,N-二甲基苯胺(25mg，0.063mmol)，室温搅拌10分钟。移除溶液A的干冰丙酮浴，将溶液B加到溶液A中，升至室温搅拌1小时，加热至85℃搅拌3小时，冷却至室温搅拌16小时。浓缩后残余物用硅胶柱色谱法以洗脱剂体系C纯化得到标题产物1d(非对映异构体混合物，50mg，产率：42％)。Solution A: Compound 1b (80mg, 0.324mmol) was dissolved in toluene (5mL), cooled to -20°C with a dry-ice acetone bath, added a tetrahydrofuran solution of lithium bistrimethylsilylamide (1M, 974.14μL), at -10 °C and stirred for 15 minutes. Solution B: Compound 5-bromo-2,3-dihydro-1H-indene 1c (64mg, 0.324mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) was dissolved in toluene (5mL), and palladium acetate (8mg, 0.324 mmol), 2-(2-dicyclohexylphosphinephenyl)-N,N-dimethylaniline (25mg, 0.063mmol), stirred at room temperature for 10 minutes. Remove the dry ice acetone bath of solution A, add solution B to solution A, raise to room temperature and stir for 1 hour, heat to 85°C and stir for 3 hours, cool to room temperature and stir for 16 hours. The residue after concentration was purified by silica gel column chromatography with eluent system C to give the title product 1d (mixture of diastereomers, 50 mg, yield: 42%).
第三步third step
(3R)-2-(2,3-二氢-1H-茚-5-基)-4,4,4-三氟-3-甲基丁酸1e(非对映异构体混合物)(3R)-2-(2,3-Dihydro-1H-inden-5-yl)-4,4,4-trifluoro-3-methylbutanoic acid 1e (mixture of diastereoisomers)
化合物1d(50mg，0.137μmol)溶于水(1mL)和二氧六环(5mL)，加入氢氧化钠(20mg，0.50mmol)，50℃搅拌16小时。浓缩，加入10mL水，10mL二氯甲烷，萃取，用1M的盐酸酸化水相至pH为3。加入10mL乙酸乙酯萃取。有机相用无水硫酸钠干燥，过滤后浓缩得到粗品标题产物1e(非对映异构体混合物，37mg)，产物不经纯化直接进行下一步反应。Compound 1d (50 mg, 0.137 μmol) was dissolved in water (1 mL) and dioxane (5 mL), added with sodium hydroxide (20 mg, 0.50 mmol), and stirred at 50° C. for 16 hours. Concentrate, add 10 mL of water and 10 mL of dichloromethane, extract, and acidify the aqueous phase to pH 3 with 1M hydrochloric acid. Add 10 mL of ethyl acetate for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude title product 1e (diastereoisomer mixture, 37 mg), which was directly subjected to the next reaction without purification.
MS m/z(ESI)：271.2[M-1]。MS m/z (ESI): 271.2 [M-1].
第四步the fourth step
(S)-3-(4-氯-3-((2S,3R)-2-(2,3-二氢-1H-茚-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸叔丁酯1g-1(S)-3-(4-chloro-3-((2S,3R)-2-(2,3-dihydro-1H-inden-5-yl)-4,4,4-trifluoro-3- Methylbutyrylamino)phenyl)-3-tert-butyl cyclopropylpropionate 1g-1
或or
(S)-3-(4-氯-3-((2R,3R)-2-(2,3-二氢-1H-茚-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸叔丁酯1g-2(S)-3-(4-chloro-3-((2R,3R)-2-(2,3-dihydro-1H-inden-5-yl)-4,4,4-trifluoro-3- Methylbutyrylamino)phenyl)-3-tert-butyl cyclopropylpropionate 1g-2
化合物1e(37mg，0.135mmol)，溶于二氯甲烷(5mL)，室温加入1-氯-N,N,2-三甲基丙烯胺(27mg，0.202mmol，上海毕得医药科技有限公司)，搅拌30分钟。加入吡啶(32mg，0.404mmol)和(S)-3-(3-氨基-4-氯苯基)-3-环丙基丙酸叔丁酯1f(39mg，0.131mmol，采用专利申请“US20130079412A1”中说明书实施例30A公开的方法制备而得)溶于二氯甲烷(1mL)的溶液。室温搅拌30分钟。浓缩后用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物1g-1或1g-2(70mg，产率：93％)。MS m/z(ESI)：572.0[M+23]。Compound 1e (37mg, 0.135mmol) was dissolved in dichloromethane (5mL), and 1-chloro-N,N,2-trimethylpropenylamine (27mg, 0.202mmol, Shanghai Beide Pharmaceutical Technology Co., Ltd.) was added at room temperature, Stir for 30 minutes. Add pyridine (32mg, 0.404mmol) and (S)-3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoic acid tert-butyl ester 1f (39mg, 0.131mmol, using patent application "US20130079412A1" prepared by the method disclosed in Example 30A of the specification) dissolved in dichloromethane (1 mL). Stir at room temperature for 30 minutes. After concentration, it was purified by silica gel column chromatography with eluent system B to obtain the title compound 1g-1 or 1g-2 (70 mg, yield: 93%). MS m/z (ESI): 572.0 [M+23].
第五步the fifth step
(S)-3-(4-氯-3-((2S,3R)-2-(2,3-二氢-1H-茚-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸1-1(S)-3-(4-chloro-3-((2S,3R)-2-(2,3-dihydro-1H-inden-5-yl)-4,4,4-trifluoro-3- Methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 1-1
或or
(S)-3-(4-氯-3-((2R,3R)-2-(2,3-二氢-1H-茚-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸1-2(S)-3-(4-chloro-3-((2R,3R)-2-(2,3-dihydro-1H-inden-5-yl)-4,4,4-trifluoro-3- Methylbutyrylamino)phenyl)-3-cyclopropylpropionic acid 1-2
化合物1g-1或者1g-2(50mg，0.09mmol)，溶于二氯甲烷(5mL)，室温加入2 mL三氟醋酸，搅拌1小时。浓缩后残余物用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18 150*30mm,5μm；流动相：水(含0.1％的三氟醋酸)；乙腈；15分钟梯度：65％-80％)纯化，得到标题化合物1-1或1-2(17mg，产率：38％)。Compound 1g-1 or 1g-2 (50 mg, 0.09 mmol) was dissolved in dichloromethane (5 mL), and 2 mL of trifluoroacetic acid was added at room temperature, and stirred for 1 hour. After concentration, the residue was subjected to high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% trifluoroacetic acid); acetonitrile; 15 minutes gradient: 65%- 80%) was purified to obtain the title compound 1-1 or 1-2 (17 mg, yield: 38%).
MS m/z(ESI)：494.1[M+1]。MS m/z (ESI): 494.1 [M+1].
1H NMR(500MHz,DMSO-d 6)δ12.02(s,1H),9.70(s,1H),7.46(d,1H),7.34(dd,1H),7.30(s,1H),7.20(s,2H),7.11–7.05(m,1H),4.05(d,1H),2.84(q,4H),2.67–2.53(m,3H),2.24(q,1H),2.06–1.94(m,2H),0.93(s,1H),0.88–0.76(m,3H),0.49(s,1H),0.26(d,2H),0.06(s,1H)。 1 H NMR (500MHz,DMSO-d 6 )δ12.02(s,1H),9.70(s,1H),7.46(d,1H),7.34(dd,1H),7.30(s,1H),7.20( s,2H),7.11–7.05(m,1H),4.05(d,1H),2.84(q,4H),2.67–2.53(m,3H),2.24(q,1H),2.06–1.94(m, 2H), 0.93(s,1H), 0.88–0.76(m,3H), 0.49(s,1H), 0.26(d,2H), 0.06(s,1H).
实施例2Example 2
(S)-3-(4-氯-3-((2S,3R)-4,4,4-三氟-3-甲基-2-(萘-2-基)丁酰胺基)苯基)-3-环丙基丙酸2-1(S)-3-(4-Chloro-3-((2S,3R)-4,4,4-trifluoro-3-methyl-2-(naphthalene-2-yl)butanylamino)phenyl) -3-cyclopropylpropionic acid 2-1
或or
(S)-3-(4-氯-3-((2R,3R)-4,4,4-三氟-3-甲基-2-(萘-2-基)丁酰胺基)苯基)-3-环丙基丙酸2-2(S)-3-(4-Chloro-3-((2R,3R)-4,4,4-trifluoro-3-methyl-2-(naphthalene-2-yl)butanylamino)phenyl) -3-cyclopropylpropionic acid 2-2
Figure PCTCN2022105987-appb-000250
Figure PCTCN2022105987-appb-000250
Figure PCTCN2022105987-appb-000251
Figure PCTCN2022105987-appb-000251
第一步first step
(3R)-4,4,4-三氟-3-甲基-2-(萘-2-基)丁酸苄酯2b(非对映异构体混合物)Benzyl (3R)-4,4,4-trifluoro-3-methyl-2-(naphthalen-2-yl)butyrate 2b (mixture of diastereoisomers)
溶液A：化合物1b(86mg，0.349mmol)，溶于甲苯(5mL)，用干冰丙酮浴冷却至-20℃，加入双三甲基硅基氨基锂的四氢呋喃溶液(1M，1mL)，在-10℃搅拌15分钟。溶液B：化合物2-溴萘2a(71mg，0.342mmol，上海毕得医药科技有限公司)溶于甲苯(5mL)，氮气氛下加入醋酸钯(8mg，0.324mmol)和2-(2-二环己基膦苯基)-N,N-二甲基苯胺(27mg，0.068mmol)，室温搅拌10分钟。移除溶液A的干冰丙酮浴，将溶液B加到溶液A中，室温搅拌1小时，85℃搅拌3小时，室温搅拌16小时。浓缩后残余物用硅胶柱色谱法以洗脱剂体系C纯化得到标题产物2b(非对映异构体混合物，50mg，产率：38％)。Solution A: Compound 1b (86mg, 0.349mmol), dissolved in toluene (5mL), cooled to -20°C with a dry ice acetone bath, added tetrahydrofuran solution of lithium bistrimethylsilylamide (1M, 1mL), at -10 °C and stirred for 15 minutes. Solution B: Compound 2-bromonaphthalene 2a (71mg, 0.342mmol, Shanghai Pide Pharmaceutical Technology Co., Ltd.) was dissolved in toluene (5mL), and palladium acetate (8mg, 0.324mmol) and 2-(2-bicyclo Hexylphosphinephenyl)-N,N-dimethylaniline (27mg, 0.068mmol), stirred at room temperature for 10 minutes. Remove the dry ice acetone bath of solution A, add solution B to solution A, stir at room temperature for 1 hour, stir at 85 °C for 3 hours, and stir at room temperature for 16 hours. The residue after concentration was purified by silica gel column chromatography with eluent system C to give the title product 2b (mixture of diastereomers, 50 mg, yield: 38%).
第二步second step
(3R)-4,4,4-三氟-3-甲基-2-(萘-2-基)丁酸2c(非对映异构体混合物)(3R)-4,4,4-Trifluoro-3-methyl-2-(naphthalen-2-yl)butanoic acid 2c (mixture of diastereomers)
化合物2b(50mg，0.137μmol)溶于水(1mL)和二氧六环(5mL)，加入氢氧化钠(40mg，1mmol)，50℃搅拌16小时。浓缩，加入10mL水，10mL二氯甲烷，萃取，用1M盐酸酸化水相至pH为3。加入10mL乙酸乙酯萃取。有机相用无 水硫酸钠干燥，过滤后浓缩得到粗品标题产物2c(非对映异构体混合物，37mg)，产物不经纯化直接进行下一步反应。Compound 2b (50 mg, 0.137 μmol) was dissolved in water (1 mL) and dioxane (5 mL), added with sodium hydroxide (40 mg, 1 mmol), and stirred at 50° C. for 16 hours. Concentrate, add 10 mL of water, 10 mL of dichloromethane, extract, and acidify the aqueous phase to pH 3 with 1M hydrochloric acid. Add 10 mL of ethyl acetate for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude title product 2c (mixture of diastereomers, 37 mg). The product was directly carried on to the next reaction without purification.
MS m/z(ESI)：281.1[M-1]。MS m/z (ESI): 281.1 [M-1].
第三步third step
(S)-3-(4-氯-3-((2S,3R)-4,4,4-三氟-3-甲基-2-(萘-2-基)丁酰胺基)苯基)-3-环丙基丙酸叔丁酯2d-1(S)-3-(4-Chloro-3-((2S,3R)-4,4,4-trifluoro-3-methyl-2-(naphthalene-2-yl)butanylamino)phenyl) - tert-butyl 3-cyclopropylpropionate 2d-1
或or
(S)-3-(4-氯-3-((2R,3R)-4,4,4-三氟-3-甲基-2-(萘-2-基)丁酰胺基)苯基)-3-环丙基丙酸叔丁酯2d-2(S)-3-(4-Chloro-3-((2R,3R)-4,4,4-trifluoro-3-methyl-2-(naphthalene-2-yl)butanylamino)phenyl) - tert-butyl 3-cyclopropylpropionate 2d-2
化合物2c(37mg，0.131mmol)，溶于二氯甲烷(5mL)，室温加入1-氯-N,N,2-三甲基丙烯胺(26mg，0.194mmol)，搅拌30分钟。加入吡啶(31mg，0.391mmol)和化合物1f(38mg，0.128mmol)溶于二氯甲烷(1mL)的溶液。室温搅拌30分钟。浓缩后残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物2d-1或2d-2(50mg，产率：68％)。Compound 2c (37 mg, 0.131 mmol) was dissolved in dichloromethane (5 mL), and 1-chloro-N,N,2-trimethylpropenylamine (26 mg, 0.194 mmol) was added at room temperature, and stirred for 30 minutes. A solution of pyridine (31 mg, 0.391 mmol) and compound If (38 mg, 0.128 mmol) dissolved in dichloromethane (1 mL) was added. Stir at room temperature for 30 minutes. The residue after concentration was purified by silica gel column chromatography with eluent system B to obtain the title compound 2d-1 or 2d-2 (50 mg, yield: 68%).
MS m/z(ESI)：582.0[M+23]。MS m/z (ESI): 582.0 [M+23].
第四步the fourth step
(S)-3-(4-氯-3-((2S,3R)-4,4,4-三氟-3-甲基-2-(萘-2-基)丁酰胺基)苯基)-3-环丙基丙酸2-1(S)-3-(4-Chloro-3-((2S,3R)-4,4,4-trifluoro-3-methyl-2-(naphthalene-2-yl)butanylamino)phenyl) -3-cyclopropylpropionic acid 2-1
或or
(S)-3-(4-氯-3-((2R,3R)-4,4,4-三氟-3-甲基-2-(萘-2-基)丁酰胺基)苯基)-3-环丙基丙酸2-2(S)-3-(4-Chloro-3-((2R,3R)-4,4,4-trifluoro-3-methyl-2-(naphthalene-2-yl)butanylamino)phenyl) -3-cyclopropylpropionic acid 2-2
化合物2d-1或2d-2(50mg，0.89mmol)，溶于二氯甲烷(5mL)，室温加入2mL三氟醋酸，搅拌1小时。浓缩后用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18 150*30mm，5μm；流动相：水(含0.1％的三氟醋酸)，乙腈；15分钟梯度：67％-77％)纯化，得到标题化合物2-1或2-2(40mg，产率：89％)。Compound 2d-1 or 2d-2 (50 mg, 0.89 mmol) was dissolved in dichloromethane (5 mL), and 2 mL of trifluoroacetic acid was added at room temperature, and stirred for 1 hour. After concentration, use high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; Mobile phase: water (containing 0.1% trifluoroacetic acid), acetonitrile; 15 minutes gradient: 67%-77% ) to obtain the title compound 2-1 or 2-2 (40 mg, yield: 89%).
MS m/z(ESI)：504.1[M+1]。MS m/z (ESI): 504.1 [M+1].
1H NMR(500MHz,DMSO-d 6)δ12.01(s,1H),9.89(s,1H),8.05–7.84(m,4H),7.62(d,1H),7.57–7.48(m,2H),7.42(d,1H),7.33(dd,1H),7.08(dd,1H),4.28(d,1H),3.49(d,1H),2.66–2.54(m,2H),2.23(d,1H),0.97–0.90(m,1H),0.84(dd,3H),0.52–0.42(m,1H),0.32–0.16(m,2H),0.04(q,1H)。 1 H NMR (500MHz,DMSO-d 6 )δ12.01(s,1H),9.89(s,1H),8.05–7.84(m,4H),7.62(d,1H),7.57–7.48(m,2H ),7.42(d,1H),7.33(dd,1H),7.08(dd,1H),4.28(d,1H),3.49(d,1H),2.66–2.54(m,2H),2.23(d, 1H), 0.97–0.90(m,1H), 0.84(dd,3H), 0.52–0.42(m,1H), 0.32–0.16(m,2H), 0.04(q,1H).
实施例3Example 3
(S)-3-(4-氯-3-((2S,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸3-1(S)-3-(4-chloro-3-((2S,3R)-2-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)- 4,4,4-Trifluoro-3-methylbutanamido)phenyl)-3-cyclopropylpropionic acid 3-1
或or
(S)-3-(4-氯-3-((2R,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸3-2(S)-3-(4-chloro-3-((2R,3R)-2-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)- 4,4,4-Trifluoro-3-methylbutanamido)phenyl)-3-cyclopropylpropionic acid 3-2
Figure PCTCN2022105987-appb-000252
Figure PCTCN2022105987-appb-000252
第一步first step
(3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酸苄酯3b(非对映异构体混合物)(3R)-2-(2,2-Difluorobenzo[d][1,3]dioxolan-5-yl)-4,4,4-trifluoro-3-methylbutanoic acid benzyl Ester 3b (mixture of diastereoisomers)
溶液A：化合物1b(3.50g，14.21mmol)溶于甲苯(100mL)。用干冰丙酮浴冷却至-20℃，加入1M双三甲基硅基氨基锂的四氢呋喃溶液(21.3mL)，在-10℃搅拌15分钟。溶液B：化合物5-溴-2,2-二氟苯并[d][1,3]二氧杂环戊烷3a(3.68g，15.53mmol)溶于甲苯(20mL)，氮气氛下加入醋酸钯(319mg，1.42mmol)、2-(2-二环己基膦苯基)-N,N-二甲基苯胺(1.12g，2.85mmol)，室温搅拌20分钟。移除溶液A的干冰丙酮浴，将溶液B加到溶液A中，升至室温搅拌1小时，加热至80℃搅拌3小时，冷却至室温搅拌2小时。浓缩后残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题产物3b(非对映异构体混合物，2.3g，产率：40.2％)。Solution A: Compound 1b (3.50 g, 14.21 mmol) was dissolved in toluene (100 mL). Cool to -20°C with a dry-ice acetone bath, add 1M tetrahydrofuran solution (21.3 mL) of lithium bistrimethylsilylamide, and stir at -10°C for 15 minutes. Solution B: Compound 5-bromo-2,2-difluorobenzo[d][1,3]dioxolane 3a (3.68 g, 15.53 mmol) was dissolved in toluene (20 mL), and acetic acid was added under nitrogen atmosphere Palladium (319 mg, 1.42 mmol), 2-(2-dicyclohexylphosphinephenyl)-N,N-dimethylaniline (1.12 g, 2.85 mmol), stirred at room temperature for 20 minutes. Remove the dry ice acetone bath of solution A, add solution B to solution A, raise to room temperature and stir for 1 hour, heat to 80°C and stir for 3 hours, cool to room temperature and stir for 2 hours. The residue after concentration was purified by silica gel column chromatography with eluent system B to obtain the title product 3b (mixture of diastereomers, 2.3 g, yield: 40.2%).
第二步second step
(3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酸3c(非对映异构体混合物)(3R)-2-(2,2-Difluorobenzo[d][1,3]dioxolan-5-yl)-4,4,4-trifluoro-3-methylbutanoic acid 3c (diastereomeric mixture)
化合物3b(2.30g，5.71mmol)溶于水(6mL)和二氧六环(30mL)，加入氢氧化钠(1.83g，45.75mmol)，60℃搅拌16小时。浓缩，加入水(10mL)，二氯甲烷萃取(30mL)，水相用1M的盐酸酸化至pH为1～2，水相用二氯甲烷萃取(30mL×2)，合并有机相，用无水硫酸钠干燥，过滤后将滤液浓缩，得到粗品标题产物3c(非对映异构体混合物，888mg)，产物不经纯化直接进行下一步反应。Compound 3b (2.30g, 5.71mmol) was dissolved in water (6mL) and dioxane (30mL), sodium hydroxide (1.83g, 45.75mmol) was added, and stirred at 60°C for 16 hours. Concentrate, add water (10mL), extract with dichloromethane (30mL), acidify the aqueous phase with 1M hydrochloric acid to pH 1-2, extract the aqueous phase with dichloromethane (30mL×2), combine the organic phases, and wash with anhydrous After drying over sodium sulfate, after filtration, the filtrate was concentrated to obtain the crude title product 3c (mixture of diastereomers, 888 mg), which was directly subjected to the next reaction without purification.
MS m/z(ESI)：311.2[M-1]。MS m/z (ESI): 311.2 [M-1].
第三步third step
(S)-3-(4-氯-3-((2S,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸叔丁酯3d-1(S)-3-(4-chloro-3-((2S,3R)-2-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)- tert-butyl 4,4,4-trifluoro-3-methylbutanylamino)phenyl)-3-cyclopropylpropanoate 3d-1
或or
(S)-3-(4-氯-3-((2R,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸叔丁酯3d-2(S)-3-(4-chloro-3-((2R,3R)-2-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)- 4,4,4-Trifluoro-3-methylbutanylamino)phenyl)-3-cyclopropylpropanoic acid tert-butyl ester 3d-2
化合物3c(888mg，2.84mmol)溶于二氯甲烷(50mL)，室温加入1-氯-N,N,2-三甲基丙烯胺(608mg，4.55mmol)，室温搅拌30分钟。加入吡啶(562mg，7.10mmol)和化合物1f(841mg，2.84mmol)的二氯甲烷(5mL)溶液。室温搅拌30分钟。浓缩后残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物3d-1或3d-2(1.22g，产率：72.7％)。Compound 3c (888mg, 2.84mmol) was dissolved in dichloromethane (50mL), 1-chloro-N,N,2-trimethylpropenylamine (608mg, 4.55mmol) was added at room temperature, and stirred at room temperature for 30 minutes. A solution of pyridine (562 mg, 7.10 mmol) and compound If (841 mg, 2.84 mmol) in dichloromethane (5 mL) was added. Stir at room temperature for 30 minutes. The residue after concentration was purified by silica gel column chromatography with eluent system B to obtain the title compound 3d-1 or 3d-2 (1.22 g, yield: 72.7%).
MS m/z(ESI)：588.4[M-1]。MS m/z (ESI): 588.4 [M-1].
第四步the fourth step
(S)-3-(4-氯-3-((2S,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸3-1(S)-3-(4-chloro-3-((2S,3R)-2-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)- 4,4,4-Trifluoro-3-methylbutanamido)phenyl)-3-cyclopropylpropionic acid 3-1
或or
(S)-3-(4-氯-3-((2R,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸3-2(S)-3-(4-chloro-3-((2R,3R)-2-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)- 4,4,4-Trifluoro-3-methylbutanamido)phenyl)-3-cyclopropylpropionic acid 3-2
化合物3d-1或3d-2(280mg，0.47mmol)，溶于二氯甲烷(10mL)，室温加入三氟醋酸(2mL)，搅拌2小时。浓缩后残余物用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18 150*30mm，5μm；流动相：水(含0.1％的三氟醋酸)；乙腈，15分钟梯度：65％-80％)纯化，得标题化合物3-1或3-2(105mg，产率：41.4％)。Compound 3d-1 or 3d-2 (280 mg, 0.47 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added at room temperature, and stirred for 2 hours. Concentrate the residue with high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; Mobile phase: water (containing 0.1% trifluoroacetic acid); Acetonitrile, 15 minutes Gradient: 65%- 80%) to obtain the title compound 3-1 or 3-2 (105 mg, yield: 41.4%).
MS m/z(ESI)：534.1[M+1]。MS m/z (ESI): 534.1 [M+1].
1H NMR(500MHz,DMSO-d 6)δ12.1-11.9(brs,1H),9.82(s,1H),7.51-7.48(m,1H),7.45-7.39(m,2H),7.38-7.33(m,1H),7.32-7.26(m,1H),7.13-7.04(m,1H),4.15(d,1H),3.37-3.32(m,1H),2.65-2.56(m,2H),2.29-2.20(m,1H),0.99-0.90(m,1H),0.82(d,3H),0.53-0.44(m,1H),0.32-0.25(m,1H),0.24-0.18(m,1H),0.10-0.02(m,1H)。 1 H NMR (500MHz,DMSO-d 6 )δ12.1-11.9(brs,1H),9.82(s,1H),7.51-7.48(m,1H),7.45-7.39(m,2H),7.38-7.33 (m,1H),7.32-7.26(m,1H),7.13-7.04(m,1H),4.15(d,1H),3.37-3.32(m,1H),2.65-2.56(m,2H),2.29 -2.20(m,1H),0.99-0.90(m,1H),0.82(d,3H),0.53-0.44(m,1H),0.32-0.25(m,1H),0.24-0.18(m,1H) ,0.10-0.02(m,1H).
实施例4Example 4
(S)-3-环丙基-3-(3-((2S,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3- 甲基丁酰胺基)-4-甲基苯基)丙酸4-1(S)-3-cyclopropyl-3-(3-((2S,3R)-2-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl )-4,4,4-trifluoro-3-methylbutanylamino)-4-methylphenyl)propionic acid 4-1
或or
(S)-3-环丙基-3-(3-((2R,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)-4-甲基苯基)丙酸4-2(S)-3-cyclopropyl-3-(3-((2R,3R)-2-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl )-4,4,4-trifluoro-3-methylbutanylamino)-4-methylphenyl)propionic acid 4-2
Figure PCTCN2022105987-appb-000253
Figure PCTCN2022105987-appb-000253
化合物3-1或3-2(30mg，0.056mmol)、三甲基环三硼氧烷(3M,189μL,0.565mmol)、1,1'-双二苯基膦二茂铁二氯化钯(8mg,0.012mmol)、磷酸钾(36mg，0.169mmol)混合于反应瓶中，加入二甲苯(2mL)，水(0.7mL)。氮气氛下，微波加热至150℃，搅拌反应0.5小时。冷却，浓缩后残余物用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18 150*30mm,5μm；流动相：水(含0.1％的三氟醋酸)，乙腈；15分钟梯度：65％-80％)纯化，得标题化合物4-1或4-2(13mg，产率：45％)。Compound 3-1 or 3-2 (30mg, 0.056mmol), trimethylboroxine (3M, 189μL, 0.565mmol), 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride ( 8mg, 0.012mmol), potassium phosphate (36mg, 0.169mmol) were mixed in a reaction flask, and xylene (2mL) and water (0.7mL) were added. Under nitrogen atmosphere, microwave heating to 150° C., stirring for 0.5 hours. After cooling, the residue was concentrated by high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% trifluoroacetic acid), acetonitrile; 15 minutes gradient: 65 %-80%) to obtain the title compound 4-1 or 4-2 (13 mg, yield: 45%).
MS m/z(ESI)：512.1[M-1]。MS m/z (ESI): 512.1 [M-1].
1H NMR(500MHz,DMSO-d 6)δ12.47-11.64(brs,1H),9.61(s,1H),7.51-7.45(m,1H),7.44-7.38(m,1H),7.30-7.24(m,1H),7.22-7.16(m,1H),7.11-7.06(m,1H),7.00-6.94(m,1H),4.00(d,1H),2.68-2.51(m,3H),2.25-2.18(m,1H),1.97(s,3H),0.99-0.88(m,1H),0.82(d,3H),0.52-0.42(m,1H),0.30-0.24(m,1H),0.23-0.14(m,1H),0.09-0.01(m,1H)。 1 H NMR (500MHz,DMSO-d 6 )δ12.47-11.64(brs,1H),9.61(s,1H),7.51-7.45(m,1H),7.44-7.38(m,1H),7.30-7.24 (m,1H),7.22-7.16(m,1H),7.11-7.06(m,1H),7.00-6.94(m,1H),4.00(d,1H),2.68-2.51(m,3H),2.25 -2.18(m,1H),1.97(s,3H),0.99-0.88(m,1H),0.82(d,3H),0.52-0.42(m,1H),0.30-0.24(m,1H),0.23 -0.14(m,1H),0.09-0.01(m,1H).
实施例5Example 5
(S)-3-(3-((2S,3R)-2-(苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)-4-氯苯基)-3-环丙基丙酸5-1(S)-3-(3-((2S,3R)-2-(Benzo[d][1,3]dioxolan-5-yl)-4,4,4-trifluoro-3 -Methylbutyramide)-4-chlorophenyl)-3-cyclopropylpropionic acid 5-1
或or
(S)-3-(3-((2R,3R)-2-(苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)-4-氯苯基)-3-环丙基丙酸5-2(S)-3-(3-((2R,3R)-2-(benzo[d][1,3]dioxolan-5-yl)-4,4,4-trifluoro-3 -Methylbutyramide)-4-chlorophenyl)-3-cyclopropylpropionic acid 5-2
Figure PCTCN2022105987-appb-000254
Figure PCTCN2022105987-appb-000254
采用实施例3的合成路线，将第一步的原料3a替换为4-溴-1,2-亚甲二氧基苯，制得标题化合物5-1或5-2(5mg,产率40％)。Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by 4-bromo-1,2-methylenedioxybenzene to obtain the title compound 5-1 or 5-2 (5mg, yield 40% ).
MS m/z(ESI)：498.1[M+1]。MS m/z (ESI): 498.1 [M+1].
1H NMR(500MHz,DMSO-d 6)δ12.04(s,1H),9.72(s,1H),7.50-7.31(m,2H),7.22-7.08(m,2H),7.00(d,1H),6.92(s,1H),6.02(d,2H),4.03(d,1H),2.68-2.56(m,2H),2.29-2.22(m,1H),0.99-0.90(m,1H),0.83(d,3H),0.53-0.47(m,1H),0.34-0.27(m,1H),0.27-0.21(m,1H),0.10-0.04(m,1H)。 1 H NMR (500MHz,DMSO-d 6 )δ12.04(s,1H),9.72(s,1H),7.50-7.31(m,2H),7.22-7.08(m,2H),7.00(d,1H ),6.92(s,1H),6.02(d,2H),4.03(d,1H),2.68-2.56(m,2H),2.29-2.22(m,1H),0.99-0.90(m,1H), 0.83(d,3H),0.53-0.47(m,1H),0.34-0.27(m,1H),0.27-0.21(m,1H),0.10-0.04(m,1H).
实施例6Example 6
3-(4-溴-3-((2S,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸6-13-(4-bromo-3-((2S,3R)-2-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-4,4, 4-Trifluoro-3-methylbutanamido)phenyl)-3-cyclopropylpropionic acid 6-1
或or
3-(4-溴-3-((2R,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸6-23-(4-bromo-3-((2R,3R)-2-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-4,4, 4-Trifluoro-3-methylbutanamido)phenyl)-3-cyclopropylpropionic acid 6-2
Figure PCTCN2022105987-appb-000255
Figure PCTCN2022105987-appb-000255
Figure PCTCN2022105987-appb-000256
Figure PCTCN2022105987-appb-000256
第一步first step
(4-溴-3-硝基苯基)(环丙基)甲基酮6b(4-Bromo-3-nitrophenyl)(cyclopropyl)methyl ketone 6b
(4-溴苯基)(环丙基)甲基酮6a(5g，22.2mmol)，称于反应瓶中，冷却至-20℃，加入发烟硝酸(7.81g，118mmol，95％)缓慢恢复至5-10℃搅拌反应2.5小时，将反应体系倒入冰水中，乙酸乙酯(50mL×3)萃取，合并有机相后用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩后残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题化合物6b(2.95g，产率：49％)。(4-Bromophenyl) (cyclopropyl) methyl ketone 6a (5g, 22.2mmol), weighed in a reaction flask, cooled to -20°C, added fuming nitric acid (7.81g, 118mmol, 95%) to recover slowly Stir the reaction at 5-10°C for 2.5 hours, pour the reaction system into ice water, extract with ethyl acetate (50mL×3), combine the organic phases, wash with saturated brine (30mL×2), dry over anhydrous sodium sulfate, and filter , and concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 6b (2.95 g, yield: 49%).
第二步second step
3-(4-溴-3-硝基苯基)-3-环丙基丙烯酸叔丁酯6c(顺反异构体混合物)tert-butyl 3-(4-bromo-3-nitrophenyl)-3-cyclopropylacrylate 6c (mixture of cis and trans isomers)
氮气氛下，将氢化钠(309mg，8.06mmol，纯度60％)分散于干燥的四氢呋喃(6mL)中，冷却至0℃，随后缓慢滴加二乙基膦酰基乙酸叔丁酯(1.82g,7.22mmol)的四氢呋喃(10mL)溶液，室温搅拌反应1小时。再次冷却至0℃，缓慢滴加化合物6b(1.5g，5.56mmol)的四氢呋喃(10mL)溶液，室温搅拌反应8小时，饱和氯化铵水溶液(30mL)淬灭反应，乙酸乙酯(50mL×3)萃取，合并有机相后饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩后残余物用硅胶柱色谱法以洗脱剂体系B 纯化得到标题化合物6c(顺反异构体混合物，1.62g，产率：79％)。Under a nitrogen atmosphere, sodium hydride (309mg, 8.06mmol, purity 60%) was dispersed in dry tetrahydrofuran (6mL), cooled to 0°C, and then tert-butyl diethylphosphonoacetate (1.82g, 7.22 mmol) in tetrahydrofuran (10 mL), stirred at room temperature for 1 hour. Cooled to 0°C again, slowly added compound 6b (1.5g, 5.56mmol) in tetrahydrofuran (10mL) dropwise, stirred at room temperature for 8 hours, quenched with saturated ammonium chloride aqueous solution (30mL), ethyl acetate (50mL×3 ) extraction, the combined organic phases were washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 6c (mixture of cis and trans isomers , 1.62g, yield: 79%).
第三步third step
(±)-3-(3-氨基-4-溴苯基)-3-环丙基丙酸叔丁酯6d(±)-tert-butyl 3-(3-amino-4-bromophenyl)-3-cyclopropylpropionate 6d
化合物6c(1.1g，2.98mmol)溶于乙酸乙酯(50mL)中，加入10％钯碳(233mg，0.119mmol)，氢气氛下，搅拌反应18小时。过滤浓缩后残余物用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18 150*30mm,5μm；流动相：水(含0.1％的碳酸氢铵)；乙腈；25分钟梯度：65％-80％)纯化，得到标题化合物6d(100mg，产率：10％)。Compound 6c (1.1 g, 2.98 mmol) was dissolved in ethyl acetate (50 mL), 10% palladium on carbon (233 mg, 0.119 mmol) was added, and the reaction was stirred for 18 hours under hydrogen atmosphere. After filtering and concentrating, the residue is subjected to high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% ammonium bicarbonate); acetonitrile; 25 minutes gradient: 65% -80%) was purified to obtain the title compound 6d (100 mg, yield: 10%).
第四步the fourth step
3-(4-溴-3-((2S,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸叔丁酯6e-1(非对映异构体混合物)3-(4-bromo-3-((2S,3R)-2-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-4,4, tert-butyl 4-trifluoro-3-methylbutanamido)phenyl)-3-cyclopropylpropanoate 6e-1 (mixture of diastereomers)
或or
3-(4-溴-3-((2R,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸叔丁酯6e-2(非对映异构体混合物)3-(4-bromo-3-((2R,3R)-2-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-4,4, tert-butyl 4-trifluoro-3-methylbutanamido)phenyl)-3-cyclopropylpropanoate 6e-2 (mixture of diastereoisomers)
将化合物3c(62mg，0.197mmol)溶于二氯甲烷(2mL)中，室温加入1-氯-N,N,2-三甲基丙烯胺(29mg，0.22mmol)，室温搅拌30分钟。加入吡啶(57mg，0.72mmol)和化合物6d(67mg，0.197mmol)的二氯甲烷(2mL)的溶液，室温搅拌30分钟。浓缩后残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题产物6e-1或6e-2(非对映异构体混合物，45mg，产率：36％)。Compound 3c (62mg, 0.197mmol) was dissolved in dichloromethane (2mL), 1-chloro-N,N,2-trimethylpropenylamine (29mg, 0.22mmol) was added at room temperature, and stirred at room temperature for 30 minutes. A solution of pyridine (57 mg, 0.72 mmol) and compound 6d (67 mg, 0.197 mmol) in dichloromethane (2 mL) was added, and stirred at room temperature for 30 minutes. The residue after concentration was purified by silica gel column chromatography with eluent system B to obtain the title product 6e-1 or 6e-2 (mixture of diastereomers, 45 mg, yield: 36%).
MS m/z(ESI)：634.3[M-1]。MS m/z (ESI): 634.3 [M-1].
第五步the fifth step
3-(4-溴-3-((2S,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸6-1(非对映异构体混合物)3-(4-bromo-3-((2S,3R)-2-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-4,4, 4-Trifluoro-3-methylbutanamido)phenyl)-3-cyclopropylpropionic acid 6-1 (mixture of diastereoisomers)
或or
3-(4-溴-3-((2R,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸6-2(非对映异构体混合物)3-(4-bromo-3-((2R,3R)-2-(2,2-difluorobenzo[d][1,3]dioxolan-5-yl)-4,4, 4-Trifluoro-3-methylbutanamido)phenyl)-3-cyclopropylpropionic acid 6-2 (mixture of diastereoisomers)
化合物6e-1或6e-2(55mg，0.086mmol)，溶于二氯甲烷(10mL)，室温加入1mL三氟醋酸，搅拌2小时。浓缩后残余物用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18 150*30mm,5μm；流动相：水(含0.1％的三氟醋酸)，乙腈；15分钟梯度：65％-80％)纯化，得到标题产物6-1或6-2(非对映异构体混合物，15mg,产率：30％)。Compound 6e-1 or 6e-2 (55 mg, 0.086 mmol) was dissolved in dichloromethane (10 mL), and 1 mL of trifluoroacetic acid was added at room temperature, and stirred for 2 hours. After concentration, the residue was subjected to high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% trifluoroacetic acid), acetonitrile; 15 minutes gradient: 65%- 80%) was purified to obtain the title product 6-1 or 6-2 (mixture of diastereomers, 15 mg, yield: 30%).
MS m/z(ESI)：578.0[M+1]。MS m/z (ESI): 578.0 [M+1].
1H NMR(500MHz,CD 3OD)δ7.47(d,1H),7.42-7.32(m,2H),7.30-7.24(m,1H),7.23-7.18(m,1H),7.12-7.02(m,1H),3.99(d,1H),3.44-3.32(m,1H),2.72-2.61(m,1H),2.61-2.52(m,1H),2.41-2.22(m,1H),1.03-0.95(m,1H),0.91(d,3H),0.61-0.49(m,1H),0.42-0.35(m,1H),0.35-0.28(m,1H),0.17-0.04(m,1H)。 1 H NMR (500MHz, CD 3 OD) δ7.47(d,1H),7.42-7.32(m,2H),7.30-7.24(m,1H),7.23-7.18(m,1H),7.12-7.02( m,1H),3.99(d,1H),3.44-3.32(m,1H),2.72-2.61(m,1H),2.61-2.52(m,1H),2.41-2.22(m,1H),1.03- 0.95(m,1H),0.91(d,3H),0.61-0.49(m,1H),0.42-0.35(m,1H),0.35-0.28(m,1H),0.17-0.04(m,1H).
实施例7Example 7
(S)-3-(4-氯-3-((2S,3R)-2-(2,2-二甲基苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸7-1(S)-3-(4-chloro-3-((2S,3R)-2-(2,2-dimethylbenzo[d][1,3]dioxolan-5-yl) -4,4,4-Trifluoro-3-methylbutanamido)phenyl)-3-cyclopropylpropionic acid 7-1
或or
(S)-3-(4-氯-3-((2R,3R)-2-(2,2-二甲基苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸7-2(S)-3-(4-chloro-3-((2R,3R)-2-(2,2-dimethylbenzo[d][1,3]dioxolan-5-yl) -4,4,4-Trifluoro-3-methylbutanamido)phenyl)-3-cyclopropylpropionic acid 7-2
Figure PCTCN2022105987-appb-000257
Figure PCTCN2022105987-appb-000257
采用实施例3的合成路线，将第一步的原料3a替换为化合物5-溴-2,2-二甲基苯并[d][1,3]二氧戊环，制得标题化合物7-1或7-2(20mg,产率：45％)。Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 5-bromo-2,2-dimethylbenzo[d][1,3]dioxolane to obtain the title compound 7- 1 or 7-2 (20 mg, yield: 45%).
MS m/z(ESI)：526.1[M+1]。MS m/z (ESI): 526.1 [M+1].
1H NMR(500MHz,CD 3OD)δ7.54(s,1H),7.33(d,1H),7.10(d,1H),6.88(s,1H),6.87(d,1H),6.73(d,1H),3.88(d,1H),3.30-3.22(m,1H),2.79-2.65(m,2H),2.38-2.29(m,1H),1.67(s,3H),1.66(s,3H),1.08-0.99(m,1H),0.93(d,3H),0.64-0.56(m,1H),0.46-0.38(m,1H),0.36-0.29(m,1H),0.20-0.12(m,1H)。 1 H NMR (500MHz, CD 3 OD) δ7.54(s, 1H), 7.33(d, 1H), 7.10(d, 1H), 6.88(s, 1H), 6.87(d, 1H), 6.73(d ,1H),3.88(d,1H),3.30-3.22(m,1H),2.79-2.65(m,2H),2.38-2.29(m,1H),1.67(s,3H),1.66(s,3H ),1.08-0.99(m,1H),0.93(d,3H),0.64-0.56(m,1H),0.46-0.38(m,1H),0.36-0.29(m,1H),0.20-0.12(m ,1H).
实施例8Example 8
(S)-3-(3-((2S,3R)-2-(苯并[d][1,3]二氧杂戊环-5-基-2,2-d 2)-4,4,4-三氟-3-甲基丁酰胺基)-4-氯苯基)-3-环丙基丙酸8-1 (S)-3-(3-((2S,3R)-2-(benzo[d][1,3]dioxolan-5-yl-2,2-d 2 )-4,4 ,4-Trifluoro-3-methylbutanylamino)-4-chlorophenyl)-3-cyclopropylpropionic acid 8-1
或or
(S)-3-(3-((2R,3R)-2-(苯并[d][1,3]二氧杂戊环-5-基-2,2-d 2)-4,4,4-三氟-3-甲基丁酰胺基)-4-氯苯基)-3-环丙基丙酸8-2 (S)-3-(3-((2R,3R)-2-(benzo[d][1,3]dioxolan-5-yl-2,2-d 2 )-4,4 ,4-Trifluoro-3-methylbutanylamino)-4-chlorophenyl)-3-cyclopropylpropionic acid 8-2
Figure PCTCN2022105987-appb-000258
Figure PCTCN2022105987-appb-000258
采用实施例3的合成路线，将第一步的原料3a替换为化合物5-溴苯并[d][1,3]二氧戊环-2,2-d 2(可由化合物4-溴-1,2-亚甲二氧基苯与氘代二溴甲烷氢氘置换而得)制得标题化合物8-1或8-2(35mg,产率：67％)。 Using the synthetic route of Example 3, the raw material 3a of the first step is replaced by compound 5-bromobenzo[d][1,3]dioxolane-2,2-d 2 (can be obtained from compound 4-bromo-1 , 2-methylenedioxybenzene and deuterated dibromomethane hydrogen deuterium replacement) to obtain the title compound 8-1 or 8-2 (35 mg, yield: 67%).
MS m/z(ESI)：500.1[M+1]。MS m/z (ESI): 500.1 [M+1].
1H NMR(500MHz,CD 3OD)δ7.53(s,1H),7.33(d,1H),7.10(d,1H),6.99(s,1H),6.93(d,1H),6.82(d,1H),3.91(d,1H),3.31-3.27(m,1H),2.79-2.64(m,2H),2.37-2.29(m,1H),1.05-1.01(m,1H),0.92(d,3H),0.63-0.56(m,1H),0.45-0.38(m,1H),0.35-0.29(m,1H),0.18-0.11(m,1H)。 1 H NMR (500MHz, CD 3 OD) δ7.53(s, 1H), 7.33(d, 1H), 7.10(d, 1H), 6.99(s, 1H), 6.93(d, 1H), 6.82(d ,1H),3.91(d,1H),3.31-3.27(m,1H),2.79-2.64(m,2H),2.37-2.29(m,1H),1.05-1.01(m,1H),0.92(d ,3H),0.63-0.56(m,1H),0.45-0.38(m,1H),0.35-0.29(m,1H),0.18-0.11(m,1H).
实施例9Example 9
(S)-3-(3-((2R,3R)-2-(苯并[b]噻吩-2-基)-4,4,4-三氟-3-甲基丁酰胺基)-4-氯苯基)-3-环丙基丙酸9-1(S)-3-(3-((2R,3R)-2-(benzo[b]thiophen-2-yl)-4,4,4-trifluoro-3-methylbutanylamino)-4 -Chlorophenyl)-3-cyclopropylpropionic acid 9-1
或or
(S)-3-(3-((2S,3R)-2-(苯并[b]噻吩-2-基)-4,4,4-三氟-3-甲基丁酰胺基)-4-氯苯基)-3-环丙基丙酸9-2(S)-3-(3-((2S,3R)-2-(Benzo[b]thiophen-2-yl)-4,4,4-trifluoro-3-methylbutanylamino)-4 -Chlorophenyl)-3-cyclopropylpropionic acid 9-2
Figure PCTCN2022105987-appb-000259
Figure PCTCN2022105987-appb-000259
采用实施例3的合成路线，将第一步的原料3a替换为化合物2-溴苯并[b]噻吩，制得标题化合物9-1或9-2(40mg，产率：40％)。Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 2-bromobenzo[b]thiophene to obtain the title compound 9-1 or 9-2 (40 mg, yield: 40%).
MS m/z(ESI)：510.4[M+1]。MS m/z (ESI): 510.4 [M+1].
1H NMR(500MHz,DMSO-d 6)δ10.02(s,1H),7.95(d,1H),7.86(d,1H),7.50(d,1H),7.44(s,1H),7.41-7.33(m,3H),7.13(dd,1H),4.62(d,1H),2.71-2.53(m,3H),2.30-2.23(m,1H),0.98(d,3H),0.96-0.91(m,1H),0.53-0.47(m,1H),0.33-0.21(m,2H),0.08(m,1H)。 1 H NMR (500MHz,DMSO-d 6 )δ10.02(s,1H),7.95(d,1H),7.86(d,1H),7.50(d,1H),7.44(s,1H),7.41- 7.33(m,3H),7.13(dd,1H),4.62(d,1H),2.71-2.53(m,3H),2.30-2.23(m,1H),0.98(d,3H),0.96-0.91( m, 1H), 0.53-0.47(m, 1H), 0.33-0.21(m, 2H), 0.08(m, 1H).
实施例10Example 10
(S)-3-(4-氯-3-((2R,3R)-2-(5-氯噻吩-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸10-1(S)-3-(4-Chloro-3-((2R,3R)-2-(5-chlorothien-2-yl)-4,4,4-trifluoro-3-methylbutanylamino) Phenyl)-3-cyclopropylpropionic acid 10-1
或or
(S)-3-(4-氯-3-((2S,3R)-2-(5-氯噻吩-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸10-2(S)-3-(4-Chloro-3-((2S,3R)-2-(5-chlorothien-2-yl)-4,4,4-trifluoro-3-methylbutanylamino) Phenyl)-3-cyclopropylpropionic acid 10-2
Figure PCTCN2022105987-appb-000260
Figure PCTCN2022105987-appb-000260
采用实施例3的合成路线，将第一步的原料3a替换为化合物2-溴-5-氯噻吩，制得标题化合物10-1或10-2(15mg，产率：32％)。Using the synthesis route of Example 3, the raw material 3a of the first step was replaced by the compound 2-bromo-5-chlorothiophene to obtain the title compound 10-1 or 10-2 (15 mg, yield: 32%).
MS m/z(ESI)：492.2[M-1]。MS m/z (ESI): 492.2 [M-1].
1H NMR(500MHz,CD 3OD)δ7.58(d,1H),7.37(d,1H),7.14(dd,1H),6.95(d,1H),6.91(d,1H),4.32(d,1H),3.21-3.12(m,1H),2.80-2.66(m,2H),2.40-2.32(m,1H),1.09-1.01(m,1H),1.04(d,3H),0.65-0.58(m,1H),0.48-0.40(m,1H),0.37-0.30(m,1H),0.21-0.13(m,1H)。 1 H NMR (500MHz, CD 3 OD) δ7.58(d,1H),7.37(d,1H),7.14(dd,1H),6.95(d,1H),6.91(d,1H),4.32(d ,1H),3.21-3.12(m,1H),2.80-2.66(m,2H),2.40-2.32(m,1H),1.09-1.01(m,1H),1.04(d,3H),0.65-0.58 (m,1H),0.48-0.40(m,1H),0.37-0.30(m,1H),0.21-0.13(m,1H).
实施例11Example 11
(S)-3-(4-氯-3-((2S,3R)-4,4,4-三氟-3-甲基-2-(1-甲基-1H-吲哚-6-基)丁酰胺基)苯基)-3-环丙基丙酸11-1(S)-3-(4-chloro-3-((2S,3R)-4,4,4-trifluoro-3-methyl-2-(1-methyl-1H-indol-6-yl )Butylamino)phenyl)-3-cyclopropylpropionic acid 11-1
或or
(S)-3-(4-氯-3-((2R,3R)-4,4,4-三氟-3-甲基-2-(1-甲基-1H-吲哚-6-基)丁酰胺基)苯基)-3-环丙基丙酸11-2(S)-3-(4-chloro-3-((2R,3R)-4,4,4-trifluoro-3-methyl-2-(1-methyl-1H-indol-6-yl )Butylamino)phenyl)-3-cyclopropylpropionic acid 11-2
Figure PCTCN2022105987-appb-000261
Figure PCTCN2022105987-appb-000261
第一步first step
(3R)-4,4,4-三氟-3-甲基-2-(1-甲基-1H-吲哚-6-基)丁酸苄酯11b(非对映异构体混合物)Benzyl (3R)-4,4,4-trifluoro-3-methyl-2-(1-methyl-1H-indol-6-yl)butanoate 11b (mixture of diastereomers)
将化合物1b(120mg，0.487mmol)、6-溴-1-甲基-1H-吲哚11a(102mg，0.49mmol)，醋酸钯(11mg，0.049mmol)以及2-(2-二环己基膦苯基)-N,N-二甲基苯胺(29mg，0.073mmol)加入反应瓶中，氮气氛下，加入干燥的甲苯(4mL)，搅拌溶解10min后用干冰丙酮浴冷却至-20℃，加入双三甲基硅基氨基锂的甲苯溶液(1mL，1M)，低温搅拌15分钟后加热至85℃搅拌反应5小时。浓缩后残余物用硅胶柱色 谱法以洗脱剂体系B纯化得到标题产物11b(非对映异构体混合物，146mg，产率：80％)。Compound 1b (120mg, 0.487mmol), 6-bromo-1-methyl-1H-indole 11a (102mg, 0.49mmol), palladium acetate (11mg, 0.049mmol) and 2-(2-dicyclohexylphosphinephenyl Base)-N,N-dimethylaniline (29mg, 0.073mmol) was added to the reaction flask, under nitrogen atmosphere, dry toluene (4mL) was added, stirred and dissolved for 10min, cooled to -20°C with dry ice acetone bath, added bis A toluene solution of lithium trimethylsilylamide (1 mL, 1 M) was stirred at low temperature for 15 minutes, then heated to 85° C. and stirred for 5 hours. The residue after concentration was purified by silica gel column chromatography with eluent system B to obtain the title product 11b (mixture of diastereomers, 146 mg, yield: 80%).
第二步second step
(3R)-4,4,4-三氟-3-甲基-2-(1-甲基-1H-吲哚-6-基)丁酸11c(非对映异构体混合物)(3R)-4,4,4-Trifluoro-3-methyl-2-(1-methyl-1H-indol-6-yl)butanoic acid 11c (mixture of diastereomers)
化合物11b(146mg，0.389mmol)溶于水(1mL)和二氧六环(5mL)中，加入氢氧化钠(78mg，1.95mmol)，60℃搅拌反应10小时。冷却至室温，浓缩，加入10mL水，二氯甲烷(30mL×3)洗涤，水相用1M的盐酸酸化至pH约为3，二氯甲烷萃取(30mL×3)。合并有机相，无水硫酸钠干燥，过滤后减压浓缩得到粗产物11c(非对映异构体混合物，102mg)。Compound 11b (146mg, 0.389mmol) was dissolved in water (1mL) and dioxane (5mL), sodium hydroxide (78mg, 1.95mmol) was added, and the reaction was stirred at 60°C for 10 hours. Cool to room temperature, concentrate, add 10 mL of water, wash with dichloromethane (30 mL×3), acidify the aqueous phase with 1M hydrochloric acid to pH about 3, and extract with dichloromethane (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product 11c (mixture of diastereomers, 102 mg).
第三步third step
(S)-3-(4-氯-3-((2S,3R)-4,4,4-三氟-3-甲基-2-(1-甲基-1H-吲哚-6-基)丁酰胺基)苯基)-3-环丙基丙酸11-1(S)-3-(4-chloro-3-((2S,3R)-4,4,4-trifluoro-3-methyl-2-(1-methyl-1H-indol-6-yl )Butylamino)phenyl)-3-cyclopropylpropionic acid 11-1
或or
(S)-3-(4-氯-3-((2R,3R)-4,4,4-三氟-3-甲基-2-(1-甲基-1H-吲哚-6-基)丁酰胺基)苯基)-3-环丙基丙酸11-2(S)-3-(4-chloro-3-((2R,3R)-4,4,4-trifluoro-3-methyl-2-(1-methyl-1H-indol-6-yl )Butylamino)phenyl)-3-cyclopropylpropionic acid 11-2
化合物11c(50mg，0.175mmol)溶于二氯甲烷(3mL)，室温加入1-氯-N,N,2-三甲基丙烯胺(23mg，0.175mmol)，室温搅拌30分钟。加入吡啶(28mg，0.35mmol)和(S)-3-(3-氨基-4-氯苯基)-3-环丙基丙酸11d(42mg，0.175mmol，可由化合物1f经三氟乙酸脱叔丁酯而得)的二氯甲烷(2mL)溶液，室温搅拌1小时。浓缩后残余物用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18 150*30mm,5μm；流动相：水(含0.1％的三氟醋酸)，乙腈；15分钟梯度：65％-80％)纯化，得标题化合物11-1或11-2(55mg，产率：62％)。Compound 11c (50 mg, 0.175 mmol) was dissolved in dichloromethane (3 mL), 1-chloro-N,N,2-trimethylpropenylamine (23 mg, 0.175 mmol) was added at room temperature, and stirred at room temperature for 30 minutes. Add pyridine (28 mg, 0.35 mmol) and (S)-3-(3-amino-4-chlorophenyl)-3-cyclopropylpropionic acid 11d (42 mg, 0.175 mmol, which can be detertiary from compound 1f via trifluoroacetic acid butyl ester) in dichloromethane (2 mL) and stirred at room temperature for 1 hour. After concentration, the residue was subjected to high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% trifluoroacetic acid), acetonitrile; 15 minutes gradient: 65%- 80%) was purified to obtain the title compound 11-1 or 11-2 (55 mg, yield: 62%).
MS m/z(ESI)：507.1[M-1]。MS m/z (ESI): 507.1 [M-1].
1H NMR(500MHz,CD 3OD)δ7.57(d,1H),7.53(s,1H),7.49(s,1H),7.30(d,1H),7.19(s,1H),7.15(d,1H),7.08(d,1H),6.44(s,1H),4.07(d,1H),3.84(s,3H),3.46-3.38(m,1H),2.75-2.60(m,2H),2.37-2.29(m,1H),1.06-0.97(m,1H),0.91(d,3H),0.63-0.55(m,1H),0.44-0.36(m,1H),0.35-0.29(m,1H),0.17-0.10(m,1H)。 1 H NMR (500MHz, CD 3 OD) δ7.57(d,1H),7.53(s,1H),7.49(s,1H),7.30(d,1H),7.19(s,1H),7.15(d ,1H),7.08(d,1H),6.44(s,1H),4.07(d,1H),3.84(s,3H),3.46-3.38(m,1H),2.75-2.60(m,2H), 2.37-2.29(m,1H),1.06-0.97(m,1H),0.91(d,3H),0.63-0.55(m,1H),0.44-0.36(m,1H),0.35-0.29(m,1H ), 0.17-0.10(m,1H).
实施例12Example 12
(S)-3-(4-氯-3-((2S,3R)-4,4,4-三氟-3-甲基-2-(1-甲基-1H-吲唑-6-基)丁酰胺基)苯基)-3-环丙基丙酸12-1(S)-3-(4-chloro-3-((2S,3R)-4,4,4-trifluoro-3-methyl-2-(1-methyl-1H-indazol-6-yl )Butylamino)phenyl)-3-cyclopropylpropionic acid 12-1
或or
(S)-3-(4-氯-3-((2R,3R)-4,4,4-三氟-3-甲基-2-(1-甲基-1H-吲唑-6-基)丁酰胺基)苯基)-3-环丙基丙酸12-2(S)-3-(4-chloro-3-((2R,3R)-4,4,4-trifluoro-3-methyl-2-(1-methyl-1H-indazol-6-yl )Butylamino)phenyl)-3-cyclopropylpropionic acid 12-2
Figure PCTCN2022105987-appb-000262
Figure PCTCN2022105987-appb-000262
采用实施例3的合成路线，将第一步的原料3a替换为化合物6-溴-1-甲基-1H-吲唑，制得标题化合物12-1或12-2(25mg，产率：36％)。Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 6-bromo-1-methyl-1H-indazole to obtain the title compound 12-1 or 12-2 (25 mg, yield: 36 %).
MS m/z(ESI)：506.1[M-1]。MS m/z (ESI): 506.1 [M-1].
1H NMR(500MHz,DMSO-d 6)δ9.84(s,1H),8.02(s,1H),7.74(d,1H),7.69(s,1H),7.42(d,1H),7.34(d,1H),7.24(d,1H),7.08(dd,1H),4.24(d,1H),4.04(s,3H),3.53-3.43(m,1H),2.67-2.53(m,2H),2.27-2.20(m,1H),0.97-0.89(m,1H),0.82(d,3H),0.51-0.44(m,1H),0.31-0.19(m,2H),0.08-0.02(m,1H)。 1 H NMR (500MHz,DMSO-d 6 )δ9.84(s,1H),8.02(s,1H),7.74(d,1H),7.69(s,1H),7.42(d,1H),7.34( d,1H),7.24(d,1H),7.08(dd,1H),4.24(d,1H),4.04(s,3H),3.53-3.43(m,1H),2.67-2.53(m,2H) ,2.27-2.20(m,1H),0.97-0.89(m,1H),0.82(d,3H),0.51-0.44(m,1H),0.31-0.19(m,2H),0.08-0.02(m, 1H).
实施例13Example 13
(S)-3-(4-氯-3-((2S,3R)-4,4,4-三氟-3-甲基-2-(1-甲基-1H-吲唑-5-基)丁酰胺基)苯基)-3-环丙基丙酸13-1(S)-3-(4-chloro-3-((2S,3R)-4,4,4-trifluoro-3-methyl-2-(1-methyl-1H-indazol-5-yl )Butylamino)phenyl)-3-cyclopropylpropionic acid 13-1
或or
(S)-3-(4-氯-3-((2R,3R)-4,4,4-三氟-3-甲基-2-(1-甲基-1H-吲唑-5-基)丁酰胺基)苯基)-3-环丙基丙酸13-2(S)-3-(4-chloro-3-((2R,3R)-4,4,4-trifluoro-3-methyl-2-(1-methyl-1H-indazol-5-yl )Butylamino)phenyl)-3-cyclopropylpropionic acid 13-2
Figure PCTCN2022105987-appb-000263
Figure PCTCN2022105987-appb-000263
采用实施例3的合成路线，将第一步的原料3a替换为化合物5-溴-1-甲基-1H-吲唑，制得标题化合物13-1或13-2(40mg，产率：27％)。Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 5-bromo-1-methyl-1H-indazole to obtain the title compound 13-1 or 13-2 (40mg, yield: 27 %).
MS m/z(ESI)：506.1[M-1]。MS m/z (ESI): 506.1 [M-1].
1H NMR(500MHz,DMSO-d 6)δ9.79(s,1H),8.07(s,1H),7.82(s,1H),7.64(d,1H),7.49(d,1H),7.43(s,1H),7.34(d,1H),7.08(d,1H)4.21(d,1H),4.04(s,3H),3.46-3.38(m,1H),2.67-2.54(m,2H),2.28-2.20(m,1H),0.97-0.89(m,1H),0.79(d,3H),0.52-0.45(m,1H),0.32-0.19(m,2H),0.09-0.02(m,1H)。 1 H NMR (500MHz,DMSO-d 6 )δ9.79(s,1H),8.07(s,1H),7.82(s,1H),7.64(d,1H),7.49(d,1H),7.43( s,1H),7.34(d,1H),7.08(d,1H),4.21(d,1H),4.04(s,3H),3.46-3.38(m,1H),2.67-2.54(m,2H), 2.28-2.20(m,1H),0.97-0.89(m,1H),0.79(d,3H),0.52-0.45(m,1H),0.32-0.19(m,2H),0.09-0.02(m,1H ).
实施例14Example 14
(S)-3-(4-氯-3-((2S,3R)-2-(5-氯吡啶-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸14-1(S)-3-(4-chloro-3-((2S,3R)-2-(5-chloropyridin-2-yl)-4,4,4-trifluoro-3-methylbutanylamino) Phenyl)-3-cyclopropylpropionic acid 14-1
或or
(S)-3-(4-氯-3-((2R,3R)-2-(5-氯吡啶-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸14-2(S)-3-(4-chloro-3-((2R,3R)-2-(5-chloropyridin-2-yl)-4,4,4-trifluoro-3-methylbutanylamino) Phenyl)-3-cyclopropylpropionic acid 14-2
Figure PCTCN2022105987-appb-000264
Figure PCTCN2022105987-appb-000264
采用实施例3的合成路线，将第一步的原料3a替换为化合物2-溴-5-氯吡啶，制得标题化合物14-1或14-2(18mg，产率：22％)。Using the synthesis route of Example 3, the raw material 3a of the first step was replaced by the compound 2-bromo-5-chloropyridine to obtain the title compound 14-1 or 14-2 (18 mg, yield: 22%).
MS m/z(ESI)：489.1[M+1]。MS m/z (ESI): 489.1 [M+1].
1H NMR(500MHz,DMSO-d 6)δ9.94(s,1H),8.67(d,1H),8.00(dd,1H),7.64(d,1H),7.44(d,1H),7.36(d,1H),7.11(dd,1H),4.33(d,1H),3.54-3.42(m,1H),2.65(dd,1H),2.58(dd,1H),2.29-2.22(m,1H),0.99-0.90(m,1H),0.86(d,3H),0.53-0.46(m,1H),0.33-0.21(m,2H),0.10-0.04(m,1H)。 1 H NMR (500MHz,DMSO-d 6 )δ9.94(s,1H),8.67(d,1H),8.00(dd,1H),7.64(d,1H),7.44(d,1H),7.36( d,1H),7.11(dd,1H),4.33(d,1H),3.54-3.42(m,1H),2.65(dd,1H),2.58(dd,1H),2.29-2.22(m,1H) ,0.99-0.90(m,1H),0.86(d,3H),0.53-0.46(m,1H),0.33-0.21(m,2H),0.10-0.04(m,1H).
实施例15Example 15
(S)-3-(4-氯-3-((2S,3R)-2-(5-氯嘧啶-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸15-1(S)-3-(4-Chloro-3-((2S,3R)-2-(5-chloropyrimidin-2-yl)-4,4,4-trifluoro-3-methylbutanylamino) Phenyl)-3-cyclopropylpropionic acid 15-1
或or
(S)-3-(4-氯-3-((2R,3R)-2-(5-氯嘧啶-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸15-2(S)-3-(4-Chloro-3-((2R,3R)-2-(5-chloropyrimidin-2-yl)-4,4,4-trifluoro-3-methylbutanylamino) Phenyl)-3-cyclopropylpropionic acid 15-2
Figure PCTCN2022105987-appb-000265
Figure PCTCN2022105987-appb-000265
采用实施例3的合成路线，将第一步的原料3a替换为化合物2-溴-5-氯嘧啶，制得标题化合物15-1或15-2(19mg，产率：26％)。Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 2-bromo-5-chloropyrimidine to obtain the title compound 15-1 or 15-2 (19 mg, yield: 26%).
MS m/z(ESI)：490.1[M+1]。MS m/z (ESI): 490.1 [M+1].
1H NMR(500MHz,DMSO-d 6)δ9.95(s,1H),9.02(s,2H),7.43(s,1H),7.36(d,1H),7.12(d,1H),4.48(d,1H),3.54-3.46(m,1H),2.70-2.55(m,2H),2.29-2.22(m,1H),0.99(d,3H),0.88-0.84(m,1H),0.54-0.46(m,1H),0.35-0.21(m,2H),0.10-0.04(m,1H)。 1 H NMR (500MHz,DMSO-d 6 )δ9.95(s,1H),9.02(s,2H),7.43(s,1H),7.36(d,1H),7.12(d,1H),4.48( d,1H),3.54-3.46(m,1H),2.70-2.55(m,2H),2.29-2.22(m,1H),0.99(d,3H),0.88-0.84(m,1H),0.54- 0.46(m,1H),0.35-0.21(m,2H),0.10-0.04(m,1H).
实施例16Example 16
(S)-3-(3-((2S,3R)-2-([1,1'-联苯基]-4-基)-4,4,4-三氟-3-甲基丁酰胺基)-4-氯苯基)-3-环丙基丙酸16-1(S)-3-(3-((2S,3R)-2-([1,1'-biphenyl]-4-yl)-4,4,4-trifluoro-3-methylbutanamide Base)-4-chlorophenyl)-3-cyclopropylpropionic acid 16-1
或or
(S)-3-(3-((2R,3R)-2-([1,1'-联苯基]-4-基)-4,4,4-三氟-3-甲基丁酰胺基)-4-氯苯基)-3-环丙基丙酸16-2(S)-3-(3-((2R,3R)-2-([1,1'-biphenyl]-4-yl)-4,4,4-trifluoro-3-methylbutanamide Base)-4-chlorophenyl)-3-cyclopropylpropionic acid 16-2
Figure PCTCN2022105987-appb-000266
Figure PCTCN2022105987-appb-000266
采用实施例3的合成路线，将第一步的原料3a替换为化合物4-溴-1,1'-联苯，制得标题化合物16-1或16-2(59mg，产率：46％)。Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 4-bromo-1,1'-biphenyl to obtain the title compound 16-1 or 16-2 (59 mg, yield: 46%) .
MS m/z(ESI)：530.2[M+1]。MS m/z (ESI): 530.2 [M+1].
1H NMR(500MHz,DMSO-d 6)δ12.02(s,1H),9.81(s,1H),7.70-7.65(m,3H),7.56-7.52(m,2H),7.48-7.43(m,3H),7.37-7.33(m,2H),7.08(dd,1H),4.17(d,1H),3.44-3.35(m,1H),2.63(dd,1H),2.55(dd,1H),2.27-2.20(m,1H),0.98-0.89(m,1H),0.84(d,3H),0.51-0.45(m,1H),0.31-0.19(m,2H),0.08-0.02(m,1H)。 1 H NMR (500MHz,DMSO-d 6 )δ12.02(s,1H),9.81(s,1H),7.70-7.65(m,3H),7.56-7.52(m,2H),7.48-7.43(m ,3H),7.37-7.33(m,2H),7.08(dd,1H),4.17(d,1H),3.44-3.35(m,1H),2.63(dd,1H),2.55(dd,1H), 2.27-2.20(m,1H),0.98-0.89(m,1H),0.84(d,3H),0.51-0.45(m,1H),0.31-0.19(m,2H),0.08-0.02(m,1H ).
实施例17Example 17
(S)-3-(3-((2S,3R)-2-(4-(2H-1,2,3-***-2-基)苯基)-4,4,4-三氟-3-甲基丁酰胺基)-4-氯苯基)-3-环丙基丙酸17-1(S)-3-(3-((2S,3R)-2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-4,4,4-trifluoro- 3-methylbutyrylamino)-4-chlorophenyl)-3-cyclopropylpropionic acid 17-1
或or
(S)-3-(3-((2R,3R)-2-(4-(2H-1,2,3-***-2-基)苯基)-4,4,4-三氟-3-甲基丁酰胺基)-4-氯苯基)-3-环丙基丙酸17-2(S)-3-(3-((2R,3R)-2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-4,4,4-trifluoro- 3-methylbutyrylamino)-4-chlorophenyl)-3-cyclopropylpropionic acid 17-2
Figure PCTCN2022105987-appb-000267
Figure PCTCN2022105987-appb-000267
采用实施例3的合成路线，将第一步的原料3a替换为化合物2-(4-溴苯基)-2H-1,2,3-***，制得标题化合物17-1或17-2(39mg，产率：42％)。Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 2-(4-bromophenyl)-2H-1,2,3-triazole to obtain the title compound 17-1 or 17-2 (39mg, Yield: 42%).
MS m/z(ESI)：521.1[M+1]。MS m/z (ESI): 521.1 [M+1].
1H NMR(500MHz,DMSO-d 6)δ9.89(s,1H),8.14(s,2H),8.07-8.02(m,2H),7.68-7.62(m,2H),7.44(d,1H),7.36(d,1H),7.11(dd,1H),4.21(d,1H),3.44-3.35(m,1H),2.68-2.54(m,2H),2.29-2.21(m,1H),0.99-0.91(m,1H),0.85(d,3H),0.53-0.46(m,1H),0.33-0.20(m,2H),0.10-0.07(m,1H)。 1 H NMR (500MHz,DMSO-d 6 )δ9.89(s,1H),8.14(s,2H),8.07-8.02(m,2H),7.68-7.62(m,2H),7.44(d,1H ),7.36(d,1H),7.11(dd,1H),4.21(d,1H),3.44-3.35(m,1H),2.68-2.54(m,2H),2.29-2.21(m,1H), 0.99-0.91(m,1H),0.85(d,3H),0.53-0.46(m,1H),0.33-0.20(m,2H),0.10-0.07(m,1H).
实施例18Example 18
(S)-3-(4-氯-3-((2S,3R)-2-(8-氯萘-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸18-1(S)-3-(4-chloro-3-((2S,3R)-2-(8-chloronaphthalen-2-yl)-4,4,4-trifluoro-3-methylbutanylamino) Phenyl)-3-cyclopropylpropionic acid 18-1
或or
(S)-3-(4-氯-3-((2R,3R)-2-(8-氯萘-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸18-2(S)-3-(4-chloro-3-((2R,3R)-2-(8-chloronaphthalen-2-yl)-4,4,4-trifluoro-3-methylbutanylamino) Phenyl)-3-cyclopropylpropionic acid 18-2
Figure PCTCN2022105987-appb-000268
Figure PCTCN2022105987-appb-000268
采用实施例3的合成路线，将第一步的原料3a替换为化合物7-溴-1-氯萘，制得标题化合物18-1或18-2(50mg，产率：43％)。Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 7-bromo-1-chloronaphthalene to obtain the title compound 18-1 or 18-2 (50 mg, yield: 43%).
MS m/z(ESI)：536.0[M-1]。MS m/z (ESI): 536.0 [M-1].
1H NMR(500MHz,DMSO-d 6)δ12.02(s,1H),9.97(s,1H),8.31(s,1H),8.06(d,1H),7.96(d,1H),7.77-7.72(m,2H),7.53(dd,1H),7.41(d,1H),7.35(d,1H),7.10(d,1H),4.40(d,1H),3.55-3.46(m,1H),2.64(dd,1H),2.57(dd,1H),2.28-2.20(m,1H),0.98-0.90(m,1H),0.83(d,3H),0.52-0.45(m,1H),0.32-0.19(m,2H),0.08-0.02(m,1H)。 1 H NMR (500MHz,DMSO-d 6 )δ12.02(s,1H),9.97(s,1H),8.31(s,1H),8.06(d,1H),7.96(d,1H),7.77- 7.72(m,2H),7.53(dd,1H),7.41(d,1H),7.35(d,1H),7.10(d,1H),4.40(d,1H),3.55-3.46(m,1H) ,2.64(dd,1H),2.57(dd,1H),2.28-2.20(m,1H),0.98-0.90(m,1H),0.83(d,3H),0.52-0.45(m,1H),0.32 -0.19(m,2H),0.08-0.02(m,1H).
实施例19Example 19
(S)-3-(4-氯-3-((2S,3R)-2-(7-氯萘-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸19-1(S)-3-(4-chloro-3-((2S,3R)-2-(7-chloronaphthalen-2-yl)-4,4,4-trifluoro-3-methylbutanylamino) Phenyl)-3-cyclopropylpropionic acid 19-1
或or
(S)-3-(4-氯-3-((2R,3R)-2-(7-氯萘-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸19-2(S)-3-(4-chloro-3-((2R,3R)-2-(7-chloronaphthalen-2-yl)-4,4,4-trifluoro-3-methylbutanylamino) Phenyl)-3-cyclopropylpropionic acid 19-2
Figure PCTCN2022105987-appb-000269
Figure PCTCN2022105987-appb-000269
采用实施例3的合成路线，将第一步的原料3a替换为化合物2-溴-7-氯萘，制得标题化合物19-1或19-2(40mg，产率：36％)。Using the synthetic route of Example 3, the raw material 3a of the first step was replaced with compound 2-bromo-7-chloronaphthalene to obtain the title compound 19-1 or 19-2 (40 mg, yield: 36%).
MS m/z(ESI)：538.2[M+1]。MS m/z (ESI): 538.2 [M+1].
1H NMR(500MHz,CDCl 3)δ8.17(s,1H),7.89-7.68(m,4H),7.54(d,1H),7.45(d,1H),7.20(d,1H),6.90(s,1H),3.89(d,1H),3.60-3.49(m,1H),2.88-2.56(m,2H),2.40-2.25(m,1H),0.98(d,3H),0.94-0.82(m,1H),0.62-0.47(m,1H),0.46-0.34(m,1H),0.32-0.18(m,1H),0.15-0.04(m,1H)。 1 H NMR (500MHz, CDCl 3 )δ8.17(s,1H),7.89-7.68(m,4H),7.54(d,1H),7.45(d,1H),7.20(d,1H),6.90( s,1H),3.89(d,1H),3.60-3.49(m,1H),2.88-2.56(m,2H),2.40-2.25(m,1H),0.98(d,3H),0.94-0.82( m, 1H), 0.62-0.47(m, 1H), 0.46-0.34(m, 1H), 0.32-0.18(m, 1H), 0.15-0.04(m, 1H).
实施例20Example 20
(S)-3-(4-氯-3-((2S,3R)-2-(6-氯萘-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸20-1(S)-3-(4-chloro-3-((2S,3R)-2-(6-chloronaphthalen-2-yl)-4,4,4-trifluoro-3-methylbutanylamino) Phenyl)-3-cyclopropylpropionic acid 20-1
或or
(S)-3-(4-氯-3-((2R,3R)-2-(6-氯萘-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸20-2(S)-3-(4-chloro-3-((2R,3R)-2-(6-chloronaphthalen-2-yl)-4,4,4-trifluoro-3-methylbutanylamino) Phenyl)-3-cyclopropylpropionic acid 20-2
Figure PCTCN2022105987-appb-000270
Figure PCTCN2022105987-appb-000270
采用实施例3的合成路线，将第一步的原料3a替换为化合物2-溴-6-氯萘，制得标题化合物20-1或20-2(45mg,产率：35％)。Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 2-bromo-6-chloronaphthalene to obtain the title compound 20-1 or 20-2 (45 mg, yield: 35%).
MS m/z(ESI)：538.2[M+1]。MS m/z (ESI): 538.2 [M+1].
1H NMR(500MHz,DMSO-d 6)δ12.02(s,1H),9.92(s,1H),8.06(s,1H),8.02(s,1H),7.99(d,1H),7.94(d,1H),7.69(d,1H),7.55(d,1H),7.42(s,1H),7.34(d,1H),7.10(d,1H),4.29(d,1H),3.55-3.45(m,1H),2.64(dd,1H),2.56(dd,1H),2.28-2.20(m,1H),0.96-0.92(m,1H),0.82(d,3H),0.52-0.45(m,1H),0.32-0.19(m,2H),0.08-0.02(m,1H)。 1 H NMR (500MHz,DMSO-d 6 )δ12.02(s,1H),9.92(s,1H),8.06(s,1H),8.02(s,1H),7.99(d,1H),7.94( d,1H),7.69(d,1H),7.55(d,1H),7.42(s,1H),7.34(d,1H),7.10(d,1H),4.29(d,1H),3.55-3.45 (m,1H),2.64(dd,1H),2.56(dd,1H),2.28-2.20(m,1H),0.96-0.92(m,1H),0.82(d,3H),0.52-0.45(m ,1H), 0.32-0.19(m,2H),0.08-0.02(m,1H).
实施例21Example 21
(S)-3-(4-氯-3-((2S,3R)-2-(5-氯萘-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸21-1(S)-3-(4-chloro-3-((2S,3R)-2-(5-chloronaphthalen-2-yl)-4,4,4-trifluoro-3-methylbutanylamino) Phenyl)-3-cyclopropylpropionic acid 21-1
或or
(S)-3-(4-氯-3-((2R,3R)-2-(5-氯萘-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸21-2(S)-3-(4-chloro-3-((2R,3R)-2-(5-chloronaphthalen-2-yl)-4,4,4-trifluoro-3-methylbutanylamino) Phenyl)-3-cyclopropylpropionic acid 21-2
Figure PCTCN2022105987-appb-000271
Figure PCTCN2022105987-appb-000271
采用实施例3的合成路线，将第一步的原料3a替换为化合物6-溴-1-氯萘，制得标题化合物21-1或21-2(60mg，产率：52％)。Using the synthetic route of Example 3, the raw material 3a of the first step was replaced with compound 6-bromo-1-chloronaphthalene to obtain the title compound 21-1 or 21-2 (60 mg, yield: 52%).
MS m/z(ESI)：536.2[M-1]。MS m/z (ESI): 536.2 [M-1].
1H NMR(500MHz,CD 3OD)δ8.28(d,1H),8.03(d 1H),7.87(d,1H),7.77(dd,1H),7.63(d,1H),7.51-7.46(m,2H),7.31(d,1H),7.09(dd,1H),4.22(d,1H),3.56-3.46(m,1H),2.73(dd,1H),2.66(dd,1H),2.34-2.28(m,1H),1.06-0.96(m,1H),0.92(d,3H),0.62-0.54(m,1H),0.43-0.35(m,1H),0.33-0.27(m,1H),0.17-0.10(m,1H)。 1 H NMR (500MHz, CD 3 OD) δ8.28(d, 1H), 8.03(d 1H), 7.87(d, 1H), 7.77(dd, 1H), 7.63(d, 1H), 7.51-7.46( m,2H),7.31(d,1H),7.09(dd,1H),4.22(d,1H),3.56-3.46(m,1H),2.73(dd,1H),2.66(dd,1H),2.34 -2.28(m,1H),1.06-0.96(m,1H),0.92(d,3H),0.62-0.54(m,1H),0.43-0.35(m,1H),0.33-0.27(m,1H) ,0.17-0.10(m,1H).
实施例22Example 22
(S)-3-(4-氯-3-((2R,3R)-2-(2,3-二氢-1H-茚-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸22-1(S)-3-(4-chloro-3-((2R,3R)-2-(2,3-dihydro-1H-inden-2-yl)-4,4,4-trifluoro-3- Methylbutanamido)phenyl)-3-cyclopropylpropionic acid 22-1
或or
(S)-3-(4-氯-3-((2S,3R)-2-(2,3-二氢-1H-茚-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸22-2(S)-3-(4-chloro-3-((2S,3R)-2-(2,3-dihydro-1H-inden-2-yl)-4,4,4-trifluoro-3- Methylbutanamido)phenyl)-3-cyclopropylpropionic acid 22-2
Figure PCTCN2022105987-appb-000272
Figure PCTCN2022105987-appb-000272
Figure PCTCN2022105987-appb-000273
Figure PCTCN2022105987-appb-000273
第一步first step
(3R)-4,4,4-三氟-2-(1H-茚-2-基)-3-甲基丁酸苄酯22b(非对映异构体混合物)Benzyl (3R)-4,4,4-trifluoro-2-(1H-inden-2-yl)-3-methylbutyrate 22b (mixture of diastereoisomers)
将化合物1b(100mg，0.406mmol)、2-溴-1H-茚22a(195mg,0.425mmol)，醋酸钯(9mg，0.040mmol)以及2-(2-二环己基膦苯基)-N,N-二甲基苯胺(31mg，0.078mmol)加入反应瓶中，氮气氛下，加入干燥的甲苯(4mL)，搅拌溶解10分钟后用干冰丙酮浴冷却至-20℃，加入双三甲基硅基氨基锂的甲苯溶液(0.6mL,1M)，低温搅拌15分钟后加热至85℃搅拌反应5小时。浓缩后残余物用硅胶柱色谱法以洗脱剂体系B纯化得到标题产物22b(非对映异构体混合物，109mg，产率：75％)。Compound 1b (100mg, 0.406mmol), 2-bromo-1H-indene 22a (195mg, 0.425mmol), palladium acetate (9mg, 0.040mmol) and 2-(2-dicyclohexylphosphinephenyl)-N,N - Dimethylaniline (31mg, 0.078mmol) was added to the reaction flask, under a nitrogen atmosphere, dry toluene (4mL) was added, stirred and dissolved for 10 minutes, cooled to -20°C with a dry ice acetone bath, and bistrimethylsilyl A toluene solution of lithium amide (0.6 mL, 1 M) was stirred at low temperature for 15 minutes, then heated to 85° C. and stirred for 5 hours. The residue after concentration was purified by silica gel column chromatography with eluent system B to obtain the title product 22b (diastereoisomer mixture, 109 mg, yield: 75%).
第二步second step
(3R)-2-(2,3-二氢-1H-茚-2-基)-4,4,4-三氟-3-甲基丁酸22c(非对映异构体混合物)(3R)-2-(2,3-Dihydro-1H-inden-2-yl)-4,4,4-trifluoro-3-methylbutanoic acid 22c (mixture of diastereomers)
化合物22b(109mg，0.302mmol)溶于乙酸乙酯(5mL)和甲醇(5mL)，加入10％钯碳(32mg，0.032mmol)，氢气氛下，搅拌反应8小时。过滤浓缩得到粗产物22c(非对映异构体混合物，46mg，产率：56％)。Compound 22b (109 mg, 0.302 mmol) was dissolved in ethyl acetate (5 mL) and methanol (5 mL), added with 10% palladium on carbon (32 mg, 0.032 mmol), and stirred for 8 hours under hydrogen atmosphere. Concentration by filtration afforded crude product 22c (mixture of diastereomers, 46 mg, yield: 56%).
第三步third step
(S)-3-(4-氯-3-((2R,3R)-2-(2,3-二氢-1H-茚-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸叔丁酯22d-1(S)-3-(4-chloro-3-((2R,3R)-2-(2,3-dihydro-1H-inden-2-yl)-4,4,4-trifluoro-3- Methylbutanamido)phenyl)-tert-butyl-3-cyclopropylpropionate 22d-1
或or
(S)-3-(4-氯-3-((2S,3R)-2-(2,3-二氢-1H-茚-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸叔丁酯22d-2(S)-3-(4-chloro-3-((2S,3R)-2-(2,3-dihydro-1H-inden-2-yl)-4,4,4-trifluoro-3- Methylbutyrylamino)phenyl)-3-tert-butyl cyclopropylpropionate 22d-2
化合物22c(46mg，0.169mmol)溶于二氯甲烷(2mL)，室温加入1-氯-N,N,2-三甲基丙烯胺(23mg，0.175mmol)，室温搅拌30分钟。加入吡啶(40mg，0.505mmol)和化合物1f(50mg，0.169mmol)的二氯甲烷(2mL)溶液，室温搅拌1小时。浓缩 后残余物用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18 150*30mm,5μm；流动相：水(含0.1％的碳酸氢铵)，乙腈；15分钟梯度：65％-80％)纯化，得标题化合物22d-1或22d-2(10mg，产率：11％)。Compound 22c (46 mg, 0.169 mmol) was dissolved in dichloromethane (2 mL), 1-chloro-N,N,2-trimethylpropenylamine (23 mg, 0.175 mmol) was added at room temperature, and stirred at room temperature for 30 minutes. A solution of pyridine (40 mg, 0.505 mmol) and compound 1f (50 mg, 0.169 mmol) in dichloromethane (2 mL) was added, and stirred at room temperature for 1 hour. After concentration, the residue was subjected to high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% ammonium bicarbonate), acetonitrile; 15 minutes gradient: 65%- 80%) to obtain the title compound 22d-1 or 22d-2 (10 mg, yield: 11%).
第四步the fourth step
(S)-3-(4-氯-3-((2R,3R)-2-(2,3-二氢-1H-茚-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸22-1(S)-3-(4-chloro-3-((2R,3R)-2-(2,3-dihydro-1H-inden-2-yl)-4,4,4-trifluoro-3- Methylbutanamido)phenyl)-3-cyclopropylpropionic acid 22-1
或or
(S)-3-(4-氯-3-((2S,3R)-2-(2,3-二氢-1H-茚-2-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸22-2(S)-3-(4-chloro-3-((2S,3R)-2-(2,3-dihydro-1H-inden-2-yl)-4,4,4-trifluoro-3- Methylbutanamido)phenyl)-3-cyclopropylpropionic acid 22-2
化合物22d-1或22d-2(10mg，0.018mmol)溶于二氯甲烷(4mL)，室温加入2mL三氟醋酸，搅拌2小时。浓缩后残余物用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18 150*30mm,5μm；流动相：水(含0.1％的三氟醋酸)，乙腈；15分钟梯度：65％-80％)纯化，得标题化合物22-1或22-2(3mg，产率：33％)。Compound 22d-1 or 22d-2 (10 mg, 0.018 mmol) was dissolved in dichloromethane (4 mL), and 2 mL of trifluoroacetic acid was added at room temperature, and stirred for 2 hours. After concentration, the residue was subjected to high performance liquid chromatography (Waters 2545, chromatographic column: SharpSil-T C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% trifluoroacetic acid), acetonitrile; 15 minutes gradient: 65%- 80%) was purified to obtain the title compound 22-1 or 22-2 (3 mg, yield: 33%).
MS m/z(ESI)：494.2[M+1]。MS m/z (ESI): 494.2 [M+1].
1H NMR(500MHz,DMSO-d 6)δ9.75(s,1H),7.74-7.65(m,1H),7.35(d,1H),7.24-7.14(m,2H),7.12-7.05(m,2H),6.65(s,1H),4.13(d,1H),3.13-3.05(m,2H),3.04-2.79(m,4H),2.29-2.23(m,1H),2.00-1.94(m,1H),1.48-1.41(m,1H),0.92-0.88(m,1H),0.86(d,3H),0.49-0.42(m,1H),0.30-0.19(m,2H),0.06-0.01(m,1H)。 1 H NMR (500MHz,DMSO-d 6 )δ9.75(s,1H),7.74-7.65(m,1H),7.35(d,1H),7.24-7.14(m,2H),7.12-7.05(m ,2H),6.65(s,1H),4.13(d,1H),3.13-3.05(m,2H),3.04-2.79(m,4H),2.29-2.23(m,1H),2.00-1.94(m ,1H),1.48-1.41(m,1H),0.92-0.88(m,1H),0.86(d,3H),0.49-0.42(m,1H),0.30-0.19(m,2H),0.06-0.01 (m,1H).
实施例23Example 23
(S)-3-(4-氯-3-((2S,3R)-4,4,4-三氟-3-甲基-2-(喹啉-7-基)丁酰胺基)苯基)-3-环丙基丙酸23-1(S)-3-(4-chloro-3-((2S,3R)-4,4,4-trifluoro-3-methyl-2-(quinolin-7-yl)butanylamino)phenyl )-3-cyclopropylpropionic acid 23-1
或or
(S)-3-(4-氯-3-((2R,3R)-4,4,4-三氟-3-甲基-2-(喹啉-7-基)丁酰胺基)苯基)-3-环丙基丙酸23-2(S)-3-(4-chloro-3-((2R,3R)-4,4,4-trifluoro-3-methyl-2-(quinolin-7-yl)butanylamino)phenyl )-3-cyclopropylpropionic acid 23-2
Figure PCTCN2022105987-appb-000274
Figure PCTCN2022105987-appb-000274
采用实施例3的合成路线，将第一步的原料3a替换为化合物7-溴喹啉，制得标题化合物23-1或23-2(25mg，产率：29％)。Using the synthetic route of Example 3, the raw material 3a of the first step was replaced with compound 7-bromoquinoline to obtain the title compound 23-1 or 23-2 (25 mg, yield: 29%).
MS m/z(ESI)：505.1[M+1]。MS m/z (ESI): 505.1 [M+1].
1H NMR(500MHz,CD 3OD)δ9.16(d,1H),9.02(d,1H),8.40(s,1H),8.31(d,1H),8.07(d,1H),7.98(s,1H),7.50(s,1H),7.31(d,1H),7.11(d,1H),4.41(d,1H),3.60-3.50(m,1H),2.74(dd,1H),2.66(dd,1H),2.34-2.27(m,1H),1.05-0.98(m,1H), 0.95(d,3H),0.63-0.53(m,1H),0.44-0.24(m,2H),0.18-0.07(m,1H)。 1 H NMR (500MHz, CD 3 OD) δ9.16(d,1H),9.02(d,1H),8.40(s,1H),8.31(d,1H),8.07(d,1H),7.98(s ,1H),7.50(s,1H),7.31(d,1H),7.11(d,1H),4.41(d,1H),3.60-3.50(m,1H),2.74(dd,1H),2.66( dd,1H),2.34-2.27(m,1H),1.05-0.98(m,1H), 0.95(d,3H),0.63-0.53(m,1H),0.44-0.24(m,2H),0.18- 0.07(m,1H).
实施例24Example 24
(S)-3-(4-氯-3-((2S,3R)-4,4,4-三氟-2-(异喹啉-3-基)-3-甲基丁酰胺基)苯基)-3-环丙基丙酸24-1(S)-3-(4-chloro-3-((2S,3R)-4,4,4-trifluoro-2-(isoquinolin-3-yl)-3-methylbutanylamino)benzene Base) -3-cyclopropylpropionic acid 24-1
或or
(S)-3-(4-氯-3-((2R,3R)-4,4,4-三氟-2-(异喹啉-3-基)-3-甲基丁酰胺基)苯基)-3-环丙基丙酸24-2(S)-3-(4-chloro-3-((2R,3R)-4,4,4-trifluoro-2-(isoquinolin-3-yl)-3-methylbutanylamino)benzene Base) -3-cyclopropylpropionic acid 24-2
Figure PCTCN2022105987-appb-000275
Figure PCTCN2022105987-appb-000275
采用实施例3的合成路线，将第一步的原料3a替换为化合物3-溴异喹啉，制得标题化合物24-1或24-2(15mg,产率：31％)。Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 3-bromoisoquinoline to obtain the title compound 24-1 or 24-2 (15 mg, yield: 31%).
MS m/z(ESI)：505.4[M+1]。MS m/z (ESI): 505.4 [M+1].
1H NMR(500MHz,CD 3OD)δ9.42(s,1H),8.22(d,1H),8.06(s,1H),8.03(d,1H),7.93-7.89(m,1H),7.81-7.77(m,1H),7.75(s,1H),7.32(d,1H),7.08(d,1H),4.33(d,1H),3.68-3.57(m,1H),2.75(dd,1H),2.67(dd,1H),2.36-2.28(m,1H),1.00(d,3H),0.95-0.88(m,1H),0.63-0.55(m,1H),0.44-0.28(m,2H),0.17-0.11(m,1H)。 1 H NMR (500MHz, CD 3 OD) δ9.42(s,1H),8.22(d,1H),8.06(s,1H),8.03(d,1H),7.93-7.89(m,1H),7.81 -7.77(m,1H),7.75(s,1H),7.32(d,1H),7.08(d,1H),4.33(d,1H),3.68-3.57(m,1H),2.75(dd,1H ),2.67(dd,1H),2.36-2.28(m,1H),1.00(d,3H),0.95-0.88(m,1H),0.63-0.55(m,1H),0.44-0.28(m,2H ),0.17-0.11(m,1H).
实施例25Example 25
(S)-3-(4-氯-3-((2S,3R)-4,4,4-三氟-3-甲基-2-(喹啉-3-基)丁酰胺基)苯基)-3-环丙基丙酸25-1(S)-3-(4-chloro-3-((2S,3R)-4,4,4-trifluoro-3-methyl-2-(quinolin-3-yl)butanylamino)phenyl )-3-cyclopropylpropionic acid 25-1
或or
(S)-3-(4-氯-3-((2R,3R)-4,4,4-三氟-3-甲基-2-(喹啉-3-基)丁酰胺基)苯基)-3-环丙基丙酸25-2(S)-3-(4-chloro-3-((2R,3R)-4,4,4-trifluoro-3-methyl-2-(quinolin-3-yl)butanylamino)phenyl )-3-cyclopropylpropionic acid 25-2
Figure PCTCN2022105987-appb-000276
Figure PCTCN2022105987-appb-000276
采用实施例3的合成路线，将第一步的原料3a替换为化合物3-溴喹啉，制得标题化合物25-1或25-2(30mg，产率：33％)。Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by the compound 3-bromoquinoline to obtain the title compound 25-1 or 25-2 (30 mg, yield: 33%).
MS m/z(ESI)：505.5[M+1]。MS m/z (ESI): 505.5 [M+1].
1H NMR(500MHz,CD 3OD)δ9.15(s,1H),8.83(s,1H),8.20-8.14(m,2H),8.02-7.97(m,1H),7.86-7.81(m,1H),7.53(s,1H),7.34(d,1H),7.13(d,1H),4.40(d,1H),3.66-3.55(m,1H),2.79-2.63(m,2H),2.36-2.27(m,1H),1.02(d,3H),0.95-0.88(m,1H),0.63-0.55(m,1H),0.44-0.27(m,2H),0.17-0.10(m,1H)。 1 H NMR (500MHz, CD 3 OD) δ9.15(s,1H),8.83(s,1H),8.20-8.14(m,2H),8.02-7.97(m,1H),7.86-7.81(m, 1H),7.53(s,1H),7.34(d,1H),7.13(d,1H),4.40(d,1H),3.66-3.55(m,1H),2.79-2.63(m,2H),2.36 -2.27(m,1H),1.02(d,3H),0.95-0.88(m,1H),0.63-0.55(m,1H),0.44-0.27(m,2H),0.17-0.10(m,1H) .
实施例26Example 26
(S)-3-(4-氯-3-((2S,3R)-2-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸26-1(S)-3-(4-chloro-3-((2S,3R)-2-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-4, 4,4-Trifluoro-3-methylbutanamido)phenyl)-3-cyclopropylpropionic acid 26-1
或or
(S)-3-(4-氯-3-((2R,3R)-2-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸26-2(S)-3-(4-chloro-3-((2R,3R)-2-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-4, 4,4-Trifluoro-3-methylbutanylamino)phenyl)-3-cyclopropylpropionic acid 26-2
Figure PCTCN2022105987-appb-000277
Figure PCTCN2022105987-appb-000277
采用实施例3的合成路线，将第一步的原料3a替换为6-溴-1,4-苯并二噁烷，制得标题化合物26-1或26-2(30mg，产率：25％)。Using the synthetic route of Example 3, the raw material 3a of the first step was replaced by 6-bromo-1,4-benzodioxane to obtain the title compound 26-1 or 26-2 (30mg, yield: 25% ).
MS m/z(ESI)：512.2[M+1]。MS m/z (ESI): 512.2 [M+1].
1H NMR(500MHz,CD 3OD)δ7.53(s,1H),7.33(d,1H),7.10(d,1H),6.97(s,1H),6.91(d,1H),6.84(d,1H),4.26(s,4H),3.86(d,1H),3.30-3.21(m,1H),2.75(dd,1H),2.68(dd,1H),2.36-2.30(m,1H),1.07-0.99(m,1H),0.91(d,3H),0.64-0.56(m,1H),0.46-0.38(m,1H),0.36-0.28(m,1H),0.19-0.12(m,1H)。 1 H NMR (500MHz, CD 3 OD) δ7.53(s, 1H), 7.33(d, 1H), 7.10(d, 1H), 6.97(s, 1H), 6.91(d, 1H), 6.84(d ,1H),4.26(s,4H),3.86(d,1H),3.30-3.21(m,1H),2.75(dd,1H),2.68(dd,1H),2.36-2.30(m,1H), 1.07-0.99(m,1H),0.91(d,3H),0.64-0.56(m,1H),0.46-0.38(m,1H),0.36-0.28(m,1H),0.19-0.12(m,1H ).
实施例27Example 27
(S)-3-(4-氯-3-((2S,3R)-4,4,4-三氟-3-甲基-2-(4-甲基-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-基)丁酰胺基)苯基)-3-环丙基丙酸27-1(S)-3-(4-chloro-3-((2S,3R)-4,4,4-trifluoro-3-methyl-2-(4-methyl-3,4-dihydro-2H -Benzo[b][1,4]oxazin-7-yl)butanamido)phenyl)-3-cyclopropylpropionic acid 27-1
或or
(S)-3-(4-氯-3-((2R,3R)-4,4,4-三氟-3-甲基-2-(4-甲基-3,4-二氢-2H-苯并[b][1,4]噁嗪-7-基)丁酰胺基)苯基)-3-环丙基丙酸27-2(S)-3-(4-chloro-3-((2R,3R)-4,4,4-trifluoro-3-methyl-2-(4-methyl-3,4-dihydro-2H -Benzo[b][1,4]oxazin-7-yl)butanamido)phenyl)-3-cyclopropylpropionic acid 27-2
Figure PCTCN2022105987-appb-000278
Figure PCTCN2022105987-appb-000278
采用实施例3的合成路线，将第一步的原料3a替换为7-溴-4-甲基-3,4-二氢-2H-1,4-苯并[b][1,4]噁嗪，制得标题化合物27-1或27-2(30mg，产率：27％)。Using the synthetic route of Example 3, the raw material 3a of the first step is replaced by 7-bromo-4-methyl-3,4-dihydro-2H-1,4-benzo[b][1,4]oxa oxazine to obtain the title compound 27-1 or 27-2 (30 mg, yield: 27%).
MS m/z(ESI)：525.1[M+1]。MS m/z (ESI): 525.1 [M+1].
1H NMR(500MHz,CD 3OD)δ7.54(s,1H),7.33(d,1H),7.09(d,1H),6.88(d,1H),6.81(s,1H),6.72(d,1H),4.32-4.29(m,2H),3.79(d,1H),3.44-3.37(m,1H),3.28-3.24(m,2H),2.90(s,3H),2.75(dd,1H),2.68(dd,1H),2.36-2.30(m,1H),1.07-1.00(m,1H),0.91(d,3H),0.63-0.56(m,1H),0.46-0.38(s,1H),0.37-0.29(m,1H),0.19-0.12(s,1H)。 1 H NMR (500MHz, CD 3 OD) δ7.54(s, 1H), 7.33(d, 1H), 7.09(d, 1H), 6.88(d, 1H), 6.81(s, 1H), 6.72(d ,1H),4.32-4.29(m,2H),3.79(d,1H),3.44-3.37(m,1H),3.28-3.24(m,2H),2.90(s,3H),2.75(dd,1H ),2.68(dd,1H),2.36-2.30(m,1H),1.07-1.00(m,1H),0.91(d,3H),0.63-0.56(m,1H),0.46-0.38(s,1H ),0.37-0.29(m,1H),0.19-0.12(s,1H).
实施例28Example 28
(S)-3-(4-氯-3-((2S,3R)-4,4,4-三氟-3-甲基-2-(4-甲基-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-基)丁酰胺基)苯基)-3-环丙基丙酸28-1(S)-3-(4-chloro-3-((2S,3R)-4,4,4-trifluoro-3-methyl-2-(4-methyl-3,4-dihydro-2H -Benzo[b][1,4]oxazin-6-yl)butanamido)phenyl)-3-cyclopropylpropionic acid 28-1
或or
(S)-3-(4-氯-3-((2R,3R)-4,4,4-三氟-3-甲基-2-(4-甲基-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-基)丁酰胺基)苯基)-3-环丙基丙酸28-2(S)-3-(4-chloro-3-((2R,3R)-4,4,4-trifluoro-3-methyl-2-(4-methyl-3,4-dihydro-2H -Benzo[b][1,4]oxazin-6-yl)butanamido)phenyl)-3-cyclopropylpropionic acid 28-2
Figure PCTCN2022105987-appb-000279
Figure PCTCN2022105987-appb-000279
采用实施例3的合成路线，将第一步的原料3a替换为化合物6-溴-4-甲基-3,4-二氢-2H-苯并[b][1,4]噁嗪，制得标题化合物28-1或28-2(20mg，产率：32％)。Using the synthetic route of Example 3, the raw material 3a of the first step is replaced by the compound 6-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine to prepare The title compound 28-1 or 28-2 (20 mg, yield: 32%) was obtained.
MS m/z(ESI)：525.6[M+1]。MS m/z (ESI): 525.6 [M+1].
1H NMR(500MHz,CD 3OD)δ7.54(s,1H),7.33(d,1H),7.10(d,1H),6.81(s,1H),6.71-6.60(m,2H),4.30-4.24(m,2H),3.83(d,1H),3.38-3.34(m,1H),3.29-3.24(m,2H),2.91(s,3H),2.75(dd,1H),2.68(dd,1H),2.37-2.30(m,1H),1.08-0.99(m,1H),0.92(d,3H),0.65-0.56(m,1H),0.46-0.38(m,1H),0.36-0.29(m,1H),0.19-0.12(m,1H)。 1 H NMR (500MHz, CD 3 OD) δ7.54(s,1H),7.33(d,1H),7.10(d,1H),6.81(s,1H),6.71-6.60(m,2H),4.30 -4.24(m,2H),3.83(d,1H),3.38-3.34(m,1H),3.29-3.24(m,2H),2.91(s,3H),2.75(dd,1H),2.68(dd ,1H),2.37-2.30(m,1H),1.08-0.99(m,1H),0.92(d,3H),0.65-0.56(m,1H),0.46-0.38(m,1H),0.36-0.29 (m,1H), 0.19-0.12(m,1H).
实施例29Example 29
(2S,3S,4S,5R)-6-(((S)-3-(4-氯-3-((2S,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5- 基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酰基)氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸29-1(2S,3S,4S,5R)-6-(((S)-3-(4-chloro-3-((2S,3R)-2-(2,2-difluorobenzo[d][1 ,3]dioxolan-5-yl)-4,4,4-trifluoro-3-methylbutanylamido)phenyl)-3-cyclopropylpropionyl)oxy)-3,4 ,5-Trihydroxytetrahydro-2H-pyran-2-carboxylic acid 29-1
或or
(2S,3S,4S,5R)-6-(((S)-3-(4-氯-3-((2R,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酰基)氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸29-2(2S,3S,4S,5R)-6-(((S)-3-(4-chloro-3-((2R,3R)-2-(2,2-difluorobenzo[d][1 ,3] dioxolan-5-yl)-4,4,4-trifluoro-3-methylbutanylamino)phenyl)-3-cyclopropylpropionyl)oxy)-3,4 ,5-Trihydroxytetrahydro-2H-pyran-2-carboxylic acid 29-2
Figure PCTCN2022105987-appb-000280
Figure PCTCN2022105987-appb-000280
第一步first step
(2S,3S,4S,5R)-6-(((S)-3-(4-氯-3-((2S,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酰基)氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸烯丙基酯29b-1(2S,3S,4S,5R)-6-(((S)-3-(4-chloro-3-((2S,3R)-2-(2,2-difluorobenzo[d][1 ,3] dioxolan-5-yl)-4,4,4-trifluoro-3-methylbutanylamino)phenyl)-3-cyclopropylpropionyl)oxy)-3,4 ,Allyl 5-trihydroxytetrahydro-2H-pyran-2-carboxylate 29b-1
或or
(2S,3S,4S,5R)-6-(((S)-3-(4-氯-3-((2R,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酰基)氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸烯丙基酯29b-2(2S,3S,4S,5R)-6-(((S)-3-(4-chloro-3-((2R,3R)-2-(2,2-difluorobenzo[d][1 ,3] dioxolan-5-yl)-4,4,4-trifluoro-3-methylbutanylamino)phenyl)-3-cyclopropylpropionyl)oxy)-3,4 ,Allyl 5-trihydroxytetrahydro-2H-pyran-2-carboxylate 29b-2
将化合物3-1或3-2(90mg，0.169mmol)和(2S,3S,4S,5R)-3,4,5,6-四羟基四氢-2H-吡喃-2-羧酸烯丙基酯29a(40mg，0.169mmol，采用文献“Journal of Organic Chemistry 2006,71(26),9628-9636”中化合物2的合成方法制备而得)溶于乙腈(8mL)，依次加入N-甲基***啉(60mg，0.591mmol)、O-(7-氮杂苯并***-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(77mg，0.202mmol)，室温搅拌反应10小时，加乙酸(41mg，0.676mmol)淬灭反应，直接浓缩，残余物用硅胶柱色谱法以洗脱剂体系A纯化得到标题化合物29b-1或29b-2(57mg，产率：45％)。Compound 3-1 or 3-2 (90mg, 0.169mmol) and (2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylic acid allyl Ethyl ester 29a (40mg, 0.169mmol, prepared by the synthesis method of compound 2 in "Journal of Organic Chemistry 2006, 71(26), 9628-9636") was dissolved in acetonitrile (8mL), and N-methyl Morpholine (60mg, 0.591mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (77mg, 0.202mmol) , stirred at room temperature for 10 hours, added acetic acid (41 mg, 0.676 mmol) to quench the reaction, concentrated directly, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 29b-1 or 29b-2 (57 mg, yielding rate: 45%).
第二步second step
(2S,3S,4S,5R)-6-(((S)-3-(4-氯-3-((2S,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酰基)氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸29-1(2S,3S,4S,5R)-6-(((S)-3-(4-chloro-3-((2S,3R)-2-(2,2-difluorobenzo[d][1 ,3] dioxolan-5-yl)-4,4,4-trifluoro-3-methylbutanylamino)phenyl)-3-cyclopropylpropionyl)oxy)-3,4 ,5-Trihydroxytetrahydro-2H-pyran-2-carboxylic acid 29-1
或or
(2S,3S,4S,5R)-6-(((S)-3-(4-氯-3-((2R,3R)-2-(2,2-二氟苯并[d][1,3]二氧杂戊环-5-基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酰基)氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸29-2(2S,3S,4S,5R)-6-(((S)-3-(4-chloro-3-((2R,3R)-2-(2,2-difluorobenzo[d][1 ,3] dioxolan-5-yl)-4,4,4-trifluoro-3-methylbutanylamino)phenyl)-3-cyclopropylpropionyl)oxy)-3,4 ,5-Trihydroxytetrahydro-2H-pyran-2-carboxylic acid 29-2
将化合物29b-1或29b-2(15mg，0.02mmol)溶于乙腈(1mL)，冷却至0℃，加入四(三苯基膦)钯(4mg，0.004mmol)和四氢吡咯(4mg，0.04mmol)，搅拌反应1小时，浓缩后残余物用高效液相色谱法(Waters SQD2，色谱柱：Welch Xtimate C18 150*30mm,5μm；流动相：水(含0.1％的三氟醋酸)，乙腈；17分钟梯度：35％-95％)纯化，得标题化合物29-1或29-2(5mg，产率：35％)。Compound 29b-1 or 29b-2 (15 mg, 0.02 mmol) was dissolved in acetonitrile (1 mL), cooled to 0° C., tetrakis(triphenylphosphine) palladium (4 mg, 0.004 mmol) and tetrahydropyrrole (4 mg, 0.04 mmol), stirred and reacted for 1 hour, concentrated residue was used for high performance liquid chromatography (Waters SQD2, chromatographic column: Welch Xtimate C18 150*30mm, 5 μm; mobile phase: water (containing 0.1% trifluoroacetic acid), acetonitrile; 17 minutes gradient: 35%-95%) purification to obtain the title compound 29-1 or 29-2 (5 mg, yield: 35%).
MS m/z(ESI)：708.0[M-1]。MS m/z (ESI): 708.0 [M-1].
1H NMR(500MHz,CD 3OD)δ7.50-7.44(m,1H),7.40-7.37(m,1H),7.36-7.27(m,2H),7.25-7.20(m,1H),7.18-7.12(m,1H),5.40-5.34(m,1H),4.07-3.99(m,1H),3.66-3.54(m,1H),3.52-3.37(m,4H),2.92-2.74(m,2H),2.46-2.37(m,1H),1.11-1.00(m,1H),0.92(d,3H),0.64-0.55(m,1H),0.46-0.32(m,2H),0.19-0.11(m,1H)。 1 H NMR (500MHz, CD 3 OD) δ7.50-7.44(m,1H),7.40-7.37(m,1H),7.36-7.27(m,2H),7.25-7.20(m,1H),7.18- 7.12(m,1H),5.40-5.34(m,1H),4.07-3.99(m,1H),3.66-3.54(m,1H),3.52-3.37(m,4H),2.92-2.74(m,2H ),2.46-2.37(m,1H),1.11-1.00(m,1H),0.92(d,3H),0.64-0.55(m,1H),0.46-0.32(m,2H),0.19-0.11(m ,1H).
实施例30Example 30
(2S,3S,4S,5R)-6-(((S)-3-(4-氯-3-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酰基)氧基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸30(2S,3S,4S,5R)-6-(((S)-3-(4-chloro-3-((2S,3R)-2-(4-chlorophenyl)-4,4,4- Trifluoro-3-methylbutanamido)phenyl)-3-cyclopropylpropionyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 30
Figure PCTCN2022105987-appb-000281
Figure PCTCN2022105987-appb-000281
采用实施例29的合成路线，将第一步的原料3-1或3-2替换为(S)-3-(4-氯-3-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)苯基)-3-环丙基丙酸 (Runcaciguat，参考文献“Journal of Medicinal Chemistry 2021,64(9),5323-5344”中化合物45的合成方式制备而得)，制得标题化合物30(20mg，产率：30％)。Using the synthetic route of Example 29, replace the raw material 3-1 or 3-2 of the first step with (S)-3-(4-chloro-3-((2S,3R)-2-(4-chlorobenzene base)-4,4,4-trifluoro-3-methylbutanamido)phenyl)-3-cyclopropylpropionic acid (Runcaciguat, reference "Journal of Medicinal Chemistry 2021,64(9), 5323- 5344", the title compound 30 (20 mg, yield: 30%) was obtained.
MS m/z(ESI)：662.0[M-1]。MS m/z (ESI): 662.0 [M-1].
1H NMR(500MHz,CD 3OD)δ7.54-7.44(m,3H),7.44-7.37(m,2H),7.34-7.27(m,1H),7.16-7.08(m,1H),5.48-5.38(m,1H),4.08-3.83(m,2H),3.61-3.50(m,1H),3.48-3.37(m,3H),2.96-2.76(m,2H),2.46-2.32(m,1H),1.10-0.98(m,1H),0.90(d,3H),0.66-0.56(m,1H),0.47-0.30(m,2H),0.19-0.09(m,1H)。 1 H NMR (500MHz, CD 3 OD) δ7.54-7.44 (m, 3H), 7.44-7.37 (m, 2H), 7.34-7.27 (m, 1H), 7.16-7.08 (m, 1H), 5.48- 5.38(m,1H),4.08-3.83(m,2H),3.61-3.50(m,1H),3.48-3.37(m,3H),2.96-2.76(m,2H),2.46-2.32(m,1H ), 1.10-0.98(m,1H), 0.90(d,3H), 0.66-0.56(m,1H), 0.47-0.30(m,2H), 0.19-0.09(m,1H).
生物学评价biological evaluation
测试例1、本公开化合物对过表达sGC的CHO-K1细胞产生cGMP的激动和/或激活效应Test Example 1. The compounds of the present disclosure produce cGMP agonistic and/or activating effects on CHO-K1 cells overexpressing sGC
以下方法用来测定本公开化合物在有血红素-依赖性sGC抑制剂1H-1,2,4-噁二唑并-(4,3a)-喹喔啉-1-酮(ODQ)时对过表达sGC的CHO-K1细胞产生cGMP的激动和/或激活效应。实验方法简述如下：The following method is used to determine the reaction of the disclosed compounds in the presence of heme-dependent sGC inhibitor 1H-1,2,4-oxadiazolo-(4,3a)-quinoxalin-1-one (ODQ) CHO-K1 cells expressing sGC produce agonistic and/or activating effects of cGMP. The experimental method is briefly described as follows:
一、实验材料及仪器1. Experimental materials and instruments
1.CHO-K1/sGC(上海恒瑞医药有限公司，NA)1. CHO-K1/sGC (Shanghai Hengrui Pharmaceutical Co., Ltd., NA)
2.cGMP kit(cisbio，62GM2PEH)2. cGMP kit (cisbio, 62GM2PEH)
3. 384孔板(Corning，4513)3. 384-well plate (Corning, 4513)
4.U型底96孔板(Corning，3795)4. U-bottom 96-well plate (Corning, 3795)
5.Earle's平衡盐溶液(EBSS)(上海源培生物科技股份有限公司，B610KJ)5. Earle's Balanced Salt Solution (EBSS) (Shanghai Yuanpei Biotechnology Co., Ltd., B610KJ)
6. 3-异丁基-1-甲基黄嘌呤(IBMX)(sigma，I7018-1G)6. 3-isobutyl-1-methylxanthine (IBMX) (sigma, I7018-1G)
7.BSA(生工生物工程股份有限公司，9048-46-8)7.BSA (Sangon Bioengineering Co., Ltd., 9048-46-8)
8.MgCl 2(sigma，68475-100ML-F) 8. MgCl 2 (sigma, 68475-100ML-F)
9.HEPES(Gibco，15630-080)9. HEPES (Gibco, 15630-080)
10.DMEM/F12培养基(GE，SH30023.01)10. DMEM/F12 medium (GE, SH30023.01)
11.G418.Sulfate(ENZO，ALX-380-013-G005)11. G418. Sulfate (ENZO, ALX-380-013-G005)
12.Hygromycin B(Thermo，10687-010)12.Hygromycin B (Thermo, 10687-010)
13.酶标仪(BMG，PHERAsta)13. Microplate reader (BMG, PHERAsta)
14.细胞计数仪(上海睿钰生物科技有限公司，IC1000)14. Cell counter (Shanghai Ruiyu Biotechnology Co., Ltd., IC1000)
二、实验步骤2. Experimental steps
CHO-K1/sGC细胞培养在完全培养基(含10％FBS，1mg/mL G418，200μg/mL Hygromycin B的DMEM/F12培养基)中，一周传代2～3次，传代比列1:8或1:15。传代时，用胰酶消化细胞后转至离心管中，1200rpm离心3分钟，弃去上清培养基残液，用完全培养基重悬细胞。CHO-K1/sGC cells were cultured in complete medium (DMEM/F12 medium containing 10% FBS, 1mg/mL G418, 200μg/mL Hygromycin B), passaged 2-3 times a week, and the passage ratio was 1:8 or 1:15. For subculture, trypsinize the cells and transfer them to a centrifuge tube, centrifuge at 1200rpm for 3 minutes, discard the supernatant medium residue, and resuspend the cells with complete medium.
实验时，用胰酶消化细胞，离心弃去上清后，用实验缓冲液(EBSS含有5mM MgCl 2，10mM HEPES，0.05％BSA，500μM IBMX)洗细胞一次，离心后弃去残液，用实验缓冲液重悬细胞。用细胞计数仪计数后调整密度为2×10 6细胞/mL，5μL/ 孔加入到384孔板中。然后在ODQ实验孔中加入用实验缓冲液稀释至0.5mM的ODQ 2μL/孔，在37℃恒温箱中孵育30分钟。将待测样品用DMSO稀释至1.11mM，然后3倍梯度稀释成10个浓度，并设置空白孔。取配制成梯度浓度的待测化合物溶液3μL加入到97μL的实验缓冲液中配制成含化合物的实验缓冲液。取3μL上述含化合物的实验缓冲液加入到384孔板中，在37℃恒温箱中孵育30分钟。然后根据cGMP kit说明书进行实验。用PHERAstar酶标仪的HTRF程序读取信号值，使用GraphPad软件处理数据，试验结果见表1。 During the experiment, digest the cells with trypsin, centrifuge to discard the supernatant, wash the cells once with the experimental buffer (EBSS containing 5mM MgCl 2 , 10mM HEPES, 0.05%BSA, 500μM IBMX), discard the residue after centrifugation, and use the experimental Buffer to resuspend cells. After counting with a cell counter, adjust the density to 2×10 6 cells/mL, and add 5 μL/well into a 384-well plate. Then, 2 μL/well of ODQ diluted to 0.5 mM with experimental buffer was added to the ODQ experimental wells, and incubated in a 37° C. incubator for 30 minutes. The sample to be tested was diluted to 1.11mM with DMSO, then 3-fold serially diluted to 10 concentrations, and blank wells were set. Take 3 μL of the test compound solution prepared in gradient concentration and add it to 97 μL of the test buffer to prepare the compound-containing test buffer. Take 3 μL of the above compound-containing experimental buffer and add it to a 384-well plate, and incubate in a 37° C. incubator for 30 minutes. Then the experiments were carried out according to the instructions of the cGMP kit. The signal value was read with the HTRF program of the PHERAstar microplate reader, and the data was processed with GraphPad software. The test results are shown in Table 1.
表1本公开化合物对过表达sGC的CHO-K1细胞产生的cGMP的激动和/或激活效应Table 1 Agonizing and/or activating effects of compounds of the present disclosure on cGMP produced by CHO-K1 cells overexpressing sGC
Figure PCTCN2022105987-appb-000282
Figure PCTCN2022105987-appb-000282
注：MEC＝最小的有效浓度Note: MEC = minimum effective concentration
结论：本公开化合物对过表达sGC的CHO-K1细胞产生了很强的cGMP的激动和/或激活效应。Conclusion: The disclosed compound has a strong cGMP agonizing and/or activating effect on CHO-K1 cells overexpressing sGC.
测试例2、本公开化合物在重组人肝细胞系HepG2中对细胞色素P450同工酶CYP3A4的诱导活性Test Example 2. Induction activity of the disclosed compound on cytochrome P450 isoenzyme CYP3A4 in the recombinant human liver cell line HepG2
核受体家族成员孕烷X受体(pregnane X receptor,PXR)是诱导细胞色素P450同工酶CYP3A4表达的主要转录调控因子，可被多种外源性物质激活。PXR通过与视黄醛X受体(retinoid X receptor,RXR)结合形成异二聚体发挥功能，PXR-RXR与CYP3A4基因上游调控序列相结合，上调CYP3A4的表达。将CYP3A4基因的 两个启动子克隆至荧光素酶基因的上游，通过与含人PXR基因的质粒共同转染人肝癌细胞系HepG2，构建荧光素酶报告基因***，通过测定荧光信号检测化合物对CYP3A4的诱导活性。Pregnane X receptor (PXR), a member of the nuclear receptor family, is the main transcriptional regulator that induces the expression of cytochrome P450 isoenzyme CYP3A4, and can be activated by a variety of exogenous substances. PXR functions by combining with the retinoid X receptor (RXR) to form a heterodimer, and PXR-RXR combines with the upstream regulatory sequence of the CYP3A4 gene to up-regulate the expression of CYP3A4. The two promoters of the CYP3A4 gene were cloned to the upstream of the luciferase gene, and the human liver cancer cell line HepG2 was co-transfected with a plasmid containing the human PXR gene to construct a luciferase reporter gene system. inducing activity.
实验方法简述如下：The experimental method is briefly described as follows:
一、试剂与仪器1. Reagents and instruments
(1)pcDNA3.1-hPXR质粒及pGL4.17-CYP3A4-5’promoter-luc质粒(内部构建，参考文献为“Biochemical Pharmacology 2004,68(12),2347–2358”)(1) pcDNA3.1-hPXR plasmid and pGL4.17-CYP3A4-5'promoter-luc plasmid (internal construction, reference is "Biochemical Pharmacology 2004, 68(12), 2347-2358")
(2)胎牛血清(Fetal Bovine Serum,FBS)(Thermo Fisher Scientific,10099-141)(2) Fetal Bovine Serum (FBS) (Thermo Fisher Scientific, 10099-141)
(3)0.25％Trypsin-EDTA(1x)，酚红(Thermo Fisher Scientific，25200-072)(3) 0.25% Trypsin-EDTA (1x), phenol red (Thermo Fisher Scientific, 25200-072)
(4)HepatoZYME-SFM(Thermo Fisher Scientific，17705-021)(4) HepatoZYME-SFM (Thermo Fisher Scientific, 17705-021)
(5)MEM(EBSS)(GE Healthcare Life Sciences，SH30024.01)(5) MEM (EBSS) (GE Healthcare Life Sciences, SH30024.01)
(6)
Figure PCTCN2022105987-appb-000283
3000转染试剂(Thermo Fisher Scientific，L3000001) (6)
Figure PCTCN2022105987-appb-000283
3000 transfection reagent (Thermo Fisher Scientific, L3000001)
(7)ONE-Glo TM Luciferase Assay System(Promega，E6110) (7) ONE-Glo TM Luciferase Assay System (Promega, E6110)
(8)DMSO(Shanghai titanchem，G75927B)(8) DMSO (Shanghai titanchem, G75927B)
(9)HepG2(ATCC,HB8065)(9) HepG2 (ATCC, HB8065)
(10)Poly-D-Lysine 96孔微板，black/clear(BD，356692)(10) Poly-D-Lysine 96-well microplate, black/clear (BD, 356692)
(11)96孔U底板(Corning,3795)(11) 96-well U-bottom plate (Corning, 3795)
(12)Opti-MEM TM I减血清培养基(Thermo Fisher Scientific，31985070) (12) Opti-MEM TM I reduced serum medium (Thermo Fisher Scientific, 31985070)
(13)酶标仪(PerkinElmer，VICTOR3)(13) Microplate reader (PerkinElmer, VICTOR3)
(14)Rifampicin(Sigma,R3501)(14) Rifampicin (Sigma, R3501)
二、实验步骤2. Experimental steps
(1)细胞培养和铺板(1) Cell culture and plating
实验第一天，将HepG2细胞用0.25％Trypsin-EDTA充分消化，离心后重悬成单细胞悬液，用细胞培养液(EMEM+10％FBS)调整活细胞密度至2×10 5细胞/mL，以100μL/孔加入96孔细胞培养板(BD,356692)，在培养箱过夜培养(37℃，5％CO 2)。 On the first day of the experiment, HepG2 cells were fully digested with 0.25% Trypsin-EDTA, centrifuged and resuspended into a single cell suspension, and the viable cell density was adjusted to 2×10 5 cells/mL with cell culture medium (EMEM+10% FBS) , add 100 μL/well to a 96-well cell culture plate (BD, 356692), and culture overnight in an incubator (37° C., 5% CO 2 ).
(2)细胞转染(2) Cell transfection
细胞用
Figure PCTCN2022105987-appb-000284
3000转染试剂共同转染CYP3A4质粒(pGL4.17-CYP3A4-5’promoter-luc)和PXR质粒(pcDNA3.1-hPXR)。取一支离心管，加入400μL Opti-MEM，再加入CYP3A4质粒6.4μg和PXR质粒1.6μg，加入16μL P3000试剂，轻轻上下吹打混匀。另取一支离心管，加入400μL Opti-MEM，再加入24μL
Figure PCTCN2022105987-appb-000285
3000转染试剂，充分混匀，室温放置5min，将两个离心管中的液体混合，室温放置10min。取出细胞培养板，更换新鲜培养液(EMEM+10％FBS)100μL/孔，再加入10μL/孔上述质粒混合物，37℃，5％CO 2条件下培养24小时。 for cells
Figure PCTCN2022105987-appb-000284
3000 transfection reagent co-transfect CYP3A4 plasmid (pGL4.17-CYP3A4-5'promoter-luc) and PXR plasmid (pcDNA3.1-hPXR). Take a centrifuge tube, add 400 μL Opti-MEM, then add 6.4 μg of CYP3A4 plasmid and 1.6 μg of PXR plasmid, add 16 μL of P3000 reagent, and gently pipette up and down to mix. Take another centrifuge tube, add 400μL Opti-MEM, then add 24μL
Figure PCTCN2022105987-appb-000285
3000 transfection reagent, mix thoroughly, and place at room temperature for 5 minutes, mix the liquids in the two centrifuge tubes, and place at room temperature for 10 minutes. Take out the cell culture plate, replace with 100 μL/well of fresh culture medium (EMEM+10% FBS), then add 10 μL/well of the above plasmid mixture, and culture at 37° C., 5% CO 2 for 24 hours.
(3)样品配制和加药(3) Sample preparation and dosing
以DMSO配制20mM浓度的阳性对照Rifampicin以及受试化合物溶液；Positive control Rifampicin and test compound solution were prepared with 20mM concentration in DMSO;
分别取20mM浓度的阳性对照Rifampicin以及受试化合物溶液10μL，加入96孔U底板中，再加入40μL DMSO，充分混匀，稀释至4mM，再取10μL的4mM溶液至90μL DMSO中，充分混匀，稀释至0.4mM，将上述4mM及0.4mM的溶液各取5μL到195μL的HepatoZYME-SFM培养基中，配制成浓度为100μM及10μM的10×化合物溶液。另外取5μL DMSO至96孔U底板中，再加入195μL HepatoZYME-SFM培养基，稀释成2.5％DMSO。Take 10 μL of the positive control Rifampicin and the test compound solution at a concentration of 20 mM, add them to a 96-well U-bottom plate, then add 40 μL DMSO, mix well, dilute to 4 mM, then take 10 μL of the 4 mM solution into 90 μL DMSO, mix well, Dilute to 0.4mM, take 5μL of the above 4mM and 0.4mM solutions into 195μL HepatoZYME-SFM medium, and prepare 10× compound solutions with concentrations of 100μM and 10μM. In addition, take 5 μL DMSO to the 96-well U-bottom plate, add 195 μL HepatoZYME-SFM medium, and dilute to 2.5% DMSO.
取出细胞培养板，更换培养液为90μL/孔的HepatoZYME-SFM，再加入10μL/孔的10×化合物溶液，化合物终浓度为10μM和1μM，阳性对照为10μM Rifampicin，阴性对照为0.25％DMSO。37℃，5％CO 2条件下培养24小时。 Take out the cell culture plate, replace the culture medium with 90 μL/well of HepatoZYME-SFM, then add 10 μL/well of 10× compound solution, the final concentration of the compound is 10 μM and 1 μM, the positive control is 10 μM Rifampicin, and the negative control is 0.25% DMSO. Incubate for 24 hours at 37°C, 5% CO 2 .
(4)读板(4) Plate reading
在96孔细胞培养板中加入50μL/孔ONE-Glo试剂，室温下在避光处放置5分钟，置于酶标仪(PerkinElmer,VICTOR3)上读取化学发光值。Add 50 μL/well ONE-Glo reagent to a 96-well cell culture plate, place it in a dark place at room temperature for 5 minutes, and read the chemiluminescence value on a microplate reader (PerkinElmer, VICTOR3).
(5)数据处理(5) Data processing
数据在GraphPad Prism8软件中处理，首先计算阴性对照(0.25％DMSO)化学发光(RLU)的平均值，将受试化合物各浓度的RLU平均值除以阴性对照RLU的平均值，求得诱导倍数(Fold of induction)，阳性对照10μM Rifampicin的诱导倍数应大于等于7，将诱导倍数减去1得到诱导增加倍数(Fold increase above DMSO control)，将受试化合物各浓度的诱导增加倍数除以阳性对照10μM Rifampicin的诱导增加倍数，再乘以100％，得到受试化合物各浓度的诱导增加倍数占10μM Rifampicin诱导增加倍数的百分比，根据10μM化合物的诱导增加倍数百分比来判定化合物诱导能力，小于15％为无诱导(Negative)，大于等于15％小于40％为微弱诱导(Weak)，大于等于40％小于69％为中等诱导(Moderate)，大于等于70％为强诱导(Strong)。Data is processed in GraphPad Prism8 software, at first calculate the mean value of negative control (0.25%DMSO) chemiluminescence (RLU), the RLU mean value of each concentration of test compound is divided by the mean value of negative control RLU, obtain induction fold ( Fold of induction), the positive control 10μM rifampicin induction fold should be greater than or equal to 7, the induction fold minus 1 to get the induction increase fold (Fold increase above DMSO control), the induction increase fold of each concentration of the test compound is divided by the positive control 10μM The induction increase factor of rifampicin is multiplied by 100%, and the induction increase factor of each concentration of the test compound accounts for the percentage of the induction increase factor of 10μM rifampicin, and the induction ability of the compound is judged according to the induction increase factor percentage of the 10μM compound, and less than 15% is no Induction (Negative), greater than or equal to 15% and less than 40% is weak induction (Weak), greater than or equal to 40% and less than 69% is moderate induction (Moderate), greater than or equal to 70% is strong induction (Strong).
三、实验结果3. Experimental results
以10μM Rifampicin为阳性对照，0.25％DMSO为阴性对照，使用HepG2荧光素酶报告基因***对本受试化合物的体外PXR激活/CYP3A4诱导活性进行检测。With 10 μM Rifampicin as the positive control and 0.25% DMSO as the negative control, the in vitro PXR activation/CYP3A4 induction activity of the test compound was detected using the HepG2 luciferase reporter gene system.
化合物Runcaciguat(参考文献“Journal of Medicinal Chemistry 2021,64(9),5323-5344”中化合物45)，结构为：
Figure PCTCN2022105987-appb-000286
Compound Runcaciguat (compound 45 in the reference "Journal of Medicinal Chemistry 2021, 64(9), 5323-5344"), the structure is:
Figure PCTCN2022105987-appb-000286
表2本公开化合物的体外PXR激活/CYP3A4诱导活性Table 2 In vitro PXR activation/CYP3A4 inducing activity of the disclosed compounds
Figure PCTCN2022105987-appb-000287
Figure PCTCN2022105987-appb-000287
结论：本公开化合物在HepG2荧光素酶报告基因***中对CYP3A4无诱导，而Runcaciguat有中等程度诱导，提示本公开化合物在药物相互作用的评估上，对CYP3A4没有潜在的诱导作用，在联合使用经过CYP3A4代谢的药物时具有更安全的优势。Conclusion: The disclosed compound has no induction of CYP3A4 in the HepG2 luciferase reporter gene system, while Runcaciguat has a moderate induction, suggesting that the disclosed compound has no potential induction effect on CYP3A4 in the evaluation of drug interaction. Drugs metabolized by CYP3A4 have the advantage of being safer.
测试例3、本公开化合物谷胱甘肽加成产物试验Test example 3, test of the glutathione addition product of the disclosed compound
一、实验材料及仪器1. Experimental materials and instruments
1、磷酸缓冲液(20×PBS，购买自生工)1. Phosphate buffer solution (20×PBS, purchased from Shenggong)
2、还原型辅酶II(以下简称NADPH，ACROS，A2646-71-1)2. Reduced coenzyme II (hereinafter referred to as NADPH, ACROS, A2646-71-1)
3、人肝微粒体(Corning Gentest，Lot No.9050002，Donor，35)3. Human liver microsomes (Corning Gentest, Lot No.9050002, Donor, 35)
4、ACQUITY BEH C 18column，2.1×100mm，1.7μm(美国Waters公司) 4. ACQUITY BEH C 18 column, 2.1×100mm, 1.7μm (Waters, USA)
5、谷胱甘肽(以下简称GSH,SIGMA,Lot No.:SLBW3322)5. Glutathione (hereinafter referred to as GSH, SIGMA, Lot No.: SLBW3322)
6、质控对照化合物(双氯芬酸，SIGMA，Lot No.:BCBB7312)6. Quality control control compound (diclofenac, SIGMA, Lot No.: BCBB7312)
7、Dionex U3000 Q-Exactive Orbitrap串联高分辨质谱仪(Thermo Fisher Scientific)7. Dionex U3000 Q-Exactive Orbitrap tandem high-resolution mass spectrometer (Thermo Fisher Scientific)
二、实验步骤2. Experimental steps
2.1.受试化合物溶液配制：取受试化合物适量，精密称定，加入适量的DMSO溶解后混合均匀，配成浓度为30mM的储备溶液。将浓度为30mM的储备液用50％乙腈/水(v/v)稀释10倍，得到浓度为3.0mM的工作溶液1。将浓度为3.0mM的工作溶液1用PBS稀释10倍，得到300μM的工作溶液2。2.1. Preparation of the test compound solution: Take an appropriate amount of the test compound, accurately weigh it, add an appropriate amount of DMSO to dissolve it, and mix it evenly to prepare a stock solution with a concentration of 30 mM. The stock solution with a concentration of 30 mM was diluted 10 times with 50% acetonitrile/water (v/v) to obtain a working solution 1 with a concentration of 3.0 mM. Working solution 1 with a concentration of 3.0 mM was diluted 10 times with PBS to obtain working solution 2 at 300 μM.
2.2.肝微粒体溶液配制：取肝微粒体储存液(浓度为20mg/mL)适量，用浓度为100mM的磷酸缓冲液(pH 7.4)稀释到1.43mg/mL微粒体溶液。2.2. Preparation of liver microsome solution: take an appropriate amount of liver microsome stock solution (concentration: 20 mg/mL), and dilute it to 1.43 mg/mL microsome solution with 100 mM phosphate buffer (pH 7.4).
2.3.NADPH cofactor溶液的配制：称取NADPH和氯化镁适量，溶于适量的浓度为100mM的磷酸缓冲液(pH值为7.4)中，使得NADPH和氯化镁的浓度分别为10mM和30mM。2.3. Preparation of NADPH cofactor solution: Take appropriate amount of NADPH and magnesium chloride and dissolve in an appropriate amount of 100mM phosphate buffer (pH 7.4), so that the concentrations of NADPH and magnesium chloride are 10mM and 30mM respectively.
2.4.GSH溶液的配制：称取GSH适量，溶于适量的浓度为100mM的磷酸缓冲液(pH 7.4)中，配成浓度为50mM溶液。2.4. Preparation of GSH solution: Weigh an appropriate amount of GSH, dissolve it in an appropriate amount of phosphate buffer (pH 7.4) with a concentration of 100 mM, and prepare a solution with a concentration of 50 mM.
2.5.体外孵育：精密移取40μL浓度为300μM的受试化合物工作液2，加入到1.5mL离心管中，再加入280μL浓度为1.43mg/mL的肝微粒体溶液，使得孵育体系中肝微粒体蛋白浓度为1mg/mL。再加入40μL浓度为10mM的NADPH溶液和40μL浓度为50mM的GSH溶液后，放入37℃恒温孵育箱中震荡孵育，并开始计时。孵育开始60min后，从孵育箱中取出孵育样品，加入1000μL冰冷乙腈溶液，终止反应并在室温放置10min后，12000rpm离心10min。移取全部上清液于离心管中，37℃真空浓缩至干。残留物用200μL 25％乙腈/水溶液复溶，12000rpm离心10min，移取上清液至1.5mL离心管中，吸取10μL进行LC/MS分析。对于空白样品，加入40μL PBS代替受试化合物工作液2。阳性对照双氯芬酸(10μM)同受试化合物。2.5. In vitro incubation: Precisely pipette 40 μL of the test compound working solution 2 with a concentration of 300 μM, add it to a 1.5 mL centrifuge tube, and then add 280 μL of a liver microsome solution with a concentration of 1.43 mg/mL, so that the liver microsomes in the incubation system The protein concentration was 1 mg/mL. After adding 40 μL of NADPH solution with a concentration of 10 mM and 40 μL of GSH solution with a concentration of 50 mM, put it into a constant temperature incubator at 37° C. for shaking incubation, and start timing. After 60 minutes of incubation, the incubation samples were taken out from the incubator, and 1000 μL of ice-cold acetonitrile solution was added to terminate the reaction and left at room temperature for 10 minutes, then centrifuged at 12000 rpm for 10 minutes. Pipette all supernatants into centrifuge tubes and concentrate to dryness in vacuo at 37°C. The residue was redissolved with 200 μL of 25% acetonitrile/water solution, centrifuged at 12000 rpm for 10 min, the supernatant was transferred to a 1.5 mL centrifuge tube, and 10 μL was drawn for LC/MS analysis. For blank samples, add 40 μL PBS instead of working solution 2 of the test compound. The positive control diclofenac (10 μM) was the same as the test compound.
采用MetWorks或者Compound discoverer软件对采集得到的数据进行处理并筛选潜在的GSH结合物。Use MetWorks or Compound discoverer software to process the collected data and screen for potential GSH binders.
表3本公开化合物的谷胱甘肽加成实验结果Table 3 Glutathione addition experimental results of the disclosed compounds
化合物编号Compound number 谷胱甘肽结合产物glutathione conjugated product
29-1或29-229-1 or 29-2 阴性Negative
3030 阳性Positive
注：阴性表示实验中未检测到谷胱甘肽结合产物，阳性表示检测到谷胱甘肽结合产物。Note: Negative means that no glutathione-conjugated products were detected in the experiment, and positive means that glutathione-conjugated products were detected.
结论：化合物29-1或29-2为化合物3-1或3-2的代谢产物，30为化合物Runcaciguat的代谢产物，本公开化合物的代谢产物与体内细胞中GSH不发生共价结合，与含游离巯基的蛋白发生共价结合引起细胞毒性的可能性低，相比Runcaciguat有更好的安全性。Conclusion: Compound 29-1 or 29-2 is a metabolite of compound 3-1 or 3-2, and 30 is a metabolite of compound Runcaciguat. The metabolites of the disclosed compound do not covalently bind to GSH in cells in the body. The possibility of cytotoxicity caused by covalent binding of proteins with free sulfhydryl groups is low, and it has better safety than Runcaciguat.

Claims (27)

  1. 一种通式(M)所示的化合物或其可药用的盐：A compound represented by general formula (M) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022105987-appb-100001
    Figure PCTCN2022105987-appb-100001
    其中：in:
    R 0为氢原子或
    Figure PCTCN2022105987-appb-100002
    优选地，R 0为氢原子或
    Figure PCTCN2022105987-appb-100003
    R 0 is a hydrogen atom or
    Figure PCTCN2022105987-appb-100002
    Preferably, R 0 is a hydrogen atom or
    Figure PCTCN2022105987-appb-100003
    Z为N或CR 4； Z is N or CR4 ;
    G为N或CR 4a； G is N or CR 4a ;
    R 1与R 2和相连的碳原子形成环A’，或者R 2与R 3和相连的碳原子形成环A，所述环A’和环A各自独立地选自环烷基、杂环基、芳基和杂芳基；其中，所述环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、羟基、烷基、卤代烷基、氘代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、氰基、氧代基、烯基、炔基、-NR 12aR 12b、-NHC(O)R 13、-C(O)R 13和-C(O)OR 13中的一个或多个相同或不同的取代基取代； R 1 and R 2 and the connected carbon atoms form ring A', or R 2 and R 3 and the connected carbon atoms form ring A, and the ring A' and ring A are each independently selected from cycloalkyl, heterocyclyl , aryl, and heteroaryl; wherein, the cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently selected from deuterium atom, halogen, hydroxyl, alkyl, haloalkyl, deuterated alkyl Alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, cyano, oxo, alkenyl, alkynyl, -NR 12a R 12b , -NHC(O)R 13 , -C( One or more identical or different substituents in O) R 13 and -C(O)OR 13 are substituted;
    当R 1与R 2和相连的碳原子形成环A’时，R 3选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氨基和硝基； When R1 and R2 and the attached carbon atom form ring A ', R3 is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano , amino and nitro;
    当R 2与R 3和相连的碳原子形成环A时，R 1选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氨基和硝基； When R2 and R3 and the carbon atom connected form ring A , R1 is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino and nitro;
    R 4和R 4a相同或不同，且各自独立地选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氨基和硝基； R 4 and R 4a are the same or different, and each independently selected from a hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino and nitro;
    R 5和R 6相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、环烷基和杂环基；其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自烯基、炔基、氰基、氨基、硝基和R b中的一个或多个相同或不同的取代基取代；或者R 5和R 6和相连的碳原子形成环烷基或杂环基； R 5 and R 6 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein The above-mentioned alkyl, alkoxy, hydroxyalkyl, cycloalkyl and heterocyclic groups are each independently optionally selected from one or more of alkenyl, alkynyl , cyano, amino, nitro and R The same or different substituents are substituted; or R 5 and R 6 and the connected carbon atoms form a cycloalkyl or heterocyclic group;
    R b选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、环烷基和杂环基；其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、羟基、氰基、氨基和硝基中的一个或多个相同或不同的取代基取代； R b is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclic; wherein said alkyl, alkoxy, hydroxyalkyl, ring Alkyl and heterocyclyl are each independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, cyano, amino and nitro The same or different substituents are substituted;
    各个R 7相同或不同，且各自独立地选自卤素、羟基、羧基、烷基、卤代烷基、 烷氧基、卤代烷氧基、羟烷基、氰基、氨基和硝基； each R is the same or different, and each independently selected from halogen, hydroxy, carboxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino, and nitro;
    R 8选自卤素、羟基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基和环烷基； R is selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cycloalkyl;
    R 9选自氢原子、卤素、羟基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基和杂环基；或者R 8和R 9和相连的碳原子形成环烷基或杂环基； R9 is selected from a hydrogen atom, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; or R8 and R9 form a ring with a connected carbon atom Alkyl or heterocyclyl;
    R 10和R 11相同或不同，且各自独立地选自氢原子、卤素、烷基和卤代烷基； R 10 and R 11 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl and haloalkyl;
    R 12a和R 12b相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基和杂环基；或者R 12a和R 12b与相连的氮原子一起形成杂环基； R 12a and R 12b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; or R 12a and R 12b form a heterocyclic group together with a connected nitrogen atom;
    R 13选自氢原子、烷基、羟烷基、环烷基和杂环基； R 13 is selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;
    n为0、1、2、3或4。n is 0, 1, 2, 3 or 4.
  2. 根据权利要求1所述的通式(M)所示的化合物或其可药用的盐，其为通式(I)所示的化合物或其可药用的盐：The compound represented by the general formula (M) according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022105987-appb-100004
    Figure PCTCN2022105987-appb-100004
    其中：in:
    G为N或CR 4a； G is N or CR 4a ;
    R 1与R 2和相连的碳原子形成环A’，或者R 2与R 3和相连的碳原子形成环A，所述环A’和环A各自独立地选自环烷基、杂环基、芳基和杂芳基；其中，所述环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、羟基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氧代基、烯基、炔基、-NR 12aR 12b、-NHC(O)R 13、-C(O)R 13和-C(O)OR 13中的一个或多个相同或不同的取代基取代； R 1 and R 2 and the connected carbon atoms form ring A', or R 2 and R 3 and the connected carbon atoms form ring A, and the ring A' and ring A are each independently selected from cycloalkyl, heterocyclyl , aryl and heteroaryl; wherein, the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy Among the group, hydroxyalkyl group, cyano group, oxo group, alkenyl group, alkynyl group, -NR 12a R 12b , -NHC(O)R 13 , -C(O)R 13 and -C(O)OR 13 Substitution by one or more identical or different substituents;
    当R 1与R 2和相连的碳原子形成环A’时，R 3选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氨基和硝基； When R1 and R2 and the attached carbon atom form ring A ', R3 is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano , amino and nitro;
    当R 2与R 3和相连的碳原子形成环A时，R 1选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氨基和硝基； When R2 and R3 and the carbon atom connected form ring A , R1 is selected from hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino and nitro;
    R 4和R 4a相同或不同，且各自独立地选自氢原子、卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氨基和硝基； R 4 and R 4a are the same or different, and each independently selected from a hydrogen atom, halogen, hydroxyl, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino and nitro;
    R 5和R 6相同或不同，且各自独立地选自氢原子、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、环烷基和杂环基；其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自烯基、炔基、氰基、氨基、硝基和R b中的一个或多个相同或不同的取代基取代；或者R 5和R 6和相连的碳原子形成环烷基或杂环基； R 5 and R 6 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein The above-mentioned alkyl, alkoxy, hydroxyalkyl, cycloalkyl and heterocyclic groups are each independently optionally selected from one or more of alkenyl, alkynyl , cyano, amino, nitro and R The same or different substituents are substituted; or R 5 and R 6 and the connected carbon atoms form a cycloalkyl or heterocyclic group;
    R b选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、环烷 基和杂环基；其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、羟基、氰基、氨基和硝基中的一个或多个相同或不同的取代基取代； R b is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclic; wherein said alkyl, alkoxy, hydroxyalkyl, ring Alkyl and heterocyclyl are each independently optionally selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, cyano, amino and nitro The same or different substituents are substituted;
    各个R 7相同或不同，且各自独立地选自卤素、羟基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氨基和硝基； each R is the same or different, and each independently selected from halogen, hydroxy, carboxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino, and nitro;
    R 8选自卤素、羟基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基和环烷基； R is selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl and cycloalkyl;
    R 9选自氢原子、卤素、羟基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基和杂环基；或者R 8和R 9和相连的碳原子形成环烷基或杂环基； R9 is selected from a hydrogen atom, halogen, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; or R8 and R9 form a ring with a connected carbon atom Alkyl or heterocyclyl;
    R 10和R 11相同或不同，且各自独立地选自氢原子、卤素、烷基和卤代烷基； R 10 and R 11 are the same or different, and are each independently selected from a hydrogen atom, halogen, alkyl and haloalkyl;
    R 12a和R 12b相同或不同，且各自独立地选自氢原子、烷基、羟烷基、环烷基和杂环基；或者R 12a和R 12b与相连的氮原子一起形成杂环基； R 12a and R 12b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; or R 12a and R 12b form a heterocyclic group together with a connected nitrogen atom;
    R 13选自氢原子、烷基、羟烷基、环烷基和杂环基； R 13 is selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;
    n为0、1、2、3或4。n is 0, 1, 2, 3 or 4.
  3. 根据权利要求1或2所述的通式(M)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：The compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022105987-appb-100005
    Figure PCTCN2022105987-appb-100005
    其中：in:
    环A选自环烷基、杂环基、芳基和杂芳基；Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
    各个R 2a相同或不同，且各自独立地选自卤素、羟基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、氰基、氧代基、烯基、炔基、-NR 12aR 12b、-NHC(O)R 13、-C(O)R 13和-C(O)OR 13； Each R 2a is the same or different, and each independently selected from halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, oxo, alkenyl, alkynyl, -NR 12a R 12b , -NHC(O)R 13 , -C(O)R 13 and -C(O)OR 13 ;
    m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
    G、R 1、R 4至R 11、R 12a、R 12b、R 13和n如权利要求1中所定义。 G, R 1 , R 4 to R 11 , R 12a , R 12b , R 13 and n are as defined in claim 1 .
  4. 根据权利要求1至3任一项所述的通式(M)所示的化合物或其可药用的盐，其中：R 6、R 9和R 11相同或不同，且各自独立地为氢原子或C 1-6烷基。 The compound represented by general formula (M) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: R 6 , R 9 and R 11 are the same or different, and each independently represents a hydrogen atom or C 1-6 alkyl.
  5. 根据权利要求1至4任一项所述的通式(M)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：The compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022105987-appb-100006
    Figure PCTCN2022105987-appb-100006
    其中：in:
    G为CR 4a； G is CR 4a ;
    环A、R 2a、R 4a、R 1、R 4、R 5、R 7、R 8、R 10、m和n如权利要求3中所定义。 Ring A, R 2a , R 4a , R 1 , R 4 , R 5 , R 7 , R 8 , R 10 , m and n are as defined in claim 3 .
  6. 根据权利要求1至5任一项所述的通式(M)所示的化合物或其可药用的盐，其为通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐：The compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which is a compound represented by the general formula (IV-1) or general formula (IV-2) or its pharmaceutically acceptable salts:
    Figure PCTCN2022105987-appb-100007
    Figure PCTCN2022105987-appb-100007
    其中：in:
    R 5a和R 5b不同，且各自独立地选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟基、羟烷基、环烷基和杂环基；其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、羟基、氰基、氨基和硝基中的一个或多个相同或不同的取代基取代； R 5a and R 5b are different, and are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein said alkyl, Alkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl are each independently optionally selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxy, cyano, One or more of the same or different substituents in amino and nitro;
    G为CR 4a； G is CR 4a ;
    环A、R 2a、R 4a、R 1、R 4、R 7、R 8、m和n如权利要求3中所定义。 Ring A, R 2a , R 4a , R 1 , R 4 , R 7 , R 8 , m and n are as defined in claim 3 .
  7. 根据权利要求6所述的通式(M)所示的化合物或其可药用的盐，其中：R 5a和R 5b不同，且各自独立地选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、3至8元环烷基和3至8元杂环基；其中所述的C 1-6烷基、C 1-6烷氧基、C 1-6羟烷基、3至8元环烷基和3至8元杂环基各自独立地任选被选自卤素、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基、氰基、氨基和硝基中的一个或多个相同或不同的取代基取代；优选地，R 5a和R 5b不同，且各自独立地为C 1-6烷基或卤代C 1-6烷基。 The compound represented by general formula (M) or a pharmaceutically acceptable salt thereof according to claim 6, wherein: R 5a and R 5b are different, and each independently selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group; wherein The C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, 3 to 8 membered cycloalkyl group and 3 to 8 membered heterocyclic group are each independently optionally selected from halogen One or more of , C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxyl, cyano, amino and nitro Substituted by the same or different substituents; preferably, R 5a and R 5b are different, and are each independently C 1-6 alkyl or halogenated C 1-6 alkyl.
  8. 根据权利要求3至7中任一项所述的通式(M)所示的化合物或其可药用的盐，其中：各个R 2a相同或不同，且各自独立地为卤素或C 1-6烷基，且m为1、2、 3或4；或者m为0。 The compound represented by general formula (M) or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 7, wherein: each R 2a is the same or different, and each independently is halogen or C 1-6 alkyl, and m is 1, 2, 3 or 4; or m is 0.
  9. 根据权利要求1至8中任一项所述的通式(M)所示的化合物或其可药用的盐，其中：环A选自6至10元芳基、5至10元杂芳基、3至8元环烷基和3至8元杂环基。According to the compound represented by the general formula (M) or its pharmaceutically acceptable salt according to any one of claims 1 to 8, wherein: ring A is selected from 6 to 10 membered aryl, 5 to 10 membered heteroaryl , 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group.
  10. 根据权利要求1至9中任一项所述的通式(M)所示的化合物或其可药用的盐，其中：各个R 7相同或不同，且各自独立地为卤素或C 1-6烷基，且n为1、2、3或4；或者n为0；优选地，R 7为卤素，且n为1。 The compound represented by general formula (M) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein: each R 7 is the same or different, and each independently represents halogen or C 1-6 Alkyl, and n is 1, 2, 3 or 4; or n is 0; preferably, R 7 is halogen, and n is 1.
  11. 根据权利要求1至10中任一项所述的通式(M)所示的化合物或其可药用的盐，其中：R 8选自C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基和3至8元环烷基；优选地；R 8为C 1-6烷基或3至8元环烷基。 The compound represented by general formula (M) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 , wherein: R is selected from C 1-6 alkyl, halogenated C 1-6 alkane radical, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl; preferably; R 8 is C 1-6 alkyl or 3 to 8-membered cycloalkyl.
  12. 根据权利要求1至11中任一项所述的通式(M)所示的化合物或其可药用的盐，其中：R 1、R 4和R 4a相同或不同，且各自独立地选自氢原子、卤素和C 1-6烷基。 The compound represented by general formula (M) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: R 1 , R 4 and R 4a are the same or different, and are each independently selected from Hydrogen atom, halogen and C 1-6 alkyl.
  13. 化合物或其可药用的盐，其选自以下任一化合物：A compound or a pharmaceutically acceptable salt thereof, which is selected from any of the following compounds:
    Figure PCTCN2022105987-appb-100008
    Figure PCTCN2022105987-appb-100008
    Figure PCTCN2022105987-appb-100009
    Figure PCTCN2022105987-appb-100009
    Figure PCTCN2022105987-appb-100010
    Figure PCTCN2022105987-appb-100010
    Figure PCTCN2022105987-appb-100011
    Figure PCTCN2022105987-appb-100011
    Figure PCTCN2022105987-appb-100012
    Figure PCTCN2022105987-appb-100012
    Figure PCTCN2022105987-appb-100013
    Figure PCTCN2022105987-appb-100013
    Figure PCTCN2022105987-appb-100014
    Figure PCTCN2022105987-appb-100014
  14. 一种通式(MA)所示的化合物或其盐：A compound or salt thereof represented by general formula (MA):
    Figure PCTCN2022105987-appb-100015
    Figure PCTCN2022105987-appb-100015
    其中：in:
    R为烷基或
    Figure PCTCN2022105987-appb-100016
    优选地，R为烷基或
    Figure PCTCN2022105987-appb-100017
    R is alkyl or
    Figure PCTCN2022105987-appb-100016
    Preferably, R is alkyl or
    Figure PCTCN2022105987-appb-100017
    R w为烷基或烯丙基；优选地，R w为烯丙基； R w is alkyl or allyl; preferably, R w is allyl;
    Z、G、R 1至R 3、R 5至R 11和n如权利要求1中所定义。 Z, G, R 1 to R 3 , R 5 to R 11 and n are as defined in claim 1 .
  15. 根据权利要求14所述的通式(MA)所示的化合物或其盐，其为通式(IA)所示的化合物或其盐：The compound or its salt shown in general formula (MA) according to claim 14, it is the compound or its salt shown in general formula (IA):
    Figure PCTCN2022105987-appb-100018
    Figure PCTCN2022105987-appb-100018
    其中：in:
    R为烷基；优选地，R为C 1-6烷基； R is an alkyl group; preferably, R is a C 1-6 alkyl group;
    G、R 1至R 11和n如权利要求2中所定义。 G, R1 to R11 and n are as defined in claim 2 .
  16. 化合物或其盐，其选自以下任一化合物：A compound or a salt thereof, which is selected from any of the following compounds:
    Figure PCTCN2022105987-appb-100019
    Figure PCTCN2022105987-appb-100019
    Figure PCTCN2022105987-appb-100020
    Figure PCTCN2022105987-appb-100020
    Figure PCTCN2022105987-appb-100021
    Figure PCTCN2022105987-appb-100021
    Figure PCTCN2022105987-appb-100022
    Figure PCTCN2022105987-appb-100022
    Figure PCTCN2022105987-appb-100023
    Figure PCTCN2022105987-appb-100023
    Figure PCTCN2022105987-appb-100024
    Figure PCTCN2022105987-appb-100024
  17. 一种通式(IVa-A)、通式(IVa-A1)或通式(IVa-A2)所示的化合物或其盐：A compound or salt thereof represented by general formula (IVa-A), general formula (IVa-A1) or general formula (IVa-A2):
    Figure PCTCN2022105987-appb-100025
    Figure PCTCN2022105987-appb-100025
    其中：in:
    R 5a和R 5b不同，且各自独立地选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、环烷基和杂环基；其中所述的烷基、烷氧基、羟烷基、环烷基和杂环基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、羟基、氰基、氨基和硝基中的一个或多个相同或不同的取代基取代；其中当R 5a和R 5b之一为甲基时，另一个不为乙基或丙基； R 5a and R 5b are different, and are each independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl and heterocyclyl; wherein said alkyl, alkoxy Each of radical, hydroxyalkyl, cycloalkyl and heterocyclyl is independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, cyano, amino and One or more identical or different substituents in the nitro group are substituted; wherein when one of R 5a and R 5b is methyl, the other is not ethyl or propyl;
    G为CR 4a； G is CR 4a ;
    环A、R 2a、m、R 4a、R 1和R 4如权利要求6中所定义。 Ring A, R 2a , m, R 4a , R 1 and R 4 are as defined in claim 6 .
  18. 化合物或其盐，其选自以下结构：A compound or a salt thereof, which is selected from the following structures:
    Figure PCTCN2022105987-appb-100026
    Figure PCTCN2022105987-appb-100026
    Figure PCTCN2022105987-appb-100027
    Figure PCTCN2022105987-appb-100027
  19. 一种制备根据权利要求1所述的通式(M)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：A method for preparing a compound represented by the general formula (M) according to claim 1 or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
    Figure PCTCN2022105987-appb-100028
    Figure PCTCN2022105987-appb-100028
    通式(MA)所示的化合物或其盐发生反应，得到通式(M)所示的化合物或其可药用的盐；A compound represented by the general formula (MA) or a salt thereof is reacted to obtain a compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof;
    其中：in:
    R为烷基或
    Figure PCTCN2022105987-appb-100029
    优选地，R为烷基或
    Figure PCTCN2022105987-appb-100030
    R is alkyl or
    Figure PCTCN2022105987-appb-100029
    Preferably, R is alkyl or
    Figure PCTCN2022105987-appb-100030
    R w为烷基或烯丙基；优选地，R w为烯丙基； R w is alkyl or allyl; preferably, R w is allyl;
    条件为，当R选自烷基时，通式(MA)所示的化合物或其盐发生酯水解反应，得到R 0为氢原子的通式(M)所示的化合物或其可药用的盐； The condition is that when R is selected from an alkyl group, the compound represented by the general formula (MA) or its salt undergoes an ester hydrolysis reaction to obtain a compound represented by the general formula (M ) whose R is a hydrogen atom or its pharmaceutically acceptable Salt;
    当R为
    Figure PCTCN2022105987-appb-100031
    通式(MA)所示的化合物或其盐脱去R w，得到R 0为
    Figure PCTCN2022105987-appb-100032
    的通式(M)所示的化合物或其可药用的盐；优选地，当R为
    Figure PCTCN2022105987-appb-100033
    时，通式(MA)所示的化合物或其盐脱去R w，得到R 0为
    Figure PCTCN2022105987-appb-100034
    的通式(M)所示的化合物或其可药用的盐；     when R is
    Figure PCTCN2022105987-appb-100031
    The compound represented by general formula (MA) or its salt removes R w , and obtains R 0 as
    Figure PCTCN2022105987-appb-100032
    A compound represented by the general formula (M) or a pharmaceutically acceptable salt thereof; preferably, when R is
    Figure PCTCN2022105987-appb-100033
    When , the compound represented by the general formula (MA) or its salt removes R w , and R 0 is obtained as
    Figure PCTCN2022105987-appb-100034
    A compound represented by general formula (M) or a pharmaceutically acceptable salt thereof;
    Z、G、R 0、R 1至R 3、R 5至R 11和n如权利要求1中所定义。 Z, G, R 0 , R 1 to R 3 , R 5 to R 11 and n are as defined in claim 1 .
  20. 一种制备根据权利要求2所述的通式(I)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 2, the method comprising the following steps:
    Figure PCTCN2022105987-appb-100035
    Figure PCTCN2022105987-appb-100035
    通式(IA)所示的化合物或其盐发生水解反应，得到通式(I)所示的化合物或其可药用的盐；The compound represented by the general formula (IA) or its salt undergoes a hydrolysis reaction to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;
    其中：in:
    R为烷基；优选地，R为C 1-6烷基； R is an alkyl group; preferably, R is a C 1-6 alkyl group;
    G、R 1至R 11和n如权利要求2中所定义。 G, R1 to R11 and n are as defined in claim 2 .
  21. 一种制备根据权利要求1所述的通式(M)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：A method for preparing a compound represented by the general formula (M) according to claim 1 or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
    Figure PCTCN2022105987-appb-100036
    Figure PCTCN2022105987-appb-100036
    通式(Ma-A)所示的化合物或其盐与通式(MB)所示的化合物或其盐发生缩合酰化反应，得到通式(M)所示的化合物或其可药用的盐；The compound represented by the general formula (Ma-A) or its salt and the compound represented by the general formula (MB) or its salt undergo condensation acylation reaction to obtain the compound represented by the general formula (M) or its pharmaceutically acceptable salt ;
    其中：in:
    Z、G、R 0、R 1至R 3、R 5至R 11和n如权利要求1中所定义。 Z, G, R 0 , R 1 to R 3 , R 5 to R 11 and n are as defined in claim 1 .
  22. 一种制备根据权利要求2所述的通式(I)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 2, the method comprising the following steps:
    Figure PCTCN2022105987-appb-100037
    Figure PCTCN2022105987-appb-100037
    通式(Ia-A)所示的化合物或其盐与通式(IB)所示的化合物或其盐发生缩合酰化反应，得到通式(I)所示的化合物或其可药用的盐；The compound represented by general formula (Ia-A) or its salt and the compound represented by general formula (IB) or its salt occur condensation acylation reaction, obtain the compound represented by general formula (I) or its pharmaceutically acceptable salt ;
    其中：in:
    G、R 1至R 11和n如权利要求2中所定义。 G, R1 to R11 and n are as defined in claim 2 .
  23. 一种药物组合物，所述药物组合物含有治疗有效量的根据权利要求1至13中任一项所述的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition containing a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, and one or more pharmaceutically acceptable carriers , diluent or excipient.
  24. 根据权利要求1至13中任一项所述的化合物或其可药用的盐或根据权利要求23所述的药物组合物在制备sGC激动剂和/或激活剂中的用途。Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 23 in the preparation of sGC agonists and/or activators.
  25. 根据权利要求1至13中任一项所述的化合物或其可药用的盐或根据权利要求23所述的药物组合物在制备用于治疗和/或预防通过激动和/或激活sGC来减轻的疾病、病况或病症的药物中的用途，所述的疾病、病况或病症选自心血管疾病、 肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；优选地，所述的疾病、病况或病症选自心血管疾病、肺动脉高压和肾病；更优选地，所述肾病为慢性肾功能衰竭或慢性肾功能不全。The compound according to any one of claims 1 to 13 or the pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 23 is used in the preparation for treatment and/or prevention by stimulating and/or activating sGC to alleviate A disease, condition or disorder selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, obesity, osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; preferably, said disease, condition or disorder is selected from cardiovascular disease, pulmonary hypertension and renal disease; more preferably, said renal disease is chronic renal failure or chronic renal insufficiency.
  26. 根据权利要求25所述的用途，其中所述心血管疾病选自高血压、动脉粥样硬化症、冠心病、腰椎管狭窄症、外周动脉疾病、间歇性跛行、重症下肢缺血、稳定或者不稳定心绞痛、心肌梗死、心力衰竭、性腺机能减退、中风、冠状动脉痉挛、大脑血管痉挛、缺血/再灌注损伤和血栓栓塞性病症；优选地，所述心血管疾病选自高血压、心肌梗死和心力衰竭。The use according to claim 25, wherein the cardiovascular disease is selected from hypertension, atherosclerosis, coronary heart disease, lumbar spinal stenosis, peripheral artery disease, intermittent claudication, critical lower extremity ischemia, stable or unstable Stable angina, myocardial infarction, heart failure, hypogonadism, stroke, coronary artery spasm, cerebral vasospasm, ischemia/reperfusion injury and thromboembolic disorders; preferably, the cardiovascular disease is selected from hypertension, myocardial infarction and heart failure.
  27. 根据权利要求25所述的用途，其中所述纤维变性病选自皮肤、肝、肾及肺的纤维变性病；所述泌尿***疾病选自膀胱过动症、良性***增生和***功能障碍；所述神经疾病选自阿尔茨海默氏病、帕金森氏病和神经病性疼痛；所述炎性疾病包括牛皮癣、多发性硬化、关节炎、哮喘、溃疡性结肠炎、克罗恩氏病和慢性阻塞性肺病。The use according to claim 25, wherein the fibrotic disease is selected from fibrotic diseases of the skin, liver, kidney and lung; the urinary system disease is selected from overactive bladder, benign prostatic hyperplasia and erectile dysfunction; The neurological disease is selected from Alzheimer's disease, Parkinson's disease and neuropathic pain; the inflammatory disease includes psoriasis, multiple sclerosis, arthritis, asthma, ulcerative colitis, Crohn's disease and chronic Obstructive lung disease.
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Citations (3)

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CN103492361A (en) * 2010-12-07 2014-01-01 拜耳知识产权有限责任公司 Substituted 1-benzylcycloalkylcarboxlic acids and use thereof
CN103796989A (en) * 2011-04-13 2014-05-14 拜耳知识产权有限责任公司 Branched 3-phenylpropionic acid derivatives and the use thereof
WO2020245342A1 (en) * 2019-06-07 2020-12-10 Bayer Aktiengesellschaft The use of sgc activators for the treatment of ophthalmologic diseases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103492361A (en) * 2010-12-07 2014-01-01 拜耳知识产权有限责任公司 Substituted 1-benzylcycloalkylcarboxlic acids and use thereof
CN103796989A (en) * 2011-04-13 2014-05-14 拜耳知识产权有限责任公司 Branched 3-phenylpropionic acid derivatives and the use thereof
WO2020245342A1 (en) * 2019-06-07 2020-12-10 Bayer Aktiengesellschaft The use of sgc activators for the treatment of ophthalmologic diseases

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