WO2023284860A1 - Composé d'acide 3-phénylpropionique, son procédé de préparation et son application médicale - Google Patents

Composé d'acide 3-phénylpropionique, son procédé de préparation et son application médicale 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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general formula
alkyl
compound represented
pharmaceutically acceptable
alkoxy
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PCT/CN2022/105987
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English (en)
Chinese (zh)
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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/zh
Publication of WO2023284860A1 publication Critical patent/WO2023284860A1/fr

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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

L'invention concerne un composé d'acide 3-phénylpropionique, son procédé de préparation et son application médicale. En particulier, l'invention concerne un composé d'acide 3-phénylpropionique représenté par la formule générale (M), un procédé de préparation associé, une composition pharmaceutique contenant le composé, et une utilisation de la composition en tant qu'agent thérapeutique, en particulier une utilisation dans la préparation d'un agoniste de guanylate cyclase soluble (sGC) et une utilisation dans la préparation d'un médicament pour le traitement et/ou la prévention de maladies, de pathologies ou de troubles médiés par sGC.
PCT/CN2022/105987 2021-07-15 2022-07-15 Composé d'acide 3-phénylpropionique, son procédé de préparation et son application médicale WO2023284860A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103492361A (zh) * 2010-12-07 2014-01-01 拜耳知识产权有限责任公司 取代的1-苄基环烷基羧酸及其用途
CN103796989A (zh) * 2011-04-13 2014-05-14 拜耳知识产权有限责任公司 支化的3-苯基丙酸衍生物和其应用
WO2020245342A1 (fr) * 2019-06-07 2020-12-10 Bayer Aktiengesellschaft Utilisation d'activateurs de sgc pour le traitement de maladies ophtalmologiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103492361A (zh) * 2010-12-07 2014-01-01 拜耳知识产权有限责任公司 取代的1-苄基环烷基羧酸及其用途
CN103796989A (zh) * 2011-04-13 2014-05-14 拜耳知识产权有限责任公司 支化的3-苯基丙酸衍生物和其应用
WO2020245342A1 (fr) * 2019-06-07 2020-12-10 Bayer Aktiengesellschaft Utilisation d'activateurs de sgc pour le traitement de maladies ophtalmologiques

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