WO2023155873A1 - 羧酸类化合物、其制备方法及其在医药上的应用 - Google Patents

羧酸类化合物、其制备方法及其在医药上的应用 Download PDF

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Publication number
WO2023155873A1
WO2023155873A1 PCT/CN2023/076748 CN2023076748W WO2023155873A1 WO 2023155873 A1 WO2023155873 A1 WO 2023155873A1 CN 2023076748 W CN2023076748 W CN 2023076748W WO 2023155873 A1 WO2023155873 A1 WO 2023155873A1
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general formula
alkyl
pharmaceutically acceptable
compound represented
acceptable salt
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PCT/CN2023/076748
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English (en)
French (fr)
Inventor
樊兴
陈远
吴晓
严晶晶
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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Publication of WO2023155873A1 publication Critical patent/WO2023155873A1/zh

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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
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • C07C233/45—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 carboxyl groups
    • C07C233/53—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 carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/55—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 carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton

Definitions

  • the disclosure belongs to the field of medicine, and relates to a carboxylic acid compound, its preparation method and its application in medicine.
  • the present disclosure relates to carboxylic acid compounds represented by general formula (I), their preparation methods, pharmaceutical compositions containing such compounds and their use as therapeutic agents, especially as soluble guanylate cyclase ( Use of sGC agonists and/or activators and use in the manufacture of a medicament for the treatment and/or prevention of diseases or conditions mediated by sGC.
  • 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.
  • Ring A is phenyl or 6-membered heteroaryl
  • R 1 and R 2 are the same or different, and are each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, deuterated alkyl, haloalkyl, haloalkoxy, -OR 7.
  • aryl groups are each independently optionally selected from deuterium atom, halogen, alkyl, -OR 7a , hydroxyalkyl, One or more substituents in deuterated alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cyano, amino and nitro;
  • Each R 3 is the same or different, and is independently selected from halogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, haloalkoxy, -OR 7 , carboxy, cyano, amino, nitro, cyclic Alkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 4 is the same or different, and each independently selected from halogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, haloalkoxy, -OR 7 , carboxy, cyano, amino, nitro, ring Alkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, alkane One or more substituents in group, -OR 7a , haloalkyl, haloalkoxy, alkenyl, alkynyl, hydroxyl, cyano, amino and nitro;
  • R 5 and R 6 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, -OR 7 , cycloalkane base and heterocyclyl;
  • R 7 and R 7a are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group;
  • n 1, 2, 3 or 4;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2 or 3.
  • the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof wherein: ring A is phenyl or pyridyl; preferably, ring A is phenyl.
  • the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n and p are as defined in the general formula (I).
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein: R 5 and R 6 are the same or different, and each independently selected from hydrogen atom, halogen and C 1-6 alkyl; preferably, R 5 and R 6 are both hydrogen atoms.
  • the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof Salt to use:
  • Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 2a is the same or different, and is independently selected from deuterium atom, halogen, alkyl, -OR 7a , hydroxyalkyl, deuterated alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cyano, amino and nitro;
  • q 0, 1, 2, 3, 4 or 5;
  • R 1 , R 3 , R 4 , R 7a , m, n and p are as defined in the general formula (I).
  • Ring B is a 6-10-membered aryl group or a 5-10-membered heteroaryl group; preferably Preferably, ring B is a 6- to 10-membered aryl group; more preferably, ring B is a phenyl group.
  • the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof which is represented by general formula (IV)
  • L is a chemical bond or an alkylene group
  • R 1a and R 1b are different and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, -OR 7a , hydroxyalkyl, deuterated alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cyano, amino and nitro;
  • Each R 2a is the same or different, and is independently selected from deuterium atom, halogen, alkyl, -OR 7a , hydroxyalkyl, deuterated alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cyano, amino and nitro;
  • q 0, 1, 2, 3, 4 or 5;
  • R 3 , R 4 , R 7a , m, n and p are as defined in the general formula (I).
  • the compound represented by general formula (I), general formula (II), general formula (III) or general formula (IV) or a pharmaceutically acceptable salt thereof which is Compounds represented by formula (IV-1) or general formula (IV-2) or pharmaceutically acceptable salts thereof:
  • L is a chemical bond or an alkylene group
  • R 1a and R 1b are different and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, -OR 7a , hydroxyalkyl, deuterated alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cyano, amino and nitro;
  • Each R 2a is the same or different, and is independently selected from deuterium atom, halogen, alkyl, -OR 7a , hydroxyalkyl, deuterated alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cyano, amino and nitro;
  • q 0, 1, 2, 3, 4 or 5;
  • R 3 , R 4 , R 7a , m, n and p are as defined in the general formula (I).
  • the compound represented by general formula (I), general formula (II), general formula (III) or general formula (IV) or a pharmaceutically acceptable salt thereof which is The compound shown in formula (V) or its pharmaceutically acceptable salt:
  • R 1a and R 1b are different and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, -OR 7a , hydroxyalkyl, deuterated alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cyano, amino and nitro;
  • R 3a is selected from halogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, haloalkoxy, -OR 7 , carboxyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 2a is the same or different, and is independently selected from hydrogen atom, deuterium atom, halogen, alkyl, -OR 7a , hydroxyalkyl, deuterated alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cyano, amino and nitro;
  • q 0, 1, 2, 3, 4 or 5;
  • R 4 , R 7 , R 7a , m and p are as defined in the general formula (I).
  • the compound represented by general formula (I), general formula (II), general formula (III), general formula (IV) or general formula (V) or its pharmaceutically acceptable A salt which is a compound represented by general formula (V-1) or general formula (V-2) or a pharmaceutically acceptable salt thereof:
  • R 1a and R 1b are different and each independently selected from hydrogen atom, deuterium atom, halogen, alkyl, -OR 7a , hydroxyalkyl, deuterated alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cyano, amino and nitro;
  • R 3a is selected from halogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, haloalkoxy, -OR 7 , carboxyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R 2a is the same or different, and is independently selected from deuterium atom, halogen, alkyl, -OR 7a , hydroxyalkyl, deuterated alkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, cyano, amino and nitro;
  • q 0, 1, 2, 3, 4 or 5;
  • R 4 , R 7 , R 7a , m and p are as defined in the general formula (I).
  • the general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V -1) or a compound represented by general formula (V-2) or a pharmaceutically acceptable salt thereof wherein each R 2a are the same or different, and are each independently selected from a deuterium atom, halogen and C 1-6 alkyl; preferably, each R 2a is the same or different, and each independently is a halogen; more preferably, R 2a is a chlorine atom .
  • the general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V -1) or a compound represented by general formula (V-2) or a pharmaceutically acceptable salt thereof wherein: q is 0; or each R 2a is the same or different, and each independently selected from deuterium atom, halogen and C 1 -6 alkyl, and q is 1, 2, 3, 4 or 5; preferably, q is 0; or each R 2a is the same or different, and each independently selected from deuterium atom, halogen and C 1-6 alkyl , and q is 1 or 2; more preferably, R 2a is halogen, and q is 1; most preferably, R 2a is Cl, and q is 1.
  • the compound represented by (V-2) or a pharmaceutically acceptable salt thereof wherein: R 1a and R 1b are different, and each independently selected from hydrogen atom, deuterium atom, halogen, C 1-6 alkyl, hydroxyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl and halogenated C 1-6 alkoxy; preferably, R 1a and R 1b is different, and each is independently C 1-6 alkyl or halogenated C 1-6 alkyl; more preferably, R 1a is C 1-6 alkyl; R 1b is halogenated C 1-6 alkyl; Most preferably, R 1a is methyl; R 1b is trifluoromethyl.
  • each R 4 is the same or different, and each independently selected from Halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl, said C 1-6 alkyl is optionally replaced by one or more cyano groups Substitution; preferably, each R 4 is the same or different, and each independently selected from halogen, C 1-6 alkyl and 3 to 6 membered cycloalkyl; more preferably, each R 4 is the same or different, and each independently selected from halogen, C 1-6 alkyl and cyclopropyl; further preferably, each R 4 is the same or different, and each independently selected from F, Cl, Br
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein: R 1 and R 2 are different and each independently selected from Hydrogen atom, deuterium atom, halogen, C 1-6 alkyl, hydroxy C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy , hydroxyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; wherein said C 1-6 alkyl, hydroxy C 1-6 Alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from deuterium atom, halogen, C 1-6 Alkyl, hydroxyl, C 1-6 alkyl, hydroxyl, C
  • R and R are different and each independently selected from C 1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered Heteroaryl;
  • said C 1-6 alkyl, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally Be selected from deuterium atom, halogen, C 1-6 alkyl, hydroxyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl Substituting with one or more substituents in the halogenated C 1-6 alkoxy group;
  • R 1 and R 2 are different, and are each independently selected from C 1-6 alkyl, 6-10 membered aryl and 5-10 membered heteroaryl; wherein said C 1-6 alkyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from deuterium atom, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl Substituting with one or more substituents in the halogenated C 1-6 alkoxy group;
  • R 1 and R 2 are different, and are each independently C 1-6 alkyl or 6-10 membered aryl; wherein said C 1-6 alkyl or 6-10 membered aryl are each independently Optionally substituted by one or more substituents selected from deuterium atom, halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 1 and R 2 are different, and are each independently C 1-6 alkyl or phenyl; wherein said C 1-6 alkyl or phenyl are each independently selected from deuterium atom, One or more substituents in halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 1 is C 1-6 alkyl; said C 1-6 alkyl is optionally substituted by one or more substituents in deuterium atom or halogen;
  • R 2 is phenyl; wherein said Phenyl is optionally substituted by one or more substituents selected from halogen, C 1-6 alkyl and halogenated C 1-6 alkyl;
  • R 1 is C 1-6 alkyl; said C 1-6 alkyl is optionally substituted by one or more halogens; R 2 is phenyl; wherein said phenyl is optionally substituted by one or Multiple halogen substitutions.
  • the compound represented by general formula (I), general formula (II) or general formula (III) or a pharmaceutically acceptable salt thereof wherein: R 1 is L is a chemical bond or a C 1-6 alkylene group; R 1a and R 1b are different, and each independently selected from deuterium atom, halogen, C 1-6 alkyl, hydroxyl, C 1-6 alkoxy, hydroxyl C 1 -6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl and halogenated C 1-6 alkoxy.
  • R 1 is L is a chemical bond or a C 1-6 alkylene group
  • R 1a and R 1b are different, and each independently selected from a hydrogen atom, a deuterium atom, a halogen, a C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkoxy group, Hydroxy C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl and halogenated C 1-6 alkoxy
  • R is R 1a and R 1b are different, and are each independently C 1-6 alkyl or halogenated C 1-6 alkyl; more preferably, R 1 is R 1a is C 1-6 alkyl; R 1b is halogenated C 1-6 alkyl.
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein: for Ring B is a 6 to 10 membered aryl group or a 5 to 10 membered heteroaryl group; L is a chemical bond or a C 1-6 alkylene group; R 1a and R 1b are different, and are each independently selected from a deuterium atom, a halogen, a C 1 -6 alkyl, hydroxy, C 1-6 alkoxy, hydroxy C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl and halogenated C 1-6 alkoxy ; q is 0; or each R 2a is the same or different, and is independently selected from deuterium atom, halogen and C 1-6 alkyl, and q is 1, 2, 3, 4 or 5.
  • the compound represented by general formula (I) or general formula (II) or its druggable Salt used of which: for Ring B is a 6-10 membered aryl group or a 5-10 membered heteroaryl group; L is a chemical bond or a C 1-6 alkylene group; R 1a and R 1b are different, and each independently selected from a hydrogen atom, a deuterium atom, a halogen , C 1-6 alkyl, hydroxyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl and halogenated C 1-6 Alkoxy; q is 0; or each R 2a is the same or different, and each independently selected from deuterium atom, halogen and C 1-6 alkyl, and q is 1, 2, 3, 4 or 5; preferably, for Ring B is a 6- to 10-membered aryl group; L is a chemical bond or a
  • R 1 is C 1-6 alkyl; said C 1-6 alkyl is optionally selected from deuterium atom, halogen, hydroxyl, C 1-6 hydroxyalkyl, One or more substituents in C 1-6 alkoxy, deuterated C 1-6 alkyl, halogenated C 1-6 alkoxy, alkenyl, alkynyl, cyano, amino and nitro;
  • R 1 is C 1-6 alkyl; said C 1-6 alkyl is optionally substituted by one or more halogens.
  • the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof wherein: R 2 is selected from 3 to 6 membered cycloalkyl, 3 to 6-membered heterocyclic group, 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group; preferably, R 2 is 6 to 10-membered aryl group or 5- to 10-membered heteroaryl group; more preferably, R 2 is 6 to 10 membered aryl; most preferably R2 is phenyl.
  • each R 3 is the same or different, and each independently selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl and halogenated C 1 -6 alkoxy; preferably, each R 3 is the same or different, and is independently halogen; more preferably, R 3 is Cl.
  • each R 3 is the same or different, and each independently selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl and halogenated C 1 -6 alkoxy, and n is 1 or 2; preferably, R 3 is halogen, and n is 1; more preferably, R 3 is Cl, and n is 1.
  • the 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: for R 3 is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl and halogenated C 1-6 alkoxy; preferably, for R 3 is halogen; more preferably, for
  • the compound represented by general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein: L is a chemical bond ; R 1a is C 1-6 alkyl; R 1b is halogenated C 1-6 alkyl; R 2a is halogen; q is 1; R 3 is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl and halogenated C 1-6 alkoxy; n is 1; R 4 is selected from halogen , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl, said C 1-6 alkyl is optionally substituted by one or more cyano groups ; m is 0 or 1; and p is 0 or 1.
  • the compound represented by general formula (IV), general formula (IV-1) or general formula (IV-2) or a pharmaceutically acceptable salt thereof wherein: L is a chemical bond ; R 1a is C 1-6 alkyl; R 1b is halogenated C 1-6 alkyl; q is 0; or each R 2a is the same or different, and each independently selected from deuterium atom, halogen and C 1-6 Alkyl, and q is 1 or 2; each R 3 is the same or different, and each independently selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl and halogenated C 1-6 alkoxy , and n is 1 or 2; m is 0; or each R 4 is the same or different, and each independently selected from halogen, C 1-6 alkyl and 3 to 6 membered cycloalkyl, and m is 1; and p is 0 or 1.
  • the compound represented by general formula (V), general formula (V-1) or general formula (V-2) or a pharmaceutically acceptable salt thereof wherein: R 1a is C 1-6 alkyl; R 1b is halogenated C 1-6 alkyl; R 2a is halogen, and q is 1; R 3a is halogen; m is 0; or each R 4 is the same or different, and each independently selected from halogen, C 1-6 alkyl and 3 to 6 membered cycloalkyl, and m is 1; and p is 0 or 1.
  • the compound represented by general formula (V), general formula (V-1) or general formula (V-2) or a pharmaceutically acceptable salt thereof wherein: R 1a is C 1-6 alkyl; R 1b is halogenated C 1-6 alkyl; R 2a is halogen, and q is 1; R 3a is halogen; m is 0; or each R 4 is the same or different, and each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl, the C 1-6 alkyl is optionally replaced by one or more cyano substitution, and m is 1; p is 0 or 1.
  • Typical compounds of the present disclosure include, but are not limited to:
  • p 1, 2 or 3;
  • Ring A, R 3 , R 4 , R 5 , R 6 , m and n are as defined in the general formula (I).
  • p 1, 2 or 3;
  • R 3 , R 4 , R 5 , R 6 , m and n are as defined in the general formula (II).
  • p 1, 2 or 3;
  • R 3 , R 4 , m and n are as defined in the general formula (III).
  • VA general formula (VA) or salts thereof:
  • p 1, 2 or 3;
  • R 3a , R 4 and m are as defined in the general formula (V).
  • Typical intermediate compounds of the present disclosure include, but are not limited to:
  • R is C 1-6 alkyl; preferably, R is methyl;
  • Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n and p are as defined in general formula (I).
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n and p are as defined in the general formula (II).
  • R is C 1-6 alkyl; preferably, R is methyl;
  • Ring B, R 1 , R 2a , R 3 , R 4 , m, n, p and q are as defined in the general formula (III).
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R 1a , R 1b , R 2a , R 3 , R 4 , m, n, p and q are as defined in the general formula (IV).
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R 1a , R 1b , R 2a , R 3a , R 4 , m, p and q are as defined in the general formula (V).
  • Another aspect of the present disclosure relates to a compound represented by general formula (V-1a) or a salt thereof:
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R 1a , R 1b , R 2a , R 3a , R 4 , m, p and q are as defined in the general formula (V-1).
  • Another aspect of the present disclosure relates to a compound represented by general formula (V-2a) or a salt thereof:
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R 1a , R 1b , R 2a , R 3a , R 4 , m, p and q are as defined in the general formula (V-2).
  • Typical intermediate compounds of the present disclosure include, but are not limited to:
  • 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 compound represented by the general formula (IA) or a salt thereof and the compound represented by the general formula (IB) or a salt thereof undergo an amidation reaction to obtain a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;
  • Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n and p are as defined in 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:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n and p 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:
  • Ring B, R 1 , R 2a , R 3 , R 4 , m, n, p and q 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 (IV) or a pharmaceutically acceptable salt thereof, the method comprising:
  • R 1a , R 1b , R 2a , R 3 , R 4 , m, n, p and q 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:
  • 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:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (VA) or a salt thereof and the compound represented by the general formula (VB) or a salt thereof undergo an amidation reaction to obtain a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof;
  • R 1a , R 1b , R 2a , R 3a , R 4 , m, p and q are as defined in the general formula (V).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • R 1a , R 1b , R 2a , R 3a , R 4 , m, p and q are as defined in the general formula (V-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V-2) or a pharmaceutically acceptable salt thereof, the method comprising:
  • R 1a , R 1b , R 2a , R 3a , R 4 , m, p and q are as defined in the general formula (V-2).
  • 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 compound represented by the general formula (Ia) or its salt undergoes a hydrolysis reaction to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n and p are as defined in 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 compound represented by the general formula (IIa) or its salt undergoes a hydrolysis reaction to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n and p 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 compound represented by the general formula (IIIa) or its salt undergoes a hydrolysis reaction to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • Ring B, R 1 , R 2a , R 3 , R 4 , m, n, p and q 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 (IV) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (IVa) or its salt undergoes a hydrolysis reaction to obtain the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R 1a , R 1b , R 2a , R 3 , R 4 , m, n, p and q 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 compound represented by the general formula (IV-1a) or its salt undergoes a hydrolysis reaction to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • 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 compound represented by the general formula (IV-2a) or its salt undergoes a hydrolysis reaction to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (Va) or its salt undergoes a hydrolysis reaction to obtain the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R 1a , R 1b , R 2a , R 3a , R 4 , m, p and q are as defined in the general formula (V).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V-1) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (V-1a) or its salt undergoes a hydrolysis reaction to obtain the compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R 1a , R 1b , R 2a , R 3a , R 4 , m, p and q are as defined in the general formula (V-1).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V-2) or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound represented by the general formula (V-2a) or its salt undergoes a hydrolysis reaction to obtain the compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R 1a , R 1b , R 2a , R 3a , R 4 , m, p and q are as defined in the general formula (V-2).
  • compositions which contains the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV- 1), the compound shown in general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and table A or its pharmaceutically acceptable salt, and a kind of or multiple pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), General formula (V-1), general formula (V-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or the purposes of the pharmaceutical composition comprising it in the preparation of sGC agonist and/or activator .
  • the present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V),
  • a disease or condition selected from cardiovascular disease, nephropathy, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, diabetic retinopathy, obesity, osteoporosis, Fibrotic disease, neurological disease, urinary system disease and sexual dysfunction;
  • the disease or disease is selected from cardiovascular disease, pulmonary hypertension and nephropathy; More preferably, the nephropathy is selected from chronic renal failure, chronic Renal insufficiency and diabetic nephropathy.
  • the present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), Compounds or pharmaceutically acceptable salts thereof shown in general formula (V-1), general formula (V-2) and Table A, or pharmaceutical compositions comprising it are used in the preparation of medicines for treating and/or preventing diseases or disorders
  • the purposes in, described disease or illness is selected from cardiovascular disease, nephropathy, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, diabetic retinopathy, obesity, osteoporosis, fibrosis, nervous disease, urinary system disease and sexual dysfunction; preferably, the disease or disease is selected from cardiovascular disease, pulmonary hypertension and nephropathy; more preferably, the nephropathy is selected from chronic renal failure, chronic renal insufficiency and diabetic nephropathy.
  • the present disclosure further relates to a method of stimulating and/or activating sGC, which comprises administering the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV- 1), the compound shown in general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and Table A or its pharmaceutically acceptable salt, or including its pharmaceutical composition.
  • the present disclosure further relates to a method of treating and/or preventing diseases or conditions alleviated by stimulating and/or activating sGC, which comprises administering the general formula (I), general formula (II), general formula (III) to patients in need , general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and shown in Table A
  • the disease or condition is selected from cardiovascular disease, nephropathy, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, diabetic retinopathy, obesity, Osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; preferably, said disease or condition is selected from cardiovascular disease, pulmonary hypertension and renal disease; more preferably, said renal disease is selected from chronic renal disease functional failure, chronic renal insufficiency, and diabetic nephropathy.
  • the present disclosure further relates to a method for treating and/or preventing diseases or diseases, which comprises administering general formula (I), general formula (II), general formula (III), general formula (IV), general formula ( IV-1), general formula (IV-2), general formula (V), general formula (V-1), general formula (V-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or A pharmaceutical composition comprising it, wherein said disease or condition is selected from the group consisting of cardiovascular disease, nephropathy, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, diabetic retinopathy, obesity, osteoporosis, fibrosis, neurological disease , urinary system disease and sexual dysfunction; preferably, the disease or disease is selected from cardiovascular disease, pulmonary hypertension and nephropathy; more preferably, the nephropathy is selected from chronic renal failure, chronic renal insufficiency and diabetic nephropathy .
  • the present disclosure further relates to a general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V ), general formula (V-1), general formula (V-2) and a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used as a medicine.
  • the present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V),
  • the present disclosure further relates to a general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V ), general formula (V-1), general formula (V-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, it is used as treatment and/or prevention by agonist And/or activate sGC to alleviate the disease or disease drug, wherein said disease or disease is selected from cardiovascular disease, nephropathy, pulmonary arterial hypertension hypertension, inflammatory disease, diabetes, glaucoma, diabetic retinopathy, obesity, osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual dysfunction; preferably, said disease or condition is selected from cardiovascular disease , pulmonary hypertension and nephropathy; more preferably, said nephropathy is selected from chronic renal failure, chronic renal insufficiency and diabetic nephropathy.
  • the present disclosure further relates to a general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V ), general formula (V-1), general formula (V-2) and a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used as a medicine for treating a disease or a disease, wherein said disease or condition is selected from the group consisting of cardiovascular disease, renal disease, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, diabetic retinopathy, obesity, osteoporosis, fibrotic disease, neurological disease, urinary system disease and sexual function Disorder;
  • the disease or condition is selected from cardiovascular disease, pulmonary hypertension and nephropathy; more preferably, the nephropathy is selected from chronic renal failure, chronic renal insufficiency and diabetic nephropathy.
  • the present disclosure further relates to general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V),
  • the present disclosure further relates to a general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V ), general formula (V-1), general formula (V-2) and the compound shown in Table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it, it is used for the treatment and/or prevention and/or activate sGC to reduce the disease or condition, wherein said disease or condition is selected from cardiovascular disease, nephropathy, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, diabetic retinopathy, obesity, osteoporosis, fiber degenerative disease, neurological disease, urinary system disease and sexual dysfunction; preferably, said disease or condition is selected from cardiovascular disease, pulmonary hypertension and nephropathy; more preferably, said nephropathy is selected from chronic renal failure, chronic renal failure Insufficiency and diabetic nephropathy.
  • the present disclosure further relates to a general formula (I), general formula (II), general formula (III), general formula (IV), general formula (IV-1), general formula (IV-2), general formula (V ), general formula (V-1), general formula (V-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 diseases or disorders, wherein
  • the disease or condition is selected from the group consisting of cardiovascular disease, nephropathy, pulmonary hypertension, inflammatory disease, diabetes, glaucoma, diabetic retinopathy, obesity, osteoporosis, fibrosis, neurological disease, urinary system disease and sexual dysfunction;
  • the disease or condition is selected from cardiovascular disease, pulmonary hypertension and nephropathy; more preferably, the nephropathy is selected from chronic renal failure, chronic renal insufficiency and diabetic nephropathy.
  • the cardiovascular disease described in the present disclosure is selected from hypertension, atherosclerosis, coronary heart disease, lumbar spinal stenosis, peripheral arterial disease, intermittent claudication, critical lower extremity ischemia, stable or unstable angina, myocardial Infarction, heart failure, hypogonadism, stroke, coronary artery spasm, cerebral vasospasm, ischemia/reperfusion injury and thromboembolic disorders; more preferably, said cardiovascular disease is selected from hypertension, myocardial infarction and cardiac Exhausted.
  • the fibrotic disease of the present disclosure is selected from fibrotic diseases of the skin, liver, kidney and lung.
  • the urinary system disease described in the present disclosure is selected from overactive bladder, benign prostatic hyperplasia and erectile dysfunction cause dysfunction.
  • the neurological disease of the present disclosure is selected from Alzheimer's disease, Parkinson's disease and neuropathic pain.
  • the inflammatory disease of the present disclosure is selected from psoriasis, multiple sclerosis, arthritis, asthma, ulcerative colitis, Crohn's disease and chronic obstructive pulmonary disease.
  • the fibrosis described in the present disclosure is selected from the fibrosis of the skin, liver, kidney and lung; the urinary system disease is selected from overactive bladder, benign prostatic hyperplasia and erectile dysfunction; the nerve The disease is selected from Alzheimer's disease, Parkinson's disease and neuropathic pain; the inflammatory disease is selected from psoriasis, multiple sclerosis, arthritis, asthma, ulcerative colitis, Crohn's disease and chronic Obstructive lung disease.
  • the peripheral arterial disease described in the present disclosure is selected from the group consisting of thromboangiitis obliterans, peripheral arterial occlusive disease, Raynaud's disease and Raynaud's syndrome.
  • 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.
  • the 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, reconstitution powder or liquid preparation.
  • 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 Deltec CADD-PLUS.TM. Model 5400 IV 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 , the patient's diet, administration time, administration method, excretion rate, drug combination, disease severity, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the pharmaceutically acceptable salt Kinds can be validated against traditional treatment regimens.
  • alkyl refers to a saturated linear or branched aliphatic hydrocarbon group having 1 to 20 (for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C 1-20 alkyl).
  • the alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, a C 1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C 1-6 alkyl group).
  • Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl base, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methyl Butyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-Dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl
  • Alkyl 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, ring One or more of alkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • alkylene refers to a divalent alkyl group, wherein alkyl is as defined above, having from 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 (ie C 1-20 alkylene).
  • the alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (ie, a C 1-12 alkylene group), more preferably an alkylene group having 1 to 6 carbon atoms (ie, a C 1-6 alkylene group).
  • Non-limiting examples include : -CH2- , -CH( CH3 )-, -C ( CH3 ) 2- , -CH2CH2-, -CH( CH2CH3 )-, -CH2CH (CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, etc.
  • the alkylene group may be substituted or unsubstituted, and when substituted, it 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 group containing at least one carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (ie C 2-12 alkenyl).
  • the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (ie, a C 2-6 alkenyl group).
  • Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like.
  • Alkenyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents being preferably selected from D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, ring One or more of alkyloxy, 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 or 12) carbon atoms (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 groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, substituents Preferably selected from D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero One or more of cyclic group, aryl group and heteroaryl group.
  • 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 full carbocycle (ie monocyclic cycloalkyl) or polycyclic ring system (ie polycyclic cycloalkyl) having 3 to 20 (eg 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 3 to 20 membered cycloalkyl).
  • the cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e. a 3 to 12 membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e. a 3 to 8 membered cycloalkyl group). ), most preferably a cycloalkyl group having 3 to 6 ring atoms (ie a 3 to 6 membered cycloalkyl group).
  • Said monocyclic cycloalkyl non-limiting examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl and cyclooctyl, etc.
  • the polycyclic cycloalkyl includes: spirocycloalkyl, condensed cycloalkyl and bridged cycloalkyl.
  • spirocycloalkyl refers to a polycyclic ring system that shares one carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds in the ring, or may contain one or more rings selected from nitrogen, Oxygen and sulfur heteroatoms (the nitrogen may be optionally oxidized, i.e. form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • the spirocycloalkyl is preferably a spirocycloalkyl having 6 to 14 ring atoms (i.e.
  • spirocycloalkyl a 6 to 14 membered spirocycloalkyl, more preferably a spirocycloalkyl having 7 to 10 ring atoms (i.e. 7 to 10 member spirocycloalkyl).
  • the spirocycloalkyl group includes single spirocycloalkyl and polyspirocycloalkyl (such as double spirocycloalkyl, etc.), preferably single spirocycloalkyl or double spirocycloalkyl, more preferably 3-membered/4-membered, 3-membered Yuan/5 yuan, 3 yuan/6 yuan, 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
  • connection point can be at any position
  • fused cycloalkyl refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl to a heterocyclic
  • cyclic groups, aryl groups or heteroaryl groups are condensed, wherein the point of attachment is on the monocyclic cycloalkyl group, which can contain one or more double bonds in the ring, and have 5 to 20 (for example, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered fused cycloalkyl).
  • the condensed cycloalkyl group is preferably a condensed cycloalkyl group having 6 to 14 ring atoms (i.e. a 6 to 14 membered fused cycloalkyl group), more preferably a fused cycloalkyl group having 7 to 10 ring atoms (i.e. 7 to 10 fused cycloalkyl).
  • the fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl , more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 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, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 y
  • bridged cycloalkyl refers to an all-carbon polycyclic ring system that shares two carbon atoms not directly connected between the rings, may contain one or more double bonds in the ring, and has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie, 5 to 20 membered bridged cycloalkyl).
  • the bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e. a 6 to 14 membered bridged cycloalkyl group), more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e.
  • the bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl .
  • Non-limiting examples include:
  • Cycloalkyl 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, alkyl, alkoxy, haloalkyl, haloalkane One of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic heterocycle (i.e. monocyclic heterocyclyl) or polycyclic heterocyclic ring system (i.e. polycyclic heterocyclyl) containing at least one (eg 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e. form nitrogen oxides; the sulfur may optionally be oxo, i.e.
  • the heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e. a 3 to 12 membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e.
  • a 3 to 8 membered heterocyclic group ); more preferably a heterocyclyl group having 3 to 6 ring atoms (ie, a 3- to 6-membered heterocyclyl group); most preferably a heterocyclyl group having 5 or 6 ring atoms (ie, a 5- or 6-membered heterocyclyl group).
  • Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl , Thiomorpholinyl and Homopiperazinyl, etc.
  • the polycyclic heterocyclic groups include spiro heterocyclic groups, condensed heterocyclic groups and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic ring system that shares one atom (called a spiro atom) between the rings, which may contain one or more double bonds in the ring, and at least one (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • the condition is that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered spiroheterocyclyl).
  • the spiroheterocyclyl is preferably a spiroheterocyclyl having 6 to 14 ring atoms (i.e.
  • the spiroheterocyclyl includes single spiroheterocyclyl and polyspiroheterocyclyl (such as double spiroheterocyclyl, etc.), preferably single spiroheterocyclyl or double spiroheterocyclyl, more preferably 3-membered/4-membered, 3-membered Yuan/5 yuan, 3 yuan/6 yuan, 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,
  • fused heterocyclyl refers to a polycyclic heterocyclic ring system which shares two adjacent atoms between the rings, which may contain one or more double bonds, and which contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • sulfoxides or sulfones but not Including -OO-, -OS- or -SS-), which is monocyclic heterocyclyl fused with one or more monocyclic heterocyclyl, or monocyclic heterocyclyl and cycloalkyl, aryl or heteroaryl
  • the fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (ie, a 6 to 14 membered fused heterocyclic group), more preferably a condensed heterocyclic group having 7 to 10 ring atoms (ie, 7 to 10 membered fused heterocyclyl).
  • the fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably bicyclic fused heterocyclic groups or tricyclic fused heterocyclic groups, more preferably 3 Yuan/4 Yuan, 3 Yuan/5 Yuan, 3 Yuan/6 Yuan, 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, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan Or a 7-membered/6-membered bicyclic condensed heterocyclic group.
  • bridged heterocyclyl refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, and may contain one or more double bonds in the ring, and at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e.
  • the bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e. a 6 to 14 membered bridged heterocyclic group), more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e. 7 to 10 bridged heterocyclyl).
  • bicyclic bridged heterocyclic group and polycyclic bridged heterocyclic group such as tricyclic bridged heterocyclic group, tetracyclic bridged heterocyclic group, etc.
  • bicyclic bridged heterocyclic group or tricyclic bridged heterocyclic group base preferably bicyclic bridged heterocyclic group or tricyclic bridged heterocyclic group base.
  • Non-limiting examples 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 D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkane One of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.
  • aryl refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aryl) or a polycyclic aromatic ring system (i.e., a polycyclic aryl) having a conjugated ⁇ -electron system, which has 6 to 14 (e.g., 6 , 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (ie 6 to 14 membered aryl).
  • the aryl group is preferably an aryl group having 6 to 10 ring atoms (ie, a 6 to 10 membered aryl group).
  • the monocyclic aryl group such as phenyl.
  • Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracenyl, phenanthrenyl and the like.
  • the polycyclic aryl also includes the condensing of phenyl with one or more of heterocyclic or cycloalkyl, or the fused of naphthyl with one or more of heterocyclic or cycloalkyl, wherein the connection point On phenyl or naphthyl, and in this case, the number of ring atoms continues to mean the number of ring atoms in a polycyclic aromatic ring system, non-limiting examples include: wait.
  • Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy one or Multiple.
  • heteroaryl refers to a monocyclic heteroaryl ring (ie, monocyclic heteroaryl) or a polycyclic heteroaryl ring system (ie, polycyclic heteroaryl) having a conjugated ⁇ -electron system, which contains at least one (eg 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e. form nitrogen oxides; the sulfur may optionally be oxo, i.e.
  • the heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e. a 5 to 10 membered heteroaryl group), more preferably a heteroaryl group having 5 or 6 ring atoms (i.e. a 5 or 6 membered heteroaryl group).
  • Non-limiting examples of the monocyclic heteroaryl include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl , pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (such as etc.), pyrazinyl, pyridazinyl, etc.
  • the polycyclic heteroaryl non-limiting examples include: indolyl, indazolyl, quinolinyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene group, quinazoline group, benzothiazolyl group, carbazolyl group, etc.
  • the polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aryls, wherein the point of attachment is on the aromatic ring, and in this case the number of ring atoms continues to represent the polycyclic heteroaryl The number of ring atoms in the system.
  • the polycyclic heteroaryl also includes monocyclic heteroaryl fused with one or more of cycloalkyl or heterocyclic, wherein the point of attachment is on the monocyclic heteroaryl ring, and in this case, the ring
  • the number of atoms continues to indicate the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include: wait.
  • Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • 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.
  • 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.
  • 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.
  • stereoisomer refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (e.g. racemates, mixtures of diastereomers) . Substituents in compounds of the present disclosure may be present with additional asymmetric atoms.
  • Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer.
  • An isomer of a certain compound in the present disclosure can be prepared by asymmetric synthesis or chiral auxiliary agents, or, when the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxyl), with appropriate optical Reactive acids or bases form diastereomeric salts, which are then resolved by conventional methods well known in the art to yield the pure isomers. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.
  • the bond Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or both Two configurations.
  • tautomer or tautomeric form
  • tautomer refers to structural isomers that exist in equilibrium and are readily converted from one isomeric form to the other. It includes all possible tautomers, ie present as single isomers or as mixtures of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactam, and the like. An example of lactam-lactim equilibrium is shown below:
  • isotopic derivatives refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass.
  • isotopes that may be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, etc., such as 2 H (deuterium, D), respectively, 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N , 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I, and 131 I, etc., preferably deuterium.
  • deuterated drugs Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing curative effect, and prolonging the biological half-life of drugs. All permutations of isotopic composition of the disclosed compounds, whether radioactive or not, are included within the scope of the present disclosure.
  • Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein the replacement of deuterium may be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.
  • the position when a position is specifically designated as “deuterium” or “D”, the position is understood to mean that the abundance of deuterium is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e. , at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (ie, at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (ie, at least 30% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (ie, at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (ie, at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (ie, at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (ie, at least 60% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (ie, at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (ie, at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (ie, at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (ie, at least 90% deuterium incorporation).
  • the abundance of deuterium per designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (ie, at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (ie, at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (ie, at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium per designated deuterium atom is greater than the abundance of deuterium At least 6633.3 times greater in natural abundance (ie, at least 99.5% deuterium incorporation).
  • alkyl optionally substituted by halogen or cyano includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen or cyano.
  • Substituted or “substituted” means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms are independently substituted by the 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 bond such as an alkene.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a pharmaceutically acceptable salt thereof, and other chemical components, such as pharmaceutically acceptable carriers 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. They can be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate 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 "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 (I) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n and p are as defined in 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:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n and p 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 B, R 1 , R 2a , R 3 , R 4 , m, n, p and q are as defined in the general formula (III).
  • 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:
  • R 1a , R 1b , R 2a , R 3 , R 4 , m, n, p and q 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 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 preparation method of the compound represented by the general formula (V) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R 1a , R 1b , R 2a , R 3a , R 4 , m, p and q are as defined in the general formula (V).
  • the preparation method of the compound represented by the general formula (V-1) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound represented by the general formula (VA) or its salt and the compound represented by the general formula (V-1B) or its salt undergo an amidation reaction in the presence of a condensing agent and a base to obtain the compound represented by the general formula (V-1). or a pharmaceutically acceptable salt thereof;
  • R 1a , R 1b , R 2a , R 3a , R 4 , m, p and q are as defined in the general formula (V-1).
  • the preparation method of the compound represented by the general formula (V-2) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • R 1a , R 1b , R 2a , R 3a , R 4 , m, p and q are as defined in the general formula (V-2).
  • 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) or its salt undergoes a hydrolysis reaction under the action of a base to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n and p are as defined in 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:
  • the compound represented by the general formula (IIa) or its salt undergoes a hydrolysis reaction under the action of a base to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n and p 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:
  • the compound represented by the general formula (IIIa) or its salt undergoes a hydrolysis reaction under the action of a base to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • Ring B, R 1 , R 2a , R 3 , R 4 , m, n, p and q are as defined in the general formula (III).
  • 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:
  • the compound represented by the general formula (IVa) or its salt undergoes a hydrolysis reaction under the action of a base to obtain the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R 1a , R 1b , R 2a , R 3 , R 4 , m, n, p and q 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:
  • a compound represented by the general formula (IV-1a) or a salt thereof undergoes a hydrolysis reaction under the action of a base to obtain a compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • 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 a hydrolysis reaction under the action of a base to obtain the compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • the preparation method of the compound represented by the general formula (V) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound represented by the general formula (Va) or its salt undergoes a hydrolysis reaction under the action of a base to obtain the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R 1a , R 1b , R 2a , R 3a , R 4 , m, p and q are as defined in the general formula (V).
  • the preparation method of the compound represented by the general formula (V-1) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound represented by the general formula (V-1a) or its salt undergoes a hydrolysis reaction under the action of a base to obtain the compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R 1a , R 1b , R 2a , R 3a , R 4 , m, p and q are as defined in the general formula (V-1).
  • the preparation method of the compound represented by the general formula (V-2) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:
  • the compound represented by the general formula (V-2a) or its salt undergoes a hydrolysis reaction under the action of a base to obtain the compound represented by the general formula (V-2) or a pharmaceutically acceptable salt thereof;
  • R is C 1-6 alkyl; preferably, R is methyl;
  • R 1a , R 1b , R 2a , R 3a , R 4 , m, p and q are as defined in the general formula (V-2).
  • the bases described in the above synthesis schemes include organic bases and inorganic bases, and the organic bases include but are not limited to triethylamine, pyridine, N,N-diisopropylethylamine, n-butyl lithium, diiso Lithium propylamide, 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 base described in scheme one to scheme nine is pyridine; scheme The base described in ten to eighteen schemes is lithium hydroxide.
  • the condensing agent described in the above synthesis scheme 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.
  • 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, Crusher Pharmaceuticals, Behringwell, Adamas, Sinopharm and other companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • 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 Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
  • 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 it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • TLC thin-layer chromatography
  • the title compound 6 (8 mg, yield: 7%) was obtained by using the synthetic route of Example 3 and replacing the raw material 3a of the first step with 2-(2-bromo-4-chlorophenyl)acetic acid.
  • Methyl 2-(4-amino-2-bromophenyl)acetate 8a (2.4g, 9.83mmol, prepared by the method disclosed in Example 154 on page 115 of the specification in WO2015049629A1) was dissolved in dichloro Methane (50mL), add triethylamine (2.99g, 29.60mmol), slowly drop di-tert-butyl dicarbonate (4.25g, 19.68mmol), stir at room temperature for 6 hours, concentrate, use column chromatography to eluent The resulting residue was purified by System B to give the title compound 8b (3 g, yield: 88%).
  • the title compound 10 (8 mg, yield: 7%) was obtained by using the synthetic route of Example 9, replacing the raw material cyclopropylboronic acid in the second step with potassium n-propyltrifluoroborate.
  • Dissolve compound 17b (9.5g, 39.90mmol), N-bromosuccinimide (16.33g, 91.76mmol) in carbon tetrachloride (100mL), add dibenzoyl peroxide (247mg, 3.99mmol) , heated to 90°C and refluxed for 8 hours, cooled and quenched with saturated aqueous sodium sulfite (20mL), extracted with dichloromethane (50mL ⁇ 3), combined the organic phases, and concentrated to obtain the crude product of the title product 17c, which was directly injected into the next step without purification reaction.
  • Reaction solution 1 Compound 1e (325mg, 1.22mmol) and N,N-dimethylformamide (8.89mg, 121.66 ⁇ mol) were dissolved in tetrahydrofuran (7mL), then oxalyl chloride (200mg, 1.58mmol) was added dropwise at room temperature Reaction for 1 hour;
  • Reaction solution 2 Dissolve compound 17i (400mg, 1.22mmol), diisopropylethylamine (629mg, 4.87mmol) in tetrahydrofuran (7mL), add dropwise triethylchlorosilane (239mg, 1.58mmol) , reacted at room temperature for 45 minutes; under the condition of 0° C., the reaction solution 2 was added dropwise to the reaction solution 1, stirred at room temperature for 8 hours, diluted with ethyl acetate (20 mL), and the organic phase was washed three times with hydrochloric acid (10 mL, 4M). After drying
  • Test Example 1 Compounds of the present disclosure produce cGMP agonizing and/or activating effects on CHO-K1 cells overexpressing sGC.
  • the following method is used to determine the compound of the present disclosure in heme-dependent sGC inhibitor 1H-1,2,4-oxadiazolo-(4,3a)-quinoxalin-1-one (ODQ) (sigma, O3636 -5MG) produces agonistic and/or activating effects of cGMP on CHO-K1 cells overexpressing sGC.
  • ODQ heme-dependent sGC inhibitor 1H-1,2,4-oxadiazolo-(4,3a)-quinoxalin-1-one
  • EBSS Eagle's Balanced Salt Solution
  • Hygromycin B (Thermo, 10687-010)
  • Microplate reader (BMG, PHERAsta)
  • CHO-K1/sGC cells were cultured in complete medium (DMEM/F12 medium containing 10% FBS, 1 mg/mL G418, 200 ⁇ g/mL hygromycin B), passaged 2 to 3 times a week, and the passage ratio was 1: 8 or 1:15.
  • complete medium DMEM/F12 medium containing 10% FBS, 1 mg/mL G418, 200 ⁇ g/mL hygromycin B
  • the passage ratio was 1: 8 or 1:15.
  • the sample to be tested was diluted to 1.11mM with DMSO, then 3-fold serially diluted to 10 concentrations, and blank wells were set. Take 3 ⁇ L of the test compound solution prepared in gradient concentration and add it to 97 ⁇ L of the test buffer to prepare the compound-containing test buffer. Take 3 ⁇ L of the above compound-containing experimental buffer and add it to a 384-well plate, and incubate in a 37° C. incubator for 30 minutes. The experiments were then performed according to the cGMP kit instructions. The signal value was read with the HTRF program of the PHERAstar microplate reader, and the data was processed with GraphPad software. The test results are shown in Table 1.
  • Table 1 Agonizing and/or activating effects of compounds of the present disclosure on cGMP produced by CHO-K1 cells overexpressing sGC
  • the disclosed compound has a strong cGMP agonizing and/or activating effect on CHO-K1 cells overexpressing sGC.
  • Test Example 2 Induction activity of the disclosed compound on cytochrome P450 isoenzyme CYP3A4 in the recombinant human liver cell line HepG2
  • Pregnane X receptor a member of the nuclear receptor family, is the main transcriptional regulator that induces the expression of cytochrome P450 isoenzyme CYP3A4, and can be activated by a variety of exogenous substances.
  • PXR functions by combining with the retinoid X receptor (RXR) to form a heterodimer, and PXR-RXR combines with the upstream regulatory sequence of the CYP3A4 gene to up-regulate the expression of CYP3A4.
  • the two promoters of the CYP3A4 gene were cloned upstream of the luciferase gene, and the human liver cancer cell line HepG2 was co-transfected with a plasmid containing the human PXR gene to construct a luciferase reporter gene system. inducing activity.
  • FBS Fetal Bovine Serum
  • HepG2 cells were fully digested with 0.25% trypsin-EDTA, centrifuged and resuspended into a single cell suspension, and the viable cell density was adjusted to 2 ⁇ 10 5 cells/cell with cell culture medium (EMEM+10% FBS). mL, 100 ⁇ L/well was added to a 96-well cell culture plate (BD, 356692), and cultured overnight in an incubator (37°C, 5% CO 2 ).
  • CYP3A4 plasmid pGL4.17-CYP3A4-5'promoter-luc
  • PXR plasmid pcDNA3.1-hPXR
  • Positive control rifampicin and test compound solution were prepared with 20mM concentration in DMSO;
  • the data were processed in GraphPad Prism8 software.
  • the average value of negative control (0.25% DMSO) chemiluminescence (RLU) was calculated, and the average value of RLU of each concentration of the test compound was divided by the average value of negative control RLU to obtain the induction factor ( Fold of induction), the induction fold of positive control 10 ⁇ M rifampicin Should be greater than or equal to 7, subtract 1 from the induction multiple to obtain the induction increase multiple (Fold increase above DMSO control), divide the induction increase multiple of each concentration of the test compound by the induction increase multiple of the positive control 10 ⁇ M rifampicin, and multiply by 100 %, the percentage of the induction increase multiple of each concentration of the test compound accounted for the induction increase multiple of 10 ⁇ M rifampicin is obtained, and the induction ability of the compound is judged according to the induction increase multiple percentage of the 10 ⁇ M compound, less than 15% is no induction (Negative), greater than or equal to 15 % less than
  • the disclosed compound has no induction of CYP3A4 in the HepG2 luciferase reporter gene system, while Runcaciguat has a moderate induction, suggesting that the disclosed compound has no potential induction effect on CYP3A4 in the evaluation of drug interaction.
  • Drugs metabolized by CYP3A4 have the advantage of being safer.

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Abstract

本申请提供羧酸类化合物、其制备方法及其在医药上的应用。具体而言，本申请提供一种通式(I)所示的羧酸类化合物、其制备方法及含有该类化合物的药物组合物以及其作为治疗剂的用途，特别是作为可溶性鸟苷酸环化酶(sGC)激动剂和/或激活剂的用途和在制备用于治疗和/或预防通过sGC介导的疾病或病症的药物中的用途。

Description

羧酸类化合物、其制备方法及其在医药上的应用 技术领域
本公开属于医药领域，涉及一种羧酸类化合物、其制备方法及其在医药上的应用。特别地，本公开涉及通式(I)所示的羧酸类化合物、其制备方法、含有该类化合物的药物组合物以及其作为治疗剂的用途，特别是作为可溶性鸟苷酸环化酶(sGC)激动剂和/或激活剂的用途和在制备用于治疗和/或预防通过sGC介导的疾病或病症的药物中的用途。
背景技术
随着人口老龄化进程的加快和高血压、冠心病、动脉粥样硬化等心血管疾病发病率的上升，心肌梗死和心力衰竭的患病率也正在逐渐升高。心肌梗死是在冠状动脉病变时，冠状动脉的血流急剧减少或中断，导致心肌出现严重且持久的缺血而坏死。心力衰竭简称心衰，是由于心脏的收缩功能或者舒张功能发生障碍，而引起心脏循环障碍症候群。心力衰竭不是一个独立的疾病，而是多种心血管疾病的终末阶段，几乎所有的心血管疾病最终都会导致心衰的发生。心衰患者面临着高死亡率的威胁，且严重影响了患者的生活质量，庞大的患者群体和相当高的死亡率给心衰治疗提出了巨大的挑战。
多年以来，心衰的药物治疗领域不断取得进展，其中包括利尿药物、减慢心率的β受体阻滞剂和血管紧张素受体阻滞药物等。在心衰患者中，可以观察到一氧化氮(NO)-可溶性鸟苷酸环化酶(sGC)-环磷鸟苷(cGMP)通路的受损，该通路受损可导致心肌和血管功能下降，引起左室重构、纤维化和炎症，并最终导致心衰的发生和发展。
NO在心血管、神经、消化、代谢、免疫等多种***都是重要的信号分子，特别是心血管***和神经***。sGC作为NO的受体，是NO信号转导通路中的一个关键核心金属酶，NO活化sGC后，催化三磷酸鸟苷酸(GTP)转化为cGMP。cGMP是一种重要的二级信使分子，可以激活其下游多种效应分子，如环核苷酸门控离子通道(CNG)、磷酸二酯酶(PDE)和cGMP依赖蛋白激酶(PKG)等，进而引发一系列级联反应，在血液循环***和神经***中发挥重要的生理功能，例如可以促进血管和平滑肌舒张，抑制血小板凝聚、血管重塑和炎症发生等。在哺乳动物体内，NO由一氧化氮合酶(NOS)合成，然后通过脂质双分子层扩散到细胞并与其受体蛋白sGC结合，从而产生大量的cGMP。然而当NO-sGC-cGMP信号通路发生异常就会引发血管内皮细胞功能紊乱，进而引发一系列的心血管疾病，如肺动脉高压和心衰等。而sGC作为NO信号通路中的关键酶，作为多种疾病的药物靶标受到越来越多的重视。
sGC遍布于哺乳动物的细胞溶质中，是由一个α亚基和一个β亚基组成的含有血红素辅基的异源二聚体，每个亚基都包含氨基端的HNOX结合域(Heme NO/Oxygen binding domain)、α-螺旋卷曲螺旋结构域和羧基端的催化域，单个亚基的表达并不具有催化活性，αβ异源二聚体是sGC行使催化活性所必需的。sGC有α1β1和α2β1两种异构体，α2β1只存在于有限的组织当中，而α1β1则在组织中表达广泛，在血管中sGC活性主要是由于α1β1的高丰度表达。
目前发现可直接作用于sGC的化合物可分为两大类：激动剂和激活剂。sGC的激活是由于NO与β1亚基上HNOX结合域的亚铁血红素相结合，使sGC构象变化、催化域激活，从而将GTP转化为cGMP。sGC激动剂是依赖于HNOX结合域的亚铁血红素并与NO气体协同激活sGC的，它可以增强sGC对NO的敏感性，在心血管药物的开发上有着重要的作用。但是人体内氧化压力可以促使sGC血红素从还原态转化为氧化态，而在高血压和高血脂等心血管疾病和II型糖尿病的人体中氧化态血红素的含量也会增加，再或者因基因的突变，都会导致sGC对NO脱敏，此时sGC激动剂就不能协同NO对sGC进行激活，而sGC激活剂就应运而生。sGC激活剂是一类可作用于氧化态或脱血红素态sGC的化合物，它不依赖与还原态血红素而主要通过结合到sGC血红素腔内激活sGC，进而催化GTP转化为cGMP，从而改善心肌和血管功能，降低心室重构、心肌肥厚、炎症和纤维化，延缓心衰进展。
公开的sGC相关的专利申请包括WO2012139888A1、US20140309307A1、US20160264515A1、WO2019105881A1、WO2020020790A1、WO2020020789A1、WO2020148379A1、CN112794848A、CN112384214A、CN111712247A和CN106459017B。
发明内容
本公开的目的在于提供一种通式(I)所示的化合物或其可药用的盐：
其中：
环A为苯基或6元杂芳基；
R1和R2相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、烯基、炔基、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、-OR7、羧基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、烷基、-OR7a、羟烷基、 氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基中的一个或多个取代基取代；
各个R3相同或不同，且各自独立地选自卤素、烷基、烯基、炔基、羟烷基、卤代烷基、卤代烷氧基、-OR7、羧基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
各个R4相同或不同，且各自独立地选自卤素、烷基、烯基、炔基、羟烷基、卤代烷基、卤代烷氧基、-OR7、羧基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、-OR7a、卤代烷基、卤代烷氧基、烯基、炔基、羟基、氰基、氨基和硝基中的一个或多个取代基取代；
R5和R6相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、羟烷基、卤代烷基、烷氧基、卤代烷氧基、-OR7、环烷基和杂环基；
R7和R7a相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
n为1、2、3或4；
m为0、1、2、3或4；且
p为0、1、2或3。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其中：环A为苯基或吡啶基；优选地，环A为苯基。
在本公开的一些实施方案中，所述的通式(I)所示的化合物或其可药用的盐，其为通式(II)所示的化合物或其可药用的盐：
其中：
R1、R2、R3、R4、R5、R6、m、n和p如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中：R5和R6相同或不同，且各自独立地选自氢原子、卤素和C1-6烷基；优选地，R5和R6均为氢原子。
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：
其中：
环B选自环烷基、杂环基、芳基和杂芳基；
各个R2a相同或不同，且各自独立地选自氘原子、卤素、烷基、-OR7a、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基；
q为0、1、2、3、4或5；
R1、R3、R4、R7a、m、n和p如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(III)所示的化合物或其可药用的盐，其中：环B为6至10元芳基或5至10元杂芳基；优选地，环B为6至10元芳基；更优选地，环B为苯基。
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其为通式(IV)所示的化合物或其可药用的盐：
其中：
L为化学键或亚烷基；
R1a和R1b不同，且各自独立地选自氢原子、氘原子、卤素、烷基、-OR7a、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基；
各个R2a相同或不同，且各自独立地选自氘原子、卤素、烷基、-OR7a、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基；
q为0、1、2、3、4或5；
R3、R4、R7a、m、n和p如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IV)所示的化合物或其可药用的盐，其为通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐：
其中：
L为化学键或亚烷基；
R1a和R1b不同，且各自独立地选自氢原子、氘原子、卤素、烷基、-OR7a、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基；
各个R2a相同或不同，且各自独立地选自氘原子、卤素、烷基、-OR7a、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基；
q为0、1、2、3、4或5；
R3、R4、R7a、m、n和p如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)或通式(IV)所示的化合物或其可药用的盐，其为通式(V)所示的化合物或其可药用的盐：
其中：
R1a和R1b不同，且各自独立地选自氢原子、氘原子、卤素、烷基、-OR7a、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基；
R3a选自卤素、烷基、烯基、炔基、羟烷基、卤代烷基、卤代烷氧基、-OR7、羧基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
各个R2a相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、-OR7a、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基；
q为0、1、2、3、4或5；
R4、R7、R7a、m和p如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)或通式(V)所示的化合物或其可药用的盐，其为通式(V-1)或通式(V-2)所示的化合物或其可药用的盐：
其中：
R1a和R1b不同，且各自独立地选自氢原子、氘原子、卤素、烷基、-OR7a、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基；
R3a选自卤素、烷基、烯基、炔基、羟烷基、卤代烷基、卤代烷氧基、-OR7、羧基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
各个R2a相同或不同，且各自独立地选自氘原子、卤素、烷基、-OR7a、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基；
q为0、1、2、3、4或5；
R4、R7、R7a、m和p如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中R1a和R1b不同，且各自独立地选自氘原子、卤素、烷基、-OR7a、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基；R7a如通式(I)中所定义。
在本公开的一些实施方案中，所述的通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中：R3a选自卤素、C1-6烷基、卤代C1-6烷基和卤代C1-6烷氧基；优选地，R3a为卤素；更优选地，R3a为氯。
在本公开的一些实施方案中，所述的通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中q为0、1或2；优选地，q为1。
在本公开的一些实施方案中，所述的通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中各个 R2a相同或不同，且各自独立地选自氘原子、卤素和C1-6烷基；优选地，各个R2a相同或不同，且各自独立地为卤素；更优选地，R2a为氯原子。
在本公开的一些实施方案中，所述的通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中：q为0；或者各个R2a相同或不同，且各自独立地选自氘原子、卤素和C1-6烷基，且q为1、2、3、4或5；优选地，q为0；或者各个R2a相同或不同，且各自独立地选自氘原子、卤素和C1-6烷基，且q为1或2；更优选地，R2a为卤素，且q为1；最优选地，R2a为Cl，且q为1。
在本公开的一些实施方案中，所述的通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中：R1a和R1b不同，且各自独立地选自氘原子、卤素、C1-6烷基、羟基、C1-6烷氧基、羟C1-6烷基、氘代C1-6烷基、卤代C1-6烷基和卤代C1-6烷氧基。
在本公开的一些实施方案中，所述的通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中：R1a和R1b不同，且各自独立地选自氢原子、氘原子、卤素、C1-6烷基、羟基、C1-6烷氧基、羟C1-6烷基、氘代C1-6烷基、卤代C1-6烷基和卤代C1-6烷氧基；优选地，R1a和R1b不同，且各自独立地为C1-6烷基或卤代C1-6烷基；更优选地，R1a为C1-6烷基；R1b为卤代C1-6烷基；最优选地，R1a为甲基；R1b为三氟甲基。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中：m为0或1；优选地，m为1。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中：R7为氢原子或C1-6烷基；优选地，R7为甲基。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中：各个R4相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基和3至6元环烷基，所述的C1-6烷基任选被一个或多个氰基取代；优选地，各个R4相同或不同，且各自独立地选自卤素、C1-6烷基和3至6元环烷基；更优选地，各个R4相同或不同，且各自独立地选自卤素、C1-6烷基和环丙基；进一步优选地，各个R4相同或不同，且各自独立地选自F、Cl、Br、甲基、丙基、叔丁基和环丙基。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中各个R4相同或不同，且各自独立地选自F、Cl、Br、甲基、丙基、叔 丁基、环丙基、异丙基、三氟甲基、甲氧基、乙基和
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中：m为0；或者各个R4相同或不同，且各自独立地选自卤素、C1-6烷基和3至6元环烷基，且m为1、2、3或4；优选地，m为0；或者各个R4相同或不同，且各自独立地选自卤素、C1-6烷基和3至6元环烷基，且m为1；更优选地，m为0；或者各个R4相同或不同，且各自独立地选自卤素、C1-6烷基和环丙基，且m为1。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中m为0；或者各个R4相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基和3至6元环烷基，所述的C1-6烷基任选被一个或多个氰基取代；且m为1；优选地，各个R4相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基和3至6元环烷基，所述的C1-6烷基任选被一个或多个氰基取代；且m为1。
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中：R1和R2不同，且各自独立地选自氢原子、氘原子、卤素、C1-6烷基、羟C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、卤代C1-6烷氧基、羟基、3至6元环烷基、3至6元杂环基、6至10元芳基和5至10元杂芳基；其中所述的C1-6烷基、羟C1-6烷基、3至6元环烷基、3至6元杂环基、6至10元芳基和5至10元杂芳基各自独立地任选被选自氘原子、卤素、C1-6烷基、羟基、C1-6烷氧基、羟C1-6烷基、氘代C1-6烷基、卤代C1-6烷基、卤代C1-6烷氧基、C2-6烯基、C2-6炔基、氰基、氨基和硝基中的一个或多个取代基取代；
优选地，R1和R2不同，且各自独立地选自C1-6烷基、3至6元环烷基、3至6元杂环基、6至10元芳基和5至10元杂芳基；其中所述的C1-6烷基、3至6元环烷基、3至6元杂环基、6至10元芳基和5至10元杂芳基各自独立地任选被选自氘原子、卤素、C1-6烷基、羟基、C1-6烷氧基、羟C1-6烷基、氘代C1-6烷基、卤代C1-6烷基和卤代C1-6烷氧基中的一个或多个取代基取代；
更优选地，R1和R2不同，且各自独立地选自C1-6烷基、6至10元芳基和5至10元杂芳基；其中所述的C1-6烷基、6至10元芳基和5至10元杂芳基各自独立地任选被选自氘原子、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基和卤代C1-6烷氧基中的一个或多个取代基取代；
进一步优选地，R1和R2不同，且各自独立地为C1-6烷基或6至10元芳基；其中所述的C1-6烷基或6至10元芳基各自独立地任选被选自氘原子、卤素、C1-6烷基和卤代C1-6烷基中的一个或多个取代基取代；
进一步优选地，R1和R2不同，且各自独立地为C1-6烷基或苯基；其中所述的C1-6烷基或苯基各自独立地任选被选自氘原子、卤素、C1-6烷基和卤代C1-6烷基中的一个或多个取代基取代；
进一步优选地，R1为C1-6烷基；所述的C1-6烷基任选被氘原子或卤素中的一个或多个取代基取代；R2为苯基；其中所述的苯基任选被选自卤素、C1-6烷基和卤代C1-6烷基中的一个或多个取代基取代；
最优选地，R1为C1-6烷基；所述的C1-6烷基任选被一个或多个卤素取代；R2为苯基；其中所述的苯基任选被一个或多个卤素取代。
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中：R1为L为化学键或C1-6亚烷基；R1a和R1b不同，且各自独立地选自氘原子、卤素、C1-6烷基、羟基、C1-6烷氧基、羟C1-6烷基、氘代C1-6烷基、卤代C1-6烷基和卤代C1-6烷氧基。
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其可药用的盐，其中：R1为L为化学键或C1-6亚烷基；R1a和R1b不同，且各自独立地选自氢原子、氘原子、卤素、C1-6烷基、羟基、C1-6烷氧基、羟C1-6烷基、氘代C1-6烷基、卤代C1-6烷基和卤代C1-6烷氧基；优选地，R1为R1a和R1b不同，且各自独立地为C1-6烷基或卤代C1-6烷基；更优选地，R1为R1a为C1-6烷基；R1b为卤代C1-6烷基。
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中：为环B为6至10元芳基或5至10元杂芳基；L为化学键或C1-6亚烷基；R1a和R1b不同，且各自独立地选自氘原子、卤素、C1-6烷基、羟基、C1-6烷氧基、羟C1-6烷基、氘代C1-6烷基、卤代C1-6烷基和卤代C1-6烷氧基；q为0；或者各个R2a相同或不同，且各自独立地选自氘原子、卤素和C1-6烷基，且q为1、2、3、4或5。
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药 用的盐，其中：为环B为6至10元芳基或5至10元杂芳基；L为化学键或C1-6亚烷基；R1a和R1b不同，且各自独立地选自氢原子、氘原子、卤素、C1-6烷基、羟基、C1-6烷氧基、羟C1-6烷基、氘代C1-6烷基、卤代C1-6烷基和卤代C1-6烷氧基；q为0；或者各个R2a相同或不同，且各自独立地选自氘原子、卤素和C1-6烷基，且q为1、2、3、4或5；优选地，为环B为6至10元芳基；L为化学键或C1-6亚烷基；R1a和R1b不同，且各自独立地为C1-6烷基或卤代C1-6烷基；q为0；或者各个R2a相同或不同，且各自独立地选自氘原子、卤素和C1-6烷基，且q为1或2；更优选地，为R1a为C1-6烷基；R1b为卤代C1-6烷基；q为0；或者各个R2a相同或不同，且各自独立地选自氘原子、卤素和C1-6烷基，且q为1或2；进一步优选地，为R1a为C1-6烷基；R1b为卤代C1-6烷基；R2a选自氘原子、卤素和C1-6烷基；进一步优选地，为R1a为C1-6烷基；R1b为卤代C1-6烷基；R2a为卤素；最优选地，为R1a为C1-6烷基；R1b为卤代C1-6烷基。
在本公开的一些实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合 物或其可药用的盐，其中：R1为C1-6烷基；所述的C1-6烷基任选被选自氘原子、卤素、羟基、C1-6羟烷基、C1-6烷氧基、氘代C1-6烷基、卤代C1-6烷氧基、烯基、炔基、氰基、氨基和硝基中的一个或多个取代基取代；优选地，R1为C1-6烷基；所述的C1-6烷基任选被一个或多个卤素取代。
在本公开的一些实施方案中，所述的通式(I)或通式(II)所示的化合物或其可药用的盐，其中：R2选自3至6元环烷基、3至6元杂环基、6至10元芳基和5至10元杂芳基；优选地，R2为6至10元芳基或5至10元杂芳基；更优选地，R2为6至10元芳基；最优选地，R2为苯基。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：各个R3相同或不同，且各自独立地选自卤素、C1-6烷基、卤代C1-6烷基和卤代C1-6烷氧基；优选地，各个R3相同或不同，且各自独立地为卤素；更优选地，R3为Cl。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中n为1或2；优选地，n为1。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：各个R3相同或不同，且各自独立地选自卤素、C1-6烷基、卤代C1-6烷基和卤代C1-6烷氧基，且n为1或2；优选地，R3为卤素，且n为1；更优选地，R3为Cl，且n为1。
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：为R3选自卤素、C1-6烷基、卤代C1-6烷基和卤代C1-6烷氧基；优选地，为R3为卤素；更优选地，为
在本公开的一些实施方案中，所述的通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中：p为0、1或2；优选地，p为0或1；更优选地，p为1。
在本公开的一些实施方案中，所述的通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：L为化学键。
在本公开的一些实施方案中，所述的通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：L为化学键；R1a为C1-6烷基；R1b为卤代C1-6烷基； R2a为卤素；q为1；R3选自卤素、C1-6烷基、卤代C1-6烷基和卤代C1-6烷氧基；n为1；R4选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基和3至6元环烷基，所述的C1-6烷基任选被一个或多个氰基取代；m为0或1；且p为0或1。
在本公开的一些实施方案中，所述的通式(IV)、通式(IV-1)或通式(IV-2)所示的化合物或其可药用的盐，其中：L为化学键；R1a为C1-6烷基；R1b为卤代C1-6烷基；q为0；或者各个R2a相同或不同，且各自独立地选自氘原子、卤素和C1-6烷基，且q为1或2；各个R3相同或不同，且各自独立地选自卤素、C1-6烷基、卤代C1-6烷基和卤代C1-6烷氧基，且n为1或2；m为0；或者各个R4相同或不同，且各自独立地选自卤素、C1-6烷基和3至6元环烷基，且m为1；且p为0或1。
在本公开的一些实施方案中，所述的通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中：R1a为C1-6烷基；R1b为卤代C1-6烷基；R2a为卤素，且q为1；R3a为卤素；m为0；或者各个R4相同或不同，且各自独立地选自卤素、C1-6烷基和3至6元环烷基，且m为1；且p为0或1。
在本公开的一些实施方案中，所述的通式(V)、通式(V-1)或通式(V-2)所示的化合物或其可药用的盐，其中：R1a为C1-6烷基；R1b为卤代C1-6烷基；R2a为卤素，且q为1；R3a为卤素；m为0；或者各个R4相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基和3至6元环烷基，所述的C1-6烷基任选被一个或多个氰基取代，且m为1；p为0或1。
表A本公开的典型化合物包括但不限于：











本公开的另一方面涉及通式(IA)所示的化合物或其盐：
其中：
p为1、2或3；
环A、R3、R4、R5、R6、m和n如通式(I)中所定义。
本公开的另一方面涉及通式(IIA)所示的化合物或其盐：
其中：
p为1、2或3；
R3、R4、R5、R6、m和n如通式(II)中所定义。
本公开的另一方面涉及通式(IIIA)所示的化合物或其盐：
其中：
p为1、2或3；
R3、R4、m和n如通式(III)中所定义。
本公开的另一方面涉及通式(VA)所示的化合物或其盐：
其中：
p为1、2或3；
R3a、R4和m如通式(V)中所定义。
表B本公开的典型中间体化合物包括但不限于：


本公开的另一方面涉及通式(Ia)所示的化合物或其盐：
其中：
R为C1-6烷基；优选地，R为甲基；
环A、R1、R2、R3、R4、R5、R6、m、n和p如通式(I)中所定义。
本公开的另一方面涉及通式(IIa)所示的化合物或其盐：
其中：
R为C1-6烷基；优选地，R为甲基；
R1、R2、R3、R4、R5、R6、m、n和p如通式(II)中所定义。
本公开的另一方面涉及通式(IIIa)所示的化合物或其盐：
其中：
R为C1-6烷基；优选地，R为甲基；
环B、R1、R2a、R3、R4、m、n、p和q如通式(III)中所定义。
本公开的另一方面涉及通式(IVa)所示的化合物或其盐：
其中：
R为C1-6烷基；优选地，R为甲基；
L、R1a、R1b、R2a、R3、R4、m、n、p和q如通式(IV)中所定义。
本公开的另一方面涉及通式(IV-1a)所示的化合物或其盐：
其中：
R为C1-6烷基；优选地，R为甲基；
L、R1a、R1b、R2a、R3、R4、m、n、p和q如通式(IV-1)中所定义。
本公开的另一方面涉及通式(IV-2a)所示的化合物或其盐：
其中：
R为C1-6烷基；优选地，R为甲基；
L、R1a、R1b、R2a、R3、R4、m、n、p和q如通式(IV-2)中所定义。
本公开的另一方面涉及通式(Va)所示的化合物或其盐：
其中：
R为C1-6烷基；优选地，R为甲基；
R1a、R1b、R2a、R3a、R4、m、p和q如通式(V)中所定义。
本公开的另一方面涉及通式(V-1a)所示的化合物或其盐：
其中：
R为C1-6烷基；优选地，R为甲基；
R1a、R1b、R2a、R3a、R4、m、p和q如通式(V-1)中所定义。
本公开的另一方面涉及通式(V-2a)所示的化合物或其盐：
其中：
R为C1-6烷基；优选地，R为甲基；
R1a、R1b、R2a、R3a、R4、m、p和q如通式(V-2)中所定义。
表C本公开的典型中间体化合物包括但不限于：




本公开的另一方面涉及一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IA)所示的化合物或其盐和通式(IB)所示的化合物或其盐发生酰胺化反应，得到通式(I)所示的化合物或其可药用的盐；
其中：
环A、R1、R2、R3、R4、R5、R6、m、n和p如通式(I)中所定义。
本公开的另一方面涉及一种制备通式(II)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIA)所示的化合物或其盐和通式(IB)所示的化合物或其盐发生酰胺化反应，得到通式(II)所示的化合物或其可药用的盐；
其中：
R1、R2、R3、R4、R5、R6、m、n和p如通式(II)中所定义。
本公开的另一方面涉及一种制备通式(III)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIIA)所示的化合物或其盐和通式(IIIB)所示的化合物或其盐发生酰胺化反应，得到通式(III)所示的化合物或其可药用的盐；
其中：
环B、R1、R2a、R3、R4、m、n、p和q如通式(III)中所定义。
本公开的另一方面涉及一种制备通式(IV)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIIA)所示的化合物或其盐和通式(IVB)所示的化合物或其盐发生酰胺化反应，得到通式(IV)所示的化合物或其可药用的盐；
其中：
L、R1a、R1b、R2a、R3、R4、m、n、p和q如通式(IV)中所定义。
本公开的另一方面涉及一种制备通式(IV-1)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIIA)所示的化合物或其盐和通式(IV-1B)所示的化合物或其盐发生酰胺化反应，得到通式(IV-1)所示的化合物或其可药用的盐；
其中：
L、R1a、R1b、R2a、R3、R4、m、n、p和q如通式(IV-1)中所定义。
本公开的另一方面涉及一种制备通式(IV-2)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIIA)所示的化合物或其盐和通式(IV-2B)所示的化合物或其盐发生酰胺化反应，得到通式(IV-2)所示的化合物或其可药用的盐；
其中：
L、R1a、R1b、R2a、R3、R4、m、n、p和q如通式(IV-2)中所定义。
本公开的另一方面涉及一种制备通式(V)所示的化合物或其可药用的盐的方法，该方法包括：
通式(VA)所示的化合物或其盐和通式(VB)所示的化合物或其盐发生酰胺化反应，得到通式(V)所示的化合物或其可药用的盐；
其中：
R1a、R1b、R2a、R3a、R4、m、p和q如通式(V)中所定义。
本公开的另一方面涉及一种制备通式(V-1)所示的化合物或其可药用的盐的方法，该方法包括：
通式(VA)所示的化合物或其盐和通式(V-1B)所示的化合物或其盐发生酰胺化反应，得到通式(V-1)所示的化合物或其可药用的盐；
其中：
R1a、R1b、R2a、R3a、R4、m、p和q如通式(V-1)中所定义。
本公开的另一方面涉及一种制备通式(V-2)所示的化合物或其可药用的盐的方法，该方法包括：
通式(VA)所示的化合物或其盐和通式(V-2B)所示的化合物或其盐发生酰胺化反应，得到通式(V-2)所示的化合物或其可药用的盐；
其中：
R1a、R1b、R2a、R3a、R4、m、p和q如通式(V-2)中所定义。
本公开的另一方面涉及一种制备通式(I)所示的化合物或其可药用的盐的方法，该方法包括：
通式(Ia)所示的化合物或其盐发生水解反应，得到通式(I)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
环A、R1、R2、R3、R4、R5、R6、m、n和p如通式(I)中所定义。
本公开的另一方面涉及一种制备通式(II)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIa)所示的化合物或其盐发生水解反应，得到通式(II)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
R1、R2、R3、R4、R5、R6、m、n和p如通式(II)中所定义。
本公开的另一方面涉及一种制备通式(III)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IIIa)所示的化合物或其盐发生水解反应，得到通式(III)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
环B、R1、R2a、R3、R4、m、n、p和q如通式(III)中所定义。
本公开的另一方面涉及一种制备通式(IV)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IVa)所示的化合物或其盐发生水解反应，得到通式(IV)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
L、R1a、R1b、R2a、R3、R4、m、n、p和q如通式(IV)中所定义。
本公开的另一方面涉及一种制备通式(IV-1)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IV-1a)所示的化合物或其盐发生水解反应，得到通式(IV-1)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
L、R1a、R1b、R2a、R3、R4、m、n、p和q如通式(IV-1)中所定义。
本公开的另一方面涉及一种制备通式(IV-2)所示的化合物或其可药用的盐的方法，该方法包括：
通式(IV-2a)所示的化合物或其盐发生水解反应，得到通式(IV-2)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
L、R1a、R1b、R2a、R3、R4、m、n、p和q如通式(IV-2)中所定义。
本公开的另一方面涉及一种制备通式(V)所示的化合物或其可药用的盐的方法，该方法包括：
通式(Va)所示的化合物或其盐发生水解反应，得到通式(V)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
R1a、R1b、R2a、R3a、R4、m、p和q如通式(V)中所定义。
本公开的另一方面涉及一种制备通式(V-1)所示的化合物或其可药用的盐的方法，该方法包括：
通式(V-1a)所示的化合物或其盐发生水解反应，得到通式(V-1)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
R1a、R1b、R2a、R3a、R4、m、p和q如通式(V-1)中所定义。
本公开的另一方面涉及一种制备通式(V-2)所示的化合物或其可药用的盐的方法，该方法包括：
通式(V-2a)所示的化合物或其盐发生水解反应，得到通式(V-2)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
R1a、R1b、R2a、R3a、R4、m、p和q如通式(V-2)中所定义。
本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐，或包含其的药物组合物在制备sGC激动剂和/或激活剂中的用途。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用盐，或包含其的药物组合物在制备用于治疗和/或预防通过激动和/或激活sGC来减轻的疾病或病症的药物中的用途，所述的疾病或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、糖尿病性视网膜病变、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；优选地，所述的疾病或病症选自心血管疾病、肺动脉高压和肾病；更优选地，所述肾病选自慢性肾功能衰竭、慢性肾功能不全和糖尿病肾病。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用盐，或包含其的药物组合物在制备用于治疗和/或预防疾病或病症的药物中的用途，所述的疾病或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、糖尿病性视网膜病变、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；优选地，所述的疾病或病症选自心血管疾病、肺动脉高压和肾病；更优选地，所述肾病选自慢性肾功能衰竭、慢性肾功能不全和糖尿病肾病。
本公开进一步涉及一种激动和/或激活sGC的方法，其包括给予所需患者通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物。
本公开进一步涉及一种治疗和/或预防通过激动和/或激活sGC来减轻的疾病或病症的方法，其包括给予所需患者通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其中所述的疾病或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、糖尿病性视网膜病变、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；优选地，所述的疾病或病症选自心血管疾病、肺动脉高压和肾病；更优选地，所述肾病选自慢性肾功能衰竭、慢性肾功能不全和糖尿病肾病。
本公开进一步涉及一种治疗和/或预防疾病或病症的方法，其包括给予所需患者通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其中所述的疾病或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、糖尿病性视网膜病变、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；优选地，所述的疾病或病症选自心血管疾病、肺动脉高压和肾病；更优选地，所述肾病选自慢性肾功能衰竭、慢性肾功能不全和糖尿病肾病。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作药物。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作激动和/或激活sGC的药物。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作治疗和/或预防通过激动和/或激活sGC来减轻的疾病或病症的药物，其中所述的疾病或病症选自心血管疾病、肾病、肺动脉高 压、炎性疾病、糖尿病、青光眼、糖尿病性视网膜病变、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；优选地，所述的疾病或病症选自心血管疾病、肺动脉高压和肾病；更优选地，所述肾病选自慢性肾功能衰竭、慢性肾功能不全和糖尿病肾病。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用作治疗疾病或病症的药物，其中所述的疾病或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、糖尿病性视网膜病变、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；优选地，所述的疾病或病症选自心血管疾病、肺动脉高压和肾病；更优选地，所述肾病选自慢性肾功能衰竭、慢性肾功能不全和糖尿病肾病。
本公开进一步涉及通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于激动和/或激活sGC。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗和/或预防通过激动和/或激活sGC来减轻的疾病或病症，其中所述的疾病或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、糖尿病性视网膜病变、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；优选地，所述的疾病或病症选自心血管疾病、肺动脉高压和肾病；更优选地，所述肾病选自慢性肾功能衰竭、慢性肾功能不全和糖尿病肾病。
本公开进一步涉及一种通式(I)、通式(II)、通式(III)、通式(IV)、通式(IV-1)、通式(IV-2)、通式(V)、通式(V-1)、通式(V-2)以及表A所示的化合物或其可药用的盐、或包括其的药物组合物，其用于治疗疾病或病症，其中所述的疾病或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、糖尿病性视网膜病变、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；优选地，所述的疾病或病症选自心血管疾病、肺动脉高压和肾病；更优选地，所述肾病选自慢性肾功能衰竭、慢性肾功能不全和糖尿病肾病。
优选地，本公开所述的心血管疾病选自高血压、动脉粥样硬化症、冠心病、腰椎管狭窄症、外周动脉疾病、间歇性跛行、重症下肢缺血、稳定或者不稳定心绞痛、心肌梗死、心力衰竭、性腺机能减退、中风、冠状动脉痉挛、大脑血管痉挛、缺血/再灌注损伤和血栓栓塞性病症；更优选地，所述的心血管疾病选自高血压、心肌梗死和心力衰竭。
优选地，本公开所述的纤维变性病选自皮肤、肝、肾及肺的纤维变性病。
优选地，本公开所述的泌尿***疾病选自膀胱过动症、良性***增生和勃 起功能障碍。
优选地，本公开所述的神经疾病选自阿尔茨海默氏病、帕金森氏病和神经性疼痛。
优选地，本公开所述的炎性疾病选自牛皮癣、多发性硬化、关节炎、哮喘、溃疡性结肠炎、克罗恩氏病和慢性阻塞性肺病。
进一步地，本公开所述的纤维变性病选自皮肤、肝、肾及肺的纤维变性病；所述的泌尿***疾病选自膀胱过动症、良性***增生和***功能障碍；所述的神经疾病选自阿尔茨海默氏病、帕金森氏病和神经性疼痛；所述的炎性疾病选自牛皮癣、多发性硬化、关节炎、哮喘、溃疡性结肠炎、克罗恩氏病和慢性阻塞性肺病。
优选地，本公开所述的外周动脉疾病选自血栓闭塞性脉管炎、外周动脉闭塞症、雷诺氏病和雷诺氏综合症。
可将活性化合物制成适合于通过任何适当途径给药的形式，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药，吸入或吹入给药的各种剂型。本公开的化合物也可以配制成持例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆等剂型。
作为一般性指导，活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1～1000mg。
本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有0.1至99重量％的活性化合物。
片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使活性成分悬浮于植物油，或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。
本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油，或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。
本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、***的速率、药物的组合、疾病的严重性等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和的直链或带有支链的脂肪族烃基，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20烷基)。所述烷基优选具有1至12个碳原子的烷基(即C1-12烷基)，更优选具有1至6个碳原子的烷基(即C1-6烷基)。非限制性的实例包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊 基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“亚烷基”指二价烷基，其中烷基如上所定义，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20亚烷基)。所述亚烷基优选具有1至12个碳原子的亚烷基(即C1-12亚烷基)，更优选具有1至6个碳原子的亚烷基(即C1-6亚烷基)。非限制性的实例包括：-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH(CH2CH3)-、-CH2CH(CH3)-、-CH2C(CH3)2-、-CH2CH2CH2-、-CH2CH2CH2CH2-等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“烯基”指分子中含有至少一个碳碳双键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C2-12烯基)。所述烯基优选具有2至6个碳原子的烯基(即C2-6烯基)。非限制性的实例包括：乙烯基、丙烯基、异丙烯基、丁烯基等。烯基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“炔基”指分子中含有至少一个碳碳三键的烷基，其中烷基的定义如上所述，其具有2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子(即C2-12炔基)。所述炔基优选具有2至6个碳原子的炔基(即C2-6炔基)。非限制性的实例包括：乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。炔基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基 优选选自D原子、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。非限制性的实例包括：甲氧基、乙氧基、丙氧基和丁氧基等。烷氧基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“环烷基”指饱和或部分不饱和的单环全碳环(即单环环烷基)或多环***(即多环环烷基)，其具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元环烷基)。所述环烷基优选具有3至12个环原子的环烷基(即3至12元环烷基)，更优选具有3至8个环原子的环烷基(即3至8元环烷基)，最优选具有3至6个环原子的环烷基(即3至6元环烷基)。
所述的单环环烷基，非限制性的实例包括：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基和环辛基等。
所述的多环环烷基包括：螺环烷基、稠环烷基和桥环烷基。
术语“螺环烷基”指环之间共用一个碳原子(称螺原子)的多环***，其环内可以含有一个或多个双键，或其环内可以含有一个或多个选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个全碳环且连接点在该全碳环上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺环烷基)。所述螺环烷基优选具有6至14个环原子的螺环烷基(即6至14元螺环烷基)，更优选具有7至10个环原子的螺环烷基(即7至10元螺环烷基)。所述螺环烷基包括单螺环烷基和多螺环烷基(如双螺环烷基等)，优选单螺环烷基或双螺环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺环烷基。非限制性的实例包括：
其连接点可在任意位置；
等。
术语“稠环烷基”指环之间共享毗邻的两个碳原子的多环***，其为单环环烷基与一个或多个单环环烷基稠合，或者单环环烷基与杂环基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环环烷基上，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠环烷基)。所述稠环烷基优选具有6至14个环原子的稠环烷基(即6至14元稠环烷基)，更优选具有7至10个环原子的稠环烷基(即7至10元稠环烷基)。所述稠环烷基包括双环稠环烷基和多环稠环烷基(如三环稠环烷基、四环稠环烷基等)，优选双环稠环烷基或三环稠环烷基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠环烷基。非限制性的实例包括：，其连接点可在任意位置；
等。
术语“桥环烷基”指环之间共用两个不直接连接的碳原子的全碳多环***，其环内可以含有一个或多个双键，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即5至20元桥环烷基)。所述桥环烷基优选具有6至14个碳原子的桥环烷基(即6至14元桥环烷基)，更优选具有7至10个碳原子的桥环烷基(即7至10元桥环烷基)。所述桥环烷基包括双环桥环烷基和多环桥环烷基(如三环桥环烷基、四环桥环烷基等)，优选双环桥环烷基或三环桥环烷基。非限制性的实例包括：
其连接点可在任意位置。
环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“杂环基”指饱和或部分不饱和的单环杂环(即单环杂环基)或多环杂环***(即多环杂环基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，且具有3至20个(例如3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即3至20元杂环基)。所述杂环基优选具有3至12个环原子的杂环基(即3至12元杂环基)；进一步优选具有3至8个环原子的杂环基(即3至8元杂环基)；更优选具有3至6个环原子的杂环基(即3至6元杂环基)；最优选具有5或6个环原子的杂环基(即5或6元杂环基)。
所述的单环杂环基，非限制性的实例包括：吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基和高哌嗪基等。
所述的多环杂环基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指环之间共用一个原子(称螺原子)的多环杂环***，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，条件是至少含有一个单环杂环基且连接点在该单环杂环基上，其具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元螺杂环基)。所述螺杂环基优选具有6至14个环原子的螺杂环基(即6至14元螺杂环基)，更优选具有7至10个环原子的螺杂环基(即7至10元螺杂环基)。所述螺杂环基包括单螺杂环基和多螺杂环基(如双螺杂环基等)，优选单螺杂环基或双螺杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元单螺杂环基。非限制性的实例包括：
等。
术语“稠杂环基”指环之间共享毗邻的两个原子的多环杂环***，其环内可以含有一个或多个双键，且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其为单环杂环基与一个或多个单环杂环基稠合，或者单环杂环基与环烷基、芳基或杂芳基中的一个或多个稠合，其中连接点在单环杂环基上，且具有5至20个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元稠杂环基)。所述稠杂环基优选具有6至14个环原子的稠杂环基(即6至14元稠杂环基)，更优选具有7至10个环原子的稠杂环基(即7至10元稠杂环基)。所述稠杂环基包括双环和多环稠杂环基(如三环稠杂环基、四环稠杂环基等)，优选双环稠杂环基或三环稠杂环基，更优选3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/3元、5元/4元、5元/5元、5元/6元、5元/7元、6元/3元、6元/4元、6元/5元、6元/6元、6元/7元、7元/5元或7元/6元双环稠杂环基。非限制性的实例包括：

等。
术语“桥杂环基”指环之间共用两个不直接连接的原子的多环杂环***，其环内可以含有一个或多个双键，并且其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至20 个(例如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)环原子(即5至20元桥杂环基)。所述桥杂环基优选具有6至14个环原子的桥杂环基(即6至14元桥杂环基)，更优选具有7至10个环原子的桥杂环基(即7至10元桥杂环基)。根据组成环的数目可以分为双环桥杂环基和多环桥杂环基(如三环桥杂环基、四环桥杂环基等)，优选双环桥杂环基或三环桥杂环基。非限制性的实例包括：
等。
杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“芳基”指具有共轭的π电子体系的单环全碳芳环(即单环芳基)或多环芳环***(即多环芳基)，其具有6至14个(例如6、7、8、9、10、11、12、13或14个)环原子(即6至14元芳基)。所述芳基优选具有6至10个环原子的芳基(即6至10元芳基)。所述的单环芳基，例如苯基。所述的多环芳基，非限制性的实例包括：萘基、蒽基、菲基等。所述多环芳基还包括苯基与杂环基或环烷基中的一个或多个稠合，或萘基与杂环基或环烷基中的一个或多个稠合，其中连接点在苯基或萘基上，并且在这种情况下，环原子个数继续表示多环芳环***中的环原子个数，非限制性的实例包括：

等。
芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氧代基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“杂芳基”指具有共轭的π电子体系的单环杂芳环(即单环杂芳基)或多环杂芳环***(即多环杂芳基)，其环内至少含有一个(例如1、2、3或4个)选自氮、氧和硫的杂原子(所述的氮可任选被氧化，即形成氮氧化物；所述的硫可任选被氧代，即形成亚砜或砜，但不包括-O-O-、-O-S-或-S-S-)，其具有5至14个(例如5、6、7、8、9、10、11、12、13或14个)环原子(即5至14元杂芳基)。所述杂芳基优选具有5至10个环原子的杂芳基(即5至10元杂芳基)，更优选具有5或6个环原子的杂芳基(即5或6元杂芳基)。
所述的单环杂芳基，非限制性的实例包括：呋喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、咪唑基、吡唑基、***基、四唑基、呋咱基、吡咯基、N-烷基吡咯基、吡啶基、嘧啶基、吡啶酮基、N-烷基吡啶酮(如等)、吡嗪基、哒嗪基等。
所述的多环杂芳基，非限制性的实例包括：吲哚基、吲唑基、喹啉基、异喹啉基、喹喔啉基、酞嗪基、苯并咪唑基、苯并噻吩基、喹唑啉基、苯并噻唑基、咔唑基等。所述多环杂芳基还包括单环杂芳基与一个或多个芳基稠合，其中连接点在芳香环上，并且在这种情况下，环原子个数继续表示多环杂芳环***中的环原子个数。所述多环杂芳基还包括单环杂芳基与环烷基或杂环基中的一个或多个稠合，其中连接点在单环杂芳环上，并且在这种情况下，环原子个数继续表示多环杂芳环***中的环原子个数。非限制性的实例包括：
等。
杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点被取代，取代基优选选自D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个。
术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。
术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“羟基”指-OH。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“氧代”或“氧代基”指“＝O”。
术语“羰基”指C＝O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基和环烷基如上所定义。
本公开化合物可以存在特定的立体异构体形式。术语“立体异构体”是指结构相同但原子在空间中的排列不同的异构体。其包括顺式和反式(或Z和E)异构体、(-)-和(+)-异构体、(R)-和(S)-对映异构体、非对映异构体、(D)-和(L)-异构体、互变异构体、阻转异构体、构象异构体及其混合物(如外消旋体、非对映异构体的混合物)。本公开化合物中的取代基可以存在另外的不对称原子。所有这些立体异构体以及它们的混合物，均包括在本公开的范围内。可以通过手性合成、手性试剂或者其他常规技术制备光学活性的(-)-和(+)-异构体、(R)-和(S)-对映异构体以及(D)-和(L)-异构体。本公开某化合物的一种异构体，可以通过不对称合成或者手性助剂来制备，或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，得到纯的异构体。此外，对映异构体和非对映异构体的分离通常是通过色谱法完成。
本公开所述化合物的化学结构中，键表示未指定构型，即如果化学结构中存在手性异构体，键可以为或者同时包含 两种构型。
本公开的化合物可以以不同的互变异构体形式存在，并且所有这样的形式包含在本公开的范围内。术语“互变异构体”或“互变异构体形式”是指平衡存在并且容易从一种异构形式转化为另一种异构形式的结构异构体。其包括所有可能的互变异构体，即以单一异构体的形式或以所述互变异构体的任意比例的混合物的形式存在。非限制性的实例包括：酮-烯醇、亚胺-烯胺、内酰胺-内酰亚胺等。内酰胺-内酰亚胺平衡实例如下所示：
如当提及吡唑基时，应理解为包括如下两种结构中的任何一种或两种互变异构体的混合物：
所有的互变异构形式在本公开的范围内，且化合物的命名不排除任何互变异构体。
本公开的化合物包括其化合物的所有合适的同位素衍生物。术语“同位素衍生物”是指至少一个原子被具有相同原子序数但原子质量不同的原子替代的化合物。可引入到本公开化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘等的稳定和放射性的同位素，例如分别为2H(氘，D)、3H(氚，T)、11C、13C、14C、15N、17O、18O、32p、33p、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I和131I等，优选氘。
相比于未氘代药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。与碳原子连接的各个可用的氢原子可独立地被氘原子替换，其中氘的替换可以是部分或完全的，部分氘的替换是指至少一个氢被至少一个氘替换。
在本公开化合物中，当一个位置被特别地指定为“氘”或“D”时，该位置应理解为氘的丰度比氘的天然丰度(其为0.015％)大至少1000倍(即，至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少1000倍(即，至少15％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少2000倍(即，至少30％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3000倍(即，至少45％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3340倍(即，至少50.1％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少3500倍(即，至少52.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4000倍(即，至少60％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少4500倍(即，至少67.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5000倍(即，至少75％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少5500倍(即，至少82.5％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6000倍(即，至少90％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6333.3倍(即，至少95％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6466.7倍(即，至少97％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的天然丰度大至少6600倍(即，至少99％的氘掺入)。在一些实施方案中，每个被指定的氘原子的氘的丰度比氘的 天然丰度大至少6633.3倍(即，至少99.5％的氘掺入)。
“任选的”或“任选”是指随后所描述的事件或环境可以但不必然发生，其包括该事件或环境发生或不发生两种情形。例如“任选被卤素或者氰基取代的烷基”包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
“取代”或“取代的”指基团中的一个或多个氢原子，优选1～6个，更优选1～3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯)结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其可药用的盐与其他化学组分的混合物，以及其他组分例如药学上可接受的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用的盐”是指本公开化合物的盐，可选自无机盐或有机盐。这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。
本文所使用的，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。
当将术语“约”应用于诸如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键时，通常仅出于说明目的给出数字，而不是限制。
本公开化合物的合成方法
为了完成本公开的目的，本公开采用如下技术方案：
方案一
本公开通式(I)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IA)所示的化合物或其盐和通式(IB)所示的化合物或其盐在缩合剂和碱的存在下发生酰胺化反应，得到通式(I)所示的化合物或其可药用的盐；
其中：
环A、R1、R2、R3、R4、R5、R6、m、n和p如通式(I)中所定义。
方案二
本公开通式(II)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IIA)所示的化合物或其盐和通式(IB)所示的化合物或其盐在缩合剂和碱的存在下发生酰胺化反应，得到通式(II)所示的化合物或其可药用的盐；
其中：
R1、R2、R3、R4、R5、R6、m、n和p如通式(II)中所定义。
方案三
本公开通式(III)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IIIA)所示的化合物或其盐和通式(IIIB)所示的化合物或其盐在缩合剂和碱的存在下发生酰胺化反应，得到通式(III)所示的化合物或其可药用的盐；
其中：
环B、R1、R2a、R3、R4、m、n、p和q如通式(III)中所定义。
方案四
本公开通式(IV)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IIIA)所示的化合物或其盐和通式(IVB)所示的化合物或其盐在缩合剂和 碱的存在下发生酰胺化反应，得到通式(IV)所示的化合物或其可药用的盐；
其中：
L、R1a、R1b、R2a、R3、R4、m、n、p和q如通式(IV)中所定义。
方案五
本公开通式(IV-1)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IIIA)所示的化合物或其盐和通式(IV-1B)所示的化合物或其盐在缩合剂和碱的存在下发生酰胺化反应，得到通式(IV-1)所示的化合物或其可药用的盐；
其中：
L、R1a、R1b、R2a、R3、R4、m、n、p和q如通式(IV-1)中所定义。
方案六
本公开通式(IV-2)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IIIA)所示的化合物或其盐和通式(IV-2B)所示的化合物或其盐在缩合剂和碱的存在下发生酰胺化反应，得到通式(IV-2)所示的化合物或其可药用的盐；
其中：
L、R1a、R1b、R2a、R3、R4、m、n、p和q如通式(IV-2)中所定义。
方案七
本公开通式(V)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(VA)所示的化合物或其盐和通式(VB)所示的化合物或其盐在缩合剂和碱的存在下发生酰胺化反应，得到通式(V)所示的化合物或其可药用的盐；
其中：
R1a、R1b、R2a、R3a、R4、m、p和q如通式(V)中所定义。
方案八
本公开通式(V-1)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(VA)所示的化合物或其盐和通式(V-1B)所示的化合物或其盐在缩合剂和碱的存在下发生酰胺化反应，得到通式(V-1)所示的化合物或其可药用的盐；
其中：
R1a、R1b、R2a、R3a、R4、m、p和q如通式(V-1)中所定义。
方案九
本公开通式(V-2)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(VA)所示的化合物或其盐和通式(V-2B)所示的化合物或其盐在缩合剂和碱的存在下发生酰胺化反应，得到通式(V-2)所示的化合物或其可药用的盐；
其中：
R1a、R1b、R2a、R3a、R4、m、p和q如通式(V-2)中所定义。
方案十
本公开通式(I)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(Ia)所示的化合物或其盐在碱的作用下发生水解反应，得到通式(I)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
环A、R1、R2、R3、R4、R5、R6、m、n和p如通式(I)中所定义。
方案十一
本公开通式(II)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IIa)所示的化合物或其盐在碱的作用下发生水解反应，得到通式(II)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
R1、R2、R3、R4、R5、R6、m、n和p如通式(II)中所定义。
方案十二
本公开通式(III)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IIIa)所示的化合物或其盐在碱的作用下发生水解反应，得到通式(III)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
环B、R1、R2a、R3、R4、m、n、p和q如通式(III)中所定义。
方案十三
本公开通式(IV)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IVa)所示的化合物或其盐在碱的作用下发生水解反应，得到通式(IV)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
L、R1a、R1b、R2a、R3、R4、m、n、p和q如通式(IV)中所定义。
方案十四
本公开通式(IV-1)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IV-1a)所示的化合物或其盐在碱的作用下发生水解反应，得到通式(IV-1)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
L、R1a、R1b、R2a、R3、R4、m、n、p和q如通式(IV-1)中所定义。
方案十五
本公开通式(IV-2)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(IV-2a)所示的化合物或其盐在碱的作用下发生水解反应，得到通式(IV-2)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
L、R1a、R1b、R2a、R3、R4、m、n、p和q如通式(IV-2)中所定义。
方案十六
本公开通式(V)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(Va)所示的化合物或其盐在碱的作用下发生水解反应，得到通式(V)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
R1a、R1b、R2a、R3a、R4、m、p和q如通式(V)中所定义。
方案十七
本公开通式(V-1)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(V-1a)所示的化合物或其盐在碱的作用下发生水解反应，得到通式(V-1)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
R1a、R1b、R2a、R3a、R4、m、p和q如通式(V-1)中所定义。
方案十八
本公开通式(V-2)所示的化合物或其可药用的盐的制备方法，包括以下步骤：
通式(V-2a)所示的化合物或其盐在碱的作用下发生水解反应，得到通式(V-2)所示的化合物或其可药用的盐；
其中：
R为C1-6烷基；优选地，R为甲基；
R1a、R1b、R2a、R3a、R4、m、p和q如通式(V-2)中所定义。
以上合成方案中所述的碱包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、吡啶、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、醋酸钠、醋酸钾、叔丁醇钠、叔丁醇钾或1,8-二氮杂二环十一碳-7-烯，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、碳酸铯、碳酸镉、氢氧化钠、一水合氢氧化锂、氢氧化锂和氢氧化钾；优选地，方案一至方案九中所述的碱为吡啶；方案十至方案十八中所述的碱为氢氧化锂。
以上合成方案中所述的缩合剂优选为1-氯-N,N,2-三甲基丙烯胺。
上述步骤的反应优选在溶剂中进行，所用的溶剂包括但不限于：吡啶、乙二醇二甲醚、醋酸、甲醇、乙醇、异丙醇、丙酮、乙腈、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、甲苯、1,4-二氧六环、水、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、1,2-二溴乙烷及其混合物。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制着本公开的 范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。
手性HPLC分析测定使用Agilent 1260 DAD高效液相色谱仪。
高效液相制备使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。
手性制备使用Shimadzu LC-20AP制备型色谱仪。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品、毕得医药、百灵威、阿达玛斯、国药等公司。
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-[1,1'-联苯]-2-甲酸1
第一步
4'-氯-3'-硝基-[1,1'-联苯]-2-甲酸1c
将2-羧基苯硼酸1a(386mg，2.3mmol，毕得)溶于12mL的1,4-二氧六环和3mL水中，加入4-溴-1-氯-2-硝基苯1b(500mg,2.1mmol，毕得)，二氯[1,1'-双(二苯基膦)二茂铁]钯(II)二氯甲烷络合物(145mg，0.2mmol，百灵威)，磷酸钾(1.4g，6.6mmol)，氩气保护。油浴80℃搅拌反应6小时，停止反应。冷却反应液，浓缩，加入饱和碳酸氢钠溶液(20mL)，用乙酸乙酯萃取(20mL×2)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物1c(272mg，产率：22％)。
第二步
3'-氨基-4'-氯-[1,1'-联苯]-2-甲酸1d
将化合物1c(128mg，0.4mmol)溶于10mL的甲醇中，加入10％钯碳(13mg)，室温氢化反应4小时后停止反应。过滤，滤液减压浓缩，使用柱层析以洗脱剂体系A纯化所得残余物，得到标题化合物1d(81mg，产率：82％)。
第三步
4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-[1,1'-联苯]-2-甲酸1
将化合物1d(50mg，0.2mmol)溶于二氯甲烷(5mL)，室温加入1-氯-N,N,2-三甲基丙烯胺(27mg，0.2mmol，毕得)，搅拌30分钟。加入(2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酸1e(53mg，0.2mmol，采用文献“Journal of Medicinal Chemistry,2021,64(9),5323-5344”公开的方法制备而得)和吡啶(32mg，0.4mmol)的二氯甲烷 (1mL)溶液，室温搅拌30分钟。浓缩后残余物用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18 150*30mm，5μm；流动相：水(含0.1％的三氟醋酸)；乙腈；15分钟梯度：65％-80％)纯化，得到标题化合物1(3mg，产率：3％)。
MS m/z(ESI)：494.1[M-1]。
1H NMR(500MHz,CDCl3)δ8.18(s,1H),7.95(d,1H),7.61(s,1H),7.58-7.53(m,1H),7.47-7.42(m,1H),7.39-7.30(m,6H),7.06(d,1H),3.67(d,1H),3.32-3.29(m,1H),0.88(d,3H)。
实施例2
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯)-4,4,4-三氟-3-甲基丁酰胺基)-[1,1'-联苯]-2-基)乙酸2
采用实施例1的合成路线，将第一步原料1a替换为2-(2-硼苯基)乙酸，制得标题化合物2(12mg，产率：6％)。
MS m/z(ESI)：512.0[M+1]。
1H NMR(500MHz,CDCl3)δ8.22(s,1H),7.65(s,1H),7.40-7.25(m,9H),7.04(d,1H),3.70(d,1H),3.66(s,2H),3.34(dq,1H),0.95(d,3H)。
实施例3
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯)-4,4,4-三氟-3-甲基丁酰胺基)-6-氟-[1,1'-联苯]-2-基)乙酸3
第一步
2-(4'-氯-6-氟-3'-硝基-[1,1'-联苯]-2-基)-乙酸3c
将2-(2-溴-3-氟苯基)乙酸3a(464mg，2.0mmol，毕得)、(4-氯-3-硝基苯基)硼酸3b(444mg，2.2mmol，毕得)、二氯[1,1'-双(二苯基膦)二茂铁]钯(II)二氯甲烷络 合物(118mg，0.16mmol，百灵威)和磷酸钾(1.3g，6.1mmol)置于反应瓶中，抽换氮气，随后加入20mL的1,4-二氧六环和5mL水，再次抽换氮气，油浴88℃搅拌反应6小时，停止反应。冷却反应液，浓缩，加入饱和氯化铵水溶液(20mL)，用乙酸乙酯萃取(20mL×2)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物3c(75mg，产率：12％)。
第二步
2-(3'-氨基-4'-氯-6-氟-[1,1'-联苯]-2-基)乙酸3d
将化合物3c(75mg，0.24mmol)溶于4mL的甲醇中，加入10％钯碳(10mg)，室温氢化反应4小时后停止反应。过滤，滤液减压浓缩，使用柱层析以洗脱剂体系A纯化所得残余物，得到标题化合物3d(68mg，产率：90％)。
第三步
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯)-4,4,4-三氟-3-甲基丁酰胺基)-6-氟-[1,1'-联苯]-2-基)乙酸3
化合物3d(50mg，0.18mmol)溶于二氯甲烷(3mL)，室温加入1-氯-N,N,2-三甲基丙烯胺(27mg，0.2mmol，毕得)，搅拌30分钟。加入化合物1e(53mg，0.2mmol)和吡啶(32mg，0.4mmol)的二氯甲烷(1mL)溶液。室温搅拌30分钟。浓缩后残余物用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18 150*30mm，5μm；流动相：水(含0.1％的三氟醋酸)；乙腈；15分钟梯度：65％-80％)纯化，得到标题化合物3(5mg，产率：5％)。
MS m/z(ESI)：529.1[M+1]。
1H NMR(500MHz,CD3OD)δ7.54-7.45(m,4H),7.42-7.33(m,3H),7.20(s,1H),7.15-7.08(m,2H),4.02(d,1H),3.54(s,2H),3.22-3.11(m,1H),0.90(d,3H)。
实施例4
2-(4',6-二氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-[1,1'-联苯]-2-基)乙酸4
采用实施例3的合成路线，将第一步原料3a替换为2-(2-溴-3-氯苯基)乙酸，制得标题化合物4(5mg，产率：4％)。
MS m/z(ESI)：545.9[M+1]。
1H NMR(500MHz,CD3OD)δ7.51-7.44(m,4H),7.44-7.38(m,3H),7.37-7.30(m,2H),7.02(dd,1H),4.03(d,1H),3.51-3.42(m,3H),0.89(d,3H)。
实施例5
2-(4,4'-二氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-[1,1'-联苯]-2-基)乙酸5
采用实施例3的合成路线，将第一步原料3a替换为2-(2-溴-5-氯苯基)乙酸，制得标题化合物5(4mg，产率：4％)。
MS m/z(ESI)：544.0[M-1]。
1H NMR(500MHz,CD3OD)δ7.55(s,1H),7.50-7.37(m,6H),7.34(d,1H),7.25(d,1H),7.14(d,1H),4.03(d,1H),3.65(s,2H),3.41-3.34(m,1H),0.90(d,3H)。
实施例6
2-(4',5-二氯-3'-((2S,3R)-2-(4-氯苯)-4,4,4-三氟-3-甲基丁酰胺基)-[1,1'-联苯]-2-基)乙酸6
采用实施例3的合成路线，将第一步原料3a替换为2-(2-溴-4-氯苯基)乙酸，可制得标题化合物6(8mg，产率：7％)。
MS m/z(ESI)：546.0[M+1]。
1H NMR(500MHz,CDCl3)δ8.21(s,1H),7.68(s,1H),7.41-7.25(m,8H),7.02(d,1H),3.71(d,1H),3.58(s,2H),3.41-3.31(m,1H),0.95(d,3H)。
实施例7
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-5-甲基-[1,1'-联苯]-2-基)乙酸7

第一步
(2-溴-4-甲基苯基)甲醇7b
将2-溴-4-甲基苯甲醛7a(1.5g，7.54mmol，阿达玛斯)溶于甲醇(50mL)，冰水浴条件下缓慢加入硼氢化钠(573mg，15.1mmol)，搅拌反应2小时，加水(5mL)淬灭，浓缩后加入饱和食盐水(15mL)，乙酸乙酯(20mL×3)萃取，合并有机相，干燥后浓缩得到标题化合物7b(1g，产率：67％)。
第二步
2-溴-1-(溴甲基)-4-甲基苯7c
将化合物7b(1g，4.97mmol)分散于6mL的氢溴酸水溶液(48％)，加热至100℃搅拌反应2小时，加入饱和碳酸氢钠水溶液(30mL)淬灭，乙酸乙酯(20mL×3)萃取，饱和食盐水洗涤后干燥，浓缩得到标题化合物7c(806mg，产率：62％)。
第三步
2-(2-溴-4-甲基苯基)乙腈7d
将化合物7c(800mg，3.03mmol)溶于乙腈(30mL)，加入三甲基氰硅烷(600mg，6.06mmol，阿达玛斯)，四丁基氟化铵(6.06mL，1M，阿达玛斯)，室温搅拌反应18小时，加饱和氯化铵溶液(20mL)淬灭反应，乙酸乙酯(25mL×3)萃取，合并有机相，饱和食盐水(15mL)洗涤，干燥后浓缩得到标题化合物7d(500mg，产率：79％)。
第四步
2-(2-溴-4-甲基苯基)乙酸甲酯7e
将化合物7d(500mg，2.38mmol)溶于甲醇(2mL)，加入氯化氢的1,4-二氧六环溶液(2mL,4M,阿达玛斯)，加热至60℃搅拌反应8小时，冷却后加饱和碳酸氢钠水溶液(30mL)淬灭，乙酸乙酯(20mL×3)萃取，干燥后浓缩得到标题化合物7e (472mg，产率：82％)。
第五步
2-(4'-氯-5-甲基-3'-硝基-[1,1'-联苯]-2-基)乙酸甲酯7f
将化合物7e(340mg，1.40mmol)、化合物3b(366mg，1.82mmol)、二氯[1,1'-双(二苯基膦)二茂铁]钯(II)二氯甲烷络合物(51mg，0.07mmol)和磷酸钾(0.482g，3.50mmol)称于反应瓶中，置换氮气，随后加入16mL的1,4-二氧六环和4mL水，再次置换氮气，油浴加热至85℃搅拌反应6小时，停止反应。冷却后浓缩，加入饱和氯化铵水溶液(20mL)，用乙酸乙酯(20mL×2)萃取，合并有机相，干燥后浓缩，使用硅胶柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物7f(250mg，产率：56％)。
第六步
2-(3'-氨基-4'-氯-5-甲基-[1,1'-联苯]-2-基)乙酸甲酯7g
将化合物7f(250mg，0.782mmol)溶于乙醇(10mL)和水(2mL)的混合溶剂中，加入氯化铵(125mg，2.34mmol)和还原铁粉(131mg，2.34mmol)，加热至60℃搅拌反应3小时，冷却后过滤浓缩，使用硅胶柱层析以洗脱剂体系A纯化所得残余物，得到标题化合物7g(207mg，产率：92％)。
MS m/z(ESI)：290.1[M+1]。
第七步
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-5-甲基-[1,1'-联苯]-2-基)乙酸甲酯7h
将化合物1e(100mg，0.374mmol)溶于二氯甲烷(5mL)，加入1-氯-N,N,2-三甲基丙烯胺(53mg，0.39mmol，毕得)，室温搅拌30分钟。加入化合物7g(108mg，0.374mmol)和吡啶(89mg，1.12mmol)的二氯甲烷(2mL)溶液，室温搅拌30分钟。浓缩后使用硅胶柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物7h(109mg，产率：52％)。
第八步
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-5-甲基-[1,1'-联苯]-2-基)乙酸7
将化合物7h(109mg，0.2mmol)溶于甲醇(5mL)和水(1mL)的混合溶剂中，加入氢氧化锂(47mg，1.12mmol，毕得)，室温搅拌反应8小时，反应液浓缩后残余物用乙腈溶解，过滤，随后滤液用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18 150*30mm，5μm；流动相：水(含0.1％的三氟醋酸)；乙腈；15分钟梯度：65％-80％)纯化，得到标题化合物7(40mg，产率：38％)。
MS m/z(ESI)：524.0[M+1]。
1H NMR(500MHz,CD3OD)δ7.53(s,1H),7.51-7.43(m,3H),7.42-7.33(m,2H),7.24(d,1H),7.19-7.13(m,2H),7.07(s,1H),4.00(d,1H),3.54(s,2H),3.34-3.30(m, 1H),2.36(s,3H),0.90(d,3H)。
实施例8
2-(5-溴-4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-[1,1'-联苯]-2-基)乙酸8
第一步
2-(2-溴-4-((叔丁氧羰基)氨基)苯基)乙酸甲酯8b
将2-(4-氨基-2-溴苯基)乙酸甲酯8a(2.4g，9.83mmol，采用专利申请“WO2015049629A1中说明书第115页实施例154”公开的方法制备而得)溶于二氯甲烷(50mL)，加入三乙胺(2.99g，29.60mmol)，缓慢滴加二碳酸二叔丁酯(4.25g，19.68mmol)，室温搅拌反应6小时，浓缩，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物8b(3g，产率：88％)。
第二步
2-(5-((叔丁氧羰基)氨基)-4'-氯-3'-硝基-[1,1'-联苯]-2-基)乙酸甲酯8c
将化合物8b(3g，8.71mmol)、化合物3b(2.28g，11.32mmol)、二氯[1,1'-双(二苯基膦)二茂铁]钯(II)二氯甲烷络合物(638mg，0.87mmol)和碳酸钾(2.41g，17.46mmol)称于反应瓶中，抽换氮气，随后加入1,4-二氧六环(50mL)和水(8mL)，再次抽换氮气，油浴加热至88℃搅拌反应6小时，停止反应。冷却浓缩，加入饱和氯 化铵水溶液(30mL)，用乙酸乙酯(50mL×2)萃取，合并有机相，干燥浓缩，使用硅胶柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物8c(2.11g，产率：57％)。
第三步
2-(5-氨基-4'-氯-3'-硝基-[1,1'-联苯]-2-基)乙酸甲酯8d
将化合物8c(2.1g，4.99mmol)溶于二氯甲烷(50mL)，加入4M氯化氢的1,4-二氧六环溶液(4mL)，室温搅拌反应3小时，直接浓缩得到标题化合物8d(1.55g，产率：97％)。
第四步
2-(5-溴-4'-氯-3'-硝基-[1,1'-联苯]-2-基)乙酸甲酯8e
将化合物8d(500mg，1.56mmol)溶于乙腈(10mL)，冷却至0℃，加入亚硝酸叔丁酯(196mg，1.90mmol,国药)，低温搅拌反应1小时，加入溴化亚铜(226mg,1.58mmol，毕得)和四丁基溴化铵(202mg，0.63mmol，毕得)，加热至60℃搅拌反应6小时，加水(40mL)淬灭反应，用二氯甲烷和甲醇(V/V＝49:1)的混合溶剂萃取(50mL×3)，合并有机相，用饱和食盐水(30mL)洗涤，干燥后浓缩，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物8e(220mg，产率：44％)。
第五步
2-(3'-氨基-5-溴-4'-氯-[1,1'-联苯]-2-基)乙酸甲酯8f
将化合物8e(120mg，0.31mmol)溶于乙醇(10mL)和水(2mL)的混合溶剂中，加入氯化铵(34mg，0.63mmol)和还原铁粉(175mg，3.13mmol)，加热至60℃搅拌反应3小时，将反应液冷却后过滤，浓缩滤液，使用柱层析以洗脱剂体系A纯化所得残余物，得到标题化合物8f(85mg，产率：77％)。
MS m/z(ESI)：354.9[M+1]。
第六步
2-(5-溴-4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-[1,1'-联苯]-2-基)乙酸甲酯8g
将化合物1e(51mg，0.19mmol)溶于二氯甲烷(2mL)，加入1-氯-N,N,2-三甲基丙烯胺(35mg，0.26mmol)，室温搅拌30分钟。加入化合物8f(68mg，0.19mmol)和吡啶(36mg，0.45mmol)的二氯甲烷(1mL)溶液，室温搅拌30分钟。浓缩后使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物8g(80mg，产率：69％)。MS m/z(ESI)：601.9[M-1]。
第七步
2-(5-溴-4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-[1,1'-联苯]-2-基)乙酸8
将化合物8g(80mg，0.13mmol)溶于甲醇(5mL)和水(1mL)的混合溶剂中，加入氢氧化锂(20mg，0.47mmol)，室温搅拌反应8小时，反应液浓缩后残余物用乙腈溶解，过滤，随后滤液用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18  150*30mm，5μm；流动相：水(含0.1％的三氟醋酸)；乙腈；15分钟梯度：65％-80％)纯化，得到标题化合物8(6mg，产率：7％)。
MS m/z(ESI)：590.0[M+1]。
1H NMR(500MHz,CD3OD)δ7.56(d,1H),7.53-7.45(m,4H),7.43(d,1H),7.42-7.38(m,2H),7.30(d,1H),7.14(dd,1H),4.04(d,1H),3.57(s,2H),3.39-3.35(m,1H),0.90(d,3H)。
实施例9
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-5-环丙基-[1,1'-联苯]-2-基)乙酸9
第一步
2-(2-(苄氧基)-4-溴苯基)乙酸甲酯9b
将2-(4-溴-2-羟基苯基)乙酸甲酯9a(3g，12.24mmol，毕得医药)溶于乙腈(60mL)，加入碳酸钾(3.4g，24.53mmol)，缓慢滴加溴化苄(2.1g，12.28mmol)，室温搅拌反应6小时，过滤，将滤液浓缩，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物9b(3.8g，产率：92％)。
第二步
2-(2-(苄氧基)-4-环丙基苯基)乙酸甲酯9c
将化合物9b(336mg，1mmol)、环丙基硼酸(105mg，1.22mmol,韶远)、醋酸钯(23mg，0.1mmol)、2-二环己基磷-2,4,6-三异丙基联苯(53mg，0.11mmol，韶远)和碳酸钾(416mg，3mmol)称于反应瓶中，抽换氮气，加入1,4-二氧六环(10mL)，加热至85℃搅拌反应6小时，将反应液过滤，浓缩滤液，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物9c(280mg，产率：94％)。
MS m/z(ESI)：297.2[M+1]。
第三步
2-(4-环丙基-2-羟苯基)乙酸甲酯9d
将化合物9c(270mg，0.91mmol)和五甲基苯(390mg，2.63mmol,阿达玛斯)溶于干燥的二氯甲烷(10mL)，冷却至-78℃，缓慢滴加三氯化硼(1.84mL，1.84mmol，1M in DCM,阿拉丁)，保持低温搅拌反应4小时，加甲醇(5mL)淬灭，浓缩，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物9d(170mg，产率：90％)。
第四步
2-(4-环丙基-2-(((三氟甲基)磺酰基)氧基)苯基)乙酸甲酯9e
将化合物9d(170mg，0.82mmol)溶于干燥的二氯甲烷(8mL)，加入2,6-二甲基吡啶(178mg，1.66mmol,阿达玛斯)，冷却至-78℃，缓慢滴加三氟甲磺酸酐(257mg，0.91mmol，韶远)，保持低温，搅拌反应2小时后自然升至室温，加饱和氯化铵溶液(20mL)淬灭反应，二氯甲烷(20mL×3)萃取，合并有机相，饱和食盐水(30mL)洗涤，干燥后过滤，浓缩滤液，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物9e(150mg，产率：54％)。
第五步
2-(4'-氯-5-环丙基-3'-硝基-[1,1'-联苯]-2-基)乙酸甲酯9f
将化合物9e(100mg，0.29mmol)、化合物3b(66mg，0.32mmol)、醋酸钯(6mg，0.02mmol)、2-二环己基磷-2,4,6-三异丙基联苯(13mg，0.03mmol)以及碳酸钾(123mg，0.89mmol)称于反应瓶中，抽换氮气，随后加入1,4-二氧六环(4mL)和水(1mL)，再次抽换氮气，加热至88℃搅拌反应6小时，停止反应。冷却后浓缩反应液，加入饱和氯化铵水溶液(20mL)，用乙酸乙酯(20mL×2)萃取，合并有机相，干燥后过滤，浓缩滤液，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物9f(46mg，产率：45％)。
第六步
2-(3'-氨基-4'-氯-5-环丙基-[1,1'-联苯]-2-基)乙酸甲酯9g
将化合物9f(120mg，0.35mmol)溶于乙醇(5mL)和水(1mL)的混合溶剂中，加入氯化铵(38mg，0.71mmol)和还原铁粉(97mg，1.73mmol)，加热至60℃搅拌 反应3小时，反应液冷却后过滤，浓缩滤液，使用柱层析以洗脱剂体系A纯化所得残余物，得到标题化合物9g(90mg，产率：82％)。
MS m/z(ESI)：316.1[M+1]。
第七步
2-(4'-氯-3'-(2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁胺基)-5-环丙基-[1,1'-联苯]-2-基)乙酸甲酯9h
将化合物1e(84mg，0.32mmol)溶于二氯甲烷(2mL)，加入1-氯-N,N,2-三甲基丙烯胺(46mg，0.34mmol)，室温搅拌30分钟。加入化合物9g(90mg，0.28mmol)和吡啶(45mg，0.57mmol)的二氯甲烷(1mL)溶液，室温搅拌30分钟。浓缩后使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物9h(120mg，产率：74％)。MS m/z(ESI)：564.1[M+1]。
第八步
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-5-环丙基-[1,1'-联苯]-2-基)乙酸9
将化合物9h(120mg，0.21mmol)溶于甲醇(5mL)和水(1mL)的混合溶剂中，加入氢氧化锂(45mg，1.05mmol)，室温搅拌反应8小时，反应液浓缩后残余物用乙腈溶解，过滤，随后滤液用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18150*30mm，5μm；流动相：水(含0.1％的三氟醋酸)；乙腈；15分钟梯度：65％-80％)纯化，得到标题化合物9(30mg，产率：26％)。
MS m/z(ESI)：549.1[M+1]。
1H NMR(500MHz,CD3OD)δ7.52-7.38(m,5H),7.35(d,1H),7.24(d,1H),7.20(d,1H),7.03(d,1H),6.95(s,1H),4.00(d,1H),3.47(s,2H),3.38-3.32(m,1H),3.22-3.10(m,1H),0.98-0.93(m,2H),0.90(d,3H),0.71-0.66(m,2H)。
实施例10
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-5-丙基-[1,1'-联苯]-2-基)乙酸10
采用实施例9的合成路线，将第二步中的原料环丙基硼酸替换为正丙基三氟硼酸钾，可制得标题化合物10(8mg，产率：7％)。
MS m/z(ESI)：552.1[M+1]。
1H NMR(500MHz,CD3OD)δ7.53(s,1H),7.50-7.38(m,5H),7.27(d,1H),7.18(d,1H),7.16(d,1H),7.07(s,1H),4.03(d,1H),3.55(s,2H),3.40-3.36(m,1H),2.62(t,2H),1.67(h,2H),0.97(t,3H),0.90(d,3H)。
实施例11
2-(5-(叔丁基)-4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺)-[1,1'-联苯]-2-基)乙酸11
第一步
(2-溴-4-(叔丁基)苯基)甲醇11b
将2-溴-4-叔丁基苯甲酸11a(1g，3.89mmol，乐研)溶于四氢呋喃(15mL)，室温条件下缓慢滴加硼烷的四氢呋喃溶液(7.8mL，1M)，搅拌反应8小时，加甲醇(5mL)淬灭，浓缩后加入饱和食盐水(10mL)，乙酸乙酯(15mL×3)萃取，合并有机相，干燥后浓缩得到标题化合物11b(900mg，产率：95％)。
第二步
2-溴-1-(溴甲基)-4-(叔丁基)苯11c
将化合物11b(470mg，1.93mmol)分散于6mL的氢溴酸水溶液(48％)，加热 至100℃搅拌反应4小时，加入饱和碳酸氢钠水溶液(30mL)淬灭，乙酸乙酯(20mL×3)萃取，干燥后浓缩得到标题化合物11c(450mg，产率：76％)。
第三步
2-(2-溴-4-(叔丁基)苯基)乙腈11d
将化合物11c(450mg，1.47mmol)溶于乙腈(12mL)，加入三甲基氰硅烷(292mg，2.94mmol)和四丁基氟化铵(2.94mL，1M)，室温搅拌反应8小时，加饱和氯化铵溶液(10mL)淬灭反应，乙酸乙酯(15mL×3)萃取，合并有机相，饱和食盐水(15mL)洗涤，有机相干燥后浓缩得到标题化合物11d(350mg，产率：94％)。
第四步
2-(2-溴-4-(叔丁基)苯基)乙酸甲酯11e
将化合物11d(800mg，3.17mmol)溶于甲醇(5mL)，加入氯化氢的1,4-二氧六环溶液(5mL，4M)，加热至70℃搅拌反应8小时，冷却后加饱和碳酸氢钠水溶液(30mL)淬灭，乙酸乙酯(20mL×3)萃取，干燥后浓缩得到标题化合物11e(778mg，产率：86％)。
第五步
2-(5-(叔丁基)-4'-氯-3'-硝基-[1,1'-联苯]-2-基)乙酸甲酯11f
将化合物11e(350mg，1.23mmol)、化合物3b(297mg，1.47mmol)、二氯[1,1'-双(二苯基膦)二茂铁]钯(II)二氯甲烷络合物(59mg，0.08mmol)和磷酸钾(0.786g，3.69mmol)称于反应瓶中，抽换氮气，随后加入20mL的1,4-二氧六环和5mL水，再次抽换氮气，油浴加热至88℃搅拌反应6小时，停止反应。冷却后浓缩，加入饱和氯化铵水溶液(20mL)，用乙酸乙酯(20mL×2)萃取，合并有机相，干燥后浓缩，使用硅胶柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物11f(160mg，产率：36％)。
第六步
2-(3'-氨基-5-(叔丁基)-4'-氯-[1,1'-联苯]-2-基)乙酸甲酯11g
将化合物11f(160mg，0.44mmol)溶于乙醇(5mL)和水(1mL)的混合溶剂中，加入氯化铵(118mg，2.2mmol)和还原铁粉(123mg，2.2mmol)，加热至60℃搅拌反应3小时，冷却后过滤，将滤液浓缩，使用硅胶柱层析以洗脱剂体系A纯化所得残余物，得到标题化合物11g(131mg，产率：90％)。
MS m/z(ESI):332.1[M+1]。
第七步
2-(5-(叔丁基)-4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺)-[1,1'-联苯]-2-基)乙酸甲酯11h
将化合物1e(130mg，0.49mmol)溶于二氯甲烷(5mL)，加入1-氯-N,N,2-三甲基丙烯胺(67mg，0.49mmol，毕得)，室温搅拌30分钟。加入化合物11g(150mg，0.45mmol)和吡啶(79mg，0.98mmol)的二氯甲烷(2mL)溶液，室温搅拌30分钟。 浓缩后使用硅胶柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物11h(120mg，产率：46％)。
MS m/z(ESI):582.1[M+1]。
第八步
2-(5-(叔丁基)-4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺)-[1,1'-联苯]-2-基)乙酸11
将化合物11h(120mg，0.2mmol)溶于甲醇(5mL)和水(1mL)的混合溶剂中，加入氢氧化锂(47mg，1.12mmol，毕得)，室温搅拌反应8小时，反应液浓缩后残余物用乙腈溶解，过滤，随后滤液用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18 150*30mm，5μm；流动相：水(含0.1％的三氟醋酸)；乙腈；15分钟梯度：65％-80％)纯化，得到标题化合物11(48mg，产率：43％)。
MS m/z(ESI):566.1[M+1]。
1H NMR(500MHz,CD3OD)δ7.53(s,1H),7.50-7.44(m,3H),7.43-7.38(m,3H),7.29(d,1H),7.26(s,1H),7.15(d,1H),4.03(d,1H),3.55(s,2H),3.40-3.34(m,1H),1.35(s,9H),0.90(d,3H)。
实施例12
2-(3,4'-二氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-[1,1'-联苯]-2-基)乙酸12
采用实施例3的合成路线，将第一步原料3a替换为2-(2-溴-6-氯苯基)乙酸，制得标题化合物12(10mg，产率：5％)。
MS m/z(ESI):543.9[M-1]。
1H NMR(500MHz,CD3OD)δ7.56(s,1H),7.51-7.45(m,4H),7.42-7.30(m,3H),7.23(d,1H),7.16(d,1H),4.03(d,1H),3.71(s,2H),3.40-3.31(m,1H),0.90(d,3H)。
实施例13
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-5-异丙基-[1,1'-联苯]-2-基)乙酸13

第一步
2-(2-(苄氧基)-4-(丙-1-烯-2-基)苯基)乙酸甲酯13a
将化合物9b(5g，14.92mmol)、异丙烯基硼酸频哪醇酯(3g，17.85mmol，韶远)、四(三苯基膦)钯(862mg，0.746mmol)以及磷酸钾(9.5g，44.75mmol)称于反应瓶中，抽换氮气，加入1,4-二氧六环(50mL)和水(10mL)，加热至85℃搅拌反应6小时，将反应液过滤，浓缩滤液，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物13a(3.8g，产率：90％)。
第二步
2-(2-羟基-4-异丙基苯基)乙酸甲酯13b
将化合物13a(3.8g，12.84mmol)溶于甲醇(70mL)，加入10％的钯碳(1.36g，1.28mmol)，加热至50℃，常压氢化搅拌反应4小时，将反应液过滤，浓缩滤液，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物13b(2.5g，产率：93％)。
第三步
2-(4-异丙基-2-(三氟甲基磺酰基)氧基)苯基)乙酸甲酯13c
将化合物13b(2.5g，12mmol)溶于干燥的二氯甲烷(40mL)，加入吡啶(2.8g，35.4mmol)，冷却至-78℃，缓慢滴加三氟甲磺酸酐(4.2g，14.8mmol)，保持低温，搅拌反应2小时后自然升至室温，加饱和氯化铵溶液(50mL)淬灭反应，二氯甲烷(30mL×3)萃取，合并有机相，饱和食盐水(30mL)洗涤，干燥后浓缩，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物13c(3g，产率：75％)。
第四步
2-(4'-氯-5-异丙基-3'-硝基-[1,1'-联苯]-2-基)乙酸甲酯13d
将化合物13c(400mg，1.17mmol)、化合物3b(470mg，2.33mmol)、二氯[1,1'-双(二苯基膦)二茂铁]钯(II)二氯甲烷络合物(86mg，0.12mmol)和磷酸钾(753mg，3.55mmol)称于反应瓶中，抽换氮气，随后加入1,4-二氧六环(10mL)和水(2mL)，再次抽换氮气，加热至88℃搅拌反应6小时，停止反应。反应液冷却后浓缩，加入饱和氯化铵水溶液(20mL)，用乙酸乙酯(20mL×2)萃取，合并有机相，干燥后浓缩，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物13d(220mg，产率：54％)。
第五步
2-(3'-氨基-4'-氯-5-异丙基-[1,1'-联苯]-2-基)乙酸甲酯13e
将化合物13d(140mg，0.4mmol)溶于乙醇(5mL)和水(1mL)的混合溶剂中，加入氯化铵(43mg，0.8mmol)和还原铁粉(113mg，2mmol)，加热至60℃搅拌反应3小时，反应液冷却后过滤，浓缩滤液，使用柱层析以洗脱剂体系A纯化所得残余物，得到标题化合物13e(80mg，产率：61％)。
MS m/z(ESI)：318.1[M+1]。
第六步
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-5-异丙基-[1,1'-联苯]-2-基)乙酸甲酯13f
将化合物1e(210mg，0.78mmol)溶于二氯甲烷(10mL)，加入1-氯-N,N,2-三甲基丙烯胺(137mg，1.02mmol)，室温搅拌30分钟。加入化合物13e(255mg，0.81mmol)和吡啶(187mg，2.36mmol)的二氯甲烷(2mL)溶液，室温搅拌30分钟。将反应液浓缩，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物13f(200mg，产率：45％)。
MS m/z(ESI)：566.0[M-1]。
第七步
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-5-异丙基-[1,1'-联苯]-2-基)乙酸13
将化合物13f(200mg，0.35mmol)溶于甲醇(5mL)和水(1mL)的混合溶剂中，加入氢氧化锂(74mg，1.75mmol)，室温搅拌反应8小时，反应液浓缩后残余物用乙腈溶解，过滤，随后滤液用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18 150*30mm，5μm；流动相：水(含0.1％的三氟醋酸)；乙腈；15分钟梯度：65％-80％)纯化，得到标题化合物13(36mg，产率：18％)。
MS m/z(ESI)：552.1[M+1]。
1H NMR(500MHz,CD3OD)δ7.53(s,1H),7.50-7.37(m,5H),7.30-7.21(m,2H),7.15(d,1H),7.11(s,1H),4.03(d,1H),3.55(s,2H),3.39-3.33(m,1H),2.99-2.89(m,1H),1.27(d,6H),0.90(d,3H)。
实施例14
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-5-三氟甲基-[1,1'-联苯]-2-基)乙酸14
采用实施例3的合成路线，将第一步原料3a替换为2-溴-4-三氟甲基苯乙酸，制得标题化合物14(30mg，产率：18％)。
MS m/z(ESI)：578.0[M+1]。
1H NMR(500MHz,DMSO-d6)δ10.02(s,1H),7.73(d,1H),7.60(d,1H),7.58-7.35(m,7H),7.16(d,1H),4.18(d,1H),3.60(s,2H),3.41-3.31(m,1H),0.80(d,3H)。
实施例15
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-5-甲氧基-[1,1'-联苯]-2-基)乙酸15
采用实施例3的合成路线，将第一步原料3a替换为2-溴-4-甲氧基苯乙酸，制得标题化合物15(12mg，产率：9％)。
MS m/z(ESI)：540.1[M+1]。
1H NMR(500MHz,CD3OD)δ7.54(s,1H),7.50-7.37(m,5H),7.26(d,1H),7.16(d,1H),6.93(d,1H),6.80(s,1H),4.03(d,1H),3.81(s,3H),3.54(s,2H),3.40-3.36(m,1H),0.90(d,3H)。
实施例16
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-5-乙基-[1,1'-联苯]-2-基)乙酸16
第一步
2-(2-(苄氧基)-4-乙烯基苯基)乙酸甲酯16a
将化合物9b(1.9g，5.67mmol)、乙烯基硼酸频哪醇酯(1.13g，7.37mmol，韶远)、四(三苯基膦)钯(327mg，0.283mmol)以及磷酸钾(2.4g，11.34mmol)称于反应瓶中，抽换氮气，加入1,4-二氧六环(40mL)和水(10mL)，加热至85℃搅拌反应6小时，将反应液过滤，浓缩滤液，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物16a(1.5g，产率：94％)。
MS m/z(ESI)：283.1[M+1]。
第二步
2-(4-乙基-2-羟基苯基)乙酸甲酯16b
将化合物16a(1.5g，5.31mmol)溶于甲醇(50mL)，加入10％的钯碳(450mg，0.427mmol)，加热至50℃，常压氢化搅拌反应4小时，将反应液过滤，浓缩滤液，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物16b(1.35g，产率：90％)。
第三步
2-(4-乙基-2-(((三氟甲基)磺酰基)氧基)苯基)乙酸甲酯16c
将化合物16b(500mg，2.57mmol)溶于干燥的二氯甲烷(20mL)，加入吡啶(509 mg，6.44mmol)，冷却至-78℃，缓慢滴加三氟甲磺酸酐(908mg，3.22mmol)，保持低温，搅拌反应2小时后自然升至室温，加饱和氯化铵溶液(30mL)淬灭反应，二氯甲烷(30mL×3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，干燥后浓缩，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物16c(588mg，产率：70％)。
第四步
2-(4'-氯-5-乙基-3'-硝基-[1,1'-联苯]-2-基)乙酸甲酯16d
将化合物16c(588mg，1.80mmol)、化合物3b(434mg，2.16mmol)、二氯[1,1'-双(二苯基膦)二茂铁]钯(II)二氯甲烷络合物(98mg，0.14mmol)和碳酸铯(1.46g，4.5mmol)，抽换氮气，随后加入1,4-二氧六环(10mL)和水(1mL)，再次抽换氮气，加热至88℃搅拌反应6小时，停止反应。冷却浓缩，加入饱和氯化铵水溶液(20mL)，用乙酸乙酯萃取(20mL×2)，合并有机相，干燥后浓缩，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物16d(246mg，产率：41％)。
第五步
2-(3'-氨基-4'-氯-5-乙基-[1,1'-联苯]-2-基)乙酸甲酯16e
将化合物16d(200mg，0.60mmol)溶于乙醇(5mL)和水(1mL)的混合溶剂中，加入氯化铵(65mg，1.20mmol)和还原铁粉(168mg，3.00mmol)，加热至60℃搅拌反应3小时，冷却后将反应液过滤，浓缩滤液，使用柱层析以洗脱剂体系A纯化所得残余物，得到标题化合物16e(124mg，产率：68％)。
第六步
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-5-乙基-[1,1'-联苯]-2-基)乙酸甲酯16f
将化合物1e(101mg，0.38mmol)溶于二氯甲烷(5mL)，加入1-氯-N,N,2-三甲基丙烯胺(55mg，0.41mmol)，室温搅拌30分钟。加入化合物16e(100mg，0.33mmol)和吡啶(60mg，0.76mmol)的二氯甲烷(1mL)溶液，室温搅拌30分钟。浓缩后使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物16f(136mg，产率：75％)。
第七步
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-5-乙基-[1,1'-联苯]-2-基)乙酸16
将化合物16f(136mg，0.25mmol)溶于甲醇(5mL)和水(1mL)的混合溶剂中，加入氢氧化锂(53mg，1.25mmol)，室温搅拌反应8小时，反应液浓缩后残余物用乙腈溶解，过滤，随后滤液用高效液相色谱法(Waters 2545，色谱柱：SharpSil-T C18 150*30mm，5μm；流动相：水(含0.1％的三氟醋酸)；乙腈；15分钟梯度：65％-80％)纯化，得到标题化合物16(20mg，产率：15％)。
MS m/z(ESI)：538.1[M+1]。
1H NMR(500MHz,CD3OD)δ7.53(d,1H),7.50-7.36(m,5H),7.27(d,1H),7.21(dd,1H),7.15(d,1H),7.09(d,1H),4.03(d,1H),3.55(s,2H),3.41-3.34(m,1H),2.68(q,2H),1.26(t,3H),0.90(d,3H)。
实施例17
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-5-(2-氰基丙烷-2-基)-[1,1'-联苯]-2-基)乙酸17
第一步
2-(3-溴-4-甲基苯基)-2-甲基丙腈17b
将2-(3-溴-4-甲基苯基)丙腈17a(10g，44.62mmol，采用专利申请“CN112239459”中说明书第73页的实施例9公开的方法制备而得)，碘甲烷(7.6g，53.55mmol)溶于N,N-二甲基甲酰胺(50mL)，冷却至0℃，随后加入氢化钠(2.14g，53.55mmol，纯度60％)，室温反应8小时，加水(50mL)淬灭，乙酸乙酯(50mL×3)萃取，合并有机相，浓缩，使用柱层析以洗脱剂体系B纯化所得残余物，得标题产物17b(1g，产率：89.4％)。
第二步
2-(3-溴-4-(二溴甲基)苯基)-2-甲基丙腈17c
将化合物17b(9.5g,39.90mmol),N-溴代丁二酰亚胺(16.33g,91.76mmol)溶于四氯化碳(100mL)，加入过氧二苯甲酰(247mg,3.99mmol)，加热至90℃回流反应8小时，冷却后加饱和亚硫酸钠水溶液(20mL)淬灭，二氯甲烷(50mL×3)萃取，合并有机相，浓缩后得标题产物17c粗品，未经纯化直接投下一步反应。
第三步
2-(3-溴-4-甲酰基苯基)-2-甲基丙腈17d
将化合物17c(16g，40.41mmol)溶于乙醇(80mL)，加入硝酸银(15.79g，92.95mmol)的水溶液(20mL)，加热回流搅拌反应2小时，冷却后过滤，滤液浓缩，残余物中加入水(100mL)和乙酸乙酯(100mL)，分离有机相，浓缩后使用柱层析以洗脱剂体系B纯化所得残余物，得标题产物17d(9.8g，产率：96.2％)。
第四步
(E)-2-(3-溴-4-(2-甲氧基乙烯基)苯基)-2-甲基丙腈17e
将(甲氧基甲基)三苯基氯化磷(27.19g，79.33mmol，上海毕得医药有限公司)溶于干燥的四氢呋喃(200mL)，加入叔丁醇钾(13.35g，119mmol)，室温搅拌反应1小时，加入化合物17d(10g，39.67mmol)的四氢呋喃(50mL)溶液，室温搅拌反应5小时，加饱和氯化铵水溶液(200mL)淬灭，乙酸乙酯(100mL×3)萃取，合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，浓缩后使用柱层析以洗脱剂体系B纯化所得残余物，得标题产物17e(9.8g，产率：81.9％)。
第五步
(E)-2-(4'-氯-6-(2-甲氧基乙烯基)-3'-硝基-[1,1'-联苯]-3-基)-2-甲基丙腈17f
将化合物17e(4g，14.28mmol)，化合物3b(3.17g，15.71mmol)，二氯[1,1'-双(二苯基膦)二茂铁]钯(II)二氯甲烷络合物(578mg，0.71mmol)，碳酸钠(3.03g，28.56mmol)置于反应瓶中，抽换氮气，随后加入1,4-二氧六环(20mL)和水(4mL)，再次抽换氮气，加热至88℃搅拌反应6小时，停止反应。冷却后浓缩，加入饱和氯化铵水溶液(50mL)，用乙酸乙酯(50mL×2)萃取，合并有机相，干燥，浓缩，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物17f(3.5g，产率：68％)。
第六步
2-(4'-氯-3'-硝基-6-(2-氧代乙基)-[1,1'-联苯]-3-基)-2-甲基丙腈17g
将化合物17f(2.5g，7.01mmol)溶于四氢呋喃(25mL)，加入3M稀盐酸(25mL，75mmol)，加热至100℃，搅拌反应8小时，冷却后缓慢滴加饱和碳酸氢钠水溶液(50mL)，用乙酸乙酯(50mL×2)萃取，有机相干燥后浓缩，使用柱层析以洗脱剂体系B纯化所得残余物，得到标题化合物17g(1.2g，产率：50％)。
第七步
2-(4'-氯-5-(2-氰基丙烷-2-基)-3'-硝基-[1,1'-联苯]-2-基)乙酸17h
将化合物17g(1.2g，3.5mmol)溶于四氢呋喃(40mL)和水(30mL)，冷却至0℃， 依次加入氨基磺酸(1.02g，10.5mmol)，亚氯酸钠(950mg，10.5mmol)的水溶液(10mL)，0℃搅拌反应20分钟，加入饱和氯化铵水溶液(50mL)，用乙酸乙酯(50mL×2)萃取，1M稀盐酸(10mL)洗涤，有机相干燥后浓缩，使用柱层析以洗脱剂体系A纯化所得残余物，得到标题化合物17h(1.2g，产率：95％)。
第八步
2-(3'-氨基-4'-氯-5-(2-氰基丙烷-2-基)-[1,1'-联苯]-2-基)乙酸17i
将化合物17h(1.1g，3.07mmol)溶于乙醇(40mL)和水(5mL)的混合溶剂中，加入氯化铵(1.64g，30.66mmol)和还原铁粉(1.71g，30.66mmol)，加热至60℃搅拌反应3小时，冷却后过滤，将滤液浓缩，使用柱层析以洗脱剂体系A纯化所得残余物，得到标题化合物17i(800mg，产率：79％)。
第九步
2-(4'-氯-3'-((2S,3R)-2-(4-氯苯基)-4,4,4-三氟-3-甲基丁酰胺基)-5-(2-氰基丙烷-2-基)-[1,1'-联苯]-2-基)乙酸17
反应液1：将化合物1e(325mg,1.22mmol)和N,N-二甲基甲酰胺(8.89mg,121.66μmol)溶于四氢呋喃(7mL)，随后滴加草酰氯(200mg,1.58mmol)，室温反应1小时；反应液2：将化合物17i(400mg,1.22mmol)，二异丙基乙胺(629mg,4.87mmol)溶于四氢呋喃(7mL)，滴加三乙基氯硅烷(239mg,1.58mmol)，室温反应45分钟；0℃条件下，将反应液2滴加到反应液1中，室温搅拌反应8小时，加入乙酸乙酯(20mL)稀释，有机相用盐酸(10mL，4M)洗涤三次，干燥后浓缩，使用柱层析以洗脱剂体系A纯化所得残余物，得标题产物17(0.52g，产率：74％)
MS m/z(ESI):578.0[M+1]。
1H NMR(500MHz,CD3OD)δ7.56(d,1H),7.53(d,1H),7.50-7.45(m,3H),7.43(d,1H),7.42-7.37(m,3H),7.17(d,1H),4.04(d,1H),3.60(s,2H),3.40-3.34(m,1H),1.76(s,6H),0.90(d,3H)。
生物学评价
测试例1、本公开化合物对过表达sGC的CHO-K1细胞产生cGMP的激动和/或激活效应。
以下方法用来测定本公开化合物在血红素-依赖性sGC抑制剂1H-1,2,4-噁二唑并-(4,3a)-喹喔啉-1-酮(ODQ)(sigma，O3636-5MG)存在时对过表达sGC的CHO-K1细胞产生cGMP的激动和/或激活效应。实验方法简述如下：
一、实验材料及仪器
1.CHO-K1/sGC(上海恒瑞医药有限公司，NA)
2.cGMP试剂盒(cisbio，62GM2PEH)
3. 384孔板(Corning，4513)
4.U型底96孔板(Corning，3795)
5.Earle's平衡盐溶液(EBSS)(上海源培生物科技股份有限公司，B610KJ)
6. 3-异丁基-1-甲基黄嘌呤(IBMX)(sigma，I7018-1G)
7.BSA(生工生物工程股份有限公司，9048-46-8)
8.MgCl2(sigma，68475-100ML-F)
9.HEPES(Gibco，15630-080)
10.DMEM/F12培养基(GE，SH30023.01)
11.G418.Sulfate(ENZO，ALX-380-013-G005)
12.潮霉素B(Hygromycin B)(Thermo，10687-010)
13.酶标仪(BMG，PHERAsta)
14.细胞计数仪(上海睿钰生物科技有限公司，IC1000)
二、实验步骤
CHO-K1/sGC细胞培养在完全培养基(含10％FBS，1mg/mL G418，200μg/mL潮霉素B的DMEM/F12培养基)中，一周传代2～3次，传代比列1:8或1:15。传代时，用胰酶消化细胞后转至离心管中，1200rpm离心3分钟，弃去上清培养基残液，用完全培养基重悬细胞。
实验时，用胰酶消化细胞，离心弃去上清后，用实验缓冲液(EBSS含有5mM MgCl2，10mM HEPES，0.05％BSA，500μM IBMX)洗细胞一次，离心后弃去残液，用实验缓冲液重悬细胞。用细胞计数仪计数后调整密度为2×106细胞/mL，5μL/孔加入到384孔板中。然后在ODQ实验孔中加入用实验缓冲液稀释至0.5mM的ODQ 2μL/孔，在37℃恒温箱中孵育30分钟。将待测样品用DMSO稀释至1.11mM，然后3倍梯度稀释成10个浓度，并设置空白孔。取配制成梯度浓度的待测化合物溶液3μL加入到97μL的实验缓冲液中配制成含化合物的实验缓冲液。取3μL上述含化合物的实验缓冲液加入到384孔板中，在37℃恒温箱中孵育30分钟。然后根据cGMP试剂盒说明书进行实验。用PHERAstar酶标仪的HTRF程序读取信号值，使用GraphPad软件处理数据，试验结果见表1。
表1本公开化合物对过表达sGC的CHO-K1细胞产生的cGMP的激动和/或激活效应

注：MEC＝最小的有效浓度
结论：本公开化合物对过表达sGC的CHO-K1细胞产生了很强的cGMP的激动和/或激活效应。
测试例2、本公开化合物在重组人肝细胞系HepG2中对细胞色素P450同工酶CYP3A4的诱导活性
核受体家族成员孕烷X受体(pregnane X receptor,PXR)是诱导细胞色素P450同工酶CYP3A4表达的主要转录调控因子，可被多种外源性物质激活。PXR通过与视黄醛X受体(retinoid X receptor,RXR)结合形成异二聚体发挥功能，PXR-RXR与CYP3A4基因上游调控序列相结合，上调CYP3A4的表达。将CYP3A4基因的两个启动子克隆至荧光素酶基因的上游，通过与含人PXR基因的质粒共同转染人肝癌细胞系HepG2，构建荧光素酶报告基因***，通过测定荧光信号检测化合物对CYP3A4的诱导活性。
实验方法简述如下：
一、试剂与仪器
(1)pcDNA3.1-hPXR质粒及pGL4.17-CYP3A4-5’promoter-luc质粒(内部构建，参考文献为“Biochemical Pharmacology 2004,68(12),2347–2358”)
(2)胎牛血清(Fetal Bovine Serum,FBS)(Thermo Fisher Scientific,10099-141)
(3)0.25％胰蛋白酶-EDTA(1x)，酚红(Thermo Fisher Scientific，25200-072)
(4)HepatoZYME-SFM(Thermo Fisher Scientific，17705-021)
(5)MEM(EBSS)(GE Healthcare Life Sciences，SH30024.01)
(6)3000转染试剂(Thermo Fisher Scientific，L3000001)
(7)ONE-GloTM Luciferase Assay System(Promega，E6110)
(8)DMSO(Shanghai titanchem，G75927B)
(9)HepG2(ATCC,HB8065)
(10)多聚-D-赖氨酸96孔微板，黑色/透明(BD，356692)
(11)96孔U底板(Corning,3795)
(12)Opti-MEMTM I减血清培养基(Thermo Fisher Scientific，31985070)
(13)酶标仪(PerkinElmer，VICTOR3)
(14)利福平(Rifampicin)(Sigma,R3501)
二、实验步骤
(1)细胞培养和铺板
实验第一天，将HepG2细胞用0.25％胰蛋白酶-EDTA充分消化，离心后重悬成单细胞悬液，用细胞培养液(EMEM+10％FBS)调整活细胞密度至2×105细胞/mL，以100μL/孔加入96孔细胞培养板(BD,356692)，在培养箱过夜培养(37℃，5％CO2)。
(2)细胞转染
细胞用3000转染试剂共同转染CYP3A4质粒(pGL4.17-CYP3A4-5’promoter-luc)和PXR质粒(pcDNA3.1-hPXR)。取一支离心管，加入400μL Opti-MEM，再加入CYP3A4质粒6.4μg和PXR质粒1.6μg，加入16μL P3000试剂，轻轻上下吹打混匀。另取一支离心管，加入400μL Opti-MEM，再加入24μL3000转染试剂，充分混匀，室温放置5min，将两个离心管中的液体混合，室温放置10min。取出细胞培养板，更换新鲜培养液(EMEM+10％FBS)100μL/孔，再加入10μL/孔上述质粒混合物，37℃，5％CO2条件下培养24小时。
(3)样品配制和加药
以DMSO配制20mM浓度的阳性对照利福平以及受试化合物溶液；
分别取20mM浓度的阳性对照利福平以及受试化合物溶液10μL，加入96孔U底板中，再加入40μL DMSO，充分混匀，稀释至4mM，再取10μL的4mM溶液至90μL DMSO中，充分混匀，稀释至0.4mM，将上述4mM及0.4mM的溶液各取5μL到195μL的HepatoZYME-SFM培养基中，配制成浓度为100μM及10μM的10×化合物溶液。另外取5μL DMSO至96孔U底板中，再加入195μL HepatoZYME-SFM培养基，稀释成2.5％DMSO。
取出细胞培养板，更换培养液为90μL/孔的HepatoZYME-SFM，再加入10μL/孔的10×化合物溶液，化合物终浓度为10μM和1μM，阳性对照为10μM利福平，阴性对照为0.25％DMSO。37℃，5％CO2条件下培养24小时。
(4)读板
在96孔细胞培养板中加入50μL/孔ONE-Glo试剂，室温下在避光处放置5分钟，置于酶标仪(PerkinElmer,VICTOR3)上读取化学发光值。
(5)数据处理
数据在GraphPad Prism8软件中处理，首先计算阴性对照(0.25％DMSO)化学发光(RLU)的平均值，将受试化合物各浓度的RLU平均值除以阴性对照RLU的平均值，求得诱导倍数(Fold of induction)，阳性对照10μM利福平的诱导倍数 应大于等于7，将诱导倍数减去1得到诱导增加倍数(Fold increase above DMSO control)，将受试化合物各浓度的诱导增加倍数除以阳性对照10μM利福平的诱导增加倍数，再乘以100％，得到受试化合物各浓度的诱导增加倍数占10μM利福平诱导增加倍数的百分比，根据10μM化合物的诱导增加倍数百分比来判定化合物诱导能力，小于15％为无诱导(Negative)，大于等于15％小于40％为微弱诱导(Weak)，大于等于40％小于69％为中等诱导(Moderate)，大于等于70％为强诱导(Strong)。
三、实验结果
以10μM利福平为阳性对照，0.25％DMSO为阴性对照，使用HepG2荧光素酶报告基因***对本受试化合物的体外PXR激活/CYP3A4诱导活性进行检测。
化合物Runcaciguat(参考文献“Journal of Medicinal Chemistry 2021,64(9),5323-5344”中化合物45)，结构为：
表2本公开化合物的体外PXR激活/CYP3A4诱导活性
结论：本公开化合物在HepG2荧光素酶报告基因***中对CYP3A4无诱导，而Runcaciguat有中等程度诱导，提示本公开化合物在药物相互作用的评估上，对CYP3A4没有潜在的诱导作用，在联合使用经过CYP3A4代谢的药物时具有更安全的优势。

Claims (24)

  1. 一种通式(I)所示的化合物或其可药用的盐：
    其中：
    环A为苯基或6元杂芳基；
    R1和R2相同或不同，且各自独立地选自氢原子、氘原子、卤素、烷基、烯基、炔基、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、-OR7、羧基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自氘原子、卤素、烷基、-OR7a、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基中的一个或多个取代基取代；
    各个R3相同或不同，且各自独立地选自卤素、烷基、烯基、炔基、羟烷基、卤代烷基、卤代烷氧基、-OR7、羧基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
    各个R4相同或不同，且各自独立地选自卤素、烷基、烯基、炔基、羟烷基、卤代烷基、卤代烷氧基、-OR7、羧基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、羟烷基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、-OR7a、卤代烷基、卤代烷氧基、烯基、炔基、羟基、氰基、氨基和硝基中的一个或多个取代基取代；
    R5和R6相同或不同，且各自独立地选自氢原子、卤素、烷基、烯基、炔基、羟烷基、卤代烷基、烷氧基、卤代烷氧基、-OR7、环烷基和杂环基；
    R7和R7a相同或不同，且各自独立地选自氢原子、烷基、卤代烷基、羟烷基、环烷基、杂环基、芳基和杂芳基；
    n为1、2、3或4；
    m为0、1、2、3或4；且
    p为0、1、2或3。
  2. 根据权利要求1所述的通式(I)所示的化合物或其可药用的盐，其中：环A为苯基或吡啶基；优选地，环A为苯基。
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其可药用的盐，其为通 式(II)所示的化合物或其可药用的盐：
    其中：
    R1、R2、R3、R4、R5、R6、m、n和p如权利要求1中所定义。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：R5和R6相同或不同，且各自独立地选自氢原子、卤素和C1-6烷基；优选地，R5和R6均为氢原子。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其可药用的盐，其为通式(III)所示的化合物或其可药用的盐：
    其中：
    环B选自环烷基、杂环基、芳基和杂芳基；
    各个R2a相同或不同，且各自独立地选自氘原子、卤素、烷基、-OR7a、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基；
    q为0、1、2、3、4或5；
    R1、R3、R4、R7a、m、n和p如权利要求1中所定义。
  6. 根据权利要求5所述的通式(I)所示的化合物或其可药用的盐，其中：环B为6至10元芳基或5至10元杂芳基；优选地，环B为苯基。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其可药用的盐，其为通式(V)所示的化合物或其可药用的盐：
    其中：
    R1a和R1b不同，且各自独立地选自氘原子、卤素、烷基、-OR7a、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基；
    R3a选自卤素、烷基、烯基、炔基、羟烷基、卤代烷基、卤代烷氧基、-OR7、羧基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
    各个R2a相同或不同，且各自独立地选自氘原子、卤素、烷基、-OR7a、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基；
    q为0、1、2、3、4或5；
    R4、R7、R7a、m和p如权利要求1中所定义。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其可药用的盐，其为通式(V-1)或通式(V-2)所示的化合物或其可药用的盐：
    其中：
    R1a和R1b不同，且各自独立地选自氘原子、卤素、烷基、-OR7a、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基；
    R3a选自卤素、烷基、烯基、炔基、羟烷基、卤代烷基、卤代烷氧基、-OR7、羧基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基；
    各个R2a相同或不同，且各自独立地选自氘原子、卤素、烷基、-OR7a、羟烷基、氘代烷基、卤代烷基、卤代烷氧基、烯基、炔基、氰基、氨基和硝基；
    q为0、1、2、3、4或5；
    R4、R7、R7a、m和p如权利要求1中所定义。
  9. 根据权利要求7或8所述的通式(I)所示的化合物或其可药用的盐，其中：R3a选自卤素、C1-6烷基、卤代C1-6烷基和卤代C1-6烷氧基；优选地，R3a为卤素。
  10. 根据权利要求5至9中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：q为0；或者各个R2a相同或不同，且各自独立地选自氘原子、卤素和C1-6烷基，且q为1或2；优选地，R2a为卤素，且q为1。
  11. 根据权利要求7至10中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：R1a为C1-6烷基；R1b为卤代C1-6烷基。
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：m为0；或者各个R4相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基和3至6元环烷基，所述的C1-6烷基任选被一个或多个氰基取代，且m为1。
  13. 根据权利要求1至6、10和12中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：R1为C1-6烷基；所述的C1-6烷基任选被一个或多个卤素取代。
  14. 根据权利要求1至6、10、12和13中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：各个R3相同或不同，且各自独立地选自卤素、C1-6烷基，卤代C1-6烷基和卤代C1-6烷氧基，且n为1或2；优选地，R3为卤素，且n为1。
  15. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其可药用的盐，其中：p为0或1。
  16. 根据权利要求1至15中任一项所述的通式(I)所示的化合物或其可药用的盐，其选自以下任一化合物：




  17. 一种通式(IA)所示的化合物或其盐：
    其中：
    p为1、2或3；
    R3、R4、R5、R6、m、n和p如权利要求1中所定义。
  18. 一种通式(Ia)所示的化合物或其盐：
    其中：
    R为C1-6烷基；优选地，R为甲基；
    环A、R1、R2、R3、R4、R5、R6、m、n和p如权利要求1中所定义。
  19. 化合物或其盐，其选自以下任一化合物：

  20. 一种制备根据权利要求1所述的通式(I)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
    通式(IA)所示的化合物或其盐和通式(IB)所示的化合物或其盐发生酰胺化反应，得到通式(I)所示的化合物或其可药用的盐；
    其中：
    环A、R1、R2、R3、R4、R5、R6、m、n和p如权利要求1中所定义。
  21. 一种制备根据权利要求1所述的通式(I)所示的化合物或其可药用的盐的方法，该方法包括以下步骤：
    通式(Ia)所示的化合物或其盐发生水解反应，得到通式(I)所示的化合物或其可药用的盐；
    其中：
    R为C1-6烷基；优选地，R为甲基；
    环A、R1、R2、R3、R4、R5、R6、m、n和p如权利要求1中所定义。
  22. 一种药物组合物，所述药物组合物含有根据权利要求1至16中任一项所述的通式(I)所示的化合物或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  23. 根据权利要求1至16中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求22所述的药物组合物在制备sGC激动剂和/或激活剂中的用途。
  24. 根据权利要求1至16中任一项所述的通式(I)所示的化合物或其可药用的盐或根据权利要求22所述的药物组合物在制备用于治疗和/或预防通过激动和/或激活sGC来减轻的疾病或病症的药物中的用途，其中所述的疾病或病症选自心血管疾病、肾病、肺动脉高压、炎性疾病、糖尿病、青光眼、糖尿病性视网膜病变、肥胖、骨质疏松、纤维变性病、神经疾病、泌尿***疾病和性功能障碍；优选地，所述的疾病或病症选自心血管疾病、肺动脉高压和肾病；其中所述的肾病优选选自慢性肾功能衰竭、慢性肾功能不全和糖尿病肾病；其中所述的心血管疾病优选 选自高血压、动脉粥样硬化症、冠心病、腰椎管狭窄症、外周动脉疾病、间歇性跛行、重症下肢缺血、稳定或者不稳定心绞痛、心肌梗死、心力衰竭、性腺机能减退、中风、冠状动脉痉挛、大脑血管痉挛、缺血/再灌注损伤和血栓栓塞性病症，更优选选自高血压、心肌梗死和心力衰竭；其中所述的纤维变性病优选选自皮肤、肝、肾及肺的纤维变性病；其中所述的泌尿***疾病优选选自膀胱过动症、良性***增生和***功能障碍；其中所述的神经病症优选选自阿尔茨海默氏病、帕金森氏病和神经性疼痛；其中所述的炎性疾病优选选自牛皮癣、多发性硬化、关节炎、哮喘、溃疡性结肠炎、克罗恩氏病和慢性阻塞性肺病。
PCT/CN2023/076748 2022-02-18 2023-02-17 羧酸类化合物、其制备方法及其在医药上的应用 WO2023155873A1 (zh)

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