WO2019233443A1 - 噻吩并[2,3-c]哒嗪-4(1H)-酮类衍生物及其应用 - Google Patents

噻吩并[2,3-c]哒嗪-4(1H)-酮类衍生物及其应用 Download PDF

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WO2019233443A1
WO2019233443A1 PCT/CN2019/090164 CN2019090164W WO2019233443A1 WO 2019233443 A1 WO2019233443 A1 WO 2019233443A1 CN 2019090164 W CN2019090164 W CN 2019090164W WO 2019233443 A1 WO2019233443 A1 WO 2019233443A1
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alkyl
compound
group
isomer
pharmaceutically acceptable
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PCT/CN2019/090164
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English (en)
French (fr)
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郑晓平
江志赶
贺海鹰
李婕
龚珍
黎健
陈曙辉
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南京明德新药研发有限公司
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Priority to CN201980037798.8A priority Critical patent/CN112218871B/zh
Priority to EP19815304.1A priority patent/EP3805230A4/en
Priority to JP2020568296A priority patent/JP7275444B2/ja
Priority to US15/734,906 priority patent/US11680070B2/en
Publication of WO2019233443A1 publication Critical patent/WO2019233443A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a thieno [2,3-c] pyridazin-4 (1H) -one derivative as an ACC1 and ACC2 inhibitor, and its application in the preparation of a medicine as an ACC1 and ACC2 inhibitor. Specifically, it relates to a compound represented by formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • Fatty acid metabolism disorders caused by increased fatty acid synthesis, reduced fatty acid oxidation, or both, are signs of a variety of metabolic disorders, including insulin resistance, liver steatosis, dyslipidemia, obesity, metabolic syndrome (MetSyn), non-alcoholic Fatty liver (NAFLD) and so on.
  • T2DM type 2 diabetes
  • NASH non-alcoholic steatohepatitis
  • atherosclerosis vascular diseases such as non-alcoholic steatohepatitis (NASH) and atherosclerosis.
  • Disturbance of fatty acid metabolism is also a sign of cancer, which can lead to abnormal and persistent proliferation of malignant tumor cells, so inhibiting fatty acid synthesis and / or stimulating oxidative metabolism of fatty acids may be beneficial for these diseases (PNAS, 2016, E1796-E1805).
  • Acetyl-CoA carboxylase catalyzes the conversion of Acetyl-CoA to malonyl-CoA, which is the first step in the synthesis of fatty acids, and it is also the decisive step.
  • ACC1 is mainly distributed in liver and adipose tissue
  • ACC2 is mainly distributed in liver, heart and muscle tissue.
  • malonyl-CoA catalyzed by ACC1 in the cytoplasm is mainly responsible for the synthesis and extension of fatty acids; malonyl-CoA catalyzed by ACC2 on the surface of mitochondria is mainly regulated by inhibiting carnitine transferase I Oxidative metabolism of fatty acids (PNAS, 2016, E1796-E1805). Therefore, inhibiting both subtypes of ACC simultaneously can reduce fatty acid synthesis and stimulate oxidative metabolism of fatty acids.
  • WO2013071169A1 discloses the application of ACC inhibitor I-181 in the treatment of related diseases.
  • the present invention provides a compound of formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof,
  • D 1 is selected from -O- and -N (R 6 )-;
  • R 1 is selected H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, wherein said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from H, F, Cl, Br, I, OH, NH 2 and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2 or 3 R b ;
  • R 3 is selected from H, F, Cl, Br, I and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 2 and R 3 are connected to each other to form a ring selected from the group consisting of C 3-7 cycloalkyl and 4- to 7-membered heterocycloalkyl, and the C 3-7 alkyl and 4- to 7-membered heterocycloalkyl Is optionally substituted with 1, 2 or 3 R d ;
  • R 4 is selected from the group consisting of OH, NH 2 , C 1-3 alkyl and C 1-3 alkylamino, wherein the C 1-3 alkyl and C 1-3 alkylamino are optionally substituted by 1, 2 or 3 R e Replace
  • R 51 , R 52 , R 53 , R 54 and R 55 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, and C 1 -6 alkoxy, wherein said C 1-6 alkyl, C 1-6 alkylamino and C 1-6 alkoxy are optionally substituted with 1, 2 or 3 R f ;
  • R a, R b, R c , R d, R e, R f and R g are each independently selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, wherein said C 1 -3 alkyl is optionally substituted with 1, 2 or 3 R;
  • R is independently selected from F, Cl, Br, I, OH, NH 2 ;
  • the 4- to 7-membered heterocycloalkyl group includes 1, 2, 3, or 4 heteroatoms or heteroatoms independently selected from -NH-, -O-, -S-, and N;
  • Carbon atoms with "*" are chiral carbon atoms and exist in the form of a single enantiomer of (R) or (S) or are rich in one enantiomer.
  • R a, R b, R c , R d, R e and R f are each independently selected from F, Cl, Br, I, OH and NH 2, the other variables are as defined in the present invention .
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
  • the aforementioned R 2 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CH 3 and Et, and other variables are as defined in the present invention.
  • R 3 is selected from H, F, Cl, Br, I, CH 3 and Et, and other variables are as defined in the present invention.
  • the above R 2 and R 3 are connected to each other to form a ring, and the ring is selected from the group consisting of C 3-6 cycloalkyl and 5- to 6-membered heterocycloalkyl, and the C 3-6 cycloalkyl and The 5- to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 Rd , and Rd and other variables are as defined in the present invention.
  • the above R 2 and R 3 are connected to each other to form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, and piperidinyl
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl and piperidinyl are optionally substituted with 1, 2 or 3 Rd , Rd and other variables such as Defined by the present invention.
  • R 2 and R 3 are connected to each other to form a ring, and the ring is selected from Other variables are as defined in the present invention.
  • R 4 is selected from OH and NH 2 , and other variables are as defined in the present invention.
  • R 51 , R 52 , R 53 , R 54 and R 55 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino and C 1-3 alkoxy, wherein the C 1-3 alkyl, C 1-3 alkylamino and C 1-3 alkoxy are optionally substituted with 1, 2 or 3 R f , R f and other variables are as defined in the present invention.
  • R 51 , R 52 , R 53 , R 54 and R 55 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 , Et and Other variables are as defined in the present invention.
  • the present invention also provides a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof,
  • R 1 is selected H, F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, wherein said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from H, F, Cl, Br, I, OH, NH 2 and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2 or 3 R b ;
  • R 3 is selected from H, F, Cl, Br, I and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 2 and R 3 are connected to each other to form a ring selected from the group consisting of C 3-7 cycloalkyl and 4- to 7-membered heterocycloalkyl, and the C 3-7 alkyl and 4- to 7-membered heterocycloalkyl Is optionally substituted with 1, 2 or 3 R d ;
  • R 4 is selected from the group consisting of OH, NH 2 , C 1-3 alkyl and C 1-3 alkylamino, wherein the C 1-3 alkyl and C 1-3 alkylamino are optionally substituted by 1, 2 or 3 R e Replace
  • R 51 , R 52 , R 53 , R 54 and R 55 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , C 1-6 alkyl, C 1-6 alkylamino, and C 1 -6 alkoxy, wherein said C 1-6 alkyl, C 1-6 alkylamino and C 1-6 alkoxy are optionally substituted with 1, 2 or 3 R f ;
  • R a, R b, R c , R d, R e and R f are each independently selected from F, Cl, Br, I, OH, NH 2 and C 1-3 alkyl, a C 1-3 alkoxy wherein said Is optionally substituted by 1, 2 or 3 R;
  • R is independently selected from F, Cl, Br, I, OH, NH 2 ;
  • the 4- to 7-membered heterocycloalkyl group includes 1, 2, 3, or 4 heteroatoms or heteroatoms independently selected from -NH-, -O-, -S-, and N;
  • Carbon atoms with "*" are chiral carbon atoms and exist in the form of a single enantiomer of (R) or (S) or are rich in one enantiomer.
  • R a, R b, R c , R d, R e and R f are each independently selected from F, Cl, Br, I, OH, NH 2, the other variables are as defined in the present invention .
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
  • the aforementioned R 2 is selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 and Et, and other variables are as defined in the present invention.
  • R 3 is selected from H, F, Cl, Br, I, CH 3 and Et, and other variables are as defined in the present invention.
  • the above R 2 and R 3 are connected to each other to form a ring selected from the group consisting of a C 3-6 cycloalkyl group and a 5- to 6-membered heterocycloalkyl group, and the C 3-6 cycloalkyl group and The 5- to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 Rd , and other variables are as defined in the present invention.
  • the above R 2 and R 3 are connected to each other to form a ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, and piperidinyl
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl and piperidinyl are optionally substituted with 1, 2 or 3 Rd , other variables are as defined in the present invention definition.
  • R 2 and R 3 are connected to each other to form a ring, and the ring is selected from Other variables are as defined in the present invention.
  • the R 4 is selected from OH and NH 2 , and other variables are as defined in the present invention.
  • R 51 , R 52 , R 53 , R 54 and R 55 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylamino and C 1-3 alkoxy, wherein the C 1-3 alkyl, C 1-3 alkylamino and C 1-3 alkoxy are optionally substituted with 1, 2 or 3 R f
  • Other variables are as defined in the present invention.
  • R 51 , R 52 , R 53 , R 54 and R 55 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 , Et and Other variables are as defined in the present invention.
  • the aforementioned compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • R 1 , R 4 , R 51 , R 52 , R 53 , R 54 , R 55 and R 6 are as defined in the present invention
  • Carbon atoms with "*" are chiral carbon atoms and exist in the form of a single enantiomer of (R) or (S) or are rich in one enantiomer.
  • the aforementioned compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • n 0, 1, 2 or 3;
  • E 1 is -O- or -NH-
  • R 1 , R 4 , R 51 , R 52 , R 53 , R 54 and R 55 are as defined in the present invention.
  • Carbon atoms with "*" are chiral carbon atoms and exist in the form of a single enantiomer of (R) or (S) or are rich in one enantiomer.
  • the aforementioned compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, the compound thereof is selected from
  • R 1 , R 4 , R 51 , R 52 , R 53 , R 54 and R 55 are as defined in the present invention.
  • Carbon atoms with "*" are chiral carbon atoms and exist in the form of a single enantiomer of (R) or (S) or are rich in one enantiomer.
  • the invention also provides a compound of the formula, an isomer thereof, or a pharmaceutically acceptable salt thereof,
  • the aforementioned compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is aforementioned compound, an isomer thereof, or a pharmaceutically acceptable salt thereof,
  • the present invention also provides the use of the aforementioned compound, its isomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament as an ACC1 and ACC2 inhibitor.
  • the compounds of the present invention have strong inhibitory activity on human ACC1 / ACC2 enzymes; compared with the control compound I-181, the plasma exposure is greatly improved; meanwhile, the compounds of the present invention have very good Anti-NASH and anti-fibrosis effects.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention.
  • base addition salts can be obtained by contacting a sufficient amount of a base with a neutral form of such compounds in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting a neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc .; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by a conventional chemical method. Generally, such salts are prepared by reacting these compounds in the form of a free acid or base with a stoichiometric appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • This invention contemplates all such compounds, including cis and trans isomers, (-)-and (+)-enantiomers, (R)-and (S) -enantiomers, diastereomers Isomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomers or diastereomeric enriched mixtures, all of which belong to the present invention Within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers in mirror image relationship to each other.
  • cis-trans isomer or “geometric isomer” are caused by the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely.
  • diastereomer refers to a stereoisomer in which a molecule has two or more centers of chirality and is in a non-mirror relationship between molecules.
  • wedge solid line keys And wedge-shaped dotted keys Represents the absolute configuration of a solid center
  • using straight solid line keys And straight dotted keys Represents the relative configuration of the solid center
  • with wavy lines Represents a wedge solid line key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid line key And straight dotted keys
  • the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2) Exists in the form of a mixture;
  • the following formula (B) indicates that the compound exists as a single isomer of the formula (B-1) or (B-2) or in the form of both (B-1) and (B-2) The isomers exist as a mixture.
  • the following formula (C) represents that the compound exists as a single isomer of the formula (C-1) or (C-2) or in the form of the two isomers of the formula (C-1) and the formula (C-2) It exists as a mixture.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be quickly converted to each other. If tautomers are possible (eg in solution), the chemical equilibrium of the tautomers can be reached.
  • proton tautomers also known as prototropic tautomers
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers include the recombination of some bonding electrons for mutual conversion.
  • a specific example of the keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched with one isomer”, “enriched with isomers”, “enriched with one enantiomer” or “enantiomerically enriched” refer to one of the isomers or the The enantiomeric content is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or more 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is 90% and the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)-and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide a pure The desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then by a conventional method known in the art Diastereomeric resolution is performed and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography that employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines) Formate).
  • the compounds of the present invention may contain atomic isotopes in unnatural proportions on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be replaced by heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have lower toxicity and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. Transformations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted refers to the replacement of any one or more hydrogen atoms on a specific atom with a substituent, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • it means that two hydrogen atoms are substituted.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
  • R when any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and R in each case has independent options.
  • combinations of substituents and / or variants are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as-(CRR) 0- , it means that the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent does not exist.
  • X in A-X indicates that the structure is actually A.
  • substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be passed through any of the pyridine rings The carbon atom is attached to a substituted group.
  • alkyl is used to indicate a straight or branched chain saturated hydrocarbon group.
  • the alkyl group is a C 1-12 alkyl group; in other embodiments , The alkyl group is a C 1-6 alkyl group; in other embodiments, the alkyl group is a C 1-3 alkyl group. It can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine).
  • alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl And t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like.
  • alkoxy refers to those alkyl groups that are each attached to the rest of the molecule through an oxygen atom.
  • C 1-6 alkoxy includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy.
  • the alkoxy group is a C 1-3 alkoxy group. Examples of alkoxy include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentoxy and S- Pentyloxy.
  • cycloalkyl includes any stable cyclic alkyl group including monocyclic, bicyclic, or tricyclic systems, where bicyclic and tricyclic systems include spiro, paracyclic, and bridged rings.
  • the cycloalkyl is C 3-8 cycloalkyl; in some embodiments, the cycloalkyl is C 3-7 cycloalkyl; in other embodiments, the cycloalkyl Alkyl is C 3-6 cycloalkyl; in other embodiments, the cycloalkyl is C 5-6 cycloalkyl. It can be univalent, bivalent, or multivalent.
  • cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] bicyclooctane, [4.4.0 ] Bicyclodecane and the like.
  • heterocycloalkyl itself or in combination with other terms respectively represents a cyclic “heteroalkyl”, which includes monocyclic, bicyclic, and tricyclic systems, where bicyclic and tricyclic systems include spiro, Parallel ring and bridge ring.
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the rest of the molecule.
  • the heterocycloalkyl is a 4- to 7-membered heterocycloalkyl; in some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl; in other embodiments
  • the heterocycloalkyl group is a 5- to 6-membered heterocycloalkyl group.
  • heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophene 2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl , Dithiaalkyl, isoxazolidinyl, isothiazolidinyl, 1,2-
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those familiar to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations: aq stands for water; HATU stands for O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate Eq stands for equivalent and equivalent; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N, N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc is ethyl acetate; EtOH is ethanol; MeOH is methanol; BOC is tert-butoxycarbonyl; an amine protecting group; HOAc is acetic acid; rt is room temperature; THF is tetrahydrofuran; Boc 2 O is di-tert-butyl di Carbonate; TFA stands for trifluoroacetic acid; mp stands
  • Step 1 Synthesis of the compound BB-1-2
  • Step 2 Synthesis of the compound BB-1-3
  • Step 3 Synthesis of the compound BB-1-4
  • Step 4 The synthesis of compound BB-1-5
  • Step 6 The synthesis of compound BB-1-7
  • Step 1 Synthesis of the compound BB-2-2
  • Step 2 Synthesis of the compound BB-2-3
  • Step 1 Synthesis of the compound BB-3-2
  • Step 2 Synthesis of the compound BB-3-3
  • the compound BB-3-3 (42.1 g, 150.19 mmol) was dissolved in methanol (300 mL), NaBH 4 (28.4 g, 750.94 mmol) was added in portions at 0 ° C, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, water (100 mL) was added dropwise at 0 ° C, and the solvent was removed under reduced pressure. Water (200 mL) was added to the residue, and dichloromethane (250 mL ⁇ 2) was extracted. The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried.
  • the compound WX001-2 (4.2 g, 9.03 mmol) and phosphorus tribromide (940 ⁇ L, 9.90 mmol) were dissolved in DCM (50 mL), and reacted at room temperature for half an hour. After completion of the reaction, the solvent was removed under reduced pressure, and the obtained residue was separated by a chromatography column to obtain the target compound WX001-3.
  • the compound WX001-3 (3.8 g, 7.20 mmol) was dissolved in DMF (10 mL), KCN (2 g, 30.71 mmol) was added, and the mixture was reacted at room temperature for 2 hours. The raw materials were still detected by TLC. KCN (1.6 g, 24.57 mmol) was added and the reaction was continued for 2.5 hours. After the reaction was completed, it was extracted with water (50 mL) at 0 ° C, and extracted with ethyl acetate (25 mL x 2). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure.
  • the compound WX001-5 (0.1 g, 197.41 ⁇ mol) was dissolved in THF (10 mL), LiHMDS (1M, 590 ⁇ L, 590 ⁇ mol) was added dropwise at -65 ° C, and the reaction was carried out for half an hour, followed by the dropwise addition of 1,4-dibromobutane ( 70 ⁇ L, 580.32 ⁇ mol), and reacted at room temperature for half an hour. After the reaction was completed, water (10 mL) was added to quench the solution at 0 ° C, and the mixture was extracted with ethyl acetate (10 mL x 2).
  • the compound WX001-6 (140 mg, 249.70 ⁇ mol) was dissolved in benzyl alcohol (1 mL), and a 1,4-dioxane hydrochloride solution (4M, 62 ⁇ L, 248 ⁇ mol) was added under a nitrogen atmosphere, and reacted at 50 ° C. for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the obtained residue was separated by preparative HPLC to obtain the target compound WX001-7 (hydrochloric acid conditions).
  • the compound WX001-7 (0.14 g, 209.02 ⁇ mol) was dissolved in methanol (10 mL), 10% Pd / C (30 mg) was added under a nitrogen atmosphere, and hydrogen was replaced three times, and then reacted at 30 ° C under a hydrogen atmosphere (30 Psi) hour.
  • the reaction solution was filtered, and the solvent was removed under reduced pressure to obtain a residue.
  • the residue was separated by preparative chromatography (hydrochloric acid conditions) to obtain the target compound WX001.
  • Compound WX001 was detected by supercritical fluid chromatography (chromatographic column: Chiralpak AD-3 100 x 4.6mm ID, 3 ⁇ m; mobile phase: A: supercritical carbon dioxide, B: 0.05% diethylamine in ethanol solution; gradient: B at 4.5 minutes From 5% to 40%, 40% was maintained for 2.5min, and returned to 5% equilibrium for 1 minute; flow rate: 2.8mL / min; column temperature: 40 ° C; wavelength: 220nm) was analyzed as a racemic compound.
  • the chiral isomers WX001A and WX001B were isolated with retention times of 3.954min and 4.388min, respectively.
  • step 6 Referring to the synthesis method of steps 6 to 8 in Example 1, different halide fragments are used in step 6 to synthesize each of the examples in the following table.
  • the structures in the table also represent their possible isomers.
  • the compound WX011-1 (10 g, 25.71 mmol) was dissolved in methanol (100 mL), lithium borohydride (2.8 g, 128.55 mmol) was added, and the mixture was reacted at room temperature for 2 hours.
  • the reaction solution was extracted with water (200 mL), methanol was removed under reduced pressure, and ethyl acetate (300 mL x 2) was extracted.
  • the organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The obtained residue was used directly in the next reaction.
  • the compound WX011-2 (8 g, 22.16 mmol) and triethylamine (6.2 mL, 44.33 mmol) were dissolved in dichloromethane (100 mL), and MsCl (2.3 mL, 29.68 mmol) was added at 0 ° C. After the addition, the reaction was continued. 1 hour. The reaction solution was extracted with ice water (100 mL), and dichloromethane (60 mL ⁇ 2) was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The obtained residue was directly used in the next reaction.
  • the compound WX011-3 (8.5 g, 19.36 mmol) was dissolved in DMF (100 mL), NaCN (4.07 g, 83.04 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, it was extracted with water (200 mL), and extracted with ethyl acetate (200 mL ⁇ 3). The organic phases were combined, washed with saturated brine (100 mL ⁇ 4), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The obtained residue was separated by a chromatography column to obtain the target compound WX011-4.
  • Compound WX011 was detected by supercritical fluid chromatography (chromatographic column: (S, S) Whelk-01, 100x4.6mm ID, 5 ⁇ m; mobile phase: A: supercritical carbon dioxide, B: 0.05% diethylamine in methanol solution; gradient: B was from 5% to 40% in 4.5 minutes, 40% was kept for 2.5 minutes, and returned to 5% equilibrium for 1 minute; flow rate: 2.8 mL / min; column temperature: 40 ° C; wavelength: 220 nm) was analyzed as a racemic compound.
  • the chiral isomers WX011A and WX011B were isolated, and their retention times were 3.078min and 3.734min, respectively.
  • step 10 Referring to the synthesis method of steps 10 and 11 in Example 1, different intermediate fragments are used in step 10 to synthesize each example in the following table.
  • the structures in the table also represent their possible isomers.
  • Protein human acetyl-CoA carboxylase 1 (hACC1) and human acetyl-CoA carboxylase 2 (hACC2).
  • the compound of the present invention has a strong inhibitory activity on human ACC1 / ACC2 enzyme.
  • test compound 0.5 mg / ml 10% DMSO, 10% polyethylene glycol stearate, 80% water
  • DMSO dimethyl sulfoxide
  • test compound 0.5 mg / ml 10% DMSO, 10% polyethylene glycol stearate, 80% water
  • a suspension or clear solution of the test compound (1 mg / ml 10% PEG400, 90% (0.5% methyl cellulose + 0.2% Tween 80)) was orally administered to 4 male C57BL / 6 mice (overnight fasting, 7-9 weeks of age), the dose is 10 mg / kg.
  • Blood was collected from two mice in a group of 4 to 5 time points. After intravenous or intragastric administration in mice, approximately 30 ⁇ L of blood was collected from saphenous vein puncture at 0.0833h (group IV only), 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 6.0h, 8.0h, and 24h. The plasma was centrifuged in an anticoagulation tube containing EDTA-K2. LC-MS / MS method was used to determine blood drug concentration, and WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to calculate the relevant pharmacokinetic parameters by non-compartment model linear logarithmic trapezoid method.
  • the compounds of the present invention can significantly improve single or partial indicators of pharmacokinetics in mice.
  • I-181 is an Acetyl-CoA Carboxylase inhibitor and is currently undergoing Phase II clinical studies of non-alcoholic fatty liver disease (NAFLD).
  • the HFD + CCl 4 mouse model used in this study is an animal model that simulates the progression of human non-alcoholic fatty liver disease to NASH.
  • High-fat feed causes fat to accumulate and degenerate in liver cells; CCl 4 (peritoneal injection, per (Twice a week) to simulate the "second hit" of liver injury.
  • the model is stable and reliable, and has a high similarity to the pathogenesis of human NASH. It has the main pathological characteristics of NASH, including steatosis, apoptosis, inflammation, and fibrosis. It also shows an increase in plasma transaminase (ALT and AST) levels. high.
  • mice are fed high-fat diets to induce non-alcoholic fatty liver. Mice weighing> 38g are selected and continue to be fed high-fat diets.
  • 25% CCl 4 was administered at 0.5 mg / kg twice a week for four weeks. The day when CCl 4 was given was set to day 0, the time to start CCl 4 was set to be 0 hour, and the day when CCl 4 was given, gastric administration was started. The dose volume of each group was 5 mL / kg per day. Once, for 4 weeks (28 days). The injection time of CCl 4 should be more than 4 hours from the first administration time point of the day.
  • the experiment was divided into 6 groups, namely healthy control group, model group, reference compound group (GS-0976), and test compound group (WX004B, three doses).
  • the healthy control group was 10 normal mice.
  • ordinary mice were fed without CCl 4 injection.
  • 50 obese mice were used in the model group and the administration group.
  • Each group consisted of 10 mice.
  • CCl was injected intraperitoneally. 4 and give different doses of drugs. Grouping and dose design are shown in Table 7.
  • WX004B achieved the same efficacy in both NAS and fibrosis dimensions as the reference compound at higher doses.

Abstract

本发明公开了一种作为ACC1和ACC2抑制剂的噻吩并[2,3-c]哒嗪-4(1H)-酮类衍生物，以及在制备作为ACC1和ACC2抑制剂的药物中的应用。具体公开了式(Ⅱ)所示化合物、其异构体或其药学上可接受的盐。

Description

噻吩并[2,3-c]哒嗪-4(1H)-酮类衍生物及其应用
本申请主张如下优先权：
CN201810570719.7，申请日：2018.06.05；
CN201811033469.X，申请日：2018.09.05。
技术领域
本发明涉及一种作为ACC1和ACC2抑制剂的噻吩并[2,3-c]哒嗪-4(1H)-酮类衍生物，以及在制备作为ACC1和ACC2抑制剂的药物中的应用。具体涉及式(Ⅱ)所示化合物、其异构体或其药学上可接受的盐。
背景技术
由脂肪酸合成增多、脂肪酸氧化降低，或者两者同时存在引起的脂肪酸代谢失调，是多种代谢紊乱的标志，包括胰岛素抵抗、肝脂肪变性、血脂异常、肥胖、代谢综合征(MetSyn)、非酒精性脂肪肝(NAFLD)等。同时可能导致2型糖尿病(T2DM)的发展，以及非酒精性脂肪肝炎(NASH)、动脉粥样硬化等血管疾病。脂肪酸代谢紊乱也是癌症的一个标志，可导致异常和持续的恶性肿瘤细胞增殖，因此抑制脂肪酸的合成和/或刺激脂肪酸的氧化代谢，有可能对这些疾病有利(PNAS,2016,E1796-E1805)。
乙酰辅酶A羧化酶(ACC)催化了乙酰辅酶A向丙二酰辅酶A的转化，这是脂肪酸合成的第一步，同时也是决速步。ACC存在两种亚型，ACC1和ACC2。ACC1主要分布于肝脏和脂肪组织中，ACC2则主要分布于肝脏、心脏及肌肉组织中。在肝脏中，由细胞质中的ACC1催化形成的丙二酰辅酶A，主要负责脂肪酸的合成及延长；由线粒体表面的ACC2催化形成的丙二酰辅酶A则主要通过抑制肉碱转移酶I，调节脂肪酸的氧化代谢(PNAS,2016,E1796-E1805)。因此，同时抑制ACC的两个亚型，可以降低脂肪酸的合成，并刺激脂肪酸的氧化代谢。
WO2013071169A1公开了ACC抑制剂I-181在治疗相关疾病中的应用。
Figure PCTCN2019090164-appb-000001
发明内容
本发明提供了式(Ⅱ)化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019090164-appb-000002
其中，
D 1选自-O-和-N(R 6)-；
R 1选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R a取代；
R 2选自H、F、Cl、Br、I、OH、NH 2和C 1-6烷基，其中所述C 1-6烷基任选被1、2或3个R b取代；
R 3选自H、F、Cl、Br、I和C 1-6烷基，其中所述C 1-6烷基任选被1、2或3个R c取代；
或者，R 2与R 3相互连接形成一个环，其环选自C 3-7环烷基和4～7元杂环烷基，所述C 3-7烷基和4～7元杂环烷基任选被1、2或3个R d取代；
R 4选自OH、NH 2、C 1-3烷基和C 1-3烷氨基，其中所述C 1-3烷基和C 1-3烷氨基任选被1、2或3个R e取代；
R 51、R 52、R 53、R 54和R 55分别独立地选自H、F、Cl、Br、I、OH、NH 2、C 1-6烷基、C 1-6烷氨基和C 1-6烷氧基，其中所述C 1-6烷基、C 1-6烷氨基和C 1-6烷氧基任选被1、2或3个R f取代；
R 6选自H、C 1-6烷基、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O)-、C 1-6烷基-S(＝O) 2-和C 1-6烷基-O-C(＝O)-，其中所述C 1-6烷基、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O)-、C 1-6烷基-S(＝O) 2-和C 1-6烷基-O-C(＝O)-任选被R g取代；
R a、R b、R c、R d、R e、R f和R g分别独立地选自F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R取代；
R分别独立地选自F、Cl、Br、I、OH、NH 2；
所述4～7元杂环烷基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明的一些方案中，上述R a、R b、R c、R d、R e和R f分别独立地选自F、Cl、Br、I、OH和NH 2，其它变量如本发明所定义。
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2和CH 3，其它变量如本发明所定义。
本发明的一些方案中，上述R 2选自H、F、Cl、Br、I、OH、NH 2、CH 3和Et，其它变量如本发明所定义。
本发明的一些方案中，上述R 3选自H、F、Cl、Br、I、CH 3和Et，其它变量如本发明所定义。
本发明的一些方案中，上述R 2与R 3相互连接形成一个环，其环选自C 3-6环烷基和5～6元杂环烷基， 所述C 3-6环烷基和5～6元杂环烷基任选被1、2或3个R d取代，R d及其它变量如本发明所定义。
本发明的一些方案中，上述R 2与R 3相互连接形成一个环，其环选自环丙基、环丁基、环戊基、环己基、四氢呋喃基、四氢吡喃基和哌啶基，其中所述环丙基、环丁基、环戊基、环己基、四氢呋喃基、四氢吡喃基和哌啶基任选被1、2或3个R d取代，R d及其它变量如本发明所定义。
本发明的一些方案中，上述R 2与R 3相互连接形成一个环，其环选自
Figure PCTCN2019090164-appb-000003
Figure PCTCN2019090164-appb-000004
其它变量如本发明所定义。
本发明的一些方案中，上述R 4选自OH和NH 2，其它变量如本发明所定义。
本发明的一些方案中，上述R 51、R 52、R 53、R 54和R 55分别独立地选自H、F、Cl、Br、I、OH、NH 2、C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基，其中所述C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基任选被1、2或3个R f取代，R f及其它变量如本发明所定义。
本发明的一些方案中，上述R 51、R 52、R 53、R 54和R 55分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3、Et和
Figure PCTCN2019090164-appb-000005
其它变量如本发明所定义。
本发明的一些方案中，上述R 6选自H、C 1-3烷基、C 1-3烷基-C(＝O)-、C 1-3烷基-S(＝O)-、C 1-3烷基-S(＝O) 2-和C 1-4烷基-O-C(＝O)-，其中所述 1-3烷基、C 1-3烷基-C(＝O)-、C 1-3烷基-S(＝O)-、C 1-3烷基-S(＝O) 2-和C 1-4烷基-O-C(＝O)-任选被R g取代，R g及其它变量如本发明所定义。
本发明的一些方案中，上述R 6选自H、CH 3、CH 3-C(＝O)-、CH 3-S(＝O) 2-、CH 3-O-C(＝O)-和
Figure PCTCN2019090164-appb-000006
其它变量如本发明所定义。
本发明还提供了式(Ⅰ)化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019090164-appb-000007
其中，
R 1选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R a取代；
R 2选自H、F、Cl、Br、I、OH、NH 2和C 1-6烷基，其中所述C 1-6烷基任选被1、2或3个R b取代；
R 3选自H、F、Cl、Br、I和C 1-6烷基，其中所述C 1-6烷基任选被1、2或3个R c取代；
或者，R 2与R 3相互连接形成一个环，其环选自C 3-7环烷基和4～7元杂环烷基，所述C 3-7烷基和4～7元杂环烷基任选被1、2或3个R d取代；
R 4选自OH、NH 2、C 1-3烷基和C 1-3烷氨基，其中所述C 1-3烷基和C 1-3烷氨基任选被1、2或3个R e取代；
R 51、R 52、R 53、R 54和R 55分别独立地选自H、F、Cl、Br、I、OH、NH 2、C 1-6烷基、C 1-6烷氨基和C 1-6烷氧基，其中所述C 1-6烷基、C 1-6烷氨基和C 1-6烷氧基任选被1、2或3个R f取代；
R a、R b、R c、R d、R e和R f分别独立地选自F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R取代；
R分别独立地选自F、Cl、Br、I、OH、NH 2；
所述4～7元杂环烷基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明的一些方案中，上述R a、R b、R c、R d、R e和R f分别独立地选自F、Cl、Br、I、OH、NH 2，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2和CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 2选自H、F、Cl、Br、I、OH、NH 2、CH 3和Et，其他变量如本发明所定义。
本发明的一些方案中，上述R 3选自H、F、Cl、Br、I、CH 3和Et，其他变量如本发明所定义。
本发明的一些方案中，上述R 2与R 3相互连接形成一个环，其环选自C 3-6环烷基和5～6元杂环烷基，所述C 3-6环烷基和5～6元杂环烷基任选被1、2或3个R d取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 2与R 3相互连接形成一个环，其环选自环丙基、环丁基、环戊基、环己基、四氢呋喃基、四氢吡喃基和哌啶基，其中所述环丙基、环丁基、环戊基、环己基、四氢呋喃基、四氢吡喃基和哌啶基任选被1、2或3个R d取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 2与R 3相互连接形成一个环，其环选自
Figure PCTCN2019090164-appb-000008
Figure PCTCN2019090164-appb-000009
其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自OH和NH 2，其他变量如本发明所定义。
本发明的一些方案中，上述R 51、R 52、R 53、R 54和R 55分别独立地选自H、F、Cl、Br、I、OH、NH 2、C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基，其中所述C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基任选被1、2或3个R f 取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 51、R 52、R 53、R 54和R 55分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3、Et和
Figure PCTCN2019090164-appb-000010
其他变量如本发明所定义。
本发明还有一些方案是有上述各变量任意组合而来。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2019090164-appb-000011
其中，
R 1、R 4、R 51、R 52、R 53、R 54、R 55和R 6如本发明所定义；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2019090164-appb-000012
其中，
m为0、1、2或3；
E 1为-O-或-NH-；
R 1、R 4、R 51、R 52、R 53、R 54和R 55如本发明所定义；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其化合物选自
Figure PCTCN2019090164-appb-000013
其中，
R 1、R 4、R 51、R 52、R 53、R 54和R 55如本发明所定义；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明还提供了下式化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019090164-appb-000014
Figure PCTCN2019090164-appb-000015
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019090164-appb-000016
Figure PCTCN2019090164-appb-000017
本发明还提供了上述化合物、其异构体或其药学上可接受的盐在制备作为ACC1和ACC2抑制剂的药物中的应用。
技术效果
作为新型的ACC1和ACC2抑制剂，本发明化合物对人源ACC1/ACC2酶很强的抑制活性；与对照化合物I-181相比，血浆暴露量得到大幅度提高；同时，本发明化合物具有很好的抗NASH和抗纤维化作用。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2019090164-appb-000018
和楔形虚线键
Figure PCTCN2019090164-appb-000019
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2019090164-appb-000020
和直形虚线键
Figure PCTCN2019090164-appb-000021
表示立体中心的相对构型，用波浪线
Figure PCTCN2019090164-appb-000022
表示楔形实线键
Figure PCTCN2019090164-appb-000023
或楔形虚线键
Figure PCTCN2019090164-appb-000024
或用波浪线
Figure PCTCN2019090164-appb-000025
表示直形实线键
Figure PCTCN2019090164-appb-000026
和直形虚线键
Figure PCTCN2019090164-appb-000027
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子 均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线
Figure PCTCN2019090164-appb-000028
连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在；下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形式存在。
Figure PCTCN2019090164-appb-000029
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。 例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。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，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，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。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、 硼(B)、-O-、-S-、C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。
除非另有规定，术语“烷基”用于表示直链或支链的饱和的碳氢基团，在一些实施方案中，所述烷基为C 1-12烷基；在另一些实施方案中，所述烷基为C 1-6烷基；在另一些实施方案中，所述烷基为C 1-3烷基。其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的实例包括但不限于甲基(Me)，乙基(Et)，丙基(包括n-丙基和异丙基)，丁基(包括n-丁基，异丁基，s-丁基和t-丁基)，戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，术语“烷氧基”是指分别通过一个氧原子连接到分子的其余部分的那些烷基基团。除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。在一些实施方案中，所述烷氧基为C 1-3烷氧基。烷氧基的实例包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
除非另有规定，“环烷基”包括任何稳定的环状烷基，其包括单环、双环或者三环体系，其中双环和三环体系包括螺环、并环和桥环。在一些实施方案中，所述环烷基为C 3-8环烷基；在一些实施方案中，所述环烷基为C 3-7环烷基；在另一些实施方案中，所述环烷基为C 3-6环烷基；在另一些实施方案中，所述环烷基为C 5-6环烷基。其可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，术语“杂环烷基”本身或者与其他术语联合分别表示环化的“杂烷基”，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。在一些实施方案中，所述杂环烷基为4～7元杂环烷基；在一些实施方案中，所述杂环烷基为4～6元杂环烷基；在另一些实施方案中，所述杂环烷基为5～6元杂环烷基。杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或氧杂环庚烷基。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐；eq代表当量、等量；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸 乙酯；EtOH代表乙醇；MeOH代表甲醇；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；r.t.代表室温；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；mp代表熔点；CHLOROFORM-d代表氘代氯仿；DMAP代表二甲基氨基吡啶；EDTA-K2代表二乙胺四乙酸二钾；PEG400代表聚乙二醇400；DBU代表1,8-二氮杂二环十一碳-7-烯；NaBH 4代表硼氢化钠；NBS代表N-溴代琥珀酰亚胺；LiHMDS代表六甲基二硅基胺基锂；BPO代表过氧化二苯甲酰；SEM-Cl代表2-(三甲基硅)乙氧基甲基氯；MsCl代表甲基磺酰氯；TBAF代表四丁基氟化铵。
化合物经手工或者
Figure PCTCN2019090164-appb-000030
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
参考例1：片段BB-1
Figure PCTCN2019090164-appb-000031
合成路线：
Figure PCTCN2019090164-appb-000032
步骤1：化合物BB-1-2的合成
将化合物BB-1-1(25g,254.67mmol)溶解在二氯甲烷(60mL)中，0℃滴加磺酰氯(43mL,430.10mmol)的二氯甲烷(10mL)溶液，室温搅拌过夜。反应完成后，减压除去溶剂得到粗品BB-1-2，直接投到下一步。 1H NMR(400MHz,CDCl 3)δ6.62(s,1H),2.14(s,3H)。
步骤2：化合物BB-1-3的合成
将化合物BB-1-2(40.1g,240.04mmol)溶解于氯仿(300mL)中，0℃加入乙酰氯(34.3mL,480.65mmol)和三氯化铝(38.4g,287.98mmol)，室温搅拌过夜。反应完成后，反应液倒入冰水(1000mL)中，室温搅拌30分钟，乙酸乙酯(500mL×2)萃取。合并的有机相用饱和食盐水(500mL)洗，无水硫酸钠干燥、过滤、减压除去溶剂，残留物通过柱色谱纯化得到BB-1-3。 1H NMR(400MHz,CDCl 3)δ2.64(s,3H),2.26(s,3H)。
步骤3：化合物BB-1-4的合成
氮气气氛下，将钠氢(12.7g,60％分散于矿物油中,317.53mmol)加入到甲苯(200mL)中，往其中加入碳酸二甲酯(17.9mL,212.63mmol)，升温至120℃，滴加化合物BB-1-3(22.2g，106.17mmol)的甲苯(50mL)溶液半小时，继续反应半小时。反应完成后，用水(300mL)萃灭，所得水相用乙酸乙酯(150mL x 2)萃取。合并的有机相用饱和食盐水(100mL×2)洗，无水硫酸钠干燥、过滤、减压除去溶剂，残留物通过柱色谱纯化得到BB-1-4。 1H NMR(400MHz,CDCl 3)δ12.13(s,1H),5.28(s,1H),3.78(s,3H),2.10(s,3H)。
步骤4：化合物BB-1-5的合成
将化合物BB-1-4(4.7g,17.59mmol)和三乙胺(2.9mL,20.84mmol)加入至乙腈(50mL)中，0℃加入对甲苯磺酰叠氮(4.2g,21.30mmol)，该温度下反应30分钟，然后室温反应2小时。反应完成后，0℃用水(50mL)萃灭，所得水相用乙酸乙酯(25mL×2)萃取。合并的有机相用饱和食盐水(10mL x 2)洗，无水硫酸钠干燥、过滤、减压除去溶剂，残留物通过柱色谱纯化得到BB-1-5。 1H NMR(400MHz,CDCl 3)δ3.83(s,3H),2.12(s,3H)。
步骤5：化合物BB-1-6的合成
将化合物BB-1-5(22.6g,77.10mmol)加到异丙醚(300mL)中，0℃滴加三丁基膦(20.9mL,84.71mmol)的正己烷(30mL)溶液，室温搅拌2小时。反应完成后，减压除去溶剂，残余物通过柱色谱纯化得到BB-1-6。 1H NMR(400MHz,CDCl 3)δ3.92(s,3H),2.12(s,3H)。
步骤6：化合物BB-1-7的合成
将化合物BB-1-6(20.1g,68.10mmol)溶于二氯甲烷(300mL)中，加入Boc 2O(17.8g,81.56mmol)和DMAP(1.7g,13.92mmol)，室温搅拌12小时。反应完成后，减压除去溶剂，残余物通过柱色谱纯化得到BB-1-7。 1H NMR(400MHz,CDCl 3)δ3.93(s,3H),2.22(s,3H),1.54(s,9H)。
步骤7：化合物BB-1的合成
将化合物BB-1-7(26.1g，66.03mmol)溶解于DMF(100mL)中，加入K 2CO 3(10.95g,79.24mmol)，80℃反应12小时。反应完成后，加入水(300mL)和HCl(1M,100mL)，所得水相用乙酸乙酯(300mL x 2)萃取。合并的有机相用无水硫酸钠干燥、过滤、减压除去溶剂，残余物通过柱色谱纯化得到目标化合物。LCMS:[M+H] +258.8。
参考例2：片段BB-2
Figure PCTCN2019090164-appb-000033
合成路线：
Figure PCTCN2019090164-appb-000034
步骤1：化合物BB-2-2的合成
将化合物BB-2-1(4g,21.49mmol)溶于乙腈(50mL)中，加入DBU(4.91g,32.23mmol)和4-乙酰氨基苯磺酰叠氮(6.19g,25.78mmol)的乙腈(10mL)溶液，室温搅拌过夜。反应完成后，减压旋干除去溶剂，残留物通过柱层析分离得到目标化合物BB-2-2。 1H NMR(400MHz,CDCl 3)δ7.56-7.53(m,1H),7.23-7.20(m,1H),7.12-7.08(m,1H),3.77(s,3H)。
步骤2：化合物BB-2-3的合成
将化合物BB-2-2(0.99g,4.67mmol)和4-四氢吡喃醇(930μL,9.29mmol)溶于二氯甲烷(50mL)中，加入醋酸铑二聚物(41mg,93μmol)，室温反应5分钟。反应完成后，减压除掉溶剂，残留物通过柱层析分离得到BB-2-3。 1H NMR(400MHz,CDCl 3)δ7.49-7.47(m,1H),7.10-7.03(m,1H),6.99-6.91(m,1H),5.39(s,1H),3.94-3.81(m,2H),3.66(s,3H),3.59-3.51(m,1H),3.41-3.28(m,2H),1.96-1.87(m,1H),1.83-1.73(m,1H),1.70-1.55(m,2H)。
步骤3：化合物BB-2的合成
将化合物BB-2-3(5.2g,18.16mmol)溶于甲醇(100mL)中，0℃加入NaBH 4(687mg,18.16mmol)，室温反应2小时。反应完毕后，0℃滴加水(50mL)萃灭反应，过滤、减压除去溶剂。往残留物中加入水(50mL)，二氯甲烷(50mL×2)萃取。合并的有机相用饱和食盐水(50mL)洗，无水硫酸钠干燥、过滤、旋干，所得残留物通过柱层析分离得到目标化合物BB-2。 1H NMR(400MHz,CDCl 3)δ7.52-7.49(m,1H),7.14-7.12(m,1H),7.05-7.01(m,1H),5.05-5.01(m,1H),3.99-3.96(m,1H),3.92-3.90(m,1H),3.72-3.70(m,1H),3.57-3.32(m,4H),2.26-2.23(m,1H),2.05-1.96(m,1H),1.79-1.63(m,2H),1.60-1.54(m,1H)。
参考例3：片段BB-3
Figure PCTCN2019090164-appb-000035
合成路线：
Figure PCTCN2019090164-appb-000036
步骤1：化合物BB-3-2的合成
将化合物BB-3-1(50g,277.47mmol)和NBS(49.39g,277.47mmol)溶于四氯化碳(1L)中，加入BPO(1.01g,4.16mmol)，80℃反应3小时。反应完成后，反应液减压除去溶剂得到目标化合物BB-3-2直接用于下步反应。 1H NMR(400MHz,CDCl 3)δ7.64-7.61(m,1H),7.37-7.30(m,1H),7.03-6.98(m,1H),6.91-6.88(m,1H),5.91(s,1H),3.89(s,3H),3.79(s,3H)。
步骤2：化合物BB-3-3的合成
将化合物BB-3-2(76.1g，293.71mmol)和4-四氢吡喃醇(58.8mL,587.24mmol)溶于二氯甲烷(1.2L)中，加入氧化银(68.1g,293.87mmol)，25℃搅拌16小时。反应完成后，过滤、减压除去溶剂，所得残留物通过柱层析纯化目标化合物BB-3-3。 1H NMR(400MHz,CDCl 3)δ7.48-7.43(m,1H),7.35-7.31(m,1H),7.02-7.01(m,1H),6.94-6.90(m,1H),5.51(s,1H),4.02-3.92(m,2H),3.87(s,3H),3.73(s,3H),3.65-3.60(m,1H),3.48-3.36(m,2H),2.03-1.94(m,1H),1.92-1.83(m,1H),1.79-1.65(m,2H)。
步骤3：化合物BB-3的合成
将化合物BB-3-3(42.1g,150.19mmol)溶解在甲醇(300mL)中，0℃分批加入NaBH 4(28.4g,750.94mmol)，室温反应2小时。反应完毕后，0℃滴加水(100mL)萃灭，减压除去溶剂。往残留物中加入水(200mL)，二氯甲烷(250mL×2)萃取。合并的有机相用饱和食盐水(100mL)洗，无水硫酸钠干燥、过滤、旋干，所得残留物经柱层析分离得到目标化合物BB-3。 1H NMR(400MHz,CDCl 3)δ7.48-7.40(m,1H),7.33-7.28(m,1H),7.03-7.00(m,1H),6.94-6.85(m,1H),5.11-5.05(m,1H),4.01-3.90(m,2H),3.84(s,3H),3.70-3.66(m,1H),3.58-3.46(m,2H),3.45-3.33(m,2H),2.38-2.19(m,1H),2.06-1.97(m,1H),1.84-1.75(m,1H),1.72-1.60(m,2H)。
实施例1：WX001
Figure PCTCN2019090164-appb-000037
合成路线：
Figure PCTCN2019090164-appb-000038
步骤1：化合物WX001-1的合成
将化合物BB-1(6.02g,23.27mmol)、化合物BB-3(5.87g,23.27mmol)和三苯基膦(12.21g,46.54mmol)加入至四氢呋喃(250mL)中，0℃下加入DIAD(9.0mL,46.29mmol)，室温反应2小时。反应完成后，过滤、减压除去溶剂，残留物通过层析柱分离得到目标化合物WX001-1。 1H NMR(400MHz,CDCl 3)δ7.56–7.54(m,1H),7.38–7.34(m,1H),7.08–7.04(m,1H),6.93–6.91(m,1H),5.44–5.41(m,1H),4.43–4.39(m,1H),4.17-4.12(m,1H),4.01(s,3H),3.90(s,3H),3.73-3.65(m,1H),3.59-3.49(m,1H),3.31–3.28(m,1H),3.27-3.20(m,2H),2.62(s,3H),1.78-1.66(m,1H),1.64-1.48(m,2H),1.29-1.23(m,1H)。
步骤2：化合物WX001-2的合成
将NaBH 4(1.73g,45.64mmol)溶解于甲醇(70mL)中，0℃分批加入化合物WX001-1(4.5g,9.13mmol)，50℃反应1小时。反应液0℃用水(20mL)萃灭，二氯甲烷(25mL×2)萃取，有机相合并，饱和食盐水(20mL)洗，无水硫酸钠干燥、过滤、减压除去溶剂，所得残留物直接用于下步反应。
步骤3：化合物WX001-3的合成
氮气气氛下，将化合物WX001-2(4.2g,9.03mmol)和三溴化磷(940μL,9.90mmol)溶在DCM(50mL)中，室温反应半小时。反应完成后，减压除去溶剂，所得残留物经层析柱分离得到目标化合物WX001-3。 1H NMR(400MHz,CDCl 3)δ7.56-7.54(m,1H),7.37-7.33(m,1H),7.07–7.03(m,1H),6.93–6.91(m,1H),5.43–5.40(m,1H),4.64(d,J＝9.2Hz,1H),4.57(d,J＝9.2Hz,1H),4.38–4.33(m,1H),4.07–4.04(m,1H),3.91(s,3H),3.75-3.65(m,1H),3.63-3.52(m,1H),3.42-3.25(m,3H),2.62(s,3H),1.74-1.64(m,1H),1.59-1.54(m,2H),1.24-1.20(m,1H)。
步骤4：化合物WX001-4的合成
将化合物WX001-3(3.8g,7.20mmol)溶于DMF(10mL)中，加入KCN(2g,30.71mmol)，室温反应2小时。TLC检测原料还在，补加KCN(1.6g，24.57mmol)，继续反应2.5小时。反应完成后，0℃用水(50mL)萃灭，乙酸乙酯(25mL×2)萃取。有机相合并，饱和食盐水(25mL)洗，无水硫酸钠干燥、过滤、减压除去溶剂，所得残留物通过层析柱分离得到目标化合物WX001-4。 1H NMR(400MHz,CDCl 3)δ7.50-7.37(m,1H),7.31-7.22(m,1H),6.98–6.94(m,1H),6.86–6.84(m,1H),5.39-5.36(m,1H),4.41-4.24(m,1H),4.05-3.99(m,1H),3.98-3.75(m,5H),3.74-3.63(m,1H),3.56-3.46(m,1H),3.33-3.29(m,1H),3.28-3.15(m,2H),2.51(s,3H),1.71-1.61(m,1H),1.59-1.41(m,2H),1.16-1.04(m,1H)。
步骤5：化合物WX001-5的合成
将化合物WX001-4(2.83g,5.97mmol)，2-(三正丁基锡)噁唑(5.35g,14.93mmol)溶于甲苯(100mL)中，加入四(三苯基膦)钯(2.07g,1.79mmol)，氮气置换3次后，升温至120℃反应1小时。反应液降至室温减压除去溶剂，所得残留物溶解于二氯甲烷(30mL)中，并用饱和氟化钾(30mL)淬灭。二氯甲烷(30mL)萃取，合并的有机相用饱和食盐水(30mL)洗，无水硫酸钠干燥、过滤、减压除去溶剂，残留物通过层析柱分离得到目标化合物WX001-5。 1H NMR(400MHz,CDCl 3)δ7.71(s,1H),7.48–7.45(m,1H),7.27-7.26(m,1H),7.21(s,1H),6.99–6.95(m,1H),6.86–6.84(m,1H),5.45-5.41(m,1H),4.42–4.38(m,1H),4.14–4.09(m,1H),3.94-3.82(m,5H),3.71-3.62(m,1H),3.54-3.43(m,1H),3.30–3.35(m,1H),3.27-3.12(m,2H),2.95(s,3H),1.70-1.60(m,1H),1.57-1.47(m,2H),1.12–1.09(m,1H)。
步骤6：化合物WX001-6的合成
将化合物WX001-5(0.1g,197.41μmol)溶解于THF(10mL)中，-65℃滴加LiHMDS(1M,590μL,590μmol)，反应半小时，随后滴加1,4-二溴丁烷(70μL,580.32μmol)，室温反应半小时。反应完成后，0℃滴加水(10mL)淬灭，乙酸乙酯(10mL×2)萃取，合并的有机相用饱和食盐水(10mL)洗，无水硫酸钠干燥，过滤除去干燥剂后，滤液减压除去溶剂，经制备板分离得到目标化合物WX001-6。LCMS(5-95/1.5min):0.973min,[M+H] +＝561.1。
步骤7：化合物WX001-7的合成
将化合物WX001-6(140mg，249.70μmol)溶解在苄醇(1mL)中，氮气气氛下加入盐酸1,4-二氧六环溶液(4M,62μL,248μmol)，50℃反应2小时。反应完毕后，减压除去溶剂，所得残留物通过制备HPLC分离得到目标化合物WX001-7(盐酸条件)。LCMS(5-95/1.5min):1.095min,[M+H] +＝670.1。
步骤8：化合物WX001的合成
将化合物WX001-7(0.14g,209.02μmol)溶解于甲醇(10mL)中，氮气气氛下加入10％Pd/C(30mg)，氢气置换3次后，于氢气气氛(30Psi)下30℃反应2小时。反应液过滤、减压除掉溶剂得到残留物，残留物经制备色谱(盐酸条件)分离得到目标化合物WX001。化合物WX001经过超临界流体色谱检测(色谱柱：Chiralpak AD-3 100 x 4.6mm I.D.,3μm；流动相：A:超临界二氧化碳，B:0.05％二乙胺的乙醇溶液；梯度：B在4.5分钟内从5％到40％，40％保持2.5min，回到5％平衡1分钟；流速：2.8mL/min；柱温：40℃；波长：220nm)分析为外消旋化合物。分离得到手性异构体WX001A和WX001B，其保留时间分别为3.954min和4.388min。
参照实施例1中步骤6～8的合成方法，在步骤6中使用不同的卤化物片段，合成下表中各实施例。表中的结构同时代表其可能的异构体。
表1.各实施例的化合物结构
Figure PCTCN2019090164-appb-000039
Figure PCTCN2019090164-appb-000040
Figure PCTCN2019090164-appb-000041
Figure PCTCN2019090164-appb-000042
表2.各实施例的NMR和MS数据
Figure PCTCN2019090164-appb-000043
Figure PCTCN2019090164-appb-000044
Figure PCTCN2019090164-appb-000045
Figure PCTCN2019090164-appb-000046
Figure PCTCN2019090164-appb-000047
Figure PCTCN2019090164-appb-000048
Figure PCTCN2019090164-appb-000049
实施例11：WX011
Figure PCTCN2019090164-appb-000050
合成路线：
Figure PCTCN2019090164-appb-000051
步骤1：化合物WX011-1的合成
将化合物BB-1(20g,77.32mmol)溶解于DMF(270mL)中，加入NaH(4.02g,60％分散于矿物油中，100.51mmol)，0℃搅拌30分钟后加入SEM-Cl(15mL,84.75mmol)，室温反应1小时。反应液用水(800mL)萃灭，乙酸乙酯(400mL×2)萃取，有机相合并后用饱和食盐水(100mL x 4)洗，无水硫酸钠干燥、过滤、减压除去溶剂，所得残留物经层析柱分离得到目标化合物WX011-1。
1HNMR(400MHz,CDCl 3)δ5.52(s,2H),3.99(s,3H),3.66–3.62(m,2H)2.59(s,3H),1.00–0.96(m,2H),0.00(s,9H)。
步骤2：化合物WX011-2的合成
将化合物WX011-1(10g，25.71mmol)溶解于甲醇(100mL)中，加入硼氢化锂(2.8g,128.55mmol)，室温反应2小时。反应液用水(200mL)萃灭，减压除去甲醇，乙酸乙酯(300mL×2)萃取，有机相合并，饱和食盐水(50mL x 2)洗，无水硫酸钠干燥、过滤、减压除去溶剂，所得残留物直接用于下步反应。 1HNMR(400MHz,CDCl 3)δ5.48(s,2H),4.77(s,2H),3.64–3.60(m,2H),2.58(s,3H),1.00–0.95(m,2H),0.01(s,9H)。
步骤3：化合物WX011-3的合成
将化合物WX011-2(8g,22.16mmol)和三乙胺(6.2mL,44.33mmol)溶解于二氯甲烷(100mL)中，0℃加入MsCl(2.3mL,29.68mmol)，加完后继续反应1小时。反应液用冰水(100mL)萃灭，二氯甲烷(60mL×2)萃取，有机相合并，无水硫酸钠干燥、过滤、减压除去溶剂，所得残留物直接用于下步反应。
步骤4：化合物WX011-4的合成
将化合物WX011-3(8.5g,19.36mmol)溶于DMF(100mL)中，加入NaCN(4.07g,83.04mmol)，室温反应2小时。反应完成后，用水(200mL)萃灭，乙酸乙酯(200mL×3)萃取。有机相合并，饱和食盐水(100mL×4)洗，无水硫酸钠干燥、过滤、减压除去溶剂，所得残留物通过层析柱分离得到目标化合物WX011-4。 1HNMR(400MHz,DMSO-d 6)δ5.51(s,2H),3.90(s,2H),3.66–3.62(m,2H),2.56(s,3H),0.99–0.95(m,2H),0.00(s,9H)。
步骤5：化合物WX011-5的合成
将化合物WX011-4(2.5g,6.76mmol)，2-(三正丁基锡)噁唑(6.05g,16.89mmol)溶于甲苯(30mL)中，加入四(三苯基膦)钯(1.56g,1.35mmol)，氮气置换3次后，升温至120℃反应4小时。降到室温，饱和氟化钾(20mL)淬灭，加入水(80mL)，乙酸乙酯(100mL x 2)萃取，有机相合并，无水硫酸钠干燥、过滤、减压除去溶剂，残留物通过层析柱分离得到目标化合物WX011-5。 1HNMR(400MHz,CDCl 3)δ7.77(s,1H),7.29(s,1H),5.60(s,2H),3.94(s,2H),3.71–3.67(m,2H),3.02(s,3H),1.02–0.98(m,2H),0.01(s,9H)。
步骤6：化合物WX011-6的合成
将化合物WX011-5(1.9g,4.72mmol)和碘甲烷(1.6mL,25.50mol)溶解于THF(20mL)中，0℃滴加叔丁醇钾溶液(1M,14.2mL,14.2mmol)，室温反应1小时。反应用水(100mL)淬灭，乙酸乙酯(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤除去干燥剂后，滤液减压除去溶剂所得残留物直接用于下步反应。 1HNMR(400MHz,CDCl 3)δ7.75(s,1H),7.29(s,1H),5.54(s,2H),3.70–3.65(m,2H),3.02(s,3H),1.64(s,6H),1.00–0.96(m,2H),0.01(s,9H)。
步骤7：化合物WX011-7的合成
将化合物WX011-6(1g，2.32mmol)加入到TBAF(1M,15mL,15mmol)的THF溶液中，室温反应1小时。反应完毕后，用水(80mL)淬灭，乙酸乙酯(100mL×2)萃取，合并的有机相用水(50mL x 5) 洗，无水硫酸钠干燥，过滤除去干燥剂后，滤液减压除去溶剂所得残留物直接用于下步反应。 1HNMR(400MHz,CDCl 3)δ7.72(s,1H),7.24(s,1H),2.95(s,3H),1.81(s,6H)。
步骤8：化合物WX011-8的合成
将化合物WX011-7(0.56g,1.86mmol)，化合物WX011-7a(786mg,2.24mmol)和三苯基膦(978mg,3.73mmol)加入至四氢呋喃(10mL)中，0℃下加入DIAD(730μL,3.75mmol)，室温反应15小时。反应完成后，减压除去溶剂，所得残留物直接用于下步反应。LCMS:[M+Na]＝656.2.
步骤9：化合物WX011-9的合成
将化合物WX011-8(0.9g，1.42mmol)溶解在苄醇(15mL)中，加入盐酸的1,4-二氧六环溶液(4M,15mL)，50℃反应1小时。反应完毕后，减压除去溶剂，所得残留物用甲基叔丁基醚(150mL)打浆得到目标化合物WX011-9。LCMS:[M+H] +＝643.4。
步骤10：化合物WX011-10的合成
往化合物WX011-9(0.1g,155.58μmol)中加入二氯甲烷(0.7mL)，加入氢氧化钠(1M,0.8mL)，加入乙酰氯(44μL,622μmol)，室温反应1小时。二氯甲烷(5mL x 2)萃取，合并的有机相用无水硫酸钠干燥，过滤除去干燥剂后，滤液减压除去溶剂。所得残留物经制备色谱(盐酸条件)分离拿到目标化合物WX011-10。LCMS:[M+H] +＝707.1.
步骤11：化合物WX011的合成
将化合物WX011-10(50mg,73.01μmol)溶解于甲醇(5mL)中，氮气气氛下加入10％的Pd/C(100mg)，氢气置换3次后，于氢气气氛(15Psi)下室温反应1小时。反应液过滤、减压除掉溶剂得到残留物，残留物经制备色谱(盐酸条件)分离拿到目标化合物WX011。
化合物WX011经过超临界流体色谱检测(色谱柱：(S,S)Whelk-01，100x 4.6mm I.D.,5μm；流动相：A:超临界二氧化碳，B:0.05％二乙胺的甲醇溶液；梯度：B在4.5分钟内从5％到40％，40％保持2.5min，回到5％平衡1分钟；流速：2.8mL/min；柱温：40℃；波长：220nm)分析为外消旋化合物。分离得到手性异构体WX011A和WX011B，其保留时间分别为3.078min，3.734min。
WX011A, 1HNMR(400MHz,CDCl 3)δ7.70(s,1H),7.47–7.42(m,1H),7.30–7.26(m,2H),6.99–6.96(m,1H),6.86–6.84(m,1H),5.47–5.42(m,1H),4.39–4.30(m,1H),4.15–4.10(m,1H),3.82(s,3H),3.47–3.00(m,5H),2.95(s,3H),1.93,1.91(2s,3H),1.54–1.19(m,10H)；LCMS(5–95AB/1.5min):Rt＝0.904；[M+Na]＝617.3。
WX011B, 1HNMR(400MHz,CDCl 3)δ7.70(s,1H)7.47–7.42(m,1H)7.30–7.26(m,2H)6.99–6.96(m,1H)6.86–6.84(m,1H)5.47–5.42(m,1H)4.39–4.33(m,1H)4.15–4.10(m,1H)3.82(s,3H)3.47–3.00(m,5H)2.95(s,3H)1.93,1.91(2s,3H)1.54–1.19(m,10H)；LCMS(5–95AB/1.5min):Rt＝0.904；[M+Na]＝617.4。
参照实施例1中步骤10，11的合成方法，在步骤10中使用不同的中间体片段，合成下表中各实施例。表中的结构同时代表其可能的异构体。
3.各实施例的化合物结构
Figure PCTCN2019090164-appb-000052
Figure PCTCN2019090164-appb-000053
表4.各实施例的NMR和MS数据
Figure PCTCN2019090164-appb-000054
Figure PCTCN2019090164-appb-000055
实验例1：体外评价
实验目的：
通过测定IC 50值来评价受试化合物对乙酰辅酶A羧化酶(ACC)的抑制能力。
实验材料：
1.蛋白：人源乙酰辅酶A羧化酶1(hACC1)和人源乙酰辅酶A羧化酶2(hACC2)。
2.底物：NaHCO 3
3.辅因子：乙酰辅酶A，ATP
4.激活剂：柠檬酸钾
实验方法：
1.在孔板的微孔中加入1倍的酶/底物/辅因子。
2.利用Acoustic技术，向上述酶的混合物中，加入化合物的DMSO溶液，预孵化15分钟。
3.向其中加入ATP引发反应，摇匀。
4.室温下孵化1小时。
5.淬灭反应后，继续孵化40分钟。
6.加入检测试剂，孵化30分钟。
7.测试荧光。
8.分析数据：基于ADP的标准曲线，将荧光信号转化成ADP产物浓度并计算酶活。利用Graphpad Prism软件拟合曲线，得到IC 50值。实验结果如表5所示。
表5.本发明化合物体外筛选试验结果
化合物 hACC1(nM) hACC2(nM)
WX001B 4.9 8
WX002 53.6 8.7
WX003B 10.9 3.4
WX004B 14.1 10.3
WX005 46.6 45
WX006 20.3 22.1
WX007B 9.1 12.6
WX008B 5.3 13.9
WX009B 5.6 11
WX010 83.9 70.7
WX011 26 10.9
WX012 14.2 5.7
WX014 26 7.2
WX015 20.2 7.0
WX016B 11.1 4.8
结论：本发明化合物对人源ACC1/ACC2酶很强的抑制活性。
实验例2：化合物的药代动力学评价
实验目的：
测试化合物在C57BL/6小鼠体内的药代动力学
实验材料：
C57BL/6小鼠(雄性,18-30g,7～9周龄，上海灵畅生物科技有限公司)
实验操作：
将试验化合物的澄清溶液(0.5mg/ml 10％DMSO、10％聚乙二醇硬脂酸酯、80％水)经尾静脉注射到4只雄性C57BL/6小鼠体内(过夜禁食，7-9周龄)，给药剂量为2.0mg/kg。将试验化合物的混悬液或澄清溶液(1mg/ml 10％PEG400、90％(0.5％甲基纤维素+0.2％Tween 80))灌胃给予4只雄性C57BL/6小鼠(过夜禁食，7-9周龄)，给药剂量为10mg/kg。
每两只小鼠一组，交叉采血，每只小鼠采4～5个时间点。小鼠静脉或灌胃给药后于0.0833h(仅IV组)、0.25h、0.5h、1.0h、2.0h、4.0h、6.0h、8.0h和24h从隐静脉穿刺采血约30μL置于添加了EDTA-K2的抗凝管中，离心分离血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TMVersion 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。
实验结果如表6所示：
表6.药代动力学测试结果
Figure PCTCN2019090164-appb-000056
结论：本发明化合物可以显著提高小鼠药代动力学单项或部分指标。
实验例3：HFD+CCl4诱导的NASH小鼠模型中的体内药效学研究
实验目的:
本研究的目的为研究化合物在HFD+CCl 4小鼠模型中对NASH及肝纤维化的改善作用，以I-181为参比化合物。
I-181为Acetyl-CoA Carboxylase抑制剂，目前正在进行非酒精性脂肪性肝疾病(Non Alcoholic Fatty Liver Disease，NAFLD)的临床II期研究。本研究所用的HFD+CCl 4小鼠模型是一种模拟人类非酒精性脂肪性肝病进展为NASH过程的动物模型，高脂饲料导致脂肪在肝细胞中堆积、变性；CCl 4(腹腔注射，每周两次)模拟肝损伤的“二次打击”。该模型稳定可靠，与人NASH的发病机制具有很高的相似性，具备了 NASH主要病理特点，包括脂肪变、凋亡、炎症和纤维化，同时也表现出血浆转氨酶(ALT和AST)水平升高。
实验设计：
本试验的造模包括高脂饲料喂养和CCl 4诱导两个步骤，首先以高脂饲料喂养小鼠诱导产生非酒精性脂肪肝，挑选体重>38g的小鼠，继续饲喂高脂饲料的同时，腹腔注射给与25％CCl 4，0.5mg/kg，每周两次，共四周。将开始给CCl 4的当天定为第0天，开始CCl 4的时间定为第0小时，在开始给CCl 4的当天，开始灌胃给药，各组的给药体积为5mL/kg，每天一次，持续4周(28天)。CCl 4的注射时间应与当天的第一次给药时间点间隔4小时以上。实验一共分为6组，即健康对照组、模型组、参比化合物组(GS-0976)、受试化合物组(WX004B，三个剂量)。健康对照组为10只正常小鼠，实验期间给予普通饲料喂养，不注射CCl 4；50只肥胖小鼠用于模型组及给药组，每组为10只小鼠，分组后开始腹腔注射CCl 4并分别给予不同剂量的药物。分组和剂量设计如表7所示。
表7.动物分组及给药方案
Figure PCTCN2019090164-appb-000057
实验结果:
在高脂饮食和CCl 4联合诱导的小鼠模型中，WX004B不论在NAS以及纤维化两个维度均达到与参比化合物更高剂量下相同的药效。

Claims (19)

  1. 式(Ⅱ)化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019090164-appb-100001
    其中，
    D 1选自-O-和-N(R 6)-；
    R 1选自H、F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R a取代；
    R 2选自H、F、Cl、Br、I、OH、NH 2和C 1-6烷基，其中所述C 1-6烷基任选被1、2或3个R b取代；
    R 3选自H、F、Cl、Br、I和C 1-6烷基，其中所述C 1-6烷基任选被1、2或3个R c取代；
    或者，R 2与R 3相互连接形成一个环，其环选自C 3-7环烷基和4～7元杂环烷基，所述C 3-7烷基和4～7元杂环烷基任选被1、2或3个R d取代；
    R 4选自OH、NH 2、C 1-3烷基和C 1-3烷氨基，其中所述C 1-3烷基和C 1-3烷氨基任选被1、2或3个R e取代；R 51、R 52、R 53、R 54和R 55分别独立地选自H、F、Cl、Br、I、OH、NH 2、C 1-6烷基、C 1-6烷氨基和C 1-6烷氧基，其中所述C 1-6烷基、C 1-6烷氨基和C 1-6烷氧基任选被1、2或3个R f取代；
    R 6选自H、C 1-6烷基、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O)-、C 1-6烷基-S(＝O) 2-和C 1-6烷基-O-C(＝O)-，其中所述C 1-6烷基、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O)-、C 1-6烷基-S(＝O) 2-和C 1-6烷基-O-C(＝O)-任选被R g取代；R a、R b、R c、R d、R e、R f和R g分别独立地选自F、Cl、Br、I、OH、NH 2和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R取代；
    R分别独立地选自F、Cl、Br、I、OH和NH 2；
    所述4～7元杂环烷基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团；
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
  2. 根据权利要求1所示化合物、其异构体或其药学上可接受的盐，其中，R a、R b、R c、R d、R e、R f和R g分别独立地选自F、Cl、Br、I、OH和NH 2。
  3. 根据权利要求1或2所示化合物、其异构体或其药学上可接受的盐，其中，R 1选自H、F、Cl、Br、I、OH、NH 2和CH 3。
  4. 根据权利要求1或2所示化合物、其异构体或其药学上可接受的盐，其中，R 2选自H、F、Cl、Br、I、 OH、NH 2、CH 3和Et。
  5. 根据权利要求1或2所示化合物、其异构体或其药学上可接受的盐，其中，R 3选自H、F、Cl、Br、I、CH 3和Et。
  6. 根据权利要求1或2所示化合物、其异构体或其药学上可接受的盐，其中，R 2与R 3相互连接形成一个环，其环选自C 3-6环烷基和5～6元杂环烷基，所述C 3-6环烷基和5～6元杂环烷基任选被1、2或3个R d取代。
  7. 根据权利要求6所示化合物、其异构体或其药学上可接受的盐，其中，R 2与R 3相互连接形成一个环，其环选自环丙基、环丁基、环戊基、环己基、四氢呋喃基、四氢吡喃基和哌啶基，其中所述环丙-基、环丁基、环戊基、环己基、四氢呋喃基、四氢吡喃基和哌啶基任选被1、2或3个R d取代。
  8. 根据权利要求7所示化合物、其异构体或其药学上可接受的盐，其中，R 2与R 3相互连接形成一个环，其环选自
    Figure PCTCN2019090164-appb-100002
  9. 根据权利要求1或2所示化合物、其异构体或其药学上可接受的盐，其中，R 4选自OH和NH 2。
  10. 根据权利要求1或2所示化合物、其异构体或其药学上可接受的盐，其中，R 51、R 52、R 53、R 54和R 55分别独立地选自H、F、Cl、Br、I、OH、NH 2、C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基，其中所述C 1-3烷基、C 1- 3烷氨基和C 1-3烷氧基任选被1、2或3个R f取代。
  11. 根据权利要求10所示化合物、其异构体或其药学上可接受的盐，其中，R 51、R 52、R 53、R 54和R 55分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3、Et和
    Figure PCTCN2019090164-appb-100003
  12. 根据权利要求1或2所示化合物、其异构体或其药学上可接受的盐，其中，R 6选自H、C 1-3烷基、C 1-3烷基-C(＝O)-、C 1-3烷基-S(＝O)-、C 1-3烷基-S(＝O) 2-和C 1-4烷基-O-C(＝O)-，其中所述 1-3烷基、C 1-3烷基-C(＝O)-、C 1-3烷基-S(＝O)-、C 1-3烷基-S(＝O) 2-和C 1-4烷基-O-C(＝O)-任选被R g取代。
  13. 根据权利要求12所示化合物、其异构体或其药学上可接受的盐，其中，R 6选自H、CH 3、CH 3-C(＝O)-、CH 3-S(＝O) 2-、CH 3-O-C(＝O)-和
    Figure PCTCN2019090164-appb-100004
  14. 根据权利要求1～13任意一项所示化合物、其异构体或其药学上可接受的盐，其化合物选自
    Figure PCTCN2019090164-appb-100005
    其中，
    R 1如权利要求1或3所定义；
    R 4如权利要求1或9所定义；
    R 51、R 52、R 53、R 54和R 55如权利要求1、10或11所定义；
    R 6如权利要求1、12或13所定义；
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
  15. 根据权利要求14所示化合物、其异构体或其药学上可接受的盐，其化合物选自
    Figure PCTCN2019090164-appb-100006
    其中，
    m为0、1、2或3；
    E 1为-O-或-NH-；
    R 1如权利要求1或3所定义；
    R 4如权利要求1或9所定义；
    R 51、R 52、R 53、R 54和R 55如权利要求1、10或11所定义；
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
  16. 根据权利要求15所示化合物、其异构体或其药学上可接受的盐，其化合物选自
    Figure PCTCN2019090164-appb-100007
    其中，
    R 1、R 4、R 51、R 52、R 53、R 54和R 55如权利要求15所定义；
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
  17. 下式化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019090164-appb-100008
    Figure PCTCN2019090164-appb-100009
  18. 根据权利要求17所述的化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019090164-appb-100010
    Figure PCTCN2019090164-appb-100011
  19. 根据权利要求1～18任意一项所述的化合物、其异构体或其药学上可接受的盐在制备作为ACC1和ACC2抑制剂的药物中的应用。
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