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WO2018228369A1 - 杂芳基并嘧啶酮类衍生物、其制备方法及其在医药上用途 - Google Patents

杂芳基并嘧啶酮类衍生物、其制备方法及其在医药上用途 Download PDF

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Publication number
WO2018228369A1
WO2018228369A1 PCT/CN2018/090804 CN2018090804W WO2018228369A1 WO 2018228369 A1 WO2018228369 A1 WO 2018228369A1 CN 2018090804 W CN2018090804 W CN 2018090804W WO 2018228369 A1 WO2018228369 A1 WO 2018228369A1
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group
aryl
cycloalkyl
heteroaryl
compound
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English (en)
French (fr)
Inventor
吕贺军
刘俊
郝旭辉
关东亮
陈磊
白骅
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Zhejiang Hisun Pharmaceutical Co Ltd
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Zhejiang Hisun Pharmaceutical Co Ltd
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Priority to CN201880030204.6A priority Critical patent/CN110709402B/zh
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    • 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
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the present invention relates to a heteroarylpyridinone derivative, a process for the preparation thereof, a pharmaceutical composition containing the same, and its use as a therapeutic agent, particularly as an acetyl-CoA carboxylase (ACC) inhibitor.
  • ACC acetyl-CoA carboxylase
  • Acetyl-CoA carboxylase is one of the important proteins involved in fatty acid metabolism. It uses biotin as a coenzyme to catalyze the production of malonyl-CoA from acetyl-CoA. This irreversible reaction (malonyl-CoA), in turn, provides a substrate for the synthesis of subsequent fatty acids or modulates the fatty acid oxidation signal, which is the first step of fatty acid metabolism and is a rate limiting step. The catalytic reaction can be divided into two steps, depending on the biotin carboxylase (BC) and carboxyltransferase (CT) activities of ACC.
  • BC biotin carboxylase
  • CT carboxyltransferase
  • ACC1 is a cytosolic enzyme that is mainly expressed in fat synthesis tissues (such as fat and breast tissue); ACC2 is localized in the mitochondrial membrane and is mainly enriched in oxidized tissues (such as the heart). In skeletal muscle, both are expressed at high levels in the liver. Therefore, ACC1 is mainly involved in the regulation of fatty acid synthesis, and ACC2 is mainly responsible for the regulation of the oxidation process of fatty acids.
  • the activity of ACC is regulated by a variety of proteins, cytokines, endocrine hormones and receptors.
  • AMPK is the main substance regulating ACC activity, which can inhibit the activity by direct phosphorylation of ACC; and protein phosphorylase 2 can dephosphorylate ACC, thereby enhancing the effect of ACC.
  • free fatty acids synthesized in the cytosol are transported to the mitochondria via the mitochondrial membrane on carnitine palmitoyltransferase 1 (CPT1) for oxidative energy supply.
  • CPT1 carnitine palmitoyltransferase 1
  • Malonyl-CoA in the cytosol allosterically inhibits CPT1, leaving its activity at a lower level, thereby limiting fatty acid oxidation.
  • the AMPK pathway can be activated immediately, and the downstream ACC is inactivated.
  • the level of malonyl-CoA is rapidly decreased, further inhibiting the inhibition of CPT1, promoting the oxidation of fatty acids, and providing the body with More ATP.
  • Increased fatty acid synthesis and fatty acid metabolism disorders caused by impaired fatty acid oxidation are common features of many metabolic diseases, including liver steatosis, dyslipidemia, obesity, metabolic syndrome, nonalcoholic fatty Hepatitis (NASH), type 2 diabetes (T2DM) and atherosclerosis.
  • abnormal fatty acid metabolism is also one of the characteristics of tumor diseases, and participates in the cell proliferation process that regulates abnormal malignant tumors.
  • ACC is a key regulatory protein of lipid metabolism
  • drug inhibition of ACC can stimulate the synthesis of fatty acids in lipid-derived tissues while stimulating the oxidation of fatty acids in oxidized tissues, thus providing treatment for the above-mentioned diseases with abnormal lipid metabolism. A very attractive treatment.
  • ACC inhibitor patents have been published, including WO2014182943, WO2014182945, WO2014182950, etc.
  • the research and application of ACC inhibitors have made some progress.
  • the current Girard company's firsocostat is in clinical phase II, but existing
  • the compounds disclosed in the technology as well as the test drugs are still unsatisfactory in terms of effectiveness, safety or applicability, and it is still necessary to continue research and development of new ACC inhibitors to meet the growing medical and health needs of people.
  • the inventors have unexpectedly discovered through experimental research that the compound of the following formula (I) can effectively inhibit ACC.
  • the present invention provides a class of heteroaryl-pyrimidinone derivatives of the formula (I):
  • X is selected from -NH-, -O- or -S-; preferably -S-;
  • Ring A is selected from cycloalkyl, and R 2 and N attached to ring A are not attached to the same carbon atom;
  • R 1 is selected from a hydrogen atom, an alkyl group or a halogen, wherein the alkyl group is further further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, cycloalkyl, heterocyclic, Aryl, heteroaryl, -NR 8 R 9 , -C(O)NR 8 R 9 , -C(O)R 10 , -OC(O)R 10 , -S(O) q NR 8 R 9 , Substituted by a substituent of -NR 8 S(O) 2 R 9 or -NR 8 C(O)R 9 ;
  • R 2 is selected from the group consisting of a hydrogen atom, a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -NR 8 R 9 , -C(O) NR 8 R 9 , -C(O)R 10 , -OC(O)R 10 , -S(O) q NR 8 R 9 , -NR 8 S(O) 2 R 9 or -NR 8 C(O) R 9 wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl , alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR
  • R 3 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is optionally further substituted with one or more substituents selected from R 7 ;
  • R 4 and R 5 are each independently selected from a hydrogen atom, an alkyl group, -OR 10 , -SR 10 , -NR 8 R 9 , -C(O)NR 8 R 9 , -C(O)R 10 , -OC (O) R 10 , -S(O) q NR 8 R 9 , -NR 8 S(O) 2 R 9 or -NR 8 C(O)R 9 ;
  • R 4 , R 5 together with the atom to which they are attached form a 3 to 8 membered saturated or partially unsaturated cycloalkyl group, or form a hetero atom having one or more selected from N, O, S(O) q a 4 to 8 membered saturated or partially unsaturated heterocyclic group; wherein the cycloalkyl or heterocyclic group is further further selected from one or more selected from the group consisting of a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, Cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 8 R 9 , -C(O)NR 8 R 9 , -C(O)R 10 , -OC(O)R 10 , -S( O) q NR 8 R 9, -NR 8 S (O) 2 R 9 or -NR 8 C (O) R 9 is substituted with a substituent;
  • R 6 is selected from the group consisting of halogen, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -NR 8 R 9 , -C(O)NR 8 R 9 , -C(O)R 10 , -OC (O) R 10 , -S(O) q NR 8 R 9 , -NR 8 S(O) 2 R 9 or -NR 8 C(O)R 9 ; preferably a heteroaryl group;
  • R 1 , R 6 together with the atom to which they are attached form a 3 to 8 membered saturated or partially unsaturated cycloalkyl group, or form a hetero atom having one or more selected from N, O, S(O) q a 4 to 8 membered saturated or partially unsaturated heterocyclic group, or a 5 to 10 membered aryl or heteroaryl group; wherein the cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further one or more One selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 8 R 9 , -C(O)NR 8 R 9 , -C(O)R 10 , -OC(O)R 10 , -S(O) q NR 8 R 9 , -NR 8 S(O) 2 R 9 or -NR
  • R 7 is each independently selected from the group consisting of hydroxyl, halogen, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 8 R 9 , -C(O) NR 8 R 9 , -C(O)R 10 , -OC(O)R 10 , -S(O) q NR 8 R 9 , -NR 8 S(O) 2 R 9 or -NR 8 C(O) R 9 wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkane Base, heterocyclic group, aryl group, heteroaryl group, -NR 8 R 9 , -C(O)NR 8 R 9 , -C(O)R 10 , -OC(O)R 10 , -
  • R 8 , R 9 and R 10 are each independently selected from a hydrogen atom, an alkyl group, -OR 13 , a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group Or a heterocyclyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Substituted with a substituent of aryl, -NR 11 R 12 , -C(O)NR 11 R 12 , -C(O)R 13 , -C(O)OR 13 or -NR 11 C(O)R 12 ;
  • R 11 , R 12 and R 13 are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group Or an aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy Substituted by a substituent of an acid or a carboxylic acid ester;
  • q 0, 1, or 2.
  • the compound of the formula (I) (and the compound of the formula (II) to the formula (IV)) also includes, in scope, stereoisomers, tautomers or pharmaceutically acceptable salts thereof.
  • the compound of formula (I) has the structure of formula (II):
  • n 1, 2, 3, 4 or 5;
  • the compound of formula (I) has a specific stereo configuration, ie, has the structure of formula (III):
  • n 1, 2, 3, 4 or 5;
  • the compound of formula (I) has the structure of formula (IV):
  • n 1, 2, 3, 4 or 5;
  • R 2 is selected from the group consisting of tetrazolyl, -C(O)OR 13 or -C(O)NR 8 R 9 ;
  • R 8 is selected from a hydrogen atom or an alkyl group
  • R 9 is selected from cyano or -OR 13 ;
  • R 13 is selected from a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optional Further substituted by one or more substituents selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid esters Replace
  • R 2 is preferably -C(O)OH.
  • Typical compounds of the invention include, but are not limited to:
  • Typical compounds described above include stereoisomers, tautomers or pharmaceutically acceptable salts thereof.
  • the present invention provides a process for the preparation of a compound of formula (I), which process comprises:
  • the compound of formula (IA) is reacted with R 6 -substituted tributylstannane such that the resulting compound is optionally further hydrolyzed, and the resulting compound is optionally further resolved to the optically pure isomer to provide a compound of formula (I);
  • X 1 is selected from halogen; and X, ring A, R 1 to R 6 are as defined in formula (I).
  • the present invention provides a compound of formula (IA):
  • X 1 is selected from halogen; and X, ring A, R 1 to R 5 are as defined in formula (I).
  • Typical compounds of formula (IA) include, but are not limited to:
  • Typical compounds described above include stereoisomers, tautomers or pharmaceutically acceptable salts thereof.
  • the present invention provides a process for the preparation of a compound of formula (IA), the process comprising:
  • the compound of formula (IB) is reacted with a compound of formula (IC) in the presence of triphenylphosphine to provide a compound of formula (IA);
  • X 1 is selected from halogen; and X, ring A, R 1 to R 5 are as defined in formula (I).
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), (III) or (IV), and optionally Pharmaceutically acceptable carriers, excipients or combinations thereof.
  • the present invention provides a method of inhibiting ACC comprising contacting ACC with a compound of formula (I), (II), (III) or (IV) of the present invention or a pharmaceutical composition thereof.
  • the invention accordingly also provides a method of preventing or treating a disease or condition associated with ACC comprising administering a compound or pharmaceutical composition according to the invention to a subject in need thereof.
  • the present invention provides the use of a compound of formula (I), (II), (III) or (IV) or a pharmaceutical composition thereof for the manufacture of a medicament for use as an ACC inhibitor.
  • the invention also provides the use of a compound of formula (I), (II), (III) or (IV) or a pharmaceutical composition thereof for the manufacture of a medicament for the prevention or treatment of a disease or condition associated with ACC, wherein said
  • the disease or condition is preferably a metabolic disease, a cancer, a fungus, a parasite or a bacterial infection, wherein the metabolic disease is preferably hepatic steatosis, nonalcoholic fatty liver, obesity, dyslipidemia, hyperlipidemia, type II Diabetes or metabolic syndrome, wherein the obesity is preferably Prader-Willi syndrome, Bardet-Biedl syndrome or Cohen syndrome Or MOMO syndrome, wherein the cancer is preferably hepatocellular carcinoma, non-small cell lung cancer, small cell lung cancer, gastric cancer, colorectal cancer, head and neck cancer, melanoma, ovarian cancer or cervical cancer, more preferably hepatocellular carcinoma And non-small cell lung cancer.
  • Alkyl as a group or part of a group means a C 1 -C 20 straight or branched C 1 -C 20 aliphatic hydrocarbon group, preferably a C 1 -C 10 alkyl group More preferably, it is a C 1 -C 6 alkyl group, and particularly preferably a C 1 -C 4 alkane.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1, 1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait.
  • the alkyl group can be substituted or unsubstituted.
  • Alkylene is a divalent alkyl group. It is preferably a C 1 -C 10 alkylene group, more preferably a C 1 -C 6 alkylene group, and particularly preferably a C 1 -C 4 alkylene group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, Acetylene and so on. The alkylene group may be substituted or unsubstituted.
  • Alkenyl refers to an alkyl radical as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like.
  • a C 2 -C 4 alkylene group is preferred.
  • the alkenyl group can be optionally substituted or unsubstituted.
  • Alkynyl as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond which may be straight or branched. Preference is given to C 2 -C 10 alkynyl, more preferably C 2 -C 6 alkynyl, most preferably C 2 -C 4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. An alkynyl group can be substituted or unsubstituted.
  • Cycloalkyl means a saturated or partially saturated monocyclic, fused, bridged or spiro carbon ring. It is preferably a C 3 -C 12 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, and most preferably a C 3 -C 6 cycloalkyl group.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • Cycloalkylene is a divalent cycloalkyl group. It is preferably a C 3 -C 12 cycloalkylene group, more preferably a C 3 -C 8 cycloalkylene group, and most preferably a C 3 -C 6 cycloalkylene group. Examples of alkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, and the like. A cycloalkylene group can be substituted or unsubstituted.
  • “Spirocycloalkyl” means a 5- to 18-membered polycyclic group having two or more cyclic structures and sharing a carbon atom (called a spiro atom) with each other, and the ring may contain 1 One or more double bonds, but none of the rings have a fully conjugated ⁇ -electron aromatic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospiro, a spiro- or a spirocycloalkyl group, preferably a mono- and bi-spirocycloalkyl group, preferably 4 yuan/5 yuan, 4, depending on the number of common spiro atoms between the rings. Yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan.
  • spirocycloalkyl include, but are not limited to, spiro[4.5]decyl, spiro[4.4]decyl, spiro[3.5]decyl, spiro[2.4]heptyl.
  • “Fused cycloalkyl” refers to a 5 to 18 membered all carbon polycyclic group having two or more cyclic structures that share a pair of carbon atoms with each other, wherein one or more of the rings may contain one or more A double bond, but none of the rings have a fully conjugated ⁇ -electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members.
  • bicyclic ring a tricyclic ring, a pyridone or a polycyclic fused ring alkyl group, preferably a bicyclic ring or a tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group.
  • fused cycloalkyl include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetradecafluorophenanyl.
  • “Bridge cycloalkyl” refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures that share two non-directly bonded carbon atoms, wherein one or more rings may contain One or more double bonds, but none of the rings have a fully conjugated ⁇ -electron aromatic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • a bicyclic ring a tricyclic ring, a pyridone or a polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a pyridone, and more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-di Ring [3.3.1] fluorenyl, bicyclo [2.2.2] octyl, (1r, 5r)-bicyclo[3.3.2] fluorenyl.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group can be optionally substituted or unsubstituted.
  • Heterocyclyl “heterocyclic” or “heterocyclic” are used interchangeably herein to refer to a non-aromatic heterocyclic group wherein one or more of the ring-forming atoms are heteroatoms such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic, fused, bridged, and spiro rings. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered double- or tricyclic ring which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetane, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine , 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and Piperazinyl.
  • the heterocyclic group may be substituted or unsubstituted.
  • “Spiroheterocyclyl” means a 5- to 18-membered polycyclic group having two or more cyclic structures and sharing one atom between the single rings, and having one or more double bonds in the ring. , but none of the rings have a fully conjugated ⁇ -electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) q (where q is selected from 0, 1 or 2) heteroatoms, the remainder The ring atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of common spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • spiroheterocyclyl include, but are not limited to, 1,7-dioxaspiro[4.5]fluorenyl, 2-oxa-7-azaspiro[4.4]decyl, 7-oxo Heterospiro[3.5]decyl and 5-oxaspiro[2.4]heptyl.
  • “Fused heterocyclic group” refers to an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other, wherein one or more of the rings may contain one or more double bonds, but none of the rings have A fully conjugated ⁇ -electron aromatic system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) q (where q is selected from 0, 1 or 2) and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bicyclic ring a tricyclic ring, a pyridone or a polycyclic fused heterocyclic group, preferably a bicyclic ring or a tricyclic ring, and more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic groups include, but are not limited to, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindenyl, 3-azabicyclo[3.1. 0] hexyl, octahydrobenzo[b][1,4]dioxine.
  • “Bridge heterocyclyl” refers to a polycyclic group of 5 to 18 members, preferably 5 to 14 members containing two or more cyclic structures and sharing two atoms which are not directly bonded to each other, wherein one or more rings An aromatic system which may contain one or more double bonds, but none of which has a fully conjugated ⁇ -electron, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) q (where q is selected from 0, 1 Or 2) a hetero atom, the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bicyclic ring a tricyclic ring, a pyridone or a polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a pyridone, and more preferably a bicyclic ring or a tricyclic ring.
  • fused heterocyclic groups include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-aza-di Ring [3.3.2] sulfhydryl.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group.
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • Heterocyclylene means a divalent heterocyclic group. It preferably has a 5- to 7-membered monocyclic heterocyclic group or a 7 to 10 membered bicyclic heterocyclic group or a tricyclic heterocyclic group which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. .
  • the heterocyclylene group may be substituted or unsubstituted.
  • Aryl means a carbocyclic aromatic system containing one or two rings wherein the rings may be joined together in a fused manner.
  • aryl includes aryl groups such as phenyl, naphthyl, tetrahydronaphthyl.
  • the aryl group is a C 6 -C 10 aryl group, more preferably the aryl group is a phenyl group and a naphthyl group, and most preferably a phenyl group.
  • the aryl group can be substituted or unsubstituted.
  • the "aryl” may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the parent structure is attached to an aryl ring, non-limiting examples include, but are not limited to:
  • Heteroaryl means an aromatic 5 to 6 membered monocyclic or 9 to 10 membered bicyclic ring which may contain from 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo Dioxolyl, benzimidazolyl, fluorenyl, isodecyl, 1,3-dioxo-isoindenyl, quinolyl, ox
  • Heteroaryl groups can be substituted or unsubstituted.
  • the heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include, but are not limited to:
  • Alkoxy means a group of (alkyl-O-). Among them, the alkyl group is defined in the relevant definition herein.
  • the C 1 -C 6 alkoxy group is preferred, and a C 1 -C 4 alkoxy group is particularly preferred. Examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
  • Hydrophilicity refers to an -OH group.
  • Halogen means fluoro, chloro, bromo and iodo, preferably chloro, bromo and iodo.
  • Amino means -NH 2 .
  • Niro means -NO 2 .
  • Benzyl refers to -CH 2 - phenyl.
  • Carboxy refers to -C(O)OH.
  • Carboxylic acid ester group means -C(O)O(alkyl) or (cycloalkyl) wherein alkyl, cycloalkyl are as defined above.
  • DMSO dimethyl sulfoxide
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms are replaced by a corresponding number of substituents independently of one another. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond such as an ethylenic bond.
  • substituted or “substituted”, unless otherwise indicated, means that the group may be substituted by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy.
  • “Pharmaceutically acceptable salt” refers to certain salts of the above compounds which retain their original biological activity and are suitable for pharmaceutical use.
  • the pharmaceutically acceptable salt of the compound of the formula (I) may be a metal salt, an amine salt formed with a suitable acid, a metal salt preferably an alkali metal or an alkaline earth metal salt, and suitable acids including inorganic acids and organic acids such as acetic acid and benzenesulfonate.
  • Acid benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid, mandelic acid , methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like.
  • Particularly preferred are hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and most preferred is the hydrochloride salt.
  • “Pharmaceutical composition” means containing one or more of the compounds described herein, including pharmaceutically acceptable salts or stereoisomers, tautomers or prodrugs thereof, and optionally other pharmaceutically active ingredients. A mixture, which may contain other optional ingredients such as pharmaceutically acceptable carriers and/or excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the term “plurality” includes two or more, such as two, three, four, and the like.
  • the preparation method of the compound of the formula (I) of the invention comprises the following steps:
  • the compound of formula (IB) is reacted with a compound of formula (IC) in the presence of triphenylphosphine to provide a compound of formula (IA);
  • the compound of formula (IA) is reacted with R 6 -substituted tributylstannane such that the resulting compound is optionally further hydrolyzed, and the resulting compound is optionally further resolved to the optically pure isomer to provide a compound of formula (I);
  • X 1 is selected from halogen; and X, ring A, R 1 to R 6 are as defined in formula (I).
  • Mass spectrometry was measured by LC/MS, and the ionization method was ESI or APCI.
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • CD 3 OD Deuterated methanol.
  • the argon atmosphere means that the reaction flask is connected to an argon balloon having a volume of about 1 L.
  • the solution in the reaction means an aqueous solution.
  • the compound is purified by silica gel column chromatography and silica gel sheet chromatography, wherein the developing solvent or eluent system is selected from the group consisting of: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: two Methyl chloride: ethyl acetate; wherein the volume ratio of the solvent varies depending on the polarity of the compound, and it may be adjusted by adding a small amount of an acidic or alkaline agent such as acetic acid or triethylamine.
  • A petroleum ether and ethyl acetate system
  • B dichloromethane and methanol system
  • C two Methyl chloride: ethyl acetate
  • the volume ratio of the solvent varies depending on the polarity of the compound, and it may be adjusted by adding a small amount of an acidic or alkaline agent such as acetic acid or triethylamine.
  • Oxazole 1e (500 mg, 7.24 mmol) was dissolved in 12 mL of tetrahydrofuran. Under nitrogen, the mixture was cooled to -78 ° C for 5 minutes, and n-butyllithium (4.56 mL, 7.29 mmol) was slowly added. After the addition, the mixture was stirred at -78 ° C for 30 minutes. Then, tributyltin chloride (1.96 mL, 7.24 mmol) was added, and the mixture was stirred at -78 ° C for 10 minutes, and allowed to react to room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. 15 mL of hexane was evaporated, and then filtered, and the filtrate was concentrated under reduced pressure to give 2-(tributylstannyl) oxazole 1f (1.8 g, pale yellow liquid), yield: 70%.
  • 3-oxocyclobutane-1-carboxylic acid 1j (5.7 g, 50 mmol), tert-butanol (9.25 g, 125 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride (11.5 g, 60 mmol) and 4-dimethylaminopyridine (3.1 g, 25 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 12 hr.
  • reaction mixture was diluted with water (100 mL), EtOAc (EtOAc) Tert-butyl butane-1-carboxylic acid tert-butyl ester 1k (8.5 g, reddish brown oil), yield: 100%.
  • 2-Amino-4-methylthiophene-3-carboxylic acid ethyl ester 1i (1.44 g, 7.8 mmol) was dissolved in 60 mL of dichloromethane, and bis(trichloromethyl) carbonate (810 mg, A solution of 2.7 mmol) in dichloromethane (10 mL) was stirred at room temperature for 30 min. Triethylamine (2.4 g, 23.4 mmol) was added at 0 ° C and stirred at room temperature for 30 min.
  • Ethyl 3-oxocyclobutane-1-carboxylate 4a (5.5 g, 40 mmol) and dibenzylamine (8.58 g, 44 mmol) were dissolved in EtOAc EtOAc Sodium triacetoxyborohydride (17.1 g, 80 mmol) and 20 mL of acetic acid were added, and the mixture was reacted at room temperature for 12 hours. The tetrahydrofuran was removed under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was adjusted to basic, ethyl acetate (50mL ⁇ 3), and the organic phase was combined and washed with 50 mL of saturated aqueous sodium chloride.
  • Ethyl (1S,3S)-3-(dibenzylamino)cyclobutane-1-carboxylate 4b (5.0 g, 15.5 mmol) was dissolved in 150 mL of ethanol, then 10% Pd-C (200 mg, 4%) The hydrogen was replaced 3 times and reacted at room temperature for 12 hours. Filtration, the residual Pd-C was removed, and the filtrate was concentrated under reduced pressure to give ethyl (1S,3S)-3-aminocyclobutane-1-carboxylate 4c (2.1 g, colorless oil), yield: 95.5%.
  • 2-Amino-4-methylthiophene-3-carboxylic acid ethyl ester 1i (2.78 g, 15.0 mmol) was dissolved in 100 mL of dichloromethane, and bis(trichloromethyl) carbonate (1.56 g) was added dropwise at 0 °C. , 5.25 mmol) in dichloromethane (20 mL), stirred at room temperature for 30 min.
  • Triethylamine (4.5 g, 45 mmol) was added at 0 ° C and stirred at room temperature for 30 min.
  • Test Example 1 Determination of IC 50 of inhibition of enzymatic activity of ACC1 and ACC2 by the compound of the present invention
  • the principle of the method is based on the reaction of AMC-catalyzed acetyl-CoA to form malonyl-CoA.
  • ATP is consumed during this reaction and ADP is produced.
  • the resulting reaction can be reconverted to ADP by the kinase using ADP-Glo TM kit from Promega (Promega) to ATP, which may be part of the kit in the ATP luciferase - luciferin reaction, and generates a chemical Illuminated signal. Therefore, by measuring the intensity of the chemiluminescent signal, the amount of ADP produced in the catalytic reaction can be reflected, thereby indirectly determining the enzymatic activity of the ACC protein and the effect of the test compound on the enzyme activity.
  • the main reagents used were: ACC1, ACC2 protein (purchased from BPS bioscience, ACC1 Cat. No. 50200, ACC2 Cat. No. 50201), Acetyl CoA (acetyl-CoA, purchased from Sigma, Cat. No. A2056), NaHCO3 (purchased from Sigma, Cat. No. S6014). ), ADP-Glo TM Kinase assay kit (purchased from Promega, Cat. No. V9102).
  • the 1x buffer required for the reaction was prepared, and its composition was as follows: 50 mM HEPES (pH 7.4 purchased from Invitrogen, Cat. No. 15630), 2 mM magnesium chloride (MgCl 2 , purchased from Sigma, article number M1028), 2 mM lemon Potassium citrate (purchased from Sigma, Cat. No. 89306), 0.01% Brij-35 detergent (available from Merck, Cat. No. 203728), 2 mM DTT (purchased from Sigma, Cat. No. D0632).
  • 50 mM HEPES pH 7.4 purchased from Invitrogen, Cat. No. 15630
  • 2 mM magnesium chloride MgCl 2
  • M1028 2 mM lemon Potassium citrate
  • 0.01% Brij-35 detergent available from Merck, Cat. No. 203728
  • 2 mM DTT purchased from Sigma, Cat. No. D0632.
  • test compound powder was dissolved in DMSO to prepare a stock solution having a concentration of 10 mM, and then subjected to a 3-fold dilution to prepare a concentration required for the test, and each compound was set at 10 concentration points in a concentration range of 10 ⁇ M to 0.5 nM.
  • ACC protein 2nM
  • concentration is provided with a duplicate well control and a solvent control (blank group) ), negative control group (DMSO group).
  • the 384-well plates were then shaken on a microplate shaker and incubated for 15 minutes at room temperature.
  • Inhibition rate % [(negative control well RLU mean - blank well RLU average) - (test well RLU mean - blank well RLU mean)] / (negative control well RLU mean - blank well RLU mean) * 100
  • the compounds of the present invention have a good inhibitory effect on both ACC1 and ACC2 enzymes.
  • Test Example 2 Inhibitory activity of the compound of the present invention for [ 14 C]-acetate incorporation into HepG2 cells
  • Reagent Vendor Reagent Sodium hydroxide Tianjin Fuchen Chemical Reagent Factory Sodium hydroxide Potassium hydroxide Beijing Jingqi Chemical Products Co., Ltd. Potassium hydroxide acetic acid Tianjin Guangfu Technology Development Co., Ltd. acetic acid Trichloromethane Beijing Chemical Factory Trichloromethane Ether Tianjin Jindong Tianzheng Fine Chemical Reagent Factory Ether Petroleum ether Tianjin Jindong Tianzheng Fine Chemical Reagent Factory Petroleum ether hydrochloric acid Beijing Xingqinghong Fine Chemical Technology Co., Ltd. hydrochloric acid Hexane Beijing Chemical Factory Hexane
  • the compounds of the invention to be tested were all dissolved in DMSO at 10 mM and stored at 4 °C prior to use.
  • HepG2 cells were purchased and purchased in the American Type Culture Collection (ATCC) resource bank. The cells were incubated in DMEM containing 10% fetal bovine serum, penicillin (100 units/mL) and streptomycin (100 ⁇ g/mL) in a 37 ° C incubator containing 5% carbon dioxide, and passaged every 2 to 3 days.
  • ATCC American Type Culture Collection
  • HepG2 cells were seeded at 2 ⁇ 105 cells per well in a 24-well plate, and incubated in a 37 ° C incubator containing 5% carbon dioxide.
  • the initial concentration of the compound of the present invention was 3 ⁇ M, 4 fold dilution, 5 concentration gradients, and a final DMSO concentration of 0.5% (v/v), and incubated for 1 hour in a 37 ° C incubator containing 5% carbon dioxide.
  • the compounds of the present invention have a significant inhibitory effect on the incorporation of [ 14 C]-acetate into HepG2 cells, which is superior to Firsocostat as a control compound.
  • Test Example 3 Oral pharmacokinetic study of ICR mice of the present invention
  • ICR mice were used as test animals, and the compounds of Example 3 and the control firsocostat were intragastrically administered by LC-MS/MS method.
  • the drug concentrations in plasma and liver were measured at different times.
  • the compounds of the present invention were studied in mice. Pharmacokinetic characteristics in vivo.
  • Healthy adult ICR male mice were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and the animal body weight was 29.3-35.4 g.
  • mice Eighteen healthy adult ICR male mice were divided into two groups. After fasting overnight, the rats were intragastrically administered at a dose of 10 mg/kg, a dose of 10 mL/kg, and a dose of 4 hours after administration.
  • mice were intragastrically administered with a preparation of 10 mg ⁇ kg -1 of the compound of Example 3, and Group B mice were orally administered with a preparation of 10 mg ⁇ kg -1 firsocostat.
  • the sampling time points are as follows:
  • Plasma 0 hours before administration, 0.5 hours after administration, 1 hour, 4 hours.
  • Blood samples were collected and placed in an EDTA-K 2 anticoagulant tube, and plasma was centrifuged (centrifugation conditions: 1500 g, 10 minutes), and the upper plasma sample was collected into a sample tube.
  • the collected biological samples were stored in a refrigerator at -40 to -20 °C before analysis.
  • the content of the test compound in the plasma and liver of the mice after the intragastric administration of the compound was analyzed by LC-MS/MS.
  • the compound of the present invention has good pharmacophore absorption and good pharmacokinetic properties; after 1 hour of administration, the drug concentration in the liver is 10740 ng/g, and the compound of Example 3 is There is a good enrichment in the liver.
  • Firsocostat The structure of Firsocostat is as follows, prepared according to WO2013071169

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Abstract

本发明涉及式 (I) 所示的杂芳基并嘧啶酮类衍生物、其制备方法及其作为治疗剂的用途，特别是作为乙酰辅酶 A 羧化酶 (ACC) 抑制剂的用途，其中式 (I) 中的各取代基的定义与说明书中的定义相同。

Description

杂芳基并嘧啶酮类衍生物、其制备方法及其在医药上用途
本申请要求于2017年6月15日提交中国专利局，申请号为201710450023.6，发明名称为“杂芳基并嘧啶酮类衍生物、其制备方法及其在医药上用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及一种杂芳基并吡啶酮类衍生物、其制备方法、含有该衍生物的药物组合物以及其作为治疗剂特别是作为乙酰辅酶A羧化酶(ACC)抑制剂的用途。
背景技术
乙酰辅酶A羧化酶(Acetyl-CoA carboxylase，ACC)是参与脂肪酸代谢过程的重要蛋白之一，它以生物素(biotin)为辅酶，催化乙酰辅酶A(acetyl-CoA)生成丙二酰辅酶A(malonyl-CoA)这一不可逆反应，进而为后续脂肪酸的合成提供底物或调节脂肪酸氧化信号，该反应为脂肪酸代谢的第一步反应且为限速步骤。该催化反应可分为两步，分别依赖于ACC所具有的生物素羧化酶(biotin carboxylase,BC)和羧基转移酶(carboxyltransferase,CT)活性。
人体中ACC存在2个亚型，分别为ACC1和ACC2，其分别由ACACA和ACACB两个基因单独编码表达。两者在组织分布和细胞内分布上存在差异，ACC1是胞浆酶，主要在脂肪合成组织(如脂肪及乳腺组织)中高水平表达；ACC2定位于线粒体膜，主要富集在氧化组织(如心脏和骨骼肌)中，在肝脏中两者均以高水平表达。因此，ACC1主要参与调节脂肪酸的合成，ACC2主要负责脂肪酸的氧化过程调节。ACC的活性受多种蛋白、细胞因子、内分泌激素及受体调控。其中AMPK是调节ACC活性的主要物质，可通过直接磷酸化ACC以抑制其活性；而蛋白磷酸化酶2可使ACC去磷酸化，从而增强ACC的作用。生理条件下，胞浆中合成的游离脂肪酸通过线粒体膜上的肉碱棕榈酰转移酶1(CPT1)运送至线粒体内进行氧化供能。而胞浆中的丙二酰辅酶A变构抑制CPTl，使其活性处于较低水平，从而限制脂肪酸氧化。当机体处于应激或能量消耗增加时，可立即激活AMPK途径，使其下游ACC失活，丙二酰辅酶A水平迅速下降，进一步解除对CPTl的抑制作用，促进脂肪酸氧化供能，为机体提供更多的ATP。
脂肪酸合成的增加和脂肪酸氧化受损所导致的脂肪酸代谢失调是多种代谢 类疾病的共同特点，其涉及的疾病包括：肝脂肪变性、血脂异常、肥胖症、代谢综合征、非酒精性脂肪性肝炎(NASH)，2型糖尿病(T2DM)以及动脉粥样硬化。此外，脂肪酸代谢异常也是肿瘤疾病的特征之一，参与调节恶性肿瘤异常的细胞增殖过程。由于ACC作为脂类代谢的关键调节蛋白，药物抑制ACC可在限制脂源组织中的脂肪酸的合成的同时，在氧化组织中刺激促进脂肪酸的氧化，因此为治疗上述存在脂类代谢异常的疾病提供了一种极具吸引力的治疗方式。
目前已经公开了一系列的ACC抑制剂专利，其中包括WO2014182943、WO2014182945、WO2014182950等，ACC抑制剂的研究和应用已取得一定的进展，例如目前吉列德公司的firsocostat处于临床II期，但是现有技术中公开的化合物以及试验药物在有效性、安全性或适用性等方面仍不能令人满意，仍有必要继续研究和开发新的ACC抑制剂，以满足人们日益增长的医疗和健康需要。
发明内容
本发明人通过实验研究意外地发现，下式(I)的化合物可以有效抑制ACC。
因此，在第一个方面，本发明提供了一类如式(I)所示的杂芳基并嘧啶酮类衍生物：
Figure PCTCN2018090804-appb-000001
包括其立体异构体、互变异构体或其可药用的盐，
其中：
X选自-NH-、-O-或-S-；优选为-S-；
环A选自环烷基，且与环A相连接的R 2和N，不连接在同一个碳原子上；
R 1选自氢原子、烷基或卤素，其中所述的烷基任选进一步被一个或多个选自卤素、羟基、氰基、硝基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9的取代基所取代；
R 2选自氢原子、羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、 芳基、杂芳基、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9，其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 11R 12、-C(O)NR 11R 12、-C(O)R 13、-C(O)OR 13或-NR 11C(O)R 12的取代基所取代；
R 3选自芳基或杂芳基，其中所述的芳基或杂芳基任选进一步被一个或多个选自R 7的取代基所取代；
R 4和R 5各自独立地选自氢原子、烷基、-OR 10、-SR 10、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9；
或者，R 4、R 5与其所连接的原子一起形成3～8元饱和或部分不饱和环烷基，或形成具有1个或多个选自N、O、S(O) q的杂原子的4～8元饱和或部分不饱和杂环基；其中所述环烷基或杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9的取代基所取代；
R 6选自卤素、氰基、环烷基、杂环基、芳基、杂芳基、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9；优选为杂芳基；
或者，R 1、R 6与其所连接的原子一起形成3～8元饱和或部分不饱和环烷基，或形成具有1个或多个选自N、O、S(O) q的杂原子的4～8元饱和或部分不饱和杂环基，或形成5～10元芳基或杂芳基；其中所述环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9的取代基所取代；
R 7各自独立地选自羟基、卤素、氰基、硝基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9，其中所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9的取代基所取代；
R 8、R 9和R 10各自独立地选自氢原子、烷基、-OR 13、氰基、环烷基、杂环基、芳基或杂芳基，其中所述烷基、环烷基、杂环基、芳基或杂芳基任选进一步被 一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 11R 12、-C(O)NR 11R 12、-C(O)R 13、-C(O)OR 13或-NR 11C(O)R 12的取代基所取代；
或者，R 8、R 9与其所连接的N原子一起形成一个4～8元杂环基，其中所述4～8元杂环内含有一个或多个N、O或S(O) q原子，并且所述4～8元杂环上进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-NR 11R 12、-C(O)NR 11R 12、-C(O)R 13、-C(O)OR 13或-NR 11C(O)R 12的取代基所取代；
R 11、R 12和R 13各自独立地选自氢原子、烷基、烯基、环烷基、杂环基、芳基或杂芳基，其中所述烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；且
q为0、1或2。
在本文中，式(I)化合物(以及式(II)至式(IV)化合物)在范围上也包括其立体异构体、互变异构体或其可药用的盐。
在本发明的一些优选方案中，所述式(I)化合物具有式(II)结构：
Figure PCTCN2018090804-appb-000002
其中：
m为1、2、3、4或5；且
环A、R 1、R 2、R 6、R 7和R 10的定义如式(I)中所述。
在本发明的一些优选方案中，所述式(I)化合物具有特定的立体构型，即具有式(III)所述的结构：
Figure PCTCN2018090804-appb-000003
其中：
m为1、2、3、4或5；且
环A、R 1、R 2、R 6、R 7和R 10的定义如式(I)中所述。
在本发明的一些优选方案中，所述式(I)化合物具有式(IV)结构：
Figure PCTCN2018090804-appb-000004
其中：
m为1、2、3、4或5；且
环A、R 1、R 2、R 6、R 7和R 10的定义如式(I)中所述。
在本发明的一些优选方案中，提供了式(I)、(II)、(III)或(IV)所述的化合物，其中R 1选自甲基或三氟甲基。
在本发明的一些优选方案中，提供了式(I)、(II)、(III)或(IV)所述的化合物，其中：
R 2选自四唑基、-C(O)OR 13或-C(O)NR 8R 9；
R 8选自氢原子或烷基；
R 9选自氰基或-OR 13；
R 13选自氢原子、烷基、烯基、环烷基、杂环基、芳基或杂芳基，其中所述烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
R 2优选为-C(O)OH。
在本发明的一些优选方案中，提供了式(I)、(II)、(III)或(IV)所述的化合物，其中环A选自如下基团：
Figure PCTCN2018090804-appb-000005
优选为
Figure PCTCN2018090804-appb-000006
在本发明的一些优选方案中，提供了式(I)、(II)、(III)或(IV)所述的化合物，其中R 6选自5元杂芳基，优选为噻唑基。
在本发明的一些优选方案中，提供了式(I)、(II)、(III)或(IV)所述的化合物，其中R 7选自卤素或烷氧基，优选为甲氧基。
在本发明的一些优选方案中，提供了式(I)、(II)、(III)或(IV)所述的化合物，其中R 10为四氢吡喃-4-基。
本发明的典型化合物包括，但不限于：
Figure PCTCN2018090804-appb-000007
Figure PCTCN2018090804-appb-000008
上述典型化合物包括其立体异构体、互变异构体或其可药用的盐。
进一步，本发明提供制备式(I)化合物的方法，该方法包括：
Figure PCTCN2018090804-appb-000009
使式(IA)化合物与R 6取代的三丁基甲锡烷反应，使得到的化合物任选进一 步水解，以及使得到的化合物任选进一步拆分光学纯异构体，得到式(I)化合物；
其中：X 1选自卤素；且X、环A、R 1～R 6的定义如式(I)中所述。
本发明提供了式(IA)所示的化合物：
Figure PCTCN2018090804-appb-000010
其中：
X 1选自卤素；且X、环A、R 1～R 5的定义如式(I)中所述。
式(IA)的典型化合物包括，但不限于：
Figure PCTCN2018090804-appb-000011
上述典型化合物包括其立体异构体、互变异构体或其可药用的盐。
进一步，本发明提供了制备式(IA)化合物的方法，所述方法包括：
Figure PCTCN2018090804-appb-000012
使式(IB)化合物与式(IC)化合物在三苯基膦存在下反应，得到式(IA)化合物；
其中：
X 1选自卤素；且X、环A、R 1～R 5的定义如式(I)中所述。
另一方面，本发明提供了一种药物组合物，所述的药物组合物含有有效剂量的式(I)、(II)、(III)或(IV)所述的化合物，以及任选的可药用的载体、赋形剂或它们的组合。
在又一方面，本发明提供一种抑制ACC的方法，包括使ACC与本发明的式(I)、(II)、(III)或(IV)化合物或其药物组合物相接触。本发明相应地还提供了一种预防或治疗与ACC相关的疾病或状况的方法，包括向有此需要的对象施用根据本发明的化合物或药物组合物。
在另一方面，本发明提供了式(I)、(II)、(III)或(IV)所述的化合物或其药物组合物在制备用作ACC抑制剂的药物中的用途。
本发明还提供了式(I)、(II)、(III)或(IV)化合物或其药物组合物在制备用于预防或治疗与ACC相关的疾病或状况的药物中的用途，其中所述疾病或状况优选为代谢类疾病，癌症，真菌、寄生虫或细菌感染，其中所述代谢类疾病优选为肝脂肪变性、非酒精性脂肪肝、肥胖症、血脂异常、高脂血症、II型糖尿病或代谢综合征，其中所述肥胖症优选为普拉德-威利综合征(Prader-Willi syndrome)、巴德-毕德氏综合征(Bardet-Biedl syndrome)或科恩综合征(Cohen syndrome)或MOMO综合征，其中所述癌症优选为肝细胞癌、非小细胞肺癌、小细胞肺癌、胃癌、结直肠癌、头颈部肿瘤、黑色素瘤、卵巢癌或宫颈癌，更优选为肝细胞癌和非小细胞肺癌。
发明的详细说明
除非有相反陈述，否则本发明在说明书和权利要求书中所使用的部分术语定义如下：
“烷基”当作一基团或一基团的一部分时是指包括C 1-C 20直链或者带有支链的C 1-C 20脂肪烃基团，优选为C 1-C 10烷基，更优选为C 1-C 6烷基，特别优选为C 1-C 4烷。烷基基团的实施例包括但不限于甲基、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、2,3-二甲基丁基等。烷基可以是取代或未取代的。
“亚烷基”是二价烷基。优选为C 1-C 10亚烷基，更优选为C 1-C 6亚烷基，特别优选为C 1-C 4亚烷基。亚烷基基团的实施例包括但不限于亚甲基、亚乙基、
Figure PCTCN2018090804-appb-000013
亚正丙基等。亚烷基可以是取代或未取代的。
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，代表性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。优选C 2-C 4亚烷基。烯基可以是任选取代的或未取代的。
“炔基”作为一基团或一基团的一部分时是指含有一个碳碳叁键的脂肪烃基团，其可为直链也可以带有支链。优先选择的是C 2-C 10炔基，更优选C 2-C 6炔基，最优选C 2-C 4炔基。炔基基团的实施例包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。炔基可以是取代或未取代的。
“环烷基”是指饱和或部分饱和的单环、稠环、桥环或螺环的碳环。优选为C 3-C 12环烷基，更优选为C 3-C 8环烷基，最优选为C 3-C 6环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环己烯基。
“亚环烷基”是二价环烷基。优选为C 3-C 12亚环烷基，更优选为C 3-C 8亚环烷基，最优选为C 3-C 6亚环烷基。亚烷基基团的实施例包括但不限于亚环丙基、亚环丁基、亚环戊基等。亚环烷基可以是取代或未取代的。
“螺环烷基”指5至18元的、含有两个或两个以上环状结构的且单环之间彼此共用一个碳原子(称螺原子)的多环基团，环内可含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺、双螺或多螺环烷基，优选为单螺和双螺环烷基，优选为4元/5元、4元/6元、5元/5元或5元/6 元。“螺环烷基”的非限制性实施例包括但不限于：螺[4.5]癸基、螺[4.4]壬基、螺[3.5]壬基、螺[2.4]庚基。
“稠环烷基”指5至18元的、含有两个或两个以上环状结构的彼此共用一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，优选为6至12元，更优选为7至10元。根据组成环的数目可以分为双环、三环、吡啶酮或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。“稠环烷基”的非限制性实施例包括但不限于：二环[3.1.0]己基、二环[3.2.0]庚-1-烯基、二环[3.2.0]庚基、十氢化萘基或十四氢菲基。
“桥环烷基”指5至18元的、含有两个或两个以上环状结构的彼此共用两个不直接相连接碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、吡啶酮或多环桥环烷基，优选为双环、三环或吡啶酮，更有选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于：(1s,4s)-二环[2.2.1]庚基、二环[3.2.1]辛基、(1s,5s)-二环[3.3.1]壬基、二环[2.2.2]辛基、(1r,5r)-二环[3.3.2]癸基。
所述环烷基环可以稠合于芳基、杂芳基或杂环基环上，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或未取代的。
“杂环基”、“杂环”或“杂环的”在本申请中可交换使用，都是指非芳香性杂环基，其中一个或多个成环的原子是杂原子，如氧、氮、硫原子等，包括单环、稠环、桥环和螺环。优选具有5至7元单环或7至10元双-或三环，其可以包含1，2或3个选自氮、氧和/或硫中的原子。“杂环基”的实例包括但不限于吗啉基，氧杂环丁烷基，硫代吗啉基，四氢吡喃基，1,1-二氧代-硫代吗啉基，哌啶基，2-氧代-哌啶基，吡咯烷基，2-氧代-吡咯烷基，哌嗪-2-酮，8-氧杂-3-氮杂-双环[3.2.1]辛基和哌嗪基。杂环基可以是取代或未取代的。
“螺杂环基”指5至18元的、含有两个或两个以上环状结构的且单环之间彼此共用一个原子的多环基团，其环内含有1个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧或S(O) q(其中q选自0、1或2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺 杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。“螺杂环基”的非限制性实施例包括但不限于：1,7-二氧杂螺[4.5]癸基、2-氧杂-7-氮杂螺[4.4]壬基、7-氧杂螺[3.5]壬基和5-氧杂螺[2.4]庚基。
“稠杂环基”指含有两个或两个以上环状结构彼此共用一对原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子为选自氮、氧或S(O) q(其中q选自0、1或2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、吡啶酮或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。“稠杂环基”的非限制性实施例包括但不限于：八氢吡咯并[3,4-c]吡咯基、八氢-1H-异吲哚基，3-氮杂二环[3.1.0]己基，八氢苯并[b][1,4]二噁英(dioxine)。
“桥杂环基”指5至18元、优选5至14元含有两个或两个以上环状结构且彼此共用两个不直接相连接的原子的多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子的芳香系统，其中一个或多个环原子选自氮、氧或S(O) q(其中q选自0、1或2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、吡啶酮或多环桥杂环基，优选为双环、三环或吡啶酮，更有选为双环或三环。“稠杂环基”的非限制性实施例包括但不限于：2-氮杂二环[2.2.1]庚基，2-氮杂二环[2.2.2]辛基和2-氮杂二环[3.3.2]癸基。所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基。杂环基可以是任选取代的或未取代的。
“亚杂环基”是指二价杂环基。优选具有5至7元单环亚杂环基或7至10元双环杂环基或三环亚杂环基，其可以包含1，2或3个选自氮、氧和/或硫中的原子。亚杂环基可以是取代或未取代的。
“芳基”是指含有一个或者两个环的碳环芳香系统，其中所述环可以以稠合的方式连接在一起。术语“芳基”包括比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C 6-C 10芳基，更优选芳基为苯基和萘基，最优选为苯基。芳基可以是取代或未取代的。所述“芳基”可与杂芳基、杂环基或环烷基稠合，其中与母体结构连接在一起的为芳基环，非限制性实施例包括但不限于：
Figure PCTCN2018090804-appb-000014
“杂芳基”是指芳香族5至6元单环或9至10元双环，其可以包含1至4个选自氮、氧和/或硫中的原子。“杂芳基”的实施例包括但不限于呋喃基，吡啶基，2-氧代-1，2-二氢吡啶基，哒嗪基，嘧啶基，吡嗪基，噻吩基，异噁唑基，噁唑基，噁二唑基，咪唑基，吡咯基，吡唑基，三唑基，四氮唑基，噻唑基，异噻唑基，1，2，3-噻二唑基，苯并间二氧杂环戊烯基，苯并咪唑基，吲哚基，异吲哚基，1，3-二氧代-异吲哚基，喹啉基，吲唑基，苯并异噻唑基，苯并噁唑基和苯并异噁唑基。杂芳基可以是取代或未取代的。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包括但不限于：
Figure PCTCN2018090804-appb-000015
“烷氧基”是指(烷基-O-)的基团。其中，烷基见本文有关定义。C 1-C 6的烷氧基为优先选择，尤其优选C 1-C 4烷氧基。其实例包括，但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“羟基”指-OH基团。
“卤素”是指氟、氯、溴和碘，优选氯、溴和碘。
“氨基”指-NH 2。
“氰基”指-CN。
“硝基”指-NO 2。
“苄基”指-CH 2-苯基。
“羧基”指-C(O)OH。
“羧酸酯基”指-C(O)O(烷基)或(环烷基)，其中烷基、环烷基的定义如上所述。
“DMSO”指二甲基亚砜。
“Et”指乙基。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基替换。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)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(如烯键)的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”，如无特别指出，均是指基团可被一个或多个选自以下的基团取代：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、＝O、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9的取代基所取代；
“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。式(I)化合物的可药用的盐可以为金属盐、与合适的酸形成的胺盐，金属盐优选碱金属、碱土金属盐，合适的酸包括无机酸和有机酸，例如乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、苹果酸、马来酸、扁桃酸、甲磺酸、硝酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等。特别优选的是盐酸、氢溴酸、磷酸和硫酸，最优选的是盐酸盐。
“药物组合物”表示含有一种或多种本文所述化合物(包括其可药用的盐或立体异构体、互变异构体或前体药物等形式)与任选的其他药物活性成分的混合物，其可以包含其他任选组分例如可药用的载体和/或赋形剂。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。
在本文中，用语“多个”包括两个或更多个，例如两个、三个、四个等。
本发明化合物的合成方法
为了完成本发明的目的，本发明采用如下技术方案：
本发明式(I)化合物的制备方法，包括以下步骤：
Figure PCTCN2018090804-appb-000016
使式(IB)化合物与式(IC)化合物在三苯基膦存在下反应，得到式(IA)化合物；
使式(IA)化合物与R 6取代的三丁基甲锡烷反应，使得到的化合物任选进一步水解，以及使得到的化合物任选进一步拆分光学纯异构体，得到式(I)化合物；
其中：X 1选自卤素；且X、环A、R 1～R 6的定义如式(I)中所述。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明，下述实施例是用于说明本发明而不是对本发明的限制。 1H NMR图谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。 1H NMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，q＝四重峰，m＝多重峰，br＝变宽的，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。
质谱是用LC/MS仪测定得到，离子化方式可为ESI或APCI。
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。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
在下列实例中，除非另有指明，所有温度为摄氏温度，除非另有指明，各种起始原料和试剂来自市售或者是根据已知的方法合成，市售原料和试剂均不经进一步纯化直接使用，除非另有指明，市售厂家包括但不限于Aldrich Chemical Company，ABCR GmbH & Co.KG，Acros Organics，广赞化工科技有限公司和景颜化工科技有限公司等。
CD 3OD：氘代甲醇。
CDCl 3：氘代氯仿。
DMSO-d 6：氘代二甲基亚砜。
氩气氛是指反应瓶连接一个约1L容积的氩气气球。
实施例中无特殊说明，反应中的溶液是指水溶液。
对化合物进行纯化，采用硅胶柱层析和硅胶薄板层析法，其中展开剂或洗脱剂体系选自：A：石油醚和乙酸乙酯体系；B：二氯甲烷和甲醇体系；C：二氯甲烷：乙酸乙酯；其中溶剂的体积比根据化合物的极性不同而不同，也可以加入少量的酸性或碱性试剂进行调节，如醋酸或三乙胺等。
实施例1
(1R,3R)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸
Figure PCTCN2018090804-appb-000017
Figure PCTCN2018090804-appb-000018
第一步
2-(2-甲氧基苯基)环氧乙烷
将2-甲氧基苯甲醛1a(20.0g，146.9mmol)溶于100mL二甲亚砜中，依次加入叔丁基硫代次碘酸盐(36.0g，173.3mmol)和氢氧化钠(24.7g，441.0mmol)，加热至80℃反应1.5小时。反应液冷却至室温，加入200mL水，用石油醚(200mL×3)萃取，合并有机相，用饱和氯化钠溶液(200mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到2-(2-甲氧基苯基)环氧乙烷1b(13.1g，无色油状物)，产率：57％。
1H NMR(400MHz,CDCl 3)δ7.27(t,J＝1.2Hz,1H),7.17(d,J＝7.6Hz,1H),6.98(t,J＝1.2Hz,1H),6.89(d,J＝7.6Hz,1H),4.22(t,J＝0.4Hz,1H),3.87(s,3H),2.71(dd, J＝5.6,2.4Hz,1H)3.14(dd,J＝5.6,2.4Hz,1H).
第二步
2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙醇
将(2-甲氧基苯基)环氧乙烷1b(26.0g，173.0mmol)加入到搅拌的四氢-2H-吡喃-4-醇1c(53.1g，519.7mmol)和三氟甲磺酸铝(4.10g，8.65mmol)中，室温反应3小时。向反应液中加入200mL二氯甲烷和200mL水，分液，有机相减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙醇1d(13.0g，白色固体)，产率：30％。
1H NMR(400MHz,CDCl 3)δ7.42(d,J＝8.0Hz,1H),7.26(t,J＝7.2Hz,1H),6.98(t,J＝7.2Hz,1H),6.87(d,J＝8.0Hz,1H),5.07(dd,J＝8.0,4.0Hz,1H),3.87-4.00(m,2H),3.83(s,3H),3.62-3.72(m,1H),3.46-3.58(m,2H),3.32-3.43(m,2H),2.35-2.37(m,1H),1.99-2.03(m,1H),1.77-1.80(m,1H),1.60-1.70(m,2H).
第三步
2-(三丁基甲锡烷基)噁唑
将噁唑1e(500mg，7.24mmol)溶于12mL四氢呋喃中。氮气保护下，冷却至-78℃搅拌5分钟，缓慢加入正丁基锂(4.56mL，7.29mmol)，加完后，在-78℃搅拌30分钟。然后加入三丁基氯化锡(1.96mL，7.24mmol)，在-78℃搅拌10分钟，升至室温反应1小时。反应液减压浓缩，向残留物中加入15mL正己烷，过滤，滤液减压浓缩，得到2-(三丁基甲锡烷基)噁唑1f(1.8g，淡黄色液体)，产率：70％。
1H NMR(400MHz,CDCl3):7.84(1H,s),7.18(1H,s),1.67-1.53(6H,m)，1.42-1.29(6H,m),1.20(6H,m),0.89(9H,t,J＝7Hz).
第四步
2-氨基-4-甲基噻吩-3-甲酸乙酯
氩气保护下，将2-氰基乙酸乙酯1g(185.5g,1.64mol)、丙酮(100g,1.72mol)、硫磺(53g,1.64mol)溶于500mL的无水乙醇中，缓慢滴加吗啉1h(149.6g,1.64mol),20分钟内加完。45℃下反应10小时。反应液冷却至室温，过滤除去剩余硫粉。将滤液减压浓缩，加入900mL75％乙醇，室温下搅拌30分钟。黄色固体析出，过滤，除去固体，减压浓缩滤液，在残留物中加入600mL 40％乙醇，70℃下搅拌30分钟，自然冷却，逐渐析出固体，过滤得到2-氨基-4-甲基噻吩-3-甲酸 乙酯1i(95g，绿色固体)，产率：31.4％。
MS m/z(ESI)：185.9[M+1]
第五步
3-氧代环丁烷-1-甲酸叔丁酯
将3-氧代环丁烷-1-甲酸1j(5.7g,50mmol)、叔丁醇(9.25g,125mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(11.5g,60mmol)和4-二甲氨基吡啶(3.1g,25mmol)溶于130mL二氯甲烷中，室温下搅拌12小时。加入100mL二氯甲烷稀释反应液，依次以水(100mL)、1N盐酸水溶液(50mL)和饱和氯化钠水溶液(50mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到3-氧代环丁烷-1-甲酸叔丁酯1k(8.5g，红棕色油状物)，产率：100％。
第六步
(1S,3S)-3-羟基环丁烷-1-甲酸叔丁酯
将3-氧代环丁烷-1-甲酸叔丁酯1k(6.5g，38.2mmol)溶于72mL四氢呋喃/甲醇(V:V＝8:1)中，0℃下分批加入硼氢化钠(0.71g,19.1mmol)，室温下反应一小时。加入80mL饱和碳酸钾水溶液，以乙酸乙酯(100mL×3)萃取，合并有机相，以饱和氯化钠水溶液(80mL)洗涤，分去水层，有机相以无水硫酸钠干燥，减压浓缩，得到(1S,3S)-3-羟基环丁烷-1-甲酸叔丁酯1l(6.58g，粘稠固体)，产率：100％；
第七步
(1R,3R)-3-(1,3-二氧代异吲哚啉-2-基)环丁烷-1-甲酸叔丁酯
将(1S,3S)-3-羟基环丁烷-1-甲酸叔丁酯1l(4.9g,28.45mmol)、异二氢吲哚-1,3-二酮1m(4.6g,31.3mmol)和三苯基膦(11.2g,42.1mmol)溶于80mL四氢呋喃中，搅拌下加入偶氮二异丙基二羧酸(8.6g,42.7mmol)，室温下反应2小时。减压浓缩，以20mL乙酸乙酯溶解残留物，加入100mL石油醚，析出大量三苯氧磷，过滤除去三苯氧磷，滤液减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(1R,3R)-3-(1,3-二氧代异吲哚啉-2-基)环丁烷-1-甲酸叔丁酯1n(7.5g，白色固体)，产率：87.5％。
第八步
(1R,3R)-3-氨基环丁烷-1-甲酸叔丁酯
将(1R,3R)-3-(1,3-二氧代异吲哚啉-2-基)环丁烷-1-甲酸叔丁酯1n(4.5g，14.9mmol)溶于45mL乙醇中，加入水合肼(2.2g,44.8mmol)，室温下反应12小时。过滤，以乙醇(10mL×2)洗涤滤饼，滤液减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(1R,3R)-3-氨基环丁烷-1-甲酸叔丁酯1o(1.2g，无色油状)，产率：66.4％。
第九步
2-(3-(1R,3R)-3-(叔丁氧基羰基)环丁基)脲基)-4-甲基噻吩-3-甲酸乙酯
将2-氨基-4-甲基噻吩-3-甲酸乙酯1i(1.44g，7.8mmol)溶于60mL二氯甲烷中，0℃下，滴加双(三氯甲基)碳酸酯(810mg,2.7mmol)的二氯甲烷溶液(10mL)，室温下下搅拌30分钟。0℃下加入三乙胺(2.4g,23.4mmol)，室温下搅拌30分钟。0℃下加入(1R,3R)-3-氨基环丁烷-1-甲酸叔丁酯1o(1.3g，7.8mmol)，室温下反应30分钟。加入100mL二氯甲烷稀释反应液，以饱和氯化钠水溶液(50mL)洗涤，分去水层，有机相以无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到2-(3-(1R,3R)-3-(叔丁氧基羰基)环丁基)脲基)-4-甲基噻吩-3-甲酸乙酯1p(2.5g，白色固体)，产率：83％。
MS m/z(ESI)：383.0[M+1]
第十步
(1R,3R)-3-(5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸叔丁酯
将2-(3-(1R,3R)-3-(叔丁氧基羰基)环丁基)脲基)-4-甲基噻吩-3-甲酸乙酯1p(250mg,0.65mmol)和碳酸铯(426mg,1.31mmol)溶于3mLN,N-二甲基甲酰胺中，100℃下反应2小时。加入50mL乙酸乙酯稀释反应液，有机相依次用水(10mL×3)和饱和氯化钠水溶液(10mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(1R,3R)-3-(5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸叔丁酯1q(200mg，白色固体)，产率：91.3％。
MS m/z(ESI)：280.9[M-55]
第十一步
(1R,3R)-3-(6-溴-5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸叔丁酯
将(1R,3R)-3-(5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸叔丁酯1q(2.2g,6.54mmol)溶于50mL二氯甲烷中，0℃下加入N-溴代琥珀酰亚胺(1.4g,7.85mmol)，在0℃下反应30分钟。加入200mL二氯甲烷稀释反应液，以饱和氯化钠水溶液(50mL)洗涤，分去水层，有机相以无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(1R,3R)-3-(6-溴-5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸叔丁酯1r(2.5g，白色固体)，产率：92.0％。
MS m/z(ESI)：358.8[M-55]
第十二步
(1R,3R)-3-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸叔丁酯
氮气保护下，将(1R,3R)-3-(6-溴-5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸叔丁酯1r(723mg,1.74mmol)、2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙醇1d(834mg,3.30mmol)和三苯基膦(912mg,3.48mmol)溶于20mL无水四氢呋喃中。冷却至0℃搅拌3分钟，加入偶氮二甲酸二异丙酯(0.69mL,3.48mmol)溶于4mL四氢呋喃的溶液，加完后，升至室温反应18小时。反应液减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(1R,3R)-3-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸叔丁酯1s(986mg，白色固体)，产率：87％。
MS m/z(ESI)：649.8[M+1]
第十三步
(1R,3R)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸叔丁酯
氮气保护下，将(1R,3R)-3-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸叔丁酯1s(986mg，1.52mmol)、2-(三丁基甲锡烷基)噁唑1f(817mg，2.28mmol)和四三苯基膦钯(245mg，0.21mmol)溶于12mL甲苯中，加热至110℃反应7小时。反应液冷却至室温，加入40mL水，用乙酸乙酯(15mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(1R,3R)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙 基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸叔丁酯1t(756mg，淡黄色固体)，产率：78％。
MS m/z(ESI)：638.8[M+1]
第十四步
(1R,3R)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸
将(1R,3R)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸叔丁酯1t(756mg，1.18mmol)溶于10mL二氯甲烷中。0℃下滴加2mL三氟乙酸，加完后，升至室温反应3小时。向反应液中加入25mL水，用乙酸乙酯(10mL×3)萃取，用水(30mL×4)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶薄板层析法(展开剂：B体系)纯化，得到(1R,3R)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸1(185mg，白色固体)，产率：27％。MS m/z(ESI)：582.2[M+1]
1H NMR(400MHz,DMSO)δ12.31(s,1H),8.23(s,1H),7.49(d,J＝7.4Hz,1H),7.39(s,1H),7.29(t,J＝7.4Hz,1H),7.13-6.89(m,2H),5.53(m,1H),5.31(m,1H),4.02(m,2H),3.78(s,3H),3.55(m,2H),3.36(m,1H),3.24(m,2H),3.07(m,3H),2.78(s,3H),2.41(s,2H),1.63(s,2H),1.42-1.12(m,2H).
实施例2和实施例3
(1R,3R)-3-(1-((S)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸
(1R,3R)-3-(1-((R)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸
Figure PCTCN2018090804-appb-000019
Figure PCTCN2018090804-appb-000020
第一步
(1R,3R)-3-(1-((S)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸
(1R,3R)-3-(1-((R)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸
将(1R,3R)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸1(120mg,0.60mmol)通过采用超临界流体色谱(SFC)法，用制备色谱和手性柱对手性异构体进行拆分(手性柱ChiralPak AS,250×30mm I.D.,5μm；70mL/min；流动相为A(对于CO 2)和B(对于甲醇)(0.1％NH 3.H 2O))，得到(1R,3R)-3-(1-((S)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸2(56.3mg,白色固体)，产率：46.9％，保留时间5.289min，ee值99.7％；(1R,3R)-3-(1-((R)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸3(63.3mg,白色固体)，产率：52.28％，保留时间4.505min，ee值99.8％。
化合物2
MS m/z(ESI)：582.2[M+1]
1H NMR(400MHz,DMSO)δ12.31(s,1H),8.23(s,1H),7.49(d,J＝7.4Hz,1H),7.39(s,1H),7.29(t,J＝7.4Hz,1H),7.13-6.89(m,2H),5.53(m,1H),5.31(m,1H),4.02(m,2H),3.78(s,3H),3.55(m,2H),3.36(m,1H),3.24(m,2H),3.07(m,3H),2.78(s,3H),2.41(s,2H),1.63(s,2H),1.42-1.12(m,2H).
化合物3
MS m/z(ESI)：582.2[M+1]
1H NMR(400MHz,DMSO)δ12.31(s,1H),8.23(s,1H),7.49(d,J＝7.4Hz,1H),7.39(s,1H),7.29(t,J＝7.4Hz,1H),7.13-6.89(m,2H),5.53(m,1H),5.31(m,1H),4.02(m,2H),3.78(s,3H),3.55(m,2H),3.36(m,1H),3.24(m,2H),3.07(m,3H),2.78(s,3H),2.41(s,2H),1.63(s,2H),1.42-1.12(m,2H).
实施例4
(1S,3S)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸
Figure PCTCN2018090804-appb-000021
第一步
3-氧代环丁烷-1-甲酸乙酯
将3-氧代环丁烷-1-甲酸1j(4.56g,40mmol)、乙醇(2.3g,50mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(9.2g,48mmol)和4-二甲氨基吡啶(2.4g,20 mmol)溶于100mL二氯甲烷中，室温下搅拌12小时。加入100mL二氯甲烷稀释反应液，依次以水(150mL)、1N盐酸水溶液(50mL)和饱和氯化钠水溶液(100mL)洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到3-氧代环丁烷-1-甲酸乙酯4a(5.5g，无色油状物)，产率：96.7％。
第二步
(1S,3S)-3-(二苄基氨基)环丁烷-1-甲酸乙酯
将3-氧代环丁烷-1-甲酸乙酯4a(5.5g,40mmol)和二苄胺(8.58g,44mmol)溶于180mL四氢呋喃中，室温下搅拌1小时。加入三乙酰基硼氢化钠(17.1g,80mmol)和20mL乙酸，室温下反应12小时。减压下除去四氢呋喃，加入饱和碳酸氢钠水溶液，调节pH至碱性，以乙酸乙酯(50mL×3)萃取，合并有机相，以50mL饱和氯化钠水溶液洗涤，有机相以无水硫酸钠干燥，减压浓缩，得到的残留物用硅胶薄板层析法(展开剂：A体系)纯化，得到(1S,3S)-3-(二苄基氨基)环丁烷-1-甲酸乙酯4b(6.0g，无色油状物)，产率：46.5％。
第三步
(1S,3S)-3-氨基环丁烷-1-甲酸乙酯
将(1S,3S)-3-(二苄基氨基)环丁烷-1-甲酸乙酯4b(5.0g,15.5mmol)溶于150mL乙醇中，加入10％Pd-C(200mg,4％)，置换氢气3次，室温下反应12小时。过滤，除去剩余Pd-C，滤液减压浓缩，得到(1S,3S)-3-氨基环丁烷-1-甲酸乙酯4c(2.1g，无色油状)，产率：95.5％。
第四步
2-(3-((1S,3S)-3-(乙氧基羰基)环丁基)脲基)-4-甲基噻吩-3-甲酸乙酯
将2-氨基-4-甲基噻吩-3-甲酸乙酯1i(2.78g，15.0mmol)溶于100mL二氯甲烷中，0℃下，滴加双(三氯甲基)碳酸酯(1.56g,5.25mmol)的二氯甲烷溶液(20mL)，室温下搅拌30分钟。0℃下加入三乙胺(4.5g,45mmol)，室温下搅拌30分钟。0℃下加入(1S,3S)-3-氨基环丁烷-1-甲酸乙酯4c(2.2g，15.5mmol)，室温下反应30分钟。加入100mL二氯甲烷稀释反应液，以饱和氯化钠水溶液(50mL)洗涤，分去水层，有机相以无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到2-(3-((1S,3S)-3-(乙氧基羰基)环丁基)脲基)-4-甲基噻吩-3-甲酸乙酯4d(4.7g，淡黄色固体)，产率：89％。
MS m/z(ESI)：354.9[M+1]
第五步
(1S,3S)-3-(5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸乙酯
将2-(3-((1S,3S)-3-(乙氧基羰基)环丁基)脲基)-4-甲基噻吩-3-甲酸乙酯4d(4.7g,13.3mmol)和碳酸铯(8.67g,26.6mmol)溶于30mLN,N-二甲基甲酰胺中，100℃下反应1小时。加入150mL乙酸乙酯稀释反应液，依次以水(50mL×3)和饱和氯化钠水溶液(50mL×1)洗涤，有机相以无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(1S,3S)-3-(5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸乙酯4e(2.0g，淡黄色固体)，产率：49.0％。
MS m/z(ESI)：308.9[M+1]
第六步
(1S,3S)-3-(6-溴-5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸乙酯
将(1S,3S)-3-(5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸乙酯4e(2.0g,6.5mmol)溶于65mL二氯甲烷中，0℃下加入N-溴代琥珀酰亚胺(1.2g,6.5mmol)，0℃下反应30分钟。加入200mL二氯甲烷稀释反应液，以饱和氯化钠水溶液(50mL)洗涤，分去水层，有机相以无水硫酸钠干燥，减压浓缩，残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(1S,3S)-3-(6-溴-5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸乙酯4f(2.0g，白色固体)，产率：80.0％。
MS m/z(ESI)：386.8[M+1]
第七步
(1S,3S)-3-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸乙酯
氮气保护下，将(1S,3S)-3-(6-溴-5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸乙酯4f(2.0mg，5.2mmol)、2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙醇1d(1.52g，6.0mmol)和三苯基膦(1.58g，6.0mmol)溶于25mL无水四氢呋喃中。冷却至0℃搅拌3分钟，加入偶氮二甲酸二异丙酯(1.2g，6.0mmol)溶于4mL四氢呋喃的溶液，加完后，升至室温反应18小时。反应液减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(1S,3S)-3-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基 -2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸乙酯4g(2.9g，白色固体)，产率：90％。
MS m/z(ESI)：621.2[M+1]
第八步
(1S,3S)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸乙酯
氮气保护下，将(1S,3S)-3-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸乙酯4g(1.24g，2.0mmol)、2-(三丁基甲锡烷基)噁唑1f(1.4g，3mmol)和四三苯基膦钯(323.5mg，0.28mmol)溶于20mL甲苯中。加热至110℃反应7小时。反应液冷却至室温，加入60mL水，用乙酸乙酯(30mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：A体系)纯化，得到(1S,3S)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸乙酯4h(936mg，淡黄色固体)，产率：78％。
MS m/z(ESI)：609.9[M+1]
第九步
(1S,3S)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸
将(1S,3S)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸乙酯4h(936mg，1.5mmol)和氢氧化锂(108mg,4.5mmol)溶于10mL四氢呋喃/甲醇中(V:V＝1:1)。室温反应12小时。减压浓缩，得到的残留物用硅胶薄板层析法(展开剂：B体系)纯化，得到(1S,3S)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸4(760mg，白色固体)，产率：87.3％。
MS m/z(ESI)：582.2[M+1]
1H NMR(400MHz,DMSO)δ12.17(s,1H),8.22(s,1H),7.49(d,J＝6.7Hz,1H),7.39(s,1H),7.30(t,J＝7.2Hz,1H),7.10-6.92(m,2H),5.33-5.26(m,1H),5.04(m, 1H),4.16-3.89(m,2H),3.78(s,3H),3.56(m,2H),3.43-3.35(m,1H),3.24(m,2H),3.00-2.81(m,3H),2.77(s,3H),2.46(m,2H),1.63(s,2H),1.34-1.13(m,2H).
实施例5和实施例6
(1S,3S)-3-(1-((S)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸
(1S,3S)-3-(1-((R)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸
Figure PCTCN2018090804-appb-000022
第一步
(1S,3S)-3-(1-((S)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸
(1S,3S)-3-(1-((R)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸
将(1S,3S)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸4(130mg,0.23mmol)通过采用超临界流体色谱(SFC)，用制备色谱和手性柱对手性异构体进行拆分(手性柱ChiralCel OJ,250×30mm I.D.,5μm；70mL/min；流动相为A(对于CO 2)和B(对于甲醇)(0.1％NH 3.H 2O))，得到(1S,3S)-3-(1-((S)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸5(59.12mg,白色固体)，产率：45.48％，保留时间3.736min，ee值100％；(1S,3S)-3-(1-((R)-2-(2-甲氧基苯 基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-6-(噁唑-2-基)-2,4-二氧代-1,2-二氢噻吩并[2,3-d]嘧啶-3(4H)-基)环丁烷-1-甲酸6(68.73mg,白色固体)，产率：52.87％，保留时间4.066min，ee值99.8％。
化合物5
MS m/z(ESI)：582.2[M+1]
1H NMR(400MHz,DMSO)δ12.17(s,1H),8.22(s,1H),7.49(d,J＝6.7Hz,1H),7.39(s,1H),7.30(t,J＝7.2Hz,1H),7.10-6.92(m,2H),5.33-5.26(m,1H),5.04(m,1H),4.16-3.89(m,2H),3.78(s,3H),3.56(m,2H),3.43-3.35(m,1H),3.24(m,2H),3.00-2.81(m,3H),2.77(s,3H),2.46(m,2H),1.63(s,2H),1.34-1.13(m,2H).
化合物6
MS m/z(ESI)：582.2[M+1]
1H NMR(400MHz,DMSO)δ12.17(s,1H),8.22(s,1H),7.49(d,J＝6.7Hz,1H),7.39(s,1H),7.30(t,J＝7.2Hz,1H),7.10-6.92(m,2H),5.33-5.26(m,1H),5.04(m,1H),4.16-3.89(m,2H),3.78(s,3H),3.56(m,2H),3.43-3.35(m,1H),3.24(m,2H),3.00-2.81(m,3H),2.77(s,3H),2.46(m,2H),1.63(s,2H),1.34-1.13(m,2H).
生物学评价
测试例1、本发明化合物对ACC1和ACC2的酶活性抑制IC 50的测定
以下方法用于测定本发明优选化合物在体外条件下对重组人源ACC1,ACC2蛋白的酶活性的抑制程度。
本方法原理基于由ACC蛋白催化乙酰辅酶A生成丙二酰辅酶A的反应。该反应过程中会消耗ATP并生成ADP。通过采用来自Promega(普洛麦格)的ADP-Glo TM激酶试剂盒可以将反应生成的ADP重新转化为ATP，这部分ATP可与试剂盒中的荧光素酶-荧光素发生反应，并生成化学发光信号。因此通过测量化学发光信号的强度，可以反映催化反应中生成的ADP量，从而间接测定ACC蛋白的酶活性以及受试化合物对于酶活性的影响。所使用的主要试剂包括：ACC1，ACC2蛋白(购于BPS bioscience，ACC1货号50200，ACC2货号50201)，乙酰辅酶A(acetyl-CoA，购于Sigma，货号A2056)，NaHCO3(购于Sigma，货号S6014)，ADP-Glo TM Kinase assay kit(购于Promega，货号V9102)。
测试流程简述如下：首先配制反应所需的1x缓冲液，其组成如下：50mM HEPES(pH7.4购于Invitrogen，货号15630)，2mM氯化镁(MgCl 2，购于Sigma，货号M1028)，2mM柠檬酸钾(Potassium citrate，购于Sigma，货号89306)，0.01％Brij-35 detergent(购于Merck，货号203728)，2mM DTT(购于Sigma，货号D0632)。将测试用化合物粉末溶解于DMSO配制为10mM浓度的贮存液，随后依次进行3倍稀释配制成测试所需浓度，每个化合物设10个浓度点，浓度范围为10μM-0.5nM。首先向384孔微孔板中加入适量的ACC蛋白(2nM)，再向各孔中加入已稀释好的不同浓度的测试化合物溶液，每个浓度设有复孔对照，同时设置溶剂对照(空白组)，阴性对照组(DMSO组)。随后将384孔板在微孔板振荡器上振荡混匀后，在室温条件下孵育15分钟。之后向各孔中加入以前述缓冲液稀释的含有ATP，乙酰辅酶A和NaHCO3的底物混合液以开始反应，三组分的终浓度分别为ATP 20μM，乙酰辅酶A 10μM，NaHCO3 30mM。在室温下反应30分钟后，依照ADP-Glo TM Kinase assay kit试剂盒说明书中的方法，向各孔中加入对应的反应液和检测液(具体操作方法可参考试剂盒说明书)，最后在Envision 2104多功能酶标仪(Perkin Elmer)上测定各孔的相对光单位(RLU)数值。某一浓度下化合物抑制ACC酶活性的百分比抑制率按以下公式进行计算：
抑制率％＝[(阴性对照孔RLU平均值-空白孔RLU平均值)-(测试孔RLU平均值-空白孔RLU平均值)]/(阴性对照孔RLU平均值-空白孔RLU平均值)*100
最后在GraphPad Prism5软件中对化合物的浓度对数值和相应浓度的百分比抑制率进行非线性回归分析得到该化合物的半数抑制浓度值(IC 50)。
表1 本发明化合物对ACC1酶和ACC2酶活性抑制的IC 50数据
实施例编号 IC 50(nM)/ACC1 IC 50(nM)/ACC2
1 1.3 ND
3 1.5 4.0
4 0.9 ND
5 ND 2.0
6 0.5 ND
备注：ND表示未测定。
结论：本发明的化合物对于ACC1酶和ACC2酶均具有较好的抑制作用。
测试例2、本发明化合物对[ 14C]-乙酸盐并入HepG2细胞抑制活性测定
以下方法用于测定本发明化合物在体外条件下对[ 14C]-乙酸盐并入HepG2细 胞抑制程度。
1.试剂与仪器
1.1.试剂与耗材
表2 试剂与耗材
Figure PCTCN2018090804-appb-000023
表3 试剂与耗材
试剂 厂商 试剂
氢氧化钠 天津市福晨化学试剂厂 氢氧化钠
氢氧化钾 北京精求化工产品有限责任公司 氢氧化钾
醋酸 天津市光复科技发展有限公司 醋酸
三氯甲烷 北京化工厂 三氯甲烷
乙醚 天津市津东天正精细化学试剂厂 乙醚
石油醚 天津市津东天正精细化学试剂厂 石油醚
盐酸 北京兴青红精细化学品科技有限公司 盐酸
正己烷 北京化工厂 正己烷
正庚烷 北京化工厂 正庚烷
无水乙醇 北京化工厂 无水乙醇
1.2.仪器
表4 仪器
仪器 厂商 货号
生物安全柜 Thermo Scientific 1300 Series A2
离心机 Eppendorf 5702
二氧化碳培养箱 Thermo Scientific 1300 SERIES A2
细胞计数仪 Invitrogen C10281
移液枪 BIOHIT Easypet
显微镜 Olympus CKX41
移液器 BIOHIT Proline Plus
涡旋震荡仪 IKA MS3 basic
MicroBeta PerkinElmer 2450
1.3本发明化合物的准备
待测的本发明化合物均以10mM溶解在DMSO中，使用前储存在4℃中。
2.实验步骤
2.1.细胞培养
HepG2细胞购置于美国模式培养物集存库(American type culture collection,ATCC)资源库购买。细胞培养在含有10％胎牛血清，青霉素(100units/mL)和链霉素(100μg/mL)的DMEM中，在含5％二氧化碳的37℃培养箱中孵育，每2～3天传代一次。
2.2.[2- 14C]-Acetate摄入实验
(1)第一天，在24孔板中按2×105个细胞每孔接种HepG2细胞，在含5％二氧化碳的37℃培养箱中孵育。
(2)第四天，更换含有化合物的培养基。本发明化合物初始浓度为3μM，4倍稀释，5个浓度梯度，DMSO终浓度为0.5％(v/v)，在含5％二氧化碳的37℃培养箱中孵育1小时。
(3)每孔加入2μCi[2- 14C]-Acetate，在含5％二氧化碳的37℃培养箱中继续孵育5小时。
(4)将培养基转移至15mL离心管中，向每孔加入0.5mL的0.1M NaOH，将细胞裂解液转移到对应的15mL离心管中。
(5)每管加入1mL乙醇和0.17mL的50％KOH，90℃水浴1小时。
(6)取出样品，待冷却到室温后每管加入5mL石油醚，颠倒数次，1000rpm离心5分钟。弃上层有机相，保留水相用于脂肪酸提取。
(7)每管加入1mL浓盐酸(确保其pH值低于1)。
(8)每管加入5mL石油醚，颠倒数次，1000转/分钟，离心5分钟，转移4mL石油醚层到新的玻璃管(18×180mm)中。
(9)重复步骤(8)。
10)将汇集的提取物放置在64℃水浴中蒸发过夜。
(11)第五天，用240μL含有200μg亚油酸的氯仿/正己烷(1:1)溶解脂肪酸。
(12)取10μL点样在硅胶板中，并在正庚烷：乙醚：醋酸(体积比90:30:1)混合液中层析10分钟。
(13)用碘蒸汽显色脂肪酸条带，并裁剪到闪烁管中，加入2mL ULTIMA GOLD室温下孵育10分钟。
14)用MicroBeta记录闪烁信号。
在GraphPad Prism5软件中对化合物的浓度和相应浓度的闪烁信号进行非线性回归分析得到该化合物的半数抑制浓度值(IC 50)。
表5 本发明化合物对[ 14C]-乙酸盐并入HepG2细胞抑制的IC 50值
实施例编号 IC 50(nM)
Firsocostat(对照化合物) 50
3 6.25
6 19.8
结论：本发明的化合物对于[ 14C]-乙酸盐并入HepG2细胞具有明显抑制作用，优于作为对照化合物的Firsocostat。
测试例3、本发明化合物ICR小鼠口服药代动力学研究
1、摘要
以ICR小鼠为受试动物，采用LC-MS/MS法测定小鼠灌胃给予实施例3化合物和对照firsocostat后，测定其不同时刻血浆和肝脏中的药物浓度，研究本发明化合物在小鼠体内的药代动力学特征。
2、实验方案
2.1实验药品与动物
实施例3化合物和Firsocostat；
健康成年ICR雄性小鼠18只，购自北京维通利华实验动物技术有限公司，动物体重：29.3～35.4g。
2.2药物配置与给药
称取适量的实验药品，加入0.5％羧甲基纤维素钠(CMC-Na)，研磨制成配制成1mg/mL悬浮液；
健康成年ICR雄性小鼠18只，分为2组，禁食过夜后分别灌胃给药，给药剂量为10mg/kg，给药体积为10mL/kg，给药后4小时给食。
A组小鼠灌胃给予10mg·kg -1实施例3化合物的给药制剂，B组小鼠灌胃给予10mg·kg -1firsocostat的给药制剂。
2.3样品采集
给药前经由眼眶采血80uL，给药后于各设定时间点经CO 2深度麻醉后经由心脏采血0.20mL，全血样品置于含EDTA-K2的抗凝管中；并立即摘取肝脏组织。采样时间点如下：
血浆：给药前0小时，给药后0.5小时，1小时，4小时。
肝脏：给药后1小时。
血液样本采集后置于含EDTA-K 2抗凝管中，离心分离血浆(离心条件：1500g，10分钟)，收集上层血浆样品至样品管中。称取部分肝脏组织样品，按比例(组织:匀浆液＝1:5,w/v)加入20％甲醇水进行匀浆。收集的生物样品分析前存放于-40～-20℃的冰箱。
采用LC-MS/MS进行分析化合物灌胃给药后小鼠血浆和肝脏中待测化合物的含量。
3、药代动力学参数结果
本发明的实施例3化合物和Firsocostat的药代动力学参数如下：
Figure PCTCN2018090804-appb-000024
结论：本发明化合实施例3与Firsocostat相比，药代吸收良好，具有较好的药代动力学性质；同时给药1小时后，肝脏中药物浓度为：10740ng/g，实施例3化合物在肝脏中有较好的富集。
备注：Firsocostat的结构如下，根据WO2013071169制备而得
Figure PCTCN2018090804-appb-000025
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (19)

  1. 式(I)所示的化合物：
    Figure PCTCN2018090804-appb-100001
    包括其立体异构体、互变异构体或其可药用的盐，
    其中：
    X选自-NH-、-O-或-S-；优选为-S-；
    环A选自环烷基，且与环A相连接的R 2和N不连接在同一个碳原子上；
    R 1选自氢原子、烷基或卤素，其中所述的烷基任选进一步被一个或多个选自卤素、羟基、氰基、硝基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9的取代基所取代；
    R 2选自氢原子、羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9，其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 11R 12、-C(O)NR 11R 12、-C(O)R 13、-C(O)OR 13或-NR 11C(O)R 12的取代基所取代；
    R 3选自芳基或杂芳基，其中所述的芳基或杂芳基任选进一步被一个或多个选自R 7的取代基所取代；
    R 4和R 5各自独立地选自氢原子、烷基、-OR 10、-SR 10、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9；
    或者，R 4、R 5与其所连接的原子一起形成3～8元饱和或部分不饱和环烷基，或形成具有1个或多个选自N、O、S(O) q的杂原子的4～8元饱和或部分不饱和杂环基，其中所述环烷基或杂环基任选进一步被一个或多个选自羟基、卤素、硝基、 氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9的取代基所取代；
    R 6选自卤素、氰基、环烷基、杂环基、芳基、杂芳基、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9，优选为杂芳基；
    或者，R 1、R 6与其所连接的原子一起形成3～8元饱和或部分不饱和环烷基，或形成具有1个或多个选自N、O、S(O) q的杂原子的4～8元饱和或部分不饱和杂环基，或形成5～10元芳基或杂芳基，其中所述环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9的取代基所取代；
    R 7各自独立地选自羟基、卤素、氰基、硝基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9，其中所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 8R 9、-C(O)NR 8R 9、-C(O)R 10、-OC(O)R 10、-S(O) qNR 8R 9、-NR 8S(O) 2R 9或-NR 8C(O)R 9的取代基所取代；
    R 8、R 9和R 10各自独立地选自氢原子、烷基、-OR 13、氰基、环烷基、杂环基、芳基或杂芳基，其中所述烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-NR 11R 12、-C(O)NR 11R 12、-C(O)R 13、-C(O)OR 13或-NR 11C(O)R 12的取代基所取代；
    或者，R 8、R 9与其所连接的N原子一起形成一个4～8元杂环基，其中所述4～8元杂环内含有一个或多个N、O、S(O) q原子，并且4～8元杂环上进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、＝O、-NR 11R 12、-C(O)NR 11R 12、-C(O)R 13、-C(O)OR 13或-NR 11C(O)R 12的取代基所取代；
    R 11、R 12和R 13各自独立地选自氢原子、烷基、烯基、环烷基、杂环基、芳基或杂芳基，其中所述烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；且
    q为0、1或2。
  2. 根据权利要求1所述的化合物，其具有式(II)结构：
    Figure PCTCN2018090804-appb-100002
    其中：
    m为1、2、3、4或5；且
    环A、R 1、R 2、R 6、R 7和R 10的定义如权利要求1中所述。
  3. 根据权利要求2所述的化合物，其具有式(III)所述结构：
    Figure PCTCN2018090804-appb-100003
    其中：
    m为1、2、3、4或5；且
    环A、R 1、R 2、R 6、R 7和R 10的定义如权利要求1中所述。
  4. 根据权利要求2所述的化合物，其具有式(IV)所述结构：
    Figure PCTCN2018090804-appb-100004
    其中：
    m为1、2、3、4或5；且
    环A、R 1、R 2、R 6、R 7和R 10的定义如权利要求1中所述。
  5. 根据权利要求1～4任一项所述的化合物，其中环A选自如下基团：
    Figure PCTCN2018090804-appb-100005
    优选为
    Figure PCTCN2018090804-appb-100006
  6. 根据权利要求1～5任一项所述的化合物，其中R 1选自甲基或三氟甲基。
  7. 根据权利要求1～6任一项所述的化合物，其中：
    R 2选自四唑基、-C(O)OR 13或-C(O)NR 8R 9；
    R 8选自氢原子或烷基；
    R 9选自氰基或-OR 13；
    R 13选自氢原子、烷基、烯基、环烷基、杂环基、芳基或杂芳基，其中所述烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧酸或羧酸酯的取代基所取代；
    R 2为-C(O)OH。
  8. 根据权利要求1～7任一项所述的化合物，其中R 6选自5元杂芳基，优选为噻唑基。
  9. 根据权利要求1～8任一项所述的化合物，其中R 7选自卤素或烷氧基，优选为甲氧基。
  10. 根据权利要求1～9任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐，其中R 10为四氢吡喃-4-基。
  11. 根据权利要求1所述的化合物，选自：
    Figure PCTCN2018090804-appb-100007
  12. 一种制备根据权利要求1所述的式(I)化合物的方法，所述方法包括：
    Figure PCTCN2018090804-appb-100008
    使式(IA)化合物与R 6取代的三丁基甲锡烷反应，使得到的化合物任选进一步水解，并将水解得到的化合物任选进一步拆分光学纯异构体，得到式(I)化合物；
    其中：X 1选自卤素；且X、环A、R 1～R 6的定义如权利要求1中所述。
  13. 式(IA)所示的化合物：
    Figure PCTCN2018090804-appb-100009
    包括其立体异构体、互变异构体或其可药用的盐，
    其中：
    X 1选自卤素；且X、环A、R 1～R 5的定义如权利要求1中所述。
  14. 根据权利要求13所述的化合物，选自：
    Figure PCTCN2018090804-appb-100010
  15. 一种制备根据权利要求13所述的式(IA)化合物的方法，所述方法包括：
    Figure PCTCN2018090804-appb-100011
    使式(IB)化合物与式(IC)化合物在三苯基膦存在下反应，得到式(IA)化合物；
    其中：
    X 1选自卤素；且X、环A、R 1～R 5的定义如权利要求1中所述。
  16. 一种药物组合物，含有有效剂量的根据权利要求1～11中任一项所述的化合物，以及任选的可药用的载体、赋形剂或它们的组合。
  17. 根据权利要求1～11中任一项所述的化合物或根据权利要求16所述的药物组合物在制备用作ACC抑制剂的药物中的用途。
  18. 根据权利要求1～11中任一项所述的化合物或根据权利要求16所述的 药物组合物在制备用于预防或治疗与ACC相关的疾病或状况的药物中的用途，其中所述疾病或状况优选为代谢类疾病，癌症，真菌、寄生虫或细菌感染；其中所述代谢类疾病优选为肝脂肪变性、非酒精性脂肪肝、肥胖症、血脂异常、高脂血症、II型糖尿病或代谢综合征，其中所述肥胖症优选为普拉德-威利综合征(Prader-Willi syndrome)、巴德-毕德氏综合征(Bardet-Biedl syndrome)或科恩综合征(Cohen syndrome)或MOMO综合征，其中所述癌症优选为肝细胞癌、非小细胞肺癌、小细胞肺癌、胃癌、结直肠癌、头颈部肿瘤、黑色素瘤、卵巢癌或宫颈癌，更优选为肝细胞癌和非小细胞肺癌。
  19. 预防或治疗与ACC相关的疾病或状况的方法，包括向有此需要的对象施用根据权利要求1至11中任一项所述的化合物或根据权利要求16所述的药物组合物。
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