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WO2018228369A1 - Dérivé hétéroarylpyrimidinone, son procédé de préparation, et son utilisation médicale - Google Patents

Dérivé hétéroarylpyrimidinone, son procédé de préparation, et son utilisation médicale 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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Prior art keywords
group
aryl
cycloalkyl
heteroaryl
compound
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English (en)
Chinese (zh)
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
Publication of WO2018228369A1 publication Critical patent/WO2018228369A1/fr
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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

La présente invention concerne un dérivé d'hétéroarylpyrimidinone représenté par la formule (I), son procédé de préparation et son utilisation en tant qu'agent thérapeutique, en particulier une utilisation en tant qu'inhibiteur de l'acétyl-CoA carboxylase (ACC), les définitions des substituants dans la formule (I) étant les mêmes que celles données dans la description.
PCT/CN2018/090804 2017-06-15 2018-06-12 Dérivé hétéroarylpyrimidinone, son procédé de préparation, et son utilisation médicale Ceased WO2018228369A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020015343A1 (fr) * 2017-07-17 2020-01-23 Nanjing Ruijie Pharmatech Co., Ltd. Nouveaux composés et leurs utilisations en tant qu'inhibiteurs de l'acc
US10759812B2 (en) 2017-01-22 2020-09-01 Sunshine Lake Pharma Co., Ltd. Thienopyrimidine derivative and use thereof in medicine
US11186587B2 (en) * 2017-07-26 2021-11-30 Nanjing Sanhome Pharmaceutical Co., Ltd. Compound as ACC inhibitor and use thereof
WO2022166761A1 (fr) * 2021-02-07 2022-08-11 正大天晴药业集团股份有限公司 Dérivé de thiénopyrimidine
US11993613B2 (en) 2022-03-31 2024-05-28 Abbvie Inc. Thiazolo[5,4-b]pyridine MALT-1 inhibitors
US12428432B2 (en) 2019-07-02 2025-09-30 Sunshine Lake Pharma Co., Ltd. Thienopyrimidine derivatives having stereo configurations and use thereof in medicine

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111808077B (zh) * 2019-04-12 2023-05-02 浙江海正药业股份有限公司 哌嗪酰胺衍生物，其制备方法及其在医药上的用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104105485A (zh) * 2011-11-11 2014-10-15 尼普斯阿波罗有限公司 Acc抑制剂和其用途
WO2017075056A1 (fr) * 2015-10-26 2017-05-04 Gilead Apollo, Llc Inhibiteurs de l'acc et utilisations associées
WO2017091600A1 (fr) * 2015-11-25 2017-06-01 Gilead Apollo, Llc Inhibiteurs de l'acc à base de pyrazole et utilisations associées

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2592404T3 (es) * 2012-05-21 2016-11-30 Bayer Pharma Aktiengesellschaft Benzotienopirimidinas sustituidas
KR101879422B1 (ko) * 2013-09-18 2018-07-17 베이징 한미 파마슈티컬 컴퍼니 리미티드 Btk 및/또는 jak3 키나제의 활성을 억제하는 화합물

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104105485A (zh) * 2011-11-11 2014-10-15 尼普斯阿波罗有限公司 Acc抑制剂和其用途
WO2017075056A1 (fr) * 2015-10-26 2017-05-04 Gilead Apollo, Llc Inhibiteurs de l'acc et utilisations associées
WO2017091600A1 (fr) * 2015-11-25 2017-06-01 Gilead Apollo, Llc Inhibiteurs de l'acc à base de pyrazole et utilisations associées

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10759812B2 (en) 2017-01-22 2020-09-01 Sunshine Lake Pharma Co., Ltd. Thienopyrimidine derivative and use thereof in medicine
WO2020015343A1 (fr) * 2017-07-17 2020-01-23 Nanjing Ruijie Pharmatech Co., Ltd. Nouveaux composés et leurs utilisations en tant qu'inhibiteurs de l'acc
US11186587B2 (en) * 2017-07-26 2021-11-30 Nanjing Sanhome Pharmaceutical Co., Ltd. Compound as ACC inhibitor and use thereof
US12428432B2 (en) 2019-07-02 2025-09-30 Sunshine Lake Pharma Co., Ltd. Thienopyrimidine derivatives having stereo configurations and use thereof in medicine
WO2022166761A1 (fr) * 2021-02-07 2022-08-11 正大天晴药业集团股份有限公司 Dérivé de thiénopyrimidine
US11993613B2 (en) 2022-03-31 2024-05-28 Abbvie Inc. Thiazolo[5,4-b]pyridine MALT-1 inhibitors

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