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WO2022078403A1 - Composé de pyridone substitué et application - Google Patents

Composé de pyridone substitué et application Download PDF

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Publication number
WO2022078403A1
WO2022078403A1 PCT/CN2021/123577 CN2021123577W WO2022078403A1 WO 2022078403 A1 WO2022078403 A1 WO 2022078403A1 CN 2021123577 W CN2021123577 W CN 2021123577W WO 2022078403 A1 WO2022078403 A1 WO 2022078403A1
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WIPO (PCT)
Prior art keywords
compound
alkyl
pharmaceutically acceptable
acceptable salt
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/CN2021/123577
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English (en)
Chinese (zh)
Inventor
李桢
唐锋
刘乐
赵春艳
陈平
唐任宏
任晋生
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Simcere Pharmaceutical Co Ltd
Original Assignee
Jiangsu Simcere Pharmaceutical Co Ltd
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Priority to CN202180070837.1A priority Critical patent/CN116782903A/zh
Publication of WO2022078403A1 publication Critical patent/WO2022078403A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention requires that it was submitted to the State Intellectual Property Office of China on October 15, 2020, the patent application number is 202011105645.3, and the name of the invention is "Substituted pyridone compounds and applications", submitted to the State Intellectual Property Office of China on February 10, 2021, The patent application number is 202110182410.2, the name of the invention is “Substituted pyridone compounds and their applications” and submitted to the State Intellectual Property Office of China on April 2, 2021, the patent application number is 202110361446.7, and the invention name is "Substituted pyridone compounds and their applications” ” of the priority of the earlier application.
  • the entire contents of the aforementioned prior application are incorporated herein by reference.
  • the invention belongs to the field of medicine, and relates to a novel pyridone compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing them and the use as a MAT2A inhibitor.
  • Methionine adenosyltransferase also known as S-adenosylmethionine synthase, is able to catalyze the reaction of methionine (Met) with ATP to generate S-adenosylmethionine S-Adenosyl-L-methionine (SAM) class of enzymes.
  • SAM is the main methyl donor in the body, which can regulate gene expression, transcription and translation through transmethylation reaction, and then have an important impact on cell growth, death and differentiation. Not only that, SAM is also involved in the biosynthesis of polyamines and glutathione.
  • MAT1A mainly exists in normal hepatocytes, while MAT2A is widely distributed in extrahepatic cells. The two isoforms differ in catalytic efficiency and regulation.
  • MAT2B does not have the ability to catalyze the synthesis of SAM, but as a regulatory subunit of MAT2A, after forming a complex with MAT2A, it regulates the catalytic activity of MAT2A.
  • MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis.
  • Marjon K, et al. Cell Reports. 2016, 15(3), 574–587) found MTAP-deficient cancer cell lines Sensitive to MAT2A inhibition.
  • MTAP also known as methylthioadenosine phosphorylase
  • MTAP is widely expressed in normal tissue cells.
  • the enzyme catalyzes the conversion of methylthioadenosine (MTA) to 5-methylthioribose-1-phosphate and adenine. This process is also an important part of the methionine compensation pathway in the human body.
  • MTA methylthioadenosine
  • MTAP is depleted, the metabolic pathway of MTA is inhibited, which in turn leads to a large accumulation of MTA in the body, and finally makes cancer cells more sensitive to MAT2A inhibition.
  • the gene encoding human MTAP is located in the chromosome 9p21 region (chr9p21), and its frequency of homozygous deletion in all tumors is about 15%, and the deletion frequency varies in different tumors.
  • Tumors with higher deletion frequencies include glioma, mesothelioma, melanoma, gastric cancer, esophageal cancer, bladder cancer, pancreatic cancer, non-small cell lung cancer, astrocytoma, osteosarcoma, head and neck cancer, and mucinous chondrosarcoma , ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, etc.
  • the 9p21 region of human chromosome contains not only the gene encoding MTAP, but also the tumor suppressor genes p16INK4A (also known as CDKN2A) and p15INK4B.
  • MTAP is also absent in 80%-90% of CDKN2A-deficient tumors.
  • MAT2A Given that the expression level of MAT2A is abnormally elevated in many types of tumors, including gastric cancer, colon cancer, liver cancer, and pancreatic cancer, and selective inhibition of MAT2A can reduce the proliferation activity of MTAP-deficient cancer cells. Therefore, selective inhibition of MAT2A can be used as an effective tumor therapy.
  • WO2018039972, WO2018045071 and WO2019191470 disclose MAT2A inhibitor heterocyclic compounds for the treatment of tumors.
  • the present invention provides a compound represented by general formula (A) or a pharmaceutically acceptable salt thereof:
  • ring Q is a 5-6-membered heterocyclic group, a C 6 -C 10 -membered aryl group or a 5-10-membered heteroaryl group, and the 5-6-membered heterocyclic group, a C 6 -C 10 -membered aryl group or a 5-10
  • a membered heteroaryl group is optionally substituted with R a selected from F, Cl, Br, I, OH, CN, C 2 -C 3 alkynyl, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl or C 1 -C 10 alkoxy, said C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl or C 1 -C 10 alkoxy optionally substituted by R b ;
  • R b is selected from F, Cl, Br, I, OH or CN;
  • R c1 is selected from deuterium, F, Cl, Br, I, CN, OH, NH 2 or the following groups optionally substituted by R c2 : C 1 -C 3 alkyl, C 1 -C 3 alkoxy, NHC (O)O(C 1 -C 6 alkyl), (C 1 -C 6 alkyl) NHC(O)O, NH(C 1 -C 3 alkyl), S(O) 2 (C 1 -C 3 alkyl), 4-10 membered heterocyclyl, 4-10 membered heterocyclyloxy, (C 3 -C 10 cycloalkyl) CH 2 O, 5-6 membered heteroaryl, 5-6 membered heterocyclyl Aryloxy;
  • X is selected from O, S or NR 2 ;
  • L is selected from O, NH or a chemical bond
  • R 1 and R 2 are independently selected from H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl or 4-10 membered heterocyclic group, the C 1 -C 10 alkyl, C 3 -C
  • the 10 -cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with Rd selected from F, Cl, Br, I, OH, CN or C1 - C3 alkyl.
  • Ring Q is 5-6 membered heterocyclyl, C6 - C10 aryl, or 5-10 membered heteroaryl, said 5-6 membered heterocyclyl, C6 - C10 aryl or 5-10 membered heteroaryl optionally substituted with R a selected from F, Cl, Br, I, OH, CN or the following groups optionally substituted with R : C 1 -C 10 alkanes base, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy;
  • R b is selected from F, Cl, Br, I, OH or CN;
  • R c1 is selected from deuterium, F, Cl, Br, I, CN, OH, NH 2 or the following groups optionally substituted by R c2 : C 1 -C 3 alkyl, C 1 -C 3 alkoxy, NHC (O)O(C 1 -C 6 alkyl), (C 1 -C 6 alkyl) NHC(O)O, NH(C 1 -C 3 alkyl), S(O) 2 (C 1 -C 3 alkyl), 4-10 membered heterocyclyl, 4-10 membered heterocyclyloxy, (C 3 -C 10 cycloalkyl) CH 2 O, 5-6 membered heteroaryl, 5-6 membered heterocyclyl Aryloxy;
  • X is selected from O, S or NR 2 ;
  • L is selected from O or NH
  • R 1 , R 2 are independently selected from H, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl, said C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl optionally being replaced by R d is substituted, and said R d is selected from F, Cl, Br, I, OH, CN or C1 - C3 alkyl.
  • Ring Q is 5-6 membered heterocyclyl, C6 - C10 aryl, or 5-10 membered heteroaryl, said 5-6 membered heterocyclyl, C6 - C10 aryl or 5-10 membered heteroaryl optionally substituted with R a selected from F, Cl, Br, I, OH, CN or the following groups optionally substituted with R : C 1 -C 10 alkanes base, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy;
  • R b is selected from F, Cl, Br, I, OH or CN;
  • Ring W is phenyl, pyridyl, pyridone or 9-10-membered heteroaryl, said phenyl, pyridyl, pyridone or 9-10-membered heteroaryl is optionally substituted by R c , said R c is selected from OH or the following groups optionally substituted by R c1 : C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, P(O)(C 1 - C 3 alkyl) 2 , 4-6 membered heterocycloalkyl;
  • R c1 is selected from F, Cl, Br, I, CN, OH, NH 2 or the following groups optionally substituted by R c2 : C 1 -C 3 alkyl, C 1 -C 3 alkoxy, NHC(O )O(C 1 -C 6 alkyl), (C 1 -C 6 alkyl) NHC(O)O, NH(C 1 -C 3 alkyl), S(O) 2 (C 1 -C 3 alkane) base), 4-10 membered heterocyclyl, 4-10 membered heterocyclyloxy, (C 3 -C 10 cycloalkyl) CH 2 O, 5-6 membered heteroaryl, 5-6 membered heteroaryl Oxygen;
  • X is selected from O, S or NR 2 ;
  • L is selected from O or NH
  • R 1 , R 2 are independently selected from H, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl, said C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl optionally being replaced by R d is substituted, and said R d is selected from F, Cl, Br, I, OH, CN or C1 - C3 alkyl.
  • Ring Q is a 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, optionally the 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl replaced by Ra .
  • Ring Q is phenyl or 5-6 membered heteroaryl optionally substituted with Ra .
  • Ring Q is piperidinyl, phenyl, or pyridyl, optionally substituted with Ra .
  • Ring Q is phenyl or pyridyl optionally substituted with Ra .
  • Ring Q is phenyl optionally substituted with Ra .
  • Ra is F, Cl, Br, I, CN, C2 - C3alkynyl , C1 - C6alkyl , C3 - C6cycloalkyl , or optionally substituted with F C 1 -C 6 alkoxy.
  • R a is F, Cl, Br, I, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkoxy optionally substituted with F.
  • Ra is F, Cl, Br, I, CN, methyl, cyclopropyl, ethynyl, prop-1-ynyl, or methoxy optionally substituted with F.
  • Ra is F, Cl, Br, I, methyl, cyclopropyl, or methoxy optionally substituted with F.
  • Ra is methoxy optionally substituted with F.
  • Ra is F, Cl, Br, I, CN, methyl, cyclopropyl, ethynyl, prop-1-ynyl, difluoromethoxy, trifluoromethoxy, or methoxy base.
  • Ra is difluoromethoxy
  • ring Q is selected from
  • ring Q is selected from
  • ring Q is selected from
  • Ring W is phenyl, pyridyl, pyrimidinyl, pyridazinyl, 2-pyridinyl, wherein ring M is a 5-10-membered heteroaryl group or a 5-10-membered heterocyclic group, the phenyl, pyridyl, pyrimidinyl, pyridazinyl, 2-pyridone, or Ring M is optionally substituted with Rc .
  • Ring W is phenyl, pyridyl, 2-pyridone, wherein ring M is a 5-6-membered heteroaryl group or a 5-10-membered heterocyclic group, and the phenyl, 2-pyridone, pyridyl, or Ring M is optionally substituted with Rc .
  • Ring W is phenyl, pyridinyl, 2-pyridonyl, or 9-10 membered heteroaryl, said phenyl, 2-pyridonyl, pyridyl, or 9-10 membered heteroaryl Optionally substituted with Rc .
  • Ring W is the following groups optionally substituted with R: Phenyl, 9-10 membered heteroaryl.
  • Ring M is a 5-6 membered heteroaryl, 9-10 membered heteroaryl, or 5-9 membered heterocyclyl, which is optionally substituted with Rc .
  • Ring M is a 5-6 membered heteroaryl or 6-8 membered heterocyclyl, which is optionally substituted with Rc .
  • Ring W is wherein Ring M is 5-6 membered heteroaryl, 9-10 membered heteroaryl or 5-9 membered heterocyclyl, and said Ring M is optionally substituted with Rc .
  • Ring W is wherein ring M is a 5-6 membered heteroaryl group or a 6-8 membered heterocyclyl group, and the ring M is optionally substituted with Rc .
  • Ring W is wherein Ring M is a 5-6 membered heteroaryl, optionally substituted with R c .
  • Ring W is the following optionally substituted with R: phenyl,
  • Ring W is the following optionally substituted with R: phenyl,
  • Ring W is the following optionally substituted with R: phenyl,
  • Ring W is the following optionally substituted with R: phenyl,
  • R c is selected from the following groups optionally substituted with R c1 : C 1 -C 6 alkyl, C 1 -C 6 alkoxy.
  • R c is selected from the following groups optionally substituted with R c1 : methyl, methoxy,
  • R c is selected from methyl optionally substituted with R c1 or methoxy optionally substituted with R c1 .
  • R c1 is selected from deuterium atoms, F, Cl, Br, I, CN, OH, NH 2 or ethoxy.
  • R c1 is selected from deuterium atoms, F, Cl, Br, I, CN, OH.
  • R c1 is selected from F, Cl, Br, I, CN, OH.
  • R c is selected from CH 2 OH, methyl, methoxy, CHF 2 or
  • R c is selected from methyl optionally substituted with OH or methoxy optionally substituted with OH.
  • Ring W is selected from
  • Ring W is selected from
  • Ring W is selected from
  • Ring W is selected from
  • Ring W is selected from
  • X is selected from O, S or NH.
  • X is selected from S or O.
  • X is selected from S.
  • R 1 is selected from H, 4-6 membered heterocyclyl, C 3 -C 6 cycloalkyl optionally substituted with C 1 -C 3 alkyl, or C 1 -C optionally substituted with F C 6 alkyl.
  • R 1 is selected from H, C 3 -C 6 cycloalkyl optionally substituted with C 1 -C 3 alkyl, or C 1 -C 6 alkyl optionally substituted with F.
  • R 1 is selected from 4-6 membered heterocyclyl or C 1 -C 6 alkyl optionally substituted with F.
  • R 1 is selected from 4-membered heterocyclyl or C 1 -C 3 alkyl optionally substituted with F.
  • R 1 is selected from C 1 -C 6 alkyl.
  • R 1 is selected from methyl, ethyl, n-propyl, or trifluoromethyl.
  • R 1 is selected from ethyl.
  • L is selected from O or a bond.
  • L is selected from O.
  • the compound represented by the general formula (A) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (B) or a pharmaceutically acceptable salt thereof:
  • rings W, R a , R 1 are as defined above, and n is selected from 0, 1, 2, 3, 4 or 5.
  • the compound represented by the general formula (A) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (C) or a pharmaceutically acceptable salt thereof:
  • Rings W, R a , R 1 are as defined above.
  • the compound of general formula (A) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (D) or a pharmaceutically acceptable salt thereof:
  • Ring W is as defined above.
  • the compound or pharmaceutically acceptable salt of the general formula (A) is selected from the following compounds or pharmaceutically acceptable salts:
  • the compound or pharmaceutically acceptable salt of the general formula (A) is selected from the following compounds or pharmaceutically acceptable salts:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by the general formula (A) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the present invention relates to the use of a compound represented by general formula (A) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating tumors.
  • the present invention relates to the use of a compound represented by general formula (A) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating tumors with reduced or absent MTAP activity.
  • the present invention relates to the use of a compound represented by the general formula (A) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating tumors.
  • the present invention relates to the use of the compound represented by the general formula (A) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of tumors with reduced or absent MTAP activity.
  • the present invention relates to a compound of general formula (A) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating tumors.
  • the present invention relates to a compound of general formula (A) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating tumors with reduced or absent MTAP activity.
  • the present invention also relates to a method of treating tumors comprising administering to a patient a therapeutically effective dose of a pharmaceutical formulation comprising a compound of general formula (A) or a pharmaceutically acceptable salt thereof described in the present invention.
  • the present invention also relates to a method for treating tumors with reduced or absent MTAP activity, the method comprising administering to a patient a therapeutically effective dose of a compound comprising the general formula (A) of the present invention or a pharmaceutically acceptable salt thereof. pharmaceutical preparations.
  • the tumors or tumors with reduced or absent MTAP activity include but are not limited to glioma, mesothelioma, melanoma, gastric cancer, esophageal cancer, bladder cancer, pancreatic cancer, non-small cell lung cancer, Astrocytoma, osteosarcoma, head and neck cancer, mucinous chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, etc.
  • pharmaceutically acceptable salts refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
  • a schematic representation of racemate or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120.
  • Use wedge and virtual wedge keys unless otherwise specified Indicate the absolute configuration of a stereocenter, using black solid and virtual bonds Indicates the relative configuration of a stereocenter (eg, cis-trans configuration of alicyclic compounds).
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include E, Z geometric isomers unless otherwise specified.
  • all tautomeric forms are included within the scope of the present invention.
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form predominates; in phenols, the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • stereoisomer refers to isomers resulting from different arrangements of atoms in a molecule in space, and includes cis-trans isomers, enantiomers, diastereomers and conformers.
  • the compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • Particular geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S) )-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as enantiomers or diastereomers Enriched mixtures, all of the above isomers and mixtures thereof are within the definition of the compounds of the present application.
  • asymmetric carbon atoms there may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups, and these isomers and their mixtures involved in all substituent groups are also included in the Within the definition of the compounds of the present application.
  • Compounds of the present application containing asymmetric atoms can be isolated in optically pure form or in racemic form, optically pure forms can be resolved from racemic mixtures, or synthesized by using chiral starting materials or chiral reagents .
  • composition means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, so long as the valence of the specified atom is normal and the compound after substitution is stable.
  • an ethyl group “optionally” substituted with halogen means that the ethyl group can be unsubstituted ( CH2CH3 ) , monosubstituted ( eg, CH2CH2F , CH2CH2Cl , etc. ) , polysubstituted (eg CHFCH2F , CH2CHF2 , CHFCH2Cl , CH2CHCl2 , etc.
  • any variable eg, Ra , Rb
  • its definition in each case is independent. For example, if a group is substituted with 2 R bs , each R b has independent options.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
  • one of the variables is selected from a chemical bond or does not exist, it means that the two groups to which it is connected are directly connected, for example, when L in A-L-Z represents a bond, it means that the structure is actually A-Z.
  • substituents When a substituent's bond is cross-linked to two atoms on a ring, the substituent can bond to any atom on the ring.
  • structural unit Indicates that R 5 can be substituted at any position on the benzene ring.
  • Cm - Cn herein means having an integer number of carbon atoms in the range mn.
  • C 1 -C 10 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n+1 .
  • the alkyl group can be straight or branched.
  • C1 - C10 alkyl is understood to mean a straight or branched chain saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the alkyl group includes, but is not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl , 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methyl pentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl base, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; "C 1 -C 6 alkane "Radical” should be understood to mean a linear
  • C 1 -C 10 alkyl group described herein may include “C 1 -C 6 alkyl group” or “C 1 -C 3 alkyl group”, and the “C 1 -C 6 alkyl group” may further include “C 1 -C 6 alkyl group” 1 - C3 alkyl”.
  • alkoxy can be understood as “alkyloxy” or “alkyl-O-", which refers to a monovalent group generated by the loss of a hydrogen atom on the hydroxyl group of linear or branched alcohols, such as the term “ C 1 -C 10 alkoxy” can be understood as “C 1 -C 10 alkyloxy” or “C 1 -C 10 alkyl-O-", the term “C 1 -C 6 alkoxy” can be understood is “C 1 -C 6 alkyloxy” or “C 1 -C 6 alkyl-O-", preferably, "C 1 -C 10 alkoxy” may contain "C 1 -C 6 alkoxy”" and "C 1 -C 3 alkoxy” and other ranges.
  • halogenated C1 - C3 alkyl includes monohalogenated C1 - C3 alkyl or polyhalogenated C1 - C3 alkyl, examples including, but not limited to, trifluoromethyl, 2,2,2 - trichloroethyl or 3-fluoropropyl.
  • alkynyl refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one triple bond.
  • C 2 -C 10 alkynyl is understood to mean a straight-chain or branched unsaturated hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • Examples of "C 2 -C 10 alkynyl” include, but are not limited to, ethynyl (-C ⁇ CH), propynyl (-C ⁇ CCH 3, -CH 2 C ⁇ CH), but-1-ynyl, butanyl -2-alkynyl or but-3-ynyl.
  • C 2 -C 10 alkynyl may include “C 2 -C 3 alkynyl", examples of “C 2 -C 3 alkynyl” include ethynyl (-C ⁇ CH), prop-1-ynyl (-C ⁇ CCH3 ), prop- 2 -ynyl (-CH2C ⁇ CH).
  • C 3 -C 10 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as decalin.
  • C3 - C6cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms.
  • cycloalkoxy is to be understood as “cycloalkyloxy” or “cycloalkyl-O-”.
  • heterocyclyl refers to a fully saturated or partially saturated (non-aromatic heteroaromatic as a whole) monocyclic, paracyclic, spirocyclic or bridged ring group containing 1-5 ring atoms
  • 4-10 membered heterocyclyl refers to a heterocyclyl with 4, 5, 6, 7, 8, 9 or 10 ring atoms, and its ring atoms contain 1-5 independently selected from the above-mentioned heteroatoms or heteroatoms.
  • 4--10-membered heterocyclic group includes “4-7-membered heterocyclic group", wherein specific examples of 4-membered heterocyclic group include but are not limited to azetidinyl or oxetanyl; 5-membered heterocyclic group Specific examples of heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl, or 2,5-dihydrooxazolyl.
  • 6-membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl , trithianyl, tetrahydropyridyl, or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclyl include, but are not limited to, diazepanyl.
  • the heterocyclic group may also be a bicyclic group, wherein specific examples of the 5,5-membered bicyclic group include but are not limited to hexahydrocyclopento[c]pyrrol-2(1H)-yl; Specific examples include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4 ,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl.
  • the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7 membered heterocyclic group, and specific examples include, but are not limited to, dihydroisoquinolinyl and the like.
  • "4-10 membered heterocyclyl” may include “5-10 membered heterocyclyl", “5-9 membered heterocyclyl", “4-6 membered heterocyclyl”, “5-6 membered heterocyclyl” “Cyclyl”, “6-9 membered heterocyclyl”, “6-8 membered heterocyclyl”, “5-10 membered heterocycloalkyl", “5-9 membered heterocycloalkyl", “4-6 membered heterocyclyl” membered heterocycloalkyl”, “5-6 membered heterocycloalkyl", “6-8 membered heterocycloalkyl” and the like.
  • some bicyclic heterocyclic groups partially contain a benzene ring or
  • heterocyclyloxy is to be understood as “heterocyclyl-O-”.
  • 4-6 membered heterocycloalkyl means a heterocycloalkyl group having 4, 5 or 6 ring atoms and containing 1-3 heteroatoms or heteroatomic groups independently selected from the above-mentioned ring atoms.
  • 4-membered heterocycloalkyl include but are not limited to azetidinyl, oxetanyl, thibutanyl
  • 5-membered heterocycloalkyl include but are not limited to tetrahydrofuranyl, tetrahydrothienyl , pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolidinyl
  • 6-membered heterocycloalkyl include but are not limited to piperidinyl , tetrahydropyranyl, tetra
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • C 6 -C 10 aryl is to be understood as preferably denoting an aromatic or partially aromatic fully carbon monocyclic or bicyclic radical having 6 to 10 carbon atoms, especially a ring having 6 carbon atoms ("C6-C10 aryl").
  • C 6 aryl such as phenyl; or a ring with 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or a ring with 10 carbon atoms (“C 10 aryl”) ”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, S, and an aromatic ring group in which the remaining ring atoms are C.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, S, and an aromatic ring group in which the remaining ring atoms are C.
  • 5-10 membered heteroaryl is understood to include monovalent monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms and it contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S. And, additionally in each case may be benzo-fused.
  • heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl Diazolyl and the like and their benzo derivatives such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinoline oxazolinyl, isoquinolinyl, etc; Naph
  • 5-6 membered heteroaryl refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1-3, preferably 1-2, heteroatoms independently selected from N, O and S.
  • 9-10 membered heteroaryl refers to an aromatic ring system having 9 or 10 ring atoms, and which contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S.
  • heteroaryloxy is to be understood as “heteroaryl-O-”.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • excipient examples include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flowability and/or stickiness.
  • typical "pharmaceutically acceptable carriers” suitable for the above-mentioned preparations are: carbohydrates, starches, cellulose and their derivatives and other commonly used adjuvants in pharmaceutical preparations.
  • treating means administering a compound or formulation described herein to prevent, ameliorate, or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying
  • the amount of a compound of the present invention that constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to its own knowledge and the present disclosure.
  • pharmaceutically acceptable excipients refers to those excipients which are not significantly irritating to the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the present application also includes isotopically-labeled compounds of the present application which are the same as those described herein, but wherein one or more atoms have been replaced by an atom having an atomic weight or mass number different from that normally found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 13 , respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and the like.
  • isotopically-labeled compounds of the present application are useful in compound and/or substrate tissue distribution assays. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron emitting isotopes such as15O , 13N , 11C and18F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present application can generally be prepared by the following procedures analogous to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets or icing core.
  • Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • the doses administered per day are 0.01 to 100 mg/kg body weight, preferably 0.05 to 50 mg/kg body weight, more preferably 0.1 to 30 mg/kg body weight, in single or divided doses form.
  • the ratio indicated by the mixed solvent is the volume mixing ratio.
  • % refers to weight percent wt %.
  • the eluent or mobile phase can be a mixed eluent or mobile phase composed of two or more solvents, and its ratio is the volume ratio of each solvent, such as "0-10% methanol/dichloromethane" means mixed eluent Or the volume ratio of methanol to dichloromethane in the mobile phase is 0:100 to 10:100.
  • the structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The units of NMR shifts are 10-6 (ppm).
  • the solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
  • TMS tetramethylsilane
  • IC50 refers to the half inhibitory concentration, the concentration at which half of the maximal inhibitory effect is achieved.
  • DCM refers to dichloromethane
  • PE refers to petroleum ether
  • EA refers to ethyl acetate.
  • Step 1 Synthesis of N-((5-bromo-6-methoxypyridin-2-yl)carbamoyl)benzamide (Intermediate 1-2)
  • the starting material 1-1 (1 g, 4.93 mmol) was dissolved in tetrahydrofuran (15 mL), benzoyl isothiocyanate (763.59 mg, 4.68 mmol) was added at 0 °C, and the reaction was stirred at 0 °C for 1 hour, and then at 0 °C. The reaction was stirred at 25°C for 16 hours. LCMS detected that the reaction of the raw materials was complete, and concentrated under reduced pressure to remove the solvent to obtain the title compound (1.8 g), which was directly used in the next step.
  • Step 2 Synthesis of 1-(5-bromo-6-methoxypyridin-2-yl)thiourea (Intermediate 1-3)
  • Step 3 Synthesis of 6-bromo-5-methoxythiazolo[4,5-b]pyridin-2-amine (Intermediate 1-4)
  • Step 8 4-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazole- Synthesis of 6-yl)thiazolo[4,5-b]pyridin-5(4H)-one (Compound 1)
  • Step 1 4-[4-(Difluoromethoxy)phenyl]-2-ethoxy-6-(4-methoxyphenyl)thiazolo[4,5-b]pyridine-5(4H )-ketone (compound 2) synthesis
  • the title compound (2.6 mg) was obtained.
  • the title compound (3.2 mg) was obtained.
  • reaction solution was filtered, concentrated to dryness under reduced pressure, and purified by preparative high performance liquid chromatography (column: Gemini NX C18 5 ⁇ m*10*150mm; mobile phase: A: water (0.225% ammonium bicarbonate v/v), B: acetonitrile; B%: 30%-50%, 11 min) to obtain the title compound (10.0 mg).
  • reaction solution was filtered, concentrated to dryness under reduced pressure, and purified by preparative high performance liquid chromatography (column: Gemini NX C18 5 ⁇ m*10*150mm; mobile phase: A: water (0.225% trifluoroacetic acid v/v), B: acetonitrile; B%: 30%-50%, 11 min) to obtain the title compound (23.0 mg).
  • Step 1 4-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboro Synthesis of Pentacyclo-2-yl)thiazolo[4,5-b]pyridin-5(4H)-one (Intermediate 6-1)
  • Step 2 4-(4-(Difluoromethoxy)phenyl)-6-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl)-2 - Synthesis of Ethoxythiazolo[4,5-b]pyridin-5(4H)-one (Compound 6)
  • reaction solution was filtered, concentrated to dryness under reduced pressure, and purified by high pressure preparative [YMC-Actus Triart C18 column 5 ⁇ m silica, 30 mm diameter, 150 mm length; a mixture of water (containing 0.05% NH 4 HCO 3 ) and acetonitrile of decreasing polarity As eluent; acetonitrile gradient ratio 55%-80%, elution time 12 minutes] to obtain the title compound (15mg).
  • Step 1 4-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl ) Synthesis of thiazolo[4,5-b]pyridin-5-(4H)-one (compound)
  • Step 1 Synthesis of 6-bromo-1-(methyl- d3 )-1H-benzo[d]imidazole (Intermediate 8-2)
  • the reactant 8-1 (5.0 g, 25.38 mmol) was dissolved in tetrahydrofuran solution (50 mL), sodium hydride (60%) (1.12 g, 27.91 mmol) was added at 0-5 °C, and the reaction solution was stirred at 5 °C for 0.5 h , CD 3 I (4.41 g, 30.45 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 12 h.
  • Step 2 4-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-(methyl- d3 )-1H-benzo[d]imidazol-6-yl ) Synthesis of Thiazolo[4,5-b]pyridin-5(4H)-one (Compound 8)
  • Step 1 N-(6-(4-(4-(difluoromethoxy)phenyl)-2-ethoxy-5-oxo-4,5-dihydrothiazolo[4,5-b] ]pyridin-6-yl)-1-methyl-1H-benzo[d]imidazol-2-yl)acetamide (compound 9)
  • reaction solution was filtered, concentrated to dryness under reduced pressure, purified by preparative high performance liquid chromatography on YMC-Actus Triart C18 column 5 ⁇ m silica, 30mm diameter, 150mm length; water (containing 0.05% NH 4 HCO 3 ) and acetonitrile with decreasing polarity
  • the mixture was used as the eluent; the acetonitrile gradient ratio was 30%-50%, the elution time was 12 minutes) to obtain the title compound (11 mg).
  • reaction solution was filtered, concentrated to dryness under reduced pressure, and purified by preparative high performance liquid chromatography [YMC-Actus Triart C18 column 5 ⁇ m silica, 30 mm diameter, 150 mm length; water (containing 0.05% NH 4 HCO) 3 ) and acetonitrile with decreasing polarity mixture as eluent; acetonitrile gradient ratio 55%-80%, elution time 14 minutes] to obtain the title compound (12 mg).
  • DCE dichloroethane
  • Step 2 4-(6-Cyclopropylpyridin-3-yl)-2-ethoxy-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiazole Synthesis of [4,5-b]pyridin-5(4H)-one (Compound 13)
  • intermediate 13-2 (40.0 mg) was dissolved in dioxane solution (0.4 mL), and intermediate 3-1 (28.8 mg), potassium phosphate (43.3 mg) were added to the reaction solution, Water (0.08 mL) and Pd(dtbpf)Cl 2 (6.7 mg) were added and the temperature was raised to 100 °C and stirred for 2 h.
  • reaction solution was filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by high pressure preparation [YMC-Actus Triart C18 column 5 ⁇ m silica, 30 mm diameter, 150 mm length; water (containing 0.05% NH 4 HCO 3 ) and acetonitrile The mixture of decreasing polarity was used as the eluent; the acetonitrile gradient ratio was 55%-80%, the elution time was 13 minutes] to obtain the title compound (2 mg).
  • Step 1 Synthesis of 6-bromo-2-(2,2-difluoroethoxy)thiazolo[4,5-b]pyridin-5(4H)-one (Intermediate 14-2)
  • reaction solution was poured into saturated aqueous ammonium chloride solution (5 mL), extracted with ethyl acetate (5 mL*3), the organic phases were combined, washed with saturated brine (10 mL), and the organic phase was dried over anhydrous sodium sulfate, Concentration to dryness under reduced pressure gave the title compound (110 mg).
  • Step 2 6-Bromo-2-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)thiazolo[4,5-b]pyridine-5(4H )-ketone (intermediate 14-4) synthesis
  • intermediate 14-4 (90 mg) was dissolved in dioxane solution (1 mL), intermediate 3-1 (56 mg), cesium carbonate (129 mg), water (0.2 mL) and Pd ( dtbpf)Cl 2 (13 mg), the temperature was raised to 100° C. and stirred for 2 hours after the addition was completed.
  • Step 1 (4-(4-(Difluoromethoxy)phenyl)-2-ethoxy-5-oxo-4,5-dihydrothiazolo[4,5-b]pyridine-6- Synthesis of boronic acid (intermediate 15-1)
  • Step 2 4-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(6-methoxypyridazin-3-yl)thiazolo[4,5-b]pyridine Synthesis of -5(4H)-one (Compound 15)
  • reaction solution was added with mercapto silica gel (50mg), stirred for 30min, filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Phenomenex Luna C18 100*30mm*5 ⁇ m; mobile phase: [water (0.05 % CF3COOH , v/v)-acetonitrile]; B%: 43%-63%, 9 min) to give the title compound (10 mg).
  • Step 2 4-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-benzo Synthesis of [d]imidazol-6-yl)thiazolo[4,5-b]pyridin-5(4H)-one (compound 17)
  • Step 3 Synthesis of 6-bromo-2-(oxetan-3-yloxy)thiazolo[4,5-b]pyridin-5(4H)-one (Intermediate 19-3)
  • Step 5 4-(4-(Difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-(oxetane-3 Synthesis of -yloxy)thiazolo[4,5-b]pyridin-5(4H)-one (Compound 19)
  • Step 1 1-(Methyl- d3 )-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo Synthesis of [d]imidazole (intermediate 23-1)
  • intermediate 8-2 (1.0 g) was dissolved in dioxane solution (10 mL), potassium acetate (917 mg), bispinacol borate (1.42 g) and Pd (dppf) were added )Cl2 (342 mg ).
  • Step 3 6-Bromo-4-(4-(difluoromethoxy)phenyl)-2-(trifluoromethyl)thiazolo[4,5-b]pyridin-5(4H)-one (intermediate Synthesis of body 23-4)
  • intermediate 23-3 (400 mg) was dissolved in DMF (5 mL), cuprous iodide (202 mg) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (204 mg) were added ).
  • Step 4 4-(4-(Difluoromethoxy)phenyl)-6-(1-(methyl- d3 )-1H-benzo[d]imidazol-6-yl)-2-(tris Synthesis of Fluoromethyl)thiazolo[4,5-b]pyridin-5(4H)-one (Compound 23)
  • intermediate 23-4 (120.0 mg) was dissolved in dioxane solution (2 mL), intermediate 23-1 (71 mg), cesium carbonate (177 mg), water (0.2 mL) and Pd were added (dtbpf)Cl2 ( 18 mg). After the addition was completed, the temperature was raised to 100 °C and stirred for 2 h.
  • Step 2 4-(4-(Difluoromethoxy)phenyl)-2-methoxy-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl) Synthesis of Thiazolo[4,5-b]pyridin-5(4H)-one (Compound 24)
  • Step 1 Synthesis of 6-bromo-2-ethoxy-4-(4-fluorophenyl)thiazolo[4,5-b]pyridin-5(4H)-one (Intermediate 25-2)
  • Step 1 Synthesis of 6-bromo-4-(3-chlorophenyl)-2-ethoxythiazolo[4,5-b]pyridin-5(4H)-one (Intermediate 26-2)
  • Step 2 4-(3-Chlorophenyl)-2-ethoxy-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiazolo[4,5 Synthesis of -b]pyridin-5(4H)-one (compound 26)
  • Step 1 Synthesis of 1-(3-hydroxypropyl)-3-(4-iodophenyl)thiourea (Intermediate 27-3)
  • Step 2 Synthesis of N-(4-iodophenyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (Intermediate 27-4)
  • Step 3 Synthesis of 7-iodo-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]oxazine (Intermediate 27-6)
  • Step 4 4-(4-(Difluoromethoxy)phenyl)-6-(3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1, 3] Synthesis of oxazin-7-yl)-2-ethoxythiazolo[4,5-b]pyridin-5(4H)-one (Compound 27)
  • Step 1 Synthesis of 2-((6-Bromo-1H-benzo[d]imidazol-2-yl)amino)ethan-1-ol (Intermediate 28-2)
  • Step 3 4-(4-(Difluoromethoxy)phenyl)-6-(2,3-dihydro-1H-benzo[d]imidazo[1,2-a]imidazol-6-yl )-2-ethoxythiazolo[4,5-b]pyridin-5(4H)-one (Compound 28)
  • Step 1 Synthesis of 1-(5-Bromo-2-nitrophenyl)pyrrolidine-2,5-dione (Intermediate 29-1)
  • Step 3 Synthesis of 7-bromo-2,3-dihydro-1H-benzo[d]pyrro[1,2-a]imidazol-1-one (Intermediate 29-3)
  • Step 5 4-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-oxo-2,3-dihydro-1H-benzo[d]pyrrole[1 Synthesis of ,2-a]imidazol-7-yl)thiazolo[4,5-b]pyridin-5(4H)-one (Compound 29)
  • intermediate 29-4 (40 mg) and intermediate 29-3 (10 mg) were added to anhydrous dioxane (6 mL), and tetrakis(triphenylphosphine) palladium (9.2 mL) was added to the reaction solution. mg). Subsequently, the reaction solution was stirred at 120° C. for 16 hours under nitrogen protection. After the reaction, the reactant was filtered and concentrated under reduced pressure to remove the solvent.
  • Step 2 4-(4-(Difluoromethoxy)phenyl)-6-(1-(methyl- d3 )-1H-benzo[d]imidazol-6-yl)-2-propoxy Synthesis of Thiazolo[4,5-b]pyridin-5(4H)-one (Compound 30)
  • intermediate 6-1 (100 mg) was dissolved in dioxane solution (1 mL), intermediate 31-1 (55 mg), cesium carbonate (140 mg), water (0.2 mL) and Pd ( dtbpf)Cl2 ( 14 mg). The reaction solution was heated to 100 °C and stirred for 2 h.
  • Step 2 4-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(ethoxymethyl)-1-methyl-1H-benzo[d] Synthesis of Imidazol-6-yl)thiazolo[4,5-b]pyridin-5(4H)-one (Compound 32)
  • intermediate 32-2 75 mg was dissolved in dioxane (1 mL), intermediate 6-1 (129 mg), cesium carbonate (182 mg), water (0.2 mL) and Pd (dtbpf) were added Cl2 ( 18 mg). The reaction solution was heated to 100 °C and stirred for 2 h.
  • intermediate 6-1 (100 mg) was dissolved in dioxane solution (1 mL), intermediate 33-2 (52 mg), cesium carbonate (140 mg), water (0.2 mL) and Pd ( dtbpf)Cl 2 (14 mg),.
  • the reaction solution was heated to 100 °C and stirred for 2 h.
  • Step 1 Synthesis of 6-bromo-2-ethoxy-4-(4-iodophenyl)thiazolo[4,5-b]pyridin-5(4H)-one (Intermediate 34-2)
  • Step 3 4-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(3-methyl-4-oxo-3,4-dihydroquinazoline-6- Synthesis of yl)thiazolo[4,5-b]pyridin-5(4H)-one (Compound 37)
  • Step 3 4-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(4-methyl-3-oxo-3,4-dihydroquinoxaline-6- Synthesis of yl)thiazolo[4,5-b]pyridin-5(4H)-one (Compound 39)
  • Step 1 Synthesis of 6-bromo-2-ethoxy-5-oxothiazolo[4,5-b]pyridine-4(5H)-carboxylate tert-butyl ester (Intermediate 40-1)
  • Step 5 4-(4-(Difluoromethoxy)-3-fluorophenyl)-2-ethoxy-6-(1-methyl-6-oxo-1,6-dihydropyridine- Synthesis of 3-yl)thiazolo[4,5-b]pyridin-5(4H)-one (Compound 40)
  • Step 4 4-(6-(Difluoromethoxy)pyridin-3-yl)-2-ethoxy-6-(1-methyl-6-oxo-1,6-dihydropyridine-3 Synthesis of -yl)thiazolo[4,5-b]pyridin-5(4H)-one (Compound 41)
  • Step 2 4-(4-(Difluoromethoxy)-3-methylphenyl)-2-ethoxy-6-(1-methyl-6-oxo-1,6-dihydropyridine Synthesis of -3-yl)thiazolo[4,5-b]pyridin-5-(4H)-one (Compound 42)
  • L-methionine and ATP can be converted into SAM, inorganic phosphate and inorganic diphosphate under the catalysis conditions of MAT2A enzyme.
  • a chromogenic reagent such as ammonium molybdate, etc.
  • MAT2A screening kit was purchased from BPS bioscience (USA); 384-well plate was purchased from Corning (USA).
  • MAT2a protein Korean Chemical (Beijing) New Drug Technology Co., Ltd.);
  • MAT2a protein was diluted with assay buffer (final concentration 4 ⁇ g/mL). Add 40 ⁇ L of 2X MAT2a solution to a 384-well plate, centrifuge at 1000 rpm for 1 minute, and re-incubate for 120 minutes.
  • PiColorLock TM reaction catalyst with PiColorLock TM buffer at 1:100 according to the instructions, add 20 ⁇ L to each well, and shake for 30 seconds. Add 8 ⁇ L of stabilization reagent and shake for 30 seconds. Signal values were detected after incubation at room temperature for 30 minutes.
  • the inhibitory effect of the test compound on MAT2A can be expressed by the IC50 value of the inhibition of the phosphate production level during the enzymatic reaction.
  • the MAT2A inhibitory activities of the compounds of the present invention are shown in Table 1.
  • Test example 2 Detection of intracellular SAM levels
  • SAM as the catalytic product of MAT2A, can reflect the inhibitory effect of the test compound on MAT2A by measuring the level of SAM generated in cells. After co-incubating the test MAT2A inhibitor with the cancer cells for a period of time, the cells were lysed with a stop reagent to quench the MAT2A enzymatic activity. Quantitative determination of MAT2A catalytic product SAM in cell lysate was performed by LC-MS/MS method to reflect the activity of MAT2A in cells.
  • HCT116 MTAP -/- cells were purchased from Kangyuan Borchuang; fetal bovine serum, McCoy's 5a medium and penicillin-streptomycin were purchased from Gibco (USA), 96-well plates were purchased from Corning (USA), PBS was purchased from Cytiva (USA).
  • HCT116 MTAP -/- cells were cultured in McCoy's 5a medium containing 10% fetal bovine serum + 1% penicillin-streptomycin at 37°C, 5% CO 2 . Cells in logarithmic growth phase can be used for experiments.
  • LC-MS/MS detection LC-MS/MS was used to detect the effect of compounds on SAM production level in HCT116 MTAP -/- cell line. The cell concentration was adjusted to 50,000 cells per well, seeded in a 96-well plate, and cultured overnight at 37°C and 5% CO 2 . Compounds were solubilized in DMSO, diluted in DMSO followed by medium and transferred to cell plates to a final concentration of 10 ⁇ M in 3-fold dilutions. Incubate for 6 hours at 37°C and 5% CO 2 . The supernatant was aspirated, and after washing with PBS, glacial acetic acid was added to lyse the cells. After the lysate was processed, the SAM concentration was determined by LC-MS/MS injection analysis.
  • Test example 3 Human colon cancer HCT116 cell proliferation inhibition test
  • the cell proliferation counting method based on ATP content was used to measure the effect of the test compound on cell proliferation.
  • HCT116 WT cells and HCT116 MTAP -/- cells were purchased from Kangyuan Borchuang; fetal bovine serum, McCoy's5a medium and penicillin-streptomycin were purchased from Gibco (USA), and 96-well plates were purchased from Corning Company (USA), Cell-Titer Glo reagent was purchased from Promega (USA).
  • HCT116 WT cells and HCT116 MTAP -/- cells were cultured in McCoy's 5a medium containing 10% fetal bovine serum + 1% penicillin-streptomycin at 37°C and 5% CO 2 . Cells in logarithmic growth phase can be used for experiments.
  • Cell-Titer Glo reagent was used to detect the inhibitory activity of compounds on the proliferation of HCT116 WT and HCT116 MTAP -/- cell lines. The cell concentration was adjusted to 400 cells per well, seeded in a 96-well plate, and cultured overnight at 37°C and 5% CO 2 .
  • HCT116 MTAP -/- cells are cells that do not express MTAP protein obtained by targeted knockout of wild-type HCT116 (HCT116 WT) cells by gene knockout. Inhibition of MAT2A and loss of MTAP can produce synthetic lethal effects, resulting in tumor cell death. The activity and selectivity of MAT2A inhibitors can be assessed by testing the antiproliferative activity of MAT2A inhibitors on HCT116 MTAP -/- cells and HCT116 WT.
  • the compounds to be tested exhibited strong proliferation inhibitory activity on HCT116 MTAP -/- cells, and showed better selectivity compared with HCT116 MTAP +/+ cells.
  • the specific anti-cell proliferation activities of the compounds to be tested are shown in Table 3.
  • Test Example 4 Measurement of metabolic stability of the compounds of the present invention in liver microsomes
  • the metabolic stability of the compounds of the present invention in liver microsomes was determined by the following test method.
  • KH 2 PO 4 (Tianjin Guangfu Institute of Fine Chemicals 20180920)
  • PBS Phosphate Buffered Saline
  • Test Example 5 Determination of membrane permeability and transport properties of the compounds of the present invention
  • membrane permeability and transport properties of the compounds of the present invention were determined using the following test methods.
  • FBS Fetal Bovine Serum
  • Lucifer Yellow Sigma MKCJ3738
  • NaHCO 3 Sigma SLBZ4647
  • HBSS Hank's Balanced Salt Solution
  • NEAA Non-Essential Amino Acids
  • Trpsin/EDTA Trypsin/EDTA
  • TEER value TEER measurement value ( ⁇ ) ⁇ film area (cm 2 )
  • the resistance of the monolayer cell membrane is less than 230 ⁇ cm 2 , indicating that the monolayer cell membrane has poor compactness and cannot be used for the test.
  • I acceptor refers to the fluorescence density on the receiving side (0.3 mL), and I donor refers to the fluorescence density on the dosing side (0.1 mL).
  • LY > 1.0% indicates poor monolayer membrane compaction and corresponding results will be excluded from the evaluation.
  • V A is the volume of the receiving end solution (A ⁇ B is 0.3 mL, B ⁇ A is 0.1 mL), Area is the membrane area of the Transwell-96-well plate (0.143 cm 2 ); incubation time is the incubation time (unit: s).
  • P app(BA) is the apparent permeability coefficient from the basal end to the apical end
  • P app(AB) is the apparent permeability coefficient from the apical end to the basal end.
  • Caco-2 is a human cloned colon adenocarcinoma cell, similar in structure and function to differentiated small intestinal epithelial cells, and can be used to perform experiments that mimic intestinal transit in vivo.
  • the results in Table 5 show that the compound of the present invention has good membrane permeability, indicating that the compound of the present invention has a strong ability to be absorbed orally.
  • Test Example 6 Inhibitory effect of the compounds of the present invention on the enzymatic activities of CYP2C9, CYP2D6 and CYP3A4
  • the inhibition of CYP2C9, CYP2D6 and CYP3A4 enzymatic activities by the compounds of the present invention was determined by the following test method.
  • PBS Phosphate Buffered Saline
  • Substrate working solutions 120 ⁇ M diclofenac, 400 ⁇ M dextromethorphan, and 200 ⁇ M midazolam
  • Substrate working solutions 120 ⁇ M diclofenac, 400 ⁇ M dextromethorphan, and 200 ⁇ M midazolam
  • Drug-drug interaction refers to the physical or chemical changes produced by two or more drugs, as well as the changes in drug efficacy caused by these changes. Understanding drug interactions can provide better pharmaceutical services for patients, promote rational drug use, and maximize the avoidance of adverse reactions. Drug interactions are mainly metabolic interactions, which are mainly related to CYP450 enzymes involved in drug metabolism. The experimental results in Table 6 show that the compounds of the present invention have weak inhibitory ability to CYP450, indicating that the compounds of the present invention have less potential risk of DDI.

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Abstract

La présente invention concerne un composé représenté dans la formule générale (A) ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique, un procédé de préparation du composé, ainsi qu'une utilisation du composé en tant qu'inhibiteur de MAT2A.
PCT/CN2021/123577 2020-10-15 2021-10-13 Composé de pyridone substitué et application Ceased WO2022078403A1 (fr)

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WO2024012507A1 (fr) * 2022-07-13 2024-01-18 上海海和药物研究开发股份有限公司 Inhibiteur de mat2a de type bicyclique et son utilisation
US11999713B2 (en) 2021-10-20 2024-06-04 Insilico Medicine Ip Limited Methionine adenosyltransferase 2a (MAT2A) inhibitors and uses thereof
WO2025011621A1 (fr) * 2023-07-12 2025-01-16 南京再明医药有限公司 Combinaison d'un composé inhibiteur de polq et d'un agent thérapeutique anticancéreux ou d'une radiothérapie
WO2025061035A1 (fr) * 2023-09-19 2025-03-27 南京再明医药有限公司 Composé d'agent de dégradation sélective de brm et son utilisation

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CN104350059A (zh) * 2012-03-27 2015-02-11 拜耳知识产权有限责任公司 具有除草和杀虫活性的噻唑并吡啶酮
CN107108654A (zh) * 2014-12-22 2017-08-29 先正达参股股份有限公司 作为除草剂的噻唑并吡啶酮
WO2018045071A1 (fr) * 2016-08-31 2018-03-08 Agios Pharmaceuticals, Inc. Inhibiteurs de processus métaboliques cellulaires
WO2018039972A1 (fr) * 2016-08-31 2018-03-08 Agios Pharmaceuticals, Inc. Inhibiteurs de processus métaboliques cellulaires

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WO2011051212A1 (fr) * 2009-10-28 2011-05-05 Basf Se Utilisation de composés hétéroaromatiques en tant qu'herbicides
CN104350059A (zh) * 2012-03-27 2015-02-11 拜耳知识产权有限责任公司 具有除草和杀虫活性的噻唑并吡啶酮
CN107108654A (zh) * 2014-12-22 2017-08-29 先正达参股股份有限公司 作为除草剂的噻唑并吡啶酮
WO2018045071A1 (fr) * 2016-08-31 2018-03-08 Agios Pharmaceuticals, Inc. Inhibiteurs de processus métaboliques cellulaires
WO2018039972A1 (fr) * 2016-08-31 2018-03-08 Agios Pharmaceuticals, Inc. Inhibiteurs de processus métaboliques cellulaires

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11999713B2 (en) 2021-10-20 2024-06-04 Insilico Medicine Ip Limited Methionine adenosyltransferase 2a (MAT2A) inhibitors and uses thereof
WO2024012507A1 (fr) * 2022-07-13 2024-01-18 上海海和药物研究开发股份有限公司 Inhibiteur de mat2a de type bicyclique et son utilisation
WO2025011621A1 (fr) * 2023-07-12 2025-01-16 南京再明医药有限公司 Combinaison d'un composé inhibiteur de polq et d'un agent thérapeutique anticancéreux ou d'une radiothérapie
WO2025061035A1 (fr) * 2023-09-19 2025-03-27 南京再明医药有限公司 Composé d'agent de dégradation sélective de brm et son utilisation

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