WO2023036289A1 - 具有enpp1抑制活性的异羟基肟酸类化合物及其用途 - Google Patents

具有enpp1抑制活性的异羟基肟酸类化合物及其用途 Download PDF

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WO2023036289A1
WO2023036289A1 PCT/CN2022/118080 CN2022118080W WO2023036289A1 WO 2023036289 A1 WO2023036289 A1 WO 2023036289A1 CN 2022118080 W CN2022118080 W CN 2022118080W WO 2023036289 A1 WO2023036289 A1 WO 2023036289A1
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ring
alkyl
halogen
cycloalkyl
hydrogen
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PCT/CN2022/118080
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French (fr)
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高善云
李晶晶
张朝波
许艳晓
屠汪洋
于冰
张毅翔
李乐平
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上海海和药物研究开发股份有限公司
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Priority to CN202280057292.5A priority Critical patent/CN117980293A/zh
Publication of WO2023036289A1 publication Critical patent/WO2023036289A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • A61P31/12—Antivirals
    • 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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/93—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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 disclosure relates to a hydroxamic acid compound, its use for inhibiting ENPP1 and a method of using the compound for preventing or treating diseases.
  • STING Stimulator of Interferon Gene
  • cGAMP cyclic GMP-AMP synthase
  • IRF3 interferon regulatory factor 3
  • Ectonucleotide pyrophosphatase/phosphodi-esterase 1 (ENPP1), one of the seven enzymes in the ENPP family, is a type II transmembrane glycoprotein. Studies have shown that ENPP1 has high hydrolysis and can decompose a variety of substrates including phosphodiester bonds and pyrophosphate bonds. ATP is also one of the main targets of ENPP1. ENPP1 not only hydrolyzes ATP into AMP and PPi, but also hydrolyzes cGAMP, inhibits the amount of cGAMP in the human body, and reduces the activity of STING. Therefore, the activity of ENPP1 inhibits the anti-tumor and anti-infectious disease immune responses of the human immune system through STING.
  • ENPP1 Inhibiting the activity of ENPP1 contributes to the stability of cGAMP and the increase of the activity of STING, thereby improving the immune system’s ability to fight against tumors and infectious diseases. Resistance to infectious diseases.
  • ENPP1 has been confirmed to have a more prominent expression in human breast tumors than usual, which not only indicates that ENPP1 is a potential predictive marker for breast cancer, but also highlights its possibility and reliability as an anticancer drug target.
  • ENPP1 In addition to the outstanding performance of ENPP1 in tumors, studies have shown that the expression of ENPP1 is related to a variety of infectious diseases caused by bacteria or viruses. Therefore, ENPP1 can also be used in the treatment of infectious diseases.
  • the present disclosure provides compounds of formula (I), pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof.
  • the inventors have surprisingly found that said compounds of formula (I) are good ENPP1 inhibitors.
  • the inventors have also surprisingly found that the disclosed compounds have good physical and chemical stability, good bioavailability (eg low clearance) and good druggability.
  • the present disclosure further provides a method of treating, preventing or ameliorating an ENPP1-mediated disease or disorder, comprising administering an effective amount of an ENPP1 inhibitor to an individual in need thereof.
  • hydroxamic acid compounds as shown in formula (I):
  • each variable X, X 1 , X 2 , X 3 , X 4 , X 5 and rings A, Y, L are as defined herein, including their stereoisomers, geometric isomers, tautomers, Pharmaceutically acceptable salts, polymorphs, solvates, hydrates or prodrugs; which are useful in the treatment or prevention of ENPP1 mediated diseases or disorders, especially cancer or infectious diseases or disorders.
  • the present disclosure also provides methods of preparing the compounds of the present disclosure, intermediates used in the preparation of the compounds of the present disclosure, and methods of preparing the intermediates.
  • compositions comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a combination, especially a pharmaceutical combination, comprising a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents.
  • the disclosed compounds can be used alone, in combination with other disclosed compounds or in combination with one or more, preferably one or two other substances simultaneously or sequentially.
  • the compounds of the present disclosure are ENPP1 inhibitors that can modulate STING activity in vivo and are therefore useful in the treatment or prevention of ENPP1 mediated diseases or disorders, especially cancer or infectious diseases or disorders.
  • the present disclosure can provide selective extracellular inhibition of ENPP1 activity to increase extracellular levels of cGAMP and activate the stimulating factor of interferon genes (STING) pathway. Examples include the use of compounds of the disclosure for enhancing a STING-mediated response in a subject, as well as methods of using the compounds of the disclosure for modulating an immune response in a subject.
  • the disclosed compounds are useful in therapy.
  • the disclosed compounds are useful for the preparation of medicaments or medicaments for the treatment or prevention of ENPP1 mediated diseases or disorders, especially cancer or infectious diseases or disorders.
  • the present disclosure also relates to a method of inhibiting ENPP1 receptor activity in an individual, wherein the method comprises administering to the individual in need thereof a therapeutically effective amount of an ENPP1 inhibitor such as a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating or preventing an ENPP1-mediated disease or disorder comprising administering to a patient in need thereof an effective amount of a first therapeutic agent and optionally a second therapeutic agent Therapeutic agents, wherein the first therapeutic agent is a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent is one or more other therapeutic agents.
  • the present disclosure relates to a method of treating or preventing a disease or disorder mediated by ENPP1, such as a method of cancer or an infectious disease or disorder, comprising administering to an individual a therapeutically effective amount of the disclosed compound compound or a pharmaceutically acceptable salt thereof.
  • a preferred method of the present disclosure is the treatment of specific types of cancer including: breast cancer, lung cancer, glioblastoma, brain and spine cancer, head and neck cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer, esophageal cancer , nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, malignant mesothelioma, sarcoma, lymphoma, adenocarcinoma, Thyroid cancer, cardiac tumors, germ cell tumors, malignant neuroendocrine tumors, malignant rhabdoid tumors, soft tissue sarcomas, midline bundle carcinomas, and carcinomas of unknown primary.
  • specific types of cancer including: breast cancer, lung cancer, glioblastoma, brain and spine cancer, head and neck cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer, e
  • ENPP1-mediated infectious diseases including: herpes simplex virus infection, vaccinia virus infection, adenovirus infection, human papillomavirus infection, hepatitis B virus infection, hepatitis D virus infection , human immunodeficiency virus infection, human cytomegalovirus infection, dengue virus infection, Ebola virus infection, Marburg virus infection, Zika virus infection, Listeria monocytogenes infection, Mycobacterium tuberculosis infection, new Francisella murderer infection, Legionella pneumophila infection, Chlamydia trachomatis infection, Streptococcus pneumoniae infection, Neisseria gonorrhoeae infection.
  • the present disclosure provides a product or kit comprising a compound of the present disclosure as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and one or more other active agents simultaneously, separately or Combination preparations used sequentially.
  • the present disclosure provides the following embodiments:
  • the disclosure provides compounds of formula (I):
  • X is N or CR 0 ;
  • X 1 is N, O, S, CR 1 or a bond
  • X 2 is N, O, S, NR 2 or CR 2 ;
  • X 3 is N, O, S, NR 3 or CR 3 ;
  • X 4 is N, O, S, NR 4 or CR 4 ;
  • X 5 is N or CR 5 ;
  • L is a bond, NR a , -NR x -CHR y - or (CR 9 R 10 ) m ; m is 1 or 2;
  • R 0 and R 5 are each independently selected from: hydrogen, halogen, CN, OH, NO 2 , NR b R c , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -SO 2 R a , -C(O)OR a , -C(O)NR b R c and C 1 -C 6 alkoxy; wherein the alkyl, cycloalkyl and alkoxy are each optionally substituted by halogen;
  • R 1 and R 2 are each independently selected from: hydrogen, halogen, CN, OH, NO 2 , NR b R c , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl and C 1 -C 4 alkane Oxy; wherein each of said alkyl, cycloalkyl and alkoxy is optionally substituted by halogen;
  • R 6 is selected from hydrogen, C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl; wherein each of said alkyl and cycloalkyl is optionally substituted by halogen;
  • R 7 and R 8 are each independently selected from: hydrogen, halogen, OH, CN, NO 2 , NR a , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 1 -C 6 alkoxy ; wherein the alkyl, cycloalkyl and alkoxy groups are each optionally substituted by halogen; or R 7 and R 8 together with the carbon atom to which they are bonded form a C 3 -C 6 ring optionally substituted by halogen Alkyl, or form a 4- to 12-membered heterocycloalkyl group comprising 1-2 heteroatoms selected from N, NRa , O and S(O) p ;
  • R 9 and R 10 are each independently selected from hydrogen, halogen, CN, OH, NO 2 , NR a R b , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl , C 2 -C 8 alkynyl, C 1 -C 8 alkoxy, 4- to 12-membered containing carbon atoms and 1-2 heteroatoms selected from N, NR a , O and S(O) p Heterocycloalkyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl and heterocycloalkyl are each represented by 0-3 substituents independently selected from halogen, hydroxyl, CN are substituted; wherein the aryl and heteroaryl are each independently selected from 0-3 halogen, C 1 -C 4 alkyl, C 3
  • R 9 and R 10 together with the carbon atom to which they are bonded form a C 3 -C 6 cycloalkyl optionally substituted by halogen, or form a C 3 -C 6 cycloalkyl group comprising 1-2 selected from N, NR a , O and S(O ) 4- to 12-membered heterocycloalkyl of the heteroatom of p ;
  • Ring A is selected from: C 4 -C 10 cycloalkyl, 4- to 12-membered heterocycloalkyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; wherein, Ring A is optionally are independently selected from halogen, CN, OH, NO 2 , NR b R c , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, 4- to 7 One or more substituents of -membered heterocycloalkyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl and C 1 -C 3 haloalkyl;
  • L together with ring A forms a C 4 -C 8 cycloalkyl, a 5- to 10-membered partially saturated heterocyclic ring containing at least one heteroatom selected from N, O or S, a 6- to 10-membered aryl group or 5- to 7-membered heteroaryl; wherein said cycloalkyl, heterocycle, aryl and heteroaryl are optionally independently selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkane Oxygen substituents are substituted one or more times; or
  • Y and ring A together form a 5- to 10-membered partially saturated heterocycle, a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, wherein the heterocycle, aryl and heteroaryl are any optionally substituted one or more times by substituents independently selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy;
  • R a , R b , R c are each independently selected from: hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl and benzyl; wherein each of the alkyl and cycloalkyl is optionally Halogen substitution; or R b and R c together with the nitrogen atom to which they are bonded form a 3- to 6-membered heterocycloalkyl optionally substituted by halogen;
  • R x and R y are each independently selected from hydrogen and C 1 -C 4 alkyl; or R x and R y form a 4- to 8-membered heterocycloalkyl together with the carbon and nitrogen atoms to which they are bonded; and
  • p 1 or 2;
  • X 1 is N, O, S or CR 1 ; preferably, X 1 is N or CR 1 .
  • Xi is N.
  • X 1 is CR 1 .
  • X 1 is a bond or CR 1 .
  • X is a bond
  • X 1 is CR 1
  • X 1 is CR 1
  • X 2 is CR 2
  • X 3 is CR 3
  • X 4 is CR 4
  • R n means R 1 for X 1 , R 2 for X 2 , R 3 for X 3 , and R 4 for X 4 .
  • R 0 and R 5 are each independently selected from: hydrogen, halogen, CN, OH, NO 2 , NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkane and C 1 -C 6 alkoxy, wherein each of the alkyl, cycloalkyl, and alkoxy is optionally substituted by 0-3 halogens.
  • R 0 and R 5 are each independently selected from hydrogen, halogen, CN, OH, NO 2 , NH 2 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkane Oxy, wherein the alkyl, cycloalkyl, and alkoxy are each optionally substituted by 0-3 halogens. More preferably, R 0 and R 5 are each independently selected from hydrogen, halogen, CN, OH, NO 2 , NH 2 , C 1 -C 3 alkyl.
  • R 1 is selected from the group consisting of hydrogen, halogen, CN, OH, NO 2 , NH 2 , C 1 -C 4 alkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkyl; preferably selected from: hydrogen, halogen, CN, OH, NH 2 , C 1 -C 3 alkyl; more preferably, R 1 is selected from: hydrogen, halogen, CN, OH.
  • R 2 is selected from the group consisting of hydrogen, halogen, CN, OH, NO 2 , NH 2 , C 1 -C 4 alkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkyl; preferably selected from: hydrogen, halogen, OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy, each of said alkyl, cycloalkyl and alkoxy optionally replaced by 0 -3 halogen substitutions. More preferably, R 2 is selected from hydrogen, halogen, C 1 -C 3 alkyl and C 1 -C 3 alkoxy.
  • R 4 is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl and C 1 -C 3 haloalkyl.
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, CN, OH, NO 2 , NH 2 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkyl; preferably, selected from hydrogen, halogen, CN, OH, NO 2 , NH 2 , C 1 -C 3 alkyl , C 3 -C 4 cycloalkyl, C 1 -C 3 alkoxy and C 1 -C 2 haloalkyl; more preferably, selected from H, F, Cl, CN, OH, NO 2 , NH 2 , methane radical, ethyl, propyl, isopropyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 2,2-di
  • R 1 is hydrogen or halogen
  • R 2 is selected from hydrogen, halogen, OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy
  • R 4 is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl and C 1 -C 4 haloalkyl
  • R 5 is selected from hydrogen, halogen, CN and C 1 -C 6 alkyl.
  • R 1 is hydrogen or halogen
  • R 2 is selected from hydrogen, halogen, OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy
  • R 4 is selected from hydrogen, halogen, C 1 -C 3 alkyl and C 1 -C 3 alkoxy.
  • R 0 and R 5 are each independently selected from hydrogen, halogen, CN and C 1 -C 6 alkyl.
  • R 0 is selected from hydrogen, halogen, CN, OH, NO 2 , NH 2 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 1 -C 4 Alkoxy;
  • R 1 is hydrogen or halogen,
  • R 2 is selected from hydrogen, halogen, OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy,
  • R 3 is selected from hydrogen, halogen, OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy;
  • R 4 is selected from hydrogen, halogen, C 1 -C 3 alkyl and C 1 -C 3 alkoxy;
  • R 5 is selected from hydrogen, halogen, CN, C 1 -C 4 alkyl.
  • R 1 is hydrogen or halogen
  • R 2 is selected from hydrogen, halogen, C 1 -C 3 alkyl and C 1 -C 3 alkoxy
  • R 4 is selected from hydrogen, halogen and C 1 -C 3 alkyl.
  • R 5 is selected from hydrogen, halogen, CN and C 1 -C 6 alkyl;
  • R 1 is hydrogen or halogen
  • R 2 is selected from hydrogen, halogen, and C 1 -C 3 alkoxy
  • R 3 is selected from hydrogen, halogen, OH, and C 1 -C 3 alkane Oxygen
  • R 4 is selected from hydrogen and halogen.
  • R 5 is selected from hydrogen, halogen, CN and C 1 -C 6 alkyl.
  • R 1 is hydrogen or halogen
  • R 2 is selected from hydrogen, halogen, OH and C 1 -C 3 alkoxy
  • R 3 is selected from hydrogen, halogen, OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy
  • R 4 is selected from hydrogen, halogen and C 1 -C 3 alkoxy
  • R 5 is selected from hydrogen, halogen, CN and C 1 -C 6 alkyl . More preferably, R 3 is selected from hydrogen, halogen, OH and C 1 -C 3 alkoxy.
  • R 2 is selected from hydrogen, halogen, C 1 -C 3 alkyl and C 1 -C 3 alkoxy;
  • R 3 is selected from hydrogen, OH and halogen;
  • R 4 is selected from hydrogen , halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 4 cycloalkyl and C 1 -C 3 haloalkyl; preferably, R 5 is selected from hydrogen, halogen, CN and C 1 -C 6 alkyl.
  • X is N or X is N.
  • X5 is N.
  • X is N.
  • Y is O, NR 6 or CR 7 R 8 .
  • R 7 and R 8 are each independently selected from hydrogen, C 1 -C 3 alkyl.
  • Y is NR 6
  • R 6 is selected from hydrogen, C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl.
  • R 6 is selected from hydrogen and C 1 -C 3 alkyl.
  • Y and ring A form a 5- to 10-membered partially saturated heterocycle, a 6- to 10-membered aryl, or a 5- to 10-membered heteroaryl, wherein the hetero Ring, aryl and heteroaryl are optionally substituted one or more times by substituents independently selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy; such as
  • Y is NR 6 , R 6 is a C 1 -C 4 alkyl group, and R 6 forms a 5- to 10-membered partially saturated heterocycle, a 6- to 10-membered aromatic ring together with the nitrogen atom to which it is bonded and ring A radical or 5- to 10-membered heteroaryl; or
  • Y is CR 7 R 8 , and R 7 or R 8 forms a 5- to 10-membered partially saturated heterocyclic ring, a 6- to 10-membered aryl group or a 5- to 10-membered carbon atom together with ring A to which it is bonded. -membered heteroaryl.
  • Y is taken with ring A to form a 7- to 10-membered partially saturated bicyclic heterocycle, naphthyl, or a 7- to 10-membered bicyclic heteroaryl.
  • Y together with ring A forms dihydrobenzofuryl, dihydroisobenzofuryl, dihydroindolyl, dihydrobenzothienyl, dihydrobenzothiazolyl, dihydrobenzopyranyl base, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydropyrido[3,4-b]pyrazinyl. More preferably, Y together with ring A forms an indolinyl.
  • Y is CR 7 R 8 , wherein R 7 and R 8 are each independently selected from: hydrogen, halogen, OH, CN, NO 2 , NH 2 , C 1 -C 6 alkyl , C 3 -C 6 cycloalkyl and C 1 -C 6 alkoxy, preferably selected from hydrogen and C 1 -C 6 alkyl; wherein the alkyl, cycloalkyl and alkoxy are each optionally is substituted with 0-3 halogens.
  • Y is CR 7 R 8 , wherein R 7 and R 8 together with the carbon atoms to which they are bonded form a C 3 -C 6 cycloalkane optionally substituted with 0-3 halogens group, or form a 5- to 6-membered heterocycloalkyl group comprising 1-2 heteroatoms selected from N, NR a , O and S(O) p ; R a is selected from hydrogen, C 1 -C 3 alkane base, p is 1 or 2.
  • R 6 is selected from hydrogen, C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl;
  • R 7 and R 8 are each independently selected from hydrogen, C 1 -C 3 alkyl. More preferably, R 6 is selected from hydrogen, C 1 -C 3 alkyl, R 7 and R 8 are each independently selected from hydrogen, C 1 -C 3 alkyl;
  • Y is O, NR 6 or CR 7 R 8 ; preferably, Y is O, NH, N(C 1- C 3 alkyl), CH 2 , CH(C 1- C 3 alkyl), or C (C 1- C 3 alkyl) (C 1- C 3 alkyl). More preferably, Y is O, NH, -NCH 3 , CH 2 , or -CHCH 3 .
  • Y is O.
  • Y is NH
  • L is a bond, NR a , -NR x -CHR y -, CR 9 R 10 , or (CR 9 R 10 ) 2 . It is understood that in (CR 9 R 10 ) 2 the two -CR 9 R 10 - units may each be the same or different, eg in -CH 2 -CH(CH 3 ).
  • L is -NR x -CHR y -, wherein R x and R y are each independently selected from: hydrogen, C 1 -C 4 alkyl, or R x and R y are bonded to The carbon and nitrogen atoms together form a 4- to 8-membered heterocycloalkyl group.
  • R x and R y are each independently selected from: hydrogen, C 1 -C 4 alkyl, or R x and R y are bonded to The carbon and nitrogen atoms together form a 4- to 8-membered heterocycloalkyl group.
  • a 4- to 6-membered heterocycloalkyl is formed; such as formed together
  • Ra is selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and benzyl, wherein each of said alkyl and cycloalkyl is optionally replaced by halogen replace.
  • R a is selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl, C 3 -C 6 halocycloalkyl and benzyl. More preferably, R a is selected from hydrogen, C 1 -C 3 alkyl and benzyl.
  • each of R 9 and R 10 is independently selected from hydrogen, halogen, CN, OH, NH 2 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 - C 8 alkoxy, 4- to 12-membered heterocycloalkyl comprising carbon atoms and 1-2 heteroatoms selected from N, NR a , O and S(O) p , preferably selected from hydrogen, halogen, OH, NH 2 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, containing carbon atoms and 1-2 selected from N, NR a , O and S ( O) 4- to 8-membered heterocycloalkyl of the heteroatom of p .
  • R 9 and R 10 together with the carbon atoms to which they are bonded form a C 3 -C 6 cycloalkyl group substituted by 0-3 halogens or contain 1-2 selected from N, 4- to 12-membered heterocycloalkyl group of heteroatoms of NR a , O and S(O) p .
  • R 9 and R 10 together with the carbon atom to which they are bonded form a C 3 -C 6 cycloalkyl or a 4 comprising 1-2 heteroatoms selected from N, NR a , O and S(O) p - to 8-membered heterocycloalkyl.
  • L is a bond
  • L is a bond or (CR 9 R 10 ) m ; m is 1 or 2.
  • L is CR 9 R 10 or (CR 9 R 10 ) 2 ; more preferably, L is CR 9 R 10 .
  • L is NR a or (CR 9 R 10 ) m ; m is 1 or 2.
  • L is NR a or CR 9 R 10 ; more preferably, L is NH or CR 9 R 10 .
  • L is NR a ;
  • R a is selected from: hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl; wherein the alkyl and cycloalkyl are each replaced by 0 -3 halogen substitutions.
  • R a is selected from hydrogen, C 1 -C 3 alkyl.
  • L is (CR 9 R 10 ) m ; m is 1 or 2;
  • R 9 and R 10 are each independently selected from hydrogen, halogen, CN, OH, NO 2 , NH 2 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 alkoxy, 4- to 12-membered heterocycles containing carbon atoms and 1-2 heteroatoms selected from N, NR a , O and S(O) p Alkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl; wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl and heterocycloalkyl are each replaced by 0- 3 substituents independently selected from halogen, hydroxyl, CN; wherein, the aryl and heteroaryl are each 0-3 independently selected from halogen, C 1 -C 4 alkyl, C 3 -C Substituent substitution of
  • R 9 and R 10 together with the carbon atoms to which they are bonded form a C 3 -C 6 cycloalkyl group substituted by 0-3 halogens, or a C 3 -C 6 cycloalkyl group containing 1-2 selected from N, NR a , O and S (O) 4- to 12-membered heterocycloalkyl of the heteroatom of p .
  • L is NH or CR 9 R 10
  • R 6 , R 7 , R 8 are each independently selected from hydrogen, C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl; preferably, R 6 , R 7 , R 8 are each independently selected from hydrogen and C 1 -C 3 alkyl; more preferably, L is CR 9 R 10 , and R 6 , R 7 , and R 8 are each independently selected from hydrogen and C 1 -C 3 alkyl.
  • L is NR a or CR 9 R 10 ;
  • L is CR 9 R 10 ; wherein, R 9 and R 10 are each independently selected from hydrogen, halogen, CN, OH, NO 2 , NH 2 , C 1 -C 6 alkyl, C 3 -C 6 ring Alkyl and C 1 -C 6 alkoxy, 4- to 12-membered heterocycloalkyl containing carbon atoms and 1-2 heteroatoms selected from N, O and S, or R 9 and R 10
  • the bonded carbon atoms together form a C 3 -C 6 cycloalkyl group substituted by 0-3 halogens (such as cyclopropane, cyclobutane, cyclopentane or cyclohexane) or contain 1-2 halogens selected from N, 4- to 12-membered heterocycloalkyl groups of heteroatoms of NR a , O and S(O) p (such as oxetane, azetidine, thietane, tetra
  • R 9 and R 10 are each independently selected from hydrogen, halogen, CN, OH, C 1 -C 6 alkyl and C 1 -C 6 alkoxy, or R 9 and R 10 together with the carbon atom to which it is bonded forms a C 3 -C 6 cycloalkyl group (eg cyclopropane, cyclobutane, cyclopentane or cyclohexane);
  • Or L is selected from -CH 2 -, -CH(OH)-, -CHF-, -CH(CN)-, -CH(CH 3 )-, -CH(OCH 3 )-, -CH(OEt)-, -C(CH 3 ) 2 -, -CH(CH(CH 3 ) 2 )-, -CH(CH 2 CH(CH 3 ) 2 )-, -C(CH 2 CH(CH 3 ) 2 ) 2 -, -C(CH(CH 3 ) 2 ) 2 -, -C(CH 2 CH 3 ) 2 - and
  • L is selected from: -CH 2 -, -CH(OH)-, -CHF-, -CH(CH 3 )-, -CH(OCH 3 )-, -CH(OEt)-, -C(CH 3 ) 2 -, -CH(CH(CH 3 ) 2 )-, -CH(CH 2 CH(CH 3 ) 2 )-, -C(CH 2 CH(CH 3 ) 2 ) 2 -, -C(CH 2 CH 3 ) 2 -, -C(CH 2 CH 3 ) 2 -,
  • L is (CR 9 R 10 ) 2 .
  • L is -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH 2 CHF-, -CH 2 CH(OCH 3 )-.
  • ring A is selected from: C 4 -C 8 cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl and 5- to 10-membered heterocycloalkyl Aryl; preferably, ring A optionally can be independently selected from halogen, CN, OH, NO 2 , NR b R c , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, 4- to 7-membered heterocycloalkyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl and C 1 -C 3 haloalkyl are substituted once or Multiple times, such as once or twice; R b and R c are each independently selected from hydrogen, C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl, wherein the alkyl and cycloalkyl are each replaced by 0 -
  • ring A is optionally substituted by a substituent independently selected from halogen, CN, OH, NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy and C 1 -C 3 haloalkyl Once or more, such as once or twice. Still further, ring A is optionally substituted once or twice with substituents independently selected from halogen, CN, C 1 -C 4 alkyl and C 1 -C 4 alkoxy.
  • ring A optionally can be independently selected from F, Cl, CN, OH, NO 2 , NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6
  • the substituents of cycloalkyl and C 1 -C 3 haloalkyl are substituted one or more times, such as once or twice; further preferably, ring A can optionally be independently selected from F, Cl, CN, OH, NO 2.
  • the substituents of NH 2 , C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl and C 1 -C 3 alkoxy are substituted one or more times, for example once or twice.
  • ring A is optionally substituted or unsubstituted cyclopentane, cyclohexane, pyrrolidine, pyrazolidine, imidazolidine, thiazolidine, pyrrole ring, furan ring, thiophene ring , pyrazole ring, thiazole ring, oxazole ring, imidazole ring, tetrahydrofuran ring, tetrahydrothiophene ring, pyran ring, pyrazine ring, tetrahydropyran ring, piperidine ring, hexahydropyrimidine, dihydrofuran ring, Dihydrothiophene ring, dihydroimidazole ring, dihydropyrazole ring, dihydropyrrole ring, dihydroindole ring, dihydroisoindole ring, dihydropyran ring, dihydropyran ring, di
  • ring A is optionally substituted or unsubstituted cyclopentane, cyclohexane, pyrrolidine, imidazolidine, pyrazole ring, pyrrole ring, imidazole ring, furan ring, thiophene ring, pyran ring, tetrahydrofuran ring , tetrahydrothiophene ring, tetrahydropyran ring, piperidine ring, pyrazine ring, piperazine ring, benzene ring, pyridine ring, pyrimidine ring or naphthalene ring;
  • ring A is optionally substituted or unsubstituted cyclopentane, cyclohexane, pyrrolidine, piperidine ring, pyrimidine ring, benzene ring, pyridine ring, piperazine ring, imidazole ring, pyrazole ring or naphthalene ring;
  • ring A is cyclopentane , ring Hexane, pyrrolidine, piperidine ring, pyrimidine ring, benzene ring, pyridine ring, piperazine ring, imidazole ring, tetrahydropyrrole ring, pyrazole ring or naphthalene ring.
  • Ring A is optionally independently selected from halogen, CN, OH, NO 2 , NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 1 - C 3 haloalkyl substituents are substituted one or more times, such as once or twice; preferably, ring A is optionally independently selected from F, Cl, CN, OH, NO 2 , NH 2 , C 1 -C 3 The substituents of alkyl and C 1 -C 3 alkoxy are substituted one or more times, for example once or twice.
  • Ring A is selected from:
  • each of R 11 may be the same or different, independently selected from halogen, CN, OH, NO 2 , NH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkyl ; q is 0, 1, or 2.
  • R 11 is selected from F, Cl, CN, C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
  • R a is selected from hydrogen and C 1 -C 4 alkyl, q is 0, 1 or 2.
  • L and ring A together form a C 4 -C 8 cycloalkyl, a 5- to 10-membered partially saturated heterocyclic ring containing at least one heteroatom selected from N, O or S, 6- to 10-membered aryl or 5- to 7-membered heteroaryl; said cycloalkyl, heterocycle, aryl and heteroaryl are optionally independently selected from halogen, C 1 -C 4 alkane Substituents of radicals, C 1 -C 4 alkoxy groups are substituted one or more times.
  • said cycloalkyl, heterocycle, aryl and heteroaryl are optionally substituted once with substituents independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy or repeatedly.
  • L and ring A together form a 5- to 10-membered partially saturated heterocyclic ring, a 6- to 10-membered aryl group containing at least one heteroatom selected from N, O or S, or 5- to 7-membered heteroaryl, said heterocycle, aryl and heteroaryl are optionally substituents independently selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy Replace once or twice.
  • L and ring A together form an optionally substituted or unsubstituted dihydrobenzofuran ring, dihydroisobenzofuran ring, dihydrobenzothiophene ring, indoline ring , dihydroisoindole ring, dihydrobenzimidazole ring, dihydrobenzoxazole ring, dihydrobenzothiazole ring, dihydrobenzopyran ring, dihydroisobenzopyran ring, tetrahydroquinone Line ring, tetrahydroisoquinoline ring, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine ring, 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine ring, tetrahydropyrido[3,4-b]pyrazine ring, dihydroindene ring, tetrahydronaphthalene ring,
  • L forms an optionally substituted or unsubstituted dihydrobenzofuran ring, dihydroisobenzofuran ring, dihydroindoline ring, dihydroisoindole ring, dihydrobenzofuran ring, dihydroisoindole ring, dihydrobenzofuran ring, Pyran ring, dihydroisobenzopyran ring, tetrahydroquinoline ring, tetrahydroisoquinoline ring, dihydroindene ring, tetrahydronaphthalene ring, 2,3-dihydrofuro[2,3-b ]pyridine ring, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine ring; further preferably, each is optionally independently selected from halogen, C 1 -C 4 alkyl, C 1 - C 4 alkoxy substituents are substituted one or more times.
  • L and ring A together form a 5- to 10-membered partially saturated heterocycle, a 6- to 10-membered aromatic ring containing at least one heteroatom selected from N, O or S as follows radical or 5- to 7-membered heteroaryl:
  • each of M and T may be the same or different, each independently being N or C; each of R 11 may be the same or different, independently selected from halogen, CN, OH, NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkyl; q is 0, 1, or 2.
  • R 11 is selected from F, Cl, CN, C 1 -C 3 alkyl or C 1 -C 3 alkoxy; q is 0, 1 or 2.
  • Y and ring A together form a group selected from:
  • M 1 is each independently N, CH or C(C 1 -C 4 alkyl).
  • Y is NR 6
  • R 6 is C 1 -C 4 alkyl
  • R 6 forms a 5- to 10-membered partially saturated heterocyclic ring, 6- to 10 -membered aryl or 5- to 10-membered heteroaryl, wherein the heterocycle, aryl and heteroaryl are optionally independently selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 Alkoxy substituents are substituted one or more times.
  • Y forms a group selected from the following group together with ring A:
  • X is N or CR 0 ;
  • X 1 is N, O, S, CR 1 or a bond
  • X 2 is N, O, S, NR 2 or CR 2 ;
  • X 3 is N, O, S, NR 3 or CR 3 ;
  • X 4 is N, O, S, NR 4 or CR 4 ;
  • X 5 is N or CR 5 ;
  • L is a bond, NR a , -NR x -CHR y - or (CR 9 R 10 ) m ; m is 1 or 2;
  • R 0 and R 5 are each independently selected from hydrogen, halogen, CN, OH, NO 2 , NH 2 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, -SO 2 R a , -C( O) OR a , -C(O)NR b R c and C 1 -C 4 alkoxy, wherein the alkyl, cycloalkyl, alkoxy are each optionally substituted by halogen;
  • R 1 and R 2 are each independently selected from H, halogen, CN, OH, NO 2 , NH 2 , C 1 -C 4 alkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkyl;
  • R 6 is selected from hydrogen, C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl
  • R 7 and R 8 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl and C 1 -C 4 alkoxy;
  • R 9 and R 10 are each independently selected from hydrogen, halogen, CN, OH, NH 2 , NO 2 , C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 alkoxy, 4- to 12-membered heterocycles containing carbon atoms and 1-2 heteroatoms selected from N, NR a , O and S(O) p Alkyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy and heterocycloalkyl are each replaced by 0- 3 substituents independently selected from halogen, OH and CN are substituted; wherein the aryl and heteroaryl are each 0-3 independently selected from halogen, C 1 -C 4 alkyl, C 3 -C 6 Substituent
  • R 9 and R 10 together with the carbon atom to which they are bonded form a C 3 -C 6 cycloalkyl optionally substituted by halogen, or form a C 3 -C 6 cycloalkyl group comprising 1-2 selected from N, NR a , O and S(O ) 4- to 12-membered heterocycloalkyl of the heteroatom of p ;
  • Ring A is selected from: C 4 -C 8 cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; wherein, ring A is optionally are independently selected from halogen, CN, OH, NO 2 , NR b R c , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, 4- to 7 One or more substituents of -membered heterocycloalkyl, 5- to 10-membered aryl and 5- to 10-membered heteroaryl and C 1 -C 3 haloalkyl;
  • L together with ring A forms a C 4 -C 8 cycloalkyl, a 5- to 10-membered partially saturated heterocyclic ring containing at least one heteroatom selected from N, O or S, a 6- to 10-membered aryl group or 5- to 7-membered heteroaryl; wherein said cycloalkyl, heterocycle, aryl and heteroaryl are optionally independently selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkane Oxygen substituents are substituted one or more times; or
  • Y and ring A together form a 5- to 10-membered partially saturated heterocycle, a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, wherein the heterocycle, aryl and heteroaryl are any optionally substituted one or more times by substituents independently selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy;
  • R a , R b , R c are each independently selected from hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl and benzyl, wherein the alkyl and cycloalkyl are each optionally replaced by halogen substituted, or R and R together with the nitrogen atom to which they are bonded form a 3- to 6-membered heterocycloalkyl optionally substituted with halogen;
  • R x and R y are each independently selected from hydrogen and C 1 -C 4 alkyl, or R x and R y form a 4- to 8-membered heterocycloalkyl together with the carbon and nitrogen atoms to which they are bonded;
  • p 1 or 2;
  • R 1 is hydrogen or halogen
  • R 2 is selected from hydrogen, halogen, OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy;
  • R 4 is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl and C 1 -C 4 haloalkyl;
  • R 5 is selected from hydrogen, halogen, CN and C 1 -C 6 alkyl
  • R 1 is hydrogen or halogen
  • R 2 is selected from hydrogen, halogen, OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy;
  • R 4 is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl and C 1 -C 4 haloalkyl;
  • R 5 is selected from hydrogen, halogen, CN and C 1 -C 6 alkyl
  • R 6 , R 7 , and R 8 are each independently selected from hydrogen, C 1 -C 3 alkyl.
  • At least one of X 1 , X 2 , X 3 , X 4 is independently selected from N, O, S and NR n (if any); wherein R n is for X 1 R 1 for X 2 , R 3 for X 3 , R 4 for X 4 .
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein, at least one of X 1 , X 2 , X 3 , X 4 is independently selected from N and NR n ( if any); wherein R n is R 1 for X 1 , R 2 for X 2 , R 3 for X 3 , and R 4 for X 4 .
  • the present disclosure provides compounds of formula (Ia):
  • At least one of X 1 , X 2 , X 3 , and X 4 is independently selected from N or NR n ; that is, among X 1 , X 2 , X 3 , and X 4 at least X 1 is N, or at least X 2 is N or NR 2 , or at least X 3 is N or NR 3 , or at least X 4 is N or NR 4 ;
  • Each variable X 5 , X, Y, A, L is as defined in formula (I).
  • At least one of X 1 , X 2 , X 3 , X 4 is independently selected from N or NR n , and R 1 is hydrogen or halogen;
  • R 2 is selected from hydrogen, halogen, C 1 -C 3 alkyl and C 1 -C 3 alkoxy;
  • R 4 is selected from hydrogen, halogen and C 1 -C 3 alkyl
  • R 5 is selected from hydrogen, halogen, CN and C 1 -C 6 alkyl
  • R a is selected from hydrogen, C 1 -C 3 alkyl
  • R 6 , R 7 , and R 8 are each independently selected from hydrogen, C 1 -C 3 alkyl.
  • At least one of X 1 , X 2 , X 3 , X 4 is independently selected from N or NR n , and R 1 is hydrogen or halogen;
  • R 2 is selected from hydrogen, halogen, OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy;
  • R 3 is selected from hydrogen, halogen, OH and C 1 -C 3 alkoxy
  • R 4 is selected from hydrogen, halogen and C 1 -C 3 alkoxy
  • R 5 is selected from hydrogen, halogen, CN and C 1 -C 6 alkyl
  • R a is selected from hydrogen, C 1 -C 3 alkyl.
  • At least one of X 1 , X 2 , X 3 , and X 4 is independently selected from N; specifically, the present disclosure provides the following formulas (Ia1), (Ia2), (Ia3) or a compound of (Ia4):
  • At least one of X 1 , X 2 , X 3 , and X 4 is independently selected from N;
  • X 1 is N or CR 1 .
  • X 1 is N or CR 1 , and at least one of X 2 , X 3 , and X 4 is independently selected from N and NR n .
  • Xi is N.
  • X 1 is N
  • X 3 is CR 3 .
  • X 2 is N or NR 2 .
  • X 2 is N; more preferably, X 2 is N, and X 3 is CR 3 ; further preferably, X 2 is N, X 3 is CR 3 , and X 4 is CR 4 ; most preferably, X 2 is N, X 3 is CR 3 , X 4 is CR 4 , and X 1 is CR 1 .
  • X 3 is N or NR 3 .
  • X 3 is N; more preferably, X 3 is N, and X 4 is CR 4 ; further preferably, X 3 is N, X 4 is CR 4 ; and X 2 is CR 2 ; most preferably, X 3 is N, X 4 is CR 4 , X 2 is CR 2 ; and X 1 is CR 1 .
  • X 4 is N or NR 4 .
  • X 4 is N; more preferably, X 4 is N, and X 3 is CR 3 ; further preferably, X 4 is N, X 3 is CR 3 , and X 2 is CR 2 ; most preferably, X 4 is N, X 3 is CR 3 , X 2 is CR 2 , and X 1 is CR 1 .
  • only one of X 1 , X 2 , X 3 , and X 4 is independently selected from N and NR n ; wherein R n is R 1 for X 1 and R 1 for X 2 is R 2 , R 3 for X 3 , and R 4 for X 4 .
  • X 1 is N
  • X 2 is CR 2
  • X 3 is CR 3
  • X 4 is CR 4 .
  • X 2 is N, O, S or NR 2
  • X 1 is a bond or CR 1
  • X 3 is CR 3
  • X 4 is CR 4 ; preferably, X 2 is N or NR 2 , and X 1 is a bond or CR 1 , X 3 is CR 3 , and X 4 is CR 4 .
  • X 3 is N, O, S or NR 3
  • X 1 is a bond or CR 1
  • X 2 is CR 2
  • X 4 is CR 4
  • X 3 is N or NR 3
  • X 1 is a bond or CR 1
  • X 2 is CR 2
  • X 4 is CR 4 ;
  • X 4 is N, O, S or NR 4 , and X 1 is a bond or CR 1 , X 2 is CR 2 , X 3 is CR 3 ; preferably, X 4 is N or NR 4 , and X 1 is a bond or CR 1 , X 2 is CR 2 , X 3 is CR 3
  • At least two of X 1 , X 2 , X 3 , X 4 are independently selected from N and NR n .
  • X 1 is N
  • X 2 is N or NR 2 .
  • X 1 is N
  • X 3 is N or NR 3 .
  • X 1 is N
  • X 4 is N or NR 4 .
  • X 2 is N or NR 2
  • X 3 is N or NR 3 .
  • X 2 is N or NR 2
  • X 4 is N or NR 4 .
  • X3 is N or NR3
  • X4 is N or NR4 .
  • X 2 is N or NR 2
  • X 3 is N or NR 3
  • X 4 is N or NR 4 .
  • X3 is NR3
  • X4 is NR4
  • X is a bond; specifically, the present disclosure provides a compound of formula (Ib):
  • Each variable X 2 , X 3 , X 4 , X 5 , X, Y, A, L is as defined in formula (I).
  • X is a bond
  • R 2 is selected from hydrogen, halogen, C 1 -C 3 alkyl and C 1 -C 3 alkoxy;
  • R is selected from hydrogen, OH and halogen
  • R 4 is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 4 cycloalkyl and C 1 -C 3 haloalkyl;
  • R 5 is selected from hydrogen, halogen, CN and C 1 -C 6 alkyl
  • R 6 is selected from hydrogen, C 1 -C 3 alkyl
  • R 7 and R 8 are each independently selected from hydrogen and C 1 -C 3 alkyl.
  • X 1 is a bond
  • at least one of X 2 , X 3 , and X 4 is independently selected from N, O, S or NR n ; that is, when X 1 is a bond, X 2 , Among X 3 and X 4 , at least X 2 is N, O, S or NR 2 , or at least X 3 is N, O, S or NR 3 , or at least X 4 is N, O, S or NR 4 .
  • X 1 is a bond, and at least one of X 2 , X 3 , and X 4 is independently selected from N or NR n ; that is, when X 1 is a bond, X 2 , X 3 , X In 4 , at least X 2 is N or NR 2 , or at least X 3 is N or NR 3 , or at least X 4 is N or NR 4 .
  • X 1 when X 1 is a bond, X 2 is N, O, S or NR 2 ; preferably, X 1 is a bond, and X 2 is N or NR 2 .
  • X 3 when X 1 is a bond, X 3 is N, O, S or NR 3 ; preferably, X 1 is a bond, X 3 is N or NR 3 ; more preferably, X 1 is a bond, X3 is N.
  • X 1 when X 1 is a bond, X 4 is N, O, S or NR 4 . ; Preferably, X 1 is a bond, and X 4 is N, O or NR 4 ; more preferably, X 1 is a bond, and X 4 is NR 4 .
  • X 1 is a bond
  • X 3 is N
  • R 2 is selected from hydrogen, halogen, C 1 -C 3 alkyl
  • R 4 is selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 4 cycloalkyl and C 1 -C 3 haloalkyl;
  • R 5 is selected from hydrogen, halogen, CN and C 1 -C 6 alkyl.
  • X 1 when X 1 is a bond, at least two of X 2 , X 3 , and X 4 are independently selected from N, O, S or NR n ; preferably, X 1 is a bond, At least two of X 2 , X 3 , and X 4 are independently selected from N or NR n .
  • one of X 2 , X 3 , and X 4 is N, and at least one of them is independently selected from N, O, S, or NR n .
  • X 1 is a bond
  • X 2 , X 3 , and X 4 are all independently selected from N, O, S, and NR n ; preferably, X 1 is a bond, and X 2 , Both X 3 and X 4 are independently selected from N and NR n .
  • X 1 is a bond
  • X 2 is N, O, S or NR 2
  • X 3 is N or NR 3 .
  • X 1 is a bond
  • X 2 is O or NR 2
  • X 3 is N.
  • X 1 is a bond
  • X 2 is NR 2
  • X 3 is N
  • X 4 is CR 4 .
  • X 1 is a bond
  • X 3 is N, O, S or NR 3
  • X 4 is N or NR 4
  • X 1 is a bond
  • X 3 is N
  • X 4 is NR 4
  • X 1 is a bond
  • X 3 is N
  • X 4 is NR 4
  • X 2 is CR 2 .
  • X 1 is a bond
  • X 2 is N, O, S or NR 2
  • X 4 is N, O, S or NR 4
  • X 1 is a bond
  • X 2 is O or N
  • X 4 is N, O, S or NR 4
  • X 1 is a bond
  • X 2 is N
  • X 4 is S, N or NR 4 .
  • X 1 is a bond, X 3 is N, and X 4 is N or NR 4 , or X 2 is N, O or NR 2 .
  • X 1 is a bond, X 3 is N, and X 4 is NR 4 ; more preferably, X 1 is a bond, X 3 is N, X 4 is NR 4 , and X 2 is CR 2 ;
  • X 1 is a bond, X 3 is N, and X 2 is O or NR 2 ; preferably, X 1 is a bond, X 3 is N, X 2 is O or NR 2 , and X 4 is CR 4 .
  • X 1 is a bond
  • X 2 , X 3 , and X 4 are all independently selected from N and NR n ; that is, X 1 is a bond, X 2 is N or NR 2 , and X 3 is N or NR 3 , and X 4 is N or NR 4 .
  • X 1 is a bond
  • X 2 is N
  • X 3 is N
  • X 4 is NR 4 .
  • X 1 is CR 1 .
  • the present disclosure provides a compound of formula (Ic)
  • Each variable R 1 , X 2 , X 3 , X 4 , X 5 , X, Y, A, L is as defined in formula (I).
  • X 1 is CR 1
  • at least one of X 2 , X 3 , and X 4 is independently selected from N and NR n ; that is, X 1 is CR 1 , and X 2 , X 3.
  • X 4 at least X 2 is N or NR 2
  • at least X 3 is N or NR 3
  • at least X 4 is N or NR 4 .
  • X 1 when X 1 is CR 1 , X 2 is N or NR 2 .
  • X 1 is CR 1
  • X 3 is CR 3 . More preferably, X 1 is CR 1 , X 2 is N, and X 3 is CR 3 .
  • X 1 when X 1 is CR 1 , X 3 is N or NR 3 .
  • X 1 is CR 1
  • X 3 is N.
  • X 1 when X 1 is CR 1 and X 3 is N or NR 3 , X 2 is CR 2 .
  • X 1 when X 1 is CR 1 and X 3 is N or NR 3 , X 2 is CR 2 and X 4 is CR 4 . More preferably, X 1 is CR 1 , X 3 is N, X 2 is CR 2 , and X 4 is CR 4 .
  • X 1 when X 1 is CR 1 , X 4 is N or NR 4 .
  • X 1 when X 1 is CR 1 , X 4 is N or NR 4 , X 3 is CR 3 ; more preferably, when X 1 is CR 1 , X 3 is CR 3 , and X 4 is N.
  • X 1 is CR 1
  • X 2 , X 3 , and X 4 are all CR n ; that is, X 1 is CR 1 , X 2 is CR 2 , and X 3 is CR 3 , X 4 is CR 4 .
  • the present disclosure provides compounds of formula (Id):
  • Each variable R 1 , R 2 , R 3 , R 4 , X 5 , X, A, L is as defined in formula (I).
  • X 1 is CR 1
  • X 2 is CR 2
  • X 3 is CR 3
  • X 4 is CR 4 ;
  • R 1 is hydrogen or halogen
  • R 2 is selected from hydrogen, halogen, OH and C 1 -C 3 alkoxy
  • R 3 is selected from hydrogen, halogen, OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy;
  • R 4 is selected from hydrogen, halogen and C 1 -C 3 alkoxy
  • R 5 is selected from hydrogen, halogen, CN and C 1 -C 6 alkyl
  • R 6 , R 7 , and R 8 are each independently selected from hydrogen, C 1 -C 3 alkyl.
  • Y is O or CH2 .
  • X 1 is CR 1
  • X 2 is CR 2
  • X 3 is CR 3
  • X 4 is CR 4 ;
  • R is hydrogen or halogen
  • R 2 is selected from hydrogen, halogen, OH and C 1 -C 3 alkoxy
  • R 3 is selected from hydrogen, halogen, OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy;
  • R 4 is selected from hydrogen, halogen and C 1 -C 3 alkoxy
  • R 5 is selected from hydrogen, halogen, CN and C 1 -C 6 alkyl
  • R 6 is selected from hydrogen, C 1 -C 3 alkyl
  • R 7 and R 8 are each independently selected from hydrogen, C 1 -C 3 alkyl; preferably, Y is O or CH 2 .
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein:
  • the present disclosure provides the following (Ie1), (Ie2), (Ie3), (Ie4), (Ie5), (Ie6) compounds:
  • each variable X 2 , R 3 , R 4 , R 5 , X, Y, A, L is as defined in formula (I).
  • L is NR a or (CR 9 R 10 ) m ; m is 1 or 2. More preferably, L is CR 9 R 10 .
  • the compound of formula (I) is selected from the following example compounds:
  • the present disclosure provides methods of making the compounds of the present disclosure.
  • the present disclosure also provides intermediates useful in the preparation of compounds of the present disclosure and methods for their preparation.
  • compositions comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of the present disclosure, or a stereoisomer, geometric isomer, tautomer, druggable Salt, crystal form, solvate, hydrate or prodrug, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition is formulated for any suitable route of administration, such as intravenous administration, intramuscular administration, oral administration, rectal administration, inhalation administration, nasal administration, topical administration, Eye or ear application.
  • the pharmaceutical composition is a tablet, pill, capsule, liquid, inhalation, nasal spray solution, suppository, solution, emulsion, ointment, eye drop, or ear drop agent.
  • the present disclosure provides pharmaceutical combinations comprising at least one compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more other active agents.
  • the present disclosure provides a compound of formula (I), or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, crystal form, solvate, hydrate or Use of the prodrug in the preparation of a medicament for preventing, treating, or alleviating a disorder or disease caused by a tumor or an infection in a patient.
  • the tumor or infection is caused by alterations in Stimulator of Interferon Genes (STING).
  • the present disclosure provides a compound of formula (I), or its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, crystal forms, solvates, hydrates or Use of a prodrug for the preparation of a medicament for preventing, treating or alleviating a disease or disorder mediated by ENPP1, such as cancer or an infectious disease or condition.
  • the disclosure provides a compound of the disclosure for use in therapy, alone or optionally in combination with other compounds of the disclosure and/or at least one other therapeutic agent, to treat an ENPP1-mediated disease or obstacle.
  • the present disclosure also provides the use of a compound of the present disclosure in the preparation of a medicament for use alone or optionally in combination with other compounds of the present disclosure and/or at least one other therapeutic agent Treating a disease or disorder mediated by ENPP1.
  • the present disclosure provides combination formulations of a compound of the present disclosure and an additional therapeutic agent or agents for use in therapy.
  • the present disclosure provides a combination of a compound of the present disclosure and an additional therapeutic agent(s), for simultaneous or separate use in therapy.
  • the present disclosure provides a combined formulation of a compound of the present disclosure and one or more additional therapeutic agents for simultaneous, separate or sequential use in the treatment of an ENPP1 mediated disease or disorder.
  • Compounds can be administered as pharmaceutical compositions described herein.
  • the present disclosure provides for treating or preventing an ENPP1-mediated disease or disorder, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present disclosure, or a stereoisomer, geometric isomer, Tautomers, pharmaceutically acceptable salts, crystal forms, solvates, hydrates or prodrugs or pharmaceutical compositions comprising them.
  • the present disclosure provides a method of treating an ENPP1-mediated disease or disorder comprising administering to a patient in need of such treatment, alone or optionally in combination with other compounds of the present disclosure and/or at least one other therapeutic agent administering a therapeutically effective amount of at least one compound of the present disclosure in combination,
  • the present disclosure provides a method of treating an ENPP1-mediated disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of a first and a second therapeutic agent, wherein the first The first therapeutic agent is a compound of the disclosure and the second therapeutic agent is another compound of the disclosure and/or at least one other therapeutic agent.
  • ENPP1-mediated diseases or disorders include, but are not limited to, tumors, infectious diseases or disorders, especially cancers, such as relapsed or refractory cancers, metastatic cancers, and the like.
  • the ENPP1 -mediated disease or disorder is relapsed or refractory cancer.
  • the ENPP1 -mediated disease or disorder is metastatic cancer.
  • the ENPP1-mediated disease or disorder is a tumor, especially a solid tumor, such as breast cancer, lung cancer, glioblastoma, brain and spine cancer, head and neck cancer, skin cancer, reproductive system cancer, Gastrointestinal system cancer, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, malignant mesothelioma, sarcoma , lymphoma, adenocarcinoma, thyroid cancer, cardiac tumors, germ cell tumors, malignant neuroendocrine tumors, malignant rhabdoid tumors, soft tissue sarcomas, midline bundle carcinomas, and unknown primary carcinomas.
  • a solid tumor such as breast cancer, lung cancer, glioblastoma, brain and spine cancer, head and neck cancer, skin cancer, reproductive system cancer, Gastro
  • the ENPP1 -mediated disease or disorder is a tumor, especially a hematological malignancy; especially leukemia, lymphoma or myeloma.
  • the ENPP1-mediated disease or disorder is an infectious disease or disorder, including but not limited to: herpes simplex virus infection, vaccinia virus infection, adenovirus infection, human papillomavirus infection, hepatitis B virus infection , hepatitis D virus infection, human immunodeficiency virus infection, human cytomegalovirus infection, dengue fever virus infection, Ebola virus infection, Marburg virus infection, Zika virus infection, Listeria monocytogenes infection, tuberculosis Mycobacterium infection, Francisella new murderer infection, Legionella pneumophila infection, Chlamydia trachomatis infection, Streptococcus pneumoniae infection, Neisseria gonorrhoeae infection.
  • infectious disease or disorder including but not limited to: herpes simplex virus infection, vaccinia virus infection, adenovirus infection, human papillomavirus infection, hepatitis B virus infection , hepatitis D virus infection, human immunodefic
  • the disclosed compounds have an IC50 value of ⁇ 5 ⁇ M, preferably an IC 50 value of ⁇ 1 ⁇ M, more preferably an IC of ⁇ 0.5 ⁇ M using the EED Alphascreen binding, LC-MS and/or ELISA assays disclosed herein 50 value, even more preferably an IC 50 value of ⁇ 0.125 ⁇ M, most preferably ⁇ 0.1 ⁇ M.
  • a dash ("-") not between two letters or symbols indicates the point of attachment of a substituent.
  • -O(C 1- C 3 alkyl) indicates that the group is attached to the rest of the molecule through an oxygen atom.
  • "-" can be omitted.
  • the wavy line indicates where the group is attached to the rest of the molecule.
  • heteroatom refers to a nitrogen (N), oxygen (O) or sulfur (S) atom, especially nitrogen or oxygen, each of which may be substituted or unsubstituted, including oxidized forms thereof.
  • halogen refers to fluoro, chloro, bromo and iodo. Preferred halogens as substituents are fluorine and chlorine.
  • alkyl refers to a fully saturated straight or branched chain monovalent hydrocarbon group.
  • the alkyl group preferably contains 1-20 carbon atoms, more preferably 1-16 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms or 1- 3 carbon atoms.
  • the number before the alkyl group indicates the number of carbon atoms.
  • C 1 -C 6 alkyl means an alkyl group with 1-6 carbon atoms
  • C 1 -C 4 alkyl means an alkyl group with 1-4 carbon atoms
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, Base, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. This definition applies whether the term "alkyl" appears by itself or as part of another group such as haloalkyl, alkoxy, etc.
  • alkenyl refers to a linear or branched monovalent hydrocarbon group containing at least one double bond.
  • the alkenyl group preferably contains 2-20 carbon atoms, more preferably 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms or 2-4 carbon atoms.
  • the number before the alkenyl group indicates the number of carbon atoms.
  • Representative examples of alkenyl include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, heptenyl, octenyl, and the like.
  • alkynyl refers to a linear or branched monovalent hydrocarbon group comprising at least one triple bond.
  • the alkynyl group preferably contains 2-20 carbon atoms, more preferably 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms or 2-4 carbon atoms. The number before the alkynyl group indicates the number of carbon atoms.
  • alkynyl include, but are not limited to, ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, isopentynyl, hexynyl, heptynyl, octynyl Base etc.
  • alkoxy refers to an alkyl group as defined herein attached through an oxygen bridge, ie, an alkyl-O- group, the number preceding the alkoxy group indicating the number of carbon atoms.
  • C 1 -C 6 alkoxy means an alkoxy group with 1-6 carbon atoms, namely -OC 1-6 alkyl
  • C 1 -C 4 alkoxy means an alkoxy group with 1-4
  • C 1 -C 3 alkoxy means an alkoxy group with 1-3 carbon atoms, namely -OC 1-3 alkyl.
  • alkoxy examples include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.
  • the alkoxy group contains about 1-6 carbons, or about 1-4 carbons, etc.
  • cycloalkyl refers to a saturated or partially saturated non-aromatic carbocyclic ring, including mono-, bi- or tricyclic, preferably having 3-12 ring carbon atoms, more preferably 3-10 ring carbon atoms , such as 3-8, 3-7, 3-6, 4-10, or 4-8 ring carbon atoms.
  • C 3 -C 8 cycloalkyl is intended to include C 3 , C 4 , C 5 , C 6 , C 7 and C 8 cycloalkyl groups;
  • C 3 -C 6 cycloalkyl is intended to include C 3 , C 4 , C 5 and C 6 cycloalkyl groups; and so on.
  • Exemplary monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like.
  • Exemplary bicyclic cycloalkyls include bornyl, tetrahydronaphthyl, decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptene base, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, etc.
  • Exemplary tricyclic cycloalkyls include adamantyl and the like.
  • haloalkyl refers to a group wherein one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6 or 7 hydrogen atoms, such as 1, 2 or 3 hydrogen atoms, are replaced by a halogen as described herein alkyl as defined, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same or different from each other.
  • C 1 -C 4 haloalkyl is intended to include C 1 , C 2 , C 3 and C 4 haloalkyl groups
  • C 1 -C 3 haloalkyl is intended to include C 1 , C 2 and C 3 haloalkyl groups group.
  • haloalkyl examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 1,1-difluoroethyl, 1,1,-difluoropropyl, and 1,1, 1-Trifluoropropyl.
  • fluoroalkyl also include "fluoroalkyl", which is intended to include an alkyl group as defined herein wherein one or more hydrogen atoms are replaced with a fluorine atom.
  • Haloalkyl herein is preferably an alkyl group in which up to three hydrogen atoms are replaced by halogen.
  • haloalkoxy means a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge, wherein one or more hydrogen atoms, for example 1, 2, 3, 4, 5, 6 or 7 Hydrogen atoms, eg 1, 2 or 3 hydrogen atoms are replaced by halogen.
  • C 1 -C 6 haloalkoxy or “C 1 to C 6 haloalkoxy” is intended to include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 haloalkoxy groups.
  • haloalkoxy examples include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy. Examples of haloalkoxy also include "fluoroalkoxy”.
  • aryl is formed by the fusion of one or more rings having 6-20, preferably 6-14, more preferably 6-12, most preferably 6-10, for example 6-9
  • Preferred aryl groups are aryl groups having 6-10 ring carbon atoms, i.e.
  • 6- to 10-membered aryl groups which include: monocyclic aryl groups (such as phenyl); or fused bicyclic ring systems in which one ring is an aromatic ring and the other ring is aromatic (eg in naphthalene, biphenyl) or non-aromatic (eg in indene, tetrahydronaphthalene).
  • aryl groups include phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indenyl, indenyl, or anthracenyl, and the like.
  • heteroaryl refers to 5-14 membered heteroatoms containing 1-8, preferably 1-4, further preferably 1-3, more preferably 1 or 2 heteroatoms selected from N, O or S , preferably 5-10 membered, more preferably 5-7 membered or 5-6 membered aromatic ring system, including monocyclic or bicyclic or fused polycyclic rings, and the remaining ring atoms are carbon atoms.
  • Heteroaryl is preferably 5-10 membered heteroaryl, more preferably 5-7 membered heteroaryl or 5-6 membered heteroaryl, each containing 1, 2 or 3 heteroatoms selected from N, O or S .
  • heteroaryl groups include, but are not limited to: pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridyl, pyranyl, pyrazine Base, pyridazinyl, pyrimidinyl, oxazinyl, oxadiazinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzoxazinyl, 2H-color Alkenes, benzopyranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, 7-azaindolyl, 6-azaindyl Indolyl, 5-azaindolyl, 4-azaindolyl, 1H
  • heterocycloalkyl is a monocyclic, bicyclic or tricyclic saturated ring having 3-20 ring atoms, such as 3-12 ring atoms, such as 3-8 ring atoms, such as 3-6 ring atoms and partially unsaturated nonaromatic rings.
  • heterocycloalkyl is preferably 4- to 12-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, preferably 4- to 8-membered heterocycloalkyl, More preferred is 4- to 7-membered, 4- to 6-membered or 5- to 6-membered heterocycloalkyl, wherein the heteroatoms are substituted or unsubstituted, for example substituted by C 1 -C 4 alkyl.
  • heterocycloalkyl groups include, but are not limited to: oxiranyl, aziridinyl, azetidinyl, oxetanyl, aziridinyl (pyrrolidinyl), Tetrahydrofuryl, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, pyrazolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, pyrrolidinyl-2-one , imidazolone, piperidinyl (hexahydropyridine), N-methylpiperidinyl, tetrahydropyranyl, oxazinyl, 1,3-oxazinyl, hexahydropyrimidinyl, piperazinyl , piperidinylone (piperidinylone), 1,4-dioxa-8-aza-s
  • Partially saturated heterocycles include such as dihydropyrrolyl, dihydrofuranyl, dihydrooxazolyl, dihydropyridyl, imidazolinyl, 1H-dihydroimidazolyl, 2H-pyranyl, 2H-chromenyl , Dihydrooxazinyl and other groups.
  • Partially saturated heterocycles also include heterocycles having fused aryl or heteroaryl rings, preferably having 9-10 ring members (e.g.
  • dihydrobenzofuranyl dihydroisobenzofuranyl, indoline Indolyl (or 2,3-dihydroindolyl), dihydrobenzothienyl, dihydrobenzothiazolyl, dihydrobenzopyranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, Tetrahydropyrido[3,4-b]pyrazinyl, etc.).
  • partially or fully saturated heterocyclic ring refers to a partially or fully hydrogenated non-aromatic ring, which may exist as a monocyclic ring, bicyclic ring (including fused rings), or a spiro ring.
  • a heterocycle is typically a 3- to 12-membered ring, preferably a 5- to 10-membered ring, containing 1 to 3, preferably 1 or 2, heteroatoms independently selected from sulfur, oxygen and/or nitrogen. Yuan ring.
  • the term “partially or fully saturated heterocycle” it is intended to include “heterocycloalkyl” and "partially saturated heterocycle”.
  • spirocycles include 2,6-diazaspiro[3.3]heptanyl, 3-azaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecyl, and the like.
  • heterocycle refers to a fully saturated or unsaturated, aromatic or non-aromatic cyclic group, which is intended to include “heterocycloalkyl”, “partially or fully saturated heterocycle”, “partially Saturated heterocycle”, “fully saturated heterocycle” and “heteroaryl”.
  • heterocycloalkyl a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic or 10- to 15-membered tricyclic ring system containing at least one heteroatom in the ring containing at least one carbon atom .
  • the heteroatom-containing ring of the heterocyclic ring may contain 1-6, preferably 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, wherein nitrogen and sulfur heteroatoms can also optionally Oxidized.
  • the heterocycle is a 4- to 7-membered monocyclic heterocycle.
  • Exemplary monocyclic heterocycles include pyrrolidine, pyrrole, pyrazole, oxetane, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, thiazole, thiadiazole, thiazolidine, isothiazole, iso Thiazolidine, furan, tetrahydrofuran, thiophene, piperidine, piperazine, 2-oxopiperazine, 2-oxopiperidine, 2-oxopyrrolidine, 4-piperidone, pyridine, pyrazine, pyrimidine, pyridoxine oxazine, tetrahydropyran, morpholine, thiomorpholine, thiomorpholino-S-monoxide, thiomorpholino-S,S-dioxide, 1,3-dioxolane and tetra Hydrogen-1,1-dioxothiophene, 1,1,4-trio
  • Exemplary bicyclic heterocycles include indole, indoline, benzothiazole, and the like.
  • heterocyclyl refers to a group formed by the loss of one or more hydrogen atoms from a heterocyclic ring as defined above.
  • a heterocyclic group can be attached at a heteroatom or a carbon atom.
  • Carbocycle refers to a saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon group of 3-12 carbon atoms. Carbocycles preferably have 3-8 ring carbon atoms, eg contain 3-7, or 4-7 ring carbon atoms. Exemplary monocyclic carbocycles include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, and the like.
  • Exemplary bicycloalkanes include tetralin, decahydronaphthalene, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, and the like.
  • Exemplary tricyclic hydrocarbon groups include adamantyl and the like.
  • substituents such as alkyl, alkenyl, alkoxy, carbocycle, cycloalkyl, heteroaryl, heterocycle, heterocyclyl, carbonyl, sulfonyl, sulfinyl and the like may be substituted by substituents, so
  • the substituents include, but are not limited to: OH, Boc, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle NRR', C(O)R, SO2R , C(O)NRR' or C(O)OR, and each R and R' is independently selected from: H and substituted or unsubstituted alkyl.
  • optionally substituted alkyl includes “unsubstituted alkyl” and “substituted alkyl” as defined herein.
  • Optionally substituted by halogen includes the case of "substituted by halogen” and the case of "not substituted by halogen", for example, substituted by 0-3 halogens.
  • any variable occurs more than one time in any constituent or formula of a compound, its definition on each occurrence is independent of its definition on every other occurrence.
  • R at each occurrence is independently selected from the definition of R.
  • substitutions applied in the definition of ring A that is, when ring A is C 4 -C 8 cycloalkyl, 4- to 8-membered heterocycloalkyl, 6- to 10-membered aryl and 5
  • these radicals are unsubstituted or substituted by one or more, eg two, at each occurrence, independently selected from the given definitions of substituent radicals. This applies similarly to the definition of other similar situations.
  • substituent When a substituent has a bond shown to be through a bond connecting two atoms in the ring, then that substituent may be bonded to any atom on the ring. When a substituent is listed without specifying the atom to which the substituent is attached to the rest of the compound of the formula shown, then the substituent may be bonded via any atom in the substituent.
  • ring structure When a dotted ring is used in a ring structure, this means that the ring structure may be saturated, partially saturated or unsaturated.
  • substituted means that one or more hydrogen atoms on a given atom or group are replaced by one or more hydrogen atoms selected from the given group of substituents Substitution of radicals, provided that the normal valence of the given atom is not exceeded.
  • two hydrogen atoms on a single atom are replaced by oxygen.
  • a chemically correct and stable compound means that the compound is sufficiently stable that it can be isolated from a reaction mixture and the chemical structure of the compound can be determined, and subsequently formulated into a preparation that is at least practical.
  • substituted means one or more hydrogen atoms on a given atom or group independently substituted by one or more, eg 1, 2, 3 or 4 substituents.
  • substituents may be the same or different.
  • pharmaceutically acceptable or “pharmaceutically acceptable” include substances or compositions that must be chemically/toxicologically compatible with the other ingredients, including the formulation, and/or the mammal treated with it.
  • Salts especially pharmaceutically acceptable salts, are also included when moieties capable of forming salts are present.
  • the presence of tautomers or internal addition products of isomers can be identified by those skilled in the art using tools such as NMR.
  • Compounds of formula (I) of the present disclosure are capable of readily forming internal addition products of tautomers and isomers as depicted herein.
  • formula (I) when formula (I) is mentioned herein, the term also includes its subforms, such as formula (Ia), (Ia1), (Ia2), (Ia3), (Ia4), (Ib), (Ic), ( Id), (Ie1), (Ie2), (Ie3), (Ie4), (Ie5) and (Ie6).
  • enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other.
  • a 1:1 mixture of a pair of enantiomers is a “racemic” mixture.
  • the term is used to denote a racemic mixture, where appropriate.
  • the conventional RS system is used to designate a single stereoisomer with known relative and absolute configuration of two chiral centers (e.g.
  • Resolved compounds of unknown absolute configuration can be assigned (+) or (-) according to the direction (dextrorotatory or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line.
  • resolved compounds can be defined by the respective retention times of the corresponding enantiomers/diastereomers via chiral HPLC.
  • Some of the compounds described herein contain one or more asymmetric centers or axes and thus can give rise to enantiomers, diastereomers, and compounds that can be defined in absolute stereochemistry as (R)- or (S)- Other stereoisomers.
  • Geometric isomers can occur when a compound contains a double bond or some other feature that confers a certain amount of structural rigidity on the molecule. If the compound contains double bonds, the substituents can be in E or Z conformation. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have either the cis or trans configuration.
  • Conformational isomers are isomers that differ by rotation about one or more valency bonds. Rotamers are conformers that differ by the rotation of only a single bond.
  • Atropisomer refers to a structural isomer based on axial or planar chirality resulting from restricted rotation in a molecule.
  • Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • Optically active forms can be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All methods used to prepare the compounds of this disclosure and intermediates prepared therein are considered part of this disclosure. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example by chromatography or fractional crystallization.
  • the end products of the present disclosure are obtained in free (neutral) or salt form.
  • the free and salt forms of these end products are within the scope of this disclosure.
  • One form of a compound can be converted to the other, if desired. Free bases or acids can be converted into salts; salts can be converted into free compounds or other salts; mixtures of isomeric compounds of the present disclosure can be separated into the individual isomers.
  • pharmaceutically acceptable and “pharmaceutically acceptable” are used interchangeably to refer to a pharmaceutical composition that is useful in the preparation of a pharmaceutical composition that is generally safe, nontoxic, and neither biologically nor otherwise undesirable , including those acceptable for veterinary and human pharmaceutical use.
  • salts that retain the biological effects and properties of the disclosed compounds and that are not biologically or otherwise undesirable.
  • Non-limiting examples of such salts include non-toxic, inorganic or organic base or acid addition salts of the disclosed compounds.
  • compounds of the present disclosure are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like.
  • Organic acids from which salts can be derived include, for example, acetic, propionic, glycolic, pyruvic, oxalic, maleic, malonic, succinic, fumaric, tartaric, citric, benzoic, cinnamic, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, such as, inter alia, isopropylamine, Trimethylamine, Diethylamine, Triethylamine, Tripropylamine, and Ethanolamine.
  • salts of the present disclosure can be synthesized from the parent compound (basic or acidic moiety) by conventional chemical methods.
  • such salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of an appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc. ) reaction or reacting the free base form of the compound with a stoichiometric amount of the appropriate acid.
  • Such reactions are usually carried out in water or organic solvents or a mixed solvent of the two.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred where practicable.
  • Other suitable salts can be found in Remington's Pharmaceutical Sciences, 20th Edition, Mack Publishing Company, Easton, Pa., (1985), which is incorporated herein by reference.
  • pharmaceutically acceptable excipient includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal), isotonic agents, Absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, said similar substances and combinations thereof, are known to those of ordinary skill in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company (Mack Printing Company), 1990, pp. 1289-1329, incorporated herein by reference) . Unless any conventional carrier is incompatible with the active ingredient, it can be considered for use in therapeutic or pharmaceutical compositions.
  • solvate refers to a physical association of a compound of the present disclosure with one or more organic or inorganic solvent molecules. This physical association includes hydrogen bonding. In some cases, solvates will be able to be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • the solvent molecules in a solvate may exist in a regular arrangement and/or a non-ordered arrangement. Solvates may contain solvent molecules in stoichiometric or non-stoichiometric amounts.
  • “Solvate” includes solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are well known in the art.
  • polymorph refers to crystalline forms that have the same chemical structure/composition but differ in the spatial arrangement of the molecules and/or ions that form the crystals.
  • Compounds of the present disclosure may be provided as amorphous solids or crystalline solids. Freeze drying can be used to provide compounds of the present disclosure as solids.
  • prodrug refers to a chemically modified active or inactive compound that, after administration to an individual, becomes a compound of the present disclosure through physiological effects in vivo (eg, hydrolysis, metabolism, etc.).
  • physiological effects in vivo eg, hydrolysis, metabolism, etc.
  • the suitability and techniques for making and using prodrugs are well known to those skilled in the art.
  • any formula given herein is also intended to represent unlabeled as well as isotopically labeled forms of the compound.
  • Isotopically labeled compounds have structures described by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number.
  • isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H (ie, D), 3 H (ie, T), 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 Cl, 125 I.
  • the present disclosure includes various isotopically labeled compounds as defined herein, for example those in which radioactive isotopes such as3H , 13C and14C are present.
  • Such isotopically labeled compounds are useful in metabolic studies (with 14 C), reaction kinetics studies (for example with 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computer Tomography (SPECT), including drug or substrate tissue distribution assays, or radiation therapy may be used in patients.
  • PET positron emission tomography
  • SPECT single photon emission computer Tomography
  • drug or substrate tissue distribution assays or radiation therapy may be used in patients.
  • 18F or labeled compounds may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of the present disclosure can generally be prepared by carrying out those procedures described in the schemes described hereinafter or in the Examples and Preparations, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art or by carrying out methods analogous to those described herein, substituting the appropriate isotopically labeled reagent for the otherwise unlabeled reagent used.
  • Such compounds have a variety of potential uses, eg, as standards and reagents for determining the ability of potential pharmaceutical compounds to bind target proteins or receptors or for imaging of disclosed compounds binding to biological receptors in vivo or in vitro.
  • a “therapeutically effective amount” of a compound of the present disclosure refers to the amount of a compound of the present disclosure that can elicit a biological or medical response in an individual or improve symptoms, slow or delay disease progression, or prevent disease, among others.
  • the "therapeutically effective amount” can be determined by the participating physician or veterinary practitioner and will vary with the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the individual, the route and form of administration, the attending physician Vary depending on factors such as the judgment of the physician or veterinary practitioner.
  • individual refers to an animal.
  • the animal is a mammal.
  • a subject also refers to, for example, primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like.
  • the individual is a human.
  • inhibitor refers to amelioration or inhibition of a particular condition, symptom or disorder or disease, or a significant reduction in the baseline activity of a biological activity or process.
  • any disease or condition refers in one embodiment to ameliorating the disease or condition (ie arresting or slowing the progression of the disease or at least one clinical symptom thereof). In another embodiment, “treating” refers to improving at least one physical parameter, which may not be perceived by the patient. In another embodiment, “treating” refers to modulating a disease or disorder either physically (eg, stabilizing a perceived symptom) or physiologically (eg, stabilizing a parameter of the body), or both.
  • prevention refers to the administration of one or more drug substances, particularly the compounds of the present disclosure and/or pharmaceutically acceptable salts thereof, to individuals having a predisposition to the disease in order to prevent the individual from suffering from the disease .
  • Treating when referring to a chemical reaction mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or desired product. It should be understood that the reaction leading to the shown and/or desired product may not necessarily result directly from the combination of the two reagents initially added, i.e. there may be one or more intermediates formed in the mixture which forms ultimately lead to the formation of the shown and/or desired products.
  • the term "about” is used herein to adjust a given numerical value by 20%, such as 10%, such as 5%, above or below the numerical value.
  • the hydroxamic acid compound of the present disclosure is an ENPP1 inhibitor compound, which has high selectivity and inhibitory activity to ENPP1, fewer side effects, high resistance to drug resistance, high bioavailability and high clinical application value.
  • Compounds of the present disclosure are useful in a variety of applications where inhibition of ENPP1 is desired.
  • the disclosed compounds can be used to treat, prevent or improve ENPP1-mediated diseases or disorders, such as ENPP1-mediated tumors (such as cancer) or infectious diseases or disorders, especially relapsed or refractory cancers or metastatic cancers.
  • ENPP1-mediated diseases or disorders such as ENPP1-mediated tumors (such as cancer) or infectious diseases or disorders, especially relapsed or refractory cancers or metastatic cancers.
  • the disclosed compounds can be used to treat, prevent or improve solid tumors, for example selected from breast cancer, lung cancer, glioblastoma, brain and spine cancer, head and neck cancer, skin cancer, reproductive system cancer, gastrointestinal system cancer Cancer, esophageal cancer, nasopharyngeal cancer, pancreatic cancer, rectal cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, colon cancer, multiple myeloma, kidney and bladder cancer, bone cancer, malignant mesothelioma, sarcoma, lymphoma , adenocarcinoma, thyroid cancer, cardiac tumors, germ cell tumors, malignant neuroendocrine tumors, malignant rhabdoid tumors, soft tissue sarcomas, midline bundle carcinomas, and carcinomas of unknown primary.
  • solid tumors for example selected from breast cancer, lung cancer, glioblastoma, brain and spine cancer, head and neck cancer, skin cancer, reproductive system cancer, gastrointestinal system
  • the disclosed compounds can also be used to treat, prevent or ameliorate hematological malignancies, for example selected from leukemia, lymphoma or myeloma.
  • the disclosed compounds can also be used to treat, prevent or improve infectious diseases or disorders, especially ENPP1-mediated infectious diseases or disorders, for example, selected from herpes simplex virus infection, vaccinia virus infection, adenovirus infection, human papillary Oncovirus infection, hepatitis B virus infection, hepatitis D virus infection, human immunodeficiency virus infection, human cytomegalovirus infection, dengue virus infection, Ebola virus infection, Marburg virus infection, Zika virus infection, mononuclear virus infection Listeria cell proliferation infection, Mycobacterium tuberculosis infection, Francisella neomurder infection, Legionella pneumophila infection, Chlamydia trachomatis infection, Streptococcus pneumoniae infection, and Gonorrhea infection.
  • infectious diseases or disorders for example, selected from herpes simplex virus infection, vaccinia virus infection, adenovirus infection, human papillary Oncovirus infection, hepatitis B virus infection, hepatitis D
  • compositions may be administered to an individual in the form of pharmaceutical compositions, which may optionally contain one or more pharmaceutically acceptable excipients.
  • the compounds of the present disclosure may be administered by various known routes, including oral, rectal, intragastric, intracranial and parenteral, eg, intravenous, intramuscular, intranasal, intradermal, subcutaneous, and the like. Oral, intranasal and parenteral administration are particularly preferred. Depending on the route of administration, different pharmaceutical formulations are required, and some of these routes of administration may require the application of a protective coating to the pharmaceutical formulation to prevent degradation of the disclosed compounds, eg, within the alimentary canal.
  • the compounds of the present disclosure can be formulated into syrup, infusion or injection, spray, tablet, capsule, lozenge, liposome or suppository and the like.
  • Particularly preferred pharmaceutical forms for administering the compounds of this disclosure are those suitable for injectable use, including sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the final solution or dispersion form must be sterile and fluid.
  • solutions or dispersions will comprise a solvent or dispersion medium containing, for example, aqueous-buffered solutions such as biocompatible buffers, ethanol or polyols such as glycerol, propylene glycol, polyethylene glycol, suitable mixtures thereof , surfactants or vegetable oils.
  • the disclosed compounds can also be formulated in liposomes, particularly for parenteral administration. Liposomes offer the advantage of increased half-life in circulation (if compared to free drug) and prolonged more uniform release of the encapsulated drug.
  • Sterilization of infusions and injections can be achieved by techniques recognized in the art, including but not limited to adding preservatives such as antibacterial or antifungal agents, such as paraben, chlorobutanol, phenol, sorbic acid or Thimerosal.
  • preservatives such as antibacterial or antifungal agents, such as paraben, chlorobutanol, phenol, sorbic acid or Thimerosal.
  • isotonic agents such as sugars or salts, especially sodium chloride, may be incorporated into infusions and injections.
  • sterile injectable solutions containing one or more compounds of the present disclosure is accomplished by incorporating each compound in the required amount in the appropriate solvent with the ingredients enumerated above, as appropriate, followed by sterilization. To obtain sterile powders, the above solutions are vacuum-dried or freeze-dried as required.
  • Preferred diluents of the present disclosure are water, physiologically acceptable buffers, physiologically acceptable buffered saline or saline solutions.
  • Preferred carriers are cocoa butter and vitebesole.
  • Excipients which may be used with the various pharmaceutical forms of the disclosed compounds may be selected from the following non-limiting list: a) Binders such as lactose, mannitol, crystalline sorbitol, hydrogen phosphate, sugars, crystalline cellulose, carboxymethyl cellulose, hydroxyethyl cellulose and/or polyvinylpyrrolidone, etc.; b) lubricants such as magnesium stearate, talc, calcium stearate, zinc stearate, stearic acid , hydrogenated vegetable oil, leucine, glycerides and sodium stearyl fumarate; c) disintegrants such as starch, croscarmellose, sodium methylcellulose, agar, bentonite, alginic acid, Carboxymethylcellulose and/or polyvinylpyrrolidone, etc.
  • Other suitable pharmaceutical carriers and their formulation are well known in the art and are described, for example, in Remington: The Science and Practice of Pharmacy 1995, edited by
  • the formulation is for oral administration, and the formulation comprises one or more or all of the following ingredients: pregelatinized starch, talc, polyvinylpyrrolidone K30, croscarmellose sodium, hard Sodium fatty alcohol fumarate, gelatin, titanium dioxide, sorbitol, monosodium citrate, xanthan gum, titanium dioxide, flavoring, sodium benzoate and sodium saccharin.
  • the compounds of the present disclosure are administered intranasally, either as a dry powder inhaler or from a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoromethane, Addition of alkanes such as 1,1,1,2-tetrafluoroethane (HFA 134A TM ) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA TM ), carbon dioxide, or other suitable gases It is administered as a spray in a pressurized container, pump, sprayer or atomizer.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoromethane, Addition of alkanes such as 1,1,1,2-tetrafluoroethane (HFA 134A TM ) or 1,1,1,2,
  • the pressurized container, pump, sprayer or atomizer may contain a solution or suspension of a compound of the present disclosure, for example using ethanol and a propellant as a solvent, which may also contain a lubricant, such as Sorbitan Trioleate.
  • Typical dosage ranges for compounds of the present disclosure are 0.001-1000 mg active ingredient/kg body weight/day.
  • the dose can be administered once a day or in divided doses.
  • the determination of the appropriate dose is determined by the attending physician as appropriate according to the type and severity of the disease to be treated, the individual's health status and previous medical history, shared drugs, the specific compound administered, and the route of administration. Amounts of compounds of the present disclosure outside this dosage range can be employed as desired.
  • the compounds of the present disclosure may be used for the uses described herein alone or in combination with one or more other active agents or therapies which may have or produce the same or different pharmacological efficacy.
  • a compound of the present disclosure may be administered simultaneously with, prior to, or subsequent to the other active agent or therapy.
  • the dosage of the other active agents administered in combination will of course vary depending on such factors as the drug(s) being co-administered, the condition being treated, the general health of the patient, the judgment of the physician or veterinarian, and the like.
  • the disclosed compounds may be administered simultaneously, separately or sequentially with the other active agents in combination by the same or different routes of administration. They may be included in the same pharmaceutical composition, or may be a combined product in separate form, eg in the form of a kit. They may be prepared and/or formulated by the same or different manufacturers.
  • the compounds of the present disclosure and other active agents may be obtained (i) (i) prior to sending the combination product to a physician (such as in the case of a kit comprising the compound of the present disclosure and the additional drug); (ii) immediately prior to administration. Incorporated into the combination therapy by the physician himself (or at the direction of the physician); (iii) by the patient himself, for example, during the sequential administration of the compound of the present disclosure and the other active agent.
  • the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more other active agents.
  • the pharmaceutical composition may comprise a pharmaceutically acceptable excipient as described above.
  • the present disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the kit comprises means for retaining said compositions separately, such as containers, divided bottles or divided foil pouches.
  • An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules and the like.
  • kits of the present disclosure can be used to administer different dosage forms, such as oral and parenteral dosage forms, for administering individual compositions at different dosage intervals, or for stepping up individual compositions relative to one another.
  • the kits of the present disclosure typically include instructions for administration.
  • the compounds of the present disclosure and other therapeutic agents may be prepared and/or formulated by the same or different manufacturers. Furthermore, the compounds of the disclosure and other therapeutic agents can be introduced together into a combination therapy, which can be done (i) before the combination product is released to a physician (e.g., for a kit containing a compound of the disclosure and the other therapeutic agent) (ii) by the physician himself (or under the direction of the physician) immediately prior to administration; (iii) by the patient himself, eg, during the sequential administration of a compound of the present disclosure and another therapeutic agent.
  • a physician e.g., for a kit containing a compound of the disclosure and the other therapeutic agent
  • the compounds of the present disclosure can be prepared by various methods, including the methods given below, the methods given in the Examples, or methods analogous thereto.
  • a suitable general synthetic scheme is depicted below.
  • Suitable reaction conditions for the individual reaction steps are known to those skilled in the art.
  • Starting materials are commercially available or may be prepared by the methods below, methods analogous to those given below or methods known in the art.
  • Each variable in the general formula has the same meaning as above, unless otherwise specified.
  • the compounds of the present disclosure can be synthesized by the following general synthetic scheme, wherein the variables are as defined herein, and the specific reaction conditions are as in the examples.
  • the compound of general formula A2 can be prepared by the following synthesis method: trimethyl orthoformate and 2,2-dimethyl-1,3-dioxane-4,6-dione are stirred and reacted at 100°C for 2 hours, The compound of general formula A1 was added and the reaction was continued at this temperature for 2 hours. After the reaction solution was cooled to room temperature, a solid precipitated out, and the solid was collected by filtration to obtain a compound of general formula A2.
  • the compound of general formula A3 can be prepared by the following synthesis method: dissolve the compound of general formula A2 in diphenyl ether, stir and react at 230°C for 1 hour, add petroleum ether after the reaction solution is cooled to room temperature, and precipitate the solid, filter, collect the solid to obtain the general A compound of formula A3.
  • the compound of general formula A4 can be prepared by the following synthetic method: after reacting the compound of general formula A3 and phosphorus oxychloride at 100° C. for 1 hour, cool to room temperature, remove excess phosphorus oxychloride to obtain a residue, and add to the residue Add ice water and ammonia water to adjust the pH to 8, extract with dichloromethane, wash the organic phase with water and saturated brine successively, dry, filter, and concentrate to obtain the crude product, which is purified by silica gel column to obtain the compound of general formula A4.
  • the compound of the general formula A6 can be prepared by the following synthetic method: in one case, the compound of the general formula A4 and the compound of the general formula A5, under DIEA, potassium carbonate or hydrochloric acid conditions, a nucleophilic substitution reaction occurs to generate the compound of the general formula A6; another In some cases, the compound of the general formula A4 and the compound of the general formula A5 undergoes a coupling reaction under palladium-catalyzed conditions to obtain the compound of the general formula A6.
  • the compound of the general formula A7 can be prepared by the following synthesis method: the compound of the general formula A6 and sodium hydroxide are hydrolyzed in an appropriate amount of solvent to obtain the compound of the general formula A7.
  • the compound of the general formula A8 can be prepared by the following synthesis method: the compound of the general formula A7 is combined with hydroxylamine, and in the presence of the condensation agent HATU, undergoes a condensation reaction to obtain the compound of the general formula A8.
  • reaction schemes depicted below provide potential routes and key intermediates for the synthesis of compounds of the present disclosure.
  • Examples section below For a more detailed description of the individual reaction steps, see the Examples section below.
  • Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds of the present disclosure.
  • specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be readily substituted to provide various derivatives and/or reaction conditions.
  • most of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
  • the experimental instrument description (for example, 1 H NMR is recorded by a Varian Mercury-300 or Varian Mercury-400 nuclear magnetic resonance instrument, and 13 C NMR is recorded by a Varian Mercury-400 or Varian Mercury-500 or Varian Mercury-600 nuclear magnetic resonance instrument.
  • the resonance instrument records, and the chemical shift is expressed in ⁇ (ppm); the mass spectrum is recorded by Finnigan/MAT-95 (EI) and Finnigan LCQ/DECA and Micromass Ultra Q-TOF (ESI) type mass spectrometer; the silica gel used for reverse-phase preparation HPLC separation is 200-300 mesh).
  • Step 1 Synthesis of 5-(((6-methoxypyridin-2-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione
  • Step 2 5-(((3-bromo-2-methoxypyridin-4-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6- Synthesis of diketones
  • Step 1 Synthesis of 5-((5-methoxypyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione
  • Step 1 5-(((2-fluoro-3-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione synthesis
  • Step 1 Synthesis of methyl 6-methoxy-2-((4-methoxybenzyl)amino)nicotinate
  • Step 3 Synthesis of methyl 2-acetamido-6-methoxynicotinate
  • compound 7a-4 (1.0 g, 4.46 mmol), anhydrous methanol (10 mL), and ammonia water (20 mL) were sequentially added into a dry one-necked bottle (50 mL). React at room temperature for 16 hours. After concentration, the residue was extracted with ethyl acetate and water, the organic phase was concentrated, the residue was slurried with a small amount of ethyl acetate, and filtered to obtain compound 7a-5 (200 mg, white solid), yield: 21%.
  • LCMS(ESI): m/z 191.8[M+H]+; RT 1.715min(3min).
  • Step 1 Synthesis of methyl 4-amino-1-methyl-1H-pyrazole-5-carboxylate
  • Step 5 Synthesis of methyl 2-(4-amino-2-methylphenyl)acetate
  • compound 11a-2 (2.0 g, 6.04 mmol) was added to a one-necked bottle (100 mL) filled with glacial acetic acid (7.5 mL) and water (5 mL), and concentrated sulfuric acid (2 mL) was added slowly. React overnight at 130°C. Remove the solvent, add 20mL of water, adjust the pH to 11-12, extract with ethyl acetate, keep the water phase; adjust the pH of the water phase to 3-4, extract with ethyl acetate, wash the organic phase with water, wash with saturated brine, and anhydrous sodium sulfate Drying and concentration afforded compound 11a-3 (1.0 g, colorless oil). Yield: 73.4%.
  • Step 4 Synthesis of methyl 2-(4-amino-2-fluorophenyl)propionate
  • Step 2 Synthesis of ethyl 6-(diphenylmethyleneamino)benzofuran-3-carboxylate
  • Step 4 Synthesis of ethyl 6-amino-2,3-dihydrobenzofuran-3-carboxylate
  • Step 1 Synthesis of ethyl 2-methyl-2-(6-nitropyridin-3-yl)propionate
  • Step 2 Synthesis of ethyl 2-(6-aminopyridin-3-yl)-2-methylpropanoate
  • Step 1 Synthesis of methyl 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-carboxylate
  • Step 2 Synthesis of methyl 4-(4-hydroxyphenyl)tetrahydro-2H-pyran-4-carboxylate
  • Step 1 Synthesis of methyl 6-methoxy-1-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylate
  • Step 2 Synthesis of methyl 6-hydroxy-1-methyl-1,2,3,4-tetralin-1-carboxylate
  • Step 1 Synthesis of tert-butyl 5-(2-(tert-butoxy)-2-oxoethyl)indole-1-carboxylate
  • Step 2 Synthesis of methyl 6-methoxy-3,4-dihydronaphthalene-1-carboxylate
  • Step 3 Synthesis of methyl 6-methoxy-1,2,3,4-tetralin-1-carboxylate
  • Step 4 Synthesis of methyl 6-hydroxy-1,2,3,4-tetralin-1-carboxylate
  • Step 1 Synthesis of methyl 2-(4-methoxyphenyl)-3-methylbutyrate
  • Step 2 Synthesis of methyl 2-(4-hydroxyphenyl)-3-methylbutyrate
  • Step 1 tert-butyl 3-(1-methoxy-1-oxopropan-2-yl)pyrrolidine-1-carboxylate
  • reaction solution was quenched with saturated ammonium chloride solution, diluted with water, extracted with ethyl acetate, the organic phase was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, and the crude product 22a-1 (150 mg, yellow solid).
  • Step 2 tert-butyl 3-(1-methoxy-2-methyl-1-oxopropan-2-yl)pyrrolidine-1-carboxylate
  • Step 4 Synthesis of ethyl 2-(4-((7-methoxypyrido[2,3-d]pyrimidin-4-yl)amino)phenyl)acetate
  • Step 5 Synthesis of N-hydroxy-2-(4-((7-methoxypyrido[2,3-d]pyrimidin-4-yl)amino)phenyl)acetamide
  • Step 1 Synthesis of methyl 2-(4-((7-methoxy-1,8-naphthyridin-4-yl)oxy)phenyl)acetate
  • Step 2 Synthesis of 2-(4-((7-methoxy-1,8-naphthyridin-4-yl)oxy)phenyl)acetic acid
  • Step 3 2-(4-((7-Methoxy-1,8-naphthyridin-4-yl)oxy)phenyl)-N-((tetrahydro-2H-pyran-2-yl) Synthesis of oxy)acetamide
  • Step 4 Synthesis of N-hydroxy-2-(4-((7-methoxy-1,8-naphthyridin-4-yl)oxy)phenyl)acetamide
  • Step 1 Synthesis of methyl 4-((7-methoxyquinolin-4-yl)oxy)benzoate
  • Step 1 Synthesis of ethyl 2-(4-(((7-methoxyquinolin-4-yl)amino)phenyl)acetate
  • Step 3 2-(4-((7-methoxyquinolin-4-yl)amino)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acetamide synthesis
  • Step 4 Synthesis of N-hydroxy-2-(4-(((7-methoxyquinolin-4-yl)amino)phenyl)acetamide
  • Embodiments 5-17 Synthesize compound 5-17 according to the method described in embodiment 1-4 respectively, the structural formula of each embodiment compound sees the previous table
  • Step 3 Synthesis of tert-butyl 3-(4-chloro-2-pivalamidoaminopyridin-3-yl)-3-hydroxypropionate
  • Step 6 Synthesis of 2-(4-((8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenyl)acetic acid
  • Step 7 N-Hydroxy-2-(4-((8-methyl-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)amino)phenyl)acetamide synthesis
  • Step 1 Synthesis of methyl 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)acetate
  • Step 2 Synthesis of methyl 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)cyclopentane-1-carboxylate
  • Step 3 Synthesis of methyl 1-(4-(hydroxymethyl)phenyl)cyclopentane-1-carboxylate
  • Step 4 Synthesis of methyl 1-(4-(bromomethyl)phenyl)cyclopentane-1-carboxylate
  • Step 5 1-(4-((4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)cyclopentane-1- Synthesis of methyl formate Add 141-4 (500mg, 1.69mmol), pinacol diborate (858mg, 3.38mmol), tetrakistriphenylphosphine palladium (195mg, 0.169mmol) and potassium carbonate (700mg , 5.07mmol), 25mL of dioxane (25mL), heated to 100°C under the protection of argon and stirred for 4 hours.
  • Step 6 Synthesis of methyl 1-(4-((7-methoxy-1,8-naphthyridin-4-yl)methyl)phenyl)cyclopentane-1-carboxylate
  • Step 7 Synthesis of N-hydroxy-1-(4-((7-methoxy-1,8-naphthyridin-4-yl)methyl)phenyl)cyclopentane-1-carboxamide
  • Step 5 2-Methyl-2-(4-((3-methylisoxazol[5,4-d]pyrimidin-4-yl)oxy)phenyl)-N-((tetrahydro-2H Synthesis of -pyran-2-yl)oxy)propionamide
  • Step 6 Synthesis of N-hydroxy-2-methyl-2-(4-((3-methylisoxazol[5,4-d]pyrimidin-4-yl)oxy)phenyl)propaneamide
  • Step 3 Methyl 2-(1-((7-methoxy-1,8-naphthyridin-4-yl)methyl)pyrrolidin-3-yl)-2-methylpropanoate
  • Step 4 2-(1-((7-Methoxy-1,8-naphthyridin-4-yl)methyl)pyrrolidin-3-yl)-2-methylpropanoic acid
  • Step 5 2-(1-((7-Methoxy-1,8-naphthyridin-4-yl)methyl)pyrrolidin-3-yl)-2-methyl-N-((tetrahydro- 2H-pyran-2-yl)oxy)propionamide
  • Step 6 N-Hydroxy-2-(1-((7-methoxy-1,8-naphthyridin-4-yl)methyl)pyrrolidin-3-yl)-2-methylpropanamide
  • Step 1 Synthesis of (4-(benzyloxy)phenyl)-L-proline methyl ester
  • Step 3 Synthesis of (4-((7-methoxy-1,8-naphthyridin-4-yl)oxy)phenyl)-L-proline methyl ester
  • Step 4 Synthesis of (S)-N-hydroxy-1-(4-((7-methoxy-1,8-naphthyridin-4-yl)oxy)phenyl)pyrrolidine-2-carboxamide
  • Examples 23-207 Compounds 19-140, 142-193, and 197-207 were synthesized according to the methods described in Examples 1-4, 18-22, respectively. For the structural formulas of the compounds in each example, see the previous table.
  • Compound 165 (420mg) was resolved by a chiral column, the column model 250*25mm 10 ⁇ m, mobile phase: methanol (+0.1% 7.0mol/L ammonia methanol), to obtain compound 210 (101.74mg) and compound 211 (117.52mg);
  • DMSO dimethyl sulfoxide
  • the initial concentration was 1 ⁇ M, 3-fold dilution, 10 concentrations, and a duplicate well test was set for each concentration.
  • a 384-well plate serially dilute the solution to a corresponding 1000-fold final concentration (1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15nM), and then use Echo550 to transfer 5nL to a 384-well reaction plate for testing. 5 nL of 100% DMSO was transferred to the smallest well (substrate only, no enzyme, minimum signal value) and largest well (substrate, enzyme, no inhibitor, maximum signal value).
  • Inhibition rate% (maximum signal - compound signal) / (maximum signal - minimum signal) ⁇ 100
  • the “minimum signal” is the mean value of negative control wells, and the “maximum signal” is the mean value of positive control wells.
  • the percentage inhibition rate is the Y-axis
  • the log (inhibitor) vs. response-variable slope of the analysis software GraphPadPrism5 is used to fit the dose-effect curve, thereby drawing the compound of the present disclosure on the enzyme activity. Inhibition IC50 values.
  • the hydroxamic acid compounds of the present disclosure are better ENPP1 inhibitors, with an IC 50 value of ⁇ 5 ⁇ M, preferably an IC 50 value of ⁇ 1 ⁇ M, more preferably an IC 50 value of ⁇ 0.5 ⁇ M, and even more IC50 values ⁇ 0.125 [mu]M, most preferably ⁇ 0.1 [mu]M are preferred.
  • the activity of the hydroxamic acid compounds disclosed in the present disclosure in inhibiting ENPP1 is significantly better than that of compound A-2.
  • Oral administration 0.25h, 0.5h, 1.0h, 2.0h, 3.0h, 4.0h, 6.0h, 8.0h and 24h after administration.
  • Intravenous administration 5min, 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 6.0h, 8.0h and 24h after administration.
  • Plasma collection and processing Take 30-40 ⁇ L of venous blood through the retroocular venous plexus of mice at the above set time points, put them in EDTA-K2 test tubes, centrifuge at 3500 rpm for 10 minutes, separate the plasma, and freeze in a -20°C refrigerator.
  • the concentration of compounds in rat plasma was determined by LC/MS/MS method.
  • the non-compartmental model of Phoenix 8.3 software (Pharsight, USA) was used to calculate the pharmacokinetic parameters after administration.
  • the compounds in the present invention have high oral bioavailability, and the oral bioavailability is greater than 20%, such as Example 2 and Example 110. It can be seen that, compared with the known phosphoric acid compounds, the hydroxamic acid compounds of the present disclosure have obvious advantages of oral absorption.
  • the pK data of some compounds are shown in Table 2.

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Abstract

公开具有ENPP1抑制活性的式(I)化合物、其药物组合物和用途。式(I)化合物可用于预防或治疗由ENPP1异常活性介导的那些疾病或障碍。

Description

具有ENPP1抑制活性的异羟基肟酸类化合物及其用途 技术领域
本公开涉及一种异羟基肟酸类化合物、其用于抑制ENPP1的用途及使用所述化合物用于预防或治疗疾病的方法。
背景技术
作为机体抵御病原体的第一道防线，人体的免疫系统在对抗肿瘤细胞的过程中起着不可忽视的作用。STING(Stimulator of Interferon Gene)是一种由378个氨基酸组成的干扰素基因刺激因子，在对肿瘤细胞的免疫中起到了重要的作用。STING可以通过与cGAMP(cyclic GMP-AMP synthase)结合而被激活，进而招募TANK结合激酶1(TANK-binding kinase 1,TBK1)，导致干扰素调节因子3(Interferon Regulatory Factor 3,IRF3))被磷酸化。被磷酸化的IRF3会生产I型干扰素(type I interferon,IFN)和其他细胞因子，这些细胞因子与IFN共同作用引发了人体适应性免疫系统对肿瘤细胞与感染性疾病的免疫反应。
膜外核苷酸焦磷酸酶-磷酸二酯酶1(Ectonucleotide pyrophosphatase/phosphodi-esterase 1,ENPP1)是ENPP家族中的7个酶之一，是一种二型转膜糖蛋白。研究表明ENPP1拥有高水解性，可以分解多种包括磷酸二酯键、焦磷酸键在内的作用物，ATP也是ENPP1的主要作用目标之一。ENPP1不仅会将ATP水解为AMP和PPi，还会将cGAMP水解，抑制人体内部cGAMP的数量，使STING的活性降低。因此，ENPP1的活动抑制了人体免疫系统通过STING进行的抗肿瘤与抗感染性疾病的免疫反应，抑制ENPP1的活性有助于cGAMP的稳定性与STING的活性上升，进而提高人体免疫系统对肿瘤与感染性疾病的抵抗力。此外，ENPP1被证实在人类乳腺肿瘤中有着较于通常情况更加突出的表达，这不仅表明ENPP1是乳腺癌潜在的预测标记，更突出了其作为抗癌药物靶点的可能性与可靠性。
除去ENPP1在肿瘤方面的突出表现外，研究表明ENPP1的表达与多种由细菌或病毒导致的感染性疾病有关。因此，ENPP1也可用于感染性疾病的治疗。
尽管癌症患者有多种治疗选择，但仍需要有效且安全的治疗剂和其在组合疗法中的优选应用。
发明内容
本公开提供了式(I)化合物、其可药用盐、其药物组合物及其组合。发明人出人意料地发现，所述式(I)化合物为良好的ENPP1抑制剂。发明人还出人意料地发现，本公开的化合物具有良好的物理和化学稳定性、良好的生物利用度(例如低的清除率)和良好的成药性。
本公开进一步提供了治疗、预防或改善ENPP1介导的疾病或障碍的方法，其包含向有需要的个体施用有效量的ENPP1抑制剂。
具体地，本公开提供了如式(I)所示的异羟基肟酸类化合物：
Figure PCTCN2022118080-appb-000001
其中，各变量X、X 1、X 2、X 3、X 4、X 5和环A、Y、L如本文所定义，包括其立体异构体、几何异构体、互变异构体、可药用盐、多晶型物、溶剂合物、水合物或前药；它们可用于治疗或预防ENPP1介导的疾病或障碍，尤其是癌症或者感染性疾病或障碍。
本公开还提供了制备本公开的化合物的方法、用于制备本公开的化合物的中间体及所述中间体的制备方法。
本公开还提供了组合物，包含至少一种本公开的化合物或其可药用盐。
本公开还提供了药物组合物，包含治疗有效量的本公开的化合物或其可药用盐，以及一种或多种可药用的载体、稀释剂或赋形剂。
在一个实施方案中，本公开提供一种药物组合物，其包含治疗有效量的本公开的化合物或其可药用盐。
在另一个实施方案中，本公开提供组合，尤其是药物组合，其包含治疗有效量的本公开的化合物或其可药用盐，及一种或多种其它治疗剂。
本公开的化合物可以单独地、与其它的本公开的化合物组合地或与一种或多种、优选一种或两种其它物质组合地同时或依次使用。
本公开的化合物为ENPP1抑制剂，可以在体内调节STING活性，并因此可用于治疗或预防ENPP1介导的疾病或障碍，尤其是癌症或者感染性疾病或障碍。因此，本公开可提供对ENPP1活性的选择性胞外抑制，以增加cGAMP的胞外水平并激活干扰素基因刺激因子(STING)途径。例如将本公开化合物用于增强受试者中STING介导的响应的用途，以及将本公开的化合物用于调节受试者中的免疫响应的方法。
本公开的化合物可用于疗法。
本公开的化合物可用于制备药剂或药物，所述药剂或药物用于治疗或预防ENPP1介导的疾病或障碍，尤其是癌症或者感染性疾病或障碍。
本公开还涉及抑制个体中的ENPP1受体活性的方法，其中，该方法包含向有需要的个体施用治疗有效量的ENPP1抑制剂如本公开的化合物或其可药用盐。
在本公开的一个实施方案中，本公开提供了治疗或预防ENPP1介导的疾病或障碍的方法，该方法包括给有需要的患者施用有效量的第一种治疗剂和任选的第二种治疗剂，其中所述第一种治疗剂是本公开的化合物或其可药用盐，并且所述第二种治疗剂是一种或多 种其它治疗剂。
在本公开的另一个实施方案中，本公开涉及治疗或预防与ENPP1介导的疾病或障碍的方法，如癌症或者感染性疾病或病症的方法，其包含向个体施用治疗有效量的本公开的化合物或其可药用盐。
本公开的一种优选方法是治疗具体类型的癌症，包括：乳腺癌、肺癌、胶质母细胞瘤、脑癌和脊椎癌、头颈癌、皮肤癌、生殖系统癌症、胃肠系统癌症、食道癌、鼻咽癌、胰腺癌、直肠癌、肝细胞癌、胆管癌、胆囊癌、结肠癌、多发性骨髓瘤、肾脏和膀胱癌、骨癌、恶性间皮瘤、肉瘤、淋巴瘤、腺癌、甲状腺癌、心脏肿瘤、生殖细胞肿瘤、恶性神经内分泌肿瘤、恶性横纹肌样瘤、软组织肉瘤、中线束癌和未知原发癌。
本公开的另一种优选方法是治疗ENPP1介导的感染性疾病，包括：单纯疱疹病毒感染、牛痘病毒感染、腺病毒感染、人乳头瘤病毒感染、B型肝炎病毒感染、D型肝炎病毒感染、人免疫缺陷病毒感染、人巨细胞病毒感染、登革热病毒感染、埃博拉病毒感染、马尔堡病毒感染、寨卡病毒感染、单核细胞增生性李斯特菌感染、结核分枝杆菌感染、新凶手弗朗西斯菌感染、嗜肺军团菌感染、沙眼衣原体感染、肺炎链球菌感染、淋球菌感染。
另外，本公开提供了产品或试剂盒，其包含如上定义的本公开的化合物或其可药用盐、或其药物组合物和一种或多种其它活性剂在抗癌疗法中同时、分开或依次使用的联合制剂。
实施方案
具体地，本公开提供了如下的实施方案：
一方面，本公开提供了式(I)化合物：
Figure PCTCN2022118080-appb-000002
或其可药用盐，其中，
Figure PCTCN2022118080-appb-000003
是单键或双键；
X为N或CR 0；
X 1为N、O、S、CR 1或键；
X 2为N、O、S、NR 2或CR 2；
X 3为N、O、S、NR 3或CR 3；
X 4为N、O、S、NR 4或CR 4；
X 5为N或CR 5；
Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-、NR 6或CR 7R 8；
L为键、NR a、-NR x-CHR y-或(CR 9R 10) m；m为1或2；
R 0、R 5各自独立地选自：氢、卤素、CN、OH、NO 2、NR bR c、C 1-C 6烷基、C 3-C 6环烷基、-SO 2R a、-C(O)OR a、-C(O)NR bR c和C 1-C 6烷氧基；其中所述烷基、环烷基和烷氧基各自任选地被卤素取代；
R 1、R 2各自独立地选自：氢、卤素、CN、OH、NO 2、NR bR c、C 1-C 4烷基、C 3-C 6环烷基和C 1-C 4烷氧基；其中所述烷基、环烷基和烷氧基各自任选地被卤素取代；
R 3、R 4各自独立地选自：氢、卤素、CN、OH、NO 2、NR bR c、＝O、C 1-C 4烷基、C 3-C 6环烷基和C 1-C 4烷氧基；其中所述烷基、环烷基和烷氧基各自任选地被卤素取代；
R 6选自氢、C 1-C 4烷基和C 3-C 6环烷基；其中所述烷基和环烷基各自任选地被卤素取代；
R 7、R 8各自独立地选自：氢、卤素、OH、CN、NO 2、NR a、C 1-C 6烷基、C 3-C 6环烷基和C 1-C 6烷氧基；其中所述烷基、环烷基和烷氧基各自任选地被卤素取代；或者R 7和R 8与其所键合的碳原子一起形成任选地被卤素取代的C 3-C 6环烷基、或形成包含1-2个选自N、NR a、O和S(O) p的杂原子的4-至12-元杂环烷基；
R 9、R 10各自独立地选自氢、卤素、CN、OH、NO 2、NR aR b、C 1-C 8烷基、C 3-C 8环烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8烷氧基、包含碳原子和1-2个选自N、NR a、O和S(O) p的杂原子的4-至12-元杂环烷基、6-至10-元芳基和5-至10-元杂芳基；其中所述烷基、烯基、炔基、烷氧基、环烷基和杂环烷基各自被0-3个独立地选自卤素、羟基、CN的取代基取代；其中所述芳基和杂芳基各自被0-3个独立地选自卤素、C 1-C 4烷基、C 3-C 6环烷基和OR a的取代基取代；
或者R 9和R 10与其所键合的碳原子一起形成任选地被卤素取代的C 3-C 6环烷基、或形成包含1-2个选自N、NR a、O和S(O) p的杂原子的4-至12-元杂环烷基；
环A选自：C 4-C 10环烷基、4-至12-元杂环烷基、6-至10-元芳基和5-至10-元杂芳基；其中，环A任选地被独立地选自卤素、CN、OH、NO 2、NR bR c、C 1-C 4烷基、C 1-C 4烷氧基、C 3-C 6环烷基、4-至7-元杂环烷基、6-至10-元芳基和5-至10-元杂芳基和C 1-C 3卤代烷基的取代基取代一次或多次；
或者
L与环A一起形成C 4-C 8环烷基、含至少一个选自N、O或S的杂原子的5-至10-元部分饱和的杂环、6-至10-元芳基或5-至7-元杂芳基；其中所述环烷基、杂环、芳基和杂芳基任选地被独立地选自卤素、C 1-C 4烷基、C 1-C 4烷氧基的取代基取代一次或多次；或
Y与环A一起形成5-至10-元部分饱和的杂环、6-至10-元芳基或5-至10-元杂芳基，其中所述杂环、芳基和杂芳基任选地被独立地选自卤素、C 1-C 4烷基、C 1-C 4烷氧基的取代基取代一次或多次；
R a、R b、R c各自独立地选自：氢、C 1-C 4烷基、C 3-C 6环烷基和苄基；其中所述烷基和环烷基各自任选地被卤素取代；或者R b和R c与其所键合的氮原子一起形成任选地被卤素 取代的3-至6-元杂环烷基；
R x、R y各自独立地选自氢和C 1-C 4烷基；或R x和R y与其所键合的碳、氮原子一起形成4-至8-元杂环烷基；和
p为1或2；
条件是，当X 1至X 4各自为CR n时，Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-或CH 2；其中R n对于X 1而言为R 1，对于X 2而言为R 2，对于X 3而言为R 3，和对于X 4而言为R 4。
在本公开的一个具体实施方案中，X 1为N、O、S或CR 1；优选地，X 1为N或CR 1。
在本公开的另一个具体实施方案中，X 1为N。
在本公开的另一个具体实施方案中，X 1为CR 1。
在本公开的另一个具体实施方案中，X 1为键或CR 1。
在本公开的另一个具体实施方案中，X 1为键。
在本公开的一些实施方案中，X 1为CR 1，且Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-或CR 7R 8；优选地，Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-或CH 2。
在本公开的另一些实施方案中，X 1为CR 1，且X 2为CR 2、X 3为CR 3、X 4为CR 4时，Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-或CH 2。
在本文中，无论何时提及R n时，其对于X 1而言表示R 1，对于X 2而言表示R 2，对于X 3而言表示R 3，和对于X 4而言表示R 4。
在本公开的另一些实施方案中，R 0、R 5各自独立地选自：氢、卤素、CN、OH、NO 2、NH 2、C 1-C 6烷基、C 3-C 6环烷基和C 1-C 6烷氧基，其中所述烷基、环烷基、烷氧基各自任选地被0-3个卤素取代。优选地，R 0、R 5各自独立地选自氢、卤素、CN、OH、NO 2、NH 2、C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4烷氧基，其中所述烷基、环烷基、烷氧基各自任选地被0-3个卤素取代。更优选地，R 0、R 5各自独立地选自氢、卤素、CN、OH、NO 2、NH 2、C 1-C 3烷基。
在本公开的另一些实施方案中，R 1选自：氢、卤素、CN、OH、NO 2、NH 2、C 1-C 4烷基、C 1-C 3烷氧基和C 1-C 3卤代烷基；优选地选自：氢、卤素、CN、OH、NH 2、C 1-C 3烷基；更优选地，R 1选自：氢、卤素、CN、OH。
在本公开的另一些实施方案中，R 2选自：氢、卤素、CN、OH、NO 2、NH 2、C 1-C 4烷基、C 1-C 3烷氧基和C 1-C 3卤代烷基；优选地选自：氢、卤素、OH、C 1-C 3烷基和C 1-C 3烷氧基，所述烷基、环烷基和烷氧基各自任选地被0-3个卤素取代。更优选地，R 2选自氢、卤素、C 1-C 3烷基和C 1-C 3烷氧基。
在本公开的另一些实施方案中，R 3、R 4各自独立地选自：氢、卤素、CN、OH、NO 2、NH 2、C 1-C 4烷基、＝O、C 3-C 6环烷基、C 1-C 3烷氧基，其中，所述烷基、环烷基、烷氧基任选地各自被0-3个卤素取代；优选地，R 3、R 4各自独立地选自：氢、卤素、CN、OH、NO 2、NH 2、＝O、C 1-C 4烷基、C 3-C 6环烷基、C 1-C 3烷氧基和C 1-C 3卤代烷基。更优选地，R 3选自氢、卤素、OH、＝O、C 1-C 3烷基和C 1-C 3烷氧基，R 4选自氢、卤素、C 1-C 3烷基、 C 1-C 3烷氧基、C 3-C 6环烷基和C 1-C 3卤代烷基。
在本公开的一些实施方案中，R 3、R 4各自独立地选自＝O。
在有些具体实施方式中，X 3为-C(＝O)-，且X 4为CH。
在其它具体实施方式中，X 4为-C(＝O)-，且X 3为CH。
在本公开的另一些实施方案中，R 1、R 2、R 3、R 4各自独立地选自氢、卤素、CN、OH、NO 2、NH 2、C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4烷氧基和C 1-C 4卤代烷基；优选地，选自氢、卤素、CN、OH、NO 2、NH 2、C 1-C 3烷基、C 3-C 4环烷基、C 1-C 3烷氧基和C 1-C 2卤代烷基；更优选地，选自H、F、Cl、CN、OH、NO 2、NH 2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、氟甲基、二氟甲基、三氟甲基、氟乙基、2,2-二氟甲基、1,2-二氟甲基、2,2,2-三氟乙基和环丙基。
在本公开的另一些实施方案中，R 1为氢或卤素，R 2选自氢、卤素、OH、C 1-C 3烷基和C 1-C 3烷氧基；R 3选自氢、卤素、OH、＝O、NR bR c、C 1-C 3烷基和C 1-C 3烷氧基；和R 4选自氢、卤素、C 1-C 3烷基、C 1-C 3烷氧基、C 3-C 6环烷基和C 1-C 4卤代烷基；优选地，R 5选自氢、卤素、CN和C 1-C 6烷基。
在本公开的另一些实施方案中，R 1为氢或卤素，R 2选自氢、卤素、OH、C 1-C 3烷基和C 1-C 3烷氧基；R 3选自氢、卤素、OH、＝O、C 1-C 3烷基和C 1-C 3烷氧基；和R 4选自氢、卤素、C 1-C 3烷基和C 1-C 3烷氧基。优选地，R 0、R 5各自独立地选自氢、卤素、CN和C 1-C 6烷基。
在本公开的另一些实施方案中，R 0选自氢、卤素、CN、OH、NO 2、NH 2、C 1-C 4烷基、C 3-C 6环烷基和C 1-C 4烷氧基；R 1为氢或卤素，R 2选自氢、卤素、OH、C 1-C 3烷基和C 1-C 3烷氧基，R 3选自氢、卤素、OH、C 1-C 3烷基和C 1-C 3烷氧基；R 4选自氢、卤素、C 1-C 3烷基和C 1-C 3烷氧基；R 5选自氢、卤素、CN、C 1-C 4烷基。
在本公开的另一些实施方案中，R 1为氢或卤素；R 2选自氢、卤素、C 1-C 3烷基和C 1-C 3烷氧基；R 3选自氢、卤素、OH、＝O、NR bR c、C 1-C 3烷基和C 1-C 3烷氧基；R 4选自氢、卤素和C 1-C 3烷基。优选地，R 5选自氢、卤素、CN和C 1-C 6烷基；
在本公开的另一些实施方案中，R 1为氢或卤素；R 2选自氢、卤素和C 1-C 3烷氧基；R 3选自氢、卤素、OH和C 1-C 3烷氧基；R 4选自氢和卤素。优选地，R 5选自氢、卤素、CN和C 1-C 6烷基。
在本公开的另一些实施方案中，R 1为氢或卤素；R 2选自氢、卤素、OH和C 1-C 3烷氧基；R 3选自氢、卤素、OH、C 1-C 3烷基和C 1-C 3烷氧基；R 4选自氢、卤素和C 1-C 3烷氧基；优选地，R 5选自氢、卤素、CN和C 1-C 6烷基。更优选地，R 3选自氢、卤素、OH和C 1-C 3烷氧基。
在本公开的另一些实施方案中，R 2选自氢、卤素、C 1-C 3烷基和C 1-C 3烷氧基；R 3选自氢、OH和卤素；R 4选自氢、卤素、C 1-C 3烷基、C 1-C 3烷氧基、C 3-C 4环烷基和C 1-C 3卤代烷基；优选地，R 5选自氢、卤素、CN和C 1-C 6烷基。
在本公开的一个具体实施方案中，X为N或X 5为N。
在本公开的另一个具体实施方案中，X 5为N。
在本公开的另一个具体实施方案中，X为N。
在本公开的一些实施方案中，Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-、NR 6或CR 7R 8；其中R 6选自氢、C 1-C 4烷基和C 3-C 6环烷基，R 7和R 8各自独立地选自氢、卤素、OH、CN、NO 2、C 1-C 6烷基、C 3-C 6环烷基和C 1-C 6烷氧基。优选地，Y为O、NR 6或CR 7R 8。
在本公开的一些实施方案中，Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-或CR 7R 8，优选为O、-C(＝O)-或CR 7R 8，更优选为O或CR 7R 8。进一步优选地，R 7、R 8各自独立地选自氢、C 1-C 3烷基。
在本公开的一些实施方案中，Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-或CH 2。
在本公开的一些实施方案中，Y为NR 6，R 6选自氢、C 1-C 4烷基和C 3-C 6环烷基。优选地，R 6选自氢和C 1-C 3烷基。
在本公开的一些实施方案中，Y与环A一起形成5-至10-元部分饱和的杂环、6-至10-元芳基或5-至10-元杂芳基，其中所述杂环、芳基和杂芳基任选地被独立地选自卤素、C 1-C 4烷基、C 1-C 4烷氧基的取代基取代一次或多次；如
Y为NR 6，R 6为C 1-C 4烷基，且R 6与其所键合的氮原子和环A一起形成5-至10-元部分饱和的杂环、6-至10-元芳基或5-至10-元杂芳基；或
Y为CR 7R 8，且R 7或R 8与其所键合的碳原子和环A一起形成5-至10-元部分饱和的杂环、6-至10-元芳基或5-至10-元杂芳基。
在本公开的一些实施方案中，Y与环A一起形成7-至10-元部分饱和的二环杂环、萘基或7-至10-元二环杂芳基。优选地，Y与环A一起形成二氢苯并呋喃基、二氢异苯并呋喃基、二氢吲哚基、二氢苯并噻吩基、二氢苯并噻唑基、二氢苯并吡喃基、四氢喹啉基、四氢异喹啉基、四氢吡啶并[3,4-b]吡嗪基。更优选地，Y与环A一起形成二氢吲哚基。
在本公开的一些实施方案中，Y为CR 7R 8，其中，R 7、R 8各自独立地选自：氢、卤素、OH、CN、NO 2、NH 2、C 1-C 6烷基、C 3-C 6环烷基和C 1-C 6烷氧基，优选地，选自氢和C 1-C 6烷基；其中所述烷基、环烷基和烷氧基各自任选地被0-3个卤素取代。
在本公开的另一些实施方案中，Y为CR 7R 8，其中，R 7和R 8与其所键合的碳原子一起形成被0-3个卤素任选取代的C 3-C 6环烷基、或形成包含1-2个选自N、NR a、O和S(O) p的杂原子的5-至6-元杂环烷基；R a选自氢、C 1-C 3烷基，p为1或2。
在本公开的另一些实施方案中，Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-、NR 6或CR 7R 8；R 6选自氢、C 1-C 4烷基和C 3-C 6环烷基；R 7、R 8各自独立地选自氢、C 1-C 3烷基。更优选地，R 6选自氢、C 1-C 3烷基，R 7、R 8各自独立地选自氢、C 1-C 3烷基；
优选地，Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-、-NH-、-N(CH 3)-、-N(乙基)-、-N(丙基)-、-N(环丙基)-、-N(环丁基)-、-N(环戊基)-、-CH 2-、-CHF-、-CH(OH)-、-CH(CH 3)-、-CH(OCH 3)-、-CH(OEt)-或-C(CH 3) 2-；更优选地，Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-、-NH-、-N(CH 3)-、-CH(CH 3)-或-CH 2-。
在本公开的一些实施方案中，Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-、NH或CH 2； 优选地，Y为O、S、-S(＝O)-、-S(＝O) 2-、NH或CH 2；更优选地，Y为O、S或NH。
在本公开的另一些实施方案中，Y为O、NR 6或CR 7R 8；优选地，Y为O、NH、N(C 1-C 3烷基)、CH 2、CH(C 1-C 3烷基)、或C(C 1-C 3烷基)(C 1-C 3烷基)。更优选地，Y为O、NH、-NCH 3、CH 2、或-CHCH 3。
在本公开的另一个具体实施方案中，Y为O。
在本公开的另一个具体实施方案中，Y为NH。
在本公开的一些实施方案中，L为键、NR a、-NR x-CHR y-、CR 9R 10或(CR 9R 10) 2。可以理解，在(CR 9R 10) 2中，两个-CR 9R 10-单元各自可以是相同或不同的，例如在-CH 2-CH(CH 3)中。
在另一些实施方案中，L为-NR x-CHR y-，其中，R x、R y各自独立地选自：氢、C 1-C 4烷基，或R x和R y与其所键合的碳、氮原子一起形成4-至8-元杂环烷基。优选地，形成4-至6-元杂环烷基；如一起形成
Figure PCTCN2022118080-appb-000004
在本公开的一些实施方案中，R a选自氢、C 1-C 4烷基、C 3-C 6环烷基和苄基，其中所述烷基和环烷基各自任选地被卤素取代。优选地，R a选自氢、C 1-C 4烷基、C 3-C 6环烷基、C 1-C 4卤代烷基、C 3-C 6卤代环烷基和苄基。更优选地，R a选自氢、C 1-C 3烷基和苄基。
在本公开的一些实施方案中，R 9、R 10各自独立地选自氢、卤素、CN、OH、NH 2、C 1-C 8烷基、C 3-C 8环烷基、C 1-C 8烷氧基、包含碳原子和1-2个选自N、NR a、O和S(O) p的杂原子的4-至12-元杂环烷基，优选选自氢、卤素、OH、NH 2、C 1-C 8烷基、C 3-C 8环烷基、C 1-C 8烷氧基、包含碳原子和1-2个选自N、NR a、O和S(O) p的杂原子的4-至8-元杂环烷基。
在本公开的另一些实施方案中，R 9和R 10与其所键合的碳原子一起形成被0-3个卤素取代的C 3-C 6环烷基或包含1-2个选自N、NR a、O和S(O) p的杂原子的4-至12-元杂环烷基。优选地，R 9和R 10与其所键合的碳原子一起形成C 3-C 6环烷基或包含1-2个选自N、NR a、O和S(O) p的杂原子的4-至8-元杂环烷基。
在本公开的一个具体实施方案中，L为键。
在本公开的一些实施方案中，L为键或(CR 9R 10) m；m为1或2。优选地，L为CR 9R 10或(CR 9R 10) 2；更优选地，L为CR 9R 10。
在本公开的一些实施方案中，L为NR a或(CR 9R 10) m；m为1或2。优选地，L为NR a或CR 9R 10；更优选地，L为NH或CR 9R 10。
在本公开的一些实施方案中，L为NR a；R a选自：氢、C 1-C 4烷基、C 3-C 6环烷基；其中所述烷基和环烷基各自被0-3个卤素取代。优选地，R a选自氢、C 1-C 3烷基。
在本公开的一些实施方案中，L为(CR 9R 10) m；m为1或2；
R 9、R 10各自独立地选自氢、卤素、CN、OH、NO 2、NH 2、C 1-C 8烷基、C 3-C 8环烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8烷氧基、包含碳原子和1-2个选自N、NR a、O和S(O) p的杂原子的4-至12-元杂环烷基、6-至10-元芳基、5-至10-元杂芳基；其中所述烷基、烯基、 炔基、烷氧基、环烷基和杂环烷基各自被0-3个独立地选自卤素、羟基、CN的取代基取代；其中，所述芳基和杂芳基各自被0-3个独立地选自卤素、C 1-C 4烷基、C 3-C 6环烷基、OR a的取代基取代；
或者，R 9和R 10与其所键合的碳原子一起形成被0-3个卤素取代的C 3-C 6环烷基、或形成包含1-2个选自N、NR a、O和S(O) p的杂原子的4-至12-元杂环烷基。
在本公开的一些实施方案中，L为NH或CR 9R 10，且Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-、NR 6或CR 7R 8；R 6、R 7、R 8各自独立地选自氢、C 1-C 4烷基和C 3-C 6环烷基；优选地，R 6、R 7、R 8各自独立地选自氢、C 1-C 3烷基；更优选地，L为CR 9R 10，R 6、R 7、R 8各自独立地选自氢、C 1-C 3烷基。
在本公开的一个优选实施方案中，其中L为NR a或CR 9R 10；
优选地，L为CR 9R 10；其中，R 9、R 10各自独立地选自氢、卤素、CN、OH、NO 2、NH 2、C 1-C 6烷基、C 3-C 6环烷基和C 1-C 6烷氧基，包含碳原子和1-2个选自N、O和S的杂原子的4-至12-元杂环烷基，或者R 9和R 10其所键合的碳原子一起形成被0-3个卤素取代的C 3-C 6环烷基(例如环丙烷、环丁烷、环戊烷或环己烷)或包含1-2个选自N、NR a、O和S(O) p的杂原子的4-至12-元杂环烷基(例如氧杂环丁烷、氮杂环丁烷、硫杂环丁烷、四氢呋喃环、吡咯烷、四氢噻吩环、吡唑烷、咪唑烷、噻唑烷、噁唑烷、哌啶环、四氢吡喃环、哌嗪环、六氢嘧啶环、噁嗪烷、哒嗪烷、吗啉环、硫代吗啉环、噻吩烷、四氢吡喃环、硫杂环己烷、氧杂环庚烷、氮杂环庚烷或硫杂环庚烷)；
或L为CR 9R 10，其中，R 9、R 10各自独立地选自氢、卤素、CN、OH、C 1-C 6烷基和C 1-C 6烷氧基，或者R 9和R 10与其所键合的碳原子一起形成C 3-C 6环烷基(例如环丙烷、环丁烷、环戊烷或环己烷)；
或者L选自-CH 2-、-CH(OH)-、-CHF-、-CH(CN)-、-CH(CH 3)-、-CH(OCH 3)-、-CH(OEt)-、-C(CH 3) 2-、-CH(CH(CH 3) 2)-、-CH(CH 2CH(CH 3) 2)-、-C(CH 2CH(CH 3) 2) 2-、-C(CH(CH 3) 2) 2-、-C(CH 2CH 3) 2-和
Figure PCTCN2022118080-appb-000005
优选地，L选自：-CH 2-、-CH(OH)-、-CHF-、-CH(CH 3)-、-CH(OCH 3)-、-CH(OEt)-、-C(CH 3) 2-、-CH(CH(CH 3) 2)-、-CH(CH 2CH(CH 3) 2)-、-C(CH 2CH(CH 3) 2) 2-、-C(CH 2CH 3) 2-、
Figure PCTCN2022118080-appb-000006
在本公开的另一些实施方案中，L为(CR 9R 10) 2。优选地，L为-CH 2CH 2-、-CH 2CH(CH 3)-、-CH(CH 3)CH 2-、-CH 2CHF-、-CH 2CH(OCH 3)-。
在本公开的一些实施方案中，环A选自：C 4-C 8环烷基、4-至8-元杂环烷基、6-至10-元芳基和5-至10-元杂芳基；优选地，环A任选地可以被独立地选自卤素、CN、OH、NO 2、NR bR c、C 1-C 4烷基、C 1-C 4烷氧基、C 3-C 6环烷基、4-至7-元杂环烷基、6-至10-元芳基和5-至10-元杂芳基和C 1-C 3卤代烷基的取代基取代一次或多次、例如一次或两次；R b、R c各自独立地选自氢、C 1-C 4烷基和C 3-C 6环烷基，其中所述烷基和环烷基各自被0-3个卤素取代，或者R b和R c与其所键合的氮原子一起形成被0-3个卤素取代的3-至6-元杂环烷基。进一步地，环A任选地被独立地选自卤素、CN、OH、NH 2、C 1-C 4烷基、C 1-C 4烷氧基和C 1-C 3卤代烷基的取代基取代一次或多次、例如一次或两次。更进一步地，环A任选地被独立地选自卤素、CN、C 1-C 4烷基和C 1-C 4烷氧基的取代基取代一次或两次。
优选地，环A任选地可以被独立地选自F、Cl、CN、OH、NO 2、NH 2、C 1-C 4烷基、C 1-C 4烷氧基、C 3-C 6环烷基和C 1-C 3卤代烷基的取代基取代一次或多次、例如一次或两次；进一步优选地，环A任选地可以被独立地选自F、Cl、CN、OH、NO 2、NH 2、C 1-C 3烷基、C 3-C 6环烷基和C 1-C 3烷氧基的取代基取代一次或多次、例如一次或两次。
在本公开的一个优选实施方案中，环A为任选取代的或无取代的环戊烷、环己烷、吡咯烷、吡唑烷、咪唑烷、噻唑烷、吡咯环、呋喃环、噻吩环、吡唑环、噻唑环、噁唑环、咪唑环、四氢呋喃环、四氢噻吩环、吡喃环、吡嗪环、四氢吡喃环、哌啶环、六氢嘧啶、二氢呋喃环、二氢噻吩环、二氢咪唑环、二氢吡唑环、二氢吡咯环、二氢吲哚环、二氢异吲哚环、二氢吡喃环、二氢吡啶环、二氢哌嗪环、哌嗪环、苯环、吡啶环、嘧啶环、萘环、喹啉环、异喹啉环、吲哚环、异吲哚环、吲唑环或苯并咪唑环；
优选地，环A为任选取代的或无取代的环戊烷、环己烷、吡咯烷、咪唑烷、吡唑环、吡咯环、咪唑环、呋喃环、噻吩环、吡喃环、四氢呋喃环、四氢噻吩环、四氢吡喃环、哌啶环、吡嗪环、哌嗪环、苯环、吡啶环、嘧啶环或萘环；
更优选地，环A为任选取代的或无取代的环戊烷、环己烷、吡咯烷、哌啶环、嘧啶环、苯环、吡啶环、哌嗪环、咪唑环、吡唑环或萘环；
进一步优选地，环A为被F、Cl、CN、OH、NO 2、NH 2、C 1-C 3烷基、或C 1-C 3烷氧基取代一次或两次的环戊烷、环己烷、吡咯烷、哌啶环、嘧啶环、苯环、吡啶环、哌嗪环、咪唑环、四氢吡咯环、吡唑环或萘环。
在本公开的一些实施方案中，环A任选被独立地选自卤素、CN、OH、NO 2、NH 2、C 1-C 3烷基、C 1-C 3烷氧基和C 1-C 3卤代烷基的取代基取代一次或多次、例如一次或两次；优选地，环A任选被独立地选自F、Cl、CN、OH、NO 2、NH 2、C 1-C 3烷基和C 1-C 3烷氧基的取代基取代一次或多次、例如一次或两次。
在本公开的一些实施方案中，环A选自：
Figure PCTCN2022118080-appb-000007
其中，R 11各自可以相同或不同，独立地选自卤素、CN、OH、NO 2、NH 2、C 1-C 4烷基、C 1-C 4烷氧基和C 1-C 4卤代烷基；q为0、1、或2。优选地，R 11选自F、Cl、CN、C 1-C 4烷基或C 1-C 4烷氧基；R a选自氢和C 1-C 4烷基，q为0、1或2。
在本公开的一些实施方案中，L与环A一起形成C 4-C 8环烷基、含至少一个选自N、O或S的杂原子的5-至10-元部分饱和的杂环、6-至10-元芳基或5-至7-元杂芳基；所述环烷基、杂环、芳基和杂芳基任选地被独立地选自卤素、C 1-C 4烷基、C 1-C 4烷氧基的取代基取代一次或多次。优选地，所述环烷基、杂环、芳基和杂芳基任选地被独立地选自卤素、C 1-C 3烷基、C 1-C 3烷氧基的取代基取代一次或多次。
在本公开的一些实施方案中，L与环A一起形成含至少一个选自N、O或S的杂原子的5-至10-元部分饱和的杂环、6-至10-元芳基或5-至7-元杂芳基，所述杂环、芳基和杂芳基任选地被独立地选自卤素、C 1-C 4烷基、C 1-C 4烷氧基的取代基取代一次或两次。
在本公开的一些实施方案中，L与环A一起形成任选取代的或无取代的二氢苯并呋喃环、二氢异苯并呋喃环、二氢苯并噻吩环、二氢吲哚环、二氢异吲哚环、二氢苯并咪唑环、二氢苯并噁唑环、二氢苯并噻唑环、二氢苯并吡喃环、二氢异苯并吡喃环、四氢喹啉环、四氢异喹啉环、2,3-二氢-1H-吡咯并[2,3-b]吡啶环、2,3-二氢-1H-吡咯并[3,2-b]吡啶环、四氢吡啶并[3,4-b]吡嗪环、二氢茚环、四氢萘环、2,3-二氢呋喃并[2,3-b]吡啶环、2,3-二氢呋喃并[3,2-b]吡啶环；优选地，各自任选被独立地选自卤素、C 1-C 4烷基、C 1-C 4烷氧基的取代基取代一次或多次。
更优选地，L与环A一起形成任选取代的或无取代的二氢苯并呋喃环、二氢异苯并呋喃环、二氢吲哚环、二氢异吲哚环、二氢苯并吡喃环、二氢异苯并吡喃环、四氢喹啉环、四氢异喹啉环、二氢茚环、四氢萘环、2,3-二氢呋喃并[2,3-b]吡啶环、2,3-二氢-1H-吡咯并[2,3-b]吡啶环；进一步优选地，各自任选被独立地选自卤素、C 1-C 4烷基、C 1-C 4烷氧基的取代基取代一次或多次。
在本公开的一个优选实施方案中，L与环A一起形成如下含至少一个选自N、O或S的杂原子的5-至10-元部分饱和的杂环、6-至10-元芳基或5-至7-元杂芳基：
Figure PCTCN2022118080-appb-000008
其中，M、T各自可以相同或不同，各自独立地为N或C；R 11各自可以相同或不同，独立地选自卤素、CN、OH、NH 2、C 1-C 3烷基、C 1-C 3烷氧基和C 1-C 3卤代烷基；q为0、1、或2。优选地，R 11选自F、Cl、CN、C 1-C 3烷基或C 1-C 3烷氧基；q为0、1或2。
在本公开的一个优选实施方案中，Y与环A一起形成选自如下的基团：
Figure PCTCN2022118080-appb-000009
其中，M 1各自独立地为N、CH或C(C 1-C 4烷基)。优选地，Y为NR 6，R 6为C 1-C 4烷基，且R 6与其所键合的氮原子和环A一起形成5-至10-元部分饱和的杂环、6-至10-元芳基或5-至10-元杂芳基，其中所述杂环、芳基和杂芳基任选地被独立地选自卤素、C 1-C 4烷基、C 1-C 4烷氧基的取代基取代一次或多次。
进一步地，Y与环A一起形成选自如下的基团：
Figure PCTCN2022118080-appb-000010
进一步地，本公开提供了式(I)化合物或其可药用盐：
Figure PCTCN2022118080-appb-000011
或其可药用盐，其中，
Figure PCTCN2022118080-appb-000012
是单键或双键；
X为N或CR 0；
X 1为N、O、S、CR 1或键；
X 2为N、O、S、NR 2或CR 2；
X 3为N、O、S、NR 3或CR 3；
X 4为N、O、S、NR 4或CR 4；
X 5为N或CR 5；
Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-、NR 6或CR 7R 8；
L为键、NR a、-NR x-CHR y-或(CR 9R 10) m；m为1或2；
R 0、R 5各自独立地选自氢、卤素、CN、OH、NO 2、NH 2、C 1-C 4烷基、C 3-C 6环烷基、-SO 2R a、-C(O)OR a、-C(O)NR bR c和C 1-C 4烷氧基，其中所述烷基、环烷基、烷氧基各自任选地被卤素取代；
R 1、R 2各自独立地选自H、卤素、CN、OH、NO 2、NH 2、C 1-C 4烷基、C 1-C 3烷氧基和C 1-C 3卤代烷基；
R 3、R 4各自独立地选自H、卤素、CN、OH、NO 2、NH 2、＝O、C 1-C 4烷基、C 3-C 6环烷基、C 1-C 3烷氧基和C 1-C 3卤代烷基；
R 6选自氢、C 1-C 4烷基和C 3-C 6环烷基；
R 7、R 8各自独立地选自氢、C 1-C 4烷基、C 3-C 6环烷基和C 1-C 4烷氧基；
R 9、R 10各自独立地选自氢、卤素、CN、OH、NH 2、NO 2、C 1-C 8烷基、C 3-C 8环烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8烷氧基、包含碳原子和1-2个选自N、NR a、O和S(O) p的杂原子的4-至12-元杂环烷基、6-至10-元芳基和5-至10-元杂芳基；其中所述烷基、烯基、炔基、环烷基、烷氧基和杂环烷基各自被0-3个独立地选自卤素、OH和CN的取代基取代；其中所述芳基和杂芳基各自被0-3个独立地选自卤素、C 1-C 4烷基、C 3-C 6环烷基和OR a的取代基取代；
或者R 9和R 10与其所键合的碳原子一起形成任选地被卤素取代的C 3-C 6环烷基、或形成包含1-2个选自N、NR a、O和S(O) p的杂原子的4-至12-元杂环烷基；
环A选自：C 4-C 8环烷基、4-至8-元杂环烷基、6-至10-元芳基和5-至10-元杂芳基；其中，环A任选地被独立地选自卤素、CN、OH、NO 2、NR bR c、C 1-C 4烷基、C 1-C 4烷氧基、C 3-C 6环烷基、4-至7-元杂环烷基、5-至10-元芳基和5-至10-元杂芳基和C 1-C 3卤代烷基的取代基取代一次或多次；
或者
L与环A一起形成C 4-C 8环烷基、含至少一个选自N、O或S的杂原子的5-至10-元部分饱和的杂环、6-至10-元芳基或5-至7-元杂芳基；其中所述环烷基、杂环、芳基和杂芳基任选地被独立地选自卤素、C 1-C 3烷基、C 1-C 3烷氧基的取代基取代一次或多次；或
Y与环A一起形成5-至10-元部分饱和的杂环、6-至10-元芳基或5-至10-元杂芳基，其中所述杂环、芳基和杂芳基任选地被独立地选自卤素、C 1-C 4烷基、C 1-C 4烷氧基的取代基取代一次或多次；
R a、R b、R c各自独立地选自氢、C 1-C 4烷基、C 3-C 6环烷基和苄基，其中所述烷基和环烷基各自任选地被卤素取代，或者R b和R c与其所键合的氮原子一起形成任选地被卤 素取代的3-至6-元杂环烷基；
R x、R y各自独立地选自氢和C 1-C 4烷基，或R x和R y与其所键合的碳、氮原子一起形成4-至8-元杂环烷基；和
p为1或2；
条件是，当X 1至X 4各自为CR n时，Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-或CH 2，其中R n对于X 1而言为R 1，对于X 2而言为R 2，对于X 3而言为R 3，和对于X 4而言为R 4。
在本公开的一个具体实施方案中，其中，
R 1为氢或卤素；
R 2选自氢、卤素、OH、C 1-C 3烷基和C 1-C 3烷氧基；
R 3选自氢、卤素、OH、NR bR c、＝O、C 1-C 3烷基和C 1-C 3烷氧基；
R 4选自氢、卤素、C 1-C 3烷基、C 1-C 3烷氧基、C 3-C 6环烷基和C 1-C 4卤代烷基；
R 5选自氢、卤素、CN和C 1-C 6烷基；
在本公开的另一个具体实施方案中，其中，
R 1为氢或卤素；
R 2选自氢、卤素、OH、C 1-C 3烷基和C 1-C 3烷氧基；
R 3选自氢、卤素、OH、＝O、C 1-C 3烷基和C 1-C 3烷氧基；
R 4选自氢、卤素、C 1-C 3烷基、C 1-C 3烷氧基、C 3-C 6环烷基和C 1-C 4卤代烷基；
R 5选自氢、卤素、CN和C 1-C 6烷基；
R 6、R 7、R 8各自独立地选自氢、C 1-C 3烷基。
在本公开的另一个具体实施方案中，X 1、X 2、X 3、X 4中至少一个独立地选自N、O、S和NR n(如果有的话)；其中R n对于X 1而言为R 1，对于X 2而言为R 2，对于X 3而言为R 3，对于X 4而言为R 4。
在本公开的另一个具体实施方案中，提供了式(I)化合物或其可药用盐：其中，X 1、X 2、X 3、X 4中至少一个独立地选自N和NR n(如果有的话)；其中R n对于X 1而言为R 1，对于X 2而言为R 2，对于X 3而言为R 3，对于X 4而言为R 4。具体地，本公开提供式(Ia)化合物：
Figure PCTCN2022118080-appb-000013
或其可药用盐；其中，
X 1、X 2、X 3、X 4中至少一个独立地选自N或NR n；即X 1、X 2、X 3、X 4中至少X 1为N、或至少X 2为N或NR 2、或至少X 3为N或NR 3、或至少X 4为N或NR 4；
各变量X 5、X、Y、A、L是如式(I)所定义的。
在本公开的一个具体实施方案中，X 1、X 2、X 3、X 4中至少一个独立地选自N或NR n，且R 1为氢或卤素；
R 2选自氢、卤素、C 1-C 3烷基和C 1-C 3烷氧基；
R 3选自氢、卤素、OH、＝O、NR bR c、C 1-C 3烷基和C 1-C 3烷氧基；
R 4选自氢、卤素和C 1-C 3烷基；
R 5选自氢、卤素、CN和C 1-C 6烷基；
R a选自氢、C 1-C 3烷基；
优选地，R 6、R 7、R 8各自独立地选自氢、C 1-C 3烷基。
在本公开的一个优选实施方案中，X 1、X 2、X 3、X 4中至少一个独立地选自N或NR n，且R 1为氢或卤素；
R 2选自氢、卤素、OH、C 1-C 3烷基和C 1-C 3烷氧基；
R 3选自氢、卤素、OH和C 1-C 3烷氧基；
R 4选自氢、卤素和C 1-C 3烷氧基；
R 5选自氢、卤素、CN和C 1-C 6烷基；
R a选自氢、C 1-C 3烷基。
在本公开的另一个具体实施方案中，X 1、X 2、X 3、X 4中至少一个独立地选自N；具体地，本公开提供如下式(Ia1)、(Ia2)、(Ia3)或(Ia4)的化合物：
Figure PCTCN2022118080-appb-000014
或其各自可药用盐；
其中，X 1、X 2、X 3、X 4中至少一个独立地选自N；
其它变量是如式(I)所定义的。
在本公开的一个具体实施方案中，X 1为N或CR 1。优选地，X 1为N或CR 1，且X 2、X 3、X 4中至少一个独立地选自N和NR n。
在本公开的一个具体实施方案中，X 1为N。优选地，X 1为N，且X 3为CR 3。
在本公开的另一个具体实施方案中，X 2为N或NR 2。优选地，X 2为N；更优选地，X 2为N，且X 3为CR 3；进一步优选地，X 2为N，X 3为CR 3，且X 4为CR 4；最优选地，X 2为N，X 3为CR 3，X 4为CR 4，且X 1为CR 1。
在本公开的另一个具体实施方案中，X 3为N或NR 3。优选地，X 3为N；更优选地，X 3为N，且X 4为CR 4；进一步优选地，X 3为N，X 4为CR 4；且X 2为CR 2；最优选地， X 3为N，X 4为CR 4，X 2为CR 2；且X 1为CR 1。
在本公开的另一个具体实施方案中，X 4为N或NR 4。优选地，X 4为N；更优选地，X 4为N，且X 3为CR 3；进一步优选地，X 4为N，X 3为CR 3，且X 2为CR 2；最优选地，X 4为N，X 3为CR 3，X 2为CR 2，且X 1为CR 1。
在本公开的一个具体实施方案中，X 1、X 2、X 3、X 4中只有一个独立地选自N和NR n；其中R n对于X 1而言为R 1，对于X 2而言为R 2，对于X 3而言为R 3，和对于X 4而言为R 4。在有些具体实施方式中，X 1为N，且X 2为CR 2，X 3为CR 3，X 4为CR 4。
在其它具体实施方式中，X 2为N、O、S或NR 2，且X 1为键或CR 1，X 3为CR 3，X 4为CR 4；优选地，X 2为N或NR 2，且X 1为键或CR 1，X 3为CR 3，X 4为CR 4。
在其它具体实施方式中，X 3为N、O、S或NR 3，且X 1为键或CR 1，X 2为CR 2，X 4为CR 4；优选地，X 3为N或NR 3，且X 1为键或CR 1，X 2为CR 2，X 4为CR 4；
在其它具体实施方式中，X 4为N、O、S或NR 4，且X 1为键或CR 1，X 2为CR 2，X 3为CR 3；优选地，X 4为N或NR 4，且X 1为键或CR 1，X 2为CR 2，X 3为CR 3
在本公开的另一个具体实施方案中，X 1、X 2、X 3、X 4中至少二个独立地选自N和NR n。
在有些具体实施方式中，X 1为N，且X 2为N或NR 2。
在其它具体实施方式中，X 1为N，且X 3为N或NR 3。
在其它具体实施方式中，X 1为N，且X 4为N或NR 4。
在其它具体实施方式中，X 2为N或NR 2，且X 3为N或NR 3。
在其它具体实施方式中，X 2为N或NR 2，且X 4为N或NR 4。
在其它具体实施方式中，X 3为N或NR 3，且X 4为N或NR 4。
在其它具体实施方式中，X 2为N或NR 2，且X 3为N或NR 3，X 4为N或NR 4。
在本公开的一个具体实施方案中，X 3为NR 3，且X 4为羰基-C(＝O)-。优选地，X 3为NH，且X 4为-C(＝O)-。
在本公开的一个具体实施方案中，X 4为NR 4，且X 3为羰基-C(＝O)-。优选地，X 4为NH，且X 3为-C(＝O)-。
在本公开的另一个具体实施方案中，X 1为键；具体地，本公开提供式(Ib)化合物：
Figure PCTCN2022118080-appb-000015
或其可药用盐；其中，
各变量X 2、X 3、X 4、X 5、X、Y、A、L是如式(I)所定义的。
在本公开的一个具体实施方案中，X 1为键，且
R 2选自氢、卤素、C 1-C 3烷基和C 1-C 3烷氧基；
R 3选自氢、OH和卤素；
R 4选自氢、卤素、C 1-C 3烷基、C 1-C 3烷氧基、C 3-C 4环烷基和C 1-C 3卤代烷基；
R 5选自氢、卤素、CN和C 1-C 6烷基；
R 6选自氢、C 1-C 3烷基；
R 7、R 8各自独立地选自氢、C 1-C 3烷基。在本公开的一个具体实施方案中，X 1为键，且X 2、X 3、X 4中至少一个独立地选自N、O、S或NR n；即X 1为键时，X 2、X 3、X 4中至少X 2为N、O、S或NR 2、或至少X 3为N、O、S或NR 3、或至少X 4为N、O、S或NR 4。
在本公开的一个具体实施方案中，X 1为键，且X 2、X 3、X 4中至少一个独立地选自N或NR n；即X 1为键时，X 2、X 3、X 4中至少X 2为N或NR 2、或至少X 3为N或NR 3、或至少X 4为N或NR 4。
在有些具体实施方式中，X 1为键时，X 2为N、O、S或NR 2；优选地，X 1为键，且X 2为N或NR 2。
在其它具体实施方式中，X 1为键时，X 3为N、O、S或NR 3；优选地，X 1为键，X 3为N或NR 3；更优选地，X 1为键，X 3为N。
在其它具体实施方式中，X 1为键时，X 4为N、O、S或NR 4。；优选地，X 1为键，且X 4为N、O或NR 4；更优选地，X 1为键，X 4为NR 4。
在本公开的一个优选实施方案中，X 1为键，且X 3为N
R 2选自氢、卤素、C 1-C 3烷基；
R 4选自氢、卤素、C 1-C 3烷基、C 1-C 3烷氧基、C 3-C 4环烷基和C 1-C 3卤代烷基；
R 5选自氢、卤素、CN和C 1-C 6烷基。
在本公开的另一个具体实施方案中，X 1为键时，X 2、X 3、X 4中至少两个独立地选自N、O、S或NR n；优选地，X 1为键，X 2、X 3、X 4中至少两个独立地选自N或NR n。
在有些具体实施方式中，X 1为键时，X 2、X 3、X 4中一个为N，另外至少一个独立地选自N、O、S或NR n。
在本公开的另一个具体实施方案中，X 1为键时，X 2、X 3、X 4均独立地选自N、O、S和NR n；优选地，X 1为键，X 2、X 3、X 4均独立地选自N和NR n。
在有些具体实施方式中，X 1为键，X 2为N、O、S或NR 2，且X 3为N或NR 3。优选地，X 1为键，且X 2为O或NR 2，X 3为N。更优选地，X 1为键，X 2为NR 2，X 3为N且X 4为CR 4。
在其它具体实施方式中，X 1为键，X 3为N、O、S或NR 3，且X 4为N或NR 4。优选地，X 1为键，且X 3为N，X 4为NR 4。更优选地，X 1为键，X 3为N，X 4为NR 4，且X 2为CR 2。
在其它具体实施方式中，X 1为键，X 2为N、O、S或NR 2，且X 4为N、O、S或NR 4。优选地，X 1为键，X 2为O或N，且X 4为N、O、S或NR 4。更优选地，X 1为键，且X 2为N，X 4为S、N或NR 4。
在其它具体实施方式中，X 1为键，X 3为N，且X 4为N或NR 4，或X 2为N、O或NR 2。优选地，X 1为键，X 3为N，且X 4为NR 4；更优选地，X 1为键，X 3为N，X 4为NR 4，且X 2为CR 2；
或者
X 1为键，X 3为N，且X 2为O或NR 2；优选地，X 1为键，X 3为N，X 2为O或NR 2，且X 4为CR 4。
在本公开的另一个具体实施方案中，X 1为键时，X 2、X 3、X 4均独立地选自N和NR n；即X 1为键，X 2为N或NR 2，且X 3为N或NR 3，X 4为N或NR 4。优选地，X 1为键，且X 2为N，X 3为N，X 4为NR 4。
在本公开的另一个具体实施方案中，X 1为CR 1。具体地，本公开提供了式(Ic)化合物
Figure PCTCN2022118080-appb-000016
或其可药用盐；
各变量R 1、X 2、X 3、X 4、X 5、X、Y、A、L是如式(I)所定义的。
在本公开的一个具体实施方案中，X 1为CR 1，且X 2、X 3、X 4中至少一个独立地选自N和NR n；即，X 1为CR 1，且X 2、X 3、X 4中至少X 2为N或NR 2、或至少X 3为N或NR 3、或至少X 4为N或NR 4。
在有些具体实施方式中，X 1为CR 1时，X 2为N或NR 2。优选地，X 1为CR 1，X 2为N或NR 2时，X 3为CR 3。更优选地，X 1为CR 1，X 2为N，X 3为CR 3。
在其它具体实施方式中，X 1为CR 1时，X 3为N或NR 3。优选地，X 1为CR 1，X 3为N。
在其它具体实施方式中，X 1为CR 1，X 3为N或NR 3时，X 2为CR 2。优选地，X 1为CR 1，X 3为N或NR 3时，X 2为CR 2，X 4为CR 4。更优选地，X 1为CR 1，X 3为N，X 2为CR 2，X 4为CR 4。
在其它具体实施方式中，X 1为CR 1时，X 4为N或NR 4。优选地，X 1为CR 1，X 4为N或NR 4时，X 3为CR 3；更优选地，X 1为CR 1时，X 3为CR 3，X 4为N。
在本公开的另一个具体实施方案中，X 1为CR 1，且X 2、X 3、X 4均为CR n；即X 1为CR 1，且X 2为CR 2，X 3为CR 3，X 4为CR 4。具体地，本公开提供了式(Id)化合物：
Figure PCTCN2022118080-appb-000017
或其可药用盐；
其中，Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-或CH 2；
各变量R 1、R 2、R 3、R 4、X 5、X、A、L是如式(I)所定义的。
在本公开的一个优选具体实施方案中，X 1为CR 1，X 2为CR 2，X 3为CR 3，X 4为CR 4；
Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-或CH 2；且
R 1为氢或卤素；
R 2选自氢、卤素、OH和C 1-C 3烷氧基；
R 3选自氢、卤素、OH、C 1-C 3烷基和C 1-C 3烷氧基；
R 4选自氢、卤素和C 1-C 3烷氧基；
R 5选自氢、卤素、CN和C 1-C 6烷基；
优选地，R 6、R 7、R 8各自独立地选自氢、C 1-C 3烷基。
在有些具体实施方式中，Y为O、S、-S(＝O)-、-S(＝O) 2-或-C(＝O)-。
在其它具体实施方式中，Y为O、S、-S(＝O)-或-S(＝O) 2-。
在有些具体实施方式中，Y为O或CH 2。
在本公开的另一个具体实施方案中，X 1为CR 1，且X 2为CR 2，X 3为CR 3，X 4为CR 4；
Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-或CH 2；
且R 1为氢或卤素；
R 2选自氢、卤素、OH和C 1-C 3烷氧基；
R 3选自氢、卤素、OH、C 1-C 3烷基和C 1-C 3烷氧基；
R 4选自氢、卤素和C 1-C 3烷氧基；
R 5选自氢、卤素、CN和C 1-C 6烷基；
R 6选自氢、C 1-C 3烷基；
R 7、R 8各自独立地选自氢、C 1-C 3烷基；优选地，Y为O或CH 2。
在本公开的一个优选具体实施方案中，本公开提供了如前所述的式(I)化合物或其可药用盐；其中：
Figure PCTCN2022118080-appb-000018
选自
Figure PCTCN2022118080-appb-000019
Figure PCTCN2022118080-appb-000020
优选地，选自
Figure PCTCN2022118080-appb-000021
Figure PCTCN2022118080-appb-000022
更优选地，选自
Figure PCTCN2022118080-appb-000023
在本公开的一个优选实施方案中，提供了式(I)化合物或其可药用盐，其中，X 1为键或CR 1。具体地，本公开提供以下(Ie1)、(Ie2)、(Ie3)、(Ie4)、(Ie5)、(Ie6)化合物：
Figure PCTCN2022118080-appb-000024
或其可药用盐；
其中，各变量X 2、R 3、R 4、R 5、X、Y、A、L是如式(I)所定义的。
优选地，L为NR a或(CR 9R 10) m；m为1或2。更优选地，L为CR 9R 10。
在本公开的一个实施方案中，所述式(I)化合物选自如下的实施例化合物：
Figure PCTCN2022118080-appb-000025
Figure PCTCN2022118080-appb-000026
Figure PCTCN2022118080-appb-000027
Figure PCTCN2022118080-appb-000028
Figure PCTCN2022118080-appb-000029
Figure PCTCN2022118080-appb-000030
Figure PCTCN2022118080-appb-000031
Figure PCTCN2022118080-appb-000032
Figure PCTCN2022118080-appb-000033
在另一方面，本公开提供了制备本公开的化合物的方法。
在一个实施方案中，本公开还提供了用于制备本公开的化合物的中间体及其制备方法。
在另一方面，本公开提供了组合物，包含至少一种本公开的化合物或其可药用盐。
在一个实施方案中，本公开提供了一种药物组合物，包含至少一种本公开的化合物或其可药用盐，以及至少一种可药用载体、稀释剂或赋形剂。
在另一个实施方案中，本公开提供了一种药物组合物，包含治疗有效量的至少一种本公开的化合物、或其立体异构体、几何异构体、互变异构体、可药用盐、晶型、溶剂合物、水合物或前药，以及至少一种可药用载体、稀释剂或赋形剂。在所述药物组合物的某些实施方案中，药物组合物被配制用于任何适宜的施用途径，例如静脉内施用、肌内施用、口服施用、直肠施用、吸入施用、鼻施用、局部施用、眼睛施用或耳施用。在所述药物组合物的其它实施方案中，药物组合物是片剂、丸剂、胶囊、液体剂、吸入剂、鼻喷雾溶液剂、栓剂、溶液剂、乳剂、软膏剂、滴眼剂或滴耳剂。
在另一方面，本公开提供了药物组合产品，包含至少一种本公开的化合物或其可药用 盐以及一种或多种其它活性剂。
在另一方面，本公开提供了如式(I)的化合物、或其立体异构体、几何异构体、互变异构体、可药用盐、晶型、溶剂合物、水合物或前药在制备用于预防、治疗、或减轻患者由肿瘤或感染引起的障碍或疾病的药物中的用途。
在一个实施方案中，所述肿瘤或感染是由干扰素基因刺激因子(STING)改变引起的。
在另一个实施方案中，本公开提供了式(I)化合物、或其立体异构体、几何异构体、互变异构体、可药用盐、晶型、溶剂合物、水合物或前药在制备用于预防、治疗或减轻由ENPP1介导的疾病或障碍、例如癌症或者感染性疾病或病症的药物中的用途。
在另一个实施方案中，本公开提供了本公开的化合物，单独地或任选与其它本公开的化合物和/或至少一种其它治疗剂组合地用于疗法中来治疗ENPP1介导的疾病或障碍。
在另一个实施方案中，本公开还提供了本公开的化合物在制备药剂中的用途，所述药剂单独地或任选与其它本公开的化合物和/或至少一种其它治疗剂组合地用于治疗ENPP1介导的疾病或障碍。
在另一个实施方案中，本公开提供了本公开的化合物和额外的一种或多种治疗剂的组合制剂，用于疗法。
在另一个实施方案中，本公开提供了本公开的化合物和额外的一种或多种治疗剂的组合，用于在疗法中同时或分别使用。
在另一个实施方案中，本公开提供了本公开的化合物和额外的一种或多种治疗剂的组合制剂，用于在治疗ENPP1介导的疾病或障碍中同时、分别或依次使用。化合物可以作为本文所述的药物组合物进行施用。
在另一方面，本公开提供了治疗或预防ENPP1介导的疾病或障碍，该方法包括给需要其的个体施用治疗有效量的本公开的化合物、或其立体异构体、几何异构体、互变异构体、可药用盐、晶型、溶剂合物、水合物或前药或者包含它们的药物组合物。
在一个实施方案中，本公开提供了治疗ENPP1介导的疾病或障碍的方法，该方法包括给需要该治疗的患者单独地或任选与其它本公开的化合物和/或至少一种其它治疗剂组合地施用治疗有效量的至少一种本公开的化合物，
在另一个实施方案中，本公开提供了治疗ENPP1介导的疾病或障碍的方法，该方法包括给需要其的患者施用治疗有效量的第一种和第二种治疗剂，其中所述第一种治疗剂是本公开的化合物，所述第二种治疗剂是其它本公开的化合物和/或至少一种其它治疗剂。
在本公开的一些实施方案中，ENPP1介导的疾病或障碍包括但不限于肿瘤、感染性疾病或障碍，尤其是癌症，如复发性或难治性癌症、转移性癌症等。
在另一个实施方案中，ENPP1介导的疾病或障碍为复发性或难治性癌症。
在另一个实施方案中，ENPP1介导的疾病或障碍为转移性癌症。
在另一个实施方案中，ENPP1介导的疾病或障碍为肿瘤，尤其是实体瘤，例如乳腺癌、肺癌、胶质母细胞瘤、脑癌和脊椎癌、头颈癌、皮肤癌、生殖系统癌症、胃肠系统癌症、食道癌、鼻咽癌、胰腺癌、直肠癌、肝细胞癌、胆管癌、胆囊癌、结肠癌、多发性骨髓瘤、 肾脏和膀胱癌、骨癌、恶性间皮瘤、肉瘤、淋巴瘤、腺癌、甲状腺癌、心脏肿瘤、生殖细胞肿瘤、恶性神经内分泌肿瘤、恶性横纹肌样瘤、软组织肉瘤、中线束癌和未知原发癌。
在另一个实施方案中，ENPP1介导的疾病或障碍为肿瘤，尤其是血液系统恶性肿瘤；尤其是白血病、淋巴瘤或骨髓瘤。
在另一个实施方案中，ENPP1介导的疾病或障碍为感染性疾病或障碍，包括但不限于：单纯疱疹病毒感染、牛痘病毒感染、腺病毒感染、人乳头瘤病毒感染、B型肝炎病毒感染、D型肝炎病毒感染、人免疫缺陷病毒感染、人巨细胞病毒感染、登革热病毒感染、埃博拉病毒感染、马尔堡病毒感染、寨卡病毒感染、单核细胞增生性李斯特菌感染、结核分枝杆菌感染、新凶手弗朗西斯菌感染、嗜肺军团菌感染、沙眼衣原体感染、肺炎链球菌感染、淋球菌感染。
在具体实施方案中，采用本文公开的EED Alphascreen结合、LC-MS和/或ELISA分析，本公开的化合物具有≤5μM的IC 50值、优选≤1μM的IC 50值、更优选≤0.5μM的IC 50值、甚至更优选≤0.125μM、最优选≤0.1μM的IC 50值。
应理解，在本公开范围内，本公开的各技术方案中定义的技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。还可以理解，实施方案的各个单独元素是其自身的独立实施方案。
本公开的其它特征在示例性实施方案的上述说明中将变得清楚，给出这些示例性实施方案是为了解释说明本公开，而不意欲限制本公开。
术语说明
在本公开中，除非另外明确地说明，本公开所使用的术语具有下面所定义的含义。本公开未明确定义的术语具有本领域技术人员所普遍理解的一般含义。
在本公开的上下文中(尤其在权利要求的上下文中)使用的术语“一个”、“一种”、“该”和类似术语被理解为包括单数和复数，除非文中另外特别指出或根据上下文明显矛盾。
不在两个字母或符号之间的短横(“-”)表示取代基的连接位点。例如，-O(C 1-C 3烷基)表示该基团通过氧原子与分子的其余部分连接。然而，当取代基的连接位点对本领域技术人员来说是显而易见的时候，例如对于卤素、羟基等取代基而言，“-”可以省略。
当基团带有波浪线
Figure PCTCN2022118080-appb-000034
时，波浪线表示该基团与分子其余部分的连接位置。
如本文所用，
Figure PCTCN2022118080-appb-000035
表示单键或双键。本领域技术人员可以根据相关环原子的化合价及所连接的基团等情况确定
Figure PCTCN2022118080-appb-000036
表示单键还是双键，这属于本领域技术人员的能力范围之内。本领域技术人员可以理解，相关的环可以是饱和的、部分饱和的或芳族的。
如本文所用，“杂原子”指氮(N)、氧(O)或硫(S)原子，特别是氮或氧，其各自可以是取代或未取代的，包括其氧化形式。杂原子的实例包括但不限于-O-、-N＝、-NR-、-S-、-S(O)-和-S(O) 2-，其中R是氢、C 1-C 4烷基或氮保护基(例如苄氧羰基、对甲氧基苄基羰基、 叔丁氧基羰基、乙酰基、苯甲酰基、苄基、对甲氧基-苄基、对甲氧基-苯基、3,4-二甲氧基苄基等)。任何具有未满足的价键的杂原子被认为具有足以满足价键的氢原子，另有指示除外。
如本文所用，“卤素”或“卤代”指氟、氯、溴和碘。优选的作为取代基的卤素是氟和氯。
如本文所用，“烷基”指完全饱和的直链或支链的一价烃基团。烷基优选包含1-20个碳原子，更优选1-16个碳原子、1-10个碳原子、1-8个碳原子、1-6个碳原子、1-4个碳原子或1-3个碳原子。烷基前的数字表示碳原子的个数。例如，“C 1-C 6烷基”表示具有1-6个碳原子的烷基，“C 1-C 4烷基”表示具有1-4个碳原子的烷基，“C 1-C 3烷基”表示具有1-3个碳原子的烷基。烷基的代表性示例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基、正癸基等。无论术语“烷基”单独出现，还是作为其它基团如卤代烷基、烷氧基等的一部分出现，均适用该定义。
如本文所用，“烯基”指包含至少一个双键的直链或支链的一价烃基团。烯基优选包含2-20个碳原子，更优选2-10个碳原子、2-8个碳原子、2-6个碳原子或2-4个碳原子。烯基前的数字表示碳原子的个数。烯基的代表性示例包括但不限于乙烯基、丙烯基、异丙烯基、丁烯基、异丁烯基、戊烯基、异戊烯基、己烯基、庚烯基、辛烯基等。
如本文所用，“炔基”指包含至少一个叁键的直链或支链的一价烃基团。炔基优选包含2-20个碳原子，更优选2-10个碳原子、2-8个碳原子、2-6个碳原子或2-4个碳原子。炔基前的数字表示碳原子的个数。炔基的代表性示例包括但不限于乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、戊炔基、异戊炔基、己炔基、庚炔基、辛炔基等。
如本文所用，“烷氧基”指通过氧桥连接的如本文所定义的烷基，即，烷基-O-基团，烷氧基前的数字表示碳原子的个数。例如，“C 1-C 6烷氧基”表示具有1-6个碳原子的烷氧基，即-O-C 1-6烷基；“C 1-C 4烷氧基”表示具有1-4个碳原子的烷氧基，即-O-C 1-4烷基；“C 1-C 3烷氧基”表示具有1-3个碳原子的烷氧基，即-O-C 1-3烷基。烷氧基的代表性示例包括但不限于甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊氧基、己氧基等。优选地，烷氧基含有约1-6个或者约1-4个碳等。
如本文所用，“环烷基”指饱和或部分饱和的非芳香族碳环，包括单-、双-或三环，优选具有3-12个环碳原子，更优选3-10个环碳原子，例如3-8个、3-7个、3-6个、4-10个、或4-8个环碳原子。"C 3-C 8环烷基"意欲包括C 3、C 4、C 5、C 6、C 7和C 8环烷基基团；"C 3-C 6环烷基"意欲包括C 3、C 4、C 5和C 6环烷基基团；以此类推。示例性的单环环烷基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基和环己烯基等。示例性的二环环烷基包括冰片基、四氢萘基、十氢萘基、二环[2.1.1]己基、二环[2.2.1]庚基、二环[2.2.1]庚烯基、6,6-二甲基二环[3.1.1]庚基、2,6,6-三甲基二环[3.1.1]庚基、二环[2.2.2]辛基等。示例性的三环环烷基包括金刚烷基等。
如本文所用，“卤代烷基”指其中一个或多个氢原子、例如1、2、3、4、5、6或7个 氢原子、例如1、2或3个氢原子被卤素替代的如本文所定义的烷基，并且当超过一个氢原子被卤素原子替代时，所述卤素原子可以彼此相同或不同。例如“C 1-C 4卤代烷基”意欲包括C 1、C 2、C 3和C 4卤代烷基基团，“C 1-C 3卤代烷基”意欲包括C 1、C 2和C 3卤代烷基基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、1,1-二氟乙基、1,1,-二氟丙基和1,1,1-三氟丙基。卤代烷基的实例还包括“氟烷基”，后者意欲包括其中一个或多个氢原子被氟原子取代的如本文定义的烷基。本文“卤代烷基”优选为烷基中至多三个氢原子被卤素替代。
如本文所用，“卤代烷氧基”表示通过氧桥连接的具有指定碳原子数的如上定义的卤代烷基，其中一个或多个氢原子、例如1、2、3、4、5、6或7个氢原子、例如1、2或3个氢原子被卤素替代。例如，“C 1-C 6卤代烷氧基”或“C 1至C 6卤代烷氧基”意欲包括C 1、C 2、C 3、C 4、C 5和C 6卤代烷氧基基团。卤代烷氧基的实例包括但不限于氟甲氧基、二氟甲氧基、三氟甲氧基、2-氟乙氧基、2,2,2-三氟乙氧基。卤代烷氧基的实例还包括“氟烷氧基”。
如本文所用，“芳基”是由一个或多个环稠合构成的具有6-20个、优选6-14个、更优选6-12个、最优选6-10个、例如6-9个环碳原子的单环、双环或三环碳环烃基，其中至少一个环是芳族环，而其它环(如果存在的话)可以是芳族或非芳族的。优选的芳基是具有6-10个环碳原子的芳基，即6-至10-元芳基，其包括：单环芳基(例如苯基)；或稠合二环系统，其中一个环是芳族环、而另一个环是芳族(例如在萘、联苯基中)或非芳族环(例如在二氢茚、四氢萘中)。芳基的非限制性示例包括苯基、联苯基、萘基、四氢萘基、茚基、二氢茚基或蒽基等。
如本文所用，“杂芳基”指含有1-8个、优选1-4个、还优选1-3个、更优选1或2个选自N、O或S的杂原子的5-14元、优选5-10元、更优选5-7元或5-6元芳香族环系，包括单环或二环或稠合多环，其余环原子为碳原子。杂芳基优选为5-10元杂芳基，更优选为5-7元杂芳基或5-6元杂芳基，各自含有1、2或3个选自N、O或S的杂原子。杂芳基的实例包括但不限于：吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、三唑基、噻唑基、异噻唑基、噁唑基、吡啶基、吡喃基、吡嗪基、哒嗪基、嘧啶基、噁嗪基、噁二嗪基、喹啉基、异喹啉基、噌啉基、喹唑啉基、喹喔啉基、苯并噁嗪基、2H-色烯、苯并吡喃基、苯并噻吩基、吲哚基、吲唑基、苯并咪唑基、苯并噁唑基、苯并噻唑基、7-氮杂吲哚基、6-氮杂吲哚基、5-氮杂吲哚基、4-氮杂吲哚基、1H-苯并[d][1,2,3]三唑基等。
如本文所用，“杂环烷基”指如本申请中所定义的环烷基，条件是一个或多个环碳被选自N、O或S的杂原子替换，所述杂原子例如是-O-、-N＝、-NR-、-S-、-S(＝O)-和-S(＝O) 2-，其中R是氢、C 1-4烷基或氮保护基(例如，苄氧羰基、对甲氧基苄基羰基、叔丁氧基羰基、乙酰基、苯甲酰基、苄基、对甲氧基-苄基、对甲氧基-苯基、3,4-二甲氧基苄基等)。优选地，杂环烷基是具有3-20个环原子、例如3-12个环原子、例如3-8个环原子、例如3-6个环原子的单环、二环或三环的饱和和部分不饱和非芳族环。更优选地，杂环烷基优选含有1、2或3个选自N、O或S的杂原子的4-至12-元杂环烷基，优选4-至8-元杂环烷基、更优 选是4-至7-元、4-至6元或5-至6-元杂环烷基，其中所述杂原子是取代或未取代的，例如被C 1-C 4烷基取代。例如，杂环烷基的实例包括但不限于：环氧乙烷基、氮丙啶基、氮杂环丁烷基、氧杂环丁烷基、氮杂环戊烷基(吡咯烷基)、四氢呋喃基、四氢噻吩基、四氢噻吩基1,1-二氧化物、吡唑烷基、咪唑烷基、噁唑烷基、噻唑烷基、异噻唑烷基、吡咯烷基-2-酮、咪唑酮基、哌啶基(六氢吡啶)、N-甲基哌啶基、四氢吡喃基、噁嗪烷基、1,3-噁嗪烷基、六氢嘧啶基、哌嗪基、哌啶酮基(piperidinylone)、1,4-二氧杂-8-氮杂-螺[4.5]癸烷-8-基、吗啉代基、硫吗啉代基、硫代吗啉代-S-单氧化物(sulfanomorpholino)、硫代吗啉代-S,S-二氧化物(sulfonomorpholino)、八氢吡咯并[3,2-b]吡咯基等。
如本文所用，“部分饱和的杂环”指部分氢化的非芳香族环，其可以作为单环或双环(包括稠环)存在。除非另有说明，否则所述部分饱和的杂环通常是含有至少一个、例如1至3个、优选1或2个选自N、O或S的杂原子的3-至12-元、优选5-至10-元、更优选9-10元的单环或双环环系，所述杂原子例如是-O-、-N＝、-NR-或-S-，其中R是氢、C 1-4烷基或氮保护基。部分饱和的杂环包括诸如二氢吡咯基、二氢呋喃基、二氢噁唑基、二氢吡啶基、咪唑啉基、1H-二氢咪唑基、2H-吡喃基、2H-色烯基、二氢噁嗪基等的基团。部分饱和的杂环还包括具有稠合的芳基或杂芳基环的杂环，优选具有9-10个环成员(例如二氢苯并呋喃基、二氢异苯并呋喃基、二氢吲哚基(或2,3-二氢吲哚基)、二氢苯并噻吩基、二氢苯并噻唑基、二氢苯并吡喃基、四氢喹啉基、四氢异喹啉基、四氢吡啶并[3,4-b]吡嗪基等)。
如本文所用，“部分或完全饱和的杂环”指部分或完全被氢化的非芳香族环，可以作为单环、双环(包括稠环)或螺环存在。除非另有说明，否则杂环通常是含有1至3个、优选1或2个独立地选自硫、氧和/或氮的杂原子的3-至12-元环、优选5-至10-元环。当使用术语"部分或完全饱和的杂环"时，其意欲包括“杂环烷基”和"部分饱和的杂环"。螺环的实例包括2,6-二氮杂螺[3.3]庚烷基、3-氮杂螺[5.5]十一烷基、3,9-二氮杂螺[5.5]十一烷基等。
如本文所用，“杂环”指完全饱和的或不饱和的、芳香的或非芳香的环状基团，其意欲包括“杂环烷基”、“部分或完全饱和的杂环”、“部分饱和的杂环”、“完全饱和的杂环”和“杂芳基”。例如其是4-至7-元单环、7-至12-元二环或10-至15-元三环的环系，该环系在包含至少一个碳原子的环上含有至少一个杂原子。杂环的包含杂原子的环可以含有1-6个，优选1、2或3个杂原子，所述杂原子选自氮原子、氧原子或硫原子，其中氮和硫杂原子还可以任选被氧化。优选地，杂环是4-至7-元单环杂环。
示例性的单环杂环包括吡咯烷、吡咯、吡唑、氧杂环丁烷、吡唑啉、咪唑、咪唑啉、咪唑烷、三唑、噻唑、噻二唑、噻唑烷、异噻唑、异噻唑烷、呋喃、四氢呋喃、噻吩、哌啶、哌嗪、2-氧代哌嗪、2-氧代哌啶、2-氧代吡咯烷、4-哌啶酮、吡啶、吡嗪、嘧啶、哒嗪、四氢吡喃、吗啉、硫吗啉、硫代吗啉代-S-单氧化物、硫代吗啉代-S,S-二氧化物、1,3-二氧戊环和四氢-1,1-二氧代噻吩、1,1,4-三氧代-1,2,5-噻二唑烷-2-等。
示例性的二环杂环包括吲哚、二氢吲哚、苯并噻唑等。
如本文所用，“杂环基”指由上述定义的杂环失去一或多个氢原子而形成的基团。杂环基团可以在杂原子或碳原子处进行连接。
如本文所用，“碳环”指饱和或不饱和的单环、二环或三环的3-12个碳原子的烃基团。碳环优选具有3-8个环碳原子，例如含有3-7、或4-7环碳原子。示例性的单环碳环包括但不限于环丙烷、环丁烷、环戊烷、环戊烯、环己烷、环己烯、环庚烷、环庚烯等。示例性的二环烷包括四氢萘、十氢萘、二环[2.1.1]己烷、二环[2.2.1]庚烷等。示例性的三环烃基团包括金刚烷基等。
如本文所用，术语“-C(＝O)”为羰基，“-S(＝O)”为亚砜基、“-S(＝O) 2”为砜基。“＝O”表示氧代基，即氧原子通过双键与其它原子连接。
在本文中，烷基、烯基、烷氧基、碳环、环烷基、杂芳基、杂环、杂环基、羰基、磺酰基、亚磺酰基等基团可被取代基取代，所述取代基包括但不限于：OH、Boc、卤素、氰基、取代或未取代的烷基、取代或未取代的烷氧基、取代或未取代的环烷基、取代或未取代的杂环基；NRR’、C(O)R、SO 2R、C(O)NRR’或C(O)OR，且各R和R’各自独立地选自：H和取代或未取代的烷基。
本文所用的“任选”、“任选的”或“任选地”意指随后描述的事件可以发生或可以不发生，并且该描述包括所述事件发生的情形以及所述事件不发生的情形。例如，“任选被取代的烷基”包括本文定义的“未取代的烷基”和“被取代的烷基”。“任选被卤素取代”包括“被卤素取代”的情形和“未被卤素取代”的情形，例如被0-3个卤素取代。本领域技术人员应当理解的是，对于含有一个或多个取代基的任意基团而言，所述基团不包括任何在空间上不切实际的、化学上不正确的、合成上不可行的和/或内在不稳定的取代模式。
当任意变量在化合物的任意构成或式中出现不止一次时，其在每次出现时的定义独立于在每次其它出现时的定义。因此，例如，如果基团显示是被0-3个R取代，则该基团可以是未取代的或被至多三个R取代，并且R在每次出现时独立地选自R的定义。例如，应用于环A定义中的一次或多次取代，即当环A是C 4-C 8环烷基、4-至8-元杂环烷基、6-至10-元芳基和5-至6-元杂芳基时，这些基团是未取代的或被一个或多个、例如两个在每次出现时独立地选自给定定义的取代基基团取代。这类似地应用于其它类似情形的定义。
当取代基的价键显示穿过环中连接两个原子的价键时，则该取代基可以与环上的任意原子键合。当列出取代基而未指明该取代基与所示式的化合物的其余部分连接的原子时，则该取代基可以经由该取代基中的任意原子键合。
取代基和/或变量的组合是允许的，只要这样的组成产生了稳定的化合物。
当在环结构中使用虚线环时，这表示环结构可以是饱和的、部分饱和的或不饱和的。
本文所用的术语“取代”、“取代的”或“被……取代”意指给定原子或基团上的一个或多个氢原子被一个或多个选自给定的取代基组的取代基替换，条件是不超过该给定原子的正常化合价。当取代基是氧代(即＝O)时，则单个原子上的两个氢原子被氧替换。在芳香族部分上不存在氧代取代基。当环系(例如碳环或杂环)被羰基基团或双键取代时，意欲羰基基团或双键是环的一部分(即，在环内)。只有当取代基和/或变量的组合导致化学上正确的且稳定的化合物时，这类组合才是允许的。化学上正确的且稳定的化合物意味着化合物足够稳定，以至于能从反应混合物中被分离出来并能确定化合物的化学结构，并且 随后能被配制成至少具有实际效用的制剂。例如，在没有明确列出取代基的情况下，本文所用的术语“取代”、“被取代的”或“被……取代”意指给定的原子或基团上的一个或多个氢原子独立地被一个或多个、例如1、2、3或4个取代基取代。当一个原子或基团被多个取代基取代时，所述取代基可以相同或不同。
术语"可药用"或“药学上可接受的”包括在化学上/毒理学上必须与其它成分、包括制剂和/或用它处理的哺乳动物相容的物质或组合物。
除非另有指出，否则术语“本公开化合物”或“本公开的化合物”指包括本公开的一种或多种本文定义的式(I)或其亚式、如式(Ia)、(Ia1)、(Ia2)、(Ia3)、(Ia4)、(Ib)、(Ic)、(Id)、(Ie1)、(Ie2)、(Ie3)、(Ie4)、(Ie5)和(Ie6)的化合物，或其可药用盐，以及所有异构体如立体异构体(包括非对映异构体、对映异构体和外消旋物)、几何异构体、构象异构体(包括旋转异构体和阻转异构体)、互变异构体、异构体的内部加成产物、前药以及同位素标记的化合物(包括氘取代)和固有形成的部分(例如多晶型物、溶剂合物和/或水合物)。当存在能够形成盐的部分时，则也包括盐、特别是可药用盐。互变异构体或异构体的内部加成产物的存在可由本领域技术人员使用诸如NMR的工具来鉴别。本公开的式(I)化合物能够容易地形成如本文所描绘的互变异构体和异构体的内部加成产物。
当本文中提及式(I)时，该称谓也包括其亚式，例如式(Ia)、(Ia1)、(Ia2)、(Ia3)、(Ia4)、(Ib)、(Ic)、(Id)、(Ie1)、(Ie2)、(Ie3)、(Ie4)、(Ie5)和(Ie6)。
本领域技术人员将认可，本公开的化合物可以含有手性中心，照此可以存在不同的异构形式。如本文所用的“异构体”指具有相同分子式、但是原子的排列和构型有区别的不同化合物。
如本文所用，“对映异构体”是相互为不可重叠的镜像的一对立体异构体。一对对映异构体的1:1混合物是"外消旋”混合物。合适时，该术语用于指外消旋混合物。当指示本公开的化合物的立体化学时，采用常规的RS系统指定了具有两个手性中心的已知的相对和绝对构型的单一立体异构体(例如(1S,2S))；具有已知的相对构型、但是绝对构型未知的单一立体异构体标示了星号(例如(1R*,2R*))；具有两个字母的外消旋物(例如(1RS,2RS)为(1R,2R)和(1S,2S)的外消旋混合物；(1RS,2SR)为(1R,2S)和(1S,2R))的外消旋混合物。"非对映异构体”是具有至少两个不对称原子、但是相互不为镜像的立体异构体。根据Cahn-lngold-Prelog R-S系统指明绝对立体化学。当化合物是纯的对映异构体时，各手性碳处的立体化学可以通过R或S说明。绝对构型未知的被拆分的化合物可以根据它们在钠D线波长处旋转平面偏振光的方向(右旋或左旋)指定为(+)或(-)。或者，被拆分的化合物可以通过相应的对映异构体/非对映异构体经由手性HPLC的各自的保留时间来定义。
本文所述的一些化合物含有一个或多个不对称中心或轴，因此可以产生对映异构体、非对映异构体和可以以绝对立体化学定义为(R)-或(S)-的其它立体异构体。
当化合物含有双键或一些其它的使得分子具有一定量结构刚性的特征时，可以发生几何异构体。如果化合物含有双键，则取代基可以是E或Z构象。如果化合物含有二取代的环烷基，则环烷基取代基可以具有顺式或反式构型。
构象异构体是通过有关一个或多个价键的旋转而不同的异构体。旋转异构体是通过仅单个价键的旋转而不同的构象异构体。
"阻转异构体"指基于分子中的旋转受限所产生的轴向或平面手性的结构异构体。
除非另有说明，否则本公开的化合物意欲包括所有这类可能的异构体，包括外消旋混合物、具有旋光活性的形式和中间体混合物。具有旋光活性的(R)-和(S)-异构体可以采用手性合成子或手性试剂进行制备，或者采用常规技术进行拆分。
本公开的化合物可以分离为具有旋光活性的形式或外消旋形式。用旋光活性的形式可以通过外消旋形式的拆分或通过由具有旋光活性的原料合成来制备。用于制备本公开的化合物的所有方法和其中制备的中间体被认为是本公开的一部分。当制备对映体或非对映异构体产物时，它们可以通过常规方法如通过色谱法或分步结晶来进行分离。
根据方法条件，本公开的终产物以游离(中性)或盐形式获得。这些终产物的游离形式和盐形式在本公开的范围内。如果期望的话，则化合物的一种形式可以转化为其它形式。游离碱或酸可以转化为盐；盐可以转化为游离化合物或其它盐；本公开的同分异构化合物的混合物可以分离为单独异构体。
可药用盐是优选的。然而，其它盐可以是有用的，例如在分离或纯化步骤中，其可以在制备期间使用，因此被考虑在本公开的范围内。
如本文所用，“药学上可接受的”与“可药用”可互换使用，指可用于制备一般是安全的、无毒的并且既非生物学也非其它方面所不希望的药物组合物，包括对兽医学以及人药用而言是可接受的。
如本文所用，“药学上可接受的盐”和“可药用盐”指保持本公开化合物的生物学效应和性能的盐，并且该盐在生物学上或其它方面不是不被期望的。所述盐的非限制性示例包括本公开化合物的无毒的、无机或有机碱或酸的加成盐。在许多情况下，由于氨基和/或羧基或与之相似的基团的存在，本公开化合物能够形成酸盐和/或碱盐。可以用无机酸和有机酸形成药学上可接受的酸加成盐。可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。可以用无机和有机碱形成药学上可接受的碱加成盐。可以由其衍生得到盐的无机碱包括例如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝等；特别优选的是铵、钾、钠、钙和镁盐。可以由其衍生得到盐的有机碱包括例如伯胺、仲胺和叔胺、取代的胺(包括天然存在的取代的胺)、环状的胺、碱性离子交换树脂等，尤其例如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺和乙醇胺。通过常规化学方法，可以从母体化合物(碱性或酸性部分)合成本公开可药用盐。一般来讲，可以如下制备所述的盐：使所述化合物的游离酸形式与化学计算量的适当的碱(例如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应或使所述化合物的游离碱形式与化学计算量的适当的酸反应。这类反应通常在水或有机溶剂或两者的混合溶剂中进行。一般来讲，在可行时，非水介质例如醚、乙酸乙酯、乙醇、异丙醇或乙腈是优选的。其它合适的盐可以见于 Remington氏药物科学(Remington's Pharmaceutical Sciences)，第20版，Mack出版公司(Mack Publishing Company)，Easton，Pa.，(1985)，将其引入文中作为参考。
如本文所用，“药学上可接受的赋形剂”包括任何和所有的溶剂、分散介质、包衣、表面活性剂、抗氧化剂、防腐剂(例如抗菌剂、抗真菌剂)、等渗剂、吸收延迟剂、盐、防腐剂、药物、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、矫味剂、染料、所述类似的物质和其组合，其是本领域普通技术人员所公知的(见，例如，Remington氏药物科学(Remington's Pharmaceutical Sciences)，第18版，Mack出版公司(Mack Printing Company)，1990，pp.1289-1329，引入文中作为参考)。除非任何常规载体是与活性成分不能共存的，可以考虑在治疗或药物组合物中使用它。
如本文所用，“溶剂合物”指本公开的化合物与一种或多种有机或无机溶剂分子的物理联合物。这种物理联合物包括氢键。在一些情况中，溶剂合物将能够分离，例如当一种或多种溶剂分子掺入结晶固体的晶格中时。溶剂合物中的溶剂分子可以以有规排列和/或非有序排列存在。溶剂合物可以包含化学计算量或非化学计算量的溶剂分子。"溶剂合物"包括溶液相和可分离的溶剂合物。示例性的溶剂合物包括但不限于水合物、乙醇化物、甲醇化物和异丙醇化物。溶剂化的方法是本领域公知的。
如本文所用，“多晶型物”指具有相同的化学结构/组成、但是形成结晶的分子和/或离子的空间排列不同的结晶形式。本公开的化合物可以作为无定型固体或结晶固体来提供。冷冻干燥法可用于提供固体的本公开的化合物。
如本文所用，“前药”是指被化学修饰的活性或非活性的化合物，给药至个体后，其经过体内的生理作用(例如水解、新成代谢等)变为本公开化合物。有关制造和使用前药的适应性和技术是本领域技术人员众所周知的。
本文所给的任意式还意欲代表化合物的未标记的形式以及同位素标记的形式。除了一个或多个原子被具有所选原子质量或质量数的原子所代替外，同位素标记的化合物具有本文所给的式所描述的结构。可以掺入到本公开的化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素，例如分别有 2H(即D)、 3H(即T)、 11C、 13C、 14C、 15N、 18F 31P、 32P、 35S、 36Cl、 125I。本公开包括如本文定义的不同的同位素标记的化合物，例如其中存在放射性同位素如 3H、 13C和 14C的那些。这类同位素标记的化合物可用于代谢研究(用 14C)、反应动力学研究(例如用 2H或 3H)、检测或显像技术、例如正电子发射断层扫描(PET)或单光子发射计算机断层扫描(SPECT)、包括药物或底物组织分布测定，或者可用于患者的放射性治疗。特别地， 18F或标记的化合物可以特别希望用于PET或SPECT研究。通常可以通过进行下文所述的流程中或实施例和制备例中所述的那些方法、用容易获得的同位素标记的试剂代替未同位素标记的试剂来制备同位素标记的本公开的化合物。
而且，被较重同位素、特别是氘(即 2H或D)所取代还可以获得由更大的代谢稳定性引起的某些治疗益处，例如延长体内半衰期或降低剂量要求或改善治疗指数。可以理解，上下文中的氘可被看作是本公开的化合物的取代基。这类较重同位素、特别是氘的浓度可以由同位素富集因子来定义。“同位素富集因子”表示指定同位素的同位素丰度和天然丰 度之间的比值。
同位素标记的本公开的化合物通常可以通过本领域技术人员已知的常规技术或通过进行与本文所述那些类似的方法、采用适当的同位素标记的试剂取代其它使用的未标记的试剂来制备。这类化合物具有多种潜在用途，例如作为标准和试剂用于测定潜在药物化合物结合靶蛋白质或受体的能力或者用于体内或体外与生物学受体结合的本公开的化合物的显像。
如本文所用，本公开化合物的“治疗有效量”指可以引起个体生物学或医学反应或改善症状、减慢或延缓疾病恶化或预防疾病等的本公开化合物的量。“治疗有效量”可以由参与医师或兽医执业者来确定，并且将随着化合物、所治疗的疾病状态、所治疗的疾病的严重程度、个体的年龄和相关健康状况、施用途径和形式、主治医师或兽医执业者的判断等因素而变化。
如本文所用，“个体”指动物。优选地，动物是哺乳动物。个体还指例如灵长类(例如人类)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠、鱼、鸟等。在一优选实施方案中，个体是人。
如本文所用，“抑制”指特定的病患、症状或病症或疾病的减轻或抑制，或者生物学活性或过程基线活性的显著降低。
如本文所用，在一个实施方案中术语"治疗"任何疾病或病症指改善疾病或病症(即阻止或减缓疾病或其至少一种临床症状的发展)。在另一个实施方案中，“治疗”指改善至少一种身体参数，其可能不为患者所察觉。在另一个实施方案中，“治疗"指身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。
如本文所用，“预防”指给具有易患所述疾病的体质的个体施用一种或多种药物物质、特别是本公开的化合物和/或其可药用盐，用以防止个体罹患该疾病。
当涉及化学反应时，“处理”、“接触”和“反应”指在适当的条件下加入或混合两种或更多种试剂，以产生所示的和/或所需的产物。应当理解的是，产生所示的和/或所需的产物的反应可能不一定直接来自最初加入的两种试剂的组合，即，在混合物中可能存在生成的一个或多个中间体，这些中间体最终导致了所示的和/或所需的产物的形成。
一般而言，术语“约”在本文中用于将所给出的数值调整至高于或低于该数值20％、例如10％、例如5％。
本文所用的未具体定义的技术和科学术语具有本公开所属领域的技术人员通常理解的含义。
功效
本公开的异羟基肟酸类化合物为ENPP1抑制剂化合物，对ENPP1具有高的选择性和抑制活性，副作用更少，具有高的抗耐药性，具有高的生物利用度并且具有高的临床应用价值。本公开的化合物可用于需要抑制ENPP1的多种应用中。
本公开的化合物可用于治疗、预防或改善ENPP1介导的疾病或障碍，例如ENPP1介 导的肿瘤(如癌症)或者感染性疾病或障碍，尤其是复发性或难治性癌症或转移性癌症。
特别地，本公开的化合物可用于治疗、预防或改善实体瘤，例如选自乳腺癌、肺癌、胶质母细胞瘤、脑癌和脊椎癌、头颈癌、皮肤癌、生殖系统癌症、胃肠系统癌症、食道癌、鼻咽癌、胰腺癌、直肠癌、肝细胞癌、胆管癌、胆囊癌、结肠癌、多发性骨髓瘤、肾脏和膀胱癌、骨癌、恶性间皮瘤、肉瘤、淋巴瘤、腺癌、甲状腺癌、心脏肿瘤、生殖细胞肿瘤、恶性神经内分泌肿瘤、恶性横纹肌样瘤、软组织肉瘤、中线束癌和未知原发癌。
本公开的化合物还可用于治疗、预防或改善血液系统恶性肿瘤，例如选自白血病、淋巴瘤或骨髓瘤。
而且，本公开的化合物还可用于治疗、预防或改善感染性疾病或病症、特别是ENPP1介导的感染性疾病或病症，例如选自单纯疱疹病毒感染、牛痘病毒感染、腺病毒感染、人乳头瘤病毒感染、B型肝炎病毒感染、D型肝炎病毒感染、人免疫缺陷病毒感染、人巨细胞病毒感染、登革热病毒感染、埃博拉病毒感染、马尔堡病毒感染、寨卡病毒感染、单核细胞增生性李斯特菌感染、结核分枝杆菌感染、新凶手弗朗西斯菌感染、嗜肺军团菌感染、沙眼衣原体感染、肺炎链球菌感染和淋球菌感染。
药物组合物和施用
本公开的化合物可以以药物组合物的形式施用于个体，所述药物组合物可任选包含一种或多种药学上可接受的赋形剂。
本公开的化合物可以通过各种已知的途径施用，包括口服、直肠、胃内、颅内和肠胃外施用，例如静脉内、肌内、鼻内、真皮内、皮下，以及类似的施用途径。特别优选的是口服、鼻内和肠胃外施用。根据施用途径的不同，需要不同的药物制剂，这些施用途径中的一些可能需要给药物制剂涂敷保护性包衣以防止本公开的化合物在例如消化道内降解。
本公开的化合物可以被配制成糖浆、输液或注射液、喷雾剂、片剂、胶囊、锭剂、脂质体或栓剂等。
用于施用本公开的化合物的特别优选的药物形式是适合注射使用的形式，包括无菌的水性溶液或分散体和用于即时制备无菌注射溶液或分散体的无菌粉末。在所有情况中，最终的溶液或分散体形式必须是无菌的并且是流体。典型地，这类溶液或分散体将包含溶剂或分散介质，其含有例如水-缓冲水溶液例如生物相容性的缓冲剂、乙醇或多元醇例如甘油、丙二醇、聚乙二醇、其适合的混合物，表面活性剂或植物油。本公开的化合物也可以被配制成脂质体，特别是用于肠胃外施用的脂质体。脂质体提供在循环中半衰期增加的优点(如果与游离药物相比)以及所包裹的药物的延长的更均匀的释放。
输液和注射液的灭菌可以通过本领域公认的技术来实现，包括但不限于加入防腐剂如抗细菌剂或抗真菌剂，例如尼泊金酯、三氯叔丁醇、苯酚、山梨酸或硫柳汞。此外，还可以在输液和注射液中掺入等张剂，例如糖或盐，特别是氯化钠。
含有一种或多种本公开的化合物的无菌注射液的生产通过以下方法完成：将所需量 的各化合物掺入酌情具有上面列出的各种成分的适宜溶剂中，然后灭菌。为了获得无菌粉末，将上述溶液按照需要真空干燥或冷冻干燥。本公开的优选的稀释剂是水、生理学上可接受的缓冲剂、生理学上可接受的缓冲盐溶液或盐溶液。优选的载体是可可脂和vitebesole。
可以与本公开的化合物的各种药物形式一起使用的赋形剂可选自下面的非限制性列表：a)粘合剂，例如乳糖、甘露醇、结晶山梨醇、磷酸氢盐、糖、微晶纤维素、羧甲基纤维素、羟乙基纤维素和/或聚乙烯吡咯烷酮等；b)润滑剂，例如硬脂酸镁、滑石粉、硬脂酸钙、硬脂酸锌、硬脂酸、氢化植物油、亮氨酸、甘油酯和硬脂酰醇富马酸钠；c)崩解剂，例如淀粉、交联羧甲基纤维素、甲基纤维素钠、琼脂、膨润土、海藻酸、羧甲基纤维素和/或聚乙烯吡咯烷酮等。其它合适的药用载体及它们的配制是本领域熟知的，例如在以下文献中有描述：Remington:The Science and Practice of Pharmacy 1995,E.W.Martin编辑,Mack Publishing Company，第19版，伊斯顿，宾夕凡尼亚州。
在一个实施方案中，制剂用于口服施用，并且制剂包含下列成分中的一种或多种或全部：预胶化淀粉、滑石粉、聚乙烯吡咯烷酮K30、交联羧甲基纤维素钠、硬脂酰醇富马酸钠、明胶、二氧化钛、山梨醇、柠檬酸一钠、黄原胶、二氧化钛、矫味剂、苯甲酸钠和糖精钠。
在一个实施方案中，本公开的化合物被鼻内施用，其可以以干粉末吸入器或来自使用适合的抛射剂例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、氢氟烷如1,1,1,2-四氟乙烷(HFA 134A TM)或1,1,1,2,3,3,3-七氟丙烷(HFA 227EA TM)、二氧化碳、或其它适合的气体的加压容器、泵、喷雾器或雾化器中的喷雾剂的形式被施用。所述的加压容器、泵、喷雾器或雾化器可以含有本公开的化合物的溶液或混悬液，例如使用乙醇和抛射剂作为溶剂的溶液或混悬液，其还可以含有润滑剂，例如三油酸山梨坦。
本公开的化合物的典型的剂量范围是0.001-1000mg活性成分/公斤体重/天。所述剂量可以每日一次或分多次给予。适宜剂量的确定由主治医师根据要治疗的疾病的种类及其严重性、个体的健康状况和既往病史、共用药物、所施用的具体化合物、和施用途径等酌情确定。根据需要，本公开的化合物的用量可以超出该剂量范围。
药物组合
本公开的化合物可以单独地或与一种或多种其它活性剂或疗法组合用于本文所述的用途，所述其它活性剂或疗法可以具有或产生相同或不同的药理学功效。本公开的化合物可以与所述其它活性剂或疗法同时、在其之前或在其之后施用。
当本公开的化合物与其它活性剂组合施用时，组合施用的其它活性剂的剂量当然将根据共用的药物、待治疗的病症、患者的一般健康状况、医师或兽医的判断等因素而变化。本公开的化合物可以与组合的其它活性剂通过相同或不同的施用途径同时、分别或依次地进行施用。它们可以被包含在同一药物组合物中，也可以是单独形式、例如药盒形式的组合产品。它们可以由相同或不同的制造商制备和/或配制。而且，本公开的化合物和其它活性剂可以(i)在将组合产品发送给医师之前(例如在包含本公开的化合物和另 外的药物的药盒的情形中)；(ii)在临施用前由医师自身(或在医师指导下)；(iii)由患者自身、例如在本公开的化合物和其它活性剂的依次施用期间一起加入组合治疗中。
在一个实施方案中，本公开提供了包含本公开的化合物或其可药用盐以及一种或多种其它活性剂的药物组合物。任选地，药物组合物可以包含如上描述的可药用赋形剂。
在一项实施方案中，本公开提供了药盒，它包含两个或多个单独的药物组合物，其中至少一个含有式(I)化合物或其可药用盐。在一项实施方案中，药盒包含用于分别保留所述组合物的器具，例如容器、分开的瓶或分开的箔袋。这类药盒的实例是泡罩包，它通常用于包装片剂、胶囊剂等。
本公开的药盒可用于施用不同的剂型、例如口服和胃肠道外剂型，用于以不同的剂量间隔施用单独的组合物，或用于相对于另一种逐步增加单独的组合物。为了帮助顺应性，本公开的药盒通常包含施用说明书。
在本公开的组合治疗中，本公开的化合物和其它治疗剂可以通过相同或不同的制造者来制备和/或配制。而且，本公开的化合物和其它治疗剂可以被一起引入组合治疗中，这可以(i)在将组合产品发放给医师之前(例如对于包含本公开的化合物和其它治疗剂的药盒而言)进行；(ii)在临施用前由医师自己(或在医师的指导下)进行；(iii)由患者自己进行，例如在依次施用本公开的化合物和其它治疗剂的过程中。
通用合成方法
本公开的化合物可以通过多种方法、包括下文给出的方法、实施例中给出的方法或与之类似的方法制备。下文描绘了适宜的通用合成方案。对于各反应步骤而言适当的反应条件是本领域技术人员已知的。原料可购买获得，或者可以通过下文的方法、与下文给出的方法类似的方法或本领域已知的方法制得。通式中的各变量具有与上文相同的含义，另有说明除外。
在一项实施方案中，本公开的化合物可通过如下通用合成方案进行合成，其中各变量如本文所定义，具体反应条件同实施例。
流程1
Figure PCTCN2022118080-appb-000037
通式A2化合物可以通过以下合成方法制备：将原甲酸三甲酯和2,2-二甲基-1,3-二噁烷-4,6-二酮，在100℃搅拌反应2小时后，加入通式化合物A1，继续在该温度下反应2小时。反应液冷却至室温后固体析出，过滤，收集固体，得到通式A2化合物。
通式A3化合物可以通过以下合成方法制备：将通式A2化合物溶解于二苯醚中，230℃搅拌反应1小时后，反应液冷却至室温后加入石油醚，固体析出，过滤，收集固体得到通式A3化合物。
通式A4化合物可以通过以下合成方法制备：将通式A3化合物和三氯氧磷在100℃下反应1小时后，冷却至室温，除去过量的三氯氧磷，得到残余物，向残余物中加入冰水，氨水调节pH为8，二氯甲烷萃取，有机相依次用水和饱和食盐水洗涤，干燥，过滤，浓缩后得到粗品，硅胶柱纯化后得到通式A4化合物。
通式A6化合物可以通过以下合成方法制备：一种情况下，通式A4与通式A5化合物，在DIEA，碳酸钾或者盐酸条件下，发生亲核取代反应，生成通式A6化合物；另外一种情况下，通式A4与通式A5化合物在钯催化条件下，发生偶联反应，得到通式A6化合物。
通式A7化合物可以通过以下合成方法制备：将通式A6化合物和氢氧化钠在适量溶剂中，发生水解反应，得到通式A7化合物。
通式A8化合物可以通过以下合成方法制备：将通式A7化合和羟胺，在缩合剂HATU存在下，发生缩合反应，得到通式A8化合物。
具体实施方式
在本申请中，当化学名称和结构式不一致时，应当以结构式所示为准，除非根据上下文可以推断化学名称而非结构式是正确的。
如本领域技术人员能够清楚理解的，为了简便，在本申请所给出的一些化合物结构式中并非所有氢原子均被明确地标示出来。当化合物中的碳原子或氮原子存在空余化合价时，其表示存在未标示出的氢。
本公开的化合物可以以有机合成领域的技术人员已知的多种方法根据本文提供的方法、反应流程和实施例进行制备。本公开的化合物可以采用下文所述的方法联合合成有机化学领域已知的合成方法或通过本领域技术人员可以理解的变通方法来合成。优选的方法包括但不限于下文所述的那些。反应在适合于所用试剂和材料并且适于所进行的转化的溶剂或溶剂混合物中进行。有机合成领域的技术人员可以理解，分子上存在的官能团应当与计划的转化相一致。这有时要求判断改变合成步骤的顺序或相对于其它选择一种具体的操作流程以获得预期的本公开的化合物。
下面结合具体实施例，进一步阐述本公开。应理解，这些实施例仅用于说明本公开而不用于限制本公开的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比、重量份数、或体积百分比(当液体时)。
为了解释说明的目的，下文描绘的反应流程提供了用于合成本公开的化合物的潜在途径以及关键中间体。对于更详细的单个反应步骤的描述，参见以下实施例部分。本领域技术人员将理解，其它合成途径可用于合成本公开的化合物。虽然在流程中描绘了并在下文讨论了具体的原料和试剂，但是其它原料和试剂可以容易地被替换以提供各种衍生物和/或反应条件。另外，通过下述方法制备的化合物的大多数可以根据本公开采用本领域技术人员熟知的常规化学进一步被修饰。
在本公开的化合物的制备中，中间体的远端官能团的保护可能是必要的。对这类保护的需求将根据远端官能团的性质、制备方法的条件而改变。对这类保护的需求容易被本领域技术人员确定。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。原料通常可以从商业来源获得或采用本领域技术人员已知的方法容易地制备。
各实施例中，实验仪器说明(例如 1H NMR由Varian Mercury-300或Varian Mercury-400型核磁共振仪记录， 13C NMR由Varian Mercury-400或Varian Mercury-500型或Varian Mercury-600型核磁共振仪记录，化学位移以δ(ppm)表示；质谱由Finnigan/MAT-95(EI)与Finnigan LCQ/DECA and Micromass Ultra Q-TOF(ESI)型质谱仪记录；反相制备HPLC分离用硅胶为200-300目)。
缩略语
Figure PCTCN2022118080-appb-000038
Figure PCTCN2022118080-appb-000039
关键中间体的合成
中间体1a：5-氯-2-甲氧基-1,8-萘啶
Figure PCTCN2022118080-appb-000040
步骤1：5-(((6-甲氧基吡啶-2-基)氨基)亚甲基)-2,2-二甲基-1,3-二噁烷-4,6-二酮的合成
在盛有原甲酸三甲酯(100mL)的单口瓶(250mL)中加入化合物2,2-二甲基-1,3-二噁烷-4,6-二酮(12.7g，88.61mmol)。100℃搅拌反应2小时，再加入化合物1a-1(5.0g，40.28mmol)，继续在该温度反应2小时。反应液冷却至室温后固体析出，过滤，收集固体得到化合物1a-2(10g，黄色固体)，收率：89％。 1H-NMR(400MHz,CDCl 3-d)：δ9.30(d,J＝13.6Hz,1H),7.63-7.59(m,1H),6.63-6.57(m,2H),3.99(s,3H),1.76(s,6H).
步骤2：7-甲氧基-1,8-萘啶-4(1H)-酮的合成
在盛有二苯醚(50mL)的单口瓶(250mL)中加入1a-2(5.0g，17.98mmol)，230℃搅拌反应1小时后，反应液冷却至室温后加入石油醚，固体析出，过滤，收集固体得到化合物1a-3(2.9g，黄色固体)，收率：94％。 1H-NMR(400MHz,CDCl 3-d)：δ11.97(s,1H),8.30(d,J＝8.8Hz,1H),7.78-7.75(m,1H),6.79(d,J＝8.8Hz,1H),6.05-6.03(m,1H),3.96(s,3H).
步骤3：5-氯-2-甲氧基-1,8-萘啶的合成
在单口瓶(100mL)中依次加入化合物1a-3(500mg，2.84mmol)和10mL三氯氧磷，100℃反应1小时后，反应液冷却至室温后，除去过量的三氯氧磷，向残余物中加入冰水，氨水调节pH为8，二氯甲烷萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩后得到粗品，硅胶柱纯化(PE：EA＝5:1)得到化合物1a(400mg，白色固体)，收率：73％。LCMS(ESI):m/z 195.1[M+H] +；RT＝1.137min(6.00min).
中间体2a：4-氯-6-氟-7-甲氧基喹啉
Figure PCTCN2022118080-appb-000041
步骤1：5-((((4-氟-3-甲氧基苯基)氨基)亚甲基)-2,2-二甲基-1,3-二噁烷-4,6-二酮的合成
在盛有IPA(50mL)的单口瓶中加入化合物2a-1(3.00g，21.3mmol)和5-(甲氧基亚甲基)-2,2-二甲基-1,3-二噁烷-4,6-二酮(4.75g，25.6mmol)，70℃搅拌反应2小时，冷却至室温，过滤，固体用甲醇洗涤，干燥，得到化合物2a-2(5.80g，黄色固体)，收率：92.3％。LCMS(ESI):m/z 256.1[M-40+H] +；RT＝1.08min(2.00min).
步骤2：6-氟-7-甲氧基喹啉-4(1H)-酮的合成
在盛有二苯醚(100mL)的单口瓶中加入化合物2a-2(5.80g，19.7mmol)，200℃搅拌2小时。冷却至室温，反应液倒入石油醚中，过滤，滤饼用氯仿打浆，得到化合物2a-3(2.80g，灰色固体)，收率：73.6％。LCMS(ESI):m/z 194.0[M+H] +；RT＝1.08min(2.00min).
步骤3：4-氯-6-氟-7-甲氧基喹啉的合成
在盛有DIEA(7mL)的单口瓶中加入化合物2a-3(1.00g，5.18mmol)和三氯氧磷(2mL)，100℃搅拌反应1小时。反应液倒入冰水中，用二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，用层析板纯化得到化合物2a(950mg，白色固体)，收率：86.9％。LCMS(ESI):m/z 212.0[M+H] +；RT＝1.15min(2.00min).
中间体3a：4-氯-7-甲氧基-1,6-萘啶
Figure PCTCN2022118080-appb-000042
步骤1：3-溴-2-甲氧基吡啶-4-胺的合成
在盛有无水乙腈(10mL)的单口瓶(100mL)中加入化合物3a-1(1.0g，8.06mmol)。冷却至0℃后向其中缓慢加入NBS(1.44g，8.06mmol)，升到室温搅拌过夜。反应液用水稀释，乙酸乙酯萃取，合并有机相，有机相依次用水，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩后柱纯化(PE：EA＝8:1)得到化合物3a-2(1.4g，黄色固体)，收率：88％。LCMS(ESI):m/z 203.0[M+H] +；RT＝0.967min(2.50min).
步骤2：5-(((3-溴-2-甲氧基吡啶-4-基)氨基)亚甲基)-2,2-二甲基-1,3-二噁烷-4,6-二酮的合成
在盛有HC(OMe) 3(10mL)的单口瓶(100mL)中加入2,2-二甲基-1,3-二噁烷-4,6-二酮(709mg，4.92mmol)，100℃搅拌反应2小时，加入化合物3a-2(500mg，2.46mmol)并继续反应2小时。反应液冷却至室温后加入石油醚，固体析出，过滤，收集固体得到化合物3a-3(679mg，白色固体)，收率：77％。LCMS(ESI):m/z 357.0 359.0[M+H] +；RT＝1.517min(2.50min).
步骤3：8-溴-7-甲氧基-1,6-萘啶-4-醇的合成
在盛有二苯醚(20mL)的单口瓶(100mL)中加入化合物3a-3(3.0g，8.40mmol)，230℃搅拌反应1小时后，反应液冷却至室温后用石油醚稀释，过滤，收集滤饼得到化合物3a- 4(2.27g，棕色固体)，收率：100％。LCMS(ESI):m/z 255.0 257.0[M+H] +；RT＝0.957min(2.50min).
步骤4：7-甲氧基-1,6-萘啶-4-醇的合成
在盛有甲醇(10mL)的单口瓶(50mL)中依次加入化合物3a-4(2.0g，7.84mmol)，甲酸铵(980mg，15.68mmol)和钯碳(300mg，wt％：10％)，60℃搅拌反应1小时后。反应液过滤，滤液浓缩用乙酸乙酯稀释，依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩后得到化合物3a-5(1.4g，黄色固体)，收率：100％。LCMS(ESI):m/z 177.1[M+H] +；RT＝0.757min(2.50min).
步骤5：4-氯-7-甲氧基-1,6-萘啶的合成
在盛有无水乙腈(10mL)的三口瓶(100mL)中依次加入化合物3a-5(900mg，0.644mmol)和DIEA(1.7mL，5.62mmol)，氮气保护下冷却至0℃后，向其中缓慢滴加三氯氧磷(0.9mL，5.62mmol)，70℃搅拌30分钟后，反应液冷却至室温，饱和碳酸氢钠调节pH＝8，乙酸乙酯萃取，合并有机相，有机相依次用水，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩后柱纯化(PE：EA＝10:1)得到化合物3a(1.0g，黄色固体)，收率：100％。LCMS(ESI):m/z 195.1[M+H] +；RT＝1.287min(2.50min).
中间体4a：8-氯-3-甲氧基-1,5-萘啶
Figure PCTCN2022118080-appb-000043
步骤1：5-((5-甲氧基吡啶-3-基)氨基)亚甲基)-2,2-二甲基-1,3-二氧六环-4,6-二酮的合成
将2,2-二甲基-1,3-二氧六环-4,6-二酮(4.64g，16.11mmol)加入到单口瓶(250mL)中，再加入原甲酸三甲酯(100mL)。105℃搅拌2小时。再加入化合物4a-1(4.00g，16.11mmol)，保持105℃搅拌过夜。室温加入石油醚稀释后，过滤，用石油醚洗涤滤饼，滤饼即为粗品4a-2(7.0g，黄色固体)。LCMS(ESI):m/z 279.1[M-H]-；RT＝0.891min(2.50min).
步骤2：7-甲氧基-1,5-萘啶-4(1H)-酮的合成
将化合物4a-2(5.00g，17.97mmol)装入三口瓶(250mL)中，加入二苯醚(100mL)在氮气保护下搅拌1小时。室温加入大量正己烷稀释，过滤，用正己烷洗涤滤饼，滤饼即粗品4a-3(2.5g，灰色固体)。
步骤3：8-氯-3-甲氧基-1,5-萘啶的合成
将化合物4a-3(3.50g，19.87mmol)装入三口瓶(250mL)中，加入三氯氧磷(70mL)，110℃搅拌12小时。冷却至室温，除去溶剂，再加入二氯甲烷和少量水。用碳酸氢钠调节pH至9-10后用乙酸乙酯萃取。有机相用盐水洗涤，无水硫酸钠干燥，除去溶剂。粗品通过正相柱(PE/EA＝3:1)纯化得到化合物4a(2.70g，黄色固体)。收率：70％。LCMS(ESI):m/z 195.1[M+H] +；RT＝1.271min(2.50min).
中间体5a：4-氯-8-氟-7-甲氧基喹啉
Figure PCTCN2022118080-appb-000044
步骤1：5-(((2-氟-3-甲氧基苯基)氨基)亚甲基)-2,2-二甲基-1,3-二噁烷-4,6-二酮的合成
室温，在干燥的单口瓶(50mL)中依次加入化合物5a-1(500mg，3.50mmol)，2,2-二甲基-1,3-二噁烷-4,6-二酮(655mg，4.55mmol)，三甲氧基甲烷(725mg，4.9mmol)，乙腈(10mL)，加热至85℃反应过夜。反应液减压浓缩。残留物用正戊烷打浆，干燥，得到粗品5a-2(1g，白色固体)。LCMS(ESI):m/z 296.1[M+H]+；RT＝6.324min(15.00min).
步骤2：8-氟-7-甲氧基喹啉-4(1H)-酮的合成
室温，在干燥的单口瓶(50mL)中依次加入化合物5a-2(1g，粗品)，二苯醚(10g)，加热至200℃反应2小时。减压浓缩，残留物用正戊烷打浆，干燥，得到化合物5a-3(600mg，棕色固体)，收率：91.70％。LCMS(ESI):m/z 194.0[M+H] +；RT＝0.94min(3.00min).
步骤3：4-氯-8-氟-7-甲氧基喹啉的合成
室温，在干燥的单口瓶(50mL)中依次加入化合物5a-3(600mg，3.11mmol)，乙腈(20mL)，DIEA(1.5mL)，三氯氧磷(3mL)后加热至80℃，反应过夜，反应液倒入冰水中，用饱和碳酸氢钠溶液调至碱性，乙酸乙酯萃取(30mL)。有机相用盐水洗涤，硫酸钠干燥，抽滤，减压浓缩。残留物硅胶柱(PE：EA＝1:1)纯化，得到化合物5a(350mg，黄色固体)，收率：53.4％。LCMS(ESI):m/z 212.0[M+H] +；RT＝1.51min(3.00min).
中间体6a：4-氯-7-甲氧基喹啉-3-甲腈
Figure PCTCN2022118080-appb-000045
步骤1：(E)-2-(((二甲氨基)亚甲基)氨基)-4-甲氧基苯甲酸甲酯的合成
将化合物6a-1(3g，17.9mmol)加入盛有DMF-DMA(30mL)的单口瓶(250mL)中，105℃搅拌4小时。冷却后浓缩得粗品6a-2(5.0g，黄色固体)。LCMS(ESI):m/z 237.1[M+H]+；RT＝0.792min(2.50min).
步骤2：7-甲氧基-4-氧代-3,4-二氢喹啉-3-甲腈的合成
-78℃，在盛有无水THF(40mL)的三口瓶中，将正丁基锂(13.7mL，34.3mmol)在十分钟内滴加完；半小时内滴加乙腈(1.46g，35.5mmol)，白色固体析出时，滴加化合物6a-2(3.0g，12.7mmol)的THF溶液(10mL)。反应40分钟，用醋酸(3mL)淬灭，浓缩，加水过滤，滤饼干燥得到粗品6a-3(1.6g，黄色固体)，收率：24％。LCMS(ESI):m/z 201.1[M+H]+；RT＝1.032min(2.50min).
步骤3：4-氯-7-甲氧基喹啉-3-甲腈的合成
将化合物6a-3(1.1g，5.5mmol)加入盛有POCl 3(15mL)的单口瓶(100mL)中，100℃搅拌1.5小时。冷却后除去溶剂，室温加入乙酸乙酯和水，饱和碳酸氢钠水溶液调节pH 至8，有机相用氯化钠洗涤，无水硫酸钠干燥，过滤。用prep-TCL纯化(PE：EA＝5:1)得粗品6a(500mg，黄色固体)，收率：42％。LCMS(ESI):m/z 219.1[M+H]+；RT＝1.662min(2.50min).
中间体7a：4-氯-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶
Figure PCTCN2022118080-appb-000046
步骤1：6-甲氧基-2-((4-甲氧苄基)氨基)烟酸甲酯的合成
室温，在干燥的单口瓶(100mL)中依次加入7a-1(5.0g，24.9mmol)，PMBNH 2(4.1g，29.9mmol)，碳酸钾(6.87g，49.8mmol)，DMF(20mL)。加热至80℃反应16小时。冷却至室温，用乙酸乙酯和水萃取，有机相用食盐水洗涤，浓缩，纯化(PE/EA＝2/1)得到化合物7a-2(7g，无色液体)，产率：92％。LCMS(ESI):m/z 303.1[M+H] +；RT＝1.98min(3min).
步骤2：甲基2-氨基-6-甲氧基尼古丁酸酯的合成
室温，在干燥的单口瓶(100mL)中依次加入化合物7a-2(7.0g，24.0mmol)，二氯甲烷(5mL)，TFA(5mL)，室温反应16小时。浓缩，残渣用二氯甲烷稀释，碳酸氢钠水溶液洗涤，有机相用无水硫酸钠干燥，过滤浓缩，纯化得到化合物7a-3(3.5g，无色液体)，产率：80％。LCMS(ESI):m/z 183.1[M+H] +；RT＝1.42min(3min).
步骤3：2-乙酰氨基-6-甲氧基尼古丁酸甲酯的合成
室温，在干燥的单口瓶(50mL)中依次加入化合物7a-3(2.0g，11.0mmol)，DIEA(7.1g，55.0mmol)，DMAP(134mg，1.1mmol)，二氯甲烷(20mL)和乙酰氯(1.7g，22.0mmol)。室温反应16小时。浓缩，残渣用乙酸乙酯和水萃取，有机相浓缩后纯化(PE/EA＝10/1-1/1)，得到化合物7a-4(1.0g，白色固体)。产率：45％。LCMS(ESI):m/z 224.8[M+H] +；RT＝1.541min(3min).
步骤4：7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4(3H)-酮的合成
室温，在干燥的单口瓶(50mL)中依次加入化合物7a-4(1.0g，4.46mmol)，无水甲醇(10mL)，氨水(20mL)。室温反应16小时。浓缩，残渣用乙酸乙酯和水萃取，有机相浓缩，残渣再用少量乙酸乙酯打浆，过滤得到化合物7a-5(200mg，白色固体)，产率：21％。LCMS(ESI):m/z 191.8[M+H]+；RT＝1.715min(3min).
步骤5：4-氯-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶的合成
室温，在干燥的单口瓶(50mL)中依次加入化合物7a-5(200mg，1.05mmol)，三氯氧磷(10mL)。加热至100℃反应16小时。浓缩，残渣用碳酸氢钠水溶液调至pH＝9，用乙酸乙酯萃取，有机相干燥，浓缩，过滤得到化合物7a(210mg，白色固体)，产率：90％。LCMS(ESI):m/z 209.8[M+H] +；RT＝2.44min(5min).
中间体8a:7-氯-1-甲基-1H-吡唑并[4,3-d]嘧啶
Figure PCTCN2022118080-appb-000047
步骤1：4-氨基-1-甲基-1H-吡唑-5-甲酸甲酯的合成
在盛有甲醇(30mL)的单口瓶中加入化合物8a-1(2.00g，10.8mmol)和钯碳(400mg)，在氢气加压(15psi)常温搅拌反应3小时。过滤，滤液浓缩，得到化合物8a-2(1.60g，白色固体)，收率：95.6％。LCMS(ESI):m/z 156.1[M+H] +；RT＝0.94min(2.00min).
步骤2：1-甲基-1H-吡唑并[4,3-d]嘧啶-7-醇的合成
在盛有正丁醇(15mL)和DIEA(15mL)的单口瓶中加入化合物8a-2(1.60g，10.3mmol)和醋酸甲脒(1.29g，12.4mmol)，110℃搅拌反应6小时。反应液冷却至室温，过滤，固体用乙醚洗涤，得到化合物8a-3(1.30g，白色固体)，收率：84.1％；LCMS(ESI):m/z 151.2[M+H] +；RT＝0.623min(2.00min).
步骤3：7-氯-1-甲基-1H-吡唑并[4,3-d]嘧啶的合成
在盛有二氯亚砜(20mL)的单口瓶中加入化合物8a-3(1.30g，8.67mmol)和DMF(0.5mL)，90℃搅拌反应2小时。除去二氯亚砜，加入二氯甲烷和水，分液。水相用二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，浓缩，得到化合物8a(1.20g，白色固体)，收率：82.4％；LCMS(ESI):m/z 169.0[M+H] +；RT＝1.20min(2.00min).
中间体9a：4-氯-1,3-二甲基-1H-吡唑并[3,4-b]吡啶
Figure PCTCN2022118080-appb-000048
步骤1：5-(((1,3-二甲基-1H-吡唑-5-基)氨基)亚甲基)-2,2-二甲基-1,3-二噁烷-4,6-二酮的合成
在盛有原甲酸三甲酯(30mL)的单口瓶(100mL)中加入2,2-二甲基-1,3-二噁烷-4,6-二酮(2.33g，16.19mmol)，100℃反应2小时后，向其中加入化合物9a-1(1.5g,13.5mmol)，100℃继续搅拌2小时。反应液冷却至室温后，石油醚稀释，过滤收集固体得到化合物9a-2(2.6g，黄色固体)，收率：74％；LCMS(ESI):m/z 264.1[M-H] +；RT＝1.004min(2.50min).
步骤2：1,3-二甲基-1H-吡唑并[3,4-b]吡啶-4-醇的合成
在盛有二苯醚(50mL)的单口瓶(100mL)中加入化合物9a-2(2.6g,9.81mmol)，230℃搅拌反应2小时，反应液冷却至室温后加入石油醚(100mL)，过滤收集固体，固体用硅胶柱纯化(DCM：甲醇＝15:1)得到化合物9a-3(0.8g，白色固体)；收率：50％；LCMS(ESI):m/z 164.2[M+H] +；RT＝0.680min(2.50min).
步骤3：4-氯-1,3-二甲基-1H-吡唑并[3,4-b]吡啶的合成
在盛有POCl 3(10mL)的单口瓶(100mL)中加入9a-3(0.7g，4.30mmol)，反应液100℃搅拌2小时。反应液浓缩后，冰浴下用饱和碳酸氢钠水溶液调节pH＝8，二氯甲烷萃取，有机相依次用水，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩后得到化合物9a(700mg，灰色固体)；收率：91％；LCMS(ESI):m/z 182.1[M+H] +；RT＝1.540min(2.50min). 中间体10a：2-(4-氨基-2-甲基苯基)乙酸甲酯
Figure PCTCN2022118080-appb-000049
步骤1：2-(2-溴-4-硝基苯基)丙二酸二乙酯的合成
在氮气保护下，将氢化钠(0.50g，2.27mmol)，DMF(10mL)依次装入三口瓶(100mL)，0℃再慢慢滴加将丙二酸二乙酯(0.47mg，2.95mmol)，搅拌30分钟。再慢慢滴加化合物10a-1(0.5g，2.27mmol)。升温至室温搅拌12小时。室温加入1mol/L盐酸调节pH至5-6后用乙酸乙酯萃取。有机相用盐水洗涤，无水硫酸钠干燥，除去溶剂得粗品10a-2(0.9g，黄色油状物)。LCMS(ESI):m/z 359.9[M-H] -；RT＝1.040min(2.50min).
步骤2：2-(2-溴-4-硝基苯)乙酸的合成
在盛有甲醇(6mL)和水(6mL)的单口瓶(100mL)中室温依次加入化合物10a-2(0.9g，2.49mmol)，氢氧化钠(0.4g，9.99mmol)，室温反应12小时后。除去溶剂，加入2mol/L盐酸水溶液调节pH＝3-4，有固体析出，过滤，用少量二氯甲烷洗涤滤饼得到粗品10a-3(600mg，黄色油状物)。LCMS(ESI):m/z 257.9[M-H] -；RT＝1.384min(2.50min).
步骤3：2-(2-溴-4-硝基苯)乙酸甲酯的合成
将4mL二氯亚砜在0℃慢慢加入盛有无水甲醇(10mL)的单口瓶(100mL)中，搅拌10分钟后。再加入化合物10a-3(170mg，0.56mmol)至单口瓶中，升至室温搅拌12小时。浓缩后得粗品10a-4(150mg，黄色固体)。LCMS(ESI):m/z 273.2，275.2[M+H] +；RT＝1.369min(2.50min).
步骤4：2-(2-甲基-4-硝基苯)乙酸甲酯的合成
将化合物10a-4(150mg，0.48mmol)装入100mL三口瓶中，分别加入1,4-二氧六环和水混合液(9mL，10/1)，MeBF 3K(99mg，0.27mmol)，碳酸钾(275mg，2.27mmol)和PdCl 2dppf(45mg，0.02mmol)。80℃搅拌8小时。加入乙酸乙酯和水萃取。有机相用盐水洗涤，无水硫酸钠干燥，除去溶剂。粗品经prep-TCL(PE/EA＝5:1)纯化得化合物10a-5(165mg，灰白色固体)。收率：97％。LCMS(ESI):m/z 210.2[M+H] +；RT＝1.456min(2.50min).
步骤5：2-(4-氨基-2-甲基苯基)乙酸甲酯的合成
将化合物10a-5(160mg，0.76mmol)加入盛有3mL甲醇的单口瓶(100mL)中，再加入钯碳(16mg)，氢气保护下30℃搅拌12小时。硅藻土过滤，甲醇洗涤，除去有机相得粗品10a(130mg，灰白色固体)。LCMS(ESI):m/z 180.2[M+H] +；RT＝0.756min(2.50min).
中间体11a：2-(4-氨基-2-氟苯基)丙酸甲酯
Figure PCTCN2022118080-appb-000050
步骤1：2-(2-氟-4-硝基苯基)-2-甲基丙二酸二乙酯的合成
将化合物11a-1(1g，6.23mmol)加入盛有DMF(15mL)的单口瓶(100mL)中，再加入2-甲基丙二酸二乙酯(1.3g,7.55mmol),氢氧化钠(377mg,9.43mmol)。室温搅拌2小时。反应液倒入水中，用乙酸乙酯萃取，有机相用水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩。用正向柱(PE：EA＝60:1)纯化得到化合物11a-2(2.0g，黄色油)。收率：100％,LCMS(ESI):m/z 314.1[M+H] +；RT＝1.832min(2.50min).
步骤2：2-(2-氟-4-硝基苯基)丙酸的合成
室温，在盛有冰醋酸(7.5mL)、水(5mL)的单口瓶(100mL)中加入化合物11a-2(2.0g，6.04mmol)，再缓慢加入浓硫酸(2mL)。130℃反应过夜。除去溶剂，加入20mL水，调节pH至11-12，乙酸乙酯萃取，保留水相；调节水相pH为3-4，乙酸乙酯萃取，有机相用水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩得到化合物11a-3(1.0g，无色油)。收率：73.4％。 1H NMR(400MHz,CDCl 3):δ8.06-8.03(m,1H),7.97-7.94(m,1H),7.55-7.51(m,1H),4.16-4.11(m,1H),1.59(d,J＝7.2Hz,3H).
步骤3：2-(2-氟-4-硝基苯基)丙酸甲酯的合成
在盛有甲醇(15mL)的单口瓶(100mL)中加入化合物11a-3(1.0g，5.49mmol)，再加入浓盐酸(0.2mL)，75℃搅拌3小时。反应液直接浓缩得到化合物11a-4(1.0g，无色油)粗品。LCMS(ESI):m/z 226.1[M-H]-；RT＝1.672min(2.50min).
步骤4：2-(4-氨基-2-氟苯基)丙酸甲酯的合成
室温，在盛有甲醇(20mL)的单口瓶(100mL)中依次加入化合物11a-4(1.0g，4.4mmol)和钯碳催化剂(100mg)，在氢气下室温反应2小时。过滤浓缩得到化合物11a粗品(900mg，无色油)。LCMS(ESI):m/z 239.2[M+H+41] +；RT＝1.309min(2.50min).
中间体12a：6-氨基-2,3-二氢苯并呋喃-3-甲酸乙酯
Figure PCTCN2022118080-appb-000051
步骤1：6-溴苯并呋喃-3-甲酸乙酯的合成
在盛有二氯甲烷(40mL)的单口瓶(250mL)中加入化合物12a-1(8g，40.0mmol)和四氟硼酸乙醚溶液(0.6mL)，再滴加重氮乙酸乙酯(9.20g，80.0mmol)的二氯甲烷(10mL)溶液，常温搅拌1小时。浓缩除去溶剂，加入浓硫酸(4mL)，常温搅拌1小时。反应液倒入冰水中，用二氯甲烷萃取，合并有机相，有机相用饱和氯化钠洗，无水硫酸钠干燥，过滤，浓缩，得到粗品经柱纯化(PE：EA＝3:1)，得到化合物12a-2(7.10g，白色固体)，收率：66％。 1H-NMR(400MHz,CDCl 3)：δ8.21(s,1H),7.92(d,J＝8.0Hz,1H),7.71(d,J＝1.6Hz,1H),7.48(dd,J＝8.4,1.6Hz,1H),4.45-4.36(m,2H),1.42(t,J＝8.0Hz,3H).
步骤2：6-(二苯基亚甲基氨基)苯并呋喃-3-甲酸乙酯的合成
在盛有1,4-二氧六环(50mL)的单口瓶(100mL)中依次加入12a-2(2.70g，10.0mmol)、二苯甲酮亚胺(2.72g，10.0mmol)、碳酸铯(6.52g，20.0mmol)、BIANP(623mg,1.0mmol) 和Pd 2dba 3(916mg，1.0mmol)，氮气保护下100℃反应16小时。除去溶剂后柱纯化(PE/EA＝1/1)得到化合物12a-3(3.40mg，黄色固体)，收率：92％；LCMS(ESI):m/z 370.3[M+H] +；RT＝1.64min(2.50min).
步骤3：6-氨基苯并呋喃-3-甲酸乙酯的合成
在盛有THF(50mL)的单口瓶(250mL)中加入12a-3(3.40g，9.21mmol)和4N盐酸(25mL)，常温搅拌3小时。除去溶剂后水相用乙酸乙酯洗，碳酸氢钠溶液调节pH至8。再EA萃取，有机相用饱和氯化钠洗涤，无水硫酸钠干燥，过滤，浓缩，得到化合物12a-4(1.70g，黄色固体)，收率：90％；LCMS(ESI):m/z 306.0[M+H] +；RT＝1.476min(2.50min).
步骤4：6-氨基-2,3-二氢苯并呋喃-3-甲酸乙酯的合成
在盛有甲醇(100mL)的单口瓶(250mL)中加入化合物12a-4(1.30g，6.34mmol)和镁屑(1.54g，63.40mmol)，常温搅拌反应4小时。加入乙酸乙酯，浓缩，得到粗品经柱纯化(PE/EA＝1/1)，得到化合物12a(1.10g，黄色油状物)，收率：84％；LCMS(ESI):m/z 208.2[M+H] +；RT＝1.18min(2.50min).
中间体13a：2-(6-氨基吡啶-3-基)-2-甲基丙酸乙酯
Figure PCTCN2022118080-appb-000052
步骤1：2-甲基-2-(6-硝基吡啶-3-基)丙酸乙酯的合成
将化合物13a-1(1.5g,7.14mmol)溶于DMF(15mL)中，在0℃分批加入氢化钠(857mg，21.42mmol)，保持0℃搅拌半小时后，缓慢滴加碘甲烷(3.04g，21.42mmol)，滴加完毕，室温搅拌3小时。倒入水中淬灭，用乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，纯化(PE/EA＝10/1)得到化合物13a-2(1.0g，黄色油状液体)，收率：59％。LCMS(ESI):m/z 239.1[M+H] +；RT＝1.56min(3min).
步骤2：2-(6-氨基吡啶-3-基)-2-甲基丙酸乙酯的合成
在干燥的单口瓶(50mL)中室温依次加入化合物13a-2(1g,4.2mmol)，无水甲醇(15mL)，10％钯碳(200mg)，氢气保护，室温反应过夜。反应物减压过滤，滤液浓缩得到化合物13a(600mg，黄色油状液体)，收率：68.7％。LCMS(ESI):m/z 209.1[M+H] +；RT＝0.99min(3min).
中间体14a:4-(4-羟基苯基)四氢-2H-吡喃-4-甲酸甲酯
Figure PCTCN2022118080-appb-000053
步骤1：4-(4-甲氧基苯基)四氢-2H-吡喃-4-甲酸甲酯的合成
在盛有20mL N-甲基吡咯烷酮的三口烧瓶中加入14a-1(5.0g，27.78mmol)，冰浴下加入氢化钠(2.8g，69.45mmol)。0℃反应半小时，加入1-溴-2-(2-溴乙氧基)乙烷(7.1g，30.56mmol)，室温反应1小时。反应液用饱和氯化铵淬灭，乙酸乙酯萃取，有机相用饱和 食盐水洗，无水硫酸钠干燥，柱层析(EA：PE＝1:3)得到化合物14a-2(2.1g，无色油)； 1H-NMR(400MHz,CDCl 3-d)：δ7.27(d,J＝8.0Hz,2H),6.88(d,J＝8.8Hz,2H),3.97-3.91(m,2H),3.84(s,3H),3.67(s,3H),3.61-3.40(m,2H),2.52-2.49(m,2H),1.99-1.93(m,2H).
步骤2：4-(4-羟基苯基)四氢-2H-吡喃-4-甲酸甲酯的合成
在盛有15mL二氯甲烷的三口烧瓶中加入化合物14a-2(1g，4.0mmol)，冰浴下加入三溴化硼(5.0g，20.0mmol)，室温反应2小时。反应液倒入水中，用二氯甲烷萃取，有机相用水洗，饱和食盐水洗，无水硫酸钠干燥，浓缩，得到粗品14a(900mg，无色油)； 1H-NMR(400MHz,DMSO-d 6)：δ9.40(s,1H),7.15(d,J＝8.4Hz,2H),6.73(d,J＝8.8Hz,2H),3.80-3.76(m,2H),3.58(s,3H),3.40-3.35(m,2H),2.36-2.32(m,2H),1.84-1.77(m,2H).
中间体15a:6-羟基-1-甲基-1,2,3,4-四氢萘-1-甲酸
Figure PCTCN2022118080-appb-000054
步骤1：6-甲氧基-1-甲基-1,2,3,4-四氢萘-1-甲酸甲酯的合成
在干燥的50mL三口烧瓶中0℃依次加入氢化钠(270mg，6.81mmol)和DMF(20mL)。氮气保护，0℃再加入化合物15a-1(500mg，2.27mmol)和碘甲烷(0.42mL，6.81mmol)的DMF(10mL)溶液。0℃搅拌30分钟，再室温搅拌16小时。将反应液倒入水中，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗产品用制备板(PE：EA＝20:1)纯化，得到化合物15a-2(500mg，黄色的油)，产率：94.01％。LCMS(ESI):m/z 235.2[M-H] -；RT＝1.567min(2.50min).
步骤2：6-羟基-1-甲基-1,2,3,4-四氢萘-1-甲酸甲酯的合成
在干燥的100mL三口烧瓶中0℃依次加入三氯化铝(1420mg，10.67mmol)，二氯甲烷(30mL)和化合物15a-2(500mg，2.13mmol)。0℃搅拌反应10分钟，再加入乙硫醇(0.79mL，10.67mmol)。室温搅拌反应2小时。将反应液倒入水中，二氯甲烷萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到化合物15a-3(430mg，黄色的油)，产率：91.48％，LCMS(ESI):m/z 221.2[M+H] +；RT＝1.506min(2.50min).
步骤3：6-羟基-1-甲基-1,2,3,4-四氢萘-1-甲酸的合成
在干燥的25mL的单口烧瓶中室温依次加入化合物15a-3(380mg，1.73mmol)，1,4-二氧六环(24mL)，水(8mL)和叔丁醇钾(968mg，8.63mmol)。加热至60℃反应24小时。反应液用1mol/L的盐酸水溶液调pH至4，乙酸乙酯萃取。收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物15a(350mg，白色固体)，产率：98.37％，LCMS(ESI):m/z 205.2[M-H] -；RT＝1.258min(2.50min).
中间体16a:2-(吲哚-5-基)乙酸甲酯
Figure PCTCN2022118080-appb-000055
步骤1：5-(2-(叔丁氧基)-2-氧乙基)吲哚-1-甲酸叔丁酯的合成
将双三甲基硅基胺基锂(2.5mL，2.50mmol)，乙酸钯(II)(催化量)和三叔丁基膦(催化量)装入100mL三口瓶中在氮气保护下，再加入无水甲苯5mL。-10℃慢慢滴加乙酸叔丁酯(269mg，2.32mmol)，搅拌20分钟。再滴加16a-1(300g，1.01mmol)，加完升温至80℃反应2小时。室温加入乙酸乙酯和水萃取。有机相用盐水洗涤，无水硫酸钠干燥，浓缩后柱纯化(PE：EA＝10：1)得16a-2(180mg，黄色油状物)。收率：54％。 1H NMR(400MHz,CDCl 3):δ7.65-7.44(m,1H),7.05-7.03(m,1H),3.99-3.96(m,2H),3.44(s,2H),3.08-3.05(m,2H),1.56(s,9H),1.47(s,9H).
步骤2：2-(吲哚-5-基)乙酸甲酯的合成
50mL单口瓶中依次加入16a-2(160mg，0.48mmol)，5mL甲醇和3滴浓硫酸。70℃搅拌过夜。冷却至室温，除去溶剂，加入水和乙酸乙酯，碳酸氢钠水溶液调pH至9。有机相用盐水洗涤，无水硫酸钠干燥，除去溶剂得16a(90mg，黄色油状物)。LCMS(ESI):m/z 192.2[M-H] -；RT＝0.645min(2.50min).
中间体17a：3-(4-甲氧基苯基)四氢呋喃-3-甲酸
Figure PCTCN2022118080-appb-000056
步骤1：3-(4-甲氧基苯基)四氢呋喃-3-醇的合成
氮气保护-78℃向含有对溴苯甲醚(2.82g，14.6mmol)的无水THF(25mL)的100mL三口瓶中缓慢滴加正丁基锂(8.7ml，13.48mmol,1.6N)，反应30分钟后，再缓慢滴加化合物17a-1(1.0g,11.23mmol)的THF溶液，-78℃搅拌10分钟，升温到室温，反应液用饱和氯化铵溶液淬灭，水稀释，乙酸乙酯和水洗萃。有机相用氯化钠洗涤，无水硫酸钠干燥，过滤。用硅胶柱纯化(PE：EA＝1:1)得化合物17a-2(2.0g，白色固体)。收率：92％。 1H NMR(400MHz,CDCl 3):δ7.41-7.38(m,2H),6.92-6.88(m,2H),4.22-4.07(m,2H),3.99-3.95(m,1H),3.86(d,J＝9.2Hz,1H),3.81(s,3H),2.42-2.35(m,1H),2.27-2.16(m,1H).
步骤2：2-(3-(4-甲氧基苯基)四氢呋喃-3-基)-5-甲基呋喃的合成
向盛有5mL无水甲苯的50mL单口瓶中依次加入化合物17a-2(200mg，1.03mmol),2-甲基呋喃(422mg,5.1mmol)，双((三氟甲基)磺酰基)氨基锂(33mg,0.11mmol)和四丁基六氟磷酸铵(22mg,0.062mmol)，氮气保护60℃反应2小时，反应液冷却至室温后加入水稀释，乙酸乙酯萃取，有机相用氯化钠洗涤，无水硫酸钠干燥，过滤。用prep-TLC纯化(PE：EA＝15:1)得化合物17a-3(220mg，黄色油状物)。收率：83％。 1H NMR(400MHz,CDCl 3):δ7.19-7.15(m,2H),6.86-6.82(m,2H),5.99(d,J＝3.2Hz,1H),5.87-5.86(m,1H),4.35(d,J＝8.4Hz,1H),4.12(d,J＝8.4Hz,1H),4.02-3.97(m,2H),3.78(s,3H),2.72-2.66(m,1H),2.42-2.35(m,1H),2.22(s,3H).
步骤3：3-(4-甲氧基苯基)四氢呋喃-3-甲酸的合成
在0℃向盛有8mL混合溶剂(正庚烷：EA：水＝1:1:2)的50mL单口瓶中依次加入化 合物17a-3(220mg，0.85mmol)，高碘酸钠(422mg，5.1mmol)和三氯化钌(催化量)，氮气保护室温反应过夜，反应液加入水稀释，乙酸乙酯萃取，有机相用氯化钠洗涤，无水硫酸钠干燥，过滤。滤液浓缩得化合物17a(200mg，黄色固体)。 1H NMR(400MHz,DMSO-d 6):δ12.51(brs,1H),7.23-7.21(m,2H),6.91-6.89(m,2H),4.50(d,J＝8.0Hz,1H),3.86-3.76(m,2H),3.73(s,3H),3.68(d,J＝8.4Hz,1H),2.84-2.78(m,1H),2.15-2.08(m,1H).
中间体18a:6-羟基-1,2,3,4-四氢萘-1-甲酸甲酯
Figure PCTCN2022118080-appb-000057
步骤1：6-甲氧基-3,4-二氢萘-1-基三氟甲磺酸酯的合成
在干燥的50mL的单口烧瓶中室温依次加入化合物18a-1(500mg，2.84mmol)，无水THF(10mL)。氮气保护，冷却至-78℃，慢慢滴加双三甲基硅基胺基锂(4.26mL，4.26mmol)，加完反应1小时。再加入N-苯基双(三氟甲烷磺酰)亚胺(2030mg，5.67mmol)后-78℃反应2小时。加入20mL水，乙酸乙酯萃取。收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤。粗产品柱层析(PE：EA＝50：1)纯化，得到化合物18a-2(800mg，黄色固体)，产率：91.46％， 1H-NMR(400MHz,CDCl 3):δ7.42-7.38(m,1H),6.78-6.73(m,2H),5.86(t,J＝4.8Hz,1H),3.81(s,3H),2.83(t,J＝8.0Hz,2H),2.50-2.45(m,2H).
步骤2：6-甲氧基-3,4-二氢萘-1-甲酸甲酯的合成
在50mL单口烧瓶中室温依次加入化合物18a-2(700mg，2.27mmol)，甲醇(20mL)，三乙胺(1.58mL，11.35mmol)和PdCl 2dppf(830mg，1.14mmol)。一氧化碳置换3次，90℃搅拌反应16小时。减压浓缩。粗产品用制备板(PE：EA＝20:1)纯化，得到化合物18a-3(300mg，黄色的油)，产率：60.53％， 1H-NMR(400MHz,CDCl 3)：δ7.74(d,J＝8.4Hz,1H),7.03(t,J＝4.8Hz,1H),6.77-6.71(m,2H),3.83(s,3H),3.81(s,3H),2.74(t,J＝8.0Hz,2H),2.40-2.35(m,2H).
步骤3：6-甲氧基-1,2,3,4-四氢萘-1-甲酸甲酯的合成
在干燥的50mL单口烧瓶中室温依次加入化合物18a-3(300mg，1.37mmol)，甲醇(10mL)和钯碳催化剂(30mg)。氢气置换3次，室温搅拌反应16小时。减压浓缩，得到化合物18a-4(240mg，黄色的油)，产率：79.27％， 1H-NMR(400MHz,CDCl 3)：δ7.08(d,J＝8.8Hz,1H),6.72-6.70(m,1H),6.63(d,J＝2.4Hz,1H),3.79-3.77(m,4H),3.71(s,3H),2.85-2.71(m,2H),2.16-2.10(m,1H),2.02-1.92(m,2H),1.78-1.72(m,1H).
步骤4：6-羟基-1,2,3,4-四氢萘-1-甲酸甲酯的合成
在50mL三口烧瓶中0℃依次加入三氯化铝(726mg，5.45mmol)，二氯甲烷(15mL)和化合物18a-4(240mg，1.09mmol)。0℃搅拌，反应10分钟，再加入乙硫醇(0.40mL，5.45mmol)，室温反应2小时。倒入水中，二氯甲烷萃取。收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到化合物18a(210mg，黄色的油)，产率：93.45％， 1H-NMR(400MHz,CDCl 3-d)：δ7.01(d,J＝8.4Hz,1H),6.61-6.58(m,1H),6.54(d,J＝2.4Hz, 1H),5.02(s,1H),3.78-3.75(m,1H),3.71(s,3H),2.81-2.64(m,2H),2.15-1.88(m,3H),1.77-1.68(m,1H).
中间体19a:2-(4-羟基苯基)-3-甲基丁酸甲酯
Figure PCTCN2022118080-appb-000058
步骤1：2-(4-甲氧基苯基)-3-甲基丁酸甲酯的合成
在干燥的100mL的单口烧瓶中0℃依次加入叔丁醇钾-THF(1.0M，8.25mL，8.25mmol)，THF(20mL)，化合物19a-1(1.00g，5.50mmol)和碘代异丙烷(1.50g，8.25mmol)。室温反应2小时。倒入50mL水中，用乙酸乙酯萃取。收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗产品层析柱(PE：EA＝5:1)纯化，得到化合物19a-2(0.86g，黄色固体)，产率：69.70％， 1H-NMR(400MHz,CDCl 3-d):δ9.60(d,J＝8.4Hz,2H),9.20(d,J＝8.4Hz,2H),6.15(s,3H),6.00(s,3H),5.46(d,J＝10.8Hz,1H),4.68-4.62(m,1H),3.38(d,J＝6.4Hz,3H),3.04(d,J＝8.8Hz,3H).
步骤2：2-(4-羟基苯基)-3-甲基丁酸甲酯的合成
在100mL的三口烧瓶中0℃依次加入三氯化铝(2.58g，19.34mmol)，DCM(100mL)和化合物19a-2(0.86g，3.87mmol)。0℃搅拌10分钟。0℃加入乙硫醇(1.43mL，19.34mmol)。室温反应2小时。反应完毕，倒入100mL水中，用乙酸乙酯萃取。收集有机相，饱和食盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩。粗产品层析柱(PE：EA＝3:1)纯化，得到化合物19a(0.68g，黄色的油)，产率：84.40％，LCMS(ESI):m/z 209.2[M+H] +；RT＝1.571min(2.50min).
中间体20a:4-(4-甲氧基苯基)氧杂环庚烷-4-甲酸
Figure PCTCN2022118080-appb-000059
步骤1：4-(4-甲氧基苯基)氧杂环庚烷-4-醇的合成
在盛有60mL THF的250mL的三口瓶中室温依次加入1-溴-4-甲氧基苯(5.9g，31.6mmol)，-78℃加入正丁基锂(14.7mL，26.3mmol)，反应半小时后加入化合物20a-1(3.0g，36.8mmol)，-78℃反应2小时，反应液用饱和氯化铵淬灭，加水稀释，用乙酸乙酯萃取，有机相用水洗，饱和食盐水洗，浓缩得到粗品20a-2(4.2g，无色油)。收率：71.9％， 1H NMR(400MHz,CDCl 3):δ7.42-7.40(m,2H),6.88-6.86(m,2H),3.94-3.88(m,2H),3.80(s,3H),3.75-3.67(m,2H),2.29-2.12(m,4H),1.93-1.88(m,2H).
步骤2：4-(4-甲氧基苯基)-4-(5-甲基呋喃-2-基)氧杂环庚烷的合成
在盛有50mL甲苯的100mL单口瓶中加入20a-2(4.2g，18.9mmol)，2-甲基呋喃(7.76g，94.6mmol)，双三氟甲烷磺酰亚胺锂(597mg，2.08mmol)和四丁基六氟磷酸铵(366mg，0.95mmol)，40℃反应2小时。过滤，滤液浓缩后柱层析得到化合物20a-3(4.7g， 无色油)。收率：86.9％， 1H NMR(400MHz,CDCl 3):δ7.09-7.06(m,2H),6.82-6.80(m,2H),5.97-5.90(m,2H),3.76-3.71(m,7H),2.40-2.29(m,4H),2.23(s,3H),1.75-1.72(m,2H).
步骤3：4-(4-甲氧基苯基)氧杂环庚烷-4-甲酸的合成
在盛有200mL正庚烷，200mL乙酸乙酯和400mL水的混合溶剂的2000mL单口瓶中室温依次加入20a-3(4.7g，16.4mmol)，冰浴加入高碘酸钠(24.6g，115mmol)，搅拌5分钟后加入三氯化钌(催化量)。反应液过滤，加水稀释，用乙酸乙酯萃取，有机相依次用水、饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到粗品20a(2.6g，黄色油)。LCMS(ESI):m/z 251.1[M+H] +；RT＝1.064min(2.50min).
中间体21a：3-(4-甲氧基苯基)-8-氧杂二环[3.2.1]辛烷-3-甲酸
Figure PCTCN2022118080-appb-000060
参考中间体20a的合成方法，采用8-氧杂二环[3.2.1]辛烷-3-酮为起始原料。 1H NMR(400MHz,DMSO-d 6):δ12.21-12.17(m,1H),7.40(d,J＝8.8Hz,2H),6.88(d,J＝8.8Hz,2H),4.33-4.29(m,2H),3.74(s,1H),2.73-2.68(m,2H),1.96-1.92(m,2H),1.69-1.66(m,2H),1.20-1.17(m,2H).
中间体22a：
Figure PCTCN2022118080-appb-000061
步骤1：3-(1-甲氧基-1-氧代丙烷-2-基)吡咯烷-1-甲酸叔丁酯
氮气保护，在100mL三口瓶中依次加入3-(2-甲氧基-2-氧代乙基)吡咯烷-1-甲酸叔丁酯(500mg，2.05mmol)，THF(5mL)，-78℃滴加二异丙基胺基锂(2M，3mL)，反应1小时后加入碘甲烷(1.75g，12.3mmol)的THF溶液(5mL)。室温反应1小时，反应液用饱和氯化铵溶液淬灭，加水稀释，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩粗品22a-1(150mg，黄色固体)。
步骤2：3-(1-甲氧基-2-甲基-1-氧代丙烷-2-基)吡咯烷-1-甲酸叔丁酯
氮气保护，在50mL三口瓶中依次加入22a-1(150mg,0.58mmol)，THF(3mL)，-78℃滴加二异丙基胺基锂(2M，0.88mL)，反应1小时后加入碘甲烷(123mg，0.87mmol)的THF溶液。室温反应1小时，反应液饱和氯化铵溶液淬灭，加水稀释，乙酸乙酯萃取，有机相依次用水、饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得化合物22a-2(105mg，透明油)； 1H NMR(400MHz,DMSO-d 6):δ3.68(d,J＝6.0Hz,3H),3.55-3.36(m,2H),3.26-3.20(m,1H),3.10-2.99(m,1H),2.45-2.37(m,1H),1.87-1.81(m,1H),1.46(s,9H),1.19(s,6H).
步骤3：2-甲基-2-(吡咯烷-3-基)丙酸甲酯盐酸盐
在盛有6mL二氯甲烷的50mL单口瓶中室温依次加入化合物22a-2(800mg，2.95 mmol)和TFA(2mL)。室温反应4小时，调节pH＝9，反应液加水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩后得到粗品化合物22a(500mg，黄色油)。
实施例1化合物1的制备
Figure PCTCN2022118080-appb-000062
步骤1：2-氨基-6-甲氧基烟酸的合成
在干燥的单口瓶(100mL)中室温依次加入2-氨基-6-氯烟酸(5.0g，29.0mmol)，甲醇钠(15.7g，290mmol)，甲醇(50mL)。加热至80℃，反应48小时。冷却至室温，减压过滤，滤饼用甲醇洗涤，真空干燥，得到化合物1-1(2.0g，白色固体)，产率：40％。LCMS(ESI):m/z 169.0[M+H] +；RT＝1.10min(3min).
步骤2：7-甲氧基吡啶并[2,3-d]嘧啶-4-酚的合成
在干燥的单口瓶(50mL)中室温依次加入1-1(1.0g，6.0mmol)和醋酸甲脒(624mg，17.8mmol)，乙二醇甲醚(10mL)。加热至100℃，反应18小时。浓缩反应液，残留物硅胶柱纯化(DCM：甲醇＝10:1)，得到化合物1-2(200mg，白色固体)，产率：20％。LCMS(ESI):m/z 177.9[M+H] +；RT＝1.502min(3min).
步骤3：4-氯-7-甲氧基吡啶并[2,3-d]嘧啶的合成
在干燥的单口瓶(50mL)中室温依次加入1-2(200mg，1.13mmol)和三氯氧磷(10mL)。加热至100℃，反应16小时。浓缩反应液，残留物用碳酸氢钠溶液碱化至pH至9，二氯甲烷萃取，有机相用硫酸钠干燥，浓缩，得到化合物1-3(200mg，白色固体)，产率：90％。LCMS(ESI):m/z 339.7[M+H] +；RT＝1.521min(3min).
步骤4：2-(4-((7-甲氧基吡啶并[2,3-d]嘧啶-4-基)氨基)苯基)乙酸乙酯的合成
在干燥的单口瓶(50mL)中室温依次加入1-3(200mg，1.02mmol)和2-(4-氨基苯基)乙酸乙酯(275mg，1.54mmol)。加热至80℃，反应16小时。反应液用乙酸乙酯和水萃取，有机相用饱和食盐水洗涤，用硫酸钠干燥，浓缩纯化(PE：EA＝10:1-1:1)得到化合物1-4(100mg，白色固体)，产率：29％，LCMS(ESI):m/z 339.1[M+H]+；RT＝1.33min(3min).
步骤5：N-羟基-2-(4-((7-甲氧基吡啶并[2,3-d]嘧啶-4-基)氨基)苯基)乙酰胺的合成
在干燥的单口瓶(50mL)中室温依次加入1-4(100mg，0.30mmol)，50％羟胺水溶液(1mL)，甲醇(2mL)和THF(2mL)，氢氧化钠(60mg，1.5mmol)。室温反应2小时。反应液用1M稀盐酸酸化至pH至7，浓缩，析出固体用甲醇洗涤，干燥，得到化合物1(20mg，白色固体)，产率：20％。LCMS(ESI):m/z 326.1[M+H]+；RT＝0.92min(3min). 1H NMR(400MHz,DMSO-d 6):δ10.67(s,1H),9.90(s,1H),8.33-8.62(m,2H),8.61(m,1H),7.70-7.69(m,2H),7.28-7.26(m,2H),7.12-7.11(m,1H),4.01(s,2H),3.28(s,2H).
实施例2化合物2的制备
Figure PCTCN2022118080-appb-000063
步骤1：2-(4-((7-甲氧基-1,8-萘啶-4-基)氧基)苯基)乙酸甲酯的合成
在盛有无水DMF(20mL)的单口瓶(100mL)中依次加入1a-3(0.5g，2.84mmol)，卡特缩合剂(2.51g，5.68mmol)和无水碳酸铯(3.7g，11.36mmol)。室温搅拌1小时后再加入2-(4-羟基苯基)乙酸甲酯(940mg，5.68mmol)和无水碳酸铯(3.7g，11.36mmol)。70℃反应6小时后，反应液冷却至室温后过滤，滤液浓缩，柱纯化(EA/PE＝2/1)得到化合物2-1(280mg，黄色固体)，收率：30％。LCMS(ESI):m/z 325.2[M+H] +；RT＝1.307min(2.50min).
步骤2：2-(4-((7-甲氧基-1,8-萘啶-4-基)氧基)苯基)乙酸的合成
在盛有5mL混合溶剂(THF/水＝3/1)的单口瓶(50mL)中依次加入2-1(280mg，0.864mmol)和氢氧化锂(42mg，1.73mmol)，室温搅拌反应过夜。反应液浓缩后用1N盐酸调节pH至4，固体析出，过滤收集固体得到化合物2-2(200mg，黄色固体)，收率：75％。LCMS(ESI):m/z 311.1[M+H] +；RT＝0.960min(2.50min).
步骤3：2-(4-((7-甲氧基-1,8-萘啶-4-基)氧基)苯基)-N-((四氢-2H-吡喃-2-基)氧基)乙酰胺的合成
在盛有无水DMF(8mL)的单口瓶(100mL)中依次加入2-2(200mg，0.644mmol)，O-(四氢-2H-吡喃-2-基)羟胺(114mg，0.966mmol和DIEA(250mg，1.93mmol)，搅拌均匀后向其中缓慢加入HATU(490mg，1.29mmol)，室温搅拌反应1小时。反应液浓缩，prep-TLC(二氯甲烷：甲醇＝20:1)纯化得化合物2-3(200mg，黄色固体)，收率：76％。LCMS(ESI):m/z 410.2[M+H] +；RT＝1.237min(2.50min).
步骤4：N-羟基-2-(4-((7-甲氧基-1,8-萘啶-4-基)氧基)苯基)乙酰胺的合成
在盛有乙腈(5mL)的单口瓶(50mL)中依次加入2-3(200mg，0.49mmol)和TsOH(252mg，1.47mmol)，室温搅拌反应2小时。反应液浓缩，粗品经反相制备分离纯化得到化合物2(30mg，白色固体)，收率：19％。LCMS(ESI):m/z 326.0[M+H] +；RT＝3.245min(6.00min). 1H-NMR(400MHz,DMSO-d 6)：δ8.69(d,J＝6.4Hz,1H),8.58(d,J＝8.8Hz,1H),7.41(d,J＝8.4Hz,2H),7.24(d,J＝8.8Hz,2H),7.15(d,J＝9.2Hz,1H),6.54(d,J＝5.2Hz,1H),4.04(s,3H),3.35(s,2H).
实施例3化合物3的制备
Figure PCTCN2022118080-appb-000064
步骤1：4-((7-甲氧基喹啉-4-基)氧基)苯甲酸甲酯的合成
在干燥的单口瓶(50mL)中室温依次加入4-氯-7-甲氧基喹啉(100mg，0.52mmol)，尼泊金甲酯(95mg，0.62mmol)，碳酸钾(143mg，1.04mmol)，DMF(5mL)；加热至130℃反应过夜。加入水(10mL)，乙酸乙酯(30mL)萃取，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残留物硅胶柱(PE：EA＝3:1)纯化，得化合物3-1(90mg，淡黄色固体)，收率：56.00％。LCMS(ESI):m/z 310.1[M+H] +；RT＝1.81min(3.00min).
步骤2：4-((7-甲氧基喹啉-4-基)氧基)苯甲酸的合成
在干燥的单口瓶(25mL)中室温依次加入3-1(90mg，0.29mmol)，THF(3mL)，水(1mL)，单水氢氧化锂(36mg，0.67mmol)。反应常温搅拌过夜。反应液用1M稀盐酸调至pH至6，减压除去THF，过滤，滤饼水洗，干燥得到化合物3-2(70mg，淡黄色固体)，产率：81.39％。LCMS(ESI):m/z 296.1[M+H] +；RT＝1.39min(3.00min).
步骤3：N-羟基-4-((7-甲氧基喹啉-4-基)氧基)苯酰胺的合成
在干燥的单口瓶(25mL)中室温依次加入3-2(30mg，0.10mmol)，DIEA(39mg，0.30mmol)，HATU(57mg，0.15mmol)和DMF(3mL)。反应液室温条件搅拌10分钟。加入50％羟胺水溶液(7mg，0.20mmol)，反应液搅拌2小时。残留物浓缩后用高效液相反相制备柱纯化，得到化合物3(11mg，乳白色固体)，产率：35.48％。LCMS(ESI):m/z 310.7[M+H] +；RT＝3.199min(15.00min). 1H-NMR(400MHz,DMSO-d 6):11.27(s,1H),9.08(s,1H),8.67-8.66(m,1H),8.16-8.14(m,1H),7.90-6.88(m,2H),7.43(s,1H),7.34-7.28(m,3H),7.61-7.60(m,1H),3.94(s,3H).
实施例4化合物4的制备
Figure PCTCN2022118080-appb-000065
步骤1：2-(4-(((7-甲氧基喹啉-4-基)氨基)苯基)乙酸乙酯的合成
将4-氯-7-甲氧基喹啉(1.50g，10.33mmol)加入盛有IPA(10mL)的单口瓶(100mL)中，再加入2-(4-氨基苯基)乙酸乙酯(1.39mg，10.33mmol)和浓盐酸(1.95mL，30.99mmol)，90℃氮气保护搅拌1.5小时。冷却后，室温加入碳酸氢钠调节pH至9-10后用石油醚-二氯甲烷(10：1,100mL)打浆，过滤，滤饼用石油醚洗涤得粗品4-1(2.0g，黄色固体)，收率58％。LCMS(ESI):m/z 337.0[M+H] +；RT＝1.120min(2.50min).
步骤2：2-(4-((7-甲氧基喹啉-4-基)氨基)苯基)乙酸的合成
在盛有THF(12mL)和水(4mL)的混合溶液的单口瓶(100mL)中室温依次加入4-1(700mg，2.08mmol)，氢氧化锂(98mg，4.14mmol)，室温反应16小时。除去溶剂，加入1mol/L盐酸水溶液调节pH至3-4。水相冻干得到粗品4-2(700mg，白色固体)。LCMS(ESI):m/z309.1[M+H] +；RT＝0.762min(2.50min).
步骤3：2-(4-((7-甲氧基喹啉-4-基)氨基)苯基)-N-((四氢-2H-吡喃-2-基)氧基)乙酰胺的合成
将4-2(200mg，0.65mmol)加入盛有DMF(5mL)的单口瓶(100mL)中，再分批加入O-(四氢-2H-吡喃-2-基)羟基胺(92mg，0.78mmol)，TEA(132mg，1.30mmol)和HATU(370mg，0.97mmol)。室温搅拌3小时。室温加入乙酸乙酯和水洗萃。有机相用氯化钠洗涤，无水硫酸钠干燥，过滤。用prep-TCL纯化(二氯甲烷：甲醇＝20:1)得化合物4-3(200mg，白色固体)，收率：76％。LCMS(ESI):m/z 408.2[M+H] +；RT＝1.137min(2.50min).
步骤4：N-羟基-2-(4-(((7-甲氧基喹啉-4-基)氨基)苯基)乙酰胺的合成
在盛有乙腈(10mL)的单口瓶(50mL)中室温依次加入4-3(100mg，0.25mmol)和TsOH(94mg，0.49mmol)，室温反应3小时。反应液经prep-HPLC(甲酸体系)纯化得到化合物4(43mg，白色固体)，收率53％。LCMS(ESI):m/z 324.0[M+H] +；RT＝3.155min(6.00min). 1H NMR(400MHz,MeOD-d 4):δ8.43(d,J＝9.2Hz,1H),8.24(d,J＝7.2Hz,1H),7.41-7.39(m,3H),7.24-7.23(m,3H),6.76(d,J＝7.2Hz,1H),4.02(s,3H),3.50(s,2H).
实施例5-17分别根据实施例1-4中所述方法合成化合物5-17，各实施例化合物的结构式参见前面的表格
Figure PCTCN2022118080-appb-000066
Figure PCTCN2022118080-appb-000067
实施例18化合物18的制备
Figure PCTCN2022118080-appb-000068
步骤1：N-(4-氯吡啶-2-基)新戊酰胺的合成
在干燥的单口瓶(100mL)中室温依次加入4-氯吡啶-2-胺(12.8g，100mmol)，三乙胺(13.1g，130mmol)，吡啶(15mL)和二氯甲烷(15mL)，在冰浴条件下逐滴加入新戊酰氯(13.2g，110mmol)，加完反应搅拌过夜。将反应液减压浓缩。残留物硅胶柱(PE/EA＝10/1)纯化，得到化合物18-1(18.5g，粉色固体)，收率：87.00％。 1H-NMR(400MHz,CDCl 3):8.36-8.35(m,1H),8.16-8.14(m,1H),8.10(s,1H),7.05-7.03(m,1H),1.30(s,9H).
步骤2：N-(4-氯-3-甲酰基吡啶-2-基)新戊酰胺的合成
在干燥的三口瓶(250mL)中室温依次加入18-1(11.4g，53.8mmol)，THF(70mL)。氮气保护，在-78℃逐滴加入正丁基锂(54mL，2.5M THF)，反应液在-78℃搅拌半小时。将含DMF(4.0g,54.0mmol)的THF(30mL)溶液加入到上述反应液中，在-78℃继续搅拌1小时。反应液升至室温加入饱和氯化铵溶液(200mL)，室温反应30分钟。反应液用乙酸 乙酯(100mL)萃取，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残留物硅胶柱(PE/EA＝3/1)纯化，得到化合物18-2(4g，黄色油状物)，产率：31.00％。LCMS(ESI):m/z 240.8[M+H] +；RT＝1.768min(3.00min).
步骤3：3-(4-氯-2-新戊酰胺氨基吡啶-3-基)-3-羟基丙酸叔丁酯的合成
在干燥的三口瓶(250mL)中室温依次加入18-2(2.28g，9.5mmol)，THF(40mL)。氮气保护，在-78℃逐滴加入LDA(10.5mL，2M THF)，反应液在-78℃搅拌半小时。将乙酸叔丁酯(1.1g，9.5mmol)的THF(20mL)溶液加入到上述反应液中，在-78℃继续搅拌1小时。升至室温加入水(40mL)，乙酸乙酯(50mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残留物硅胶柱(PE/EA＝2/1)纯化，得到化合物18-3(2.2g，黄色固体)，产率：65.00％，LCMS(ESI):m/z 356.7[M+H] +；RT＝1.871min(3.00min).
步骤4：5-氯-1,8-萘啶-2(1H)-酮的合成
在干燥的单口瓶(50mL)中室温依次加入18-3(1.9g，5.34mmol)，3M盐酸(20mL)，100℃反应8小时，反应液冷却过滤，依次用饱和碳酸氢钠溶液(5mL)，水(5mL)洗涤，干燥得到化合物18-4(440mg，白色固体)，产率：46.00％。LCMS(ESI):m/z 181.0[M+H] +；RT＝1.20min(3.00min).
步骤5：5-氯-1-甲基-1,8-萘啶-2(1H)-酮的合成
在干燥的单口瓶(25mL)中室温依次加入18-4(150mg，0.84mmol)，碘甲烷(153mg，1.08mmol)，碳酸钾(231mg，1.58mmol)，DMF(3mL)，室温搅拌过夜。加入水(10mL)，乙酸乙酯(20mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残留物硅胶柱(PE：EA＝2:1)纯化，得到化合物18-5(150mg，白色固体)，产率：92.60％。LCMS(ESI):m/z 194.8[M+H] +；RT＝1.621min(3.00min).
步骤6：2-(4-((8-甲基-7-氧代-7,8-二氢-1,8-萘啶-4-基)氨基)苯基)乙酸的合成
在干燥的单口瓶(50mL)中室温依次加入18-5(110mg，0.57mmol)，4-氨基苯乙酸乙酯(101mg，0.57mmol)，Pd 2(dba) 3(52mg，0.057mmol)，x-PHOS(54mg，0.11mmol)，叔丁醇钠(109mg，1.14mmol)，二氧六环(5mL)。氮气保护下加热至100℃搅拌过夜。反应液减压浓缩。残留物硅胶柱(DCM:MeOH＝40:1)纯化，得到化合物18-6(70mg，黄色固体)，产率：40.00％。LCMS(ESI):m/z 309.7[M+H] +；RT＝1.433min(3.00min).
步骤7：N-羟基-2-(4-((8-甲基-7-氧代-7,8-二氢-1,8-萘啶-4-基)氨基)苯基)乙酰胺的合成
室温，在干燥的单口瓶(25mL)中依次加入18-6(70mg，0.23mmol)，DIEA(89mg，0.69mmol)，HATU(131mg，0.34mmol)和DMF(3mL)。反应液室温条件搅拌10分钟。加入50％羟胺水溶液(30mg，0.45mmol)搅拌1小时。浓缩反应液，残留物用高效液相反相制备柱纯化(0.1％甲酸/乙腈/水梯度洗脱)，得到化合物18(15mg，黄色固体)，产率：20.00％。LCMS(ESI):m/z 325.0[M+H] +；RT＝3.16min(15.00min). 1HNMR(400MHz,DMSO-d 6):10.66(s,1H),9.04(s,1H),8.84(s,1H),8.34-8.32(m,1H),8.17-8.16(m,1H),7.31-7.22(m,4H),6.69-6.68(m,1H),6.59-6.57(m,1H),3.63(s,3H),3.29(s,2H).
实施例19化合物141的制备
Figure PCTCN2022118080-appb-000069
步骤1：2-(4-(((叔丁基二甲基甲硅烷基)氧基)甲基)苯基)乙酸甲酯的合成
将2-(4-(羟甲基)苯基)乙酸甲酯(4g,22.22mmol)和咪唑(3.02g,44.44mmol)溶于DMF(25mL)中，氮气，冰浴下缓慢滴加TBSCl(4.03g,26.67mmol)的DMF(10mL)溶液，加完室温搅拌2小时。反应液加水稀释，乙酸乙酯萃取，有机相用水、稀盐酸(1M)水溶液、饱和氯化钠水溶液洗。无水硫酸钠干燥，浓缩，柱层析纯化(EA：PE＝1:20)得化合物141-1(5.3g，18.03mmol)，无色油状物，产率：81％。 1H NMR(400MHz,DMSO-d 6)δ7.20-7.12(m,4H),4.61(s,2H),3.58(s,2H),3.53(s,3H),0.86-0.78(m,9H),0.03-0.05(m,6H).
步骤2：1-(4-(((叔丁基二甲基甲硅烷基)氧基)甲基)苯基)环戊烷-1-甲酸甲酯的合成
将化合物141-1(2g，6.80mmol)溶于DMF(20mL)中，冰盐浴下加入NaH(680mg,17mmol)，滴加1,4-二溴丁烷(1.47g,6.8mmol)，滴加完室温搅拌3小时。反应液先缓慢滴加水淬灭，再用乙酸乙酯萃取，有机相浓缩，柱层析纯化(EA：PE＝1:20)得化合物141-2(1.1g，3.16mmol),无色油状物，产率：46％。 1H NMR(600MHz,DMSO-d 6)δ7.23-7.16(m,4H),4.60(s,2H),3.46(s,3H),2.47-2.43(m,2H),1.77(ddd,J＝12.4,8.2,6.0Hz,2H),1.64-1.50(m,4H),0.84-0.81(m,9H),0.02-0.01(m,6H).
步骤3：1-(4-(羟甲基)苯基)环戊烷-1-甲酸甲酯的合成
将化合物141-2(500mg，1.436mmol)溶于甲醇(10mL)中，0℃加入HCl/MeOH(2mL，4M)，在0℃搅拌1h，减压浓缩除去溶剂和多余的盐酸，真空干燥得化合物141-3(336mg，1.436mmol)，收率：100％。LCMS(ESI):m/z 235.1[M+H] +；RT＝1.54min(3.0min)
步骤4：1-(4-(溴甲基)苯基)环戊烷-1-甲酸甲酯的合成
将化合物141-3(500mg,2.14mmol溶于二氯甲烷(15mL)中，0℃缓慢滴加PBr 3(577mg,2.14mmol)，冰浴搅拌2小时。反应液先加水淬灭，水相用二氯甲烷萃取，有机相浓缩，柱层析纯化(EA：PE＝1:20)得化合物141-4(530mg，1.78mmol)，无色油状物，产率：83％。 1H NMR(400MHz,DMSO)δ7.44-7.37(m,2H),7.36–7.28(m,2H),4.69(s,2H),3.55(s,3H),2.58–2.51(m,2H),1.86(m,2H),1.74-1.53(m,4H).
步骤5：1-(4-((4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)甲基)苯基)环戊烷-1-甲酸甲酯的合成50mL单口瓶中加入141-4(500mg，1.69mmol),联硼酸频那醇酯(858mg,3.38mmol),四三苯基膦钯(195mg,0.169mmol)和碳酸钾(700mg，5.07mmol)，25mL二氧六环(25mL)， 氩气保护下加热至100℃搅拌4小时。冷却至室温，加水稀释，乙酸乙酯萃取，有机相浓缩，柱层析纯化(MeOH：DCM＝1:10)得化合物141-5(350mg，1.017mmol)，白色固体，产率：60％。 1H NMR(400MHz,DMSO-d 6)δ7.23-7.17(m,2H),7.09(m,2H),3.58(s,3H),2.54-2.50(m,2H),2.20(s,2H),1.86(m,2H),1.74-1.62(m,4H),1.22(s,12H).
步骤6：1-(4-((7-甲氧基-1,8-萘啶-4-基)甲基)苯基)环戊烷-1-甲酸甲酯的合成
50mL单口瓶中加入化合物141-5(480mg,1.395mmol)，1a(271mg,1.395mmol)，PdCl 2dppf(102mg,0.140mmol)和碳酸钾(578mg，4.185mmol)，二氧六环/水(15mL/5mL)，氩气保护下加热至100℃搅拌8小时。反应液冷却至室温，加水稀释，用乙酸乙酯萃取，有机相浓缩，柱层析纯化(EA：PE＝1:2)得化合物141-6(80mg，0.212mmol)，黄色油状物，产率：15.2％。LCMS(ESI):m/z 377.1[M+H] +；RT＝1.85min(3.0min).
步骤7：N-羟基-1-(4-((7-甲氧基-1,8-萘啶-4-基)甲基)苯基)环戊烷-1-甲酰胺的合成
将141-6(80mg，0.265mmol)加入到10mL的单口瓶中，加入甲醇/THF(1mL/1mL)，搅拌并依次加入50％的羟胺水溶液(0.5mL)和氢氧化钠(21mg,0.53mmol)，室温反应8小时，用1M的稀盐酸调pH至7-8，反相柱纯化(乙腈:水(1‰HCOOH)＝35：65)，得化合物141(30mg，0.0796mmol)，白色固体，产率：30％。LCMS(ESI):m/z 378.2[M+H] +；RT＝1.39min(3.0min). 1H NMR(400MHz,DMSO-d 6)δ10.38(s,1H),8.82(d,J＝4.6Hz,1H),8.62–8.51(m,2H),8.14(s,1H),7.28(m,3H),7.18(m,2H),7.12(d,J＝9.0Hz,1H),4.41(s,2H),4.01(s,3H),2.46(s,2H),1.73(m,2H),1.57(m,4H).
实施例20化合物194的制备
Figure PCTCN2022118080-appb-000070
步骤1：5-氨基-3-甲基异噁唑-4-甲腈的合成
将盐酸羟胺(2.55g，36.72mmol)溶解在25mL氢氧化钠溶液(1.50M)中，加入50mL乙醇，在搅拌同时缓慢加入2-(1-乙氧基亚乙基)丙二腈(5.00g,36.72mmol)。加热至50℃反应30分钟，随后室温反应过夜。除去溶剂，过滤收集固体并用清水洗涤，干燥后得化合物194-1(3.75g,白色固体)，收率：82.85％；LCMS(ESI):m/z 124.3[M+H] +；RT＝0.897min(2.50min). 1H-NMR(400MHz,DMSO-d 6)：δ8.33(s,2H),2.13(s,3H).
步骤2：5-氨基-3-甲基异噁唑-4-甲酰胺的合成
将化合物194-1(3.6g，29.24mmol)溶于100mL水和100mL乙醇中，同时缓慢加入氢氧化钠(9.36g,233.93mmol)，100℃反应3小时。除去乙醇，反应液用水稀释后调pH＝8，乙酸乙酯萃取，收集有机相，干燥，过滤后得化合物194-2(1.07g，白色固体)，收 率：25.90％；LCMS(ESI):m/z 142.3[M+H] +；RT＝0.557min(2.50min).
步骤3：3-甲基异噁唑[5,4-d]嘧啶-4-醇的合成
将化合物194-2(1.00g，7.09mmol)，原甲酸三乙酯(2.10g，14.17mmol)溶于20mL乙酸酐中，120℃加热反应3小时。冷却至室温，加入冰水稀释，用NaOH(2M)调pH＝8，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥后，浓缩，纯化后得化合物194-3(260mg，白色固体)，收率：24.30％；LCMS(ESI):m/z 152.2[M+H] +；RT＝0.827min(2.50min). 1H-NMR(400MHz,CDCl 3)：δ11.38(s,1H),8.17(s,1H),2.63(s,3H).
步骤4：4-氯-3-甲基异噁唑并[5,4-d]嘧啶的合成
将化合物194-3(260mg，1.72mmol)溶于10mL三氯氧磷中，90℃搅拌2小时。冷却至室温，除去溶剂后加入冰水稀释，用2M氢氧化钠溶液调节pH＝8。乙酸乙酯萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，prep-TLC(PE：EA＝3:1)纯化后得化合物194-4(227mg，棕色固体)，收率：77.90％；LCMS(ESI):m/z 170.2[M+H] +；RT＝1.337min(2.50min).
步骤5：2-甲基-2-(4-((3-甲基异恶唑[5,4-d]嘧啶-4-基)氧基)苯基)-N-((四氢-2H-吡喃-2-基)氧基)丙酰胺的合成
将化合物194-4(50mg，0.29mmol)，2-(4-羟基苯基)-2-甲基-N-((四氢-2H-吡喃-2-基)氧基)丙酰胺(99mg，0.35mmol)，碳酸铯(192mg，0.59mmol)溶于3mL DMF中，80℃反应2小时。冷却至室温过滤，乙酸乙酯萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥后过滤浓缩，prep-TLC(PE：EA＝1:1)纯化后得化合物194-5(92mg,透明油状物)，收率：75.65％；LCMS(ESI):m/z 411.1[M-H] -；RT＝1.571min(2.50min).
步骤6：N-羟基-2-甲基-2-(4-((3-甲基异恶唑[5,4-d]嘧啶-4-基)氧基)苯基)丙烷酰胺的合成
将化合物194-5(65mg，0.16mmol)，TFA(1mL)溶解在3mL无水二氯甲烷中，室温搅拌2小时。乙酸乙酯萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，prep-HPLC(FA)纯化后得化合物194，收率：30.92％；LCMS(ESI):m/z 328.95[M+H] +；RT＝3.933min(6min). 1H-NMR(400MHz,DMSO-d 6)：δ10.42(s,1H),8.71(s,1H),8.70(s,1H),7.44(d,J＝8.4Hz,2H),7.28(d,J＝8.8Hz,2H),2.68(s,3H),1.49(s,6H).
实施例21化合物195的制备
Figure PCTCN2022118080-appb-000071
步骤1：(7-甲氧基-1,8-萘啶-4-基)甲醇
在盛有10mL二氧六环的50mL三口瓶中室温依次加入化合物1a(808mg，4.2mmol)、 氟化钾(732mg,12.6mmol)和(三丁基)甲醇(1.6g,5.0mmol)，再加入PdCl 2dppf(307mg，0.42mmol)，100℃反应过夜，过滤，滤液浓缩后柱层析纯化(EA：PE＝1:2)得化合物1a-4(200mg，黄色固体)，LCMS(ESI):m/z 191.1[M+H] +；RT＝0.307min(2.50min).
步骤2：7-甲氧基-1,8-萘啶-4-甲醛
在盛有7mL二氯甲烷的50mL单口瓶中室温依次加入化合物1a-4(90mg,0.26mmol)和戴斯-马丁氧化剂(535mg，1.26mmol)，室温反应3小时，反应液加水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩后得到化合物1a-5(180mg，白色固体)，收率：90.9％， 1H NMR(400MHz,DMSO–d 6):δ10.41(s,1H),9.25-9.23(m,2H),7.73(d,J＝4.0Hz,1H),7.17(d,J＝9.2Hz,1H),4.19(s,3H).
步骤3：2-(1-((7-甲氧基-1,8-萘啶-4-基)甲基)吡咯烷-3-基)-2-甲基丙酸甲酯
在盛有1,2-二氯乙烷(3mL)的50mL单口瓶中依次加入化合物1a-5(60mg,0.33mmol)，化合物22a(82mg,0.48mmol)和氰基硼氢化钠(42mg，0.66mmol)，室温反应2小时，加水稀释，二氯甲烷萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩柱层析纯化(PE：EA＝4:1)得到化合物195-1(105mg，透明油)，LCMS(ESI):m/z 344.1[M+H] +；RT＝0.880min(2.50min)
步骤4：2-(1-((7-甲氧基-1,8-萘啶-4-基)甲基)吡咯烷-3-基)-2-甲基丙酸
在盛有1,4-二氧六环/水(3：1，3mL)的50mL单口瓶中室温依次加入化合物195-1(80mg，0.23mmol)和氢氧化锂(11mg,0.47mmol)。80℃反应10小时，用盐酸水溶液(1M)调节pH＝5，反应液加水稀释，乙酸乙酯萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩后得到粗品195-2(50mg，白色固体)，LCMS(ESI):m/z 320.2[M+H] +；RT＝0.807min(2.50min).
步骤5：2-(1-((7-甲氧基-1,8-萘啶-4-基)甲基)吡咯烷-3-基)-2-甲基-N-((四氢-2H-吡喃-2-基)氧基)丙酰胺
在盛有15mL DMF的单口烧瓶中加入化合物195-2(60mg，0.18mmol)、O-(四氢-2H-吡喃-2-基)羟胺(26mg，0.22mmol)、二异丙基乙胺(46mg，0.36mmol)和HATU(102mg，0.27mmol)，室温搅拌3小时，反应液倒入水中，用乙酸乙酯萃取，有机相用水、饱和食盐水洗，无水硫酸钠干燥，浓缩，用层析板(EA)纯化得到化合物195-3(30mg，白色固体)，收率：38.4％；LCMS(ESI):m/z 429.2[M+H] +；RT＝0.360min(2.50min).
步骤6：N-羟基-2-(1-((7-甲氧基-1,8-萘啶-4-基)甲基)吡咯烷-3-基)-2-甲基丙酰胺
在单口烧瓶中加入2mL二氯甲烷，195-3(40mg，0.09mmol)和TFA(0.6mL)，室温搅拌3小时。除去溶剂，粗品经反相柱(甲酸)纯化得到化合物195(8.5mg，白色固体)，收率：26.4％；LCMS(ESI):m/z 345.05[M+H] +；RT＝1.978min(6.00min). 1H NMR(400MHz,DMSO-d 6):δ10.41(s,1H),8.91(s,1H),8.69-8.61(m,2H),7.53(s,1H),7.19(d,J＝7.6Hz,1H),4.04(s,3H),3.34(s,2H),2.51(s,4H),1.79-1.63(m,3H),1.03(d,J＝6.0Hz,6H).
实施例22化合物196的制备
Figure PCTCN2022118080-appb-000072
步骤1：(4-(苄氧基)苯基)-L-脯氨酸甲基酯的合成
在干燥的50mL单口烧瓶中依次加入1-(苄氧基)-4-溴苯(500mg，1.9mmol)，(S)-5-氧代吡咯烷-2-甲酸(549mg，4.8mmol)，碘化亚铜(72mg，0.38mmol)，磷酸钾(1.6g，7.6mmol)，二甲基亚砜(10mL)，氮气保护下加热至100℃过夜，加入DMF(10mL)，碘甲烷(1.3g，9.5mmol)，加热至60℃反应2小时。反应液加入水，乙酸乙酯萃取，食盐水洗涤，无水硫酸钠干燥，减压浓缩，残留物硅胶柱(PE：EA＝1：10)纯化，得化合物196-1(350mg，黄色固体)，收率：59.0％。LCMS(ESI):m/z 312.1[M+H] +；RT＝1.94min(3.00min)。
步骤2：(4-羟基苯基)-L-脯氨酸甲基酯的合成
在干燥的50mL单口烧瓶中室温依次加入196-1(350mg，1.1mmol)，10％钯碳(35mg)，甲醇(10mL)，氢气保护下室温搅拌2小时，滤液浓缩，得化合物196-2(220mg，黄色固体)，收率：88.0％。LCMS(ESI):m/z 222.1[M+H] +；RT＝1.36min(3.00min)。
步骤3：(4-((7-甲氧基-1,8-萘啶-4-基)氧基)苯基)-L-脯氨酸甲基酯的合成
在干燥的50mL单口烧瓶中室温依次加入196-2(220mg，1.0mmol)，5-氯-2-甲氧基-1,8-萘啶(194mg，1.0mmol)，碳酸钾(276mg,2mmol)，DMF(5mL)，加热至100℃搅拌过夜，反应液加入水，乙酸乙酯萃取，食盐水(10mL)洗涤，无水硫酸钠干燥，减压浓缩，残留物硅胶柱(PE：EA＝1：1)纯化，得化合物196-3(100mg，黄色油状物)，收率：26.0％。LCMS(ESI):m/z 380.1[M+H] +；RT＝1.66min(3.00min)。
步骤4：(S)-N-羟基-1-(4-((7-甲氧基-1,8-萘啶-4-基)氧基)苯基)吡咯烷-2-甲酰胺的合成
在干燥的25mL的单口烧瓶中室温依次加入196-3(100mg，0.26mmol)，THF(1.0mL)，甲醇(1.0mL)，50％羟胺水溶液(0.5mL)，氢氧化钠(21mg，0.52mmol)。常温搅拌1小时。反应液用1M稀盐酸调pH＝8，残留物用高效液相反相制备柱纯化(0.1％甲酸)，干燥得化合物196(17mg，黄色固体)，产率：17％。LCMS(ESI):m/z 381.1[M+H] +；RT＝4.27min(15.00min). 1H-NMR(400MHz,DMSO-d 6)：δ10.70(s,1H),8.70(s,1H),8.68-8.59(m,2H),7.15-7.12(m,3H),6.61-6.59(m,2H),6.45-6.44(m,1H),4.05-3.98(m,4H),3.58-3.55(m,1H),3.23-3.19(m,1H),2.08-2.00(m,1H),1.99-1.96(m,3H).
实施例23-207:分别根据实施例1-4、18-22中所述方法合成化合物19-140、142-193、197-207，各实施例化合物的结构式参见前面的表格。
Figure PCTCN2022118080-appb-000073
Figure PCTCN2022118080-appb-000074
Figure PCTCN2022118080-appb-000075
Figure PCTCN2022118080-appb-000076
Figure PCTCN2022118080-appb-000077
Figure PCTCN2022118080-appb-000078
Figure PCTCN2022118080-appb-000079
Figure PCTCN2022118080-appb-000080
Figure PCTCN2022118080-appb-000081
Figure PCTCN2022118080-appb-000082
Figure PCTCN2022118080-appb-000083
Figure PCTCN2022118080-appb-000084
Figure PCTCN2022118080-appb-000085
Figure PCTCN2022118080-appb-000086
Figure PCTCN2022118080-appb-000087
Figure PCTCN2022118080-appb-000088
Figure PCTCN2022118080-appb-000089
Figure PCTCN2022118080-appb-000090
实施例208化合物208、209的制备
Figure PCTCN2022118080-appb-000091
步骤：将化合物131拆分得到化合物208(异构体1)和化合物209(异构体2)
将化合物131(92mg)通过手性柱拆分，柱子型号CHIRALCEL OZ-H(OZH0CE-RJ014)，0.46cm I.D.×25cm L，流动相：Hexane/EtOH/TFA/DEA＝50/50/0.1/0.05，得到化合物208(20mg)和化合物209(22mg)；
化合物208：出峰时间9.688min；ee％>99,LCMS(ESI):m/z 382.20[M+H] +； 1H NMR(400MHz,DMSO-d 6):δ10.80(s,1H),8.97(s,1H),8.79-8.80(m,1H),8.65(d,J＝9.2Hz,1H),7.53(d,J＝8.8Hz,2H),7.36(d,J＝8.8Hz,2H),7.24(d,J＝9.2Hz,1H),6.66(d,J＝5.6Hz,1H),4.58(d,J＝8.8Hz,1H),4.04(s,3H),3.94-3.86(m,3H),2.97-2.59(m,1H),2.32-2.27(m,1H).
化合物209：出峰时间14.023min；ee％>99,LCMS(ESI):m/z 382.20[M+H] +； 1H NMR(600MHz,DMSO-d 6):δ10.73(s,1H),8.97(s,1H),8.74(d,J＝3.6Hz,1H),8.61(d,J＝5.6Hz,1H),7.48-7.46(m,2H),7.32(d,J＝8.8Hz,2H),7.21(d,J＝6.0Hz,1H),6.63(d,J＝4.0Hz,1H),4.50(d,J＝5.6Hz,1H),4.07(s,3H),3.87-3.78(m,3H),2.90-2.86(m,1H),2.23-2.18(m,1H).
实施例209化合物210、211的制备
Figure PCTCN2022118080-appb-000092
步骤：将化合物165拆分得到化合物210(异构体1)和化合物211(异构体2)
将化合物165(420mg)通过手性柱拆分，柱子型号
Figure PCTCN2022118080-appb-000093
250*25mm 10μm，流动相：甲醇(+0.1％7.0mol/L氨甲醇)，得到化合物210(101.74mg)和化合物211(117.52mg)；
化合物210：出峰时间4.478min；ee％>86,LCMS(ESI):m/z 382.00[M+H] +；(DMSO-d 6):δ10.38(s,1H),8.71-8.67(m,2H),8.58(d,J＝9.2Hz,1H),7.35(d,J＝8.8Hz,2H),7.25(d, J＝8.8Hz,2H),6.53(d,J＝5.2Hz,1H),4.04(s,3H),2.74-2.67(m,1H),1.41(s,3H),0.91(d,J＝6.4Hz,3H),0.56(d,J＝6.8Hz,3H)；
化合物211：出峰时间5.364min；ee％>97,LCMS(ESI):m/z 382.00[M+H] +；(DMSO-d 6):δ10.38(s,1H),8.71-8.68(m,2H),8.58(d,J＝8.8Hz,1H),7.55(d,J＝8.8Hz,2H),7.25(d,J＝8.8Hz,2H),7.15(d,J＝8.8Hz,1H),6.53(d,J＝5.2Hz,1H),4.04(s,3H),2.74-2.67(m,1H),1.41(s,3H),0.91(d,J＝6.8Hz,3H),0.56(d,J＝7.2Hz,3H).
实施例210化合物212、213的制备
Figure PCTCN2022118080-appb-000094
步骤：将化合物130拆分得到化合物212(异构体1)和化合物213(异构体2)
将化合物130(100mg)通过手性柱拆分，柱子型号
Figure PCTCN2022118080-appb-000095
250*25mm 10μm，流动相：甲醇(+0.1％7.0mol/L氨甲醇)，得到化合物212(18.03mg)和化合物213(24.55mg)；
化合物212：出峰时间4.970min；ee％>99,LCMS(ESI):m/z 368.05[M+H] +；(MeOD-d 4):δ8.63-8.60(m,2H),7.54(d,J＝8.4Hz,2H),7.20(d,J＝8.4Hz,2H),7.10(d,J＝9.2Hz,1H),6.56(d,J＝1.6Hz,1H),4.12(s,3H),2.90(d,J＝10.0Hz,1H),2.43-2.37(m,1H),1.07(d,J＝6.4Hz,3H),0.77(d,J＝6.8Hz,3H)；
化合物213：出峰时间5.665min；ee％>99,LCMS(ESI):m/z 368.00[M+H] +；(MeOD-d 4):δ8.63-8.60(m,2H),7.54(d,J＝8.8Hz,2H),7.20(d,J＝8.4Hz,2H),7.10(d,J＝8.8Hz,1H),6.57(d,J＝5.6Hz,1H),4.12(s,3H),2.90(d,J＝11.2Hz,1H),2.43-2.37(m,1H),1.07(d,J＝6.4Hz,3H),0.77(d,J＝6.8Hz,3H).
实施例211化合物214、215的制备
Figure PCTCN2022118080-appb-000096
步骤：将化合物177拆分得到化合物214(异构体1)和化合物215(异构体2)
将化合物177(500mg)通过手性柱拆分，柱子型号
Figure PCTCN2022118080-appb-000097
250*25mm 10μm，流动相：甲醇(+0.1％7.0mol/l氨甲醇)，得到化合物214(112mg)和化合物215(232mg)；
化合物214：出峰时间2.174min；ee％>99,LCMS(ESI):m/z 367.20[M+H] +；(DMSO- d 6):δ10.65(s,1H),9.44(d,J＝20.4Hz,2H),8.83(s,1H),8.43(d,J＝2.4Hz,1H),7.40(d,J＝8.0Hz,2H),7.32(d,J＝8.0Hz,2H),7.00(s,1H),6.67(d,J＝4.0Hz,1H),3.97(s,3H),2.84(d,J＝10.8Hz,1H),2.33-2.08(m,1H),0.97(d,J＝6.4Hz,3H),0.687(d,J＝6.8Hz,3H)；
化合物215：出峰时间7.057min；ee％>99,LCMS(ESI):m/z 367.10[M+H] +；(DMSO-d 6):δ10.70(s,1H),9.66(s,2H),8.86(s,1H),8.43(d,J＝6.8Hz,1H),7.51(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),7.08(s,1H),6.23(d,J＝7.2Hz,1H),4.04(s,3H),2.90(d,J＝10.4Hz,1H),2.34-2.25(m,1H),0.98(d,J＝6.8Hz,3H),0.68(d,J＝6.8Hz,3H).
生物学实施例
评估化合物的ENPP1抑制活性
在底物2’,3’-cGAMP检测中对本公开化合物的ENPP1抑制活性进行测试
实验目的：根据已建立的实验方法，以2’,3’-cGAMP为底物，检测了本申请的化合物对ENPP1的抑制IC 50值。以STF-32作为阳性对照化合物(STF-32源自文献Cell Chemical Biology 2020(27),1347-1358)。
实验试剂：hENPP1-ECD-His(ChemPartner,cat.202103121201)；AMP-Glo TM Assay Kit(Promega,cat:V5011)；DMSO(Sigma,cat.D8418-1L)；384-孔白色板(PerkinElmer,cat.6007290)，2’3’-cGAMP(MCE，cat.HY-100564A)
实验方法：
1.配制1×反应溶液：50mM Tris-HCl(pH 7.5)，10mM NaCl，0.5mM CaCl 2，1μM ZnCl 2，0.01％吐温-20，0.01％BSA。
2.化合物浓度梯度的配制：待测化合物用DMSO(二甲基亚砜)溶解至起始浓度为10μM，3倍稀释，10个浓度，设置单孔或复孔测试。阳性对照化合物STF-32测试中浓度为1μM起始，3倍稀释，10个浓度，每个浓度设置复孔测试。在384孔板中梯度稀释成相应1000倍终浓度的溶液(1000、333.33、111.11、37.04、12.35、4.12、1.37、0.46、0.15nM)，然后用Echo550转移5nL到384孔反应板中待测。最小孔(只有底物，没有酶，信号值为最小)，最大孔(有底物，有酶，无抑制剂，信号值为最大)中转移5nL的100％DMSO。
3.用1×反应溶液配制2×hENPP1-ECD-His蛋白溶液20nM。
4.用1×反应溶液配制2×2’3’-cGAMP底物溶液40μM。
5.向反应板各化合物孔和最大孔中加入2.5μL的2×蛋白溶液，最小孔中加入2.5μL的1×反应溶液。
6. 1000rpm离心1min，室温孵育15分钟。
7.向反应板各孔中加入2.5μL的2×2’3’-cGAMP底物溶液，1000rpm离心1min，室温孵育60分钟。
8.向反应板各孔中加入5μL的R1溶液(来自AMP-Glo TM Kit，1000rpm离心1min，室温孵育120分钟。
9.反应板各孔中加入10μL的R2溶液(来自AMP-Glo TM Kit，1000rpm离心1min， 室温孵育30分钟。
10.使用多功能酶标仪(2104EnVision)检测，记录测试结果。
数据分析
抑制率用以下公式计算：
抑制率％＝(最大信号–化合物信号)/(最大信号–最小信号)×100
其中“最小信号”为阴性对照孔均值，“最大信号”为阳性对照孔均值。
拟合量效曲线：
以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPadPrism5的log(抑制剂)vs.响应-可变斜率拟合量效曲线，从而得出本公开的化合物对酶活性的抑制IC 50值。
拟合公式为：Y＝底+(顶-底)/(1+10^((logIC 50-X)*HillSlope))，其中，底、顶分别为拟合的最小值、最大值。
在该实验中，相同检测条件下，还检测了已知文献中报道的磺酰胺类化合物Ex58，(见WO2019/046778 A1)，以及化合物A-1、A-2对ENPP1的抑制IC50值。如表1所示，本公开的异羟基肟酸类化合物显示出了对ENPP1激酶较好的抑制作用。
Figure PCTCN2022118080-appb-000098
表1.本公开的化合物对ENPP1激酶的抑制作用
Figure PCTCN2022118080-appb-000099
Figure PCTCN2022118080-appb-000100
Figure PCTCN2022118080-appb-000101
由表1可知，本公开的异羟基肟酸类化合物是较好的ENPP1抑制剂，具有≤5μM的IC 50值、优选≤1μM的IC 50值、更优选≤0.5μM的IC 50值、甚至更优选≤0.125μM、最优选≤0.1μM的IC 50值。本公开的异羟基肟酸类化合物抑制ENPP1的活性要显著优于化合物A-2。
初步药代动力学测试实验
1.取健康ICR小鼠6只，雄性，体重30-35g，随机分成2组，每组3只，分别灌胃(5mg/kg)和静脉注射(1mg/kg)给予被测试化合物：
试验前禁食12h，自由饮水。给药后4h统一进食。
2.采血时间点及样品处理
灌胃给药：给药后0.25h，0.5h，1.0h，2.0h，3.0h，4.0h，6.0h，8.0h和24h。
静脉给药：给药后5min，0.25h，0.5h，1.0h，2.0h，4.0h，6.0h，8.0h和24h。
连续取血，每时间点采集3只动物。血浆采集和处理：在以上设定时间点经小鼠眼球后静脉丛取静脉血30-40μL，置EDTA-K2试管中，3500rpm离心10min，分离血浆，于-20℃冰箱中冷冻。
3.样品测试和数据分析
采用LC/MS/MS法测定大鼠血浆中化合物的浓度。采用Phoenix 8.3软件(美国Pharsight公司)的非房室模型计算给药后的药代动力学参数。
4.实验结果
本发明中的化合物具有较高的口服生物利用度，且口服生物利用度大于20％，如实施例2和实施例110。由此可见，本公开的异羟基肟酸类化合物相较于已知磷酸类化合物有明显的口服吸收的优势。部分化合物的pK数据如表2所示。
表2.本公开化合物的口服给药(5mg/kg)药代动力学
化合物 T 1/2(hr) Cmax(ng/mL) AUC 0-t(hr*ng/mL) F％
2 3.26 736 619 57.2
42 1.30 1488 887 46.0
68 2.44 244 161 20.2
107 2.0 640 463 23.5
110 3.9 2370 1589 46.3

Claims (25)

  1. 一种如通式(I)所示的化合物：
    Figure PCTCN2022118080-appb-100001
    或其可药用盐，其中，
    Figure PCTCN2022118080-appb-100002
    是单键或双键；
    X为N或CR 0；
    X 1为N、O、S、CR 1或键；
    X 2为N、O、S、NR 2或CR 2；
    X 3为N、O、S、NR 3或CR 3；
    X 4为N、O、S、NR 4或CR 4；
    X 5为N或CR 5；
    Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-、NR 6或CR 7R 8；
    L为键、NR a、-NR x-CHR y-、或(CR 9R 10) m；m为1或2；
    R 0、R 5各自独立地选自：氢、卤素、CN、OH、NO 2、NR bR c、C 1-C 6烷基、C 3-C 6环烷基、-SO 2R a、-C(O)OR a、-C(O)NR bR c和C 1-C 6烷氧基；其中所述烷基、环烷基和烷氧基各自任选地被卤素取代；
    R 1、R 2各自独立地选自：氢、卤素、CN、OH、NO 2、NR bR c、C 1-C 4烷基、C 3-C 6环烷基和C 1-C 4烷氧基；其中所述烷基、环烷基和烷氧基各自任选地被卤素取代；
    R 3、R 4各自独立地选自：氢、卤素、CN、OH、NO 2、NR bR c、＝O、C 1-C 4烷基、C 3-C 6环烷基和C 1-C 4烷氧基；其中所述烷基、环烷基和烷氧基各自任选地被卤素取代；
    R 6选自氢、C 1-C 4烷基和C 3-C 6环烷基；其中所述烷基和环烷基各自任选地被卤素取代；
    R 7、R 8各自独立地选自：氢、卤素、OH、CN、NO 2、NR a、C 1-C 6烷基、C 3-C 6环烷基和C 1-C 6烷氧基；其中所述烷基、环烷基和烷氧基各自任选地被卤素取代；或者R 7和R 8与其所键合的碳原子一起形成任选地被卤素取代的C 3-C 6环烷基、或形成包含1-2个选自N、NR a、O和S(O) p的杂原子的4-至12-元杂环烷基；
    R 9、R 10各自独立地选自氢、卤素、CN、OH、NO 2、NR aR b、C 1-C 8烷基、C 3-C 8环烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8烷氧基、包含碳原子和1-2个选自N、NR a、O和S(O) p 的杂原子的4-至12-元杂环烷基、6-至10-元芳基和5-至10-元杂芳基；其中所述烷基、烯基、炔基、烷氧基、环烷基和杂环烷基各自被0-3个独立地选自卤素、羟基、CN的取代基取代；其中所述芳基和杂芳基各自被0-3个独立地选自卤素、C 1-C 4烷基、C 3-C 6环烷基和OR a的取代基取代；
    或者R 9和R 10与其所键合的碳原子一起形成任选地被卤素取代的C 3-C 6环烷基、或形成包含1-2个选自N、NR a、O和S(O) p的杂原子的4-至12-元杂环烷基；
    环A选自：C 4-C 10环烷基、4-至12-元杂环烷基、6-至10-元芳基和5-至10-元杂芳基；其中，环A任选地被独立地选自卤素、CN、OH、NO 2、NR bR c、C 1-C 4烷基、C 1-C 4烷氧基、C 3-C 6环烷基、4-至7-元杂环烷基、6-至10-元芳基和5-至10-元杂芳基和C 1-C 3卤代烷基的取代基取代一次或多次；
    或者
    L与环A一起形成C 4-C 8环烷基、含至少一个选自N、O或S的杂原子的5-至10-元部分饱和的杂环、6-至10-元芳基或5-至7-元杂芳基；其中所述环烷基、杂环、芳基和杂芳基任选地被独立地选自卤素、C 1-C 4烷基、C 1-C 4烷氧基的取代基取代一次或多次；或
    Y与环A一起形成5-至10-元部分饱和的杂环、6-至10-元芳基或5-至10-元杂芳基，其中所述杂环、芳基和杂芳基任选地被独立地选自卤素、C 1-C 4烷基、C 1-C 4烷氧基的取代基取代一次或多次；
    R a、R b、R c各自独立地选自：氢、C 1-C 4烷基、C 3-C 6环烷基和苄基；其中所述烷基和环烷基各自任选地被卤素取代；或者R b和R c与其所键合的氮原子一起形成任选地被卤素取代的3-至6-元杂环烷基；
    R x、R y各自独立地选自氢和C 1-C 4烷基，或R x和R y与其所键合的碳、氮原子一起形成4-至8-元杂环烷基；和
    p为1或2；
    条件是，当X 1至X 4各自为CR n时，Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-或CH 2；其中R n对于X 1而言为R 1，对于X 2而言为R 2，对于X 3而言为R 3，和对于X 4而言为R 4。
  2. 如权利要求1所述的如通式(I)所示的化合物：
    Figure PCTCN2022118080-appb-100003
    或其可药用盐，其中，
    Figure PCTCN2022118080-appb-100004
    是单键或双键；
    X为N或CR 0；
    X 1为N、O、S、CR 1或键；
    X 2为N、O、S、NR 2或CR 2；
    X 3为N、O、S、NR 3或CR 3；
    X 4为N、O、S、NR 4或CR 4；
    X 5为N或CR 5；
    Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-、NR 6或CR 7R 8；
    L为键、NR a或(CR 9R 10) m；m为1或2；
    R 0、R 5各自独立地选自：氢、卤素、CN、OH、NO 2、NR bR c、C 1-C 6烷基、C 3-C 6环烷基、-SO 2R a、-C(O)OR a、-C(O)NR bR c和C 1-C 6烷氧基；其中所述烷基、环烷基和烷氧基各自任选地被卤素取代；
    R 1、R 2各自独立地选自：氢、卤素、CN、OH、NO 2、NR bR c、C 1-C 4烷基、C 3-C 6环烷基和C 1-C 4烷氧基；其中所述烷基、环烷基和烷氧基各自任选地被卤素取代；
    R 3、R 4各自独立地选自：氢、卤素、CN、OH、NO 2、NR bR c、＝O、C 1-C 4烷基、C 3-C 6环烷基和C 1-C 4烷氧基；其中所述烷基、环烷基和烷氧基各自任选地被卤素取代；
    R 6选自氢、C 1-C 4烷基和C 3-C 6环烷基；其中所述烷基和环烷基各自任选地被卤素取代；
    R 7、R 8各自独立地选自：氢、卤素、OH、CN、NO 2、NR a、C 1-C 6烷基、C 3-C 6环烷基和C 1-C 6烷氧基；其中所述烷基、环烷基和烷氧基各自任选地被卤素取代；或者R 7和R 8与其所键合的碳原子一起形成任选地被卤素取代的C 3-C 6环烷基、或形成包含1-2个选自N、NR a、O和S(O) p的杂原子的4-至12-元杂环烷基；
    R 9、R 10各自独立地选自氢、卤素、CN、OH、NO 2、NR aR b、C 1-C 8烷基、C 3-C 8环烷基、C 2-C 8烯基、C 2-C 8炔基、C 1-C 8烷氧基、包含碳原子和1-2个选自N、NR a、O和S(O) p的杂原子的4-至12-元杂环烷基、6-至10-元芳基和5-至10-元杂芳基；其中所述烷基、烯基、炔基、烷氧基、环烷基和杂环烷基各自被0-3个独立地选自卤素、羟基、CN的取代基取代；其中所述芳基和杂芳基各自被0-3个独立地选自卤素、C 1-C 4烷基、C 3-C 6环烷基和OR a的取代基取代；
    或者R 9和R 10与其所键合的碳原子一起形成任选地被卤素取代的C 3-C 6环烷基、或形成包含1-2个选自N、NR a、O和S(O) p的杂原子的4-至12-元杂环烷基；
    环A选自：C 4-C 10环烷基、4-至12-元杂环烷基、6-至10-元芳基和5-至10-元杂芳基；其中，环A任选地被独立地选自卤素、CN、OH、NO 2、NR bR c、C 1-C 4烷基、C 1-C 4烷氧基、C 3-C 6环烷基、4-至7-元杂环烷基、6-至10-元芳基和5-至10-元杂芳基和C 1-C 3卤代烷基的取代基取代一次或多次；
    或者
    L与环A一起形成C 4-C 8环烷基、含至少一个选自N、O或S的杂原子的5-至10-元 部分饱和的杂环、6-至10-元芳基或5-至7-元杂芳基；其中所述环烷基、杂环、芳基和杂芳基任选地被独立地选自卤素、C 1-C 4烷基、C 1-C 4烷氧基的取代基取代一次或多次；
    R a、R b、R c各自独立地选自：氢、C 1-C 4烷基和C 3-C 6环烷基；其中所述烷基和环烷基各自任选地被卤素取代；或者R b和R c与其所键合的氮原子一起形成任选地被卤素取代的3-至6-元杂环烷基；和
    p为1或2；
    条件是，当X 1至X 4各自为CR n时，Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-或CH 2；其中R n对于X 1而言为R 1，对于X 2而言为R 2，对于X 3而言为R 3，和对于X 4而言为R 4。
  3. 如前述权利要求所述的化合物或其可药用盐，其中
    R 0、R 5各自独立地选自氢、卤素、CN、OH、NO 2、NH 2、C 1-C 4烷基、C 3-C 6环烷基、-SO 2R a、-C(O)OR a、-C(O)NR bR c和C 1-C 4烷氧基，其中所述烷基、环烷基、烷氧基各自任选地被卤素取代；优选地，R 0、R 5各自独立地选自氢、CN、卤素和C 1-C 4烷基；
    R 1、R 2各自独立地选自H、卤素、CN、OH、NO 2、NH 2、C 1-C 4烷基、C 1-C 3烷氧基和C 1-C 3卤代烷基，优选选自H、卤素、C 1-C 4烷基和C 1-C 3烷氧基；
    R 3、R 4各自独立地选自H、卤素、CN、OH、NO 2、NH 2、＝O、C 1-C 4烷基、C 3-C 6环烷基、C 1-C 3烷氧基和C 1-C 3卤代烷基，优选选自H、卤素、OH、＝O、C 1-C 4烷基、C 3-C 6环烷基、C 1-C 3烷氧基和C 1-C 3卤代烷基；
    R 6选自氢、C 1-C 4烷基和C 3-C 6环烷基，优选选自氢和C 1-C 4烷基；
    R 7、R 8各自独立地选自氢、C 1-C 4烷基、C 3-C 6环烷基和C 1-C 4烷氧基，优选选自氢和C 1-C 4烷基。
  4. 如前述权利要求所述的化合物或其可药用盐，其中，
    X 1、X 2、X 3、X 4中至少一个独立地选自N、O、S和如果有的话NR n；优选地，X 1、X 2、X 3、X 4中至少一个独立地选自N和如果有的话NR n；其中R n对于X 2而言为R 2，对于X 3而言为R 3，和对于X 4而言为R 4；
    R 1为氢或卤素；
    R 2选自氢、卤素、C 1-C 3烷基和C 1-C 3烷氧基；
    R 3选自氢、卤素、OH、＝O、NR bR c、C 1-C 3烷基和C 1-C 3烷氧基；
    R 4选自氢、卤素和C 1-C 3烷基；
    R 5选自氢、卤素、CN和C 1-C 6烷基。
  5. 如前述权利要求任一项所述的化合物或其可药用盐，其中，X 1、X 2、X 3、X 4中至少一个独立地选自N；或者，X 1、X 2、X 3、X 4中只有一个独立地选自N和如果有的话NR n。
  6. 如前述权利要求所述的化合物或其可药用盐，其中，X 2为N或NR 2；优选地，X 2为N；更优选地，X 2为N，且X 3为CR 3；进一步优选地，X 2为N，X 3为CR 3，且X 4为CR 4；最优选地，X 2为N，X 3为CR 3，X 4为CR 4，且X 1为CR 1。
  7. 如前述权利要求所述的化合物或其可药用盐，其中，X 4为N或NR 4；优选地，X 4 为N；更优选地，X 4为N，且X 3为CR 3；进一步优选地，X 4为N，X 3为CR 3，且X 2为CR 2；最优选地，X 4为N，X 3为CR 3，X 2为CR 2，且X 1为CR 1。
  8. 如权利要求1或2所述的化合物或其可药用盐，其中，
    X 1为键；
    R 2选自氢、卤素、C 1-C 3烷基和C 1-C 3烷氧基；
    R 3选自氢、OH和卤素；
    R 4选自氢、卤素、C 1-C 3烷基、C 1-C 3烷氧基、C 3-C 4环烷基和C 1-C 3卤代烷基；
    R 5选自氢、卤素、CN和C 1-C 6烷基。
  9. 如前述权利要求任一项所述的化合物或其可药用盐，其中，X 1为键时，X 2、X 3、X 4中至少两个独立地选自N和NR n；
    例如，X 1为键，X 3为N，且X 4为NR 4；优选地，X 1为键，X 3为N，X 4为NR 4，且X 2为CR 2；
    或者
    例如，X 1为键，X 3为N，且X 2为NR 2；优选地，X 1为键，X 3为N，X 2为NR 2，且X 4为CR 4。
  10. 如前述权利要求1或2所述的化合物或其可药用盐，其中
    X 1为CR 1，X 2为CR 2，X 3为CR 3，X 4为CR 4；
    Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-或CH 2；
    R 1为氢或卤素；
    R 2选自氢、卤素、OH和C 1-C 3烷氧基；
    R 3选自氢、卤素、OH、C 1-C 3烷基和C 1-C 3烷氧基；
    R 4选自氢、卤素和C 1-C 3烷氧基；
    R 5选自氢、卤素、CN和C 1-C 6烷基。
  11. 如前述权利要求任一项所述的化合物或其可药用盐，其中，
    Figure PCTCN2022118080-appb-100005
    选自
    Figure PCTCN2022118080-appb-100006
    Figure PCTCN2022118080-appb-100007
    优选地，选自
    Figure PCTCN2022118080-appb-100008
  12. 如前述权利要求任一项所述的化合物或其可药用盐，其中，
    Y为O、NR 6或CR 7R 8，优选为O、NH、N(C 1-C 3烷基)、CH 2、CH(C 1-C 3烷基)、或C(C 1-C 3烷基)(C 1-C 3烷基)；或者
    Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-、-NH-、-N(CH 3)-、-N(乙基)-、-N(丙基)-、-N(环丙基)-、-N(环丁基)-、-N(环戊基)-、-CH 2-、-CHF-、-CH(OH)-、-CH(CH 3)-、-CH(OCH 3)-、-CH(OEt)-或-C(CH 3) 2-；或者
    Y为O、S、-S(＝O)-、-S(＝O) 2-、-C(＝O)-、-NH-、-N(CH 3)-、-CH(CH 3)-或-CH 2-。
  13. 如前述权利要求任一项所述的化合物或其可药用盐，其中L为键、NR a、-NR x-CHR y-、CR 9R 10或(CR 9R 10) 2，其中R a选自氢、C 1-C 4烷基、C 3-C 6环烷基和苄基，优选选自氢、C 1-C 3烷基和苄基；R x、R y各自独立地选自氢和C 1-C 4烷基，或R x和R y与其所键合的碳、氮原子一起形成4-至8-元杂环烷基；R 9、R 10各自独立地选自氢、卤素、OH、NH 2、C 1-C 8烷基、C 3-C 8环烷基、C 1-C 8烷氧基、包含碳原子和1-2个选自N、NR a、O和S(O) p的杂原子的4-至8-元杂环烷基；或者，R 9和R 10与其所键合的碳原子一起形成C 3-C 6环烷基或包含1-2个选自N、NR a、O和S(O) p的杂原子的4-至8-元杂环烷基；
    或者，L为CR 9R 10，其中R 9和R 10各自独立地选自氢、卤素、CN、OH、NO 2、NH 2、C 1-C 6烷基、C 3-C 6环烷基和C 1-C 6烷氧基，包含碳原子和1-2个选自N、O和S的杂原子的4-至7-元杂环烷基，或者R 9和R 10与其所键合的碳原子一起形成被0-3个卤素取代的C 3-C 6环烷基(例如环丙烷、环丁烷、环戊烷或环己烷)或包含1-2个选自N、NR a、O和S(O) p的杂原子的4-至12-元杂环烷基(例如氧杂环丁烷、氮杂环丁烷、硫杂环丁烷、四氢呋喃环、吡咯烷、四氢噻吩环、吡唑烷、咪唑烷、噻唑烷、噁唑烷、哌啶环、四氢吡喃环、哌嗪环、六氢嘧啶环、噁嗪烷、哒嗪烷、吗啉环、硫代吗啉环、噻吩烷、四氢吡喃环、硫杂环己烷、氧杂环庚烷、氮杂环庚烷或硫杂环庚烷)；
    或者，L为CR 9R 10，其中R 9和R 10各自独立地选自氢、卤素、CN、OH、C 1-C 6烷基和C 1-C 6烷氧基，或者R 9和R 10与其所键合的碳原子一起形成C 3-C 6环烷基(例如环丙烷、环丁烷、环戊烷或环己烷)；
    或者，L选自-CH 2-、-CH(OH)-、-CHF-、-CH(CH 3)-、-CH(OCH 3)-、-CH(OEt)-、-C(CH 3) 2-、-CH(CH(CH 3) 2)-、-CH(CH 2CH(CH 3) 2)-、-C(CH 2CH(CH 3) 2) 2-、-C(CH 2CH 3) 2-、
    Figure PCTCN2022118080-appb-100009
  14. 如前述权利要求任一项所述的化合物或其可药用盐，其中环A选自C 4-C 10环烷基、4-至12-元杂环烷基、6-至10-元芳基和5-至10-元杂芳基，所述环A任选地被独立地选自卤素、CN、OH、NH 2、C 1-C 4烷基、C 1-C 4烷氧基和C 1-C 3卤代烷基的取代基、优选选自卤素、CN、C 1-C 4烷基和C 1-C 4烷氧基的取代基取代一次或多次；或者
    环A选自环戊烷、环己烷、吡唑烷、咪唑烷、吡咯环、呋喃环、噻吩环、吡唑环、咪唑环、四氢呋喃环、吡咯烷、四氢噻吩环、吡喃环、四氢吡喃环、哌啶环、六氢嘧啶、 哌嗪环、苯环、吡啶环、嘧啶环、萘环、喹啉环、异喹啉环、吲哚环、异吲哚环、吲唑环和苯并咪唑环；优选地选自环戊烷、环己烷、吡咯烷、吡咯环、哌啶环、嘧啶环、苯环、吡啶环、哌嗪环、咪唑环、吡唑环和萘环；其中，环A任选被独立地选自卤素、CN、OH、NO 2、NH 2、C 1-C 3烷基、C 1-C 3烷氧基和C 1-C 3卤代烷基的取代基取代一次或多次、例如一次或两次；优选地，环A任选被独立地选自F、Cl、CN、OH、NO 2、NH 2、C 1-C 3烷基和C 1-C 3烷氧基的取代基取代一次或多次、例如一次或两次。
  15. 如前述权利要求任一项所述的化合物或其可药用盐，其中，环A选自：
    Figure PCTCN2022118080-appb-100010
    其中，R 11各自可以相同或不同，独立地选自卤素、CN、OH、NO 2、NH 2、C 1-C 3烷基、C 1-C 3烷氧基和C 1-C 3卤代烷基，优选选自F、Cl、CN、C 1-C 3烷基和C 1-C 3烷氧基；q为0、1或2。
  16. 如前述权利要求任一项所述的化合物或其可药用盐，其中，所述L与环A一起形成二氢苯并呋喃环、二氢异苯并呋喃环、二氢苯并噻吩环、二氢吲哚环、二氢异吲哚环、二氢苯并咪唑环、二氢苯并噁唑环、二氢苯并噻唑环、二氢苯并吡喃环、二氢异苯并吡喃环、四氢喹啉环、四氢异喹啉环、2,3-二氢-1H-吡咯并[2,3-b]吡啶环、2,3-二氢-1H-吡咯并[3,2-b]吡啶环、四氢吡啶并[3,4-b]吡嗪环、二氢茚环、四氢萘环、2,3-二氢呋喃并[2,3-b]吡啶环或2,3-二氢呋喃并[3,2-b]吡啶环，各自任选被独立地选自卤素、C 1-C 4烷基、C 1-C 4烷氧基的取代基取代一次或多次；
    优选地，L与环A一起形成二氢苯并呋喃环、二氢异苯并呋喃环、二氢吲哚环、二氢异吲哚环、二氢苯并吡喃环、二氢异苯并吡喃环、四氢喹啉环、四氢异喹啉环、二氢茚环、四氢萘环、2,3-二氢呋喃并[2,3-b]吡啶环或2,3-二氢-1H-吡咯并[2,3-b]吡啶环，各自任选被独立地选自卤素、C 1-C 4烷基、C 1-C 4烷氧基的取代基取代一次或多次。
  17. 如前述权利要求任一项所述的化合物或其可药用盐，其中，Y与环A一起形成7-至10-元部分饱和的二环杂环、萘基或7-至10-元二环杂芳基，其中所述杂环、芳基和杂芳基任选地被独立地选自卤素、C 1-C 4烷基、C 1-C 4烷氧基的取代基取代一次或多次；
    优选地，Y与环A一起形成选自如下的基团：
    Figure PCTCN2022118080-appb-100011
    其中，M 1各自独立地为N、CH或C(C 1-C 4烷基)；
    更优选地，Y与环A一起形成选自如下的基团：
    Figure PCTCN2022118080-appb-100012
  18. 化合物或其可药用盐，其中，所述化合物选自：
    Figure PCTCN2022118080-appb-100013
    Figure PCTCN2022118080-appb-100014
    Figure PCTCN2022118080-appb-100015
    Figure PCTCN2022118080-appb-100016
    Figure PCTCN2022118080-appb-100017
    Figure PCTCN2022118080-appb-100018
    Figure PCTCN2022118080-appb-100019
    Figure PCTCN2022118080-appb-100020
    Figure PCTCN2022118080-appb-100021
  19. 一种药物组合物，包括前述权利要求任一项所述的化合物或其可药用盐，以及一种或多种可药用载体。
  20. 前述权利要求1-18中任一项所述的化合物或其可药用盐在制备用于治疗或预防ENPP1介导的疾病或障碍的药物中的用途。
  21. 治疗或预防ENPP1介导的疾病或障碍的方法，该方法包括给需要其的个体施用治疗有效量的前述权利要求1-18中任一项所述的化合物或其可药用盐。
  22. 如权利要求20所述的用途或权利要求21所述的方法，其中，所述ENPP1介导的疾病或障碍为实体瘤，例如选自乳腺癌、肺癌、胶质母细胞瘤、脑癌和脊椎癌、头颈癌、皮肤癌、生殖系统癌症、胃肠系统癌症、食道癌、鼻咽癌、胰腺癌、直肠癌、肝细胞癌、胆管癌、胆囊癌、结肠癌、多发性骨髓瘤、肾脏和膀胱癌、骨癌、恶性间皮瘤、肉瘤、淋巴瘤、腺癌、甲状腺癌、心脏肿瘤、生殖细胞肿瘤、恶性神经内分泌肿瘤、恶性横纹肌样瘤、软组织肉瘤、中线束癌和未知原发癌。
  23. 如权利要求20所述的用途或权利要求21所述的方法，其中，所述ENPP1介导的疾病或障碍是血液系统恶性肿瘤，例如选自白血病、淋巴瘤或骨髓瘤。
  24. 如权利要求20所述的用途或权利要求21所述的方法，其中，所述ENPP1介导的疾病或障碍是感染性疾病，例如选自：单纯疱疹病毒感染、牛痘病毒感染、腺病毒感染、人乳头瘤病毒感染、B型肝炎病毒感染、D型肝炎病毒感染、人免疫缺陷病毒感染、人巨细胞病毒感染、登革热病毒感染、埃博拉病毒感染、马尔堡病毒感染、寨卡病毒感染、单核细胞增生性李斯特菌感染、结核分枝杆菌感染、新凶手弗朗西斯菌感染、嗜肺军团菌感染、沙眼衣原体感染、肺炎链球菌感染、淋球菌感染。
  25. 药物组合产品，包含如前述权利要求1-18任一项所述的化合物或其可药用盐以及一种或多种其它活性剂。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107513064A (zh) * 2017-09-27 2017-12-26 南昌大学 一种嘌呤异羟肟酸衍生物及其制备方法和应用
WO2019046778A1 (en) 2017-08-31 2019-03-07 Mavupharma, Inc. INHIBITORS OF ECTONUCLEOTIDE PYROPHOSPHATASE-PHOSPHODIESTERASE (ENPP-1) AND USES THEREOF
WO2020008391A1 (en) * 2018-07-06 2020-01-09 Pfizer Inc. Manufacturing process and intermediates for a pyrrolo[2,3- d]pyrimidine compound and use thereof
WO2020058290A1 (fr) * 2018-09-17 2020-03-26 Centre National De La Recherche Scientifique Médicament-conjugué comprenant des dérivés de quinoline
WO2020160333A1 (en) * 2019-02-01 2020-08-06 The Board Of Trustees Of The Leland Stanford Junior University Enpp1 inhibitors and methods of modulating immune response
CN112390781A (zh) * 2020-11-18 2021-02-23 中国药科大学 二芳基取代的1,1-乙烯类化合物、制备方法及用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019046778A1 (en) 2017-08-31 2019-03-07 Mavupharma, Inc. INHIBITORS OF ECTONUCLEOTIDE PYROPHOSPHATASE-PHOSPHODIESTERASE (ENPP-1) AND USES THEREOF
CN107513064A (zh) * 2017-09-27 2017-12-26 南昌大学 一种嘌呤异羟肟酸衍生物及其制备方法和应用
WO2020008391A1 (en) * 2018-07-06 2020-01-09 Pfizer Inc. Manufacturing process and intermediates for a pyrrolo[2,3- d]pyrimidine compound and use thereof
WO2020058290A1 (fr) * 2018-09-17 2020-03-26 Centre National De La Recherche Scientifique Médicament-conjugué comprenant des dérivés de quinoline
WO2020160333A1 (en) * 2019-02-01 2020-08-06 The Board Of Trustees Of The Leland Stanford Junior University Enpp1 inhibitors and methods of modulating immune response
CN112390781A (zh) * 2020-11-18 2021-02-23 中国药科大学 二芳基取代的1,1-乙烯类化合物、制备方法及用途

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 1995, MACK PUBLISHING COMPANY
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING COMPANY, pages: 1289 - 1329
CELL CHEMICAL BIOLOGY, no. 27, 2020, pages 1347 - 1358
LI, SHUNDA ET AL.: "Development of selective HDAC6 inhibitors with in vitro and in vivo anti-multiple myeloma activity", BIOORGANIC CHEMISTRY, vol. 116, 19 August 2021 (2021-08-19), XP086829615, ISSN: 0045-2068, DOI: 10.1016/j.bioorg.2021.105278 *
ZENG, HUIJU ET AL.: "Synthesis and biological evaluation of acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer's disease", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 192, 29 February 2020 (2020-02-29), XP086102471, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2020.112193 *

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