WO2022184103A1 - Tricyclic compound and pharmaceutical composition and use thereof - Google Patents

Tricyclic compound and pharmaceutical composition and use thereof Download PDF

Info

Publication number
WO2022184103A1
WO2022184103A1 PCT/CN2022/078854 CN2022078854W WO2022184103A1 WO 2022184103 A1 WO2022184103 A1 WO 2022184103A1 CN 2022078854 W CN2022078854 W CN 2022078854W WO 2022184103 A1 WO2022184103 A1 WO 2022184103A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
mmol
alkyl
cycloalkyl
added
Prior art date
Application number
PCT/CN2022/078854
Other languages
French (fr)
Chinese (zh)
Inventor
袁建栋
方华祥
黄仰青
顾家宁
杭文明
张清泉
Original Assignee
武汉誉祥医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 武汉誉祥医药科技有限公司 filed Critical 武汉誉祥医药科技有限公司
Publication of WO2022184103A1 publication Critical patent/WO2022184103A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a class of tricyclic compounds, a pharmaceutical composition containing the compounds and their application in the field of medicine.
  • PARP poly-ADP-ribose polymerase
  • poly-ADP-ribose polymerase poly-ADP-ribose polymerase
  • the protein family consists of 17 members, all of which contain a common catalytic domain of about 230 amino acids, and are mainly divided into polyPARPs and monoPARPs.
  • PARP6, PARP7, PARP8, PARP9, PARP10, PAPR11, PARP12, PAPR14, PARP15, PARP16 twelve subtypes.
  • PARP1/2 inhibitors targeting PARP1/2 have been approved and marketed for the treatment of many different types of tumors.
  • the MonoPARP protein family plays a role in multiple stress responses associated with the development of cancer, inflammatory and neurodegenerative diseases, and its member PARP7 has been shown to be overactivated in tumors and plays a key role in cancer cell survival.
  • PARP7 has been shown to be overactivated in tumors and plays a key role in cancer cell survival.
  • PARP7 can inhibit TBK1 protein activity, thereby preventing interferon secretion.
  • Inhibiting PARP7 can effectively inhibit the growth of cancer cells and restore interferon signaling, effectively activate T cell-mediated anti-tumor immune effects, and prevent tumor cells from escaping immune system surveillance. Therefore, PARP7 has great practical value as a target for tumor therapy.
  • the present invention aims to provide a class of tricyclic compounds with novel structures used as PARP7 inhibitors, which exhibit good inhibitory activity on tumor cells and good druggability, and are expected to be used for non-small cell lung cancer, digestive tract cancer,
  • the treatment of pancreatic cancer and other cancers has broad prospects for drug development.
  • the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, wherein
  • A is selected from C 6 -C 10 aryl and 6-10 membered heteroaryl
  • R 1 is selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy and C 1 -C 6 haloalkyl, wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyi oxy and haloalkyl are each optionally substituted with at least 1 R 8 ;
  • R 2 is selected from hydrogen, C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl, wherein said alkyl and cycloalkyl are each optionally substituted with at least 1 R 8 ; or, quilt replace;
  • Each of R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C(O)R 9 , C(O)NR 9 R 10 , C( O)OR 9 , OC(O)R 9 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl and 6-10 membered heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, ary
  • R 7 is selected from hydrogen, halogen, cyano, hydroxyl, amino, carbamoyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyne base, C 1 -C 6 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 -aryl and 6-10-membered heteroaryl, preferably hydrogen, halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3
  • L 1 , L 2 and L 3 are each independently selected from -(CH 2 ) o -(A) p -(CH 2 ) q -, wherein A is selected from O, C(R 8 ) 2 or NR 8 , o, p and q are each independently any integer from 0 to 3;
  • X 1 is selected from O, C(R 8 ) 2 and NR 8 ;
  • X 2 is selected from CR 8 and N;
  • n and n are each independently selected from 0, 1, 2, 3, 4 and 5;
  • R 8 and R 9 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3 -C 8 cycloalkoxy and 3-8 membered heterocycloalkoxy, wherein the alkyl, heteroalkane alkenyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy and heterocycloalkoxy are each optionally substituted with at least 1 R 10 ;
  • R 10 is selected from hydrogen, chlorine, fluorine, cyano, hydroxyl, amino, isopropyl, cyclopropyl, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy and phenyl.
  • the compound of formula I when Y 1 is a single bond and m is not 0, R 3 or R 4 on the carbon atom of Y 1 is directly connected to R 2 to form a ring, and at this time the formula
  • the compound I is represented by the formula I", wherein B is a 3-6 membered heterocycloalkyl group (such as a 4-membered azetidine group, a 5-membered pyrrolidinyl group, a 6-membered morpholinyl group, etc.), preferably a 4-5 membered heterocycloalkyl group Cycloalkyl, more preferably 4-membered heterocycloalkyl, further preferably azetidinyl.
  • B is a 3-6 membered heterocycloalkyl group (such as a 4-membered azetidine group, a 5-membered pyrrolidinyl group, a 6-membered morpholinyl group, etc.), preferably a 4-5 membered heterocycl
  • A is a 6-8-membered heteroaryl group, preferably a 6-membered heteroaryl group, more preferably a pyridyl group.
  • R 1 is selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy and C 1 -C 3 haloalkyl, preferably C 1 -C 3 fluoroalkyl, more preferably trifluoromethyl (-CF 3 ).
  • R 2 is hydrogen
  • each of R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, C 1 -C 3 alkyl, C 1 - C 3 heteroalkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkoxy; preferably, each of R 3 , R 4 , R 5 and R 6 is each independently is selected from hydrogen, C1 - C3 alkyl and C1 - C3 heteroalkyl ; more preferably, each of R3 , R4, R5 and R6 is independently selected from hydrogen, methyl ( - CH3 ) and methoxymethyl ( -CH2OCH3 ) .
  • R 7 is selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 3 -C 8 cycloalkyl, preferably hydrogen, halogen, cyano, hydroxyl, amino, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl and C 3 -C 6 cycloalkyl, more preferably hydrogen, Fluorine, chlorine, bromine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl and cyclopentane base.
  • R 8 and R 9 are each independently selected from hydrogen and C 1 -C 6 alkyl, preferably hydrogen and C 1 -C 3 alkyl, More preferred are hydrogen and methyl.
  • the fragment is selected from one of the following fragments:
  • the fragment is selected from one of the following fragments:
  • the present invention provides the following specific compounds:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula I, I' or I" or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound represented by formula I, I' or I" or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable adjuvant.
  • the present invention provides a compound represented by formula I, I' or I" or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or Use of a prodrug or a pharmaceutical composition comprising the same in the manufacture of a medicament (eg, a PARP7 inhibitor) for preventing and/or treating a disease or disorder caused by PARP7 overexpression.
  • a medicament eg, a PARP7 inhibitor
  • the present invention provides a compound represented by formula I, I' or I" or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or A prodrug or a pharmaceutical composition comprising the same for the prevention and/or treatment of a disease or disorder caused by overexpression of PARP7.
  • the present invention provides a method for preventing and/or treating a disease or condition caused by overexpression of PARP7, comprising adding a preventive and/or therapeutically effective amount of a compound of formula I, I' or I"
  • a preventive and/or therapeutically effective amount of a compound of formula I, I' or I" The compound shown, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition comprising the same, is administered to an individual in need thereof.
  • the disease or disorder caused by overexpression of PARP7 is cancer.
  • the cancer is one or more of hematological tumor, pancreatic cancer, colorectal cancer and lung cancer.
  • the present invention provides a series of tricyclic compounds with novel structures. It is proved by relevant enzyme and cell activity tests that the compounds of the present invention not only have good PARP7 enzyme inhibitory activity, but also have excellent cell proliferation inhibitory activity. In vitro experiments , the IC 50 value for cell proliferation is ideal, and some compounds can even reach the nM level, which can be well used in a variety of tumors. In addition, the compounds of the present invention also show good in vivo efficacy and are suitable for being prepared as PARP7 inhibitors for the prevention and/or treatment of diseases or conditions related to PARP7 activation, such as cancer (including but not limited to hematological tumors, pancreatic cancer, gastrointestinal tumors, colorectal cancer, and lung cancer).
  • diseases or conditions related to PARP7 activation such as cancer (including but not limited to hematological tumors, pancreatic cancer, gastrointestinal tumors, colorectal cancer, and lung cancer).
  • Alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms, for example, may be 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms carbon atoms, straight and branched chain groups of 1 to 6 carbon atoms or 1 to 4 carbon atoms.
  • alkyl may be a monovalent, divalent or trivalent group.
  • Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl and various branched chain isomers, etc.
  • Non-limiting examples also include, but are not limited to, methylene, methine, ethylene, ethylene, propylene, propylene, butylene, butylene, and various branched chain isomers thereof.
  • alkyl may be optionally substituted or unsubstituted.
  • Alkoxy refers to a “-O-alkyl” group, wherein “alkyl” is as defined above.
  • alkoxy may be optionally substituted or unsubstituted.
  • alkenyl refers to unsaturated aliphatic hydrocarbon groups, straight and branched chain groups comprising 2 to 20 carbon atoms and at least 1 carbon-carbon double bond, for example, may be 1 to 18 carbon atoms, 1 to Straight and branched chain groups of 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • alkenyl may be a monovalent, divalent or trivalent group.
  • alkenyl may be optionally substituted or unsubstituted.
  • Alkynyl refers to unsaturated aliphatic hydrocarbon groups, straight and branched chain groups comprising 2 to 20 carbon atoms and at least 1 carbon-carbon triple bond, for example, may be 1 to 18 carbon atoms, 1 to Straight and branched chain groups of 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • alkynyl may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, ethynyl (-C ⁇ CH), propynyl (-C ⁇ C- CH3 ), butynyl pentynyl and various branched chain isomers.
  • Non-limiting examples also include, but are not limited to, ethynylene (-C ⁇ C-), propynylene butynylene and its various branched-chain isomers.
  • alkynyl may be optionally substituted or unsubstituted.
  • Heteroalkyl refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 2 to 20 atoms, for example, may be 2 to 18 atoms, 2 to 12 atoms atoms, 2 to 8 atoms, 2 to 6 atoms, or 2 to 4 atoms of straight and branched chain groups, wherein one or more atoms are selected from nitrogen, oxygen or S(O) m (where m is 0, 1 or 2) and the rest are carbon.
  • “heteroalkyl” may be a monovalent, divalent or trivalent group.
  • Non-limiting examples include, but are not limited to, methoxymethyl (2-oxapropyl), methylthiomethyl (2-thiapropyl), methylaminomethyl (2-azapropyl), and various Branched chain isomers, etc.
  • heteroalkyl may be optionally substituted or unsubstituted.
  • Cycloalkyl means a saturated or partially unsaturated, monocyclic or polycyclic, aliphatic hydrocarbon group comprising 3 to 12 ring atoms, eg, 3 to 12, 3 to 10, or 3 to 6 Ring atoms (ie, 3 to 6 membered rings).
  • monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclopentyl Heptatrienyl, cyclooctyl, etc.
  • cycloalkyl may be optionally substituted or unsubstituted.
  • Cycloalkylene refers to a divalent group formed by the loss of a hydrogen atom from a “cycloalkyl”.
  • monocyclic cycloalkylenes include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cyclohexanediol Alkenyl, cycloheptylene, cycloheptatrienylene, cyclooctylene, etc.
  • "cycloalkylene” may be optionally substituted or unsubstituted.
  • Heterocycloalkyl refers to a saturated or partially unsaturated, monocyclic or polycyclic aliphatic hydrocarbon group comprising 3 to 20 ring atoms, for example, may be 3 to 16 , 3 to 12, 3 to 10 or 3 to 6 ring atoms, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or S(O) m (wherein m is 0, 1 or 2) , the remaining ring atoms are carbon; preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 10 ring atoms, most preferably 5 or 6 ring atoms, of which 1 to 4, preferably 1 to 3, more preferably 1 to 2 ring atoms are heteroatoms.
  • Non-limiting examples of monocyclic heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • Non-limiting examples of polycyclic heterocycloalkyls include, but are not limited to, heterocycloalkyl (fused ring), spirocyclic, or bridged.
  • heterocycloalkyl may be optionally substituted or unsubstituted.
  • Heterocycloalkylene refers to a divalent group formed by the loss of a hydrogen atom from a “heterocycloalkyl”.
  • Non-limiting examples of monocyclic heterocycloalkylenes include, but are not limited to, azetidine, pyrrolidylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, homopiperidine Azinyl etc.
  • Non-limiting examples of polycyclic heterocycloalkylenes include, but are not limited to, cyclo (fused), spiro, or bridged heterocycloalkylenes.
  • "heterocycloalkylene” may be optionally substituted or unsubstituted.
  • Halogen means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
  • Haloalkyl or haloalkoxy refers to an alkyl or alkoxy group substituted with one or more of the same or different halogen atoms
  • preferred examples of haloalkyl or haloalkoxy include, but are not limited to, trifluoromethane group, trifluoroethyl, trifluoromethoxy, etc.
  • Cyano refers to the "-CN” group.
  • amino refers to the " -NH2 " group.
  • amino may be optionally substituted or unsubstituted.
  • “carbamoyl” may be optionally substituted or unsubstituted.
  • Niro refers to the " -NO2 " group.
  • Aryl refers to a carbocyclic ring system containing 6-14, preferably 6-10, more preferably 6-7 ring atoms. Monocyclic, bicyclic and tricyclic carbocyclic ring systems of ring atoms, wherein at least one of the ring systems is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more points of attachment to The rest of the molecule is connected. Examples include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like. In addition, in the present invention, "aryl” may be optionally substituted or unsubstituted.
  • Arylene refers to a divalent group formed by the loss of a hydrogen atom from an “aryl” group. Examples include, but are not limited to, phenylene, naphthylene, anthracene, and the like. In addition, in the present invention, the "arylene group” may be optionally substituted or unsubstituted.
  • Aryloxy refers to a "-O-aryl” group, wherein “aryl” is as defined above. Examples include, but are not limited to, phenoxy, naphthyloxy, anthraceneoxy, and the like. In addition, in the present invention, “aryloxy” may be optionally substituted or unsubstituted. “Aryleneoxy” refers to a divalent group formed by the loss of a hydrogen atom from the aryl moiety of an "aryloxy”. Examples include, but are not limited to, phenoxy, naphthyleneoxy, anthracyleneoxy, and the like. In addition, in the present invention, “aryleneoxy” may be optionally substituted or unsubstituted.
  • Heteroaryl refers to monocyclic, bicyclic, and tricyclic ring systems containing 5-14, preferably 5-10, ring atoms, wherein at least one ring system is aromatic, and at least one ring system comprises one or more heteroatoms selected from nitrogen, oxygen or S(O) m (where m is 0, 1 or 2), wherein each ring system comprises a ring of 5-7 atoms, and There is one or more junction points to the rest of the molecule. Examples include, but are not limited to, furanyl, imidazolyl, pyridyl, pyrimidinyl, thiazolyl, purinyl, quinolinyl, and the like.
  • Heteroarylene refers to bivalent monocyclic, bicyclic and tricyclic ring systems containing 5 to 14, preferably 5 to 10, ring atoms formed by the loss of a hydrogen atom from a “heteroaryl” group. Examples include, but are not limited to, furanylene, imidazolylide, pyridylene, pyrimidinylene, thiazolylylene, purinylene, quinolinylene, and the like.
  • heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not be, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents.
  • “Pharmaceutically acceptable salts” refers to salts prepared from compounds of the present invention with relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting their free forms with a sufficient amount of base in neat solution or in a suitable inert solvent .
  • Non-limiting examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, ammonium, calcium, magnesium, organic amine, or similar salts.
  • acid addition salts can be obtained by contacting their free forms with a sufficient amount of acid in neat solution or in a suitable inert solvent .
  • Non-limiting examples of pharmaceutically acceptable acid addition salts include, but are not limited to, inorganic acid salts (eg, hydrochloride, hydrobromide, hydroiodide, nitrate, carbonate, bicarbonate, phosphate) , monohydrogen phosphate, dihydrogen phosphate, phosphite, sulfate, hydrogen sulfate, etc.), organic acid salts (such as acetate, propionate, isobutyrate, malonate, succinate , Suberate, Maleate, Fumarate, Citrate, Tartrate, Lactate, Mandelate, Benzoate, Phthalate, Mesylate, Benzene Sulfonate acid salts, p-toluenesulfonic acid salts, glucuronic acid, etc.) and amino acid salts (eg, arginine salts, etc.).
  • inorganic acid salts eg, hydrochloride, hydrobromide, hydroiodide, n
  • the pharmaceutically acceptable salt of the compound represented by formula I is an acid addition salt, preferably hydrochloride, hydrobromide, phosphate or sulfate, more preferably hydrochloride.
  • “Pharmaceutical composition” refers to a pharmaceutically acceptable composition comprising one or more compounds of Formula I or a pharmaceutically acceptable form thereof (eg, a salt, hydrate, solvate, stereoisomer isomers, tautomers, metabolites, prodrugs, etc.), and other components (eg, pharmaceutically acceptable excipients).
  • auxiliary materials refer to auxiliary materials widely used in the field of pharmaceutical production.
  • the main purpose of using excipients is to provide a pharmaceutical composition that is safe to use, stable in properties and/or has specific functionality, and also to provide a method so that after the drug is administered to a subject, the active ingredient can be The rate of dissolution, or the promotion of effective absorption of the active ingredient in the subject to which it is administered.
  • Pharmaceutically acceptable excipients can be inert fillers or functional ingredients that provide a certain function for the pharmaceutical composition (eg, stabilizing the overall pH of the composition or preventing the degradation of active ingredients in the composition).
  • Non-limiting examples of pharmaceutically acceptable adjuvants include, but are not limited to, binders, suspending agents, emulsifiers, diluents (or fillers), granulating agents, sizing agents, disintegrating agents, lubricants, anti-adhering agents , glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors, sweeteners, etc.
  • compositions of the present invention can be prepared using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, attenuating, encapsulating, entrapping and/or lyophilizing processes.
  • the purpose of using the pharmaceutical composition is to promote the administration to the living body, facilitate the absorption of the active ingredient, and then exert biological activity.
  • the pharmaceutical compositions of the present invention can be administered in any form, including injection (intraarterial, intravenous, intramuscular, intraperitoneal, subcutaneous), mucosal, oral (oral solid, oral liquid), rectal, inhalation, implant , topical (eg ocular) administration, etc.
  • oral solid formulations include, but are not limited to, powders, capsules, lozenges, granules, tablets, and the like.
  • Non-limiting examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, tinctures, elixirs, solutions, and the like.
  • Non-limiting examples of formulations for topical administration include, but are not limited to, creams, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations.
  • Non-limiting examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry powders for injection, suspensions for injection, emulsions for injection, and the like.
  • the pharmaceutical compositions of the present invention can also be formulated in controlled release or delayed release dosage forms (eg, liposomes or microspheres).
  • a compound of the present invention or a pharmaceutical composition comprising the same is administered orally or intravenously to an individual in need thereof.
  • other modes of administration may also be employed or even preferred.
  • transdermal administration would be a very important mode of administration.
  • the administration channel can be varied or adjusted in any suitable manner to meet the needs of the nature of the drug, the convenience of the patient and medical staff, and other relevant factors.
  • the compounds of the present invention or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, metabolites or prodrugs or pharmaceutical compositions comprising them have excellent PARP7 enzyme inhibitory activity and It has cell proliferation inhibitory activity and shows good in vivo efficacy, and can be used as a PARP7 inhibitor for preventing and/or treating diseases or conditions caused by overexpression of PARP7, and has good clinical and medical applications.
  • a non-limiting example of a disease or disorder caused by overexpression of PARP7 is cancer, including but not limited to hematological tumors, pancreatic cancer, colorectal cancer, and lung cancer.
  • the preparation of the compounds of the present invention can be achieved by synthetic methods well known to those skilled in the art, including but not limited to the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
  • the known starting materials used in the present invention can be synthesized by methods known in the art, or purchased by conventional commercial means (for example, purchased from Shaoyuan Chemical Technology, Beijing Coupling Technology, etc.). Unless otherwise specified, the reactions were carried out in an argon atmosphere or a nitrogen atmosphere.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the reaction temperature is room temperature, and the temperature range is 20°C-30°C.
  • Monitoring the progress of the reaction can be accomplished by synthetic methods well known to those skilled in the art, including but not limited to thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the thin layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate.
  • the developing solvent system includes but is not limited to A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent can be determined according to the polarity of the compound. adjust.
  • the separation and purification of the compounds of the present invention can be achieved by synthetic methods well known to those skilled in the art, including but not limited to column chromatography (CC), high performance liquid chromatography (HPLC), ultra-high performance liquid chromatography (UPLC) Wait.
  • Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the carrier.
  • the eluent system includes but is not limited to A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent can be based on the compound.
  • the polarity can be adjusted, and a small amount of acidic or basic anti-tailing reagents can also be added for adjustment.
  • HPLC chromatogram was determined using an Agilent 1200 DAD HPLC chromatograph (chromatographic column: Sunfire C18, 150 ⁇ 4.6mm, 5 ⁇ m) or a Waters 2695-2996 HPLC chromatograph (chromatographic column: Gimini C18, 150 ⁇ 4.6mm, 5 ⁇ m).
  • Structural identification of the compounds of the present invention can be accomplished by methods well known to those skilled in the art, including but not limited to nuclear magnetic resonance (NMR), mass spectrometry (MS), and the like.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR spectrum was determined by Bruker AVANCE-400 or Varian Oxford-300 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ) or deuterated methanol (CD 3 OD), The internal standard is tetramethylsilane (TMS), and the chemical shifts are in 10-6 (ppm).
  • MS spectra were determined using an Agilent SQD (ESI) mass spectrometer (model: 6110) or a Shimadzu SQD (ESI) mass spectrometer (model: 2020).
  • Step 8 Synthesis of compound INT-1
  • intermediate INT-2 refers to the synthesis steps of intermediate INT-1, wherein in the sixth step, L-aminopropanol is used instead of DL-aminopropanol to obtain intermediate INT-2.
  • intermediate INT-9 refers to the synthesis steps of intermediate INT-8, wherein the first step uses (R)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester (CAS:278788-66- 2) Instead of compound INT-8A, intermediate INT-9 is obtained.
  • intermediate INT-10 refers to the synthesis procedure of intermediate INT-8, in which 2,3-difluoro-5-chloropyridine (CAS: 89402-43-7) is used in the first step instead of 2,3-difluoro- 5-(Trifluoromethyl)pyridine to yield intermediate INT-10.
  • intermediate INT-11 refers to the synthesis procedure of intermediate INT-8, in which 2,3-difluoro-5-chloropyridine (CAS: 89402-43-7) was used in the first step instead of 2,3-difluoro- 5-(Trifluoromethyl)pyridine and substituting (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (CAS:278788-66-2) for compound INT-8A to give intermediate INT-11.
  • intermediate INT-12 refers to the synthesis steps of intermediate INT-8, wherein the first step uses (S)-3-(2-hydroxyethyl)piperazine-1-carboxylate tert-butyl ester (CAS:1273577- 11-9) Substitute compound INT-8A to obtain intermediate INT-12.
  • intermediate INT-13 refers to the synthesis steps of intermediate INT-8, wherein the first step uses (R)-3-(2-hydroxyethyl)piperazine-1-carboxylate tert-butyl ester (CAS:1272421- 10-9) Substitute compound INT-8A to obtain intermediate INT-13.
  • intermediate INT-14 refers to the synthesis steps of intermediate INT-8, wherein the first step uses (S)-3-(2-hydroxyethyl)piperazine-1-carboxylate tert-butyl ester (CAS:1273577- 11-9) in place of compound INT-8A and 2,3-difluoro-5-chloropyridine (CAS:89402-43-7) in place of 2,3-difluoro-5-(trifluoromethyl)pyridine to give Intermediate INT-14.
  • intermediate INT-15 refers to the synthesis steps of intermediate INT-8, wherein the first step uses (R)-3-(2-hydroxyethyl)piperazine-1-carboxylate tert-butyl ester (CAS:1272421- 10-9) in place of compound INT-8A and 2,3-difluoro-5-chloropyridine (CAS:89402-43-7) in place of 2,3-difluoro-5-(trifluoromethyl)pyridine to give Intermediate INT-15.
  • reaction solution was poured into a mixed solvent of ethyl acetate (80ml) and saturated sodium chloride (80ml), stirred, and the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (60ml ⁇ 2).
  • reaction solution was poured into a mixed solution of ethyl acetate (120 ml) and saturated sodium chloride (160 ml), the organic layer was separated after stirring, and the aqueous layer was extracted with ethyl acetate (60 ml*2). The combined organic phases were washed with water (60 ml) and saturated brine (40 ml), dried over anhydrous sodium sulfate and concentrated to obtain crude compound INT-16C (1.8 g, pale yellow liquid, yield 49.7%).
  • intermediate INT-17 refers to the synthesis procedure of intermediate INT-16, wherein in the first step, (R)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester is used instead of (S)-3- (Hydroxymethyl)piperazine-1-carboxylate tert-butyl ester to yield intermediate INT-17.
  • the synthesis of compound 6 refers to the synthesis steps of compound 1 in Example 1, wherein in the fourth step, compound 1E is replaced by INT-10, and compound INT-1 is replaced by compound INT-2 to obtain compound 6.
  • the synthesis of compound 7 refers to the synthesis steps of compound 1 in Example 1, wherein compound INT-11 is used to replace compound 1E in the fourth step, and compound INT-2 is used to replace compound INT-1 to obtain compound 7.
  • the synthesis of compound 11 refers to the synthesis steps of compound 41 in Example 41, wherein compound INT-10 is replaced by compound INT-14 in the first step to obtain compound 11.
  • the synthesis of compound 12 refers to the synthesis steps of compound 10 in Example 10, wherein compound INT-8 is used instead of compound INT-10 in the fifth step to obtain compound 12.
  • the synthesis of compound 13 refers to the synthesis steps of compound 10 in Example 10, wherein in the first step, (S)-N-Boc-L-prolinol (CAS: 69610-40-8) is used instead of compound 10A, and in the fifth step, Compound INT-8 was substituted for compound INT-10 to give compound 13.
  • the synthesis of compound 14 refers to the synthesis steps of compound 10 in Example 10, wherein in the first step, compound 10A is replaced by tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (CAS: 473923-56-7), and the first step is to replace compound 10A.
  • Compound 14 was obtained by replacing compound INT-10 with compound INT-8 in five steps.
  • the synthesis of compound 15 refers to the synthesis steps of compound 8 in Example 8, wherein compound INT-8 is used instead of compound INT-10 in the first step to obtain compound 15.
  • the synthesis of compound 16 refers to the synthesis steps of compound 9 in Example 9, wherein compound INT-8 is used instead of compound INT-10 in the fifth step to obtain compound 16.
  • the synthesis of compound 19 refers to the synthesis procedure of compound 17 in Example 17, wherein in the first step, compound 17A is replaced by 1-Boc-3-pyrrolidinecarboxylic acid (CAS: 59378-75-5) to obtain compound 19.
  • the reaction solution was diluted with ethyl acetate, slowly added dropwise to an ice-bath saturated aqueous sodium bicarbonate solution (40 mL), extracted with ethyl acetate (30 mL ⁇ 3), the organic phase was dried over anhydrous sodium sulfate, and then reduced Pressure desolvation, the obtained crude product was purified by HPLC (Waters Sunfire OBD 100x30mm, 5 ⁇ m, mobile phase A: 0.1% TFA aqueous solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile run to 1 min, 52%-52% acetonitrile Running to 10 min, 95% acetonitrile to 14 min, 10% acetonitrile to 16 min end) to obtain compound 20 (11.0 mg, white solid, yield: 25%).
  • HPLC Waters Sunfire OBD 100x30mm, 5 ⁇ m, mobile phase A: 0.1% TFA aqueous solution, mobile phase B: acetonitrile, gradient: 10% acet
  • the synthesis of compound 21 refers to the synthesis steps of compound 1 in example 1, wherein compound INT-15 is used to replace compound 1E in the fourth step, and compound INT-2 is used to replace compound INT-1 to obtain compound 21.
  • reaction solution was diluted with ethyl acetate and slowly added dropwise to an ice-bath saturated aqueous sodium bicarbonate solution to adjust the pH between 7-8, extracted with ethyl acetate (30 mL), the organic phase was added anhydrous It was dried with sodium sulfate, desolvated under reduced pressure, and the obtained crude product was purified by HPLC (Waters Sunfire OBD 100 ⁇ 30 mm, 5 ⁇ m, mobile phase A: 0.1% aqueous TFA solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52% acetonitrile). -52% acetonitrile run to 10min, 95% acetonitrile run to 14min, 10% acetonitrile run to 16min end) to obtain compound 22. (9.0 mg, pale yellow oil, yield: 22%).
  • the synthesis of compound 23 refers to the synthesis procedure of compound 18 in Example 18, wherein in the first step, methyl methacrylate (CAS: 80-62-6) is used instead of methyl acrylate, and N-Boc-L-alaninol ( CAS: 79069-13-9) instead of compound 18A gave compound 23.
  • the synthesis of compound 24 refers to the synthesis procedure of compound 17 in Example 17, wherein in the first step, N-Boc-4-piperidinecarboxylic acid (CAS: 84358-13-4) was used instead of compound 17A to obtain compound 24.
  • reaction solution was diluted with ethyl acetate and slowly added dropwise to an ice-bath saturated aqueous sodium bicarbonate solution to adjust the pH between 7-8, extracted with ethyl acetate (30 mL), the organic phase was added anhydrous It was dried with sodium sulfate, desolvated under reduced pressure, and the obtained crude product was purified by HPLC (Waters Sunfire OBD 100 ⁇ 30 mm, 5 ⁇ m, mobile phase A: 0.1% TFA aqueous solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile to run for 1 min, 52 %-52% acetonitrile run to 10min, 95% acetonitrile run to 14min, 10% acetonitrile run to 16min end) to obtain compound 26. (9.0 mg, pale yellow oil, yield: 22%).
  • reaction solution was diluted with ethyl acetate and slowly added dropwise to an ice-bath saturated aqueous sodium bicarbonate solution to adjust the pH between 7-8, extracted with ethyl acetate (30 mL), the organic phase was added anhydrous It was dried with sodium sulfate, desolvated under reduced pressure, and the obtained crude product was purified by HPLC (Waters Sunfire OBD 100 ⁇ 30 mm, 5 ⁇ m, mobile phase A: 0.1% TFA aqueous solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile to run for 1 min, 52 %-52% acetonitrile run to 10min, 95% acetonitrile run to 14min, 10% acetonitrile run to 16min end) to obtain compound 27. (10.0 mg, pale yellow oil, yield: 24%).
  • the obtained residue was purified by HPLC (Waters Sunfire OBD 100 ⁇ 30 mm, 5 ⁇ m, mobile phase A: 0.1% TFA aqueous solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile run to 1 min, 52%-52% acetonitrile run to 10 min, 95% acetonitrile run to 14 min, 10% acetonitrile run to 16 min end) to obtain compound 28 ( 27 mg, white solid, 23.07% yield).
  • HPLC Waters Sunfire OBD 100 ⁇ 30 mm, 5 ⁇ m, mobile phase A: 0.1% TFA aqueous solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile run to 1 min, 52%-52% acetonitrile run to 10 min, 95% acetonitrile run to 14 min, 10% acetonitrile run to 16 min end
  • the 29C crude product (130.0 mg) was dissolved in 8% mass fraction of ethyl acetate hydrochloride (6.0 mL) and methanol (1.5 mL), and then stirred at room temperature for 0.5 hours. After TLC showed that the reaction was over, the reaction was quenched with saturated sodium bicarbonate until the pH reached 7-8, then extracted with dichloromethane (10 mL ⁇ 3), the combined organic phases were washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. , filtered to remove the desiccant, and desolvated under reduced pressure to obtain the crude product of compound 28D (175.0 mg, yellow solid). used directly in the next step.
  • Cuprous bromide (1.66 g, 11.55 mmol) was added to acetonitrile (20 mL), and isoamyl nitrite (1.35 g, 11.55 mmol) was added dropwise. After the dropping was completed, the mixture was stirred at 25°C for 20 minutes, and the compound was added dropwise. A solution of 30C (2.5 g, 7.7 mmol) in acetonitrile (10 mL) was then heated to 60 °C and stirred for 5 hours.
  • reaction solution was diluted with ethyl acetate and slowly added dropwise to an ice-bath saturated aqueous sodium bicarbonate solution to adjust the pH between 7-8, extracted with ethyl acetate (30 mL), the organic phase was added anhydrous It was dried with sodium sulfate, desolvated under reduced pressure, and the obtained crude product was purified by HPLC (Waters Sunfire OBD 100 ⁇ 30 mm, 5 ⁇ m, mobile phase A: 0.1% TFA aqueous solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile to run for 1 min, 52 %-52% acetonitrile run to 10min, 95% acetonitrile run to 14min, 10% acetonitrile run to 16min end) to obtain compound 32. (12.0 mg, pale yellow oil).
  • the synthesis of compound 33 refers to the synthesis steps of compound 1 in Example 1, wherein in the fourth step, compound 1E is replaced by INT-16, and compound INT-1 is replaced by compound INT-2 to obtain compound 33.
  • the synthesis of compound 34 refers to the synthesis steps of compound 1 in Example 1, wherein compound INT-14 is used to replace compound 1E in the fourth step, and compound INT-2 is used to replace compound INT-1 to obtain compound 34.
  • the synthesis of compound 35 refers to the synthesis steps of compound 10 in Example 10, wherein compound INT-14 is used instead of compound INT-10 in the fifth step to obtain compound 35.
  • the synthesis of compound 36 refers to the synthesis steps of compound 9 in Example 9, wherein compound INT-14 is used instead of compound INT-10 in the fifth step to obtain compound 36.
  • the synthesis of compound 37 refers to the synthesis steps of compound 9 in Example 9, wherein compound INT-12 is used instead of compound INT-10 in the fifth step to obtain compound 37.
  • the synthesis of compound 38 refers to the synthesis steps of compound 10 in Example 10, wherein compound INT-17 is replaced by compound INT-10 in the fifth step to obtain compound 38.
  • the synthesis of compound 39 refers to the synthesis steps of compound 8 in Example 8, wherein compound INT-14 is used instead of compound INT-10 in the first step to obtain compound 39.
  • the synthesis of compound 40 refers to the synthesis steps of compound 8 in Example 8, wherein in the first step, compound INT-12 is used instead of compound INT-10 to obtain compound 40.
  • the synthesis of compound 42 refers to the synthesis steps of compound 41 in Example 41, wherein compound INT-12 is used instead of compound INT-14 in the first step to obtain compound 42.
  • the synthesis of compound 43 refers to the synthesis steps of compound 9 in Example 9, wherein compound INT-17 is used instead of compound INT-10 in the fifth step to obtain compound 43.
  • the synthesis of compound 44 refers to the synthesis steps of compound 41 in Example 41, wherein compound INT-17 is used instead of compound INT-14 in the first step to obtain compound 44.
  • This assay was used to examine the potency of compounds to inhibit PARP7 enzymatic activity, with lower IC50 values indicating high potency of compounds as PARP7 inhibitors in the following assay setup.
  • PARP7 chemiluminescence detection kit was purchased from BPS Bioscience.
  • PBST buffer preparation 1X PBS contains 0.05% Tween 20, that is, 5 ⁇ L of 100% Tween 20 is added to 10 mL of PBS.
  • Compound solution preparation The compounds to be tested were diluted 3-fold with DMSO solution to the eighth concentration, that is, from 300 ⁇ M to 137 nM. Then use 1X test buffer to dilute each compound to be tested into a working solution with 10% DMSO. 2.5 ⁇ L/well was added to the corresponding well. Add 12.5 ⁇ L/well substrate mixture solution (1.25 ⁇ L 10X PARP test buffer; 1.25 ⁇ L 10X PARP experimental mixture; 10 ⁇ L double distilled water) to each well. Dilute PARP7 enzyme to 6ng/ ⁇ L, and add 10 ⁇ L/well to the corresponding well. At this time, the final compound concentration gradient is 3 ⁇ M to 1.37nM, PARP7 (60ng), and the reaction system is incubated at 25°C for 60 minutes;
  • the inhibition rate was calculated using the luminescence information value, and the concentration and inhibition rate were fitted by nonlinear regression curve using Graphpad Prism software to obtain the IC 50 value.
  • Table 2 shows the inhibitory effects of some compounds prepared in the present invention and the PARP7 enzyme inhibitor RBN-2397 commonly used in the art on PARP7 enzyme activity.
  • the cell line NCI-H1373 was purchased from Kebai.
  • RPMI1640 medium, penicillin/streptomycin antibiotics were purchased from Proxa.
  • Fetal bovine serum was purchased from Biosera.
  • CellTiter-Glo (Cell Viability Chemiluminescence Detection Reagent) reagent was purchased from Promega.
  • the EnVision Multilabel Analyzer was purchased from PerkinElmer.
  • NCI-H1373 cells were seeded in a white 96-well plate, 80 ⁇ L of cell suspension/well, which contained 2000 NCI-H1373 cells. Cell plates were incubated overnight in a carbon dioxide incubator. The compound to be tested was diluted 3-fold to the ninth concentration, that is, from 600 ⁇ M to 91.45 nM, and a double-well experiment was set up. Add 78 ⁇ L of medium to the middle plate, and then transfer 2 ⁇ L/well of the compound to the middle plate according to the corresponding position. After mixing, transfer 20 ⁇ L/well to the cell plate. Compound concentrations transferred to the cell plate ranged from 3 [mu]M to 0.46 nM. The cell plates were placed in a carbon dioxide incubator for 6 days.
  • Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis.
  • the inhibition rate was calculated using the luminescence information value, and the concentration and inhibition rate were fitted by nonlinear regression curve using Graphpad Prism software to obtain the IC 50 value.
  • Table 3 shows the inhibitory effect of the compound prepared in the present invention and the PARP7 enzyme inhibitor RBN-2397 commonly used in the art on the anti-proliferation of NCI-H1373 cells.
  • the compounds of the present invention can inhibit the proliferation of NCI-H1373 cells well, and the cell proliferation inhibition activity of some compounds is better than that of RBN-2397.
  • test compounds on the subcutaneous xenograft tumor model of human lung cancer adenocarcinoma cells NCI-H1373 cells was evaluated.
  • NCI-H1373 tumor cells were resuspended in PBS to prepare a cell suspension at a density of 1 ⁇ 10 7 cells/mL, and 0.2 mL of the cell suspension was subcutaneously inoculated on the right back of each mouse (adding matrix). glue, 1:1 by volume), waiting for tumor growth. Randomization was initiated when the mean tumor volume reached approximately 113 mm3 . After administration, the tumor diameter was measured with a vernier caliper twice a week, and the tumor volume was calculated as follows:
  • V 0.5a ⁇ b 2 , where a and b represent the long and short diameters of the tumor, respectively.
  • TGI tumor growth inhibition rate
  • TGI(%) [(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment in the solvent control group-at the beginning of treatment in the solvent control group Mean tumor volume)] ⁇ 100%.
  • the compound of the present invention has a very significant tumor inhibitory effect, and the TGI can reach more than about 70%, and the highest can even reach 101%, indicating that the compound of the present invention is effective in human lung cancer adenocarcinoma cells NCI.
  • -H1373 subcutaneous xenograft tumor model shows good in vivo efficacy and has great clinical application prospects.

Abstract

The present invention relates to the field of pharmaceutical chemistry, and relates to a tricyclic compound and a pharmaceutical composition and use thereof. The compound is a compound as represented by formula I, has good PARP7 inhibitory activity, thus can be used as a PARP7 inhibitor, and is used for treating and/or preventing a disease or disorder (such as cancer) caused by overexpression of PARP7.

Description

三并环化合物及其药物组合物和应用Tricyclic compounds and their pharmaceutical compositions and applications
相关申请的交叉引用CROSS-REFERENCE TO RELATED APPLICATIONS
本发明要求2021年03月03日在中国提交的，名称为“三并环化合物及其药物组合物和应用”、申请号为202110237007.5的发明专利申请的优先权，通过引用的方式将该专利申请的全部内容并入本文。The present invention claims the priority of the invention patent application entitled "Tricyclic Compounds and Pharmaceutical Compositions and Applications thereof" and the application number is 202110237007.5, which was filed in China on March 3, 2021, and the patent application is by reference The entire contents of this article are incorporated herein.
技术领域technical field
本发明属于药物化学领域，具体涉及一类三并环化合物、包含该类化合物的药物组合物及其在医药领域中的应用。The invention belongs to the field of medicinal chemistry, and specifically relates to a class of tricyclic compounds, a pharmaceutical composition containing the compounds and their application in the field of medicine.
背景技术Background technique
PARP全称为poly-ADP-ribose polymerase，即多聚ADP核糖聚合酶，参与了包括DNA修复、基因表达、蛋白降解、细胞应激反应等多种重要的细胞过程。该蛋白家族由17个成员组成，它们都包含一个约230个氨基酸的共同催化结构域，主要分为polyPARPs和monoPARPs，polyPARPs包括PARP1/2、PARP5a/5b四种亚型，而monoPARPs包括PARP3、PARP4、PARP6、PARP7、PARP8、PARP9、PARP10、PAPR11、PARP12、PAPR14、PARP15、PARP16十二种亚型。以PARP1/2为靶点的PARP1/2抑制剂已有多个药物获批上市，用于治疗多个不同类型肿瘤。The full name of PARP is poly-ADP-ribose polymerase, which is poly-ADP-ribose polymerase, which is involved in a variety of important cellular processes including DNA repair, gene expression, protein degradation, and cellular stress response. The protein family consists of 17 members, all of which contain a common catalytic domain of about 230 amino acids, and are mainly divided into polyPARPs and monoPARPs. , PARP6, PARP7, PARP8, PARP9, PARP10, PAPR11, PARP12, PAPR14, PARP15, PARP16 twelve subtypes. PARP1/2 inhibitors targeting PARP1/2 have been approved and marketed for the treatment of many different types of tumors.
MonoPARP蛋白家族在与癌症、炎性疾病和神经退行性疾病发展相关的多种应激反应中起作用，其成员PARP7被证明在肿瘤中过度活化，且在癌细胞生存中起着关键作用。研究发现，许多癌细胞都依赖PARP7来实现内在的细胞存活，PARP7在多种肿瘤细胞中高表达，而PARP7过度活化或高表达则使肿瘤细胞过度增殖，抑制T细胞激活，使癌细胞能够逃避免疫***监视。PARP7可以抑制TBK1蛋白活性，从而阻止干扰素分泌，抑制PARP7可有效抑制癌细胞的生长并恢复干扰素信号传导，有效激活T细胞介导的抗肿瘤免疫效应，防止肿瘤细胞逃脱免疫***监视。因此，PARP7作为肿瘤治疗的靶点，有较大的实用价值。The MonoPARP protein family plays a role in multiple stress responses associated with the development of cancer, inflammatory and neurodegenerative diseases, and its member PARP7 has been shown to be overactivated in tumors and plays a key role in cancer cell survival. Studies have found that many cancer cells rely on PARP7 for intrinsic cell survival, and PARP7 is highly expressed in a variety of tumor cells, while PARP7 overactivation or high expression causes tumor cells to proliferate excessively, inhibit T cell activation, and enable cancer cells to evade immunity. System monitoring. PARP7 can inhibit TBK1 protein activity, thereby preventing interferon secretion. Inhibiting PARP7 can effectively inhibit the growth of cancer cells and restore interferon signaling, effectively activate T cell-mediated anti-tumor immune effects, and prevent tumor cells from escaping immune system surveillance. Therefore, PARP7 has great practical value as a target for tumor therapy.
发明内容SUMMARY OF THE INVENTION
发明要解决的问题Invention to solve problem
本发明旨在提供一类结构新颖的用作PARP7抑制剂的三并环化合物，其表现出对肿瘤细胞很好的抑制活性，且成药性好，有望用于非小细胞肺癌、消化道癌症、胰腺癌等癌症的治疗，具有广阔的药物开发前景。The present invention aims to provide a class of tricyclic compounds with novel structures used as PARP7 inhibitors, which exhibit good inhibitory activity on tumor cells and good druggability, and are expected to be used for non-small cell lung cancer, digestive tract cancer, The treatment of pancreatic cancer and other cancers has broad prospects for drug development.
用于解决问题的方案solution to the problem
第一方面，本发明提供了一种如式I所示的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药，其中In a first aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, wherein
Figure PCTCN2022078854-appb-000001
Figure PCTCN2022078854-appb-000001
A选自C 6-C 10芳基和6-10元杂芳基； A is selected from C 6 -C 10 aryl and 6-10 membered heteroaryl;
R 1选自氢、卤素、氰基、羟基、氨基、C 1-C 6烷基、C 1-C 6杂烷基、C 3-C 8环烷基、3-8元杂环烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基和C 1-C 6卤代烷基，其中所述烷基、杂烷基、环烷基、杂环烷基、烷氧基、卤代烷氧基和卤代烷基各自任选地被至少1个R 8取代； R 1 is selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy and C 1 -C 6 haloalkyl, wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyi oxy and haloalkyl are each optionally substituted with at least 1 R 8 ;
R 2选自氢、C 1-C 6烷基和C 3-C 8环烷基，其中所述烷基和环烷基各自任选地被至少1个R 8取代；或者，
Figure PCTCN2022078854-appb-000002
被
Figure PCTCN2022078854-appb-000003
代替； R 2 is selected from hydrogen, C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl, wherein said alkyl and cycloalkyl are each optionally substituted with at least 1 R 8 ; or,
Figure PCTCN2022078854-appb-000002
quilt
Figure PCTCN2022078854-appb-000003
replace;
每一个R 3、R 4、R 5和R 6各自独立地选自氢、卤素、氰基、羟基、氨基、硝基、C(O)R 9、C(O)NR 9R 10、C(O)OR 9、OC(O)R 9、C 1-C 6烷基、C 1-C 6杂烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基、C 3-C 8环烷基、3-8元杂环烷基、C 6-C 10芳基和6-10元杂芳基，其中所述烷基、杂烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环烷基、芳基或杂芳基各自任选地被至少1个R 8取代；或者，当Y 1为单键且m不为0时，直接连接Y 1的碳原子上的R 3或R 4与R 2连接成3-8元杂环烷基； Each of R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C(O)R 9 , C(O)NR 9 R 10 , C( O)OR 9 , OC(O)R 9 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl and 6-10 membered heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optional is substituted by at least 1 R 8 ; or, when Y 1 is a single bond and m is not 0, directly connecting R 3 or R 4 and R 2 on the carbon atom of Y 1 is connected to form a 3-8 membered heterocycloalkane base;
R 7选自氢、卤素、氰基、羟基、氨基、氨基甲酰基、C 1-C 6烷基、C 1-C 6杂烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基、C 3-C 8环烷基、3-8元杂环烷基、C 6-C 10芳基和6-10元杂芳基，优选氢、卤素、氰基、羟基、氨基、C 1-C 6烷基、C 1-C 6杂烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基、C 3-C 8环烷基、3-8元杂环烷基、C 6-C 10芳基和6-10元杂芳基，其中所述烷基、杂烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环烷基、芳基和杂芳基各自任选地被至少1个R 8取代； R 7 is selected from hydrogen, halogen, cyano, hydroxyl, amino, carbamoyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyne base, C 1 -C 6 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 -aryl and 6-10-membered heteroaryl, preferably hydrogen, halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl , C 6 -C 10 aryl and 6-10 membered heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycle Alkyl, aryl and heteroaryl are each optionally substituted with at least 1 R;
L 1、L 2和L 3各自独立地选自-(CH 2) o-(A) p-(CH 2) q-，其中A选自O、C(R 8) 2或NR 8，o、p和q各自独立地为0至3中的任一整数； L 1 , L 2 and L 3 are each independently selected from -(CH 2 ) o -(A) p -(CH 2 ) q -, wherein A is selected from O, C(R 8 ) 2 or NR 8 , o, p and q are each independently any integer from 0 to 3;
Y 1、Y 2和Y 3各自独立地选自单键、O、S、NR 10、C(＝O)、C(＝O)O、C(＝O)NR 10、S(＝O)、S(＝O) 2、S(＝O)NR 10、S(＝O) 2NR 10、NR 10C(＝O)NR 10、C 3-C 8亚环烷基、3-8元亚杂环烷基、C 6-C 10亚芳氧基和5-10元亚杂芳基；优选地，Y 1、Y 2和Y 3各自独立地选自单键、O、S、NR 10、C(＝O)、C(＝O)O、C(＝O)NR 10、S(＝O)、S(＝O) 2、S(＝O)NR 10、S(＝O) 2NR 10和NR 10C(＝O)NR 10； Y 1 , Y 2 and Y 3 are each independently selected from single bond, O, S, NR 10 , C(=O), C(=O)O, C(=O)NR 10 , S(=O), S(=O) 2 , S(=O)NR 10 , S(=O) 2 NR 10 , NR 10 C(=O)NR 10 , C 3 -C 8 cycloalkylene, 3-8 membered heteroalkylene Cycloalkyl, C 6 -C 10 aryleneoxy and 5-10 membered heteroarylene; preferably, Y 1 , Y 2 and Y 3 are each independently selected from single bond, O, S, NR 10 , C (=O), C(=O)O, C(=O)NR 10 , S(=O), S(=O) 2 , S(=O)NR 10 , S(=O) 2 NR 10 and NR 10 C(=O)NR 10 ;
X 1选自O、C(R 8) 2和NR 8； X 1 is selected from O, C(R 8 ) 2 and NR 8 ;
X 2选自CR 8和N； X 2 is selected from CR 8 and N;
m和n各自独立地选自0、1、2、3、4和5；m and n are each independently selected from 0, 1, 2, 3, 4 and 5;
R 8和R 9各自独立地选自氢、卤素、氰基、羟基、氨基、C 1-C 6烷基、C 1-C 6杂烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、3-8元杂环烷基、C 3-C 8环烷氧基和3-8元杂环烷氧基，其中所述烷基、杂烷基、烯基、炔基、环烷基、杂环烷基、环烷氧基和杂环烷氧基各自任选地被至少1个R 10取代； R 8 and R 9 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3 -C 8 cycloalkoxy and 3-8 membered heterocycloalkoxy, wherein the alkyl, heteroalkane alkenyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy and heterocycloalkoxy are each optionally substituted with at least 1 R 10 ;
R 1至R 9中所述杂烷基、杂环烷基、杂环烷氧基和杂芳基以及Y 1至Y 3中所述亚杂环烷基和亚杂芳基中所含的杂原子或杂原子团分别独立地选自-C(＝O)N(R 10)-、-N(R 10)-、-N＝、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O) 2-和-N(R 10)C(＝O)N(R 10)-，且所述杂原子或杂原子团的数目分别独立地选自1、2和3； The heteroalkyl groups, heterocycloalkyl groups, heterocycloalkoxy groups, and heteroaryl groups described in R 1 to R 9 and the heterocyclic groups contained in the heterocycloalkylene groups and heteroarylene groups described in Y 1 to Y 3 The atoms or heteroatomic groups are each independently selected from -C(=O)N(R 10 )-, -N(R 10 )-, -N=, -O-, -S-, -C(=O)O- , -C(=O)-, -C(=S)-, -S(=O)-, -S(=O) 2 - and -N(R 10 )C(=O)N(R 10 ) -, and the number of said heteroatoms or heteroatoms is independently selected from 1, 2 and 3;
R 10选自氢、氯、氟、氰基、羟基、氨基、异丙基、环丙基、甲基、二氟甲基、三氟甲基、甲氧基、三氟甲氧基、乙氧基、2,2-二氟乙氧基、2,2,2-三氟乙氧基和苯基。 R 10 is selected from hydrogen, chlorine, fluorine, cyano, hydroxyl, amino, isopropyl, cyclopropyl, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy and phenyl.
进一步地，在所述式I化合物中，
Figure PCTCN2022078854-appb-000004
被
Figure PCTCN2022078854-appb-000005
代替，此时所述式I化合物如式I’所示。 Further, in the compound of formula I,
Figure PCTCN2022078854-appb-000004
quilt
Figure PCTCN2022078854-appb-000005
Instead, the compound of formula I is now represented by formula I'.
Figure PCTCN2022078854-appb-000006
Figure PCTCN2022078854-appb-000006
进一步地，在所述式I化合物中，当Y 1为单键且m不为0时，直接连接Y 1的碳原子上的R 3或R 4与R 2连接成环，此时所述式I化合物如式I”所示，其中B为3-6元杂环烷基(例如4元的吖丁啶基、5元的吡咯烷基、6元的吗啉基等)，优选4-5元杂环烷基，更优选4元杂环烷基，进一步优选吖丁啶基。 Further, in the compound of formula I, when Y 1 is a single bond and m is not 0, R 3 or R 4 on the carbon atom of Y 1 is directly connected to R 2 to form a ring, and at this time the formula The compound I is represented by the formula I", wherein B is a 3-6 membered heterocycloalkyl group (such as a 4-membered azetidine group, a 5-membered pyrrolidinyl group, a 6-membered morpholinyl group, etc.), preferably a 4-5 membered heterocycloalkyl group Cycloalkyl, more preferably 4-membered heterocycloalkyl, further preferably azetidinyl.
Figure PCTCN2022078854-appb-000007
Figure PCTCN2022078854-appb-000007
进一步地，在所述式I、式I’或式I”化合物中，A为6-8元杂芳基，优选6元杂芳基，更优选吡啶基。Further, in the compound of formula I, formula I' or formula I", A is a 6-8-membered heteroaryl group, preferably a 6-membered heteroaryl group, more preferably a pyridyl group.
进一步地，在所述式I、式I’或式I”化合物中，R 1选自C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3 卤代烷氧基和C 1-C 3卤代烷基，优选C 1-C 3氟代烷基，更优选三氟甲基(-CF 3)。 Further, in the compound of formula I, formula I' or formula I", R 1 is selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy and C 1 -C 3 haloalkyl, preferably C 1 -C 3 fluoroalkyl, more preferably trifluoromethyl (-CF 3 ).
进一步地，在所述式I化合物中，R 2为氢。 Further, in the compound of formula I, R 2 is hydrogen.
进一步地，在所述式I、式I’或式I”化合物中，每一个R 3、R 4、R 5和R 6各自独立地选自氢、C 1-C 3烷基、C 1-C 3杂烷基、C 1-C 3卤代烷基、C 1-C 3烷氧基和C 1-C 3卤代烷氧基；优选地，每一个R 3、R 4、R 5和R 6各自独立地选自氢、C 1-C 3烷基和C 1-C 3杂烷基；更优选地，每一个R 3、R 4、R 5和R 6各自独立地选自氢、甲基(-CH 3)和甲氧甲基(-CH 2OCH 3)。 Further, in the compound of formula I, formula I' or formula I", each of R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, C 1 -C 3 alkyl, C 1 - C 3 heteroalkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkoxy; preferably, each of R 3 , R 4 , R 5 and R 6 is each independently is selected from hydrogen, C1 - C3 alkyl and C1 - C3 heteroalkyl ; more preferably, each of R3 , R4, R5 and R6 is independently selected from hydrogen, methyl ( - CH3 ) and methoxymethyl ( -CH2OCH3 ) .
进一步地，在所述式I、式I’或式I”化合物中，R 7选自氢、卤素、氰基、羟基、氨基、C 1-C 6烷基、C 1-C 6卤代烷基和C 3-C 8环烷基，优选氢、卤素、氰基、羟基、氨基、C 1-C 3烷基、C 1-C 3卤代烷基和C 3-C 6环烷基，更优选氢、氟、氯、溴、氰基、羟基、氨基、甲基、乙基、丙基、异丙基、氟甲基、二氟甲基、三氟甲基、环丙基、环丁基和环戊基。 Further, in the compound of formula I, formula I' or formula I", R 7 is selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 3 -C 8 cycloalkyl, preferably hydrogen, halogen, cyano, hydroxyl, amino, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl and C 3 -C 6 cycloalkyl, more preferably hydrogen, Fluorine, chlorine, bromine, cyano, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl and cyclopentane base.
进一步地，在所述式I、式I’或式I”化合物中，R 8和R 9各自独立地选自氢和C 1-C 6烷基，优选氢和C 1-C 3烷基，更优选氢和甲基。 Further, in the compound of formula I, formula I' or formula I", R 8 and R 9 are each independently selected from hydrogen and C 1 -C 6 alkyl, preferably hydrogen and C 1 -C 3 alkyl, More preferred are hydrogen and methyl.
进一步地，在所述式I或式I’化合物中，Y 1、Y 2和Y 3各自独立地选自单键、O、S、C(＝O)、C(＝O)O、S(＝O)、S(＝O) 2、C 3-C 6亚环烷基和C 6-C 8亚芳氧基，优选单键、O、C(＝O)、亚环丁基和亚苯氧基，更优选单键、O和C(＝O)。 Further, in the compound of formula I or formula I', Y 1 , Y 2 and Y 3 are each independently selected from single bond, O, S, C(=O), C(=O)O, S( =O), S(=O) 2 , C 3 -C 6 cycloalkylene and C 6 -C 8 aryleneoxy, preferably single bonds, O, C(=O), cyclobutylene and phenylene Oxygen, more preferably single bond, O and C(=O).
进一步地，在所述式I”化合物中，Y 2和Y 3各自独立地选自O、S、C(＝O)、C(＝O)O、S(＝O)、S(＝O) 2、C 3-C 6亚环烷基和C 6-C 8亚芳氧基，优选O、C(＝O)、亚环丁基和亚苯氧基，更优选O和C(＝O)。 Further, in the compound of formula I", Y 2 and Y 3 are each independently selected from O, S, C(=O), C(=O)O, S(=O), S(=O) 2 , C 3 -C 6 cycloalkylene and C 6 -C 8 aryleneoxy, preferably O, C(=O), cyclobutylene and phenoxy, more preferably O and C(=O) .
进一步地，在所述式I、式I’或式I”化合物中，R 1至R 9中所述杂烷基、杂环烷基、杂环烷氧基和杂芳基以及Y 1至Y 3中所述亚杂环烷基和亚杂芳基中所含的杂原子或杂原子团分别独立地选自-N＝、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-和-S(＝O) 2-，优选-N＝、-O-、-C(＝O)O-和-C(＝O)-，且所述杂原子或杂原子团的数目分别独立地选自1、2和3，优选1和2。 Further, in the compound of formula I, formula I' or formula I", the heteroalkyl, heterocycloalkyl, heterocycloalkoxy and heteroaryl in R 1 to R 9 and Y 1 to Y The heteroatoms or heteroatomic groups contained in the heterocycloalkylene and heteroarylene described in 3 are independently selected from -N=, -O-, -S-, -C(=O)O-, - C(=O)-, -C(=S)-, -S(=O)- and -S(=O) 2- , preferably -N=, -O-, -C(=O)O- and -C(=O)-, and the number of said heteroatoms or heteroatomic groups is independently selected from 1, 2 and 3, preferably 1 and 2, respectively.
进一步地，在所述式I或式I’化合物中，
Figure PCTCN2022078854-appb-000008
片段选自如下片段之一： Further, in the compound of formula I or formula I',
Figure PCTCN2022078854-appb-000008
The fragment is selected from one of the following fragments:
Figure PCTCN2022078854-appb-000009
Figure PCTCN2022078854-appb-000009
Figure PCTCN2022078854-appb-000010
优选如下片段之一：
Figure PCTCN2022078854-appb-000010
One of the following fragments is preferred:
Figure PCTCN2022078854-appb-000011
Figure PCTCN2022078854-appb-000012
更优选如下片段之一：
Figure PCTCN2022078854-appb-000011
Figure PCTCN2022078854-appb-000012
More preferably one of the following fragments:
Figure PCTCN2022078854-appb-000013
Figure PCTCN2022078854-appb-000013
进一步地，在所述式I”化合物中，
Figure PCTCN2022078854-appb-000014
片段选自如下片段之一： Further, in the compound of formula I ",
Figure PCTCN2022078854-appb-000014
The fragment is selected from one of the following fragments:
Figure PCTCN2022078854-appb-000015
Figure PCTCN2022078854-appb-000016
优选如下片段之一：
Figure PCTCN2022078854-appb-000015
Figure PCTCN2022078854-appb-000016
One of the following fragments is preferred:
Figure PCTCN2022078854-appb-000017
更优选如下片段：
Figure PCTCN2022078854-appb-000017
More preferred are the following fragments:
Figure PCTCN2022078854-appb-000018
Figure PCTCN2022078854-appb-000018
进一步地，在所述式I、式I’或式I”化合物中，
Figure PCTCN2022078854-appb-000019
片段选自如下片段之一： Further, in the compound of formula I, formula I' or formula I",
Figure PCTCN2022078854-appb-000019
The fragment is selected from one of the following fragments:
Figure PCTCN2022078854-appb-000020
Figure PCTCN2022078854-appb-000020
Figure PCTCN2022078854-appb-000021
优选如下片段之一：
Figure PCTCN2022078854-appb-000021
One of the following fragments is preferred:
Figure PCTCN2022078854-appb-000022
Figure PCTCN2022078854-appb-000022
第二方面，本发明提供了下列具体化合物：In a second aspect, the present invention provides the following specific compounds:
Figure PCTCN2022078854-appb-000023
Figure PCTCN2022078854-appb-000023
Figure PCTCN2022078854-appb-000024
Figure PCTCN2022078854-appb-000024
Figure PCTCN2022078854-appb-000025
Figure PCTCN2022078854-appb-000025
第三方面，本发明提供了一种药物组合物，其包含如式I、I’或I”所示的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药中的一种或多种。In a third aspect, the present invention provides a pharmaceutical composition comprising a compound represented by formula I, I' or I" or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or pharmaceutically acceptable salt thereof. One or more of a variant, metabolite or prodrug.
优选地，所述药物组合物中还包含至少一种药学上可接受的辅料。Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable adjuvant.
第四方面，本发明提供了如式I、I’或I”所示的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药或者包含其的药物组合物在制备用于预防和/或治疗由PARP7过度表达引起的疾病或病症的药物(例如PARP7抑制剂) 中的用途。In the fourth aspect, the present invention provides a compound represented by formula I, I' or I" or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or Use of a prodrug or a pharmaceutical composition comprising the same in the manufacture of a medicament (eg, a PARP7 inhibitor) for preventing and/or treating a disease or disorder caused by PARP7 overexpression.
第五方面，本发明提供了如式I、I’或I”所示的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药或者包含其的药物组合物，其用于预防和/或治疗由PARP7过度表达引起的疾病或病症。In a fifth aspect, the present invention provides a compound represented by formula I, I' or I" or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or A prodrug or a pharmaceutical composition comprising the same for the prevention and/or treatment of a disease or disorder caused by overexpression of PARP7.
第六方面，本发明提供了一种用于预防和/或治疗由PARP7过度表达引起的疾病或病症的方法，其包括将预防和/或治疗有效量的如式I、I’或I”所示的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药或者包含其的药物组合物施用于对其有需要的个体。In a sixth aspect, the present invention provides a method for preventing and/or treating a disease or condition caused by overexpression of PARP7, comprising adding a preventive and/or therapeutically effective amount of a compound of formula I, I' or I" The compound shown, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition comprising the same, is administered to an individual in need thereof.
优选地，所述由PARP7过度表达引起的疾病或病症为癌症。Preferably, the disease or disorder caused by overexpression of PARP7 is cancer.
更优选地，所述癌症为血液肿瘤、胰腺癌、结直肠癌和肺癌中的一种或多种。More preferably, the cancer is one or more of hematological tumor, pancreatic cancer, colorectal cancer and lung cancer.
发明的效果effect of invention
本发明提供了一系列结构新颖的三并环化合物，经相关的酶和细胞活性试验证明，本发明的化合物不但具有良好的PARP7酶抑制活性，而且具有优良的细胞增殖抑制活性，在体外实验中，对细胞增殖的IC 50值较为理想，部分化合物甚至可以达到nM级别，能够在多种肿瘤中获得良好的应用。另外，本发明的化合物还显示出良好的体内药效，适于制备成PARP7抑制剂，用于预防和/或治疗与PARP7激活相关的疾病或病症，例如癌症(包括但不限于血液肿瘤、胰腺癌、消化道肿瘤、结直肠癌和肺癌)。 The present invention provides a series of tricyclic compounds with novel structures. It is proved by relevant enzyme and cell activity tests that the compounds of the present invention not only have good PARP7 enzyme inhibitory activity, but also have excellent cell proliferation inhibitory activity. In vitro experiments , the IC 50 value for cell proliferation is ideal, and some compounds can even reach the nM level, which can be well used in a variety of tumors. In addition, the compounds of the present invention also show good in vivo efficacy and are suitable for being prepared as PARP7 inhibitors for the prevention and/or treatment of diseases or conditions related to PARP7 activation, such as cancer (including but not limited to hematological tumors, pancreatic cancer, gastrointestinal tumors, colorectal cancer, and lung cancer).
具体实施方式Detailed ways
一般术语和定义General terms and definitions
除非有相反陈述，否则在本发明中所使用的术语具有下述含义。Unless stated to the contrary, terms used in the present invention have the following meanings.
“烷基”是指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团，例如可以是1至18个碳原子、1至12个碳原子、1至8个碳原子、1至6个碳原子或1至4个碳原子的直链和支链基团。在本发明中，“烷基”可以是一价、二价或三价基团。非限制性实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基及其各种支链异构体等。非限制性实例还包括但不限于亚甲基、次甲基、亚乙基、次乙基、亚丙基、次丙基、亚丁基、次丁基及其各种支链异构体。另外，在本发明中，“烷基”可以是任选取代的或未取代的。"Alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms, for example, may be 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms carbon atoms, straight and branched chain groups of 1 to 6 carbon atoms or 1 to 4 carbon atoms. In the present invention, "alkyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl and various branched chain isomers, etc. Non-limiting examples also include, but are not limited to, methylene, methine, ethylene, ethylene, propylene, propylene, butylene, butylene, and various branched chain isomers thereof. In addition, in the present invention, "alkyl" may be optionally substituted or unsubstituted.
“烷氧基”是指“-O-烷基”基团，其中“烷基”的定义如上所述。另外，在本发明中，“烷氧基”可以是任选取代的或未取代的。"Alkoxy" refers to a "-O-alkyl" group, wherein "alkyl" is as defined above. In addition, in the present invention, "alkoxy" may be optionally substituted or unsubstituted.
“烯基”是指不饱和的脂族烃基团，包括2至20个碳原子以及至少1个碳碳双键的直链和支链基团，例如可以是1至18个碳原子、1至12个碳原子、1至8个碳原子、1至6个碳原子或1至4个碳原子的直链和支链基团。在本发明中，“烯基”可以是一价、二价或三价基团。非限制性实例包括但不限于乙烯基(-CH＝CH 2)、丙烯-1-基(-CH＝CH-CH 3)、丙烯-2-基(-C(CH 3)＝CH 2)、丁烯-1-基(-CH＝CH-CH 2-CH 3)、丁烯-2-基(-C(C 2H 5)＝CH 2)、 1-甲基丙烯-1-基(-C(CH 3)＝CH-CH 3)及其各种支链异构体等。非限制性实例还包括但不限于1,1-亚乙烯基(＝C＝CH 2)、1,2-亚乙烯基(-CH＝CH-)、1,1-亚丙烯基(＝C＝CH-CH 3)、1,2-亚丙烯基(-CH＝C(CH 3)-)、1,3-亚丙烯基(-CH＝CH-CH 2-)及其各种支链异构体。另外，在本发明中，“烯基”可以是任选取代的或未取代的。 "Alkenyl" refers to unsaturated aliphatic hydrocarbon groups, straight and branched chain groups comprising 2 to 20 carbon atoms and at least 1 carbon-carbon double bond, for example, may be 1 to 18 carbon atoms, 1 to Straight and branched chain groups of 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In the present invention, "alkenyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, vinyl (-CH=CH 2 ), propen-1-yl (-CH=CH-CH 3 ), propen-2-yl (-C(CH 3 )=CH 2 ), Buten-1-yl (-CH=CH-CH 2 -CH 3 ), buten-2-yl (-C(C 2 H 5 )=CH 2 ), 1-methylpropen-1-yl (- C(CH 3 )=CH-CH 3 ) and various branched chain isomers thereof. Non-limiting examples also include, but are not limited to, 1,1-vinylene (=C=CH 2 ), 1,2-vinylene (-CH=CH-), 1,1-propenylene (=C= CH-CH 3 ), 1,2-propenylene (-CH=C(CH 3 )-), 1,3-propenylene (-CH=CH-CH 2 -) and various branched isomers thereof body. In addition, in the present invention, "alkenyl" may be optionally substituted or unsubstituted.
“炔基”是指不饱和的脂族烃基团，包括2至20个碳原子以及至少1个碳碳叁键的直链和支链基团，例如可以是1至18个碳原子、1至12个碳原子、1至8个碳原子、1至6个碳原子或1至4个碳原子的直链和支链基团。在本发明中，“炔基”可以是一价、二价或三价基团。非限制性实例包括但不限于乙炔基(-C≡CH)、丙炔基(-C≡C-CH 3)、丁炔基
Figure PCTCN2022078854-appb-000026
戊炔基
Figure PCTCN2022078854-appb-000027
及其各种支链异构体等。非限制性实例还包括但不限于亚乙炔基(-C≡C-)、亚丙炔基
Figure PCTCN2022078854-appb-000028
亚丁炔基
Figure PCTCN2022078854-appb-000029
及其各种支链异构体。另外，在本发明中，“炔基”可以是任选取代的或未取代的。 "Alkynyl" refers to unsaturated aliphatic hydrocarbon groups, straight and branched chain groups comprising 2 to 20 carbon atoms and at least 1 carbon-carbon triple bond, for example, may be 1 to 18 carbon atoms, 1 to Straight and branched chain groups of 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In the present invention, "alkynyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡C- CH3 ), butynyl
Figure PCTCN2022078854-appb-000026
pentynyl
Figure PCTCN2022078854-appb-000027
and various branched chain isomers. Non-limiting examples also include, but are not limited to, ethynylene (-C≡C-), propynylene
Figure PCTCN2022078854-appb-000028
butynylene
Figure PCTCN2022078854-appb-000029
and its various branched-chain isomers. In addition, in the present invention, "alkynyl" may be optionally substituted or unsubstituted.
“杂烷基”(或“烷杂基”)是指饱和的脂族烃基团，包括2至20个原子的直链和支链基团，例如可以是2至18个原子、2至12个原子、2至8个原子、2至6个原子或2至4个原子的直链和支链基团，其中一个或多个原子为选自氮、氧或S(O) m(其中m为0、1或2)的杂原子，其余为碳。在本发明中，“杂烷基”可以是一价、二价或三价基团。非限制性实例包括但不限于甲氧甲基(2-氧杂丙基)、甲硫甲基(2-硫杂丙基)、甲氨甲基(2-氮杂丙基)及其各种支链异构体等。另外，在本发明中，“杂烷基”可以是任选取代的或未取代的。 "Heteroalkyl" (or "alkhetero") refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 2 to 20 atoms, for example, may be 2 to 18 atoms, 2 to 12 atoms atoms, 2 to 8 atoms, 2 to 6 atoms, or 2 to 4 atoms of straight and branched chain groups, wherein one or more atoms are selected from nitrogen, oxygen or S(O) m (where m is 0, 1 or 2) and the rest are carbon. In the present invention, "heteroalkyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, methoxymethyl (2-oxapropyl), methylthiomethyl (2-thiapropyl), methylaminomethyl (2-azapropyl), and various Branched chain isomers, etc. In addition, in the present invention, "heteroalkyl" may be optionally substituted or unsubstituted.
“环烷基”是指饱和或部分不饱和的、单环或多环的脂族烃基团，包括3至12个环原子，例如可以是3至12个、3至10个或3至6个环原子(即3至6元环)。单环环烷基的非限制性实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。另外，在本发明中，“环烷基”可以是任选取代的或未取代的。“亚环烷基”是指“环烷基”失去一个氢原子后形成的二价基团。单环亚环烷基的非限制性实例包括但不限于亚环丙基、亚环丁基、亚环戊基、亚环戊烯基、亚环己基、亚环己烯基、亚环己二烯基、亚环庚基、亚环庚三烯基、亚环辛基等。另外，在本发明中，“亚环烷基”可以是任选取代的或未取代的。"Cycloalkyl" means a saturated or partially unsaturated, monocyclic or polycyclic, aliphatic hydrocarbon group comprising 3 to 12 ring atoms, eg, 3 to 12, 3 to 10, or 3 to 6 Ring atoms (ie, 3 to 6 membered rings). Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclopentyl Heptatrienyl, cyclooctyl, etc. In addition, in the present invention, "cycloalkyl" may be optionally substituted or unsubstituted. "Cycloalkylene" refers to a divalent group formed by the loss of a hydrogen atom from a "cycloalkyl". Non-limiting examples of monocyclic cycloalkylenes include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cyclohexanediol Alkenyl, cycloheptylene, cycloheptatrienylene, cyclooctylene, etc. In addition, in the present invention, "cycloalkylene" may be optionally substituted or unsubstituted.
“杂环烷基”(或“环杂烷基”)是指饱和或部分不饱和的、单环或多环的脂族烃基团，包括3至20个环原子，例如可以是3至16个、3至12个、3至10个或3至6个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m为0、1或2)的杂原子，其余环原子为碳；优选包括3至12个环原子，其中1至4个环原子是杂原子；更优选包括3至10个环原子，最优选包括5或6个环原子，其中1至4个，优选1至3个，更优选1至2个环原子是杂原子。单环杂环烷基的非限制性实例包括但不限于吖丁啶基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环烷基的非限制性实例包括但不限于并环(稠环)、螺环或桥环的杂环烷基。另外，在本发明中，“杂环烷基”可以是任选取代的或未取代的。“亚杂环烷基”是指“杂环烷基”失去一个氢原子后形成的二价基团。单环亚杂环烷基的非限制性实例包括但不限于亚吖丁啶基、亚吡咯烷基、亚哌 啶基、亚哌嗪基、亚吗啉基、亚硫代吗啉基、亚高哌嗪基等。多环亚杂环烷基的非限制性实例包括但不限于并环(稠环)、螺环或桥环的亚杂环烷基。另外，在本发明中，“亚杂环烷基”可以是任选取代的或未取代的。 "Heterocycloalkyl" (or "cycloheteroalkyl") refers to a saturated or partially unsaturated, monocyclic or polycyclic aliphatic hydrocarbon group comprising 3 to 20 ring atoms, for example, may be 3 to 16 , 3 to 12, 3 to 10 or 3 to 6 ring atoms, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or S(O) m (wherein m is 0, 1 or 2) , the remaining ring atoms are carbon; preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 10 ring atoms, most preferably 5 or 6 ring atoms, of which 1 to 4, preferably 1 to 3, more preferably 1 to 2 ring atoms are heteroatoms. Non-limiting examples of monocyclic heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Non-limiting examples of polycyclic heterocycloalkyls include, but are not limited to, heterocycloalkyl (fused ring), spirocyclic, or bridged. In addition, in the present invention, "heterocycloalkyl" may be optionally substituted or unsubstituted. "Heterocycloalkylene" refers to a divalent group formed by the loss of a hydrogen atom from a "heterocycloalkyl". Non-limiting examples of monocyclic heterocycloalkylenes include, but are not limited to, azetidine, pyrrolidylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, homopiperidine Azinyl etc. Non-limiting examples of polycyclic heterocycloalkylenes include, but are not limited to, cyclo (fused), spiro, or bridged heterocycloalkylenes. In addition, in the present invention, "heterocycloalkylene" may be optionally substituted or unsubstituted.
“卤素”是指氟、氯、溴和碘，优选氟、氯和溴。"Halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
“卤代烷基”或“卤代烷氧基”是指烷基或烷氧基基团被一个或多个相同或不同的卤素原子取代，优选的卤代烷基或卤代烷氧基的实例包括但不限于三氟甲基、三氟乙基、三氟甲氧基等。“氰基”是指“-CN”基团。"Haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more of the same or different halogen atoms, preferred examples of haloalkyl or haloalkoxy include, but are not limited to, trifluoromethane group, trifluoroethyl, trifluoromethoxy, etc. "Cyano" refers to the "-CN" group.
“羟基”是指“-OH”基团。"Hydroxy" refers to the "-OH" group.
“氨基”是指“-NH 2”基团。另外，在本发明中，“氨基”可以是任选取代的或未取代的。 "Amino" refers to the " -NH2 " group. In addition, in the present invention, "amino" may be optionally substituted or unsubstituted.
“氨基甲酰基”是指“-(C＝O)-NH 2”基团。另外，在本发明中，“氨基甲酰基”可以是任选取代的或未取代的。 "Carbamoyl" refers to a "-(C=O) -NH2 " group. In addition, in the present invention, "carbamoyl" may be optionally substituted or unsubstituted.
“硝基”是指“-NO 2”基团。 "Nitro" refers to the " -NO2 " group.
“芳基”是指含有6-14个，优选6-10个，更优选6-7个环原子的碳环体系。环原子的单环、双环和三环的碳环体系、其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环，且有一个或多个连接点与分子的其余部分相连。实例包括但不限于苯基、萘基、蒽基等。另外，在本发明中，“芳基”可以是任选取代的或未取代的。“亚芳基”是指“芳基”失去一个氢原子后形成的二价基团。实例包括但不限于亚苯基、亚萘基、亚蒽基等。另外，在本发明中，“亚芳基”可以是任选取代的或未取代的。"Aryl" refers to a carbocyclic ring system containing 6-14, preferably 6-10, more preferably 6-7 ring atoms. Monocyclic, bicyclic and tricyclic carbocyclic ring systems of ring atoms, wherein at least one of the ring systems is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more points of attachment to The rest of the molecule is connected. Examples include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like. In addition, in the present invention, "aryl" may be optionally substituted or unsubstituted. "Arylene" refers to a divalent group formed by the loss of a hydrogen atom from an "aryl" group. Examples include, but are not limited to, phenylene, naphthylene, anthracene, and the like. In addition, in the present invention, the "arylene group" may be optionally substituted or unsubstituted.
“芳氧基”是指“-O-芳基”基团，其中“芳基”的定义如上所述。实例包括但不限于苯氧基、萘氧基、蒽氧基等。另外，在本发明中，“芳氧基”可以是任选取代的或未取代的。“亚芳氧基”是指“芳氧基”的芳基部分失去一个氢原子后形成的二价基团。实例包括但不限于亚苯氧基、亚萘氧基、亚蒽氧基等。另外，在本发明中，“亚芳氧基”可以是任选取代的或未取代的。"Aryloxy" refers to a "-O-aryl" group, wherein "aryl" is as defined above. Examples include, but are not limited to, phenoxy, naphthyloxy, anthraceneoxy, and the like. In addition, in the present invention, "aryloxy" may be optionally substituted or unsubstituted. "Aryleneoxy" refers to a divalent group formed by the loss of a hydrogen atom from the aryl moiety of an "aryloxy". Examples include, but are not limited to, phenoxy, naphthyleneoxy, anthracyleneoxy, and the like. In addition, in the present invention, "aryleneoxy" may be optionally substituted or unsubstituted.
“杂芳基”(或“芳杂基”)是指含有5-14个，优选5-10个环原子的单环、双环和三环体系，其中，至少一个环体系是芳香族的，且至少一个环体系包含一个或多个选自氮、氧或S(O) m(其中m为0、1或2)的杂原子，其中每一个环体系包含5-7个原子组成的环，且有一个或多个连接点与分子的其余部分相连。实例包括但不限于呋喃基、咪唑基、吡啶基、嘧啶基、噻唑基、嘌呤基、喹啉基等。“亚杂芳基”是指“杂芳基”失去一个氢原子后形成的含有5-14个，优选5-10个环原子的二价单环、双环和三环体系。实例包括但不限于亚呋喃基、亚咪唑基、亚吡啶基、亚嘧啶基、亚噻唑基、亚嘌呤基、亚喹啉基等。 "Heteroaryl" (or "heteroaryl") refers to monocyclic, bicyclic, and tricyclic ring systems containing 5-14, preferably 5-10, ring atoms, wherein at least one ring system is aromatic, and at least one ring system comprises one or more heteroatoms selected from nitrogen, oxygen or S(O) m (where m is 0, 1 or 2), wherein each ring system comprises a ring of 5-7 atoms, and There is one or more junction points to the rest of the molecule. Examples include, but are not limited to, furanyl, imidazolyl, pyridyl, pyrimidinyl, thiazolyl, purinyl, quinolinyl, and the like. "Heteroarylene" refers to bivalent monocyclic, bicyclic and tricyclic ring systems containing 5 to 14, preferably 5 to 10, ring atoms formed by the loss of a hydrogen atom from a "heteroaryl" group. Examples include, but are not limited to, furanylene, imidazolylide, pyridylene, pyrimidinylene, thiazolylylene, purinylene, quinolinylene, and the like.
“各自独立地”意味着随后所描述的事件或动作的主体具有相对独立性，其中一个(或一些)主体所经历的事件或发出的动作不会影响另一个(或另一些)主体所经历的事件或发出的动作。同时，需要说明的是，上述主体既可以是属于不同概念下或范畴内的个体，也可以是属于同一概念下或范畴内的不同个体。例如，“(每一个)A和B各自独立地为氢或甲基”意味着不但当只有一组A和B存在时，二者可以独立地为氢或甲基，而且当存在两组以上A和B时，不同组中的多个A(和/或不同组中的多个B)也可以独立地为氢或甲基。"Independently" means that the subjects of the subsequently described event or action are relatively independent, wherein the event or action experienced by one (or some) subjects does not affect what the other (or other) subjects experience. An event or an emitted action. At the same time, it should be noted that the above-mentioned subjects may be individuals under different concepts or categories, or may be different individuals under the same concept or category. For example, "(each) A and B are each independently hydrogen or methyl" means that not only when only one set of A and B is present, both can be independently hydrogen or methyl, but also when more than two sets of A are present and B, multiple A's in different groups (and/or multiple B's in different groups) can also independently be hydrogen or methyl.
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的情形。例如，“任选被烷基取代的杂环基团”意味着烷基可以但并非必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance does or does not occur. For example, "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may, but need not be, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
“取代的”是指基团中的一个或多个氢原子，优选最多5个，更优选1至3个氢原子彼此独立地被相应数目的取代基取代。"Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents.
“药学上可接受的盐”是指由本发明中的化合物与相对无毒的酸或碱制备得到的盐。当本发明中的化合物含有相对偏酸性的官能团(例如羧基或磺酸基)时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与其游离形式接触的方式获得碱加成盐。药学上可接受的碱加成盐的非限制性实例包括但不限于钠盐、钾盐、铵盐、钙盐、镁盐、有机胺盐或类似的盐。当本发明中的化合物含有相对偏碱性的官能团(例如氨基或胍基)时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与其游离形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的非限制性实例包括但不限于无机酸盐(例如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸盐、碳酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、亚磷酸盐、硫酸盐、硫酸氢盐等)、有机酸盐(例如乙酸盐、丙酸盐、异丁酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、马来酸盐、富马酸盐、柠檬酸盐、酒石酸盐、乳酸盐、扁桃酸盐、苯甲酸盐、邻苯二甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、葡糖醛酸等)以及氨基酸盐(例如精氨酸盐等)。药学上可接受的盐的具体形式还可参见Berge et al.,“Pharmaceutical Salts”,Journal of Pharmaceutical Science,1977,66:1-19)。本发明的某些特定化合物含有碱性和酸性的官能团，从而可以被转换成任一碱加成盐或酸加成盐。优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。根据本发明的实施例，优选如式I所示的化合物的药学上可接受的盐为酸加成盐，优选盐酸盐、氢溴酸盐、磷酸盐或硫酸盐，更优选盐酸盐。"Pharmaceutically acceptable salts" refers to salts prepared from compounds of the present invention with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups (such as carboxyl or sulfonic acid groups), base addition salts can be obtained by contacting their free forms with a sufficient amount of base in neat solution or in a suitable inert solvent . Non-limiting examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, ammonium, calcium, magnesium, organic amine, or similar salts. When the compounds of the present invention contain relatively basic functional groups such as amino or guanidino groups, acid addition salts can be obtained by contacting their free forms with a sufficient amount of acid in neat solution or in a suitable inert solvent . Non-limiting examples of pharmaceutically acceptable acid addition salts include, but are not limited to, inorganic acid salts (eg, hydrochloride, hydrobromide, hydroiodide, nitrate, carbonate, bicarbonate, phosphate) , monohydrogen phosphate, dihydrogen phosphate, phosphite, sulfate, hydrogen sulfate, etc.), organic acid salts (such as acetate, propionate, isobutyrate, malonate, succinate , Suberate, Maleate, Fumarate, Citrate, Tartrate, Lactate, Mandelate, Benzoate, Phthalate, Mesylate, Benzene Sulfonate acid salts, p-toluenesulfonic acid salts, glucuronic acid, etc.) and amino acid salts (eg, arginine salts, etc.). See also Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66: 1-19) for specific forms of pharmaceutically acceptable salts. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts. Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound. The parent form of a compound differs from its various salt forms by certain physical properties, such as solubility in polar solvents. According to embodiments of the present invention, preferably the pharmaceutically acceptable salt of the compound represented by formula I is an acid addition salt, preferably hydrochloride, hydrobromide, phosphate or sulfate, more preferably hydrochloride.
“药物组合物”是指可供药用的组合物，其包含一种或多种如式I所示的化合物或其药学上可接受的形式(例如盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物、前药等)，以及其他组分(例如药学上可接受的辅料)。"Pharmaceutical composition" refers to a pharmaceutically acceptable composition comprising one or more compounds of Formula I or a pharmaceutically acceptable form thereof (eg, a salt, hydrate, solvate, stereoisomer isomers, tautomers, metabolites, prodrugs, etc.), and other components (eg, pharmaceutically acceptable excipients).
在本发明中，“药学上可接受的辅料”是指在药物生产领域中广泛采用的辅助物料。使用辅料的主要目的在于提供一种使用安全、性质稳定和/或具有特定功能性的药物组合物，还在于提供一种方法，以便在为受试者施用药物之后，活性成分能够以所期望的速率溶出，或者促进活性成分在接受给药的受试者体内得到有效吸收。药学上可接受的辅料可以是具有惰性的填充剂，也可以是为药用组合物提供某种功能(例如稳定组合物的整体pH值或防止组合物中活性成分的降解)的功效成分。药学上可接受的辅料的非限制性实例包括但不限于粘合剂、助悬剂、乳化剂、稀释剂(或填充剂)、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂、甜味剂等。In the present invention, "pharmaceutically acceptable auxiliary materials" refer to auxiliary materials widely used in the field of pharmaceutical production. The main purpose of using excipients is to provide a pharmaceutical composition that is safe to use, stable in properties and/or has specific functionality, and also to provide a method so that after the drug is administered to a subject, the active ingredient can be The rate of dissolution, or the promotion of effective absorption of the active ingredient in the subject to which it is administered. Pharmaceutically acceptable excipients can be inert fillers or functional ingredients that provide a certain function for the pharmaceutical composition (eg, stabilizing the overall pH of the composition or preventing the degradation of active ingredients in the composition). Non-limiting examples of pharmaceutically acceptable adjuvants include, but are not limited to, binders, suspending agents, emulsifiers, diluents (or fillers), granulating agents, sizing agents, disintegrating agents, lubricants, anti-adhering agents , glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors, sweeteners, etc.
本发明中的药物组合物可以使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋和/或冻干工艺。The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, attenuating, encapsulating, entrapping and/or lyophilizing processes.
在本发明中，使用药物组合物的目的在于促进针对生物体的给药，有利于活性成分的吸收，进而发挥生物活性。本发明的药物组合物可以通过任何形式给药，包括注射(动脉内、静脉内、肌肉内、腹膜内、皮下)、粘膜、口服(口服固体制剂、口服液体制剂)、直肠、吸入、植入、局部(例如眼部)给药等。口服固体制剂的非限制性实例包括但不限于散剂、胶囊剂、锭剂、颗粒剂、片剂等。口服或粘膜给药的液体制剂的非限制性实例包括但不限于混悬剂、酊剂、酏剂、溶液剂等。局部给药制剂的非限制性实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药制剂的非限制性实例包括但不限于注射用溶液剂、注射用干粉剂、注射用悬浮液、注射用乳剂等。本发明的药物组合物还可以制成控制释放或延迟释放剂型(例如脂质体或微球)。In the present invention, the purpose of using the pharmaceutical composition is to promote the administration to the living body, facilitate the absorption of the active ingredient, and then exert biological activity. The pharmaceutical compositions of the present invention can be administered in any form, including injection (intraarterial, intravenous, intramuscular, intraperitoneal, subcutaneous), mucosal, oral (oral solid, oral liquid), rectal, inhalation, implant , topical (eg ocular) administration, etc. Non-limiting examples of oral solid formulations include, but are not limited to, powders, capsules, lozenges, granules, tablets, and the like. Non-limiting examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, tinctures, elixirs, solutions, and the like. Non-limiting examples of formulations for topical administration include, but are not limited to, creams, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations. Non-limiting examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry powders for injection, suspensions for injection, emulsions for injection, and the like. The pharmaceutical compositions of the present invention can also be formulated in controlled release or delayed release dosage forms (eg, liposomes or microspheres).
优选地，本发明中的化合物或包含其的药物组合物以口服或静脉内给药的方式施用于对其有需要的个体。取决于给药对象的具体情况，也可以应用甚至优选其它施用途经。例如，对于健忘或对口服药物易发怒的患者，经皮施用将是非常重要的给药方式。在本发明中，施用途经能够以任何适用的方式进行变化或调整，以满足药物的性质、患者和医务人员的便利以及其它相关因素的需求。Preferably, a compound of the present invention or a pharmaceutical composition comprising the same is administered orally or intravenously to an individual in need thereof. Depending on the particular circumstances of the subject being administered, other modes of administration may also be employed or even preferred. For example, for patients who are forgetful or irritable with oral medications, transdermal administration would be a very important mode of administration. In the present invention, the administration channel can be varied or adjusted in any suitable manner to meet the needs of the nature of the drug, the convenience of the patient and medical staff, and other relevant factors.
本发明的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药或者包含其的药物组合物具有优良的PARP7酶抑制活性及细胞增殖抑制活性，并且显示出良好的体内药效，能够作为PARP7抑制剂，用于预防和/或治疗由PARP7过度表达引起的疾病或病症，具有良好的临床应用和医药用途。优选地，由PARP7过度表达引起的疾病或病症非限制性实例为癌症，包括但不限于血液肿瘤、胰腺癌、结直肠癌和肺癌。The compounds of the present invention or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, metabolites or prodrugs or pharmaceutical compositions comprising them have excellent PARP7 enzyme inhibitory activity and It has cell proliferation inhibitory activity and shows good in vivo efficacy, and can be used as a PARP7 inhibitor for preventing and/or treating diseases or conditions caused by overexpression of PARP7, and has good clinical and medical applications. Preferably, a non-limiting example of a disease or disorder caused by overexpression of PARP7 is cancer, including but not limited to hematological tumors, pancreatic cancer, colorectal cancer, and lung cancer.
以下将结合具体实施例来阐述本发明的技术方案，下列实施例的提供旨在进一步说明本发明，而非用于限制本发明的范围。对本领域技术人员而言，在不脱离本发明的精神和范围的情况下，针对本发明的具体实施方式进行各种变化和改进将是显而易见的。The technical solutions of the present invention will be described below with reference to specific embodiments. The following embodiments are provided to further illustrate the present invention, but not to limit the scope of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present invention without departing from the spirit and scope of the invention.
本发明的化合物的制备可以通过本领域技术人员所熟知的合成方法来实现，包括但不限于下面列举的具体实施方式、其与其他化学合成方法相结合而形成的实施方式以及本领域技术人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。本发明中所使用的已知的起始原料可以提供本领域已知的方法来合成，或者通过常规的商业手段来购买(例如购自韶远化学科技、北京偶合科技等公司)。如无特殊说明，反应均在氩气氛或氮气氛下进行。氢化反应通常抽真空，充入氢气，反复操作3次。反应的温度为室温，温度范围是20℃-30℃。反应进程的监测可以通过本领域技术人员所熟知的合成方法来实现，包括但不限于薄层色谱法(TLC)。薄层层析硅胶板使用青岛海洋GF254硅胶板，展开剂体系包括但不限于A：二氯甲烷和甲醇体系；B：石油醚和乙酸乙酯体系，溶剂的体积比可以根据化合物的极性进行调节。The preparation of the compounds of the present invention can be achieved by synthetic methods well known to those skilled in the art, including but not limited to the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art. Well-known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention. The known starting materials used in the present invention can be synthesized by methods known in the art, or purchased by conventional commercial means (for example, purchased from Shaoyuan Chemical Technology, Beijing Coupling Technology, etc.). Unless otherwise specified, the reactions were carried out in an argon atmosphere or a nitrogen atmosphere. The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times. The reaction temperature is room temperature, and the temperature range is 20°C-30°C. Monitoring the progress of the reaction can be accomplished by synthetic methods well known to those skilled in the art, including but not limited to thin layer chromatography (TLC). The thin layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate. The developing solvent system includes but is not limited to A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvent can be determined according to the polarity of the compound. adjust.
本发明的化合物的分离纯化可以通过本领域技术人员所熟知的合成方法来实现，包括但不限于柱色谱法(CC)、高效液相色谱法(HPLC)、超高效液相色谱法(UPLC)等。柱色谱法一般使用青岛海洋200-300目硅胶作为载体，洗脱剂体系包括但不限于A： 二氯甲烷和甲醇体系；B：石油醚和乙酸乙酯体系，溶剂的体积比可以根据化合物的极性进行调节，也可以加入少量的酸性或碱性防拖尾试剂进行调节。HPLC图谱采用Agilent 1200 DAD HPLC色谱仪(色谱柱：Sunfire C18,150×4.6mm,5μm)或Waters 2695-2996 HPLC色谱仪(色谱柱：Gimini C18,150×4.6mm,5μm)测定。The separation and purification of the compounds of the present invention can be achieved by synthetic methods well known to those skilled in the art, including but not limited to column chromatography (CC), high performance liquid chromatography (HPLC), ultra-high performance liquid chromatography (UPLC) Wait. Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the carrier. The eluent system includes but is not limited to A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvent can be based on the compound. The polarity can be adjusted, and a small amount of acidic or basic anti-tailing reagents can also be added for adjustment. The HPLC chromatogram was determined using an Agilent 1200 DAD HPLC chromatograph (chromatographic column: Sunfire C18, 150×4.6mm, 5μm) or a Waters 2695-2996 HPLC chromatograph (chromatographic column: Gimini C18, 150×4.6mm, 5μm).
本发明的化合物的结构鉴定可以通过本领域技术人员所熟知的方法来实现，包括但不限于核磁共振(NMR)、质谱(MS)等。NMR图谱采用Bruker AVANCE-400或Varian Oxford-300核磁仪测定，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDC1 3)或氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)，化学位移以10 -6(ppm)计。MS图谱采用Agilent SQD(ESI)质谱仪(型号：6110)或Shimadzu SQD(ESI)质谱仪(型号：2020)测定。 Structural identification of the compounds of the present invention can be accomplished by methods well known to those skilled in the art, including but not limited to nuclear magnetic resonance (NMR), mass spectrometry (MS), and the like. The NMR spectrum was determined by Bruker AVANCE-400 or Varian Oxford-300 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ) or deuterated methanol (CD 3 OD), The internal standard is tetramethylsilane (TMS), and the chemical shifts are in 10-6 (ppm). MS spectra were determined using an Agilent SQD (ESI) mass spectrometer (model: 6110) or a Shimadzu SQD (ESI) mass spectrometer (model: 2020).
中间体的制备Preparation of intermediates
[中间体INT-1的制备][Preparation of Intermediate INT-1]
Figure PCTCN2022078854-appb-000030
Figure PCTCN2022078854-appb-000030
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000031
Figure PCTCN2022078854-appb-000031
制备方法：Preparation:
第一步：合成化合物INT-1BStep 1: Synthesis of compound INT-1B
将化合物INT-1A(25.4g,100mmol)溶于DMF(250mL)中，冰浴下冷却到5℃，然后分批加入钠氢(6g,150mmol,质量分数60％)，加完后25℃反应1小时，再冰浴下冷却到5℃，滴加4-甲氧基氯苄(23.4g,150mmol)，然后将反应液保持在25℃反应 3小时。TLC显示反应结束后，加入1L的水，析出固体，过滤，收集固体，并用冰甲醇洗涤固体，再干燥，得到化合物INT-1B(28.5g，灰色固体，产率76％)。Compound INT-1A (25.4g, 100mmol) was dissolved in DMF (250mL), cooled to 5°C under ice bath, then sodium hydrogen (6g, 150mmol, mass fraction 60%) was added in batches, and the reaction was performed at 25°C after the addition was complete. After 1 hour, it was cooled to 5°C under an ice bath, 4-methoxybenzyl chloride (23.4 g, 150 mmol) was added dropwise, and the reaction solution was kept at 25°C for 3 hours. After TLC showed that the reaction was completed, 1 L of water was added to precipitate a solid, and the solid was collected by filtration, washed with ice methanol, and then dried to obtain compound INT-1B (28.5 g, gray solid, yield 76%).
MS(ESI):m/z 375.2[M+1] +。 MS(ESI): m/z 375.2[M+1] + .
第二步：合成化合物INT-1CStep 2: Synthesis of compound INT-1C
将化合物INT-1B(28.0g,74.6mmol)溶于MeOH(300mL)中，25℃下加入氢氧化钾(12.5g,225mmol)，并保持25℃反应3h。TLC显示反应结束后，减压蒸除甲醇后，将得到的固体加入到水(200mL)中，充分搅拌，过滤得到固体，固体再用冰甲醇洗涤，然后干燥，得到化合物INT-1C(22.3g，白色固体，产率92％)。Compound INT-1B (28.0 g, 74.6 mmol) was dissolved in MeOH (300 mL), potassium hydroxide (12.5 g, 225 mmol) was added at 25 °C, and the reaction was kept at 25 °C for 3 h. After TLC showed that the reaction was over, methanol was evaporated under reduced pressure, the obtained solid was added to water (200 mL), stirred well, filtered to obtain a solid, the solid was washed with ice methanol, and then dried to obtain compound INT-1C (22.3 g) , white solid, 92% yield).
MS(ESI):m/z 325.1[M+1] +。 MS(ESI): m/z 325.1[M+1] + .
第三步：合成化合物INT-1DStep 3: Synthesis of compound INT-1D
将化合物INT-1C(22g,67.6mmol)加入到NMP(220mL)中，然后加入2,2-二氟-2-(氟磺酰基)乙酸甲酯(39g,203mmol,cas:680-15-9)和碘化亚铜(6.4g,33.8mmol)，加完后氮气保护下100℃反应3小时。TLC显示反应结束后，将反应液冷却，加入1L的水，并用乙酸乙酯萃取(500ml×3)，合并的有机相再依次用水(500ml×2)和饱和氯化钠水溶液(500ml×2)洗涤，有机相用硫酸钠干燥后减压脱溶，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3:1(体积比))，得到化合物INT-1D(15.3g，黄色油状物，产率72％)。Compound INT-1C (22 g, 67.6 mmol) was added to NMP (220 mL) followed by methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (39 g, 203 mmol, cas: 680-15-9 ) and cuprous iodide (6.4 g, 33.8 mmol), and reacted at 100° C. for 3 hours under nitrogen protection after the addition. After TLC showed that the reaction was over, the reaction solution was cooled, 1L of water was added, and extracted with ethyl acetate (500ml×3), the combined organic phases were followed by water (500ml×2) and saturated aqueous sodium chloride solution (500ml×2) Washed, the organic phase was dried with sodium sulfate, and then desolvated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1 (volume ratio)) to obtain compound INT-1D ( 15.3 g, yellow oil, 72% yield).
MS(ESI):m/z 315.2[M+1] +。 MS(ESI): m/z 315.2[M+1] + .
第四步：合成化合物INT-1EStep 4: Synthesis of compound INT-1E
将化合物INT-1D(15g,47.7mmol)加入到DMF(150mL)中，然后滴加TMSI(12.3g,62mmol)，加完后升温到85℃，并反应24小时。TLC显示反应结束后，将反应液冷却，加入1L的水，并用DCM萃取(500ml×3)，合并的有机相再依次用水(500ml×2)和饱和氯化钠水溶液(500ml×2)洗涤，有机相用硫酸钠干燥后减压脱溶，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3:1(体积比))，得到化合物粗品后，再用甲基叔丁基醚打浆，得到化合物INT-1E(10.3g，白色固体，产率74％)。Compound INT-1D (15 g, 47.7 mmol) was added to DMF (150 mL), then TMSI (12.3 g, 62 mmol) was added dropwise, and the temperature was raised to 85° C. and reacted for 24 hours. After TLC showed that the reaction was over, the reaction solution was cooled, 1L of water was added, and extracted with DCM (500ml×3), the combined organic phases were washed with water (500ml×2) and saturated aqueous sodium chloride solution (500ml×2) in turn, The organic phase was dried with sodium sulfate, and then desolvated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 3:1 (volume ratio)) to obtain the crude compound, which was then used for Base tert-butyl ether was slurried to obtain compound INT-1E (10.3 g, white solid, 74% yield).
MS(ESI):m/z 301.1[M+1] +。 MS(ESI): m/z 301.1[M+1] + .
第五步：合成化合物INT-1FStep 5: Synthesis of compound INT-1F
将化合物INT-1E(10g,33.2mmol)加入到DMF(50mL)中，然后冰浴下冷却5℃，并缓慢滴加草酰氯(8.5g,66.5mmol)。加完后，撤掉冰浴，升温到25℃，反应8小时。TLC显示反应结束后，将反应液缓慢加入到水(300ml)中，析出大量固体，过滤，收集固体，干燥，得到化合物INT-1F(9.85g，白色固体，产率93％)。Compound INT-1E (10 g, 33.2 mmol) was added to DMF (50 mL), then cooled at 5°C under an ice bath, and oxalyl chloride (8.5 g, 66.5 mmol) was slowly added dropwise. After the addition, the ice bath was removed, the temperature was raised to 25°C, and the reaction was carried out for 8 hours. After TLC showed that the reaction was completed, the reaction solution was slowly added to water (300 ml), a large amount of solid was precipitated, filtered, collected the solid, and dried to obtain compound INT-1F (9.85 g, white solid, yield 93%).
MS(ESI):m/z 319.2[M+1] +。 MS(ESI): m/z 319.2[M+1] + .
第六步：合成化合物INT-1GStep 6: Synthesis of compound INT-1G
将化合物INT-1F(5g,15.6mmol)加入到THF(50mL)中，然后加入三乙胺(4.7g,47mmol)和DL-氨基丙醇(1.4g,18.72mmol)，然后加热到65℃反应2小时。TLC显示反应结束后，将反应液冷却，加入水(250ml)中，并用乙酸乙酯萃取(100ml×3)，合并的有机相再用饱和氯化钠水溶液(100ml×2)洗涤，有机相用硫酸钠干燥后减压脱溶， 所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3:1(体积比))，得到化合物INT-1G(4.6g，黄色油状物，产率82％)。Compound INT-1F (5 g, 15.6 mmol) was added to THF (50 mL), then triethylamine (4.7 g, 47 mmol) and DL-aminopropanol (1.4 g, 18.72 mmol) were added, and then heated to 65 ° C to react 2 hours. After TLC showed that the reaction was over, the reaction solution was cooled, added to water (250ml), and extracted with ethyl acetate (100ml×3). The combined organic phases were washed with saturated aqueous sodium chloride solution (100ml×2), and the organic phase was washed with After drying over sodium sulfate, the solution was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 3:1 (volume ratio)) to obtain compound INT-1G (4.6 g, yellow oil). product, yield 82%).
MS(ESI):m/z 358.2[M+1] +。 MS(ESI): m/z 358.2[M+1] + .
第七步：合成化合物INT-1HStep 7: Synthesis of compound INT-1H
将化合物INT-1G(4.5g,12.6mmol)加入到乙腈(50mL)中，然后加入碳酸铯(4.9g,15mmol)和丙烯酸乙酯(12.6g,126mmol)，反应液在25℃反应12小时。TLC显示反应结束后，将反应液减压浓缩，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3：1(体积比))，得到化合物INT-1H(3.6g，淡黄色液体，产率63％)。Compound INT-1G (4.5 g, 12.6 mmol) was added to acetonitrile (50 mL), then cesium carbonate (4.9 g, 15 mmol) and ethyl acrylate (12.6 g, 126 mmol) were added, and the reaction solution was reacted at 25° C. for 12 hours. After TLC showed that the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 3:1 (volume ratio)) to obtain compound INT-1H (3.6 g) , pale yellow liquid, yield 63%).
MS(ESI):m/z 458.2[M+1] +。 MS(ESI): m/z 458.2[M+1] + .
第八步：合成化合物INT-1Step 8: Synthesis of compound INT-1
室温下，将化合物INT-1H(3.5g,7.6mmol)加入到3N盐酸(35mL)和异丙醇(3.5ml)的混合溶剂中，然后加热到90℃反应16小时。TLC显示反应结束后，乙酸乙酯稀释反应液，水萃取，盐水洗，用无水硫酸钠干燥有机相，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1:2(体积比))，得到化合物INT-1(2.2g，淡黄色液体，产率66％)。Compound INT-1H (3.5 g, 7.6 mmol) was added to a mixed solvent of 3N hydrochloric acid (35 mL) and isopropanol (3.5 mL) at room temperature, and then heated to 90° C. to react for 16 hours. After TLC showed that the reaction was over, the reaction solution was diluted with ethyl acetate, extracted with water, washed with brine, the organic phase was dried with anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1: 2 (volume ratio)) to obtain compound INT-1 (2.2 g, pale yellow liquid, yield 66%).
MS(ESI):m/z 428.1[M-1] -。 MS(ESI): m/z 428.1[M-1] - .
[中间体INT-2的制备][Preparation of Intermediate INT-2]
Figure PCTCN2022078854-appb-000032
Figure PCTCN2022078854-appb-000032
中间体INT-2的合成参考中间体INT-1的合成步骤，其中第六步用L-氨基丙醇代替DL-氨基丙醇，得到中间体INT-2。The synthesis of intermediate INT-2 refers to the synthesis steps of intermediate INT-1, wherein in the sixth step, L-aminopropanol is used instead of DL-aminopropanol to obtain intermediate INT-2.
MS(ESI):m/z 428.2[M-1] -。 MS(ESI): m/z 428.2[M-1] - .
[中间体INT-3的制备][Preparation of Intermediate INT-3]
Figure PCTCN2022078854-appb-000033
Figure PCTCN2022078854-appb-000033
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000034
Figure PCTCN2022078854-appb-000034
第一步：合成化合物INT-3BStep 1: Synthesis of compound INT-3B
将化合物INT-3A(1g，5.35mmol，1eq)加入到CH 3CN(10mL)中，再加化合物丙烯酸甲酯(2.68g，26.75mmol，5eq)，然后冰浴下加入Cs 2CO 3(5.24g，16.05mmol，3eq)，将反应液升至室温下搅拌2h。TLC显示反应结束后，把反应液过滤，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1(体积比))，得到化合物INT-3B(460mg，无色油状液体，产率：32％)。 Compound INT-3A (1 g, 5.35 mmol, 1 eq) was added to CH 3 CN (10 mL), followed by compound methyl acrylate (2.68 g, 26.75 mmol, 5 eq), followed by adding Cs 2 CO 3 (5.24 under ice bath) g, 16.05mmol, 3eq), the reaction solution was warmed to room temperature and stirred for 2h. After TLC showed that the reaction was over, the reaction solution was filtered, desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 (volume ratio)) to obtain compound INT-3B (460 mg, colorless oily liquid, yield: 32%).
MS(ESI):m/z 274.2[M+H] +。 MS (ESI): m/z 274.2 [M+H] + .
第二步：合成化合物INT-3CStep 2: Synthesis of compound INT-3C
将化合物INT-3B(460mg，1.68mmol，1eq)加入到质量分数为8％HCl/EA(6mL)中，室温下搅拌2h。TLC显示反应结束后，将反应液减压脱溶，得到化合物INT-3C(292mg，无色油状液体)。粗品直接投下一步反应。Compound INT-3B (460 mg, 1.68 mmol, 1 eq) was added to 8% HCl/EA (6 mL), and stirred at room temperature for 2 h. After TLC showed that the reaction was completed, the reaction solution was desolubilized under reduced pressure to obtain compound INT-3C (292 mg, colorless oily liquid). The crude product was directly put into the next reaction.
MS(ESI):m/z 174.2[M+H] +。 MS (ESI): m/z 174.2 [M+H] + .
第三步：合成化合物INT-3DStep 3: Synthesis of Compound INT-3D
将化合物INT-3C(292mg，1.68mmol，1eq)溶于THF(6mL)中，然后加入化合物INT-1F(456mg，1.43mmol，0.85eq)，再加入TEA(510mg，5mmol，3eq)。加完后将反应液升温至60℃，搅拌2h。TLC显示反应结束后，将反应液减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1(体积比))，得到化合物INT-3D(268mg，淡黄色油状液体，产率：35％)。Compound INT-3C (292 mg, 1.68 mmol, 1 eq) was dissolved in THF (6 mL), then compound INT-1F (456 mg, 1.43 mmol, 0.85 eq) was added, followed by TEA (510 mg, 5 mmol, 3 eq). After the addition, the reaction solution was heated to 60 °C and stirred for 2 h. After TLC showed that the reaction was completed, the reaction solution was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 (volume ratio)) to obtain compound INT-3D (268 mg) , pale yellow oily liquid, yield: 35%).
MS(ESI):m/z 456.2[M+H] +。 MS(ESI): m/z 456.2 [M+H] + .
第四步：合成化合物INT-3Step 4: Synthesis of compound INT-3
将化合物INT-3D(268mg，0.59mmol，1eq)溶于MeOH/H 2O(2mL/2mL)中，然后加入LiOH.H 2O(74mg，1.92mmol，3eq)，反应液室温下反应0.5h。TLC显示结束后，使用1N稀盐酸调pH至5，用EA萃取，有机相加无水硫酸钠干燥，减压脱溶，得到化合物INT-3(240mg，淡黄色油状液体，产率：92％)。 Compound INT-3D (268 mg, 0.59 mmol, 1 eq) was dissolved in MeOH/H 2 O (2 mL/2 mL), then LiOH.H 2 O (74 mg, 1.92 mmol, 3 eq) was added, and the reaction solution was reacted at room temperature for 0.5 h . After TLC showed that the pH was adjusted to 5 with 1N dilute hydrochloric acid, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, and desolvated under reduced pressure to obtain compound INT-3 (240 mg, pale yellow oily liquid, yield: 92%) ).
MS(ESI):m/z 442.2[M+H] +。 MS(ESI): m/z 442.2 [M+H] + .
[中间体INT-4的制备][Preparation of Intermediate INT-4]
Figure PCTCN2022078854-appb-000035
Figure PCTCN2022078854-appb-000035
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000036
Figure PCTCN2022078854-appb-000036
第一步：合成化合物INT-4BStep 1: Synthesis of compound INT-4B
将化合物INT-1F(10g，31.3mmol)溶于乙醇(100mL)中，加入化合物INT-4A(3.74g，31.3mmol)和三乙胺(6.35g，62.6mmol)，然后将反应液升至50℃反应2h。TLC显示反应结束后，将反应液减压脱溶，得到化合物INT-4B(13g，粗品)，直接用于下一步。Compound INT-1F (10 g, 31.3 mmol) was dissolved in ethanol (100 mL), compound INT-4A (3.74 g, 31.3 mmol) and triethylamine (6.35 g, 62.6 mmol) were added, and the reaction solution was raised to 50 ℃ reaction 2h. After TLC showed that the reaction was completed, the reaction solution was desolvated under reduced pressure to obtain compound INT-4B (13 g, crude product), which was directly used in the next step.
MS(ESI):m/z 402.2[M+H] +。 MS (ESI): m/z 402.2 [M+H] + .
第二步：合成化合物INT-4CStep 2: Synthesis of compound INT-4C
将化合物INT-4B粗品(13g，32.4mmol)溶于无水THF(100mL)中，冰浴下滴加硼烷二甲硫醚(10M，6.5mL，64.8mmol)，然后将反应液升至室温反应2h。TLC显示反应结束后，冰浴下慢慢滴加甲醇，待没有气体放出后，硼烷淬灭完毕，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1:1(体积比))，得到化合物INT-4C(9g，黄色油状，两步产率74％)。The crude compound INT-4B (13 g, 32.4 mmol) was dissolved in anhydrous THF (100 mL), borane dimethyl sulfide (10 M, 6.5 mL, 64.8 mmol) was added dropwise under ice bath, and then the reaction solution was warmed to room temperature The reaction was carried out for 2h. After TLC showed that the reaction was completed, methanol was slowly added dropwise under an ice bath. After no gas was released, the quenching of borane was completed, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate). ester = 1:1 (volume ratio)) to obtain compound INT-4C (9 g, yellow oil, 74% yield for two steps).
MS(ESI):m/z 388.2[M+H] +。 MS (ESI): m/z 388.2 [M+H] + .
1H-NMR(400MHz,DMSO-d 6):δ7.93(s,1H),7.26-7.16(m,2H),6.92-6.82(m,2H),5.04(s,2H),4.91-4.79(m,1H),3.84-3.76(m,1H),3.71(s,3H),3.70-3.64(m,1H),3.36-3.30(m,2H),3.25(s,3H). 1 H-NMR (400MHz, DMSO-d 6 ): δ7.93(s, 1H), 7.26-7.16(m, 2H), 6.92-6.82(m, 2H), 5.04(s, 2H), 4.91-4.79 (m,1H),3.84-3.76(m,1H),3.71(s,3H),3.70-3.64(m,1H),3.36-3.30(m,2H),3.25(s,3H).
第三步：合成化合物INT-4DStep 3: Synthesis of compound INT-4D
将化合物INT-4C(9g，23.2mmol)加入到乙腈(90mL)中，再加入丙烯酸甲酯(12g，140mmol)和碳酸铯(9.1g，28mmol)，室温反应2h。TLC显示反应结束后，将反应液过滤，滤饼用乙酸乙酯洗涤，有机相减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1(体积比))，得到化合物INT-4D(6.8g，淡黄色油状物，产率62％)。Compound INT-4C (9 g, 23.2 mmol) was added to acetonitrile (90 mL), then methyl acrylate (12 g, 140 mmol) and cesium carbonate (9.1 g, 28 mmol) were added, and the reaction was carried out at room temperature for 2 h. After TLC showed that the reaction was over, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the organic phase was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5/1 ( volume ratio)) to obtain compound INT-4D (6.8 g, pale yellow oil, yield 62%).
MS(ESI):m/z 474.2[M+H] +。 MS (ESI): m/z 474.2 [M+H] + .
第四步：合成化合物INT-4Step 4: Synthesis of compound INT-4
将化合物INT-4D(6.8g，14.4mmol)加入到甲醇(30mL)和水(30mL)的混合溶剂中，冰浴下加入LiOH(516mg，21.5mmol)，将反应液升至室温，反应2h。TLC显示反应结束后，冰浴下用1M HCl溶液将反应液pH调为6-7，用二氯甲烷萃取3次，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3:1(体积比))，得到化合物INT-4(4.8g，淡黄色油状，产率72.7％)。Compound INT-4D (6.8 g, 14.4 mmol) was added to a mixed solvent of methanol (30 mL) and water (30 mL), LiOH (516 mg, 21.5 mmol) was added under ice bath, and the reaction solution was warmed to room temperature for 2 h. After TLC showed that the reaction was completed, the pH of the reaction solution was adjusted to 6-7 with 1M HCl solution under ice bath, extracted with dichloromethane 3 times, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate) =3:1 (volume ratio)) to obtain compound INT-4 (4.8 g, pale yellow oil, yield 72.7%).
MS(ESI):m/z 460.2[M+H] +。 MS(ESI): m/z 460.2 [M+H] + .
[中间体INT-5的制备][Preparation of Intermediate INT-5]
Figure PCTCN2022078854-appb-000037
Figure PCTCN2022078854-appb-000037
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000038
Figure PCTCN2022078854-appb-000038
第一步：合成化合物INT-5BStep 1: Synthesis of compound INT-5B
将化合物INT-5A(2g,19.2mmol)溶于N,N-二甲基甲酰胺(10mL)中，0℃下分批加入钠氢(0.77g,19.2mmol)，然后继续0℃下反应30分钟。随后将对甲基苄氯的N,N-二甲基甲酰胺(3mL)溶液在0℃下缓慢滴加到上述反应液中，然后在室温下搅拌过夜。TLC显示原料反应完全，将反应液倒入100mL冰水中，然后用乙酸乙酯(100mL×3)萃取，合并有机相用饱和氯化钠(50mL×3)洗，无水硫酸钠干燥，过滤除去干燥剂，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1(体积比))，得到化合物INT-5B(2.8g，无色液体，产率65％)。Compound INT-5A (2 g, 19.2 mmol) was dissolved in N,N-dimethylformamide (10 mL), sodium hydrogen (0.77 g, 19.2 mmol) was added in portions at 0 °C, and the reaction was continued at 0 °C for 30 minute. Subsequently, a solution of p-methylbenzyl chloride in N,N-dimethylformamide (3 mL) was slowly added dropwise to the above reaction solution at 0°C, followed by stirring at room temperature overnight. TLC showed that the reaction of the raw materials was complete. The reaction solution was poured into 100 mL of ice water, and then extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with saturated sodium chloride (50 mL×3), dried over anhydrous sodium sulfate, and removed by filtration. The drying agent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 (volume ratio)) to obtain compound INT-5B (2.8 g, colorless liquid, yield 65%).
MS(ESI):m/z 225.2[M+H] +。 MS (ESI): m/z 225.2 [M+H] + .
第二步：合成化合物INT-5CStep 2: Synthesis of compound INT-5C
将化合物INT-5B(2.8g,12.5mmol)溶于四氢呋喃(40mL)中，在0℃下分批加入氢化锂铝(475mg，12.5mmol)，然后在0℃搅拌30分钟。TLC显示反应结束后，在0℃ 下缓慢加入十水硫酸钠，直至没有气泡产生为止，然后在室温下搅拌30分钟，过滤，减压脱溶，得到化合物INT-5C(2g，无色油状，产率82％)。Compound INT-5B (2.8 g, 12.5 mmol) was dissolved in tetrahydrofuran (40 mL), and lithium aluminum hydride (475 mg, 12.5 mmol) was added portionwise at 0°C, followed by stirring at 0°C for 30 minutes. After TLC showed that the reaction was completed, sodium sulfate decahydrate was slowly added at 0°C until no bubbles were generated, then stirred at room temperature for 30 minutes, filtered, and desolvated under reduced pressure to obtain compound INT-5C (2 g, colorless oily, yield 82%).
MS(ESI):m/z 197.2[M+H] +。 MS (ESI): m/z 197.2 [M+H] + .
第三步：合成化合物INT-5DStep 3: Synthesis of compound INT-5D
将化合物INT-5C(1.9g,9.7mmol)加入到乙腈(20mL)中，然后加入碳酸铯(9.5g，29.1mmol)和丙烯酸甲酯(8.7mL，97mmol)，随后室温反应2小时。TLC显示反应结束后，反应液过滤，滤液减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1(体积比))，得到化合物INT-5D(1.3g，无色液体，产率47％)。Compound INT-5C (1.9 g, 9.7 mmol) was added to acetonitrile (20 mL), then cesium carbonate (9.5 g, 29.1 mmol) and methyl acrylate (8.7 mL, 97 mmol) were added, followed by reaction at room temperature for 2 hours. After TLC showed that the reaction was completed, the reaction solution was filtered, the filtrate was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1 (volume ratio)) to obtain compound INT-5D (1.3 g, colorless liquid, 47% yield).
MS(ESI):m/z 283.2[M+H] +。 MS(ESI): m/z 283.2 [M+H] + .
第四步：合成化合物INT-5EStep 4: Synthesis of compound INT-5E
将三氟乙酸(6mL)加入到化合物INT-5D(1.2g,4.3mmol)中，然后室温反应3小时。TLC显示反应结束后，反应液用饱和碳酸氢钠淬灭，直至没有气体产生为止，然后用二氯甲烷(60mL×3)萃取，合并有机相用饱和氯化钠(50mL)洗，无水硫酸钠干燥，过滤除去干燥剂，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1(体积比))，得到粗产品化合物INT-5E(700mg，浅黄色油状)。直接用于下一步，无需进一步纯化。Trifluoroacetic acid (6 mL) was added to compound INT-5D (1.2 g, 4.3 mmol), and then reacted at room temperature for 3 hours. After TLC showed that the reaction was over, the reaction solution was quenched with saturated sodium bicarbonate until no gas was generated, then extracted with dichloromethane (60 mL×3), the combined organic phases were washed with saturated sodium chloride (50 mL), and anhydrous sulfuric acid dried over sodium, filtered to remove the desiccant, desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 (volume ratio)) to obtain the crude product compound INT-5E ( 700mg, pale yellow oil). Used directly in the next step without further purification.
第五步：合成化合物INT-5FStep 5: Synthesis of compound INT-5F
将化合物INT-5E(700mg,4.32mmol)加入到N,N-二甲基甲酰胺(10mL)中，然后加入N,N-二异丙基乙胺(2.3mL，13mmol)和化合物INT-1F(1.38g，4.32mmol)。然后反应在氮气气球保护下80℃反应过夜。TLC显示反应结束后，反应液冷却至室温，然后倒入水(60mL)中，用乙酸乙酯(60mL×3)萃取，合并有机相用饱和氯化钠(50mL×3)洗，无水硫酸钠干燥，过滤除去干燥剂，减压脱溶，然后残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1(体积比))，得到化合物INT-5F(310mg，浅黄色油状，产率16％)。Compound INT-5E (700 mg, 4.32 mmol) was added to N,N-dimethylformamide (10 mL), followed by N,N-diisopropylethylamine (2.3 mL, 13 mmol) and compound INT-1F (1.38 g, 4.32 mmol). The reaction was then reacted overnight at 80°C under the protection of a nitrogen balloon. After TLC showed that the reaction was over, the reaction solution was cooled to room temperature, then poured into water (60 mL), extracted with ethyl acetate (60 mL×3), the combined organic phases were washed with saturated sodium chloride (50 mL×3), and anhydrous sulfuric acid dried over sodium, filtered to remove the desiccant, desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/1 (volume ratio)) to obtain compound INT-5F (310 mg) , pale yellow oil, 16% yield).
MS(ESI):m/z 445.2[M+H] +。 MS (ESI): m/z 445.2 [M+H] + .
第六步：合成化合物INT-5Step 6: Synthesis of compound INT-5
将化合物INT-5F(180mg，0.41mmol)溶于二氧六环2mL)和4M HCl(2mL)中，然后在80℃下搅拌2h。TLC显示结束后，反应冷却至室温，然后向反应液中加入水(5mL)，再用二氯甲烷(15mL×3)萃取，合并有机相用饱和氯化钠(50mL×3)洗，无水硫酸钠干燥，过滤除去干燥剂，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：PE:EA＝1:1(体积比))，得到化合物INT-5(103mg，无色油状，产率59.19％)。Compound INT-5F (180 mg, 0.41 mmol) was dissolved in dioxane 2 mL) and 4M HCl (2 mL), then stirred at 80 °C for 2 h. After the completion of TLC, the reaction was cooled to room temperature, and water (5 mL) was added to the reaction solution, followed by extraction with dichloromethane (15 mL×3), the combined organic phases were washed with saturated sodium chloride (50 mL×3), and anhydrous It was dried over sodium sulfate, filtered to remove the desiccant, desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE:EA=1:1 (volume ratio)) to obtain compound INT-5 (103 mg, colorless) oil, yield 59.19%).
MS(ESI):m/z 431.2[M+H] +。 MS (ESI): m/z 431.2 [M+H] + .
[中间体INT-6的制备][Preparation of Intermediate INT-6]
Figure PCTCN2022078854-appb-000039
Figure PCTCN2022078854-appb-000039
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000040
Figure PCTCN2022078854-appb-000040
第一步：合成化合物INT-6BStep 1: Synthesis of compound INT-6B
将化合物INT-6A(10g，96mmol)溶于DCM(100mL)中，冰浴下加入TBSCl(17.37g，115mmol)和咪唑(8.5g，125mmol)，然后将反应液升至室温过夜。TLC显示反应结束后，将反应液减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10:1(体积比))，得到化合物INT-6B(19.5g，无色油状，产率95％)。Compound INT-6A (10 g, 96 mmol) was dissolved in DCM (100 mL), TBSCl (17.37 g, 115 mmol) and imidazole (8.5 g, 125 mmol) were added under ice bath, and then the reaction solution was warmed to room temperature overnight. After TLC showed that the reaction was completed, the reaction solution was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1 (volume ratio)) to obtain compound INT-6B (19.5 g, colorless oil, 95% yield).
MS(ESI):m/z 219.2[M+H] +。 MS(ESI): m/z 219.2 [M+H] + .
第二步：合成化合物INT-6CStep 2: Synthesis of compound INT-6C
将化合物INT-6B(10g，45.8mmol)溶于THF(100mL)中，冰浴下加入硼氢化锂(761mg，36.6mmol)和硼氢化钠(843g，22.9mmol)，然后将反应液升至室温过夜。TLC显示反应结束后，将反应液减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10:1(体积比))，得到化合物INT-6C(8.5g，无色油状，产率97％)。Compound INT-6B (10 g, 45.8 mmol) was dissolved in THF (100 mL), lithium borohydride (761 mg, 36.6 mmol) and sodium borohydride (843 g, 22.9 mmol) were added under ice bath, and then the reaction solution was warmed to room temperature overnight. After TLC showed that the reaction was completed, the reaction solution was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1 (volume ratio)) to obtain compound INT-6C (8.5 g, colorless oil, 97% yield).
1H-NMR(400MHz,CDCl 3):3.94-3.86(m,1H),3.54-3.50(m,1H),3.48-3.32(m,1H),2.00-1.96(m,1H),1.13-0.97(m,3H),0.90-0.86(m,9H),0.11-0.01(m,6H)。 1 H-NMR (400MHz, CDCl 3 ): 3.94-3.86 (m, 1H), 3.54-3.50 (m, 1H), 3.48-3.32 (m, 1H), 2.00-1.96 (m, 1H), 1.13-0.97 (m, 3H), 0.90-0.86 (m, 9H), 0.11-0.01 (m, 6H).
第三步：合成化合物INT-6DStep 3: Synthesis of compound INT-6D
将化合物INT-6C(8.5g，44.5mmol)加入到乙腈(80mL)中，再加入丙烯酸乙酯(26.8g，268mmol)和碳酸铯(17.5g，53.6mmol)，室温反应2h。TLC显示反应结束后，过滤碳酸铯，滤饼用乙酸乙酯洗涤，有机相减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1(体积比))，得到化合物INT-6D(9g，淡黄色油状物，产率69.4％)。Compound INT-6C (8.5 g, 44.5 mmol) was added to acetonitrile (80 mL), then ethyl acrylate (26.8 g, 268 mmol) and cesium carbonate (17.5 g, 53.6 mmol) were added, and the reaction was carried out at room temperature for 2 h. After TLC showed that the reaction was complete, cesium carbonate was filtered, the filter cake was washed with ethyl acetate, the organic phase was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5/1 (volume) ratio)) to obtain compound INT-6D (9 g, pale yellow oil, yield 69.4%).
MS(ESI):m/z 291.2[M+H] +。 MS(ESI): m/z 291.2 [M+H] + .
第四步：合成化合物INT-6Step 4: Synthesis of compound INT-6
将化合物INT-6D(9g，31mmol)加入到甲醇(40mL)和水(40mL)的混合溶剂中，冰浴下加入LiOH(890mg，37mmol)，将反应液升至室温，反应2h。TLC显示反应结束后，冰浴下用1M HCl溶液将反应液pH调为6-7，用二氯甲烷萃取3次，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3:1(体积比))，得到化合物INT-6(6g，淡黄色油状，产率75％)。Compound INT-6D (9 g, 31 mmol) was added to a mixed solvent of methanol (40 mL) and water (40 mL), LiOH (890 mg, 37 mmol) was added under ice bath, and the reaction solution was warmed to room temperature for 2 h. After TLC showed that the reaction was completed, the pH of the reaction solution was adjusted to 6-7 with 1M HCl solution under ice bath, extracted with dichloromethane 3 times, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate) =3:1 (volume ratio)) to obtain compound INT-6 (6 g, pale yellow oil, yield 75%).
MS(ESI):m/z 263.2[M+H] +。 MS(ESI): m/z 263.2 [M+H] + .
[中间体INT-7的制备][Preparation of Intermediate INT-7]
Figure PCTCN2022078854-appb-000041
Figure PCTCN2022078854-appb-000041
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000042
Figure PCTCN2022078854-appb-000042
第一步：合成化合物INT-7BStep 1: Synthesis of compound INT-7B
冰浴下，将钠块(2.66g，52.15mmol)加入到MeOH(220mL)中，搅拌10分钟，钠溶解后，然后分批加入化合物INT-7A(20g，63.21mmol)，升温至60℃反应5小时。TLC显示反应结束后，将反应液中的大部分溶剂减压蒸除，乙酸乙酯稀释后缓慢加入冰水中，乙酸乙酯萃取，用无水硫酸钠干燥有机相，减压脱溶，得到化合物INT-7B(18.23g，白色固体，产率：83％)。Under ice bath, sodium block (2.66 g, 52.15 mmol) was added to MeOH (220 mL) and stirred for 10 minutes. After the sodium was dissolved, compound INT-7A (20 g, 63.21 mmol) was added in batches, and the temperature was raised to 60 °C for reaction. 5 hours. After TLC showed that the reaction was over, most of the solvent in the reaction solution was evaporated under reduced pressure, diluted with ethyl acetate, slowly added to ice water, extracted with ethyl acetate, dried with anhydrous sodium sulfate, and desolvated under reduced pressure to obtain the compound INT-7B (18.23 g, white solid, yield: 83%).
1H-NMR(300MHz,CDCl 3):δ7.47-7.40(m,6H),7.34-7.27(m,6H),7.26-7.20(m,3H),4.02-3.88(m,1H),3.51-3.41(m,2H),3.37-3.34(m,3H),3.19(d,J＝5.5Hz,2H). 1 H-NMR (300 MHz, CDCl 3 ): δ 7.47-7.40 (m, 6H), 7.34-7.27 (m, 6H), 7.26-7.20 (m, 3H), 4.02-3.88 (m, 1H), 3.51 -3.41(m, 2H), 3.37-3.34(m, 3H), 3.19(d, J=5.5Hz, 2H).
第二步：合成化合物INT-7CStep 2: Synthesis of compound INT-7C
将化合物INT-7B(18.23g，52.32mmol)溶于DMF(200mL)中，然后冷却到0℃，分批次缓慢加入NaH(3.14g，78.48mmol)，加完后混合液放在室温下搅拌30分钟，然后将PMBCl(12.29g，78.48mmol，1.5eq)缓慢滴加入反应液中，加完后冰浴下反应18h。TLC显示反应结束后，反应液用乙酸乙酯(100mL)稀释后缓慢加入冰水(600mL)中，用乙酸乙酯(300mL)萃取，有机层用饱和氯化钠溶液洗涤三次，有机相用无水硫酸钠干燥，减压脱溶，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/0～5/1(体积比))，得到化合物INT-7C(23.75g，无色油状液体，产率：96％)。Compound INT-7B (18.23 g, 52.32 mmol) was dissolved in DMF (200 mL), then cooled to 0 °C, NaH (3.14 g, 78.48 mmol) was slowly added in batches, and the mixture was stirred at room temperature after the addition. After 30 minutes, PMBCl (12.29 g, 78.48 mmol, 1.5 eq) was slowly added dropwise to the reaction solution, and the reaction was performed under ice bath for 18 h after the addition. After TLC showed that the reaction was over, the reaction solution was diluted with ethyl acetate (100 mL), slowly added to ice water (600 mL), extracted with ethyl acetate (300 mL), the organic layer was washed three times with saturated sodium chloride solution, and the organic phase was washed with It was dried over sodium sulfate, desolvated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/0～5/1 (volume ratio)) to obtain compound INT-7C (23.75 g, Colorless oily liquid, yield: 96%).
MS(ESI):m/z 469.2[M+H] +。 MS(ESI): m/z 469.2 [M+H] + .
第三步：合成化合物INT-7DStep 3: Synthesis of compound INT-7D
将化合物INT-7C(23.75g)溶于乙酸乙酯(100mL)中，冰浴下搅拌5分钟，然后缓慢加入质量分数为8％盐酸乙酸乙酯溶液(100mL)，加完后搅拌5分钟，然后将反应液升温到室温，搅拌16小时。TLC显示反应结束后，将反应液减压脱溶，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/0～3/1(体积比))，得到化合物INT-7D(6.02g，无色油状液体，产率：52％)。Compound INT-7C (23.75 g) was dissolved in ethyl acetate (100 mL), stirred under ice bath for 5 minutes, then slowly added with 8% hydrochloric acid ethyl acetate solution (100 mL), and stirred for 5 minutes after adding, The reaction solution was then warmed to room temperature and stirred for 16 hours. After TLC showed that the reaction was completed, the reaction solution was desolvated under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/0～3/1 (volume ratio)) to obtain compound INT-7D (6.02 g, colorless oily liquid, yield: 52%).
MS(ESI):m/z 227.2[M+H] +。 MS(ESI): m/z 227.2 [M+H] + .
第四步：合成化合物INT-7EStep 4: Synthesis of compound INT-7E
将化合物INT-7D(6.02g，26.61mmol)加入到乙腈(100mL)中，然后加入丙烯酸乙酯(15.98g，159.63mmol)，冰浴搅拌下，向反应液中加入碳酸铯(10.4g，31.93mmol)，把反应液升温到50℃下反应3小时。TLC显示结束后，过滤固体，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/0～1/1(体积比))，得到化合物INT-7E(4g，无色液体，产率：46％)。Compound INT-7D (6.02 g, 26.61 mmol) was added to acetonitrile (100 mL), then ethyl acrylate (15.98 g, 159.63 mmol) was added, and under stirring in an ice bath, cesium carbonate (10.4 g, 31.93 mmol) was added to the reaction solution mmol), the reaction solution was heated to 50 °C for 3 hours. After TLC showed the end, the solid was filtered, desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/0～1/1 (volume ratio)) to obtain compound INT- 7E (4 g, colorless liquid, yield: 46%).
MS(ESI):m/z 327.2[M+H] +。 MS(ESI): m/z 327.2 [M+H] + .
第五步：合成化合物INT-7Step 5: Synthesis of compound INT-7
将化合物INT-7E(4g，12.26mmol，1eq)加入到甲醇-水(体积比＝20mL：20mL)混合溶剂中，冰浴下加入氢氧化锂(294mg，12.26mmol，1eq)，然后把反应液升到室温反应3小时。TLC显示反应结束后，将反应液置于冰浴中搅拌，缓慢加入1N盐酸调节pH至6，用乙酸乙酯萃取，有机相减压脱溶，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1～1/1(体积比))，得到化合物INT-7(1.98g，无色液体，产率：54％)。Compound INT-7E (4g, 12.26mmol, 1eq) was added to methanol-water (volume ratio = 20mL: 20mL) mixed solvent, lithium hydroxide (294mg, 12.26mmol, 1eq) was added under ice bath, and then the reaction solution was added Raised to room temperature for 3 hours. After TLC showed that the reaction was complete, the reaction solution was stirred in an ice bath, 1N hydrochloric acid was slowly added to adjust the pH to 6, extracted with ethyl acetate, the organic phase was desolvated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5/1 to 1/1 (volume ratio)) to obtain compound INT-7 (1.98 g, colorless liquid, yield: 54%).
MS(ESI):m/z 299.2[M+H] +。 MS (ESI): m/z 299.2 [M+H] + .
[中间体INT-8的制备][Preparation of Intermediate INT-8]
Figure PCTCN2022078854-appb-000043
Figure PCTCN2022078854-appb-000043
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000044
Figure PCTCN2022078854-appb-000044
第一步：合成化合物INT-8BStep 1: Synthesis of compound INT-8B
将化合物INT-8A(10g,46.2mmol)溶于DMSO(110mL)中，加入2,3-二氟-5-(三氟甲基)吡啶(12.7g,69.3mmol)和DIEA(7.17g,55.5mmol)，反应升温至100℃搅拌18h。TLC显示反应结束后，将反应液倒入水中，用乙酸乙酯萃取，用无水硫酸钠干燥有机相，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3:1(体积比))，得到化合物INT-8B(14g，淡黄色油状物，产率80％)。Compound INT-8A (10 g, 46.2 mmol) was dissolved in DMSO (110 mL), 2,3-difluoro-5-(trifluoromethyl)pyridine (12.7 g, 69.3 mmol) and DIEA (7.17 g, 55.5 mmol) were added mmol), the reaction was warmed to 100 °C and stirred for 18 h. After TLC showed that the reaction was over, the reaction solution was poured into water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/acetic acid) ethyl ester=3:1 (volume ratio)) to obtain compound INT-8B (14 g, pale yellow oil, yield 80%).
MS(ESI):m/z 380.2[M+H] +。 MS (ESI): m/z 380.2 [M+H] + .
第二步：合成化合物INT-8CStep 2: Synthesis of compound INT-8C
将化合物INT-8B(14g,36.9mmol)加入到DMF(200mL)中，冰浴下加入60％钠氢(1.8g,44.3mmol)，室温搅拌15min，然后升至50℃搅拌1h。TLC显示反应结束后，加入水，用乙酸乙酯萃取，用无水硫酸钠干燥有机相，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5:1(体积比))，得到化合物INT-8C(10g，淡黄色油状物，产率75％)。Compound INT-8B (14 g, 36.9 mmol) was added to DMF (200 mL), 60% sodium hydrogen (1.8 g, 44.3 mmol) was added under ice bath, stirred at room temperature for 15 min, and then heated to 50 °C and stirred for 1 h. After TLC showed that the reaction was completed, water was added, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, and desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5 : 1 (volume ratio)) to obtain compound INT-8C (10 g, pale yellow oil, yield 75%).
MS(ESI):m/z 360.2[M+H] +。 MS(ESI): m/z 360.2 [M+H] + .
第三步：合成化合物INT-8Step 3: Synthesis of compound INT-8
将化合物INT-8C(10g,27.8mmol)加入到EtOH(100mL)中，冰浴下滴加8％盐酸乙酸乙酯(100mL)，室温搅拌16h。TLC显示反应结束后，减压脱溶，残余物使用石油醚/乙酸乙酯＝1:1(100mL)打浆，得到化合物INT-8(8g，白色固体，产率97％)。Compound INT-8C (10 g, 27.8 mmol) was added to EtOH (100 mL), 8% hydrochloric acid ethyl acetate (100 mL) was added dropwise under ice bath, and the mixture was stirred at room temperature for 16 h. After TLC showed that the reaction was completed, the solution was removed under reduced pressure, and the residue was slurried with petroleum ether/ethyl acetate = 1:1 (100 mL) to obtain compound INT-8 (8 g, white solid, yield 97%).
MS(ESI):m/z 260.2[M+H] +。 MS(ESI): m/z 260.2 [M+H] + .
[中间体INT-9的制备][Preparation of Intermediate INT-9]
Figure PCTCN2022078854-appb-000045
Figure PCTCN2022078854-appb-000045
中间体INT-9的合成参考中间体INT-8的合成步骤，其中第一步用(R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(CAS:278788-66-2)代替化合物INT-8A，得到中间体INT-9。The synthesis of intermediate INT-9 refers to the synthesis steps of intermediate INT-8, wherein the first step uses (R)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester (CAS:278788-66- 2) Instead of compound INT-8A, intermediate INT-9 is obtained.
MS(ESI):m/z 260[M+H] +。 MS(ESI): m/z 260 [M+H] + .
[中间体INT-10的制备][Preparation of Intermediate INT-10]
Figure PCTCN2022078854-appb-000046
Figure PCTCN2022078854-appb-000046
中间体INT-10的合成参考中间体INT-8的合成步骤，其中第一步用2,3-二氟-5-氯吡啶(CAS:89402-43-7)代替2,3-二氟-5-(三氟甲基)吡啶，得到中间体INT-10。The synthesis of intermediate INT-10 refers to the synthesis procedure of intermediate INT-8, in which 2,3-difluoro-5-chloropyridine (CAS: 89402-43-7) is used in the first step instead of 2,3-difluoro- 5-(Trifluoromethyl)pyridine to yield intermediate INT-10.
MS(ESI):m/z 226.2[M+H] +。 MS(ESI): m/z 226.2 [M+H] + .
[中间体INT-11的制备][Preparation of Intermediate INT-11]
Figure PCTCN2022078854-appb-000047
Figure PCTCN2022078854-appb-000047
中间体INT-11的合成参考中间体INT-8的合成步骤，其中第一步用2,3-二氟-5-氯吡啶(CAS:89402-43-7)代替2,3-二氟-5-(三氟甲基)吡啶，并用(R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(CAS:278788-66-2)代替化合物INT-8A，得到中间体INT-11。The synthesis of intermediate INT-11 refers to the synthesis procedure of intermediate INT-8, in which 2,3-difluoro-5-chloropyridine (CAS: 89402-43-7) was used in the first step instead of 2,3-difluoro- 5-(Trifluoromethyl)pyridine and substituting (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (CAS:278788-66-2) for compound INT-8A to give intermediate INT-11.
MS(ESI):m/z 226.2[M+H] +。 MS(ESI): m/z 226.2 [M+H] + .
[中间体INT-12的制备][Preparation of Intermediate INT-12]
Figure PCTCN2022078854-appb-000048
Figure PCTCN2022078854-appb-000048
中间体INT-12的合成参考中间体INT-8的合成步骤，其中第一步用(S)-3-(2-羟乙基) 哌嗪-1-羧酸叔丁酯(CAS:1273577-11-9)代替化合物INT-8A，得到中间体INT-12。The synthesis of intermediate INT-12 refers to the synthesis steps of intermediate INT-8, wherein the first step uses (S)-3-(2-hydroxyethyl)piperazine-1-carboxylate tert-butyl ester (CAS:1273577- 11-9) Substitute compound INT-8A to obtain intermediate INT-12.
MS(ESI):m/z 274.2[M+H] +。 MS (ESI): m/z 274.2 [M+H] + .
[中间体INT-13的制备][Preparation of Intermediate INT-13]
Figure PCTCN2022078854-appb-000049
Figure PCTCN2022078854-appb-000049
中间体INT-13的合成参考中间体INT-8的合成步骤，其中第一步用(R)-3-(2-羟乙基)哌嗪-1-羧酸叔丁酯(CAS:1272421-10-9)代替化合物INT-8A，得到中间体INT-13。The synthesis of intermediate INT-13 refers to the synthesis steps of intermediate INT-8, wherein the first step uses (R)-3-(2-hydroxyethyl)piperazine-1-carboxylate tert-butyl ester (CAS:1272421- 10-9) Substitute compound INT-8A to obtain intermediate INT-13.
MS(ESI):m/z 274.2[M+H] +。 MS (ESI): m/z 274.2 [M+H] + .
[中间体INT-14的制备][Preparation of Intermediate INT-14]
Figure PCTCN2022078854-appb-000050
Figure PCTCN2022078854-appb-000050
中间体INT-14的合成参考中间体INT-8的合成步骤，其中第一步用(S)-3-(2-羟乙基)哌嗪-1-羧酸叔丁酯(CAS:1273577-11-9)代替化合物INT-8A，并用2,3-二氟-5-氯吡啶(CAS:89402-43-7)代替2,3-二氟-5-(三氟甲基)吡啶，得到中间体INT-14。The synthesis of intermediate INT-14 refers to the synthesis steps of intermediate INT-8, wherein the first step uses (S)-3-(2-hydroxyethyl)piperazine-1-carboxylate tert-butyl ester (CAS:1273577- 11-9) in place of compound INT-8A and 2,3-difluoro-5-chloropyridine (CAS:89402-43-7) in place of 2,3-difluoro-5-(trifluoromethyl)pyridine to give Intermediate INT-14.
MS(ESI):m/z 240.0[M+H] +。 MS (ESI): m/z 240.0 [M+H] + .
[中间体INT-15的制备][Preparation of intermediate INT-15]
Figure PCTCN2022078854-appb-000051
Figure PCTCN2022078854-appb-000051
中间体INT-15的合成参考中间体INT-8的合成步骤，其中第一步用(R)-3-(2-羟乙基)哌嗪-1-羧酸叔丁酯(CAS:1272421-10-9)代替化合物INT-8A，并用2,3-二氟-5-氯吡啶(CAS:89402-43-7)代替2,3-二氟-5-(三氟甲基)吡啶，得到中间体INT-15。The synthesis of intermediate INT-15 refers to the synthesis steps of intermediate INT-8, wherein the first step uses (R)-3-(2-hydroxyethyl)piperazine-1-carboxylate tert-butyl ester (CAS:1272421- 10-9) in place of compound INT-8A and 2,3-difluoro-5-chloropyridine (CAS:89402-43-7) in place of 2,3-difluoro-5-(trifluoromethyl)pyridine to give Intermediate INT-15.
MS(ESI):m/z 240.0[M+H] +。 MS (ESI): m/z 240.0 [M+H] + .
[中间体INT-16的制备][Preparation of intermediate INT-16]
Figure PCTCN2022078854-appb-000052
Figure PCTCN2022078854-appb-000052
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000053
Figure PCTCN2022078854-appb-000053
第一步：合成化合物INT-16BStep 1: Synthesis of compound INT-16B
将化合物INT-16A(4.0g，16.74mmol)溶于DMSO(40mL)中，再向反应液中依次加入(S)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(4.34g，20.08mmol)，氟化铯(6.54g，20.08mmol)，将反应加热到80℃搅拌16小时。TLC显示反应结束后，把反应液倒入乙酸乙酯(80ml)和饱和氯化钠(80ml)的混合溶剂中，搅拌后分出有机层，水层用乙酸乙酯(60ml×2)萃取。合并的有机相用水(60ml)，饱和食盐水(40ml)洗涤，无水硫酸钠干燥后浓缩，残余物用硅胶柱(洗脱剂：石油醚/乙酸乙酯＝10/1,5/1,3/1)层析纯化，得到化合物INT-16B(5.2g，淡黄色固体，产率：80.3％)。Compound INT-16A (4.0 g, 16.74 mmol) was dissolved in DMSO (40 mL), and (S)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester (4.34 g) was added to the reaction solution successively. g, 20.08 mmol), cesium fluoride (6.54 g, 20.08 mmol), and the reaction was heated to 80°C and stirred for 16 hours. After TLC showed that the reaction was completed, the reaction solution was poured into a mixed solvent of ethyl acetate (80ml) and saturated sodium chloride (80ml), stirred, and the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (60ml×2). The combined organic phases were washed with water (60 ml), saturated brine (40 ml), dried over anhydrous sodium sulfate and concentrated, and the residue was washed with silica gel column (eluent: petroleum ether/ethyl acetate = 10/1, 5/1, 3/1) Purification by chromatography to obtain compound INT-16B (5.2 g, pale yellow solid, yield: 80.3%).
MS(ESI):m/z 388.1[M+H] +。 MS (ESI): m/z 388.1 [M+H] + .
第二步：合成化合物INT-16CStep 2: Synthesis of compound INT-16C
将化合物INT-16B(3.6g，9.3mmol)溶于无水四氢呋喃(60mL)中，在-60℃下缓慢滴加二异丁基氢化铝(18.6ml，18.6mmol，1M正己烷溶液)，滴加完毕后，体系在-60℃搅拌0.5小时。TLC显示反应结束后，低温下滴加10ml甲醇，搅拌5分钟用来淬灭过量的二异丁基氢化铝，再滴加20ml饱和的酒石酸钾钠溶液，继续搅拌，直至反应体系升至室温。把反应液倒入乙酸乙酯(120ml)和饱和氯化钠(160ml)的混合溶液中，搅拌后分出有机层，水层用乙酸乙酯(60ml*2)萃取。合并的有机相用水(60ml)，饱和食盐水(40ml)洗涤，无水硫酸钠干燥后浓缩，得到粗品化合物INT-16C(1.8g，淡黄色液体，产率49.7％)。Compound INT-16B (3.6 g, 9.3 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL), and diisobutylaluminum hydride (18.6 ml, 18.6 mmol, 1M n-hexane solution) was slowly added dropwise at -60 °C. After the addition was complete, the system was stirred at -60°C for 0.5 hour. After TLC showed that the reaction was completed, 10 ml of methanol was added dropwise at low temperature, and stirred for 5 minutes to quench excess diisobutylaluminum hydride, and then 20 ml of saturated potassium sodium tartrate solution was added dropwise, and stirring was continued until the reaction system reached room temperature. The reaction solution was poured into a mixed solution of ethyl acetate (120 ml) and saturated sodium chloride (160 ml), the organic layer was separated after stirring, and the aqueous layer was extracted with ethyl acetate (60 ml*2). The combined organic phases were washed with water (60 ml) and saturated brine (40 ml), dried over anhydrous sodium sulfate and concentrated to obtain crude compound INT-16C (1.8 g, pale yellow liquid, yield 49.7%).
MS(ESI):m/z 390.1[M+H] +。 MS (ESI): m/z 390.1 [M+H] + .
第三步：合成化合物INT-16DThe third step: Synthesis of compound INT-16D
将化合物INT-16C(1.6g，4.12mmol)溶于二氯甲烷(15ml)中，室温下依次向反应液中滴加入三乙基硅烷(2.86g，24.72mmol)，三氟乙酸(1.4g，12.36mmol)，滴加完毕后，反应在室温(25℃)下搅拌16小时。TLC显示反应结束后，将反应液倒入100ml冰水中，用饱和碳酸氢钠溶液调节至pH＝7-8，二氯甲烷(60ml*2)萃取。合并的有机相用水(60ml)，饱和食盐水(40ml)洗涤，无水硫酸钠干燥后浓缩，残余物用硅胶柱(洗脱剂：石油醚/乙酸乙酯＝10/1,5/1)层析纯化，浓缩，得到化合物INT-16D(1.2g，白色固体，产率：78.1％)。Compound INT-16C (1.6 g, 4.12 mmol) was dissolved in dichloromethane (15 ml), and triethylsilane (2.86 g, 24.72 mmol), trifluoroacetic acid (1.4 g, 12.36 mmol), after the addition was complete, the reaction was stirred at room temperature (25°C) for 16 hours. After TLC showed that the reaction was completed, the reaction solution was poured into 100 ml of ice water, adjusted to pH=7-8 with saturated sodium bicarbonate solution, and extracted with dichloromethane (60 ml*2). The combined organic phases were washed with water (60 ml) and saturated brine (40 ml), dried over anhydrous sodium sulfate and concentrated, and the residue was applied to a silica gel column (eluent: petroleum ether/ethyl acetate = 10/1, 5/1) Chromatographic purification and concentration gave compound INT-16D (1.2 g, white solid, yield: 78.1%).
MS(ESI):m/z 374.2[M+H] +。 MS (ESI): m/z 374.2 [M+H] + .
第四步：合成化合物INT-16Step 4: Synthesis of compound INT-16
将化合物INT-16D(300mg，0.80mmol)溶于二氯甲烷(3.0mL)中，室温滴加三氟乙酸(0.6ml)，然后室温搅拌反30分钟。TLC显示反应结束后，把反应液倒入冰水(20ml)中，加饱和碳酸氢钠溶液至pH＝8。用二氯甲烷(20ml*3)萃取，合并的有机相用饱和食盐水(20ml)洗涤，无水硫酸钠干燥后浓缩，得到化合物INT-16(208mg，淡黄色液体，产率94.5％)。Compound INT-16D (300 mg, 0.80 mmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (0.6 ml) was added dropwise at room temperature, followed by stirring at room temperature for 30 minutes. After TLC showed that the reaction was complete, the reaction solution was poured into ice water (20 ml), and saturated sodium bicarbonate solution was added to pH=8. Extracted with dichloromethane (20ml*3), the combined organic phases were washed with saturated brine (20ml), dried over anhydrous sodium sulfate and concentrated to obtain compound INT-16 (208mg, pale yellow liquid, yield 94.5%).
MS(ESI):m/z 274.2[M+H] +。 MS (ESI): m/z 274.2 [M+H] + .
[中间体INT-17的制备][Preparation of Intermediate INT-17]
Figure PCTCN2022078854-appb-000054
Figure PCTCN2022078854-appb-000054
中间体INT-17的合成参考中间体INT-16的合成步骤，其中第一步用(R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯代替(S)-3-(羟甲基)哌嗪-1-羧酸叔丁酯，得到中间体INT-17。The synthesis of intermediate INT-17 refers to the synthesis procedure of intermediate INT-16, wherein in the first step, (R)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester is used instead of (S)-3- (Hydroxymethyl)piperazine-1-carboxylate tert-butyl ester to yield intermediate INT-17.
MS(ESI):m/z 274.2[M+H] +。 MS (ESI): m/z 274.2 [M+H] + .
化合物的制备Preparation of compounds
实施例1：化合物1的制备Example 1: Preparation of Compound 1
Figure PCTCN2022078854-appb-000055
Figure PCTCN2022078854-appb-000055
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000056
Figure PCTCN2022078854-appb-000056
制备方法：Preparation:
第一步：合成化合物1CStep 1: Synthesis of Compound 1C
将化合物1A(2.6g,10mmol)和1B(2.6g,12mmol)溶于DMSO(30mL)中，然 后加入氟化铯(3g,20mmol)，升温到100℃反应2小时。TLC显示反应结束后，将反应液冷却，加入到水(150ml)中，并用乙酸乙酯萃取(100ml×3)，合并的有机相再用饱和氯化钠水溶液(100ml×2)洗涤，有机相用硫酸钠干燥后减压脱溶，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1:1(体积比))，得到化合物1C(2.9g，黄色固体，产率67％)。Compounds 1A (2.6 g, 10 mmol) and 1B (2.6 g, 12 mmol) were dissolved in DMSO (30 mL), then cesium fluoride (3 g, 20 mmol) was added, and the temperature was raised to 100 °C for 2 hours. After TLC showed that the reaction was over, the reaction solution was cooled, added to water (150ml), and extracted with ethyl acetate (100ml×3). The combined organic phases were washed with saturated aqueous sodium chloride solution (100ml×2). After drying with sodium sulfate, the solution was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1:1 (volume ratio)) to obtain compound 1C (2.9 g, yellow solid, yield 67%).
MS(ESI):m/z 440.2[M+1] +。 MS(ESI): m/z 440.2[M+1] + .
第二步：合成化合物1DStep 2: Synthesis of Compound 1D
将化合物1C(2.2g,5mmol)溶于二氧六环(25mL)中，依次加入碳酸铯(3.26g,10mmol)、xantphos(289mg,0.5mmol,cas:161265-03-8)和乙酸钯(112mg,0.5mmol)，然后氮气保护下，升温到100℃，反应16小时。TLC显示反应结束后，减压脱溶反应液，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3:1(体积比))，得到化合物1D(1.16g，黄色固体，产率62％)。Compound 1C (2.2 g, 5 mmol) was dissolved in dioxane (25 mL), cesium carbonate (3.26 g, 10 mmol), xantphos (289 mg, 0.5 mmol, cas: 161265-03-8) and palladium acetate ( 112 mg, 0.5 mmol), then under the protection of nitrogen, the temperature was raised to 100 °C, and the reaction was carried out for 16 hours. After TLC showed that the reaction was completed, the reaction solution was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 3:1 (volume ratio)) to obtain compound 1D (1.16 g, yellow solid, 62% yield).
MS(ESI):m/z 360.1[M+1] +。 MS(ESI): m/z 360.1[M+1] + .
第三步：合成化合物1EStep 3: Synthesis of Compound 1E
将化合物1D(1.1g,3mmol)加入到EA(10mL)中，冰浴下滴加质量分数为8％HCl-EA(10mL)，室温反应12h。TLC显示反应结束后，将反应液减压脱溶，得到化合物1E(0.7g，黄色固体，产率94％)。Compound 1D (1.1 g, 3 mmol) was added to EA (10 mL), 8% HCl-EA (10 mL) was added dropwise under ice bath, and the reaction was carried out at room temperature for 12 h. After TLC showed that the reaction was completed, the reaction solution was desolvated under reduced pressure to obtain compound 1E (0.7 g, yellow solid, yield 94%).
MS(ESI):m/z 260.2[M+1] +。 MS(ESI): m/z 260.2[M+1] + .
第四步：合成化合物1FStep 4: Synthesis of Compound 1F
将化合物INT-1(200mg,0.47mmol)加入到DMF(3mL)中，然后加入DIEA(129mg,1mmol)和HATU(380mg,1mmol)，反应液室温反应20分钟。再加入上一步得到的化合物1E(146mg,0.56mmol)，室温反应3小时。TLC显示反应结束后，将反应液加入到水(20ml)中，并用乙酸乙酯萃取(10ml×3)，合并的有机相再用饱和氯化钠水溶液(10ml×2)洗涤，有机相用硫酸钠干燥后减压脱溶，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1:2(体积比))，得到化合物1F(177mg，黄色固体，产率56％)。Compound INT-1 (200 mg, 0.47 mmol) was added to DMF (3 mL), then DIEA (129 mg, 1 mmol) and HATU (380 mg, 1 mmol) were added, and the reaction solution was reacted at room temperature for 20 minutes. Compound 1E (146 mg, 0.56 mmol) obtained in the previous step was added, and the reaction was carried out at room temperature for 3 hours. After TLC showed that the reaction was over, the reaction solution was added to water (20ml) and extracted with ethyl acetate (10ml×3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10ml×2), and the organic phase was washed with sulfuric acid. After drying with sodium, the solution was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:2 (volume ratio)) to obtain compound 1F (177 mg, yellow solid, yield 56). %).
MS(ESI):m/z 671[M+1] +。 MS(ESI): m/z 671[M+1] + .
第五步：合成化合物1Step 5: Synthesis of Compound 1
室温下，将化合物1F(150mg,0.22mmol)加入到三氟乙酸(2mL)中，然后加入三氟甲磺酸(0.3ml)。加完后，室温反应2h。TLC显示反应结束后，加入水(10ml)，用饱和碳酸钾水溶液调PH到8-9，再并用乙酸乙酯萃取(10ml×3)，合并的有机相再用饱和氯化钠水溶液(10ml×2)洗涤，有机相用硫酸钠干燥后减压脱溶，得到黄色固体粗品，通过制备硅胶板纯化(展开剂：石油醚/乙酸乙酯＝1:2(体积比)，得到化合物1(53mg，白色固体，产率44％)。Compound IF (150 mg, 0.22 mmol) was added to trifluoroacetic acid (2 mL) followed by trifluoromethanesulfonic acid (0.3 mL) at room temperature. After the addition, the reaction was carried out at room temperature for 2h. After TLC showed that the reaction was over, water (10 ml) was added, the pH was adjusted to 8-9 with saturated aqueous potassium carbonate solution, and then extracted with ethyl acetate (10 ml×3), and the combined organic phases were then washed with saturated aqueous sodium chloride solution (10 ml×3). 2) Washing, the organic phase was dried with sodium sulfate and desolvated under reduced pressure to obtain a yellow solid crude product, which was purified by preparing a silica gel plate (developing solvent: petroleum ether/ethyl acetate = 1:2 (volume ratio) to obtain compound 1 (53 mg) , white solid, 44% yield).
MS(ESI):m/z 551[M+1] +。 MS(ESI): m/z 551[M+1] + .
1H-NMR(400MHz,DMSO-d6):12.44(s,1H),8.07(s,1H),7.91(s,1H),7.28(s,1H),6.25(s,1H),4.51-4.29(m,3H),4.16-4.13(m,1H),4.03-3.95(m,2H),3.77-3.65(m,2H),3.49-3.47 (m,2H),3.43-3.40(m,1H),3.17-3.11(m,1H),2.91-2.85(m,1H),2.79-2.71(m,1H),2.68-2.60(m,2H),1.15(d,J＝8H,3H)。 1 H-NMR (400MHz, DMSO-d6): 12.44(s, 1H), 8.07(s, 1H), 7.91(s, 1H), 7.28(s, 1H), 6.25(s, 1H), 4.51-4.29 (m, 3H), 4.16-4.13 (m, 1H), 4.03-3.95 (m, 2H), 3.77-3.65 (m, 2H), 3.49-3.47 (m, 2H), 3.43-3.40 (m, 1H) , 3.17-3.11 (m, 1H), 2.91-2.85 (m, 1H), 2.79-2.71 (m, 1H), 2.68-2.60 (m, 2H), 1.15 (d, J=8H, 3H).
利用购买得到的不同手性原料，采用合成化合物1的路线和条件，得到表1所示化合物：Utilize the different chiral raw materials obtained by purchasing, adopt the route and condition of synthesizing compound 1, obtain the compound shown in Table 1:
表1Table 1
Figure PCTCN2022078854-appb-000057
Figure PCTCN2022078854-appb-000057
实施例6：化合物6的制备Example 6: Preparation of Compound 6
Figure PCTCN2022078854-appb-000058
Figure PCTCN2022078854-appb-000058
化合物6的合成参考实施例1中化合物1的合成步骤，其中第四步用INT-10代替化合物1E，并用化合物INT-2代替化合物INT-1，得到化合物6。The synthesis of compound 6 refers to the synthesis steps of compound 1 in Example 1, wherein in the fourth step, compound 1E is replaced by INT-10, and compound INT-1 is replaced by compound INT-2 to obtain compound 6.
MS(ESI):m/z 517[M+1] +。 MS(ESI): m/z 517[M+1] + .
1H-NMR(300MHz,DMSO-d 6):δ12.46(s,1H),7.90(s,1H),7.74(d,J＝2.2Hz,1H),7.17(d,J＝2.2Hz,1H),6.32-6.25(m,1H),4.50-4.26(m,4H),4.16-4.05(m,1H),4.06-3.89(m,2H),3.69-3.60(m,2H),3.50-3.44(m,2H),3.23-3.09(m,1H),2.85-2.65(m,1H),2.63-2.55(s,3H),1.13(d,J＝6.5Hz,3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 12.46 (s, 1H), 7.90 (s, 1H), 7.74 (d, J=2.2Hz, 1H), 7.17 (d, J=2.2Hz, 1H), 6.32-6.25(m, 1H), 4.50-4.26(m, 4H), 4.16-4.05(m, 1H), 4.06-3.89(m, 2H), 3.69-3.60(m, 2H), 3.50- 3.44(m, 2H), 3.23-3.09(m, 1H), 2.85-2.65(m, 1H), 2.63-2.55(s, 3H), 1.13(d, J=6.5Hz, 3H).
实施例7：化合物7的制备Example 7: Preparation of Compound 7
Figure PCTCN2022078854-appb-000059
Figure PCTCN2022078854-appb-000059
化合物7的合成参考实施例1中化合物1的合成步骤，其中第四步用化合物INT-11代替化合物1E，并用化合物INT-2代替化合物INT-1，得到化合物7。The synthesis of compound 7 refers to the synthesis steps of compound 1 in Example 1, wherein compound INT-11 is used to replace compound 1E in the fourth step, and compound INT-2 is used to replace compound INT-1 to obtain compound 7.
MS(ESI):m/z 517[M+1] +。 MS(ESI): m/z 517[M+1] + .
1H-NMR(300MHz,DMSO-d 6):δ12.46(s,1H),7.90(s,1H),7.74(d,J＝2.1Hz,1H),7.16(d,J＝2.1Hz,1H),6.32-6.26(m,1H),4.48-4.28(m,4H),4.16-4.09(m,1H),4.06-3.90(m,2H),3.69-3.62(m,2H),3.50-3.45(m,2H),3.25-3.03(m,1H),2.88-2.70(m,1H),2.65-2.55(m,3H),1.13(d,J＝6.4Hz,3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.46(s, 1H), 7.90(s, 1H), 7.74(d, J=2.1Hz, 1H), 7.16(d, J=2.1Hz, 1H), 6.32-6.26(m, 1H), 4.48-4.28(m, 4H), 4.16-4.09(m, 1H), 4.06-3.90(m, 2H), 3.69-3.62(m, 2H), 3.50- 3.45(m, 2H), 3.25-3.03(m, 1H), 2.88-2.70(m, 1H), 2.65-2.55(m, 3H), 1.13(d, J=6.4Hz, 3H).
实施例8：化合物8的制备Example 8: Preparation of Compound 8
Figure PCTCN2022078854-appb-000060
Figure PCTCN2022078854-appb-000060
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000061
Figure PCTCN2022078854-appb-000061
制备方法：Preparation:
第一步：合成化合物8AStep 1: Synthesis of Compound 8A
将化合物INT-5(200mg,0.47mmol)加入到DMF(3mL)中，然后加入DIEA(129mg,1mmol)和HATU(380mg,1mmol)，反应液室温反应20分钟。再加入上一步得到的化合物INT-10(146mg,0.56mmol)，室温反应3小时。TLC显示反应结束后，将反应液加入到水(20ml)中，并用乙酸乙酯萃取(10ml×3)，合并的有机相再用饱和氯化钠水溶液(10ml×2)洗涤，有机相用硫酸钠干燥后减压脱溶，所得残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1:2(体积比))，得到化合物8A(177mg，黄色固体，产率56％)。Compound INT-5 (200 mg, 0.47 mmol) was added to DMF (3 mL), then DIEA (129 mg, 1 mmol) and HATU (380 mg, 1 mmol) were added, and the reaction solution was reacted at room temperature for 20 minutes. The compound INT-10 (146 mg, 0.56 mmol) obtained in the previous step was added, and the reaction was carried out at room temperature for 3 hours. After TLC showed that the reaction was over, the reaction solution was added to water (20ml) and extracted with ethyl acetate (10ml×3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10ml×2), and the organic phase was washed with sulfuric acid. After drying with sodium, the solution was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1:2 (volume ratio)) to obtain compound 8A (177 mg, yellow solid, yield 56). %).
MS(ESI):m/z 638.2[M+1] +。 MS(ESI): m/z 638.2[M+1] + .
第二步：合成化合物8Step 2: Synthesis of Compound 8
室温下，将化合物8A(150mg,0.22mmol)加入到三氟乙酸(2mL)中，然后加入三氟甲磺酸(0.3ml)。加完后，室温反应2h。TLC显示反应结束后，加入水(10ml)，用饱和碳酸钾水溶液调PH到8-9，再并用乙酸乙酯萃取(10ml×3)，合并的有机相再用 饱和氯化钠水溶液(10ml×2)洗涤，有机相用硫酸钠干燥后减压脱溶，得到黄色固体粗品，通过制备硅胶板纯化(展开剂：石油醚/乙酸乙酯＝1:2(体积比)，得到化合物8(53mg，白色固体，产率44％)。Compound 8A (150 mg, 0.22 mmol) was added to trifluoroacetic acid (2 mL) followed by trifluoromethanesulfonic acid (0.3 mL) at room temperature. After the addition, the reaction was carried out at room temperature for 2h. After TLC showed that the reaction was over, water (10 ml) was added, the pH was adjusted to 8-9 with saturated aqueous potassium carbonate solution, and then extracted with ethyl acetate (10 ml×3), and the combined organic phases were then washed with saturated aqueous sodium chloride solution (10 ml×3). 2) Washing, the organic phase was dried with sodium sulfate and then desolvated under reduced pressure to obtain a yellow solid crude product, which was purified by preparing a silica gel plate (developing solvent: petroleum ether/ethyl acetate = 1:2 (volume ratio) to obtain compound 8 (53 mg) , white solid, 44% yield).
MS(ESI):m/z 518[M+H] +。 MS (ESI): m/z 518 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ13.25(s,1H),8.27-8.22(m,1H),7.74(d,J＝2.2Hz,1H),7.16(d,J＝1.8Hz,1H),5.15-5.09(m,1H),4.43-4.30(m,4H),3.99-3.95(m,2H),3.78-3.47(m,5H),3.16-3.02(m,1H),2.81-2.73(m,1H),2.60-2.54(m,2H),1.28-1.12(m,3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 13.25 (s, 1H), 8.27-8.22 (m, 1H), 7.74 (d, J=2.2Hz, 1H), 7.16 (d, J=1.8 Hz,1H),5.15-5.09(m,1H),4.43-4.30(m,4H),3.99-3.95(m,2H),3.78-3.47(m,5H),3.16-3.02(m,1H), 2.81-2.73(m,1H),2.60-2.54(m,2H),1.28-1.12(m,3H).
实施例9：化合物9的制备Example 9: Preparation of Compound 9
Figure PCTCN2022078854-appb-000062
Figure PCTCN2022078854-appb-000062
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000063
Figure PCTCN2022078854-appb-000063
制备方法：Preparation:
第一步：合成化合物9BStep 1: Synthesis of Compound 9B
将化合物INT-1F(10g，31.3mmol)溶于乙醇(100mL)中，加入化合物9A(3.74g，31.3mmol)和三乙胺(6.35g，62.6mmol)，然后将反应液升至50℃反应2h。TLC显示反应结束后，将反应液减压脱溶，得到化合物9B(13g，粗品)，直接用于下一步。Compound INT-1F (10 g, 31.3 mmol) was dissolved in ethanol (100 mL), compound 9A (3.74 g, 31.3 mmol) and triethylamine (6.35 g, 62.6 mmol) were added, and the reaction solution was raised to 50 °C for reaction 2h. After TLC showed that the reaction was completed, the reaction solution was desolvated under reduced pressure to obtain compound 9B (13 g, crude product), which was directly used in the next step.
MS(ESI):m/z 402[M+H] +。 MS(ESI): m/z 402[M+H] + .
第二步：合成化合物9CStep 2: Synthesis of Compound 9C
将化合物9B(13g，32.4mmol)溶于无水THF(100mL)中，冰浴下滴加硼烷二甲硫醚(10M，6.5mL，64.8mmol)，然后将反应液升至室温反应2h。TLC显示反应结束后，冰浴下慢慢滴加甲醇，待没有气体放出后，硼烷淬灭完毕，减压脱溶溶剂，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1:1(体积比))，得到化合物9C(9g，黄色油状，两步产率74％)。Compound 9B (13 g, 32.4 mmol) was dissolved in anhydrous THF (100 mL), borane dimethyl sulfide (10 M, 6.5 mL, 64.8 mmol) was added dropwise under ice bath, and then the reaction solution was warmed to room temperature for 2 h. After TLC showed that the reaction was over, methanol was slowly added dropwise under an ice bath. After no gas was released, the quenching of borane was completed, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/acetic acid). ethyl ester = 1:1 (volume ratio)) to give compound 9C (9 g, yellow oil, 74% yield for two steps).
1H-NMR(400MHz,DMSO-d 6):δ7.93(s,1H),7.26-7.16(m,2H),6.92-6.82(m,2H),5.04(s,2H),4.91-4.79(m,1H),3.84-3.76(m,1H),3.71(s,3H),3.70-3.64(m,1H),3.36-3.30(m,2H),3.25(s,3H). 1 H-NMR (400MHz, DMSO-d 6 ): δ7.93(s, 1H), 7.26-7.16(m, 2H), 6.92-6.82(m, 2H), 5.04(s, 2H), 4.91-4.79 (m,1H),3.84-3.76(m,1H),3.71(s,3H),3.70-3.64(m,1H),3.36-3.30(m,2H),3.25(s,3H).
第三步：合成化合物9DStep 3: Synthesis of Compound 9D
将化合物9C(9g，23.2mmol)加入到乙腈(90mL)中，再加入丙烯酸甲酯(12g，140mmol)和碳酸铯(9.1g，28mmol)，室温反应2h。TLC显示反应结束后，将反应液过滤，滤饼用乙酸乙酯洗涤，有机相减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1(体积比))，得到化合物9D(6.8g，淡黄色油状物，产率62％)。Compound 9C (9 g, 23.2 mmol) was added to acetonitrile (90 mL), then methyl acrylate (12 g, 140 mmol) and cesium carbonate (9.1 g, 28 mmol) were added, and the reaction was carried out at room temperature for 2 h. After TLC showed that the reaction was over, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the organic phase was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5/1 ( volume ratio)) to obtain compound 9D (6.8 g, pale yellow oil, yield 62%).
MS(ESI):m/z 474[M+H] +。 MS (ESI): m/z 474 [M+H] + .
第四步：合成化合物9EStep 4: Synthesis of Compound 9E
将化合物9D(6.8g，14.4mmol)加入到甲醇(30mL)和水(30mL)的混合溶剂中，冰浴下加入LiOH(516mg，21.5mmol)，将反应液升至室温，反应2h。TLC显示反应结束后，冰浴下用1M HCl溶液将反应液pH调为6-7，用二氯甲烷萃取3次，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3:1(体积比))，得到化合物9E(4.8g，淡黄色油状，产率72.7％)。Compound 9D (6.8 g, 14.4 mmol) was added to a mixed solvent of methanol (30 mL) and water (30 mL), LiOH (516 mg, 21.5 mmol) was added under ice bath, and the reaction solution was warmed to room temperature for 2 h. After TLC showed that the reaction was completed, the pH of the reaction solution was adjusted to 6-7 with 1M HCl solution under ice bath, extracted with dichloromethane 3 times, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate) =3:1 (volume ratio)) to obtain compound 9E (4.8 g, pale yellow oil, yield 72.7%).
MS(ESI):m/z 460[M+H] +。 MS(ESI): m/z 460 [M+H] + .
第五步：合成化合物9FStep 5: Synthesis of Compound 9F
将化合物9E(1g，2.2mmol)加入到DMF(10mL)中，冰浴下加入HATU(1g，2.6mmol)和DIEA(844mg，6.5mmol)，0℃反应15min，加入化合物INT-10(564mg，2.2mmol)，0℃反应10min。TLC显示反应结束后，加入水和乙酸乙酯萃取，有机相用盐水洗涤三次，用无水硫酸钠干燥，减压蒸除溶剂，残余物用硅胶柱层析纯化(展开剂：石油醚/乙酸乙酯＝1:1(体积比))，得到化合物9F(1.4g，黄色油状，产率91.8％)。Compound 9E (1 g, 2.2 mmol) was added to DMF (10 mL), HATU (1 g, 2.6 mmol) and DIEA (844 mg, 6.5 mmol) were added under ice bath, the reaction was carried out at 0°C for 15 min, and compound INT-10 (564 mg, 2.2 mmol), and reacted at 0 °C for 10 min. After TLC showed that the reaction was completed, water and ethyl acetate were added for extraction. The organic phase was washed three times with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: petroleum ether/acetic acid). ethyl ester = 1:1 (volume ratio)) to obtain compound 9F (1.4 g, yellow oil, yield 91.8%).
MS(ESI):m/z 701.2[M+H] +。 MS (ESI): m/z 701.2 [M+H] + .
第六步：合成化合物9Step 6: Synthesis of Compound 9
将化合物9F(1.4g，2mmol)加入到TFA(15mL)中，冰浴下滴加三氟甲磺酸(1.5mL)，室温反应5min。TLC显示反应结束后，冰浴下滴加碳酸氢钠水溶液，调节pH为6-7，用乙酸乙酯萃取有机相，减压脱溶，再用HPLC制备纯化(Waters Sunfire OBD 100x30mm，5μm，流动相A：0.1％TFA水溶液，流动相B：乙腈，梯度：10％乙腈运行至1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物9(420mg，白色固体，产率36％)。Compound 9F (1.4 g, 2 mmol) was added to TFA (15 mL), trifluoromethanesulfonic acid (1.5 mL) was added dropwise under an ice bath, and the reaction was carried out at room temperature for 5 min. After TLC showed that the reaction was over, an aqueous solution of sodium bicarbonate was added dropwise under an ice bath to adjust the pH to 6-7, the organic phase was extracted with ethyl acetate, desolvated under reduced pressure, and purified by HPLC (Waters Sunfire OBD 100×30 mm, 5 μm, flowing Phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile run to 1 min, 52%-52% acetonitrile run to 10 min, 95% acetonitrile run to 14 min, 10% acetonitrile run to 16 min end), get Compound 9 (420 mg, white solid, 36% yield).
MS(ESI):m/z 547.2[M+H] +。 MS (ESI): m/z 547.2 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ12.49(s,1H),7.91(s,1H),7.74(d,J＝2.2Hz,1H),7.17(d,J＝2.2Hz,1H),6.28-6.17(m,1H),4.49-4.18(m,5H),4.05-3.92(m,2H),3.70-3.62(m,3H),3.57-3.47(m,2H),3.48-3.40(m,2H),3.25(s,3H),3.21-3.05(m,1H),2.90-2.67(m,1H),2.60(s,2H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 12.49 (s, 1H), 7.91 (s, 1H), 7.74 (d, J=2.2Hz, 1H), 7.17 (d, J=2.2Hz, 1H), 6.28-6.17(m, 1H), 4.49-4.18(m, 5H), 4.05-3.92(m, 2H), 3.70-3.62(m, 3H), 3.57-3.47(m, 2H), 3.48- 3.40(m, 2H), 3.25(s, 3H), 3.21-3.05(m, 1H), 2.90-2.67(m, 1H), 2.60(s, 2H).
实施例10：化合物10的制备Example 10: Preparation of Compound 10
Figure PCTCN2022078854-appb-000064
Figure PCTCN2022078854-appb-000064
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000065
Figure PCTCN2022078854-appb-000065
制备方法：Preparation:
第一步：合成化合物10BStep 1: Synthesis of Compound 10B
将化合物10A(1g，5.35mmol，1eq)加入到CH 3CN(10mL)中，再加化合物丙烯酸甲酯(2.68g，26.75mmol，5eq)，然后冰浴下加入Cs 2CO 3(5.24g，16.05mmol，3eq)，将反应液升至室温下搅拌2h。TLC显示反应结束后，把反应液过滤减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1(体积比))，得到化合物10B(460mg，无色油状液体，产率：32％)。 Compound 10A (1 g, 5.35 mmol, 1 eq) was added to CH 3 CN (10 mL), followed by compound methyl acrylate (2.68 g, 26.75 mmol, 5 eq), then Cs 2 CO 3 (5.24 g, 5.24 g, 5 eq) was added under ice bath. 16.05mmol, 3eq), the reaction solution was raised to room temperature and stirred for 2h. After TLC showed that the reaction was completed, the reaction solution was filtered and desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 (volume ratio)) to obtain compound 10B (460 mg, Colorless oily liquid, yield: 32%).
MS(ESI):m/z 274.2[M+H] +。 MS (ESI): m/z 274.2 [M+H] + .
第二步：合成化合物10CStep 2: Synthesis of compound 10C
将化合物10B(460mg，1.68mmol，1eq)加入到质量分数为8％HCl/EA(6mL)中，室温下搅拌2h。TLC显示反应结束后，把反应液减压脱溶，得到化合物10C(292mg，无色油状液体)。粗品直接投下一步反应。Compound 10B (460 mg, 1.68 mmol, 1 eq) was added to 8% HCl/EA (6 mL), and stirred at room temperature for 2 h. After TLC showed that the reaction was completed, the reaction solution was desolubilized under reduced pressure to obtain compound 10C (292 mg, colorless oily liquid). The crude product was directly put into the next reaction.
MS(ESI):m/z 174.2[M+H] +。 MS (ESI): m/z 174.2 [M+H] + .
第三步：合成化合物10DStep 3: Synthesis of Compound 10D
将化合物10C(292mg，1.68mmol，1eq)溶于THF(6mL)中，然后加入INT-1F(456mg，1.43mmol，0.85eq)，再加入TEA(510mg，5mmol，3eq)。加完后将反应液升温至60℃，搅拌2h。TLC显示反应结束后，将反应液减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1(体积比))，得到化合物10D(268mg，淡黄色油状液体，产率：35％)。Compound 10C (292 mg, 1.68 mmol, 1 eq) was dissolved in THF (6 mL), then INT-1F (456 mg, 1.43 mmol, 0.85 eq) was added, followed by TEA (510 mg, 5 mmol, 3 eq). After the addition, the reaction solution was heated to 60 °C and stirred for 2 h. After TLC showed that the reaction was completed, the reaction solution was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 (volume ratio)) to obtain compound 10D (268 mg, pale Yellow oily liquid, yield: 35%).
MS(ESI):m/z 456.2[M+H] +。 MS(ESI): m/z 456.2 [M+H] + .
第四步：合成化合物10EStep 4: Synthesis of Compound 10E
将化合物10D(268mg，0.59mmol，1eq)溶于MeOH/H 2O中(2mL/2mL)，然后加入一水合氢氧化锂(74mg，1.92mmol，3eq)，反应液室温下反应0.5h。TLC显示结束后，使用1N稀盐酸调pH至5，用EA萃取，有机相加无水硫酸钠干燥，减压脱溶，得到化合物10E(240mg，淡黄色油状液体，产率：92％)。 Compound 10D (268 mg, 0.59 mmol, 1 eq) was dissolved in MeOH/H 2 O (2 mL/2 mL), then lithium hydroxide monohydrate (74 mg, 1.92 mmol, 3 eq) was added, and the reaction solution was reacted at room temperature for 0.5 h. After TLC showed that the pH was adjusted to 5 with 1N dilute hydrochloric acid, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, and desolvated under reduced pressure to obtain compound 10E (240 mg, pale yellow oily liquid, yield: 92%).
MS(ESI):m/z 442.2[M+H] +。 MS(ESI): m/z 442.2 [M+H] + .
第五步：合成化合物10FStep 5: Synthesis of Compound 10F
将化合物10E(100mg，0.23mmol，1eq)加入到DMF(3mL)中，然后再加入HATU(105mg，0.27mmol，1.2eq)，冰浴下滴加DIEA(88mg，0.69mmol，3eq)，室温下搅拌5min，加入化合物INT-10(60mg，0.23mmol，1eq)，把反应液拿到室温下反应30min。TLC显示反应结束后，用EA和饱和NaCl溶液萃取，有机相加无水硫酸钠干燥，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1(体积比))，得到化合物10F(120mg，淡黄色油状液体，产率：77％)。Compound 10E (100 mg, 0.23 mmol, 1 eq) was added to DMF (3 mL), then HATU (105 mg, 0.27 mmol, 1.2 eq) was added, DIEA (88 mg, 0.69 mmol, 3 eq) was added dropwise under ice bath, at room temperature After stirring for 5 min, compound INT-10 (60 mg, 0.23 mmol, 1 eq) was added, and the reaction solution was brought to room temperature to react for 30 min. After TLC showed that the reaction was over, it was extracted with EA and saturated NaCl solution, the organic phase was dried over anhydrous sodium sulfate, desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/ 1 (volume ratio)) to obtain compound 10F (120 mg, pale yellow oily liquid, yield: 77%).
MS(ESI):m/z 649.2[M+H] +。 MS(ESI): m/z 649.2 [M+H] + .
第六步：合成化合物10Step 6: Synthesis of Compound 10
将化合物10F(120mg，0.18mmol，1eq)在冰浴下滴加到TFA(2mL)中，然后在冰浴下加入三氟甲磺酸(0.2mL)，加完后将反应液升至室温，搅拌10min。TLC显示反应结束后，加入饱和NaHCO 3调pH至7，用EA萃取，有机相用无水Na 2SO 4干燥，减压脱溶，经prep-HPLC(FA)纯化，得到化合物10(25mg，白色固体，产率：25％)。 Compound 10F (120 mg, 0.18 mmol, 1 eq) was added dropwise to TFA (2 mL) under ice bath, then trifluoromethanesulfonic acid (0.2 mL) was added under ice bath, and the reaction solution was warmed to room temperature after the addition was complete, Stir for 10 minutes. After TLC showed that the reaction was over, saturated NaHCO was added to adjust the pH to 7 , extracted with EA, the organic phase was dried over anhydrous Na 2 SO 4 , desolvated under reduced pressure, and purified by prep-HPLC (FA) to give compound 10 (25 mg, White solid, yield: 25%).
MS(ESI):m/z 529.2[M+H] +。 MS (ESI): m/z 529.2 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ12.36(s,1H),7.74(d,J＝2.2Hz,1H),7.64(s,1H),7.17(d,J＝2.3Hz,1H),4.84-4.78(m,1H),4.36-4.27(m,4H),4.10-3.82(m,4H),3.75-3.69(m,5H),3.22-3.05(m,1H),3.80-2.70(m,1H),2.67-2.59(m,2H),2.43-2.38(m,1H),2.02-1.88(m,1H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.36(s, 1H), 7.74(d, J=2.2Hz, 1H), 7.64(s, 1H), 7.17(d, J=2.3Hz, 1H), 4.84-4.78(m, 1H), 4.36-4.27(m, 4H), 4.10-3.82(m, 4H), 3.75-3.69(m, 5H), 3.22-3.05(m, 1H), 3.80- 2.70(m,1H),2.67-2.59(m,2H),2.43-2.38(m,1H),2.02-1.88(m,1H).
实施例11：化合物11的制备Example 11: Preparation of Compound 11
Figure PCTCN2022078854-appb-000066
Figure PCTCN2022078854-appb-000066
化合物11的合成参考实施例41中化合物41的合成步骤，其中第一步用化合物INT-10代替化合物INT-14，得到化合物11。The synthesis of compound 11 refers to the synthesis steps of compound 41 in Example 41, wherein compound INT-10 is replaced by compound INT-14 in the first step to obtain compound 11.
MS(ESI):m/z 548.2[M+H] +。 MS (ESI): m/z 548.2 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ13.24(s,1H),8.27(s,1H),7.74(d,J＝2.2Hz,1H),7.17(d,J＝2.2Hz,1H),5.20-5.11(m,1H),4.47-4.28(m,4H),4.01-3.89(m,2H),3.68-3.49(m,8H),3.24(s,3H),3.20-3.02(m,1H),2.59-2.57(m,1H),2.56-2.54(m,1H). 1 H-NMR (300MHz, DMSO-d 6 ): δ13.24(s, 1H), 8.27(s, 1H), 7.74(d, J=2.2Hz, 1H), 7.17(d, J=2.2Hz, 1H), 5.20-5.11(m, 1H), 4.47-4.28(m, 4H), 4.01-3.89(m, 2H), 3.68-3.49(m, 8H), 3.24(s, 3H), 3.20-3.02( m,1H),2.59-2.57(m,1H),2.56-2.54(m,1H).
实施例12：化合物12的制备Example 12: Preparation of Compound 12
Figure PCTCN2022078854-appb-000067
Figure PCTCN2022078854-appb-000067
化合物12的合成参考实施例10中化合物10的合成步骤，其中第五步用化合物INT-8代替化合物INT-10，得到化合物12。The synthesis of compound 12 refers to the synthesis steps of compound 10 in Example 10, wherein compound INT-8 is used instead of compound INT-10 in the fifth step to obtain compound 12.
MS(ESI):m/z 563.2[M+H] +。 MS(ESI): m/z 563.2 [M+H] + .
1H-NMR(400MHz,DMSO-d 6):δ12.35(s,1H),8.07(s,1H),7.66(s,1H),7.29(s,1H),4.84-4.81(m,1H),4.53-4.46(m,3H),4.35-4.20(m,1H),4.13-3.92(m,2H),3.91-3.81(m,1H),3.81-3.62(m,4H),3.60-3.37(m,1H),3.22-3.08(m,1H),2.95-2.84(m,1H),2.79-2.61(m,3H),2.45-2.40(m,1H),2.03-1.93(m,1H). 1 H-NMR (400MHz, DMSO-d 6 ): δ12.35(s, 1H), 8.07(s, 1H), 7.66(s, 1H), 7.29(s, 1H), 4.84-4.81(m, 1H) ),4.53-4.46(m,3H),4.35-4.20(m,1H),4.13-3.92(m,2H),3.91-3.81(m,1H),3.81-3.62(m,4H),3.60-3.37 (m,1H), 3.22-3.08(m,1H), 2.95-2.84(m,1H), 2.79-2.61(m,3H), 2.45-2.40(m,1H), 2.03-1.93(m,1H) .
实施例13：化合物13的制备Example 13: Preparation of Compound 13
Figure PCTCN2022078854-appb-000068
Figure PCTCN2022078854-appb-000068
化合物13的合成参考实施例10中化合物10的合成步骤，其中第一步用(S)-N-Boc-L-脯氨醇(CAS:69610-40-8)代替化合物10A，第五步用化合物INT-8代替化合物INT-10，得到化合物13。The synthesis of compound 13 refers to the synthesis steps of compound 10 in Example 10, wherein in the first step, (S)-N-Boc-L-prolinol (CAS: 69610-40-8) is used instead of compound 10A, and in the fifth step, Compound INT-8 was substituted for compound INT-10 to give compound 13.
MS(ESI):m/z 577.2[M+H] +。 MS (ESI): m/z 577.2 [M+H] + .
1H-NMR(300MHz,CDCl 3):δ10.60-10.38(m,1H),8.04(s,1H),7.93(s,1H),7.12(d,J＝2.1Hz,1H),4.74-4.61(m,2H),4.46-4.26(m,2H),4.05-3.55(m,6H),3.50-3.33(m,3H),3.29-3.17(m,1H),3.01-2.71(m,2H),2.61-2.40(m,3H),2.28-2.16(m,1H),2.06-1.90(m,1H),1.75-1.67(m,1H). 1 H-NMR (300MHz, CDCl 3 ): δ10.60-10.38(m, 1H), 8.04(s, 1H), 7.93(s, 1H), 7.12(d, J=2.1Hz, 1H), 4.74- 4.61(m, 2H), 4.46-4.26(m, 2H), 4.05-3.55(m, 6H), 3.50-3.33(m, 3H), 3.29-3.17(m, 1H), 3.01-2.71(m, 2H ), 2.61-2.40(m, 3H), 2.28-2.16(m, 1H), 2.06-1.90(m, 1H), 1.75-1.67(m, 1H).
实施例14：化合物14的制备Example 14: Preparation of Compound 14
Figure PCTCN2022078854-appb-000069
Figure PCTCN2022078854-appb-000069
化合物14的合成参考实施例10中化合物10的合成步骤，其中第一步用3-(羟甲基)吗啉-4-甲酸叔丁酯(CAS:473923-56-7)代替化合物10A，第五步用化合物INT-8代替哈化合物INT-10，得到化合物14。The synthesis of compound 14 refers to the synthesis steps of compound 10 in Example 10, wherein in the first step, compound 10A is replaced by tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (CAS: 473923-56-7), and the first step is to replace compound 10A. Compound 14 was obtained by replacing compound INT-10 with compound INT-8 in five steps.
MS(ESI):m/z 593.2[M+H]+。MS(ESI): m/z 593.2 [M+H]+.
1H-NMR(400MHz,DMSO-d 6):δ12.66(s,1H),8.08(s,1H),7.92(s,1H),7.29(s,1H), 4.57-4.37(m,3H),4.04-3.74(m,6H),3.71-3.40(m,8H),3.17-3.08(m,2H),2.93-2.60(m,3H). 1 H-NMR (400MHz, DMSO-d 6 ): δ 12.66(s, 1H), 8.08(s, 1H), 7.92(s, 1H), 7.29(s, 1H), 4.57-4.37(m, 3H) ),4.04-3.74(m,6H),3.71-3.40(m,8H),3.17-3.08(m,2H),2.93-2.60(m,3H).
实施例15：化合物15的制备Example 15: Preparation of Compound 15
Figure PCTCN2022078854-appb-000070
Figure PCTCN2022078854-appb-000070
化合物15的合成参考实施例8中化合物8的合成步骤，其中第一步用化合物INT-8代替化合物INT-10，得到化合物15。The synthesis of compound 15 refers to the synthesis steps of compound 8 in Example 8, wherein compound INT-8 is used instead of compound INT-10 in the first step to obtain compound 15.
MS(ESI):m/z 552.2[M+H] +。 MS (ESI): m/z 552.2 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ13.23(s,1H),8.32-8.18(m,1H),8.06(s,1H),7.27(s,1H),5.15-5.09(m,1H),4.44-4.36(m,5H),4.08-3.92(m,2H),3.85-3.55(m,4H),3.25-3.00(m,1H),2.98-2.66(m,3H),1.31-1.07(m,3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ13.23(s, 1H), 8.32-8.18(m, 1H), 8.06(s, 1H), 7.27(s, 1H), 5.15-5.09(m ,1H),4.44-4.36(m,5H),4.08-3.92(m,2H),3.85-3.55(m,4H),3.25-3.00(m,1H),2.98-2.66(m,3H),1.31 -1.07(m,3H).
实施例16：化合物16的制备Example 16: Preparation of Compound 16
Figure PCTCN2022078854-appb-000071
Figure PCTCN2022078854-appb-000071
化合物16的合成参考实施例9中化合物9的合成步骤，其中第五步用化合物INT-8代替化合物INT-10，得到化合物16。The synthesis of compound 16 refers to the synthesis steps of compound 9 in Example 9, wherein compound INT-8 is used instead of compound INT-10 in the fifth step to obtain compound 16.
MS(ESI):m/z 581.2[M+H] +。 MS (ESI): m/z 581.2 [M+H] + .
1H-NMR(300MHz,DMSO):δ12.49(s,1H),8.06(s,1H),7.92(s,1H),7.28(s,1H),6.23(s,1H),4.67-4.15(m,5H),4.06-3.92(m,2H),3.72-3.68(m,2H),3.55-3.51(m,2H),3.47-3.41(m,2H),3.25(s,3H),3.18-3.08(m,1H),2.91-2.70(m,2H),2.65-2.55(m,2H). 1 H-NMR (300MHz, DMSO): δ12.49(s,1H), 8.06(s,1H), 7.92(s,1H), 7.28(s,1H), 6.23(s,1H), 4.67-4.15 (m,5H),4.06-3.92(m,2H),3.72-3.68(m,2H),3.55-3.51(m,2H),3.47-3.41(m,2H),3.25(s,3H),3.18 -3.08(m,1H),2.91-2.70(m,2H),2.65-2.55(m,2H).
实施例17：化合物17的制备Example 17: Preparation of Compound 17
Figure PCTCN2022078854-appb-000072
Figure PCTCN2022078854-appb-000072
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000073
Figure PCTCN2022078854-appb-000073
制备方法：Preparation:
第一步：合成化合物17BStep 1: Synthesis of compound 17B
将化合物INT-8(0.2g,0.77mmol)溶于DMF(4mL)中，加入化合物17A(0.17g,0.85mmol)和HATU(0.35g,0.92mmol)，冰浴下滴加DIEA(0.3g,2.3mmol)，反应升温至30℃搅拌1h。TLC显示反应结束后，将反应液倒入水中(30.0mL)，用乙酸乙酯(10.0mL×3)萃取，合并有机相，用无水硫酸钠干燥有机相，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1:1(体积比))，得到化合物17B(0.22g，淡黄色油状物，产率64％)。Compound INT-8 (0.2 g, 0.77 mmol) was dissolved in DMF (4 mL), compound 17A (0.17 g, 0.85 mmol) and HATU (0.35 g, 0.92 mmol) were added, and DIEA (0.3 g, 0.92 mmol) was added dropwise under ice bath. 2.3 mmol), the reaction was warmed to 30 °C and stirred for 1 h. After TLC showed that the reaction was over, the reaction solution was poured into water (30.0 mL), extracted with ethyl acetate (10.0 mL×3), the organic phases were combined, the organic phases were dried with anhydrous sodium sulfate, desolvated under reduced pressure, and the residue was used Purification by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1:1 (volume ratio)) to obtain compound 17B (0.22 g, pale yellow oil, yield 64%).
MS(ESI):m/z 443.2[M+H] +。 MS (ESI): m/z 443.2 [M+H] + .
第二步：合成化合物17CStep 2: Synthesis of compound 17C
将化合物17B(0.22g,0.5mmol)加入到DCM(3.0mL)中，冰浴下加入三氟乙酸(1.0mL)，室温搅拌1.0h。TLC显示反应结束后，缓慢倒入水中(30.0mL)，用饱和碳酸氢钠水溶液调pH至8，用乙酸乙酯(10.0mL×3)萃取，用无水硫酸钠干燥有机相，减压脱溶，得到化合物17C(0.15g，氮黄色油状物，产率88％)。直接用于下一步。Compound 17B (0.22 g, 0.5 mmol) was added to DCM (3.0 mL), trifluoroacetic acid (1.0 mL) was added under ice bath, and the mixture was stirred at room temperature for 1.0 h. After TLC showed that the reaction was over, slowly poured into water (30.0 mL), adjusted pH to 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (10.0 mL×3), dried the organic phase with anhydrous sodium sulfate, evaporated under reduced pressure Dissolved to give compound 17C (0.15 g, nitrogen-yellow oil, 88% yield). used directly in the next step.
MS(ESI):m/z 343.2[M+H] +。 MS (ESI): m/z 343.2 [M+H] + .
第三步：合成化合物17EStep 3: Synthesis of Compound 17E
将化合物17C(0.15g,0.41mmol)和化合物17D(0.11g,0.61mmol)加入到MeOH(4.0mL)中，滴加一滴醋酸，室温搅拌2h，然后冰浴下分批加入氰基硼氢化钠(0.05g,0.82mmol)，升至室温搅拌1h。TLC显示反应结束后，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝10:1(体积比))，得到化合物17E(0.15g，淡黄色油状物，产率73％)。Compound 17C (0.15 g, 0.41 mmol) and compound 17D (0.11 g, 0.61 mmol) were added to MeOH (4.0 mL), a drop of acetic acid was added dropwise, stirred at room temperature for 2 h, and then sodium cyanoborohydride was added in portions under ice bath (0.05 g, 0.82 mmol), warmed to room temperature and stirred for 1 h. After TLC showed that the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10:1 (volume ratio)) to obtain compound 17E (0.15 g, pale yellow oily substance) , the yield is 73%).
MS(ESI):m/z 500.2[M+H] +。 MS (ESI): m/z 500.2 [M+H] + .
第四步：合成化合物17FStep 4: Synthesis of Compound 17F
将化合物17E(0.15g,0.3mmol)加入到甲醇(4.0mL)中，冰浴下滴加质量分数为8％的盐酸乙酸乙酯(2.0mL)溶液，升至室温搅拌6h。TLC显示反应结束后，减压脱溶，得到化合物17F(0.11g，淡黄色油状物，产率91％)，直接用于下一步。Compound 17E (0.15 g, 0.3 mmol) was added to methanol (4.0 mL), 8% hydrochloric acid ethyl acetate (2.0 mL) solution was added dropwise under ice bath, and the mixture was heated to room temperature and stirred for 6 h. TLC showed that after the reaction was completed, the solution was removed under reduced pressure to obtain compound 17F (0.11 g, pale yellow oil, yield 91%), which was directly used in the next step.
MS(ESI):m/z 400.2[M+H] +。 MS (ESI): m/z 400.2 [M+H] + .
第五步：合成化合物17GStep 5: Synthesis of Compound 17G
将化合物17F(0.11g,0.28mmol)和化合物INT-1F(95mg,0.3mmol)加入到乙腈(4.0mL)中，冰浴下滴加三乙胺(0.08g,0.82mmol)，升至60℃搅拌3h。TLC显示反应结束后，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝10:1(体积比))，得到化合物17G(0.15g，淡黄色油状物，产率80％)。Compound 17F (0.11 g, 0.28 mmol) and compound INT-1F (95 mg, 0.3 mmol) were added to acetonitrile (4.0 mL), triethylamine (0.08 g, 0.82 mmol) was added dropwise under ice bath, and the temperature was raised to 60 °C Stir for 3h. After TLC showed that the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol = 10:1 (volume ratio)) to obtain compound 17G (0.15 g, pale yellow oil) , the yield is 80%).
MS(ESI):m/z 682.2[M+H] +。 MS(ESI): m/z 682.2 [M+H] + .
第六步：合成化合物17Step 6: Synthesis of Compound 17
将化合物17G(0.15g,0.22mmol)溶于三氟乙酸(2.0mL)中，冰浴下滴加三氟甲磺酸(0.2mL)，升至室温搅拌0.5h。TLC显示反应结束后，缓慢倒入水中(30.0mL)，用饱和碳酸氢钠水溶液调pH至7-8，用乙酸乙酯(10.0mL×3)萃取，合并有机相，并用无水硫酸钠干燥有机相，减压脱溶，得到的残余物再用HPLC制备纯化(Waters Sunfire OBD 100x30mm，5μm，流动相A：0.1％TFA水溶液，流动相B：乙腈，梯度：10％乙腈运行至1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物17(50mg，白色固体，产率40％)。Compound 17G (0.15 g, 0.22 mmol) was dissolved in trifluoroacetic acid (2.0 mL), trifluoromethanesulfonic acid (0.2 mL) was added dropwise under an ice bath, and the mixture was heated to room temperature and stirred for 0.5 h. After TLC showed that the reaction was over, slowly poured into water (30.0 mL), adjusted pH to 7-8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (10.0 mL×3), combined the organic phases and dried over anhydrous sodium sulfate The organic phase was desolvated under reduced pressure, and the obtained residue was purified by HPLC (Waters Sunfire OBD 100×30 mm, 5 μm, mobile phase A: 0.1% TFA aqueous solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile, run to 1 min, 52 %-52% acetonitrile run to 10min, 95% acetonitrile run to 14min, 10% acetonitrile run to 16min end) to give compound 17 (50mg, white solid, 40% yield).
MS(ESI):m/z 562.2[M+H] +。 MS(ESI): m/z 562.2 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ12.54(s,1H),8.12(s,1H),8.06(s,1H),7.91(s,1H),7.30(d,J＝2.0Hz,1H),6.47(s,1H),4.55-4.36(m,3H),4.14-3.88(m,3H),3.72(s,5H),3.43(s,2H),3.11-3.05(m,2H),2.87-2.71(m,1H),2.79-2.71(m,1H),1.13(d,J＝6.4Hz,3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.54(s, 1H), 8.12(s, 1H), 8.06(s, 1H), 7.91(s, 1H), 7.30(d, J=2.0 Hz, 1H), 6.47(s, 1H), 4.55-4.36(m, 3H), 4.14-3.88(m, 3H), 3.72(s, 5H), 3.43(s, 2H), 3.11-3.05(m, 2H), 2.87-2.71(m, 1H), 2.79-2.71(m, 1H), 1.13(d, J=6.4Hz, 3H).
实施例18：化合物18的制备Example 18: Preparation of Compound 18
Figure PCTCN2022078854-appb-000074
Figure PCTCN2022078854-appb-000074
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000075
Figure PCTCN2022078854-appb-000075
制备方法：Preparation:
第一步：合成化合物18BStep 1: Synthesis of compound 18B
将化合物18A(550mg，2.94mmol)加入到CH 3CN(10.0mL)中，再加化合物丙烯酸甲酯(1.27g，14.7mmol)，然后冰浴下加入Cs 2CO 3(1.12g，3.53mmol)，把反应液拿到室温下反应2h。TLC显示反应结束后，把反应液减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1(体积比))，得到化合物18B(576mg，无色油状液体，产率：72.2％)。 Compound 18A (550 mg, 2.94 mmol) was added to CH 3 CN (10.0 mL), compound methyl acrylate (1.27 g, 14.7 mmol) was added, and Cs 2 CO 3 (1.12 g, 3.53 mmol) was added under ice bath , the reaction solution was taken to room temperature for 2h. After TLC showed that the reaction was completed, the reaction solution was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 (volume ratio)) to obtain compound 18B (576 mg, without color oily liquid, yield: 72.2%).
MS(ESI):m/z 274.2[M+1] +。 MS(ESI): m/z 274.2[M+1] + .
第二步：合成化合物18CStep 2: Synthesis of compound 18C
将化合物18B(300mg，1.09mmol)加入到质量分数为8％的盐酸乙酸乙酯溶液(8.0mL)中，室温下反应2h。TLC显示反应结束后，将反应液减压脱溶，得到化合物18C(190mg,无色油状液体，产率：100％)。粗品直接投下一步反应。Compound 18B (300 mg, 1.09 mmol) was added to 8% hydrochloric acid ethyl acetate solution (8.0 mL), and reacted at room temperature for 2 h. After TLC showed that the reaction was completed, the reaction solution was desolubilized under reduced pressure to obtain compound 18C (190 mg, colorless oily liquid, yield: 100%). The crude product was directly put into the next reaction.
MS(ESI):m/z 174.2[M+1] +。 MS(ESI): m/z 174.2[M+1] + .
第三步：合成化合物18DStep 3: Synthesis of Compound 18D
将化合物18C(190mg，1.09mmol)溶于CH 3CN(4.0mL)中，然后加入化合物INT-1F(280mg，0.87mmol)，再加入TEA(333mg，3.27mmol)，加完后将反应液升温至60℃，搅拌2h。TLC显示反应结束后，将反应液减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1(体积比))，得到化合物18D(297mg，淡黄色油状液体，产率：59％)。 Compound 18C (190 mg, 1.09 mmol) was dissolved in CH 3 CN (4.0 mL), then compound INT-1F (280 mg, 0.87 mmol) was added, and TEA (333 mg, 3.27 mmol) was added. After the addition, the reaction solution was warmed up to 60°C and stirred for 2h. After TLC showed that the reaction was completed, the reaction solution was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 (volume ratio)) to obtain compound 18D (297 mg, pale Yellow oily liquid, yield: 59%).
MS(ESI):m/z 456.2[M+1] +。 MS(ESI): m/z 456.2[M+1] + .
第四步：合成化合物18EStep 4: Synthesis of Compound 18E
将化合物18D(297mg，0.65mmol)溶于MeOH(2.5mL)和H 2O(2.5mL)的混合溶剂(2.5mL/2.5mL)中，然后加入一水合氢氧化锂(83mg，1.95mmol)，反应液室 温下反应0.5h。TLC显示结束后，用乙酸乙酯(30.0mL×3)萃取，合并的有机相加无水硫酸钠干燥，然后减压脱溶，得到化合物18E(140mg，淡黄色油状液体，产率：49％)。 Compound 18D (297 mg, 0.65 mmol) was dissolved in a mixed solvent (2.5 mL/2.5 mL) of MeOH (2.5 mL) and H 2 O (2.5 mL), and then lithium hydroxide monohydrate (83 mg, 1.95 mmol) was added, The reaction solution was reacted at room temperature for 0.5h. After TLC showed the end, it was extracted with ethyl acetate (30.0 mL×3), the combined organic phases were dried over anhydrous sodium sulfate, and then desolvated under reduced pressure to obtain compound 18E (140 mg, pale yellow oily liquid, yield: 49%) ).
MS(ESI):m/z 442.2[M+1] +。 MS(ESI): m/z 442.2[M+1] + .
第五步：合成化合物18FStep 5: Synthesis of Compound 18F
将化合物18E(140mg，0.32mmol)加入到DMF(5.0mL)中，然后再加入HATU(146mg，0.38mmol)，冰浴下滴加DIEA(124mg，0.96mmol)，室温下搅拌5min，加入化合物INT-8(67mg，0.32mmol)，升至室温搅拌30min。TLC显示反应结束后，用乙酸乙酯(30.0mL×3)萃取，合并有的有机相用饱和NaCl溶液洗涤，有机相加无水硫酸钠干燥，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1(体积比)加一滴氨水)，得到化合物18F(106mg，淡黄色油状液体，产率：49％)。Compound 18E (140 mg, 0.32 mmol) was added to DMF (5.0 mL), then HATU (146 mg, 0.38 mmol) was added, DIEA (124 mg, 0.96 mmol) was added dropwise under ice bath, stirred at room temperature for 5 min, and compound INT was added -8 (67 mg, 0.32 mmol), warmed to room temperature and stirred for 30 min. After TLC showed that the reaction was over, it was extracted with ethyl acetate (30.0 mL×3), the combined organic phase was washed with saturated NaCl solution, the organic phase was dried over anhydrous sodium sulfate, and desolvated under reduced pressure, and the residue was subjected to silica gel column chromatography Purification (eluent: petroleum ether/ethyl acetate=1/1 (volume ratio) plus a drop of ammonia water) to obtain compound 18F (106 mg, pale yellow oily liquid, yield: 49%).
MS(ESI):m/z 683.2[M+1] +。 MS(ESI): m/z 683.2[M+1] + .
第六步：合成化合物18Step 6: Synthesis of Compound 18
将化合物18F(106mg，0.16mmol)在冰浴下滴加到三氟乙酯(2.0mL)中，然后冰浴下加入三氟甲磺酸(0.2mL)，加完后将反应液升至室温搅拌10min。TLC显示反应结束后，加入饱和NaHCO 3水溶液调pH至7-8，用乙酸乙酯(30.0mL×3)萃取，有机相用无水NaSO 4干燥，减压脱溶，得到的粗品再用HPLC制备纯化(Waters Sunfire OBD100x30mm，5μm，流动相A：0.1％TFA水溶液，流动相B：乙腈，梯度：10％乙腈运行至1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物18(27mg，白色固体，产率：31％)。 Compound 18F (106 mg, 0.16 mmol) was added dropwise to trifluoroethyl ester (2.0 mL) under ice bath, then trifluoromethanesulfonic acid (0.2 mL) was added under ice bath, and the reaction solution was warmed to room temperature after the addition was complete Stir for 10 minutes. After TLC showed that the reaction was over, saturated aqueous NaHCO 3 solution was added to adjust the pH to 7-8, extracted with ethyl acetate (30.0 mL×3), the organic phase was dried with anhydrous NaSO 4 , and desolvated under reduced pressure, and the obtained crude product was re-used by HPLC Preparative purification (Waters Sunfire OBD 100x30 mm, 5 μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile run to 1 min, 52%-52% acetonitrile run to 10 min, 95% acetonitrile run to 14 min, 10% acetonitrile was run to the end of 16 min) to give compound 18 (27 mg, white solid, yield: 31%).
MS(ESI):m/z 563.2[M+H] +。 MS(ESI): m/z 563.2 [M+H] + .
1H-NMR(400MHz,DMSO-d 6):δ12.53(s,1H),8.07(s,1H),7.73(s,1H),7.29(s,1H),6.84(s,1H),4.56-4.35(m,3H),4.31-3.94(m,3H),3.88-3.62(m,2H),3.60-3.48(m,2H),3.45-3.41(m,1H),3.20-3.12(m,1H),2.96-2.85(m,1H),2.8-2.6(m,4H),2.36-2.31(m,1H),2.05-1.95(m,1H). 1 H-NMR (400MHz, DMSO-d 6 ): δ12.53(s,1H), 8.07(s,1H), 7.73(s,1H), 7.29(s,1H), 6.84(s,1H), 4.56-4.35(m, 3H), 4.31-3.94(m, 3H), 3.88-3.62(m, 2H), 3.60-3.48(m, 2H), 3.45-3.41(m, 1H), 3.20-3.12(m ,1H),2.96-2.85(m,1H),2.8-2.6(m,4H),2.36-2.31(m,1H),2.05-1.95(m,1H).
实施例19：化合物19的制备Example 19: Preparation of Compound 19
Figure PCTCN2022078854-appb-000076
Figure PCTCN2022078854-appb-000076
化合物19的合成参考实施例17中化合物17的合成步骤，其中第一步用1-Boc-3-吡咯烷甲酸(CAS:59378-75-5)代替化合物17A，得到化合物19。The synthesis of compound 19 refers to the synthesis procedure of compound 17 in Example 17, wherein in the first step, compound 17A is replaced by 1-Boc-3-pyrrolidinecarboxylic acid (CAS: 59378-75-5) to obtain compound 19.
MS(ESI):m/z 576.2[M+H] +。 MS (ESI): m/z 576.2 [M+H] + .
1H-NMR(400MHz,DMSO-d6):δ12.45(s,1H),8.14(s,1H),8.07(s,1H),7.91(s,1H),7.29(s,1H),6.40(s,1H),4.55-4.42(m,3H),4.07-3.90(m,4H),3.18-3.10(m,2H),2.94-2.85(m,2H),2.79-2.56(m,6H),2.01-1.92(m,2H),1.18(d,J＝6.0Hz,3H). 1 H-NMR (400MHz, DMSO-d6): δ12.45(s,1H), 8.14(s,1H), 8.07(s,1H), 7.91(s,1H), 7.29(s,1H), 6.40 (s,1H),4.55-4.42(m,3H),4.07-3.90(m,4H),3.18-3.10(m,2H),2.94-2.85(m,2H),2.79-2.56(m,6H) ,2.01-1.92(m,2H),1.18(d,J＝6.0Hz,3H).
实施例20：化合物20的制备Example 20: Preparation of Compound 20
Figure PCTCN2022078854-appb-000077
Figure PCTCN2022078854-appb-000077
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000078
Figure PCTCN2022078854-appb-000078
制备方法：Preparation:
第一步：合成化合物20BStep 1: Synthesis of Compound 20B
将化合物20A(600mg，3.42mmol)加入到DMF(6.0mL)中，再加入2,4-二氯嘧啶(562mg，3.77mmol)，冰浴下加入碳酸铯(2.23g，6.85mmol)，然后把反应液拿到室温下反应2h。TLC显示反应结束后，反应液加水(20mL)，用乙酸乙酯(30mL×3)萃取，有机层用饱和氯化钠溶液洗涤(30mL×3)，有机相用无水硫酸钠干燥，减压脱溶，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/0～5/1(体积比))，得到化合物20B(750mg，淡黄色油状液体，产率：76％)。Compound 20A (600 mg, 3.42 mmol) was added to DMF (6.0 mL), 2,4-dichloropyrimidine (562 mg, 3.77 mmol) was added, cesium carbonate (2.23 g, 6.85 mmol) was added under ice bath, and then The reaction solution was reacted at room temperature for 2h. After TLC showed that the reaction was completed, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the organic layer was washed with saturated sodium chloride solution (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, and the pressure was reduced. Precipitate and purify by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/0～5/1 (volume ratio)) to obtain compound 20B (750 mg, pale yellow oily liquid, yield: 76%) ).
MS(ESI):m/z 288.2[M+H] +。 MS(ESI): m/z 288.2 [M+H] + .
第二步：合成化合物20CStep 2: Synthesis of compound 20C
将化合物20B(750mg，2.61mmol)溶于DMF(8.0mL)中，加入化合物INT-8(676mg，2.61mmol)，随后冰浴下加入碳酸钾(721mg,5.21mmol)，加完后升至60℃反应2h。TLC显示反应结束后。反应液加水(30mL)，用乙酸乙酯(30mL×3)萃取，有机层用饱和氯化钠溶液洗涤(30mL×3)，有机相用无水硫酸钠干燥，减压脱溶，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1～0/1(体积比))，得到化合物20C(1.0g，淡黄色油状液体，产率：75％)。Compound 20B (750 mg, 2.61 mmol) was dissolved in DMF (8.0 mL), compound INT-8 (676 mg, 2.61 mmol) was added, then potassium carbonate (721 mg, 5.21 mmol) was added under ice bath, and the temperature rose to 60 ℃ reaction 2h. TLC showed that the reaction was complete. The reaction solution was added with water (30 mL), extracted with ethyl acetate (30 mL×3), the organic layer was washed with saturated sodium chloride solution (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, desolvated under reduced pressure, and washed with silica gel column. Purification by chromatography (eluent: petroleum ether/ethyl acetate = 3/1 to 0/1 (volume ratio)) to obtain compound 20C (1.0 g, pale yellow oily liquid, yield: 75%).
MS(ESI):m/z 511.2[M+H] +。 MS(ESI): m/z 511.2 [M+H] + .
第三步：合成化合物20DStep 3: Synthesis of Compound 20D
将化合物20C(1.0g)溶于乙酸乙酯(10mL)中，冰浴下加入质量分数为8％的盐酸乙酸乙酯(10.0mL)，然后把反应液升至室温下反应30分钟。TLC显示结束后，将反应液减压脱溶，得到化合物20D(0.9g，白色固体,产率：99％)。粗品直接用于下一 步。Compound 20C (1.0 g) was dissolved in ethyl acetate (10 mL), 8% hydrochloric acid ethyl acetate (10.0 mL) was added under ice bath, and then the reaction solution was warmed to room temperature and reacted for 30 minutes. After the completion of TLC, the reaction solution was desolvated under reduced pressure to obtain compound 20D (0.9 g, white solid, yield: 99%). The crude product was used directly in the next step.
MS(ESI):m/z 411.2[M+1] +。 MS(ESI): m/z 411.2[M+1] + .
第四步：合成化合物20EStep 4: Synthesis of Compound 20E
将化合物20D(42mg，0.1mmol)加入到乙腈(1.0mL)中，再加入化合物INT-1F(33mg，0.1mmol)，冰浴下滴加三乙胺(21mg，0.2mmol)，然后把反应液拿到60℃下反应2小时。TLC显示反应结束后，把反应液减压脱溶，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1～0/1(体积比))，得到化合物20E(53mg，淡黄色油状，产率：75％)。Compound 20D (42 mg, 0.1 mmol) was added to acetonitrile (1.0 mL), then compound INT-1F (33 mg, 0.1 mmol) was added, triethylamine (21 mg, 0.2 mmol) was added dropwise under an ice bath, and then the reaction solution was mixed. The reaction was carried out at 60°C for 2 hours. After TLC showed that the reaction was completed, the reaction solution was desolvated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1～0/1 (volume ratio)) to obtain compound 20E (53 mg , pale yellow oil, yield: 75%).
MS(ESI):m/z 693[M+H] +。 MS (ESI): m/z 693 [M+H] + .
第四步：合成化合物20Step 4: Synthesis of Compound 20
将化合物20E(53.0mg)溶于三氟乙酸(1mL)中，冰浴下滴加三氟甲磺酸(0.1mL)，然后把反应液升至室温下反应10分钟。TLC显示结束后，将反应液用乙酸乙酯稀释后缓慢滴加入冰浴的饱和碳酸氢钠水溶液(40mL)，用乙酸乙酯(30mL×3)萃取，有机相加无水硫酸钠干燥，减压脱溶，得到的粗产物再用HPLC制备纯化(Waters Sunfire OBD100x30mm，5μm，流动相A：0.1％TFA水溶液，流动相B：乙腈，梯度：10％乙腈运行至1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物20(11.0mg，白色固体，产率：25％)。Compound 20E (53.0 mg) was dissolved in trifluoroacetic acid (1 mL), trifluoromethanesulfonic acid (0.1 mL) was added dropwise under an ice bath, and the reaction solution was warmed to room temperature for 10 minutes. After TLC showed the end, the reaction solution was diluted with ethyl acetate, slowly added dropwise to an ice-bath saturated aqueous sodium bicarbonate solution (40 mL), extracted with ethyl acetate (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and then reduced Pressure desolvation, the obtained crude product was purified by HPLC (Waters Sunfire OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA aqueous solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile run to 1 min, 52%-52% acetonitrile Running to 10 min, 95% acetonitrile to 14 min, 10% acetonitrile to 16 min end) to obtain compound 20 (11.0 mg, white solid, yield: 25%).
MS(ESI):m/z 573.2[M+H] +。 MS (ESI): m/z 573.2 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ12.52(s,1H),8.18-8.06(m,2H),7.97(s,1H),7.31(s,1H),6.46(s,1H),6.08(s,1H),4.78-4.66(m,2H),4.50-4.30(m,5H),4.11-3.90(m,1H),3.60-3.50(m,1H),3.05-2.78(m,3H),1.28(s,3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.52(s, 1H), 8.18-8.06(m, 2H), 7.97(s, 1H), 7.31(s, 1H), 6.46(s, 1H) ),6.08(s,1H),4.78-4.66(m,2H),4.50-4.30(m,5H),4.11-3.90(m,1H),3.60-3.50(m,1H),3.05-2.78(m ,3H),1.28(s,3H).
实施例21：化合物21的制备Example 21: Preparation of Compound 21
Figure PCTCN2022078854-appb-000079
Figure PCTCN2022078854-appb-000079
化合物21的合成参考实施例1中化合物1的合成步骤，其中第四步用化合物INT-15代替化合物1E，并用化合物INT-2代替化合物INT-1，得到化合物21。The synthesis of compound 21 refers to the synthesis steps of compound 1 in example 1, wherein compound INT-15 is used to replace compound 1E in the fourth step, and compound INT-2 is used to replace compound INT-1 to obtain compound 21.
MS(ESI):m/z 531.2[M+H]+。MS(ESI): m/z 531.2 [M+H]+.
1H-NMR(300MHz,DMSO-d 6):δ12.47(s,1H),7.92-7.85(m,2H),7.23(s,1H),6.28(s,1H),4.25-4.13(m,3H),3.80-3.61(m,7H),3.52-3.42(m,4H),2.55-2.51(m,2H),2.10-1.89(m,2H),1.13(d,J＝5.7Hz,3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.47(s, 1H), 7.92-7.85(m, 2H), 7.23(s, 1H), 6.28(s, 1H), 4.25-4.13(m ,3H),3.80-3.61(m,7H),3.52-3.42(m,4H),2.55-2.51(m,2H),2.10-1.89(m,2H),1.13(d,J=5.7Hz,3H ).
实施例22：化合物22的制备Example 22: Preparation of Compound 22
Figure PCTCN2022078854-appb-000080
Figure PCTCN2022078854-appb-000080
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000081
Figure PCTCN2022078854-appb-000081
制备方法：Preparation:
第一步：合成化合物22AStep 1: Synthesis of Compound 22A
将化合物20A(1.0g，5.71mmol)加入到DCM(10.0mL)中，冰浴搅拌下依次加入DMAP(35.0mg，0.29mmol)，三乙胺(1.15g，11.41mmol)和TsCl(1.31g，6.85mmol)，然后把反应液拿到室温下反应2小时。TLC显示反应结束后，反应液减压脱溶拌样,用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1～1/1(体积比))，得到化合物22A(1.02g，白色固体，产率：54.0％)。Compound 20A (1.0 g, 5.71 mmol) was added to DCM (10.0 mL), DMAP (35.0 mg, 0.29 mmol), triethylamine (1.15 g, 11.41 mmol) and TsCl (1.31 g, 6.85 mmol), and then the reaction solution was brought to room temperature to react for 2 hours. After TLC showed that the reaction was completed, the reaction solution was removed under reduced pressure and stirred, and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1～1/1 (volume ratio)) to obtain compound 22A ( 1.02 g, white solid, yield: 54.0%).
MS(ESI):m/z 330.2[M+H] +。 MS (ESI): m/z 330.2 [M+H] + .
第二步：合成化合物22CStep 2: Synthesis of compound 22C
将化合物22A(660mg，2.0mmol)溶于DMF(7.0mL)中，加入化合物22B(305mg，2.0mmol)，随后冰浴下加入碳酸铯(1.31g,4.01mmol)，升至80℃反应2h。TLC显示反应结束后，反应液加水(30.0mL)，用乙酸乙酯(30.0mL)萃取，有机层用饱和氯化钠溶液洗涤三次，有机相用无水硫酸钠干燥，减压脱溶，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1～1/1(体积比))，得到化合物22C(315mg，无色油状，产 率：51.0％)。Compound 22A (660 mg, 2.0 mmol) was dissolved in DMF (7.0 mL), compound 22B (305 mg, 2.0 mmol) was added, then cesium carbonate (1.31 g, 4.01 mmol) was added under ice bath, and the temperature was raised to 80 °C for 2 h. After TLC showed that the reaction was completed, water (30.0 mL) was added to the reaction solution, extracted with ethyl acetate (30.0 mL), the organic layer was washed three times with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, desolvated under reduced pressure, and the Purification by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1 to 1/1 (volume ratio)) to obtain compound 22C (315 mg, colorless oil, yield: 51.0%).
MS(ESI):m/z 310.2[M+H] +。 MS (ESI): m/z 310.2 [M+H] + .
第三步：合成化合物22DStep 3: Synthesis of Compound 22D
将化合物22C(315mg，1.0mmol)溶于乙酸乙酯(4.0mL)中，冰浴下加入质量分数为8％的盐酸乙酸乙酯(4.0mL)溶液，然后把反应液升至室温下反应30分钟。TLC显示结束后，将反应液减压脱溶，用石油醚：乙酸乙酯＝3：1(体积比)打浆，过滤固体，真空干燥，得到化合物22D(200mg，白色固体，产率：99％)。Compound 22C (315 mg, 1.0 mmol) was dissolved in ethyl acetate (4.0 mL), 8% hydrochloric acid ethyl acetate (4.0 mL) solution was added under ice bath, and then the reaction solution was raised to room temperature and reacted for 30 minute. After TLC showed the end, the reaction solution was desolvated under reduced pressure, slurried with petroleum ether:ethyl acetate=3:1 (volume ratio), filtered the solid, and dried in vacuo to obtain compound 22D (200 mg, white solid, yield: 99%) ).
MS(ESI):m/z 210.2[M+H] +。 MS(ESI): m/z 210.2 [M+H] + .
第四步：合成化合物22EStep 4: Synthesis of Compound 22E
将化合物22D(287mg，1.37mmol)加入到乙腈(3.0mL)中，再加入化合物INT-1F(437mg，1.37mmol)，冰浴下滴加三乙胺(278mg，2.74mmol)，然后把反应液拿到60℃下反应2小时。TLC显示反应结束后，把反应液减压脱溶，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1～0/1(体积比))，得到化合物22E。(282mg，淡黄色油状，产率：42.1％)。Compound 22D (287 mg, 1.37 mmol) was added to acetonitrile (3.0 mL), then compound INT-1F (437 mg, 1.37 mmol) was added, triethylamine (278 mg, 2.74 mmol) was added dropwise under ice bath, and then the reaction solution was mixed. The reaction was carried out at 60°C for 2 hours. After TLC showed that the reaction was completed, the reaction solution was desolvated under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1～0/1 (volume ratio)) to obtain compound 22E. (282 mg, pale yellow oil, yield: 42.1%).
MS(ESI):m/z 492.2[M+H] +。 MS (ESI): m/z 492.2 [M+H] + .
第五步：合成化合物22FStep 5: Synthesis of compound 22F
将化合物22E(282mg，573.79μmol)加入到甲醇-水(体积比＝2mL：2mL)混合溶剂中，冰浴下加入一水合氢氧化锂(42mg，1.72mmol)，然后把反应液升到室温反应3小时。TLC显示反应结束后，将反应液置于冰浴中搅拌，缓慢加入1N盐酸调节PH至6-7，用乙酸乙酯(30.0mL×3)萃取，合并有机相后，有机相减压脱溶，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1～0/1(体积比))，得到化合物22F(127mg，淡黄色油状，产率：46.2％)。Compound 22E (282 mg, 573.79 μmol) was added to methanol-water (volume ratio = 2 mL: 2 mL) mixed solvent, lithium hydroxide monohydrate (42 mg, 1.72 mmol) was added under ice bath, and then the reaction solution was raised to room temperature for reaction 3 hours. After TLC showed that the reaction was over, the reaction solution was stirred in an ice bath, 1N hydrochloric acid was slowly added to adjust the pH to 6-7, extracted with ethyl acetate (30.0 mL×3), the organic phases were combined, and the organic phases were removed under reduced pressure. , purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1～0/1 (volume ratio)) to obtain compound 22F (127 mg, pale yellow oil, yield: 46.2%).
MS(ESI):m/z 478.2[M+H] +。 MS (ESI): m/z 478.2 [M+H] + .
第六步：合成化合物22GStep 6: Synthesis of Compound 22G
将化合物22F(127mg，266μmol)加入到DMF(2mL)中，冰浴下分批加HUTA(152mg，399μmol)，随后冰浴下滴加DIEA(81mg，798.01μmol)，冰浴下搅拌30分钟后加入化合物INT-8(152mg，399μmol)，然后把反应液拿到室温下反应5分钟。TLC显示反应结束后，反应液加水(20mL)，用乙酸乙酯(30.0mL×3)萃取，有机层用饱和氯化钠溶液洗涤三次，有机相用无水硫酸钠干燥，减压脱溶，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1～0/1(体积比))，得到化合物22G(49mg，淡黄色油状，产率：26％)。Compound 22F (127 mg, 266 μmol) was added to DMF (2 mL), HUTA (152 mg, 399 μmol) was added in portions under an ice bath, followed by dropwise addition of DIEA (81 mg, 798.01 μmol) under an ice bath, and the mixture was stirred under an ice bath for 30 minutes. Compound INT-8 (152 mg, 399 μmol) was added, and then the reaction solution was brought to room temperature to react for 5 minutes. After TLC showed that the reaction was completed, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30.0 mL×3), the organic layer was washed three times with saturated sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, and desolvated under reduced pressure, Purification by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5/1 to 0/1 (volume ratio)) gave compound 22G (49 mg, pale yellow oil, yield: 26%).
MS(ESI):m/z 719.2[M+H] +。 MS (ESI): m/z 719.2 [M+H] + .
第七步：合成化合物22Step 7: Synthesis of Compound 22
将化合物22G(49mg)溶于TFA(1.0mL)中，冰浴下滴加三氟甲磺酸(0.1mL)，然后把反应液升至室温下反应30分钟。TLC显示结束后，将反应液用乙酸乙酯稀释后缓慢滴加入冰浴的饱和碳酸氢钠水溶液中，调节PH在7-8之间，用乙酸乙酯(30mL)萃取，有机相加无水硫酸钠干燥，减压脱溶，得到的粗品再用HPLC制备纯化(Waters Sunfire  OBD 100x30mm，5μm，流动相A：0.1％TFA水溶液，流动相B：乙腈，梯度：10％乙腈运行1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物22。(9.0mg，淡黄色油状，产率：22％)。Compound 22G (49 mg) was dissolved in TFA (1.0 mL), trifluoromethanesulfonic acid (0.1 mL) was added dropwise under an ice bath, and then the reaction solution was warmed to room temperature and reacted for 30 minutes. After TLC showed the end, the reaction solution was diluted with ethyl acetate and slowly added dropwise to an ice-bath saturated aqueous sodium bicarbonate solution to adjust the pH between 7-8, extracted with ethyl acetate (30 mL), the organic phase was added anhydrous It was dried with sodium sulfate, desolvated under reduced pressure, and the obtained crude product was purified by HPLC (Waters Sunfire OBD 100×30 mm, 5 μm, mobile phase A: 0.1% aqueous TFA solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52% acetonitrile). -52% acetonitrile run to 10min, 95% acetonitrile run to 14min, 10% acetonitrile run to 16min end) to obtain compound 22. (9.0 mg, pale yellow oil, yield: 22%).
MS(ESI):m/z 599.2[M+1] +。 MS(ESI): m/z 599.2[M+1] + .
1H-NMR(400MHz,DMSO-d 6):δ12.49(s,1H),8.08(s,1H),8.01(s,1H),7.38(t,J＝7.9Hz,1H),7.31(s,1H),7.05-6.95(m,3H),6.51-6.45(m,1H),4.61-4.41(m,4H),4.14-4.09(m,2H),3.72-3.56(m,2H),3.0-2.70(m,2H),1.29(d,J＝7.9Hz,3H). 1 H-NMR (400MHz, DMSO-d 6 ): δ 12.49(s, 1H), 8.08(s, 1H), 8.01(s, 1H), 7.38(t, J=7.9Hz, 1H), 7.31( s,1H),7.05-6.95(m,3H),6.51-6.45(m,1H),4.61-4.41(m,4H),4.14-4.09(m,2H),3.72-3.56(m,2H), 3.0-2.70(m, 2H), 1.29(d, J=7.9Hz, 3H).
实施例23：化合物23的制备Example 23: Preparation of Compound 23
Figure PCTCN2022078854-appb-000082
Figure PCTCN2022078854-appb-000082
化合物23的合成参考实施例18中化合物18的合成步骤，其中第一步用甲基丙烯酸甲酯(CAS:80-62-6)代替丙烯酸甲酯，并用N-Boc-L-丙氨醇(CAS：79069-13-9)代替化合物18A，得到化合物23。The synthesis of compound 23 refers to the synthesis procedure of compound 18 in Example 18, wherein in the first step, methyl methacrylate (CAS: 80-62-6) is used instead of methyl acrylate, and N-Boc-L-alaninol ( CAS: 79069-13-9) instead of compound 18A gave compound 23.
MS(ESI):m/z 565.2[M+1] +。 MS(ESI): m/z 565.2[M+1] + .
1H-NMR(300MHz,DMSO-d 6):δ12.45(s,1H),8.06(s,1H),7.89(d,J＝5.9Hz,1H),7.28(s,1H),6.35-6.18(m,1H),4.54-4.32(m,3H),4.21-4.04(m,2H),4.01-3.85(m,1H),3.64-3.48(m,1H),3.48-3.39(m,2H),3.19-3.01(m,1H),2.96-2.75(m,1H),2.97-2.59(m,1H),1.14-1.08(m,3H),1.01-0.89(m,3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.45(s, 1H), 8.06(s, 1H), 7.89(d, J=5.9Hz, 1H), 7.28(s, 1H), 6.35- 6.18(m, 1H), 4.54-4.32(m, 3H), 4.21-4.04(m, 2H), 4.01-3.85(m, 1H), 3.64-3.48(m, 1H), 3.48-3.39(m, 2H ),3.19-3.01(m,1H),2.96-2.75(m,1H),2.97-2.59(m,1H),1.14-1.08(m,3H),1.01-0.89(m,3H).
实施例24：化合物24的制备Example 24: Preparation of Compound 24
Figure PCTCN2022078854-appb-000083
Figure PCTCN2022078854-appb-000083
化合物24的合成参考实施例17中化合物17的合成步骤，其中第一步用N-Boc-4-哌啶甲酸(CAS:84358-13-4)代替化合物17A，得到化合物24。The synthesis of compound 24 refers to the synthesis procedure of compound 17 in Example 17, wherein in the first step, N-Boc-4-piperidinecarboxylic acid (CAS: 84358-13-4) was used instead of compound 17A to obtain compound 24.
MS(ESI):m/z 590.2[M+H] +。 MS (ESI): m/z 590.2 [M+H] + .
1H-NMR(400MHz,DMSO-d 6):δ12.43(s,1H),8.14(s,1H),8.07(s,1H),7.91(s,1H),7.29(s,1H),6.41(s,1H),4.56-4.33(m,3H),4.22-3.92(m,3H),3.65-3.35(s,3H),3.22-3.16(m,1H),3.01-2.83(m,3H),2.77-2.60(m,2H),2.34-2.08(m,2H),1.70-1.40(m,4H),1.17(d,J＝5.9Hz,3H). 1 H-NMR (400MHz, DMSO-d 6 ): δ12.43(s,1H), 8.14(s,1H), 8.07(s,1H), 7.91(s,1H), 7.29(s,1H), 6.41(s, 1H), 4.56-4.33(m, 3H), 4.22-3.92(m, 3H), 3.65-3.35(s, 3H), 3.22-3.16(m, 1H), 3.01-2.83(m, 3H ), 2.77-2.60(m, 2H), 2.34-2.08(m, 2H), 1.70-1.40(m, 4H), 1.17(d, J=5.9Hz, 3H).
实施例25：化合物25的制备Example 25: Preparation of Compound 25
Figure PCTCN2022078854-appb-000084
Figure PCTCN2022078854-appb-000084
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000085
Figure PCTCN2022078854-appb-000085
制备方法：Preparation:
第一步：合成化合物25BStep 1: Synthesis of Compound 25B
将化合物25A(2.0g，10.98mmol)加入到DMF(20.0mL)中，再加化合物1B(2.84g，13.13mmol)，然后冰浴下滴加DIEA(2.82g，21.9mmol)，将反应液升至60℃搅拌1h。TLC显示反应结束后，把反应液过滤，减压脱溶，残余物用硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝3/1(体积比))纯化，得到化合物25B(1.83g，黄色固体，产率：45％)。Compound 25A (2.0 g, 10.98 mmol) was added to DMF (20.0 mL), followed by compound 1B (2.84 g, 13.13 mmol), and then DIEA (2.82 g, 21.9 mmol) was added dropwise under ice bath, and the reaction solution was liter Stir to 60 °C for 1 h. After TLC showed that the reaction was over, the reaction solution was filtered, desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 (volume ratio)) to obtain compound 25B (1.83 g, yellow solid, yield: 45%).
MS(ESI):m/z 363.1[M+1] +。 MS(ESI): m/z 363.1[M+1] + .
第二步：合成化合物25CStep 2: Synthesis of compound 25C
将化合物25B(0.4g，1.1mmol)加入到DMF(7.0mL)中，冰浴下分批加入NBS(0.24g,1.3mmol)，将反应液升至室温搅拌2h。TLC显示反应结束后，把反应液过滤，减压脱溶，残余物用硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝5/1(体积比))纯化，得到化合物25C(0.23g，白色固体，产率：47％)。Compound 25B (0.4 g, 1.1 mmol) was added to DMF (7.0 mL), NBS (0.24 g, 1.3 mmol) was added in portions under ice bath, and the reaction solution was warmed to room temperature and stirred for 2 h. After TLC showed that the reaction was completed, the reaction solution was filtered, desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1 (volume ratio)) to obtain compound 25C (0.23 g, white solid, yield: 47%).
MS(ESI):m/z 441.0[M+1] +,443.0[M+3] +。 MS(ESI): m/z 441.0[M+1] + , 443.0[M+3] + .
第三步：合成化合物25DStep 3: Synthesis of Compound 25D
将化合物25C(0.23g，0.52mmol)加入到1,4-二氧六环(4.0mL)中，加入碳酸铯(341mg，1.04mmol)，Xantphos(30.2mg，0.05mmol)，Pd(OAc) 2(5.87mg，0.05mmol)，将反应液升至90℃搅拌12h。TLC显示反应结束后，把反应液过滤，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1(体积比))，得到化合物25D(0.16g，淡黄色固体，产率：85％)。 Compound 25C (0.23 g, 0.52 mmol) was added to 1,4-dioxane (4.0 mL), cesium carbonate (341 mg, 1.04 mmol), Xantphos (30.2 mg, 0.05 mmol), Pd(OAc) 2 (5.87 mg, 0.05 mmol), the reaction solution was raised to 90 °C and stirred for 12 h. After TLC showed that the reaction was completed, the reaction solution was filtered, desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1 (volume ratio)) to obtain compound 25D (0.16 g, pale yellow solid, yield: 85%).
MS(ESI):m/z 361.1[M+1] +。 MS(ESI): m/z 361.1[M+1] + .
第四步：合成化合物25EStep 4: Synthesis of Compound 25E
将化合物25D(0.16g，0.4mmol)加入到二氯甲烷(3.0mL)中，冰浴下滴加三氟乙酸(1.0mL)，将反应液升至室温搅拌1h。TLC显示反应结束后，把反应液缓慢加入到饱和碳酸氢钠水溶液中，调pH至7-8，乙酸乙酯萃取，有机相经无水硫酸钠干燥，减压脱溶，得到化合物25E(0.1g，淡黄色油状物，产率：88％)。Compound 25D (0.16 g, 0.4 mmol) was added to dichloromethane (3.0 mL), trifluoroacetic acid (1.0 mL) was added dropwise under ice bath, and the reaction solution was warmed to room temperature and stirred for 1 h. After TLC showed that the reaction was completed, the reaction solution was slowly added to saturated aqueous sodium bicarbonate solution, adjusted to pH 7-8, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and desolvated under reduced pressure to obtain compound 25E (0.1 g, pale yellow oil, yield: 88%).
MS(ESI):m/z 261.1[M+1] +。 MS(ESI): m/z 261.1[M+1] + .
第五步：合成化合物25FStep 5: Synthesis of Compound 25F
将化合物25E(0.1g，0.38mmol)和化合物INT-1(0.18g，0.42mmol)，HATU(0.24g，0.63mmol)加入到DMF(3mL)中，冰浴下滴加DIEA(0.16g，1.26mmol)，将反应液升至室温搅拌0.5h。TLC显示反应结束后，把反应液缓慢加入到水中，乙酸乙酯萃取，有机相经无水硫酸钠干燥，减压脱溶，残余物用硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝5/1(体积比))纯化，得到化合物25F(0.21g，淡黄色固体，产率：77％)。Compound 25E (0.1 g, 0.38 mmol), compound INT-1 (0.18 g, 0.42 mmol), HATU (0.24 g, 0.63 mmol) were added to DMF (3 mL), DIEA (0.16 g, 1.26 mmol) was added dropwise under ice bath mmol), the reaction solution was warmed to room temperature and stirred for 0.5 h. After TLC showed that the reaction was over, the reaction solution was slowly added to water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, desolvated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate) Ester = 5/1 (volume ratio)) was purified to obtain compound 25F (0.21 g, pale yellow solid, yield: 77%).
MS(ESI):m/z 671.2[M+1] +。 MS(ESI): m/z 671.2[M+1] + .
第六步：合成化合物25Step 6: Synthesis of Compound 25
将化合物25F(210mg，0.3mmol)溶于三氟乙酸(2.0mL)中，然后冰浴下加入三氟甲磺酸(0.2mL)，加完后将反应液升至室温，搅拌30min。TLC显示反应结束后，加入饱和NaHCO 3调pH至7-8，用乙酸乙酯萃取，有机相用无水Na 2SO 4干燥，减压脱溶，得到的粗品再用制备型HPLC(Waters Sunfire OBD 100x30mm，5μm，流动相A：0.1％TFA水溶液，流动相B：乙腈，梯度：10％乙腈运行至1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)纯化，得到化合物25(65mg，白色固体，产率：36％)。 Compound 25F (210 mg, 0.3 mmol) was dissolved in trifluoroacetic acid (2.0 mL), and then trifluoromethanesulfonic acid (0.2 mL) was added under ice bath. After the addition, the reaction solution was warmed to room temperature and stirred for 30 min. After TLC showed that the reaction was over , saturated NaHCO was added to adjust the pH to 7-8, extracted with ethyl acetate, the organic phase was dried over anhydrous Na 2 SO 4 , and desolvated under reduced pressure. OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile run to 1 min, 52%-52% acetonitrile run to 10 min, 95% acetonitrile run to 14 min, 10% acetonitrile run to the end of 16 min) and purified to give compound 25 (65 mg, white solid, yield: 36%).
MS(ESI):m/z 551.2[M+1] +。 MS(ESI): m/z 551.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.46(s,1H),8.16(s,1H),7.90(s,1H),6.31-6.27(m,1H),4.71-4.31(m,2H),4.24-3.92(m,3H),3.69-3.50(m,3H),3.48-3.44(m,2H),3.34-3.30(m,2H),3.2-2.8(m,2H),2.64-2.58(m,2H),1.20-1.09(m,3H). 1 H NMR (400MHz, DMSO-d 6 )δ12.46(s,1H), 8.16(s,1H), 7.90(s,1H), 6.31-6.27(m,1H), 4.71-4.31(m,2H) ),4.24-3.92(m,3H),3.69-3.50(m,3H),3.48-3.44(m,2H),3.34-3.30(m,2H),3.2-2.8(m,2H),2.64-2.58 (m,2H),1.20-1.09(m,3H).
实施例26：化合物26的制备Example 26: Preparation of Compound 26
Figure PCTCN2022078854-appb-000086
Figure PCTCN2022078854-appb-000086
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000087
Figure PCTCN2022078854-appb-000087
制备方法：Preparation:
第一步：合成化合物26BStep 1: Synthesis of compound 26B
将化合物26A(1.0g,4.63mmol)溶于DMSO(10.0mL)，然后依次加入化合物1B(1.2g,5.56mmol)，DIEA(1.2g,9.26mmol)，加完后将反应液加热至80℃搅拌16h。TLC显示反应结束后，将反应液冷至室温后加入30mL的水稀释，然后用乙酸乙酯(20mLx3)萃取三次，有机相再用饱和食盐水(10mLx2)洗涤两次，再干燥，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1(体积比))，得到化合物26B(1.8g,淡黄色固体，产率98.4％)。Compound 26A (1.0 g, 4.63 mmol) was dissolved in DMSO (10.0 mL), and then compound 1B (1.2 g, 5.56 mmol) and DIEA (1.2 g, 9.26 mmol) were added in sequence, and the reaction solution was heated to 80° C. Stir for 16h. After TLC showed that the reaction was over, the reaction solution was cooled to room temperature, diluted with 30 mL of water, and then extracted with ethyl acetate (20 mL×3) for three times. The organic phase was washed twice with saturated brine (10 mL×2), then dried and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 (volume ratio)) to obtain compound 26B (1.8 g, pale yellow solid, yield 98.4%).
MS(ESI):m/z 397.0[M+H] +，399.0[M+3H] +。 MS (ESI): m/z 397.0 [M+H] + , 399.0 [M+3H] + .
第二步：合成化合物26CStep 2: Synthesis of compound 26C
将化合物26B(1.8g,4.55mmol)溶于1,4-二氧六环(20.0mL)中，室温下依次加入碳酸铯(2.96g,9.09mmol)，Xantphos(0.32g,0.55mmol,)，Pd(OAc) 2(0.062g,0.273mmol)，N 2置换3次后，加热至90℃，氮气保护下搅拌反应5h。TLC显示反应结束后，冷却到室温，反应液用水(50mL)稀释，乙酸乙酯(30mLx3)萃取，合成有机相，并用无水硫酸钠干燥，减压脱溶，得到的残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1(体积比))，得到化合物26C(1.4g，淡黄色固体，产率97.9％)。 Compound 26B (1.8 g, 4.55 mmol) was dissolved in 1,4-dioxane (20.0 mL), and cesium carbonate (2.96 g, 9.09 mmol), Xantphos (0.32 g, 0.55 mmol, ) were added successively at room temperature, Pd(OAc) 2 (0.062 g, 0.273 mmol) was replaced by N 2 for 3 times, heated to 90° C., and stirred for 5 h under nitrogen protection. After TLC showed that the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (30 mL×3), the organic phase was synthesized, dried over anhydrous sodium sulfate, and desolvated under reduced pressure. Analytical purification (eluent: petroleum ether/ethyl acetate=3/1 (volume ratio)) gave compound 26C (1.4 g, pale yellow solid, yield 97.9%).
MS(ESI):m/z 317.2[M+H] +。 MS (ESI): m/z 317.2 [M+H] + .
第三步：合成化合物26DStep 3: Synthesis of Compound 26D
将化合物26C(370.0mg,1.17mmol)加入到乙酸乙酯(4.0mL)中，冷却到0℃，逐滴滴加质量分数为8％的盐酸乙酸乙酯(4.0mL)溶液，滴完后升温至45℃反应2h。TLC显示反应结束后，把反应液减压脱溶，然后用乙酸乙酯打浆，过滤固体，得到化合物26D(240.0mg，白色固体，产率：94.46％)。Compound 26C (370.0 mg, 1.17 mmol) was added to ethyl acetate (4.0 mL), cooled to 0 °C, and a solution of 8% hydrochloric acid in ethyl acetate (4.0 mL) was added dropwise. After dropping, the temperature was increased. Reaction at 45°C for 2h. After TLC showed that the reaction was completed, the reaction solution was desolvated under reduced pressure, then slurried with ethyl acetate, and the solid was filtered to obtain compound 26D (240.0 mg, white solid, yield: 94.46%).
MS(ESI):m/z 216.2[M+1] +。 MS(ESI): m/z 216.2[M+1] + .
第四步：合成化合物26EStep 4: Synthesis of Compound 26E
将化合物INT-2(116.0mg，0.27mmol)加入到DMF(2.0mL)中，冰浴下分批加HUTA(152.0mg，0.4mmol)，随后冰浴下滴加DIEA(81.0mg，0.8mmol)，冰浴下搅拌30分钟后加入化合物26D(86.4mg，0.4mmol)，然后把反应液拿到室温下反应5分钟。TLC显示反应结束后，反应液加水(20mL)，用乙酸乙酯(30.0mL×3)萃取，有机层用饱和氯化钠溶液洗涤三次，有机相用无水硫酸钠干燥，减压脱溶，用硅胶柱层析 纯化(洗脱剂：石油醚/乙酸乙酯＝5/1～0/1(体积比))，得到化合物26E(50.3mg，淡黄色油状，产率：27％)。Compound INT-2 (116.0 mg, 0.27 mmol) was added to DMF (2.0 mL), HUTA (152.0 mg, 0.4 mmol) was added in portions under ice bath, followed by dropwise addition of DIEA (81.0 mg, 0.8 mmol) under ice bath , after stirring for 30 minutes in an ice bath, compound 26D (86.4 mg, 0.4 mmol) was added, and then the reaction solution was brought to room temperature to react for 5 minutes. After TLC showed that the reaction was completed, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30.0 mL×3), the organic layer was washed three times with saturated sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, and desolvated under reduced pressure, It was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1～0/1 (volume ratio)) to obtain compound 26E (50.3 mg, pale yellow oil, yield: 27%).
MS(ESI):m/z 628.2[M+1] +。 MS(ESI): m/z 628.2[M+1] + .
第五步：合成化合物26Step 5: Synthesis of Compound 26
将化合物26E(45.0mg)溶于TFA(1.0mL)中，冰浴下滴加三氟甲磺酸(0.1mL)，然后把反应液升至室温下反应30分钟。TLC显示结束后，将反应液用乙酸乙酯稀释后缓慢滴加入冰浴的饱和碳酸氢钠水溶液中，调节PH在7-8之间，用乙酸乙酯(30mL)萃取，有机相加无水硫酸钠干燥，减压脱溶，得到的粗品再用HPLC制备纯化(Waters Sunfire OBD 100x30mm，5μm，流动相A：0.1％TFA水溶液，流动相B：乙腈，梯度：10％乙腈运行至1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物26。(9.0mg，淡黄色油状，产率：22％)。Compound 26E (45.0 mg) was dissolved in TFA (1.0 mL), trifluoromethanesulfonic acid (0.1 mL) was added dropwise under an ice bath, and then the reaction solution was warmed to room temperature and reacted for 30 minutes. After TLC showed the end, the reaction solution was diluted with ethyl acetate and slowly added dropwise to an ice-bath saturated aqueous sodium bicarbonate solution to adjust the pH between 7-8, extracted with ethyl acetate (30 mL), the organic phase was added anhydrous It was dried with sodium sulfate, desolvated under reduced pressure, and the obtained crude product was purified by HPLC (Waters Sunfire OBD 100×30 mm, 5 μm, mobile phase A: 0.1% TFA aqueous solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile to run for 1 min, 52 %-52% acetonitrile run to 10min, 95% acetonitrile run to 14min, 10% acetonitrile run to 16min end) to obtain compound 26. (9.0 mg, pale yellow oil, yield: 22%).
MS(ESI):m/z 508.2[M+1] +。 MS(ESI): m/z 508.2[M+1] + .
1H-NMR(300MHz,DMSO-d 6):δ12.45(s,1H),8.16(s,1H),7.90(s,1H),7.39(s,1H),6.27(s,1H),4.48-4.37(m,3H),4.20-4.08(m,1H),4.04-3.91(m,2H),3.69-3.63(m,2H),3.50-3.44(m,3H),3.15-3.12(m,1H),2.90-2.70(m,2H),2.68-2.53(m,2H),1.13(d,J＝6.3Hz,3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.45(s,1H), 8.16(s,1H), 7.90(s,1H), 7.39(s,1H), 6.27(s,1H), 4.48-4.37(m, 3H), 4.20-4.08(m, 1H), 4.04-3.91(m, 2H), 3.69-3.63(m, 2H), 3.50-3.44(m, 3H), 3.15-3.12(m ,1H),2.90-2.70(m,2H),2.68-2.53(m,2H),1.13(d,J=6.3Hz,3H).
实施例27：化合物27的制备Example 27: Preparation of Compound 27
Figure PCTCN2022078854-appb-000088
Figure PCTCN2022078854-appb-000088
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000089
Figure PCTCN2022078854-appb-000089
制备方法：Preparation:
第一步：合成化合物27BStep 1: Synthesis of compound 27B
将化合物27A(4.84g,18.99mmol)溶于DMSO(48.0mL)中，然后加入3-(((叔丁基二甲基硅烷基)氧基)甲基)哌嗪-1-甲酸叔丁酯(7.16g,22.79mmol)，再加入DIEA(2.94g,22.79mmol)，N 2保护下120℃反应过夜。TLC显示反应完全后，将反应液倒入水(100mL)中，然后加入乙酸乙酯(50mL×3)萃取，分出有机相，有机相用饱和NaCl溶液(30mL×2)洗涤，最后将有机相用无水硫酸钠干燥，减压脱溶，得到的残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10:1(体积比))，得到无色液体27B(4.57g，收率43％)。 Compound 27A (4.84 g, 18.99 mmol) was dissolved in DMSO (48.0 mL), followed by the addition of tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate (7.16 g, 22.79 mmol), then DIEA (2.94 g, 22.79 mmol) was added, and the reaction was carried out at 120 °C overnight under the protection of N 2 . After TLC showed that the reaction was complete, the reaction solution was poured into water (100 mL), then ethyl acetate (50 mL×3) was added for extraction, the organic phase was separated, the organic phase was washed with saturated NaCl solution (30 mL×2), and finally the organic The phase was dried over anhydrous sodium sulfate, and desolvated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10:1 (volume ratio)) to obtain a colorless liquid 27B ( 4.57 g, 43% yield).
MS(ESI):m/z 564.0[M+H] +。 MS(ESI): m/z 564.0 [M+H] + .
第二步：合成化合物27CStep 2: Synthesis of compound 27C
将化合物27B(4.57g，8.08mmol)溶于THF(45mL)中，然后滴加TBAF(16ml，16.16mmol)，N 2保护下25℃反应30min。TLC显示反应完全后，将反应液倒入水(50mL)中，然后加入乙酸乙酯(30mL×3)萃取，分出有机相，将有机相干燥，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3:1(体积比))，得到淡黄色油状液体27C(1.49g，收率41％)。 Compound 27B (4.57 g, 8.08 mmol) was dissolved in THF (45 mL), then TBAF (16 ml, 16.16 mmol) was added dropwise, and the reaction was carried out at 25 °C for 30 min under the protection of N 2 . After TLC showed that the reaction was complete, the reaction solution was poured into water (50 mL), then ethyl acetate (30 mL×3) was added for extraction, the organic phase was separated, the organic phase was dried, desolvated under reduced pressure, and the residue was layered on a silica gel column Analytical purification (eluent: petroleum ether/ethyl acetate = 3:1 (volume ratio)) to obtain pale yellow oily liquid 27C (1.49 g, yield 41%).
MS(ESI):m/z 450.0[M+H] +。 MS (ESI): m/z 450.0 [M+H] + .
第三步：合成化合物27DStep 3: Synthesis of Compound 27D
将化合物27C(1.49g，3.30mmol)溶于1,4-二氧六环(45.0mL)中，然后依次加入Pd(OAc) 2(44.0mg，0.2mmol)，Xantphos(229.0mg,0.4mmol)和Cs 2CO 3(2.15g，6.6mmol)，加完后N 2保护下80℃反应过夜。TLC显示反应完全后，过滤反应液。将滤液减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3:1(体积比))，得到黄色固体27D(330.0mg，收率27％)。 Compound 27C (1.49 g, 3.30 mmol) was dissolved in 1,4-dioxane (45.0 mL), then Pd(OAc) 2 (44.0 mg, 0.2 mmol), Xantphos (229.0 mg, 0.4 mmol) were added sequentially and Cs 2 CO 3 (2.15 g, 6.6 mmol), and reacted at 80°C overnight under the protection of N 2 after the addition. After TLC showed that the reaction was complete, the reaction solution was filtered. The filtrate was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 3:1 (volume ratio)) to obtain yellow solid 27D (330.0 mg, yield 27%).
MS(ESI):m/z 370.2[M+H] +。 MS (ESI): m/z 370.2 [M+H] + .
第四步：合成化合物27EStep 4: Synthesis of Compound 27E
将化合物27D(330.0mg，0.9mmol)溶于1,4-二氧六环(5.0mL)中，然后依次加入环丙基硼酸(230.0mg，2.67mmol)，K 2CO 3(308.0mg，2.23mmol)，Pd(dppf)Cl 2DCM(73.0mg，89.13μmol)和H 2O(1.0mL)，N 2保护下100度反应2h。TLC显示反应结束后，将反应液倒入水(10.0mL)中，然后加入乙酸乙酯(10.0mL×3)萃取，分出有机相，将有机相干燥，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5:1(体积比))，得到黄色油状液体27E(310mg，收率95％)。 Compound 27D (330.0 mg, 0.9 mmol) was dissolved in 1,4-dioxane (5.0 mL), then cyclopropylboronic acid (230.0 mg, 2.67 mmol), K 2 CO 3 (308.0 mg, 2.23 mmol) were added sequentially mmol), Pd(dppf)Cl 2 DCM (73.0 mg, 89.13 μmol) and H 2 O (1.0 mL), reacted at 100 degrees for 2 h under N 2 protection. After TLC showed that the reaction was over, the reaction solution was poured into water (10.0 mL), then ethyl acetate (10.0 mL×3) was added for extraction, the organic phase was separated, the organic phase was dried, desolvated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography (eluent: petroleum ether/ethyl acetate=5:1 (volume ratio)) gave 27E as a yellow oily liquid (310 mg, yield 95%).
MS(ESI):m/z 332.2[M+H] +。 MS(ESI): m/z 332.2 [M+H] + .
第五步：合成化合物27FStep 5: Synthesis of compound 27F
将化合物27E(300.0mg,1.17mmol)加入到乙酸乙酯(4.0mL)溶液中，冷却到0℃，逐滴滴加质量分数为8％的盐酸乙酸乙酯(4.0mL)溶液，滴完后升温至45℃反应2h。TLC显示反应结束后，把反应液减压脱溶，然后用乙酸乙酯打浆，过滤固体，得到化合物27F(240.0mg，白色固体，产率：94.2％)。Compound 27E (300.0 mg, 1.17 mmol) was added to ethyl acetate (4.0 mL) solution, cooled to 0 °C, and 8% mass fraction of ethyl acetate (4.0 mL) solution was added dropwise. The temperature was raised to 45°C for 2h. After TLC showed that the reaction was completed, the reaction solution was desolvated under reduced pressure, then slurried with ethyl acetate, and the solid was filtered to obtain compound 27F (240.0 mg, white solid, yield: 94.2%).
MS(ESI):m/z 232.2[M+1] +。 MS(ESI): m/z 232.2[M+1] + .
第六步：合成化合物27GStep 6: Synthesis of Compound 27G
将化合物INT-2(116.0mg，0.27mmol)加入到DMF(2.0mL)中，冰浴下分批加HUTA(152.0mg，0.4mmol)，随后冰浴下滴加DIEA(81.0mg，0.8mmol)，冰浴下搅拌30分钟后加入化合物27F(92.4mg，0.4mmol)，然后把反应液拿到室温下反应5分钟。TLC显示反应结束后，反应液加水(20mL)，用乙酸乙酯(30.0mL×3)萃取，有机层用饱和氯化钠溶液洗涤三次，有机相用无水硫酸钠干燥，减压脱溶，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1～0/1(体积比))，得到化合物27G(53.2mg，淡黄色油状，产率：27％)。Compound INT-2 (116.0 mg, 0.27 mmol) was added to DMF (2.0 mL), HUTA (152.0 mg, 0.4 mmol) was added in portions under ice bath, followed by dropwise addition of DIEA (81.0 mg, 0.8 mmol) under ice bath , and stirred for 30 minutes in an ice bath, compound 27F (92.4 mg, 0.4 mmol) was added, and the reaction solution was brought to room temperature for 5 minutes. After TLC showed that the reaction was completed, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30.0 mL×3), the organic layer was washed three times with saturated sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, and desolvated under reduced pressure, Purification by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5/1 to 0/1 (volume ratio)) to obtain compound 27G (53.2 mg, pale yellow oil, yield: 27%).
MS(ESI):m/z 643.2[M+1] +。 MS(ESI): m/z 643.2[M+1] + .
第七步：合成化合物27Step 7: Synthesis of Compound 27
将化合物27G(45.0mg)溶于TFA(1.0mL)中，冰浴下滴加三氟甲磺酸(0.1mL)，然后把反应液升至室温下反应30分钟。TLC显示结束后，将反应液用乙酸乙酯稀释后缓慢滴加入冰浴的饱和碳酸氢钠水溶液中，调节PH在7-8之间，用乙酸乙酯(30mL)萃取，有机相加无水硫酸钠干燥，减压脱溶，得到的粗品再用HPLC制备纯化(Waters Sunfire OBD 100x30mm，5μm，流动相A：0.1％TFA水溶液，流动相B：乙腈，梯度：10％乙腈运行至1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物27。(10.0mg，淡黄色油状，产率：24％)。Compound 27G (45.0 mg) was dissolved in TFA (1.0 mL), trifluoromethanesulfonic acid (0.1 mL) was added dropwise under an ice bath, and then the reaction solution was warmed to room temperature and reacted for 30 minutes. After TLC showed the end, the reaction solution was diluted with ethyl acetate and slowly added dropwise to an ice-bath saturated aqueous sodium bicarbonate solution to adjust the pH between 7-8, extracted with ethyl acetate (30 mL), the organic phase was added anhydrous It was dried with sodium sulfate, desolvated under reduced pressure, and the obtained crude product was purified by HPLC (Waters Sunfire OBD 100×30 mm, 5 μm, mobile phase A: 0.1% TFA aqueous solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile to run for 1 min, 52 %-52% acetonitrile run to 10min, 95% acetonitrile run to 14min, 10% acetonitrile run to 16min end) to obtain compound 27. (10.0 mg, pale yellow oil, yield: 24%).
MS(ESI):m/z 523.2[M+1] +。 MS(ESI): m/z 523.2[M+1] + .
1H-NMR(300MHz,DMSO-d 6):δ12.44(s,1H),7.90(s,1H),7.58(s,1H),6.64(s,1H),6.27(s,1H),4.48-4.28(m,2H),4.15-4.10(m,1H),4.00-3.79(m,2H),3.71-3.61(m,2H),3.51-3.42(m,2H),3.33-2.95(m,3H),2.80-2.50(m,4H),1.85-1.70(m,1H),1.13(d,J＝6.4Hz,3H),0.90-0.75(m,2H),0.62-0.46(m,2H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.44(s,1H), 7.90(s,1H), 7.58(s,1H), 6.64(s,1H), 6.27(s,1H), 4.48-4.28(m, 2H), 4.15-4.10(m, 1H), 4.00-3.79(m, 2H), 3.71-3.61(m, 2H), 3.51-3.42(m, 2H), 3.33-2.95(m ,3H),2.80-2.50(m,4H),1.85-1.70(m,1H),1.13(d,J=6.4Hz,3H),0.90-0.75(m,2H),0.62-0.46(m,2H) ).
实施例28：化合物28的制备Example 28: Preparation of Compound 28
Figure PCTCN2022078854-appb-000090
Figure PCTCN2022078854-appb-000090
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000091
Figure PCTCN2022078854-appb-000091
制备方法：Preparation:
第一步：合成化合物28BStep 1: Synthesis of compound 28B
将化合物27D(160.0mg,0.43mmol)溶于二氧六环(5.0mL)和水(1.0mL)的混合溶剂中，依次加入碳酸钾(144.0mg，1.04mmol)，Pd(dppf) 2Cl 2·DCM(32.0mg，0.04mmol)和化合物28A(224mg，1.33mmol)，然后在氮气保护下加热到100℃反应2小时。TLC显示结束后，向反应液中加入水(5.0mL)，再用二氯甲烷(5.0mLx2)萃取，合并的有机相用饱和食盐水(10.0mLx2)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚:乙酸乙酯＝3:1(体积比))，得到化合物28B(140.0mg，白色固体，产率97.6％)。 Compound 27D (160.0 mg, 0.43 mmol) was dissolved in a mixed solvent of dioxane (5.0 mL) and water (1.0 mL), followed by potassium carbonate (144.0 mg, 1.04 mmol), Pd(dppf) 2 Cl 2 · DCM (32.0 mg, 0.04 mmol) and compound 28A (224 mg, 1.33 mmol), then heated to 100° C. for 2 hours under nitrogen protection. After the completion of TLC, water (5.0 mL) was added to the reaction solution, followed by extraction with dichloromethane (5.0 mL×2). The combined organic phases were washed with saturated brine (10.0 mL×2), dried over anhydrous sodium sulfate, and filtered to remove dryness. solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1 (volume ratio)) to obtain compound 28B (140.0 mg, white solid, yield 97.6%) ).
MS(ESI):m/z 332.2[M+H] +。 MS(ESI): m/z 332.2 [M+H] + .
第二步：合成化合物28CStep 2: Synthesis of compound 28C
把化合物28B(140.0mg，0.42mmol)溶于甲醇(5.0mL)中，加入质量分数为5％的Pd/C(8.0mg)，然后在氢气下室温搅拌2小时。TLC显示反应结束后，把反应液过滤，再用DCM(5mLx3)洗涤滤饼，滤液浓缩，得到化合物28C(147.0mg，无色油状)。Compound 28B (140.0 mg, 0.42 mmol) was dissolved in methanol (5.0 mL), 5% Pd/C (8.0 mg) was added, and the mixture was stirred at room temperature under hydrogen for 2 hours. After TLC showed that the reaction was completed, the reaction solution was filtered, the filter cake was washed with DCM (5 mL×3), and the filtrate was concentrated to obtain compound 28C (147.0 mg, colorless oil).
MS(ESI):m/z 334.2[M+H] +。 MS (ESI): m/z 334.2 [M+H] + .
第三步：合成化合物28DStep 3: Synthesis of Compound 28D
把化合物28C(147.0mg)溶于质量分数8％的盐酸乙酸乙酯(6.0mL)和甲醇(1.5mL)中，然后室温下搅拌0.5小时。TLC显示反应结束后，反应用饱和碳酸氢钠淬灭，直至pH达到7-8，然后用二氯甲烷(10mLx3)萃取，合并的有机相再用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压脱溶，得到化合物28D粗产品(140.0mg，黄色固体)。直接用于下一步。Compound 28C (147.0 mg) was dissolved in 8% mass fraction of hydrochloric acid in ethyl acetate (6.0 mL) and methanol (1.5 mL), followed by stirring at room temperature for 0.5 hour. After TLC showed that the reaction was over, the reaction was quenched with saturated sodium bicarbonate until the pH reached 7-8, then extracted with dichloromethane (10 mL×3), the combined organic phases were washed with saturated brine (10 mL), and anhydrous sodium sulfate After drying, the desiccant was removed by filtration, and the solution was removed under reduced pressure to obtain a crude product of compound 28D (140.0 mg, yellow solid). used directly in the next step.
MS(ESI):m/z 234.2[M+H] +。 MS(ESI): m/z 234.2 [M+H] + .
第四步：合成化合物28EStep 4: Synthesis of Compound 28E
把化合物28D粗产品(257.0mg，0.6mmol)加入到N,N-二甲基甲酰胺(4.0mL)中，在0℃下加入HATU(342.0mg，0.90mmol)和N,N-二异丙基乙胺(386mg，3mmol)，然后室温下搅拌10分钟，随后在0℃下加入化合物INT-2(140mg，0.6mmol)，室温下反应30分钟。TLC显示反应结束后，在反应液中加入水(10mL)，再用二氯甲烷(10 mLx2)萃取，合并的有机相再用食盐水(10mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压脱溶，得到化合物28E粗产品(144mg，白色油状)。直接用于下一步。The crude product of compound 28D (257.0 mg, 0.6 mmol) was added to N,N-dimethylformamide (4.0 mL), HATU (342.0 mg, 0.90 mmol) and N,N-diisopropyl were added at 0°C ethylamine (386 mg, 3 mmol), then stirred at room temperature for 10 minutes, then added compound INT-2 (140 mg, 0.6 mmol) at 0° C., and reacted at room temperature for 30 minutes. After TLC showed that the reaction was over, water (10 mL) was added to the reaction solution, followed by extraction with dichloromethane (10 mL×2). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered to remove the desiccant. , and desolvated under reduced pressure to obtain the crude product of compound 28E (144 mg, white oil). used directly in the next step.
MS(ESI):m/z 645.2[M+H] +。 MS(ESI): m/z 645.2 [M+H] + .
第五步：合成化合物28Step 5: Synthesis of Compound 28
将化合物28E粗产品(144mg)溶于三氟乙酸(7mL)中，在0℃下加入三氟甲磺酸(0.7mL)，然后在室温下搅拌10分钟。TLC显示反应结束后，用饱和碳酸氢钠淬灭反应，直至pH＝7，然后用DCM(10mLx3)萃取。合并的有机相再用食盐水(10mLx2)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压脱溶，得到的残余物再用HPLC制备纯化(Waters Sunfire OBD 100x30mm，5μm，流动相A：0.1％TFA水溶液，流动相B：乙腈，梯度：10％乙腈运行至1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物28(27mg，白色固体，产率23.07％)。The crude compound 28E (144 mg) was dissolved in trifluoroacetic acid (7 mL), and trifluoromethanesulfonic acid (0.7 mL) was added at 0°C, followed by stirring at room temperature for 10 minutes. After TLC showed the reaction was complete, the reaction was quenched with saturated sodium bicarbonate until pH=7, then extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (10 mL×2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and desolvated under reduced pressure. The obtained residue was purified by HPLC (Waters Sunfire OBD 100×30 mm, 5 μm, mobile phase A: 0.1% TFA aqueous solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile run to 1 min, 52%-52% acetonitrile run to 10 min, 95% acetonitrile run to 14 min, 10% acetonitrile run to 16 min end) to obtain compound 28 ( 27 mg, white solid, 23.07% yield).
MS(ESI):m/z 525.2[M+H] +。 MS(ESI): m/z 525.2 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ12.46(s,1H),7.90(s,1H),7.59(d,J＝2.0Hz,1H),7.08(d,J＝2.0Hz,1H),6.29-6.27(m,1H),4.46-4.39(m,1H),4.35-4.30(m,2H),4.03-4.00(m,1H),3.98-3.95(m,1H),3.93-3.88(m,1H),3.68-3.63(m,2H),3.47(d,J＝5.5Hz,2H),3.30-3.08(m,1H),2.85-2.74(m,2H),2.71-2.65(m,1H),2.64-2.57(m,2H),2.46-2.34(m,1H),1.15-1.12(m,9H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.46(s, 1H), 7.90(s, 1H), 7.59(d, J=2.0Hz, 1H), 7.08(d, J=2.0Hz, 1H),6.29-6.27(m,1H),4.46-4.39(m,1H),4.35-4.30(m,2H),4.03-4.00(m,1H),3.98-3.95(m,1H),3.93- 3.88(m,1H),3.68-3.63(m,2H),3.47(d,J=5.5Hz,2H),3.30-3.08(m,1H),2.85-2.74(m,2H),2.71-2.65( m,1H),2.64-2.57(m,2H),2.46-2.34(m,1H),1.15-1.12(m,9H).
实施例29：化合物29的制备Example 29: Preparation of Compound 29
Figure PCTCN2022078854-appb-000092
Figure PCTCN2022078854-appb-000092
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000093
Figure PCTCN2022078854-appb-000093
制备方法：Preparation:
第一步:合成化合物29BStep 1: Synthesis of Compound 29B
将化合物27D(220mg，0.59mmol)溶于1,4-二氧六环(5ml)中，然后依次加入化合物29A(610mg，1.78mmol)，K 2CO 3(206mg，1.49mmol)，Pd(dppf) 2Cl 2·DCM(49mg， 0.06mmol)和H 2O(1ml)，在N 2保护下于100℃反应2h。TLC显示反应结束后，将反应液倒入水(10mL)中，然后加入乙酸乙酯(10mL×3)萃取，分出有机相，将有机相干燥，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3:1(体积比))，得到黄色油状液体29B(310mg，收率95％)。 Compound 27D (220 mg, 0.59 mmol) was dissolved in 1,4-dioxane (5 ml), then compound 29A (610 mg, 1.78 mmol), K 2 CO 3 (206 mg, 1.49 mmol), Pd (dppf) were added sequentially ) 2 Cl 2 ·DCM (49 mg, 0.06 mmol) and H 2 O (1 ml) were reacted at 100° C. for 2 h under N 2 protection. After TLC showed that the reaction was over, the reaction solution was poured into water (10 mL), then ethyl acetate (10 mL×3) was added for extraction, the organic phase was separated, the organic phase was dried, desolvated under reduced pressure, and the residue was layered with silica gel column Analytical purification (eluent: petroleum ether/ethyl acetate = 3:1 (volume ratio)) to obtain yellow oily liquid 29B (310 mg, yield 95%).
MS(ESI):m/z 507.2[M+H] +。 MS (ESI): m/z 507.2 [M+H] + .
第二步：合成化合物29CStep 2: Synthesis of compound 29C
将化合物29B(310mg，0.61mmol)溶于MeOH(10mL)中，然后加入质量分数为10％的Pd/C(30mg)，加完后氢气置换三次，在氢气下于30℃反应过夜。TLC显示反应完全后，向反应体系中滴加质量分数为30％的甲醛溶液(100mg)，加完后H 2保护下于30℃反应3h，将反应液减压脱溶，得到黄色油状液体29C粗产品(180mg，收率57％)。直接用于下一步。 Compound 29B (310 mg, 0.61 mmol) was dissolved in MeOH (10 mL), and then 10% Pd/C (30 mg) was added. After the addition, hydrogen was replaced three times, and the reaction was carried out at 30° C. overnight under hydrogen. After TLC showed that the reaction was complete, a 30% mass fraction of formaldehyde solution (100 mg) was added dropwise to the reaction system. After the addition, the reaction was carried out at 30 °C for 3 h under the protection of H 2 , and the reaction solution was desolvated under reduced pressure to obtain a yellow oily liquid 29C Crude product (180 mg, 57% yield). used directly in the next step.
MS(ESI):m/z 389.2[M+H] +。 MS (ESI): m/z 389.2 [M+H] + .
第三步：合成化合物29DStep 3: Synthesis of Compound 29D
将29C粗产品(130.0mg)溶于到质量分数8％的盐酸乙酸乙酯(6.0mL)和甲醇(1.5mL)中，然后室温下搅拌0.5小时。TLC显示反应结束后，反应用饱和碳酸氢钠淬灭直至pH达到7-8，然后用二氯甲烷(10mLx3)萃取，合并的有机相再用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压脱溶，得到化合物28D粗产品(175.0mg，黄色固体)。直接用于下一步。The 29C crude product (130.0 mg) was dissolved in 8% mass fraction of ethyl acetate hydrochloride (6.0 mL) and methanol (1.5 mL), and then stirred at room temperature for 0.5 hours. After TLC showed that the reaction was over, the reaction was quenched with saturated sodium bicarbonate until the pH reached 7-8, then extracted with dichloromethane (10 mL×3), the combined organic phases were washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. , filtered to remove the desiccant, and desolvated under reduced pressure to obtain the crude product of compound 28D (175.0 mg, yellow solid). used directly in the next step.
MS(ESI):m/z 289.2[M+H] +。 MS(ESI): m/z 289.2 [M+H] + .
第四步：合成化合物29EStep 4: Synthesis of Compound 29E
把化合物INT-2(140mg，0.6mmol)加入到N,N-二甲基甲酰胺(4.0mL)中，在0℃下加入HATU(342.0mg，0.90mmol)和N,N-二异丙基乙胺(386mg，3mmol)，然后在室温搅拌10分钟，随后在0℃下加入化合物29D(173.0mg,0.6mmol)，室温下反应30分钟。TLC显示反应结束后，在反应液中加入水(10mL)，再用二氯甲烷(10mLx2)萃取，合并的有机相再用食盐水(10mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压脱溶，得到化合物29E粗产品(120mg，白色油状)。直接用于下一步。Compound INT-2 (140 mg, 0.6 mmol) was added to N,N-dimethylformamide (4.0 mL), HATU (342.0 mg, 0.90 mmol) and N,N-diisopropyl were added at 0°C Ethylamine (386 mg, 3 mmol) was then stirred at room temperature for 10 minutes, then compound 29D (173.0 mg, 0.6 mmol) was added at 0°C, and the reaction was performed at room temperature for 30 minutes. After TLC showed that the reaction was completed, water (10 mL) was added to the reaction solution, followed by extraction with dichloromethane (10 mL×2), the combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, Precipitation under reduced pressure gave the crude product of compound 29E (120 mg, white oil). used directly in the next step.
MS(ESI):m/z 700.2[M+H] +。 MS (ESI): m/z 700.2 [M+H] + .
第五步：合成化合物29Step 5: Synthesis of Compound 29
把化合物29E粗产品(120mg)溶于三氟乙酸(7mL)中，在0℃下加入三氟甲磺酸(0.7mL)，然后在室温下搅拌10分钟。TLC显示反应结束后，用饱和碳酸氢钠淬灭反应，直至pH＝7，然后用DCM(10mLx3)萃取。合并的有机相再用食盐水(10mLx2)洗，无水硫酸钠干燥，过滤除去干燥剂，减压脱溶，残余物用HPLC制备纯化(Waters Sunfire OBD 100x30mm，5μm，流动相A：0.1％TFA水溶液，流动相B：乙腈，梯度：10％乙腈运行至1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物29(22mg，白色固体)。The crude compound 29E (120 mg) was dissolved in trifluoroacetic acid (7 mL), and trifluoromethanesulfonic acid (0.7 mL) was added at 0°C, followed by stirring at room temperature for 10 minutes. After TLC showed the reaction was complete, the reaction was quenched with saturated sodium bicarbonate until pH=7, then extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (10 mL×2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, desolvated under reduced pressure, and the residue was purified by HPLC (Waters Sunfire OBD 100×30 mm, 5 μm, mobile phase A: 0.1% TFA) Aqueous solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile run to 1min, 52%-52% acetonitrile run to 10min, 95% acetonitrile run to 14min, 10% acetonitrile run to 16min end) to give compound 29 (22mg, white solid).
MS(ESI):m/z 580.2[M+H] +。 MS (ESI): m/z 580.2 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ12.46(s,1H),7.90(s,1H),7.62(s,1H),6.90(s,1H), 6.26(s,1H),4.51-4.29(m,3H),4.15-4.11(m,1H),4.02-3.85(m,2H),3.70-3.58(m,3H),3.51-3.41(m,4H),3.25-3.08(m,4H),2.90-2.70(m,1H),2.63-2.55(m,3H),2.52(s,3H),2.43-2.25(m,1H),1.84-1.55(m,4H),1.13(d,J＝6.4Hz,3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.46(s,1H), 7.90(s,1H), 7.62(s,1H), 6.90(s,1H), 6.26(s,1H), 4.51-4.29(m, 3H), 4.15-4.11(m, 1H), 4.02-3.85(m, 2H), 3.70-3.58(m, 3H), 3.51-3.41(m, 4H), 3.25-3.08(m ,4H),2.90-2.70(m,1H),2.63-2.55(m,3H),2.52(s,3H),2.43-2.25(m,1H),1.84-1.55(m,4H),1.13(d ,J=6.4Hz,3H).
实施例30：化合物30的制备Example 30: Preparation of Compound 30
Figure PCTCN2022078854-appb-000094
Figure PCTCN2022078854-appb-000094
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000095
Figure PCTCN2022078854-appb-000095
制备方法：Preparation:
第一步：合成化合物30BStep 1: Synthesis of Compound 30B
将化合物30A(2g,11.33mmol)溶于二甲基亚砜(20mL)中，加入化合物3-(羟甲基)哌嗪-1-羧酸叔丁酯(2.94g,13.6mmol)和N,N-二异丙基乙胺(1.75g,13.6mmol)，然后将反应液加热至80℃反应16小时。TLC显示反应结束后，向反应液中加入水(30mL)和乙酸乙酯(50mL)，有机相用饱和食盐水(20mL×2)洗涤，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：PE:EA＝3:1(体积比))，得到化合物30B(3.35g，淡黄色油状，产率：82.98％)。Compound 30A (2 g, 11.33 mmol) was dissolved in dimethyl sulfoxide (20 mL), compound 3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester (2.94 g, 13.6 mmol) and N, N-diisopropylethylamine (1.75 g, 13.6 mmol), and then the reaction solution was heated to 80° C. for 16 hours. After TLC showed that the reaction was completed, water (30 mL) and ethyl acetate (50 mL) were added to the reaction solution, the organic phase was washed with saturated brine (20 mL×2), desolvated under reduced pressure, and the residue was purified by silica gel column chromatography ( Eluent: PE:EA=3:1 (volume ratio)) to obtain compound 30B (3.35 g, pale yellow oil, yield: 82.98%).
MS(ESI):m/z 357.2[M+1] +。 MS(ESI): m/z 357.2[M+1] + .
第二步：合成化合物30CStep 2: Synthesis of compound 30C
将化合物30B(3.35g,9.4mmol)加入到甲醇(35mL)中，再加入10％的湿钯碳(300mg)，加完后，用氮气和氢气依次置换三次，最后在氢气(压力30psi)下于25℃搅拌反应16小时。TLC显示反应结束后，把反应液过滤，滤饼用甲醇(5mL)洗涤，滤液减压脱溶，得到化合物30C(2.68g，淡棕色油体，产率：87.35％)。Compound 30B (3.35 g, 9.4 mmol) was added to methanol (35 mL), and then 10% wet palladium on carbon (300 mg) was added. After the addition, it was replaced with nitrogen and hydrogen for three times, and finally, under hydrogen (pressure 30 psi) The reaction was stirred at 25°C for 16 hours. After TLC showed that the reaction was completed, the reaction solution was filtered, the filter cake was washed with methanol (5 mL), and the filtrate was desolvated under reduced pressure to obtain compound 30C (2.68 g, light brown oil, yield: 87.35%).
MS(ESI):m/z 327.2[M+1] +。 MS(ESI): m/z 327.2[M+1] + .
第三步：合成化合物30DStep 3: Synthesis of Compound 30D
将溴化亚铜(1.66g,11.55mmol)加入到乙腈(20mL)中，再滴入亚硝酸异戊酯(1.35g,11.55mmol)，滴完后25℃下搅拌20分钟，再滴加化合物30C(2.5g,7.7mmol)的乙腈(10mL)溶液，然后将反应液加热至60℃搅拌5小时。TLC显示反应结束后，向反应液中加入水(20mL)和乙酸乙酯(30mL)，水相用乙酸乙酯(10mL×2)萃取，然后合并有机相，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：PE:EA＝3:1(体积比))，得到化合物30D(40mg，淡棕色油体物，产率：18.2％)。Cuprous bromide (1.66 g, 11.55 mmol) was added to acetonitrile (20 mL), and isoamyl nitrite (1.35 g, 11.55 mmol) was added dropwise. After the dropping was completed, the mixture was stirred at 25°C for 20 minutes, and the compound was added dropwise. A solution of 30C (2.5 g, 7.7 mmol) in acetonitrile (10 mL) was then heated to 60 °C and stirred for 5 hours. After TLC showed that the reaction was over, water (20 mL) and ethyl acetate (30 mL) were added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×2), and then the organic phases were combined and desolvated under reduced pressure, and the residue was washed with silica gel Purification by column chromatography (eluent: PE:EA=3:1 (volume ratio)) gave compound 30D (40 mg, light brown oil, yield: 18.2%).
MS(ESI):m/z 390.1[M+1] +，392.1[M+3] +。 MS(ESI): m/z 390.1[M+1] + , 392.1[M+3] + .
第四步：合成化合物30EStep 4: Synthesis of Compound 30E
将化合物30D(540mg,1.38mmol)加入到1,4-二氧六环(6mL)中，再加入碳酸铯(905mg,2.76mmol)，然后加入4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽(96.4mg,0.166mmol)，最后加入醋酸钯(18.7mg,0.083mmol)，将反应液用氮气置换三次，在氮气保护下加热至100℃反应16小时。TLC显示反应结束后，把反应液减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：PE:EA＝3:1(体积比))，得到化合物30E(360mg，白色固体，产率：84.10％)Compound 30D (540 mg, 1.38 mmol) was added to 1,4-dioxane (6 mL), followed by cesium carbonate (905 mg, 2.76 mmol), followed by 4,5-bis(diphenylphosphino)- 9,9-Dimethylxanthene (96.4 mg, 0.166 mmol), finally added palladium acetate (18.7 mg, 0.083 mmol), the reaction solution was replaced with nitrogen three times, heated to 100° C. for 16 hours under nitrogen protection. After TLC showed that the reaction was completed, the reaction solution was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE:EA=3:1 (volume ratio)) to obtain compound 30E (360 mg, white solid, product rate: 84.10%)
MS(ESI):m/z 310.3[M+1] +。 MS(ESI): m/z 310.3[M+1] + .
第五步：合成化合物30FStep 5: Synthesis of Compound 30F
将化合物30E(360mg,1.17mmol)加入到乙酸乙酯(4mL)中，冷却到0℃，逐滴滴加8％盐酸/乙酸乙酯(4mL)溶液，滴完后升温至45℃反应2h。TLC显示反应结束后，把反应液减压脱溶，然后用乙酸乙酯打浆，过滤固体，得到化合物30F(240mg，白色固体，产率：94.46％)。Compound 30E (360 mg, 1.17 mmol) was added to ethyl acetate (4 mL), cooled to 0° C., 8% hydrochloric acid/ethyl acetate (4 mL) solution was added dropwise, and the temperature was raised to 45° C. and reacted for 2 h. After TLC showed that the reaction was completed, the reaction solution was desolvated under reduced pressure, then slurried with ethyl acetate, and the solid was filtered to obtain compound 30F (240 mg, white solid, yield: 94.46%).
MS(ESI):m/z 210.2[M+1] +。 MS(ESI): m/z 210.2[M+1] + .
第六步：合成化合物30GStep 6: Synthesis of Compound 30G
把化合物INT-2(140mg，0.6mmol)加入到N,N-二甲基甲酰胺(4.0mL)中，在0℃下加入HATU(342.0mg，0.90mmol)和N,N-二异丙基乙胺(386mg，3mmol)，然后在室温搅拌10分钟，随后在0℃下加入化合物30F(130.0mg,0.6mmol)，室温下反应30分钟。TLC显示反应结束后，在反应液中加入水(10mL)，再用二氯甲烷(10mLx2)萃取，合并的有机相再用食盐水(10mL)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压脱溶，得到化合物30G粗产品(130mg，白色油状)。直接用于下一步。Compound INT-2 (140 mg, 0.6 mmol) was added to N,N-dimethylformamide (4.0 mL), HATU (342.0 mg, 0.90 mmol) and N,N-diisopropyl were added at 0°C Ethylamine (386 mg, 3 mmol) was then stirred at room temperature for 10 minutes, then compound 30F (130.0 mg, 0.6 mmol) was added at 0°C, and the reaction was performed at room temperature for 30 minutes. After TLC showed that the reaction was over, water (10 mL) was added to the reaction solution, and then extracted with dichloromethane (10 mL×2). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered to remove the desiccant. Precipitation under reduced pressure gave a crude product of compound 30G (130 mg, white oil). used directly in the next step.
MS(ESI):m/z 621.2[M+H] +。 MS(ESI): m/z 621.2 [M+H] + .
第七步：合成化合物30Step 7: Synthesis of Compound 30
把化合物30G粗产品(120mg)溶于三氟乙酸(7mL)中，在0℃下加入三氟甲磺酸(0.7mL)，然后在室温下搅拌10分钟。TLC显示反应结束后，反应用饱和碳酸氢钠淬灭反应，直至pH＝7，然后用DCM(10mLx3)萃取。合并的有机相再用食盐水(10mLx2)洗涤，无水硫酸钠干燥，过滤除去干燥剂，减压脱溶，残余物用HPLC制备纯化(Waters Sunfire OBD 100x30mm，5μm，流动相A：0.1％TFA水溶液，流动相B：乙腈， 梯度：10％乙腈运行至1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物30(21mg，白色固体)。The crude compound 30G (120 mg) was dissolved in trifluoroacetic acid (7 mL), and trifluoromethanesulfonic acid (0.7 mL) was added at 0°C, followed by stirring at room temperature for 10 minutes. After TLC showed the reaction was complete, the reaction was quenched with saturated sodium bicarbonate until pH=7, then extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (10 mL×2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, desolvated under reduced pressure, and the residue was purified by HPLC (Waters Sunfire OBD 100×30 mm, 5 μm, mobile phase A: 0.1% TFA) Aqueous solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile run to 1 min, 52%-52% acetonitrile run to 10 min, 95% acetonitrile run to 14 min, 10% acetonitrile run to 16 min end) to give compound 30 (21 mg, white solid).
MS(ESI):m/z 501.2[M+H] +。 MS (ESI): m/z 501.2 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ12.45(s,1H),7.90(s,1H),7.73(d,J＝2.6Hz,1H),7.11(dd,J＝9.3,2.6Hz,1H),6.32-6.22(m,1H),4.50-4.26(m,3H),4.20-4.05(m,1H),4.04-3.88(m,2H),3.72-3.58(m,2H),3.47(d,J＝5.5Hz,2H),3.29-3.05(m,2H),2.84-2.54(m,4H),1.13(d,J＝6.4Hz,3H). 1 H-NMR (300 MHz, DMSO-d 6 ): δ 12.45 (s, 1H), 7.90 (s, 1H), 7.73 (d, J=2.6 Hz, 1H), 7.11 (dd, J=9.3, 2.6 Hz,1H),6.32-6.22(m,1H),4.50-4.26(m,3H),4.20-4.05(m,1H),4.04-3.88(m,2H),3.72-3.58(m,2H), 3.47(d,J=5.5Hz,2H),3.29-3.05(m,2H),2.84-2.54(m,4H),1.13(d,J=6.4Hz,3H).
实施例31：化合物31的制备Example 31: Preparation of Compound 31
Figure PCTCN2022078854-appb-000096
Figure PCTCN2022078854-appb-000096
化合物31的合成参考实施例27中化合物27的合成步骤，其中第四步用甲基硼酸代替环丙基硼酸，得到化合物31。For the synthesis of compound 31, refer to the synthesis procedure of compound 27 in Example 27, wherein in the fourth step, methylboronic acid is used instead of cyclopropylboronic acid to obtain compound 31.
MS(ESI):m/z 497.2[M+1] +。 MS(ESI): m/z 497.2[M+1] + .
1H-NMR(300MHz,DMSO-d 6):δ12.46(s,1H),7.90(s,1H),7.55(d,J＝1.0Hz,1H),6.85(d,J＝1.6Hz,1H),6.33-6.20(m,1H),4.51-4.41(m,1H),4.39-4.28(m,2H),4.20-4.05(m,1H),4.00-3.83(m,2H),3.70-3.60(m,2H),3.52-4.40(m,2H),3.30-3.05(m,2H),2.85-2.70(m,1H),2.65-2.55(m,3H),2.10(s,3H),1.13(d,J＝6.5Hz,3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.46(s, 1H), 7.90(s, 1H), 7.55(d, J=1.0Hz, 1H), 6.85(d, J=1.6Hz, 1H), 6.33-6.20(m, 1H), 4.51-4.41(m, 1H), 4.39-4.28(m, 2H), 4.20-4.05(m, 1H), 4.00-3.83(m, 2H), 3.70- 3.60(m, 2H), 3.52-4.40(m, 2H), 3.30-3.05(m, 2H), 2.85-2.70(m, 1H), 2.65-2.55(m, 3H), 2.10(s, 3H), 1.13(d,J=6.5Hz,3H).
实施例32：化合物32的制备Example 32: Preparation of Compound 32
Figure PCTCN2022078854-appb-000097
Figure PCTCN2022078854-appb-000097
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000098
Figure PCTCN2022078854-appb-000098
制备方法：Preparation:
第一步：合成化合物32AStep 1: Synthesis of compound 32A
将化合物26C(0.5g,1.58mmol)溶于DMSO(5mL)中，然后在0℃下依次分批加入碳酸钾(0.436g,3.16mmol)，质量分数为30％的H 2O 2(1.05g,9.26mmol)，室温反应30min。TLC显示反应结束后，向反应体系中加入H 2O(30mL)稀释，然后加入DCM:MeOH＝10:1(20mLx3)萃取三次，合并有机相，然后用饱和食盐水(15mLx2)洗涤两次，干燥，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1(体积比))，得到化合物32A(0.47g，1.41mmol，淡黄色固体，产率89％)。 Compound 26C (0.5 g, 1.58 mmol) was dissolved in DMSO (5 mL), then potassium carbonate (0.436 g, 3.16 mmol) was added in batches at 0 °C, and the mass fraction was 30% H 2 O 2 (1.05 g) , 9.26mmol), and the reaction was carried out at room temperature for 30min. After TLC showed that the reaction was over, H 2 O (30 mL) was added to the reaction system to dilute, then DCM:MeOH=10:1 (20 mL×3) was added to extract three times, the organic phases were combined, and then washed twice with saturated brine (15 mL×2), It was dried, removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1 (volume ratio)) to obtain compound 32A (0.47 g, 1.41 mmol, pale yellow solid, 89% yield).
MS(ESI):m/z 335[M+H] +。 MS (ESI): m/z 335 [M+H] + .
1H-NMR(400MHz,CDCl 3):δ7.21(s,1H),7.12(s,1H),7.07(s,1H),6.91-6.89(m,1H),6.82-6.80(m,1H),5.62-5.57(m,1H),5.51(br.s,1H),4.89-4.31(m,4H),3.87(s,2H),2.57(s,3H),1.65(d,3H). 1 H-NMR (400MHz, CDCl 3 ): δ7.21(s,1H), 7.12(s,1H), 7.07(s,1H), 6.91-6.89(m,1H), 6.82-6.80(m,1H) ), 5.62-5.57(m, 1H), 5.51(br.s, 1H), 4.89-4.31(m, 4H), 3.87(s, 2H), 2.57(s, 3H), 1.65(d, 3H).
第二步：合成化合物32BStep 2: Synthesis of Compound 32B
将化合物32A(470.0mg,1.4mmol)加入到乙酸乙酯(4.0mL)溶液中，冷却到0℃，逐滴滴加质量分数为8％的盐酸乙酸乙酯(4.0mL)，滴完后升温至45℃反应2h。TLC显示反应结束后，把反应液减压脱溶，然后用乙酸乙酯打浆，过滤固体，得到化合物32B(316.0mg，白色固体，产率：95％)。Compound 32A (470.0 mg, 1.4 mmol) was added to ethyl acetate (4.0 mL) solution, cooled to 0 °C, 8% mass fraction of ethyl acetate (4.0 mL) was added dropwise, and the temperature was raised after dropping Reaction at 45°C for 2h. After TLC showed that the reaction was completed, the reaction solution was desolubilized under reduced pressure, then slurried with ethyl acetate, and the solid was filtered to obtain compound 32B (316.0 mg, white solid, yield: 95%).
MS(ESI):m/z 235.2[M+1] +。 MS(ESI): m/z 235.2[M+1] + .
第三步：合成化合物32CThe third step: synthesis of compound 32C
将化合物INT-2(116.0mg，0.27mmol)加入到DMF(2.0mL)中，冰浴下分批加HUTA(152.0mg，0.4mmol)，随后冰浴下滴加DIEA(81.0mg，0.8mmol)，冰浴下搅拌30分钟后加入化合物32B(94mg，0.4mmol)，然后把反应液拿到室温下反应5分钟。TLC显示反应结束后，反应液加水(20mL)，用乙酸乙酯(30.0mL×3)萃取，有机层用饱和氯化钠溶液洗涤三次，有机相用无水硫酸钠干燥，减压脱溶，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1～0/1(体积比))，得到化合物32C(55.3mg，淡黄色油状，产率：27％)。Compound INT-2 (116.0 mg, 0.27 mmol) was added to DMF (2.0 mL), HUTA (152.0 mg, 0.4 mmol) was added in portions under ice bath, followed by dropwise addition of DIEA (81.0 mg, 0.8 mmol) under ice bath , and stirred for 30 minutes in an ice bath, compound 32B (94 mg, 0.4 mmol) was added, and the reaction solution was brought to room temperature for 5 minutes. After TLC showed that the reaction was completed, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30.0 mL×3), the organic layer was washed three times with saturated sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, and desolvated under reduced pressure, Purification by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5/1 to 0/1 (volume ratio)) to obtain compound 32C (55.3 mg, pale yellow oil, yield: 27%).
MS(ESI):m/z 646.2[M+1] +。 MS(ESI): m/z 646.2[M+1] + .
第四步：合成化合物32Step 4: Synthesis of Compound 32
将化合物32C(45.0mg)溶于TFA(1.0mL)中，冰浴下滴加三氟甲磺酸(0.1mL)，然后把反应液升至室温下反应30分钟。TLC显示结束后，将反应液用乙酸乙酯稀释后缓慢滴加入冰浴的饱和碳酸氢钠水溶液中，调节PH在7-8之间，用乙酸乙酯(30mL)萃取，有机相加无水硫酸钠干燥，减压脱溶，得到的粗品再用HPLC制备纯化(Waters Sunfire OBD 100x30mm，5μm，流动相A：0.1％TFA水溶液，流动相B：乙腈，梯度：10％乙腈运行至1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物32。(12.0mg，淡黄色油状)。Compound 32C (45.0 mg) was dissolved in TFA (1.0 mL), trifluoromethanesulfonic acid (0.1 mL) was added dropwise under an ice bath, and the reaction solution was warmed to room temperature and reacted for 30 minutes. After TLC showed the end, the reaction solution was diluted with ethyl acetate and slowly added dropwise to an ice-bath saturated aqueous sodium bicarbonate solution to adjust the pH between 7-8, extracted with ethyl acetate (30 mL), the organic phase was added anhydrous It was dried with sodium sulfate, desolvated under reduced pressure, and the obtained crude product was purified by HPLC (Waters Sunfire OBD 100×30 mm, 5 μm, mobile phase A: 0.1% TFA aqueous solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile to run for 1 min, 52 %-52% acetonitrile run to 10min, 95% acetonitrile run to 14min, 10% acetonitrile run to 16min end) to obtain compound 32. (12.0 mg, pale yellow oil).
MS(ESI):m/z 525.2[M+1] +。 MS(ESI): m/z 525.2[M+1] + .
1H-NMR(400MHz,DMSO-d 6):δ12.45(s,1H),8.28(d,J＝1.8Hz,1H),7.91(s,1H),7.77(s,1H),7.42(d,J＝1.4Hz,1H),7.20(s,1H),6.32-6.23(m,1H),4.53-4.34(m,3H),4.20- 4.09(m,1H),4.06-3.89(m,2H),3.75-3.58(m,2H),3.55-3.30(m,3H),3.22-3.01(m,1H),2.95-2.75(m,1H),2.68-2.60(m,2H),2.48-2.37(m,1H),1.16(d,J＝6.1Hz,3H). 1 H-NMR (400MHz, DMSO-d 6 ): δ12.45(s, 1H), 8.28(d, J=1.8Hz, 1H), 7.91(s, 1H), 7.77(s, 1H), 7.42( d, J＝1.4Hz, 1H), 7.20(s, 1H), 6.32-6.23(m, 1H), 4.53-4.34(m, 3H), 4.20- 4.09(m, 1H), 4.06-3.89(m, 2H), 3.75-3.58(m, 2H), 3.55-3.30(m, 3H), 3.22-3.01(m, 1H), 2.95-2.75(m, 1H), 2.68-2.60(m, 2H), 2.48- 2.37(m,1H),1.16(d,J=6.1Hz,3H).
实施例33：化合物33的制备Example 33: Preparation of Compound 33
Figure PCTCN2022078854-appb-000099
Figure PCTCN2022078854-appb-000099
化合物33的合成参考实施例1中化合物1的合成步骤，其中第四步用INT-16代替化合物1E，并用化合物INT-2代替化合物INT-1，得到化合物33。The synthesis of compound 33 refers to the synthesis steps of compound 1 in Example 1, wherein in the fourth step, compound 1E is replaced by INT-16, and compound INT-1 is replaced by compound INT-2 to obtain compound 33.
MS(ESI):m/z 565.2[M+H] +。 MS (ESI): m/z 565.2 [M+H] + .
1H-NMR(400MHz,DMSO-d 6):δ12.45(s,1H),8.40(d,J＝12Hz,1H),7.91(s,1H),7.79(d,J＝12Hz,1H),6.26(q,J＝4Hz,1H),4.90(t,J＝16Hz,1H),4.52(dd,J＝12,4Hz,1H),4.20-4.10(m,1H),4.07-3.87(m,3H),3.87-3.55(m,7H),3.55-3.38(m,3H),2.61-2.52(m,2H),1.14(d,J＝8Hz,3H). 1 H-NMR (400MHz, DMSO-d 6 ): δ12.45(s, 1H), 8.40(d, J=12Hz, 1H), 7.91(s, 1H), 7.79(d, J=12Hz, 1H) ,6.26(q,J＝4Hz,1H),4.90(t,J＝16Hz,1H),4.52(dd,J＝12,4Hz,1H),4.20-4.10(m,1H),4.07-3.87(m ,3H),3.87-3.55(m,7H),3.55-3.38(m,3H),2.61-2.52(m,2H),1.14(d,J=8Hz,3H).
实施例34：化合物34的制备Example 34: Preparation of Compound 34
Figure PCTCN2022078854-appb-000100
Figure PCTCN2022078854-appb-000100
化合物34的合成参考实施例1中化合物1的合成步骤，其中第四步用化合物INT-14代替化合物1E，并用化合物INT-2代替化合物INT-1，得到化合物34。The synthesis of compound 34 refers to the synthesis steps of compound 1 in Example 1, wherein compound INT-14 is used to replace compound 1E in the fourth step, and compound INT-2 is used to replace compound INT-1 to obtain compound 34.
MS(ESI):m/z 531.2[M+H]+。MS(ESI): m/z 531.2 [M+H]+.
1H-NMR(300MHz,DMSO-d 6):δ12.46(s,1H),7.92-7.87(m,1H),7.86-7.81(m,1H),7.25-7.20(m,1H),6.30-6.26(m,1H),4.27-4.23(m,2H),4.16-4.12(m,1H),3.82-3.74(m,1H),3.70-3.60(m,5H),3.50-3.40(m,4H),3.28-3.17(m,1H),2.58-2.52(m,2H),2.08-1.98(m,1H),1.91-1.75(m,1H),1.14-1.10(m,3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.46(s, 1H), 7.92-7.87(m, 1H), 7.86-7.81(m, 1H), 7.25-7.20(m, 1H), 6.30 -6.26(m, 1H), 4.27-4.23(m, 2H), 4.16-4.12(m, 1H), 3.82-3.74(m, 1H), 3.70-3.60(m, 5H), 3.50-3.40(m, 4H), 3.28-3.17(m, 1H), 2.58-2.52(m, 2H), 2.08-1.98(m, 1H), 1.91-1.75(m, 1H), 1.14-1.10(m, 3H).
实施例35：化合物35的制备Example 35: Preparation of Compound 35
Figure PCTCN2022078854-appb-000101
Figure PCTCN2022078854-appb-000101
化合物35的合成参考实施例10中化合物10的合成步骤，其中第五步用化合物INT-14代替化合物INT-10，得到化合物35。The synthesis of compound 35 refers to the synthesis steps of compound 10 in Example 10, wherein compound INT-14 is used instead of compound INT-10 in the fifth step to obtain compound 35.
MS(ESI):m/z 543.2[M+1] +。 MS(ESI): m/z 543.2[M+1] + .
1H-NMR(300MHz,DMSO-d 6):δ12.36(s,1H),7.85(s,1H),7.65(s,1H),7.23(s,1H),4.82-4.75(m,1H),4.40-4.15(m,3H),3.82-3.65(m,9H),3.55-3.40(m,2H),3.30-3.20(s,1H),2.61-2.54(m,2H),2.45-2.35(m,1H),2.15-1.75(m,3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.36(s, 1H), 7.85(s, 1H), 7.65(s, 1H), 7.23(s, 1H), 4.82-4.75(m, 1H) ),4.40-4.15(m,3H),3.82-3.65(m,9H),3.55-3.40(m,2H),3.30-3.20(s,1H),2.61-2.54(m,2H),2.45-2.35 (m,1H),2.15-1.75(m,3H).
实施例36：化合物36的制备Example 36: Preparation of Compound 36
Figure PCTCN2022078854-appb-000102
Figure PCTCN2022078854-appb-000102
化合物36的合成参考实施例9中化合物9的合成步骤，其中第五步用化合物INT-14代替化合物INT-10，得到化合物36。The synthesis of compound 36 refers to the synthesis steps of compound 9 in Example 9, wherein compound INT-14 is used instead of compound INT-10 in the fifth step to obtain compound 36.
MS(ESI):m/z 561.2[M+H] +。 MS(ESI): m/z 561.2 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ12.49(s,1H),7.91(s,1H),7.87-7.81(m,1H),7.23(s,1H),6.28-6.17(m,1H),4.33-4.19(m,4H),3.81-3.74(m,1H),3.70-3.63(m,5H),3.55-3.49(m,2H),3.48-3.41(m,2H),3.41-3.20(m,1H),3.25(s,3H),2.60-2.53(m,1H),2.15-1.96(m,1H),1.90-1.78m,1H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.49(s, 1H), 7.91(s, 1H), 7.87-7.81(m, 1H), 7.23(s, 1H), 6.28-6.17(m ,1H),4.33-4.19(m,4H),3.81-3.74(m,1H),3.70-3.63(m,5H),3.55-3.49(m,2H),3.48-3.41(m,2H),3.41 -3.20(m, 1H), 3.25(s, 3H), 2.60-2.53(m, 1H), 2.15-1.96(m, 1H), 1.90-1.78m, 1H).
实施例37：化合物37的制备Example 37: Preparation of Compound 37
Figure PCTCN2022078854-appb-000103
Figure PCTCN2022078854-appb-000103
化合物37的合成参考实施例9中化合物9的合成步骤，其中第五步用化合物INT-12代替化合物INT-10，得到化合物37。The synthesis of compound 37 refers to the synthesis steps of compound 9 in Example 9, wherein compound INT-12 is used instead of compound INT-10 in the fifth step to obtain compound 37.
MS(ESI):m/z 595.2[M+H] +。 MS (ESI): m/z 595.2 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ12.49(s,1H),8.14(s,1H),7.92(s,1H),7.35(s,1H),6.23(s,1H),4.31-4.17(m,3H),4.10-3.95(m,1H),3.76-3.44(m,12H),3.26(s,3H),2.62-2.54(m,2H),2.12-1.87(m,2H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.49(s,1H), 8.14(s,1H), 7.92(s,1H), 7.35(s,1H), 6.23(s,1H), 4.31-4.17(m, 3H), 4.10-3.95(m, 1H), 3.76-3.44(m, 12H), 3.26(s, 3H), 2.62-2.54(m, 2H), 2.12-1.87(m, 2H ).
实施例38：化合物38的制备Example 38: Preparation of Compound 38
Figure PCTCN2022078854-appb-000104
Figure PCTCN2022078854-appb-000104
化合物38的合成参考实施例10中化合物10的合成步骤，其中第五步用化合物INT-17代替化合物INT-10，得到化合物38。The synthesis of compound 38 refers to the synthesis steps of compound 10 in Example 10, wherein compound INT-17 is replaced by compound INT-10 in the fifth step to obtain compound 38.
MS(ESI):m/z 577.2[M+1] +。 MS(ESI): m/z 577.2[M+1] + .
1H-NMR(300MHz,DMSO-d 6):δ12.36(s,1H),8.45-8.33(s,1H),7.89-7.71(m,1H),7.64(s,1H),4.98-4.72(m,2H),4.58-4.42(m,1H),4.30-4.24(m,1H),3.42-3.90(m,2H),3.88-3.57(m,12H),2.69-2.56(m,2H),2.45-3.33(m,1H),2.0-1.88(m,1H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.36(s,1H), 8.45-8.33(s,1H), 7.89-7.71(m,1H), 7.64(s,1H), 4.98-4.72 (m,2H),4.58-4.42(m,1H),4.30-4.24(m,1H),3.42-3.90(m,2H),3.88-3.57(m,12H),2.69-2.56(m,2H) ,2.45-3.33(m,1H),2.0-1.88(m,1H).
实施例39：化合物39的制备Example 39: Preparation of Compound 39
Figure PCTCN2022078854-appb-000105
Figure PCTCN2022078854-appb-000105
化合物39的合成参考实施例8中化合物8的合成步骤，其中第一步用化合物INT-14代替化合物INT-10，得到化合物39。The synthesis of compound 39 refers to the synthesis steps of compound 8 in Example 8, wherein compound INT-14 is used instead of compound INT-10 in the first step to obtain compound 39.
MS(ESI):m/z 532.2[M+H] +。 MS (ESI): m/z 532.2 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ13.40-13.20(m,1H),8.30-8.21(m,1H),7.85-7.82(m,1H),7.23-7.20(m,1H),5.15-5.08(m,1H),4.42-4.17(m,3H),3.80-3.60(m,8H),3.52-3.44(m,2H),3.61-3.53(m,2H),2.17-1.95(m,1H),1.91-1.76(m,1H),1.24-1.09(m,3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ13.40-13.20(m,1H), 8.30-8.21(m,1H), 7.85-7.82(m,1H), 7.23-7.20(m,1H) ,5.15-5.08(m,1H),4.42-4.17(m,3H),3.80-3.60(m,8H),3.52-3.44(m,2H),3.61-3.53(m,2H),2.17-1.95( m,1H),1.91-1.76(m,1H),1.24-1.09(m,3H).
实施例40：化合物40的制备Example 40: Preparation of Compound 40
Figure PCTCN2022078854-appb-000106
Figure PCTCN2022078854-appb-000106
化合物40的合成参考实施例8中化合物8的合成步骤，其中第一步用化合物INT-12代替化合物INT-10，得到化合物40。The synthesis of compound 40 refers to the synthesis steps of compound 8 in Example 8, wherein in the first step, compound INT-12 is used instead of compound INT-10 to obtain compound 40.
MS(ESI):m/z 566.2[M+H] +。 MS(ESI): m/z 566.2 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ13.38-13.20(m,1H),8.30-8.20(m,1H),8.13(s,1H),7.34(s,1H),5.14-5.10(m 1H),4.38-4.22(m,3H),4.04-3.97(m,1H),3.78-3.53(m,9H),2.67-2.50(m,2H),2.20-1.76(m,2H),1.30-1.10(m,3H). 1 H-NMR (300MHz, DMSO-d 6 ): δ13.38-13.20(m,1H), 8.30-8.20(m,1H), 8.13(s,1H), 7.34(s,1H), 5.14-5.10 (m 1H), 4.38-4.22(m, 3H), 4.04-3.97(m, 1H), 3.78-3.53(m, 9H), 2.67-2.50(m, 2H), 2.20-1.76(m, 2H), 1.30-1.10(m,3H).
实施例41：化合物41的制备Example 41: Preparation of Compound 41
Figure PCTCN2022078854-appb-000107
Figure PCTCN2022078854-appb-000107
合成路线：synthetic route:
Figure PCTCN2022078854-appb-000108
Figure PCTCN2022078854-appb-000108
制备方法Preparation
第一步：合成化合物41AStep 1: Synthesis of compound 41A
将化合物INT-7(200mg，0.67mmol)加入到DMF(3mL)中，冰浴下分批加HUTA(306mg，804.46μmol)，随后冰浴下滴加DIEA(174mg，1.34mmol)，冰浴下搅拌30分钟后加入化合物INT-14(161mg，0.67mmol)，然后把反应液升至室温下反应15分钟。TLC显示反应结束后，反应液加水，用乙酸乙酯萃取，有机层用饱和氯化钠溶液洗涤三次，有机相用无水硫酸钠干燥，减压脱溶，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1～0/1(体积比))，得到化合物41A(303mg，淡黄色油状，产率：87％)。Compound INT-7 (200 mg, 0.67 mmol) was added to DMF (3 mL), and HUTA (306 mg, 804.46 μmol) was added in portions under ice bath, followed by dropwise addition of DIEA (174 mg, 1.34 mmol) under ice bath, under ice bath. After stirring for 30 minutes, compound INT-14 (161 mg, 0.67 mmol) was added, and then the reaction solution was warmed to room temperature and reacted for 15 minutes. After TLC showed that the reaction was complete, water was added to the reaction solution, extracted with ethyl acetate, the organic layer was washed three times with saturated sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, desolvated under reduced pressure, and purified by silica gel column chromatography (eluting Agent: petroleum ether/ethyl acetate=5/1～0/1 (volume ratio)) to obtain compound 41A (303 mg, pale yellow oil, yield: 87%).
MS(ESI):m/z 520.2[M+H] +。 MS (ESI): m/z 520.2 [M+H] + .
第二步：合成化合物41BStep 2: Synthesis of compound 41B
将化合物41A(303mg,0.58mmol)溶于DCM(2mL)中，冰浴下滴加TFA(1mL)，然后把反应液升至室温下反应30分钟。TLC显示结束后，将反应液用乙酸乙酯稀释后缓慢滴加入冰浴的饱和碳酸氢钠水溶液中，调pH至7，用乙酸乙酯萃取，有机相加无水硫酸钠干燥，过滤后减压脱溶，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1～0/1(体积比))，得到化合物41B(185mg，淡黄色油状，产率：79％)。Compound 41A (303 mg, 0.58 mmol) was dissolved in DCM (2 mL), TFA (1 mL) was added dropwise in an ice bath, and then the reaction solution was warmed to room temperature and reacted for 30 minutes. After TLC showed the end, the reaction solution was diluted with ethyl acetate, slowly added dropwise to an ice-bath saturated aqueous sodium bicarbonate solution, adjusted to pH 7, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, reduced Pressure-desolved, purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1～0/1 (volume ratio)) to obtain compound 41B (185 mg, pale yellow oil, yield: 79%) ).
MS(ESI):m/z 400.2[M+1] +。 MS(ESI): m/z 400.2[M+1] + .
第三步：合成化合物41CThe third step: synthesis of compound 41C
将化合物41B(185mg，0.46mmol)和化合物INT-1F(177mg，0.56mmol)溶于THF(2mL)中，冰浴搅拌5分钟后加入叔丁醇钾(104mg，0.92mmol)，然后把反应液升至室温下反应1小时。TLC显示反应结束后，将有机相减压脱溶，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1～0/1(体积比))，得到化合物41C(263mg，淡黄色油状，产率：83％)。Compound 41B (185 mg, 0.46 mmol) and compound INT-1F (177 mg, 0.56 mmol) were dissolved in THF (2 mL), stirred in an ice bath for 5 minutes, potassium tert-butoxide (104 mg, 0.92 mmol) was added, and the reaction solution was mixed. The reaction was raised to room temperature for 1 hour. After TLC showed that the reaction was completed, the organic phase was desolvated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1～0/1 (volume ratio)) to obtain compound 41C (263 mg , pale yellow oil, yield: 83%).
MS(ESI):m/z 682.2[M+1] +。 MS(ESI): m/z 682.2[M+1] + .
第四步：合成化合物41Step 4: Synthesis of Compound 41
将化合物41C(263mg)溶于三氟乙酸(3mL)中，冰浴下滴加三氟甲磺酸(0.3mL)， 然后把反应液升至室温下反应10分钟。TLC显示结束后，将反应液用乙酸乙酯稀释后缓慢滴加入冰浴的饱和碳酸氢钠水溶液中，调PH至7，用乙酸乙酯萃取，有机相加无水硫酸钠干燥，减压脱溶，再用HPLC制备纯化(Waters Sunfire OBD 100x30mm，5μm，流动相A：0.1％TFA水溶液，流动相B：乙腈，梯度：10％乙腈运行至1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物41(41mg，白色固体，产率：19％)。Compound 41C (263 mg) was dissolved in trifluoroacetic acid (3 mL), trifluoromethanesulfonic acid (0.3 mL) was added dropwise under an ice bath, and the reaction solution was warmed to room temperature and reacted for 10 minutes. After TLC showed the end, the reaction solution was diluted with ethyl acetate and slowly added dropwise to an ice-bath saturated aqueous sodium bicarbonate solution, adjusted to pH 7, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and evaporated under reduced pressure. dissolved, and then purified by HPLC preparative purification (Waters Sunfire OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA aqueous solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile run to 1 min, 52%-52% acetonitrile run to 10 min, 95 % acetonitrile run to 14 min, 10% acetonitrile run to 16 min end) to give compound 41 (41 mg, white solid, yield: 19%).
MS(ESI):m/z 562.2[M+1] +。 MS(ESI): m/z 562.2[M+1] + .
1H-NMR(300MHz,DMSO-d 6):δ13.24(s,1H),8.27(s,1H),7.86-7.83(m,1H),7.24-7.21(m,1H),5.21-5.11(m,1H),4.34-4.15(m,2H),3.80-3.60(m,9H),3.56-3.43(m,4H),3.24(s,3H)，2.55-2.51(m,2H),2.14-1.97(m,1H),1.91-1.76(m,1H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 13.24(s, 1H), 8.27(s, 1H), 7.86-7.83(m, 1H), 7.24-7.21(m, 1H), 5.21-5.11 (m,1H), 4.34-4.15(m,2H), 3.80-3.60(m,9H), 3.56-3.43(m,4H), 3.24(s,3H), 2.55-2.51(m,2H), 2.14 -1.97(m,1H),1.91-1.76(m,1H).
实施例42：化合物42的制备Example 42: Preparation of Compound 42
Figure PCTCN2022078854-appb-000109
Figure PCTCN2022078854-appb-000109
化合物42的合成参考实施例41中化合物41的合成步骤，其中第一步用化合物INT-12代替化合物INT-14，得到化合物42。The synthesis of compound 42 refers to the synthesis steps of compound 41 in Example 41, wherein compound INT-12 is used instead of compound INT-14 in the first step to obtain compound 42.
MS(ESI):m/z 596.2[M+H] +。 MS(ESI): m/z 596.2 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ13.24(s,1H),8.27(s,1H),8.14(s,1H),7.34(s,1H),5.22-5.10(m,1H),4.34-4.16(m,2H),4.04-3.97(m,1H),3.86-3.46(m,12H),3.24(s,3H),2.55-2.51(m,2H),2.06-1.76(m,2H). 1 H-NMR (300MHz, DMSO-d 6 ): δ 13.24(s, 1H), 8.27(s, 1H), 8.14(s, 1H), 7.34(s, 1H), 5.22-5.10(m, 1H) ), 4.34-4.16(m, 2H), 4.04-3.97(m, 1H), 3.86-3.46(m, 12H), 3.24(s, 3H), 2.55-2.51(m, 2H), 2.06-1.76(m , 2H).
实施例43：化合物43的制备Example 43: Preparation of Compound 43
Figure PCTCN2022078854-appb-000110
Figure PCTCN2022078854-appb-000110
化合物43的合成参考实施例9中化合物9的合成步骤，其中第五步用化合物INT-17代替化合物INT-10，得到化合物43。The synthesis of compound 43 refers to the synthesis steps of compound 9 in Example 9, wherein compound INT-17 is used instead of compound INT-10 in the fifth step to obtain compound 43.
MS(ESI):m/z 595.2[M+H] +。 MS (ESI): m/z 595.2 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ12.47(s,1H),8.46-8.32(m,1H),7.93-7.89(m,1H),7.82-7.72(m,1H),6.28-6.18(m,1H),4.95-4.83(m,1H),4.58-4.43(m,1H),4.32-4.17(m,1H),4.04-3.62(m,10H),3.54-3.42(m,5H),3.28-3.22(m,3H),2.57-2.52(m,2H). 1 H-NMR (300MHz, DMSO-d 6 ): δ12.47(s, 1H), 8.46-8.32(m, 1H), 7.93-7.89(m, 1H), 7.82-7.72(m, 1H), 6.28 -6.18(m, 1H), 4.95-4.83(m, 1H), 4.58-4.43(m, 1H), 4.32-4.17(m, 1H), 4.04-3.62(m, 10H), 3.54-3.42(m, 5H), 3.28-3.22(m, 3H), 2.57-2.52(m, 2H).
实施例44：化合物44的制备Example 44: Preparation of Compound 44
Figure PCTCN2022078854-appb-000111
Figure PCTCN2022078854-appb-000111
化合物44的合成参考实施例41中化合物41的合成步骤，其中第一步用化合物INT-17代替化合物INT-14，得到化合物44。The synthesis of compound 44 refers to the synthesis steps of compound 41 in Example 41, wherein compound INT-17 is used instead of compound INT-14 in the first step to obtain compound 44.
MS(ESI):m/z 596.2[M+H] +。 MS(ESI): m/z 596.2 [M+H] + .
1H-NMR(300MHz,DMSO-d 6):δ13.25(s,1H),8.51-8.33(m,1H),8.32-8.20(m,1H),7.88-7.68(m,1H),5.28-5.08(m,1H),5.17-4.77(m,1H),4.52-4.40(m,1H),4.11-3.95(m,2H),3.90-3.52(m,13H),3.24(s,3H),2.55-2.52(m,2H). 1 H-NMR (300MHz, DMSO-d 6 ): δ13.25(s, 1H), 8.51-8.33(m, 1H), 8.32-8.20(m, 1H), 7.88-7.68(m, 1H), 5.28 -5.08(m, 1H), 5.17-4.77(m, 1H), 4.52-4.40(m, 1H), 4.11-3.95(m, 2H), 3.90-3.52(m, 13H), 3.24(s, 3H) ,2.55-2.52(m,2H).
试验例1：PARP7酶活性测试实验Test Example 1: PARP7 Enzyme Activity Test Experiment
此测定法用于检查化合物抑制PARP7酶活性的效力，其中较低的IC 50值表示作为PARP7抑制剂的化合物在以下测定设置中的高效力。 This assay was used to examine the potency of compounds to inhibit PARP7 enzymatic activity, with lower IC50 values indicating high potency of compounds as PARP7 inhibitors in the following assay setup.
1.实验材料：1. Experimental materials:
PARP7化学荧光检测试剂盒购自BPS Bioscience。PARP7 chemiluminescence detection kit was purchased from BPS Bioscience.
2.实验方法：2. Experimental method:
PBST缓冲液配制：1X PBS中包含0.05％吐温20，即10mL PBS中加入5μL 100％吐温20。PBST buffer preparation: 1X PBS contains 0.05% Tween 20, that is, 5 μL of 100% Tween 20 is added to 10 mL of PBS.
将试剂盒中组蛋白溶液按照1份溶液加4份PBS，取25μL/孔稀释液，置于4℃过夜孵育。使用前去掉稀释液，用100μL/孔PBST洗板3次后，加100μL/孔封闭液，置于25℃孵育90分钟。结束孵育后，加100μL/孔PBST洗板3次，弃去孔中残留液体。Add 4 parts of PBS to 1 part of the histone solution in the kit, take 25 μL/well of diluent, and incubate at 4°C overnight. Remove the diluent before use, wash the plate three times with 100 μL/well PBST, add 100 μL/well blocking solution, and incubate at 25°C for 90 minutes. After the incubation, add 100 μL/well PBST to wash the plate 3 times, and discard the residual liquid in the well.
1X测试缓冲液配制：将10X PARP测试缓冲液用双蒸水进行10倍稀释；1X test buffer preparation: Dilute 10X PARP test buffer 10 times with double distilled water;
化合物溶液配制：将待测化合物用DMSO溶液进行3倍稀释至第8个浓度，即从300μM稀释至137nM。再用1X测试缓冲液将待测化合物各梯度稀释成DMSO为10％的工作液。2.5μL/孔加到对应孔中。每孔加入12.5μL/孔底物混合溶液(1.25μL 10X PARP测试缓冲液；1.25μL 10X PARP实验混合液；10μL双蒸水)。将PARP7酶稀释到6ng/μL，取10μL/孔加入到对应孔中此时化合物终浓度梯度为3μM至1.37nM，PARP7(60ng)，反应体系置于25℃孵育60分钟；Compound solution preparation: The compounds to be tested were diluted 3-fold with DMSO solution to the eighth concentration, that is, from 300 μM to 137 nM. Then use 1X test buffer to dilute each compound to be tested into a working solution with 10% DMSO. 2.5 μL/well was added to the corresponding well. Add 12.5 μL/well substrate mixture solution (1.25 μL 10X PARP test buffer; 1.25 μL 10X PARP experimental mixture; 10 μL double distilled water) to each well. Dilute PARP7 enzyme to 6ng/μL, and add 10μL/well to the corresponding well. At this time, the final compound concentration gradient is 3μM to 1.37nM, PARP7 (60ng), and the reaction system is incubated at 25°C for 60 minutes;
结束孵育后，弃去孔中液体，取100μL/孔PBST洗板3次，弃去孔中残留液体；将Streptavidin-HRP用封闭液进行50倍稀释，然后取25μL/孔到对应孔中，置于25℃孵育30分钟；结束孵育后，弃去孔中液体，取100μL/孔PBST洗板3次，弃去孔中残留液体；冰上按照1:1(v/v)混匀ELISA ECL底物A和ELISA ECL底物B，取50μL/孔到对应孔中，读取化学发光值。After the incubation, discard the liquid in the well, take 100 μL/well of PBST to wash the plate 3 times, and discard the residual liquid in the well; Dilute Streptavidin-HRP 50 times with blocking solution, and then take 25 μL/well into the corresponding well, set Incubate at 25°C for 30 minutes; after the incubation, discard the liquid in the well, wash the plate 3 times with 100 μL/well PBST, and discard the residual liquid in the well; mix ELISA ECL bottom at 1:1 (v/v) on ice Substrate A and ELISA ECL substrate B, take 50 μL/well into the corresponding well, and read the chemiluminescence value.
3.实验数据处理方法：3. Experimental data processing method:
利用发光信息值计算抑制率，将浓度以及抑制率使用Graphpad Prism软件进行非线 性回归归曲线拟合，得到IC 50值。 The inhibition rate was calculated using the luminescence information value, and the concentration and inhibition rate were fitted by nonlinear regression curve using Graphpad Prism software to obtain the IC 50 value.
其中本发明制备得到的部分化合物以及本领域常用的PARP7酶抑制剂RBN-2397对于PARP7酶活性的抑制效果如表2所示。Table 2 shows the inhibitory effects of some compounds prepared in the present invention and the PARP7 enzyme inhibitor RBN-2397 commonly used in the art on PARP7 enzyme activity.
表2.本发明的化合物对PARP7酶抑制的IC 50数据 Table 2. IC50 data for PARP7 enzyme inhibition by compounds of the invention
化合物编号Compound number IC 50(nM) IC50 (nM)
RBN-2397RBN-2397 31.3131.31
化合物1Compound 1 38.7438.74
化合物2Compound 2 30.8030.80
化合物3Compound 3 28.2528.25
化合物4Compound 4 19.3619.36
化合物5Compound 5 23.6723.67
化合物15Compound 15 9.039.03
化合物35Compound 35 7.307.30
化合物40Compound 40 9.29.2
由表2可知，本发明的化合物对PARP7酶具有较好的抑制作用，绝大部分化合物的PARP7酶抑制活性优于RBN-2397，具有良好的临床应用前景。It can be seen from Table 2 that the compounds of the present invention have a good inhibitory effect on PARP7 enzyme, and the PARP7 enzyme inhibitory activity of most of the compounds is better than that of RBN-2397, which has a good clinical application prospect.
试验例2：NCI-H1373细胞抗增殖实验Test Example 2: NCI-H1373 Cell Anti-Proliferation Experiment
1.实验材料：1. Experimental materials:
细胞株NCI-H1373购自科佰。RPMI1640培养基，盘尼西林/链霉素抗生素购自普诺赛。胎牛血清购自Biosera。CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。EnVision多标记分析仪购自PerkinElmer。The cell line NCI-H1373 was purchased from Kebai. RPMI1640 medium, penicillin/streptomycin antibiotics were purchased from Proxa. Fetal bovine serum was purchased from Biosera. CellTiter-Glo (Cell Viability Chemiluminescence Detection Reagent) reagent was purchased from Promega. The EnVision Multilabel Analyzer was purchased from PerkinElmer.
2.实验方法：2. Experimental method:
将NCI-H1373细胞种于白色96孔板中，80μL细胞悬液/孔，其中包含2000个NCI-H1373细胞。细胞板置于二氧化碳培养箱中过夜培养。将待测化合物用排枪进行3倍稀释至第9个浓度，即从600μM稀释至91.45nM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL/孔的梯度稀释化合物至中间板，混匀后转移20μL/孔到细胞板中。转移到细胞板中的化合物浓度范围是3μM到0.46nM。细胞板置于二氧化碳培养箱中培养6天。另准备一块细胞板，在加药当天读取信号值作为最大值(下面方程式中Max值)参与数据分析。向此细胞板每孔加入25μL细胞活率化学发光检测试剂，室温孵育10分钟，使发光信号稳定。采用多标记分析仪读数。加入化合物的细胞板结束孵育后，向细胞板中加入每孔25μL的细胞活率化学发光检测试剂，室温孵育10分钟，使发光信号稳定。采用多标记分析仪读数。NCI-H1373 cells were seeded in a white 96-well plate, 80 μL of cell suspension/well, which contained 2000 NCI-H1373 cells. Cell plates were incubated overnight in a carbon dioxide incubator. The compound to be tested was diluted 3-fold to the ninth concentration, that is, from 600 μM to 91.45 nM, and a double-well experiment was set up. Add 78 μL of medium to the middle plate, and then transfer 2 μL/well of the compound to the middle plate according to the corresponding position. After mixing, transfer 20 μL/well to the cell plate. Compound concentrations transferred to the cell plate ranged from 3 [mu]M to 0.46 nM. The cell plates were placed in a carbon dioxide incubator for 6 days. Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis. Add 25 μL of cell viability chemiluminescence detection reagent to each well of the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer. After the incubation of the cell plate with the compound added, 25 μL of cell viability chemiluminescence detection reagent was added to the cell plate, and incubated at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer.
3.实验数据处理方法：3. Experimental data processing method:
利用发光信息值计算抑制率，将浓度以及抑制率使用Graphpad Prism软件进行非线性回归归曲线拟合，得到IC 50值。 The inhibition rate was calculated using the luminescence information value, and the concentration and inhibition rate were fitted by nonlinear regression curve using Graphpad Prism software to obtain the IC 50 value.
其中本发明制备得到的化合物以及本领域常用的PARP7酶抑制剂RBN-2397对于NCI-H1373细胞抗增殖的抑制效果如表3所示。Table 3 shows the inhibitory effect of the compound prepared in the present invention and the PARP7 enzyme inhibitor RBN-2397 commonly used in the art on the anti-proliferation of NCI-H1373 cells.
表3.本发明的化合物对NCI-H1373细胞抗增殖实验的IC 50数据 Table 3. IC 50 data of the compounds of the present invention on NCI-H1373 cell anti-proliferation experiments
化合物编号Compound number IC 50(nM) IC50 (nM) 化合物编号Compound number IC 50(nM) IC50 (nM)
RBN-2397RBN-2397 271271 化合物22Compound 22 588588
化合物1Compound 1 349349 化合物23Compound 23 974974
化合物2Compound 2 595595 化合物25Compound 25 106106
化合物3Compound 3 516516 化合物26Compound 26 250250
化合物4Compound 4 263263 化合物27Compound 27 537537
化合物5Compound 5 283283 化合物28Compound 28 346346
化合物6Compound 6 2525 化合物30Compound 30 263263
化合物7Compound 7 23twenty three 化合物31Compound 31 924924
化合物8Compound 8 176176 化合物33Compound 33 500500
化合物9Compound 9 168168 化合物34Compound 34 3030
化合物10Compound 10 3939 化合物35Compound 35 22
化合物11Compound 11 299299 化合物36Compound 36 163163
化合物12Compound 12 66 化合物37Compound 37 3636
化合物13Compound 13 200200 化合物38Compound 38 55
化合物15Compound 15 1616 化合物39Compound 39 8080
化合物16Compound 16 3333 化合物40Compound 40 1616
化合物18Compound 18 398398 化合物41Compound 41 107107
化合物19Compound 19 14961496 化合物42Compound 42 7070
化合物20Compound 20 17761776 化合物43Compound 43 104104
化合物21Compound 21 645645 化合物44Compound 44 114114
由表3可知，本发明的化合物对NCI-H1373细胞增殖有较好的抑制，部分化合物的细胞增殖抑制活性优于RBN-2397，具有非常大的抗肿瘤潜力，产生良好的临床应用前景。It can be seen from Table 3 that the compounds of the present invention can inhibit the proliferation of NCI-H1373 cells well, and the cell proliferation inhibition activity of some compounds is better than that of RBN-2397.
实验例3：体内药效学实验Experimental Example 3: In vivo pharmacodynamic experiment
1.实验目的：1. Experimental purpose:
评价受试化合物在人肺癌腺癌细胞NCI-H1373细胞皮下异体移植肿瘤模型上的体内药效。The in vivo efficacy of the test compounds on the subcutaneous xenograft tumor model of human lung cancer adenocarcinoma cells NCI-H1373 cells was evaluated.
2.实验动物：2. Experimental animals:
CB-17 SCID雌小鼠，8-10周龄，体重19-23克，由北京维通利华科技股份有限公司提供。CB-17 SCID female mice, 8-10 weeks old, weighing 19-23 grams, were provided by Beijing Weitong Lihua Technology Co., Ltd.
3.实验方法：3. Experimental method:
将3x10 6个NCI-H1373肿瘤细胞重悬于PBS中，制备成密度为1×10 7个/mL的细胞悬液，皮下接种0.2mL细胞悬液于每只小鼠的右后背(加入基质胶，体积比为1：1)，等待肿瘤生长。在肿瘤平均体积达到约113mm 3时，开始进行随机分组给药。给药后， 每周两次用游标卡尺测量肿瘤直径，肿瘤体积的计算公式如下： 3×10 6 NCI-H1373 tumor cells were resuspended in PBS to prepare a cell suspension at a density of 1×10 7 cells/mL, and 0.2 mL of the cell suspension was subcutaneously inoculated on the right back of each mouse (adding matrix). glue, 1:1 by volume), waiting for tumor growth. Randomization was initiated when the mean tumor volume reached approximately 113 mm3 . After administration, the tumor diameter was measured with a vernier caliper twice a week, and the tumor volume was calculated as follows:
V＝0.5a×b 2，其中a和b分别表示肿瘤的长径和短径。 V=0.5a×b 2 , where a and b represent the long and short diameters of the tumor, respectively.
化合物的抑瘤疗效用TGI(％)评价，TGI(％)反映了肿瘤生长抑制率，其计算如下：The tumor-inhibitory efficacy of a compound was evaluated by TGI (%), which reflects the tumor growth inhibition rate and was calculated as follows:
TGI(％)＝[(1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100％。TGI(%)=[(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment in the solvent control group-at the beginning of treatment in the solvent control group Mean tumor volume)] × 100%.
4.实验结果：4. Experimental results:
相关结果如表4所示。The related results are shown in Table 4.
表4.体内药效实验结果Table 4. In vivo efficacy test results
Figure PCTCN2022078854-appb-000112
Figure PCTCN2022078854-appb-000112
5.实验结论：5. Experimental conclusion:
开始给药31天后，在同等剂量下，本发明的化合物具有非常显著的肿瘤抑制效果，TGI可以达到约70％以上，最高甚至能达到101％，表明本发明的化合物在人肺癌腺癌细胞NCI-H1373皮下异体移植肿瘤模型上展示出良好的体内药效，极具临床应用前景。31 days after the start of administration, under the same dose, the compound of the present invention has a very significant tumor inhibitory effect, and the TGI can reach more than about 70%, and the highest can even reach 101%, indicating that the compound of the present invention is effective in human lung cancer adenocarcinoma cells NCI. -H1373 subcutaneous xenograft tumor model shows good in vivo efficacy and has great clinical application prospects.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制。在不脱离本发明的原理和宗旨的情况下，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型，这些变化、修改、替换和变型均涵盖在本发明的范围之中。Although the embodiments of the present invention have been shown and described above, it is to be understood that the above-described embodiments are exemplary and should not be construed to limit the present invention. Without departing from the principles and spirit of the present invention, those of ordinary skill in the art can make changes, modifications, substitutions and alterations to the above-mentioned embodiments within the scope of the present invention, and these changes, modifications, substitutions and modifications are all covered in within the scope of the present invention.

Claims (18)

  1. 如式I所示的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药，其中A compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, wherein
    Figure PCTCN2022078854-appb-100001
    Figure PCTCN2022078854-appb-100001
    A选自C 6-C 10芳基和6-10元杂芳基； A is selected from C 6 -C 10 aryl and 6-10 membered heteroaryl;
    R 1选自氢、卤素、氰基、羟基、氨基、C 1-C 6烷基、C 1-C 6杂烷基、C 3-C 8环烷基、3-8元杂环烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基和C 1-C 6卤代烷基，其中所述烷基、杂烷基、环烷基、杂环烷基、烷氧基、卤代烷氧基和卤代烷基各自任选地被至少1个R 8取代； R 1 is selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy and C 1 -C 6 haloalkyl, wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkyi oxy and haloalkyl are each optionally substituted with at least 1 R 8 ;
    R 2选自氢、C 1-C 6烷基和C 3-C 8环烷基，其中所述烷基和环烷基各自任选地被至少1个R 8取代；或者，
    Figure PCTCN2022078854-appb-100002
    被
    Figure PCTCN2022078854-appb-100003
    代替；     R 2 is selected from hydrogen, C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl, wherein said alkyl and cycloalkyl are each optionally substituted with at least 1 R 8 ; or,
    Figure PCTCN2022078854-appb-100002
    quilt
    Figure PCTCN2022078854-appb-100003
    replace;
    每一个R 3、R 4、R 5和R 6各自独立地选自氢、卤素、氰基、羟基、氨基、硝基、C(O)R 9、C(O)NR 9R 10、C(O)OR 9、OC(O)R 9、C 1-C 6烷基、C 1-C 6杂烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基、C 3-C 8环烷基、3-8元杂环烷基、C 6-C 10芳基和6-10元杂芳基，其中所述烷基、杂烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环烷基、芳基或杂芳基各自任选地被至少1个R 8取代；或者，当Y 1为单键且m不为0时，直接连接Y 1的碳原子上的R 3或R 4与R 2连接成3-8元杂环烷基； Each of R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C(O)R 9 , C(O)NR 9 R 10 , C( O)OR 9 , OC(O)R 9 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl and 6-10 membered heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optional is substituted by at least 1 R 8 ; or, when Y 1 is a single bond and m is not 0, directly connecting R 3 or R 4 and R 2 on the carbon atom of Y 1 is connected to form a 3-8 membered heterocycloalkane base;
    R 7选自氢、卤素、氰基、羟基、氨基、氨基甲酰基、C 1-C 6烷基、C 1-C 6杂烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基、C 3-C 8环烷基、3-8元杂环烷基、C 6-C 10芳基和6-10元杂芳基，优选氢、卤素、氰基、羟基、氨基、C 1-C 6烷基、C 1-C 6杂烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基、C 3-C 8环烷基、3-8元杂环烷基、C 6-C 10芳基和6-10元杂芳基，其中所述烷基、杂烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环烷基、芳基和杂芳基各自任选地被至少1个R 8取代； R 7 is selected from hydrogen, halogen, cyano, hydroxyl, amino, carbamoyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyne base, C 1 -C 6 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 -aryl and 6-10-membered heteroaryl, preferably hydrogen, halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl , C 6 -C 10 aryl and 6-10 membered heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycle Alkyl, aryl and heteroaryl are each optionally substituted with at least 1 R;
    L 1、L 2和L 3各自独立地选自-(CH 2) o-(A) p-(CH 2) q-，其中A选自O、C(R 8) 2或NR 8，o、p和q各自独立地为0至3中的任一整数； L 1 , L 2 and L 3 are each independently selected from -(CH 2 ) o -(A) p -(CH 2 ) q -, wherein A is selected from O, C(R 8 ) 2 or NR 8 , o, p and q are each independently any integer from 0 to 3;
    Y 1、Y 2和Y 3各自独立地选自单键、O、S、NR 10、C(＝O)、C(＝O)O、C(＝O)NR 10、S(＝O)、S(＝O) 2、S(＝O)NR 10、S(＝O) 2NR 10、NR 10C(＝O)NR 10、C 3-C 8亚环烷基、3-8元亚杂环烷基、C 6-C 10亚芳氧基和5-10元亚杂芳基；优选地，Y 1、Y 2和Y 3各自独立地选自单键、O、S、NR 10、C(＝O)、C(＝O)O、C(＝O)NR 10、S(＝O)、S(＝O) 2、S(＝O)NR 10、S(＝O) 2NR 10和NR 10C(＝O)NR 10； Y 1 , Y 2 and Y 3 are each independently selected from single bond, O, S, NR 10 , C(=O), C(=O)O, C(=O)NR 10 , S(=O), S(=O) 2 , S(=O)NR 10 , S(=O) 2 NR 10 , NR 10 C(=O)NR 10 , C 3 -C 8 cycloalkylene, 3-8 membered heteroalkylene Cycloalkyl, C 6 -C 10 aryleneoxy and 5-10 membered heteroarylene; preferably, Y 1 , Y 2 and Y 3 are each independently selected from single bond, O, S, NR 10 , C (=O), C(=O)O, C(=O)NR 10 , S(=O), S(=O) 2 , S(=O)NR 10 , S(=O) 2 NR 10 and NR 10 C(=O)NR 10 ;
    X 1选自O、C(R 8) 2和NR 8； X 1 is selected from O, C(R 8 ) 2 and NR 8 ;
    X 2选自CR 8和N； X 2 is selected from CR 8 and N;
    m和n各自独立地选自0、1、2、3、4和5；m and n are each independently selected from 0, 1, 2, 3, 4 and 5;
    R 8和R 9各自独立地选自氢、卤素、氰基、羟基、氨基、C 1-C 6烷基、C 1-C 6杂烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 8环烷基、3-8元杂环烷基、C 3-C 8环烷氧基和3-8元杂环烷氧基，其中所述烷基、杂烷基、烯基、炔基、环烷基、杂环烷基、环烷氧基和杂环烷氧基各自任选地被至少1个R 10取代； R 8 and R 9 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3 -C 8 cycloalkoxy and 3-8 membered heterocycloalkoxy, wherein the alkyl, heteroalkane alkenyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy and heterocycloalkoxy are each optionally substituted with at least 1 R 10 ;
    R 1至R 9中所述杂烷基、杂环烷基、杂环烷氧基和杂芳基以及Y 1至Y 3中所述亚杂环烷基和亚杂芳基中所含的杂原子或杂原子团分别独立地选自-C(＝O)N(R 10)-、-N(R 10)-、-N＝、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O) 2-和-N(R 10)C(＝O)N(R 10)-，且所述杂原子或杂原子团的数目分别独立地选自1、2和3； The heteroalkyl groups, heterocycloalkyl groups, heterocycloalkoxy groups, and heteroaryl groups described in R 1 to R 9 and the heterocyclic groups contained in the heterocycloalkylene groups and heteroarylene groups described in Y 1 to Y 3 The atoms or heteroatomic groups are each independently selected from -C(=O)N(R 10 )-, -N(R 10 )-, -N=, -O-, -S-, -C(=O)O- , -C(=O)-, -C(=S)-, -S(=O)-, -S(=O) 2 - and -N(R 10 )C(=O)N(R 10 ) -, and the number of said heteroatoms or heteroatoms is independently selected from 1, 2 and 3;
    R 10选自氢、氯、氟、氰基、羟基、氨基、异丙基、环丙基、甲基、二氟甲基、三氟甲基、甲氧基、三氟甲氧基、乙氧基、2,2-二氟乙氧基、2,2,2-三氟乙氧基和苯基。 R 10 is selected from hydrogen, chlorine, fluorine, cyano, hydroxyl, amino, isopropyl, cyclopropyl, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy and phenyl.
  2. 根据权利要求1所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药，其特征在于，The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, characterized in that,
    R 2选自氢、C 1-C 6烷基和C 3-C 8环烷基，其中所述烷基和环烷基各自任选地被至少1个R 8取代； R 2 is selected from hydrogen, C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl, wherein each of said alkyl and cycloalkyl is optionally substituted with at least 1 R 8 ;
    每一个R 3、R 4、R 5和R 6各自独立地选自氢、卤素、氰基、羟基、氨基、硝基、C(O)R 9、C(O)NR 9R 10、C(O)OR 9、OC(O)R 9、C 1-C 6烷基、C 1-C 6杂烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基、C 3-C 8环烷基、3-8元杂环烷基、C 6-C 10芳基和6-10元杂芳基，其中所述烷基、杂烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环烷基、芳基或杂芳基各自任选地被至少1个R 8取代； Each of R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C(O)R 9 , C(O)NR 9 R 10 , C( O)OR 9 , OC(O)R 9 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl and 6-10 membered heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optional is substituted by at least 1 R 8 ;
    R 7选自氢、卤素、氰基、羟基、氨基、C 1-C 6烷基、C 1-C 6杂烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基、C 3-C 8环烷基、3-8元杂环烷基、C 6-C 10芳基和6-10元杂芳基，其中所述烷基、杂烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环烷基、芳基和杂芳基各自任选地被至少1个R 8取代； R 7 is selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl and 6-10 membered heteroaryl, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl each is optionally substituted with at least 1 R;
    Y 1、Y 2和Y 3各自独立地选自单键、O、S、NR 10、C(＝O)、C(＝O)O、C(＝O)NR 10、S(＝O)、S(＝O) 2、S(＝O)NR 10、S(＝O) 2NR 10和NR 10C(＝O)NR 10； Y 1 , Y 2 and Y 3 are each independently selected from single bond, O, S, NR 10 , C(=O), C(=O)O, C(=O)NR 10 , S(=O), S(=O) 2 , S(=O)NR 10 , S(=O) 2 NR 10 and NR 10 C(=O)NR 10 ;
    A、R 1、R 8、R 9、R 10、L 1、L 2、L 3、X 1、X 2、m和n如权利要求1中所定义。 A, R 1 , R 8 , R 9 , R 10 , L 1 , L 2 , L 3 , X 1 , X 2 , m and n are as defined in claim 1 .
  3. 根据权利要求1所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药，其特征在于，The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, characterized in that,
    所述化合物如式I’所示，其中The compound is shown in formula I', wherein
    Figure PCTCN2022078854-appb-100004
    Figure PCTCN2022078854-appb-100004
    每一个R 3、R 4、R 5和R 6各自独立地选自氢、卤素、氰基、羟基、氨基、硝基、C(O)R 9、C(O)NR 9R 10、C(O)OR 9、OC(O)R 9、C 1-C 6烷基、C 1-C 6杂烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基、C 3-C 8环烷基、3-8元杂环烷基、C 6-C 10芳基和6-10元杂芳基，其中所述烷基、杂烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环烷基、芳基或杂芳基各自任选地被至少1个R 8取代； Each of R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C(O)R 9 , C(O)NR 9 R 10 , C( O)OR 9 , OC(O)R 9 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl and 6-10 membered heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optional is substituted by at least 1 R 8 ;
    A、R 1、R 7、R 8、R 9、R 10、L 1、L 2、L 3、Y 1、Y 2、Y 3、X 1、X 2、m和n如权利要求1中所定义。 A, R 1 , R 7 , R 8 , R 9 , R 10 , L 1 , L 2 , L 3 , Y 1 , Y 2 , Y 3 , X 1 , X 2 , m and n as claimed in claim 1 definition.
  4. 根据权利要求1所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药，其特征在于，The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, characterized in that,
    所述化合物如式I”所示，其中The compound is shown in formula I", wherein
    Figure PCTCN2022078854-appb-100005
    Figure PCTCN2022078854-appb-100005
    B为3-6元杂环烷基，优选4-5元杂环烷基，更优选4元杂环烷基，进一步优选吖丁啶基；B is a 3-6-membered heterocycloalkyl, preferably a 4-5-membered heterocycloalkyl, more preferably a 4-membered heterocycloalkyl, further preferably an azetidinyl;
    每一个R 3、R 4、R 5和R 6各自独立地选自氢、卤素、氰基、羟基、氨基、硝基、C(O)R 9、C(O)NR 9R 10、C(O)OR 9、OC(O)R 9、C 1-C 6烷基、C 1-C 6杂烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6卤代烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基、C 3-C 8环烷基、3-8元杂环烷基、C 6-C 10芳基和6-10元杂芳基，其中所述烷基、杂烷基、烯基、炔基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环烷基、芳基或杂芳基各自任选地被至少1个R 8取代； Each of R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, nitro, C(O)R 9 , C(O)NR 9 R 10 , C( O)OR 9 , OC(O)R 9 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 Haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl and 6-10 membered heteroaryl, wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optional is substituted by at least 1 R 8 ;
    Y 2和Y 3各自独立地选自单键、O、S、NR 10、C(＝O)、C(＝O)O、C(＝O)NR 10、S(＝O)、S(＝O) 2、S(＝O)NR 10、S(＝O) 2NR 10、NR 10C(＝O)NR 10、C 3-C 8亚环烷基、3-8元亚杂环烷基、C 6-C 10亚芳氧基和5-10元亚杂芳基；优选地，Y 2和Y 3各自独立地选自单键、O、S、NR 10、C(＝O)、C(＝O)O、C(＝O)NR 10、S(＝O)、S(＝O) 2、S(＝O)NR 10、S(＝O) 2NR 10和NR 10C(＝O)NR 10； Y 2 and Y 3 are each independently selected from single bond, O, S, NR 10 , C(=O), C(=O)O, C(=O)NR 10 , S(=O), S(=O) O) 2 , S(=O)NR 10 , S(=O) 2 NR 10 , NR 10 C(=O)NR 10 , C 3 -C 8 cycloalkylene, 3-8 membered heterocycloalkylene , C 6 -C 10 aryleneoxy and 5-10 membered heteroarylene; preferably, Y 2 and Y 3 are each independently selected from single bond, O, S, NR 10 , C(=O), C (=O)O, C(=O)NR 10 , S(=O), S(=O) 2 , S(=O)NR 10 , S(=O) 2 NR 10 and NR 10 C(=O )NR 10 ;
    m选自1、2、3、4和5；m is selected from 1, 2, 3, 4 and 5;
    n选自0、1、2、3、4和5；n is selected from 0, 1, 2, 3, 4 and 5;
    A、R 1、R 7、R 8、R 9、R 10、L 1、L 2、L 3、X 1和X 2如权利要求1中所定义。 A, R 1 , R 7 , R 8 , R 9 , R 10 , L 1 , L 2 , L 3 , X 1 and X 2 are as defined in claim 1 .
  5. 根据权利要求1-4中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药，其特征在于，The compound according to any one of claims 1-4 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, characterized in that,
    A为6-8元杂芳基，优选6元杂芳基，更优选吡啶基。A is a 6- to 8-membered heteroaryl group, preferably a 6-membered heteroaryl group, more preferably a pyridyl group.
  6. 根据权利要求1-5中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药，其特征在于，The compound according to any one of claims 1-5 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, characterized in that,
    R 1选自C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基和C 1-C 3卤代烷基，优选C 1-C 3氟代烷基，更优选三氟甲基。 R 1 is selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy and C 1 -C 3 haloalkyl, preferably C 1 -C 3 fluoroalkyl, more Trifluoromethyl is preferred.
  7. 根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药，其特征在于，The compound according to claim 1 or 2 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, characterized in that,
    R 2为氢。 R 2 is hydrogen.
  8. 根据权利要求1-7中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药，其特征在于，The compound according to any one of claims 1-7 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, characterized in that,
    每一个R 3、R 4、R 5和R 6各自独立地选自氢、C 1-C 3烷基、C 1-C 3杂烷基、C 1-C 3卤代烷基、C 1-C 3烷氧基和C 1-C 3卤代烷氧基；优选地，每一个R 3、R 4、R 5和R 6各自独立地选自氢、C 1-C 3烷基和C 1-C 3杂烷基；更优选地，每一个R 3、R 4、R 5和R 6各自独立地选自氢、甲基和甲氧甲基。 Each of R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 3 heteroalkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkoxy; preferably, each of R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, C 1 -C 3 alkyl and C 1 -C 3 hetero alkyl ; more preferably, each of R3 , R4 , R5 and R6 is independently selected from hydrogen, methyl and methoxymethyl.
  9. 根据权利要求1-8中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药，其特征在于，The compound according to any one of claims 1-8 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, characterized in that,
    R 7选自氢、卤素、氰基、羟基、氨基、C 1-C 6烷基、C 1-C 6卤代烷基和C 3-C 8环烷基，优选氢、卤素、氰基、羟基、氨基、C 1-C 3烷基、C 1-C 3卤代烷基和C 3-C 6环烷基，更优选氢、氟、氯、溴、氰基、羟基、氨基、甲基、乙基、丙基、异丙基、氟甲基、二氟甲基、三氟甲基、环丙基、环丁基和环戊基。 R 7 is selected from hydrogen, halogen, cyano, hydroxyl, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 3 -C 8 cycloalkyl, preferably hydrogen, halogen, cyano, hydroxyl, amino, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl and C 3 -C 6 cycloalkyl, more preferably hydrogen, fluorine, chlorine, bromine, cyano, hydroxy, amino, methyl, ethyl, Propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl and cyclopentyl.
  10. 根据权利要求1-9中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药，其特征在于，The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, characterized in that,
    R 8和R 9各自独立地选自氢和C 1-C 6烷基，优选氢和C 1-C 3烷基，更优选氢和甲基。 R 8 and R 9 are each independently selected from hydrogen and C 1 -C 6 alkyl, preferably hydrogen and C 1 -C 3 alkyl, more preferably hydrogen and methyl.
  11. 根据权利要求1-3中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药，其特征在于，The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, characterized in that,
    Figure PCTCN2022078854-appb-100006
    片段选自如下片段之一：
    Figure PCTCN2022078854-appb-100006
    The fragment is selected from one of the following fragments:
    Figure PCTCN2022078854-appb-100007
    Figure PCTCN2022078854-appb-100008
    优选如下片段之一：
    Figure PCTCN2022078854-appb-100007
    Figure PCTCN2022078854-appb-100008
    One of the following fragments is preferred:
    Figure PCTCN2022078854-appb-100009
    Figure PCTCN2022078854-appb-100010
    更优选
    Figure PCTCN2022078854-appb-100011
    Figure PCTCN2022078854-appb-100009
    Figure PCTCN2022078854-appb-100010
    more preferred
    Figure PCTCN2022078854-appb-100011
  12. 根据权利要求4所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药，其特征在于，The compound of claim 4 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, characterized in that,
    Figure PCTCN2022078854-appb-100012
    片段选自如下片段之一：
    Figure PCTCN2022078854-appb-100012
    The fragment is selected from one of the following fragments:
    Figure PCTCN2022078854-appb-100013
    Figure PCTCN2022078854-appb-100014
    优选如下片段之一：
    Figure PCTCN2022078854-appb-100013
    Figure PCTCN2022078854-appb-100014
    One of the following fragments is preferred:
    Figure PCTCN2022078854-appb-100015
    更优选如下片段：
    Figure PCTCN2022078854-appb-100015
    More preferred are the following fragments:
    Figure PCTCN2022078854-appb-100016
    Figure PCTCN2022078854-appb-100016
  13. 根据权利要求1-12中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药，其特征在于，The compound according to any one of claims 1-12 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, characterized in that,
    Figure PCTCN2022078854-appb-100017
    片段选自如下片段之一：
    Figure PCTCN2022078854-appb-100017
    The fragment is selected from one of the following fragments:
    Figure PCTCN2022078854-appb-100018
    Figure PCTCN2022078854-appb-100019
    优选如下片段之一：
    Figure PCTCN2022078854-appb-100018
    Figure PCTCN2022078854-appb-100019
    One of the following fragments is preferred:
    Figure PCTCN2022078854-appb-100020
    Figure PCTCN2022078854-appb-100020
  14. 下列化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药：The following compounds or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, metabolites or prodrugs:
    Figure PCTCN2022078854-appb-100021
    Figure PCTCN2022078854-appb-100021
    Figure PCTCN2022078854-appb-100022
    Figure PCTCN2022078854-appb-100022
    Figure PCTCN2022078854-appb-100023
    Figure PCTCN2022078854-appb-100023
  15. 一种药物组合物，其包含根据权利要求1至14中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药；A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite thereof or prodrugs;
    优选地，所述药物组合物还包含至少一种药学上可接受的辅料。Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable adjuvant.
  16. 根据权利要求1至14中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药或者根据权利要求15所述的药物组合物在制备用于预防和/或治疗由PARP7过度表达引起的疾病或病症的药物中的用途。A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof or according to claim 15 Use of the pharmaceutical composition in the preparation of a medicament for preventing and/or treating diseases or conditions caused by overexpression of PARP7.
  17. 根据权利要求1至14中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药或者根据权利要求15所述的药物组合物，其用于预防和/或治疗由PARP7过度表达引起的疾病或病症。A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof or according to claim 15 The pharmaceutical composition is used for preventing and/or treating diseases or conditions caused by overexpression of PARP7.
  18. 一种用于预防和/或治疗由PARP7过度表达引起的疾病或病症的方法，其包括将预防和/或治疗有效量的根据权利要求1至14中任一项所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药或者根据权利要求15所述的药物组合物施用于对其有需要的个体。A method for preventing and/or treating a disease or condition caused by overexpression of PARP7, comprising applying a preventive and/or therapeutically effective amount of a compound according to any one of claims 1 to 14 or pharmaceutically The acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug or pharmaceutical composition of claim 15 is administered to an individual in need thereof.
PCT/CN2022/078854 2021-03-03 2022-03-02 Tricyclic compound and pharmaceutical composition and use thereof WO2022184103A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110237007.5A CN115028648A (en) 2021-03-03 2021-03-03 Tricyclic compound, and pharmaceutical composition and application thereof
CN202110237007.5 2021-03-03

Publications (1)

Publication Number Publication Date
WO2022184103A1 true WO2022184103A1 (en) 2022-09-09

Family

ID=83117749

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/078854 WO2022184103A1 (en) 2021-03-03 2022-03-02 Tricyclic compound and pharmaceutical composition and use thereof

Country Status (2)

Country Link
CN (1) CN115028648A (en)
WO (1) WO2022184103A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019055966A2 (en) * 2017-09-18 2019-03-21 Goldfinch Bio, Inc. Pyridazinones and methods of use thereof
CN111386273A (en) * 2017-09-27 2020-07-07 因赛特公司 Salts of pyrrolotriazine derivatives useful as TAM inhibitors
WO2020223229A1 (en) * 2019-04-29 2020-11-05 Ribon Therapeutics, Inc. Solid forms of a parp7 inhibitor
CN112424188A (en) * 2018-04-30 2021-02-26 里邦医疗公司 Pyridazinones as PARP7 inhibitors

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106008479B (en) * 2015-03-06 2020-01-10 南京圣和药业股份有限公司 Substituted pyrimidine compound as phosphatidylinositol 3-kinase delta inhibitor and application thereof
WO2018214866A1 (en) * 2017-05-24 2018-11-29 上海和誉生物医药科技有限公司 Azaaryl derivative, preparation method therefor, and application thereof for use in pharmacy
CN109761986B (en) * 2017-11-10 2021-10-08 上海翰森生物医药科技有限公司 Tricyclic derivative inhibitor, preparation method and application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019055966A2 (en) * 2017-09-18 2019-03-21 Goldfinch Bio, Inc. Pyridazinones and methods of use thereof
CN111386273A (en) * 2017-09-27 2020-07-07 因赛特公司 Salts of pyrrolotriazine derivatives useful as TAM inhibitors
CN112424188A (en) * 2018-04-30 2021-02-26 里邦医疗公司 Pyridazinones as PARP7 inhibitors
WO2020223229A1 (en) * 2019-04-29 2020-11-05 Ribon Therapeutics, Inc. Solid forms of a parp7 inhibitor

Also Published As

Publication number Publication date
CN115028648A (en) 2022-09-09

Similar Documents

Publication Publication Date Title
CN114630823A (en) GLP-1R modulating compounds
WO2021218110A1 (en) Benzothiazolyl biaryl compound, and preparation method and use
EP2964223B1 (en) Compounds inhibiting leucine-rich repeat kinase enzyme activity
CN112341457A (en) KRAS mutein inhibitors
TW202144345A (en) Kras mutant protein inhibitors
CN112552295A (en) KRAS mutein inhibitors
EP3412663B1 (en) Nitrogen-containing heterocycle and carbocycle derivatives having trka inhibitory activity
CN113286794A (en) KRAS mutein inhibitors
CN113748114A (en) Quinazoline compound and application thereof in medicine
CN111499634B (en) Quinazoline compound and application thereof in medicine
EP3854796A1 (en) Imidazo[1,2-a]pyridine compounds, compositions comprising them, methods for treating diseases using them, and methods for preparing them
JP2023508097A (en) Methods of making and using proteolytic compounds
WO2023025116A1 (en) Heterocyclic derivative, preparation method therefor and use thereof in medicine
WO2020182159A1 (en) Jak kinase inhibitor, preparation method for same, and applications thereof in field of medicine
WO2021244634A1 (en) Imidazopyridine compound and use thereof
WO2022063212A1 (en) Pyrimidyl derivative, preparation method therefor and use thereof
WO2020020377A1 (en) Fused ring derivative used as fgfr4 inhibitor
WO2022048631A1 (en) Compound having antitumor activity and use thereof
US20200199123A1 (en) Compounds, compositions, methods for treating diseases, and methods for preparing compounds
WO2020259703A1 (en) Pyrazolopyrimidine compound, preparation method for same, and applications thereof
WO2023030453A1 (en) Compound for degradation of bcl-2 family proteins and medical application thereof
WO2019085996A1 (en) Pyridopyrimidine compounds acting as mtorc 1/2 double-kinase inhibitors
WO2022184103A1 (en) Tricyclic compound and pharmaceutical composition and use thereof
WO2022222911A1 (en) Pyrimidone compound and use thereof
WO2022171118A1 (en) Compound having anti-tumor activity and use thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22762566

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22762566

Country of ref document: EP

Kind code of ref document: A1