WO2023109521A1 - Parp抑制剂、包含其的药物组合物及其用途 - Google Patents

Parp抑制剂、包含其的药物组合物及其用途 Download PDF

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WO2023109521A1
WO2023109521A1 PCT/CN2022/135894 CN2022135894W WO2023109521A1 WO 2023109521 A1 WO2023109521 A1 WO 2023109521A1 CN 2022135894 W CN2022135894 W CN 2022135894W WO 2023109521 A1 WO2023109521 A1 WO 2023109521A1
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compound
ring
alkylene
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methyl
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French (fr)
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邓永奇
田元
贾岩林
朱时俊
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Keythera Suzhou Bio Pharmaceuticals Co Ltd
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Keythera Suzhou Bio Pharmaceuticals Co Ltd
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Priority to CA3241338A priority Critical patent/CA3241338A1/en
Priority to US18/720,020 priority patent/US20250051324A1/en
Priority to AU2022411308A priority patent/AU2022411308A1/en
Priority to JP2024536154A priority patent/JP7804371B2/ja
Priority to CN202280083306.0A priority patent/CN118382624A/zh
Priority to KR1020247023665A priority patent/KR20240144125A/ko
Priority to EP22906271.6A priority patent/EP4450498A4/en
Publication of WO2023109521A1 publication Critical patent/WO2023109521A1/zh
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention relates to PARP inhibitors, pharmaceutical compositions containing them, and uses thereof for preventing or treating diseases that can be improved by inhibiting PARP.
  • Polyadenosine diphosphate-ribose polymerase can catalyze the transfer of ADP-ribose residues from NAD+ to the target substrate, and perform ribosylation modification on proteins.
  • This polyadenosine diphosphate-ribosylation is a protein post-translational modification widely present in various physiological and pathological processes.
  • PARP can polyadenosine diphosphate-ribosylation on a variety of nucleoproteins (including histones, RNA polymerase, DNA polymerase, DNA ligase, etc.).
  • PARP is activated by recognizing damaged DNA fragments, causing glycosylation modification of nucleoproteins, thereby completing the function of DNA repair. Since there are other DNA repair functions in normal cells, for example, DNA repair can also be completed through the BRCA pathway to enable cells to survive, and inhibition of PARP will not have a significant impact on DNA repair in normal cells. In some cancer patients, when BRCA gene mutation occurs, the gene repair of tumor cells mainly depends on the PARP mechanism. In these patients, PARP inhibitors can block DNA repair function and cause apoptosis of tumor cells. In recent years, PARP inhibitors have been used to treat ovarian and breast cancer patients with BRCA mutations and have achieved significant efficacy.
  • the currently approved first-generation PARP inhibitors have a certain inhibitory effect on bone marrow hematopoietic function, which limits the combination therapy with chemotherapy drugs that also inhibit bone marrow hematopoietic function.
  • PARP inhibitors can also be used for the treatment of diseases related to these functions, including Diseases characterized by oxidative stress (eg, ischemia-reperfusion injury, inflammatory diseases, burns, Parkinson's disease, Huntington's disease, Alzheimer's disease, and toxic injuries); inflammatory diseases (asthma, arthritis, Colitis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, atherosclerosis, cardiac remodeling after myocardial infarction, sepsis, endotoxic shock, hemorrhagic shock, graft-versus-host disease, encephalomyelitis, and autoimmune nephritis ); viral infections (anti-human immunodeficiency virus 1, Venezuelan equine encephalitis virus, herpes simplex virus, human hepatitis B virus, and human cytomegalovirus infection
  • the present invention provides PARP inhibitors, which are useful for preventing or treating diseases that can be improved by inhibiting PARP.
  • the compounds of the invention have selective inhibitory activity against PARP-1.
  • the compounds of the present invention also have better physicochemical properties (such as solubility, physical and/or chemical stability), improved pharmacokinetic properties (such as improved bioavailability, suitable half-life and duration of action) , improved safety (lower toxicity (such as reduced cardiotoxicity) and/or fewer side effects), less prone to drug resistance and other superior properties.
  • One aspect of the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein
  • the compound has the structure of formula (I):
  • X is N or CR 5 ;
  • Y is N or CR 5 '
  • Z is CR 6 or N
  • V when When it is a single bond, V is CR 7 R A or NRA ; when When it is a double bond, V is CR A ;
  • Ring A is a C 3-6 hydrocarbon ring, a 3-10 membered heterocyclic ring, a C 6-10 aromatic ring or a 5-14 membered heteroaromatic ring;
  • R 3 and RA together with the group they are connected to optionally together constitute a C 3-6 hydrocarbon ring, a 3-10 membered heterocyclic ring, a C 6-10 aromatic ring or a 5-14 membered heteroaromatic ring;
  • R 3 and R 4 together with the groups connected to them optionally together form a C 3-6 hydrocarbon ring, a 3-10 membered heterocyclic ring, a C 6-10 aromatic ring or a 5-14 membered heteroaromatic ring;
  • R a and R b are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered hetero Cyclic group, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;
  • R c and R d are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 aralkyl; and
  • n are each independently an integer of 0, 1, 2, 3 or 4.
  • compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, Solvates, metabolites, isotope-labeled compounds or prodrugs and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.
  • Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Use of a prodrug or a pharmaceutical composition according to the invention for the preparation of a medicament for use as a PARP inhibitor, preferably as a PARP1 selective inhibitor.
  • Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Prodrugs or pharmaceutical compositions of the invention for use as PARP inhibitors (preferably as PARP1 selective inhibitors).
  • Another aspect of the present invention provides a method of preventing or treating a disease ameliorated by inhibiting PARP (preferably PARP-1), said method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable Accepted salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs or pharmaceutical compositions of the invention.
  • PARP preferably PARP-1
  • Figure 1 shows the effect of Compound 1 on inhibiting tumor growth in the MDA-MB-436 breast cancer mouse tumor model.
  • Figure 2 shows the effect of Compound 1 on the body weight of mice in the MDA-MB-436 breast cancer mouse tumor model.
  • Figure 3 shows the effect of compound 1 on inhibiting tumor growth in breast cancer PDX model.
  • Figure 4 shows the effect of Compound 1 on the body weight of mice in the PDX model of breast cancer.
  • alkylene means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or Butylene.
  • alkyl is defined as a straight or branched chain saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12, eg, 1 to 6 carbon atoms.
  • C 1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl group, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as halogen (in which case the group group is referred to as "haloalkyl” ) ( eg CF3 , C2F5 , CHF2 , CH2F , CH2CF3 , CH2Cl or -CH2CH2
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • alkenyl denotes a hydrocarbon group comprising one or more double bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, eg vinyl, propenyl or allyl.
  • alkenyl group When a compound of the present invention contains an alkenyl group, the compound may exist in pure E (ent ought) form, pure Z (zusammen) form, or any mixture thereof.
  • alkenylene denotes a divalent hydrocarbon group containing one or more double bonds.
  • heteroalkyl refers to an optionally substituted alkyl group having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof . Numerical ranges may be given (eg Ci_6heteroalkyl ) referring to the number of carbons in the chain, including 1 to 6 carbon atoms in this example. For example, a -CH2OCH2CH3 group is referred to as a C3heteroalkyl . Linkage to the rest of the molecule can be through a heteroatom or a carbon atom in the heteroalkyl chain.
  • heteroalkylene represents a corresponding divalent group, including, for example, “C 1-6 heteroalkylene", “C 1-4 heteroalkylene", etc., preferably -CH 2 OCH 2 -.
  • cycloalkylene means ring carbons having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Atoms of saturated (i.e., “cycloalkylene” and “cycloalkyl”) or unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings, which Including but not limited to (ylidene)cyclopropyl (ring), (ylidene)cyclobutyl (ring), ((ylidene)cyclopentyl (ring), ((ylidene)cyclohexyl (ring), (ylidene)cycloheptyl ( (ring), (sub)cyclooctyl (ring), (sub)cyclononyl (ring), (sub)cyclohexenyl (ring), etc.
  • cycloalkyl refers to a saturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1] ]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), which are optionally substituted by 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl
  • the cycloalkyl has 3 to 15 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropane) of 3 to 6 ring-forming carbon atoms. group, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, for example methyl-substituted cyclopropyl.
  • a 3-10 membered heterocyclic group is a group with 3-10 carbon atoms and heteroatoms in the ring, such as but not limited to oxiranyl, aziridinyl, azetidinyl ( azetidinyl), oxetanyl (oxetanyl), tetrahydrofuryl, dioxolinyl (dioxolinyl), pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyrrolidinyl pyryl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
  • heterocyclyl or “heterocycle” encompasses a fused ring structure, the point of attachment of the fused ring structure to other groups may be on any ring in the fused ring structure. Therefore, the heterocyclyl group of the present invention also includes, but is not limited to, heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, for example 3-7 membered (single) heterocyclic group and 3-7 membered (single) heterocyclic group, 3-7 membered (single) heterocyclic group and (single) cycloalkyl group, 3-7 membered (single) heterocyclic group C 4-6 (mono)cycloalkyl, examples of which include, but are not limited to, pyrrolidinocyclopropyl, cyclopentylaziridine,
  • heterocyclyl or “heterocycle” encompasses bridged and spiroheterocyclyl groups.
  • bridged heterocycle refers to two saturated rings that share two ring atoms that are not directly connected and contain one or more (eg, 1, 2, 3, or 4) heteroatoms. (such as oxygen atom, nitrogen atom and/or sulfur atom) ring structure, including but not limited to 7-10 membered bridged heterocycle, 8-10 membered bridged heterocycle, 7-10 membered nitrogen-containing bridged heterocycle, 7- 10-membered oxygen-containing bridged heterocycle, 7-10-membered sulfur-containing bridged heterocycle, etc., for example wait.
  • the "nitrogen-containing bridged heterocycle", “oxygen-containing bridged heterocycle”, and “sulfur-containing bridged heterocycle” optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.
  • spiroheterocycle refers to a heterocyclic ring formed by two or more saturated rings sharing one ring atom and containing one or more (for example, 1, 2, 3 or 4) heteroatoms (such as oxygen atom, nitrogen atom, sulfur atom), including but not limited to 5-10 membered spiroheterocycle, 6-10 membered spiroheterocycle, 6-10 membered nitrogen-containing spiroheterocycle, 6-10 membered spiroheterocycle, Oxygen-containing spiroheterocycle, 6-10 membered sulfur-containing spiroheterocycle, etc., for example
  • the "nitrogen-containing spiroheterocycle", “oxygen-containing spiroheterocycle”, and “sulfur-containing spiroheterocycle” optionally further contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur.
  • 6-10 membered nitrogen-containing spiroheterocyclyl refers to a spiroheterocyclyl group containing a total of 6-10 ring atoms, at least one of which is a nitrogen atom.
  • aryl or “aromatic ring” refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system.
  • C 6-14 aryl means an aromatic group containing 6 to 14 carbon atoms, such as phenyl or naphthyl.
  • Aryl is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg, halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • aralkyl preferably denotes an aryl-substituted alkyl group, wherein said aryl and said alkyl are as defined herein.
  • the aryl group may have 6-14 carbon atoms
  • the alkyl group may have 1-6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • heteroaryl or “heteroaromatic ring” refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contain at least one heteroatom which may be the same or different (the heteroatom is for example oxygen, nitrogen or sulfur), and, additionally, in each case may be benzo-fused.
  • heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, Diazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives.
  • heteroaryl or “heteroaryl ring” encompasses a fused ring structure, the point of attachment of the fused ring structure to other groups may be on any ring in the fused ring structure.
  • the heteroaryl groups of the present invention also include, but are not limited to, (mono)heteroaryl and (mono)heteroaryl, (mono)heteroaryl and (monocyclic)aryl, (mono)heteroaryl and (mono)aryl, (mono)heteroaryl and (mono) ) heterocyclyl and (mono)heteroaryl and (mono)cycloalkyl, such as 5-6 membered (mono)heteroaryl and 5-6 membered (mono)heteroaryl, 5-6 membered (mono)hetero Aryl aphenyl, 5-6 yuan (single) heteroaryl and 5-6 yuan (s
  • halo or halogen group is defined to include F, Cl, Br or I.
  • alkylthio as used herein means an alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom.
  • Representative examples of C 1-6 alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.
  • the nitrogen-containing heterocyclic ring is preferably a saturated nitrogen-containing monocyclic ring.
  • a 3- to 14-membered nitrogen-containing heterocycle is a group having 3-14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to a three-membered nitrogen-containing heterocycle (such as Aziridinyl), four-membered nitrogen-containing heterocycle (such as azetidinyl), five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidinyl ring), pyrrolinyl, pyrrolidonyl, imidazole group, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidinyl ring), morpholinyl, thiomorpholinyl, piperazinyl) , Seven-membered nitrogen-containing heterocycle, etc.
  • substituted means that one or more (e.g., one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is present.
  • the normal valences of the cases and such substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Selected optional substituents are substituted. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected Substituent substitution.
  • each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms have been labeled with the same atomic number but an atomic mass or mass number different from the atomic mass prevailing in nature. or mass number of atomic substitutions.
  • isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. deuterium (D, 2 H), tritium (T, 3 H)); isotopes of carbon (e.g.
  • isotopes of chlorine such as 36 Cl
  • isotopes of fluorine such as 18 F
  • isotopes of iodine such as 123 I and 125 I
  • isotopes of nitrogen such as 13 N and 15 N
  • phosphorus isotopes eg 32 P
  • sulfur isotopes eg 35 S.
  • Certain isotopically-labeled compounds of the invention eg, those incorporating radioactive isotopes
  • are useful in drug and/or substrate tissue distribution studies eg, assays).
  • the radioisotopes tritium ( ie3H ) and carbon-14 ( ie14C ) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron-emitting isotopes such as 11 C, 18 F, 15 O, and 13 N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.
  • Pharmaceutically acceptable solvates of the invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O , acetone- d6 or DMSO- d6 .
  • stereoisomer means isomers formed as a result of at least one asymmetric center.
  • compounds with one or more (e.g., one, two, three or four) asymmetric centers which can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereoisomers.
  • Certain individual molecules may also exist as geometric isomers (cis/trans).
  • compounds of the present invention may exist as mixtures of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers wait. It is to be understood that the scope of this application encompasses all such ratios in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) %) isomers or mixtures thereof.
  • Solid lines can be used in this article solid wedge or imaginary wedge Depicting the carbon-carbon bonds of the compounds of the invention.
  • the use of a solid line to delineate a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, specific enantiomers, racemic mixtures, etc.).
  • the use of solid or dashed wedges to delineate bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, solid and imaginary wedges are used to define relative rather than absolute stereochemistry.
  • the compounds of the present invention are intended to be stereoisomers (which include cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof).
  • the compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof, such as racemic mixtures and pairs of diastereoisomers.
  • the present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.
  • compositions of the invention may exist in free form for use in therapy, or, where appropriate, as pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which can directly Or indirectly provide a compound of the invention or a metabolite or residue thereof. Therefore, when a "compound of the present invention" is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate/carbonate, bisulfate/sulfate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluoro Phosphate, hydrobromide/bromide, hydroiodide/iodide, maleate, malonate, methylsulfate, naphthylate, nicotinate, nitrate , orotate, oxalate, palmitate and other similar salts.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, meglumine salts, potassium salts, and other similar salts.
  • esters means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (hydrolyzable under physiological conditions to release the free acid or alcohol form of the present invention) compound).
  • the compounds of the invention may also themselves be esters.
  • the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise a polar solvent, such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • a polar solvent such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • metabolites of the compounds of the present invention ie substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic hydrolysis, etc., of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolite thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which themselves may have little or no pharmacological activity when administered into or on the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound which are readily converted in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by E.B. Roche, American Pharmaceutical Association).
  • prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as "pro-moiety (such as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))". Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention which contain protecting groups.
  • protecting groups such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 Protecting groups, these references are incorporated herein by reference.
  • Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • the term "about” means within ⁇ 10%, preferably within ⁇ 5%, more preferably within ⁇ 2% of the stated numerical value.
  • the present application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or pro Drug, wherein said compound has the structure of formula (I):
  • X is N or CR 5 ;
  • Y is N or CR 5 '
  • Z is CR 6 or N
  • V when When it is a single bond, V is CR 7 R A or NRA ; when When it is a double bond, V is CR A ;
  • Ring A is a C 3-6 hydrocarbon ring, a 3-10 membered heterocyclic ring, a C 6-10 aromatic ring or a 5-14 membered heteroaromatic ring;
  • R 3 and RA together with the group they are connected to optionally together constitute a C 3-6 hydrocarbon ring, a 3-10 membered heterocyclic ring, a C 6-10 aromatic ring or a 5-14 membered heteroaromatic ring;
  • R 3 and R 4 together with the groups connected to them optionally together form a C 3-6 hydrocarbon ring, a 3-10 membered heterocyclic ring, a C 6-10 aromatic ring or a 5-14 membered heteroaromatic ring;
  • R a and R b are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, 3-10 membered hetero Cyclic group, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;
  • R c and R d are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 aralkyl; and
  • n are each independently an integer of 0, 1, 2, 3 or 4.
  • the present application provides the above-mentioned compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds or Prodrug, wherein said compound has the structure of formula (I)-1
  • the compound has the structure of formula (II), (III), (IV) or (V):
  • the present application provides the above-mentioned compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds or Prodrug, wherein R 1 and R 2 are each independently halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl; for example, R 1 and R 2 are each independently C 1-6 alkyl or C 1-6 haloalkyl;
  • R and R are each independently F, -CN, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl or isopropyl; for example, R and R are each independently is methyl, trifluoromethyl, ethyl, n-propyl or isopropyl;
  • R1 is trifluoromethyl and R2 is methyl; or both R1 and R2 are methyl.
  • R 3 and RA together with the groups to which they are attached, optionally form a 5-6 membered heteroaromatic ring (preferably a triazole ring), which is optionally replaced by C 1-6 haloalkyl ( preferably trifluoromethyl) substituted
  • the present application provides the above-mentioned compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds or Prodrug, wherein R 6 and R 7 are each independently selected from H, halogen, -OH, -CN, -C 1-6 alkylene-OR a and -C 1-6 alkylene- NR a R b ;
  • R6 and R7 are independently selected from H, -F, -OH, -CN, -CH2OH and -CH2NH2 .
  • the present application provides the above-mentioned compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds or Prodrugs, of which selected from
  • the two R 4 together with the group connected to them optionally together constitute
  • the two R 4 together with the group connected to them optionally together constitute
  • R 3 and R 4 together with the groups connected to them optionally form a 5-6 membered heteroaromatic ring, preferably an imidazole ring.
  • the present application provides the above-mentioned compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds or Prodrug, wherein ring A is C 4-6 hydrocarbon ring, 5-6 membered heterocyclic ring, C 6 aromatic ring or 5-6 membered heteroaromatic ring, more preferably bicyclic [1.1.1] pentane ring, piperidine ring, benzene ring, imidazole ring, thiazole ring, pyridine ring, pyrazine ring, pyridazine ring or pyrimidine ring, most preferably bicyclo[1.1.1]pentane ring, piperidine ring, benzene ring, imidazole ring, thiazole ring ring, pyridine ring, pyridazine ring or pyrimidine ring.
  • the present application provides the above-mentioned compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds or Prodrugs, of which for
  • the present invention encompasses compounds resulting from any combination of the various embodiments.
  • the present invention provides the above compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrugs, wherein the compound is selected from:
  • compositions and methods of treatment are provided.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorphic form thereof Compounds, solvates, metabolites, isotope-labeled compounds or prodrugs and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, a liquid preparation or a transdermal preparation.
  • the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled
  • a compound or prodrug or a pharmaceutical composition of the invention for the manufacture of a medicament for use as a PARP inhibitor, preferably as a PARP1 selective inhibitor.
  • the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled Compounds or prodrugs or pharmaceutical compositions of the invention for use as PARP inhibitors (preferably as PARP1 selective inhibitors).
  • the present invention provides a method of preventing or treating a disease ameliorated by inhibiting PARP, preferably PARP-1, comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically effective amount thereof.
  • the diseases that can be improved by inhibiting PARP are, for example, cancers, including but not limited to ovarian cancer, breast cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, lung cancer, head and neck cancer , thyroid cancer, malignant glioma, leukemia, lymphoma, multiple myeloma.
  • “Pharmaceutically acceptable carrier” in the present invention refers to a diluent, adjuvant, excipient or vehicle administered together with a therapeutic agent, and it is suitable for contacting human beings and/or Tissues from other animals without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol etc.
  • the composition if desired, can also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents.
  • Oral formulations can contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the invention may act systemically and/or locally.
  • they may be administered by a suitable route, for example by injection (e.g. intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, transdermal Nasally, transmucosally, topically, in the form of ophthalmic formulations or by inhalation.
  • the pharmaceutical composition of the present invention can be administered in an appropriate dosage form.
  • the dosage forms include but are not limited to tablets, capsules, lozenges, hard lozenges, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions , Injectable solutions, elixirs, syrups.
  • an effective amount refers to the amount of a compound which, when administered, alleviates to some extent one or more symptoms of the condition being treated.
  • Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may comprise single or multiple doses. It is further understood that for any given individual, the specific dosing regimen will be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • the amount of a compound of this invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician.
  • the effective dosage is about 0.0001 to about 50 mg per kg body weight per day, for example about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg human this would amount to about 0.007 mg/day to about 3500 mg/day, eg about 0.7 mg/day to about 700 mg/day.
  • Dosage levels up to the lower limit of the foregoing range may be sufficient in some cases, while in other cases larger doses may still be employed without causing any deleterious side effects, provided that the larger dose is first administered.
  • the dose is divided into several smaller doses to be administered throughout the day.
  • the content or amount of the compound of the present invention in the pharmaceutical composition can be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2mg, 4mg, 10mg, 25mg, etc.
  • treating means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term applies or one or more symptoms of such disorder or condition, or preventing such A disorder or condition or one or more symptoms of such a disorder or condition.
  • “Individual” as used herein includes a human or non-human animal.
  • Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • compositions of the present invention may also comprise one or more additional therapeutic or prophylactic agents.
  • the experimental methods not indicating specific conditions in the examples of the present invention are usually carried out according to conventional conditions, or according to the conditions suggested by raw material or commodity manufacturers.
  • Reagents whose specific sources were not indicated were conventional reagents available in the market. All evaporations were performed under vacuum using a rotary evaporator. Analytical samples were dried under vacuum (1-5 mmHg) at room temperature. Thin layer chromatography (prep-TLC) or high performance liquid chromatography (HPLC) separations were performed on preparative silica gel plates. Purification by flash column chromatography is carried out by using SEPAFLASH prepacked silica gel column, and the mixed solvent system is reported by volume ratio.
  • NMR spectra were recorded using a Varian NMR System 400MHz high-resolution nuclear magnetic resonance instrument. Chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • the determination solvent is deuterated chloroform (CDCl 3 ), hexadeuterated dimethyl sulfoxide (DMSO-d 6 ) or deuterated methanol (CD 3 OD).
  • the internal standard was tetramethylsilane (TMS).
  • TMS tetramethylsilane
  • the splitting multiplicity of 1 H NMR peaks is abbreviated as follows: s for singlet, bs for broad singlet, d for doublet, t for triplet, q for quartet, m for multiplet, dd for doublet heavy peak etc.
  • liquid-mass spectrometer used is an Agilent 1260 series 6135 mass spectrometer with electrospray ionization, and the analysis method is as follows:
  • Agilent LC-MS 1260-6135 column: Agilent ZORBAX SB-C18 (50 millimeters ⁇ 2.1 millimeters ⁇ 5 microns); Column temperature: 25 °C; Flow rate: 1.5mL/min; Mobile phase: within 2.5 minutes from 95% [ The mixed solvent of water + 0.1% trifluoroacetic acid] and 5% [acetonitrile + 0.1% trifluoroacetic acid] was changed to the mixture of 5% [water + 0.05% trifluoroacetic acid] and 95% [acetonitrile + 0.05% trifluoroacetic acid] solvent.
  • the high-performance liquid chromatograph used is Hanbang 50ml binary semi-preparative liquid chromatography system, column type: Hedera ODS-2 250*10mm*10 ⁇ m; mobile phase: A phase [water + 0.1% trifluoroacetic acid], B phase [ Acetonitrile+0.1% trifluoroacetic acid];
  • the thin-layer chromatography silica gel plate used Huanghai GF254 silica gel plate.
  • the monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC) or liquid spectrometry (LC-MS).
  • TLC thin layer chromatography
  • LC-MS liquid spectrometry
  • Example 14 N-methyl-1'-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl )methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-6-formamide (compound (14))
  • Example 15 4-methyl-7-((4-(3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)piperazine-1- base)methyl)-3-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (compound (15))
  • Example 18 4-methyl-7-((4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)piperazine-1- base)methyl)-3-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (compound (18))
  • 2-Cyanopiperazine-1-carboxylic acid tert-butyl ester ((21)-1) (260 mg) was dissolved in 1,4-dioxane (5 mL), and 5-bromo-picolinate methyl ester ( 169mg), tris(dibenzylideneacetone)dipalladium (228mg), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (234mg) and cesium carbonate ( 1.22g), reacted at 100°C for 3h.
  • Methyl 6-chloropyridazine-3-carboxylate (200 mg) and tert-butyl 2-methylpiperazine-1-carboxylate (243.7 mg) were dissolved in dimethyl sulfoxide (4 mL), followed by the addition of potassium carbonate (480.5mg), react at 100°C for 1h.
  • Example 28 N-methyl-5-(3-methyl-4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5 Preparation of -naphthyridin-3-yl)methyl)piperazin-1-yl)pyrimidine-2-carboxamide (compound (28))
  • Examples 55 and 56 N-Methyl-8-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridine-3- base)methyl)-6,7,8,9-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyrazine-3-carboxamide and N-methyl -7-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-6,7, Preparation of 8,9-tetrahydropyrido[4',3':4,5]imidazo[1,2-a]pyrazine-3-carboxamide
  • Methyl 4,5-diaminopicolinate (900mg) and benzyloxycarbonylglycine (1.24g) were dissolved in dichloromethane (20mL), and EDCI (1.67g), HOBt (1.98g) and TEA (1.45 g), react at 40°C for 3h, pour the reaction solution into water, and filter to obtain a crude white solid (800mg).
  • Example 57 N-Methyl-5-(3-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridine-3 Preparation of -yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-yl)pyridineamide (compound (57))
  • Example 69 N,6'-Dimethyl-1'-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridine Preparation of -3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (compound (69))
  • Example 70 N-methyl-5-(2-methyl-1-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5 Preparation of -naphthyridin-3-yl)methyl)piperidin-4-yl)pyridinamide (compound (70))
  • Example 76 N-Methyl-5-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridine-3 Preparation of -yl)methyl)-2-(trifluoromethyl)piperazin-1-yl)pyridineamide (compound (76))
  • Example 78 N-Methyl-5-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridine-3 Preparation of -yl)methyl)-4,7-diazaspiro[2.5]octane-7-yl)pyridineamide (compound (78))
  • Examples 80 and 81 N,3'-Dimethyl-1'-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5- Naphthyridin-3-yl)methyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (compound (80)) and N,5 '-Dimethyl-1'-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl)methyl )-1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-6-carboxamide (compound (81))
  • Example 82 N-Methyl-1'-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridin-3-yl )methyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridyl]-5-formamide (compound (82))
  • Example 83 5-Methyl-2-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5-naphthyridine-3 Preparation of -yl)methyl)piperazin-1-yl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-4-one (compound (83))
  • Example 84 4-Methyl-7-((4-(2-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl) Preparation of piperazin-1-yl)methyl)-3-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (compound (84))
  • Compound (85) was prepared from 6-acetyl-5-aminonicotinic acid methyl ester ((85)-2) by a method similar to step 6-8 of the synthetic route of compound (1).
  • reaction solution was poured into a saturated ammonium chloride solution, extracted with dichloromethane, and the solvent was evaporated under reduced pressure to obtain a crude product on a silica gel column [eluent: dichloromethane-methanol (100:1-10:1 )] for purification, collect the eluate, and evaporate the solvent under reduced pressure to obtain a yellow solid ((94)-4) (150mg, yield: 63.1%) MS-ESI m/z: 208.4[M+H] + .
  • Example 96 N-(2-Hydroxyethyl)-5-(4-((8-methyl-6-oxo-7-(trifluoromethyl)-5,6-dihydro-1,5 Preparation of -naphthyridin-3-yl)methyl)piperazin-1-yl)pyridineamide ((compound (96))
  • Example 100 5-(4-((7-(Difluoromethyl)-8-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl ) Preparation of piperazin-1-yl)-N-methylpicolinamide ((compound (100))
  • Example 104 (R)-5-(4-((7-(difluoromethyl)-8-methyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3- Preparation of base) methyl)-3-methylpiperazin-1-yl)-N-methylpyridinamide ((compound (104))
  • Example 106 1'-((7-(Difluoromethyl)-8-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)- Preparation of N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-6-carboxamide ((compound (106))
  • PARP1 kit was purchased from the 384-well chemiluminescent assay kit (Cat. No.: #80551) from BPS Bioscience, USA.
  • PARP can catalyze the transfer of ADP ribose residues from NAD+ to the target substrate, and perform ribosylation modification on proteins.
  • PARP1 enzymatic activity was measured by detecting the polyadenosine diphosphate-ribosylation of histone by PARP1.
  • Preparation of reagents and test compounds Dilute the 10x detection buffer contained in the kit to 1x with distilled water.
  • the compound to be tested (with a storage concentration of 10 mM) was diluted to 10 ⁇ M with DMSO solution, and serially diluted 1:3, and then the serially diluted compound was diluted 10 times with 1x detection buffer.
  • inhibition rate% 100*(average luminescence signal value of positive control group-compound luminescence signal value)/(average luminescence signal value of positive control group-average luminescence signal value of negative control group), with IC50 values were obtained by plotting log values of compound concentrations versus percent inhibition.
  • test compound PARP-1IC50(nM) 1 2.78 2 3.14 3 1.53 5 27.18 6 34.32 8 2.55 10 2.79 11 0.96
  • inhibition rate (%) (compound group reading-blank group reading)/(vehicle control group reading-blank group reading)
  • MDA-MB-436 or UWB1.289 cell lines were purchased from Kebai Biotechnology Co., Ltd. (Nanjing, China), and the STR identification results were completely matched, and the mycoplasma test was negative.
  • MDA-MB-436 cells were cultured in DMEM complete medium containing 10% fetal bovine serum, 1% penicillin streptomycin, 1% insulin and 16 ⁇ g/mL glutathione;
  • UWB1.289 cells were cultured in 10% fetal RMPI1640 complete medium with bovine serum and 1% penicillin-streptomycin.
  • MDA-MB-436 or UWB1.289 was cultured in the above medium (cultivation conditions: 37°C, air containing 5.0% carbon dioxide) until the cells reached the logarithmic growth phase, digested with trypsin containing 0.25% EDTA, Centrifuge at 1000 rpm, discard the supernatant, add cell culture medium, and adjust the cell suspension to 2x 10 4 /ml after counting. 135 ⁇ L of cell suspension/well was taken and cultured in a 96-well cell culture plate for 16 hours (culture conditions: 37° C., air containing 5.0% carbon dioxide).
  • test compound Dilute the test compound with a storage concentration of 10 mM 2.5 times with DMSO, and make a 1:3 serial dilution (9 gradients). The samples after gradient dilution were further diluted 40 times with serum-free medium, and 15 ⁇ L was added to a 96-well cell culture plate. The positive control group was added with DMSO serum-free medium containing the same concentration, and the negative control group was medium without cells. , and the cells were further cultured for 7 days.
  • inhibition rate% 100*(average luminescence signal value of positive control group-compound luminescence signal value)/(average luminescence signal value of positive control group-average luminescence signal value of negative control group), with IC50 values were obtained by plotting log values of compound concentrations versus percent inhibition.
  • test compound UWB1.289 cell IC 50 (nM) 1 0.66 2 2.76 8 12.62 10 14.98 11 28.50 14 4.93 20 26.58 52 11.17 53 13.62 54 3.34 71 8.13 93 2.67
  • test compound MDA-MB-436 cell IC 50 (nM) 1 1.59 2 2.32 14 2.38 twenty four 4.32 52 5.05 54 4.32 72 8.18 73 14.52 79 18.53 80 13.91 81 13.16 82 5.83 85 16.45 86 14.83 87 5.73 88 5.75 89 1.06 90 7.26 91 3.24 93 0.83 94 5.69 95 2.13 96 9.34 97 2.12 98 1.22 99 1.69 100 2.05 101 8.99 103 3.76 104 6.50 105 4.93 106 0.78
  • mice liver microsomal enzyme protein was purchased from Xenotech Company (#M1000), and NADPH was purchased from Abmole Company (#M9076).
  • test compound Dilute the test compound with a stock concentration of 10 mM to 100 ⁇ M with DMSO, then add 2.5 ⁇ L of the diluted test compound to the reaction system, mix well, and shake in a 37° C. water bath.
  • t 1/2 -0.693/k. (k: slope of the linear regression of the natural logarithm of the percentage of drug remaining versus the incubation time).
  • mice The purpose of the experiment: to test the pharmacokinetics of the compounds of the examples of the present application in mice. By detecting the drug concentration in mouse plasma, the pharmacokinetic behavior of the compound of the present invention in mice is studied, and its pharmacokinetic characteristics are evaluated.
  • Drug preparation for oral gavage First, weigh an appropriate amount of the test compound and dissolve it in DMSO (Macklin cas: 67-68-5) to prepare a 20 mg/mL solution. Take 75 ⁇ L of the above solution and add it to 150 ⁇ L Solutol (Sigma cas: 70142- 34-6), then add 1.275mL 20% Captisol (Selleck cas: 182410-00-0) to finally obtain 1mg/mL drug.
  • Drug preparation for intravenous injection First, weigh an appropriate amount of the test compound and dissolve it in DMSO (Macklin cas: 67-68-5) to prepare a 30 mg/mL solution. Take 15 ⁇ L of the above solution and add it to 150 ⁇ L Solutol (Sigma cas: 70142-34 -6), add 1.335mL 20% Captisol (Selleck cas: 182410-00-0) to finally obtain 0.3mg/mL drug.
  • mice were fasted overnight without water, and they resumed eating two hours after administration.
  • Blood was collected at different times after intravenous injection or oral gavage of the test compound to determine the concentration of the compound in plasma.
  • About 50 ⁇ L of blood was collected from each animal through the orbital vein with a capillary sampling tube, anticoagulated with heparin sodium. After the blood sample was collected, it was placed on ice, centrifuged at 3500r/min for 10min to separate the plasma, and 20 ⁇ L of the collected plasma was added to 200 ⁇ L of acetonitrile (Merck cas: 75-05-8), and then centrifuged at 8000r/min for 20min.
  • acetonitrile Merck cas: 75-05-8
  • test compound is sequentially diluted with DMSO, the concentration covers the concentration of the compound in the plasma to be determined, and a blank sample (only containing DMSO) is set
  • Calculation of pharmacokinetic parameters Calculate the concentration of the compound in plasma at different times after intravenous injection or oral gavage of the test compound in ICR mice according to the above standard curve, and use the Phoenix WinNonlin 8.1 non-compartmental analysis model to calculate the drug concentration.
  • Kinetic parameters T 1/2 , Cmax, AUC, etc.).
  • test compound AUC 0- ⁇ (ng hr/mL) Cmax(ng/mL) t 1/2 (hr) AZD5305* 356,592 37,283 8.25 1 972,211 39,635 17.9 11 1,497,448 55,884 18.9 14 2,716,871 127,992 27.8 twenty four 1,100,248 26,344 28.69 52 1,548,502 50,212 25.91 54 987,363 48,164 17.9 79 2,421,942 56,956 30.5 88 1,649,634 38,163 26.32 90 1,362,843 49,892 20.24 93 795,715 31,876 18.37 95 2,048,283 37,508 37.95
  • the purpose of the experiment to test the pharmacokinetics of the compounds of the examples of the present application in rats. By detecting the drug concentration in rat plasma, the pharmacokinetic behavior of the compound of the present invention in rats is studied, and its pharmacokinetic characteristics are evaluated.
  • Test animals 6-8 weeks male SD rats
  • Drug preparation for oral gavage First, weigh an appropriate amount of the test compound and dissolve it in DMSO (Macklin cas: 67-68-5) to prepare a 100 mg/mL solution. Take 100 ⁇ L of the above solution and add it to 200 ⁇ L Solutol (Sigma cas: 70142- 34-6), and then add 1.7mL 20% Captisol (Selleck cas: 182410-00-0) to finally obtain 5mg/mL of the drug.
  • Drug preparation for intravenous injection First, weigh an appropriate amount of the test compound and dissolve it in DMSO (Macklin cas: 67-68-5) to prepare a 60 mg/mL solution. Take 50 ⁇ L of the above solution and add it to 100 ⁇ L Solutol (Sigma cas: 70142-34 -6), add 850 ⁇ L of 20% Captisol (Selleck cas: 182410-00-0) to finally obtain 3 mg/mL of the drug.
  • test compound is sequentially diluted with DMSO, the concentration covers the concentration of the compound in the plasma to be determined, and a blank sample (only containing DMSO) is set
  • the purpose of the experiment To evaluate the drug effect of the compound on the human breast cancer (MDA-MB-436) cell line mouse subcutaneous xenograft tumor model.
  • Test compound Olaparib (Olaparib), compound 1
  • Feeding and management The experimental animals were kept in a clean room with constant temperature and humidity of SPF level, using independent ventilation cages IVC, and no more than 5 animals were kept in each cage. Temperature/humidity: controlled in the range of (23 ⁇ 3)°C/40-70%.
  • Feed and drinking water SPF rat feed, sterilized by cobalt 60 irradiation. Drinking water is purified by ultrafiltration and autoclaved. Animals had free access to sterile food and water. Animal ID: Ear tag marking.
  • Tumor cell line and tumor model MDA-MB-436 cells (Nanjing Kebai Biotechnology Co., Ltd., Cat.No: CBP60385) were mixed with 10% fetal bovine serum, 1% penicillin streptomycin, 1% insulin, 16 ⁇ g/ mL of glutathione in DMEM complete medium for in vitro culture and proliferation (37°C, 5% CO 2 ). After the cells meet the requirements of the in vivo drug efficacy experiment, the cells are collected, counted, and made into a PBS cell suspension. 0.9x10 7 cells/animal were inoculated subcutaneously in the right flank of 5-6 week NOD SCID mice. After inoculation, the tumors were measured 3 times/week, and the tumor volume was calculated. When the tumor grows to a volume of about 200-300mm 3 , the drugs are administered in groups.
  • mice This experiment is divided into vehicle control group; Olaparib, 100mg/kg group; Compound 1, 0.1mg/kg dosage group; Compound 1, 0.3mg/kg dosage group; Compound 1, 1.0mg/kg dosage group ; All groups were administered orally orally, once a day. After the administration, the tumor volume and body weight were measured 3 times a week, and the exercise, drinking water and food intake of the mice were observed. After 28 days of administration, the tumor inhibition rate (TGI%) was calculated according to the tumor volume of the mice, and the results were calculated by Excel and other software. The antitumor effect was statistically analyzed.
  • TGI% tumor inhibition rate
  • TGI ⁇ 1-(tumor volume at the end of the administration group-tumor volume at the end of the administration group)/(tumor volume at the end of the control group-tumor volume at the end of the control group) ⁇ x100%
  • Table 8 MDA-MB-436 breast cancer mouse model tumor growth inhibition rate after administration for 28 days
  • mice NOD SCID mice, female, 6-8 weeks old, weighing 18-20 grams. Provided by Beijing Weitong Lihua Experimental Animal Co., Ltd. After the animals arrived, they were raised in the experimental environment for 3 to 7 days before the experiment began. Animals were kept in IVC (independent ventilation system) cages (4 per cage) in SPF grade animal room. All cages, bedding and drinking water should be sterilized before use. Cages, feed and drinking water were changed twice a week.
  • the breeding environment and light conditions are as follows: temperature: 20-26°C, humidity: 40-70%, light cycle: 12 hours light, 12 hours no light.
  • BR-05-0044E model The establishment of human breast cancer BR-05-0044E model was originally derived from surgically resected clinical samples. After the tumor tissue was expanded in the mouse, a BR-05-0044E tumor tissue block of 20-30 mm 3 was subcutaneously inoculated on the right back of each mouse. Waiting for the tumor to grow, the average volume of the tumor reached about 150-200mm 3 and began randomized administration. Animals were weighed before administration, and tumor volume was measured. Randomized grouping according to tumor volume (random block design).
  • Experimental grouping The experiment was divided into 1. Vehicle control group, 2. Compound 1 0.1mg/kg, 3. Compound 1 0.3mg/kg, 4. Compound 1 1.0mg/kg; each group was administered by oral gavage, daily 1 time. Routine examinations included observing the effects of tumor growth and drug treatment on the daily behavior of the animals (such as behavioral activity, food and water intake, body weight change (measure body weight twice a week), appearance signs or other abnormalities). Animal deaths and side effects within groups were recorded based on the number of animals in each group.
  • TGI tumor growth inhibition rate
  • Table 9 Inhibitory rate of tumor growth in PDX model of breast cancer after administration for 21 days
  • test compound Oral Dosage Tumor Growth Inhibition Rate TGI Compound 1 0.1mg/kg 105% Compound 1 0.3mg/kg 106% Compound 1 1.0mg/kg 107%
  • Test compound Olaparib (Olaparib), compound 1
  • Experimental animals Sprague Dawley rats, male, purchased from Victoria Liver. Feeding and management: The experimental animals were kept in a clean room with constant temperature and humidity of SPF level, using independent ventilation cages IVC, and no more than 5 animals were kept in each cage. Temperature/humidity: controlled in the range of (23 ⁇ 3)°C/40-70%.
  • Feed and drinking water SPF rat feed, sterilized by cobalt 60 irradiation. Drinking water is purified by ultrafiltration and autoclaved. Animals had free access to sterile food and water. Animal ID: Ear tag marking.
  • mice The experiment was divided into the following 5 groups: vehicle group, Olaparib (Olaparib) 100mg/kg, compound 1 0.1mg/kg, compound 1 0.3mg/kg, compound 1 1.0mg/kg. All treatments were administered by oral gavage, once a day, for 4 days. Blood was collected before and after treatment to detect the number of peripheral blood reticulocytes.
  • Table 10 shows the changes in peripheral blood reticulocytes in rats after 4 days of administration. After 4 days of administration in rats, olaparib 100mg/kg significantly reduced peripheral blood reticulocytes (p ⁇ 0.01), suggesting its inhibitory effect on bone marrow hematopoietic function. Compound 1 0.1mg/kg, compound 1 0.3mg/kg and 1.0mg/kg had no significant effect on peripheral blood reticulocytes (p>0.05). Combined with the results of pharmacodynamic experiments, compound 1 showed a larger therapeutic window than olaparib.
  • test compound Oral Dosage reticulocyte inhibition rate Olaparib 100mg/kg 91.6% Compound 1 0.1mg/kg 12.2% Compound 1 0.3mg/kg 33.8% Compound 1 1.0mg/kg 41.9%

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Abstract

式(I)的化合物、包含其的药物组合物及其用作PARP抑制剂，优选用作PARP1选择性抑制剂的用途。

Description

PARP抑制剂、包含其的药物组合物及其用途 发明领域
本发明涉及PARP抑制剂、包含其的药物组合物及其用于预防或治疗可通过抑制PARP而改善的疾病的用途。
发明背景
聚腺苷二磷酸核糖聚合酶(poly(ADP-ribose)polymerase，PARP)能够催化ADP核糖残基从NAD+转移到目标底物上，对蛋白质进行核糖化修饰。这种聚腺苷二磷酸核糖基化(ADP-ribosylation)是一种广泛存在于各种生理和病理过程的蛋白质翻译后修饰。PARP可以对多种核蛋白(包括组蛋白、RNA聚合酶、DNA聚合酶，DNA连接酶等)进行聚腺苷二磷酸核糖基化。PARP通过识别损伤的DNA片段而被激活，引起核蛋白的糖基化修饰，从而完成DNA修复的功能。由于正常细胞中存在其他DNA修复功能，例如通过BRCA通路也可以完成DNA修复而使细胞存活，抑制PARP对正常细胞DNA修复不会产生明显影响。在一些癌症患者中，当BRCA发生基因突变时，肿瘤细胞的基因修复主要依赖PARP机制完成。在这些患者中，PARP抑制剂可以阻断DNA修复功能，引起肿瘤细胞的凋亡。近年来，PARP抑制剂被用于治疗携带BRCA突变的卵巢癌和乳腺癌患者并取得显著疗效。
目前获批的第一代PARP抑制剂对骨髓造血功能有一定的抑制作用，限制了与同样有骨髓造血功能抑制的化疗药物的联合治疗。
另外由于PARP还参与多种生理病理过程的调节(氧化应激反应、促进炎症反应、加重病毒感染和葡萄糖稳定的控制)，PARP抑制剂也可以用于与这些机能相关的疾病的治疗，包括以氧化应激为特征的疾病(例如，缺血-再灌注损伤、炎性疾病、烧伤、帕金森病、亨廷顿氏病、阿尔茨海默病和毒性损伤)；炎症类疾病(哮喘、关节炎、结肠炎、慢性阻塞性肺病、急性呼吸窘迫综合征、动脉粥样硬化、心肌梗塞后贲门重塑、败血症、内毒素休克、失血性休克、移植物抗宿主病、脑脊髓炎和自身免疫性肾炎)；病毒感染(抗人免疫缺陷病毒1、委内瑞拉马脑炎病毒、单纯疱疹病毒、人乙型肝炎病毒和人巨细胞病毒感染)；和代谢异常疾病(代谢综合征和II型糖尿病及其随后的并发症，例如糖尿病性神经、肾脏和眼部并发症)。
发明概述
本发明提供PARP抑制剂，其可用于预防或治疗可通过抑制PARP而改善的疾病。优选地，本发明的化合物具有针对PARP-1的选择性抑制活性。此外，本发明的化合物还具有更好的物理化学性质(例如溶解度、物理和/或化学稳定性)、改善的药物代谢动力学性质(例如改善的生物利用度、合适的半衰期和作用持续时间)、改善的安全性(较低的毒性(例如降低的心脏毒性)和/或较少的副作用)、较不易产生耐药性等更优异的性质。
本发明的一个方面提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(I)的结构：
Figure PCTCN2022135894-appb-000001
其中：
Figure PCTCN2022135894-appb-000002
为单键或双键；
X为N或CR 5；
Y为N或CR 5’；
Z为CR 6或N；
当
Figure PCTCN2022135894-appb-000003
为单键时，V为CR 7R A或NR A；当
Figure PCTCN2022135894-appb-000004
为双键时，V为CR A；
R A选自H、卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂 环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b、-O-C 1-6亚烷基-NR aR b和
Figure PCTCN2022135894-appb-000005
环A为C 3-6烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环；
R和R’在每次出现时各自独立地选自H、卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b；优选地，R和R’各自独立地选自H、-CN和C 1-6烷基；
R 1和R 2各自独立地选自卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b；
R 3在每次出现时各自独立地选自卤素、-OH、＝O、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b；
当m>1时，两个R 3任选地共同构成-C 1-6亚烷基-或-C 2-6亚烯基-，所述亚烷基链和亚烯基链任选地被一个或多个独立地选自O、C(＝O)、C(＝O)O、NR、S、S＝O和S(＝O) 2的基团间隔；
或者，R 3与R A连同其所连接的基团任选地共同构成C 3-6烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环；
R 4在每次出现时各自独立地选自卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3- 6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b；当有两个R 4在环A上处于邻位时，所述两个R 4连同其所连接的基团任选地共同构成3-10元杂环或5-14元杂芳环；
或者，R 3与R 4连同其所连接的基团任选地共同构成C 3-6烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环；
R 5、R 5’、R 6和R 7在每次出现时各自独立地选自H、卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b；
R a和R b在每次出现时各自独立地选自H、C 1-6烷基、C 2-6烯基、C 1-6卤代烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
上述烷基、亚烷基、卤代烷基、烯基、亚烯基、烃环、环烃基、杂环、杂环基、芳基、芳环、杂芳基、杂芳环和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R c、-OC(＝O)R c、-C(＝O)OR c、-OR c、-SR c、-S(＝O)R c、-S(＝O) 2R c、-S(＝O) 2NR cR d、-NR cR d、-C(＝O)NR cR d、-NR c-C(＝O)R d、-NR c-C(＝O)OR d、-NR c-S(＝O) 2-R d、-NR c-C(＝O)-NR cR d、-C 1-6亚烷基-OR c、-C 1-6亚烷基-NR cR d和-O-C 1-6亚烷基-NR cR d，所述烷基、亚烷基、卤代烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
R c和R d在每次出现时各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 3-10环烃基、3-10元杂环 基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；并且
m和n各自独立地为0、1、2、3或4的整数。
本发明的另一方面提供药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选是固体制剂、液体制剂或透皮制剂。
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物在制备用作PARP抑制剂(优选用作PARP1选择性抑制剂)的药物中的用途。
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物，其用作PARP抑制剂(优选用作PARP1选择性抑制剂)。
本发明的另一方面提供预防或治疗可通过抑制PARP(优选PARP-1)而改善的疾病的方法，所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物。
附图简要说明
图1显示化合物1在MDA-MB-436乳腺癌小鼠肿瘤模型中抑制肿瘤生长的效果。
图2显示化合物1在MDA-MB-436乳腺癌小鼠肿瘤模型中对小鼠体重的影响。
图3显示化合物1在乳腺癌PDX模型中抑制肿瘤生长的效果。
图4显示化合物1在乳腺癌PDX模型中对小鼠体重的影响。
发明详述
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
如本文中所使用，术语“亚烷基”表示饱和二价烃基，优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基，例如亚甲基、亚乙基、亚丙基或亚丁基。
如本文中所使用，术语“烷基”定义为直链或支链饱和脂肪族烃。在一些实施方案中，烷基具有1至12个，例如1至6个碳原子。例如，如本文中所使用，术语“C 1-6烷基”指1至6个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基)，其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CF 3、C 2F 5、CHF 2、CH 2F、CH 2CF 3、CH 2Cl或-CH 2CH 2CF 3等)。术语“C 1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
如本文中所使用，术语“烯基”表示包含一个或多个双键的烃基，其优选具有2、3、4、5或6个碳原子，例如乙烯基、丙烯基或烯丙基。当本发明的化合物含有烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。术语“亚烯基”表示包含一个或多个双键的二价烃基。
如本文中所使用，术语“杂烷基”指任选被取代的烷基，其具有一个或多个选自除碳以外的原子的骨架链原子，例如氧、氮、硫、磷或其组合。可以给出数值范围(例如C 1-6杂烷基)是指链中的碳数目，在此实例中包括1-6个碳原子。例如，-CH 2OCH 2CH 3基团被称为C 3杂烷基。与分子其余部分的连接可以通过杂烷基链中的杂原子或碳原子进行。术语“亚杂烷基”表示相应的二价基团，包括例如“C 1-6亚杂烷基”、“C 1-4亚杂烷基”等，优选-CH 2OCH 2-。
如本文中所使用，术语“亚环烃基”、“环烃基”和“烃环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环碳原子的饱和(即，“亚环烷基”和“环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环烃环，其包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环己烯基(环)等。
如本文中所使用，术语“环烷基”指饱和的非芳族单环或多环(诸如双环)烃环(例如单环，诸如环 丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)，其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如，术语“C 3-6环烷基”指3至6个成环碳原子的饱和或不饱和的非芳族单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。
如本文中所使用，术语“杂环基”或“杂环”指饱和或不饱和的一价单环或双环基团，其在环中具有2、3、4、5、6、7、8或9个碳原子和一个或多个(例如一个、两个、三个或四个)选自C(＝O)、O、S、S(＝O)、S(＝O) 2和NR’的含杂原子的基团，其中R’表示氢原子或C 1-6烷基或卤代-C 1-6烷基；所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，3-10元杂环基为在环中具有3-10个碳原子及杂原子的基团，例如但不限于环氧乙烷基、氮丙啶基、氮杂环丁烷基(azetidinyl)、氧杂环丁烷基(oxetanyl)、四氢呋喃基、二氧杂环戊烯基(dioxolinyl)、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、吡咯啉基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基或三噻烷基(trithianyl)。
如本文中所使用，术语“杂环基”或“杂环”涵盖并环结构，所述并环结构与其他基团的连接点可以在并环结构中的任一环上。因此，本发明的杂环基还包括但不限于杂环基并杂环基、杂环基并环烷基、单杂环基并单杂环基、单杂环基并单环烷基，例如3-7元(单)杂环基并3-7元(单)杂环基、3-7元(单)杂环基并(单)环烷基、3-7元(单)杂环基并C 4-6(单)环烷基，其实例包括但不限于吡咯烷基并环丙基、环戊基并氮杂环丙基、吡咯烷基并环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、哌啶基并吗啉基、
Figure PCTCN2022135894-appb-000006
如本文中所使用，术语“杂环基”或“杂环”涵盖桥杂环基和螺杂环基。
如本文中所使用，术语“桥杂环”是指两个饱和环共用两个不直接相连的环原子形成的含有一个或多个(例如1个、2个、3个或4个)杂原子(例如氧原子、氮原子和/或硫原子)的环状结构，包括但不限于7-10元桥杂环、8-10元桥杂环、7-10元含氮桥杂环、7-10元含氧桥杂环、7-10元含硫桥杂环等，例如
Figure PCTCN2022135894-appb-000007
Figure PCTCN2022135894-appb-000008
等。所述“含氮桥杂环”、“含氧桥杂环”、“含硫桥杂环”任选地还含有一个或多个选自氧、氮和硫的其他杂原子。
如本文中所使用，术语“螺杂环”是指由两个或两个以上饱和环共用一个环原子形成的含有一个或多个(例如1个、2个、3个或4个)杂原子(例如氧原子、氮原子、硫原子)的环状结构，包括但不限于5-10元螺杂环、6-10元螺杂环、6-10元含氮螺杂环、6-10元含氧螺杂环、6-10元含硫螺杂环等，例如
Figure PCTCN2022135894-appb-000009
Figure PCTCN2022135894-appb-000010
Figure PCTCN2022135894-appb-000011
所述“含氮螺杂环”、“含氧螺杂环”、“含硫螺杂环”任选地还含有一个或多个选自氧、氮、硫的其他杂原子。术语“6-10元含氮螺杂环基”是指含有共计6-10个环原子并且其中至少一个环原子为氮原子的螺杂环基。
如本文中所使用，术语“芳基”或“芳环”指具有共轭π电子系统的全碳单环或稠合环多环芳族基 团。例如，如本文中所使用，术语“C 6-14芳基”意指含有6至14个碳原子的芳族基团，诸如苯基或萘基。芳基任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO 2、C 1-6烷基等)取代。
术语“芳烷基”优选表示芳基取代的烷基，其中所述芳基和所述烷基如本文中所定义。通常，所述芳基可具有6-14个碳原子，并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基。
如本文中所使用，术语“杂芳基”或“杂芳环”指一价单环、双环或三环芳族环系，其具有5、6、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)，并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等，以及它们的苯并衍生物；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物。
如本文中所使用，术语“杂芳基”或“杂芳环”涵盖并环结构，所述并环结构与其他基团的连接点可以在并环结构中的任一环上。因此，本发明的杂芳基还包括但不限于(单)杂芳基并(单)杂芳基、(单)杂芳基并(单环)芳基、(单)杂芳基并(单)杂环基和(单)杂芳基并(单)环烷基，例如5-6元(单)杂芳基并5-6元(单)杂芳基、5-6元(单)杂芳基并苯基、5-6元(单)杂芳基并5-6元(单)杂环基或5-6元(单)杂芳基并C 4-6(单)环烷基(例如5-6元杂芳基并环丁基、5-6元杂芳基并环戊基或5-6元杂芳基并环己基)，其实例包括但不限于吲哚基、异吲哚基、吲唑基、苯并咪唑、喹啉基、异喹啉基、
Figure PCTCN2022135894-appb-000012
Figure PCTCN2022135894-appb-000013
Figure PCTCN2022135894-appb-000014
等。
如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
如本文中所使用，术语“烷基硫基”意指通过硫原子连接至母体分子部分的如上文所定义的烷基。C 1-6烷基硫基的代表性实例包括但不限于甲硫基、乙硫基、叔丁硫基及己硫基。
如本文中所使用，术语“含氮杂环”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子，其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C＝O、S、S＝O和S(＝O) 2的环成员；所述含氮杂环通过氮原子与分子的其余部分连接。所述含氮杂环优选为饱和含氮单环。特别地，3至14元含氮杂环为在环中具有3-14个碳原子及杂原子(其中至少一个为氮原子)的基团，其包括但不限于三元含氮杂环(如氮丙啶基)、四元含氮杂环(如氮杂环丁烷基)、五元含氮杂环(如吡咯基、吡咯烷基(吡咯烷环)、吡咯啉基、吡咯烷酮基、咪唑基、咪唑烷基、咪唑啉基、吡唑基、吡唑啉基)、六元含氮杂环(如哌啶基(哌啶环)、吗啉基、硫吗啉基、哌嗪基)、七元含氮杂环等。
术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
如果取代基被描述为“任选地被取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。
如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘(D， 2H)、氚(T， 3H))；碳的同位素(例如 11C、 13C及 14C)；氯的同位素(例如 36Cl)；氟的同位素(例如 18F)；碘的同位素(例如 123I及 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 15O、 17O及 18O)；磷的同位素(例如 32P)；及硫的同位素(例如 35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即 3H)及碳-14(即 14C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如 11C、 18F、 15O及 13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D 2O、丙酮-d 6或DMSO-d 6。
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
本文中可使用实线
Figure PCTCN2022135894-appb-000015
实楔形
Figure PCTCN2022135894-appb-000016
或虚楔形
Figure PCTCN2022135894-appb-000017
描绘本发明的化合物的碳-碳键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。
适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括天冬氨酸盐、苯甲酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、氢溴酸盐/溴化物、氢碘酸盐/碘化物、顺丁烯二酸盐、丙二酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐及其它类似的盐。
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、胆碱盐、二乙胺盐、赖氨酸盐、镁盐、葡甲胺盐、钾盐及其它类似的盐。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计 量比或非化学计量比存在。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱脂化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)及“Bioreversible Carriers in Drug Design,”Pergamon Press,1987(E.B.Roche编辑，American Pharmaceutical Association)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；和T.W.Greene & P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
如本文中所使用，术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
化合物
在一些实施方案中，本申请提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(I)的结构：
Figure PCTCN2022135894-appb-000018
其中：
Figure PCTCN2022135894-appb-000019
为单键或双键；
X为N或CR 5；
Y为N或CR 5’；
Z为CR 6或N；
当
Figure PCTCN2022135894-appb-000020
为单键时，V为CR 7R A或NR A；当
Figure PCTCN2022135894-appb-000021
为双键时，V为CR A；
R A选自H、卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b、-O-C 1-6亚烷基-NR aR b和
Figure PCTCN2022135894-appb-000022
环A为C 3-6烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环；
R和R’在每次出现时各自独立地选自H、卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b；优选地，R和R’各自独立地选自H、-CN和C 1-6烷基；
R 1和R 2各自独立地选自卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、 3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b；
R 3在每次出现时各自独立地选自卤素、-OH、＝O、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b；
当m>1时，两个R 3任选地共同构成-C 1-6亚烷基-或-C 2-6亚烯基-，所述亚烷基链和亚烯基链任选地被一个或多个独立地选自O、C(＝O)、C(＝O)O、NR、S、S＝O和S(＝O) 2的基团间隔；
或者，R 3与R A连同其所连接的基团任选地共同构成C 3-6烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环；
R 4在每次出现时各自独立地选自卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3- 6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b；当有两个R 4在环A上处于邻位时，所述两个R 4连同其所连接的基团任选地共同构成3-10元杂环或5-14元杂芳环；
或者，R 3与R 4连同其所连接的基团任选地共同构成C 3-6烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环；
R 5、R 5’、R 6和R 7在每次出现时各自独立地选自H、卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b；
R a和R b在每次出现时各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
上述烷基、亚烷基、卤代烷基、烯基、亚烯基、烃环、环烃基、杂环、杂环基、芳基、芳环、杂芳基、杂芳环和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R c、-OC(＝O)R c、-C(＝O)OR c、-OR c、-SR c、-S(＝O)R c、-S(＝O) 2R c、-S(＝O) 2NR cR d、-NR cR d、-C(＝O)NR cR d、-NR c-C(＝O)R d、-NR c-C(＝O)OR d、-NR c-S(＝O) 2-R d、-NR c-C(＝O)-NR cR d、-C 1-6亚烷基-OR c、-C 1-6亚烷基-NR cR d和-O-C 1-6亚烷基-NR cR d，所述烷基、亚烷基、卤代烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
R c和R d在每次出现时各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；并且
m和n各自独立地为0、1、2、3或4的整数。
在一些实施方案中，本申请提供上述化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R A选自C 1-6卤代烷基(优选
Figure PCTCN2022135894-appb-000023
)、-C(＝O)R a(优选
Figure PCTCN2022135894-appb-000024
)和
Figure PCTCN2022135894-appb-000025
在一些实施方案中，本申请提供上述化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(I)-1的结构
Figure PCTCN2022135894-appb-000026
优选地，所述化合物具有式(II)、(III)、(IV)或(V)的结构：
Figure PCTCN2022135894-appb-000027
在一些实施方案中，本申请提供上述化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 1和R 2各自独立地为卤素、-CN、C 1-6烷基或C 1-6卤代烷基；例如，R 1和R 2各自独立地为C 1-6烷基或C 1-6卤代烷基；
优选地，R 1和R 2各自独立地为F、-CN、甲基、二氟甲基、三氟甲基、乙基、正丙基或异丙基；例如，R 1和R 2各自独立地为甲基、三氟甲基、乙基、正丙基或异丙基；
最优选地，R 1为三氟甲基，并且R 2为甲基；或者R 1和R 2均为甲基。
在一些实施方案中，本申请提供上述化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 3在每次出现时各自独立地为卤素、-OH、＝O、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a或-C 1-6亚烷基-NR aR b；当m>1时，两个R 3任选地共同构成-C 1-4亚烷基-；
优选地，R 3在每次出现时各自独立地为＝O、-CN、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a或-C 1-6亚烷基-NR aR b；当m>1时，两个R 3任选地共同构成-C 1-4亚烷基-；
更优选地，R 3在每次出现时各自独立地为＝O、-CN、-CH 3、-CF 3、-CH 2CN、-CH 2NH 2、-CH 2CH 2NH 2、-CH 2OH、-CH 2CH 2OH或-CH 2OCH 3；当m>1时，两个R 3任选地共同构成-CH 2CH 2-。
在一些实施方案中，R 3与R A连同其所连接的基团任选地共同构成5-6元杂芳环(优选三氮唑环)，其任选地被C 1-6卤代烷基(优选三氟甲基)取代
在一些实施方案中，本申请提供上述化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 6和R 7在每次出现时各自独立地选自H、卤素、-OH、-CN、-C 1-6亚烷基-OR a和-C 1-6亚烷基-NR aR b；
R 6和R 7在每次出现时各自独立地选自H、-F、-OH、-CN、-CH 2OH和-CH 2NH 2。
在一些实施方案中，本申请提供上述化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中
Figure PCTCN2022135894-appb-000028
选自
Figure PCTCN2022135894-appb-000029
Figure PCTCN2022135894-appb-000030
优选地，
Figure PCTCN2022135894-appb-000031
选自
Figure PCTCN2022135894-appb-000032
Figure PCTCN2022135894-appb-000033
在一些实施方案中，本申请提供上述化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 4在每次出现时各自独立地为卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、5-14元杂芳基、-S(＝O) 2NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b-NR a-C(＝O)-NR aR b或-C 1-6亚烷基-OR a；当有两个R 4在环A上处于邻位时，所述两个R 4连同其所连接的基团任选地共同构成5-6元杂环或5-6元杂芳环；
优选地，R 4在每次出现时各自独立地为F、-CN、-CH 3、-CF 3、
Figure PCTCN2022135894-appb-000034
-S(＝O) 2NHCH 3、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)NHCD 3、-C(＝O)NHCH 2CH 3、-C(＝O)NHCH 2CF 3、-C(＝O)NHCH 2CH 2OH、-C(＝O)NH(环丙基)、-NHC(＝O)CH 3、-NHC(＝O)(环丙基)、-NHC(＝O)NHCH 3、-CH 2OH、
Figure PCTCN2022135894-appb-000035
当有两个R 4在环A上处于邻位时，所述两个R 4连同其所连接的基团任选地共同构成
Figure PCTCN2022135894-appb-000036
更优选地，R 4在每次出现时各自独立地为F、-CN、-CH 3、-CF 3、
Figure PCTCN2022135894-appb-000037
-S(＝O) 2NHCH 3、-C(＝O)NH 2、-C(＝O)NHCH 3、-NHC(＝O)CH 3、-NHC(＝O)(环丙基)、-NHC(＝O)NHCH 3、-CH 2OH、
Figure PCTCN2022135894-appb-000038
当有两个R 4在环A上处于邻位时，所述两个R 4连同其所连接的基团任选地共同构成
Figure PCTCN2022135894-appb-000039
或者，R 3与R 4连同其所连接的基团任选地共同构成5-6元杂芳环，优选咪唑环。
在一些实施方案中，本申请提供上述化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中环A为C 4-6烃环、5-6元杂环、C 6芳环或5-6元杂芳环，更优选地为双环[1.1.1]戊烷环、哌啶环、苯环、咪唑环、噻唑环、吡啶环、吡嗪环、哒嗪环或嘧啶环，最优选地为双环[1.1.1]戊烷环、哌啶环、苯环、咪唑环、噻唑环、吡啶环、哒嗪环或嘧啶环。
在一些实施方案中，本申请提供上述化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中
Figure PCTCN2022135894-appb-000040
为
Figure PCTCN2022135894-appb-000041
Figure PCTCN2022135894-appb-000042
优选地，
Figure PCTCN2022135894-appb-000043
为
Figure PCTCN2022135894-appb-000044
Figure PCTCN2022135894-appb-000045
本发明涵盖对各个实施方案进行任意组合所得的化合物。
在优选的实施方案中，本发明提供上述化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物选自：
Figure PCTCN2022135894-appb-000046
Figure PCTCN2022135894-appb-000047
Figure PCTCN2022135894-appb-000048
Figure PCTCN2022135894-appb-000049
Figure PCTCN2022135894-appb-000050
药物组合物和治疗方法
在一些实施方案中，本发明提供药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选是固体制剂、液体制剂或透皮制剂。
在一些实施方案中，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物在制备用作PARP抑制剂(优选用作PARP1选择性抑制剂)的药物中的用途。
在一些实施方案中，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物，其用作PARP抑制剂(优选用作PARP1选择性抑制剂)。
在一些实施方案中，本发明提供预防或治疗可通过抑制PARP(优选PARP-1)而改善的疾病的方法，所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物。
所述可通过抑制PARP(优选PARP-1)而改善的疾病例如为癌症，其包括但不限于卵巢癌、乳腺癌、前列腺癌、肾癌、肝癌、胰腺癌、胃癌、肺癌、头颈部癌、甲状腺癌、恶性胶质瘤、白血病、淋巴瘤、多发性骨髓瘤。
本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。
本发明的药物组合物可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射(如静脉内、动脉内、皮下、腹膜内、肌内注射，包括滴注)或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
对于这些给药途径，可以适合的剂型给药本发明的药物组合物。
所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂。
如本文中所使用的术语“有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg，例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计为约0.007mg/日至约3500mg/日，例如约0.7mg/日至约700mg/日。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而在其它情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。
本发明的化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg，适合地是0.1-500mg，优选0.5-300mg，更优选1-150mg，特别优选1-50mg，例如1.5mg、2mg、4mg、10mg、25mg等。
除非另外说明，否则如本文中所使用，术语“治疗”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
在另种实施方案中，本发明的药物组合物还可以包含一种或多种另外的治疗剂或预防剂。
实施例
以下结合实施例进一步描述本发明，但提供这些实施例并非意在限制本发明的范围。
本发明实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件进行。未注明具体来源的试剂为市场可购得的常规试剂。所有蒸发均使用旋转蒸发器在真空下进行。将分析样品在室温下真空(1-5mmHg)下干燥。在制备硅胶板上进行薄层色谱法(prep-TLC)或高效液相色谱法(HPLC)分离。快速柱层析纯化通过使用SEPAFLASH预填装硅胶柱进行，混合溶剂体系按体积比报告。
化合物的结构是通过核磁共振波谱(NMR)或质谱(MS)进行确证。
使用Varian NMR System 400MHz高分辨核磁共振仪记录核磁共振波谱。化学位移(δ)以百万分之一(ppm)为单位给出。测定溶剂为氘代氯仿(CDCl 3)、六氘代二甲基亚砜(DMSO-d 6)或氘代甲醇(CD 3OD)。内标为四甲基硅烷(TMS)。 1H NMR波谱峰的裂分重数缩写如下：s为单峰，bs为宽单峰，d为二重峰，t为三重峰，q为四重峰，m为多重峰，dd为双二重峰等。
所用液质联用仪(LC-MS)是具有电喷雾电离的Agilent 1260系列6135质谱仪，分析方法如下：
Agilent LC-MS 1260-6135，柱：Agilent ZORBAX SB-C18(50毫米×2.1毫米×5微米)；柱温：25℃；流速：1.5mL/min；流动相：在2.5分钟内从95％[水+0.1％三氟乙酸]和5％[乙腈+0.1％三氟乙酸]的混合溶剂换至5％[水+0.05％三氟乙酸]和95％[乙腈+0.05％三氟乙酸]的混合溶剂。
所用高效液相色谱仪是汉邦50ml二元半制备液相色谱系统，柱型：Hedera ODS-2 250*10mm*10μm；流动相：A相[水+0.1％三氟乙酸]，B相[乙腈+0.1％三氟乙酸]；
薄层色谱硅胶板使用黄海GF254硅胶板。
实施例中如无特殊说明，反应均在氮气氛下进行。
实施例中的反应进程的监测采用薄层色谱法(TLC)或液质联用仪(LC-MS)。
本发明中的缩写具有以下含义：
缩写 含义
ACN/MeCN 乙腈
Ac 2O 乙酸酐
AcOH/CH 3COOH 乙酸/醋酸
aq. 水溶液
Bn 苄基
Boc 叔丁氧羰基
(Boc) 2O 二碳酸二叔丁酯
n-Bu 正丁基
n-BuOH 正丁醇
Cbz 苄氧羰基
CDI N,N'-羰基二咪唑
Cs 2CO 3 碳酸铯
DAST 二乙胺基三氟化硫
DCM 二氯甲烷
DEAD 偶氮二甲酸二乙酯
DIEA/DIPEA N,N-二异丙基乙胺
DMA N,N-二甲基乙酰胺
DMAc N,N-二甲基乙酰胺
DMAP 4-二甲氨基吡啶
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
DOX/1,4-dioxane 1,4-二氧六环
EA/EtOAc 乙酸乙酯
EDCI N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐
Et 3N 三乙胺
EtNH 2 乙胺
EtOH 乙醇
h 小时
H 2 氢气
HATU O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐
HCl 盐酸
H 2O 水
HOAc  
HOBT 1-羟基苯并三唑
HPLC 高效液相色谱法
I 2 碘
K 2CO 3 碳酸钾
KF 氟化钾
KI 碘化钾
KOH 氢氧化钾
K 3PO 4 磷酸钾
LDA 二异丙基氨基锂
LAH/LiAlH 4 氢化铝锂
LiBH 4 硼氢化锂
LiOH 氢氧化锂
m-CPBA 间氯过氧苯甲酸
MeMgBr 甲基溴化镁
MeOH 甲醇
MeNH 2 甲胺
min 分钟
MnO 2 二氧化锰
Mn(OAc) 3·2H 2O 醋酸锰(III)二水合物
MsOH 甲磺酸
MW 微波
NaH 氢化钠
NaHCO 3 碳酸氢钠
NaOH 氢氧化钠
NBS N-溴代丁二酰亚胺
NH 3 氨气
N 2H 4-H 2O 水合肼
NH 4OAc 乙酸铵
NH 4OH 氨水
NMP N-甲基吡咯烷酮
o/n 过夜
Pd/C 钯/碳
Pd 2(dba) 3 三(二亚苄基丙酮)二钯
Pd(dppf)Cl 2 [1,1’-双(二苯基膦基)二茂铁]二氯化钯
Pd(OH) 2 氢氧化钯
Pd(PPh 3) 2Cl 2 双三苯基磷二氯化钯
PE 石油醚
PhMe 甲苯
POCl 3 三氯氧磷
PPh 3 三苯基膦
RuPhos 2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯
SEM 2-(三甲基硅烷基)乙氧甲基
SEMCl 2-(三甲基硅烷基)乙氧甲基氯
SFC 超临界流体色谱法
SOCl 2 氯化亚砜
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
TLC 薄层色谱法
TMSCN 三甲基氰硅烷
r.t./rt 室温
Xantphos 4,5-双二苯基膦-9,9-二甲基氧杂蒽
XeF 2 二氟化氙
Xphos 2-二环己基磷-2',4',6'-三异丙基联苯
ZnI 2 二碘化锌
实施例1：N-甲基-5-(4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰胺(化合物(1))的制备
Figure PCTCN2022135894-appb-000051
步骤1.化合物(1)-2的制备
将6-氯-5-硝基吡啶-3-甲酸乙酯((1)-1)(3g)、三丁基(1-乙氧基乙烯)锡(5.8g)和Pd(PPh 3) 2Cl 2(91.3mg)溶于乙腈(15mL)，氮气置换，65℃反应2h，反应完毕，用10％的KF水溶液淬灭，过滤，乙酸乙酯淋洗，浓缩，经柱层析分离[洗脱剂：石油醚-乙酸乙酯＝20:1]纯化，收集洗脱液，减压蒸除溶剂，得浅紫色液体(1)-2(3.1g,收率89.6％)。MS-ESI m/z:267.2[M+H] +。
步骤2.化合物(1)-3的制备
将(1)-2(3.1g)溶于AcOH(30mL)中，加入3M盐酸(16mL)，室温反应1h，反应完毕，浓缩，用KOH和碳酸氢钠水溶液调节pH至8～9，乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，减压蒸除溶剂，得褐色液体(1)-3(3.05g,收率100％)。MS-ESI m/z:239.2[M+H] +。
步骤3.化合物(1)-4的制备
将(1)-3(750mg)溶于乙醇(10mL)，加入10％Pd/C(75mg)，在氢气氛围下，室温搅拌过夜，反应完毕，硅藻土过滤，乙醇淋洗，浓缩，得黄色固体(1)-4(580mg,收率89％)。MS-ESI m/z:209.2[M+H] +。
步骤4.化合物(1)-5的制备
将(1)-4(580mg)和3,3,3-三氟丙酰氯(1.1g)溶于THF(15mL)，0℃反应5min，加入DIPEA(260mg)，恢复室温，反应2h。反应完毕，加水淬灭，乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，经柱层析分离[洗脱剂：石油醚-乙酸乙酯＝9:1]纯化，收集洗脱液，减压蒸除溶剂，得白色固体(1)-5(950mg,收率100％)。MS-ESI m/z:319.2[M+H] +。
步骤5.化合物(1)-6的制备
将(1)-5(4.7g)溶于DMF(305mL)中，加入碳酸钾(10.68g)，60℃反应1小时，反应完毕，加入水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经柱层析分离[洗脱剂：二氯甲烷-甲醇＝20:1]纯化，收集洗脱液，减压蒸除溶剂，得淡黄色固体(1)-6(2.3g,收率52％)。MS-ESI m/z:301.2[M+H] +。
步骤6.化合物(1)-7的制备
将(1)-6(100mg)溶于THF(3mL)，0℃分批次加入LiAlH 4(25.3mg)，0℃反应1h，反应完毕，十水合硫酸钠淬灭，硅藻土抽滤，二氯甲烷-甲醇(10:1)清洗滤饼，滤液浓缩，经制备硅胶板分离[展开剂：二氯甲烷-甲醇＝20:1]，得浅黄色固体(1)-7(50mg,收率58％)。MS-ESI m/z:259.2[M+H] +。
步骤7.化合物(1)-8的制备
将(1)-7(50mg)和DMF(1.5mg)溶于DCM(2mL)，0℃加入二氯亚砜(138mg)，室温反应0.5h，反应完毕，浓缩得粗品灰色固体(1)-8(70mg)，直接用于下一步。MS-ESI m/z:277.2[M+H] +。
步骤8.化合物(1)的制备
将粗产物(1)-8、(1)-R(48mg)、KI(6mg)和DIPEA(0.21mL)溶于乙腈(3mL)，75℃反应20min，反应完毕，浓缩，经制备HPLC分离，得白色固体(1)(2.4mg,收率2.8％)。MS-ESI m/z:461.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.58(s,1H),8.39(d,J＝4.8Hz,1H),8.27(d,J＝2.9Hz,1H),7.83(d,J＝8.8Hz,1H),7.69(s,1H),7.42–7.37(m,1H),3.72(s,2H),2.86–2.70(m,5H),2.62–2.54(m,4H),2.53–2.50(m,6H)。
实施例2：N-甲基-5-(4-((4-甲基-2-氧代-3-(三氟甲基)-1,2-二氢-1,6-萘啶-7-基)甲基)哌嗪-1-基)吡啶酰胺(化合物(2))的制备
Figure PCTCN2022135894-appb-000052
步骤1～7.化合物(2)的制备
由4-氨基-5-溴吡啶-2-羧酸甲酯((2)-1)为原料，经与化合物(1)合成路线类似的方法制备得到化合物(2)。MS-ESI m/z:461.2[M+H] +。 1H NMR(400MHz,Chloroform-d)δ11.00(s,1H),9.12(s,1H),8.18(d,J＝2.9Hz,1H),8.08(d,J＝8.7Hz,1H),7.82(d,J＝5.5Hz,1H),7.41(s,1H),7.23(dd,J＝8.8,2.9Hz,1H),3.84(s,2H),3.40(t,J＝5.0Hz,4H),3.04(d,J＝5.1Hz,3H),2.83–2.79(m,3H),2.79–2.73(m,4H)。
实施例3：5-(3-(氰甲基)-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(化合物(3))的制备
Figure PCTCN2022135894-appb-000053
步骤1.化合物(3)-2的制备
将2-(氰甲基)哌嗪-1-羧酸叔丁酯((3)-1)(760mg)溶于1,4-二氧六环(10mL)中，加入5-溴吡啶-2-羧酸甲酯(728.7mg)、Pd 2(dba) 3(617mg)、RuPhos(629mg)和碳酸铯(3.3g)，100℃反应3h，加水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，经硅胶柱层析[洗脱剂：二氯甲烷-甲醇＝20:1]纯化，收集洗脱液，减压蒸除溶剂，得到黄色油状物(3)-2(1.1g,收率90％)。MS-ESI m/z:361.2[M+H] +。
步骤2.化合物(3)-3的制备
将(3)-2(1.1g)溶于甲醇(10mL)，加入甲胺水溶液(5mL,40％wt)，密封反应，90℃反应1.5h，反应完毕，浓缩得到黄色油状物(3)-3(920mg,收率：83％)。MS-ESI m/z:360.2[M+H] +。
步骤3.化合物(3)-4的制备
将(3)-3(580mg)溶于二氯甲烷(4mL)，0℃加入三氟乙酸(4mL)，室温反应，反应结束，浓缩，残余物加水和二氯甲烷稀释，水相加入氨水调节至pH 10左右，二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩，得到淡黄色油状物(3)-4(280mg,收率67％)。MS-ESI m/z:260.1[M+H] +。
步骤4.化合物(3)的制备
将(1)-8(20mg)溶于乙腈(2mL)，加入(3)-4(28.1mg)、DIPEA(28mg)和碘化钾(18mg),80℃反应1h，完毕后，用水稀释，二氯甲烷萃取，无水硫酸钠干燥，过滤浓缩，经硅胶柱[洗脱剂：二氯甲烷-甲醇＝9:1]纯化，收集洗脱液，浓缩，得淡黄色固体(3)(2.7mg,收率1％)。MS-ESI m/z:500.2[M+H] +。 1H NMR(400MHz,Chloroform-d)δ12.31(s,1H),8.65(d,J＝2.0Hz,1H),8.20(d,J＝2.8Hz,1H),8.09(d,J＝8.8Hz,1H),7.81(s,2H),7.30–7.27(m,1H),4.02(d,J＝14.8Hz,1H),3.82(d,J＝14.8Hz,1H),3.57(dd,J＝12.4,5.0Hz,1H),3.47(dd,J＝12.4,3.3Hz,1H),3.40–3.28(m,2H),3.24(m,1H),3.02(d,J＝5.2Hz,3H),2.99–2.94(m,1H),2.90(q,J＝3.2Hz,3H),2.85(m,1H),2.74–2.62(m,2H)。
实施例5：5-(3-(2-羟乙基)-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(化合物(5))的制备
Figure PCTCN2022135894-appb-000054
步骤1.化合物(5)-2的制备
由2-(1-BOC-2-哌嗪基)乙酸甲酯((5)-1)为原料，经与化合物((3)-2)合成路线类似的方法制备得到化合物(5)-2。MS-ESI m/z:394.2[M+H] +。
步骤2.化合物(5)-3的制备
将一水合氯化锂(491mg)和硼氢化钠(615mg)溶于甲醇-四氢呋喃(4mL,v/v 2:1)中，于冰浴下缓慢加入到(5)-2(400mg)的甲醇:四氢呋喃(8mL,v/v 2:1)溶液中，冰浴反应1h，加水淬灭，乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤浓缩，经硅胶柱层析[洗脱剂：石油醚-乙酸乙酯＝1:1]纯化，得黄色固体(5)-3(70mg，收率19％)。MS-ESI m/z:366.2[M+H] +。
步骤3～5.化合物(5)的制备
由(5)-3为原料，经与化合物(3)制备方法中步骤2-4类似的方法制备得到化合物(5)。MS-ESI m/z:505.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.20(s,1H),8.57(d,J＝1.9Hz,1H),8.15(d,J＝2.4Hz,1H),7.93(d,J＝4.9Hz,1H),7.70(d,J＝1.9Hz,1H),7.29(d,J＝2.9Hz,2H),5.20(t,J＝5.8Hz,1H),4.45(d,J＝5.8Hz,2H),3.81(dd,J＝142.3,14.7Hz,4H),3.30(s,3H),3.15(d,J＝22.0Hz,3H),2.88–2.64(m,4H),2.59(d,J＝4.5Hz,2H)。
实施例6：5-(3-(羟甲基)-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(化合物(6))的制备
Figure PCTCN2022135894-appb-000055
步骤1～5.化合物(6)的制备
由N-1-Boc-2-哌嗪甲酸甲酯((6)-1)为原料，经与化合物(5)合成路线类似的方法制备得到化合物(6)。MS-ESI m/z:491.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.31(s,1H),8.66(s,1H),8.17(d,J＝2.8Hz,1H),8.12–8.05(m,1H),7.65(s,1H),7.34(dd,J＝8.7,2.9Hz,1H),7.31–7.25(m,1H),5.22–5.17(m,1H),3.90(d,J＝26.0Hz,1H),3.62–3.55(m,1H),3.52–3.44(m,2H),3.16–3.11(m,1H),3.09–3.03(m,1H),2.90–2.81(m,2H),2.80–2.75(m,2H),2.68–2.61(m,3H),2.56–2.51(m,3H),2.37-2.30(m,1H)。
实施例8：5-(3-(甲氧基甲基)-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(化合物(8))的制备
Figure PCTCN2022135894-appb-000056
步骤1～4.化合物(8)的制备
由2-(甲氧基甲基)哌嗪-1-羧酸叔丁酯((8)-1)为原料，经与化合物(3)合成路线类似的方法制备得到化合物(8)。MS-ESI m/z:505.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.10(s,1H),8.59(d,J＝1.8Hz,1H),8.39(t,J＝4.9Hz,1H),8.25(d,J＝2.8Hz,1H),7.84(d,J＝8.7Hz,1H),7.73(d,J＝1.9Hz,1H),7.38(dd,J＝8.8,2.9Hz,1H),4.17(d,J＝14.7Hz,1H),3.69–3.58(m,2H),3.50(dd,J＝9.9,5.4Hz,2H),3.35(s,2H),3.25(s,3H),3.12(dt,J＝12.8,7.0Hz,2H),2.78(dd,J＝4.2,2.8Hz,5H),2.51(s,3H)。
实施例9：N-甲基-5-(4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)-3-(三氟甲基)哌嗪-1-基)吡啶酰胺(化合物(9))的制备
Figure PCTCN2022135894-appb-000057
步骤1～4.化合物(9)的制备
由2-三氟甲基哌嗪-1-甲酸叔丁酯为原料，经与化合物(3)合成路线类似的方法制备得到化合物(9)MS-ESI m/z:529.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.22(s,1H),8.60(d,J＝2.0Hz,1H),8.39(q,J＝4.8Hz,1H),8.22(d,J＝2.8Hz,1H),7.85(d,J＝8.8Hz,1H),7.74(d,J＝2.0Hz,1H),7.39–7.34(m,1H),4.18(d,J＝15.2Hz,1H),4.08(d,J＝15.2Hz,1H),3.98–3.92(m,1H),3.90–3.83(m,1H),3.63–3.52(m,2H),3.26–3.12(m,2H),3.03(d,J＝10.0Hz,1H),2.78(t,J＝4.0Hz,6H)。
实施例10：N-甲基-5-(2-甲基-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰胺(化合物(10))的制备
Figure PCTCN2022135894-appb-000058
步骤1～4.化合物(10)的制备
由3-甲基哌嗪-1-羧酸叔丁酯((10)-1)为原料，经与化合物(3)合成路线类似的方法制备得到化合物(10)。MS-ESI m/z:475.2[M+H] +。 1H NMR(400MHz,Chloroform-d)δ12.79(s,1H),8.65(d,J＝2.0Hz,1H),8.12(d,J＝2.8Hz,1H),8.05(d,J＝8.8Hz,1H),7.83(d,J＝2.0Hz,1H),7.77(dd,J＝5.2Hz,1H),7.17(dd,J＝8.8,2.8Hz,1H),4.10(dd,J＝6.8,3.2Hz,1H),3.80–3.59(m,2H),3.50–3.40(m,1H),3.27(td,J＝11.6,3.2Hz,1H),3.01(d,J＝5.2Hz,3H),2.98–2.93(m,1H),2.91(q,J＝3.2Hz,3H),2.77(dt,J＝10.8,2.4Hz,1H),2.55(dd,J＝11.2,3.6Hz,1H),2.38(td,J＝11.2,3.6Hz,1H),1.25(d,J＝6.8Hz,3H)。
实施例11：N-甲基-5-(3-甲基-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰胺(化合物(11))的制备
Figure PCTCN2022135894-appb-000059
步骤1～4.化合物(11)的制备
由N-1-Boc-2-甲基哌嗪((11)-1)为原料，经与化合物(3)合成路线类似的方法制备得到化合物(11)。MS-ESI m/z:475.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.21(s,1H),8.59(s,1H),8.42–8.35(m,1H),8.27(d,J＝2.9Hz,1H),7.82(d,J＝8.8Hz,1H),7.71(d,J＝1.8Hz,1H),7.50-7.30(m,1H),4.15(d, J＝14.6Hz,1H),3.72(d,J＝11.7Hz,1H),3.61(d,J＝12.2Hz,1H),3.45(d,J＝14.6Hz,1H),2.99(t,J＝10.0Hz,1H),2.80–2.75(m,7H),2.62(d,J＝6.2Hz,1H),2.36–2.28(m,2H),1.18(d,J＝6.1Hz,3H)。
实施例12：N-甲基-5-(8-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)吡啶酰胺(化合物(12))的制备
Figure PCTCN2022135894-appb-000060
步骤1～4.化合物(12)的制备
由3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯((12)-1)为原料，经与化合物(3)合成路线类似的方法制备得到化合物(12)。MS-ESI m/z:487.2[M+H] +。 1H NMR(400MHz,Chloroform-d)δ12.37(s,1H),8.65(s,1H),8.10–8.00(m,2H),7.90(s,1H),7.81–7.74(m,1H),7.10(dd,J＝8.8,2.8Hz,1H),3.78(s,2H),3.50–3.43(m,2H),3.42–3.33(m,2H),3.20(d,J＝10.8Hz,2H),3.02(d,J＝5.2Hz,3H),2.93–2.84(m,3H),2.18–2.03(m,2H),1.92–1.81(m,2H)。
实施例13：N-甲基-4-(4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)苯磺酰胺(化合物(35))的制备
Figure PCTCN2022135894-appb-000061
步骤1.化合物(13)的制备
将(1)-8(30mg)、N-甲基-4-(哌嗪-1-基)苯磺酰胺((13)-1)(27mg)溶解于无水乙腈(3mL)中，依次加入KI(18mg)和DIPEA(42mg)，90℃反应30min，反应停止，加水稀释，乙酸乙酯萃取，无水硫酸钠干燥，过滤浓缩，经制备硅胶板分离纯化，得到白色固体(13)(15.5mg，收率28％)。MS-ESI m/z:496.5[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.18(s,1H),8.58(d,J＝1.9Hz,1H),7.69(d,J＝1.9Hz,1H),7.59–7.53(m,2H),7.11(q,J＝5.3Hz,1H),7.08–7.02(m,2H),3.71(s,2H),3.31-3.25(m,4H),2.87-2.67(m,3H),2.55(t,J＝5.1Hz,4H),2.35(d,J＝5.0Hz,3H)。
实施例14：N-甲基-1'-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)-1',2',3',6'-四氢-[3,4'-联吡啶]-6-甲酰胺(化合物(14))的制备
Figure PCTCN2022135894-appb-000062
步骤1～3.化合物(14)的制备
由1'-(叔丁基)6-甲基3',6'-二氢-[3,4'-联吡啶]-1',6(2'H)-二羧酸酯((14)-1)为原料，经与化合物(3)合成路线中步骤2-4类似的方法制备得到化合物(14)。MS-ESI m/z:458.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.21(s,1H),8.74–8.64(m,2H),8.57(d,J＝1.9Hz,1H),7.98(s,2H),7.70(s,1H),6.68–6.31(m,1H),3.78(s,2H),3.21–3.17(m,2H),2.81(d,J＝4.9Hz,3H),2.77(q,J＝3.5Hz,3H),2.72(t,J＝5.6Hz,2H),2.59–2.53(s,2H)。
实施例15：4-甲基-7-((4-(3-氧代-2,3-二氢-1H-吡咯并[3,4-c]吡啶-6-基)哌嗪-1-基)甲基)-3-(三氟甲基)-1,5-萘啶-2(1H)-酮(化合物(15))的制备
Figure PCTCN2022135894-appb-000063
步骤1.化合物(15)-1的制备
将(1)-8(450mg)溶于乙腈(6mL)，加入1-叔丁氧羰基哌嗪(606mg)、DIEA(630mg)和KI(27mg)，氮气保护，80℃反应1h，反应完毕，加水稀释，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤浓缩，经硅胶柱层析[洗脱剂：石油醚-乙酸乙酯＝2:1]纯化，得白色固体(15)-1(350mg,收率50.4％)。MS-ESI m/z:427.2[M+H] +。
步骤2.化合物(15)-2的制备
将(15)-1(350mg)溶于CH 2Cl 2(1mL)，冰浴下缓慢滴加三氟乙酸(1mL)，室温下搅拌1h，浓缩，加水稀释，氨水调pH至10左右，二氯甲烷萃取，无水硫酸钠干燥，过滤浓缩，得到粗品黄色油状(15)-2(230mg)，直接用于下一步。MS-ESI m/z:327.1[M+H] +。
步骤3.化合物(15)的制备
将6-溴-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮((15)-R)(30mg)溶于NMP(1mL)，加入(15)-2(92.58mg)和DIEA(54.95mg)，150℃下微波反应1h后，加水稀释，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩过滤，经制备型HPLC纯化，得白色固体(15)(1.0mg，收率1.5％)。MS-ESI m/z:：459.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.21(s,1H),8.58(d,J＝1.8Hz,1H),8.39(s,1H),8.17(s,1H),7.70(d,J＝1.9Hz,1H),6.94(s,1H),4.29(s,2H),3.74–3.57(m,2H),3.17(d,J＝5.2Hz,6H),2.76(d,J＝6.9,3.3Hz,2H),2.51(s,3H)。
实施例17：2-(4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-5,6-二氢-4H-吡咯并[3,4-d]噻唑-4-酮(化合物(17))的制备
Figure PCTCN2022135894-appb-000064
步骤1.化合物(17)-1的制备
将2-溴-5-甲基噻唑-4-羧酸甲酯(900mg)溶于四氯化碳(10mL)中，加入N-溴代丁二酰亚胺(746mg)和过氧化二苯甲酰(92.3mg)，80℃反应过夜，反应完毕，浓缩，残余物经硅胶柱层析[洗脱剂：PE-EA＝10:1]纯化，收集洗脱液，减压蒸除溶剂，得到淡黄色固体(17)-1(900mg，收率：74.9％)。MS-ESI m/z:315.9[M+H] +。
步骤2.化合物(17)-2的制备
将(17)-1(900mg)溶于无水四氢呋喃(10mL)，加入苄胺(520mg)和碳酸钾(671mg)，80℃反应4小时，加水稀释，饱和碳酸氢钠溶液调节PH至10，二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩，残余物经硅胶柱层析[洗脱剂：PE-EA＝1:1]纯化，收集洗脱液，减压蒸除溶剂，得到淡黄色固体(17)-2(720mg,收率：74％)。MS-ESI m/z:340.9[M+H] +。
步骤3.化合物(17)-3的制备
将(17)-2(720mg)溶于四氢呋喃(7mL)和水(3.5mL)，加入一水和氢氧化锂(273mg)，室温反应4小时，加稀盐酸，浓缩，得到粗品无色油状物(17)-3。MS-ESI m/z:326.9[M+H] +。
步骤4.化合物(17)-4的制备
将(17)-3溶于N,N-二甲基甲酰胺(8mL)，加入EDCI(707mg)、HOBT(293mg)、DIPEA(658mg)和DMAP(53mg),65℃反应4h。反应结束，加水稀释，二氯甲烷萃取，有机相用无水硫酸钠干燥， 过滤浓缩，残余物经硅胶柱层析[洗脱剂：DCM-MeOH＝25:1]纯化，收集洗脱液，减压蒸除溶剂，得到淡黄色固体(17)-4(200mg,收率：30％)。MS-ESI m/z:308.9[M+H] +。
步骤5～7.化合物(17)-7的制备
由(17)-4为原料，经与化合物(3)合成路线类似的方法制备得到化合物(17)-7。MS-ESI m/z:555.1[M+H] +。
步骤8.化合物(17)的制备
将(17)-7(20mg)溶于甲磺酸(1mL)，加入三氟乙酸(1mL)，80℃反应16h，反应结束，浓缩，残余物加水和二氯甲烷稀释，水相加入氨水调节至pH 10左右，二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩，经硅胶柱层析[洗脱剂：二氯甲烷-甲醇＝10:1]纯化，收集洗脱液，浓缩，得淡黄色固体(17)(1.8mg,收率11％)。MS-ESI m/z:465.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.18(s,1H),8.58(d,J＝2.0Hz,1H),8.25(s,1H),7.69–7.66(m,1H),4.30(s,2H),3.72(s,2H),3.53–3.42(m,4H),2.86–2.73(m,2H),2.55(d,J＝5.2Hz,4H)。
实施例18：4-甲基-7-((4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-5-基)哌嗪-1-基)甲基)-3-(三氟甲基)-1,5-萘啶-2(1H)-酮(化合物(18))的制备
Figure PCTCN2022135894-appb-000065
步骤1.化合物(18)的制备
由5-(哌嗪-1-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2(3H)-酮((18)-1)为原料，经与化合物(3)合成路线步骤4类似的方法制备得到化合物(18)。MS-ESI m/z:460.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.22(s,1H),10.92(s,1H),10.35(s,1H),8.57(s,1H),7.69(s,1H),7.09(d,J＝8.4Hz,1H),6.35(d,J＝8.4Hz,1H),3.69(s,2H),3.52–3.38(m,4H),2.84–2.70(m,3H),2.55–2.52(m,4H)。
实施例19：4-甲基-3-(三氟甲基)-7-((4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)甲基)-1,5-萘啶-2(1H)-酮(化合物(19))的制备
Figure PCTCN2022135894-appb-000066
步骤1.化合物(19)的制备
将2-氯-5-三氟甲基嘧啶(10mg)溶于NMP(1mL)，加入(15)-2(19.67mg)和碳酸钾(15.14mg)，80℃搅拌2h，反应完毕，加水稀释，二氯甲烷萃取，饱和食盐水洗，无水硫酸钠干燥，过滤浓缩，通过制备型HPLC纯化，得白色固体(19)(6.3mg，收率24.4％)。MS-ESI m/z:473.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.23(s,1H),8.70(d,J＝1.0Hz,2H),8.58(d,J＝1.9Hz,1H),7.69(d,J＝1.9Hz,1H),3.86(t,J＝5.2Hz,4H),3.70(s,2H),3.40-3.20(m,4H),2.77(q,J＝3.5Hz,3H)。
实施例20：6-(4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)烟腈(化合物(20))的制备
Figure PCTCN2022135894-appb-000067
步骤1.化合物(20)的制备
由5-氰基-2-氟吡啶为原料，经与化合物(19)合成路线类似的方法制备得到化合物(20)。MS-ESI m/z:429.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.22(s,1H),8.57(d,J＝1.8Hz,1H),8.48(d,J＝2.3Hz,1H),7.85(dd,J＝9.1,2.4Hz,1H),7.68(d,J＝1.9Hz,1H),6.93(d,J＝9.1Hz,1H),3.79–3.55(m6H),2.77(q,J＝3.5Hz,4H),2.48(s,3H)。
实施例21：5-(3-氰基-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(化合物(21))的制备
Figure PCTCN2022135894-appb-000068
步骤1.化合物(21)-2的制备
将2-氰基哌嗪-1-羧酸叔丁酯((21)-1)(260mg)溶于1,4-二氧六环(5mL)中，加入5-溴-吡啶甲酸甲酯(169mg)、三(二亚苄基丙酮)二钯(228mg)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(234mg)和碳酸铯(1.22g)，100℃反应3h。将反应液加水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，经硅胶柱层析[洗脱剂：PE-EA＝1:1]纯化，收集洗脱液，减压蒸除溶剂，得到黄色油状物(21)-2(300mg,收率：69％)。MS-ESI m/z:347.2[M+H] +.
步骤2.化合物(21)-3的制备
将(21)-2(300mg)溶于甲醇(4mL)，加入甲胺水溶液(2mL,40％wt)，50℃封管反应1h。反应完毕后，将反应液浓缩，经硅胶柱层析[洗脱剂：DCM-MeOH＝20:1]纯化，收集洗脱液，减压蒸除溶剂，得到黄色固体(21)-3(150mg,收率：50％)。MS-ESI m/z:346.2[M+H] +.
步骤3.化合物(21)-4的制备
将(21)-3(100mg)溶于二氯甲烷(4mL)，0℃加入三氟乙酸(1mL)，室温反应1h。反应结束后，将反应液加水和二氯甲烷稀释，水相加入氨水调节至pH 10左右，二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，浓缩，得到粗品淡黄色油状物(21)-4，直接用于下一步。MS-ESI m/z:246.2[M+H] +。
步骤4.化合物(21)的制备
将(1)-8(20mg)溶于乙腈(2mL)，加入粗品(21)-4、DIPEA(28mg)和碘化钾(2.4mg)，80℃反应1h。反应完毕后，将反应液用水稀释，二氯甲烷萃取，无水硫酸钠干燥，过滤浓缩，经硅胶柱[洗脱剂：二氯甲烷-甲醇＝9:1]纯化，收集洗脱液，浓缩，得白色固体(21)(1.0mg,收率：3％)。MS-ESI m/z:486.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.27(s,1H),8.61(s,1H),8.45(d,J＝5.2Hz,1H),8.33(d,J＝2.8Hz,1H),7.86(d,J＝8.8Hz,1H),7.71(s,1H),7.48(dd,J＝8.8,2.8Hz,1H),4.32(s,1H),4.16(d,J＝12.8Hz,2H),3.90(d,J＝14.0Hz,1H),3.82(d,J＝14.0Hz,1H),3.11(dd,J＝12.8,3.2Hz,2H),2.89–2.83(m,2H),2.78(q,J＝4.0Hz,6H).
实施例23：5-(3-甲基-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰胺(化合物(23))的制备
Figure PCTCN2022135894-appb-000069
步骤1～4.化合物(23)的制备
由5-溴吡啶甲酸甲酯为原料，经与化合物(3)合成路线类似的方法制备得到化合物(23)。MS-ESI m/z:461.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.15(s,1H),8.57(s,1H),8.29–8.24(m,1H),7.83(d,J＝8.7Hz,1H),7.77–7.61(m,2H),7.41–7.33(m,1H),7.29(s,1H),3.67–3.53(m,2H),3.21–3.10(m,5H),2.84–2.78(m,1H),2.78–2.72(m,3H),2.67–2.60(m,1H),1.24–1.21(m,3H)。
实施例24：N-甲基-5-(4-(1-(8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)乙基)哌嗪-1-基)吡啶酰胺(化合物(24))的制备
Figure PCTCN2022135894-appb-000070
步骤1.化合物(24)-1的制备
将(1)-7(1g)溶于乙酸乙酯(20mL)，随后加入活性二氧化锰(5.05g)，50℃反应3小时。反应完毕后，滤去固体，将反应液浓缩，经硅胶柱层析[洗脱剂：二氯甲烷-甲醇＝20:1]纯化，收集洗脱液，减压蒸除溶剂，得到淡黄色固体(24)-1(550mg,收率55％)。MS-ESI m/z:257.1[M+H] +。
步骤2.化合物(24)-2的制备
将(24)-1(550mg)溶于无水四氢呋喃(11mL)，0℃下滴加入甲基溴化镁溶液(5.4mL,1M in THF),25℃反应1小时。反应完毕后，用饱和氯化铵水溶液淬灭反应，而后用饱和碳酸氢钠水溶液调节pH～7，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，经硅胶柱层析[洗脱剂：二氯甲烷-甲醇＝20:1]纯化，收集洗脱液，减压蒸除溶剂，得到黄色固体(24)-2(558mg,收率95％)。MS-ESI m/z:273.1[M+H] +。
步骤3.化合物(24)-3的制备
将(24)-2(558mg)溶于氯化亚砜(10mL)，25℃反应1小时，反应完毕，将反应液浓缩旋干得到黄色固体(24)-3(590mg)。MS-ESI m/z:291.0[M+H] +。
步骤4：化合物(24)的制备
将(24)-3(568.4mg)溶于乙腈(20mL)，加入(1)-R(500.0mg)、DIPEA(1.14mL)和碘化钾(57.1mg)，80℃反应16小时，完毕后，用水稀释，二氯甲烷萃取，无水硫酸钠干燥，过滤浓缩，经硅胶柱[洗脱剂：二氯甲烷-甲醇＝20:1]纯化，收集洗脱液，浓缩，得淡黄色固体(24)(340.0mg,收率42％)。MS-ESI m/z:475.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.21(s,1H),8.63(d,J＝2.0Hz,1H),8.44–8.35(m,1H),8.25(d,J＝2.8Hz,1H),7.82(d,J＝8.8Hz,1H),7.68(d,J＝2.0Hz,1H),7.37(dd,J＝8.8,2.8Hz,1H),3.80–3.67(m,1H),3.34–3.27(m,4H),2.82–2.68(m,5H),2.69–2.56(m,2H),2.48–2.43(m,3H),1.38(d,J＝6.8Hz,3H).
实施例90和91：(R)-N-甲基-5-(4-(1-(8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)乙基)哌嗪-1-基)吡啶酰胺(化合物(90))和(S)-N-甲基-5-(4-(1-(8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)乙基)哌嗪-1-基)吡啶酰胺(化合物(91))的制备
Figure PCTCN2022135894-appb-000071
将(24)(340mg)经过手性HPLC拆分得到两个立体异构体化合物(90)和化合物(91)。
实施例25：5-(4-(氰基(8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(化合物(25))的制备
Figure PCTCN2022135894-appb-000072
步骤1.化合物(25)的制备
将(24)-1(25mg)溶于四氢呋喃(1mL)，加入三甲基氰硅烷(11.6mg)和二碘化锌(1.6mg)，氮气置换三次，随后在0℃下搅拌5分钟，而后滴加入(1)-R(23.6mg)和三乙胺(9.9mg)的甲醇溶液(2mL)，50℃反应16小时。反应完毕后，将反应液用饱和碳酸钾水溶液淬灭，乙酸乙酯萃取，无水硫酸钠干燥，过滤浓缩，经硅胶柱[洗脱剂：二氯甲烷-甲醇＝15:1]纯化，收集洗脱液，浓缩，得白色固体(25)(1.2mg,收率2.5％)。MS-ESI m/z:486.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.26(s,1H),8.68(d,J＝2.0Hz,1H),8.43(q,J＝4.8Hz,1H),8.29(d,J＝3.2Hz,1H),7.88(d,J＝2.0Hz,1H),7.84(d,J＝8.8Hz,1H),7.42(dd,J＝8.8,3.2Hz,1H),5.82(s,1H),3.58–3.47(m,4H),2.81–2.70(m,5H),2.61–2.54(m,2H),2.52–2.51(m,3H).
实施例26：N-甲基-6-(3-甲基-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)哒嗪-3-甲酰胺(化合物(26))的制备
Figure PCTCN2022135894-appb-000073
步骤1化合物(26)-1的制备
将6-氯哒嗪-3-甲酸甲酯(200mg)和2-甲基哌嗪-1-羧酸叔丁酯(243.7mg)溶于二甲基亚砜(4mL)中，随后加入碳酸钾(480.5mg)，100℃反应1h。反应完毕，加水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，经硅胶柱层析[洗脱剂：石油醚-乙酸乙酯＝5:1]纯化，收集洗脱液，减压蒸除溶剂，得到白色固体(26)-1(200.6mg,收率51％)。MS-ESI m/z:337.2[M+H] +。
步骤2～4.化合物(26)的制备
由(26)-1为原料，经与化合物(3)合成路线中步骤2-4类似的方法制备得到化合物(26)。MS-ESI m/z:476.2[M+H] +。 1H NMR(400MHz,Chloroform-d)δ12.53(s,1H),8.65(d,J＝2.0Hz,1H),8.01(d,J＝9.6Hz,1H),7.92–7.85(m,1H),7.80(d,J＝2.0Hz,1H),6.95(d,J＝9.6Hz,1H),4.23–4.12(m,2H),4.02(d,J＝12.8Hz,1H),3.48(d,J＝14.8Hz,1H),3.45–3.37(m,1H),3.22(dd,J＝13.2,8.8Hz,1H),3.03(d,J＝5.2Hz,3H),2.92–2.85(m,3H),2.82(dt,J＝11.6,3.6Hz,1H),2.77–2.67(m,1H),2.39(ddd,J＝11.6,9.6,3.2Hz,1H),1.24(d,J＝6.0Hz,3H)。
实施例28：N-甲基-5-(3-甲基-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)嘧啶-2-甲酰胺(化合物(28))的制备
Figure PCTCN2022135894-appb-000074
步骤1～4.化合物(28)的制备
由5-溴嘧啶-2-甲酸甲酯和2-甲基哌嗪-1-碳酸叔丁酯为原料，经与化合物(3)合成路线类似的方法制备得到化合物(28)。MS-ESI m/z:476.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.16(s,1H),8.55(d,J＝2.0Hz,1H),8.52–8.47(m,3H),7.67(d,J＝2.0Hz,1H),4.10(d,J＝14.8Hz,1H),3.75(d,J＝12.0Hz,1H),3.64(d,J＝8.8Hz,1H),3.42(d,J＝14.8Hz,1H),3.06–2.95(m,1H),2.81(dd,J＝12.4,8.8Hz,1H),2.81–2.68(m,6H),2.66–2.54(m,1H),2.34–2.23(m,1H),1.13(d,J＝6.0Hz,3H)。
实施例29：5-(4-((7,8-二甲基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(化合物(29))的制备
Figure PCTCN2022135894-appb-000075
步骤1～3.化合物(29)-3的制备
由6-氯-5-硝基吡啶-3-甲酸甲酯为原料，经与化合物(1)合成路线中步骤1-3类似的方法制备得到化合物(29)-3。MS-ESI m/z:195.1[M+H] +。
步骤4.化合物(29)-4的制备
将(29)-3(400mg)和2-(二乙基膦酰)丙酸(432.9mg)溶于DMF(10mL)，加入EDCI(790mg)、DMAP(503.3mg)和三乙胺(625.3mg)，60℃反应16h，反应完毕，用水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，经硅胶柱层析[洗脱剂：石油醚-乙酸乙酯＝10:1]纯化，收集洗脱液，减压蒸除溶剂，得到淡黄色固体(29)-4(323.3mg,收率41％)。MS-ESI m/z:387.1[M+H] +。
步骤5.化合物(29)-5的制备
将(29)-4(323.3mg)溶于四氢呋喃(160mL)，加入氢化钠(341.6mg，60％wt)，室温反应8h，反应完毕，饱和氯化铵水溶液淬灭，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，经硅胶柱层析[洗脱剂：二氯甲烷-甲醇＝20:1]纯化，收集洗脱液，减压蒸除溶剂，得到白色固体(29)-5(76mg,收率39％)。MS-ESI m/z:233.1[M+H] +。
步骤6～8.化合物(29)的制备
由(29)-5为原料，经与化合物(1)合成路线中步骤6-8类似的方法制备得到化合物(29)。MS-ESI m/z:407.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ11.74(s,1H),8.47–8.35(m,2H),8.26(d,J＝2.8Hz,1H),7.82(d,J＝8.8Hz,1H),7.60(d,J＝2.0Hz,1H),7.38(dd,J＝8.8,2.8Hz,1H),3.64(s,2H),3.33(t,J＝5.2Hz,4H),2.77(d,J＝4.8Hz,3H),2.57–2.53(m,4H),2.49(d,J＝1.2Hz,3H),2.13(d,J＝1.2Hz,3H)。
实施例51：(R)-N-甲基-5-(3-甲基-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰胺(化合物(51))的制备
Figure PCTCN2022135894-appb-000076
步骤1～4.化合物(51)的制备
由(R)-1-N-Boc-2-甲基哌嗪((51)-1)为原料，经与化合物(3)合成路线类似的方法制备得到化合物(51)。MS-ESI m/z:475.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.19(s,1H),8.56(s,1H),8.47-8.27(m,1H),8.25(d,J＝2.9Hz,1H),7.81(d,J＝8.7Hz,1H),7.69(s,1H),7.43–7.34(m,1H),4.12(d,J＝ 14.6Hz,1H),3.70(d,J＝12.0Hz,1H),3.59(d,J＝12.2Hz,2H),3.06–2.88(m,2H),2.84-2.64(m,7H),2.61(s,1H),2.40-2.20(m,1H),1.16(d,J＝6.1Hz,3H)。
实施例52：(S)-N-甲基-5-(3-甲基-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰胺(化合物(52))的制备
Figure PCTCN2022135894-appb-000077
步骤1～4.化合物(52)的制备
由(S)-1-N-Boc-2-甲基哌嗪((52)-1)为原料，经与化合物(3)合成路线类似的方法制备得到化合物(52)。MS-ESI m/z:475.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.19(s,1H),8.56(s,1H),8.47-8.27(m,1H),8.25(d,J＝2.9Hz,1H),7.81(d,J＝8.7Hz,1H),7.69(s,1H),7.43–7.34(m,1H),4.12(d,J＝14.6Hz,1H),3.70(d,J＝12.0Hz,1H),3.59(d,J＝12.2Hz,2H),3.06–2.88(m,2H),2.84-2.64(m,7H),2.61(s,1H),2.40-2.20(m,1H),1.16(d,J＝6.1Hz,3H)。
实施例53：(S)-N-甲基-5-(2-甲基-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰胺(化合物(53))的制备
Figure PCTCN2022135894-appb-000078
步骤1～4.化合物(53)的制备
由(S)-4-N-叔丁氧羰基-2-甲基哌嗪((53)-1)为原料，经与化合物(3)合成路线类似的方法制备得到化合物(53)。MS-ESI m/z:475.2[M+H] +。 1H NMR(400MHz,Chloroform-d)δ12.84(s,1H),8.65(d,J＝2.0Hz,1H),8.11(d,J＝2.8Hz,1H),8.05(d,J＝8.8Hz,1H),7.84(d,J＝2.0Hz,1H),7.80–7.74(m,1H),7.17(dd,J＝8.8,2.8Hz,1H),4.15–4.06(m,1H),3.80–3.63(m,2H),3.48–3.40(m,1H),3.31–3.20(m,1H),3.01(d,J＝5.2Hz,3H),2.97–2.93(m,1H),2.93–2.89(m,3H),2.81–2.72(m,1H),2.55(dd,J＝11.2,3.6Hz,1H),2.44–2.32(m,1H),1.25(d,J＝6.8Hz,3H)。
实施例54：(R)-N-甲基-5-(2-甲基-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰胺(化合物(54))的制备
Figure PCTCN2022135894-appb-000079
步骤1～4.化合物(54)的制备
由(R)-4-N-叔丁氧羰基-2-甲基哌嗪((54)-1)为原料，经与化合物(3)合成路线类似的方法制备得到化合物(54)。MS-ESI m/z:475.2[M+H] +。 1H NMR(400MHz,Chloroform-d)δ12.84(s,1H),8.65(d,J＝2.0Hz,1H),8.11(d,J＝2.8Hz,1H),8.05(d,J＝8.8Hz,1H),7.84(d,J＝2.0Hz,1H),7.80–7.74(m,1H),7.17(dd,J＝8.8,2.8Hz,1H),4.15–4.06(m,1H),3.80–3.63(m,2H),3.48–3.40(m,1H),3.31–3.20(m,1H),3.01(d,J＝5.2Hz,3H),2.97–2.93(m,1H),2.93–2.89(m,3H),2.81–2.72(m,1H),2.55(dd,J＝11.2,3.6Hz,1H),2.44–2.32(m,1H),1.25(d,J＝6.8Hz,3H)。
实施例55和56：N-甲基-8-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)-6,7,8,9-四氢吡啶并[3',4':4,5]咪唑并[1,2-a]吡嗪-3-甲酰胺和N-甲基-7-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)-6,7,8,9-四氢吡啶并[4',3':4,5]咪唑并[1,2-a]吡嗪-3-甲酰胺的制备
Figure PCTCN2022135894-appb-000080
步骤1.化合物(55)-1的制备
将4,5-二氨基吡啶甲酸甲酯(900mg)和苄氧基羰基甘氨酸(1.24g)溶于二氯甲烷(20mL)中，加入EDCI(1.67g)、HOBt(1.98g)和TEA(1.45g)，40℃反应3h，将反应液倒入水中，过滤，得到粗品白色固体(800mg)。MS-ESI m/z:359.35[M+H] +。将所得粗品(500mg)溶于乙酸(5mL)，120℃反应2h,冷却后浓缩，经硅胶柱层析[洗脱剂：二氯甲烷-甲醇＝10:1]纯化，收集洗脱液，减压蒸除溶剂，得到淡黄色油状物(55)-1(320mg,收率：67％)。MS-ESI m/z:341.34[M+H] +。
步骤2.化合物(55)-2的制备
将(55)-1(300mg)溶于N,N-二甲基甲酰胺(6mL)，加入碳酸铯(574mg)和1,2-二溴乙烷(497mg)，80℃反应5h，反应完毕，加水稀释，乙酸乙酯萃取，饱和食盐水洗涤，干燥浓缩，经硅胶柱层析[洗脱剂：二氯甲烷-甲醇＝20:1]纯化，收集洗脱液，减压蒸除溶剂，得到白色固体(55)-2(220mg,收率：68％)。MS-ESI m/z:367.38[M+H] +。
步骤3.化合物(55)-3的制备
将(55)-2(220mg)溶于甲醇(5mL)，加入甲胺水溶液(2mL,40％wt)，密封反应，90℃反应1h，反应完毕，浓缩，经硅胶柱层析[洗脱剂：二氯甲烷-甲醇＝10:1]纯化，收集洗脱液，减压蒸除溶剂，得到淡黄色油状物(55)-3(180mg,收率82％)。MS-ESI m/z:366.39[M+H] +。
步骤4.化合物(55)-4的制备
将(55)-3(180mg)溶于甲醇(5mL)，加入10％湿钯/碳(20mg)，氢气球氛围下，室温反应过夜，反应完毕，经硅藻土过滤，浓缩后得到白色固体(55)-4(90mg)，直接用于下一步反应。MS-ESI m/z:232.26[M+H] +。
步骤5.化合物(55)和(56)的制备
将(55)-4(90mg)溶于乙腈(5mL)，加入(1)-8(60mg)、DIPEA(130mg)和碘化钾(54mg)，80℃反应1h，完毕后，用水稀释，二氯甲烷萃取，无水硫酸钠干燥，过滤浓缩，经硅胶柱[洗脱剂：二氯甲烷-甲醇＝10:1]纯化，收集洗脱液，浓缩，得白色固体(55)(18mg)和白色固体(56)(16mg)(收率33％)。
(55)：MS-ESI m/z:472.44[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.26(s,1H),8.89(s,1H),8.83-8.63(m,1H),8.63(d,J＝1.9Hz,1H),8.17(s,1H),7.74(d,J＝1.9Hz,1H),4.35(t,J＝5.4Hz,2H),4.01(d,J＝10.0Hz,4H),3.10(t,J＝5.4Hz,2H),2.84(d,J＝4.8Hz,3H),2.87-2.67(m,3H)。
(56)：MS-ESI m/z:472.44[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.26(s,1H),8.87(d,J＝1.0Hz,1H),8.87-8.67(m,1H),8.63(d,J＝1.8Hz,1H),8.25(d,J＝1.0Hz,1H),7.74(d,J＝1.9Hz,1H),4.31(t,J＝5.5Hz,2H),4.00(d,J＝3.3Hz,4H),3.14–3.06(m,2H),2.85(d,J＝4.9Hz,3H),2.88-2.78(m,3H)。
实施例57：N-甲基-5-(3-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)吡啶酰胺(化合物(57))的制备
Figure PCTCN2022135894-appb-000081
步骤1～4.化合物(57)的制备
由5-溴吡啶甲酸甲酯为原料，经与化合物(3)合成路线类似的方法制备得到化合物(57)。MS-ESI m/z:487.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.28(s,1H),8.51(d,J＝1.8Hz,1H),8.34(d,J＝4.9Hz,1H),8.16(d,J＝2.8Hz,1H),7.80(d,J＝8.7Hz,1H),7.71(d,J＝1.9Hz,1H),7.29(d,J＝6.0Hz,1H),3.56(s,2H),2.99(d,J＝5.2Hz,1H),2.82–2.71(m,6H),2.56–2.54(m,1H),2.42–2.39(m,2H),2.14–2.04(m,4H),1.98–1.89(m,2H)。
实施例69：N,6'-二甲基-1'-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)-1',2',3',6'-四氢-[3,4'-联吡啶]-6-甲酰胺(化合物(69))的制备
Figure PCTCN2022135894-appb-000082
步骤1～3：化合物(69)的制备
由1'-(叔丁基)6-甲基6'-甲基-3',6'-二氢-[3,4'-联吡啶]-1',6(2'H)-二羧酸酯((69)-1)为原料，经与化合物(14)合成路线类似的方法制备得到化合物(69)。MS-ESI m/z:472.4[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.18(s,1H),8.74–8.65(m,2H),8.55-8.61(m,1H),8.04–7.96(m,2H),7.70-7.76(m,1H),6.40–6.35(m,1H),3.95–3.90(m,2H),3.19(s,1H),3.01–2.91(m,2H),2.84–2.80(m,3H),2.73-2.79(m,3H),2.28(s,1H),1.94-2.05(m,1H),1.13(m,3H).
实施例70：N-甲基-5-(2-甲基-1-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌啶-4-基) 吡啶酰胺(化合物(70))的制备
Figure PCTCN2022135894-appb-000083
步骤1：化合物(70)-1的制备
将(69)-2(49mg)溶于无水甲醇(3mL)中，加入wt 10％的湿钯碳，氢气气氛下室温下反应1h，反应完毕，硅藻土过滤后，浓缩，得到粗品((70)-1)(50mg)，直接进行下一步反应。MS-ESI m/z:334.4[M+H] +。
步骤2～3：化合物(70)的制备
由((70)-1)为原料，经与化合物(69)合成路线步骤2-3类似的方法制备得到化合物(70)。MS-ESI m/z:474.50[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.19(s,1H),8.69(d,J＝5.5Hz,1H),8.56-8.62(m,1H),8.49-8.55(m,1H),7.92-7.99(m,1H),7.86(m,1H),7.74–7.68(m,1H),4.22(d,J＝14.5Hz,1H),3.84(d,J＝14.9Hz,1H),3.72(d,J＝14.7Hz,1H),3.18(m,1H),2.98-3.1(m,1H),2.85–2.73(m,6H),2.62-2.67(m,1H),1.99(m,1H),1.79–1.59(m,3H),1.17(m,3H).
实施例71：N-甲基-5-(1-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌啶-4-基)吡啶酰胺(化合物(71))的制备
Figure PCTCN2022135894-appb-000084
步骤1～3：化合物(71)的制备
由((14)-2)为原料，经与化合物(70)合成路线类似的方法制备得到化合物(71)。MS-ESI m/z:460.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ12.24(s,1H),8.74–8.67(m,1H),8.57(d,J＝1.8Hz,1H),8.52(d,J＝2.2Hz,1H),7.95(d,J＝8.1Hz,1H),7.89–7.82(m,1H),7.67(s,1H),3.68(s,2H),3.19–3.10(m,1H),2.94(d,J＝10.6Hz,2H),2.84–2.69(m,6H),2.22–2.10(m,2H),1.86–1.66(m,4H).
实施例72：5-(2-氰基-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(化合物(72))的制备
Figure PCTCN2022135894-appb-000085
步骤1～4：化合物(72)的制备
由3-氰基哌嗪-1-羧酸叔丁酯((72)-1)为原料，经与化合物(21)合成路线类似的方法制备得到化合物(72)。MS-ESI m/z:486.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ8.62(s,1H),8.55(d,J＝4.9Hz,1H),8.42(d,J＝2.7Hz,1H),7.94(d,J＝8.7Hz,1H),7.72(s,1H),7.60(d,J＝8.9Hz,1H),5.48(s,1H),3.81(d,J＝14.3Hz,2H),3.15(d,J＝11.8Hz,1H),3.05-2.95(m,2H),2.83–2.74(m,6H),2.69(s,1H),2.58–2.53(m,1H),2.38–2.30(m,1H),2.21–2.12(m,1H).
实施例73：5-(2-(氰基甲基)-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(化合物(73))的制备
Figure PCTCN2022135894-appb-000086
步骤1～4：化合物(73)的制备
由3-(氰基甲基)哌嗪-1-甲酸叔丁酯((73)-1)为原料，经与化合物(72)合成路线类似的方法制备得到化合物(73)。MS-ESI m/z:500.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ12.28(s,1H),8.61(s,1H),8.42(d,J＝4.9Hz,1H),8.31(d,J＝2.9Hz,1H),7.84(d,J＝8.8Hz,1H),7.73(s,1H),7.49–7.40(m,1H),4.63(s,1H),3.78(s,1H),3.67(d,J＝11.0Hz,2H),3.21–3.10(m,1H),3.05–2.64(m,9H),2.43–2.24(m,3H).
实施例74：5-(2-(甲氧基甲基)-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(化合物(74))的制备
Figure PCTCN2022135894-appb-000087
步骤1～4：化合物(74)的制备
由3-(甲氧基甲基)哌嗪-1-甲酸叔丁酯((74)-1)为原料，经与化合物(73)合成路线类似的方法制备得到化合物(74)。MS-ESI m/z:505.3[M+H] +. 1H NMR(400MHz,Chloroform-d)δ12.98(s,1H),8.63(d,J＝1.8Hz,1H),8.13(d,J＝2.9Hz,1H),8.04(d,J＝8.7Hz,1H),7.86(s,1H),7.78(q,J＝5.0Hz,1H),7.18(dd,J＝8.9,2.9Hz,1H),4.08–4.00(m,1H),3.87(t,J＝9.0Hz,1H),3.80–3.67(m,2H),3.50(d,J＝12.4Hz,1H),3.35(dd,J＝8.9,4.1Hz,1H),3.27(s,3H),3.20(dd,J＝12.0,3.5Hz,1H),3.10(d,J＝11.5Hz,1H),3.00(d,J＝5.1Hz,3H),2.90(d,J＝3.3Hz,3H),2.43(dd,J＝11.3,3.5Hz,1H),2.39-2.32(m,J＝11.4,3.4Hz,1H),2.10-2.02(m,1H).
实施例75：5-(2-(羟甲基)-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(化合物(75))的制备
Figure PCTCN2022135894-appb-000088
步骤1～4：化合物(75)的制备
由3-(羟甲基)哌嗪-1-羧酸叔丁酯((75)-1)为原料，经与化合物(21)合成路线类似的方法制备得到化合物(75)。MS-ESI m/z:491.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ12.23(s,1H),8.56(d,J＝10.2Hz,2H),8.26(d,J＝2.8Hz,1H),7.96(d,J＝8.7Hz,1H),7.66(s,1H),7.51(dd,J＝8.7,2.9Hz,1H),6.27–6.01(m,1H),4.14–3.94(m,2H),3.65(s,2H),3.45(s,3H),3.12(d,J＝7.8Hz,1H),2.96–2.61(m,7H),2.18–1.93(m,2H).
实施例76：N-甲基-5-(4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)-2-(三氟甲基)哌嗪-1-基)吡啶酰胺(化合物(76))的制备
Figure PCTCN2022135894-appb-000089
步骤1～4：化合物(76)的制备
由3-(三氟甲基)哌嗪-1-甲酸叔丁酯((76)-1)为原料，经与化合物(21)合成路线类似的方法制备得到化合物(76)。MS-ESI m/z:529.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ12.34(s,1H),8.57(d,J＝2.0Hz,1H),8.43(q,J＝4.8Hz,1H),8.37(d,J＝2.8Hz,1H),7.85(d,J＝8.8Hz,1H),7.69(d,J＝2.0Hz,1H),7.50(dd,J＝8.8,2.8Hz,1H),5.25–5.07(m,1H),3.81–3.68(m,2H),3.63(d,J＝12.4Hz,1H),3.35–3.26(m,2H),3.15(d,J＝12.4Hz,1H),2.96(d,J＝11.2Hz,1H),2.84–2.68(m,5H),2.47–2.44(m,1H),2.31–2.20(m,1H).
实施例77：5-(3,3-二甲基-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(化合物(77))的制备
Figure PCTCN2022135894-appb-000090
步骤1～4：化合物(77)的制备
由2,2-二甲基哌嗪-1-甲酸叔丁酯((77)-1)为原料，经与化合物(21)合成路线类似的方法制备得到化合物(77)。MS-ESI m/z:489.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ12.20(s,1H),8.59(s,1H),8.36(q,J＝4.8Hz,1H),8.26(d,J＝2.9Hz,1H),7.81(d,J＝8.8Hz,1H),7.71(s,1H),7.39(d,J＝5.9Hz,1H),3.70(s,2H),3.31–3.24(m,2H),3.21(s,2H),2.81–2.73(m,6H),2.54–2.50(m,2H),1.17(s,6H).
实施例78：N-甲基-5-(4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)-4,7-二氮杂螺[2.5]辛烷-7-基)吡啶酰胺(化合物(78))的制备
Figure PCTCN2022135894-appb-000091
步骤1～4：化合物(78)的制备
由4,7-二氮杂螺[2.5]辛烷-4-羧酸叔丁酯((78)-1)为原料，经与化合物(21)合成路线类似的方法制备得到化合物(78)。MS-ESI m/z:487.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ12.17(s,1H),8.55(d,J＝1.8Hz,1H),8.40(q,J＝4.9Hz,1H),8.27(d,J＝2.9Hz,1H),7.84(d,J＝8.8Hz,1H),7.65(d,J＝1.9Hz,1H),7.39(dd,J＝8.9,2.9Hz,1H),4.04(s,2H),3.45(s,3H),3.26(s,2H),2.91(t,J＝5.3Hz,2H),2.78(dd,J＝8.2,4.2Hz,5H),0.77–0.59(m,4H).
实施例79：N-甲基-5-(1-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)-1,2,3,6-四氢吡啶-4-基)吡嗪-2-甲酰胺(化合物(79))的制备
Figure PCTCN2022135894-appb-000092
步骤1～3：化合物(79)的制备
由5-(1-(叔丁氧羰基)-1,2,3,6-四氢吡啶-4-基)吡嗪-2-羧酸甲酯((79)-1)为原料，经与化合物(14)合成路线类似的方法制备得到化合物(79)。MS-ESI m/z:459.5[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.22(s,1H),9.07(d,J＝1.5Hz,1H),8.89(d,J＝1.5Hz,1H),8.81(d,J＝5.0Hz,1H),8.59(d,J＝1.9Hz,1H),7.72(d,J＝1.8Hz,1H),7.00(s,1H),3.81(s,2H),3.26(s,2H),2.82(d,J＝4.8Hz,3H),2.78(q,J＝3.5Hz,3H),2.72(d,J＝5.4Hz,2H),2.66(s,2H).
实施例80和81：N,3'-二甲基-1'-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)-1',2',3',6'-四氢-[3,4'-联吡啶]-6-甲酰胺(化合物(80))和N,5'-二甲基-1'-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)-1',2',3',6'-四氢-[3,4'-联吡啶]-6-甲酰胺(化合物(81))的制备
Figure PCTCN2022135894-appb-000093
步骤1.化合物(80)-2的制备
将包含两种双键异构体的((80)-1)(250mg)、(6-(甲氧基羰基)吡啶-3-基)硼酸(157.2mg)、Pd(PPh 3) 4(83mg)、Na 2CO 3(153mg)和LiCl(61mg)依次加入到圆底烧瓶中，加入四氢呋喃(5mL)和水(1mL)，氮气保护下，80℃反应2h，反应完毕。加入水，乙酸乙酯萃取有机相，有机相经过干燥、过滤、浓缩，经硅胶柱[洗脱剂：石油醚-乙酸乙酯＝1:1]纯化，收集洗脱液，浓缩，得淡黄色油状物(100mg,收率:41％)。MS-ESI m/z:333.40[M+H] +。
步骤2～4.化合物(80)和化合物(81)的制备
由含两种双键异构体的原料((80)-2)，经与化合物(14)合成路线类似的方法制备得到化合物(80)和化合物(81)。
化合物(80):MS-ESI m/z:472.4[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.28(s,1H),8.71(s,1H),8.66(d,J＝9.5Hz,1H),8.60(s,1H),7.97(s,2H),7.74(s,1H),6.21(s,1H),3.83(d,J＝14.3Hz,1H),3.72(d,J＝14.2Hz,1H),3.61(s,2H),3.14(s,2H),2.99(s,1H),2.81(d,J＝4.9Hz,3H),2.78(d,J＝3.4Hz,3H),0.99(d,J＝6.9Hz,3H).
化合物(81):MS-ESI m/z:472.4[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.23(s,1H),8.73(s,1H),8.59(s,1H),8.46(s,2H),7.98(s,1H),7.77(d,J＝49.1Hz,1H),3.77(s,2H),3.61(m,2H),3.14(m,J＝4.6Hz,2H),3.01(m,2H),2.81(d,J＝4.4Hz,3H),2.78(m,3H),1.23–1.16(s,3H).
实施例82：N-甲基-1'-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)-1',2',3',6'-四氢-[2,4'-联吡啶]-5-甲酰胺(化合物(82))的制备
Figure PCTCN2022135894-appb-000094
步骤1～3：化合物(82)的制备
由1'-(叔丁基)5-甲基3',6'-二氢-[2,4'-联吡啶]-1',5(2'H)-二羧酸酯((82)-1)为原料，经与化合物(14)合成路线类似的方法制备得到化合物(82)。MS-ESI m/z:458.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ12.22(s,1H),8.93(d,J＝2.3Hz,1H),8.66–8.51(m,2H),8.13(dd,J＝8.4,2.3Hz,1H),7.71(d,J＝1.9Hz,1H),7.63(d,J＝8.4Hz,1H),6.82(s,1H),3.79(s,2H),3.37(s,2H),3.21(s,2H),2.80–2.75(m,3H),2.51(s,3H),2.73–2.61(m,2H).
实施例83：5-甲基-2-(4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-5,6-二氢-4H-吡咯并[3,4-d]噻唑-4-酮(化合物(83))的制备
Figure PCTCN2022135894-appb-000095
步骤1～7：化合物(83)的制备
由2-溴-5-甲基噻唑-4-羧酸甲酯((83)-1)为原料，经与化合物(17)合成路线步骤1-7类似的方法制备得到化合物(83)。MS-ESI m/z:479.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.26(s,1H),8.58(s,1H),7.69(s,1H),4.38(s,2H),3.72(s,2H),3.49–3.44(m,4H),2.99(s,3H),2.77(q,J＝3.5Hz,3H),2.56(t,J＝5.1Hz,4H).
实施例84：4-甲基-7-((4-(2-甲基-3-氧代-2,3-二氢-1H-吡咯并[3,4-c]吡啶-6-基)哌嗪-1-基)甲基)-3-(三氟甲基)-1,5-萘啶-2(1H)-酮(化合物(84))的制备
Figure PCTCN2022135894-appb-000096
步骤1.化合物(84)的制备
由6-溴-2-甲基-1,2-二氢-3H-吡咯并[3,4-c]吡啶-3-酮((84)-1)为原料，经与化合物(15)合成路线步骤3类似的方法制备得到化合物(84)。MS-ESI m/z:473.4[M+H] +. 1H NMR(400MHz,Chloroform-d)δ11.5(s,1H)8.66(d,J＝14.4Hz,1H),7.72(s,1H),6.99(d,J＝8.3Hz,1H),6.63(s,1H),4.31(s,2H),3.73(d,J＝11.5Hz,4H),3.12(d,J＝26.9Hz,2H),2.86(d,J＝50.8Hz,2H),2.64(s,2H),2.33(d,J＝40.0Hz,3H),2.06(s,3H).
实施例85：5-(4-((7-氰基-8-甲基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(化合物(85))的制备
Figure PCTCN2022135894-appb-000097
步骤1.化合物(85)-2的制备
将((85)-1)(50mg)和2-氰基乙酰氯(53mg)溶于THF(2mL)，0℃反应5min，加入DIPEA(66mg)，恢复室温，反应2h。反应完毕，加水淬灭，乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干 燥，过滤，浓缩，经柱层析分离[洗脱剂：石油醚-乙酸乙酯＝9:1]纯化，收集洗脱液，减压蒸除溶剂，得白色固体((85)-2)(40mg,收率:64％)。MS-ESI m/z:244.1[M+H] +。
步骤2～4.化合物(85)的制备
由6-乙酰基-5-氨基烟酸甲酯((85)-2)为原料，经与化合物(1)合成路线步骤6-8类似的方法制备得到化合物(85)。MS-ESI m/z:418.2[M+H] +。 1H NMR(400MHz,Chloroform-d)δ12.58(s,1H),8.71(d,J＝1.8Hz,1H),8.15(d,J＝2.8Hz,1H),8.05(d,J＝8.7Hz,1H),7.90(d,J＝1.8Hz,1H),7.79(d,J＝5.3Hz,1H),7.21(dd,J＝8.8,2.9Hz,1H),3.79(s,2H),3.35(t,J＝5.1Hz,4H),3.01(d,J＝5.1Hz,3H),2.93(s,3H),2.69(t,J＝5.0Hz,4H).
实施例86：(S)-5-(2-氰基-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(化合物(86))的制备
Figure PCTCN2022135894-appb-000098
步骤1～4.化合物(86)的制备
由(S)-3-氰基哌嗪-1-羧酸叔丁酯((86)-1)为原料，经与化合物(21)合成路线类似的方法制备得到化合物(86)。MS-ESI m/z:486.1[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ12.35(s,1H),8.63(d,J＝1.9Hz,1H),8.56(q,J＝4.8Hz,1H),8.43(d,J＝2.8Hz,1H),7.95(d,J＝8.8Hz,1H),7.72(d,J＝1.9Hz,1H),7.60(dd,J＝8.9,2.9Hz,1H),5.42(s,1H),3.85–3.70(m,3H),3.16(d,J＝11.9Hz,1H),3.01(d,J＝11.0Hz,3H),2.82–2.76(m,5H),2.56(dd,J＝12.1,3.3Hz,1H),2.40–2.32(m,1H).
实施例87：(R)-N-甲基-5-(3-甲基-4-((4-甲基-2-氧代-3-(三氟甲基)-1,2-二氢-1,6-萘啶-7-基)甲基)哌嗪-1-基)吡啶酰胺((化合物(87))的制备
Figure PCTCN2022135894-appb-000099
步骤1.化合物(87)的制备
由((2)-7)和(51)-4为原料，经与化合物(2)合成路线步骤7类似的方法制备得到化合物(87)。MS-ESI m/z:475.4[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.25(s,1H),9.12(s,1H),8.39(d,J＝4.9Hz,1H),8.28(d,J＝2.8Hz,1H),7.83(d,J＝8.8Hz,1H),7.44–7.36(m,2H),4.09(d,J＝15.3Hz,1H),3.73(d,J＝10.4Hz,1H),3.66(d,J＝12.4Hz,1H),3.58(d,J＝15.3Hz,1H),3.02(t,J＝9.6Hz,1H),2.86–2.84(m,2H),2.82–2.75(m,4H),2.74–2.70(m,3H),2.70–2.65(m,1H),1.16(d,J＝6.1Hz,3H).
实施例88：(R)-N-甲基-5-(2-甲基-4-((4-甲基-2-氧代-3-(三氟甲基)-1,2-二氢-1,6-萘啶-7-基)甲基)哌嗪-1-基)吡啶酰胺((化合物(88))的制备
Figure PCTCN2022135894-appb-000100
步骤1.化合物(88)的制备
由((2)-7)和(54)-4为原料，经与化合物(2)合成路线步骤7类似的方法制备得到化合物(88)。MS-ESI m/z:475.4[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.87–11.74(m,1H),9.12(s,1H),8.38(d,J＝4.9Hz,1H),8.23(d,J＝2.7Hz,1H),7.84(d,J＝8.8Hz,1H),7.46(s,1H),7.36(dd,J＝8.9,2.7Hz,1H),4.25(s,1H),3.79(d,J＝15.4Hz,1H),3.64(dd,J＝13.6,8.0Hz,2H),3.15–3.07(m,1H),2.99(d,J＝11.2Hz,1H),2.79(d,J＝4.8Hz,4H),2.72(d,J＝2.6Hz,3H),2.42(dd,J＝11.2,3.3Hz,1H),2.37–2.26(m,1H),1.20(d,J＝6.5Hz,3H).
实施例89：N-甲基-1'-((4-甲基-2-氧代-3-(三氟甲基)-1,2-二氢-1,6-萘啶-7-基)甲基)-1',2',3',6'-四氢- [3,4'-联吡啶]-6-甲酰胺((化合物(89))的制备
Figure PCTCN2022135894-appb-000101
步骤1.化合物(89)的制备
由((2)-7)和(14)-3为原料，经与化合物(2)合成路线步骤7类似的方法制备得到化合物(89)。MS-ESI m/z:458.4[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.30(s,1H),9.13(s,1H),8.77–8.68(m,1H),8.06–7.95(m,2H),7.40(s,1H),6.47(s,1H),6.04(d,J＝6.3Hz,1H),3.82(s,2H),3.57(s,1H),3.25(d,J＝2.8Hz,2H),2.82(d,J＝4.9Hz,3H),2.77–2.74(m,1H),2.74–2.70(m,3H),2.65–2.60(m,2H).
实施例92：(S)-5-(3-氰基-4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺((化合物(92))的制备
Figure PCTCN2022135894-appb-000102
步骤1～4.化合物(92)的制备
由(S)-2-氰基哌嗪-1-羧酸叔丁酯((92)-1)为原料，经与化合物(21)合成路线类似的方法制备得到化合物(92)。MS-ESI m/z:486.1[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ12.30(s,1H),8.62(d,J＝1.9Hz,1H),8.48(d,J＝4.9Hz,1H),8.33(d,J＝2.9Hz,1H),7.87(d,J＝8.7Hz,1H),7.71(d,J＝1.9Hz,1H),7.48(dd,J＝8.8,2.9Hz,1H),4.33(s,1H),4.23–4.11(m,2H),3.95–3.80(m,3H),3.19–3.08(m,2H),2.94–2.81(m,3H),2.81–2.74(m,4H).
实施例93：6-氟-N-甲基-5-(4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰胺((化合物(93))的制备
Figure PCTCN2022135894-appb-000103
步骤1～3.化合物(93)的制备
由4-(2-氟-6-(甲氧羰基)吡啶-3-基)哌嗪-1-甲酸叔丁酯((93)-1)为原料，经与化合物(21)合成路线步骤2-4类似的方法制备得到化合物(93)。MS-ESI m/z:479.5[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.18(s,1H),8.58(s,1H),8.42(d,J＝4.9Hz,1H),7.85(d,J＝7.7Hz,1H),7.69(s,1H),7.64–7.52(m,1H),3.73–7.68(m,3H),3.19(s,4H),2.77(t,J＝4.0Hz,6H),2.60(s,3H).
实施例94：5-(4-((4-氟-3-甲基-2-氧代-1,2-二氢喹啉-7-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺((化合物(94))的制备
Figure PCTCN2022135894-appb-000104
步骤1.化合物((94)-2)的制备
在三口瓶中，加入正丙酸乙酯(3.82g)和超干四氢呋喃(150mL)，在氮气保护下降温至-78℃，向反应体系中滴加二异丙基氨基锂(2M,28.12mL)，随后缓慢滴加((94)-1)(2.24g)的四氢呋喃溶液(40mL)，缓慢升至室温反应过夜。用饱和氯化铵水溶液淬灭反应，过滤，乙酸乙酯萃取，减压蒸除溶剂，得粗品，经柱层析[洗脱剂：石油醚-乙酸乙酯(20:1-10:1)]纯化，得黄色固体((94)-2)(540mg,收率:22.5％)。MS-ESI m/z:256.2[M+H] +.
步骤2.化合物((94)-3)的制备
在高压釜中，依次加入((94)-2)(520mg)、Pd(dppf)Cl 2(149mg)、三乙胺(618mg)、N,N-二甲基甲酰胺(10mL)和甲醇(5mL)，在一氧化碳(2MPa)氛围下，加热到100℃搅拌过夜。反应完毕后，减压蒸除溶剂，得粗品，硅胶柱[洗脱剂：石油醚-乙酸乙酯(10:1-3:1)]纯化，收集洗脱液，减压蒸除溶剂，得黄色固体((94)-3)(270mg,收率:56.4％)。MS-ESI m/z:236.3[M+H] +.
步骤3.化合物((94)-4)的制备
在反应瓶中，加入((94)-3)(270mg)和四氢呋喃(6mL)，冰浴下滴加LiBH 4的四氢呋喃溶液(1.73mL，2M in THF)，室温下搅拌1小时。反应完毕后，将反应液倒入饱和氯化铵溶液中，二氯甲烷萃取，减压蒸除溶剂，得粗品，硅胶柱[洗脱剂：二氯甲烷-甲醇(100:1-10:1)]纯化，收集洗脱液，减压蒸除溶剂，得黄色固体((94)-4)(150mg,收率:63.1％)MS-ESI m/z:208.4[M+H] +.
步骤4.化合物((94)-5)的制备
在反应瓶中，加入((94)-4)(150mg)和氯化亚砜(5mL)，加热至70℃搅拌1小时。反应完毕，减压蒸除溶剂，得淡黄色固体((94)-5)(165mg,收率:100％)。MS-ESI m/z:226.3[M+H] +.
步骤5.化合物(94)的制备
在反应瓶中，加入((94)-5)(165mg)、(1)-R(240mg)、碳酸钾(250mg)和乙腈(10mL)，加热至80℃搅拌过夜。反应完毕后，减压蒸除溶剂，得粗品，经硅胶柱[洗脱剂：二氯甲烷-甲醇(100:1-10:1)]和制备HPLC纯化，得白色固体(94)(60mg,收率:20.3％)。MS-ESI m/z:410.3[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ:11.91(s,1H),8.42-8.37(m,1H),8.27(d,J＝2.8Hz,1H),7.84(d,J＝8.8Hz,1H),7.69(d,J＝8.4Hz,1H),7.41-7.36(m,2H),7.26(dd,J＝9.6,6.8Hz,1H),3.62(s,2H),3.38-3.33(m,4H),2.78(d,J＝4.8Hz,3H),2.56-2.53(m,4H),2.02(d,J＝2.4Hz,3H).
实施例95：N-(甲基-d 3)-5-(4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰胺((化合物(95))的制备
Figure PCTCN2022135894-appb-000105
步骤1.化合物(95)的制备
由N-(甲基-d 3)-5-(哌嗪-1-基)吡啶酰胺((95)-1)为原料，经与化合物(1)合成路线步骤8类似的方法制备得到化合物(95)。MS-ESI m/z:464.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ12.23(s,1H),8.58(d,J＝2.0Hz,1H),8.36(s,1H),8.27(d,J＝2.8Hz,1H),7.83(d,J＝8.8Hz,1H),7.69(d,J＝2.0Hz,1H),7.39(dd,J＝8.8,2.9Hz,1H),3.72(s,2H),3.38–3.26(m,6H),2.83–2.72(m,2H),2.57–2.52(m,3H).
实施例96：N-(2-羟乙基)-5-(4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰胺((化合物(96))的制备
Figure PCTCN2022135894-appb-000106
步骤1.化合物(96)-2的制备
将((96)-1)(100mg)溶于DMF(2mL)，随后加入乙醇胺(38mg)、HATU(237mg)、二异丙基乙基胺(201mg)，室温反应2h。反应完毕，加入二氯甲烷和水分液，水相用二氯甲烷萃取三次，有机相用无水硫酸钠干燥，过滤，浓缩，经制备色谱板[洗脱剂：石油醚-乙酸乙酯＝1:2]纯化，得白色固体((96)-2)(100mg，收率：88％)。MS-ESI m/z:351.2[M+H] +.
步骤2～3.化合物(96)的制备
由5-(4-(叔丁氧羰基)哌嗪-1-基)吡啶甲酸((96)-2)为原料，经与化合物(21)合成路线步骤3-4类似的方法制备得到化合物(96)。MS-ESI m/z:491.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ12.23(s,1H),8.58(d,J＝1.6Hz,1H),8.34(t,J＝6.0Hz,1H),8.29(d,J＝2.8Hz,1H),7.84(d,J＝8.8Hz,1H),7.69(d,J＝1.6Hz,1H),7.40(dd,J＝8.8,2.8Hz,1H),4.78(t,J＝5.2Hz,1H),3.72(s,2H),3.56–3.45(m,2H),3.39–3.26(m,6H),2.85–2.74(m,3H),2.58–2.55(m,3H).
实施例97：5-(4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(2,2,2-三氟乙基)吡啶酰胺((化合物(97))的制备
Figure PCTCN2022135894-appb-000107
步骤1.化合物(97)-1的制备
将((96)-1)(400mg)溶于二氯甲烷(4mL)中，冰浴下滴加DMF(20mg)和草酰氯(330mg)，室温下反应20min，浓缩，得到粗品((97)-1)，将其直接用于下一步反应。
步骤2.化合物(97)-2的制备
将粗品((97)-1)(200mg)溶于乙腈(4ml)，加DIPEA(238mg)，冰水浴下缓慢滴加三氟乙基胺(121.6mg)，室温下搅拌20min。加水淬灭，二氯甲烷萃取三次，有机相合并，无水硫酸钠干燥，过滤浓缩，经硅胶柱[洗脱剂：二氯甲烷-甲醇＝15:1)]纯化，得白色固体((97)-2)(30mg)。MS-ESI m/z:389.2[M+H]+.
步骤3～4.化合物(97)的制备
由(97)-2为原料，经与化合物(96)合成路线步骤2-3类似的方法制备得到化合物(97)。MS-ESI m/z:529.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ12.24(s,1H),8.92(t,J＝6.8Hz,1H),8.58(d,J＝1.6Hz,1H),8.33(d,J＝3.2Hz,1H),7.88(d,J＝8.8Hz,1H),7.72–7.67(m,1H),7.43(dd,J＝8.8,3.2Hz,1H),4.16–3.96(m,2H),3.73(s,2H),3.44–3.36(m,3H),3.31(s,1H),2.83–2.74(m,4H),2.63–2.55(m,3H).
实施例98：N-乙基-5-(4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰 胺((化合物(98))的制备
Figure PCTCN2022135894-appb-000108
步骤1～3.化合物(98)的制备
由((97)-1)和EtNH 2为原料，经与化合物(97)合成路线步骤2-4类似的方法制备得到化合物(98)。MS-ESI m/z:475.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ12.23(s,1H),8.58(d,J＝1.8Hz,1H),8.42(t,J＝6.0Hz,1H),8.27(d,J＝2.8Hz,1H),7.83(d,J＝8.7Hz,1H),7.70(s,1H),7.40(dd,J＝9.0,2.8Hz,1H),3.72(s,2H),3.31–3.2(m,8H),2.87–2.73(m,2H),2.60–2.55(m,3H),1.25–1.08(m,3H).
实施例99：N-环丙基-5-(4-((8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶酰胺((化合物(99))的制备
Figure PCTCN2022135894-appb-000109
步骤1～3.化合物(99)的制备
由((97)-1)为原料，经与化合物(97)合成路线步骤2-4类似的方法制备得到化合物(99)。MS-ESI m/z:487.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ12.23(s,1H),8.58(d,J＝1.8Hz,1H),8.42(t,J＝6.0Hz,1H),8.27(d,J＝2.8Hz,1H),7.83(d,J＝8.7Hz,1H),7.70(s,1H),7.40(dd,J＝9.0,2.8Hz,1H),3.72(s,1H),3.31–3.2(m,9H),2.87–2.73(m,1H),2.60–2.55(m,3H),1.25–1.08(m,4H).
实施例100：5-(4-((7-(二氟甲基)-8-甲基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺((化合物(100))的制备
Figure PCTCN2022135894-appb-000110
步骤1.化合物((100)-1)的制备
将((29)-3)(1g)溶于二氯甲烷(40mL)，0℃加入(2-氯-2-氧代乙基)膦酸二乙酯(3.3g)，再缓慢滴加三乙胺(2.61g)，恢复室温。反应完毕后，将反应加水淬灭，二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，抽滤，浓缩，经硅胶柱[洗脱剂：EA/PE＝(10％-40％)]纯化，收集洗脱液，减压蒸除溶剂，得深黄色液体((100)-1)(860mg,收率44.8％)。MS-ESI m/z:373.2[M+H] +.
步骤2.化合物((100)-2)的制备
将((100)-1)(410mg)和碳酸钾(760.9mg)溶于N,N-二甲基乙酰胺(15mL)，80℃反应1小时，反应完毕，浓缩，经硅胶柱[洗脱剂：DCM/MeOH＝20:1]纯化，收集洗脱液，减压蒸除溶剂，得白色固体((100)-2)(150mg,收率:62.5％)。MS-ESI m/z:219.2[M+H] +.
步骤3.化合物((100)-3)的制备
将((100)-2)(50mg)、三氟代甲烷亚磺酸钠(63.3mg)和Mn(OAc) 3·2H 2O(184.3mg)溶于乙酸(2mL)，50℃反应15分钟。反应完毕后，将反应液浓缩，加水稀释，乙酸乙酯萃取两次，有机相浓缩，经硅 胶板分离纯化[展开剂：PE/EA＝1:1]，得棕色固体((100)-3)(16mg,收率26.2％)。MS-ESI m/z:269.2[M+H] +.
步骤4～6.化合物(100)的制备
由((100)-3)为原料，经与化合物(1)合成路线步骤6-8类似的方法制备得到化合物(100)。MS-ESI m/z:443.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ12.10(s,1H),8.55(s,1H),8.42–8.37(m,1H),8.27(d,J＝2.9Hz,1H),7.83(d,J＝8.7Hz,1H),7.69(s,1H),7.47–7.33(m,1H),3.75-3.65(m,3H),2.81-2.75(m,4H),2.72-2.65(m,4H),2.61–2.54(m,3H),2.49–2.45(m,3H)。
实施例101：5-(4-((4-氟-8-甲基-6-氧代-7-(三氟甲基)-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺((化合物(101))的制备
Figure PCTCN2022135894-appb-000111
步骤1.化合物((101)-2)的制备
将((101)-1)(200mg)悬浮于二氯甲烷(6mL)，在冰浴条件下加入三氟化硼乙醚(990mg)和二氟化氙(233.6mg)，室温反应过夜，反应完毕，加入饱和碳酸氢钠溶液，调节pH～7，二氯甲烷萃取后收集有机相，经干燥、浓缩后，经硅胶柱[洗脱剂：DCM/MeOH＝20:1]纯化，收集洗脱液，减压蒸除溶剂，得到淡黄色固体((101)-2)(90mg,收率：42％)。MS-ESI m/z:305.2[M+H] +
步骤2～4.化合物(101)的制备
由((100)-2)为原料，经与化合物(1)合成路线步骤6-8类似的方法制备得到化合物(101)。MS-ESI m/z:479.4[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.60–12.04(m,1H),8.41(d,J＝4.9Hz,1H),8.29(d,J＝2.8Hz,1H),7.98(d,J＝8.4Hz,1H),7.84(d,J＝8.8Hz,1H),7.41(dd,J＝8.9,2.9Hz,1H),3.71(s,2H),3.37(s,4H),2.78(d,J＝4.9Hz,3H),2.69–2.60(m,7H).
实施例102：5-(4-((4-氟-2-氧代-3-(三氟甲基)-1,2-二氢喹啉-7-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺((化合物(102))的制备
Figure PCTCN2022135894-appb-000112
步骤1.化合物((102)-2)的制备
在三口瓶中，加入乙酸乙酯(3.52g)和超干四氢呋喃(150mL)，在氮气保护下降温至-78℃，向反应体系中滴加二异丙基氨基锂(2M,30.0mL)，随后缓慢滴加((102)-1)(2.39g)的四氢呋喃溶液(40mL)，缓慢升至室温，反应过夜。用饱和氯化铵水溶液淬灭反应，过滤，乙酸乙酯萃取，减压蒸除溶剂，得粗品，经柱层析[洗脱剂：石油醚-乙酸乙酯＝20:1]纯化，得黄色固体((102)-2)(570mg,收率:23.7％)。MS-ESI m/z:242.2[M+H] +.
步骤2.化合物((102)-3)的制备
在反应瓶中，加入((102)-2)(492mg)、三氟甲基亚磺酸钠(955mg)和醋酸(10mL)，随后缓慢加入Mn(OAc) 3·2H 2O(2.19g)，室温下搅拌过夜。减压蒸除溶剂，乙酸乙酯萃取，合并有机相，干燥后，得粗品，硅胶柱[洗脱剂：石油醚-乙酸乙酯＝20:1]收集洗脱液，减压蒸除溶剂，得白色固体((102)-3)(140mg,收率:22.2％)MS-ESI m/z:310.0[M+H] +.
步骤3.化合物((102)-4)的制备
在反应瓶中，依次加入((102)-3)(119mg，0.39mmol)、双三苯基磷二氯化钯(27mg)、叔丁基二甲基[(三丁基锡基)甲氧基]硅烷(335mg)和1,4-二氧六环(5mL)，在氮气保护下，加热到100℃搅拌过夜。反应完毕后，恢复至室温，缓慢滴加10％的KF水溶液淬灭，固体析出，过滤，滤液用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，得粗品，经硅胶柱[洗脱剂：石油醚-乙酸乙酯＝30:1]纯化，收集洗脱液，减压蒸除溶剂，得黄色固体((102)-4)(90mg,收率:62.5％)MS-ESI m/z:376.1[M+H] +.
步骤4.化合物((102)-5)的制备
在反应瓶中，加入((102)-4)(90mg)、四氢呋喃(3mL)和盐酸水溶液(2M,1mL)，室温下搅拌1小时。反应完毕，加入饱和碳酸氢钠溶液，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，减压蒸除溶剂，得粗品，硅胶柱[洗脱剂：二氯甲烷-甲醇＝100:1]纯化，收集洗脱液，减压蒸除溶剂，得淡黄色固体((102)-5)(51mg,收率:81.5％)。MS-ESI m/z:262.1[M+H] +.
步骤5～6.化合物(102)的制备
由((102)-5)为原料，经与化合物(1)合成路线步骤7-8类似的方法制备得到化合物(102)。MS-ESI m/z:464.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ:12.75(s,1H),8.50-8.45(m,1H),8.34(d,J＝3.2Hz,1H),8.03(d,J＝8.4Hz,1H),7.90(d,J＝8.8Hz,1H),7.70(d,J＝8.4Hz,1H),7.55(s,1H),7.50(dd,J＝11.6,6.0Hz,1H),4.53(s,1H),4.13-4.02(m,2H),3.43-3.31(m,4H),3.25-3.16(m,3H),2.80(d,J＝5.2Hz,3H).
实施例103：5-(4-((8-氟-7-甲基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺((化合物(103))的制备
Figure PCTCN2022135894-appb-000113
步骤1～5.化合物(103)的制备
由5-氯-2-(三氟甲基)吡啶-3-胺((103)-1)为原料，经与化合物(102)合成路线步骤1和步骤3-6类似的方法制备得到化合物(103)。MS-ESI m/z:411.4[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ:12.02(s,1H),8.48(d,J＝1.6Hz,1H),8.41(d,J＝4.8Hz,1H),8.27(d,J＝2.8Hz,1H),7.84(d,J＝8.8Hz,1H),7.70(s,1H),7.41(dd,J＝12.0,6.4Hz,1H),3.69(s,2H),3.44-3.34(m,4H),2.79(d,J＝4.8Hz,3H),2.58-2.56(m,4H),2.07(d,J＝2.8,3H).
实施例104：(R)-5-(4-((7-(二氟甲基)-8-甲基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-3-甲基哌嗪-1-基)-N-甲基吡啶酰胺((化合物(104))的制备
Figure PCTCN2022135894-appb-000114
步骤1.化合物(104)的制备
由((100)-5)为原料，经与化合物(1)合成路线类似的方法制备得到化合物(104)。MS-ESI m/z:457.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.08(s,1H),8.56(d,J＝1.9Hz,1H),8.36(d,J＝5.0Hz,1H),8.26(d,J＝2.8Hz,1H),7.82(d,J＝8.7Hz,1H),7.70(d,J＝1.9Hz,1H),7.43–7.34(m,1H),4.13(d,J＝14.5Hz,1H),3.70(d,J＝12.0Hz,1H),3.59(d,J＝12.3Hz,1H),3.43(d,J＝14.5Hz,2H),3.06–2.87(m,2H),2.78(d,J＝4.9Hz,3H),2.71(s,3H),2.69–2.56(m,3H),1.17(d,J＝6.1Hz,3H).
实施例105：(R)-5-(4-((7-(二氟甲基)-8-甲基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶酰胺((化合物(105))的制备
Figure PCTCN2022135894-appb-000115
步骤1.化合物(105)的制备
由((100)-5)为原料，经与化合物(1)合成路线步骤8类似的方法制备得到化合物(105)。MS-ESI m/z:457.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.19(s,1H),8.56(d,J＝1.8Hz,1H),8.37–8.35(m,1H),8.20(d,J＝2.8Hz,1H),7.82(d,J＝8.8Hz,1H),7.73(d,J＝1.9Hz,1H),7.33(dd,J＝8.9,2.9Hz,1H),4.22(d,J＝7.6Hz,1H),3.75(d,J＝14.4Hz,1H),3.66–3.54(m,2H),3.20–3.04(m,2H),2.94(d,J＝10.7Hz,1H),2.78(d,J＝4.8Hz,3H),2.72(d,J＝2.5Hz,3H),2.40–2.35(m,2H),2.30–2.20(m,1H),1.14(d,J＝6.5Hz,3H).
实施例106：1'-((7-(二氟甲基)-8-甲基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-N-甲基-1',2',3',6'-四氢-[3,4'-联吡啶]-6-甲酰胺((化合物(106))的制备
Figure PCTCN2022135894-appb-000116
步骤1.化合物(106)的制备
由((100)-5)为原料，经与化合物(1)合成路线步骤8类似的方法制备得到化合物(106)。MS-ESI m/z:440.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ12.13(s,1H),8.70–8.67(m,2H),8.56(d,J＝1.9Hz,1H),7.98(dd,J＝3.4,1.5Hz,2H),7.70(d,J＝1.9Hz,1H),7.23(m,1H),6.42(s,1H),3.77(s,2H),3.32-3.29(m,2H),3.17(dd,J＝5.8,3.0Hz,2H),2.81(d,J＝4.9Hz,3H),2.71(s,3H),2.58-2.54(m,2H).
实施例107：(R)-5-(4-((7,8-二甲基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-3-甲基哌嗪-1-基)-N-甲基吡啶酰胺(化合物(107))的制备
Figure PCTCN2022135894-appb-000117
步骤1：化合物(107)的制备
以(29)-7和(51)-4为原料，经与化合物(29)合成路线步骤8类似的方法制备得到化合物(107)。MS-ESI m/z:421.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ11.70(s,1H),8.44(d,J＝2.0Hz,1H),8.38(q,J＝4.8Hz,1H),8.26(d,J＝2.8Hz,1H),7.82(d,J＝8.8Hz,1H),7.62(d,J＝2.0Hz,1H),7.39(dd,J＝8.8,2.8Hz,1H),4.10(d,J＝14.4Hz,1H),3.70(d,J＝12.0Hz,1H),3.59(d,J＝12.0Hz,1H),3.41–3.38(m,2H),3.02–2.91(m,1H),2.84–2.69(m,4H),2.64–2.55(m,1H),2.52–2.51(m,3H),2.34–2.24(m,1H),2.13(s,3H),1.19(d,J＝6.0Hz,3H).
实施例108：(S)-5-(4-((7,8-二甲基-6-氧代-5,6-二氢-1,5-萘啶-3-基)甲基)-3-甲基哌嗪-1-基)-N-甲基吡啶酰胺(化合物(108))的制备
Figure PCTCN2022135894-appb-000118
步骤1：化合物(108)的制备
以(29)-7和(52)-4为原料，经与化合物(29)合成路线步骤8类似的方法制备得到化合物(108)。MS-ESI m/z:421.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ11.70(s,1H),8.44(d,J＝2.0Hz,1H),8.38(q,J＝4.8Hz,1H),8.26(d,J＝2.8Hz,1H),7.82(d,J＝8.8Hz,1H),7.62(d,J＝2.0Hz,1H),7.39(dd,J＝8.8,2.8Hz,1H),4.10(d,J＝14.4Hz,1H),3.70(d,J＝12.0Hz,1H),3.59(d,J＝12.0Hz,1H),3.41–3.38(m,2H),3.02–2.91(m,1H),2.84–2.69(m,4H),2.64–2.55(m,1H),2.52–2.51(m,3H),2.34–2.24(m,1H),2.13(s,3H),1.19(d,J＝6.0Hz,3H).
生物学测试
实验例一：PARP酶活性实验及Trapping实验
1.PARP酶活性测试
实验材料：PARP1试剂盒购自美国BPS Bioscience公司的384孔化学发光分析试剂盒(货号：#80551)。
实验原理：PARP能够催化ADP核糖残基从NAD+转移到目标底物上，对蛋白质进行核糖化修饰。本实验通过检测PARP1对组蛋白的聚腺苷二磷酸核糖基化，测定PARP1酶活性。
试剂及待测化合物的准备：用蒸馏水将试剂盒中包含的10x检测缓冲液稀释成1x。取待测化合物(储存浓度为10mM)用DMSO溶液将其稀释成10μM，并按1:3进行梯度稀释，然后将梯度稀释后的化合物用1x检测缓冲液稀释10倍。
实验方法：按照试剂盒的说明书操作：
1.用PBS将5x组蛋白混合液稀释成1x溶液，在384孔板中每孔加入25μL，4℃孵育过夜。
2.孵育结束后，每孔加入100μL PBST(0.05％吐温20)进行洗涤，重复洗涤三次。然后每孔加入100μL封闭液，室温孵育90分钟。
3.孵育结束后，PBST重复洗涤三次，然后向每孔加入1.25μL 10x检测缓冲液，1.25μL 10x PARP测试混合液、2.5μL活化DNA(5x)和7.5μL蒸馏水。
4.然后再向每孔加入2.5μL稀释后待测化合物，阳性对照组和阴性对照组加入含相同浓度DMSO的1x检测缓冲液。
5.然后再向待测化合物及阳性对照组分别加入10μL 2.5ng/μL的PARP1酶，阴性对照组加入10μL的1x检测缓冲液，室温孵育60分钟。
6.用封闭液按照1:50稀释链霉亲和素-HRP，待孵育结束后用PBST清洗板子三遍，然后每孔加入25μL稀释好的链霉亲和素-HRP溶液，室温孵育30分钟。
7.孵育结束后用PBST清洗板子三遍，加入50μL等体积混合的底物A和底物B，立即在Synergy HTX多功能酶标仪上读取发光信号值。
8.数据分析采用GraphPad Prism 8.0软件，抑制率％＝100*(阳性对照组平均发光信号值-化合物发光信号值)/(阳性对照组平均发光信号值-阴性对照组平均发光信号值)，以化合物浓度的对数值对百分抑制率作图拟合得出IC 50值。
实验结果：化合物对PARP1的酶抑制作用见表1。
表1：化合物对PARP1的酶抑制活性
受试化合物 PARP-1IC50(nM)
1 2.78
2 3.14
3 1.53
5 27.18
6 34.32
8 2.55
10 2.79
11 0.96
12 2.25
13 7.37
14 0.83
15 3.48
18 15.91
19 5.48
20 1.26
2.PARP1/PARP2Trapping实验
实验材料和试剂：
试剂 供应商 货号
PARP1 BPS Bioscience 80501
PARP2 BPS Bioscience 80502
NAD Sigma 10127965001
PARP1探针 Generay N/A
PARP2探针 Generay N/A
GST-Tb抗体 Cisbio 61GSTTLA
缓冲液配制：
10mM磷酸钾(pH＝7.9),50mM氯化钠，1mM乙二胺四乙酸，0.05％十二烷基聚乙二醇醚,1mM二硫苏糖醇。
实验方法：
1.用缓冲液配置4x酶反应混合液，包括PARP1、PARP2和GST-Tb抗体，向384孔板中加入4微升酶反应混合液。
2.用缓冲液配置4x的PARP1和PARP2探针反应液，向384孔板中加入4微升该探针反应液。
3.配制一系列梯度稀释的化合物，向384孔板中加入4微升稀释好的化合物，室温下孵育45分钟。
4.孵育结束后，向384孔板中加入4微升4x NAD反应液，室温下孵育10分钟。
5.孵育结束后，放入酶标仪中进行读数。
6.数据分析：百分抑制率计算：抑制率(％)＝(化合物组读数-空白组读数)/(溶媒对照组读数-空白组读数)
实验结果：化合物对PARP1和PARP2Trapping的抑制作用分别见表2-1和表2-2
表2-1：化合物对PARP1Trapping的抑制作用
Figure PCTCN2022135894-appb-000119
表2-2：化合物对PARP2Trapping的抑制作用
Figure PCTCN2022135894-appb-000120
实验结论:本申请中的实施例化合物对PARP1酶活性具有显著的抑制作用；在PARP1和PARP2的trapping实验中，实施例化合物对PARP1功能抑制较对PARP2的抑制具有明显的选择性。
实验例二：细胞增殖实验
实验材料：MDA-MB-436或UWB1.289细胞株购自科佰生物公司(南京，中国)，STR鉴定结果完全匹配，支原体检测呈阴性。MDA-MB-436细胞培养在含有10％胎牛血清、1％青霉素链霉素、1％胰岛素和16μg/mL谷胱甘肽的DMEM完全培养基中；UWB1.289细胞培养在含有10％胎牛血清和1％青霉素链霉素的RMPI1640完全培养基中。
实验方法：
1.MDA-MB-436或UWB1.289在上述培养基中培养(培养条件：37℃，含5.0％二氧化碳的空气)至细胞达到对数生长期后，用含有0.25％EDTA的胰酶消化，1000rpm离心，弃掉上清液，加入细胞培养液，计数后将细胞悬液调整为2x 10 4/毫升。取135μL细胞悬液/孔，在96孔细胞培养板中培养16小时(培养条件：37℃，含5.0％二氧化碳的空气)。
2.将储存浓度为10mM的待测化合物用DMSO稀释2.5倍，并按1:3梯度稀释(9个梯度)。将梯度稀释后样本分别用无血清培养基进一步稀释40倍，取15μL加入96孔细胞培养板中，阳性对照组加入含有相同浓度的DMSO无血清培养基，阴性对照组为不含细胞的培养基，再将细胞继续培养7天。
3.培养结束后，将细胞培养板置于室温30分钟，然后向每孔加入100μL CellCounting-Lite 2.0试剂(Vazyme,#DD1101)，充分混匀后室温避光放置10分钟，放置在Synergy HTX多功能酶标仪上读取发光信号值。
4.数据分析采用GraphPad Prism 8.0软件，抑制率％＝100*(阳性对照组平均发光信号值-化合物发光信号值)/(阳性对照组平均发光信号值-阴性对照组平均发光信号值)，以化合物浓度的对数值对百分抑制率作图拟合得出IC 50值。
实验结果：化合物对UWB1.289卵巢癌细胞的增殖抑制活性见表3。
表3：细胞增殖抑制活性
受试化合物 UWB1.289细胞IC 50(nM)
1 0.66
2 2.76
8 12.62
10 14.98
11 28.50
14 4.93
20 26.58
52 11.17
53 13.62
54 3.34
71 8.13
93 2.67
化合物对MDA-MB-436乳腺癌细胞的增殖抑制活性见表4。
表4：细胞增殖抑制活性
受试化合物 MDA-MB-436细胞IC 50(nM)
1 1.59
2 2.32
14 2.38
24 4.32
52 5.05
54 4.32
72 8.18
73 14.52
79 18.53
80 13.91
81 13.16
82 5.83
85 16.45
86 14.83
87 5.73
88 5.75
89 1.06
90 7.26
91 3.24
93 0.83
94 5.69
95 2.13
96 9.34
97 2.12
98 1.22
99 1.69
100 2.05
101 8.99
103 3.76
104 6.50
105 4.93
106 0.78
实验结论：本申请中的实施例化合物对UWB1.289卵巢癌细胞和MDA-MB-436乳腺癌细胞具有较强的增殖抑制活性。
实验例三：肝微粒体代谢实验测试
实验材料：混合CD1小鼠肝微粒体酶蛋白购自Xenotech公司(#M1000)，NADPH购自Abmole公司(#M9076)。
实验方法：
1.向肝微粒体酶反应体系中加入210μL磷酸盐缓冲液，12.5μL浓度为20mg/mL的肝微粒体酶，再向体系中加入25μL浓度为10mM的NADPH，混匀后37℃水浴震荡10分钟。
2.用DMSO将储存浓度为10mM的待测化合物稀释成100μM，然后向反应体系中加入2.5μL稀释后的待测化合物，混匀后37℃水浴并震荡。
3.分别在0.5、5、10、20、30和60分钟时取25μL酶反应液到125μL含有地塞米松作为内标的冷乙腈中，4000g离心20分钟，取上清与等体积蒸馏水混合。取混合后样本进行液相质谱定量测定。
4.体外药物代谢半衰期和药物清除率的计算：
t 1/2＝-0.693/k。(k：药物剩余百分比的自然对数与孵育时间线性回归的斜率)。
体外药物清除率＝(0.693/t 1/2)*(酶反应体积/肝微粒体酶的含量)。
实验结果：见表5。
[根据细则91更正 04.04.2023]
表5：小鼠肝微粒体酶清除率数据
Figure PCTCN2022135894-appb-000121
*AZD5305(参见Jeffrey W.Johannes等人,J.Med.Chem.,2021,64,14498-14612)为参比化合物，且具有以下结构
Figure PCTCN2022135894-appb-000122
实验结果表明，本申请的实施例化合物具有良好的药物代谢动力学性质。
实验例四：小鼠体内药代动力学实验评价
实验目的：测试本申请实施例化合物在小鼠体内的药代动力学。通过检测小鼠血浆中药物浓度，研究本发明化合物在小鼠体内的药代动力学行为，评价其药动学特征。
受试动物：6～8周雄性ICR(CD1)小鼠
实验方法：
口服灌胃药物配制：首先称取适量受试化合物溶到DMSO(Macklin cas:67-68-5)中，配制成20mg/mL的溶液，取75μL上述溶液加入到150μL Solutol(Sigma cas:70142-34-6)中，再加入1.275mL 20％Captisol(Selleck cas:182410-00-0)，最终得到1mg/mL的药物。
静脉注射药物配制：首先称取适量受试化合物溶到DMSO(Macklin cas:67-68-5)中，配制成30mg/mL的溶液，取15μL上述溶液加入到150μL Solutol(Sigma cas:70142-34-6)中，再加入1.335mL 20％Captisol(Selleck cas:182410-00-0)，最终得到0.3mg/mL的药物。
具体操作：实验前对小鼠进行过夜禁食不禁水，给药后两小时恢复其进食。小鼠静脉注射或口服灌胃给予受试化合物后不同时刻采血，测定血浆中的化合物浓度。每只动物用毛细采样管经眼眶静脉采集约50μL血液，肝素钠抗凝。血液样本采集后置于冰上，3500r/min离心10min分离血浆，取收集的血浆20μL加入到200μL含有200nM地塞米松(Selleck cas:50-02-2)为内标物的乙腈(Merck cas:75-05-8)中，然后8000r/min离心20min。离心后取150μL上清液至新的离心管中，加入150μL 0.1％甲酸(Fisher cas:207868)。混匀后取5μL样本进行液相质谱化合物定量检测(Q-TOF LC/MS)。
标准曲线测定：
1.将受试化合物用DMSO依次进行梯度稀释，浓度涵盖待测定血浆中化合物浓度，且设置空白样本(只含有DMSO)
2.取上述稀释后不同浓度的样本2μL分别加入到18μL正常ICR小鼠血浆中混匀，然后加入200μL含有200nM地塞米松(Selleck cas:50-02-2)为内标物的乙腈(Merck cas:75-05-8)中。离心20min(8000r/min)。取150μL上清液至新的离心管中，加入150μL 0.1％甲酸(Fisher cas:207868)混匀后取5μL样本进行液相质谱化合物定量检测(Q-TOF LC/MS)。
3.最终以受试化合物各稀释后浓度为横坐标，测定所得各化合物与内标物(地塞米松)信号比值为纵坐标，利用软件GraphPad Prism 8使用线性回归的方法(R2>0.9900)做出标准曲线。
数据分析：药代动力学参数的计算：依据上述标准曲线计算出ICR小鼠静脉注射或口服灌胃给予受试化合物后不同时刻血浆中的化合物浓度，采用Phoenix WinNonlin 8.1非房室分析模型计算药代动力学参数(T 1/2、Cmax、AUC等)。
实验结果：见表6。
表6：小鼠灌胃药代动力学数据(PO,10mpk)
受试化合物 AUC 0-∞(ng·hr/mL) Cmax(ng/mL) t 1/2(hr)
AZD5305* 356,592 37,283 8.25
1 972,211 39,635 17.9
11 1,497,448 55,884 18.9
14 2,716,871 127,992 27.8
24 1,100,248 26,344 28.69
52 1,548,502 50,212 25.91
54 987,363 48,164 17.9
79 2,421,942 56,956 30.5
88 1,649,634 38,163 26.32
90 1,362,843 49,892 20.24
93 795,715 31,876 18.37
95 2,048,283 37,508 37.95
*AZD5305(参见Jeffrey W.Johannes等人,J.Med.Chem.,2021,64,14498-14612)为参比化合物，且具有以下结构
Figure PCTCN2022135894-appb-000123
实验结论：本申请实施例化合物在小鼠中的暴露量和半衰期显著优于参比化合物AZD5305。
实验例五：大鼠体内药代动力学评价
实验目的：测试本申请实施例化合物在大鼠体内的药代动力学。通过检测大鼠血浆中药物浓度，研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。
受试动物：6～8周雄性SD大鼠
实验方法：
口服灌胃药物配制：首先称取适量受试化合物溶到DMSO(Macklin cas:67-68-5)中，配制成100mg/mL的溶液，取100μL上述溶液加入到200μL Solutol(Sigma cas:70142-34-6)中，再加入1.7mL 20％Captisol(Selleck cas:182410-00-0)，最终得到5mg/mL的药物。
静脉注射药物配制：首先称取适量受试化合物溶到DMSO(Macklin cas:67-68-5)中，配制成60mg/mL的溶液，取50μL上述溶液加入到100μL Solutol(Sigma cas:70142-34-6)中，再加入850μL 20％Captisol(Selleck cas:182410-00-0)，最终得到3mg/mL的药物。
具体操作：实验前对大鼠进行过夜禁食不禁水，给药后两小时恢复其进食。大鼠静脉注射或口服灌胃给予受试化合物后不同时刻采血，测定血浆中的化合物浓度。每只动物用毛细采样管经眼眶静脉采集约50μL血液，肝素钠抗凝。血液样本采集后置于冰上，3500r/min离心10min分离血浆，取收集的血浆20μL加入到200μL含有200nM地塞米松(Selleck cas:50-02-2)为内标物的乙腈(Merck cas:75-05-8)中，然后8000r/min离心20min。离心后取150μL上清液至新的离心管中，加入150μL 0.1％甲酸(Fisher cas:207868)。混匀后取5μL样本进行液相质谱化合物定量检测(Q-TOF LC/MS)。
标准曲线测定：
1.将受试化合物用DMSO依次进行梯度稀释，浓度涵盖待测定血浆中化合物浓度，且设置空白样本(只含有DMSO)
2.取上述稀释后不同浓度的样本2μL分别加入到18μL正常SD大鼠血浆中混匀，然后加入200μL含有200nM地塞米松(Selleck cas:50-02-2)为内标物的乙腈(Merck cas:75-05-8)中。离心20min(8000r/min)。取150μL上清液至新的离心管中，加入150μL 0.1％甲酸(Fisher cas:207868)混匀后取5μL样本进行液相质谱化合物定量检测(Q-TOF LC/MS)。
3.最终以受试化合物各稀释后浓度为横坐标，测定所得各化合物与内标物(地塞米松)信号比值为纵坐标，利用软件GraphPad Prism 8使用线性回归的方法(R2>0.9900)做出标准曲线。
数据分析，药代动力学参数的计算：依据上述标准曲线计算出SD大鼠静脉注射或口服灌胃给予受试化合物后不同时刻血浆中的化合物浓度，采用Phoenix WinNonlin 8.1非房室分析模型计算药代动力学参数(T1/2、Cmax、AUC等)。
实验结果：见表7。
表7：大鼠灌胃药代动力学数据(PO,1mpk)
Figure PCTCN2022135894-appb-000124
实验结果表明，本申请的实施例化合物具有良好的药物代谢动力学性质。
实验例六：体内药效实验
1.小鼠CDX肿瘤模型
实验目的：评价化合物对人乳腺癌(MDA-MB-436)细胞株小鼠皮下移植瘤模型的药效。
测试化合物：奥拉帕尼(Olaparib),化合物1
实验动物：NOD SCID小鼠，雌性，4-5周，购自南京集萃。
饲养管理：实验动物饲养在SPF级恒温恒湿的清洁房间内，使用独立的通风笼具IVC，每笼饲养不超过5只。温度/湿度：控制在(23±3)℃/40-70％范围。饲料和饮水：SPF级鼠料，钴60照射消毒。饮用水为超滤净化水，并经过高压灭菌处理。动物可以自由摄取无菌食物和饮水。动物编号：耳标标记。
肿瘤细胞株及肿瘤模型：将MDA-MB-436细胞(南京科佰生物科技有限公司，Cat.No:CBP60385)在含有10％胎牛血清、1％青霉素链霉素、1％胰岛素、16μg/mL谷胱甘肽的DMEM完全培养基中进行体外培养增殖(37℃，5％CO 2)。待细胞达到体内药效实验需求后，收集细胞，计数，并制成PBS细胞悬液。按照0.9x10 7个细胞/只动物接种于5～6周NOD SCID鼠右侧肋部皮下。接种后量瘤3次/周，计算肿瘤体积。在肿瘤生长至体积200-300mm 3左右时分组给药。
实验分组：本实验分为溶媒对照组；奥拉帕尼，100mg/kg组；化合物1，0.1mg/kg剂量组；化合物1，0.3mg/kg剂量组；化合物1，1.0mg/kg剂量组；各组均经口灌胃给药，每天1次。给药后每周测量3次肿瘤体积及体重，并观察小鼠运动、饮水及进食情况，待给药28天后根据小鼠肿瘤体积，计算抑瘤率(TGI％)，并通过Excel等软件对抑瘤效果进行统计分析。
TGI＝{1-(给药组结束时肿瘤体积-给药组分组时肿瘤体积)/(对照组结束时肿瘤体积-对照组分组时肿瘤体积)}x100％
实验结果：如表8所示，化合物1对肿瘤生长显示出抑制作用，并呈剂量依赖型。化合物1 0.1mg/kg的抑瘤效果与奥拉帕尼100mg/kg的抑瘤效果相接近。化合物1 0.3mg/kg及1.0mg/kg剂量治疗28天对肿瘤产生完全抑制。各药物治疗组与溶媒对照组之间的体重无显著差异。具体结果见附图1和附图2。
表8：MDA-MB-436乳腺癌小鼠肿瘤模型给药28天后肿瘤生长抑制率
受试化合物 口服给药剂量 肿瘤生长抑制率TGI
奥拉帕尼(Olaparib) 100mg/kg 89％
化合物1 0.1mg/kg 89％
化合物1 0.3mg/kg 113％
化合物1 1.0mg/kg 115％
2.人乳腺癌PDX小鼠模型
实验目的：评价测试化合物在乳腺癌BR-05-0044E皮下异种移植肿瘤NOD SCID小鼠模型上的体内药效。
测试化合物：化合物1
实验动物：NOD SCID小鼠，雌性，6～8周龄，体重18～20克。由北京维通利华实验动物有限公司提供。动物到达后在实验环境饲养3～7天后开始实验。动物在SPF级动物房以IVC(独立送风系统)笼具饲养(每笼4只)。所有笼具、垫料及饮水在使用前均需灭菌。笼具、饲料及饮水每周更换两次。饲养环境及光照情况如下：温度：20～26℃，湿度：40～70％，光照周期：12小时光照，12小时无光照。
PDX模型建立：人源乳腺癌BR-05-0044E模型的建立最初来源于外科手术切除的临床样本。肿 瘤组织在小鼠体内扩增后，将20～30mm 3的BR-05-0044E肿瘤组织块皮下接种于每只小鼠的右后背。等待肿瘤生长，肿瘤平均体积达到约150～200mm 3时开始进行随机分组给药。给药前称重动物，测量瘤体积。根据瘤体积随机分组(随机区组设计)。
实验分组：实验分为1.溶媒对照组，2.化合物1 0.1mg/kg，3.化合物1 0.3mg/kg，4.化合物1 1.0mg/kg；各组均经口灌胃给药，每天1次。例行检查包括观察肿瘤生长和药物治疗对动物日常行为表现的影响(如行为活动、摄食摄水量、体重变化(每周测量两次体重)、外观体征或其它不正常情况)。基于各组动物数量记录组内动物死亡数和副作用。
实验指标：实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用肿瘤体积和肿瘤生长抑制率(TGI)评价。TGI(％)的计算：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))/(溶媒对照组治疗结束时平均瘤体积－溶媒对照组开始治疗时平均瘤体积)]×100％。
实验结果：在BR-05-0044E FP5乳腺癌小鼠PDX模型中，化合物1(0.1、0.3、1.0mg/kg)经口灌胃，每天1次，治疗21天。所有测试剂量都对肿瘤生长产生完全抑制，治疗组小鼠肿瘤完全消失。停药后继续观察2周，治疗组小鼠未见肿瘤生长。各药物治疗组与溶媒对照组之间的体重无显著差异。具体结果见表9，附图3和附图4。
表9：乳腺癌PDX模型给药21天后肿瘤生长抑制率
受试化合物 口服给药剂量 肿瘤生长抑制率TGI
化合物1 0.1mg/kg 105％
化合物1 0.3mg/kg 106％
化合物1 1.0mg/kg 107％
实验例七：化合物对大鼠网织红细胞的影响
实验目的：通过评价化合物对外周血网织红细胞的影响，判断其对骨髓造血功能的作用。
测试化合物：奥拉帕尼(Olaparib),化合物1
实验动物：Sprague Dawley大鼠，雄性，购于维通利华。饲养管理：实验动物饲养在SPF级恒温恒湿的清洁房间内，使用独立的通风笼具IVC，每笼饲养不超过5只。温度/湿度：控制在(23±3)℃/40-70％范围。饲料和饮水：SPF级鼠料，钴60照射消毒。饮用水为超滤净化水，并经过高压灭菌处理。动物可以自由摄取无菌食物和饮水。动物编号：耳标标记。
实验方法：实验分为以下5组：溶媒组，奥拉帕尼(Olaparib)100mg/kg，化合物1 0.1mg/kg，化合物1 0.3mg/kg，化合物1 1.0mg/kg。所有治疗经口灌胃给药，每天1次，给药4天。治疗前后分别采血检测外周血网织红细胞数量。
实验结果：表10是大鼠给药4天后外周血网织红细胞的变化。大鼠给药4天后，奥拉帕尼100mg/kg显著降低外周血网织红细胞(p<0.01)，提示其对骨髓造血功能的抑制作用。化合物1 0.1mg/kg、化合物1 0.3mg/kg和1.0mg/kg对外周血网织红细胞没有显著影响(p>0.05)。结合药效学实验结果，化合物1显示出较奥拉帕尼更大的治疗窗。
表10：化合物对大鼠外周血网织红细胞的影响
受试化合物 口服给药剂量 网织红细胞抑制率
奥拉帕尼(Olaparib) 100mg/kg 91.6％
化合物1 0.1mg/kg 12.2％
化合物1 0.3mg/kg 33.8％
化合物1 1.0mg/kg 41.9％
除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (14)

  1. 化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(I)的结构：
    Figure PCTCN2022135894-appb-100001
    其中：
    Figure PCTCN2022135894-appb-100002
    为单键或双键；
    X为N或CR 5；
    Y为N或CR 5’；
    Z为CR 6或N；
    当
    Figure PCTCN2022135894-appb-100003
    为单键时，V为CR 7R A或NR A；当
    Figure PCTCN2022135894-appb-100004
    为双键时，V为CR A；
    R A选自H、卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b、-O-C 1-6亚烷基-NR aR b和
    Figure PCTCN2022135894-appb-100005
    环A为C 3-6烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环；
    R和R’在每次出现时各自独立地选自H、卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b；优选地，R和R’各自独立地选自H、-CN和C 1-6烷基；
    R 1和R 2各自独立地选自卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b；
    R 3在每次出现时各自独立地选自卤素、-OH、＝O、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b；
    当m>1时，两个R 3任选地共同构成-C 1-6亚烷基-或-C 2-6亚烯基-，所述亚烷基链和亚烯基链任选地被一个或多个独立地选自O、C(＝O)、C(＝O)O、NR、S、S＝O和S(＝O) 2的基团间隔；
    或者，R 3与R A连同其所连接的基团任选地共同构成C 3-6烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环；
    R 4在每次出现时各自独立地选自卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3- 6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b；当有两个R 4在环A上处于邻位时，所述两个R 4连同其所连接的基团任选地共同构成3-10元杂环或5-14元杂芳环；
    或者，R 3与R 4连同其所连接的基团任选地共同构成C 3-6烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环；
    R 5、R 5’、R 6和R 7在每次出现时各自独立地选自H、卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b；
    R a和R b在每次出现时各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
    上述烷基、亚烷基、卤代烷基、烯基、亚烯基、烃环、环烃基、杂环、杂环基、芳基、芳环、杂芳基、杂芳环和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R c、-OC(＝O)R c、-C(＝O)OR c、-OR c、-SR c、-S(＝O)R c、-S(＝O) 2R c、-S(＝O) 2NR cR d、-NR cR d、-C(＝O)NR cR d、-NR c-C(＝O)R d、-NR c-C(＝O)OR d、-NR c-S(＝O) 2-R d、-NR c-C(＝O)-NR cR d、-C 1-6亚烷基-OR c、-C 1-6亚烷基-NR cR d和-O-C 1-6亚烷基-NR cR d，所述烷基、亚烷基、卤代烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
    R c和R d在每次出现时各自独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；并且
    m和n各自独立地为0、1、2、3或4的整数。
  2. 权利要求1的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R A选自C 1-6卤代烷基(优选
    Figure PCTCN2022135894-appb-100006
    )、-C(＝O)R a(优选
    Figure PCTCN2022135894-appb-100007
    )和
    Figure PCTCN2022135894-appb-100008
  3. 权利要求1或2的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(I)-1的结构
    Figure PCTCN2022135894-appb-100009
    优选地，所述化合物具有式(II)、(III)、(IV)或(V)的结构：
    Figure PCTCN2022135894-appb-100010
  4. 权利要求1-3中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 1和R 2各自独立地为卤素、-CN、C 1-6烷基或C 1-6卤代烷基；例如，R 1和R 2各自独立地为C 1-6烷基或C 1-6卤代烷基；
    优选地，R 1和R 2各自独立地为F、-CN、甲基、二氟甲基、三氟甲基、乙基、正丙基或异丙基； 例如，R 1和R 2各自独立地为甲基、三氟甲基、乙基、正丙基或异丙基；
    最优选地，R 1为三氟甲基，并且R 2为甲基；或者R 1和R 2均为甲基。
  5. 权利要求1-4中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 3在每次出现时各自独立地为卤素、-OH、＝O、-NH 2、-CN、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a或-C 1- 6亚烷基-NR aR b；当m>1时，两个R 3任选地共同构成-C 1-4亚烷基-；
    优选地，R 3在每次出现时各自独立地为＝O、-CN、C 1-6烷基、C 1-6卤代烷基、-C 1-6亚烷基-CN、-C 1-6亚烷基-OR a或-C 1-6亚烷基-NR aR b；当m>1时，两个R 3任选地共同构成-C 1-4亚烷基-；
    更优选地，R 3在每次出现时各自独立地为＝O、-CN、-CH 3、-CF 3、-CH 2CN、-CH 2NH 2、-CH 2CH 2NH 2、-CH 2OH、-CH 2CH 2OH或-CH 2OCH 3；当m>1时，两个R 3任选地共同构成-CH 2CH 2-；
    或者，R 3与R A连同其所连接的基团任选地共同构成5-6元杂芳环(优选三氮唑环)，其任选地被C 1-6卤代烷基(优选三氟甲基)取代。
  6. 权利要求1-5中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 6和R 7在每次出现时各自独立地选自H、卤素、-OH、-CN、-C 1-6亚烷基-OR a和-C 1-6亚烷基-NR aR b；
    R 6和R 7在每次出现时各自独立地选自H、-F、-OH、-CN、-CH 2OH和-CH 2NH 2。
  7. 权利要求1-6中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中
    Figure PCTCN2022135894-appb-100011
    选自
    Figure PCTCN2022135894-appb-100012
    Figure PCTCN2022135894-appb-100013
    Figure PCTCN2022135894-appb-100014
    优选地，
    Figure PCTCN2022135894-appb-100015
    选自
    Figure PCTCN2022135894-appb-100016
    Figure PCTCN2022135894-appb-100017
  8. 权利要求1-7中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 4在每次出现时各自独立地为卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、5-14元杂芳基、-S(＝O) 2NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)-NR aR b或-C 1-6亚烷基-OR a；当有两个R 4在环A上处于邻位时，所述两个R 4连同其所连接的基团任选地共同构成5-6元杂环或5-6元杂芳环；
    优选地，R 4在每次出现时各自独立地为F、-CN、-CH 3、-CF 3、
    Figure PCTCN2022135894-appb-100018
    -S(＝O) 2NHCH 3、-C(＝O)NH 2、-C(＝O)NHCH 3、-C(＝O)NHCD 3、-C(＝O)NHCH 2CH 3、-C(＝O)NHCH 2CF 3、-C(＝O)NHCH 2CH 2OH、-C(＝O)NH(环丙基)、-NHC(＝O)CH 3、-NHC(＝O)(环丙基)、-NHC(＝O)NHCH 3、-CH 2OH、
    Figure PCTCN2022135894-appb-100019
    当有两个R 4在环A上处于邻位时，所述两个R 4连同其所连接的基团任选地共同构成
    Figure PCTCN2022135894-appb-100020
    更优选地，R 4在每次出现时各自独立地为F、-CN、-CH 3、-CF 3、
    Figure PCTCN2022135894-appb-100021
    S(＝O) 2NHCH 3、-C(＝O)NH 2、-C(＝O)NHCH 3、-NHC(＝O)CH 3、-NHC(＝O)(环丙基)、-NHC(＝O)NHCH 3、-CH 2OH、
    Figure PCTCN2022135894-appb-100022
    当有两个R 4在环A上处于邻位时，所述两个R 4连同其所连接的基团任选地共同构成
    Figure PCTCN2022135894-appb-100023
    或者，R 3与R 4连同其所连接的基团任选地共同构成5-6元杂芳环，优选咪唑环。
  9. 权利要求1-8中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中环A为C 4-6烃环、5-6元杂环、C 6芳环或5-6元杂芳环，更优选地为双环[1.1.1]戊烷环、哌啶环、苯环、咪唑环、噻唑环、吡啶环、吡嗪环、哒嗪环或嘧啶环，最优选地为双环[1.1.1]戊烷环、哌啶环、苯环、咪唑环、噻唑环、吡啶环、哒嗪环或嘧啶环。
  10. 权利要求1-9中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中
    Figure PCTCN2022135894-appb-100024
    为
    Figure PCTCN2022135894-appb-100025
    Figure PCTCN2022135894-appb-100026
    优选地，
    Figure PCTCN2022135894-appb-100027
    为
    Figure PCTCN2022135894-appb-100028
    Figure PCTCN2022135894-appb-100029
  11. 权利要求1-10中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物选自：
    Figure PCTCN2022135894-appb-100030
    Figure PCTCN2022135894-appb-100031
    Figure PCTCN2022135894-appb-100032
    Figure PCTCN2022135894-appb-100033
    Figure PCTCN2022135894-appb-100034
    Figure PCTCN2022135894-appb-100035
    Figure PCTCN2022135894-appb-100036
  12. 药物组合物，其包含预防或治疗有效量的权利要求1-11中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选是固体制剂、液体制剂或透皮制剂。
  13. 权利要求1-11中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者权利要求12的药物组合物在制备用作PARP抑制剂(优选用作PARP1选择性抑制剂)的药物中的用途。
  14. 权利要求13的用途，其中所述药物用于治疗癌症；优选地，所述癌症选自卵巢癌、乳腺癌、前列腺癌、肾癌、肝癌、胰腺癌、胃癌、肺癌、头颈部癌、甲状腺癌、恶性胶质瘤、白血病、淋巴瘤、多发性骨髓瘤。
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