WO2022048498A1 - Usp7抑制剂 - Google Patents

Usp7抑制剂 Download PDF

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Publication number
WO2022048498A1
WO2022048498A1 PCT/CN2021/114936 CN2021114936W WO2022048498A1 WO 2022048498 A1 WO2022048498 A1 WO 2022048498A1 CN 2021114936 W CN2021114936 W CN 2021114936W WO 2022048498 A1 WO2022048498 A1 WO 2022048498A1
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Prior art keywords
methyl
cycloalkyl
alkyl
compound
chloro
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PCT/CN2021/114936
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English (en)
French (fr)
Inventor
侯登
袁保昆
段小伟
王静晗
闵汪洋
陈三许
刘希杰
刘爽
孙颖慧
Original Assignee
首药控股(北京)股份有限公司
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Priority claimed from CN202010908542.4A external-priority patent/CN114195800A/zh
Priority claimed from CN202011334132.XA external-priority patent/CN114539283A/zh
Priority claimed from CN202011541873.5A external-priority patent/CN114656479A/zh
Priority claimed from CN202110181139.0A external-priority patent/CN114907368A/zh
Priority claimed from CN202110429367.5A external-priority patent/CN115215883A/zh
Application filed by 首药控股(北京)股份有限公司 filed Critical 首药控股(北京)股份有限公司
Priority to CN202180053342.8A priority Critical patent/CN116057061A/zh
Publication of WO2022048498A1 publication Critical patent/WO2022048498A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present application relates to a USP7 inhibitor, its preparation method and its therapeutic use in tumor diseases.
  • Post-translational modification is generally the enzymatic modification of a protein after protein biosynthesis.
  • PTMs include methylation, acetylation, phosphorylation, glycosylation, ubiquitination, S-nitrosylation, etc.
  • ubiquitination involves proteolytic machinery within the cell and regulates many physical activities within the cell.
  • the process of adding ubiquitin to a substrate protein is called ubiquitination, which aids in the degradation of the protein.
  • a cascade reaction consisting of ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin ligase (E3) can catalyze the ubiquitination of target proteins.
  • ubiquitin is activated by E1 with the participation of adenosine triphosphate and transferred to E2 through a trans-sulfation reaction, and then binds to lysine or ⁇ -amino groups of substrate proteins in the presence of E3.
  • protein tags with more than four ubiquitin molecules can be recognized and influenced by the 26S proteasome, where they are degraded, producing small polypeptides.
  • DUBs Deubiquitinating enzymes
  • USPS ubiquitin-specific proteases
  • UCHs ubiquitin C-terminal hydrolases
  • OTUS ovarian tumor proteases
  • MJDS Machado-Joseph disease protease
  • JAMMS JAB1/MPN/Mov34
  • the USPS family is the largest of all the DUB subfamilies. These members all include conserved domains, the three main functional domains of the Cys, His, and Asp/Asn boxes, which are responsible for the reorganization of ubiquitin-binding molecules.
  • the ubiquitin-specific protease USP7 also known as herpes-associated ubiquitin-specific protease (HAUSP) is a unique deubiquitinase discovered in 1997. A new member of herpes simplex virus type 1 immediate early protein (Vmw110) interaction. Later, USP7 was found to interact with other viral proteins such as Epstein-Barr nuclear antigen 1 (EBNA1) of Epstein-Barr virus (EBV) and vIRF1 (viral interferon regulatory factor 1) of Kaposi's sarcoma-associated herpes virus (KSHV).
  • EBNA1 Epstein-Barr nuclear antigen 1
  • vIRF1 viral interferon regulatory factor 1
  • KSHV Kaposi's sarcoma-associated herpes virus
  • USP7 is highly expressed in a variety of cancers and affects cancer disease progression. Furthermore, USP7 plays different roles in different tumors. In prostate cancer, high expression of USP7 is directly correlated with tumor aggressiveness. USP7 plays a key role in carcinogenesis through a p53-dependent pathway in non-small cell lung cancer (NSCLC). Studies have shown that, in vivo, changes in USP7 regulate colon cancer growth and apoptosis sensitivity. USP7 maintains the DNA damage response and promotes cervical cancer, and is positively associated with poor survival in cervical cancer patients. USP7 regulates human erythroid terminal differentiation by stabilizing GATA1, providing a certain treatment for leukemia. In short, USP7 plays an important role in a variety of pathological processes and is an excellent target from a therapeutic standpoint.
  • NSCLC non-small cell lung cancer
  • USP7 play a role in regulating cellular pathways such as viral proteins, immune responses, oncogenes, and DNA damage, but it is also aberrantly expressed in a variety of cancers, making it a promising target.
  • due to the lack of protein co-crystal structure between USP7 and small molecule inhibitors no effective and selective USP7 inhibitor has been found for a long time.
  • the crystal structures of some USP7 small molecule inhibitors and their complexes with USP7 have been published, which provide guidance for obtaining structure-based small molecule inhibitors.
  • USP7 small molecule inhibitors have not yet entered clinical trials due to unsatisfactory in vivo efficacy data. Therefore, USP7 inhibitors with good in vivo activity need to be developed for the early treatment of cancer patients with abnormal USP7 expression.
  • the compound of the present invention is a USP7 deubiquitinase inhibitor, which can inhibit the USP7 deubiquitinase with high selectivity, thereby safely and effectively treating tumor patients with abnormal USP7 expression.
  • the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof,
  • Y 1 , Y 2 , Y 3 and Y 4 is CR 30 , the remaining three are each independently selected from N and CR 3 ,
  • Rings A and B are aromatic rings
  • X 1 and X 2 are each independently selected from CR 4 and N,
  • X3 and X4 are each independently selected from C and N,
  • X 5 and X 6 are each independently selected from N, NR 5 , O, S and CR 6 , and X 5 and X 6 are not simultaneously CR 6 ,
  • L 1 and L 2 are each independently selected from -(CR 12 R 13 ) n -, -O-, -S-, -NR 10 -, -(CO)-, -(CO)NR 10 -, -(CO )O-, -S(O) 2 - and -S(O) 2 NR 10 -,
  • n 0, 1, 2, 3, or 4
  • R 1 and R 3 are each independently selected from H, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 10 , -NR 10 R 11 , C 3 -8 cycloalkyl and 3-8 membered heterocycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be optionally replaced by halogen, -CN, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, -OR 10 , -NR 10 R 11 , C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl substituted,
  • R 4 is selected from H, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 10 , -NR 10 R 11 , C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be optionally replaced by halogen, -CN, C 1-6 alkyl, C 2-6 alkene group, C 2-6 alkynyl, -OR 10 , -NR 10 R 11 , C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl,
  • R 5 is selected from H, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl, the alkane alkenyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl can be optionally replaced by halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 10 , -NR 10 R 11 , C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl substituted,
  • R 6 is selected from H, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 10 , -NR 10 R 11 , C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl, the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be optionally replaced by halogen, -CN, C 1-6 alkyl, C 2-6 alkene group, C 2-6 alkynyl, -OR 10 , -NR 10 R 11 , C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl,
  • R 7 is a 5-12-membered heteroaryl, 3-12-membered cycloalkyl or 3-12-membered heterocycloalkyl, and may be optionally substituted by R 40 , the cycloalkyl and heterocycloalkyl may be any Optionally fused with 5-10 membered aryl or 5-12 membered heteroaryl, aryl or heteroaryl fused with cycloalkyl or heterocycloalkyl may be optionally substituted by R40 ,
  • R 10 and R 11 are each independently selected from H, C 1-6 alkyl and C 3-8 cycloalkyl,
  • R 12 and R 13 are each independently selected from H, halogen and C 1-6 alkyl,
  • p 0, 1, or 2.
  • the C ring is a 5- or 6-membered aromatic or non-aromatic ring containing 1 N;
  • the C ring is a 5- or 6-membered aromatic or non-aromatic ring containing 2 Ns;
  • the C ring is a 5- or 6-membered aromatic or non-aromatic ring containing 1 O;
  • L 1 and L 2 are each independently selected from -(CR 12 R 13 ) n -;
  • R 1 and R 3 are each independently selected from H, halogen, -CN, C 1-6 alkyl, -OR 10 , -NR 10 R 11 , C 3-8 cycloalkyl, and 3- 8-membered heterocycloalkyl;
  • each R 4 is independently selected from H, halogen, and C 1-6 alkyl
  • R 5 is each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, and 3-8 membered heterocycloalkyl;
  • R 6 is selected from H, halogen, C 1-6 alkyl, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl;
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof,
  • Rings A and B are aromatic rings
  • X 1 and X 2 are each independently selected from CR 4 and N,
  • X 3 and X 4 are each independently selected from C or N,
  • X 5 and X 6 are each independently selected from N, NR 5 , O, S and CR 6 , and X 5 and X 6 are not simultaneously CR 6 ,
  • Y 2 , Y 3 and Y 4 are each independently selected from N and CR 3 ,
  • L 1 and L 2 are each independently selected from -(CR 12 R 13 ) n -,
  • n 0, 1, 2, 3, or 4
  • R 1 and R 3 are each independently selected from H, halogen, -CN, C 1-6 alkyl, -OR 10 , -NR 10 R 11 , C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl ,
  • R 4 is selected from H, halogen and C 1-6 alkyl
  • R 5 is selected from H, C 1-6 alkyl, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl,
  • R 6 is selected from H, halogen, C 1-6 alkyl, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl,
  • R 10 and R 11 are each independently selected from H, C 1-6 alkyl and C 3-8 cycloalkyl,
  • R 12 and R 13 are each independently selected from H, halogen and C 1-6 alkyl,
  • p 0, 1, or 2;
  • n is each independently 0, 1 or 2, preferably 1 or 2, more preferably 1;
  • p is 0 or 1;
  • X 5 is CR 6
  • X 6 is S
  • R 6 is selected from H, halogen, C 1-6 alkyl, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl, preferably from H, halogen and C 1-6 alkyl;
  • X 1 and X 2 are each independently CR 4 , X 3 and X 4 are each independently C, X 5 is CR 6 , X 6 is S, and R 4 is selected from H, halogen, and C 1 -6 alkyl, R 6 is selected from H, halogen and C 1-6 alkyl; in some embodiments, R 4 is H;
  • R 2 is a 3-12 membered heterocycloalkyl, which may be optionally substituted with halogen, -OR 10 , -NR 10 R 11 , or C 1-6 alkyl,
  • R 10 and R 11 are each independently selected from H and C 1-6 alkyl
  • R 7 is
  • Y 2 , Y 3 and Y 4 are each independently selected from CR 3 , and R 3 is each independently selected from H, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, and 3- 8-membered heterocycloalkyl;
  • Y 2 , Y 3 and Y 4 are each independently selected from CR 3 , and R 3 is each independently selected from H, halogen, and C 1-6 alkyl;
  • R 10 and R 11 are each independently selected from H and C 1-6 alkyl
  • R 12 and R 13 are hydrogen
  • the compound of formula (I) is the following compound, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof,
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, and optionally a pharmaceutically acceptable accepted carrier;
  • the present invention provides a method of treating a disease associated with USP7 activity, the method comprising administering to a subject an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph or isoform thereof Construct, or the pharmaceutical composition of the present invention;
  • the disease associated with USP7 activity is ovarian cancer, breast cancer, lung cancer, pancreatic cancer, kidney cancer, melanoma, liver cancer, colon cancer, sarcoma, Brain cancer, prostate cancer, leukemia, lymphoma, or multiple myeloma;
  • the subject to which the invention relates is a mammal including a human;
  • the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a pharmaceutical composition of the present invention, prepared for the treatment of a disease associated with USP7 activity.
  • a disease associated with USP7 activity is ovarian cancer, breast cancer, lung cancer, pancreatic cancer, kidney cancer, melanoma, liver cancer, colon cancer, sarcoma, brain cancer, prostate cancer cancer, leukemia, lymphoma, or multiple myeloma.
  • optionally substituted alkyl means “unsubstituted alkyl” or “substituted alkyl”.
  • optionally substituted groups can be unsubstituted (eg: -CH2CH3 ) , fully substituted (eg: -CF2CF3 ) , monosubstituted (eg : -CH2CH2F ) or Any hierarchy between mono- and full substitution (eg : -CH2CHF2 , -CF2CH3 , -CFHCHF2 , etc. ) . It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.
  • substituents When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2- .
  • group refers to a specific moiety or functional group of a molecule. Chemical groups are often thought of as chemical entities embedded or attached to a molecule.
  • C1 - C6 alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms.
  • the total number of carbon atoms shown in the abbreviated symbols does not include carbon atoms on possible substituents.
  • the compounds of the present invention may contain one or more (eg, one, two, three or four) isotopic substitutions.
  • H can be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium);
  • C can be in any isotopic form, including 12 C, 13 C, and 14 C ;
  • O can be in any isotopic form, including 16 O and 18 O, etc.
  • halogen refers to bromine, chlorine, fluorine or iodine.
  • aromatic refers to a planar ring or ring moieties having 4n+2 A delocalized electron conjugate system of electrons, where n is an integer.
  • Aromatic rings can be formed from 5, 6, 7, 8, 9, or more than 9 atoms.
  • Aromatic compounds can be optionally substituted and can be monocyclic or fused-ring polycyclic.
  • aromatic compound includes all carbocyclic rings (eg, benzene rings) and rings containing one or more heteroatoms (eg, pyridine).
  • heteroatom refers to atoms other than carbon and hydrogen.
  • the heteroatoms are independently selected from, but are not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin.
  • the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.
  • fused or "fused ring” as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.
  • spiro or "spirocycle” as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
  • alkyl refers to an optionally substituted straight or branched monovalent saturated hydrocarbon having 1-12 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms, linked to the rest of the molecule by single bonds, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, etc.
  • Alkenyl as defined herein appears in a numerical range, such as "C2 - C6 alkenyl” or "C2-6 alkenyl” means that it can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms Atoms or alkenyl groups of 6 carbon atoms, alkenyl groups herein also encompass cases where no numerical range is specified.
  • alkynyl refers to an optionally substituted linear or branched monovalent hydrocarbon group having one or more C ⁇ C triple bonds and having from 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl, and the like.
  • aryl refers to an all-carbon monocyclic or fused ring having a fully conjugated pi-electron system, having 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms .
  • Aryl groups may be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, sulfonyl , sulfinyl, phosphoryl and heteroalicyclic groups.
  • substituents examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, sulfonyl , sulfinyl, phosphoryl and heteroalicyclic groups.
  • Non-limiting examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthy
  • heteroaryl refers to a monocyclic or fused ring of 5-12 ring atoms, having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms containing 1, 2, 3 or 4 ring atoms selected from N, O, S, the remaining ring atoms are C, and have a fully conjugated ⁇ -electron system.
  • Heteroaryl groups can be unsubstituted or substituted, including but not limited to alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl and hetero Alicyclic.
  • Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, iso Quinolinyl, tetrazolyl, triazinyl.
  • cycloalkyl refers to a stable monovalent non-aromatic monocyclic or polycyclic hydrocarbon radical containing only carbon and hydrogen atoms, and may include fused, spiro or bridged ring systems, including 3-15 ring carbon atoms, preferably 3-10 ring carbon atoms, more preferably 3-8 ring carbon atoms, may be saturated or unsaturated, connected to the rest of the molecule by a single bond.
  • Non-limiting examples of "cycloalkyl” include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • heterocyclyl refers to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1 -6 heteroatoms selected from nitrogen, oxygen and sulfur.
  • a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused, spiro or bridged ring systems, with nitrogen, carbon or sulfur selectivity on the heterocyclyl group is oxidized, the nitrogen atom can be selectively quaternized, and the heterocyclic group can be partially or fully saturated.
  • a heterocyclyl group can be attached to the rest of the molecule by a single bond through a carbon atom or a heteroatom in the ring.
  • a heterocyclyl group containing a fused ring may contain one or more aromatic or heteroaromatic rings, so long as the attachment to the remainder of the molecule is an atom on a non-aromatic ring.
  • the heterocyclyl group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclyl examples include azepanyl, azetidinyl, decahydroisoquinolyl, dihydrofuranyl, indoline, dioxolane, 1,1 -Dioxy-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, Piperazinyl, piperidinyl, 4-piperidinyl, pyranyl, pyrazolidine, pyrrolidinyl, quinazinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like.
  • polymorph or “polymorph (phenomenon)" means that the compounds of the present invention have a variety of crystal lattice morphologies. Some of the compounds of the present invention may have more than one crystalline form, and the present invention encompasses all polymorphic forms or mixtures thereof.
  • the olefinic double bonds contained in the compounds of the present invention include both E and Z isomers.
  • the compounds of the present invention may contain asymmetric centers. These asymmetric centers can independently be in the R or S configuration. Some of the compounds of the present invention may also exhibit cis-trans isomerism, as will be apparent to those skilled in the art. It is to be understood that the compounds of the present invention include their individual geometric and stereoisomers as well as mixtures thereof, including racemic mixtures. These isomers can be isolated from their mixtures by practicing or modifying known methods, such as chromatographic techniques and recrystallization techniques, or they can be prepared separately from the appropriate isomers of their intermediates.
  • pharmaceutically acceptable salt includes both added and base salts.
  • “Pharmaceutically acceptable addition salts” refers to those that retain the biological potency and properties of the compound's free base, are not biologically or otherwise undesirable, and are associated with inorganic acids such as, but not limited to, hydrochloric acid, hydrogen Bromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, Salts of capric acid, caproic acid, carbonic acid, cinnamic acid, citric acid, etc.
  • inorganic acids such as, but not limited to, hydrochloric acid, hydrogen Bromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
  • organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alg
  • “Pharmaceutically acceptable base-added salts” refers to those salts that retain the biological potency and properties of the free acid of the compound and are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic or organic base. Salts formed by reaction with inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and manganese salts.
  • Organic bases that form salts include, but are not limited to, primary, secondary, tertiary, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine , Dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline and caffeine.
  • Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
  • solvate refers to a complex formed by combining one or more molecules of a compound of the present invention with one or more molecules of a solvent.
  • the solvent may be water, in which case the solvate is a hydrate.
  • an organic solvent may be used.
  • the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms.
  • the compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may only accidentally retain water or a mixture of water and some other solvent.
  • the compounds of the present invention can be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
  • the term "pharmaceutical composition” refers to a formulation that combines a compound of the present invention with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal, such as a human.
  • This medium contains all pharmaceutically acceptable carriers.
  • the term "pharmaceutically acceptable” refers to a substance (eg, a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing adverse biological effects React or interact in an undesirable manner with any component contained in the composition.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, adjuvants, carriers, excipients, auxiliaries, deodorants, diluents, preservatives, Dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers.
  • the terms "subject,” “patient,” “subject,” or “individual” refer to an individual, including mammals and non-mammals, suffering from a disease, disorder, condition, or the like.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (eg, chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals , such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs.
  • non-human mammals include, but are not limited to, birds, fish, and the like.
  • the mammal is a human.
  • treatment refers to the treatment of an associated disease or disorder in mammals, particularly humans, including
  • disease and “disorder” can be used interchangeably or have different meanings, because some specific diseases or conditions have no known causative agent (so the cause of the disease is not clear), so they cannot be considered as A disease can only be seen as an unwanted condition or syndrome which has more or less specific symptoms that have been confirmed by clinical researchers.
  • an "effective amount” for treatment is that amount of a composition comprising a compound disclosed herein required to provide clinically significant relief of a condition.
  • An effective amount appropriate in any individual case can be determined using techniques such as dose escalation assays.
  • administering refers to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
  • Example 1 3-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione
  • Example 2 The compound synthesis method in Example 2 is the same as that in Step 6 and Step 7 in Example 1.
  • compound 34 was prepared by the synthetic methods of step 6 and step 7 in the synthetic method of the compound of Example 1.
  • Example 6 The compound in Example 6 was prepared from compound 33 by the methods of step 5, step 6, and step 7 in Example 1.
  • compound 38 can be prepared by the synthesis method of step 6 and step 7 in the synthesis method of the compound of Example 1.
  • Example 8 3-((7-(5-Chloro-2-((4-fluoropiperidin-4-yl)methyl)-2H-indazol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione
  • Example 8 Using compound 37b as a raw material, the compound in Example 8 can be prepared through the synthesis methods of Step 6 and Step 7 in the synthesis method of the compound of Example 1.
  • 1 H NMR 400 MHz, CD 3 OD
  • 7.57(d, J 2.0Hz, 1H)
  • 7.53(s, 1H) 4.84(s, 2H), 4.76(d, J 20.8Hz, 2H), 3.38-3.45 (m, 2H), 3.15-3.23 (m, 2H), 2.46 (s, 2H), 1.93-2.13 (m, 4H), 1.20 (s, 3H), 1.04 (s, 3H).
  • Example 10 3-((7-(5-Chloro-1-((3-fluoro-8-azabicyclo[3.2.1]octan-3-yl)methyl)-1H-indole-7 -yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dionetri Fluoroacetate
  • Example 11 The synthesis method of Example 11 is the same as that of Example 9.
  • Example 12 3-((7-(5-Chloro-1-((4-methylpiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2- b]Pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate
  • Example 12 The synthesis method of Example 12 is the same as that of Example 9.
  • Step 2 Polyphosphoric acid (10 mL) was added to compound 44, and the reaction solution was heated to 150° C. for 30 min. After the reaction, water (100 mL) was added to dilute the reaction solution, and the aqueous phase was extracted with ethyl acetate (100 mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash silica gel column chromatography to obtain compounds 45a and 45b (1.3 g in total, about 1:1).
  • Step 5 To a solution of methyltriphenylphosphonium bromide (826 mg) in anhydrous tetrahydrofuran (10 mL) was added dropwise n-butyllithium (2 mL, 2.5 M) at -78°C under nitrogen protection. After the dropwise addition was completed, the temperature of the reaction solution was raised to 0°C, and the reaction was continued for 30 min. The reaction solution was then cooled to -78°C, and a solution of a mixture of 47a and 47b (500 mg) in THF (5 mL) was added dropwise thereto, and then the reaction solution was warmed to room temperature and reacted overnight.
  • Example 15 3-((7-(6-Chloro-3-((4-fluoropiperidin-4-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[ d]imidazol-4-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2, 4-diketone hydrochloride
  • compound 58 was prepared by the synthetic method of step 6 and step 7 in the synthetic method of the compound of Example 1.
  • Example 18 3-((7-(5-Chloro-3-fluoro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3 ,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione
  • Example 19 The synthesis method of Example 19 is the same as that of Example 9.
  • Example 20 The synthesis method of Example 20 is the same as that of Example 9.
  • Example 22 3-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-1-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione trifluoroacetate
  • Example 22 The synthesis method of Example 22 is the same as that of Example 21.
  • Example 23 3-((7-(1-(2-(azetidin-3-yl)ethyl)-5-chloro-1H-indol-7-yl)thieno[3,2- b]Pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate
  • Example 23 The synthesis method of Example 23 is the same as that of Example 9.
  • Example 24 The synthesis method of Example 24 is the same as that of Example 9.
  • Example 25 4-((5-Chloro-7-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-3-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 25 The synthesis method of Example 25 is the same as that of Example 9.
  • Example 26 3-((7-(5-Chloro-3-fluoro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3 ,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate
  • Example 27 The synthesis method of Example 27 is the same as that of Example 9.
  • Example 28 3-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)indolin-7-yl)thieno[3,2-b]pyridine -2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate
  • compound 76 was prepared by the synthetic method of step 6 and step 7 in the synthetic method of the compound of Example 1.
  • Example 29 The synthesis method of Example 29 is the same as that of Example 21.
  • Example 30 7-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-3-yl)methyl)thieno[3 ,2-b]pyridin-7-yl)-1-((4-fluoropiperidin-4-yl)methyl)-1H-indole-5-carbonitrile
  • Example 30 The synthesis method of Example 30 is the same as that of Example 9.
  • Example 31 The synthesis method of Example 31 is the same as that of Example 9.
  • Example 32 The synthesis method of Example 32 is the same as that of Example 14.
  • 1 H NMR 400 MHz, CD 3 OD
  • 8.68-8.77 m, 1H
  • 7.50 s, 1H
  • 7.38-7.41 m, 2H
  • 5.30 s, 1H
  • 4.77-4.88 m, 2H
  • 3.07-3.13(m, 1H) 2.95-3.01(m, 1H), 2.59-2.65(m, 1H), 2.47-2.50(m, 2H), 2.31-2.44(m, 3H)
  • 1.07(s, 3H) 1.07(s, 3H).
  • Example 33 The synthesis method of Example 33 is the same as that of Example 17.
  • 1 H NMR 400MHz, CD 3 OD
  • 8.62-8.70 m, 1H
  • 7.58 s, 1H
  • 6.90 s,1H
  • 3.35 3
  • 2.65-2.68(m, 2H) 2.47(s, 2H), 1.21(s, 3H), 1.05(s, 3H).
  • Example 34 The synthesis method of Example 34 is the same as that of Example 9.
  • Example 35 The synthesis method of Example 35 is the same as that of Example 18.
  • Example 36 3-((7-(5-Chloro-3-fluoro-1-(((S)-morpholin-2-yl)methyl)-1H-indol-7-yl)thieno[ 3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate
  • Example 36 The synthesis method of Example 36 is the same as that of Example 18.
  • 1 H NMR 400MHz, DMSO-d 6 ), 8.74-8.78(m,1H), 7.80-8.30(br,2H), 7.78-7.79(m,1H), 7.55-7.57(m,1H), 7.43- 7.50(m, 2H), 7.17-7.19(m, 1H), 4.70-4.79(m, 2H), 3.48-3.62(m, 2H), 3.07-3.28(m, 3H), 2.85-2.92(m, 1H ), 2.47-2.66(m, 3H), 2.34-2.42(m, 0.5H), 2.06-2.17(m, 1.5H), 1.11-1.15(m, 3H), 0.96-1.11(m, 3H).
  • Example 37 The synthesis method of Example 37 is the same as that of Example 9.
  • Example 38 4-((5-Chloro-7-(2-((2,5-oxo-3-(2,2,2-trifluoroethyl)imidazolin-1-yl)methyl) Thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 39 The synthesis method of Example 39 is the same as that of Example 9.
  • Example 40 The synthesis method of Example 40 is the same as that of Example 5.
  • Example 42 3-((7-(6-Chloro-3-(((R)-morpholin-2-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo [d]imidazol-4-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2 ,4-diketone trifluoroacetate
  • Example 42 The synthesis method of Example 42 is the same as that of Example 15.
  • Example 43 The synthesis method of Example 43 is the same as that of Example 17.
  • 1 H NMR 400MHz, CD 3 OD
  • 8.67(d, J 5.2Hz, 1H)
  • 7.86(s, 1H) 7.83(s, 1H)
  • 7.64(s, 1H) 7.54(s, 1H)
  • 7.54(s, 1H) 7.54(s, 1H)
  • 7.47(d,J 4.8Hz,1H)
  • 4.86(s,2H) 3.37-3.43(m,2H),2.90-3.02(m,4H),2.47(s,2H),2.21-2.31(m , 1H), 1.98-2.06 (m, 2H), 1.48-1.57 (m, 2H), 1.21 (s, 3H), 1.05 (s, 3H).
  • Example 44 The synthesis method of Example 44 is the same as that of Example 14.
  • 1 H NMR 400MHz, CD 3 OD
  • Example 45 The synthesis method of Example 45 is the same as that of Example 21.
  • 1 H NMR 400MHz, CD 3 OD
  • Example 46 The synthesis method of Example 46 is the same as that of Example 18.
  • Example 47 The synthesis method of Example 47 is the same as that of Example 18.
  • Example 48 3-((7-(5-Chloro-1-(((S)-morpholin-2-yl)methyl)-1H-indazol-7-yl)thieno[3,2- b]Pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione
  • Example 49 The synthesis method of Example 49 is the same as that of Example 21.
  • Example 50 The synthesis method of Example 50 is the same as that of Example 5.
  • Example 51 The synthesis method of Example 51 is the same as that of Example 21.
  • 1 H NMR 400MHz, CD 3 OD
  • 8.58(d, J 4.4Hz, 1H)
  • 7.20(d, J 4.8Hz, 1H)
  • 6.64(d, J 2.8Hz, 1H)
  • 3.93(t, J 16.0Hz, 1H)
  • 3.29-3.80 m, 3H
  • Example 54 3-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-1-(2,2,2-trifluoroethyl)imidazoline-2,4-dione trifluoroacetate
  • Example 54 The synthesis method of Example 54 is the same as that of Example 21.
  • Example 55 4-((5-Chloro-7-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-3-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-benzo[d]imidazol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 55 The synthesis method of Example 55 is the same as that of Example 5.
  • Example 56 The synthesis method of Example 56 is the same as that of Example 9.
  • Example 57 3-((7-(6-Chloro-3-((4-cyclopropylpiperazin-1-yl)methyl)benzofuran-4-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione
  • Example 57 The synthesis method of Example 57 is the same as that of Example 14.
  • 1 H NMR 400MHz, CD 3 OD
  • 8.68-8.76 (m, 1H)
  • 7.74(d, J 1.6Hz, 1H)
  • 7.35(d, J 1.6Hz, 1H)
  • 4.85(s, 2H) 3.28-3.35(m, 1H)
  • 2.49(s, 2H) 1.65-2.08(m, 8H), 1.51-1.63(m, 1H), 1.23(s, 3H), 1.14(s, 3H), 0.50-0.72(m, 4H).
  • Example 58 3-((7-(6-Chloro-3-((4-isopropylpiperazin-1-yl)methyl)benzofuran-4-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione
  • Example 59 3-((7-(6-Chloro-3-(((R)-morpholin-2-yl)methyl)-2-thio-2,3-dihydro-1H-benzo [d]imidazol-4-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2 ,4-diketone trifluoroacetate
  • Example 59 The synthesis method of Example 59 is the same as that of Example 15.
  • 1 H NMR (400MHz, CDCl 3 ), 12.40-12.59(br,1H), 9.08-9.99(br,2H), 8.76-8.85(m,1H), 7.63(s,0.5H), 7.61(s,0.5 H), 7.38-7.46(m, 1H), 7.34(s, 0.5H), 7.28(d, J 4.8Hz, 0.5H), 7.10(s, 0.5H), 7.03(s, 0.5H), 4.75 -4.91(m, 2H), 4.19-4.34(m, 1H), 3.22-3.82(m, 4H), 2.51-3.18(m, 4H), 2.35-2.44(m, 2H), 1.23(s, 1.5H ), 1.21(s, 1.5H), 1.17(s, 1.5H), 1.09(s, 1.5H).
  • Example 60 3-((7-(6-Chloro-3-(((S)-morpholin-2-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo [d]imidazol-4-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2 ,4-diketone trifluoroacetate
  • Example 61 3-((7-(6-Chloro-3-(((S)-morpholin-2-yl)methyl)-2-thio-2,3-dihydro-1H-benzo [d]imidazol-4-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2 ,4-diketone trifluoroacetate
  • Example 61 The synthesis method of Example 61 is the same as that of Example 15.
  • 1 H NMR (400MHz, CDCl 3 ), 12.40-12.59(br,1H), 9.08-9.99(br,2H), 8.76-8.85(m,1H), 7.63(s,0.5H), 7.61(s,0.5 H), 7.38-7.46(m, 1H), 7.34(s, 0.5H), 7.28(d, J 4.8Hz, 0.5H), 7.10(s, 0.5H), 7.03(s, 0.5H), 4.75 -4.91(m, 2H), 4.19-4.34(m, 1H), 3.22-3.82(m, 4H), 2.51-3.18(m, 4H), 2.35-2.44(m, 2H), 1.23(s, 1.5H ), 1.21(s, 1.5H), 1.17(s, 1.5H), 1.09(s, 1.5H).
  • Example 62 3-((7-(5-Chloro-1-(((3,4-trans)-3-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl) Thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione
  • Example 64 4-((5-Chloro-7-(2-((3,3,4,4-tetramethyl-2,5-dioxopyrrolidin-1-yl)methyl)thieno [3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 64 The synthesis method of Example 64 was the same as that of Example 21.
  • Example 65 4-((5-Chloro-7-(2-((4,4-dimethyl-2,6-dioxopiperidin-1-yl)methyl)thieno[3,2 -b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 65 The synthesis method of Example 65 is the same as that of Example 21.
  • Example 66 4-((5-Chloro-7-(2-((5,7-dioxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 66 The synthesis method of Example 66 is the same as that of Example 21.
  • Example 67 The synthesis method of Example 67 is the same as that of Example 21.
  • Example 68 6-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione trifluoroacetate
  • Example 68 The synthesis method of Example 68 is the same as that of Example 21.
  • Example 69 The synthesis method of Example 69 is the same as that of Example 9. MS(ESI): [M+H] + : 537.2.
  • Example 70 4-((5-Chloro-7-(2-((4-methyl-2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b] Pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 70 The synthesis method of Example 70 is the same as that of Example 21.
  • 1 H NMR 400 MHz, CD 3 OD
  • Example 71 3-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-1-cyclopropylimidazoline-2,4-dione trifluoroacetate
  • Example 71 The synthesis method of Example 71 is the same as that of Example 21.
  • Example 72 2-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione trifluoroacetate
  • Example 72 The synthesis method of Example 72 is the same as that of Example 21.
  • Example 73 The synthesis method of Example 73 is the same as that of Example 21.
  • Example 74 4-((5-Chloro-7-(2-((3-cyclopropyl-2,5-dioxoimidazolin-1-yl)methyl)thieno[3,2-b ]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 74 The synthesis method of Example 74 is the same as that of Example 21.
  • Example 75 4-((5-Chloro-7-(2-((3,3-dimethyl-2,6-dioxopiperidin-1-yl)methyl)thieno[3,2 -b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 75 The synthesis method of Example 75 is the same as that of Example 21.
  • Example 76 4-((5-Chloro-7-(2-((3,3-dimethyl-2,5-dioxopyrrolidin-1-yl)methyl)thieno[3,2 -b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 76 The synthesis method of Example 76 is the same as that of Example 21.
  • Example 77 4-((5-Chloro-7-(2-((1,3-dioxohexahydrocyclopenteno[c]pyrrol-2(1H)-yl)methyl)thieno[ 3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 77 The synthesis method of Example 77 is the same as that of Example 21.
  • Example 78 4-((5-Chloro-7-(2-((3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl) Thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 78 The synthesis method of Example 78 is the same as that of Example 21.
  • Example 79 The synthesis method of Example 79 is the same as that of Example 21.
  • 1 H NMR 400 MHz, CD 3 OD
  • Example 80 4-((5-Chloro-7-(2-((2,4-dioxo-3-azabicyclo[3.2.0]heptan-3-yl)methyl)thieno[ 3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 80 The synthesis method of Example 80 is the same as that of Example 21.
  • Example 81 4-((5-Chloro-7-(2-((3-methyl-2,5-dioxoimidazolin-1-yl)methyl)thieno[3,2-b] Pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 81 The synthesis method of Example 81 is the same as that of Example 21.
  • Example 82 4-((5-Chloro-7-(2-((5,7-dioxo-6-azaspiro[2.5]oct-6-yl)methyl)thieno[3,2 -b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 82 The synthesis method of Example 82 is the same as that of Example 21.
  • Example 83 6-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-6-azaspiro[2.5]octane-5,7-dione trifluoroacetate
  • Example 83 The synthesis method of Example 83 is the same as that of Example 21.
  • Example 84 4-((5-Chloro-7-(2-((3,5-dioxomorpholine)methyl)thieno[3,2-b]pyridin-7-yl)-1H- Indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 84 The synthesis method of Example 84 is the same as that of Example 21.
  • Example 85 3-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetate
  • Example 85 The synthesis method of Example 85 is the same as that of Example 21.
  • Example 86 4-((5-Chloro-7-(2-((2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl)methyl)thieno[ 3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 86 The synthesis method of Example 86 is the same as that of Example 21.
  • Example 87 4-((5-Chloro-7-(2-((1,3-dioxo-1,3,4,5,6,7-hexahydro-2H-isoindole-2- yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 87 The synthesis method of Example 87 is the same as that of Example 21.
  • 1 H NMR 400 MHz, CD 3 OD
  • Example 88 4-((7-(2-((4-Amino-1,3-dioxoisoindol-2-yl)methyl)thieno[3,2-b]pyridine-7- yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 88 The synthesis method of Example 88 is the same as that of Example 21.
  • 1 H NMR 400MHz, CD 3 OD
  • Example 89 The synthesis method of Example 89 is the same as that of Example 21.
  • Example 90 2-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-2-azaspiro[4.4]nonane-1,3-dione trifluoroacetate
  • Example 90 The synthesis method of Example 90 is the same as that of Example 21.
  • 1 H NMR 400 MHz, CD 3 OD
  • Example 91 4-((5-Chloro-7-(2-((4,6-dioxo-4H-thieno[3,4-c]pyrrol 1-5(6H)-yl)methyl) )thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 91 The synthesis method of Example 91 is the same as that of Example 21.
  • Example 92 5-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione trifluoroacetate
  • Example 92 The synthesis method of Example 92 is the same as that of Example 21.
  • Example 93 4-((5-Chloro-7-(2-((3-methoxy-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl )thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 93 The synthesis method of Example 93 is the same as that of Example 21.
  • Example 94 The synthesis method of Example 94 is the same as that of Example 21.
  • Example 95 4-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)morpholine-3,5-dione trifluoroacetate
  • Example 95 The synthesis method of Example 95 is the same as that of Example 21.
  • Example 96 1-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-3-methylpyrrolidine-2,5-dione
  • Example 96 The synthesis method of Example 96 is the same as that of Example 21.
  • Example 97 1-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-4-cyclopropylpiperazine-2,6-dione trifluoroacetate
  • Example 97 The synthesis method of Example 97 is the same as that of Example 21.
  • Example 98 The synthesis method of Example 98 is the same as that of Example 21.
  • Example 99 The synthesis method of Example 99 is the same as that of Example 21.
  • Example 100 4-((5-Chloro-7-(2-((4-ethyl-2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b] Pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 100 The synthesis method of Example 100 is the same as that of Example 21.
  • Example 101 4-((5-Chloro-7-(2-((3-methyl-2,5-dioxopyrrolidin-1-yl)methyl)thieno[3,2-b] Pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 101 The synthesis method of Example 101 is the same as that of Example 21.
  • Example 102 1-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)piperazine-2,6-dione
  • Example 102 The synthesis method of Example 102 is the same as that of Example 21.
  • 1 H NMR 400 MHz, CD 3 OD
  • 8.81 s, 1H
  • 7.64 s, 1H
  • 7.35 s,1H
  • 3.66( ddd, J 21.2Hz, 16.0Hz, 1H)
  • 3.08-3.16 2.82-2.93
  • m, 2H 1.16-1.48 (m, 3H)
  • 0.84-0.89 m, 1H).
  • Example 103 1-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indole-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-3-phenyl-1H-pyrrole-2,5-dione trifluoroacetate
  • Example 103 The synthesis method of Example 103 is the same as that of Example 21.
  • Example 104 4-((5-Chloro-7-(2-((2,5-dioxo-3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)methyl) Thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 104 The synthesis method of Example 104 is the same as that of Example 21.
  • Example 105 1-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)-4-isopropylpiperazine-2,6-dione hydrochloride
  • Example 105 The synthesis method of Example 105 is the same as that of Example 21.
  • Example 106 4-((5-Chloro-7-(2-((4-isopropyl-2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b ]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 106 The synthesis method of Example 106 is the same as that of Example 21.
  • Example 107 4-((5-Chloro-7-(2-((2,6-dioxopiperidin-1-yl)methyl)thieno[3,2-b]pyridin 7-yl) -1H-Indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 96 The synthesis method of Example 96 is the same as that of Example 21.
  • 1 H NMR 400 MHz, CD 3 OD
  • Example 108 4-((5-Chloro-7-(2-((3-methoxy-2,5-dioxopyrrolidin-1-yl)methyl)thieno[3,2-b ]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 96 The synthesis method of Example 96 is the same as that of Example 21.
  • Example 109 1-((7-(5-Chloro-1-((4-fluoropiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3,2-b ]pyridin-2-yl)methyl)pyrrolidin-2-one trifluoroacetate
  • Example 110 3-((7-(5-Chloro-1-((4-fluoropyrrol-3-yl)methyl)-1H-indol-7-yl)thieno[3,2-b] Pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione
  • Example 110 The synthesis method of Example 110 is the same as that of Example 21.
  • Example 111 4-((5-Chloro-7-(2-((2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b]pyridin-7-yl )-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 111 The synthesis method of Example 111 is the same as that of Example 21.
  • Example 112 4-((7-(2-((4-Acetyl-2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b]pyridine-7- yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 112 The synthesis method of Example 112 is the same as that of Example 21.
  • Example 113 3-((5-Chloro-7-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3- yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)pyrrolidine-3-carbonitrile
  • Example 113 The synthesis method of Example 113 is the same as that of Example 21.
  • Example 114 4-((5-Chloro-7-(2-((3,4-Dimethyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) Methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 114 The synthesis method of Example 114 is the same as that of Example 21.
  • Example 115 4-((5-Chloro-7-(2-((3,4-dimethyl-2,5-dioxopyrrol-1-yl)methyl)thieno[3,2- b]Pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 115 The synthesis method of Example 115 is the same as that of Example 21.
  • Example 116 4-((5-Chloro-7-(2-((3,5-dioxothiomorpholine)methyl)thieno[3,2-b]pyridin-7-yl)- 1H-Indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 116 The synthesis method of Example 116 is the same as that of Example 21.
  • Example 117 4-((5-Chloro-7-(2-((3,4-Dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl) Methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 117 The synthesis method of Example 117 is the same as that of Example 21.
  • Example 118 The synthesis method of Example 118 is the same as that of Example 21.
  • Example 119 The synthesis method of Example 119 is the same as that of Example 21.
  • Example 120 The synthesis method of Example 120 is the same as that of Example 21.
  • Example 121 4-((7-(2-((3-Allyl-2,5-dioxopyrrolidin-1-yl)methyl)thieno[3,2-b]pyridine-7 -yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 121 The synthesis method of Example 121 is the same as that of Example 21.
  • Example 122 4-((5-Chloro-7-(2-((4,6-dioxo-5-azaspiro[2.4]hept-5-yl)methyl)thieno[3,2 -b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 122 The synthesis method of Example 122 is the same as that of Example 21.
  • Example 123 4-((7-(2-((4-(sec-butyl)-2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b] Pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 123 The synthesis method of Example 123 is the same as that of Example 21.
  • Example 124 Benzyl (R)-(1-((7-(5-chloro-1-((4-cyanopiperidin-4-yl)methyl)-1H-indol-7-yl) Thieno[3,2-b]pyridin-2-yl)methyl)-2,5-dioxopyrrolidin-3-yl)carbamate trifluoroacetate
  • Example 124 The synthesis method of Example 124 is the same as that of Example 21.
  • Example 125 The synthesis method of Example 125 is the same as that of Example 21.
  • Example 126 4-((5-Chloro-7-(2-((2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6-dihydropyrimidine- 1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 126 The synthesis method of Example 126 is the same as that of Example 21.
  • Example 127 The synthesis method of Example 127 is the same as that of Example 21.
  • Example 128 4-((5-Chloro-7-(2-((1,1-dioxo-3,5-dioxothiomorpholine)methyl)thieno[3,2-b ]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 128 The synthesis method of Example 128 is the same as that of Example 21.
  • Example 129 4-((5-Chloro-7-(2-((3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidine-1( 2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 129 The synthesis method of Example 129 is the same as that of Example 21.
  • Example 130 4-((7-(2-((4-Allyl-2,6-dioxopiperazin-1-yl)methyl)thieno[3,2-b]pyridine-7- yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 130 The synthesis method of Example 130 is the same as that of Example 21.
  • Example 131 4-((5-Chloro-7-(2-((5,7-dioxo-6-azaspiro[3.4]octan-6-yl)methyl)thieno[3,2 -b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 131 The synthesis method of Example 131 is the same as that of Example 21.
  • Example 132 4-((5-Chloro-7-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-3-yl) Methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)-1-isopropylpiperidine-4-carbonitrile
  • Example 132 The synthesis method of Example 132 is the same as that of Example 13.
  • Example 133 N-(1-((7-(5-Chloro-1-((4-cyanopiperidin-4-yl)methyl)-1H-indol-7-yl)thieno[3 ,2-b]pyridin-2-yl)methyl)-2,5-dioxopyrrolidin-3-yl)cyclopropylcarboxamide trifluoroacetate
  • Example 133 The synthesis method of Example 133 is the same as that of Example 21.
  • Example 134 The synthesis method of Example 134 was the same as that of Example 21.
  • Example 135 4-((5-Chloro-7-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)-4-cyano-1,1-dimethylpiperidine-1- iodide
  • Example 135 The synthesis method of Example 135 is the same as that of Example 13.
  • Example 136 4-((5-Chloro-7-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)-1-methylpiperidine-4-carbonitrile
  • Example 136 The synthesis method of Example 136 is the same as that of Example 13.
  • Example 137 4-((5-Chloro-7-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)-1-(cyclopropylmethyl)piperidine-4-carbonitrile
  • Example 137 The synthesis method of Example 137 is the same as that of Example 13.
  • Example 138 4-((5-Chloro-7-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)-1-(2,2,2-trifluoroethyl)piperidine- 4-carbonitrile
  • Example 138 The synthesis method of Example 138 is the same as that of Example 13.
  • Example 139 4-((5-Chloro-7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)-1-ethylpiperidine-4-carbonitrile
  • Example 139 The synthesis method of Example 139 is the same as that of Example 13.
  • Example 140 4-((5-Chloro-7-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)-1-cyclopropylpiperidine-4-carbonitrile
  • Example 140 The synthesis method of Example 140 is the same as that of Example 13.
  • Example 141 4-((5-Chloro-7-(2-((3-ethyl-3-methyl-2,5-dioxopyrrolidin-1-yl)methyl)thieno[3, 2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 141 The synthesis method of Example 141 is the same as that of Example 21.
  • Example 142 3-((7-(5-Chloro-1-(2-hydroxy-3-(piperazin-1-yl)propyl)-1H-indol-7-yl)thieno[3, 2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione
  • Example 142 The synthesis method of Example 142 is the same as that of Example 9.
  • Example 143 3-((7-(5-Chloro-1-(2,3-dihydroxypropyl)-1H-indol-7-yl)thieno[3,2-b]pyridine-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione
  • Example 143 The synthesis method of Example 143 is the same as that of Example 9.
  • 1 H NMR 400MHz, CDCl 3 ), 8.67-8.74 (m, 1H), 7.69 (s, 1H), 7.54-7.56 (m, 1H), 7.13-7.25 (m, 2H), 7.03-7.05 (m, 1H), 6.50-6.58(m, 1H), 4.74-4.81(m, 2H), 3.24-3.57(m, 3H), 2.68-3.04(m, 2H), 2.34(s, 2H), 1.21(s, 3H), 1.06-1.14 (m, 3H).
  • Example 144 4-((5-Chloro-7-(2-((3-(cyclopropylmethyl)-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 144 The synthesis method of Example 144 was the same as that of Example 21.
  • Example 145 4-((5-Chloro-7-(2-((3,5-dimethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methan yl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 145 The synthesis method of Example 145 was the same as that of Example 21.
  • Example 146 4-((5-Chloro-7-(2-((3-(cyclopropylmethyl)-5-methyl-2,6-dioxo-3,6-dihydropyrimidine-1 (2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 146 The synthesis method of Example 146 was the same as that of Example 21.
  • Example 148 4-(2-(5-Chloro-7-(2-((6,6-Dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-3 -yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)ethyl)piperidine-4-carbonitrile
  • Example 148 The synthesis method of Example 148 is the same as that of Example 9.
  • Example 149 4-((5-Chloro-7-(2-((5-fluoro-3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl) Methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 149 The synthesis method of Example 149 is the same as that of Example 21.
  • Example 150 4-((5-Chloro-7-(2-((3-(cyclopropylmethyl)-5-fluoro-2,6-dioxo-3,6-dihydropyrimidine-1( 2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 150 The synthesis method of Example 150 is the same as that of Example 21.
  • Example 151 4-((7-(2-((5-Bromo-3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thiophene [3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 151 The synthesis method of Example 151 was the same as that of Example 21.
  • Example 152 4-((7-(2-((5-Bromo-3-(cyclopropylmethyl)-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl )methyl)thieno[3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 152 The synthesis method of Example 152 was the same as that of Example 21.
  • Example 153 4-((5-Chloro-7-(2-((3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thiophene [3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 128 The synthesis method of Example 128 is the same as that of Example 21.
  • Example 154 4-((5-Chloro-7-(2-((4-methyl-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H )-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 154 The synthesis method of Example 154 was the same as that of Example 21.
  • Example 155 4-((5-Chloro-7-(2-((3-(cyclopropylmethyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidine-1 (2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 155 The synthesis method of Example 155 was the same as that of Example 21.
  • Example 156 4-((5-Chloro-7-(2-((4-methyl-3-(methyl-d3)-2,6-dioxo-3,6-dihydropyrimidine-1( 2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 156 The synthesis method of Example 156 was the same as that of Example 21.
  • Example 157 4-((5-Chloro-7-(2-((5-methyl-2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6- Dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 157 The synthesis method of Example 157 was the same as that of Example 21.
  • Example 158 4-((5-Chloro-7-(2-((3-Cyclopropyl-5-methyl-2,6-dioxo-3,6-dihydropyrimidine-1(2H)- yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 158 The synthesis method of Example 158 was the same as that of Example 21.
  • Example 159 4-((5-Chloro-7-(2-((5-fluoro-2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6-di Hydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 159 The synthesis method of Example 159 is the same as that of Example 21.
  • Example 160 4-((5-Chloro-7-(2-((3-(deuteromethyl)-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl) Methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 160 The synthesis method of Example 160 is the same as that of Example 21.
  • Example 161 4-((5-Chloro-7-(2-((5-Chloro-3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl) Methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 161 The synthesis method of Example 161 is the same as that of Example 21.
  • Example 162 4-((5-Chloro-7-(2-((5-Chloro-3-(cyclopropylmethyl)-2,6-dioxo-3,6-dihydropyrimidine-1( 2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 162 The synthesis method of Example 162 is the same as that of Example 21.
  • Example 163 4-((5-Chloro-7-(2-((5-Chloro-2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6-di Hydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 163 The synthesis method of Example 163 was the same as that of Example 21.
  • Example 164 4-((5-Chloro-7-(2-((4-methyl-2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6- Dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 164 The synthesis method of Example 164 was the same as that of Example 21.
  • Example 165 4-((5-Chloro-7-(2-((3-isopropyl-4-methyl-2,6-dioxo-3,6-dihydropyrimidine-1(2H)- yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 165 The synthesis method of Example 165 was the same as that of Example 21.
  • Example 166 4-((5-Chloro-7-(2-((2,6-dioxo-3-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)- 3,6-Dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4 - Formonitrile
  • Example 166 The synthesis method of Example 166 was the same as that of Example 21.
  • Example 167 4-((5-Chloro-7-(2-((3-ethyl-2,6-dioxo-5-(trifluoromethyl)-3,6-dihydropyrimidine-1( 2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 167 The synthesis method of Example 167 is the same as that of Example 21.
  • Example 168 4-((5-Chloro-7-(2-((5-Chloro-3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl) Methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 168 The synthesis method of Example 168 was the same as that of Example 21.
  • Example 169 4-((5-Chloro-7-(2-((3-ethyl-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 169 The synthesis method of Example 169 is the same as that of Example 21.
  • Example 170 4-((7-(2-((5-Bromo-2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6-dihydropyrimidine-1 (2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 170 The synthesis method of Example 170 is the same as that of Example 21.
  • Example 171 4-((5-Chloro-7-(2-((3-isopropyl-5-methyl-2,6-dioxo-3,6-dihydropyrimidine-1(2H)- yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 171 The synthesis method of Example 171 is the same as that of Example 21.
  • Example 172 4-((5-Chloro-7-(2-((3-Cyclopropyl-5-fluoro-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 172 The synthesis method of Example 172 was the same as that of Example 21.
  • Example 173 4-((5-Chloro-7-(2-((3-cyclopropyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl) Thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 173 The synthesis method of Example 173 was the same as that of Example 21.
  • Example 174 4-((5-Chloro-7-(2-((3-(2-chloroethyl)-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile trifluoroacetate
  • Example 174 The synthesis method of Example 174 was the same as that of Example 21.
  • Example 175 4-((5-Chloro-7-(2-((3-ethyl-5-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 175 The synthesis method of Example 175 was the same as that of Example 21.
  • Example 176 4-((5-Chloro-7-(2-((3-isopropyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl) Thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 176 The synthesis method of Example 176 was the same as that of Example 21.
  • Example 177 4-((5-Chloro-7-(2-((5-Chloro-3-isopropyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 177 The synthesis method of Example 177 was the same as that of Example 21.
  • Example 178 4-((5-Chloro-7-(2-((3-isopropyl-2,6-dioxo-5-(trifluoromethyl)-3,6-dihydropyrimidine-1 (2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 178 The synthesis method of Example 178 was the same as that of Example 21.
  • Example 179 4-((5-Chloro-7-(2-((5-Chloro-3-cyclopropyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl ) methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 179 The synthesis method of Example 179 was the same as that of Example 21.
  • Example 180 4-((5-Chloro-7-(2-((4-isobutyl-2,6-dioxopiperidin-1-yl)methyl)thieno[3,2-b] Pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 180 The synthesis method of Example 180 is the same as that of Example 21.
  • Example 181 4-((5-Chloro-7-(2-((5-Chloro-2,6-dioxo-3-propyl-3,6-dihydropyrimidin-1(2H)-yl) Methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 181 The synthesis method of Example 181 is the same as that of Example 21.
  • Example 182 4-((5-Chloro-7-(2-((5-Chloro-3-(2,2-difluoroethyl)-2,6-dioxo-3,6-dihydropyrimidine -1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 182 The synthesis method of Example 182 was the same as that of Example 21.
  • Example 183 4-((5-Chloro-7-(2-((5-Fluoro-3-isopropyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 183 The synthesis method of Example 183 was the same as that of Example 21.
  • Example 184 4-((5-Chloro-7-(2-((3-ethyl-5-fluoro-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl) Methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 184 The synthesis method of Example 184 was the same as that of Example 21.
  • Example 185 4-((5-Chloro-7-(2-((2-methyl-3,5-dioxo-2,5-dihydro-1,2,4-triazine-4(3H )-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 185 The synthesis method of Example 185 was the same as that of Example 21.
  • Example 186 4-((7-(2-((5-Bromo-3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thiophene [3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 186 The synthesis method of Example 186 was the same as that of Example 21.
  • Example 187 4-((5-Chloro-7-(2-((3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)thiophene [3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 187 The synthesis method of Example 187 was the same as that of Example 21.
  • Example 188 4-((5-Chloro-7-(2-(((3-(2,2-difluoroethyl)-2,6-dioxo-3,6-dihydropyrimidine-1(2H )-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 188 The synthesis method of Example 188 was the same as that of Example 21.
  • Example 189 4-((7-(2-((5-Bromo-3-isopropyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl) Thieno[3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 189 The synthesis method of Example 189 was the same as that of Example 21.
  • Example 190 4-((5-Chloro-7-(2-(((3-(2,2-difluoroethyl)-5-methyl-2,6-dioxo-3,6-dihydro) Pyrimidine-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 190 The synthesis method of Example 190 is the same as that of Example 21.
  • Example 191 4-((5-Chloro-7-(2-(((3-(2,2-difluoroethyl)-5-fluoro-2,6-dioxo-3,6-dihydropyrimidine) -1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 191 The synthesis method of Example 191 is the same as that of Example 21.
  • Example 192 4-((5-Chloro-7-(2-((4-Chloro-3-ethyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl) Methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 192 The synthesis method of Example 192 is the same as that of Example 21.
  • Example 193 4-((5-Chloro-7-(2-((4-Chloro-3-(2,2-difluoroethyl)-2,6-dioxo-3,6-dihydropyrimidine -1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 193 The synthesis method of Example 193 was the same as that of Example 21.
  • Example 194 4-((5-Chloro-7-(2-(((3-(2,2-difluoroethyl)-2,6-dioxo-5-(trifluoromethyl)-3, 6-Dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-methyl Nitrile
  • Example 194 The synthesis method of Example 194 was the same as that of Example 21.
  • Example 195 4-((5-Chloro-7-(2-((4-Chloro-3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl) Methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 195 The synthesis method of Example 195 is the same as that of Example 21.
  • Example 196 4-((5-Chloro-7-(2-((4-Chloro-2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6-di Hydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 196 The synthesis method of Example 196 was the same as that of Example 21.
  • Example 197 4-((5-Chloro-7-(2-(((3-(2,2-difluoroethyl)-4-methyl-2,6-dioxo-3,6-dihydro) Pyrimidine-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 197 The synthesis method of Example 197 is the same as that of Example 21.
  • Example 198 4-((5-Chloro-7-(2-((3-ethyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidine-1( 2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 198 The synthesis method of Example 198 is the same as that of Example 21.
  • Example 199 4-((7-(2-((5-Bromo-3-(2,2-difluoroethyl)-2,6-dioxo-3,6-dihydropyrimidine-1(2H )-yl)methyl)thieno[3,2-b]pyridin-7-yl)-5-chloro-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 199 The synthesis method of Example 199 is the same as that of Example 21.
  • Example 200 4-((5-Chloro-7-(2-((3-ethyl-4-methoxy-2,6-dioxo-3,6-dihydropyrimidine-1(2H)- yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 200 The synthesis method of Example 200 is the same as that of Example 21.
  • Example 201 4-((5-Chloro-7-(2-((6,8-dioxo-5-(2,2,2-trifluoroethyl)-5,7-diazaspiro[ 3.4] Octan-7-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 201 The synthesis method of Example 201 is the same as that of Example 21.
  • Example 202 4-((5-Chloro-7-(2-((2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl) Thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • the obtained target compound was used to remove the N-tert-butoxycarbonyl group in other examples, and the tert-butoxycarbonyl protecting group was removed by trifluoroacetic acid to obtain the compound of Example 202 (35 mg).
  • Example 203 4-((5-Chloro-7-(2-(((3-(2-hydroxy-2-methylpropyl)-5-methyl-2,6-dioxo-3,6- Dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 203 The synthesis method of Example 203 is the same as that of Example 21.
  • Example 204 4-((5-Chloro-7-(2-((3-(methyl-d3)-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydro Pyrimidine-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 204 The synthesis method of Example 204 is the same as that of Example 21.
  • Example 205 4-((5-Chloro-7-(2-((7-methyl-1,3-dioxohexahydroimidazo[1,5-a]piperazin-2(3H)-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 205 The synthesis method of Example 205 is the same as that of Example 21.
  • Example 206 4-((5-Chloro-7-(2-((2-(2,2-difluoroethyl)-3,5-dioxo-2,5-dihydro-1,2, 4-Triazin-4(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 206 The synthesis method of Example 206 is the same as that of Example 21.
  • Example 207 4-((5-Chloro-7-(2-((3,5-dioxo-2-(2,2,2-trifluoroethyl)-2,5-dihydro-1, 2,4-Triazin-4(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4- Formonitrile
  • Example 207 The synthesis method of Example 207 is the same as that of Example 21.
  • Example 208 4-((5-Chloro-7-(2-((2-ethyl-3,5-dioxo-2,5-dihydro-1,2,4-triazine-4(3H) -yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 208 The synthesis method of Example 208 is the same as that of Example 21.
  • Example 209 4-((5-Chloro-7-(2-((2-isopropyl-3,5-dioxo-2,5-dihydro-1,2,4-triazine-4( 3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 209 The synthesis method of Example 209 is the same as that of Example 21.
  • Example 210 4-((5-Chloro-7-(2-((2-(cyclopropylmethyl)-3,5-dioxo-2,5-dihydro-1,2,4-tri Azin-4(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 210 The synthesis method of Example 210 is the same as that of Example 21.
  • Example 211 4-((5-Chloro-7-(2-((4-methoxy-3-methyl-2,6-dioxo-3,6-dihydropyrimidine-1(2H)- yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 211 The synthesis method of Example 211 is the same as that of Example 21.
  • Example 212 4-((5-Chloro-7-(2-((4-cyclopropyl-3-methyl-2,6-dioxo-3,6-dihydropyrimidine-1(2H)- yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 212 The synthesis method of Example 212 is the same as that of Example 21.
  • Example 213 4-((5-Chloro-7-(2-((4-methoxy-2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6 -Dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 213 The synthesis method of Example 213 is the same as that of Example 21.
  • Example 214 4-((5-Chloro-7-(2-((4-Chloro-3-isopropyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl )methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 214 The synthesis method of Example 214 is the same as that of Example 21.
  • Example 215 4-((5-Chloro-7-(2-((3-isopropyl-2,4,6-trioxotetrahydropyrimidin-1(2H)-yl)methyl)thieno [3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 215 The synthesis method of Example 215 is the same as that of Example 21.
  • Example 216 4-((5-Chloro-7-(2-((4-cyclopropyl-2,6-dioxo-3-(2,2,2-trifluoroethyl)-3,6 -Dihydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 216 The synthesis method of Example 216 is the same as that of Example 21.
  • Example 217 4-((5-Chloro-7-(2-((4-cyclopropyl-3-ethyl-2,6-dioxo-3,6-dihydropyrimidine-1(2H)- yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 217 The synthesis method of Example 217 is the same as that of Example 21.
  • Example 218 4-((5-Chloro-7-(2-((3,5-dioxo-4-(2,2,2-trifluoroethyl)-4,5-dihydro-1, 2,4-Triazin-2(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4- Formonitrile
  • Example 218 The synthesis method of Example 218 is the same as that of Example 21.
  • Example 219 4-((5-Chloro-7-(2-(((3-(2,2-difluoroethyl)-4-methoxy-2,6-dioxo-3,6-di Hydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 219 The synthesis method of Example 219 is the same as that of Example 21.
  • Example 220 4-((5-Chloro-7-(2-((4-cyclopropyl-3-(2,2-difluoroethyl)-2,6-dioxo-3,6-di Hydropyrimidin-1(2H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 220 The synthesis method of Example 220 is the same as that of Example 21.
  • Example 221 4-((5-Chloro-7-(2-((2-(deuteromethyl)-3,5-dioxo-2,5-dihydro-1,2,4-triazine -4(3H)-yl)methyl)thieno[3,2-b]pyridin-7-yl)-1H-indol-1-yl)methyl)piperidine-4-carbonitrile
  • Example 221 The synthesis method of Example 221 is the same as that of Example 21.
  • the enzymatic activity detection of USP7 in this patent is carried out by a fast fluorescence method, using Ubiquitin-Rhodamine 110 as an alternative substrate for the reaction and optimized to establish a high-throughput screening platform.
  • Assays for the inhibitory activity of compounds against USP7 were performed on this platform.
  • the specific method is as follows: the compound was diluted 5 times with 100% DMSO starting from 1mM (7 concentrations in total), and 2 ⁇ L of each concentration was added to 48 ⁇ L of reaction buffer (20mM Tris, pH 8.0, 2mM CaCl 2 , 1mM reduced glutathione, 0.01% (v/v) Triton X-100, 0.01% (w/v) BSA) for dilution and mixing.
  • Human acute lymphoblastic leukemia cell line RS4; 11 cells were used RPMI-1640 medium plus 10% fetal bovine serum (FBS, purchased from Biological Industries, BI) and 1% penicillin/streptomycin (P/S, purchased from Thermo Fisher Scientific) at 37°C, 5% CO 2 .
  • FBS fetal bovine serum
  • P/S penicillin/streptomycin
  • RS4;11 cells were plated in 96-well plates (Cat. #3917, from CORNING) at a concentration of 4000 cells/195 ⁇ L/well. After 24 hours, the compounds were diluted and mixed by 3 times with 100% DMSO starting from 10 mM (10 concentrations in total), and then 4 ⁇ L of each concentration was added to 96 ⁇ L of RPMI-1640 medium for dilution and mixing.
  • mice Male SD rats were obtained from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. The rats were divided into groups, 3 rats in each group, and the test sample suspension (5 mg/kg) was orally administered to each group by oral gavage. Animals were fasted overnight before the experiment, and the fasting period was from 10 hours before dosing to 4 hours after dosing. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. After anesthesia with isoflurane in a small animal anesthesia machine, 0.3 mL of whole blood was collected through the fundus venous plexus and placed in a heparin anticoagulation tube.
  • Plasma samples were centrifuged at 4°C and 4000 rpm for 5 min, and the plasma was transferred to a centrifuge tube and placed in a -80 Store at °C until analysis. Plasma samples were extracted using protein precipitation and the extracts were analyzed by LC/MS/MS.

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Abstract

本申请涉及式（I）所示的USP7抑制剂，及其制备方法和其在肿瘤疾病中的治疗用途。在制备过程中，通过取代、偶联、还原、脱保护等一系列反应，得到本发明化合物。

Description

USP7抑制剂
交叉引用
本申请要求2020年9月2日提交的专利名称为“USP7抑制剂”的第202010908542.4号中国专利申请、2020年11月24日提交的专利名称为“USP7抑制剂”的第202011334132.X号中国专利申请、2020年12月23日提交的专利名称为“USP7抑制剂”的第202011541873.5号中国专利申请、2021年2月9日提交的专利名称为“USP7抑制剂”的第202110181139.0号中国专利申请、2021年4月21日提交的专利名称为“USP7抑制剂”的第202110429367.5号中国专利申请的优先权，其全部公开内容通过引用整体并入本文。
技术领域
本申请涉及一种USP7抑制剂，及其制备方法和其在肿瘤疾病中的治疗用途。
背景技术
翻译后修饰(PTM)一般是在蛋白质生物合成后对蛋白质进行酶修饰。PTM的包括甲基化、乙酰化、磷酸化、糖基化、泛素化、S-亚硝基化等。作为研究最多的PTM之一，泛素化涉及细胞内的蛋白水解机制，并调节细胞内的许多物理活动。将泛素加到底物蛋白质上的过程称为泛素化，这有助于蛋白质的降解。泛素激活酶(E1)、泛素结合酶(E2)和泛素连接酶(E3)组成的级联反应可以催化靶蛋白的泛素化。首先，泛素在三磷酸腺苷的参与下被E1激活，并通过反式硫基化反应转移到E2，然后在E3的存在下与底物蛋白的赖氨酸或α-氨基结合。最终，具有四个以上泛素分子的蛋白质标记可以被识别，并受到26S蛋白酶体的影响，在那里它们被降解，产生小的多肽。
去泛素化酶(DUBS)负责去除泛素，并通过将泛素降解来保持底物的稳定性。到目前为止，已鉴定出约100个DUB，根据它们的Ub蛋白酶结构域可以分为五个亚类：泛素特异性蛋白酶(USPS)、泛素C末端水解酶(UCHs)、卵巢肿瘤蛋白酶(OTUS)、半胱氨酸依赖蛋白酶的Machado-Joseph病蛋白酶(MJDS)和锌金属蛋白酶的JAB1/MPN/Mov34(JAMMS)。
拥有将近50个成员的USPS家族是所有DUB亚家族中最大的一个。这些成员都包括保守结构域，即Cys、His和Asp/Asn盒的三个主要功能结构域，它们负责泛素结合分子的重组。
在USP家族成员中，泛素特异性蛋白酶USP7，又称疱疹相关泛素特异性蛋白酶(HAUSP)，是1997年发现的一种独特的去泛素酶，它是泛素特异性蛋白酶家族中与单纯疱疹病毒1型即刻早期蛋白(Vmw110)相互作用的新成员。后来，USP7被发现与其他病毒蛋白相互作用，如Epstein-Barr病毒(EBV)的Epstein-Barr核抗原1(EBNA1)和卡波西肉瘤相关疱疹病毒(KSHV)的vIRF1(病毒干扰素调节因子1)蛋白，因此表明它是疱疹病毒的通用靶标，并将其命名为疱疹相关泛素特异性蛋白酶。到目前为止，USP7是研究最广泛的去泛素酶，被认为是促进肿瘤生长和影响患者对肿瘤的免疫反应的癌基因。
USP7在多种癌症中高度表达，并影响癌症疾病的进展。此外，USP7在不 同的肿瘤中扮演不同的角色。在前列腺癌中，USP7的高表达与肿瘤的侵袭性直接相关。USP7在非小细胞肺癌(NSCLC)中通过p53依赖通路在癌变中发挥关键作用。研究表明，在体内，USP7的变化调节结肠癌的生长和凋亡敏感性。USP7维持DNA损伤反应并促进宫颈癌，并与宫颈癌患者的低生存率呈正相关。USP7通过稳定GATA1调节人类红系终末分化，为白血病提供一定的治疗。简而言之，USP7在多种病理过程中起着重要作用，从治疗的角度来看是一个很好的靶点。
USP7不仅在调节病毒蛋白、免疫反应、癌基因和DNA损伤等细胞通路中发挥作用，而且在多种癌症中的异常表达，因此是一个很有前途的靶点。但是，由于缺少USP7和小分子抑制剂之间的蛋白共晶结构，很长一段时间没有发现有效的选择性USP7抑制剂。几年来，一些USP7小分子抑制剂及其与USP7复合物的晶体结构结构陆续发表，这些结构为获得基于结构的小分子抑制剂提供了指导。近年来，虽然有一些USP7小分子抑制剂报道出来，但是这些USP7抑制剂由于体内药效数据不尽如人意，因此目前尚无USP7小分子抑制剂进入临床试验。因此，具有良好体内活性的USP7抑制剂亟待开发，以尽早用于USP7异常表达的肿瘤患者的治疗。
本发明所属化合物是USP7去泛素化酶抑制剂，可以高选择性的抑制USP7去泛素化酶，从而安全、有效的治疗USP7异常表达的肿瘤患者。
发明内容
在一个方面，本发明提供式(II)化合物或其药学上可接受的盐、溶剂化物、多晶型物、或异构体，
Figure PCTCN2021114936-appb-000001
其中，
C环为含有1-2个N的5元或6元芳香环或非芳香环，C环上的碳原子可任选地被氧代(＝O)或硫代(＝S)，
或，
C环为含有O或S的5元或6元芳香环或非芳香环，C环上的碳原子可任选地被氧代(＝O)或硫代(＝S)，
Y 1、Y 2、Y 3和Y 4中的一个为CR 30，剩余的三个各自独立地选自N和CR 3，
R 30为
Figure PCTCN2021114936-appb-000002
A环和B环为芳香环，
X 1和X 2各自独立地选自CR 4和N，
X 3和X 4各自独立地选自C和N，
X 5和X 6各自独立地选自N、NR 5、O、S和CR 6，并且X 5和X 6不同时为CR 6，
L 1和L 2各自独立地选自-(CR 12R 13) n-、-O-、-S-、-NR 10-、-(CO)-、-(CO)NR 10-、-(CO)O-、-S(O) 2-和-S(O) 2NR 10-，
n为0、1、2、3、或4，
R 1和R 3各自独立地选自H、卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基和3-8元杂环烷基，所述烷基、烯基、炔基、环烷基和杂环烷基可任选地被卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基、或者3-8元杂环烷基取代，
R 4选自H、卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基和3-8元杂环烷基，所述烷基、烯基、炔基、环烷基和杂环烷基可任选地被卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基、或者3-8元杂环烷基取代，
R 5选自H、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基和3-8元杂环烷基，所述烷基、烯基、炔基、环烷基和杂环烷基可任选地被卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基、或者3-8元杂环烷基取代，
R 6选自H、卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基和3-8元杂环烷基，所述烷基、烯基、炔基、环烷基和杂环烷基可任选地被卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基、或者3-8元杂环烷基取代，
R 2为3-12元环烷基或者3-12元杂环烷基，所述环烷基和杂环烷基可任选地被(＝O)、卤素、-CN、-O-R 10、-NR 10R 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基、或者3-8元杂环烷基取代，所述环烷基和杂环烷基上任选取代的烷基、烯基、炔基、环烷基、或者杂环烷基可任选地被卤素、-CN、-O-R 10、-NR 10R 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基、或者3-8元杂环烷基取代，
R 7为5-12元杂芳基、3-12元环烷基或者3-12元杂环烷基，并且可任选地被R 40取代，所述环烷基和杂环烷基可任选地与5-10元芳基或者5-12元杂芳基稠和，与环烷基或者杂环烷基稠和的芳基或者杂芳基可任选地被R 40取代，
R 40选自(＝O)、卤素、-CN、-O-R 10、-NR 10R 11、-NR 10(COR 11)、C 1-6烷基、C 2-6烯基、C 2-6炔基、6-10元芳基、5-12元杂芳基、C 3-8环烷基、或者3-8元杂环烷基，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、或者杂环烷基可任选地被(＝O)、卤素、-CN、-O-R 10、-NH-(CO)-C 1-6烷基、-NH-Cbz、-NR 10R 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基、或者3-8元杂环烷基取代，
R 10和R 11各自独立地选自H、C 1-6烷基和C 3-8环烷基，
R 12和R 13各自独立地选自H、卤素和C 1-6烷基，
p为0、1、或2。
在一些实施方式中，R 40选自(＝O)、卤素、-CN、-O-R 10、-NR 10(COR 11)、C 1-6烷基、C 2-6烯基、C 2-6炔基、6-10元芳基、5-12元杂芳基、C 3-8环烷基、或者3-8元杂环烷基，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、或者杂环烷基可任选地被(＝O)、卤素、-CN、-O-R 10、-NH-(CO)-C 1-6烷基、-NH-Cbz、-NR 10R 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基、或者3-8元杂环烷基取代，
在一些实施方式中，R 40选自(＝O)、卤素、-CN、-O-R 10、-NR 10R 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、或者3-8元杂环烷基，所述烷基、烯基、炔基、环烷基、或者杂环烷基可任选地被卤素、-CN、-O-R 10、-NR 10R 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基、或者3-8元杂环烷基取代，
在一些实施方式中，C环为含有1个N的5元或6元芳香环或非芳香环；
在一些实施方式中，C环为含有2个N的5元或6元芳香环或非芳香环；
在一些实施方式中，C环为含有1个O的5元或6元芳香环或非芳香环；
在一些实施方式中，L 1和L 2各自独立地选自-(CR 12R 13) n-；
在一些实施方式中，R 1和R 3各自独立地选自H、卤素、-CN、C 1-6烷基、-O-R 10、-NR 10R 11、C 3-8环烷基和3-8元杂环烷基；
在一些实施方式中，R 4各自独立地选自H、卤素和C 1-6烷基；
在一些实施方式中，R 5各自独立地选自H、C 1-6烷基、C 3-8环烷基和3-8元杂环烷基；
在一些实施方式中，R 6选自H、卤素、C 1-6烷基、C 3-8环烷基和3-8元杂环烷基；
在一些实施方式中，R 2为3-12元环烷基或者3-12元杂环烷基，所述环烷基和杂环烷基可任选地被(＝O)、卤素、-CN、-O-R 10、-NR 10R 11、或者C 1-6烷基取代，所述烷基可任选地被卤素、-CN、-O-R 10、或者-NR 10R 11取代；
在一些实施方式中，R 7为3-12元环烷基或者3-12元杂环烷基，所述环烷基和杂环烷基可任选地被(＝O)、卤素、或者C 1-6烷基取代，所述烷基可任选地被卤素、-CN、-O-R 10、或者-NR 10R 11取代；
在另一方面，本发明提供式(I)化合物或其药学上可接受的盐、溶剂化物、多晶型物、或异构体，
Figure PCTCN2021114936-appb-000003
其中，
A环和B环为芳香环，
C环为含有1-2个N的5元或6元芳香环或非芳香环，C环上的碳原子可任选地被氧代(＝O)或硫代(＝S)，
X 1和X 2各自独立地选自CR 4和N，
X 3和X 4各自独立地选自C或N，
X 5和X 6各自独立地选自N、NR 5、O、S和CR 6，并且X 5和X 6不同时为CR 6，
Y 2、Y 3和Y 4各自独立地选自N和CR 3，
L 1和L 2各自独立地选自-(CR 12R 13) n-，
n为0、1、2、3、或4，
R 1和R 3各自独立地选自H、卤素、-CN、C 1-6烷基、-O-R 10、-NR 10R 11、C 3-8环烷基和3-8元杂环烷基，
R 4选自H、卤素和C 1-6烷基，
R 5选自H、C 1-6烷基、C 3-8环烷基和3-8元杂环烷基，
R 6选自H、卤素、C 1-6烷基、C 3-8环烷基和3-8元杂环烷基，
R 2为3-12元环烷基或者3-12元杂环烷基，所述环烷基和杂环烷基可任选地被(＝O)、卤素、-CN、-O-R 10、-NR 10R 11、或者C 1-6烷基取代，所述烷基可任选地被卤素、-CN、-O-R 10、或者-NR 10R 11取代，
R 7为3-12元环烷基或者3-12元杂环烷基，所述环烷基和杂环烷基可任选地被(＝O)、卤素、或者C 1-6烷基取代，所述烷基可任选地被卤素、-CN、-O-R 10、或者-NR 10R 11取代，
R 10和R 11各自独立地选自H、C 1-6烷基和C 3-8环烷基，
R 12和R 13各自独立地选自H、卤素和C 1-6烷基，
p为0、1、或2；
在一些实施方式中，n各自独立地为0、1或2，优选为1或2，更优选为1；
在一些实施方式中，p为0或1；
在一些实施方式中，X 5为CR 6，X 6为S，R 6选自H、卤素、C 1-6烷基、C 3-8环烷基和3-8元杂环烷基，优选自H、卤素和C 1-6烷基；
在一些实施方式中，X 1和X 2各自独立地为CR 4，X 3和X 4各自独立地为C，X 5为CR 6，X 6为S，R 4选自H、卤素和C 1-6烷基，R 6选自H、卤素和C 1-6烷基；在一些实施方式中，R 4为H；
在一些实施方式中，R 2为3-12元杂环烷基，所述杂环烷基可任选地被卤素、-O-R 10、-NR 10R 11、或者C 1-6烷基取代，
R 10和R 11各自独立地选自H和C 1-6烷基；
在一些实施方式中，R 7为3-12元杂环烷基，所述杂环烷基可任选地被(＝O)、或者C 1-6烷基取代；
在一些实施方式中，R 7为
Figure PCTCN2021114936-appb-000004
在一些实施方式中，Y 2、Y 3和Y 4各自独立地选自CR 3，R 3各自独立地选自H、卤素、C 1-6烷基、C 3-8环烷基和3-8元杂环烷基；
在一些实施方式中，Y 2、Y 3和Y 4各自独立地选自CR 3，R 3各自独立地选自H、卤素和C 1-6烷基；
在一些实施方式中，R 10和R 11各自独立地选自H和C 1-6烷基；
在一些实施方式中，R 12和R 13为氢；
在一些实施方式中，式(I)化合物为以下化合物或其药学上可接受的盐、溶剂化物、多晶型物、或异构体，
Figure PCTCN2021114936-appb-000005
Figure PCTCN2021114936-appb-000006
Figure PCTCN2021114936-appb-000007
Figure PCTCN2021114936-appb-000008
Figure PCTCN2021114936-appb-000009
Figure PCTCN2021114936-appb-000010
Figure PCTCN2021114936-appb-000011
在另一方面，本发明提供了一种药物组合物，其包含本发明化合物或其药学上可接受的盐、溶剂化物、多晶型物、或异构体，并任选地包含药学上可接受的载体；
在另一方面，本发明提供了治疗跟USP7活性相关的疾病的方法，所述方法包含给对象施用有效量的本发明化合物或其药学上可接受的盐、溶剂化物、多晶 型物或异构体、或者本发明的药物组合物；在一些实施方式中，所述跟USP7活性相关的疾病为卵巢癌、乳腺癌、肺癌、胰腺癌、肾癌、黑色素瘤、肝癌、结肠癌、肉瘤、脑癌、前列腺癌、白血病、淋巴瘤、或者多发性骨髓瘤；
在本发明的一些实施方式中，本发明涉及的所述对象为包括人类的哺乳动物；
在另一方面，本发明提供了本发明化合物或其药学上可接受的盐、溶剂化物、多晶型物或异构体、或者本发明的药物组合物在制备用来治疗跟USP7活性相关的疾病的药物中的用途；在一些实施方式中，所述跟USP7活性相关的疾病为卵巢癌、乳腺癌、肺癌、胰腺癌、肾癌、黑色素瘤、肝癌、结肠癌、肉瘤、脑癌、前列腺癌、白血病、淋巴瘤、或者多发性骨髓瘤。
发明详述
在下文的发明详述中陈述了利用本发明原理的示例性实施方式。通过参考以下发明内容可更好地理解本发明的特征和优点。
应理解本发明各个方面的保护范围由权利要求书决定，并且这些权利要求范围内的方法和结构以及其等价的方法和结构均在本权利要求书涵盖的范围之内。
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解，上述简述和下文的详述都是示例性的、解释性的，而不是对任何本发明主题的限制。除非另有具体说明，否则使用单数形式时也包括复数。除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
某些化学术语
术语“任选”、“任选的”或“任选地”是指随后描述的事件或情况可能发生也可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，“任选取代的烷基”表示“未取代的烷基”或“取代的烷基”。并且，任选取代的基团可以是未取代的(例如：-CH 2CH 3)、完全取代的(例如：-CF 2CF 3)、单取代的(例如：-CH 2CH 2F)或者介于单取代和完全取代之间的任意层级(例如：-CH 2CHF 2、-CF 2CH 3、-CFHCHF 2等)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、核磁、高效液相色谱、红外和紫外/可见光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和医药化学的有关术语以及实验步骤和技术是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送、以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。
本文所用术语“基团”、“化学基团”是指分子的一个特定的部分或官能团。化 学基团经常被认作为嵌入或附加到一个分子中的化学实体。
一些在此命名的化学基团可以用简略记号表示碳原子的总个数。例如，C 1-C 6烷基描述了一个烷基基团，如下定义的那样，具有总共1到6个碳原子。简略记号所示碳原子总个数不包括可能的取代基上的碳原子。
本发明的化合物可以包含一个或多个(例如一个、两个、三个或四个)同位素置换。例如，在所述化合物中，H可以是任何同位素形式，包括 1H、 2H(D或氘)和 3H(T或氚)；C可是任何同位素形式，包括 12C、 13C和 14C；O可是任何同位素形式，包括 16O和 18O等。
术语“卤素”、“卤代”或“卤化物”是指溴、氯、氟或碘。
本文使用的术语“芳香”、“芳香环”、“芳香的”、“芳香性的”、“芳香环的”是指平面的一个环或多个环的环部分，其具有含4n+2个电子的离域化电子共扼体系，其中n为整数。芳环可由5、6、7、8、9或9个以上的原子形成。芳族化合物可被任选地取代，并可为单环或稠合环的多环。术语芳族化合物包括所有碳环(如苯环)和含一个或多个杂原子的环(如吡啶)。
本文单独或作为其它成分的一部分使用的术语“杂原子”或“杂”是指除碳和氢之外的原子。杂原子独立地选自氧、氮、硫、磷、硅、硒和锡，但不限于这些原子。在出现两个或更多杂原子的实施方案中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的一些或全部彼此不同。
本文单独或组合使用的术语“稠”或“稠环”是指两个或更多个环共享一个或更多个键的环状结构。
本文单独或组合使用的术语“螺”或“螺环”是指两个或更多个环共享一个或更多个原子的环状结构。
本文单独或作为其它组分的一部分(比如：单烷基氨基)使用的术语“烷基”是指任选取代的直链或任选取代的支链的一价饱和烃，其具有1-12个碳原子，优选1-8个碳原子，更优选1-6个碳原子，通过单键与分子的其它部分相连，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、正己基、正庚基、2-甲基己基、3甲基己基、正辛基，正壬基、正癸基等。
本文单独或组合使用的术语“烯基”是指任选取代的直链或任选取代的支链的一价烃基，其具有一个或多个C＝C双键并具有2-约10个碳原子，更优选2-约6个碳原子。这些基团中的双键可以为顺式或反式构象，并应被理解为包含所述两种异构体。实例包括但不限于乙烯基(CH＝CH 2)、1-丙烯基(CH 2CH＝CH 2)、异丙烯基(C(CH 3)＝CH 2)、丁烯基和1,3-丁二烯基等。本文定义的烯基出现数字范围时，例如“C 2-C 6烯基”或“C 2- 6烯基”是指可由2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子构成的烯基，本文的烯基也涵盖未指定数字范围的情况。
本文单独或组合使用的术语“炔基”是指任选取代的直链或支链的一价烃基，其具有一个或多个C≡C三键并具有2-约10个碳原子，更优选2-约6个碳原子。实例包括但不限于乙炔基、2-丙炔基、2-丁炔基和1,3-丁二炔基等。本文定义的炔基出现数字范围时，例如“C 2-C 6炔基”或“C 2- 6炔基”是指可由2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子构成的炔基基团，本文的炔基也涵盖未指定数字范围的情况。
术语“芳基”是指具有完全共轭的π电子体系的全碳单环或稠合环，其具有6-14个碳原子，优选具有6-12个碳原子，最优选具有6个碳原子。芳基可以是非取代的或被一个或多个取代基所取代，所述取代基的实例包括但不限于烷基、 烷基氧基、芳基、芳烷基、氨基、卤素、羟基、磺酰基、亚磺酰基、磷酰基和杂脂环基。非取代的芳基的非限制性实例包括但不限于苯基、萘基和蒽基。
术语“杂芳基”是指5-12个环原子的单环或稠合环，具有5、6、7、8、9、10、11或12个环原子，其中含有1、2、3或4个选自N、O、S的环原子，其余环原子为C，且具有完全共轭的π-电子体系。杂芳基可以是非取代的或取代的，所述的取代基包括但不限于烷基、烷基氧基、芳基、芳烷基、氨基、卤素、羟基、氰基、硝基、羰基和杂脂环基。非取代的杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三嗪基。
本文单独或组合使用的术语“环烷基”是指稳定的单价非芳香单环或多环碳氢基团，只包含碳原子和氢原子，可能包括稠环、螺环或桥环系统，包含3-15个成环碳原子，优选包含3-10个成环碳原子，更优选包含3-8个成环碳原子，可饱和也可不饱和，通过单键与分子的其它部分相连。“环烷基”的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基和环庚基等。
本文单独或作为其它成分的一部分使用的术语“杂环基”、“杂环烷基”、“杂环”是指稳定的3-18元单价非芳香环，包括2-12个碳原子，1-6个选自氮、氧和硫的杂原子。除非另作说明，杂环基基团可以是单环、双环、三环或四环系统，其可能包含稠环、螺环或桥环系统，杂环基上的氮、碳或硫可选择性的被氧化，氮原子可选择性的被季铵化，杂环基可以部分或完全饱和。杂环基可以通过环上的碳原子或杂原子与分子的其余部分通过一个单键连接。包含稠环的杂环基中可以包含一个或多个芳环或杂芳环，只要与分子的其余部分连接的是非芳香环上的原子。为了本申请，杂环基优选的是一个稳定的4-11元单价非芳香单环或二环，其包含1-3个选自氮、氧和硫的杂原子，更优选的是一个稳定的4-8元单价非芳香单环，其包含1-3个选自氮、氧和硫的杂原子。杂环基的的非限制性实例包括氮杂环庚烷基、氮杂环丁基、十氢异喹啉基、二氢呋喃基、二氢吲哚基、二氧戊烷基、1,1-二氧-硫代吗啉基、咪唑烷基、咪唑啉基、异噻唑烷基、异恶唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、恶嗪基、哌嗪基、哌啶基、4-哌啶酮基、吡喃基、吡唑烷基、吡咯烷基、喹嗪基、奎宁环基、四氢呋喃基、四氢吡喃基等。
本发明使用的术语“多晶型物”或“多晶型(现象)”是指本发明的化合物具有多种晶格形态。本发明的一些化合物可能有一个以上的晶体形式，本发明涵盖所有的多晶型态或其混合物。
本发明化合物的中间体化合物及其多晶形物也在本发明的范围内。
除非另有指定，本发明化合物所含有的烯烃双键包括E和Z异构体。
应理解，本发明化合物可能含有不对称中心。这些不对称中心可以独立的为R或S构型。一些本发明化合物也可显示出顺-反异构现象，这对于本领域技术人员而言是显而易见的。应理解，本发明化合物包括它们的单独的几何异构体和立体异构体以及它们的混合物，包括外消旋混合物。通过实施或修改已知方法，例如层析技术和重结晶技术可以从它们的混合物中分离这些异构体，或者可以由它们的中间体的合适的异构体分别制备它们。
本文所用术语“药学上可接受的盐”既包括加酸盐，也包括加碱盐。
“药学上可接受的加酸盐”是指那些保留了化合物的游离碱的生物效力和特性、在生物学上或其它方面并非不合需要、跟无机酸，例如但是不限于，氢氯酸、氢溴酸、硫酸、硝酸、磷酸等，或有机酸，例如但不限于，乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、癸酸、己酸、碳酸、 肉桂酸、柠檬酸等形成的盐。“药学上可接受的加碱盐”是指那些保留了化合物的游离酸的生物效力和特性、在生物学上或其它方面并非不合需要的盐。这些盐通过游离酸跟无机碱或有机碱反应制备。通过跟无机碱反应生成的盐包括，但不限于，钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐、和锰盐。
形成盐的有机碱包括，但不限于，伯胺、仲胺、叔胺、环胺等，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、乙醇胺、二环己胺、乙二胺、嘌呤、哌嗪、哌啶、胆碱和咖啡因等。特别优选的有机碱为异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
结晶经常产生本发明化合物的溶剂化物。本文所用术语“溶剂化物”是指由一个或多个本发明化合物分子和一个或多个溶剂分子组合而成的合体。
溶剂可以是水，这种情况下，溶剂化物是水合物。另外还可以是有机溶剂。因此，本发明化合物可作为水合物存在，包括一水合物、二水合物、半水合物、三水合物、四水合物等，以及相应的溶剂化形态。本发明化合物可以是真溶剂化物，但在其它一些情况下，本发明化合物也可能只是偶然保留了水或水跟一些其它溶剂的混合物。本发明化合物可在一种溶剂中反应或在一种溶剂中沉淀或结晶。本发明化合物的溶剂化物也包括在本发明的范围内。
本文所用术语“药物组合物”是指混合有本发明化合物和通常在本领域被接受的用来将具有生物活性的化合物传送给哺乳动物(比如人类)的介质的制剂。这种介质包含所有药学上可接受的载体。
本文所用的跟制剂、组合物或成分相关的术语“可接受的”是指对治疗主体的总体健康没有持续的有害影响。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
“药学上可接受的载体”包括但不限于已经被相关政府行政部门批准的可以被用于人类和驯养动物的佐剂、载体、赋形剂、助剂、脱臭剂、稀释剂、保鲜剂、染料/着色剂、风味增强剂、表面活性剂和润湿剂、分散剂、悬浮剂、稳定剂、等渗剂、溶剂、或乳化剂。
本文所用术语“主体”、“患者”、“对象”或“个体”是指患有疾病、紊乱或病症等的个体，包括哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物为人。
本文所用术语“治疗”是指对哺乳动物特别是人类的相关疾病或病症的治疗，包括
(i)预防哺乳动物，特别是之前已经暴漏在某个疾病或病症下但尚未被诊断患有该疾病或病症的哺乳动物，产生相应的疾病或病症；
(ii)抑制疾病或病症，即，控制其发展；
(iii)缓解疾病或病症，即，使疾病或病症消退；
(iv)缓解疾病或病症引起的症状。
本文所用术语“疾病”和“病症”可以互相替代，也可以是不同意思，因为某些特定疾病或病症还没有已知的致病因子(所以发病原因尚不清楚)，所以还不能 被认作疾病而只能被看做不想要的状况或综合症，所述综合症或多或少有一些具体症状已经被临床研究人员证实。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
本发明化合物的制备
应了解，以下描述中，只有在形成稳定化合物的情况下才允许取代基团和/或所述分子式的变量进行组合。
本领域的技术人员也应了解，中间体化合物的官能团可能需要被合适的保护基团保护。保护基团可以通过本领域技术人员知道的标准技术方法加上或去掉。
实施例1：3-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000012
Figure PCTCN2021114936-appb-000013
步骤1：化合物3的合成
在0℃下，向化合物1(6.00g)、化合物2(6.29g)和三苯基膦(11.84g)的THF(150mL)溶液中滴加DIAD(9.14g)。随后，将反应液升至室温，并在室温下搅拌过夜。将反应液真空浓缩，所得残留物加入乙酸乙酯(500mL)溶解，并分别用5％Na 2CO 3水溶液(100mL×3)和饱和食盐水(100mL×3)洗涤，然后用无水硫酸钠干燥，过滤，滤液减压浓缩。所得残留物通过快速硅胶柱层析纯化(二氯甲烷：甲醇＝100:1–100:2)，获得淡黄色固体3(11.7g)。
步骤2：化合物5的合成
在氮气保护下，将化合物3(1.00g)、化合物4(1.62g)、Pd(dppf)Cl 2(234mg)和无水醋酸钾(940mg)的二氧六环(30mL)溶液加热至100℃，并在该温度下搅拌过夜。冷却至室温，反应液不进行进一步纯化直接用于下一步反应。
步骤3：化合物7的合成
在-40℃，氮气保护下，向化合物6(1.0g)的四氢呋喃(200mL)溶液中加入1M乙烯基溴化镁四氢呋喃溶液(14mL)。反应液在-40℃下继续反应1小时。随后加入饱和氯化铵水溶液(20mL)淬灭反应。反应液减压浓缩，并加入乙酸乙酯/水(80mL/80mL)。有机相分离，水相用乙酸乙酯萃取(80mL×2)。有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物通过快速硅胶柱层析(石油醚：乙酸乙酯＝10:1)分离纯化，获得化合物7(1.1g)。
步骤4：化合物9的合成
室温下，向化合物7(1.0g)和化合物8(1.2g)的DMF(20mL)溶液中加入氢化钠(0.27g)。将反应液加热至70℃搅拌1小时。将反应液减压浓缩，所得残留物通过过快速硅胶柱层析分离纯化(二氯甲烷：甲醇＝15：1)，获得目标化合物9(1.6g)。
步骤5：化合物10的合成
在0℃下，向化合物9(1.6g)的的二氯甲烷(50mL)溶液中缓慢滴加DAST(0.9mL)。反应液在此温度下继续搅拌1小时。随后加入饱和NaHCO 3水溶液 (30mL)淬灭反应。有机相分离，水相用二氯甲烷萃取(50mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物通过快速硅胶柱层析分离纯化(二氯甲烷：甲醇＝15:1)，获得化合物10(0.82g)。
步骤6：化合物11的合成
在氮气保护下，将化合物10(820mg)、化合物5(1.52g)、四三苯基膦钯(212mg)和无水碳酸钠(390mg)在二氧六环/水(20mL/5mL)中的混合物加热至80℃，并搅拌过夜。降至室温，将反应液减压浓缩，所得残留物通过快速硅胶柱层析分离纯化(石油醚：乙酸乙酯＝5:1至1:1)，获得化合物20(410mg)。
步骤7：化合物12的合成
向化合物11(410mg)的二氯甲烷(10mL)溶液中滴加三氟乙酸(1mL)，反应液于室温下搅拌2小时。将反应液减压浓缩，所得残留物通过快速硅胶柱层析进行分离纯化(二氯甲烷：甲醇＝20:1至10:1)，获得化合物12(215mg)。 1H NMR(400MHz,CDCl 3),8.82(d,J＝4.8Hz,1H),7.69(d,J＝2.4Hz,1H),7.58(s,1H),7.34(d,J＝4.8Hz,1H),7.11-7.14(m,1H),7.05(d,J＝2.0Hz,1H),6.61(d,J＝3.6Hz,1H),4.73-4.81(m,2H),3.76(dd,J＝21.6Hz,15.6Hz,1H),3.49(dd,J＝24.4Hz,15.6Hz,1H),3.08-3.17(m,2H),2.80-2.92(m,2H),2.34-2.37(m,2H),1.32-1.48(m,3H),1.21(s,3H),1.08(s,3H),0.98-1.06(m,1H)。
实施例2：3-((7-(5-氯-1-((4-羟基哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000014
实施例2中的化合物合成方法同实施例1中的步骤6、步骤7相同。 1H NMR(400MHz,CDCl 3),8.88-9.09(br,1H),8.80(d,J＝4.8Hz,1H),7.70(d,J＝2.0Hz,1H),7.56(s,1H),7.39-7.49(m,1H),7.37(d,J＝4.8Hz,1H),7.02(d,J＝2.0Hz,1H),6.62(d,J＝3.6Hz,1H),4.74-4.82(m,2H),3.64(d,J＝15.2Hz,1H),3.33(d,J＝15.2Hz,1H),2.76-3.06(m,4H),2.33-2.37(m,2H),1.23-1.39(m,3H),1.21(s,3H),1.09(s,3H),0.84-0.94(m,1H)。
实施例3：3-((7-(5-氯-1-((4-羟基哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩[3,2-b] 吡啶-2-基)甲基)-1-(2,2,2-三氟乙基)嘧啶-2,4(1H,3H)-二酮
Figure PCTCN2021114936-appb-000015
实施例3的合成方法同实施例2相同。 1H NMR(400MHz,DMSO-d 6),8.75(d,J＝4.8Hz,1H),7.77(d,J＝2.4Hz,1H),7.71(d,J＝8.0Hz,1H),7.53(s,1H),7.47(d,J＝3.2Hz,1H),7.44(d,J＝4.4Hz,1H),7.03(d,J＝1.6Hz,1H),6.63(d,J＝3.2Hz,1H),5.84(d,J＝8.0Hz,1H),5.26(d,J＝14.8Hz,1H),5.17(d,J＝14.8Hz,1H),4.94(s,1H),4.61-4.68(m,2H),3.65(d,J＝14.8Hz,1H),3.28(d,J＝14.8Hz,1H),2.65-2.87(m,4H),0.74-0.83(m,3H),0.59-0.67(m,1H)。
实施例4:3-((7-(6-氯-2-((4-羟基哌啶-4-基)甲基)-1,2,3,4-四氢异喹啉-8-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000016
Figure PCTCN2021114936-appb-000017
步骤1：化合物17的制备
将化合物15(5.0g)和化合物16(2.4g)的甲苯溶液(50mL)加热至120℃，并用分水器分去生成的水。反应液在此温度下继续反应4小时。冷却至室温，将反应液减压浓缩，获得化合物17(7.5g)粗品。该粗品不经进一步纯化直接用于下一步反应中。
步骤2：化合物18的制备
在0℃下，向化合物17粗品(7.5g)的甲醇(100mL)溶液中分批次加入硼氢化钠固体(1.4g)。加入完毕后，将反应液温度升至室温，并在室温下继续搅拌3小时。将反应液减压浓缩，并向其加入水(200mL)。水相用二氯甲烷萃取(100mL×3)。合并有机相，加入无水硫酸钠干燥，过滤，滤液减压浓缩，获得化合物18(7.5g)粗品。该粗品不经进一步纯化直接用于下一步反应中。
步骤3：化合物19的合成
在0℃下，向化合物18(7.5g)、DMAP(0.15g)和三乙胺(6.75)的二氯甲烷(150mL)溶液中加入TsCl(4.6g)。反应液于室温下搅拌过夜。将反应液减压浓缩。所得残留物通过快速硅胶柱层析分离纯化(石油醚：乙酸乙酯＝100:1至20:1)，获得化合物19(8.5g)。
步骤4：化合物20的合成
在0℃下，向化合物19(4.76g)的二氯甲烷(100mL)溶液中加入无水氯化铝(6.6g)。反应液于室温下继续搅拌16小时。随后，将反应液减压浓缩，所得残留物通过快速硅胶柱层析(石油醚：乙酸乙酯＝20:1至5:1)分离纯化，获得化合物20(1.2g)。
步骤5：化合物21的合成
在0℃下，向化合物20(1.2g)的甲醇(50mL)溶液中加入氰基硼氰化钠(1.56g)。反应液在该温度下继续搅拌20分钟，随后在此温度下，向该溶液 中滴加三氟化硼乙醚(3mL)。所得溶液在该温度下继续搅拌1小时，随后将反应液加热至回流搅拌4小时。冷却至室温，向反应液中加入饱和碳酸钠水溶液(50mL)。减压浓缩除去有机溶剂。水相用二氯甲烷(100mL×3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩。所得残留物通过快速硅胶柱层析分离纯化(二氯甲烷：甲醇＝100:1至20:1)，获得化合物21(1.2g)。
步骤6：化合物22的合成
向化合物21(1.2g)的二氯甲烷(50mL)溶液中加入三乙胺(1.5g)和Boc 2O(1.1g)，反应液于室温下搅拌过夜。将反应液减压浓缩，所得残留物通过快速硅胶柱层析(石油醚：乙酸乙酯＝100:1至30:1)分离纯化，获得化合物22(1.1g)。
步骤7：化合物23的合成
在氮气保护下，将化合物22(1.1g)、化合物4(1.2g)、Pd(dppf)Cl 2(231mg)和无水醋酸钾(780mg)的二氧六环(20mL)溶液加热至100℃搅拌过夜。所得溶液冷却至室温无需进一步纯化直接用于下一步反应中。
步骤8：化合物24的合成
在氮气保护下，将化合物23(354mg)、化合物3(282mg)、四(三苯基膦)钯(86mg)和无水碳酸钠(158mg)在二氧六环/水(8mL/2mL)中的溶液加热至100℃搅拌过夜。将反应液降至室温，减压浓缩，所得残留物通过快速硅胶柱层析进行分离纯化(二氯甲烷：甲醇＝200:1至50:1)，获得化合物24(180mg)。
步骤9：化合物25的合成
向化合物24(180mg)中加入4N HCl的二氧六环溶液(5mL)，反应液于室温下搅拌4小时。将反应液减压浓缩，获得化合物25(95mg)。
步骤10：化合物26的合成
将化合物25(75mg)、化合物8(90mg)和无水碳酸钾(50mg)的乙醇(5mL)溶液加热至80℃搅拌过夜。降至室温，减压浓缩，所得残留物通过快速减压柱层析进行纯化(二氯甲烷：甲醇＝200:1至50:1)，获得化合物26(52mg)。
步骤11：化合物27的合成
向化合物26(52mg)中加入4N HCl的二氧六环溶液(2mL)，反应液于室温下搅拌4小时。反应结束后，将反应液减压浓缩，获得化合物27(23mg)。 1H NMR(400MHz,CD 3OD),8.89(d,J＝4.8Hz,1H),7.71(s,1H),7.65(d,J＝4.8Hz,1H),7.60(s,1H),7.47(s,1H),4.90-4.94(m,2H),3.58-3.74(m,3H),3.14-3.47(m,9H),2.50(s,2H),1.76-1.98(m,4H),1.24(s,3H),1.12(s,3H)。
实施例5:3-((7-(5-氯-1-((4-羟基哌啶-4-基)甲基)-1H-苯并[d]咪唑-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000018
步骤1：化合物29的合成
将化合物28(3.00g)和28％氨水(30.0mL)加入100mL封管中，升温至70℃反应3小时。冷却至室温，将反应液直接浓缩得化合物29粗品(3.2g)，直接用于下一步反应。
步骤2：化合物30的合成
将化合物29(0.99g)溶于二氯甲烷(50mL)，依次加入5-氯-2-氟硝基苯(1.20g)和三乙胺(0.16mL)，室温搅拌过夜。反应液减压浓缩，残留物通过快速硅胶柱层析分离纯化(石油醚：乙酸乙酯＝3:1至1:1)，得到化合物30(0.90g)。
步骤3：化合物31的合成
将化合物30(0.90g)溶于乙酸(20mL)中，加入NBS(0.50g)，室温搅拌过夜。反应液减压浓缩，残留物通过快速硅胶柱层析分离纯化(石油醚：乙酸乙酯＝3:1至1:1)得到化合物31(0.80g)。
步骤4：化合物32的合成
将化合物31(0.80g)溶于乙酸(20mL)中，加入铁粉(0.46g)，室温搅拌过夜。将反应液倒入乙酸乙酯(50mL)中稀释，过滤，滤液依次用水(50mL)和饱和碳酸氢钠水溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(石油醚：乙酸乙酯＝3:1至1:1)得到化合物32(0.60 g)。
步骤5：化合物34的合成
将化合物32(0.60g)溶于原甲酸三甲酯(20mL)中，加入对甲苯磺酸(5mg)，升温至80℃搅拌2小时。降至室温，反应液倒入乙酸乙酯(100mL)中稀释，然后依次用水(50mL)和饱和碳酸氢钠水溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(石油醚：乙酸乙酯＝5:1至3:1)得到化合物33(0.50g)。随后采用实施例1化合物合成方法中的步骤6、步骤7的合成方法制备获得化合物34。 1H NMR(400MHz,DMSO-d 6)8.84-8.93(m,2H),8.76(s,1H),8.37-8.50(m,1H),8.01(d,J＝2.0Hz,1H),7.63(s,1H),7.61(d,J＝4.8Hz,1H),7.43(d,J＝2.0Hz,1H),4.78(s,2H),3.86(d,J＝14.8Hz,1H),3.52(d,J＝14.8Hz,1H),2.74-2.869(m,2H),2.59-2.73(m,2H),2.54-2.57(m,2H),1.16-1.25(m,1H),1.13(s,3H),1.02-1.09(m,1H),0.99(s,3H),0.82-0.98(m,2H)。
实施例6：3-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-苯并[d]咪唑-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000019
实施例6中的化合物以化合物33为原料通过实施例1中步骤5、步骤6、步骤7方法制备获得。 1H NMR(400MHz,DMSO-d 6),8.92-9.01(br,1H),8.72-8.88(m,2H),8.47(s,1H),7.96(d,J＝1.2Hz,1H),7.60(s,1H),7.53(d,J＝4.8Hz,1H),7.36(d,J＝1.6Hz,1H),4.76(s,2H),4.13-4.21(m,1H),3.71-3.80(m,1H),2.92-3.05(m,2H),2.36-2.66(m,5H),1.30-1.62(m,2H),1.15-1.24(m,1H),1.13(s,3H),1.02-1.10(m,1H),0.97(s,1H)。
实施例7：3-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲唑-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000020
步骤1：化合物37a和37b的合成
将化合物35(123mg)、化合物36(200mg)和碳酸铯(253mg)的二氧六环(3mL)溶液加热至90℃，并在该条件下继续搅拌60小时。降至室温，减压浓缩，所得残留物通过快速硅胶柱层析进行分离纯化(石油醚：乙酸乙酯＝3:1至1:1)，获得化合物37a(70mg)和化合物37b(53mg)。
步骤2：化合物38的合成
以化合物37a为原料，通过实施例1化合物的合成方法中步骤6、步骤7的合成方法即可制备出化合物38。 1H NMR(400MHz,CDCl 3),8.77(d,J＝4.8Hz,1H),8.06(s,1H),7.80(d,J＝2.0Hz,1H),7.57(s,1H),7.28(d,J＝2.0Hz,1H),7.23-7.26(m,1H),4.80(d,J＝15.2Hz,1H),4.74(d,J＝15.2Hz,1H),4.09(dd,J＝21.6Hz,15.6Hz,1H),3.72(t,J＝15.6Hz,1H),3.06-3.17(m,2H),2.66-2.84(m,2H),2.33-2.36(m,2H),1.71-1.92(m,2H),1.37-1.47(m,1H),1.20(s,3H),1.02-1.14(m,4H)。
实施例8：3-((7-(5-氯-2-((4-氟哌啶-4-基)甲基)-2H-吲唑-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000021
以化合物37b为原料，通过实施例1化合物的合成方法中步骤6、步骤7的合成方法即可制备出实施例8中的化合物。 1H NMR(400MHz,CD 3OD),8.68(d,J＝4.8Hz,1H),8.41(d,J＝1.2Hz,1H),7.93(d,J＝1.6Hz,1H),7.70(d,J＝5.2Hz,1H),7.57(d,J＝2.0Hz,1H),7.53(s,1H),4.84(s,2H),4.76(d,J＝20.8Hz,2H), 3.38-3.45(m,2H),3.15-3.23(m,2H),2.46(s,2H),1.93-2.13(m,4H),1.20(s,3H),1.04(s,3H)。
实施例9：3-((7-(5-氯-1-(哌啶基-4-基甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000022
步骤1：化合物40的合成
将化合物7(200mg)、化合物39(640mg)、碘化钾(14mg)和碳酸铯(850mg)的二氧六环(5mL)溶液加热至80℃，反应液在该温度下继续搅拌36小时。降至室温，减压浓缩，所得残留物加入乙酸乙酯(50mL)稀释，所得有机溶液分别用水(20mL)、饱和硫代硫酸钠溶液(20mL)和饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。所得残留物通过快速硅胶柱层析进行分离纯化(石油醚：乙酸乙酯＝3:1至2:1)，获得化合物40(153mg)。 1H NMR(400MHz,CDCl 3),8.68-8.92(m,3H),7.70(d,J＝2.4Hz,1H),7.62(s,1H),7.27(d,J＝4.4Hz,1H),7.08(d,J＝2.0Hz,1H),6.98(d,J＝3.2Hz,1H),6.51(d,J＝3.2Hz,1H),4.79(s,2H),3.51(dd,J＝14.4Hz,5.6Hz,1H),3.30(dd,J＝14.4Hz,8.4Hz,1H),3.17-3.25(m,1H),3.07-3.15(m,1H),2.30-2.44(m,3H),1.96-2.10(m,1H),1.13-1.32(m,5H),1.12(s,3H),0.96-1.09(m,1H),0.83-0.92(m,1H),0.49-0.58(m,1H)。
实施例10：3-((7-(5-氯-1-((3-氟-8-氮杂双环[3.2.1]辛烷-3-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000023
实施例10的合成方法同实施例1相同。 1H NMR(400MHz,DMSO-d 6),8.75(d,J＝4.8Hz,1H),8.45-8.72(br,2H),7.78(d,J＝2.0Hz,1H),7.53(s,1H),7.38-7.42(m,2H),7.06(d,J＝2.0Hz,1H),6.66(d,J＝3.2Hz,1H),4.72(s,2H),3.73-3.81(m,2H),3.21-3.43(m,2H),2.51-2.53(m,2H),1.59-1.85(m,5H),1.44-1.54(m,1H),1.12(s,3H),1.01-1.08(m,2H),0.98(s,3H)。
实施例11：3-((7-(5-氯-1-(((R)-吗啉-2-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000024
实施例11的合成方法同实施例9相同。 1H NMR(400MHz,CDCl 3),8.72-8.76(m,1H),7.67(d,J＝2.0Hz,1H),7.56(d,J＝5.6Hz,1H),7.24-7.28(m,1H),7.10-7.12(m,1H),7.01-7.03(m,1H),6.51-6.53(m,1H),4.74-4.82(m,2H),3.57-3.65(m,1H),3.47-3.53(m,0.5H),3.35-3.45(m,1H),3.08-3.23(m,2H),2.99-3.06(m,0.5H),2.54-2.64(m,2H),2.32-2.36(m,2H),1.82-2.01(m,1H),1.79-1.84(m,0.5H),1.62-1.66(m,0.5H),1.22(s,1.5H),1.21(s,1.5H),1.13(s,1.5H),1.08(s,1.5H)。
实施例12：3-((7-(5-氯-1-((4-甲基哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000025
实施例12的合成方法同实施例9相同。 1H NMR(400MHz,DMSO-d 6),8.77(d,J＝4.4Hz,1H),8.15-8.26(br,1H),7.81-7.95(br,1H),7.80(d,J＝2.0Hz,1H),7.55(s,1H),7.50(d,J＝4.4Hz,1H),7.44(d,J＝3.2Hz,1H),7.10(d,J＝2.0Hz,1H),6.67(d,J＝3.2Hz,1H),4.73(s,2H),3.62(d,J＝14.8Hz,1H),3.29(d,J＝14.8Hz,1H),2.65-2.92(m,4H),2.53(s,2H),1.13(s,3H),1.06-1.11(m,1H),0.92-1.03(m,5H),0.59-0.67(m,1H),0.31(s,3H)。
实施例13：3-((7-(5-氯-1-((1-乙基-4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000026
向化合物12(30mg)和无水碳酸钾(38mg)的DMF(1mL)溶液中滴加溴乙烷(12μL)。反应液于室温下反应过夜。反应结束后将反应液减压浓缩。所得残留物通过快速硅胶柱层析进行纯化(二氯甲烷：甲醇＝30:1至10:1)，获得化合物41(15mg)。 1H NMR(400MHz,CDCl 3),8.79(d,J＝4.8Hz,1H),7.68(d,J ＝2.0Hz,1H),7.55(s,1H),7.31(d,J＝4.8Hz,1H),7.11(s,1H),7.05(d,J＝2.0Hz,1H),6.60(d,J＝3.2Hz,1H),4.71-4.82(m,2H),3.78(dd,J＝21.2Hz,15.6Hz,1H),3.49(dd,J＝23.6Hz,16.0Hz,1H),2.60-3.26(m,4H),2.35-2.59(m,2H),2.33(s,2H),1.38-1.72(m,4H),1.20-1.27(m,6H),1.08(s,3H)。
实施例14：3-((7-(6-氯-3-(哌啶-4-基烯甲基)苯并呋喃-4-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000027
步骤1：0℃下向化合物42(2.0g)的丙酮溶液(100mL)中依次加入碳酸钾(2.64g)和溴丙酮(2.64g)。随后，反应液在室温下搅拌10min，并升温至60℃过夜。反应结束后将反应液过滤，获得滤液。所得滤液减压浓缩后通过快速硅胶柱层析进行纯化(石油醚：乙酸乙酯＝50:1)，获得化合物44(2.6g)。
步骤2：向化合物44中加入多聚磷酸(10mL)，反应液升温至150℃反应30min。反应结束后，加水(100mL)稀释反应液，水相用乙酸乙酯萃取(100mL×3)。合并有机相，加入无水硫酸钠干燥，过滤，滤液减压浓缩。所得残留物通过快速硅胶柱层析纯化，获得化合物45a和45b(共1.3g，约1:1)。
步骤3：在氮气保护下，向45a和45b的混合物(1.3g)的四氯化碳(100mL) 溶液中加入NBS(2.0g)和BPO(50mg)。将反应液温度升高至70℃反应过夜。冷却至室温，将反应液减压浓缩，所得残留物通过快速硅胶柱层析纯化(石油醚：乙酸乙酯＝30:1)，获得目标产物46a和46b(800mg)。
步骤4：向化合物46a和46b混合物(800mg)的四氢呋喃(5mL)溶液中加入1N HCl(5mL)。随后将反应液升温至70℃反应1h。冷却至室温，向反应液中加入水(50mL)稀释，水相用乙酸乙酯萃取(30mL×3)。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩。所得残留物通过快速硅胶柱层析纯化(石油醚：乙酸乙酯＝20:1至5:1)，获得目标产物47a和47b混合物(共500mg)。
步骤5：在-78℃，氮气保护下，向甲基三苯基溴化鏻(826mg)的无水四氢呋喃(10mL)溶液中滴加正丁基锂(2mL，2.5M)。滴加完成后，将反应液温度升至0℃，并继续反应30min。随后将反应液冷却至-78℃，并向其中滴加47a和47b混合物(500mg)的THF(5mL)溶液，随后将反应液升温至室温反应过夜。反应结束后，向反应液中加入饱和氯化铵溶液(100mL)淬灭，水相用乙酸乙酯萃取(50mL×3)。合并有机相，加入无水硫酸钠干燥，过滤，滤液减压浓缩。所得残留物通过快速硅胶柱层析纯化(石油醚：乙酸乙酯＝50:1至20:1)，获得混合物48a和48b(300mg)。
步骤6：在氮气保护下，向化合物48a和48b混合物(300mg)的二氯甲烷溶液(10mL)中加入化合物49(919mg)和Hoveyda-Grubbs二代催化剂(109mg)。随后将反应液升温至40℃搅拌过夜。反应结束后，将反应液减压浓缩。所得残留物通过快速硅胶柱层析纯化(乙酸乙酯：石油醚＝10:1至2:1)，获得混合物50a和50b(150mg)。
步骤7：在氮气保护下，将化合物50a和50b的混合物(150mg)、化合物5(100mg)、碳酸钠(80mg)和四三苯基膦钯(30mg)溶于1,4-二氧六环和水(5mL，v/v 4:1)中，反应液加热至80℃反应过夜。冷却至室温，将反应液减压浓缩，所得残留物通过快速硅胶柱层析纯化(二氯甲烷：甲醇＝200:1至100:1)，获得51a和51b混合物(100mg)。
步骤8：在室温下，向51a和51b混合物(100mg)的二氯甲烷(5mL)溶液中，加入三氟乙酸(0.5mL)，搅拌1h至反应完成。加入饱和碳酸氢钠水溶液(10mL)淬灭反应，水相用二氯甲烷萃取(10mL×3)。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩。所得残留物通过制备薄层色谱分离纯化(二氯甲烷：甲醇＝15:1)，分别得到实施例14化合物52a(20mg)和副产物52b(10mg)。化合物52a： 1H NMR(400MHz,CD 3OD),8.66(d,J＝4.4Hz,1H),7.91(s,1H),7.85(d,J＝3.6Hz,1H),7.61(d,J＝3.6Hz,1H),7.53(s,1H),7.44-7.48(m,1H),6.70-6.74(m,1H),4.86(s,2H),3.31-3.34(m,2H),3.23-3.26(m,2H),2.71-2.76(m,4H),2.48(s,2H),1.21(s,3H),1.05(s,3H)。
实施例15：3-((7-(6-氯-3-((4-氟哌啶-4-基)甲基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮盐酸盐
Figure PCTCN2021114936-appb-000028
步骤1：化合物54的合成
将化合物53(0.99g)溶于二氯甲烷(50mL)中，依次加入5-氯-2-氟硝基苯(1.20g)和三乙胺(0.16mL)，室温反应过夜，LC-MS监测反应完全，反应液直接浓缩，残留物通过快速硅胶柱层析分离纯化(石油醚：乙酸乙酯＝5:1至3:1)，得到化合物54(1.1g)。
步骤2：化合物55的合成
将化合物30(1.1g)溶于乙酸(20mL)中，加入NBS(0.60g)，室温反应过夜，LC-MS监测反应完全，反应液直接浓缩，残留物通过快速硅胶柱层析分离纯化(石油醚：乙酸乙酯＝5:1至3:1)得到化合物55(0.75g)。
步骤3：化合物56的合成
将化合物55(0.75g)溶于乙酸(20mL)中，加入铁粉(0.46g)，室温反应过夜，LC-MS监测反应完全，反应液倒入乙酸乙酯中稀释(50mL)，过滤，滤液依次用水洗(50mL)和饱和碳酸氢钠洗(50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(石油醚：乙酸乙酯＝5:1至1:1)得到化合物56(0.53g)。
步骤4：化合物58的合成
在0℃下，将化合物56(0.53g)溶于无水四氢呋喃(10mL)中，向其加入三光气(0.18g)，升温至室温反应过夜，LC-MS监测反应完全，反应液倒入乙酸乙酯中稀释(100mL)，然后依次用水洗(50mL)和饱和碳酸氢钠洗(50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过柱层析分离纯化(石油醚：乙酸乙酯＝5:1至1:1)得到化合物57(0.23g)。随后采用实施例1化合物合成方法中的步骤6，步骤7的合成方法制备获得化合物58。 1H NMR(400MHz,DMSO-d 6),11.67(s,1H),8.79-8.88(br,1H),8.73(d,J＝4.4Hz,1H),8.42-8.55(br,1H),7.54(s,1H),7.41(d,J＝4.4Hz,1H),7.20(s,1H),7.02(s,1H),4.76(s,2H),3.62-3.76(m,2H),3.28-3.40(m,2H),2.94-3.05(m,2H),2.42-2.64(m,4H),1.44-1.64(m,2H),1.13(s,3H),0.96(s,3H)。
实施例16：3-((7-(6-氯-3-((4-氟哌啶-4-基)甲基)-1-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000029
在0℃下，向化合物57(100mg)的四氢呋喃(2mL)溶液中加入氢化钠(13mg)。反应液在此温度下继续搅拌30min，随后向其中滴加碘甲烷(40μL)。将反应液温度升至室温并反应过夜。反应结束后将反应液减压浓缩，所得残留物通过快速硅胶柱层析分离纯化(石油醚：乙酸乙酯＝10:1至2:1)，获得化合物59(55mg)。随后采用实施例1化合物合成方法中的步骤6，步骤7的合成方法制备获得化合物60。 1H NMR(400MHz,DMSO-d 6),8.70-8.85(m,2H),8.34-8.50(br,1H),7.52-7.56(m,2H),7.40(d,J＝4.4Hz,1H),7.07(d,J＝1.6Hz,1H),4.76(s,2H),3.68-3.80(m,2H),3.35-3.47(m,5H),2.95-3.05(m,2H),2.42-2.64(m,4H),1.42-1.65(m,2H),1.07(s,3H),0.96(s,3H)。
实施例17：3-((7-(4-氯-3-(哌啶-4-基烯甲基)苯并呋喃-6-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000030
采用实施例14制备方法获得化合物51b即为实施例16化合物。 1H NMR(400MHz,CD 3OD),8.66(d,J＝4.4Hz,1H),7.91(s,1H),7.85(d,J＝3.6Hz,1H),7.61(d,J＝3.2Hz,1H),7.53(s,1H),7.45-7.47(m,1H),6.72(s,1H),4.85(s,2H),3.31-3.34(m,2H),3.23-3.26(m,2H),2.71-2.76(m,4H),2.48(s,2H),1.21(s,3H),1.05(s,3H)。
实施例18：3-((7-(5-氯-3-氟-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000031
Figure PCTCN2021114936-appb-000032
步骤1：化合物62的合成
在70℃下，向化合物61(5g)的乙醇(80mL)溶液中滴加液溴(4.2mL)。反应液在70℃下搅拌1h后将反应液温度降至室温，并向其中加入浓盐酸(80mL)。反应液在室温下继续搅拌30min后过滤。所得滤饼用水洗涤(20mL×3)并真空干燥，获得化合物62(5.9g)。
步骤2：化合物63的合成
在室温下，向化合物62(1g)的二氯甲烷(30mL)溶液中缓慢滴加DAST(2.5mL)。反应液于室温下反应4h。反应结束后，向反应液中加入甲醇(3mL)淬灭反应。随后将反应液减压浓缩，所得残留物通过快速硅胶柱层析进行纯化(石油醚：乙酸乙酯＝10:1)，获得化合物63(580mg)。
步骤3：化合物65的合成
在0℃下，向化合物63(500mg)的四氢呋喃(5mL)溶液中滴加硼烷二甲硫醚溶液(4.4mL，2M)，反应液于室温下反应过夜。反应结束后，将反应液用甲醇(5mL)淬灭，随后将反应液减压浓缩。所得残留物通过快速硅胶柱层析纯化(石油醚：乙酸乙酯＝100:1)，获得化合物64(360mg)。
以化合物64为原料，采用实施例7的合成方法即获得化合物65。 1H NMR(400MHz,CDCl 3),8.77(d,J＝4.8Hz,1H),7.69(d,J＝1.6Hz,1H),7.57(s,1H),7.27(d,J＝4.8Hz,1H),7.06(d,J＝1.6Hz,1H),6.98(s,1H),4.81(d,J＝14.8Hz,1H),4.75(d,J＝14.8Hz,1H),3.54(dd,J＝21.2Hz,15.6Hz,1H),3.36(dd,J＝24.0Hz,15.6Hz,1H),2.58-2.65(m,4H),2.34(s,2H),1.16-1.26(m,4H),1.08(s,3H),0.75-0.98(m,3H)。
实施例19：3-((7-(5-氯-1-(((S)-吗啉-2-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000033
实施例19的合成方法同实施例9相同。 1H NMR(400MHz,CDCl 3),8.72-8.75(m,1H),7.67(d,J＝2.4Hz,1H),7.56(d,J＝5.6Hz,1H),7.24-7.28(m,1H),7.10-7.12(m,1H),7.01-7.03(m,1H),6.51-6.52(m,1H),4.74-4.82(m,2H),3.57-3.64(m,1H),3.47-3.53(m,0.5H),3.35-3.45(m,1H),3.08-3.24(m,2H), 0.97-3.05(m,0.5H),2.53-2.63(m,2H),2.32-2.35(m,2H),1.82-2.01(m,1H),1.79-1.84(m,0.5H),1.62-1.66(m,0.5H),1.22(s,1.5H),1.21(s,1.5H),1.13(s,1.5H),1.08(s,1.5H)。
实施例20：3-((7-(5-氯-1-(吡咯烷-3-基甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮盐酸盐
Figure PCTCN2021114936-appb-000034
实施例20的合成方法同实施例9相同。 1H NMR(400MHz,DMSO-d 6),8.48-8.90(m,3H),7.80(d,J＝2.0Hz,1H),7.57(s,1H),7.51-7.52(m,2H),7.08-7.10(m,1H),6.61-6.62(m,1H),4.70-4.79(m,2H),3.88-4.01(m,1H),3.55-3.71(m,1H),3.21-3.36(m,1H),2.72-3.12(m,3H),2.44-2.54(m,3.5H),2.24-2.34(m,0.5H),1.86-1.98(m,1H),1.13(s,1.5H),1.12(s,1.5H),0.97(s,1.5H),0.95(s,1.5H)。
实施例21：1-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)吡咯烷-2,5-二酮
Figure PCTCN2021114936-appb-000035
步骤1：化合物66的合成
将化合物7(200mg)、化合物36(504mg)、碘化钾(14mg)和碳酸铯(565 mg)的二氧六环(5mL)溶液加热至80℃，反应液在该温度下继续搅拌36h至反应完成。反应结束后，减压浓缩，所得残留物加入乙酸乙酯稀释(50mL)，所得有机溶液分别用水(20mL)、饱和硫代硫酸钠溶液(20mL)、饱和食盐水(20mL)洗涤。所得有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。所得残留物通过快速硅胶柱层析进行分离纯化(石油醚：乙酸乙酯＝3:1至2:1)，获得化合物66(210mg)。
步骤2：化合物68的合成
在氮气保护下，将化合物66(210mg)、化合物67(286mg)、四三苯基膦钯(54mg)和无水碳酸钠(100mg)在二氧六环/水8mL/2mL)中的混合物加热至80℃，并搅拌过夜。降至室温，将反应液减压浓缩，所得残留物通过快速硅胶柱层析进行分离纯化(二氯甲烷：甲醇＝100:1至100:3)，获得化合物68(204mg)。
步骤3：化合物69的合成
在室温下，向化合物68(204mg)的四氢呋喃(3mL)溶液中加入TBAF(100mg)。反应液在室温下继续搅拌过夜至反应结束。将反应液减压浓缩，所得残留物通过快速硅胶柱层析进行分离纯化(二氯甲烷：甲醇＝100:1至100:3)获得化合物69(115mg)。
步骤4：化合物71的合成
在0℃下，向化合物69(110mg)、化合物70(41mg)和三苯基膦(108mg)的无水四氢呋喃(2mL)溶液中滴加DIAD(84mg)。随后将反应液升温至室温，并搅拌过夜。反应结束后，将反应液浓缩。所得残留物通过快速硅胶柱层析进行分离纯化(二氯甲烷：甲醇＝200:1至100:1)，获得化合物71(65mg)。
步骤5：化合物72的合成
室温下，向化合物71(65mg)的二氯甲烷(2mL)溶液中加入三氟乙酸(0.2mL)。反应液于室温下继续搅拌2h至反应完成。反应完成后，将反应液减压浓缩，并通过快速硅胶柱层析进行分离纯化(二氯甲烷：甲醇＝100:1至10:1)，获得化合物72(26mg)。 1H NMR(400MHz,CD 3OD),8.54-8.99(m,1H),7.71(s,1H),7.42-7.62(m,2H),7.31(s,1H),7.08(s,1H),6.65(d,J＝2.8Hz,1H),4.85-4.95(m,2H),3.99(dd,J＝20.8Hz,16.0Hz,1H),3.62(dd,J＝22.0Hz,15.2Hz,1H),3.24-3.39(m,4H),3.07-3.14(m,2H),2.80-2.92(m,2H),1.11-1.43(m,4H)。
实施例22：3-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-1-(2,2,2-三氟乙基)嘧啶-2,4(1H,3H)-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000036
实施例22的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.75(d,J＝4.8Hz,1H),8.31-8.71(br,2H),7.79(d,J＝2.0Hz,1H),7.71(d,J＝8.0Hz,1H),7.54(s,1H),7.40-7.43(m,2H),7.06(d,J＝2.4Hz,1H),6.67(d,J＝3.2Hz, 1H),5.84(d,J＝8.0Hz,1H),5.27(d,J＝15.2Hz,1H),5.15(d,J＝15.2Hz,1H),4.61-4.68(m,2H),3.96-4.05(m,1H),3.39-3.50(m,1H),2.97-3.05(m,2H),2.58-2.70(m,2H),0.85-1.34(m,4H)。
实施例23：3-((7-(1-(2-(氮杂环丁-3-基)乙基)-5-氯-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000037
实施例23的合成方法同实施例9相同。 1H NMR(400MHz,DMSO-d 6),8.77(d,J＝4.4Hz,1H),8.42-8.67(br,2H),7.78(d,J＝2.0Hz,1H),7.56(s,1H),7.54(d,J＝4.8Hz,1H),7.44(d,J＝3.2Hz,1H),7.07(d,J＝1.6Hz,1H),6.60(d,J＝2.4Hz,1H),4.74(s,2H),3.46-3.61(m,3H),2.98-3.19(m,3H),2.54(s,2H),1.92-2.04(m,1H),1.33-1.39(m,2H),1.12(s,3H),0.96(s,3H)。
实施例24：3-((7-(1-((3-氮杂双环[3.1.0]己-6-基)甲基)-5-氯-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000038
实施例24的合成方法同实施例9相同。 1H NMR(400MHz,DMSO-d 6),8.73(d,J＝4.4Hz,1H),7.76(d,J＝2.0Hz,1H),7.55(s,1H),7.52(d,J＝4.8Hz,1H),7.47(d,J＝3.2Hz,1H),7.04(d,J＝2.4Hz,1H),6.58(d,J＝3.6Hz,1H),4.73(s,2H),3.23(d,J＝6.8Hz,2H),2.52(s,2H),2.38-2.48(m,4H),1.12(s,3H),0.93-0.99(s,4H),0.88-0.92(m,1H),0.46-0.52(m,1H)。
实施例25：4-((5-氯-7-(2-((6,6-二甲基-2,4-二氧代-3-氮杂双环[3.1.0]己-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000039
实施例25的合成方法同实施例9相同。 1H NMR(400MHz,DMSO-d 6),8.81 (d,J＝4.4Hz,1H),7.81(d,J＝2.0Hz,1H),7.56(s,1H),7.50-7.53(m,2H),7.09(d,J＝2.0Hz,1H),6.70(d,J＝3.2Hz,1H),4.68-4.769m,2H),3.89(d,J＝15.2Hz,1H),3.40(d,J＝15.2Hz,1H),2.60-2.66(m,2H),2.52(s,2H),2.22-2.32(m,2H),2.01-2.18(br,1H),1.24-1.31(m,1H),1.12(s,3H),0.96(s,3H),0.69-0.84(m,3H)。
实施例26：3-((7-(5-氯-3-氟-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000040
在室温下，向化合物35(1.2g)和冰醋酸(1mL)的乙腈(100mL)溶液中加入选择氟试剂(3.5g)。反应液加热至80℃反应24h。降至室温，将反应液减压浓缩，所得残留物通过快速硅胶柱色谱进行纯化(石油醚：乙酸乙酯＝20:1至10:1)，获得化合物73(705mg)。
以化合物73为原料，用实施例7的合成方法合成化合物74。 1H NMR(400MHz,CDCl 3),9.10-9.60(br,2H),8.78(d,J＝3.6Hz,1H),7.76(d,J＝2.0Hz,1H),7.59(s,1H),7.33(d,J＝2.0Hz,1H),7.25-7.26(m,1H),4.74-4.84(m,2H),3.84-3.94(m,1H),3.57(t,J＝16.0Hz,1H),3.01-3.22(m,2H),2.67-2.91(m,2H),2.35-2.38(m,2H),1.71-1.95(m,2H),1.44-1.52(m,1H),1.21(s,3H),1.11-1.18(m,1H),1.08(s,3H)。
实施例27：3-((7-(5-氯-1-(2-(哌啶-2-基)乙基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000041
实施例27的和合成方法同实施例9相同。 1H NMR(400MHz,CDCl 3),8.97-9.47(br,1.5H),8.67-8.92(m,1.5H),7.61-7.71(m,2H),7.43-7.58(m,1H),7.33(d,J＝3.2Hz,0.5H),7.20(d,J＝3.2Hz,0.5H),7.06(d,J＝2.0Hz,0.5H),7.03(d,J＝2.0Hz,0.5H),6.49(d,J＝2.0Hz,1H),4.75-4.87(m,2H),3.51-3.78(m,2H),3.10-3.22(m,1H),2.48-2.69(m,1.5H),2.14-2.43(m,4.5H),1.96-2.12(m,1H),1.37-1.88(m,5H),1.20-1.24(m,3H),1.13(s,1.5H),1.11(s,1.5H)。
实施例28：3-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)吲哚啉-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000042
在室温下，向化合物10(200mg)的三氟乙酸(5mL)溶液中加入氰基硼氢化钠(45mg)。随后将反应液加热至70℃，反应1h至反应结束。降至室温，将反应液减压浓缩，并向其加入饱和碳酸氢钠溶液(20mL)。水相用二氯甲烷萃取(30mL×3)。合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩。将所得残留物溶解于二氯甲烷(5mL)中，并依次加入DMAP(5mg)、三乙胺(0.2mL)和Boc酸酐(150mg)，反应液于室温下反应过夜并减压浓缩。所得残留物通过快速硅胶柱层析纯化，获得化合物75(110mg)。
以化合物75为原料，采用实施例1化合物合成方法中的步骤6，步骤7的合成方法制备获得化合物76。 1H NMR(400MHz,CDCl 3),9.63-9.82(br,1H),9.13-9.23(m,1H),8.10-8.33(br,1H),7.89-7.97(m,1H),7.53-7.62(m,1H),7.16(s,1H),6.96(s,1H),4.88(s,2H),3.38-3.61(m,4H),2.98-3.15(m,4H),2.66(d,J＝23.2Hz,2H),2.43(s,2H),1.90-1.98(m,4H),1.24(s,3H),1.14(s,3H)。
实施例29：1-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-3,3-二甲基吡咯烷-2,5-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000043
实施例29的和合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.01-9.42(br,2H),8.70-8.80(m,1H),7.67(d,J＝2.0Hz,1H),7.54(s,1H),7.35(d,J＝4.4Hz,1H),7.08-7.12(m,1H),7.05(d,J＝2.0Hz,1H),6.60(d,J＝3.2Hz,1H),4.80-4.92(m,2H),3.80(dd,J＝20.8Hz,16.0Hz,1H),3.46(dd,J＝24.8Hz,16.0Hz,1H),2.98-3.12(m,2H),2.72-2.88(m,2H),2.54(s,2H),1.30-1.60(m,3H),1.26(s,3H),1.24(s,3H),0.92-1.12(m,1H)。
实施例30：7-(2-((6,6-二甲基-2,4-二氧代-3-氮杂双环[3.1.0]己-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-5-甲腈
Figure PCTCN2021114936-appb-000044
实施例30的合成方法同实施例9相同。 1H NMR(400MHz,DMSO-d 6),8.77(d,J＝4.8Hz,1H),8.28(d,J＝1.2Hz,1H),7.55(s,1H),7.52(d,J＝3.2Hz,1H),7.43-7.47(m,2H),6.81(d,J＝3.2Hz,1H),4.73(s,2H),3.87(dd,J＝21.6Hz,15.2Hz,1H),3.43(dd,J＝20.0Hz,15.6Hz,1H),2.52(s,2H),2.39-2.47(m,2H),2.20-2.33(m,2H),1.12(s,3H),0.81-1.1(m,6H),0.62-0.71(m,1H)。
实施例31：3-((7-(7-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-5-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000045
实施例31的合成方法同实施例9相同。 1H NMR(400MHz,CDCl 3),8.67(d,J＝4.8Hz,1H),7.89(d,J＝1.2Hz,1H),7.57(s,1H),7.47(d,J＝1.6Hz,1H),7.26-7.28(m,2H),6.65(d,J＝3.2Hz,1H),4.83(s,2H),4.81(d,J＝23.2Hz,2H),2.83-2.97(m,4H),2.34(s,2H),1.54-1.74(m,4H),1.20(s,3H),1.08(s,3H)。
实施例32：3-((7-(6-氯-3-(哌啶-4-基烯甲基)苯并[b]噻吩-4-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000046
实施例32的合成方法同实施例14相同。 1H NMR(400MHz,CD 3OD),8.68-8.77(m,1H),8.13(d,J＝1.2Hz,1H),7.50(s,1H),7.38-7.41(m,2H),7.36(d,J＝2.0Hz,1H),5.30(s,1H),4.77-4.88(m,2H),3.07-3.13(m,1H),2.95-3.01(m,1H),2.59-2.65(m,1H),2.47-2.50(m,2H),2.31-2.44(m,3H),1.93-2.01(m,1H),1.63-1.70(m,1H),1.21(s,3H),1.07(s,3H)。
实施例33：3-((7-(4-氯-3-(哌啶-4-基烯甲基)苯并[b]噻吩-6-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000047
实施例33的合成方法同实施例17相同。 1H NMR(400MHz,CD 3OD), 8.62-8.70(m,1H),8.23(d,J＝1.6Hz,1H),7.72(d,J＝1.2Hz,1H),7.58(s,1H),7.52(s,1H),7.47(d,J＝5.2Hz,1H),6.90(s,1H),4.85(s,2H),3.32-3.35(m,2H),3.20-3.23(m,2H),2.71-2.74(m,2H),2.65-2.68(m,2H),2.47(s,2H),1.21(s,3H),1.05(s,3H)。
实施例34：3-((7-(5-氯-1-((1,2,3,6-四氢吡啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000048
实施例34的和合成方法同实施例9相同。 1H NMR(400MHz,DMSO-d 6),8.74(d,J＝4.4Hz,1H),8.38-8.52(br,2H),7.80(d,J＝2.0Hz,1H),7.56(s,1H),7.41-7.44(m,2H),7.08(d,J＝2.4Hz,1H),6.64(d,J＝2.8Hz,1H),4.70-4.80(m,2H),4.24-4.32(m,1H),4.11(s,1H),3.84-3.90(m,1H),3.14(s,2H),2.80-2.88(m,1H),2.57-2.66(m,1H),2.56(s,2H),1.32-1.42(m,1H),1.19-1.28(m,1H),1.14(s,3H),1.00(s,3H)。
实施例35：3-((7-(5-氯-3-氟-1-(吡咯烷-3-基甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000049
实施例35的和合成方法同实施例18相同。 1H NMR(400MHz,DMSO-d 6),8.76-8.79(m,1H),8.30-8.54(br,2H),7.80-7.82(m,1H),7.55-7.59(m,2H),7.53(d,J＝4.8Hz,1H),7.20-7.21(m,1H),4.70-4.79(m,2H),3.42-3.55(m,1H),3.02-3.24(m,2H),2.75-2.98(m,2H),2.51-2.60(m,3H),2.23-2.31(m,1H),1.89-2.01(m,2H),1.10-1.16(m,3H),0.98(s,1.5H),0.95(s,1.5H)。
实施例36：3-((7-(5-氯-3-氟-1-(((S)-吗啉-2-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000050
实施例36的和合成方法同实施例18相同。 1H NMR(400MHz,DMSO-d 6),8.74-8.78(m,1H),7.80-8.30(br,2H),7.78-7.79(m,1H),7.55-7.57(m,1H),7.43-7.50(m,2H),7.17-7.19(m,1H),4.70-4.79(m,2H),3.48-3.62(m,2H), 3.07-3.28(m,3H),2.85-2.92(m,1H),2.47-2.66(m,3H),2.34-2.42(m,0.5H),2.06-2.17(m,1.5H),1.11-1.15(m,3H),0.96-1.11(m,3H)。
实施例37：1-((4-氰基哌啶-4-基)甲基)-7-(2-((6,6-二甲基-2,4-二氧代-3-氮杂双环[3.1.0]己烷-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-5-甲腈
Figure PCTCN2021114936-appb-000051
实施例37的合成方法同实施例9相同。 1H NMR(400MHz,DMSO-d 6),8.84(d,J＝4.8Hz,1H),8.33(d,J＝1.6Hz,1H),7.68(d,J＝3.6Hz,1H),7.58(s,1H),7.55(d,J＝4.8Hz,1H),7.51(d,J＝1.6Hz,1H),6.91(d,J＝2.8Hz,1H),4.75(d,J＝15.6Hz,1H),4.70(d,J＝15.6Hz,1H),4.13(d,J＝14.8Hz,1H),3.44(d,J＝14.8Hz,1H),3.04-3.15(m,2H),2.56-2.66(m,2H),2.53(s,2H),1.63-1.70(m,1H),1.14-1.26(m,2H),1.13(s,3H),0.98-1.06(m,1H),0.96(s,3H)。
实施例38：4-((5-氯-7-(2-((2,5-氧代-3-(2,2,2-三氟乙基)咪唑啉-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000052
实施例38的合成方法同实施例9相同。 1H NMR(400MHz,CDCl 3),9.34-9.85(br,2H),8.82(d,J＝5.2Hz,1H),7.71(d,J＝2.0Hz,1H),7.61(s,1H),7.48(d,J＝4.8Hz,1H),7.28(d,J＝3.6Hz,1H),7.09(d,J＝2.0Hz,1H),6.70(d,J＝3.6Hz,1H),4.94(d,J＝15.6Hz,1H),4.90(d,J＝15.6Hz,1H),4.04(s,2H),3.92-3.99(m,2H),3.83(d,J＝15.2Hz,1H),3.54(d,J＝15.2Hz,1H),3.21(t,J＝14.8Hz,2H),2.83-2.92(m,2H),1.62-1.70(m,1H),1.34-1.50(m,2H),1.02-1.09(m,1H)。
实施例39：4-((5-氯-7-(2-((2,5-二氧代吡咯烷-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000053
实施例39的合成方法同实施例9相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.4Hz,1H),7.80(s,1H),7.57(s,1H),7.46-7.55(m,2H),7.09(s,1H), 6.68-6.73(m,1H),4.84(d,J＝16.0Hz,1H),4.74(d,J＝16.0Hz,1H),3.95(d,J＝14.8Hz,1H),3.86(d,J＝14.8Hz,1H),2.51-2.54(m,6H),2.05-2.08(m,2H),1.25-1.35(m,2H),0.74-0.85(m,2H)。
实施例40：3-((7-(5-氯-1-(((R)-吗啉-2-基)甲基)-1H-苯并[d]咪唑-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000054
实施例40的合成方法同实施例5相同。 1H NMR(400MHz,CDCl 3),8.94-11.06(br,2H),8.66-8.81(m,1H),8.06(s,0.33H),7.96(s,0.67H),7.91(s,1H),7.57(s,0.67H),7.54(s,0.33H),7.35(d,J＝4.8Hz,0.67H),7.38(d,J＝4.8Hz,0.33H),7.22(d,J＝1.6Hz,0.33H),7.20(d,J＝1.6Hz,0.67H),4.74-4.84(m,2H),3.82-3.92(m,1H),3.42-3.74(m,3H),3.25-3.34(m,0.67H),3.08-3.21(m,1H),2.81-2.97(m,1.33H),2.18-2.44(m,4H),1.23(s,1H),1.21(s,2H),1.14(s,1H),1.10(s,2H)。
实施例41：3-((7-(5-氯-1-(((R)-吗啉-2-基)甲基)-1H-吲唑-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000055
实施例41的合成方法同实施例7相同。 1H NMR(400MHz,CDCl 3),8.72-8.79(m,1H),8.05(s,1H),7.81(d,J＝2.0Hz,0.5H),7.80(d,J＝2.0Hz,0.5H),7.58(s,0.5H),7.56(s,0.5H),7.25-7.28(m,2H),4.73-4.82(m,2H),3.87-3.92(m,1H),3.35-3.74(m,4H),2.93-2.99(m,1H),2.85(d,J＝12.8Hz,0.5H),2.61-2.76(m,1.5H),2.28-2.37(m,3H),1.20(s,3H),1.10(s,1.5H),1.09(s,1.5H)。
实施例42：3-((7-(6-氯-3-(((R)-吗啉-2-基)甲基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000056
实施例42的合成方法同实施例15相同。 1H NMR(400MHz,CDCl 3),11.27(s, 0.5H),11.21(s,0.5H),9.36-10.02(br,2H),8.79(d,J＝5.2Hz,0.5H),8.77(d,J＝5.2Hz,0.5H),7.63(s,0.5H),7.59(s,0.5H),7.32(d,J＝4.8Hz,0.5H),7.27(d,J＝4.8Hz,0.5H),7.20(d,J＝2.0Hz,0.5H),7.18(d,J＝2.0Hz,0.5H),6.97(d,J＝2.0Hz,0.5H),6.94(d,J＝2.0Hz,0.5H),4.73-4.88(m,2H),3.41-3.63(m,3H),3.22-3.32(m,1H),2.95-3.19(m,3H),2.76-2.90(m,0.5H),2.58-2.72(m,0.5H),2.34-2.54(m,3H),1.23(s,1.5H),1.22(s,1.5H),1.14(s,1.5H),1.10(s,1.5H)。
实施例43：3-((7-(4-氯-3-(哌啶-4-基甲基)苯并[b]噻吩-6-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000057
实施例43的合成方法同实施例17相同。 1H NMR(400MHz,CD 3OD),8.67(d,J＝5.2Hz,1H),7.86(s,1H),7.83(s,1H),7.64(s,1H),7.54(s,1H),7.47(d,J＝4.8Hz,1H),4.86(s,2H),3.37-3.43(m,2H),2.90-3.02(m,4H),2.47(s,2H),2.21-2.31(m,1H),1.98-2.06(m,2H),1.48-1.57(m,2H),1.21(s,3H),1.05(s,3H)。
实施例44：3-((7-(6-氯-3-(哌啶-4-基甲基)苯并呋喃-4-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000058
实施例44的合成方法同实施例14相同。 1H NMR(400MHz,CD 3OD),8.75(d,J＝4.8Hz,1H),7.74(d,J＝2.4Hz,1H),7.70(s,1H),7.57(d,J＝2.0Hz,1H),7.43(d,J＝5.2Hz,1H),7.30(s,1H),4.85(s,2H),3.04-3.17(m,2H),2.39-2.51(m,3H),2.19-2.28(m,1H),2.09(dd,J＝14.4Hz,6.0Hz,1H),1.92(dd,J＝14.4Hz,7.2Hz,1H),1.28-1.32(m,1H),1.22(s,3H),1.10(s,3H),1.11-1.17(m,1H),0.93-0.98(m,1H),0.82-0.87(m,1H),0.62-0.74(m,1H)。
实施例45：3-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)噁唑啉-2,4-二酮
Figure PCTCN2021114936-appb-000059
实施例45的合成方法同实施例21相同。 1H NMR(400MHz,CD 3OD),8.76(d,J＝4.8Hz,1H),7.72(d,J＝2.4Hz,1H),7.60(s,1H),7.47(d,J＝4.8Hz,1H), 7.30-7.32(m,1H),7.12(d,J＝2.0Hz,1H),6.67(d,J＝2.4Hz,1H),4.93-5.01(m,2H),4.82(s,2H),4.01(dd,J＝20.0Hz,15.6Hz,1H),3.64(dd,J＝22.0Hz,16.0Hz,1H),3.08-3.14(m,2H),2.82-2.91(m,2H),1.12-1.53(m,4H)。
实施例46：3-((7-(5-氯-3-氟-1-(((R)-吗啉-2-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000060
实施例46的合成方法同实施例18相同。 1H NMR(400MHz,DMSO-d 6),8.77(d,J＝4.8Hz,0.4H),8.75(d,J＝4.8Hz,0.6H),7.77-7.78(m,1H),7.55-7.57(m,1H),7.42-7.49(m,2H),7.17-7.18(m,1H),4.74(s,2H),3.46-3.59(m,2H),3.02-3.22(m,3H),2.74-2.81(m,1H),2.39-2.58(m,3H),1.92-2.04(m,2H),1.11-1.15(m,3H),0.99(s,1.8H),0.97(s,1.2H)。
实施例47：4-((5-氯-7-(2-((6,6-二甲基-2,4-二氧-3-氮杂双环[3.1.0]己-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-3-氟-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000061
实施例47的合成方法同实施例18相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝4.4Hz,1H),7.81(d,J＝2.0Hz,1H),7.55-7.58(m,2H),7.53(d,J＝4.4Hz,1H),7.20(d,J＝2.0Hz,1H),4.69-4.77(m,2H),3.78(d,J＝15.2Hz,1H),3.33(d,J＝15.2Hz,1H),2.60-2.68(m,2H),2.53(s,2H),2.23-2.32(m,2H),1.27-1.34(m,1H),1.13(s,3H),0.96(s,3H),0.70-0.86(m,3H)。
实施例48：3-((7-(5-氯-1-(((S)-吗啉-2-基)甲基)-1H-吲唑-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000062
实施例48的合成方法同实施例7相同。 1H NMR(400MHz,CDCl 3),8.76(d,J＝4.8Hz,1H),8.05(s,1H),7.81(d,J＝1.6Hz,0.5H),7.80(d,J＝1.6Hz,0.5H),7.58(s,0.5H),7.56(s,0.5H),7.26-7.28(m,2H),4.73-4.83(m,2H),3.78-3.96(m,1.5H),3.60-3.74(m,2.5H),3.34-3.58(m,1.5H),2.59-2.98(m,2.5H),2.28-2.36(m,3H),1.22-1.25(m,3H),1.10(s,1.5H),1.09(s,1.5H)。
实施例49：3-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-1-甲基咪唑啉-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000063
实施例49的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.73-9.98(br,1H),8.89-9.09(br,1H),8.82-8.89(m,1H),7.71(d,J＝2.0Hz,1H),7.67(s,1H),7.40-7.44(m,1H),7.13-7.17(m,1H),7.08(d,J＝2.0Hz,1H),6.63(d,J＝3.2Hz,1H),4.88-4.97(m,2H),3.91(s,2H),3.72-3.82(m,1H),3.56(dd,J＝23.6Hz,16.0Hz,1H),3.04-3.14(m,2H),2.97(s,3H),2.76-2.93(m,2H),1.05-1.56(m,4H)。
实施例50：3-((7-(5-氯-1-(((S)-吗啉-2-基)甲基)-1H-苯并[d]咪唑-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000064
实施例50的合成方法同实施例5相同。 1H NMR(400MHz,DMSO-d 6),9.32-9.52(br,1H),8.98-9.18(br,1H),8.79-8.81(m,1H),8.41(s,0.4H),8.31(s,0.6H),7.93(s,1H),7.51-7.60(m,2H),7.33(s,1H),4.71-4.80(m,2H),3.97-4.03(m,0.6H),3.75-3.82(m,1H),3.26-3.60(m,4H),2.92-3.02(m,1.4H),2.63-2.71(m,1H),2.55(s,1.2H),2.4(s,0.8H),2.19-2.32(m,1H),1.13(s,3H),1.00(s,1.8H),0.98(s,1.2H)。
实施例51：2-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)环戊-1,3-二酮
Figure PCTCN2021114936-appb-000065
实施例51的合成方法同实施例21相同。 1H NMR(400MHz,CD 3OD),8.58(d,J＝4.4Hz,1H),7.68-7.70(m,1H),7.35(s,1H),7.31(s,1H),7.20(d,J＝4.8Hz,1H),7.08(s,1H),6.64(d,J＝2.8Hz,1H),3.93(t,J＝16.0Hz,1H),3.29-3.80(m,3H),2.79-3.11(m,4H),2.29(s,4H),1.48-1.57(m,1H),0.92-1.33(m,4H)。
实施例52：3-((7-(1-(氮杂环丁-3-基甲基)-5-氯-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000066
实施例52的合成方法同实施例7相同。 1H NMR(400MHz,DMSO-d 6),8.75(d,J＝5.2Hz,1H),8.21-8.53(br,2H),7.80(d,J＝2.0Hz,1H),7.56(s,1H),7.50(d,J＝4.8Hz,1H),7.48(d,J＝3.2Hz,1H),7.08(d,J＝2.0Hz,1H),6.63(d,J＝3.6Hz,1H),4.78(d,J＝15.6Hz,1H),4.72(d,J＝15.6Hz,1H),3.82(dd,J＝14.8Hz,8.0Hz,1H),3.31-3.50(m,5H),2.53-2.61(m,3H),1.13(s,3H),0.98(s,3H)。
实施例53：3-((5-氯-7-(2-((6,6-二甲基-2,4-二氧代-3-氮杂双环[3.1.0]己-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)氮杂环丁基-3-甲腈
Figure PCTCN2021114936-appb-000067
实施例53的合成方法同实施例7相同。 1H NMR(400MHz,DMSO-d 6),8.77(d,J＝4.4Hz,1H),7.81(d,J＝2.0Hz,1H),7.55(s,1H),7.51(d,J＝3.6Hz,1H),7.47(d,J＝4.8Hz,1H),7.09(d,J＝2.0Hz,1H),6.70(d,J＝3.2Hz,1H),4.73(s,2H),4.16(d,J＝15.6Hz,1H),3.67(d,J＝15.6Hz,1H),3.25(d,J＝8.0Hz,1H),3.15(d,J＝8.0Hz,1H),3.12(d,J＝8.0Hz,1H),2.99(d,J＝8.0Hz,1H),2.53(s,2H),1.12(s,3H),0.95(s,3H)。
实施例54：3-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-1-(2,2,2-三氟乙基)咪唑啉-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000068
实施例54的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.43-9.78(br,1H),8.98-9.33(br,1H),8.68-8.86(m,1H),7.69(d,J＝1.6Hz,1H),7.57-7.62(m,1H),7.33(s,1H),7.11(s,1H),7.07(d,J＝2.0Hz,1H),6.62(d,J＝3.2Hz,1H),4.89-4.97(m,2H),4.05(s,2H),3.93-4.01(m,2H),3.80(dd,J＝21.6Hz,16.0Hz,1H),3.53(dd,J＝24.0Hz,16.0Hz,1H),2.98-3.10(m,2H),2.75-2.90(m,2H),1.22-1.58(m,3H),0.99-1.08(m,1H)。
实施例55：4-((5-氯-7-(2-((6,6-二甲基-2,4-二氧代-3-氮杂双环[3.1.0]己-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-苯并[d]咪唑-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000069
实施例55的合成方法同实施例5相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝5.2Hz,1H),8.38-8.56(m,2H),8.14-8.33(br,1H),7.98(d,J＝2.0Hz,1H),7.58(s,1H),7.54(d,J＝4.8Hz,1H),7.36(d,J＝2.0Hz,1H),4.70-4.79(m,2H),4.24(d,J＝15.2Hz,1H),3.70(d,J＝15.2Hz,1H),3.07-3.16(m,2H),2.60-2.72(m,2H),2.54(s,2H),1.64-1.71(m,1H),1.10-1.26(m,6H),0.99(s,3H)。
实施例56：3-((7-(5-氯-1-((3-氟氮杂环丁基-3-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000070
实施例56的合成方法同实施例9相同。 1H NMR(400MHz,DMSO-d 6),8.72(d,J＝4.8Hz,1H),7.78(d,J＝2.0Hz,1H),7.53(s,1H),7.49(d,J＝3.2Hz,1H),7.41(d,J＝4.8Hz,1H),7.07(d,J＝2.4Hz,1H),6.65(d,J＝3.2Hz,1H),4.73(s,2H),4.09(dd,J＝22.0Hz,15.6Hz,1H),3.77(dd,J＝21.2Hz,15.6Hz,1H),3.05-3.23(m,4H),2.53(s,2H),1.12(s,3H),0.95(s,3H)。
实施例57：3-((7-(6-氯-3-((4-环丙基哌嗪-1-基)甲基)苯并呋喃-4-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000071
实施例57的合成方法同实施例14相同。 1H NMR(400MHz,CD 3OD),8.68-8.76(m,1H),7.82(s,1H),7.74(d,J＝1.6Hz,1H),7.56(s,1H),7.37(d,J＝5.2Hz,1H),7.35(d,J＝1.6Hz,1H),4.85(s,2H),3.28-3.35(m,1H),2.91-3.01(m,1H),2.49(s,2H),1.65-2.08(m,8H),1.51-1.63(m,1H),1.23(s,3H),1.14(s,3H),0.50-0.72(m,4H)。
实施例58：3-((7-(6-氯-3-((4-异丙基哌嗪-1-基)甲基)苯并呋喃-4-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000072
实施例58的合成方法同实施例14相同。 1H NMR(400MHz,CD 3OD),8.73(d, J＝5.2Hz,1H),7.85(s,1H),7.76(d,J＝2.0Hz,1H),7.56(s,1H),7.39(d,J＝4.8Hz,1H),7.37(d,J＝1.6Hz,1H),4.84(s,2H),3.29(s,2H),2.88-3.19(m,4H),2.51(s,2H),2.14-2.30(m,1H),1.78-2.10(m,4H),1.24(s,3H),1.16(d,J＝6.8Hz,6H),1.13(s,3H)。
实施例59：3-((7-(6-氯-3-(((R)-吗啉-2-基)甲基)-2-硫代-2,3-二氢-1H-苯并[d]咪唑-4-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000073
实施例59的合成方法同实施例15相同。 1H NMR(400MHz,CDCl 3),12.40-12.59(br,1H),9.08-9.99(br,2H),8.76-8.85(m,1H),7.63(s,0.5H),7.61(s,0.5H),7.38-7.46(m,1H),7.34(s,0.5H),7.28(d,J＝4.8Hz,0.5H),7.10(s,0.5H),7.03(s,0.5H),4.75-4.91(m,2H),4.19-4.34(m,1H),3.22-3.82(m,4H),2.51-3.18(m,4H),2.35-2.44(m,2H),1.23(s,1.5H),1.21(s,1.5H),1.17(s,1.5H),1.09(s,1.5H)。
实施例60：3-((7-(6-氯-3-(((S)-吗啉-2-基)甲基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000074
实施例60的合成方法同实施例15相同。 1H NMR(400MHz,CDCl 3),11.27(s,0.5H),11.21(s,0.5H),9.36-10.02(br,2H),8.79(d,J＝5.2Hz,0.5H),8.77(d,J＝5.2Hz,0.5H),7.63(s,0.5H),7.59(s,0.5H),7.32(d,J＝4.8Hz,0.5H),7.27(d,J＝4.8Hz,0.5H),7.20(d,J＝2.0Hz,0.5H),7.18(d,J＝2.0Hz,0.5H),6.97(d,J＝2.0Hz,0.5H),6.94(d,J＝2.0Hz,0.5H),4.73-4.88(m,2H),3.41-3.63(m,3H),3.22-3.32(m,1H),2.95-3.19(m,3H),2.76-2.90(m,0.5H),2.58-2.72(m,0.5H),2.34-2.54(m,3H),1.23(s,1.5H),1.22(s,1.5H),1.14(s,1.5H),1.10(s,1.5H)。
实施例61：3-((7-(6-氯-3-(((S)-吗啉-2-基)甲基)-2-硫代-2,3-二氢-1H-苯并[d]咪唑-4-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000075
实施例61的合成方法同实施例15相同。 1H NMR(400MHz,CDCl 3),12.40-12.59(br,1H),9.08-9.99(br,2H),8.76-8.85(m,1H),7.63(s,0.5H),7.61(s,0.5H),7.38-7.46(m,1H),7.34(s,0.5H),7.28(d,J＝4.8Hz,0.5H),7.10(s,0.5H),7.03(s,0.5H),4.75-4.91(m,2H),4.19-4.34(m,1H),3.22-3.82(m,4H),2.51-3.18(m,4H),2.35-2.44(m,2H),1.23(s,1.5H),1.21(s,1.5H),1.17(s,1.5H),1.09(s,1.5H)。
实施例62：3-((7-(5-氯-1-(((3,4-trans)-3-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000076
实施例62的合成方法同实施例9相同。 1H NMR(400MHz,DMSO-d 6),8.70(d,J＝4.8Hz,0.5H),8.67(d,J＝4.8Hz,0.5H),7.75-7.77(m,1H),7.53(s,0.5H),7.52(s,0.5H),7.49(d,J＝4.8Hz,0.5H),7.40-7.42(m,1.5H),7.06(d,J＝2.0Hz,0.5H),7.02(d,J＝2.0Hz,0.5H),6.53-6.55(m,1H),4.69-4.79(m,2H),3.94(dd,J＝14.0Hz,4.8Hz,0.5H),3.56-3.82(m,1.5H),3.42-3.52(m,1H),2.68-2.84(m,1H),2.46-2.56(m,2.5H),2.38-2.45(m,1H),1.86-2.00(m,1H),1.63-1.74(m,1H),1.44-1.52(m,0.5H),1.13(s,1.5H),1.12(s,1.5H),1.03(s,1.5H),0.98(s,1.5H),0.60-0.73(m,1H),0.28-0.38(m,1H)。
实施例63：3-((7-(5-氯-1-(((3,4-cis)-3-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000077
实施例63的合成方法同实施例9相同。 1H NMR(400MHz,DMSO-d 6),8.75(d,J＝4.4Hz,0.5H),8.73(d,J＝4.4Hz,0.5H),7.79(s,1H),7.57(d,J＝4.0Hz,1H),7.54(d,J＝4.4Hz,0.5H),7.49(d,J＝4.4Hz,0.5H),7.36-7.39(m,1H),7.10(d,J＝2.0Hz,0.5H),7.08(d,J＝2.0Hz,0.5H),6.57(d,J＝3.6Hz,1H),4.70-4.80(m,2H),3.60-3.65(m,0.5H),3.48-3.54(m,0.5H),3.38-3.45(m,0.5H),3.15-3.21(m,0.5H),2.60-2.85(m,2H),2.51-2.54(m,2H),1.80-2.09(m,2.5H),1.50-1.59(m,0.5H),1.13 (s,3H),1.02(s,1.5H),0.98(s,1.5H),0.78-0.94(m,2H),0.09-0.16(m,0.5H),-0.29-0.16(m,0.5H)。
实施例64：4-((5-氯-7-(2-((3,3,4,4-四甲基-2,5-二氧代吡咯烷-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000078
实施例64的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),7.81(d,J＝1.6Hz,1H),7.50-7.54(m,3H),7.13(d,J＝2.4Hz,1H),6.71(d,J＝3.2Hz,1H),4.78-4.86(m,2H),3.95(d,J＝15.2Hz,1H),3.45(d,J＝15.2Hz,1H),2.66-2.76(m,2H),2.28-2.38(m,2H),1.17-1.33(m,3H),1.02(s,12H),0.85-0.94(m,1H)。
实施例65：4-((5-氯-7-(2-((4,4-二甲基-2,6-二氧代哌啶-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000079
实施例65的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.80(d,J＝4.8Hz,1H),7.81(s,1H),7.50-7.52(m,3H),7.10(s,1H),6.71(d,J＝3.6Hz,1H),5.00(d,J＝15.2Hz,1H),5.02(d,J＝15.2Hz,1H),3.98(d,J＝15.2Hz,1H),3.42(d,J＝15.2Hz,1H),2.76-2.85(m,2H),2.52(s,4H),2.35-2.45(m,2H),1.40-1.46(m,1H),1.21-1.28(m,1H),0.80-1.00(m,8H)。
实施例66：4-((5-氯-7-(2-((5,7-二氧代-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000080
实施例66的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.94(d,J＝4.0Hz,1H),8.81(d,J＝4.4Hz,1H),8.50-8.63(br,1H),8.24-8.39(m,2H),7.81(d,J＝1.6Hz,1H),7.76(dd,J＝7.6Hz,5.2Hz,1H),7.71(s,1H),7.55(d,J＝3.2Hz,1H),7.51(d,J＝4.8Hz,1H),7.10(d,J＝1.6Hz,1H),6.73(d,J＝3.2Hz,1H),5.10(d,J＝16.8Hz,1H),5.02(d,J＝16.4Hz,1H),4.13(d,J＝15.2Hz,1H), 3.50(d,J＝15.2Hz,1H),3.09-3.20(m,2H),2.58-2.72(m,2H),1.66-1.75(m,1H),1.03-1.30(m,3H)。
实施例67：1-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]哌啶-2-基)甲基)-4,4-二甲基哌啶-2,6-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000081
实施例67的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.44-9.60(br,1H),9.12-9.30(br,1H),8.68-8.86(m,1H),7.68(d,J＝1.6Hz,1H),7.59(s,1H),7.30-7.38(m,1H),7.08-7.11(m,1H),7.05(d,J＝2.0Hz,1H),6.61(d,J＝3.2Hz,1H),5.21(d,J＝15.2Hz,1H),5.13(d,J＝15.2Hz,1H),3.78(dd,J＝20.8Hz,16.0Hz,1H),3.46(dd,J＝24.4Hz,16.0Hz,1H),2.99-3.11(m,2H),2.74-2.89(m,2H),2.50(s,4H),1.34-1.60(m,3H),1.01(s,6H),0.92-1.00(m,1H)。
实施例68：6-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-5H-吡咯并[3,4-b]吡啶-5,7(6H)-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000082
实施例68的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.52-9.65(br,1H),9.09-9.24(br,1H),8.95(dd,J＝4.8Hz,1.6Hz,1H),8.79(d,J＝4.8Hz,1H),8.17(dd,J＝8.0Hz,1.6Hz,1H),7.67(d,J＝2.0Hz,1H),7.66(s,1H),7.62(dd,J＝7.6Hz,4.8Hz,1H),7.34(d,J＝4.4Hz,1H),7.10-7.14(m,1H),7.04(d,J＝2.0Hz,1H),6.60(d,J＝2.8Hz,1H),5.18(d,J＝16.0Hz,1H),5.13(d,J＝16.0Hz,1H),3.78(dd,J＝21.6Hz,16.0Hz,1H),3.52(dd,J＝24.0Hz,16.0Hz,1H),3.02-3.12(m,2H),2.77-2.91(m,2H),1.31-1.60(m,3H),0.99-1.08(m,1H)。
实施例69：3-((7-(5-氯-1-((3-氟吡咯烷-3-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000083
实施例69的合成方法同实施例9相同。MS(ESI)：[M+H] +:537.2。
实施例70：4-((5-氯-7-(2-((4-甲基-2,6-二氧代哌嗪-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000084
实施例70的合成方法同实施例21相同。 1H NMR(400MHz,CD 3OD),8.78(d,J＝4.4Hz,1H),7.76(d,J＝2.4Hz,1H),7.56(d,J＝4.8Hz,1H),7.53(s,1H),7.47(d,J＝3.6Hz,1H),7.13(d,J＝2.0Hz,1H),6.74(d,J＝3.6Hz,1H),5.19(d,J＝15.2Hz,1H),5.15(d,J＝15.2Hz,1H),4.02(d,J＝15.2Hz,1H),3.62(d,J＝15.2Hz,1H),3.41(s,4H),3.10-3.19(m,2H),2.77-2.86(m,2H),2.33(s,3H),1.69-1.76(m,1H),1.12-1.32(m,3H)。
实施例71：3-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-1-环丙基咪唑啉-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000085
实施例71的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.48-9.84(br,1H),9.02-9.32(br,1H),8.70-8.83(m,1H),7.68(s,1H),7.54(s,1H),7.30(d,J＝3.6Hz,1H),7.11(s,1H),7.05(s,1H),6.61(d,J＝2.4Hz,1H),4.82-4.92(m,2H),3.84(s,2H),3.76(dd,J＝22.0Hz,16.0Hz,1H),3.52(dd,J＝24.0Hz,16.0Hz,1H),2.97-3.12(m,2H),2.76-2.92(m,2H),2.54-2.62(m,1H),1.30-1.55(m,3H),0.96-1.07(m,1H),0.66-0.88(m,4H)。
实施例72：2-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-1H-吡咯并[3,4-c]吡啶-1,3(2H)-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000086
实施例72的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.42-9.55(br,1H),9.12-9.30(m,2H),9.04-9.10(m,1H),8.82-8.90(m,1H),7.76(d,J＝4.8Hz,1H),7.68-7.74(m,2H),7.41-7.47(m,1H),7.11-7.14(m,1H),7.04(d,J＝2.0Hz,1H),6.63(d,J＝3.2Hz,1H),5.15(d,J＝16.0Hz,1H),5.10(d,J＝16.0Hz,1H),3.76-3.87(m,1H),3.49(dd,J＝25.2Hz,15.2Hz,1H),2.95-3.17(m,2H),2.74-2.91(m,2H),1.35-1.68(m,3H),0.95-1.06(m,1H)。
实施例73：1-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-3,3-二甲基哌啶-2,6-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000087
实施例73的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.86-9.27(br,2H),8.70-8.84(m,1H),7.69(s,1H),7.49-7.62(m,1H),7.31-7.44(m,1H),7.11(s,1H),7.05(s,1H),6.57-6.64(m,1H),5.19(d,J＝14.8Hz,1H),5.09(d,J＝14.8Hz,1H),3.71-3.86(m,1H),3.44(dd,J＝24.4Hz,15.2Hz,1H),3.02-3.22(m,2H),2.63-2.92(m,4H),1.73-1.83(m,2H),1.11-1.60(m,9H),0.90-1.02(m,1H)。
实施例74：4-((5-氯-7-(2-((3-环丙基-2,5-二氧代咪唑啉-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000088
实施例74的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.4Hz,1H),7.81(d,J＝2.4Hz,1H),7.57(s,1H),7.51-7.53(m,2H),7.10(d,J＝2.0Hz,1H),6.71(d,J＝3.6Hz,1H),4.82(d,J＝16.0Hz,1H),4.73(d,J＝16.0Hz,1H),3.99(d,J＝15.2Hz,1H),3.94(s,2H),3.47(d,J＝15.2Hz,1H),2.73-2.81(m,2H),2.54-2.60(m,1H),2.33-2.43(m,2H),1.37-1.44(m,1H),1.20-1.28(m,1H),0.80-0.98(m,2H),0.60-0.66(m,4H)。
实施例75：4-((5-氯-7-(2-((3,3-二甲基-2,6-二氧代哌啶-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000089
实施例75的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.79(d,J＝4.8Hz,1H),7.81(d,J＝1.6Hz,1H),7.52(d,J＝3.6Hz,1H),7.49(d,J＝4.4Hz,1H),7.47(s,1H),7.11(d,J＝1.6Hz,1H),6.71(d,J＝3.2Hz,1H),5.07(d,J＝15.2Hz,1H),4.97(d,J＝15.2Hz,1H),3.99(d,J＝14.8Hz,1H),3.45(d,J＝14.8Hz,1H),2.73-2.82(m,2H),2.67(t,J＝6.4Hz,2H),2.33-2.43(m,2H),1.71(t,J＝6.4Hz,2H),1.34-1.42(m,1H),1.20-1.26(m,1H),1.10(s,6H),0.80-0.95(m,2H)。
实施例76：4-((5-氯-7-(2-((3,3-二甲基-2,5-二氧代吡咯烷-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000090
实施例76的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.4Hz,1H),7.81(d,J＝2.0Hz,1H),7.55(s,1H),7.51-7.53(m,2H),7.12(d,J＝2.0Hz,1H),6.72(d,J＝3.2Hz,1H),4.84(d,J＝16.0Hz,1H),4.76(d,J＝16.0Hz,1H),4.01(d,J＝14.8Hz,1H),3.46(d,J＝14.8Hz,1H),2.79-2.86(m,2H),2.59(s,2H),2.36-2.46(m,2H),1.39-1.45(m,1H),1.20-1.28(m,1H),1.14(s,6H),0.85-1.04(m,2H)。
实施例77：4-((5-氯-7-(2-((1,3-二氧代六氢环戊烯并[c]吡咯-2(1H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000091
实施例77的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),7.81(d,J＝2.4Hz,1H),7.51-7.54(m,3H),7.11(d,J＝2.4Hz,1H),6.72(d,J＝2.8Hz,1H),4.81(d,J＝16.0Hz,1H),4.76(d,J＝16.0Hz,1H),4.01(d,J＝14.8Hz,1H),3.45(d,J＝14.8Hz,1H),3.15-3.22(m,2H),2.88-2.96(m,2H),2.42-2.52(m,2H),1.68-1.85(m,3H),1.54-1.63(m,1H),1.46-1.52(m,1H),1.20-1.28(m,1H),0.90-1.14(m,4H)。
实施例78：4-((5-氯-7-(2-((3-甲基-2,5-二氧代-2,5-二氢-1H-吡咯-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000092
实施例78的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.36-9.88(br,2H),8.78-8.90(m,1H),7.71(d,J＝2.0Hz,1H),7.57(s,1H),7.49-7.52(m,1H),7.29(d,J＝3.2Hz,1H),7.07(d,J＝1.6Hz,1H),6.69(d,J＝3.2Hz,1H),3.34(d,J＝1.6Hz,1H),4.88(d,J＝16.0Hz,1H),4.86(d,J＝16.0Hz,1H),3.84(d,J＝15.2Hz,1H),3.50(d,J＝15.2Hz,1H),3.16-3.30(m,2H),2.80-2.95(m,2H),2.05(d,J＝2.0Hz,3H),1.66-1.72(m,1H),1.38-1.54(m,2H),0.97-1.05(m,1H)。
实施例79：1-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-4-甲基哌嗪-2,6-二酮
Figure PCTCN2021114936-appb-000093
实施例79的合成方法同实施例21相同。 1H NMR(400MHz,CD 3OD),8.74(d,J＝4.4Hz,1H),7.73(d,J＝1.6Hz,1H),7.51(s,1H),7.45(d,J＝4.4Hz,1H),7.31-7.34(m,1H),7.10(d,J＝2.0Hz,1H),6.68(d,J＝3.2Hz,1H),5.20(d,J＝15.2Hz,1H),5.15(d,J＝15.2Hz 1H),4.01(dd,J＝20.0Hz,16.0Hz,1H),3.62(dd,J＝22.0Hz,16.0Hz,1H),3.42(s,4H),3.08-3.14(m,2H),2.82-2.92(m,2H),2.34(s,3H),1.01-1.39(m,4H)。
实施例80：4-((5-氯-7-(2-((2,4-二氧代-3-氮杂双环[3.2.0]庚烷-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000094
实施例80的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝4.4Hz,1H),8.48-8.58(br,1H),8.26-8.39(br,1H),7.82(d,J＝2.0Hz,1H),7.59(s,1H),7.56(d,J＝3.6Hz.1H),7.52(d,J＝4.8Hz,1H),7.13(d,J＝2.0Hz,1H),6.74(d,J＝3.6Hz,1H),4.90(d,J＝16.0Hz,1H),4.82(d,J＝16.0Hz,1H),4.12(d,J＝15.2Hz,1H),3.49(d,J＝15.2Hz,1H),3.24-3.30(m,2H),3.09-3.18(m,2H),2.58-2.71(m,2H),2.44-2.54(m,2H),1.86-1.92(m,2H),1.64-1.72(m,1H),1.05-1.30(m,3H)。
实施例81：4-((5-氯-7-(2-((3-甲基-2,5-二氧代咪唑啉-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000095
实施例81的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.4Hz,1H),8.28-8.58(br,2H),7.82(s,1H),7.59(s,1H),7.56(d,J＝3.2Hz,1H),7.52(d,J＝4.8Hz,1H),7.11(s,1H),6.74(d,J＝3.2Hz,1H),4.84(d,J＝16.0Hz,1H),4.75(d,J＝16.0Hz,1H),4.12(d,J＝14.8Hz,1H),3.96(s,2H),3.48(d,J＝14.8Hz,1H),3.08-3.18(m,2H),2.79(s,3H),2.60-2.70(m,2H),1.67-1.73(m,1H),1.01-1.30(m,3H)。
实施例82：4-((5-氯-7-(2-((5,7-二氧代-6-氮杂螺[2.5]辛-6-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000096
实施例82的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.18-9.76(br,2H),8.83(s,1H),7.72(d,J＝2.0Hz,1H),7.50-7.65(m,2H),7.30(d,J＝2.8Hz,1H),7.08(d,J＝1.6Hz,1H),6.69(d,J＝3.2Hz,1H),5.24(d,J＝14.8Hz,1H),5.13(d,J＝14.8Hz,1H),3.86(d,J＝14.8Hz,1H),3.48(d,J＝14.8Hz,1H),3.17-3.34(m,2H),2.79-2.95(m,2H),2.51(s,4H),1.64-1.74(m,1H),1.36-1.56(m,2H),0.98-1.07(m,1H),0.49(s,4H)。
实施例83：6-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6-氮杂螺[2.5]辛烷-5,7-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000097
实施例83的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.24-9.46(br,1H),8.95-9.20(br,1H),8.74-8.86(m,1H),7.70(d,J＝2.0Hz,1H),7.60-7.66(m,1H),7.41-7.48(m,1H),7.09-7.15(m,1H),7.06(d,J＝2.0Hz,1H),6.62(d,J＝3.2Hz,1H),5.25(d,J＝15.2Hz,1H),5.16(d,J＝15.2Hz,1H),3.74-3.88(m,1H),3.47(dd,J＝24.4Hz,15.6Hz,1H),3.01-3.17(m,2H),2.74-2.90(m,2H),2.53(s,4H),1.34-1.64(m,3H),0.92-1.03(m,1H),0.50(s,4H)。
实施例84：4-((5-氯-7-(2-((3,5-二氧代吗啉)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000098
实施例84的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.4Hz,1H),7.81(d,J＝2.0Hz,1H),7.57(s,1H),7.54(d,J＝3.2Hz,1H),7.52(d,J＝4.8Hz,1H),7.10(d,J＝2.0Hz,1H),6.73(d,J＝3.2Hz,1H),5.12(d,J＝15.2Hz,1H),5.02(d,J＝15.2Hz,1H),4.40(s,4H),4.06(d,J＝14.8Hz,1H),3.48(d,J＝14.8Hz,1H),2.88-2.99(m,2H),2.46-2.55(m,2H),1.51-1.58(m,1H),0.88-1.16(m,3H)。
实施例85：3-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-3-氮杂双环[3.1.0]己烷-2,4-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000099
实施例85的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.62-9.73(br,1H),9.17-9.36(br,1H),8.84-8.90(m,1H),7.70(d,J＝2.0Hz,1H),7.55(s,1H),7.42(d,J＝3.6Hz,1H),7.12-7.14(m,1H),7.07(d,J＝1.6Hz,1H),6.62(d,J＝3.2Hz,1H),4.79(d,J＝15.2Hz,1H),4.74(d,J＝15.2Hz,1H),3.80(dd,J＝20.8Hz,15.6Hz,1H),3.50(dd,J＝25.2Hz,15.6Hz,1H),3.07-3.17(m,2H),2.78-2.90(m,2H),2.49-2.52(m,2H),1.18-1.69(m,5H),0.96-1.03(m,1H)。
实施例86：4-((5-氯-7-(2-((2,4-二氧代-3-氮杂双环[3.1.0]己烷-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000100
实施例86的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.87(d,J＝4.4Hz,1H),7.70(s,1H),7.50(s,1H),7.47(d,J＝4.8Hz,1H),7.31(d,J＝2.8Hz,1H),7.08(d,J＝1.6Hz,1H),6.68(d,J＝3.2Hz,1H),4.74(d,J＝16.0Hz,1H),4.71(d,J＝16.0Hz,1H),3.80(d,J＝15.2Hz,1H),3.50(d,J＝15.2Hz,1H),3.08-3.20(m,2H),2.75-2.88(m,2H),2.47-2.50(m,2H),1.58-1.64(m,1H),1.50-1.56(m,1H),1.17-1.39(m,3H),0.91-0.99(m,1H)。
实施例87：4-((5-氯-7-(2-((1,3-二氧代-1,3,4,5,6,7-六氢-2H-异吲哚-2-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000101
实施例87的合成方法同实施例21相同。 1H NMR(400MHz,CD 3OD),8.79(d,J＝5.2Hz,1H),7.75(d,J＝2.0Hz,1H),7.58(d,J＝4.8Hz,1H),7.50(d,J＝1.2Hz,1H),7.48(d,J＝3.6Hz,1H),7.13(d,J＝2.0Hz,1H),6.74(d,J＝3.6Hz,1H),4.86-4.95(m,2H),4.05(d,J＝15.2Hz,1H),3.63(d,J＝15.2Hz,1H),3.19-3.28(m,2H),2.83-2.92(m,2H),2.24-2.32(m,4H),1.69-1.80(m,5H),1.20-1.40(m,3H)。
实施例88：4-((7-(2-((4-氨基-1,3-二氧代异吲哚-2-基)甲基)噻吩并[3,2-b]吡啶-7-基)-5-氯-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000102
实施例88的合成方法同实施例21相同。 1H NMR(400MHz,CD 3OD),8.78(d, J＝4.8Hz,1H),7.71-7.73(m,1H),7.53-7.56(m,2H),7.44(d,J＝3.2Hz,1H),7.39(t,J＝7.6Hz,1H),7.11(d,J＝2.0Hz,1H),6.99(d,J＝7.2Hz,1H),6.94(d,J＝8.8Hz,1H),6.70(d,J＝3.6Hz,1H),4.99-5.06(m,2H),3.97(d,J＝15.2Hz,1H),3.60(d,J＝15.2Hz,1H),3.03-3.13(m,2H),2.71-2.80(m,2H),1.62-1.69(m,1H),1.08-1.32(m,3H)。
实施例89：4-((5-氯-7-(2-((1,3-二氧代-2-氮杂螺[4.4]壬烷-2-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000103
实施例89的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.4Hz,1H),7.82(d,J＝2.0Hz,1H),7.52-7.54(m,3H),7.12(d,J＝2.4Hz,1H),6.72(d,J＝3.6Hz,1H),4.86(d,J＝16.0Hz,1H),4.78(d,J＝16.0Hz,1H),4.04(d,J＝14.8Hz,1H),3.46(d,J＝14.8Hz,1H),2.87-2.94(m,2H),2.65(s,2H),2.43-2.53(m,2H),1.76-1.86(m,2H),1.56-1.74(m,6H),1.46-1.53(m,1H),0.89-1.14(m,3H)。
实施例90：2-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-2-氮杂螺[4.4]壬烷-1,3-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000104
实施例90的合成方法同实施例21相同。 1H NMR(400MHz,CD 3OD),8.77(d,J＝4.8Hz,1H),7.96-8.56(br,2H),7.79(d,J＝2.0Hz,1H),7.52(s,1H),7.42-7.45(m,2H),7.09(d,J＝2.0Hz,1H),6.67(d,J＝3.2Hz,1H),4.86(d,J＝16.0Hz,1H),4.78(d,J＝16.0Hz,1H),4.00(dd,J＝19.2Hz,16.0Hz,1H),3.46(dd,J＝21.2Hz,15.6Hz,1H),2.89-2.96(m,2H),2.66(s,2H),2.53-2.62(m,2H),1.75-1.86(m,2H),1.54-1.74(m,6H),1.08-1.46(m,3H),0.84-0.91(m,1H)。
实施例91：4-((5-氯-7-(2-((4,6-二氧代-4H-噻吩并[3,4-c]吡咯l-5(6H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000105
实施例91的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.20-9.96(br,2H),8.82(d,J＝4.0Hz,1H),7.86(s,2H),7.69(d,J＝2.0Hz,1H),7.61(s,1H),7.46(d,J＝4.4Hz,1H),7.28(d,J＝3.2Hz,1H),7.07(d,J＝2.0Hz, 1H),6.68(d,J＝3.2Hz,1H),5.04(d,J＝16.0Hz,1H),4.98(d,J＝16.0Hz,1H),3.82(d,J＝15.2Hz,1H),3.53(d,J＝15.2Hz,1H),3.22(t,J＝12.0Hz,2H),2.88(q,J＝12.0Hz,2H),1.64-1.72(m,1H),1.34-1.50(m,2H),0.99-1.07(m,1H)。
实施例92：5-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-4H-噻吩并[3,4-c]吡咯-4,6(5H)-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000106
实施例92的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.59-9.76(br,1H),9.01-9.20(br,1H),8.78(d,J＝3.6Hz,1H),7.88(s,2H),7.67(d,J＝2.0Hz,1H),7.61(s,1H),7.32(d,J＝4.4Hz,1H),7.09-7.11(m,1H),7.05(d,J＝2.0Hz,1H),6.60(d,J＝2.8Hz,1H),5.05(d,J＝16.0Hz,1H),4.99(d,J＝16.0Hz,1H),3.78(dd,J＝21.2Hz,16.0Hz,1H),3.51(dd,J＝24.8Hz,16.0Hz,1H),2.98-3.10(m,2H),2.74-2.91(m,2H),1.30-1.58(m,3H),0.98-1.07(m,1H)。
实施例93：4-((5-氯-7-(2-((3-甲氧基-2,5-二氧代-2,5-二氢-1H-吡咯-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000107
实施例93的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.4Hz,1H),8.46-8.56(br,1H),8.23-8.37(br,1H),7.82(d,J＝2.4Hz,1H),7.57(s,1H),7.55(d,J＝3.6Hz,1H),7.51(d,J＝4.8Hz,1H),7.12(d,J＝2.0Hz,1H),6.74(d,J＝3.6Hz,1H),5.87(s,1H),4.87(d,J＝16.8Hz,1H),4.80(d,J＝16.8Hz,1H),4.13(d,J＝14.8Hz,1H),3.85(s,3H),3.48(d,J＝14.8Hz,1H),3.10-3.19(m,2H),2.59-2.73(m,2H),1.67-1.74(m,1H),1.04-1.30(m,3H)。
实施例94：1-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-3-甲氧基吡咯烷-2,5-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000108
实施例94的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),7.76(d,J＝5.2Hz,1H),8.44-8.56(br,1H),8.20-8.36(br,1H),7.80(d,J＝2.0Hz,1H),7.56(s,1H),7.43-7.45(m,2H),7.09(d,J＝2.0Hz,1H),6.68(d,J＝2.8Hz,1H),4.87(dd,J＝16.0Hz,7.6Hz,1H),4.77(dd,J＝16.0Hz,7.6Hz,1H),4.34-4.38(m,1H),3.98-4.07(m,1H),3.42-3.52(m,1H),3.37(s,3H),2.93-3.06(m,3H),2.54-2.72 (m,3H),1.08-1.45(m,3H),0.86-0.96(m,1H)。
实施例95：4-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)吗啉-3,5-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000109
实施例95的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.77(d,J＝4.4Hz,1H),8.34-8.72(br,2H),7.79(d,J＝2.0Hz,1H),7.55(s,1H),7.41-7.47(m,2H),7.07(d,J＝2.0Hz,1H),6.67(d,J＝3.6Hz,1H),5.12(d,J＝15.6Hz,1H),5.02(d,J＝15.6Hz,1H),4.41(s,4H),4.02(dd,J＝20.4Hz,15.6Hz,1H),3.46(dd,J＝20.8Hz,15.6Hz,1H),2.92-3.02(m,2H),2.55-2.66(m,2H),1.09-1.48(m,3H),0.84-0.92(m,1H)。
实施例96：1-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-3-甲基吡咯烷-2,5-二酮
Figure PCTCN2021114936-appb-000110
实施例96的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.78(d,J＝4.4Hz,1H),7.68(d,J＝2.0Hz,1H),7.55(s,1H),7.30(d,J＝4.8Hz,1H),7.17-7.18(m,1H),7.05(d,J＝2.0Hz,1H),6.59(d,J＝3.6Hz,1H),4.93(d,J＝15.2Hz,1H),4.86(d,J＝15.2Hz,1H),3.70(dd,J＝22.0Hz,15.6Hz,1H),3.48(ddd,J＝23.6Hz,15.6Hz,2.0Hz,1H),2.84-2.97(m,2H),2.58-2.65(m,4H),2.33(dd,J＝17.6Hz,4.0Hz,1H),1.30-1.32(m,3H),1.16-1.23(m,1H),0.81-1.06(m,3H)。
实施例97：1-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-4-环丙基哌嗪-2,6-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000111
实施例97的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.76(d,J＝4.8Hz,1H),8.33-8.61(br,2H),7.79(d,J＝2.0Hz,1H),7.52(s,1H), 7.42-7.43(m,2H),7.07(d,J＝1.6Hz,1H),6.68(d,J＝3.2Hz,1H),5.11(d,J＝15.6Hz,1H),4.98(d,J＝15.6Hz,1H),3.97-4.06(m,1H),3.59(s,4H),3.39-3.48(m,1H),2.97-3.03(m,2H),2.57-2.68(m,2H),1.80-1.84(m,1H),1.09-1.47(m,3H),0.82-0.91(m,1H),0.37-0.42(m,2H),0.31-0.36(m,2H)。
实施例98：1-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-4-乙基哌嗪-2,6-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000112
实施例98的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.76(d,J＝4.8Hz,1H),8.41-8.71(br,2H),7.79(d,J＝2.0Hz,1H),7.51(s,1H),7.43-7.44(m,2H),7.08(d,J＝2.4Hz,1H),6.68(d,J＝3.2Hz,1H),5.11(d,J＝15.2Hz,1H),4.99(d,J＝15.2Hz,1H),4.02(dd,J＝20.0Hz,15.6Hz,1H),3.40-3.49(m,5H),2.96-3.03(m,2H),2.56-2.68(m,2H),2.42(q,J＝7.2Hz,2H),1.13-1.48(m,3H),0.86-0.94(m,4H)。
实施例99：4-((5-氯-7-(2-((4-环丙基-2,6-二氧代哌嗪-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000113
实施例99的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),7.81(d,J＝2.0Hz,1H),7.51-7.53(m,3H),7.09(d,J＝2.0Hz,1H),6.72(d,J＝3.2Hz,1H),5.11(d,J＝15.2Hz,1H),4.99(d,J＝15.2Hz,1H),4.03(d,J＝15.2Hz,1H),3.58(s,4H),3.45(d,J＝15.2Hz,1H),2.85-2.94(m,2H),2.42-2.50(m,2H),1.78-1.84(m,1H),1.46-1.53(m,1H),0.89-1.16(m,3H),0.37-0.41(m,2H),0.31-0.35(m,2H)。
实施例100：4-((5-氯-7-(2-((4-乙基-2,6-二氧代哌嗪-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000114
实施例100的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.4Hz,1H),7.82(d,J＝2.0Hz,1H),7.51-7.54(m,3H),7.11(d,J＝1.6Hz,1H),6.73(d,J＝3.2Hz,1H),5.11(d,J＝15.2Hz,1H),4.99(d,J＝15.2Hz,1H),4.05(d,J＝14.8Hz,1H),3.46(d,J＝14.8Hz,1H),3.43(s,4H),2.89-2.98(m,2H),2.39-2.53(m,4H),1.50-1.57(m,1H),0.90-1.11(m,6H)。
实施例101：4-((5-氯-7-(2-((3-甲基-2,5-二氧代吡咯烷-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000115
实施例101的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.80(d,J＝5.2Hz,1H),7.68(d,J＝2.0Hz,1H),7.55(s,1H),7.37(d,J＝4.8Hz,1H),7.35(d,J＝3.2Hz,1H),7.07(d,J＝2.0Hz,1H),6.64(d,J＝2.8Hz,1H),4.91(d,J＝15.6Hz,1H),4.84(d,J＝15.6Hz,1H),3.73(d,J＝14.8Hz,1H),3.53(dd,J＝14.8Hz,2.4Hz,1H),2.76-2.95(m,4H),2.58-2.68(m,2H),2.29-2.34(m,1H),1.36-1.42(m,1H),1.29-1.31(m,3H),0.92-0.96(m,1H),0.74-0.84(m,2H)。
实施例102：1-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)哌嗪-2,6-二酮
Figure PCTCN2021114936-appb-000116
实施例102的合成方法同实施例21相同。 1H NMR(400MHz,CD 3OD),8.81(s,1H),7.75(d,J＝2.0Hz,1H),7.64(s,1H),7.60(d,J＝5.2Hz,1H),7.35(s,1H),7.13(d,J＝2.0Hz,1H),6.69(d,J＝2.8Hz,1H),5.20-5.29(m,2H),3.99-4.05(m,5H),3.66(dd,J＝21.2Hz,16.0Hz,1H),3.08-3.16(m,2H),2.82-2.93(m,2H),1.16-1.48(m,3H),0.84-0.89(m,1H)。
实施例103：1-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-yl)噻吩并[3,2-b]吡啶-2-基)甲基)-3-苯基-1H-吡咯-2,5-二酮三氟乙酸盐
Figure PCTCN2021114936-appb-000117
实施例103的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.39-9.59(br,1H),8.89(s,1H),8.42-8.68(br,1H),7.85-7.88(m,2H),7.67-7.71(m,2H),7.38-7.46(m,4H),7.14(s,1H),7.04(d,J＝2.0Hz,1H),6.75(s,1H),6.60(d,J＝3.6Hz,1H),5.00(d,J＝15.6Hz,1H),4.96(d,J＝15.6Hz,1H),3.82(dd,J＝20.4Hz,16.0Hz,1H),3.50(dd,J＝25.2Hz,15.6Hz,1H),3.16-3.27(m,2H),2.80-2.96(m,2H),1.38-1.72(m,3H),0.97-1.06(m,1H)。
实施例104：4-((5-氯-7-(2-((2,5-二氧代-3-苯基-2,5-二氢-1H-吡咯-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000118
实施例104的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.88(d,J＝4.8Hz,1H),7.85-7.87(m,2H),7.67(d,J＝2.4Hz,1H),7.61(s,1H),7.50(d,J＝4.8Hz,1H),7.38-7.44(m,3H),7.31(d,J＝3.6Hz,1H),7.06(d,J＝2.0Hz,1H),6.74(s,1H),6.66(d,J＝3.2Hz,1H),4.98(d,J＝12.0Hz,1H),4.94(d,J＝12.0Hz,1H),3.85(d,J＝15.2Hz,1H),3.50(d,J＝15.2Hz,1H),3.27-3.35(m,2H),2.81-2.92(m,2H),1.66-1.69(m,1H),1.34-1.51(m,2H),0.97-1.01(m,1H)。
实施例105：1-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-4-异丙基哌嗪-2,6-二酮盐酸盐
Figure PCTCN2021114936-appb-000119
实施例105的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),9.11-9.35(br,2H),8.89(d,J＝4.8Hz,1H),7.83(d,J＝2.0Hz,1H),7.77(s,1H), 7.66(d,J＝5.2Hz,1H),7.47(d,J＝2.4Hz,1H),7.11(d,J＝2.0Hz,1H),6.69(d,J＝3.2Hz,1H),5.14(d,J＝15.6Hz,1H),5.09(d,J＝15.6Hz,1H),4.21(s,4H),4.07(dd,J＝21.2Hz,15.6Hz,1H),3.48-3.64(m,2H),2.92-3.03(m,2H),2.53-2.69(m,2H),1.19-1.60(m,9H),0.89-0.98(m,1H)。
实施例106：4-((5-氯-7-(2-((4-异丙基-2,6-二氧代哌嗪-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000120
实施例106的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.73-10.06(br,1H),9.33-9.70(br,1H),8.91(s,1H),7.70(d,J＝1.6Hz,1H),7.61(s,1H),7.50-7.54(m,1H),7.32(d,J＝3.2Hz,1H),7.09(d,J＝1.6Hz,1H),6.69(d,J＝3.2Hz,1H),5.09-5.17(m,2H),3.86(d,J＝15.2Hz,1H),3.44-3.57(m,5H),3.26-3.35(m,2H),2.77-2.97(m,3H),1.26-1.65(m,4H),1.04-1.06(m,6H)。
实施例107：4-((5-氯-7-(2-((2,6-二氧代哌啶-1-基)甲基)噻吩并[3,2-b]吡啶7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000121
实施例96的合成方法同实施例21相同。 1H NMR(400MHz,CD 3OD),8.77(d,J＝4.8Hz,1H),7.75(d,J＝2.0Hz,1H),7.55(d,J＝4.8Hz,1H),7.47-7.49(m,2H),7.15(d,J＝2.0Hz,1H),6.73(d,J＝3.6Hz,1H),4.67(d,J＝16.0Hz,1H),4.58(d,J＝16.0Hz,1H),4.03(d,J＝15.2Hz,1H),3.66(d,J＝15.2Hz,1H),3.13-3.22(m,2H),2.79-2.87(m,2H),2.30(t,J＝7.2Hz,2H),2.25(t,J＝7.2Hz,2H),1.81-1.88(m,2H),1.69-1.73(m,1H),1.15-1.23(m,2H),0.84-0.88(m,1H)。
实施例108：4-((5-氯-7-(2-((3-甲氧基-2,5-二氧代吡咯烷-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000122
实施例96的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝4.4Hz,1H),8.54-8.69(br,1H),8.30-8.46(br,1H),7.83(d,J＝1.6Hz,1H),7.58(s,1H),7.56(d,J＝3.2Hz,1H),7.52(d,J＝4.8Hz,1H),7.12(s,1H),6.74(d,J＝3.6Hz,1H),4.86(dd,J＝16.0Hz,5.6Hz,1H),4.77(dd,J＝15.6Hz,7.2Hz,1H),4.34-4.37(m,1H),4.13(d,J＝14.8Hz,1H),3.49(dd,J＝15.2Hz,4.4Hz,1H),3.38(s,3H),3.10-3.20(m,2H),3.01(dd,J＝17.6Hz,8.0Hz,1H),2.58-2.72(m,3H),1.69-1.73(m,1H),1.05-1.30(m,3H)。
实施例109：1-((7-(5-氯-1-((4-氟哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)吡咯烷-2-酮三氟乙酸盐
Figure PCTCN2021114936-appb-000123
步骤1：化合物77的合成
在0℃下，向化合物69(100mg)的二氯甲烷(2mL)溶液中，依次加入三苯基膦(59mg)和四溴化碳(81mg)。反应液升至室温搅拌过夜。反应完成后，将反应液减压浓缩，所得残留物通过快速减压柱色谱进行分离纯化(二氯甲烷：甲醇＝200:1至50:1)。获得化合物69(14mg)。
步骤2：化合物78的合成
在0℃下，向2-吡咯烷酮(280mg)的四氢呋喃(2mL)溶液中加入氢化钠(170mg)，反应液在该温度下继续搅拌30分钟。随后向反应液中滴加化合物77(14mg)的四氢呋喃(0.2mL)溶液。将反应液温度升至室温搅拌过夜。反应结束后，向反应液中加入饱和氯化铵水溶液(1mL)淬灭反应。所得溶液用乙酸乙酯萃取(5mL×3)。合并有机相，用无水硫酸钠干燥并减压浓缩。所得 残留物通过快速硅胶柱层析分离纯化(二氯甲烷：甲醇＝200:1至50:1)。获得化合物78(7.3mg)。
步骤3：化合物79的合成
在室温下，向化合物78(7.3mg)的二氯甲烷(2mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌2小时。将反应液减压浓缩，所得残留物通过快速硅胶柱层析进行分离纯化(二氯甲烷：甲醇＝30:1至10:1)。获得化合物79(2.4mg)。 1H NMR(400MHz,CD 3OD),8.83(d,J＝4.4Hz,1H),7.73(d,J＝1.6Hz,1H),7.67(s,1H),7.52(d,J＝4.8Hz,1H),7.33-7.34(m,1H),7.13(d,J＝2.0Hz,1H),6.67(d,J＝3.6Hz,1H),4.82(d,J＝16.0Hz,1H),4.69(d,J＝15.6Hz,1H),4.03(dd,J＝20.8Hz,16.0Hz,1H),3.62(dd,J＝21.6Hz,16.0Hz,1H),3.44-3.50(m,2H),3.10-3.16(m,2H),2.81-2.91(m,2H),2.38(t,J＝8.0Hz,2H),2.00-2.08(m,2H),1.13-1.56(m,3H),0.84-0.88(m,1H)。
实施例110：3-((7-(5-氯-1-((4-氟吡咯-3-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000124
实施例110的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.77(d,J＝4.8Hz,0.5H),8.73(d,J＝4.8Hz,0.5H),7.68(d,J＝2.0Hz,1H),7.56(s,1H),7.28(d,J＝4.8Hz,0.5H),7.24(d,J＝4.8Hz,0.5H),7.11(d,J＝2.4Hz,1H),7.06(d,J＝2.0Hz,0.5H),7.02(d,J＝2.0Hz,0.5H),6.54(d,J＝3.2Hz,1H),4.72-4.82(m,2H),4.22-4.44(m,1H),3.74-3.83(m,1H),3.57(dd,J＝14.8Hz,5.2Hz,0.5H),3.28(dd,J＝14.8Hz,5.2Hz,0.5H),2.78-3.13(m,3H),2.22-2.35(m,3.5H),1.65-2.00(m,1.5H),1.21(s,1.5H),1.20(s,1.5H),1.11(s,1.5H),1.07(s,1.5H)。
实施例111：4-((5-氯-7-(2-((2,6-二氧代哌嗪-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000125
实施例111的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝5.2Hz,1H),8.18-8.59(br,2H),7.82(d,J＝2.0Hz,1H),7.55-7.56(m,2H),7.51(d,J＝4.8Hz,1H),7.10(d,J＝2.0Hz,1H),6.74(d,J＝3.6Hz,1H),5.10(d,J ＝15.6Hz,1H),4.96(d,J＝15.6Hz,1H),4.16(d,J＝14.8Hz,1H),3.52(s,4H),3.47(d,J＝15.2Hz,1H),3.11-3.17(m,2H),2.63-2.67(m,2H),1.70-1.75(m,1H),1.04-1.30(m,3H)。
实施例112：4-((7-(2-((4-乙酰基-2,6-二氧代哌嗪-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-5-氯-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000126
实施例112的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.4Hz,1H),7.82(s,1H),7.51-7.57(m,3H),7.09(d,J＝1.6Hz,1H),6.74(d,J＝3.2Hz,1H),5.09(d,J＝15.2Hz,1H),4.96(d,J＝15.2Hz,1H),4.46(s,2H),4.36(s,2H),4.10(d,J＝15.6Hz,1H),3.45(d,J＝15.6Hz,1H),3.00-3.10(m,2H),2.52-2.64(m,2H),2.01(s,3H),1.61-1.65(m,1H),1.06-1.17(m,2H),0.97-1.01(m,1H)。
实施例113：3-((5-氯-7-(2-((6,6-二甲基-2,4-二氧代-3-氮杂双环[3.1.0]己烷-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)吡咯烷-3-甲腈
Figure PCTCN2021114936-appb-000127
实施例113的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.78(d,J＝4.0Hz,1H),7.70-7.71(m,1H),7.57(s,1H),7.73(d,J＝3.2Hz,0.5H),7.34-7.36(m,1.5H),7.07-7.08(m,1H),6.67-6.69(m,1H),4.81(d,J＝15.2Hz,1H),4.74(d,J＝15.2Hz,1H),3.75-3.83(m,1H),3.63-3.66(m,1H),2.77-3.03(m,2H),2.11-2.63(m,5H),1.83-1.92(m,0.5H),1.72-1.81(m,0.5H),1.22(s,1.5H),1.21(s,1.5H),1.10(s,3H)。
实施例114：4-((5-氯-7-(2-((3,4-二甲基-2,5-二氧代-2,5-二氢-1H-吡咯-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000128
实施例114的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.78(d,J＝4.4Hz,1H),7.67(s,1H),7.51(s,1H),7.34-7.36(m,2H),7.06(s,1H),6.64(d,J＝2.4Hz,1H),4.91(d,J＝15.6Hz,1H),4.84(d,J＝15.6Hz,1H),3.72(d,J＝7.2Hz,1H),3.54(d,J＝7.2Hz,1H),2.73-2.81(m,2H),2.57-2.65(m,2H),1.92(s,6H),1.35-1.39(m,1H),0.92-0.96(m,1H),0.70-0.80(m,2H)。
实施例115：4-((5-氯-7-(2-((3,4-二甲基-2,5-二氧代吡咯-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000129
实施例115的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.79(d,J＝4.8Hz,1H),7.67(d,J＝2.0Hz,1H),7.52(s,1H),7.38(d,J＝4.4Hz,1H),7.33(d,J＝3.2Hz,1H),7.06(d,J＝2.0Hz,1H),6.64(d,J＝3.6Hz,1H),4.79-4.91(m,2H),3.73(d,J＝14.8Hz,1H),3.48-3.53(m,1H),2.90-2.96(m,1H),2.77-2.85(m,2H),2.58-2.68(m,2H),2.32-2.48(m,2H),1.38-1.43(m,1H),1.27-1.29(m,3H),1.15-1.18(m,3H),0.77-0.94(m,3H)。
实施例116：4-((5-氯-7-(2-((3,5-二氧代硫代吗啉)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000130
实施例116的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.22-9.72(br,2H),8.82(d,J＝4.0Hz,1H),7.71(d,J＝2.0Hz,1H),7.60(s,1H),7.51(d,J＝4.8Hz,1H),7.30(d,J＝3.2Hz,1H),7.08(d,J＝1.6Hz,1H),6.69(d,J＝3.6Hz,1H),5.23(d,J＝15.2Hz,1H),5.14(d,J＝15.2Hz,1H),3.85(d,J＝14.8Hz,1H),3.50(d,J＝14.8Hz,1H),3.52(s,4H),3.18-3.31(m,2H),2.80-2.94(m,2H), 1.69-1.72(m,1H),1.36-1.52(m,2H),1.01-1.04(m,1H)。
实施例117：4-((5-氯-7-(2-((3,4-二甲基-2,6-二氧代-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000131
实施例117的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.80(d,J＝4.8Hz,1H),7.80(d,J＝2.0Hz,1H),7.55(s,1H),7.52(d,J＝3.2Hz,1H),7.50(d,J＝4.8Hz,1H),7.08(d,J＝2.4Hz,1H),6.71(d,J＝3.2Hz,1H),5.61(s,1H),5.24(d,J＝14.8Hz,1H),5.14(d,J＝14.8Hz,1H),4.00(d,J＝14.8Hz,1H),3.16(d,J＝14.8Hz,1H),3.23(s,3H),2.76-2.82(m,2H),2.37-2.43(m,2H),2.17(s,3H),1.42-1.46(m,1H),0.80-1.01(m,3H)。
实施例118：(S)-4-((5-氯-7-(2-((1,3-二氧代四氢-1H-吡咯并[1,2-c]咪唑-2(3H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000132
实施例118的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.80(d,J＝5.2Hz,1H),7.68(d,J＝2.4Hz,1H),7.55(s,1H),7.35-7.38(m,2H),7.08(d,J＝2.0Hz,1H),6.64(d,J＝2.8Hz,1H),4.80-4.93(m,2H),4.06-4.11(m,1H),3.69-3.76(m,1H),3.60-3.68(m,1H),3.53(d,J＝14.8Hz,1H),3.19-3.25(m,1H),2.76-2.83(m,2H),2.59-2.66(m,2H),2.18-2.26(m,1H),1.94-2.11(m,3H),1.61-1.69(m,1H),1.35-1.42(m,1H),0.92-0.98(m,1H),0.72-0.85(m,2H)。
实施例119：4-((5-氯-7-(2-((1-氧代-3,5-二氧代硫代吗啉)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000133
实施例119的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.20-8.80(br,2H),7.82(d,J＝2.0Hz,1H),7.52-7.55(m,3H),7.11(d,J＝2.0Hz,1H),6.73(d,J＝3.2Hz,1H),5.23(d,J＝15.6Hz,1H),5.14(d,J＝15.6Hz,1H),4.33-4.38(m,2H),4.22-4.26(m,2H),4.13(d,J＝15.2Hz,1H),3.43(d,J＝15.6Hz,1H),3.02-3.13(m,2H),2.50-2.61(m,2H),1.64-1.68(m,1H),1.19-1.28(m,2H),0.91-0.96(m,1H)。
实施例120：(R)-4-((5-氯-7-(2-((3-甲基-2,5-二氧代吡咯烷-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000134
实施例120的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.80(d,J＝4.8Hz,1H),7.80(d,J＝1.6Hz,1H),7.56(s,1H),7.51-7.52(m,2H),7.10(s,1H),6.70(d,J＝3.2Hz,1H),4.83(d,J＝16.0Hz,1H),4.74(d,J＝16.0Hz,1H),3.94(d,J＝14.8Hz,1H),3.47(dd,J＝14.8Hz,5.2Hz,1H),2.81-2.91(m,2H),2.61-2.68(m,2H),2.22-2.35(m,3H),1.26-1.31(m,1H),1.13(d,J＝6.0Hz,3H),0.73-0.85(m,3H)。
实施例121：4-((7-(2-((3-烯丙基-2,5-二氧代吡咯烷-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-5-氯-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000135
实施例121的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),7.80(d,J＝2.0Hz,1H),7.56(s,1H),7.51-7.52(m,2H),7.09(s,1H),6.70(d,J＝3.2Hz,1H),5.59-5.70(m,1H),5.03(d,J＝17.2Hz,1H),4.93(d,J＝9.6Hz,1H),4.84(d,J＝16.0Hz,1H),4.76(d,J＝16.0Hz,1H),3.92-3.96(m,1H),3.43-3.48(m,1H),2.94-3.01(m,1H),2.75-2.82(m,1H),2.62-2.66(m,2H),2.20-2.44(m,5H),1.27-1.31(m,1H),0.74-0.86(m,3H)。
实施例122：4-((5-氯-7-(2-((4,6-二氧代-5-氮杂螺[2.4]庚-5-基)甲基)噻吩并 [3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000136
实施例122的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),7.81(d,J＝2.0Hz,1H),7.57(s,1H),7.51-7.52(m,2H),7.11(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),4.90(d,J＝15.6Hz,1H),4.81(d,J＝15.6Hz,1H),3.94(d,J＝15.2Hz,1H),3.50(d,J＝15.2Hz,1H),2.82(s,2H),2.63-2.67(m,2H),2.26-2.32(m,2H),1.27-1.31(m,1H),1.14-1.17(m,2H),1.04-1.07(m,2H),0.72-0.86(m,3H)。
实施例123：4-((7-(2-((4-(仲-丁基)-2,6-二氧代哌嗪-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-5-氯-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000137
实施例123的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.80(d,J＝4.8Hz,1H),7.80(d,J＝1.6Hz,1H),7.50-7.52(m,3H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.10(d,J＝15.2Hz,1H),4.99(d,J＝15.2Hz,1H),3.97(d,J＝14.8Hz,1H),3.38-3.48(m,5H),2.71-2.77(m,2H),2.49-2.53(m,1H),2.35(t,J＝12.0Hz,2H),1.35-1.41(m,2H),1.17-1.22(m,1H),0.79-0.92(m,6H),0.73(t,J＝7.2Hz,3H)。
实施例124：苄基(R)-(1-((7-(5-氯-1-((4-氰基哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-2,5-二氧代吡咯烷-3-基)氨基甲酸酯三氟乙酸盐
Figure PCTCN2021114936-appb-000138
实施例124的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝4.4Hz,1H),8.06-8.44(br,2H),7.98(d,J＝8.0Hz,1H),7.82(t,J＝1.6Hz,1H),7.60(s,1H),7.55-7.56(m,1H),7.52(d,J＝4.8Hz,1H),7.28-7.35(m,4H),7.15-7.26(br,1H),7.12(d,J＝2.0Hz,1H),6.73-6.74(m,1H),4.99(d,J＝1.2Hz,2H),4.87(dd,J＝16.0Hz,6.4Hz,1H),4.77(dd,J＝16.0Hz,7.2Hz,1H),4.44-4.51(m,1H),4.16(d,J＝14.8Hz,1H),3.48(d,J＝14.8Hz,1H),3.08-3.16(m,2H),2.97-3.04(m,1H),2.55-2.69(m,3H),1.68-1.74(m,1H),1.01-1.29(m,3H)。
实施例125：(R)-N-(1-((7-(5-氯-1-((4-氰基哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-2,5-二氧代吡咯烷-3-基)乙酰胺三氟乙酸盐
Figure PCTCN2021114936-appb-000139
实施例125的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝5.2Hz,1H),8.60-8.63(m,1H),8.50-8.59(br,1H),8.29-8.43(br,1H),7.83(d,J＝2.0Hz,1H),7.61(d,J＝5.2Hz,1H),7.55-7.57(m,1H),7.51(d,J＝4.8Hz,1H),7.13(d,J＝2.0Hz,1H),6.74(d,J＝3.2Hz,1H),4.74-4.88(m,2H),4.36-4.42(m,1H),4.18(dd,J＝14.8Hz,5.2Hz,1H),3.44-3.50(m,1H),3.10-3.20(m,2H),2.91-2.98(m,1H),2.54-2.72(m,3H),1.81(s,3H),1.69-1.78(m,1H),1.01-1.30(m,3H)。
实施例126：4-((5-氯-7-(2-((2,6-二氧代-3-(2,2,2-三氟乙基)-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000140
实施例126的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.81(d,J＝4.8Hz,1H),7.68(d,J＝2.0Hz,1H),7.65(s,1H),7.37(d,J＝4.8Hz,1H),7.35(d,J＝3.2Hz,1H),7.13(d,J＝8.4Hz,1H),7.06(d,J＝2.0Hz,1H),6.65(d,J＝3.2Hz,1H),5.84(d,J＝8.4Hz,1H),5.39(d,J＝14.4Hz,1H),5.31(d,J＝14.4Hz,1H),4.30-4.41(m,2H),3.73(d,J＝14.8Hz,1H),3.55(d,J＝14.8Hz,1H),2.80-2.82(m,2H),2.61-2.68(m,2H),1.38-1.42(m,1H),0.92-0.98(m,1H),0.76-0.88(m,2H)。
实施例127：(S)-4-((5-氯-7-(2-((3-甲基-2,5-二氧代吡咯烷-1-基)甲基)噻吩并 [3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000141
实施例127的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.4Hz,1H),8.01-8.34(br,2H),7.82(d,J＝2.0Hz,1H),7.57(s,1H),7.56(d,J＝3.6Hz,1H),7.52(d,J＝4.8Hz,1H),7.12(d,J＝2.0Hz,1H),6.74(d,J＝3.2Hz,1H),4.84(,d J＝16.0Hz,1H),4.74(d,J＝16.0Hz,1H),4.12(d,J＝14.8Hz,1H),3.44-3.49(m,1H),3.04-3.14(m,2H),2.81-2.91(m,2H),2.57-2.64(m,2H),2.30-2.38(m,1H),1.64-1.68(m,1H),1.01-1.27(m,6H)。
实施例128：4-((5-氯-7-(2-((1,1-二氧代-3,5-二氧代硫代吗啉)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000142
实施例128的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝4.8Hz,1H),8.18-8.48(br,2H),7.83(d,J＝2.0Hz,1H),7.56(d,J＝3.6Hz,1H),7.52-7.54(m,2H),7.12(d,J＝2.0Hz,1H),6.75(d,J＝3.6Hz,1H),5.24(d,J＝16.0Hz,1H),5.12(d,.J＝16.0Hz,1H),4.88(s,4H),4.15(d,J＝15.2Hz,1H),3.44(d,J＝15.2Hz,1H),3.10-3.18(m,2H),2.59-2.71(m,2H),1.71-1.74(m,1H),1.02-1.26(m,3H)。
实施例129：4-((5-氯-7-(2-((3-甲基-2,6-二氧-4-(三氟甲基)-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000143
实施例129的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.82(d,J＝4.4Hz,1H),7.68-7.69(m,2H),7.39(d,J＝4.8Hz,1H),7.35(d,J＝3.2Hz,1H), 7.06(d,J＝2.0Hz,1H),6.65(d,J＝3.6Hz,1H),6.23(s,1H),5.40(d,J＝14.8Hz,1H),5.29(d,J＝14.8Hz,1H),3.75(d,J＝14.8Hz,1H),3.54(d,J＝14.8Hz,1H),3.47(s,3H),2.80-2.88(m,2H),2.62-2.71(m,2H),2.36-2.59(br,1H),1.42-1.47(m,1H),0.81-0.96(m,3H)。
实施例130：4-((7-(2-((4-烯丙基-2,6-二氧哌嗪-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-5-氯-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000144
实施例130的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.4Hz,1H),8.44-8.57(br,1H),8.23-8.40(br,1H),7.83(d,J＝2.0Hz,1H),7.26(d,J＝3.2Hz,1H),7.54(s,1H),7.51(d,J＝4.8Hz,1H),7.11(d,J＝2.4Hz,1H),6.74(d,J＝3.2Hz,1H),5.65-5.74(m,1H),5.08-5.13(m,3H),4.99(d,J＝15.2Hz,1H),4.13(d,J＝15.2Hz,1H),3.46(d,J＝15.2Hz,1H),3.45(s,4H),3.12-3.18(m,2H),3.02-3.08(m,2H),2.60-2.72(m,2H),1.69-1.74(m,1H),1.04-1.30(m,3H)。
实施例131：4-((5-氯-7-(2-((5,7-二氧-6-氮杂螺[3.4]辛烷-6-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000145
实施例131的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.4Hz,1H),8.53-8.69(br,1H),8.29-8.48(br,1H),7.82(d,J＝2.0Hz,1H),7.56(d,J＝3.2Hz,1H),7.55(s,1H),7.52(d,J＝4.8Hz,1H),7.12(d,J＝2.0Hz,1H),6.74(d,J＝3.6Hz,1H),4.84(d,J＝16.0Hz,1H),4.73(d,J＝16.0Hz,1H),4.13(d,J＝14.8Hz,1H),3.47(d,J＝14.8Hz,1H),3.09-3.18(m,2H),2.89(s,2H),2.59-2.70(m,2H),2.26-2.36(m,2H),2.01-2.05(m,2H),1.86-1.94(m,2H),1.66-1.73(m,1H),1.05-1.30(m,3H)。
实施例132：4-((5-氯-7-(2-((6,6-二甲基-2,4-二氧-3-氮杂双环[3.1.0]己-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)-1-异丙基哌啶-4-甲腈
Figure PCTCN2021114936-appb-000146
实施例132的合成方法同实施例13相同。 1H NMR(400MHz,CDCl 3),8.84(d,J＝4.0Hz,1H),7.68(d,J＝2.0Hz,1H),7.58(s,1H),7.46-7.54(m,1H),7.23-7.26(m,1H),7.05(d,J＝2.0Hz,1H),6.65(d,J＝3.2Hz,1H),4.79(d,J＝15.2Hz,1H),4.71(d,J＝15.2Hz,1H),3.72(d,J＝14.8Hz,1H),3.50(d,J＝14.8Hz,1H),2.62-3.22(m,3H),2.24-2.58(m,4H),1.56-1.74(m,2H),1.20(s,3H),0.97-1.19(m,9H),0.81-0.91(m,2H)。
实施例133：N-(1-((7-(5-氯-1-((4-氰基哌啶-4-基)甲基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-2,5-二氧吡咯烷-3-基)环丙基甲酰胺三氟乙酸盐
Figure PCTCN2021114936-appb-000147
实施例133的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82-8.92(br,1H),8.81(d,J＝4.4Hz,1H),8.54-8.68(br,1H),7.82(d,J＝2.0Hz,1H),7.58(d,J＝2.8Hz,1H),7.56(d,J＝3.2Hz,1H),7.52(d,J＝4.8Hz,1H),7.10-7.11(m,1H),6.74(d,J＝3.2Hz,1H),4.83-4.88(m,1H),4.72-4.78(m,1H),4.44-4.51(m,1H),4.14-4.18(m,1H),3.44-3.47(m,1H),3.13-3.22(m,2H),2.92-2.98(m,1H),2.50-2.72(m,3H),1.70-1.78(m,1H),1.47-1.56(m,1H),1.14-1.35(m,2H),1.01-1.08(m,1H),0.54-0.70(m,4H)。
实施例134：(R)-4-((5-氯-7-(2-((1,3-二氧四氢-1H-吡咯并[1,2-c]咪唑-2(3H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000148
实施例134的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝4.4Hz,1H),8.43-8.59(br,1H),8.21-8.39(br,1H),7.83(d,J＝2.0Hz,1H), 7.56-7.58(m,2H),7.52(d,J＝5.2Hz,1H),7.13(d,J＝2.0Hz,1H),6.74(d,J＝3.6Hz,1H),4.71-4.88(m,2H),4.20-4.24(m,1H),4.12(d,J＝15.2Hz,1H),3.50(d,J＝15.2Hz,1H),3.38-3.46(m,1H),3.07-3.18(m,3H),2.59-2.72(m,2H),2.01-2.09(m,1H),1.87-1.98(m,2H),1.66-1.72(m,1H),1.52-1.62(m,1H),1.07-1.29(m,3H)。
实施例135：4-((5-氯-7-(2-((6,6-二甲基-2,4-二氧-3-氮杂双环[3.1.0]己烷-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)-4-氰基-1,1-二甲基哌啶-1-碘化物
Figure PCTCN2021114936-appb-000149
实施例135的合成方法同实施例13相同。 1H NMR(400MHz,CDCl 3),8.74-9.01(m,1H),7.71(s,1H),7.61-7.68(m,1H),7.50-7.58(m,1H),7.38-7.46(m,1H),7.12(d,J＝1.2Hz,1H),6.65(s,1H),4.84(d,J＝14.8Hz,1H),4.73(d,J＝14.8Hz,1H),3.52-3.84(m,4H),3.25(s,3H),2.94-3.16(m,5H),2.37(s,2H),1.74-2.08(m,3H),1.50-1.60(m,1H),1.22(s,3H),1.12(s,3H)。
实施例136：4-((5-氯-7-(2-((6,6-二甲基-2,4-二氧-3-氮杂双环[3.1.0]己烷-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)-1-甲基哌啶-4-甲腈
Figure PCTCN2021114936-appb-000150
实施例136的合成方法同实施例13相同。 1H NMR(400MHz,CDCl 3),8.80-8.88(m,1H),7.69(d,J＝1.6Hz,1H),7.59(s,1H),7.41-7.49(m,1H),7.29-7.34(m,1H),7.06(d,J＝2.0Hz,1H),6.66(d,J＝3.2Hz,1H),4.80(d,J＝14.8Hz,1H),4.73(d,J＝14.8Hz,1H),3.75(d,J＝15.2Hz,1H),3.49(d,J＝15.2Hz,1H),1.96-2.80(m,9H),1.21(s,3H),1.07(s,3H),1.48-1.68(m,2H),0.81-0.93(m,2H)。
实施例137：4-((5-氯-7-(2-((6,6-二甲基-2,4-二氧-3-氮杂双环[3.1.0]己烷-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)-1-(环丙基甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000151
实施例137的合成方法同实施例13相同。 1H NMR(400MHz,CDCl 3),8.82(d,J＝4.4Hz,1H),7.69(d,J＝2.4Hz,1H),7.58(s,1H),7.42(d,J＝4.4Hz,1H),7.32(d,J＝3.2Hz,1H),7.06(d,J＝2.0Hz,1H),6.65(d,J＝3.2Hz,1H),4.80(d,J＝15.2Hz,1H),4.72(d,J＝15.2Hz,1H),3.71(d,J＝14.8Hz,1H),3.49(d,J＝14.8Hz,1H),2.71-2.88(m,2H),2.33(s,2H),1.96-2.18(m,4H),1.48-1.57(m,1H),1.21(s,3H),1.07(s,3H),0.78-1.06(m,3H),0.65-0.76(m,1H),0.40-0.50(m,2H),-0.03-0.05(m,2H)。
实施例138：4-((5-氯-7-(2-((6,6-二甲基-2,4-二氧-3-氮杂双环[3.1.0]己烷-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)-1-(2,2,2-三氟乙基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000152
实施例138的合成方法同实施例13相同。 1H NMR(400MHz,CDCl 3),8.80(d,J＝4.4Hz,1H),7.69(d,J＝2.0Hz,1H),7.59(s,1H),7.36(d,J＝4.8Hz,1H),7.33(d,J＝3.2Hz,1H),7.08(d,J＝2.0Hz,1H),6.66(d,J＝3.2Hz,1H),4.81(d,J＝15.2Hz,1H),4.71(d,J＝15.2Hz,1H),3.72(d,J＝15.2Hz,1H),3.56(d,J＝15.2Hz,1H),2.83(q,J＝9.6Hz,2H),2.62-2.71(m,2H),2.36-2.44(m,2H),2.34(s,2H),1.31-1.37(m,1H),1.21(s,3H),1.09(s,3H),0.80-1.01(m,3H)。
实施例139：4-((5-氯-7-(2-((6,6-二甲基-2,4-二氧-3-氮杂双环[3.1.0]己烷-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)-1-乙基哌啶-4-甲腈
Figure PCTCN2021114936-appb-000153
实施例139的合成方法同实施例13相同。 1H NMR(400MHz,CDCl 3),8.84(d, J＝4.8Hz,1H),7.69(d,J＝2.0Hz,1H),7.58(s,1H),7.48(d,J＝4.4Hz,1H),7.28(d,J＝3.2Hz,1H),7.06(d,J＝2.0Hz,1H),6.66(d,J＝3.6Hz,1H),4.79(d,J＝15.2Hz,1H),4.72(d,J＝15.2Hz,1H),3.74(d,J＝15.2Hz,1H),3.50(d,J＝15.2Hz,1H),2.78-3.02(m,2H),2.41-2.61(m,2H),2.32-2.34(m,2H),2.12-2.29(m,2H),1.59-1.63(m,1H),1.20(s,3H),1.02-1.15(m,6H),0.80-0.95(m,3H)。
实施例140：4-((5-氯-7-(2-((6,6-二甲基-2,4-二氧-3-氮杂双环[3.1.0]己烷-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)-1-环丙基哌啶-4-甲腈
Figure PCTCN2021114936-appb-000154
实施例140的合成方法同实施例13相同。 1H NMR(400MHz,CDCl 3),8.80(d,J＝4.8Hz,1H),7.69(d,J＝2.4Hz,1H),7.58(s,1H),7.38-7.44(m,1H),7.30(d,J＝2.4Hz,1H),7.05(d,J＝2.0Hz,1H),6.65(d,J＝3.6Hz,1H),4.80(d,J＝15.2Hz,1H),4.72(d,J＝15.2Hz,1H),3.69(d,J＝15.2Hz,1H),3.49(d,J＝15.2Hz,1H),2.66-2.82(m,2H),2.32-2.35(m,2H),2.17-2.31(m,2H),1.42-1.57(m,2H),1.21(s,3H),1.07(s,3H),0.78-0.96(m,3H),0.32-0.43(m,2H),0.19-0.30(m,2H)。
实施例141：4-((5-氯-7-(2-((3-乙基-3-甲基-2,5-二氧吡咯烷-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000155
实施例141的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.82(d,J＝4.4Hz,1H),7.70(d,J＝1.6Hz,1H),7.55(s,1H),7.40(d,J＝4.8Hz,1H),7.35(d,J＝3.6Hz,1H),7.09(d,J＝2.4Hz,1H),6.66(d,J＝3.6Hz,1H),4.92(d,J＝15.2Hz,1H),4.85(d,J＝15.2Hz,1H),3.72-3.76(m,1H),3.49-3.54(m,1H),2.80-2.89(m,2H),2.61-2.72(m,3H),2.43(d,J＝18.4Hz,1H),2.12-2.32(br,1H),1.66-1.74(m,1H),1.52-1.62(m,1H),1.40-1.46(m,1H),1.27(s,1.5H),1.26(s,1.5H),0.78-0.97(m,6H)。
实施例142：3-((7-(5-氯-1-(2-羟基-3-(哌嗪-1-基)丙基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000156
实施例142的合成方法同实施例9相同。 1H NMR(400MHz,CDCl 3),8.72-8.74(m,1H),7.68-7.69(m,1H),7.58(s,0.5H),7.55(s,0.5H),7.22-7.25(m,2H),7.05(d,J＝2.0Hz,0.5H),7.00(d,J＝2.0Hz,0.5H),6.55-6.56(m,1H),4.69-4.83(m,2H),3.56-3.61(m,0.5H),3.37-3.48(m,1.5H),3.19-3.27(m,1H),2.68-2.86(m,4H),2.35-2.43(m,3H),2.09-2.21(m,2H),1.89-2.01(br,1H),1.65-1.69(m,1H),1.30-1.34(m,1H),1.23(s,1.5H),1.21(s,1.5H),1.14(s,1.5H),1.06-1.13(m,2.5H),0.82-0.85(m,1H)。
实施例143：3-((7-(5-氯-1-(2,3-二羟基丙基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000157
实施例143的合成方法同实施例9相同。 1H NMR(400MHz,CDCl 3),8.67-8.74(m,1H),7.69(s,1H),7.54-7.56(m,1H),7.13-7.25(m,2H),7.03-7.05(m,1H),6.50-6.58(m,1H),4.74-4.81(m,2H),3.24-3.57(m,3H),2.68-3.04(m,2H),2.34(s,2H),1.21(s,3H),1.06-1.14(m,3H)。
实施例144：4-((5-氯-7-(2-((3-(环丙基甲基)-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000158
实施例144的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝4.8Hz,1H),8.56-8.73(br,1H),8.33-8.51(br,1H),7.82(d,J＝2.0Hz,1H),7.75(d,J＝8.0Hz,1H),7.57(s,1H),7.55(d,J＝3.6Hz,1H),7.52(d,J＝4.8Hz,1H),7.10(d,J＝2.0Hz,1H),6.74(d,J＝3.2Hz,1H),5.69(d,J＝8.0Hz,1H),5.28 (d,J＝15.2Hz,1H),5.16(d,J＝15.2Hz,1H),4.13(d,J＝15.2Hz,1H),3.54(d,J＝7.2Hz,2H),3.47(d,J＝15.2Hz,1H),3.10-3.20(m,2H),2.60-2.71(m,2H),1.69-1.76(m,1H),1.13-1.32(m,2H),1.02-1.08(m,2H),0.38-0.43(m,2H),0.26-0.29(m,2H)。
实施例145：4-((5-氯-7-(2-((3,5-二甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000159
实施例145的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.18-9.95(br,2H),8.74-8.94(m,1H),7.64-7.75(m,2H),7.47-7.58(m,1H),7.30(d,J＝2.4Hz,1H),7.06(s,1H),6.98(s,1H),6.69(d,J＝3.2Hz,1H),5.29-5.41(m,2H),3.84(d,J＝14.8Hz 1H),3.53(d,J＝14.8Hz,1H),3.16-3.36(m,5H),2.81-2.96(m,2H),1.88(s,3H),1.66-1.76(m,1H),1.38-1.55(m,2H),1.0-1.10(m,1H)。
实施例146：4-((5-氯-7-(2-((3-(环丙基甲基)-5-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000160
实施例146的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.40-8.50(br,1H),8.18-8.31(br,1H),7.82(d,J＝2.0Hz,1H),7.64(d,J＝1.2Hz,1H),7.55-7.56(m,2H),7.51(d,J＝4.8Hz,1H),7.10(d,J＝2.0Hz,1H),6.75(d,J＝3.6Hz,1H),5.30(d,J＝14.8Hz,1H),5.17(d,J＝14.8Hz,1H),4.13(d,J＝14.8Hz,1H),3.47-3.52(m,3H),3.10-3.19(m,2H),2.60-2.74(m,2H),1.71-1.76(m,4H),1.02-1.29(m,4H),0.38-0.43(m,2H),0.26-0.30(m,2H)。
实施例147：3-((7-(5-氯-1-(2-(哌嗪-1-基)乙基)-1H-吲哚-7-基)噻吩并[3,2-b]吡啶-2-基)甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2,4-二酮
Figure PCTCN2021114936-appb-000161
实施例147的合成方法同实施例9相同。 1H NMR(400MHz,DMSO-d 6),8.73(d,J＝4.8Hz,1H),7.76(d,J＝2.4Hz,1H),7.56(s,1H),7.48(d,J＝4.8Hz,1H),7.46(d,J＝2.8Hz,1H),7.04(d,J＝2.0Hz,1H),6.57(d,J＝3.2Hz,1H),4.70-4.79(m,2H),3.58-3.65(m,1H),3.45-3.52(m,1H),2.54(s,2H),2.38-2.41(m,4H),1.94-2.01(m,1H),1.78-1.86(m,1H),1.63-1.70(m,4H),1.13(s,3H),0.98(s,3H)。
实施例148：4-(2-(5-氯-7-(2-((6,6-二甲基-2,4-二氧-3-氮杂双环[3.1.0]己烷-3-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)乙基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000162
实施例148的合成方法同实施例9相同。 1H NMR(400MHz,DMSO-d 6),8.74(d,J＝4.8Hz,1H),7.78(d,J＝2.0Hz,1H),7.56(s,1H),7.53(d,J＝3.2Hz,1H),7.50(d,J＝4.4Hz,1H),7.06(d,J＝2.0Hz,1H),6.63(d,J＝3.2Hz,1H),4.70-4.79(m,2H),3.67-3.75(m,1H),3.56-3.63(m,1H),2.58-2.68(m,2H),2.53(s,2H),2.30-2.39(m,2H),2.11-2.29(br,1H),1.43-1.51(m,1H),1.19-1.28(m,1H),1.03-1.13(m,5H),1.00(s,3H),0.69-0.76(m,1H),0.52-0.59(m,1H)。
实施例149：4-((5-氯-7-(2-((5-氟-3-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000163
实施例149的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.14(d,J＝6.8Hz,1H),7.81(d,J＝2.0Hz,1H),7.60(s,1H),7.51-7.52(m,2H),7.09(d,J＝2.4Hz,1H),6.71(d,J＝3.2Hz,1H),5.27(d,J＝15.2Hz,1H),5.17(d,J＝15.2Hz,1H),3.94(d,J＝14.8Hz,1H),3.48(d,J＝14.8Hz,1H),3.21(s,3H),2.62-2.69(m,2H),2.26-2.35(m,2H),1.29-1.33(m,1H),0.74-0.87(m,3H)。
实施例150：4-((5-氯-7-(2-((3-(环丙基甲基)-5-氟-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000164
实施例150的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.22(d,J＝6.8Hz,1H),7.81(d,J＝2.4Hz,1H),7.60(s,1H),7.51-7.52(m,2H),7.09(d,J＝2.4Hz,1H),6.71(d,J＝3.2Hz,1H),5.29(d,J＝15.2Hz,1H),5.19(d,J＝15.2Hz,1H),3.94(d,J＝15.2Hz,1H),3.47-3.52(m,3H),2.62-2.68(m,2H),2.26-2.34(m,2H),1.28-1.33(m,1H),1.03-1.12(m,1H),0.76-0.86(m,3H),0.39-0.43(m,2H),0.28-0.32(m,2H)。
实施例151：4-((7-(2-((5-溴-3-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-5-氯-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000165
实施例151的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝5.2Hz,1H),8.25(s,1H),7.80(d,J＝2.4Hz,1H),7.59(s,1H),7.52(s,1H),7.51(d,J＝2.8Hz,1H),7.08(d,J＝2.0Hz,1H),6.71(d,J＝3.6Hz,1H),5.29(d,J＝15.2Hz,1H),5.19(d,J＝15.2Hz,1H),3.93(d,J＝14.8Hz,1H),3.49(d,J＝14.8Hz,1H),3.25(s,3H),2.60-2.67(m,2H),2.26-2.34(m,2H),1.27-1.30(m,1H),0.74-0.84(m,3H)。
实施例152：4-((7-(2-((5-溴-3-(环丙基甲基)-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-5-氯-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000166
实施例152的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.32(s,1H),7.80(d,J＝2.0Hz,1H),7.60(s,1H),7.52(d,J＝2.4Hz,1H),7.51(s,1H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.6Hz,1H),5.31(d,J＝15.2Hz,1H),5.21(d,J＝15.2Hz,1H),3.93(d,J＝15.2Hz,1H),3.55(d,J＝7.2Hz,2H),3.50(d,J＝15.2Hz,1H),2.60-2.70(m,2H),2.26-2.34(m,2H),1.94-1.98(m,1H),1.19-1.32(m,1H),1.05-1.14(m,1H),0.74-0.85(m,2H),0.38-0.43(m,2H),0.28-0.31(m,2H)。
实施例153：4-((5-氯-7-(2-((3-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000167
实施例128的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.80(d,J＝4.8Hz,1H),7.80(d,J＝2.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.57(s,1H),7.50-7.52(m,2H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.65(d,J＝8.0Hz,1H),5.25(d,J＝15.2Hz,1H),5.15(d,J＝15.2Hz,1H),3.95(d,J＝14.8Hz,1H),3.49(d,J＝14.8Hz,1H),3.23(s,3H),2.64-2.71(m,2H),2.28-2.36(m,2H),1.30-1.37(m,1H),0.75-0.89(m,3H)。
实施例154：4-((5-氯-7-(2-((4-甲基-3,5-二氧-4,5-二氢-1,2,4-三嗪-2(3H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000168
实施例154的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.84(d,J＝4.8Hz,1H),7.71(d,J＝2.0Hz,1H),7.65(s,1H),7.41(d,J＝4.8Hz,1H),7.39(s,1H),7.37(d,J＝3.6Hz,1H),7.09(d,J＝2.0Hz,1H),6.67(d,J＝3.6Hz,1H),5.32-5.40(m,2H),3.75(d,J＝15.2Hz,1H),3.57(d,J＝15.2Hz,1H),3.30(s,3H),2.76-2.84(m,2H),2.60-2.70(m,2H),1.36-1.43(m,1H),0.95-1.01(m,1H),0.78-0.89(m,2H)。
实施例155：4-((5-氯-7-(2-((3-(环丙基甲基)-4-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000169
实施例155的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.79(d,J＝4.4Hz,1H),7.68(d,J＝2.0Hz,1H),7.63(s,1H),7.36(d,J＝3.6Hz,1H),7.34(d,J＝4.4Hz,1H),7.07(d,J＝2.0Hz,1H),6.65(d,J＝2.8Hz,1H),5.60(s,1H),5.29-5.41(m,2H),3.71-3.76(m,3H),3.58(d,J＝14.8Hz,1H),2.80-2.87(m,2H),2.60-2.71(m,2H),2.26(s,3H),1.37-1.41(m,1H),0.96-1.06(m,2H),0.76-0.89(m,2H),0.50-0.55(m,2H),0.36-0.40(m,2H)。
实施例156：4-((5-氯-7-(2-((4-甲基-3-(甲基-d3)-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000170
实施例156的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.79(d,J＝4.8Hz,1H),7.68(d,J＝2.0Hz,1H),7.65(s,1H),7.37(d,J＝3.2Hz,1H),7.34(d,J＝4.4Hz,1H),7.06(d,J＝2.4Hz,1H),6.65(d,J＝3.2Hz,1H),5.61(s,1H),5.28-5.40(m,2H),3.72(d,J＝15.2Hz,1H),3.58(d,J＝15.2Hz,1H),2.78-2.84(m,2H),2.60-2.70(m,2H),2.20(s,3H),1.36-1.42(m,1H),0.94-1.00(m,1H),0.75-0.89(m,2H)。
实施例157：4-((5-氯-7-(2-((5-甲基-2,6-二氧-3-(2,2,2-三氟乙基)-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000171
实施例157的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.80(d,J＝4.8Hz,1H),7.69(d,J＝1.6Hz,1H),7.65(s,1H),7.35-7.37(m,2H),7.08(d,J＝2.0Hz,1H),6.98(s,1H),6.66(d,J＝3.6Hz,1H),5.42(d,J＝14.8Hz,1H),5.34(d,J＝14.8Hz,1H),4.28-4.40(m,2H),3.74(d,J＝15.2Hz,1H),3.57(d,J＝15.2Hz, 1H),2.78-2.86(m,2H),2.61-2.71(m,2H),1.94(s,3H),1.38-1.44(m,1H),0.95-1.01(m,1H),0.75-0.89(m,2H)。
实施例158：4-((5-氯-7-(2-((3-环丙基-5-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000172
实施例158的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.42-8.56(br,1H),8.22-8.37(br,1H),7.83(d,J＝2.0Hz,1H),7.55-7.58(m,2H),7.51(d,J＝4.8Hz,1H),7.47(s,1H),7.11(d,J＝2.4Hz,1H),6.75(d,J＝3.2Hz,1H),5.26(d,J＝14.8Hz,1H),5.14(d,J＝14.8Hz,1H),4.14(d,J＝14.8Hz,1H),3.49(d,J＝14.8Hz,1H),3.10-3.20(m,2H),3.01-3.06(m,1H),2.60-2.74(m,2H),1.70-1.78(m,4H),1.04-1.31(m,3H),0.81-0.88(m,2H),0.74-0.78(m,2H)。
实施例159：4-((5-氯-7-(2-((5-氟-2,6-二氧-3-(2,2,2-三氟乙基)-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000173
实施例159的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝5.2Hz,1H),8.19(d,J＝6.4Hz,1H),7.81(d,J＝2.0Hz,1H),7.61(s,1H),7.51-7.53(m,2H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.29(d,J＝15.2Hz,1H),5.19(d,J＝15.2Hz,1H),4.55-4.62(m,2H),3.94(d,J＝15.2Hz,1H),3.49(d,J＝15.2Hz,1H),2.63-2.72(m,2H),2.28-2.37(m,2H),1.30-1.36(m,1H),0.78-0.88(m,3H)。
实施例160：4-((5-氯-7-(2-((3-(氘代甲基)-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000174
实施例160的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝5.2Hz,1H),7.81(d,J＝2.4Hz,1H),7.64(d,J＝8.4Hz,1H),7.57(s,1H),7.52(d,J＝3.6Hz,1H),7.50(d,J＝4.8Hz,1H),7.09(d,J＝2.0Hz,1H),6.72(d,J＝3.6Hz,1H),5.65(d,J＝8.0Hz,1H),5.25(d,J＝15.2Hz,1H),5.15(d,J＝15.2Hz,1H),3.98(d,J＝14.8Hz,1H),3.48(d,J＝14.8Hz,1H),2.72-2.81(m,2H),2.34-2.43(m,2H),1.37-1.44(m,1H),0.77-0.96(m,3H)。
实施例161：4-((5-氯-7-(2-((5-氯-3-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000175
实施例161的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.19(s,1H),7.80(d,J＝2.4Hz,1H),7.60(s,1H),7.50-7.52(m,2H),7.08(d,J＝2.4Hz,1H),6.71(d,J＝3.2Hz,1H),5.28(d,J＝15.2Hz,1H),5.18(d,J＝15.2Hz,1H),3.92(d,J＝14.8Hz,1H),3.48(d,J＝14.8Hz,1H),3.25(s,3H),2.58-2.66(m,2H),2.23-2.33(m,2H),1.98-2.19(br,1H),1.26-1.29(m,1H),0.73-0.82(m,3H)。
实施例162：4-((5-氯-7-(2-((5-氯-3-(环丙基甲基)-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000176
实施例162的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.25(s,1H),7.80(d,J＝2.0Hz,1H),7.60(s,1H),7.50-7.52(m,2H),7.09(d,J＝2.0Hz,1H),6.70(d,J＝3.6Hz,1H),5.30(d,J＝15.2Hz,1H),5.21(d,J＝15.2Hz,1H),3.91(d,J＝15.2Hz,1H),3.56(d,J＝7.6Hz,2H),3.50(d,J＝ 15.2Hz,1H),2.58-2.65(m,2H),2.23-2.31(m,2H),1.88-2.02(br,1H),1.24-1.28(m,1H),1.04-1.14(m,1H),0.72-0.85(m,3H),0.39-0.43(m,2H),0.28-0.32(m,2H)。
实施例163：4-((5-氯-7-(2-((5-氯-2,6-二氧-3-(2,2,2-三氟乙基)-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000177
实施例163的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.24(s,1H),7.80(d,J＝2.0Hz,1H),7.61(s,1H),7.50-7.52(m,2H),7.08(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.31(d,J＝15.2Hz,1H),5.20(d,J＝15.2Hz,1H),4.59-4.66(m,2H),3.91(d,J＝14.8Hz,1H),3.49(d,J＝14.8Hz,1H),2.58-2.66(m,2H),2.24-2.32(m,2H),1.92-2.06(br,1H),1.25-1.30(m,1H),0.72-0.84(m,3H)。
实施例164：4-((5-氯-7-(2-((4-甲基-2,6-二氧-3-(2,2,2-三氟乙基)-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000178
实施例164的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.81(d,J＝4.8Hz,1H),7.69(d,J＝2.0Hz,1H),7.64(s,1H),7.36-7.38(m,2H),7.07(d,J＝2.0Hz,1H),6.65(d,J＝3.2Hz,1H),5.69(s,1H),5.38(d,J＝14.8Hz,1H),5.31(d,J＝14.8Hz,1H),4.43-4.56(m,2H),3.73(d,J＝15.2Hz,1H),5.60(d,J＝15.2Hz,1H),2.78-2.86(m,2H),2.61-2.70(m,2H),2.26(s,3H),1.37-1.43(m,1H),0.76-0.99(m,3H)。
实施例165：4-((5-氯-7-(2-((3-异丙基-4-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000179
实施例165的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.79(d,J＝4.4Hz,1H),7.68(d,J＝2.0Hz,1H),7.62(s,1H),7.36(d,J＝3.6Hz,1H),7.34(d,J＝4.4Hz,1H),7.08(d,J＝2.0Hz,1H),6.65(d,J＝2.8Hz,1H),5.54(s,1H),5.35(d,J＝14.8Hz,1H),5.27(d,J＝14.8Hz,1H),4.22-4.36(m,1H),3.74(d,J＝14.8Hz,1H),3.57(d,J＝14.8Hz,1H),2.77-2.84(m,2H),2.60-2.69(m,2H),2.21(s,3H),1.48-1.51(m,6H),1.35-1.42(m,1H),0.92-0.99(m,1H),0.74-0.89(m,2H)。
实施例166：4-((5-氯-7-(2-((2,6-二氧-3-(2,2,2-三氟乙基)-5-(三氟甲基)-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000180
实施例166的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝4.8Hz,1H),8.53(s,1H),7.81(d,J＝2.4Hz,1H),7.62(s,1H),7.50-7.53(m,2H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.29(d,J＝15.2Hz,1H),5.17(d,J＝15.2Hz,1H),4.68-4.76(m,2H),3.92(d,J＝15.2Hz,1H),3.48(d,J＝15.2Hz,1H),2.60-2.65(m,2H),2.24-2.32(m,2H),1.26-1.30(m,1H),0.73-0.84(m,3H)。
实施例167：4-((5-氯-7-(2-((3-乙基-2,6-二氧-5-(三氟甲基)-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000181
实施例167的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.45(s,1H),7.81(d,J＝2.0Hz,1H),7.60(s,1H),7.50-7.52(m,2H),7.10(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.27(d,J＝15.2Hz,1H),5.17(d,J＝15.2Hz,1H),3.93(d,J＝14.8Hz,1H),3.79(q,J＝7.6Hz,2H),3.51(d,J＝14.8Hz,1H),2.60-2.66(m,2H),2.24-2.34(m,2H),1.24-1.31(m,1H),1.15(t,J＝7.2Hz,3H),0.74-0.86(m,3H)。
实施例168：4-((5-氯-7-(2-((5-氯-3-乙基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000182
实施例168的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.23(s,1H),7.80(d,J＝2.4Hz,1H),7.59(s,1H),7.50-7.52(m,2H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.29(d,J＝15.2Hz,1H),5.19(d,J＝15.2Hz,1H),3.91(d,J＝15.2Hz,1H),3.71(q,J＝7.2Hz,2H),3.50(d,J＝15.2Hz,1H),2.56-2.65(m,2H),2.22-2.32(m,2H),1.87-1.94(br,1H),1.22-1.29(m,1H),1.13(t,J＝7.2Hz,3H),0.72-0.85(m,3H)。
实施例169：4-((5-氯-7-(2-((3-乙基-4-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000183
实施例169的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.79(d,J＝4.8Hz,1H),7.68(d,J＝2.0Hz,1H),7.64(s,1H),7.37(d,J＝3.2Hz,1H),7.34(d,J＝4.4Hz,1H),7.07(d,J＝2.0Hz,1H),6.65(d,J＝3.2Hz,1H),5.59(s,1H),5.38(d,J＝14.4Hz,1H),5.30(d,J＝14.4Hz,1H),3.86(q,J＝7.2Hz,2H),3.73(d,J＝15.2Hz,1H),3.58(d,J＝15.2Hz,1H),2.78-2.84(m,2H),2.60-2.70(m,2H),2.23(s,3H),1.36-1.42(m,1H),1.24(t,J＝7.2Hz,3H),0.94-1.00(m,1H),0.75-0.89(m,2H)。
实施例170：4-((7-(2-((5-溴-2,6-二氧-3-(2,2,2-三氟乙基)-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-5-氯-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000184
实施例170的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.31(s,1H),7.81(d,J＝2.0Hz,1H),7.60(s,1H),7.50-7.52(m,2H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.31(d,J＝15.2Hz,1H),5.20(d,J＝15.2Hz,1H),4.59-4.66(m,2H),3.93(d,J＝14.8Hz,1H),3.49(d,J＝14.8 Hz,1H),2.64-2.70(m,2H),2.26-2.36(m,2H),1.28-1.33(m,1H),0.75-0.87(m,3H)。
实施例171：4-((5-氯-7-(2-((3-异丙基-5-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000185
实施例171的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.80(d,J＝4.8Hz,1H),7.80(d,J＝2.0Hz,1H),7.63(d,J＝1.2Hz,1H),7.56(s,1H),7.49-7.51(m,2H),7.09(d,J＝2.4Hz,1H),6.71(d,J＝3.2Hz,1H),5.27(d,J＝15.2Hz,1H),5.18(d,J＝15.2Hz,1H),4.60-4.67(m,1H),3.93(d,J＝15.2Hz,1H),3.51(d,J＝15.2Hz,1H),2.59-2.67(m,2H),2.24-2.34(m,2H),1.78(s,3H),1.26-1.32(m,1H),1.18-1.20(m,6H),0.72-0.84(m,3H)。
实施例172：4-((5-氯-7-(2-((3-环丙基-5-氟-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000186
实施例172的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.82(d,J＝4.0Hz,1H),7.67-7.71(m,2H),7.39(d,J＝4.4Hz,1H),7.36(d,J＝3.2Hz,1H),7.28(d,J＝5.6Hz,1H),7.07(d,J＝2.0Hz,1H),6.66(d,J＝3.2Hz,1H),5.40(d,J＝14.4Hz,1H),5.30(d,J＝14.4Hz,1H),3.75(d,J＝15.2Hz,1H),3.56(d,J＝15.2Hz,1H),3.06-3.12(m,1H),2.82-2.92(m,2H),2.63-2.73(m,2H),1.42-1.46(m,1H),1.04-1.09(m,2H),0.8-1.01(m,5H)。
实施例173：4-((5-氯-7-(2-((3-环丙基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000187
实施例173的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.45-9.80(br,1H),8.78-9.26(br,2H),7.78-7.98(m,3H),7.42(s,1H),7.23-7.27(m,1H),7.12(s,1H),6.76(d,J＝2.0Hz,1H),5.71(d,J＝2.8Hz,1H),5.31-5.44(m,2H),3.91-3.95(m,1H),3.49-3.58(m,1H),3.26-3.44(m,2H),3.03-3.10(m,1H),2.84-3.02(m,2H),1.42-1.74(m,3H),1.14-1.30(m,1H),1.02-1.10(m,2H),0.78-0.85(m,2H)。
实施例174：4-((5-氯-7-(2-((3-(2-氯乙基)-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈三氟乙酸盐
Figure PCTCN2021114936-appb-000188
实施例174的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),9.50-10.8(br,1H),8.68-9.48(br,2H),7.74-7.95(m,3H),7.39-7.44(m,1H),7.22-7.25(m,1H),7.13(s,1H),6.76(d,J＝2.8Hz,1H),5.77(d,J＝8.0Hz,1H),5.39(s,2H),3.87-4.12(m,3H),3.75-3.81(m,2H),3.48-3.58(m,1H),3.21-3.44(m,2H),2.84-3.02(m,2H),1.58-1.72(m,1H),1.14-1.36(m,3H)。
实施例175：4-((5-氯-7-(2-((3-乙基-5-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000189
实施例175的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.79(d,J＝4.8Hz,1H),7.68(d,J＝2.0Hz,1H),7.65(s,1H),7.36(d,J＝3.6Hz,1H),7.35(d,J＝4.4Hz,1H),7.07(d,J＝2.0Hz,1H),6.97(d,J＝1.2Hz,1H),6.65(d,J＝3.2Hz,1H),5.42(d,J＝14.8Hz,1H),5.32(d,J＝14.8Hz,1H),3.72-3.78(m,3H),3.58(d,J＝14.8Hz,1H),2.78-2.86(m,2H),2.61-2.70(m,2H),1.91(s,3H),1.36-1.43(m,1H),1.26(t,J＝7.2Hz,3H),0.93-1.00(m,1H),0.79-0.89(m,2H)。
实施例176：4-((5-氯-7-(2-((3-异丙基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000190
实施例176的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.80(d,J＝4.8Hz,1H),7.81(d,J＝2.4Hz,1H),7.75(d,J＝8.4Hz,1H),7.56(s,1H),7.50-7.52(m,2H),7.10(d,J＝2.0Hz,1H),6.71(d,J＝3.6Hz,1H),5.70(d,J＝8.4Hz,1H),5.26(d,J＝14.8Hz,1H),5.16(d,J＝14.8Hz,1H),4.58-4.65(m,1H),3.95(d,J＝14.8Hz,1H),3.51(d,J＝14.8Hz,1H),2.64-2.72(m,2H),2.27-2.36(m,2H),1.29-1.35(m,1H),1.18-1.21(m,6H),0.75-0.90(m,3H)。
实施例177：4-((5-氯-7-(2-((5-氯-3-异丙基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000191
实施例177的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.19(s,1H),7.80(d,J＝2.0Hz,1H),7.60(s,1H),7.50-7.52(m,2H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.29(d,J＝14.8Hz,1H),5.19(d,J＝14.8Hz,1H),4.60-4.67(m,1H),3.92(d,J＝14.8Hz,1H),3.51(d,J＝14.8Hz,1H),2.58-2.66(m,2H),2.23-2.32(m,2H),1.21-1.28(m,7H),0.73-0.85(m,3H)。
实施例178：4-((5-氯-7-(2-((3-异丙基-2,6-二氧-5-(三氟甲基)-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000192
实施例178的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.22(s,1H),7.81(d,J＝2.0Hz,1H),7.61(s,1H),7.52(s,1H),7.51(s,1H),7.10(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.27(d,J＝15.2Hz,1H),5.17(d,J＝15.2Hz,1H),4.60-4.67(m,1H),3.939d,J＝14.8Hz,1H),3.51(d,J＝14.8Hz,1H),2.58-2.66(m,2H),2.23-2.32(m,2H),1.21-1.28(m,7H),0.72-0.84(m,3H)。
实施例179：4-((5-氯-7-(2-((5-氯-3-环丙基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基) 甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000193
实施例179的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.02(s,1H),7.81(d,J＝2.4Hz,1H),7.60(s,1H),7.51-7.52(m,2H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.27(d,J＝15.2Hz,1H),5.17(d,J＝15.2Hz,1H),3.94(d,J＝14.8Hz,1H),3.49(d,J＝14.8Hz,1H),3.04-3.10(m,1H),2.62-2.69(m,2H),2.26-2.35(m,2H),1.26-1.34(m,1H),0.74-0.88(m,7H)。
实施例180：4-((5-氯-7-(2-((4-异丁基-2,6-二氧哌啶-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000194
实施例180的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.79(d,J＝4.8Hz,1H),7.80(d,J＝2.0Hz,1H),7.49-7.51(m,3H),7.07(d,J＝2.0Hz,1H),6.70(d,J＝3.2Hz,1H),5.09(d,J＝15.2Hz,1H),4.98(d,J＝15.2Hz,1H),3.94(d,J＝15.2Hz,1H),3.47(d,J＝15.2Hz,1H),2.60-2.68(m,4H),2.24-2.40(m,4H),2.02-2.13(m,1H),1.49-1.56(m,1H),1.25-1.31(m,1H),1.06(t,J＝7.2Hz,2H),0.70-0.85(m,9H)。
实施例181：4-((5-氯-7-(2-((5-氯-2,6-二氧-3-丙基-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000195
实施例181的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.23(s,1H),7.80(d,J＝2.0Hz,1H),7.59(s,1H),7.51-7.52(m,2H),7.09(d,J＝2.4Hz,1H),6.71(d,J＝3.2Hz,1H),5.28(d,J＝15.2Hz,1H),5.19(d,J＝15.2Hz,1H),3.91(d,J＝14.8Hz,1H),3.64(t,J＝7.2Hz,2H),3.49(d,J＝14.8Hz,1H),2.58-2.65(m,2H),2.23-2.32(m,2H),1.50-1.60(m,2H),1.24-1.28(m,1H),0.72-0.84(m,6H)。
实施例182：4-((5-氯-7-(2-((5-氯-3-(2,2-二氟乙基)-2,6-二氧-3,6-二氢嘧啶 -1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000196
实施例182的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.21(s,1H),7.81(d,J＝2.4Hz,1H),7.61(s,1H),7.50-7.52(m,2H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.6Hz,1H),6.07-6.37(m,1H),5.29(d,J＝15.2Hz,1H),5.19(d,J＝15.2Hz,1H),4.12-4.22(m,2H),3.92(d,J＝15.2Hz,1H),3.48(d,J＝15.2Hz,1H),2.58-2.66(m,2H),2.22-2.32(m,2H),1.24-1.30(m,1H),0.72-0.84(m,3H)。
实施例183：4-((5-氯-7-(2-((5-氟-3-异丙基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000197
实施例183的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.20(d,J＝6.8Hz,1H),7.81(d,J＝2.0Hz,1H),7.60(s,1H),7.52(s,1H),7.51(s,1H),7.10(d,J＝2.4Hz,1H),6.71(d,J＝3.6Hz,1H),5.27(d,J＝15.2Hz,1H),5.18(d,J＝15.2Hz,1H),4.61-4.68(m,1H),3.93(d,J＝14.8Hz,1H),3.51(d,J＝14.8Hz,1H),2.60-2.67(m,2H),2.24-2.33(m,2H),1.24-1.30(m,1H),1.18-1.21(m,6H),0.74-0.86(m,3H)。
实施例184：4-((5-氯-7-(2-((3-乙基-5-氟-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000198
实施例184的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.18(d,J＝6.8Hz,1H),7.80(d,J＝2.0Hz,1H),7.59(s,1H),7.52(s,1H),7.51(s,1H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.27(d,J ＝15.2Hz,1H),5.18(d,J＝15.2Hz,1H),3.93(d,J＝15.2Hz,1H),3.64-3.70(m,2H),3.50(d,J＝15.2Hz,1H),2.60-2.67(m,2H),2.24-2.34(m,2H),1.26-1.31(m,1H),1.12(t,J＝7.2Hz,3H),0.73-0.86(m,3H)。
实施例185：4-((5-氯-7-(2-((2-甲基-3,5-二氧-2,5-二氢-1,2,4-三嗪-4(3H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000199
实施例185的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝4.8Hz,1H),7.81(d,J＝2.4Hz,1H),7.64(s,1H),7.55(s,1H),7.52(d,J＝1.6Hz,1H),7.51(s,1H),7.08(d,J＝2.4Hz,1H),6.71(d,J＝3.2Hz,1H),5.23(d,J＝15.2Hz,1H),5.13(d,J＝15.2Hz,1H),3.94(d,J＝15.2Hz,1H),3.48(d,J＝15.2Hz,1H),3.45(s,3H),2.62-2.69(m,2H),2.26-2.35(m,2H),1.28-1.33(m,1H),0.76-0.88(m,3H)。
实施例186：4-((7-(2-((5-溴-3-乙基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-5-氯-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000200
实施例186的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.28(s,1H),7.80(d,J＝2.4Hz,1H),7.59(s,1H),7.51(s,1H),7.50(d,J＝1.2Hz,1H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.6Hz,1H),5.29(d,J＝15.2Hz,1H),5.20(d,J＝15.2Hz,1H),3.92(d,J＝15.2Hz,1H),3.71(q,J＝7.2Hz,2H),3.50(d,J＝15.2Hz,1H),2.59-2.66(m,2H),2.24-2.34(m,2H),1.25-1.30(m,1H),1.12(t,J＝7.2Hz,3H),0.72-0.85(m,3H)。
实施例187：4-((5-氯-7-(2-((3-乙基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000201
实施例187的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.80 (d,J＝4.8Hz,1H),7.81(d,J＝2.0Hz,1H),7.70(d,J＝7.6Hz,1H),7.56(s,1H),7.50-7.52(m,2H),7.10(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.68(d,J＝7.6Hz,1H),5.25(d,J＝14.8Hz,1H),5.16(d,J＝14.8Hz,1H),3.95(d,J＝14.4Hz,1H),3.69(q,J＝7.6Hz,2H),3.49(d,J＝14.4Hz,1H),2.62-2.74(m,2H),2.28-2.36(m,2H),1.30-1.37(m,1H),1.10(t,J＝7.2Hz,3H),0.76-0.87(m,3H)。
实施例188：4-((5-氯-7-(2-((3-(2,2-二氟乙基)-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000202
实施例188的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),7.81(d,J＝2.0Hz,1H),7.66(d,J＝7.6Hz,1H),7.57(s,1H),7.50-7.52(m,2H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),6.06-6.36(m,1H),5.75(d,J＝9.2Hz,1H),5.26(d,J＝15.2Hz,1H),5.16(d,J＝15.2Hz,1H),4.13-4.22(m,2H),3.93(d,J＝14.8Hz,1H),3.49(d,J＝14.8Hz,1H),2.62-2.70(m,2H),2.25-2.35(m,2H),1.27-1.34(m,1H),0.73-0.87(m,3H)。
实施例189：4-((7-(2-((5-溴-3-异丙基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-5-氯-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000203
实施例189的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝5.2Hz,1H),8.23(s,1H),7.80(d,J＝2.4Hz,1H),7.59(s,1H),7.51(s,1H),7.50(d,J＝1.6Hz,1H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.30(d,J＝15.2Hz,1H),5.20(d,J＝15.2Hz,1H),4.59-4.66(m,1H),3.92(d,J＝15.2Hz,1H),3.51(d,J＝15.2Hz,1H),2.59-2.66(m,2H),2.24-2.32(m,2H),1.22-1.29(m,7H),0.72-0.84(m,3H)。
实施例190：4-((5-氯-7-(2-((3-(2,2-二氟乙基)-5-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000204
实施例190的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.80(d,J＝4.8Hz,1H),7.81(d,J＝2.0Hz,1H),7.56-7.57(m,2H),7.50-7.52(m,2H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),6.21(tt,J＝54.8Hz,4.0Hz,1H),5.28(d,J＝14.8Hz,1H),5.18(d,J＝14.8Hz,1H),4.08-4.18(m,2H),3.93(d,J＝14.8Hz,1H),3.49(d,J＝14.8Hz,1H),2.59-2.68(m,2H),2.24-2.34(m,2H),1.76(s,3H),1.26-1.32(m,1H),0.72-0.85(m,3H)。
实施例191：4-((5-氯-7-(2-((3-(2,2-二氟乙基)-5-氟-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000205
实施例191的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝4.8Hz,1H),8.17(d,J＝6.0Hz,1H),7.81(d,J＝2.4Hz,1H),7.61(s,1H),7.52(d,J＝2.4Hz,1H),7.51(s,1H),7.09(d,J＝2.4Hz,1H),6.71(d,J＝3.6Hz,1H),6.22(tt,J＝55.2Hz,3.6Hz,1H),5.28(d,J＝15.2Hz,1H),5.18(d,J＝55.2Hz,1H),4.08-4.18(m,2H),3.48(d,J＝14.8Hz,1H),3.28(d,J＝14.8Hz,1H),2.63-2.70(m,2H),2.26-2.35(m,2H),1.28-1.34(m,1H),0.75-0.84(m,3H)。
实施例192：4-((5-氯-7-(2-((4-氯-3-乙基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000206
实施例192的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝4.4Hz,1H),7.82(d,J＝2.0Hz,1H),7.59(s,1H),7.54(d,J＝2.8Hz,1H),7.53(d,J＝4.8Hz,1H),7.10(d,J＝2.4Hz,1H),6.73(d,J＝3.2Hz,1H),6.08(s,1H),5.23(d,J＝15.2Hz,1H),5.13(d,J＝15.2Hz,1H),4.07(d,J＝14.8Hz,1H),3.95(q,J＝7.2Hz,2H),3.47(d,J＝14.8Hz,1H),2.92-3.02(m,2H),2.47-2.56(m,2H),1.54-1.61(m,1H),1.01-1.18(m,5H),0.90-0.97(m,1H)。
实施例193：4-((5-氯-7-(2-((4-氯-3-(2,2-二氟乙基)-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000207
实施例193的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝4.8Hz,1H),7.81(d,J＝2.0Hz,1H),7.60(s,1H),7.53(s,1H),7.52(d,J＝2.0Hz,1H),7.09(d,J＝2.4Hz,1H),6.72(d,J＝3.2Hz,1H),6.22(tt,J＝54.8Hz,3.6Hz,1H),6.20(s,1H),5.24(d,J＝15.2Hz,1H),5.14(d,J＝15.2Hz,1H),4.37(td,J＝14.0Hz,3.6Hz,2H),3.99(d,J＝15.2Hz,1H),3.47(d,J＝15.2Hz,1H),2.73-2.82(m,2H),2.32-2.43(m,2H),1.37-1.44(m,1H),0.78-0.98(m,3H)。
实施例194：4-((5-氯-7-(2-((3-(2,2-二氟乙基)-2,6-二氧-5-(三氟甲基)-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000208
实施例194的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝4.8Hz,1H),8.47(s,1H),7.81(d,J＝2.0Hz,1H),7.62(s,1H),7.50-7.53(m,2H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.6Hz,1H),6.24(tt,J＝54.8Hz,4.0Hz,1H),5.28(d,J＝15.2Hz,1H),5.16(d,J＝15.2Hz,1H),4.23-4.32(m,2H),3.94(d,J＝15.2Hz,1H),3.49(d,J＝15.2Hz,1H),2.62-2.70(m,2H),2.26-2.34(m,2H),1.27-1.34(m,1H),0.73-0.84(m,3H)。
实施例195：4-((5-氯-7-(2-((4-氯-3-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000209
实施例195的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),7.81(d,J＝2.4Hz,1H),7.59(s,1H),7.52(s,1H),7.51(s,1H),7.08(d,J＝1.6Hz,1H),6.71(d,J＝3.2Hz,1H),6.08(s,1H),5.24(d,J＝15.2Hz,1H),5.13(d,J＝15.2Hz,1H),3.95(d,J＝14.8Hz,1H),3.46(d,J＝14.8Hz,1H),3.37(s,3H),2.62-2.69(m,2H),2.26-2.34(m,2H),1.30-1.35(m,1H),0.72-0.88(m,3H)。
实施例196：4-((5-氯-7-(2-((4-氯-2,6-二氧-3-(2,2,2-三氟乙基)-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000210
实施例196的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),7.81(d,J＝2.4Hz,1H),7.60(s,1H),7.51-7.53(m,2H),7.08(d,J＝2.0Hz,1H),6.71(d,J＝3.6Hz,1H),6.27(s,1H),5.25(d,J＝15.2Hz,1H),5.15(d,J＝15.2Hz,1H),4.81(q,J＝8.8Hz,2H),3.93(d,J＝14.8Hz,1H),3.47(d,J＝14.8Hz,1H),2.60-2.66(m,2H),2.25-2.33(m,2H),1.26-1.34(m,1H),0.73-0.86(m,3H)。
实施例197：4-((5-氯-7-(2-((3-(2,2-二氟乙基)-4-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000211
实施例197的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.80(d,J＝4.8Hz,1H),7.80(d,J＝2.0Hz,1H),7.57(s,1H),7.51(s,1H),7.50(s,1H),7.08(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),6.20(tt,J＝55.2Hz,4.0Hz,1H),5.71(s,1H),5.25(d,J＝15.2Hz,1H),5.16(d,J＝15.2Hz,1H),4.21(td,J＝14.4Hz,3.6Hz,2H),3.92(d,J＝15.2Hz,1H),3.19(d,J＝15.2Hz,1H),2.58-2.66(m,2H),2.24-2.32(m,2H),2.20(s,3H),1.25-1.31(m,1H),0.71-0.85(m,3H)。
实施例198：4-((5-氯-7-(2-((3-乙基-2,6-二氧-4-(三氟甲基)-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000212
实施例198的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.82(d,J＝4.8Hz,1H),7.69(d,J＝1.6Hz,1H),7.68(s,1H),7.38(d,J＝4.8Hz,1H),7.37(d,J＝3.6Hz,1H),7.08(d,J＝1.6Hz,1H),6.66(d,J＝3.6Hz,1H),6.22(s,1H),5.41(d,J＝14.4Hz,1H),5.30(d,J＝14.4Hz,1H),3.94(q,J＝7.2Hz,2H),3.75(d,J＝14.8Hz,1H),3.56(d,J＝14.8Hz,1H),2.77-2.84(m,2H),2.60-2.70(m,2H),1.38-1.44(m,1H),1.28(t,J＝7.2Hz,3H),0.92-0.99(m,1H),0.75-0.89(m,2H)。
实施例199：4-((7-(2-((5-溴-3-(2,2-二氟乙基)-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-5-氯-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000213
实施例199的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),8.27(s,1H),7.81(d,J＝2.0Hz,1H),7.60(s,1H),7.52(s,1H),7.51(s,1H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),6.22(tt,J＝55.2Hz,3.2Hz,1H),5.30(d,J＝15.2Hz,1H),5.20(d,J＝15.2Hz,1H),4.13-4.23(m,2H),3.93(d,J＝14.8Hz,1H),3.49(d,J＝14.8Hz,1H),2.62-2.69(m,2H),2.25-2.35(m,2H),1.26-1.33(m,1H),0.68-0.84(m,3H)。
实施例200：4-((5-氯-7-(2-((3-乙基-4-甲氧基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000214
实施例200的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.80(d,J＝4.8Hz,1H),7.81(d,J＝2.0Hz,1H),7.55(s,1H),7.52(d,J＝3.6Hz,1H),7.50(d,J＝4.8Hz,1H),7.09(d,J＝2.0Hz,1H),6.72(d,J＝3.2Hz,1H),5.23(d,J＝14.4Hz,1H),5.21(s,1H),5.14(d,J＝14.4Hz,1H),3.99(d,J＝14.4Hz,1H),3.84(s,3H),3.76(q,J＝7.2Hz,2H),3.49(d,J＝14.4Hz,1H),2.72-2.80(m,2H),2.33-2.43(m,2H),1.36-1.44(m,1H),1.04(t,J＝7.2Hz,3H),0.80-0.94(m,3H)。
实施例201：4-((5-氯-7-(2-((6,8-二氧-5-(2,2,2-tri氟乙基)-5,7-二氮杂螺[3.4]辛烷-7-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000215
实施例201的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝4.8Hz,1H),7.81(d,J＝1.6Hz,1H),7.57(s,1H),7.50-7.54(m,2H),7.12(d,J＝2.4Hz,1H),6.71(d,J＝3.2Hz,1H),4.91(d,J＝16.4Hz,1H),4.83(d,J＝16.4Hz,1H),4.31(q,J＝9.6Hz,2H),3.93(d,J＝14.8Hz,1H),3.50(d,J＝14.8Hz,1H),2.50-2.68(m,4H),2.24-2.33(m,2H),2.14-2.21(m,2H),1.89-1.99(m,1H),1.66-1.76(m,1H),1.24-1.31(m,1H),0.70-0.84(m,3H)。
实施例202：4-((5-氯-7-(2-((2-氧-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000216
在冰浴下，向叔丁基-4-((5-氯-7-(2-(羟甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)-4-氰基哌啶-1-甲酸酯(0.2g)和三乙胺(0.1mL)的二氯甲烷(2mL)溶液中加入甲磺酸酐(98mg)。反应液在冰浴下继续搅拌1.5小时。反应结束后 加入水(15mL)淬灭反应，并分取有机相。水相用二氯甲烷萃取(10mL×3)。合并有机相，用无水硫酸钠干燥，过滤并减压浓缩。所得残留物无需进行进一步纯化，直接用于下一步反应中。向上述残留物的乙腈溶液(3mL)中加入7-氮杂吲哚酮(75mg)和无水碳酸铯(243mg)。反应液在50℃下搅拌2h。反应结束后，将上述反应液冷却至室温，并倒入水中。所得水相用乙酸乙酯萃取(20mL×3)，并合并有机相。有机相加入无水硫酸钠干燥，过滤，并减压浓缩。所得残留物通过快速硅胶柱层析进行分离纯化(二氯甲烷：甲醇＝100:1至20:1)，得目标化合物(75mg)。所得目标化合物利用其它实施例中脱除N-叔丁氧羰基的方法，通过三氟乙酸脱除叔丁氧羰基保护基，得实施例202化合物(35mg)。 1H NMR(400MHz,CDCl 3),8.78(d,J＝4.4Hz,1H),8.14(d,J＝4.4Hz,1H),7.64-7.70(m,2H),7.47(d,J＝7.2Hz,1H),7.32-7.38(m,2H),7.06(s,1H),6.93-6.96(m,1H),6.65(d,J＝2.8Hz,1H),5.27(d,J＝15.6Hz,1H),5.20(d,J＝15.6Hz,1H),3.75(d,J＝15.2Hz,1H),3.52-3.60(m,3H),2.82-2.95(m,2H),2.63-2.74(m,2H),1.39-1.46(m,1H),0.80-1.02(m,3H)。
实施例203：4-((5-氯-7-(2-((3-(2-羟基-2-甲基丙基)-5-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000217
实施例203的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.80(d,J＝4.8Hz,1H),7.80(d,J＝2.4Hz,1H),7.55(s,1H),7.49-7.51(m,2H),7.43(s,1H),7.08(d,J＝1.6Hz,1H),6.71(d,J＝3.2Hz,1H),5.29(d,J＝15.2Hz,1H),5.20(d,J＝15.2Hz,1H),4.61-4.72(br,1H),3.95(d,J＝14.8Hz,1H),3.61(s,2H),3.48(d,J＝14.8Hz,1H),2.69-2.76(m,2H),2.30-2.40(m,2H),1.75(s,3H),1.34-1.42(m,1H),0.99(s,6H),0.77-0.92(m,3H)。
实施例204：4-((5-氯-7-(2-((3-(甲基-d3)-2,6-二氧-4-(三氟甲基)-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000218
实施例204的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.81(d,J＝5.2Hz,1H),7.68-7.70(m,2H),7.36-7.39(m,2H),7.07(d,J＝2.0Hz,1H),6.66(d,J＝3.2Hz,1H),6.23(s,1H),5.40(d,J＝14.8Hz,1H),5.31(d,J＝14.8Hz,1H),3.74(d,J＝15.2Hz,1H),3.56(d,J＝15.2Hz,1H),2.77-2.84(m,2H),2.60-2.70(m,2H),1.38-1.44(m,1H),0.93-0.99(m,1H),0.76-0.89(m,2H)。
实施例205：4-((5-氯-7-(2-((7-甲基-1,3-二氧六氢咪唑并[1,5-a]哌嗪-2(3H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000219
实施例205的合成方法同实施例21相同。 1H NMR(400MHz,CDCl 3),8.85(d,J＝4.8Hz,1H),7.70(s,1H),7.56(s,1H),7.44(d,J＝2.0Hz,1H),7.34(d,J＝1.6Hz,1H),7.09(s,1H),6.67(d,J＝3.2Hz,1H),4.83-5.00(m,2H),3.98-4.11(m,3H),3.79(d,J＝14.8Hz,1H),3.54(d,J＝14.8Hz,1H),2.96-3.18(m,4H),2.68-2.82(m,3H),2.59(t,J＝7.2Hz,1H),2.32(s,3H),1.78-1.98(m,2H),0.76-0.90(m,2H)。
实施例206：4-((5-氯-7-(2-((2-(2,2-二氟乙基)-3,5-二氧-2,5-二氢-1,2,4-三嗪-4(3H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000220
实施例206的合成方法同实施例21相同。1H NMR(400MHz,DMSO-d 6), 8.82(d,J＝4.4Hz,1H),7.81(d,J＝2.0Hz,1H),7.67(s,1H),7.65(s,1H),7.51-7.53(m,2H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),6.24(tt,J＝55.2Hz,4.0Hz,1H),5.24(d,J＝15.2Hz,1H),5.13(d,J＝15.2Hz,1H),4.23-4.32(m,2H),3.93(d,J＝14.8Hz,1H),3.48(d,J＝14.8Hz,1H),2.61-2.70(m,2H),2.24-2.34(m,2H),1.26-1.32(m,1H),0.74-0.85(m,3H).
实施例207：4-((5-氯-7-(2-((3,5-二氧-2-(2,2,2-三氟乙基)-2,5-二氢-1,2,4-三嗪-4(3H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000221
实施例207的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝4.4Hz,1H),7.81(d,J＝2.0Hz,1H),7.71(s,1H),7.65(s,1H),7.51-7.53(m,2H),7.08(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.25(d,J＝15.2Hz,1H),5.14(d,J＝15.2Hz,1H),4.70-4.77(m,2H),3.93(d,J＝14.8Hz,1H),3.49(d,J＝14.8Hz,1H),2.61-2.69(m,2H),2.26-2.35(m,2H),1.26-1.33(m,1H),0.75-0.86(m,3H)。
实施例208：4-((5-氯-7-(2-((2-乙基-3,5-二氧-2,5-dihydro-1,2,4-三嗪-4(3H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000222
实施例208的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),7.81(d,J＝2.0Hz,1H),7.64(s,1H),7.58(s,1H),7.52(d,J＝2.8Hz,1H),7.51(s,1H),7.09(d,J＝2.4Hz,1H),6.71(d,J＝3.2Hz,1H),5.23(d,J＝15.2Hz,1H),5.14(d,J＝15.2Hz,1H),3.93(d,J＝15.2Hz,1H),3.83-3.89(m,2H),3.50(d,J＝15.2Hz,1H),2.60-2.67(m,2H),2.24-2.34(m,2H),1.24-1.30(m,1H),1.16(t,J＝7.2Hz,3H),0.74-0.86(m,3H)。
实施例209：4-((5-氯-7-(2-((2-异丙基-3,5-二氧-2,5-二氢-1,2,4-三嗪-4(3H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000223
实施例209的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),7.81(d,J＝2.0Hz,1H),7.64(s,1H),7.62(s,1H),7.50-7.53(m,2H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.24(d,J＝14.8Hz,1H),5.13(d,J＝14.8Hz,1H),4.70-4.76(m,1H),3.92(d,J＝15.2Hz,1H),3.51(d,J＝15.2Hz,1H),2.58-2.66(m,2H),2.22-2.32(m,2H),1.22-1.29(m,1H),1.17-1.19(m,6H),0.72-0.85(m,3H)。
实施例210：4-((5-氯-7-(2-((2-(环丙基甲基)-3,5-二氧-2,5-二氢-1,2,4-三嗪-4(3H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000224
实施例210的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),7.81(d,J＝2.0Hz,1H),7.64(s,1H),7.59(s,1H),7.50-7.53(m,2H),7.09(d,J＝2.0Hz,1H),6.71(d,J＝3.6Hz,1H),5.25(d,J＝15.2Hz,1H),5.15(d,J＝15.2Hz,1H),3.91(d,J＝15.2Hz,1H),3.70(d,J＝6.8Hz,2H),3.50(d,J＝15.2Hz,1H),2.58-2.66(m,2H),2.22-2.32(m,2H),1.22-1.30(m,1H),1.04-1.14(m,1H),0.72-0.85(m,3H),0.39-0.44(m,2H),0.25-0.29(m,2H)。
实施例211：4-((5-氯-7-(2-((4-甲氧基-3-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000225
实施例211的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.80(d,J＝5.2Hz,1H),7.80(d,J＝1.6Hz,1H),7.56(s,1H),7.50-7.52(m,2H),7.08(d,J＝1.6Hz,1H),6.71(d,J＝3.2Hz,1H),5.23(d,J＝15.2Hz,1H),5.20(s,1H),5.14 (d,J＝15.2Hz,1H),3.95(d,J＝15.2Hz,1H),3.82(s,3H),3.47(d,J＝15.2Hz,1H),3.14(s,3H),2.63-2.71(m,2H),2.26-2.36(m,2H),1.30-1.38(m,1H),0.73-0.86(m,3H)。
实施例212：4-((5-氯-7-(2-((4-环丙基-3-甲基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000226
实施例212的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.80(d,J＝4.8Hz,1H),7.80(d,J＝2.0Hz,1H),7.56(s,1H),7.49-7.51(m,2H),7.07(d,J＝1.6Hz,1H),6.70(d,J＝3.2Hz,1H),5.44(s,1H),5.24(d,J＝14.8Hz,1H),5.14(d,J＝14.8Hz,1H),3.92(d,J＝14.8Hz,1H),3.48(d,J＝14.8Hz,1H),3.39(s,3H),2.57-2.65(m,2H),2.22-2.32(m,2H),1.81-1.88(m,1H),1.24-1.31(m,1H),0.89-0.94(m,2H),0.70-0.86(m,5H)。
实施例213：4-((5-氯-7-(2-((4-甲氧基-2,6-二氧-3-(2,2,2-三氟乙基)-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000227
实施例213的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),7.81(d,J＝2.0Hz,1H),7.56(s,1H),7.52(s,1H),7.51(d,J＝2.4Hz,1H),7.08(d,J＝2.0Hz,1H),6.71(d,J＝3.6Hz,1H),5.34(s,1H),5.25(d,J＝15.2Hz,1H),5.16(d,J＝15.2Hz,1H),4.58(q,J＝8.4Hz,2H),3.95(d,J＝14.8Hz,1H),3.87(s,3H),3.48(d,J＝14.8Hz,1H),2.67-2.74(m,2H),2.30-2.39(m,2H),1.37-1.40(m,1H),0.77-0.92(m,3H)。
实施例214：4-((5-氯-7-(2-((4-氯-3-异丙基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000228
实施例214的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81 (d,J＝5.2Hz,1H),7.81(d,J＝2.0Hz,1H),7.58(s,1H),7.52(d,J＝2.4Hz,1H),7.51(s,1H),7.10(d,J＝2.0Hz,1H),6.71(d,J＝3.6Hz,1H),6.04(s,1H),5.21(d,J＝14.8Hz,1H),5.12(d,J＝14.8Hz,1H),4.80-4.94(m,1H),3.95(d,J＝14.8Hz,1H),3.49(d,J＝14.8Hz,1H),2.63-2.70(m,2H),2.26-2.36(m,2H),1.38-1.40(m,6H),1.28-1.34(m,1H),0.75-0.87(m,3H)。
实施例215：4-((5-氯-7-(2-((3-异丙基-2,4,6-三氧代四氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000229
实施例215的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),9.25(s,1H),8.63(d,J＝4.4Hz,1H),7.78(d,J＝2.4Hz,1H),7.52(d,J＝3.6Hz,1H),7.25(s,1H),7.18(d,J＝4.8Hz,1H),7.09(d,J＝2.0Hz,1H),6.74(d,J＝3.2Hz,1H),4.94-5.02(m,1H),3.98(d,J＝14.0Hz,1H),3.80(d,J＝16.0Hz,1H),3.68(d,J＝16.0Hz,1H),3.40(d,J＝14.0Hz,1H),3.06-3.14(m,2H),2.58-2.68(m,3H),1.36-1.44(m,1H),1.25(d,J＝6.8Hz,6H),1.02-1.08(m,1H),0.78-0.85(m,1H),0.54-0.64(m,1H)。
实施例216：4-((5-氯-7-(2-((4-环丙基-2,6-二氧-3-(2,2,2-三氟乙基)-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000230
实施例216的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.80(d,J＝4.8Hz,1H),7.80(d,J＝2.0Hz,1H),7.56(s,1H),7.51(d,J＝2.0Hz,1H),7.50(s,1H),7.08(d,J＝2.0Hz,1H),6.70(d,J＝3.2Hz,1H),5.57(s,1H),5.26(d,J＝14.8Hz,1H),5.15(d,J＝14.8Hz,1H),4.87(q,J＝8.8Hz,2H),3.91(d,J＝14.8Hz,1H),3.48(d,J＝14.8Hz,1H),2.57-2.66(m,2H),2.22-2.32(m,2H),1.76-1.83(m,1H),1.24-1.29(m,1H),0.96-1.01(m,2H),0.70-0.86(m,5H)。
实施例217：4-((5-氯-7-(2-((4-环丙基-3-乙基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-yl)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000231
实施例217的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.80(d,J＝4.8Hz,1H),7.80(d,J＝2.4Hz,1H),7.55(s,1H),7.49-7.51(m,2H),7.08(d,J＝2.0Hz,1H),6.70(d,J＝3.2Hz,1H),5.43(s,1H),5.24(d,J＝14.8Hz,1H),5.14(d,J＝14.8Hz,1H),3.99(q,J＝7.2Hz,2H),3.92(d,J＝14.8Hz,1H),3.50(d,J＝14.8Hz,1H),2.57-2.66(m,2H),2.23-2.32(m,2H),1.83-1.90(m,1H),1.24-1.30(m,1H),1.14(t,J＝7.2Hz,3H),0.91-0.96(m,2H),0.71-0.84(m,5H)。
实施例218：4-((5-氯-7-(2-((3,5-二氧-4-(2,2,2-三氟乙基)-4,5-二氢-1,2,4-三嗪-2(3H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000232
实施例218的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.83(d,J＝4.4Hz,1H),7.81(d,J＝2.0Hz,1H),7.71(s,1H),7.70(s,1H),7.54(d,J＝4.4Hz,1H),7.51(d,J＝3.2Hz,1H),7.10(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),5.40(d,J＝16.0Hz,1H),5.34(d,J＝16.0Hz,1H),4.55(q,J＝8.8Hz,2H),3.94(d,J＝14.8Hz,1H),3.48(d,J＝14.8Hz,1H),2.60-2.67(m,2H),2.24-2.34(m,2H),1.27-1.32(m,1H),0.73-0.86(m,3H)。
实施例219：4-((5-氯-7-(2-((3-(2,2-二氟乙基)-4-甲氧基-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000233
实施例219的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.81(d,J＝4.8Hz,1H),7.81(d,J＝2.0Hz,1H),7.56(s,1H),7.50-7.52(m,2H),7.08(d, J＝2.0Hz,1H),6.71(d,J＝3.6Hz,1H),6.16(tt,J＝55.6Hz,4.0Hz,1H),5.29(s,1H),2.54(d,J＝15.2Hz,1H),5.15(d,J＝15.2Hz,1H),4.16(td,J＝14.4Hz,4.0Hz,2H),3.97(d,J＝14.8Hz,1H),3.85(s,3H),3.48(d,J＝14.8Hz,1H),2.69-2.76(m,2H),2.31-2.40(m,2H),1.35-1.42(m,1H),0.77-0.94(m,3H)。
实施例220：4-((5-氯-7-(2-((4-环丙基-3-(2,2-二氟乙基)-2,6-二氧-3,6-二氢嘧啶-1(2H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000234
实施例220的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.80(d,J＝4.8Hz,1H),7.80(d,J＝2.4Hz,1H),7.57(s,1H),7.51(s,1H),7.50(s,1H),7.08(d,J＝2.0Hz,1H),6.71(d,J＝3.2Hz,1H),6.24(tt,J＝55.6Hz,4.0Hz,1H),5.54(s,1H),5.24(d,J＝14.8Hz,1H),5.14(d,J＝14.8Hz,1H),4.40(td,J＝14.0Hz,4.0Hz,2H),3.93(d,J＝14.8Hz,1H),3.48(d,J＝14.8Hz,1H),2.59-2.66(m,2H),2.24-2.33(m,2H),1.76-1.83(m,1H),1.26-1.32(m,1H),0.94-0.98(m,2H),0.72-0.85(m,5H)。
实施例221：4-((5-氯-7-(2-((2-(氘代甲基)-3,5-二氧-2,5-二氢-1,2,4-三嗪-4(3H)-基)甲基)噻吩并[3,2-b]吡啶-7-基)-1H-吲哚-1-基)甲基)哌啶-4-甲腈
Figure PCTCN2021114936-appb-000235
实施例221的合成方法同实施例21相同。 1H NMR(400MHz,DMSO-d 6),8.82(d,J＝4.8Hz,1H),7.81(d,J＝2.0Hz,1H),7.64(s,1H),7.55(s,1H),7.52(d,J＝2.0Hz,1H),7.51(s,1H),7.08(d,J＝2.0Hz,1H),6.71(d,J＝2.4Hz,1H),5.23(d,J＝15.2Hz,1H),5.13(d,J＝15.2Hz,1H),3.94(d,J＝15.2Hz,1H),3.48(d,J＝15.2Hz,1H),2.62-2.68(m,2H),2.26-2.34(m,2H),1.26-1.33(m,1H),0.77-0.86(m,3H)。
生物活性实验：
1.化合物抑制USP7体外酶学活性测定
本专利中USP7的酶学活性检测采用快速荧光法进行，使用Ubiquitin-Rhodamine 110作为替代底物进行反应并且优化建立了高通量的筛选平台。化合物对USP7的抑制活性的检测在此平台进行操作。具体方法如下：将化合物从1mM开始用100％DMSO进行5倍的梯度稀释(共7个浓度)，每个浓度取2μL的化合物加入到48μL的反应缓冲液(20mMTris,pH 8.0,2mM CaCl 2,1mM reduced glutathione,0.01％(v/v)Triton X-100,0.01％(w/v)BSA)中进行稀释混匀。取5μL最终稀释后的化合物加入到黑色384孔板中(OptiPlate-384,货号6007270，购自PerkinElmer)，然后加入10μL的His-USP7(终浓度为0.05nM)。将384孔板放于孵育箱中23℃反应30分钟后，每孔加入5μL替代底物Ubiquitin-Rhodamine 110(货号U-555，购自Boston Biochem，终浓度10nM)，23℃孵育箱中继续反应1.5小时。每孔加入5μL柠檬酸终止反应(货号77-92-9，购自国药集团，终浓度10mM)，利用BMG ClariostarMicroplate Reader读取荧光值(excitation485nm/emission 535nm)。使用GraphPad Prism软件计算得到该化合物对USP7酶学活性抑制的IC 50值。
表1.实施例化合物对USP7的抑制作用
Figure PCTCN2021114936-appb-000236
Figure PCTCN2021114936-appb-000237
2.化合物抑制RS4；11细胞增殖的活性测定
人急性淋巴细胞白血病细胞系RS4；11细胞使用RPMI-1640培养基加10％的胎牛血清(FBS，购自Biological Industries，BI)和1％青霉素/链霉素(P/S，购自Thermo Fisher Scientific)进行培养，培养条件为37℃，5％CO 2。将RS4；11细胞以4000个细胞/195μL/孔的浓度铺于96孔板(货号#3917，购自CORNING)中。24小时后将化合物从10mM开始用100％DMSO进行3倍的梯度稀释混匀(共10个浓度)，然后每个浓度取4μL的化合物加入到96μL的RPMI-1640培养基中进行稀释混匀。稀释后的化合物每个浓度取5μL加入铺好的细胞悬液中，将化合物与细胞在细胞培养箱中共孵育72小时(3天)。之后加入35μL的Cell-Titer
Figure PCTCN2021114936-appb-000238
(货号G7570，购自Promega)试剂，室温摇床反应5-10分钟。在BMG ClariostarMicroplate Reader上读取化学发光值，数据使用GraphPad Prism软件进行处理，计算得到该化合物对细胞增殖抑制的IC 50值。
表2.化合物对RS4；11细胞系的抑制作用
Figure PCTCN2021114936-appb-000239
Figure PCTCN2021114936-appb-000240
3.药代动力学数据
雄性SD大鼠来源于北京维通利华实验动物技术有限公司，将大鼠分组，每组3只，分别口服单次灌胃给予待测样品混悬液(5mg/kg)。动物在实验前禁食过夜，禁食时间从给药前10小时至给药后4小时。给药后0.25、0.5、1、2、4、6、8、和24小时采血。使用小动物麻醉机经异氟烷麻醉后通过眼底静脉丛采取0.3mL全血，放于肝素抗凝管中，样品于4℃、4000rpm离心5min，血浆转移至离心管中，并放于-80℃保存直到分析。血浆中样品使用蛋白质沉淀法萃取，萃取液通过LC/MS/MS分析。
Figure PCTCN2021114936-appb-000241

Claims (13)

  1. 式(II)化合物或其药学上可接受的盐、溶剂化物、多晶型物、或异构体，
    Figure PCTCN2021114936-appb-100001
    其中，
    C环为含有1-2个N的5元或6元芳香环或非芳香环，C环上的碳原子可任选地被氧代(＝O)或硫代(＝S)，
    Y 1、Y 2、Y 3和Y 4中的一个为CR 30，剩余的三个各自独立地选自N和CR 3，R 30为
    Figure PCTCN2021114936-appb-100002
    A环和B环为芳香环，
    X 1和X 2各自独立地选自CR 4和N，
    X 3和X 4各自独立地选自C和N，
    X 5和X 6各自独立地选自N、NR 5、O、S和CR 6，并且X 5和X 6不同时为CR 6，
    L 1和L 2各自独立地选自-(CR 12R 13) n-、-O-、-S-、-NR 10-、-(CO)-、-(CO)NR 10-、-(CO)O-、-S(O) 2-和-S(O) 2NR 10-，
    n为0、1、2、3、或4，
    R 1和R 3各自独立地选自H、卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基和3-8元杂环烷基，所述烷基、烯基、炔基、环烷基和杂环烷基可任选地被卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基、或者3-8元杂环烷基取代，
    R 4选自H、卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基和3-8元杂环烷基，所述烷基、烯基、炔基、环烷基和杂环烷基可任选地被卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基、或者3-8元杂环烷基取代，
    R 5选自H、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基和3-8元杂环烷基，所述烷基、烯基、炔基、环烷基和杂环烷基可任选地被卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基、或者3-8元杂环烷基取代，
    R 6选自H、卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基和3-8元杂环烷基，所述烷基、烯基、炔基、环烷基和杂环烷基可任选地被卤素、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷 基、或者3-8元杂环烷基取代，
    R 2为3-12元环烷基或者3-12元杂环烷基，所述环烷基和杂环烷基可任选地被(＝O)、卤素、-CN、-O-R 10、-NR 10R 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基、或者3-8元杂环烷基取代，所述环烷基和杂环烷基上任选取代的烷基、烯基、炔基、环烷基、或者杂环烷基可任选地被卤素、-CN、-O-R 10、-NR 10R 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基、或者3-8元杂环烷基取代，
    R 7为5-12元杂芳基、3-12元环烷基或者3-12元杂环烷基，并且可任选地被R 40取代，所述环烷基和杂环烷基可任选地与5-10元芳基或者5-12元杂芳基稠和，与环烷基或者杂环烷基稠和的芳基或者杂芳基可任选地被R 40取代，
    R 40选自(＝O)、卤素、-CN、-O-R 10、-NR 10R 11、-NR 10(COR 11)、C 1-6烷基、C 2-6烯基、C 2-6炔基、6-10元芳基、5-12元杂芳基、C 3-8环烷基、或者3-8元杂环烷基，所述烷基、烯基、炔基、芳基、杂芳基、环烷基、或者杂环烷基可任选地被(＝O)、卤素、-CN、-O-R 10、-NH-(CO)-C 1-6烷基、-NH-Cbz、-NR 10R 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基、或者3-8元杂环烷基取代，
    R 10和R 11各自独立地选自H、C 1-6烷基和C 3-8环烷基，
    R 12和R 13各自独立地选自H、卤素和C 1-6烷基，
    p为0、1、或2。
  2. 式(II)化合物或其药学上可接受的盐、溶剂化物、多晶型物、或异构体，
    Figure PCTCN2021114936-appb-100003
    其中，
    C环为含有O或S的5元或6元芳香环或非芳香环，C环上的碳原子可任选地被氧代(＝O)或硫代(＝S)，其它基团如权利要求1所定义。
  3. 根据权利要求1所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或异构体，其中R 40选自(＝O)、卤素、-CN、-O-R 10、-NR 10R 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、或者3-8元杂环烷基，所述烷基、烯基、炔基、环烷基、或者杂环烷基可任选地被卤素、-CN、-O-R 10、-NR 10R 11、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-R 10、-NR 10R 11、C 3-8环烷基、或者3-8元杂环烷基取代。
  4. 式(I)化合物或其药学上可接受的盐、溶剂化物、多晶型物、或异构体，其具有式(I)结构，
    Figure PCTCN2021114936-appb-100004
    其中，
    A环和B环为芳香环，
    C环为含有1-2个N的5元或6元芳香环或非芳香环，C环上的碳原子可任选地被氧代(＝O)或硫代(＝S)，
    X 1和X 2各自独立地选自CR 4和N，
    X 3和X 4各自独立地选自C和N，
    X 5和X 6各自独立地选自N、NR 5、O、S和CR 6，并且X 5和X 6不同时为CR 6，
    Y 2、Y 3和Y 4各自独立地选自N和CR 3，
    L 1和L 2各自独立地为-(CR 12R 13) n-，
    n为0、1、2、3、或4，
    R 1和R 3各自独立地选自H、卤素、-CN、C 1-6烷基、-O-R 10、-NR 10R 11、C 3-8环烷基和3-8元杂环烷基，
    R 4选自H、卤素和C 1-6烷基，
    R 5选自H、C 1-6烷基、C 3-8环烷基和3-8元杂环烷基，
    R 6选自H、卤素、C 1-6烷基、C 3-8环烷基和3-8元杂环烷基，
    R 2为3-12元环烷基或者3-12元杂环烷基，所述环烷基和杂环烷基可任选地被(＝O)、卤素、-CN、-O-R 10、-NR 10R 11、或者C 1-6烷基取代，所述烷基可任选地被卤素、-CN、-O-R 10、或者-NR 10R 11取代，
    R 7为3-12元环烷基或者3-12元杂环烷基，所述环烷基和杂环烷基可任选地被(＝O)、卤素、或者C 1-6烷基取代，所述烷基可任选地被卤素、-CN、-O-R 10、或者-NR 10R 11取代，
    R 10和R 11各自独立地选自H、C 1-6烷基和C 3-8环烷基，
    R 12和R 13各自独立地选自H、卤素和C 1-6烷基，
    p为0、1、或2。
  5. 根据权利要求1-4中任一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或异构体，其中n为1或2，R 12和R 13为氢，R 4为H。
  6. 根据权利要求1-4中任一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或异构体，其中X 5为CR 6，X 6为S，R 6选自H、卤素和C 1-6烷基。
  7. 根据权利要求1-4中任一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或异构体，其中R 7为3-12元杂环烷基，所述杂环烷基可任选地被(＝O)、或者C 1-6烷基取代。
  8. 根据权利要求1-4中任一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或异构体，其中Y 2、Y 3和Y 4各自独立地选自CR 3，R 3各自独立 地选自H、卤素和C 1-6烷基。
  9. 根据权利要求1-4中任一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或异构体，其中R 10和R 11各自独立地选自H和C 1-6烷基。
  10. 以下化合物或其药学上可接受的盐、溶剂化物、多晶型物、或异构体，
    Figure PCTCN2021114936-appb-100005
    Figure PCTCN2021114936-appb-100006
    Figure PCTCN2021114936-appb-100007
    Figure PCTCN2021114936-appb-100008
    Figure PCTCN2021114936-appb-100009
    Figure PCTCN2021114936-appb-100010
    Figure PCTCN2021114936-appb-100011
  11. 一种药物组合物，其包含根据权利要求1-10中任一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或异构体，并任选地包含药学上可接受的载体。
  12. 根据权利要求1-10中任一项所述的化合物或其药学上可接受的盐、溶剂化物、多晶型物、或异构体或者根据权利要求11所述的药物组合物在制备用来治疗跟USP7活性相关的疾病的药物中的用途。
  13. 根据权利要求12所述的用途，其中所述跟USP7活性相关的疾病为卵巢癌、乳腺癌、肺癌、胰腺癌、肾癌、黑色素瘤、肝癌、结肠癌、肉瘤、脑癌、前列腺癌、白血病、淋巴瘤、或者多发性骨髓瘤。
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