WO2022188889A1 - Compound as parp7 inhibitor - Google Patents

Compound as parp7 inhibitor Download PDF

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Publication number
WO2022188889A1
WO2022188889A1 PCT/CN2022/080732 CN2022080732W WO2022188889A1 WO 2022188889 A1 WO2022188889 A1 WO 2022188889A1 CN 2022080732 W CN2022080732 W CN 2022080732W WO 2022188889 A1 WO2022188889 A1 WO 2022188889A1
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Prior art keywords
alkyl
hydrogen
cycloalkyl
compound
alkynyl
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PCT/CN2022/080732
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French (fr)
Chinese (zh)
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张汉承
贾薇
蔡聪聪
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杭州英创医药科技有限公司
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Priority to CN202280021065.7A priority Critical patent/CN117425648A/en
Priority to CN202211105078.0A priority patent/CN116789647A/en
Publication of WO2022188889A1 publication Critical patent/WO2022188889A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of medicinal chemistry; in particular, the present invention relates to a novel derivative containing a tricyclic heteroaryl group, its synthesis method and its use as a PARP7 inhibitor in the preparation of medicines for the treatment of tumors and other related diseases applications in .
  • ADP ribosylation is a kind of post-translational modification on various amino acid residues. Ribosylation leads to the reversible attachment of ADP ribose to the substrate protein, and regulates various physiological functions such as gene expression, protein degradation and cellular stress response. , mediated by members of the PARP (Poly(ADP-ribose)polymerases) family.
  • the human PARP family contains 17 members. According to the catalytic mode and activity, the PARP family proteins can be divided into three categories. One class catalyzes the multi-ADP ribosylation of substrates, including PARP1, PARP2, PARP5a, and PARP5b; one class catalyzes the substrates.
  • PARP1 has become an effective target in DNA damage-related tumor types.
  • PARP1 inhibitor anti-tumor drugs There are currently four PARP1 inhibitor anti-tumor drugs on the market, and multiple PARP1 inhibitors are in clinical trials.
  • PARP7 plays an important role in neuronal development, stem cell maintenance, resistance to viral infection, and cancer.
  • the expression of PARP7 is regulated by transcription factors and signaling pathways, including transcription factors AHR (Aryl hydrogen receptor), androgen receptor, HIF1 (Hypoxia inducible factor 1) and platelet-derived growth factor signaling pathways.
  • AHR is a ligand-activated transcription factor involved in the regulation of physiological processes such as pro-inflammatory responses and foreign body metabolism.
  • AHR can be activated by a variety of ligands, such as endogenous tryptophan metabolites kynurenine and TCDD (2,3,7,8tetrachlorodibenzo-p-dioxin).
  • AHR Activation of AHR induces the expression of various metabolism-related genes, such as cytochrome P450A1 and P450B1.
  • AHR-induced expression of PARP7 as a negative feedback regulator of AHR, inhibits the transcriptional activation activity of AHR.
  • the PARP7 gene is located on chromosome 3 (3q25), a locus that is frequently amplified in squamous cancer types. Genomic association assays identified the 3q25 locus as a susceptibility locus for ovarian cancer, suggesting a role for PARP7 in this cancer type. Mechanistically, PARP7 may regulate the stability of tubulin by ribosylating Tubulin, as well as inhibit the type 1 interferon signaling pathway, inhibit the body's anti-tumor immunity, and promote tumor growth and survival.
  • PARP7 is highly expressed in the brain. Knockout of PARP7 in mice results in abnormal cortical development and reduced proliferation and migration of neural progenitors. PARP7 also plays an important role in maintaining the expression of stemness genes such as Nanog, Sox2, Stella and Zfp42. In the absence of PARP7, the stemness of embryonic stem cells is difficult to maintain, showing a tendency to differentiate. PARP7 can also modify the liver X receptor (LXR), co-activate the LXR signaling pathway, and promote physiological processes such as cholesterol and fat metabolism. TBK1 (TANK binding kinase 1) is a major kinase in the pattern recognition receptor signaling pathway, mediating the activation of type 1 interferon and antiviral immunity. PARP7 inhibits the innate antiviral immune response by ribosylating TBK1 and inhibiting the activation of TBK1.
  • LXR liver X receptor
  • TBK1 TANK binding kinase 1
  • PARP7 inhibits
  • PARP7 Based on the role of PARP7 in the innate immune response, the role of PARP7 in tumor immunity has also received increasing attention. Aberrantly expressed or activated PARP7 can inhibit T cell-mediated antitumor immunity by inhibiting the innate immune response. In a large-scale genetic screen, PARP7 was also identified as a suppressor of T cell activation. Knockdown of PARP7 in melanoma cells enhanced proliferation and growth of co-cultured T cells.
  • PARP7 is a promising target for anti-tumor and viral diseases.
  • the object of the present invention is to provide a new class of PARP7 inhibitors.
  • the first aspect of the present invention provides a compound of the following formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate thereof. :
  • A is selected from -NR 3 -, -O-, -CR 4 R 5 -, or 3- to 8-membered heterocyclyl; wherein, R 3 is selected from hydrogen or C 1-4 alkyl; R 4 and R 5 each independently selected from hydrogen, halogen, or C 1-4 alkyl;
  • R 6 and R 7 are each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy C 1-4 alkyl, C 1-4 haloalkoxy C 1-4 alkyl, hydroxy C 1-4 alkyl, C 3-6 cycloalkane group, C 3-6 cycloalkyl C 1-4 alkyl, 4- to 8-membered heterocyclyl, or 4- to 8-membered heterocyclyl C 1-4 alkyl; or R 6 and R 7 and their The attached carbon atoms together form a 3- to -6-membered cycloalkyl group, or a 4- to 8-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S;
  • D is selected from -(CR 8 R 9 ) p -Y-(CR 10 R 11 ) q -; wherein, Y is selected from -O-, -NR 12 -, -CR 13 R 14 -, C 3-6 cycloalkane radical, 3- to 8-membered heterocyclyl, aryl, or heteroaryl; p and q are each independently selected from 0, 1, 2, 3, 4, or 5; each R8 and R9 are each independently selected from hydrogen, halogen, hydroxy, or C 1-4 alkyl; each R 10 and R 11 are each independently selected from hydrogen, halogen, hydroxy, or C 1-4 alkyl; or to which R 8 and R 9 are attached Carbon atoms, or R 10 and R 11 together with the carbon atoms to which they are attached form a 3- to -6-membered cycloalkyl group, or a 4- to 8-membered heterocyclic group, the heterocyclic group contains 1 or 2 members selected from the group consisting of A heteroatom of
  • E is selected from chemical bonds or -C(O)-;
  • F is selected from chemical bonds or -NR b -; wherein, R b is selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 8-membered heterocyclic group, aryl group, heteroaryl group, C(O)R c , or S(O) 2 R c ; or R b and R 10 or R 11 and the nitrogen atom and carbon atom to which they are connected together with E to form a 4- to 8-membered heterocyclic group, this heterocyclic group contains 1 N atom and 0 or 1 heteroatom selected from N, O, S; R c is selected from C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4- to 8- membered heterocyclic group; the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl, and hetero
  • G is selected from N or CR e ; wherein, R e is selected from hydrogen or C 1-4 alkyl;
  • T is selected from N or CR 15 ; wherein, R 15 is selected from hydrogen, halogen, or C 1-4 alkyl;
  • X and Z are each independently selected from N or CR;
  • Each R is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2 -4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy Oxy C 1-4 alkyl, C 1-4 haloalkoxy C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, NR h Rh , CN, NO 2 , SR h , C(O)R t , C(O)OR h , C(O)NR h Rh , NR h C(O)R t , NR h S(O) 2 R t , or S(O ) 2
  • R 1 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 halo Alkynyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy, C 1-4 alkyl, or C 1-4 haloalkoxy C 1-4 alkyl;
  • R 2 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl;
  • n are each independently selected from 0, 1, or 2;
  • k is selected from 0, 1, or 2;
  • h is selected from 0, 1, 2, 3, or 4;
  • each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups is optionally and each independently selected from 1-3 groups each independently selected from the following Substituent substitution of the group: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered Heterocyclyl, aryl, heteroaryl, CN, NO2, ORh , SRh , NRhRh , C(O) Rt , C(O ) ORh , C ( O ) NRhRh , NR h C(O)R t , NR h S(O) 2 R t , or S(O) 2 R t , provided that the chemical structure formed is stable and meaningful; where Rh and R t
  • the above-mentioned aryl group is an aromatic group containing 6-12 carbon atoms;
  • the heteroaryl group is a 5- to 15-membered (preferably 5- to 12-membered) heteroaromatic group;
  • the cyclic structure is Saturated or unsaturated, heteroatom-containing or heteroatom-free cyclic groups.
  • formula (I) is formula (IIA):
  • Q is selected from -NR 16 -, -O-, -CR 17 R 18 -; wherein, R 16 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocycle R 17 and R 18 are each independently selected from hydrogen , halogen , or C 1-4 alkyl;
  • f and g are each independently selected from 0, 1, or 2; provided that f and g cannot be 0 at the same time;
  • j and t are each independently selected from 0, 1, or 2;
  • formula (I) is formula (IIIA):
  • p is selected from 0, 1, or 2;
  • j and t are each independently selected from 0, 1, or 2;
  • formula (I) is formula (IVA):
  • R 6 and R 7 are each independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy C 1-4 alkyl, C 1-4 alkoxy C 1- 4 alkyl, hydroxy C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 alkyl, 4- to 8-membered heterocyclyl, or 4- to 8- membered heterocyclyl C 1-4 alkyl;
  • p is selected from 0, 1, or 2;
  • j and t are each independently selected from 0, 1, or 2;
  • formula (I) is formula (VA):
  • R b is as defined above;
  • formula (I) is formula (VIA):
  • R b is selected from C 3-6 cycloalkyl, 4- to 8-membered heterocyclyl, aryl, or heteroaryl; the cycloalkyl, heterocyclyl, aryl, and heteroaryl are any optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4- to 8-membered heterocyclyl, NR d R d , CN, OR d , SR d , C(O)R t , or S(O) 2 R t ; wherein R t is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4- to 8-membered heterocyclyl; each R d is independently hydrogen or C 1-4 alkyl;
  • q is selected from 0, 1, 2, or 3;
  • formula (I) is formula (VIIA):
  • R c is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4- to 8-membered heterocyclyl; the alkyl , alkenyl, alkynyl, cycloalkyl and heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, C1-4alkyl , C2-4alkenyl , C2- 4alkynyl , C3-6cycloalkyl , 4- to 8-membered heterocyclyl, NRdRd , CN, ORd , SRd , C ( O) Rt , or S(O ) 2R t ;
  • j is selected from 0, 1, or 2;
  • formula (I) is formula (VIIIA):
  • R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
  • R 2 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl;
  • R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, hydroxy, and C 1-4 alkyl;
  • X is selected from N or CR
  • R is each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, CN.
  • formula (I) is formula (IXA):
  • R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
  • R 2 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl;
  • R 6 and R 7 are each independently selected from hydrogen, C 1-4 alkyl
  • R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, hydroxy, and C 1-4 alkyl;
  • X is selected from N or CR
  • R is each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, CN.
  • formula (I) is formula (XA):
  • R b is selected from C 3-6 cycloalkyl, 4- to 8-membered heterocyclyl, aryl, or heteroaryl; the cycloalkyl, heterocyclyl, aryl, and heteroaryl are any optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-4 alkyl, NR d R d , CN, OR d , C(O)R t , or S(O) 2 R t ; wherein, R t is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4- to 8-membered heterocyclyl; each R d is each independently hydrogen or C 1-4 alkyl;
  • R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
  • R 2 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl;
  • R 6 and R 7 are each independently selected from hydrogen, C 1-4 alkyl;
  • R 8 , R 9 , R 10 , R 11 are each independently selected from hydrogen, hydroxyl, C 1-4 alkyl ; or
  • the carbon atom to which R 6 and R 7 are attached, the carbon atom to which R 8 and R 9 are attached, or the carbon atom to which R 10 and R 11 are attached together form a 3- to -6-membered cycloalkyl, or a 4- to 8-membered heterocyclic group, this heterocyclic group contains 1 or 2 heteroatoms selected from N, O, S;
  • X is selected from N or CR
  • R is each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, CN.
  • R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
  • R 2 is H;
  • X is selected from N or CH
  • R is each independently selected from trifluoromethyl, CN, C2-4alkynyl , C3-6cycloalkylalkynyl , 3- to 8-membered heterocyclylalkynyl, C3-6cycloalkyl .
  • formula (I) is formula (XIA):
  • R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
  • R 2 is selected from hydrogen
  • R 6 and R 7 are each independently selected from hydrogen, C 1-4 alkyl
  • R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, hydroxy, and C 1-4 alkyl;
  • X is selected from N or CH
  • R is each independently selected from C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 3-6 cycloalkane base, 3- to 8-membered heterocyclyl.
  • the compound of formula (I) is selected from the following group:
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated Derivatives, hydrates, solvates, and pharmaceutically acceptable carriers.
  • the third aspect of the present invention provides a compound according to the first aspect of the present invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate thereof. , for preparing a pharmaceutical composition for treating diseases, disorders or conditions related to the activity or expression of PARP7.
  • the disease, disorder or condition is selected from the group consisting of multiple myeloma, B-cell lymphoma, T-cell lymphoma, acute and chronic myeloid leukemia, acute and chronic lymphocytic leukemia, and monocytic leukemia , polycythemia splenomegaly, eosinophilic leukemia syndrome, fibrosarcoma, salivary gland cancer, liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer , prostate cancer, glioblastoma, ovarian cancer, head and neck cancer, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, stomach cancer and other hematological and solid tumors, as well as various types of heart disease, viral infection, neurodegenerative disease, inflammation and pain, especially those disease types associated with PARP7 overexpression or abnormal activation.
  • the inventors After long-term and in-depth research, the inventors have unexpectedly discovered a class of compounds with novel structures as PARP7 inhibitors, as well as their preparation methods and applications.
  • the compounds of the present invention can be applied to the treatment of various diseases related to the activities of the ADP and glycosyltransferases. Based on the above findings, the inventors have completed the present invention.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • alkyl refers to a straight chain (ie, unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight and branched chain groups .
  • a carbon number limitation eg, C 1-10
  • C 1-8 alkyl refers to an alkyl group containing 1-8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.
  • alkenyl refers to a straight or branched, carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When an alkenyl group is preceded by a carbon number limitation (eg, C2-8 ), it means that the alkenyl group contains 2-8 carbon atoms.
  • C 2-8 alkenyl refers to an alkenyl group containing 2-8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or the like group.
  • alkynyl refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond.
  • the alkynyl group can be straight or branched, or a combination thereof.
  • a carbon number limitation eg, C 2-8 alkynyl
  • C 2-8 alkynyl refers to straight or branched chain alkynyl groups having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.
  • cycloalkyl refers to a monocyclic, bicyclic or polycyclic (fused, bridged or spiro) ring system group having saturated or partially saturated .
  • a cycloalkyl group is preceded by a carbon number limitation (eg C 3-10 ), it means that the cycloalkyl group contains 3-10 carbon atoms.
  • C 3-8 cycloalkyl refers to saturated or partially unsaturated monocyclic or bicycloalkyl having 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclo pentyl, cycloheptyl, or similar groups.
  • “Spirocycloalkyl” refers to a bicyclic or polycyclic group in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings, these may contain one or more double bonds, but none of the rings have fully conjugated pi electrons system.
  • “Fused cycloalkyl” refers to an all-carbobicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more bicyclic bonds, but none of the rings have a fully conjugated pi electron system.
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system .
  • the atoms contained in the cycloalkyl group are all carbon atoms.
  • the following are some examples of cycloalkyl groups, and the present invention is not limited to the following cycloalkyl groups.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, such as phenyl and naphthyl.
  • the aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be in a conjugated pi-electron system on the carbon atom of the ring.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic monocyclic or polycyclic group containing one to more heteroatoms (optionally selected from nitrogen, oxygen and sulfur), or a heterocyclic group containing one to more heteroatoms A polycyclic group formed by condensing nitrogen, oxygen and sulfur) with an aryl group, and the attachment site is located on the aryl group. Heteroaryl groups can be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited to the following heteroaryl groups.
  • Heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur and the remaining ring atoms are carbon.
  • monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl.
  • Polycyclic heterocyclyl refers to heterocyclyl including spiro, fused and bridged rings.
  • “Spirocyclic heterocyclyl” refers to a polycyclic heterocyclic group in which each ring in the system shares one atom (called a spiro atom) with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur, the remaining ring atoms are carbon.
  • “Fused-ring heterocyclyl” refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but no A ring has a fully conjugated pi electron system and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.
  • “Bridged heterocyclyl” refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system , and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If both saturated and aromatic rings are present in the heterocyclyl group (for example, the saturated and aromatic rings are fused together), the point of attachment to the parent must be on the saturated ring. Note: When the point of attachment to the parent is on an aromatic ring, it is called a heteroaryl group, not a heterocyclyl group. The following are some examples of heterocyclic groups, and the present invention is not limited to the following heterocyclic groups.
  • halogen refers to F, Cl, Br, and I.
  • substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Particular substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples. Unless otherwise specified, an optionally substituted group may have at any substitutable position of the group a substituent selected from a specified group, which may be the same or different at each position.
  • a cyclic substituent such as a heterocyclyl
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are for example (but not limited to): C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl , aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 aldehyde group, C 2-10 acyl group, C 2-10 ester group, amino group.
  • a pharmaceutically acceptable salt refers to a salt suitable for contact with the tissue of a subject (eg, a human) without undue side effects.
  • a pharmaceutically acceptable salt of a compound of the present invention includes a salt of a compound of the present invention that has an acidic group (eg, potassium, sodium, magnesium, calcium) or has a basic salts of compounds of the invention (eg, sulfates, hydrochlorides, phosphates, nitrates, carbonates).
  • the present invention provides a class of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if present), hydrates , the use of a pharmaceutically acceptable carrier or excipient for inhibiting PARP7.
  • the compounds of the present invention are useful as a PARP7 inhibitor.
  • the present invention is a single inhibitor of PARP7, and achieves the purpose of preventing, relieving or curing diseases by regulating the enzymatic activity of PARP7.
  • Indicated diseases include multiple myeloma, B-cell lymphoma, T-cell lymphoma, acute and chronic myeloid leukemia, acute and chronic lymphocytic leukemia, monocytic leukemia, polycythemia splenomegaly, eosinophilic leukemia syndrome, fibrosis Sarcoma, salivary gland cancer, liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, glioblastoma, ovarian cancer, head and neck cancer , cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, gastric cancer and other hematological tumors and solid tumors, as well as various
  • compositions may be combined with pharmaceutically acceptable excipients or The carriers are formulated together and the resulting compositions can be administered in vivo to mammals, such as men, women and animals, for the treatment of conditions, symptoms and diseases.
  • the compositions may be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injectable solutions. Sterile powder, etc.
  • the pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin (increase), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicates and high molecular polyethylene glycol), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic) and lubricants such as magnesium stearate, glycerin and talc.
  • disintegrants such as starch, croscarmellose sodium, complex silicates and high molecular polyethylene glycol
  • granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic
  • lubricants such as magnesium stearate, glycerin and talc.
  • the pharmaceutical composition is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, powders.
  • the amount of a compound or pharmaceutical composition of the present invention administered to a patient is not fixed, but is usually administered in a pharmaceutically effective amount. Meanwhile, the amount of the compound actually administered can be determined by the physician according to the actual situation, including the condition to be treated, the route of administration selected, the actual compound administered, the individual condition of the patient, and the like.
  • the dosage of a compound of the present invention will depend upon the particular use of the treatment, the mode of administration, the patient's condition, and the judgment of the physician.
  • the ratio or concentration of a compound of the present invention in a pharmaceutical composition depends on a variety of factors, including dosage, physicochemical properties, route of administration, and the like.
  • the reagents and conditions of each compound synthesis step can be selected from the conventional reagents or conditions in the art for such preparation methods.
  • the reactants, solvents, bases, the amount of the used compound, the reaction temperature, and the required reaction conditions Selection of time and the like can be performed by those skilled in the art according to the knowledge in the art.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention pertains.
  • compositions and methods of administration are provided.
  • the compound of the present invention Since the compound of the present invention has excellent inhibitory activity against an ADP ribosyltransferase, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention
  • the pharmaceutical composition in which the compound of the invention is the main active ingredient can be used for the treatment, prevention and alleviation of diseases related to the activity or expression of PARP7.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 5 to 500 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • a PARP7 inhibitor with novel structure, preparation and application thereof, the inhibitor can inhibit the activity of PARP7 at a very low concentration.
  • a pharmaceutical composition for treating diseases related to PARP7 activity is provided.
  • Some representative compounds of the present invention can be prepared by the following synthetic methods.
  • the reagents and conditions of each step can be selected from conventional reagents or conditions in the field for such preparation methods.
  • the above selection can be made by those skilled in the art according to the knowledge in the art.
  • Some compounds of the present invention can be prepared by the following methods.
  • DIPEA N,N-diisopropylamine
  • HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxyhexafluorophosphate
  • Compound 1j was synthesized by the method of patent US20190330194.
  • Compound 5 was prepared by referring to a method similar to Example 7, substituting the corresponding structural fragment.
  • Compound 6 was prepared by referring to a method similar to Example 7, substituting the corresponding structural fragment.

Abstract

The present invention provides a compound as a PARP7 inhibitor. Specifically, the present invention provides is a compound having a structure as represented by formula (I) below, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate or solvate thereof. The compound can be used for treating or preventing diseases or disorders associated with the activity or expression level of PARP7.

Description

作为PARP7抑制剂的化合物Compounds that are PARP7 inhibitors 技术领域technical field
本发明涉及药物化学领域；具体地说，本发明涉及一类新型含有三环杂芳基的衍生物，其合成方法及其作为一种PARP7抑制剂在制备药物用于***等相关多种疾病中的应用。The present invention relates to the field of medicinal chemistry; in particular, the present invention relates to a novel derivative containing a tricyclic heteroaryl group, its synthesis method and its use as a PARP7 inhibitor in the preparation of medicines for the treatment of tumors and other related diseases applications in .
背景技术Background technique
ADP核糖基化是一类在多种氨基酸残基上进行的翻译后修饰，核糖基化修饰导致ADP核糖可逆的连接到底物蛋白上，调控基因表达、蛋白降解和细胞压力响应等多种生理功能，由PARP(Poly(ADP-ribose)polymerases)家族成员介导。人的PARP家族包含17个成员，根据催化方式和活性，PARP家族蛋白可分为三类，一类催化底物的多ADP核糖基化，包括PARP1、PARP2、PARP5a和PARP5b；一类催化底物的单ADP核糖基化，包括PARP3、PARP4、PARP7和PARP12等；PARP13比较特殊，体内体外均未发现其催化活性。PARP1在DNA损伤相关的肿瘤类型中已成为有效的靶点，目前有四款PARP1抑制剂抗肿瘤药物上市，多个PARP1抑制剂处于临床试验当中。ADP ribosylation is a kind of post-translational modification on various amino acid residues. Ribosylation leads to the reversible attachment of ADP ribose to the substrate protein, and regulates various physiological functions such as gene expression, protein degradation and cellular stress response. , mediated by members of the PARP (Poly(ADP-ribose)polymerases) family. The human PARP family contains 17 members. According to the catalytic mode and activity, the PARP family proteins can be divided into three categories. One class catalyzes the multi-ADP ribosylation of substrates, including PARP1, PARP2, PARP5a, and PARP5b; one class catalyzes the substrates. The single ADP ribosylation of PARP, including PARP3, PARP4, PARP7 and PARP12, etc.; PARP13 is special, and its catalytic activity has not been found in vivo or in vitro. PARP1 has become an effective target in DNA damage-related tumor types. There are currently four PARP1 inhibitor anti-tumor drugs on the market, and multiple PARP1 inhibitors are in clinical trials.
PARP7在神经元发育、干细胞维持、抗病毒感染和癌症中都发挥着重要的作用。PARP7的表达受到转录因子和信号通路的调控，包括转录因子AHR(Aryl hydrocarbon receptor)、雄激素受体、HIF1(Hypoxia inducible factor 1)和血小板衍生生长因子信号通路等。AHR是一种配体激活型的转录因子，参与调控促炎响应和异物代谢等生理过程。AHR可以被多种配体激活，如内源色氨酸代谢产物犬尿氨酸和TCDD(2,3,7,8tetrachlorodibenzo-p-dioxin)等。AHR的激活诱导多种代谢相关基因的表达，如细胞色素P450A1和P450B1等。AHR诱导表达的PARP7，作为AHR的负反馈调控因子，抑制AHR的转录激活活性。PARP7 plays an important role in neuronal development, stem cell maintenance, resistance to viral infection, and cancer. The expression of PARP7 is regulated by transcription factors and signaling pathways, including transcription factors AHR (Aryl hydrogen receptor), androgen receptor, HIF1 (Hypoxia inducible factor 1) and platelet-derived growth factor signaling pathways. AHR is a ligand-activated transcription factor involved in the regulation of physiological processes such as pro-inflammatory responses and foreign body metabolism. AHR can be activated by a variety of ligands, such as endogenous tryptophan metabolites kynurenine and TCDD (2,3,7,8tetrachlorodibenzo-p-dioxin). Activation of AHR induces the expression of various metabolism-related genes, such as cytochrome P450A1 and P450B1. AHR-induced expression of PARP7, as a negative feedback regulator of AHR, inhibits the transcriptional activation activity of AHR.
PARP7基因位于3号染色体(3q25)上，此基因座位置在鳞状癌症类型中多有扩增。基因组关联试验鉴定3q25基因座为卵巢癌的易感位点，提示PARP7在此癌症种类中发挥作用。机制上，PARP7可能通过核糖基化Tubulin，调控微管蛋白的稳定性，以及抑制一型干扰素信号通路，抑制机体的抗肿瘤免疫，促进肿瘤的生长和存活。The PARP7 gene is located on chromosome 3 (3q25), a locus that is frequently amplified in squamous cancer types. Genomic association assays identified the 3q25 locus as a susceptibility locus for ovarian cancer, suggesting a role for PARP7 in this cancer type. Mechanistically, PARP7 may regulate the stability of tubulin by ribosylating Tubulin, as well as inhibit the type 1 interferon signaling pathway, inhibit the body's anti-tumor immunity, and promote tumor growth and survival.
PARP7在大脑中表达较高。在小鼠中敲除PARP7后，小鼠脑皮质发育异常，神经祖细胞增殖和迁移减少。PARP7对于维持Nanog、Sox2、Stella和Zfp42等干性基因的表达也起着重要的作用。在缺失PARP7的条件下，胚胎干细胞的干性难以维持，表现出分化的倾向。PARP7还可以修饰肝脏X受体(LXR)，共激活LXR信号通路，促进胆固醇和脂肪代谢等生理进程。TBK1(TANK binding kinase 1)是模式识别受体信号通路中的主要激酶，介导一型干扰素和抗病毒免疫的激活。PARP7通过核糖基化TBK1，抑制TBK1的激活，从而抑制先天性抗病毒免疫反应。PARP7 is highly expressed in the brain. Knockout of PARP7 in mice results in abnormal cortical development and reduced proliferation and migration of neural progenitors. PARP7 also plays an important role in maintaining the expression of stemness genes such as Nanog, Sox2, Stella and Zfp42. In the absence of PARP7, the stemness of embryonic stem cells is difficult to maintain, showing a tendency to differentiate. PARP7 can also modify the liver X receptor (LXR), co-activate the LXR signaling pathway, and promote physiological processes such as cholesterol and fat metabolism. TBK1 (TANK binding kinase 1) is a major kinase in the pattern recognition receptor signaling pathway, mediating the activation of type 1 interferon and antiviral immunity. PARP7 inhibits the innate antiviral immune response by ribosylating TBK1 and inhibiting the activation of TBK1.
基于PARP7在先天性免疫反应中的作用，PARP7在肿瘤免疫中的作用也越来越受到关注。异常表达或激活的PARP7可以通过抑制先天性免疫反应，进而抑制T细胞介导的抗肿瘤免疫。在大规模基因筛选中，PARP7也被鉴定为T细胞激活的抑制因子。在黑色素瘤细胞中敲除PARP7，可以增强共培养的T细胞的增殖和生长。Based on the role of PARP7 in the innate immune response, the role of PARP7 in tumor immunity has also received increasing attention. Aberrantly expressed or activated PARP7 can inhibit T cell-mediated antitumor immunity by inhibiting the innate immune response. In a large-scale genetic screen, PARP7 was also identified as a suppressor of T cell activation. Knockdown of PARP7 in melanoma cells enhanced proliferation and growth of co-cultured T cells.
综上，PARP7是一个很有前景的抗肿瘤和病毒等多种疾病类型的靶点。In conclusion, PARP7 is a promising target for anti-tumor and viral diseases.
发明内容SUMMARY OF THE INVENTION
本发明的目的是提供一类新型的PARP7抑制剂。The object of the present invention is to provide a new class of PARP7 inhibitors.
本发明的第一方面，提供了一种如下式(I)所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物：The first aspect of the present invention provides a compound of the following formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate thereof. :
Figure PCTCN2022080732-appb-000001
Figure PCTCN2022080732-appb-000001
式(I)中：In formula (I):
A选自-NR 3-、-O-、-CR 4R 5-、或3-至8-元杂环基；其中，R 3选自氢或C 1-4烷基；R 4和R 5各自独立地选自氢、卤素、或C 1-4烷基； A is selected from -NR 3 -, -O-, -CR 4 R 5 -, or 3- to 8-membered heterocyclyl; wherein, R 3 is selected from hydrogen or C 1-4 alkyl; R 4 and R 5 each independently selected from hydrogen, halogen, or C 1-4 alkyl;
B选自-CR 6R 7-或化学键；其中，R 6和R 7各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4卤代烷氧基C 1-4烷基、羟基C 1-4烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、4-至8-元杂环基、或4-至8-元杂环基C 1-4烷基；或R 6和R 7与其连接的碳原子一起形成3-至-6元的环烷基、或4-至8-元的杂环基，此杂环基含有1或2个选自N、O、S的杂原子； B is selected from -CR 6 R 7 - or a chemical bond; wherein, R 6 and R 7 are each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy C 1-4 alkyl, C 1-4 haloalkoxy C 1-4 alkyl, hydroxy C 1-4 alkyl, C 3-6 cycloalkane group, C 3-6 cycloalkyl C 1-4 alkyl, 4- to 8-membered heterocyclyl, or 4- to 8-membered heterocyclyl C 1-4 alkyl; or R 6 and R 7 and their The attached carbon atoms together form a 3- to -6-membered cycloalkyl group, or a 4- to 8-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S;
D选自-(CR 8R 9) p-Y-(CR 10R 11) q-；其中，Y选自-O-、-NR 12-、-CR 13R 14-、C 3-6环烷基、3-至8-元杂环基、芳基、或杂芳基；p和q各自独立地选自0、1、2、3、4、或5；各个R 8和R 9各自独立地选自氢、卤素、羟基、或C 1-4烷基；各个R 10和R 11各自独立地选自氢、卤素、羟基、或C 1-4烷基；或R 8和R 9与其连接的碳原子、或R 10和R 11与其连接的碳原子一起形成3-至-6元的环烷基、或4-至8-元的杂环基，此杂环基含有1或2个选自N、O、S的杂原子；R 12选自氢、C 1-4烷基、C 3-6环烷基、或4-至8-元的杂环基；R 13和R 14各自独立地选自氢、卤素、或C 1-4烷基；或R 13和R 14与其连接的碳原子一起形成3-至-6元的环烷基、或4-至8-元的杂环基，此杂环基含有1或2个选自N、O、S的杂原子； D is selected from -(CR 8 R 9 ) p -Y-(CR 10 R 11 ) q -; wherein, Y is selected from -O-, -NR 12 -, -CR 13 R 14 -, C 3-6 cycloalkane radical, 3- to 8-membered heterocyclyl, aryl, or heteroaryl; p and q are each independently selected from 0, 1, 2, 3, 4, or 5; each R8 and R9 are each independently selected from hydrogen, halogen, hydroxy, or C 1-4 alkyl; each R 10 and R 11 are each independently selected from hydrogen, halogen, hydroxy, or C 1-4 alkyl; or to which R 8 and R 9 are attached Carbon atoms, or R 10 and R 11 together with the carbon atoms to which they are attached form a 3- to -6-membered cycloalkyl group, or a 4- to 8-membered heterocyclic group, the heterocyclic group contains 1 or 2 members selected from the group consisting of A heteroatom of N, O, S; R 12 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or a 4- to 8-membered heterocyclic group; R 13 and R 14 are each independently is selected from hydrogen, halogen, or C 1-4 alkyl; or R 13 and R 14 together with the carbon atom to which they are attached form a 3- to -6-membered cycloalkyl, or a 4- to 8-membered heterocyclyl, This heterocyclyl group contains 1 or 2 heteroatoms selected from N, O, S;
E选自化学键或-C(O)-；E is selected from chemical bonds or -C(O)-;
F选自化学键或-NR b-；其中，R b选自氢、C 1-4烷基、C 1-4烷氧基C 1-4烷基、C 3-6环烷基、4-至8-元的杂环基、芳基、杂芳基、C(O)R c、或S(O) 2R c；或R b与R 10或R 11及其相连接的氮原子、碳原子及E一起形成4-至8-元的杂环基，此杂环基含有1个N原子和0或1个选自N、O、S的杂原子；R c选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、或4-至8-元的杂环基；R b或R c中所述的烷基、烯基、炔基、环烷基、杂环基、芳基、和杂芳基任选地被一个或多个选自下组的取代基取代：卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、4-至8-元的杂环基、NR dR d、CN、OR d、SR d、C(O)R t、或S(O) 2R t；各个R d各自独立为氢或C 1-4烷基；R t选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基、芳基、或杂芳基； F is selected from chemical bonds or -NR b -; wherein, R b is selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 8-membered heterocyclic group, aryl group, heteroaryl group, C(O)R c , or S(O) 2 R c ; or R b and R 10 or R 11 and the nitrogen atom and carbon atom to which they are connected together with E to form a 4- to 8-membered heterocyclic group, this heterocyclic group contains 1 N atom and 0 or 1 heteroatom selected from N, O, S; R c is selected from C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4- to 8- membered heterocyclic group; the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, C1-4alkyl , C2-4alkenyl , C 2-4 alkynyl, C 3-6 cycloalkyl, 4- to 8-membered heterocyclyl, NR d R d , CN, OR d , SR d , C(O)R t , or S( O) 2 R t ; each R d is independently hydrogen or C 1-4 alkyl; R t is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclyl, aryl, or heteroaryl;
G选自N或CR e；其中，R e选自氢或C 1-4烷基； G is selected from N or CR e ; wherein, R e is selected from hydrogen or C 1-4 alkyl;
各个R a各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4卤代烯基、C 2-4炔基、C 2-4卤代炔基、羟基、羟基C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氧基C 1-4烷基、NR hR h、CN；各个R h各自独立为氢、或C 1-4烷基；或两个R h与其连接的氮原子一起形成3-至-8元杂环基，此杂环基含有1或2个N原子以及0或1个选自O、S的杂原子；或连接在同一个碳原子上的二个R a与碳原子一起共同形成C＝M；其中，M选自O或CR jR k；其中，R j和R k各自独立地选自下组：氢、卤素、或C 1-4烷基；或连接在不同碳原子上的二个R a连接在一起形成桥环结构； Each R is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl, hydroxy, hydroxy C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy C 1-4 alkyl, NR h R h , CN; each R h is independently hydrogen, or C 1-4 alkyl; or two R h and the nitrogen atom to which they are attached together form a 3- to -8 membered heterocyclyl group containing 1 or 2 N atoms and 0 or 1 heteroatom selected from O, S; or two R a connected to the same carbon atom together with the carbon atom to form C=M; wherein, M is selected from O or CR j R k ; wherein, R j and R k are each independently selected from the group consisting of hydrogen, halogen, or C 1-4 alkyl; or two R a connected to different carbon atoms are connected together to form a bridged ring structure;
T选自N或CR 15；其中，R 15选自氢、卤素、或C 1-4烷基； T is selected from N or CR 15 ; wherein, R 15 is selected from hydrogen, halogen, or C 1-4 alkyl;
X和Z各自独立地选自N或CR；X and Z are each independently selected from N or CR;
各个R各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4卤代烯基、C 2-4炔基、C 2-4卤代炔基、C 3-6环烷基炔基、3-至8-元杂环基炔基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4卤代烷氧基C 1-4烷基、C 3-6环烷基、3-至8-元杂环基、NR hR h、CN、NO 2、SR h、C(O)R t、C(O)OR h、C(O)NR hR h、NR hC(O)R t、NR hS(O) 2R t、或S(O) 2R t；其中，R h和R t的定义如上所述； Each R is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2 -4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy Oxy C 1-4 alkyl, C 1-4 haloalkoxy C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, NR h Rh , CN, NO 2 , SR h , C(O)R t , C(O)OR h , C(O)NR h Rh , NR h C(O)R t , NR h S(O) 2 R t , or S(O ) 2 R t ; wherein, Rh and R t are as defined above;
R 1选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4卤代烯基、C 2-4炔基、C 2-4卤代炔基、C 3-6环烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氧基C 1-4烷基、或C 1-4卤代烷氧基C 1-4烷基； R 1 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 halo Alkynyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy, C 1-4 alkyl, or C 1-4 haloalkoxy C 1-4 alkyl;
R 2选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基； R 2 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl;
m和n各自独立地选自0、1、或2；m and n are each independently selected from 0, 1, or 2;
k选自0、1、或2；k is selected from 0, 1, or 2;
h选自0、1、2、3、或4；h is selected from 0, 1, 2, 3, or 4;
或式(I)中结构片段
Figure PCTCN2022080732-appb-000002
选自下式： or structural fragment in formula (I)
Figure PCTCN2022080732-appb-000002
selected from the following formula:
Figure PCTCN2022080732-appb-000003
Figure PCTCN2022080732-appb-000003
其中，d选自0、1、或2；e选自1、2、3、或4；wherein, d is selected from 0, 1, or 2; e is selected from 1, 2, 3, or 4;
其中，除非特别说明，各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR h、SR h、NR hR h、C(O)R t、C(O)OR h、C(O)NR hR h、NR hC(O)R t、NR hS(O) 2R t、或S(O) 2R t，前提条件是所形成的化学结构是稳定的和有意义的；其中，R h和R t的定义如上所述； wherein, unless otherwise specified, each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups is optionally and each independently selected from 1-3 groups each independently selected from the following Substituent substitution of the group: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered Heterocyclyl, aryl, heteroaryl, CN, NO2, ORh , SRh , NRhRh , C(O) Rt , C(O ) ORh , C ( O ) NRhRh , NR h C(O)R t , NR h S(O) 2 R t , or S(O) 2 R t , provided that the chemical structure formed is stable and meaningful; where Rh and R t is defined as above;
除非特别说明，上述的芳基为含有6-12个碳原子的芳香基团；杂芳基为5-至15-元(优选为5-至12-元)杂芳香基团；环状结构为饱和的或不饱和的、含杂原子或不含杂原子的环状基团。Unless otherwise specified, the above-mentioned aryl group is an aromatic group containing 6-12 carbon atoms; the heteroaryl group is a 5- to 15-membered (preferably 5- to 12-membered) heteroaromatic group; the cyclic structure is Saturated or unsaturated, heteroatom-containing or heteroatom-free cyclic groups.
在另一优选例中，式(I)为式(IIA)：In another preferred embodiment, formula (I) is formula (IIA):
Figure PCTCN2022080732-appb-000004
Figure PCTCN2022080732-appb-000004
Q选自-NR 16-、-O-、-CR 17R 18-；其中，R 16选自氢、C 1-4烷基、C 3-6环烷基、3-至8-元杂环基、芳基、杂芳基、C(O)R t、或S(O) 2R t；R 17和R 18各自独立地选自氢、卤素、或C 1-4烷基； Q is selected from -NR 16 -, -O-, -CR 17 R 18 -; wherein, R 16 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocycle R 17 and R 18 are each independently selected from hydrogen , halogen , or C 1-4 alkyl;
f和g各自独立地选自0、1、或2；前提条件是f和g不能同时为0；f and g are each independently selected from 0, 1, or 2; provided that f and g cannot be 0 at the same time;
j和t各自独立地选自0、1、或2；j and t are each independently selected from 0, 1, or 2;
其它各基团的定义如上文中所述。The other groups are as defined above.
在另一优选例中，式(I)为式(IIIA)：In another preferred embodiment, formula (I) is formula (IIIA):
Figure PCTCN2022080732-appb-000005
Figure PCTCN2022080732-appb-000005
p选自0、1、或2；p is selected from 0, 1, or 2;
j和t各自独立地选自0、1、或2；j and t are each independently selected from 0, 1, or 2;
其它各基团的定义如上文中所述。The other groups are as defined above.
在另一优选例中，式(I)为式(IVA)：In another preferred embodiment, formula (I) is formula (IVA):
Figure PCTCN2022080732-appb-000006
Figure PCTCN2022080732-appb-000006
R 6和R 7各自独立地选自氢、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基C 1-4烷基、C 1-4烷氧基C 1-4烷基、羟基C 1-4烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、4-至8-元杂环基、或4-至8-元杂环基C 1-4烷基； R 6 and R 7 are each independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy C 1-4 alkyl, C 1-4 alkoxy C 1- 4 alkyl, hydroxy C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 alkyl, 4- to 8-membered heterocyclyl, or 4- to 8- membered heterocyclyl C 1-4 alkyl;
p选自0、1、或2；p is selected from 0, 1, or 2;
j和t各自独立地选自0、1、或2；j and t are each independently selected from 0, 1, or 2;
其它各基团的定义如上文中所述。The other groups are as defined above.
在另一优选例中，式(I)为式(VA)：In another preferred example, formula (I) is formula (VA):
Figure PCTCN2022080732-appb-000007
Figure PCTCN2022080732-appb-000007
R b的定义如上文中所述； R b is as defined above;
各基团的定义如上文中所述。The definitions of each group are as described above.
在另一优选例中，式(I)为式(VIA)：In another preferred embodiment, formula (I) is formula (VIA):
Figure PCTCN2022080732-appb-000008
Figure PCTCN2022080732-appb-000008
R b选自C 3-6环烷基、4-至8-元的杂环基、芳基、或杂芳基；所述的环烷基、杂环基、芳基、和杂芳基任选地被一个或多个选自下组的取代基取代：卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、4-至8-元的杂环基、NR dR d、CN、OR d、SR d、C(O)R t、或S(O) 2R t；其中，R t选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、或4-至8-元的杂环基；各个R d各自独立为氢或C 1-4烷基； R b is selected from C 3-6 cycloalkyl, 4- to 8-membered heterocyclyl, aryl, or heteroaryl; the cycloalkyl, heterocyclyl, aryl, and heteroaryl are any optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4- to 8-membered heterocyclyl, NR d R d , CN, OR d , SR d , C(O)R t , or S(O) 2 R t ; wherein R t is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4- to 8-membered heterocyclyl; each R d is independently hydrogen or C 1-4 alkyl;
q选自0、1、2、或3；q is selected from 0, 1, 2, or 3;
其它各基团的定义如上文中所述。The other groups are as defined above.
在另一优选例中，式(I)为式(VIIA)：In another preferred embodiment, formula (I) is formula (VIIA):
Figure PCTCN2022080732-appb-000009
Figure PCTCN2022080732-appb-000009
R c选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、或4-至8-元的杂环基；所述的烷基、烯基、炔基、环烷基和杂环基任选地被一个或多个选自下组的取代基取代：卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、4-至8-元的杂环基、NR dR d、CN、OR d、SR d、C(O)R t、或S(O) 2R t； R c is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4- to 8-membered heterocyclyl; the alkyl , alkenyl, alkynyl, cycloalkyl and heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, C1-4alkyl , C2-4alkenyl , C2- 4alkynyl , C3-6cycloalkyl , 4- to 8-membered heterocyclyl, NRdRd , CN, ORd , SRd , C ( O) Rt , or S(O ) 2R t ;
j选自0、1、或2；j is selected from 0, 1, or 2;
其它各基团的定义如上文中所述。The other groups are as defined above.
在另一优选例中，式(I)为式(VIIIA)：In another preferred embodiment, formula (I) is formula (VIIIA):
Figure PCTCN2022080732-appb-000010
Figure PCTCN2022080732-appb-000010
R 1选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 2-4炔基； R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
R 2选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4炔基； R 2 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl;
R 8、R 9、R 10、R 11各自独立地选自氢、羟基、C 1-4烷基； R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, hydroxy, and C 1-4 alkyl;
X选自N或CR；X is selected from N or CR;
R各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4炔基、C 2-4卤代炔基、C 3-6环烷基炔基、3-至8-元杂环基炔基、C 1-4烷氧基、C 1-4卤代烷氧基、C 3-6环烷基、3-至8-元杂环基、CN。 R is each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, CN.
在另一优选例中，式(I)为式(IXA)：In another preferred embodiment, formula (I) is formula (IXA):
Figure PCTCN2022080732-appb-000011
Figure PCTCN2022080732-appb-000011
R 1选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 2-4炔基； R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
R 2选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4炔基； R 2 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl;
R 6和R 7各自独立地选自氢、C 1-4烷基； R 6 and R 7 are each independently selected from hydrogen, C 1-4 alkyl;
R 8、R 9、R 10、R 11各自独立地选自氢、羟基、C 1-4烷基； R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, hydroxy, and C 1-4 alkyl;
X选自N或CR；X is selected from N or CR;
R各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4炔基、C 2-4卤代炔基、C 3-6环烷基炔基、3-至8-元杂环基炔基、C 1-4烷氧基、C 1-4卤代烷氧基、C 3-6环烷基、3-至8-元杂环基、CN。 R is each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, CN.
在另一优选例中，式(I)为式(XA)：In another preferred embodiment, formula (I) is formula (XA):
Figure PCTCN2022080732-appb-000012
Figure PCTCN2022080732-appb-000012
R b选自C 3-6环烷基、4-至8-元的杂环基、芳基、或杂芳基；所述的环烷基、杂环基、芳基、和杂芳基任选地被一个或多个选自下组的取代基取代：卤素、C 1-4烷基、NR dR d、CN、OR d、C(O)R t、或S(O) 2R t；其中，R t选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、或4-至8-元的杂环基；各个R d各自独立为氢或C 1-4烷基； R b is selected from C 3-6 cycloalkyl, 4- to 8-membered heterocyclyl, aryl, or heteroaryl; the cycloalkyl, heterocyclyl, aryl, and heteroaryl are any optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-4 alkyl, NR d R d , CN, OR d , C(O)R t , or S(O) 2 R t ; wherein, R t is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4- to 8-membered heterocyclyl; each R d is each independently hydrogen or C 1-4 alkyl;
R 1选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 2-4炔基； R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
R 2选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4炔基； R 2 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl;
R 6和R 7各自独立地选自氢、C 1-4烷基；R 8、R 9、R 10、R 11各自独立地选自氢、羟基、C 1- 4烷基；或 R 6 and R 7 are each independently selected from hydrogen, C 1-4 alkyl; R 8 , R 9 , R 10 , R 11 are each independently selected from hydrogen, hydroxyl, C 1-4 alkyl ; or
R 6和R 7与其连接的碳原子、R 8和R 9与其连接的碳原子、或R 10和R 11与其连接的碳原子一起形成3-至-6元的环烷基、或4-至8-元的杂环基，此杂环基含有1或2个选自N、O、S的杂原子； The carbon atom to which R 6 and R 7 are attached, the carbon atom to which R 8 and R 9 are attached, or the carbon atom to which R 10 and R 11 are attached together form a 3- to -6-membered cycloalkyl, or a 4- to 8-membered heterocyclic group, this heterocyclic group contains 1 or 2 heteroatoms selected from N, O, S;
X选自N或CR；X is selected from N or CR;
R各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4炔基、C 2-4卤代炔基、C 3-6环烷基炔基、3-至8-元杂环基炔基、C 1-4烷氧基、C 1-4卤代烷氧基、C 3-6环烷基、3-至8-元杂环基、CN。 R is each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, CN.
在另一优选例中，In another preferred embodiment,
R 1选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 2-4炔基；R 2为H； R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl; R 2 is H;
X选自N或CH；X is selected from N or CH;
R各自独立地选自三氟甲基、CN、C 2-4炔基、C 3-6环烷基炔基、3-至8-元杂环基炔基、C 3-6环烷基。 R is each independently selected from trifluoromethyl, CN, C2-4alkynyl , C3-6cycloalkylalkynyl , 3- to 8-membered heterocyclylalkynyl, C3-6cycloalkyl .
在另一优选例中，式(I)为式(XIA)：In another preferred embodiment, formula (I) is formula (XIA):
Figure PCTCN2022080732-appb-000013
Figure PCTCN2022080732-appb-000013
R 1选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 2-4炔基； R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
R 2选自氢； R 2 is selected from hydrogen;
R 6和R 7各自独立地选自氢、C 1-4烷基； R 6 and R 7 are each independently selected from hydrogen, C 1-4 alkyl;
R 8、R 9、R 10、R 11各自独立地选自氢、羟基、C 1-4烷基； R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, hydroxy, and C 1-4 alkyl;
或R 6和R 7与其连接的碳原子、R 8和R 9与其连接的碳原子、或R 10和R 11与其连接的碳原子一起形成3-至-6元的环烷基、或4-至8-元的杂环基，此杂环基含有1或2个选自N、O、S的杂原子； or the carbon atom to which R 6 and R 7 are attached, the carbon atom to which R 8 and R 9 are attached, or the carbon atom to which R 10 and R 11 are attached together to form a 3- to -6-membered cycloalkyl, or a 4- to an 8-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S;
X选自N或CH；X is selected from N or CH;
R各自独立地选自C 2-4炔基、C 2-4卤代炔基、C 3-6环烷基炔基、3-至8-元杂环基炔基、C 3-6环烷基、3-至8-元杂环基。 R is each independently selected from C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 3-6 cycloalkane base, 3- to 8-membered heterocyclyl.
在另一优选例中，所述的式(I)化合物选自下组：In another preference, the compound of formula (I) is selected from the following group:
Figure PCTCN2022080732-appb-000014
Figure PCTCN2022080732-appb-000014
Figure PCTCN2022080732-appb-000015
Figure PCTCN2022080732-appb-000015
Figure PCTCN2022080732-appb-000016
Figure PCTCN2022080732-appb-000016
“*”表示手性中心。"*" indicates a chiral center.
本发明的第二方面，提供了一种药物组合物，所述药物组合物包含本发明第一方面所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，以及药学上可接受的载体。The second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated Derivatives, hydrates, solvates, and pharmaceutically acceptable carriers.
本发明的第三方面，提供了一种如本发明第一方面所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，其用于制备治疗与PARP7 活性或表达量相关的疾病，病症或病状的药物组合物。The third aspect of the present invention provides a compound according to the first aspect of the present invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate thereof. , for preparing a pharmaceutical composition for treating diseases, disorders or conditions related to the activity or expression of PARP7.
在另一优选例中，所述疾病，病症或病状选自下组：多发性骨髓瘤、B细胞淋巴瘤、T细胞淋巴瘤、急慢性髓系白血病、急慢性淋巴系白血病、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征、纤维肉瘤、唾液腺癌、肝癌、直肠癌、膀胱癌、咽喉癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、***癌、神经胶质细胞瘤、卵巢癌、头颈癌、***、食管癌、肾癌、胰腺癌、结肠癌、皮肤癌、胃癌等各种血液瘤和实体瘤，以及各种类型的心脏病、病毒感染、神经退行性疾病、炎症和疼痛等，尤其是那些与PARP7过表达或异常激活相关的疾病类型。In another preferred embodiment, the disease, disorder or condition is selected from the group consisting of multiple myeloma, B-cell lymphoma, T-cell lymphoma, acute and chronic myeloid leukemia, acute and chronic lymphocytic leukemia, and monocytic leukemia , polycythemia splenomegaly, eosinophilic leukemia syndrome, fibrosarcoma, salivary gland cancer, liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer , prostate cancer, glioblastoma, ovarian cancer, head and neck cancer, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, stomach cancer and other hematological and solid tumors, as well as various types of heart disease, viral infection, neurodegenerative disease, inflammation and pain, especially those disease types associated with PARP7 overexpression or abnormal activation.
具体实施方式Detailed ways
本发明人经过长期而深入的研究，意外地发现了一类结构新颖的化合物作为PARP7抑制剂，以及它们的制备方法和应用。本发明化合物可以应用于与所述ADP和糖基转移酶的活性相关的各种疾病的治疗。基于上述发现，发明人完成了本发明。After long-term and in-depth research, the inventors have unexpectedly discovered a class of compounds with novel structures as PARP7 inhibitors, as well as their preparation methods and applications. The compounds of the present invention can be applied to the treatment of various diseases related to the activities of the ADP and glycosyltransferases. Based on the above findings, the inventors have completed the present invention.
术语the term
除特别说明之处，本文中提到的“或”具有与“和/或”相同的意义(指“或”以及“和”)。Unless otherwise specified, "or" referred to herein has the same meaning as "and/or" (meaning "or" and "and").
除特别说明之处，本发明的所有化合物之中，各手性碳原子(手性中心)可以任选地为R构型或S构型，或R构型和S构型的混合物。Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom (chiral center) may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
如本文所用，在单独或作为其他取代基一部分时，术语“烷基”指只含碳原子的直链(即，无支链)或支链饱和烃基，或直链和支链组合的基团。当烷基前具有碳原子数限定(如C 1-10)时，指所述的烷基含有1-10个碳原子。例如，C 1-8烷基指含有1-8个碳原子的烷基，包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。 As used herein, the term "alkyl", alone or as part of other substituents, refers to a straight chain (ie, unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight and branched chain groups . When an alkyl group is preceded by a carbon number limitation (eg, C 1-10 ), it means that the alkyl group contains 1-10 carbon atoms. For example, C 1-8 alkyl refers to an alkyl group containing 1-8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.
如本文所用，在单独或作为其他取代基一部分时，术语“烯基”是指直链或支链，具有至少一个碳-碳双键的碳链基团。烯基可以是取代的或未取代的。当烯基前具有碳原子数限定(如C 2-8)时，指所述的烯基含有2-8个碳原子。例如，C 2-8烯基指含有2-8个碳原子烯基，包括乙烯基、丙烯基、1,2-丁烯基、2,3-丁烯基、丁二烯基、或类似基团。 As used herein, the term "alkenyl", alone or as part of other substituents, refers to a straight or branched, carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When an alkenyl group is preceded by a carbon number limitation (eg, C2-8 ), it means that the alkenyl group contains 2-8 carbon atoms. For example, C 2-8 alkenyl refers to an alkenyl group containing 2-8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or the like group.
如本文所用，在单独或作为其他取代基一部分时，术语“炔基”是指具有至少一个碳-碳三键的脂肪族碳氢基团。所述的炔基可以是直链或支链的，或其组合。当炔基前具有碳原子数限定(如C 2-8炔基)时，指所述的炔基含有2-8个碳原子。例如，术语“C 2-8炔基”指具有2-8个碳原子的直链或支链炔基，包括乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、仲丁炔基、叔丁炔基、或类似基团。 As used herein, the term "alkynyl", alone or as part of other substituents, refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group can be straight or branched, or a combination thereof. When an alkynyl group is preceded by a carbon number limitation (eg, C 2-8 alkynyl), it means that the alkynyl group contains 2-8 carbon atoms. For example, the term "C 2-8 alkynyl" refers to straight or branched chain alkynyl groups having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.
如本文所用，在单独或作为其他取代基一部分时，术语“环烷基”指具有饱和的或部分饱和的单元环，二环或多环(稠环、桥环或螺环)环系基团。当某个环烷基前具有碳原子数限定(如C 3-10)时，指所述的环烷基含有3-10个碳原子。在一些优选实施例中，术语“C 3-8环烷基”指具有3-8个碳原子的饱和或部分不饱和的单环或二环烷基，包括环丙基、环丁基、环戊基、环庚基、或类似基团。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的二环或多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。“稠环烷基”指***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳二环或多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。所述环烷基所含原子全部为碳原子。如下是环烷基的一些例子，本发明并不仅局限下述的 环烷基。 As used herein, the term "cycloalkyl", alone or as part of other substituents, refers to a monocyclic, bicyclic or polycyclic (fused, bridged or spiro) ring system group having saturated or partially saturated . When a cycloalkyl group is preceded by a carbon number limitation (eg C 3-10 ), it means that the cycloalkyl group contains 3-10 carbon atoms. In some preferred embodiments, the term "C 3-8 cycloalkyl" refers to saturated or partially unsaturated monocyclic or bicycloalkyl having 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclo pentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings, these may contain one or more double bonds, but none of the rings have fully conjugated pi electrons system. "Fused cycloalkyl" refers to an all-carbobicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more bicyclic bonds, but none of the rings have a fully conjugated pi electron system. "Bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system . The atoms contained in the cycloalkyl group are all carbon atoms. The following are some examples of cycloalkyl groups, and the present invention is not limited to the following cycloalkyl groups.
Figure PCTCN2022080732-appb-000017
Figure PCTCN2022080732-appb-000017
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环)，但不能含有杂原子如氮，氧，或硫，同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。如下是芳基的一些例子，本发明并不仅局限下述的芳基。Unless stated to the contrary, the following terms used in the specification and claims have the following meanings. "Aryl" refers to an all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be in a conjugated pi-electron system on the carbon atom of the ring. Aryl groups can be substituted or unsubstituted. The following are some examples of aryl groups, and the present invention is not limited to the following aryl groups.
Figure PCTCN2022080732-appb-000018
Figure PCTCN2022080732-appb-000018
“杂芳基”指包含一个到多个杂原子(任选自氮、氧和硫)的具有芳香性的单环或多环基团，或者包含杂环基(含一个到多个杂原子任选自氮、氧和硫)与芳基稠合形成的多环基团，且连接位点位于芳基上。杂芳基可以是任选取代的或未取代的。如下是杂芳基的一些例子，本发明并不仅局限下述的杂芳基。"Heteroaryl" refers to an aromatic monocyclic or polycyclic group containing one to more heteroatoms (optionally selected from nitrogen, oxygen and sulfur), or a heterocyclic group containing one to more heteroatoms A polycyclic group formed by condensing nitrogen, oxygen and sulfur) with an aryl group, and the attachment site is located on the aryl group. Heteroaryl groups can be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited to the following heteroaryl groups.
Figure PCTCN2022080732-appb-000019
Figure PCTCN2022080732-appb-000019
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基。多环杂环基指包括螺环、稠环和桥环的杂环基。“螺环杂环基”指***中的每个环与体系中的其他环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。“稠环杂环基”指***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基 团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，而且其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。“桥环杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，而且其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。如果杂环基里同时有饱和环和芳环存在(比如说饱和环和芳环稠合在一起)，连接到母体的点一定是在饱和的环上。注：当连接到母体的点在芳环上时，称为杂芳基，不称为杂环基。如下是杂环基的一些例子，本发明并不仅局限下述的杂环基。"Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl. Polycyclic heterocyclyl refers to heterocyclyl including spiro, fused and bridged rings. "Spirocyclic heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares one atom (called a spiro atom) with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur, the remaining ring atoms are carbon. "Fused-ring heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but no A ring has a fully conjugated pi electron system and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. "Bridged heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system , and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If both saturated and aromatic rings are present in the heterocyclyl group (for example, the saturated and aromatic rings are fused together), the point of attachment to the parent must be on the saturated ring. Note: When the point of attachment to the parent is on an aromatic ring, it is called a heteroaryl group, not a heterocyclyl group. The following are some examples of heterocyclic groups, and the present invention is not limited to the following heterocyclic groups.
Figure PCTCN2022080732-appb-000020
Figure PCTCN2022080732-appb-000020
如本文所用，在单独或作为其他取代基一部分时，术语“卤素”指F、Cl、Br和I。As used herein, alone or as part of other substituents, the term "halogen" refers to F, Cl, Br, and I.
如本文所用，术语“取代”(在有或无“任意地”修饰时)指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个任意取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取代基，例如杂环基，可以与另一个环相连，例如环烷基，从而形成螺二环系，即两个环具有一个共用碳原子。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8环烷基、3-至12-元杂环基，芳基、杂芳基、卤素、羟基、羧基(-COOH)、C 1-8醛基、C 2-10酰基、C 2-10酯基、氨基。 As used herein, the term "substituted" (with or without "optionally" modification) refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Particular substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples. Unless otherwise specified, an optionally substituted group may have at any substitutable position of the group a substituent selected from a specified group, which may be the same or different at each position. A cyclic substituent, such as a heterocyclyl, can be attached to another ring, such as a cycloalkyl, to form a spirobicyclic ring system, ie, the two rings have one carbon atom in common. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. The substituents are for example (but not limited to): C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl , aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 aldehyde group, C 2-10 acyl group, C 2-10 ester group, amino group.
为了方便以及符合常规理解，术语“任意取代”或“任选取代”只适用于能够被取代基所取代的位点，而不包括那些化学上不能实现的取代。For convenience and conventional understanding, the terms "optionally substituted" or "optionally substituted" apply only to sites that can be substituted by substituents, and do not include those chemically infeasible substitutions.
如本文所用，除非特别说明，术语“药学上可接受的盐”指适合与对象(例如，人)的组织接触，而不会产生不适度的副作用的盐。在一些实施例中，本发明的某一化合物的药学上可接受的盐包括具有酸性基团的本发明的化合物的盐(例如，钾盐，钠盐，镁盐，钙盐)或具有碱性基团的本发明的化合物的盐(例如，硫酸盐，盐酸盐，磷酸盐，硝酸盐，碳酸盐)。As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt suitable for contact with the tissue of a subject (eg, a human) without undue side effects. In some embodiments, a pharmaceutically acceptable salt of a compound of the present invention includes a salt of a compound of the present invention that has an acidic group (eg, potassium, sodium, magnesium, calcium) or has a basic salts of compounds of the invention (eg, sulfates, hydrochlorides, phosphates, nitrates, carbonates).
用途：use:
本发明提供了一类式(I)化合物，或它们的氘代衍生物、它们的盐、异构体(对映异构体或非对映异构体，如果存在的情况下)、水合物、可药用载体或赋形剂用于抑制PARP7的用途。The present invention provides a class of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if present), hydrates , the use of a pharmaceutically acceptable carrier or excipient for inhibiting PARP7.
本发明化合物可用作一种PARP7抑制剂。The compounds of the present invention are useful as a PARP7 inhibitor.
本发明是PARP7的单一抑制剂，通过调节PARP7的酶活性达到预防、缓解或治愈疾病的目的。所指疾病包括多发性骨髓瘤、B细胞淋巴瘤、T细胞淋巴瘤、急慢性髓系白血病、急慢性淋巴系白血病、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征、纤维肉瘤、唾液腺癌、肝癌、直肠癌、膀胱癌、咽喉癌、非小细胞肺 癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、***癌、神经胶质细胞瘤、卵巢癌、头颈癌、***、食管癌、肾癌、胰腺癌、结肠癌、皮肤癌、胃癌等各种血液瘤和实体瘤，以及各种类型的心脏病、病毒感染、神经退行性疾病、炎症和疼痛等，尤其是那些与PARP7过表达或异常激活相关的疾病类型。The present invention is a single inhibitor of PARP7, and achieves the purpose of preventing, relieving or curing diseases by regulating the enzymatic activity of PARP7. Indicated diseases include multiple myeloma, B-cell lymphoma, T-cell lymphoma, acute and chronic myeloid leukemia, acute and chronic lymphocytic leukemia, monocytic leukemia, polycythemia splenomegaly, eosinophilic leukemia syndrome, fibrosis Sarcoma, salivary gland cancer, liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, glioblastoma, ovarian cancer, head and neck cancer , cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, gastric cancer and other hematological tumors and solid tumors, as well as various types of heart disease, viral infection, neurodegenerative diseases, inflammation and pain, etc., Especially those disease types associated with PARP7 overexpression or abnormal activation.
可将本发明化合物及其氘代衍生物，以及药学上可接受的盐或其异构体(如果存在的情况下)或其水合物和/或组合物与药学上可接受的赋形剂或载体配制在一起，得到的组合物可在体内给予哺乳动物，例如男人、妇女和动物，用于治疗病症、症状和疾病。组合物可以是：片剂、丸剂、混悬剂、溶液剂、乳剂、胶囊、气雾剂、无菌注射液。无菌粉末等。一些实施例中，药学上可接受的赋形剂包括微晶纤维素、乳糖、柠檬酸钠、碳酸钙、磷酸氢钙、甘露醇、羟丙基-β-环糊精、β-环糊精(增加)、甘氨酸、崩解剂(如淀粉、交联羧甲基纤维素钠、复合硅酸盐和高分子聚乙二醇)，造粒粘合剂(如聚乙烯吡咯烷酮、蔗糖、明胶和***胶)和润滑剂(如硬脂酸镁、甘油和滑石粉)。在优选的实施方式中，所述药物组合物是适于口服的剂型，包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。向患者施用本发明化合物或药物组合物的量不固定，通常按药用有效量给药。同时，实际给予的化合物的量可由医师根据实际情况决定，包括治疗的病症、选择的给药途径、给予的实际化合物、患者的个体情况等。本发明化合物的剂量取决于治疗的具体用途、给药方式、患者状态、医师判断。本发明化合物在药物组合物中的比例或浓度取决于多种因素，包括剂量、理化性质、给药途径等。Compounds of the present invention and deuterated derivatives thereof, as well as pharmaceutically acceptable salts or isomers thereof (if present) or hydrates and/or compositions thereof, may be combined with pharmaceutically acceptable excipients or The carriers are formulated together and the resulting compositions can be administered in vivo to mammals, such as men, women and animals, for the treatment of conditions, symptoms and diseases. The compositions may be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injectable solutions. Sterile powder, etc. In some embodiments, the pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin (increase), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicates and high molecular polyethylene glycol), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic) and lubricants such as magnesium stearate, glycerin and talc. In a preferred embodiment, the pharmaceutical composition is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, powders. The amount of a compound or pharmaceutical composition of the present invention administered to a patient is not fixed, but is usually administered in a pharmaceutically effective amount. Meanwhile, the amount of the compound actually administered can be determined by the physician according to the actual situation, including the condition to be treated, the route of administration selected, the actual compound administered, the individual condition of the patient, and the like. The dosage of a compound of the present invention will depend upon the particular use of the treatment, the mode of administration, the patient's condition, and the judgment of the physician. The ratio or concentration of a compound of the present invention in a pharmaceutical composition depends on a variety of factors, including dosage, physicochemical properties, route of administration, and the like.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions.
化合物的通用合成方法General Synthesis of Compounds
各个化合物合成步骤的试剂和条件可以选用本领域进行该类制备方法常规的试剂或条件，在本发明的化合物结构公开后，反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等选择可以由本领域技术人员根据本领域知识进行。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易地进行。The reagents and conditions of each compound synthesis step can be selected from the conventional reagents or conditions in the art for such preparation methods. After the compound structure of the present invention is disclosed, the reactants, solvents, bases, the amount of the used compound, the reaction temperature, and the required reaction conditions Selection of time and the like can be performed by those skilled in the art according to the knowledge in the art. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention pertains.
药物组合物和施用方法Pharmaceutical compositions and methods of administration
由于本发明化合物具有优异的对一种ADP核糖基转移酶的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与PARP7活性或表达量相关的疾病。Since the compound of the present invention has excellent inhibitory activity against an ADP ribosyltransferase, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention The pharmaceutical composition in which the compound of the invention is the main active ingredient can be used for the treatment, prevention and alleviation of diseases related to the activity or expression of PARP7.
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount. The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花 生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2022080732-appb-000021
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as
Figure PCTCN2022080732-appb-000021
), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is The administration dose is usually 1 to 2000 mg, preferably 5 to 500 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
本发明的主要优点包括：The main advantages of the present invention include:
1.提供了一种如式I所示的化合物。1. A compound of formula I is provided.
2.提供了一种结构新颖的PARP7抑制剂，及其制备和应用，所述的抑制剂在极低浓度下即可抑制PARP7的活性。2. Provided is a PARP7 inhibitor with novel structure, preparation and application thereof, the inhibitor can inhibit the activity of PARP7 at a very low concentration.
3.提供了一类治疗与PARP7活性相关疾病的药物组合物。3. A pharmaceutical composition for treating diseases related to PARP7 activity is provided.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
本发明的部分代表性化合物可以通过下面合成方法制备而得，下述各反应式中，各步骤的试剂和条件可以选用本领域进行该类制备方法常规的试剂或条件，在本发明的化合物结构公开后，上述选择可以由本领域技术人员根据本领域知识进行。Some representative compounds of the present invention can be prepared by the following synthetic methods. In the following reaction formulas, the reagents and conditions of each step can be selected from conventional reagents or conditions in the field for such preparation methods. In the compound structure of the present invention After disclosure, the above selection can be made by those skilled in the art according to the knowledge in the art.
实施例：Example:
本发明的部分化合物可以通过以下方法制备得到。Some compounds of the present invention can be prepared by the following methods.
缩写abbreviation
Boc 2O＝二碳酸二叔丁酯 Boc 2 O = di-tert-butyl dicarbonate
Cs 2CO 3＝碳酸铯 Cs 2 CO 3 = cesium carbonate
DCM＝二氯甲烷DCM = dichloromethane
DIPEA＝N,N-二异丙基胺DIPEA=N,N-diisopropylamine
DMA＝N,N-二甲基乙酰胺DMA=N,N-dimethylacetamide
DMF＝N,N-二甲基甲酰胺DMF=N,N-dimethylformamide
DMSO＝二甲基亚砜DMSO = dimethyl sulfoxide
EtOAc＝乙酸乙酯EtOAc = ethyl acetate
HATU＝1-[双(二甲基氨基)亚甲基]-1H-1,2,3-***并[4,5-b]吡啶鎓3-氧化六氟磷酸盐HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxyhexafluorophosphate
SEM＝2-(三甲基硅烷基)乙氧甲基SEM = 2-(trimethylsilyl)ethoxymethyl
PMB＝4-甲氧基苄基PMB=4-methoxybenzyl
TEA＝三乙胺TEA = triethylamine
TFA＝三氟乙酸TFA = trifluoroacetic acid
TsOH＝4-甲基苯磺酸TsOH=4-methylbenzenesulfonic acid
戴斯马丁氧化剂＝1,1,1-三(乙酰氧基)-1,1-二氢-1,2-苯碘酰-3-(1H)-酮Dess Martin's Oxidant = 1,1,1-Tris(acetoxy)-1,1-dihydro-1,2-phenyliodoyl-3-(1H)-one
实施例1:化合物1的制备Example 1: Preparation of Compound 1
Figure PCTCN2022080732-appb-000022
Figure PCTCN2022080732-appb-000022
将化合物1a(1.0g,5.48mmol)、化合物1b(1.02g,5.48mmol)和碳酸钾(1.51g,10.96mmol)加入N-甲基吡咯烷酮(8mL)中加热至80℃搅拌2小时。待反应液冷却至室温，加入水稀释。该混合液经乙酸乙酯萃取(3x25mL)，所得有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤、减压浓缩。所得粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯＝15:1)得到白色固体化合物1c(1.71g，收率94％)。MS m/z 333.3[M+H] +。 Compound 1a (1.0 g, 5.48 mmol), compound 1b (1.02 g, 5.48 mmol) and potassium carbonate (1.51 g, 10.96 mmol) were added to N-methylpyrrolidone (8 mL) and heated to 80° C. and stirred for 2 hours. After the reaction solution was cooled to room temperature, water was added for dilution. The mixture was extracted with ethyl acetate (3×25 mL), and the obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=15:1) to obtain compound 1c (1.71 g, yield 94%) as a white solid. MS m/z 333.3 [M+H] + .
将化合物1c(1.71g,5.15mmol)溶于二氯甲烷(15mL)中，然后加入氯化氢的1,4-二氧六环溶液(4M,6mL)。反应混合液在室温下搅拌过夜。待反应完毕后，反应混合液经过滤、二氯甲烷洗涤后得到白色固体产物1d(1.54g，收率100％)。MS m/z 233.3[M+H] +。 Compound 1c (1.71 g, 5.15 mmol) was dissolved in dichloromethane (15 mL), followed by the addition of hydrogen chloride in 1,4-dioxane (4M, 6 mL). The reaction mixture was stirred at room temperature overnight. After the completion of the reaction, the reaction mixture was filtered and washed with dichloromethane to obtain a white solid product 1d (1.54 g, yield 100%). MS m/z 233.3 [M+H] + .
将化合物1d(100mg,0.29mmol)和三乙胺(148mg,1.46mmol)溶于二氯甲烷(3mL)中，置于-40℃下搅拌再缓慢滴加丙烯酸酐1e(44mg,0.35mmol)。反应混合液在-40℃下搅拌30分钟。反应完毕后，待升至室温，反应混合液加入水稀释。该混合液经二氯甲烷萃取(3x15mL)，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤、减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷：乙酸乙酯＝8:1)得到白色固体产品1f(77mg，收率92％)。MS m/z 287.2[M+H] +。 Compound 1d (100 mg, 0.29 mmol) and triethylamine (148 mg, 1.46 mmol) were dissolved in dichloromethane (3 mL), stirred at -40°C and then slowly added dropwise acrylic anhydride 1e (44 mg, 0.35 mmol). The reaction mixture was stirred at -40°C for 30 minutes. After the reaction was completed, the reaction mixture was diluted with water after warming to room temperature. The mixture was extracted with dichloromethane (3×15 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:ethyl acetate=8:1) to obtain a white solid product 1f (77 mg, yield 92%). MS m/z 287.2 [M+H] + .
依次将化合物1f(77mg,0.27mmol)、1g(101mg,0.54mmol)和碳酸铯(105mg,0.32mmol)加入乙腈(3mL)中，加热至60℃搅拌过夜。待冷却至室温后，反应液过滤。所得滤液减压浓缩后经硅胶柱层析分离纯化(二氯甲烷:乙酸乙酯＝3:1)得到无色油状产品1h(47mg，收率37％)。MS m/z 474.5[M+H] +。 Compound 1f (77 mg, 0.27 mmol), 1 g (101 mg, 0.54 mmol) and cesium carbonate (105 mg, 0.32 mmol) were successively added to acetonitrile (3 mL), heated to 60°C and stirred overnight. After cooling to room temperature, the reaction solution was filtered. The obtained filtrate was concentrated under reduced pressure and separated and purified by silica gel column chromatography (dichloromethane:ethyl acetate=3:1) to obtain a colorless oily product for 1 h (47 mg, yield 37%). MS m/z 474.5 [M+H] + .
将化合物1h(47mg,0.10mmol)溶于二氯甲烷(2mL)中，再加入氯化氢的1,4-二氧六环溶液(4M,0.5mL)，混合液在室温下搅拌2小时。待反应完毕，加入适量氨水调节pH至7左右。该混合液经减压浓缩，所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝25:1,2％氨水)得到白色固体产品1i(33mg，收率89％)。MS m/z 374.4[M+H] +。 Compound 1h (47 mg, 0.10 mmol) was dissolved in dichloromethane (2 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction is completed, an appropriate amount of ammonia water is added to adjust the pH to about 7. The mixture was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=25:1, 2% ammonia water) to obtain a white solid product 1i (33 mg, yield 89%). MS m/z 374.4 [M+H] + .
化合物1j采用专利US20190330194的方法合成。Compound 1j was synthesized by the method of patent US20190330194.
依次将化合物1j(31mg,0.10mmol)、化合物1i(33mg,0.09mmol)和三乙胺(40mg,0.40mmol)加入乙腈(2mL)中，室温下搅拌过夜。反应混合液减压浓缩后经硅胶柱层析分离纯化(二氯甲烷:甲醇＝25:1)得到白色固体产品1k(32mg，收率55％)。MS m/z 656.7[M+H] +。 Compound 1j (31 mg, 0.10 mmol), compound 1i (33 mg, 0.09 mmol) and triethylamine (40 mg, 0.40 mmol) were sequentially added to acetonitrile (2 mL) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, separated and purified by silica gel column chromatography (dichloromethane:methanol=25:1) to obtain a white solid product 1k (32 mg, yield 55%). MS m/z 656.7 [M+H] + .
将化合物1k(32mg,0.05mmol)加入三氟乙酸(1.5mL)中，再滴加三氟甲磺酸(5滴)，反应混合液在室温下搅拌1小时。待反应完毕后，滴加适量氨水调节pH至7左右。该混合液经二氯甲烷萃取(3×15mL)，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤、减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝25:1)得到白色固体产品1(8mg，收率31％)。 1H NMR(500MHz,CDCl 3)δ10.10(s,1H),8.52(s,2H),8.11(s,1H),6.35-6.15(m,1H),3.96-3.89(m,4H),3.84(t,J＝6.1Hz,2H),3.73-3.70(m,2H),3.57-3.51(m,4H),2.61(t,J＝6.1Hz,2H),1.04-1.02(m,2H),1.01-0.99(m,2H)ppm。MS m/z 536.5[M+H] +。 Compound 1k (32 mg, 0.05 mmol) was added to trifluoroacetic acid (1.5 mL), then trifluoromethanesulfonic acid (5 drops) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, an appropriate amount of ammonia water was added dropwise to adjust the pH to about 7. The mixture was extracted with dichloromethane (3×15 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=25:1) to obtain white solid product 1 (8 mg, yield 31%). 1 H NMR (500MHz, CDCl 3 )δ10.10(s,1H), 8.52(s,2H), 8.11(s,1H), 6.35-6.15(m,1H), 3.96-3.89(m,4H), 3.84(t,J＝6.1Hz,2H),3.73-3.70(m,2H),3.57-3.51(m,4H),2.61(t,J＝6.1Hz,2H),1.04-1.02(m,2H) ,1.01-0.99(m,2H)ppm. MS m/z 536.5 [M+H] + .
实施例2:化合物2的制备Example 2: Preparation of Compound 2
Figure PCTCN2022080732-appb-000023
Figure PCTCN2022080732-appb-000023
将化合物2a(0.500g,3.62mmol)、化合物1b(0.675g,3.62mmol)和碳酸钾(0.850g,6.12mmol)加入DMA(10mL)中加热至80℃搅拌3小时。将反应液冷却至室温，加入乙酸乙酯(40mL)稀释、水洗(10mL×2)，有机层用硫酸钠干燥、过滤、浓缩，粗品经硅胶柱层析(0-10％乙酸乙酯/石油醚)纯化得到白色固体产品2b(0.7g，收率67％)。 1H NMR(500MHz,CDCl 3)δ8.42(d,J＝2.2Hz,1H),7.64(dd,J＝9.0,2.2Hz,1H),6.60(d,J＝9.0Hz,1H),3.74–3.64(m,4H),3.62–3.45(m,4H),1.49(s,9H)ppm。 Compound 2a (0.500 g, 3.62 mmol), compound 1b (0.675 g, 3.62 mmol) and potassium carbonate (0.850 g, 6.12 mmol) were added to DMA (10 mL) and heated to 80°C and stirred for 3 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (40 mL), washed with water (10 mL×2), the organic layer was dried over sodium sulfate, filtered and concentrated, and the crude product was subjected to silica gel column chromatography (0-10% ethyl acetate/petroleum ether) to give the product 2b as a white solid (0.7 g, 67% yield). 1 H NMR (500MHz, CDCl 3 ) δ 8.42 (d, J=2.2Hz, 1H), 7.64 (dd, J=9.0, 2.2Hz, 1H), 6.60 (d, J=9.0Hz, 1H), 3.74 -3.64(m,4H),3.62-3.45(m,4H),1.49(s,9H)ppm.
化合物2b(200mg，0.69mmol)和4N HCl的1,4-二氧六环(1mL,4mmol)溶于二氯甲烷(5mL)于室温搅拌3小时。将反应液减压浓缩真空干燥得到白色固体化合物2c(156mg,收率100％)。 1H NMR(500MHz,DMSO-d 6)δ9.43(s,2H),8.56(d,J＝2.2Hz,1H),7.96(dd,J＝9.0,2.2Hz,1H),7.03(d,J＝9.0Hz,1H),4.00–3.84(m,4H),3.17(s,4H)ppm。 Compound 2b (200 mg, 0.69 mmol) and 4N HCl in 1,4-dioxane (1 mL, 4 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and vacuum-dried to obtain compound 2c (156 mg, yield 100%) as a white solid. 1 H NMR (500MHz, DMSO-d 6 ) δ 9.43(s, 2H), 8.56(d, J=2.2Hz, 1H), 7.96(dd, J=9.0, 2.2Hz, 1H), 7.03(d, J = 9.0 Hz, 1H), 4.00–3.84 (m, 4H), 3.17 (s, 4H) ppm.
将化合物2c(177mg,0.78mmol)和三乙胺(316mg,3.13mmol)溶于二氯甲烷(6mL)中，置于-40℃下搅拌再缓慢滴加丙烯酸酐1e(128mg,1.02mmol)。反应混合液在-40℃下搅拌1小时。反应完毕后，待升至室温，反应混合液加入水稀释。该混合液经二氯甲烷萃取(3×20mL)，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤、减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:乙酸乙酯＝10:1)得到白色固体产品2d(154mg，收率81％)。Compound 2c (177 mg, 0.78 mmol) and triethylamine (316 mg, 3.13 mmol) were dissolved in dichloromethane (6 mL), stirred at -40°C and then slowly added dropwise acrylic anhydride 1e (128 mg, 1.02 mmol). The reaction mixture was stirred at -40°C for 1 hour. After the reaction was completed, the reaction mixture was diluted with water after warming to room temperature. The mixture was extracted with dichloromethane (3×20 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:ethyl acetate=10:1) to obtain a white solid product 2d (154 mg, yield 81%).
依次将化合物2d(154mg,0.64mmol)、1g(238mg,1.27mmol)和碳酸铯(248mg,0.76mmol)加入乙腈(4mL)中，加热至65℃搅拌过夜。待冷却至室温后，反应液过滤。所得滤液减压浓缩后经硅胶柱层析分离纯化(二氯甲烷:乙酸乙酯＝3:1)得到白色固体产品2e(50mg，收率17％)。MS m/z 430.5[M+H] +。 Compound 2d (154 mg, 0.64 mmol), 1 g (238 mg, 1.27 mmol) and cesium carbonate (248 mg, 0.76 mmol) were successively added to acetonitrile (4 mL), heated to 65°C and stirred overnight. After cooling to room temperature, the reaction solution was filtered. The obtained filtrate was concentrated under reduced pressure, separated and purified by silica gel column chromatography (dichloromethane:ethyl acetate=3:1) to obtain a white solid product 2e (50 mg, yield 17%). MS m/z 430.5 [M+H] + .
将化合物2e(50mg,0.10mmol)溶于二氯甲烷(2mL)中，再加入HCl的1,4-二氧六环溶液(4M,0.5mL)，混合液在室温下搅拌2小时。待反应完毕，加入适量氨水调节pH至7左右。该混合液经减压浓缩，所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝25:1,2％氨水)得到白色固体产品2f(28mg，收率81％)。MS m/z 330.4[M+H] +。 Compound 2e (50 mg, 0.10 mmol) was dissolved in dichloromethane (2 mL), HCl in 1,4-dioxane solution (4 M, 0.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction is completed, an appropriate amount of ammonia water is added to adjust the pH to about 7. The mixture was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=25:1, 2% ammonia water) to obtain a white solid product 2f (28 mg, yield 81%). MS m/z 330.4 [M+H] + .
依次将化合物1j(30mg,0.09mmol)、化合物2f(28mg,0.08mmol)和三乙胺(39mg,0.39mmol)加入乙腈(2mL)中，室温下搅拌过夜。反应混合液减压浓缩后经硅胶柱层析分离纯化(二氯甲烷:甲醇＝25:1)得到白色固体产品2g(12mg，收率23％)。MS m/z 612.7[M+H] +。 Compound 1j (30 mg, 0.09 mmol), compound 2f (28 mg, 0.08 mmol) and triethylamine (39 mg, 0.39 mmol) were sequentially added to acetonitrile (2 mL) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, separated and purified by silica gel column chromatography (dichloromethane:methanol=25:1) to obtain 2g (12mg, yield 23%) of a white solid product. MS m/z 612.7 [M+H] + .
将化合物2g(12mg,0.02mmol)加入三氟乙酸(1mL)中，再滴加三氟甲磺酸(3滴)，反应混合液在室温下搅拌1小时。待反应完毕后，滴加适量氨水调节pH至7左右。该混合液经二氯甲烷萃取(3×15mL)，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤、减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝25:1)得到白色固体产品1(2mg，收率21％)。MS m/z 492.4[M+H] +。 Compound 2g (12 mg, 0.02 mmol) was added to trifluoroacetic acid (1 mL), then trifluoromethanesulfonic acid (3 drops) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, an appropriate amount of ammonia water was added dropwise to adjust the pH to about 7. The mixture was extracted with dichloromethane (3×15 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=25:1) to obtain white solid product 1 (2 mg, yield 21%). MS m/z 492.4 [M+H] + .
实施例3:化合物3的制备Example 3: Preparation of Compound 3
Figure PCTCN2022080732-appb-000024
Figure PCTCN2022080732-appb-000024
将化合物3a(0.200g,1.29mmol)、化合物1b(0.240g,1.29mmol)和碳酸铯(0.840g,2.58mmol)加入DMA(10mL)中加热至80℃搅拌16小时。将反应液冷却至室温，加入乙酸乙酯(50mL)稀释、水洗(10mL×3)，有机层用硫酸钠干燥、过滤、浓缩，粗品经硅胶柱层析(0-20％乙酸乙酯/石油醚)纯化得到白色固体产品3b(0.320g，收率82％)。MS m/z 305.39[M+H] +。 Compound 3a (0.200 g, 1.29 mmol), compound 1b (0.240 g, 1.29 mmol) and cesium carbonate (0.840 g, 2.58 mmol) were added to DMA (10 mL) and heated to 80 °C and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (10 mL×3), the organic layer was dried over sodium sulfate, filtered and concentrated, and the crude product was subjected to silica gel column chromatography (0-20% ethyl acetate/petroleum ether) to give the product 3b as a white solid (0.320 g, 82% yield). MS m/z 305.39 [M+H] + .
化合物3b(220mg，0.72mmol)和4N氯化氢的1,4-二氧六环(1mL,4mmol)溶于二氯甲烷(1mL)于室温搅拌3小时。将反应液减压浓缩真空干燥得到白色固体化合物3c(176mg,收率100％)。 1H NMR(500MHz,DMSO-d 6)δ9.38(s,2H),8.31(s,2H),4.00-3.96(m,4H),3.19(brs,4H),1.92-1.80(m,1H),0.97-0.93(m,2H),0.76-0.68(m,2H)ppm。MS m/z 205.31[M+H] +。 Compound 3b (220 mg, 0.72 mmol) and 4N hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and vacuum-dried to obtain compound 3c (176 mg, yield 100%) as a white solid. 1 H NMR (500MHz, DMSO-d 6 )δ9.38(s,2H), 8.31(s,2H), 4.00-3.96(m,4H), 3.19(brs,4H), 1.92-1.80(m,1H) ), 0.97-0.93 (m, 2H), 0.76-0.68 (m, 2H) ppm. MS m/z 205.31 [M+H] + .
将化合物3c(150mg,0.63mmol)和三乙胺(192mg,1.89mmol)溶于二氯甲烷(5mL)中，置于-40℃下搅拌再缓慢滴加丙烯酸酐1e(87mg,0.69mmol)。反应混合液在-40℃下搅拌1小时。反应完毕后，待升至室温，反应混合液加入水稀释。该混合液经二氯甲烷萃取(3×20mL)，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤、减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝20:1)得到白色固体产品3d(162mg，收率99％)。MS m/z 259.4[M+H] +。 Compound 3c (150 mg, 0.63 mmol) and triethylamine (192 mg, 1.89 mmol) were dissolved in dichloromethane (5 mL), stirred at -40°C and then slowly added dropwise acrylic anhydride 1e (87 mg, 0.69 mmol). The reaction mixture was stirred at -40°C for 1 hour. After the reaction was completed, the reaction mixture was diluted with water after warming to room temperature. The mixture was extracted with dichloromethane (3×20 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain a white solid product 3d (162 mg, yield 99%). MS m/z 259.4 [M+H] + .
依次将化合物3d(162mg,0.63mmol)、化合物3e(220mg,1.25mmol)和碳酸铯(245mg,0.75mmol)加入乙腈(4mL)中，加热至65℃搅拌过夜。待冷却至室温后，反应液过滤。所得滤液减压浓缩后经硅胶柱层析分离纯化(二氯甲烷:乙酸乙酯＝3:1)得到白色固体产品3f(183mg，收率67％)。MS m/z 434.6[M+H] +。 Compound 3d (162 mg, 0.63 mmol), compound 3e (220 mg, 1.25 mmol) and cesium carbonate (245 mg, 0.75 mmol) were successively added to acetonitrile (4 mL), heated to 65°C and stirred overnight. After cooling to room temperature, the reaction solution was filtered. The obtained filtrate was concentrated under reduced pressure, separated and purified by silica gel column chromatography (dichloromethane:ethyl acetate=3:1) to obtain a white solid product 3f (183 mg, yield 67%). MS m/z 434.6 [M+H] + .
将化合物3f(183mg,0.42mmol)溶于二氯甲烷(4mL)中，再加入氯化氢的1,4-二氧六环溶液(4M，1.0mL)，混合液在室温下搅拌2小时。待反应完毕，加入适量氨水调节pH至7左右。该混合液经减压浓缩，所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1,2％氨水)得到白色固体产品3g(100mg，收率71％)。MS m/z 334.5[M+H] +。 Compound 3f (183 mg, 0.42 mmol) was dissolved in dichloromethane (4 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 M, 1.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction is completed, an appropriate amount of ammonia water is added to adjust the pH to about 7. The mixture was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1, 2% ammonia water) to obtain 3g (100mg, yield 71%) of white solid product. MS m/z 334.5 [M+H] + .
化合物a采用专利US20190330194的方法合成。Compound a was synthesized by the method of patent US20190330194.
依次将化合物a(57mg,0.18mmol)、化合物3g(50mg,0.15mmol)和三乙胺(46mg,0.45mmol)加入乙腈(2.5mL)中，室温下搅拌2天。反应混合液减压浓缩后经硅胶柱层析分离纯化(二氯甲烷：甲醇＝25:1)得到黄色油状产品3h(95mg，纯度85％，收率87％)。MS m/z 616.7[M+H] +。 Compound a (57 mg, 0.18 mmol), compound 3g (50 mg, 0.15 mmol) and triethylamine (46 mg, 0.45 mmol) were sequentially added to acetonitrile (2.5 mL) and stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and separated and purified by silica gel column chromatography (dichloromethane:methanol=25:1) to obtain a yellow oily product for 3h (95mg, purity 85%, yield 87%). MS m/z 616.7 [M+H] + .
将化合物3h(95mg,纯度85％，0.13mmol)加入三氟乙酸(1.5mL)中，再滴加三氟甲磺酸(4滴)，反应混合液在室温下搅拌1小时。待反应完毕后，滴加适量氨水调节pH至7左右。该混合液经二氯甲烷萃取(3×15mL)，合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤、减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷：甲醇＝25:1)得到白色固体产品3(20mg，收率31％)。 1H NMR(500MHz,CDCl 3)δ10.35(s,1H),8.14(s,2H),7.66(s,1H),5.87-5.80(m,1H),3.95-3.76(m,7H),3.72-3.68(m,2H),3.66-3.63(m,1H),3.55-3.48(m,3H),2.64(t,J＝6.3Hz,2H),1.77-1.68(m,1H),1.30(d,J＝6.6Hz,3H),0.95-0.90(m,2H),0.62-0.58(m,2H)ppm。MS m/z 496.5[M+H] +。 Compound 3h (95 mg, 85% purity, 0.13 mmol) was added to trifluoroacetic acid (1.5 mL), then trifluoromethanesulfonic acid (4 drops) was added dropwise, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, an appropriate amount of ammonia water was added dropwise to adjust the pH to about 7. The mixture was extracted with dichloromethane (3×15 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=25:1) to obtain white solid product 3 (20 mg, yield 31%). 1 H NMR (500MHz, CDCl 3 ) δ 10.35(s, 1H), 8.14(s, 2H), 7.66(s, 1H), 5.87-5.80(m, 1H), 3.95-3.76(m, 7H), 3.72-3.68(m, 2H), 3.66-3.63(m, 1H), 3.55-3.48(m, 3H), 2.64(t, J=6.3Hz, 2H), 1.77-1.68(m, 1H), 1.30( d, J=6.6Hz, 3H), 0.95-0.90 (m, 2H), 0.62-0.58 (m, 2H) ppm. MS m/z 496.5 [M+H] + .
实施例4:化合物4的制备Example 4: Preparation of Compound 4
Figure PCTCN2022080732-appb-000025
Figure PCTCN2022080732-appb-000025
参照与实施例7类似的方法，替换对应结构片段制备化合物4。Referring to a method similar to Example 7, compound 4 was prepared by substituting the corresponding structural fragment.
实施例5:化合物5的制备Example 5: Preparation of Compound 5
Figure PCTCN2022080732-appb-000026
Figure PCTCN2022080732-appb-000026
参照与实施例7类似的方法，替换对应结构片段制备化合物5。Compound 5 was prepared by referring to a method similar to Example 7, substituting the corresponding structural fragment.
实施例6:化合物6的制备Example 6: Preparation of Compound 6
Figure PCTCN2022080732-appb-000027
Figure PCTCN2022080732-appb-000027
参照与实施例7类似的方法，替换对应结构片段制备化合物6。Compound 6 was prepared by referring to a method similar to Example 7, substituting the corresponding structural fragment.
实施例7:化合物7的制备Example 7: Preparation of Compound 7
Figure PCTCN2022080732-appb-000028
Figure PCTCN2022080732-appb-000028
将化合物7a(600mg，4.11mmol)溶于四氢呋喃(10mL)和水(10mL)中，再加入过硫酸氢钾(2.15g，6.21mmol)。反应混合物室温搅拌3小时。将混合物过 滤，滤液加水稀释，用乙酸乙酯萃取两次，合并后的有机相经饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩。所得粗品黄色油状化合物7b(426mg)直接用于下一步反应。Compound 7a (600 mg, 4.11 mmol) was dissolved in tetrahydrofuran (10 mL) and water (10 mL), and potassium hydrogen persulfate (2.15 g, 6.21 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was filtered, the filtrate was diluted with water, extracted twice with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude yellow oily compound 7b (426 mg) was directly used in the next reaction.
将化合物7b(200mg，1.72mmol)、化合物1d(461mg，1.72mmol)溶于乙腈(10mL)中，滴加N,N-二异丙基乙胺(877mg，6.88mmol)，再加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(981mg，2.58mmol)。反应液室温搅拌1小时。将反应液减压浓缩，所得粗品经硅胶柱层析分离纯化得白色固体化合物7c(420mg，收率74％)。MS m/z 331.0[M+H] +。 Compound 7b (200 mg, 1.72 mmol) and compound 1d (461 mg, 1.72 mmol) were dissolved in acetonitrile (10 mL), N,N-diisopropylethylamine (877 mg, 6.88 mmol) was added dropwise, and 2-( 7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (981 mg, 2.58 mmol). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography to obtain compound 7c (420 mg, yield 74%) as a white solid. MS m/z 331.0 [M+H] + .
将化合物7c(100mg，0.30mmol)、N,N-二异丙基乙胺(116mg，0.90mmol)溶于二氯甲烷(3mL)中，冰浴下滴加甲磺酰氯(52g，0.45mmol)。反应液室温搅拌1小时。将反应液减压浓缩，所得粗品经硅胶柱层析分离纯化得黄色固体化合物7d(112mg，收率91％)。MS m/z 408.9[M+H] +。 Compound 7c (100 mg, 0.30 mmol) and N,N-diisopropylethylamine (116 mg, 0.90 mmol) were dissolved in dichloromethane (3 mL), and methanesulfonyl chloride (52 g, 0.45 mmol) was added dropwise under ice bath. . The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography to obtain compound 7d (112 mg, yield 91%) as a yellow solid. MS m/z 408.9 [M+H] + .
将化合物7d(112mg，0.28mmol)溶于甲基叔丁基醚(5mL)，再在冰浴下加入叔丁醇钾(38mg，0.34mmol)。反应混合物室温搅拌过夜。将反应混合物减压浓缩，所得粗品经硅胶柱层析分离纯化得黄色固体化合物7e(71mg，收率83％)。 1H NMR(500MHz,CDCl 3)δ8.52(s,2H),6.60(s,1H),3.98-3.93(m,4H),3.84-3.65(m,4H),1.47-1.42(m,2H),1.24-1.20(m,2H)。MS m/z 313.1[M+H] +。 Compound 7d (112 mg, 0.28 mmol) was dissolved in methyl tert-butyl ether (5 mL), and potassium tert-butoxide (38 mg, 0.34 mmol) was added under an ice bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography to obtain compound 7e (71 mg, yield 83%) as a yellow solid. 1 H NMR (500MHz, CDCl 3 ) δ 8.52(s, 2H), 6.60(s, 1H), 3.98-3.93(m, 4H), 3.84-3.65(m, 4H), 1.47-1.42(m, 2H) ), 1.24-1.20 (m, 2H). MS m/z 313.1 [M+H] + .
将化合物3e(25mg，0.14mmol)溶于四氢呋喃(3mL)，冰浴下加入钠氢(60％，7.5mg，0.19mmol)。反应混合物冰浴搅拌20分钟，再加入化合物7e(30mg，0.10mmol)。反应混合物室温搅拌1小时。将反应混合物减压浓缩，经硅胶柱层析分离纯化得黄色固体化合物7f(44mg，收率94％)。MS m/z 488.1[M+H] +。 Compound 3e (25 mg, 0.14 mmol) was dissolved in tetrahydrofuran (3 mL), and sodium hydrogen (60%, 7.5 mg, 0.19 mmol) was added under ice bath. The reaction mixture was stirred in an ice bath for 20 minutes, and then compound 7e (30 mg, 0.10 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain compound 7f (44 mg, yield 94%) as a yellow solid. MS m/z 488.1 [M+H] + .
将化合物7f(44mg，0.09mmol)溶于二氯甲烷(3mL)，滴加盐酸二氧六环(0.5mL)。反应液室温搅拌2小时。将反应液减压浓缩，经硅胶柱层析分离纯化得黄色油状化合物7g(30mg，收率86％)。 1H NMR(500MHz,CD 3OD)δ8.60(s,2H),4.03-3.89(m,4H),3.76-3.66(m,4H),3.58-3.52(m,1H),3.36-3.32(m,1H),3.13-3.05(m,1H),2.86(d,J＝2.1Hz,2H),1.10(d,J＝6.6Hz,3H),0.94-0.88(m,2H),0.70-0.63(m,2H)。MS m/z 388.1[M+H] +。 Compound 7f (44 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), and dioxane hydrochloride (0.5 mL) was added dropwise. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain 7 g of a yellow oily compound (30 mg, yield 86%). 1 H NMR (500MHz, CD 3 OD) δ8.60(s, 2H), 4.03-3.89(m, 4H), 3.76-3.66(m, 4H), 3.58-3.52(m, 1H), 3.36-3.32( m,1H),3.13-3.05(m,1H),2.86(d,J=2.1Hz,2H),1.10(d,J=6.6Hz,3H),0.94-0.88(m,2H),0.70-0.63 (m, 2H). MS m/z 388.1 [M+H] + .
将化合物7g(30mg，0.08mmol)、化合物b(38mg，0.11mmol)溶于乙腈(2mL)，再滴加N,N-二异丙基乙胺(31mg，0.24mmol)。反应液40℃加热搅拌1小时。将反应液减压浓缩，经制备型薄层板分离纯化得黄色油状化合物7h(15mg，收率29％)。MS m/z 680.0[M+H] +。 Compound 7g (30 mg, 0.08 mmol) and compound b (38 mg, 0.11 mmol) were dissolved in acetonitrile (2 mL), and N,N-diisopropylethylamine (31 mg, 0.24 mmol) was added dropwise. The reaction solution was heated and stirred at 40°C for 1 hour. The reaction solution was concentrated under reduced pressure, and separated and purified by preparative thin-layer plate to obtain yellow oily compound 7h (15 mg, yield 29%). MS m/z 680.0 [M+H] + .
将化合物7h(15mg，0.02mmol)溶于二氯甲烷(1mL)中，再滴加三氟乙酸(0.5mL)。反应液室温搅拌过夜。将反应液减压浓缩，经制备型薄层板分离纯化得白色固体化合物7(1mg，收率8％)。 1H NMR(500MHz,CD 3OD)δ8.59(s,2H),7.90(s,1H),4.11-4.06(m,1H),3.97-3.89(m,4H),3.71-3.66(m,4H),3.60-3.56(m,1H),3.40-3.30(m,1H),2.86(d,J＝5.1Hz,2H),1.23(d,J＝6.6Hz,3H),0.88-0.84(m,2H),0.69-0.66(m,2H)。MS m/z 550.0[M+H] +。 Compound 7h (15 mg, 0.02 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added dropwise. The reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and separated and purified by preparative thin layer plate to obtain compound 7 (1 mg, yield 8%) as a white solid. 1 H NMR (500MHz, CD 3 OD) δ8.59(s, 2H), 7.90(s, 1H), 4.11-4.06(m, 1H), 3.97-3.89(m, 4H), 3.71-3.66(m, 4H), 3.60-3.56(m, 1H), 3.40-3.30(m, 1H), 2.86(d, J=5.1Hz, 2H), 1.23(d, J=6.6Hz, 3H), 0.88-0.84(m , 2H), 0.69-0.66 (m, 2H). MS m/z 550.0 [M+H] + .
实施例8:化合物8的制备Example 8: Preparation of Compound 8
Figure PCTCN2022080732-appb-000029
Figure PCTCN2022080732-appb-000029
将化合物8a(1.03g，5.0mmol)溶于N,N-二甲基甲酰胺(10mL)中冷却至0℃，加入钠氢(60％，240mg，6mmol)反应15分钟，加入溴乙酸叔丁酯8b(732mg，6.0mmol)，缓慢升至室温反应16小时。加入饱和碳酸钠水溶液淬灭，水相用乙酸乙酯萃取两次，合并后的有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。所得粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯＝8:2)得到化合物8c(250mg,收率17％)。Compound 8a (1.03 g, 5.0 mmol) was dissolved in N,N-dimethylformamide (10 mL) and cooled to 0 °C, sodium hydrogen (60%, 240 mg, 6 mmol) was added to react for 15 minutes, and tert-butyl bromoacetic acid was added. Ester 8b (732 mg, 6.0 mmol) was slowly warmed to room temperature and reacted for 16 hours. Saturated aqueous sodium carbonate solution was added to quench, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=8:2) to obtain compound 8c (250 mg, yield 17%).
将化合物8c(250mg，0.65mmol)溶于三氟乙酸(2mL)中室温下反应2小时。将反应液减压浓缩，所得粗品经硅胶柱层析纯分离纯化得到化合物8d(140mg，收率82％)。 1H NMR(500MHz,DMSO-d 6)δ12.57(s,1H),7.90-7.78(m,4H),4.50-4.38(m,1H),3.97(d,J＝2.8Hz,2H),3.91(t,J＝9.6Hz,1H),3.68-3.66(m,1H),1.36(d,J＝7.1Hz,3H)ppm。 Compound 8c (250 mg, 0.65 mmol) was dissolved in trifluoroacetic acid (2 mL) and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain compound 8d (140 mg, yield 82%). 1 H NMR (500MHz, DMSO-d 6 ) δ 12.57(s, 1H), 7.90-7.78(m, 4H), 4.50-4.38(m, 1H), 3.97(d, J=2.8Hz, 2H), 3.91 (t, J=9.6 Hz, 1H), 3.68-3.66 (m, 1H), 1.36 (d, J=7.1 Hz, 3H) ppm.
将化合物4b(245mg，1.0mmol)溶于乙醇(5mL)中，加入氯化氢的1,4-二氧六环溶液(4M，0.5mL)和环丙胺(114mg，2.0mmol)，再加入氰基硼氢化钠(126mg，2.0mmol)，在室温下反应16小时。加入饱和碳酸钠水溶液淬灭，水相用乙酸乙酯萃取两次，合并后的有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝10:1)得到化合物8f(140mg，收率50％)。 1H NMR(500MHz,CDCl 3)δ8.45(d,J＝0.6Hz,2H),4.71-4.67(m,2H),3.19-3.03(m,2H),2.93-2.89(m,1H),2.24-2.12(m,1H),2.10-1.95(m,2H),1.35-1.32(m,2H),0.54-0.42(m,2H),0.38-0.27(m,2H)ppm。 Compound 4b (245 mg, 1.0 mmol) was dissolved in ethanol (5 mL), hydrogen chloride in 1,4-dioxane (4 M, 0.5 mL) and cyclopropylamine (114 mg, 2.0 mmol) were added, followed by cyanoboron Sodium hydride (126 mg, 2.0 mmol) was reacted at room temperature for 16 hours. Saturated aqueous sodium carbonate solution was added to quench, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain compound 8f (140 mg, yield 50%). 1 H NMR (500 MHz, CDCl 3 ) δ 8.45 (d, J=0.6 Hz, 2H), 4.71-4.67 (m, 2H), 3.19-3.03 (m, 2H), 2.93-2.89 (m, 1H), 2.24-2.12(m,1H), 2.10-1.95(m,2H), 1.35-1.32(m,2H), 0.54-0.42(m,2H), 0.38-0.27(m,2H)ppm.
将化合物8f(70mg，0.25mmol)溶于N,N-二甲基甲酰胺(1mL)中，加入化合物8d(79mg，0.3mmol)、三乙胺(75mg，0.75mmol)和HATU(140mg，0.37mmol)，在室温下反应16小时。加水淬灭，水相用乙酸乙酯萃取，合并后的有机相经饱和食盐水萃取，无水硫酸钠干燥，过滤，减压浓缩。所得粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯＝3:7)得到化合物8g(80mg，收率60％)。MS m/z 532.7[M+H] + Compound 8f (70 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (1 mL), compound 8d (79 mg, 0.3 mmol), triethylamine (75 mg, 0.75 mmol) and HATU (140 mg, 0.37 mmol) were added mmol) and reacted at room temperature for 16 hours. Water was added to quench, the aqueous phase was extracted with ethyl acetate, the combined organic phases were extracted with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:7) to obtain compound 8g (80 mg, yield 60%). MS m/z 532.7[M+H] +
将化合物8g(40mg，0.075mmol)溶于甲醇(1mL)，加入水和肼(80％，0.1mL)，加热至35℃反应2小时。将反应液减压浓缩，所得粗品经硅胶柱层析分离纯化 (二氯甲烷:甲醇＝10:1，1％氨水)得到化合物8h(20mg，收率66％)。 1H NMR(500MHz,CD 3OD)δ8.54(s,2H),4.96(d,J＝13.6Hz,2H),4.44(d,J＝2.1Hz,2H),4.18-4.07(m,1H),3.65-3.59(m,1H),3.44-3.31(m,2H),2.97(t,J＝12.9Hz,2H),2.71-2.61(br,1H),2.18-2.06(m,2H),1.84-1.77(m,2H),1.21-1.15(m,3H),0.92-0.85(m,2H),0.84-0.77(m,2H)ppm。 Compound 8g (40 mg, 0.075 mmol) was dissolved in methanol (1 mL), water and hydrazine (80%, 0.1 mL) were added, and the mixture was heated to 35° C. to react for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=10:1, 1% ammonia water) to obtain compound 8h (20 mg, yield 66%). 1 H NMR (500MHz, CD 3 OD) δ 8.54 (s, 2H), 4.96 (d, J=13.6 Hz, 2H), 4.44 (d, J=2.1 Hz, 2H), 4.18-4.07 (m, 1H) ),3.65-3.59(m,1H),3.44-3.31(m,2H),2.97(t,J=12.9Hz,2H),2.71-2.61(br,1H),2.18-2.06(m,2H), 1.84-1.77 (m, 2H), 1.21-1.15 (m, 3H), 0.92-0.85 (m, 2H), 0.84-0.77 (m, 2H) ppm.
将化合物8h(10mg，0.025mmol)溶于乙腈(1mL)中，加入化合物b(采用专利US20210024502中的方法合成，10mg，0.03mmol)和三乙胺(12mg，0.12mmol)，室温下反应16小时。将反应液减压浓缩，得到的混合物经硅胶柱层析色谱分离纯化(石油醚:乙酸乙酯＝1:1)得到化合物8i(10mg，收率57％)。 1H NMR(500MHz,CD 3OD)δ8.55(s,2H),8.05(s,1H),5.35(s,2H),4.97(d,J＝13.5Hz,2H),4.42(d,J＝4.4Hz,2H),4.28–4.07(m,2H),3.75–3.64(m,3H),3.61-3.53(m,1H),2.98(t,J＝12.1Hz,2H),2.68-2.57(m,1H),2.14-2.02(m,2H),1.86-1.74(m,2H),1.39-1.26(m,3H),0.94–0.91(m,2H),0.90-0.80(m,4H),0.01(s,9H)ppm。 Compound 8h (10 mg, 0.025 mmol) was dissolved in acetonitrile (1 mL), compound b (synthesized by the method in patent US20210024502, 10 mg, 0.03 mmol) and triethylamine (12 mg, 0.12 mmol) were added, and the reaction was carried out at room temperature for 16 hours . The reaction solution was concentrated under reduced pressure, and the obtained mixture was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain compound 8i (10 mg, yield 57%). 1 H NMR (500MHz, CD 3 OD) δ 8.55(s, 2H), 8.05(s, 1H), 5.35(s, 2H), 4.97(d, J=13.5Hz, 2H), 4.42(d, J =4.4Hz,2H),4.28-4.07(m,2H),3.75-3.64(m,3H),3.61-3.53(m,1H),2.98(t,J=12.1Hz,2H),2.68-2.57( m,1H),2.14-2.02(m,2H),1.86-1.74(m,2H),1.39-1.26(m,3H),0.94-0.91(m,2H),0.90-0.80(m,4H), 0.01(s, 9H) ppm.
将化合物8i(7mg，0.01mmol)溶于三氟乙酸(0.5mL)中，室温下反应1小时。将反应混合物减压浓缩，所得混合物重新溶于二氯甲烷，加入少量氨水调节至碱性，用制备型硅胶薄层板分离纯化(二氯甲烷:甲醇＝20:1)得到目标化合物8(5.13mg,收率90％)。 1H NMR(500MHz,CD 3OD)δ8.54(s,2H),7.99(s,1H),4.96(d,J＝13.5Hz,2H),4.42(d,J＝5.5Hz,2H),4.24–4.07(m,2H),3.68-3.63(m,1H),3.58-3.55(m,1H),2.97(t,J＝12.3Hz,2H),2.63(br,1H),2.14-2.05(m,2H),1.81-1.79(m,2H),1.29(d,J＝6.5Hz,3H),0.89–0.85(m,2H),0.83-0.76(m,2H)ppm。 Compound 8i (7 mg, 0.01 mmol) was dissolved in trifluoroacetic acid (0.5 mL) and reacted at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained mixture was redissolved in dichloromethane, adjusted to basicity by adding a small amount of ammonia water, and separated and purified by preparative silica gel thin-layer plate (dichloromethane:methanol=20:1) to obtain the target compound 8 (5.13 mg, yield 90%). 1 H NMR (500MHz, CD 3 OD) δ8.54(s, 2H), 7.99(s, 1H), 4.96(d, J=13.5Hz, 2H), 4.42(d, J=5.5Hz, 2H), 4.24-4.07(m, 2H), 3.68-3.63(m, 1H), 3.58-3.55(m, 1H), 2.97(t, J=12.3Hz, 2H), 2.63(br, 1H), 2.14-2.05( m, 2H), 1.81-1.79 (m, 2H), 1.29 (d, J=6.5Hz, 3H), 0.89-0.85 (m, 2H), 0.83-0.76 (m, 2H) ppm.
实施例9:化合物9的制备Example 9: Preparation of Compound 9
Figure PCTCN2022080732-appb-000030
Figure PCTCN2022080732-appb-000030
将化合物4b(245mg，1.0mmol)溶于乙醇(5mL)中，加入氯化氢的1,4-二氧六环溶液(4M，0.5mL)和化合物9a(146mg,2.0mmol)，再加入氰基硼氢化钠(126mg，2.0mmol)，在室温下反应16小时。加入饱和碳酸钠水溶液淬灭，用乙酸乙酯萃取，合并后的有机相经饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，混合物 经硅胶柱层析色谱分离纯化(二氯甲烷:甲醇＝10:1)得到化合物9b(70mg,收率23％)。 1H NMR(500MHz,CDCl 3)δ8.47(s,2H),4.85(t,J＝6.9Hz,2H),4.75-4.73(m,2H),4.48(t,J＝6.4Hz,2H),4.15-4.10(m,1H),3.11-2.99(m,2H),2.83-2.79(m,1H),1.91-1.85(m,2H),1.40-1.29(m,2H)ppm。 Compound 4b (245 mg, 1.0 mmol) was dissolved in ethanol (5 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.5 mL) and compound 9a (146 mg, 2.0 mmol) were added, followed by cyanoboron Sodium hydride (126 mg, 2.0 mmol) was reacted at room temperature for 16 hours. Saturated aqueous sodium carbonate solution was added to quench, and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was separated and purified by silica gel column chromatography (dichloromethane:methanol) =10:1) to obtain compound 9b (70 mg, yield 23%). 1 H NMR (500 MHz, CDCl 3 ) δ 8.47 (s, 2H), 4.85 (t, J=6.9 Hz, 2H), 4.75-4.73 (m, 2H), 4.48 (t, J=6.4 Hz, 2H) ,4.15-4.10(m,1H),3.11-2.99(m,2H),2.83-2.79(m,1H),1.91-1.85(m,2H),1.40-1.29(m,2H)ppm.
将化合物9b(50mg,0.166mmol)溶于N,N-二甲基甲酰胺(1mL)中，加入化合物8d(44mg,0.166mmol)、三乙胺(50mg,0.5mmol)，再加入HATU(95mg,0.25mmol)，在室温下反应16小时。加水淬灭，水相用乙酸乙酯萃取，合并后的有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩。混合物经硅胶柱层析分离纯化(石油醚:乙酸乙酯＝3:7)纯化得到化合物9c(50mg,收率55％)。MS m/z 548.6[M+H] +。 Compound 9b (50 mg, 0.166 mmol) was dissolved in N,N-dimethylformamide (1 mL), compound 8d (44 mg, 0.166 mmol), triethylamine (50 mg, 0.5 mmol) were added, and HATU (95 mg) was added , 0.25mmol), and reacted at room temperature for 16 hours. Water was added to quench, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The mixture was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:7) to obtain compound 9c (50 mg, yield 55%). MS m/z 548.6 [M+H] + .
将化合物9c(30mg，0.054mmol)溶于甲醇(1mL)中，加入水合肼(80％水溶液，0.1mL)后加热至35℃反应16小时。将反应混合物加压浓缩，得到的混合物经硅胶柱层析分离纯化(二氯甲烷:甲醇＝10:1)纯化得到化合物9d(8mg，收率40％)。MS m/z 418.5[M+H] +。 Compound 9c (30 mg, 0.054 mmol) was dissolved in methanol (1 mL), hydrazine hydrate (80% aqueous solution, 0.1 mL) was added, and the reaction was heated to 35° C. for 16 hours. The reaction mixture was concentrated under pressure, and the obtained mixture was separated and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain compound 9d (8 mg, yield 40%). MS m/z 418.5 [M+H] + .
将化合物9d(5mg，粗产品)溶于乙腈(1mL)中，加入化合物b(4mg，0.12mmol)和三乙胺(6mg，0.06mmol)，室温下反应16小时。加水淬灭，水相用乙酸乙酯萃取两次，合并后的有机相经饱和食盐水洗涤，加无水硫酸钠干燥，过滤，减压浓缩。粗品经制备型硅胶薄层板分离纯化(石油醚:乙酸乙酯＝1:1)得到化合物9e(4mg,收率73％)。将化合物9e(2.0mg，0.03mmol)溶于四正丁基氟化铵(0.5mL)中，滴加一滴乙二胺，置于封管中加热至85℃反应5小时。反应混合物减压浓缩后经制备型硅胶薄层板分离纯化(石油醚:乙酸乙酯＝1:3)得到目标化合物9(0.67mg，收率40％)。MS m/z 580.5[M+H] +。 Compound 9d (5 mg, crude product) was dissolved in acetonitrile (1 mL), compound b (4 mg, 0.12 mmol) and triethylamine (6 mg, 0.06 mmol) were added, and the reaction was carried out at room temperature for 16 hours. Water was added to quench, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by preparative silica gel thin-layer plate (petroleum ether:ethyl acetate=1:1) to obtain compound 9e (4 mg, yield 73%). Compound 9e (2.0 mg, 0.03 mmol) was dissolved in tetra-n-butylammonium fluoride (0.5 mL), a drop of ethylenediamine was added dropwise, and the mixture was placed in a sealed tube and heated to 85° C. to react for 5 hours. The reaction mixture was concentrated under reduced pressure and separated and purified by preparative silica gel thin-layer plate (petroleum ether:ethyl acetate=1:3) to obtain the target compound 9 (0.67 mg, yield 40%). MS m/z 580.5 [M+H] + .
实施例10:化合物10的制备Example 10: Preparation of Compound 10
Figure PCTCN2022080732-appb-000031
Figure PCTCN2022080732-appb-000031
将化合物3e(1g，5.71mmol)、化合物10a(2.39g，11.41mmol)和四丁基硫酸氢铵(186mg，0.57mmol)溶于氢氧化钠溶液(25％，9.13g)中，反应混合液65℃下搅拌过夜。待反应完毕后，加入乙酸乙酯稀释。混合液经乙酸乙酯萃取(3×30mL)。合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤后减压浓缩。所得粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯＝5:1)得到黄色油状产物10b(750mg，收率43％)。MS m/z 326.0[M+Na] +。 Compound 3e (1 g, 5.71 mmol), compound 10a (2.39 g, 11.41 mmol) and tetrabutylammonium hydrogen sulfate (186 mg, 0.57 mmol) were dissolved in sodium hydroxide solution (25%, 9.13 g), the reaction mixture was Stir overnight at 65°C. After the reaction was completed, ethyl acetate was added for dilution. The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain yellow oily product 10b (750 mg, yield 43%). MS m/z 326.0 [M+Na] + .
将化合物10b(750mg，2.47mmol)溶于二氯甲烷(6mL)中，加入三氟乙酸(3mL)，反应混合液室温下搅拌1小时。待反应完毕，反应液减压浓缩得到粗品产物10c直接进行下一步反应。MS m/z 120.0[M+H] +。 Compound 10b (750 mg, 2.47 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (3 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product 10c, and the next step was carried out directly. MS m/z 120.0 [M+H] + .
将粗品10c(理论产量：295mg，2.47mmol)和化合物b(814mg，2.47mmol)溶于乙腈(8mL)中，再加入N,N-二异丙基乙胺(960mg，7.43mmol)，反应混合液40℃下搅拌1小时。待反应完毕，反应液减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:乙酸乙酯＝6:1)得到黄色油状产物10d(390mg，收率38％)。MS m/z434.0[M+Na] +。 Crude product 10c (theoretical yield: 295 mg, 2.47 mmol) and compound b (814 mg, 2.47 mmol) were dissolved in acetonitrile (8 mL), and N,N-diisopropylethylamine (960 mg, 7.43 mmol) was added, and the reaction was mixed The solution was stirred at 40 °C for 1 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:ethyl acetate=6:1) to obtain yellow oily product 10d (390 mg, yield 38%). MS m/z 434.0 [M+Na] + .
氮气保护下，将化合物10d(50mg，0.12mmol)溶于二氯甲烷(2mL)中，加入戴斯马丁氧化剂(103mg，0.24mmol)，反应混合液室温下搅拌1小时。待反应完毕，依次加入饱和碳酸钠溶液和饱和亚硫酸钠溶液。混合液经二氯甲烷萃取(3×15mL)。合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤后减压浓缩。所得粗品产物10e直接进行下一步反应。Under nitrogen protection, compound 10d (50 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), Dess Martin oxidant (103 mg, 0.24 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, saturated sodium carbonate solution and saturated sodium sulfite solution were added in sequence. The mixture was extracted with dichloromethane (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product 10e was directly subjected to the next reaction.
将粗品10e(理论产量：50mg，0.12mmol)和10f(采用WO2016077375中的方法合成，30mg，0.12mmol)溶于二氯甲烷(3mL)中，加入乙酸(7mg，0.12mmol)后反应液在室温下搅拌1小时。将反应液置于0℃下，加入三乙酰氧基硼氢化钠(78mg，0.37mmol)，反应液在室温下再搅拌30分钟。待反应完毕，加水淬灭。混合液经二氯甲烷萃取(3×15mL)。合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤后减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1)得到无色油状产物10g(3mg，收率4％)。MS m/z 640.6[M+H] +。 Crude product 10e (theoretical yield: 50 mg, 0.12 mmol) and 10f (synthesized by the method in WO2016077375, 30 mg, 0.12 mmol) were dissolved in dichloromethane (3 mL), and acetic acid (7 mg, 0.12 mmol) was added to the reaction solution at room temperature. under stirring for 1 hour. The reaction solution was placed at 0°C, sodium triacetoxyborohydride (78 mg, 0.37 mmol) was added, and the reaction solution was stirred at room temperature for an additional 30 minutes. After the reaction was completed, water was added to quench. The mixture was extracted with dichloromethane (3 x 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain 10 g (3 mg, yield 4%) of a colorless oily product. MS m/z 640.6 [M+H] + .
冰水浴条件下，将化合物10g(3mg，0.005mmol)溶于二氯甲烷(1.5mL)中，加入N,N-二异丙基乙胺(2mg，0.014mmol)后搅拌。再缓慢滴加乙酰氯10h(0.4mg，0.005mmol)的二氯甲烷稀释液(1mL)。反应液在室温下搅拌15分钟。待反应完毕，加少量甲醇淬灭。混合液减压浓缩。所得粗品经制备型薄层色谱分离纯化(二氯甲烷:甲醇＝20:1)得到白色固体产物10i(2mg，收率63％)。MS m/z 682.2[M+H] +。 Under ice-water bath conditions, 10 g of the compound (3 mg, 0.005 mmol) was dissolved in dichloromethane (1.5 mL), N,N-diisopropylethylamine (2 mg, 0.014 mmol) was added, and the mixture was stirred. A dichloromethane dilution (1 mL) of acetyl chloride for 10 h (0.4 mg, 0.005 mmol) was slowly added dropwise. The reaction solution was stirred at room temperature for 15 minutes. After the reaction was completed, a small amount of methanol was added to quench. The mixture was concentrated under reduced pressure. The obtained crude product was separated and purified by preparative thin layer chromatography (dichloromethane:methanol=20:1) to obtain white solid product 10i (2 mg, yield 63%). MS m/z 682.2 [M+H] + .
将化合物10i(2mg,0.003mmol)溶于二氯甲烷(1mL)中，加入三氟乙酸(0.2mL)，反应混合液室温下搅拌20分钟。反应液减压浓缩后，再溶于甲醇(1mL)中，滴加2滴氨水，室温下搅拌2分钟。待反应完毕，反应液减压浓缩。所得粗品经制备型薄层色谱分离纯化(二氯甲烷:甲醇＝20:1)得到白色固体产物10(1mg，收率62％)。MS m/z 552.1[M+H] +。 Compound 10i (2 mg, 0.003 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.2 mL) was added, and the reaction mixture was stirred at room temperature for 20 minutes. After the reaction solution was concentrated under reduced pressure, it was redissolved in methanol (1 mL), 2 drops of ammonia water were added dropwise, and the mixture was stirred at room temperature for 2 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained crude product was separated and purified by preparative thin layer chromatography (dichloromethane:methanol=20:1) to obtain white solid product 10 (1 mg, yield 62%). MS m/z 552.1 [M+H] + .
实施例11:化合物11的制备Example 11: Preparation of Compound 11
Figure PCTCN2022080732-appb-000032
Figure PCTCN2022080732-appb-000032
化合物11的合成参照化合物10的合成方法，由化合物10g得到化合物11(0.8mg,白色固体)。 1H NMR(500MHz,CD 3OD)δ8.54(s,2H),7.91(s,1H),6.19(dd,J＝16.7,1.8Hz,1H),5.77-5.63(m,2H),4.97(d,J＝12.5Hz,2H),4.45-4.35(m,1H),4.23-4.08(m,2H),3.64-3.46(m,5H),3.04-2.92(m,2H),2.06-1.99(m,1H),1.95-1.82(m,1H),1.81-1.74(m,2H),1.23(d,J＝5.7Hz,3H)ppm。MS m/z 564.0[M+H] +。 Synthesis of compound 11 Referring to the synthesis method of compound 10, compound 11 (0.8 mg, white solid) was obtained from compound 10 g. 1 H NMR (500MHz, CD 3 OD) δ 8.54 (s, 2H), 7.91 (s, 1H), 6.19 (dd, J=16.7, 1.8 Hz, 1H), 5.77-5.63 (m, 2H), 4.97 (d, J＝12.5Hz, 2H), 4.45-4.35(m, 1H), 4.23-4.08(m, 2H), 3.64-3.46(m, 5H), 3.04-2.92(m, 2H), 2.06-1.99 (m, 1H), 1.95-1.82 (m, 1H), 1.81-1.74 (m, 2H), 1.23 (d, J=5.7Hz, 3H) ppm. MS m/z 564.0 [M+H] + .
实施例12:PARP7酶抑制活性测试Example 12: PARP7 enzyme inhibitory activity test
准备组蛋白包被的384孔板：将25μL组蛋白溶液加入到384孔板中，4℃孵育过夜。使用PBST溶液洗组蛋白包被好的384孔板三次，每孔添加50μL封闭溶液，室温下封闭1小时，然后用PBST溶液洗三次384孔板。将化合物用100％的DMSO配置成10mM的储液，并按照一定的浓度梯度稀释。将5μL化合物转移到384孔板中。准备PARP7酶溶液((BPS,Cat.No.80527))，25℃孵育十分钟。转移10μL酶溶液到384孔板中，和化合物一起在室温下孵育十分钟。加入10μL 2.5x的Biotin-NAD+(R&D,Cat.No.6573)到每个孔中，25℃孵育60分钟。使用PBST溶液洗384孔板三次。加入20μL抗多聚/单-ADP核糖兔单抗，在室温下孵育1.5小时，使用PBST溶液洗三次。再加入20μL 1:2000稀释的辣根过氧化物酶连接的抗兔IgG，室温下孵育1小时。使用PBST溶液洗384孔板三次。加入25μL 1:1混合的Femto-ECL底物A和Femto-ECL底物B(THERMO PIERCE,Cat.No.37074)，立即用Envision读取荧光数值。在Excel中使用公式inhibition％＝(Max-Signal)/(Max-Min)*100计算化合物的抑制率。其中max是指DMSO对照的数值，min是指无酶活对照的数值。使用XL-Fit软件拟合曲线并计算IC 50。公式为：Y＝Bottom+(Top-Bottom)/(1+(IC 50/X)*HillSlope)。Y是百分比抑制率，X是化合物的浓度。部分代表性化合物的活性如表1所示。 Prepare histone-coated 384-well plate: Add 25 μL of histone solution to the 384-well plate and incubate at 4°C overnight. The histone-coated 384-well plate was washed three times with PBST solution, 50 μL of blocking solution was added to each well, blocked for 1 hour at room temperature, and then the 384-well plate was washed three times with PBST solution. Compounds were prepared as 10 mM stock solutions in 100% DMSO and diluted according to a certain concentration gradient. Transfer 5 μL of compound to a 384-well plate. PARP7 enzyme solution ((BPS, Cat. No. 80527)) was prepared and incubated at 25°C for ten minutes. Transfer 10 μL of enzyme solution to a 384-well plate and incubate with compounds for ten minutes at room temperature. 10 μL of 2.5x Biotin-NAD+ (R&D, Cat. No. 6573) was added to each well and incubated at 25°C for 60 minutes. Wash the 384-well plate three times with PBST solution. Add 20 μL of anti-poly/mono-ADP ribose rabbit mAb, incubate for 1.5 hours at room temperature, and wash three times with PBST solution. Then 20 μL of 1:2000 diluted horseradish peroxidase-conjugated anti-rabbit IgG was added and incubated for 1 hour at room temperature. Wash the 384-well plate three times with PBST solution. 25 μL of a 1:1 mixture of Femto-ECL Substrate A and Femto-ECL Substrate B (THERMO PIERCE, Cat. No. 37074) was added and the fluorescence values were read immediately with the Envision. Inhibition of compounds was calculated in Excel using the formula inhibition%=(Max-Signal)/(Max-Min)*100. where max refers to the value of DMSO control, and min refers to the value of no enzyme activity control. Curves were fitted and IC50 calculated using XL-Fit software. The formula is: Y=Bottom+(Top-Bottom)/(1+( IC50 /X)*HillSlope). Y is the percent inhibition and X is the concentration of the compound. The activities of some representative compounds are shown in Table 1.
表1 PARP7酶抑制活性Table 1 PARP7 enzyme inhibitory activity
化合物compound IC 50或抑制率 IC50 or inhibition rate
11 12.5nM的抑制率为95％95% inhibition at 12.5nM
33 IC 50<1nM IC50 <1nM
77 12.5nM的抑制率为70％70% inhibition at 12.5nM
88 IC 50<1nM IC50 <1nM
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (16)

  1. 一种如下式(I)所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物：A compound of the structure shown in the following formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate:
    Figure PCTCN2022080732-appb-100001
    Figure PCTCN2022080732-appb-100001
    式(I)中：In formula (I):
    A选自-NR 3-、-O-、-CR 4R 5-、或3-至8-元杂环基；其中，R 3选自氢或C 1-4烷基；R 4和R 5各自独立地选自氢、卤素、或C 1-4烷基； A is selected from -NR 3 -, -O-, -CR 4 R 5 -, or 3- to 8-membered heterocyclyl; wherein, R 3 is selected from hydrogen or C 1-4 alkyl; R 4 and R 5 each independently selected from hydrogen, halogen, or C 1-4 alkyl;
    B选自-CR 6R 7-或化学键；其中，R 6和R 7各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4卤代烷氧基C 1-4烷基、羟基C 1-4烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、4-至8-元杂环基、或4-至8-元杂环基C 1-4烷基；或R 6和R 7与其连接的碳原子一起形成3-至-6元的环烷基、或4-至8-元的杂环基，此杂环基含有1或2个选自N、O、S的杂原子； B is selected from -CR 6 R 7 - or a chemical bond; wherein, R 6 and R 7 are each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy C 1-4 alkyl, C 1-4 haloalkoxy C 1-4 alkyl, hydroxy C 1-4 alkyl, C 3-6 cycloalkane group, C 3-6 cycloalkyl C 1-4 alkyl, 4- to 8-membered heterocyclyl, or 4- to 8-membered heterocyclyl C 1-4 alkyl; or R 6 and R 7 and their The attached carbon atoms together form a 3- to -6-membered cycloalkyl group, or a 4- to 8-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S;
    D选自-(CR 8R 9) p-Y-(CR 10R 11) q-；其中，Y选自-O-、-NR 12-、-CR 13R 14-、C 3-6环烷基、3-至8-元杂环基、芳基、或杂芳基；p和q各自独立地选自0、1、2、3、4、或5；各个R 8和R 9各自独立地选自氢、卤素、羟基、或C 1-4烷基；各个R 10和R 11各自独立地选自氢、卤素、羟基、或C 1-4烷基；或R 8和R 9与其连接的碳原子、或R 10和R 11与其连接的碳原子一起形成3-至-6元的环烷基、或4-至8-元的杂环基，此杂环基含有1或2个选自N、O、S的杂原子；R 12选自氢、C 1-4烷基、C 3-6环烷基、或4-至8-元的杂环基；R 13和R 14各自独立地选自氢、卤素、或C 1-4烷基；或R 13和R 14与其连接的碳原子一起形成3-至-6元的环烷基、或4-至8-元的杂环基，此杂环基含有1或2个选自N、O、S的杂原子； D is selected from -(CR 8 R 9 ) p -Y-(CR 10 R 11 ) q -; wherein, Y is selected from -O-, -NR 12 -, -CR 13 R 14 -, C 3-6 cycloalkane radical, 3- to 8-membered heterocyclyl, aryl, or heteroaryl; p and q are each independently selected from 0, 1, 2, 3, 4, or 5; each R8 and R9 are each independently selected from hydrogen, halogen, hydroxy, or C 1-4 alkyl; each R 10 and R 11 are each independently selected from hydrogen, halogen, hydroxy, or C 1-4 alkyl; or to which R 8 and R 9 are attached Carbon atoms, or R 10 and R 11 together with the carbon atoms to which they are attached form a 3- to -6-membered cycloalkyl group, or a 4- to 8-membered heterocyclic group, the heterocyclic group contains 1 or 2 members selected from the group consisting of A heteroatom of N, O, S; R 12 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or a 4- to 8-membered heterocyclic group; R 13 and R 14 are each independently is selected from hydrogen, halogen, or C 1-4 alkyl; or R 13 and R 14 together with the carbon atom to which they are attached form a 3- to -6-membered cycloalkyl, or a 4- to 8-membered heterocyclyl, This heterocyclyl group contains 1 or 2 heteroatoms selected from N, O, S;
    E选自化学键或-C(O)-；E is selected from chemical bonds or -C(O)-;
    F选自化学键或-NR b-；其中，R b选自氢、C 1-4烷基、C 1-4烷氧基C 1-4烷基、C 3-6环烷基、4-至8-元的杂环基、芳基、杂芳基、C(O)R c、或S(O) 2R c；或R b与R 10或R 11及其相连接的氮原子、碳原子及E一起形成4-至8-元的杂环基，此杂环基含有1个N原子和0或1个选自N、O、S的杂原子；R c选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、或4-至8-元的杂环基；R b或R c中所述的烷基、烯基、炔基、环烷基、杂环基、芳基、和杂芳基任选地被一个或多个选自下组的取代基取代：卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、4-至8-元的杂环基、NR dR d、CN、OR d、SR d、C(O)R t、或S(O) 2R t；各个R d各自独立为氢或C 1-4烷基；R t选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基、芳基、或杂芳基； F is selected from chemical bonds or -NR b -; wherein, R b is selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 8-membered heterocyclic group, aryl group, heteroaryl group, C(O)R c , or S(O) 2 R c ; or R b and R 10 or R 11 and the nitrogen atom and carbon atom to which they are connected together with E to form a 4- to 8-membered heterocyclic group, this heterocyclic group contains 1 N atom and 0 or 1 heteroatom selected from N, O, S; R c is selected from C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4- to 8- membered heterocyclic group; the alkyl, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, C1-4alkyl , C2-4alkenyl , C 2-4 alkynyl, C 3-6 cycloalkyl, 4- to 8-membered heterocyclyl, NR d R d , CN, OR d , SR d , C(O)R t , or S( O) 2 R t ; each R d is independently hydrogen or C 1-4 alkyl; R t is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclyl, aryl, or heteroaryl;
    G选自N或CR e；其中，R e选自氢或C 1-4烷基； G is selected from N or CR e ; wherein, R e is selected from hydrogen or C 1-4 alkyl;
    各个R a各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4卤代烯基、C 2-4炔基、C 2-4卤代炔基、羟基、羟基C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氧基C 1-4烷基、NR hR h、CN；各个R h各自独立为氢、或C 1-4烷基；或两个R h与其连接的氮原子一起形成3-至-8元杂环基，此杂环基含有1或2个N原子以及0或1个选自O、S的杂原 子；或连接在同一个碳原子上的二个R a与碳原子一起共同形成C＝M；其中，M选自O或CR jR k；其中，R j和R k各自独立地选自下组：氢、卤素、或C 1-4烷基；或连接在不同碳原子上的二个R a连接在一起形成桥环结构； Each R is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl, hydroxy, hydroxy C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy C 1-4 alkyl, NR h R h , CN; each R h is independently hydrogen, or C 1-4 alkyl; or two R h and the nitrogen atom to which they are attached together form a 3- to -8 membered heterocyclyl group containing 1 or 2 N atoms and 0 or 1 heteroatom selected from O, S; or two R a connected to the same carbon atom together with the carbon atom to form C=M; wherein, M is selected from O or CR j R k ; wherein, R j and R k are each independently selected from the group consisting of hydrogen, halogen, or C 1-4 alkyl; or two R a connected to different carbon atoms are connected together to form a bridged ring structure;
    T选自N或CR 15；其中，R 15选自氢、卤素、或C 1-4烷基； T is selected from N or CR 15 ; wherein, R 15 is selected from hydrogen, halogen, or C 1-4 alkyl;
    X和Z各自独立地选自N或CR；X and Z are each independently selected from N or CR;
    各个R各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4卤代烯基、C 2-4炔基、C 2-4卤代炔基、C 3-6环烷基炔基、3-至8-元杂环基炔基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氧基C 1-4烷基、C 1-4卤代烷氧基C 1-4烷基、C 3-6环烷基、3-至8-元杂环基、NR hR h、CN、NO 2、SR h、C(O)R t、C(O)OR h、C(O)NR hR h、NR hC(O)R t、NR hS(O) 2R t、或S(O) 2R t；其中，R h和R t的定义如上所述； Each R is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2 -4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy Oxy C 1-4 alkyl, C 1-4 haloalkoxy C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, NR h Rh , CN, NO 2 , SR h , C(O)R t , C(O)OR h , C(O)NR h Rh , NR h C(O)R t , NR h S(O) 2 R t , or S(O ) 2 R t ; wherein, Rh and R t are as defined above;
    R 1选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4卤代烯基、C 2-4炔基、C 2-4卤代炔基、C 3-6环烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氧基C 1-4烷基、或C 1-4卤代烷氧基C 1-4烷基； R 1 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 halo Alkynyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy, C 1-4 alkyl, or C 1-4 haloalkoxy C 1-4 alkyl;
    R 2选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基； R 2 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl;
    m和n各自独立地选自0、1、或2；m and n are each independently selected from 0, 1, or 2;
    k选自0、1、或2；k is selected from 0, 1, or 2;
    h选自0、1、2、3、或4；h is selected from 0, 1, 2, 3, or 4;
    或式(I)中结构片段
    Figure PCTCN2022080732-appb-100002
    选自下式：     or structural fragment in formula (I)
    Figure PCTCN2022080732-appb-100002
    selected from the following formula:
    Figure PCTCN2022080732-appb-100003
    Figure PCTCN2022080732-appb-100003
    其中，d选自0、1、或2；e选自1、2、3、或4；wherein, d is selected from 0, 1, or 2; e is selected from 1, 2, 3, or 4;
    其中，除非特别说明，各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR h、SR h、NR hR h、C(O)R t、C(O)OR h、C(O)NR hR h、NR hC(O)R t、NR hS(O) 2R t、或S(O) 2R t，前提条件是所形成的化学结构是稳定的和有意义的；其中，R h和R t的定义如上所述； wherein, unless otherwise specified, each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups is optionally and each independently selected from 1-3 groups each independently selected from the following Substituent substitution of the group: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- to 8-membered Heterocyclyl, aryl, heteroaryl, CN, NO2, ORh , SRh , NRhRh , C(O) Rt , C(O ) ORh , C ( O ) NRhRh , NR h C(O)R t , NR h S(O) 2 R t , or S(O) 2 R t , provided that the chemical structure formed is stable and meaningful; where Rh and R t is defined as above;
    除非特别说明，上述的芳基为含有6-12个碳原子的芳香基团；杂芳基为5-至15-元(优选为5-至12-元)杂芳香基团；环状结构为饱和的或不饱和的、含杂原子或不含杂原子的环状基团。Unless otherwise specified, the above-mentioned aryl group is an aromatic group containing 6-12 carbon atoms; the heteroaryl group is a 5- to 15-membered (preferably 5- to 12-membered) heteroaromatic group; the cyclic structure is Saturated or unsaturated, heteroatom-containing or heteroatom-free cyclic groups.
  2. 如权利要求1所述的化合物，其特征在于，式(I)为式(IIA)：The compound of claim 1, wherein formula (I) is formula (IIA):
    Figure PCTCN2022080732-appb-100004
    Figure PCTCN2022080732-appb-100004
    Q选自-NR 16-、-O-、-CR 17R 18-；其中，R 16选自氢、C 1-4烷基、C 3-6环烷基、3-至8-元杂环基、芳基、杂芳基、C(O)R t、或S(O) 2R t；R 17和R 18各自独立地选自氢、卤素、或C 1-4烷基； Q is selected from -NR 16 -, -O-, -CR 17 R 18 -; wherein, R 16 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocycle R 17 and R 18 are each independently selected from hydrogen , halogen , or C 1-4 alkyl;
    f和g各自独立地选自0、1、或2；前提条件是f和g不能同时为0；f and g are each independently selected from 0, 1, or 2; provided that f and g cannot be 0 at the same time;
    j和t各自独立地选自0、1、或2；j and t are each independently selected from 0, 1, or 2;
    其它各基团的定义如权利要求1所述。The definitions of other groups are as described in claim 1 .
  3. 如权利要求1所述的化合物，其特征在于，式(I)为式(IIIA)：The compound of claim 1, wherein formula (I) is formula (IIIA):
    Figure PCTCN2022080732-appb-100005
    Figure PCTCN2022080732-appb-100005
    p选自0、1、或2；p is selected from 0, 1, or 2;
    j和t各自独立地选自0、1、或2；j and t are each independently selected from 0, 1, or 2;
    其它各基团的定义如权利要求1所述。The definitions of other groups are as described in claim 1 .
  4. 如权利要求1所述的化合物，其特征在于，式(I)为式(IVA)：The compound of claim 1, wherein formula (I) is formula (IVA):
    Figure PCTCN2022080732-appb-100006
    Figure PCTCN2022080732-appb-100006
    R 6和R 7各自独立地选自氢、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基C 1-4烷基、C 1-4烷氧基C 1-4烷基、羟基C 1-4烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、4-至8-元杂环基、或4-至8-元杂环基C 1-4烷基； R 6 and R 7 are each independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy C 1-4 alkyl, C 1-4 alkoxy C 1- 4 alkyl, hydroxy C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 alkyl, 4- to 8-membered heterocyclyl, or 4- to 8- membered heterocyclyl C 1-4 alkyl;
    p选自0、1、或2；p is selected from 0, 1, or 2;
    j和t各自独立地选自0、1、或2；j and t are each independently selected from 0, 1, or 2;
    其它各基团的定义如权利要求1所述。The definitions of other groups are as described in claim 1 .
  5. 如权利要求1所述的化合物，其特征在于，式(I)为式(VA)：The compound of claim 1, wherein formula (I) is formula (VA):
    Figure PCTCN2022080732-appb-100007
    Figure PCTCN2022080732-appb-100007
    R b的定义如权利要求1所述； The definition of R b is as described in claim 1;
    各基团的定义如权利要求4所述。The definition of each group is as described in claim 4 .
  6. 如权利要求1所述的化合物，其特征在于，式(I)为式(VIA)：The compound of claim 1, wherein formula (I) is formula (VIA):
    Figure PCTCN2022080732-appb-100008
    Figure PCTCN2022080732-appb-100008
    R b选自C 3-6环烷基、4-至8-元的杂环基、芳基、或杂芳基；所述的环烷基、杂环基、芳基、和杂芳基任选地被一个或多个选自下组的取代基取代：卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、4-至8-元的杂环基、NR dR d、CN、OR d、SR d、C(O)R t、或S(O) 2R t；其中，R t选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、或4-至8-元的杂环基；各个R d各 自独立为氢或C 1-4烷基； R b is selected from C 3-6 cycloalkyl, 4- to 8-membered heterocyclyl, aryl, or heteroaryl; the cycloalkyl, heterocyclyl, aryl, and heteroaryl are any optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 4- to 8-membered heterocyclyl, NR d R d , CN, OR d , SR d , C(O)R t , or S(O) 2 R t ; wherein R t is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4- to 8-membered heterocyclyl; each R d is independently hydrogen or C 1-4 alkyl;
    q选自0、1、2、或3；q is selected from 0, 1, 2, or 3;
    其它各基团的定义如权利要求4所述。The definitions of other groups are as described in claim 4 .
  7. 如权利要求1所述的化合物，其特征在于，式(I)为式(VIIA)：The compound of claim 1, wherein formula (I) is formula (VIIA):
    Figure PCTCN2022080732-appb-100009
    Figure PCTCN2022080732-appb-100009
    R c选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、或4-至8-元的杂环基；所述的烷基、烯基、炔基、环烷基和杂环基任选地被一个或多个选自下组的取代基取代：卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、4-至8-元的杂环基、NR dR d、CN、OR d、SR d、C(O)R t、或S(O) 2R t； R c is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4- to 8-membered heterocyclyl; the alkyl , alkenyl, alkynyl, cycloalkyl and heterocyclyl optionally substituted with one or more substituents selected from the group consisting of halogen, C1-4alkyl , C2-4alkenyl , C2- 4alkynyl , C3-6cycloalkyl , 4- to 8-membered heterocyclyl, NRdRd , CN, ORd , SRd , C ( O) Rt , or S(O ) 2R t ;
    j选自0、1、或2；j is selected from 0, 1, or 2;
    其它各基团的定义如权利要求4所述。The definitions of other groups are as described in claim 4 .
  8. 如权利要求1所述的化合物，其特征在于，式(I)为式(VIIIA)：The compound of claim 1, wherein formula (I) is formula (VIIIA):
    Figure PCTCN2022080732-appb-100010
    Figure PCTCN2022080732-appb-100010
    R 1选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 2-4炔基； R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
    R 2选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4炔基； R 2 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl;
    R 8、R 9、R 10、R 11各自独立地选自氢、羟基、C 1-4烷基； R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, hydroxy, and C 1-4 alkyl;
    X选自N或CR；X is selected from N or CR;
    R各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4炔基、C 2-4卤代炔基、C 3-6环烷基炔基、3-至8-元杂环基炔基、C 1-4烷氧基、C 1-4卤代烷氧基、C 3-6环烷基、3-至8-元杂环基、CN。 R is each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, CN.
  9. 如权利要求1所述的化合物，其特征在于，式(I)为式(IXA)：The compound of claim 1, wherein formula (I) is formula (IXA):
    Figure PCTCN2022080732-appb-100011
    Figure PCTCN2022080732-appb-100011
    R 1选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 2-4炔基； R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
    R 2选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4炔基； R 2 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl;
    R 6和R 7各自独立地选自氢、C 1-4烷基； R 6 and R 7 are each independently selected from hydrogen, C 1-4 alkyl;
    R 8、R 9、R 10、R 11各自独立地选自氢、羟基、C 1-4烷基； R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, hydroxy, and C 1-4 alkyl;
    X选自N或CR；X is selected from N or CR;
    R各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4炔基、C 2-4卤代炔基、C 3-6环烷基炔基、3-至8-元杂环基炔基、C 1-4烷氧基、C 1-4卤代烷氧基、C 3-6环烷基、3-至8-元杂环基、CN。 R is each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, CN.
  10. 如权利要求1所述的化合物，其特征在于，式(I)为式(XA)：The compound of claim 1, wherein formula (I) is formula (XA):
    Figure PCTCN2022080732-appb-100012
    Figure PCTCN2022080732-appb-100012
    R b选自C 3-6环烷基、4-至8-元的杂环基、芳基、或杂芳基；所述的环烷基、杂环基、芳基、和杂芳基任选地被一个或多个选自下组的取代基取代：卤素、C 1-4烷基、NR dR d、CN、OR d、C(O)R t、或S(O) 2R t；其中，R t选自C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、或4-至8-元的杂环基；各个R d各自独立为氢或C 1-4烷基； R b is selected from C 3-6 cycloalkyl, 4- to 8-membered heterocyclyl, aryl, or heteroaryl; the cycloalkyl, heterocyclyl, aryl, and heteroaryl are any optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-4 alkyl, NR d R d , CN, OR d , C(O)R t , or S(O) 2 R t ; wherein, R t is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, or 4- to 8-membered heterocyclyl; each R d is each independently hydrogen or C 1-4 alkyl;
    R 1选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 2-4炔基； R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
    R 2选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4炔基； R 2 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl;
    R 6和R 7各自独立地选自氢、C 1-4烷基；R 8、R 9、R 10、R 11各自独立地选自氢、羟基、C 1- 4烷基；或 R 6 and R 7 are each independently selected from hydrogen, C 1-4 alkyl; R 8 , R 9 , R 10 , R 11 are each independently selected from hydrogen, hydroxyl, C 1-4 alkyl ; or
    R 6和R 7与其连接的碳原子、R 8和R 9与其连接的碳原子、或R 10和R 11与其连接的碳原子一起形成3-至-6元的环烷基、或4-至8-元的杂环基，此杂环基含有1或2个选自N、O、S的杂原子； The carbon atom to which R 6 and R 7 are attached, the carbon atom to which R 8 and R 9 are attached, or the carbon atom to which R 10 and R 11 are attached together form a 3- to -6-membered cycloalkyl, or a 4- to 8-membered heterocyclic group, this heterocyclic group contains 1 or 2 heteroatoms selected from N, O, S;
    X选自N或CR；X is selected from N or CR;
    R各自独立地选自氢、卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4炔基、C 2-4卤代炔基、C 3-6环烷基炔基、3-至8-元杂环基炔基、C 1-4烷氧基、C 1-4卤代烷氧基、C 3-6环烷基、3-至8-元杂环基、CN。 R is each independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, CN.
  11. 如权利要求1-10任一所述的化合物，其特征在于，The compound of any one of claims 1-10, wherein
    R 1选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 2-4炔基；R 2为H； R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl; R 2 is H;
    X选自N或CH；X is selected from N or CH;
    R各自独立地选自三氟甲基、CN、C 2-4炔基、C 3-6环烷基炔基、3-至8-元杂环基炔基、C 3-6环烷基。 R is each independently selected from trifluoromethyl, CN, C2-4alkynyl , C3-6cycloalkylalkynyl , 3- to 8-membered heterocyclylalkynyl, C3-6cycloalkyl .
  12. 如权利要求1所述的化合物，其特征在于，式(I)为式(XIA)：The compound of claim 1, wherein formula (I) is formula (XIA):
    Figure PCTCN2022080732-appb-100013
    Figure PCTCN2022080732-appb-100013
    R 1选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 2-4炔基； R 1 is selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 2-4 alkynyl;
    R 2选自氢； R 2 is selected from hydrogen;
    R 6和R 7各自独立地选自氢、C 1-4烷基； R 6 and R 7 are each independently selected from hydrogen, C 1-4 alkyl;
    R 8、R 9、R 10、R 11各自独立地选自氢、羟基、C 1-4烷基； R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, hydroxy, and C 1-4 alkyl;
    或R 6和R 7与其连接的碳原子、R 8和R 9与其连接的碳原子、或R 10和R 11与其连接的碳原子一起形成3-至-6元的环烷基、或4-至8-元的杂环基，此杂环基含有1或2个选自N、O、S的杂原子； or the carbon atom to which R 6 and R 7 are attached, the carbon atom to which R 8 and R 9 are attached, or the carbon atom to which R 10 and R 11 are attached together to form a 3- to -6-membered cycloalkyl, or a 4- to an 8-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S;
    X选自N或CH；X is selected from N or CH;
    R各自独立地选自C 2-4炔基、C 2-4卤代炔基、C 3-6环烷基炔基、3-至8-元杂环基炔基、C 3-6环烷基、3-至8-元杂环基。 R is each independently selected from C 2-4 alkynyl, C 2-4 haloalkynyl, C 3-6 cycloalkylalkynyl, 3- to 8-membered heterocyclylalkynyl, C 3-6 cycloalkane base, 3- to 8-membered heterocyclyl.
  13. 如权利要求1所述的任一化合物，其特征在于，所述的式(I)化合物选自下组：Any compound as claimed in claim 1, is characterized in that, described compound of formula (I) is selected from following group:
    Figure PCTCN2022080732-appb-100014
    Figure PCTCN2022080732-appb-100014
    Figure PCTCN2022080732-appb-100015
    Figure PCTCN2022080732-appb-100015
    Figure PCTCN2022080732-appb-100016
    Figure PCTCN2022080732-appb-100016
    Figure PCTCN2022080732-appb-100017
    Figure PCTCN2022080732-appb-100017
    “*”表示手性中心。"*" indicates a chiral center.
  14. 一种药物组合物，其特征在于，包含权利要求1至13中任一项所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，以及药学上可接受的载体。A pharmaceutical composition, characterized in that it comprises the compound according to any one of claims 1 to 13, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvates, and pharmaceutically acceptable carriers.
  15. 一种权利要求1至13中任一项的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，其特征在于，用于制备治疗与PARP7活性或表达量相关的疾病，病症或病状的药物组合物。A compound of any one of claims 1 to 13, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a use of a solvate, characterized in that, using For the preparation of pharmaceutical compositions for treating diseases, disorders or conditions related to the activity or expression of PARP7.
  16. 如权利要求15所述的用途，其特征在于，所述疾病，病症或病状选自下组：多发性骨髓瘤、B细胞淋巴瘤、T细胞淋巴瘤、急慢性髓系白血病、急慢性淋巴系白血病、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征、纤维肉瘤、唾液腺癌、肝癌、直肠癌、膀胱癌、咽喉癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、***癌、神经胶质细胞瘤、卵巢癌、头颈癌、***、食管癌、肾癌、胰腺癌、结肠癌、皮肤癌、胃癌等各种血液瘤和实体瘤，以及各种类型的心脏病、病毒感染、神经退行性疾病、炎症和疼痛等，尤其是那些与PARP7过表达或异常激活相关的疾病类型。The use of claim 15, wherein the disease, disorder or condition is selected from the group consisting of multiple myeloma, B-cell lymphoma, T-cell lymphoma, acute and chronic myeloid leukemia, acute and chronic lymphoid Leukemia, monocytic leukemia, polycythemia splenomegaly, eosinophilic leukemia syndrome, fibrosarcoma, salivary gland cancer, liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, Lung squamous cell carcinoma, breast cancer, prostate cancer, glioblastoma, ovarian cancer, head and neck cancer, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, stomach cancer and other hematological tumors and solid tumors, As well as various types of heart disease, viral infections, neurodegenerative diseases, inflammation and pain, especially those associated with PARP7 overexpression or abnormal activation.
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