WO2024022234A1 - 吡唑并吡啶类化合物在制备治疗包括中枢神经系统疾病的btk相关疾病的药物中的用途 - Google Patents

吡唑并吡啶类化合物在制备治疗包括中枢神经系统疾病的btk相关疾病的药物中的用途 Download PDF

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WO2024022234A1
WO2024022234A1 PCT/CN2023/108520 CN2023108520W WO2024022234A1 WO 2024022234 A1 WO2024022234 A1 WO 2024022234A1 CN 2023108520 W CN2023108520 W CN 2023108520W WO 2024022234 A1 WO2024022234 A1 WO 2024022234A1
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diseases
nervous system
central nervous
compound
lymphoma
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PCT/CN2023/108520
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English (en)
French (fr)
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魏霞蔚
姜宁
魏于全
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成都嘉葆药银医药科技有限公司
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Publication of WO2024022234A1 publication Critical patent/WO2024022234A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the invention belongs to the technical field of chemical medicine, and specifically relates to the use of a pyrazolopyridine compound in the preparation of drugs for the treatment of BTK-related diseases, and in particular to its use in the preparation of drugs for the treatment of central nervous system diseases.
  • BTK Bruton's tyrosine kinase
  • BCR B cell receptor
  • BTK irreversible inhibitors covalently bind to the active site of the kinase, Cys-481, to inhibit BTK activity. , thereby effectively inhibiting excessive proliferation of B cells and achieving anti-tumor or anti-inflammatory effects.
  • BTK is important for the development and function of immune cells such as B lymphocytes, macrophages, and microglia involved in the pathological processes of autoimmune diseases and lymphoma.
  • ibrutinib is an irreversible BTK inhibitor jointly developed by Pharmacyclis and Johnson & Johnson. It is approved by the FDA for mantle cell lymphoma, chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, disease, chronic graft-versus-host disease, etc.
  • ibrutinib also has strong inhibitory effects on other kinases besides BTK.
  • inhibition of kinases such as EGFR, ITK, and TEC can lead to more serious adverse reactions such as rash, diarrhea, and bleeding. Therefore, there is an urgent need to develop a highly active BTK inhibitor with good kinase selectivity for the treatment of lymphoma and autoimmune diseases.
  • the blood-brain barrier (BBB) is an important obstacle to drug development for these diseases.
  • the blood-brain barrier (BBB) is formed by the brain capillary endothelium and is a dynamic diffusion barrier that is crucial for protecting and maintaining brain homeostasis.
  • the BBB binds more than 100% of macromolecule therapeutics and 98% of The above small molecule drugs are excluded from the brain, so most central nervous system diseases lack effective treatment options.
  • permeability issues even if a compound is able to cross a barrier, it must remain at a therapeutically relevant concentration at the target site to elicit its desired effect.
  • BTK inhibitors that are highly active, can penetrate the blood-brain barrier and have good kinase selectivity for the treatment of lymphoma, autoimmune system and other diseases including central nervous system diseases.
  • BTK inhibitors have synergistic effects with many types of compounds and drugs with different mechanisms, and their combined use has good effects on the various diseases mentioned above.
  • the compound of formula (I) of the present invention has high activity and selectivity for BTK kinase, and has significant therapeutic effect on BTK-related diseases such as lymphoma, leukemia, autoimmune diseases, inflammatory diseases or metabolic diseases.
  • BTK-related diseases such as lymphoma, leukemia, autoimmune diseases, inflammatory diseases or metabolic diseases.
  • central nervous system diseases have always been a difficulty in the medical field due to their particularity.
  • the research of the present invention has found that pyrazolopyridine compounds can effectively penetrate the blood-brain barrier and maintain high concentrations in brain tissue, so the compounds can achieve therapeutic effects on diseases of the central nervous system.
  • the present invention provides compounds represented by formula (I), their isomers, pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof (as known in the art, pharmaceutical compositions refer to compounds including a therapeutically effective amount, their isomers body or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable excipient) in the preparation of a medicament for preventing or treating BTK-related diseases including central nervous system diseases, wherein the BTK-related diseases include lymphoma , leukemia, autoimmune diseases, inflammatory diseases or metabolic diseases;
  • T 1 is independently selected from N and CH;
  • R 2 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, which C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl The groups are independently optionally substituted by 1, 2 or 3 R a ;
  • Ring A is selected from phenyl and 5-6 membered heteroaryl
  • M is independently selected from C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, and the C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R b substitutions;
  • R 1 and R 3 are independently selected from F, Cl, Br, I, OH, NH 2 and CN;
  • n and m are independently selected from 0, 1, 2 or 3, and n and m are not 0 at the same time;
  • R a is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino, the C 1- 3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino are each independently optionally substituted by 1, 2 or 3 R;
  • R b is selected from F, Cl, Br, I, CH 3 ;
  • R is selected from H, F, Cl, Br, I;
  • the BTK-related diseases include central nervous system diseases and non-central nervous system diseases.
  • the central nervous system diseases include central nervous system lymphoma, central nervous system diffuse large B-cell lymphoma, Burkitt lymphoma originating in the central nervous system, autoimmune encephalitis, multiplex Sclerosis or neuromyelitis optica spectrum disorders.
  • the non-central nervous system diseases include B-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, follicular Lymphoma, Burkitt lymphoma arising in the collar bone, craniofacial bones or abdominal organs, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, multiple myeloma, rheumatoid arthritis, systemic erythema Lupus, lupus nephritis, Sjogren's syndrome, IgG4-related diseases, chronic spontaneous urticaria, idiopathic thrombocytopenic purpura, immune thrombocytopenia, pemphigus, asthma, graft-versus-host disease, scleroderma, Novel coronavirus infection, granulomatosis with polyangiitis,
  • Burkitt lymphoma (Burkit lymphoma) is a highly malignant B-cell tumor that may originate from follicular germinal center cells and mostly occurs in African children. There are more men than women, and in our country they are mostly children and young people.
  • the histological characteristics of tumors related to EBV are diffuse medium-sized lymphoid cells, with scattered macrophages engulfing debris among the tumor cells, forming the so-called starry sky image. It usually occurs in the collar bones, craniofacial bones, abdominal organs and central nervous system. It generally does not involve peripheral lymph nodes and spleen, and leukemia is rare.
  • B-cell lymphoma includes non-Hodgkin lymphoma
  • non-Hodgkin lymphoma includes diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, Waldenstrom's giant Globulinemia, mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, Burkitt lymphoma.
  • the present invention also provides the use of the compound represented by formula (I), its isomer, its pharmaceutically acceptable salt or its pharmaceutical composition in combination with at least one second drug for the preparation of preventive or Use in drugs to treat BTK-related diseases including central nervous system diseases;
  • the second drug is selected from CD-20 inhibitors or antibodies, BCL-2 inhibitors, SYK inhibitors, PI3K inhibitors, immunosuppressants, chemotherapy Drugs or autoimmune checkpoint inhibitors.
  • the compound represented by formula (I) and the second drug can be administered continuously (the compound represented by formula (I) can be administered first, or the second drug can be administered first) or simultaneously. Therefore, when the compound represented by formula (I) is combined with the second drug , the compound represented by formula (I) and the second drug can be prepared as a whole, or as separate entities.
  • the mass ratio of the compound represented by formula (I) to the second drug is 1-100:100-1.
  • the mass ratio of the compound represented by formula (I) to the second drug is 1-10:10-1.
  • the CD-20 inhibitor or antibody includes rituximab, utuximab, orelizumab, itumolizumab, otuzumab, ofatumumab monoclonal antibody or Marshalllizumab.
  • the BCL-2 inhibitor includes venetoclax, APG-2575, BGB-11417, ICP-248, FCN-338 or LP-108.
  • the SYK inhibitor includes fostatinib, Entospletinib, PRT-2761, HMPL-523, SKI-O-703, IC-265 or GSK-2646264.
  • the PI3K inhibitors include copanlisib, alpelisib, dunsib, idelanib, alpelisib, parsaclisib, linprolisib, eganelisib, BAY 10-82439, buparlisib, dactolisib, bis- Tinita or prquinitinib.
  • the immunosuppressant includes lenalidomide, pomalidomide, and thalidomide.
  • the chemotherapy drugs include temozolomide, cyclophosphamide, chlorambucil, bendamustine, ifosfamide, prednisone, dexamethasone, cisplatin, carboplatin, oxambucil Liplatin, fludarabine, pentostatin, cladribine, cytarabine, gemcitabine, methotrexate, pralatrexate, anthracyclines, doxorubicin, liposomal doxorubicin, Vincristine, mitoxantrone, etoposide, or bleomycin.
  • the autoimmune checkpoint inhibitors include pembrolizumab, nivolumab, camrelizumab, toripalimab, cimepilimab, Dewar Lumumab, velumab, sintilimab, tislelizumab, cepalizumab, durvalumab, atezolizumab, envolizumab, power Rizumab, Slulimumab, pembrolizumab, serrelimab, zimberizumab, jiprolimab, badalizumab, proglimumab, puxolitimab, can Cibelimab, AUNP-12, relevacizumab, retifarimab, dotalizumab, cardonizumab, soxakizumab, adebrumab, ipilimumab anti- or tremelimumab.
  • R a is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , OCH 3 , NH(CH 3 ) and N(CH 3 ) 2 .
  • R 2 is independently selected from H, C 1-3 alkyl, C 2-4 alkenyl and C 2-4 alkynyl.
  • the C 1-3 alkyl, C 2-4 alkenyl and C 2-4 alkynyl groups are each independently optionally substituted by 1, 2 or 3 R a .
  • R 2 is independently selected from H, CH 3 , vinyl and propynyl.
  • M is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidyl and morpholinyl, and the cyclopropyl base, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl and morpholinyl are each independently optionally substituted by 1, 2 or 3 R b .
  • M is independently selected from piperidinyl and morpholinyl.
  • ring A is selected from phenyl and pyridyl.
  • the compound of formula (I) is selected from:
  • R 1 and R 3 are as defined above;
  • n and m are independently selected from 0, 1, 2 or 3, and n and m are not 0 at the same time;
  • R 2 is as defined above;
  • L 1 and L 2 are as defined above.
  • the compound of formula (I) is selected from:
  • n, m, R 1 , R 2 , R 3 , L 1 and L 2 are as defined above.
  • the compound of formula (I) is selected from:
  • the compound of formula (I) is selected from:
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, phosphorus Acid monohydrogen, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, the organic acids include acetic acid, propionic acid, isobutyric acid, maleic acid, propylene glycol, etc.
  • Acid benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and similar acids; Also included are salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the term "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect.
  • the "effective amount” of an active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • SXRD single crystal X-ray diffraction
  • the light source is CuK ⁇ radiation
  • the scanning mode is: ⁇ / ⁇ scanning.
  • Shelxs97 can confirm the absolute configuration by analyzing the crystal structure.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
  • diastereomer refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
  • wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center
  • using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line
  • wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key or straight dotted key
  • the terms “enriched in an isomer,” “enantiomerically enriched,” “enriched in an enantiomer,” or “enantiomerically enriched” refer to one of the isomers or enantiomers.
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then the salt is formed by conventional methods known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally combined with chemical derivatization methods (e.g., generation of amino groups from amines). formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R's, with independent options for R in each case.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • the substituent can be bonded to any atom in the ring, e.g., structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • the substituent can be bonded through any atom thereof.
  • a pyridyl group as a substituent can be bonded through any one of the pyridine rings. The carbon atom is attached to the substituted group.
  • the direction of connection is arbitrary, for example,
  • the middle linking group L is -MW-.
  • -MW- can be connected to ring A and ring B in the same direction as the reading order from left to right. You can also connect ring A and ring B in the opposite direction to the reading order from left to right.
  • the linking group, substituent and/or variant thereof Combinations are permitted only if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • connection mode of the chemical bond is non-positioned and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced correspondingly with the number of connected chemical bonds and become the corresponding valence. group.
  • the chemical bond connecting the site to other groups can be a straight solid line bond straight dashed key or wavy lines express.
  • the straight solid line bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted bond in means that it is connected to other groups through both ends of the nitrogen atoms in the group;
  • the wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • the number of atoms in a ring is usually defined as the number of ring members.
  • a "5- to 7-membered ring” refers to a “ring” with 5 to 7 atoms arranged around it.
  • C 1-6 alkyl is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it can Is it monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • C 1-3 alkyl is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • the C 3-6 cycloalkyl group includes C 3-5 , C 4-5 and C 5-6 cycloalkyl groups, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • C 2-6 alkenyl is used to mean a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond. Can be located anywhere on the group.
  • the C 2-6 alkenyl group includes C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkenyl groups, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 2-6 alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene, hexadienyl, and the like.
  • C 2-4 alkenyl is used to mean a straight or branched hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon double bond. Can be located anywhere on the group.
  • the C 2-4 alkenyl group includes C 2-3 , C 4 , C 3 and C 2 alkenyl groups, etc.; the C 2-4 alkenyl group can be monovalent, divalent or multivalent. Examples of C 2-4 alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, butadienyl, and the like.
  • C 2-6 alkynyl is used to mean a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, carbon-carbon triple bond Can be located anywhere on the group.
  • the C 2-6 alkynyl group includes C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkynyl groups, etc. It can be monovalent, bivalent or polyvalent. Examples of C 2-6 alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
  • C 2-4 alkynyl is used to mean a straight-chain or branched hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon triple bond. Can be located anywhere on the group.
  • the C 2-4 alkynyl group includes C 2-3 , C 4 , C 3 and C 2 alkynyl groups, etc. It can be monovalent, bivalent or polyvalent. Examples of C 2-4 alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.
  • C 1-3 alkoxy means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups, etc.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-3 alkylamino means those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups, etc.
  • Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH 2 (CH 3 ) 2 etc.
  • 3-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms. are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e. NO and S(O) p , p is 1 or 2). It includes single-ring and double-ring systems, where the double-ring system includes spiro rings, parallel rings and bridged rings.
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 3-6-membered heterocycloalkyl group includes 4-6-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups, etc.
  • Examples of 3-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidin
  • 5-6 membered heteroaromatic ring and “5-6 membered heteroaryl” may be used interchangeably in the present invention
  • a 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include but are not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl).
  • azolyl group, etc. imidazolyl group (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl) Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyrid
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the compound of the present invention has high activity and selectivity for BTK kinase, and has significant therapeutic effect on BTK-related diseases such as lymphoma, leukemia, autoimmune diseases, inflammatory diseases or metabolic diseases, and it interacts with many types of different mechanisms
  • BTK-related diseases such as lymphoma, leukemia, autoimmune diseases, inflammatory diseases or metabolic diseases
  • the compounds and drugs of the present invention all have synergistic effects; in addition, the compounds of the present invention can effectively penetrate the blood-brain barrier and maintain high concentrations in brain tissue, so they can achieve therapeutic effects on diseases of the central nervous system; through drug efficacy tests,
  • the compound of the present invention has shown significant effects in the treatment of central nervous system diseases such as multiple sclerosis and central nervous system lymphoma, and is expected to be used as a new treatment method for such central nervous system diseases.
  • Figure 1 shows the clinical scores of MOG35-55-induced autoimmune encephalomyelitis mice in Experimental Example 2.
  • Figure 2 is a diagram of the brain luminescence intensity of the Namalwa intracranial model experimental in vivo imaging in Experimental Example 4.
  • Dissolve compound I-1 (3kg, 23.06mol) in toluene (5L), add 50% (mass fraction) NaOH aqueous solution (1.84kg, 23.06mol) under stirring, and raise the external temperature to 135°C for reaction.
  • the reaction solution was transferred to a 3L single-neck bottle and concentrated to dryness under reduced pressure. Transfer the concentrate to the reaction bottle, add compound I-2 (6.00kg, 25.43mol) and DMF (2.5L), raise the external temperature to 145°C to melt the reaction system, add Cu (147.00g, 2.31mol) and CuBr (330.00g, 2.30mol) and then kept at 145°C for 64 hours.
  • the concentrate is subjected to vacuum distillation in batches (external temperature 170°C). First, preheat the concentrate for 1 hour to 150°C, and then perform vacuum distillation with a water pump and an oil pump in sequence. Discard the distilled fraction and collect the residue. The residue was purified through silica gel column to obtain compound I-3.
  • the obtained aqueous phase was extracted with 8.2L dichloromethane, the organic phase was collected, and the two batches of organic phases collected above were mixed.
  • the mixed organic phase was washed with 12.3L of semisaturated brine.
  • the organic phase was dried over anhydrous sodium sulfate, filtered, the filter cake was washed with 2.05L dichloromethane, and the combined filtrate was concentrated to dryness under reduced pressure.
  • the solid obtained after separation was dissolved in 16.4L methylene chloride, washed with water (8.2L*2), and the organic phase was collected.
  • the organic phase was dried over anhydrous sodium sulfate and filtered. The filter cake was washed with 2.05L dichloromethane.
  • the combined filtrate was concentrated to dryness under reduced pressure. Dissolve the obtained oil in 16L of ethyl acetate, add potassium carbonate (493.05g, 3.56mol), and stir at room temperature 10 to 20°C for 16 hours. Add 8L of water and continue stirring for 10 minutes. After stopping stirring, the liquids were separated and the organic phase was collected. The organic phase was washed with 8L of semi-saturated saline. The organic phase was dried with anhydrous sodium sulfate and filtered. The filter cake was washed with 1.6L of ethyl acetate. The combined filtrate was concentrated under reduced pressure. to about 4L.
  • the obtained filter cake was vacuum dried at 65-75°C to a constant weight to obtain compound 1A.
  • the absolute configuration parameter Flack value is 0.04(3).
  • Standard protocols were used to test the pharmacokinetic characteristics of the compounds in plasma, brain and cerebrospinal fluid after oral administration.
  • the candidate compounds were formulated into a nearly clear dosage solution with a concentration of 1 mg/mL and given to rats for a single oral administration. (Dose 10mg/kg).
  • the oral vehicle is a mixed solution of 5% DMSO, 10% solutol HS15, 20% PEG400 and 65% water.
  • Whole blood, brain and cerebrospinal fluid were collected at three time points: 0.5 hour, 1 hour and 6 hours after administration.
  • LC-MS/MS analysis method Centrifuge the whole blood sample at 3200 g for 10 minutes, separate the supernatant to obtain a plasma sample, add a certain volume of acetonitrile solution containing an internal standard to precipitate the protein, centrifuge the supernatant and inject a sample, and quantitatively analyze the blood drug concentration using LC-MS/MS analysis method.
  • Brain tissue was collected using the perfusion method, and homogenized using a high-throughput tissue homogenizer at a 4-fold homogenization ratio under wet ice conditions. Tissue homogenates will be maintained at -60°C or lower until brain tissue concentration is quantified by LC-MS/MS analysis.
  • Cerebrospinal fluid was collected from animals under isoflurane anesthesia, and 50-100 ⁇ L CSF was collected at each sampling time point. The collected cerebrospinal fluid was stored at -60°C or lower until quantitative analysis of cerebrospinal fluid concentration by LC-MS/MS analysis. Drug concentrations, plasma/brain tissue ratio and plasma/cerebrospinal fluid ratio were calculated for the three matrices at different sampling time points. The experimental results are shown in Table 1.
  • Compound 1A can effectively penetrate the blood-brain barrier, and can be distributed in brain tissue after oral administration, and the concentration in brain tissue is as high as 835ng/g, so it is expected to achieve therapeutic effects on diseases of the central nervous system.
  • EAE autoimmune encephalomyelitis
  • EAE Experimental autoimmune encephalomyelitis
  • This pharmacodynamic model has the same characteristics as human MS in many aspects such as clinical, biochemical, immune and pathological aspects, and is currently internationally recognized as an ideal animal model of MS.
  • the mouse EAE model was induced and constructed by subcutaneous injection of MOG 35-55 on Day 0 of the experiment and administration was started in groups.
  • the mice On Day 12 after immunization, the mice began to develop clinical symptoms of autoimmune encephalomyelitis. The average clinical score of the vehicle control group gradually increased in the early stages of the experiment, reaching 3.11 points on Day 20, indicating the success of the MOG 35-55- induced autoimmune encephalomyelitis model.
  • the subjects were randomly divided into 5 groups according to body weight, namely vehicle control group, dexamethasone (Dex) group, Compound 1A 20mg/kg group, and Compound 1A 40mg/kg group. and Compound 1A 60 mg/kg group.
  • Another group of mice without MOG 35-55 modeling was set up as the normal control group. This experiment started from Day 0 of mouse immune modeling and was administered continuously for 26 days. The drug efficacy was evaluated through EAE clinical scores and other indicators.
  • mice in the vehicle control group developed severe EAE clinical symptoms from Day 12 to Day 26 after immunization with MOG 35-55 , indicating that the EAE model was successfully established.
  • Continuous administration of Compound 1A for 26 days can significantly improve the clinical symptoms of EAE mice.
  • the experimental results are shown in Figure 1.
  • the compound of the present invention has a significant therapeutic effect on autoimmune encephalomyelitis model mice after continuous administration for 26 days; the compound of the present invention shows significant effect in the treatment of multiple sclerosis and is expected to be used as a treatment for multiple sclerosis new method.
  • Human diffuse large B-cell lymphoma OCI-LY10 cells were cultured in IMDM medium containing 20% FBS and maintained in a 37°C saturated humidity incubator with 5% CO2 .
  • Test compound group Weigh a quantitative amount of the test compound into a brown dispensing bottle, add a corresponding volume of solvent and vortex to obtain a uniform suspension or clear solution.
  • Tumor diameter was measured twice weekly using vernier calipers.
  • the calculation formula of tumor volume is: 1/2 ⁇ a ⁇ b 2 , where a and b are the measured length and width of the tumor respectively.
  • TGI (%) [1-(average tumor volume at the end of administration in a certain treatment group - average tumor volume at the beginning of administration in this treatment group)/(at the end of treatment in the solvent control group) Average tumor volume - average tumor volume in the solvent control group at the beginning of treatment)] ⁇ 100%.
  • Compound 1A of the present invention has a significant tumor inhibitory effect on the OCI-LY10 cell subcutaneous xenograft tumor model, and the dose-effect relationship is obvious. However, it can be seen from Experimental Example 1 that the compound can penetrate the blood-brain barrier and maintain a high concentration in brain tissue. Combining the results of Experimental Examples 1 and 3 shows that the compound of the present application can treat central nervous system lymphoma.
  • Namalwa intracranial model experimental protocol Model in nude mice by injecting 500,000 Namalwa cells expressing luciferase through the carotid artery. On the third day after modeling, the animals were randomly divided into a solvent control group and a Compound 1A treatment group. Treatment was started by intragastric administration once a day. The dose of Compound 1A was 150 mg/kg. In vivo imaging observations were performed 7 days, 14 days and 19 days after modeling, and the results are shown in Figure 2.
  • the Compound 1A treatment group's inhibitory ability against human Burkitt's lymphoma cells in the model of Burkitt's lymphoma occurring in the central nervous system was significantly stronger than that of the solvent control group.
  • the compound of the present invention has shown effects in the treatment of Burkitt's lymphoma and is expected to be used as a new treatment method for Burkitt's lymphoma.

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Abstract

式(Ⅰ)所示化合物在制备治疗包括中枢神经系统疾病的BTK相关疾病的药物中的用途，属于化学医药技术领域。式(Ⅰ)化合物对BTK激酶具有高活性和高选择性，其对淋巴瘤、白血病、自身免疫性疾病、炎性疾病或代谢疾病等BTK相关疾病，具有显著的治疗作用，且与多类不同机制的化合物和药物均有协同增效的作用；特别是其可以有效穿透血脑屏障，并且在脑组织保持高浓度，因此可以对中枢神经系统的疾病达到治疗效果；经细胞实验，式(Ⅰ)化合物在治疗多发性硬化、中枢神经系统淋巴瘤等中枢神经系统疾病中展现了显著作用，能够成为这类中枢神经系统的疾病的治疗新方法。

Description

吡唑并吡啶类化合物在制备治疗包括中枢神经系统疾病的BTK相关疾病的药物中的用途
本申请基于申请号为CN202210903508.7、申请日为2022年7月28日的中国专利申请提出，并要求该中国专利申请的优先权，该中国专利申请的全部内容在此引入本申请作为参考。
技术领域
本发明属于化学医药技术领域，具体涉及一种吡唑并吡啶类化合物在制备治疗BTK相关疾病的药物中的用途，特别是涉及其在制备治疗中枢神经系统疾病的药物中的用途。
背景技术
布鲁顿酪氨酸激酶(Bruton’s tyrosine kinase，BTK)是B细胞受体(BCR)信号通路的关键激酶，BTK不可逆抑制剂与激酶的活性位点Cys-481以共价键结合，抑制BTK活性，从而有效地抑制B细胞过度增殖，达到抗肿瘤或抗炎症功效。BTK作为B细胞受体信号通路中的一个关键激酶，对B淋巴细胞、巨噬细胞及小胶质等参与自免疫疾病和淋巴瘤病理过程免疫细胞的发育和功能都很重要。在目前已上市的药物中，依鲁替尼(ibrutinib)由Pharmacyclis和强生公司联合开发的一种不可逆BTK抑制剂，被FDA批准用于套细胞淋巴瘤、慢性淋巴细胞白血病、华氏巨球蛋白血症、慢性移植物抗宿主病等的治疗。但依鲁替尼除对BTK外的其他激酶也有较强的抑制作用，尤其对EGFR、ITK和TEC等激酶的抑制可导致较为严重的皮疹、腹泻和出血等不良反应。因此，亟待开发一种高活性的、并具有良好激酶选择性的BTK抑制剂，以用于淋巴瘤和自免疫疾病的治疗。
此外，一些主要影响大脑的疾病，是所有疾病中最普遍、最具破坏性但治疗效果不佳的疾病。尽管基础神经科学知识方面取得了极大进步，但针对重要中枢神经系统(CNS)疾病的新药的失败率仍然超过了大多数其他药物发现领域。血脑屏障(BBB)是这些疾病药物开发的一个重要障碍。血脑屏障(BBB)由脑毛细血管内皮形成，是一种动态扩散屏障，对于保护和维持大脑稳态至关重要，BBB将100％以上的大分子治疗药物和98％ 以上的小分子药物排除在脑外，因此绝大多数的中枢神经系统疾病均缺乏有效的治疗方案。此外除了渗透性问题之外，即使化合物能够穿过屏障，它也必须在靶位保持治疗相关浓度以引发其所需的作用。
因此本领域需要发展一类新的高活性，可穿透血脑屏障的同时具有良好激酶选择性的BTK抑制剂用于治疗包括中枢神经系统疾病的淋巴瘤、自身免疫系统等疾病。同时，BTK抑制剂与多类不同机制的化合物和药物均有协同增效的作用，联合使用对前述各类疾病有良好的效果。
发明内容
本发明式(Ⅰ)化合物对BTK激酶具有高活性和高选择性，其对淋巴瘤、白血病、自身免疫性疾病、炎性疾病或代谢疾病等BTK相关疾病，具有显著的治疗作用。此外，中枢神经系统疾病由于其特殊性，一直是医疗领域内的难点。本发明研究发现，吡唑并吡啶类化合物可以有效穿透血脑屏障，并且在脑组织保持高浓度，因此该化合物能够对中枢神经系统的疾病达到治疗效果。
本发明提供了式(Ⅰ)所示化合物、其异构体、其药学上可接受的盐或其药物组合物(本领域皆知，药物组合物是指包括治疗有效量的化合物、其异构体或其药学上可接受的盐作为活性成分以及药学上可接受的辅料)在制备预防或治疗包括中枢神经系统疾病的BTK相关疾病的药物中的用途，其中，所述BTK相关疾病包括淋巴瘤、白血病、自身免疫性疾病、炎性疾病或代谢疾病；
式(Ⅰ)化合物结构如下：
其中，
T1独立地选自N和CH；
R2独立地选自H、C1-6烷基、C2-6烯基和C2-6炔基，所述C1-6烷基、C2-6烯基和C2-6炔基分别独立地任选被1、2或3个Ra取代；
环A选自苯基和5-6元杂芳基；
M独立地选自C3-6环烷基和3-6元杂环烷基，所述C3-6环烷基和3-6元杂环烷基分别独立地任选被1、2或3个Rb取代；
R1和R3分别独立地选自F、Cl、Br、I、OH、NH2、CN；
n和m分别独立地选自0、1、2或3，且n、m不同时为0；
L1、L2分别独立地选自-CH2-、-CH2CH2-、-O-、-C(＝O)-和-C(＝O)-NH-；
Ra独立地选自H、F、Cl、Br、I、OH、NH2、CN、C1-3烷基、C1-3烷氧基和C1-3烷氨基，所述C1-3烷基、C1-3烷氧基和C1-3烷氨基分别独立地任选被被1、2或3个R取代；
Rb选自F、Cl、Br、I、CH3；
R选自H、F、Cl、Br、I；
所述5-6元杂芳基和3-6元杂环烷基分别独立地包含1、2、3或4个独立选自-NH-、-O-、-S-、-C(＝O)-、-S(＝O)-、和N的杂原子或杂原子团。
其中，上述用途中，所述BTK相关疾病包括中枢神经系统疾病和非中枢神经系统疾病。
其中，上述用途中，所述中枢神经系统疾病包括中枢神经系统淋巴瘤、中枢神经系统弥漫型大B细胞淋巴瘤、发于中枢神经系统的伯基特淋巴瘤、自身免疫性脑炎、多发性硬化症或视神经脊髓炎谱系疾病。
其中，上述用途中，所述非中枢神经系统疾病包括B细胞淋巴瘤、慢性淋巴细胞白血病/小淋巴细胞淋巴瘤、套细胞淋巴瘤、华氏巨球蛋白血症、边缘区淋巴瘤、滤泡性淋巴瘤、发于领骨、颅面骨或腹腔器官的伯基特淋巴瘤、非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、多发性骨髓瘤、类风湿性关节炎、系统性红斑狼疮、狼疮性肾炎、干燥综合症、IgG4相关疾病、慢性自发性荨麻疹、特发性血小板减少性紫癜、免疫性血小板减少症、天疱疮、哮喘、移植物抗宿主病、硬皮症、新型冠状病毒感染、肉芽肿性多血管炎、特发性肺纤维化、银屑病、动脉粥样硬化或糖尿病。
伯基特淋巴瘤(Burkit淋巴瘤)是可能来源于滤泡生发中心细胞的高度恶性的B细胞肿瘤,多发生于非洲儿童。男多于女，在我国多为儿童和青年人。与EB病毒有关肿瘤的组织学特点是弥漫性的中等大小、淋巴样细胞组成，瘤细胞间有散在的巨噬细胞吞噬碎片，形成所谓满天星图像。好发于领骨、颅面骨、腹腔器官和中枢神经系统，一般不累及外周淋巴结和脾，白血病像少见。
上述非中枢神经系统疾病中，B细胞淋巴瘤包括了非霍奇金淋巴瘤，非霍奇金淋巴瘤包括了弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、边缘区淋巴瘤、华氏巨球蛋白血症、套细胞淋巴瘤、慢性淋巴细胞白血病/小淋巴细胞淋巴瘤、伯基特淋巴瘤。
在上述基础上，本发明还提供了将式(Ⅰ)所示化合物、其异构体、其药学上可接受的盐或其药物组合物，与至少一种第二药物联合用于制备预防或治疗包括中枢神经系统疾病的BTK相关疾病的药物中的用途；所述第二药物选自CD-20抑制剂或抗体、BCL-2抑制剂、SYK抑制剂、PI3K抑制剂、免疫抑制剂、化疗药物或自免疫检查点抑制剂。
式(Ⅰ)所示化合物与第二药物可以连续(可首先施用式(I)所示化合物，或者先施用第二药物)或同时施用，因此式(Ⅰ)所示化合物与第二药物联合时，可将式(I)所示化合物和第二药物制备为整体，也可制备为单独个体。
其中，上述用途中，式(I)所示化合物与第二药物的质量比为1～100：100～1。
优选的，上述用途中，式(I)所示化合物与第二药物的质量比为1～10：10～1。
其中，上述用途中，所述CD-20抑制剂或抗体包括利妥昔单抗、乌妥昔单抗、奥瑞利珠单抗、替伊莫单抗、奥妥珠单抗、奥法木单抗或维得利珠单抗。
其中，上述用途中，所述BCL-2抑制剂包括维奈克拉、APG-2575、BGB-11417、ICP-248、FCN-338或LP-108。
其中，上述用途中，所述SYK抑制剂包括福他替尼、Entospletinib、PRT-2761、HMPL-523、SKI-O-703、IC-265或GSK-2646264。
其中，上述用途中，所述PI3K抑制剂包括copanlisib、厄布利塞、度恩西布、艾德拉尼、alpelisib，parsaclisib、林普利司、eganelisib、BAY 10-82439、buparlisib、dactolisib、双替尼他或普喹替尼。
其中，上述用途中，所述免疫抑制剂包括来那度胺、泊马度胺、沙利度胺。
其中，上述用途中，所述化疗药物包括替莫唑胺、环磷酰胺、苯丁酸氮芥、苯达莫司汀、异环磷酰胺、强的松、地塞米松、顺铂、卡铂、奥沙利铂、氟达拉滨、喷司他丁、克拉屈滨、阿糖胞苷、吉西他滨、甲氨蝶呤、普拉曲沙、蒽环类、阿霉素、脂质体多柔比星、长春新碱、米托蒽醌、依托泊苷或博来霉素。
其中，上述用途中，所述自免疫检查点抑制剂包括帕博利珠单抗、纳武尤利单抗、卡瑞丽珠单抗、特瑞普利单抗、西米普利单抗、杜瓦鲁单抗、维鲁单抗、信迪利单抗、替雷丽珠单抗、赛帕利单抗、度伐利尤单抗、阿替利珠单抗、恩沃利单抗、舒格利单抗、 斯鲁利单抗、派安普利单抗、赛瑞单抗、津伯利单抗、吉普诺利单抗、巴达珠单抗、普罗格利单抗、普可替尼单抗、可西贝利单抗、AUNP-12、瑞拉单抗、瑞替凡利单抗、多塔利单抗、卡多尼单抗、索卡唑单抗、阿德布雷单抗、易普利单抗或曲美木单抗。
其中，上述用途中，Ra独立地选自H、F、Cl、Br、I、OH、NH2、CN、CH3、OCH3、NH(CH3)和N(CH3)2。
其中，上述用途中，R2独立地选自H、C1-3烷基、C2-4烯基和C2-4炔基，所述C1-3烷基、C2-4烯基和C2-4炔基分别独立地任选被1、2或3个Ra取代。
优选的，上述用途中，R2独立地选自H、CH3、乙烯基和丙炔基。
其中，上述用途中，M独立地选自环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、哌啶基和吗啉基，所述环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、哌啶基和吗啉基分别独立地任选被1、2或3个Rb取代。
优选的，上述用途中，M独立地选自哌啶基和吗啉基。
其中，上述用途中，L1选自-O-和-C(＝O)-NH-。
其中，上述用途中，L2选自-C(＝O)-和-C(＝O)-NH-。
其中，上述用途中，环A选自苯基和吡啶基。
优选的，上述用途中，结构单元选自
更优选的，上述用途中，结构单元选自
其中，上述用途中，式(Ⅰ)化合物选自：
其中，
R1、R3如前述所定义；
n和m分别独立地选自0、1、2或3，且n、m不同时为0；
R2如前述所定义；
L1、L2如前述所定义。
其中，上述用途中，式(Ⅰ)化合物选自：
其中，n、m、R1、R2、R3、L1、L2如前述所定义。
其中，上述用途中，式(Ⅰ)化合物选自：
其中，上述用途中，式(Ⅰ)化合物选自：
定义和说明：
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷 酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：φ/ω扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型，用波浪线表示楔形实线键或楔形虚线键或用波浪线表示直形实线键或直形虚线键
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。
当一个取代基数量为0时，表示该取代基是不存在的，比如-A-(R)0表示该结构实际上是-A。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基的键可以交叉连接到一个环上的两一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元表示其取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成所述连接基团、取代基和/或其变体的 组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键直形虚线键或波浪线表示。例如-OCH3中的直形实线键表示通过该基团中的氧原子与其他基团相连；中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括这4种连接方式，即使-N-上画出了H原子，但是仍包括这种连接方式的基团，只是在连接1个化学键时，该位点的的H会对应减少1个变成相应的一价哌啶基。
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。
除非另有规定，术语“C1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C1-6烷基包括C1-5、C1-4、C1-3、C1-2、C2-6、C2-4、C6和C5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，术语“C1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C1-3烷基包括C1-2和C2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。
除非另有规定，“C3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其 为单环和双环体系，其中碳原子可任选被氧化(即C＝O)。所述C3-6环烷基包括C3-5、C4-5和C5-6环烷基等；其可以是一价、二价或者多价。C3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。
除非另有规定，“C2-6烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至6个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C2-6烯基包括C2-4、C2-3、C4、C3和C2烯基等；其可以是一价、二价或者多价。C2-6烯基的实例包括但不限于乙烯基、丙烯基、丁烯基、戊烯基、己烯基、丁间二烯基、戊间二烯基、己间二烯基等。
除非另有规定，“C2-4烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至4个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C2-4烯基包括C2-3、C4、C3和C2烯基等；所述C2-4烯基可以是一价、二价或者多价。C2-4烯基的实例包括但不限于乙烯基、丙烯基、丁烯基、丁间二烯基等。
除非另有规定，“C2-6炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至6个碳原子组成的碳氢基团，碳-碳三键可以位于该基团的任何位置上。所述C2-6炔基包括C2-4、C2-3、C4、C3和C2炔基等。其可以是一价、二价或者多价。C2-6炔基的实例包括但不限于乙炔基、丙炔基、丁炔基、戊炔基等。
除非另有规定，“C2-4炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至4个碳原子组成的碳氢基团，碳-碳三键可以位于该基团的任何位置上。所述C2-4炔基包括C2-3、C4、C3和C2炔基等。其可以是一价、二价或者多价。C2-4炔基的实例包括但不限于乙炔基、丙炔基、丁炔基等。
除非另有规定，术语“C1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氧基包括C1-2、C2-3、C3和C2烷氧基等。C1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，术语“C1-3烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氨基包括C1-2、C3和C2烷氨基等。C1-3烷氨基的实例包括但不限于-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH3)CH2CH3、-NHCH2CH2CH3、-NHCH2(CH3)2等。
除非另有规定，术语“3-6元杂环烷基”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO 和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-6元杂环烷基包括4-6元、5-6元、4元、5元和6元杂环烷基等。3-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C＝O、NO和S(O)p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。
本发明采用下述缩略词：aq代表水；eq代表当量、等量；DCM代表二氯甲烷；PE代表石油醚；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；Cbz代表苄氧羰基，是一种胺保护基团；Boc代表叔丁氧羰基，是一种胺保护基团；HOAc代表乙酸；THF代表四氢呋喃；LDA代 表二异丙基胺基锂。
化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。
说明：本发明式(I)化合物可参考WO2021/057893A1中的化合物通式及相关具体化合物。
有益效果：
本发明化合物对BTK激酶具有高活性和高选择性，其对淋巴瘤、白血病、自身免疫性疾病、炎性疾病或代谢疾病等BTK相关疾病，具有显著的治疗作用，并且其与多类不同机制的化合物和药物均有协同增效的作用；此外，本发明化合物可以有效穿透血脑屏障，并且在脑组织保持高浓度，因此可以对中枢神经系统的疾病达到治疗效果；经药效试验，本发明化合物在治疗多发性硬化、中枢神经系统淋巴瘤等中枢神经系统疾病中展现了显著作用，有望用作这类中枢神经系统的疾病的治疗新方法。
附图说明
图1为实验例2中MOG35-55诱导的自身免疫性脑脊髓炎小鼠临床评分。
图2为实验例4中Namalwa颅内模型实验活体成像脑部发光强度图。
具体实施方式
实施例1
合成路线如下：
步骤1.I-3的合成
将化合物I-1(3kg，23.06mol)溶于甲苯(5L)中，在搅拌下加入50％(质量分数)NaOH水溶液(1.84kg，23.06mol)，外温升至135℃反应，反应过程中用油水分离器分离出水，共反应96小时。将反应液转移至3L单口瓶中减压浓缩干。将浓缩物转移至反应瓶中，加入化合物I-2(6.00kg，25.43mol)和DMF(2.5L)，外温升至145℃使反应体系融化，加入Cu(147.00g，2.31mol)和CuBr(330.00g，2.30mol)后保持145℃反应64小时。关闭加热和搅拌，反应液冷却至室温并使固体沉降后倒出上清液。加入1.5L正庚烷搅拌5分钟后再次倒出上清液，再重复此操作4次。合并所有上清液并转移至50L分液器中，用2.5L氨水(含量25％～28％)和2.5L水的混合溶液洗涤，重复5次，再用10L半饱和食盐水洗涤，收集有机相，合并水相，水相用10L正庚烷萃取，合并上述两次有机相，用无水硫酸钠干燥，过滤出上清液，减压浓缩干。浓缩物分批进行减压蒸馏(外温170℃)，先将浓缩物预热1小时至150℃后再依次用水泵和油泵进行减压蒸馏，丢弃蒸馏出的馏分，收集残留物。残留物经硅胶柱纯化，得到化合物I-3。
1H NMR(400MHz,DMSO-d6)δppm 7.56(d,J＝8.78Hz,2H),7.17-7.37(m,2H),6.90-7.11(m,3H)。
步骤2.I-5的合成
在反应瓶中加入DCM(3.2L)，依次加入化合物I-4(800g，3.72mol)和TEMPO(5.97g，37.94mmol)，向所得溶液中加入KBr水溶液(2M，192.00mL)，移至冰浴中，加入NaHCO3(44.00g，523.75mmol)，降温至低于10℃后保持10～40℃滴加NaClO(4.84kg，5.20mol，4.00L，8％纯度)，滴加约30min，滴加完毕后自然降温至30℃反应10min。反应液分液，水相用3.2L二氯甲烷萃取，合并的有机相依次用1.6L盐酸(1M，含有KI(616.85g，3.72mol)和1.6L硫代硫酸钠溶液(10％)洗涤，得到的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩干，得到化合物I-5。
1H NMR(400MHz,CDCl3)δppm 9.68(s,1H),3.79-4.02(m,1H),3.55-3.71(m,1H),3.25-3.39(m,1H),3.01-3.15(m,1H),2.34-2.48(m,1H),1.87-2.01(m,1H),1.61-1.71(m,2H),1.41-1.49(m,10H)。
步骤3.I-7的合成
将化合物I-6(1.68kg，14.60mol)溶于THF(11.25L)中并加入到50L反应釜中。用干冰乙醇浴降温至-73～-63℃。通氮气，在微弱的氮气流下将n-BuLi(2.5M，6.09L)通过蠕动泵加入到反应釜中，并保持温度低于-50℃。滴加完毕后保持-68～-50℃反应1小时。将化合物I-5(3kg，14.07mol)溶于THF(3.75L)中，并通过蠕动泵加入到反应釜中，保 持温度低于-50℃。滴加完毕后撤去干冰乙醇浴使反应缓慢升至0℃反应2小时。在反应液中滴加10L饱和氯化铵溶液，搅拌0.5小时后浓缩，浓缩至剩～15L溶液后转移至分液器中，加入10L盐酸(1M)，用乙酸乙酯(10L*2)萃取，合并的有机相用10L半饱和食盐水洗涤，得到的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩干，得到I-7。
LCMS(ESI)m/z:273.1(M-56)；1H NMR(400MHz,CDCl3)δppm 8.25-8.38(m,2H),4.79-4.91(m,1H),4.01-4.15(m,0.5H),3.79-3.96(m,1H),3.66-3.74(m,0.5H),3.38-3.54(m,1H),2.75-2.87(m,0.5H),2.50-2.65(m,0.5H),2.15(br d,J＝12.05Hz,1H),1.98-2.08(m,1H),1.54-1.80(m,2H),1.42-1.52(m,10H)。
步骤4.I-8的合成
在反应釜中加入化合物I-7(4kg，12.18mol)和TEMPO(19.20g，122.10mmol)的DCM(10L)溶液，然后加入KBr(2M，630mL)(水溶液)和NaHCO3(144g，1.71mol，66.67mL)，保持10～30℃用蠕动泵加入NaClO(15.87kg，17.05mol，13.12L，8％纯度)，保持25～30℃反应30min。将反应液分液，水相用10L二氯甲烷萃取，合并的有机相依次用10L盐酸(1M，含有2kg KI和10L硫代硫酸钠溶液(10％)洗涤，得到的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩干，得到化合物I-8。
LCMS(ESI)m/z:271.1(M-56)；1H NMR(400MHz,CDCl3)δppm 8.38-8.50(m,2H),4.02-4.20(m,1H),3.73-3.86(m,1H),3.08-3.25(m,1H),2.88-3.04(m,2H),1.91-2.03(m,1H),1.68-1.85(m,2H),1.41(s,10H)。
步骤5.I-9的合成
在化合物I-8(5kg，15.32mol)的二氧六环(25L)溶液中加入水合肼(1kg，16.98mol，970.87mL，85％含量)，升温至93℃反应16小时。降至室温后将反应液减压浓缩干。将浓缩物溶于15L二氯甲烷并加入到分液器中，加入5L水，用1M的NaOH溶液调节pH至8左右，分液，收集有机相。将有机相用无水硫酸钠干燥，过滤，滤饼用0.5L二氯甲烷洗涤，合并的滤液减压浓缩干，得到粗产品。将粗产品分散于6L乙酸乙酯中，搅拌下加入18L正庚烷，室温搅拌3小时后过滤，滤饼用4L混合溶剂(正庚烷：乙酸乙酯＝3:1)洗涤，滤饼抽滤至干，收集滤饼，合并的滤液减压浓缩干。将浓缩物经硅胶柱纯化(正庚烷：乙酸乙酯＝1:0～1:1，添加20％二氯甲烷)。将过柱所得产物馏分减压浓缩干，浓缩物与上述滤饼分散于正庚烷(8L)中室温(20℃)搅拌1小时后过滤，滤饼用油泵抽滤至干，移至真空干燥箱50℃干燥16小时。得到化合物I-9。
LCMS(ESI)m/z:321.2(M+1)；1H NMR(400MHz,CDCl3)δppm 11.95-12.70(m,1 H),8.79(br s,1H),8.09(br s,1H),4.23-4.61(m,1H),4.11(br d,J＝13.05Hz,1H),3.13-3.45(m,2H),2.90(br t,J＝11.42Hz,1H),2.20(br d,J＝10.54Hz,1H),1.84(br s,2H),1.60-1.71(m,1H),1.37-1.59(m,9H)。
步骤6.I-10的合成
将16L无水二氧六环、化合物I-3(3033g，10.37mol)、化合物I-9(3250g，10.14mol)、N,N’-二甲基乙二胺(482.5g，5.47mol)、碘化亚铜(482.5g，2.53mol)、磷酸钾(3900g，18.37mol)依次加入反应釜，调节反应温度至95～105℃，搅拌16小时。将反应液温度降低至15～25℃，反应液经硅藻土过滤，滤饼用二氯甲烷(1.6L*3)洗涤，将滤液减压浓缩。将固体溶于16L二氯甲烷，转移至分液器中，依次用氨水(质量分数25％～28％)(1.6L*3)和半饱和食盐水16L洗涤。将有机相用无水硫酸钠干燥，过滤，滤饼用二氯甲烷1.6L洗涤，合并的滤液减压浓缩至得到粗品。所得粗品分散于32L混合溶剂(正庚烷：乙酸乙酯＝7:1)中，在室温10～20℃下搅拌16小时，过滤，滤饼用混合溶剂(正庚烷：乙酸乙酯＝7:1，3.2L*3)洗涤，收集滤饼。将滤饼分散于20.8L混合溶剂(正庚烷：乙酸乙酯＝7:1)中，在室温10～20℃下搅拌16小时，过滤，滤饼用混合溶剂(正庚烷：乙酸乙酯＝7:1，2.08L*3)洗涤，收集滤饼，于55～65℃下真空烘干至恒重，得到化合物I-10。
LCMS(ESI)m/z:525.2(M+1)；1H NMR(400MHz,CDCl3)δppm 8.95(s,1H),8.20(s,1H),7.60-7.80(m,2H),7.14-7.24(m,2H),6.98-7.13(m,2H),6.86-6.94(m,1H),4.39(br s,1H),4.12(br d,J＝12.30Hz,1H),3.31-3.43(m,1H),3.21(br t,J＝11.17Hz,1H),2.83-2.98(m,1H),2.26(br d,J＝13.05Hz,1H),1.89(br d,J＝10.29Hz,2H),1.65-1.75(m,1H),1.44(br s,9H)。
步骤7.I-11的合成
将4M氯化氢/二氧六环溶液(16.4L)加入到反应釜中，内温10～30℃下分批加入化合物I-10(4100g，7.81mol)，保持内温10～30℃搅拌0.5小时。将反应液减压浓缩干，加入8.2L二氯甲烷后继续减压浓缩干。将所得油状物溶于12.3L水，用碳酸钠固体调节PH至8～9。继续搅拌0.5小时后用16.4L二氯甲烷萃取，有机相用8.2L水洗涤，收集有机相。所得水相用8.2L二氯甲烷萃取，收集有机相，将上述收集的两批有机相混合。混合的有机相用12.3L半饱和食盐水洗涤。将有机相用无水硫酸钠干燥，过滤，滤饼用2.05L二氯甲烷洗涤，合并的滤液减压浓缩干。经过超临界流体色谱检测(色谱柱：Chiralpak IG-350×4.6mmI.D，3μm；流动相：A:超临界二氧化碳，B:0.05％二乙胺的乙醇溶液；梯度： 梯度：B在2分钟内从5％到40％，在0.5min内从到5％，40％保持1.2min,5％保持0.8min；流速：4mL/min；柱温：35℃；波长：220nm)分析为外消旋化合物，经SFC分离(色谱柱：DAICEL CHIRALPAK AD(250mm*50mm,10μm)；流动相：A：超临界二氧化碳，B：[0.1％NH3H2O MeOH]；B％:50％-50％)纯化。将分离后所得固体溶于16.4L二氯甲烷中，用水(8.2L*2)洗涤，收集有机相。合并两次洗涤所得水相，用8.2L二氯甲烷萃取，收集有机相，将上述收集的两批有机相混合，用16.4L半饱和食盐水洗涤。将有机相用无水硫酸钠干燥，过滤，滤饼用2.05L二氯甲烷洗涤，合并的滤液减压浓缩干，得到化合物I-11，经过超临界流体色谱检测(色谱柱：Chiralpak IG-3 50×4.6mmI.D，3μm；流动相：A:超临界二氧化碳，B:0.05％二乙胺的乙醇溶液；梯度：梯度：B在2分钟内从5％到40％，在0.5min内从到5％，40％保持1.2min,5％保持0.8min；流速：4mL/min；柱温：35℃；波长：220nm)分析为单一构型化合物，保留时间为2.584min。
LCMS(ESI)m/z:425.2(M+1)；1H NMR(400MHz,DMSO-d6)δppm 9.18-10.35(m,1H),9.02-9.15(m,1H),8.33(s,1H),7.86(d,J＝8.88Hz,2H),7.19-7.45(m,4H),7.09(br t,J＝7.57Hz,1H),3.69-3.84(m,1H),3.61(br d,J＝12.01Hz,1H),3.18-3.38(m,2H),2.88-3.02(m,1H),2.22(br d,J＝11.26Hz,1H),1.88-2.03(m,2H),1.72-1.88(m,1H)。
步骤8.化合物1A的合成
搭建好重蒸装置，将化合物I-12(500g)加入反应瓶，外温升至90～110℃开始重蒸，丢弃蒸汽温度小于40℃的馏分，收集蒸汽温度40～80℃的馏分，收集至瓶底约15mL为止。将收集的馏分转移至重蒸装置中进行第二次重蒸，丢弃蒸汽温度小于40℃的馏分，收集蒸汽温度40～80℃的馏分，收集至瓶底约15mL为止。将收集的馏分转移至重蒸装置中进行第三次重蒸，丢弃蒸汽温度小于40℃的馏分，收集蒸汽温度40～80℃的馏分，收集至瓶底约15mL为止，得到的馏分备用。将化合物I-11(1600g，3.56mol)溶于四氢呋喃(16L)和水(8L)的混合溶液中，将上述溶液加入到反应釜中，向反应釜中加入磷酸钾(1513g，7.13mol)，将内温降至5～15℃。将重蒸后的I-12(322g，3.56mol)溶于四氢呋喃(3.2L)并将所得溶液滴加到反应釜中，滴加时保持内温5～15℃，滴加30分钟。滴加完毕后继续在5～15℃搅拌10分钟。将反应液分液，收集有机相和水相，水相用乙酸乙酯(8L*2)萃取，收集有机相，将上述收集的两批有机相混合。混合的有机相依次用半饱和柠檬酸溶液8L、饱和碳酸钠溶液8L*2、半饱和食盐水8L洗涤，将有机相用无水硫酸钠干燥，过滤，滤饼用乙酸乙酯1.6L洗涤，合并的滤液减压浓缩干。将所得油状物溶于16L乙酸乙酯中，加入碳酸钾(493.05g，3.56mol)，在室温10～20℃下搅拌16小时， 加入8L水后继续搅拌10分钟。停止搅拌后分液，收集有机相，有机相用8L半饱和食盐水洗涤，有机相将有机相用无水硫酸钠干燥，过滤，滤饼用1.6L乙酸乙酯洗涤，合并的滤液减压浓缩至约4L。将200～300目硅胶1600g铺在布氏漏斗中，用1.6L乙酸乙酯湿润。将上述浓缩液过滤，滤饼用8L乙酸乙酯洗涤，合并的滤液用布氏漏斗过滤，滤液减压浓缩干。在55～65℃下，将浓缩得到的油状物溶于3.2L乙醇中，降至室温10～20℃后向乙醇溶液中缓慢滴加4.8L水，有油状物析出，加入晶种100mg，调节搅拌速度至400转/分钟，逐渐有固体析出，继续室温搅拌16小时。过滤，滤饼用混合溶剂(乙醇：水＝2:3)1.6L洗涤，收集滤饼，于75～85℃下真空烘干16小时。将烘干的粗品过24目筛。
过筛后得到的粉末分散于混合溶剂(正庚烷：乙酸乙酯＝10:1)8.8L中，升温至50～60℃搅拌1小时后搅拌下降温至25～35℃，过滤，滤饼用混合溶剂(正庚烷：乙酸乙酯＝10:1)1.76L洗涤，收集滤饼，滤饼再重复上述打浆操作。所得滤饼于65～75℃下真空烘干至恒重，得到化合物1A。经过超临界流体色谱检测(色谱柱：Cellulose 2 150×4.6mmI.D，5μm；流动相：A:超临界二氧化碳，B:0.05％二乙胺的乙醇溶液；梯度：B在5分钟内从5％到40％，40％保持2.5min，回到5％平衡2.5分钟；流速：2.5mL/min；柱温：35℃；波长：220nm)分析为单一构型化合物，保留时间为6.916min。
LCMS(ESI)m/z:479.2(M+1)；1H NMR(400MHz,DMSO-d6)δppm 9.09(br s,1H),8.32(br s,1H),7.85(br d,J＝8.78Hz,2H),7.19-7.44(m,4H),7.09(br t,J＝7.65Hz,1H),6.75-6.96(m,1H),6.09(br t,J＝16.19Hz,1H),5.53-5.77(m,1H),3.99-4.80(m,2H),3.33-3.55(m,1H),3.13-3.30(m,1H),2.89-3.12(m,1H),2.22(br d,J＝11.29Hz,1H),1.74-2.09(m,2H),1.46-1.66(m,1H)。
化合物1A构型确证：
室温下，将化合物1A(100mg，209.00μmol)溶于DCM(0.3mL)，搅拌下滴加入正庚烷(1.5mL)，有明显粘稠物出现，加热(40～50℃)仍未溶清，冷至室温并静置过夜，有黄色油状物出现。继续在室温避光静置七个月，体系中有透明晶体出现，取出测单晶衍射，经确认为上述构型。
单晶衍射试验：
仪器型号：单晶X射线衍射仪(SC-XRD)(D8VENTURE)
结论：化合物1A的分子式为C26H21F3N4O2，晶系Monoclinic，空间群C2，晶胞参数α＝γ＝90°，β＝90.4900(10)°，体积绝对构型参数Flack值为0.04(3)。
生物测试数据
实验例1：
实验目的：
研究受试化合物在脑组织中的分布情况。
实验材料：
Sprague Dawley大鼠(雌性,200-300g,6～9周龄，北京维通利华)。
实验操作：
以标准方案测试化合物口服给药后在血浆、大脑和脑脊液中的药代动力学特征，实验中候选化合物配成浓度为1mg/mL的接近澄清的给药溶液，给予大鼠单次口服给药(剂量10mg/kg)。口服溶媒为5％的DMSO，10％的solutol HS15，20％的PEG400和65％的水的混合溶液。收集给药后0.5小时、1小时和6小时三个时间点的全血、脑和脑脊液。全血样品3200g离心10分钟，分离上清得血浆样品，加入一定体积含内标的乙腈溶液沉淀蛋白，离心取上清进样，以LC-MS/MS分析方法定量分析血药浓度。采用灌注法采集脑组织，使用高通量组织匀浆器按照4倍匀浆比例在湿冰条件进行匀浆。组织匀浆将保持在-60℃或更低温度，直到以LC-MS/MS分析方法定量分析脑组织浓度。动物在异氟醚麻醉下收集脑脊液，每个采样时间点采集50-100μL CSF。收集的脑脊液保存在-60℃或更低温度下储存，直到以LC-MS/MS分析方法定量分析脑脊液浓度。计算三种基质在不同采样时间点的药物浓度，血浆/脑组织比例和血浆/脑脊液比例。实验结果见表1。
表1.灌胃给药后不同时间点雌性大鼠脑组织中的分布情况
实验结论：化合物1A可以有效穿透血脑屏障，口服给药后可以分布于脑组织，并且在脑组织浓度高达835ng/g，因此有望对中枢神经系统的疾病达到治疗效果。
实验例2：
实验目的：
本实验评价了受试化合物在小鼠实验性自身免疫性脑脊髓炎(experimental  autoimmune encephalomyelitis,EAE)模型中的药效。实验性自身免疫性脑脊髓炎(EAE)是一种以特异性致敏的CD4+T细胞介导为主，对实验动物进行髓鞘蛋白免疫构建的疾病模型。该药效模型与人类MS在临床、生化、免疫及病理等诸多方面具有相同的特征，是目前国际公认的MS理想的动物模型。
实验材料：
C57BL/6小鼠(雌性，16-18g，上海吉辉实验动物饲养有限公司)。
实验操作：
通过在实验Day 0皮下注射MOG35-55诱导构建小鼠EAE模型并开始分组给药，免疫后Day 12，小鼠开始出现自身免疫性脑脊髓炎临床症状。溶媒对照组的平均临床评分在实验中前期逐渐升高，至Day 20达到3.11分，提示MOG35-55诱导的自身免疫性脑脊髓炎模型的成功。在MOG35-55免疫后第0天(Day 0)，根据体重随机分为5组，分别为溶媒对照组，地塞米松(Dex)组，化合物1A 20mg/kg组，化合物1A 40mg/kg组和化合物1A 60mg/kg组。另设一组未经MOG35-55造模的小鼠为正常对照组。本实验从小鼠免疫造模Day0开始，连续给药26天，通过EAE临床评分等指标进行药效评价。
实验结果显示，溶媒对照组的小鼠从在MOG35-55免疫后Day 12至Day 26出现严重的EAE临床症状，表明EAE模型建模成功。化合物1A连续给药26天可显著改善EAE小鼠临床症状。实验结果见附图1。
实验结论：本发明化合物连续给药26天对自身免疫性脑脊髓炎模型小鼠有显著治疗效果；本发明化合物在治疗多发性硬化症中展现了显著作用，有望用作多发性硬化症的治疗新方法。
实验例3：
实验目的：
本实验使用OCI-LY10细胞皮下异种移植肿瘤SCID小鼠模型评价化合物的抗肿瘤作用。
实验操作：
(1)细胞培养：
人弥漫性大B细胞淋巴瘤OCI-LY10细胞培养于含20％FBS的IMDM培养基中，维持在5％CO2的37℃饱和湿度培养箱中
(2)肿瘤细胞接种：
收集对数生长期OCI-LY10细胞，重悬于IMDM基础培养基中，1:1加入Matrigel， 调整细胞浓度至4×107/mL。在无菌条件下，接种0.1mL细胞悬液至SCID鼠右侧背部皮下，接种浓度为4×106/0.1mL/小鼠。
(3)受试物的配制：
待测化合物组：称量定量的受试化合物于棕色配药瓶内，加入相应体积的溶媒后涡旋，得到均匀混悬液或澄清溶液。
每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：1/2×a×b2，其中a、b分别为肿瘤测量的长和宽。
化合物的抑瘤疗效用TGI(％)评价。抑瘤率TGI(％)计算公式为：TGI(％)＝[1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。
统计分析：
本研究中，实验数据均以Mean±SEM表示。
统计分析基于实验结束时RTV的数据运用IBM SPSS Statistics软件进行分析。两组间比较用T test进行分析，三组或多组间比较用one-way ANOVA进行分析，如果方差齐(F值无显著性差异)，应用Tukey’s法进行分析，如果方差不齐(F值有显著性差异)，应用Games-Howell法进行检验。p<0.05认为有显著性差异。实验结果见表2。
表2本发明化合物对OCI-LY10细胞皮下异种移植瘤模型的作用
结论：本发明化合物1A对OCI-LY10细胞皮下异种移植瘤模型有显著性抑瘤作用，量效关系明显。但由实验例1可知，该化合物可以穿透血脑屏障，并在脑组织中保持高浓度，结合实验例1和3结果可以说明本申请化合物可以治疗中枢神经系统淋巴瘤。
实验例4
Namalwa颅内模型实验方案：通过颈动脉注射50万个表达荧光素酶的Namalwa细胞在裸鼠内建模。建模后第三天随机分为溶剂对照组和化合物1A治疗组，开始灌胃进行治疗，每天给药一次。化合物1A的剂量为150mg/kg。在建模后7天、14天和19天进行活体成像观察，结果如图2。
实验结果：第7天时未观察到脑部信号。溶剂对照组的脑部肿瘤信号在第14天和 19天时明显高于化合物1A治疗组，两组在第14天时无统计学差异，在第19天时有统计学差异(p＝0.035)。溶剂对照组老鼠从第21天开始死亡，因此无后续数据。
实验结论：
经治疗后，化合物1A治疗组在发于中枢神经系统的伯基特淋巴瘤的模型中对人Burkitt's淋巴瘤细胞的抑制能力显著强于溶剂对照组。本发明化合物在治疗伯基特淋巴瘤中展现了作用，有望用作伯基特淋巴瘤的治疗新方法。

Claims (14)

  1. 式(Ⅰ)所示化合物、其异构体、其药学上可接受的盐或其药物组合物在制备预防或治疗BTK相关疾病的药物中的用途，其特征在于：所述BTK相关疾病包括淋巴瘤、白血病、自身免疫性疾病、炎性疾病或代谢疾病；
    式(Ⅰ)化合物结构如下：
    其中，
    T1独立地选自N和CH；
    R2独立地选自H、C1-6烷基、C2-6烯基和C2-6炔基，所述C1-6烷基、C2-6烯基和C2-6炔基分别独立地任选被1、2或3个Ra取代；
    环A选自苯基和5-6元杂芳基；
    M独立地选自C3-6环烷基和3-6元杂环烷基，所述C3-6环烷基和3-6元杂环烷基分别独立地任选被1、2或3个Rb取代；
    R1和R3分别独立地选自F、Cl、Br、I、OH、NH2、CN；
    n和m分别独立地选自0、1、2或3，且n、m不同时为0；
    L1、L2分别独立地选自-CH2-、-CH2CH2-、-O-、-C(＝O)-和-C(＝O)-NH-；
    Ra独立地选自H、F、Cl、Br、I、OH、NH2、CN、C1-3烷基、C1-3烷氧基和C1-3烷氨基，所述C1-3烷基、C1-3烷氧基和C1-3烷氨基分别独立地任选被被1、2或3个R取代；
    Rb选自F、Cl、Br、I、CH3；
    R选自H、F、Cl、Br、I；
    所述5-6元杂芳基和3-6元杂环烷基分别独立地包含1、2、3或4个独立选自-NH-、-O-、-S-、-C(＝O)-、-S(＝O)-、和N的杂原子或杂原子团。
  2. 根据权利要求1所述的用途，其特征在于：所述BTK相关疾病包括中枢神经系统疾病和非中枢神经系统疾病。
  3. 根据权利要求2所述的用途，其特征在于：所述中枢神经系统疾病包括中枢神经系统淋巴瘤、中枢神经系统弥漫型大B细胞淋巴瘤、发于中枢神经系统的伯基特淋巴瘤、自身免疫性脑炎、多发性硬化症或视神经脊髓炎谱系疾病；所述非中枢神经系统疾病包括B细胞淋巴瘤、慢性淋巴细胞白血病/小淋巴细胞淋巴瘤、套细胞淋巴瘤、华氏巨球蛋白血症、边缘区淋巴瘤、滤泡性淋巴瘤、发于领骨、颅面骨或腹腔器官的伯基特淋巴瘤、非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、多发性骨髓瘤、类风湿性关节炎、系统性红斑狼疮、狼疮性肾炎、干燥综合症、IgG4相关疾病、慢性自发性荨麻疹、特发性血小板减少性紫癜、免疫性血小板减少症、天疱疮、哮喘、移植物抗宿主病、硬皮症、新型冠状病毒感染、肉芽肿性多血管炎、特发性肺纤维化、银屑病、动脉粥样硬化或糖尿病。
  4. 根据权利要求1～3任一项所述的用途，其特征在于：将式(Ⅰ)所示化合物、其异构体、其药学上可接受的盐或其药物组合物，与至少一种第二药物联合制备预防或治疗BTK相关疾病的药物；所述第二药物选自CD-20抑制剂或抗体、BCL-2抑制剂、SYK抑制剂、PI3K抑制剂、免疫抑制剂、化疗药物或自免疫检查点抑制剂。
  5. 根据权利要求4所述的用途，其特征在于：式(I)所示化合物与第二药物的质量比为1～100：100～1；优选为1～10：10～1。
  6. 根据权利要求4所述的用途，其特征在于：至少满足下列的一项：
    所述CD-20抑制剂或抗体包括利妥昔单抗、乌妥昔单抗、奥瑞利珠单抗、替伊莫单抗、奥妥珠单抗、奥法木单抗或维得利珠单抗；
    所述BCL-2抑制剂包括维奈克拉、APG-2575、BGB-11417、ICP-248、FCN-338或LP-108；
    所述SYK抑制剂包括福他替尼、Entospletinib、PRT-2761、HMPL-523、SKI-O-703、IC-265或GSK-2646264；
    所述PI3K抑制剂包括copanlisib、厄布利塞、度恩西布、艾德拉尼、alpelisib，parsaclisib、林普利司、eganelisib、BAY 10-82439、buparlisib、dactolisib、双替尼他或普喹替尼；
    所述免疫抑制剂包括来那度胺、泊马度胺、沙利度胺；
    所述化疗药物包括替莫唑胺、环磷酰胺、苯丁酸氮芥、苯达莫司汀、异环磷酰胺、强的松、地塞米松、顺铂、卡铂、奥沙利铂、氟达拉滨、喷司他丁、克拉屈滨、阿糖胞苷、吉西他滨、甲氨蝶呤、普拉曲沙、蒽环类、阿霉素、脂质体多柔比星、长春新碱、米托蒽醌、依托泊苷或博来霉素；
    所述自免疫检查点抑制剂包括帕博利珠单抗、纳武尤利单抗、卡瑞丽珠单抗、特瑞普利单抗、西米普利单抗、杜瓦鲁单抗、维鲁单抗、信迪利单抗、替雷丽珠单抗、赛帕利单抗、度伐利尤单抗、阿替利珠单抗、恩沃利单抗、舒格利单抗、斯鲁利单抗、派安普利单抗、赛瑞单抗、津伯利单抗、吉普诺利单抗、巴达珠单抗、普罗格利单抗、普可替尼单抗、可西贝利单抗、AUNP-12、瑞拉单抗、瑞替凡利单抗、多塔利单抗、卡多尼单抗、索卡唑单抗、阿德布雷单抗、易普利单抗或曲美木单抗。
  7. 根据权利要求1所述的用途，其特征在于：Ra独立地选自H、F、Cl、Br、I、OH、NH2、CN、CH3、OCH3、NH(CH3)和N(CH3)2。
  8. 根据权利要求1所述的用途，其特征在于：R2独立地选自H、C1-3烷基、C2-4烯基和C2-4炔基，所述C1-3烷基、C2-4烯基和C2-4炔基分别独立地任选被1、2或3个Ra取代；优选的，R2独立地选自H、CH3、乙烯基和丙炔基。
  9. 根据权利要求1所述的用途，其特征在于：M独立地选自环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、哌啶基和吗啉基，所述环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、哌啶基和吗啉基分别独立地任选被1、2或3个Rb取代；优选的，M独立地选自哌啶基和吗啉基。
  10. 根据权利要求1所述的用途，其特征在于：至少满足下列的一项：L1选自-O-和-C(＝O)-NH-；L2选自-C(＝O)-和-C(＝O)-NH-。
  11. 根据权利要求1所述的用途，其特征在于：环A选自苯基和吡啶基；优选的，结构单元选自更优选的，结构单元选自
  12. 根据权利要求1～11任一项所述的用途，其特征在于：式(Ⅰ)化合物选自：
    其中，
    R1、R3如权利要求1所定义；
    n和m分别独立地选自0、1、2或3，且n、m不同时为0；
    R2如权利要求1或5任意一项所定义；
    L1、L2如权利要求1或7所定义。
  13. 根据权利要求12所述的用途，其特征在于：式(Ⅰ)化合物选自：
    其中，n、m、R1、R2、R3、L1、L2如权利要求9所定义。
  14. 根据权利要求13所述的用途，其特征在于：式(Ⅰ)化合物选自：

    优选的，式(Ⅰ)化合物选自：
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