WO2019042445A1 - 一类具有抑制并降解布鲁顿酪氨酸蛋白激酶Btk活性的化合物 - Google Patents

一类具有抑制并降解布鲁顿酪氨酸蛋白激酶Btk活性的化合物 Download PDF

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WO2019042445A1
WO2019042445A1 PCT/CN2018/103710 CN2018103710W WO2019042445A1 WO 2019042445 A1 WO2019042445 A1 WO 2019042445A1 CN 2018103710 W CN2018103710 W CN 2018103710W WO 2019042445 A1 WO2019042445 A1 WO 2019042445A1
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substituent
group
hydrocarbon group
integer
compound
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PCT/CN2018/103710
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English (en)
French (fr)
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舒永志
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上海美志医药科技有限公司
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Priority to JP2020512719A priority Critical patent/JP2020532552A/ja
Priority to CN201880004080.4A priority patent/CN110461846B/zh
Priority to EP18852458.1A priority patent/EP3677584A4/en
Publication of WO2019042445A1 publication Critical patent/WO2019042445A1/zh
Priority to US16/808,338 priority patent/US11155561B2/en
Priority to US17/396,278 priority patent/US20210363148A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a compound having the activity of degrading tyrosine protein kinase Btk and its preparation and application.
  • Btk (Bruton's tyrosine kinase) is a Bruton's tyrosine protein kinase, a member of the Tec family of non-receptor tyrosine kinases, essential for cell differentiation and proliferation, and in B-cell lymphoma, acute lymphoblastic leukemia (ALL). ) and plasma cell tumors are expressed.
  • Btk is a key component of the B cell receptor (BCR) signaling pathway and is a good site for the targeted treatment of B cell lymphoma and other diseases.
  • Btk is a key regulator of B cell development, activation, signaling, and survival, and is involved in the regulation of angiogenesis, cell proliferation and apoptosis, and cell movement.
  • Btk is involved in many other hematopoietic signaling pathways, for example, involved in Toll-like receptors and cytokine receptor-mediated signaling pathways in macrophages, and is involved in IgE receptor signaling in mast cells.
  • Btk signaling pathway is currently non-Hodgkin's lymphoma (NHL), especially chronic lymphocytic leukemia (CLL), B-cell lymphoma and autoimmune diseases (rheumatoid arthritis, psoriasis, etc.) New hotspots in clinical treatment research (Deng Rong, Zhao Lizhi. Research progress of Btk inhibitors. Pharmaceutical Research, 2014, 33(6): 359-372.).
  • NHL non-Hodgkin's lymphoma
  • CLL chronic lymphocytic leukemia
  • B-cell lymphoma rheumatoid arthritis, psoriasis, etc.
  • h is an integer between 0 and 30;
  • R 22 and R 23 are each independently selected from the group consisting of H, cyano, hydroxy, amino, C 1-8 with or without a substituent, Or a C 1-8 cycloalkyl group having no substituent, a C 1-8 heterocyclic hydrocarbon group with or without a substituent, a C 1-8 alkoxy group with or without a substituent
  • X4 is H, halogen, cyano, nitro, hydroxy, with or without a substituent C 1-8 alkoxy, with or without a substituent C 1-8 alkoxycarbonyl; Or without a substituent C 1-8 amine group, with or without a substituent C 1-8 ester group, with
  • R 1 is selected from H, a C 1-10 hydrocarbon group with or without a substituent, a cyclic hydrocarbon group with or without a substituent, a heterocyclic hydrocarbon group with or without a substituent, with or without a C 1-6 acyl group having a substituent;
  • R 2 and R 5 are each independently selected from the group consisting of hydrogen, OR 33 , NR 34 R 35 , cyano, halogen, C 1-8 hydrocarbon group with or without a substituent, with or without a substituent. a cycloalkyl group, a heterocyclic hydrocarbon group with or without a substituent, a C 1-6 acyl group with or without a substituent, an amide group with or without a substituent; wherein R 33 , R 34 , R 35 each independently selected from H, a C 1-8 hydrocarbon group with or without a substituent, a cyclic hydrocarbon group with or without a substituent, a heterocyclic hydrocarbon group with or without a substituent;
  • R 4 is selected from the group consisting of H, a cyano group, a carboxyl group, a C 1-10 hydrocarbon group with or without a substituent, a hydrocarbon oxycarbonyl group with or without a substituent;
  • a is an integer between 0 and 5 (eg 1, 2, 3, 4, 5);
  • b is an integer between 0 and 3 (eg 1, 2, 3);
  • c is an integer between 0 and 30 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9);
  • d is an integer between 0 and 9 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9);
  • e is an integer between 0 and 3 (eg 1, 2, 3);
  • f is an integer between 0 and 3 (eg 1, 2, 3).
  • A is deleted;
  • Y is (CR 22 R 23) h, Wherein R 22 and R 23 are each independently selected from H, a hydroxyl group, a C 1-4 hydrocarbon group with or without a substituent, and h is an integer between 1 and 6;
  • Z is (CR 24 R 25 ) i And wherein R 24 and R 25 are each independently selected from H, a hydroxyl group, a C 1-4 hydrocarbon group with or without a substituent, i is an integer between 1 and 6; and c is 0.
  • A is deleted; W is deleted or is O; Y is (CR 22 R 23 ) h , wherein R 22 and R 23 are each independently selected from H, hydroxy, with or without a substituent. a hydrocarbon group of C 1-4 , h is an integer between 0 and 3; B is O; Z is (CR 24 R 25 ) i , wherein R 24 and R 25 are each independently selected from H, hydroxy, with or without a hydrocarbon group of C 1-4 having a substituent, i is an integer between 0 and 3; and c is an integer between 1 and 6.
  • A is SO 2 X1, wherein X1 is deleted or selected from O, and S; W is deleted or is O; Y is (CR 22 R 23 ) h , wherein R 22 and R 23 are independently selected From H, a hydroxyl group, a C 1-4 hydrocarbon group with or without a substituent, h is an integer between 1 and 6; Z is (CR 24 R 25 ) i , wherein R 24 and R 25 are each independently a hydrocarbon group of C 1-4 selected from H, a hydroxyl group, with or without a substituent, i is an integer between 0 and 3; c is 0.
  • A is deleted;
  • W is NR 17 , wherein R 17 is H, or a C 1-4 hydrocarbon group with or without a substituent;
  • Y is (CR 22 R 23 ) h , wherein R 22 , R 23 are each independently selected from H, a hydroxyl group, a C 1-4 hydrocarbon group with or without a substituent, h is an integer between 0 and 3;
  • Z is (CR 24 R 25 ) i , wherein R 24 and R 25 are each independently selected from H, a hydroxyl group, a C 1-4 hydrocarbon group with or without a substituent, i is an integer between 0 and 4;
  • B is O; and c is 1 to 6 An integer between.
  • A is deleted; W is deleted; Y is (CR 22 R 23 ) h , wherein R 22 and R 23 are each independently selected from H, hydroxy, C 1- with or without a substituent. a hydrocarbon group of 4 , h is an integer between 0 and 3; Z is (CR 24 R 25 ) i , wherein R 24 and R 25 are each independently selected from H, hydroxy, C 1 with or without a substituent a hydrocarbon group of -4 , i is an integer between 0 and 3; B is O; and c is an integer between 1 and 10 (preferably between 1 and 6).
  • a substituent preferably, such as a pyridine ring, or 1,2
  • 3-triazole ring 3- to 8-membered aromatic ring
  • any of the substituents are selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1-C6 alkoxy, unsubstituted or halogen C2-C6 alkoxyalkyl, unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C2-C6 alkylcarbonyl, unsubstituted or halogenated C1-C6 alkylene- A hydroxy, unsubstituted or C1-C6 alkyl substituted amine group.
  • the compound structure is as shown in Formula I':
  • R 1 is selected from the group consisting of: H, and a C 1-4 alkyl group with or without a substituent.
  • R 2 and R 5 are each independently selected from the group consisting of hydrogen, and a C 1-4 alkyl group with or without a substituent.
  • R 3 is selected from the group consisting of: hydrogen, and a C 1-4 alkyl group with or without a substituent.
  • R 6 is selected from the group consisting of: hydrogen, C 1-4 alkyl with or without a substituent, OR 29 wherein R 29 is selected from H, C 1 with or without a substituent -6 alkyl.
  • R 7 is selected from the group consisting of hydrogen, C 1-4 alkyl with or without a substituent, and NR 28 R 29 , wherein R 28 and R 29 are each independently selected from: H, Or a C 1-4 hydrocarbon group with or without a substituent.
  • R 8 is selected from the group consisting of hydrogen, halogen, and C 1-4 alkyl with or without a substituent.
  • R 9 is selected from the group consisting of hydrogen, halogen, and C 1-4 alkyl with or without a substituent.
  • R 10 is selected from the group consisting of hydrogen, halogen, cyano, nitro, and C 1-4 alkyl with or without a substituent.
  • R 11 is selected from the group consisting of hydrogen, halogen, cyano, nitro, and C 1-4 alkyl with or without a substituent.
  • R 4 is selected from H, cyano, C 1-6 alkyl with or without a substituent.
  • a pharmaceutical composition comprising the compound of the first aspect, or a pharmaceutically acceptable salt thereof, a prodrug, and a pharmaceutically acceptable carrier are provided.
  • the effective amount means a therapeutically effective amount or an inhibitory effective amount, preferably 0.01 to 99.99%.
  • the pharmaceutical composition further comprises another one or more anti-tumor agents.
  • the pharmaceutical composition is for inhibiting the activity of Bruton's tyrosine protein kinase (Btk).
  • the pharmaceutical composition is for treating a disease associated with Bruton's tyrosine protein kinase (Btk) activity or expression level.
  • Btk Bruton's tyrosine protein kinase
  • the disease comprises a tumor, an autoimmune disease; preferably, the tumor comprises non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), B cell lymphoma, etc.;
  • NHL non-Hodgkin's lymphoma
  • CLL chronic lymphocytic leukemia
  • B cell lymphoma etc.
  • the autoimmune diseases include rheumatoid arthritis, psoriasis and the like.
  • each group is as defined above, and M 1 is a leaving group.
  • the method further includes the steps of:
  • a method for inhibiting or degrading Bruton's tyrosine protein kinase (Btk) activity comprising the steps of: administering an inhibitory effective amount of a method according to the first aspect of the invention to a subject of inhibition A compound, or a pharmaceutically acceptable salt thereof, or an inhibitory effective amount of a pharmaceutical composition according to the fourth aspect of the invention, administered to a subject.
  • Btk Bruton's tyrosine protein kinase
  • the inhibition is non-therapeutic inhibition in vitro.
  • the inhibitory effective amount is from 0.001 to 500 nmol/L. It is preferably from 0.01 to 200 nmol/L.
  • the invention provides a method of treating a disease associated with Bruton's tyrosine protein kinase (Btk) activity or expression, the method comprising: administering to a subject a therapeutically effective amount of the invention A compound of formula I according to the first aspect, or a pharmaceutical composition according to the fourth invention of the invention.
  • Btk Bruton's tyrosine protein kinase
  • the subject is a mammal; preferably, the mammal is a human.
  • the disease associated with Bruton's tyrosine protein kinase (Btk) activity or expression is a tumor or an autoimmune disease.
  • a seventh aspect of the invention provides a method of inhibiting tumor cells in vitro, the method comprising: administering an inhibitory effective amount of a compound of formula I according to the first aspect of the invention to a subject, or a second invention according to the invention
  • the pharmaceutical composition of aspect is provided.
  • the inventors have conducted extensive and intensive research to prepare a class of compounds having the structure of formula I and found that they have Bruton's tyrosine protein kinase (Btk) inhibition and degradation activity. Moreover, the compound has an inhibitory effect on Bruton's tyrosine protein kinase (Btk) at a very low concentration, and the inhibitory activity is quite excellent, and thus it can be used for treatment with Bruton's tyrosine protein kinase (Btk). Sexual or expression-related diseases such as tumors. The present invention has been completed on this basis.
  • the present invention discloses a novel class of compounds and their use for inhibiting and degrading Bruton's tyrosine protein kinase (Btk). These compounds inhibit and degrade Btk and are useful in the treatment of tumors or autoimmune diseases.
  • Btk Bruton's tyrosine protein kinase
  • C 1-8 hydrocarbon group means a functional group containing only two atoms of carbon and hydrogen, wherein the number of carbon atoms is from 1 to 8.
  • the hydrocarbon group may be regarded as a radical remaining after the corresponding hydrocarbon loses one hydrogen atom, and may be an alkyl group, a cycloalkyl group, an alkenyl group or an alkynyl group; the structure may be linear, branched or cyclic; It is aliphatic or aromatic.
  • C 1-6 alkyl refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl. , tert-butyl, or the like.
  • alkoxy as used herein includes O-alkyl, wherein “alkyl” is as defined above.
  • halo as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo.
  • the compounds of the invention may contain double bonds. When such double bonds are present, the compounds of the invention are present in cis, trans or mixtures thereof.
  • Halogens described herein include fluorine, chlorine, bromine, and iodine.
  • alkyl moieties and alkyl moieties of the alkoxy groups referred to herein may be straight chain, branched or cyclic.
  • cycloalkyl group means a functional group containing two atoms of carbon and hydrogen. These include cycloalkyl, cycloalkenyl (having at least one carbon-carbon double bond) and aryl. They can be monocyclic, bicyclic and polycyclic. They can be either spiro rings or fused rings.
  • heterocyclic hydrocarbon group means a functional group containing carbon, hydrogen, and at least one hetero atom other than carbon and hydrogen. These include heterocycloalkyl, heterocycloalkenyl (having at least one carbon-carbon double bond) and heteroaryl.
  • One or more of the ring-forming atoms in the ring are heteroatoms.
  • Heteroatoms can be O, N and S atoms, as well as various combinations thereof. They can be monocyclic, bicyclic and polycyclic. They can be either spiro rings or fused rings.
  • substituted includes, but is not limited to, fluorine, chlorine, bromine, cyano, hydroxy, amino, C 1-6 alkoxy, C 1-6 halohydrocarbyl, C 1-6 acyl, C 1 -6 sulfonyl group.
  • hydrocarbyloxy refers to an O-hydrocarbyl group, wherein “hydrocarbyl” is as defined above.
  • amino refers to N (H or hydrocarbyl 1) (H or hydrocarbyl 2), wherein “hydrocarbyl” is as defined above.
  • the terms "containing”, “comprising” or “including” mean that the various ingredients may be used together in the mixture or composition of the present invention. Therefore, the terms “consisting essentially of” and “consisting of” are encompassed by the term “contains.”
  • the term "pharmaceutically acceptable” ingredient means a substance which is suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reaction), that is, a reasonable benefit/risk ratio.
  • the term "effective amount" means an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect.
  • the precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition, and the combination of therapeutic and/or therapeutic agents selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given condition, routine experimentation can be used to determine the effective amount that the clinician can determine.
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, unsubstituted or halogenated C 1-6 alkyl, Unsubstituted or halogenated C 2-6 acyl, unsubstituted or halogenated C 1-6 alkyl-hydroxy.
  • each of the chiral carbon atoms may be optionally in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • compound of the invention refers to a compound of formula I.
  • the term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.
  • the term "pharmaceutically acceptable salt” refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid,
  • the present invention relates to a compound of the formula I or a pharmaceutically acceptable salt thereof;
  • a hydrocarbyl group a C 1-8 heterocyclic hydrocarbon group with or without a substituent, a C 1-8 alkoxy group with or without a substituent;
  • X 4 H, halogen, cyano, nitro , hydroxy, with or without a substituent C 1-8 alkoxy, with or without a substituent C 1-8 alkoxycarbonyl, with or without a substituent C 1-8 , With or without a substituent C 1-8 ester group, with or without a substituent C 1-8 aminocarbonyl group, with or without a substituent C 1-8 hydrocarbon group, with or without a substituted C 1-8 cycloalkyl group, with or without a substituent C 1-8 heterocycloalkyl;
  • R 1 is selected from H, a C 1-10 hydrocarbon group with or without a substituent, a cyclic hydrocarbon group with or without a substituent, a heterocyclic hydrocarbon group with or without a substituent, with or without a C 1-6 acyl group having a substituent;
  • R 2 and R 5 are each independently selected from the group consisting of hydrogen, OR 33 , NR 34 R 35 , cyano, halogen, C 1-8 hydrocarbon group with or without a substituent, with or without a substituent. a cycloalkyl group, a heterocyclic hydrocarbon group with or without a substituent, a C 1-6 acyl group with or without a substituent, an amide group with or without a substituent; wherein R 33 , R 34 , R 35 each independently selected from H, a C 1-8 hydrocarbon group with or without a substituent, a cyclic hydrocarbon group with or without a substituent, a heterocyclic hydrocarbon group with or without a substituent;
  • R 4 is selected from the group consisting of H, a cyano group, a carboxyl group, a C 1-10 hydrocarbon group with or without a substituent, a hydrocarbon oxycarbonyl group with or without a substituent;
  • a is an integer between 0 and 5 (eg 1, 2, 3, 4, 5);
  • b is an integer between 0 and 3 (eg 1, 2, 3);
  • c is an integer between 0 and 30 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9);
  • d is an integer between 0 and 9 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9);
  • e is an integer between 0 and 3 (eg 1, 2, 3);
  • f is an integer between 0 and 3 (eg 1, 2, 3).
  • each of the C1-8 cycloalkyl groups is preferably a C3-8 cycloalkyl group (e.g., a C3-8 cycloalkyl group).
  • each of the C1-8 heterocycloalkyl groups is preferably a C3-8 heterocycloalkyl group (e.g., a 4-10 membered heterocycloalkyl group having 3 to 8 carbon atoms).
  • the compound is selected from the group consisting of:
  • the compound package of the present invention may form a pharmaceutically acceptable salt with an inorganic acid, an organic acid or a base.
  • the inorganic acid includes, but not limited to, hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid;
  • the organic acid includes but not limited to methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzene.
  • the base includes, but is not limited to, inorganic Salts and amines.
  • pharmaceutically acceptable salts refers to those salts which, according to medical judgment, are suitable for contact with tissues of humans and mammals without undue toxicity, irritation, allergic response and the like. Pharmaceutically acceptable salts are well known in the art.
  • the invention also encompasses pharmaceutical compositions comprising a prodrug of a compound of formula I.
  • Prodrugs include compounds in which the precursor molecule is covalently bonded to the free carboxyl group of the compound of formula I via a carbonate linkage, a urethane linkage, an amide linkage, an alkyl ester linkage, a phosphate linkage, a phosphoramidate linkage, On a hydroxyl group, an amino group or an amine group.
  • reaction scheme illustrates the preparation of the compounds of the invention. Unless otherwise indicated, A, B, W, Y, Z, X, M 1 , M 2 , a, b, c, d, e, f, g, R 1 , R 2 in the reaction scheme and subsequent discussion R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as defined above.
  • W is an amide, an alkoxycarbonylamine (OCONH) and a urea
  • compound I when A is bonded to a nitrogen atom by a CN bond, it can be prepared by direct substitution or reductive amination; when A is bonded to a nitrogen atom in the form of an amide, urea, carbamate, sulfonamide or sulfamide, Prepared with the corresponding acid chloride, activated ester (amide), carboxylic acid, isocyanate, sulfonyl chloride, sulfuryl chloride.
  • the compound I can also be obtained by first reacting the formula IV with the intermediate chain and then reacting with the formula III.
  • the chemical synthesis method used is as described above.
  • the compounds of formula III, IV can be obtained by known synthetic methods or are readily commercially available.
  • the disease associated with Bruton's tyrosine protein kinase (Btk) activity or expression is a tumor, preferably a tumor selected from the group consisting of non-small cell lung cancer, inflammatory muscle fibers. Cell tumors, etc.
  • the compounds of formula I of the present invention are useful in the preparation of a pharmaceutical composition comprising: (i) an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof; and (ii) pharmaceutically acceptable Carrier.
  • the effective amount refers to a therapeutically effective amount or an inhibitory effective amount.
  • the compounds of formula I of the present invention may also be used in a method of inhibiting or degrading Bruton's tyrosine protein kinase (Btk), which is either non-therapeutic inhibition in vitro or therapeutic inhibition.
  • Btk Bruton's tyrosine protein kinase
  • the inhibitory effective amount when an inhibitory effective amount of a compound of formula I of the present invention, or a pharmaceutically acceptable salt thereof, is administered to a subject, is from 0.001 to 500 nmol/L, preferably 0.01. -200nmol/L.
  • the present invention also provides a method of treating a disease associated with Bruton's tyrosine protein kinase (Btk) activity or expression, the method comprising: administering to a subject a therapeutically effective amount of a compound of formula I, Or a pharmaceutical composition comprising the compound of formula I as an active ingredient.
  • Btk Bruton's tyrosine protein kinase
  • the compound of the present invention has excellent inhibitory activity against Bruton's tyrosine protein kinase (Btk), the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates And a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the treatment, prevention, and alleviation of diseases associated with Btk activity or expression.
  • Btk Bruton's tyrosine protein kinase
  • the compounds of the invention are useful in the treatment of diseases including tumors and the like.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 5 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition 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 mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, 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 elixirs.
  • the liquid dosage form 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 a mixture of these substances.
  • 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, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 5 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • a pharmaceutical composition for treating a disease associated with Btk enzyme activity is provided.
  • kinase reaction buffer 50 mM HEPES, pH 7.5; 0.0015% Brij-35
  • kinase reaction stop solution 100 mM HEPES, pH 7.5; 0.0015% Brij-35; 0.2% Coating Reagent; 50 mM EDTA
  • Experimental samples were configured: 100 ⁇ L of a 5 ⁇ M sample solution (100% DMSO dissolved) was added to a 96-well plate to obtain a 50 ⁇ sample solution. Two wells containing only 100 ⁇ L of 100% DMSO were placed on the same plate as controls. One was used as no sample control and the other was used as no enzyme control. A 10 ⁇ L sample and 90 ⁇ L of 1 ⁇ Kinase Reaction Buffer were added to a 96-well plate as a transfer plate. Shake the transfer plate for 10 minutes.
  • Test plate Take 5 ⁇ L of the sample prepared in the 96-well transfer plate to the 384-well plate.
  • Kinase reaction Add 10 ⁇ L of 2.5 ⁇ Btk kinase solution (kinase diluted with 1 ⁇ kinase reaction buffer) in 5 ⁇ L of 5 ⁇ compound solution (dissolved in DMSO, diluted 10-fold with water), incubate for 10 min at room temperature, then add 10 ⁇ L of 2.5 ⁇ substrate peptide solution (FAM-labeled peptide and ATP diluted in 1 ⁇ kinase reaction buffer).
  • the kinase reaction was terminated: 25 ⁇ L of the kinase reaction stop solution was added after a reaction at 28 ° C for a while.
  • Fluorescence (F) was tested on a Caliper and data was collected.
  • RPMI8226 cell line was cultured in RPMI1640 medium containing 10% calf serum at 37 ° C, 5% CO 2 , and a humidified humidity incubator.
  • the DMSO control group and the compound intervention group (10 ⁇ M) were set. After collecting the cells for 24 hours, 100 ⁇ L of pre-cooled cell lysate was added, and the cells were lysed on ice for 30 min to extract the total protein of the cells, and the protein concentration was determined by the bisquinolinecarboxylic acid (BCA) method. Quantitative. Glue, sample, electrophoresis, then transfer, block, add rabbit anti-human Btk (1:500), incubate overnight at 4 ° C, rinse and add horseradish peroxidase-labeled goat anti-rabbit IgG (1: 5000), ECL developer development after rinsing, Bio-Rad gel imaging system scanning imaging, computer software processing analysis. Glyceraldehyde phosphate dehydrogenase (GAPDH) internal reference control.
  • Glyceraldehyde phosphate dehydrogenase Glyceraldehyde phosphate dehydrogenase (GAPDH) internal
  • the gray scale analysis of each strip was performed using Image J software to calculate the degradation rate of the compound degraded Btk protein.
  • Compound number Degradation activity Compound number Degradation activity 3 ++++ 28 +++ 7 ++++ 29 ++++ 14 ++++ 30 ++++ 15 ++++ 31 ++++ 16 ++++ 32 +++ 17 +++ 33 ++++ 18 +++ 34 ++++ 19 +++ 35 ++++ 20 +++ 36 +++ twenty one +++ 37 ++++ twenty two +++ 39 ++++ twenty three ++++ 40 +++ twenty four ++++ 41 +++ 25 ++++ 43 ++++ 26 ++++ 44 +++ 27 ++++ Control compound -
  • the proliferation inhibition effect of the compound on RPMI 8226 cells was determined in vitro by the CCK8 assay. Specific steps are as follows:
  • RPMI 8226 cells were cultured in 1640 medium of 10% calf serum, seeded in 96-well plates, 2 x 10 5 cells/well, and placed in a 37 ° C, 5% CO 2 incubator.
  • the compound was dissolved in dimethyl sulfoxide (DMSO) to obtain a solution having a concentration of 10 mM, and then diluted to a desired concentration with a phosphate buffer, and added to the above 96-well plate at a concentration of 2 wells each, 10 ⁇ l per well. The concentrations were tested in two parallels.
  • the DMSO was diluted as a gradient and added to the plate as a control.
  • the relative survival rate of the cells after compound treatment was calculated based on the light absorption value.
  • the activity assay data indicates that the compounds of the present invention have significant inhibitory activity against ibrutinib-resistant cell lines, and thus the compounds of the present invention are useful for treating tumors resistant to ibrutinib.
  • Example 8 Inhibition of proliferation of DOHH2 cells (human B cell lymphoma cells) and SU-DHL-6 (human B cell lymphoma cells) by CTG assay
  • the proliferation inhibition effect of the compounds on DOHH2 cells (available from ATCC) and SU-DHL-6 cells (commercially available from ATCC) was determined in vitro by the CCK8 assay.
  • Cell culture and compound preparation Referring to Example 7, the cell plating density DOHH2 cells were 1 ⁇ 10 4 cells/well, and the SU-DHL-6 cells were 1.5 ⁇ 10 4 cells/well.
  • the culture time after administration was 72 hours. Then, an appropriate amount of CTG reagent was added, the luminescence value was measured, and the inhibition rate was calculated.

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Abstract

一类具有抑制并降解布鲁顿酪氨酸蛋白激酶Btk活性的式I化合物，其具有很好的Btk抑制活性并能将Btk降解，可以用于制备治疗间Btk活性相关的疾病的药物。 (I)

Description

一类具有抑制并降解布鲁顿酪氨酸蛋白激酶Btk活性的化合物 技术领域
本发明属于医药领域，具体地涉及一类具有降解酪氨酸蛋白激酶Btk活性的化合物及其制备和应用。
背景技术
Btk(Bruton's tyrosine kinase)即布鲁顿酪氨酸蛋白激酶，是非受体酪氨酸激酶Tec家族的成员,为细胞分化和增值所必需基因，且在B细胞淋巴瘤、急性淋巴细胞白血病(ALL)和浆细胞瘤中均有表达。Btk为B细胞受体(BCR)信号通路的关键组成部分，是靶向治疗B细胞淋巴瘤等疾病的很好位点。
Btk是B细胞发育、激活、信号传导和存活的关键调节物，参与对血管生成、细胞增殖和凋亡以及细胞运动的调节。除此之外，Btk还参与到许多其他造血细胞信号途径，例如，参与巨噬细胞中Toll样受体和细胞因子受体介导的信号通路，参与肥大细胞中IgE受体的信号传导等。
近年来研究显示，Btk信号通路是目前非霍奇金淋巴瘤(NHL)，特别是慢性淋巴细胞白血病(CLL)、B细胞淋巴瘤及自身免疫疾病(类风湿性关节炎、银屑病等)临床治疗研究中的新热点(邓容，赵利枝.Btk抑制剂的研究进展.药学研究,2014,33(6):359-372.)。
因此，本领域技术人员致力于开发能够抑制Btk活性的化合物。
发明内容
本发明的目的就是提供一种能够抑制并降解Btk的化合物，及其制备和应用。
在本发明的第一方面，提供了一种如下式I所示的化合物，或其药学上可接受的盐：
Figure PCTCN2018103710-appb-000001
其中：
Figure PCTCN2018103710-appb-000002
表示单键
Figure PCTCN2018103710-appb-000003
表示单键或双键
A缺失或选自C(＝O)、C(＝O)X1、SOX1、SO 2X1、带有或不带有取代基的C 1-8烃基、带有或不带有取代基的C 1-8环烃基、和带有或不带有取代基的C 1-8杂环烃基；其中X1缺失或选自(CR 12R 13) jO、(CR 12R 13) j、带有或不带有取代基的3～8元杂芳基(优选地如吡啶基、或1，2，3-三氮唑基)、带有或不带有取代基的3～8元芳基(优选地如苯基)和NR 14；其中R 12、R 13、R 14各自独立的为H、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、和带有或不带有取代基的C 1-8的杂环烃基；j为0至3之间的整数；
W缺失或选自O、NR 17、-X2C(＝O)X3、-X2S(＝O) gX3；其中R 17为H、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、带有或不带有取代基的C 1-8的杂环烃基；其中X2、X3各自独立的缺失或选自O、S、NR 18；其中g为0至2的整数；其中R 18为H、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、带有或不带有取代基的C 1-8的杂环烃基；
Y为(CR 22R 23) h、CHX4(CR 22R 23) h、CX4＝CH(CR 22R 23) h、C(＝CH2)(CR 22R 23) h或(CR 22R 23) h；其中h为0至30之间的整数；其中R 22、R 23各自独立的选自H、氰基、羟基、氨基、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、带有或不带有取代基的C 1-8的杂环烃基、带有或不带有取代基的C 1-8的烃氧基；其中X4为H、卤素、氰基、硝基、羟基、带有或不带 有取代基C 1-8烃氧基、带有或不带有取代基C 1-8烃氧羰基、带有或不带有取代基C 1-8胺基、带有或不带有取代基C 1-8酯基、带有或不带有取代基C 1-8胺基羰基、带有或不带有取代基C 1-8烃基、带有或不带有取代基C 1-8环烃基、带有或不带有取代基C 1-8杂环烃基；
Z为(CR 24R 25) i、CHX5(CR 24R 25) i、CX5＝CH(CR 24R 25) i或C≡C(CR 24R 25) i；其中i为0至30之间的整数；其中R 24、R 25各自独立的选自H、氰基、羟基、氨基、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基C 1-8环烃基、带有或不带有取代基C 1-8杂环烃基、带有或不带有取代基C 1-8烃氧基；其中X5＝H、卤素、氰基、硝基、羟基、带有或不带有取代基C 1-8的烃氧基、带有或不带有取代基C 1-8烃氧羰基、带有或不带有取代基C 1-8胺基、带有或不带有取代基C 1-8酯基、带有或不带有取代基C 1-8胺基羰基、带有或不带有取代基C 1-8烃基、带有或不带有取代基C 1-8环烃基、带有或不带有取代基C 1-8杂环烃基；
B缺失或选自O、C＝O、S、NR 15、-NR 15C(＝O)-、-C(＝O)NR 15-、-C(＝O)O-、OC(＝O)O-、-NR 15C(＝O)O-、-OC(＝O)NR 15-、-NR 15C(＝O)NR 16-、带有或不带有取代基的C 1-12的烃基、带有或不带有取代基的C 1-12的环烃基、和带有或不带有取代基的C 1-12的杂环烃基；其中R 15、R 16各自独立的选自H、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、和带有或不带有取代基的C 1-8的杂环烃基；
X选自CR 19R 20、C(＝O)、S(＝O)、SO 2、NR 21；其中R 19、R 20各自独立的选自H、氰基、羟基、氨基、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、带有或不带有取代基的C 1-8的杂环烃基、带有或不带有取代基的C 1-8的烃氧基；其中R 21选自H、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、带有或不带有取代基的C 1-8的杂环烃基；
R 1选自H、带有或不带有取代基的C 1～8烃基、带有或不带有取代基的环烃基、带有或不带有取代基的杂环烃基、带有或不带有取代基的C 1-6酰基；
R 2、R 5各自独立的选自：氢、OR 33、NR 34R 35、氰基、卤素、带有或不带有取代基的C 1～8烃基、带有或不带有取代基的环烃基、带有或不带有取代基的杂环烃基、带有或不带有取代基的C 1-6酰基、带有或不带有取代基的酰胺基；其中R 33、R 34、R 35各自独立的选自H、带有或不带有取代基的C 1～8的烃基、带有或不带有取代基的环烃基、带有或不带有取代基的杂环烃基；
R 3、R 6、R 7、R 8、R 9、R 10、R 11各自独立的选自：H、OR 27、NR 28R 29、氰基、卤素、硝基、带有或不带有取代基的C 1～8烃基、带有或不带有取代基的环烃基、带有或不带有取代基的杂环烃基、X6S(＝O) kR 30、X6C(＝O)R 31；其中k＝0-2；其中R 27，R 28，R 29，R 30，R 31各自独立的选自H、带有或不带有取代基的C 1～8烃基、环烃基、杂环烃基；其中X6缺失或选自O、S、NR 32；其中R 32为H、带有或不带有取代基的C 1～8的烃基、带有或不带有取代基的环烃基、和带有或不带有取代基的杂环烃基；
R 4选自H、氰基、羧基、带有或不带有取代基的C 1～8的烃基、带有或不带有取代基的烃氧羰基；
a为0至5之间的整数(如1、2、3、4、5)；
b为0至3之间的整数(如1、2、3)；
c为0至30之间的整数(如1、2、3、4、5、6、7、8、9)；
d为0至9之间的整数(如1、2、3、4、5、6、7、8、9)；
e为0至3之间的整数(如1、2、3)；
f为0至3之间的整数(如1、2、3)。
在另一优选例中，A缺失；W为-X2C(＝O)X3，其中，X2为NR 18、X3缺失，或者X3为NR 18、并且X2缺失；Y为(CR 22R 23) h，其中R 22、R 23各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，h为1至6之间的整数；Z为(CR 24R 25) i，其中R 24、R 25各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，i为1至6之间的整数；c为0。
在另一优选例中，A缺失；W缺失或为O；Y为(CR 22R 23) h，其中R 22、R 23各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，h为0至3之间的整数；B为O；Z为(CR 24R 25) i，其中R 24、R 25各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，i为0至3之间的整数；c为1至6之间的整数。
在另一优选例中，A为SO 2X1，其中X1缺失或选自O、和S；W缺失或为O；Y为(CR 22R 23) h，其中R 22、R 23各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，h为1至6之间的整数；Z为(CR 24R 25) i，其中R 24、R 25各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，i为0至3之间的整数；c为0。
在另一优选例中，A缺失；W为NR 17，其中R 17为H、或带有或不带有取代基的C 1-4的烃基；Y为(CR 22R 23) h，其中R 22、R 23各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，h为0至3之间的整数；Z为(CR 24R 25) i，其中R 24、R 25各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，i为0至4之间的整数；B为O；c为1至6之间的整数。
在另一优选例中，A缺失；W缺失；Y为(CR 22R 23) h，其中R 22、R 23各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，h为0至3之间的整数；Z为(CR 24R 25) i，其中R 24、R 25各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，i为0至3之间的整数；B为O；c为1至10之间(优选为1至6之间)的整数。
在另一优选例中，A为C(＝O)X1-，其中X1缺失或选自带有或不带有取代基的3～8元杂芳环(优选地如吡啶环、或1，2，3-三氮唑环)、和带有或不带有取代基的3～8元芳环(优选地如苯环)。
在另一优选例中，A为C(＝O)，Y为C(＝CH2)(CR 22R 23) h，其中h为0至10之间的整数(优选为0至5之间的整数)。
在另一优选例中，所述的任一取代基选自下组：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C1-C6烷氧基、未取代或卤代的C2-C6烷氧基烷基、未取代或卤代的C3-C8环烷基、未取代或卤代的C2-C6烷基羰基、未取代或卤代的C1-C6亚烷基-羟基、未取代或C1-C6烷基取代的胺基。
在另一优选例中，所述化合物结构如式I’所示：
Figure PCTCN2018103710-appb-000004
其中，各基团定义如上所述。
在另一优选例中，所述化合物结构如式I”所示：
Figure PCTCN2018103710-appb-000005
其中，各基团定义如上所述。
在另一优选例中，所述化合物结构如式I”’所示：
Figure PCTCN2018103710-appb-000006
其中，各基团定义如上所述。
在另一优选例中，式I、I’、I”或I”’中，
Figure PCTCN2018103710-appb-000007
表示单键。
在另一优选例中，所述X为C(＝O)。
在另一优选例中，R 1选自：H、和带有或不带有取代基的C 1-4烷基。
在另一优选例中，R 2、R 5各自独立的选自：氢、和带有或不带有取代基的C 1-4烷基。
在另一优选例中，R 3选自：氢、和带有或不带有取代基的C 1-4烷基。
在另一优选例中，R 6选自：氢、带有或不带有取代基的C 1-4烷基、OR 29其中R 29选自H、带有或不带有取代基的C 1-6烷基。
在另一优选例中，R 7选自：氢、带有或不带有取代基的C 1-4烷基、和NR 28R 29，其中R 28、R 29各自独立的选自：H、或带有或不带有取代基的C 1-4的烃基。
在另一优选例中，R 8选自：氢、卤素、和带有或不带有取代基的C 1-4烷基。
在另一优选例中，R 9选自：氢、卤素、和带有或不带有取代基的C 1-4烷基。
在另一优选例中，R 10选自：氢、卤素、氰基、硝基、和带有或不带有取代基的C 1-4烷基。
在另一优选例中，R 11选自：氢、卤素、氰基、硝基、和带有或不带有取代基的C 1-4烷基。
在另一优选例中，R 4选自H、氰基、带有或不带有取代基的C 1-6烷基。
本发明的第二方面，提供一种药物组合物，所述的组合物含有第一方面所述的化合物或其药学上可接受的盐、前药，以及药学上可接受的载体。
在另一优选例中，所述的有效量是指治疗有效量或抑制有效量，较佳地为0.01～99.99％。
在另一优选例中，所述药物组合物，还包含另外一种或多种抗肿瘤剂。
在另一优选例中，所述的药物组合物用于抑制布鲁顿酪氨酸蛋白激酶(Btk)的活性。
在另一优选例中，所述的药物组合物用于治疗布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病。
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的用途，用于：
(a)制备治疗与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病的药物；
(b)制备布鲁顿酪氨酸蛋白激酶(Btk)靶向抑制剂或降解剂；
(c)体外非治疗性地抑制或降解布鲁顿酪氨酸蛋白激酶(Btk)的活性；
(d)体外非治疗性地抑制肿瘤细胞增殖；和/或
(e)治疗与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病。
在另一优选例中，所述的疾病包括肿瘤、自身免疫疾病；优选地，所述肿瘤包括非霍奇金淋巴瘤(NHL)、慢性淋巴细胞白血病(CLL)、B细胞淋巴瘤等；所述自身免疫疾病包括类风湿性关节炎、银屑病等。
本发明的第四方面，提供了一种如本发明第一方面所述的式I化合物的制备方法，包括步骤：
Figure PCTCN2018103710-appb-000008
(a)在惰性溶剂中，用式IV化合物和式II化合物反应，得到式I化合物；
上述各式中，各基团的定义如上所述，M 1为离去基团。
在另一优选例中，所述方法还包括步骤：
Figure PCTCN2018103710-appb-000009
(b)在惰性溶剂中，用式III化合物和式V化合物反应，得到式II化合物，M 1、M 2为离去基 团。
本发明的第五方面，提供了一种抑制或降解布鲁顿酪氨酸蛋白激酶(Btk)活性的方法，包括步骤：对抑制对象施用抑制有效量的如本发明第一方面所述的式I化合物或其药学上可接受的盐，或对抑制对象施用抑制有效量的如本发明第四方面所述的药物组合物。
在另一优选例中，所述的抑制是体外非治疗性的抑制。
在另一优选例中，当对抑制对象施用抑制有效量的如本发明第一方面所述的式I化合物或其药学上可接受的盐时，所述的抑制有效量为0.001-500nmol/L，较佳地为0.01-200nmol/L。
本发明的第六方面，提供了一种治疗与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病的方法，所述方法包括：对治疗对象施用治疗有效量的如本发明第一方面所述的式I化合物，或如本发明第四发明所述的药物组合物。
在另一优选例中，所述对象为哺乳动物；优选地，所述哺乳动物为人。
在另一优选例中，所述与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病为肿瘤或自身免疫疾病。
本发明的第七方面，提供了一种体外抑制肿瘤细胞的方法，所述方法包括：对抑制对象施用抑制有效量的如本发明第一方面所述的式I化合物，或如本发明第二方面所述的药物组合物。
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。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过广泛而深入的研究，制备了一类具有式I所示结构的化合物，并发现其具有布鲁顿酪氨酸蛋白激酶(Btk)抑制和降解活性。且所述的化合物在极低浓度下，即对布鲁顿酪氨酸蛋白激酶(Btk)产生抑制作用，抑制活性相当优异，因而可以用于治疗与布鲁顿酪氨酸蛋白激酶(Btk)性或表达量相关的疾病如肿瘤。在此基础上完成了本发明。
本发明公开一类新化合物及其能抑制并降解布鲁顿酪氨酸蛋白激酶(Btk)的用途。这些化合物能抑制并降解Btk，可用于治疗肿瘤或自身免疫性疾病。
术语
本发明中，术语“C 1-8烃基”是指只含有碳、氢两种原子的官能团，其中，碳原子的个数为1～8。烃基可以看作是相应的烃失去一个氢原子后剩下的自由基，其可为烷基、环烷基、烯基或炔基等；其结构可为直链、支链或环状；可以是脂肪族的，也可以是芳香族的。
术语“C 1-6烷基”指具有1～6个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基，或类似基团。
本文所用的术语“烷氧基”包括O-烷基，其中的“烷基”是如上所定义的。
本发明所用术语“卤代”除非另有指示，包括氟代、氯代、溴代或碘代。
本发明的化合物可以含有双键。当含有这类双键时，本发明的化合物以顺式、反式或其混合物存在。
本文所述卤素包括氟、氯、溴和碘。
除非另有指示，本文所指烷基以及烷氧基的烷基部分可以是直链、支链或是环状的。
本发明中，术语“环烃基”是指含有碳、氢两种原子的官能团。包括环烷基、环烯基(至少含有一个碳碳双键)和芳基。它们可以是单环、双环和多环。它们可以是螺环，也可以是稠环。
本发明中，术语“杂环烃基”是指含有碳、氢及除碳、氢外至少一种杂原子的官能团。包括杂环烷基、杂环烯基(至少含有一个碳碳双键)和杂芳基。环中的一个或多个成环原子为杂原子。杂原子可以是O、N和S原子，以及它们的各种组合。它们可以是单环、双环和多环。它们可以是螺环，也可以是稠环。
本发明中，术语“取代基”包括但不限于氟、氯、溴、氰基、羟基、氨基、C 1-6烃氧基、C 1-6卤代烃基、C 1-6酰基、C 1-6磺酰基。
本文所用的术语“烃氧基”是指O-烃基，其中的“烃基”是如上所定义的。
本文所用的术语“烃氧羰基”是指C(＝O)O-烃基，其中的“烃基”是如上所定义的。
本文所用的术语“胺基”是指N(H或烃基1)(H或烃基2)，其中的“烃基”是如上所定义的。
本文所用的术语“胺基羰基”是指C(＝O)-胺基，其中的“胺基”是如上所定义的。
本文所用的术语“酰胺基”是指N(H或烃基)-C(＝O)-烃基，其中的“烃基”是如上所定义的。
本发明中，术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含有”中。
本发明中，术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应)，即有合理的效益/风险比的物质。
本发明中，术语“有效量”指治疗剂治疗、缓解或预防目标疾病或状况的量，或是表现出可检测的治疗或预防效果的量。对于某一对象的精确有效量取决于该对象的体型和健康状况、病症的性质和程度、以及选择给予的治疗剂和/或治疗剂的组合。因此，预先指定准确的有效量是没用的。然而，对于某给定的状况而言，可以用常规实验来确定该有效量，临床医师是能够判断出来的。
在本文中，除特别说明之处，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、未取代或卤代的C 1-6烷基、未取代或卤代的C 2-6酰基、未取代或卤代的C 1-6烷基-羟基。
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的光学异构体，如单一手性的化合物，或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化合物之中，各手性碳原子可以任选地为R构型或S构型，或R构型和S构型的混合物。
如本文所用，术语“本发明化合物”指式I所示的化合物。该术语还包括及式I化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
化合物及其药学上可接受的盐
本发明涉及下式I化合物或其药学上可接受的盐；
Figure PCTCN2018103710-appb-000010
其中：
Figure PCTCN2018103710-appb-000011
表示单键
Figure PCTCN2018103710-appb-000012
表示单键或双键
A缺失或选自C(＝O)、C(＝O)X1－、SOX1－、SO 2X1－、带有或不带有取代基的C 1-8烃基、带有或不带有取代基的C 1-8环烃基、和带有或不带有取代基的C 1-8杂环烃基；其中X1缺失或选自(CR 12R 13) jO、(CR 12R 13) j、带有或不带有取代基的3～8元杂芳基(优选地如吡啶基、或1，2，3-三氮唑基)、带有或不带有取代基的3～8元芳基(优选地如苯基)和NR 14；其中R 14为H、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、和带有或不带有取代基的C 1-8的杂环烃基；
W缺失或选自O、NR 17、-X2C(＝O)X3、-X2S(＝O) gX3；其中R 17为H、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、带有或不带有取代基的C 1-8的杂环烃基；其 中X2、X3各自独立的缺失或选自O、S、NR 18；其中g为0至2的整数；其中R 18为H、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、带有或不带有取代基的C 1-8的杂环烃基；
Y为(CR 22R 23) h、CHX4(CR 22R 23) h、CX4＝CH(CR 22R 23) h或(CR 22R 23) h；其中h为0至30之间的整数；其中R 22、R 23各自独立的选自H、氰基、羟基、氨基、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、带有或不带有取代基的C 1-8的杂环烃基、带有或不带有取代基的C 1-8的烃氧基；其中X4＝H、卤素、氰基、硝基、羟基、带有或不带有取代基C 1-8烃氧基、带有或不带有取代基C 1-8烃氧羰基、带有或不带有取代基C 1-8胺基、带有或不带有取代基C 1-8酯基、带有或不带有取代基C 1-8胺基羰基、带有或不带有取代基C 1-8烃基、带有或不带有取代基C 1-8环烃基、带有或不带有取代基C 1-8杂环烃基；
Z为(CR 24R 25) i、CHX5(CR 24R 25) i、CX5＝CH(CR 24R 25) i或C≡C(CR 24R 25) i；其中i为0至30之间的整数；其中R 24、R 25各自独立的选自H、氰基、羟基、氨基、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基C 1-8环烃基、带有或不带有取代基C 1-8杂环烃基、带有或不带有取代基C 1-8烃氧基；其中X5＝H、卤素、氰基、硝基、羟基、带有或不带有取代基C 1-8的烃氧基、带有或不带有取代基C 1-8烃氧羰基、带有或不带有取代基C 1-8胺基、带有或不带有取代基C 1-8酯基、带有或不带有取代基C 1-8胺基羰基、带有或不带有取代基C 1-8烃基、带有或不带有取代基C 1-8环烃基、带有或不带有取代基C 1-8杂环烃基；
B缺失或选自O、C＝O、S、NR 15、-NR 15C(＝O)-、-C(＝O)NR 15-、-C(＝O)O-、OC(＝O)O-、-NR 15C(＝O)O-、-OC(＝O)NR 15-、-NR 15C(＝O)NR 16-、带有或不带有取代基的C 1-12的烃基、带有或不带有取代基的C 1-12的环烃基、和带有或不带有取代基的C 1-12的杂环烃基；其中R 15、R 16各自独立的选自H、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、和带有或不带有取代基的C 1-8的杂环烃基；
X选自CR 19R 20、C(＝O)、S(＝O)、SO 2、NR 21；其中R 19、R 20各自独立的选自H、氰基、羟基、氨基、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、带有或不带有取代基的C 1-8的杂环烃基、带有或不带有取代基的C 1-8的烃氧基；其中R 21选自H、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、带有或不带有取代基的C 1-8的杂环烃基；
R 1选自H、带有或不带有取代基的C 1～8烃基、带有或不带有取代基的环烃基、带有或不带有取代基的杂环烃基、带有或不带有取代基的C 1-6酰基；
R 2、R 5各自独立的选自：氢、OR 33、NR 34R 35、氰基、卤素、带有或不带有取代基的C 1～8烃基、带有或不带有取代基的环烃基、带有或不带有取代基的杂环烃基、带有或不带有取代基的C 1-6酰基、带有或不带有取代基的酰胺基；其中R 33、R 34、R 35各自独立的选自H、带有或不带有取代基的C 1～8的烃基、带有或不带有取代基的环烃基、带有或不带有取代基的杂环烃基；
R 3、R 6、R 7、R 8、R 9、R 10、R 11各自独立的选自：H、OR 27、NR 28R 29、氰基、卤素、硝基、带有或不带有取代基的C 1～8烃基、带有或不带有取代基的环烃基、带有或不带有取代基的杂环烃基、X6S(＝O) kR 30、X6C(＝O)R 31；其中k＝0-2；其中R 27，R 28，R 29，R 30，R 31各自独立的选自H、带有或不带有取代基的C 1～8烃基、环烃基、杂环烃基；其中X6缺失或选自O、S、NR 32；其中R 32为H、带有或不带有取代基的C 1～8的烃基、带有或不带有取代基的环烃基、和带有或不带有取代基的杂环烃基；
R 4选自H、氰基、羧基、带有或不带有取代基的C 1～8的烃基、带有或不带有取代基的烃氧羰基；
a为0至5之间的整数(如1、2、3、4、5)；
b为0至3之间的整数(如1、2、3)；
c为0至30之间的整数(如1、2、3、4、5、6、7、8、9)；
d为0至9之间的整数(如1、2、3、4、5、6、7、8、9)；
e为0至3之间的整数(如1、2、3)；
f为0至3之间的整数(如1、2、3)。
如无特殊说明，本文中所述整数为0、1、2、3、4、5、6、7、8、或9。在另一优选例中，所述各C1-8环烃基优选为C3-8环烃基(如C3-8环烷基)。
在另一优选例中，所述各C1-8杂环烃基优选为C3-8杂环烃基(如含3-8个碳原子的4-10元杂环烷基)。
在本发明的一个优选地实施方式中，所述化合物选自下组：
Figure PCTCN2018103710-appb-000013
Figure PCTCN2018103710-appb-000014
Figure PCTCN2018103710-appb-000015
本发明的化合物包可以与无机酸、有机酸或碱形成药学上可接受的盐。所述的无机酸包括但不限于盐酸、氢溴酸、硝酸、高氯酸、硫酸或磷酸等；所述的有机酸包括但不限于甲磺酸、三氟甲磺酸、乙磺酸、苯磺酸、对-甲苯磺酸、富马酸、草酸、乙酸、马来酸、抗坏血酸、乳酸、 酒石酸、丙二酸、乙醇酸、琥珀酸和丙酸等；所述的碱包括但不限于无机盐和胺类。
术语药学上可接受的盐指根据医学判断适用于接触人和哺乳动物的组织而无过度毒性、刺激、过敏反应等的那些盐。药学上可接受的盐为本领域公知的。
本发明还涵盖含有式I化合物的前体药物的药物组合物。前体药物包括这样的化合物，其中前体分子通过碳酸酯键、氨基甲酸酯键、酰胺键、烷基酯键、磷酸酯键、氨基磷酸酯键共价结合到式I化合物的游离羧基、羟基、氨基或胺基上。
化合物的制备
制备方法
下面更具体地描述本发明式I结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。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的进行。
下列反应流程阐述本发明化合物的制备。除非另有指示，反应流程和随后的讨论中的A、B、W、Y、Z、X、M 1、M 2、a、b、c、d、e、f、g、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11是如上述定义的。
一般而言，可以如下述方案中所述的从式III获得式I的化合物：
Figure PCTCN2018103710-appb-000016
在化合物II中，当W为醚时，可采用式III(W1＝OH)在碱作用下与含有离去基团的中间体直接亲核取代制备，或采用光延反应与醇反应来制备；当W为酯、氨基甲酸酯(NHCO 2)时，可采用式III(W1＝OH)在碱作用下与酰氯、活化酯(酰胺)、羧酸、异氰酸酯反应制备；当W为胺时，可采用式III(W1＝NH 2)在碱作用下与含有离去基团的中间体直接亲核取代制备，也可采用式III(W1＝NH 2)与醛/酮进行还原胺化反应来制备；当W为酰胺、烷氧羰基胺(OCONH)及脲时，可采用式III(W1＝NH 2)在碱作用下与相应酰氯、活化酯(酰胺)、羧酸、异氰酸酯反应制备。
在化合物I中，当A与氮原子以C-N键连接时，可用直接取代或还原胺化制备；当A与氮原子以酰胺、脲、氨基甲酸酯、磺酰胺、硫酰胺方式连接时，可用相应的酰氯、活化酯(酰胺)、羧酸、异氰酸酯、磺酰氯、硫酰氯制备。
一般的，根据连接结构A与W的情况，化合物I也可以通过先把式IV与中间的链连接，再与式III反应得到。所用化学合成方法同上所述。
式III、IV的化合物可通过已知的合成方法获得或容易通过商业购买获得。
式I化合物的应用
所述的式I化合物可用于以下的一种或多种用途：
(a)制备治疗与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病的药物；
(b)制备布鲁顿酪氨酸蛋白激酶(Btk)靶向抑制剂或降解剂；
(c)体外非治疗性地抑制或降解布鲁顿酪氨酸蛋白激酶(Btk)的活性；
(d)体外非治疗性地抑制肿瘤细胞增殖；和/或
(e)治疗与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病。
在另一优选例中，所述与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病为肿瘤，较佳地为选自下组的肿瘤：非小细胞肺癌、炎性肌纤维细胞瘤等。
本发明的式I化合物可用于制备一种药物组合物，所述的药物组合物包括：(i)有效量的式I化合物，或其药学上可接受的盐；和(ii)药学上可接受的载体。
在另一优选例中，所述的有效量是指治疗有效量或抑制有效量。
本发明的式I化合物还可以用于抑制或降解布鲁顿酪氨酸蛋白激酶(Btk)的方法，所述的抑制是体外非治疗性的抑制也可以是治疗性的抑制。
在另一优选例中，当对抑制对象施用抑制有效量的本发明的式I化合物或其药学上可接受的盐时，所述的抑制有效量为0.001-500nmol/L，较佳地为0.01-200nmol/L。
特别地，本发明还提供了一种治疗与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病的方法，所述方法包括：对治疗对象施用治疗有效量的式I化合物，或所述含有式I化合物作为有效成分的药物组合物。
药物组合物和施用方法
由于本发明化合物具有优异的对布鲁顿酪氨酸蛋白激酶(Btk)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、预防以及缓解由与Btk活性或表达量相关的疾病。根据现有技术，本发明化合物可用于治疗包括肿瘤等的疾病。
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。
“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
Figure PCTCN2018103710-appb-000017
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。
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。
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、蔗糖和阿拉伯胶；(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。
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。
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。
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、娇味剂和香料。
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。
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。
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。
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。
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。
本发明的主要优点包括：
1.提供了一种如式I所示的化合物。
2.提供了一种结构新颖的Btk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Btk的活性。
3.提供了一类治疗与Btk酶活性相关疾病的药物组合物。
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，否则百分比和份数是重量百分比和重量份数。
实施例1 化合物3的制备
Figure PCTCN2018103710-appb-000018
第一步:
将2.14g 6-溴己酰氯和1.37g泊马度胺溶于50ml四氢呋喃中，搅拌回流8h，降至室温，浓缩后40℃真空干燥得化合物(1)1.22g。MS(ESI):450[M+H] +。
第二步：
将860mg化合物(1)、1g化合物(2)和0.60g二异丙基乙胺溶于30ml DMF(N,N-二甲基甲酰胺)中，80℃搅拌6h，降至室温，浓缩后经柱层析得化合物(3)408mg，收率：31.2％。MS(ESI):756[M+H] +。 1H NMR(400MHz,CDCl3)δ10.32-10.14(m,1H),9.43(s,1H),8.83(d,J＝8Hz,1H),8.42(d,J＝8Hz,1H),7.67(t,1H),8.83(d,J＝8Hz,2H),7.55(d,J＝8Hz,1H),7.39(t,3H),7.17(m,3H),7.08(d,J＝8Hz,2H),5.81(s,2H),5.02-4.95(m,2H),3.17(d,J＝8Hz,1H),2.86-2.76(m,2H),2.66-2.55(m,1H),2.49-2.46(m,3H),2.19-2.06(m,3H),1.86(m,2H),1.80-1.76(m,2H),1.59-1.56(m,2H),1.44-1.42(m,2H),1.29-1.26(m,1H),0.8-0.7(m，1H).
实施例2 化合物7的制备
Figure PCTCN2018103710-appb-000019
第一步：
将4-羟基沙利度胺100mg，三甘醇单苄醚96mg，三苯基膦100mg溶解在10ml无水THF中，滴加DIAD(偶氮二甲酸二异丙酯)95mg，室温反应2h。减压去除THF，柱层析纯化后得化合物(4)110mg。MS(ESI):497[M+H] +。
第二步：
将100mg化合物(4)及10％Pd-C 100mg加入甲醇10ml中，室温氢化过夜。过滤，滤液浓缩，残余物经柱层析纯化后得化合物(5)40mg.MS(ESI):407[M+H] +。
第三步：
将化合物(5)30mg溶于二氯甲烷5ml中，加入Dess-martin氧化剂47mg，室温反应3h。加入NaHCO 3饱和水溶液和Na 2S 2O 3饱和水溶液，搅拌5min,，分出有机层，经无水Na 2S 2O 3干燥，浓缩至干，得化合物(6)直接用于下部反应。
将化合物(6)用二氯甲烷7ml溶解后，加入原料(2)50mg以及NaBH(OAc) 330mg，室温反应过夜，减压蒸除二氯甲烷，柱层析纯化后得化合物(7)，35mg。MS(ESI):775[M+H] +。 1H NMR(400MHz,CDCl3)δ9.63-9.96(br,1H),8.38(d,J＝7.6Hz,1H),7.60-7.66(m,3H),7.44(d,J＝7.2Hz,1H),7.38(m,2H),7.22(dd,J＝8.4,1.6Hz,1H),7.11-7.19(m,3H),7.07(d,J＝8.4Hz,2H),5.75(br,2H),4.91-5.05(m,2H),4.29(t,J＝4.8Hz,2H),3.91(m,2H),3.75(m,2H),3.62(m,4H),3.21(br,1H),2.97(br,1H),2.60-2.91(m,6H),2.05-2.20(m,4H),1.83(m,2H)。
实施例3 化合物10的制备
Figure PCTCN2018103710-appb-000020
第一步：
将2-(2-(2-溴乙氧基)乙氧基)乙酸苄酯174mg、碳酸钾100mg、碘化钾20mg与泊马度胺100mg加入20ml DMF(N,N-二甲基甲酰胺)中，80℃反应过夜。反应液经柱层析纯化后得化合物(8)113mg。MS(ESI):510[M+H] +。
第二步：
将100mg化合物(8)及10％Pd-C100mg加入10ml甲醇中，室温氢化过夜。过滤，滤液浓缩，残余物经柱层析纯化后得化合物(9)73mg。MS(ESI负离子):418[M-H] -。
第三步：
将化合物(9)50mg及原料(2)50mg溶于二氯甲烷5ml中，加入HOBt(1-羟基苯并三唑)20mg及EDC(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)40mg，室温反应过夜。减压蒸除二氯甲烷，柱层析纯化后得化合物(10)，41mg.MS(ESI):788[M+H] +。 1H NMR(400MHz,CDCl3)δ9.90-10.22(br,1H),8.37(d,J＝7.6Hz,1H),7.62(m,2H),7.45(m,1H),7.38(t,J＝7.6Hz,2H),7.04-7.18(m,6H),6.87(d,J＝8.8Hz,1H),6.47(m,1H),5.81(br,2H),5.01(m,1H),4.90(m,1H),4.65(s,2H),3.63-3.72(m,6H),3.25(br,1H),2.62-3.04(m,7H),2.06-2.20(m,4H),1.83(m,2H)。
实施例4 化合物13的制备
Figure PCTCN2018103710-appb-000021
第一步：
将原料(2)200mg溶解于二氯甲烷20ml，加入三乙胺100mg及5-苄氧基戊烷磺酰氯150mg，室温反应过夜。减压蒸除溶剂，柱层析纯化后得化合物(11)233mg。MS(ESI):627[M+H] +。
第二步：
将200mg化合物(11)及10％Pd-C 200mg加入甲醇20ml中，室温氢化反应过夜。过滤，滤液浓缩，柱层析纯化后得化合物(12)155mg.MS(ESI):536[M+H] +。
第三步：
将4-羟基沙利度胺50mg，三苯基膦50mg和化合物(12)80mg溶解在5ml无水四氢呋喃中，滴加DIAD(偶氮二甲酸二异丙酯)50mg，室温反应3h。减压去除四氢呋喃，柱层析纯化后得化合物(13)41mg。MS(ESI):793[M+H] +。 1H NMR(400MHz,CDCl3)δ9.83-9.95(br,1H),8.38(d,J＝7.6Hz,1H),7.60-7.75(m,3H),7.45(m,1H),7.39(t,J＝7.2Hz,2H),7.00-7.19(m,5H),6.85(d,J＝8.4Hz,1H),5.81(br,2H),5.03(m,1H),4.92(m,1H),3.95(t,J＝7.2Hz,2H),3.45(m,2H),3.26(br,1H),2.60-3.02(m,7H),2.06-2.20(m,4H),1.70-1.95(m,4H),1.35(br,2H)。
同理，通过类似上述实施例的方法制备以下化合物:
Figure PCTCN2018103710-appb-000022
Figure PCTCN2018103710-appb-000023
Figure PCTCN2018103710-appb-000024
Figure PCTCN2018103710-appb-000025
Figure PCTCN2018103710-appb-000026
实施例5 用Caliper assay法测试化合物对Btk的抑制活性
实验步骤如下：
配置1×激酶反应缓冲液(50mM HEPES,PH 7.5；0.0015％Brij-35)和激酶反应终止液(100mM HEPES,PH 7.5；0.0015％Brij-35；0.2％Coating Reagent；50mM EDTA)；
配置实验样品：在96孔板中加入100μL 5μM的样品溶液(100％DMSO溶解)，得到50×样品溶液。在同一块板上设置两个只含有100μL 100％DMSO的孔作为对照。一个作为不加样品对照，另一个作为不加酶对照。在96孔板中加入10μL样品和90μL 1×激酶反应缓冲液，作为中转板。将此中转板震荡10分钟。
准备试验板：取96孔中转板中配置好的样品各5μL至384孔板中。
激酶反应：在5μL 5×化合物溶液(用DMSO溶解，用水稀释10倍)中加入10μL的2.5×的Btk激酶溶液(激酶用1×激酶反应缓冲液稀释),室温孵育10min后再加入10μL的2.5×底物肽溶液(在1×激酶反应缓冲液稀释的FAM标记肽和ATP)。
终止激酶反应：在28℃下反应一段时间后加入25μL激酶反应终止液。
在Caliper上测试荧光度(F)，并收集数据。
计算激酶活性抑制率：对激酶活性的百分抑制率＝(F DMSO对照-F 样品)/(F DMSO对照-F 阴性对照)×100，以DMSO为溶液对照，以不加激酶为阴性对照。
结果显示，化合物(100nM)对Btk的抑制活性见下表：
化合物编号 抑制率(％)
3 92
7 99
14 99
15 98
16 95
实施例6 用Western blot检测化合物降解Btk蛋白的活性
细胞株：RPMI8226细胞株用含10％小牛血清的RPMI1640培养基于37℃、5％CO 2、饱和湿度孵育箱内培养。
设置DMSO对照组、化合物干预组(10μM)，处理24小时收集细胞后加入100μL预冷的细胞裂解液，冰上裂解30min，提取细胞总蛋白，二喹啉甲酸(BCA)法测定蛋白浓度并进行定量。常规制胶、上样、电泳，然后转膜，封闭，分别加入兔抗人Btk(1∶500)，4℃孵育过夜，漂洗后加入辣根过氧化物酶标记的山羊抗兔IgG(1∶5000)，漂洗后ECL显影液显色，Bio-Rad凝胶成像系统扫描成像，计算机软件处理分析。以磷酸甘油醛脱氢酶(GAPDH)内参对照。
使用Image J软件对各条带进行灰度分析，计算化合物降解Btk蛋白的降解率。
结果显示，化合物(10μM)对RPMI8226细胞中Btk蛋白的降解活性见下表：
化合物编号 降解活性 化合物编号 降解活性
3 ++++ 28 +++
7 ++++ 29 ++++
14 ++++ 30 ++++
15 ++++ 31 ++++
16 ++++ 32 +++
17 +++ 33 ++++
18 +++ 34 ++++
19 +++ 35 ++++
20 +++ 36 +++
21 +++ 37 ++++
22 +++ 39 ++++
23 ++++ 40 +++
24 ++++ 41 +++
25 ++++ 43 ++++
26 ++++ 44 +++
27 ++++ 对照化合物 -
备注：上述表格中，“-”代表无降解活性，“+”代表降解率为10％-30％，“++”代表降解率为30％-50％，“+++”代表降解率为50％-90％，“++++”代表降解率为大于90％。对照化合物结构如下：
Figure PCTCN2018103710-appb-000027
实施例7 CCK8法检测式化合物对RPMI 8226细胞(人多发性骨髓瘤细胞)增殖的抑制作用
在体外用CCK8法实验测定化合物对RPMI 8226细胞(可购自ATCC)的增殖抑制作用。具体步骤如下：
取RPMI 8226细胞培养于10％小牛血清的1640培养基中，接种于96孔板，2×10 5细胞/孔，置于37℃，5％CO 2孵化箱中。将化合物溶解于二甲亚砜(DMSO)中，得到浓度为10mM的溶液，再用磷酸缓冲液稀释至所需浓度，分别加入上述96孔板中，每个浓度2孔，每孔10μl，每个浓度作两个平行测试。将DMSO相应作梯度稀释后加入板中，作为对照。
将上述96孔板在37℃、5％CO 2细胞培养箱中培养48小时后，每孔中加入10μl CCK8溶液，继续在培养箱中保温1～4小时。测定465nm光吸收值。
根据光吸收值计算化合物处理后细胞相对存活率。
通过软件计算化合物对RPMI 8226细胞的IC 50。
合成的化合物对RPMI 8226细胞的体外增殖抑制作用见下表：
化合物编号 IC 50(μM)
3 34
7 83
14 6
活性检测数据表明，本发明化合物对依鲁替尼耐药细胞株具有显著的抑制活性，因而本发明化合物可用于治疗对依鲁替尼耐药的肿瘤。
实施例8 CTG法检测式化合物对DOHH2细胞(人B细胞淋巴瘤细胞)和SU-DHL-6(人B细胞淋巴瘤细胞)增殖的抑制作用
在体外用CCK8法实验测定化合物对DOHH2细胞(可购自ATCC)和SU-DHL-6细胞(可购自ATCC)的增殖抑制作用。细胞培养及化合物配制参照实施例7，细胞铺板密度DOHH2细胞为1×10 4细胞/孔，SU-DHL-6细胞为1.5×10 4细胞/孔。给药后的培养时间为72小时。随后加入适量的CTG试剂，测量发光值，计算抑制率。
合成的化合物(10μM)对DOHH2和SU-DHL-6细胞的体外增殖抑制作用见下表：
Figure PCTCN2018103710-appb-000028
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。

Claims (10)

  1. 一种如下式I所示的化合物，或其药学上可接受的盐：
    Figure PCTCN2018103710-appb-100001
    其中：
    Figure PCTCN2018103710-appb-100002
    表示单键
    Figure PCTCN2018103710-appb-100003
    表示单键或双键
    A缺失或选自C(＝O)、C(＝O)X1、SOX1、SO 2X1、带有或不带有取代基的C 1-8烃基、带有或不带有取代基的C 1-8环烃基、和带有或不带有取代基的C 1-8杂环烃基；其中X1缺失或选自(CR 12R 13) jO、(CR 12R 13) jS、带有或不带有取代基的3～8元杂芳基、带有或不带有取代基的3～8元芳基和NR 14；其中R 12、R 13、R 14各自独立的为H、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、和带有或不带有取代基的C 1-8的杂环烃基；j为0至3之间的整数；
    W缺失或选自O、NR 17、-X2C(＝O)X3、-X2S(＝O) gX3；其中R 17为H、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、带有或不带有取代基的C 1-8的杂环烃基；其中X2、X3各自独立的缺失或选自O、S、NR 18；其中g为0至2的整数；其中R 18为H、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、带有或不带有取代基的C 1-8的杂环烃基；
    Y为(CR 22R 23) h、CHX4(CR 22R 23) h、CX4＝CH(CR 22R 23) h、C(＝CH2)(CR 22R 23) h或(CR 22R 23) h；其中h为0至30之间的整数；其中R 22、R 23各自独立的选自H、氰基、羟基、氨基、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、带有或不带有取代基的C 1-8的杂环烃基、带有或不带有取代基的C 1-8的烃氧基；其中X4为H、卤素、氰基、硝基、羟基、带有或不带有取代基C 1-8烃氧基、带有或不带有取代基C 1-8烃氧羰基、带有或不带有取代基C 1-8胺基、带有或不带有取代基C 1-8酯基、带有或不带有取代基C 1-8胺基羰基、带有或不带有取代基C 1-8烃基、带有或不带有取代基C 1-8环烃基、带有或不带有取代基C 1-8杂环烃基；
    Z为(CR 24R 25) i、CHX5(CR 24R 25) i、CX5＝CH(CR 24R 25) i或C≡C(CR 24R 25) i；其中i为0至30之间的整数；其中R 24、R 25各自独立的选自H、氰基、羟基、氨基、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基C 1-8环烃基、带有或不带有取代基C 1-8杂环烃基、带有或不带有取代基C 1-8烃氧基；其中X5＝H、卤素、氰基、硝基、羟基、带有或不带有取代基C 1-8的烃氧基、带有或不带有取代基C 1-8烃氧羰基、带有或不带有取代基C 1-8胺基、带有或不带有取代基C 1-8酯基、带有或不带有取代基C 1-8胺基羰基、带有或不带有取代基C 1-8烃基、带有或不带有取代基C 1-8环烃基、带有或不带有取代基C 1-8杂环烃基；
    B缺失或选自O、C＝O、S、NR 15、-NR 15C(＝O)-、-C(＝O)NR 15-、-C(＝O)O-、OC(＝O)O-、 -NR 15C(＝O)O-、-OC(＝O)NR 15-、-NR 15C(＝O)NR 16-、带有或不带有取代基的C 1-12的烃基、带有或不带有取代基的C 1-12的环烃基、和带有或不带有取代基的C 1-12的杂环烃基；其中R 15、R 16各自独立的选自H、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、和带有或不带有取代基的C 1-8的杂环烃基；
    X选自CR 19R 20、C(＝O)、S(＝O)、SO 2、NR 21；其中R 19、R 20各自独立的选自H、氰基、羟基、氨基、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、带有或不带有取代基的C 1-8的杂环烃基、带有或不带有取代基的C 1-8的烃氧基；其中R 21选自H、带有或不带有取代基的C 1-8的烃基、带有或不带有取代基的C 1-8的环烃基、带有或不带有取代基的C 1-8的杂环烃基；
    R 1选自H、带有或不带有取代基的C 1～8烃基、带有或不带有取代基的环烃基、带有或不带有取代基的杂环烃基、带有或不带有取代基的C 1-6酰基；
    R 2、R 5各自独立的选自：氢、OR 33、NR 34R 35、氰基、卤素、带有或不带有取代基的C 1～8烃基、带有或不带有取代基的环烃基、带有或不带有取代基的杂环烃基、带有或不带有取代基的C 1-6酰基、带有或不带有取代基的酰胺基；其中R 33、R 34、R 35各自独立的选自H、带有或不带有取代基的C 1～8的烃基、带有或不带有取代基的环烃基、带有或不带有取代基的杂环烃基；
    R 3、R 6、R 7、R 8、R 9、R 10、R 11各自独立的选自：H、OR 27、NR 28R 29、氰基、卤素、硝基、带有或不带有取代基的C 1～8烃基、带有或不带有取代基的环烃基、带有或不带有取代基的杂环烃基、X6S(＝O) kR 30、X6C(＝O)R 31；其中k＝0-2；其中R 27，R 28，R 29，R 30，R 31各自独立的选自H、带有或不带有取代基的C 1～8烃基、环烃基、杂环烃基；其中X6缺失或选自O、S、NR 32；其中R 32为H、带有或不带有取代基的C 1～8的烃基、带有或不带有取代基的环烃基、和带有或不带有取代基的杂环烃基；
    R 4选自H、氰基、羧基、带有或不带有取代基的C 1～8的烃基、带有或不带有取代基的烃氧羰基；
    a为0至5之间的整数；
    b为0至3之间的整数；
    c为0至30之间的整数；
    d为0至9之间的整数；
    e为0至3之间的整数；
    f为0至3之间的整数。
  2. 如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于：
    所述式I中，A缺失；W为-X2C(＝O)X3，其中，X2为NR 18，X3缺失；Y为(CR 22R 23) h，其中R 22、R 23各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，h为1至6之间的整数；Z为(CR 24R 25) i，其中R 24、R 25各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，i为1至6之间的整数；c为0；或者
    所述式I中，A缺失；W缺失或为O；Y为(CR 22R 23) h，其中R 22、R 23各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，h为0至3之间的整数；B为O；Z为(CR 24R 25) i，其中R 24、R 25各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，i为0至3之间的整数；c为1至6之间的整数；或者
    所述式I中，A缺失；W为NR 17，其中R 17为H、或带有或不带有取代基的C 1-4的烃基；Y为(CR 22R 23) h，其中R 22、R 23各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，h为0至3之间的整数；Z为(CR 24R 25) i，其中R 24、R 25各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，i为0至4之间的整数；B为O；c为1至6之间的整数；或者
    所述式I中，A缺失；W缺失；Y为(CR 22R 23) h，其中R 22、R 23各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，h为0至3之间的整数；Z为(CR 24R 25) i，其 中R 24、R 25各自独立的选自H、羟基、带有或不带有取代基的C 1-4的烃基，i为0至3之间的整数；B为O；c为1至10之间(优选为1至6之间)的整数。
  3. 如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，式I中，X为C(＝O)。
  4. 如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，R 1选自：H、和带有或不带有取代基的C 1-4烷基。
  5. 如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，R 4选自H、氰基、带有或不带有取代基的C 1-6烷基。
  6. 如权利要求1所述的化合物，或其药学上可接受的盐，其特征在于，所述化合物选自下组：
    Figure PCTCN2018103710-appb-100004
    Figure PCTCN2018103710-appb-100005
    Figure PCTCN2018103710-appb-100006
  7. 一种药物组合物，其特征在于，所述的组合物含有权利要求1所述的化合物或其药学上可接受的盐、前药，以及药学上可接受的载体。
  8. 一种如权利要求1所述的化合物或其药学上可接受的盐的用途，用于：
    (a)制备治疗与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病的药物；
    (b)制备布鲁顿酪氨酸蛋白激酶(Btk)靶向抑制剂或降解剂；
    (c)体外非治疗性地抑制或降解布鲁顿酪氨酸蛋白激酶(Btk)的活性；
    (d)体外非治疗性地抑制肿瘤细胞增殖；和/或
    (e)治疗与布鲁顿酪氨酸蛋白激酶(Btk)活性或表达量相关的疾病。
  9. 如权利要求8所述的用途，其特征在于，所述的疾病包括肿瘤、自身免疫疾病；优选地，所述肿瘤包括非霍奇金淋巴瘤(NHL)、慢性淋巴细胞白血病(CLL)、B细胞淋巴瘤等；所述自身免疫疾病包括类风湿性关节炎、银屑病等。
  10. 一种体外抑制肿瘤细胞的方法，所述方法包括：对抑制对象施用抑制有效量的如权利要求1所述的式I化合物，或如权利要求7所述的药物组合物。
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