WO2021068380A1 - 一种靶向btk蛋白降解化合物的制备及其在治疗自身免疫***疾病与肿瘤中的应用 - Google Patents

一种靶向btk蛋白降解化合物的制备及其在治疗自身免疫***疾病与肿瘤中的应用 Download PDF

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WO2021068380A1
WO2021068380A1 PCT/CN2019/121627 CN2019121627W WO2021068380A1 WO 2021068380 A1 WO2021068380 A1 WO 2021068380A1 CN 2019121627 W CN2019121627 W CN 2019121627W WO 2021068380 A1 WO2021068380 A1 WO 2021068380A1
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alkyl
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aryl
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饶燏
刘万里
杨子默
孙永汇
倪智豪
朱璨
杨冰
李雨欣
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清华大学
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    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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Definitions

  • the present invention relates to the field of biomedicine. Specifically, the present invention relates to the preparation of a compound targeting BTK protein degradation and its application in the treatment of autoimmune system diseases and tumors.
  • PROTAC Proteinolysis Targeting Chimeras
  • protein targeted degradation technology is a new chemical biology or drug discovery method that uses the ubiquitin-proteasome system to induce protein degradation in recent years.
  • the role of PROTAC small molecules is based on the process of E3 ubiquitin ligase ligating a certain protein.
  • One end of the PROTAC small molecule chimera can specifically bind to the target protein, and the other end recruits E3 ubiquitin ligase. Bring it close to the target protein, and then the subsequent degradation process occurs.
  • the PROTAC chimera is synthesized on the basis of selective small molecule inhibitors. Through clever design, it can distinguish highly homologous proteins.
  • PROTAC technology gives PROTAC technology a certain advantage in the application of biological tools; in addition, PROTAC molecules and The target proteins are non-covalently bonded. After the degradation of one molecule of protein, it can be dissociated to degrade another molecule of target protein. This catalytic amount of protein degradation is the development of high-activity and low-toxic drug molecules. It provides the possibility that PROTAC technology has received widespread attention and application because it is more direct and fast.
  • BTK is a member of the non-receptor tyrosine kinase family and a key kinase in the B cell antigen receptor (BCR) signaling pathway. It can control the development and differentiation of B cells by activating positive cell cycle regulators and differentiation factors. It can regulate the survival and proliferation of B cells through the expression of pro-apoptotic and anti-apoptotic proteins.
  • BCR B cell antigen receptor
  • Non-Hodgkin's lymphoma is a blood system cancer, which is the general term for all lymphomas except Hodgkin's lymphoma. In the United States, 2.1% of people’s lives are affected by it. In 2015, 4.3 million people suffered from non-Hodgkin's lymphoma, and 231400 were killed. Most clinical non-Hodgkin's lymphomas are B-cell type, accounting for 70%-85% of the total. Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma (NHL). In the United States and the United Kingdom, 7-8 people out of 100,000 people are affected each year.
  • DLBCL Diffuse large B-cell lymphoma
  • Ibrutinib has been approved by the FDA for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and Waldenstrom's macroglobulinemia (WM) indications. And there are reports that ibrutinib can effectively inhibit the proliferation of some types of DLBCL. Ibrutinib works by covalently cross-linking its acrylamide structure with the sulfhydryl group of the cysteine 481 of the BTK protein in the cell, so that BTK loses its ability to phosphorylate downstream signaling proteins, thereby exerting anti-cell proliferation. The role of.
  • ibrutinib shows strong inhibitory activity against BTK kinase
  • the drug itself can cause many side effects due to its strong off-target effect.
  • the IC 50 value for EGFR is 5.6 nM, which can cause severe diarrhea and rash
  • the IC 50 value for ITK is 10.7 nM, which can cause loss of natural killer cell function
  • the IC 50 value for TEC is 78 nM, which can cause coagulation defects
  • Autoimmune diseases refer to diseases caused by the body's immune response to self-antigens and damage to its own tissues, including pulmonary hemorrhagic nephritis syndrome, pemphigus and other organ-specific autoimmune diseases, arthritis, systemic lupus erythematosus and other systems
  • the specific mechanism of sexual autoimmune diseases is not yet fully clarified, and one of the possible mechanisms is that the excessive expression of BTK activates the BCR signaling pathway abnormally, which in turn causes B cell dysfunction, changes in immune tolerance, and transforms into autoreactive B Cells secrete large amounts of autoantibodies to induce disease.
  • BTK has become the most common target for clinical drugs in the field of autoimmune diseases except TNF (tumor necrosis factor) and CD20. It is expected to become a new target for the treatment of autoimmune diseases in the future. This is also the PROTAC technology that can efficiently degrade BTK protein. Provides opportunities and challenges.
  • BTK kinase degradation agents have good prospects as drugs for anti-tumor or treatment of autoimmune diseases and need further development.
  • Targets such as EGFR, ITK, and TEC also have varying degrees of effect, with obvious side effects.
  • the inventors proposed a new compound that uses a dual-target molecular structure. The structure is shown in Figure 1. One end of this type of molecule is targeted to bind E3 ligase, and the other end is a target.
  • the structures at these two ends are connected by a linker to form a complete compound molecule.
  • the compound has a strong effect on the degradation of wild-type BTK, and has no inhibitory or degradation effect on other targets such as EGFR, ITK, TEC, etc., and has the effect of specifically targeting BTK protein.
  • the present invention proposes a compound, which is a compound represented by formula I or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates , Solvates, metabolites, pharmaceutically acceptable salts or prodrugs:
  • the Y is
  • the X is
  • the Z is:
  • d is an integer between 0 and 30, where,
  • W is CH 2 , O, S, NH or Se
  • b is an integer between 0 and 30
  • d is an integer between 0 and 30
  • the X is
  • the Z is:
  • W is CH 2 , O, S, NH or Se
  • b is an integer between 0 and 30
  • d is an integer between 0 and 30
  • the X is
  • the X is
  • Each R a is independently hydrogen, C1-4 alkyl, halo C1-4 alkyl, C1-4 alkyl group or a hydroxyl group;
  • Each t2 is independently 0, 1, 2, 3 or 4;
  • Each t1 is independently 0, 1 or 2;
  • Each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , and Q is independently CH, CH 2 , O, S, N, NH or Se;
  • Each R 1 , R 2 , R 3 , R 4 , R 5 is independently H, deuterium, amino, C1-4 amide, C1-4 alkyl, C1-4 heteroalkyl, C3-8 cycloalkyl, C2-10 heterocyclyl, C6-10 aryl, C1-9 heteroaryl, C6-10 aryl, C1-4 alkoxy, C1-4 alkenyl, C1-4 alkynyl, wherein, the C1-4 alkyl, C1-4 heteroalkyl, C3-8 cycloalkyl, C2-10 heterocyclyl, C6-10 aryl, C1-9 heteroaryl, C6-10 aryl, C1-4 alkane
  • the oxy, C1-4 alkenyl, and C1-4 alkynyl groups can be optionally selected by one or more selected from deuterium, hydroxyl, amino, oxo, F, Cl, Br, I, cyano, C1-6 alkyl , C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6
  • Each A is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, hydroxy, nitro, amino, cyano, halogen, carboxy, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkylthio Group, C1-4 alkyl acyl group, C3-12 cycloalkyl group, optionally substituted C3-9 heterocyclic group, optionally substituted C6-12 aryl group, optionally substituted C1-9 heteroaryl group;
  • Each R b is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, hydroxy, nitro, amino, cyano, halogen, carboxy, C1-4 alkoxy, C1-4 alkylamino, C1-4 Alkylthio, C1-4 alkyl acyl, C3-12 cycloalkyl, C3-9 heterocyclyl, C6-12 aryl, C1-9 heteroaryl, amino C1-4 alkyl, hydroxy C1-4 alkane Group, sulfonic acid group, aminosulfonyl group or aminoacyl group;
  • Each of a, c, e, and f is independently an integer between 0-30.
  • the above-mentioned compound may further include at least one of the following additional technical features:
  • each L 1 is independently a bond, -O-, -S-, -NH-,
  • Each R a is independently hydrogen, C1-2 alkyl, halo C1-2 alkyl, C1-2 alkyl group or a hydroxyl group,
  • Each R 1 , R 2 , R 3 , R 4 is independently H, amino, C1-4 alkyl, C1-4 heteroalkyl, C5-7 cycloalkyl, C5-7 heterocyclyl, C6-7 aromatic Group, C5-7 heteroaryl, wherein the C1-4 alkyl, C1-4 heteroalkyl, C5-7 cycloalkyl, C5-7 heterocyclyl, C6-7 aryl, C5-7 hetero
  • the aryl group may be optionally substituted with one or more substituents selected from deuterium, hydroxyl, amino, oxo, F, Cl, Br, I, cyano.
  • each X is independently a compound as shown below:
  • each A is independently hydrogen, optionally substituted C5-7 heterocyclyl, C5-7 cycloalkyl, optionally substituted C6-7 aryl, optionally substituted C5-7 heteroaryl base,
  • Each R 5 is independently H, amino, C1-4 alkyl, C1-4 heteroalkyl, C5-7 cycloalkyl, C5-7 heterocyclyl, C6-7 aryl, C5-7 heteroaryl, wherein, the C1-4 alkyl group, C1-4 heteroalkyl group, C5-7 cycloalkyl group, C5-7 heterocyclic group, C6-7 aryl group, C5-7 heteroaryl group may be optionally substituted by one or Multiple selected from deuterium, hydroxyl, amino, oxo, F, Cl, Br, I, cyano, C5-7 aryl, C5-7 heteroaryl, halogen substituted C5-7 aryl, halogen substituted C5-7 Heteroaryl, halogen-substituted C5-7 heterocyclyl substituents;
  • Each R a is independently hydrogen, C1-2 alkyl, halo C1-2 alkyl, C1-2 alkyl group or a hydroxyl group.
  • each A is independently
  • Each R c is independently hydrogen or C1-2 alkyl.
  • each Z is independently a compound as shown below:
  • each E is independently an amide group, an ester group, a carbamate group, a ureido group, a guanidino group, a heterocyclic group, a cycloalkyl group or a C6-C8 aryl group; each E is optionally 1, Replaced by 2, 3 or 4 independent R b,
  • Each R b is independently hydrogen, C1-2 alkyl, C1-2 haloalkyl, hydroxy, nitro, amino, cyano, halogen, carboxy, C1-2 alkoxy, C1-2 alkylamino, C1-2 Alkylthio, C1-2 alkyl acyl, C5-7 cycloalkyl, C5-7 heterocyclyl, C6-7 aryl, C5-7 heteroaryl, amino C1-2 alkyl, hydroxy C1-2 alkane Group, sulfonic acid group, aminosulfonyl group or aminoacyl group,
  • Each R a is independently hydrogen, C1-2 alkyl, halo C1-2 alkyl, C1-2 alkyl group or a hydroxyl group.
  • each Y is independently
  • the X is
  • the Z is
  • the Y is
  • n1 is an integer between 0-10.
  • the compound includes the compound represented by any one of formulas (1) to (15) or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, Solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • n1 is an integer between 0-10.
  • the present invention proposes a compound.
  • it is a compound represented by any one of formulas 1-18 or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, Pharmaceutically acceptable salts or prodrugs,
  • the compound according to the embodiment of the present invention has a strong effect on the degradation of wild-type BTK, and has no inhibitory or degradation effect on other targets such as EGFR, ITK, TEC, etc., and has the effect of specifically targeting and degrading BTK protein.
  • the present invention provides a pharmaceutical composition comprising the compound described above.
  • the pharmaceutical composition according to the embodiment of the present invention has a strong effect on the degradation of wild-type BTK, and has no inhibitory or degradation effect on other targets such as EGFR, ITK, TEC, etc., and has the effect of specifically targeting and degrading BTK protein.
  • the above-mentioned pharmaceutical composition may further include at least one of the following additional technical features:
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.
  • the pharmaceutical composition further includes other drugs for treating or preventing non-Hodgkin's lymphoma or autoimmune diseases.
  • the autoimmune disease is arthritis, pulmonary hemorrhage, systemic lupus erythematosus, corpus sores, chronic lymphatic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, chronic ulcerative disease Colitis, pernicious anemia with chronic atrophic gastritis, primary biliary cirrhosis, multiple cerebrospinal sclerosis or acute idiopathic polyneuritis.
  • the autoimmune disease is arthritis or pulmonary hemorrhage.
  • the other drugs for treating or preventing non-Hodgkin's lymphoma or autoimmune diseases include ibrutinib.
  • the present invention proposes the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a medicine, which is used to degrade BTK or inhibit BTK.
  • the compound or pharmaceutical composition according to the embodiment of the present invention has a strong effect on the degradation of wild-type BTK, and has no inhibitory or degradation effect on other targets such as EGFR, ITK, TEC, etc., and has the effect of specifically targeting the BTK protein.
  • the present invention proposes the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a medicine for the treatment or prevention of BTK-related diseases.
  • the compound or pharmaceutical composition according to the embodiment of the present invention has a strong effect on the degradation of wild-type BTK, and has no inhibitory or degradation effect on other targets such as EGFR, ITK, TEC, etc., and has the effect of specifically targeting the BTK protein.
  • Related diseases have good therapeutic or preventive effects.
  • the above-mentioned use may further include at least one of the following additional technical features:
  • the BTK-related disease is non-Hodgkin's lymphoma or an autoimmune disease.
  • the compounds or pharmaceutical compositions according to the embodiments of the present invention have better treatment or prevention effects on non-Hodgkin's lymphoma or autoimmune diseases.
  • the autoimmune disease is arthritis, pulmonary hemorrhage, systemic lupus erythematosus, corpus sores, chronic lymphatic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, chronic ulcerative disease Colitis, pernicious anemia with chronic atrophic gastritis, primary biliary cirrhosis, multiple cerebrospinal sclerosis or acute idiopathic polyneuritis.
  • the autoimmune disease is arthritis or pulmonary hemorrhage.
  • the inventor found that the compound or pharmaceutical composition described above can prevent and treat the symptoms of arthritis and pulmonary hemorrhage in a mouse model, and the prevention and improvement of the situation are significantly better than ibrutinib.
  • the present invention proposes a general procedure for the synthesis of the compound represented by formula I.
  • the compound represented by formula I can be connected by click reaction or amide condensation reaction between Pomalidomide or Lenanidomide or RG-7112 terminal derivative and Ibrutinib terminal derivative, as shown in Figure 2, where,
  • Pomalidomide terminal derivatives please refer to Literature & Biology 22,755-763 (2015).
  • Lenalidomide terminal derivatives please refer to the literature J.
  • Figure 1 is a basic technical route of PROTACs according to an embodiment of the present invention.
  • Fig. 2 is a schematic diagram showing the construction of Formula I through a click reaction and an amide condensation reaction according to an embodiment of the present invention
  • Fig. 3 is the inhibitory result of the compound according to an embodiment of the present invention on the release of inflammatory factors in THP-1 cells stimulated by LPS;
  • Fig. 4 shows the degradation effect of compounds according to examples of the present invention on BTK.
  • the salt or prodrug or the aforementioned pharmaceutical composition refers to the introduction of a predetermined amount of a substance into a patient in a suitable manner.
  • the composition can be administered by any common route, as long as it can reach the desired tissue.
  • the present invention is not limited to these exemplified modes of administration.
  • the active ingredient of the oral administration composition should be coated or formulated to prevent it from being degraded in the stomach.
  • the compound of formula I or the pharmaceutical composition of the present invention can be administered using a specific device that delivers the active ingredient to the target cell.
  • the administration frequency and dosage of the pharmaceutical composition of the present invention can be determined by a number of related factors, including the type of disease to be treated, the route of administration, the patient’s age, sex, body weight, and the severity of the disease, as well as the active ingredient Type of drug.
  • therapeutically effective amount refers to an amount of a compound that is sufficient to significantly improve certain symptoms associated with a disease or disorder, that is, an amount that provides a therapeutic effect for a given disorder and dosage regimen.
  • a therapeutically effective amount of the drug or compound does not need to cure the disease or condition, but will provide treatment for the disease or condition so that the onset of the disease or condition of the individual is delayed, prevented, or prevented, or the symptoms of the disease or condition are alleviated, or the disease or condition The duration of the illness is changed, or, for example, the disease or illness becomes less serious, or recovery is accelerated.
  • treatment is used to refer to obtaining the desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of completely or partially preventing the disease or its symptoms, and/or may be therapeutic in terms of partially or completely curing the disease and/or adverse effects caused by the disease.
  • Treatment encompasses the treatment of diseases in mammals, especially humans, including: (a) preventing the occurrence of diseases or disorders in individuals who are susceptible to but have not yet been diagnosed with the disease; (b) inhibiting the disease; or (c) Alleviate the disease, such as alleviating the symptoms associated with the disease.
  • Treatment encompasses any medication that administers a drug or compound to an individual to treat, cure, alleviate, ameliorate, alleviate, or inhibit the individual’s disease, including but not limited to combining compounds or drugs containing formula I or formula II as described herein The giving of things to individuals in need.
  • the excipients include pharmaceutically acceptable excipients, lubricants, fillers, diluents, disintegrants, stabilizers, preservatives, emulsifiers, cosolvents, and coloring agents that are well-known in the formulation field. , Sweetener, made into tablets, pills, capsules, injections and other different dosage forms.
  • the articles “a”, “an” and “said” used herein are intended to include “at least one” or “one or more.” Therefore, the articles used herein refer to articles of one or more than one (ie at least one) object.
  • a component refers to one or more components, that is, more than one component may be considered to be adopted or used in the embodiment of the described embodiment.
  • Stereoisomers refer to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • Chiral refers to a molecule that can not overlap with its mirror image; and “achiral” refers to a molecule that can overlap with its mirror image.
  • Enantiomers refer to two isomers of a compound that cannot overlap but are mirror images of each other.
  • Diastereoisomers refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers.
  • the prefixes d and l or (+) and (-) are symbols used to specify the rotation of plane-polarized light caused by a compound, where (-) or l indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (for example, carbon, etc.) of the compound disclosed in the present invention may exist in a racemic or enantiomerically enriched form, such as (R)-, (S)- or (R,S)-configuration form exist.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the present invention can be used as one of the possible isomers or their mixtures, such as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms).
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may have an E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may have a cis or trans configuration.
  • Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physical and chemical properties of the components, for example, by chromatography Method and/or fractional crystallization method.
  • racemate of any final product or intermediate obtained can be resolved into optical enantiomers by a method familiar to those skilled in the art using known methods, for example, by performing diastereomeric salts of the obtained diastereomers. Separate.
  • the racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E.
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversion through the recombination of some bond-forming electrons.
  • keto-enol tautomerism are the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • the compounds of the present invention can be optionally substituted by one or more substituents, such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples.
  • substituents such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples.
  • substituents such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples.
  • a class of compounds can be understood that the term “optionally substituted” and the term “substituted or unsubstituted” can be used interchangeably. Generally speaking, the term “substituted” means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, then the
  • C1-6 alkyl specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
  • Each of a, b, c, d, e, and f is each independently an integer between 0-30. In one embodiment, each of a, b, c, d, e, and f is each independently an integer between 0-25. In another embodiment, each of a, b, c, d, e, and f is each independently an integer between 0-20. In another embodiment, each of a, b, c, d, e, f is each independently an integer between 0-15. In another embodiment, each of a, b, c, d, e, and f is each independently an integer between 0-10. In another embodiment, each of a, b, c, d, e, and f is each independently an integer between 0-5.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition of the variable lists “alkyl” or “aryl” it should be understood that the “alkyl” or “aryl” respectively represents the attached Alkylene group or arylene group.
  • alkyl or “alkyl group” used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally Ground is substituted by one or more substituents described in this invention. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in another embodiment, the alkyl group contains 1 -4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2
  • alkylene refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon group. Unless otherwise specified, alkylene groups contain 1-12 carbon atoms. In one embodiment, the alkylene group contains 1-6 carbon atoms; in another embodiment, the alkylene group contains 1-4 carbon atoms; in another embodiment, the alkylene group The group contains 1-3 carbon atoms; in yet another embodiment, the alkylene group contains 1-2 carbon atoms. Examples of this include methylene (-CH2-), ethylene (-CH2CH2-), isopropylidene (-CH(CH3)CH2-), and the like.
  • alkenyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one site of unsaturation, that is, a carbon-carbon sp2 double bond, wherein the alkenyl group It may be optionally substituted by one or more substituents described in the present invention, including the positioning of "cis” and “tans", or the positioning of "E” and "Z".
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms.
  • alkynyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturation site, that is, a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted by one or more substituents described in the present invention.
  • the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), etc. .
  • heteroalkyl means that one or more heteroatoms are inserted into the alkyl chain, wherein the alkyl group and the heteroatom have the meanings as described in the present invention.
  • the heteroalkyl group contains 2-10 carbon atoms.
  • the heteroalkyl group contains 2-8 carbon atoms.
  • the heteroalkyl group contains 2 -6 carbon atoms, in other embodiments, the heteroalkyl group contains 2-4 carbon atoms, and in other embodiments, the heteroalkyl group contains 2-3 carbon atoms.
  • Such examples include, but are not limited to, CH 3 OCH 2 -, CH 3 CH 2 OCH 2 -, CH 3 SCH 2 -, (CH 3 ) 2 NCH 2 -, (CH 3 ) 2 CH 2 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 3 CH 2 OCH 2 CH 2 -and so on.
  • alkenylene refers to an alkene group obtained by removing two hydrogen atoms from a linear or branched alkene. And the alkenylene group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, Alkenyl, alkynyl, heterocyclyl, mercapto, nitro or aryloxy.
  • carbocyclylene (cycloalkylene) means a monocyclic ring containing 3-12 carbon atoms or a bicyclic ring containing 7-12 carbon atoms, which is a saturated divalent hydrocarbon ring obtained by removing two hydrogen atoms, Where carbocyclyl or cycloalkyl has the meaning as described in the present invention, such examples include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, 1-cyclopenta-1-ylidene Alkenyl, 1-cyclopent-2-alkenylene, etc.
  • heterocyclylene means a monocyclic, bicyclic or tricyclic ring system in which one or more atoms in the ring are independently selected from heteroatoms, and may be fully saturated or contain one or more unsaturations, but not It belongs to the aromatic group and has two connection points connected to the rest of the molecule, and the heterocyclic group has the meaning as described in the present invention.
  • Such examples include, but are not limited to, piperidine-1,4-diyl, piperazine-1,4-diyl, tetrahydrofuran-2,4-diyl, tetrahydrofuran-3,4-diyl, aza Cyclobutane-1,3-diyl, pyrrolidine-1,3-diyl, etc.
  • alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described in this invention.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-but Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-(
  • haloalkyl means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms. Examples of such include, but are not limited to, Trifluoromethyl, trifluoromethoxy, etc.
  • hydroxyalkyl and "hydroxy-substituted alkyl” means that an alkyl group is substituted with one or more hydroxy groups, wherein the alkyl group has the meaning described in the present invention.
  • alkyl group has the meaning described in the present invention.
  • examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, and the like.
  • Carbocyclic group or "carbocyclic ring” means a monovalent or multivalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms.
  • Carbobicyclic groups include spirocarbonbicyclic groups and fused carbobicyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl.
  • carbocyclic groups further include, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl Group, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
  • cycloalkyl means a monovalent or multivalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. In one embodiment, the cycloalkyl group contains 3-12 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; in another embodiment, the cycloalkyl group contains 3-6 carbon atoms. carbon atom.
  • the cycloalkyl group may be independently unsubstituted or substituted with one or more substituents described in the present invention.
  • heterocyclic group and “heterocyclic ring” are used interchangeably herein, and both refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3-12 ring atoms, wherein at least one ring atom is selected from Nitrogen, sulfur and oxygen atoms.
  • the heterocyclic group may be a carbon group or a nitrogen group, and the -CH2- group may be optionally replaced by -C(O)-.
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , Pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxanyl, disulfide ring Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , Dioxanyl, Dithianyl, Thioxanyl, Homopiperazinyl, Homopiperidin
  • heterocyclic groups where the -CH2- group is substituted by -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl , 3,5-dioxopiperidinyl and pyrimidinedione.
  • Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl.
  • the heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
  • the heterocyclic group is a heterocyclic group consisting of 4-7 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 4-7 ring atoms, wherein at least one ring atom is selected from nitrogen and sulfur. And oxygen atoms.
  • the heterocyclic group composed of 4-7 atoms may be a carbon group or a nitrogen group, and the -CH2- group may be optionally replaced by -C(O)-.
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • heterocyclic groups composed of 4-7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrroline Group, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Cyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine Group, dioxanyl, dithianyl, thiazinyl, homopiperazinyl, homopiperid
  • heterocyclic groups where the -CH2- group is substituted by -C(O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl , 3,5-dioxopiperidinyl and pyrimidinedione.
  • Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl.
  • the heterocyclic group composed of 4-7 atoms can be optionally substituted by one or more substituents described in the present invention.
  • the heterocyclic group is a 4-atom heterocyclic group, which refers to a saturated or partially unsaturated monocyclic ring containing 4 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms Replaced.
  • the 4-atom heterocyclic group may be a carbon group or a nitrogen group, and the -CH2- group may be optionally replaced by -C(O)-.
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • 4-atom heterocyclic groups include, but are not limited to: azetidinyl, oxetanyl, and thietanyl.
  • the 4-atom heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
  • the heterocyclic group is a 5-atom heterocyclic group, which refers to a saturated or partially unsaturated monocyclic ring containing 5 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms .
  • the 5-atom heterocyclic group may be a carbon group or a nitrogen group, and the -CH2- group may be optionally replaced by -C(O)-.
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • Examples of 5-atom heterocyclic groups include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolinyl, Tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxanyl, dithiocyclopentyl.
  • Examples of heterocyclic groups where the -CH2- group is substituted by -C(O)- include, but are not limited to, 2-oxopyrrolidinyl and oxo-1,3-thiazolidinyl.
  • Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, a sulfolane group.
  • the 5-atom heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
  • the heterocyclic group is a 6-atom heterocyclic group, which refers to a saturated or partially unsaturated monocyclic ring containing 6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms .
  • the 6-atom heterocyclic group may be a carbon group or a nitrogen group, and the -CH2- group may be optionally replaced by -C(O)-.
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • 6-atom heterocyclic groups include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazinyl.
  • Examples of the -CH2- group substituted by -C(O)- in the heterocyclic group include, but are not limited to, 2-piperidonyl, 3,5-dioxopiperidinyl, and pyrimidinedionyl.
  • Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, 1,1-dioxothiomorpholinyl.
  • the 6-atom heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
  • the heterocyclic group is a heterocyclic group composed of 7-12 atoms, which refers to a saturated or partially unsaturated spiro bicyclic or fused bicyclic ring containing 7-12 ring atoms, in which at least one ring atom Selected from nitrogen, sulfur and oxygen atoms.
  • the heterocyclic group composed of 7-12 atoms may be a carbon group or a nitrogen group, and the -CH2- group may be optionally replaced by -C(O)-.
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • heterocyclic groups composed of 7-12 atoms include, but are not limited to: indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxenyl, 2- Oxa-5-azabicyclo[2.2.1]heptan-5-yl.
  • the heterocyclic group composed of 7-12 atoms can be optionally substituted by one or more substituents described in the present invention.
  • fused bicyclic ring refers to monovalent or multivalent saturated or partially unsaturated bridged ring systems, so
  • the bridged ring system refers to a non-aromatic bicyclic ring system.
  • Such a system may contain independent or conjugated unsaturated systems, but its core structure does not contain aromatic rings or aromatic heterocycles (but aromatic groups can be used as substituents on it).
  • spirocyclyl refers to a monovalent or multivalent saturated or partially unsaturated ring system in which one ring originates from another A specific ring carbon atom on a ring.
  • a saturated bridged ring system (rings B and B') is called a “fused bicyclic ring”
  • ring A and ring B share a carbon atom in the two saturated ring systems and are It is called “spiro ring” or "spiro double ring”.
  • Each ring in the fused bicyclic group and the spiro bicyclic group may be a carbocyclic group or a heterocyclic group, and each ring is optionally substituted with one or more substituents described in the present invention.
  • heterocycloalkyl refers to a monovalent or multivalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur or oxygen atoms.
  • n typically describes the number of ring atoms in a molecule, and the number of ring atoms in the molecule is n.
  • piperidinyl is a 6-atom heterocycloalkyl group
  • 1,2,3,4-tetrahydronaphthalene is a 10-atom cycloalkyl group.
  • unsaturated means that the group contains one or more degrees of unsaturation.
  • heteroatom refers to O, S, N, P and Si, including any oxidation state of N, S and P; primary, secondary, tertiary amine and quaternary ammonium salt forms; or on the nitrogen atom in the heterocyclic ring
  • the form in which hydrogen is substituted for example, N (like the N in 3,4-dihydro-2H-pyrrolyl), NH (like the NH in the pyrrolidinyl group) or NR (like the N-substituted pyrrolidinyl group NR).
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • aryl means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic Family, where each ring system contains a ring composed of 3-7 atoms, and there are one or more attachment points connected to the rest of the molecule.
  • aryl can be used interchangeably with the term “aromatic ring”. Examples of aryl groups may include phenyl, naphthyl, and anthracene. The aryl group may be independently optionally substituted with one or more substituents described in the present invention.
  • heteroaryl refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, in which at least one ring system is aromatic, And at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring composed of 5-7 atoms, and has one or more attachment points connected to the rest of the molecule.
  • heteroaryl can be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic compound”.
  • the heteroaryl group is optionally substituted with one or more substituents described in the present invention.
  • the 5-10 atom heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • carboxy whether used alone or in combination with other terms, such as “carboxyalkyl”, means -CO 2 H;
  • alkylamino includes “N-alkylamino” and "N,N-dialkylamino” in which the amino groups are each independently substituted with one or two alkyl groups.
  • the alkylamino group is a lower alkylamino group with one or two Ci-6 alkyl groups attached to the nitrogen atom.
  • the alkylamino group is a C 1-3 lower alkylamino group.
  • Suitable alkylamino groups can be monoalkylamino or dialkylamino. Examples of such include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N -Diethylamino and so on.
  • arylamino means that the amino group is substituted with one or two aryl groups. Examples of this include, but are not limited to, N-phenylamino. In some examples, the aromatic ring on the arylamino group may be further substituted.
  • aminoalkyl includes C 1-10 straight or branched chain alkyl groups substituted with one or more amino groups. Some examples are that the aminoalkyl group is a C 1-6 "lower aminoalkyl group" substituted with one or more amino groups. Examples of this include, but are not limited to, aminomethyl, ammonia Ethyl, aminopropyl, aminobutyl and aminohexyl.
  • prodrug used in the present invention represents the conversion of a compound into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the maternal structure in the blood or tissues.
  • the prodrug compounds of the present invention can be esters.
  • esters can be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, that is, it can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters.
  • these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group.
  • prodrugs refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.
  • Metal refers to the product obtained by the metabolism of a specific compound or its salt in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, amidating, deamidating, esterifying, degreasing, enzymatic cleavage and the like of the administered compound.
  • the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods described in books and literature such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 -Phenylpropylprop
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates the quaternary ammonium salt formed by any compound containing the N group.
  • Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to the association formed by the solvent molecule being water.
  • treating any disease or condition as used in the present invention, in some embodiments refers to ameliorating the disease or condition (ie slowing down or preventing or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treatment” refers to the regulation of a disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters) or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, such as acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/ Carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, glucose Saccharate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate Acid salt, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalic acid Salt, palmitate, pa
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid , Ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from groups I to XII of the periodic table.
  • the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.
  • Organic bases from which salts can be derived include primary amines, secondary amines, and tertiary amines.
  • Substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins.
  • Certain organic amines include, for example, isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine .
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods. Generally speaking, such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxide, carbonate, bicarbonate, etc.) of Na, Ca, Mg or K, or by reacting These compounds are prepared by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two.
  • a suitable base such as hydroxide, carbonate, bicarbonate, etc.
  • non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.
  • a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.
  • the compounds disclosed in the present invention can also be obtained in the form of their hydrates or in the form of containing their solvents (for example, ethanol, DMSO, etc.), and used for their crystallization.
  • their solvents for example, ethanol, DMSO, etc.
  • the compounds disclosed in the present invention can form solvates inherently or by design with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include solvated and unsolvated forms.
  • any structural formula given in the present invention is also intended to represent the non-isotopically enriched form and the isotopically enriched form of these compounds.
  • the isotope-enriched compound has the structure described by the general formula given in the present invention, except that one or more atoms are replaced by atoms having the selected atomic weight or mass number.
  • Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the compounds of the present invention include isotopically enriched compounds as defined in the present invention, for example, those compounds in which radioactive isotopes such as 3 H, 14 C and 18 F are present, or non-radioactive isotopes such as 2 H and 13 C.
  • isotopically-enriched compounds can be used for metabolism studies (using 14 C), reaction kinetics studies (using, for example, 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or including drugs or Single-photon emission computed tomography (SPECT), which measures the distribution of substrate tissue, may be used in radiotherapy of patients.
  • 18 F-enriched compounds are particularly ideal for PET or SPECT research.
  • the isotope-enriched compound of Formula I or Formula II can be prepared by conventional techniques familiar to those skilled in the art or as described in the examples and preparation process of the present invention, using a suitable isotope-labeled reagent instead of the previously used unlabeled reagent .
  • the substitution of heavier isotopes can provide certain therapeutic advantages due to higher metabolic stability.
  • the isotope enrichment factor can be used to define the concentration of such heavier isotopes, especially deuterium.
  • the compound has at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), for each designated deuterium atom, At least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping) Deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) isotope enrichment factor.
  • the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, such as D 2 O, acetone-d 6 , DMSO-d 6 .
  • the present invention relates to an intermediate for preparing the compound contained in Formula I or Formula II.
  • the present invention relates to methods for the preparation, separation and purification of compounds contained in formula I or formula II.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.
  • the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.
  • “Combination” means a fixed combination in a single dosage unit form or a kit of parts for combined administration, wherein the compound disclosed in the present invention and the combination partner can be administered independently at the same time or can be administered separately within a certain time interval, In particular, make joint partners show cooperation, such as synergy.
  • co-administration or “co-administration” and the like are intended to encompass the administration of the selected combination partner to a single individual (eg patient) in need thereof, and are intended to include treatment regimens in which the substances do not have to be administered via the same route of administration or simultaneously .
  • pharmaceutical combination as used herein means a product obtained by mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients.
  • fixed combination means that the active ingredients such as the compound disclosed in the present invention and the combination partner are simultaneously administered to the patient in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients such as the compound disclosed in the present invention and the combination partner are both administered to the patient simultaneously, jointly or sequentially without a specific time limit as separate entities, wherein the administration provides a therapeutically effective level of the two compounds in the patient .
  • the Pomalidomide terminal derivatives used in the following examples were prepared according to the method disclosed in the literature Chemistry & Biology 22, 755-763 (2015). Lenalidomide terminal derivatives were prepared according to the method disclosed in the document J. Med. Chem (DOI: 10.1021/acs.jmedchem. 6b01816). The RG-7112 terminal carboxylic acid derivative was prepared according to the document Bioorg.Med.Chem.Lett.18,5904 -5908 (2008). and ACS Med. Chem. Lett. 4, 466-469 (2013).
  • the terminal derivatives of Ibrutinib used in the following examples were prepared according to the following method:
  • the terminal alkynes required by Click chemistry were connected to the Ibrutinib intermediate (cas: 1022150-12-4) through an amide condensation reaction.
  • the specific preparation process is as follows:
  • reaction was quenched by adding 100 mL saturated sodium bicarbonate aqueous solution, the mixture was extracted three times with 50 mL ⁇ 3 dichloromethane, the organic phases were combined, dried with anhydrous sodium sulfate, spin-dried solvent, and separated using 200-300 mesh silica gel column
  • the intermediate is dissolved in 4mL methanol and 1mL DMF, 20mg palladium carbon is added, and the reaction is carried out in hydrogen at 38°C for 8 hours.
  • the reaction solution was filtered with diatomaceous earth, the solvent was spin-dried, and the 200-300 mesh silica gel column was used for separation and purification.
  • the intermediate is dissolved in 4mL methanol and 1mL DMF, 20mg palladium carbon is added, and the reaction is carried out in hydrogen at 38°C for 8 hours.
  • the reaction solution was filtered with diatomaceous earth, the solvent was spin-dried, and the 200-300 mesh silica gel column was used for separation and purification.
  • Example 2 The biological activity test of the compound at the Western Blot level
  • Collect the cells scrape the treated cells in the culture medium, fully suspend the cells and collect them by centrifugation at 300g for 5 minutes. After washing with PBS, discard the PBS.
  • Cell lysis Add 150 ⁇ l of 2 ⁇ Loading Buffer to each sample, shake and mix thoroughly, denature at 95°C for 15 minutes, mix well and store at -20°C or use it directly for Western Blot detection.
  • 5 ⁇ Loading Buffer 250mM Tris-HCl(pH6.8), 10%(W/V)SDS, 0.5%(W/V) bromophenol blue, 50%(V/V) glycerin, 5%( W/V) ⁇ -Mercaptoethanol (2-ME).
  • 2 ⁇ Loading Buffer is prepared by adding 1.5 times the volume of dd water to 5 ⁇ Loading Buffer.
  • Electrophoresis When the power is turned on, the voltage of the protein sample in the concentrated gel is 83 volts. When the protein sample enters the separation gel, we adjust the voltage to 110 volts to continue electrophoresis. Stop the electrophoresis when the bromophenol blue almost completely runs out of the PAGE gel.
  • the compound according to the embodiment of the present invention has a strong effect on the degradation of wild-type BTK, and can detect obvious degradation under 10-50 nM, and has no inhibitory or degradation effect on other targets such as EGFR, ITK, TEC, etc., and has specific targeting
  • the effect of degrading BTK protein some of the results are shown in Figure 4, where L18I represents the compound
  • the ELISA plate already contains 5 microliters of compound in 10% DMSO.
  • Inhibition rate (max-conversion value)/(max-min)*100.
  • the compounds according to the embodiments of the present invention have an IC 50 of 10-100 nM for inhibitory activity against BTK kinase, and the IC 50 values for ITK and EGFR are both higher than 1000 nM, indicating that the compounds according to the embodiments of the present invention have no obvious side effects on Ibrutinib. Inhibition.
  • Reagents RPIM 1640 medium; DMEM medium; 100 ⁇ non-essential amino acids (NEAA); 100 ⁇ penicillin streptomycin mixture; 50 mM ⁇ -mercaptoethanol; calf serum (FBS, previously inactivated).
  • DMEM medium 450ml + 100 x NEAA (5ml) + 100 x penicillin mixture (5ml) + calf serum (50ml) + 50mM ⁇ mercaptoethanol (0.5ml).
  • Table 1 MTT experiment (GI50 value) of the inhibitory ability of compounds represented by formula 1 to formula 18 on HBL-1 cell line and Ramos cell line:
  • N.D means that no inhibitory activity was detected.
  • Example 5 Inhibition of the compound on the release of inflammatory factors by THP-1 upon LPS stimulation
  • PCR primers designed to detect IL-1 ⁇ , TNF ⁇ , IL-6, IL-10 and internal reference GAPDH are designed according to the gene sequence of human pro-inflammatory cytokines, and the designed primers are used for fluorescence quantitative PCR (see table for specific conditions) 3).
  • the results of inhibition of the release of cellular inflammatory factors by the compounds of the present invention measured by the above methods are shown in Figure 3 and Table 4.
  • the exemplary compounds have different RNA levels of IL-1 ⁇ , TNF ⁇ , IL-6, and IL-10 in cells.
  • the degree of down-regulation, in which the compound represented by formula 10 inhibits the release of inflammatory factors is the most obvious, indicating that the compounds of the present invention can inhibit the BTK pathway and thereby inhibit the release of inflammatory factors.
  • target gene refers to target gene
  • species refers to species
  • primer name refers to the name of the guide
  • sequence refers to the sequence of the guide.
  • Table 4 Compounds' regulation of inflammatory factor mRNA levels
  • down means down.
  • mice Fully emulsify bovine type II collagen (CII) with an equal volume of complete Freund's adjuvant (CFA) to prepare an emulsion containing 1 mg/mL CII.
  • CFA complete Freund's adjuvant
  • Ibrutinib can significantly improve the symptoms of foot swelling in mice. Compared with the blank group, the example compound can improve the symptoms of arthritis.
  • mice were divided into healthy group (3 mice), blank group (7 mice), ibrutinib group (7 mice) and example compound group (7 mice). Except for the healthy group, all mice were injected intraperitoneally with 1ml at a time Norphytane, the blank group, ibrutinib group and the example compound were injected with vehicle, ibrutinib and the example compound respectively one week before the administration of norphytane, intraperitoneal injection at 100 mg/kg per day, and continuous injection after the injection of norphytane The mice were sacrificed 18 days after the injection, the lungs and spleen were taken out, weighed, and the bleeding in the lungs was observed.

Abstract

一种化合物，该化合物为式I所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，该化合物针对野生型BTK降解作用效果强，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向降解BTK蛋白的功效。 X-Y-Z 式I

Description

一种靶向BTK蛋白降解化合物的制备及其在治疗自身免疫***疾病与肿瘤中的应用 技术领域
本发明涉及生物医药领域，具体地，本发明涉及一种靶向BTK蛋白降解化合物的制备及其在治疗自身免疫***疾病与肿瘤中的应用。
背景技术
PROTAC(Proteolysis Targeting Chimeras)技术即蛋白靶向降解技术，是近年来新兴的利用泛素-蛋白酶体***诱导蛋白降解的一种化学生物学或药物发现手段。PROTAC小分子发挥作用是基于E3泛素连接酶为某种蛋白进行泛素连接这一过程的，PROTAC小分子嵌合体一端能够特异性地与靶蛋白结合，另一端则招募E3泛素连接酶，使其与靶蛋白相互靠近，进而发生后续的降解进程。PROTAC嵌合体是在选择性小分子抑制剂的基础上合成的，通过巧妙的设计可实现对高度同源蛋白的区分，这让PROTAC技术在生物工具的应用中具有一定的优势；另外PROTAC分子与靶蛋白之间为非共价结合，在实现一分子蛋白的降解之后可解离下来进行另一分子靶蛋白的降解，这种催化量实现蛋白降解的手段为高活性、低毒药物分子的开发提供了可能PROTAC技术因更为直接和快速而受到广泛关注和应用。
BTK是非受体酪氨酸激酶家族的成员，是B细胞抗原受体(BCR)信号通路中的关键激酶，可通过激活细胞周期正向调控因子和分化因子来控制B细胞的发育、分化，也能通过促凋亡和抗凋亡蛋白的表达来调控B细胞的存活和增殖。BTK的持续激活是很多血液病以及自身免疫疾病发展的先决条件，因此对BTK蛋白的调控对于治疗血液恶性肿瘤和自身免疫失调疾病具有良好的前景。
非霍奇金淋巴瘤(NHL)是一种血液***癌症，是除霍奇金淋巴瘤外所有淋巴瘤的总称。在美国，2.1％人群的生活受到其影响。2015年，430万人群患有非霍奇金淋巴瘤，231400被夺去生命。临床大多数非霍奇金淋巴瘤为B细胞型，占总数70％～85％。弥漫大B细胞淋巴瘤(DLBCL)是最常见的非霍奇金淋巴瘤(NHL)，在美国和英国，每年10万人群中有7-8人发病。依鲁替尼(Ibrutinib)是已经被FDA批准上市的用于治疗慢性淋巴细胞白血病(CLL)、套细胞淋巴瘤(MCL)以及华氏巨球蛋白血症适应症(WM)。并且有报道称，依鲁替尼可以有效抑制部分种类DLBCL的增殖。依鲁替尼发挥作用的机制是通过其丙烯酰胺结构与细胞中BTK蛋白481位半胱氨酸的巯基发生共价交联，从而使BTK失去磷酸化下游信号蛋白的功能，从而发挥抗细胞增殖的作用。
尽管依鲁替尼表现出来很强的针对BTK激酶的抑制活性，但是这种药物本身由于脱靶作用很强，会引起很多副作用。针对EGFR的IC 50值为5.6nM，能够引起严重腹泻和皮疹；针对ITK的IC 50值为10.7nM，能够引起自然杀伤细胞功能缺失；针对TEC的IC 50值为78nM，能够引起凝血缺陷，而PROTAC作为一种能够精准并快速降解靶蛋白的技术，在实现高效抗肿瘤并减少脱靶副作用方面具有巨大的优势。
自身免疫性疾病是指机体对自身抗原发生免疫反应而导致自身组织损害所引起的疾病，包括肺出血肾炎综合征、天疱疮等器官特异性自身免疫病以及关节炎、***性红斑狼疮等***性自身免疫病，其具体机制尚未完全明确，而其中一种可能机制是BTK的大量表达使BCR信号通路异常激活，进而使B细胞功能失调、免疫耐受状态改变，并转化为自身反应性B细胞，分泌大量自身抗体诱发疾病的发生。
基于以上机理，近几年BTK抑制剂应用于自身免疫性疾病(包括类风湿性关节炎)的研究也越来越多。虽然目前仅依鲁替尼以自身免疫性疾病(慢性移植物抗宿主病(cGVHD))于2017年获FDA批准上市，但目前已有十几种小分子抑制剂进入临床阶段。BTK已成为自身免疫性疾病领域除TNF(肿瘤坏死因子)和CD20之外临床药物最多的靶点，有望成为未来治疗自身免疫性疾病的新靶点，这也为能够高效降解BTK蛋白的PROTAC技术提供了机会和挑战。
因此，BTK激酶降解剂作为抗肿瘤或治疗自身免疫性疾病的药物有良好的前景并需要进一步开发。
发明内容
本申请是基于发明人对以下事实和问题的发现和认识作出的：
现有技术中Ibrutinib可以抑制BTK激酶，但是文献(N.Engl.J.Med.370,2352-2254(2014).)报道Ibrutinib对C481S突变的BTK抑制能力IC 50＝1μM，且该药物对于其他靶点，如EGFR、ITK、TEC也有不同程度的作用，副作用明显。基于上述问题的发现，发明人提出了一种新的化合物，该化合物采用的是双靶点分子结构，结构如图1所示，该类分子一端结构靶向结合E3连接酶，另一端结构靶向结合所要降解的目标蛋白(BTK蛋白)，这两端的结构通过链(linker)相连，形成一个完整的化合物分子。该化合物针对野生型BTK降解作用效果强，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向BTK蛋白的功效。
为此，在本发明的第一方面，本发明提出了一种化合物，其为式I所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：
X-Y-Z
式I
其中：
所述Y为
Figure PCTCN2019121627-appb-000001
且各E独立地为酰胺基，酯基，氨基甲酯基，脲基，胍基，杂环基，环烷基，螺杂双环基，稠合杂双环基，桥杂双环基或C6-10芳基；各E任选地被1，2，3或4个独立的R b所取代；各W为O、S、NH或Se，b为1～30之间的整数，d为0～30之间的整数，L 6、L 7独立为键，-O-，-S(＝O) t1-，-S-，-N(R a)-，-C(＝O)O-，-N(R a)-C(＝O)-，-C(＝O)-(CH 2) t2-，-CH 2-，-C(＝O)-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)-，-(CH 2) t2-C(＝O)-或者三氮唑基，
所述X为
Figure PCTCN2019121627-appb-000002
所述Z为：
Figure PCTCN2019121627-appb-000003
或者所述Y为
Figure PCTCN2019121627-appb-000004
d为0～30之间的整数，其中，
d＝6，L 6、L 7独立为-N(R a)-，-C(＝O)时-，所述X为
Figure PCTCN2019121627-appb-000005
Figure PCTCN2019121627-appb-000006
Figure PCTCN2019121627-appb-000007
所述Z为：
Figure PCTCN2019121627-appb-000008
Figure PCTCN2019121627-appb-000009
d≠6，L 6、L 7独立为键，-O-，-S(＝O) t1-，-S-，-N(R a)-，-C(＝O)O-，-N(R a)-C(＝O)-，-CH 2-，-C(＝O)-，-OC(＝O)-， -C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)-或者三氮唑基时，所述X为
Figure PCTCN2019121627-appb-000010
Figure PCTCN2019121627-appb-000011
Figure PCTCN2019121627-appb-000012
所述Z为：
Figure PCTCN2019121627-appb-000013
Figure PCTCN2019121627-appb-000014
或者所述Y为
Figure PCTCN2019121627-appb-000015
且W为CH 2、O、S、NH或Se，b为0～30之间的整数，d为0～30之间的整数，
所述X为
Figure PCTCN2019121627-appb-000016
所述Z为：
Figure PCTCN2019121627-appb-000017
或者所述Y为
Figure PCTCN2019121627-appb-000018
且W为CH 2、O、S、NH或Se，b为0～30之间的整数，d为0～30之间的整数，
所述X为
Figure PCTCN2019121627-appb-000019
Figure PCTCN2019121627-appb-000020
时，所述Z为：
Figure PCTCN2019121627-appb-000021
所述X为
Figure PCTCN2019121627-appb-000022
Figure PCTCN2019121627-appb-000023
时，所述Z为
Figure PCTCN2019121627-appb-000024
其中，各L 1、L 2、L 3独立为键，-O-，-S(＝O) t1-，-S-，-N(R a)-，-C(＝O)O-，-N(R a)-C(＝O)-，-C(＝O)-(CH 2) t2-，-CH 2-，-C(＝O)-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)-，-(CH 2) t2-C(＝O)-或者三氮唑基；
各R a独立地为氢，C1-4烷基，卤代C1-4烷基，C1-4烷基酰基或羟基；
各t2独立地为0，1，2，3或4；
各t1独立地为0，1或2；
各X 1、X 2、X 3、X 4、X 5、X 6、X 7、X 8、Q独立地为CH，CH 2，O，S，N，NH或Se；
各R 1、R 2、R 3、R 4、R 5独立地为H、氘、氨基、C1-4酰胺基、C1-4烷基、C1-4杂烷基、C3-8环烷基、C2-10杂环基、C6-10芳基、C1-9杂芳基、C6-10芳基、C1-4烷氧基、C1-4烯基、C1-4炔基，其中，所述的C1-4烷基、C1-4杂烷基、C3-8环烷基、C2-10杂环基、C6-10芳基、C1-9杂芳基、C6-10芳基、C1-4烷氧基、C1-4烯基、C1-4炔基可以任选地被一个或多个选自氘、羟基、氨基、氧代、F、Cl、Br、I、氰基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6烷氧基C1-6烷基、C1-6烷氨基C1-6烷基、C6-10芳基C1-6烷基、C1-9杂芳基C1-6烷基、C2-10杂环基 C1-6烷基、C3-10环烷基C1-6烷基、C1-6烷氧基、C1-6烷氨基、C6-10芳基、C6-10芳氧基、C6-10芳氨基、C1-9杂芳基、C1-9杂芳氧基、C2-6烯基、C3-10环烷基、卤素取代C6-10芳基、卤素取代C1-9杂芳基、卤素取代C2-10杂环基或C2-10杂环基的取代基所取代；
各A独立为氢，C1-4烷基，C1-4卤代烷基，羟基，硝基，氨基，氰基，卤素，羧基，C1-4烷氧基，C1-4烷氨基，C1-4烷硫基，C1-4烷基酰基，C3-12环烷基，任选取代的C3-9杂环基，任选取代的C6-12芳基，任选取代的C1-9杂芳基；
各R b独立地为氢，C1-4烷基，C1-4卤代烷基，羟基，硝基，氨基，氰基，卤素，羧基，C1-4烷氧基，C1-4烷氨基，C1-4烷硫基，C1-4烷基酰基，C3-12环烷基，C3-9杂环基，C6-12芳基，C1-9杂芳基，氨基C1-4烷基，羟基C1-4烷基，磺酸基，氨基磺酰基或氨基酰基；
各a、c、e、f独立地为0～30之间的整数。
根据本发明的实施例，上述化合物还可进一步包括如下附加技术特征至少之一：
根据本发明的实施例，各L 1独立地为键，-O-，-S-，-NH-，
各L 2独立地为键、-(C＝O)CH＝CH 2-，-O-，-S-，-S(＝O)-，-S(＝O) 2-，-NRa-，-C(＝O)-，-C(＝O)O-，-N(R a)-C(＝O)-，-CH 2-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)或者三氮唑基，
各R a独立地为氢，C1-2烷基，卤代C1-2烷基，C1-2烷基酰基或羟基，
各R 1、R 2、R 3、R 4独立地为H、氨基、C1-4烷基、C1-4杂烷基、C5-7环烷基、C5-7杂环基、C6-7芳基、C5-7杂芳基，其中，所述C1-4烷基、C1-4杂烷基、C5-7环烷基、C5-7杂环基、C6-7芳基、C5-7杂芳基可以任选地被一个或多个选自氘、羟基、氨基、氧代、F、Cl、Br、I、氰基取代基取代。
根据本发明的实施例，各X分别独立地为如下所示的化合物：
Figure PCTCN2019121627-appb-000025
Figure PCTCN2019121627-appb-000026
根据本发明的实施例，各A独立为氢，任选取代的C5-7杂环基，C5-7环烷基，任选取代的C6-7芳基，任选取代的C5-7杂芳基，
各R 5独立地为H、氨基、C1-4烷基、C1-4杂烷基、C5-7环烷基、C5-7杂环基、C6-7芳基、C5-7杂芳基，其中，所述C1-4烷基、C1-4杂烷基、C5-7环烷基、C5-7杂环基、C6-7芳基、C5-7杂芳基可以任选地被一个或多个选自氘、羟基、氨基、氧代、F、Cl、Br、I、氰基、C5-7芳基、C5-7杂芳基、卤素取代C5-7芳基、卤素取代C5-7杂芳基、卤素取代C5-7杂环基的取代基取代；
各L 3独立地为键、-(C＝O)CH＝CH 2-，-O-，-S-，-S(＝O)-，-S(＝O) 2-，-NRa-，-C(＝O)-，-C(＝O)O-，-N(R a)-C(＝O)-，-CH 2-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)或者三氮唑基，
各R a独立地为氢，C1-2烷基，卤代C1-2烷基，C1-2烷基酰基或羟基。
根据本发明的实施例，各A分别独立地为
Figure PCTCN2019121627-appb-000027
Figure PCTCN2019121627-appb-000028
各R c独立地为氢或C1-2烷基。
根据本发明的实施例，各Z分别独立地为如下所示的化合物：
Figure PCTCN2019121627-appb-000029
Figure PCTCN2019121627-appb-000030
根据本发明的实施例，各E独立为酰胺基，酯基，氨基甲酯基，脲基，胍基，杂环基，环烷基或C6-C8芳基；各E任选地被1，2，3或4个独立的R b所取代，
各R b独立地为氢，C1-2烷基，C1-2卤代烷基，羟基，硝基，氨基，氰基，卤素，羧基，C1-2烷氧基，C1-2烷氨基，C1-2烷硫基，C1-2烷基酰基，C5-7环烷基，C5-7杂环基，C6-7芳基，C5-7杂芳基，氨基C1-2烷基，羟基C1-2烷基，磺酸基，氨基磺酰基或氨基酰基，
各R a独立地为氢，C1-2烷基，卤代C1-2烷基，C1-2烷基酰基或羟基。
根据本发明的实施例，各Y分别独立地为
Figure PCTCN2019121627-appb-000031
根据本发明的实施例，所述X为
Figure PCTCN2019121627-appb-000032
Figure PCTCN2019121627-appb-000033
在一些实施例中，所述Z为
Figure PCTCN2019121627-appb-000034
Figure PCTCN2019121627-appb-000035
在一些实施例中，所述Y为
Figure PCTCN2019121627-appb-000036
其中，m1为1～10之间的整数，n1为0～10之间的整数。
根据本发明的实施例，所述化合物包括式(1)～(15)任一项所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，
Figure PCTCN2019121627-appb-000037
Figure PCTCN2019121627-appb-000038
Figure PCTCN2019121627-appb-000039
Figure PCTCN2019121627-appb-000040
Figure PCTCN2019121627-appb-000041
其中，m1为1～10之间的整数，n1为0～10之间的整数。
在本发明的第二方面，本发明提出了一种化合物。根据本发明的实施例，其为式1～18任一项所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，
Figure PCTCN2019121627-appb-000042
Figure PCTCN2019121627-appb-000043
Figure PCTCN2019121627-appb-000044
Figure PCTCN2019121627-appb-000045
根据本发明实施例的化合物针对野生型BTK降解作用效果强，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向降解BTK蛋白的功效。
在本发明的第三方面，本发明提出了一种药物组合物，所述药物组合物包括前面所描述所述的化合物。根据本发明实施例的药物组合物针对野生型BTK降解作用效果强，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向降解BTK蛋白的功效。
根据本发明的实施例，上述药物组合物还可进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述药物组合物进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。
根据本发明的实施例，所述药物组合物进一步包括其他治疗或预防非霍奇金淋巴瘤或自身免疫疾病的药物。发明人发现，联合用药，其治疗或预防非霍奇金淋巴瘤或自身免疫疾病的效果更好。
根据本发明的实施例，所述自身免疫疾病为关节炎、肺出血、***性红斑狼疮、天胞疮、慢性淋巴性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、慢性溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、原发性胆汁性肝硬变、多发性脑脊髓硬化症或急性特发性多神经炎。在一些实施例中，所述自身免疫疾病为关节炎或肺出血。
根据本发明的实施例，所述其他治疗或预防非霍奇金淋巴瘤或自身免疫疾病的药物包括依鲁替尼。
在本发明的第四方面，本发明提出了前面所描述的化合物或前面所描述的药物组合物在制备药物中的用途，所述药物用于降解BTK或抑制BTK。根据本发明实施例的化合物或者药物组合物针对野生型BTK降解作用效果强，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向BTK蛋白的功效。
在本发明的第五方面，本发明提出了前面所描述的化合物或前面所描述的药物组合物在制备药物中的用途，所述药物用于治疗或预防BTK相关性疾病。根据本发明实施例的化合物或者药物组合物针对野生型BTK降解作用效果强，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向BTK蛋白的功效，对BTK相关性疾病具有良好的治疗或预防效果。
根据本发明的实施例，上述用途还可进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述BTK相关性疾病为非霍奇金淋巴瘤或自身免疫疾病。根据本发明实施例的化合物或药物组合物对非霍奇金淋巴瘤或自身免疫疾病的治疗或预防效果更好。
根据本发明的实施例，所述自身免疫疾病为关节炎、肺出血、***性红斑狼疮、天胞疮、慢性淋巴性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、慢性溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、原发性胆汁性肝硬变、多发性脑脊髓硬化症或急性特发性多神经炎。
根据本发明的实施例，所述自身免疫疾病为关节炎或肺出血。发明人发现前面所描述的化合物或药物组合物可预防和治疗小鼠模型中的关节炎和肺出血症状，且预防和改善情况明显优于依鲁替尼。
在本发明的又一方面，本发明提出了式I所示化合物的合成一般步骤。根据本发明的实施例，式I所示化合物可通过Pomalidomide或Lenanidomide或RG-7112端衍生物和Ibrutinib端衍生物之间的click反应或酰胺缩合反应连接而成，如图2所示，其中，Pomalidomide端衍生物的制备方法可参考文献Chemistry&Biology 22,755-763(2015).，Lenalidomide端衍生物的制备方法可参考文献J.Med.Chem(DOI:10.1021/acs.jmedchem.6b01816).，RG-7112端衍生物的制备方法可参考文献Bioorg.Med.Chem.Lett.18,5904-5908(2008).ACS Med.Chem.Lett.4,466-469(2013).，Ibrutinib端衍生物的合成路线可参考专利PCT Int.Appl.,2013003629,03Jan 2013。Click chemistry所需的端炔烃则通过酰胺缩合反应连接到Ibrutinib母核的哌啶环上，制备方法可参考文献J.Chem.Inf.Model.50,446(2010).PCT Int.Appl.,2013170115,14 Nov 2013。
附图说明
图1是根据本发明实施例的PROTACs的基本技术路线；
图2是根据本发明实施例的通过click反应和酰胺缩合反应构建式I所示的示意图；
图3是根据本发明实施例的化合物对LPS刺激的THP-1细胞炎性因子释放的抑制结果；
图4是根据本发明实施例的化合物对BTK的降解作用。
具体实施方式
下面详细描述本发明的实施例，所述实施例的示例在附图中示出。下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
在本文中所使用的术语“给予患者前面所述的化合或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药或前面所述的药物组合物”指将预定量的物质通过某种适合的方式引入病人。本发明的式I所述化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药或者药物组合物可以通过任何常见的途径被给药，只要它可以到达预期的组织。给药的各种方式是可以预期的，包括腹膜，静脉，肌肉，皮下，皮层，口服，局部，鼻腔，肺部和直肠，但是本发明不限于这些已举例的给药方式。然而，由于口服给药时，口服给药的组合物的活性成分应该被包被或被配制以防止其在胃部被降解。此外，本发明的式I所述化合物或者所述药物组合物可以使用将活性成分传送到靶细胞的特定器械来给药。
本发明的药物组合物的给药频率和剂量可以通过多个相关因素被确定，该因素包括要被治疗的疾病类型，给药途径，病人年龄，性别，体重和疾病的严重程度以及作为活性成分的药物类型。
术语“治疗有效量”是指化合物足以显著改善某些与疾病或病症相关的症状的量，也即为给定病症和给药方案提供治疗效果的量。治疗有效量的药物或化合物不需要治愈疾病或病症，但将为疾病或病症提供治疗，使得个体的疾病或病症的发作被延缓、阻止或预防，或者疾病或病症的症状得以缓解，或者疾病或病症的期限被改变，或者例如疾病或病症变得不严重，或者加速康复。
术语“治疗”用于指获得期望的药理学和/或生理学效果。所述效果就完全或部分预防疾病或其症状而言可以是预防性的，和/或就部分或完全治愈疾病和/或疾病导致的不良作用而言可以是治疗性的。本文使用的“治疗”涵盖哺乳动物、特别是人的疾病的治疗，包括：(a)在容易患病但是尚未确诊得病的个体中预防疾病或病症发生；(b)抑制疾病；或(c)缓解疾病，例如减轻与疾病相关的症状。本文使用的“治疗”涵盖将药物或化合物给予个体以治疗、治愈、缓解、改善、减轻或抑制个体的疾病的任何用药，包括但不限于将含本文所述式I或式II化合物或药物组合物的给予有需要的个体。
根据本发明的实施例，所述辅料包括制剂领域公知的可药用的赋形剂、润滑剂、填充剂、稀释剂、崩解剂、稳定剂、防腐剂、乳化剂、助溶剂、着色剂、甜味剂，制成片剂、丸剂、胶囊剂、注射剂等不同剂型。
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中 以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明，应当应用本文所使用得下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基， 环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2 nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C1-6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。
各a、b、c、d、e、f各自独立地为0～30之间的整数。在一实施方案中，各a、b、c、d、e、f各自独立地为0～25之间的整数。在另一实施方案中，各a、b、c、d、e、f各自独立地为0～20之间的整数。在另一实施方案中，各a、b、c、d、e、f各自独立地为0～15之间的整数。在另一实施方案中，各a、b、c、d、e、f各自独立地为0～10之间的整数。在另一实施方案中，各a、b、c、d、e、f各自独立地为0～5之间的整数。
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
本发明使用的术语“烷基”或“烷基基团”，表示含有1至20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明，烷基基团含有1-20个碳原子。在一实施方案中，烷基基团含有1-12个碳原子；在另一实施方案中，烷基基团含有1-6个碳原子；在又一实施方案中，烷基基团含有1-4个碳原子；还在一实施方案中，烷基基团含有1-3个碳原子。
烷基基团的实例包含，但并不限于，甲基(Me、-CH 3)，乙基(Et、-CH 2CH 3)，正丙基(n-Pr、-CH 2CH 2CH 3)，异丙基(i-Pr、-CH(CH 3) 2)，正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2)，仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu、-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。除非另外详细说明，亚烷基基团含有1-12个碳原子。在一实施方案中，亚烷基基团含有1-6个碳原子；在另一实施方案中，亚烷基基团含有1-4个碳原子；在又一实施方案中，亚烷基基团含有1-3个碳原子；还在一实施方案中，亚烷基基团含有1-2个碳原子。这样的实例包括亚甲基(-CH2-)，亚乙基(-CH2CH2-)，亚异丙基(-CH(CH3)CH2-)等等。
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp2双键，其中，所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代，其包括“cis”和“tans”的定位，或者"E"和"Z"的定位。在一实施方案中，烯基基团包含2-8个碳原子；在另一实施方案中，烯基基团包含2-6个碳原子；在又一实施方案中，烯基基团包含2-4个碳原子。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH 2)、烯丙基(-CH 2CH＝CH 2)等等。
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，炔基基团包含2-8个碳原子；在另一实施方案中，炔基基团包含2-6个碳原子；在又一实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH 2C≡CH)、1-丙炔基(-C≡C-CH 3)等等。
术语“杂烷基”表示烷基链中***一个或多个杂原子，其中烷基基团和杂原子具有如本发明所述的含义。除非另外详细说明，杂烷基基团含有2-10个碳原子，另外一些实施方案是，杂烷基基团含有2-8个碳原子，另外一些实施方案是，杂烷基基团含有2-6个碳原子，另外一些实施方案是，杂烷基基团含有2-4个碳原子，另外一些实施方案是，杂烷基基团含有2-3个碳原子。这样的实例包括，但并不限于，CH 3OCH 2-，CH 3CH 2OCH 2-，CH 3SCH 2-，(CH 3) 2NCH 2-，(CH 3) 2CH 2OCH 2-，CH 3OCH 2CH 2-，CH 3CH 2OCH 2CH 2-等。
术语“亚烯基”表示从直链或支链的烯烃中去掉两个氢原子所得到的烯烃基基团。并且所述亚烯基可以是取代或非取代的，其中取代基可以是，但并不限于，氘、羟基、氨基、卤素、氰基、芳基、杂芳基、烷氧基、烷基、烯基、炔基、杂环基、巯基、硝基或芳氧基。这样的实例包括，但并不限于，亚乙烯基(-CH＝CH-)、亚异丙烯基(-C(CH3)＝CH-)、3-甲氧基丙烯-1,1-二基、2-甲基丁烯-1,1-二基等等。
术语“亚碳环基”(“亚环烷基”)表示含有3-12个碳原子的单环或7-12个碳原子的双环去掉两个氢原子所得到的饱和二价碳氢环，其中碳环基或环烷基具有如本发明所述的含义，这样的实例包括，但并不限于，亚环丙基、亚环丁基、亚环戊基、1-环戊-1-亚烯基、1-环戊-2-亚烯基等。
术语“亚杂环基”表示单环、双环或三环体系，其中环上一个或多个原子独立地选自杂原子，并且可以是完全饱和的或包含一个或多个不饱和度，但不属于芳香族类，具有两个连接点与分子其余部分相连，其中杂环基基团具有如本发明所述的含义。这样的实例包括，但并不限于，哌啶-1,4-二基、哌嗪-1,4-二基、四氢呋喃-2,4-二基、四氢呋喃-3,4-二基、氮杂环丁烷-1,3-二基、吡咯烷-1,3-二基等。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一实施方案中，烷氧基基团含有1-6个碳原子；在另一实施方案中，烷氧基基团含有1-4个碳原子；在又一实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。
烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH 3)，乙氧基(EtO、-OCH 2CH 3)，1-丙氧基(n-PrO、n-丙氧基、-OCH 2CH 2CH 3)，2-丙氧基(i-PrO、i-丙氧基、-OCH(CH 3) 2)，1-丁氧基(n-BuO、n-丁氧基、-OCH 2CH 2CH 2CH 3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH 2CH(CH 3) 2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH 3)CH 2CH 3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH 3) 3)，1-戊氧基(n-戊氧基、-OCH 2CH 2CH 2CH 2CH 3)，2-戊氧基(-OCH(CH 3)CH 2CH 2CH 3)，3-戊氧基(-OCH(CH 2CH 3) 2)，2-甲基-2-丁氧基(-OC(CH 3) 2CH 2CH 3)，3-甲基-2-丁氧基(-OCH(CH 3)CH(CH 3) 2)，3-甲基-l-丁氧基(-OCH 2CH 2CH(CH 3) 2)，2-甲基-l-丁氧基(-OCH 2CH(CH 3)CH 2CH 3)，等等。
术语“卤代烷基”，“卤代烯基”或“卤代烷氧基”表示烷基，烯基或烷氧基基团被一个或多个卤素原子所取代，这样的实例包含，但并不限于，三氟甲基、三氟甲氧基等。
术语“羟烷基”卓“羟基取代的烷基”表示烷基基团被一个或多个羟基基团所取代，其中烷基基团具有本发明所述的含义。这样的实例包含，但并不限于羟甲基、羟乙基、1,2-二羟基乙基等。
术语“碳环基”或“碳环”表示含有3-12个碳原子的，单价或多价的非芳香性的饱和或部分不饱和单环、双环或者三环体系。碳双环基包括螺碳双环基和稠合碳双环基，合适的碳环基基团包括，但并不限于，环烷基、环烯基和环炔基。碳环基基团的实例进一步包括，环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-1-烯基、1-环己基-2-烯基、1-环己基-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基，等等。
术语“环烷基”表示含有3-12个碳原子的，单价或多价的饱和单环，双环或三环体系。在一实施方案中，环烷基包含3-12个碳原子；在另一实施方案中，环烷基包含3-8个碳原子；在又一实施方案中，环烷基包含3-6个碳原子。所述环烷 基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
术语“杂环基”和“杂环”在此处可交换使用，都是指包含3-12个环原子的饱和或部分不饱和的单环、双环或三环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。杂环基的实例包括，但不限于：环氧乙烷基、氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
Figure PCTCN2019121627-appb-000046
基，二氮杂
Figure PCTCN2019121627-appb-000047
基，硫氮杂
Figure PCTCN2019121627-appb-000048
基，吲哚啉基，1,2,3,4-四氢异喹啉基、1,3-苯并二噁茂基、2-氧杂-5-氮杂双环[2.2.1]庚-5-基。杂环基中-CH2-基团被-C(O)-取代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
在一实施方案中，杂环基为4-7个原子组成的杂环基，是指包含4-7个环原子的饱和或部分不饱和的单环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，4-7个原子组成的杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。4-7个原子组成的杂环基的实例包括，但不限于：氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
Figure PCTCN2019121627-appb-000049
基，二氮杂
Figure PCTCN2019121627-appb-000050
基，硫氮杂
Figure PCTCN2019121627-appb-000051
基。杂环基中-CH2-基团被-C(O)-取代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代硫代吗啉基。所述的4-7个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
在另一实施方案中，杂环基为4个原子组成的杂环基，是指包含4个环原子的饱和或部分不饱和的单环，其中至少一个环原子选自氮、硫和氧原子所取代。除非另外说明，4个原子组成的杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。4个原子组成的杂环基的实例包括，但不限于：氮杂环丁基，氧杂环丁基，硫杂环丁基。所述的4个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
在另一实施方案中，杂环基为5个原子组成的杂环基，是指包含5个环原子的饱和或部分不饱和的单环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，5个原子组成的杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。5个原子组成的杂环基的实例包括，但不限于：吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基。杂环基中-CH2-基团被-C(O)-取代的实例包括，但 不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基。所述的5个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
在另一实施方案中，杂环基为6个原子组成的杂环基，是指包含6个环原子的饱和或部分不饱和的单环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，6个原子组成的杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。6个原子组成的杂环基的实例包括，但不限于：四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基。杂环基中-CH2-基团被-C(O)-取代的实例包括，但不限于，2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括，但不限于，1,1-二氧代硫代吗啉基。所述的6个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
还在一实施方案中，杂环基为7-12个原子组成的杂环基，是指包含7-12个环原子的饱和或部分不饱和的螺双环或稠合双环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，7-12个原子组成的杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。7-12个原子组成的杂环基的实例包括，但不限于：吲哚啉基，1,2,3,4-四氢异喹啉基、1,3-苯并二噁茂基、2-氧杂-5-氮杂双环[2.2.1]庚-5-基。所述的7-12个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
术语“稠合双环”，“稠环”，“稠合双环基”和“稠环基”在此处可交换使用，都是指单价或多价的饱和或部分不饱和的桥环体系，所述桥环体系是指非芳香族的双环体系。这样的体系可以包含独立的或共轭的不饱和体系，但其核心结构不包含芳香环或芳杂环(但是芳香族基团可以作为其上的取代基)。
术语“螺环基”，“螺环”，“螺双环基”或“螺双环”在此处可交换使用，是指单价或多价的饱和或部分不饱和环体系，其中一个环起源于另一个环上特定的环碳原子。例如，像下面所描述的，一个饱和的桥环体系(环B和B’)被称为“稠合双环”，而环A和环B在两个饱和的环体系中共享一个碳原子，被称为“螺环”或“螺双环”。稠合双环基和螺双环基中的每个环都可以是碳环基或杂环基，并且每个环任选地被一个或多个本发明所描述的取代基所取代。
Figure PCTCN2019121627-appb-000052
术语“杂环烷基”是指含有3-12个环原子的单价或多价的饱和单环、双环或者三环体系，其中至少一个环原子选自氮、硫或氧原子。
术语“n个原子组成的”，其中n是整数，典型地描述分子中成环原子的数目，在所述分子中成环原子的数目是n。例如，哌啶基是6个原子组成的杂环烷基，而1,2,3,4-四氢萘是10个原子组成的环烷基基团。
在本发明中所使用的术语“不饱和的”表示基团中含有一个或多个不饱和度。
术语“杂原子”是指O、S、N、P和Si，包括N、S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代 的吡咯烷基中的NR)。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽。所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“杂芳基”表示含有5-12个环原子，或5-10个环原子，或5-6个环原子的单环、双环和三环体系，其中至少一个环体系是芳香族的，且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含5-7个原子组成的环，且有一个或多个附着点与分子其余部分相连。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中，5-10个原子组成的杂芳基包含1，2，3或4个独立选自O，S和N的杂原子。
杂芳基基团的实例包括，但并不限于，2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、***基(如2-***基和5-***基)、2-噻吩基、3-噻吩基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-***基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]***并[4,3-b]哒嗪基、[1,2,4]***并[1,5-a]嘧啶基、[1,2,4]***并[1,5-a]吡啶基，等等。
术语“羧基”，无论是单独使用还是和其他术语连用，如“羧烷基”，表示-CO 2H；术语“羰基”，无论是单独使用还是和其他术语连用，如“氨基羰基”或“酰氧基”，表示-(C＝O)-。
术语“烷基氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代。其中一些实施例是，烷基氨基是一个或两个C 1-6烷基连接到氮原子上的较低级的烷基氨基基团。另外一些实施例是，烷基氨基是C 1-3的较低级的烷基氨基基团。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于，N-甲氨基，N-乙氨基，N,N-二甲氨基，N,N-二乙氨基等等。
术语“芳氨基”表示氨基基团被一个或两个芳基基团所取代，这样的实例包括，但并不限于N-苯氨基。其中一些实施例是，芳氨基上的芳环可以进一步被取代。
术语“氨基烷基”包括被一个或多个氨基所取代的C 1-10直链或支链烷基基团。其中一些实施例是，氨基烷基是被一个或多个氨基基团所取代的C 1-6“较低级的氨基烷基”，这样的实例包括，但并不限于，氨甲基，氨乙基，氨丙基，氨丁基和氨己基。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解 或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或 上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
可药用的酸加成盐可与无机酸和有机酸形成，例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、氯茶碱盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、磺基水杨酸等。
可药用碱加成盐可与无机碱和有机碱形成。
可以由其衍生得到盐的无机碱包括，例如铵盐和周期表的I族至XII族的金属。在某些实施方案中，该盐衍生自钠、钾、铵、钙、镁、铁、银、锌和铜；特别适合的盐包括铵、钾、钠、钙和镁盐。
可以由其衍生得到盐的有机碱包括伯胺、仲胺和叔胺，取代的胺包括天然存在的取代的胺、环状胺、碱性离子交换树脂等。某些有机胺包括，例如，异丙胺、苄星青霉素(benzathine)、胆碱盐(cholinate)、二乙醇胺、二乙胺、赖氨酸、葡甲胺(meglumine)、哌嗪和氨丁三醇。
本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言，该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应，或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地，在适当的情况中，需要使用非水性介质如***、乙酸乙酯、乙醇、异丙醇或乙腈。在例如“Remington′s Pharmaceutical Sciences”，第20版，Mack Publishing Company，Easton，Pa.，(1985)；和“药用盐手册：性质、选择和应用(Handbook of Pharmaceutical Salts：Properties，Selection，and Use)”，Stahl and Wermuth(Wiley-VCH，Weinheim，Germany，2002)中可找到另外一些适宜盐的列表。
另外，本发明公开的化合物，包括它们的盐，也可以以它们的水合物形式或包含其溶剂(例如乙醇、DMSO，等等)的形式得到，用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物；因此，本发明旨在包括溶剂化的和未溶剂化的形式。
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如 2H， 3H， 11C， 13C， 14C， 15N， 17O， 18O， 18F， 31P， 32P， 35S， 36Cl和 125I。
另一方面，本发明所述化合物包括同位素富集的本发明所定义的化合物，例如，其中存在放射性同位素，如 3H， 14C和 18F的那些化合物，或者其中存在非放射性同位素，如 2H和 13C。该类同位素富集的化合物可用于代谢研究(使用 14C)、 反应动力学研究(使用例如 2H或 3H)、检测或成像技术，如正电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT)，或可用于患者的放疗中。 18F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的式I或式II所示化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。
此外，较重同位素特别是氘(即， 2H或D)的取代可提供某些治疗优点，这些优点是由代谢稳定性更高带来的。例如，体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。如果本发明化合物的取代基被指定为氘，该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5％的氘掺入)、至少4000(60％的氘掺入)、至少4500(67.5％的氘掺入)，至少5000(75％的氘掺入)，至少5500(82.5％的氘掺入)、至少6000(90％的氘掺入)、至少6333.3(95％的氘掺入)、至少6466.7(97％的氘掺入)、至少6600(99％的氘掺入)或至少6633.3(99.5％的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D 2O、丙酮-d 6、DMSO-d 6的那些溶剂化物。
另一方面，本发明涉及制备式I或式II所包含的化合物的中间体。
另一方面，本发明涉及式I或式II所包含的化合物的制备、分离和纯化的方法。
另一方面，本发明提供一种药物组合物，所述药物组合物包含本发明化合物，药学上可接受的载体，赋形剂，稀释剂，辅剂，溶媒，或它们的组合。在一些实施方案，药物组合物可以是液体，固体，半固体，凝胶或喷雾剂型。
“联合”表示在单个剂量单位形式中的固定组合或用于组合施用的部分的药盒，其中本发明公开的化合物和组合伴侣可以在同一时间独立施用或者可以在一定的时间间隔内分别施用，特别是使联合伴侣表现出合作、例如协同作用。如术语“共同给药”或“联合给药”等意欲囊括将所选的组合伴侣施用于需要其的单个个体(例如患者)，并且意欲包括其中物质不必通过相同施用途径或同时施用的治疗方案。如本文所用的术语“药物组合”表示将一种以上活性成分混合或组合所得到的产品，并且既包括活性成分的固定组合也包括非固定组合。术语“固定联合”表示活性成分如本发明公开化合物和组合伴侣以单一实体或剂量的形式同时施用于患者。术语“非固定联合”表示活性成分如本发明公开化合物和组合伙伴均作为单独实体同时、共同或无特定时间限制地先后施用于患者，其中该施用在患者体内提供了两种化合物的治疗有效水平。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
下述实施例中使用的Pomalidomide端衍生物根据文献Chemistry&Biology 22,755-763(2015).中公开的方法制备。Lenalidomide端衍生物根据文献J.Med.Chem(DOI:10.1021/acs.jmedchem.6b01816).中公开的方法制备，RG-7112端羧酸衍生物根据文献Bioorg.Med.Chem.Lett.18,5904-5908(2008).及ACS Med.Chem.Lett.4,466-469(2013).中公开的方法制备。
下述实施例中使用的Ibrutinib端衍生物按照如下方法制备：Click chemistry所需的端炔烃通过酰胺缩合反应连接到Ibrutinib中间体(cas：1022150-12-4)上。具体制备过程如下：
(1)中间体1a的制备
Figure PCTCN2019121627-appb-000053
在25mL圆底烧瓶中加入193mg Ibrutinib中间体(cas：1022150-12-4)、3mL无水氯仿和31μL丙炔酸。将103mg DCC溶解于2mL无水氯仿中，保持反应液在0摄氏度的搅拌条件下，将DCC的无水氯仿溶液缓慢加入到上述反应液中，保持0摄氏度搅拌1小时。将反应液冷却至-20度，过滤后保留滤液，重复过滤两次，将滤液旋干后使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝60：1，即得中间体1a，产率72％。
中间体1b的制备
Figure PCTCN2019121627-appb-000054
在25mL圆底烧瓶中加入193mg Ibrutinib中间体(cas：1022150-12-4)、3mL无水氯仿和42mg丙炔酸。将103mg DCC溶解于2mL无水氯仿中，保持反应液在0摄氏度的搅拌条件下，将DCC的无水氯仿溶液缓慢加入到上述反应液中，保持0摄氏度搅拌1小时。将反应液冷却至-20度，过滤后保留滤液，重复过滤两次，将滤液旋干后使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝60：1，即得中间体1b，产率62％。
中间体1c的制备
Figure PCTCN2019121627-appb-000055
在25mL圆底烧瓶中加入193mg Ibrutinib中间体(cas：1022150-12-4)、3mL无水DMF、75mg HOBT、106mg EDCI、49mg戊炔酸、77μL三乙胺和10mg DMAP。保持反应液在室温的条件下搅拌24小时。加入15mL饱和氯化钠水溶液猝灭反应，将混合物用15mL×3乙酸乙酯萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝40：1，即得中间体1c，产率61％。
中间体1d的制备
Figure PCTCN2019121627-appb-000056
在25mL圆底烧瓶中加入193mg Ibrutinib中间体(cas：1022150-12-4)、3mL无水DMF、75mg HOBT、106mg EDCI、56mg己炔酸、77μL三乙胺和10mg DMAP。保持反应液在室温的条件下搅拌24小时。加入15mL饱和氯化钠水溶液猝灭反应，将混合物用15mL×3乙酸乙酯萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝40：1，即得中间体1d，产率71％。
(2)中间体2a的制备
Figure PCTCN2019121627-appb-000057
在100mL圆底烧瓶中加入2.67mL 3-aminopropan-1-ol、50mL无水二氯甲烷，将反应液冷却至0摄氏度，加入6.8mL三乙胺和9.7mL Boc 2O。将反应液在搅拌的条件下自然回升到在室温，继续搅拌12小时。加入100mL饱和碳酸氢钠水溶液猝灭反应，将混合物用50mL×3二氯甲烷萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝20：1，即得中间体2a，产率72％。
中间体2b的制备
Figure PCTCN2019121627-appb-000058
在100mL圆底烧瓶中加入3.22mL 4-aminobutan-1-ol、50mL无水二氯甲烷，将反应液冷却至0摄氏度，加入6.8mL三乙胺和9.7mL Boc 2O。将反应液在搅拌的条件下自然回升到在室温，继续搅拌12小时。加入100mL饱和碳酸氢钠水溶液猝灭反应，将混合物用50mL×3二氯甲烷萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝20：1，即得中间体2b，产率81％。
中间体2c的制备
Figure PCTCN2019121627-appb-000059
在100mL圆底烧瓶中加入1.6g叠氮化钠和25mL水，加入4.9g 2-(2-hydroxyethoxy)ethyl-4-methylbenzenesulfonate。将反应液在90摄氏度搅拌24小时。加入50mL饱和碳酸氢钠水溶液猝灭反应，将混合物用40mL×3二氯甲烷萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，即得中间体，产率46％。在50mL圆底烧瓶中加入所得的产品787mg，8mL无水二氯甲烷和1.67mL三乙胺，在搅拌的条件下将1.72g TsCl的无水二氯甲烷溶液缓慢加入到上述反应液中，室 温搅拌24小时。加入100mL饱和碳酸氢钠水溶液猝灭反应，将混合物用50mL×3二氯甲烷萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为石油醚：乙酸乙酯＝5：1，即得中间体2c，产率67％。
中间体2d的制备
Figure PCTCN2019121627-appb-000060
在50mL圆底烧瓶中加入526mg中间体2a和15mL无水THF，在0摄氏度搅拌的条件下缓慢加入150mg NaH(60％，分散在矿物油中)，将反应液在0摄氏度搅拌1小时，将285mg中间体2c的无水THF溶液缓慢加入到上述反应液中，将反应液在搅拌的条件下自然回升到在室温，继续搅拌15小时。在反应液中滴加入甲醇猝灭反应，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为石油醚：乙酸乙酯＝6：1，即得中间体，产率26％。在25mL圆底烧瓶中加入所得的产品230mg，5mL二氯甲烷和0.5mL三氟乙酸，室温搅拌6小时。加入15mL甲苯，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝10：1，即得中间体2d，产率62％。
中间体2e的制备
Figure PCTCN2019121627-appb-000061
在100mL圆底烧瓶中加入2.8g中间体2b和50mL无水THF，在0摄氏度搅拌的条件下缓慢加入800mg NaH(60％，分散在矿物油中)，将反应液在0摄氏度搅拌1小时，将1.43g中间体2c的无水THF溶液缓慢加入到上述反应液中，将反应液在搅拌的条件下自然回升到在室温，继续搅拌15小时。在反应液中滴加入甲醇猝灭反应，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为石油醚：乙酸乙酯＝6：1，即得中间体，产率22％。在25mL圆底烧瓶中加入所得的产品800mg，15mL二氯甲烷和1.5mL三氟乙酸，室温搅拌2小时。加入25mL甲苯，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝10：1，即得中间体2e，产率66％。
(3)中间体4a的制备
Figure PCTCN2019121627-appb-000062
在5mL圆底烧瓶中加入24mg 8-aminooctanoic acid、70μL DIEA、0.3mL DMF和35mg 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione。保持反应液在90摄氏度的条件下搅拌3小时。加入5mL饱和氯化钠水溶液猝灭反应，将混合物用5mL×3乙酸乙酯萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝40：1，即得中间体4a，产率22％。
中间体4b的制备
Figure PCTCN2019121627-appb-000063
在5mL圆底烧瓶中加入26mg 9-aminooctanoic acid、70μL DIEA、0.3mL DMF和35mg 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione。保持反应液在90摄氏度的条件下搅拌3小时。加入5mL饱和氯化钠水溶液猝灭反应，将混合物用5mL×3乙酸乙酯萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝40：1，即得中间体4b，产率31％。
(4)中间体5a的制备
Figure PCTCN2019121627-appb-000064
在100mL圆底烧瓶中加入3g octane-1,8-diol、20mL无水THF和1.3g叔丁醇钾。保持反应液在氩气保护室温的条件下搅拌15分钟，滴加入1.2g 3-溴丙炔。保持反应液在氩气保护室温的条件下搅拌12小时。旋干溶剂，加入30mL饱和氯化钠水溶液猝灭反应，采用1M HCl将pH值调至3-5，将混合物用30mL×3二氯甲烷萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为石油醚：乙酸乙酯＝3：1，即得中间体5a，产率55％。
中间体5b的制备
Figure PCTCN2019121627-appb-000065
在100mL圆底烧瓶中加入12.6g 2,2'-(ethane-1,2-diylbis(oxy))bis(ethan-1-ol)、50mL无水THF和5g叔丁醇钾。保持反应液在氩气保护室温的条件下搅拌15分钟，滴加入3.5mL 3-溴丙炔。保持反应液在氩气保护室温的条件下搅拌12小时。旋干溶剂，加入30mL饱和氯化钠水溶液猝灭反应，采用1M HCl将pH值调至3-5，将混合物用30mL×3二氯甲烷萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为石油醚：乙酸乙酯＝3：1，即得中间体5b，产率77％。
中间体5c的制备
Figure PCTCN2019121627-appb-000066
在100mL圆底烧瓶中加入4.4mL pentane-1,5-diol、30mL无水THF和2.5g叔丁醇钾。保持反应液在氩气保护室温的条件下搅拌15分钟，滴加入1.73mL 3-溴丙炔。保持反应液在氩气保护室温的条件下搅拌12小时。旋干溶剂，加入30mL饱和氯化钠水溶液猝灭反应，采用1M HCl将pH值调至3-5，将混合物用30mL×3二氯甲烷萃取三遍，将有机相合并， 使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为石油醚：乙酸乙酯＝3：1，即得中间体5c，产率74％。
(4)中间体6a的制备
Figure PCTCN2019121627-appb-000067
在25mL圆底烧瓶中加入276mg乙炔锂乙二胺络合物溶于8mLDMSO中，放入冰浴冷却至0℃，将6-溴己酸溶于8mLDMSO中，缓慢滴加入反应液中，在冰浴中继续搅拌10分钟，缓慢升至室温搅拌2小时。将反应液倒入冰水中，用1M盐酸酸化，混合物用30mL×3二氯甲烷萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为石油醚：乙酸乙酯＝10：1，即得中间体6a，产率35％。
中间体6b的制备
Figure PCTCN2019121627-appb-000068
在250mL圆底烧瓶中加入7.3g methyl 3-bromo-2-methylbenzoate，6.5g NBS和529mg AIBN，加入100mL干燥氯仿溶解后在90℃回流5小时。旋干溶剂后加入60mL饱和氯化钠水溶液猝灭反应，将混合物用60mL×3二氯甲烷萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，即得中间体。将所得中间体7.6g与5.3g 2,6-Dioxopiperidine-3-ammonium chloride，4.6mL Et 3N混合，加入90mL干燥乙腈，反应液在80℃下搅拌10小时。旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝20：1～5：1，即得中间体6b，产率60％。
中间体6c的制备
Figure PCTCN2019121627-appb-000069
在25mL圆底烧瓶中加入35mg中间体6b，30mg中间体6a，5mg碘化亚铜，15mg Pd(dppf) 2Cl 2,6mL DMF和3mL Et 3N，在氮气保护下80℃反应3小时。旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝25：1，即得中间体6c，产率82％。
中间体6d的制备
Figure PCTCN2019121627-appb-000070
在25mL圆底烧瓶中加入35mg中间体6b，30mg中间体6a，5mg碘化亚铜，15mg Pd(dppf) 2Cl 2,6mL DMF和3mL Et 3N，在氮气保护下80℃反应3小时。旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝25：1，即得中间体6d，产率81％。
实施例1、式1-式18所示化合物的制备
Figure PCTCN2019121627-appb-000071
在10mL圆底烧瓶中加入50mg Ibrutinib中间体(cas：1022150-12-4)，56mg中间体4b，21mg HOBT，30mg EDCI，20μl Et 3N，2mg DMAP，2ml DMF溶解后室温下搅拌12小时。反应液加入10mL饱和氯化钠水溶液，将混合物用10mL×3乙酸乙酯萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝40：1，即得式10，产率85％。
Figure PCTCN2019121627-appb-000072
在10mL圆底烧瓶中加入50mg Ibrutinib中间体(cas：1022150-12-4)，54mg中间体4a，21mg HOBT，30mg EDCI，20μl Et 3N，2mg DMAP，2ml DMF溶解后室温下搅拌12小时。反应液加入10mL饱和氯化钠水溶液，将混合物用10mL×3乙酸乙酯萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝40：1，即得式12，产率86％。
Figure PCTCN2019121627-appb-000073
在10mL圆底烧瓶中加入30mg Ibrutinib中间体(cas：1022150-12-4)，30mg中间体6d，13mg HOBT，18mg EDCI，15μl Et 3N，6mg DMAP，2ml DMF溶解后室温下搅拌12小时。反应液加入10mL饱和氯化钠水溶液，将混合物用10mL×3乙酸乙酯萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝30：1，即得中间体，将中间体溶于4mL甲醇与1mL DMF中，加入20mg钯碳，38℃在氢气中反应8小时。反应液用硅藻土过滤，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝30：1，即得式16，产率72％。
Figure PCTCN2019121627-appb-000074
在10mL圆底烧瓶中加入30mg Ibrutinib中间体(cas：1022150-12-4)，30mg中间体6d，13mg HOBT，18mg EDCI，15μl Et 3N，6mg DMAP，2ml DMF溶解后室温下搅拌12小时。反应液加入10mL饱和氯化钠水溶液，将混合物用10mL×3乙酸乙酯萃取三遍，将有机相合并，使用无水硫酸钠干燥，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝30：1，即得中间体，将中间体溶于4mL甲醇与1mL DMF中，加入20mg钯碳，38℃在氢气中反应8小时。反应液用硅藻土过滤，旋干溶剂，使用200-300目硅胶色谱柱进行分离纯化，流动相为二氯甲烷：甲醇＝30：1，即得式18，产率69％。
实施例2、化合物在Western Blot水平的生物活性测试
细胞处理(野生型细胞)：
Set up对数生长期的Ramos或HBL-1或Mino或IgE MM或Jurkat或HeLa细胞于6孔板里，加化合物处理；48h后收细胞。
细胞处理(C481S或C481A突变BTK质粒瞬转细胞)：
Set up对数生长期的293T或HeLa细胞于6孔板里，18小时后待细胞贴壁后更换培养液，1.5小时后每孔加入新制的含有PEI和质粒的Opti-MEM培养基500微升(含有PEI和质粒的Opti-MEM培养基制备方法如下所示)，混匀，8小时后更换正常培养液并加化合物，处理48小时；更换培养液并加化合物，再处理48小时后收细胞。
含有PEI和质粒的Opti-MEM培养基制备方法：
将0.2微克或0.5微克质粒加到250微升预热的Opti-MEM培养基，轻摇混匀后静置5分钟；将0.6微克或1.5微克PEI加到250微升预热的Opti-MEM培养基，轻摇混匀后静置5分钟；将含有PEI的Opti-MEM培养基缓慢加入到含有质粒的Opti-MEM培养基中，边加边轻摇混匀，静置30分钟即得。
细胞全蛋白抽提：
收集细胞：将处理后的细胞于培养基中刮下，充分混悬后300g离心5分钟收集，PBS洗一遍后，弃去PBS。
裂解细胞：每一样品加入150μl的2×Loading Buffer，充分震荡混匀，95℃变性15分钟，混匀后于-20℃保存或直接用于Western Blot检测。
5×Loading Buffer的配方为：250mM Tris-HCl(pH6.8)，10％(W/V)SDS，0.5％(W/V)溴酚蓝，50％(V/V)甘油，5％(W/V)β-巯基乙醇(2-ME)。2×Loading Buffer的制备是将1.5倍体积的dd水加入到5×Loading Buffer中即得。
Western Blot检测的具体步骤如下：
1)配制合适浓度的SDS-PAGE胶。参考《分子克隆实验指南》(科学出版社，第二版)第883页表18.3制备合适浓度的分离胶，参考第883页表18.4制备浓度为4％的浓缩胶。
2)制备样品。根据实验要求制备蛋白样品，95℃变性15分钟，离心、混匀并上样于SDS-PAGE胶上样孔中。根据蛋白定量结果适量调整上样体积，通常每个孔上样量为4μl。
3)电泳。接通电源，蛋白样品在浓缩胶中电压为83伏特，待蛋白样品进入分离胶时，我们把电压调整为110伏特继续电泳。待溴酚蓝几乎完全跑出PAGE胶时终止电泳。
4)转膜。电泳结束后取下凝胶，按下列顺序安装转膜装置：(负极)、滤纸、凝胶、活化的PVDF膜、滤纸、(正极)。切记凝胶和PVDF膜之间绝对不能气泡。然后夹紧转移装置置于转膜缓冲液中，最后放入冰盒，置于4℃冷库100V恒压通电1.5小时。
5)封闭。转膜结束后，取出PVDF膜，将膜浸没在含5％的脱脂奶粉的TBST缓冲液里，室温下摇床振荡1小时。
6)一抗孵育。封闭结束后，用TBST缓冲液荡洗3次，然后加入适度稀释比例的一抗，4℃过夜。回收一抗，将PVDF膜用TBST缓冲液荡洗3次，每次振荡10分钟。
7)二抗孵育。弃去TBST缓冲液，加入一定稀释比(通常是1：3000～1：5000)的二抗(鼠抗或者兔抗，由一抗决定)，室温下摇床振荡1小时。弃去二抗，将PVDF膜用TBST缓冲液荡洗3次，每次振荡10分钟。最后用TBST缓冲液荡洗10分钟。
8)显色并压片。将ECL显色底物均匀覆盖在PVDF膜上，室温显色0.5～15分钟。
根据本发明实施例的化合物对BTK的降解活性如下：
根据本发明实施例的化合物针对野生型BTK降解作用效果强，在10-50nM下可检测到明显降解，并且对其他靶点如EGFR、ITK、TEC等无抑制或降解作用，具有特异性靶向降解BTK蛋白的功效，部分结果如图4所示，其中，L18I代表化合物
Figure PCTCN2019121627-appb-000075
实施例3、化合物对BTK、ITK、EGFR的抑制
1.准备1x激酶基质缓冲液和终止缓冲液。
1)1x激酶基质缓冲液
50mM HEPES,pH 7.5
0.01％Brij-35
2)终止缓冲液
100mM HEPES,pH 7.5
0.015％Brij-35
0.2％Coating Reagent#3
50mM EDTA
2.准备化合物。
1)使用100％DMSO稀释化合物，到达反应中最终所需抑制剂最高浓度的50X。如果化合物在1μM测试，在这一步骤中制备化合物50μM的DMSO溶液。
2)以3倍的梯度连续稀释化合物，得到总共10个浓度。
3)在96孔板的2个空孔中加入100微升100％DMSO作为无化合物对照和无酶对照。
4)准备中间板。
将10微升化合物从源板转移到一块新的96孔板，作为中间板。
在中间板的每个孔里加入90微升1x激酶缓冲液。
在振动器上将中间板中化合物混匀10分钟
3.准备酶联板。
1)将96孔中间板每个孔取5微升转移到384孔板，一式两份。例如，96孔板A1转移到384孔板A1和A2，96孔板A2转移到384孔板A3和A4，以此类推。
4.激酶反应。
1)准备2.5x酶溶液
将酶加入到1x激酶基质缓冲液。
2)准备2.5x肽溶液
将FAM标记的肽和ATP加入到1x激酶基质缓冲液。
3)将2.5x酶溶液转移到酶联板。
4)酶联板已经包含5微升化合物在10％DMSO里。
5)在384孔酶联板的每个孔里加入10微升2.5x酶溶液。
6)室温孵育10分钟。
7)将2.5x肽溶液转移到酶联板。
在384孔酶联板的每个孔里加入10微升2.5x肽溶液。
8)激酶反应及停止
在28摄氏度孵育指定的时间。
加入25微升终止缓冲液终止反应。
9)在Caliper上收集数据。
5.曲线拟合
1)从Caliper程序拷贝转换数据。
2)将转换值转变成抑制值。
抑制率＝(max-转换值)/(max-min)*100.
“max”代表DMSO对照；“min”代表low control.
3)在XLfit excel add-in version 5.4.0.8拟合数据得到IC 50值。
采用的方程式为
Y＝Bottom+(Top-Bottom)/(1+(LogIC 50/X)*HillSlope))
Ibrutinib对BTK的抑制活性IC 50为1.4nM；Ibrutinib的对ITK的抑制活性IC 50为34nM，对EGFR的抑制活性IC 50为1.3nM。根据本发明实施例的化合物对BTK激酶的抑制活性IC 50为10-100nM，对ITK、EGFR的IC 50值均高于1000nM，说明根据本发明实施例的化合物对Ibrutinib存在副作用的靶点无明显抑制作用。
实施例4、式1-式18所示化合物对细胞增殖的抑制
MTT实验试剂：
试剂：RPIM 1640 medium；DMEM medium；100×非必需氨基酸(NEAA)；100×青链霉素混合液；50mMβ巯基乙醇；小牛血清(FBS，事先经过失活处理)。
A培养基(500ml)：RPIM 1640 medium(450ml)+100×NEAA(5ml)+100×青链霉素混合液(5ml)+小牛血清(50ml)+50mMβ巯基乙醇(0.5ml)。
B培养基(500ml)：DMEM medium(450ml)+100×NEAA(5ml)+100×青链霉素混合液(5ml)+小牛血清(50ml)+50mMβ巯基乙醇(0.5ml)。。
CCK-8试剂盒(Cell Counting Kit-8)
MTT实验流程(Ramos cell与HBL-1cell)：
1)收集对数期细胞，用A培养基调节细胞悬液浓度6.6×10 4/ml。
2)用A培养基2倍梯度稀释小分子浓度为100nM至2nM。配置成小分子溶液。
3)将45μL的细胞悬液加入到96孔板(边缘孔用灭菌PBS填充，3000个细胞/孔)。每板设阴性对照(45μL细胞悬液和45μL的A培养基)，每组设定3复孔。
4)置37℃，5％CO 2孵育1小时后，在96孔板的每个孔中加入45μL对应的小分子溶液。然后再在37℃，5％CO 2孵育72-96小时。体系中，小分子浓度呈2倍梯度稀释，浓度从50nM至1nM。
每孔加入10μl cck-8溶液，继续培养4h。直接酶联免疫检测仪OD490nm测量各孔的吸光值。
通过上述方法测得的根据本发明实施例的化合物对细胞增殖抑制结果如表1中所示。
表1：式1-式18所示化合物对HBL-1细胞系和Ramos细胞系抑制能力的MTT实验(GI50值)：
Figure PCTCN2019121627-appb-000076
Figure PCTCN2019121627-appb-000077
Figure PCTCN2019121627-appb-000078
Figure PCTCN2019121627-appb-000079
其中，N.D表示未检测抑制活性。
由上表1可知，根据本发明的实施例的化合物对于HBL-1细胞增殖的抑制能力与Ibrutinib相当甚至更优。
实施例5、化合物对LPS刺激时THP-1释放炎性因子的抑制
1.准备LPS。
在LPS固体粉末中加入不含FBS的RPMI1640培养基，终浓度为1mg/ml，分装保存。
2.准备化合物(化合物结构及编号见表2)。
1)使用100％DMSO稀释化合物，到达反应中最终所需抑制剂最高浓度的100X。如果化合物在100nM测试，在这一步骤中制备化合物10μM的DMSO溶液。
2)以培养基按100倍的比例稀释化合物。
3.药物处理细胞。
1)将THP-1细胞稀释至所需浓度，六孔板中每个孔接种1X10^6个细胞，补充培养基至2ml。
2)取稀释好的药物以及DMSO对照500ul于相应孔中，同时设置不加药物与DMSO的空白对照组，37℃培养箱孵育24h。每组重复3次。
4.LPS刺激。
取相应体积的1mg/ml LPS溶液，培养基稀释后加入六孔板中始终浓度为0.5ug/ml，孵育24小时。
5.RT-PCR检测炎性因子水平
1)将处理过的THP-1细胞收集，100g离心5分钟，PBS清洗2次，使用Trizol法提取细胞总RNA，然后以CWBIO EasyQuick RT MasterMix合成cDNA，作为qPCR的模板。
2)根据人促炎性细胞因子的基因序列设计用来检测IL-1β，TNFα，IL-6，IL-10以及内参GAPDH的PCR引物，利用已设计的引物做荧光定量PCR(具体条件见表3)。
通过上述方法测得本发明化合物对细胞炎性因子释放抑制结果如图3及表4中所示，示例化合物对细胞中IL-1β，TNFα，IL-6，IL-10的RNA水平均有不同程度的下调，其中式10所示化合物对炎性因子释放的抑制最为明显，说明本发明化合物可抑制BTK通路进而抑制炎性因子的释放。
表2：化合物结构及编号
Figure PCTCN2019121627-appb-000080
Figure PCTCN2019121627-appb-000081
表3：RT-PCR
Figure PCTCN2019121627-appb-000082
其中，target gene指靶基因，species指种类，primer name指引物名称，sequence指引物序列。
表4：化合物对炎性因子mRNA水平的调节
  P9I L8I mL8I
IL-1β down down down
TNFα down down down
IL-6 down down down
IL-10 down down down
其中，down表示下调。
实施例6、化合物在小鼠关节炎、肺出血模型中的作用
1、关节炎
实验方案：将牛Ⅱ型胶原(type II collagen,CⅡ)与等体积的弗氏完全佐剂(complete Freund’s adjuvant，CFA)充分乳化，制成含CⅡ1mg/mL的乳剂。各组小鼠在无菌条件下，尾根部注射100μL，模型诱导成功后将小鼠随机分为4组，即对照组、依鲁替尼组、示例化合物50mg/kg组、示例化合物100mg/kg组，并分别注射相应药物。每天对各组小鼠进行关节炎(arthritis index，AI)评分：0分，正常；1分，踝关节出现红斑和轻微肿胀；2分，踝关节到跖关节或掌关节出现红斑和和轻微肿胀；3分，踝关节到跖趾关节或掌关节出现红斑和中度肿胀；4分，踝关节到趾关节出现红斑和重度肿胀；每鼠最大评分16分。
实验结果：依鲁替尼可显著改善小鼠足部肿胀的症状，与空白组相比，示例化合物可改善关节炎症状。
2、肺出血
实验验方案：B6小鼠分为健康组(3只)、空白组(7只)、依鲁替尼组(7只)以及示例化合物组(7只)，除健康组均一次性腹腔注射1ml降植烷，空白组、依鲁替尼组以及示例化合物分别在给降植烷前一周开始注射溶媒、依鲁替尼以及示例化合物，腹腔注射，每天100mg/kg，降植烷注射后又连续注射18天后处死小鼠，取出肺和脾，称重并观察肺部出血情况。
实验结果：在小鼠肺出血模型中，以依鲁替尼为对照，示例化合物能有效改善肺出血的症状，肺重和脾重也明显低于对照组合依鲁替尼组。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (18)

  1. 一种化合物，其为式I所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：
    X-Y-Z
    式I
    其中：
    所述Y为
    Figure PCTCN2019121627-appb-100001
    且各E独立地为酰胺基，酯基，氨基甲酯基，脲基，胍基，杂环基，环烷基，螺杂双环基，稠合杂双环基，桥杂双环基或C6-10芳基；各E任选地被1，2，3或4个独立的R b所取代；各W为O、S、NH或Se，b为1～30之间的整数，d为0～30之间的整数，L 6、L 7独立为键，-O-，-S(＝O) t1-，-S-，-N(R a)-，-C(＝O)O-，-N(R a)-C(＝O)-，-C(＝O)-(CH 2) t2-，-CH 2-，-C(＝O)-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)-，-(CH 2) t2-C(＝O)-或者三氮唑基，
    所述X为
    Figure PCTCN2019121627-appb-100002
    Figure PCTCN2019121627-appb-100003
    所述Z为：
    Figure PCTCN2019121627-appb-100004
    Figure PCTCN2019121627-appb-100005
    或者所述Y为
    Figure PCTCN2019121627-appb-100006
    d为0～30之间的整数，其中，
    d＝6，L 6、L 7独立为-N(R a)-，-C(＝O)时-，所述X为
    Figure PCTCN2019121627-appb-100007
    Figure PCTCN2019121627-appb-100008
    Figure PCTCN2019121627-appb-100009
    Figure PCTCN2019121627-appb-100010
    所述Z为：
    Figure PCTCN2019121627-appb-100011
    Figure PCTCN2019121627-appb-100012
    d≠6，L 6、L 7独立为键，-O-，-S(＝O) t1-，-S-，-N(R a)-，-C(＝O)O-，-N(R a)-C(＝O)-，-CH 2-，-C(＝O)-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)-或者三氮唑基时，所述X为
    Figure PCTCN2019121627-appb-100013
    Figure PCTCN2019121627-appb-100014
    Figure PCTCN2019121627-appb-100015
    Figure PCTCN2019121627-appb-100016
    所述Z为：
    Figure PCTCN2019121627-appb-100017
    Figure PCTCN2019121627-appb-100018
    或者所述Y为
    Figure PCTCN2019121627-appb-100019
    且W为CH 2、O、S、NH或Se，b为0～30之间的整数，d为0～30之间的整数，
    所述X为
    Figure PCTCN2019121627-appb-100020
    Figure PCTCN2019121627-appb-100021
    所述Z为：
    Figure PCTCN2019121627-appb-100022
    Figure PCTCN2019121627-appb-100023
    Figure PCTCN2019121627-appb-100024
    或者所述Y为
    Figure PCTCN2019121627-appb-100025
    且W为CH 2、O、S、NH或Se，b为0～30之间的整数，d为0～30之间的整数，
    所述X为
    Figure PCTCN2019121627-appb-100026
    Figure PCTCN2019121627-appb-100027
    时，所述Z为：
    Figure PCTCN2019121627-appb-100028
    所述X为
    Figure PCTCN2019121627-appb-100029
    Figure PCTCN2019121627-appb-100030
    时，所述Z为
    Figure PCTCN2019121627-appb-100031
    其中，各L 1、L 2、L 3独立为键，-O-，-S(＝O) t1-，-S-，-N(R a)-，-C(＝O)O-，-N(R a)-C(＝O)-，-C(＝O)-(CH 2) t2-，-CH 2-，-C(＝O)-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)-，-(CH 2) t2-C(＝O)-或者三氮唑基；
    各R a独立地为氢，C1-4烷基，卤代C1-4烷基，C1-4烷基酰基或羟基；
    各t2独立地为0，1，2，3或4；
    各t1独立地为0，1或2；
    各X 1、X 2、X 3、X 4、X 5、X 6、X 7、X 8、Q独立地为CH，CH 2，O，S，N，NH或Se；
    各R 1、R 2、R 3、R 4、R 5独立地为H、氘、氨基、C1-4酰胺基、C1-4烷基、C1-4杂烷基、C3-8环烷基、C2-10杂环基、C6-10芳基、C1-9杂芳基、C6-10芳基、C1-4烷氧基、C1-4烯基、C1-4炔基，其中，所述的C1-4烷基、C1-4杂烷基、C3-8环烷基、C2-10杂环基、C6-10芳基、C1-9杂芳基、C6-10芳基、C1-4烷氧基、C1-4烯基、C1-4炔基可以任选地被一个或多个选自氘、羟基、氨基、氧代、F、Cl、Br、I、氰基、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6氨基烷基、C1-6烷氧基C1-6烷基、C1-6烷氨基C1-6烷基、C6-10芳基C1-6烷基、C1-9杂芳基C1-6烷基、C2-10杂环基C1-6烷基、C3-10环烷基C1-6烷基、C1-6烷氧基、C1-6烷氨基、C6-10芳基、C6-10芳氧基、C6-10芳氨基、C1-9杂芳基、C1-9杂芳氧基、C2-6烯基、C3-10环烷基、卤素取代C6-10芳基、卤素取代C1-9杂芳基、卤素取代C2-10杂环基或C2-10杂环基的取代基所取代；
    各A独立为氢，C1-4烷基，C1-4卤代烷基，羟基，硝基，氨基，氰基，卤素，羧基，C1-4烷氧基，C1-4烷氨基，C1-4烷硫基，C1-4烷基酰基，C3-12环烷基，任选取代的C3-9杂环基，任选取代的C6-12芳基，任选取代的C1-9杂芳基；
    各R b独立地为氢，C1-4烷基，C1-4卤代烷基，羟基，硝基，氨基，氰基，卤素，羧基，C1-4烷氧基，C1-4烷氨基， C1-4烷硫基，C1-4烷基酰基，C3-12环烷基，C3-9杂环基，C6-12芳基，C1-9杂芳基，氨基C1-4烷基，羟基C1-4烷基，磺酸基，氨基磺酰基或氨基酰基；
    各a、c、e、f独立地为0～30之间的整数。
  2. 根据权利要求1所述的化合物，其特征在于，
    各L 1独立地为键，-O-，-S-，-NH-，
    各L 2独立地为键、-(C＝O)CH＝CH 2-，-O-，-S-，-S(＝O)-，-S(＝O) 2-，-NRa-，-C(＝O)-，-C(＝O)O-，-N(R a)-C(＝O)-，-CH 2-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)或者三氮唑基，
    各R a独立地为氢，C1-2烷基，卤代C1-2烷基，C1-2烷基酰基或羟基，
    各R 1、R 2、R 3、R 4独立地为H、氨基、C1-4烷基、C1-4杂烷基、C5-7环烷基、C5-7杂环基、C6-7芳基、C5-7杂芳基，其中，所述C1-4烷基、C1-4杂烷基、C5-7环烷基、C5-7杂环基、C6-7芳基、C5-7杂芳基可以任选地被一个或多个选自氘、羟基、氨基、氧代、F、Cl、Br、I、氰基取代基取代。
  3. 根据权利要求1所述的化合物，其特征在于，各X分别独立地为如下所示的化合物：
    Figure PCTCN2019121627-appb-100032
  4. 根据权利要求1所述的化合物，其特征在于，
    各A独立为氢，任选取代的C5-7杂环基，C5-7环烷基，任选取代的C6-7芳基，任选取代的C5-7杂芳基，
    各R 5独立地为H、氨基、C1-4烷基、C1-4杂烷基、C5-7环烷基、C5-7杂环基、C6-7芳基、C5-7杂芳基，其中，所述C1-4烷基、C1-4杂烷基、C5-7环烷基、C5-7杂环基、C6-7芳基、C5-7杂芳基可以任选地被一个或多个选自氘、羟基、氨基、氧代、F、Cl、Br、I、氰基、C5-7芳基、C5-7杂芳基、卤素取代C5-7芳基、卤素取代C5-7杂芳基、卤素取代C5-7杂环基的取代基取代；
    各L 3独立地为键、-(C＝O)CH＝CH 2-，-O-，-S-，-S(＝O)-，-S(＝O) 2-，-NRa-，-C(＝O)-，-C(＝O)O-，-N(R a)-C(＝O)-，-CH 2-，-OC(＝O)-，-C(＝S)-，-C(＝O)-N(R a)-，-C(＝S)-N(R a)或者三氮唑基，
    各R a独立地为氢，C1-2烷基，卤代C1-2烷基，C1-2烷基酰基或羟基。
  5. 根据权利要求1所述的化合物，其特征在于，各A分别独立地为
    Figure PCTCN2019121627-appb-100033
    Figure PCTCN2019121627-appb-100034
    各R c独立地为氢或C1-2烷基。
  6. 根据权利要求1所述的化合物，其特征在于，各Z分别独立地为如下所示的化合物：
    Figure PCTCN2019121627-appb-100035
    Figure PCTCN2019121627-appb-100036
  7. 根据权利要求1所述的化合物，其特征在于，
    各E独立为酰胺基，酯基，氨基甲酯基，脲基，胍基，杂环基，环烷基或C6-C8芳基；各E任选地被1，2，3或4个独立的R b所取代，
    各R b独立地为氢，C1-2烷基，C1-2卤代烷基，羟基，硝基，氨基，氰基，卤素，羧基，C1-2烷氧基，C1-2烷氨基，C1-2烷硫基，C1-2烷基酰基，C5-7环烷基，C5-7杂环基，C6-7芳基，C5-7杂芳基，氨基C1-2烷基，羟基C1-2烷基，磺酸基，氨基磺酰基或氨基酰基，
    各R a独立地为氢，C1-2烷基，卤代C1-2烷基，C1-2烷基酰基或羟基。
  8. 根据权利要求1所述的化合物，其特征在于，各Y分别独立地为
    Figure PCTCN2019121627-appb-100037
  9. 根据权利要求1所述的化合物，其特征在于，所述X为
    Figure PCTCN2019121627-appb-100038
    Figure PCTCN2019121627-appb-100039
    任选地，所述Z为
    Figure PCTCN2019121627-appb-100040
    任选地，所述Y为
    Figure PCTCN2019121627-appb-100041
    其中，m1为1～10之间的整数，n1为0～10之间的整数。
  10. 根据权利要求1-9任一项所述的化合物，其特征在于：包括式(1)～(15)任一项所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，
    Figure PCTCN2019121627-appb-100042
    Figure PCTCN2019121627-appb-100043
    Figure PCTCN2019121627-appb-100044
    Figure PCTCN2019121627-appb-100045
    Figure PCTCN2019121627-appb-100046
    其中，m1为1～10之间的整数，n1为0～10之间的整数。
  11. 一种化合物，其特征在于，其为式1～18任一项所示化合物或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药，
    Figure PCTCN2019121627-appb-100047
    Figure PCTCN2019121627-appb-100048
    Figure PCTCN2019121627-appb-100049
    Figure PCTCN2019121627-appb-100050
  12. 一种药物组合物，其特征在于，包括权利要求1～11任一项所述的化合物。
  13. 根据权利要求12所述的药物组合物，其特征在于，进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。
  14. 根据权利要求12所述的药物组合物，其特征在于，进一步包括其他治疗或预防非霍奇金淋巴瘤或自身免疫疾病的药物；
    任选地，所述自身免疫疾病为关节炎、肺出血、***性红斑狼疮、天胞疮、慢性淋巴性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、慢性溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、原发性胆汁性肝硬变、多发性脑脊髓硬化症或急性特发性多神经炎；
    任选地，所述自身免疫疾病为关节炎或肺出血；
    任选地，所述其他治疗或预防非霍奇金淋巴瘤或自身免疫疾病的药物包括依鲁替尼。
  15. 权利要求1-11任一项所述化合物或权利要求12～14任一项所述的药物组合物在制备药物中的用途，所述药物用于降解BTK或抑制BTK。
  16. 权利要求1-11任一项所述化合物或权利要求12～14任一项所述的药物组合物在制备药物中的用途，所述药物用于治疗或预防BTK相关性疾病。
  17. 根据权利要求16所述的用途，其特征在于，所述BTK相关性疾病为非霍奇金淋巴瘤或自身免疫疾病。
  18. 根据权利要求17所述的用途，其特征在于，所述自身免疫疾病为关节炎、肺出血、***性红斑狼疮、天胞疮、慢性淋巴性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、重症肌无力、慢性溃疡性结肠炎、恶性贫血伴慢性萎缩性胃炎、原发性胆汁性肝硬变、多发性脑脊髓硬化症或急性特发性多神经炎；
    任选地，所述自身免疫疾病为关节炎或肺出血。
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