WO2021068380A1 - Préparation d'un composé de dégradation ciblant la protéine btk, et utilisation de celui-ci dans le traitement de maladies et de tumeurs auto-immunes - Google Patents

Préparation d'un composé de dégradation ciblant la protéine btk, et utilisation de celui-ci dans le traitement de maladies et de tumeurs auto-immunes 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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group
alkyl
independently
compound
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
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
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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.

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Abstract

La présente invention concerne un composé, qui est un composé représenté par la formule I, ou un stéréoisomère, un isomère géométrique, un tautomère, un oxyde d'azote, un hydrate, un solvate, un métabolite, un sel pharmaceutiquement acceptable ou un promédicament de celui-ci. Le composé a un fort effet de dégradation sur BTK de type sauvage, n'a pas d'effets d'inhibition ou de dégradation sur d'autres cibles telles que EGFR, ITK et TEC, et a un effet de ciblage spécifique et de dégradation de protéines BTK. X-Y-Z formule I
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CN115304606B (zh) * 2021-06-21 2024-04-19 清华大学 一种同时靶向btk和gspt1蛋白的降解剂
WO2022270994A1 (fr) * 2021-06-25 2022-12-29 한국화학연구원 Nouveau composé hétérocyclique bifonctionnel ayant une fonction de dégradation de btk par l'intermédiaire d'une voie de protéasome d'ubiquitine, et son utilisation
KR20230000983A (ko) * 2021-06-25 2023-01-03 한국화학연구원 유비퀴틴 프로테오좀 경로를 통해 비티케이 분해작용을 가지는 신규한 이작용성 헤테로사이클릭 화합물과 이의 용도
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