Classifications

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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/08—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/08—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the present invention relates to heterocyclic compounds or pharmaceutically acceptable salts thereof as immunomodulators.
• the present invention also relates to a process for the preparation of said compound or a pharmaceutically acceptable salt thereof.
• the present invention further relates to uses and methods of using the compounds or pharmaceutically acceptable salts thereof in immunomodulation, anticancer and anti-inflammatory.
• Lenalidomide is an immunomodulatory drug (IMiD) with various mechanisms of action.
• IMD immunomodulatory drug
• these immunomodulators regulate the function of the CRL4 CRBN -E3 ubiquitin ligase complex by binding to E3 ubiquitin ligase, resulting in Ikaros (IKZF1), Aiolos (IKZF3), protein kinase CK1 ⁇ (CK1 ⁇ ),
• the transformation termination factor GSPT1 is ubiquitinated and degraded by the 26S proteasome, thereby changing the secretion of various cytokines (such as IL-2, IL-6, IL-10, TNF ⁇ , IL-1 ⁇ , etc.) and affecting the activity of immune cells.
• cytokines such as IL-2, IL-6, IL-10, TNF ⁇ , IL-1 ⁇ , etc.
• dommine compounds can inhibit the angiogenesis of tumor cells by inhibiting vascular endothelial growth factor (VEGF), and can also directly inhibit the proliferation of tumor cells and induce the decomposition of abnormal cells.
• VEGF vascular endothelial growth factor
• duramide compounds have received extensive attention in the treatment of many types of malignant tumors and immune diseases, such as multiple myeloma, myelodysplastic syndrome, hematological tumors/solid tumors (such as lymphoma, non-small cell lung cancer, pancreas, prostate, brain, kidney, ovary, etc.), and systemic lupus erythematosus.
• duramide compounds can also be used in combination with other drugs to treat diseases, such as small molecule targeted drugs, chemotherapy drugs, macromolecular drugs (such as PD-1 antibody, CD20 antibody, CD19 antibody, etc.).
• the present invention relates to a compound with a structure represented by general formula (I), which is used as an immunomodulator to effectively regulate the expression of IL-2, IL-6, IL-10, TNF ⁇ , VEGF and other proteins by combining with E3 ubiquitin ligase. expression and/or biological function.
• general formula (I) which is used as an immunomodulator to effectively regulate the expression of IL-2, IL-6, IL-10, TNF ⁇ , VEGF and other proteins by combining with E3 ubiquitin ligase. expression and/or biological function.
• C xy represents the range of carbon atoms, where x and y are integers, for example, C 3-8 cycloalkyl represents a cycloalkyl group with 3-8 carbon atoms, that is, with 3, 4, 5, 6, Cycloalkyl of 7 or 8 carbon atoms. It should also be understood that, “C 3-8” further includes any sub-range comprised therein, e.g. C 3-7, C 3- 6, C 4-7, C 4-6, C 5-6 and the like.
• Alkyl refers to a saturated straight or branched chain hydrocarbyl group containing 1 to 20 carbon atoms, eg, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
• alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, etc
• Alkylene refers to a divalent group of a straight or branched chain saturated hydrocarbon containing 1 to 20 carbon atoms, eg, 1 to 6 carbon atoms or 1 to 4 carbon atoms.
• alkylene groups include -CH 2 -, - CH (CH 3) -, - CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, - (CH 3) C (CH 3) -, -CH 2 CH 2 CH 2 CH 2 -, - CH 2 CH (CH 3) CH 2 - and the like.
• Cycloalkyl refers to a saturated cyclic hydrocarbyl substituent containing 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocarbocyclic rings, typically containing 3 to 8, 3 to 7 or 3 to 6 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Cycloalkyl may also be bi- or tricyclic fused, bridged or spiro together, such as decalinyl, bicyclo[2.2.2]octane, spiro[3.3]heptane, and the like.
• Heterocyclyl or heterocycle refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic group comprising 3 to 20 ring atoms, such as may be 3 to 14, 3 to 12, 3 to 10 , 3 to 8, 3 to 6, or 5 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) m (wherein m is an integer from 0 to 2), but not including The ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
• It preferably includes 3 to 12 ring atoms, more preferably 3 to 10 ring atoms, more preferably 4 to 7 ring atoms, more preferably 4 to 6 ring atoms, most preferably 5 or 6 ring atoms, of which 1 to 4 is a heteroatom, more preferably 1 to 3 are heteroatoms, and most preferably 1 to 2 are heteroatoms.
• Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpho Linoyl, homopiperazinyl, azetidinyl, etc.
• Polycyclic heterocyclic groups include fused, bridged or spiro polycyclic heterocyclic groups such as octahydrocyclopentadieno[c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, 3,8-diaza Heterobicyclo[3.2.1]octane, 5-azaspiro[2.4]heptane, 2-oxa-7-azaspiro[3.5]nonane, etc.
• Aryl or aromatic ring refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl.
• the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples include:
• Heteroaryl or heteroaromatic ring refers to a heteroaromatic system comprising 5 to 14 ring atoms, wherein 1 to 4 ring atoms are selected from heteroatoms including oxygen, sulfur and nitrogen.
• Heteroaryl is preferably 5 to 10-membered, more preferably heteroaryl is 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, tetra oxazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl and the like.
• the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl
• Halogen refers to fluorine, chlorine, bromine or iodine.
• Cyano refers to -CN.
• Carbonyl refers to a -C(O)- group.
• heterocyclic group optionally substituted with alkyl means that an alkyl group may, but need not, be present, and the expression includes both instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group .
• Substituted means that one or more hydrogen atoms in a group, preferably 5, more preferably 1 to 3 hydrogen atoms, independently of each other, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
• the substituents include but are not limited to halogen, cyano, nitro, oxo, -SF 5 , C 1-4 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5 -6-membered heteroaryl, etc.
• “Isomers” refer to compounds that have the same molecular formula but differ in the nature or order in which their atoms are bonded or in the spatial arrangement of their atoms. Isomers that differ in the arrangement of atoms in space are called “stereoisomers”. Stereoisomers include optical isomers, geometric isomers and conformational isomers.
• the compounds of the present invention may exist in the form of optical isomers.
• Optical isomers include enantiomers and diastereomers.
• Enantiomers are two stereoisomers that are mirror images of each other but are not mutually superimposable.
• a racemic mixture or racemate refers to a mixture of equal numbers of left and right-handed enantiomers of a chiral molecule.
• Diastereomer means that two stereoisomers are not mirror images of each other and are not superimposable.
• optical isomer When the optical isomer is a single isomer and its absolute configuration is determined, it is the absolute configuration of "R” or “S” according to the configuration of the substituent on the chiral carbon atom; when the absolute configuration of the optical isomer is The configuration is not determined, it is (+) or (-) depending on the optical rotation value measured. Methods for the preparation and separation of optical isomers are known in the art.
• the compounds of the present invention may also exist as geometric isomers.
• the present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are assigned the Z or E configuration, and substituents around cycloalkyl or heterocycles are assigned the cis or trans configuration.
• the compounds of the present invention may also exhibit tautomerism, such as keto-enol tautomerism.
• the present invention includes any tautomeric or stereoisomeric forms and mixtures thereof, and is not limited to any one tautomeric or stereoisomeric form used in the naming of the compounds or chemical structural formulae.
• isotopes refer to all isotopes of atoms occurring in the compounds of the present invention. Isotopes include those atoms with the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to, 2 H(D), 3 H, 13 C, 14 C, 15 N, respectively , 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
• Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying Examples, using the appropriate isotopically labeled reagent in place of the non-isotopically labeled reagent.
• Such compounds have various potential uses, such as as standards and reagents in the determination of biological activity.
• stable isotopes such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.
• Deuterium (D) is a preferred isotope in the present invention, eg the hydrogen in methyl, methylene or methine may be replaced by deuterium.
• prodrugs refers to a derivative that is converted to a biologically active compound of the present invention under physiological conditions in vivo, eg, by oxidation, reduction, hydrolysis, etc., each with or without enzymes.
• prodrugs are compounds wherein the amino group in the compounds of the invention is acylated, alkylated or phosphorylated, such as eicosanoylamino, alanylamino, pivaloyloxymethylamino, or Where the hydroxyl group is acylated, alkylated, phosphorylated or converted to a borate, e.g.
• “Pharmaceutically acceptable salts” or “pharmaceutically acceptable salts” refer to salts prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the present invention contain one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically acceptable salts. Thus, the compounds of the invention which contain acidic groups can exist in salt form and can be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium, potassium, calcium, magnesium or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids.
• the compounds according to the invention which contain basic groups can exist in salt form and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
• suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propylene acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, Adipic acid and other acids known to those skilled in the art.
• the present invention includes, in addition to the salt forms mentioned, inner or betaine salts.
• the respective salts can be obtained by conventional methods known to those skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.
• a “pharmaceutical composition” refers to a compound containing one or more of the compounds described herein, or pharmaceutically acceptable salts, stable isotope derivatives, isomers, prodrugs, and mixtures thereof, and other components such as pharmaceutically acceptable A combination of carriers and excipients.
• the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
• a compound of the present invention or “a compound of the present invention” in this application, it includes all such compound forms, such as pharmaceutically acceptable salts, stable isotope derivatives, isomers thereof body, prodrugs and mixtures thereof.
• Carcer/tumor includes, but is not limited to, digestive/gastrointestinal cancer, colon cancer, liver cancer, skin cancer (including mast cell tumor and squamous cell carcinoma), breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia (including acute myeloid leukemia and chronic myeloid leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma (including oral and metastatic melanoma), Kaposi's sarcoma (including Myeloma of multiple myeloma), myeloproliferative diseases, proliferative diabetic retinopathy, vascular proliferation-related disorders/tumors, etc.
• leukemia including acute myeloid leukemia and chronic myeloid leukemia
• kidney cancer including acute myeloid leukemia and chronic myeloid leukemia
• kidney cancer including acute myeloid leukemia and chronic myeloid leukemia
• kidney cancer including acute myeloid leukemia and chronic myeloid leukemia
• “Inflammatory disease” includes, but is not limited to, arthritis, Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goode Pascius disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves disease, primary biliary cirrhosis, hepatitis, primary sclerosing cholangitis, chronic invasive hepatitis, non- Alcoholic fatty liver disease, nonalcoholic steatohepatitis, ulcerative colitis, membranous glomerulopathy, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, Sjögren's syndrome, Wright syndrome, Polymyositis, dermatomyositis, type I interferon disease including Aicardi-Goutines syndrome and other systemic s
• a “therapeutically effective amount” is meant to include an amount of a compound of the invention effective to treat or prevent the disease.
• Patient refers to mammals, especially humans.
• the present invention relates to a compound represented by general formula (I), or a pharmaceutically acceptable salt, stable isotope derivative, isomer and prodrug thereof:
• Ring A is a 4-10 membered heterocycle containing N;
• R 1 is D or halogen
• R 2 and R 3 are each independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl or 3-8 membered heterocyclyl, but both cannot be H and / or D, or R 2 and R 3 and the carbon atoms to which they are attached together form a C 3-6 cycloalkane or a 3-8 membered heterocyclic ring;
• R 4 is D, halogen, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -C(O)C 1-6 alkyl, -C (O)C 3-6 cycloalkyl, -S(O) 2 C 1-6 alkyl, -S(O) 2 C 3-6 cycloalkyl, aryl or heteroaryl, wherein the alkyl , cycloalkyl, aryl and heteroaryl optionally substituted with D, halogen, cyano, C 1-2 alkyl or fluoro C 1-2 alkyl at one or more hydrogens;
• n is an integer 0-4;
• n is an integer 0-2.
• Ring A is a 4-10 membered monocyclic heterocycle containing one N atom, or a fused, bridged or spirobicyclic heterocycle (such as morpholine, piperidine, thiomorpholine-1,1- dioxide, 2-oxa-5-azabicyclo [2.2.1] heptane and the like); R 4 is H, D, halo, oxo, -CF 3 or C 1- 6 alkyl.
• Ring A is a 6-10 membered monoheterocycle containing two N atoms, or a fused, bridged, or spirobicyclic heterocycle (eg, piperazine, 3,6-diazabicyclo[3.1.
• R 4 is C 1-6 alkyl, C 3-6 cycloalkyl, -C ( O)C 1-6 alkyl, -C(O)C 3-6 cycloalkyl, -S(O) 2 C 1-6 alkyl, -S(O) 2 C 3-6 cycloalkyl, benzene or 5-6 membered heteroaryl containing N, O and/or S, wherein one or more hydrogens of the alkyl, cycloalkyl, phenyl and heteroaryl are optionally replaced by D, halogen, cyano , C 1-2 alkyl or fluoro C 1-2 alkyl substituted.
• Ring A is piperazinyl;
• C R 4 is a piperazine and the second N atom 1-6 alkyl, C 3-6 cycloalkyl, -C (O) C 1- 6 alkyl, -C(O)C 3-6 cycloalkyl, -S(O) 2 C 1-6 alkyl, phenyl, pyridyl or pyrimidinyl, wherein the alkyl, cycloalkyl, benzene
• One or more hydrogens of the radical, pyridyl or pyrimidinyl are optionally substituted with D, halogen, cyano or C1-2 alkyl; n is 0 or 1.
• R 2 is H;
• R 3 is cyano, C 1-6 alkyl or C 3-6 cycloalkyl.
• R 2 and R 3 are methyl.
• R 2 and R 3 together form a C 3-6 cycloalkane with the carbon atom to which they are attached.
• n is zero.
• the compound of general formula (I) has the structure shown in the following general formula (II):
• R 5 is H, C 1-6 alkyl, C 3-6 cycloalkyl, -C(O)C 1-6 alkyl, -C(O)C 3-6 cycloalkyl, -S(O) 2 C 1-6 alkyl, phenyl or 5-6 membered heteroaryl containing N, O and/or S, wherein one or more hydrogens of the alkyl, cycloalkyl, phenyl and heteroaryl optionally replaced by D, halogen, cyano or C 1-2 substituted alkyl.
• R 5 is phenyl, pyridyl or pyrimidinyl, wherein said phenyl, optionally one or two hydrogen pyridinyl and pyrimidinyl is substituted with F or cyano.
• the present invention further relates to the following compounds 1-22, or pharmaceutically acceptable salts, stable isotope derivatives, isomers, prodrugs and mixtures thereof:
• the compounds of the present invention can effectively inhibit the proliferation of NCI-H929 cells, preferably with an IC 50 of less than 50 nM, more preferably with an IC 50 of less than 10 nM.
• the compounds of the present invention have a significant inhibitory effect on the secretion of TNF ⁇ in human PBMC cells, preferably with an IC 50 of less than 20 nM, more preferably with an IC 50 of less than 10 nM.
• Compounds of the invention also has a human PBMC cells secreting IL-2 stimulation significantly, preferably less than 50 nM EC 50, EC 50 and more preferably less than 10nM.
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, stable isotope derivatives, isomers, prodrugs and mixtures thereof, and a or multiple pharmaceutically acceptable carriers or excipients.
• One aspect of the present invention provides a compound represented by general formula (I) or a pharmaceutically acceptable salt, stable isotope derivative, isomer, prodrug and mixture thereof, or the pharmaceutical composition for regulating or inhibiting E3
• the activity of ubiquitin ligase thereby affecting the expression and/or biological function of proteins including but not limited to Aiolos, Ikaros, Helios, CK1 ⁇ , GSPT1, IL-2, IL-6, TNF ⁇ , IFN ⁇ , VEGF, etc.
• Another aspect of the present invention provides a method for treating or preventing related diseases mediated by Aiolos, Ikaros, Helios, CK1 ⁇ , GSPT1, IL-2, IL-6, TNF ⁇ , IFN ⁇ , VEGF, etc.
• diseases include but are not limited to hematological tumors (such as multiple myeloma, lymphoma, leukemia, etc.), solid tumors (such as lung cancer, prostate cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, colon cancer, Rectal cancer, gastric cancer, esophageal cancer, brain cancer, liver cancer, kidney cancer, skin cancer, epithelial cancer, bladder cancer, neuroblastoma, etc.), autoimmune diseases (such as system
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, stable isotope derivatives, isomers, prodrugs and mixtures thereof and at least one An additional drug, wherein the at least one additional drug can be a small molecule chemotherapeutic agent (such as NSAIDs, steroid anti-inflammatory drugs, kinase targeting drugs, cytotoxic drugs, DNA damage related drugs, etc.) or macromolecular immune and/or inflammatory modulators (such as PD-1 antibody, CD20 antibody, CD19 antibody, TNF ⁇ antibody, IL-6 antibody, etc.).
• a small molecule chemotherapeutic agent such as NSAIDs, steroid anti-inflammatory drugs, kinase targeting drugs, cytotoxic drugs, DNA damage related drugs, etc.
• macromolecular immune and/or inflammatory modulators such as PD-1 antibody, CD20 antibody, CD19 antibody, TNF ⁇ antibody, IL-6 antibody, etc.
• the drug can be in any pharmaceutical dosage form, including but not limited to tablets, capsules, solutions, freeze-dried preparations, and injections.
• the pharmaceutical formulations of the present invention may be administered in dosage unit form containing a predetermined amount of active ingredient per dosage unit.
• a unit may contain, for example, from 0.1 mg to 500 mg, preferably from 0.5 mg to 100 mg, of a compound of the invention, depending on the condition to be treated, the method of administration and the age, weight and condition of the patient.
• pharmaceutical formulations of this type can be prepared using methods known in the pharmaceutical art, such as by admixing the active ingredient with one or more excipients and/or adjuvants.
• compositions of the present invention may be suitable for administration by any desired suitable method, such as oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods of administration.
• oral including buccal or sublingual
• rectal including buccal or sublingual
• nasal including buccal, sublingual or transdermal
• vaginal or parenteral including subcutaneous, intramuscular, intravenous or intradermal
• the present invention also provides methods for preparing the compounds.
• the preparation of compounds of formula (I) of the present invention can be accomplished by the following illustrative methods and examples, which should not be construed in any way as limiting the scope of the invention.
• the compounds of the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of methods known in the art and methods of the present invention are used.
• the products obtained in each step of the reaction are obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, and the like.
• the starting materials and chemical reagents required for the synthesis can be routinely synthesized or purchased according to the literature (available from SciFinder).
• the heterocyclic compounds described in the general formula (I) of the present invention can be synthesized according to the following route: 1) amine compound A1 and intermediate B with a leaving group X (such as halogen) in a base (such as halogen) Potassium carbonate) catalyzed heating substitution reaction to obtain the target compound A4, of which the amine compound A1 can be purchased or synthesized according to literature methods (eg CN107739389).
• the target compound A4 can also be obtained by performing a substitution reaction between compound A2 and intermediate B to obtain A3, and A3 is then heated to close the ring under the catalysis of an acid (such as TsOH), wherein compound A2 can be purchased or synthesized according to literature methods (such as WO2014025978).
• Intermediate B can be synthesized according to the route shown below: 1) Starting material B1 and a starting material or reagent with a double leaving group X (such as halogen) under basic conditions (such as an organic base DIPEA or an inorganic base in DMF) Potassium carbonate) heating cyclization to generate intermediate B2; 2) the methanol solution of B2 is catalyzed by a palladium catalyst (such as PdCl 2 (dppf)) to carry out carbon monoxide intercalation reaction in carbon monoxide atmosphere to obtain intermediate ester B3, B3 can also be obtained by B4 and containing The raw materials or reagents of NH heterocycle A are obtained by substitution reaction under the catalysis of base (such as potassium carbonate); 3) The ester group in B3 is reduced by LAH to form intermediate alcohol B5; 4) B5 is further halogenated (such as using CBr 4 ) /PPh 3 or SOCl 2 ), thereby obtaining an important intermediate B.
• the starting materials of the present invention can be synthesized according to methods known in the art, or can be purchased from chemical companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), Beijing Coupling and other chemical companies .
• the structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
• NMR nuclear magnetic resonance
• MS mass spectrometry
• reaction temperature is room temperature (20°C-30°C).
• the reactions were carried out in an argon atmosphere or a nitrogen atmosphere.
• Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
• the hydrogen atmosphere means that after the reaction bottle is evacuated and then filled with hydrogen (repeated 3 times), a hydrogen balloon with a volume of about 1 L is connected.
• the microwave reaction used a CEM Discover-SP type microwave reactor.
• the compounds were purified by column chromatography or thin-layer chromatography, wherein the column chromatography used 200-300 mesh silica gel of Qingdao Ocean, and the thin-layer chromatography used GF254 silica gel plate of Qingdao Ocean with a thickness of 0.4-0.5 mm.
• Column chromatography or thin layer chromatography developing solvent systems usually have a) dichloromethane and methanol system, b) petroleum ether and ethyl acetate system, or as shown in the examples.
• the volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be further adjusted by adding a small amount of triethylamine, or other acidic or basic reagents.
• Compounds were also purified using a Waters mass spectrometry-guided automatic preparation system (mass detector: SQD2), with an appropriate acetonitrile/water (containing 0.1% trifluoroacetic acid or formic acid, or 0.05% ammonia water) gradient in 20 mL/water according to the polarity of the compound.
• a reversed-phase high pressure column (XBridge-C18, 19 ⁇ 150 mm, 5 ⁇ m) was eluted at a flow rate of min.
• Some of the examples can be purified using an automated prep system by adding 1N dilute hydrochloric acid, and then removing the solvent under reduced pressure to give the hydrochloride salt.
• PdCl 2 refers to [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride.
• LAH lithium aluminum hydride
• DIPEA N,N-diisopropylethylamine
• TsOH ⁇ H 2 O refers to p-toluenesulfonic acid monohydrate.
• THF tetrahydrofuran
• DMF refers to N,N-dimethylformamide
• the characterization data for 18 are as follows:
• the characterization data for 19 are as follows:
• Compound 22 was synthesized according to the experimental procedures of steps 1 to 5 in compound 21, but in the third step 6-chloro-5-fluoronicotinonitrile was used instead of 2-cyano-5-fluoropyridine.
• the experimental method is outlined as follows:
• NCI-H929 (Nanjing Kebai, Cat. No. CBP60243) cells were cultured in RPMI 1640 complete medium [containing 10% FBS (GBICO, Cat. No. 10099-141) and 100 units/mL penicillin-streptomycin mixture (Thermo Fisher, Item No. 15140122)]. Cells (15,000 cells/mL) were seeded in 90 ⁇ L of complete medium in a 96-well plate. After overnight culture, 10 ⁇ L of compound solution was added to each well, and the cells were incubated at 37°C in a 5% CO 2 incubator for 6 days.
• - Glo (CTG) kit Promega, Cat. No.
• hPBMC peripheral blood mononuclear cells
• the experimental method is outlined as follows:
• Peripheral blood was collected from healthy volunteers with EDTA anticoagulant tubes, diluted with phosphate buffered saline (PBS) containing 2% fetal bovine serum (Gibco, Cat. No. 10099-141) in an equal volume, and then transferred 30 mL to the pre-added 15 mL density Gradient centrifuge (Sigma, Catalog No. 10771) was placed in a Sepmate-50 centrifuge tube (Stemcell, Catalog No. 86450), centrifuged at 1200 ⁇ g for 10 minutes at room temperature, and the PBMC-containing liquid in the upper layer was transferred to a new 50 mL centrifuge tube.
• PBS phosphate buffered saline
• Gibco Gibco, Cat. No. 10099-141
• the compounds were dissolved and diluted in DMSO to 5mM (IC 50 values lower if the compound can reduce this initial concentration), followed by 4-fold dilution series to a minimum concentration of 0.31 ⁇ M with DMSO, and then each concentration point RPMI 1640 medium was diluted 50 times, and 10 ⁇ L was added to the cells in the above 96-well plate.
• the 96 well plate was placed 37 °C, 5% CO 2 incubator After incubation of 1 hour, 10 ⁇ L a concentration of 100ng / mL of LPS (Sigma, Product Number L-2880), at 37 °C, 5% CO 2 in Continue to incubate overnight in the incubator. The supernatant was collected for the detection of TNF ⁇ .
• TNF ⁇ and IL-2 were carried out according to the instructions of the respective ELISA kits (R&D, product numbers DY210 and DY202, respectively), and the OD450 value of each well was obtained. Taking the medium group containing 0.2% DMSO as 0% inhibition or stimulation, use XLfit software to draw compound inhibition or stimulation curves and calculate the corresponding IC 50 or EC 50 . The experimental results are shown in Table 1.
• the experimental method is outlined as follows:
• Compound solution The compound to be tested was dissolved in DMSO and made into a 10 mM stock solution, which was then diluted to 3 mM with DMSO, and then diluted to a 3 ⁇ M solution with extracellular fluid for subsequent use.
• HEK293 cell line stably overexpressing the hERG potassium channel (Creacell, Cat. No. A-0320) was cultured in cells containing 10% fetal bovine serum (Gibco, Cat. No. 1428478) and 0.8 mg/mL G418 (Amresco, Cat. No. E859-5G). ) in DMEM medium (Gibco, product number 11995-065) at a temperature of 37°C and a carbon dioxide concentration of 5%. The old medium was removed and washed once with PBS (Gibco, Cat. No. 1009-141), then 1 mL of TrypLETM Express solution (Gibco, Cat. No.
• Voltage stimulation protocol for whole-cell patch-clamp recording of whole-cell hERG potassium currents The cell membrane voltage was clamped at -80mV after the formation of the whole-cell seal. The clamping voltage was depolarized from -80mV to -50mV and held for 0.5 seconds (as leakage current detection), then stepped to 30mV and held for 2.5 seconds, and then quickly returned to -50mV and held for 4 seconds to excite the tail current of the hERG channel ( Peak tail current), hERG potassium current was recorded every 10 seconds. Experimental data were acquired with an EPC-10 amplifier (HEKA) and stored in PatchMaster (HEKA v2x73) software.
• HEKA EPC-10 amplifier
• PatchMaster HEKA v2x73
• a capillary glass tube (Sutter Instruments) was drawn into a recording electrode using a microelectrode puller (Sutter Instruments).
• Cell-laden coverslips were removed from the 24-well plate placed in the incubator and placed under an inverted microscope.
• the recording electrode was perfused with the liquid in the electrode, and then the microelectrode manipulator (Sutter Instruments) was manipulated to touch the recording electrode to the cell surface and give negative pressure suction to form a G ⁇ seal; then perform rapid capacitance compensation; then continue to give negative pressure suction Aspirate until the cell membrane is broken to form a whole-cell recording mode.
• test compound was dissolved in 5% DMA + 20% Solutol + 75% Saline vehicle to prepare a 0.5 mg/mL dosing solution.
• Sprague-Dawley rats Three fed male Sprague-Dawley rats were given 2 mL/kg of the dosing solution by intravenous injection (IV) at a dose of 1 mg/kg, respectively, at 0.083, 0.25, 0.5, 1, 2, 4, 8 and Blood samples were collected 24 hours.
• IV intravenous injection
• Three other fed male Sprague-Dawley rats were given 10 mL/kg of the dosing solution by gavage (PO) at a dose of 5 mg/kg, respectively, at 0.25, 0.5, 1, 2, 4, 8, and 24 post-dose. Blood samples were collected every hour.

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