WO2024051816A1 - 双环类prmt5抑制剂 - Google Patents

双环类prmt5抑制剂 Download PDF

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WO2024051816A1
WO2024051816A1 PCT/CN2023/117714 CN2023117714W WO2024051816A1 WO 2024051816 A1 WO2024051816 A1 WO 2024051816A1 CN 2023117714 W CN2023117714 W CN 2023117714W WO 2024051816 A1 WO2024051816 A1 WO 2024051816A1
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alkyl
cycloalkyl
compound
following group
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French (fr)
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牛成山
陈明涛
郑茂林
王国辉
董胜利
梁阿朋
陈少清
李钧
吴豫生
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郑州同源康医药有限公司
浙江同源康医药股份有限公司
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Publication of WO2024051816A1 publication Critical patent/WO2024051816A1/zh

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    • 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
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • 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
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention relates to the field of medical technology, specifically to bicyclic compounds used as PRMT5 inhibitors, and pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing such compounds and salts, and to their uses and their use in regulating PRMT5. Applications in the activity or treatment of PRMT5-related diseases.
  • Protein arginine N-methyltransferase 5 is a type II arginine methyltransferase that catalyzes the conversion of a methyl group from S-adenosyl-L-methionine Transfer of an acid (SAM) to the guanidino-functional ⁇ -nitrogen of a protein L-arginine residue ( ⁇ -monomethylation) and transfer of a second methyl group to another ⁇ -nitrogen, resulting in symmetric dimethyl Arginine (sDMA).
  • SAM S-adenosyl-L-methionine Transfer of an acid
  • sDMA symmetric dimethyl Arginine
  • PRMT5 forms a complex with MEP50 (methyl body protein 50), which is required for substrate recognition and orientation and is also required for the histone 2A and histone 4 methyltransferase activity catalyzed by PRMT5 (e.g., see Ho et al., (2013) PLOS ONE 8(8):10.1371/annotation/e6b5348e-9052-44ab-8f06-90d01dc88fc2).
  • Methionine adenosyltransferase also known as S-adenosylmethionine synthase, can catalyze the reaction of methionine (Met) and ATP to generate S-adenosylmethionine.
  • SAM can serve as the main methyl donor for methyltransferases in the body, regulating gene expression, transcription and translation through transmethylation reactions, thereby having an important impact on cell growth, death and differentiation.
  • Protein arginine N-methyltransferase 5 is a methyltransferase that uses SAM as a substrate, and it plays an important regulatory role in the proliferation of tumor cells.
  • Homozygous loss of tumor suppressor genes is a key driver of cancer, often resulting in collateral loss of passenger genes located near tumor suppressor genes. Deleting these passenger genes could create therapeutic accessibility, particularly to tumor cells.
  • Homozygous deletion of the chromosome 9p2I locus which contains the well-known tumor suppressor CDKN2A (cyclin-dependent kinase inhibitor 2A)
  • CDKN2A cyclin-dependent kinase inhibitor 2A
  • MTAP methylthioadenosine phosphorylase
  • the loss of MTAP leads to the accumulation of its substrate methylthioadenosine (MTA).
  • MTA has close structural similarity with the methyl donor s-adenosylmethionine (SAM), a substrate of type II methyltransferase PRMT5.
  • SAM methyl donor s-adenosylmethionine
  • Loss of MTAP leads to an increase in MTA levels, which selectively competes with SAM for binding to PRMT5, leaving the methyltransferase in a low-activity state and susceptible to further inhibition by PRMT5 inhibitors.
  • a multi-genome-scale shRNA drop-out screen performed on a large panel of tumor cell lines found a strong correlation between MTAP loss and cell line dependence on PRMT5.
  • PRMT5 is a known cellular essential gene, and PRMT5 knockdown and siRNA knockdown studies have shown that inhibiting PRMT5 in normal tissues (such as pancytopenia, infertility, skeletal muscle loss, cardiac hypertrophy, etc.) may be associated with significant related to side effects. Therefore, new strategies are needed to exploit this metabolic vulnerability and preferentially target PRMT5 in MTAP-deficient tumors while sparing PRMT5 in normal tissues (MTAP WT).
  • Targeting PRMT5 using MTAP synergistic small molecule inhibitors can preferentially target the MTA-binding state of PRMT5 enriched in MTAP-deficient tumor cells, while providing a higher therapeutic index than normal cells with normal MTAP and lower MTA levels.
  • the object of the present invention is to provide a compound represented by formula (I), a preparation method thereof, and its use in PRMT5 inhibitor drugs.
  • a first aspect of the present invention provides a compound, which is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,
  • R is selected from the following group: H, -NH 2 , C 1-3 alkyl, -OC 1-3 alkyl, C 1-3 fluoroalkyl, -OC 1-3 fluoroalkyl;
  • R 1 is selected from the following substituted or unsubstituted groups: monocyclic group A, bicyclic group B;
  • the monocyclic group A is selected from the following group: C 3-8 cycloalkyl, C 5-8 aryl, containing A 3-8-membered heterocyclyl group containing 1-4 heteroatoms selected from N, O or S, a 5-8-membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S;
  • the bicyclic Group B is selected from the following group: C 5-12 cycloalkyl, C 8-12 aryl, 5-12 membered heterocyclyl containing 1-4 heteroatoms selected from N, O or S, 1-4 An 8-12 membered heteroaryl group with a heteroatom selected from N, O or S; wherein, when substituted, the substitutions each independently refer to substitution by R a1 ;
  • R 2 is selected from the following group: H, halogen, -CN, C 1-6 alkyl, -OR a2 ; or R 2 and the C to which it is attached together form a C 3-6 cycloalkyl group or contain 1-4 selected from A 3-6 membered heterocycloalkyl group with a heteroatom of N, O or S; wherein the alkyl group, cycloalkyl group and heterocycloalkyl group are optionally substituted with a substituent selected from the following group: deuterium, halogen, -CN, -OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 fluoroalkyl, C 1-3 fluoroalkoxy, C 3-5 cycloalkyl, containing 1 - 4-6 membered heterocycloalkyl with 2 heteroatoms selected from N, O or S;
  • R 3 and the atom to which it is attached or R 3 and the aza to which it is attached together form a 3-10 membered carbocyclic ring or heterocyclic ring, and the carbocyclic ring or heterocyclic ring and the nitrogen heterocyclic ring form a bridged ring, a parallel ring or a spiro ring;
  • R 5 is selected from the following group: H, deuterium, halogen, -CN, C 1-3 alkyl, C 3-5 cycloalkyl, 3-6 containing 1-4 heteroatoms selected from N, O or S One-membered heterocycloalkyl, -OR a5 , wherein the alkyl, cycloalkyl, heterocycloalkyl is optionally substituted with a group selected from the following group: deuterium, halogen, -CN, -OH, C 1 -3 alkyl, C 1-3 fluoroalkyl;
  • Each x 1 , x 2 , x 3 , x 4 is independently selected from the following group: O, C(R a6 ) m , N(R a6 ) m ;
  • Each R a2 , R a3 , R a4 , R a5 is independently selected from the following group: H, C 1-6 alkyl, C 1-6 heteroalkane containing 1-2 heteroatoms selected from N, O or S base, C 3-6 cycloalkyl, 3-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, wherein the alkyl, heteroalkyl, cycloalkyl, hetero The ring group is optionally substituted by 1, 2 or 3 R b1 ;
  • Each R c1 is independently selected from the following group: H, C 1-6 alkyl, C 3-6 cycloalkyl;
  • Each L is independently a bond or a C 1-6 alkylene group, wherein the C 1-6 alkylene group is optionally substituted with a substituent selected from the group consisting of: deuterium, halogen, -CN, -OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 fluoroalkyl, C 1-3 fluoroalkoxy;
  • Each R a6 is independently selected from the group consisting of: H, deuterium, halogen, -CN, C 1-3 alkyl, C 1-3 fluoroalkyl Base, C 1-3 alkoxy group, C 1-3 fluoroalkoxy group;
  • Each m is independently selected from the following group: 0, 1, 2;
  • n is selected from the following group: 0, 1, 2, 3.
  • R 1 , R 2 , R 3 , x 4 and n are as defined in claim 1.
  • x 4 is C(R a6 ) m , preferably CH 2 .
  • R 1 , R 2 , R 3 and n are as defined above.
  • x 4 is 0.
  • R 1 , R 2 , R 3 and n are as defined above.
  • x 4 is N(R a6 ) m , preferably NCH 3 .
  • R 1 , R 2 , R 3 and n are as defined above.
  • the compound has a structure selected from the following group:
  • R 1 , R 2 , R 3 , R 4 , R 5 , x 1 , x 2 , x 3 , x 4 , R, and n are as defined in claim 1.
  • the compound has a structure selected from the following group:
  • R 1 , R 2 , R 3 , R 4 and x 2 are as defined in claim 1.
  • R 1 is selected from substituted or unsubstituted bicyclic group B, wherein, when substituted, each of the substitutions independently refers to substitution by R a1 ;
  • the compound has a structure selected from the group consisting of:
  • R 2 , R 3 , R 4 , R a1 and x 2 are as defined in claim 1.
  • the monocyclic group A has a structure selected from the following group:
  • the bicyclic group B has a structure selected from the group consisting of:
  • R 1 is independently substituted by 0-3 R a1
  • R 1 is independently substituted by 0-3 R a1
  • R 1 is independently substituted by 0-3 R a1
  • R 1 is independently substituted by 0-3 R a1
  • R 1 is independently substituted by 0-3 R a1
  • Each L is independently a bond or C 1-6 alkylene group
  • the cycloalkyl group in R a1 has a structure selected from the following group:
  • the heterocyclic group described in R a1 has a structure selected from the following group:
  • the heteroaryl group described in R a1 has a structure selected from the following group:
  • heteroalkyl group described in R b2 has a structure selected from the following group:
  • the cycloalkyl group in R b2 has the following structure:
  • the heterocyclyl group described in R b2 has a structure selected from the following group:
  • R is selected from the following group: H, -NH 2 , C 1-3 alkyl, -OC 1-3 alkyl;
  • R 2 is selected from the following group: H, C 1-6 alkyl, -OR a2 ; or R 2 together with the C to which it is attached forms a C 3-6 cycloalkyl group or contains 1-4 selected from N, O or S 3-6 membered heterocycloalkyl of heteroatom; R a2 is as defined in claim 1;
  • R 3 is selected from the following group: H, halogen, C 1-6 alkyl; alternatively, two R 3 and the atom to which it is attached or R 3 and the group attached to the nitrogen heterocycle to which it is attached together form 3- 10-membered carbocyclic or heterocyclic ring;
  • R 5 is selected from the group consisting of: H, halogen, -CN, C 1-3 alkyl.
  • R is -NH 2 .
  • R 2 is C 1-6 alkyl.
  • R 3 is selected from the following group: F, -CH 3 .
  • R 5 is selected from the following group: H, -CH 3 , F.
  • x 1 is selected from the following group: C(R a6 ) m , N(R a6 ) m , preferably CH.
  • x 2 is selected from the following group: C(R a6 ) m , N(R a6 ) m , preferably CH.
  • x 3 is selected from the following group: C(R a6 ) m , N(R a6 ) m , preferably CH.
  • the compound is selected from the following group:
  • a second aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds described in the first aspect of the present invention and a pharmaceutically acceptable carrier.
  • a third aspect of the present invention provides a use of the compound described in the first aspect of the present invention for preparing a medicament for regulating PRMT5 activity or treating PRMT5-related diseases.
  • the PRMT5-related disease is cancer or tumor.
  • the cancer or tumor is selected from the group consisting of prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc., and more specifically, can be treated by the compounds and methods of the present invention
  • Cancers include, but are not limited to, tumor types such as astrocytic cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cavity cancer carcinoma, ovarian, prostate and thyroid cancer and sarcoma.
  • Heart sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas and teratomas;
  • Lungs bronchial carcinoma ( Squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilaginous hamartoma, mesothelioma;
  • gastrointestinal tract Diseases Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinom
  • the inventor unexpectedly prepared a bicyclic compound with excellent PRMT5 inhibitory activity and a preparation method thereof. Specifically, through structural optimization, the inventors obtained a class of compounds with excellent PRMT5 selective inhibitory activity. On this basis, the inventor completed the present invention.
  • halogen refers to F, Cl, Br or I.
  • C 1-6 alkyl refers to a straight-chain or branched alkyl group including 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isopropyl, etc. Butyl, tert-butyl, neopentyl, ppentyl, or similar groups.
  • C 1-3 alkyl has a similar meaning.
  • C 2-6 alkenyl refers to a straight-chain or branched alkenyl group containing one double bond with 2-6 carbon atoms, including without limitation vinyl, propenyl, butene base, isobutenyl, pentenyl and hexenyl, etc.
  • C 2-6 alkynyl refers to a straight-chain or branched-chain alkynyl group with 2-6 carbon atoms and containing a triple bond, including without limitation ethynyl, propynyl, butyl Alkynyl, isobutynyl, pentynyl and hexynyl, etc.
  • halogenated means substituted by halogen.
  • fluoro means substituted by F.
  • C 3-6 cycloalkyl refers to a cyclic alkyl group with 3-6 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl et al.
  • the terms "C 3-5 cycloalkyl”, “C 3-8 cycloalkyl”, “C 5-12 cycloalkyl”, “C 3-9 cycloalkyl” have similar meanings.
  • aromatic ring or “aryl” has the same meaning, preferably “C 6-10 aryl”.
  • C 6-10 aryl refers to an aromatic ring group with 6-10 carbon atoms that does not contain heteroatoms on the ring, such as phenyl, naphthyl, etc.
  • C 5-8 aryl and “C 8-12 aryl” have similar meanings.
  • heterocyclyl or “heterocycloalkyl” refers to a 3-12-membered heterocyclyl containing 1-4 heteroatoms selected from N, O, and S, including (but not limited to) The following groups:
  • aromatic heterocycle or “heteroaryl” have the same meaning and refer to heteroaromatic groups containing one to more heteroatoms.
  • C3-C10 heteroaryl refers to an aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen and 3 to 10 carbon atoms.
  • Non-limiting examples include: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring.
  • Heteroaryl groups may be optionally substituted or unsubstituted.
  • C 1-6 alkoxy refers to a straight-chain or branched chain alkoxy group with 1-6 carbon atoms, including without limitation methoxy, ethoxy, propoxy , isopropoxy and butoxy, etc.
  • C 1-3 alkoxy has a similar meaning.
  • C 1-6 heteroalkyl refers to a straight-chain or branched alkyl group with 1-6 carbon atoms containing heteroatoms selected from N, O or S, including, but not limited to, methane.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • Specific substituents are the substituents described accordingly in the foregoing text, or the substituents appearing in each embodiment.
  • a substituted group may be Any substitutable position of the group has a substituent selected from a specific group, and the substituents may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are for example (but not limited to): halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, etc.
  • the term 1-6 means 1, 2, 3, 4, 5 or 6. Other similar terms have similar meanings.
  • the present invention provides a compound, which is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , x 1 , x 2 , x 3 , x 4 , R, and n are as defined above.
  • any one of R 1 , R 2 , R 3 , R 4 , R 5 , x 1 , x 2 , x 3 , x 4 , R and n is independently The corresponding specific group in the specific compound.
  • salts refers to salts of compounds of the invention with acids or bases suitable for use as pharmaceuticals.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • One preferred class of salts are the salts of the compounds of the invention with acids.
  • Acids suitable for forming salts include, but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid; and proline Acid, phenylalanine, aspartic acid, glutamic acid and other amino acids.
  • salts of the compounds of the invention with bases for example alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. magnesium or calcium salts), ammonium salts (e.g.
  • lower alkanol ammonium salts salts and other pharmaceutically acceptable amine salts
  • amine salts such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt
  • Ammonium salt ethylene glycol Amine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine respectively.
  • solvate refers to a complex in which a compound of the invention is coordinated with solvent molecules to form a complex in a specific proportion.
  • the compounds of the present invention also include prodrugs of the compounds represented by formula (I).
  • prodrug includes a class of compounds which may themselves be biologically active or inactive, and which, when taken in an appropriate manner, undergo metabolism or chemical reactions in the human body and are converted into compounds of formula (I), or A salt or solution composed of a compound of formula (I).
  • the prodrugs include (but are not limited to) carboxylates, carbonates, phosphates, nitrates, sulfates, sulfone esters, sulfoxide esters, amino compounds, carbamates, and azo compounds of the compounds. , phosphoramide, glucoside, ether, acetal and other forms.
  • the compounds of the present invention can be prepared through the process flow shown in the examples, in which the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
  • compositions and methods of administration are provided.
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds and a pharmaceutically acceptable carrier.
  • the compound of the present invention has excellent anti-tumor activity, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and drugs containing the compound of the present invention as the main active ingredient
  • the compositions can be used to treat, prevent, and alleviate tumor-related diseases.
  • the pharmaceutical composition of the present invention contains a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier within a safe and effective amount.
  • the “safe and effective dose” refers to the amount of compound that is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, it contains 10-1000 mg of the compound of the present invention/dose.
  • the "dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility” here means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • solid lubricants such as
  • the pharmaceutical composition is an injection, capsule, tablet, pill, powder or granule.
  • administration mode of the compounds or pharmaceutical compositions of the present invention is not particularly limited.
  • Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, such as paraffin; (f) Absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl mono
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils,
  • compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions may contain, in addition to the active compound, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).
  • the treatment method of the present invention can be administered alone or in combination with other treatment methods or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage when administered is a pharmaceutically effective dosage.
  • a mammal such as a human
  • the daily dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
  • the present invention has the following main advantages:
  • the compound has excellent PRMT5 selective inhibitory activity against MTAP deletion.
  • the reaction system is heated to room temperature, the reaction solution is diluted with saturated saline, extracted three times with dichloromethane, the organic phases are combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified to obtain 9.2g of the product.
  • int10-1 (15g, 47.61mmol) was slowly added to 35mL trifluoroacetic acid, and stirred at room temperature for 1.5h. After the reaction of the raw materials is complete, cool it in an ice-water bath, add ice water until a white solid precipitates, filter with suction, wash the filter cake with water several times, dissolve the filter cake in 60 mL of methylene chloride, add anhydrous sodium sulfate, dry, and filter. The filtrate was used directly for the next reaction.
  • reaction system After the reaction of the raw materials is complete, the reaction system is lowered to room temperature, and after concentration under reduced pressure, the reaction solution is diluted with saturated brine, extracted three times with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the purified product. 220mg of product.
  • the separation conditions are as follows:
  • injection concentration 20mg/mL
  • injection volume 200 ⁇ L
  • the reaction system is lowered to room temperature, the solvent DMF is evaporated under reduced pressure, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 80 mg of the purified product.
  • Dissolve compound C11-1 (15g, 49.67mmol) in 150mL of anhydrous tetrahydrofuran. Under cooling in an ice-water bath, slowly add 1M tetrabutylammonium fluoride solution in tetrahydrofuran (53mL, 52.65mmol). After the addition is completed, keep the temperature and continue stirring. 15 minutes. Add water to quench the reaction, stir the reaction solution to room temperature, and then extract it three times with methyl tert-butyl ether. Combine the organic phases, dry over anhydrous sodium sulfate, and filter. The filtrate is concentrated under reduced pressure and purified to obtain the crude product, which is directly dissolved in 150mL N,N-dimethylformamide was used for the next reaction.
  • the DMF solution of C11-2 obtained in the previous step was cooled in an ice-water bath, and 60% sodium hydride (3g, 74.5mmol) was added. Under nitrogen protection, the temperature was maintained and stirred for 30 minutes, and then 100mL of C11-3 (17.37 g, 74.5 mmol) of DMF solution, raise the reaction solution to room temperature and stir for 3 hours, add water to quench the reaction, extract with methyl tert-butyl ether three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. After purification, 4.18 g of product was obtained.
  • the separation conditions are as follows:
  • a) Prepare a gradient dilution solution of the compound to be tested: use 10mM as the stock solution. Then use 2.5 ⁇ L stock solution to dissolve in 497.5 ⁇ L DMSO-free culture medium, and then perform 4-fold serial gradient dilution with 0.1% DMSO culture medium, for a total of 9 concentrations.
  • the diluted compound concentration is as follows:
  • %Cell Survival 100% ⁇ (OD_Sample-OD_LCave)/(OD_HC-OD_LCave)
  • OD_HC Cell readings in 0.1 ⁇ DMSO control group
  • A represents IC 50 ⁇ 100nM
  • B represents 100nM ⁇ IC 50 ⁇ 1000nM
  • C represents 1000nM ⁇ IC 50 ⁇ 5000nM
  • D represents 5000nM ⁇ IC 50
  • the drug is diluted according to the reference concentration, and the diluted solution is used as the first point, diluted 3 times at a time, for a total of 10+0 points.
  • the enzyme activity test results are as follows.
  • A represents IC 50 ⁇ 10nM
  • B represents 10nM ⁇ IC 50 ⁇ 50nM
  • C represents 50nM ⁇ IC 50 ⁇ 500nM
  • D represents 500nM ⁇ IC 50 ;
  • ND not detected
  • the present invention provides a series of compounds with excellent PRMT5 activity and selectivity.
  • the series of compounds have good inhibitory effects and selectivity on MTAP-deficient cells and have broad application prospects.

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Abstract

提供了一种双环类PRMT5抑制剂，其为具有式(I)所示结构的化合物，还提供了所述化合物的制备方法及其在调节PRMT5活性或治疗PRMT5相关疾病方面的用途。

Description

双环类PRMT5抑制剂 技术领域
本发明涉及医药技术领域，具体涉及用作PRMT5抑制剂的双环类化合物，及其药学上可接受的盐，涉及包含这样的化合物和盐的药物组合物，和涉及其用途，及其在调节PRMT5活性或治疗PRMT5相关疾病方面的应用。
背景技术
蛋白质精氨酸N-甲基转移酶(protein arginine N-methyltransferase 5,PRMT5)是一种II型精氨酸甲基转移酶，其催化甲基基团从S-腺苷-L-甲硫氨酸(SAM)转移到蛋白质L-精氨酸残基的胍基功能的ω-氮(ω-单甲基化)以及第二甲基基团转移到另一个ω-氮，产生对称二甲基精氨酸(sDMA)。PRMT5与MEP50(甲基小体蛋白50)形成复合物，这是底物识别和定向所必需的并且也是PRMT5催化的组蛋白2A和组蛋白4甲基转移酶活性所必需的(例如，参见Ho等人，(2013)PLOS ONE 8(8):10.1371/annotation/e6b5348e-9052-44ab-8f06-90d01dc88fc2)。
甲硫氨酸腺苷转移酶(methionine adenosyltransferase,MAT),又称S-腺苷甲硫氨酸合成酶,是能够催化甲硫氨酸(methionine,Met)与ATP反应生成S-腺苷甲硫氨酸(S-AdenosylL-methionine,SAM)的一类酶。SAM能够作为体内甲基转移酶的主要甲基供体,通过转甲基反应调控基因的表达、转录与翻译,进而对细胞的生长、死亡及分化产生重要影响。蛋白精氨酸N-甲基转移酶5即是以SAM为底物的甲基转移酶,其在肿瘤细胞的增殖等方面起到重要的调控作用。
肿瘤抑制基因的纯合性缺失是癌症的一个关键驱动因素，经常导致位于肿瘤抑制基因附近的乘客基因的附带损失。删除这些乘客基因可以产生治疗上的可及性，特别是对肿瘤细胞。染色体9p2I位点的纯合性缺失，包含了著名的肿瘤抑制因子CDKN2A(cyclin依赖激酶抑制剂2A)，在15％的肿瘤中发生，经常包括乘客基因MTAP(甲基硫腺苷磷酸化酶)，这是蛋氨酸和腺嘌呤挽救途径的关键酶。MTAP的缺失导致其底物甲基硫腺苷(MTA)的积累。MTA与II型甲基转移酶PRMT5的底物甲基供体s-腺苷甲硫氨酸(SAM)在结构上有密切的相似性。MTAP缺失导致MTA水平升高，选择性地与SAM竞争与PRMT5结合，使甲基转移酶处于低活性状态，易受PRMT5抑制剂进一步抑制。在大型肿瘤细胞系面板上进行的多基因组规模的shRNA drop out筛选发现MTAP缺失与细胞系对PRMT5的依赖性之间存在很强的相关性。然而，PRMT5是已知的细胞必需基因，敲除PRMT5和siRNA敲除研究表明，在正常组织(如泛细胞减少症、不孕症、骨骼肌损失、心肌肥厚等)中抑制PRMT5可能与显著 的副作用有关。因此，需要新的策略来利用这种代谢脆弱性，优先靶向MTAP缺失的肿瘤中的PRMT5，同时保留正常组织中的PRMT5(MTAP WT)。利用MTAP协同的小分子抑制剂靶向PRMT5，可以优先靶向MTAP缺失的肿瘤细胞中富集的PRMT5的MTA结合状态，同时比MTAP正常且MTA水平较低的正常细胞提供更高的治疗指数。
因此，开发新的MTA协同的PRMT5抑制剂，其能够在升高的MTA浓度的情况下更好的抑制PRMT5活性，特别是在MTAP缺失的细胞中。具有广泛的应用前景。
发明内容
本发明的目的在于提供一种式(I)所示化合物及其制备方法和其在用于PRMT5抑制剂药物方面的用途。
本发明的第一方面，提供了一种化合物，所述化合物为式(Ⅰ)化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，
其中：
R选自下组：H、-NH2、C1-3烷基、-OC1-3烷基、C1-3氟代烷基、-OC1-3氟代烷基；
R1选自取代或未取代的下组基团：单环组A、双环组B；所述单环组A选自下组：C3-8环烷基、C5-8芳基、含1-4个选自N、O或S的杂原子的3-8元杂环基、含1-4个选自N、O或S的杂原子的5-8元杂芳基；所述双环组B选自下组：C5-12环烷基、C8-12芳基、含1-4个选自N、O或S的杂原子的5-12元杂环基、含1-4个选自N、O或S的杂原子的8-12元杂芳基；其中，当被取代时，所述取代各自独立地指被Ra1取代；
R2选自下组：H、卤素、-CN、C1-6烷基、-ORa2；或者R2与其所连接的C一起形成C3-6环烷基或含有1-4个选自N、O或S的杂原子的3-6元杂环烷基；其中，所述烷基、环烷基、杂环烷基任选地被选自下组的取代基取代：氘、卤素、-CN、-OH、C1-3烷基、C1-3烷氧基、C1-3氟代烷基、C1-3氟代烷氧基、C3-5环烷基、含有1-2个选自N、O或S的杂原子的4-6元杂环烷基；
各R3独立地选自下组：H、氘、＝O、卤素、-CN、C1-6烷基、含有1-2个选自N、O或S的杂原子的C1-6杂烷基、-ORa3、-N(Ra3)2，其中，所述烷基、杂烷基任选地被选自下组的取代基取代：氘、卤素、-CN、-OH、C1-3烷基、C1-3烷氧基、C1-3氟代烷基、C1-3氟代烷氧基；
或者，两个R3与其所连接的原子或者R3与连接在其所连接的氮杂 环上的基团一起形成3-10元碳环或杂环，所述碳环或杂环与所述氮杂环形成桥环、并环或螺环；
R4选自下组：H、氘、卤素、-CN、C1-3烷基、C2-6炔基、C3-5环烷基、含有1-4个选自N、O或S的杂原子的3-6元杂环烷基、-ORa4、-C(＝O)N(Ra4)2、-S(＝O)2N(Ra4)2，其中，所述烷基、环烷基、杂环烷基任选地被选自下组的基团取代：氘、卤素、-CN、-OH、C1-3烷基、C1-3氟代烷基；
R5选自下组：H、氘、卤素、-CN、C1-3烷基、C3-5环烷基、含有1-4个选自N、O或S的杂原子的3-6元杂环烷基、-ORa5，其中，所述烷基、环烷基、杂环烷基任选地被选自下组的基团取代：氘、卤素、-CN、-OH、C1-3烷基、C1-3氟代烷基；
各x1、x2、x3、x4独立地选自下组：O、C(Ra6)m、N(Ra6)m；
各Ra2、Ra3、Ra4、Ra5独立地选自下组：H、C1-6烷基、含有1-2个选自N、O或S的杂原子的C1-6杂烷基、C3-6环烷基、含有1-2个选自N、O或S的杂原子的3-7元杂环基，其中，所述烷基、杂烷基、环烷基、杂环基任选地被1、2或3个Rb1取代；
各Rb1独立地选自下组：＝O、卤素、-CN、C1-6烷基、含有1-2个选自N、O或S的杂原子的C1-6杂烷基、C1-6卤代烷基、-ORc1、-N(Rc1)2；
各Rc1独立地选自下组：H、C1-6烷基、C3-6环烷基；
各Ra1独立地选自下组：氘、卤素、-CN、＝O、-OH、C1-6烷基、含有1-2个选自N、O或S的杂原子的C1-6杂烷基、C1-6卤代烷基、-L-C3-9环烷基、-L-(含1-4个选自N、O或S的杂原子的饱和或部分饱和的3-10元杂环基)、-L-C6-10芳基、-L-(含1-4个选自N、O或S的杂原子的5-10元杂芳基)、-O-L-(含1-4个选自N、O或S的杂原子的3-10元杂环基)、-ORb2、-N(Rb2)2、-L-N(Rb2)2、-C(＝O)Rb2、-C(＝O)ORb2、-P(＝O)(Rb2)2、-NRb2C(＝O)Rb2、-NRb2C(＝O)ORb2、-C(＝O)N(Rb2)2、-OC(＝O)N(Rb2)2、-S(＝O)Rb2、-S(＝O)2Rb2、-SRb2、-S(＝O)(＝NRb2)Rb2、-NRb2S(＝O)2Rb2、-S(＝O)2N(Rb2)2，其中，所述烷基、杂烷基、环烷基、杂环基、芳基、杂芳基任选地被选自下组的取代基取代：＝O、氘、卤素、-CN、-OH、-NH2、-NHC1-3烷基、-N(C1-3烷基)2、C1-6烷基、C3-6环烷基、含有1-4个选自N、O或S的杂原子的3-6元杂环基、-OC1-6烷基、含有1-2个选自N、O或S的杂原子的C1-6杂烷基、-OC1-6卤代烷基、C1-6卤代烷基、含有1-2个选自N、O或S的杂原子的C1-6卤代杂烷基、-C(＝O)Me、-C(＝O)NHMe、-NHC(＝O)Me；
各Rb2独立地选自下组：H、C1-6烷基、C1-6卤代烷基、被0-1个＝O取代的含有1-2个选自N、O或S的杂原子的C1-6杂烷基、C3-9环烷基、任选地被＝O或-CH3取代的含1-4个选自N、O或S的杂原子的3-10元杂环基；
各L独立地为键或C1-6亚烷基，其中，所述C1-6亚烷基任选地被选自下组的取代基取代：氘、卤素、-CN、-OH、C1-3烷基、C1-3烷氧基、C1-3氟代烷基、C1-3氟代烷氧基；
各Ra6独立地选自下组：H、氘、卤素、-CN、C1-3烷基、C1-3氟代烷 基、C1-3烷氧基、C1-3氟代烷氧基；
各m独立地选自下组：0、1、2；
n选自下组：0、1、2、3。
在另一优选例中，式具有选自下组所示结构：
其中，R1、R2、R3、x4、n如权利要求1所定义。
在另一优选例中，x4为C(Ra6)m，优选为CH2。
在另一优选例中，式具有选自下组所示结构：
其中，R1、R2、R3、n如上文所定义。
在另一优选例中，x4为O。
在另一优选例中，式具有选自下组所示结构：
其中，R1、R2、R3、n如上文所定义。
在另一优选例中，x4为N(Ra6)m，优选为NCH3。
在另一优选例中，式具有选自下组所示结构：
其中，R1、R2、R3、n如上文所定义。
在另一优选例中，所述化合物具有选自下组所示结构：
其中，R1、R2、R3、R4、R5、x1、x2、x3、x4、R、n如权利要求1所定义。
在另一优选例中，所述化合物具有选自下组所示结构：
其中，R1、R2、R3、R4、x2如权利要求1所定义。
在另一优选例中，R1选自取代或未取代的双环组B，其中，当被取代时，所述取代各自独立地指被Ra1取代；
所述化合物具有选自下组所示结构：
其中，R2、R3、R4、Ra1、x2如权利要求1所定义。
在另一优选例中，所述单环组A具有选自下组的结构：
所述双环组B具有选自下组的结构：
在另一优选例中，R1为被0-3个Ra1独立取代的
在另一优选例中，R1为被0-3个Ra1独立取代的
在另一优选例中，R1为被0-3个Ra1独立取代的
在另一优选例中，R1为被0-3个Ra1独立取代的
在另一优选例中，R1为被0-3个Ra1独立取代的
在另一优选例中，各Ra1独立地选自下组：卤素、＝O、-OH、C1-6烷基、C1-6卤代烷基、-L-C3-9环烷基、-L-(含1-4个选自N、O或S的杂原子的饱和或部分饱和的3-10元杂环基)、-L-(含1-4个选自N、O或S的杂原子的5-10元杂芳基)、-O-L-(含1-4个选自N、O或S的杂原子的3-10元杂环基)、-ORb2、-N(Rb2)2、-L-N(Rb2)2、-C(＝O)Rb2、-NRb2C(＝O)Rb2、-NRb2S(＝O)2Rb2，其中，所述烷基、杂烷基、环烷基、杂环基、芳基、杂芳基任选地被选自下组的取代基取代：＝O、卤素、-OH、-NH2、-NHC1-3烷基、-N(C1-3烷基)2、C1-6烷基、C3-6环烷基、含有1-4个选自N、O或S的杂原子的3-6元杂环基、-OC1-6烷基、含有1-2个选自N、O或S的杂原子的C1-6杂烷基、-OC1-6卤代烷基、C1-6卤代烷基、含有1-2个选自N、O或S的杂原子的C1-6卤代杂烷基、-C(＝O)Me、-C(＝O)NHMe、-NHC(＝O)Me；
各L独立地为键或C1-6亚烷基；
各Rb2独立地选自下组：H、C1-6烷基、C1-6卤代烷基、被0-1个＝O取代的含有1-2个选自N、O或S的杂原子的C1-6杂烷基、C3-9环烷基、任选地被＝O或-CH3取代的含1-4个选自N、O或S的杂原子的3-10元杂环基。
在另一优选例中，Ra1中所述环烷基具有选自下组的结构：
Ra1中所述杂环基具有选自下组的结构：
Ra1中所述杂芳基具有选自下组的结构：
在另一优选例中，Rb2中所述的杂烷基具有选自下组的结构：
Rb2中所述环烷基具有如下结构：
Rb2中所述杂环基具有选自下组的结构：
在另一优选例中，R选自下组：H、-NH2、C1-3烷基、-OC1-3烷基；
R2选自下组：H、C1-6烷基、-ORa2；或者R2与其所连接的C一起形成C3-6环烷基或含有1-4个选自N、O或S的杂原子的3-6元杂环烷基；Ra2如权利要求1所定义；
R3选自下组：H、卤素、C1-6烷基；或者，两个R3与其所连接的原子或者R3与连接在其所连接的氮杂环上的基团一起形成3-10元碳环或杂环；
R4选自下组：卤素、-CN、C1-3烷基、C2-6炔基、C3-5环烷基、含有1-4个选自N、O或S的杂原子的3-6元杂环烷基、-ORa4、-C(＝O)N(Ra4)2、-S(＝O)2N(Ra4)2；Ra4如权利要求1所定义；
R5选自下组：H、卤素、-CN、C1-3烷基。
在另一优选例中，R为-NH2。
在另一优选例中，R2为C1-6烷基。
在另一优选例中，R3选自下组：F、-CH3。
在另一优选例中，R4选自下组：-CH3、-CH2CH3、-C(＝O)NH2。
在另一优选例中，R5选自下组：H、-CH3、F。
在另一优选例中，x1选自下组：C(Ra6)m、N(Ra6)m，优选地为CH。
在另一优选例中，x2选自下组：C(Ra6)m、N(Ra6)m，优选地为CH。
在另一优选例中，x3选自下组：C(Ra6)m、N(Ra6)m，优选地为CH。
在另一优选例中，所述化合物选自下组：










本发明的第二方面，提供了一种药物组合物，包含治疗有效量的一种或多种本发明第一方面所述的化合物以及药学上可接受的载体。
本发明的第三方面，提供了一种本发明第一方面所述的化合物的用途，用于制备用于调节PRMT5活性或治疗PRMT5相关疾病的药物。
在另一优选例中，所述PRMT5相关疾病为癌症或肿瘤。
在另一优选例中，所述癌症或肿瘤选自下组：前列腺癌、乳腺癌、脑癌、皮肤癌、宫颈癌、睾丸癌等，更具体地说，可以通过本发明的化合物和方法治疗的癌症包括但不限于肿瘤类型，如星形细胞癌、乳腺癌、宫颈癌、结直肠癌、子宫内膜癌、食管癌、胃癌、头颈部癌、肝细胞癌、喉癌、肺癌、口腔癌、卵巢癌、前列腺癌和甲状腺癌和肉瘤。更具体地说，这些化合物可用于治疗：心脏：肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、黏液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤；肺部：支气管癌(鳞状细胞癌、未分化小细胞癌、未分化大细胞癌、腺癌)、肺泡(细支气管)癌、支气管腺瘤、肉瘤、淋巴瘤、软骨错构瘤、间皮瘤；胃肠道类疾病：食管(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃(癌、淋巴瘤、平滑肌肉瘤)、胰腺(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌肿瘤、舒血管肠肽瘤)、小肠(腺癌、淋巴瘤、类癌肿瘤、卡波济肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠(腺癌、管状腺瘤、绒毛腺瘤、错构瘤、平滑肌瘤)；泌尿生殖系统：肾脏(腺癌、肾母细胞瘤、淋巴瘤、白血病)、膀胱和尿道鳞状细胞癌、移行细胞癌、腺癌)、前列腺癌(腺癌、肉瘤)、睾丸(精原细胞瘤、畸胎瘤、胚胎癌、畸胎癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样肿瘤、脂肪瘤)；肝：肝癌(肝细胞癌)、胆管癌、肝母细胞瘤、血管肉瘤、肝细胞腺瘤、血管瘤；胆道：胆囊癌、壶腹癌、胆管癌；骨：骨源性肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤因氏肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、骨巨细胞瘤脊索瘤、良性软骨瘤、软骨母细胞瘤、软骨黏液纤维瘤、骨样骨瘤和巨细 胞瘤；神经系统：颅骨(骨瘤、血管瘤、肉芽肿、黄色瘤、畸形骨炎)、脑膜(脑膜瘤、脑膜肉瘤、胶质瘤)、大脑(星形细胞瘤、髓母细胞瘤、胶质瘤、室管膜瘤、生发细胞瘤(松果体瘤)、多形胶质母细胞瘤、少突胶质母细胞瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤)、脊髓神经纤维瘤、脑膜瘤、胶质瘤、肉瘤)；妇科：子宫(子宫内膜癌)，宫颈(宫颈癌，肿瘤前宫颈发育不良)，卵巢(卵巢癌(浆液性囊腺癌，粘液性囊腺癌，未分类癌)，肉芽鞘细胞肿瘤，支持间质细胞肿瘤，无性生殖细胞瘤，恶性畸胎瘤)，外阴(鳞状细胞癌，上皮内癌，腺癌，纤维肉瘤，黑色素瘤)，阴道(透明细胞癌，鳞状细胞癌，葡萄状肉瘤(胚胎横纹肌肉瘤)，输卵管(癌)；血液学：血液(髓系白血病(急性和慢性)、急性淋巴细胞白血病、慢性淋巴细胞白血病、骨髓增生性疾病、多发性骨髓瘤、骨髓增生异常综合征)、霍奇金病、非霍奇金淋巴瘤(恶性淋巴瘤)；皮肤：恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西氏肉瘤、痣发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕疙瘩、牛皮癣；肾上腺：成神经细胞瘤。在某些病例中，肿瘤为弥漫大B细胞淋巴瘤(DLBCL)。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地制备了一种具有优异PRMT5抑制活性的双环类化合物及其制备方法。具体地，通过结构优化，本发明人获得了一类具有优异PRMT5选择抑制活性的化合物。在此基础上，发明人完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“卤素”指F、Cl、Br或I。
在本发明中，“C1-6烷基”是指包括1-6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基、或类似基团。术语“C1-3烷基”具有类似含义。
在本发明中，术语“C2-6烯基”是指具有2-6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。
在本发明中，术语“C2-6炔基”是指具有2-6个碳原子的含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。
在本发明中，术语“卤代”是指被卤素取代。
在本发明中，术语“氟代”是指被F取代。
在本发明中，术语“C3-6环烷基”是指在环上具有3-6个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基等。术语“C3-5环烷基”、“C3-8环烷基”、“C5-12环烷基”、“C3-9环烷基”具有类似含义。
在本发明中，术语“芳环”或“芳基”具有相同的含义，优选为“C6-10芳基”。术语“C6-10芳基”是指在环上不含杂原子的具有6-10个碳原子的芳香族环基，如苯基、萘基等。术语“C5-8芳基”、“C8-12芳基”具有类似含义。
在本发明中，术语“杂环基”或者“杂环烷基”为含1-4个选自N、O、S的杂原子的3-12元杂环基，包括(但并不限于)如下基团：
在本发明中，术语“芳香杂环”或“杂芳基”具有相同的含义，指包含一个到多个杂原子的杂芳族基团。例如“C3-C10杂芳基”是指含有1～4个选自氧、硫和氮中的杂原子以及3-10个碳原子的芳香杂环。非限制性例子包括：呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中，术语“C1-6烷氧基”是指具有1-6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。术语“C1-3烷氧基”具有类似含义。
在本发明中，术语“C1-6杂烷基”是指含有选自N、O或S杂原子的具有1-6个碳原子的直链或支链烷基，非限制性地包括甲氧基甲基、乙氧基甲基、丙氧基甲基、异丙氧基甲基、丁氧基甲基、-CH2OH、-CH2NH2、-CH2NHCH3、-CH2N(CH3)2、-CH2CH2OCH3、-CH2CH2NHCH3、-CH2CH2N(CH3)2等。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基 团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。
在本发明中，术语1-6个指1、2、3、4、5或6个。其他类似术语具有类似含义。
应理解，当某一基团同时存在于化合物的多个不同位置时，其在各位置的定义是相互独立地，可以相同也可以不同。亦即，术语“选自下组：”与术语“各独立地选自下组：”具有相同含义。
化合物
本发明提供了一种化合物，所述化合物为式(Ⅰ)化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，
其中，R1、R2、R3、R4、R5、x1、x2、x3、x4、R、n如上文定义。
在另一优选例中，所述的化合物中，R1、R2、R3、R4、R5、x1、x2、x3、x4、R、n中任一个分别独立地为所述具体化合物中所对应的具体基团。
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二 胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂化物”指本发明化合物与溶剂分子配位形成特定比例的配合物。
此外，本发明化合物还包括式(Ⅰ)所示的化合物的前药。术语“前药”包括其本身可以是具有生物学活性的或非活性的，当用适当的方法服用后，其在人体内进行代谢或化学反应而转变成式(Ⅰ)的一类化合物，或式(Ⅰ)的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
应理解，本发明式(Ⅰ)化合物的具体制备方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
典型地，本发明化合物可通过实施例所示的工艺流程制备，其中所用原料和试剂如无特殊说明，均可通过商业途径购买。
药物组合物和施用方法
本发明还提供了一种药物组合物，包含治疗有效量的一种或多种所述的化合物以及药学上可接受的载体。
由于本发明化合物具有优异的抗肿瘤活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与肿瘤相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的其他化合物(如抗肿瘤药物)联合给药。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
与现有技术相比，本发明具有以下主要优点：
1)所述化合物具有优异的针对MTAP缺失的PRMT5选择抑制活性。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例合成路线
除非另有说明，所有手性原子的绝对立体化学定义如下。标记为(or)或(rel)的化合物是任意指定绝对立体化学的单一对映体(例如，基于例子部分所述的手性SFC洗脱)。标有(&)或(rac)的化合物是对映体的混合物，其相对立体化学如文中所示。用(abs)标记的化合物是单对映体，其中绝对立体化学如文中所示。
中间体的合成
中间体int1的合成：
1、int1-2的合成
将int1-1(5g,28.25mmol)溶于100mL无水四氢呋喃中，氮气保护下,将反应液降温到-78℃，然后缓慢滴加双(三甲基硅基)氨基钠(21.19mL,56.3mmol，2M in THF),滴毕保持温度搅拌0.5h后，缓慢滴加N-溴代琥珀酰亚胺(6.54g,36.73mmol)的四氢呋喃溶液500mL,滴毕保持温度-78℃搅拌2h，待原料反应完全后，将反应体系升温至室温，滴加2M稀盐酸淬灭反应，乙酸乙酯萃取三 次，饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到3.94g产物。Ms[M+H]+255.9 1H NMR(400MHz,DMSO-d6)δ5.92(d,J＝16.3Hz,1H),4.32-4.14(m,4H),1.31(m,6H).
2、int1-4的合成
将氢化钠(927mg,23.18mmol)溶于40mL的无水四氢呋喃中，氮气保护冰水浴冷却下,缓慢滴加int1-2(3.94g,15.45mmol)的四氢呋喃溶液(70mL)，滴毕保持温度搅拌0.5h，再缓慢滴加int1-3(2.77g,23.18mmol)的四氢呋喃溶液(50mL)，滴毕缓慢升温到25℃反应0.5h，待原料反应完全后，将反应体系升至室温，反应液用饱和食盐水稀释，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到2.8g产物。Ms[M+H]+280.9 1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.38(d,J＝2.0Hz,1H),8.02(dd,J＝8.8,2.0Hz,1H),7.54(d,J＝8.8Hz,1H),7.12(s,2H),3.88(s,3H).
3、int1-5的合成
将int1-4(2.8g,10mmol)溶解到280mL二氧六环中，然后依次加入甲基硼酸(11.97g，20mmol)、碳酸钠(3.18g,30mmol)、Pd(dppf)Cl2(732mg,1mmol)，氮气保护下，置换3次，将反应液缓慢升温至100℃反应3h。待原料反应完全后，将反应体系降温至室温,减压浓缩后经纯化得到1.4g产物。Ms[M+H]+217.0。1H NMR(400MHz,DMSO-d6)δ8.21(d,J＝2.0Hz,1H),7.86(dd,J＝8.7,2.1Hz,1H),7.82(s,1H),7.42(d,J＝8.7Hz,1H),6.68(s,2H),3.80(s,3H),2.16(s,3H).
4、int1的合成
将int1-5(1.4g,6.48mmol)溶于四氢呋喃、甲醇和水(2:1:1)的组成的100mL混合溶剂中，加入氢氧化锂(1.09g,25.92mmol)，25℃下搅拌12h，待原料反应完全后，用浓度为2M的稀盐酸调至pH＝7,有大量白色固体析出，过滤，滤饼经真空干燥后得到0.7g产物。Ms[M+H]+202.9 1H NMR(400MHz,DMSO-d6)δ8.24(d,J＝2.0Hz,1H),7.91(dd,J＝8.7,2.0Hz,1H),7.86(s,1H),7.46(d,J＝8.7Hz,1H),6.66(s,2H),2.22(d,J＝1.1Hz,3H).
中间体int2的合成：
将草酰氯(9.4g,73.8mmol)溶于600mL二氯甲烷中，氮气保护下，将反应液降温到-78℃，然后缓慢滴加二甲基亚砜(16.8g,199.45mmol)，滴毕保持温度-78℃搅拌1h后，缓慢滴加int2-1(9.3g，39.89mmol)的二氯甲烷溶液100mL,然后保持温度-78℃搅拌0.5h,再滴加三乙胺(20g，199.45mmol)，待原料反应完全后，将反应体系升温至室温,反应液用饱和食盐水稀释，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到9.2g产物。
1H NMR(400MHz,DMSO-d6)δ9.65(d,J＝6.4Hz,1H),3.88(d,J＝13.6Hz,2H),3.01(s,2H),1.79(dd,J＝9.2,4.2Hz,2H),1.76-1.65(m,2H),1.40(d,J＝5.2Hz,9H).
中间体int3合成：
1、int3-2的合成
将int3-1(3g,26.5mmol)溶于75mL无水四氢呋喃中，氮气保护下，将反应液冷却至-78℃，缓慢滴加正丁基锂(10.6mL,26.5mmol，2.5M in THF)，滴毕，继续搅拌30min，然后保持温度-78℃，缓慢滴加溶于36mL四氢呋喃的二碳酸二叔丁酯(8.7g,39.8mmol)溶液，滴毕，继续搅拌40min，加饱和氯化铵溶液淬灭反应，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到3.96g产物。Ms[M+H]+236.1 1H NMR(400MHz,Chloroform-d)δ3.83-3.75(m,1H),3.16-3.06(m,1H),2.57-2.52(m,1H),2.52-2.46(m,1H),2.02-1.93(m,1H),1.92-1.84(m,1H),1.53(s,9H),1.44-1.39(m,1H),1.04(d,J＝6.6Hz,3H).
2、int3的合成
将int3-2(4g,18.77mmol)溶于40mL无水四氢呋喃溶液中，氮气保护下，将反应液冷却至-78℃，缓慢滴加双(三甲基硅烷基)氨基锂(28.2mL,28.16mmol,1M in THF)，继续搅拌1.5h，然后保持温度缓慢滴加20mL N-苯基双(三氟甲磺酰亚胺)(4.2g,23.46mmol)的四氢呋喃溶液，继续反应2h，滴加饱和氯化铵溶液淬灭反应，将升至室温，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到4.28g产物。Ms[M+H]+346.1 1H NMR(400MHz,Chloroform-d)δ5.25(t,J＝3.8Hz,1H),3.87(dd,J＝12.8,3.3Hz,1H),3.00(dd,J＝12.7,9.1Hz,1H),2.44-2.34(m,1H),1.98-1.78(m,2H),1.49(s,9H),0.99(d,J＝6.6Hz,3H).
中间体int4的合成：
1、int4-2的合成
将int4-1(3g,15.31mmol)溶于50mL N,N-二甲基甲酰胺中，加入N,N-二甲基甲酰胺二甲基缩醛，氮气保护下，反应液升温至90℃反应2h。原料反应完全后，将反应体系降至室温，减压浓缩后经纯化得到3.69g产物。Ms[M+H]+252.0 1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.22(s,1H),8.14(d,J＝13.0Hz,1H),5.85(d,J＝13.0Hz,1H),3.88(s,3H),3.25-2.80(m,6H).
2、int4-3的合成
将int4-2(3.69g,14.7mmol)溶于50mL四氢呋喃和50mL水组成的混合溶剂中，反应液于室温搅拌过夜。原料反应完全后，冰水浴冷却下，加入饱和碳酸氢钠溶液调至pH＝8,抽滤，滤饼用乙酸乙酯洗涤，滤液用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到2.67g粗产物。1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.47(s,1H),8.33(s,1H),3.97(s,3H).
3、int4-4的合成
将int4-3(2.67g,12.8mmol)溶于140mL醋酸中,加入铁粉(7.12g,127mmol)，氮气保护下，反应液升温至50℃反应30min。原料反应完全后，将反应体系降至室温，抽滤，滤饼用乙酸乙酯洗涤，减压蒸干滤液，然后将残渣溶于乙酸乙酯中，冰水浴冷却下，加入饱和碳酸氢钠溶液调至pH＝8，乙酸乙酯萃取，合并有机相，减压浓缩后经纯化得到1.3g产物。Ms[M+H]+181.0 1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.31(s,1H),8.26(s,1H),7.81(s,2H),3.82(s,3H).
4、int4-6的合成
冰水浴冷却下，将氢化钠(433mg,10.83mmol)溶于40mL N,N-二甲基甲酰胺中，氮气保护下，向反应体系中缓慢滴加int4-5(4.7g,18.41mmol)的四氢呋喃溶液(40mL)，搅拌30min后，缓慢滴加int4-4(1.3g,7.22mmol)，继续搅拌2h。原料反应完全后，冰水冷却浴下，滴加水淬灭反应后，将反应体系升至室温，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到1.4g产物。Ms[M+H]+281.9 1H NMR(400MHz,DMSO-d6)δ8.87(d,J＝0.8Hz,1H),8.67(s,1H),8.40(s,1H),7.42(s,2H),3.89(s,3H).
5、int4-7的合成
将int4-6(1.2g,4.27mmol),甲基硼酸(512mg,8.54mmol),碳酸钾(1.7g,12.81mmol)以及：[1,1'-双(二苯基膦)二茂铁]二氯化钯(307mg,0.42mmol)，溶于60mL乙二醇二甲醚溶液中，氮气保护下，反应液升温至85℃反应3h。原料反应完全后，将反应体系降至室温，抽滤，滤饼用乙酸乙酯洗涤，滤液减压浓缩后经纯化得到900mg产物。Ms[M+H]+218 1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),8.31(s,1H),7.96(s,1H),7.03(s,2H),3.87(s,3H),2.26(s,3H).
6、int4的合成
将int4-7(900mg,4.12mmol)溶于20mL四氢呋喃，10mL甲醇和10mL水组成的混合溶剂中，加入一水合氢氧化锂(260mg,6.18mmol)，室温搅拌3h。待原料反应完全后，减压浓缩得到1.0g粗品产物。Ms[M+H]+204 1H NMR(400MHz,D2O)δ8.60(s,1H),7.97(s,1H),7.64(s,1H),2.12(s,3H).
中间体int5的合成
1、int5-2的合成
将int5-1(23g,106.83mmol)溶于460mL二氯甲烷中，氮气保护下，将反应液冷却至0℃，加入三乙胺(16.18g,160.25mmol)后，再缓慢滴加甲基磺酰氯(14.68g,128.20mmol)；滴毕，将反应液自然升至室温搅拌12h，待原料反应完全后，加水淬灭反应，静置，分出二氯甲烷相待用。水相用二氯甲烷萃取三次，分液，合并二氯甲烷相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后经纯化得到30g产物。Ms[M+H-56]+238.0。1H NMR(400MHz,Chloroform-d)δ4.16-4.04(m,2H),4.01-3.88(m,1H),3.81(d,J＝13.2Hz,1H),3.03(s,3H),2.93-2.96(m,1H),2.80(s,1H),2.01-1.90(m,1H),1.88-1.77(m,1H),1.68-1.71(m,2H),1.46(s,9H),1.37-1.23(m,1H).
2、int5-3的合成
将int5-2(5g,17.06mmol)溶于100mL无水四氢呋喃中，氮气保护下，将反应液冷却至-30℃，缓慢滴加三乙基硼氢化锂(107mL,106.63mmol,1M in THF)；滴毕，缓慢升至室温搅拌12h。原料反应完全后，滴加水淬灭反应，然后用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到1.6g产物。Ms[M+H-56]+144.1。1H NMR(400MHz,Chloroform-d)δ3.92(dd,J＝17.2,10.2Hz,2H),2.69-2.73(m,1H),2.25(d,J＝20.3Hz,1H),1.81-1.68(m,1H),1.67-1.50(m,2H),1.46(s,9H),1.31-1.18(m,1H),1.11-0.92(m,1H),0.87(d,J＝6.7Hz,3H).
3、int5-4的合成
将int5-3(1.6g,8.03mmol)和高碘酸钠(5.84g,27.30mmol)溶于30mL的乙酸乙酯和30mL的水中，最后加入氧化钌(IV)*水合物(122mg,0.81mmol)，氮气保护下，室温搅拌12h。待原料反应完全后，加饱和亚硫酸钠水溶液淬灭反 应，然后用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到790mg产物。Ms[M+H-56]+158.1。1H NMR(400MHz,Chloroform-d)δ3.79(dd,J＝12.7,4.8Hz,1H),3.12(dd,J＝12.6,10.3Hz,1H),2.67-2.39(m,2H),1.95-1.98(m,1H),1.94-1.78(m,1H),1.53(s,9H),1.47-1.38(m,1H),1.04(d,J＝6.6Hz,3H).
4、int5的合成
将int5-4(0.79g,3.71mmol)溶于50mL无水四氢呋喃溶液中，氮气保护下，降温至-78℃，缓慢滴加六甲基二硅氮烷锂盐(5.57mL,5.57mmol,1M in THF)，继续搅拌0.5h，然后保持温度-78℃，缓慢滴加N-苯基双(三氟甲烷磺酰)亚胺(1.66g,4.64mmol)的20mL无水四氢呋喃溶液；滴毕，继续保持温度反应0.5h，然后升至室温搅拌3h。待原料反应完全，滴加水淬灭反应，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到化合物1.2g。Ms[M+H-56]+290.0。1H NMR(400MHz,Chloroform-d)δ5.25(t,J＝3.8Hz,1H),3.87(dd,J＝12.8,3.3Hz,1H),3.00(dd,J＝12.7,9.1Hz,1H),2.44-2.34(m,1H),1.98-1.85(m,1H),1.85-1.78(m,1H)，1.49(s,9H),0.99(d,J＝6.6Hz,3H).
中间体int6的合成
1、int6-2的合成
将int6-1(500mg,4.42mmol)溶于20mL无水四氢呋喃中，氮气保护下，将反应液冷却至-78℃，缓慢滴加正丁基锂(1.8mL,4.42mmol,2.5M in THF)，滴毕，继续搅拌30min，然后保持温度-78℃，缓慢滴加溶于80mL四氢呋喃的二碳酸二叔丁酯(1.44g,6.63mmol)溶液，滴毕，继续搅拌40min；保持温度-78℃，滴加饱和氯化铵溶液淬灭反应，然后搅拌升至室温，反应液用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到500mg产物。Ms[M+H]+213.1。1H NMR(400MHz,Chloroform-d)δ4.25-4.34(m,1H),2.57-2.34(m,2H),2.01-1.82(m,2H),1.82-1.64(m,2H),1.53(s,9H),1.28(d,J＝6.6Hz,3H).
2、C5-3的合成
将int6-2(500mg,2.35mmol)溶于40mL无水四氢呋喃溶液中，氮气保护下，将反应液冷却至-78℃，缓慢滴加双(三甲基硅烷基)氨基锂(3.45mL,3.45mmol,1M in THF)，滴毕继续搅拌1.5h，然后保持温度缓慢滴加20mL N-苯基双(三氟甲磺酰亚胺)(1.05g,2.88mmol)的四氢呋喃溶液，继续反应2h；反应结束后，保持温度-78℃，滴加饱和氯化铵溶液淬灭反应，然后搅拌升至室温，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到800mg产物。Ms[M+H]+346.1
中间体int7的合成
1、int7-2的合成
将(S)-(-)-1-氨基-2-丙醇(1.00g,13.30mmol)和三乙胺(3.7mL,26.60mmol)溶于20mL的无水二氯甲烷中，氮气保护，冰水浴冷却下加入三苯基氯甲烷(3.90g,14.0mmol)中，然后升至室温搅拌过夜。反应结束后，加入水稀释反应液，二氯甲烷萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后经纯化得3.86g产物。1H NMR(400MHz,Chloroform-d)δ7.51-7.40(m,6H),7.34-7.24(m,6H),7.24-7.14(m,2H),3.80(m,1H),2.23-2.11(m,2H),1.11(d,J＝6.2Hz,3H).
2、int7-3的合成
冰水浴冷却下，将含量为60％的氢化钠(388mg,9.70mmol)加入到5mL的无水N,N-二甲基甲酰胺中，氮气保护下，滴加int7-2溶液(1.54g,4.85mmol，in 15mL DMF)，升至室温搅拌1小时；然后在冰浴冷却下，滴加三丁基(碘甲基)锡烷(2.30g，5.34mmol)，升至室温搅拌4小时。反应结束后，加入饱和氟化钾溶液淬灭反应，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后经纯化即得1.96g产物。1H NMR(400MHz,Chloroform-d)δ7.60-7.40(m,6H),7.33-7.21(m,6H),7.19-7.07(m,3H), 3.78-3.64(m,1H),3.45(d,J＝9.9Hz,1H),3.36(dq,J＝6.8,3.4Hz,1H),2.23(dd,J＝11.8,3.5Hz,1H),2.09(dd,J＝11.8,7.2Hz,1H),1.60-1.39(m,6H),1.32-1.26(m,6H),1.10(d,J＝6.2Hz,3H),0.90-0.82(m,15H).3、int7的合成
将int7-3(1.96g,3.16mmol)溶于14mL/4mL/2mL的二氯甲烷/2,2,2-三氟乙醇/乙酸的混合溶剂中，然后将反应液加热至50℃搅拌18h。反应结束后，冰浴冷却下，加入饱和的碳酸氢钠溶液调至弱碱性，再用二氯甲烷萃取三次，合并二氯甲烷相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后经柱层析得834mg产物。Ms[M+H]+380.1。1H NMR(400MHz,Chloroform-d)δ3.83(d,J＝9.8Hz,1H),3.55(d,J＝9.8Hz,1H),3.32-3.12(m,1H),2.78(dd,J＝13.1,3.6Hz,1H),2.62(dd,J＝13.0,7.4Hz,1H),1.61-1.39(m,7H),1.38-1.24(m,7H),1.10(d,J＝6.2Hz,3H),0.90(td,J＝7.8,3.6Hz,15H).
中间体int8的合成
1、int8-2的合成
将(R)-(-)-2-氨基-1-丙醇(500mg,6.67mmol)溶于30mL的无水二氯甲烷中，冰水浴冷却下依次加入三乙胺(1.87mL,13.34mmol)和三苯基氯甲烷(1.95g,6.70mmol)中，然后室温搅拌18h。反应结束后，加入水淬灭反应，二氯甲烷萃取三次，饱和食盐水洗涤有机相，无水硫酸钠干燥，减压浓缩后经柱层析纯化得1.94g产物。1H NMR(400MHz,Chloroform-d)δ7.61-7.48(m,6H),7.29-7.22(m,6H),7.21-7.13(m,3H),3.15(dd,J＝10.5,4.2Hz,1H),3.04(dd,J＝10.6,4.9Hz,1H),2.79-2.72(m,1H),0.66(d,J＝6.5Hz,3H).
2、int8-3的合成
冰水浴冷却下，将含量为60％的氢化钠(367mg,9.18mmol)加入到12mL的无水N,N-二甲基甲酰胺中，氮气保护下，再将8mL化合物int8-2(1.94g, 6.12mmol)的无水N,N-二甲基甲酰胺溶液滴加到反应液中，升至室温搅拌1小时；然后在冰水浴冷却下，滴加三丁基(碘甲基)锡烷(2.9g,6.73mmol)，然后室温搅拌2小时。反应结束后，加入饱和氟化钾溶液淬灭反应，乙酸乙酯萃取三次，饱和食盐水洗涤有机相，无水硫酸钠干燥，减压浓缩后经柱层析纯化即得3.24g产物。1H NMR(400MHz,Chloroform-d)δ7.60-7.52(m,6H),7.28-7.22(m,6H),7.19-7.12(m,3H),3.46-3.38(m,2H),2.94(dd,J＝8.9,4.7Hz,1H),2.64(dd,J＝6.5,4.8Hz,1H),2.44(dd,J＝8.9,5.0Hz,1H),1.51-1.40(m,6H),1.28-1.22(m,6H),0.91-0.84(m,15H),0.76(d,J＝6.5Hz,3H).
3、int8的合成
将化合物int8-3(3.24g,5.22mmol)溶于14mL/4mL/2mL的二氯甲烷/2,2,2-三氟乙醇/乙酸的混合溶剂中，然后将反应液加热至50℃搅拌2h。反应结束后，降至室温，冰浴冷却下，加入饱和的碳酸氢钠溶液调至弱碱性，再用二氯甲烷萃取三次，合并二氯甲烷相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后经柱层析得1.41g产物。1H NMR(400MHz,Chloroform-d)δ3.77-3.68(m,2H),3.31-3.20(m,1H),3.16-3.03(m,2H),1.62-1.41(m,6H),1.35-1.26(m,6H),1.05(d,J＝6.2Hz,3H),0.96-0.82(m,15H).
中间体int9的合成
将int3(1.5g,4.37mmol)，联硼酸频那醇酯(1.29g,5.25mmol)，碳酸钾(900mg,6.56mmol)，三苯基膦(70mg,0.16mmol)以及二(三苯基膦)二氯化钯(92mg,0.13mmol)溶于30mL二氧六环溶液中，氮气保护下，反应液升温至90℃反应7h。原料反应完全后，将反应体系降温至室温，抽滤，滤饼用乙酸乙酯洗涤，滤液减压浓缩后经纯化得到1.03g产物。1H NMR(400MHz,DMSO-d6)δ5.00(s,1H),3.61-3.53(m,1H),2.84(dd,J＝12.4,9.5Hz,1H), 2.12-2.01(m,1H),1.82-1.72(m,1H),1.65-1.55(m,1H),1.15(s,12H),0.90(d,3H).
中间体int10的合成
冰水浴冷却下，将int10-1(15g,47.61mmol)缓慢加入到35mL三氟乙酸中，室温搅拌1.5h。待原料反应完全后，冰水浴冷却下，加入冰水至有白色固体析出，抽滤，滤饼用水洗涤多次，滤饼溶于60mL的二氯甲烷后，加入无水硫酸钠干燥，过滤，滤液直接用于下一步反应。
实施例1
本发明的化合物
合成路线及实验过程如下：
1、C1-2A和C1-2B的合成
将C1-1(4.16g,26.06mmol)溶于120mL N，N-二甲基甲酰胺中，然后依次加入int2(6.05g,26.06mmol)以及乙酸(3.08g,52.12mmol)，氮气保护下，将反应液缓慢升温至120℃搅拌12h。待原料反应完全后，将反应体系降温至室温，反应液用饱和食盐水稀释，甲基叔丁基醚萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到化合物2.3g C1-2A和3.15g化合物C1-2B。
C1-2A:Ms[M+H]+371.0 1H NMR(400MHz,DMSO-d6)δ8.22(d,J＝8.6Hz,1H),8.15(d,J＝2.1Hz,1H),7.56(dd,J＝8.7,2.1Hz,1H),3.98(d,J＝13.4Hz,2H),3.20(dd,J＝23.4,6.1Hz,2H),2.25-2.09(m,4H),1.44(s,9H).C1-2B:Ms[M+H]+369.0 1H NMR(400MHz,DMSO-d6)δ8.12(d,J＝8.6Hz,1H),8.03(d,J＝2.0Hz,1H),7.47(dd,J＝8.6,2.1Hz,1H),6.50(s,1H),3.89(d,J＝13.2Hz,2H),3.25-3.01(m,2H),2.07-1.93(m,2H),1.80(d,J＝13.4Hz,2H),1.43(s,9H).
2、C1-3的合成
将C1-2A(2.3g,6.21mmol)溶于10mL甲醇中，加入10mL的4M氯化氢-二氧六环溶液,冰水浴冷却下，反应液搅拌2h。待原料反应完全后，将反应体系升至室温,减压浓缩得到2g产物。Ms[M+H]+271.0
3、C1-4的合成
将C1-3(2g,7.41mmol)溶解到100mL的甲醇中，加入含量为37％的甲醛甲醇溶液(1.8g,22.23mmol)，然后再依次加入乙酸钠(668mg,8.15mmol)，乙酸(1.3g,22.23mmol),氮气保护冰水浴冷却下，将反应液搅拌1h；然后加入氰基硼氢化钠(931mg,14.82mmol)，将反应液升温至30℃反应0.5h。待反应结束，将反应体系降至室温，反应液用饱和碳酸钾溶液调至pH＝8后，用二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到1.35g产物。Ms[M+H]+285.0 1H NMR(400MHz,DMSO-d6)δ8.10(d,J＝8.6Hz,1H),8.04(d,J＝2.0Hz,1H),7.44(dd,J＝8.6,2.1Hz,1H),2.80-2.67(m,2H),2.36-2.24(m,2H),2.22(s,3H),2.18-2.00(m,4H).
4、C1-5的合成
将C1-4(1.35g,4.75mmol)和双联频哪醇硼酸酯(2.17g，8.55mmol)溶于50mL二氧六环中,然后依次加入X-phos(452.2mg，0.9 5mmol)、乙酸钾(932.33mg,9.5mmol)以及Pd2(dba)3(435mg,0.475mmol),氮气保护下，将反应液缓慢升至90℃搅拌5h。待原料反应完全后，将反应液降至室温，减压浓缩后经纯化得到1.33g产物。Ms[M+H]+377.2
5、C1-6的合成
将C1-5(1.1g,2.92mmol)和int3(1.21g，3.51mmol)溶于50mL的二氧六环中,然后依次加入碳酸钠(0.93g,8.76mmol)以及Pd(dppf)Cl2(107mg,0.146mmol)，氮气保护下，将反应液缓慢升至90℃搅拌5h。待原料反应完全后，将反应液降至室温，饱和食盐水稀释，然后用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到1.28g产物。Ms[M+H]+446.2 1H NMR(400MHz,DMSO-d6)δ8.06(d,J＝8.3Hz,1H),7.86(d,J＝1.7Hz,1H),7.37(dd,J＝8.4,1.7Hz,1H),5.47(s,1H),4.10(s,1H),3.92-3.94(m,2H),3.18(s,3H),3.06(dd,J＝2.3,8.8Hz,1H),2.74(d,J＝9.0Hz,2H),2.46-2.27(m,3H),2.25(s,3H),2.13(t,2H),1.96-1.80(m,2H),1.07(s,9H).
6、C1-7的合成
将C1-6(1.2g,4.5mmol)溶于10mL三氟乙酸中，30℃下反应1h。待原料反应完全后，将反应体系降至室温,减压浓缩后，加入饱和碳酸氢钠调至pH＝8， 然后用二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后得到粗产物844mg。Ms[M+H]+346.2
7、C1-8的合成
将C1-7(844mg,2.45mmol)溶于10mL甲醇中，加入硼氢化钠(186mg,4.89mmol)30℃下反应1h。待原料反应完全后，将反应体系降至室温，减压浓缩后，反应液用饱和食盐水稀释，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后得到粗产物1.0g。Ms[M+H]+348.1 1H NMR(400MHz,DMSO-d6)δ8.04(d,J＝8.2Hz,1H),7.99(s,1H),7.54-7.47(m,1H),3.64(d,J＝10.9Hz,1H),3.04(d,J＝11.2Hz,1H),2.75(d,J＝9.0Hz,2H),2.33(d,J＝12.8Hz,2H),2.26(s,3H),2.13(d,J＝11.8Hz,2H),1.77(d,J＝12.8Hz,3H),1.56(s,1H),1.39(d,J＝12.1Hz,2H),0.85(d,J＝6.6Hz,3H).
8、C1-9的合成
将C1-8(100mg,0.5mmol)溶于5mL N，N-二甲基甲酰胺中，依次加入三乙胺(101mg,1mmol)，化合物8(260mg,0.75mmol)，最后加入六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(390mg,0.75mmol)，30℃下搅拌1h。待原料反应完全后，将反应体系降至室温，减压浓缩后，反应液用饱和食盐水稀释，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后得到经纯化得到220mg产物。
9、C1和C2的合成
将化合物C1-9通过手性高效液相色谱分离制备分别得到化合物C1和C2。C1：Ms[M+H]+532.3 1H NMR(400MHz,DMSO-d6)δ8.18(d,J＝8.5Hz,1H),7.98(s,1H),7.81(s,1H),7.72(d,J＝1.5Hz,1H),7.48(dd,J＝5.6,1.4Hz,3H),6.47(s,2H),4.05(s,1H),3.76(s,1H),3.15(d,J＝13.3Hz,1H),2.82-2.64(m,2H),2.47-2.27(m,4H),2.25(s,3H),2.23(s,3H),2.15(t,2H),2.04-1.91(m,1H),1.82(s,1H),1.68(d,J＝13.3Hz,1H)1.36(d,J＝13.2Hz,1H),1.23(s,2H),0.99(d,J＝6.9Hz,3H).
C2：Ms[M+H]+532.3 1H NMR(400MHz,DMSO-d6)δ8.18(d,J＝8.5Hz,1H),7.98(s,1H),7.81(s,1H),7.71(d,J＝1.5Hz,1H),7.48(dd,J＝5.6,1.4Hz,3H),6.47(s,2H),3.76(s,1H),3.15(d,J＝13.3Hz,1H),2.77(d,J＝10.2Hz,2H),2.38-2.27(m,4H),2.25(s,3H),2.21(s,3H),2.14(t,2H),2.07-1.92(m,1H),1.82(s,1H),1.70(t,1H),1.36(d,J＝13.2Hz,1H),1.23(s,2H),0.99(d,J＝6.9Hz,3H).
分离条件如下：
仪器：Agilent 1260 Ⅱ
色谱柱：Phenomenex5μm Amylose-1(250 X 30mm)
流动相：正己烷:乙醇＝75:25
流速15mL/min，检测波长：254nm
柱温：25℃，溶剂：乙醇
进样浓度：20mg/mL，进样量：200μL
出峰时间：22.556min(C1)、26.334min(C2)
采用上述合成方法合成下表中化合物：

实施例2
本发明的化合物
合成路线及实验过程如下：
1、C7-3的合成
将C7-1(10g,35.33mmol)和C7-2(7.38g,35.33mmol)溶于120mL四氢呋喃中，依次加入碘化亚铜(1.34g,7.07mmol)、四三苯基膦钯(4g,3.5mmol)和三乙胺(15mL,106mmol)，氮气保护下,室温搅拌20h。待原料反应完全后,抽滤，滤液减压浓缩后经纯化得到4.3g产物。Ms[M+H]+365.1。1H NMR(400MHz,DMSO-d6)δ8.65(dd,J＝2.4,0.8Hz,1H),8.04(dd,J＝8.4,2.5Hz,1H),7.45(dd,J＝8.4,0.8Hz,1H),3.70-3.58(m,2H),3.18-3.06(m,2H),2.94-2.85(m,1H),1.89-1.79(m,2H),1.57-1.48(m,2H),1.40(s,9H).
2、C7-4的合成
向新制的int10(4eq)二氯甲烷溶液(60mL)中，冰水浴冷却下缓慢滴加溶于25mL二氯甲烷的C7-3(3.1g,8.5mmol)溶液,滴加完毕，继续搅拌1.5h。加石油醚时有固体析出，抽滤，滤饼减压干燥得1.5g产物。
3、C7-5的合成
冰水浴冷却下，将C7-4(1.5g,3.9mmol)溶解到15mL N,N-二甲基甲酰胺中，缓慢加入碳酸钾(1g,7.9mmol),将反应继续搅拌1h。反应结束后，冰水浴 下，加水淬灭反应，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到1.23g产物。Ms[M+H]+324.0。1H NMR(400MHz,DMSO-d6)δ8.98-8.93(m,1H),7.58(dd,J＝9.4,0.8Hz,1H),7.28(dd,J＝9.3,1.7Hz,1H),6.52(s,1H),4.06-3.95(m,2H),3.01-2.83(m,3H),1.99-1.89(m,2H),1.60-1.49(m,2H),1.41(s,9H).
4、C7-6的合成
将C7-5(1.23g,3.25mmol)溶于8mL甲醇中，冰水浴冷却下加入4M的盐酸-二氧六环溶液(8mL)，于50℃反应30min。待原料反应完全后，直接减压浓缩得到1.3g粗品产物。
5、C7-7的合成
冰水浴冷却下，将C7-6(900mg,3.25mmol)溶解到33mL的甲醇中，加入37％甲醛的甲醇溶液(800mg,9.76mmol)，以及乙酸(0.55mL,9.76mmol)，乙酸钠(295mg,3.58mmol),反应0℃反应1h,然后加入氰基硼氢化钠(410mg,6.5mmol),将反应继续搅拌1h。反应结束后，冰水浴冷却下，反应液用饱和碳酸氢钠溶液淬灭，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到650mg产物。Ms[M+H]+294.0。1H NMR(400MHz,DMSO-d6)δ9.00-8.97(m,1H),7.60(dd,J＝9.3,0.8Hz,1H),7.30(dd,J＝9.4,1.7Hz,1H),6.53(s,1H),3.11(d,J＝11.8Hz,2H),2.97-2.83(m,1H),2.81-2.70(m,1H),2.46(s,3H),2.12-2.00(m,2H),1.91-1.81(m,2H),1.75-1.64(m,1H).
6、C7-8的合成
将C7-7(300mg,1.02mmol)，int9(500mg,1.53mmol)，碳酸钠(325mg,3.06mmol)以及[1,1'-双(二苯基膦)二茂铁]二氯化钯(37mg,0.51mmol)，溶于12mL二氧六环和3mL水组成的混合溶剂中，氮气保护下，反应液升至85℃反应1.5h。原料反应完全后，将反应体系降至室温，抽滤，滤饼用乙酸乙酯洗涤，滤液减压浓缩后经纯化得到160mg产物。Ms[M+H]+411.0
7、C7-9的合成
冰水浴冷却下，将C7-8(160mg,0.45mmol)溶于5mL二氯甲烷中，缓慢加入2mL三氟乙酸，室温搅拌1.5h。待原料反应完全后，减压浓缩，所得残 渣用饱和碳酸氢钠调节pH＝8，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后得到140mg粗品产物。
8、C7-10的合成
冰水浴冷却下，将C7-9(160mg,0.45mmol)溶于甲醇(6mL)中，缓慢加入硼氢化钠(34mg,0.9mmol)，反应液于0℃搅拌5min。待原料反应完全后，冰水浴冷却下，加水淬灭反应，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到60mg粗产物。Ms[M+H]+313.2
9、C7-11的合成
将C7-10(60mg,0.19mmol)溶于5mL N,N-二甲基甲酰胺中，依次加入INT4(60mg,0.29mmol),三乙胺(60mg,0.57mmol)和N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(108mg,0.29mmol),将体系室温搅拌5h。待原料反应完全后，反应液减压浓缩后得到粗品产物。Ms[M+H]+497.1。
10、C7和C8的合成
将化合物C7-11通过手性高效液相色谱分离制备分别得到化合物C7和C8。分离条件如下：
仪器：Agilent 1260 Ⅱ
色谱柱：Phenomenex5μm Amylose-1(250 X 30mm)
流动相：正己烷:乙醇(0.1％二乙胺)＝3:7
流速15mL/min，检测波长：254nm
柱温：25℃，溶剂：乙醇
进样浓度：12mg/mL，进样量：700μL
出峰时间：19.04min(C7)、14.65min(C8)
C7：Ms[M+H]+497.1 1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),7.81(s,1H),7.71(s,1H),7.63(d,J＝9.3Hz,1H),7.55-7.41(m,2H),7.18-7.07(m,1H),6.46(d,J＝15.3Hz,3H),5.53(s,1H),3.72-3.60(m,1H),3.19-2.98(m,3H),2.88-2.77(m,1H),2.43(s,3H),2.26-2.21(m,4H),2.09-1.96(m,2H),1.89-1.70(m,4H),1.39-1.31(m,1H),1.26-1.22(m,1H),1.17-1.08(m,2H),0.96(d,J＝6.8Hz,3H).
C8：Ms[M+H]+497.1 1H NMR(400MHz,DMSO-d6)δ8.49(s,1H),7.82(s,1H),7.72(d,J＝1.7Hz,1H),7.64(d,J＝9.2Hz,1H),7.49(d,J＝2.3Hz,2H),7.19-7.11(m,1H),6.50(s,2H),6.46(s,1H),5.54(s,1H),3.74-3.64(m,1H),3.19-3.06(m,3H),2.90-2.80(m,1H),2.44(s,3 H),2.22(s,3H),2.15(s,1H),2.10-2.01(m,2H),1.90-1.72(m,4H),1.41-1.33(m,1H),1.27-1.22(m,1H),1.16-1.09(m,2H),0.97(d,J＝6.7Hz,3H).
实施例3
本发明的化合物
合成路线及实验过程如下：
1、C9-2的合成
将int6(680mg,1.97mmol)和C9-1(400mg,1.64mmol)溶于9mL的1,4二氧六环和3mL水组成的混合溶剂中，然后依次加入碳酸钠(521mg,4.92mmol)以及Pd(dppf)Cl2(59.94mg,0.082mmol)，氮气保护下，将反应液缓慢升至90℃搅拌2h。待原料反应完全后，将反应液降至室温，加入饱和食盐水稀释，然后用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到470mg产物。Ms[M+H]+314.1。1H NMR(400MHz,DMSO-d6)δ8.44(d,J＝1.4Hz,1H),7.96(d,J＝2.3Hz,1H),7.64(d,J＝9.2Hz,1H),7.04(dd,J＝9.1,1.6Hz,1H),6.59(d,J＝2.2Hz,1H),5.5(t,1H),4.65-4.59(m,1H),2.93(dd,J＝13.0,6.6Hz,1H),2.22-2.16(m,2H),1.82-1.63(m,2H),1.20-1.14(m,3H),1.01(s,9H).
2、C9-3的合成
将C9-2(450mg,1.44mmol)溶于5mL三氟乙酸中，室温反应1h。待原料反应完全后，将反应体系减压浓缩后，所得残渣中加入饱和碳酸氢钠溶液调至pH＝8，然后用二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后得310mg粗产物。Ms[M+H]+214.1
3、C9-4的合成
将C9-3(280mg,1.31mmol)溶于10mL甲醇中，加入硼氢化钠(99.9mg,2.63mmol)冰水浴冷却下反应1h。待原料反应完全后，将反应体系降至室温，减压浓缩蒸去溶剂后，反应液用饱和食盐水稀释，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩后经纯化得到产物270mg。Ms[M+H]+216.1。1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),7.93(d,J＝2.3Hz,1H),7.62(dd,J＝9.2,0.9Hz,1H),7.24(dd,J＝9.1,1.5Hz,1H),6.54(dd,J＝2.3,0.9Hz,1H),3.64(dd,J＝11.0,2.6Hz,1H),2.74-2.71(m,1H),1.85-1.68(m,2H),1.61-1.54(m,1H),1.52-1.38(m,1H),1.34-1.21(m,2H),1.04(d,J＝6.2Hz,3H).
4、C9-5的合成
将C9-4(100mg,0.47mmol)溶于5mL N，N-二甲基甲酰胺中，依次加入三乙胺(140.9mg,1.39mmol)、int4(190.82mg,0.94mmol)，最后加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(357mg,0.94mmol)，70℃下搅拌5h。待原料反应完全后，将反应体系降至室温，减压蒸去溶剂DMF后，加入乙酸乙酯稀释，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后得到经纯化得到80mg产物。
5、C9和C10的合成
将化合物C9-5通过手性高效液相色谱分离制备分别得到化合物C9和C10。分离条件如下：
仪器：Agilent 1260 Ⅱ
色谱柱：Phenomenex5μm Cellulose-4(250 X 21.2mm)
流动相：正己烷:乙醇＝40:60
流速15mL/min，检测波长：254nm
柱温：25℃，溶剂：异丙醇
进样浓度：15mg/mL，进样量：600μL
运行时间：34min
出峰时间：17.08min(C9)、27.77min(C10)
C9：Ms[M+H]+401.2 1H NMR(400MHz,DMSO-d6)δ8.8(s,1H),8.63(s,1H),7.95(d,J＝23.1Hz,2H),7.69(d,J＝9.3Hz,1H),7.25(d,J＝9.3Hz,2H),6.58(s,1H),5.82(d,J＝48.7Hz,2H),4.23(s,1H),2.61(s,1H),2.29(s,3H),1.88(s,2H),1.69(d,J＝43.1Hz,2H),1.48(d,J＝12.5Hz,1H),1.2(s,1H),0.84(d,J＝6.7Hz,3H).
C10：Ms[M+H]+401.2 1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.63(s,1H),8.16-7.86(m,2H),7.77-7.40(m,2H),7.25(d,J＝9.1Hz,1H),6.58(s,1H),5.82(d,J＝46.4Hz,2H),4.18(s,1H),2.61(s,1H),2.3(s,3H),1.87(d,J＝10.9Hz,2H),1.69(d,J＝42.2Hz,2H),1.48(s,1H),1.23(s,1H),0.84(d,J＝6.7Hz,3H).
实施例4
本发明的化合物
合成路线及实验过程如下：
1、C11-2的合成
将化合物C11-1(15g,49.67mmol)溶于150mL无水四氢呋喃中，冰水浴冷却下，缓慢加入1M四丁基氟化铵的四氢呋喃溶液(53mL,52.65mmol)，加毕，保持温度继续搅拌15min。加水淬灭反应，将反应液搅拌升至室温，然后用甲基叔丁基醚萃取三次，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩后经纯化得到粗品产物，直接溶于150mL N,N-二甲基甲酰胺进行下一步反应。
2、C11-4的合成
将上一步所得C11-2的DMF溶液，冰水浴冷却下，加入含量为60％的氢化钠(3g,74.5mmol)，氮气保护下，保持温度继续搅拌30min，然后滴加100mL C11-3(17.37g,74.5mmol)的DMF溶液，将反应液升至室温搅拌3h后，加水淬灭反应，甲基叔丁基醚萃取三次，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩后经纯化得到4.18g的产物。1H NMR(400MHz,DMSO-d6)δ6.74(t,J＝2.2Hz,1H),6.64(t,J＝2.6Hz,1H),6.02(s,2H),5.93(dd,J＝2.9,2.0Hz,1H).
3、C11-6的合成
将C11-4(4.18g,26.13mmol)溶解到40mL冰乙酸中，缓慢滴加C11-5(3.1g,31.35mmol),将反应液于25℃搅拌20h。反应结束后，加水淬灭反应，乙酸乙酯萃取三次，合并有机相，于冰水浴冷却下，加饱和碳酸氢钠水溶液调至pH 8, 分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩后经纯化得到270mg的产物。1H NMR(400MHz,DMSO-d6)δ8.20(dd,J＝4.4,1.7Hz,1H),8.06(dd,J＝1.7,0.6Hz,1H),7.96-7.91(m,1H),6.75(dd,J＝9.1,4.4Hz,1H),6.69(d,J＝1.7Hz,1H).
4、C11-7的合成
将C11-6(270mg,1.38mmol)，int9(667mg,2.07mmol)，碳酸钠(438mg,4.14mmol)以及二(三苯基膦)二氯化钯(98mg,0.14mmol)加入到27mL乙二醇二甲醚和6.5mL水组成的混合溶剂中，氮气保护下，反应液升温至53℃反应1h。反应结束后，将反应体系降至室温，过滤，滤饼用乙酸乙酯洗涤，滤液减压浓缩后经纯化得到180mg产物。Ms[M+H]+314.2。1H NMR(400MHz,DMSO-d6)δ8.06(dd,J＝4.4,1.7Hz,1H),7.86(dd,J＝8.9,1.7Hz,1H),7.73(d,J＝1.7Hz,1H),6.60(dd,J＝9.0,4.4Hz,1H),6.43(d,J＝1.7Hz,1H),5.46(t,J＝3.6Hz,1H),3.89-3.82(m,1H),3.06-2.96(m,1H),2.43-2.33(m,1H),1.94-1.78(m,2H),1.07(s,9H),0.96(d,J＝6.4Hz,3H).
5、C11-8的合成
冰水浴冷却下，将C11-7(180mg,0.57mmol)溶于5mL二氯甲烷中，缓慢加入2mL三氟乙酸后，反应液室温搅拌2h。待原料反应完全后，减压蒸去溶剂，所得残渣用饱和碳酸氢钠溶液调节pH 8，然后用二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩后得到140mg粗品。Ms[M+H]+214.1
6、C11-9的合成
冰水浴冷却下，将C11-8(140mg,0.66mmol)溶于6ML甲醇中，分批加入硼氢化钠(50mg,1.31mmol)，反应液于0℃搅拌5min。待原料反应完全后，冰水浴冷却下，加水淬灭反应，反应液用二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩后经纯化得到110mg粗产物。Ms[M+H]+216.11H NMR(400MHz,DMSO-d6)δ8.09(dd,J＝4.4,1.8Hz,1H),7.88(dd,J＝9.0,1.8Hz,1H),7.79(s,1H),6.66-6.57(m,1H),6.51(s,1H),3.79-3.70(m,1H),3.09-3.00(m,1H),2.35(t,J＝11.4Hz,1H),1.97-1.89(m,1H),1.87-1.78(m,1H),1.63-1.52(m,1H),1.55-1.43(m,1H),1.23-1.09(m,1H),0.86(d,J＝6.6Hz,3H).
6、C11-10的合成
将C1-9(60mg,0.28mmol)溶于5mL N,N-二甲基甲酰胺中，依次加入int1(85mg,0.41mmol),三乙胺(85mg,0.84mmol)和N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(155mg,0.41mmol),反应液于室温搅拌3h。待原料反应完全后，反应液减压浓缩后经纯化得粗品化合物。
7、C11和C12的合成
将化合物C11-10通过手性高效液相色谱分离制备分别得到化合物C11和C12。
分离条件如下：
仪器：Agilent 1260 Ⅱ
色谱柱：Phenomenex5μm Amylose-1(250 X 21.2mm)
流动相：正己烷:乙醇(0.1％EDA)＝2:8
流速15mL/min，检测波长：254nm
柱温：25℃，溶剂：异丙醇：甲醇＝2：1
进样浓度：2mg/mL，进样量：3600μL
出峰时间：20.7min(C11)、51.0min(C12)
C11：Ms[M+H]+400.2。1H NMR(400MHz,DMSO-d6)δ8.13(dd,J＝4.4,1.7Hz,1H),7.92(dd,J＝9.0,1.8Hz,1H),7.81(d,J＝5.5Hz,2H),7.72(s,1H),7.52-7.45(m,2H),6.68-6.63(m,1H),6.50-6.42(m,3H),3.21-3.06(m,1H),2.21(s,3H),2.18-2.05(m,2H),1.85-1.72(m,2H),1.45-1.20(m,3H),1.00(d,3H).
C12：Ms[M+H]+400.2。1H NMR(400MHz,DMSO-d6)δ8.13(dd,J＝4.4,1.7Hz,1H),7.92(dd,J＝9.0,1.8Hz,1H),7.81(d,J＝5.6Hz,2H),7.72(s,1H),7.53-7.44(m,2H),6.69-6.63(m,1H),6.50-6.42(m,3H),3.23-3.11(m,1H),2.24-2.18(m,3H),2.18-2.03(m,2H),1.86-1.71(m,2H),1.43-1.20(m,3H),1.00(d,J＝6.3Hz,3H).
采用上述合成方法合成下表中化合物：


实施例5
本发明的化合物
合成路线及实验过程如下：
1、C17-2的合成
将3-甲氧基哒嗪(15.5g,0.14mol)溶于280mL的甲醇中，冰水浴冷却下 滴加丁炔二酸二甲酯(79.0g,0.56mol)，滴加完毕，升至室温搅拌27h。反应结束后，将反应液冷却至-20℃后，抽滤，用冷甲醇洗涤滤饼，然后将滤饼干燥后即得21.17g产物。Ms[M+H]+323.2
2、C17-3的合成
将C17-2(23.74g,73.73mmol)溶于240mL四氢呋喃和240mL水组成的混合溶剂中，冰水浴冷却下，加入氢氧化钾(41.44g,0.74mol)，然后反应液升至80℃搅拌4小时。反应结束后，反应液降至室温，减压浓缩后，加水稀释至澄清。冰浴下加入浓盐酸调节pH1后，过滤，滤饼水洗后真空干燥得21.36g产物。Ms[M+H]+281.0
3、C17-4的合成
将C17-3(21.36g,76.28mmol)溶于240mL的浓盐酸中，然后将反应液加热至110℃搅拌反应4小时。反应结束后，降至室温，过滤，将滤饼水洗后，真空干燥后得14.15g产物。Ms[M+H]+193.0。1H NMR(400MHz,DMSO-d6)δ12.34(s,1H),7.99(dd,J＝1.8,0.6Hz,1H),7.92(d,J＝9.6Hz,1H),6.82(d,J＝1.8Hz,1H),6.46(d,J＝9.6Hz,1H),3.90(s,3H).
4、C17-5的合成
氮气保护冰水浴冷却下，将C17-4(14.15g,73.69mmol)溶于100mL无水四氢呋喃溶液中，缓慢滴加到180mL氢化铝锂(5.60g，147.39mmol)的四氢呋喃悬浊液中，室温搅拌反应4小时。反应结束后，冰水浴冷却下加入大量无水硫酸钠后，加水淬灭反应，搅拌30分钟，过滤，滤液减压浓缩后经纯化得7.07g产物。Ms[M+H]+178.0
5、C17-6的合成
将C17-5(1.5g,8.43mmol)溶于20mL无水二氯甲烷中，加入戴斯-马丁氧化剂(5.36g，12.64mmol)，室温搅拌反应3小时。反应结束后，加入饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取三次后，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后经纯化得504mg产物。Ms[M+H]+176.0
6、C17-7的合成
氮气保护冰水浴冷却下，将C17-6(504mg,2.86mmol)溶于10mL的无水二氯甲烷中，加入int8(1.08g，2.86mmol)和烘干的4A分子筛粉末(286mg，100mg/mmol)，将反应液室温搅拌2h，TLC监测反应。反应结束后，过滤，滤液减压浓缩后得1.58g粗产物，无需纯化直接用于下一步。
7、C17-8的合成
氮气保护下,将烘干的无水三氟甲磺酸铜(1.03g,2.86mmol)悬浮于12mL六氟异丙醇中，加入2,6-二甲基吡啶(306mg,2.86mmol)，室温搅拌1h后呈蓝色浊液；再将C17-7的无水二氯甲烷溶液(10mL)滴加到反应液中，室温搅拌8h。反应结束后，加氨水淬灭反应，用二氯甲烷萃取三次，合并二氯甲烷相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后经纯化得440mg产物。Ms[M+H]+248.1
8、C17-9的合成
将C17-8(327mg,1.32mmol)和int4(403mg,1.98mmol)溶于8mL的无水N,N-二甲基甲酰胺中，室温条件下，依次加入三乙胺(0.55mL,3.96mmol)后,2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(752mg,1.98mmol)，反应液70℃搅拌3h。反应结束后，加水淬灭反应，用乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后经纯化得304mg产物。Ms[M+H]+433.2。1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),7.92(d,J＝14.0Hz,2H),7.81(d,J＝9.4Hz,1H),7.58(s,1H),6.85(s,2H),6.44(d,J＝22.0Hz,1H),6.32(d,J＝9.5Hz,1H),5.72(s,1H),4.54(d,J＝11.9Hz,1H),4.18(s,1H),3.87(s,4H),3.68(s,2H),2.27(s,3H),0.92(d,J＝6.9Hz,3H).
9、C17-10的合成
将C17-9(456mg,1.06mmol)溶于10mL的N-甲基吡咯烷酮中，室温下滴加入正十二烷硫醇(1.07g,5.30mmol)，滴加完毕，加入乙硫醇钠(445mg,5.30mmol)，升至100℃搅拌3小时。反应结束后，将反应液降至室温，加入饱和的氯化铵溶液淬灭，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，减压蒸干有机相后经纯化得272mg产物。Ms[M+H]+419.0
10、C17-11的合成
将C17-10(143mg,0.34mmol)溶于3mL无水N,N-二甲基甲酰胺中，加入三乙胺(0.14mL,1.02mol)，然后冰水浴冷却下，加入N-苯基双(三氟甲烷磺酰)亚胺(153mg,0.43mol)，升至室温搅拌1小时。反应结束后，冰水浴冷却下，滴加水淬灭反应，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，减压蒸干有机相后经纯化得187mg产物。Ms[M+H]+551.0
11、C17-12的合成
将C17-11(187mg,0.34mmol)溶于8mL的二氧六环和1.6mL的水组成的混合溶剂中，依次加入int9(152mg,0.68mmol)，1,1'-二(二苯膦基)二茂铁二氯化钯(25mg,0.03mmol)和碳酸钠(108mg,1.02mmol)，氮气保护下，将反应液加热至90℃搅拌反应3小时。反应结束后，降至室温，加水淬灭，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，减压蒸干有机相后经纯化得142mg产物。Ms[M+H]+498.0。1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),7.90(s,2H),7.88-7.57(m,2H),7.01(d,J＝9.5Hz,1H),6.87(s,2H),6.62(s,1H),6.53(s,1H),5.76(s,1H),4.58(s,1H),3.95-3.79(m,1H),3.69(s,2H),3.07(d,J＝3.5Hz,2H),2.65-2.51(m,6H),2.28(d,J＝7.1Hz,6H),0.91(d,J＝7.0Hz,3H).
12、C17的合成
将C17-12(132mg,0.27mmol)溶于5mL甲醇中，加入钯含量为10％的湿钯碳(40mg，30mol％)，置于氢气氛围下室温搅拌18小时。反应结束后，将反应液通过硅藻土过滤，甲醇洗涤滤饼，滤液减压浓缩后经纯化得18mg产物。Ms[M+H]+500.0。1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),7.95(s,1H),7.90(s,1H),7.82(d,J＝9.1Hz,1H),7.71(s,1H),6.86(s,2H),6.63(d,J＝9.3Hz,1H),6.50(s,1H),5.76(s,1H),4.56(s,1H),3.86(d,J＝11.8Hz,1H),3.69(s,2H),2.86(d,J＝10.8Hz,2H),2.51(s,2H),2.27(s,3H),2.19(s,3H),2.05-1.88(m,2H),1.86-1.63(m,4H),0.91(d,J＝7.0Hz,3H).
采用上述合成方法合成下表中化合物：




实施例6
本发明的化合物
合成路线及实验过程如下：
1、C33-2的合成
氮气保护下，将int7(834mg,2.20mmol)溶于10mL的无水二氯甲烷中，加入1,3-苯并噻唑-5-甲醛(359mg，2.20mmol)和烘干的4A分子筛粉末(220mg，100mg/mmol)，将反应液室温搅拌2h，TLC检测且反应结束后，过滤，滤液减压浓缩后得1.15g产物。
2、C33-3的合成
氮气保护下,将烘干的无水三氟甲磺酸铜(795mg,2.20mmol)悬浮于8.80mL六氟异丙醇中，加入2,6-二甲基吡啶(235mg,2.20mmol)，室温搅拌1h后呈蓝绿色浊液；再将C33-2(1.15g,2.20mmol)的无水二氯甲烷溶液(10mL)滴加到反应液中，室温搅拌18h。反应结束后，加氨水淬灭反应，用二氯甲烷萃取三次，合并二氯甲烷相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后经纯化得417mg产物。Ms[M+H]+235.0。1H NMR(400MHz,Chloroform-d)δ9.01(s,1H),8.18(d,J＝1.6Hz,1H),7.92(d,J＝8.3Hz,1H),7.51(dd,J＝8.4,1.6Hz,1H),4.07(dd,J＝10.2,3.2Hz,1H),3.93(dd,J＝11.2,3.2Hz,1H),3.78-3.71(m,1H),3.53(t,J＝10.7Hz,1H),3.10(dd,J＝11.7,2.4Hz,1H),2.80(dd,J＝11.6,10.1Hz,1H),1.22(d, J＝6.3Hz,3H).
3、C33的合成
将C33-3(117mg,0.50mmol)和int1(131mg,0.65mmol)溶于4mL的超干N,N-二甲基甲酰胺中，室温加入三乙胺(101mg,2.0mmol)后,然后分批加入1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(390mg,0.75mmol)，再将反应液室温搅拌1h。反应结束后，加水稀释，用乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后，加入甲醇打浆半小时，过滤，滤饼真空干燥后经纯化得38mg产物。Ms[M+H]+419.1。1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.21-8.11(m,2H),7.80(s,1H),7.75(d,J＝1.7Hz,1H),7.55(dd,J＝8.4,1.7Hz,1H),7.53-7.43(m,2H),6.50(s,2H),5.37(t,J＝4.6Hz,1H),4.18(dd,J＝12.4,4.4Hz,1H),4.11-3.96(m,2H),3.66-3.56(m,1H),3.50(d,J＝13.5Hz,1H),2.21(d,J＝1.1Hz,3H),1.19(d,J＝6.5Hz,3H).
采用同样的合成方法合成了化合物C34，如下所示：
C34：Ms[M+H]+402.1。1H NMR(400MHz,DMSO-d6)δ8.70(t,1H),8.00(d,J＝2.3Hz,1H),7.80(s,1H),7.75(d,J＝1.7Hz,1H),7.70(dd,J＝9.2,0.9Hz,1H),7.55-7.39(m,2H),7.25(dd,J＝9.2,1.6Hz,1H),6.60(dd,J＝2.3,0.9Hz,1H),6.51(s,2H),5.29(t,J＝4.4Hz,1H),4.15(dd,J＝12.4,4.3Hz,1H),4.09-3.98(m,2H),3.58(dd,J＝13.7,4.1Hz,1H),3.44(dd,J＝13.6,3.2Hz,1H),2.21(d,J＝1.1Hz,3H),1.18(d,J＝6.5Hz,3H).
细胞增殖抑制试验
一、实验材料

二、实验方案
1、细胞铺板
a)制备细胞悬液
b)去除培养瓶中的培养基；
c)用PBS润洗细胞一遍；
d)加胰酶消化离心收集；
e)用培养基重悬，计数并调整到合适浓度。
f)将细胞悬液加入96孔板每孔体积100uL，每种细胞铺一块板子。37℃,5％CO2培养箱中培养过夜。
2、化合物处理
化合物稀释
a)配制受测化合物梯度稀释溶液：以10mM为储液。然后用2.5μL储液溶解于497.5μL无DMSO培养液中，再以0.1％DMSO培养液进行4倍连续梯度稀释，共9个浓度，稀释后化合物浓度如下：
50000nM，12500nM，3125nM，781.25nM，195.31nM，48.82nM，12.2nM，3.05nM，0.76nM
b)充分混匀后分别取25μL化合物溶液加入含有100μL细胞的细胞培养板中，每个浓度3个复孔。化合物最终浓度如下：
10000nM，2500nM，625nM，156.25nM，39.06nM，9.77nM，2.44nM，0.61nM，0.15nM
c)将细胞转移至培养箱孵育3天，贴壁细胞再进行换液，吸走上清，每孔加入100μL培养基，再按以上化合物稀释方式，加入25μL化合物溶液。悬浮细胞进行补液，加入等浓度的化合物溶液。
d)将细胞转移至培养箱孵育4天。
3、CTG检测
a)取出细胞培养板在96孔板中加入25μL CTG,室温摇床10分钟，读板。
4、数据分析
使用如下公式计算存率(％Cell Survival):
％Cell Survival＝100％×(OD_Sample-OD_LCave)/(OD_HC-OD_LCave)
OD_HC：0.1‰DMSO对照组细胞读数
OD_Sample：加入化合物的细胞读数
OD_LC：空白培养基读数
Analyed by Prizm：Dose-response-Inhibition-Log(inhibitor)vs response(three parameters for the best fit)。
细胞增殖抑制试验结果如下表1。
表1

A表示IC50≤100nM；B表示100nM＜IC50≤1000nM；C表示1000nM＜IC50≤5000nM；D表示5000nM＜IC50
实验结果表明：对于非MTAP缺失的细胞系HCC70，实施例化合物抑制作用不明显，而对MTAP缺失的细胞系LN-18，实施例化合物则活性较好，表现出了化合物良好的选择性。
酶活性测试
试剂耗材
准备化合物：
按照下表中实验方案准备化合物。
实验步骤：
a)药物按参考浓度稀释，并将稀释溶液作为第一点，一次稀释3倍，一共10+0个点。
b)将20nL化合物转移到384板，每列有2个重复孔。将384分析板在1000rpm下离心。
c)每孔加入2μL PRMT5/MEP50和MTA溶液，25℃孵育15min。
d)每孔加入2μL Bio-H4(1-21)和SAM溶液，25℃孵育180min。
e)每孔加1μL 5X MTase-GloTM试剂,384板在1000rpm下离心。
f)25℃孵育30分钟。
g)每孔加入5μL MTase-GloTM检测液，384板1000rpm下离心。
h)25℃孵育30分钟。
i)用读板式发光计测量发光。
数据分析：
由非线性回归方程拟合化合物IC50：
％inh＝100％-(cmpds-Low control)/(Low control-high control)*100％
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hillslope))
X：化合物浓度的Log值
Y：比665/615nm
Top and Bottom：与Y单位相同的高原
LogIC50：与X相同的单位
Hillslop：斜率因子或坡度
酶活性试验结果如下表。
表2
A表示IC50≤10nM；B表示10nM＜IC50≤50nM；C表示50nM＜IC50≤500nM；D表示500nM＜IC50；ND：未检测
实验结果表明：在高浓度的MTA下，本专利的化合物表现出对PRMT5.MTP复合物的较好的抑制活性，与正常浓度的MTA对照表现出良好的选择性。
本发明提供了一种具有优异的PRMT5活性和选择性的系列化合物，该系列化合物对MTAP缺失的细胞具有良好的抑制作用和选择性，具有广泛的应用前景。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种化合物，其特征在于，所述化合物为式(Ⅰ)化合物、或其药学上可接受的盐、立体异构体，
    其中：
    R选自下组：H、-NH2、C1-3烷基、-OC1-3烷基、C1-3氟代烷基、-OC1-3氟代烷基；
    R1选自取代或未取代的下组基团：单环组A、双环组B；所述单环组A选自下组：C3-8环烷基、C5-8芳基、含1-4个选自N、O或S的杂原子的3-8元杂环基、含1-4个选自N、O或S的杂原子的5-8元杂芳基；所述双环组B选自下组：C5-12环烷基、C8-12芳基、含1-4个选自N、O或S的杂原子的5-12元杂环基、含1-4个选自N、O或S的杂原子的8-12元杂芳基；其中，当被取代时，所述取代各自独立地指被Ra1取代；
    R2选自下组：H、卤素、-CN、C1-6烷基、-ORa2；或者R2与其所连接的C一起形成C3-6环烷基或含有1-4个选自N、O或S的杂原子的3-6元杂环烷基；其中，所述烷基、环烷基、杂环烷基任选地被选自下组的取代基取代：氘、卤素、-CN、-OH、C1-3烷基、C1-3烷氧基、C1-3氟代烷基、C1-3氟代烷氧基、C3-5环烷基、含有1-2个选自N、O或S的杂原子的4-6元杂环烷基；
    各R3独立地选自下组：H、氘、＝O、卤素、-CN、C1-6烷基、含有1-2个选自N、O或S的杂原子的C1-6杂烷基、-ORa3、-N(Ra3)2，其中，所述烷基、杂烷基任选地被选自下组的取代基取代：氘、卤素、-CN、-OH、C1-3烷基、C1-3烷氧基、C1-3氟代烷基、C1-3氟代烷氧基；
    或者，两个R3与其所连接的原子或者R3与连接在其所连接的氮杂环上的基团一起形成3-10元碳环或杂环，所述碳环或杂环与所述氮杂环形成桥环、并环或螺环；
    R4选自下组：H、氘、卤素、-CN、C1-3烷基、C2-6炔基、C3-5环烷基、含有1-4个选自N、O或S的杂原子的3-6元杂环烷基、-ORa4、-C(＝O)N(Ra4)2、-S(＝O)2N(Ra4)2，其中，所述烷基、环烷基、杂环烷基任选地被选自下组的基团取代：氘、卤素、-CN、-OH、C1-3烷基、C1-3氟代烷基；
    R5选自下组：H、氘、卤素、-CN、C1-3烷基、C3-5环烷基、含有1-4个选自N、O或S的杂原子的3-6元杂环烷基、-ORa5，其中，所述烷基、环烷基、杂环烷基任选地被选自下组的基团取代：氘、卤素、-CN、-OH、 C1-3烷基、C1-3氟代烷基；
    各x1、x2、x3、x4独立地选自下组：O、C(Ra6)m、N(Ra6)m；
    各Ra2、Ra3、Ra4、Ra5独立地选自下组：H、C1-6烷基、含有1-2个选自N、O或S的杂原子的C1-6杂烷基、C3-6环烷基、含有1-2个选自N、O或S的杂原子的3-7元杂环基，其中，所述烷基、杂烷基、环烷基、杂环基任选地被1、2或3个Rb1取代；
    各Rb1独立地选自下组：＝O、卤素、-CN、C1-6烷基、含有1-2个选自N、O或S的杂原子的C1-6杂烷基、C1-6卤代烷基、-ORc1、-N(Rc1)2；
    各Rc1独立地选自下组：H、C1-6烷基、C3-6环烷基；
    各Ra1独立地选自下组：氘、卤素、-CN、＝O、-OH、C1-6烷基、含有1-2个选自N、O或S的杂原子的C1-6杂烷基、C1-6卤代烷基、-L-C3-9环烷基、-L-(含1-4个选自N、O或S的杂原子的饱和或部分饱和的3-10元杂环基)、-L-C6-10芳基、-L-(含1-4个选自N、O或S的杂原子的5-10元杂芳基)、-O-L-(含1-4个选自N、O或S的杂原子的3-10元杂环基)、-ORb2、-N(Rb2)2、-L-N(Rb2)2、-C(＝O)Rb2、-C(＝O)ORb2、-P(＝O)(Rb2)2、-NRb2C(＝O)Rb2、-NRb2C(＝O)ORb2、-C(＝O)N(Rb2)2、-OC(＝O)N(Rb2)2、-S(＝O)Rb2、-S(＝O)2Rb2、-SRb2、-S(＝O)(＝NRb2)Rb2、-NRb2S(＝O)2Rb2、-S(＝O)2N(Rb2)2，其中，所述烷基、杂烷基、环烷基、杂环基、芳基、杂芳基任选地被选自下组的取代基取代：＝O、氘、卤素、-CN、-OH、-NH2、-NHC1-3烷基、-N(C1-3烷基)2、C1-6烷基、C3-6环烷基、含有1-4个选自N、O或S的杂原子的3-6元杂环基、-OC1-6烷基、含有1-2个选自N、O或S的杂原子的C1-6杂烷基、-OC1-6卤代烷基、C1-6卤代烷基、含有1-2个选自N、O或S的杂原子的C1-6卤代杂烷基、-C(＝O)Me、-C(＝O)NHMe、-NHC(＝O)Me；
    各Rb2独立地选自下组：H、C1-6烷基、C1-6卤代烷基、被0-1个＝O取代的含有1-2个选自N、O或S的杂原子的C1-6杂烷基、C3-9环烷基、任选地被＝O或-CH3取代的含1-4个选自N、O或S的杂原子的3-10元杂环基；
    各L独立地为键或C1-6亚烷基，其中，所述C1-6亚烷基任选地被选自下组的取代基取代：氘、卤素、-CN、-OH、C1-3烷基、C1-3烷氧基、C1-3氟代烷基、C1-3氟代烷氧基；
    各Ra6独立地选自下组：H、氘、卤素、-CN、C1-3烷基、C1-3氟代烷基、C1-3烷氧基、C1-3氟代烷氧基；
    各m独立地选自下组：0、1、2；
    n选自下组：0、1、2、3。
  2. 如权利要求1所述的化合物，其特征在于，所述化合物具有选自下组所示结构：
    其中，R1、R2、R3、R4、R5、x1、x2、x3、x4、R、n如权利要求1所定义。
  3. 如权利要求2所述的化合物，其特征在于，所述化合物具有选自下组所示结构：
    其中，R1、R2、R3、R4、x2如权利要求1所定义。
  4. 如权利要求3所述的化合物，其特征在于，R1选自取代或未取代的双环组B，其中，当被取代时，所述取代各自独立地指被Ra1取代；
    所述化合物具有选自下组所示结构：
    其中，R2、R3、R4、Ra1、x2如权利要求1所定义。
  5. 如权利要求1所述的化合物，其特征在于，所述单环组A具有选自下组的结构：
    所述双环组B具有选自下组的结构：
  6. 如权利要求1所述的化合物，其特征在于，Ra1中所述环烷基具有选自下组的结构：
    Ra1中所述杂环基具有选自下组的结构：
    Ra1中所述杂芳基具有选自下组的结构：
  7. 如权利要求1所述的化合物，其特征在于，R选自下组：H、-NH2、C1-3烷基、-OC1-3烷基；
    R2选自下组：H、C1-6烷基、-ORa2；或者R2与其所连接的C一起形成C3-6环烷基或含有1-4个选自N、O或S的杂原子的3-6元杂环烷基；Ra2如权利要求1所定义；
    R3选自下组：H、卤素、C1-6烷基；或者，两个R3与其所连接的原子或者R3与连接在其所连接的氮杂环上的基团一起形成3-10元碳环或杂环；
    R4选自下组：卤素、-CN、C1-3烷基、C2-6炔基、C3-5环烷基、含有1-4个选自N、O或S的杂原子的3-6元杂环烷基、-ORa4、-C(＝O)N(Ra4)2、-S(＝O)2N(Ra4)2；Ra4如权利要求1所定义；
    R5选自下组：H、卤素、-CN、C1-3烷基。
  8. 如权利要求1所述的化合物，其特征在于，所述化合物选自下组：











  9. 一种药物组合物，其特征在于，包含治疗有效量的一种或多种权利要求1所述的化合物以及药学上可接受的载体。
  10. 一种权利要求1所述的化合物的用途，其特征在于，用于制备用于调节PRMT5活性或治疗PRMT5相关疾病的药物。
PCT/CN2023/117714 2022-09-08 2023-09-08 双环类prmt5抑制剂 WO2024051816A1 (zh)

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