Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/26—Androgens
• • 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
• • 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
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • 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
  • A61P35/04—Antineoplastic agents specific for metastasis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—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
  • 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
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/08—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
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• R D is selected from H, CN, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, the C 1-6 alkyl , C 1-6 alkoxy, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
• R 1 is selected from H, F, Cl, Br, I and C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted with 1, 2 or 3 R;
• G is selected from H, F, Cl, Br, I, and C 1-6 alkyl, the C 1-6 alkyl is optionally substituted with 1, 2 or 3 R;
• Each R D1 , R D2 , and R D3 is independently selected from H, CN, halogen, C 1-6 alkyl and C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 alkoxy The group is optionally substituted with 1, 2 or 3 R;
• R is independently selected from H, F, Cl, Br, I, OH, NH 2 and C 1-6 alkyl, the C 1-6 alkyl is optionally substituted with 1, 2 or 3 R′;
• the present invention also provides compounds represented by formula (III-A-1) or formula (III-A-2), their optical isomers and their pharmacologically acceptable salts, wherein, R 1 , R 3 , R 4 , R D1 , R D2 , R D3 , G, L 1 , L 2 , L 3 , X 1 , X 2 , X 3 , X 4 are as defined in the present invention.
• the present invention also proposes the compound represented by formula (I-A), its optical isomers and their pharmacologically acceptable salts,
• R 1 is selected from H, F, Cl, Br, I and C 1-6 alkyl, and the C 1-6 alkyl is optionally substituted with 1, 2 or 3 R;
• R is independently selected from H, F, Cl, Br, I, OH, NH 2 and C 1-6 alkyl, the C 1-6 alkyl is optionally substituted with 1, 2 or 3 R′;
• the present invention also provides compounds represented by formula (I-B), their optical isomers and their pharmacologically acceptable salts,
• G is selected from H, F, Cl, Br, I, and C 1-6 alkyl, the C 1-6 alkyl is optionally substituted with 1, 2 or 3 R;
• Each R D1 , R D2 , and R D3 is independently selected from H, CN, halogen, C 1-6 alkyl and C 1-6 alkoxy, the C 1-6 alkyl or C 1-6 alkoxy The group is optionally substituted with 1, 2 or 3 R;
• R D4 are each independently selected from H, CN, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, the C 1- 6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
• R' is independently selected from H, halogen, C 1-6 alkyl, OH, NH 2 , CH 3 , CH 2 F, CHF 2 and CF 3 ;
• R 2 is selected from H, methyl and ethyl, and other variables are as defined in the present invention.
• the above-mentioned ring B is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, and the phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally Replaced by 1, 2 or 3 R, other variables are as defined in the present invention.
• the group, 4-8 membered heterocycloalkyl group, phenyl group or 5-6 membered heteroaryl group is optionally substituted with 1, 2 or 3 RL , and other variables are as defined in the present invention.
• the 1-3 alkylamino group is optionally substituted with 1, 2 or 3 R', and other variables are as defined in the present invention.
• the present invention also proposes the use of the aforementioned compounds, their optical isomers and their pharmacologically acceptable salts in the preparation of drugs for the prevention and/or treatment of cancer or Kennedy’s disease .
• the present invention also proposes a method for treating cancer (such as prostate cancer and breast cancer, etc.) or Kennedy's disease.
• the method includes administering the aforementioned compounds, optical isomers, and pharmacologically acceptable salts thereof to the patient.
• pharmaceutically acceptable salt refers to the salt of the compound of the present invention, which is prepared from the compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
• the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a base in a pure solution or a suitable inert solvent.
• Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
• the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a solution or a suitable inert solvent.
• the organic acid includes such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid , Suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and other similar acids; also includes amino acids (such as arginine Acids, etc.), and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, which can be converted into any base or acid addition salt.
• the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
• the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
• Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
• the compound of the present invention may be specific.
• tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached.
• proton tautomer proton tautomer
• proton transfer tautomer includes interconversion through proton migration, such as keto-enol isomerization and imine-ene Amine isomerization.
• Valence isomers include some recombination of bond electrons to carry out mutual transformation.
• keto-enol tautomerization is the tautomerization between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one, or For example It is a tautomer.
• the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
• the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
• the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
• compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
• deuterium can be substituted for hydrogen to form deuterated drugs.
• the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
• deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
• “Optional” or “optionally” means that the event or condition described later may but does not necessarily occur, and the description includes a situation in which the event or condition occurs and a situation in which the event or condition does not occur.
• the valence bond of the group has a dotted line
• the dashed line indicates the point of attachment of the group to other parts of the molecule.
• the dotted line represents a single bond or does not exist, which also means Represents a single key Or double bond
• any variable such as R
• its definition in each case is independent.
• said group may optionally be substituted with 1 or 2 or 3 R', and R'in each case All have independent options.
• substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
• substituents When the listed substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
• a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
• the number of atoms in a ring is generally defined as the number of ring members.
• “3-6 membered ring” refers to a “ring” in which 3-6 atoms are arranged around.
• C 1-4 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 4 carbon atoms.
• the C 1-4 alkyl group includes C 1-2 , C 1-3 , C 3-4 and C 2-3 alkyl group, etc.; it can be monovalent (such as CH 3 ), divalent (-CH 2- ) Or multi-price (like times ).
• Examples of C 1-4 alkyl include but are not limited to CH 3 , Wait.
• C 2-3 alkenyl is used to mean a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, and a carbon-carbon double bond It can be located at any position of the group.
• the C 2-3 alkenyl group includes C 3 and C 2 alkenyl groups; the C 2-3 alkenyl group may be monovalent, divalent or multivalent. Examples of C 2-3 alkenyl include but are not limited to Wait.
• C 2-3 alkynyl is used to mean a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, and a carbon-carbon triple bond It can be located in any position of the group. It can be univalent, bivalent, or multivalent.
• the C 2-3 alkynyl group includes C 3 and C 2 alkynyl groups. Examples of C 2-3 alkynyl include but are not limited to Wait.
• C 1-6 alkoxy examples include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) Oxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy and the like.
• C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
• the C 1-3 alkoxy group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkoxy and the like.
• Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
• C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group.
• the C 1-3 alkylamino group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkylamino group and the like.
• Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 ,- NHCH 2 (CH 3 ) 2 and so on.
• C 1-6 alkylthio refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through a sulfur atom.
• the C 1-6 alkylthio group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkane Sulfur-based etc.
• Examples of C 1-6 alkylthio include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 and the like.
• C 1-3 alkylthio refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through a sulfur atom.
• the C 1-3 alkylthio group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkylthio and the like.
• Examples of C 1-3 alkylthio include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 and the like.
• C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
• Examples of C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
• C 4-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 4 to 6 carbon atoms, which is a monocyclic and bicyclic ring system.
• the C 4-6 cycloalkyl includes C 4-5 , C 4-6 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
• Examples of C 4-6 cycloalkyl groups include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl and the like.
• a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
• the 3-10 membered heterocycloalkyl group includes 3-9 members, 3-8 members, 3-6 members, 3-5 members, 4-6 members, 5-6 members, 4 members, 5 members and 6 members. Cycloalkyl and so on.
• 3-10 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazolidin
• the term "4-8 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 4 to 8 ring atoms, with 1, 2, 3 or 4 ring atoms.
• heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
• a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
• the 4-8 membered heterocycloalkyl group includes 4-6 membered, 5-6 membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, and the like.
• 3-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms.
• heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
• C 6-10 aromatic ring and “C 6-10 aryl” in the present invention can be used interchangeably, and the term “C 6-10 aromatic ring” or “C 6-10 aryl” means that A cyclic hydrocarbon group with a conjugated ⁇ -electron system composed of 6 to 10 carbon atoms, which can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. It may be monovalent, divalent or multivalent, and C 6-10 aryl groups include C 6-9 , C 9 , C 10 and C 6 aryl groups and the like. Examples of C 6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl, 2-naphthyl, etc.).
• 5-12 membered heteroaryl ring and “5-12 membered heteroaryl group” can be used interchangeably in the present invention.
• the term “5-12 membered heteroaryl group” means a ring consisting of 5-12 members.
• Examples of the 5-12 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thi
• 5-6 membered heteroaryl ring and “5-6 membered heteroaryl group” can be used interchangeably in the present invention.
• the term “5-6 membered heteroaryl group” means a ring consisting of 5 to 6 ring atoms. It is composed of a monocyclic group with a conjugated ⁇ -electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
• the 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
• the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
• Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,
• 5-10 membered heteroaryl ring and “5-10 membered heteroaryl group” can be used interchangeably in the present invention.
• the term “5-10 membered heteroaryl group” means a ring consisting of 5 to 10 ring atoms. It is composed of a monocyclic group with a conjugated ⁇ -electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
• Examples of the 5-10 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thi
• C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, for example, C 1- 12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; similarly, from n to n +m member means that the number of atoms in the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, and 9-membered ring, and 9
• protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
• amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
• Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl group, such as trimethylsilyl (TMS) and tert-butyldi
• hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
• Representative hydroxy protecting groups include but are not limited to: alkyl, such as methyl, ethyl and tert-butyl; acyl, such as alkanoyl (such as acetyl); arylmethyl, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
• alkyl such as methyl, ethyl and tert-butyl
• acyl such as alkanoyl (such as acetyl)
• arylmethyl such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
• the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
• the solvent used in the present invention is commercially available.
• the compound is used according to the conventional naming principle in the field or The software is named, and the commercially available compounds use the supplier catalog name.
• reaction solution was washed with saturated sodium bicarbonate aqueous solution (30.0 mL), water (30.0 mL), saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product of Intermediate I-1, which was directly used in the next reaction without purification.
• reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL ⁇ 3), and the organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, and the residue was separated and purified by silica gel chromatography to obtain Intermediate I-14.
• reagent 2 (777mg, 4.11mmol) was dissolved in N,N-dimethylformamide (15mL), and sodium hydride (296mg, 60% content, 7.40mmol) was added at 0°C under nitrogen protection, After stirring for 30 minutes, 4-fluoro-2-(trifluoromethyl)benzonitrile (1.00g, 4.11mmol) was added, and the mixture was stirred at 40°C for 3 hours.
• Water 50mL was added to the reaction solution, and ethyl acetate (50mL ⁇ 3) Extract, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate.
• reaction solution was diluted with water (20 mL), extracted with ethyl acetate (50 mL ⁇ 3), and the organic phase was dried and filtered. The organic solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel chromatography to obtain Intermediate I-40.
• the compound 5-fluoropyridine-2-carboxylic acid methyl ester (900 mg, 5.80 mmol) was dissolved in N,N-dimethylformamide (50 mL), and the compound 4-methanol piperidine (670 mg, 5.82 mmol) and diisopropyl were added. Propylethylamine (2.87 mL, 17.4 mmol).
• the reaction mixture was stirred at 100°C for 16 hours. After concentration, it was diluted with water (100 mL), and extracted with ethyl acetate (100 mL ⁇ 3). The organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a residue. The residue was separated and purified by silica gel chromatography to obtain intermediate I-42.
• 2,2,6,6-Tetramethylpiperidine (4.42g, 31-3mmol) was dissolved in anhydrous tetrahydrofuran (150mL), and butyllithium (1.6M) (19.6mL, 31.3) was added dropwise at -60°C mmol). After the addition was completed, the mixture was stirred and reacted under the protection of argon at -60°C for 1 hour.
• a solution of bromobenzoic acid (3.00 g, 14.9 mmol) in tetrahydrofuran (50 mL) was added dropwise at -60°C, and the mixture was stirred and reacted at -60°C under argon protection for 1 hour.
• N,N-dimethylformamide (4.36g, 59.6mmol) was added dropwise at -60°C. After the addition was completed, the mixture was slowly raised to room temperature, and stirred at room temperature for 0.5 hour. The reaction was quenched with water (500 mL) at 0°C, the product was extracted with ethyl acetate (200 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product.
• the intermediate I-57 was obtained by separation and purification by chromatography.
• hydroxylamine hydrochloride (8.69g, 125mmol) was dissolved in water (130mL), anhydrous sodium acetate (13.6g, 166mmol) was added, the mixture was stirred at room temperature for 10 minutes, and ethyl p-cyclohexanone formate (13.0 g, 83.2 mmol).
• the reaction system was protected by argon, and the reaction was stirred at 45°C for 16 hours.
• reaction solution was cooled to room temperature, the product was extracted with ethyl acetate (100mL ⁇ 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product, which was separated and purified by silica gel chromatography to obtain the intermediate I-105.
• Methyl 5-bromopyridine-2-carboxylate (10.0g, 46.3mmol) was dissolved in dry toluene (200mL), 4-piperidine methanol (10.7g, 92.6mmol), anhydrous potassium carbonate (19.2 g, 139mmol), tris(dibenzylideneacetone)dipalladium (848mg, 0.926mmol), 2-dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl (864mg , 1.85 mmol), the mixture was stirred at 100°C for 16 hours under the protection of argon.
• I-125 8.00g, 28.8mmol was dissolved in N,N-dimethylacetamide (100mL), potassium fluoride (8.36g, 143.9mmol), 18-crown-6( 3.04g, 11.5mmol), heated to 120°C and reacted for 16 hours. After cooling, add water (200 mL). The above reaction solution was extracted with ethyl acetate (100 mL ⁇ 3). The organic phases were combined, and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography to obtain Intermediate I-126.
• I-126 (1.50 g, 6.12 mmol) was dissolved in dimethyl sulfoxide (25 mL) and water (5 mL), and the temperature was raised to 100°C to react for 5 hours. After cooling, water (200 mL) was added to the reaction solution, and it was extracted with ethyl acetate (200 mL ⁇ 3). The organic phases were combined, and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Intermediate I-127.
• the crude product was first separated and purified by silica gel chromatography, and then purified by beating with anhydrous acetonitrile (15.0 mL) , Suction filtration, drying the filter cake, and finally separation and purification by preparative HPLC (containing formic acid) to obtain compound 20.
• mice show a longer T 1/2 , a higher body exposure AUC 0-inf and oral bioavailability F.

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