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WO2025067483A1 - 酰胺类化合物 - Google Patents

酰胺类化合物 Download PDF

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Publication number
WO2025067483A1
WO2025067483A1 PCT/CN2024/121910 CN2024121910W WO2025067483A1 WO 2025067483 A1 WO2025067483 A1 WO 2025067483A1 CN 2024121910 W CN2024121910 W CN 2024121910W WO 2025067483 A1 WO2025067483 A1 WO 2025067483A1
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Prior art keywords
alkyl
compound
pharmaceutically acceptable
stereoisomer
formula
Prior art date
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PCT/CN2024/121910
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English (en)
French (fr)
Inventor
张雁
焦宇
黄炼成
赵思奇
唐锋
刘乐
陈亚东
陆涛
彭少平
王峰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
China Pharmaceutical University
Jiangsu Simcere Pharmaceutical Co Ltd
Original Assignee
China Pharmaceutical University
Jiangsu Simcere Pharmaceutical Co Ltd
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Publication of WO2025067483A1 publication Critical patent/WO2025067483A1/zh
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Classifications

    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K31/435—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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
    • A61P5/28—Antiandrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles

Definitions

  • the present disclosure relates to the field of pharmaceutical chemistry, and in particular to a class of amide compounds or stereoisomers or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and their use as androgen receptor (AR) antagonists.
  • AR androgen receptor
  • Androgen receptor is a member of the nuclear receptor family. AR contains four main regions: N-terminal active transcription control region (NTD), DNA binding region (DBD), hinge region and C-terminal ligand binding domain (LBD). Its activation is closely related to the occurrence of benign prostatic hyperplasia, prostate cancer, seborrhea, acne, premenstrual syndrome, lung cancer, polycyclic ovarian syndrome, hirsutism and alopecia. Therefore, androgen receptor is an important target in many fields of drug discovery.
  • NTD N-terminal active transcription control region
  • DBD DNA binding region
  • LBD C-terminal ligand binding domain
  • AGA Androgenic alopecia
  • Finasteride is a type II 5- ⁇ reductase inhibitor that reduces the level of dihydrotestosterone in serum and scalp and is used to treat male AGA.
  • long-term use of finasteride can cause erectile and ejaculatory dysfunction and decreased libido in men, which discourages patients with hair loss. Therefore, studying the antagonistic activity of new molecules on AR is of great significance for the study of androgenic alopecia.
  • the present disclosure provides a compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • X is selected from CH or N;
  • Y is selected from OH, COOH, -CONH 2 , -COOR 3 or -CONR 3' R 3 ;
  • R 1 is selected from OH or -OC 1 -C 6 alkyl
  • R2 is selected from H, deuterium, C1 - C6 alkyl, C1 - C6 deuterated alkyl or C1 - C6 haloalkyl;
  • R 3 is selected from C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl is optionally substituted with R 3a ;
  • R 3a is selected from halogen, OH, CN, NH 2 , -COR 3b , -COOR 3b , -NHCOR 3b , -CONHR 3b , -OC 1 -C 6 alkyl, C 1 -C 6 alkyl, phenyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 1 -C 6 alkyl, phenyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted by R 3c ;
  • R 3b is selected from H or C 1 -C 6 alkyl
  • R 3c is selected from halogen, OH, C 1 -C 6 alkyl or -OC 1 -C 6 alkyl;
  • R 4 is selected from NO 2 , CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or -OC 1 -C 6 alkyl;
  • R 5 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -COOC 1 -C 6 alkyl, -SC 1 -C 6 alkyl, -OC 1 -C 6 alkyl, -Se-C 1 -C 6 alkyl, -S(O)-C 1 -C 6 alkyl or -S(O) 2 -C 1 -C 6 alkyl;
  • R 6 is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or -OC 1 -C 6 alkyl;
  • n is selected from 1, 2, 3, 4, 5, 6, 7, 8 or 9;
  • n is selected from 1, 2 or 3.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method for preventing or treating a disease mediated by androgen receptor in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal in need of such treatment.
  • the present disclosure provides use of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating androgen receptor-mediated diseases.
  • the present disclosure provides a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating androgen receptor-mediated diseases.
  • the present disclosure provides use of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating androgen receptor-mediated diseases.
  • the present disclosure provides a compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • X is selected from CH or N;
  • Y is selected from OH, COOH, -CONH 2 , -COOR 3 or -CONR 3' R 3 ;
  • R 1 is selected from OH or -OC 1 -C 6 alkyl
  • R2 is selected from H, deuterium, C1 - C6 alkyl, C1 - C6 deuterated alkyl or C1 - C6 haloalkyl;
  • R 3 is selected from C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl is optionally substituted with R 3a ;
  • R 3a is selected from halogen, OH, CN, NH 2 , -COR 3b , -COOR 3b , -NHCOR 3b , -CONHR 3b , -OC 1 -C 6 alkyl, C 1 -C 6 alkyl, phenyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C 1 -C 6 alkyl, phenyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted by R 3c ;
  • R 3b is selected from H or C 1 -C 6 alkyl
  • R 3c is selected from halogen, OH, C 1 -C 6 alkyl or -OC 1 -C 6 alkyl;
  • R 3' is selected from H or C 1 -C 6 alkyl
  • R 4 is selected from NO 2 , CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or -OC 1 -C 6 alkyl;
  • R 5 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -COOC 1 -C 6 alkyl, -SC 1 -C 6 alkyl, -OC 1 -C 6 alkyl, -Se-C 1 -C 6 alkyl, -S(O)-C 1 -C 6 alkyl or -S(O) 2 -C 1 -C 6 alkyl;
  • R 6 is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or -OC 1 -C 6 alkyl;
  • n is selected from 1, 2, 3, 4, 5, 6, 7, 8 or 9;
  • n is selected from 1, 2 or 3.
  • X is N.
  • Y is selected from COOH, -CONH 2 , -COOR 3 , or -CONR 3' R 3 . In some embodiments, Y is selected from -CONH 2 , -COOR 3 , or -CONR 3' R 3 .
  • Y is selected from -COOR 3 or -CONR 3' R 3 .
  • Y is -COOR 3 .
  • Y is selected from OH, COOH, -COOCH2CH3 , -COOCH3 , -COOCH ( CH3 ) 2 , -COOC( CH3 ) 3 , -CONHCH3 , or -CONH2 . In some embodiments, Y is selected from -COOCH2CH3 , -COOCH3 , -COOCH ( CH3 ) 2 , -COOC( CH3 ) 3 , or -CONHCH3 .
  • Y is selected from -COOCH2CH3 , -COOCH3 , -COOCH( CH3 ) 2 , or -COO( CH3 ) 3 .
  • R 1 is OH
  • R 2 is selected from C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, or C 1 -C 6 haloalkyl.
  • R 2 is selected from H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, R 2 is selected from H, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl.
  • R 2 is selected from C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments, R 2 is selected from C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
  • R 2 is selected from H, CH 3 , or CF 3 .
  • R 2 is selected from CH 3 or CF 3. In some embodiments, R 2 is selected from CH 3 .
  • R 1 is OH and R 2 is CH 3 .
  • R 3 is selected from C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 6 -C 10 aryl or 5-6 membered heteroaryl, and the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 6 -C 10 aryl or 5-6 membered heteroaryl is optionally substituted with R 3a .
  • R 3 is selected from C 1 -C 6 alkyl or C 1 -C 6 deuterated alkyl, said C 1 -C 6 alkyl being optionally substituted with R 3a .
  • R 3 is C 1 -C 6 alkyl. In some embodiments, R 3 is C 1 -C 4 alkyl, which is optionally substituted with R 3a .
  • R 3 is unsubstituted C 1 -C 6 alkyl. In some embodiments, R 3 is unsubstituted C 1 -C 4 alkyl.
  • R3 is selected from methyl, ethyl, isopropyl or tert-butyl. In some embodiments, R3 is selected from unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl or unsubstituted tert-butyl.
  • R 3′ is H or C 1 -C 4 alkyl. In some embodiments, R 3′ is H.
  • R 3a is selected from halogen, OH, CN, NH 2 , -COR 3b , -COOR 3b , -NHCOR 3b , -CONHR 3b , -OC 1 -C 6 alkyl, or C 1 -C 6 alkyl, said C 1 -C 6 alkyl being optionally substituted with R 3c .
  • R 3a is selected from halogen, OH, CN, NH 2 , -OC 1 -C 6 alkyl, or C 1 -C 6 alkyl, said C 1 -C 6 alkyl being optionally substituted with R 3c .
  • R 4 is selected from halogen or CN.
  • R 4 is selected from F, Cl or CN.
  • R 4 is CN
  • R 5 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -COOC 1 -C 6 alkyl, -SC 1 -C 6 alkyl, or -OC 1 -C 6 alkyl.
  • R 5 is selected from C 1 -C 6 haloalkyl, -SC 1 -C 6 alkyl, -OC 1 -C 6 alkyl, -Se-C 1 -C 6 alkyl, -S(O)-C 1 -C 6 alkyl, or -S(O) 2 -C 1 -C 6 alkyl.
  • R 5 is selected from C 1 -C 3 haloalkyl, -SC 1 -C 3 alkyl, -OC 1 -C 3 alkyl, -Se-C 1 -C 3 alkyl, -S(O)-C 1 -C 3 alkyl, or -S(O) 2 -C 1 -C 3 alkyl.
  • R 5 is selected from C 1 -C 3 haloalkyl, -SC 1 -C 3 alkyl, -OC 1 -C 3 alkyl, or -Se-C 1 -C 3 alkyl.
  • R 5 is selected from C 1 -C 6 haloalkyl, -SC 1 -C 6 alkyl, or -OC 1 -C 6 alkyl. In some embodiments, R 5 is selected from C 1 -C 3 haloalkyl, -SC 1 -C 3 alkyl, or -OC 1 -C 3 alkyl.
  • R 5 is selected from CF 3 , —S—CH 3 , —O—CH 3 , —Se—CH 3 , —S(O)—CH 3 , or —S(O) 2 —CH 3 .
  • R 5 is selected from CF 3 , —S—CH 3 , or —O—CH 3 . In some embodiments, R 5 is selected from CF 3 or —S—CH 3 . In some embodiments, R 5 is CF 3 .
  • R 6 is selected from H or halogen.
  • R 6 is selected from H, F or Cl.
  • R6 is H.
  • n is selected from 1, 2, or 3.
  • n is selected from 1 or 2.
  • n is 2.
  • X is selected from CH or N;
  • Y is selected from OH, COOH, -CONH 2 , -COOR 3 , or -CONR 3' R 3 , wherein R 3 is unsubstituted C 1 -C 6 alkyl, and R 3' is H or C 1 -C 6 alkyl;
  • R 1 is OH;
  • R 2 is selected from H, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl;
  • R 4 is CN;
  • R 5 is selected from C 1 -C 3 haloalkyl, -SC 1 -C 3 alkyl, -OC 1 -C 3 alkyl, -Se-C 1 -C 3 alkyl, -S(O)-C 1 -C 3 alkyl, or -S(O) 2 -C 1 -C 3 alkyl; and
  • R 6 is H.
  • X is selected from CH or N;
  • Y is selected from OH, COOH, -COOCH2CH3 , -COOCH3 , -COOCH( CH3 ) 2 , -COOC( CH3 ) 3 , -CONHCH3 , or -CONH2 ;
  • R1 is OH;
  • R2 is selected from H, CH3 , or CF3 ;
  • R4 is CN;
  • R5 is selected from CF3 , -S- CH3 , -O- CH3 , -Se- CH3 , -S(O) -CH3 , or -S(O) 2 - CH3 ; and
  • R6 is H.
  • X is selected from CH or N; Y is selected from OH or -COOR 3 , wherein R 3 is unsubstituted C 1 -C 6 alkyl; R 1 is OH; R 2 is selected from H or C 1 -C 3 alkyl; R 4 is CN; R 5 is selected from C 1 -C 3 haloalkyl, -SC 1 -C 3 alkyl, -OC 1 -C 3 alkyl, -Se-C 1 -C 3 alkyl; and R 6 is H.
  • X is selected from CH or N;
  • Y is selected from OH, -COOCH2CH3 , -COOCH3 , -COOCH( CH3 ) 2 , or -COOC( CH3 ) 3 ;
  • R1 is OH;
  • R2 is selected from H or CH3 ;
  • R4 is CN;
  • R5 is selected from CF3 , -S- CH3 , -O- CH3 , or -Se- CH3 ; and
  • R6 is H.
  • the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (II) or its stereoisomer or its pharmaceutically acceptable salt
  • the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds or their stereoisomers or their pharmaceutically acceptable salts:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I) or (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method for preventing or treating a disease mediated by androgen receptor in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.
  • the present disclosure provides use of a compound of formula (I) or (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating androgen receptor-mediated diseases.
  • the present disclosure provides use of a compound of formula (I) or (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating androgen receptor-mediated diseases.
  • the present disclosure provides a compound of formula (I) or (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating an androgen receptor-mediated disease.
  • the androgen receptor mediated disease is selected from androgenic alopecia.
  • any embodiment of any aspect of the present disclosure can be combined with other embodiments without contradiction.
  • any technical feature can be applied to the technical feature in other embodiments without contradiction.
  • tautomer refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present disclosure may exhibit tautomerism.
  • Tautomeric compounds may exist in two or more interconvertible species.
  • Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates.
  • the present disclosure includes all tautomeric forms of the compounds.
  • stereoisomer refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.
  • the compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • Specific geometric or stereoisomeric forms may be cis and trans isomers, E-type and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and their mixtures.
  • asymmetric carbon atoms asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of these isomers and their mixtures involved in all substituents are also included within the definition of the compounds of the present invention.
  • the compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • Asterisk "*" herein represents a chiral center, indicating that the absolute configuration of the position is either S-configuration or R-configuration.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group may be unsubstituted (CH 2 CH 3 ), monosubstituted (CH 2 CH 2 F, CH 2 CH 2 Cl, etc.), polysubstituted (CHFCH 2 F, CH 2 CHF 2 , CHFCH 2 Cl, CH 2 CHCl 2 , etc.) or fully substituted (CF 2 CF 3 , CF 2 CCl 3 , CCl 2 CCl 3 , etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or cannot be synthesized will be introduced.
  • any variable eg, Ra , Rb
  • its definition is independent at each occurrence. For example, if a group is substituted with 2 Rb , each Rb has an independent option.
  • Cm - Cn refers to an integer number of carbon atoms in the range of mn.
  • C1 - C10 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 , which may be linear or branched.
  • C1 - C10 alkyl is understood to mean a linear or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 1 -C 1 -C 1 -C 1 -C 1
  • C 1 -C 3 alkyl may be understood to mean a straight or branched saturated alkyl group having 1, 2 or 3 carbon atoms.
  • the "C 1 -C 10 alkyl” may include a range such as “C 1 -C 6 alkyl” or “C 1 -C 3 alkyl”, and the “C 1 -C 6 alkyl” may further include “C 1 -C 3 alkyl”.
  • deuterated alkyl means that hydrogen on an alkyl group is replaced by deuterium, including monodeuterated alkyl and polydeuterated alkyl.
  • C 1 -C 6 deuterated alkyl means C 1 -C 6 alkyl as defined above substituted by one or more deuterium, including but not limited to CD 3 , CH 2 CD 3 and the like.
  • haloalkyl is intended to include monohaloalkyl and polyhaloalkyl.
  • C 1 -C 6 haloalkyl means C 1 -C 6 alkyl as defined above substituted with one or more halogens, including but not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl and pentachloroethyl, etc.
  • cycloalkyl refers to a fully saturated carbocyclic ring that exists in the form of a monocyclic, cyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is generally a 3 to 10-membered ring.
  • C 3 -C 10 cycloalkyl is understood to mean a saturated monocyclic, cyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • C 3 -C 6 cycloalkyl may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms. Specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • heterocyclyl refers to a fully saturated or partially saturated (heteroaromatic as a whole that is not aromatic) monocyclic, fused, spiro or bridged ring group, which contains 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups (i.e., heteroatom-containing atomic groups) in the ring atoms
  • 3-10 membered heterocyclyl refers to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned in the ring atoms.
  • “3-10 membered heterocyclic group” includes “4-7 membered heterocyclic group”, wherein specific examples of 4 membered heterocyclic group include but are not limited to azetidinyl, thietanyl or oxetanyl; specific examples of 5 membered heterocyclic group include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; 6-membered heterocyclic group includes but is not limited to azetidinyl, thietanyl or oxetanyl; specific examples of 5 membered heterocyclic group include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl
  • the heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrole-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl.
  • the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7-membered heterocyclic group, specific examples of which include, but are not limited to, dihydroisoquinolinyl and the like.
  • “4-10 membered heterocyclyl” may include “5-10 membered heterocyclyl”, “4-7 membered heterocyclyl”, “5-6 membered heterocyclyl”, “6-8 membered heterocyclyl”, “4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered heterocycloalkyl”, etc., and “4-7 membered heterocyclyl” may further include “4-6 membered heterocyclyl", “5-6 membered heterocyclyl”, “4-7 membered heterocycloalkyl”, “4-6 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, etc. Although some bicyclic heterocyclyls in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl as a whole is still non-aromatic.
  • a ring having 6 carbon atoms such as phenyl; or a ring having 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl; or a ring having 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring having 13 carbon atoms (“C 13 aryl”), such as fluorenyl; or a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or azinyl, in
  • halo or halogen refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to a -CN group.
  • amino refers to a -NH2 group.
  • the amount of a compound of the disclosure that constitutes a "therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on his or her knowledge and this disclosure.
  • treatment means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.
  • examples of the term "mammal” include, but are not limited to, any member of the class Mammalian: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable acid addition or base addition salts, including salts formed between a compound and an inorganic acid or an organic acid, and salts formed between a compound and an inorganic base or an organic base.
  • composition refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient.
  • the purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • the present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, etc., respectively.
  • Certain isotopically labeled compounds of the present disclosure can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability.
  • Positron emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present disclosure can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.
  • compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or dragee core.
  • suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.
  • the daily dosage is 0.01 mg/kg to 500 mg/kg body weight, in the form of single or divided doses.
  • the compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining the embodiments with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples disclosed herein.
  • the ratio of mixed solvents is a volume ratio.
  • % refers to wt %.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the unit of NMR shift is 10 - 6 (ppm).
  • the solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 " refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
  • TBAF tetrabutylammonium fluoride
  • THF tetrahydrofuran
  • TsOH p-toluenesulfonic acid
  • BnBr benzyl bromide
  • DMF N,N-dimethylformamide
  • Cy 2 NH dicyclohexylamine
  • AcCl acetyl chloride
  • EtOH ethanol
  • EA ethyl acetate
  • DMAc N,N-dimethylacetamide
  • LiOH.H2O lithium hydroxide monohydrate
  • BnOH benzyl alcohol
  • DCC N,N'-dicyclohexylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • DCM dichloromethane
  • ACN acetonitrile
  • RuCl 3 ruthenium trichloride
  • MeOH methanol
  • i-PrOH isopropanol
  • t-BuOH te
  • Step 2 Synthesis of 6-[tert-butyl(dimethyl)silyl]oxy-N-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-2-hydroxy-2-methyl-hexanamide
  • reaction solution (33.3 mL) from the previous step was slowly added dropwise to a tetrahydrofuran solution (20 mL) of N-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-2-oxo-propionamide (compound 1-3, 1.0 g, 3.89 mmol) at -78 °C under nitrogen protection.
  • the mixture was added dropwise over 15 minutes. After completion, the reaction solution was stirred at -78 ° C for 1 h.
  • Step 2 Synthesis of N-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-3-(1,3-dioxolan-2-yl)-2-hydroxy-2-methylpropanamide
  • reaction solution 200 mL of the previous step was slowly added dropwise to a solution of N-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-2-oxo-propionamide (compound 1-3, 2.0 g, 7.78 mmol) in tetrahydrofuran (20 mL). After the addition, the reaction solution was heated to 70 ° C and stirred for 18 hours. LCMS showed that the reaction was complete.
  • the reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (50 mL*2), the organic phase was washed once with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the intermediate compound 2-4 (100 mg, 331.98 ⁇ mol) was added to tetrahydrofuran (1 mL).
  • Sodium borohydride (18.84 mg, 497.97 ⁇ mol) was added under ice-water bath.
  • the reaction solution was stirred under ice-water bath for 18 h. 2 mL of water was added under ice-water bath to quench.
  • the reaction solution was concentrated and the residue was purified by Prep-HPLC [Phenomenex C18, 5 ⁇ m silica, 30 mm diameter, 80 mm length; a mixture of water (containing 7 mmol/L NH 4 HCO 3 ) and acetonitrile with decreasing polarity was used as the eluent; the acetonitrile gradient ratio was 60%-70%, and the elution time was 9 minutes] to obtain the target compound 002 (8.2 mg).
  • Step 2 Synthesis of ethyl 5-(benzyloxy)-4,5-dioxopentanoate
  • the intermediate compound 3-2 (1g, 4.23mmol) was dissolved in anhydrous ethanol (10mL), and acetyl chloride (365mg, 4.66mmol) was added under ice-water bath conditions, and the mixture was kept warm and stirred for 3h. LC-MS showed that the reaction was complete.
  • Step 4 Synthesis of ethyl 5-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-4,5-dioxopentanoate
  • the intermediate compound 3-4 (300 mg, 2.05 mmol) was dissolved in N, N-dimethylacetamide (12 mL), cooled to -10 ° C, added dichlorothionyl (244.22 mg, 2.05 mmol), stirred for 10 minutes, added 5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile (384 mg, 2.05 mmol), and continued to stir for 3 hours.
  • LC-MS showed that the reaction was complete.
  • Step 5 Synthesis of ethyl 5-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-4-hydroxy-4-methyl-5-oxopentanoate
  • the intermediate compound 3-5 (100 mg, 291.32 ⁇ mol) was dissolved in tetrahydrofuran (10 mL), cooled to -78 °C, methylmagnesium bromide (0.5 M in THF, 1.40 mL) was added dropwise, the reaction was kept warm for 2 h, the temperature was slowly raised to room temperature, and stirred overnight. LC-MS showed that the reaction was complete. The reaction solution was poured into ice water (40 mL), extracted with ethyl acetate (15 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • the residue was purified by Prep-HPLC [YMC-TAR column 5 ⁇ m silica, 30 mm diameter, 150 mm length; a mixture of water (containing 7 mmol/L NH 4 HCO 3 ) and acetonitrile with decreasing polarity as the eluent; acetonitrile gradient ratio 45%-75%, elution time: 9 minutes] to obtain the target compound 003 (15 mg).
  • Disperse compound 003 (80 mg, 222.65 ⁇ mol) in a mixed solution of tetrahydrofuran (3 mL) and water (1 mL), add lithium hydroxide monohydrate (8.55 mg, 203.76 ⁇ mol), and stir at room temperature for 3 h.
  • LC-MS shows that the reaction is complete. Pour the reaction solution into 0.5 M hydrochloric acid solution (15 mL), extract with ethyl acetate (5 mL*3) three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate.
  • the residue is purified by RP-FLASH [chromatographic column: 40 g C18 Column, 20-35 ⁇ m, Mobile phase A: pure water, mobile phase B: acetonitrile; flow rate: 18 mL/min; gradient: 30% B to 50% B, elution time: 10 minutes] to obtain the target compound 004 (15 mg).
  • Step 1 Synthesis of cyclopent-1-ene-1-carboxylic acid benzyl ester
  • the starting material 5-1 (8 g, 71.35 mmol) was dissolved in dichloromethane (200 mL), and benzyl alcohol (9.26 g, 85.62 mmol), N,N'-dicyclohexylcarbodiimide (17.67 g, 85.62 mmol) and 4-dimethylaminopyridine (871.64 mg, 7.13 mmol) were added, and stirred at room temperature overnight.
  • the intermediate compound 5-2 (5 g, 24.72 mmol) was dissolved in a mixed solvent of carbon tetrachloride (120 mL) and acetonitrile (120 mL). At 0°C, an aqueous solution (120 mL) of sodium periodate (10.58 g, 49.44 mmol) was added dropwise. After the addition, ruthenium trichloride (512.79 mg, 2.47 mmol) solid was added, the temperature was slowly raised to room temperature, and stirring was continued for 6 h. LC-MS showed that the reaction was complete.
  • reaction solution was poured into water (300 mL), extracted with dichloromethane (150 mL*3), the organic phases were combined, washed three times with water (100 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Step 5 Synthesis of ethyl 6-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-5,6-dioxohexanoate
  • the intermediate compound 5-5 (360 mg, 1.91 mmol) was dissolved in N, N-dimethylacetamide (7.97 mL), cooled to -10 ° C, and thionyl chloride (273.12 mg, 2.30 mmol) was added dropwise. After the addition, 5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile (357.98 mg, 1.91 mmol) solid was added, and the mixture was stirred and reacted for 2 h. LC-MS showed that the reaction was complete.
  • Step 6 Synthesis of ethyl 6-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-5-hydroxy-5-methyl-6-oxohexanoate
  • the intermediate 5-6 was prepared on an enlarged scale using the method described in step 1-5.
  • the intermediate compound 5-6 (17 g, 47.58 mmol) was dissolved in tetrahydrofuran (200 mL), cooled to -78 ° C under a nitrogen atmosphere, and a tetrahydrofuran solution of methyl magnesium bromide (3M, 47.58 mL) was added dropwise. The mixture was stirred and reacted overnight. LC-MS showed that the reaction was complete. At -78 ° C, a saturated aqueous solution of ammonium chloride (350 mL) was slowly added to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL*3).
  • Step 7 Synthesis of (6S)/(6R)-6-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-5-hydroxy-5-methyl-6-oxohexanoic acid ethyl ester
  • Chiral-HPLC [Chromatographic column: AD-RH (Dacelide 150 ⁇ 4.6mm, 5 ⁇ m); mobile phase: A: water; B: acetonitrile, gradient: mobile phase B: 10% to 90%, elution 35 minutes; flow rate: 1.0mL/min; column temperature: 25°C] retention time: 24.980min.
  • Chiral-HPLC [Chromatographic column: AD-RH (Dacelide 150 ⁇ 4.6mm, 5 ⁇ m); mobile phase: A: water; B: acetonitrile, gradient: mobile phase B: 10% to 90%, elution 35 minutes; flow rate: 1.0mL/min; column temperature: 25°C] retention time: 16.224min.
  • Step 1 Synthesis of (6S)/(6R)-6-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-5-hydroxy-5-methyl-6-oxohexanoic acid
  • Disperse compound 005 (or 006) (270 mg, 723.23 ⁇ mol) in a mixed solvent of tetrahydrofuran (3 mL) and water (1 mL), add lithium hydroxide monohydrate (34.66 mg, 826.02 ⁇ mol), and stir at room temperature overnight.
  • LC-MS shows that the reaction is complete. Pour the reaction solution into 0.1M hydrochloric acid solution (15 mL), extract with ethyl acetate (5 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 7-1 (or 8-1) (240 mg).
  • Step 2 Synthesis of (6S)/(6R)-6-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-5-hydroxy-5-methyl-6-oxohexanoic acid methyl ester
  • the intermediate compound 7-1 (or 8-1) (50 mg, 144.81 ⁇ mol) was dissolved in methanol (4 mL), and thionyl chloride (51.69 mg, 434.44 ⁇ mol) was added dropwise at room temperature, and the temperature was raised to 60°C, and the reaction was stirred for 2 h. LC-MS showed that the reaction was complete.
  • the solvent was evaporated under reduced pressure, and the residue was purified by Prep-HPLC [YMC-TAR column 5 ⁇ m silica, 30 mm diameter, 150 mm length; a mixture of water (containing 7 mmol/L NH 4 HCO 3 ) and acetonitrile with decreasing polarity as the eluent; acetonitrile gradient ratio 40%-70%, elution time: 9.5 minutes] to obtain the target compound 007 (12 mg) (or 008 (15 mg)).
  • Chiral-HPLC [Chromatographic column: AD-RH (Dacelide 150 ⁇ 4.6mm, 5 ⁇ m); mobile phase: A: water; B: acetonitrile, gradient: mobile phase B: 10% to 90%, elution 35 minutes; flow rate: 1.0mL/min; column temperature: 25°C] retention time: 23.394min.
  • Chiral-HPLC [Chromatographic column: AD-RH (Dacelid 150 ⁇ 4.6 mm, 5 ⁇ m); mobile phase: A: water; B: acetonitrile, gradient: Mobile phase B: 10% to 90%, elution time 35 minutes; flow rate: 1.0 mL/min; column temperature: 25°C] retention time: 15.201 min.
  • the intermediate compound 7-1 (or 8-1) (50 mg, 144.81 ⁇ mol) was dissolved in isopropanol (4 mL), and thionyl chloride (52 mg, 434.44 ⁇ mol) was added dropwise at room temperature, and the temperature was raised to 60°C, and the reaction was stirred for 2 h. LC-MS showed that the reaction was complete.
  • the solvent was evaporated under reduced pressure, and the residue was purified by Prep-HPLC [YMC-TAR column 5 ⁇ m silica, 30 mm diameter, 150 mm length; a mixture of water (containing 7 mmol/L NH 4 HCO 3 ) and acetonitrile with decreasing polarity as the eluent; acetonitrile gradient ratio 45%-75%, elution time: 11 minutes] to obtain the target compound 009 (10 mg) (or 010 (12 mg)).
  • Chiral-HPLC [Chromatographic column: AD-RH (Dacelide 150 ⁇ 4.6mm, 5 ⁇ m); mobile phase: A: water; B: acetonitrile, gradient: mobile phase B: 10% to 90%, elution 35 minutes; flow rate: 1.0mL/min; column temperature: 25°C] retention time: 26.011min.
  • Chiral-HPLC [Chromatographic column: AD-RH (Daiclide 150 ⁇ 4.6mm, 5 ⁇ m); mobile phase: A: water; B: acetonitrile, gradient: mobile phase B: 10% to 90%, elution 35 minutes; flow rate: 1.0mL/min; column temperature: 25°C] retention time: 16.601min.
  • Example 11 & 12 Synthesis of (6S)/(6R)-6-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-5-hydroxy-5-methyl-6-oxohexanoic acid tert-butyl ester (Compound 011 & 012)
  • the intermediate compound 7-1 (or 8-1) (300.00 mg, 868.88 ⁇ mol), O-tert-butyl-N,N'-diisopropylisourea (1.74 g, 8.69 mmol) were added to dichloromethane (7.5 mL) and tert-butyl alcohol (644.01 mg, 8.69 mmol) and stirred at room temperature for 15 h.
  • Chiral-HPLC [Chromatographic column: AD-RH (Dacelide 150 ⁇ 4.6mm, 5 ⁇ m); mobile phase: A: water; B: acetonitrile, gradient: mobile phase B: 10% to 90%, elution 35 minutes; flow rate: 1.0mL/min; column temperature: 25°C] retention time: 32.009min.
  • Chiral-HPLC [Chromatographic column: AD-RH (Dacelide 150 ⁇ 4.6mm, 5 ⁇ m); mobile phase: A: water; B: acetonitrile, gradient: mobile phase B: 10% to 90%, elution 35 minutes; flow rate: 1.0mL/min; column temperature: 25°C] retention time: 17.147min.
  • 5-Fluoropyridine-3-amine 13.0 g, 116 mmol was dissolved in N, N-dimethylformamide (60 mL), and then placed in an ice bath to cool.
  • N-bromosuccinimide (20.64 g, 116 mmol) in N, N-dimethylformamide (50 mL) was slowly added dropwise under the ice bath, and then the ice bath was kept to continue the reaction for 30 minutes.
  • LC-MS monitoring was performed until the reaction was complete.
  • the reaction solution was poured into 500 mL of water and extracted with ethyl acetate (200 mL*3).
  • Step 4 Synthesis of ethyl 6-(6-cyano-5-(methylthio)pyridin-3-yl)amino)-5,6-dioxohexanoate
  • Step 5 Synthesis of ethyl 6-((6-cyano-5-(methylthio)pyridin-3-yl)amino)-5-hydroxy-5-methyl-6-oxohexanoate
  • Step 6 Synthesis of (6S)/(6R)-6-((6-cyano-5-(methylthio)pyridin-3-yl)amino)-5-hydroxy-5-methyl-6-oxohexanoic acid ethyl ester
  • Chiral-HPLC [Chromatographic column: AD-RH (Daikolu 150 ⁇ 4.6mm, 5 ⁇ m); mobile phase: A: water; B: acetonitrile, gradient: mobile phase B: 10% to 90%, elution 35 minutes; flow rate: 1.0mL/min; column temperature: 25°C] retention time: 21.615min.
  • Chiral-HPLC [Chromatographic column: AD-RH (Daiclide 150 ⁇ 4.6mm, 5 ⁇ m); mobile phase: A: water; B: acetonitrile, gradient: mobile phase B: 10% to 90%, elution 35 minutes; flow rate: 1.0mL/min; column temperature: 25°C] retention time: 15.077min.
  • Step 1 Synthesis of (6S)/(6R)-6-((6-cyano-5-(methylthio)pyridin-3-yl)amino)-5-hydroxy-5-methyl-6-oxohexanoic acid
  • Disperse compound 013 (or compound 014) (100 mg, 284.56 ⁇ mol) in a mixed solvent of tetrahydrofuran (3 mL) and water (1 mL), add lithium hydroxide monohydrate (35.82 mg, 853.68 ⁇ mol), and stir at room temperature for 3 h.
  • LC-MS shows that the reaction is complete. Pour the reaction solution into 0.1 M hydrochloric acid solution (15 mL), extract with ethyl acetate (5 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 15-1 (90 mg) (or 16-1).
  • Step 2 Synthesis of methyl (6S)/(6R)-6-((6-cyano-5-(methylthio)pyridin-3-yl)amino)-5-hydroxy-5-methyl-6-oxohexanoate
  • Example 17 & 18 Synthesis of (6S)/(6R)-6-((6-cyano-5-(methylthio)pyridin-3-yl)amino)-5-hydroxy-5-methyl-6-oxohexanoic acid isopropyl ester (Compound 017 & 018)
  • the intermediate compound 15-1 (or 16-1) (140 mg, 432.94 ⁇ mol) was added to isopropanol (4 mL), and thionyl chloride (51.51 mg, 432.94 ⁇ mol) was added dropwise, and the temperature was raised to 60°C and stirred for 4 hours.
  • LC-MS showed that the reaction was complete.
  • the reaction solution was cooled to room temperature, diluted with ethyl acetate (10 mL*3), washed with water (10 mL*3) three times, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Chiral-HPLC [chromatographic column: AD-RH (Daiclide 150 ⁇ 4.6mm, 5 ⁇ m); mobile phase: A: water; B: acetonitrile, gradient: mobile phase B: 10% to 90%, elution 35 minutes; flow rate: 1.0mL/min; column temperature: 25°C], retention time: 22.544min.
  • Chiral-HPLC [chromatographic column: AD-RH (Dacelide 150 ⁇ 4.6mm, 5 ⁇ m); mobile phase: A: water; B: acetonitrile, gradient: mobile phase B: 10% to 90%, elution 35 minutes; flow rate: 1.0mL/min; column temperature: 25°C], retention time: 15.406min.
  • Step 1 Synthesis of 6-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-5-hydroxy-5-methyl-6-oxohexanoic acid
  • Step 2 Synthesis of tert-butyl 6-((6-cyano-5-(methylthio)pyridin-3-yl)amino)-5-hydroxy-5-methyl-6-oxohexanoate
  • Step 1 Synthesis of ethyl 6-[(6-cyano-5-(methoxy)pyridin-3-yl)amino]-5,6-dioxohexanoate
  • Step 2 Synthesis of 6-[(6-cyano-5-(methoxy)pyridin-3-yl)amino]-5-hydroxy-5-methyl-6-oxo-hexanoic acid ethyl ester
  • the intermediate compound 5-6 (50 mg, 139.94 ⁇ mol) and (trifluoromethyl)trimethylsilane (59 mg, 419.83 ⁇ mol) were added to tetrahydrofuran (0.5 mL), and cesium fluoride (5 mg, 32.91 ⁇ mol) was added under nitrogen atmosphere, and the reaction solution was stirred at 25°C for 3 h. LCMS showed that the reaction was complete. Water (0.5 mL) was added to the reaction solution for dilution, the reaction solution was filtered, and the filtrate was concentrated.
  • the residue was purified by Prep-HPLC [Phenomenex C 18 , 5 ⁇ m silica, 30 mm diameter, 80 mm length; using a mixture of water (containing 7 mmol/L NH 4 HCO 3 ) and acetonitrile (acetonitrile content: 60%-70%) as eluent, elution time: 8 minutes] to obtain the target compound 021 (5 mg).
  • Step 1 Synthesis of 6-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-5-hydroxy-5-methyl-6-oxohexanoic acid
  • Step 2 Synthesis of N 1 -(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-N 6 ,2-dimethyladipamide
  • the intermediate compound 22-1 (50 mg, 144.81 ⁇ mol) was dissolved in tetrahydrofuran (4 mL), cooled to 0°C, and thionyl chloride (18 mg, 151.31 ⁇ mol) was added dropwise. The reaction was allowed to react at room temperature for 6 h. Methylamine solution (1M in THF, 1.5 mL) was added to the reaction solution and stirred at room temperature for 3 h. LC-MS showed that the reaction was complete.
  • the reaction solution was poured into an iced 1M hydrochloric acid solution (30 mL), extracted with ethyl acetate (10 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • the residue was separated and purified by Prep-HPLC [YMC-TAR column 5 ⁇ m silica, 30 mm diameter, 150 mm length; a mixture of water (containing 7 mmol/L NH 4 HCO 3 ) and acetonitrile with decreasing polarity was used as the eluent; the acetonitrile gradient ratio was 30%-60%, and the elution time was 7 minutes] to obtain the target compound 022 (15 mg).
  • the residue was separated and purified by Prep-HPLC [YMC-TAR column 5 ⁇ m silica, 30 mm diameter, 150 mm length; a mixture of water (containing 7 mmol/L NH 4 HCO 3 ) and acetonitrile with decreasing polarity was used as the eluent; the acetonitrile gradient ratio was 40%-70%, and the elution time was 12 minutes] to obtain the target compound 023 (15 mg).
  • 6-Bromo-5-fluoropyridin-3-amine (5 g, 26.18 mmol), zinc cyanide (6.15 g, 52.36 mmol), zinc powder (166.47 mg, 2.54 mmol), tris(dibenzylideneacetone)dipalladium (1.2g, 1.31mmol) and 1,1'-bis(diphenylphosphino)ferrocene (1.45g, 2.62mmol) were added to N,N-dimethylformamide (50mL), and the reaction solution was reacted at 100°C for 16 hours under argon atmosphere. LCMS showed that the reaction was complete.
  • the reaction solution was poured into water (500mL), extracted with ethyl acetate (200mL*4), and the organic phases were combined and washed with saturated brine (400mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Step 3 Synthesis of ethyl 6-[(6-cyano-5-methylselenopyridin-3-yl)amino]-5,6-dioxohexanoate
  • 6-Ethoxy-2,6-dioxohexanoic acid (166.34 mg, 883.94 ⁇ mol) and 5-amino-3-(methylseleno)pyridine-2-carbonitrile (100 mg, 471.45 ⁇ mol) were dissolved in N,N-dimethylacetamide (3 mL), and thionyl chloride (112.18 mg, 942.91 ⁇ mol) was added dropwise at -10°C. The reaction solution was stirred at -10°C for 18 hours. LCMS showed that the reaction was complete.
  • reaction solution was poured into water (50 mL), extracted with ethyl acetate (30 mL*4), the organic phases were combined and washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound 24-4 (220 mg).
  • Step 4 Synthesis of 6-[(6-cyano-5-methylselenopyridin-3-yl)amino]-5-hydroxy-5-methyl-6-oxohexanoic acid ethyl ester
  • the crude product was separated and purified by prep-HPLC [Phenomenex C18, 5 ⁇ m silica, 30 mm diameter, 80 mm length; using a mixture of water (containing 0.05% ammonium bicarbonate) and acetonitrile (acetonitrile content: 38-68%) as eluent] to obtain the target compound 024 (60 mg).
  • Example 25 (5R)-6-[(6-cyano-5-methylsulfonylpyridin-3-yl)amino]-5-hydroxy-5-methyl-6-oxo-hexanoic acid ethyl ester or (5S)-6-[(6-cyano-5-methylsulfonylpyridin-3-yl)amino]-5-hydroxy-5-methyl-6-oxo-hexanoic acid ethyl ester (Compound 025)
  • Example 26 (5R)-6-[(6-cyano-5-methylsulfinylpyridin-3-yl)amino]-5-hydroxy-5-methyl-6-oxo-hexanoic acid ethyl ester or (5S)-6-[(6-cyano-5-methylsulfinylpyridin-3-yl)amino]-5-hydroxy-5-methyl-6-oxo-hexanoic acid ethyl ester (Compound 026)
  • the starting material 27-1 (2 g, 9.89 mmol) was added to tetrahydrofuran (10 mL), and sodium ethoxide (672.45 mg, 9.89 mmol) was added under an ice-water bath. Stir at room temperature for 30 minutes, and diethyl oxalate (1.45 g, 9.89 mmol) was added. The reaction solution was stirred at room temperature for 18 hours. 20 mL of water was added to the reaction solution for dilution, and ethyl acetate (20 mL*3) was used for extraction. The organic layers were combined and washed with water (30 mL*2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 27-2 (2.99 g).
  • Step 5 Synthesis of ethyl 7-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-6,7-dioxoheptanoate
  • reaction solution was poured into ice water, extracted with ethyl acetate (5 mL*3), the organic layers were combined and washed with water (40 mL*2), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 27-6 (400 mg).
  • Step 6 Synthesis of ethyl 7-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-6-hydroxy-6-methyl-7-oxoheptanoate
  • Step 1 Synthesis of 6-(4-cyano-3-methylthio-anilino)-5,6-dioxo-hexanoic acid ethyl ester
  • Step 2 Synthesis of 6-(4-cyano-3-methylthio-anilino)-5-hydroxy-5-methyl-6-oxohexanoic acid ethyl ester
  • the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the crude product was separated and purified by Prep-HPLC [Phenomenex C18, 5 ⁇ m silica, 30 mm diameter, 80 mm length; a mixture of water (containing 0.05% ammonium bicarbonate) and acetonitrile (acetonitrile content: 50-80%) was used as the eluent] to obtain the target compound 029 (110 mg).
  • Step 1 Synthesis of 6-(4-cyano-3-methoxy-anilino)-5,6-dioxo-hexanoic acid ethyl ester
  • 6-Ethoxy-2,6-dioxohexanoic acid (971.24 mg, 5.16 mmol) was added to N,N-dimethylacetamide (5 mL), and the reaction solution was cooled to -10 °C.
  • Dichlorothionyl (802.97 mg, 6.75 mmol) was added dropwise, and 4-amino-2-methoxy-benzonitrile (500 mg, 3.37 mmol) was added, and the reaction solution was stirred at -78 °C for 15 hours.
  • LCMS showed that the reaction was complete.
  • Saturated sodium bicarbonate solution 50 mL was quenched and extracted with ethyl acetate (50 mL*4).
  • Step 2 Synthesis of 6-(4-cyano-3-methoxy-anilino)-5-hydroxy-5-methyl-6-oxohexanoic acid ethyl ester
  • the crude product was separated and purified by Prep-HPLC [Phenomenex C18, 5 ⁇ m silica, 30 mm diameter, 80 mm length; a mixture of water (containing 0.05% ammonium bicarbonate) and acetonitrile (acetonitrile content: 50-80%) was used as the eluent] to obtain the target compound 030 (110 mg).
  • Step 2 Synthesis of isopropyl 6-((6-cyano-5-(methylthio)pyridin-3-yl)amino)-5-hydroxy-6-oxohexanoate
  • Lipo 3000 and P3000 (Lipofectamine TM 3000) transfection reagents and AR and PSA ARE1 reporter gene plasmids (Anhui Biotechnology Co., Ltd.) (a total of 2.5 ⁇ g of plasmids and 1.25 ⁇ g of each plasmid were added to each well) were incubated at room temperature for 10 minutes, and then 250 ⁇ L of the above transfection reagents were added to each well containing cells.
  • the cells were washed with PBS and the medium was replaced with RPMI-1640 without phenol red and 5% charcoal-stripped serum.
  • the cells were re-plated into 96-well plates (Corning, 3603) according to the number of cells to be plated (2 ⁇ 10 4 cells/well).
  • test compound or DMSO or positive control drug
  • DHT dihydrotestosterone
  • test compound 10mM stock solution, the final concentration is 3.3 ⁇ M or 6.7 ⁇ M.
  • Negative control 0.1% DMSO.
  • Positive control 30 ⁇ M Enzalutamide.
  • test compound or DMSO or positive control drug
  • DHT DHT
  • the luciferase signal was detected using Vazyme Bright-Lite substrate. 70 ⁇ L of culture medium was added to each well and the luciferase signal was read after shaking for 2 minutes.
  • Ave_H Ave(DMSO)
  • Ave_L Ave (30000nM Enzalutamide)
  • Inhibition rate (%) (Ave_H-Sample)/(Ave_H-Ave_L) x 100%
  • Ave_H measured value of negative control (0.1% DMSO);
  • Ave_L measured value of the positive control (30 ⁇ M enzalutamide);
  • the metabolic stability of the disclosed compounds in liver microsomes was determined using the following test method.
  • Source of liver microsomes human liver microsomes (Corning 452117)
  • KH 2 PO 4 (Tianjin Guangfu Fine Chemical Research Institute 20180920)
  • in vitro T 1/2 0.693/k
  • the compounds disclosed in the present invention have the characteristics of high clearance rate and rapid metabolism, which can avoid the accumulation of drugs in the body due to long-term administration, thereby affecting the systemic androgen receptor signaling pathway, thereby improving the safety of the drug.
  • a 1 mM stock solution of the test compound was prepared in DMSO, and a 1 mM stock solution of the reference compound propantheline was prepared in acetonitrile.
  • test compound stock solution or control compound stock solution
  • 796 ⁇ L of pre-incubated whole blood CD-1 mouse whole blood or human whole blood
  • the final concentration of the solvent was 0.5%.
  • 50 ⁇ L of aliquots of the whole blood with samples were added to new test tubes and incubated in a 37°C water bath with shaking at 60 rpm. The experiment was repeated twice.
  • peak area ratio t min the peak area ratio of the reference compound and the test compound at t minutes
  • Peak area ratio 0min the peak area ratio of the control compound and the test compound at the zero time point.
  • the slope value was determined by linear regression of the natural logarithm of the remaining percentage of the test compound versus the incubation time curve.
  • the compounds of the present disclosure have a short half-life in CD-1 mice and human whole blood, and have the characteristics of high clearance rate and rapid metabolism in the blood, which avoids the accumulation of drugs in the body due to long-term administration, thereby affecting the systemic androgen receptor signaling pathway, thereby improving the safety of the drug.
  • mice C57BL/6 mice, male, 6 weeks old, weighing approximately 18-20 g, were purchased from Shanghai Lingchang Biotechnology Co., Ltd. The mice were housed in an SPF-grade environment with separate ventilation in each cage, and all animals had free access to standard certified commercial laboratory diets and free drinking water.
  • Skin preparation After the mice have been adaptively raised for 1-2 weeks, use a shaver to remove the hair in a 2cm*3cm area on the back of the mice, and confirm that the hair of the mice is in the resting phase (the skin is pink) and the skin is not damaged.
  • mice were divided and dosed on the third day after shaving.
  • the disclosed compound 010 was applied to the shaved area twice a day in the morning and evening at a concentration of 0.5 wt% for 32 days, and the control group was applied with the control solvent.
  • Each group had 12 mice.
  • mice in each group was observed to see if there were any rashes, cracks, or dandruff on the skin;
  • mice After administration of Compound 010, mice were weighed, hair growth scores were performed, and photos were taken on days 10, 13, 16, 20, 23, 27, and 32;
  • the scoring criteria are as follows:
  • the skin in the shaved area is black (greater than 20% and less than 40%);
  • the skin in the shaved area is black with a little hair growth (greater than 40% and less than 60%);
  • the skin in the shaved area is black with some hair growth (greater than 60% and less than 80%);
  • the hair in the shaved area has basically grown completely (80% to 100% growth).
  • the compound 010 of the present disclosure in mice whose hair growth is in the resting phase, the compound 010 of the present disclosure at a concentration of 0.5wt%, 20 ⁇ L/ cm2 , and BID administration by skin application has a significant promoting effect on hair growth.
  • Compound 010 can significantly promote hair growth starting from 32 days of administration (P ⁇ 0.01).
  • the compound 010 of the present disclosure did not significantly affect the weight of mice at the doses tried, nor did it cause any skin rash, cracking, dandruff, etc.
  • Other compounds of the present disclosure also have a significant promoting effect on hair growth.

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Abstract

提供式(I)所示化合物或其立体异构体或其药学上可接受的盐，含有它们的药物组合物以及它们作为雄激素受体(AR)拮抗剂在治疗或预防雄激素受体介导的疾病中的用途，优选用于治疗雄激素受体介导的脱发，如雄激素性脱发。

Description

酰胺类化合物
相关申请的交叉引用
本公开要求向中国国家知识产权局递交的以下中国专利申请的优先权和权益：2023年09月28日递交的第202311282820.X号中国专利申请以及2024年07月05日递交的第202410900706.7号中国专利申请。上述专利申请的全文通过援引整体并入本文中。
技术领域
本公开涉及药物化学领域，具体涉及一类酰胺类化合物或其立体异构体或药学上可接受的盐，含有它们的药物组合物以及它们作为雄激素受体(AR)拮抗剂的用途。
背景技术
雄激素受体(Androgen receptor，AR)是核受体家族成员之一，AR包含四个主要区域：N端活性转录控制区域(N-terminal domain，NTD)、DNA结合区域(DNA binding domain，DBD)、铰链区以及C末端的配体结合区(Ligand binding domain，LBD)。其激活与良性前列腺增生，前列腺癌，皮脂溢，痤疮，经前综合症，肺癌，卵巢多环综合症，多毛症和脱发等疾病的发生紧密相关。因此，雄激素受体是药物发现的多个领域中的重要靶标。
雄激素性脱发(androgenitic alopecia，AGA)是目前临床上最常见的一种脱发类型，但其具体发病机制仍然不完全清楚，多数研究人员认为与雄激素的代谢有关。研究表明，由于脱发区毛囊内雄激素受体基因表达升高和/或Ⅱ型5α还原酶基因表达升高，从而导致雄激素对易感毛囊的作用增大。对于雄激素性脱发而言，易感毛囊中真皮成分细胞内含有特定的Ⅱ型5α还原酶，可以将血液中循环至该区域的雄激素睾酮转化为二氢睾酮，通过与细胞内的雄激素受体结合引起一系列反应，进而使毛囊出现进展性的微型化和脱发直至秃发。目前，FDA仅批准了米诺地尔和非那雄安用于治疗雄激素性脱发。米诺地尔是一种钾通道开放剂，它在雄激素性脱发中有效的确切机制尚未完全了解，作为外用药物涂抹于患处。但起效时间长，且存在瘙痒、接触性皮炎、停药后脱发加重等不良反应。非那雄胺是一种Ⅱ型5-α还原酶抑制剂，降低血清和头皮中二氢睾酮的水平，用于男性AGA的治疗。但长期服用非那雄安所导致的男性勃起和射精功能障碍，性欲减退，令脱发患者望而却步。因此，研究新型分子对AR的拮抗活性，对雄激素性脱发的研究具有重要意义。
发明内容
一方面，本公开提供了式(I)所示化合物或其立体异构体或其药学上可接受的盐，
其中，
X选自CH或N；
Y选自OH、COOH、-CONH2、-COOR3或-CONR3’R3；
R1选自OH或-O-C1-C6烷基；
R2选自H、氘、C1-C6烷基、C1-C6氘代烷基或C1-C6卤代烷基；
R3选自C1-C6烷基、C1-C6氘代烷基、C3-C6环烷基、4-10元杂环基、C6-C10芳基或5-10元杂芳基，所述C1-C6烷基、C3-C6环烷基、4-10元杂环基、C6-C10芳基或5-10元杂芳基任选地被R3a取代；
R3a选自卤素、OH、CN、NH2、-COR3b、-COOR3b、-NHCOR3b、-CONHR3b、-O-C1-C6烷基、C1-C6烷基、苯基、4-6元杂环基或5-6元杂芳基，所述C1-C6烷基、苯基、4-6元杂环基或5-6元杂芳基任选地被R3c取代；
R3b选自H或C1-C6烷基；
R3c选自卤素、OH、C1-C6烷基或-O-C1-C6烷基；
R3’选自H或C1-C6烷基；
R4选自NO2、CN、卤素、C1-C6烷基、C1-C6卤代烷基或-O-C1-C6烷基；
R5选自卤素、C1-C6烷基、C1-C6卤代烷基、-COOC1-C6烷基、-S-C1-C6烷基、-O-C1-C6烷基、-Se-C1-C6烷基、-S(O)-C1-C6烷基或-S(O)2-C1-C6烷基；
R6选自H、卤素、C1-C6烷基、C1-C6卤代烷基或-O-C1-C6烷基；
n选自1、2、3、4、5、6、7、8或9；
条件是，当Y选自OH时，n选自1、2或3。
另一方面，本公开提供药物组合物，所述药物组合物包含所述的式(I)化合物或其立体异构体或其药学上可接受的盐以及药学上可接受的辅料。
还一方面，本公开提供用于预防或者治疗哺乳动物由雄激素受体介导的疾病的方法，包括对需要该治疗的哺乳动物施用治疗有效量的式(I)化合物或其立体异构体或其药学上可接受的盐、或其药物组合物。
还一方面，本公开提供式(Ⅰ)化合物或其立体异构体或其药学上可接受的盐、或其药物组合物在制备用于预防或者治疗雄激素受体介导的疾病的药物中的用途。
再一方面，本公开提供用于预防或者治疗雄激素受体介导的疾病的式(Ⅰ)化合物或其立体异构体或其药学上可接受的盐、或其药物组合物。
再一方面，本公开提供式(Ⅰ)化合物或其立体异构体或其药学上可接受的盐、或其药物组合物在预防或者治疗雄激素受体介导的疾病中的用途。
详细说明
本公开提供了式(I)所示化合物或其立体异构体或其药学上可接受的盐，
其中，
X选自CH或N；
Y选自OH、COOH、-CONH2、-COOR3或-CONR3’R3；
R1选自OH或-O-C1-C6烷基；
R2选自H、氘、C1-C6烷基、C1-C6氘代烷基或C1-C6卤代烷基；
R3选自C1-C6烷基、C1-C6氘代烷基、C3-C6环烷基、4-10元杂环基、C6-C10芳基或5-10元杂芳基，所述C1-C6烷基、C3-C6环烷基、4-10元杂环基、C6-C10芳基或5-10元杂芳基任选地被R3a取代；
R3a选自卤素、OH、CN、NH2、-COR3b、-COOR3b、-NHCOR3b、-CONHR3b、-O-C1-C6烷基、C1-C6烷基、苯基、4-6元杂环基或5-6元杂芳基，所述C1-C6烷基、苯基、4-6元杂环基或5-6元杂芳基任选地被R3c取代；
R3b选自H或C1-C6烷基；
R3c选自卤素、OH、C1-C6烷基或-O-C1-C6烷基；
R3’选自H或C1-C6烷基；
R4选自NO2、CN、卤素、C1-C6烷基、C1-C6卤代烷基或-O-C1-C6烷基；
R5选自卤素、C1-C6烷基、C1-C6卤代烷基、-COOC1-C6烷基、-S-C1-C6烷基、-O-C1-C6烷基、-Se-C1-C6烷基、-S(O)-C1-C6烷基或-S(O)2-C1-C6烷基；
R6选自H、卤素、C1-C6烷基、C1-C6卤代烷基或-O-C1-C6烷基；
n选自1、2、3、4、5、6、7、8或9；
条件是，当Y选自OH时，n选自1、2或3。
在一些实施方案中，X为N。
在一些实施方案中，Y选自COOH、-CONH2、-COOR3或-CONR3’R3。在一些实施方案中，Y选自-CONH2、-COOR3或-CONR3’R3。
在一些实施方案中，Y选自-COOR3或-CONR3’R3。
在一些实施方案中，Y为-COOR3。
在一些实施方案中，Y选自OH、COOH、-COOCH2CH3、-COOCH3、-COOCH(CH3)2、-COOC(CH3)3、-CONHCH3或-CONH2。在一些实施方案中，Y选自-COOCH2CH3、-COOCH3、-COOCH(CH3)2、-COOC(CH3)3或-CONHCH3。
在一些实施方案中，Y选自-COOCH2CH3、-COOCH3、-COOCH(CH3)2或-COO(CH3)3。
在一些实施方案中，R1为OH。
在一些实施方案中，R2选自C1-C6烷基、C1-C6氘代烷基或C1-C6卤代烷基。
在一些实施方案中，R2选自H、C1-C6烷基或C1-C6卤代烷基。在一些实施方案中，R2选自H、C1-C3烷基或C1-C3卤代烷基。
在一些实施方案中，R2选自C1-C6烷基或C1-C6卤代烷基。在一些实施方案中，R2选自C1-C3烷基或C1-C3卤代烷基。
在一些实施方案中，R2选自H、CH3或CF3。
在一些实施方案中，R2选自CH3或CF3。在一些实施方案中，R2选自CH3。
在一些实施方案中，R1为OH，R2为CH3。
在一些实施方案中，R3选自C1-C6烷基、C1-C6氘代烷基、C3-C6环烷基、4-6元杂环基、C6-C10芳基或5-6元杂芳基，所述C1-C6烷基、C3-C6环烷基、4-6元杂环基、C6-C10芳基或5-6元杂芳基任选地被R3a取代。
在一些实施方案中，R3选自C1-C6烷基或C1-C6氘代烷基，所述C1-C6烷基任选地被R3a取代。
在一些实施方案中，R3为C1-C6烷基。在一些实施方案中，R3为C1-C4烷基，所述C1-C4烷基任选地被R3a取代。
在一些实施方案中，R3为未取代的C1-C6烷基。在一些实施方案中，R3为未取代的C1-C4烷基。
在一些实施方案中，R3选自甲基、乙基、异丙基或叔丁基。在一些实施方案中，R3选自未取代的甲基、未取代的乙基、未取代的异丙基或未取代的叔丁基。
在一些实施方案中，R3’为H或C1-C4烷基。在一些实施方案中，R3’为H。
在一些实施方案中，R3a选自卤素、OH、CN、NH2、-COR3b、-COOR3b、-NHCOR3b、-CONHR3b、-O-C1-C6烷基或C1-C6烷基，所述C1-C6烷基任选地被R3c取代。
在一些实施方案中，R3a选自卤素、OH、CN、NH2、-O-C1-C6烷基或C1-C6烷基，所述C1-C6烷基任选地被R3c取代。
在一些实施方案中，R4选自卤素或CN。
在一些实施方案中，R4选自F、Cl或CN。
在一些实施方案中，R4为CN。
在一些实施方案中，R5选自卤素、C1-C6烷基、C1-C6卤代烷基、-COOC1-C6烷基、-S-C1-C6烷基或-O-C1-C6烷基。
在一些实施方案中，R5选自C1-C6卤代烷基、-S-C1-C6烷基、-O-C1-C6烷基、-Se-C1-C6烷基、-S(O)-C1-C6烷基或-S(O)2-C1-C6烷基。在一些实施方案中，R5选自C1-C3卤代烷基、-S-C1-C3烷基、-O-C1-C3烷基、-Se-C1-C3烷基、-S(O)-C1-C3烷基或-S(O)2-C1-C3烷基。在一些实施方案中，R5选自C1-C3卤代烷基、-S-C1-C3烷基、-O-C1-C3烷基或-Se-C1-C3烷基。
在一些实施方案中，R5选自C1-C6卤代烷基、-S-C1-C6烷基或-O-C1-C6烷基。在一些实施方案中，R5选自C1-C3卤代烷基、-S-C1-C3烷基或-O-C1-C3烷基。
在一些实施方案中，R5选自CF3、-S-CH3、-O-CH3、-Se-CH3、-S(O)-CH3或-S(O)2-CH3。
在一些实施方案中，R5选自CF3、-S-CH3或-O-CH3。在一些实施方案中，R5选自CF3或-S-CH3。在一些实施方案中，R5为CF3。
在一些实施方案中，R6选自H或卤素。
在一些实施方案中，R6选自H、F或Cl。
在一些实施方案中，R6为H。
在一些实施方案中，n选自1、2或3。
在一些实施方案中，n选自1或2。
在一些实施方案中，n为2。
在一些实施方案中，X选自CH或N；Y选自OH、COOH、-CONH2、-COOR3或-CONR3’R3，其中R3为未取代的C1-C6烷基，以及R3’为H或C1-C6烷基；R1为OH；R2选自H、C1-C3烷基或C1-C3卤代烷基；R4为CN；R5选自C1-C3卤代烷基、-S-C1-C3烷基、-O-C1-C3烷基、-Se-C1-C3烷基、-S(O)-C1-C3烷基或-S(O)2-C1-C3烷基；以及R6为H。
在一些实施方案中，X选自CH或N；Y选自OH、COOH、-COOCH2CH3、-COOCH3、-COOCH(CH3)2、-COOC(CH3)3、-CONHCH3或-CONH2；R1为OH；R2选自H、CH3或CF3；R4为CN；R5选自CF3、-S-CH3、-O-CH3、-Se-CH3、-S(O)-CH3或-S(O)2-CH3；以及R6为H。
在一些实施方案中，X选自CH或N；Y选自OH或-COOR3，其中R3为未取代的C1-C6烷基；R1为OH；R2选自H或C1-C3烷基；R4为CN；R5选自C1-C3卤代烷基、-S-C1-C3烷基、-O-C1-C3烷基、-Se-C1-C3烷基；以及R6为H。
在一些实施方案中，X选自CH或N；Y选自OH、-COOCH2CH3、-COOCH3、-COOCH(CH3)2或-COOC(CH3)3；R1为OH；R2选自H或CH3；R4为CN；R5选自CF3、-S-CH3、-O-CH3或-Se-CH3；以及R6为H。
在一些实施方案中，式(I)所示化合物或其立体异构体或其药学上可接受的盐选自式(II)所示化合物或其立体异构体或其药学上可接受的盐，
其中，X、R1、R2、R3、R4、R5、R6、n如上文的定义。
在一些实施方案中，式(I)所示化合物或其立体异构体或其药学上可接受的盐选自以下化合物或其立体异构体或其药学上可接受的盐：

另一方面，本公开提供药物组合物，所述药物组合物包含所述的式(I)或(II)化合物或其立体异构体或其药学上可接受的盐以及药学上可接受的辅料。
另一方面，本公开提供用于预防或者治疗哺乳动物由雄激素受体介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，施用治疗有效量的式(I)或(II)化合物或其立体异构体或其药学上可接受的盐、或其药物组合物。
另一方面，本公开提供式(Ⅰ)或(II)化合物或其立体异构体或其药学上可接受的盐、或其药物组合物在制备用于预防或者治疗雄激素受体介导的疾病的药物中的用途。
另一方面，本公开提供式(Ⅰ)或(II)化合物或其立体异构体或其药学上可接受的盐、或其药物组合物在预防或者治疗雄激素受体介导的疾病中的用途。
另一方面，本公开提供用于预防或者治疗雄激素受体介导的疾病的式(Ⅰ)或(II)化合物或其立体异构体或其药学上可接受的盐、或其药物组合物。
在一些实施方案中，所述的雄激素受体介导的疾病选自雄激素性脱发。
本公开的任一方面的任一实施方案，在不出现矛盾的前提下，均可以与其他实施方案进行组合。此外，在本公开任一方面的任一实施方案中，在不出现矛盾的前提下，任一技术特征可以适用于其他实施方案中的该技术特征。
术语的定义和说明
除非另有说明，本公开中所用的术语具有下列含义，本公开中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚楔键表示一个立体中心的绝对构型，用黑实键和虚键表示一个立体中心的相对构型(如脂环化合物的顺反构型)。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本公开化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本公开包含化合物的所有互变异构形式。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和非对映异构体。
本公开的化合物可以具有不对称原子如碳原子、硫原子、氮原子、磷原子或不对称双键，因此本公开的化合物可以存在特定的几何或立体异构体形式。特定的几何或立体异构体形式可以是顺式和反式异构体、E型和Z型几何异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，以及其外消旋混合物或其它混合物，例如对映异构体或非对映体富集的混合物，以上所有这些异构体以及它们的混合物都属于本公开化合物的定义范围之内。烷基等取代基中可存在另外的不对称碳原子、不对称硫原子、不对称氮原子或不对称磷原子，所有取代基中涉及到的这些异构体以及它们的混合物，也均包括在本公开化合物的定义范围之内。本公开的含有不对称原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来，光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
本文中星号“*”代表手性中心，表明所述位置的绝对构型为S-构型或者R-构型中的一种。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，是指乙基可以是未被取代的(CH2CH3)、单取代的(CH2CH2F、CH2CH2Cl等)、多取代的(CHFCH2F、CH2CHF2、CHFCH2Cl、CH2CHCl2等)或完全被取代的(CF2CF3、CF2CCl3、CCl2CCl3等)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
当任何变量(例如Ra、Rb)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。例如，如果一个基团被2个Rb所取代，则每个Rb都有独立的选项。
一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元表示在环上1或2的任意一个位置上的H被R6取代。
本文中表示连接位点。
本文中的Cm-Cn是指具有m-n范围中的整数个碳原子。例如“C1-C10”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。
术语“烷基”是指通式为CnH2n+1的烃基，该烷基可以是直链或支链的。术语“C1-C10烷基”可理解为表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和烃基。所述烷基的具体实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1，2-二甲基丙基、新戊基、1，1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、2，3-二甲基丁基、1，3-二甲基丁基或1，2-二甲基丁基等；术语“C1-C6烷基”可理解为表示具有1、2、3、4、5或6个碳原子的烷基，具体实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等。术语“C1-C3烷基”可理解为表示具有1、2或3个碳原子的直链或支链饱和烷基。所述“C1-C10烷基”可以包含“C1-C6烷基”或“C1-C3烷基”等范围，所述“C1-C6烷基”可以进一步包含“C1-C3烷基”。
术语“氘代烷基”是指烷基上的氢被氘取代，包括单氘代烷基和多氘代烷基。例如，术语“C1-C6氘代烷基”意指被一个或多个氘取代的如上所定义的C1-C6烷基，包括但不仅限于CD3、CH2CD3等等。
术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“C1-C6卤代烷基”意指被一个或多个卤素取代的如上所定义的C1-C6烷基，包括但不仅限于三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基、三氯甲基、五氟乙基和五氯乙基等等。
术语“环烷基”是指完全饱和的且以单环、并环、桥环或螺环等形式存在的碳环。除非另有指示，该碳环通常为3至10元环。术语“C3-C10环烷基”可理解为表示饱和的单环、并环、螺环或桥环，其具有3、4、5、6、7、8、9或10个碳原子。所述环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基，降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、螺[4.5]癸烷基等。术语“C3-C10环烷基”可以包含“C3-C6环烷基”，术语“C3-C6环烷基”可理解为表示饱和的单环或双环烃环，其具有3、4、5或6个碳原子，具体实例包括但不限于环丙基、环丁基、环戊基或环己基等。
术语“杂环基”是指完全饱和的或部分饱和的(整体上不是具有芳香性的杂芳族)单环、并环、螺环或桥环基团，其环原子中含有1、2、3、4或5个杂原子或杂原子团(即含有杂原子的原子团)，所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(＝O)2-、-S(＝O)-、-P(＝O)2-、-P(＝O)-、-NH-、-S(＝O)(＝NH)-、-C(＝O)NH-或-NHC(＝O)NH-等。术语“3-10元杂环基”是指环原子数目为3、4、5、6、7、8、9或10的杂环基，且其环原子中含有1、2、3、4或5个独立选自上文所述的杂原子或杂原子团。“3-10元杂环基”包括“4-7元杂环基”，其中，4元杂环基的具体实例包括但不限于氮杂环丁烷基、硫杂环丁烷基或氧杂环丁烷基；5元杂环基的具体实例包括但不限于四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、4,5-二氢噁唑基或2,5-二氢-1H-吡咯基；6 元杂环基的具体实例包括但不限于四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、三噻烷基、四氢吡啶基或4H-[1,3,4]噻二嗪基；7元杂环基的具体实例包括但不限于二氮杂环庚烷基。所述杂环基还可以是双环基，其中，5,5元双环基的具体实例包括但不限于六氢环戊并[c]吡咯-2(1H)-基；5,6元双环基的具体实例包括但不限于六氢吡咯并[1,2-a]吡嗪-2(1H)-基、5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪基或5,6,7,8-四氢咪唑并[1,5-a]吡嗪基。任选地，所述杂环基可以是上述4-7元杂环基的苯并稠合环基，具体实例包括但不限于二氢异喹啉基等。“4-10元杂环基”可以包含“5-10元杂环基”、“4-7元杂环基”、“5-6元杂环基”、“6-8元杂环基”、“4-10元杂环烷基”、“5-10元杂环烷基”、“4-7元杂环烷基”、“5-6元杂环烷基”、“6-8元杂环烷基”等范围，“4-7元杂环基”进一步可以包含“4-6元杂环基”、“5-6元杂环基”、“4-7元杂环烷基”、“4-6元杂环烷基”、“5-6元杂环烷基”等范围。本公开中尽管有些双环类杂环基部分地含有一个苯环或一个杂芳环，但所述杂环基整体上仍是无芳香性的。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。术语“C6-C20芳基”可理解为具有6～20个碳原子的芳基。特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或者具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基；或者具有13个碳原子的环(“C13芳基”)，例如芴基；或者是具有14个碳原子的环(“C14芳基”)，例如蒽基。术语“C6-C10芳基”可理解为具有6～10个碳原子的芳基。特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或者具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基。术语“C6-C20芳基”可以包含“C6-C10芳基”。
术语“杂芳基”是指具有芳香性的单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C的芳香环基。术语“5-10元杂芳基”可理解为包括这样的单环或双环芳族环系：其具有5、6、7、8、9或10个环原子，特别是5或6或9或10个环原子，且其包含1、2、3、4或5个，优选1、2或3个独立选自N、O和S的杂原子。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基或噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基或异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基或三嗪基等以及它们的苯并衍生物，例如喹啉基、喹唑啉基或异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基或吩噁嗪基等。术语“5-6元杂芳基”指具有5或6个环原子的芳族环系，且其包含1、2或3个，优选1-2个独立选自N、O和S的杂原子。
术语“卤”或“卤素”是指氟、氯、溴或碘。
术语“羟基”是指-OH基团。
术语“氰基”是指-CN基团。
术语“氨基”是指-NH2基团。
术语“治疗有效量”意指
(i)治疗特定疾病、病况或病症，(ii)减轻、改善或消除特定疾病、病况或病症的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病况或病症的一种或多种症状发作的本公开化合物的用量。
构成“治疗有效量”的本公开化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“治疗”意为将本公开所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本公开所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，包括预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
本公开中，术语“哺乳动物”的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指药学上可接受的酸加成或碱加成的盐，包括化合物与无机酸或有机酸形成的盐，以及化合物与无机碱或有机碱形成的盐。
术语“药物组合物”是指一种或多种本公开的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体施用本公开的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising可理解为开放的、非排他性的意义，即“包括但不限于”。
本公开还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。
某些同位素标记的本公开化合物(例如用3H及14C标记)可用于化合物和/或底物组织分布分析中。氚化(即3H)和碳-14(即14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本公开化合物。
本公开的药物组合物可通过将本公开的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
施用本公开化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本公开的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本公开的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
本文所述的通式(Ⅰ)化合物的所有施用方法中，每天给药的剂量为0.01mg/kg到500mg/kg体重，以单独或分开剂量的形式。
本公开的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其它化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本公开的实施例。
本公开的具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本公开的化学变化及其所需的试剂和物料。为了获得本公开的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
实施例
下面通过实施例对发明进行详细描述，但并不意味着对本公开任何不利限制。本文已经详细地描述了本公开，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本公开精神和范围的情况下针对本公开具体实施方式进行各种改变和改进将是显而易见的。
本公开所使用的所有试剂是市售的，无需进一步纯化即可使用。
除非另作说明，混合溶剂表示的比例是体积混合比例。下文的洗脱剂可由两种或多种溶剂形成混合洗脱剂，其比值为各溶剂的体积比，如“乙酸乙酯/石油醚＝5/1”表示梯度洗脱过程中，混合洗脱剂中的乙酸乙酯与石油醚的体积用量比为5:1。
除非另作说明，否则，％是指wt％。
化合物经手工或软件命名，市售化合物采用供应商目录名称。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10- 6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)；“IC50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。
缩略词：
TBAF：四丁基氟化铵；THF：四氢呋喃；TsOH：对甲苯磺酸；BnBr：溴化苄；DMF：N,N-二甲基甲酰胺；Cy2NH：二环己基胺；AcCl：乙酰氯；EtOH：乙醇；EA：乙酸乙酯；DMAc：N,N-二甲基乙酰胺；LiOH.H2O：氢氧化锂一水合物；BnOH：苯甲醇；DCC:N,N'-二环己基碳二亚胺；DMAP：4-二甲氨基吡啶；DCM：二氯甲烷；ACN：乙腈；RuCl3：三氯化钌；MeOH：甲醇；i-PrOH：异丙醇；t-BuOH：叔丁醇；TMSCHN2：三甲基硅基重氮甲烷；Toluene：甲苯；TEA：三乙胺；TMSCF3：(三氟甲基)三甲基硅烷；CsF：氟化铯；Pd2(dba)3：三(二亚苄基丙酮)二钯；dppf：1,1'-双(二苯基膦)二茂铁；DIEA:N,N-二异丙基乙胺；SOCl2：氯化亚砜；MeMgBr:甲基溴化镁；m-CPBA：间氯过氧苯甲酸；NaBH4：硼氢化钠；EtONa：乙醇钠；Acetone：丙酮；NaIO4：高碘酸钠；DMSO：二甲基亚砜。
实施例1:N-[6-氰基-5-(三氟甲基)吡啶-3-基]-2,6-二羟基-2-甲基-己酰胺(化合物001)的合成
步骤1：溴-[4-[叔丁基(二甲基)甲硅烷基]氧丁基]镁的合成
在氮气保护下，将镁(545mg，22.42mmol)和4-溴丁氧基-叔丁基-二甲基硅烷(5.0g，18.71mmol)溶于四氢呋喃(50mL)，在25℃下，加入碘单质(1粒)，加完，反应液在70℃搅拌4小时。将反应液冷却至室温，直接用于下一步反应。
步骤2：6-[叔丁基(二甲基)甲硅烷基]氧基-N-[6-氰基-5-(三氟甲基)吡啶-3-基]-2-羟基-2-甲基-己酰胺的合成
在-78℃、氮气保护下，将上一步反应液(33.3mL)缓慢滴加到N-[6-氰基-5-(三氟甲基)吡啶-3-基]-2-氧代-丙酰胺(化合物1-3，1.0g，3.89mmol)的四氢呋喃溶液(20mL)中，15分钟滴加 完，反应液在-78℃搅拌1h。LCMS显示反应完毕，反应液用饱和氯化铵水溶液淬灭，用乙酸乙酯(50mL*2)萃取，有机相用饱和食盐水洗一次，有机相用无水硫酸钠干燥，过滤，浓缩。粗产品经柱层析(二氧化硅，乙酸乙酯/石油醚＝1/1)纯化得化合物1-4(550mg)。
MS(ESI):m/z＝446.20[M+H]+.
步骤3：N-[6-氰基-5-(三氟甲基)吡啶-3-基]-2,6-二羟基-2-甲基-己酰胺的合成
将四丁基氟化铵(1.11mL,1M in THF)和中间体化合物1-4(450mg，1.01mmol)溶于四氢呋喃(15mL)中，反应液在25℃搅拌1h。将反应液浓缩，粗产品经柱层析(二氧化硅，乙酸乙酯/石油醚＝1/1)纯化得到目标化合物001(115mg)。
MS(ESI):m/z＝332.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),9.40(d,J＝2.2Hz,1H),8.92(d,J＝2.2Hz,1H),5.85(s,1H),4.33(t,J＝5.1Hz,1H),3.36(d,J＝5.7Hz,2H),1.81–1.69(m,1H),1.67–1.53(m,1H),1.53–1.43(m,1H),1.43–1.32(m,5H),1.28–1.14(m,1H).
实施例2:N-[6-氰基-5-(三氟甲基)吡啶-3-基]-2,4-二羟基-2-甲基-丁酰胺(化合物002)的合成
步骤1：((1,3-二氧戊环-2-基)甲基)溴化镁的合成
在氮气保护下，将2-(溴甲基)-1,3-二氧戊环(20g,119.76mmol)，氯化锂(10.15g,239.52mmol)和镁粉(3.49g,143.71mmol)加入到四氢呋喃(200mL)中。反应液在70℃搅拌4h。反应液可直接用于下一步反应。
步骤2：N-[6-氰基-5-(三氟甲基)吡啶-3-基]-3-(1,3-二氧戊环-2-基)-2-羟基-2-甲基丙酰胺的合成
在-78℃、氮气保护下，将上一步反应液(200mL)溶液缓慢滴加到N-[6-氰基-5-(三氟甲基)吡啶-3-基]-2-氧代-丙酰胺(化合物1-3，2.0g，7.78mmol)的四氢呋喃(20mL)溶液中。滴毕，将反应液升温至70℃，搅拌反应18h。LCMS显示反应结束。反应液用饱和氯化铵水溶液淬灭，用乙酸乙酯(50mL*2)萃取，有机相用饱和食盐水洗涤一次，有机相用无水硫酸钠干燥，过滤，浓缩。粗产品经柱层析(二氧化硅，乙酸乙酯/石油醚＝1/1)纯化得目标化合物2-3(220mg)。
MS(ESI):m/z＝346.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),9.36(d,J＝2.2Hz,1H),8.87(d,J＝2.2Hz,1H),6.06(s,1H),5.06–4.98(m,1H),3.89–3.62(m,4H),2.12–2.05(m,1H),1.98–1.89(m,1H),1.40(s,3H).
步骤3：N-[6-氰基-5-(三氟甲基)吡啶-3-基]-2-羟基-2-甲基-4-氧代丁酰胺的合成
将中间体化合物2-3(150mg,434.44μmol)和对甲苯磺酸(22.63mg,434.44μmol)加入到四氢呋喃(10mL)中。反应液于室温下搅拌18h。LCMS显示反应结束，依次加入水(60mL)和 乙酸乙酯(80mL)，有机相用水(30mL*2)洗涤，洗涤后的有机相用无水硫酸钠干燥，过滤，浓缩滤液得化合物2-4(120mg)。
MS(ESI):m/z＝302.1[M+H]+.
步骤4：N-[6-氰基-5-(三氟甲基)吡啶-3-基]-2,4-二羟基-2-甲基-丁酰胺的合成
将中间体化合物2-4(100mg,331.98μmol)加入到四氢呋喃(1mL)中。冰水浴下加入硼氢化钠(18.84mg,497.97μmol)。反应液于冰水浴下搅拌18h。冰水浴下加入2mL水淬灭。将反应液浓缩，残留物经Prep-HPLC[Phenomenex C18，5μm二氧化硅，30mm直径，80mm长度；用水(含7mmol/L NH4HCO3)和乙腈的极性递减的混合物作为洗脱液；乙腈梯度比例60％-70％，洗脱时间：9分钟]纯化得到目标化合物002(8.2mg)。
MS(ESI):m/z＝304.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ9.36(d,J＝2.2Hz,1H),8.89(d,J＝2.2Hz,1H),6.05(s,1H),3.62–3.43(m,2H),2.05–1.93(m,1H),1.85–1.73(m,1H),1.37(s,3H).
实施例3：5-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-4-羟基-4-甲基-5-氧代戊酸乙酯(化合物003)的合成
步骤1：5-(苄氧基)-4,5-二氧代戊酸的合成
将2-酮戊二酸(2g,13.69mmol)溶于N,N-二甲基甲酰胺(80mL)，依次加入二环己基胺(1.24g,6.84mmol,1.36mL)和溴化苄(1.17g,6.84mmol)，升温至50℃搅拌过夜。LC-MS显示反应结束。将反应液倒入甲基叔丁基醚(300mL)中，水(100mL*3)洗三次，无水硫酸钠干燥有机相，过滤，浓缩滤液。残留物经柱层析(二氧化硅，乙酸乙酯/石油醚＝1/2)分离纯化得到化合物3-2(1.1g)。
MS(ESI):m/z＝235.00[M-H]-.
1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),7.48–7.32(m,5H),5.26(s,2H),3.09-3.01(m,2H),2.52–2.46(m,2H).
步骤2：5-(苄氧基)-4,5-二氧代戊酸乙酯的合成
将中间体化合物3-2(1g,4.23mmol)溶于无水乙醇(10mL)中，冰水浴条件下，加入乙酰氯(365mg,4.66mmol)，保温，继续搅拌反应3h。LC-MS显示反应结束。用乙酸乙酯(100mL)稀释反应液，用饱和碳酸氢钠水溶液(50mL*3)洗涤三次，无水硫酸钠干燥有机相，过滤，浓缩滤液，残留物经柱层析(二氧化硅，乙酸乙酯/石油醚＝1/5)分离纯化得到化合物3-3(700mg)。
MS(ESI):m/z＝282.1[M+NH4]+.
1H NMR(400MHz,Chloroform-d)δ7.45–7.25(m,5H),5.30(s,2H),4.20–4.05(m,2H),3.20–3.12(m,2H),2.70–2.62(m,2H),1.29–1.21(m,3H).
步骤3：5-乙氧基-2,5-二氧代戊酸的合成
将中间体化合物3-3(500mg,1.89mmol)溶于乙酸乙酯(10mL)中，加入Pd/C(46mg)，氢气氛围下，搅拌反应15分钟。TLC显示反应结束(展开剂：二氯甲烷/甲醇＝10/1，Rf＝0.4)。将反应液过滤，浓缩滤液得到化合物3-4(300mg)。
1H NMR(400MHz,Chloroform-d)δ4.2–4.08(m,2H),3.26–3.12(m,2H),2.77–2.62(m, 2H),1.31–1.20(m,3H).
步骤4：5-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-4,5-二氧代戊酸乙酯的合成
将中间体化合物3-4(300mg,2.05mmol)溶于N,N-二甲基乙酰胺(12mL)中，冷却至-10℃，加入二氯亚砜(244.22mg,2.05mmol)，搅拌10分钟，加入5-氨基-3-(三氟甲基)吡啶-2-甲腈(384mg,2.05mmol)，保温继续搅拌3h。LC-MS显示反应结束。将反应液倒入冰水(100mL)中，用乙酸乙酯(30mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。残留物经柱层析(二氧化硅，乙酸乙酯/石油醚＝1/2)分离纯化得到化合物3-5(300mg)。
MS(ESI):m/z＝344.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),9.40(d,J＝2.2Hz,1H),8.91(d,J＝2.3Hz,1H),4.11–4.02(m,2H),3.32–3.16(m,2H),2.68–2.60(m,2H),1.25–1.15(m,3H).
步骤5：5-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-4-羟基-4-甲基-5-氧代戊酸乙酯的合成
将中间体化合物3-5(100mg,291.32μmol)溶于四氢呋喃(10mL)中，冷却至-78℃，滴加甲基溴化镁(0.5M in THF,1.40mL)，保温反应2h,缓慢升温至室温，搅拌过夜。LC-MS显示反应结束。将反应液倒入冰水(40mL)中，用乙酸乙酯(15mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液，残留物经Prep-HPLC[YMC-TAR柱5μm二氧化硅，30mm直径，150mm长度；用水(含7mmol/L NH4HCO3)和乙腈的极性递减的混合物作为洗脱液；乙腈梯度比例45％-75％，洗脱时间：9分钟]纯化得到目标化合物003(15mg)。
MS(ESI):m/z＝360.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ9.37(d,J＝2.3Hz,1H),8.89(d,J＝2.3Hz,1H),6.01(s,1H),4.06–3.95(m,2H),2.47–2.39(m,1H)，2.29–2.18(m,1H),2.10–1.97(m,1H),1.94–1.81(m,1H),1.37(s,3H),1.18–1.10(m,3H).
实施例4：5-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-4-羟基-4-甲基-5-氧代戊酸(化合物004)的合成
将化合物003(80mg,222.65μmol)分散于四氢呋喃(3mL)和水(1mL)的混合溶液中，加入氢氧化锂一水合物(8.55mg,203.76μmol)，室温搅拌3h。LC-MS显示反应结束。将反应液倒入0.5M盐酸溶液(15mL)中，用乙酸乙酯(5mL*3)萃取三次，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。残留物经RP-FLASH[色谱柱:40g C18 Column,20-35μm,流动相A:纯水,流动相B:乙腈；流速:18mL/min；梯度:30％ B to 50％B,洗脱时间：10分钟]纯化得到目标化合物004(15mg)。
MS(ESI):m/z＝332.0[M+H]+。
1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),9.38(d,J＝2.2Hz,1H),8.92–8.88(m,1H),2.43–2.32(m,1H),2.22–2.12(m,1H),2.06–1.93(m,1H),1.91–1.80(m,1H),1.37(s,3H).
实施例5&6：(6S)/(6R)-6-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸乙酯(化合物005&006)的合成
步骤1：环戊-1-烯-1-羧酸苄酯的合成
将起始物料5-1(8g,71.35mmol)溶于二氯甲烷(200mL)中，加入苯甲醇(9.26g,85.62mmol)、N,N'-二环己基碳二亚胺(17.67g,85.62mmol)和4-二甲氨基吡啶(871.64mg,7.13mmol)，室温搅拌过夜。TLC(展开剂：乙酸乙酯/石油醚＝1/3,Rf＝0.6)显示反应结束。浓缩反应液，残留物经柱层析(二氧化硅，乙酸乙酯/石油醚＝0/1～1/4)纯化得到标题化合物5-2(13g)。
1H NMR(400MHz,Chloroform-d)δ7.42–7.27(m,5H),6.87–6.79(m,1H),5.19(s,2H),2.65–2.55(m,2H),2.55–2.45(m,2H),2.02–1.90(m,2H).
步骤2：6-(苄氧基)-5,6-二氧代己酸的合成
将中间体化合物5-2(5g,24.72mmol)溶于四氯化碳(120mL)和乙腈(120mL)的混合溶剂中，0℃条件下，滴加高碘酸钠(10.58g,49.44mmol)的水溶液(120mL)。滴毕，再加入三氯化钌(512.79mg,2.47mmol)固体，缓慢升温至室温，继续搅拌6h。LC-MS显示反应完毕。将反应液倒入水(300mL)中，用二氯甲烷(150mL*3)萃取,合并有机相，水(100mL*3)洗三次，无水硫酸钠干燥，过滤，浓缩滤液。残留物经柱层析(二氧化硅，乙酸乙酯：石油醚＝0/1～1/1)纯化得到标题化合物5-3(2.5g)。
MS(ESI):m/z＝249.10[M-H]-.
1H NMR(400MHz,Chloroform-d)δ7.44–7.31(m,5H),5.28(s,2H),2.99–2.88(m,2H),2.47–2.38(m,2H),2.07–1.90(m,2H).
步骤3：2-氧代己二酸1-苄基-6-乙酯的合成
将中间体化合物5-3(1g,4.00mmol)溶于无水乙醇(10mL)中，冰水浴条件下，滴加乙酰氯(378.83mg,4.82mmol)，保温，继续反应5h。LC-MS显示反应结束。将反应液倒入二氯甲烷(30mL)中，水(10mL*2)洗两次，无水硫酸钠干燥，过滤，浓缩滤液。残留物经柱层析(二氧化硅，乙酸乙酯/石油醚＝0/1～1/1)分离纯化得到标题化合物5-4(800mg)。
MS(ESI):m/z＝279.10[M+H]+.
1H NMR(400MHz,Chloroform-d)δ7.44–7.31(m,5H),5.28(s,2H),4.17–4.07(m,2H),2.97–2.89(m,2H),2.42–2.32(m,2H),2.03–1.90(m,2H),1.41–1.20(m,3H).
步骤4：6-乙氧基-2,6-二氧代己酸的合成
将中间体化合物5-4(350mg,1.26mmol)溶于乙酸乙酯(4mL)中，加入Pd/C(30mg)，氢气氛围下，搅拌反应15min。TLC(展开剂：甲醇/二氯甲烷＝1/10,Rf＝0.3)显示原料反应完毕。过滤，浓缩滤液得标题化合物5-5(220mg)。
1H NMR(400MHz,Chloroform-d)δ4.19–4.09(m,2H),3.07–2.99(m,2H),2.44–2.35(m,2H),2.07–1.94(m,2H),1.30–1.22(m,3H).
步骤5：6-(6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-5,6-二氧代己酸乙酯的合成
将中间体化合物5-5(360mg,1.91mmol)溶于N,N-二甲基乙酰胺(7.97mL)，冷却至-10℃，滴加二氯亚砜(273.12mg,2.30mmol)。滴毕，加入5-氨基-3-(三氟甲基)吡啶-2-甲腈(357.98mg,1.91mmol)固体，保温搅拌反应2h。LC-MS显示反应结束。用乙酸乙酯(50mL)稀释反应液，水(20mL*3)洗三次,无水硫酸钠干燥，过滤，浓缩滤液。残留物经柱层析(二氧化硅，乙酸乙酯/石油醚＝0/1～1/1)分离纯化得到标题化合物5-6(450mg)。
MS(ESI):m/z＝358.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),9.39(d,J＝2.3Hz,1H),8.85(d,J＝2.3Hz,1H),4.11–3.98(m,2H),3.02–2.94(m,2H),2.42–2.33(m,2H),1.88–1.76(m,2H),1.21–1.15(m,3H).
步骤6：6-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸乙酯的合成
采用步骤1-5描述的方法以放大的规模制备得到中间体5-6，取中间体化合物5-6(17g,47.58mmol)溶于四氢呋喃(200mL)中，氮气氛围下，冷却至-78℃，滴加甲基溴化镁的四氢呋喃溶液(3M,47.58mL)，保温搅拌反应过夜。LC-MS显示反应结束。-78℃条件下，缓慢加入饱和氯化铵水溶液(350mL)淬灭反应，用乙酸乙酯(100mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液，残留物经柱层析(二氧化硅，乙酸乙酯/石油醚＝0/1～1/1)分离纯化得到标题化合物5-7(11g)。
MS(ESI):m/z＝374.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),9.40(d,J＝2.2Hz,1H),8.91(d,J＝2.3Hz,1H),5.92(s,1H),4.07–3.97(m,2H),2.31–2.22(m,2H),1.81–1.65(m,3H),1.50–1.38(m,1H),1.36(s,3H),1.20–1.11(m,3H).
步骤7：(6S)/(6R)-6-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸乙酯的合成
化合物5-7(1g)经SFC拆分[色谱柱:Chiral Cel OJ-H 150×4.6mm I.D.,5μm；流动相:A:二氧化碳；B:甲醇(0.05％二乙醇胺)，梯度：流动相B：5％to 40％，洗脱4.5分钟；流动相B：5％，洗脱1.5分钟；流速:2.5mL/min；柱温：40℃]得到化合物005(310mg)和化合物006(330mg)：
化合物005：
SFC保留时间：2.247min.
Chiral-HPLC[色谱柱:AD-RH(大赛璐150×4.6mm,5μm)；流动相:A:水；B:乙腈，梯度：流动相B：10％to 90％，洗脱35分钟；流速:1.0mL/min；柱温：25℃]保留时间：24.980min.
MS(ESI):m/z＝374.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),9.40(d,J＝2.2Hz,1H),8.91(d,J＝2.3Hz,1H),5.92(s,1H),4.07–3.97(m,2H),2.31–2.22(m,2H),1.81–1.65(m,3H),1.50–1.38(m,1H),1.36(s,3H),1.20–1.11(m,3H).
化合物006：
SFC保留时间：3.064min.
Chiral-HPLC[色谱柱:AD-RH(大赛璐150×4.6mm,5μm)；流动相:A:水；B:乙腈，梯度：流动相B：10％to 90％，洗脱35分钟；流速:1.0mL/min；柱温：25℃]保留时间：16.224min.
MS(ESI):m/z＝374.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),9.40(d,J＝2.2Hz,1H),8.91(d,J＝2.3Hz,1H),5.92(s,1H),4.07–3.97(m,2H),2.31–2.22(m,2H),1.81–1.65(m,3H),1.50–1.38(m,1H),1.36(s,3H),1.20–1.11(m,3H).
实施例7&8：(6S)/(6R)-6-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸甲酯(化合物007&008)的合成
步骤1：(6S)/(6R)-6-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸的合成
将化合物005(或006)(270mg,723.23μmol)分散于四氢呋喃(3mL)和水(1mL)的混合溶剂中，加入氢氧化锂一水合物(34.66mg,826.02μmol)，室温搅拌过夜。LC-MS显示反应结束。将反应液倒入0.1M盐酸溶液(15mL)中，用乙酸乙酯(5mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液得到化合物7-1(或8-1)(240mg)。
化合物7-1：
MS(ESI):m/z＝346.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),10.70(s,1H),9.40(d,J＝2.2Hz,1H),8.91(d,J＝2.3Hz,1H),5.90(s,1H),2.19(t,J＝7.1Hz,2H),1.81–1.54(m,3H),1.48–1.37(m,1H),1.37(s,3H).
化合物8-1：
MS(ESI):m/z＝346.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),10.69(s,1H),9.39(d,J＝2.2Hz,1H),8.91(d,J＝2.2Hz,1H),5.90(s,1H),2.19(t,J＝7.1Hz,2H),1.82–1.54(m,3H),1.48–1.38(m,1H),1.36(s,3H).
步骤2：(6S)/(6R)-6-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸甲酯的合成
将中间体化合物7-1(或8-1)(50mg,144.81μmol)溶于甲醇(4mL)中，室温滴加二氯亚砜(51.69mg,434.44μmol)，升温至60℃，搅拌反应2h。LC-MS显示反应完毕。减压蒸除溶剂，残留物经Prep-HPLC[YMC-TAR柱5μm二氧化硅，30mm直径，150mm长度；用水(含7mmol/L NH4HCO3)和乙腈的极性递减的混合物作为洗脱液；乙腈梯度比例40％-70％，洗脱时间：9.5分钟]纯化得到目标化合物007(12mg)(或008(15mg))。
化合物007：
Chiral-HPLC[色谱柱:AD-RH(大赛璐150×4.6mm,5μm)；流动相:A:水；B:乙腈，梯度：流动相B：10％to 90％，洗脱35分钟；流速:1.0mL/min；柱温：25℃]保留时间：23.394min.
MS(ESI):m/z＝360.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),9.40(d,J＝2.2Hz,1H),8.91(d,J＝2.2Hz,1H),5.91(s,1H),3.56(s,3H),2.33–2.25(m,2H),1.83–1.55(m,3H),1.51–1.39(m,1H),1.36(s,3H).
化合物008：
Chiral-HPLC[色谱柱:AD-RH(大赛璐150×4.6mm,5μm)；流动相:A:水；B:乙腈，梯度： 流动相B：10％to 90％，洗脱35分钟；流速:1.0mL/min；柱温：25℃]保留时间：15.201min.
MS(ESI):m/z＝360.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),9.40(d,J＝2.2Hz,1H),8.91(d,J＝2.3Hz,1H),5.94(s,1H),3.56(s,3H),2.32–2.24(m,2H),1.81–1.53(m,3H),1.50–1.38(m,1H),1.36(s,3H).
实施例9&10：(6S)/(6R)-6-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸异丙酯(化合物009&010)的合成
将中间体化合物7-1(或8-1)(50mg,144.81μmol)溶于异丙醇(4mL)中，室温滴加二氯亚砜(52mg,434.44μmol)，升温至60℃，搅拌反应2h。LC-MS显示反应完毕。减压蒸除溶剂，残留物经Prep-HPLC[YMC-TAR柱5μm二氧化硅，30mm直径，150mm长度；用水(含7mmol/L NH4HCO3)和乙腈的极性递减的混合物作为洗脱液；乙腈梯度比例45％-75％，洗脱时间：11分钟]纯化得到目标化合物009(10mg)(或010(12mg))。
化合物009：
Chiral-HPLC[色谱柱:AD-RH(大赛璐150×4.6mm,5μm)；流动相:A:水；B:乙腈，梯度：流动相B：10％to 90％，洗脱35分钟；流速:1.0mL/min；柱温：25℃]保留时间：26.011min.
MS(ESI):m/z＝388.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),9.39(d,J＝2.2Hz,1H),8.91(d,J＝2.3Hz,1H),5.91(s,1H),4.93–4.79(m,1H),2.28–2.17(m,2H),1.83–1.53(m,3H),1.50–1.38(m,1H),1.36(s,3H),1.18–1.12(m,6H).
化合物010：
Chiral-HPLC[色谱柱:AD-RH(大赛璐150×4.6mm,5μm)；流动相:A:水；B:乙腈，梯度：流动相B：10％to 90％，洗脱35分钟；流速:1.0mL/min；柱温：25℃]保留时间：16.601min.
MS(ESI):m/z＝388.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),9.39(d,J＝2.2Hz,1H),8.91(d,J＝2.3Hz,1H),5.91(s,1H),4.93–4.80(m,1H),2.28–2.17(m,2H),1.81–1.54(m,3H),1.49–1.39(m,1H),1.36(s,3H),1.18–1.11(m,6H).
实施例11&12：(6S)/(6R)-6-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸叔丁酯(化合物011&012)的合成
将中间体化合物7-1(或8-1)(300.00mg,868.88μmol)、O-叔丁基-N,N'-二异丙基异脲(1.74g,8.69mmol)加入到二氯甲烷(7.5mL)和叔丁醇(644.01mg,8.69mmol)中，室温搅拌15h。LCMS显示反应完全，过滤反应液，滤液浓缩，残留物经Prep-HPLC[Phenomenex C18，5μm二氧化硅，30mm直径，80mm长度；使用纯水和乙腈的混合物(乙腈含量：60％-70％)作为洗脱液，洗脱时间：8分钟]纯化得到目标化合物011(150mg)(或012(110mg))。
化合物011：
Chiral-HPLC[色谱柱:AD-RH(大赛璐150×4.6mm,5μm)；流动相:A:水；B:乙腈，梯度：流动相B：10％to 90％，洗脱35分钟；流速:1.0mL/min；柱温：25℃]保留时间：32.009min.
MS(ESI):m/z＝400.1[M-H]-.
1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),9.39(s,1H),9.01–8.88(m,1H),5.90(s,1H),2.22–2.13(m,2H),1.82–1.48(m,4H),1.44–1.32(m,12H).
化合物012：
Chiral-HPLC[色谱柱:AD-RH(大赛璐150×4.6mm,5μm)；流动相:A:水；B:乙腈，梯度：流动相B：10％to 90％，洗脱35分钟；流速:1.0mL/min；柱温：25℃]保留时间：17.147min.
MS(ESI):m/z＝400.1[M-H]-.
1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),9.39(s,1H),9.00–8.84(m,1H),5.89(s,1H),2.22–2.11(m,2H),1.83–1.49(m,4H),1.46–1.32(m,12H).
实施例13&14：(6S)/(6R)-6-((6-氰基-5-(甲硫基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸乙酯(化合物013&014)的合成
步骤1：6-溴-5-氟吡啶-3-胺的合成
将5-氟吡啶-3-胺(13.0g,116mmol)溶于N,N-二甲基甲酰胺(60mL)中，然后放入冰浴中冷却，冰浴下向其中缓慢滴加N-溴代丁二酰亚胺(20.64g,116mmol)的N,N-二甲基甲酰胺溶液(50mL)，然后保持冰浴继续反应30分钟。LC-MS监测至反应完全。将反应液倒入500mL水中，用乙酸乙酯(200mL*3)萃取，有机相合并后依次用水(300mL*2)洗涤，饱和食盐水(300mL*2)洗涤，无水硫酸钠干燥，过滤，减压浓缩滤液后得棕黄色粗品，经柱层析色谱(二氧化硅，石油醚/乙酸乙酯＝10/1～1/1)纯化得到中间体13-2(8.4g)。
MS(ESI):m/z＝190.90,192.90[M+H]+。
步骤2：5-氨基-3-氟吡啶-2-甲腈的合成
将中间体13-2(6g,31.41mmol)，氰化亚铜(11.25g,125.64mmol)，分散于N,N-二甲基甲酰胺(100mL)，然后装上氮气球，置换气体三次，气体保护下放入130℃油浴中反应6小时。LC-MS显示反应结束。将反应液冷却至室温，过滤，减压浓缩滤液，残留物经柱层析色谱纯化(二氧化硅，石油醚/乙酸乙酯＝1/2)得到标题化合物13-3(2.6g)。
MS(ESI):m/z＝138.0[M+H]+。
步骤3：5-氨基-3-(甲硫基)吡啶-2-甲腈合成
将化合物13-3(2g,14.59mmol)加入到反应瓶中，加入N,N-二甲基甲酰胺(30mL)溶解，室温搅拌下加入甲硫醇钠(2.04g,29.11mmol)，所得反应液在室温下搅拌12小时。将反应液倒入水(200mL)中，用乙酸乙酯(80mL*5)萃取，合并有机相后，依次用水(200mL*2)洗涤，饱和食盐水(400mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩滤液得标题化合物13-4(1.7g)。
MS(ESI):m/z＝166.0[M+H]+。
1H NMR(400MHz,DMSO-d6)δ7.75(d,J＝2.3Hz,1H),6.84(d,J＝2.3Hz,1H),6.47(s,2H),2.50(s,3H).
步骤4：6-(6-氰基-5-(甲硫基)吡啶-3-基)氨基)-5,6-二氧代己酸乙酯的合成
将中间体化合物5-5(1.37g,7.28mmol)溶于N,N-二甲基乙酰胺(15mL)，冷却至-10℃，滴加二氯亚砜(1.04g,8.72mmol)，滴毕，加入化合物13-4(1.2g,7.26mmol)固体，搅拌反应12h。LC-MS显示反应可行。用乙酸乙酯(30mL)稀释，水洗(20mL*3)三次,无水硫酸钠干燥，过滤，浓缩滤液。残留物经柱层析(二氧化硅，乙酸乙酯：石油醚＝0/1～1/1)分离纯化得到化合物13-5(1.6g)。
MS(ESI):m/z＝336.0[M+H]+.
1H NMR(400MHz,Chloroform-d)δ8.96(s,1H),8.41(s,2H),4.19–4.07(m,2H),3.13–3.04(m,2H),2.60(s,3H),2.46–2.38(m,2H),2.09–1.96(m,2H),1.31–1.22(m,3H).
步骤5：6-((6-氰基-5-(甲硫基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸乙酯的合成
将中间体化合物13-5(1g,2.98mmol)溶于四氢呋喃(20mL)中，冷却至-78℃，滴加甲基溴化镁(3M in Et2O,2.98mL)，缓慢升温至室温搅拌过夜。LC-MS显示反应可行。0℃环境下，加入饱和氯化铵水溶液(50ml)淬灭反应，恢复室温，用乙酸乙酯(20mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。残留物经柱层析(二氧化硅，乙酸乙酯：石油醚＝1/4)纯化得到化合物13-6(600mg)。
MS(ESI):m/z＝352.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.95(d,J＝2.1Hz,1H),8.41(d,J＝2.1Hz,1H),5.86(s,1H),4.08–3.97(m,2H),2.58(s,3H),2.26(t,J＝7.1Hz,2H),1.80–1.66(m,2H),1.64–1.53(m,1H),1.44(d,J＝7.6Hz,1H),1.35(s,3H),1.20–1.11(m,3H).
步骤6：(6S)/(6R)-6-((6-氰基-5-(甲硫基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸乙酯的合成
化合物13-6(1g)经SFC拆分[色谱柱:Chiral Cel OJ-H 150×4.6mm I.D.,5μm；流动相:A:二氧化碳；B:乙醇(0.05％二乙醇胺)，梯度：流动相B：5％to 40％，洗脱4.5分钟；流动相B： 5％，洗脱1.5分钟；流速:2.5mL/min；柱温：40℃]得到化合物013(350mg)和化合物014(370mg)。
化合物013：
SFC保留时间：3.468min.
Chiral-HPLC[色谱柱:AD-RH(大赛璐150×4.6mm,5μm)；流动相:A:水；B:乙腈，梯度：流动相B：10％to 90％，洗脱35分钟；流速:1.0mL/min；柱温：25℃]保留时间：21.615min.
MS(ESI):m/z＝352.00[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.95(d,J＝2.1Hz,1H),8.41(d,J＝2.1Hz,1H),5.86(s,1H),4.08–3.97(m,2H),2.58(s,3H),2.31–2.22(m,2H),1.80–1.66(m,2H),1.64–1.53(m,1H),1.47–1.40(m,1H),1.35(s,3H),1.20–1.11(m,3H).
化合物014：
SFC保留时间：4.292min.
Chiral-HPLC[色谱柱:AD-RH(大赛璐150×4.6mm,5μm)；流动相:A:水；B:乙腈，梯度：流动相B：10％to 90％，洗脱35分钟；流速:1.0mL/min；柱温：25℃]保留时间：15.077min.
MS(ESI):m/z＝352.00[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.95(d,J＝2.1Hz,1H),8.41(d,J＝2.1Hz,1H),5.86(s,1H),4.08–3.97(m,2H),2.58(s,3H),2.31–2.22(m,2H),1.80–1.66(m,2H),1.64–1.53(m,1H),1.47–1.40(m,1H),1.35(s,3H),1.20–1.11(m,3H).
实施例15&16：(6S)/(6R)-6-((6-氰基-5-(甲硫基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸甲酯(化合物015&016)的合成
步骤1：(6S)/(6R)-6-((6-氰基-5-(甲硫基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸的合成
将化合物013(或化合物014)(100mg,284.56μmol)分散于四氢呋喃(3mL)和水(1mL)的混合溶剂中，加入氢氧化锂一水合物(35.82mg,853.68μmol)，室温搅拌3h。LC-MS显示反应结束。将反应液倒入0.1M盐酸溶液(15mL)中，用乙酸乙酯(5mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液得到化合物15-1(90mg)(或16-1)。
化合物15-1：
MS(ESI):m/z＝324.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),10.31(s,1H),8.95(d,J＝2.1Hz,1H),8.41(d,J＝2.1Hz,1H),5.84(s,1H),2.58(s,3H),2.19(t,J＝7.1Hz,2H),1.81–1.52(m,3H),1.46–1.37(m,1H),1.35(s,3H).
化合物16-1：
MS(ESI):m/z＝324.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),10.31(s,1H),8.95(d,J＝2.1Hz,1H),8.41(d,J＝2.1Hz,1H),5.84(s,1H),2.58(s,3H),2.19(t,J＝7.1Hz,2H),1.81–1.52(m,2H),1.47–1.38(m,1H),1.35(s,3H).
步骤2：(6S)/(6R)-6-((6-氰基-5-(甲硫基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸甲酯的合成
将化合物15-1(或16-1)(90mg,278.32μmol)溶于甲苯(4mL)和甲醇(1mL)的混合溶剂中，冷却至0℃，滴加三甲基硅基重氮甲烷(2M in正己烷,278.32μL)，保温搅拌反应2h。LC-MS显示反应结束。滴加两滴醋酸淬灭反应，再用乙酸乙酯(20mL)稀释反应液，水洗(10mL*3)三次，无水硫酸钠干燥有机相，过滤，浓缩。残留物经柱层析(二氧化硅，乙酸乙酯/石油醚＝1/1)纯化得到化合物015(65mg)(或016(65mg))。
化合物015：
Chiral-HPLC保留时间:19.582min.
MS(ESI):m/z＝338.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.95(d,J＝2.1Hz,1H),8.41(d,J＝2.1Hz,1H),5.86(s,1H),3.56(s,3H),2.58(s,3H),2.33–2.22(m,2H),1.81–1.64(m,2H),1.64–1.52(m,1H),1.48–1.38(m,1H),1.35(s,3H).
化合物016：
Chiral-HPLC保留时间:13.855min.
MS(ESI):m/z＝338.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.95(d,J＝2.1Hz,1H),8.41(d,J＝2.1Hz,1H),5.86(s,1H),3.56(s,3H),2.58(s,3H),2.33–2.24(m,2H),1.81–1.63(m,2H),1.63–1.53(m,1H),1.52–1.38(m,1H),1.35(s,3H).
实施例17&18：(6S)/(6R)-6-((6-氰基-5-(甲硫基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸异丙酯(化合物017&018)的合成
将中间体化合物15-1(或16-1)(140mg,432.94μmol)加入到异丙醇(4mL)中，滴加二氯亚砜(51.51mg,432.94μmol)，升温至60℃搅拌反应4h。LC-MS显示反应结束。将反应液冷却至室温，加入用乙酸乙酯(10mL*3)稀释，水(10mL*3)洗三次，有机相经无水硫酸钠干燥，过滤，浓缩滤液，残留物经柱层析(二氧化硅，石油醚/乙酸乙酯＝1/1)纯化得到化合物017(130mg)(或018(125mg))。
化合物017：
Chiral-HPLC[色谱柱:AD-RH(大赛璐150×4.6mm,5μm)；流动相:A:水；B:乙腈，梯度：流动相B：10％to 90％，洗脱35分钟；流速:1.0mL/min；柱温：25℃]，保留时间：22.544mim.
MS(ESI):m/z＝366.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.95(d,J＝2.1Hz,1H),8.41(d,J＝2.1Hz,1H),5.85(s,1H),4.91–4.80(m,1H),2.58(s,3H),2.27–2.18(m,2H),1.81–1.63(m,2H),1.63–1.52(m,1H),1.50–1.37(m,1H),1.35(s,3H),1.19–1.12(m,6H).
化合物18：
Chiral-HPLC[色谱柱:AD-RH(大赛璐150×4.6mm,5μm)；流动相:A:水；B:乙腈，梯度：流动相B：10％to 90％，洗脱35分钟；流速:1.0mL/min；柱温：25℃]，保留时间：15.406min.
MS(ESI):m/z＝366.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.95(d,J＝2.0Hz,1H),8.41(d,J＝2.1Hz,1H),5.87(s,1H),4.92–4.79(m,1H),2.58(s,3H),2.27–2.19(m,2H),1.81–1.66(m,2H),1.64–1.53(m,1H),1.49–1.40(m,1H),1.35(s,3H),1.19–1.12(m,6H).
实施例19：6-((6-氰基-5-(甲硫基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸叔丁酯(化合物019)的合成
步骤1：6-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸的合成
将中间体化合物13-6(300mg,853.68μmol)分散于四氢呋喃(4mL)和水(1mL)的混合溶剂中，加入氢氧化锂一水合物(38.51mg,917.78μmol)，室温搅拌过夜。LC-MS显示反应结束。将反应液倒入0.1M盐酸溶液(15mL)中，用乙酸乙酯(5mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液得到标题化合物19-1(253mg)。
MS(ESI):m/z＝324.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.96(d,J＝2.1Hz,1H),8.41(d,J＝2.1Hz,1H),2.58(s,3H),2.21–2.12(m,2H),1.81–1.53(m,3H),1.46–1.37(m,1H),1.34(s,3H).
步骤2：6-((6-氰基-5-(甲硫基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸叔丁酯的合成
将中间体化合物19-1(100mg,309.25μmol)和O-叔丁基-N,N'-二异丙基异脲(619.48mg,3.09mmol)溶于二氯甲烷(5mL)和叔丁醇(0.5mL)的混合溶剂中，反应液于室温搅拌过夜。LC-MS显示反应结束。将反应液浓缩，残留物经柱层析(二氧化硅，乙酸乙酯/石油醚＝1/9～4/5)纯化得到化合物019(35mg)。
MS(ESI):m/z＝380.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.96(d,J＝2.1Hz,1H),8.41(d,J＝2.1Hz,1H),5.85(s,1H),2.58(s,3H),2.21–2.12(m,2H),1.80–1.69(m,1H),1.69–1.61(m,1H),1.61–1.51(m,1H),1.43–1.32(m,13H)
实施例20:6-[(6-氰基-5-(甲氧基)吡啶-3-基)氨基]-5-羟基-5-甲基-6-氧代己酸乙酯(化合物020)的合成
步骤1：6-[(6-氰基-5-(甲氧基)吡啶-3-基)氨基]-5,6-二氧代己酸乙酯的合成
将中间体化合物20-1(946.25mg,6.34mmol)加入到四氢呋喃(20mL)中，0℃下预冷15min，加入氯化亚砜(1.20g,10.06mmol)，0℃下搅拌2h。加入三乙胺(1.36g,13.41mmol)， 冰浴下搅拌10min，加入中间体化合物5-5(500mg,2.65mmol)，转至室温搅拌12h，LCMS显示反应转化完成。反应液加入水(50mL)稀释，用乙酸乙酯(50mL*3)萃取，合并有机相并浓缩，残留物经柱层析(二氧化硅，石油醚/乙酸乙酯＝1/1)纯化得到标题化合物20-2(940mg)。
MS(ESI):m/z＝320.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.76(d,J＝1.9Hz,1H),8.24(d,J＝1.9Hz,1H),4.08–4.01(m,2H),3.94(s,3H),2.97(t,J＝7.2Hz,2H),2.37(t,J＝7.4Hz,2H),1.86–1.76(m,2H),1.19–1.17(m,3H).
步骤2：6-[(6-氰基-5-(甲氧基)吡啶-3-基)氨基]-5-羟基-5-甲基-6-氧代-己酸乙酯的合成
将中间体化合物20-2(200mg,626.35μmol)加入到四氢呋喃(8mL)，于-50℃下加入甲基溴化镁(3M in Et2O,627μL)，控温在-40℃并搅拌反应12h。LCMS显示反应转化完成。用饱和氯化铵溶液淬灭反应，加入水(20mL)稀释，用乙酸乙酯(20mL*3)萃取，合并有机相并浓缩，残留物经柱层析(二氧化硅，石油醚/乙酸乙酯＝3/1)纯化得到目标化合物020(90mg)。
MS(ESI):m/z＝336.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.75(d,J＝1.9Hz,1H),8.29(d,J＝1.9Hz,1H),5.85(s,1H),4.07–3.99(m,2H),3.93(s,3H),2.33–2.21(m,2H),1.82–1.63(m,2H),1.63–1.40(m,2H),1.35(s,3H),1.20–1.10(m,3H).
实施例21:5-[[6-氰基-5-(三氟甲基)吡啶-3-基]氨基甲酰基]-6,6,6-三氟-5-羟基己酸乙酯化合物(化合物021)的合成
将中间体化合物5-6(50mg,139.94μmol)和(三氟甲基)三甲基硅烷(59mg,419.83μmol)加入到四氢呋喃(0.5mL)中，氮气氛围下加入氟化铯(5mg,32.91μmol)，反应液于25℃搅拌3h。LCMS显示反应完全。向反应液中加入水(0.5mL)稀释，过滤反应液，浓缩滤液，所得残留物经Prep-HPLC[Phenomenex C18，5μm二氧化硅，30mm直径，80mm长度；使用水(含7mmol/L NH4HCO3)和乙腈的混合物(乙腈含量：60％-70％)作为洗脱液，洗脱时间：8分钟]纯化得到目标化合物021(5mg)。
MS(ESI):m/z＝428.00[M+H]+.
1H NMR(400MHz,Chloroform-d)δ9.45(s,1H),9.00–8.93(m,1H),8.83–8.75(m,1H),6.16(s,1H),4.36–4.08(m,2H),2.59–2.38(m,3H),2.01–1.89(m,1H),1.71–1.58(m,2H),1.39–1.24(m,3H).
实施例22：N1-(6-氰基-5-(三氟甲基)吡啶-3-基)-2-羟基-N6,2-二甲基己二酰胺(化合物022)的合成
步骤1：6-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-5-羟基-5-甲基-6-氧代己酸的合成
将化合物5-7(100mg,267.86μmol)分散于四氢呋喃(3mL)和水(1mL)的混合溶剂中，加入氢氧化锂一水合物(12.84mg,306.01μmol)，室温搅拌过夜。LC-MS显示反应结束。将反应液倒入0.1M氯化氢水溶液(15mL)中，用乙酸乙酯(5mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液得到化合物22-1(80mg)。
MS(ESI):m/z＝346.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ9.40(d,J＝2.2Hz,1H),8.91(d,J＝2.3Hz,1H),2.22–2.13(m,2H),1.81–1.54(m,3H),1.48–1.36(m,1H),1.36(s,3H).
步骤2：N1-(6-氰基-5-(三氟甲基)吡啶-3-基)-2-羟基-N6,2-二甲基己二酰胺的合成
将中间体化合物22-1(50mg,144.81μmol)溶于四氢呋喃(4mL)中，冷却至0℃，滴加二氯亚砜(18mg,151.31μmol)，室温反应6h，将甲胺溶液(1M in THF,1.5mL)加入到反应液中，室温搅拌3h。LC-MS显示反应结束。将反应液倒入冰的1M盐酸溶液(30mL)中，用乙酸乙酯(10mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。残留物经Prep-HPLC[YMC-TAR柱5μm二氧化硅，30mm直径，150mm长度；用水(含7mmol/L NH4HCO3)和乙腈的极性递减的混合物作为洗脱液；乙腈梯度比例30％-60％，洗脱时间：7分钟]分离纯化得到目标化合物022(15mg)。
MS(ESI):m/z＝359.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.91(d,J＝2.3Hz,1H),7.69(s,1H),5.90(s,1H),2.55-2.51(m,3H),2.10-2.01(m,2H),1.74-1.50(m,3H),1.42-1.32(m,4H).
实施例23：N1-(6-氰基-5-(三氟甲基)吡啶-3-基)-2-羟基-2-甲基己二酰胺(化合物023)的合成
将化合物22-1(50mg,144.81μmol)溶于四氢呋喃(4mL)中，冷却至0℃，滴加二氯亚砜(18mg,151.31μmol)，室温反应6h，将氨水(2mL,含量35％)加入到反应液中，室温搅拌3h。LC-MS显示反应结束。将反应液倒入冰的1M盐酸溶液(30mL)中，用乙酸乙酯(10mL*3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液。残留物经Prep-HPLC[YMC-TAR柱5μm二氧化硅，30mm直径，150mm长度；用水(含7mmol/L NH4HCO3)和乙腈的极性递减的混合物作为洗脱液；乙腈梯度比例40％-70％，洗脱时间：12分钟]分离纯化得到目标化合物023(15mg)。
MS(ESI):m/z＝345.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),9.40(d,J＝2.3Hz,1H),8.91(d,J＝2.3Hz,1H),7.23(s,1H),6.69(s,1H),5.92(s,1H),2.06-1.97(m,2H),1.79-1.52(m,3H),1.43-1.33(m,4H).
实施例24:6-[(6-氰基-5-甲硒基吡啶-3-基)氨基]-5-羟基-5-甲基-6-氧代己酸乙酯(化合物024)
步骤1：5-氨基-3-氟吡啶-2-甲腈的合成
将6-溴-5-氟吡啶-3-胺(5g,26.18mmol)，氰化锌(6.15g,52.36mmol)，锌粉(166.47mg,2.54 mmol)，三(二亚苄基丙酮)二钯(1.2g,1.31mmol)和1,1'-双(二苯基膦)二茂铁(1.45g,2.62mmol)加入到N,N-二甲基甲酰胺(50mL)中，反应液在氩气氛围下于100℃反应16小时。LCMS显示反应完全。将反应液倒入水(500mL)中，使用乙酸乙酯(200mL*4)萃取，合并有机相后，用饱和食盐水(400mL*2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩。粗品经柱层析色谱纯化(二氧化硅，石油醚/乙酸乙酯＝10/1～1/1)得到标题化合物24-2(2.9g)。
MS(ESI):m/z＝138.10[M+H]+.
步骤2：5-氨基-3-(甲基硒基)吡啶-2-甲腈的合成
将5-氨基-3-氟吡啶-2-甲腈(1.6g,11.67mmol)，二甲基二硒醚(6.68g,35.53mmol)，N,N-二异丙基乙胺(4.52g,35.01mmol)和碳酸钾(4.83g,35.01mmol)加入到N,N-二甲基甲酰胺(20mL)中，反应液于100℃搅拌18小时。LCMS显示反应完全。将反应液倒入水中，使用乙酸乙酯(200mL*4)萃取，有机相合并后用饱和食盐水(500mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩。粗品经柱层析色谱(二氧化硅，石油醚/乙酸乙酯＝10/1～1/1)纯化得到标题化合物24-3(2g)。
MS(ESI):m/z＝214.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ7.79(d,J＝2.3Hz,1H),6.95(d,J＝2.4Hz,1H),6.49(s,2H),2.39(s,3H).
步骤3：6-[(6-氰基-5-甲硒基吡啶-3-基)氨基]-5,6-二氧代己酸乙酯合成
将6-乙氧基-2,6-二氧代己酸(166.34mg,883.94μmol)和5-氨基-3-(甲基硒基)吡啶-2-甲腈(100mg，471.45μmol)溶于N,N-二甲基乙酰胺(3mL)中，-10℃下滴加氯化亚砜(112.18mg,942.91μmol)，反应液于-10℃搅拌18小时。LCMS显示反应完全。将反应液倒入水(50mL)中，使用乙酸乙酯萃取(30mL*4)，有机相合并后用饱和食盐水(60mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，得到标题化合物24-4(220mg)。
MS(ESI):m/z＝384.10[M+H]+.
步骤4：6-[(6-氰基-5-甲硒基吡啶-3-基)氨基]-5-羟基-5-甲基-6-氧代己酸乙酯合成
将中间体24-4(200mg,523.18μmol)加入到四氢呋喃(5mL)中，-78℃下滴入甲基溴化镁四氢呋喃溶液(3M,524μL)。反应液于-78℃搅拌18小时。LCMS显示反应完全。用乙酸乙酯(10mL)稀释反应液，低温加入饱和氯化铵溶液(10mL)淬灭，使用乙酸乙酯萃取(20mL*4)。将有机相合并，使用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩。粗品经prep-HPLC[Phenomenex C18，5μm二氧化硅，30mm直径，80mm长度；使用水(含有0.05％碳酸氢铵)和乙腈的混合物(乙腈含量：38-68％)作为洗脱液]分离纯化得到目标化合物024(60mg)。
MS(ESI):m/z＝400.10[M+H]+.
1H NMR(400MHz,Chloroform-d)δ9.15(s,1H),8.59(d,J＝2.3Hz,1H),8.40(d,J＝2.3Hz,1H),4.18–4.12(m,2H),3.55(s,1H),2.48(s,3H),2.42–2.35(m,2H),2.10–2.01(m,1H),1.82–1.62(m,3H),1.51(s,3H),1.26(t,J＝7.2Hz,3H).
实施例25:(5R)-6-[(6-氰基-5-甲基磺酰基吡啶-3-基)氨基]-5-羟基-5-甲基-6-氧代-己酸乙酯或(5S)-6-[(6-氰基-5-甲基磺酰基吡啶-3-基)氨基]-5-羟基-5-甲基-6-氧代-己酸乙酯(化合物025)
将化合物014(90.00mg,256.10μmol)加入到二氯甲烷(1mL)中，冰浴下加入间氯过氧苯甲酸(155.99mg,768.31μmol,含量85％)，反应液于室温搅拌4小时。过滤反应液，滤液用水洗涤(1mL*2)，有机相用无水硫酸钠干燥，过滤，滤液浓缩，残留物经柱层析色谱(二氧化硅，石油醚/乙酸乙酯＝2/1)纯化，得到化合物025(59mg)。
MS(ESI):m/z＝384.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),9.39–9.30(m,1H),9.13–9.05(m,1H),5.89(s,1H),4.10–3.95(m,2H),3.44(s,3H),2.31–2.23(m,2H),1.81–1.66(m,2H),1.64–1.54(m,1H),1.50–1.39(m,1H),1.36(s,3H),1.20–1.11(m,3H).
实施例26:(5R)-6-[(6-氰基-5-甲基亚磺酰基吡啶-3-基)氨基]-5-羟基-5-甲基-6-氧代-己酸乙酯或(5S)-6-[(6-氰基-5-甲基亚磺酰基吡啶-3-基)氨基]-5-羟基-5-甲基-6-氧代-己酸乙酯(化合物026)
将化合物014(50mg,142.28μmol)加入到二氯甲烷(0.5mL)中，冰浴下加入间氯过氧苯甲酸(23.11mg,113.82μmol,含量85％)，反应液于室温搅拌4小时。过滤反应液，滤液用水洗涤(1mL*2)，有机相用无水硫酸钠干燥，过滤，滤液浓缩，经柱层析色谱(二氧化硅，石油醚/乙酸乙酯＝2/1)纯化，得到化合物026(5mg)。
MS(ESI):m/z＝368.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),9.21–9.11(m,1H),9.03–8.90(m,1H),5.85(s,1H),4.14–3.91(m,2H),2.91(s,3H),2.32–2.23(m,2H),1.84–1.65(m,2H),1.65–1.54(m,1H),1.50–1.41(m,1H),1.36(s,3H),1.20–1.11(m,3H).
实施例27：7-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-6-羟基-6-甲基-7-氧代庚酸乙酯(化合物027)
步骤1：1-氧代戊烷-1,2,5-三羧酸三乙酯的合成
将起始物料27-1(2g,9.89mmol)加入到四氢呋喃(10mL)中，冰水浴下加入乙醇钠(672.45mg,9.89mmol)。室温搅拌30分钟，加入草酸二乙酯(1.45g,9.89mmol)。反应液于室温搅拌18小时。向反应液中加入20mL水稀释，使用乙酸乙酯(20mL*3)萃取，合并有机层并用水(30mL*2)洗涤，饱和食盐水(50mL)洗涤，无水硫酸钠干燥、过滤、减压浓缩得到标题化合物27-2(2.99g)。
1H NMR(400MHz,Chloroform-d)δ4.45–4.29(m,2H),4.25–4.09(m,4H),4.02(t,J＝7.0 Hz,1H),2.42–2.27(m,2H),2.04–1.85(m,2H),1.79–1.59(m,2H),1.44–1.17(m,9H)
步骤2：2-氧代庚二酸的合成
将中间体27-2(6g,19.85mmol)加入到4M HCl水溶液(60mL)中，反应液于70℃搅拌18小时。LCMS显示反应完全。加入20mL水稀释，使用乙酸乙酯(20mL*3)萃取，合并有机层并用水(30mL*2)洗涤，饱和食盐水(50mL)洗涤，无水硫酸钠干燥。过滤、减压浓缩得到标题化合物27-3(3g)。
MS(ESI):m/z＝173.00[M-H]-.
步骤3：2-氧代庚二酸二乙酯的合成
将中间体27-3(2.8g,16.08mmol)和浓硫酸(3.15g,32.16mmol,1.71mL)加入到乙醇(25mL)中。反应液于50℃搅拌18小时。LCMS显示反应完全。将反应液冷却后倒入水(20mL)中，使用乙酸乙酯(30mL*3)萃取，合并有机层并用水(40mL*2)洗涤，饱和食盐水(40mL)洗涤，无水硫酸钠干燥。过滤、减压浓缩，经柱层析色谱(二氧化硅，乙酸乙酯/石油醚＝3/1)纯化，得到标题化合物27-4(1.6g)。
MS(ESI):m/z＝231.1[M+H]+.
1H NMR(400MHz,Chloroform-d)δ4.37–4.22(m,2H),4.18–4.08(m,2H),2.92–2.81(m,2H),2.37–2.24(m,2H),1.75–1.55(m,4H),1.44–1.19(m,6H).
步骤4：7-乙氧基-2,7-二氧代庚酸的合成
将中间体27-4(166mg,720.93μmol)加入到乙醇(2mL)和水(1mL)中，0℃加入氢氧化钾(40.45mg,720.93μmol)，反应液于室温搅拌1小时。LCMS显示反应结束。将反应液用乙酸乙酯(20mL)萃洗一次，用稀盐酸(10mL)将水相调至酸性(pH＝2-3)，使用乙酸乙酯(20mL*3)萃取，合并有机相并用无水硫酸钠干燥，过滤、减压浓缩，得到标题化合物27-5(130mg)。
MS(ESI):m/z＝201.20[M-H]-.
1H NMR(400MHz,Chloroform-d)δ4.27–4.07(m,2H),3.01–2.92(m,2H),2.39–2.31(m,2H),1.78–1.59(m,2H),1.35–1.18(m,3H).
步骤5：7-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-6,7-二氧代庚酸乙酯的合成
将中间体27-5(324.18mg,1.60mmol)和5-氨基-3-(三氟甲基)吡啶-2-甲腈(200mg,1.07mmol)加入到N,N-二甲基乙酰胺(3mL)中。冰水浴下加入二氯亚砜(216.17mg,1.82mmol)。反应液于冰水浴下搅拌18小时。LCMS显示反应结束。将反应液倒入冰水中，用乙酸乙酯(5mL*3)萃取，合并有机层并用水(40mL*2)洗涤，饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩，得到标题化合物27-6(400mg)。
MS(ESI):m/z＝372.10[M+H]+.
步骤6：7-((6-氰基-5-(三氟甲基)吡啶-3-基)氨基)-6-羟基-6-甲基-7-氧代庚酸乙酯的合成
将中间体27-6(200mg,538.63μmol)加入到四氢呋喃(3mL)中。反应液于-78℃加入甲基溴化镁四氢呋喃溶液(3M,540μL)。反应液于-78℃搅拌18小时。LCMS显示反应完全。向反应液中加入30mL饱和氯化铵水溶液，使用乙酸乙酯(50mL*3)萃取，合并有机相并用无水硫酸钠干燥，过滤、减压浓缩，残留物经柱层析色谱(二氧化硅，乙酸乙酯/石油醚＝5/1)纯化，得到标题化合物027(40mg)。
MS(ESI):m/z＝388.10[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),9.39(d,J＝2.2Hz,1H),8.91(d,J＝2.3Hz,1H),5.87(s,1H),4.01(q,J＝7.1Hz,2H),2.30–2.22(m,2H),1.82–1.70(m,1H),1.68–1.41(m,3H),1.36(s,3H),1.29–1.06(m,5H).
实施例28:5-[(6-氰基-5-甲硫基吡啶-3-基)氨基甲酰基]-6,6,6-三氟-5-羟基己酸乙酯(化合物028)
将中间体13-5(1g,2.98mmol)，(三氟甲基)三甲基硅烷(2.12g,14.91mmol)加入到四氢呋喃(20mL)中，氮气氛围下加入氟化铯(9.85mg,64.84μmol)，反应液于25℃下搅拌3小时。LCMS显示反应完全，将反应液倒入乙酸乙酯(20mL)和水(20mL)中，分层，水相用乙酸乙酯(20mL)萃取两次，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，浓缩，粗品经硅胶柱层析(二氧化硅，石油醚/乙酸乙酯＝3/2)纯化，得到化合物028(120mg)。
MS(ESI):m/z＝406.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.66(s,1H),9.01–8.89(m,1H),8.48–8.31(m,1H),7.65(s,1H),4.09–3.94(m,2H),2.60(s,3H),2.37–2.29(m,2H),2.20–2.06(m,1H),1.89–1.68(m,2H),1.47–1.34(m,1H),1.20–1.12(m,3H).
实施例29：6-(4-氰基-3-甲硫基-苯胺基)-5-羟基-5-甲基-6-氧代己酸乙酯(化合物029)
步骤1：6-(4-氰基-3-甲硫基-苯胺基)-5,6-二氧代-己酸乙酯的合成
将中间体5-5(1.01g,5.36mmol)加入到N,N-二甲基乙酰胺(5mL)中，-10℃下加入二氯亚砜(724.42mg,6.09mmol)，加入4-氨基-2-甲硫基-苄腈(29-1，500mg,3.04mmol)，反应液于-78℃搅拌15小时。LCMS显示反应完全。加入乙酸乙酯(50mL)稀释，饱和碳酸氢钠溶液(50mL)淬灭，使用乙酸乙酯(50mL*4)萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经柱层析纯化(二氧化硅，石油醚/乙酸乙酯＝1/1)，得到中间体29-2(600mg)。
MS(ESI):m/z＝335.20[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),7.96(d,J＝1.9Hz,1H),7.84(dd,J＝8.6,1.9Hz,1H),7.77(d,J＝8.5Hz,1H),4.06(q,J＝7.1Hz,2H),2.97(t,J＝7.2Hz,2H),2.56(s,3H),2.36(t,J＝7.4Hz,2H),1.85–1.75(m,2H),1.18(t,J＝7.1Hz,3H).
步骤2：6-(4-氰基-3-甲硫基-苯胺基)-5-羟基-5-甲基-6-氧代己酸乙酯的合成
将中间体29-2(400mg,1.20mmol)加入到四氢呋喃(4mL)中，降温至-78℃，控温加入甲基溴化镁的乙醚溶液(3M，1.2mL)。反应液于-78℃搅拌15小时。LCMS显示反应完全。加入乙酸乙酯(50mL)稀释，低温下加入饱和氯化铵溶液(50mL)淬灭，乙酸乙酯(50mL*4)萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经Prep-HPLC[Phenomenex C18，5μm二氧化硅，30mm直径，80mm长度；使用水(含有0.05％碳酸氢铵)和乙腈的混合物(乙腈含量：50-80％)作为洗脱液]分离纯化得到目标化合物029(110mg)。
MS(ESI):m/z＝351.20[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),7.88(d,J＝1.9Hz,1H),7.79(dd,J＝8.6,1.9Hz,1H),7.65(d,J＝8.5Hz,1H),5.76(s,1H),3.97(q,J＝7.1Hz,2H),2.50(s,3H),2.21(t,J＝7.1Hz,2H),1.73–1.58(m,2H),1.55–1.47(m,1H),1.41–1.31(m,1H),1.28(s,3H),1.10(t,J＝7.1Hz,3H).
实施例30：6-(4-氰基-3-甲氧基-苯胺基)-5-羟基-5-甲基-6-氧代己酸乙酯(化合物030)
步骤1：6-(4-氰基-3-甲氧基-苯胺基)-5,6-二氧代-己酸乙酯的合成
将6-乙氧基-2,6-二氧代己酸(971.24mg,5.16mmol)加入到N,N-二甲基乙酰胺(5mL)中，反应液降温至-10℃。滴加二氯亚砜(802.97mg,6.75mmol)，加入4-氨基-2-甲氧基-苄腈(500mg,3.37mmol)，反应液于-78℃搅拌15小时。LCMS显示反应完全。饱和碳酸氢钠溶液(50mL)淬灭，使用乙酸乙酯(50mL*4)萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经柱层析纯化(二氧化硅，石油醚/乙酸乙酯＝1/1)，得到中间体30-2(600mg)。
MS(ESI):m/z＝319.20[M+H]+.
1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),7.79(d,J＝1.8Hz,1H),7.69(d,J＝8.5Hz,1H),7.59(dd,J＝8.6,1.8Hz,1H),4.05(q,J＝7.1Hz,2H),3.87(s,3H),2.95(t,J＝7.2Hz,2H),2.35(t,J＝7.4Hz,2H),1.84–1.73(m,2H),1.17(t,J＝7.1Hz,3H).
步骤2：6-(4-氰基-3-甲氧基-苯胺基)-5-羟基-5-甲基-6-氧代己酸乙酯的合成
将中间体30-2(500mg,1.57mmol)加入到四氢呋喃(5mL)中，-78℃下，加入甲基溴化镁四氢呋喃溶液(3M,1.57mL)。反应液于-78℃搅拌15小时。LCMS显示反应完全。加入乙酸乙酯(50mL)稀释，低温下加入饱和氯化铵溶液(50mL)淬灭，乙酸乙酯(50mL*4)萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经Prep-HPLC[Phenomenex C18，5μm二氧化硅，30mm直径，80mm长度；使用水(含有0.05％碳酸氢铵)和乙腈的混合物(乙腈含量：50-80％)作为洗脱液]分离纯化得到目标化合物030(110mg)。
MS(ESI):m/z＝335.20[M+H]+.
1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),7.80(d,J＝1.7Hz,1H),7.66–7.56(m,2H),5.81(s,1H),4.02(q,J＝7.1Hz,2H),3.86(s,3H),2.26(t,J＝7.1Hz,2H),1.79–1.65(m,2H),1.61–1.38(m,2H),1.33(s,3H),1.15(t,J＝7.1Hz,3H).
实施例31：6-((6-氰基-5-(甲硫基)吡啶-3-基)氨基)-5-羟基-6-氧代己酸乙酯(化合物031)
将化合物13-5(10mg,29.82μmol)加入到甲醇(1mL)中。冰水浴下加入硼氢化钠(2.26mg,59.63μmol)。反应液于室温搅拌1小时。LCMS显示反应完全。冰水浴下向反应液中加入10mL水淬灭，使用乙酸乙酯萃取(200mL*3)，合并有机相，使用饱和食盐水洗涤(10mL*2)，无水硫酸钠干燥，过滤，滤液减压浓缩得到标题化合物031(9mg)。
MS(ESI):m/z＝338.20[M+H]+.
实施例32：6-((6-氰基-5-(甲硫基)吡啶-3-基)氨基)-5-羟基-6-氧代己酸异丙酯(化合物032)
步骤1：6-(6-氰基-5-(甲硫基)吡啶-3-基)氨基)-5-羟基-6-氧代己酸的合成
将化合物031(50mg,148.19μmol)和氢氧化锂一水合物(7.11mg,169.45μmol)加入到四氢 呋喃(1mL)和去离子水(1mL)中。反应液于室温搅拌2小时。LCMS显示反应结束。加入10mL水稀释，使用乙酸乙酯(50mL)萃取，向水相中加入1M HCl盐酸水溶液(10mL)将体系调至酸性(pH＝2-3)，使用乙酸乙酯萃取(20mL*3)，合并有机相，使用饱和食盐水洗涤(20mL*2)，无水硫酸钠干燥，过滤，滤液减压浓缩得到标题化合物32-1(35mg)。
MS(ESI):m/z＝309.6[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.89(d,J＝2.1Hz,1H),8.36(d,J＝2.1Hz,1H),4.11–4.03(m,1H),2.57(s,3H),2.14–2.05(m,2H),1.78–1.71(m,1H),1.65–1.55(m,3H).
步骤2：6-((6-氰基-5-(甲硫基)吡啶-3-基)氨基)-5-羟基-6-氧代己酸异丙酯的合成
将中间体32-1(50mg,161.63μmol)和浓硫酸(15.85mg,161.63μmol)加入到异丙醇(1mL)中。反应液于室温搅拌6小时。LCMS显示反应结束。将反应液过滤，滤液经Prep-HPLC[Phenomenex C18，5μm二氧化硅，30mm直径，80mm长度；使用纯水和乙腈的混合物(乙腈含量：60％-70％)作为洗脱液]纯化得到目标化合物032(10mg)。
MS(ESI):m/z＝351.7[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.89(d,J＝2.1Hz,1H),8.35(d,J＝2.1Hz,1H),6.03(s,1H),4.93–4.82(m,1H),4.13–4.05(m,1H),2.58(s,3H),2.33–2.22(m,2H),1.79–1.68(m,1H),1.70–1.53(m,3H),1.20–1.14(m,6H).
实验例1：本公开化合物对AR拮抗活性的作用效果
(1).材料与试剂：
(2).仪器:
(3).实验方法：
第一天：细胞铺板
在六孔板(Corning，3516)的每孔铺8x105个LNCaP细胞。
第二天：转染
采用Lipo 3000和P3000(LipofectamineTM3000)转染试剂与AR和PSA ARE1报告基因质粒(生物(安徽)股份有限公司)(其中，每孔添加总共2.5μg质粒，各质粒1.25μg)静置室温孵育10分钟后，滴加250μL上述转染试剂至含有细胞每孔中。
第三天：细胞处理、铺板及加药
通过PBS洗涤细胞，更换含有RPMI-1640无酚红和5％碳吸附血清的培养基。根据铺板细胞数目(2x104个细胞/孔)，将细胞重新铺至96孔板(Corning，3603)中。
在细胞铺板后，首先加入待测化合物(或DMSO或阳性对照药)，至少孵育30分钟后(培养箱，37℃，5％CO2)再添加最终浓度为1nM的DHT(二氢睾酮)进入培养体系中，继续在二氧化碳培养箱中培养。最终孔板种的体系体积为100μL。
其中，待测化合物：10mM储备液，最终浓度为3.3μM或6.7μM。阴性对照：0.1％ DMSO。阳性对照：30μM恩杂鲁胺(Enzalutamide)。
第四天：荧光素酶信号检测及数据处理
将待测化合物(或DMSO或阳性对照药)和DHT共同培养6小时或24小时后，使用Vazyme Bright-Lite底物检测荧光素酶信号。每孔加入70μL培养基，震动2分钟后读取荧光素酶信号。
(4).数据处理：
使用DMSO和低浓度对照数据检查试验耐用性：
Ave_H＝Ave(DMSO)
Ave_L＝Ave(30000nM恩杂鲁胺)
抑制率(％)＝(Ave_H-Sample)/(Ave_H-Ave_L)x 100％
Ave_H：阴性对照物的测定数值(0.1％ DMSO)；
Ave_L：阳性对照物的测定数值(30μM恩杂鲁胺)；
Sample：待测化合物的测定数值；
测试化合物相应的活性测试结果具体见表1。
表1本公开化合物相应的活性测试结果

注：a表示孵育时间：24h,测试浓度：3.3μM；b表示孵育时间：6h,测试浓度：6.7
μM；c表示孵育时间：24h,测试浓度:6.7μM。
由以上结果可知，本公开化合物具有AR拮抗活性。
实验例2：本公开的化合物肝微粒体中的代谢稳定性测定
本公开化合物在肝微粒体中的代谢稳定性采用如下试验方法测定。
一、试验材料及仪器
1.肝微粒体来源：人肝微粒体(Corning 452117)
2.Na2HPO4(天津市光复精细化工研究所20180130)
3.KH2PO4(天津市光复精细化工研究所20180920)
4.MgCl2(天津市光复精细化工研究所20191216)
5.NADPH(Solarbio 1216C022)
6.阳性对照化合物：维拉帕米(Sigma MKBV4993V)
7.AB Sciex Triple Quad 4000液质联用仪
二、试验步骤
1. 100mM磷酸缓冲液(PBS)的配制：称取7.098g Na2HPO4，加入500mL纯水超声溶解，作为溶液A。称取3.400g KH2PO4，加入250mL纯水超声溶解，作为溶液B。将溶液A放置在搅拌器上缓慢加入溶液B直到pH值达到7.4，配制成100mM的PBS缓冲液。
2.反应体系的配制
按下表配制反应体系
3.将反应体系置于37℃水浴中预孵育10分钟。向反应体系中加入40μL 10mM NADPH溶液(NADPH由100mM的磷酸缓冲液溶解)，NADPH的最终浓度为1mM。用40μL磷酸缓冲液代替NADPH溶液作为阴性对照。阴性对照的作用是排除化合物自身化学稳定性的影响。
4.在反应体系中加入4μL 100μM的本公开化合物和阳性对照化合物维拉帕米启动反应，化合物的最终浓度为1μM。
5.在0.5、15、30、45和60分钟，涡旋振荡器充分混匀后，分别取出50μL孵育样品，用4倍的含有内标的冰乙腈终止反应。样品在3,220g转速下离心45分钟。离心结束后转移90μL上清液到进样板，加入90μL超纯水混匀，用于LC-MS/MS分析。
所有的数据均通过Microsoft Excel软件进行计算。通过提取离子图谱检测峰面积。通过对待测化合物消除百分比的自然对数与时间进行线性拟合，检测待测化合物的体外半衰期(T1/2)。
体外半衰期(in vitro T1/2)通过斜率k计算：
in vitro T1/2＝0.693/k
体外固有清除率(in vitro CLint，单位：μL/min/mg protein)用下列公式计算：
in vitro CLint＝k×孵育液体积/酶蛋白的含量；
经上述公式计算得到的T1/2和CLint值见表2。
表2本公开化合物肝微粒体中的半衰期值和固有清除率值
由以上结果可知，本公开化合物具有高清除率快代谢的特点，避免长期给药导致药物在体内的蓄积，从而造成对全身雄激素受体信号通路的影响，进而提高药物的安全性。
实验例3全血稳定性
试验步骤：
1.储备溶液的制备
在DMSO中制备1mM待测化合物储备溶液，在乙腈中制备1mM对照化合物丙胺太林储备溶液。
2.稳定性测定方法
将4μL待测化合物储备溶液(或对照化合物储备溶液)加入至796μL预孵育的全血(CD-1小鼠全血或人全血)中，以达到5μM的最终浓度。溶剂的最终浓度为0.5％。在不同时间点(包括5、15、30、60和120min)，将50μL等份加样品的全血加入新试管中，并在37℃水浴中以60rpm振摇孵育。试验重复进行两次。在指定时间点，向加样品的全血样本中加入300μL室温淬灭溶液(含内标物(100nM阿普唑仑、500nM拉贝洛尔和2μM酮洛芬)的乙腈溶液)终止反应。将50μL加样品的全血加入含300μL室温淬灭溶液的新试管中，制备时间0分钟样本。所有样品涡旋5分钟。将平板中的样品在4℃下以3220g离心30分钟沉淀蛋白。取100μL上清液转移至含100μL水的新96孔板中，用于LC-MS/MS分析。
3.数据分析
使用Microsoft Excel进行所有计算。根据提取离子色谱图测定峰面积比。通过以下公式计算各时间点剩余化合物的百分比：
剩余百分比t min(％)＝峰面积比t min/峰面积比0min×100％
其中，峰面积比t min：t分钟时对照品化合物和待测化合物的峰面积比；
峰面积比0min：零时间点对照化合物和待测化合物的峰面积比。
通过待测化合物剩余百分比的自然对数与孵育时间曲线的线性回归确定斜率值。
根据斜率值确定体外半衰期(体外t1/2)：
in vitro t1/2＝0.693/k
式中：k为速率常数(k＝-斜率值)
本公开化合物所测得的在CD-1小鼠或者人全血中的半衰期见表3。
表3.本公开化合物在CD-1小鼠和人全血中的稳定性
由以上结果可知，本公开的化合物在CD-1小鼠和人全血中半衰期短，血液中具有高清除率快代谢的特点，避免长期给药导致药物在体内的蓄积，从而造成对全身雄激素受体信号通路的影响，进而提高药物的安全性。
实验例4体内药效研究
4.1实验试剂
溶媒：丙二醇/乙醇(30:70,v/v)
4.2实验方法
动物信息：C57BL/6小鼠，雄性，6周，体重约18-20克，动物购自上海灵畅生物科技有限公司，将小鼠饲养在SPF级的环境中，每个笼位单独送排风，所有动物都可以自由获取标准认证的商业实验室饮食和自由饮水。
备皮：小鼠适应性饲养1-2周后，用剃毛器除去小鼠背部2cm*3cm区域毛发，确认小鼠毛发处于休止期(皮肤为粉红色)且皮肤无破损。
给药：剃毛后第3天进行分组给药。本公开化合物010按照0.5wt％浓度每天早晚两次涂抹于剃毛区域，持续32天，对照组涂抹对照溶媒，每组12只小鼠。
4.3小鼠状态观察及毛发生长评分
实验期间观察各组小鼠状态，皮肤是否有红疹、开裂、起皮屑等现象；
化合物010给药后分别于第10、13、16、20、23、27、32天对小鼠进行称重，进行毛发生长评分并拍摄照片；
评分标准如下：
0分:未生长，剃毛区皮肤呈粉色；
1分:剃毛区皮肤呈灰色(小于20％的增长)；
2分:剃毛区皮肤呈黑色(大于20％小于40％)；
3分:剃毛区皮肤呈黑色并有少许毛发生长(大于40％小于60％)；
4分:剃毛区皮肤呈黑色并有部分毛发生长(大于60％小于80％)；
5分:剃毛区毛发基本完全生长(80％～100％的生长)。
4.4实验结果
本公开化合物对小鼠毛发生长的结果见表4。
表4本公开化合物对小鼠毛发生长评分

*P<0.05，**P<0.01，vs.溶媒对照组
4.5实验结论
在毛发生长处于休止期的小鼠中，本公开化合物010在0.5wt％的浓度下，20μL/cm2，按BID给药方式，皮肤涂抹给药对毛发生长具有显著促进作用。其中化合物010给药32天开始可显著促进毛发增长(P<0.01)。本公开化合物010在所尝试剂量下未显著影响小鼠体重，也未引起任何皮肤红疹、开裂、起皮屑等现象。本公开的其他化合物对毛发增长也具有显著促进作用。
虽然已举例说明和描述了本公开的具体实施方案，但是本领域技术人员应知晓，在可行的情况下，一个实施方案中描述的技术特征可以应用于另一实施方案，或与另一实施方案中描述的技术特征相组合，因此，本领域技术人员能够在不脱离本公开的实质和范围的情况下对本公开的实施方案作出各种变化和修改。

Claims (19)

  1. 式(I)所示化合物或其立体异构体或其药学上可接受的盐，
    其中，
    X选自CH或N；
    Y选自OH、COOH、-CONH2、-COOR3或-CONR3’R3；
    R1选自OH或-O-C1-C6烷基；
    R2选自H、氘、C1-C6烷基、C1-C6氘代烷基或C1-C6卤代烷基；
    R3选自C1-C6烷基、C1-C6氘代烷基、C3-C6环烷基、4-10元杂环基、C6-C10芳基或5-10元杂芳基，所述C1-C6烷基、C3-C6环烷基、4-10元杂环基、C6-C10芳基或5-10元杂芳基任选地被R3a取代；
    R3a选自卤素、OH、CN、NH2、-COR3b、-COOR3b、-NHCOR3b、-CONHR3b、-O-C1-C6烷基、C1-C6烷基、苯基、4-6元杂环基或5-6元杂芳基，所述C1-C6烷基、苯基、4-6元杂环基或5-6元杂芳基任选地被R3c取代；
    R3b选自H或C1-C6烷基；
    R3c选自卤素、OH、C1-C6烷基或-O-C1-C6烷基；
    R3’选自H或C1-C6烷基；
    R4选自NO2、CN、卤素、C1-C6烷基、C1-C6卤代烷基或-O-C1-C6烷基；
    R5选自卤素、C1-C6烷基、C1-C6卤代烷基、-COOC1-C6烷基、-S-C1-C6烷基、-O-C1-C6烷基、-Se-C1-C6烷基、-S(O)-C1-C6烷基或-S(O)2-C1-C6烷基；
    R6选自H、卤素、C1-C6烷基、C1-C6卤代烷基或-O-C1-C6烷基；
    n选自1、2、3、4、5、6、7、8或9；
    条件是，当Y选自OH时，n选自1、2或3。
  2. 根据权利要求1所述的式(I)所示化合物或其立体异构体或其药学上可接受的盐，其中，Y选自COOH、-CONH2、-COOR3或-CONR3’R3；
    或者，Y选自CONH2、-COOR3或-CONR3’R3；
    或者，Y选自-COOR3或-CONR3’R3；
    或者，Y为-COOR3；
    或者，Y选自OH、COOH、-COOCH2CH3、-COOCH3、-COOCH(CH3)2、-COOC(CH3)3、-CONHCH3或-CONH2；
    或者，Y选自-COOCH2CH3、-COOCH3、-COOCH(CH3)2、-COOC(CH3)3、或-CONHCH3；
    或者，Y选自-COOCH2CH3、-COOCH3、-COOCH(CH3)2或-COO(CH3)3。
  3. 根据权利要求1-2中任一项所述的式(I)所示化合物或其立体异构体或其药学上可接受的盐，其中，R1为OH。
  4. 根据权利要求1-3中任一项所述的式(I)所示化合物或其立体异构体或其药学上可接受的盐，其中，R2选自H、C1-C6烷基或C1-C6卤代烷基；或者，
    R2选自C1-C6烷基、C1-C6氘代烷基或C1-C6卤代烷基；
    或者，R2选自C1-C6烷基或C1-C6卤代烷基；
    或者，R2选自H、CH3或CF3；
    或者，R2选自CH3或CF3。
  5. 根据权利要求1-4中任一项所述的式(I)所示化合物或其立体异构体或其药学上可接受 的盐，其中，R3选自C1-C6烷基、C1-C6氘代烷基、C3-C6环烷基、4-6元杂环基、C6-C10芳基或5-6元杂芳基，所述C1-C6烷基、C3-C6环烷基、4-6元杂环基、C6-C10芳基或5-6元杂芳基任选地被R3a取代；
    或者，R3选自C1-C6烷基或C1-C6氘代烷基，所述C1-C6烷基任选地被R3a取代；
    或者，R3为未取代的C1-C6烷基；
    或者，R3选自未取代的甲基、未取代的乙基、未取代的异丙基或未取代的叔丁基。
  6. 根据权利要求1-5中任一项所述的式(I)所示化合物或其立体异构体或其药学上可接受的盐，其中，R3a选自卤素、OH、CN、NH2、-COR3b、-COOR3b、-NHCOR3b、-CONHR3b、-O-C1-C6烷基或C1-C6烷基，所述C1-C6烷基任选地被R3c取代。
  7. 根据权利要求1-6中任一项所述的式(I)所示化合物或其立体异构体或其药学上可接受的盐，其中，R3’为H或C1-C4烷基；或者，R3’为H。
  8. 根据权利要求1-7中任一项所述的式(I)所示化合物或其立体异构体或其药学上可接受的盐，其中，R4选自卤素或CN；或者，R4选自F、Cl或CN；或者，R4为CN。
  9. 根据权利要求1-8中任一项所述的式(I)所示化合物或其立体异构体或其药学上可接受的盐，其中，R5选自卤素、C1-C6烷基、C1-C6卤代烷基、-COOC1-C6烷基、-S-C1-C6烷基或-O-C1-C6烷基；
    或者，R5选自C1-C6卤代烷基、-S-C1-C6烷基、-O-C1-C6烷基、-Se-C1-C6烷基、-S(O)-C1-C6烷基或-S(O)2-C1-C6烷基；
    或者，R5选自C1-C3卤代烷基、-S-C1-C3烷基、-O-C1-C3烷基或-Se-C1-C3烷基；
    或者，R5选自C1-C6卤代烷基、-S-C1-C6烷基或-O-C1-C6烷基；
    或者，R5选自CF3、-S-CH3、-O-CH3、-Se-CH3、-S(O)-CH3或-S(O)2-CH3；
    或者，R5选自CF3、-S-CH3、-O-CH3或-Se-CH3。
  10. 根据权利要求1-9中任一项所述的式(I)所示化合物或其立体异构体或其药学上可接受的盐，其中，R6选自H或卤素；或者，R6为H。
  11. 根据权利要求1-10中任一项所述的式(I)所示化合物或其立体异构体或其药学上可接受的盐，其中，n选自1、2或3；
    或者，n选自1或2；
    或者，n为2。
  12. 根据权利要求1-11中任一项所述的式(I)所示化合物或其立体异构体或其药学上可接受的盐，其中，X为N。
  13. 根据权利要求1-12中任一项所述的式(I)所示化合物或其立体异构体或其药学上可接受的盐，其中，式(I)所示化合物或其立体异构体或其药学上可接受的盐选自式(II)所示化合物或其立体异构体或其药学上可接受的盐，
    其中，X、R1、R2、R3、R4、R5、R6、n如权利要求1-12中任一项的定义。
  14. 根据权利要求1所述的式(I)所示化合物或其立体异构体或其药学上可接受的盐，其中，式(I)所示化合物或其立体异构体或其药学上可接受的盐选自以下化合物或其立体异构体或其药学上可接受的盐：


  15. 药物组合物，其包含权利要求1-14中任一项所述的式(I)化合物或其立体异构体或其药学上可接受的盐以及药学上可接受的辅料。
  16. 如权利要求1-14中任一项所述的式(Ⅰ)化合物或其立体异构体或其药学上可接受的盐、或权利要求15所述的药物组合物在制备用于预防或者治疗雄激素受体介导的疾病的药物中的用途。
  17. 预防或治疗哺乳动物的由雄激素受体介导的疾病的方法，包括对需要所述治疗的哺乳动物，优选人类，施用治疗有效量的权利要求1-14中任一项所述的式(I)化合物或其立体异构体或其药学上可接受的盐、或权利要求15所述的药物组合物。
  18. 用于预防或治疗哺乳动物的由雄激素受体介导的疾病的权利要求1-14中任一项所述的式(I)化合物或其立体异构体或其药学上可接受的盐、或权利要求15所述的药物组合物。
  19. 根据权利要求16所述的用途或者权利要求17所述的方法或者权利要求18所述的式(I)化合物或其立体异构体或其药学上可接受的盐或药物组合物，其中，所述的雄激素受体介导的疾病选自雄激素性脱发。
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