WO2020259675A1 - 神经激肽-1拮抗剂 - Google Patents

神经激肽-1拮抗剂 Download PDF

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WO2020259675A1
WO2020259675A1 PCT/CN2020/098460 CN2020098460W WO2020259675A1 WO 2020259675 A1 WO2020259675 A1 WO 2020259675A1 CN 2020098460 W CN2020098460 W CN 2020098460W WO 2020259675 A1 WO2020259675 A1 WO 2020259675A1
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compound
alkyl
aryl
heteroaryl
cycloalkyl
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PCT/CN2020/098460
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English (en)
French (fr)
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黄建
祝令建
邹洋
唐应刚
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上海盛迪医药有限公司
上海森辉医药有限公司
江苏恒瑞医药股份有限公司
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Priority to EP20831251.2A priority Critical patent/EP3991730A4/en
Priority to MX2021015827A priority patent/MX2021015827A/es
Priority to AU2020308397A priority patent/AU2020308397A1/en
Priority to CA3144247A priority patent/CA3144247A1/en
Priority to BR112021026554A priority patent/BR112021026554A2/pt
Priority to JP2021577929A priority patent/JP2022539570A/ja
Priority to CN202080040881.3A priority patent/CN113905735B/zh
Priority to US17/623,205 priority patent/US20220380393A1/en
Priority to KR1020227003091A priority patent/KR20220054287A/ko
Publication of WO2020259675A1 publication Critical patent/WO2020259675A1/zh

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65615—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing a spiro condensed ring system of the formula where at least one of the atoms X or Y is a hetero atom, e.g. S
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    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

  • the present disclosure relates to an antagonist of the neuropeptide neurokinin-1 (NK1 or NK-1) receptor.
  • Tachykinin is a peptide ligand for neurokinin receptors.
  • Neurokinin receptors such as NK1, NK2 and NK3, are involved in various biological processes. They can be found in the nervous and circulatory system of mammals and in surrounding tissues. Therefore, the modulation of such receptors has been studied for potential treatment or prevention of various diseases in mammals.
  • Typical neurokinin receptor antagonists and their uses include: US5760018 (1998) (pain, inflammation, migraine and vomiting), US5620989 (1997) (pain, nociception and inflammation), WO95/19344 (1995), WO 94/13639 (1994) and WO 94/10165 (1994).
  • NK1 receptor antagonists include: Wu et al., Tetrahedron 56, 3043-3051 (2000); Rombouts et al., Tetrahedron Letters 42, 7397-7399 (2001); and Rogiers et al., Tetrahedron 57, 8971 8981 (2001).
  • US7049320 provides an effective, selective, and beneficial therapeutic and pharmacological properties and good metabolic stability of NK1 antagonist (5S, 8S)-8-[ ⁇ (1R)-1-(3,5 -Bis-(trifluoromethyl)phenyl)-ethoxy ⁇ -methyl]-8-phenyl-1,7-diazaspiro[4.5]dec-2-one (compound of formula I), which The compound can take the form of a free base or a pharmaceutically acceptable salt form, and is a formulation suitable for parenteral administration.
  • US9101615 provides a prodrug of a compound of formula I, that is, a prodrug and a salt thereof in which the hydrogen of the free amine (or two amines) of the compound of formula I is replaced by a group selected from -Y and -X, wherein Y is selected from -P( O)(OH) 2 , -S(O) n1 R 1 , -C(O)(C 1-6 alkyl)X, -C(O)(C 1-6 alkyl)(aryl),- C(O)OR 4 ; X is selected from -NR 2 R 3 , -P(O)(OH) 2 or -S(O) n1 R 1 ; R 1 is H or C 1-6 alkyl; R 2 is H or C 1-6 alkyl; R 3 is H or C 1-6 alkyl; R 4 is H or C 1-6 alkyl; n1 is 0-4.
  • the prodrug can be used in a suitable liquid formulation (including
  • Drug hemolysis is caused by the massive destruction of red blood cells caused by immune factors after the drug enters the human body.
  • hemolysis such as anemia, jaundice, soy sauce and urine appears.
  • Drug-induced hemolytic anemia can be divided into the following three types: (1) drug-induced immunity, which leads to antibody-mediated hemolytic reactions; (2) drugs acting on red blood cells with genetic enzyme defects (such as G6PD deficiency); (3) The hemolytic reaction of drugs to abnormal hemoglobin.
  • the key to treating this disease is to stop the use of related drugs and control the occurrence of hemolysis to prevent complications.
  • CN102573475 discloses an improved prescription containing polyethylene glycol 15-hydroxystearate and medium chain triglycerides.
  • the hemolysis of the pharmaceutical composition is still not completely resolved, even if the compound of formula I is prepared as a prodrug containing phosphate.
  • This application provides a new NK1 antagonist prodrug compound that is effective in treating various physiological disorders, symptoms and diseases with minimal side effects.
  • X is selected from hydrogen, heterocyclyl, aryl, heteroaryl, -C(O)OA m R 3 , -C(O)NR 4 A m R 3 , -A m [C(R 1 )( R 2 )]C(O)OA n R 3 , -A m OC(O)[C(R 1 )(R 2 )]A n R 3 , -A m C(O)NR 4 A n R 3 , -A m NR 4 C(O)A n R 3 or -A m R 5 , the heterocyclic group, aryl group or heteroaryl group is optionally selected by one or more selected from alkyl, cycloalkyl, alkoxy Group, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R"), COOR' or CONR' or CON
  • Y is selected from hydrogen, -C(O)OA m R 3 , -C(O)NR 4 A m R 3 , -A m [C(R 1 )(R 2 )]C(O)OA n R 3 , -A m OC(O)[C(R 1 )(R 2 )]A n R 3 , -A m C(O)NR 4 A n R 3 , -A m NR 4 C(O)A n R 3 Or -A m R 5 ;
  • A is independently selected from -C(R 1 )(R 2 )(B) p -or -(B) q C(R 1 )(R 2 )-,
  • R 1 , R 2 or R 4 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl or hetero
  • the aryl group is optionally selected by one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR ', NR'(R”), COOR' or CONR'(R”) replaced;
  • R 3 is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, poly(ethyleneoxyethyleneoxy) Poly(ethyleneoxy) OPO(R 6 ) 2 , PO(R 6 ) 2 , OSO 2 (R 6 ) 2 , SO 2 (R 6 ) 2 , OC(O)R 6 or C(O)OR 6 , the alkyl group, ring Alkyl, heterocyclyl, aryl or heteroaryl is optionally selected by one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, Nitro, nitrile, hydroxyl, halogen, SR', NR'(R”), COOR' or CONR'(R”) substituted;
  • R 5 is selected from heterocyclic group, heteroaryl group, OSO 2 R 7 , OC(O)R 7 , SR', SO 2 R'or NR'(R”);
  • R 6 is each independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, hydroxyalkyl or NR'(R”), the alkyl, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally selected by one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, Heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R"), COOR' or CONR'(R”) substituted;
  • R 7 is each independently selected from alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyalkyl or NR'(R"), the alkyl, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl or heteroaryl optionally selected by one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro , Nitrile, hydroxyl, halogen, SR', NR'(R”), COOR' or CONR'(R”);
  • R'or R" are independently selected from hydrogen, hydroxyl, alkyl (preferably from C 1-12 alkyl, including but not limited to methyl, ethyl or isopropyl), alkoxy (preferably from C 1-12 Alkoxy), alkenyl, acyl;
  • B is each independently selected from O, N, SC(O)
  • n, o are each independently selected from 1-10, and can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; p, q are each independently selected from 0 or 1;
  • X and Y are not hydrogen at the same time.
  • the compound represented by formula II of the present disclosure has better solubility than the parent drug formula I compound, and therefore, it is suitable for intravenous administration.
  • the aforementioned compounds after the aforementioned compounds are made into intravenous preparations and enter the human body, they degrade and release the parent drug under physiological conditions, delaying the release of the drug and prolonging the release period of the drug.
  • the compound represented by formula II wherein X is selected from hydrogen, heterocyclyl, aryl, heteroaryl, -C(O)O[C(R 1 )(R 2 )( O) p ] m R 3 , -C(O)NR 4 [C(R 1 )(R 2 )(O) p ] m R 3 , -[C(R 1 )(R 2 )(O) p ] m C(O)[C(R 1 )(R 2 )(O) p ] n R 3 , -[C(R 1 )(R 2 )(O) p ] m [C(R 1 )(R 2 )]C(O)[(O) q C(R 1 )(R 2 )] n R 3 , -[C(R 1 )(R 2 )(O) p ] m C(O)NR 4 [C (R 1 )
  • Y is selected from hydrogen, -C(O)O[C(R 1 )(R 2 )(O) p ] m R 3 , -C(O)NR 4 [C(R 1 )(R 2 )(O) p ] m R 3 , -[C(R 1 )(R 2 )(O) p ] m C(O)[C(R 1 )(R 2 )(O) p ] n R 3 , -[C( R 1 )(R 2 )(O) p ] m C(O)[(O) q C(R 1 )(R 2 )] n R 3 , -[C(R 1 )(R 2 )(O) p ] m C(O)NR 4 [C(R 1 )(R 2 )(O) p ] n R 3 or -[C(R 1 )(R 2 )(O) p ] m R 5
  • the compound represented by formula II wherein Y is selected from -C(O)O[C(R 1 )(R 2 )] m R 3 , -C(O)NR 4 [C (R 1 )(R 2 )] m R 3 , -[C(R 1 )(R 2 )O] m C(O)[C(R 1 )(R 2 )] n R 3 , -[C( R 1 )(R 2 )] m C(O)[OC(R 1 )(R 2 )] n R 3 , -[C(R 1 )(R 2 )N] m C(O)[C(R 1 )(R 2 )] n R 3 , [C(R 1 )(R 2 )N] m C(O)[OC(R 1 )(R 2 )] n R 3 , [C(R 1 )(R 2 )N] m C(O)[OC(R 1 )
  • the compound represented by formula II wherein Y is selected from -C(O)O[C(R 1 )(R 2 )] m R 3 , -C(O)NR 4 [C (R 1 )(R 2 )] m R 3 , -[C(R 1 )(R 2 )O] m C(O)[C(R 1 )(R 2 )] n R 3 , -[C( R 1 )(R 2 )] m C(O)[OC(R 1 )(R 2 )] n R 3 , -[C(R 1 )(R 2 )N] m C(O)[C(R 1 )(R 2 )] n R 3 , [C(R 1 )(R 2 )N] m C(O)[OC(R 1 )(R 2 )] n R 3 , [C(R 1 )(R 2 )N] m C(O)[OC(R 1 )
  • the compound represented by formula II wherein Y is selected from -C(O)O[C(R 1 )(R 2 )] m R 3 , -C(O)NR 4 [C (R 1 )(R 2 )] m R 3 , -[C(R 1 )(R 2 )O] m C(O)[C(R 1 )(R 2 )] n R 3 , -[C( R 1 )(R 2 )] m C(O)[OC(R 1 )(R 2 )] n R 3 , -[C(R 1 )(R 2 )N] m C(O)[C(R 1 )(R 2 )] n R 3 , [C(R 1 )(R 2 )N] m C(O)[OC(R 1 )(R 2 )] n R 3 , [C(R 1 )(R 2 )N] m C(O)[OC(R 1 )
  • the compound represented by formula II wherein Y is selected from -C(O)O[C(R 1 )(R 2 )]R 3 , -C(O)NR 4 [C( R 1 )(R 2 )]R 3 , -[C(R 1 )(R 2 )O]C(O)[C(R 1 )(R 2 )]R 3 , -[C(R 1 )( R 2 )]C(O)[OC(R 1 )(R 2 )]R 3 , -[C(R 1 )(R 2 )N]C(O)[C(R 1 )(R 2 )] R 3 , [C(R 1 )(R 2 )N]C(O)[OC(R 1 )(R 2 )]R 3 , [C(R 1 )(R 2 )N]C(O)[ NC(R 1 )(R 2 )]R 3 , -[
  • the compound represented by formula II wherein Y is selected from -C(O)O[C(R 1 )(R 2 )] 2 R 3 , -C(O)NR 4 [C (R 1 )(R 2 )] 2 R 3 , -[C(R 1 )(R 2 )O] 2 C(O)[C(R 1 )(R 2 )] 2 R 3 , -[C( R 1 )(R 2 )] 2 C(O)[OC(R 1 )(R 2 )] 2 R 3 , -[C(R 1 )(R 2 )N] 2 C(O)[C(R 1 )(R 2 )] 2 R 3 , [C(R 1 )(R 2 )N] 2 C(O)[OC(R 1 )(R 2 )] 2 R 3 , [C(R 1 )( R 2 )N] 2 C(O)[OC(R 1 )(R 2 )] 2 R 3 ,
  • the compound represented by formula II wherein X is selected from -C(O)O[C(R 1 )(R 2 )] m R 3 , -C(O)NR 4 [C (R 1 )(R 2 )] m R 3 , -[C(R 1 )(R 2 )O] m C(O)[C(R 1 )(R 2 )] n R 3 , -[C( R 1 )(R 2 )] m C(O)[OC(R 1 )(R 2 )] n R 3 or -[C(R 1 )(R 2 )] n R 5 , Y is hydrogen.
  • the compound represented by formula II wherein X is selected from -C(O)O[C(R 1 )(R 2 )] m R 3 , -C(O)NR 4 [C (R 1 )(R 2 )] m R 3 , -[C(R 1 )(R 2 )O] m C(O)[C(R 1 )(R 2 )] n R 3 , -[C( R 1 )(R 2 )] m C(O)[OC(R 1 )(R 2 )] n R 3 or -[C(R 1 )(R 2 )] n R 5 ; Y is hydrogen; m, n, o are each independently selected from 1, 2, 3, 4, 5, or 6; p, q are each independently selected from 0.
  • the compound represented by formula II wherein X is selected from -[C(R 1 )(R 2 )]C(O)[OC(R 1 )(R 2 )]R 3 , -C(O)O[C(R 1 )(R 2 )]R 3 , -C(O)NR 4 [C(R 1 )(R 2 )]R 3 , -[C(R 1 )(R 2 )O]C(O)[C(R 1 )(R 2 )]R 3 , -[C(R 1 )(R 2 )]C(O)NR 4 [C(R 1 )(R 2 ) ]R 3 or -[C(R 1 )(R 2 )]R 5 , Y is hydrogen.
  • the compound represented by formula II wherein Y is selected from -C(O)O[C(R 1 )(R 2 )] m R 3 , -C(O)NR 4 [C (R 1 )(R 2 )] m R 3 , -[C(R 1 )(R 2 )O] m C(O)[C(R 1 )(R 2 )] n R 3 , -[C( R 1 )(R 2 )] m C(O)[OC(R 1 )(R 2 )] n R 3 , -[C(R 1 )(R 2 )N] m C(O)[C(R 1 )(R 2 )] n R 3 , [C(R 1 )(R 2 )N] m C(O)[OC(R 1 )(R 2 )] n R 3 , [C(R 1 )(R 2 )N] m C(O)[OC(R 1 )
  • the compound represented by formula II wherein Y is selected from [C(R 1 )(R 2 )(O) p ] n R 5 , and R 5 is selected from C 6-10 heterocyclyl , OPO(R 6 ) 2 , OSO 2 R 6 , SR', SO 2 R', OC(O)R 7 or NR'(R”).
  • the compound represented by formula II wherein Y is selected from [C(R 1 )(R 2 )] n R 5 , and R 5 is selected from C 6-10 heterocyclyl, OPO(R 6 ) 2 , OSO 2 R 6 , SR', SO 2 R', OC(O)R 7 or NR'(R”).
  • the compound represented by formula II wherein Y is selected from [C(R 1 )(R 2 )O] n R 5 , and R 5 is selected from C 6-10 heterocyclyl, OPO( R 6 ) 2 , OSO 2 R 6 , SR', SO 2 R', OC(O)R 7 or NR'(R”).
  • the compound represented by Formula II wherein R 5 is selected from C 6-10 heterocyclyl, OPO(R 6 ) 2 , OSO 2 R 6 , SR', SO 2 R', OC(O)R 7 or NR'(R”).
  • R 6 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclic group (such as piperidine), OR' or NR'(R"), R', R" are as defined in the compound represented by formula II.
  • the compound represented by formula II, wherein R'and R" are selected from hydrogen or alkyl, and the alkyl group is preferably C 1-10 alkyl, more preferably C 1-6 alkane Group, such as methyl, ethyl, propyl, isopropyl.
  • R'and R" are selected from hydrogen or alkyl, and the alkyl is preferably C 1-10 alkyl, more preferably C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl .
  • R 3 is selected from OPO(R 6 ) 2
  • R 6 is selected from hydroxyl, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy or 3 To 7-membered heterocyclic group.
  • R 1 or R 2 in the compound shown in II are each independently selected from hydrogen, C 1-6 alkyl, or C 3-7 cycloalkyl.
  • the compound of formula II is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 or R 2 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl
  • the group is optionally selected by one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR' , NR'(R”), COOR' or CONR'(R”);
  • R'or R" is independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl, acyl;
  • n 1, 2, 3 or 4.
  • R 6 in the compound of formula II is selected from
  • R'and R" are selected from hydrogen or alkyl, and the alkyl is preferably C 1-10 alkyl, more preferably C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl .
  • the compound of formula III is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 or R 2 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl
  • the group is optionally selected by one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, SR' , NR'(R”), COOR' or CONR'(R”);
  • R 6 is each independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, hydroxyalkyl or NR'(R”), the alkyl, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally selected by one or more selected from alkyl, cycloalkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, Heteroaryl, nitro, nitrile, hydroxyl, halogen, SR', NR'(R"), COOR' or CONR'(R”) substituted;
  • R'or R" is independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl, acyl.
  • R 6 in the compound represented by formula IV is selected from C 1-12 alkyl (including but not limited to methyl, ethyl, propyl or isopropyl), C 3-12 ring Alkyl (including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), 3 to 12 membered heterocyclyl (including but not limited to pyrrolyl), C 6-12 aryl (including but not limited to phenyl, naphthalene) Group), 3- to 12-membered heteroaryl (including but not limited to pyridine, piperidine), C 1-12 alkoxy (including but not limited to methoxy, ethoxy, propoxy or isopropoxy) , C 1-12 hydroxyalkyl or NR'(R"), the alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally selected from one or more C 1 -6 alkyl, C 3-6 ring Alkyl (including
  • the compound represented by formula IV wherein said R 6 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclic group (such as piperidine) , OR' or NR'(R”).
  • the compound represented by formula IV, wherein R'and R" are selected from hydrogen or alkyl, and the alkyl group is preferably C 1-10 alkyl, more preferably C 1-6 alkane Group, such as methyl, ethyl, propyl, isopropyl.
  • R 6 in the compound of formula IV is selected from
  • R'and R" are selected from hydrogen or alkyl, and the alkyl is preferably C 1-10 alkyl, more preferably C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl .
  • the compound represented by formula IV wherein said R 6 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclic group (such as piperidine) , OR' or NR'(R”).
  • the compound represented by formula IV, wherein R'and R" are selected from hydrogen or alkyl, and the alkyl group is preferably C 1-10 alkyl, more preferably C 1-6 alkane Group, such as methyl, ethyl, propyl, isopropyl.
  • R 6 in the compound of formula IV is selected from
  • R'and R" are selected from hydrogen or alkyl, and the alkyl is preferably C 1-10 alkyl, more preferably C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl .
  • Typical compounds represented by formula II include but are not limited to:
  • the compounds of the present disclosure have higher solubility and better in vivo conversion than known compounds.
  • the compound of the present disclosure has a low hemolytic effect, reduces the side effects of the drug during administration, and is beneficial to improve patient administration compliance.
  • the present disclosure also provides a pharmaceutical composition, which includes at least one therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the hydrogen in the functional group of the compound described in the present disclosure can be deuterated to obtain the corresponding deuterated compound.
  • the deuterated compound retains the selectivity and potential equivalent to the hydrogen analog; the deuterium bond is more stable, making “ADME” namely The "toxic pharmacokinetics” are different, thereby providing clinically beneficial effects.
  • Toxic pharmacokinetics refers to the absorption, distribution, metabolism, and excretion of foreign chemicals.
  • the present disclosure also relates to the use of the compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the above-mentioned scheme in the preparation of a medicine for the treatment of a physiological disorder, disorder or disease in a patient, wherein the physiological disorder, disorder or disease is a respiratory disease , Cough, inflammatory diseases, skin disorders, eye disorders, depression, anxiety, phobias, bipolar disorder, alcohol dependence, substance abuse with a significant effect on nerves, epilepsy, nociception, psychosis, schizophrenia, Alzheimer’s Mer’s disease, dementia associated with AIDs, Towne’s disease, tension-related disorders, obsessive-compulsive/compulsive disorder, bulemia, anorexia nervosa, eating frenzy, mania, premenstrual syndrome, gastrointestinal dysfunction, Atherosclerosis, fibrotic disorders, obesity, type II diabetes, headache, neuropathic pain, post-action pain, chronic pain syndrome, bladder disorders, genitourinary disorders, vomiting or nausea. Further,
  • the pharmaceutically acceptable salt of the compound is selected from inorganic salt or organic salt.
  • the compound described in the present disclosure reacts with an acid such as trifluoroacetic acid to form a corresponding salt, and the acid is selected from but not limited to acetic acid, hydrochloric acid, salicylic acid, Malic acid, ascorbic acid, phosphoric acid, citric acid, benzoic acid or fumaric acid.
  • the compound described in the present disclosure reacts with a base such as N-methyl-D meglumine or dicyclohexylamine to form the corresponding salt, and the base is selected from but not limited to sodium, alkaline earth metals, amino acids (such as arginine, lysine) ).
  • the present disclosure also includes the same as those described in the present disclosure, but one or more atoms are replaced by an isotope-labeled compound of an atom whose atomic weight or mass number is different from the atomic weight or mass number commonly found in nature.
  • isotopes that can be incorporated into the compounds of the present application 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.
  • the compounds of the present disclosure may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of this application, whether radioactive or not, are included in the scope of this application.
  • substitution with heavier isotopes can provide certain therapeutic advantages resulting from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations
  • deuterium substitution can be partial or complete
  • partial deuterium substitution refers to the substitution of at least one hydrogen with at least one deuterium.
  • Alkyl refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 12 carbon atoms is preferred, and an alkyl group containing 1 to 6 carbon atoms is more preferred.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, and various branched isomers Wait.
  • Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point, preferably one or more of the following groups, independently selected from aryl and heteroaryl , Substituted by halogen.
  • alkenyl includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups.
  • C 2-6 alkenyl means an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 Carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptyl group, etc. Cycloalkyl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • groups are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthi
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) heteroatoms, but does not include the ring part of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably it contains 3 to 6 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably piperidinyl and pyrrolidinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples thereof include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • Alkynyl includes branched and straight chain alkynyl groups having 2 to 12 carbon atoms or alkene containing aliphatic hydrocarbon groups, or if the number of carbon atoms is specified, it means that specific number. For example, ethynyl, propynyl (e.g. 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl and 1-methylpent-2-ynyl.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 12 members, such as benzene Base and naphthyl.
  • the aryl ring may be fused on a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group, carboxyl group or carboxylate group, preferably phenyl group.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 6 to 12 members, more preferably 5 members or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, Pyrimidine, thiadiazole, pyrazinyl, etc. are preferably imidazolyl, pyrazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl or thiazolyl.
  • the heteroaryl ring may be fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • the heteroaryl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where the definition of alkyl is as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • haloalkyl refers to an alkyl substituted by halogen, where alkyl is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with a deuterium atom, where the alkyl group is as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. Shape agent. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.
  • the known starting materials in the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from companies such as AcrosOrganics or Aldrich Chemical Company or obtained by the method in reference CN102775401A.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR shift ( ⁇ ) is given in units of 10-6 (ppm).
  • NMR is measured with BrukerAVANCE-400 nuclear magnetic instrument, the solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), the internal standard is tetramethyl Silane (TMS);
  • ESI-MS was measured with a FINNIGANLCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: FinniganLCQadvantageMAX), and LCMS used high performance liquid chromatography (manufacturer: Agilent, model: 1200) for gradient elution to Scanning in positive ion mode, the mass scanning range is 100 ⁇ 1500.
  • Figure 1 A trend graph of the conversion of the compound of Example 5 in human plasma.
  • the experimental methods that do not indicate specific conditions are usually in accordance with conventional conditions or in accordance with the conditions recommended by the raw material or commodity manufacturers.
  • Reagents without specific sources are conventional reagents purchased on the market.
  • the reaction solution was cooled, poured into ethyl acetate and water, separated, extracted with ethyl acetate, washed with an aqueous solution of sodium sulfite, washed with water and brine in turn, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain 3.73g of yellow foam.
  • the yield was 107%.
  • compound 3 (1.95g, 2.543mmol, 1eq) was dissolved in dichloromethane (40mL) into a 100mL single-necked flask, and trifluoroacetic acid (1.45mL, 19.52mmol, 8eq) was slowly added under ice water cooling ), stirred until the reaction is complete, and concentrated to obtain 2.29 g of oily substance, and separated and purified to obtain 1.39 g of white foamy solid with a yield of 83.5%.
  • Potassium carbonate (11.7g, 84.66mmol, 8.47eq) was dissolved in water (40mL) for later use. Under the protection of N 2 , compound 1 (5.55 g, 10 mmol, 1 eq) was suspended in ethyl acetate (80 mL), the above potassium carbonate aqueous solution was added dropwise under ice-cooling, the reaction solution gradually became clear under stirring, and then Cbz-Cl was added dropwise (1.7mL, 12mmol, 1.2eq), after adding and stirring for 10min, stirring at room temperature overnight, the reaction solution was separated, extracted with ethyl acetate, combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, column chromatography to obtain 4.3g white solid, yield 56%.
  • the target compound was synthesized by replacing Boc-L-valine with Boc-L-alanine.
  • Boc-L-proline was used instead of Boc-L-valine to synthesize the target compound.
  • pH 3.0: Phosphate buffer solution: 100ml 20mmol/L NaH 2 PO 4 , 0.1M H 3 PO 4 adjust the pH to 3.0.
  • the concentration is 160, 400, 1600, 4000, 8000, 16000, 32000ng/mL
  • the QC working solution concentration is set to 480, 1920, 25600ng/mL.
  • Example 4 The compounds of Example 4, Example 6, Example 10 and Example 11
  • the experiment is set to 7 time points of 0, 15, 30, 60, 90, 120, 180 min, and two parallel samples are set at each time point.
  • the reaction system is divided into two groups for each compound, and 75 ⁇ L of plasma is added to each compound, and 5 ⁇ L of the above preparation
  • Standard curve configuration Take the previously diluted 1600 ⁇ M solution I and acetonitrile diluted to 1.5 ⁇ M/mL solution III as the standard curve for use; the standard curve concentration is set to 0.32, 0.8, 1.6, 4.0, 8, 12, 16, 42uM; After each concentration of the standard curve is diluted, add 75 ⁇ L of plasma to 5 ⁇ L of each concentration point to make the final concentration respectively 0.02, 0.05, 0.1, 0.25, 0.75, 1.0, 1.5uM, quickly add 300 ⁇ L stop solution, centrifuge at 3700rpm 10min, take the supernatant LC-MSMS analysis. The data are shown in Table 3.
  • the plasma concentration of the compound in the example a and the plasma concentration of lorapitan after the compound in the example b is metabolized.
  • Example 4 The compounds in Example 4, Example 10 and Example 11 are relatively stable in plasma and have a longer metabolic time, but only a few of these three compounds are metabolized to lorapitan in plasma.
  • the compound in Example 6 can be metabolized to lorapitan in plasma, but from the above data, the overall metabolism in plasma is relatively small.
  • Example 2 Refer to the test method in Test Example 2 to test the metabolism of the compounds of Example 1, Example 2 and Example 8 in the plasma of mice (Mouse), rats (Rat) and humans. The data are shown in Table 4.
  • the plasma concentration of the compound in the example a and the plasma concentration of lorapitan after the compound in the example b is metabolized.
  • Example 8 can be converted into lorapitan in the plasma of mice, rats and humans, especially the conversion rate in human plasma is nearly 46%, while the compounds of Example 1 and Example 2 are in human plasma. Basically, there is no conversion to Lolapitan, or only a slight conversion.
  • the LC/MS/MS method was used to determine the drug concentration in plasma at different times after injection of the compounds of Example 1 and Example 2. Study the pharmacokinetic behavior of the compound in rats and evaluate its pharmacokinetic characteristics.
  • Intravenous bolus injection the bolus injection time is about 5 minutes, the administration dose is 2 mg/kg, the administration concentration is 0.4 mg/ml, and the administration volume is 5 ml/kg.
  • the pharmacokinetic parameters of the compounds in the example a in the rat, and the compounds in the example b are metabolized to the pharmacokinetic parameters of lorapitan in the rat.
  • Example 1 Although the compound of Example 1 is basically not metabolized to the active substance of Lorapitant in in vitro plasma, especially in human plasma, it can show excellent pharmacokinetic data of Lorapitant in rats, indicating the implementation Example 1
  • the compound has been metabolized to lorapitan in the body, and from the data of AUC 0- ⁇ , AUC 0-t and T 1/2 , the metabolic cycle, absorption and exposure level in the body after the administration of compound 1 is longer than that of lorapitan. Tan is quite.
  • Test Example 6 Pharmacokinetic test of the compound in cynomolgus monkey
  • the LC/MS/MS method was used to determine the drug concentration in plasma at different times after injection of the compound of Example 5. To study the pharmacokinetic behavior of the compound in cynomolgus monkeys and evaluate its pharmacokinetic characteristics.
  • Intravenous drip the bolus time is about 30 minutes, the dosage is 2mg/kg, the dosage is 0.4mg/ml, and the dosage is 5ml/kg.
  • Red blood cells randomly sample (EDTA whole blood) 10ml from the rabbit jugular vein or central auricular artery, put it in a conical flask of glass beads and shake for 10 minutes to remove fibrinogen and make defibrinated blood. Add about 10 times the amount of sodium chloride injection, shake well, centrifuge at 1500 rpm for 10 minutes, remove the supernatant, and wash the precipitated red blood cells with sodium chloride injection 3 times as described above until the supernatant does not show red . The obtained red blood cells were prepared into a 2% (v/v) suspension with sodium chloride injection for use.
  • test samples (the compound of Example 5 and the compound of Example 19) respectively and dissolve them in PBS (pH 7.4 or pH 5), and filter to prepare 0.4mg/ml, 0.8mg/ml, 1.2mg/ml, 1.6mg/ml and 2mg /ml, to spare.
  • test sample solution A certain amount of test sample solution is added to the above hemoglobin to test in the supernatant.
  • the solution in the test tube is clear and red, and there are no residual cells or a small amount of red blood cells at the bottom of the tube, it indicates that hemolysis has occurred; if all the red blood cells sink and the supernatant liquid is colorless and clear, it indicates that no hemolysis has occurred. If there are brown-red or red-brown flocculent precipitates in the solution, gently invert 3-5 times and still do not disperse, indicating that red blood cell aggregation may have occurred; further observation under a microscope, if visible red blood cells are aggregated.
  • the compound provided in the present disclosure uses this method to determine hemolysis.
  • the compound of Example 19 has no hemolysis at concentrations up to 2 mg/ml, and the compound of Example 5 has hemolysis at concentrations of 0.04 mg/ml and above.
  • Lorapitant emulsion (prescription: 4.4% polyethylene glycol-15 hydroxystearate, 1.1% medium chain triglyceride and 0.66% soybean oil), and prepare 0.18mg/ml with PBS. 0.09mg/ml, 0.045mg/ml, 0.023mg/ml, 0.011mg/ml, 0.056mg/ml and 0.028mg/ml for use.
  • Test Example 10 Pharmacokinetic test in cynomolgus monkey
  • the LC/MS/MS method was used to determine the drug concentration in plasma at different times after injection of the compound prepared by the method in Example 19. To study the pharmacokinetic behavior of the compound in cynomolgus monkeys and evaluate its pharmacokinetic characteristics.
  • Intravenous drip the bolus time is about 30 minutes, the dosage is 3.54mg/kg, the dosage is 2mg/ml, and the dosage is 5ml/kg.
  • blood Before administration and 5min, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h and 24h after administration, blood shall be collected through femoral vein. Each sample shall be collected about 0.6mL. Heparin sodium is anticoagulated. After collection Put it on ice immediately. After the blood sample is collected, it is placed in a labeled centrifuge tube, and the plasma is separated by centrifugation (centrifugal force 2200g, centrifugation 10min, 2-8°C).
  • the pharmacokinetic parameters of the compounds in the example a in cynomolgus monkeys, and the pharmacokinetic parameters of the compounds in the example b are metabolized to lorapitan in cynomolgus monkeys.

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Abstract

式II所示化合物或其药学上可接受的盐，及其制备方法。式II所示化合物是神经激肽-1受体的拮抗剂，可用于与神经激肽-1受体有关的疾病的治疗，可避免药物的溶血作用，降低药物给药时的副作用。

Description

神经激肽-1拮抗剂 技术领域
本公开中涉及一种神经肽神经激肽-1(NK1或NK-1)受体的拮抗剂。
背景技术
速激肽是神经激肽受体的肽配体。神经激肽受体，比如NK1，NK2和NK3，与各种生物过程有关。可在哺乳动物的神经和循环系统以及在周围组织中发现它们。因此，这类受体的调节已被研究用于潜在地治疗或预防哺乳动物的各种疾病。典型的神经激肽受体拮抗剂和它们的用途包括：US5760018(1998)(疼痛，炎症，偏头痛和呕吐)，US5620989(1997)(疼痛，伤害感受和炎症)，WO95/19344(1995)，WO 94/13639(1994)和WO 94/10165(1994)。其它NK1受体拮抗剂的种类还包括：Wu等人，Tetrahedron 56，3043-3051(2000)；Rombouts等人，Tetrahedron Letters 42，7397-7399(2001)；和Rogiers等人，Tetrahedron 57，8971-8981(2001)。
US7049320提供一种有效的、选择性的、和具有有益的治疗和药理学性质和良好代谢性稳定性的NK1拮抗剂(5S,8S)-8-[{(1R)-1-(3,5-双-(三氟甲基)苯基)-乙氧基}-甲基]-8-苯基-l,7-二氮杂螺[4.5]癸-2-酮(式I化合物)，该化合物可采用游离碱形式或药学上可接受的盐形式，适合胃肠外给药的制剂，
Figure PCTCN2020098460-appb-000001
US9101615提供式I化合物的前药，即，式I化合物游离胺(或两个胺)的氢被选自-Y、-X的基团置换的前药及其盐，其中Y选自-P(O)(OH) 2、-S(O) n1R 1、-C(O)(C 1-6烷基)X、-C(O)(C 1-6烷基)(芳基)、-C(O)OR 4；X选自-NR 2R 3、-P(O)(OH) 2或-S(O) n1R 1；R 1是H或C 1-6烷基；R 2是H或C 1-6烷基；R 3是H或C 1-6烷基；R 4是H或C 1-6烷基；n1是0-4。该前药可用于合适的液体制剂(包括或不包括所述胃肠外递药载体)中治疗需要其治疗的患者。
另一方面，药物溶血性是药物进入人体后免疫因素导致的红细胞大量破坏引起的，临床上出现了贫血、黄疸、酱油和尿液等溶血现象。药物性溶血性贫血可分为以下三种类型:(1)药物性免疫，导致抗体介导的溶血性反应；(2)药物作用于具有遗传酶缺陷的红细胞(例如G6PD缺陷)；(3)药物对异常血红蛋白的溶血反应。治疗这种疾病的关键在于停止使用相关药物，控制溶血的发生，以防止并发症的发生。为了解决式I化合物在生理pH溶剂度低的问题，研究人员采用含有Captisol、丙二醇和乙醇的共溶剂基制剂明显提高化合物1的溶解度，但是共溶剂制剂在静脉内给药后有明显的溶血作用。CN102573475公开了一种改进处方，含有聚乙二醇15-羟基硬脂酸酯、中链甘油三酯。但药物组合物的溶血作用仍然没有彻底解决，即便将式I化合物制备成含有磷酸酯的前药。
本申请提供一种新的对治疗各种生理失调、病征和疾病有效而副作用最小的NK1拮抗剂 前药化合物。
发明内容
本公开(The disclosure)提供了式II所示化合物：
Figure PCTCN2020098460-appb-000002
或其可药用的盐或其立体异构体、旋转异构体或互变异构体或其氘代物，
其中，X选自氢、杂环基、芳基、杂芳基、-C(O)OA mR 3、-C(O)NR 4A mR 3、-A m[C(R 1)(R 2)]C(O)OA nR 3、-A mOC(O)[C(R 1)(R 2)]A nR 3、-A mC(O)NR 4A nR 3、-A mNR 4C(O)A nR 3或-A mR 5，所述杂环基、芳基或杂芳基任选被一个或多个选自烷基、环烷基、烷氧基、羟烷基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
Y选自氢、-C(O)OA mR 3、-C(O)NR 4A mR 3、-A m[C(R 1)(R 2)]C(O)OA nR 3、-A mOC(O)[C(R 1)(R 2)]A nR 3、-A mC(O)NR 4A nR 3、-A mNR 4C(O)A nR 3或-A mR 5；
A独立地选自-C(R 1)(R 2)(B) p-或-(B) qC(R 1)(R 2)-，
R 1、R 2或R 4各自独立地选自氢、烷基、环烷基、杂环基、芳基或杂芳基，所述烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自烷基、环烷基、烷氧基、羟烷基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
R 3选自氢、烷基、环烷基、杂环基、芳基、杂芳基、聚(亚氧基亚乙氧基)
Figure PCTCN2020098460-appb-000003
聚(亚乙氧基)
Figure PCTCN2020098460-appb-000004
OPO(R 6) 2、PO(R 6) 2、OSO 2(R 6) 2、SO 2(R 6) 2、OC(O)R 6或C(O)OR 6，所述烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自烷基、环烷基、烷氧基、羟烷基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
R 5选自杂环基、杂芳基、OSO 2R 7、OC(O)R 7、SR'、
Figure PCTCN2020098460-appb-000005
SO 2R'或NR'(R”)；
R 6各自独立地选自氢、羟基、烷基、环烷基、杂环基、芳基、杂芳基、烷氧基、羟烷基或NR'(R”)，所述烷基、羟烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自烷基、环烷基、烷氧基、羟烷基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
R 7各自独立地选自烷基、羟基、环烷基、杂环基、芳基、杂芳基、羟烷基或NR'(R”)， 所述烷基、羟烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自烷基、环烷基、烷氧基、羟烷基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
R'或R”独立地选自氢、羟基、烷基(优选自C 1-12烷基，包括但不限于甲基、乙基或异丙基)、烷氧基(优选自C 1-12烷氧基)、烯基、酰基；
B各自独立地选自O，N，SC(O)
m，n，o各自独立地选自1～10，可为1、2、3、4、、5、6、7、8、9或10；p，q各自独立地选自0或1；
且，X和Y不同时为氢。
本公开式II所示化合物具有优于母药式I化合物的溶解度，因此，可适用于静脉内给药。另外，前述化合物制成静脉制剂进入人体后，在生理条件下降解并释放母药，延缓药物的释放，延长药物的释放周期。
在本公开可选实施方案中，式II所示的化合物，其中X选自氢、杂环基、芳基、杂芳基、-C(O)O[C(R 1)(R 2)(O) p] mR 3、-C(O)NR 4[C(R 1)(R 2)(O) p] mR 3、-[C(R 1)(R 2)(O) p] mC(O)[C(R 1)(R 2)(O) p] nR 3、-[C(R 1)(R 2)(O) p] m[C(R 1)(R 2)]C(O)[(O) qC(R 1)(R 2)] nR 3、-[C(R 1)(R 2)(O) p] mC(O)NR 4[C(R 1)(R 2)(O) p] nR 3或-[C(R 1)(R 2)(O) p] mR 5，所述烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自烷基(优选自C 1-12烷基，包括但不限于甲基、乙基或异丙基)、环烷基(优选自C 1-12环烷基，如环已烷基、环戊烷基)、烷氧基(优选自C 1-12烷氧基)、羟烷基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
Y选自氢、-C(O)O[C(R 1)(R 2)(O) p] mR 3、-C(O)NR 4[C(R 1)(R 2)(O) p] mR 3、-[C(R 1)(R 2)(O) p] mC(O)[C(R 1)(R 2)(O) p] nR 3、-[C(R 1)(R 2)(O) p] mC(O)[(O) qC(R 1)(R 2)] nR 3、-[C(R 1)(R 2)(O) p] mC(O)NR 4[C(R 1)(R 2)(O) p] nR 3或-[C(R 1)(R 2)(O) p] mR 5，且X和Y不同时为氢。
在本公开可选实施方案中，式II所示的化合物，其中Y选自-C(O)O[C(R 1)(R 2)] mR 3、-C(O)NR 4[C(R 1)(R 2)] mR 3、-[C(R 1)(R 2)O] mC(O)[C(R 1)(R 2)] nR 3、-[C(R 1)(R 2)] mC(O)[OC(R 1)(R 2)] nR 3、-[C(R 1)(R 2)N] mC(O)[C(R 1)(R 2)] nR 3、[C(R 1)(R 2)N] mC(O)[OC(R 1)(R 2)] nR 3、[C(R 1)(R 2)N] mC(O)[NC(R 1)(R 2)] nR 3、-[C(R 1)(R 2)(O) p] mC(O)NR 4[C(R 1)(R 2)(O) p] nR 3或-[C(R 1)(R 2)(O) p] nR 5，X为氢、3至6元杂环基。
在本公开可选实施方案中，式II所示的化合物，其中Y选自-C(O)O[C(R 1)(R 2)] mR 3、-C(O)NR 4[C(R 1)(R 2)] mR 3、-[C(R 1)(R 2)O] mC(O)[C(R 1)(R 2)] nR 3、-[C(R 1)(R 2)] mC(O)[OC(R 1)(R 2)] nR 3、-[C(R 1)(R 2)N] mC(O)[C(R 1)(R 2)] nR 3、[C(R 1)(R 2)N] mC(O)[OC(R 1)(R 2)] nR 3、[C(R 1)(R 2)N] mC(O)[NC(R 1)(R 2)] nR 3、-[C(R 1)(R 2)(O) p] mC(O)NR 4[C(R 1)(R 2)(O) p] nR 3或-[C(R 1)(R 2)(O) p] nR 5，X为氢、3至6元杂环基；m，n，o各自独立地选自1、2、3、4、5或6；p，q各自独立地选自0。
在本公开可选实施方案中，式II所示的化合物，其中Y选自-C(O)O[C(R 1)(R 2)] mR 3、-C(O)NR 4[C(R 1)(R 2)] mR 3、-[C(R 1)(R 2)O] mC(O)[C(R 1)(R 2)] nR 3、-[C(R 1)(R 2)] mC(O)[OC(R 1)(R 2)] nR 3、-[C(R 1)(R 2)N] mC(O)[C(R 1)(R 2)] nR 3、[C(R 1)(R 2)N] mC(O)[OC(R 1)(R 2)] nR 3、[C(R 1)(R 2)N] m C(O)[NC(R 1)(R 2)] nR 3、-[C(R 1)(R 2)(O) p] mC(O)NR 4[C(R 1)(R 2)(O) p] nR 3或-[C(R 1)(R 2)(O) p] nR 5，X为氢、3至6元杂环基；m，n，o各自独立地选自1、2、3、4、5或6；p，q各自独立地选自1。
在本公开可选实施方案中，式II所示的化合物，其中Y选自-C(O)O[C(R 1)(R 2)]R 3、-C(O)NR 4[C(R 1)(R 2)]R 3、-[C(R 1)(R 2)O]C(O)[C(R 1)(R 2)]R 3、-[C(R 1)(R 2)]C(O)[OC(R 1)(R 2)]R 3、-[C(R 1)(R 2)N]C(O)[C(R 1)(R 2)]R 3、[C(R 1)(R 2)N]C(O)[OC(R 1)(R 2)]R 3、[C(R 1)(R 2)N]C(O)[NC(R 1)(R 2)]R 3、-[C(R 1)(R 2)(O) p]C(O)NR 4[C(R 1)(R 2)(O) p]R 3或-[C(R 1)(R 2)(O) p]R 5，X为氢、3至6元杂环基。
在本公开可选实施方案中，式II所示的化合物，其中Y选自-C(O)O[C(R 1)(R 2)] 2R 3、-C(O)NR 4[C(R 1)(R 2)] 2R 3、-[C(R 1)(R 2)O] 2C(O)[C(R 1)(R 2)] 2R 3、-[C(R 1)(R 2)] 2C(O)[OC(R 1)(R 2)] 2R 3、-[C(R 1)(R 2)N] 2C(O)[C(R 1)(R 2)] 2R 3、[C(R 1)(R 2)N] 2C(O)[OC(R 1)(R 2)] 2R 3、[C(R 1)(R 2)N] 2C(O)[NC(R 1)(R 2)] 2R 3、-[C(R 1)(R 2)(O) p] 2C(O)NR 4[C(R 1)(R 2)(O) p] 2R 3或-[C(R 1)(R 2)(O) p] 2R 5，X为氢、3至6元杂环基。
在本公开可选实施方案中，式II所示的化合物，其中X选自-C(O)O[C(R 1)(R 2)] mR 3、-C(O)NR 4[C(R 1)(R 2)] mR 3、-[C(R 1)(R 2)O] mC(O)[C(R 1)(R 2)] nR 3、-[C(R 1)(R 2)] mC(O)[OC(R 1)(R 2)] nR 3或-[C(R 1)(R 2)] nR 5，Y为氢。
在本公开可选实施方案中，式II所示的化合物，其中X选自-C(O)O[C(R 1)(R 2)] mR 3、-C(O)NR 4[C(R 1)(R 2)] mR 3、-[C(R 1)(R 2)O] mC(O)[C(R 1)(R 2)] nR 3、-[C(R 1)(R 2)] mC(O)[OC(R 1)(R 2)] nR 3或-[C(R 1)(R 2)] nR 5；Y为氢；m，n，o各自独立地选自1、2、3、4、5或6；p，q各自独立地选自0。
在本公开可选实施方案中，式II所示的化合物，其中X选自-[C(R 1)(R 2)]C(O)[OC(R 1)(R 2)]R 3、-C(O)O[C(R 1)(R 2)]R 3、-C(O)NR 4[C(R 1)(R 2)]R 3、-[C(R 1)(R 2)O]C(O)[C(R 1)(R 2)]R 3、-[C(R 1)(R 2)]C(O)NR 4[C(R 1)(R 2)]R 3或-[C(R 1)(R 2)]R 5，Y为氢。
进一步地，在本公开可选实施方案中，式II所示的化合物，其中R 3选自氢、聚(亚氧基亚乙氧基)
Figure PCTCN2020098460-appb-000006
聚(亚乙氧基)
Figure PCTCN2020098460-appb-000007
OPO(R 6) 2、PO(R 6) 2、OSO 2(R 6) 2、SO 2(R 6) 2、OC(O)R 6或C(O)OR 6，R 6如式II所示化合物中所定义。
在本公开可选实施方案中，式II所示的化合物，其中Y选自-C(O)O[C(R 1)(R 2)] mR 3、-C(O)NR 4[C(R 1)(R 2)] mR 3、-[C(R 1)(R 2)O] mC(O)[C(R 1)(R 2)] nR 3、-[C(R 1)(R 2)] mC(O)[OC(R 1)(R 2)] nR 3、-[C(R 1)(R 2)N] mC(O)[C(R 1)(R 2)] nR 3、[C(R 1)(R 2)N] mC(O)[OC(R 1)(R 2)] nR 3、[C(R 1)(R 2)N] mC(O)[NC(R 1)(R 2)] nR 3、-[C(R 1)(R 2)(O) p] mC(O)NR 4[C(R 1)(R 2)(O) p] nR 3或-[C(R 1)(R 2)(O) p] nR 5，X为氢、3至6元杂环基；R 3选自氢、聚(亚氧基亚乙氧基)
Figure PCTCN2020098460-appb-000008
聚(亚乙氧基)
Figure PCTCN2020098460-appb-000009
OPO(R 6) 2、PO(R 6) 2、OSO 2(R 6) 2、SO 2(R 6) 2、OC(O)R 6或C(O)OR 6，R 6如式II所示化合物中所定义。
在本公开可选实施方案中，式II所示的化合物，其中Y选自[C(R 1)(R 2)(O) p] nR 5，R 5选自 C 6-10杂环基、OPO(R 6) 2、OSO 2R 6、SR'、SO 2R'、
Figure PCTCN2020098460-appb-000010
OC(O)R 7或NR'(R”)。
在本公开可选实施方案中，式II所示的化合物，其中Y选自[C(R 1)(R 2)] nR 5，R 5选自C 6-10杂环基、OPO(R 6) 2、OSO 2R 6、SR'、SO 2R'、
Figure PCTCN2020098460-appb-000011
OC(O)R 7或NR'(R”)。
在本公开可选实施方案中，式II所示的化合物，其中Y选自[C(R 1)(R 2)O] nR 5，R 5选自C 6-10杂环基、OPO(R 6) 2、OSO 2R 6、SR'、SO 2R'、
Figure PCTCN2020098460-appb-000012
OC(O)R 7或NR'(R”)。
在本公开可选实施方案中，式II所示的化合物，其中R 5选自C 6-10杂环基、OPO(R 6) 2、OSO 2R 6、SR'、SO 2R'、
Figure PCTCN2020098460-appb-000013
OC(O)R 7或NR'(R”)。
进一步地，式II所示的化合物，其中所述R 6选自氢、C 1-6烷基、C 3-6环烷基、3至6元杂环基(如派啶)、OR'或NR'(R”)，R'、R”如式II所示化合物中定义。
在本公开可选实施方案中，式II所示的化合物，其中R'、R”选自氢或烷基，所述烷基优选自C 1-10烷基，更优自C 1-6烷基，如甲基、乙基、丙基、异丙基。
在本公开可选实施方案中，式II所示的化合物，其中m＝1、2、3或4，n＝1、2、3或4，o＝1～8。
在一些实施方案中，式II所示化合物，其中R 6和R 7各自独立地选自
Figure PCTCN2020098460-appb-000014
Figure PCTCN2020098460-appb-000015
其中，R'、R”选自氢或烷基，所述烷基优选自C 1-10烷基，更优自C 1-6烷基，如甲基、乙基、丙基、异丙基。
一些实施方案提供II所示化合物中R 3选自OPO(R 6) 2，R 6选自羟基、C 1-6烷基、C 3-7环烷基、C 1-6烷氧基或3至7元杂环基。
另一些实施方案提供II所示化合物中m＝1、2、3或4。
另一些实施方案提供II所示化合物中R 1或R 2各自独立地选自氢、C 1-6烷基或C 3-7环烷基。
在另一些实施方案中，其中式II所示化合物为
Figure PCTCN2020098460-appb-000016
或其可药用的盐或其立体异构体、旋转异构体或互变异构体或其氘代物，
其中，R 1或R 2各自独立地选自氢、烷基、环烷基、杂环基、芳基或杂芳基，所述烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自烷基、环烷基、烷氧基、羟烷基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
R'或R”独立地选自氢、羟基、烷基、烷氧基、烯基、酰基；
m＝1、2、3或4。
在一些实施方案中，式II所示化合物中R 6选自
Figure PCTCN2020098460-appb-000017
Figure PCTCN2020098460-appb-000018
其中，R'、R”选自氢或烷基，所述烷基优选自C 1-10烷基，更优自C 1-6烷基，如甲基、乙基、丙基、异丙基。
在另一些实施方案中，式III所示化合物为
Figure PCTCN2020098460-appb-000019
或其可药用的盐或其立体异构体、旋转异构体或互变异构体或其氘代物，
其中，R 1或R 2各自独立地选自氢、烷基、环烷基、杂环基、芳基或杂芳基，所述烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自烷基、环烷基、烷氧基、羟烷基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
R 6各自独立地选自氢、羟基、烷基、环烷基、杂环基、芳基、杂芳基、烷氧基、羟烷基或NR'(R”)，所述烷基、羟烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自烷基、环烷基、烷氧基、羟烷基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
R'或R”独立地选自氢、羟基、烷基、烷氧基、烯基、酰基。
进一步地，在可选实施方案中，式IV所示化合物中R 6选自C 1-12烷基(包括但不限于甲基、乙基、丙基或异丙基)、C 3-12环烷基(包括但不限于环丙基、环戊基、环己基)、3至12元杂环基(包括但不限于吡咯基)、C 6-12芳基(包括但不限于苯基、萘基)、3至12元杂芳基(包括但不限于吡啶、派啶)、C 1-12烷氧基(包括但不限于甲氧基、乙氧基、丙氧基或异丙氧基)、C 1-12羟烷基或NR'(R”)，所述烷基、羟烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自C 1-6烷基、C 3-6环烷基、3至12元杂环基、C 1-12烷氧基、C 1-6羟烷基、C 2-4烯基、C 2-4炔基、C 6-10芳基、3至10元杂芳基、硝基、腈基、羟基、卤素、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；R'或R”独立地选自氢、C 1-6烷基、C 1-6烷氧基、C 2-4烯基、C 1-6烷酰基(如乙酰基、甲酰基)、苯甲酰基、对甲苯酰基。
在本公开优选实施方案中，式IV所示化合物，其中所述R 6选自氢、C 1-6烷基、C 3-6环烷基、3至6元杂环基(如派啶)、OR'或NR'(R”)。
在本公开可选实施方案中，式IV所示的化合物，其中R'、R”选自氢或烷基，所述烷基优选自C 1-10烷基，更优自C 1-6烷基，如甲基、乙基、丙基、异丙基。
在一些实施方案中，式IV所示化合物中R 6选自
Figure PCTCN2020098460-appb-000020
Figure PCTCN2020098460-appb-000021
Figure PCTCN2020098460-appb-000022
其中，R'、R”选自氢或烷基，所述烷基优选自C 1-10烷基，更优自C 1-6烷基，如甲基、乙基、丙基、异丙基。
在本公开优选实施方案中，式IV所示化合物，其中所述R 6选自氢、C 1-6烷基、C 3-6环烷基、3至6元杂环基(如派啶)、OR'或NR'(R”)。
在本公开可选实施方案中，式IV所示的化合物，其中R'、R”选自氢或烷基，所述烷基优选自C 1-10烷基，更优自C 1-6烷基，如甲基、乙基、丙基、异丙基。
在另一些实施方案中，式IV所示化合物中R 6选自
Figure PCTCN2020098460-appb-000023
Figure PCTCN2020098460-appb-000024
其中，R'、R”选自氢或烷基，所述烷基优选自C 1-10烷基，更优自C 1-6烷基，如甲基、乙基、丙基、异丙基。
式II所示典型化合物，包括但不限于：
Figure PCTCN2020098460-appb-000025
Figure PCTCN2020098460-appb-000026
Figure PCTCN2020098460-appb-000027
Figure PCTCN2020098460-appb-000028
Figure PCTCN2020098460-appb-000029
或其可药用的盐或其立体异构体、旋转异构体或互变异构体。
进一步地，式IA所示化合物为：
Figure PCTCN2020098460-appb-000030
或其可药用的盐。
另一方面，本公开化合物相比已知化合物具有更高溶解度、体内转化更为优异。在一些实施方案中，本公开化合物具有低溶血作用，降低在给药时药物的副作用，利于提高患者给药顺从性。
本公开中还提供了一种药物组合物，包括至少一种治疗有效量的前述化合物或其可药用的盐以及药学上可接受的载体、稀释剂或赋形剂。
另一方面，本公开所述化合物的官能团中氢可被氘代，获得相应氘代化合物，氘代化合物保留了与氢类似物相当的选择性和潜力；氘键更稳定，使得"ADME"即"毒药物动力学"不同，从而提供临床上有益效果。
毒药物动力学，指机体对外源化学物的吸收(absorption)、分布(distribution)、代谢(metabolism)及排泄(excretion)过程。
本公开中还涉及上述方案中所述化合物或其可药用盐，或药物组合物在制备治疗患者中的生理失调，病症或疾病的药物中的用途，其中生理失调、病症或疾病是呼吸道疾病、咳嗽、炎性疾病、皮肤障碍、眼科障碍、抑郁症、焦虑、恐怖症，双向障碍，酒精依赖，对神经起显著作用的物质滥用，癫痫，伤害感受，精神病，精神分裂症，阿尔茨海默氏病，与AIDs有关的痴呆，Towne′s疾病，与紧张有关的障碍，强迫性/强制性障碍，bulemia，神经性厌食症，疯狂进食，狂躁，经前期综合征，胃肠机能紊乱，动脉粥样硬化，纤维化障碍，肥胖，II型糖尿病，头痛，神经性疼痛，动作后疼痛，慢性疼痛综合症，膀胱障碍，泌尿生殖器障碍，呕吐或恶心。进一步地，用于制备治疗哮喘，呕吐，恶心，忧郁症，焦虑，咳嗽或偏头痛的药物的用途。
另一方面，化合物的可药用盐选自无机盐或有机盐，本公开所述化合物与酸如三氟乙酸反应成相应盐，所述酸选自但不限于乙酸、盐酸、水杨酸、苹果酸、抗坏血酸、磷酸、柠檬酸、苯甲酸或富马酸。本公开所述化合物与碱如N-甲基-D葡甲胺或二环已胺反应成相应盐，所述碱选自但不限于钠、碱土金属、氨基酸(如精氨酸、赖氨酸)。
另一方面，本公开还包括与本公开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申请化合物。可结合到本申请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。
本公开的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本申请的化合物的所有同位素组成的变换，无论放射性与否，都包括在本申请的范围之内。
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。
术语解释：
“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团。优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基，及其各种支链异构体等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自芳基、杂芳基、卤素所取代。“烯基”包括具有2至12个碳原子的支链和直链烯烃或含有脂族烃基团的烯烃。例如“C 2-6烯基”表示具有2、3、4、5或6个碳原子的烯基。烯基的实例包括但不限于，乙烯基、烯丙基、1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基丁-2-烯基、3-甲基丁-1-烯基、1-戊烯基、3-戊烯基及4-己烯基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸 酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括―O―O―、―O―S―或―S―S―的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至6个环原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等，优选哌啶基、吡咯烷基。多环杂环基包括螺环、稠环和桥环的杂环基。
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2020098460-appb-000031
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
“炔基”包括具有2至12个碳原子的支链和直链炔基或含有脂族烃基的烯烃，或若规定指定碳原子数，则意指该特定数目。例如乙炔基、丙炔基(例如1-丙炔基、2-丙炔基)、3-丁炔基、戊炔基、己炔基及1-甲基戊-2-炔基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至12元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2020098460-appb-000032
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基，优选苯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为6至12元，更优选为5元或6元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、吡唑基、嘧啶基或噻唑基；更优选为吡唑基或噻唑基。所述杂芳基环可以稠合 于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2020098460-appb-000033
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指―O―(烷基)和―O―(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“卤代烷基”指被卤素取代的烷基，其中烷基如上所定义。
术语“氘代烷基”指被氘原子取代的烷基，其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本公开中的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自 AcrosOrganics或AldrichChemicalCompany等公司或参考文献CN102775401A中方法获取。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用BrukerAVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)；ESI-MS的测定用FINNIGANLCQAd(ESI)质谱仪(生产商：Thermo，型号：FinniganLCQadvantageMAX)，LCMS采用高效液相色谱(生产商：Agilent，型号：1200)进行梯度洗脱，以正离子模式扫描，质量扫描范围为100～1500。
附图说明：
图1：实施例5化合物于人血浆中转化的趋势图。
具体实施方式
以下结合实施例进一步描述本公开中，但这些实施例并非限制本公开中的范围。
本公开中实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例1：
Figure PCTCN2020098460-appb-000034
第一步：
Figure PCTCN2020098460-appb-000035
在N 2保护下，于100mL三口瓶中称取化合物1(2.43g，4.86mmol，1eq)溶于二氯甲烷(36mL)中，加入二异丙基乙胺(5g，38.76mmol，8eq)，冷却到-30℃，加入三甲基氯硅烷(1.36g，12.52mmol，2.6eq)，室温下搅拌2h。再冷却到-25℃，滴加氯甲酸氯甲酯(0.77g，6mmol，1.23eq)的二氯甲烷溶液，控温-20℃～-5℃搅拌至反应完毕，将反应液倒入冰水中，分液，二氯甲烷萃取，加入水和1N的盐酸溶液，分液，再依次用食盐水、饱和碳酸氢钠水溶液和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，得到3.0g黄色胶状物，收率104％。
第二步：
Figure PCTCN2020098460-appb-000036
在N 2保护下，于500mL三口瓶中加入化合物2(2.8g，4.53mmol，1eq)，四丁基碘化铵(1.68g，4.55mmol，1eq)，磷酸二叔丁酯钾盐(5.63g，22.67mmol，5eq)和二氧六环(84mL)，加热至55℃下搅拌4h。反应液降温，倒入乙酸乙酯和水中，分液，用乙酸乙酯萃取，用亚硫酸钠的水溶液洗涤，再依次用水、食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到3.73g黄色泡沫，收率107％。
第三步：
Figure PCTCN2020098460-appb-000037
在N 2保护下，于100mL单口瓶中加入化合物3(1.95g，2.543mmol，1eq)溶于二氯甲烷(40mL)中，冰水冷却下缓慢加入三氟乙酸(1.45mL，19.52mmol，8eq)，搅拌至反应完毕，浓缩，得到2.29g油状物，分离纯化得到1.39g白色泡沫状固体，收率83.5％。
1H-NMR(400MHz，CD 3OD):δ(ppm)7.89(s，2H)，7.86(s，1H)，7.41-7.27(m，5H)，5.66(d，J＝12Hz，1H)，5.50-5.47(m，1H)，4.60(d，J＝8Hz，1H)，4.20-3.88(m，3H)，2.51-2.10(m，5H)，1.86-1.66(m，3H)，1.44-1.31(m，4H).
第四步：
Figure PCTCN2020098460-appb-000038
于50mL单口瓶中加入化合物4(111mg，0.17mmol)，葡甲胺(59.6mg，0.305mmol)溶于甲醇(5mL)中，室温下搅拌1.5h，浓缩，得到174mg白色固体盐。
实施例2：
Figure PCTCN2020098460-appb-000039
第一步：
Figure PCTCN2020098460-appb-000040
将化合物1(5g，10mmol，1eq)置于250mL的三口瓶中，加入50mL的二氯甲烷，N 2置换，加入二异丙基乙基胺(5.1g，40mmol，4eq)，冷却至0℃，慢慢滴入氯甲酸-3-氯丙酯(4.71g，30mmol，3eq)搅拌至反应完毕，反应液用20mL×2水洗，用无水硫酸钠干燥后浓缩，粗品用20mL的叔丁基甲醚打浆，过滤干燥后得到5.3g产品，白色固体，收率85.5％，HPLC纯度95.2％。
第二步：
Figure PCTCN2020098460-appb-000041
将化合物2(500mg，0.833mmol，1eq)置于25mL的圆底烧瓶中，加入5mL的二甲基甲酰胺、5mg碘化钾和二叔丁酯磷酸四丁基季铵盐(564mg，1.25mmol，1.5eq)，升温至100℃反应完毕，浓缩，高效液相制备得到370mg产品，收率57.8％，HPLC纯度97％。
第三步：
Figure PCTCN2020098460-appb-000042
化合物3(2g，2.52mmol)溶于盐酸二氧六环溶液(25mL，4M)，室温搅拌反应30min后减压蒸干，得到化合物4(1.4g，2.05mmol)，收率81％。
第四步：
Figure PCTCN2020098460-appb-000043
25℃下将化合物4(700mg，1.025mmol)，葡甲胺(310mg，2mmol)用甲醇(10mL)溶解，搅拌反应1h，减压浓缩干得到化合物5粗品(1.1g)，将其用甲基叔丁基醚打浆并过滤抽干，得到化合物5的纯品(1g，0.932mmol)，收率91％。
1H-NMR(400MHz，CD 3OD):δ7.90-7.84(m,3H),7.32-7.25(m,5H),4.14-3.61(m,25H),2.81(m,5H),2.47-2.29(m,12H),1.79-1.63(m,5H),1.46-1.29(m,3H),1.21-1.12(m,6H).
实施例3：
Figure PCTCN2020098460-appb-000044
在25ml烧瓶中，加入2毫升丙酮和100毫克化合物1，开启搅拌；分批加入固体碳酸钾(42mg，0.3mmol，1.5eq)后，室温搅拌半小时；将36毫克的化合物2加入到反应瓶里，室温搅拌反应完毕，约18小时，柱层析纯化得50毫克3(产率40.8％)。
1H-NMR(400MHz，CDCl 3):δ＝7.79(s，1H)，7.72(s，2H)，7.42-7.40(d，J＝8Hz,2H)，7.31-7.27(m,2H)，7.27-7.21(m,1H)，5.58(s，1H)，4.55-4.53(m，1H)，4.06-3.99(m，2H)，3.69-3.67(d，J＝8Hz,1H)，3.53-3.49(d，J＝16Hz,1H)，3.25-3.21(d，J＝16Hz，1H)，2.77-2.74(d，J＝12Hz，1H)，2.59-2.57(d，J＝8Hz，1H)，2.34-2.31(m，3H)，1.97-1.71(m，7H)，1.46-1.45(d，J＝4Hz，3H).
实施例4：
Figure PCTCN2020098460-appb-000045
第一步：
Figure PCTCN2020098460-appb-000046
在氮气氛围下，将750mg的化合物1、2.1ml二异丙基乙胺加入到三口瓶中，然后加入12毫升的无水二氯甲烷，降温到-40℃，滴入0.5ml三甲基氯硅烷完毕后，室温并搅拌反应两个小时。再降温到-30至-20℃，将0.024毫升的氯甲酸氯乙酯溶于3毫升的无水二氯甲烷里，滴入到反应液中完毕后，在-20至5℃搅拌至反应完毕，加入水淬灭反应，分液，依次用浓度为1N的稀盐酸、饱和食盐水、饱和碳酸氢钠水溶液，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，真空干燥得1克白色固体2。
第二步：
Figure PCTCN2020098460-appb-000047
将1g化合物2以及0.99g碘化钠溶于10毫升的二甲基甲酰胺中，加入1.15ml二异丙基乙胺以及0.75ml甲基哌嗪，加热至90℃搅拌反应完毕，反应液直接浓缩后经高效液相制备得430mg化合物3。
1H-NMR(400MHz，CDCl 3)：δ7.77(s,1H),7.73(s,2H),7.37-7.26(m,5H),6.56(s,1H),4.44-4.40(m,1H),4.29-4.24(m,2H),4.10-4.07(m,1H),3.90-3.87(d,J＝12Hz,1H),3.79-3.76(d,J＝12Hz,1H),3.01-2.97(d,J＝16Hz,1H),2.52-2.32(m,15H),1.93-1.65(m,6H),1.29-1.28(d,J＝4Hz,3H).
实施例5：
Figure PCTCN2020098460-appb-000048
第一步：
Figure PCTCN2020098460-appb-000049
氮气氛围下，取750mg化合物1以及2.1ml二异丙基乙胺溶于13ml无水二氯甲烷里，冷却到-10℃，逐滴加0.5ml三甲基氯硅烷，加完后升到室温并搅拌三个小时，再次降温到-10℃，滴加3ml氯甲酸氯甲酯(0.288g)的二氯甲烷的溶液，滴完后，在-10℃反应完毕，水淬灭反应，分液，依次用稀盐酸、饱和食盐水、饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩,纯化得400毫克白色固体化合物2。
第二步：
Figure PCTCN2020098460-appb-000050
将147mg化合物3以及203mg碘化钠加入到2毫升的二甲基甲酰胺中，随后加入136毫克的碳酸氢钾，室温搅拌半个小时，随后将溶于10ml二甲基甲酰胺的400mg化合物2滴入到反应体系里，反应过夜，加入水淬灭反应，乙酸乙酯萃取两次，有机相合并，无水硫酸钠干燥过滤浓缩后，过硅胶柱纯化得450mg油状化合物4。
第三步：
Figure PCTCN2020098460-appb-000051
将405mg化合物4溶于18ml二氯甲烷里，冰浴冷却下滴加4.5ml三氟醋酸，滴完后反应升到室温，搅拌两个小时，浓缩后经柱层析纯化得330mg产物化合物5，产率80％。
1H-NMR(400MHz，CDCl 3)：δ8.34(s,1H),7.72(s,1H),7.63(s,2H),7.40-7.28(m,5H),6.19(s,1H),5.68-5.67(d,J＝4Hz,1H),4.30-4.29(d,J＝4Hz,1H),4.20-4.17(d,J＝12Hz,1H),3.99-3.91(m,2H),3.79(s,1H),2.70-2.67(d,J＝12Hz,1H),2.49-2.21(m,8H),1.83-1.70(m,4H), 1.29-1.28(m,3H),1.09-1.07(m,6H).
实施例6：
Figure PCTCN2020098460-appb-000052
第一步：
Figure PCTCN2020098460-appb-000053
将1.294g三光气溶于7.5ml无水四氢呋喃里，冰浴冷却，氮气置换三次。随后逐滴加入0.33ml吡啶。滴完后，再将溶于7.5ml无水四氢呋喃的500mg化合物1溶液滴入到反应液里，滴完后反应在5℃搅拌3个小时。加入30ml二氯甲烷稀释，依次用稀盐酸、水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得粗品700mg。
第二步：
Figure PCTCN2020098460-appb-000054
将128mg化合物3加入到2ml无水四氢呋喃里，氮气保护下置换三次。反应冷却到-65摄氏度左右，滴入0.28ml六甲基二硅氨基锂(1摩尔每升，溶于正己烷)并搅拌半个小时。另取前一步的粗品60mg化合物2溶于1ml无水四氢呋喃里，氮气保护下置换三次后冷却到-65℃。将前面制取化合物3的锂盐转移进酰氯化合物2反应瓶里，加完后在-65℃反应完毕，加入饱和氯化铵水溶液淬灭，乙酸乙酯萃取，有机相浓缩后直接过柱纯化得62mg化合物4。第三步：
Figure PCTCN2020098460-appb-000055
将62mg化合物4以及31mg 20％湿的氢氧化钯一起加入到1.5ml乙酸乙酯里，开启搅拌，氢气球置换三次后室温搅拌5个小时，过滤，滤饼用乙酸乙酯洗涤，滤液浓缩后制备得41mg白色固体化合物5。
1H-NMR(400MHz，CDCl 3)δ＝7.72(s，1H)，7.57(s，2H)，7.50-7.41(m，5H)，4.80-4.59(m，3H)，4.17-4.13(d，J＝16Hz，1H)，3.83-3.80(d，J＝12Hz，1H)，3.62-3.59(d，J＝12Hz，1H)，3.26-3.22(d，J＝16Hz，1H)，2.60-2.47(m，4H)，2.26-2.18(m，2H)，1.85-1.80(m，2H)，1.45-1.43(d，J＝8Hz，3H)，0.89-0.83(m，1H).
实施例7：
Figure PCTCN2020098460-appb-000056
将碳酸钾(11.7g，84.66mmol，8.47eq)溶于水(40mL)中备用。在N 2保护下，化合物1(5.55g,10mmol,1eq)悬浮于乙酸乙酯(80mL)中，冰浴冷却下滴加上述碳酸钾水溶液，搅拌下反应液逐渐澄清，再滴加Cbz-Cl(1.7mL，12mmol，1.2eq)，加完搅拌10min，室温搅拌反应过夜，将反应液分液，用乙酸乙酯提取，合并有机相，无水硫酸钠干燥，过滤，浓缩，柱层析得到4.3g白色固体，收率56％。
实施例8：
Figure PCTCN2020098460-appb-000057
Figure PCTCN2020098460-appb-000058
氮气保护下，于50mL单口瓶中加入化合物1(317mg,0.5mmol)和THF(7.2mL)，搅拌溶解并冷至-20℃。滴加NaHMDS(2M,0.5mL,1mmol)，搅拌至反应完全，饱和氯化铵淬灭反应，甲基叔丁基醚萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩，经柱层析纯化得化合物2(250mg)，收率68％。
Figure PCTCN2020098460-appb-000059
于50mL单口瓶中，加入化合物2(250mg，0.34mmol)、甲醇(10mL)，钯炭(10％，250mg)，室温下氢气氛围下搅拌至反应完毕，过滤，浓缩得化合物3(150mg)，收率74％。
LCMS：601[M+1]。
实施例9：
Figure PCTCN2020098460-appb-000060
在N 2保护下，于50mL反应瓶中加入化合物1(215mg，0.339mmol，1eq)，无水碳酸钾(55mg，0.396mmol，1.1eq)、多聚甲醛(37mg，1.23mmol，3.3eq)和THF(5ml)，加热搅拌至反应完毕，过滤，浓缩得到粗品，柱层析纯化得到216mg油状物2，收率95％。
Figure PCTCN2020098460-appb-000061
在N 2保护下，于反应瓶中加入化合物2(66mg，0.1mmol，1eq)和THF(5ml)中，冰浴冷条件下滴加LiHMDS(1M in THF，0.2ml,0.2mmol，2eq)，再加入化合物3(40mg，0.37mmol，3.7eq)，搅拌至反应完毕，乙酸乙酯萃取，浓缩得到粗品，柱层析纯化得到27mg油状物粗品4，收率36％。
Figure PCTCN2020098460-appb-000062
室温下，反应瓶中加入化合物4(27mg,0.367mmol,1eq)，Pd/C(33mg)和甲醇(5ml)中，氢气氛围下搅拌至反应完毕，过滤，浓缩得到粗品，经柱层析得13mg油状物5，收率58.8％。
LCMS：602[M+1]。
实施例10：
Figure PCTCN2020098460-appb-000063
按照实施例5的方法，以氯甲酸氯丙酯代替氯甲酸氯甲酯，合成得到该目标化合物。LCMS：702[M+1]。
实施例11：
Figure PCTCN2020098460-appb-000064
按照实施例5的方法，以氯甲酸氯乙酯代替氯甲酸氯甲酯，合成得到该目标化合物。LCMS：688[M+1]。
实施例12：
Figure PCTCN2020098460-appb-000065
按照实施例5的方法，以N-Boc-甘氨酸代替Boc-L-缬氨酸，合成得到该目标化合物。LCMS：632[M+1]。
实施例13：
Figure PCTCN2020098460-appb-000066
按照实施例5的方法，以Boc-L-丙氨酸代替Boc-L-缬氨酸，合成得到该目标化合物。LCMS：646[M+1]。
实施例14：
Figure PCTCN2020098460-appb-000067
按照实施例5的方法，以1-氯乙基氯甲酸酯代替氯甲酸氯甲酯，合成得到该目标化合物(异构体大约1/1)。LCMS：688[M+1]。
实施例15：
Figure PCTCN2020098460-appb-000068
按照实施例5的方法，以Boc-L-蛋氨酸代替Boc-L-缬氨酸，合成得到该目标化合物。LCMS：706[M+1]。
实施例16：
Figure PCTCN2020098460-appb-000069
按照实施例5的方法，以Boc-L-脯氨酸代替Boc-L-缬氨酸，合成得到该目标化合物。LCMS：672[M+1]。
实施例17：
Figure PCTCN2020098460-appb-000070
按照实施例5的方法，以(S)-2,6-二叔丁基羰基氨基己酸代替Boc-L-缬氨酸，合成得到该目标化合物。LCMS：703[M+1]。
实施例18：
Figure PCTCN2020098460-appb-000071
按照实施例5的方法，以Boc-D-缬氨酸代替Boc-L-缬氨酸，合成得到该目标化合物。LCMS：674[M+1]。
测试例1：水溶性数据和化学稳定性
1.1配制试剂
试剂：NaH 2PO 4·2H 2O
1.2配制方法
按100ml规格配制如下：
pH＝3.0：磷酸盐缓冲溶液：100ml 20mmol/L NaH 2PO 4，0.1M H 3PO 4调节pH至3.0。
pH＝4.0：磷酸盐缓冲溶液：100ml 20mmol/L NaH 2PO 4，0.1M H 3PO 4调节pH至4.0。
pH＝7.0：超纯水
pH＝9.0：磷酸盐缓冲溶液：100ml 20mmol/L Na2HPO 4，0.1M NaOH溶液调节pH至9.0
1.3测试方法
精确称取适量待测化合物，少量多次加入溶液搅拌等待化合物溶解，测定溶液中化合物含量。数据见表1。
2.1化合物稳定性实验
称取约1mg样品至小瓶中，放置真空袋中抽真空，再放入装有变色硅胶的容器内，密封，平行配制两份。按取样时间点配制足够的份数，分别放置在4度和室温下。数据见表1。
表1
序号 水溶性 化学稳定性
实施例1 >10mg/ml(PH＝5) 较好
实施例2 9.05mg/ml(PH＝5) 较好
实施例3 <0.1mg/ml(PH＝5) 较好
实施例4 2.08mg/mL(PH＝3) 较好
实施例5 >10mg/ml(PH＝4) 较好
实施例6 1.12mg/mL(PH＝3) 较好
实施例7 NA NA
实施例8 1.37mg/ml(PH＝5) 中等
实施例9 <0.1mg/ml(PH＝3) 较好
实施例10 1.86mg/mL(PH＝3) 较好
实施例11 2.81mg/mL(PH＝3) 较好
实施例12 NA 较差
实施例13 NA 中等
实施例14 4.5mg/ml(PH＝4) 较好
实施例15 NA 较差
实施例16 NA 较差
实施例17 NA 中等
实施例18 2.62mg/mL(PH＝4) 较好
备注：较好放置7天，纯度降低<0.5％；中等放置7天，纯度降低0.5％～2.0％；较差放置7天，纯度降低>2.0％
测试例2：血浆代谢评价
试验方案
1.1试验药品
实施例5化合物和式I化合物。
1.2试验血浆
人新鲜血浆由志愿者在之情同意下捐献。
1.3化合物溶液配制
称取一定量实施例5化合物，加入DMSO配制成30mM储备液，取一定体积储备液，用DMSO稀释成浓度为1600μM的溶液I；再取一定体积的1600μM的溶液I用45％的甲醇稀释成浓度为16μM的工作溶液II。用上述方法配制式I化合物30mM储备液和1600μM的溶液II。
1.4样本孵育
取16μM实施例5化合物的工作液5μL，分别加入到75μL的血浆中，使化合物的终浓度为1μM。样本于37℃水浴中孵育0，15，30，60，90，120，180min。孵育结束后加入240μL含内标的乙腈，然后摇床800rpm摇10min，离心机3700rpm，4℃离心20min，上清采用LC-MS分析，进样体积为2μL。
1.5标准曲线的配制
取之前稀释好的1600μM溶液I，用乙腈稀释制备标准曲线工作液，浓度为160，400，1600，4000，8000，16000，32000ng/mL，QC工作液浓度设为480，1920，25600ng/mL。分别取标准曲线及QC工作液5μL加入到75μL血浆中，得终浓度分别为10，25，100，250，500，1000，2000ng/mL的标准曲线样本和终浓度为30，120，1600ng/mL的QC样本；迅速加入240μL含内标的乙腈，然后摇床800rpm摇10min，离心机3700rpm，4℃离心20min。取上清采用LC-MS分析，进样体积为2μL。
用上述方法准备式I化合物标准曲线及QC样本。
2.结果
本发明实施例5化合物在人新鲜血浆中转化情况如下，数据见表2：
表2
时间点(min) 实施例5化合物(μM) 式I化合物(μM)
0 1 0.00
15 0.53 0.78
30 0.12 1.18
60 0.01 1.22
90 0.00 1.31
120 0.00 1.28
180 0.00 1.02
结论：在人新鲜血浆中30min左右全部转化为式I化合物。
测试例3：血浆稳定性试验
1.1试验药品
实施例4、实施例6、实施例10和实施例11化合物
1.2试验血浆
人新鲜血浆由志愿者在知情同意下捐献
1.3实验步骤
1)表3中待测化合物分别用DMSO配成30mM的储备液备用。
2)用DMSO溶液将浓度30mM的储备液稀释成浓度为1600μM的溶液I，再用乙腈(ACN)，将浓度为1600μM的溶液I稀释成浓度为16μM的工作溶液II。
3)实验设置0、15、30、60、90、120、180min 7个时间点，每个时间点设两个平行样，反应体系是每个化合物分两组，各加入75μL血浆，5μL上述配制好的浓度为16μM的工作溶液II，37℃孵育，计时开始到时的时候，用含内标的ACN的溶液300μL终止反应。离心机3700rpm离心10min，取上清分析。
4)标准曲线配置：取之前稀释好的1600μM的溶液I用乙腈稀释到1.5μM/mL的溶液III作为标准曲线备用；标准曲线浓度设为0.32、0.8、1.6、4.0、8、12、16、42uM；标准曲线各浓度稀释好后，分别75μL血浆加入5μL各浓度点，使终浓度分别为为0.02、0.05、0.1、0.25、0.75、1.0、1.5uM，迅速加入300μL终止液，离心机3700rpm离心10min，取上清LC-MSMS分析。数据见表3。
表3
Figure PCTCN2020098460-appb-000072
注：a实施例中化合物在血浆浓度，b实施例化合物代谢后罗拉匹坦在血浆浓度。
结论：实施例4、实施例10和实施例11中化合物在血浆中较稳定，代谢时间较长，但是该三种化合物在血浆中只有少数的被代谢为罗拉匹坦。实施例6中化合物在血浆中能代谢为罗拉匹坦，但从上述数据看来，其在血浆整体代谢量较少。
测试例4：
参照测试例2中试验方法分别测试实施例1、实施例2和实施例8化合物在小鼠(Mouse)、大鼠(Rat)和人的血浆中的代谢情况，数据见表4。
Figure PCTCN2020098460-appb-000073
(实施例1)
Figure PCTCN2020098460-appb-000074
(实施例8)
表4
Figure PCTCN2020098460-appb-000075
注：a实施例中化合物在血浆浓度，b实施例化合物代谢后罗拉匹坦在血浆浓度。
结论：实施例8化合物在小鼠、大鼠和人的血浆中均可转化为罗拉匹坦，尤其在人的血浆中转化率近46％，而实施例1和实施例2化合物在人的血浆中基本没有转化为罗拉匹坦，或者只有稍许转化。
测试例5：大鼠体内药代动力学测试
以大鼠为受试动物，应用LC/MS/MS法测定了注射给予实施例1和实施例2化合物后不同时刻血浆中的药物浓度。研究该化合物在大鼠体内的药代动力学行为，评价其药动学特征。
药物配制
称取一定量实施例1和实施例2化合物，用20mmol/L磷酸二氢钠配制成pH＝4.0溶液，以备用。
1.1给药
静脉推注，推注时间约5min，给药剂量2mg/kg，给药浓度0.4mg/ml，给药体积5ml/kg。
1.2操作
给药前及给药结束后5min、0.25h、0.5h、1h、2h、4h、6h、8h、10h、24h和48h，经眼眶静脉采血，每个样品采集约0.6mL，肝素钠抗凝，采集后马上放置冰上。血液样本采集后放置于标记好的离心管中，离心分离血浆(离心条件：离心力2200g，离心10min，2-8℃)。
1.3药代动力学参数结果
表5
Figure PCTCN2020098460-appb-000076
注：a实施例中化合物在大鼠体内药代动力参数，b实施例化合物代谢为罗拉匹坦在大鼠体内药代动力参数。
结论：虽然实施例1化合物在体外血浆，尤其是人的血浆中基本没有代谢为罗拉匹坦活性物，但是在大鼠体内中却能表现出优异的罗拉匹坦药代动力学数据，说明实施例1化合物在体内已经被代谢为罗拉匹坦，且从AUC 0-∞、AUC 0-t和T 1/2数据来看，化合物1给药后体内代谢周期长、吸收和暴露水平与罗拉匹坦相当。
测试例6：化合物在食蟹猴中的药代动力学测试
以食蟹猴为受试动物，应用LC/MS/MS法测定了注射给予实施例5化合物后不同时刻血浆中的药物浓度。研究该化合物在食蟹猴体内的药代动力学行为，评价其药动学特征。
药物配制
称取一定量实施例5化合物，用20mmol/L磷酸二氢钠配制成pH＝4.0溶液，以备用。
1.1给药
静脉滴注，推注时间约30min，给药剂量2mg/kg，给药浓度0.4mg/ml，给药体积5ml/kg。
1.2操作
给药前及给药结束后5min、0.25h、0.5h、1h、2h、4h、6h、8h、10h、24h和48h，经股静脉采血，每个样品采集约0.6mL，肝素钠抗凝，采集后马上放置冰上。血液样本采集后放置于标记好的离心管中，离心分离血浆(离心条件：离心力2200g，离心10min，2-8℃)。
应用LC/MS/MS测定血浆样品中的实施例5化合物和罗拉匹坦的含量。
1.3药代动力学参数结果
表6
化合物 实施例5化合物 罗拉匹坦(式I化合物)
Tmax(h) 0.11±0.12 0.14±0.10
Cmax(ng/mL) 2.28±0.39 315.25±97.08
AUC 0-t(ng/mL*h) 0.77±0.29 4326.87±1820.65
结论：实施例5化合物在食蟹猴体内药代动力学研究中，在食蟹猴绝大部分迅速转化为活性代谢产物罗拉匹坦，其具有良好的药代动力学性质。
实施例19：
参照实施例1中步骤1-2制备获得化合物3，再在在N 2保护下，于500mL单口瓶中加入化合物3(6.65g，8.67mmol，1eq)溶于二氯甲烷(200mL)中，冰水冷却下缓慢加入三氟乙酸(9.89g，86.7mmol，10.0eq)，搅拌至反应完毕，浓缩，得到2.29g油状物，经反相硅胶柱(C18)纯化(A溶液：20mmol NH 4HCO 3水溶液，B溶液：乙腈)纯化，再用1M磷酸调节pH＝1～2，用二氯甲烷萃取，饱和盐水洗涤，无水硫酸钠干燥，过滤，浓缩得目标产物2.7g。
Figure PCTCN2020098460-appb-000077
测试例7：溶解度
参数测试例1溶解度测试方法，测得实施例19化合物在不同pH值下溶解度，数据如下：
表7
pH 溶解度 饱和溶解度
7.4 26mg/ml 19.8mg/ml
9.0 28mg/ml 21.4mg/ml
测试例8：溶血作用
红血球(RBC)随机地从兔颈静脉或耳中央动脉采取(EDTA全血)10ml，放入玻璃珠的三角烧瓶中振摇10分钟，除去纤维蛋白原，使成脱纤血液。加入氯化钠注射液约10倍量，摇匀，1500转/分钟离心10分钟，除去上清液，沉淀的红细胞再用氯化钠注射液按上述方法洗涤3次，至上清液不显红色。将所得红细胞用氯化钠注射液配成2％(v/v)的混悬液，以备用。
取测试样品(实施例5化合物和实施例19化合物)分别溶于PBS(pH 7.4或pH 5)，过滤，配制0.4mg/ml、0.8mg/ml、1.2mg/ml、1.6mg/ml和2mg/ml，以备用。
取一定量的测试样品溶液加入上述血红蛋白在上清液中测试。
若试管中的溶液呈澄明红色，管底无细胞残留或有少量红细胞残留，表明有溶血发生；如红细胞全部下沉，上清液体无色澄明，表明无溶血发生。若溶液中有棕红色或红棕色絮状沉淀，轻轻倒转3-5次仍不分散，表明可能有红细胞凝聚发生；应进一步置显微镜下观察，如可见红细胞聚集为凝聚。本公开提供的化合物采用该方法测定溶血作用。
结论：实施例19化合物在浓度高至2mg/ml都没有出现溶血作用，实施例5化合物在0.04mg/ml及以上浓度出现溶血作用。
测试例9：罗拉匹坦乳剂溶血性作用
参照CN102573475中方法制备罗拉匹坦乳剂(处方为：4.4％聚乙二醇-15羟基硬脂酸酯、1.1％中链甘油三酸酯和0.66％大豆油)，用PBS配制0.18mg/ml、0.09mg/ml、0.045mg/ml、0.023mg/ml、0.011mg/ml、0.056mg/ml和0.028mg/ml，以备用。
参照测试例8中方法测定溶血作用。
结论：所有浓度的罗拉匹坦乳剂均存在溶血作用。
测试例10：食蟹猴中的药代动力学测试
以食蟹猴为受试动物，应用LC/MS/MS法测定了注射给予参照实施例19方法制备的化合物后不同时刻血浆中的药物浓度。研究该化合物在食蟹猴体内的药代动力学行为，评价其药动学特征。
药物配制
称取一定量待测化合物，用20mmol/L磷酸二氢钠配制成pH＝4.0溶液，以备用。
1.1给药
静脉滴注，推注时间约30min，给药剂量3.54mg/kg，给药浓度2mg/ml，给药体积5ml/kg。
1.2操作
给药前及给药结束后5min、0.25h、0.5h、1h、2h、4h、6h、8h、10h和24h，经股静脉采血，每个样品采集约0.6mL，肝素钠抗凝，采集后马上放置冰上。血液样本采集后放置于标记好的离心管中，离心分离血浆(离心条件：离心力2200g，离心10min，2-8℃)。
应用LC/MS/MS测定血浆样品中的实施例24化合物和罗拉匹坦的含量。
1.3药代动力学参数结果
表8
Figure PCTCN2020098460-appb-000078
注：a实施例中化合物在食蟹猴体内药代动力参数，b实施例化合物代谢为罗拉匹坦在食蟹猴体内药代动力参数。
结论：该化合物在食蟹猴体内药代动力学研究中，在食蟹猴绝大部分迅速转化为活性代谢产物罗拉匹坦，其具有良好的药代动力学性质。另外，相比实施例5化合物，该化合物在食蟹猴体内生物利用度更高。

Claims (14)

  1. 式II化合物，
    Figure PCTCN2020098460-appb-100001
    或其可药用的盐或其立体异构体、旋转异构体或互变异构体或其氘代物，
    其中，X选自氢、杂环基、芳基、杂芳基、-C(O)OA mR 3、-C(O)NR 4A mR 3、-A m[C(R 1)(R 2)]C(O)OA nR 3、-A mOC(O)[C(R 1)(R 2)]A nR 3、-A mC(O)NR 4A nR 3、-A mNR 4C(O)A nR 3或-A mR 5，所述杂环基、芳基或杂芳基任选被一个或多个选自烷基、环烷基、烷氧基、羟烷基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
    Y选自氢、-C(O)OA mR 3、-C(O)NR 4A mR 3、-A m[C(R 1)(R 2)]C(O)OA nR 3、-A mOC(O)[C(R 1)(R 2)]A nR 3、-A mC(O)NR 4A nR 3、-A mNR 4C(O)A nR 3或-A mR 5；
    A独立地选自-C(R 1)(R 2)(B) p-或-(B) qC(R 1)(R 2)-，
    R 1、R 2或R 4各自独立地选自氢、烷基、环烷基、杂环基、芳基或杂芳基，所述烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自烷基、环烷基、烷氧基、羟烷基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
    R 3选自氢、烷基、环烷基、杂环基、芳基、杂芳基、聚(亚乙氧基)
    Figure PCTCN2020098460-appb-100002
    聚(亚氧基亚乙氧基)
    Figure PCTCN2020098460-appb-100003
    OPO(R 6) 2、PO(R 6) 2、OSO 2(R 6) 2、SO 2(R 6) 2、OC(O)R 6或C(O)OR 6，所述烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自烷基、环烷基、烷氧基、羟烷基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
    R 5选自杂环基、杂芳基、OSO 2R 7、OC(O)R 7、SR'、
    Figure PCTCN2020098460-appb-100004
    SO 2R'或NR'(R”)；
    R 6各自独立地选自氢、羟基、烷基、环烷基、杂环基、芳基、杂芳基、烷氧基、羟烷基或NR'(R”)，所述烷基、羟烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自烷基、环烷基、烷氧基、羟烷基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
    R 7各自独立地选自烷基、羟基、环烷基、杂环基、芳基、杂芳基、羟烷基或NR'(R”)， 所述烷基、羟烷基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自烷基、环烷基、烷氧基、羟烷基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
    R'或R”独立地选自氢、羟基、烷基、烷氧基、烯基、酰基；
    B各自独立地选自O，N，SC(O)；
    m，n，o各自独立地选自1～10；p，q各自独立地选自0或1；
    且，X和Y不同时为氢。
  2. 如权利要求1所述的化合物，其中X选自氢、杂环基、芳基、杂芳基、-C(O)O[C(R 1)(R 2)(O) p] mR 3、-C(O)NR 4[C(R 1)(R 2)(O) p] mR 3、-[C(R 1)(R 2)(O) p] mC(O)[C(R 1)(R 2)(O) p] nR 3、-[C(R 1)(R 2)(O) p] m[C(R 1)(R 2)]C(O)[(O) qC(R 1)(R 2)] nR 3、-[C(R 1)(R 2)(O) p] mC(O)NR 4[C(R 1)(R 2)(O) p] nR 3或-[C(R 1)(R 2)(O) p] mR 5，所述环烷基、杂环基、芳基或杂芳基任选被一个或多个选自烷基、环烷基、烷氧基、羟烷基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
    Y选自氢、-C(O)O[C(R 1)(R 2)(O) p] mR 3、-C(O)NR 4[C(R 1)(R 2)(O) p] mR 3、-[C(R 1)(R 2)(O) p] mC(O)[C(R 1)(R 2)(O) p] nR 3、-[C(R 1)(R 2)(O) p] mC(O)[(O) qC(R 1)(R 2)] nR 3、-[C(R 1)(R 2)(O) p] mC(O)NR 4[C(R 1)(R 2)(O) p] nR 3或-[C(R 1)(R 2)(O) p] mR 5，且X和Y不同时为氢。
  3. 如权利要求1或2所述的化合物，其中Y选自-C(O)O[C(R 1)(R 2)] mR 3、-C(O)NR 4[C(R 1)(R 2)] mR 3、-[C(R 1)(R 2)O] mC(O)[C(R 1)(R 2)] nR 3、-[C(R 1)(R 2)] mC(O)[OC(R 1)(R 2)] nR 3、-[C(R 1)(R 2)N] mC(O)[C(R 1)(R 2)] nR 3、[C(R 1)(R 2)N] mC(O)[OC(R 1)(R 2)] nR 3、[C(R 1)(R 2)N] mC(O)[NC(R 1)(R 2)] nR 3、-[C(R 1)(R 2)(O) p] mC(O)NR 4[C(R 1)(R 2)(O) p] nR 3或-[C(R 1)(R 2)(O) p] nR 5，X为氢、3至6元杂环基。
  4. 如权利要求1-3任一项所述的化合物，其中X选自-C(O)O[C(R 1)(R 2)] mR 3、-C(O)NR 4[C(R 1)(R 2)] mR 3、-[C(R 1)(R 2)O] mC(O)[C(R 1)(R 2)] nR 3、-[C(R 1)(R 2)] mC(O)[OC(R 1)(R 2)] nR 3或-[C(R 1)(R 2)] mC(O)NR 4[C(R 1)(R 2)] nR 3或-[C(R 1)(R 2)] mR 5，Y为氢。
  5. 如权利要求1-4任一项所述的化合物，其中R 3选自氢、聚(亚氧基亚乙氧基)
    Figure PCTCN2020098460-appb-100005
    聚(亚乙氧基)
    Figure PCTCN2020098460-appb-100006
    OPO(R 6) 2、PO(R 6) 2、OSO 2(R 6) 2、SO 2(R 6) 2、OC(O)R 6或C(O)OR 6，R 6如权利要求1中所述。
  6. 如权利要求1-5任一项所述的化合物，其中R 3选自OPO(R 6) 2，R 6选自羟基、C 1-6烷基、C 3-7环烷基、C 1-6烷氧基或3至7元杂环基。
  7. 如权利要求1-4任一项所述的化合物，其中m＝1、2、3或4。
  8. 如权利要求1-3任一项所述的化合物，其中R 1或R 2各自独立地选自氢、C 1-6烷基或C 3-7环烷基。
  9. 如权利要求1所述的化合物，其中m＝1、2、3或4，n＝1、2、3或4，o＝1～8。
  10. 如权利要求1-9所述的化合物，其中式II所示化合物为：
    Figure PCTCN2020098460-appb-100007
    或其可药用的盐或其立体异构体、旋转异构体或互变异构体，其中，m＝1、2、3或4；R 1、R 2如权利要求1所述。
  11. 如权利要求1-10任一项所示的化合物，其中式II所示化合物选自：
    Figure PCTCN2020098460-appb-100008
    Figure PCTCN2020098460-appb-100009
    Figure PCTCN2020098460-appb-100010
    Figure PCTCN2020098460-appb-100011
    Figure PCTCN2020098460-appb-100012
    或其可药用的盐、其立体异构体、旋转异构体或互变异构体或其氘代物。
  12. 一种药物组合物，包括至少一种治疗有效量的如权利要求1-11任一项所述的化合物以及药学上可接受的载体、稀释剂或赋形剂。
  13. 权利要求1-11任一项所述的化合物，或权利要求12所述的药物组合物在制备治疗患者中的生理失调，病症或疾病的药物中的用途，其中生理失调、病症或疾病是呼吸道疾病、咳嗽、炎性疾病、皮肤障碍、眼科障碍、抑郁症、焦虑、恐怖症、双向障碍、酒精依赖、对神经起显著作用的物质滥用、癫痫、伤害感受、精神病、精神分裂症、阿尔茨海默氏病、与 AIDs有关的痴呆、Towne′s疾病、与紧张有关的障碍、强迫性/强制性障碍、bulemia、神经性厌食症、疯狂进食、狂躁、经前期综合征、胃肠机能紊乱、动脉粥样硬化、纤维化障碍、肥胖、II型糖尿病、头痛、神经性疼痛、动作后疼痛、慢性疼痛综合症、膀胱障碍、泌尿生殖器障碍或呕吐或恶心。
  14. 如权利要求13的用途，其选自用于治疗哮喘，呕吐，恶心，忧郁症，焦虑，咳嗽或偏头痛。
PCT/CN2020/098460 2019-06-28 2020-06-28 神经激肽-1拮抗剂 WO2020259675A1 (zh)

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