WO2014146494A1 - Β-aminocarbonyl compound, preparation method, pharmaceutical composition and use thereof - Google Patents

Β-aminocarbonyl compound, preparation method, pharmaceutical composition and use thereof Download PDF

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Publication number
WO2014146494A1
WO2014146494A1 PCT/CN2014/000303 CN2014000303W WO2014146494A1 WO 2014146494 A1 WO2014146494 A1 WO 2014146494A1 CN 2014000303 W CN2014000303 W CN 2014000303W WO 2014146494 A1 WO2014146494 A1 WO 2014146494A1
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Prior art keywords
group
membered
membered heteroaryl
aryl
alkyl
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PCT/CN2014/000303
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French (fr)
Chinese (zh)
Inventor
朱维良
沈敬山
王贺瑶
蒋涛
周雨人
陈筑熙
蒋翔锐
孙鹏
张强
王震
张容霞
李剑锋
索瑾
徐志建
李波
刘颖涛
蒋华良
陈凯先
Original Assignee
中国科学院上海药物研究所
南京派乐兴医药科技有限公司
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Application filed by 中国科学院上海药物研究所, 南京派乐兴医药科技有限公司 filed Critical 中国科学院上海药物研究所
Priority to CN201480016980.2A priority Critical patent/CN105051046B/en
Publication of WO2014146494A1 publication Critical patent/WO2014146494A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C225/18—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings the carbon skeleton containing also rings other than six-membered aromatic rings
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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Definitions

  • the invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a novel ⁇ -aminocarbonyl compound represented by Formula I, or a tautomer, an enantiomer, a racemate thereof, or a pharmaceutically acceptable salt thereof, and a process for the preparation thereof , pharmaceutical compositions and their use as inhibitors of dipeptidyl peptidase IV (DPP-4).
  • DPP-4 dipeptidyl peptidase IV
  • Such a compound or a pharmaceutical composition thereof can be used as a DPP-4 inhibitor for the treatment of diabetes mellitus, hyperglycemia, obesity or insulin resistance.
  • Diabetes are caused by genetic factors, immune dysfunction, microbial infections and their toxins, free radical toxins, mental factors and other pathogenic factors that cause the body to cause islet dysfunction, insulin resistance, etc., caused by sugar, protein,
  • a series of metabolic disorders such as fat, water and electrolytes are clinically characterized by hyperglycemia.
  • polyuria, polydipsia, polyphagia, and wasting may occur, that is, symptoms of "three more and one less”.
  • Diabetes blood sugar
  • blood sugar once not well controlled, can cause complications, leading to depletion of kidneys, eyes, feet, etc., and can not be cured.
  • hypoglycemic drugs used in clinical practice have different degrees of side effects and limitations: sulfonylureas and insulin hypoglycemic drugs increase body weight and accompany the risk of hypoglycemia; representative drugs of thiazolidinedione insulin sensitizers - Luo Glindroxone may increase the risk of cardiovascular disease in diabetic patients, but it may be delisted or restricted globally; pioglitazone also marks bladder cancer risk in 2011; metformin and a glycosidase inhibitors have varying degrees of digestive tract Reaction; insulin cannot be administered orally. DPP-4 inhibitors have become the most popular antidiabetic drugs due to their good glycemic control, low risk of hypoglycemia and no weight gain.
  • DPP-4 inhibitors have been marketed for the treatment of diabetes, which are sitagliptin (sitagli P ti n ), vildagliptin, saxagliptin, and argan. Alogliptin, Hnagliptin.
  • An object of the present invention is to provide a novel compound having a DPP-4 inhibitory activity and which can be used for a therapeutic or palliative drug for diabetes and the like.
  • One object of the present invention is to provide a ⁇ -aminocarbonyl compound represented by the formula I or a tautomer, an enantiomer thereof, a racemate or a pharmaceutically acceptable salt thereof.
  • Another object of the invention is to provide a process for the preparation of the compounds provided herein.
  • a further object of the present invention is to provide a ⁇ -aminocarbonyl compound of the formula I or a tautomer, an enantiomer, a racemate thereof or a pharmaceutically acceptable salt thereof as a DPP-4 inhibitor.
  • Still another object of the present invention is to provide one or more of a ⁇ -aminocarbonyl compound represented by the formula or a tautomer, an enantiomer, a racemate thereof or a pharmaceutically acceptable salt thereof.
  • a ⁇ -aminocarbonyl compound represented by the formula or a tautomer an enantiomer, a racemate thereof or a pharmaceutically acceptable salt thereof.
  • A is selected from a C6-C10 aryl group, a saturated or unsaturated C3-C10 cycloalkyl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group; the heterocyclic group or heteroaryl group contains 1-4 selected a hetero atom derived from N, S and O;
  • A is preferably a phenyl group, a 5- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, more preferably a phenyl group, a pyridyl group or a cyclopentadienyl group;
  • W is a S, O, or C1-C4 linear hydrocarbon group
  • a dotted line between W and Q when present, indicates that it is an unsaturated bond (such as a double bond), and when it does not exist, it indicates that it is a saturated bond (single bond), preferably does not exist;
  • Y is N or CR 7 ;
  • X is N or CR 7 ;
  • R4 are each independently H; halogen; trifluoromethyl; hydroxy; nitro; nitrile; carboxy; -C(O)OCl-C10 alkyl; amino; C1-C10 alkoxy; C1-C10 alkyl C1-C10 decanoyl (gp-c(o)ci-cioalkyl); C1-C10 nonanoyloxy (ie -OC(O)Cl-C10 fluorenyl); sulfonyl; C1-C10 mercaptosulfonate Acyl; C6-C10 aryl; 4-10 membered heterocyclic; or 4-10 membered heteroaryl; above -C(O)OCl-C10 fluorenyl, amino, C1-C10 alkoxy, C1-C10 ⁇ , C1-C10 alkanoyl, C1-C10 nonanoyloxy, sulfonyl, C1-C10 decyl
  • an amino acid residue an amino acid ester residue; or an aminoamide residue, and optionally one or more selected from the group consisting of C1-C6 fluorenyl, C1-C6 ⁇ a substituent substituted with a base-substituted amino group, a C1-C10 decanoyl group, a benzyl group, a benzyloxycarbonyl group, and a t-butoxycarbonyl group;
  • R 15 and R 16 are each independently H; C1-C10 fluorenyl; C3-C10 cyclodecyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and attached thereto
  • the N atoms together form a 4-10 membered heterocyclic group; a 4-10 membered heteroaryl group; wherein, the C1-C10 alkyl group, the C3-C10 cyclodecyl group, the 4-10 membered heterocyclic group, and the 4-10 membered heterocyclic group;
  • R 7 is -(CH 2 ) m R réelle, -(CH 2 ) m O(CH 2 ) n R n or -(CH 2 ) m NHR 11 ;
  • Rii is H; halogen; nitro; nitrile; carboxyl; -C(O)OCl-C10 fluorenyl; C2-C10 alkenyl; C2-C10 alkynyl; C1-C10 nonanoyl; C1-C10 fluorenyl Sulfonyl; amino C1-C10 decanoyl; C1-C10 fluorenyl; C6-C10 aryl; 4-10 membered heterocyclic; or 4-10 membered heteroaryl; above -C(O)OCl-C10 fluorenyl , C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 decanoyl, C1-C10 decylsulfonyl, amino C1-C10 alkanoyl, C1-C10 alkyl, C6-C10 aryl, 4-10
  • the heterocyclic group or the 4-10 membered heteroaryl group may be optional
  • R 8 is -(CH 2 ) m R 12 , -(CH 2 ) m O(CH 2 ) procurRi 2 or —(CH 2 ) m NHR 12;
  • C1-C10 alkyl Ph(CH 2 ) m - ; s ⁇ . ; 4-10 membered heterocyclic group; or 4-10 membered heteroaryl; above -C(O)OCl-C10 fluorenyl, C2-C10 Alkenyl, C2-C10 alkynyl, C1-C10 decanoyl, C1-C10 alkylsulfonyl, amino C1-C10 decanoyl, C1-C10 decyl, Ph(CH 2 ) m -, ,
  • the 4-10 membered heterocyclyl or 4-10 membered heteroaryl may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxyl, C1-C10 alkoxy , C1-C10 nonanoyloxy, -C(O)OCl-C10 alkyl, C1-C10 alkano
  • Each m and each n are each independently an integer from 0 to 5;
  • q is an integer from 0-4.
  • each R 7 may be the same or different.
  • each group may include a substituted or unsubstituted form, such as a C1-C10 alkyl group, including an unsubstituted or substituted C1-C10 'alkyl group, for a C6-C10 aryl group. And a C6-C10 aroyl group, a 4-10 membered heterocyclic group, and a 4-10 membered heteroaryl group, including an unsubstituted or substituted C6-C10 aryl group, a C6-C10 aroyl group, and a 4-10 membered heterocyclic group. ,
  • the fluorenyl group includes a linear, branched fluorenyl group
  • the C6-C10 aryl group is a phenyl group, a fused ring aryl group, and the aryl group may optionally be one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile Base, carboxyl group, C1-C10 alkoxy group, C1-C10 alkanoyloxy group, -C(O)OCl-C10 fluorenyl group, -C(0)NR 15 R 16 , C1-C10 decanoyl group, C1-C10 ⁇ Sulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 decyl, hydroxy C1-C10 alkyl, amino C1- a substituent in the C10 fluorenyl group and a C6-
  • the aroyl group is an acyl group substituted by an aryl group, wherein the aryl group is as defined above.
  • the ⁇ -aminocarbonyl compound of the formula I has one or more of the following characteristics - (1)
  • A is a C6-C10 aryl group, a saturated or unsaturated C3-C10 cyclic hydrocarbon group, a 4-10 membered heteroaryl group; and the 4-10 membered heteroaryl group contains 1-4 selected from N, S and O Heteroatoms in
  • R 8 is -(CH 2 ) m R 12 , -(CH 2 ) m O(CH 2 ) n R 12 or - ⁇ ! ? ⁇ ; where R 12 is H, halogen,
  • Y is N or CR 7 , wherein R 7 is -(CH 2 ) m R u , -(CH 2 ) m O(CH 2 ) n R n or -(CH 2 ) m NHR 11 ; Rn 3 ⁇ 4 H, C6-C10 aryl, 4-10 membered heterocyclic, carboxy, amino C1-C10 alkanoyl, -C(O)OCl-C10 alkyl, halogen, nitro or 4-10 membered heteroaryl
  • X is N or CR 7; wherein R 7 is -(CH 2 ) m R n , wherein, H, m is 0;
  • R 5 and X attached thereto constitute a glucosamine group; an amino acid residue; an amino acid ester residue; or an aminoamide residue, and optionally one or more selected from a C1-C6 alkyl group, C1 Substituted with a substituent in the C6 mercapto substituted amino group, a C1-C10 alkanoyl group, a benzyl group, a benzyloxycarbonyl group and a tert-butoxycarbonyl group;
  • R 5 and Re form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group and a 4-10 membered heterocyclic ring or a 4-10 membered heteroaryl group, 4-10.
  • a 4-10 membered heterocyclic acyl group a 4-10 membered heteroaroyl group or a COB; the above amino group, C1-C10 decyloxy group, C6-C10 aryloxy group, C1-C10 alkanoyloxy group, -C(O) OCl-C10 fluorenyl, -C(0)NH 2 , C1-C10 decanoyl, C1-C10 decylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 fluorenyl, hydroxy C1-C10 alkyl, amino C1-C10 alkyl, C6-C10 aryl C1-C10 fluorenyl, C6-C10 aryl, 4- 10 membered heterocyclic group, 4-10 membered heteroaryl group,
  • R 15 and R 16 are each independently H; C1-C10 alkyl; C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and attached thereto
  • the N atoms together form a 4-10 membered heterocyclic group; a 4-10 membered heteroaryl group; wherein, the C1-C10 alkyl group, the C3-C10 cycloalkyl group, the 4-10 membered heterocyclic group, and the 4-10 membered heterocyclic group;
  • the ⁇ -aminocarbonyl compound represented by Formula I further has one or more of the following characteristics:
  • ⁇ is phenyl, pyridyl or cyclopentadienyl
  • R 2 , R 3 and R 4 are each independently H, halogen, trifluoromethyl, hydroxy, nitrile, amino, C1-C10 fluorenyl;
  • 1 8 is -(03 ⁇ 4) complaint3 ⁇ 4 2; wherein, 1 12 is 11, halogen, C1-C10 yard base; q is an integer of 0-4; m is an integer of 0-5;
  • Y is CR 7 , where R 7 is -(CH 2 ) m R u , ! ⁇ is 11, halogen, m is an integer from 0-5.
  • the compound of the formula I is preferably a compound of the formula IA:
  • R, R 2 , R 3 , R 4 , R 5 , Re, R 8 , X and q are as defined in the formula I;
  • R 7 is -(CH 2 ) m R n , -(CH 2 ) m O(CH 2 ) n personally or -(C3 ⁇ 4) m NHR remember;
  • R n is H; halogen; nitro; nitrile; carboxyl; -C(0)0C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 nonanoyl; C1-C4 ⁇ Alkylsulfonyl; amino C1-C4 decanoyl; C1-C4 alkyl; C6-C10 aryl; 4-10 membered heterocyclic; or 4-10 membered heteroaryl; above -C(0)0C1-C4 , C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 decanoyl, C1-C4 alkylsulfonyl, amino C1-C4 decanoyl, C1-C4 alkyl, C6-C10 aryl, 4-10
  • the heterocyclic group or the 4-10 membered heteroaryl group may be optionally selected from one or more selected from the group consist
  • n and n are each independently an integer of 0-5.
  • the compound represented by the formula IA is further preferably a compound represented by the formula IB:
  • X is N or CR 7 ;
  • Ri, R 2 , R 3 and R 4 are each independently preferably H; halogen; trifluoromethyl; hydroxy; nitro; nitrile; carboxy; -C(0)0C1-C4 fluorenyl; amino; C1-C4 alkane ⁇ ; C1-C4 alkyl; C1-C4 decanoyl; C1-C4 alkanoyloxy; sulfonyl; or C1-C4 mercaptosulfonyl; above -C(0)0C1-C4 alkyl, amino, C1 -C4 methoxy, C1-C4 alkyl, C1-C4 decanoyl, C1-C4 alkanoyloxy, sulfonyl or C1-C4 alkylsulfonyl may be optionally selected from one or more selected from the group consisting of halogen, Fluoromethyl, hydroxy, nitro, amino, nitrile, carboxyl, C1-C
  • a heterocyclic group or a 4-10 membered heteroaryl and 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile group, carboxyl group, C1-C4 alkoxy group, -C(0)OCl-
  • Ris, Ri 6 are each independently H ; C1-C4 alkyl; C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and N attached thereto
  • the atoms together form a 4-10 membered heterocyclic group; a 4-10 membered heteroaryl group; wherein, the C1-C4 alkyl group, the C3-C10 cyclodecyl group, the 4-10 membered heterocyclic group, and the 4-10 membered heteroaryl group;
  • R 7 is -(CH 2 ) m R u , -(CH 2 ) m O(CH 2 ) n R honor or -(CH 2 ) m NHR réelle;
  • R u is H; halogen; nitro; nitrile; carboxyl; -C(0)OCl-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkanoyl; C1-C4 alkane Alkylsulfonyl; amino C1-C4 decanoyl; C1-C4 fluorenyl; C6-C10 aryl; 4-10 membered heterocyclic; or 4-10 membered heteroaryl; above -C(0)0C1-C4 ⁇ , C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkanoyl, C1-C4 nonylsulfonyl, amino C1-C4 alkanoyl, C1-C4 alkyl, C6-C10 aryl, 4-10
  • the heterocyclic or 4-10 membered heteroaryl may be optionally selected from one or more selected from the group consisting
  • Rs is -(CH 2 ) m R 12 , -(CH 2 ) m O(CH 2 ) n 12 or -(CH 2 ) m HR 12;
  • C1-C4 alkyl Ph(CH 2 ) m - ; ; 4-10 membered heterocyclic group; or 4-10 membered heteroaryl; above -C(0)OCl-C4 fluorenyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 decanoyl, C1- C4 alkylsulfonyl, amino C1-C4 decanoyl,
  • a C1-C4 alkyl group, a Ph(CH 2 ) m -, , 0 ⁇ , 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group may be optionally selected from one or more selected from the group consisting of halogen and trifluoromethyl.
  • n and n are each independently preferably an integer of 0 to 3; most preferably 0, 1 or 2; q is preferably an integer of 0 to 2.
  • the C1-C10 fluorenyl group is preferably a methyl group; an ethyl group; a propyl group; Butyl; isobutyl or tert-butyl; the C6-C10 aryl is preferably phenyl;
  • the 4-10 membered heterocyclic group or 4-10 membered heteroaryl group contains 1 to 4 hetero atoms selected from N S and 0, preferably the following groups
  • the 4-10 membered heterocyclyl spiro or heteroaryl spiro is preferably the group:
  • the aryl group is preferably the following group:
  • the [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [4-10 membered heterocyclic group or 4-10 membered heteroaryl group] is preferably the following group
  • Each of the above rings may be bonded to another group at any position on the ring, or may be substituted at any position by a substituent as defined above.
  • the compound represented by the formula IA or IB is still further preferably of the formula IA-1, IA-2, IA-3,
  • Z is a N atom or a C atom
  • R 2 , R 3 and R 4 are each independently more preferably H; F; CI; Br; trifluoromethyl; hydroxy; nitrile; amino; C1-C4 decyloxy; C1-C4, or C1; -C4 alkanoyl; most preferably H or halogen;
  • Ri and R4 are most preferably H, and R 2 and R 3 are most preferably F;
  • R is -(CH 2 ) m R 10; -(CH 2 ) m CO(CH 2 ) n R 10 ; -(CH 2 ) m O(CH 2 ) n 10 ; -(CH 2 ) m HC(O (CH 2 ) admir R, 0 ; or —(CH 2 ) m NSO 2 (CH 2 ) n R 10; m is preferably an integer from 0 to 3; most preferably 0, 1 or 2;
  • the heteroheteroaryl-C6-C10 aryl group, the 4-10 membered heterocyclic acyl group, the 4-10 membered heteroaroyl group or the mono-COEt may optionally be one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, Nitro, -NR 15 R 16 , nitrile group, carboxyl group, C1-C4 alkoxy group, C6-C10 aryloxy group, C1-C4 alkanoyloxy group, -C(0)0C1-C4 alkyl group, -C( 0) NR 15 R 16 , C1-C4 alkanoyl group, C1-C4 decylsulfonyl group, C6-C10 arylsulfonyl group, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl group , C1-C4 fluorenyl, hydroxy
  • R 15 and R 16 are each independently H; C1-C4 fluorenyl; C3-C10 cyclodecyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and attached thereto
  • the N atoms together form a 4-10 membered heterocyclic group; a 4-10 membered heteroaryl group; wherein, the C1-C4 fluorenyl group, the C3-C10 cyclodecyl group, the 4-10 membered heterocyclic group, and the 4-10 membered heterocyclic group;
  • R is most preferably H; F; CI; Br or trifluoromethyl, or a compound of the formula I, formula I:
  • R, R 2 , R 3 and R4 are as defined in the formula IA-1;
  • a preferred class of specific compounds are the compounds of Examples 1 to 378, or the tautomers, enantiomers, racemates thereof or pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salt is a salt of the compound with an acid selected from the group consisting of phosphoric acid, malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, citric acid, tartaric acid, acetic acid or Trifluoroacetic acid, preferably a phosphate, hydrochloride or trifluoroacetate salt.
  • the compounds of formula I may contain one or more chiral centers and, therefore, may exist as stereoisomers, i.e., enantiomers, diastereomers or mixtures thereof. If the compound of the formula I contains an alkenyl group or an alkenylene group, cis (E) and trans (Z) isomerism may also exist. Therefore, the compound of the formula I of the present invention may be a single isomer or a mixture of the respective isomers.
  • the compounds of formula I may exist in the form of tautomers, and the invention includes mixtures thereof and single tautomers.
  • the present invention includes radiolabeled derivatives of the compounds of formula I which are useful in biological research.
  • the present invention provides pharmaceutically acceptable salts of the compounds of formula I, for example, with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and non-toxic acids formed with organic carboxylic acids or organic sulfonic acids. Salt formation, preferably phosphoric acid, malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid, more preferably phosphate, methanesulfonate, hydrochloride or trihydrate Fluoroacetate.
  • the compound of formula I can also be reacted with a base to provide a pharmaceutically acceptable metal salt, particularly a non-toxic alkali metal salt (e.g., a sodium salt and a potassium salt).
  • the invention includes any prodrug form of the compound of formula I.
  • the invention also includes pharmaceutically acceptable solvates (e.g., hydrates) of the compounds of formula I. (here is a solvate of formula I)
  • the invention also includes pharmaceutically acceptable oxides of the compounds of formula I, and pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof. (here is the salt and solvate of pharmaceutically acceptable oxides)
  • the invention also includes a plurality of crystalline forms of the compound of formula I and various salts.
  • Another object of the invention is to provide a process for the preparation of a compound of formula I.
  • the compound of the formula 1 of the present invention can be produced by the following method, however, the conditions of the method, such as the reactant, the solvent, the base, the amount of the compound used, the reaction temperature, the time required for the reaction, and the like are not limited to the following description.
  • the process of the invention comprises reacting in a suitable inert solvent at a suitable reaction temperature (e.g., -80 Torr to reflux temperature, preferably -20 to reflux temperature) for a period of time (e.g., 0.1-72 hours, preferably 0.2-24 hours).
  • a suitable reaction temperature e.g., -80 Torr to reflux temperature, preferably -20 to reflux temperature
  • a period of time e.g., 0.1-72 hours, preferably 0.2-24 hours.
  • the compounds of the present invention can be conveniently prepared by combining various synthetic methods described in the specification or known in the art.
  • the method of the invention comprises:
  • A, Ri, R 2 , R 3 , R 5 , R6, W, Q > Y and X are as defined in the formula I, and the reductive amination reaction can be carried out in ammonia methanol/ammonium acetate, In the presence of sodium cyanoborohydride
  • Ri 3 is a hydroxyl group, a halogen, a C1-C10 alkoxy group, C6-C10 aryloxy or C1-C10 nonanoyloxy;
  • reaction of the compound of the formula III with the compound of the formula S can be carried out under basic conditions
  • A, R 2 , R 3 , R 4 , W, Q and Y are as defined in the formula I; R 13 is halogen, CI-C10 decyloxy, C6-C10 aryloxy or C1 -C10 alkanoyloxy.
  • the compound of the formula III when the compound of the formula III is prepared by the compound of the formula V, the compound of the formula V can be condensed and eliminated with the potassium salt of the monoalkyl malonate to obtain the compound of the formula III;
  • the compound of the formula IV when the compound of the formula IV is prepared, the compound of the formula V is first subjected to condensation reaction with the michroic acid in the presence of a condensing agent to obtain a compound of the formula IV, and then the compound of the formula IV is subjected to ring-opening decarboxylation under acidic conditions to obtain a product of the formula quinone;
  • the compound of the formula V can be purchased from the market or prepared by referring to the preparation method of the compound of the formula VA below.
  • the present invention also provides another process for the preparation of a compound of formula I, which comprises - a compound of formula I which can be obtained by deprotection of a compound of formula VI,
  • R 14 is an amino protecting group, preferably benzyloxy Carbonyl or tert-butoxycarbonyl;
  • the reaction of the deprotecting group can be carried out under acidic conditions to obtain a salt of the compound of the formula I or the compound of the formula I, the salt of the compound of the formula I is freed under basic conditions to give a compound of the formula I; a compound of formula VI
  • R 14 is an amino-protecting group, preferably a benzyloxycarbonyl group. Or tert-butoxycarbonyl;
  • the compound of the formula VII and the compound of the formula S are subjected to a condensation reaction or an acylation reaction to obtain a compound of the formula VI, and the reaction can be carried out under basic conditions or in the presence of a condensing agent;
  • A, Ri, R 2 , R 3 , R 8 , W, Q, Y and X are as defined in the formula I;
  • R 13 is halogen, C1-C10-decyloxy, C6-C10 An aryloxy group or a C1-C10 nonanoyloxy group;
  • R 14 is an amino protecting group, preferably a benzyloxycarbonyl group or a tert-butoxycarbonyl group;
  • the compound of the above formula III is subjected to reductive amination reaction to obtain an amino compound (compound of the formula IX), and then the amino group of the compound of the formula IX is protected with a protecting group to obtain a compound of the formula VIII, and finally the compound of the formula VIII is subjected to a hydrolysis reaction to obtain a deprotecting group.
  • the product of the formula VII, reductive amination conditions, deprotection conditions can refer to method one;
  • the compound of the formula I can also be obtained by functional group transformation of other compounds of the formula I.
  • the A ring in the compound of the formula I is a benzene ring
  • the compound of the formula IA is prepared by the following method: (1)
  • Compounds of the general formula VA can be purchased from the market or prepared by the following methods:
  • the compound of the formula VA can be prepared from the compound of the formula IXA by reference to the literature (J. Med. Chem. 2003, 46, 399-408):
  • R 7 X is halogen
  • the compound of the formula IA can be prepared by the following procedure by the general formula , compound, the specific preparation method is the same as the preparation method of the compound of the above formula I (method 2);
  • Method 1 The compound of the formula I is subjected to column chromatography to separate the diastereomers to obtain two pairs of enantiomers, respectively, which are then separated by chiral preparative column to obtain a single optical isomer. a compound of formula I,
  • the present invention also includes reacting the obtained compound of the general formula I in an organic solvent of an acid to obtain an acid addition product salt thereof, wherein the acid is selected from the group consisting of phosphoric acid, malic acid, lactic acid, maleic acid, hydrochloric acid, and A Sulfonic acid, sulfuric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid, preferably phosphoric acid, hydrochloric acid or trifluoroacetic acid.
  • the acid is selected from the group consisting of phosphoric acid, malic acid, lactic acid, maleic acid, hydrochloric acid, and A Sulfonic acid, sulfuric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid, preferably phosphoric acid, hydrochloric acid or trifluoroacetic acid.
  • Still another object of the present invention is to provide a ⁇ -aminocarbonyl compound of the formula II, III, VI or VII or a tautomer thereof.
  • the fluorene is selected from a C6-C10 aryl group, a saturated or unsaturated C3-C10 cycloalkyl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group; the heterocyclic group or heteroaryl group contains 1-4 selected Heteroatoms from N, S and O;
  • W is a S, 0 or C1-C4 linear hydrocarbon group
  • 0 is a 1 ⁇ , S, O or C atom
  • Y is N or CR 7;
  • X is N or CR 7 ;
  • R4 are each independently H; halogen; trifluoromethyl; hydroxy; nitro; nitrile; carboxy; -C(O)OCl-C10 alkyl; amino; C1-C10 alkoxy; C1-C10 alkyl ; C1-C10 decanoyl (ie, -C(O)Cl-C10 alkyl); C1-C10 nonanoyloxy (ie, -OC(O)Cl-C10 alkyl); sulfonyl; C1-C10 mercaptosulfonate Acyl; C6-C10 aryl; 4-10 membered heterocyclic; or 4-10 membered heteroaryl; above -C(O)OCl-C10 alkyl, amino, C1-C10 decyloxy, C1-C10 alkane Base, C1-C10 decanoyl, C1-C10 decanoyloxy, sulfonyl, C1-C
  • R 5 and R 6 together with the X to which they are attached form an glucosamine group; an amino acid residue; an amino acid ester residue; or an amino amide residue, and optionally one or more selected from the group consisting of C1-C6 fluorenyl groups, C1 Substituted with a substituent in the C6 mercapto substituted amino group, a C1-C10 alkanoyl group, a benzyl group, a benzyloxycarbonyl group and a tert-butoxycarbonyl group;
  • R 5 and Re form a C6-C10 aryl group with the X to which they are attached; a C3-C10 cycloalkyl group; a C3-C10 cycloalkyl group and a C3-C10 cycloalkyl group; a C3-C10 cycloalkyl group and a C6-C10 aryl group; ; C6-C10 aryl and C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; 4-10 membered heterocyclyl spiro; 4-10 membered heteroaryl spiro; 4 -10 membered heterocyclic group or 4-10 membered heteroaryl and C3-C10 cycloalkyl; C3-C10 cycloalkyl and 4-10 membered heterocyclic or 4-10 membered heteroaryl and C3-C10 cycloalkyl; C3-C10 cycloalkyl and 4-10
  • a 4-10 membered heterocyclic acyl group, a 4-10 membered heteroaroyl group or a ⁇ -COEt may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile group, carboxyl group, C1-C10 decyloxy group, C6-C10 aryloxy group, C1-C10 alkanoyloxy group, -C(O)OCl-C10 alkyl group, -C(0)NR 15 R 16 , C1 -C10 decanoyl, C1-C10 decylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 Ri 6 , C6-C10 aroyl, C1-C10 alkyl, hydroxy C1-C10 fluorenyl, amino C1-C10 flu
  • R 15 and R 16 are each independently H; C1-C10 alkyl; C3-C10 cyclodecyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and attached thereto
  • the N atoms together form a 4-10 membered heterocyclic group; a 4-10 membered heteroaryl group; wherein, the C1-C10 fluorenyl group, the C3-C10 cycloalkyl group, the 4-10 membered heterocyclic group, and the 4-10 membered heterocyclic group;
  • R 7 is -(CH 2 ) m R u , -(CH ⁇ C CH ⁇ Ru or -(CH 2 ) m NHR remember;
  • R n is H; halogen; nitro; nitrile; carboxyl; -C(O)OCl-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C1-C10 nonanoyl; C1-C10 alkane Alkylsulfonyl; amino C1-C10 alkanoyl; C1-C10 alkyl; C6-C10 aryl; 4-10 membered heterocyclyl; or 4-10 membered heteroaryl; above -C(O)OCl-C10 , C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkanoyl, C1-C10 decylsulfonyl, amino C1-C10 alkanoyl, C1-C10 alkyl, C6-C10 aryl, 4-10
  • the heterocyclic or 4-10 membered heteroaryl may be optionally selected from one or more selected from the
  • R 8 is -(CH 2 ) m R 12 , -(CH 2 ) m O(CH 2 ) n R 12 or -(CH 2 ) m NHR 12;
  • n and n are each independently an integer of 0-5, and q is selected from an integer of 0-4;
  • Ri 3 is halogen, C1-C10 alkoxy, C6-C10 aryloxy or C1-C10 alkanoyloxy;
  • R 14 is an amino protecting group, preferably a benzyloxycarbonyl group or a tert-butoxycarbonyl group.
  • R!, R 2 , R 3 , R 4 , R 5 , R 8 , R 12 , R 13 , X and q are as defined in the formula II, III, VI or VII;
  • R 7 is -(CH 2 ) m R réelle, -(CH 2 ) m O(CH 2 ) n R n or -(CH 2 ) m NHR discretion;
  • R u is H; halogen; nitro; nitrile; carboxyl; -C(0)OCl-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 nonanoyl; C1-C4 ⁇ Alkylsulfonyl; amino C1-C4 alkanoyl; C1-C4 alkyl; C6-C10 aryl; a 4-10 membered heterocyclic group; or a 4-10 membered heteroaryl group; the above -C(0)OCl-C4 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C1-C4 decanoyl group, C1-C4 A mercaptosulfonyl group, an amino C1-C4 decanoyl group, a C1-C4 fluorenyl group, a C6-C10 aryl group, a 4-10 membered heterocycl
  • n and n are each independently an integer of 0-5.
  • the compound represented by the formula ⁇ , IIIA, VIA or VIIA is more preferably represented by the formula IIB, IIIB, VIB or VIIB
  • X is N or CR 7 ,
  • R 2 , R 3 and R 4 are each independently preferably H ; halogen; trifluoromethyl; hydroxy; nitro; nitrile; carboxy: -C(0)OCl-C4 fluorenyl; amino; C1-C4 alkoxy C1-C4 fluorenyl; C1-C4 alkanoyl; C1-C4 nonanoyloxy; sulfonyl; or C1-C4 mercaptosulfonyl; -C(0)0C1-C4 fluorenyl, amino, C1- The C4 alkoxy group, the C1-C4 fluorenyl group, the C1-C4 decanoyl group, the C1-C4 alkanoyloxy group, the sulfonyl group or the C1-C4 fluorenylsulfonyl group may be optionally selected from one or more selected from the group consisting of halogen and trifluoro.
  • Ri, R 2 , R 3 and R 4 are each independently more preferably H ; halogen; hydroxy; nitrile; amino; C1-C4 alkoxy; C1-C4 fluorenyl; or C1-C4 decanoyl; Or halogen;
  • R 5 and each independently are -(CH 2 ) m R 9 or -(CH 2 ) m CO(CH 2 ) n R 9 , wherein, is a halogen; a hydroxyl group; a nitro group; an amino group; a nitrile group; a carboxyl group; (0)OCl-C4 fluorenyl; C1-C4 decanoyl; C1-C4 decylsulfonyl; C1-C4 fluorenyl; C2-C4 alkenyl; C2-C4 alkynyl; C6-C10 aroyl; C1-C4 Alkoxy; C6-C10 arylsulfonyl, -S0 2 NR 15 Ri6, -R 15 S0 2 Ri 6 ; C6-C10 aryl; 4-10 membered heterocyclic group; 4-10 membered heteroaryl; 4 -10 membered heterocyclic or 4-10 membered heteroaryl and C
  • R 5 and Re together with the X to which they are bonded form a C6-C10 aryl group; a C3-C10 cycloalkyl group; a C3-C10 cycloalkyl group and a C3-C10 cycloalkyl group; a C3-C10 cycloalkyl group and a C6-C10 aryl group; C6-C10 aryl and C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; 4-10 membered heterocyclyl spiro; 4-10 membered heteroaryl spiro; a 10-membered heterocyclic group or a 4-10 membered heteroaryl][C3-C10cycloalkyl]; [C3-C10cycloalkyl][4-10 membered heterocyclic or 4-10 membered heteroaryl]; [4-10 membered heterocyclic group or 4-10 membered heteroaryl]
  • a 4-, 4-membered heterocyclic acyl group a 4-10 membered heteroaroyl group or a mono-COEt; the above amino group, C1-C4 decyloxy group, C6-C10 aryloxy group, C1-C4 alkanoyloxy group, -C (0) 0C1-C4 alkyl, -C(0)NH 2 , C1-C4 alkanoyl, C1-C4 nonylsulfonyl,
  • C6-C10 arylsulfonyl -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C4 fluorenyl, hydroxy C1-C4 fluorenyl, amino C1-C4 alkyl, C6-C10 aryl C1-C4 fluorenyl, C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6 -C10 aryl, 4-10 membered heterocyclic acyl group, 4-10 membered heteroaroyl group Ph
  • a heteroaryl group and a C6-C10 aryl group a 4-10 membered heterocyclic acyl group, a 4-10 membered heteroaroyl group or a -COEt;
  • Ris, Ri 6 are each independently H ; C1-C4 ortho; C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and N
  • the atoms together form a 4-10 membered heterocyclic group; a 4-10 membered heteroaryl group; wherein, the C1-C4 fluorenyl group, the C3-C10 cycloalkyl group, the 4-10 membered heterocyclic group, and the 4-10 membered heteroaryl group;
  • R 8 is -(CH 2 ) m R 12 , -(CH 2 ) m O(CH 2 ) n R 12 or -(CH 2 ) m NHR 12 ,
  • the C1-C4 alkyl group, Ph(CH 2 ) m -, 0, 4-10 membered heterocyclic group or 4-10 membered heteroaryl group may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, and hydroxy.
  • Ph(CH 2 ) m -; 0; ;; hydrazine; dihydroanthracene; pyrrole; furan; thiophene; thiazole; imidazole; oxazole; isoxazole; pyrazole; pyridine; pyrazine; pyrimidine; pyridazine; pyran; R 1 () is more preferably H; halogen; 0 (oxo);
  • n and n are each independently preferably an integer of 0 to 3; most preferably 0, 1 or 2; q is preferably an integer of 0 to 2;
  • R 13 is halogen, C1-C4 decyloxy, C6-C4 aryloxy or C1-C4 alkanoyloxy;
  • R 14 is an amino protecting group, preferably benzyloxycarbonyl or tert-butoxycarbonyl.
  • the present invention provides the use of a ⁇ -aminocarbonyl compound of the formula I or a tautomer, an enantiomer, a racemate thereof or a pharmaceutically acceptable salt thereof, Its use as a DPP-4 inhibitor, and in the preparation of a medicament for the treatment of diseases such as type II diabetes, hyperglycemia, obesity or insulin resistance.
  • the present invention provides a therapeutically effective amount of a ⁇ -aminocarbonyl compound of the formula I or a tautomer thereof, an enantiomer, a racemate or a pharmaceutically thereof thereof.
  • the ⁇ -aminocarbonyl compound of the formula I or a pharmaceutically acceptable salt thereof is administered in the pharmaceutical composition at a dose of from 1 to 500 mg/day.
  • a DPP-4 inhibitor comprising a therapeutically effective amount of a ⁇ -aminocarbonyl compound of the formula I or a tautomer thereof, enantiomer thereof
  • a ⁇ -aminocarbonyl compound of the formula I or a tautomer thereof enantiomer thereof
  • the inhibitor may optionally comprise a pharmaceutically acceptable carrier or excipient.
  • the composition consists of a therapeutically effective amount of one or more ⁇ -aminocarbonyl compounds of the formula I (or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof) and at least one pharmaceutically acceptable excipient composition.
  • the choice of pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, and is usually a filler, a diluent, a binder, a wetting agent, a disintegrant, a lubricant, an emulsifier, a suspending agent, and the like.
  • the proportion of the compound of the formula I, its pharmaceutically acceptable salt or its solvate in the above composition is from 0.1% to 99.9%, preferably from 1% to 99%, by total weight.
  • the pharmaceutically acceptable carrier refers to a pharmaceutical carrier conventional in the pharmaceutical field, such as: a diluent such as water; a filler such as starch, sucrose, etc.; a binder such as a cellulose derivative, an alginate, gelatin, a polyvinylpyrrolidone; a humectant such as glycerin; a disintegrant such as agar, calcium carbonate and sodium hydrogencarbonate; an absorption enhancer such as a quaternary ammonium compound; a surfactant such as hexadecanol; an adsorbent carrier such as kaolin and soap. Clay; lubricants such as talc, calcium stearate and magnesium stearate, and polyethylene glycol. In addition, other adjuvants such as flavoring agents, sweeteners and the like may also be added to the pharmaceutical composition.
  • a diluent such as water
  • a filler such as starch, sucrose, etc.
  • the present invention also provides a process for producing a pharmaceutically acceptable composition of the ⁇ -aminocarbonyl compound of the formula I, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • the ⁇ -aminocarbonyl compound represented by the formula I, a pharmaceutically acceptable salt thereof or a solvate thereof is usually mixed with a pharmaceutically acceptable adjuvant, and is prepared in a form suitable for a certain route by a conventional preparation method (formulation form) ).
  • the dosage form includes tablets, capsules, granules, pills, solutions, suspensions, emulsions, ointments, films, creams, aerosols, injections, suppositories, and the like. Preference is given to tablets and capsules.
  • the compound of the present invention is usually administered in a dose of from 1 to 500 mg, preferably from 10 to 100 mg per day, in single or multiple doses. However, if necessary, the above doses may be appropriately deviated. Professionals can determine the optimal dose based on the specific situation and expertise. These conditions include the severity of the disease, individual differences in the patient, characteristics of the formulation, and route of administration.
  • the present invention provides the use of the ⁇ -aminocarbonyl compound represented by the formula I, a pharmaceutically acceptable salt thereof or a solvate thereof, or a pharmaceutically acceptable composition thereof as a human drug.
  • the present invention provides a method of treating or treating diabetes, hyperglycemia, obesity or insulin resistance, the method comprising administering a therapeutically effective amount of a ⁇ -amino group represented by Formula I
  • the carbonyl compound or one or more of its tautomers, enantiomers, racemates or pharmaceutically acceptable salts thereof or the pharmaceutical composition of the present invention is administered to a patient.
  • the compounds or compositions provided herein can be administered orally, by injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, buccal, rectal, transurethral, vaginal, nasal, inhalation or topical routes.
  • the preferred route is oral.
  • it can be formulated into a conventional solid preparation such as a tablet, a powder, a granule, a capsule, or the like, or as a liquid preparation such as a water or oil suspension, or other liquid preparation such as syrup;
  • parenteral administration it may be prepared as a solution for injection, water or an oily suspension, or the like.
  • the compound is further used in combination with other drugs (antidiabetic drugs).
  • the present invention provides a method for inhibiting the catalytic activity of dipeptidyl peptidase IV, which comprises the dipeptidyl peptidase and the ⁇ -aminocarbonyl group represented by Formula I Contacting one or more of the compounds or their tautomers, enantiomers, racemates or pharmaceutically acceptable salts thereof.
  • the present invention also provides the use of the ⁇ -aminocarbonyl compound of the formula I, a pharmaceutically acceptable salt thereof or a solvate thereof, for the preparation of a medicament for human use of a DPP-4 inhibitor.
  • the present invention utilizes molecular docking techniques to assess the ability of a designed compound to bind to DPP-4.
  • the structure of the compound obtained by the fragment growth technique was used.
  • the fragment growth was carried out by using molecular fragments of the Comprehensive Medicinal Chemistry (CMC) and other molecular fragments collected by the inventors from different starting points of the fragments. And evaluated by molecular docking techniques.
  • CMC Comprehensive Medicinal Chemistry
  • the calculation results show that the compound of the present invention has a good DPP-4 inhibitory activity, which is in agreement with the in vitro activity test results.
  • the ⁇ -aminocarbonyl compound represented by the formula I, a pharmaceutically acceptable salt thereof or a solvate thereof has DPP-4 inhibitory activity, and more importantly, some of the compounds have a stronger DPP-4 than sitagliptin. Inhibition activity, better selectivity, and It has obvious hypoglycemic effect in in vivo experiments. Therefore, the compounds provided by the present invention are expected to exhibit better safety and efficacy in clinical practice, and have broad clinical application prospects.
  • Fig. 1 (a) and Fig. 1 (b) are graphs showing the results of oral glucose tolerance test of the compound prepared in Example 5 of the present invention; wherein Inh. is inhibition.
  • Fig. 2 (a) and Fig. 2 (b) are graphs showing the results of acute toxicity test of the compound prepared in Example 5 of the present invention. Detailed ways
  • 5,6-Difluoro-1-indanone was prepared by using 3.4-difluorobenzaldehyde as a raw material according to the literature (J. Med. Chem. 2003, 46, 399-408).
  • Compound 7-1 was prepared using 5,6-difluoro-1-indanone as a starting material by the method (ORG LETT. 2007, 9, 2915-2918).
  • the monoethyl malonate potassium salt (81 g) was suspended in acetonitrile (300 ml), triethylamine (94 ml), magnesium chloride (43 g), and stirred at room temperature for two hours.
  • Compound S1 (42g) was suspended in acetonitrile (150ml), CDI (52g) was added, and the reaction was completed in 30min, added to the above reaction solution of monoethyl malonate potassium salt. After the reaction was completed, 1M HCl solution was added to clarify, layering. The residue was evaporated to dryness.
  • the compound S-4 (9.0 g) was dissolved in methanol (20 ml), sodium hydroxide (2.9 g) was dissolved in water (10 ml), and then slowly added to the reaction mixture, stirred at room temperature, and the reaction was completed, and the methanol was evaporated to dryness in an ice water bath.
  • the KHS0 4 solution was adjusted to pH 2, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and evaporated.
  • the compound S-5 was subjected to chiral resolution using an HPLC chiral preparative liquid phase column (column type AD-H) to obtain the single chiral isomers S-5a and S-5b, respectively.
  • S-26-1 S-26-2 S-26 Compound S-26-1 (200mg) was dissolved in CH 2 C1 2 , triethylamine (0.14ml) was added, and benzenesulfonyl chloride (176mg) was added dropwise in an ice bath. The CH 2 C1 2 solution was added dropwise, and the ice bath was removed. The reaction was completed in lh, and the mixture was diluted with CH 2 C1 2 . The organic layer was washed with 1M HCl solution and brine, dried over anhydrous sodium sulfate, and concentrated. 310 mg of compound S-26-2.
  • the compound S-50 was synthesized in the same manner as in Preparation 18 using S-50-1 as a reagent.
  • the compound S-64 was synthesized by the same method as in Preparation Example 24 using S-64-1 as a reagent.
  • the compound S-69 c was synthesized by the same method as in Preparation Example 7 using p-methoxybenzoic acid as a reagent.
  • Compound S-70 was synthesized in the same manner as in Preparation Example 7 using 3.4-difluorobenzoic acid as a reagent.
  • the compound S-71 MS was synthesized in the same manner as in Preparation 7 using m-methylbenzoic acid as a reagent: m/e 205 [M+H] + .
  • the compound S-83 was synthesized by the same method as in Preparation Example 14 using 2,4-difluorobenzoic acid as a reagent.
  • Lithium hydroxide (1.4g) was dissolved in water, and a solution of compound S-94-6 (2g) in THF was added. The reaction was completed in lh, THF was evaporated, and 4M HCl solution was added to adjust pH ⁇ 4, EA was extracted, and EA was washed with saturated brine. The layer was dried over anhydrous sodium sulfate and concentrated to give 2 g of Compounds.
  • the compound S-94-8 (500 mg;) was dissolved in methanol, Pd/C (100 mg) was added, and hydrogen was passed, and the reaction was completed for lh.
  • N-Boc-1.2-ethylenediamine 200 mg was dissolved in DMF, and then DIPEA (0.53 ml), compound S-96-2 (350 mg), HOBT (254 mg), EDCI (360 mg), stirred at room temperature overnight, next day Add 1M HC1 solution to the reaction solution and extract with EA.
  • the EA layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate and evaporated.
  • Lithium tetrahydroaluminum (5 g) was suspended in dry THF (150 ml), and the mixture was stirred in ice-bath, and the compound S-97-l (8 g) was added in portions. After the addition, the reaction mixture was moved to room temperature, and the reaction was completed in 5 h, and water (10 ml) was added dropwise. After quenching, a solution of 1 M NaOH (10 ml) was added, sodium sulfate was added thereto, and the mixture was filtered, and the residue was washed with EA several times, concentrated, and then purified by column chromatography to yield 3.5 g of Compound S-97-2.
  • Lithium hydroxide (2g) was dissolved in water, and a solution of compound S-101-4 (2.7g) in THF was added. The reaction was completed in lh, THF was evaporated, 4M HCl solution was added to adjust pH ⁇ 4, EA was extracted, and EA was washed with saturated brine. The layer was dried over anhydrous sodium sulfate and evaporated.
  • 2-methyl-3-nitrobenzoic acid (5 g) was dissolved in methanol (50 ml), concentrated sulfuric acid (5 ml) was added, and the mixture was heated to reflux overnight. The next day, the reaction was stopped, the methanol was evaporated, the EA was dissolved, and the EA layer was saturated. The sodium hydrogencarbonate solution was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated.
  • the compound S-103-2 was dissolved in a methanol solution, and a solution of ammonia in methanol was added thereto, and the mixture was heated under reflux, and the reaction was completed for 2 hours.
  • the product was filtered, and the filtrate was concentrated to give 3.6 g of Compound Compound S-103-3.
  • Compound S-106 was synthesized in the same manner as in Preparation 14 using 3-fluorobenzoic acid as a reagent.
  • Compound S-110 was synthesized in the same manner as in Preparation 14 using Compound S-110-2 as a reagent.
  • the EA layer was washed with saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and evaporated.
  • Compound S-115 was synthesized in the same manner as in Preparation 14 using Compound S-115-2 as a reagent.
  • the compound S-126-2 (0.3 g) was dissolved in dichloromethane (10 ml), trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 6 hr. The dichloromethane and excess trifluoroacetic acid were directly dried to give the trifluoroacetic acid salt of Compound S-126.
  • the compound was synthesized in the same manner as in Preparation 51 using the compound 2-nitro-4-trifluoromethylbenzoic acid as a reagent. S-128.
  • Compound S-129-6 was synthesized in the same manner as in Preparation 56 using the compound 2-nitro-4-bromobenzoic acid as a reagent.
  • Compound S-129-6 (300mg) was dissolved in acetonitrile, sodium iodide (800mg) was added, trimethylchlorosilane (0.8ml) was added dropwise, the reaction was completed, water was added, EA was extracted, and the EA layer was washed with saturated brine. Drying over sodium sulfate, concentration and column chromatography gave 150 mg of Compound S-129.
  • Compound S-130 was synthesized in the same manner as in Preparation 14 using Compound S-130-2 as a reagent.
  • Example 1 The compound of Example 1 was subjected to silica gel column chromatography to obtain a mixture of a pair of enantiomers of compound 2 and compound 3; and another mixture of enantiomers of compound 4 and compound 5.
  • Compounds 2, 3 and 4, 5 are diastereomers.
  • Example 4 compound ee value > 98%.
  • Example 5 compound ee value > 98%.
  • Example 8 Compound 7 (720mg) was dissolved in methanol (10ml) was added HgCl 2 (550mg), 30min the reaction was complete, filtered, and the filtrate was concentrated and column chromatography, to obtain the title compound of Example 8 embodiment 450mg.
  • the compound 8 (260 mg) was dissolved in methanol (5 ml), and sodium borohydride (40 mg) was added under ice-cooling, and the reaction was completed for 30 min.
  • the reaction mixture was concentrated, dissolved in CH 2 C1 2 and the organic phase was washed sequentially with water and brine. The mixture was dried over sodium sulfate and concentrated to give the object.
  • the compound ll-2 (60 mg) was dissolved in CH 2 C1 2 and trifluoroacetic acid (0.3 ml) was added. After the reaction was completed, the mixture was diluted with CH 2 C 2 2 and layered, and the CH 2 C 2 2 layer was successively washed with saturated sodium hydrogen carbonate solution. The mixture was washed with brine, dried over anhydrous sodium sulfate
  • the compound 12-2 (4.5 g) was dissolved in methanol (20 ml), 7-(20 ml), sodium hydroxide (1.3 g) was added, and refluxed. After the reaction was completed, methanol was evaporated to dryness, and pH was adjusted to 2 with 1M HCl solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated.
  • the monoethyl malonate potassium salt (1.62 g) was suspended in acetonitrile (5 ml), triethylamine (2.1 ml), magnesium chloride (1.13 g).
  • Compound 12-3 (1.3 g) was suspended in acetonitrile (10 ml), CDI (0.9 g) was added, and the mixture was stirred at room temperature until the reaction was completed and added to the reaction mixture. Stir overnight, add 13% HCl solution to the next day to clarify, layer, concentrate the organic layer, residue
  • the EA was dissolved in EA. The aqueous layer was extracted with EA, and then EA layer was evaporated.
  • the monoethyl malonate potassium salt (1.62 g) was suspended in acetonitrile (5 ml), triethylamine (2.1 ml), magnesium chloride (1.13 g), and stirred at room temperature for 2 h.
  • Compound 13-2 (1.3 g) was suspended in acetonitrile (10 ml), and CDI (0.9 g) was added and stirred at room temperature until the reaction was completed. It is added to the above reaction liquid.
  • the monoethyl malonate potassium salt (10.9 g) was suspended in acetonitrile (30 ml), and 11 ml of triethylamine and 6.1 g of magnesium chloride were added, and the mixture was stirred at room temperature for 2 h.
  • Compound 14-2 (8.5 g) was suspended in acetonitrile (30 ml), and CDI (4.98 g) was added, and the mixture was stirred at room temperature until the reaction was completed and added to the reaction mixture.
  • the compound 15-2 (100 mg) was dissolved in a methanolic solution of hydrogen chloride. After 2h, the reaction was completed. The solvent was evaporated to dryness, evaporated, evaporated, evaporated, evaporated.
  • ⁇ MR 300 MHZ, CD 3 OD: ⁇ 8.32 (1 ⁇ , d), 7.30 (1 ⁇ , t), 7.16(1 ⁇ , t), 6.63(1 ⁇ , d), 5.07(1 ⁇ , d), 3.95-4.40 (6 ⁇ , m), 3.38-3.47(1 ⁇ , m), 2.84-3.02(3 ⁇ , m), 2.33-2.58(2 ⁇ , m), 1.96-2.13 (2 ⁇ , m), 1.81-1.93(lH, m) .
  • the trifluoroacetic acid salt of the compound 31 was dissolved in CH 2 C1 2 , washed with saturated sodium hydrogen carbonate solution and washed with saturated brine, and the organic phase was dried and concentrated to give Compound 31.
  • Example 1 In the same manner as in Example 31, the compound S-5 of Preparation Example 5 was used as a starting material, and Compound 57 was synthesized using S-57 as a reagent.

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Abstract

The present invention belongs to the field of medicinal chemistry. In particular, the present invention relates to a novel β-aminocarbonyl compound as represented by general formula I, or tautomer, enantiomer, racemate and pharmaceutically acceptable salt thereof, preparation method and pharmaceutical composition thereof, and use thereof as a dipeptidyl peptidase IV (DPP-4) inhibitor. The compound or pharmaceutical composition thereof can be used as a DPP-4 inhibitor to treat type II diabetes, hyperglycaemia, obesity, or insulin-resistance syndromes.

Description

P-氨基羰基类化合物、 其制备方法、 药物组合物及其用途 技术领域  P-aminocarbonyl compound, preparation method thereof, pharmaceutical composition and use thereof
本发明属于药物化学领域。具体而言， 本发明涉及一种通式 I所示的新的 β-氨基羰基类 化合物或其互变异构体、 对映体、 消旋体或其药学上可接受的盐， 其制备方法， 药物组合物 及其作为二肽基肽酶 IV(DPP-4)抑制剂的用途。 该类化合物或其药物组合物作为 DPP-4抑制 剂可用于治疗 Π型糖尿病、 高血糖症、 肥胖症或胰岛素抵抗症。  The invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a novel β-aminocarbonyl compound represented by Formula I, or a tautomer, an enantiomer, a racemate thereof, or a pharmaceutically acceptable salt thereof, and a process for the preparation thereof , pharmaceutical compositions and their use as inhibitors of dipeptidyl peptidase IV (DPP-4). Such a compound or a pharmaceutical composition thereof can be used as a DPP-4 inhibitor for the treatment of diabetes mellitus, hyperglycemia, obesity or insulin resistance.
背景技术  Background technique
糖尿病 (diabetes)是由遗传因素、 免疫功能紊乱、 微生物感染及其毒素、 自由基毒素、 精 神因素等等各种致病因子作用于机体导致胰岛功能减退、胰岛素抵抗等而引发的糖、蛋白质、 脂肪、 水和电解质等一系列代谢紊乱综合征， 临床上以高血糖为主要特点， 典型病例可出现 多尿、 多饮、 多食、 消瘦等表现， 即"三多一少"症状。 糖尿病 (血糖)一旦控制不好会引发并 发症， 导致肾、 眼、 足等部位的衰竭病变， 且无法治愈。  Diabetes (diabetes) are caused by genetic factors, immune dysfunction, microbial infections and their toxins, free radical toxins, mental factors and other pathogenic factors that cause the body to cause islet dysfunction, insulin resistance, etc., caused by sugar, protein, A series of metabolic disorders such as fat, water and electrolytes are clinically characterized by hyperglycemia. In typical cases, polyuria, polydipsia, polyphagia, and wasting may occur, that is, symptoms of "three more and one less". Diabetes (blood sugar), once not well controlled, can cause complications, leading to depletion of kidneys, eyes, feet, etc., and can not be cured.
近年来， 糖尿病的发病率逐年攀升， 成为 21世纪人类健康的主要威胁之一， 其中 II型 糖尿病占 90%以上。 胰岛素抵抗和胰岛素分泌功能受损是 II型糖尿病发病和病理过程之中 的两个重要现象。 目前临床上使用的降糖药物都存在不同程度的副作用和局限性： 磺脲类和 胰岛素类降糖药物增加体重并伴随低血糖风险；噻唑垸二酮类胰岛素增敏剂的代表药物—— 罗格列酮因可能增加糖尿病患者心血管疾病的风险， 而在全球范围内退市或被限制使用； 吡 格列酮也在 2011年标注膀胱癌风险； 二甲双胍和 a糖苷酶抑制剂则存在不同程度的消化道 反应； 胰岛素不能口服给药。 DPP-4抑制剂因具有良好的血糖控制、 低血糖发生风险小和不 影响体重等优势已成为当下最热门的抗糖尿病药物。  In recent years, the incidence of diabetes has risen year by year, becoming one of the major threats to human health in the 21st century, with type II diabetes accounting for more than 90%. Impaired insulin resistance and insulin secretion are two important phenomena in the pathogenesis and pathogenesis of type 2 diabetes. Currently, the hypoglycemic drugs used in clinical practice have different degrees of side effects and limitations: sulfonylureas and insulin hypoglycemic drugs increase body weight and accompany the risk of hypoglycemia; representative drugs of thiazolidinedione insulin sensitizers - Luo Glindroxone may increase the risk of cardiovascular disease in diabetic patients, but it may be delisted or restricted globally; pioglitazone also marks bladder cancer risk in 2011; metformin and a glycosidase inhibitors have varying degrees of digestive tract Reaction; insulin cannot be administered orally. DPP-4 inhibitors have become the most popular antidiabetic drugs due to their good glycemic control, low risk of hypoglycemia and no weight gain.
目前， 已有 5个 DPP-4抑制剂上市用于治疗糖尿病， 它们分别是西他列汀 (sitagliPtin)、 维达列汀 (vildagliptin)、 沙格列汀 (saxagliptin)、 阿格列汀 (alogliptin)、 利拉利汀 (Hnagliptin)。 Currently, five DPP-4 inhibitors have been marketed for the treatment of diabetes, which are sitagliptin (sitagli P ti n ), vildagliptin, saxagliptin, and argan. Alogliptin, Hnagliptin.
本发明的目的在于提供一种新的具有 DPP-4抑制活性，可用于糖尿病及类似疾病的治疗 或缓解性药物的化合物。  SUMMARY OF THE INVENTION An object of the present invention is to provide a novel compound having a DPP-4 inhibitory activity and which can be used for a therapeutic or palliative drug for diabetes and the like.
发明内容  Summary of the invention
发明目的  Purpose of the invention
本发明的一个目的是提供一种通式 I所示的 β-氨基羰基类化合物或其互变异构体、对映 体、 消旋体或其药学上可接受的盐。  SUMMARY OF THE INVENTION One object of the present invention is to provide a β-aminocarbonyl compound represented by the formula I or a tautomer, an enantiomer thereof, a racemate or a pharmaceutically acceptable salt thereof.
本发明的另一个目的是提供本发明提供的化合物的制备方法。  Another object of the invention is to provide a process for the preparation of the compounds provided herein.
本发明的又一个目的是提供通式 I所示的 β-氨基羰基类化合物或其互变异构体、对映体、 消旋体或其药学上可接受的盐作为 DPP-4抑制剂的用途， 以及在制备治疗 Π型糖尿病、 高 血糖症、 肥胖症或胰岛素抵抗症药物中的应用。  A further object of the present invention is to provide a β-aminocarbonyl compound of the formula I or a tautomer, an enantiomer, a racemate thereof or a pharmaceutically acceptable salt thereof as a DPP-4 inhibitor. Use, and in the preparation of a medicament for the treatment of diabetes, hyperglycemia, obesity or insulin resistance.
本发明的再一个目的是提供包含通式〖所示的 β-氨基羰基类化合物或其互变异构体、对 映体、 消旋体或其药学上可接受的盐中的一种或多种的药物组合物。  Still another object of the present invention is to provide one or more of a β-aminocarbonyl compound represented by the formula or a tautomer, an enantiomer, a racemate thereof or a pharmaceutically acceptable salt thereof. Kind of pharmaceutical composition.
本发明的再一个目的是提供一种治疗 II型糖尿病、高血糖症、肥胖症或胰岛素抵抗症的 方法。  It is still another object of the present invention to provide a method of treating type II diabetes, hyperglycemia, obesity or insulin resistance.
技术方案  Technical solutions
根据本发明的一个方面，提供了一种通式 I所示的 β-氨基羰基类化合物或其互变异构体、 对映体、 消旋体或其药学上可接受的盐- 确认本
Figure imgf000004_0001
According to one aspect of the present invention, there is provided a β-aminocarbonyl compound of the formula I or a tautomer, an enantiomer, a racemate thereof or a pharmaceutically acceptable salt thereof - confirmation
Figure imgf000004_0001
其中- among them-
A选自 C6-C10芳基、 饱和或不饱和 C3-C10环烃基、 4-10元杂环基或 4-10元杂芳基； 所述杂环基或杂芳基含有 1-4个选自 N、 S和 O的杂原子； A优选为苯基、 5~6元杂环基或 5~6元杂芳基， 更优选为苯基、 吡啶基或环戊二烯基； A is selected from a C6-C10 aryl group, a saturated or unsaturated C3-C10 cycloalkyl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group; the heterocyclic group or heteroaryl group contains 1-4 selected a hetero atom derived from N, S and O; A is preferably a phenyl group, a 5- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, more preferably a phenyl group, a pyridyl group or a cyclopentadienyl group;
W为 、 S、 O或 C1-C4直链烃基；  W is a S, O, or C1-C4 linear hydrocarbon group;
(3为^^、 S、 O或 C原子；  (3 is ^^, S, O or C atom;
W与 Q之间的虚线存在或不存在，存在时表示此处是不饱和键 (如双键)，不存在时表示 此处是饱和键 (单键)， 优选为不存在；  The presence or absence of a dotted line between W and Q, when present, indicates that it is an unsaturated bond (such as a double bond), and when it does not exist, it indicates that it is a saturated bond (single bond), preferably does not exist;
Y为 N或 CR7; Y is N or CR 7 ;
X为 N或 CR7; X is N or CR 7 ;
和 R4各自独立地为 H;卤素；三氟甲基;羟基；硝基；腈基；羧基； -C(O)OCl-C10 烷基； 氨基； C1-C10烷氧基； C1-C10烷基； C1-C10垸酰基 (gp-c(o)ci-cio烷基)； C1-C10 垸酰氧基 (即 -OC(O)Cl-C10垸基)； 磺酰基； C1-C10垸基磺酰基； C6-C10芳基； 4-10元杂环 基；或 4-10元杂芳基；上述 -C(O)OCl-C10垸基、氨基、 C1-C10烷氧基、 C1-C10垸基、 C1-C10 烷酰基、 C1-C10垸酰氧基、 磺酰基、 C1-C10垸基磺酰基、 C6-C10芳基、 4-10元杂环基或 4-10元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧 基、 C1-C10烷基、 C1-C10烷氧基、 C1-C10垸酰氧基、 -C(0)OCl- C10垸基、 C1-C10垸酰 基、 磺酰基、 C1-C10垸基磺酰基、 苯基和苯甲基中的取代基取代；  And R4 are each independently H; halogen; trifluoromethyl; hydroxy; nitro; nitrile; carboxy; -C(O)OCl-C10 alkyl; amino; C1-C10 alkoxy; C1-C10 alkyl C1-C10 decanoyl (gp-c(o)ci-cioalkyl); C1-C10 nonanoyloxy (ie -OC(O)Cl-C10 fluorenyl); sulfonyl; C1-C10 mercaptosulfonate Acyl; C6-C10 aryl; 4-10 membered heterocyclic; or 4-10 membered heteroaryl; above -C(O)OCl-C10 fluorenyl, amino, C1-C10 alkoxy, C1-C10垸, C1-C10 alkanoyl, C1-C10 nonanoyloxy, sulfonyl, C1-C10 decylsulfonyl, C6-C10 aryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl Must be one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 nonanoyloxy, - Substituted by a substituent in C(0)OCl-C10 fluorenyl, C1-C10 decanoyl, sulfonyl, C1-C10 decylsulfonyl, phenyl and benzyl;
R5和 各自独立地为 -(CH2)mR9; -(CH2)mCO(CH2)nR9;
Figure imgf000004_0002
其中 i=l~5的 整数， j=l~3的整数， R9为 H; 素； 羟基； 硝基； 氨基； 腈基； 羧基； -C(O)OCl-C10垸 基； C1-C10垸酰基； C1-C10垸基磺酰基； C1-C10烷基； C2-C10烯基； C2-C10炔基； C3-C10 环垸基； C3-C8内酰胺基； C1-C10垸氨基磺酰基； C1-C10垸氨酰基； C6-C10芳酰基； C1-C10 垸氧基； C6-C10芳基磺酰基、 -S02NR15R16、 -NRI5S02R16; C6-C10芳基； 4-10元杂环基; 4-10元杂芳基； -10元杂环基或 4-10元杂芳基并 C3-C10环烃基；或者 4-10元杂环基或 4-10 元杂芳基并 4-10元杂环基或 4-10元杂芳基； 上述氨基、 -C(O)OCl-C10垸基、 C1-C10烷酰 基、 C1-C10垸基磺酰基、 C1-C10烷基、 C2-C10烯基、 C2-C10炔基、 C3-C10环垸基、 C3-C8 内酰胺基、 C1-C10烷氨基磺酰基、 C1-C10烷氨酰基、 C6-C10芳酰基、 C1-C10烷氧基、 C6-C10 芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C3-C10环烃基或者 4-10元杂环基或 4-10元杂芳基并 4-10 元杂环基或 4-10 元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 -NR15R16、 腈基、 羧基、 C1-C10烷氧基、 C6-C10芳氧基、 C1-C10垸酰氧基、 -C(O)OCl-C10 烷基、 -C(0)NR15R16、 C1-C10烷酰基、 C1-C10垸基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 - R15S02R16、 C6-C10芳酰基、 C1-C10垸基、羟基 C1-C10垸基、氨基 C1-C10烷基、 C6-C10 芳基 C1-C10垸基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取 代基取代； 上述 C6-C10芳基、 C6-C10芳酰基和 C6-C10芳基磺酰基可非必须地被一个或多 个选自卤素、 三氟甲基、 羟基、 硝基、 -NR15R16、 腈基、 羧基、 C1-C10垸氧基、 C1-C10垸 酰氧基、 -C(O)OCl-C10垸基、 -C(0)NR15R16、 Cl-ClO ;^酰基、 C1-C10垸基磺酰基、 C6-C10 芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C10烷基、羟基 C1-C10垸基、 氨基 C1-C10烷基和 C6-C10芳基 C1-C10垸基中的取代基取代； R 5 and each independently are -(CH 2 ) m R 9; -(CH 2 ) m CO(CH 2 ) n R 9;
Figure imgf000004_0002
Wherein i=l~5 integer, j=l~3 integer, R 9 is H; 素; hydroxy; nitro; amino; nitrile; carboxyl; -C(O)OCl-C10 fluorenyl; C1-C10 Decanoyl; C1-C10 mercaptosulfonyl; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cyclodecyl; C3-C8 lactam; C1-C10 guanylaminosulfonyl C1-C10 valyl; C6-C10 aroyl; C1-C10 decyloxy; C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR I5 S0 2 R 16 ; C6-C10 aryl 4-10 membered heterocyclic group; 4-10 membered heteroaryl; -10 membered heterocyclic group or 4-10 membered heteroaryl and C3-C10 cyclic hydrocarbon group; or 4-10 membered heterocyclic group or 4-10 a heteroaryl group and a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group; the above amino group, -C(O)OCl-C10 fluorenyl group, C1-C10 alkanoyl group, C1-C10 decylsulfonyl group, C1 -C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cyclodecyl, C3-C8 lactam, C1-C10 alkylaminosulfonyl, C1-C10 alkanoyl, C6-C10 aromatic Acyl, C1-C10 alkoxy, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aryl, 4-10 membered heterocyclic, 4-10 Meta-heteroaryl, 4-10 yuan Heterocyclyl or 4-10 membered heteroaryl and C3-C10 cycloalkyl or 4-10 membered heterocyclic or 4-10 membered heteroaryl and 4-10 membered heterocyclic or 4-10 membered heteroaryl Optionally, one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile, carboxyl, C1-C10 alkoxy, C6-C10 aryloxy, C1-C10 Nonanoyloxy, -C(O)OCl-C10 Alkyl, -C(0)NR 15 R 16 , C1-C10 alkanoyl, C1-C10 decylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , - R 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 fluorenyl, hydroxy C1-C10 fluorenyl, amino C1-C10 alkyl, C6-C10 aryl C1-C10 fluorenyl, =0 (oxo), =S (thio ), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6-C10 aryl, 4-10 member Substituted with a heterocyclic acyl group and a substituent in a 4-10 membered heteroaroyl group; the above C6-C10 aryl group, C6-C10 aroyl group and C6-C10 aryl sulfonyl group may be optionally selected from one or more selected from the group consisting of halogen, Trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile group, carboxyl group, C1-C10 decyloxy group, C1-C10 decanoyloxy group, -C(O)OCl-C10 fluorenyl group, -C( 0) NR 15 R 16 , Cl-ClO ; acyl group, C1-C10 decylsulfonyl group, C6-C10 arylsulfonyl group, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aryl a substituent substituted with an acyl group, a C1-C10 alkyl group, a hydroxy C1-C10 fluorenyl group, an amino C1-C10 alkyl group, and a C6-C10 aryl C1-C10 fluorenyl group;
或者， 和 与它们相连的 X共同构成氨基葡萄糖基； 氨基酸残基； 氨基酸酯残基； 或氨基酰胺残基，且非必须地被一个或多个选自 C1-C6垸基、 C1-C6垸基取代的氨基、 C1-C10 垸酰基、 苄基、 苄氧羰基和叔丁氧羰基中的取代基取代；  Or, together with the X to which they are attached, constitute an glucosyl group; an amino acid residue; an amino acid ester residue; or an aminoamide residue, and optionally one or more selected from the group consisting of C1-C6 fluorenyl, C1-C6垸a substituent substituted with a base-substituted amino group, a C1-C10 decanoyl group, a benzyl group, a benzyloxycarbonyl group, and a t-butoxycarbonyl group;
或者， R5和 与连接它们的 X—起形成 C6-C10芳基； C3-C10环烃基； C3-C10环烃 基并 C3-C10环烃基； C3-C10环烃基并 C6-C10芳基； C6-C10芳基并 C3-C10环烃基； 4-10 元杂环基； 4-10元杂芳基； 4-10元杂环基螺环； 4-10元杂芳基螺环； 4-10元杂环基或 4-10 元杂芳基并 C3-C10环烃基； C3-C10环烃基并 4-10元杂环基或 4-10元杂芳基； 4-10元杂环 基或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基； C6-C10芳基并 4-10元杂环基或 4-10 元杂芳基； 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基； [4-10元杂环基或 4-10元杂芳基] 并 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]; 或者 [4-10元杂环基 或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]并 [C6-C10芳基]; 上述基团可非必须地 被一个或多个 R，取代， R，选自 -(CH2)mR1() ; -(CH2)mCO(CH2)nR10 ; -(CH2)mO(CH2)„R10； -(CH2)mNHC(O)(CH2)nR10; 和 -(CH2)mNSO2(CH2)nR10; Or, R 5 and X-linked to form a C6-C10 aryl group; C3-C10 cycloalkyl; C3-C10 cycloalkyl and C3-C10 cycloalkyl; C3-C10 cycloalkyl and C6-C10 aryl; C6 -C10 aryl and C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; 4-10 membered heterocyclyl spiro; 4-10 membered heteroaryl spiro; 4-10 a heterocyclic or 4-10 membered heteroaryl and C3-C10 cycloalkyl; C3-C10 cycloalkyl and 4-10 membered heterocyclic or 4-10 membered heteroaryl; 4-10 membered heterocyclyl or 4 -10 membered heteroaryl and 4-10 membered heterocyclic group or 4-10 membered heteroaryl; C6-C10 aryl and 4-10 membered heterocyclic group or 4-10 membered heteroaryl; 4-10 membered hetero a cyclic or 4-10 membered heteroaryl and C6-C10 aryl; [4-10 membered heterocyclic or 4-10 membered heteroaryl] and [4-10 membered heterocyclic or 4-10 membered heteroaryl) And [4-10 membered heterocyclic or 4-10 membered heteroaryl]; or [4-10 membered heterocyclyl or 4-10 membered heteroaryl] and [4-10 membered heterocyclyl or 4 -10 membered heteroaryl]and [C6-C10 aryl]; the above group may be optionally substituted by one or more R, R, selected from -(CH 2 ) m R 1(); -(CH 2 ) m CO(CH 2 ) n R 10 ; -(CH 2 ) m O(CH 2 )„R 10 ; -(CH 2 ) m NHC(O)(CH 2 ) n R 10 ; and -(CH 2 ) m NSO 2 (CH 2 ) n R 10;
其中， R10为氢、 卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C10烷氧基、 C6-C10芳氧基、 C1-C10垸酰氧基、 -C(O)OCl-C10烷基、 -C(0)NH2、 C1-C10烷酰基、 C1-C10 垸基磺酰基、 C6-C10芳基磺酰基、 -S02 R15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C10垸 基、羟基 C1-C10烷基、 氨基 C1-C10烷基、 C6-C10芳基 C1-C10烷基、 =0 (氧代)、 =S (硫 代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10 Wherein R 10 is hydrogen, halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C10 alkoxy, C6-C10 aryloxy, C1-C10 nonanoyloxy, -C (O)OCl-C10 alkyl, -C(0)NH 2 , C1-C10 alkanoyl, C1-C10 decylsulfonyl, C6-C10 arylsulfonyl, -S0 2 R 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 fluorenyl, hydroxy C1-C10 alkyl, amino C1-C10 alkyl, C6-C10 aryl C1-C10 alkyl, =0 (oxo), = S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6-C10
Ph  Ph
芳基、 4-10元杂环酰基、 4-10元杂芳酰基或一 -COEt ; 上述氨基、 C1-C10烷氧基、 C6-C10 芳氧基、 C1-C10垸酰氧基、 -C(O)OCl-C10烷基、 -C(0)NH2、 C1-C10垸酰基、 C1-C10烷基 磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C10烷基、 羟基 C1-C10垸基、 氨基 C1-C10烷基、 C6-C10芳基 C1-C10 '烷基、 C6-C10芳基、 4-10元杂 环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基、 Aryl, 4-10 membered heterocyclic acyl, 4-10 membered heteroaroyl or mono-COEt ; above amino, C1-C10 alkoxy, C6-C10 aryloxy, C1-C10 nonanoyloxy, -C (O)OCl-C10 alkyl, -C(0)NH 2 , C1-C10 decanoyl, C1-C10 alkylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 alkyl, hydroxy C1-C10 decyl, amino C1-C10 alkyl, C6-C10 aryl C1-C10 'alkyl, C6-C10 aryl, 4 a 10-membered heterocyclic group, a 4-10 membered heteroaryl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, a C6-C10 aryl group, a 4-10 membered heterocyclic acyl group,
Ph  Ph
4-10元杂芳酰基或一^ -COEt可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 - R15R16、 腈基、 羧基、 C1-C10垸氧基、 C6-C10芳氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10 垸基、 -C(0)NR15R16、 C1-C10垸酰基、 C1-C10垸基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C10垸基、羟基 C1-C10垸基、氨基 C1-C10烷基、 C6-C10 芳基 C1-C10垸基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取 代基取代； The 4-10 membered heteroaroyl or mono-COEt may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -R 15 R 16 , nitrile, carboxy, C1-C10 垸Oxy, C6-C10 aryloxy, C1-C10 alkanoyloxy, -C(O)OCl-C10 fluorenyl, -C(0)NR 15 R 16 , C1-C10 decanoyl, C1-C10 fluorenyl Sulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 fluorenyl, hydroxy C1-C10 decyl, amino C1-C10 Alkyl, C6-C10 aryl C1-C10 fluorenyl, =0 (oxo), =S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, a substituent of a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group and a C6-C10 aryl group, a 4-10 membered heterocyclic acyl group, and a 4-10 membered heteroaroyl group;
R15、 R16各自独立地为 H; C1-C10垸基； C3-C10环垸基； 4-10元杂环基； 4-10元杂芳 基； 或者 R15、 R16与连接它们的 N原子一起形成 4-10元杂环基； 4-10元杂芳基； 其中， 所 述 C1-C10烷基、 C3-C10环垸基、 4-10元杂环基和 4-10元杂芳基可非必须地被 1个或多个 卤素； 羟基； 腈基； 氨基； C1-C10垸基； =0 (氧代)； =S (硫代)； C1-C10烷氧基取代；R 15 and R 16 are each independently H; C1-C10 fluorenyl; C3-C10 cyclodecyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and attached thereto The N atoms together form a 4-10 membered heterocyclic group; a 4-10 membered heteroaryl group; wherein, the C1-C10 alkyl group, the C3-C10 cyclodecyl group, the 4-10 membered heterocyclic group, and the 4-10 membered heterocyclic group; The aryl group may be optionally substituted by one or more halogens; a hydroxyl group; a nitrile group; an amino group; a C1-C10 alkyl group; =0 (oxo); =S (thio); a C1-C10 alkoxy group;
R7为 -(CH2)mR„、 -(CH2)mO(CH2)nRn或 -(CH2)mNHR11 ; R 7 is -(CH 2 ) m R„, -(CH 2 ) m O(CH 2 ) n R n or -(CH 2 ) m NHR 11 ;
其中， Rii为 H; 卤素； 硝基； 腈基； 羧基； -C(O)OCl-C10垸基; C2-C10烯基; C2-C10 炔基； C1-C10垸酰基； C1-C10垸基磺酰基； 氨基 C1-C10垸酰基； C1-C10垸基； C6-C10 芳基； 4-10元杂环基； 或 4-10元杂芳基； 上述 -C(O)OCl-C10垸基、 C2-C10烯基、 C2-C10 炔基、 C1-C10垸酰基、 C1-C10垸基磺酰基、 氨基 C1-C10烷酰基、 C1-C10烷基、 C6-C10 芳基、 4-10元杂环基或 4-10元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、氨基、腈基、羧基、 C1-C10烷氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10烷基、 C1-C10 垸酰基、 C1-C10垸基磺酰基、 =o (氧代)、 =S (硫代)和 C1-C10烷基中的取代基取代； Wherein, Rii is H; halogen; nitro; nitrile; carboxyl; -C(O)OCl-C10 fluorenyl; C2-C10 alkenyl; C2-C10 alkynyl; C1-C10 nonanoyl; C1-C10 fluorenyl Sulfonyl; amino C1-C10 decanoyl; C1-C10 fluorenyl; C6-C10 aryl; 4-10 membered heterocyclic; or 4-10 membered heteroaryl; above -C(O)OCl-C10 fluorenyl , C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 decanoyl, C1-C10 decylsulfonyl, amino C1-C10 alkanoyl, C1-C10 alkyl, C6-C10 aryl, 4-10 The heterocyclic group or the 4-10 membered heteroaryl group may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxyl, C1-C10 alkoxy, C1- C10 alkanoyloxy, -C(O)OCl-C10 alkyl, C1-C10 decanoyl, C1-C10 decylsulfonyl, =o (oxo), =S (thio) and C1-C10 alkyl Substituted in the substituent;
R8为 -(CH2)mR12、 -(CH2)mO(CH2)„Ri2或 -(CH2)mNHR12; R 8 is -(CH 2 ) m R 12 , -(CH 2 ) m O(CH 2 )„Ri 2 or —(CH 2 ) m NHR 12;
其中， R12为 H; 卤素； 硝基； 腈基； 羧基； =0 (氧代)； =S (硫代)； -C(O)OCl-C10 垸基； C2-C10烯基； C2-C10炔基； C1-C10垸酰基； C1-C10垸基磺酰基； 氨基 C1-C10烷 Wherein R 12 is H; halogen; nitro; nitrile; carboxyl; =0 (oxo); =S (thio); -C(O)OCl-C10 fluorenyl; C2-C10 alkenyl; C10 alkynyl; C1-C10 decanoyl; C1-C10 decylsulfonyl; amino C1-C10 alkane
C1-C10烷基； Ph(CH2)m-; s^ . ； 4-10元杂环基； 或 4-10元杂芳基； 上述 -C(O)OCl-C10垸基、 C2-C10烯基、 C2-C10炔基、 C1-C10垸酰基、 C1-C10烷基磺酰基、 氨基 C1-C10垸酰基、 C1-C10垸基、 Ph(CH2)m -、 、
Figure imgf000006_0001
4-10元杂环基或 4-10元杂 芳基可非必须地被一个或多个选自卤素、三氟甲基、羟基、硝基、氨基、腈基、羧基、 C1-C10 烷氧基、 C1-C10垸酰氧基、 -C(O)OCl-C10烷基、 C1-C10烷酰基、 C1-C10烷基磺酰基、 = 0 (氧代)、 =S (硫代)和 C1-C10垸基中的取代基取代； C1-C10 alkyl; Ph(CH 2 ) m - ; s^ . ; 4-10 membered heterocyclic group; or 4-10 membered heteroaryl; above -C(O)OCl-C10 fluorenyl, C2-C10 Alkenyl, C2-C10 alkynyl, C1-C10 decanoyl, C1-C10 alkylsulfonyl, amino C1-C10 decanoyl, C1-C10 decyl, Ph(CH 2 ) m -, ,
Figure imgf000006_0001
The 4-10 membered heterocyclyl or 4-10 membered heteroaryl may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxyl, C1-C10 alkoxy , C1-C10 nonanoyloxy, -C(O)OCl-C10 alkyl, C1-C10 alkanoyl, C1-C10 alkylsulfonyl, = 0 (oxo), =S (thio) and C1 a substituent in the -C10 fluorenyl group;
各个 m和各个 n各自独立地为 0-5的整数；  Each m and each n are each independently an integer from 0 to 5;
q为 0-4的整数。  q is an integer from 0-4.
X为 CR7、 Y为 R7时， 各 R7可以相同也可以不同。 When X is CR 7 and Y is R 7 , each R 7 may be the same or different.
本发明中， 未特别指出， 各基团均可包括取代或未取代的形式， 如对于 C1-C10烷基而 言， 包括未取代或取代的 C1-C10 '烷基， 对于 C6-C10芳基、 C6-C10芳酰基、 4-10元杂环基、 4-10元杂芳基而言， 包括未取代或取代的 C6-C10芳基、 C6-C10芳酰基、 4-10元杂环基、 In the present invention, unless otherwise specified, each group may include a substituted or unsubstituted form, such as a C1-C10 alkyl group, including an unsubstituted or substituted C1-C10 'alkyl group, for a C6-C10 aryl group. And a C6-C10 aroyl group, a 4-10 membered heterocyclic group, and a 4-10 membered heteroaryl group, including an unsubstituted or substituted C6-C10 aryl group, a C6-C10 aroyl group, and a 4-10 membered heterocyclic group. ,
4-10元杂芳基， 其中， 取代方式如通式 I所示的化合物中所定义。 A 4-10 membered heteroaryl group, wherein the substitution mode is as defined in the compound of the formula I.
其中， 除非特别指出， 所述垸基包括直链、 支链垸基；  Wherein, unless otherwise specified, the fluorenyl group includes a linear, branched fluorenyl group;
所述 C6-C10芳基为苯基、 稠环芳基， 所述芳基可非必须地被一个或多个选自卤素、 三 氟甲基、羟基、硝基、 -NR15R16、腈基、羧基、 C1-C10烷氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10 垸基、 -C(0)NR15R16、 C1-C10垸酰基、 C1-C10垸基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C10垸基、羟基 C1-C10烷基、氨基 C1-C10垸基和 C6-C10 芳基 C1-C10烷基中的取代基取代； The C6-C10 aryl group is a phenyl group, a fused ring aryl group, and the aryl group may optionally be one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile Base, carboxyl group, C1-C10 alkoxy group, C1-C10 alkanoyloxy group, -C(O)OCl-C10 fluorenyl group, -C(0)NR 15 R 16 , C1-C10 decanoyl group, C1-C10垸Sulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 decyl, hydroxy C1-C10 alkyl, amino C1- a substituent in the C10 fluorenyl group and a C6-C10 aryl C1-C10 alkyl group;
所述芳酰基为被芳基取代的酰基， 其中的芳基定义同前。  The aroyl group is an acyl group substituted by an aryl group, wherein the aryl group is as defined above.
在一优选例中， 通式 I所示的 β-氨基羰基类化合物具有以下一个或多个特征- (1) A为 C6-C10芳基、饱和或不饱和 C3-C10环烃基、 4-10元杂芳基； 所述 4-10元杂芳 基含有 1-4个选自 N、 S和 O中的杂原子； In a preferred embodiment, the β-aminocarbonyl compound of the formula I has one or more of the following characteristics - (1) A is a C6-C10 aryl group, a saturated or unsaturated C3-C10 cyclic hydrocarbon group, a 4-10 membered heteroaryl group; and the 4-10 membered heteroaryl group contains 1-4 selected from N, S and O Heteroatoms in
(2) Rj, R2、 R3和 各自独立地为 H、 卤素、 三氟甲基、 羟基、 硝基、 腈基、 羧基、 氨 基、 C1-C10垸氧基、 C1-C10烷基; (2) Rj, R 2 , R 3 and each independently H, halogen, trifluoromethyl, hydroxy, nitro, nitrile, carboxy, amino, C1-C10 decyloxy, C1-C10 alkyl;
(3) R8为 -(CH2)mR12、 -(CH2)mO(CH2)nR12或-^^ ！?^; 其中， R12为 H、 卤素、(3) R 8 is -(CH 2 ) m R 12 , -(CH 2 ) m O(CH 2 ) n R 12 or -^^ ! ?^; where R 12 is H, halogen,
Ph(CH2)m -、 °^0、 4-10元杂环基、 =0 (氧代)、 = S (硫代)、 C1-C10垸基； 以上 Ph(CH2)m -、Ph(CH 2 ) m -, °^0, 4-10 membered heterocyclic group, =0 (oxo), = S (thio), C1-C10 fluorenyl; above Ph(CH 2 ) m -,
°= 5、 4-10元杂环基、 C1-C10烷基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C10烷氧基、 =o ( )、 =S (硫代)、 C1-C10烷基中的取代 基取代； （在另一优选例中， 所述 4-10元杂环基为
Figure imgf000007_0001
吲哚基或吡咯基)； °= 5, 4-10 membered heterocyclyl, C1-C10 alkyl may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxyl, C1-C10 Substituted with a substituent in an alkoxy group, =o ( ), =S (thio), or a C1-C10 alkyl group; (In another preferred embodiment, the 4-10 membered heterocyclic group is
Figure imgf000007_0001
Mercapto or pyrrolyl);
(4) Y为 N或 CR7， 其中， R7为 -(CH2)mRu、 -(CH2)mO(CH2)nRn或 -(CH2)mNHR11 ; 其中， Rn ¾ H, C6-C10芳基、 4-10元杂环基、 羧基、 氨基 C1-C10烷酰基、 -C(O)OCl-C10烷基、 卤素、 硝基或 4-10元杂芳基； 上述 C6-C10芳基、 4-10元杂环基、 氨基 C1-C10垸酰基、 -C(O)OCl-C10垸基、或 4-10元杂芳基可非必须地被一个或多个选自卤素、三氟甲基、羟基、 =0 (氧代)、 =S (硫代)、 C1-C10垸基、 C1-C10烷氧基硝基、 和氨基中的取代基取代； m和 n各自独立地为 0-5的整数； (4) Y is N or CR 7 , wherein R 7 is -(CH 2 ) m R u , -(CH 2 ) m O(CH 2 ) n R n or -(CH 2 ) m NHR 11 ; Rn 3⁄4 H, C6-C10 aryl, 4-10 membered heterocyclic, carboxy, amino C1-C10 alkanoyl, -C(O)OCl-C10 alkyl, halogen, nitro or 4-10 membered heteroaryl The above C6-C10 aryl, 4-10 membered heterocyclic group, amino C1-C10 decanoyl group, -C(O)OCl-C10 fluorenyl group, or 4-10 membered heteroaryl group may be optionally one or more Substituents selected from the group consisting of halogen, trifluoromethyl, hydroxy, =0 (oxo), =S (thio), C1-C10 decyl, C1-C10 alkoxy nitro, and amino; m And n are each independently an integer from 0 to 5;
(5) X为 N或 CR7; 其中， R7为 -(CH2)mRn， 其中， 为 H， m为 0; (5) X is N or CR 7; wherein R 7 is -(CH 2 ) m R n , wherein, H, m is 0;
(6) R5和 R6各自独立地为 -(CH2)mR9; -(CH2)mCO(CH2)nR9; 或 -[(CH2),0]jH， 其中 i=l~5 的整数， j=l~3的整数， m和 n各自独立地为 0-5的整数； 为11、 C6-C10芳基、 4-10元杂 环基、 C1-C10垸基、 C2-C10烯基、 4-10杂芳基、 C1-C10垸酰基、 C3-C8内酰胺基、 4-10 元杂环基或 4-10元杂芳基并 C3-C10环烃基、 4-10元杂环基或 4-10元杂芳基并 4-10元杂环 基或 4-10元杂芳基； (6) R 5 and R 6 are each independently -(CH 2 ) m R 9; -(CH 2 ) m CO(CH 2 ) n R 9; or -[(CH 2 ),0]jH, where i= An integer of l~5, an integer of j=l~3, m and n are each independently an integer of 0-5; 11 is a C6-C10 aryl group, a 4-10 membered heterocyclic group, a C1-C10 fluorenyl group, C2-C10 alkenyl, 4-10 heteroaryl, C1-C10 decanoyl, C3-C8 lactam, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C3-C10 cycloalkyl, 4- a 10-membered heterocyclic group or a 4-10 membered heteroaryl group 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group;
上述 C6-C10芳基、 4-10元杂环基、 4-10杂芳基、 C1-C10垸基、 C2-C10烯基、 C1-C10 垸酰基、 C3-C8内酰胺基、 4-10元杂环基或 4-10元杂芳基并 C3-C10环烃基、 4-10元杂环基 或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基可非必须地被一个或多个选自 4-10元杂 环基、 腈基、 羧基、 C1-C10烷基、 =0 (氧代)、 = S (硫代)、 C6-C10芳基、 卤素、三氟甲基、 -C(O)OCl-C10烷基、 -C(0)NR15R16、 -S02NR15R16、 -NR15R16、 -NRi5S02R16、 C1-C10烷基磺 酰基、 羟基中的取代基取代； The above C6-C10 aryl, 4-10 membered heterocyclic group, 4-10 heteroaryl, C1-C10 fluorenyl, C2-C10 alkenyl, C1-C10 decanoyl, C3-C8 lactam, 4-10 A heterocyclic group or a 4-10 membered heteroaryl and C3-C10 cycloalkyl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group. Optionally, one or more selected from the group consisting of 4-10 membered heterocyclyl, nitrile, carboxyl, C1-C10 alkyl, =0 (oxo), =S (thio), C6-C10 aryl, Halogen, trifluoromethyl, -C(O)OCl-C10 alkyl, -C(0)NR 15 R 16 , -S0 2 NR 15 R 16 , -NR 15 R 16 , -NRi 5 S0 2 R 16 , a C1-C10 alkylsulfonyl group, a substituent in the hydroxy group;
(7) R5和 与它们相连的 X共同构成氨基葡萄糖基； 氨基酸残基； 氨基酸酯残基； 或 氨基酰胺残基，且非必须地被一个或多个选自 C1-C6烷基、 C1-C6垸基取代的氨基、 C1-C10 烷酰基、 苄基、 苄氧羰基和叔丁氧羰基中的取代基取代； (7) R 5 and X attached thereto constitute a glucosamine group; an amino acid residue; an amino acid ester residue; or an aminoamide residue, and optionally one or more selected from a C1-C6 alkyl group, C1 Substituted with a substituent in the C6 mercapto substituted amino group, a C1-C10 alkanoyl group, a benzyl group, a benzyloxycarbonyl group and a tert-butoxycarbonyl group;
(8) R5和 Re与连接它们的 X—起形成 4-10元杂环基或 4-10元杂芳基并 4-10元杂环棊 或 4-10元杂芳基、 4-10元杂环基、 C6-C10芳基并 4-10元杂环基或 4-10元杂芳基、 C6-C10 芳基、 C3-C10环烃基、 C3-C10环烃基并 C3-C10环烃基、 C3-C10环烃基并 C6-C10芳基、 C6-C10芳基并 C3-C10环烃基、 4-10元杂芳基、 4-10元杂环基螺环、 4-10元杂芳基螺环、 4-10元杂环基或 4-10元杂芳基并 C3-C10环径基、 C3-C10环烃基并 4-10元杂环基或 4-10 元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 [4-10元杂环基或 4-10元杂芳基] 并 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]、 或者 [4-10元杂环基 或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]并 [C6-C10芳基]; 上述基团可非必须地 被一个或多个 R，取代， R，选自 -(CH^RtQ； -(CH2)mCO(CH2)n i0； -(CH2)mO(CH2)nR10； -(CH2)mNHC(O)(CH2)nR10； 和 -(CH2)mNS02(CH2)nR1(); 其中， m和 n各自独立地为 0-5的整 数； (8) R 5 and Re form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group and a 4-10 membered heterocyclic ring or a 4-10 membered heteroaryl group, 4-10. A heterocyclic group, a C6-C10 aryl-4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, a C6-C10 aryl group, a C3-C10 cycloalkyl group, a C3-C10 cycloalkyl group and a C3-C10 cyclic hydrocarbon group. , C3-C10 cycloalkyl and C6-C10 aryl, C6-C10 aryl and C3-C10 cycloalkyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl spiro, 4-10 membered heteroaryl Spiro, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C3-C10 ring, C3-C10 cycloalkyl and 4-10 membered heterocyclic or 4-10 membered heteroaryl, 4- 10 membered heterocyclic group or 4-10 membered heteroaryl and C6-C10 aryl group, [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [4-10 membered heterocyclic group or 4-10 (heteroaryl)][4-10 membered heterocyclic or 4-10 membered heteroaryl], or [4-10 membered heterocyclic or 4-10 membered heteroaryl][4-10 membered heterocyclic ring Or a 4-10 membered heteroaryl][C6-C10 aryl]; the above group may be optionally With one or more R, substituents, R, is selected from - (CH ^ RtQ; - ( CH 2) m CO (CH 2) n i 0; - (CH 2) m O (CH 2) n R 10; - (CH 2 ) m NHC(O)(CH 2 ) n R 10 ; and -(CH 2 ) m NS0 2 (CH 2 ) n R 1(); wherein m and n are each independently an integer of 0-5 ;
R10为氢、 卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C10烷氧基、 C6-C10 芳氧基、 C1-C10垸酰氧基、 -C(O)OCl-C10垸基、 -C(0)NH2、、 C1-C10垸酰基、 C1-C10垸 基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C10垸基、 羟基 C1-C10垸基、 氨基 C1-C10烷基、 C6-C10芳基 C1-C10垸基、 =0 (氧代)、 = s (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳 R 10 is hydrogen, halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C10 alkoxy, C6-C10 aryloxy, C1-C10 nonanoyloxy, -C(O OCl-C10 fluorenyl, -C(0)NH 2 , C1-C10 decanoyl, C1-C10 decylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 fluorenyl, hydroxy C1-C10 fluorenyl, amino C1-C10 alkyl, C6-C10 aryl C1-C10 fluorenyl, =0 (oxo), = s (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6-C10
Ph  Ph
基、 4-10元杂环酰基、 4-10元杂芳酰基或一 COB ; 上述氨基、 C1-C10垸氧基、 C6-C10 芳氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10垸基、 -C(0)NH2、、 C1-C10垸酰基、 C1-C10垸 基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、、 C6-C10芳酰基、 C1-C10垸 基、 羟基 C1-C10烷基、 氨基 C1-C10烷基、 C6-C10芳基 C1-C10垸基、 C6-C10芳基、 4-10 元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰 a 4-10 membered heterocyclic acyl group, a 4-10 membered heteroaroyl group or a COB; the above amino group, C1-C10 decyloxy group, C6-C10 aryloxy group, C1-C10 alkanoyloxy group, -C(O) OCl-C10 fluorenyl, -C(0)NH 2 , C1-C10 decanoyl, C1-C10 decylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 fluorenyl, hydroxy C1-C10 alkyl, amino C1-C10 alkyl, C6-C10 aryl C1-C10 fluorenyl, C6-C10 aryl, 4- 10 membered heterocyclic group, 4-10 membered heteroaryl group, 4-10 membered heterocyclic group or 4-10 membered heteroaryl and C6-C10 aryl group, 4-10 membered heterocyclic acyl group
Ph  Ph
基、 4-10元杂芳酰基或一^ -COB可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝 基、 -NR15R16、、腈基、羧基、 C1-C10烷氧基、 C6-C10芳氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10 垸基、 -C(0)NR15R16、 C1-C10垸酰基、 C1-C10烷基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C10院基、羟基 C1-C10烷基、氨基 C1-C10焼基、 C6-C10 芳基 C1-C10垸基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取 代基取代； The base, 4-10 membered heteroaroyl or mono-COB may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile, carboxyl, C1 -C10 alkoxy, C6-C10 aryloxy, C1-C10 alkanoyloxy, -C(O)OCl-C10 fluorenyl, -C(0)NR 15 R 16 , C1-C10 decanoyl, C1- C10 alkylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10, hydroxy C1-C10 alkyl, amino C1-C10 fluorenyl, C6-C10 aryl C1-C10 fluorenyl, =0 (oxo), =S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered Substituted with an aryl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, a C6-C10 aryl group, a 4-10 membered heterocyclic acyl group, and a 4-10 membered heteroaroyl group;
R15、 R16各自独立地为 H; C1-C10烷基； C3-C10环烷基； 4-10元杂环基； 4-10元杂芳 基； 或者 R15、 R16与连接它们的 N原子一起形成 4-10元杂环基； 4-10元杂芳基； 其中， 所 述 C1-C10烷基、 C3-C10环烷基、 4-10元杂环基和 4-10元杂芳基可非必须地被 1个或多个 卤素； 羟基； 腈基； 氨基； C1-C10烷基； =0 (氧代)； =S (硫代)； C1-C10垸氧基取代； 在另一优选例中， 通式 I所示的 β-氨基羰基类化合物还具有以下一个或多个特征：R 15 and R 16 are each independently H; C1-C10 alkyl; C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and attached thereto The N atoms together form a 4-10 membered heterocyclic group; a 4-10 membered heteroaryl group; wherein, the C1-C10 alkyl group, the C3-C10 cycloalkyl group, the 4-10 membered heterocyclic group, and the 4-10 membered heterocyclic group; An aryl group may optionally be substituted by one or more halogens; a hydroxyl group; a nitrile group; an amino group; a C1-C10 alkyl group; =0 (oxo); =S (thio); a C1-C10 decyloxy group; In another preferred embodiment, the β-aminocarbonyl compound represented by Formula I further has one or more of the following characteristics:
(1) Α为苯基、 吡啶基或环戊二烯基； (1) Α is phenyl, pyridyl or cyclopentadienyl;
(2) 、 R2、 R3和 R4各自独立地为 H、 卤素、 三氟甲基、 羟基、 腈基、 氨基、 C1-C10 焼基； (2), R 2 , R 3 and R 4 are each independently H, halogen, trifluoromethyl, hydroxy, nitrile, amino, C1-C10 fluorenyl;
(3) W为 CH;  (3) W is CH;
(4) Q为 C;  (4) Q is C;
(5) 1 8为-(0¾)„¾2; 其中， 1 12为11、 卤素、 C1-C10院基； q为 0-4的整数； m为 0-5 的整数; (5) 1 8 is -(03⁄4)„3⁄4 2; wherein, 1 12 is 11, halogen, C1-C10 yard base; q is an integer of 0-4; m is an integer of 0-5;
(6) Y为 CR7， 其中， R7为 -(CH2)mRu， ！^为11、 卤素， m为 0-5的整数。 (6) Y is CR 7 , where R 7 is -(CH 2 ) m R u , ! ^ is 11, halogen, m is an integer from 0-5.
在所述通式 I中， 通式 I所示的化合物优选为通式 IA所示的化合物：
Figure imgf000009_0001
In the above formula I, the compound of the formula I is preferably a compound of the formula IA:
Figure imgf000009_0001
其中， R,、 R2、 R3、 R4、 R5、 Re、 R8、 X和 q的定义同其在通式 I中的定义； Wherein R, R 2 , R 3 , R 4 , R 5 , Re, R 8 , X and q are as defined in the formula I;
R7为 -(CH2)mRn、 -(CH2)mO(CH2)n „或 -(C¾)mNHR„； R 7 is -(CH 2 ) m R n , -(CH 2 ) m O(CH 2 ) n „ or -(C3⁄4) m NHR„;
其中， Rn为 H; 卤素； 硝基； 腈基； 羧基； -C(0)0C1-C4烷基； C2-C4烯基； C2-C4 炔基； C1-C4垸酰基； C1-C4垸基磺酰基； 氨基 C1-C4垸酰基； C1-C4烷基； C6-C10芳基； 4-10元杂环基；或 4-10元杂芳基；上述 -C(0)0C1-C4烷基、 C2-C4烯基、 C2-C4炔基、 C1-C4 垸酰基、 C1-C4烷基磺酰基、 氨基 C1-C4垸酰基、 C1-C4烷基、 C6-C10芳基、 4-10元杂环 基或 4-10元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈 基、 羧基、 C1-C4烷氧基、 C1-C4烷酰氧基、 -C(0)0C1-C4垸基、 C1-C4烷酰基、 C1-C4烷 基磺酰基、 =0 (氧代)、 =S (硫代)、 C1-C4烷基中的取代基取代； Wherein R n is H; halogen; nitro; nitrile; carboxyl; -C(0)0C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 nonanoyl; C1-C4垸Alkylsulfonyl; amino C1-C4 decanoyl; C1-C4 alkyl; C6-C10 aryl; 4-10 membered heterocyclic; or 4-10 membered heteroaryl; above -C(0)0C1-C4 , C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 decanoyl, C1-C4 alkylsulfonyl, amino C1-C4 decanoyl, C1-C4 alkyl, C6-C10 aryl, 4-10 The heterocyclic group or the 4-10 membered heteroaryl group may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxyl, C1-C4 alkoxy, C1. -C4 alkanoyloxy, -C(0)0C1-C4 fluorenyl, C1-C4 alkanoyl, C1-C4 alkylsulfonyl, =0 (oxo), =S (thio), C1-C4 alkane a substituent in the group;
其中， m和 n各自独立地为 0-5的整数。  Wherein m and n are each independently an integer of 0-5.
在所述通式 I中， 通式 IA所示的化合物进一步优选为通式 IB所示的化合物：  In the above formula I, the compound represented by the formula IA is further preferably a compound represented by the formula IB:
Figure imgf000009_0002
Figure imgf000009_0002
其中，  among them,
X为 N或 CR7; X is N or CR 7 ;
Ri, R2、 R3和 R4各自独立地优选为 H; 卤素； 三氟甲基； 羟基； 硝基； 腈基； 羧基； -C(0)0C1-C4垸基； 氨基； C1-C4烷氧基； C1-C4烷基； C1-C4垸酰基； C1-C4烷酰氧基； 磺酰基； 或 C1-C4垸基磺酰基； 上述 -C(0)0C1-C4烷基、氨基、 C1-C4垸氧基、 C1-C4烷基、 C1-C4垸酰基、 C1-C4烷酰氧基、磺酰基或 C1-C4烷基磺酰基可非必须地被一个或多个选自 卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C4垸基、 C1-C4垸氧基、 C1-C4烷 酰氧基、 -C(0)OCl-C4烷基、 C1-C4烷酰基、 磺酰基、 C1-C4垸基磺酰基、 苯基和苯甲基中 的取代基取代； Ri, R 2 , R 3 and R 4 are each independently preferably H; halogen; trifluoromethyl; hydroxy; nitro; nitrile; carboxy; -C(0)0C1-C4 fluorenyl; amino; C1-C4 alkane氧基; C1-C4 alkyl; C1-C4 decanoyl; C1-C4 alkanoyloxy; sulfonyl; or C1-C4 mercaptosulfonyl; above -C(0)0C1-C4 alkyl, amino, C1 -C4 methoxy, C1-C4 alkyl, C1-C4 decanoyl, C1-C4 alkanoyloxy, sulfonyl or C1-C4 alkylsulfonyl may be optionally selected from one or more selected from the group consisting of halogen, Fluoromethyl, hydroxy, nitro, amino, nitrile, carboxyl, C1-C4 fluorenyl, C1-C4 decyloxy, C1-C4 alkanoyloxy, -C(0)OCl-C4 alkyl, C1- Substituted with a substituent in a C4 alkanoyl group, a sulfonyl group, a C1-C4 decylsulfonyl group, a phenyl group, and a benzyl group;
R5和 Re各自独立地为 -(CH2)mR9; -(CH2)mCO(CH2)nR9; 或 -[(CH^C^H, 其中 i=l~5的 整数， j=l~3的整数， 为11； 卤素； 羟基； 硝基； 氨基； 腈基； 羧基； -C(0)OCl-C4垸基； C1-C4垸酰基； C1-C4垸基磺酰基； C1-C4垸基； C2-C4烯基； C2-C4炔基； C3-C10环垸基； C3-C8内酰胺基； C1-C4烷氨基磺酰基； C1-C4垸氨酰基； C6-C10芳酰基； C1-C4烷氧基； C6-C10芳基磺酰基、 -S02 R15R16、 -NR15S02R16; C6-C10芳基； 4-10元杂环基； 4-10元杂 芳基； 4-10元杂环基或 4-10元杂芳基并 C3-C8环烃基； 或者 4-10元杂环基或 4-10元杂芳 基并 4-10元杂环基或 4-10元杂芳基； 上述氨基、 -C(0)0C1-C4垸基、 C1-C4烷酰基、 C1-C4 烷基磺酰基、 C1-C4烷基、 C2-C4烯基、 C2-C4炔基、 C3-C10环烷基、 C3-C8内酰胺基、R 5 and Re are each independently -(CH 2 ) m R 9; -(CH 2 ) m CO(CH 2 ) n R 9 ; or -[(CH^C^H, where i=l~5 integer , j=l~3, an integer of 11; halogen; hydroxy; nitro; amino; nitrile; carboxy; -C(0)OCl-C4 fluorenyl; C1-C4 decanoyl; C1-C4 decylsulfonyl ; C1-C4 fluorenyl; C2-C4 alkenyl; C2-C4 alkynyl; C3-C10 cyclodecyl; C3-C8 lactam; C1-C4 alkylaminosulfonyl; C1-C4 valyl; C6-C10 aroyl; C1-C4 alkoxy; C6-C10 arylsulfonyl, -S0 2 R 15 R 16 -NR 15 S0 2 R 16; C6-C10 aryl; 4-10 membered heterocyclic group; 4-10 membered heteroaryl; 4-10 membered heterocyclic group or 4-10 membered heteroaryl group and C3-C8 a cycloalkyl group; or a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group; the above amino group, -C(0)0C1-C4 fluorenyl group, C1-C4 alkanoyl, C1-C4 alkylsulfonyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C10 cycloalkyl, C3-C8 lactam,
C1-C4烷氨基磺酰基、 C1-C4烷氨酰基、 C6-C10芳酰基、 C1-C4垸氧基、 C6-C10芳基磺酰 基、 -S02 R15R16、 -NR15S02R16、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂 环基或 4-10元杂芳基并 C3-C8环烃基或者 4-10元杂环基或 4-10元杂芳基并 4-10元杂环基 或 4-10元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 -NR15R16、 腈 基、 羧基、 C1-C4烷氧基、 -C(0)OCl-C4垸基、 -C(0)NR15R16、 C1-C4烷酰基、 C1-C4烷基 磺酰基、 -S02NR15R16、 -NR15S02R16、 C1 -C4烷基、羟基 C1-C4垸基、氨基 C1-C4垸基、 C6-C10 芳基 C1-C4垸基、 =0 (氧代)、 = S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取 代基取代； 上述 C6-C10芳基、 C6-C10芳酰基和 C6-C10芳基磺酰基可非必须地被一个或多 个选自卤素、 三氟甲基、 羟基、 硝基、 -NR15R16、 腈基、 羧基、 C1-C4垸氧基、 C1-C4烷酰 氧基、 -C(0)OCl-C4烷基、 -C(0)NR15R16、 C1-C4垸酰基、 C1-C4垸基磺酰基、 C6-C10芳基 磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C4垸基、 羟基 C1-C4烷基、 氨基 C1-C4垸基和 C6-C10芳基 C1-C4烷基中的取代基取代； C1-C4 alkylaminosulfonyl, C1-C4 alkanoyl, C6-C10 aroyl, C1-C4 decyloxy, C6-C10 arylsulfonyl, -S0 2 R 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C3-C8 cycloalkyl or 4-10 membered A heterocyclic group or a 4-10 membered heteroaryl and 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile group, carboxyl group, C1-C4 alkoxy group, -C(0)OCl-C4 fluorenyl group, -C(0)NR 15 R 16 , C1-C4 alkanoyl group, C1-C4 alkyl group Sulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C1 -C4 alkyl, hydroxy C1-C4 fluorenyl, amino C1-C4 fluorenyl, C6-C10 aryl C1-C4 fluorenyl, =0 (oxo), = S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl Substituted with a substituent in a C6-C10 aryl group, a 4-10 membered heterocyclic acyl group and a 4-10 membered heteroaroyl group; the above C6-C10 aryl group, C6-C10 aroyl group and C6-C10 aryl sulfonyl group Optionally, one or more selected from halogen Trifluoromethyl, hydroxy, nitro, -NR 15 R 16, nitrile, carboxyl, C1-C4 alkoxy embankment, C1-C4 alkanoyloxy, -C (0) OCl-C4 alkyl, -C ( 0) NR 15 R 16 , C1-C4 decanoyl group, C1-C4 decylsulfonyl group, C6-C10 arylsulfonyl group, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl group a substituent in the C1-C4 fluorenyl group, a hydroxy C1-C4 alkyl group, an amino C1-C4 fluorenyl group, and a C6-C10 aryl C1-C4 alkyl group;
或者， R5和 与连接它们的 X—起形成 C6-C10芳基； C3-C10环烃基； C3-C10环烃 基并 C3-C10环烃基； C3-C10环烃基并 C6-C10芳基； C6-C10芳基并 C3-C10环烃基； 4-10 元杂环基； 4-10元杂芳基； 4-10元杂环基螺环； 4-10元杂芳基螺环； 4-10元杂环基或 4-10 元杂芳基并 C3-C10环烃基； C3-C10环烃基并 4-10元杂环基或 4-10元杂芳基； 4-10元杂环 基或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基； C6-C10芳基并 4-10元杂环基或 4-10 元杂芳基； 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基； [4-10元杂环基或 4-10元杂芳基] 并 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]; 或者 [4-10元杂环基 或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]并 [C6-C10芳基]; 上述基团可非必须地 被一个或多个 R'取代， R'选自 -(CH2)mR1() ; -(CH2)mCO(CH2)„R10 ; -(CH2)mO(CH2)„R10； -(CH2)m HC(O)(CH2)„R10; 和 -(CH2)mNSO2(C¾)nR10; Or, R 5 and X-linked to form a C6-C10 aryl group; C3-C10 cycloalkyl; C3-C10 cycloalkyl and C3-C10 cycloalkyl; C3-C10 cycloalkyl and C6-C10 aryl; C6 -C10 aryl and C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; 4-10 membered heterocyclyl spiro; 4-10 membered heteroaryl spiro; 4-10 a heterocyclic or 4-10 membered heteroaryl and C3-C10 cycloalkyl; C3-C10 cycloalkyl and 4-10 membered heterocyclic or 4-10 membered heteroaryl; 4-10 membered heterocyclyl or 4 -10 membered heteroaryl and 4-10 membered heterocyclic group or 4-10 membered heteroaryl; C6-C10 aryl and 4-10 membered heterocyclic group or 4-10 membered heteroaryl; 4-10 membered hetero a cyclic or 4-10 membered heteroaryl and C6-C10 aryl; [4-10 membered heterocyclic or 4-10 membered heteroaryl] and [4-10 membered heterocyclic or 4-10 membered heteroaryl) And [4-10 membered heterocyclic or 4-10 membered heteroaryl]; or [4-10 membered heterocyclyl or 4-10 membered heteroaryl] and [4-10 membered heterocyclyl or 4 -10 membered heteroaryl] and [C6-C10 aryl]; the above group may be optionally substituted by one or more R', and R' is selected from -(CH 2 ) m R 1(); -(CH 2 ) m CO(CH 2 )„R 10 ; —(CH 2 ) m O(CH 2 )„R 10 ; —(CH 2 ) m HC(O)(CH 2 )„R 10 ; and —(CH 2 ) m NSO 2 (C3⁄4) n R 10;
其中， Ru)为氢、 卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C4垸氧基、 C6-C10芳氧基、 C1-C4烷酰氧基、 -C(0)0C1-C4垸基、 -C(0)NH2、 C1-C4垸酰基、 C1-C4 院基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C4垸 基、羟基 C1-C4烷基、氨基 C1-C4烷基、 C6-C10芳基 C1-C4垸基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳 Wherein Ru) is hydrogen, halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C4 decyloxy, C6-C10 aryloxy, C1-C4 alkanoyloxy, -C (0) 0C1-C4 fluorenyl, -C(0)NH 2 , C1-C4 decanoyl, C1-C4 sulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C4 fluorenyl, hydroxy C1-C4 alkyl, amino C1-C4 alkyl, C6-C10 aryl C1-C4 fluorenyl, =0 (oxo), = S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6-C10
Ph  Ph
基、 4-10元杂环酰基、 4-10元杂芳酰基或一^-COEt ; 上述氨基、 C1_C4垸氧基、 C6-C10芳 氧基、 C1-C4烷酰氧基、 -C(0)0C1-C4垸基、 -C(0)NH2、、 C1-C4烷酰基、 C1-C4烷基磺酰 基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C4烷基、 羟基 C1-C4垸基、氨基 C1-C4垸基、 C6-C10芳基 C1-C4烷基、 C6-C10芳基、 4-10元杂环基、 4-10 元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基、 4-10元杂芳 P Group, a 4-10 membered heterocyclic group, 4-10 membered heteroaryl, or a group ^ -COEt; of the amino, C1 _C4 embankment group, C6-C10 aryloxy group, C1-C4 alkanoyloxy, -C ( 0) 0C1-C4 fluorenyl, -C(0)NH 2 , C1-C4 alkanoyl, C1-C4 alkylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C4 alkyl, hydroxy C1-C4 fluorenyl, amino C1-C4 fluorenyl, C6-C10 aryl C1-C4 alkyl, C6-C10 aryl, 4- 10 membered heterocyclic group, 4-10 membered heteroaryl group, 4-10 membered heterocyclic group or 4-10 membered heteroaryl group and C6-C10 aryl group, 4-10 membered heterocyclic acyl group, 4-10 membered heteroaryl group P
酰基或一^ -COB可非必须地被一个或多个选自卤素、三氟甲基、羟基、 硝基、 -NR15R16、 腈 基、羧基、 C1-C4烷氧基、 C6-C10芳氧基、 C1-C4垸酰氧基、 -C(0)0C1-C4垸基、 -C(0)NR15R16、 C1-C4烷酰基、 C1-C4烷基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10 芳酰基、 C1-C4垸基、羟基 C1-C4烷基、氨基 C1-C4垸基、 C6-C10芳基 C1-C4烷基、 = 0 (氧 代)、 = S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂 芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取代基取代； The acyl group or the mono-COB may optionally be one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile, carboxyl, C1-C4 alkoxy, C6-C10 Aryloxy, C1-C4 nonanoyloxy, -C(0)0C1-C4 fluorenyl, -C(0)NR 15 R 16 , C1-C4 alkanoyl, C1-C4 alkylsulfonyl, C6-C10 Arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C4 fluorenyl, hydroxy C1-C4 alkyl, amino C1-C4 decyl, C6-C10 Aryl C1-C4 alkyl, = 0 (oxo), = S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic Substituted or substituted with a 4-10 membered heteroaryl and C6-C10 aryl group, a 4-10 membered heterocyclic acyl group and a 4-10 membered heteroaroyl group;
Ris、 Ri6各自独立地为 H; C1-C4烷基； C3-C10环烷基； 4-10元杂环基； 4-10元杂芳 基； 或者 R15、 R16与连接它们的 N原子一起形成 4-10元杂环基； 4-10元杂芳基； 其中， 所 述 C1-C4烷基、 C3-C10环垸基、 4-10元杂环基和 4-10元杂芳基可非必须地被 1个或多个卤 素； 羟基； 腈基； 氨基； C1-C4烷基； = 0 (氧代)； = S (硫代)； C1-C4烷氧基取代； Ris, Ri 6 are each independently H ; C1-C4 alkyl; C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and N attached thereto The atoms together form a 4-10 membered heterocyclic group; a 4-10 membered heteroaryl group; wherein, the C1-C4 alkyl group, the C3-C10 cyclodecyl group, the 4-10 membered heterocyclic group, and the 4-10 membered heteroaryl group; The group may be optionally substituted by one or more halogens; a hydroxyl group; a nitrile group; an amino group; a C1-C4 alkyl group; = 0 (oxo); = S (thio); a C1-C4 alkoxy group;
R7为 -(CH2)mRu、 -(CH2)mO(CH2)nR„或 -(CH2)mNHR„； R 7 is -(CH 2 ) m R u , -(CH 2 ) m O(CH 2 ) n R„ or -(CH 2 ) m NHR„;
其中， Ru为 H; 卤素； 硝基； 腈基； 羧基； -C(0)OCl-C4烷基； C2-C4烯基； C2-C4 炔基； C1-C4烷酰基； C1-C4烷基磺酰基； 氨基 C1-C4垸酰基； C1-C4浣基； C6-C10芳基； 4-10元杂环基；或 4-10元杂芳基；上述 -C(0)0C1-C4垸基、 C2-C4烯基、 C2-C4炔基、 C1-C4 烷酰基、 C1-C4垸基磺酰基、 氨基 C1-C4烷酰基、 C1-C4烷基、 C6-C10芳基、 4-10元杂环 基或 4-10元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈 基、 羧基、 C1-C4垸氧基、 C1-C4烷酰氧基、 -C(0)0C1-C4垸基、 C1-C4烷酰基、 C1-C4垸 基磺酰基、 =0 (氧代)、 = S (硫代)和 C1-C4垸基中的取代基取代； Wherein R u is H; halogen; nitro; nitrile; carboxyl; -C(0)OCl-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkanoyl; C1-C4 alkane Alkylsulfonyl; amino C1-C4 decanoyl; C1-C4 fluorenyl; C6-C10 aryl; 4-10 membered heterocyclic; or 4-10 membered heteroaryl; above -C(0)0C1-C4垸, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkanoyl, C1-C4 nonylsulfonyl, amino C1-C4 alkanoyl, C1-C4 alkyl, C6-C10 aryl, 4-10 The heterocyclic or 4-10 membered heteroaryl may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C4 decyloxy, C1. -C4 alkanoyloxy, -C(0)0C1-C4 fluorenyl, C1-C4 alkanoyl, C1-C4 decylsulfonyl, =0 (oxo), =S (thio) and C1-C4垸a substituent in the group;
Rs为 -(CH2)mR12、 -(CH2)mO(CH2)n 12或 -(CH2)m HR12; Rs is -(CH 2 ) m R 12 , -(CH 2 ) m O(CH 2 ) n 12 or -(CH 2 ) m HR 12;
其中， R12优选为 H; 卤素； 硝基； 腈基； 羧基； =〇（氧代)； = S (硫代)； -C(0)OCl-C4 垸基； C2-C4烯基； C2-C4炔基； C1-C4烷酰基； C1-C4垸基磺酰基； 氨基 C1-C4烷酰基； Wherein R 12 is preferably H; halogen; nitro; nitrile; carboxyl; = oxime (oxo); = S (thio); -C(0)OCl-C4 fluorenyl; C2-C4 alkenyl; -C4 alkynyl; C1-C4 alkanoyl; C1-C4 mercaptosulfonyl; amino C1-C4 alkanoyl;
C1-C4烷基； Ph(CH2)m-; ；
Figure imgf000011_0001
； 4-10元杂环基；或 4-10元杂芳基；上述 -C(0)OCl-C4 垸基、 C2-C4烯基、 C2-C4炔基、 C1-C4垸酰基、 C1-C4烷基磺酰基、 氨基 C1-C4垸酰基、 C1-C4 alkyl; Ph(CH 2 ) m - ; ;
Figure imgf000011_0001
4-10 membered heterocyclic group; or 4-10 membered heteroaryl; above -C(0)OCl-C4 fluorenyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 decanoyl, C1- C4 alkylsulfonyl, amino C1-C4 decanoyl,
s、  s,
C1-C4烷基、 Ph(CH2)m -、 、 0 ^、 4-10元杂环基或 4-10元杂芳基可非必须地被一个 或多个选自卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C4烷氧基、 C1-C4垸酰 氧基、 -C(0)OCl-C4烷基、 C1-C4垸酰基、 C1-C4院基磺酰基、 = 0 (氧代)、 = S (硫代)和 C1-C4烷基中的取代基取代； R12进一步优选为 H; 卤素； = 0 (氧代)； C1-C4垸酰基； C1-C4 烷基； Ph(CH2)m -; s^ . °^ ; 吲哚； 二氢吲哚； 吡咯； 呋喃； 噻吩； 噻唑； 咪唑； 噁 唑； 异噁唑； 吡唑； 吡啶； 吡嗪； 嘧啶； 哒嗪； 吡喃； 吲哚； 或喹啉； R1()更优选为 H; 卤 素； = 0 (氧代)； C1-C4烷基； 苯基； 苄基； s^ ; °^ , B引噪； 二氢吲哚； 或吡咯； R12 最优选为 H; A C1-C4 alkyl group, a Ph(CH 2 ) m -, , 0 ^, 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group may be optionally selected from one or more selected from the group consisting of halogen and trifluoromethyl. , hydroxy, nitro, amino, nitrile, carboxyl, C1-C4 alkoxy, C1-C4 nonanoyloxy, -C(0)OCl-C4 alkyl, C1-C4 decanoyl, C1-C4 Substituted by a substituent in the sulfonyl group, = 0 (oxo), = S (thio) and a C1-C4 alkyl group; R 12 is further preferably H; halogen; = 0 (oxo); C1-C4 nonanoyl; C1-C4 alkyl; Ph (CH 2) m - ;. s ^ ° ^; indole; indoline; pyrrole; furyl; thienyl; thiazole; imidazole; oxazolyl; isoxazolyl; pyrazole; pyridine; Pyrazine; pyrimidine; pyridazine; pyran; hydrazine; or quinoline; R 1 ( ) is more preferably H; halogen; = 0 (oxo); C1-C4 alkyl; phenyl; benzyl; ; ° ^ , B noise extraction; dihydroanthracene; or pyrrole; R 12 is most preferably H;
m和 n各自独立地优选为 0-3的整数； 最优选为 0、 1或 2; q优选为 0-2的整数。  m and n are each independently preferably an integer of 0 to 3; most preferably 0, 1 or 2; q is preferably an integer of 0 to 2.
在所述通式 I、 通式 IA或通式 IB所示的化合物中，
Figure imgf000012_0001
In the compound of the formula I, formula IA or formula IB,
Figure imgf000012_0001
其中， 在 R! R2 R3 R4 R5 R7 R8 R9 R10 Rii和 R12的定义中， 优选地， 所述 C1-C10垸基优选为甲基； 乙基； 丙基； 异丙基； 丁基； 异丁基或叔丁基； 所述 C6-C10芳基优选苯基； Wherein, in the definition of R! R 2 R 3 R 4 R 5 R 7 R 8 R 9 R 10 Rii and R12, preferably, the C1-C10 fluorenyl group is preferably a methyl group; an ethyl group; a propyl group; Butyl; isobutyl or tert-butyl; the C6-C10 aryl is preferably phenyl;
所述 C  Said C
Figure imgf000012_0002
Figure imgf000012_0002
所述 4-10元杂环基或 4-10元杂芳基含有 1-4个选自 N S和 0的杂原子， 优选为以下 基团  The 4-10 membered heterocyclic group or 4-10 membered heteroaryl group contains 1 to 4 hetero atoms selected from N S and 0, preferably the following groups
Figure imgf000012_0003
Figure imgf000012_0003
所述 4-10元杂环基螺环或杂芳基螺环优选为以下基团:
Figure imgf000012_0004
The 4-10 membered heterocyclyl spiro or heteroaryl spiro is preferably the group:
Figure imgf000012_0004
所述 [4-10元杂环基或 4-10元杂芳基]并 [C3-C10环烃基]或者 [C3-C10环烃基]并 [4-10元 杂环基或 4-10元杂芳基]优选为以下基团： The [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [C3-C10 cycloalkyl] or [C3-C10 cycloalkyl][4-10 membered heterocyclic or 4-10 membered hetero The aryl group is preferably the following group:
Figure imgf000013_0001
Figure imgf000013_0001
所述 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]优选为以下基
Figure imgf000013_0002
The [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [4-10 membered heterocyclic group or 4-10 membered heteroaryl group] is preferably the following group
Figure imgf000013_0002
所述 [4-10元杂环基或 4-10元杂芳基]并 [C6-C10芳基]或者 [C6-C10芳基]并 [4-10元杂环
Figure imgf000013_0003
The [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [C6-C10 aryl] or [C6-C10 aryl] and [4-10 membered heterocyclic ring
Figure imgf000013_0003
所述 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环
Figure imgf000013_0004
所述 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]并 [C6-C10芳基] The [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [4-10 membered heterocyclic ring]
Figure imgf000013_0004
The [4-10 membered heterocyclic group or 4-10 membered heteroaryl]and [4-10 membered heterocyclic group or 4-10 membered heteroaryl][C6-C10 aryl]
Figure imgf000014_0001
Figure imgf000014_0001
上述各环可通过环上任意位置与其他基团相连，也可以在任意位置被如上所定义的取代 基所取代。  Each of the above rings may be bonded to another group at any position on the ring, or may be substituted at any position by a substituent as defined above.
在所述通式 I中， 通式 IA或 IB所示的化合物更进一步优选为通式 IA-1、 IA-2、 IA-3、  In the above formula I, the compound represented by the formula IA or IB is still further preferably of the formula IA-1, IA-2, IA-3,
Figure imgf000014_0002
Figure imgf000014_0002
其中， Z为 N原子或 C原子；  Wherein Z is a N atom or a C atom;
Ri> R2、 R3和 R4各自独立地更优选为 H; F; CI; Br; 三氟甲基； 羟基； 腈基； 氨基； C1-C4垸氧基； C1-C4院基； 或 C1-C4烷酰基； 最优选为 H或卤素； Ri> R 2 , R 3 and R 4 are each independently more preferably H; F; CI; Br; trifluoromethyl; hydroxy; nitrile; amino; C1-C4 decyloxy; C1-C4, or C1; -C4 alkanoyl; most preferably H or halogen;
Ri和 R4最优选为 H， R2和 R3最优选为 F; Ri and R4 are most preferably H, and R 2 and R 3 are most preferably F;
R，为 -(CH2)mR10; -(CH2)mCO(CH2)nR10; -(CH2)mO(CH2)n 10; -(CH2)m HC(O)(CH2)„R,0; 或 -(CH2)mNSO2(CH2)nR10; m优选为 0-3的整数； 最优选为 0、 1或 2; R, is -(CH 2 ) m R 10; -(CH 2 ) m CO(CH 2 ) n R 10 ; -(CH 2 ) m O(CH 2 ) n 10 ; -(CH 2 ) m HC(O (CH 2 ) „ R, 0 ; or —(CH 2 ) m NSO 2 (CH 2 ) n R 10; m is preferably an integer from 0 to 3; most preferably 0, 1 or 2;
其中， 所述 Ru)更优选为氢、 卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C4 垸氧基、 苯氧基、 C1-C4垸酰氧基、 -C(0)0C1-C4垸基、 -C(0)NH2、 C1-C4垸酰基、 C1-C4 垸基磺酰基、 苯磺酰基、 苯甲酰基、 C1-C4烷基、 羟基 C1-C4烷基、 氨基 C1-C4垸基、 苄 基、 =θ (氧代)、 =S (硫代)、 苯基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10 Wherein, the Ru) is more preferably hydrogen, halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C4 decyloxy, phenoxy, C1-C4 nonanoyloxy, - C(0)0C1-C4 fluorenyl, -C(0)NH 2 , C1-C4 decanoyl, C1-C4 decylsulfonyl, phenylsulfonyl, benzoyl, C1-C4 alkyl, hydroxy C1-C4 Alkyl, amino C1-C4 fluorenyl, benzyl Base, =θ (oxo), =S (thio), phenyl, 4-10 membered heterocyclyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl or 4-10
Ph  Ph
元杂芳基并 C6-C10芳基、 4-10元杂环酰基、 4-10元杂芳酰基或一 - COEt；上述氨基、 C1-C4 垸氧基、 苯氧基、 C1-C4垸酰氧基、 -C(0)0C1-C4烷基、 -C(0)NH2、 C1-C4烷酰基、 C1-C4 垸基磺酰基、 苯磺酰基、 苯甲酰基、 C1-C4烷基、 羟基 C1-C4垸基、 氨基 C1-C4 '垸基、 苄 基、 =0 (氧代)、 =S (硫代)、 苯基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10 a heteroaryl group and a C6-C10 aryl group, a 4-10 membered heterocyclic acyl group, a 4-10 membered heteroaroyl group or a mono-COEt; the above amino group, C1-C4 decyloxy group, phenoxy group, C1-C4 decanoyl group Oxy, -C(0)0C1-C4 alkyl, -C(0)NH 2 , C1-C4 alkanoyl, C1-C4 decylsulfonyl, phenylsulfonyl, benzoyl, C1-C4 alkyl, Hydroxy C1-C4 fluorenyl, amino C1-C4 'fluorenyl, benzyl, =0 (oxo), =S (thio), phenyl, 4-10 membered heterocyclyl, 4-10 membered heteroaryl 4-10 membered heterocyclic group or 4-10
Ph  Ph
元杂芳基并 C6-C10芳基、 4-10元杂环酰基、 4-10元杂芳酰基或一 -COEt可非必须地被一 个或多个选自卤素、三氟甲基、羟基、硝基、 -NR15R16、腈基、羧基、 C1-C4烷氧基、 C6-C10 芳氧基、 C1-C4烷酰氧基、 -C(0)0C1-C4烷基、 -C(0)NR15R16、 C1-C4烷酰基、 C1-C4垸基 磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C4垸基、 羟基 C1-C4烷基、 氨基 C1-C4垸基、 C6-C10芳基 C1-C4垸基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳 基、 4-10元杂环酰基和 4-10元杂芳酰基中的取代基取代； The heteroheteroaryl-C6-C10 aryl group, the 4-10 membered heterocyclic acyl group, the 4-10 membered heteroaroyl group or the mono-COEt may optionally be one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, Nitro, -NR 15 R 16 , nitrile group, carboxyl group, C1-C4 alkoxy group, C6-C10 aryloxy group, C1-C4 alkanoyloxy group, -C(0)0C1-C4 alkyl group, -C( 0) NR 15 R 16 , C1-C4 alkanoyl group, C1-C4 decylsulfonyl group, C6-C10 arylsulfonyl group, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl group , C1-C4 fluorenyl, hydroxy C1-C4 alkyl, amino C1-C4 fluorenyl, C6-C10 aryl C1-C4 fluorenyl, =0 (oxo), =S (thio), C6-C10 aryl a 4-10 membered heterocyclyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl or 4-10 membered heteroaryl and C6-C10 aryl, 4-10 membered heterocyclic acyl and 4- Substituent substitution in a 10-membered heteroaroyl;
R15、 R16各自独立地为 H; C1-C4垸基； C3-C10环垸基； 4-10元杂环基； 4-10元杂芳 基； 或者 R15、 R16与连接它们的 N原子一起形成 4-10元杂环基； 4-10元杂芳基； 其中， 所 述 C1-C4垸基、 C3-C10环垸基、 4-10元杂环基和 4-10元杂芳基可非必须地被 1个或多个卤 素； 羟基； 腈基； 氨基； C1-C4垸基； =0 (氧代)； =S (硫代)； C1-C4烷氧基取代； R 15 and R 16 are each independently H; C1-C4 fluorenyl; C3-C10 cyclodecyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and attached thereto The N atoms together form a 4-10 membered heterocyclic group; a 4-10 membered heteroaryl group; wherein, the C1-C4 fluorenyl group, the C3-C10 cyclodecyl group, the 4-10 membered heterocyclic group, and the 4-10 membered heterocyclic group; The aryl group may optionally be substituted by one or more halogens; a hydroxyl group; a nitrile group; an amino group; a C1-C4 alkyl group; =0 (oxo); =S (thio); a C1-C4 alkoxy group;
其中， 通式 IA-1或 IB-1所示的化合物中， R，最优选为 H; F; CI; Br或三氟甲基， 或者通式 I、 通式 I 4所示的化合物：  Wherein, in the compound of the formula IA-1 or IB-1, R is most preferably H; F; CI; Br or trifluoromethyl, or a compound of the formula I, formula I:
Figure imgf000015_0001
Figure imgf000015_0001
其中， R 、 R2、 R3和 R4定义同其在通式 IA-1中的定义； Wherein R, R 2 , R 3 and R4 are as defined in the formula IA-1;
R5和 R6各自独立地为 -(CH2)mR9; -(CH2)mCO(CH2)„R9; 或 -[(CI¾C¾H， 其中 i=l~5的整 数， j=l~3的整数， R9更优选为 H; 羟基； 腈基； C2-C4烯基； C6-C10芳酰基； C6-C10芳 基； 4-10元杂环基; 4-10元杂芳基； 4-10元杂环基或 4-10元杂芳基并 C3-C8环烃基； 或者 4-10元杂环基或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基；上述 C2-C4烯基、 C6-C10 芳酰基、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C3-C8环烃基或者 4-10元杂环基或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基可非必 须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 -NR15R16、 腈基、 羧基、 C1-C4烷氧 基、 -C(0)0C1-C4烷基、 -C(0)NRi5R16、 C1-C4垸酰基、 C1-C4烷基磺酰基、 -S02NR15R16、 -NR15S02R16、 C1-C4垸基、 羟基 C1-C4烷基、 氨基 C1-C4垸基、 C6-C10芳基 C1-C4烷基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10 元杂芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取代基取代。 在所述通式 I所示的化合物中， 特别优选的具体化合物包括以下化合物， 或其互变异构 对映体、 消旋体或其药学上可接受的盐：R 5 and R 6 are each independently -(CH 2 ) m R 9; -(CH 2 ) m CO(CH 2 )„R 9 ; or -[(CI3⁄4C3⁄4H, where i=integer of l~5, j=l An integer of ~3, R 9 is more preferably H; hydroxy; nitrile group; C2-C4 alkenyl group; C6-C10 aroyl group; C6-C10 aryl group; 4-10 membered heterocyclic group; 4-10 membered heteroaryl group 4-10 membered heterocyclic or 4-10 membered heteroaryl and C3-C8 cycloalkyl; or 4-10 membered heterocyclic or 4-10 membered heteroaryl and 4-10 membered heterocyclic or 4- 10-membered heteroaryl; above C2-C4 alkenyl, C6-C10 aroyl, C6-C10 aryl, 4-10 membered heterocyclyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl or 4 -10-membered heteroaryl and C3-C8 cycloalkyl or 4-10 membered heterocyclic or 4-10 membered heteroaryl and 4-10 membered heterocyclic or 4-10 membered heteroaryl may be optionally Or a plurality selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile, carboxyl, C1-C4 alkoxy, -C(0)0C1-C4 alkyl, -C(0 )NRi 5 R 16 , C1-C4 decanoyl, C1-C4 alkylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C1-C4 fluorenyl, hydroxy C1-C4 alkyl, amino C1-C4 fluorenyl, C6-C10 aryl C1-C4 alkyl, =0 (oxo), =S (thio), C6-C10 aryl, 4-10 membered heterocyclic group, 4-10 membered heteroaryl, 4-10 membered heterocyclic group or 4-10 membered heteroaryl and C6-C10 aryl group, 4-10 membered heterocyclic ring Substituents in the acyl group and the 4-10 membered heteroaroyl group are substituted. Among the compounds of the formula I, particularly preferred specific compounds include the following compounds, or their tautomeric enantiomers, racemates or pharmaceutically acceptable salts thereof:
Figure imgf000016_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000017_0001
C0C000/M0ZN3/X3d Μ / ΟΖ OAV C0C000/M0ZN3/X3d Μ / ΟΖ OAV
Figure imgf000018_0001
Figure imgf000018_0001
C0C000/M0ZN3/X3d Μ / ΟΖ OAV LI C0C000/M0ZN3/X3d Μ / ΟΖ OAV LI
Figure imgf000019_0001
Figure imgf000019_0001
C0C000/M0ZN3/X3d 1^9 / 0Z OAV C0C000/M0ZN3/X3d 1^9 / 0Z OAV
Figure imgf000020_0001
Figure imgf000020_0001
C0C000/M0ZN3/X3d Μ / ΟΖ OAV 61 C0C000/M0ZN3/X3d Μ / ΟΖ OAV 61
Figure imgf000021_0001
Figure imgf000021_0001
C0C000/M0ZN3/X3d Μ / ΟΖ OAV C0C000/M0ZN3/X3d Μ / ΟΖ OAV
Figure imgf000022_0001
Figure imgf000022_0001
20 20
Figure imgf000023_0001
Figure imgf000023_0001
C0C000/M0ZN3/X3d M / OZ OAV zz C0C000/M0ZN3/X3d M / OZ OAV Zz
Figure imgf000024_0001
Figure imgf000024_0001
C0C000/M0ZN3/X3d C0C000/M0ZN3/X3d
Figure imgf000025_0001
Figure imgf000025_0001
C0C000/M0ZN3/X3d Μ / ΟΖ OAV C0C000/M0ZN3/X3d Μ / ΟΖ OAV
Figure imgf000026_0001
Figure imgf000026_0001
C0C000/M0ZN3/X3d Μ / ΟΖ OAV C0C000/M0ZN3/X3d Μ / ΟΖ OAV
Figure imgf000027_0001
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000027_0002
Figure imgf000027_0003
Figure imgf000027_0003
一类优选的具体化合物为实施例化合物 1至实施例化合物 378， 或其互变异构体、 对映 体、 消旋体或其药学上可接受的盐。  A preferred class of specific compounds are the compounds of Examples 1 to 378, or the tautomers, enantiomers, racemates thereof or pharmaceutically acceptable salts thereof.
其中， 所述药学上可接受的盐为所述化合物与选自以下的酸形成的盐： 磷酸、 苹果酸、 乳酸、 马来酸、 盐酸、 甲磺酸、 硫酸、 柠檬酸、 酒石酸、 乙酸或三氟乙酸， 优选为磷酸盐、 盐酸盐或三氟乙酸盐。  Wherein the pharmaceutically acceptable salt is a salt of the compound with an acid selected from the group consisting of phosphoric acid, malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, citric acid, tartaric acid, acetic acid or Trifluoroacetic acid, preferably a phosphate, hydrochloride or trifluoroacetate salt.
通式 I所示的化合物可含有一个或多个手性中心， 因此可存在立体异构体， 即对映异构 体、 非对映异构体或其混合物。若通式 I所示的化合物中含有链烯基或亚烯基， 则还可以存 在顺式 (E)和反式 (Z)异构现象。 因此， 本发明式 I所示的化合物可以为单个异构体或各异构 体的混合物。  The compounds of formula I may contain one or more chiral centers and, therefore, may exist as stereoisomers, i.e., enantiomers, diastereomers or mixtures thereof. If the compound of the formula I contains an alkenyl group or an alkenylene group, cis (E) and trans (Z) isomerism may also exist. Therefore, the compound of the formula I of the present invention may be a single isomer or a mixture of the respective isomers.
利用常规工艺可以实现非对映异构体或顺式和反式异构体的分离，例如通式 I所示的化 合物或其适合的盐或衍生物的立体异构体的混合物的分步结晶、 色谱或 HPLC。 通式 I所示 的化合物还可以这样制备： 从对应的旋光纯中间体制备， 或者利用适合的手性载体拆分对应 的外消旋物，例如通过 HPLC或者分步结晶由对应的外消旋物与适合的旋光活性酸或碱的反 应所生成的非对映异构盐。 Separation of diastereomers or cis and trans isomers by conventional techniques, such as fractional crystallization of a mixture of stereoisomers of a compound of formula I or a suitable salt or derivative thereof , chromatography or HPLC. Formula I The compounds can also be prepared by preparing from the corresponding optically pure intermediates or by resolution of the corresponding racemates using suitable chiral carriers, for example by HPLC or fractional crystallization from the corresponding racemates and suitable optical rotations. A diastereomeric salt formed by the reaction of an active acid or base.
通式 I所示的化合物可存在互变异构体的形式，而本发明包括了其混合物和单一的互变 异构体。  The compounds of formula I may exist in the form of tautomers, and the invention includes mixtures thereof and single tautomers.
本发明包括通式 I所示的化合物的放射标记衍生物， 这些衍生物 用于生物学研究。 本发明提供了通式 I所示的化合物的药用盐，例如， 与无机酸如盐酸、氢溴酸、氢碘酸、 硫酸和磷酸， 与有机羧酸或有机磺酸形成的无毒酸加成盐， 优选磷酸、 苹果酸、 乳酸、 马来 酸、 盐酸、 甲磺酸、硫酸、 柠檬酸、 酒石酸、 乙酸或三氟乙酸， 更优选为磷酸盐、 甲磺酸盐、 盐酸盐或三氟乙酸盐。通式 I所示的化合物还可与碱反应提供药用金属盐， 特别是无毒碱金 属盐 (例如钠盐和钾盐)。  The present invention includes radiolabeled derivatives of the compounds of formula I which are useful in biological research. The present invention provides pharmaceutically acceptable salts of the compounds of formula I, for example, with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and non-toxic acids formed with organic carboxylic acids or organic sulfonic acids. Salt formation, preferably phosphoric acid, malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid, more preferably phosphate, methanesulfonate, hydrochloride or trihydrate Fluoroacetate. The compound of formula I can also be reacted with a base to provide a pharmaceutically acceptable metal salt, particularly a non-toxic alkali metal salt (e.g., a sodium salt and a potassium salt).
本发明包括通式 I所示的化合物的任何前药形式。  The invention includes any prodrug form of the compound of formula I.
本发明还包括通式 I的化合物的可药用溶剂化物 (例如水合物)。（这里是通式 I的溶剂化 物）  The invention also includes pharmaceutically acceptable solvates (e.g., hydrates) of the compounds of formula I. (here is a solvate of formula I)
本发明也包括通式 I所示的化合物的可药用氧化物， 及其可药用盐和可药用溶剂化物。 (这里是可药用氧化物的盐及溶剂化物）  The invention also includes pharmaceutically acceptable oxides of the compounds of formula I, and pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof. (here is the salt and solvate of pharmaceutically acceptable oxides)
本发明还包括通式 I所示的化合物和各种盐的多种晶型。  The invention also includes a plurality of crystalline forms of the compound of formula I and various salts.
本发明的另一个目的是提供通式 I化合物的制备方法。  Another object of the invention is to provide a process for the preparation of a compound of formula I.
本发明通式 1所示化合物可通过如下的方法制得， 然而该方法的条件， 例如反应物、 溶 剂、 碱、 所用化合物的量、 反应温度、 反应所需时间等不限于下面的说明。  The compound of the formula 1 of the present invention can be produced by the following method, however, the conditions of the method, such as the reactant, the solvent, the base, the amount of the compound used, the reaction temperature, the time required for the reaction, and the like are not limited to the following description.
通常， 本发明方法包括在合适的惰性溶剂中， 在合适的反应温度 (如 -80Ό至回流温度， 较佳地 -20至回流温度)下， 反应一段时间 (如 0.1-72小时， 较佳地 0.2-24小时)。 此外， 本发 明化合物可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的 制得。  In general, the process of the invention comprises reacting in a suitable inert solvent at a suitable reaction temperature (e.g., -80 Torr to reflux temperature, preferably -20 to reflux temperature) for a period of time (e.g., 0.1-72 hours, preferably 0.2-24 hours). Furthermore, the compounds of the present invention can be conveniently prepared by combining various synthetic methods described in the specification or known in the art.
典型地， 本发明方法包括：  Typically, the method of the invention comprises:
(1)方法一：  (1) Method one:
通式 I化合物可  a compound of formula I
Figure imgf000028_0001
Figure imgf000028_0001
其中， A、 Ri、 R2、 R3 、 R5、 R6、 、 W、 Q> Y和 X的定义同其在通式 I中的定 所述还原氨化反应可以在氨甲醇 /乙酸铵、 氰基硼氢化钠存在的条件下进行 < Wherein, A, Ri, R 2 , R 3 , R 5 , R6, W, Q > Y and X are as defined in the formula I, and the reductive amination reaction can be carried out in ammonia methanol/ammonium acetate, In the presence of sodium cyanoborohydride
其中， 通式 II化合物可以通过通式 III化合物与通式 S化合物反应得到：
Figure imgf000029_0001
Wherein the compound of the formula II can be obtained by reacting a compound of the formula III with a compound of the formula S:
Figure imgf000029_0001
其中， A、 Ri、 R2、 R3、 、 R5 、 、 W、 Q、 Y和 X的定义同其在通式 I中的定 义； Ri3为羟基、 卤素、 C1-C10烷氧基、 C6-C10芳氧基或 C1-C10垸酰氧基； Wherein, A, Ri, R 2 , R 3 , , R 5 , , W, Q, Y and X are as defined in the formula I; Ri 3 is a hydroxyl group, a halogen, a C1-C10 alkoxy group, C6-C10 aryloxy or C1-C10 nonanoyloxy;
所述通式 III化合物与通式 S化合物的反应可以在碱性条件下进行；  The reaction of the compound of the formula III with the compound of the formula S can be carried out under basic conditions;
其中， 通式 III化 化合物制备：  Wherein, the compound of formula III is prepared:
Figure imgf000029_0002
Figure imgf000029_0002
其中， A、 、 R2、 R3、 R4、 W、 Q和 Y的定义同其在通式 I中的定义； R13为卤素、 CI- C10焼氧基、 C6-C10芳氧基或 C1-C10烷酰氧基。 Wherein, A, R 2 , R 3 , R 4 , W, Q and Y are as defined in the formula I; R 13 is halogen, CI-C10 decyloxy, C6-C10 aryloxy or C1 -C10 alkanoyloxy.
其中， 当通式 III化合物通过通式 V化合物制备时， 通式 V化合物可与丙二酸单烷基酯 的钾盐进行缩合消除反应， 得到产物通式 III化合物； 当通式 III化合物通过通式 IV化合物 制备时， 通式 V化合物先与米氏酸在缩合剂存在下发生缩合反应得到通式 IV化合物， 然后 通式 IV化合物在酸性条件下进行开环脱羧反应得到产物通式 ΙΠ化合物；  Wherein, when the compound of the formula III is prepared by the compound of the formula V, the compound of the formula V can be condensed and eliminated with the potassium salt of the monoalkyl malonate to obtain the compound of the formula III; When the compound of the formula IV is prepared, the compound of the formula V is first subjected to condensation reaction with the michroic acid in the presence of a condensing agent to obtain a compound of the formula IV, and then the compound of the formula IV is subjected to ring-opening decarboxylation under acidic conditions to obtain a product of the formula quinone;
通式 V化合物可以由市场购买， 或者参照下述式 VA化合物的制备方法制备，  The compound of the formula V can be purchased from the market or prepared by referring to the preparation method of the compound of the formula VA below.
(2)方法二：  (2) Method 2:
本发明还提供了通式 I化合物的另一种制备方法， 所述方法包括- 通式 I化合物可以由通式 VI化合物经过脱保护基反应得到，  The present invention also provides another process for the preparation of a compound of formula I, which comprises - a compound of formula I which can be obtained by deprotection of a compound of formula VI,
Figure imgf000029_0003
Figure imgf000029_0003
其中， A、 R2、 R3、 R4、 R5、 Re、 R8、 W、 Q、 Y和 X的定义同其在通式 I中的定 义； R14为氨基保护基， 优选为苄氧羰基或叔丁氧羰基； Wherein A, R 2 , R 3 , R 4 , R 5 , Re, R 8 , W, Q, Y and X are as defined in the formula I; R 14 is an amino protecting group, preferably benzyloxy Carbonyl or tert-butoxycarbonyl;
所述脱保护基的反应可以在酸性条件下进行， 得到通式 I化合物或通式 I化合物的盐， 该通式 I化合物的盐在碱性条件下游离得到通式 I化合物； 通式 VI化合物可 The reaction of the deprotecting group can be carried out under acidic conditions to obtain a salt of the compound of the formula I or the compound of the formula I, the salt of the compound of the formula I is freed under basic conditions to give a compound of the formula I; a compound of formula VI
Figure imgf000030_0001
Figure imgf000030_0001
其中， A、 R!、 R2、 R3、 、 R5、 、 、 W、 Q、 Y和 X的定义同其在通式 I中的定 义； R14为氨基保护基， 优选为苄氧羰基或叔丁氧羰基； Wherein, A, R!, R 2 , R 3 , R 5 , , , W, Q, Y and X are as defined in the formula I; R 14 is an amino-protecting group, preferably a benzyloxycarbonyl group. Or tert-butoxycarbonyl;
所述式 VII化合物与通式 S化合物经缩合反应或者酰化反应得到通式 VI化合物， 反应 可以在碱性条件下进行， 也可以在缩合剂存在条件下进行；  The compound of the formula VII and the compound of the formula S are subjected to a condensation reaction or an acylation reaction to obtain a compound of the formula VI, and the reaction can be carried out under basic conditions or in the presence of a condensing agent;
其  Its
Figure imgf000030_0002
Figure imgf000030_0002
其中， A、 Ri, R2、 R3、 、 R8、 W、 Q、 Y和 X的定义同其在通式 I中的定义； R13为 卤素、 C1-C10垸氧基、 C6-C10芳氧基或 C1-C10垸酰氧基； R14为氨基保护基， 优选为苄氧 羰基或叔丁氧羰基； Wherein, A, Ri, R 2 , R 3 , R 8 , W, Q, Y and X are as defined in the formula I; R 13 is halogen, C1-C10-decyloxy, C6-C10 An aryloxy group or a C1-C10 nonanoyloxy group; R 14 is an amino protecting group, preferably a benzyloxycarbonyl group or a tert-butoxycarbonyl group;
上述通式 III化合物进行还原氨化反应得到氨基物 (通式 IX化合物)， 然后通式 IX化合 物的氨基用保护基团保护得到通式 VIII化合物， 最后通式 VIII化合物进行水解反应脱保护 基得到产物通式 VII化合物， 还原氨化条件、 脱保护基条件可参照方法一；  The compound of the above formula III is subjected to reductive amination reaction to obtain an amino compound (compound of the formula IX), and then the amino group of the compound of the formula IX is protected with a protecting group to obtain a compound of the formula VIII, and finally the compound of the formula VIII is subjected to a hydrolysis reaction to obtain a deprotecting group. The product of the formula VII, reductive amination conditions, deprotection conditions can refer to method one;
其中， 通式 III化合物的制备方法参见方法一，  Wherein, the preparation method of the compound of the general formula III is as described in the first method.
(3)方法三： 当 R8为氧代或取代氨基时， 可由 R8=H的通式 V化合物经官能团变换得到 Rs为氧代或取代氨基的通式 V化合物， 再参照方法一得到通式 I化合物， (3) Method 3: When R 8 is an oxo or substituted amino group, a compound of the formula V wherein Rs is an oxo or substituted amino group can be obtained by a functional group conversion of a compound of the formula V wherein R 8 =H, and then obtained by referring to the first method. a compound of formula I,
(4)方法四： 通式 I化合物还可以由其他通式 I化合物经过官能团变换得到。 优选地， 当通式 I化合物中的 A环为苯环时， 通式 IA化合物通过以下方法制备： (1)  (4) Method 4: The compound of the formula I can also be obtained by functional group transformation of other compounds of the formula I. Preferably, when the A ring in the compound of the formula I is a benzene ring, the compound of the formula IA is prepared by the following method: (1)
Figure imgf000030_0003
Figure imgf000030_0003
其中， 通式 ΠΙΑ化合物可以通过通式 V化合物制备: Wherein the general formula 制备 compound can be prepared by the compound of formula V:
Figure imgf000031_0001
通式 VA化合物可以由市场购买， 或者由以下方法制备：
Figure imgf000031_0001
Compounds of the general formula VA can be purchased from the market or prepared by the following methods:
当 R7为 H时， 通式 VA化合物可由通式 IXA化合物参照文献 (J. Med. Chem. 2003, 46, 399-408)方法制备 化合物： When R 7 is H, the compound of the formula VA can be prepared from the compound of the formula IXA by reference to the literature (J. Med. Chem. 2003, 46, 399-408):
Figure imgf000031_0002
其中， 通式 IXA化合物可由市场购买得到；
Figure imgf000031_0002
Wherein the compound of the formula IXA is commercially available;
当 R7不为 H时， 通式 VA化合物可由通式 VA'化合物 (R7=H)经酯化后与 R7X反应制备 得到通 XIA化合物后再水解制备通式 VA化合物。 其中， R7X中的 X为卤素， When R 7 is not H, the compound of the formula VA can be obtained by reacting a compound of the formula VA' (R 7 =H) with R 7 X to obtain a compound of the formula XA, followed by hydrolysis to prepare a compound of the formula VA. Wherein X in R 7 X is halogen,
Figure imgf000031_0003
Figure imgf000031_0003
(2)方法二：  (2) Method 2:
通式 IA化合物可以通过通式 ΙΠΑ化合物经以下步骤制备， 具体制备方法同前述通式 I 化合物的制备方法 (方法二)； The compound of the formula IA can be prepared by the following procedure by the general formula , compound, the specific preparation method is the same as the preparation method of the compound of the above formula I (method 2);
Figure imgf000032_0001
Figure imgf000032_0001
其中通式 ΙΠΑ化合物的制备方法同通式 ΙΠ化合物的制备方法，  Wherein the preparation method of the oxime compound is the same as the preparation method of the ruthenium compound of the formula,
(3)方法三： 当 为氧代或取代氨基时， 可由 R8=H的通式 V化合物经官能团变换得到 R8为氧代或取代氨基的通式 V化合物， 再参照方法一得到通式 I化合物， (3) Method 3: When oxo or substituted amino group, a compound of the formula V wherein R 8 is an oxo or substituted amino group can be obtained by functional group conversion of a compound of the formula V wherein R 8 =H, and the general formula is obtained by referring to the first method. I compound,
(4)方法四： 通式 I化合物还可以由其他通式 I化合物经过官能团变换得到。 单一手性异构体的通式 I化合物可通过以下方式制备：  (4) Method 4: The compound of the formula I can also be obtained by functional group transformation of other compounds of the formula I. Compounds of formula I of a single chiral isomer can be prepared in the following manner:
(1)方法一： 通式 I化合物经过柱层析， 分离非对映异构体， 分别得到两对对映体， 该对 对映体再经手性制备柱拆分得到单一光学异构体的通式 I化合物，  (1) Method 1: The compound of the formula I is subjected to column chromatography to separate the diastereomers to obtain two pairs of enantiomers, respectively, which are then separated by chiral preparative column to obtain a single optical isomer. a compound of formula I,
(2)方法二： 或者， 通式 VIIIA化合物经手性制备柱拆分得到光学异构体通式 VIIIA'化合 物和式 VIIIA  (2) Method 2: Alternatively, the compound of the formula VIIIA is resolved by chiral preparative column to obtain an optical isomer of the formula VIIIA' compound and the formula VIIIA
Figure imgf000032_0002
Figure imgf000032_0002
VIIIA VIIIA' VIIIA"  VIIIA VIIIA' VIIIA"
通式 VIIIA'化合物或通式 VIIIA"化合物再与通式 S化合物反应， 得到单一手性的通式 IA化合  The compound of the formula VIIIA' or the compound of the formula VIIIA" is further reacted with a compound of the formula S to give a single chiral formula IA
Figure imgf000032_0003
本发明还包括将所述得到的通式 I化合物在酸的有机溶剂中反应，得到其酸加成产物盐， 其中所述的酸选自磷酸、 苹果酸、 乳酸、 马来酸、 盐酸、 甲磺酸、 硫酸、 柠檬酸、 酒石酸、 乙酸或三氟乙酸， 优选磷酸、 盐酸或三氟乙酸。
Figure imgf000032_0003
The present invention also includes reacting the obtained compound of the general formula I in an organic solvent of an acid to obtain an acid addition product salt thereof, wherein the acid is selected from the group consisting of phosphoric acid, malic acid, lactic acid, maleic acid, hydrochloric acid, and A Sulfonic acid, sulfuric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid, preferably phosphoric acid, hydrochloric acid or trifluoroacetic acid.
本发明的还一目的是提供一种通式 II、 III、 VI或 VII所示的 β-氨基羰基类化合物或其 互变  Still another object of the present invention is to provide a β-aminocarbonyl compound of the formula II, III, VI or VII or a tautomer thereof.
Figure imgf000033_0001
Figure imgf000033_0001
Α选自 C6-C10芳基、 饱和或不饱和 C3-C10环烃基、 4-10元杂环基或 4-10元杂芳基； 所述杂环基或杂芳基含有 1-4个选自 N、 S和 O的杂原子；  The fluorene is selected from a C6-C10 aryl group, a saturated or unsaturated C3-C10 cycloalkyl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group; the heterocyclic group or heteroaryl group contains 1-4 selected Heteroatoms from N, S and O;
W为^ S、 0或 C1-C4直链烃基；  W is a S, 0 or C1-C4 linear hydrocarbon group;
0为1^、 S、 O或 C原子；  0 is a 1^, S, O or C atom;
W与 Q之间的虚线存在或不存在， 存在时表示此处是不饱和键， 不存在时表示此处是 饱和键， 优选为不存在；  The presence or absence of a dotted line between W and Q, when present, indicates that it is an unsaturated bond, and when it does not exist, it indicates that it is a saturated bond, preferably does not exist;
Y为 N或 CR7; Y is N or CR 7;
X为 N或 CR7; X is N or CR 7 ;
和 R4各自独立地为 H;卤素；三氟甲基；羟基；硝基；腈基；羧基； -C(O)OCl-C10 烷基； 氨基； C1-C10烷氧基; C1-C10烷基; C1-C10垸酰基 (即 -C(O)Cl-C10烷基)； C1-C10 垸酰氧基 (即 -OC(O)Cl-C10烷基)； 磺酰基； C1-C10垸基磺酰基； C6-C10芳基； 4-10元杂环 基；或 4-10元杂芳基；上述 -C(O)OCl-C10烷基、氨基、 C1-C10垸氧基、 C1-C10烷基、 C1-C10 垸酰基、 C1-C10垸酰氧基、 磺酰基、 C1-C10垸基磺酰基、 C6-C10芳基、 4-10元杂环基或 4-10元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧 基、 C1-C10烷基、 C1-C10垸氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10烷基、 C1-C10垸酰 基、 磺酰基、 C1-C10垸基磺酰基、 苯基和苯甲基中的取代基取代；  And R4 are each independently H; halogen; trifluoromethyl; hydroxy; nitro; nitrile; carboxy; -C(O)OCl-C10 alkyl; amino; C1-C10 alkoxy; C1-C10 alkyl ; C1-C10 decanoyl (ie, -C(O)Cl-C10 alkyl); C1-C10 nonanoyloxy (ie, -OC(O)Cl-C10 alkyl); sulfonyl; C1-C10 mercaptosulfonate Acyl; C6-C10 aryl; 4-10 membered heterocyclic; or 4-10 membered heteroaryl; above -C(O)OCl-C10 alkyl, amino, C1-C10 decyloxy, C1-C10 alkane Base, C1-C10 decanoyl, C1-C10 decanoyloxy, sulfonyl, C1-C10 decylsulfonyl, C6-C10 aryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl Must be one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C10 alkyl, C1-C10 decyloxy, C1-C10 alkanoyloxy, - Substituted by a substituent in C(O)OCl-C10 alkyl, C1-C10 decanoyl, sulfonyl, C1-C10 decylsulfonyl, phenyl and benzyl;
R5和 各自独立地为 -(CH2)mR9 ; -(CH2)mCO(CH2)nR9; 或 -[(Ο¾)ί0¾Η， 其中 i=l~5的 整数， j=l~3的整数， R9为 H; 素； 羟基； 硝基； 氨基； 腈基； 羧基； -C(O)OCl-C10烷 基； C1-C10垸酰基； C1-C10垸基磺酰基； C1-C10垸基； C2-C10烯基； C2-C10炔基； C3-C10 环垸基； C3-C8内酰胺基； C1-C10垸氨基磺酰基； C1-C10烷氨酰基； C6-C10芳酰基； C1-C10 垸氧基； C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16； C6-C10芳基; 4-10元杂环基; 4-10元杂芳基； 4-10元杂环基或 4-10元杂芳基并 C3-C10环烃基；或者 4-10元杂环基或 4-10 元杂芳基并 4-10元杂环基或 4-10元杂芳基； 上述氨基、 -C(O)OCl-C10垸基、 C1-C10垸酰 基、 C1-C10院基磺酰基、 C1-C10烷基、 C2-C10烯基、 C2-C10炔基、 C3-C10环垸基、 C3-C8 内酰胺基、 C1-C10烷氨基磺酰基、 C1-C10垸氨酰基、 C6-C10芳酰基、 C1-C10垸氧基、 C6-C10 芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C3-C10环烃基或者 4-10元杂环基或 4-10元杂芳基并 4-10 元杂环基或 4-10 元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 -NR15Ri6、 腈基、 羧基、 C1-C10垸氧基、 C6-C10芳氧基、 C1-C10垸酰氧基、 -C(O)OCl-C10 垸基、 -C(O)NR15Rl6、Cl-C10烷酰基、 C1-C10烷基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C10垸基、羟基 C1-C10垸基、氨基 C1-C10垸基、 C6-C10 芳基 C1-C10烷基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取 代基取代； 上述 C6-C10芳基、 C6-C10芳酰基和 C6-C10芳基磺酰基可非必须地被一个或多 个选自卤素、 三氟甲基、 羟基、 硝基、 -NR15R16、 腈基、 羧基、 C1-C10垸氧基、 C1-C10烷 酰氧基、 -C(O)OCl-C10烷基、 -C(0)NR15R16、 C1-C10烷酰基、 C1-C10烷基磺酰基、 C6-C10 芳基磺酰基、 -S02NR15R16、 -NRI5S02Ri6、 C6-C10芳酰基、 C1-C10垸基、羟基 C1-C10垸基、 氨基 C1-C10烷基和 C6-C10芳基 C1-C10烷基中的取代基取代； R 5 and each independently are -(CH 2 ) m R 9 ; -(CH 2 ) m CO(CH 2 ) n R 9; or -[(Ο3⁄4) ί03⁄4Η, where i = an integer of 1 to 5, j= An integer of l~3, R 9 is H; a hydroxy group; a nitro group; an amino group; a nitrile group; a carboxyl group; a C(O)OCl-C10 alkyl group; a C1-C10 decanoyl group; a C1-C10 decylsulfonyl group; C1-C10 fluorenyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cyclodecyl; C3-C8 lactam; C1-C10 guanylaminosulfonyl; C1-C10 alkanoyl; C6-C10 Aroyl; C1-C10 decyloxy; C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 ; C6-C10 aryl; 4-10 membered heterocyclic; 4- 10 membered heteroaryl; 4-10 membered heterocyclic or 4-10 membered heteroaryl and C3-C10 cycloalkyl; or 4-10 membered heterocyclic or 4-10 membered heteroaryl and 4-10 membered a cyclic group or a 4-10 membered heteroaryl group; the above amino group, -C(O)OCl-C10 fluorenyl group, C1-C10 decanoyl group, C1-C10-based sulfonyl group, C1-C10 alkyl group, C2-C10 alkenyl group , C2-C10 alkynyl, C3-C10 cyclodecyl, C3-C8 lactam, C1-C10 alkylaminosulfonyl, C1-C10 prolyl, C6-C10 aroyl, C1-C10 decyloxy, C6 -C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C3- A C10 cycloalkyl group or a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group and a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group may be optionally selected from one or more selected from the group consisting of halogen and trifluoro. Methyl, hydroxy, nitro, -NR 15 Ri6, nitrile group, carboxyl group, C1-C10 decyloxy group, C6-C10 aryloxy group, C1-C10 decanoyloxy group, -C(O)OCl-C10 Mercapto, -C(O)NR 15 R l6 , Cl-C10 alkanoyl, C1-C10 alkylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 fluorenyl, hydroxy C1-C10 fluorenyl, amino C1-C10 fluorenyl, C6-C10 aryl C1-C10 alkyl, =0 (oxo), =S (thio ), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6-C10 aryl, 4-10 member Substituted with a heterocyclic acyl group and a substituent in a 4-10 membered heteroaroyl group; the above C6-C10 aryl group, C6-C10 aroyl group and C6-C10 aryl sulfonyl group may be optionally selected from one or more selected from the group consisting of halogen, Trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile, carboxyl, C1-C10 decyloxy, C1-C10 alkanoyloxy, -C(O)OCl-C10 alkyl, -C( 0) NR 15 R 16 , C1-C10 alkanoyl group, C1-C10 alkylsulfonyl group, C6-C10 arylsulfonyl group, -S0 2 NR 15 R 16 , -NR I5 S0 2 Ri6, C6-C10 aroyl group, Substituent substitution in a C1-C10 fluorenyl group, a hydroxy C1-C10 fluorenyl group, an amino C1-C10 alkyl group, and a C6-C10 aryl C1-C10 alkyl group;
或者， R5和 R6与它们相连的 X共同构成氨基葡萄糖基； 氨基酸残基； 氨基酸酯残基； 或氨基酰胺残基，且非必须地被一个或多个选自 C1-C6垸基、 C1-C6垸基取代的氨基、 C1-C10 烷酰基、 苄基、 苄氧羰基和叔丁氧羰基中的取代基取代； Alternatively, R 5 and R 6 together with the X to which they are attached form an glucosamine group; an amino acid residue; an amino acid ester residue; or an amino amide residue, and optionally one or more selected from the group consisting of C1-C6 fluorenyl groups, C1 Substituted with a substituent in the C6 mercapto substituted amino group, a C1-C10 alkanoyl group, a benzyl group, a benzyloxycarbonyl group and a tert-butoxycarbonyl group;
或者， R5和 Re与连接它们的 X—起形成 C6-C10芳基； C3-C10环经基； C3-C10环烃 基并 C3-C10环烃基； C3-C10环烃基并 C6-C10芳基； C6-C10芳基并 C3-C10环烃基； 4-10 元杂环基； 4-10元杂芳基； 4-10元杂环基螺环； 4-10元杂芳基螺环； 4-10元杂环基或 4-10 元杂芳基并 C3-C10环烃基； C3-C10环烃基并 4-10元杂环基或 4-10元杂芳基； 4-10元杂环 基或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基； C6-C10芳基并 4-10元杂环基或 4-10 元杂芳基； 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基； [4-10元杂环基或 4-10元杂芳基] 并 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]; 或者 [4-10元杂环基 或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]并 [C6-C10芳基]; 上述基团可非必须地 被一个或多个 R'取代， R，选自 -(CH2)mR10 ; -(CH2)mCO(CH2)nR10 ; -(CH2)mO(CH2)n 10； -(CH2)m HC(O)(CH2)nRi0； 和 -(CH2)mNSO2(CH2)nR10; Alternatively, R 5 and Re form a C6-C10 aryl group with the X to which they are attached; a C3-C10 cycloalkyl group; a C3-C10 cycloalkyl group and a C3-C10 cycloalkyl group; a C3-C10 cycloalkyl group and a C6-C10 aryl group; ; C6-C10 aryl and C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; 4-10 membered heterocyclyl spiro; 4-10 membered heteroaryl spiro; 4 -10 membered heterocyclic group or 4-10 membered heteroaryl and C3-C10 cycloalkyl; C3-C10 cycloalkyl and 4-10 membered heterocyclic or 4-10 membered heteroaryl; 4-10 membered heterocyclic group Or a 4-10 membered heteroaryl and 4-10 membered heterocyclic group or a 4-10 membered heteroaryl; C6-C10 aryl and 4-10 membered heterocyclic or 4-10 membered heteroaryl; 4-10 a heterocyclic group or a 4-10 membered heteroaryl and C6-C10 aryl; [4-10 membered heterocyclic or 4-10 membered heteroaryl] and [4-10 membered heterocyclic or 4-10 membered Heteroaryl][4-10 membered heterocyclic or 4-10 membered heteroaryl]; or [4-10 membered heterocyclic or 4-10 membered heteroaryl][4-10 membered heterocyclic group Or 4-10 membered heteroaryl] and [C6-C10 aryl]; the above group may be optionally substituted by one or more R', R, selected from -(CH 2 ) m R 10 ; -(CH 2 ) m CO(CH 2 ) n R 10 ; -(CH 2 ) m O(CH 2 ) n 10 ; -(CH 2 ) m HC(O)(CH 2 ) n Ri 0 ; and -(CH 2 ) m NS O 2 (CH 2 ) n R 10;
其中， R1()为氢、 卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C10烷氧基、 C6-C10芳氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10垸基、 -C(0)NH2、 C1-C10烷酰基、 C1-C10 垸基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C10垸 基、羟基 C1-C10烷基、 氨基 C1-C10垸基、 C6-C10芳基 C1-C10烷基、 =0 (氧代)、 =S (硫 代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10 Wherein R 1() is hydrogen, halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C10 alkoxy, C6-C10 aryloxy, C1-C10 alkanoyloxy, -C(O)OCl-C10 fluorenyl, -C(0)NH 2 , C1-C10 alkanoyl, C1-C10 decylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 fluorenyl, hydroxy C1-C10 alkyl, amino C1-C10 decyl, C6-C10 aryl C1-C10 alkyl, =0 (oxo) , =S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6-C10
Ph  Ph
芳基、 4-10元杂环酰基、 4-10元杂芳酰基或一 -COEt ; 上述氨基、 C1-C10烷氧基、 C6-C10 芳氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10烷基、 -C(0)NH2、 C1-C10垸酰基、 C1-C10垸基 磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C10烷基、 羟基 C1-CI0烷基、 氨基 C1-C10垸基、 C6-C10芳基 C1-C10垸基、 =0 (氧代)、 = s (硫代)、Aryl, 4-10 membered heterocyclic acyl, 4-10 membered heteroaroyl or mono-COEt ; above amino, C1-C10 alkoxy, C6-C10 aryloxy, C1-C10 alkanoyloxy, -C (O)OCl-C10 alkyl, -C(0)NH 2 , C1-C10 decanoyl, C1-C10 decylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 alkyl, hydroxy C1-CI0 alkyl, amino C1-C10 fluorenyl, C6-C10 aryl C1-C10 fluorenyl, =0 (oxo), = s (thio),
C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳 C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6-C10
Ph  Ph
基、 4-10元杂环酰基、 4-10元杂芳酰基或一^- COEt可非必须地被一个或多个选自卤素、 三 氟甲基、 羟基、 硝基、 -NR15R16、 腈基、 羧基、 C1-C10垸氧基、 C6-C10芳氧基、 C1-C10烷 酰氧基、 -C(O)OCl-C10烷基、 -C(0)NR15R16、 C1-C10垸酰基、 C1-C10垸基磺酰基、 C6-C10 芳基磺酰基、 -S02NR15R16、 -NR15S02Ri6、 C6-C10芳酰基、 C1-C10烷基、羟基 C1-C10垸基、 氨基 C1-C10垸基、 C6-C10芳基 C CIO烷基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10 元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰 基和 4-10元杂芳酰基中的取代基取代； a 4-10 membered heterocyclic acyl group, a 4-10 membered heteroaroyl group or a ^-COEt may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile group, carboxyl group, C1-C10 decyloxy group, C6-C10 aryloxy group, C1-C10 alkanoyloxy group, -C(O)OCl-C10 alkyl group, -C(0)NR 15 R 16 , C1 -C10 decanoyl, C1-C10 decylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 Ri 6 , C6-C10 aroyl, C1-C10 alkyl, hydroxy C1-C10 fluorenyl, amino C1-C10 fluorenyl, C6-C10 aryl C CIO alkyl, =0 (oxo), =S (thio), C6-C10 aryl, 4-10 a heterocyclic group, a 4-10 membered heteroaryl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl and C6-C10 aryl group, a 4-10 membered heterocyclic acyl group and a 4-10 membered heteroaroyl group. Substituted in the substituent;
R15、 R16各自独立地为 H; C1-C10烷基； C3-C10环垸基； 4-10元杂环基； 4-10元杂芳 基； 或者 R15、 R16与连接它们的 N原子一起形成 4-10元杂环基； 4-10元杂芳基； 其中， 所 述 C1-C10垸基、 C3-C10环烷基、 4-10元杂环基和 4-10元杂芳基可非必须地被 1个或多个 卤素； 羟基； 腈基； 氨基； C1-C10烷基； =0 (氧代)； =S (硫代)； C1-C10垸氧基取代；R 15 and R 16 are each independently H; C1-C10 alkyl; C3-C10 cyclodecyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and attached thereto The N atoms together form a 4-10 membered heterocyclic group; a 4-10 membered heteroaryl group; wherein, the C1-C10 fluorenyl group, the C3-C10 cycloalkyl group, the 4-10 membered heterocyclic group, and the 4-10 membered heterocyclic group; The aryl group may be optionally substituted by one or more halogens; a hydroxyl group; a nitrile group; an amino group; a C1-C10 alkyl group; =0 (oxo); =S (thio); a C1-C10 decyloxy group;
R7为 -(CH2)mRu、 -(CH^C CH^Ru或 -(CH2)mNHR„； R 7 is -(CH 2 ) m R u , -(CH^C CH^Ru or -(CH 2 ) m NHR„;
其中， Rn为 H; 卤素； 硝基； 腈基； 羧基； -C(O)OCl-C10烷基; C2-C10烯基； C2-C10 炔基； C1-C10垸酰基； C1-C10烷基磺酰基； 氨基 C1-C10烷酰基； C1-C10垸基； C6-C10 芳基； 4-10元杂环基； 或 4-10元杂芳基； 上述 -C(O)OCl-C10烷基、 C2-C10烯基、 C2-C10 炔基、 C1-C10烷酰基、 C1-C10垸基磺酰基、 氨基 C1-C10烷酰基、 C1-C10烷基、 C6-C10 芳基、 4-10元杂环基或 4-10元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、氨基、腈基、羧基、 C1-C10烷氧基、 C1-C10垸酰氧基、 -C(O)OCl-C10烷基、 C1-C10 垸酰基、 C1-C10垸基磺酰基、 =0 (氧代)、 =s (硫代;)和 C1-C10垸基中的取代基取代；Wherein R n is H; halogen; nitro; nitrile; carboxyl; -C(O)OCl-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C1-C10 nonanoyl; C1-C10 alkane Alkylsulfonyl; amino C1-C10 alkanoyl; C1-C10 alkyl; C6-C10 aryl; 4-10 membered heterocyclyl; or 4-10 membered heteroaryl; above -C(O)OCl-C10 , C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkanoyl, C1-C10 decylsulfonyl, amino C1-C10 alkanoyl, C1-C10 alkyl, C6-C10 aryl, 4-10 The heterocyclic or 4-10 membered heteroaryl may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxyl, C1-C10 alkoxy, C1. -C10 nonanoyloxy, -C(O)OCl-C10 alkyl, C1-C10 decanoyl, C1-C10 decylsulfonyl, =0 (oxo), =s (thio;) and C1-C10 a substituent in the thiol group;
R8为 -(CH2)mR12、 -(CH2)mO(CH2)nR12或 -(CH2)mNHR12; R 8 is -(CH 2 ) m R 12 , -(CH 2 ) m O(CH 2 ) n R 12 or -(CH 2 ) m NHR 12;
其中， R12为 H; 卤素； 硝基； 腈基； 羧基； =0 (氧代)； =S (硫代)； -C(O)OCl-C10 垸基； C2-C10烯基； C2-C10炔基； C1-C10垸酰基； C1-C10烷基磺酰基； 氨基 C1-C10烷 酰基； C1-C10烷基； Ph(CH2)ra -; s」；
Figure imgf000035_0001
4-10元杂环基； 或 4-10元杂芳基； 上述 -C(O)OCl-C10垸基、 C2-C10烯基、 C2-C10炔基、 C1-C10垸酰基、 C1-C10垸基磺酰基、 氨基 C1-C10垸酰基、 C1-C10烷基、 Ph(CH2)m -、 s」、 °^0、 4-10元杂环基或 4-10元杂 芳基可非必须地被一个或多个选自卤素、三氟甲基、羟基、硝基、氨基、腈基、羧基、 C1-C10 烷氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10垸基、 C1-C10垸酰基、 C1-C10烷基磺酰基、 = 0 (氧代)、 =S (硫代)和 C1-C10垸基中的取代基取代； Wherein R 12 is H; halogen; nitro; nitrile; carboxyl; =0 (oxo); =S (thio); -C(O)OCl-C10 fluorenyl; C2-C10 alkenyl; C10 alkynyl; C1-C10 decanoyl; C1-C10 alkylsulfonyl; amino C1-C10 alkanoyl; C1-C10 alkyl; Ph(CH 2 ) ra -; s";
Figure imgf000035_0001
4-10 membered heterocyclic group; or 4-10 membered heteroaryl; above -C(O)OCl-C10 fluorenyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 decanoyl, C1-C10 Mercaptosulfonyl, amino C1-C10 decanoyl, C1-C10 alkyl, Ph(CH 2 ) m -, s", °^0, 4-10 membered heterocyclic or 4-10 membered heteroaryl Must be one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxyl, C1-C10 alkoxy, C1-C10 alkanoyloxy, -C(O)OCl- a substituent substituted with a C10 thiol group, a C1-C10 decanoyl group, a C1-C10 alkylsulfonyl group, = 0 (oxo), =S (thio), and a C1-C10 fluorenyl group;
m和 n各自独立地为 0-5的整数， q选自 0-4的整数；  m and n are each independently an integer of 0-5, and q is selected from an integer of 0-4;
Ri3为卤素、 C1-C10烷氧基、 C6-C10芳氧基或 C1-C10烷酰氧基； Ri 3 is halogen, C1-C10 alkoxy, C6-C10 aryloxy or C1-C10 alkanoyloxy;
R14为氨基保护基， 优选为苄氧羰基或叔丁氧羰基。 R 14 is an amino protecting group, preferably a benzyloxycarbonyl group or a tert-butoxycarbonyl group.
所 物：  Things:
Figure imgf000035_0002
Figure imgf000035_0002
其中， R!、 R2、 R3、 R4、 R5、 、 R8、 R12、 R13、 X和 q的定义同其在通式 II、 III、 VI 或 VII中的定义； Wherein R!, R 2 , R 3 , R 4 , R 5 , R 8 , R 12 , R 13 , X and q are as defined in the formula II, III, VI or VII;
R7为 -(CH2)mR„、 -(CH2)mO(CH2)nRn或 -(CH2)mNHR„； R 7 is -(CH 2 ) m R„, -(CH 2 ) m O(CH 2 ) n R n or -(CH 2 ) m NHR„;
其中， Ru为 H; 卤素； 硝基； 腈基； 羧基； -C(0)OCl-C4烷基； C2-C4烯基； C2-C4 炔基； C1-C4垸酰基； C1-C4垸基磺酰基； 氨基 C1-C4烷酰基； C1-C4烧基； C6-C10芳基； 4-10元杂环基；或 4-10元杂芳基；上述 -C(0)OCl-C4烷基、 C2-C4烯基、 C2-C4炔基、 C1-C4 垸酰基、 C1-C4垸基磺酰基、 氨基 C1-C4垸酰基、 C1-C4垸基、 C6-C10芳基、 4-10元杂环 基或 4-10元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈 基、 羧基、 C1-C4垸氧基、 C1-C4垸酰氧基、 -C(0)OCl-C4垸基、 C1-C4垸酰基、 C1-C4烷 基磺酰基、 =0 (氧代)、 = S (硫代)和 C1-C4垸基中的取代基取代； Wherein R u is H; halogen; nitro; nitrile; carboxyl; -C(0)OCl-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 nonanoyl; C1-C4垸Alkylsulfonyl; amino C1-C4 alkanoyl; C1-C4 alkyl; C6-C10 aryl; a 4-10 membered heterocyclic group; or a 4-10 membered heteroaryl group; the above -C(0)OCl-C4 alkyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C1-C4 decanoyl group, C1-C4 A mercaptosulfonyl group, an amino C1-C4 decanoyl group, a C1-C4 fluorenyl group, a C6-C10 aryl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group may be optionally selected from one or more selected from Halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxyl, C1-C4 decyloxy, C1-C4 nonanoyloxy, -C(0)OCl-C4 fluorenyl, C1-C4 decanoyl Substituted with a substituent in the C1-C4 alkylsulfonyl group, =0 (oxo), =S (thio) and C1-C4 fluorenyl;
其中， m和 n各自独立地为 0-5的整数。  Wherein m and n are each independently an integer of 0-5.
所述通式 ΠΑ、 IIIA、 VIA或 VIIA所示的化合物更优选为通式 IIB、 IIIB、 VIB或 VIIB 所示的  The compound represented by the formula ΠΑ, IIIA, VIA or VIIA is more preferably represented by the formula IIB, IIIB, VIB or VIIB
Figure imgf000036_0001
Figure imgf000036_0001
X为 N或 CR7, X is N or CR 7 ,
、 R2、 R3和 R4各自独立地优选为 H; 卤素； 三氟甲基； 羟基； 硝基； 腈基； 羧基： -C(0)OCl-C4垸基； 氨基； C1-C4烷氧基； C1-C4垸基； C1-C4烷酰基； C1-C4垸酰氧基； 磺酰基； 或 C1-C4垸基磺酰基； 上述 -C(0)0C1-C4垸基、氨基、 C1-C4烷氧基、 C1-C4垸基、 C1-C4垸酰基、 C1-C4烷酰氧基、磺酰基或 C1-C4垸基磺酰基可非必须地被一个或多个选自 卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C4垸基、 C1-C4垸氧基、 C1-C4垸 酰氧基、 -C(0)OCl-C4烷基、 C1-C4垸酰基、 磺酰基、 C1-C4垸基磺酰基、 苯基和苯甲基中 的取代基取代。 And R 2 , R 3 and R 4 are each independently preferably H ; halogen; trifluoromethyl; hydroxy; nitro; nitrile; carboxy: -C(0)OCl-C4 fluorenyl; amino; C1-C4 alkoxy C1-C4 fluorenyl; C1-C4 alkanoyl; C1-C4 nonanoyloxy; sulfonyl; or C1-C4 mercaptosulfonyl; -C(0)0C1-C4 fluorenyl, amino, C1- The C4 alkoxy group, the C1-C4 fluorenyl group, the C1-C4 decanoyl group, the C1-C4 alkanoyloxy group, the sulfonyl group or the C1-C4 fluorenylsulfonyl group may be optionally selected from one or more selected from the group consisting of halogen and trifluoro. Methyl, hydroxy, nitro, amino, nitrile, carboxyl, C1-C4 fluorenyl, C1-C4 decyloxy, C1-C4 nonanoyloxy, -C(0)OCl-C4 alkyl, C1-C4 Substituted in a decanoyl group, a sulfonyl group, a C1-C4 decylsulfonyl group, a phenyl group, and a benzyl group.
Ri、 R2、 R3和 R4各自独立地更优选为 H; 卤素； 羟基； 腈基； 氨基； C1-C4烷氧基； C1-C4垸基； 或 C1-C4垸酰基； 最优选为 H或卤素； Ri, R 2 , R 3 and R 4 are each independently more preferably H ; halogen; hydroxy; nitrile; amino; C1-C4 alkoxy; C1-C4 fluorenyl; or C1-C4 decanoyl; Or halogen;
R5和 各自独立地为 -(CH2)mR9或 -(CH2)mCO(CH2)nR9， 其中， 为 卤素； 羟基； 硝基； 氨基； 腈基； 羧基； -C(0)OCl-C4垸基； C1-C4垸酰基； C1-C4垸基磺酰基； C1-C4 垸基； C2-C4烯基； C2-C4炔基； C6-C10芳酰基； C1-C4烷氧基； C6-C10芳基磺酰基、 -S02NR15Ri6、 - R15S02Ri6; C6-C10芳基； 4-10元杂环基； 4-10元杂芳基； 4-10元杂环基 或 4-10元杂芳基并 C3-C8环烃基； 或者 4-10元杂环基或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基； 上述氨基、 -C(0)OCl-C4烷基、 C1-C4垸酰基、 C1-C4垸基磺酰基、 C1-C4 垸基、 C2-C4烯基、 C2-C4炔基、 C6-C10芳酰基、 C1-C4烷氧基、 C6-C10芳基磺酰基、 -S02NRi5R16、 -NRi5S02R16、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基 或 4-10元杂芳基并 C3-C8环烃基或者 4-10元杂环基或 4-10元杂芳基并 4-10元杂环基或 4-10 元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 -NR15R16、 腈基、 羧 基、 C1-C4垸氧基、 -C(0)OCl-C4烷基、 -C(0)NR15R16、 C1-C4烷酰基、 C1-C4烷基磺酰基、R 5 and each independently are -(CH 2 ) m R 9 or -(CH 2 ) m CO(CH 2 ) n R 9 , wherein, is a halogen; a hydroxyl group; a nitro group; an amino group; a nitrile group; a carboxyl group; (0)OCl-C4 fluorenyl; C1-C4 decanoyl; C1-C4 decylsulfonyl; C1-C4 fluorenyl; C2-C4 alkenyl; C2-C4 alkynyl; C6-C10 aroyl; C1-C4 Alkoxy; C6-C10 arylsulfonyl, -S0 2 NR 15 Ri6, -R 15 S0 2 Ri 6 ; C6-C10 aryl; 4-10 membered heterocyclic group; 4-10 membered heteroaryl; 4 -10 membered heterocyclic or 4-10 membered heteroaryl and C3-C8 cycloalkyl; or 4-10 membered heterocyclic or 4-10 membered heteroaryl and 4-10 membered heterocyclic or 4-10 membered a heteroaryl group; the above amino group, -C(O)OCl-C4 alkyl group, C1-C4 decanoyl group, C1-C4 decylsulfonyl group, C1-C4 fluorenyl group, C2-C4 alkenyl group, C2-C4 alkynyl group, C6-C10 aroyl, C1-C4 alkoxy, C6-C10 arylsulfonyl, -S0 2 NRi 5 R 16 , -NRi 5 S0 2 R 16 , C6-C10 aryl, 4-10 membered heterocyclic group , 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C3-C8 cycloalkyl or 4-10 membered heterocyclic or 4-10 membered heteroaryl and 4-10 A heterocyclic group or a 4-10 membered heteroaryl group may optionally be one or more From halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16, nitrile, carboxyl, C1-C4 alkoxy embankment, -C (0) OCl-C4 alkyl, -C (0) NR 15 R 16 , a C1-C4 alkanoyl group, a C1-C4 alkylsulfonyl group,
-S02NR15R16、 -NR15S02R16、 C1-C4垸基、 羟基 C1-C4垸基、 氨基 C1-C4垸基、 C6-C10芳 基 C1-C4垸基、 =0 (氧代)、 = S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10 元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取代基 取代； 更优选为 H; 羟基； 腈基； C2-C4烯基； C6-C10芳酰基； C6-C10芳基； 4-10元杂 环基； 4-10元杂芳基； 4-10元杂环基或 4-10元杂芳基并 C3-C8环烃基； 或者 4-10元杂环基 或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基；上述 C2-C4烯基、 C6-C10芳酰基、 C6-C10 芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C3-C8环烃基或者 4-10元杂环基或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基可进一步被卤素、三氟甲基、 羟基、 硝基、 -NR15R16、 腈基、 羧基、 C1-C4垸氧基、 -C(0)OCl-C4垸基、 -C(0)NR15R16、 C1-C4垸酰基、 C1-C4垸基磺酰基、 -S02NR15R16、 -NR15S02R16、 C1-C4垸基、 羟基 C1-C4 烷基、 氨基 C1-C4垸基、 C6-C10芳基 C1-C4烷基、 =0 (氧代)、 = S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂 环酰基和 4-10元杂芳酰基中的取代基取代； -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C1-C4 fluorenyl, hydroxy C1-C4 fluorenyl, amino C1-C4 fluorenyl, C6-C10 aryl C1-C4 fluorenyl, =0 ( Oxo), = S (thio), C6-C10 aryl, 4-10 membered heterocyclyl, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6 Substituted with a substituent in a C10 aryl group, a 4-10 membered heterocyclic acyl group and a 4-10 membered heteroaroyl group; more preferably H; a hydroxy group; a nitrile group; a C2-C4 alkenyl group; a C6-C10 aroyl group; C10 aryl; 4-10 membered heterocyclic group; 4-10 membered heteroaryl; 4-10 membered heterocyclic group or 4-10 membered heteroaryl and C3-C8 cyclic hydrocarbon group; or 4-10 membered heterocyclic group Or a 4-10 membered heteroaryl and 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group; the above C2-C4 alkenyl group, C6-C10 aroyl group, C6-C10 Aryl, 4-10 membered heterocyclyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl or 4-10 membered heteroaryl and C3-C8 cycloalkyl or 4-10 membered heterocyclyl or 4 a -10 membered heteroaryl group and a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group may be further substituted by halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile group, carboxyl group, C1- C4 methoxy, -C(0)OCl-C4 fluorenyl, -C(0)NR 15 R 16 , C1-C4 decanoyl, C1-C4 decylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C1-C4 fluorenyl, hydroxy C1-C4 alkyl, amino C1-C4 fluorenyl, C6-C10 aryl C1-C4 alkyl, =0 (oxo), = S (thio) , C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6-C10 aryl, 4-10 membered a substituent in the cyclic acyl group and a 4-10 membered heteroaroyl group;
或者， R5和 Re与连接它们的 X—起形成 C6-C10芳基； C3-C10环烃基； C3-C10环烃 基并 C3-C10环烃基； C3-C10环烃基并 C6-C10芳基； C6-C10芳基并 C3-C10环烃基； 4-10 元杂环基； 4-10元杂芳基； 4-10元杂环基螺环； 4-10元杂芳基螺环； [4-10元杂环基或 4-10 元杂芳基]并 [C3-C10环烃基]; [C3-C10环烃基]并 [4-10元杂环基或 4-10元杂芳基]; [4-10元 杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]; [C6-C10芳基]并 [4-10元杂环 基或 4-10元杂芳基]; [4-10元杂环基或 4-10元杂芳基]并 [C6-C10芳基]; [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]; [4-10 元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]并 [C6-C10芳基]; 上述基团可 非必须地被一个或多个 R，取代， R，选自 -(CH2)mR1(); -(CH2)mCO(CH2)„Rlo; -(CH2)mO(CH2)nRlo; -(CH2)mNHC(O)(CH2)nR10; 和 -(C¾)mNSO2(CH2)nR10; Or, R 5 and Re together with the X to which they are bonded form a C6-C10 aryl group; a C3-C10 cycloalkyl group; a C3-C10 cycloalkyl group and a C3-C10 cycloalkyl group; a C3-C10 cycloalkyl group and a C6-C10 aryl group; C6-C10 aryl and C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; 4-10 membered heterocyclyl spiro; 4-10 membered heteroaryl spiro; a 10-membered heterocyclic group or a 4-10 membered heteroaryl][C3-C10cycloalkyl]; [C3-C10cycloalkyl][4-10 membered heterocyclic or 4-10 membered heteroaryl]; [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [4-10 membered heterocyclic group or 4-10 membered heteroaryl]; [C6-C10 aryl] and [4-10 membered hetero Cycloalkyl or 4-10 membered heteroaryl]; [4-10 membered heterocyclyl or 4-10 membered heteroaryl] and [C6-C10 aryl]; [4-10 membered heterocyclyl or 4-10 (heteroaryl)][4-10 membered heterocyclic or 4-10 membered heteroaryl][4-10 membered heterocyclic or 4-10 membered heteroaryl]; [4-10 membered heterocyclic group] Or a 4-10 membered heteroaryl] and [4-10 membered heterocyclyl or 4-10 membered heteroaryl] and [C6-C10 aryl]; the above group may be optionally one or more R, Substituting, R, selected from -(CH 2 ) m R 1(); -(CH 2 ) m CO(CH 2 )„R lo; -(CH 2 ) m O(CH 2 ) n R lo; -(CH 2 ) m NHC(O)(CH 2 ) n R 10; and -(C3⁄4) m NSO 2 (CH 2 ) n R 10;
其中， 所述 R10为氢、 卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C4烷氧 基、 C6-C10芳氧基、 C1-C4烷酰氧基、 -C(0)OCl-C4烷基、 -C(0)NH2、 C1-C4垸酰基、 C1-C4 垸基磺酰基、 C6-C10芳基磺酰基、 -S02NR15Ri6、 -NR15S02R16、 C6-C10芳酰基、 CI- C4垸 基、羟基 C1-C4垸基、氨基 C1-C4烷基、 C6-C10芳基 C1-C4垸基、 =0 (氧代)、 = S (硫代)、Wherein R 10 is hydrogen, halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C4 alkoxy, C6-C10 aryloxy, C1-C4 alkanoyloxy, -C(0)OCl-C4 alkyl, -C(0)NH 2 , C1-C4 decanoyl, C1-C4 decylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 Ri 6 , NR 15 S0 2 R 16 , C6-C10 aroyl, CI-C4 fluorenyl, hydroxy C1-C4 fluorenyl, amino C1-C4 alkyl, C6-C10 aryl C1-C4 fluorenyl, =0 (oxo) , = S (thio),
C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳 C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6-C10
Ph  Ph
基、 4-10元杂环酰基、 4-10元杂芳酰基或一^- COEt ; 上述氨基、 C1-C4垸氧基、 C6-C10芳 氧基、 C1-C4烷酰氧基、 -C(0)0C1-C4烷基、 -C(0)NH2、 C1-C4烷酰基、 C1-C4垸基磺酰基、a 4-, 4-membered heterocyclic acyl group, a 4-10 membered heteroaroyl group or a mono-COEt; the above amino group, C1-C4 decyloxy group, C6-C10 aryloxy group, C1-C4 alkanoyloxy group, -C (0) 0C1-C4 alkyl, -C(0)NH 2 , C1-C4 alkanoyl, C1-C4 nonylsulfonyl,
C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C4垸基、羟基 C1-C4 垸基、 氨基 C1-C4烷基、 C6-C10芳基 C1-C4垸基、 C6-C10芳基、 4-10元杂环基、 4-10元 杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基、 4-10元杂芳酰 Ph C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C4 fluorenyl, hydroxy C1-C4 fluorenyl, amino C1-C4 alkyl, C6-C10 aryl C1-C4 fluorenyl, C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6 -C10 aryl, 4-10 membered heterocyclic acyl group, 4-10 membered heteroaroyl group Ph
基或一 可非必须地被一个或多个选自卤素、三氟甲基、羟基、硝基、 -NR15R16、腈基、 羧基、 C1-C4垸氧基、 C6-C10芳氧基、 C1-C4垸酰氧基、 -C(0)0C1-C4垸基、 -C(0)NR15R16> C1-C4烷酰基、 C1-C4垸基磺酰基、 C6-C10芳基磺酰基、 -S02 R15R16、 -NR15S02R16、 C6-C10 芳酰基、 C1-C4垸基、羟基 C1-C4烷基、氨基 C1-C4烷基、 C6-C10芳基 C1-C4烷基、 =0 (氧 代)、 = S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂 芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取代基取代； 所述 R1()更优选 为卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C4垸氧基、 苯氧基、 C1-C4烷酰 氧基、 -C(0)0C1-C4 垸基、 -C(0) H2、 C1-C4 垸酰基、 C1-C4 烷基磺酰基、 苯磺酰基、 -S02 R15Ri6 -NR15S02R16、 苯甲酰基、 C1-C4烷基、 羟基 C1-C4烷基、 氨基 C1-C4烷基、 苄基、 =0 (氧代)、 =S (硫代)、 苯基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10 Or one or more optionally selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile, carboxyl, C1-C4 decyloxy, C6-C10 aryloxy , C1-C4 nonanoyloxy, -C(0)0C1-C4 fluorenyl, -C(0)NR 15 R 16 > C1-C4 alkanoyl, C1-C4 decylsulfonyl, C6-C10 aryl sulfonate Acyl, -S02 R 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C4 fluorenyl, hydroxy C1-C4 alkyl, amino C1-C4 alkyl, C6-C10 aryl C1- C4 alkyl, =0 (oxo), = S (thio), C6-C10 aryl, 4-10 membered heterocyclyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl or 4- Substituted with a 10-membered heteroaryl group and a C6-C10 aryl group, a 4-10 membered heterocyclic acyl group and a 4-10 membered heteroaroyl group; the R 1 () is more preferably a halogen, a trifluoromethyl group or a hydroxy group. , nitro, amino, nitrile, carboxyl, C1-C4 alkoxy, phenoxy, C1-C4 alkanoyloxy, -C(0)0C1-C4 fluorenyl, -C(0)H 2 , C1 -C4 decanoyl, C1-C4 alkylsulfonyl, phenylsulfonyl, -S0 2 R 15 Ri6 -NR 15 S0 2 R 16 , benzoyl, C1-C4 alkyl, hydroxy C1-C4 alkyl, amino C1 -C4 alkyl, Benzyl, =0 (oxo), =S (thio), phenyl, 4-10 membered heterocyclyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl or 4-10
Ph  Ph
元杂芳基并 C6-C10芳基、 4-10元杂环酰基、 4-10元杂芳酰基或一 - COEt； a heteroaryl group and a C6-C10 aryl group, a 4-10 membered heterocyclic acyl group, a 4-10 membered heteroaroyl group or a -COEt;
Ris、 Ri6各自独立地为 H; C1-C4院基； C3-C10环烷基； 4-10元杂环基； 4-10元杂芳 基； 或者 R15、 R16与连接它们的 N原子一起形成 4-10元杂环基； 4-10元杂芳基； 其中， 所 述 C1-C4垸基、 C3-C10环烷基、 4-10元杂环基和 4-10元杂芳基可非必须地被 1个或多个卤 素； 羟基； 腈基； 氨基； C1-C4垸基； =0 (氧代)； =S (硫代)； C1-C4烷氧基取代； Ris, Ri 6 are each independently H ; C1-C4 ortho; C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and N The atoms together form a 4-10 membered heterocyclic group; a 4-10 membered heteroaryl group; wherein, the C1-C4 fluorenyl group, the C3-C10 cycloalkyl group, the 4-10 membered heterocyclic group, and the 4-10 membered heteroaryl group; The base may be optionally substituted by one or more halogens; a hydroxyl group; a nitrile group; an amino group; a C1-C4 alkyl group; =0 (oxo); =S (thio); a C1-C4 alkoxy group;
R8为 -(CH2)mR12、 -(CH2)mO(CH2)nR12或 -(CH2)mNHR12， R 8 is -(CH 2 ) m R 12 , -(CH 2 ) m O(CH 2 ) n R 12 or -(CH 2 ) m NHR 12 ,
其中， R12优选为 H; 卤素； 硝基； 腈基； 羧基； =0 (氧代)； =S (硫代)； -C(0)0C1-C4 烷基； C2-C4烯基； C2-C4炔基； C1-C4垸酰基； C1-C4垸基磺酰基； 氨基 C1-C4烷酰基； C1-C4烷基； Ph(CH2)m-; °=0; 4-10元杂环基； 或 4-10元杂芳基； 上述 -C(0)0C1-C4 垸基、 C2-C4烯基、 C2-C4炔基、 C1-C4烷酰基、 C1-C4垸基磺酰基、 氨基 C1-C4垸酰基、Wherein R 12 is preferably H; halogen; nitro; nitrile; carboxyl; =0 (oxo); =S (thio); -C(0)0C1-C4 alkyl; C2-C4 alkenyl; -C4 alkynyl; C1-C4 decanoyl; C1-C4 mercaptosulfonyl; amino C1-C4 alkanoyl; C1-C4 alkyl; Ph(CH 2 ) m -; °=0; 4-10 membered heterocyclic Or a 4-10 membered heteroaryl; the above -C(0)0C1-C4 fluorenyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkanoyl, C1-C4 decylsulfonyl, amino C1-C4 decanoyl,
C1-C4烧基、 Ph(CH2)m-, 0、 4-10元杂环基或 4-10元杂芳基可非必须地被一个或多 个选自卤素、 三氟甲基、羟基、硝基、 氨基、 腈基、 羧基、 C1-C4垸氧基、 C1-C4垸酰氧基、 -C(0)0C1-C4烷基、 C1-C4烷酰基、 C1-C4垸基磺酰基、 =0 (氧代)、 =S (硫代)和 C1-C4 烷基中的取代基取代； R12进一步优选为 H; 卤素； =0 (氧代)； C1-C4烷酰基； C1-C4烷基；The C1-C4 alkyl group, Ph(CH 2 ) m -, 0, 4-10 membered heterocyclic group or 4-10 membered heteroaryl group may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, and hydroxy. , nitro, amino, nitrile, carboxyl, C1-C4 decyloxy, C1-C4 nonanoyloxy, -C(0)0C1-C4 alkyl, C1-C4 alkanoyl, C1-C4 decylsulfonyl , =0 (oxo), =S (thio) and a substituent in the C1-C4 alkyl group; R 12 is further preferably H; halogen; =0 (oxo); C1-C4 alkanoyl; C1- C4 alkyl;
Ph(CH2)m -; 0； 。^； 吲哚； 二氢吲哚； 吡咯； 呋喃； 噻吩； 噻唑； 咪唑； 噁唑； 异噁唑； 吡唑； 吡啶； 吡嗪； 嘧啶； 哒嗪； 吡喃； 吲哚； 或喹啉； R1()更优选为 H; 卤素； =0 (氧代)；Ph(CH 2 ) m -; 0; ;; hydrazine; dihydroanthracene; pyrrole; furan; thiophene; thiazole; imidazole; oxazole; isoxazole; pyrazole; pyridine; pyrazine; pyrimidine; pyridazine; pyran; R 1 () is more preferably H; halogen; =0 (oxo);
C1-C4焼基； 苯基； 苄基； 0; 0=0; 吲哚； 二氢吲哚； 或吡咯； R12最优选为 H; C1-C4 fluorenyl; phenyl; benzyl; 0; 0 = 0; hydrazine; dihydroanthracene; or pyrrole; R 12 is most preferably H;
m和 n各自独立地优选为 0-3的整数； 最优选为 0、 1或 2; q优选为 0-2的整数；  m and n are each independently preferably an integer of 0 to 3; most preferably 0, 1 or 2; q is preferably an integer of 0 to 2;
R13为卤素、 C1-C4垸氧基、 C6-C4芳氧基或 C1-C4烷酰氧基； R 13 is halogen, C1-C4 decyloxy, C6-C4 aryloxy or C1-C4 alkanoyloxy;
R14为氨基保护基， 优选苄氧羰基或叔丁氧羰基。 R 14 is an amino protecting group, preferably benzyloxycarbonyl or tert-butoxycarbonyl.
根据本发明的又一方面，本发明提供了通式 I所示的 β-氨基羰基类化合物或其互变异构 体、对映体、 消旋体或其药学上可接受的盐的用途， 其作为 DPP-4抑制剂的用途， 和在制备 用于治疗 II型糖尿病、 高血糖症、 肥胖症或胰岛素抵抗症等疾病的药物中的用途。  According to still another aspect of the present invention, the present invention provides the use of a β-aminocarbonyl compound of the formula I or a tautomer, an enantiomer, a racemate thereof or a pharmaceutically acceptable salt thereof, Its use as a DPP-4 inhibitor, and in the preparation of a medicament for the treatment of diseases such as type II diabetes, hyperglycemia, obesity or insulin resistance.
根据本发明的再一方面，本发明还提供了一种包含治疗有效量的通式 I所示的 β-氨基羰 基类化合物或其互变异构体、对映体、消旋体或其药学上可接受的盐中的一种或多种的药物 组合物，其可以作为 DPP-4抑制剂， 以及该组合物可以任选包含药学上可接受的载体或赋形 剂。  According to a further aspect of the present invention, the present invention provides a therapeutically effective amount of a β-aminocarbonyl compound of the formula I or a tautomer thereof, an enantiomer, a racemate or a pharmaceutically thereof thereof. A pharmaceutical composition of one or more of the above acceptable salts, which may act as a DPP-4 inhibitor, and the composition may optionally comprise a pharmaceutically acceptable carrier or excipient.
在另一优选例中，式 I所示的 β-氨基羰基类化合物或其药学上可接受的盐在所述药物组 合物中的剂量为 l〜500mg/天。  In another preferred embodiment, the β-aminocarbonyl compound of the formula I or a pharmaceutically acceptable salt thereof is administered in the pharmaceutical composition at a dose of from 1 to 500 mg/day.
根据本发明的另一方面， 本发明还提供了一种 DPP-4抑制剂， 其含治疗有效量的通式 I 所示的 β-氨基羰基类化合物或其互变异构体、对映体、消旋体或其药学上可接受的盐中的一 种或多种， 以及该抑制剂可以任选包含药学上可接受的载体或赋形剂。  According to a further aspect of the invention there is also provided a DPP-4 inhibitor comprising a therapeutically effective amount of a β-aminocarbonyl compound of the formula I or a tautomer thereof, enantiomer thereof One or more of the racemates or pharmaceutically acceptable salts thereof, and the inhibitor may optionally comprise a pharmaceutically acceptable carrier or excipient.
该组合物由治疗有效量的一种或多种通式 I所示的 β-氨基羰基类化合物 (或其可药用盐， 或它们的可药用溶剂化物)与至少一种可药用辅料组成。 药用辅料的选择因施用途径和作用 特点而异， 通常是填充剂、稀释剂、 粘合剂、 润湿剂、 崩解剂、 润滑剂、 乳化剂、 助悬剂等。 式 I化合物、 其药学上可接受的盐或其溶剂化物在上述组合物中的所占的比例为总重量的 0.1%~99.9%, 优选 1%~99%。 所述药学上可接受的载体是指药学领域常规的药物载体， 例如： 稀释剂， 如水等； 填充 剂， 如淀粉、 蔗糖等； 粘合剂， 如纤维素衍生物、藻酸盐、 明胶、 聚乙烯吡咯烷酮； 湿润剂， 如甘油； 崩解剂， 如琼脂、 碳酸钙和碳酸氢钠； 吸收促进剂， 如季铵化合物； 表面活性剂， 如十六垸醇； 吸附载体， 如高岭土和皂粘土； 润滑剂， 如滑石粉、 硬脂酸钙和硬脂酸镁、 和 聚乙二醇等。 另外， 还可以在所述药物组合物中加入其它辅剂， 如香味剂和甜味剂等。 The composition consists of a therapeutically effective amount of one or more β-aminocarbonyl compounds of the formula I (or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof) and at least one pharmaceutically acceptable excipient composition. The choice of pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, and is usually a filler, a diluent, a binder, a wetting agent, a disintegrant, a lubricant, an emulsifier, a suspending agent, and the like. The proportion of the compound of the formula I, its pharmaceutically acceptable salt or its solvate in the above composition is from 0.1% to 99.9%, preferably from 1% to 99%, by total weight. The pharmaceutically acceptable carrier refers to a pharmaceutical carrier conventional in the pharmaceutical field, such as: a diluent such as water; a filler such as starch, sucrose, etc.; a binder such as a cellulose derivative, an alginate, gelatin, a polyvinylpyrrolidone; a humectant such as glycerin; a disintegrant such as agar, calcium carbonate and sodium hydrogencarbonate; an absorption enhancer such as a quaternary ammonium compound; a surfactant such as hexadecanol; an adsorbent carrier such as kaolin and soap. Clay; lubricants such as talc, calcium stearate and magnesium stearate, and polyethylene glycol. In addition, other adjuvants such as flavoring agents, sweeteners and the like may also be added to the pharmaceutical composition.
本发明还提供了通式 I所示的 β-氨基羰基类化合物、其药学上可接受的盐或其溶剂化物 的可药用的组合物的制备方法。通常将通式 I所示的 β-氨基羰基类化合物、其药学上可接受 的盐或其溶剂化物与可药用辅料相混合， 经常规的制备方法制成适于一定途径施用的形式 (剂型)。 剂型包括片剂、 胶囊剂、 颗粒剂、 丸剂、 溶液剂、 混悬剂、 乳剂、 软膏、 膜剂、 霜 剂、 气雾剂、 注射剂、 栓剂等。 优选片剂和胶囊剂。  The present invention also provides a process for producing a pharmaceutically acceptable composition of the β-aminocarbonyl compound of the formula I, a pharmaceutically acceptable salt thereof or a solvate thereof. The β-aminocarbonyl compound represented by the formula I, a pharmaceutically acceptable salt thereof or a solvate thereof is usually mixed with a pharmaceutically acceptable adjuvant, and is prepared in a form suitable for a certain route by a conventional preparation method (formulation form) ). The dosage form includes tablets, capsules, granules, pills, solutions, suspensions, emulsions, ointments, films, creams, aerosols, injections, suppositories, and the like. Preference is given to tablets and capsules.
本发明化合物的使用剂量一般为每天 l~500mg， 优选 10~100mg， 分单次或多次使用。 但在必要时， 可适当偏离上述剂量。 专业人员可根据具体情况和专业知识， 确定最佳剂量。 这些情况包括疾病的严重程度、 患者的个体差异、 制剂的特性和给药途径等。  The compound of the present invention is usually administered in a dose of from 1 to 500 mg, preferably from 10 to 100 mg per day, in single or multiple doses. However, if necessary, the above doses may be appropriately deviated. Professionals can determine the optimal dose based on the specific situation and expertise. These conditions include the severity of the disease, individual differences in the patient, characteristics of the formulation, and route of administration.
此外， 本发明还提供了通式 I所示的 β-氨基羰基类化合物、 其可药用盐或其溶剂化物， 或其可药用的组合物作为人用药物的用途。  Further, the present invention provides the use of the β-aminocarbonyl compound represented by the formula I, a pharmaceutically acceptable salt thereof or a solvate thereof, or a pharmaceutically acceptable composition thereof as a human drug.
根据本发明的又一方面， 本发明还提供了治疗治疗 Π型糖尿病、高血糖症、肥胖症或胰 岛素抵抗症的方法，所述方法包括施用治疗有效量的通式 I所示的 β-氨基羰基类化合物或其 互变异构体、对映体、消旋体或其药学上可接受的盐中的一种或多种或者本发明的所述药物 组合物给患者。  According to still another aspect of the present invention, the present invention provides a method of treating or treating diabetes, hyperglycemia, obesity or insulin resistance, the method comprising administering a therapeutically effective amount of a β-amino group represented by Formula I The carbonyl compound or one or more of its tautomers, enantiomers, racemates or pharmaceutically acceptable salts thereof or the pharmaceutical composition of the present invention is administered to a patient.
本发明提供的化合物或组合物可以口服、注射 (静脉、肌肉、 皮下和冠状动脉内)、舌下、 经颊、 经直肠、 经尿道、 经阴道、 经鼻、 吸入或局部途径施用。 优选的途径是口服。 用于口 服时， 可以将其制成常规的固体制剂， 如片剂、 粉剂、 粒剂、 胶囊等， 或制成液体制剂， 如 水或油悬浮剂， 或其它液体制剂， 如糖浆等； 用于肠外给药时， 可将其制成注射用的溶液、 水或油性悬浮剂等。  The compounds or compositions provided herein can be administered orally, by injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, buccal, rectal, transurethral, vaginal, nasal, inhalation or topical routes. The preferred route is oral. When used orally, it can be formulated into a conventional solid preparation such as a tablet, a powder, a granule, a capsule, or the like, or as a liquid preparation such as a water or oil suspension, or other liquid preparation such as syrup; For parenteral administration, it may be prepared as a solution for injection, water or an oily suspension, or the like.
在另一优选例中， 该化合物进一步与其他药物 （抗糖尿病药物） 联用。  In another preferred embodiment, the compound is further used in combination with other drugs (antidiabetic drugs).
根据本发明的再一方面， 本发明提供了一种抑制二肽基肽酶 IV催化活性的方法， 该方 法包括将所述的二肽基肽酶与通式 I所示的 β-氨基羰基类化合物或其互变异构体、 对映体、 消旋体或其药学上可接受的盐中的一种或多种接触。  According to still another aspect of the present invention, the present invention provides a method for inhibiting the catalytic activity of dipeptidyl peptidase IV, which comprises the dipeptidyl peptidase and the β-aminocarbonyl group represented by Formula I Contacting one or more of the compounds or their tautomers, enantiomers, racemates or pharmaceutically acceptable salts thereof.
本发明还提供了通式 I所示的 β-氨基羰基类化合物、其可药用盐或其溶剂化物， 在制备 DPP-4抑制剂的人用药物中的用途。  The present invention also provides the use of the β-aminocarbonyl compound of the formula I, a pharmaceutically acceptable salt thereof or a solvate thereof, for the preparation of a medicament for human use of a DPP-4 inhibitor.
本发明利用分子对接技术评估设计的化合物对 DPP-4的结合能力。在设计中参考了利用 碎片生长技术获得的化合物结构， 碎片生长采用了综合药物化学三维结构数据库 (Comprehensive Medicinal Chemistry, CMC)的分子碎片及发明人收集的其他分子碎片从不同 的片段起点进行延伸生长， 并通过分子对接技术进行评估。 计算结果表明本发明中的化合 物具有较好的 DPP-4抑制活性， 与体外活性实验结果吻合。  The present invention utilizes molecular docking techniques to assess the ability of a designed compound to bind to DPP-4. In the design, the structure of the compound obtained by the fragment growth technique was used. The fragment growth was carried out by using molecular fragments of the Comprehensive Medicinal Chemistry (CMC) and other molecular fragments collected by the inventors from different starting points of the fragments. And evaluated by molecular docking techniques. The calculation results show that the compound of the present invention has a good DPP-4 inhibitory activity, which is in agreement with the in vitro activity test results.
体外活性实验结果表明，本发明中的化合物对 DPP-4有不同程度的抑制作用；体外选择 性实验结果表明， 本发明中的化合物对 DPP-8和 DPP-9有较好的选择性； 体内活性实验表 明本发明部分化合物显著增强了小鼠口服葡萄糖耐量。  The results of in vitro activity experiments show that the compounds of the present invention have different degrees of inhibition on DPP-4; the results of in vitro selectivity experiments show that the compounds of the present invention have better selectivity for DPP-8 and DPP-9; Activity experiments indicate that some of the compounds of the invention significantly enhance oral glucose tolerance in mice.
通式 I所示的 β-氨基羰基类化合物、其药学上可接受的盐或其溶剂化物具有 DPP-4抑制 活性， 更重要的是， 部分化合物具有比西他列汀更强的 DPP-4抑制活性， 更好的选择性， 且 在体内实验中具有明显的降糖作用。因此本发明提供的化合物可望在临床上表现出更佳的安 全性和有效性， 临床应用前景广阔。 附图说明 The β-aminocarbonyl compound represented by the formula I, a pharmaceutically acceptable salt thereof or a solvate thereof has DPP-4 inhibitory activity, and more importantly, some of the compounds have a stronger DPP-4 than sitagliptin. Inhibition activity, better selectivity, and It has obvious hypoglycemic effect in in vivo experiments. Therefore, the compounds provided by the present invention are expected to exhibit better safety and efficacy in clinical practice, and have broad clinical application prospects. DRAWINGS
图 1(a)和图 1(b)为本发明实施例 5制备的化合物的口服葡萄糖耐量实验结果图；其中 Inh. 为抑制 (inhibition)。  Fig. 1 (a) and Fig. 1 (b) are graphs showing the results of oral glucose tolerance test of the compound prepared in Example 5 of the present invention; wherein Inh. is inhibition.
图 2(a)和图 2(b)为本发明实施例 5制备的化合物的小鼠急性毒性实验结果图。 具体实施方式  Fig. 2 (a) and Fig. 2 (b) are graphs showing the results of acute toxicity test of the compound prepared in Example 5 of the present invention. Detailed ways
下列实施例进一步解释了本发明的化合物及其中间体的合成方法，但并不限制本发明的 范围。 1H NMR在 Mercury-400或 Mercury-300核磁共振波谱仪 (Varian公司）上完成。 常规缩 写如下： s, 单峰； d， 双峰； t， 三重峰； q， 四重峰； m， 多重峰； br， 宽峰。  The following examples further illustrate the synthesis of the compounds of the present invention and intermediates thereof, but do not limit the scope of the invention. 1H NMR was performed on a Mercury-400 or Mercury-300 NMR spectrometer (Varian). Conventional abbreviations are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.
5,6-二氟 -1-茚酮是以 3.4-二氟苯甲醛为原料， 参照文献 (J. Med. Chem. 2003, 46， 399-408) 方法制备。 化合物 7-1以 5,6-二氟 -1-茚酮为原料， 参照文献 (ORG LETT. 2007, 9, 2915-2918) 方法制备。  5,6-Difluoro-1-indanone was prepared by using 3.4-difluorobenzaldehyde as a raw material according to the literature (J. Med. Chem. 2003, 46, 399-408). Compound 7-1 was prepared using 5,6-difluoro-1-indanone as a starting material by the method (ORG LETT. 2007, 9, 2915-2918).
制备例 1 :
Figure imgf000040_0001
Preparation Example 1:
Figure imgf000040_0001
5,6-二氟 -1-茚酮 (61g)溶于二氯甲垸， 冰浴下加入碘化锌 (3.54g)， 搅拌， 滴加三甲基硅氰 (183ml), 氮气保护， 逐渐升至室温， 反应 2h, 二氯甲烷稀释反应液， 饱和碳酸氢钠水溶液 洗涤有机层， 饱和食盐水洗涤有机层， 无水硫酸钠干燥， 浓缩。  5,6-Difluoro-1-indanone (61g) was dissolved in dichloromethane, and zinc iodide (3.54g) was added under ice bath, stirred, and trimethylsilyl cyanide (183ml) was added dropwise, protected by nitrogen. The mixture was warmed to room temperature, and the mixture was evaporated to dryness.
上步浓缩物溶于冰醋酸 (100ml)中， 加入氯化亚锡 (200g)， 浓盐酸 (100ml)， 油浴 140°C， 反应完全后， 冷至室温， 过滤， 二氯甲垸洗去杂质， 碱水层冰浴下， 3N盐酸调 PH=3， 二 氯甲垸萃取， 洗涤有机层， 浓缩， 浓缩物溶于二氧六烷 (100ml)， 加入 40%氢氧化钾溶液， 回流， 反应完全后， 冷至室温， 乙酸乙酯冰分层， 有机层 5%氢氧化钠溶液洗涤， 合并有机 相， EA洗涤， 水相用 3N盐酸调 pH=2， EA萃取， 饱和食盐水洗涤有机层， 无水硫酸钠干 燥， 浓缩得 39g化合物 S-l。  The concentrate is dissolved in glacial acetic acid (100ml), stannous chloride (200g), concentrated hydrochloric acid (100ml), oil bath 140 ° C, after the reaction is completed, cooled to room temperature, filtered, washed with dichloromethane Impurity, alkaline water layer under ice bath, 3N hydrochloric acid adjusted to pH = 3, dichloromethane extract, the organic layer was washed, concentrated, concentrated in dioxane (100 ml), added 40% potassium hydroxide solution, reflux, After the reaction was completed, it was cooled to room temperature, ethyl acetate was iced, and the organic layer was washed with 5% sodium hydroxide solution. The organic phase was combined, washed with EA, and the aqueous phase was adjusted to pH=2 with 3N hydrochloric acid, and extracted with EA. The layer was dried over anhydrous sodium sulfate and evaporated.
1H M (300MHZ, CDC13): δ 7.22(1Η, dd), 7.01(1Η， dd), 4.02(1Η， t), 2.99-3.09(1Η, m)， 2.81-2.93 (1Η, m), 2.34-2.51(2H, m). 1H M (300MHZ, CDC1 3 ): δ 7.22(1Η, dd), 7.01(1Η, dd), 4.02(1Η, t), 2.99-3.09(1Η, m), 2.81-2.93 (1Η, m), 2.34 -2.51(2H, m).
MS: m/e 197 [M+H]-.  MS: m/e 197 [M+H]-.
制备例 2:
Figure imgf000040_0002
Preparation Example 2:
Figure imgf000040_0002
丙二酸单乙酯钾盐 (81g)悬浮于乙腈 (300ml)中， 加入三乙胺 (94ml)， 氯化镁 (43g)， 室温 搅拌两小时。 化合物 S-l(42g)悬浮于乙腈 (150ml)， 加入 CDI(52g), 30min反应完全， 加入到 上述丙二酸单乙酯钾盐反应液中， 反应完全后， 加入 1M HC1溶液至澄清， 分层， 蒸干上层， 乙酸乙酯溶解；水层用乙酸乙酯萃取，合并乙酸乙酯层，饱和食盐水洗涤，无水硫酸钠干燥， 浓缩， 柱层析得 46g化合物 S-2。 1H NMR(300MHZ, CDC13): δ 7.09(1H, dd), 7.02(1H, dd), 4.19(2H, q), 3.52(1H, s), 2.94-3.06(lH, m), 2.81-2.93(1H, m), 2.27-2.51(2H, m)， 1.27(3H, t). The monoethyl malonate potassium salt (81 g) was suspended in acetonitrile (300 ml), triethylamine (94 ml), magnesium chloride (43 g), and stirred at room temperature for two hours. Compound S1 (42g) was suspended in acetonitrile (150ml), CDI (52g) was added, and the reaction was completed in 30min, added to the above reaction solution of monoethyl malonate potassium salt. After the reaction was completed, 1M HCl solution was added to clarify, layering. The residue was evaporated to dryness. 1H NMR (300MHZ, CDC1 3 ): δ 7.09 (1H, dd), 7.02 (1H, dd), 4.19 (2H, q), 3.52 (1H, s), 2.94-3.06 (lH, m), 2.81-2.93 (1H, m), 2.27-2.51(2H, m), 1.27(3H, t).
MS: m/e 267 [M+H]".  MS: m/e 267 [M+H]".
制备例 3:
Figure imgf000041_0001
Preparation Example 3:
Figure imgf000041_0001
化合物 S-2(20g)溶于甲醇 (50ml)， 加入氨甲醇溶液 (30ml)， 加入乙酸铵 (16g)， 65°C下反 应， 2h反应完全， 冷至室温， 加入氰基硼氢化钠 (9g)， 加入醋酸 (3ml)调 pH=5， 反应过夜， 次日蒸干溶剂， 用二氯甲烷溶解， 有机层依次用饱和 NaHC03溶液、 饱和食盐水洗涤， 无水 硫酸钠干燥， 浓缩， 柱层析得 16.5g化合物 S-3。 The compound S-2 (20 g) was dissolved in methanol (50 ml), added to a methanol solution of methanol (30 ml), and then added with ammonium acetate (16 g), and reacted at 65 ° C, the reaction was completed in 2 h, cooled to room temperature, and sodium cyanoborohydride was added. 9g), was added acetic acid (3ml) adjust pH = 5, the reaction overnight, the next day the solvent was evaporated to dryness, dissolved in methylene chloride, the organic layer was washed with saturated NaHC0 3 solution, saturated brine, dried over anhydrous sodium sulfate, and concentrated Column chromatography gave 16.5 g of compound S-3.
1H NMR(300MHZ, CDC13): δ 7.05(1Η, dd), 6.98(1Η, dd), 4.16(2Η, q)， 3.62-3.73(1Η, m)， 3.20 (1Η， br), 2.73 -2.97(2Η, m), 2.27-2.51(2Η, m), 1.92-2.14 (2Η, m)， 1.26(3Η, t). 1H NMR (300MHZ, CDC1 3 ): δ 7.05(1Η, dd), 6.98(1Η, dd), 4.16(2Η, q), 3.62-3.73(1Η, m), 3.20 (1Η, br), 2.73 -2.97 (2Η, m), 2.27-2.51(2Η, m), 1.92-2.14 (2Η, m), 1.26(3Η, t).
MS: m/e 270 [M+H]+. MS: m/e 270 [M+H] + .
制备例 4:
Figure imgf000041_0002
Preparation Example 4:
Figure imgf000041_0002
化合物 S-3(7.1g)溶于甲醇 (25ml)， 加入三乙胺 (4.5ml)， (Boc)20(6.5g), 待反应完全后蒸 干甲醇， 残留物用乙酸乙酯溶解， 依次用 KHS04溶液， 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 柱层析， 得 9.0g化合物 S-4。 The compound S-3 (7.1 g) was dissolved in methanol (25 ml), triethylamine (4.5 ml), (Boc) 2 0 (6.5 g), and the mixture was evaporated to dryness. KHS0 4 solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to give 9.0g compound S-4.
1H NMR(300MHZ, CDC13): δ7.05(1Η, dd), 6.98(1H, dd), 4.14(2H, q), 3.30-3.41(lH, m), 2.87-3.00 (IH, br), 2.70 -2.83(1H, m)， 2.45-2.50(2H, m), 2.14-2.27 (IH, m), 1.84-1.96(1H, m), 1.39(9H, s), 1.26(3H, t). 1H NMR (300MHZ, CDC1 3 ): δ7.05(1Η, dd), 6.98(1H, dd), 4.14(2H, q), 3.30-3.41(lH, m), 2.87-3.00 (IH, br), 2.70 -2.83(1H, m), 2.45-2.50(2H, m), 2.14-2.27 (IH, m), 1.84-1.96(1H, m), 1.39(9H, s), 1.26(3H, t).
制备例 5:
Figure imgf000041_0003
Preparation Example 5:
Figure imgf000041_0003
化合物 S-4(9.0g)溶于甲醇 (20ml)， 氢氧化钠 (2.9g)溶于水 (10ml)后缓慢加至反应液， 室温 搅拌， 反应完全后蒸干甲醇， 于冰水浴中加 KHS04溶液调至 pH约为 2， 用乙酸乙酯萃取， 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 得 8.74 g化合物 S-5。 The compound S-4 (9.0 g) was dissolved in methanol (20 ml), sodium hydroxide (2.9 g) was dissolved in water (10 ml), and then slowly added to the reaction mixture, stirred at room temperature, and the reaction was completed, and the methanol was evaporated to dryness in an ice water bath. The KHS0 4 solution was adjusted to pH 2, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and evaporated.
1H MR(300MHZ, CDC13): δ 7.07(1H, dd), 6.97(1Η, dd), 4.19-4.30(1Η, m), 3.39(1Η, br), 2.86-3.01 (IH, m), 2.71 -2.85(1H, m)， 2.55(2H, d), 2.14-2.28 (IH, m), 1.84-2.01(1H, m), 1.40(9H, s). 1H MR (300MHZ, CDC1 3 ): δ 7.07(1H, dd), 6.97(1Η, dd), 4.19-4.30(1Η, m), 3.39(1Η, br), 2.86-3.01 (IH, m), 2.71 -2.85(1H, m), 2.55(2H, d), 2.14-2.28 (IH, m), 1.84-2.01(1H, m), 1.40(9H, s).
MS: m/e340 [M+H]".  MS: m/e340 [M+H]".
制备例 6:
Figure imgf000042_0001
Preparation Example 6:
Figure imgf000042_0001
将化合物 S-5采用 HPLC手性制备液相仪 (色谱柱型号为 AD-H)进行手性拆分， 分别得 到单一手性异构体 S-5a和 S-5b。 色谱保留时间分别为 tR=13.5min， tR=20.0min。 The compound S-5 was subjected to chiral resolution using an HPLC chiral preparative liquid phase column (column type AD-H) to obtain the single chiral isomers S-5a and S-5b, respectively. The chromatographic retention times were t R = 13.5 min and t R = 20.0 min, respectively.
S-5a: 比旋光度 -21 °(C=0.5)。 S-5b: 比旋光度 +21 °(C=0.5)。  S-5a: Specific optical rotation -21 ° (C = 0.5). S-5b: Specific optical rotation +21 ° (C=0.5).
制备例 7: 1-(3，5-二硝基苯甲酰基) -哌嗪 (S-18)的制备
Figure imgf000042_0002
Preparation 7: Preparation of 1-(3,5-dinitrobenzoyl)-piperazine (S-18)
Figure imgf000042_0002
S-18-1 S-18  S-18-1 S-18
N-Boc 哌嗪 (290mg)， 3.5-二硝基苯甲酸苯甲酸 (300mg)， HOBT(191mg), N-甲基吗啉 (0.17ml)溶于 DMF(5ml)中， 加入 EDCI(407mg)， 室温搅拌， 反应完全， 加水， EA萃取， EA 层依次用饱和 NaHC03溶液洗涤， 饱和食盐水洗搽， 无水硫酸钠干燥， 浓缩， 柱层析得化合 物 S-18-l(203mg)。 N-Boc piperazine (290 mg), 3.5-dinitrobenzoic acid benzoic acid (300 mg), HOBT (191 mg), N-methylmorpholine (0.17 ml) dissolved in DMF (5 ml), EDCI (407 mg) stirring at room temperature, the reaction was complete, water was added, extracted with EA, EA layer was washed with saturated NaHC0 3 solution and brine paint, dried over anhydrous sodium sulfate, and concentrated by column chromatography to give compound S-18-l (203mg) .
化合物 S-18-1 (203mg)溶于 CH2C12， 加入 CF3COOH(0.5ml)， lh反应完全， 加入 CH2C12 稀释， 依次用饱和 NaHC03溶液洗涤， 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩得 167mg 1-(3，5-二硝基苯甲酰基) -哌嗪 (S-18)。 MS: m/e 281 [M+H]+. The compound S-18-1 (203 mg) was dissolved in CH 2 C1 2 , and added to CF 3 COOH (0.5 ml), and the reaction was completed in lh, diluted with CH 2 C1 2 , washed successively with saturated NaHCO 3 solution, and washed with saturated brine. The aqueous sodium sulfate was dried and concentrated to give 167 mg of 1-(3,5-dinitrobenzoyl)-piperazine (S-18). MS: m/e 281 [M+H] + .
制备例 8: l-(2-乙氧基苯甲酰基)哌嗪 (S-19)的制备
Figure imgf000042_0003
Preparation 8: Preparation of l-(2-ethoxybenzoyl)piperazine (S-19)
Figure imgf000042_0003
N-Boc哌嗪 (393mg)， 邻乙氧基苯甲酰氯 (0.25ml)， 三乙胺溶 (0.56ml)于二氯甲烷 (5ml)， 室温搅拌， 反应完全后， 加入 CH2C12稀释， 依次用 1M HC1溶液、 饱和食盐水洗涤， 无水 硫酸钠千燥， 浓缩得 372mg化合物 S-19-l。 N-Boc piperazine (393 mg), o-ethoxybenzoyl chloride (0.25 ml), triethylamine (0.56 ml) in dichloromethane (5 ml), stirred at room temperature, after completion of reaction, diluted with CH 2 C1 2 The mixture was washed with a 1M EtOAc solution and brine, dried over anhydrous sodium sulfate.
化合物 I-2(372mg)溶于 CH2C12， 加入 CF3COOH(L5ml)， lh反应完全， 加入 CH2C12稀 释， 依次用饱和 NaHC03溶液、 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩得 333mg 1-(2-乙 氧基苯甲酰基)哌嗪 (S-19)。 MS: m/e 235 [M+H]+. Compound I-2 (372mg) was dissolved in CH 2 C1 2, was added CF 3 COOH (L5ml), lh the reaction was complete, 2 C1 2 was added diluted CH, washed with saturated NaHC0 3 solution, saturated brine, dried over anhydrous sodium sulfate Concentrated to give 333 mg of 1-(2-ethoxybenzoyl)piperazine (S-19). MS: m/e 235 [M+H] + .
制备例 9: l-(2-硝基苯甲酰基)哌嗪 (S-20)的制备
Figure imgf000042_0004
Preparation 9: Preparation of l-(2-nitrobenzoyl)piperazine (S-20)
Figure imgf000042_0004
S-20-1 S-20  S-20-1 S-20
按照与制备例 7 相同的方法， 以 2-硝基苯甲酸为试剂合成 1-(2-硝基苯甲酰基)哌嗪 (S-20)。 MS: m/e 236 [M+H]+. 1-(2-Nitrobenzoyl)piperazine (S-20) was synthesized in the same manner as in Preparation 7 using 2-nitrobenzoic acid as a reagent. MS: m/e 236 [M+H] + .
制备例 10: l-(3-氯苯甲酰基)哌嗪 (S-21)的制备
Figure imgf000043_0001
Preparation 10: Preparation of l-(3-chlorobenzoyl)piperazine (S-21)
Figure imgf000043_0001
S-21-1 S-21  S-21-1 S-21
按照与制备例 7相同的方法， 以间氯苯甲酸为试剂合成 1-(3-氯苯甲酰基)哌嗪 (S-21) MS: m/e 225 [M+H]+. 1-(3-Chlorobenzoyl)piperazine (S-21) MS was synthesized in the same manner as in Preparation 7 using m-chlorobenzoic acid as a reagent: m/e 225 [M+H] + .
制备例 11 : 1- (吡啶 -2-基-酰基)哌嗉 (S-22)的制备
Figure imgf000043_0002
Preparation 11 : Preparation of 1-(pyridin-2-yl-acyl)piperidinium (S-22)
Figure imgf000043_0002
按照与制备例 7相同的方法， 以 2-吡啶甲酸为试剂合成 1- (吡啶 -2-基-酰基)哌嗪 (S-22)c MS: m/e 192[M+H]+. 1-(Pyridin-2-yl-acyl)piperazine (S-22) c MS: m/e 192 [M+H] + was synthesized in the same manner as in Preparation 7.
制备例 12: l-(吡嗪 -2-基-酰基;)哌嗪 (S-23)的制备
Figure imgf000043_0003
Preparation 12: Preparation of l-(pyrazin-2-yl-acyl;) piperazine (S-23)
Figure imgf000043_0003
按照与制备例 7相同的方法， 以吡嗪单羧酸为试剂合成 1- (吡嗪 -2-基-酰基)哌嗪 (S-23)c MS: m/e 193[M+H]+. Synthesis of 1-(pyrazin-2-yl-acyl)piperazine (S-23)c MS using the same procedure as in Preparation 7 using pyrazine monocarboxylic acid as a reagent: m/e 193 [M+H] + .
制备例 13: 3-腈基 -2-(((S)-吡咯 -2-基)甲氧基)吡啶 (S-24)的制备  Preparation 13: Preparation of 3-cyano-2-((S)-pyrrol-2-yl)methoxy)pyridine (S-24)
Figure imgf000043_0004
Figure imgf000043_0004
化合物 S-24- 1(1.5g)溶于 CH2C12， 加入三乙胺 (2.5ml), 加入 Boc20(3g)， 反应过夜， 加 CH2C12稀释， 有机层依次用 1M HC1溶液、 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 短柱 层析得 1.39g化合物 S-24-2。 The compound S-24-1 (1.5 g) was dissolved in CH 2 C1 2 , triethylamine (2.5 ml) was added, and Boc 2 0 (3 g) was added, and the reaction was allowed to stand overnight, diluted with CH 2 C1 2 , and the organic layer was sequentially taken with 1M HCl. The solution was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated.
化合物 S-24-2 (1.38g)溶于 THF(10ml)， 冰浴下滴加 BH3-THF(7ml)溶液， 反应完全后， 冰浴下加入甲醇淬灭， 蒸干， EA溶解， EA层依次用饱和 NaHC03溶液、 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩得 1.28g化合物 S-24-3。 Compound S-24-2 (1.38g) was dissolved in THF (10ml), under ice-cooling was added dropwise BH 3 -THF (7ml) was, after the completion of the reaction, methanol was quenched in an ice bath, evaporated to dryness, dissolved EA, EA layer was washed with saturated NaHC0 3 solution, saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 1.28g compound S-24-3.
NaH(180 mg)悬浮于 DMF(5ml)中，冰浴下加入化合物 S-24-3 (250mg)的 DMF溶液 (3ml)， lOmin后， 加入 2-氯 -3-氰基吡啶 (166mg)的 DMF溶液 (3ml)， 反应完全， 加入 N C1溶液淬 灭， EA萃取， 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 柱层析得 308mg化合物 S-24-4。  NaH (180 mg) was suspended in DMF (5 mL). EtOAc (EtOAc m. DMF solution (3 ml), the reaction was completed, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated.
化合物 S-24-34(308mg)溶于 CH2C12，滴加 CF3COOH(lml)， 30min反应完全，蒸干， CH2C12 溶解， 依次用饱和 NaHC03溶液、 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 短柱层析得 184mg 3-腈基 -2-(((S)-吡咯 -2-基)甲氧基)吡啶 (S-24)。 MS: m/e 204 [M+H]+. The compound S-24-34 (308 mg) was dissolved in CH 2 C1 2 , and CF 3 COOH (1 ml) was added dropwise, and the reaction was completed in 30 min, evaporated to dryness, and dissolved in CH 2 C1 2 and washed successively with saturated NaHCO 3 and saturated brine. Dry over anhydrous sodium sulfate, concentrate and EtOAc EtOAc EtOAc EtOAc EtOAc MS: m/e 204 [M+H] + .
制备例 14: 3- (甲磺酰基) -N-(((S)-吡咯 -2-基)甲基)苯甲酰胺 (S-25)的制备 Boc、Preparation 14: Preparation of 3-(methylsulfonyl)-N-(((S)-pyrrol-2-yl)methyl)benzamide (S-25) Boc,
0
Figure imgf000044_0001
0
Figure imgf000044_0001
化合物 S-25-1 (207mg)溶于 DMF， 依次加入 DIPEA(0.9ml)， HOBT(210mg) , EDCI(298mg), 3-甲砜基苯甲酸 (207mg)， 室温搅拌， 反应完全后， 加入 1M HCl溶液， EA 萃取， EA层依次用饱和 NaHC03溶液、饱和食盐水洗涤 EA层，干燥浓缩，柱层析得 141mg 化合物 S-25-2。 The compound S-25-1 (207 mg) was dissolved in DMF, and then DIPEA (0.9 ml), HOBT (210 mg), EDCI (298 mg), 3-methylsulfonylbenzoic acid (207 mg), stirred at room temperature, after the reaction was completed, 1 M HCl solution, EA extraction, EA layer was washed successively with saturated NaHC0 3 solution and saturated brine, dried and concentrated, and 141 mg of compound S-25-2.
化合物 S-25-12(141mg)溶于 CH2C12， 加入 CF3COOH(0.2ml)， 30min反应完全， 蒸干， CH2C12溶解， 有机层依次用饱和 NaHC03溶液、 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 短柱层析得 104mg 3- (甲磺酰基) -N-(((S)-吡咯 -2-基)甲基)苯甲酰胺 (S-25)。 Compound S-25-12 (141 mg) was dissolved in CH 2 C1 2 , CF 3 COOH (0.2 ml) was added, the reaction was completed in 30 min, evaporated to dryness, CH 2 C1 2 was dissolved, and the organic layer was successively washed with saturated NaHC0 3 and saturated brine. This was washed with anhydrous sodium sulfate and concentrated, and then evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
MS: m/e 283 [M+H]+.  MS: m/e 283 [M+H]+.
制备例 15: N-( — NH2 Preparation 15: N-(-NH 2
Boc、 . Boc, .
Figure imgf000044_0002
Figure imgf000044_0002
S-26-1 S-26-2 S-26 化合物 S-26-l(200mg)溶于 CH2C12，加入三乙胺 (0.14ml)，冰浴下滴加苯甲磺酰氯 (176mg) 的 CH2C12溶液， 滴加完毕， 撤冰浴， lh反应完全， CH2C12稀释， 有机层依次用 1M HC1溶 液、 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 柱层析得 310mg化合物 S-26-2。 S-26-1 S-26-2 S-26 Compound S-26-1 (200mg) was dissolved in CH 2 C1 2 , triethylamine (0.14ml) was added, and benzenesulfonyl chloride (176mg) was added dropwise in an ice bath. The CH 2 C1 2 solution was added dropwise, and the ice bath was removed. The reaction was completed in lh, and the mixture was diluted with CH 2 C1 2 . The organic layer was washed with 1M HCl solution and brine, dried over anhydrous sodium sulfate, and concentrated. 310 mg of compound S-26-2.
化合物 S-26-2(310mg)溶于 CH2C12, 滴加 CF3COOH(0.5ml)， 30min反应完全， 蒸干， CH2C12溶解， 有机层依次用 NaHC03溶液、饱和食盐水洗涤， 干燥浓缩， 短柱层析得 180mg N-(((S)-吡咯 -2-基)甲基)苯磺酰胺 (S-26)。 MS: m/e 241 [M+H]+. Compound S-26-2 (310mg) was dissolved in CH 2 C1 2 , CF 3 COOH (0.5ml) was added dropwise, the reaction was completed in 30min, evaporated to dryness, CH 2 C1 2 was dissolved, and the organic layer was sequentially treated with NaHC0 3 solution and saturated brine. Washing, concentration by drying, and short column chromatography gave 180 mg of N-(((S)-pyrrol-2-yl)methyl)benzenesulfonamide (S-26). MS: m/e 241 [M+H] + .
制备例 16: 3-氯 -N-(((S)-吡咯 -2-基)甲基)苯甲酰胺 (S-27)的制备  Preparation Example 16: Preparation of 3-chloro-N-(((S)-pyrrol-2-yl)methyl)benzamide (S-27)
Boc、 「ΝΗ2 Boc, "ΝΗ 2
+ +
Figure imgf000044_0003
Figure imgf000044_0003
S-27-1 S-27-2 S-27 按照与制备例 14相同的方法， 以间氯苯甲酸为试剂合成 3-氯 -N-(((S)-吡咯 -2-基)甲基) 苯甲酰胺 (S-27)。 MS: m/e 239 [M+H]+. S-27-1 S-27-2 S-27 Synthesis of 3-chloro-N-(((S)-pyrrol-2-yl)methyl) using m-chlorobenzoic acid as reagent in the same manner as in Preparation 14 Benzoylamide (S-27). MS: m/e 239 [M+H] + .
制备例 17:  Preparation 17:
Figure imgf000044_0004
Figure imgf000044_0004
S-49-1 S-49-2 S-49  S-49-1 S-49-2 S-49
3-甲砜基苯甲酸 (60mg)溶于 DMF， 加入 NEt3(60ul)， HATU(lOOmg), 反应完全后， 加入 化合物 S-49-1 (56mg)， 反应完全， 加入 1M HCl溶液， EA萃取， EA层依次用 NaHC03溶液， 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 柱层析得 50mg化合物 S-49-2。 化合物 S-49-2(50mg)溶于 CH2C12， 加入 CF3COOH(0.3ml)， 反应完全后， 蒸干得化合 物 S-49。 MS: m/e 269[M+H]+. 3-Methylsulfonylbenzoic acid (60 mg) was dissolved in DMF, NEt 3 (60 ul), HATU (100 mg) was added. After the reaction was completed, compound S-49-1 (56 mg) was added, the reaction was completed, and 1 M HCl solution was added, EA. The EA layer was washed with a NaHC0 3 solution, brine, dried over anhydrous sodium sulfate, and evaporated The compound S-49-2 (50 mg) was dissolved in CH 2 C1 2 and then added to CF 3 COOH (0.3 ml). MS: m/e 269 [M+H] + .
制  System
Figure imgf000045_0001
Figure imgf000045_0001
按照与制备例 18相同的方法， 以 S-50-1为试剂合成化合物 S-50  The compound S-50 was synthesized in the same manner as in Preparation 18 using S-50-1 as a reagent.
MS: m/e 327[M+H]+. MS: m/e 327 [M+H] + .
制备例 19: 化合物 S-57的制备  Preparation 19: Preparation of Compound S-57
CF3COOH
Figure imgf000045_0002
CF 3 COOH
Figure imgf000045_0002
化合物 S-57-1 (500mg)溶于 CH2C12， 加入 NEt3(1.68ml)， 加入 Boc20(884mg)， 过夜， 反 应完全， 加入 1M HC1溶液洗涤， 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩得 l.lg化合物 S-57-l o Compound S-57-1 (500mg) was dissolved in CH 2 C1 2, were added NEt 3 (1.68ml), was added Boc 2 0 (884mg), overnight, the reaction was complete, the solution was washed with 1M HC1, saturated brine, dried over anhydrous Dry over sodium sulfate and concentrate to give l.lg compound S-57-lo
NaH(26mg)悬浮于干燥 THF中， 冰浴下加入化合物 S-57-1 (lOOmg)的 THF溶液， lOmin 后， 加入 2-氯 -3-氰基吡啶 (74mg)的 THF溶液， 5h反应完全， 加入饱和氯化铵溶液淬灭， 蒸 干 THF， EA萃取， 饱和食盐水洗涤 EA层， 无水硫酸钠干燥， 浓缩得化合物 S-57-3。  NaH (26 mg) was suspended in dry THF. A solution of compound S-57-1 (100 mg) in THF was added to the mixture. After 10 min, a solution of 2-chloro-3-cyanopyridine (74 mg) in THF was added. After quenching with a saturated aqueous solution of ammonium chloride, THF was evaporated, EtOAc was evaporated.
化合物 S-57-3溶于 CH2C12，加入 CF3COOH，反应完全后，蒸干，柱层析得化合物 S-57。 MS: m/e 190 [M+H]+. The compound S-57-3 was dissolved in CH 2 C1 2 , and CF 3 COOH was added. After the reaction was completed, the mixture was evaporated to dryness and then purified to afford compound S-57. MS: m/e 190 [M+H] + .
制备例 20:
Figure imgf000045_0003
Preparation Example 20:
Figure imgf000045_0003
2-哌啶甲酸 (lg)溶于甲醇中， 加入三乙胺 (1.42ml)， Boc20(1.85g), 反应过夜， 反应完全 后蒸干， CH2C12溶解， 1M HC1溶液洗涤， 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩得白色 固体， 石油醚洗涤得 1.59g化合物 S-58-l。 Pipecolic acid (LG) was dissolved in methanol and washed with triethylamine (1.42ml), Boc 2 0 ( 1.85g), the reaction overnight, evaporated to dryness after the reaction was complete, CH 2 C1 2 was dissolved, 1M HC1 solution, The mixture was washed with brine, dried over anhydrous sodium sulfate
化合物 S-58-1 (500mg)溶于干燥 THF， 冰浴下加入硼垸四氢呋喃溶液 (lml)， 反应完全， 加入甲醇淬灭， 蒸干， 柱层析得 250mg化合物 S-58-2。  The compound S-58-1 (500 mg) was dissolved in dry THF. EtOAc EtOAc (EtOAc)
化合物 S-58-2(40mg)溶于 CH2C12， 加入 CF3COOH(0.2ml)， lh反应完全， 蒸干得化合物 S-58。 MS: m/e 116 [M+H]+. The compound S-58-2 (40 mg) was dissolved in CH 2 C1 2 and then added to CF 3 COOH (0.2 ml). MS: m/e 116 [M+H] + .
制备例 21 : 化合物 S-62的制备
Figure imgf000046_0001
Preparation 21: Preparation of Compound S-62
Figure imgf000046_0001
S-62-4 S-62  S-62-4 S-62
化合物 S-62-l(300mg)溶于甲醇， 加入 NEt3(0.15ml)， Boc20(229mg), 反应完全， 蒸干 溶剂， EA溶解， EA层依次用 1M HC1溶液， 饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 浓缩 得 330mg化合物 S-62-2。 Compound S-62-l (300mg) was dissolved in methanol, was added NEt 3 (0.15ml), Boc 2 0 (229mg), the reaction was complete, solvent was evaporated to dryness, dissolved EA, EA layer was washed with 1M HC1 solution, saturated sodium chloride The solution was washed, dried over anhydrous sodium sulfate and evaporated
化合物 S-62-2 (330mg)溶于干燥 THF, 冰浴下加入硼烷四氢呋喃溶液 (2ml)， 反应完全， 加入甲醇淬灭， 蒸干， 柱层析得 150mg化合物 S-62-3。  The compound S-62-2 (330 mg) was dissolved in dry THF. EtOAc EtOAc (EtOAc)
NaH(45mg)悬浮于干燥 TH 中， 冰浴下加入化合物 S-62-3(110mg)的 THF溶液， lOmin 后， 加入 2-氯 -3-氰基吡啶 (52mg)的 THF溶液， 室温搅拌， 18h后反应完全， 饱和氯化铵溶 液淬灭， 蒸干 THF， EA萃取， 饱和食盐水洗涤 EA层， 无水硫酸钠干燥， 浓缩， 柱层析得 40mg化合物 S-62-4。  NaH (45 mg) was suspended in dry TH, and a solution of compound S-62-3 (110 mg) in THF was added to the mixture. After 10 min, a solution of 2-chloro-3-cyanopyridine (52 mg) in THF was added and stirred at room temperature. After 18 h, the reaction was completed. EtOAc (EtOAc m.).
化合物 S-62-4(40mg)溶于 CH2C12， 加入 CF3COOH(0.2ml)， lh反应完全， 蒸干得化合物 S-62。 MS: m/e 294 [M+H]+. The compound S-62-4 (40 mg) was dissolved in CH 2 C1 2 and then added to CF 3 COOH (0.2 ml). MS: m/e 294 [M+H] + .
制备例 22: 化合物 S-63的制备
Figure imgf000046_0002
Preparation 22: Preparation of Compound S-63
Figure imgf000046_0002
S-63-1 S-63-2 S-63  S-63-1 S-63-2 S-63
化合物 S-63-l(150mg)溶于 DMF， 加入 H4Cl(218mg)， DIPEA(0.37ml), 冰浴下加入 HATU(293mg), 反应完全后， 加入 IM HCr溶液， EA萃取， EA层依次用 NaHC03溶液， 饱 和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 柱层析得 40mg化合物 S-63-2。 Compound S-63-l (150 mg) was dissolved in DMF, H 4 Cl (218 mg), DIPEA (0.37 ml) was added, and HATU (293 mg) was added to the ice bath. After the reaction was completed, IM HCr solution was added, EA extraction, EA layer washed successively with NaHC0 3 solution, saturated brine, dried over anhydrous sodium sulfate, and concentrated, to give 40mg column chromatography to compound S-63-2.
化合物 S-63-2(40mg)溶于 CH2C12， 加入 CF3COOH(0.2ml)， 反应完全后， 蒸干得化合物 S-63。 MS: m/e 129 [M+H]+. Compound S-63-2 (40 mg) was dissolved in CH 2 C1 2 and then added to CF 3 COOH (0.2 ml). MS: m/e 129 [M+H] + .
制备例 23: 化合物 S-64的制备  Preparation 23: Preparation of Compound S-64
Figure imgf000046_0003
Figure imgf000046_0003
按照与制备例 24相同的方法， 以 S-64-1为试剂合成化合物 S-64  The compound S-64 was synthesized by the same method as in Preparation Example 24 using S-64-1 as a reagent.
MS: m/e 205[M+H]+. MS: m/e 205 [M+H] + .
制备例 24: 化合物 S-65的制备
Figure imgf000047_0001
Preparation 24: Preparation of Compound S-65
Figure imgf000047_0001
化合物 S-65-1 (300mg)溶于丙酮， 加入 K2C03(385mg)， CH3I(0.6ml)， 过夜， 反应完全， 蒸干溶剂， EA萃取，饱和氯化钠溶液洗涤 EA层，无水硫酸钠干燥，浓缩，短柱层析得 190mg 化合物 S-65-2。 Compound S-65-1 (300 mg) was dissolved in acetone, K 2 CO 3 (385 mg), CH 3 I (0.6 ml) was added, overnight, the reaction was completed, the solvent was evaporated, EA was extracted, and the EA layer was washed with saturated sodium chloride solution. Drying over anhydrous sodium sulfate, concentration and short column chromatography gave 190 mg of compound S-65-2.
化合物 S-65-2 (190mg)溶于二氯甲垸， -78°C冷却， 滴加 DAST(0.17ml)试剂， 室温搅拌， 反应完全后， 加冰水淬灭， 分液， 饱和食盐水洗涤有机层， 无水硫酸钠干燥， 浓缩， 柱层析 得 150mg化合物 S-65-3。  Compound S-65-2 (190mg) was dissolved in dichloromethane, cooled at -78 ° C, DAST (0.17ml) reagent was added dropwise, stirred at room temperature, after completion of reaction, quenched with ice water, liquid separation, saturated brine The organic layer was washed, dried over anhydrous sodium sulfate and evaporated.
化合物 S-65-3 (28mg)溶于 CH2C12， 加入 CF3COOH(0.2ml)， lh反应完全， 蒸干得化合 物 S-65。 MS: m/e 166 [M+H]+. The compound S-65-3 (28 mg) was dissolved in CH 2 C1 2 and then added to CF 3 COOH (0.2 ml). MS: m/e 166 [M+H] + .
制备例 25: 化合物 S-68的制备  Preparation 25: Preparation of Compound S-68
Figure imgf000047_0002
Figure imgf000047_0002
按照与制备例 7相同的方法， 以对甲氧基苯甲酸为试剂合成化合物 S-68。  In the same manner as in Preparation Example 7, the compound S-68 was synthesized using p-methoxybenzoic acid as a reagent.
MS: m/e 221 [M+H]+.  MS: m/e 221 [M+H]+.
制备例 26: 化合物 S-69的制备  Preparation 26: Preparation of Compound S-69
Figure imgf000047_0003
Figure imgf000047_0003
S-69-1 S-69  S-69-1 S-69
按照与制备例 7相同的方法， 以对甲氧基苯甲酸为试剂合成化合物 S-69 c  The compound S-69 c was synthesized by the same method as in Preparation Example 7 using p-methoxybenzoic acid as a reagent.
MS: m/e 235 [Μ+Η]+·  MS: m/e 235 [Μ+Η]+·
制备例 27: 化合 S-70的制备  Preparation 27: Preparation of compound S-70
Figure imgf000047_0004
Figure imgf000047_0004
按照与制备例 7相同的方法， 以 3.4-二氟苯甲酸为试剂合成化合物 S-70。  Compound S-70 was synthesized in the same manner as in Preparation Example 7 using 3.4-difluorobenzoic acid as a reagent.
MS: m/e 227 [M+H]+. 制备例 28: 化合 S-71的制备 MS: m/e 227 [M+H] + . Preparation 28: Preparation of Compound S-71
Figure imgf000048_0001
Figure imgf000048_0001
按照与制备例 7相同的方法， 以间甲基苯甲酸为试剂合成化合物 S-71 MS: m/e 205[M+H]+. The compound S-71 MS was synthesized in the same manner as in Preparation 7 using m-methylbenzoic acid as a reagent: m/e 205 [M+H] + .
制备例 29: 化合物 S-72的制备 Preparation 29: Preparation of Compound S-72
Figure imgf000048_0002
Figure imgf000048_0002
按照与制备例 7相同的方法， 以 S-72-1为试剂合成化合物 S-72 MS: m/e 245[M+H]+. In the same manner as in Preparation Example 7, the compound S-72 MS was synthesized using S-72-1 as a reagent: m/e 245 [M+H] + .
制备例 30: 化合物 S-73的制备 Preparation 30: Preparation of Compound S-73
Figure imgf000048_0003
Figure imgf000048_0003
按照与制备例 7相同的方法， 以 S-73-1为试剂合成化合物 S-73。 Compound S-73 was synthesized in the same manner as in Preparation Example 7 using S-73-1 as a reagent.
MS: m/e 246[M+H]+. MS: m/e 246 [M+H] + .
制备例 31 : 化合物 S-74的制备 Preparation 31: Preparation of Compound S-74
Figure imgf000048_0004
Figure imgf000048_0004
按照与制备例 7相同的方法， 以 S-74-1为试剂合成化合物 S-74。 Compound S-74 was synthesized in the same manner as in Preparation Example 7 using S-74-1 as a reagent.
MS: m/e 244 [M+H]+. MS: m/e 244 [M+H] + .
制备例 32： 化合物 S-75的制备
Figure imgf000049_0001
Preparation 32: Preparation of Compound S-75
Figure imgf000049_0001
按照与制备例 7相同的方法， 以 S-75-1为试剂合成化合物 S-75 Synthesis of Compound S-75 using S-75-1 as a reagent in the same manner as in Preparation Example 7.
MS: m/e 301[M+H]+. MS: m/e 301 [M+H] + .
制备例 33 : Preparation Example 33:
Figure imgf000049_0002
Figure imgf000049_0002
S-76-2  S-76-2
按照与制备例 7相同的方法， 以 S-76-1试剂合成化合物 S-76。 Compound S-76 was synthesized in the same manner as in Preparation Example 7 using the S-76-1 reagent.
MS: m/e 208 [M+H]+.  MS: m/e 208 [M+H]+.
制备例 34: 化合物 S-77的制备 Preparation 34: Preparation of Compound S-77
Figure imgf000049_0003
Figure imgf000049_0003
按照与制备例 7相同的方法， 以 S-77-1为试剂合成化合物 S-77。 Compound S-77 was synthesized in the same manner as in Preparation Example 7 using S-77-1 as a reagent.
MS: m/e 390 [M+H]+. MS: m/e 390 [M+H] + .
制备例 35: 化合物 S-78的制备 Preparation 35: Preparation of Compound S-78
,o、  , o,
HO、  HO,
、CT  , CT
HN O S-78-1 Boc- 、  HN O S-78-1 Boc- ,
-。、 CF3COOH HN -. , CF 3 COOH HN
N、 DIPEA N M、 N, DIPEA N M,
' HOBT 、r 、0 EDCI o 0 ' HOBT , r , 0 EDCI o 0
S-78-2 S-78 按照与制备例 7相同的方法， 以 S-78-1为试剂合成化合物 S-78。 S-78-2 S-78 Compound S-78 was synthesized in the same manner as in Preparation Example 7 using S-78-1 as a reagent.
MS: m/e 249[M+H]+. MS: m/e 249 [M+H] + .
制备例 36: 化合物 S-79的制备
Figure imgf000050_0001
Preparation 36: Preparation of Compound S-79
Figure imgf000050_0001
S-79-2 S-79  S-79-2 S-79
按照与制备例 7相同的方法， 以 S-79-1为试剂合成化合物 S-79。 MS m/e 323[M+H]' 制备例 37: 化合物 S-80的制备 Compound S-79 was synthesized in the same manner as in Preparation Example 7 using S-79-1 as a reagent. MS m/e 323 [M+H]' Preparation 37: Preparation of compound S-80
Figure imgf000050_0002
Figure imgf000050_0002
S-80-2 S-80  S-80-2 S-80
按照与制备例 7相同的方法， 以 S-80-1为试剂合成化合物 S-80。 MS m/e 337[M+H] 制备例 38: 化合物 S-81的制备 Compound S-80 was synthesized in the same manner as in Preparation Example 7 using S-80-1 as a reagent. MS m/e 337 [M+H] Preparation 38: Preparation of Compound S-81
Figure imgf000050_0003
Figure imgf000050_0003
S-81 -2 S-81  S-81 -2 S-81
按照与制备例 7相同的方法， 以 S-81-1为试剂合成化合物 S-81。 MS m/e 235[Μ+Η]+ σ 制备例 39: 化合物 S-82的制备 In the same manner as in Preparation Example 7, the compound S-81 was synthesized using S-81-1 as a reagent. MS m/e 235 [Μ+Η] + σ Preparation 39: Preparation of Compound S-82
Boc、 ίBoc, ί
Figure imgf000050_0004
Figure imgf000050_0004
S-82-1 S-82-2 S-B2  S-82-1 S-82-2 S-B2
按照与制备例 14相同方法，以 3-吡啶甲酸为试剂合成化合物 S-82。MS m/e 206 [M+H] 制备例 40: 化合物 S-83的制备 Compound S-82 was synthesized in the same manner as in Preparation 14 using 3-pyridinecarboxylic acid as a reagent. MS m/e 206 [M+H] Preparation 40: Preparation of Compound S-83
Boc、 ί — ΝΗ2 Boc, ί — ΝΗ 2
Figure imgf000050_0005
Figure imgf000050_0005
S-83-1 S-83-2 S-83 S- 83 - 1 S-83-2 S-83
按照与制备例 14相同方法， 以 2,4-二氟苯甲酸为试剂合成化合物 S-83 The compound S-83 was synthesized by the same method as in Preparation Example 14 using 2,4-difluorobenzoic acid as a reagent.
MS m/e 241 [M+H]+。  MS m/e 241 [M+H]+.
制备例 41 : 化合物 S-84的制备 Boc、 —
Figure imgf000051_0001
Preparation 41: Preparation of Compound S-84 Boc, —
Figure imgf000051_0001
S-8 -1 S-84-2 S-B4-3 S-84 按照与制备例 14相同的方法， 以化合物 S-84-2为试剂合成化合物 S-84 MS m/e 284[M+H]+。 S-8 -1 S-84-2 S-B4-3 S -84 The compound S-84 MS m/e 284 [M+H] was synthesized using the compound S-84-2 as a reagent in the same manner as in Preparation 14. ]+.
制备例 42: 化合物 S-85的制备
Figure imgf000051_0002
Preparation 42: Preparation of Compound S-85
Figure imgf000051_0002
S-85-1 S-85-2 S-85-3 S-85 按照与制备例 14相同的方法， 以化合物 S-85-2为试剂合成化合物 S-85。 MS m/e 340[M+H]+ o S-85-1 S-85-2 S-85-3 S-85 Compound S-85 was synthesized in the same manner as in Preparation 14 using Compound S-85-2. MS m/e 340[M+H] + o
制备例 43: 化合物 S-86的制备 Preparation 43: Preparation of Compound S-86
Boc、 — NH2
Figure imgf000051_0003
Boc, — NH 2
Figure imgf000051_0003
S-86-1 S-86-2 S-86-3 S-86 按照与制备例 14相同的方法， 以化合物 S-86-2为试剂合成化合物 S-86 MS m/e 302[M+H]+ o S-86-1 S-86-2 S-86-3 S-86 The compound S-86 was synthesized in the same manner as in Preparation 14 using the compound S-86-2 as a reagent. MS m/e 302 [M+H ] + o
制备例 44: 化合物 S-87的制备
Figure imgf000051_0004
Preparation 44: Preparation of Compound S-87
Figure imgf000051_0004
S-87-1 S-87-2 S-87-3 s-87 按照与制备例 14相同的方法， 以化合物 S-87-2为试剂合成化合物 S-87t S-87-1 S-87-2 S-87-3 s-87 Compound S-87 t was synthesized by the same procedure as in Preparation 14 using the compound S-87-2 as a reagent.
Figure imgf000051_0005
Figure imgf000051_0005
S-88-1 S-88-2 S-88-3 s-88 按照与制备例 14相同的方法， 以化合物 S-88-2为试剂合成化合物 S-88。 S-88-1 S-88-2 S-88-3 s-88 Compound S-88 was synthesized in the same manner as in Preparation 14 using Compound S-88-2.
MS m/e 320[M+H]+ o MS m/e 320[M+H] + o
制备例 46: 化 Preparation 46:
Boc、 ί H2 Boc, ί H 2
+ +
Figure imgf000051_0006
Figure imgf000051_0006
S-89-1 S-89-2 S-89-3 S-89 按照与制备例 14相同的方法， 以化合物 S-89-2为试剂合成化合物 S-89。 S-89-1 S-89-2 S-89-3 S-89 Compound S-89 was synthesized in the same manner as in Preparation 14 using Compound S-89-2 as a reagent.
Figure imgf000052_0001
Figure imgf000052_0001
按照与制备例 14相同的方法， 以化合物 S-90-2为试剂合成化合物 S-90c Synthesis of Compound S-90 c using Compound S-90-2 as a reagent in the same manner as in Preparation 14
Figure imgf000052_0002
Figure imgf000052_0002
按照与制备例 14相同的方法， 以化合物 S-91-2为试剂合成化合物 S-91 MS m/e 344[M+H]+。 The compound S-91 MS m/e 344 [M+H]+ was synthesized in the same manner as in Preparation 14 using Compound S-91-2.
制备例 49: 化合物 S-92的制备 Preparation 49: Preparation of Compound S-92
Boc、 ί -一 Boc, ί - one
S-92-1
Figure imgf000052_0003
S-92-1
Figure imgf000052_0003
同的方法， 以化合物 S-92-2为试剂合成化合物 S-92
Figure imgf000052_0004
The same method, using the compound S-92-2 as a reagent to synthesize the compound S-92
Figure imgf000052_0004
制备例 50: 化合物 S-93的制备 Preparation 50: Preparation of Compound S-93
Boc, 厂 Boc, factory
S-93-1
Figure imgf000052_0005
S-93-1
Figure imgf000052_0005
按照与制备例 14相同的方法， 以化合物 S-93-2为试剂合成化合物 S-93
Figure imgf000052_0006
Synthesis of Compound S-93 using Compound S-93-2 as a reagent in the same manner as in Preparation 14
Figure imgf000052_0006
制备例 51: 化合物 S-94的制备 Preparation 51: Preparation of Compound S-94
Figure imgf000053_0001
Figure imgf000053_0001
S-94-8 S-94  S-94-8 S-94
化合物 S-94-l(30.45g)溶于的无水 THF(300ml)， 加入 NaBH4(17.1g)， 搅拌降温到 0°C , 滴加三氟化硼乙醚溶液 (72mL),0.3h滴加完毕，自然升至室温， 3h反应完全，慢慢滴入 NaOH 水溶液淬灭反应， 无气泡产生后加快速度， 调 PH值中性， 乙酸乙酯提取， 饱和食盐水水洗， 无水硫酸钠干燥， 旋干， 得 26g化合物 S-94-2。  The compound S-94-l (30.45 g) was dissolved in anhydrous THF (300 ml), NaBH4 (17.1 g) was added, and the mixture was stirred and cooled to 0 ° C, and boron trifluoride diethyl ether solution (72 mL) was added dropwise. After completion, naturally rise to room temperature, 3h reaction is complete, slowly drip into the NaOH aqueous solution to quench the reaction, speed up after no bubble generation, adjust the pH value neutral, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, Spin dry to give 26 g of compound S-94-2.
化合物 S-94-2(28g), 加入甲苯 (250mL)和的氯化亚砜 (40mL)， 室温开始迅速反应， 搅拌 40min，气体产生速度减慢后升温至 60°C， 每小时升温 10°C， 温度达到 90°C时， 反应完全， 降温， 水洗三次， 无水硫酸钠干燥， 活性炭脱色， 旋干， 得 30g化合物 S-94-3。  Compound S-94-2 (28 g), adding toluene (250 mL) and thionyl chloride (40 mL), reacted rapidly at room temperature, stirred for 40 min, the gas generation rate was slowed, and then the temperature was raised to 60 ° C, and the temperature was raised by 10 ° per hour. C, when the temperature reaches 90 ° C, the reaction is complete, the temperature is lowered, washed three times with water, dried over anhydrous sodium sulfate, decolorized with activated carbon, and dried to give 30 g of compound S-94-3.
化合物 S-94-3(30g)溶于 DMF(200mL),加入甘氨酸甲酯盐酸盐 (22g)， 0°C下 滴加三乙胺 (60M1)到反应瓶中， 完毕后 室温搅拌 30min,升温到 60°C， 过夜反应， 反应结束后降温， 加 水， 乙酸乙酯提取， 合并有机相， 无水硫酸钠干燥， 活性炭脱色， 旋干， 过柱， 得 8g化合 物 S-94-4  Compound S-94-3 (30 g) was dissolved in DMF (200 mL), and glycine methyl ester hydrochloride (22 g) was added. Triethylamine (60 M1) was added dropwise to the reaction flask at 0 ° C, and then stirred at room temperature for 30 min. The temperature was raised to 60 ° C, and the reaction was carried out overnight. After the reaction was completed, the temperature was lowered, water was added, ethyl acetate was extracted, and the organic phase was combined, dried over anhydrous sodium sulfate, decolorized with activated carbon, dried, and passed through a column to obtain 8 g of compound S-94-4
化合物 S-94-4(260mg)溶于 2.5ml的 1,4-二氧六垸， NaHC03(178mg)加入水中溶解， 加 入到反应瓶中， 搅拌降温到 0°C， 加入 CBZ-C1(0.25M1)， 反应结束后， 减压蒸出二氧六环， 乙酸乙酯提取， 合并有机相， 饱和食盐水洗涤， 无水硫酸钠干燥， 旋干， 得 400mg黄色油 状液体， 过柱分离， 得 300mg化合物 S-94-5  Compound S-94-4 (260 mg) was dissolved in 2.5 ml of 1,4-dioxane, NaHC03 (178 mg) was dissolved in water, added to the reaction flask, stirred and cooled to 0 ° C, and added to CBZ-C1 (0.25 M1), after the reaction is completed, the dioxane is distilled off under reduced pressure, ethyl acetate is extracted, and the organic phase is combined, washed with saturated brine, dried over anhydrous sodium sulfate, and dried to give 400 mg of a yellow oily liquid. 300mg compound S-94-5
化合物 S-94-5 (8.2g), Fe粉 (6.4g)中加入甲醇 (50ml)， 醋酸 (5ml)， 升温至 70°C， 加入氯 化铵 (12g)水溶液， 反应完全后蒸干溶剂， 加入二氯甲烷溶解， 过滤， 浓缩， 柱层析得 6.7g 化合物 S-94-6。  To a solution of compound S-94-5 (8.2 g), Fe powder (6.4 g), methanol (50 ml), acetic acid (5 ml), warmed to 70 ° C, and added ammonium chloride (12 g) aqueous solution. It was dissolved in dichloromethane, filtered, concentrated, and purified by column chromatography to yield 6.7 g of Compound S-94-6.
氢氧化锂 (1.4g)溶于水中，加入化合物 S-94-6 (2g)的 THF溶液， lh反应完全，蒸干 THF, 加 4M HC1溶液调 PH<4， EA萃取， 饱和食盐水洗涤 EA层， 无水硫酸钠干燥， 浓缩得 2g 化合物 S-94-7。  Lithium hydroxide (1.4g) was dissolved in water, and a solution of compound S-94-6 (2g) in THF was added. The reaction was completed in lh, THF was evaporated, and 4M HCl solution was added to adjust pH <4, EA was extracted, and EA was washed with saturated brine. The layer was dried over anhydrous sodium sulfate and concentrated to give 2 g of Compounds.
化合物 S-94-7 (2g)溶于二氯甲垸， 冰浴下， 加入 HOBT(1.3g)， EDCI(1.6g), 5min后加 入 DIPEA(2.6ml)， 撤冰浴， 30min反应完全， 加二氯甲烷稀释， 反应也依次用 1M HC1溶液， 饱和碳酸氢钠溶液，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析得 1.37g化合物 S-94-8。  Compound S-94-7 (2g) was dissolved in dichloromethane, added to HOBT (1.3g), EDCI (1.6g), and then added to DIPEA (2.6ml) after 5min, and the reaction was completed in 30min. The mixture was diluted with methylene chloride, and the mixture was washed with 1M EtOAc (EtOAc m.
化合物 S-94-8(500mg;)溶于甲醇， 加入 Pd/C(100mg)， 通入氢气， lh反应完全， 过滤， 浓缩得 400mg化合物 S-94。  The compound S-94-8 (500 mg;) was dissolved in methanol, Pd/C (100 mg) was added, and hydrogen was passed, and the reaction was completed for lh.
制备例 52: 化合物 S-95的制备
Figure imgf000054_0001
Preparation 52: Preparation of Compound S-95
Figure imgf000054_0001
S-95-7 S-95  S-95-7 S-95
NaH(7.7g)悬浮于干燥 DMF(200ml)中， 加入 2-氯 -3-硝基吡啶 (30g)， 缓慢滴加丙二酸二 甲酯 (21ml)， 搅拌过夜， 加水淬灭， EA萃取， 饱和食盐水洗涤 EA层， 浓缩， 柱层析得 20g 化合物 S-95- 1。  NaH (7.7 g) was suspended in dry DMF (200 mL), EtOAc (EtOAc) (EtOAc) The EA layer was washed with saturated brine, concentrated and purified by column chromatography to afford 20 g of compound S-95-1.
化合物 S-95-l(13g)溶于 6N盐酸溶液中， 100°C加热， TLC监测至反应完全， 加入 6N NaOH溶液中和， CH2C12萃取， 饱和食盐水洗涤有机层， 无水硫酸钠干燥， 浓缩得 llg 化合物 S-95-2。 Compound S-95-l (13g) was dissolved in 6N hydrochloric acid solution, heated at 100 ° C, TLC was monitored until the reaction was complete, neutralized with 6N NaOH solution, extracted with CH 2 C1 2 , washed with saturated brine, anhydrous sulfuric acid The sodium was dried and concentrated to give llg of compound S-95-2.
化合物 S-95-2(5.5g)， NBS(9.9g)悬浮于 CCl4(100ml)， 加入 AIBN(1.32g), 回流 ld， 停止 反应， 过滤， 洗涤滤渣， 蒸干溶剂， 柱层析得 8g化合物 S-95-2与化合物 S-95-3混合物。 Compound S-95-2 (5.5g), NBS (9.9g) was suspended in CCl 4 (100ml), AIBN (1.32g) was added, refluxed ld, the reaction was stopped, filtered, the filter residue was washed, the solvent was evaporated, and the column was obtained. 8 g of a mixture of the compound S-95-2 and the compound S-95-3.
化合物 S-95-3 (8g)与化合物 BNO-Br混合物溶于 DMF,加入甘氨酸甲酯盐酸盐 (5g)， 0°C 下， 滴加三乙胺 (15ml)， 室温搅拌至反应完全， 加入 H20， EA萃取， 饱和食盐水洗涤洗涤 EA层， 无水硫酸钠干燥， 浓缩， 柱层析得 1.63g化合物 S-95-4。 A mixture of the compound S-95-3 (8 g) and the compound BNO-Br was dissolved in DMF, and glycine methyl ester hydrochloride (5 g) was added thereto, and triethylamine (15 ml) was added dropwise at 0 ° C, and the mixture was stirred at room temperature until the reaction was completed. was added H 2 0, EA extracted EA layer was washed with water, washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain 1.63g compound by column chromatography to S-95-4.
化合物 S-95-4(1.6g)溶于 1.4-二氧六烷， 加入 NaHC03(lg)的水溶液， 冰浴下， 滴加 CBZ-Cl(1.2ml), 室温搅拌至反应完全， 蒸干溶剂， 加入 H20， EA萃取， 饱和食盐水洗涤 EA 层， 无水硫酸钠干燥， 浓缩， 柱层析得 2g化合物 S-95-5。 The compound S-95-4 (1.6 g) was dissolved in 1.4-dioxane, and an aqueous solution of NaHC0 3 (lg) was added thereto. CBZ-Cl (1.2 ml) was added dropwise under ice-cooling, and stirred at room temperature until the reaction was completed and evaporated. The solvent was added H 2 0, EA extracted EA layer was saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to give compound 2g S-95-5.
化合物 S-95-5(2.3g)溶于甲醇 (50ml)， 加入醋酸 (lml)， 加入: Fe粉 (2g)， 升温至 70°C， 加 入氯化铵 (3g)的水溶液， 反应完全， 蒸干溶剂， EA溶解， 过滤， 浓缩， 柱层析得 2g化合物 S-95-6。  Compound S-95-5 (2.3 g) was dissolved in methanol (50 ml), acetic acid (1 ml) was added, Fe powder (2 g) was added, the temperature was raised to 70 ° C, and an aqueous solution of ammonium chloride (3 g) was added, and the reaction was completed. The solvent was evaporated to dryness, EA was evaporated, filtered, concentrated,
化合物 S-95-6(1.8g)溶于 AcOH(20ml)， 120°C加热回流， TLC监测至反应完全， 蒸千溶 剂， EA溶解， EA层依次用饱和碳酸氢钠溶液， 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 柱层析得 1.2g化合物 S-95-7。  Compound S-95-6 (1.8g) was dissolved in AcOH (20ml), heated to reflux at 120 ° C, TLC was monitored until the reaction was completed, the solvent was evaporated, EA was dissolved, and the EA layer was washed with saturated sodium hydrogen carbonate solution and saturated brine. Drying over anhydrous sodium sulfate, concentration and column chromatography gave 1.2 g of Compound S-95-7.
化合物 S-95-7(470mg)溶于甲醇， 加入 Pd/C(70mg)， 通入 H2， 室温搅拌至反应完全， 过 滤， 浓缩得 420mg化合物 S-95。 Compound S-95-7 (470mg) was dissolved in methanol, was added Pd / C (70mg), into H 2, stirred at room temperature until the reaction was complete, filtered, and concentrated to give 420mg compound S-95.
制备例 53: 化合物 S-96的制备
Figure imgf000055_0001
Preparation 53: Preparation of Compound S-96
Figure imgf000055_0001
S-96  S-96
氯磺酸 (10ml)滴加至 2.4-二氟苯甲酸 (5g)中， 升至 150°C， 2h后反应完全， 冷至室温， 反应液缓慢滴加至冰中， EA萃取， 饱和食盐水洗涤 EA层， 无水硫酸钠干燥， 浓缩得 4.8g 产物 S-96-1。  Chlorosulfonic acid (10ml) was added dropwise to 2.4-difluorobenzoic acid (5g), and raised to 150 ° C. After 2h, the reaction was completed, cooled to room temperature, and the reaction solution was slowly added dropwise to ice, EA extraction, saturated brine The EA layer was washed, dried over anhydrous sodium sulfate and evaporated.
冰浴下， 浓氨水 (6ml)中分批加入化合物 S-96-l(400mg)， 撤冰浴， lh反应完全， 蒸除部 分溶剂， 加浓盐酸调 PH=1， 过滤， 水洗， 蒸干得 340mg化合物 S-96-2。  Under ice bath, add compound S-96-l (400mg) in concentrated ammonia (6ml), remove the ice bath, lh reaction is complete, distill off part of the solvent, add concentrated hydrochloric acid to adjust PH=1, filter, wash, steam dry 340 mg of compound S-96-2 were obtained.
N-Boc-1.2-乙二胺 (200mg)溶于 DMF， 依次加入 DIPEA(0.53ml)、化合物 S-96-2(350mg)、 HOBT(254mg). EDCI(360mg), 室温搅拌过夜， 次日， 反应液中加 1M HC1溶液， EA萃取， N-Boc-1.2-ethylenediamine (200 mg) was dissolved in DMF, and then DIPEA (0.53 ml), compound S-96-2 (350 mg), HOBT (254 mg), EDCI (360 mg), stirred at room temperature overnight, next day Add 1M HC1 solution to the reaction solution and extract with EA.
EA层依次用饱和碳酸氢钠溶液， 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 短柱层析得化 合物 S-96-3。 The EA layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate and evaporated.
化合物 S-96-3(70mg)中加入 2ml HC1乙醇溶液， 搅拌至反应完全， 蒸干得化合物 S-96。  To the compound S-96-3 (70 mg), 2 ml of a HCl solution of ethanol was added, and the mixture was stirred until the reaction was completed, and evaporated to dryness to give Compound S-96.
Figure imgf000055_0002
Figure imgf000055_0002
3-氨基吡嗪 -2-羧酸 (15g)溶于硫酸甲醇溶液中 (CH3OH:H2SO4=10:l)， 加热回流过夜， 次 日蒸干甲醇， EA溶解， EA层依次用饱和碳酸氢钠溶液，饱和食盐水洗涤，无水硫酸钠干燥， 浓缩得 8g化合物 S-97-l。 3-aminopyrazine-2-carboxylic acid (15g) was dissolved in a solution of sulfuric acid in methanol (CH 3 OH:H 2 SO 4 =10:1), heated to reflux overnight, the next day evaporated to dry methanol, EA dissolved, EA layer The mixture was washed with a saturated aqueous solution of sodium bicarbonate and brine and dried over anhydrous sodium sulfate.
四氢铝锂 (5g)悬浮于干燥 THF(150ml)中， 冰浴， 分批加入化合物 S-97-l(8g)， 加完后， 反应液移至室温， 5h反应完全， 滴加水 (10ml)淬灭， 加入 1M NaOH(lOml)溶液， 加入硫酸 钠， 过滤， EA洗涤滤渣多次， 浓缩， 柱层析得 3.5g化合物 S-97-2。  Lithium tetrahydroaluminum (5 g) was suspended in dry THF (150 ml), and the mixture was stirred in ice-bath, and the compound S-97-l (8 g) was added in portions. After the addition, the reaction mixture was moved to room temperature, and the reaction was completed in 5 h, and water (10 ml) was added dropwise. After quenching, a solution of 1 M NaOH (10 ml) was added, sodium sulfate was added thereto, and the mixture was filtered, and the residue was washed with EA several times, concentrated, and then purified by column chromatography to yield 3.5 g of Compound S-97-2.
氯化亚砜 (2ml)溶于 THF(lOOml), 冰浴下滴加化合物 S-97-2(2.9g)的 THF溶液， 滴加完 毕， 移至室温， lh反应完全， 蒸干， 柱层析得 2.7g化合物 S-97-3。  Chlorosulfoxide (2ml) was dissolved in THF (100 ml), and a solution of compound S-97-2 (2.9 g) in THF was added dropwise under ice-cooling. After the dropwise addition, the mixture was transferred to room temperature, lh reaction was completed, evaporated to dryness, column 2.7 g of compound S-97-3 were isolated.
化合物 S-97-3(2.5g)溶于 DMF,加入甘氨酸甲酯盐酸盐 (2.6g)，冰浴下，滴加三乙胺 (8ml)， 滴加完毕， 移至室温， 8h反应完全， 加水， EA萃取， 浓缩， 柱层析得 570mg化合物 -S-97-4。 化合物 S-97-4(540mg)溶于 1.4-二氧六垸， 加入 NaHCO3(460mg)的水溶液， 冰浴下， 滴 加 CBZ-Cl(0.42ml)， 室温搅拌至反应完全， 蒸干溶剂， 加入 H20， EA萃取， 饱和食盐水洗 涤 EA层， 无水硫酸钠干燥， 浓缩， 柱层析得化合物 S-97-5。 Compound S-97-3 (2.5 g) was dissolved in DMF, and glycine methyl ester hydrochloride (2.6 g) was added, and triethylamine (8 ml) was added dropwise. After the completion of the dropwise addition, the mixture was transferred to room temperature, and the reaction was completed in 8 h. water was added, extracted with EA, and concentrated, and the column was chromatographed to give 570 mg of Compound-S-97-4. The compound S-97-4 (540 mg) was dissolved in 1.4-dioxane, and an aqueous solution of NaHCO 3 (460 mg) was added, and CBZ-Cl (0.42 ml) was added dropwise thereto, and the mixture was stirred at room temperature until the reaction was completed, and the solvent was evaporated. The mixture was extracted with H 2 0, EA, EtOAc (EtOAc) evaporated.
化合物 S-97-5 (1.2g)溶于 AcOH, 加入 DMAP(80mg)， 120°C加热回流， 3d反应完全， 蒸干 AcOH， EA溶解， EA层依次用饱和碳酸氢钠溶液， 饱和食盐水洗涤， 浓缩， 柱层析得 Compound S-97-5 (1.2g) was dissolved in AcOH, DMAP (80mg) was added, and the mixture was heated to reflux at 120 °C. The reaction was completed in 3d. Evaporation of AcOH, EA was dissolved, and the EA layer was washed with saturated sodium hydrogen carbonate solution and saturated brine. Washing, concentration, column chromatography
370mg化合物 S-97-6。 370 mg of compound S-97-6.
化合物 S-97-6(370mg)溶于甲醇， 加入 Pd/C(50mg), 通入氢气， 反应完全后， 过滤， 浓 缩得 170mg化合物 S-97。 Compound S-97-6 (370 mg) was dissolved in methanol, Pd/C (50 mg) was added, and hydrogen was passed, and after the reaction was completed, it was filtered and concentrated to yield 170 mg of Compound S-97.
Figure imgf000056_0001
Figure imgf000056_0001
化合物 S-32(450mg)溶于 CH2C12，加入三乙胺 (0.5ml)，冰浴下，滴加氯甲酸苄酯 (0.4ml), 反应完全， 加 CH2C12稀释， 有机层依次用 1M HC1溶液， 饱和食盐水洗涤， 无水硫酸钠干 燥， 浓缩得 700mg化合物 S- 100- 1。 The compound S-32 (450 mg) was dissolved in CH 2 C1 2 , triethylamine (0.5 ml) was added, and benzyl chloroformate (0.4 ml) was added dropwise in an ice bath. The reaction was completed and diluted with CH 2 C 1 2 , organic layer The mixture was washed with aq. EtOAc (EtOAc m.
NaH(70mg)悬浮于干燥 DMF中， 冰浴下， 滴加化合物 S-100-l(450mg)的 DMF溶液， 室 温搅拌 lh， 冰浴， 滴加碘甲垸 (80ul)， 室温搅拌 lh， 反应完全， 冰浴， 滴加饱和氯化铵溶液 淬灭， EA萃取， 饱和食盐水洗涤 EA层， 无水硫酸钠干燥， 浓缩， 柱层析得 350mg化合物 S- 100-2。  NaH (70 mg) was suspended in dry DMF, and a solution of compound S-100-l (450 mg) in DMF was added dropwise, and the mixture was stirred at room temperature for 1 hour, ice-cooled, and iodine (80 ul) was added dropwise at room temperature for 1 h. Completely, ice-bath, quenched with saturated aqueous ammonium chloride solution, extracted with EA, EA layer washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 350 mg of compound S-100-2.
化合物 S-100-2(350mg)溶于甲醇， 加入 Pd/C(40mg)， 通入 H2, 反应完全， 过滤， 浓缩 得 llOmg化合物 S-100。 Compound S-100-2 (350mg) was dissolved in methanol, was added Pd / C (40mg), into H 2, the reaction was complete, filtered, and concentrated to afford llOmg compound S-100.
制备例 56: 化合物 S-101的制备  Preparation 56: Preparation of Compound S-101
Figure imgf000056_0002
Figure imgf000056_0002
2-硝基 -4-氟甲苯 (5.5g)溶于四氯化碳， 加入 NBS(7.7g)， AIBN(lg), 76°C加热， 次日， 停 止反应， 冷至室温， 过滤， 浓缩， 柱层析得 4.6g化合物 S-101-1. 2-Nitro-4-fluorotoluene (5.5g) was dissolved in carbon tetrachloride, added to NBS (7.7g), AIBN (lg), heated at 76 ° C, the next day, the reaction was stopped, cooled to room temperature, filtered, concentrated , column chromatography gave 4.6 g of compound S-101-1.
化合物 S-101-1 (4.6g)溶于 DMF, 加入 2.7g甘氨酸甲酯盐酸盐， 冰浴下， 滴加三乙胺 (8.3ml), 室温搅拌过夜， 次日反应完全， 加入水， EA萃取， 饱和食盐水洗涤 EA层， 无水 硫酸钠干燥， 浓縮， 柱层析得 2.6g化合物 S-101-2.  The compound S-101-1 (4.6 g) was dissolved in DMF, and 2.7 g of glycine methyl ester hydrochloride was added. Under ice bath, triethylamine (8.3 ml) was added dropwise, and the mixture was stirred overnight at room temperature, and the reaction was completed the next day, and water was added. EA extraction, washing the EA layer with saturated brine, dried over anhydrous sodium sulfate, and concentrated.
化合物 S-101-2(2.6g)溶于 C¾C12， 滴加 Boc20(1.83g)， 室温搅拌至反应完全， 力卩 CH2C12 稀释， 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 短柱层析得化合物 S-101-3. Compound S-101-2 (2.6g) was dissolved in C3⁄4C1 2 , Boc 2 0 (1.83g) was added dropwise, and stirred at room temperature until the reaction was complete, CH 2 C1 2 Dilute, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, short-column chromatography to give compound S-101-3.
化合物 S-101-3(2.83g)溶于甲醇， 加 Pd/C(300mg)，通入 H2， 反应完全， 过滤浓缩得 2.7g 化合物 S-101-4。 The compound S-101-3 (2.83 g) was dissolved in methanol, and then Pd/C (300 mg) was added, and H 2 was passed, and the reaction was completed, and concentrated by filtration to give 2.7 g of Compound S-101-4.
氢氧化锂 (2g)溶于水中，加入化合物 S-101-4(2.7g)的 THF溶液， lh反应完全，蒸干 THF, 加 4M HC1溶液调 PH<4， EA萃取， 饱和食盐水洗涤 EA层， 无水硫酸钠干燥， 浓缩得化合 物 S-101-5。  Lithium hydroxide (2g) was dissolved in water, and a solution of compound S-101-4 (2.7g) in THF was added. The reaction was completed in lh, THF was evaporated, 4M HCl solution was added to adjust pH <4, EA was extracted, and EA was washed with saturated brine. The layer was dried over anhydrous sodium sulfate and evaporated.
化合物 S-101-5溶于二氯甲垸， 冰浴下， 加入 HOBT(1.5g)， EDCI(2.1g), 5min后加入 DIPEA(1.3ml), 撤冰浴， 30min反应完全， 加二氯甲烷稀释， 反应液依次用 1M HC1溶液， 饱和碳酸氢钠溶液，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，柱层析得 lg化合物 S-101-6。  Compound S-101-5 was dissolved in dichloromethane, ice bath, HOBT (1.5 g), EDCI (2.1 g) was added. After 5 min, DIPEA (1.3 ml) was added, the ice bath was removed, and the reaction was completed in 30 min. The mixture was diluted with methylene chloride. The reaction mixture was washed with EtOAc EtOAc EtOAc.
化合物 S-101-6(70mg)溶于 CH2C12， 加入三氟醋酸 (0.2ml)， 反应完全， 蒸干得化合物 S-lOl o The compound S-101-6 (70 mg) was dissolved in CH 2 C1 2 , trifluoroacetic acid (0.2 ml) was added, and the reaction was completed and evaporated to give compound S-lOl.
制备例 57: 化合物 S-102的制备  Preparation 57: Preparation of Compound S-102
Figure imgf000057_0001
Figure imgf000057_0001
对硝基苯甲酸 (5.1g)悬浮于干燥 CH2Cl2(50ml)中， 加入 DMF(2滴)， 滴加草酰氯 (8ml)， 反应完全， 蒸干。 40%甲胺水溶液 (5ml)， 加入三乙胺， 冰浴下， 滴加酰氯的 THF溶液， 反 应完全，蒸干 THF，EA萃取，饱和食盐水洗涤 EA层，无水硫酸钠干燥，浓缩得化合物 S-102-1。 P-nitrobenzoic acid (5.1 g of) was suspended in dried CH 2 Cl 2 (50ml), was added DMF (2 drops) was added dropwise oxalyl chloride (8ml), the reaction was complete, evaporated to dryness. 40% aqueous solution of methylamine (5 ml), added with triethylamine, and a solution of the acid chloride in THF was added dropwise, and the reaction was completed. THF was evaporated, EtOAc was evaporated. Compound S-102-1.
化合物 S-102-1 (lg)溶于甲醇， 加入 Pd/C(100mg)， 通入 H2， 反应完全， 过滤， 浓缩得 化合物化合物 S-102。 The compound S-102-1 (lg) was dissolved in methanol, Pd/C (100 mg) was added, and H 2 was passed, and the reaction was completed, filtered, and concentrated to give compound compound S-102.
制备例 58: 化合物 S-103的制备  Preparation 58: Preparation of Compound S-103
Figure imgf000057_0002
Figure imgf000057_0002
2-甲基 -3-硝基苯甲酸 (5g)溶于甲醇 (50ml)， 加入浓硫酸 (5ml)， 加热回流过夜， 次日， 停 止反应， 蒸干甲醇， EA溶解， EA层依次用饱和碳酸氢钠溶液， 饱和食盐水洗涤， 无水硫酸 钠干燥， 浓缩得 4g化合物 S-103-1。 2-methyl-3-nitrobenzoic acid (5 g) was dissolved in methanol (50 ml), concentrated sulfuric acid (5 ml) was added, and the mixture was heated to reflux overnight. The next day, the reaction was stopped, the methanol was evaporated, the EA was dissolved, and the EA layer was saturated. The sodium hydrogencarbonate solution was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated.
化合物 S-103-l(3.5g)溶于 CC14， 加入 BS(3.5g)， AIBN(600mg), 加热回流过夜， 次日 停止反应， 冷至室温， 过滤， 滤液加 CH2C12稀释， 饱和食盐水洗涤， 无水硫酸钠干燥， 浓 缩得化合物 S- 103-2。 Compound S-103-l (3.5g) was dissolved in CC1 4, was added BS (3.5g), AIBN (600mg ), heated at reflux overnight, the following day the reaction was stopped, cooled to room temperature, filtered, the filtrate was diluted with CH 2 C1 2 was added, The mixture was washed with brine, dried over anhydrous sodium sulfate
化合物 S-103-2溶于甲醇溶液，加入氨甲醇溶液， 加热回流， 2h反应完全，过滤得产物， 滤液浓缩， 柱层析， 合并得 3.6g化合物化合物 S-103-3。  The compound S-103-2 was dissolved in a methanol solution, and a solution of ammonia in methanol was added thereto, and the mixture was heated under reflux, and the reaction was completed for 2 hours. The product was filtered, and the filtrate was concentrated to give 3.6 g of Compound Compound S-103-3.
化合物化合物 S-103-3(1.5g)溶于甲醇， 加入 Pd/C(200mg)， 通入 H2， 反应完全， 过滤， 浓缩得 1 g化合物化合物 S- 103。 制备例 59: 化合物 S-104的制备
Figure imgf000058_0001
The compound compound S-103-3 (1.5 g) was dissolved in methanol, Pd/C (200 mg) was added, and H 2 was passed, and the reaction was completed, filtered, and concentrated to give 1 g of Compound Compound S-103. Preparation 59: Preparation of Compound S-104
Figure imgf000058_0001
S-104- S-104-2 S-104-3 S-104  S-104- S-104-2 S-104-3 S-104
按照与制备例 58相同的方法， 以 2-甲基 -4-硝基苯甲酸为试剂合成化合物  The compound was synthesized using 2-methyl-4-nitrobenzoic acid as a reagent in the same manner as in Preparation 58
MS m/e 149[M+H]+  MS m/e 149[M+H]+
制备例 60: 化合物 S-105的制备  Preparation 60: Preparation of Compound S-105
— H2 — H 2
Boc；、 Boc;,
Figure imgf000058_0002
Figure imgf000058_0002
S-105-1 S-105-2 S-105  S-105-1 S-105-2 S-105
按照与制备例 14相同的方法， 以 2-噻唑甲酸为试剂合成化合物 S-105 £ In the same method as in Preparation Example 14, using 2-thiazolecarboxylic acid as the reagent Synthesis of compound S-105 £
MS m/e 212[M+H]+ MS m/e 212[M+H] +
制备例 61: 化合物 S-106的制备  Preparation 61: Preparation of Compound S-106
Boc、 ί — ΝΗ2 Boc, ί — ΝΗ 2
Figure imgf000058_0003
Figure imgf000058_0003
S-106-1  S-106-1
S-106-2 S-106  S-106-2 S-106
按照与制备例 14相同的方法， 以 3-氟苯甲酸为试剂合成化合物 S-106。  Compound S-106 was synthesized in the same manner as in Preparation 14 using 3-fluorobenzoic acid as a reagent.
MS m/e 223[M+H]+ MS m/e 223[M+H] +
制备例 62: 化合物 S-107的制备
Figure imgf000058_0004
Preparation 62: Preparation of Compound S-107
Figure imgf000058_0004
S-101-6 S-107-1 S-107  S-101-6 S-107-1 S-107
钠氢 (96mg)悬浮于干燥 DMF(lOml)中， 冰浴下， 滴加化合物 S-101-6(500mg)的 DMF溶 液， 室温 lh， 冰浴， 滴加碘甲垸 (0.1ml), 移至室温， 反应完全， 冰浴， 滴加氯化钹溶液淬 灭， EA萃取， 浓缩， 柱层析得 550mg化合物 S-107-l。  The sodium hydrogen (96 mg) was suspended in dry DMF (10 ml), and the solution of the compound S-101-6 (500 mg) in DMF was added dropwise, and the mixture was stirred at room temperature for 1 h, ice bath, and iodine (0.1 ml) was added dropwise. To the room temperature, the reaction was completed, ice-bath, quenched with EtOAc (EtOAc), EtOAc, EtOAc (EtOAc)
化合物 S-107-l (100mg)溶于二氯甲垸中， 加入三氟醋酸， 反应完全， 过滤， 浓缩得化合 物 S-107。  The compound S-107-l (100 mg) was dissolved in dichloromethane, trifluoroacetic acid was added, and the reaction was completed, filtered, and concentrated to give compound S-107.
制备例 63: 化合物 S-108的制备  Preparation 63: Preparation of Compound S-108
Figure imgf000058_0005
Figure imgf000058_0005
S-94-8 S-108-1 S— 1 08 S-94-8 S-108-1 S — 1 08
钠氢 (96mg)悬浮于干燥 DMF(l Oml)中，冰浴下，滴加化合物 S-94-8(500mg)的 DMF溶液， 室温 lh， 冰浴， 滴加碘甲烷 (0.1ml), 移至室温， 反应完全， 冰浴， 滴加氯化铵溶液淬灭， EA萃取， 浓缩， 柱层析得 570mg化合物 S-108-l。 Sodium hydrogen (96 mg) was suspended in dry DMF (10 ml), and a solution of compound S-94-8 (500 mg) in DMF was added dropwise. Room temperature lh, ice bath, dropwise addition of methyl iodide (0.1 ml), transferred to room temperature, the reaction was completed, ice-cooled, quenched with ammonium chloride solution, extracted with EA, concentrated, and purified by column chromatography to give 570 mg of compound S-108-l .
化合物 S-108-l(570mg)溶于甲醇中， 加入 Pd/C(60mg), 通入氢气， 反应完全， 过滤， 浓 缩得 280mg化合物 S-108。  The compound S-108-l (570 mg) was dissolved in methanol, Pd/C (60 mg) was added, and hydrogen was passed, and the reaction was completed, filtered, and concentrated to yield 280 mg of Compound S-108.
Figure imgf000059_0001
Figure imgf000059_0001
S-109-1 S-109-2 S-109-3 S-109 按照与制备例 14相同的方法， 以化合物 S-109-2为试剂合成化合物 S-109。  S-109-1 S-109-2 S-109-3 S-109 Compound S-109 was synthesized in the same manner as in Preparation 14 using Compound S-109-2.
MS m/e 388[M+H]+ MS m/e 388[M+H] +
制备例 65: 化合物 S-110的制备  Preparation 65: Preparation of Compound S-110
Figure imgf000059_0002
Figure imgf000059_0002
按照与制备例 14相同的方法， 以化合物 S-110-2为试剂合成化合物 S-110。  Compound S-110 was synthesized in the same manner as in Preparation 14 using Compound S-110-2 as a reagent.
MS m/e 390[M+H]+  MS m/e 390[M+H]+
制备例 66: 化合物 S-lll的制备  Preparation 66: Preparation of Compound S-111
Figure imgf000059_0003
Figure imgf000059_0003
S-11 " S-111  S-11 " S-111
间氨基苯甲酸 (2g)溶于甲醇， 冰浴， 滴加氯化亚砜 (0.93ml)， 回流过夜， 次日反应完全， 蒸干， EA溶解， 依次用饱和碳酸氢钠溶液， 饱和食盐水不洗涤， 无水硫酸钠干燥， 浓缩得 化合物 S-111-1。  m-Aminobenzoic acid (2g) was dissolved in methanol, ice bath, thionyl chloride (0.93ml) was added dropwise, refluxed overnight, the reaction was completed the next day, evaporated to dryness, EA was dissolved, and then saturated sodium bicarbonate solution and saturated brine Without washing, it was dried over anhydrous sodium sulfate and concentrated to give compound S-111-1.
化合物 S-U1-1 (lg)溶于 CH2C12， 冰浴， 加入吡啶 (1.43ml)， 甲磺酰氯 (0.54ml)， lh后移 至室温， 反应完全， 加入 CH2C12稀释， 依次用 1M HC1溶液， 饱和食盐水洗涤， 干燥， 浓 缩得化合物 S-111-2。 Compound S-U1-1 (lg) was dissolved in CH 2 C1 2, an ice bath was added pyridine (1.43 ml), methanesulfonyl chloride (0.54 mL of), brought to room temperature After lh, the reaction was complete, 2 C1 2 was added diluted CH, The mixture was washed successively with 1 M HCl solution, brine, dried and evaporated.
化合物 S-lll-2(1.3g)溶于甲醇， 加入氢氧化锂 (0.45g)的水溶液， 搅拌至反应完全， EA 萃除杂质， 水层用浓盐酸调 PH-2， EA萃取， 饱和食盐水洗涤 EA层， 干燥浓缩得化合物 S-lll-3。 Compound S-111-2 (1.3 g) was dissolved in methanol, aqueous solution of lithium hydroxide (0.45 g) was added and stirred until the reaction was complete, EA The impurities were extracted, and the aqueous layer was adjusted to pH-2 with concentrated hydrochloric acid, extracted with EA, and the EA layer was washed with saturated brine and dried to give compound S-lll-3.
化合物 S-ll l-3(300mg)溶于 DMF， 依次加入三乙胺 (0.54ml)， HBOT(261mg), EDCI(3 7 0 mg), N-Boc乙二胺 (227mg)， 室温搅拌过夜， 次日， 加入 lM HC 溶液， EA萃取， Compound S-ll l-3 (300 mg) was dissolved in DMF, and then triethylamine (0.54 ml), HBOT (261 mg), EDCI (370 mg), N-Boc ethylenediamine (227 mg), and stirred overnight at room temperature On the next day, add lM HC solution, EA extraction,
EA层用饱和碳酸氢钠溶液， 饱和食盐水不洗涤， 无水硫酸钠干燥， 浓缩， 柱层析得化合物 S-lll-4。 The EA layer was washed with saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and evaporated.
化合物 S-l ll-4(66mg)溶于 CH2C12,加入三氟醋酸 (0.3ml)，反应完全，蒸干得化合物 S-111 制备例 67: 化合物 S-112的制备 Compound Sl ll-4 (66 mg) was dissolved in CH 2 C1 2 , trifluoroacetic acid (0.3 ml) was added, and the reaction was completed and evaporated to give compound S-111. Preparation 67: Preparation of Compound S-112
Figure imgf000060_0001
Figure imgf000060_0001
S-112-4 S-112  S-112-4 S-112
按照与制备例 66相同的方法， 以化合物 2-氟 -5-氨基苯甲酸为试剂合成化合物 S-112。 制备例 68: 化合物 S-113的制备  The compound S-112 was synthesized in the same manner as in Preparation 66 using the compound 2-fluoro-5-aminobenzoic acid as a reagent. Preparation 68: Preparation of Compound S-113
Figure imgf000060_0002
Figure imgf000060_0002
按照与制备例 66相同的方法， 以化合物 3-氨基 -4-氯 -苯甲酸为试剂合成化合物 S-113。 制备例 69: 化合物 S-114的制备
Figure imgf000060_0003
The compound S-113 was synthesized in the same manner as in Preparation 66 using the compound 3-amino-4-chloro-benzoic acid as a reagent. Preparation 69: Preparation of Compound S-114
Figure imgf000060_0003
S-11 -1 S-114-2 S-114-3 S-114 按照与制备例 14相同的方法， 以化合物 S-114-2为试剂合成化合物 S-114,  S-11-1 S-114-2 S-114-3 S-114 The compound S-114 was synthesized in the same manner as in Preparation 14 using the compound S-114-2 as a reagent.
MS m/e 360[M+H]+
Figure imgf000061_0001
MS m/e 360[M+H] +
Figure imgf000061_0001
S-115-1  S-115-1
S-115-2 S-115-3 S-115  S-115-2 S-115-3 S-115
按照与制备例 14相同的方法， 以化合物 S-115-2为试剂合成化合物 S-115。  Compound S-115 was synthesized in the same manner as in Preparation 14 using Compound S-115-2 as a reagent.
MS m/e 388[M+H]+ MS m/e 388[M+H] +
制备例 71: 化合物 S-116的制备  Preparation 71: Preparation of Compound S-116
Figure imgf000061_0002
Figure imgf000061_0002
化合物 S-116-l(10g)溶于甲醇， 加入浓盐酸 (5.1ml), 加入 Pd/C(lg)， 通入氢气， 2h反应 完全， 过滤， 浓缩得 6g化合物 S- 116-2。  The compound S-116-l (10 g) was dissolved in methanol, concentrated hydrochloric acid (5.1 ml) was added, and Pd/C (lg) was added thereto, and hydrogen was introduced thereto, and the reaction was completed in 2 hours, filtered, and concentrated to give 6 g of Compounds.
化合物 S-116-2(lg)溶于 CH2C12，加入三乙胺 (1.5ml)，冰浴下，滴加三氟乙酸酐 (0.68ml)， 反应不完全， 补加三乙胺与三氟乙酸酐， 反应完全， 蒸干， 加入 CH2C12稀释， 加水分层， 饱和食盐水洗涤有机层， 干燥， 浓缩， 短柱层析得 1.2g化合物 S-116-3。 Compound S-116-2 (lg) was dissolved in CH 2 C1 2 , triethylamine (1.5 ml) was added, and trifluoroacetic anhydride (0.68 ml) was added dropwise in an ice bath. The reaction was incomplete and triethylamine was added. Trifluoroacetic acid anhydride, the reaction was completed, evaporated to dryness, diluted with CH 2 C1 2 , water layer was added, and the organic layer was washed with saturated brine, dried and concentrated,
化合物 S-116-3(1.2g)溶于醋酸 (5ml)， 冰浴下， 加入浓硫酸 (2ml)， lOmin后， 加入多聚甲 醛 (0.2g)， 室温 2h不反应， 60Ό加热反应， 反应完全， 反应液倒入冰水中， EA萃取， 饱和 食盐水洗涤， 无水硫酸钠干燥， 浓缩， 柱层析得化合物 S-116-4。  Compound S-116-3 (1.2g) was dissolved in acetic acid (5ml), added to concentrated sulfuric acid (2ml) under ice bath, lOmin, then added paraformaldehyde (0.2g), no reaction at room temperature for 2h, 60 Ό heating reaction, reaction After completion, the reaction mixture was poured into ice water, extracted with EA, washed with brine, dried over anhydrous sodium sulfate and evaporated.
化合物 S-116-4(800mg)溶于甲醇， 加入碳酸钾的水溶液， 反应完全， 蒸干甲醇， EA萃 取， 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩得化合物 S-116。  The compound S-116-4 (800 mg) was dissolved in MeOH. EtOAc (EtOAc m.
制备例 72: 化合物 S-117的制备  Preparation 72: Preparation of Compound S-117
Figure imgf000061_0003
Figure imgf000061_0003
LDA的 THF溶液 (2M,25ml)， 冷至 -78°C， 滴加 l-N-Boc-3-哌啶酮 (10g)的 THF溶液， 滴 加完毕， 搅拌 20min， 滴加三氟乙酸乙酯 (6ml)， 移至室温， 反应 2h， 加水淬灭， 稀盐酸中 和反应液， EA萃取， 饱和食盐水洗涤 EA层， 无水硫酸钠干燥， 浓缩得化合物 S-117-l。 LDA in THF (2M, 25 ml), cooled to -78 ° C, and then dropwiselylylylylylylylylylylylylylylylylylylylylylylylylylylylyly 6 ml), the mixture was allowed to react to room temperature, and the mixture was stirred for 2 h. EtOAc was evaporated.
三氟乙脒 (200mg)中加入化合物 S-117-l(296mg)的吡啶溶液， 80°C反应， 2h后反应完全， 蒸干溶剂， EA溶解， EA层依次用 1M HC1溶液、饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 柱层析得 280mg化合物 S- 117-2. A solution of the compound S-117-l (296 mg) in pyridine was added to trifluoroacetic acid (200 mg), and the reaction was carried out at 80 ° C. After 2 h, the reaction was complete. The solvent was evaporated to dryness, and EA was evaporated. EA layer was washed with 1M HCl solution and brine, dried over anhydrous sodium sulfate, and concentrated.
化合物 S-117-2(280mg)中加入氯化氢乙酸乙酯溶液 (10ml)， 室温搅拌， 反应完全， 蒸干 得化合物 S-117。  To the compound S-117-2 (280 mg), EtOAc (EtOAc m.
制备例 73: 化合物 S-118
Figure imgf000062_0001
Preparation Example 73: Compound S-118
Figure imgf000062_0001
化合物 S-118-l(0.10g)溶解到无水四氢呋喃 （5ml ) 中， 氮气保护， 冰水下加入 BH3 THF(1.2ml),再在冰水下搅拌 15分钟，然后加热回流 12小时。反应液中慢慢加入甲醇， 淬灭未反应完的硼烷， 旋蒸去甲醇与四氢呋喃， 剩余物中加入甲醇和盐酸， 再回流 3小时。 旋蒸去溶剂后， 剩余物加水， DCM提取 3次， 水相调节 PH=12, 再用 DCM提起 3次， 合 并有机相， 水洗， 盐水洗， 干燥， 浓缩， 柱层析（DCM: MeOH: TEA= 100: 2: 0.2)得化合物 S-118 (35mg)0 Compound S-118-l (0.10g) was dissolved in anhydrous tetrahydrofuran (5ml), nitrogen protection, was added under ice BH 3 THF (1.2ml), stirred under ice for 15 minutes and then heated to reflux for 12 hours. Methanol was slowly added to the reaction mixture, the unreacted borane was quenched, methanol and tetrahydrofuran were distilled off, and methanol and hydrochloric acid were added to the residue, followed by reflux for 3 hours. After the solvent was distilled off, the residue was added with water, DCM was extracted three times, water phase was adjusted to pH = 12, and then was taken up three times with DCM. The organic phase was combined, washed with water, dried, concentrated, and purified by column chromatography (DCM : MeOH : TEA= 100 : 2 : 0.2) Compound S-118 (35mg) 0
1H NMR (400 MHz,CDCl3): δ 7.16-7.08 (m, 2H), 6.86 (td，lH)， 6.80 (dd, IH), 3.94 (s, 2H), 3.18 -3.06 (m, 4H). 1H NMR (400 MHz, CDCl 3 ): δ 7.16-7.08 (m, 2H), 6.86 (td, lH), 6.80 (dd, IH), 3.94 (s, 2H), 3.18 -3.06 (m, 4H).
MS m/e 149 [M+H]+, 297 [2M+H]+ MS m/e 149 [M+H] + , 297 [2M+H] +
制  System
Figure imgf000062_0002
Figure imgf000062_0002
化合物 S-119-l(0.78g)， 甘氨酸甲酯盐酸盐 (0.70g)和 HOBT(0.82g)溶解到无水二氯甲垸 (10ml)中， 再加入三乙胺 (2.1ml)， 冰水冷却下加入 EDCI(1.16g)， 自然升温， 搅拌过夜。 TLC 反应完全。 反应液中加水淬灭， 二氯甲烷提取 3次， 合并有机相， PH=1的盐酸水溶液洗， 饱和 NaHC03洗，水洗，盐水洗，干燥，浓缩得粗产品。固体用乙醚洗，过滤得化合物 S-119-2。 Compound S-119-l (0.78 g), glycine methyl ester hydrochloride (0.70 g) and HOBT (0.82 g) were dissolved in anhydrous dichloromethane (10 ml), and then triethylamine (2.1 ml) was added. EDCI (1.16 g) was added under ice-cooling, and the mixture was warmed and stirred overnight. The TLC reaction is complete. The reaction mixture was quenched with water, extracted three times with dichloromethane, organic phases were combined, PH = 1, aqueous hydrochloric acid wash, wash with saturated NaHCO 3, water, brine, dried and concentrated to give the crude product. The solid was washed with diethyl ether and filtered to give compound S- </RTI>
1H NMR (400 MHz, CDC13) :δ 7.47-7.37 (m, IH), 6.49 (bs, IH), 6,42-6,33 (m， 2H), 5.74 (bs， 2H), 4.21 (d, J = 5.05 Hz, 2H), 3.83 (s, 3H).。 1H NMR (400 MHz, CDC1 3 ) : δ 7.47-7.37 (m, IH), 6.49 (bs, IH), 6,42-6,33 (m, 2H), 5.74 (bs, 2H), 4.21 (d , J = 5.05 Hz, 2H), 3.83 (s, 3H).
MS m/e 227 [M+H]+， 249 [M+Na]+, 193 [M-H]- 化合物 S-119-2(93mg)溶于醋酸 （5ml) 中， 加热至 120度， 搅拌过夜。 TLC反应完全。 旋蒸去醋酸后， 加入乙醚搅拌， 过滤得化合物 S-119-3。 MS m/e 227 [M+H]+, 249 [M+Na] + , 193 [MH]- Compound S-119-2 (93 mg) dissolved in acetic acid (5 ml), warmed to 120 ° and stirred overnight. The TLC reaction is complete. After evaporating to acetic acid, diethyl ether was added and stirred, and filtered to give Compound S-119-3.
1H NMR (400 MHz, DMSO-d6): δ 10.48 (s, IH), 8.56 (t, J = 5.97 Hz, IH), 7.82 (dd, J = 6.64, 8.83 Hz, IH), 7.08 (td, J = 2.57, 8.47 Hz, IH), 6.90 (dd, J = 2.54, 10.40 Hz, IH), 3.63 (d， J = 5.77 Hz, 2H).  1H NMR (400 MHz, DMSO-d6): δ 10.48 (s, IH), 8.56 (t, J = 5.97 Hz, IH), 7.82 (dd, J = 6.64, 8.83 Hz, IH), 7.08 (td, J = 2.57, 8.47 Hz, IH), 6.90 (dd, J = 2.54, 10.40 Hz, IH), 3.63 (d, J = 5.77 Hz, 2H).
MS m/e 195 [M+H]+, 193 [M-H]" MS m/e 195 [M+H] + , 193 [MH]"
化合物 S-119-3(0.17g) 溶解到无水四氢呋喃 (5ml)中， 冰水下加入 BH3 HF(4.4ml), 再 在冰水下搅拌 15分钟， 然后加热回流 12小时。 TLC反应完全。 反应液中慢慢加入甲醇， 淬 灭未反应完的硼烷，旋蒸去甲醇与四氢呋喃，剩余物中加入甲醇和盐酸，再回流 3小时。 TLC 反应完全。 旋蒸去溶剂后， 剩余物加水， DCM提取 3次， 水相调节 PH=12, 再用 DCM提 起 3次， 合并有机相， 水洗， 盐水洗， 干燥， 浓缩， 柱层析得化合物 S-119。 IH NMR (400 MHz, CDC13): δ 7.11-7.03 (m, IH), 6.58-6.45 (m, 2H), 3.98 (bs, IH), 3.89 (s; 2H), 3.18-3.11 (m, 2H), 3.12-3.05 (m, 2H), 1.72 (bs, IH). Compound S-119-3 (0.17 g) was dissolved in anhydrous tetrahydrofuran (5 ml), EtOAc (EtOAc) The TLC reaction is complete. Methanol was slowly added to the reaction mixture, the unreacted borane was quenched, methanol and tetrahydrofuran were distilled off, and methanol and hydrochloric acid were added to the residue, followed by reflux for 3 hours. The TLC reaction is complete. After steaming off the solvent, the residue was added with water, DCM was extracted 3 times, the water phase was adjusted to pH=12, and then was taken up 3 times with DCM. The organic phase was combined, washed with water, washed with brine, dried, concentrated and purified by column chromatography. . IH NMR (400 MHz, CDC1 3 ): δ 7.11-7.03 (m, IH), 6.58-6.45 (m, 2H), 3.98 (bs, IH), 3.89 (s ; 2H), 3.18-3.11 (m, 2H ), 3.12-3.05 (m, 2H), 1.72 (bs, IH).
MS m/e 167 [M+H]+  MS m/e 167 [M+H]+
Figure imgf000063_0001
Figure imgf000063_0001
S-120-1 S-120-2 S-120-3 S-120 按照与制备例 74相同的方法， 以 S-120-1为原料， 合成化合物 S-120。  S-120-1 S-120-2 S-120-3 S-120 In the same manner as in Preparation Example 74, Compound S-120 was synthesized from S-120-1.
S-120-2  S-120-2
Ή NMR (400 MHz, CDC13): δ 7.52 (d, J = 8.15 Hz, 1H)， 6.93 (s, 1H)， 6.90 (d, J = 8.92 Hz, IH), 6.65 (bs, IH), 5.71 (bs, 2H), 4.23 (d, J = 5.06 Hz, 2H), 3.83 (s, 3H). NMR NMR (400 MHz, CDC1 3 ): δ 7.52 (d, J = 8.15 Hz, 1H), 6.93 (s, 1H), 6.90 (d, J = 8.92 Hz, IH), 6.65 (bs, IH), 5.71 (bs, 2H), 4.23 (d, J = 5.06 Hz, 2H), 3.83 (s, 3H).
MS m/e 277 [M+H]+, 275 [M-H]" MS m/e 277 [M+H] + , 275 [MH]"
S-120-3  S-120-3
Ή NMR (400 MHz, DMSO-d6): δ 10.58 (s, IH), 8.77 (t, J = 5.87 Hz, I H), 7.96 (d, J = 8.21 Hz, 1H)， 7.61 -7.51 (m, IH), 7.49-7.42 (m, IH), 3.67 (d, J = 5.77 Hz, 2H).  NMR NMR (400 MHz, DMSO-d6): δ 10.58 (s, IH), 8.77 (t, J = 5.87 Hz, IH), 7.96 (d, J = 8.21 Hz, 1H), 7.61 -7.51 (m, IH ), 7.49-7.42 (m, IH), 3.67 (d, J = 5.77 Hz, 2H).
MS m/e 243 [M-H]"  MS m/e 243 [M-H]"
S-120  S-120
Ή NMR (400 MHz, CDC13)： δ 7.22 (d, J = 7.74 Hz, IH), 7.08 (d, J = 7.23 Hz, IH), 7.03 (s, IH), 4.10 (bs, IH), 3.96 (s, 2H), 3.19- 3.13 (m, 2H), 3.13-3.06 (m, 2H). NMR NMR (400 MHz, CDC1 3 ): δ 7.22 (d, J = 7.74 Hz, IH), 7.08 (d, J = 7.23 Hz, IH), 7.03 (s, IH), 4.10 (bs, IH), 3.96 (s, 2H), 3.19- 3.13 (m, 2H), 3.13-3.06 (m, 2H).
MS m/e 217 [M+H]+, 215 [M-H]" MS m/e 217 [M+H] + , 215 [MH]"
Figure imgf000063_0002
Figure imgf000063_0002
S-121-1 S-121 -2 S-121 -3 S-121  S-121-1 S-121 -2 S-121 -3 S-121
按照与制备例 74相同的方法， 以 S-121-1为原料， 合成化合物 S-121。  In the same manner as in Preparation Example 74, Compound S-121 was synthesized from S-121-1.
S-121-2  S-121-2
1H NMR (400 MHz, CDC13)： δ 7.34 (d, J = 8.44 Hz, IH), 6.69 (d, J = 2.01 Hz, IH), 6.63 (dd, J = 2.02, 8.44 Hz, 1H)， 6.59 (bs, IH), 5.67 (bs, 2H), 4.20 (d， J = 5.09 Hz, 2H), 3.82 (s， 3H). 1H NMR (400 MHz, CDC1 3 ): δ 7.34 (d, J = 8.44 Hz, IH), 6.69 (d, J = 2.01 Hz, IH), 6.63 (dd, J = 2.02, 8.44 Hz, 1H), 6.59 (bs, IH), 5.67 (bs, 2H), 4.20 (d, J = 5.09 Hz, 2H), 3.82 (s, 3H).
MS m/e 243 [M+H]+, 241 [M-H]" MS m/e 243 [M+H] + , 241 [MH]"
S-121-3  S-121-3
1H NMR (400 MHz, DMSO-d6): δ 10.47 (s, IH), 8.62 (t, J = 6.04 Hz, IH), 7.77 (d, J = 8.48 Hz, IH), 7.28 (dd, J = 2.06, 8.48 Hz, IH), 7.16 (d, J = 2.05 Hz, IH), 3.63 (d, J = 5.78 Hz, 2H).  1H NMR (400 MHz, DMSO-d6): δ 10.47 (s, IH), 8.62 (t, J = 6.04 Hz, IH), 7.77 (d, J = 8.48 Hz, IH), 7.28 (dd, J = 2.06 , 8.48 Hz, IH), 7.16 (d, J = 2.05 Hz, IH), 3.63 (d, J = 5.78 Hz, 2H).
MS m/e 209 [M-H]- S-121  MS m/e 209 [M-H]- S-121
1H NMR (400 MHz, CDC13)： δ 7.04 (d, J = 7.76 Hz, IH), 6.84-6.76 (m, 2H), 3.97 (bs, IH), 3.89 (s, 2H), 3.17-3.04 (m, 4H). 1H NMR (400 MHz, CDC1 3 ): δ 7.04 (d, J = 7.76 Hz, IH), 6.84-6.76 (m, 2H), 3.97 (bs, IH), 3.89 (s, 2H), 3.17-3.04 ( m, 4H).
MS m/e 183 [M+H]+ MS m/e 183 [M+H] +
制备例 77: 化合物 S-122的制备 19 Preparation 77: Preparation of Compound S-122 19
Figure imgf000064_0001
Figure imgf000064_0001
Ιη+ν 6L\ ^sn Ιη+ν 6L\ ^sn
'∞ εο·ε-6θ·ε Xm '" ζιτ 'to 's) βι c(m 's) Α8·ε '(HI 'sq) ζβ '(HI ' wz = r 'ρ) 9ε·9 '(HI 'ZH 8Γ8 'ιςτ = r 'PP) iV9 '(HI 'ZH er8 = r 'p) WL δ :(ειοαο 'zroM oot) - mK H, '∞ εο·ε-6θ·ε Xm '" ζιτ 'to 's) βι c (m 's) Α8·ε '(HI 'sq) ζβ '(HI ' wz = r 'ρ) 9ε·9 '( HI 'ZH 8Γ8 'ιςτ = r 'PP) iV9 '(HI 'ZH er8 = r 'p) WL δ :( ε ιοαο 'zroM oot) - mK H,
επ-s Επ-s
■+[H+IM] LOZ s■ + [H+IM] LOZ s
Figure imgf000064_0002
Figure imgf000064_0002
89S = r 'ρ) 8 ·ε 'to 's) βυζ '(HI 'ZH ςνζ = r 'p) £99 '(HI '¾ 6/8 'svz = r 'PP) ZS9 '(HI 'ZH 89S = r 'ρ) 8 ·ε 'to 's) βυζ '(HI 'ZH ςνζ = r 'p) £99 '(HI '3⁄4 6/8 'svz = r 'PP) ZS9 '(HI 'ZH
LL% = f 'P) ILL '(HI 'ZH 89'S = Γ Ί) Z,£'8 '(HI 's) 6Γ01 S: (卯 -OS CI 'zfflAt OOt i Ht LL% = f 'P) ILL '(HI 'ZH 89'S = Γ Ί) Z, £'8 '(HI 's) 6Γ01 S: (卯-OS CI 'zfflAt OOt i H t
•+[H+1A[] 6£Z 3/m sn •+[H+1A[] 6£Z 3/m sn
乙  B
°iz\-s呦 劐 ι-ίζι-s a ' ^m L um m^  °iz\-s呦 ι ι-ίζι-s a ' ^m L um m^
Figure imgf000064_0003
Figure imgf000064_0003
+[H+ ] 6ZZ 'LZl SPM + [H+ ] 6ZZ 'LZl SPM
(ΗΣ: '" SO - 60· ε Xm '« ore -sn XBZ 'S) L Z '(HI 'sq) 96 ε X '« 68'9-∑;o , 9 -(HDOD 'm OOP) ^svm HT
Figure imgf000064_0004
(ΗΣ: '" SO - 60· ε Xm '« ore -sn XBZ 'S) LZ '(HI 'sq) 96 ε X '« 68'9-∑;o , 9 -(HDOD 'm OOP) ^svm H T
Figure imgf000064_0004
(HZ 'ZH 6 5 = f 'P) Z9 £ '(HI 'ZH Z-8'ΐ =f 'Ρ) l£'L '(HI ¾ί 1 ·8 'S81 = f 'PP) Tt^'A '(HI 'zH 117-8 = f 'Ρ) 897, '(HI ' 185 = Γ ¾ Ζ9·8 '(HI 's) V0l 9 :(9P-OSWa 'zHJM 00^) ¾WM Ht (HZ 'ZH 6 5 = f 'P) Z9 £ '(HI 'ZH Z-8'ΐ =f 'Ρ) l£'L '(HI 3⁄4ί 1 ·8 'S81 = f 'PP) Tt^'A '(HI 'zH 117-8 = f 'Ρ) 897, '(HI ' 185 = Γ 3⁄4 Ζ9·8 '(HI 's) V0l 9 :(9P-OSWa 'zHJM 00^) 3⁄4WM H t
£-ZZ\S lu-n] L2Z 'ssz [ +n\ \u '6οε '+[Η+ΙΛΙ] 6SZ CLSZ s (He 's) zs'z X 'm so-? = r 'p) oz '(HZ; 'sq) '(HI 'sq) ςς·9 '(HI ' 0^8 Ό61 = r£-ZZ\S lu-n] L2Z 'ssz [ +n\ \u '6οε '+[Η+ΙΛΙ] 6SZ C LSZ s (He 's) zs'z X 'm so-? = r 'p) Oz '(HZ;'sq)'(HI'sq) ςς·9 '(HI ' 0^8 Ό61 = r
'PP) 6L 9 '(HI 'ZH 681 =Γ 'Ρ)乙 8·9 '(HI 'ZH LV = Γ 'Ρ) LZL S： (£D D '^H H OO ) ¾匪 ΗΧ 'PP) 6L 9 '(HI 'ZH 681 =Γ 'Ρ) B8·9 '(HI 'ZH LV = Γ 'Ρ) LZL S: ( £ DD '^HH OO ) 3⁄4匪Η Χ
Figure imgf000064_0005
Figure imgf000064_0005
C0C000/M0ZN3/X3d 1^9 / 0Z OAV 按照与制备例 74相同的方法， 以 S-124-1为原料， 合成化合物 S-124。 C0C000/M0ZN3/X3d 1^9 / 0Z OAV In the same manner as in Preparation Example 74, the compound S-124 was synthesized from S-124-1.
S- 124-2  S- 124-2
1H NMR (400 MHz, CDC13):5 7.52 (d, J = 2.24 Hz, 1H), 7.30 (dd, J = 2.15, 8.57 Hz, 1H), 6.59 (d, J = 8.65 Hz, 1H), 5.54 (bs, 2H), 4.20 (d, J = 5.13 Hz, 2H), 3.82 (s, 3H). 1H NMR (400 MHz, CDC1 3 ): 5 7.52 (d, J = 2.24 Hz, 1H), 7.30 (dd, J = 2.15, 8.57 Hz, 1H), 6.59 (d, J = 8.65 Hz, 1H), 5.54 (bs, 2H), 4.20 (d, J = 5.13 Hz, 2H), 3.82 (s, 3H).
MS m/e 287, 289 [M+H]+, 309, 311 [M+Na]+, 285, 287 [M-H]" MS m/e 287, 289 [M+H] + , 309, 311 [M+Na] + , 285, 287 [MH]"
S-124-3  S-124-3
Ή NMR (400 MHz, DMSO-d6): δ 10.48 (s, 1H), 8.68 (t, J = 5.83 Hz, 1H), 7.83 (d, J = 2.44 Hz, 1H), 7.70 (dd, J = 2.47, 8.62 Hz, 1H), 7.07 (d, J = 8.65 Hz, 1H), 3.62 (d, J = 5.78 Hz, 2H).  NMR NMR (400 MHz, DMSO-d6): δ 10.48 (s, 1H), 8.68 (t, J = 5.83 Hz, 1H), 7.83 (d, J = 2.44 Hz, 1H), 7.70 (dd, J = 2.47 , 8.62 Hz, 1H), 7.07 (d, J = 8.65 Hz, 1H), 3.62 (d, J = 5.78 Hz, 2H).
MS m/e 253, 255 [M-H]".  MS m/e 253, 255 [M-H]".
S-124  S-124
1H NMR (400 MHz, CDC13): δ 7.24 (d, J = 2.36 Hz, 1H), 7.18 (dd, J = 2.34, 8.29 Hz, 1H), 6.67 (d， J = 8.30 Hz, 1H), 3.94 (bs, 1H), 3.87 (s, 2H), 3.15-3.04 (m, 4H). 1H NMR (400 MHz, CDC1 3 ): δ 7.24 (d, J = 2.36 Hz, 1H), 7.18 (dd, J = 2.34, 8.29 Hz, 1H), 6.67 (d, J = 8.30 Hz, 1H), 3.94 (bs, 1H), 3.87 (s, 2H), 3.15-3.04 (m, 4H).
MS m/e 227, 229 [M+H]+. MS m/e 227, 229 [M+H] + .
Figure imgf000065_0001
Figure imgf000065_0001
化合物 S-125(1.15g, 5.0mmol), 溶解到无水 N-甲基吡咯垸酮 (18ml)中， 氮气保护下加入 CuCN(1.35g, 15.0mmol), 加热到 200度反应 3.5小时。 TLC反应完全。 反应液冷却后慢慢 加入到乙二胺水溶液 (15%)中， 搅拌 1小时后， 乙酸乙酯提取 3次， 合并有机相， 氨水 (10%) 洗两次， 盐水洗， 干燥， 浓缩， 过柱得化合物 S-125 ( 150mg)o  Compound S-125 (1.15 g, 5.0 mmol) was dissolved in anhydrous N-methylpyrrolidone (18 ml). EtOAc (1. The TLC reaction is complete. After the reaction solution was cooled, it was slowly added to an aqueous solution of ethylenediamine (15%). After stirring for 1 hour, ethyl acetate was extracted three times, and the organic phase was combined, washed twice with ammonia (10%), brine, dried and concentrated. Pass the column to obtain the compound S-125 ( 150mg) o
1H NMR (400 MHz, CDC13)： δ 7.38 (d, J = 1.89 Hz, 1H), 7.35 (dd, J = 1.96, 8.16 Hz, 1H), 6.76 (d, J = 8.15 Hz, 1H), 4.35 (bs, 1H), 3.92 (s, 2H), 3.25 (m, 2H), 3.14 -3.03 (m, 2H). 1H NMR (400 MHz, CDC1 3 ): δ 7.38 (d, J = 1.89 Hz, 1H), 7.35 (dd, J = 1.96, 8.16 Hz, 1H), 6.76 (d, J = 8.15 Hz, 1H), 4.35 (bs, 1H), 3.92 (s, 2H), 3.25 (m, 2H), 3.14 -3.03 (m, 2H).
EIMS m/e 173 [M]+.  EIMS m/e 173 [M]+.
制  System
Figure imgf000065_0002
化合物 S-121(1.2g， 6.6mmol)溶于二氯甲垸 (15ml)中， 冰水下冷却， 加入三乙胺 (2.74ml， 0.2mol), 再加入 Boc20， 自然升温， 搅拌过夜。 TLC显示反应完全。 反应液倒入水中， 二 氯甲烷提取 3次， 合并有机相， PH=1的盐酸洗， 饱和碳酸氢钠洗， 水洗， 盐水洗， 干燥， 浓缩得化合物 S- 126-1。
Figure imgf000065_0002
Compound S-121 (1.2g, 6.6mmol) was dissolved in of dichloromethane (15ml) cooled with ice water, was added triethylamine (2.74ml, 0.2mol), was added Boc 2 0, natural temperature rise, stirring overnight . TLC showed the reaction was complete. The reaction solution was poured into water, extracted with dichloromethane three times, and the organic phase was combined, washed with hydrochloric acid of pH 1, washed with saturated sodium hydrogen carbonate, washed with water, brine, dried and concentrated to give compound S- 126-1.
1H NMR (400 MHz, CDC13)： δ 7.14 (m, 1H), 6,84 (dd, J = 1.98, 7.96 Hz, 1H), 6.78 (d, J = 6.67 Hz, 1H), 4.35 (d, 2H), 3.95 (bs, 1H), 3.64 (dd, J = 3.52, 6.00 Hz, 2H), 3.16 (s, 2H), 1.43 (s, 9H). 1H NMR (400 MHz, CDC1 3 ): δ 7.14 (m, 1H), 6,84 (dd, J = 1.98, 7.96 Hz, 1H), 6.78 (d, J = 6.67 Hz, 1H), 4.35 (d, 2H), 3.95 (bs, 1H), 3.64 (dd, J = 3.52, 6.00 Hz, 2H), 3.16 (s, 2H), 1.43 (s, 9H).
MS m/e 281 [M-H]-.  MS m/e 281 [M-H]-.
化合物 S-126-l(0.5g， 1.77mmol)溶于 DMF(lOml)中， 再加入碳酸钾 (0.73g， 5.3mmol), 冰水冷却下加入碘甲烷 (0.13ml， 2.1mmol), 自然升温， 搅拌过夜， 补加碘甲垸 (0.13ml， 2.1mmol), 加热到 60度， 反应 10小时， TLC显示有部分原料未反应。 反应液倒入水中， 二 氯甲烷提取 3次，合并有机相，水洗，盐水洗，干燥，浓缩，柱层析得化合物 S-126-2 (0.3g)。 Compound S-126-l (0.5 g, 1.77 mmol) was dissolved in DMF (10 mL), then potassium carbonate (0.73 g, 5.3 mmol) was added, and iodine methane (0.13 ml, 2.1 mmol) Stir overnight, add iodothymidine (0.13ml, 2.1 mmol), heated to 60 ° C, and reacted for 10 hours, TLC showed that some of the starting materials were unreacted. The reaction mixture was poured into water, extracted with dichloromethane (3×), and then evaporated.
化合物 S-126-2(0.3g)溶于二氯甲烷 (10ml)中，加入三氟乙酸 (lml)，室温搅拌 6小时， TLC 检测反应完全。 直接旋干二氯甲烷和过量的三氟乙酸， 得到化合物 S-126的三氟乙酸盐。  The compound S-126-2 (0.3 g) was dissolved in dichloromethane (10 ml), trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 6 hr. The dichloromethane and excess trifluoroacetic acid were directly dried to give the trifluoroacetic acid salt of Compound S-126.
1H MR (400 MHz, DMSO-d6): δ 9.00 (bs, 2H), 7.36 (d, 1H), 7.01-6.99 (m， 2H), 4,18 (bs， 2H), 3.31-3.16 (m, 4H), 2.89 (s, 3H).  1H MR (400 MHz, DMSO-d6): δ 9.00 (bs, 2H), 7.36 (d, 1H), 7.01-6.99 (m, 2H), 4,18 (bs, 2H), 3.31-3.16 (m, 4H), 2.89 (s, 3H).
MS m/e 197 [M+H]+.  MS m/e 197 [M+H]+.
制备例 82: 化合物 S-127的制备  Preparation 82: Preparation of Compound S-127
Figure imgf000066_0001
Figure imgf000066_0001
化合物 S-126-l(0.1g， 0.35mmol)溶解到无水吡啶 (3ml)中，再加入醋酸酐 (80μί， 0.84mmol, Compound S-126-l (0.1 g, 0.35 mmol) was dissolved in anhydrous pyridine (3 mL), and then acetic anhydride (80 μί, 0.84 mmol,
2.4eq)加热到 100度 3小时， TLC反应完全。反应液冰水中冷却，用盐酸缓慢的调节至 PH=3， 二氯甲垸提取 3次， 合并有机相， 饱和碳酸氢钠洗， 水洗， 盐水洗， 干燥， 浓缩， 过柱得化 合物 S-127-2(100mg) 2.4 eq) was heated to 100 degrees for 3 hours and the TLC reaction was complete. The reaction solution was cooled in ice water, slowly adjusted to pH = 3 with hydrochloric acid, and extracted twice with dichloromethane. The organic phase was combined, washed with saturated sodium hydrogen carbonate, washed with water, washed with brine, dried and concentrated. -2 (100mg)
1H NMR (400 MHz, CDC13)： δ 7.30 (m, 2Η), 7.25 (m， 1H), 4.92-4.58 (m, 2H), 4.30-3.80 (m, 2H), 3.41-3.10 (m, 1H), 2.75 (m, 1H)， 1.97 (s, 3H), 1.65-1.35 (m, 9H). 1H NMR (400 MHz, CDC1 3 ): δ 7.30 (m, 2Η), 7.25 (m, 1H), 4.92-4.58 (m, 2H), 4.30-3.80 (m, 2H), 3.41-3.10 (m, 1H) ), 2.75 (m, 1H), 1.97 (s, 3H), 1.65-1.35 (m, 9H).
MS m/e 347 [M+Na]+. MS m/e 347 [M+Na] + .
化合物 S-127-2(100mg)溶于二氯甲烷 (10ml)中， 再加入三氟乙酸 (lml)， 室温搅拌过夜。 TLC显示反应完全。 旋蒸去二氯甲垸和过量的三氟乙酸， 固体用乙醚洗， 过滤， 烘干， 得化 合物 S-127。  Compound S-127-2 (100 mg) was dissolved in dichloromethane (10 mL). TLC showed the reaction was complete. Dichloromethane and excess trifluoroacetic acid were distilled off, and the solid was washed with diethyl ether, filtered, and dried to give compound S-127.
1H NMR (400 MHz, DMSO-d6): δ 7.71 (d, J = 2.12 Hz, 1H), 7.62 (d, J - 8.23 Hz, 1H), 7.51 (dd， J = 2.11, 8.22 Hz, 1H), 4.67 (d, J = 14.88 Hz, 1H), 4.34 (s, 2H), 3.38 (d， J = 13.50 Hz, 1H), 3.20 (t, J = 12.47 Hz, 1H), 2.91 (t, J = 13.32 Hz, 1H)， 1.90 (s, 3H).  1H NMR (400 MHz, DMSO-d6): δ 7.71 (d, J = 2.12 Hz, 1H), 7.62 (d, J - 8.23 Hz, 1H), 7.51 (dd, J = 2.11, 8.22 Hz, 1H), 4.67 (d, J = 14.88 Hz, 1H), 4.34 (s, 2H), 3.38 (d, J = 13.50 Hz, 1H), 3.20 (t, J = 12.47 Hz, 1H), 2.91 (t, J = 13.32 Hz, 1H), 1.90 (s, 3H).
MS m/e 225 [M+H]+.  MS m/e 225 [M+H]+.
制备例 83: 化合物 S-128的制备  Preparation Example 83: Preparation of Compound S-128
Figure imgf000066_0002
Figure imgf000066_0002
按照与制备例 51 相同的方法， 以化合物 2-硝基 -4-三氟甲基苯甲酸为试剂合成化合物 S-128。 The compound was synthesized in the same manner as in Preparation 51 using the compound 2-nitro-4-trifluoromethylbenzoic acid as a reagent. S-128.
制备例 84: 化合物 S-129的制备  Preparation 84: Preparation of Compound S-129
Figure imgf000067_0001
Figure imgf000067_0001
按照与制备例 56相同的方法， 以化合物 2-硝基 -4-溴苯甲酸为试剂合成化合物 S-129-6。 化合物 S-129-6(300mg)溶于乙腈， 加入碘化钠 (800mg)， 滴加三甲基氯硅烷 (0.8ml)， 反 应完全， 加水， EA萃取， 饱和食盐水洗涤 EA层， 无水硫酸钠干燥， 浓缩， 柱层析得 150mg 化合物 S-129。
Figure imgf000067_0002
Compound S-129-6 was synthesized in the same manner as in Preparation 56 using the compound 2-nitro-4-bromobenzoic acid as a reagent. Compound S-129-6 (300mg) was dissolved in acetonitrile, sodium iodide (800mg) was added, trimethylchlorosilane (0.8ml) was added dropwise, the reaction was completed, water was added, EA was extracted, and the EA layer was washed with saturated brine. Drying over sodium sulfate, concentration and column chromatography gave 150 mg of Compound S-129.
Figure imgf000067_0002
按照与制备例 14相同的方法， 以化合物 S-130-2为试剂合成化合物 S-130。  Compound S-130 was synthesized in the same manner as in Preparation 14 using Compound S-130-2 as a reagent.
MS m/e 385[M+H]+. MS m/e 385 [M+H] + .
制备例 86: 化合物 S-131的制备
Figure imgf000067_0003
Preparation 86: Preparation of Compound S-131
Figure imgf000067_0003
S-129-6 S-131-1  S-129-6 S-131-1
化合物 S-129-6(30mg)溶于 DMF， 加入氰化锌 (150mg)， 四三苯基膦钯 (100mg)， 氮气保 护， 80°C， 反应过夜， 次日加水， EA萃取， 饱和食盐水洗涤 EA层， 无水硫酸钠干燥， 浓 缩， 柱层析得化合物 S-131-l。 化合物 S-131-1溶于甲醇， 加入 Pd/C， 通入 H2， 反应 12h， 过滤， 浓缩， 柱层析得化合物 S-131。 Compound S-129-6 (30 mg) was dissolved in DMF, added with zinc cyanide (150 mg), tetratriphenylphosphine palladium (100 mg), protected with nitrogen, 80 ° C, reaction overnight, water added the next day, EA extraction, saturated salt The EA layer was washed with water, dried over anhydrous sodium sulfate. The compound S-131-1 was dissolved in methanol, Pd/C was added thereto, H 2 was added thereto, and the mixture was reacted for 12 hours, filtered, concentrated, and subjected to column chromatography to yield Compound S-131.
以下化合物 由 市场采购或 由上海特化医药科技有 限公司提供：  The following compounds are purchased by the market or by Shanghai Specialized Medical Technology Co., Ltd.:
Figure imgf000067_0004
Figure imgf000068_0001
实施例 1 :
Figure imgf000067_0004
Figure imgf000068_0001
Example 1:
Figure imgf000068_0002
Figure imgf000068_0002
制备例 2的化合物 S-2(42g)溶于甲苯 (250ml)， 加入 DMAP(5g), 3- (三氟甲基) -5,6,7,8-四 氢 -[1,2,4]三唑并 [4,3-a]吡嗪盐酸盐 (39g)， 三乙胺 (36ml)， 氮气保护， 120°C回流 5h后， 蒸干 溶剂， 残留物用乙酸乙酯溶解， 乙酸乙酯相依次用 1M HC1溶液、 饱和食盐水洗涤， 无水硫 酸钠干燥， 浓缩， 柱层析得 35g产物 1-1  The compound S-2 (42 g) of Preparation Example 2 was dissolved in toluene (250 ml), and DMAP (5 g), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4 was added. Triazolo[4,3-a]pyrazine hydrochloride (39g), triethylamine (36ml), EtOAc (3HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The ethyl ester phase was washed successively with 1M HCl solution and brine, dried over anhydrous sodium sulfate, and concentrated,
上述产物 (20g)溶于甲醇 (50ml)，加入氨甲醇溶液 (30ml)，加入乙酸铵 (16g)， 65°C下反应， 2h反应完全， 冷至室温， 加入氰基硼氢化钠 (9g)， 加入醋酸 (3ml)调 pH=5， 反应过夜， 次日 蒸干溶剂， 残留物用二氯甲垸溶解， 有机层依次用饱和 NaHC03溶液、 饱和食盐水洗涤， 无 水硫酸钠干燥， 浓缩， 柱层析得实施例 1标题化合物 (16.5g)。 The above product (20g) was dissolved in methanol (50ml), added to ammonia methanol solution (30ml), ammonium acetate (16g) was added, the reaction was carried out at 65 ° C, the reaction was completed in 2 h, cooled to room temperature, sodium cyanoborohydride (9 g) was added. Add acetic acid (3ml) to adjust pH=5, react overnight, the next day The solvent was evaporated, the residue was dissolved with of dichloromethane, the organic layer was washed with saturated NaHC0 3 solution, saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to give the title compound of Example 1 (16.5 g of) embodiments.
1H雇 R(300 MHZ, CD3OD):5 7.14(1H, dd), 7.05(1H, dd), 4.18-5.14(2H, m), 4.27-4.36(2H, m), 4.00-4.14(2H,m), 3.69-3.78(lH,m), 2.77-3.00(2H, m), 2.53-2.75 (2H, m)， 2.03-2.27(2H, m). 1H hire R (300 MHZ, CD 3 OD): 5 7.14 (1H, dd), 7.05 (1H, dd), 4.18-5.14 (2H, m), 4.27-4.36 (2H, m), 4.00-4.14 (2H , m), 3.69-3.78(lH,m), 2.77-3.00(2H, m), 2.53-2.75 (2H, m), 2.03-2.27(2H, m).
MS m/e 416 [M+H]+. MS m/e 416 [M+H] + .
Figure imgf000069_0001
Figure imgf000069_0001
将实施例 1的化合物经硅胶柱层析得一对对映体化合物 2和化合物 3的混合物；以及另 -对对映体化合物 4和化合物 5的混合物。 化合物 2、 3与 4、 5为非对映异构体。  The compound of Example 1 was subjected to silica gel column chromatography to obtain a mixture of a pair of enantiomers of compound 2 and compound 3; and another mixture of enantiomers of compound 4 and compound 5. Compounds 2, 3 and 4, 5 are diastereomers.
实施例  Example
Figure imgf000069_0002
Figure imgf000069_0002
将实施例 1的化合物采用 HPLC手性制备液相仪 (色谱柱型号为 AD-H)进行手性拆分， 分别得到单一手性异构体实施例 4 化合物和实施例 5 化合物。 色谱保留时间分别为 tR=48.0min, tR=35.0min。 The compound of Example 1 was subjected to chiral resolution using an HPLC chiral preparative liquid phase column (column type AD-H) to give a single chiral isomer of Example 4 compound and the compound of Example 5, respectively. Chromatographic retention time of tR = 48.0min, t R = 35.0min .
实施例 4化合物： e.e.值〉 98%。 1H NMR(300 MHZ, CD3OD):5 7.07(1H, dd), 7.00(1 H, dd), 4.89-5.16(2H, m), 3.90-4.31(4H, m)， 3.81(1H, br), 3.25(1H, br), 2.78-2.96(2H, m), 2.50 (2H, d), 2.03-2.22(2H, m). MS: m/e 416 [M+H]+. 比旋光度 +25°(C=0.5)。 Example 4 compound: ee value > 98%. 1H NMR (300 MHZ, CD 3 OD): 5 7.07 (1H, dd), 7.00 (1H, dd), 4.89-5.16 (2H, m), 3.90-4.31 (4H, m), 3.81 (1H, br ), 3.25(1H, br), 2.78-2.96(2H, m), 2.50 (2H, d), 2.03-2.22(2H, m). MS: m/e 416 [M+H] + . +25° (C=0.5).
实施例 5化合物： e.e.值〉 98%。 1H MR(300 MHZ, CD3OD):S 7.06(1H, dd), 6.99(1H, dd), 4.89-5.14(2H, m), 3.86-4.31(4H, m)， 3.80(1H, br), 3.25(1H, br), 2.77-3.00(2H, m)， 2.50 (2H, d), 2.03-2.19(2H, m). MS: m/e 416 [M+H]+. 比旋光度 -25 °(C=0.5)。 Example 5 compound: ee value > 98%. 1H MR (300 MHZ, CD 3 OD): S 7.06 (1H, dd), 6.99 (1H, dd), 4.89-5.14 (2H, m), 3.86-4.31 (4H, m), 3.80 (1H, br) , 3.25(1H, br), 2.77-3.00(2H, m), 2.50 (2H, d), 2.03-2.19(2H, m). MS: m/e 416 [M+H] + . Specific optical rotation - 25 ° (C = 0.5).
Figure imgf000069_0003
Figure imgf000069_0003
S-5a 5-1 5  S-5a 5-1 5
制备例 6的化合物 S-5a(100mg)溶于 DMF， 加入 NEt3(0.1ml), HATU(123mg), 5min反 应完全， 加入 3- (三氟甲基) -5,6,7,8-四氢 -[1,2,4]三唑并 [4,3-a]吡嗪盐酸盐 (68mg)， 室温搅拌过 夜， 反应完全， 加入 1M HC1溶液， EA萃取， EA层依次用 NaHC03溶液， 饱和食盐水洗涤， 无水硫酸钠千燥， 浓缩， 柱层析得化合物 5-l(77mg)。 化合物 5-l(77mg)溶于 CH2C12， 加入 CF3COOH(0.3ml)， lh反应完全， 加入二氯甲烷稀 释，饱和碳酸氢钠溶液洗涤，饱和食盐水洗涤，无水硫酸钠干燥，柱层析得化合物 5 (50mg)。 e.e.值〉 98%。 Preparation of Compound S-5a 6 (100mg) was dissolved in of DMF, NEt 3 (0.1ml), HATU ( 123mg), 5min the reaction was complete, 3- (trifluoromethyl) -5,6,7,8 Tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (68mg), stirred at room temperature overnight, the reaction was completed, 1M HCl solution was added, EA was extracted, and EA layer was sequentially treated with NaHC0 3 The solution was washed with saturated brine, dried over anhydrous sodium sulfate. The compound 5-1 (77 mg) was dissolved in CH 2 C1 2 , EtOAc ( 3 mL), EtOAc (EtOAc) Column chromatography gave compound 5 (50 mg). The ee value is > 98%.
实施例  Example
Figure imgf000070_0001
Figure imgf000070_0001
化合物 7-l(l lg)悬浮于 C Cl2(150ml)中， 加入 1 ,2-乙二硫醇 (6.6ml), 加入 BF3'Et20溶 液 (2.1ml)， 室温搅拌， 次日反应完全， 加入 CH2C12稀释， 依次用水， 饱和食盐水洗涤有机 层， 无水硫酸钠干燥， 浓缩， 用 CH2C12/PE重结晶， 得 10.8g化合物 7-2。 Compound 7-l (l lg) was suspended in CCl 2 (150 ml), 1 ,2-ethanedithiol (6.6 ml) was added, BF 3 'Et 2 0 solution (2.1 ml) was added, and stirred at room temperature, the next day the reaction was complete, diluted with CH 2 C1 2, washed with water, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, CH 2 C1 2 / PE recrystallized from 10.8g compound 7-2.
化合物 7-2(10.8g)溶于 CH2Cl2(100ml)中， 加入 DMAP(6.8g)， 米氏酸 (5.6g), 冰浴下滴加 DCC(8.4g)的 CH2C12溶液 (50ml)， 自然升至常温， 反应完全后， 过滤， 滤液依次用 1M HC1 洗漆， 饱和食盐水洗涤有机层， 无水硫酸钠干燥， 浓缩， 用石油醚-乙酸乙酯结晶得 9.2g化 合物 7-3。 Compound 7-2 (10.8 g) was dissolved in CH 2 Cl 2 (100 ml), DMAP (6.8 g), M.s. (5.6 g) was added, and DCC (8.4 g) of CH 2 C1 2 solution was added dropwise in an ice bath. (50ml), naturally rose to room temperature, after the reaction was completed, the filtrate was filtered, and the filtrate was washed with 1M EtOAc (EtOAc). 7-3.
化合物 7-3(9.2g)， TsOH(2g)， EtOH(50ml), 80°C加热， 溶液逐渐澄清， lh后反应完 全， 蒸干溶剂， 柱层析得 8.8g产物 7-4。  Compound 7-3 (9.2 g), TsOH (2 g), EtOH (50 ml), heated at 80 ° C, the solution was gradually clarified, and the reaction was completed after lh, and the solvent was evaporated to give 8.8 g of product 7-4.
化合物 7- 4(8.8g)溶于甲苯 (100ml)中，加入 DMAP(0.9g)， 3- (三氟甲基) -5，6,7，8-四氢 -[1,2,4] 三唑并 [4,3-a]吡嗪盐酸盐 (7.1g)， 三乙胺 (5.2ml)， N2保护， 120°C加热， 6h后， 蒸干溶剂， 乙 酸乙酯溶解， 有机层依次用 1M HC1溶液， 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 柱层 析得 9.3g产物 7-5。 Compound 7-4 (8.8 g) was dissolved in toluene (100 ml), DMAP (0.9 g), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4] Triazolo[ 4 ,3- a ]pyrazine hydrochloride (7.1g), triethylamine (5.2ml), N 2 protection, heated at 120 ° C, 6h, evaporated to dryness, ethyl acetate dissolved, organic The layers were washed successively with a 1M EtOAc solution, brine, dried over anhydrous sodium sulfate.
化合物 7-5(9.2g)溶于氨甲醇溶液 (30ml)中，加入甲醇 (50ml)，加入醋酸铵 (5.8g)， N2保护， 65 °C下反应， lh后反应完全， 冷至室温， 加入 NaBH3CN(3.5g)， 用醋酸调 pH=5， 室温搅拌， 次日反应完全， 浓缩反应液， 用饱和 NaHC〇3溶液中和醋酸， 加入二氯甲垸， 分层， 有机相 依次用水、 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 柱层析得 7.5g目标物 7。 Compound 7-5 (9.2g) was dissolved in ammonia methanol solution (30ml), methanol (50ml) was added, ammonium acetate (5.8g) was added, N 2 protection, reaction at 65 °C, reaction was complete after lh, cooled to room temperature Add NaBH 3 CN (3.5g), adjust pH=5 with acetic acid, stir at room temperature, complete the reaction the next day, concentrate the reaction solution, neutralize acetic acid with saturated NaHC〇 3 solution, add dichloromethane, layer, organically The mixture was washed with water and brine, dried over anhydrous sodium sulfate and evaporated.
Ή顺 R(300 MHZ, CD3OD):6 7.43(1H, dd)， 7.37(1H， dd)， 5.04(2H, s), 4.25(1H, br), 4.13(1H, br), 4.01 (2H, br), 3.72(1H, br), 3.52-3.67(4H, m), 3.07-3.18(1H, m), 3.39-3.47 (1H, m), 2.91-3.01(2H, m), 2.58-2.67 (1H， m). MS: m/e 506 [M+H]+. Ή R (300 MHZ, CD 3 OD): 6 7.43 (1H, dd), 7.37 (1H, dd), 5.04 (2H, s), 4.25 (1H, br), 4.13 (1H, br), 4.01 ( 2H, br), 3.72(1H, br), 3.52-3.67(4H, m), 3.07-3.18(1H, m), 3.39-3.47 (1H, m), 2.91-3.01(2H, m), 2.58- 2.67 (1H, m). MS: m/e 506 [M+H] + .
实施例 8:
Figure imgf000071_0001
化合物 7(720mg)溶于甲醇 (10ml)中， 加入 HgCl2(550mg)， 30min反应完全， 过滤， 浓缩 滤液， 柱层析， 得实施例 8的标题化合物 450mg。 Example 8
Figure imgf000071_0001
Compound 7 (720mg) was dissolved in methanol (10ml) was added HgCl 2 (550mg), 30min the reaction was complete, filtered, and the filtrate was concentrated and column chromatography, to obtain the title compound of Example 8 embodiment 450mg.
1H NMR(300 MHZ, CD3OD): δ 7.74(1H, dd), 7.63(1H, dd), 5.04(2H, s), 4.34(2H, br), 4.24(1H, t), 4.06(1H, t), 3.90(1H, br), 3.15-3.21(1H, m), 3.12(1H, t), 2.87-3.05(2H, m), 2.69(1H, dt). MS: m/e 430 [M+H]+. 1H NMR (300 MHZ, CD 3 OD): δ 7.74 (1H, dd), 7.63 (1H, dd), 5.04 (2H, s), 4.34 (2H, br), 4.24 (1H, t), 4.06 (1H) , t), 3.90(1H, br), 3.15-3.21(1H, m), 3.12(1H, t), 2.87-3.05(2H, m), 2.69(1H, dt). MS: m/e 430 [ M+H] + .
实施例 9:  Example 9
Figure imgf000071_0002
Figure imgf000071_0002
化合物 8(260mg)溶于甲醇 (5ml)中， 冰浴下加入硼氢化钠 (40mg)， 30min反应完全， 浓缩 反应液， 加入 CH2C12溶解， 有机相依次用水、 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩得 目标物 230mg。 The compound 8 (260 mg) was dissolved in methanol (5 ml), and sodium borohydride (40 mg) was added under ice-cooling, and the reaction was completed for 30 min. The reaction mixture was concentrated, dissolved in CH 2 C1 2 and the organic phase was washed sequentially with water and brine. The mixture was dried over sodium sulfate and concentrated to give the object.
1H NMR(300 MHZ, CD3OD):S 7.18-7.30(2H, m), 5.04(2H, br), 4.99(1H, br), 4.34(1H, br), 4.24(1H, r), 4.06(2H, br), 3.76(1H, br), 3.34(1H, m)， 2.78(1H, dd), 2.62(1H, dd), 2.45-2.57(lH, m); 1.84-1.95 (lH, m). MS: m/e 432 [M+H]+. 1H NMR (300 MHZ, CD 3 OD): S 7.18-7.30 (2H, m), 5.04 (2H, br), 4.99 (1H, br), 4.34 (1H, br), 4.24 (1H, r), 4.06 (2H, br), 3.76(1H, br), 3.34(1H, m), 2.78(1H, dd), 2.62(1H, dd), 2.45-2.57(lH, m) ; 1.84-1.95 (lH, m MS: m/e 432 [M+H] + .
实施例 10:  Example 10
Figure imgf000071_0003
Figure imgf000071_0003
化合物 10-l(100mg)， 苄胺 (75mg)， 对甲苯磺酸 (20mg), 甲苯 (5ml)， 110°C回流反应， 5h 反应完全， 冷却， 过滤， 蒸干溶剂， 残留物用甲醇溶解， 冰浴下加入硼氢化钠 (60mg)， 反应 完全后， 蒸干溶剂， 用 CH2C12溶解， 饱和食盐水洗涤有机层， 无水硫酸钠干燥， 浓缩， 柱 层析得 20mg化合物 10-2。 Compound 10-l (100 mg), benzylamine (75 mg), p-toluenesulfonic acid (20 mg), toluene (5 ml), refluxed at 110 ° C, 5 h complete reaction, cooled, filtered, evaporated to dryness. , sodium borohydride (60mg) column chromatography to obtain a compound of 20mg was added under ice bath, after completion of the reaction, the solvent was evaporated to dryness, dissolved with CH 2 C1 2, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to 10- 2.
化合物 10-2(20mg)溶于 CH2Cl2(lml)， 加入三氟醋酸 (0.2ml)， lh反应完全， 蒸干溶剂， 用甲基叔丁基醚结晶， 得化合物 10.CF3COOH(15mg)。 1H MR(300 MHZ, CD3OD): δ 7.42-7.64(7H, m), 5.04(2H, br), 4.99(1H, br), 4.34 (1H, br), 4.24(1H, r), 4,06(4H, br), 3.76(1H, br), 3.34(1H, m), 2.78(1H, dd), 2.62(1H, dd), 2.45-2.57(lH, m)， 1.84-1.95 (1H, m). MS: m/e 521 [M+H]+. Compound 10-2 (20mg) was dissolved in CH 2 Cl 2 (lml), was added trifluoroacetic acid (0.2ml), lh the reaction was complete, solvent was evaporated to dryness, crystallized from methyl tert-butyl ether, 10.CF 3 COOH to give compound (15mg). 1H MR (300 MHZ, CD 3 OD): δ 7.42-7.64 (7H, m), 5.04 (2H, br), 4.99 (1H, br), 4.34 (1H, br), 4.24(1H, r), 4 , 06(4H, br), 3.76(1H, br), 3.34(1H, m), 2.78(1H, dd), 2.62(1H, dd), 2.45-2.57(lH, m), 1.84-1.95 (1H , m). MS: m/e 521 [M+H] + .
化合物 10.CF3COOH用饱和碳酸氢钠游离， 得碱式化合物 10。 Compound 10.CF 3 COOH was taken up in saturated sodium bicarbonate to give compound 10 as a base.
实施例 11  Example 11
Figure imgf000072_0001
Figure imgf000072_0001
11-1 11-2 11  11-1 11-2 11
化合物 ll-l(330mg)溶于 CH2Cl2(10ml)， 冰浴下滴加 DAST试剂 (0.1ml), 30min反应完 全， 加水淬灭， CH2C12稀释， 分层， 饱和食盐水洗涤 CH2C12层， 无水硫酸钠干燥， 浓缩， 柱层析得 60mg化合物 11-2。 Compound 11-l (330 mg) was dissolved in CH 2 Cl 2 (10 ml), and DAST reagent (0.1 ml) was added dropwise in an ice bath, and the reaction was completed in 30 min, quenched with water, diluted with CH 2 C1 2 , layered, washed with saturated brine. The CH 2 C1 2 layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography.
化合物 ll-2(60mg)溶于 CH2C12， 加入三氟醋酸 (0.3ml)， 反应完全后， 加入 CH2C12稀释， 分层， CH2C12层依次用饱和碳酸氢钠溶液、饱和食盐水洗涤，无水硫酸钠干燥，浓缩得 34mg 化合物 11。 The compound ll-2 (60 mg) was dissolved in CH 2 C1 2 and trifluoroacetic acid (0.3 ml) was added. After the reaction was completed, the mixture was diluted with CH 2 C 2 2 and layered, and the CH 2 C 2 2 layer was successively washed with saturated sodium hydrogen carbonate solution. The mixture was washed with brine, dried over anhydrous sodium sulfate
1H MR(300 MHZ, CD3OD): δ 7.56(1H, t), 7.35(1Η, t), 7.02(1Η, d), 6.7(1Η, dd), 5.04 (2Η, br), 4.34(1H, br), 4.24(1H, r), 4.06(2H, br), 3.76(1H, br), 3.34(1H, m), 2.78(1H, dd), 2.62(1H, dd). 1H MR (300 MHZ, CD 3 OD): δ 7.56 (1H, t), 7.35 (1Η, t), 7.02 (1Η, d), 6.7 (1Η, dd), 5.04 (2Η, br), 4.34(1H , br), 4.24(1H, r), 4.06(2H, br), 3.76(1H, br), 3.34(1H, m), 2.78(1H, dd), 2.62(1H, dd).
MS: m/e 414 [M+H]+. MS: m/e 414 [M+H] + .
实施例 1  Example 1
Figure imgf000072_0002
Figure imgf000072_0002
NaHMDS(19ml)溶于干燥 THF(50ml)中，氮气置换， -78°C下冷却，滴加化合物 12-l(4.1g) 的 THF溶液， 搅拌 45min， 滴加苄溴 (3ml)的 THF溶液， 30min后自然升温， 反应完全后， 加入氯化铵溶液淬灭， 蒸干 THF， 用乙酸乙酯萃取， 饱和食盐水洗涤有机层， 无水硫酸钠干 燥， 浓缩， 柱层析得 4.5g化合物 12-2。  NaHMDS (19 ml) was dissolved in dry THF (50 ml), EtOAc (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH After 30 minutes, the mixture was heated to dryness. After the reaction was completed, the mixture was stirred and evaporated to dryness. EtOAc was evaporated, evaporated, evaporated, evaporated. 12-2.
化合物 12-2(4.5g)溶于甲醇 (20ml)， 7_( (20ml)中， 加入氢氧化钠 (1.3g)， 回流， 反应完全 后， 蒸干甲醇， 用 1M HC1溶液调 pH=2， 用乙酸乙酯萃取， 饱和食盐水洗涤有机层， 无水 硫酸钠干燥， 浓缩得 4g化合物 12-3。  The compound 12-2 (4.5 g) was dissolved in methanol (20 ml), 7-(20 ml), sodium hydroxide (1.3 g) was added, and refluxed. After the reaction was completed, methanol was evaporated to dryness, and pH was adjusted to 2 with 1M HCl solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated.
丙二酸单乙酯钾盐 (1.62g)悬浮于乙腈 (5ml)中， 加入三乙胺 (2.1 ml), 氯化镁 (1.13g)， 室 温搅拌 2h。 化合物 12-3(1.3g)悬浮于乙腈 (10ml)中， 加入 CDI(0.9g)， 室温搅拌至反应完全， 加至上述反应液中。 搅拌过夜， 次日滴加 13% HC1溶液至澄清， 分层， 浓缩有机层， 残留 物用 EA溶解； EA萃取水层，合并 EA层， 饱和食盐水洗涤 EA层， 无水硫酸钠干燥，浓缩， 柱层析得 1.3g化合物 12-4。 The monoethyl malonate potassium salt (1.62 g) was suspended in acetonitrile (5 ml), triethylamine (2.1 ml), magnesium chloride (1.13 g). Compound 12-3 (1.3 g) was suspended in acetonitrile (10 ml), CDI (0.9 g) was added, and the mixture was stirred at room temperature until the reaction was completed and added to the reaction mixture. Stir overnight, add 13% HCl solution to the next day to clarify, layer, concentrate the organic layer, residue The EA was dissolved in EA. The aqueous layer was extracted with EA, and then EA layer was evaporated.
化合物 12-4(lg)溶于甲苯 (20ml)， 加入 DMAP(94mg)， 3- (三氟甲基) -5，6,7,8-四氢 -[1,2,4] 三唑并 [4,3-a]吡嗪盐酸盐 (738mg)， 三乙胺 (0.5ml)， 氮气保护， 120°C回流， 5h后， 蒸干溶剂， 残留物用乙酸乙酯溶解，依次用 1M HC1溶液、饱和食盐水洗涤，干燥，浓缩，柱层析得 915mg 化合物 12-5。  Compound 12-4 (lg) was dissolved in toluene (20 ml), and DMAP (94 mg), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazole was added. [4,3-a]pyrazine hydrochloride (738 mg), triethylamine (0.5 ml), nitrogen-purified, refluxed at 120 ° C. After 5 h, the solvent was evaporated to dryness. The solution was washed with a HCl solution and brine, dried and concentrated.
化合物 12-5(550mg)溶于氨甲醇溶液 (10ml)， 加入乙酸铵 (600mg)， 65°C下回流， 24h反 应完全， 冷至室温， 加入氰基硼氢化钠 (198mg), 乙酸调 pH=5, 室温搅拌， 次日蒸干溶剂， 残留物用二氯甲烷溶解， 依次用饱和碳酸氢钠溶液、 饱和食盐水洗涤有机层， 无水硫酸钠干 燥， 浓缩， 柱层析得目标物。  Compound 12-5 (550 mg) was dissolved in ammonia methanol solution (10 ml), ammonium acetate (600 mg) was added, refluxed at 65 ° C, and the reaction was completed 24 h, cooled to room temperature, sodium cyanoborohydride (198 mg) was added, and pH was adjusted with acetic acid. The mixture was stirred at room temperature, and the solvent was evaporated to dryness. The residue was evaporated, evaporated, evaporated, evaporated, evaporated
1H NMR(300 MHZ, CD3OD): δ 7.16-7.30(4Η, m), 6.87-7.08(3Η, t), 4.89-5.14(2Η, m), 4.13-4.22(2Η, m), 3.96-4.16(2Η, m), 3.68(1Η, br), 3.18-3.24(1Η, m), 2.75-3.00(2Η, m), 2.26-2.74(4Η, m), 2.03-2.30 (2Η, m). MS: m/e 506 [M+H]+. 1H NMR (300 MHZ, CD 3 OD): δ 7.16-7.30 (4Η, m), 6.87-7.08 (3Η, t), 4.89-5.14 (2Η, m), 4.13-4.22(2Η, m), 3.96- 4.16(2Η, m), 3.68(1Η, br), 3.18-3.24(1Η, m), 2.75-3.00(2Η, m), 2.26-2.74(4Η, m), 2.03-2.30 (2Η, m). MS: m/e 506 [M+H] + .
实施例 13:  Example 13
Figure imgf000073_0001
Figure imgf000073_0001
NaHMDS(19ml)溶于干燥 THF(50ml)中， 氮气置换， -78Ό下， 滴加化合物 12-l(3.9g)的 THF溶液， 搅拌 45min， 滴加邻氯氯苄 (2.5ml)的 THF溶液， 搅拌 30min， 反应完全后， 加入 氯化铵溶液淬灭， 蒸干 THF， EA萃取， 饱和食盐水洗涤有机层， 无水硫酸钠干燥， 浓缩， 柱层析得产物 4.5g化合物 13-1。 NaHMDS (19 ml) was dissolved in dry THF (50 ml), EtOAc (EtOAc) (EtOAc) After stirring for 30 min, the reaction was completed, and the mixture was evaporated to dryness.
化合物 13-l(4.5g)溶于甲醇 (20ml)， 水 (20ml)中， 加入氢氧化钠 (1.3g)， 回流， 反应完全 后， 蒸干甲醇， 1M HC1溶液调 PH=2， EA萃取， 饱和食盐水洗涤有机层， 无水硫酸钠干燥， 浓缩得 4g化合物 13-2。  The compound 13-1 (4.5 g) was dissolved in methanol (20 ml), water (20 ml), sodium hydroxide (1.3 g) was added, and refluxed. After the reaction was completed, methanol was evaporated to dryness, and 1M HCl solution was adjusted to pH = 2, EA extraction The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated.
丙二酸单乙酯钾盐 (1.62g)悬浮于乙腈 (5ml)中， 加入三乙胺 (2.1 ml), 氯化镁 (1.13g)， 室 温搅拌 2h。 化合物 13-2(1.3g)悬浮于乙腈 (10ml)中， 加入 CDI(0.9g)， 室温搅拌至反应完全。 加至上述反应液中。搅拌过夜， 次日滴加 13% HC1溶液至澄清， 分层： 蒸干上层， EA溶解； EA萃取下层， 合并 EA层， 饱和食盐水洗涤有机层， 无水硫酸钠干燥， 浓縮， 柱层析得 1.3g 化合物 13-3。  The monoethyl malonate potassium salt (1.62 g) was suspended in acetonitrile (5 ml), triethylamine (2.1 ml), magnesium chloride (1.13 g), and stirred at room temperature for 2 h. Compound 13-2 (1.3 g) was suspended in acetonitrile (10 ml), and CDI (0.9 g) was added and stirred at room temperature until the reaction was completed. It is added to the above reaction liquid. Stir overnight, add 13% HCl solution to clarify the next day, stratify: Evaporate the upper layer, dissolve EA; extract the lower layer of EA, combine the EA layer, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, concentrate, column 1.3 g of compound 13-3 was isolated.
化合物 13-3(lg)溶于 20ml 甲苯， 加入 DMAP(94mg)， 3- (三氟甲基) -5,6,7,8-四氢 -[1,2,4] 三唑并 [4,3-a]吡嗪盐酸盐 (738mg)， 三乙胺 (0.5ml)， 氮气保护， 120°C回流， 5h后， 蒸干溶剂， EA溶解， EA层依次用 lM HC 溶液、 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 柱层析得 915mg化合物 13-4。 化合物 13-4(550mg)溶于氨甲醇溶液 (10ml), 加入乙酸铵 (600mg)， 65°C下回流， 24h反 应完全， 冷至室温， 加入氰基硼氢化钠 (198mg)， 乙酸调 PH=5,室温搅拌， 次日蒸干溶剂， 二氯甲烷溶解， 饱和碳酸氢钠溶液洗涤有机层， 饱和食盐水洗涤有机层， 无水硫酸钠干燥， 浓缩， 柱层析得化合物 13。 Compound 13-3 (lg) was dissolved in 20 ml of toluene, DMAP (94 mg), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4 , 3-a]pyrazine hydrochloride (738mg), triethylamine (0.5ml), nitrogen protection, reflux at 120 ° C, after 5h, the solvent is evaporated to dryness, EA is dissolved, EA layer is sequentially used 1M HC solution, saturated salt The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. Compound 13-4 (550 mg) was dissolved in ammonia methanol solution (10 ml), ammonium acetate (600 mg) was added, refluxed at 65 ° C, and the reaction was completed 24 h, cooled to room temperature, sodium cyanoborohydride (198 mg) was added, and acetic acid was adjusted to pH. The mixture is stirred at room temperature, and the solvent is evaporated to dryness. The title compound is evaporated.
1H NMR(300MHZ, CD3OD): δ 7.92(1H, br), 7.16-7.30(2H, m), 6.87-7.08(3H, t), 4.89-5.14(2H, m), 4.13-4.22(2H, m), 3.96-4.16 (2H, m), 3,68(1H， br), 3.18-3.24 (1H, m), 2.75-3.00 (2H, m), 2.26-2.74(4H, m)， 2.03-2.30 (2H, m). MS: m/e 540 [M+H]+. 1H NMR (300MHZ, CD 3 OD): δ 7.92 (1H, br), 7.16-7.30 (2H, m), 6.87-7.08 (3H, t), 4.89-5.14 (2H, m), 4.13-4.22 (2H , m), 3.96-4.16 (2H, m), 3,68(1H, br), 3.18-3.24 (1H, m), 2.75-3.00 (2H, m), 2.26-2.74(4H, m), 2.03 -2.30 (2H, m). MS: m/e 540 [M+H] + .
实施例 14  Example 14
Figure imgf000074_0001
Figure imgf000074_0001
NaHMDS(60ml)溶于干燥 THF(50ml)， -78°C冷却， 滴加化合物 12-l(12g)的 50ml THF溶 液， 滴加完毕， 搅拌 45min， 滴加 2-苄氧基溴乙垸 (13.4g)的 THF(50ml)溶液， 滴加完毕， 搅 拌半小时后自然升温， 反应完全后， 饱和氯化铵溶液淬灭， 蒸干 THF, EA溶解， 饱和食盐 水洗涤有机层， 无水硫酸钠干燥， 浓缩， 柱层析得 9.4g化合物 14-1。  NaHMDS (60 ml) was dissolved in dry THF (50 ml), cooled at -78 ° C, and then a solution of compound 12-1 (12 g) in 50 ml of THF was added dropwise, and the mixture was stirred for 45 min, and 2-benzyloxybromoacetamidine was added dropwise. 13.4g) THF (50ml) solution, after the addition is completed, stir for half an hour and then naturally warm up. After the reaction is completed, the saturated ammonium chloride solution is quenched, THF is evaporated, EA is dissolved, and the organic layer is washed with saturated brine. The sodium was dried, concentrated and purified by column chromatography to yield 9.4 g of Compound 14-1.
化合物 14-l(9.4g)溶于甲醇 (40ml)， 水 (40ml)中， 加入 NaOH(3g)， 79°C回流， lh反应完 全， 蒸干溶剂， 1M调 PH=2-3， EA萃取， 饱和食盐水洗涤有机层， 无水硫酸钠干燥， 浓缩 得 8.5g化合物 14-2。  Compound 14-1 (9.4g) was dissolved in methanol (40ml), water (40ml), NaOH (3g), refluxed at 79 ° C, lh reaction complete, evaporate dry solvent, 1M adjusted pH = 2-3, EA extraction The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated.
丙二酸单乙酯钾盐 (10.9g)悬浮于乙腈 (30ml)中， 加入 11 ml三乙胺， 6.1g氯化镁， 室温 搅拌 2h。 化合物 14-2(8.5g)悬浮于乙腈 (30ml)中， 加入 CDI(4.98g), 室温搅拌至反应完全， 加 至上述反应液中。 搅拌过夜， 次日滴加 1M HC1溶液至澄清， 分层： 蒸干上层， EA溶解； EA萃取下层， 合并 EA层， 饱和食盐水洗涤有机层， 无水硫酸钠干燥， 浓缩， 柱层析得 7.6g 化合物 14-3。  The monoethyl malonate potassium salt (10.9 g) was suspended in acetonitrile (30 ml), and 11 ml of triethylamine and 6.1 g of magnesium chloride were added, and the mixture was stirred at room temperature for 2 h. Compound 14-2 (8.5 g) was suspended in acetonitrile (30 ml), and CDI (4.98 g) was added, and the mixture was stirred at room temperature until the reaction was completed and added to the reaction mixture. Stir overnight, add 1M HCl solution to clarify the next day, stratify: Evaporate the upper layer, EA dissolve; EA extract the lower layer, combine EA layer, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, 7.6 g of compound 14-3.
化合物 14-3(7.5g)溶于甲苯 (100ml),加入 DMAP(0.7g)， 3- (三氟甲基) -5，6，7,8-四氢 -[1，2，4] 三唑并 [4,3-a]吡嗪盐酸盐 (10g)， 三乙胺 (7ml)， 氮气保护， 120°C回流， 5h后， 蒸干溶剂， EA 溶解， EA层依次用 1M HC1溶液、 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 柱层析得 10g 化合物 14-4。  Compound 14-3 (7.5 g) was dissolved in toluene (100 ml), DMAP (0.7 g), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4] Zylobo[4,3-a]pyrazine hydrochloride (10g), triethylamine (7ml), nitrogen-protected, refluxed at 120 ° C, 5h, evaporated to dryness, EA dissolved, EA layer with 1M HCl solution The mixture was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated.
化合物 14-4(1 Og)溶于甲醇 (50ml)， 加入氨甲醇溶液 (50ml)， 乙酸铵 (7.1g)， N2保护， 65°C 加热至反应完全， 冷至室温， 加入氰基硼氢化钠 (3.2g)， 加入醋酸调 PH=5， 反应完全， 蒸干 溶剂， lMNaOH溶液调 PH至碱性， EA萃取， 饱和食盐水洗涤 EA层， 无水硫酸钠干燥， 浓缩， 柱层析得 3.4g化合物 14。 1H NMR(300 MHZ, CD3OD): δ 7.14-7.31(5H, m), 7.03-7.12(2H, m), 4.98(2H, d), 4.37 (2H; s), 4.16-4.28 (2H, m), 4.04-4.14(lH, m), 3.95-4.01(lH, m), 3.66(1H, dd), 3.34-3.43 (2H, m): 2.83-2.92 (3H, m), 2.29-2.39 (2H, m)， 1.95-2.05(3H, m). MS: m/e 550 [M+H]+ . Compound 14-4 (1 Og) was dissolved in methanol (50 ml), added with ammonia methanol solution (50 ml), ammonium acetate (7.1 g), N 2 protected, heated at 65 ° C until the reaction was completed, cooled to room temperature, and added to cyano boron Sodium hydride (3.2g), add acetic acid to adjust PH=5, complete the reaction, evaporate the solvent, adjust the pH to alkaline with lM NaOH solution, extract with EA, wash the EA layer with saturated brine, dry over anhydrous sodium sulfate, concentrate, column chromatography 3.4 g of compound 14 were obtained. 1H NMR (300 MHZ, CD 3 OD): δ 7.14-7.31 (5H, m), 7.03-7.12 (2H, m), 4.98 (2H, d), 4.37 (2H ; s), 4.16-4.28 (2H, m), 4.04-4.14(lH, m), 3.95-4.01(lH, m), 3.66(1H, dd), 3.34-3.43 (2H, m): 2.83-2.92 (3H, m), 2.29-2.39 ( 2H, m), 1.95-2.05(3H, m). MS: m/e 550 [M+H]+ .
实施  Implementation
Figure imgf000075_0001
Figure imgf000075_0001
14(16.8g)溶于甲醇 (20ml)， 加入三乙胺 (5.1ml)， Boc20(7.3g), 室温搅拌， lh反应完全， 蒸干溶剂， EA溶解， 1M HC1溶液洗涤有机层， 饱和食盐水洗涤有机层， 无水硫酸钠干燥， 浓缩， 短柱层析得 11.5g化合物 15-1。 14 (16.8g) was dissolved in methanol (20ml), added triethylamine (5.1ml), Boc 2 0 (7.3g), stirred at room temperature, lh reaction was completed, the solvent was evaporated, EA was dissolved, and the organic layer was washed with 1M HCl solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated
化合物 15-1(11.5g)溶于甲醇 (50ml)， 加入 Pd/C(1.2g)， 醋酸 (lml)， 通入氢气， 40°C加热， 搅拌 30h后反应完全， 过滤， 蒸干溶剂得 10g化合物 15-2。  Compound 15-1 (11.5g) was dissolved in methanol (50ml), Pd/C (1.2g), acetic acid (1ml) was added, hydrogen was added, heated at 40 ° C, stirred for 30h, the reaction was complete, filtered, evaporated to dryness 10 g of compound 15-2.
化合物 15-2(100mg)溶于氯化氢甲醇溶液， 2h后反应完全， 蒸干溶剂， 二氯甲烧溶解， 碳酸氢钠溶液洗涤， 饱和食盐水洗涤， 干燥浓缩， 柱层析得 60mg化合物 15。  The compound 15-2 (100 mg) was dissolved in a methanolic solution of hydrogen chloride. After 2h, the reaction was completed. The solvent was evaporated to dryness, evaporated, evaporated, evaporated, evaporated, evaporated.
1H M (300 MHZ, CD3OD): δ 7.24(1H, dd), 7.16(1H, dd), 5.07(2H, d), 4.37(1H, br), 4.24(1H, br), 4.04-4.17(2H, m), 3.67(1 H, d), 3.50-3.59(lH, m), 3.38-3.47(lH, m), 2.84-3.02 (3H, m), 2.33-2.58(2H, m), 1.96-2.13(2H, m), 1.81-1.93(1H, m). MS: m/e 460 [M+H]+. 1H M (300 MHZ, CD3OD): δ 7.24(1H, dd), 7.16(1H, dd), 5.07(2H, d), 4.37(1H, br), 4.24(1H, br), 4.04-4.17(2H , m), 3.67(1 H, d), 3.50-3.59(lH, m), 3.38-3.47(lH, m), 2.84-3.02 (3H, m), 2.33-2.58(2H, m), 1.96- 2.13(2H, m), 1.81-1.93(1H, m). MS: m/e 460 [M+H] + .
实施例 16:  Example 16:
Figure imgf000075_0002
Figure imgf000075_0002
NaH(30mg)溶于 THF(4ml), 冰浴下加入化合物 15-2(220mg)的 THF(3ml)溶液， 滴加 2- 氯氯苄 (0.1ml), 移至室温， 后 40°C加热， 反应完全后， 饱和氯化铵溶液淬灭， 蒸干 THF， 二氯甲烷萃取， 饱和食盐水洗漆有机层， 无水硫酸钠干燥， 浓缩， 柱层析得 120mg化合物 NaH (30 mg) was dissolved in THF (4 ml). EtOAc (3 ml). After the reaction is completed, the saturated ammonium chloride solution is quenched, the THF is evaporated to dryness, and the organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated.
16-1。 16-1.
化合物 16-l(120mg)溶于二氯甲垸 (3ml)， 滴加三氟醋酸 (0.3ml)， 2h反应完全， 加入二氯 甲垸稀释， 饱和碳酸氢钠溶液洗涤， 饱和食盐水洗涤， 干燥浓缩， 短柱层析得 46mg化合物 16。  The compound 16-1 (120 mg) was dissolved in dichloromethane (3 ml), trifluoroacetic acid (0.3 ml) was added dropwise, and the reaction was completed in 2 h, diluted with dichloromethane, washed with saturated sodium bicarbonate and washed with saturated brine. Dry and concentrated, short column chromatography gave 46 mg of Compound 16.
1H MR (300 MHZ, CD3OD): δ 7.24(1H, dd), 7.16(1Η, dd), 5.07(2Η, d), 4.37(1Η, br),1H MR (300 MHZ, CD 3 OD): δ 7.24 (1H, dd), 7.16 (1Η, dd), 5.07 (2Η, d), 4.37 (1Η, br),
4.24(1Η, br), 4.04-4.17(2Η, m), 3.67(1Η, d)， 3.50-3.59(1Η, m), 3.38-3.47(1Η, m), 2.84-3.02(3Η, m), 2.33-2.58(2Η, m), 1.96-2.13(2Η, m), 1.81-1.93(1Η, m). MS: m/e 584 [M+H]+. 4.24(1Η, br), 4.04-4.17(2Η, m), 3.67(1Η, d), 3.50-3.59(1Η, m), 3.38-3.47(1Η, m), 2.84-3.02(3Η, m), 2.33-2.58(2Η, m), 1.96-2.13(2Η, m), 1.81-1.93(1Η, m). MS: m/e 584 [M+H] + .
实施例 17:
Figure imgf000076_0001
Example 17
Figure imgf000076_0001
NaH(36mg)溶于 THF(4ml)， 冰浴下加入化合物 15-2(250mg)的 THF(3ml)溶液， 滴加 4， 6-二氯嘧啶 (74mg)的 THF(2ml)溶液， 30min反应完全， 冰浴下， 饱和氯化铵溶液淬灭， 蒸干 THF, 二氯甲烷萃取， 饱和食盐水洗涤有机层， 无水硫酸钠干燥， 浓縮， 柱层析得 170mg化 合物 17-1 NaH (36 mg) was dissolved in THF (4 ml). EtOAc (3 mL) EtOAc. Completely, quenched with a saturated aqueous solution of ammonium chloride, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated.
化合物 17-l(170mg)溶于二氯甲烷 (5ml)， 滴加三氟醋酸 (0.3ml)， 2h反应完全， 加入二氯 甲烷稀释， 饱和碳酸氢钠溶液洗涤， 饱和食盐水洗涤， 无水硫酸钠干燥， 柱层析得 57mg化 合物 17。  The compound 17-1 (170 mg) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (0.3 ml) was added dropwise, and the reaction was completed in 2 h, diluted with dichloromethane, washed with saturated sodium bicarbonate, washed with saturated brine, anhydrous Drying over sodium sulfate and column chromatography gave 57 mg of Compound 17.
Ή MR(300 MHZ, CD3OD): δ 8.32(1Η, d), 7.30(1Η, t), 7.16(1Η, t), 6.63(1Η, d), 5.07(1Η, d)， 3.95-4.40 (6Η， m), 3.38-3.47(1Η, m), 2.84-3.02(3Η, m), 2.33-2.58(2Η, m), 1.96-2.13 (2Η, m), 1.81-1.93(lH, m). Ή MR (300 MHZ, CD 3 OD): δ 8.32 (1Η, d), 7.30 (1Η, t), 7.16(1Η, t), 6.63(1Η, d), 5.07(1Η, d), 3.95-4.40 (6Η, m), 3.38-3.47(1Η, m), 2.84-3.02(3Η, m), 2.33-2.58(2Η, m), 1.96-2.13 (2Η, m), 1.81-1.93(lH, m) .
MS: m/e 572 [M+H]+. MS: m/e 572 [M+H] + .
Figure imgf000076_0002
Figure imgf000076_0002
l-(3,5-二硝基苯甲酰基) -哌嗪 (S-18)(52mg)溶于 DMF(3ml)， 依次加入 HOBT(38mg)， DIPEA(0.16ml), EDCI(54mg), 制备例 5的化合物 S-5(64mg)， 室温搅拌， 反应完全后， 加 入 1M HC1溶液， EA萃取三次， EA层依次用饱和 NaHC03溶液洗涤， 饱和食盐水洗涤， 无 水硫酸钠干燥， 浓缩， 柱层析得 52mg化合物 18-1。 L-(3,5-Dinitrobenzoyl)-piperazine (S-18) (52 mg) was dissolved in DMF (3 mL). EtOAc (EtOAc) preparation of compound S-5 5 (64 mg of), stirred at room temperature. after completion of the reaction, the solution was added 1M HC1, and extracted three times with EA, EA layer was washed with saturated NaHC0 3 solution, saturated brine, dried over anhydrous sodium sulfate, and concentrated Column chromatography gave 52 mg of compound 18-1.
化合物 18-l(52mg)溶于二氯甲烷 (3ml)， 滴入 CF3COOH(0.3ml)， 30min反应完全， 加入 二氯甲院稀释，饱和碳酸氢钠溶液洗涤，饱和食盐水洗涤，无水硫酸钠干燥，柱层析得 40mg 化合物 18。 Compound 18-1 (52mg) was dissolved in dichloromethane (3ml), added dropwise to CF 3 COOH (0.3ml), the reaction was completed in 30min, diluted with dichloromethane, washed with saturated sodium bicarbonate solution, washed with saturated brine, no Drying with sodium sulfate and column chromatography gave 40 mg of Compound 18.
1H NMR(300 MHZ, CD3OD): δ 9.07(1Η, t), 8.70(2Η, d)， 7.26(1Η, t), 7.17(1Η, t)， 3.42-3.91 (8Η, m), 3.20(1Η， s)， 2.62-3.07(4Η, m), 2.36(1Η, br), 1.93-2.10(2Η, m). 1H NMR (300 MHZ, CD 3 OD): δ 9.07 (1Η, t), 8.70 (2Η, d), 7.26 (1Η, t), 7.17 (1Η, t), 3.42-3.91 (8Η, m), 3.20 (1Η, s), 2.62-3.07(4Η, m), 2.36(1Η, br), 1.93-2.10(2Η, m).
MS: m/e 504 [M+H]+. MS: m/e 504 [M+H] + .
实施例  Example
Figure imgf000076_0003
按照与实施例 18相同的方法， 以制备例 5的化合物 S-5为原料， 以 1-(2-乙氧基苯甲酰 基)哌嗪 (S-19)为试剂合成化合物 19。
Figure imgf000076_0003
In the same manner as in Example 18, Compound 19 was synthesized from the compound S-5 of Preparation Example 5, using 1-(2-ethoxybenzoyl)piperazine (S-19) as a reagent.
1H NMR (300MHZ, CD3OD): δ 7.41(1H, t), 7.22(2H, t)， 6.98-7.16(3H, m), 4.04-4.18 (2H, m)， 3.42-3.91 (8H， m)， 3.39(1H, br), 2.53-3.07(5H, m), 2.17-2.33(1H, m), 1.98-2.12 (1H， m), 1.28(3H, t). 1H NMR (300MHZ, CD 3 OD): δ 7.41(1H, t), 7.22(2H, t), 6.98-7.16(3H, m), 4.04-4.18 (2H, m), 3.42-3.91 (8H, m ), 3.39(1H, br), 2.53-3.07(5H, m), 2.17-2.33(1H, m), 1.98-2.12 (1H, m), 1.28(3H, t).
MS: m/e 458 [M+H]+. MS: m/e 458 [M+H] + .
实施例 20  Example 20
Figure imgf000077_0001
Figure imgf000077_0001
按照与实施例 18相同的方法， 以制备例 5的化合物 S-5为原料， 以 1-(2-硝基苯甲酰基) 哌嗪 (S-20)为试剂合成化合物 20。  In the same manner as in Example 18, the compound S-5 of Preparation 5 was used as a starting material, and Compound 20 was synthesized using 1-(2-nitrobenzoyl)piperazine (S-20) as a reagent.
1H MR(300MHZ, CD3OD): δ 8.25(1H, dd), 7.84(1Η, td), 7.71 (1Η， td), 7.53(1Η, dd)， 7.20(1Η, q), 7.10 (1Η, q), 3,50-3.98(8H， m), 3.35(1H, br), 2.48-3.01(5H, m), 2.14-2.28 (1H, m), 1.98-2.12(lH, m). 1H MR (300MHZ, CD 3 OD): δ 8.25(1H, dd), 7.84(1Η, td), 7.71 (1Η, td), 7.53(1Η, dd), 7.20(1Η, q), 7.10 (1Η, q), 3,50-3.98(8H, m), 3.35(1H, br), 2.48-3.01(5H, m), 2.14-2.28 (1H, m), 1.98-2.12(lH, m).
MS: m/e 459 [M+H]+. MS: m/e 459 [M+H] + .
实施 21 :  Implementation 21 :
Figure imgf000077_0002
Figure imgf000077_0002
按照与实施例 18相同的方法， 以制备例 5的化合物 S-5为原料， 以 1-(3-氯苯甲酰基) 哌嗪 (S-21)为试剂合成化合物 21。  In the same manner as in Example 18, the compound S-5 of Preparation 5 was used as a starting material, and Compound 21 was synthesized using 1-(3-chlorobenzoyl)piperazine (S-21) as a reagent.
1H NMR(300MHZ, CD3OD): δ 7.42-7.54(2H, m)7.37(lH, d), 7.23(1H, t)， 7.13(1H, t), 3.91(1H, br), 3.38-3.84(7H, m), 2.56-3.07(5H, m)， 2.18-2.36(1H, m), 1.96-2.13(1H, m). 1H NMR (300MHZ, CD 3 OD): δ 7.42-7.54 (2H, m) 7.37 (lH, d), 7.23 (1H, t), 7.13 (1H, t), 3.91 (1H, br), 3.38-3.84 (7H, m), 2.56-3.07(5H, m), 2.18-2.36(1H, m), 1.96-2.13(1H, m).
MS: m/e 448 [M+H]+. MS: m/e 448 [M+H] + .
实施例
Figure imgf000077_0003
Example
Figure imgf000077_0003
制备例 5的化合物 S-5(45mg)溶于 DMF, 加入 NEt3(0.1ml)， HATU(53mg), 5min反应完 全， 加入 1- (吡啶 -2-基-酰基)哌嗪 (S-22)(50mg), 18°C搅拌过夜， 反应完全， 加入 1M HC1溶 液， EA萃取， EA层依次用 NaHC03溶液， 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 柱 层析得 37mg化合物 22-1。 Preparation Example Compound S-5 (45mg) 5 was dissolved in of DMF, NEt 3 (0.1ml), HATU ( 53mg), 5min the reaction was complete, was added 1- (pyridin-2-yl - acyl) piperazine (S-22 (50mg), stirring at 18 ° C overnight, the reaction was completed, 1M HCl solution was added, EA was extracted, EA layer was washed with NaHC0 3 solution, saturated brine, dried over anhydrous sodium sulfate, and concentrated. -1.
化合物 22-l(37mg)溶于 CH2C12， 加入 CF3COOH(0.3ml)， lh反应完全， 加入二氯甲烷稀 释， 饱和碳酸氢钠溶液洗涤， 饱和食盐水洗涤， 无水硫酸钠干燥， 柱层析得 30mg化合物 22。 Ή NMR(300MHZ, CD3OD): δ 8.86(1H, br), 8.48 (IH, br), 8.09(1H, br), 7.99(1H, br), 7.29 (IH, t), 7.18 (IH, t), 4.08(1H, br), 3.47-3.95(7H, m)， 2.75-3.09(5H, m), 2.29-2.45(lH, m), 1.95-2.10(2H, m). The compound 22-1 (37 mg) was dissolved in CH 2 C1 2 , EtOAc ( 3 mL), EtOAc (EtOAc) Column chromatography gave 30 mg of compound 22. NMR NMR (300 MHZ, CD 3 OD): δ 8.86 (1H, br), 8.48 (IH, br), 8.09 (1H, br), 7.99 (1H, br), 7.29 (IH, t), 7.18 (IH, t), 4.08(1H, br), 3.47-3.95(7H, m), 2.75-3.09(5H, m), 2.29-2.45(lH, m), 1.95-2.10(2H, m).
MS: m/e 415 [M+H]+.  MS: m/e 415 [M+H]+.
实施 23:
Figure imgf000078_0001
Implementation 23:
Figure imgf000078_0001
按照与实施例 22相同的方法， 以制备例 5的化合物 S-5为原料， 以 1- (吡嗪 -2-基-酰基) 哌嗪 (S-23)为试剂合成化合物 23。  In the same manner as in Example 22, the compound S-5 of Preparation 5 was used as a starting material, and Compound 23 was synthesized using 1-(pyrazin-2-yl-acyl)piperazine (S-23) as a reagent.
1H MR(300MHZ, CD3OD): δ 8.89(1H, br), 8.71(1H, br), 8.65(1H, br), 7.28 (IH, t), 7.17(1H, t), 4.06 (IH, br), 3.47-3.95(7H, m), 2.68-3.07(5H, m), 2.29-2.45(lH, m), 1.95-2.10(2H, m).  1H MR (300MHZ, CD3OD): δ 8.89 (1H, br), 8.71 (1H, br), 8.65 (1H, br), 7.28 (IH, t), 7.17 (1H, t), 4.06 (IH, br) , 3.47-3.95(7H, m), 2.68-3.07(5H, m), 2.29-2.45(lH, m), 1.95-2.10(2H, m).
MS: m/e 416 [M+H]+. MS: m/e 416 [M+H] + .
实施例
Figure imgf000078_0002
Example
Figure imgf000078_0002
按照与实施例 22相同的方法， 以制备例 5的化合物 S-5为原料， 以 3-腈基 -2-(((S)-吡咯 -2-基)甲氧基)吡啶 (S-24)为试剂合成化合物 24。  In the same manner as in Example 22, the compound S-5 of Preparation Example 5 was used as a starting material, and 3-nitryl-2-(((S)-pyrrol-2-yl)methoxy)pyridine (S-24) ) Synthesis of Compound 24 as a reagent.
1H MR(300MHZ, CD3OD): δ 8.32-8.42(1Η, m), 8.02-8.11(1H, m), 7.17-7.27 (IH, m), 7.05-7.17 (2H, m), 4.68(1H, td), 4.45-4.51(lH, m), 3.92-4.01(lH, m), 3.53-3.70(2H, m), 3.41-3.53(1H, m), 2.92-3.04(lH, m), 2.80- 2.92(2H, m), 2.61-2.73(1H, m), 2.22-2.38(2H, m), 1.95-2.18(5H, m). 1H MR (300MHZ, CD 3 OD): δ 8.32-8.42(1Η, m), 8.02-8.11(1H, m), 7.17-7.27 (IH, m), 7.05-7.17 (2H, m), 4.68(1H , td), 4.45-4.51(lH, m), 3.92-4.01(lH, m), 3.53-3.70(2H, m), 3.41-3.53(1H, m), 2.92-3.04(lH, m), 2.80 - 2.92(2H, m), 2.61-2.73(1H, m), 2.22-2.38(2H, m), 1.95-2.18(5H, m).
MS: m/e 427 [M+H]+. MS: m/e 427 [M+H] + .
实施 25 :
Figure imgf000078_0003
Implementation 25 :
Figure imgf000078_0003
按照与实施例 22相同的方法，以制备例 5的化合物 S-5为原料，以 3- (甲磺酰基) -N-(((S)- 吡咯 -2-基)甲基)苯甲酰胺 (S-25)为试剂合成化合物 25。  In the same manner as in Example 22, the compound S-5 of Preparation Example 5 was used as the starting material, and 3-(methylsulfonyl)-N-(((S)-pyrrol-2-yl)methyl)benzamide (S-25) A compound 25 was synthesized as a reagent.
1H NMR(300MHZ, CD3OD): δ 8.39(1H, br), 8.07-8.21(2H, m), 7.68-7.80 (IH, m), 7.27 (1H， t), 7.10(1H, t), 4.42(1H, d), 4.02-4.25(1 H, m), 3.41-3.70 (5H, m), 3.20(1H, s)， 3.16(3H, s), 2.79-3.09(3H, m), 2.60-2.76(lH, m), 2.26-2.43(lH, m), 1.88-2.22(5H, m). 1H NMR (300MHZ, CD 3 OD): δ 8.39 (1H, br), 8.07-8.21 (2H, m), 7.68-7.80 (IH, m), 7.27 (1H, t), 7.10 (1H, t), 4.42(1H, d), 4.02-4.25(1 H, m), 3.41-3.70 (5H, m), 3.20(1H, s), 3.16(3H, s), 2.79-3.09(3H, m), 2.60 -2.76(lH, m), 2.26-2.43(lH, m), 1.88-2.22(5H, m).
MS: m/e 506 [M+H]+. MS: m/e 506 [M+H] + .
实施例 26: LL Example 26: LL
Figure imgf000079_0001
Figure imgf000079_0001
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Figure imgf000079_0002
Figure imgf000079_0002
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Figure imgf000079_0003
Figure imgf000079_0003
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Figure imgf000079_0004
Figure imgf000079_0004
C0C000/M0ZN3/X3d 1^9 / 0Z OAV Ή NMR(300MHZ, CD3OD): δ 7.24(1H, t), 7.18(1H, t), 5.72-5.84(2H, m), 3.96-4.12 (2H, m); 3.49-3.71 (4H, m), 2.86-3.05(3H, m), 2.63-2.77(lH, m)， 2.29-2.42(4H, m), 1.95-2.07(1H, m), 1.84-1.93(lH, m). C0C000/M0ZN3/X3d 1^9 / 0Z OAV NMR NMR (300 MHZ, CD 3 OD): δ 7.24 (1H, t), 7.18 (1H, t), 5.72-5.84 (2H, m), 3.96-4.12 (2H, m) ; 3.49-3.71 (4H, m ), 2.86-3.05(3H, m), 2.63-2.77(lH, m), 2.29-2.42(4H, m), 1.95-2.07(1H, m), 1.84-1.93(lH, m).
MS: m/e 321 [M+H]+ . MS: m/e 321 [M+H] + .
实施例 30:
Figure imgf000080_0001
Example 30:
Figure imgf000080_0001
按照与实施例 22相同的方法， 以制备例 5的化合物 S-5为原料， 以 4，5,6，7-四氢噻吩并 [2，3-c]吡啶 (S-30)为试剂合成化合物 30。  In the same manner as in Example 22, the compound S-5 of Preparation Example 5 was used as a starting material, and 4,5,6,7-tetrahydrothieno[2,3-c]pyridine (S-30) was used as a reagent. Compound 30.
1H MR(300MHZ, CD3OD): δ 7.21-7.29(2H, m)， 7.13-7.20(1H, m), 6.81-6.87(1H, m), 4.59-4.74(2H, m), 4.08(1H, br), 3.84-4.01(lH, m), 3.80(1H, q), 3.56(1H, br), 2.72-3.08(6H, m), 2.32-2.43(lH, m), 1.95-2.06(1H, m).  1H MR (300MHZ, CD3OD): δ 7.21-7.29(2H, m), 7.13-7.20(1H, m), 6.81-6.87(1H, m), 4.59-4.74(2H, m), 4.08(1H, br ), 3.84-4.01(lH, m), 3.80(1H, q), 3.56(1H, br), 2.72-3.08(6H, m), 2.32-2.43(lH, m), 1.95-2.06(1H, m ).
MS: m/e 363 [M+H]+. MS: m/e 363 [M+H] + .
实施例
Figure imgf000080_0002
Example
Figure imgf000080_0002
制备例 5的化合物 S-5(120mg)溶于 DMF， 加入 NEt3(0.15ml)， HATU(150mg), 5min反 应完全， 加入 l-(2,3-二氯苯基)哌嗪盐酸 (S-31, 104mg)， 18°C搅拌至反应完全， 加入 1M HC1 溶液， EA萃取， EA层依次用 NaHC03溶液， 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩， 柱层析得 70mg化合物 31-1。 Preparation of Compound S-5 5 (120 mg of) was dissolved in of DMF, NEt 3 (0.15ml), HATU ( 150mg), 5min the reaction was complete, was added l- (2,3- dichlorophenyl) piperazine hydrochloride (S -31, 104 mg), stirred at 18 ° C until the reaction was completed. 1M HCl solution was added, EA was extracted, EA layer was washed with NaHC0 3 solution, saturated brine, dried over anhydrous sodium sulfate, and concentrated. -1.
化合物 31-l(70mg)溶于 CH2C12， 加入 CF3COOH(0.3ml)， lh反应完全， 蒸千， 甲基叔丁 基醚结晶得化合物 31的三氟乙酸盐 (46mg)。 Compound 31-l (70mg) was dissolved in CH 2 C1 2, was added CF 3 COOH (0.3ml), lh the reaction was complete, distilled Qian, methyl tertiary butyl ether to give the crystalline compound 31 trifluoroacetate (46mg).
1H MR(300MHZ, CD3OD): δ 7.21 -7.31(3H, m)， 7.17(1Η, t)， 7·08(1Η, t), 4.03-4.12 (1Η, m): 3.79(2H, br), 3.69(2H, br), 2.89-3.11(7H, m), 2.70-2.80(lH, m), 2.31-2.43(1H, m), 1.96-2.09(2H, m). 1H MR (300MHZ, CD3OD): δ 7.21 -7.31(3H, m), 7.17(1Η, t), 7·08(1Η, t), 4.03-4.12 (1Η, m) : 3.79(2H, br), 3.69(2H, br), 2.89-3.11(7H, m), 2.70-2.80(lH, m), 2.31-2.43(1H, m), 1.96-2.09(2H, m).
MS: m/e 454 [M+H]+. MS: m/e 454 [M+H] + .
1H NMR(300MHZ, d6-DMSO): δ 7.85(3H, br), 7,46(1H, dd), 7.28-7.37(3H, m), 7.14(1H, t), 1H NMR (300MHZ, d6-DMSO): δ 7.85 (3H, br), 7,46 (1H, dd), 7.28-7.37 (3H, m), 7.14 (1H, t),
3.92 (1H, br), 3.54-3.69(4H, m), 3.42-3.52 (1H， m)， 2.64-3.05(8H, m), 2.16-2.28(1H, m)， 1.96-2.09(lH, m). 3.92 (1H, br), 3.54-3.69(4H, m), 3.42-3.52 (1H, m), 2.64-3.05(8H, m), 2.16-2.28(1H, m), 1.96-2.09(lH, m ).
MS: m/e 454 [M+H]+. MS: m/e 454 [M+H] + .
将化合物 31的三氟乙酸盐溶于 CH2C12， 饱和碳酸氢钠溶液洗涤， 饱和食盐水洗涤， 将 有机相干燥、 浓缩， 得化合物 31。 The trifluoroacetic acid salt of the compound 31 was dissolved in CH 2 C1 2 , washed with saturated sodium hydrogen carbonate solution and washed with saturated brine, and the organic phase was dried and concentrated to give Compound 31.
1H NMR(300MHZ, d6-DMSO): δ 7.28-7.40(3H, m)， 7.23(1Η, t), 7.14(1Η, t), 3.58-3.72(4Η, m)， 3.54 (1Η, br), 3.34(2H, m), 3.17(1H, br), 2.64-3.05(6H, m)， 2.30-2.48(2H, m), 1.96-2.09(2H, m).  1H NMR (300MHZ, d6-DMSO): δ 7.28-7.40 (3H, m), 7.23 (1Η, t), 7.14 (1Η, t), 3.58-3.72 (4Η, m), 3.54 (1Η, br), 3.34(2H, m), 3.17(1H, br), 2.64-3.05(6H, m), 2.30-2.48(2H, m), 1.96-2.09(2H, m).
MS: m/e 454 [M+H]+. MS: m/e 454 [M+H] + .
实施例 32: 6L Example 32: 6L
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按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-46为试剂合成化 合物 46。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 46 was synthesized using S-46 as a reagent.
1H 丽 R(300匪 Z， CD3OD): δ 7.34(1H, t), 7.20(1H, t), 4.04-4.32(2H, m), 3.90(2H, br), 3.55-3.85(8H， m), 3.43-3.55(3H, m), 2.79-3.29(7H, m), 2.33-2.48(lH, m), 1.98-2.15 (IH, m) . 1H 丽R(300匪Z, CD 3 OD): δ 7.34(1H, t), 7.20(1H, t), 4.04-4.32(2H, m), 3.90(2H, br), 3.55-3.85(8H, m), 3.43-3.55 (3H, m), 2.79-3.29 (7H, m), 2.33-2.48 (lH, m), 1.98-2.15 (IH, m) .
MS: m/e 398 [M+H]+. MS: m/e 398 [M+H] + .
实施例
Figure imgf000085_0002
Example
Figure imgf000085_0002
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-47为试剂合成化 合物 47。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 47 was synthesized using S-47 as a reagent.
1H NM (300MHZ, CD3OD): δ 7.33(1H, t), 7.19(1H, t), 3.73-4.18(llH, m), 3.53-3.66(3H, m): 3.44(2H, br), 3.10-3.21(3H, m), 2.85-3.09(3H, m)， 2.33-2.48(lH, m), 1.98-2.11(1H, m). 1H NM (300MHZ, CD 3 OD): δ 7.33(1H, t), 7.19(1H, t), 3.73-4.18(llH, m), 3.53-3.66(3H, m) : 3.44(2H, br), 3.10-3.21(3H, m), 2.85-3.09(3H, m), 2.33-2.48(lH, m), 1.98-2.11(1H, m).
MS: m/e 398 [M+H]+. MS: m/e 398 [M+H] + .
实施例 48  Example 48
Figure imgf000085_0003
Figure imgf000085_0003
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-48为试剂合成化 合物 48。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 48 was synthesized using S-48 as a reagent.
1HNMR(300MHZ, CD3OD): δ 7·33(1Η， t), 7.19(1Η, t), 3.73-4.18(11Η, m), 3.53-3.66(3Η, m): 3.44(2Η, br), 3.10-3.21(3Η, m)， 2.85-3.09(3Η, m), 2.33-2.48(1Η, m), 1.98-2.11(1Η, m). 1H NMR (300 MHZ, CD 3 OD): δ 7·33 (1Η, t), 7.19 (1Η, t), 3.73-4.18 (11Η, m), 3.53-3.66 (3Η, m) : 3.44 (2Η, br) , 3.10-3.21(3Η, m), 2.85-3.09(3Η, m), 2.33-2.48(1Η, m), 1.98-2.11(1Η, m).
MS: m/e 429 [M+H]+. MS: m/e 429 [M+H] + .
实施
Figure imgf000085_0004
Implementation
Figure imgf000085_0004
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-49为试剂合成化 合物 49。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 49 was synthesized using S-49 as a reagent.
1H NMR(300MHZ, CD3OD): δ 8.40(1H, br), 8.14-8.20(1Η, m), 8.12 (IH, d), 7.74 (IH, td), 7.26(1H, t), 7.16(1H, t), 4.54-4·66(1Η， m), 4.04(1H, br), 3.79-3.95 (IH, m), 3.46-3.77(4H, m), 3.16(3H, s), 2.95-3.06 (IH, m), 2.80-2.95(2H, m), 2.61-2.74(1H, m), 2.25-2.43(2H, m), 2.13-2.22(1H, m)， 1.97-2.08(1H, m). 1H NMR (300MHZ, CD 3 OD): δ 8.40 (1H, br), 8.14-8.20 (1 Η, m), 8.12 (IH, d), 7.74 (IH, td), 7.26 (1H, t), 7.16 ( 1H, t), 4.54-4·66(1Η, m), 4.04(1H, br), 3.79-3.95 (IH, m), 3.46-3.77(4H, m), 3.16(3H, s), 2.95- 3.06 (IH, m), 2.80-2.95(2H, m), 2.61-2.74(1H, m), 2.25-2.43(2H, m), 2.13-2.22(1H, m), 1.97-2.08(1H, m ).
MS: m/e 492 [M+H]+. fr8
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MS: m/e 492 [M+H] + . Fr8
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呦导  Guide
Figure imgf000086_0005
Figure imgf000086_0005
■'θς國  ■'θς国
C0C000/M0ZN3/X3d 1^9 / 0Z OAV 1H M (300MHZ, CD3OD): δ 7.25(1H, dt), 7.17(1H, t), 4.19(1H, dt)， 3.99(2H, br),C0C000/M0ZN3/X3d 1^9 / 0Z OAV 1H M (300MHZ, CD 3 OD): δ 7.25(1H, dt), 7.17(1H, t), 4.19(1H, dt), 3.99(2H, br),
3.63-3.69 (3H, m)， 3.52(1H, br), 2.79-3.08(4H, m), 2.42-2.75(4H, m), 2.28-2.39(lH, m), 1.94-2.07(2H, m). 3.63-3.69 (3H, m), 3.52(1H, br), 2.79-3.08(4H, m), 2.42-2.75(4H, m), 2.28-2.39(lH, m), 1.94-2.07(2H, m ).
MS: m/e 381 [M+H]+. MS: m/e 381 [M+H] + .
实施例 54
Figure imgf000087_0001
Example 54
Figure imgf000087_0001
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-54为试剂合成化 合物 54。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 54 was synthesized using S-54 as a reagent.
1H MR(300MHZ, CD3OD): δ 7.28(1H, dt), 7.18(1Η, t), 4.49-4.62(1Η, m), 3.88-4.21(2Η, m), 3.67-3.80 (3Η, m), 3.44-3.67(2H, m), 2.79-3.12(3H, m), 2.56-2.75(lH, m), 2.28-2.52(2H, m), 2.12-2.25(1H, m), 1.94-2.11(1H, m). 1H MR (300MHZ, CD 3 OD): δ 7.28(1H, dt), 7.18(1Η, t), 4.49-4.62(1Η, m), 3.88-4.21(2Η, m), 3.67-3.80 (3Η, m ), 3.44-3.67(2H, m), 2.79-3.12(3H, m), 2.56-2.75(lH, m), 2.28-2.52(2H, m), 2.12-2.25(1H, m), 1.94-2.11 (1H, m).
MS: m/e 367 [M+H]+. MS: m/e 367 [M+H] + .
实施例 55  Example 55
Figure imgf000087_0002
Figure imgf000087_0002
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-55为试剂合成化 合物 55。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 55 was synthesized using S-55 as a reagent.
MS: m/e 483[M+H]+. MS: m/e 483 [M+H] + .
实施例 5
Figure imgf000087_0003
Example 5
Figure imgf000087_0003
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-56为试剂合成化 合物 56。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 56 was synthesized using S-56 as a reagent.
1H NMR(300MHZ, CD3OD): δ 7.24(1H, dt), 7.16(1H, t), 3.95-4.06(lH, m)， 3.67-3.75(lH, m)， 3.50-3.60 (2H, m)， 3.45(2H, dd), 2.73-3.06(3H, m), 2.56-2.69(lH, m), 2.28-2.42(lH, m), 1.97-2.09 (1H, m), 1.41-1.57 (2H, m), 1.05(3H, s), 0.93(3H, d).  1H NMR (300MHZ, CD3OD): δ 7.24(1H, dt), 7.16(1H, t), 3.95-4.06(lH, m), 3.67-3.75(lH, m), 3.50-3.60 (2H, m), 3.45(2H, dd), 2.73-3.06(3H, m), 2.56-2.69(lH, m), 2.28-2.42(lH, m), 1.97-2.09 (1H, m), 1.41-1.57 (2H, m ), 1.05(3H, s), 0.93(3H, d).
MS: m/e 335 [M+H]+. MS: m/e 335 [M+H] + .
实施例
Figure imgf000087_0004
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-57为试剂合成化 合物 57。 Example
Figure imgf000087_0004
In the same manner as in Example 31, the compound S-5 of Preparation Example 5 was used as a starting material, and Compound 57 was synthesized using S-57 as a reagent.
1H NMR(300MHZ, CD3OD): δ 8.41(1H, br), 8.09(1Η, d), 7.27 (IH, br), 7.09-7.21(2H, m), 5.78(1H, d), 4.06(1H, br), 3.78(3H, br), 3.57(1H, br), 2.60-3.50(4H, m)， 2.17-2.42(3H, m), 1.97-2.12(2H, m). 1H NMR (300MHZ, CD 3 OD ): δ 8.41 (1H, br), 8.09 (1Η, d), 7.27 (IH, br), 7.09-7.21 (2H, m), 5.78 (1H, d), 4.06 ( 1H, br), 3.78(3H, br), 3.57(1H, br), 2.60-3.50(4H, m), 2.17-2.42(3H, m), 1.97-2.12(2H, m).
MS: m/e 413 [M+H]+. MS: m/e 413 [M+H] + .
实施 58:
Figure imgf000088_0001
Implementation 58:
Figure imgf000088_0001
58- 58  58- 58
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-58为试剂合成化 合物 58。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 58 was synthesized using S-58 as a reagent.
1H NMR(300MHZ, CD3OD): δ 8.09(1H, dd), 7.74(1H, dd), 7.37(1H, t), 7.19(1H, t), 6.46(1H, t), 4.40-4.54 (IH, m), 4.23-4.35(2H, m), 3.68(1H, br), 3.50-3.61(lH, m), 3.36-3.44 (IH, m), 2.84-3.10 (3H, m), 2.32-2.48 (IH, m), 1.69-2.11(9H, m). 1H NMR (300MHZ, CD 3 OD): δ 8.09 (1H, dd), 7.74 (1H, dd), 7.37 (1H, t), 7.19 (1H, t), 6.46 (1H, t), 4.40-4.54 ( IH, m), 4.23-4.35(2H, m), 3.68(1H, br), 3.50-3.61(lH, m), 3.36-3.44 (IH, m), 2.84-3.10 (3H, m), 2.32- 2.48 (IH, m), 1.69-2.11 (9H, m).
MS: m/e 441 [M+H]+.  MS: m/e 441 [M+H]+.
实施  Implementation
Figure imgf000088_0002
Figure imgf000088_0002
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-59为试剂合成化 合物 59。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 59 was synthesized using S-59 as a reagent.
Ή NMR(300MHZ, CD3OD): δ 7.29(1H, t), 7·17(1Η， t), 7.07(1H, t)， 6.79(2H, d), 4.07 (IH, br), 3.65-3.84 (4H, m), 3.58(1H, br), 3.16-3.26(3H, m), 2.72-3.08(5H, m), 2.29-2.44 (IH, m), 1.98-2.14 (lH, m). NMR NMR (300 MHZ, CD 3 OD): δ 7.29 (1H, t), 7·17 (1 Η, t), 7.07 (1H, t), 6.79 (2H, d), 4.07 (IH, br), 3.65- 3.84 (4H, m), 3.58(1H, br), 3.16-3.26(3H, m), 2.72-3.08(5H, m), 2.29-2.44 (IH, m), 1.98-2.14 (lH, m).
MS: m/e 466 [M+H]+. MS: m/e 466 [M+H] + .
实施例  Example
Figure imgf000088_0003
Figure imgf000088_0003
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-60为试剂合成化 合物 60。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 60 was synthesized using S-60 as a reagent.
1H MR(300MHZ, CD3OD): δ 7.27(1H, t), 7.17(1H, t)， 4.56(1H, d), 3.97-4.17 (2H， m), 3.54(1H, br), 2.14- 3.08(9H, m), 1.92-2.07 (2H, m). MS: m/e 366 [M+H]十. 1H MR (300MHZ, CD3OD): δ 7.27(1H, t), 7.17(1H, t), 4.56(1H, d), 3.97-4.17 (2H, m), 3.54(1H, br), 2.14- 3.08( 9H, m), 1.92-2.07 (2H, m). MS: m/e 366 [M+H] 十.
实施 61 :  Implementation 61 :
Figure imgf000089_0001
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-61为试剂合成化 合物 61。
Figure imgf000089_0001
In the same manner as in Example 31, the compound S-5 of Preparation Example 5 was used as a starting material, and Compound 61 was synthesized using S-61 as a reagent.
1H MR(300MHZ, CD3OD): δ 7.29(1H, t), 7.17(1H, t), 4.18(1H, br), 3.84-4.10 (3H, m), 3.71(1H, d), 3.50- 3.67(2H, m), 3.32-3.49(4H, m), 2.82-3.07(3H, m), 2.43-2.74(3H, m), 2.25-2.42(lH, m), 1.94-2.10 (1H, m). 1H MR (300 MHZ, CD 3 OD): δ 7.29 (1H, t), 7.17 (1H, t), 4.18 (1H, br), 3.84-4.10 (3H, m), 3.71 (1H, d), 3.50- 3.67(2H, m), 3.32-3.49(4H, m), 2.82-3.07(3H, m), 2.43-2.74(3H, m), 2.25-2.42(lH, m), 1.94-2.10 (1H, m ).
MS: m/e 415 [M+H]+.  MS: m/e 415 [M+H]+.
实施  Implementation
Figure imgf000089_0002
Figure imgf000089_0002
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-62为试剂合成化 合物 62。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 62 was synthesized using S-62 as a reagent.
!H NMR(300MHZ, CD3OD): δ 8.35(1H, dd), 8.06(1Η， dd), 7.20-7.28(1Η, m), 7.06-7.17(2Η, m) 4.48-4, .58 (2Η, m), 3.96-4.07 (2H, m), 3.90(1H, dd), 3.35-3.47(6H, m), 2.82-3.02 (4H， m), 2.77-2.81 (1H, m), 2.61-2.67 (2H, m), 2.27-2.41 (1H, m), 1.96-2.05 (1H, m). ! H NMR (300MHZ, CD 3 OD): δ 8.35 (1H, dd), 8.06 (1Η, dd), 7.20-7.28 (1Η, m), 7.06-7.17 (2Η, m) 4.48-4, .58 ( 2Η, m), 3.96-4.07 (2H, m), 3.90(1H, dd), 3.35-3.47(6H, m), 2.82-3.02 (4H, m), 2.77-2.81 (1H, m), 2.61- 2.67 (2H, m), 2.27-2.41 (1H, m), 1.96-2.05 (1H, m).
MS: m/e 517 [M+H]+. MS: m/e 517 [M+H] + .
实施 63:  Implementation 63:
Figure imgf000089_0003
Figure imgf000089_0003
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-63为试剂合成化 合物 63。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 63 was synthesized using S-63 as a reagent.
'H MRCBOOMHZ, CD3OD): δ 7.27(1H, t), 7.16(1H, t), 4.36-4.52(lH, m), 3.94-4.17 (2H, m): 3.62-3.76 (1H, m), 3.48-3.61(lH, m)， 2.78-3.10(4H, m), 2.47-2.77(2H, m), 2.29-2.44(lH, m), 1.96-2.13 (lH, m).  'H MRCBOOMHZ, CD3OD): δ 7.27(1H, t), 7.16(1H, t), 4.36-4.52(lH, m), 3.94-4.17 (2H, m): 3.62-3.76 (1H, m), 3.48 -3.61(lH, m), 2.78-3.10(4H, m), 2.47-2.77(2H, m), 2.29-2.44(lH, m), 1.96-2.13 (lH, m).
MS: m/e 352 [M+H]+. MS: m/e 352 [M+H] + .
实施例 64:
Figure imgf000090_0001
Example 64:
Figure imgf000090_0001
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-64为试剂合成化 合物 64。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 64 was synthesized using S-64 as a reagent.
1H MR(300MHZ, CD3OD): δ 7.29(1H, t), 7.17(1Η, t), 4.49(1Η, t), 4.01(1Η, d)， 3.90 (IH, d); 3.47-3.58 (IH, m), 3.41(4H, br), 3.20(1H, q), 2.63-3.07(5H, m), 2.39-2.49(lH, m)， 2.27-2.38(1 H, m), 1.96-2.10 (lH, m). 1H MR (300MHZ, CD 3 OD): δ 7.29(1H, t), 7.17(1Η, t), 4.49(1Η, t), 4.01(1Η, d), 3.90 (IH, d) ; 3.47-3.58 ( IH, m), 3.41(4H, br), 3.20(1H, q), 2.63-3.07(5H, m), 2.39-2.49(lH, m), 2.27-2.38(1 H, m), 1.96-2.10 (lH, m).
MS: m/e 428 [M+H]+ MS: m/e 428 [M+H] +
实施例  Example
Figure imgf000090_0002
Figure imgf000090_0002
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-65为试剂合成化 合物 65。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 65 was synthesized using S-65 as a reagent.
1H MR(300MHZ, CD3OD): δ 7.29(1H, t), 7·16(1Η， t), 3.91-4.12(3Η, m), 3.71-3.78 (3Η， m): 3.57(1Η, br), 2.47-3.10(7Η, m), 2.28-2.45(1Η, m), 1.93-2.08 (IH, m). 1 H MR(300MHZ, CD 3 OD): δ 7.29(1H, t), 7·16(1Η, t), 3.91-4.12(3Η, m), 3.71-3.78 (3Η, m) : 3.57(1Η, Br), 2.47-3.10(7Η, m), 2.28-2.45(1Η, m), 1.93-2.08 (IH, m).
MS: m/e 389 [M+H]+. MS: m/e 389 [M+H] + .
实施例  Example
Figure imgf000090_0003
Figure imgf000090_0003
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-66为试剂合成化 合物 66。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 66 was synthesized using S-66 as a reagent.
1H NMR(300MHZ, CD3OD): δ 7.27(1H, t), 7.18(1Η, t), 5.20(1Η, d)， 3.99(1Η, br), 3.79(1Η, d)， 3.53(1Η, br), 2.82-3.08(3Η, m), 2.63-2.81(1Η, m), 2.22-2.45(2Η, m), 1.94-2.07 (IH, m), 1.39-1.82 (6H, m). 1H NMR (300MHZ, CD 3 OD): δ 7.27 (1H, t), 7.18 (1Η, t), 5.20(1Η, d), 3.99(1Η, br), 3.79(1Η, d), 3.53(1Η, Br), 2.82-3.08(3Η, m), 2.63-2.81(1Η, m), 2.22-2.45(2Η, m), 1.94-2.07 (IH, m), 1.39-1.82 (6H, m).
MS: m/e 352 [M+H]+. MS: m/e 352 [M+H] + .
实施例 67: 68 Example 67: 68
Figure imgf000091_0001
Figure imgf000091_0001
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Figure imgf000092_0004
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L T-Z&l '(m 'ΐΐϋόΖτ-ΖνΖ '(s ¾£)WZ '("I 'HS) 6T-8S-Z; '(UI 8) ILI-LZZ 'Ηΐ)Ι6·£ 'ΐ{Ζ)Ρ ί-9νί X∞ 'Η£)5£-ί-ζ ί '(1 ^WL '(-«q 'Hi^S L 9 :(9P-OS d 'ZHWOOE) m Hi L TZ&l '(m 'ΐΐϋόΖτ-ΖνΖ '(s 3⁄4£)WZ '("I 'HS) 6T-8S-Z; '(UI 8) ILI-LZZ 'Ηΐ)Ι6·£ 'ΐ{Ζ)Ρ ί -9νί X∞ 'Η£)5£-ί-ζ ί '(1 ^WL '(-«q 'Hi^SL 9 :( 9 P-OS d 'ZHWOOE) m Hi
°  °
Figure imgf000092_0005
Figure imgf000092_0005
(m 'Hi) L0T-£6-\ 'ΗΙ)6 Π·ζ '(^ 'HS) 6 -8S ∞ Ήζ ίΖ-βΠ 'Η8) if£-L£-£(m 'Hi) L0T-£6-\ 'ΗΙ)6 Π·ζ '(^ 'HS) 6 -8S ∞ Ήζ ίΖ-βΠ 'Η8) if£-L£-£
'(•iq ¾ι)【6·ε ' 'Η ΙΓΑ '(^ ¾t "乙 -9 Δ '(-iq ε)8·Δ δ :(9p-oswa 'ΖΗίΜθοε) ¾WK Η, '(•iq 3⁄4ι)[6·ε ''Η ΙΓΑ '(^ 3⁄4t "B-9 Δ '(-iq ε)8·Δ δ :( 9 p-oswa 'ΖΗίΜθοε) 3⁄4WK Η,
°0Δ  °0Δ
C0C000/M0ZN3/X3d 16 C0C000/M0ZN3/X3d 16
'-LL闘 SZ •+[H+W]I£ /«i :SW '-LL闘 SZ •+[H+W]I£ /«i :SW
'(1"¾1) -£6'1  '(1"3⁄41) -£6'1
'(ui ¾ΐ)6ΓΠΓΖ; '(ui 'ΐίζ)ί6'Ζ-ίζτ '( ^Z i-LZ'i '(·«¾ 'Ηΐ)Ι6·ε '(Ρ 'ΉΖ)£ζ 9 '(ΐ 'Ηΐ) οε 'ηύ νί ' )9 , '(jq ε)ε8 '(-iq ' )6· ？ :(9p-osiMa 'ζΐϋΜθοε) '(ui 3⁄4ΐ)6ΓΠΓΖ; '(ui 'ΐίζ)ί6'Ζ-ίζτ '( ^Z i-LZ'i '(·«3⁄4 'Ηΐ)Ι6·ε '(Ρ 'ΉΖ)£ζ 9 '(ΐ 'Ηΐ) οε 'ηύ νί ' )9 , '(jq ε)ε8 '(-iq ' )6· ? :( 9 p-osiMa 'ζΐϋΜθοε)
°9Δ 导 0∑：  °9Δ Guide 0∑:
Figure imgf000093_0001
Figure imgf000093_0001
■-9L m^
Figure imgf000093_0002
■-9L m^
Figure imgf000093_0002
¾s)乙 6· 8ς·ζ '(ui ¾8) 6ζ/ε-8ε·ε '(Jq ¾ι)ΐ6·ε ¾ι)Δ8·9 ' » 3⁄4s) B 6·8ς·ζ '(ui 3⁄48) 6ζ/ε-8ε·ε '( J q 3⁄4ι)ΐ6·ε 3⁄4ι)Δ8·9 ' »
Ή ςπ-ίνί Ό 'Ηύοε Χ∞ 'm^YL-iZ'L '(-iq )8 ^^-os a ) ¾醒 Ή ςπ-ίνί Ό 'Ηύοε Χ∞ 'm^YL-iZ'L '(-iq )8 ^^-os a ) 3⁄4 wake up
° 呦  ° 呦
[H+Vi\L9 :SVi [H+Vi\L9 : SVi
(«ι'Η Δο -εόΐ  («ι'Η Δο -εόΐ
'(ui Ή όΖΎ-ΖνΖ ∞ 'US)L6'Z- T 'H8) 6L £S£ £ '(s ¾£)£8 'C 'ΗΙ)£6·ε Ό 'Hl)SfZ, '  '(ui Ή όΖΎ-ΖνΖ ∞ 'US)L6'Z- T 'H8) 6L £S£ £ '(s 3⁄4£)£8 'C 'ΗΙ)£6·ε Ό 'Hl)SfZ, '
Ήύίζ ' ΉΌζ -ί '(m ' ξξ-ί-βί-ί ¾)68-^-89'^ δ :(9p-osiMa 'z讓 οοε) ¾醒 Ht Ήύίζ ' ΉΌζ -ί '(m ' ξξ-ί-βί-ί 3⁄4)68-^-89'^ δ :( 9 p-osiMa 'z let οοε) 3⁄4 wake up H t
° (  ° (
Figure imgf000093_0004
Figure imgf000093_0004
C0C000/M0ZN3/X3d 1^9 / 0Z OAV
Figure imgf000094_0001
C0C000/M0ZN3/X3d 1^9 / 0Z OAV
Figure imgf000094_0001
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-77为试剂合成化 合物 77。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 77 was synthesized using S-77 as a reagent.
Ή丽 R (300MHZ, DMSO-d6): δ 7.87(1H, br), 7.82(3H, br), 7.72(1H, br), 7.44(1 H, dd), 7.42(1H, d), 7.30 (1H, dd), 3.91(1H, br), 3.38-3.77 (8H, m)， 2.67-2.97(5H, m)， 2.4(3H, s)， 2.12-2.29(1H, m), 1.93-2.07 (IH, m). Ή R (300MHZ, DMSO-d 6 ): δ 7.87 (1H, br), 7.82 (3H, br), 7.72 (1H, br), 7.44 (1 H, dd), 7.42 (1H, d), 7.30 (1H, dd), 3.91(1H, br), 3.38-3.77 (8H, m), 2.67-2.97(5H, m), 2.4(3H, s), 2.12-2.29(1H, m), 1.93-2.07 (IH, m).
MS: m/e 613[M+H]+. MS: m/e 613 [M+H] + .
实  Real
Figure imgf000094_0002
Figure imgf000094_0002
78-1 78  78-1 78
按照与实施例 31相同的方法， 以制备例 5的化合物 S-5为原料， 以 S-78为试剂合成化 合物 78。  In the same manner as in Example 31, Compound S-5 of Preparation Example 5 was used as a starting material, and Compound 78 was synthesized using S-78 as a reagent.
1H NMR (300MHZ, DMSO-d6): δ 7.85(3H, br), 7.46(1H, t), 7.31(1H, t), 6.85(4H, br), 5.27(1H, br), 4.39(1H, br), 4.20(1H, br), 3.91(1H, br), 3.34-3.79 (8H， m), 2.58-2.97(5H, m), 2.12-2.29(1H, m), 1.93-2.07 (IH, m). 1H NMR (300MHZ, DMSO-d 6): δ 7.85 (3H, br), 7.46 (1H, t), 7.31 (1H, t), 6.85 (4H, br), 5.27 (1H, br), 4.39 (1H , br), 4.20(1H, br), 3.91(1H, br), 3.34-3.79 (8H, m), 2.58-2.97(5H, m), 2.12-2.29(1H, m), 1.93-2.07 (IH , m).
MS: m/e 472[M+H]+. MS: m/e 472 [M+H] + .
实施例 79~124:  Examples 79~124:
以制备例 6的手性化合物 S-5a为原料， 与不同的含 N化合物 (试剂 S)反应， 参照实施例 18制备消旋化合物的制备方法， 制备以下单一手性化合物， 具体试剂 S及对应合成的实施 例化合物详见下表-  The chiral compound S-5a of Preparation Example 6 was used as a raw material, and reacted with a different N-containing compound (Reagent S). The preparation method of the racemic compound was carried out in accordance with Example 18 to prepare the following single chiral compound, specific reagent S and corresponding The synthesized example compounds are detailed in the table below -
Figure imgf000094_0003
Figure imgf000095_0001
Figure imgf000094_0003
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000096_0001
实施例 125~154:  Examples 125~154:
以制备例 6的手性化合物 S-5a为原料， 与不同的含 N化合物 (试剂 S)反应， 参照实施 例 31的制备方法， 制备以下单一手性化合物， 具体试剂 S及对应合成的化合物详见下表：  The chiral compound S-5a of Preparation Example 6 was used as a raw material, and reacted with a different N-containing compound (Reagent S). The following single chiral compound was prepared by the preparation method of Example 31, and the specific reagent S and the corresponding synthesized compound were prepared in detail. See the table below:
Figure imgf000096_0002
S6
Figure imgf000096_0002
S6
Figure imgf000097_0001
εοεοοο/ΜθΖΝ3/ΐ3<ι
Figure imgf000097_0001
Εοεοοο/ΜθΖΝ3/ΐ3<ι
Figure imgf000098_0001
Figure imgf000098_0001
C0C000/M0ZN3/X3d 1^9 / 0Z OAV /S/u ioooHOSld OAV C0C000/M0ZN3/X3d 1^9 / 0Z OAV /S/u ioooHOSld OAV
Figure imgf000099_0001
Figure imgf000099_0001
86 86
Figure imgf000100_0001
Figure imgf000100_0001
C0C000/M0ZN3/X3d
Figure imgf000101_0001
以制备例 6的手性化合物 S-5a和化合物 155-1为原料合成化合物 155-2。 C0C000/M0ZN3/X3d
Figure imgf000101_0001
Compound 155-2 was synthesized from the chiral compound S-5a and the compound 155-1 of Preparation Example 6.
化合物 155-2(150mg)溶于甲醇， 加入 Pd/C(20mg)， 通入 ， 反应完全， 过滤， 浓缩， 柱层析得 23mg化合物 155-3。  Compound 155-2 (150 mg) was dissolved in methanol, EtOAc (EtOAc, EtOAc)
化合物 155-3(23mg)溶于 CH2C12， 加入三氟醋酸 (0.2ml)， 反应完全， 蒸干， EA溶解，Compound 155-3 (23 mg) was dissolved in CH 2 C1 2 , trifluoroacetic acid (0.2 ml) was added, the reaction was completed, evaporated and evaporated.
EA层依次用饱和碳酸氢钠溶液， 饱和食盐水洗涤， 干燥浓缩， 溶于甲醇， 加入草酸 (4mg；)， 搅拌 10min， 浓缩得化合物 155。 1H NMR (300MHZ,DMSO-d6): δ 9.03(lH,d),8.16-8.31(2H,m),7.56-7.69 (lH,m), 7.21-7.45 (2H,m),4.24(lH,br), 3.76(lH,br),3.37-3.57(4H,m),3.06(4H,br),2.69-2.93(3H,m), 2.53-2.61(lH,m), 2.34(4H，br)， 1.75-2.11(7H,m). MS m/e 612[M+H]+. The EA layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried and evaporated, evaporated, evaporated, evaporated. 1H NMR (300MHZ, DMSO-d 6): δ 9.03 (lH, d), 8.16-8.31 (2H, m), 7.56-7.69 (lH, m), 7.21-7.45 (2H, m), 4.24 (lH, Br), 3.76 (lH, br), 3.37-3.57 (4H, m), 3.06 (4H, br), 2.69-2.93 (3H, m), 2.53-2.61 (lH, m), 2.34 (4H, br) , 1.75-2.11(7H,m). MS m/e 612[M+H] + .
实施例 156~162:  Examples 156~162:
以制备例 6的手性化合物 S-5a为原料， 与不同的含 N化合物 (试剂 S)反应， 参照实施例 31的制备方法， 制备以下单一手性化合物， 具体试剂 S及对应合成的化合物详见下表-  The chiral compound S-5a of Preparation Example 6 was used as a raw material, and reacted with a different N-containing compound (Reagent S). The following single chiral compound was prepared by the preparation method of Example 31, and the specific reagent S and the corresponding synthesized compound were prepared in detail. See the table below -
Figure imgf000102_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000103_0001
参照实施例 31的制备方法， 以制备例 6的手性化合物 S-5a和 S-116为原料合成化合物 163。 1H MR (300MHZ, CD3OD-d4)： δ 7.88(lH,dd), 7.11-7.47(4H,m),4.72-5.25(2H,m), 3.89(3H,s)， 3.71-3.82(2H,m),3.54 (lH,br), 2.71-3.07(6H,m), 2.31-2.42(lH,m),1.97-2.09(2H,m). Referring to the preparation method of Example 31, the compound 163 was synthesized from the chiral compounds S-5a and S-116 of Preparation Example 6. 1H MR (300MHZ, CD 3 OD-d 4 ): δ 7.88 (lH, dd), 7.11-7.47 (4H, m), 4.72-5.25 (2H, m), 3.89 (3H, s), 3.71-3.82 ( 2H, m), 3.54 (lH, br), 2.71-3.07 (6H, m), 2.31-2.42 (lH, m), 1.97-2.09 (2H, m).
MS m/e 415[M+H]+. MS m/e 415 [M+H] + .
实施
Figure imgf000103_0002
化合物 163-1溶于甲醇， 加入氢氧化锂的水溶液， 反应完全， 加入 1M HC1溶液调 pH 至酸性， EA萃取， 饱和食盐水洗？条， 干燥浓缩 164-1。 Implementation
Figure imgf000103_0002
The compound 163-1 was dissolved in methanol, and an aqueous solution of lithium hydroxide was added thereto. The reaction was completed. The pH was adjusted to be acidic by adding a 1 M HCl solution, extracted with EA, and washed with saturated brine. Strip, dry and concentrated 164-1.
化合物 164-1溶于 CH2C12， 加入三氟醋酸 (0.2ml)， 反应完全， 蒸干， EA溶解， 饱和碳 酸氢钠溶液洗涤， 饱和食盐水洗涤， 干燥， 浓缩得化合物 164。 The compound 164-1 was dissolved in CH 2 C1 2 , and then trifluoroacetic acid (0.2 ml) was added, and the reaction mixture was evaporated to dryness, evaporated, evaporated, evaporated, evaporated
^ NMR OONfflZ, CD3OD- I4): δ 7.92(lH,dd), 7.1 l-7.47(4H,m),5.05-5.25(2H,m), 3.71-3.86 (2H,m),3.58 (lH,br), 2.71-3.10(6H,m), 2.32-2.45(lH,m),1.97-2.09(2H,m).  ^ NMR OONfflZ, CD3OD- I4): δ 7.92 (lH, dd), 7.1 l-7.47 (4H, m), 5.05-5.25 (2H, m), 3.71-3.86 (2H, m), 3.58 (lH, br ), 2.71-3.10(6H,m), 2.32-2.45(lH,m),1.97-2.09(2H,m).
MS m e 401[M+H]+. MS me 401[M+H] + .
实施  Implementation
Figure imgf000103_0003
参照实施例 31的制备方法， 以制备例 6的手性化合物 S-5a和 S-117为原料合成化合物
Figure imgf000103_0003
Referring to the preparation method of Example 31, the chiral compounds S-5a and S-117 of Preparation Example 6 were used as raw materials to synthesize the compound.
165。 165.
'H NMR (300MHZ, DMSO-d6): δ 7.91(3H,br), 7.48(lH,t), 7.32(lH,t), 4.92(2H,d),3.81-3.97 (2H,m),3.14 (lH,br), 2.66-3.03(5H,m), 1.92-2.26(4H,m). 'H NMR (300MHZ, DMSO-d 6 ): δ 7.91 (3H, br), 7.48 (1H, t), 7.32 (1H, t), 4.92 (2H, d), 3.81-3.97 (2H, m), 3.14 (lH, br), 2.66-3.03 (5H, m), 1.92-2.26 (4H, m).
MS m/e 495[M+H]+. MS m/e 495 [M+H] + .
实施 Implementation
Figure imgf000104_0001
Figure imgf000104_0001
制备例 6的手性化合物 S-5a (50mg， 0.147mmol),化合物 S-119(26mg， 0.176mmol,1.2eq) 和 HOBt(25mg， 1.25eq)溶解到无水二氯甲烷 (5ml)中， 再加入二异丙基乙胺 (72 μ 1， 3eq), 冰 水冷却下加入 EDCI(35mg， 1.25eq), 自然升温， 搅泮过夜。 TLC反应完全。 反应液中加水 淬灭， 二氯甲垸提取 3次， 合并有机相， pH=l的盐酸水溶液洗， 饱和 NaHC03洗， 水洗， 盐水洗， 干燥， 浓缩， 柱层析得化合物 166-l(58mg)。  The chiral compound S-5a (50 mg, 0.147 mmol) from Preparation 6 was dissolved in methylene chloride (5 ml). Further, diisopropylethylamine (72 μl, 3 eq) was added, and EDCI (35 mg, 1.25 eq) was added under ice-cooling, and the mixture was warmed and stirred overnight. The TLC reaction is complete. The reaction solution was quenched with water, and the mixture was extracted three times. The organic phase was combined, washed with aqueous hydrochloric acid of pH=l, washed with saturated NaHC03, washed with water, washed with brine, dried, concentrated, and purified by column chromatography. ).
MS m/e 494 [M+Na]+. MS m/e 494 [M+Na] + .
化合物 166-1溶于二氯甲烷（10ml ) 中， 加入浓盐酸（lml)， 搅拌过夜。 TLC显示反应 完全。 旋蒸去二氯甲垸和过量的盐酸， 加水溶解后再次旋干， 残余物中再加入乙醚分散， 搅 拌， 离心， 得化合物 166。  Compound 166-1 was dissolved in dichloromethane (10 ml). TLC showed the reaction was complete. Dichloromethane and excess hydrochloric acid were distilled off, dissolved in water, and then spun dry again. The residue was further added with diethyl ether, stirred, and centrifuged to give Compound 166.
1H NMR (400 MHz, DMSO-d6)： δ 7.36-7.17 (m, 1H), 7.10-6.81 (m, 4H)， 4.64-4.45 (m, 2H), 4.01-3.69 (m, 3H), 3.49-3.24 (m, 3H), 2.95-2.62 (m, 4H), 2.28-2.10 (m, 1H), 1.91-1.77 (m, 1H). 1H NMR (400 MHz, DMSO-d 6 ): δ 7.36-7.17 (m, 1H), 7.10-6.81 (m, 4H), 4.64-4.45 (m, 2H), 4.01-3.69 (m, 3H), 3.49 -3.24 (m, 3H), 2.95-2.62 (m, 4H), 2.28-2.10 (m, 1H), 1.91-1.77 (m, 1H).
MS m/e 390 [M+H]+. MS m/e 390 [M+H] + .
实施例 167〜185 : Examples 167~185:
以制备例 6的手性化合物 S-5a为原料， 与不同的含 N化合物 (试剂 S)反应， 参照实施例 31或者实施例 166的制备方法， 制备以下单一手性化合物， 具体试剂 S及对应合成的化合 物详见下表：  The chiral compound S-5a of Preparation Example 6 was used as a raw material, and reacted with a different N-containing compound (Reagent S). Referring to the preparation method of Example 31 or Example 166, the following single chiral compound, specific reagent S and corresponding The synthesized compounds are detailed in the table below:
Figure imgf000104_0002
Figure imgf000105_0001
Figure imgf000106_0001
:H NMR (400 MHz, DMSO-d6): 5 7.13 (m,
Figure imgf000104_0002
Figure imgf000105_0001
Figure imgf000106_0001
: H NMR (400 MHz, DMSO-d 6 ): 5 7.13 (m,
182 S-136 2H), 4.63 (m, 1H), 4.33-4.20 (m, 2H), 4.09 182 S-136 2H), 4.63 (m, 1H), 4.33-4.20 (m, 2H), 4.09
(dd, J = 7.36, 11.31 Hz, 2H), 3.99 (q, J = 6.24 Hz, 1H), 3.46 (dd, J = 5.26, 8.52 Hz, 1H), (dd, J = 7.36, 11.31 Hz, 2H), 3.99 (q, J = 6.24 Hz, 1H), 3.46 (dd, J = 5.26, 8.52 Hz, 1H),
H2N、 H H 2 N, H
2.84 (m, 2H), 2.77-2.59 (m, 2H)， 2.28 (m, 1H), 1.95-1 .83 (m, 1H).  2.84 (m, 2H), 2.77-2.59 (m, 2H), 2.28 (m, 1H), 1.95-1 .83 (m, 1H).
HRMS (ESI): Calcd for C15H20ON3F2: HRMS (ESI): Calcd for C 15 H 20 ON 3 F 2 :
296.1569. Found: 296.1564.  296.1569. Found: 296.1564.
工 Ή NMR (400 MHz, DMSO-d6): δ 7.25-6.99Work NMR (400 MHz, DMSO-d 6 ): δ 7.25-6.99
183 S-137 (m， 2H), 4.43-4.09 (m, 1H), 4.06-3.84 (m, 183 S-137 (m, 2H), 4.43-4.09 (m, 1H), 4.06-3.84 (m,
2H), 3.78-3.14 (m, 4H), 2.94-2.74 (m, 2H)， 2.74-2.40 (m, 2H), 2.33-2.19 (m， 1H), 2H), 3.78-3.14 (m, 4H), 2.94-2.74 (m, 2H), 2.74-2.40 (m, 2H), 2.33-2.19 (m, 1H),
H2N 工 H 2 N work
1.93-1.79 (m, 1H).  1.93-1.79 (m, 1H).
HRMS (ESI): Calcd for Ci5H1902N2F2: HRMS (ESI): Calcd for Ci 5 H 19 0 2 N 2 F 2 :
二z工 , 297.1409. Found: 297.1407. Two workers z, 297.1409 Found:. 297.1407.
lB NMR (400 MHz, DMSO-d6): δ 7.21-7.02lB NMR (400 MHz, DMSO-d 6 ): δ 7.21-7.02
184 S-138 X > o -o7 (m, 2H), 4.05-3.92 (m， 1H), 3.68-3.43 (m, 184 S-138 X > o -o 7 (m, 2H), 4.05-3.92 (m, 1H), 3.68-3.43 (m,
3H), 3.37-2.96 (m, 2H), 2.96-2.63 (m, 4H), 3H), 3.37-2.96 (m, 2H), 2.96-2.63 (m, 4H),
H2N H 2 N
2.62-2.43 (m, 1H), 2.34-2.20 (m, 1 H), 2.00-1.82 (m, 2H), 1.81-1.35 (m, 3H).  2.62-2.43 (m, 1H), 2.34-2.20 (m, 1 H), 2.00-1.82 (m, 2H), 1.81-1.35 (m, 3H).
MS m/e 353 [M+H]+. MS m/e 353 [M+H] + .
Ή NMR(400 MHz, DMSO-d6)： δ Ή NMR (400 MHz, DMSO-d 6 ): δ
185 S-139 7.08 (m, 2H), 4.63 (s, 2H), 3.99 (m, 1H), 3.44  185 S-139 7.08 (m, 2H), 4.63 (s, 2H), 3.99 (m, 1H), 3.44
(m, 1H), 2.91-2.77 (m, 2H), 2.77-2.59 (m， (m, 1H), 2.91-2.77 (m, 2H), 2.77-2.59 (m,
2H), 2.25 (m, 1H), 1.87 (m, 1H). 2H), 2.25 (m, 1H), 1.87 (m, 1H).
HRMS (ESI): Calcd for C14H15ON6F2 (M-H):HRMS (ESI): Calcd for C 14 H 15 ON 6 F 2 (MH):
321.1270. Found: 321.1279. 321.1270. Found: 321.1279.
实施例 186-246:  Example 186-246:
以制备例 5化合物 S-5为原料， 与不同的含 N化合物 （试剂 S ) 反应， 参照实施例 18 或实施例 31或实施例 166的制备方法， 制备以下化合物， 具体试剂 S及对应合成的化合物 详见下表：  Using the compound S-5 of Preparation Example 5 as a raw material, and reacting with a different N-containing compound (Reagent S), the following compounds were prepared according to the preparation method of Example 18 or Example 31 or Example 166, the specific reagent S and the corresponding synthetic The compounds are detailed in the table below:
Figure imgf000107_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000108_0001
C0C000/M0ZN3/X3d Μ / ΟΖ OAV LOl C0C000/M0ZN3/X3d Μ / ΟΖ OAV LOl
Figure imgf000109_0001
Figure imgf000109_0001
C0C000/M0ZN3/X3d
Figure imgf000110_0001
C0C000/M0ZN3/X3d
Figure imgf000110_0001
分子对接技术评估化合物活性  Molecular docking technique for evaluating compound activity
计算机辅助药物设计是合理药物设计的主要方法和工具。本发明通过反复尝试各种对接 程序、确定了分子对接方法， 优化了分子对接参数， 获得了 DPP-4抑制剂的构效关系， 可用 于设计符合通式 I所示的新型 DPP-4抑制剂。 优选的对接用计算程序为 Schrodinger 2010版 中的 glide(Schr6dinger, LLC, New York, NY)。对接靶点选用与 sitagliptin共结晶的 DPP-4 蛋 白结构 (PDB ID: 1X70)。 对接的范围设置为一个包括 DPP-4催化结合位点中的 Sl、 PI和 P2 口袋的立方体。 所有设计的化合物结构在 SchrSdinger软件中构建， 并利用 Ligprep模块在 保持手性不变的前提下在 PH=7±2范围内进行结构优化。对关键的氨基手动指定其质子化状 态为带 1各单位的正电荷。  Computer-aided drug design is the primary method and tool for rational drug design. The invention optimizes the molecular docking parameters by repeatedly trying various docking procedures, determines the molecular docking method, obtains the structure-activity relationship of the DPP-4 inhibitor, and can be used to design a novel DPP-4 inhibitor conforming to the formula I. . A preferred docking calculation program is glide (Schr6dinger, LLC, New York, NY) in the Schrodinger 2010 edition. The DPP-4 protein structure (PDB ID: 1X70) co-crystallized with sitagliptin was used for the docking target. The docking range is set to a cube that includes the Sl, PI, and P2 pockets in the DPP-4 catalytic binding site. All designed compound structures were constructed in the SchrSdinger software, and the Ligprep module was used to optimize the structure in the range of pH=7±2 while maintaining the chirality. The key amino group is manually assigned its protonation state as a positive charge with 1 unit.
对接计算采用 XP精度。 在对接中， 每个化合物分子产生 8000个构象， 将前 1000个优 势构象进行能量优化并重新评估。将非极性氢原子的半径缩小为标准值的 80%以获得更多的 输出构象类型。综合考虑分子对接所提供的信息，包括化合物与 DPP-4活性口袋中关键氨基 酸残基的作用、与口袋形状契合程度以及疏水基团伸出口袋外部的特征等， 选择了部分化合 物分子进行化学合成和生物学检测。新合成化合物分子的生物活性测试结果表明， 当计算打 分函数 Gsocre优于 -10 kcal/mol 时， 化合物将具有抑制 DPP-4活性能力。 下表中列出了计 算打分函数 Gsocre优于 -10 kcal/mol的化合物， 但本申请不限于这些化合物分子。Docking calculations use XP precision. In docking, each compound molecule produces 8000 conformations, and the first 1000 dominant conformations are energy optimized and reevaluated. The radius of the non-polar hydrogen atoms is reduced to 80% of the standard value to obtain more output conformation types. Considering the information provided by molecular docking, including the interaction of the compound with key amino acid residues in the DPP-4 active pocket, the degree of fit with the pocket shape, and the characteristics of the hydrophobic group extending out of the pocket, some of the compound molecules were selected for chemical synthesis. And biological testing. The bioactivity test results of the newly synthesized compound molecules show that when calculating When the fractional function Gsocre is better than -10 kcal/mol, the compound will have the ability to inhibit DPP-4 activity. The compounds in which the scoring function Gsocre is better than -10 kcal/mol are listed in the table below, but the application is not limited to these compound molecules.
Figure imgf000111_0001
0X1
Figure imgf000111_0001
0X1
Figure imgf000112_0001
Figure imgf000112_0001
C0C000/M0ZN3/X3d 1^9 / 0Z OAV Ill C0C000/M0ZN3/X3d 1^9 / 0Z OAV Ill
Figure imgf000113_0001
Figure imgf000113_0001
C0C000/M0ZN3/X3d 1^9 / 0Z OAV s/u Oooosld9siAV C0C000/M0ZN3/X3d 1^9 / 0Z OAV s/u Oooosld9siAV
Figure imgf000114_0001
Figure imgf000114_0001
επ Επ
Figure imgf000115_0001
Figure imgf000115_0001
C0C000/M0ZN3/X3d 1^9 / 0Z OAV 347 -12.5 348 -10.5 349 -12.5 C0C000/M0ZN3/X3d 1^9 / 0Z OAV 347 -12.5 348 -10.5 349 -12.5
350 -11.1 351 -12.5 352 -13.4 350 -11.1 351 -12.5 352 -13.4
353 -11.8 354 -10.5 355 -10.5 353 -11.8 354 -10.5 355 -10.5
356 -11.4 357 -10.8 358 -13.5 356 -11.4 357 -10.8 358 -13.5
359 -11.1 360 -10.5 361 -11.3 359 -11.1 360 -10.5 361 -11.3
362 -11.9 363 -12.5 364 -12.6 362 -11.9 363 -12.5 364 -12.6
365 -12.8 366 -13.2 367 -11.0 365 -12.8 366 -13.2 367 -11.0
368 -12.9 369 -13.2 370 -11.1 入 368 -12.9 369 -13.2 370 -11.1
371 -10.9 372 -13.0 373 -11.5  371 -10.9 372 -13.0 373 -11.5
374 -12.7 375 374 -12.7 375
-10.5 378 、 -11.7 376 -10.8 -10.5 378, -11.7 376 -10.8
377 -11.6 377 -11.6
生物学评价 Biological evaluation
1. 本发明中部分化合物对 DPP-4的抑制活性测定 本发明使用人结肠癌细胞株 Caco-2的细胞裂解液作为 DPP-4酶的来源 (Thomas, L., M. Eckardt, et al, The Journal of Pharmacology and Experimental Therapeutics 325(1): 175-182,2008)。 在 96孔板 100 孔的筛药体系中， H-Gly-Pro-AMC底物 (AnaSpec)的终浓 度为 0.1mg/ml， 加入不同浓度的待测化合物 37°C孵育 30 min后， 以激发波长 380 rnn/发射 波长 460 nm检测荧光信号强度。 根据检测获得的荧光值计算受试样品对 DPP-4的酶活抑制 率 (％)， 并将酶活性抑制率达到 50 %时的浓度定为该化合物作用的 IC5Q值。 抑制率 (％)根据 下式进行- 抑制率％=(RFU空白- RFU化合物 )/(RFU空白- RFU隱对照 )X100% 1. Determination of the inhibitory activity of some compounds of the present invention against DPP-4 The present invention uses a cell lysate of human colon cancer cell line Caco-2 as a source of DPP-4 enzyme (Thomas, L., M. Eckardt, et al, The Journal of Pharmacology and Experimental Therapeutics 325(1): 175-182 , 2008). In a 96-well plate 100-well sieve system, the final concentration of H-Gly-Pro-AMC substrate (AnaSpec) was 0.1 mg/ml, and the test compound was added at different concentrations for 37 min at 37 ° C to stimulate The fluorescence signal intensity is detected at a wavelength of 380 rnn/emission wavelength of 460 nm. The enzyme activity inhibition rate (%) of the test sample against DPP-4 was calculated based on the fluorescence value obtained by the detection, and the concentration at which the enzyme activity inhibition rate reached 50% was determined as the IC 5Q value of the action of the compound. The inhibition rate (%) was calculated according to the following formula - inhibition rate % = (RFU blank - RFU compound) / (RFU blank - RFU implicit control) X100%
RFU化 、 RFU空自和 RFU瞧 ffl分别表示化合物孔、空白孔和不加酶的阴性对照孔 30min 与 Omin的荧光值之差 RFU, RFU, and RFU瞧ffl represent the difference between the fluorescence value of 30 min and Omin in the compound well, blank well, and non-enzymatic negative control well, respectively.
经过以上方法检测 DPP-4酶活， 结果显示多个化合物对 DPP-4有不同程度的抑制活性， 其中实施例 5化合物的活性较好， 对 DPP-4的抑制活性的 IC5o值为 19.9nM; 以上市 DPP-4 抑制剂 Sitagliptin作为阳性对照，在该平台上测得的阳性药 IC5o为 34.1nM，与文献值接近 (Kim， D., L. Wang, et al. J. Med. Chem 48(1): 141-151.2005)。 After the above method was used to detect the activity of DPP-4, the results showed that a plurality of compounds had different degrees of inhibitory activity against DPP-4, wherein the compound of Example 5 had a good activity, and the IC 5 value of the inhibitory activity against DPP-4 was 19.9. nM ; with the listed DPP-4 inhibitor, Sitagliptin as a positive control, the IC 5 o of the positive drug measured on this platform was 34.1 nM, which is close to the literature value (Kim, D., L. Wang, et al. J. Med). Chem 48(1): 141-151.2005).
本发明的化合物对 DPP-4的抑制活性的测试结果列在表 1中。  The test results of the inhibitory activity of the compound of the present invention against DPP-4 are shown in Table 1.
表 1： 化合物各浓度对 DPP-4抑制率 (％)a Table 1: Inhibition rate of DPP-4 by each concentration of compound (%) a
Figure imgf000117_0001
化合物编号 ΙμΜ ΙΟΟηΜ ΙΟηΜ 实施例 38 77.37±6.91 32.00±2.85 16.86±1.95 实施例 39 56.09±4.22 23.79±2.52 25.47±1.28 实施例 40 80.36士 3.18 51.03±1.95 18.55±1.48 实施例 41 80.12±5.72 31.87±2.98
Figure imgf000117_0001
Compound No. ΙμΜ ΙΟΟηΜ ΙΟηΜ Example 38 77.37±6.91 32.00±2.85 16.86±1.95 Example 39 56.09±4.22 23.79±2.52 25.47±1.28 Example 40 80.36±3.18 51.03±1.95 18.55±1.48 Example 41 80.12±5.72 31.87±2.98
实施例 42 59.77±1.74 19.27±4.24  Example 42 59.77±1.74 19.27±4.24
实施例 43 71.86±2.45 32.04±10.06  Example 43 71.86±2.45 32.04±10.06
实施例 45 85.11±1.63 48.56±8.43  Example 45 85.11±1.63 48.56±8.43
实施例 46 66.99±1.15 26.09±0.04  Example 46 66.99±1.15 26.09±0.04
实施例 47 57.18±1.80  Example 47 57.18±1.80
实施例 48 66.35±0.86 24.57±1.62 24.73±1.46 实施例 49 56.26±1.31  Example 48 66.35±0.86 24.57±1.62 24.73±1.46 Example 49 56.26±1.31
实施例 50 79.60±0.51 52.25±1.62  Example 50 79.60±0.51 52.25±1.62
实施例 51 53.90±1.86  Example 51 53.90±1.86
实施例 52 72.84±2.01 30.47±0.28  Example 52 72.84±2.01 30.47±0.28
实施例 53 58.40±0.24  Example 53 58.40±0.24
实施例 54 52.82±1.64  Example 54 52.82±1.64
实施例 56 61.56±2.68 21.08±2.71  Example 56 61.56±2.68 21.08±2.71
实施例 57 79.81±7.32 39.82±0.47  Example 57 79.81±7.32 39.82±0.47
实施例 58 48.19±1.39  Example 58 48.19±1.39
实施例 59 59·53±1·81  Example 59 59·53±1·81
实施例 60 62.73±1.22 26.95±1.12  Example 60 62.73±1.22 26.95±1.12
实施例 61 70.52±4.03 35.80±0.89  Example 61 70.52±4.03 35.80±0.89
实施例 62 78.48±0.40 68.65±0.98 21.20±4.10 实施例 63 55.10±1.21  Example 62 78.48±0.40 68.65±0.98 21.20±4.10 Example 63 55.10±1.21
实施例 64 52.57±0.21  Example 64 52.57±0.21
实施例 65 73.79±0.78 38.97±1.07  Example 65 73.79±0.78 38.97±1.07
实施例 66 68·85±0·75 30.90±0.63  Example 66 68·85±0·75 30.90±0.63
实施例 67 73.75±0.40 37.98±0.92  Example 67 73.75±0.40 37.98±0.92
实施例 85 50.92±2.29 实施例 87 88.90 ±0.04 58.81 ±0.62  EXAMPLE 85 50.92±2.29 Example 87 88.90 ±0.04 58.81 ±0.62
实施例 93 69.27±2.75 66.83±2.25 44.41±0.61 实施例 115 77.82± 0.88  Example 93 69.27±2.75 66.83±2.25 44.41±0.61 Example 115 77.82±0.88
实施例 119 73·33 ±0·31 Example 119 73·33 ±0·31
实施例 120 80.01 ± 1.82 63.10±0.96 Example 120 80.01 ± 1.82 63.10 ± 0.96
实施例 124 73.97±0.05 Example 124 73.97±0.05
实施例 125 80.90 ±0.66 36.11 ± 1.02 Example 125 80.90 ±0.66 36.11 ± 1.02
实施例 126 82.29± 1.10 43.11 ±3.15 10.57±2.31 实施例 127 80.44 ±0.54 51.59±4.19 化合物编号 ΙμΜ ΙΟΟηΜ ΙΟηΜ 实施例 128 85.34±0.85 80·45±0·85 54.18±1.01 实施例 129 82.93 ±0.32 74.04 ±0.89 38.40 ±2.45 实施例 130 85.63±0.79 85·19±0·67 73.08±0.62 实施例 131 82.84 ±2.92 85.96±2.68 63·59±0.74 实施例 132 87.47 ±0.76 84.84±3.97 77.23土 1.81 实施例 133 84.98 ±0.87 81.74±0.61 64.47 ±1.25 实施例 134 84.77±0.85 83.78±0.83 80.36 + 0.23 实施例 135 87.64±0.41 83.91 ±2.53 76.62土 0.50 实施例 136 86.77 ±0.63 75.89 ±1.72 30.94 ±0.74 实施例 137 82.54±6.16 80.65 ±2.78 31.74±4·16 实施例 138 85.25 ±0.54 83.19±1.13 74.47 ±1.70 实施例 139 84.20 ±1.71 84.71 ±4.20 68·25±0·86 实施例 140 84.80±0.88 75.04土 0.55 38.26 + 2.45 实施例 141 91.83土 0.24 49.46 + 0.93 Example 126 82.29 ± 1.10 43.11 ± 3.15 10.57 ± 2.31 Example 127 80.44 ± 0.54 51.59 ± 4.19 Compound No. ΙμΜ ΙΟΟηΜ ΙΟηΜ Example 128 85.34±0.85 80·45±0·85 54.18±1.01 Example 129 82.93 ±0.32 74.04 ±0.89 38.40 ±2.45 Example 130 85.63±0.79 85·19±0·67 73.08±0.62 Implementation Example 131 82.84 ± 2.92 85.96 ± 2.68 63 · 59 ± 0.74 Example 132 87.47 ± 0.76 84.84 ± 3.97 77.23 Soil 1.81 Example 133 84.98 ± 0.87 81.74 ± 0.61 64.47 ± 1.25 Example 134 84.77 ± 0.85 83.78 ± 0.83 80.36 + 0.23 Implementation Example 135 87.64 ± 0.41 83.91 ± 2.53 76.62 soil 0.50 Example 136 86.77 ± 0.63 75.89 ± 1.72 30.94 ± 0.74 Example 137 82.54 ± 6.16 80.65 ± 2.78 31.74 ± 4.16 Example 138 85.25 ± 0.54 83.19 ± 1.13 74.47 ± 1.70 Implementation Example 139 84.20 ±1.71 84.71 ±4.20 68·25±0·86 Example 140 84.80±0.88 75.04 Soil 0.55 38.26 + 2.45 Example 141 91.83 Soil 0.24 49.46 + 0.93
实施例 142 96.84士 0.51 75.94±1.15 40.37±3.06 实施例 143 88.99 ±0.23 44.83 ±0,73 EXAMPLES 142 96.84 ± 0.51 75.94 ± 1.15 40.37 ± 3.06 Example 143 88.99 ± 0.23 44.83 ± 0, 73
实施例 144 48.57±2.32 26·82±5·94 22.09 ±1.70 实施例 145 56.81 ±4.62 26.25±1.11 26.62 ±8.48 实施例 146 70.53 + 3.20 76.14±0.36 67.04 ±0.43 实施例 147 73·98±5·33 74.03 ±0.68 42.04± 12.61 实施例 148 66.70±0.00 30.95 + 0.76 17.99±0.75 实施例 149 73.78±1.91 45·53±6.48 24.00 ±1.23 实施例 150 63.38±1.32 37.35 ±12.93 20.23 ±7.40 实施例 151 74.70 ±4.02 61·86±3·19 24.62 ±6.78 实施例 152 64.97±4.35 51.70 ±8.48 14.45 ±0.22 实施例 153 76.62 ±8.47 69.60 ±2.25 69.60 ±2.25 实施例 154 71·54±0.45 71.54 ±0.45 36.24±3.61 实施例 155 79.20 ±1.87 72.06 ±1.06 42.87±7.96 实施例 156 79.35 ±0.64 76.43 ±1.24 66.47±1.71 实施例 157 78.52 ±0.60 76.59±0·37 73.14±1.75 实施例 158 66.23 ±5.70 41.06±2.95 41.27±2.99 实施例 159 71.42 ±0.27 52.38±3.43 38.60±3·31 实施例 160 79.85 ±5.77 57.43 ±1.52 28.96±2.47 实施例 161 88.75 ±9.82 77.52±8.81 72.90 ±5.29 实施例 162 69.79 ±2.25 79.33±3.10 55.25 + 2.37 实施例 163 64.29 + 1.02 32.72±3.07 25.68±4.70 实施例 164 64.24 ±1.95 31.17± 12.95 27.84 ±8.94 实施例 165 64.16±1.18 59.34±5.17 37.38±11.39 化合物编号 ΙμΜ ΙΟΟηΜ ΙΟηΜ 实施例 166 35.27± 18.78 Example 144 48.57±2.32 26·82±5·94 22.09 ±1.70 Example 145 56.81 ±4.62 26.25±1.11 26.62 ±8.48 Example 146 70.53 + 3.20 76.14±0.36 67.04 ±0.43 Example 147 73·98±5·33 74.03 ±0.68 42.04± 12.61 Example 148 66.70±0.00 30.95 + 0.76 17.99±0.75 Example 149 73.78±1.91 45·53±6.48 24.00 ±1.23 Example 150 63.38±1.32 37.35 ±12.93 20.23 ±7.40 Example 151 74.70 ±4.02 61·86±3·19 24.62 ±6.78 Example 152 64.97±4.35 51.70 ±8.48 14.45 ±0.22 Example 153 76.62 ±8.47 69.60 ±2.25 69.60 ±2.25 Example 154 71·54±0.45 71.54 ±0.45 36.24±3.61 Example 155 79.20 ±1.87 72.06 ±1.06 42.87±7.96 Example 156 79.35 ±0.64 76.43 ±1.24 66.47±1.71 Example 157 78.52 ±0.60 76.59±0·37 73.14±1.75 Example 158 66.23 ±5.70 41.06±2.95 41.27±2.99 Example 159 71.42 ± 0.27 52.38 ± 3.43 38.60 ± 3.31 Example 160 79.85 ± 5.77 57.43 ± 1.52 28.96 ± 2.47 Example 161 88.75 ± 9.82 77.52 ± 8.81 72.90 ± 5.29 Example 162 69.79 ± 2.25 79.33 ± 3.10 55.25 + 2.37 Example 163 64.29 + 1.02 32.72±3.07 25.68±4.70 Example 164 64.24 ±1.95 31.17± 12.95 27.84 ±8.94 Example 165 64.16±1.18 59.34±5.17 37.38±11.39 Compound No. ΙμΜ ΙΟΟηΜ ΙΟηΜ Example 166 35.27± 18.78
实施例 167 53.06+ 1.18 21·19± 12.50  Example 167 53.06+ 1.18 21·19± 12.50
实施例 168 49.42 ± 9.39  Example 168 49.42 ± 9.39
实施例 170 41.00± 13.70 41.00+ 13.70  Example 170 41.00± 13.70 41.00+ 13.70
实施例 171 54.28 ± 10.07 33.70± 1 ·81 25.05 ±2.47 实施例 172 47.58 ± 0.22 47.58 ±0.22  EXAMPLES 171 54.28 ± 10.07 33.70± 1 ·81 25.05 ±2.47 Example 172 47.58 ± 0.22 47.58 ±0.22
实施例 173 48.67±6.55 30.21 ±4.41 实施例 174 38.94± 14.70  EXAMPLE 173 48.67±6.55 30.21 ±4.41 Example 174 38.94± 14.70
实施例 175 65.67 ± 3.42 54.83 ± 13.96  Example 175 65.67 ± 3.42 54.83 ± 13.96
实施例 176 85.15±0.22 74.33±0.48 25.76±1.57 实施例 177 84.37±0.83 67.99±0.89 24.26±3.08 实施例 178 86.21±1.41 85.40±1.25 83.17±0.04 实施例 179 84.15±1.29 73·53±0.46 35.03±4.18 实施例 180 59.96±0.66  EXAMPLE 176 85.15±0.22 74.33±0.48 25.76±1.57 Example 177 84.37±0.83 67.99±0.89 24.26±3.08 Example 178 86.21±1.41 85.40±1.25 83.17±0.04 Example 179 84.15±1.29 73·53±0.46 35.03±4.18 Example 180 59.96±0.66
实施例 181 77.85±0.95 44.65±4.54  Example 181 77.85±0.95 44.65±4.54
实施例 182 61.15±1.16 22.58±0.27  Example 182 61.15±1.16 22.58±0.27
实施例 183 72.92±3.51 21.90±5.61 11.12± 1.78 实施例 184 55·52± 3·89  EXAMPLE 183 72.92±3.51 21.90±5.61 11.12± 1.78 Example 184 55·52±3·89
实施例 185 51.26± 1.90  Example 185 51.26± 1.90
a实验结果 (抑制率)用 (平均值±标准差)表示 ( 2)  a Experimental result (inhibition rate) is expressed by (mean ± standard deviation) ( 2)
2. 实施例化合物对 DPP-8和 DPP-9的选择性测定 2. Selective Determination of DPP-8 and DPP-9 by Example Compounds
DPP-8、 DPP-9与 DPP-4同属于丝氨酸蛋白酶家族， DPP-8和 DPP-9的抑制会引起多器 官毒性和严重的免疫毒性 (Lankas, G. R.， B. Leiting, et al. Diabetes 54: 2988-2994. 2005)， 所以 DPP-4抑制剂的选择性非常重要。 人重组 DPP-8酶购自 abeam, 人重组 DPP-9酶购自 R&D Systems 在 96孔板 100μΙ7孔的筛药体系中， H-Gly-Pro-AMC底物的终浓度为 0.1mg/ml， 加入不同浓度的待测化合物 37°C孵育 30 min后，以激发波长 (EX)380nm/发射波长 (EM)460nm 检测荧光信号。 根据体系的荧光值计算受试样品对 DPP-8和 DPP-9的抑制率(％)， 并将酶活 性抑制率达到 50 %时的浓度定为该化合物作用的 IC5Q值。 抑制率(％)根据下式进行： DPP-8, DPP-9 and DPP-4 belong to the serine protease family, and inhibition of DPP-8 and DPP-9 causes multi-organ toxicity and severe immunotoxicity (Lankas, GR, B. Leiting, et al. Diabetes 54 : 2988-2994. 2005), so the selectivity of DPP-4 inhibitors is very important. Human recombinant DPP-8 enzyme was purchased from abeam, human recombinant DPP-9 enzyme was purchased from R&D Systems. In a 96-well plate 100 μΙ 7-well sieve system, the final concentration of H-Gly-Pro-AMC substrate was 0.1 mg/ml. After incubating for 30 min at 37 ° C with different concentrations of the test compound, the fluorescence signal was detected at an excitation wavelength (EX) of 380 nm / emission wavelength (EM) of 460 nm. The inhibition rate (%) of the test sample against DPP-8 and DPP-9 was calculated according to the fluorescence value of the system, and the concentration at which the inhibition rate of the enzyme activity reached 50% was determined as the IC 5Q value of the action of the compound. The inhibition rate (%) is based on the following formula:
抑制率％=(1^1；空^ RFU化合物 )/(RFU空 RFU 隨对照 )X100%  Inhibition rate%=(1^1; empty^RFU compound)/(RFU empty RFU with control) X100%
RFU RFU s和 RFU 分别表示化合物孔、空白孔和不加酶的阴性对照孔 30min 与 Omin的荧光值之差。 The RFU RFU s and RFU represent the difference between the fluorescence values of the compound well, the blank well, and the non-enzymatic negative control well for 30 min and Omin, respectively.
以 Sitagliptin作为阳性对照， 比较化合物对 DPP-8/9的选择性。  The selectivity of the compounds for DPP-8/9 was compared using Sitagliptin as a positive control.
实验结果见表 2、 表 3和表 4， 表 2为实施例 5化合物和 Sitagliptin对 DPP-8和 DPP-9 的抑制活性的 IC5。， 如表 3所示， 实施例 5化合物对于 DPP-8的抑制活性的 IC5Q与 DPP-4 的 IC5o之比约为 3296倍， 对于 DPP-9的抑制活性的 IC5o与 DPP-4的 IC5o之比大于 5000倍 而阳性药 Sitagliptin相应的分别仅有约 1139倍和大于 2900倍， 说明实施例 5化合物比阳性 药 Sitagliptin具有更好的选择性。 表 4为其他实施例化合物对 DDP8和 DPP-9的抑制率。 表 2: 小分子抑制剂对 DDP8和 DPP-9的抑制率 (IC5o: 单位： μΜ) The experimental results are shown in Table 2, Table 3 and Table 4. Table 2 shows the IC 5 of the inhibitory activity of the compound of Example 5 and Siteagliptin on DPP-8 and DPP-9. As shown in Table 3, the ratio of IC 5Q of the inhibitory activity of the compound of Example 5 to DPP-8 to IC 5 o of DPP-4 was about 3296 times, and IC 5 o and DPP- for the inhibitory activity of DPP-9. The IC 5 o ratio of 4 is more than 5000 times and the positive drug sitagliptin is only about 1139 times and more than 2900 times respectively, indicating that the compound of Example 5 has better selectivity than the positive drug Siteagliptin. Table 4 shows the inhibition rates of the compounds of the other examples for DDP8 and DPP-9. Table 2: Inhibition of DDP8 and DPP-9 by small molecule inhibitors (IC 5 o: unit: μΜ)
Figure imgf000121_0001
Figure imgf000121_0001
表 3: 小分子抑制剂对 DDP8和 DPP-9的选择性倍数  Table 3: Selective multiples of small molecule inhibitors for DDP8 and DPP-9
IC50比值 实施例 5化合物 Sitagliptin IC 50 ratio Example 5 compound Sitagliptin
DPP-8/ DPP-4 3296 Π30  DPP-8/ DPP-4 3296 Π30
DPP-9/ DPP-4 >5032 >2933  DPP-9/ DPP-4 >5032 >2933
表 4: 小分子抑制剂对 DDP8和 DPP-9的抑制率  Table 4: Inhibition of DDP8 and DPP-9 by small molecule inhibitors
Figure imgf000121_0002
Figure imgf000121_0002
3. 实施例化合物改善 C57BLKS/J小鼠口服糖耐量水平  3. Example compounds improve oral glucose tolerance levels in C57BLKS/J mice
6-8周龄雄性 C57BLKS/J小鼠按上海药物研究所 SPF级动物饲养标准操作规程饲养。小 鼠随机分组， 每组 6-8只， 测量体重， 禁食 12h后， 尾静脉取血， 利用罗氏血糖仪及血糖试 纸测空腹血糖水平。  6-8 weeks old male C57BLKS/J mice were housed according to the Shanghai Institute of Materia Medica SPF-level animal feeding standard operating procedures. The mice were randomly divided into groups of 6-8, measuring body weight, and after 12 hours of fasting, blood was taken from the tail vein, and fasting blood glucose levels were measured using a Roche blood glucose meter and a blood glucose test paper.
受试化合物按不同剂量灌胃给药， 给药后 60分钟， 各组小鼠进行口服糖耐量实验 (Oral glucose tolerance test, OGTT)。 具体步骤为： 化合物灌胃给药后 60分钟， 再次测定各组小鼠 的血糖水平， 同时灌胃给予 5g kg体重葡萄糖溶液， 并计为 0时间点， 然后分别在 20、 40 和 80分钟， 尾静脉取血测血糖水平， 绘制 OGTT曲线， 计算曲线下面积 （AUC)， 利用单 因素方差分析计算各组差异。  The test compounds were intragastrically administered at different doses, and 60 minutes after administration, each group of mice was subjected to an oral glucose tolerance test (OGTT). The specific steps are as follows: 60 minutes after the compound is administered by gavage, the blood glucose level of each group of mice is measured again, and 5 g kg of body weight glucose solution is administered by gavage, and is counted as 0 time point, and then at 20, 40 and 80 minutes, respectively. Blood glucose levels were measured from the tail vein, OGTT curves were plotted, area under the curve (AUC) was calculated, and differences were calculated using one-way analysis of variance.
对实施例 5化合物 (代号 TPN6573)进行详细的浓度梯度实验， 以 Sitagliptin为阳性对照， 得到实验结果如图 1(a)和图 1(b)所示， 实施例 5化合物 (代号 TPN6573)能够显著改善小鼠的 葡萄糖耐受， 在较低剂量下 (1 mg/kg)仍然有很强的体内活性。  A detailed concentration gradient experiment was carried out on the compound of Example 5 (code TPN6573), and Sitagliptin was used as a positive control, and the experimental results were obtained as shown in Fig. 1 (a) and Fig. 1 (b), and the compound of Example 5 (code TPN6573) was remarkable. It improved glucose tolerance in mice and still had strong in vivo activity at lower doses (1 mg/kg).
对其他实施例化合物，给药剂量 10mg/kg，检测其在小鼠模型上对急性糖耐量的作用（表 5)， 其中 AUC抑制百分比 = (对照组 AUC-化合物组 AUC) /对照组 AUC*100%。  For the other example compounds, a dose of 10 mg/kg was administered to test its effect on acute glucose tolerance in a mouse model (Table 5), wherein the percentage of AUC inhibition = (control group AUC-compound group AUC) / control group AUC* 100%.
表 5 实施例化合物对血糖的抑制作用  Table 5 Inhibition of blood glucose by the compounds of the examples
实施例 降糖作用 （AUC抑制百分比）  EXAMPLES Hypoglycemic effect (% of AUC inhibition)
Sitagliptin 26%  Sitagliptin 26%
实施例 86 22%  Example 86 22%
实施例 199 28%  Example 199 28%
实施例 200 32% 由上表可见， 实施例化合物显著改善了小鼠糖耐量， 显示了较强的体内降糖活性。 Example 200 32% As can be seen from the above table, the compounds of the examples significantly improved the glucose tolerance in mice and showed a strong in vivo hypoglycemic activity.
4. 实施例 5化合物 (代号 TPN6573)单剂量 C57BLKS/J小鼠急性毒性实验  4. Example 5 Compound (code TPN6573) single dose C57BLKS/J mice acute toxicity test
6-8周龄雄性 C57BLKS/J小鼠按上海药物研究所 SPF级动物词养标准操作规程饲养。小 鼠随机分为 2组， 每组 10只， 测量体重， 过夜禁食 14h后， 口服灌胃给药 2000mg/kg的实 施例 5化合物 (代号 TPN6573), 和同等剂量的阳性药 sitagliptin作为对照。 观察两组小鼠的 健康状况； 两周之后摘眼球取血， 检测丙氨酸转移酶 (ALT)和天门冬氨酸转移酶 (AST)活性。  6-8 weeks old male C57BLKS/J mice were housed according to the Shanghai Institute of Materia Medica SPF class animal wording standard operating procedures. The mice were randomly divided into 2 groups, 10 rats in each group, and the body weight was measured. After 14 hours of fasting overnight, the compound of Example 5 (code name TPN6573) was administered orally at 2000 mg/kg, and the positive drug sitagliptin of the same dose was used as a control. The health status of the two groups of mice was observed; two weeks later, the eyeballs were taken for blood sampling, and alanine transferase (ALT) and aspartate transferase (AST) activities were measured.
两周内两组小鼠并无死亡， 进食和饮水都没有明显的异常。 测量 ALT和 AST的结果如 图 2(a)和图 2(b)所示：实验结果表明，与阳性药 sitagliptin相比，实施例 5化合物 (代号 TPN6573) 并没有明显的毒性。  There were no deaths in the two groups of mice within two weeks, and there were no significant abnormalities in eating and drinking. The results of measuring ALT and AST are shown in Fig. 2(a) and Fig. 2(b): The experimental results show that the compound of Example 5 (code TPN6573) has no significant toxicity compared to the positive drug sitagliptin.

Claims

权利要求 Rights request
1、 一种如下通式 I所示的 β-氨基羰基类化合物或其互变异构体、 对映体、 消旋体或其 药学上可接受的盐：  A β-aminocarbonyl compound represented by the following formula I or a tautomer, an enantiomer thereof, a racemate or a pharmaceutically acceptable salt thereof:
Figure imgf000123_0001
Figure imgf000123_0001
其中，  among them,
Α为 C6-C10芳基、 饱和或不饱和 C3-C10环烃基、 4-10元杂环基或 4-10元杂芳基； 所 述杂环基或杂芳基含有 1-4个选自 N、 S和 0中的杂原子； A优选为苯基、 5~6元杂环基或 5~6元杂芳基， 更优选为苯基、 吡啶基或环戊二烯基；  Α is a C6-C10 aryl group, a saturated or unsaturated C3-C10 cycloalkyl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group; and the heterocyclic group or heteroaryl group contains from 1 to 4 selected from the group consisting of a hetero atom in N, S and 0; A is preferably a phenyl group, a 5- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, more preferably a phenyl group, a pyridyl group or a cyclopentadienyl group;
W为^、 S、 0或 C1-C4直链烃基；  W is a linear hydrocarbon group of ^, S, 0 or C1-C4;
<3为>^、 S、 O或 C原子；  <3 is >^, S, O or C atom;
W与 Q之间的虚线存在或不存在， 存在时表示此处是不饱和键， 不存在时表示此处是 饱和键， 优选为不存在；  The presence or absence of a dotted line between W and Q, when present, indicates that it is an unsaturated bond, and when it does not exist, it indicates that it is a saturated bond, preferably does not exist;
Y为 N或 CR7; Y is N or CR 7 ;
X为 N或 CR7; X is N or CR 7 ;
和 R4各自独立地为 H;卤素；三氟甲基；羟基；硝基；腈基；羧基； -C(O)OCl-C10 烷基； 氨基； C1-C10烷氧基; C1-C10烷基; C1-C10垸酰基 (即 -C(O)Cl-C10烷基)； C1-C10 烷酰氧基 (即 -OC(O)Cl-C10烷基)； 磧酰基； C1-C10垸基磺酰基； C6-C10芳基； 4-10元杂环 基；或 4-10元杂芳基；上述 -C(O)OCl-C10垸基、氨基、 C1-C10垸氧基、 C1-C10垸基、 CI- C10 垸酰基、 C1 -C10垸酰氧基、 磺酰基、 C1-C10垸基磺酰基、 C6-C10芳基、 4-10元杂环基或 4-10元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧 基、 C1-C10烷基、 C1-C10烷氧基、 C1-C10垸酰氧基、 -C(O)OCl-C10烷基、 C1-C10垸酰 基、 磺酰基、 C1-C10烷基磺酰基、 苯基和苯甲基中的取代基取代；  And R4 are each independently H; halogen; trifluoromethyl; hydroxy; nitro; nitrile; carboxy; -C(O)OCl-C10 alkyl; amino; C1-C10 alkoxy; C1-C10 alkyl C1-C10decanoyl (ie, -C(O)Cl-C10 alkyl); C1-C10 alkanoyloxy (ie, -OC(O)Cl-C10 alkyl); decanoyl; C1-C10 mercaptosulfonate Acyl; C6-C10 aryl; 4-10 membered heterocyclic; or 4-10 membered heteroaryl; above -C(O)OCl-C10 fluorenyl, amino, C1-C10 decyloxy, C1-C10垸, CI-C10 decanoyl, C1-C10 decanoyloxy, sulfonyl, C1-C10 decylsulfonyl, C6-C10 aryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl Must be one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 nonanoyloxy, - Substituted by a substituent in C(O)OCl-C10 alkyl, C1-C10 decanoyl, sulfonyl, C1-C10 alkylsulfonyl, phenyl and benzyl;
R5和 Re各自独立地为 -(CH2)mR9 ; -(CH2)mCO(CH2)„ 9 ; 或 -[(CH^C^H, 其中 i=l~5的 整数， j=l~3的整数， R9为 H; 素； 羟基； 硝基； 氨基； 腈基； 羧基； -C(O)OCl-C10垸 基； C1-C10烷酰基； C1-C10烷基磺酰基； C1-C10烷基； C2-C10烯基； C2-C10炔基； C3-C10 环烷基； C3-C8内酰胺基； C1-C10垸氨基磺酰基； C1-C10烷氨酰基； C6-C10芳酰基； C1-C10 烷氧基； C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16; C6-C10芳基； 4-10元杂环基； 或者 4-10元杂芳基； 4-10元杂环基或 4-10元杂芳基并 C3-C10环烃基； 或者 4-10元杂环基 或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基；上述氨基、 -C(O)OCl-C10垸基、 C1-C10 垸酰基、 C1-C10垸基磺酰基、 C1-C10垸基、 C2-C10烯基、 C2-C10炔基、 C3-C10环垸基、R 5 and Re are each independently -(CH 2 ) m R 9 ; -(CH 2 ) m CO(CH 2 ) „ 9 ; or —[(CH^C^H, where i = an integer of 1 to 5, An integer of j=l~3, R 9 is H; a hydroxy group; a nitro group; an amino group; a nitrile group; a carboxyl group; a C(O)OCl-C10 fluorenyl group; a C1-C10 alkanoyl group; Acyl; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cycloalkyl; C3-C8 lactam; C1-C10 guanylaminosulfonyl; C1-C10 alkanoyl; -C10 aroyl; C1-C10 alkoxy; C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16; C6-C10 aryl; 4-10 membered heterocyclic; Or 4-10 membered heteroaryl; 4-10 membered heterocyclic or 4-10 membered heteroaryl and C3-C10 cycloalkyl; or 4-10 membered heterocyclic or 4-10 membered heteroaryl and 4- a 10-membered heterocyclic group or a 4-10 membered heteroaryl group; the above amino group, -C(O)OCl-C10 fluorenyl group, C1-C10 decanoyl group, C1-C10 decylsulfonyl group, C1-C10 fluorenyl group, C2- C10 alkenyl, C2-C10 alkynyl, C3-C10 cyclodecyl,
C3-C8内酰胺基、 C1-C10烷氨基磺酰基、 C1-C10垸氨酰基、 C6-C10芳酰基、 C1-C10烷氧 基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳基、 4-10元杂环基、 4-10 元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C3-C10环烃基或者 4-10元杂环基或 4-10元杂 芳基并 4-10元杂环基或 4-10元杂芳基可非必须地被一个或多个选自卤素、三氟甲基、羟基、 硝基、 -NR15R16、腈基、羧基、 C1-C10垸氧基、 C6-C10芳氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10 垸基、 -C(0)NR15R16、 C1-C10烷酰基、 C1-C10垸基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、、 C6-C10芳酰基、 C1-C10烷基、羟基 C1-C10垸基、氨基 C1-C10垸基、 C6-C10 芳基 C1-C10垸基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10杂芳基、 4-10元杂环基或 4-10杂芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取代 基取代； 上述 C6-C10芳基、 C6-C10芳酰基和 C6-C10芳基磺酰基可非必须地被一个或多个 选自卤素、 三氟甲基、 羟基、 硝基、 -NR15R16、 腈基、 羧基、 C1-C10垸氧基、 C1-C10垸酰 氧基、 -C(O)OCl-C10垸基、 -C(0)NR15R16、 C1-C10烷酰基、 C1-C10烷基磺酰基、 C6-C10 芳基磺酰基、 -S02NR15Ri6、 -NR15S02R16、 C6-C10芳酰基、 C1-C10烷基、羟基 C1-C10垸基、 氨基 C1-C10烷基和 C6-C10芳基 C1-C10烷基中的取代基取代； C3-C8 lactam group, C1-C10 alkylaminosulfonyl group, C1-C10 prolyl group, C6-C10 aroyl group, C1-C10 alkoxy group, C6-C10 arylsulfonyl group, -S0 2 NR 15 R 16 -NR 15 S0 2 R 16 , C6-C10 aryl, 4-10 membered heterocyclic group, 4-10 a heteroaryl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl and C3-C10 cycloalkyl group or a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group 4-10 membered heterocyclic group Or a 4-10 membered heteroaryl group may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile, carboxyl, C1-C10 decyloxy, C6 -C10 aryloxy, C1-C10 alkanoyloxy, -C(O)OCl-C10 fluorenyl, -C(0)NR 15 R 16 , C1-C10 alkanoyl, C1-C10 decylsulfonyl, C6 -C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 alkyl, hydroxy C1-C10 decyl, amino C1-C10 fluorenyl, C6-C10 aryl C1-C10 fluorenyl, =0 (oxo), =S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 heteroaryl, 4-10 Substituted by a heterocyclic group or a 4-10 heteroaryl-C6-C10 aryl group, a 4-10 membered heterocyclic acyl group and a 4-10 membered heteroaroyl group; the above C6-C10 aryl group, C6-C10 aroyl group And a C6-C10 arylsulfonyl group may optionally be one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile, carboxyl, C1-C10 decyloxy, C1 -C10垸Group, -C (O) OCl-C10 alkyl with, -C (0) NR 15 R 16, C1-C10 alkanoyl, C1-C10 alkylsulfonyl, C6-C10 arylsulfonyl group, -S0 2 NR 15 Ri 6 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 alkyl, hydroxy C1-C10 decyl, amino C1-C10 alkyl and C6-C10 aryl C1-C10 alkyl Substituent substitution;
或者， R5和 与它们相连的 X共同构成氨基葡萄糖基； 氨基酸残基； 氨基酸酯残基； 或氨基酰胺残基，且非必须地被一个或多个选自 C1-C6烷基、 C1-C6烷基取代的氨基、 C1-C10 垸酰基、 苄基、 苄氧羰基和叔丁氧羰基中的取代基取代； Alternatively, R 5 and X attached thereto form an glucosamine group; an amino acid residue; an amino acid ester residue; or an aminoamide residue, and optionally one or more selected from the group consisting of C1-C6 alkyl groups, C1- Substituted with a C6 alkyl-substituted amino group, a C1-C10 decanoyl group, a benzyl group, a benzyloxycarbonyl group, and a t-butoxycarbonyl group;
或者， R5和 与连接它们的 X—起形成 C6-C10芳基； C3-C10环烃基； C3-C10环烃 基并 C3-C10环烃基； C3-C10环烃基并 C6-C10芳基； C6-C10芳基并 C3-C10环烃基； 4-10 元杂环基； 4-10元杂芳基； 4-10元杂环基螺环； 4-10元杂芳基螺环； 4-10元杂环基或 4-10 元杂芳基并 C3-C10环烃基； C3-C10环烃基并 4-10元杂环基或 4-10元杂芳基； 4-10元杂环 基或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基； C6-C10芳基并 4-10元杂环基或 4-10 元杂芳基； 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基； [4-10元杂环基或 4-10元杂芳基] 并 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]; 或者 [4-10元杂环基 或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]并 [C6-C10芳基]; 上述基团可非必须地 被一个或多个 R'取代， R'选自 -(CH2)mR10 ; -(CH2)mCO(CH2)nR10 ; -(CH2)mO(CH2)nR10； -(CH2)mNHC(O)(CH2)nRi0； 和 -(CH2)mNSO2(CH2)nR10; Or, R 5 and X-linked to form a C6-C10 aryl group; C3-C10 cycloalkyl; C3-C10 cycloalkyl and C3-C10 cycloalkyl; C3-C10 cycloalkyl and C6-C10 aryl; C6 -C10 aryl and C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; 4-10 membered heterocyclyl spiro; 4-10 membered heteroaryl spiro; 4-10 a heterocyclic or 4-10 membered heteroaryl and C3-C10 cycloalkyl; C3-C10 cycloalkyl and 4-10 membered heterocyclic or 4-10 membered heteroaryl; 4-10 membered heterocyclyl or 4 -10 membered heteroaryl and 4-10 membered heterocyclic group or 4-10 membered heteroaryl; C6-C10 aryl and 4-10 membered heterocyclic group or 4-10 membered heteroaryl; 4-10 membered hetero a cyclic or 4-10 membered heteroaryl and C6-C10 aryl; [4-10 membered heterocyclic or 4-10 membered heteroaryl] and [4-10 membered heterocyclic or 4-10 membered heteroaryl) And [4-10 membered heterocyclic or 4-10 membered heteroaryl]; or [4-10 membered heterocyclyl or 4-10 membered heteroaryl] and [4-10 membered heterocyclyl or 4 -10 membered heteroaryl] and [C6-C10 aryl]; the above group may be optionally substituted by one or more R', and R' is selected from -(CH 2 ) m R 10 ; -(CH 2 ) m CO(CH 2 ) n R 10 ; -(CH 2 ) m O(CH 2 ) n R 10 ; -(CH 2 ) m NHC(O)(CH 2 ) n Ri 0 ; and -(CH 2 ) m NSO 2 (CH 2 ) n R 10;
其中， R1()为氢、 卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C10垸氧基、 C6-C10芳氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10垸基、 -C(0)NH2、 C1-C10烷酰基、 C1-C10 烷基磺酰基、 C6-C10 芳基磺酰基、 -S02NR15R16、 -NRi5S02R16、、 C6-C10 芳酰基、 C1-C10 垸基、羟基 C1-C10垸基、氨基 C1-C10垸基、 C6-C10芳基 C1-C10烷基、 =0 (氧代)、 =s (硫 代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10 Wherein R 1() is hydrogen, halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C10 decyloxy, C6-C10 aryloxy, C1-C10 alkanoyloxy, -C(O)OCl-C10 fluorenyl, -C(0)NH 2 , C1-C10 alkanoyl, C1-C10 alkylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , NRi 5 S0 2 R 16 , C6-C10 aroyl, C1-C10 fluorenyl, hydroxy C1-C10 fluorenyl, amino C1-C10 fluorenyl, C6-C10 aryl C1-C10 alkyl, =0 (oxo generation ), =s (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6-C10
Ph  Ph
芳基、 4-10元杂环酰基、 4-10元杂芳酰基或一 -COEt ; 上述氨基、 C1-C10烷氧基、 C6-C10 芳氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10烷基、 -C(0)NH2、 C1-C10垸酰基、 C1-C10垸基 磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、、 C6-C10芳酰基、 C1-C10垸基、 羟基 C1-C10垸基、 氨基 C1-C10垸基、 C6-C10芳基 C1-C10垸基、 C6-C10芳基、 4-10元杂 环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基、 Aryl, 4-10 membered heterocyclic acyl, 4-10 membered heteroaroyl or mono-COEt ; above amino, C1-C10 alkoxy, C6-C10 aryloxy, C1-C10 alkanoyloxy, -C (O)OCl-C10 alkyl, -C(0)NH 2 , C1-C10 decanoyl, C1-C10 decylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 fluorenyl, hydroxy C1-C10 fluorenyl, amino C1-C10 fluorenyl, C6-C10 aryl C1-C10 fluorenyl, C6-C10 aryl, 4 a 10-membered heterocyclic group, a 4-10 membered heteroaryl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, a C6-C10 aryl group, a 4-10 membered heterocyclic acyl group,
Ph  Ph
4-10元杂芳酰基或一l^-COEt可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 -NR15R16、 腈基、 羧基、 C1-C10 氧基、 C6-C10芳氧基、 C1-C10垸酰氧基、 -C(O)OCl-C10 垸基、 -C(0)NR15Ri6、 C1-C10烷酰基、 C1-C10烷基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 - R15S02R16、 C6-C10芳酰基、 Cl-ClO烷基、羟基 Cl-ClO烷基、氨基 C1-C10院基、 C6-C10 芳基 C1-C10垸基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取 代基取代； The 4-10 membered heteroaroyl group or a group of 1 -COEt may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile, carboxyl, C1-C10 Oxy, C6-C10 aryloxy, C1-C10 decanoyloxy, -C(O)OCl-C10 fluorenyl, -C(0)NR 15 Ri6, C1-C10 alkanoyl, C1-C10 alkyl sulfonate Acyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , - R 15 S0 2 R 16 , C6-C10 aroyl, Cl-ClO alkyl, hydroxy-Cl-ClO alkyl, amino C1-C10, C6-C10 aryl C1-C10 fluorenyl, =0 (oxo ), =S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6-C10 a substituent in the aryl group, a 4-10 membered heterocyclic acyl group, and a 4-10 membered heteroaroyl group;
RI5、 R16各自独立地为 H; C1-C10烷基； C3-C10环烷基； 4-10元杂环基； 4-10元杂芳 基； 或者 R15、 R16与连接它们的 N原子一起形成 4-10元杂环基； 4-10元杂芳基； 其中， 所 述 C1-C10垸基、 C3-C10环烷基、 4-10元杂环基和 4-10元杂芳基可非必须地被 1个或多个 卤素； 羟基； 腈基； 氨基； C1-C10垸基； =0 (氧代)； =S (硫代)； C1-C10垸氧基取代；
Figure imgf000125_0001
-(CH2)mO(CH2)„Rn或 -(CH2)mNHR11 ; R I5 and R 16 are each independently H; C1-C10 alkyl; C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and attached thereto The N atoms together form a 4-10 membered heterocyclic group; a 4-10 membered heteroaryl group; wherein, the C1-C10 fluorenyl group, the C3-C10 cycloalkyl group, the 4-10 membered heterocyclic group, and the 4-10 membered heterocyclic group; The aryl group may optionally be substituted by one or more halogens; a hydroxyl group; a nitrile group; an amino group; a C1-C10 fluorenyl group; =0 (oxo); =S (thio); a C1-C10 decyloxy group;
Figure imgf000125_0001
-(CH 2 ) m O(CH 2 )„R n or -(CH 2 ) m NHR 11 ;
其中， Ru为 H; 卤素； 硝基； 腈基； 羧基； -C(O)OCl-C10烷基； C2-C10烯基； C2-C10 炔基； C1-C10烷酰基； C1-C10垸基磺酰基； 氨基 C1-C10烷酰基； C1-C10垸基； C6-C10 芳基； 4-10元杂环基； 或 4-10元杂芳基； 上述 -C(O)OCl-C10烷基、 C2-C10烯基、 C2-C10 炔基、 C1-C10烷酰基、 C1-C10垸基磺酰基、 氨基 C1-C10垸酰基、 C1-C10垸基、 C6-C10 芳基、 4-10元杂环基或 4-10元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 氨基、腈基、羧基、 C1-C10垸氧基、 C1-C10垸酰氧基、 -C(O)OCl-C10烷基、 C1-C10 垸酰基、 C1-C10焼基磺酰基、 =0 (氧代)、 =S (硫代)和 C1-C10烷基中的取代基取代；Wherein R u is H; halogen; nitro; nitrile; carboxyl; -C(O)OCl-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C1-C10 alkanoyl; C1-C10垸Alkylsulfonyl; amino C1-C10 alkanoyl; C1-C10 alkyl; C6-C10 aryl; 4-10 membered heterocyclyl; or 4-10 membered heteroaryl; above -C(O)OCl-C10 , C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkanoyl, C1-C10 decylsulfonyl, amino C1-C10 decanoyl, C1-C10 decyl, C6-C10 aryl, 4-10 The heterocyclic or 4-10 membered heteroaryl may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C10 decyloxy, C1. -C10 nonanoyloxy, -C(O)OCl-C10 alkyl, C1-C10 decanoyl, C1-C10 decylsulfonyl, =0 (oxo), =S (thio) and C1-C10 alkane a substituent in the group;
R8为 _(CH2)mR12、 -(CH2)mO(CH2)„R12或 -(CH2)mNHR12; R 8 is _(CH 2 ) m R 12 , -(CH 2 ) m O(CH 2 )„R 12 or —(CH 2 ) m NHR 12;
其中， R12为 H; 卤素； 硝基； 腈基； 羧基； =0 (氧代)； =S (硫代)； -C(O)OCl-C10 烷基； C2-C10烯基； C2-C10炔基； C1-C10垸酰基； C1-C10垸基磺酰基； 氨基 C1-C10垸 酰基； C1-C10烷基； Ph(CH2)m -; s^ . 4-10元杂环基； 或 4-10元杂芳基； 上述Wherein R 12 is H; halogen; nitro; nitrile; carboxyl; =0 (oxo); =S (thio); -C(O)OCl-C10 alkyl; C2-C10 alkenyl; C10 alkynyl; C1-C10 decanoyl; C1-C10 decylsulfonyl; amino C1-C10 decanoyl; C1-C10 alkyl; Ph(CH 2 ) m -; s^. 4-10 membered heterocyclic; Or 4-10 membered heteroaryl;
-C(O)OCl-C10垸基、 C2-C10烯基、 C2-C10炔基、 C1-C10烷酰基、 C1-C10垸基磺酰基、 氨基 C1-C10垸酰基、 C1-C10烷基、 Ph(CH2)m-、 s 、
Figure imgf000125_0002
4-10元杂环基或 4-10元杂 芳基可非必须地被一个或多个选自卤素、三氟甲基、羟基、硝基、氨基、腈基、羧基、 C1-C10 垸氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10垸基、 C1-C10垸酰基、 C1-C10浣基磺酰基、 = 0 (氧代)、 =S (硫代)、 C1-C10烷基中的取代基取代； -C(O)OCl-C10 fluorenyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkanoyl, C1-C10 decylsulfonyl, amino C1-C10 decanoyl, C1-C10 alkyl, Ph(CH 2 ) m -, s ,
Figure imgf000125_0002
The 4-10 membered heterocyclic group or the 4-10 membered heteroaryl group may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxyl, C1-C10 oxirane. , C1-C10 alkanoyloxy, -C(O)OCl-C10 fluorenyl, C1-C10 decanoyl, C1-C10 decylsulfonyl, = 0 (oxo), =S (thio), C1 a substituent in a -C10 alkyl group;
各 m和各 n各自独立地为 0-5的整数；  Each m and each n are each independently an integer from 0 to 5;
q为 0-4的整数。  q is an integer from 0-4.
2、 根据权利要求 1所述的 β-氨基羰基类化合物或其互变异构体、 对映体、 消旋体或其 药学上可接受的盐， 其特征在于， 具有以下一个或多个特征- The β-aminocarbonyl compound or a tautomer thereof, an enantiomer, a racemate thereof or a pharmaceutically acceptable salt thereof according to claim 1, which has one or more of the following characteristics -
(1) Α为 C6-C10芳基、饱和或不饱和 C3-C10环烃基、 4-10元杂芳基； 所述 4-10元杂芳 基含有 1-4个选自 N、 S和 Ο中的杂原子； (1) Α is a C6-C10 aryl, saturated or unsaturated C3-C10 cycloalkyl, 4-10 membered heteroaryl; the 4-10 membered heteroaryl contains 1-4 selected from N, S and Ο Heteroatoms in
(2) R! R2、 R3和 R4各自独立地为 H、 卤素、 三氟甲基、 羟基、 硝基、 腈基、 羧基、 氨 基、 C1-C10垸氧基、 C1-C10烷基; (2) R! R 2 , R 3 and R 4 are each independently H, halogen, trifluoromethyl, hydroxy, nitro, nitrile, carboxy, amino, C1-C10 decyloxy, C1-C10 alkyl;
(3) R8为-^!!^!^、 -(CH2)mO(CH2)nR12或 -(CH2)mNHR12 ; 其中， R12为 H、 卤素、 (3) R 8 is -^!!^!^, -(CH 2 ) m O(CH 2 ) n R 12 or -(CH 2 ) m NHR 12 ; wherein R 12 is H, halogen,
Ph(CH2)m -、 °^^、 4-10元杂环基、 =0 (氧代)、 =S (硫代)、 C1-C10垸基； 以上 Ph(CH2)m -、 Ph(CH 2 ) m -, °^^, 4-10 membered heterocyclic group, =0 (oxo), =S (thio), C1-C10 fluorenyl; above Ph(CH 2 ) m -,
4-10元杂环基、 C1-C10烷基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C10垸氧基、 =0 (氧代)、 = S (硫代)、 C1-C10烷基中的取代 基取代； The 4-10 membered heterocyclic group, C1-C10 alkyl group may optionally be one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, Nitro, amino, nitrile, carboxyl, C1-C10 decyloxy, =0 (oxo), = S (thio), substituted with a C1-C10 alkyl group;
(4) Y为 N或 CR7， 其中， R7为 -(CH2)mRu、 -(CI^ C CHARu或-(〇¾)„^1 1 11 ; 其中， n ¾ H, C6-C10芳基、 4-10元杂环基、 羧基、 氨基 C1-C10垸酰基、 -C(O)OCl-C10烷基、 卤素、 硝基或 4-10元杂芳基； 上述 C6-C10芳基、 4-10元杂环基、 氨基 C1-C10垸酰基、(4) Y is N or CR 7 , wherein R 7 is -(CH 2 ) m R u , -(CI^ C CHARu or -(〇3⁄4)„^1 1 11 ; wherein, n 3⁄4 H, C6- C10 aryl, 4-10 membered heterocyclic group, carboxy group, amino C1-C10 decanoyl group, -C(O)OCl-C10 alkyl group, halogen, nitro group or 4-10 membered heteroaryl group; above C6-C10 aryl Base, 4-10 membered heterocyclic group, amino C1-C10 decanoyl group,
-C(O)OCl-C10垸基、或 4-10元杂芳基可非必须地被一个或多个选自卤素、三氟甲基、羟基、 =0 (氧代)、 =S (硫代)、 C1-C10烷基、 C1-C10垸氧基硝基、 和氨基中的取代基取代；-C(O)OCl-C10 fluorenyl, or 4-10 membered heteroaryl may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, =0 (oxo), =S (sulfur Substituted, substituted with a C1-C10 alkyl group, a C1-C10 methoxy nitro group, and an amino group;
(5) X为 N或 CR7; 其中， R7为 -(CH mRu, 其中， Ru为 H， m为 0; (5) X is N or CR 7; wherein R 7 is -(CH mRu, wherein R u is H and m is 0;
(6) 和 各自独立地为 -(CH2)mR9; -(CH2)mCO(CH2)nR9;或 -[(CH^C^H,其中 R9为 H、 C6-C10芳基、 4-10元杂环基、 C1-C10烷基、 C2-C10烯基、 4-10杂芳基、 C1-C10垸酰基、(6) and each independently are -(CH 2 ) m R 9; -(CH 2 ) m CO(CH 2 ) n R 9; or -[(CH^C^H, where R 9 is H, C6- C10 aryl, 4-10 membered heterocyclic group, C1-C10 alkyl group, C2-C10 alkenyl group, 4-10 heteroaryl group, C1-C10 decanoyl group,
C3-C8内酰胺基、 4-10元杂环基或 4-10元杂芳基并 C3-C10环经基、 4-10元杂环基或 4-10 元杂芳基并 4-10元杂环基或 4-10元杂芳基； a C3-C8 lactam group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group and a C3-C10 cycloalkyl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group and 4-10 members. a heterocyclic group or a 4-10 membered heteroaryl group;
上述 C6-C10芳基、 4-10元杂环基、 4-10杂芳基、 C1-C10垸基、 C2-C10烯基、 C1-C10 烷酰基、 C3-C8内酰胺基、 4-10元杂环基或 4-10元杂芳基并 C3-C10环烃基、 4-10元杂环基 或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基可非必须地被一个或多个选自 4-10元杂 环基、 腈基、 羧基、 C1-C10院基、 =0 (氧代)、 = S (硫代)、 C6-C10芳基、 卤素、 三氟甲基、 -C(O)OCl-C10烷基、 -C(0)NR15R16、 -S02 R15R16、 - 15R16、 -NR15S02Ri6、 C1-C10烷基磺 酰基、 羟基中的取代基取代； The above C6-C10 aryl, 4-10 membered heterocyclic group, 4-10 heteroaryl group, C1-C10 fluorenyl group, C2-C10 alkenyl group, C1-C10 alkanoyl group, C3-C8 lactam group, 4-10 A heterocyclic group or a 4-10 membered heteroaryl and C3-C10 cycloalkyl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group. Optionally, one or more selected from the group consisting of 4-10 membered heterocyclyl, nitrile, carboxyl, C1-C10, =0 (oxo), =S (thio), C6-C10 aryl, Halogen, trifluoromethyl, -C(O)OCl-C10 alkyl, -C(0)NR 15 R 16 , -S0 2 R 15 R 16 , - 15 R 16 , -NR 15 S0 2 Ri 6 , C1 a -C10 alkylsulfonyl group, a substituent in the hydroxy group;
(7) R5和 与它们相连的 X共同构成氨基葡萄糖基； 氨基酸残基； 氨基酸酯残基； 或 氨基酰胺残基， 且非必须地被一个或多个选自 C1-C6垸基、 C1-C6垸基取代的氨基、 C1-C10 烷酰基、 苄基、 苄氧羰基和叔丁氧羰基中的取代基取代； (7) R 5 and X attached thereto constitute a glucosyl group; an amino acid residue; an amino acid ester residue; or an amino amide residue, and optionally one or more selected from the group consisting of C1-C6 fluorenyl, C1 Substituted with a substituent in the C6 mercapto substituted amino group, a C1-C10 alkanoyl group, a benzyl group, a benzyloxycarbonyl group and a tert-butoxycarbonyl group;
(8) R5和 与连接它们的 X—起形成 4-10元杂环基或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基、 4-10元杂环基、 C6-C10芳基并 4-10元杂环基或 4-10元杂芳基、 C6-C10芳 基、 C3-C10环烃基、 C3-C10环烃基并 C3-C10环烃基、 C3-C10环烃基并 C6-C10芳基、 C6-C10 芳基并 C3-C10环烃基、 4-10元杂芳基、 4-10元杂环基螺环、 4-10元杂芳基螺环、 4-10元杂 环基或 4-10元杂芳基并 C3-C10环烃基、 C3-C10环烃基并 4-10元杂环基或 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 [4-10元杂环基或 4-10元杂芳基]并 [4-10元 杂环基或 4_10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]、 或者 [4-10元杂环基或 4-10元 杂芳基]并 [4-10元杂环基或 4-10元杂芳基]并 [C6-C10芳基]; 上述基团可非必须地被一个或 多个 R，取代 ， R，选 自 -(CH2)mR10 ； -(CH2)mCO(CH2)nR10 ； -(CH2)mO(CH2)nR10 ；(8) R 5 and X-linked to form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group and a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, 4-10 members Heterocyclyl, C6-C10 aryl and 4-10 membered heterocyclic or 4-10 membered heteroaryl, C6-C10 aryl, C3-C10 cycloalkyl, C3-C10 cycloalkyl and C3-C10 cycloalkyl, C3-C10 cycloalkyl and C6-C10 aryl, C6-C10 aryl and C3-C10 cycloalkyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl spiro, 4-10 membered heteroaryl snail Ring, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C3-C10 cycloalkyl, C3-C10 cycloalkyl and 4-10 membered heterocyclic or 4-10 membered heteroaryl, 4-10 membered Heterocyclyl or 4-10 membered heteroaryl and C6-C10 aryl, [4-10 membered heterocyclyl or 4-10 membered heteroaryl] and [4-10 membered heterocyclyl or 4-10 membered heteroaryl) And [4-10 membered heterocyclic or 4-10 membered heteroaryl], or [4-10 membered heterocyclyl or 4-10 membered heteroaryl] and [4-10 membered heterocyclyl or 4- 10 membered heteroaryl] and [C6-C10 aryl]; the above group may be optionally substituted by one or more R, R, selected from -(CH 2 ) m R 10 ; -(CH 2 ) m CO(CH 2 ) n R 10 ; -(CH 2 ) m O(CH 2 ) n R 10 ;
-(CH2)mNHC(0)(CH2)nRlo; 和 -(CH2)mNSO2(CH2)nR10; 其中， -(CH 2 ) m NHC(0)(CH 2 ) n R lo; and -(CH 2 ) m NSO 2 (CH 2 ) n R 10; wherein
R10为氢、 卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C10垸氧基、 C6-C10 芳氧基、 C1-C10垸酰氧基、 -C(O)OCl-C10烷基、 -C(0)NH2、 C1-C10垸酰基、 C1-C10垸基 磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C10垸基、 羟基 C1-C10垸基、 氨基 C1-C10烷基、 C6-C10芳基 C1-C10垸基、 =0 (氧代)、 = S (硫代)、R 10 is hydrogen, halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C10 decyloxy, C6-C10 aryloxy, C1-C10 nonanoyloxy, -C(O OCl-C10 alkyl, -C(0)NH 2 , C1-C10 decanoyl, C1-C10 decylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 fluorenyl, hydroxy C1-C10 fluorenyl, amino C1-C10 alkyl, C6-C10 aryl C1-C10 fluorenyl, =0 (oxo), = S ( Thio),
C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳 C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6-C10
Ph  Ph
基、 4-10元杂环酰基、 4-10元杂芳酰基或一 - COB ; 上述氨基、 C1_C10垸氧基、 C6— C10 芳氧基、 C1-C10垸酰氧基、 -C(O)OCl-C10垸基、 -C(0)NH2、 C1-C10垸酰基、 C1-C10垸基 磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C10烷基、 羟基 C1-C10烷基、 氨基 C1-C10垸基、 C6-C10芳基 C1-C10烷基、 C6-C10芳基、 4-10元杂 环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基、 Group, a 4-10 membered heterocyclic group, 4-10 membered heteroaryl, or a group - COB; of the amino, C1 _ C10 embankment group, C6 - C10 aryloxy group, C1-C10 acyloxy embankment, -C ( O) OCl-C10 fluorenyl, -C(0)NH 2 , C1-C10 decanoyl, C1-C10 decylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 alkyl, Hydroxy C1-C10 alkyl, amino C1-C10 alkyl, C6-C10 aryl C1-C10 alkyl, C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 a heterocyclic group or a 4-10 membered heteroaryl-C6-C10 aryl group, a 4-10 membered heterocyclic acyl group,
Ph  Ph
4-10元杂芳酰基或一^! -COB可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 -NR15R16、 腈基、 羧基、 C1-C10烷氧基、 C6-C10芳氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10 烷基、 -C(0)NR15R16、 C1-C10烷酰基、 C1-C10烷基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、4-10 membered heteroaroyl or mono-! -COB may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile, carboxyl, C1-C10 Alkoxy, C6-C10 aryloxy, C1-C10 alkanoyloxy, -C(O)OCl-C10 alkyl, -C(0)NR 15 R 16 , C1-C10 alkanoyl, C1-C10 alkane Sulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 ,
- R15S02R16、 C6-C10芳酰基、 C1-C10烷基、羟基 C1-C10垸基、氨基 C1-C10烷基、 C6-C10 芳基 C1-C10垸基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取 代基取代； - R 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 alkyl, hydroxy C1-C10 decyl, amino C1-C10 alkyl, C6-C10 aryl C1-C10 decyl, =0 (oxo ), =S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6-C10 a substituent in the aryl group, a 4-10 membered heterocyclic acyl group, and a 4-10 membered heteroaroyl group;
R15、 R16各自独立地为 H; C1-C10烷基； C3-C10环烷基； 4-10元杂环基； 4-10元杂芳 基； 或者 R15、 R16与连接它们的 N原子一起形成 4-10元杂环基； 4-10元杂芳基； 其中， 所 述 C1-C10烷基、 C3-C10环烷基、 4-10元杂环基和 4-10元杂芳基可非必须地被 1个或多个 卤素； 羟基； 腈基； 氨基； C1-C10烷基； =o (氧代)； =S (硫代)； C1-C10烷氧基取代。 R 15 and R 16 are each independently H; C1-C10 alkyl; C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and attached thereto The N atoms together form a 4-10 membered heterocyclic group; a 4-10 membered heteroaryl group; wherein, the C1-C10 alkyl group, the C3-C10 cycloalkyl group, the 4-10 membered heterocyclic group, and the 4-10 membered heterocyclic group; The aryl group may optionally be substituted by one or more halogens; hydroxy; nitrile; amino; C1-C10 alkyl; = o (oxo); =S (thio);
3、 根据权利要求 2所述的 β-氨基羰基类化合物或其互变异构体、 对映体、 消旋体或其 药学上可接受的盐， 其特征在于， 具有以下一个或多个特征：  The β-aminocarbonyl compound or a tautomer thereof, an enantiomer, a racemate thereof or a pharmaceutically acceptable salt thereof according to claim 2, which has one or more of the following characteristics :
(1) Α为苯基、 吡啶基或环戊二烯基；  (1) Α is phenyl, pyridyl or cyclopentadienyl;
(2) Ri, R2、 和 1^各自独立地为 H、 卤素、 三氟甲基、 羟基、 腈基、 氨基、 C1-C10 院基； (2) Ri, R 2 , and 1 are each independently H, halogen, trifluoromethyl, hydroxy, nitrile, amino, C1-C10;
(3) W为 CH;  (3) W is CH;
(4) Q为 C;  (4) Q is C;
(5) R8为 -(CH2)mR12; 其中， 2为11、 卤素、 C1-C10垸基; q为 0-4的整数； m为 0-5 的整数； (5) R 8 is -(CH 2 ) m R 12; wherein 2 is 11, halogen, C1-C10 fluorenyl; q is an integer from 0 to 4; m is an integer from 0 to 5;
(6) Y为 CR7， 其中， R7为- (CH2)mRu， ！^为！!、 卤素， m为 0-5的整数。 (6) Y is CR 7 , where R 7 is - (CH 2 ) m R u , ! ^For! !, halogen, m is an integer from 0-5.
4、 根据权利要求 1~3所述的 β-氨基羰基类化合物或其互变异构体、 对映体、 消旋体或 其药学上可接受的盐， 其中， 的化合物：  The β-aminocarbonyl compound or a tautomer thereof, an enantiomer, a racemate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein:
Figure imgf000127_0001
Figure imgf000127_0001
其中， 、 R2、 R3、 R4、 R5、 、 R8、 X和 q的定义同其在通式 I中的定义； Wherein, R 2 , R 3 , R 4 , R 5 , R 8 , X and q are as defined in the formula I;
R7为 -(CH2)mRu、 -(CH2)mO(CH2)nR„或 -(CP^ NHRu； R 7 is -(CH 2 ) m R u , -(CH 2 ) m O(CH 2 ) n R„ or -(CP^ NHRu;
其中， Ru为 H; 卤素； 硝基； 腈基； 羧基； -C(0)OCl-C4垸基； C2-C4烯基； C2-C4 炔基； C1-C4垸酰基； C1-C4垸基磺酰基； 氨基 C1-C4烷酰基； C1-C4院基； C6-C10芳基；Wherein, R u is H; halogen; nitro; nitrile; carboxyl; -C(0)OCl-C4 fluorenyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 nonanoyl; C1-C4垸Alkylsulfonyl; amino C1-C4 alkanoyl; C1-C4 ortho; C6-C10 aryl;
4-10元杂环基；或 4-10元杂芳基；上述 -C(0)OCl-C4垸基、 C2-C4烯基、 C2-C4炔基、 C1-C4 垸酰基、 C1-C4烷基磺酰基、 氨基 C1-C4烷酰基、 C1-C4垸基、 C6-C10芳基、 4-10元杂环 基或 4-10元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈 基、 羧基、 C1-C4垸氧基、 C1-C4烷酰氧基、 -C(0)OCl-C4烷基、 C1-C4烷酰基、 C1-C4烷 基磺酰基、 =0 (氧代)、 = S (硫代)和 C1-C4烷基中的取代基取代； 4-10 membered heterocyclic group; or 4-10 membered heteroaryl; above -C(0)OCl-C4 fluorenyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 Decanoyl, C1-C4 alkylsulfonyl, amino C1-C4 alkanoyl, C1-C4 fluorenyl, C6-C10 aryl, 4-10 membered heterocyclyl or 4-10 membered heteroaryl may be optionally One or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C4 decyloxy, C1-C4 alkanoyloxy, -C(O)OCl-C4 alkyl a C1-C4 alkanoyl group, a C1-C4 alkylsulfonyl group, a substituent substituted in the =0 (oxo), =S (thio) and C1-C4 alkyl groups;
m和 n各自独立地为 0-5的整数。  m and n are each independently an integer of 0-5.
5、 根据权利要求 4所述的 β-氨基羰基类化合物或其互变异构体、 对映体、 消旋体或其 药学上可接受的盐， 其中， 通式 ΙΑ所示的化合物为通式 IB所示的化合物：  The β-aminocarbonyl compound or a tautomer thereof, an enantiomer, a racemate thereof or a pharmaceutically acceptable salt thereof according to claim 4, wherein the compound represented by the formula 为 is a pass. Compounds of formula IB:
Figure imgf000128_0001
Figure imgf000128_0001
其中，  among them,
X为 N或 CR7; X is N or CR 7 ;
Ri, R2、 R3和 R4各自独立地优选为 H; 卤素； 三氟甲基； 羟基； 硝基； 腈基； 羧基； -C(0)OCl-C4烷基； 氨基； C1-C4垸氧基； C1-C4烧基； C1-C4烷酰基； C1-C4烷酰氧基； 磺酰基； 或 C1-C4烷基磺酰基； 上述 -C(0)OCl-C4垸基、氨基、 C1-C4烷氧基、 C1-C4烷基、 C1-C4垸酰基、 C1-C4烷酰氧基、磺酰基或 C1-C4垸基磺酰基可非必须地被一个或多个选自 卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C4烷基、 C1-C4垸氧基、 C1-C4院 酰氧基、 -C(0)OCl-C4烷基、 C1-C4烷酰基、 磺酰基、 C1-C4烷基磺酰基、 苯基或苯甲基中 的取代基取代； Ri, R 2 , R 3 and R 4 are each independently preferably H; halogen; trifluoromethyl; hydroxy; nitro; nitrile; carboxy; -C(0)OCl-C4 alkyl; amino; C1-C4垸Alkyl; C1-C4 alkyl; C1-C4 alkanoyl; C1-C4 alkanoyloxy; sulfonyl; or C1-C4 alkylsulfonyl; -C(0)OCl-C4 fluorenyl, amino, C1 -C4 alkoxy, C1-C4 alkyl, C1-C4 decanoyl, C1-C4 alkanoyloxy, sulfonyl or C1-C4 mercaptosulfonyl may optionally be selected from one or more selected from the group consisting of halogen, three Fluoromethyl, hydroxy, nitro, amino, nitrile, carboxyl, C1-C4 alkyl, C1-C4 decyloxy, C1-C4 acyloxy, -C(0)OCl-C4 alkyl, C1- Substituted with a substituent in a C4 alkanoyl group, a sulfonyl group, a C1-C4 alkylsulfonyl group, a phenyl group or a benzyl group;
R5和 各自独立地为 -(CH2)raR9; -(CH2)mCO(CH2)„R9; 或 -[(CH2),0]」H， 其中 1=为 1~5 的整数， j=l~3的整数， R9为 H; [¾素； 羟基； 硝基； 氨基； 腈基； 羧基； -C(0)OCl-C4垸 基； C1-C4垸酰基； C1-C4烷基磺酰基； C1-C4垸基； C2-C4晞基； C2-C4炔基； C3-C10环 烷基； C3-C8 内酰胺基； C1-C4垸氨基磺酰基； C1-C4垸氨酰基； C6-C10芳酰基； C1-C4 垸氧基； C6-C10芳基磺酰基； -S02 R15R16; -NR15S02R16; C6-C10芳基； 4-10元杂环基； 4-10元杂芳基； 4-10元杂环基或 4-10元杂芳基并 C3-C8环烃基； 或者 4-10元杂环基或 4-10 元杂芳基并 4-10元杂环基或 4-10元杂芳基； 上述氨基、 -C(0)OCl-C4烷基、 C1-C4垸酖基、 C1-C4烷基磺酰基、 C1-C4垸基、 C2-C4稀基、 C2-C4炔基、 C3-C10环垸基、 C3-C8内酰胺 基、 C1-C4烷氨基磺酰基、 C1-C4垸氨酰基、 C6-C10芳酰基、 C1-C4垸氧基、 C6-C10芳基 磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10 元杂环基、 4-10元杂芳基并 C3-C8环烃基或者 4-10元杂环基或 4-10元杂芳基并 4-10元杂 环基或 4-10元杂芳基可非必须地被一个或多个选自卤素、三氟甲基、羟基、硝基、 -NR15R16、 腈基、 羧基、 C1-C4垸氧基、 -C(0)OCl-C4烷基、 -C(0)NR15R16、 C1-C4垸酰基、 C1-C4院 基磺酰基、 -S02NR15R16、 -NR15S02R16、 C1-C4烷基、 羟基 C1-C4烷基、 氨基 C1-C4垸基、 C6-C10芳基 C1-C4垸基、 =0 (氧代)、 = S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元 杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰 基中的取代基取代； 上述 C6-C10芳基、 C6-C10芳酰基和 C6-C10芳基磺酰基可非必须地被 一个或多个选自卤素、三氟甲基、羟基、硝基、 - R15R16、腈基、羧基、 C1-C4烷氧基、 C1-C4 垸酰氧基、 -C(0)OCl-C4垸基、 -C(0)NR15R16、 C1-C4烷酰基、 C1-C4垸基磺酰基、 C6-C10 芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C4烷基、 羟基 C1-C4垸基、 氨基 C1-C4烷基和 C6-C10芳基 C1-C4烷基中的取代基取代； R 5 and each independently are -(CH 2 ) ra R 9; -(CH 2 ) m CO(CH 2 )„R 9 ; or —[(CH 2 ),0]”H, where 1= is 1~ An integer of 5, an integer of j=l~3, R 9 is H; [3⁄4素; hydroxy; nitro; amino; nitrile; carboxy; -C(0)OCl-C4 fluorenyl; C1-C4 decanoyl; C1-C4 alkylsulfonyl; C1-C4 fluorenyl; C2-C4 fluorenyl; C2-C4 alkynyl; C3-C10 cycloalkyl; C3-C8 lactam; C1-C4 guanylaminosulfonyl; C4 valyl; C6-C10 aroyl; C1-C4 decyloxy; C6-C10 arylsulfonyl; -S0 2 R 15 R 16; -NR 15 S0 2 R 16; C6-C10 aryl; 10 membered heterocyclic group; 4-10 membered heteroaryl; 4-10 membered heterocyclic group or 4-10 membered heteroaryl and C3-C8 cyclic hydrocarbon group; or 4-10 membered heterocyclic group or 4-10 membered hetero Aryl and 4-10 membered heterocyclic or 4-10 membered heteroaryl; above amino, -C(0)OCl-C4 alkyl, C1-C4 alkyl, C1-C4 alkylsulfonyl, C1- C4 thiol, C2-C4 dilute, C2-C4 alkynyl, C3-C10 cyclodecyl, C3-C8 lactam, C1-C4 alkylsulfonyl, C1-C4 prolyl, C6-C10 aroyl , C1-C4 decyloxy, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, 4-10 membered heteroaryl and C3-C8 cycloalkyl or 4 a -10 membered heterocyclic group or a 4-10 membered heteroaryl group and a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, Nitro, -NR 15 R 16 , nitrile group, carboxyl group, C1-C4 decyloxy group, -C(0)OCl-C4 alkyl group, -C(0)NR 15 R 16 , C1-C4 decanoyl group, C1- C4-based sulfonyl group, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C1-C4 alkyl group, hydroxy C1-C4 alkyl group, amino C1-C4 fluorenyl group, C6-C10 aryl group C1-C4 Sulfhydryl, =0 (oxo), = S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 Substituent substitution in a heteroaryl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl and C6-C10 aryl group, a 4-10 membered heterocyclic acyl group and a 4-10 membered heteroaroyl group; The C10 aryl group, the C6-C10 aroyl group and the C6-C10 arylsulfonyl group may optionally be one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -R 15 R 16 , nitrile, carboxyl , C1-C4 alkoxy, C1-C4 nonanoyloxy, -C(0)OCl-C4 fluorenyl, -C(0)NR15R16, C1-C4 alkanoyl, C1-C4 decylsulfonyl, C6- C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C4 alkyl, hydroxy C1-C4 fluorenyl, amino C1-C4 alkyl and C6- Substituent substitution in a C10 aryl C1-C4 alkyl group;
或者， R5和 Re与连接它们的 X—起形成 C6-C10芳基； C3-C10环烃基； C3-C10环烃 基并 C3-C10环烃基； C3-C10环烃基并 C6-C10芳基； C6-C10芳基并 C3-C10环烃基； 4-10 元杂环基； 4-10元杂芳基； 4-10元杂环基螺环； 4-10元杂芳基螺环； 4-10元杂环基或 4-10 元杂芳基并 C3-C10环烃基； C3-C10环烃基并 4-10元杂环基或 4-10元杂芳基； 4-10元杂环 基或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基； C6-C10芳基并 4-10元杂环基或 4-10 元杂芳基； 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基； [4-10元杂环基或 4-10元杂芳基] 并 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]; 或者 [4-10元杂环基 或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]并 [C6-C10芳基]; 上述基团可非必须地 被一个或多个 R'取代， R'选自 -(CH^Ru) ; -(CH2)mCO(CH2)n 10 ; -(CH2)mO(CH2)n 10； -(CH2)m HC(0)(CH2)nR, 0； 和 -(CH2)mNSO2(C¾)nR10； Or, R 5 and Re together with the X to which they are bonded form a C6-C10 aryl group; a C3-C10 cycloalkyl group; a C3-C10 cycloalkyl group and a C3-C10 cycloalkyl group; a C3-C10 cycloalkyl group and a C6-C10 aryl group; C6-C10 aryl and C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; 4-10 membered heterocyclyl spiro; 4-10 membered heteroaryl spiro; 4- a 10-membered heterocyclic group or a 4-10 membered heteroaryl group and a C3-C10 cycloalkyl group; a C3-C10 cycloalkyl group and a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group; a 4-10 membered heterocyclic group or 4-10 membered heteroaryl and 4-10 membered heterocyclic group or 4-10 membered heteroaryl; C6-C10 aryl and 4-10 membered heterocyclic group or 4-10 membered heteroaryl; 4-10 membered Heterocyclyl or 4-10 membered heteroaryl and C6-C10 aryl; [4-10 membered heterocyclic or 4-10 membered heteroaryl] and [4-10 membered heterocyclic or 4-10 membered hetero Aryl]and [4-10 membered heterocyclic or 4-10 membered heteroaryl]; or [4-10 membered heterocyclyl or 4-10 membered heteroaryl] and [4-10 membered heterocyclyl or 4-10 membered heteroaryl] and [C6-C10 aryl]; the above group may be optionally substituted by one or more R', and R' is selected from -(CH^Ru); -(CH 2 ) m CO(CH 2 ) n 10 ; -(CH 2 ) m O(CH 2 ) n 10 ; -(CH 2 ) m HC(0)(CH 2 ) n R, 0 ; and -(CH 2 ) m NSO 2 (C3⁄4) n R 10 ;
其中， Ru)为氢、 卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C4垸氧基、 C6-C10芳氧基、 C1-C4垸酰氧基、 -C(0)OCl-C4垸基、 -C(0)NH2、 C1-C4垸酰基、 C1-C4 垸基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C4垸 基、羟基 C1-C4烷基、氨基 C1-C4垸基、 C6-C10芳基 C1-C4垸基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳 Wherein Ru) is hydrogen, halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C4 decyloxy, C6-C10 aryloxy, C1-C4 nonanoyloxy, -C (0) OCl-C4 fluorenyl, -C(0)NH 2 , C1-C4 decanoyl, C1-C4 decylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C4 fluorenyl, hydroxy C1-C4 alkyl, amino C1-C4 fluorenyl, C6-C10 aryl C1-C4 fluorenyl, =0 (oxo), = S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6-C10
Ph  Ph
基、 4-10元杂环酰基、 4-10元杂芳酰基或一l^-COEt ; 上述氨基、 C1-C4垸氧基、 C6-C10芳 氧基、 C1-C4垸酰氧基、 -C(0)0C1-C4垸基、 -C(0)NH2、 C1-C4垸酰基、 C1-C4垸基磺酰基、 C6-C10芳基磺酰基、 -S02 R15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C4垸基、羟基 C1-C4 垸基、 氨基 C1-C4烷基、 C6-C10芳基 C1-C4烷基、 C6-C10芳基、 4-10元杂环基、 4-10元 杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基、 4-10元杂芳酰 Ph a 4-10 membered heterocyclic acyl group, a 4-10 membered heteroaroyl group or a 1,4-COEt ; the above amino group, C1-C4 decyloxy group, C6-C10 aryloxy group, C1-C4 nonanoyloxy group, - C(0)0C1-C4 fluorenyl, -C(0)NH 2 , C1-C4 decanoyl, C1-C4 decylsulfonyl, C6-C10 arylsulfonyl, -S0 2 R 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C4 fluorenyl, hydroxy C1-C4 fluorenyl, amino C1-C4 alkyl, C6-C10 aryl C1-C4 alkyl, C6-C10 aryl, 4 -10 membered heterocyclic group, 4-10 membered heteroaryl group, 4-10 membered heterocyclic group or 4-10 membered heteroaryl and C6-C10 aryl group, 4-10 membered heterocyclic acyl group, 4-10 membered hetero Aroyl Ph
基或一 -COEt可非必须地被一个或多个选自卤素、三氟甲基、羟基、硝基、 -NR15R16、腈基、 羧基、 C1-C4垸氧基、 C6-C10芳氧基、 C1-C4垸酰氧基、 -C(0)OCl-C4烷基、 -C(0)NR15R16、 C1-C4烷酰基、 C1-C4烷基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10 芳酰基、 C1-C4垸基、羟基 C1-C4垸基、氨基 C1-C4垸基、 C6-C10芳基 C1-C4烷基、 =0 (氧 代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂 芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取代基取代； The base or mono-COEt may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile, carboxyl, C1-C4 decyloxy, C6-C10 aryl Oxyl, C1-C4 nonanoyloxy, -C(0)OCl-C4 alkyl, -C(0)NR 15 R 16 , C1-C4 alkanoyl, C1-C4 alkylsulfonyl, C6-C10 aromatic Sulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C4 fluorenyl, hydroxy C1-C4 fluorenyl, amino C1-C4 fluorenyl, C6-C10 aryl Base C1-C4 alkyl, =0 (oxo), =S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic Or a substituent of a 4-10 membered heteroaryl group and a C6-C10 aryl group, a 4-10 membered heterocyclic acyl group, and a 4-10 membered heteroaroyl group;
R15、 Ri6各自独立地为 H; C1-C4烷基； C3-C10环垸基； 4-10元杂环基； 4-10元杂芳 基； 或者 R15、 R16与连接它们的 N原子一起形成 4-10元杂环基； 4-10元杂芳基； 其中， 所 述 C1-C4烷基、 C3-C10环烷基、 4-10元杂环基和 4-10元杂芳基可非必须地被 1个或多个卤 素； 羟基； 腈基； 氨基； C1-C4垸基； =0 (氧代)； =S (硫代)； C1-C4垸氧基取代； R 15 and Ri 6 are each independently H; C1-C4 alkyl; C3-C10 cyclodecyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and N bonded thereto The atoms together form a 4-10 membered heterocyclic group; a 4-10 membered heteroaryl group; wherein, the C1-C4 alkyl group, the C3-C10 cycloalkyl group, the 4-10 membered heterocyclic group, and the 4-10 membered heteroaryl group; The base may be optionally substituted by one or more halogens; a hydroxyl group; a nitrile group; an amino group; a C1-C4 alkyl group; =0 (oxo); =S (thio); a C1-C4 methoxy group;
各 R7独立地为 -(CH2)mRu、 -(CH2)raO(CH2)nR„或 -(CH2)mNHR„； 其中， Ru为 H; 卤素； 硝基； 腈基； 羧基； -C(0)OCl-C4烧基； C2-C4 j:希基； C2-C4 炔基； C1-C4垸酰基； C1-C4垸基磺酰基； 氨基 C1-C4垸酰基； C1-C4烷基； C6-C10芳基； 4-10元杂环基；或 4-10元杂芳基；上述 -C(0)0C1-C4垸基、 C2-C4稀基、 C2-C4炔基、 C1-C4 烷酰基、 C1-C4垸基磺酰基、 氨基 C1-C4烷酰基、 C1-C4烷基、 C6-C10芳基、 4-10元杂环 基或 4-10元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈 基、 羧基、 C1-C4垸氧基、 C1-C4垸酰氧基、 -C(0)OCl-C4烷基、 C1-C4烷酰基、 C1-C4烷 基磺酰基、 =0 (氧代)、 = S (硫代)和 C1-C4垸基中的取代基取代； Each R 7 is independently -(CH 2 ) m R u , -(CH 2 ) ra O(CH 2 ) n R„ or -(CH 2 ) m NHR„; Wherein, R u is H; halogen; nitro; nitrile group; carboxyl group; -C(0)OCl-C4 alkyl group; C2-C4 j: heptyl group; C2-C4 alkynyl group; C1-C4 decanoyl group; C4 mercaptosulfonyl; amino C1-C4 decanoyl; C1-C4 alkyl; C6-C10 aryl; 4-10 membered heterocyclic; or 4-10 membered heteroaryl; above -C(0)0C1- C4 mercapto, C2-C4 dilute, C2-C4 alkynyl, C1-C4 alkanoyl, C1-C4 mercaptosulfonyl, amino C1-C4 alkanoyl, C1-C4 alkyl, C6-C10 aryl, 4 The -10 membered heterocyclic group or the 4-10 membered heteroaryl group may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C4 decyloxy. , C1-C4 nonanoyloxy, -C(0)OCl-C4 alkyl, C1-C4 alkanoyl, C1-C4 alkylsulfonyl, =0 (oxo), =S (thio) and C1- a substituent in the C4 fluorenyl group;
R8为 -(CH2)mR12、 -(CH2)mO(CH2)nR12或 -(CH2)mNHR12; R 8 is -(CH 2 ) m R 12 , -(CH 2 ) m O(CH 2 ) n R 12 or -(CH 2 ) m NHR 12;
其中， R12为 H; 卤素； 硝基； 腈基； 羧基； =0 (氧代)； =S (硫代)； -C(0)OCl-C4烷 基； C2-C4烯基； C2-C4炔基； C1-C4垸酰基； C1-C4烷基磺酰基；氨基 C1-C4烷酰基； C1-C4 Wherein R 12 is H; halogen; nitro; nitrile; carboxyl; =0 (oxo); =S (thio); -C(0)OCl-C4 alkyl; C2-C4 alkenyl; C4 alkynyl; C1-C4 decanoyl; C1-C4 alkylsulfonyl; amino C1-C4 alkanoyl; C1-C4
,s、  , s,
垸基； Ph(CH2)m-; 'sz ; - 4-10元杂环基； 或 4-10元杂芳基； 上述 -C(0)OCl-C4 烷基、 C2-C4烯基、 C2-C4炔基、 C1-C4垸酰基、 C1-C4烷基磺酰基、 氨基 C1-C4垸酰基、 Thiol; Ph(CH 2 ) m - ; 'sz ; - 4-10 membered heterocyclic group; or 4-10 membered heteroaryl; above -C(0)OCl-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 decanoyl, C1-C4 alkylsulfonyl, amino C1-C4 decanoyl,
C1-C4垸基、 Ph(CH2)m -、 、 ― \ 、 4-10元杂环基或 4-10元杂芳基可非必须地被一个 或多个选自卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C4烷氧基、 C1-C4烷酰 氧基、 -C(0)OCl-C4烷基、 C1-C4垸酰基、 C1-C4垸基磺酰基、 =0 (氧代)、 = S (硫代)和 C1-C4烷基中的取代基取代； The C1-C4 fluorenyl group, Ph(CH 2 ) m -, , ― \ , 4-10 membered heterocyclic group or 4-10 membered heteroaryl group may be optionally selected from one or more selected from the group consisting of halogen and trifluoromethyl. , hydroxy, nitro, amino, nitrile, carboxyl, C1-C4 alkoxy, C1-C4 alkanoyloxy, -C(0)OCl-C4 alkyl, C1-C4 decanoyl, C1-C4 fluorenyl Substituted with a sulfonyl group, =0 (oxo), = S (thio), and a C1-C4 alkyl group;
各 m和各 n各自独立地为 0-3的整数； 最优选为 0、 1或 2; q为 0-2的整数。 Each m and each n are each independently an integer from 0 to 3; most preferably 0, 1 or 2 ; q is an integer from 0 to 2.
6、 根据权利要求 1~5中任一项所述的 β-氨基羰基类化合物或其互变异构体、 对映体、 消旋体  The β-aminocarbonyl compound or the tautomer, enantiomer or racemate thereof according to any one of claims 1 to 5.
Figure imgf000130_0001
Figure imgf000130_0001
其中， 在 R!、 R2、 R3、 R4、 R5、 、 R7、 R8、 R9、 R10、 Rii和 R12的定义中， 所述 C1-C10垸基优选为甲基； 乙基； 丙基； 异丙基； 丁基； 异丁基； 或叔丁基; Wherein, in the definitions of R!, R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , Rii and R 12 , the C1-C10 fluorenyl group is preferably a methyl group; Ethyl; propyl; isopropyl; butyl; isobutyl; or tert-butyl;
所述 C6-C10芳基优选为苯基；  The C6-C10 aryl group is preferably a phenyl group;
Figure imgf000130_0002
Figure imgf000130_0002
所述 C3-C10环烃基并 C6-C10芳基或 C6-C10芳基并 C3-C10环烃基优选为以下基团:
Figure imgf000131_0001
The C3-C10 cycloalkyl and C6-C10 aryl or C6-C10 aryl and C3-C10 cycloalkyl groups are preferably the following groups:
Figure imgf000131_0001
所述 4-10元杂环基或 4-10元杂芳基含有 1-4个选自 N、 S和 0的杂原子， 优选为以下 基团:  The 4-10 membered heterocyclic group or 4-10 membered heteroaryl group contains 1 to 4 hetero atoms selected from N, S and 0, preferably the following groups:
Figure imgf000131_0002
Figure imgf000131_0002
所述 4-10元杂环基螺环或 4-10元杂芳基螺环优选为以下基团:
Figure imgf000131_0003
The 4-10 membered heterocyclyl spiro or 4-10 membered heteroaryl spiro is preferably the group:
Figure imgf000131_0003
所述 [4-10元杂环基或 4-10元杂芳基]并 [C3-C10环烃基]或者 [C3-C10环烃基]并 [4-10元  The [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [C3-C10 cycloalkyl group] or [C3-C10 cyclic hydrocarbon group] and [4-10 yuan]
Figure imgf000131_0004
Figure imgf000131_0004
所述 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]优选为以下基  The [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [4-10 membered heterocyclic group or 4-10 membered heteroaryl group] is preferably the following group.
Figure imgf000131_0005
所述 [4-10元杂环基或 4-10元杂芳基]并 [C6-C10芳基]或者 [C6-C10芳基]并 [4-10元杂环
Figure imgf000131_0005
The [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [C6-C10 aryl] or [C6-C10 aryl] and [4-10 membered heterocyclic ring
Figure imgf000132_0001
Figure imgf000132_0001
所述 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环  The [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [4-10 membered heterocyclic ring]
Figure imgf000132_0002
Figure imgf000132_0002
所述 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]并 [C6-C10芳基]  The [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [C6-C10 aryl]
Figure imgf000132_0003
Figure imgf000132_0003
上述各环可通过环上任意位置与其他基团相连，也可以在任意位置被如上所定义的取代 基所取代。  Each of the above rings may be bonded to another group at any position on the ring, or may be substituted at any position by a substituent as defined above.
7、 根据权利要求 1 5中任一项所述的 β-氨基羰基类化合物或其互变异构体、 对映体、 消旋体或其药学上可接受的盐，其中，通式 I、通式 ΙΑ或通式 IB所示的化合物为通式 ΙΑ-1、 ΙΑ-2  The β-aminocarbonyl compound or a tautomer thereof, an enantiomer, a racemate thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, wherein The compound of the formula 通式 or formula IB is of the formula ΙΑ-1, ΙΑ-2
Figure imgf000132_0004
Figure imgf000133_0001
Figure imgf000132_0004
Figure imgf000133_0001
其中， Z为 N或 C; Where Z is N or C;
, R2、 R3和 R4各自独立地更优选为 H; F; CI; Br; 三氟甲基； 羟基； 腈基； 氨基； C1-C4垸氧基； C1-C4垸基； 或 C1-C4烷酰基； 优选为 H、 F、 CI或 Br; 1^和 最优选为 H, R2和 R3最优选为 F; R 2 , R 3 and R 4 are each independently more preferably H; F; CI; Br ; trifluoromethyl; hydroxy; nitrile; amino; C1-C4 methoxy; C1-C4 fluorenyl; C4 alkanoyl; preferably H, F, CI or Br; 1^ and most preferably H, R 2 and R 3 are most preferably F;
R，为 -(CH2)mR10; -(CH2)mCO(CH2)nRi0; -(CH2)mO(CH2)„R10; -(CH2)mNHC(O)(CH2)nR10; 或 -(CH2)mNS02(CH2)nR1(); m优选为 0-3的整数； 最优选为 0、 1或 2; R, is -(CH 2 ) m R 10; -(CH 2 ) m CO(CH 2 ) n Ri 0; -(CH 2 ) m O(CH 2 )„R 10 ; -(CH 2 ) m NHC( O) (CH 2 ) n R 10; or -(CH 2 ) m NS0 2 (CH 2 ) n R 1 (); m is preferably an integer from 0 to 3; most preferably 0, 1 or 2;
其中， R1()为氢、 卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C4垸氧基、 苯氧基、 C1-C4垸酰氧基、 -C(0)0C1-C4垸基、 -C(0)NH2、 C1-C4垸酰基、 C1-C4垸基磺酰 基、苯磺酰基、苯甲酰基、 C1-C4院基、羟基 C1-C4垸基、氨基 C1-C4烷基、苄基、 =0 (氧 代)、 =S (硫代)、 苯基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 Wherein R 1() is hydrogen, halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C4 decyloxy, phenoxy, C1-C4 nonanoyloxy, -C( 0) 0C1-C4 fluorenyl, -C(0)NH 2 , C1-C4 decanoyl, C1-C4 decylsulfonyl, phenylsulfonyl, benzoyl, C1-C4, hydroxy-C1-C4 fluorenyl , amino C1-C4 alkyl, benzyl, =0 (oxo), =S (thio), phenyl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic Base or 4-10 membered heteroaryl
Ph  Ph
C6-C10芳基、 4-10元杂环酰基、 4-10元杂芳酰基或一^- COEt ; 上述氨基、 C1-C4垸氧基、 苯氧基、 C1-C4烷酰氧基、 -C(0)0C1-C4烷基、 -C(0)NH2、 C1-C4烷酰基、 C1-C4烷基磺酰 基、 苯磺酰基、 苯甲酰基、 C1-C4烷基、 羟基 C1-C4烷基、 氨基 C1-C4烷基、 苄基、 苯基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂 C6-C10 aryl, 4-10 membered heterocyclic acyl, 4-10 membered heteroaroyl or mono-COEt; above amino, C1-C4 decyloxy, phenoxy, C1-C4 alkanoyloxy, - C(0)0C1-C4 alkyl, -C(0)NH 2 , C1-C4 alkanoyl, C1-C4 alkylsulfonyl, phenylsulfonyl, benzoyl, C1-C4 alkyl, hydroxy C1-C4 Alkyl, amino C1-C4 alkyl, benzyl, phenyl, 4-10 membered heterocyclyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl or 4-10 membered heteroaryl and C6- C10 aryl, 4-10 yuan
Ph  Ph
环酰基、 4-10元杂芳酰基或一^- COEt可非必须地被一个或多个选自卤素、三氟甲基、羟基、 硝基、 - R15R16>腈基、羧基、 C1-C4烷氧基、 C6-C10芳氧基、 C1-C4垸酰氧基、 -C(0)0C1-C4 垸基、 -C(0)NR15R16、 C1-C4垸酰基、 C1-C4烷基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C4烷基、 羟基 C1-C4烷基、 氨基 C1-C4垸基、 C6-C10 芳基 C1-C4烷基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取 代基取代； The cyclic acyl group, the 4-10 membered heteroaroyl group or the mono-COEt may optionally be one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -R 15 R 16 >nitrile, carboxyl, C1 -C4 alkoxy, C6-C10 aryloxy, C1-C4 nonanoyloxy, -C(0)0C1-C4 fluorenyl, -C(0)NR 15 R 16 , C1-C4 decanoyl, C1- C4 alkylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C4 alkyl, hydroxy C1-C4 alkyl, amino C1-C4 fluorenyl, C6-C10 aryl C1-C4 alkyl, =0 (oxo), =S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered Substituted with an aryl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, a C6-C10 aryl group, a 4-10 membered heterocyclic acyl group, and a 4-10 membered heteroaroyl group;
Ri5、 Ri6各自独立地为 H; C1-C4烷基； C3-C10环垸基； 4-10元杂环基； 4-10元杂芳 基； 或者 R15、 R16与连接它们的 N原子一起形成 4-10元杂环基； 4-10元杂芳基； 其中， 所 述 C1-C4垸基、 C3-C10环烷基、 4-10元杂环基和 4-10元杂芳基可非必须地被 1个或多个卤 素； 羟基； 腈基； 氨基； C1-C4烷基； =0 (氧代)； =S (硫代)； C1-C4烷氧基取代； Ri5, Ri 6 are each independently H ; C1-C4 alkyl; C3-C10 cyclodecyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and N attached thereto The atoms together form a 4-10 membered heterocyclic group; a 4-10 membered heteroaryl group; wherein, the C1-C4 fluorenyl group, the C3-C10 cycloalkyl group, the 4-10 membered heterocyclic group, and the 4-10 membered heteroaryl group; The group may be optionally substituted by one or more halogens; a hydroxyl group; a nitrile group; an amino group; a C1-C4 alkyl group; =0 (oxo); =S (thio); a C1-C4 alkoxy group;
其中， 在通式 IA-1或 IB-1所示的化合物中， R，优选为 H; F; CI; Br; 或三氟甲基， 或者通式 I、 通式 IA或通式 IB所示的化合物为通式 IA-4或 IB-4所示的化合物：  Wherein, in the compound of the formula IA-1 or IB-1, R, preferably H; F; CI; Br; or trifluoromethyl, or the formula I, formula IA or formula IB The compound is a compound of the formula IA-4 or IB-4:
Figure imgf000133_0002
其中， R、 R2、 R3和 R4定义同其在同其在通式 IA-1或 IB-1中的定义； R5和 各自独立地为 -(CH2)mR9; -(CH2)mCO(CH2)nR9; 或 -[(CH^OIH, 其中 i=l~5的 整数， 1~3的整数；
Figure imgf000133_0002
Wherein R, R 2 , R 3 and R 4 are as defined in the formula IA-1 or IB-1; R 5 and each independently are -(CH 2 ) m R 9; -(CH 2 ) m CO(CH 2 ) n R 9; or -[(CH^OIH, where i=integer of l~5, an integer of 1~3;
Rg为 H; 羟基； 腈基； C2-C4熾基； C6-C10芳酰基； C6-C10芳基； 4-10元杂环基； 4-10 元杂芳基； 4-10元杂环基或 4-10元杂芳基并 C3-C8环烃基； 或者 4-10元杂环基或 4-10元 杂芳基并 4-10元杂环基或 4-10元杂芳基； 上述 C2-C4烯基、 C6-C10芳酰基、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C3-C8环烃基或者 4-10 元杂环基或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基可非必须地被一个或多个选自卤 素、 三氟甲基、 羟基、 硝基、 -NR15R16、 腈基、 羧基、 C1-C4垸氧基、 -C(0)OCl-C4垸基、 -C(0)NR15R16、 C1-C4烷酰基、 C1-C4烷基磺酰基、 -S02NR15R16、 -NR15S02R16、 C1-C4垸 基、羟基 C1-C4垸基、氨基 C1-C4烷基、 C6-C10芳基 C1-C4烷基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳 基、 4-10元杂环酰基和 4-10元杂芳酰基中的取代基取代。 Rg is H; hydroxy; nitrile group; C2-C4 thiol; C6-C10 aroyl; C6-C10 aryl; 4-10 membered heterocyclic group; 4-10 membered heteroaryl; 4-10 membered heterocyclic group Or a 4-10 membered heteroaryl and C3-C8 cycloalkyl; or a 4-10 membered heterocyclic or 4-10 membered heteroaryl and 4-10 membered heterocyclic or 4-10 membered heteroaryl; -C4 alkenyl, C6-C10 aroyl, C6-C10 aryl, 4-10 membered heterocyclyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl or 4-10 membered heteroaryl and C3 -C8 cycloalkyl or 4-10 membered heterocyclic or 4-10 membered heteroaryl and 4-10 membered heterocyclic or 4-10 membered heteroaryl optionally substituted by one or more selected from halogen, Fluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile group, carboxyl group, C1-C4 decyloxy group, -C(0)OCl-C4 fluorenyl group, -C(0)NR 15 R 16 , C1- C4 alkanoyl, C1-C4 alkylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C1-C4 fluorenyl, hydroxy C1-C4 fluorenyl, amino C1-C4 alkyl, C6- C10 aryl C1-C4 alkyl, =0 (oxo), =S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered a cyclic or 4-10 membered heteroaryl and C6-C10 aryl group, a 4-10 membered heterocyclic acyl group and 4-10 Heteroaryl acyl substituents.
8、 根据权利要求 1所述的 β-氨基羰基其化合物的互变异构体、 对映体、 消旋体或其药 学上可接受的盐， 其中， 通式 I所示的化合物选自： 化合物 1至化合物 378、 它们的互变异 构体、 对映体、 消旋体或其药学上可接受的盐。  The β-aminocarbonyl group according to claim 1 which is a tautomer, an enantiomer, a racemate or a pharmaceutically acceptable salt thereof, wherein the compound of the formula I is selected from the group consisting of: Compound 1 to compound 378, their tautomers, enantiomers, racemates or pharmaceutically acceptable salts thereof.
9、 一种权利要求 1所述的通式 I所示的 β-氨基羰基类化合物的制备方法， 所述制备方 法为如下任意一种：  A method for producing a β-aminocarbonyl compound of the formula I according to claim 1, wherein the preparation method is any one of the following:
(1)方法一：  (1) Method one:
通式 I化合物可  a compound of formula I
Figure imgf000134_0001
Figure imgf000134_0001
其中， A、 Ri, R2、 R3、 R4、 R5、 Re、 R«、 W、 Q、 Y和 X的定义同其在通式 I中的定 所述还原氨化反应可以在氨甲醇 /乙酸铵、 氰基硼氢化钠存在的条件下进行; Wherein A, Ri, R 2 , R 3 , R 4 , R 5 , Re, R«, W, Q, Y and X are as defined in the formula I in the reductive amination reaction in ammonia methanol / in the presence of ammonium acetate, sodium cyanoborohydride;
其中， 通式 II ：  Wherein, the general formula II:
Figure imgf000134_0002
Figure imgf000134_0002
其中， A、 R, , R2、 R3、 R4、 R5、 、 、 W、 Q、 Y和 X的定义同其在通式 I中的定 义； R13为羟基、 卤素、 C1-C10烷氧基、 C6-C10芳氧基或 C1-C10烷酰氧基； Wherein, A, R, R 2 , R 3 , R 4 , R 5 , , , W, Q, Y and X are as defined in the formula I; R 13 is a hydroxyl group, a halogen, a C1-C10 alkane An oxy group, a C6-C10 aryloxy group or a C1-C10 alkanoyloxy group;
所述通式 III化合物与通式 S化合物的反应可以在碱性条件下进行；  The reaction of the compound of the formula III with the compound of the formula S can be carried out under basic conditions;
其中， 通式 III化合物可以通过通式 V化合物制备， 或者通过通式 IV化合物制备： Wherein the compound of formula III can be prepared by a compound of formula V or by a compound of formula IV:
Figure imgf000135_0001
Figure imgf000135_0001
其中， A、 R,, R2、 R3、 、 W、 Q和 Y的定义同其在通式 I中的定义； R13为卤素、 C1-C10烷氧基、 C6-C10芳氧基或 C1-C10垸酰氧基； Wherein, A, R,, R 2 , R 3 , , W, Q and Y are as defined in the formula I; R 13 is halogen, C1-C10 alkoxy, C6-C10 aryloxy or C1-C10 nonanoyloxy;
其中， 当通式 III化合物通过通式 V化合物制备时， 通式 V化合物可与丙二酸单烷基酯 的钾盐进行缩合消除反应， 得到产物通式 III化合物； 当通式 III化合物通过通式 IV化合物 制备时， 通式 V化合物先与米氏酸在缩合剂存在下发生缩合反应得到通式 IV化合物， 然后 通式 IV化合物在酸性条件下进行开环脱羧反应得到产物 III；  Wherein, when the compound of the formula III is prepared by the compound of the formula V, the compound of the formula V can be condensed and eliminated with the potassium salt of the monoalkyl malonate to obtain the compound of the formula III; When the compound of the formula IV is prepared, the compound of the formula V is first subjected to condensation reaction with the michroic acid in the presence of a condensing agent to obtain a compound of the formula IV, and then the compound of the formula IV is subjected to ring-opening decarboxylation under acidic conditions to obtain the product III;
通式 V化合物可以由市场购买， 或者参照下述通式 VA化合物的制备方法制备， The compound of the formula V can be purchased from the market or prepared by referring to the preparation method of the compound of the formula VA below.
(2)方法二： (2) Method 2:
本发明还提供了通式 I化合物的另一个制备方法， 所述方法包括- 通式 I化合物  The invention also provides another process for the preparation of a compound of formula I, which comprises - a compound of formula I
Figure imgf000135_0002
Figure imgf000135_0002
其中， A、 R2、 R3、 、 R5、 、 、 W、 Q、 Y和 X的定义同其在通式 I中的定 义； R14为氨基保护基， 优选为苄氧羰基或叔丁氧羰基； Wherein A, R 2 , R 3 , R 5 , , , W, Q, Y and X are as defined in the formula I; R 14 is an amino protecting group, preferably benzyloxycarbonyl or tert-butyl Oxycarbonyl group;
所述脱保护基的反应可以在酸性条件下进行， 得到通式 I化合物或通式 I化合物的盐， 该通式 I化合物的盐在碱性条件下游离得到式 I化合物；  The reaction of the deprotecting group can be carried out under acidic conditions to obtain a salt of the compound of the formula I or the compound of the formula I, the salt of the compound of the formula I is freed under basic conditions to give the compound of the formula I;
通式 VI化合物  Compound of formula VI
Figure imgf000135_0003
Figure imgf000135_0003
其中， A、 R、 R2、 R3、 、 R5、 R6、 、 W、 Q、 Y和 X的定义同其在通式 I中的定 义； R14为氨基保护基， 优选为苄氧羰基或叔丁氧羰基； 所述通式 VII化合物与通式 S化合物经缩合反应或者酰化反应得到通式 VI化合物， 反 应可以在碱性条件下进行， 也可以在缩合剂存在条件下进行； Wherein, A, R, R 2 , R 3 , R 5 , R 6 , , W, Q, Y and X are as defined in the formula I; R 14 is an amino-protecting group, preferably a benzyloxycarbonyl group. Or tert-butoxycarbonyl; The compound of the formula VII and the compound of the formula S are subjected to a condensation reaction or an acylation reaction to obtain a compound of the formula VI, and the reaction can be carried out under basic conditions or in the presence of a condensing agent;
其  Its
Figure imgf000136_0001
Figure imgf000136_0001
其中， A、 、 R2、 R3、 I¾、 R8、 W、 Q、 Y和 X的定义同其在通式 I中的定义； R13为 卤素、 C1-C10垸氧基、 C6-C10芳氧基或 C1-C10垸酰氧基； R14为氨基保护基， 优选为苄氧 羰基或叔丁氧羰基； Wherein, A, R 2 , R 3 , I3⁄4, R 8 , W, Q, Y and X are as defined in the formula I; R 13 is halogen, C1-C10-decyloxy, C6-C10 An aryloxy group or a C1-C10 nonanoyloxy group; R 14 is an amino protecting group, preferably a benzyloxycarbonyl group or a tert-butoxycarbonyl group;
上述通式 III化合物进行还原氨化反应得到氨基物 (通式 IX化合物)， 然后通式 IX化合 物的氨基用保护基团保护得到通式 VIII化合物， 最后通式 VIII化合物进行水解反应脱保护 基得到产物通式 VII化合物； 其中还原氨化条件、 脱保护基条件可参照方法一；  The compound of the above formula III is subjected to reductive amination reaction to obtain an amino compound (compound of the formula IX), and then the amino group of the compound of the formula IX is protected with a protecting group to obtain a compound of the formula VIII, and finally the compound of the formula VIII is subjected to a hydrolysis reaction to obtain a deprotecting group. The product of the formula VII; wherein the reductive amination conditions, deprotection conditions can refer to method one;
其中， 通式 III化合物的制备方法参见方法一，  Wherein, the preparation method of the compound of the general formula III is as described in the first method.
(3)方法三： 当 Rs为氧代、 取代氨基时， 可由 R8=H的通式 V化合物经官能团变换得到 R8为氧代、 取代氨基的通式 V化合物， 再参照方法一得到式 I化合物， (3) Method 3: When Rs is an oxo group or a substituted amino group, a compound of the formula V wherein R 8 is an oxo group or a substituted amino group can be obtained by a functional group conversion of a compound of the formula V wherein R 8 =H, and the method is as follows. I compound,
(4)方法四： 通式 I化合物还可以由其他通式 I化合物经过官能团变换得到；  (4) Method 4: The compound of the formula I can also be obtained by functional group transformation of other compounds of the formula I;
较佳地， 所述通式 I所示的化合物为通式 IA所示的化合物时， 所述制备方法为如下任 意一种：  Preferably, when the compound represented by the formula I is a compound represented by the formula IA, the preparation method is any one of the following:
(1)  (1)
Figure imgf000136_0002
Figure imgf000136_0002
其中， 通式 ΙΠΑ化合物可以通过通式 V化合物制备: Wherein the general formula 制备 compound can be prepared by the compound of formula V:
Figure imgf000137_0001
通式 VA化合物可以由市场购买， 或者由以下方法制备：
Figure imgf000137_0001
Compounds of the general formula VA can be purchased from the market or prepared by the following methods:
当 R7为 H时， 通式 VA化合物可由通式 IXA化合物参照文献 (J. Med. Chem. 2003, 46, 399-408)方法制备 化合物- When R 7 is H, the compound of the formula VA can be prepared by the method of the compound of the formula IXA (J. Med. Chem. 2003, 46, 399-408).
Figure imgf000137_0002
Figure imgf000137_0002
其中， 通式 IXA化合物可由市场购买得到；  Wherein the compound of the formula IXA is commercially available;
当 R7不为 H时， 通式 VA化合物可由通式 VA'化合物 (R7=H)经酯化后与 R7X反应制备 得到通 XIA化合物后再水解制备通式 VA化合物， 其中， R7X中的 X为卤素， When R 7 is not H, the compound of the formula VA can be obtained by reacting a compound of the formula VA' (R 7 =H) with R 7 X to obtain a compound of the formula XA, and then hydrolyzing to prepare a compound of the formula VA, wherein R . 7 X X is a halogen,
Figure imgf000137_0003
Figure imgf000137_0003
(2)方法二：  (2) Method 2:
通式 IA化合物可以通过式 ΙΠΑ化合物经以下步骤制备， 具体制备方法同前述通式 I化 合物的制备方法中的方法二- The compound of the formula IA can be prepared by the following procedure in the preparation of the compound of the formula I, and the specific preparation method is the same as the method 2 in the preparation method of the compound of the above formula I -
Figure imgf000138_0001
Figure imgf000138_0001
其中通式 ΙΠΑ化合物的制备方法同通式 III化合物的制备方法，  Wherein the preparation method of the general formula 同 compound is the same as the preparation method of the compound of the general formula III,
(3)方法三： 当 为氧代、 取代氨基时， 可由 R8=H的通式 V化合物经官能团变换得到 为氧代、 取代氨基的通式 V化合物， 再参照方法一得到式 I化合物， (3) Method 3: When oxo or substituted amino group, a compound of the formula V which is an oxo-substituted amino group can be obtained by functional group conversion of a compound of the formula V wherein R 8 =H, and a compound of the formula I can be obtained by referring to the first method.
(4)方法四： 通式 I化合物还可以由其他通式 I化合物经过官能团变换得到； 更佳地， 通式 IA所示的化合物为通式 IB所示的化合物时，所述制备方法为以下任意一 种：  (4) Method 4: The compound of the formula I can also be obtained by functional group transformation of other compounds of the formula I; more preferably, when the compound of the formula IA is a compound of the formula IB, the preparation method is as follows Any one:
单一手性异构体的式 I化合物可通过以下方式制备- Compounds of formula I which are a single chiral isomer can be prepared by -
(1)方法一： 通式 I化合物经过柱层析， 分离非对映异构体， 分别得到两对对映体， 该对 对映体再经手性制备柱拆分得到单一光学异构体的式 I化合物， (1) Method 1: The compound of the formula I is subjected to column chromatography to separate the diastereomers to obtain two pairs of enantiomers, respectively, which are then separated by chiral preparative column to obtain a single optical isomer. a compound of formula I,
(2)方法二： 或者， 通式 VIIIA化合物经手性制备柱拆分得到光学异构体通式 VIIIA'化合 物和通式 VIII  (2) Method 2: Alternatively, the compound of the formula VIIIA is resolved by chiral preparative column to obtain an optical isomer of the formula VIIIA' compound and formula VIII.
Figure imgf000138_0002
Figure imgf000138_0002
VIIIA VIIIA' VIIIA"  VIIIA VIIIA' VIIIA"
通式 VIIIA'化合物或通式 VIIIA"化合物再与通式 S化合物反应， 得到单一手性的通式 IA化  The compound of the formula VIIIA' or the compound of the formula VIIIA" is further reacted with a compound of the formula S to give a single chiral formula.
Figure imgf000138_0003
Figure imgf000138_0003
10、 一种如下通式 II、 III、 VI或 VII所示的 β-氨基羰基类化合物或其互变异构体、 对 映体、 10. A β-aminocarbonyl compound of the formula II, III, VI or VII, or a tautomer, enantiomer thereof,
Figure imgf000139_0001
Figure imgf000139_0001
其中，  among them,
Α为 C6-C10芳基、 饱和或不饱和 C3-C10环烃基、 4-10元杂环基或 4-10元杂芳基； 所 述杂环基或杂芳基含有 1-4个选自 N、 S和 O的杂原子；  Α is a C6-C10 aryl group, a saturated or unsaturated C3-C10 cycloalkyl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group; and the heterocyclic group or heteroaryl group contains from 1 to 4 selected from the group consisting of Heteroatoms of N, S and O;
\¥为 ^、 S、 0或 C1-C4直链烃基；  \¥ is ^, S, 0 or C1-C4 linear hydrocarbon group;
0为>}、 S、 0或 C原子；  0 is >}, S, 0 or C atom;
W与 Q之间的虚线存在或不存在， 存在时表示此处是不饱和键， 不存在时表示此处是 饱和键， 优选为不存在；  The presence or absence of a dotted line between W and Q, when present, indicates that it is an unsaturated bond, and when it does not exist, it indicates that it is a saturated bond, preferably does not exist;
Y为 N或 CR7; Y is N or CR 7 ;
X为 N或 CR7; X is N or CR 7 ;
和 R4各自独立地为 H;卤素；三氟甲基；羟基；硝基；腈基；羧基； -C(O)OCl-C10 烷基； 氨基； C1-C10烷氧基; C1-C10烷基; C1-C10垸酰基 (即 -C(O)Cl-C10烷基); C1-C10 烷酰氧基 (即 -OC(O)Cl-C10垸基)； 磺酰基； C1-C10烷基磺酰基； C6-C10芳基； 4-10元杂环 基；或 4-10元杂芳基；上述 -C(O)OCl-C10烷基、氨基、 C1-C10垸氧基、 C1-C10垸基、 C1-C10 烷酰基、 C1-C10垸酰氧基、 磺酰基、 C1-C10烷基磺酰基、 C6-C10芳基、 4-10元杂环基或 4-10元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧 基、 C1-C10垸基、 C1-C10烷氧基、 C1-C10垸酰氧基、 -C(O)OCl-C10烷基、 C1-C10垸酰 基、 磺酰基、 C1-C10垸基磺酰基、 苯基和苯甲基中的取代基取代；  And R4 are each independently H; halogen; trifluoromethyl; hydroxy; nitro; nitrile; carboxy; -C(O)OCl-C10 alkyl; amino; C1-C10 alkoxy; C1-C10 alkyl ; C1-C10 decanoyl (ie, -C(O)Cl-C10 alkyl); C1-C10 alkanoyloxy (ie, -OC(O)Cl-C10 fluorenyl); sulfonyl; C1-C10 alkyl sulfonate Acyl; C6-C10 aryl; 4-10 membered heterocyclic; or 4-10 membered heteroaryl; above -C(O)OCl-C10 alkyl, amino, C1-C10 decyloxy, C1-C10垸, C1-C10 alkanoyl, C1-C10 nonanoyloxy, sulfonyl, C1-C10 alkylsulfonyl, C6-C10 aryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl Must be one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C10 decyl, C1-C10 alkoxy, C1-C10 nonanoyloxy, - Substituted by a substituent in C(O)OCl-C10 alkyl, C1-C10 decanoyl, sulfonyl, C1-C10 decylsulfonyl, phenyl and benzyl;
R5和 各自独立地为 -(CH2)mR9; -(CH2)mCO(CH2)„R9; 或 -[(CH^OIH, 其中 i=l~5的 整数， j=l~3的整数， R9为 H; 卤素； 羟基； 硝基； 氨基； 腈基； 羧基； -C(O)OCl-C10烷 基； C1-C10垸酰基； C1-C10烷基磺酰基； C1-C10烷基； C2-C10烯基； C2-C10炔基； C3-C10 环垸基； C3-C8内酰胺基； C1-C10烷氨基磺酰基； C1-C10垸氨酰基； C6-C10芳酰基； C1-C10 浣氧基； C6-C10芳基磺酰基、 -S02NR15R16、 - R15S02Ri6; C6-C10芳基； 4-10元杂环基； 4-10元杂芳基; 4-10元杂环基或 4-10元杂芳基并 C3-C10环烃基；或者 4-10元杂环基或 4-10 元杂芳基并 4-10元杂环基或 4-10元杂芳基； 上述氨基、 -C(O)OCl-C10烷基、 C1-C10烷酰 基、 C1-C10垸基磺酰基、 C1-C10烷基、 C2-C10烯基、 C2-C10炔基、 C3-C10环烷基、 C3-C8 内酰胺基、 C1-C10烷氨基磺酰基、 C1-C10垸氨酰基、 C6-C10芳酰基、 C1-C10垸氧基、 C6-C10 芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C3-C10环烃基或者 4-10元杂环基或 4-10元杂芳基并 4-10 元杂环基或 4-10 元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 -NR15R16、 腈基、 羧基、 C1-C10垸氧基、 C6-C10芳氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10 烷基、 -C(0)NR15R16、 C1-C10垸酰基、 C1-C10垸基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 - R15S02Ri6、 C6-C10芳酰基、 C1-C10垸基、羟基 C1-C10垸基、氨基 C1-C10烷基、 C6-C10 芳基 C1-C10垸基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取 代基取代； 上述 C6-C10芳基、 C6-C10芳酰基和 C6-C10芳基磺酰基可非必须地被一个或多 个选自卤素、 三氟甲基、 羟基、 硝基、 -NR15R16、 腈基、 羧基、 C1-C10烷氧基、 C1-C10垸 酰氧基、 -C(O)OCl-C10烷基、 -C(0)NR15R16、 C1-C10烷酰基、 C1-C10垸基磺酰基、 C6-C10 芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C10烷基、羟基 C1 -C10烷基、 氨基 C1-C10烷基和 C6-C10芳基 C1-C10烷基中的取代基取代； R 5 and each independently are -(CH 2 ) m R 9; -(CH 2 ) m CO(CH 2 )„R 9; or —[(CH^OIH, where i=integer of l~5, j= An integer of 1 to 3, R 9 is H; halogen; hydroxy; nitro; amino; nitrile; carboxy; -C(O)OCl-C10 alkyl; C1-C10 decanoyl; C1-C10 alkylsulfonyl; C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C3-C10 cyclodecyl; C3-C8 lactam; C1-C10 alkylaminosulfonyl; C1-C10 prolyl; C6-C10 Aroyl; C1-C10 decyloxy; C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , - R 15 S0 2 Ri 6 ; C6-C10 aryl; 4-10 membered heterocyclic; 4- 10 membered heteroaryl; 4-10 membered heterocyclic or 4-10 membered heteroaryl and C3-C10 cycloalkyl; or 4-10 membered heterocyclic or 4-10 membered heteroaryl and 4-10 membered a cyclic group or a 4-10 membered heteroaryl group; the above amino group, -C(O)OCl-C10 alkyl group, C1-C10 alkanoyl group, C1-C10 decylsulfonyl group, C1-C10 alkyl group, C2-C10 alkenyl group , C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C8 lactam, C1-C10 alkylaminosulfonyl, C1-C10 valyl, C6-C10 aroyl, C1-C10 decyloxy, C6 -C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C3-C10 ring A hydrocarbyl group or a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group may be optionally selected from one or more selected from the group consisting of halogen and trifluoromethyl. , hydroxy, nitro, -NR 15 R 16 , nitrile group, carboxyl group, C1-C10 decyloxy group, C6-C10 aryloxy group, C1-C10 alkanoyloxy group, -C(O)OCl-C10 alkyl group, -C(0)NR 15 R 16 , C1-C10 decanoyl, C1-C10 decylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , - R 15 S0 2 Ri6, C6-C10 Aroyl, C1-C10 fluorenyl, hydroxy C1-C10 fluorenyl, amino C1-C10 alkyl, C6-C10 aryl C1-C10 fluorenyl, =0 (oxo), =S (thio), C6- C10 aryl, 4-10 membered heterocyclic group, 4-10 membered heteroaryl, a substituent of a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group and a C6-C10 aryl group, a 4-10 membered heterocyclic acyl group, and a 4-10 membered heteroaroyl group; the above C6-C10 aryl group, The C6-C10 aroyl group and the C6-C10 arylsulfonyl group may be optionally one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile group, carboxyl group, C1-C10 Alkoxy, C1-C10 nonanoyloxy, -C(O)OCl-C10 alkyl, -C(0)NR 15 R 16 , C1-C10 alkanoyl, C1-C10 decylsulfonyl, C6-C10 Arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C10 alkyl, hydroxy C1-C10 alkyl, amino C1-C10 alkyl and C6-C10 Substituent substitution in an aryl C1-C10 alkyl group;
或者， R5和 R6与它们相连的 X共同构成氨基葡萄糖基； 氨基酸残基； 氨基酸酯残基； 或氨基酰胺残基，且非必须地被一个或多个选自 C1-C6垸基、 C1-C6烷基取代的氨基、 C1-C10 垸酰基、 苄基、 苄氧羰基和叔丁氧羰基中的取代基取代； Alternatively, R 5 and R 6 together with the X to which they are attached form an glucosamine group; an amino acid residue; an amino acid ester residue; or an amino amide residue, and optionally one or more selected from the group consisting of C1-C6 fluorenyl groups, C1 Substituted with a substituent in a C6 alkyl-substituted amino group, a C1-C10 decanoyl group, a benzyl group, a benzyloxycarbonyl group, and a tert-butoxycarbonyl group;
或者， R5和 Re与连接它们的 X—起形成 C6-C10芳基； C3-C10环烃基； C3-C10环烃 基并 C3-C10环烃基； C3-C10环烃基并 C6-C10芳基； C6-C10芳基并 C3-C10环烃基； 4-10 元杂环基； 4-10元杂芳基； 4-10元杂环基螺环； 4-10元杂芳基螺环； 4-10元杂环基或 4-10 元杂芳基并 C3-C10环烃基； C3-C10环烃基并 4-10元杂环基或 4-10元杂芳基； 4-10元杂环 基或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基； C6-C10芳基并 4-10元杂环基或 4-10 元杂芳基； 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基； [4-10元杂环基或 4-10元杂芳基] 并 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]; 或者 [4-10元杂环基 或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]并 [C6-C10芳基]； 上述基团可非必须地 被一个或多个 R，取代， R，选自 -(CH^Rt。； -(CH2)mCO(CH2)nR10 ; -(CH2)mO(CH2)nR10； -(CH2)mNHC(O)(CH2)nR10; 和 -(CH2)mNSO2(CH2)nR10; Or, R 5 and Re together with the X to which they are bonded form a C6-C10 aryl group; a C3-C10 cycloalkyl group; a C3-C10 cycloalkyl group and a C3-C10 cycloalkyl group; a C3-C10 cycloalkyl group and a C6-C10 aryl group; C6-C10 aryl and C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; 4-10 membered heterocyclyl spiro; 4-10 membered heteroaryl spiro; 4- a 10-membered heterocyclic group or a 4-10 membered heteroaryl group and a C3-C10 cycloalkyl group; a C3-C10 cycloalkyl group and a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group; a 4-10 membered heterocyclic group or 4-10 membered heteroaryl and 4-10 membered heterocyclic group or 4-10 membered heteroaryl; C6-C10 aryl and 4-10 membered heterocyclic group or 4-10 membered heteroaryl; 4-10 membered Heterocyclyl or 4-10 membered heteroaryl and C6-C10 aryl; [4-10 membered heterocyclic or 4-10 membered heteroaryl] and [4-10 membered heterocyclic or 4-10 membered hetero Aryl]and [4-10 membered heterocyclic or 4-10 membered heteroaryl]; or [4-10 membered heterocyclyl or 4-10 membered heteroaryl] and [4-10 membered heterocyclyl or 4-10 membered heteroaryl]and [C6-C10 aryl]; the above group may be optionally substituted by one or more R, R, selected from -(CH^Rt.; -(CH 2 ) m CO(CH 2 ) n R 10 ; -(CH 2 ) m O(CH 2 ) n R 10 ; -(CH 2 ) m NHC(O)(CH 2 ) n R 10 ; and -(CH 2 ) m N SO 2 (CH 2 ) n R 10;
其中， Ru)为氢、 卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 CI- C10垸氧基、 Wherein Ru) is hydrogen, halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxyl, CI-C10 decyloxy,
C6-C10芳氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10垸基、 -C(0)NH2、 C1-C10烷酰基、 C1-C10 垸基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16 C6-C10芳酰基、 C1-C10烷 基、羟基 C1-C10烷基、 氨基 C1-C10烷基、 C6-C10芳基 C1-C10烷基、 =0 (氧代)、 =S (硫 代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10 C6-C10 aryloxy, C1-C10 alkanoyloxy, -C(O)OCl-C10 fluorenyl, -C(0)NH 2 , C1-C10 alkanoyl, C1-C10 decylsulfonyl, C6- C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 C6-C10 aroyl, C1-C10 alkyl, hydroxy C1-C10 alkyl, amino C1-C10 alkyl, C6-C10 Aryl C1-C10 alkyl, =0 (oxo), =S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic Base or 4-10 membered heteroaryl and C6-C10
Ph  Ph
芳基、 4-10元杂环酰基、 4-10元杂芳酰基或一l^-COEt ; 上述氨基、 C1-C10垸氧基、 C6-C10 芳氧基、 C1-C10垸酰氧基、 -C(O)OCl-C10垸基、 -C(0)NH2、 C1-C10烷酰基、 C1-C10院基 磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C10烷基、 羟基 C1-C10烷基、 氨基 C1-C10烷基、 C6-C10芳基 C1-C10烷基、 C6-C10芳基、 4-10元杂 环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基、 An aryl group, a 4-10 membered heterocyclic acyl group, a 4-10 membered heteroaroyl group or a 1,4-COEt; the above amino group, C1-C10 decyloxy group, C6-C10 aryloxy group, C1-C10 decanoyloxy group, -C(O)OCl-C10 fluorenyl, -C(0)NH 2 , C1-C10 alkanoyl, C1-C10-based sulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , NR 15 S0 2 R 16 , C6-C10 aroyl group, C1-C10 alkyl group, hydroxy C1-C10 alkyl group, amino C1-C10 alkyl group, C6-C10 aryl C1-C10 alkyl group, C6-C10 aryl group, 4-10 membered heterocyclic group, 4-10 membered heteroaryl group, 4-10 membered heterocyclic group or 4-10 membered heteroaryl and C6-C10 aryl group, 4-10 membered heterocyclic acyl group,
Ph  Ph
4-10元杂芳酰基或一l^-COEt可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、A 4-10 membered heteroaroyl group or a 1^-COEt may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro,
-NR15R16、 腈基、 羧基、 C1-C10垸氧基、 C6-C10芳氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10 垸基、 -C(0)NR15R16、 C1-C10垸酰基、 C1-C10烷基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C10垸基、羟基 C1-C10烷基、氨基 C1-C10垸基、 C6-C10 芳基 C1-C10烷基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取 代基取代； -NR 15 R 16 , cyano group, carboxyl group, C1-C10 decyloxy group, C6-C10 aryloxy group, C1-C10 alkanoyloxy group, -C(O)OCl-C10 fluorenyl group, -C(0)NR 15 R 16 , C1-C10decanoyl, C1-C10 alkylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1- C10 fluorenyl, hydroxy C1-C10 alkyl, amino C1-C10 decyl, C6-C10 aryl C1-C10 alkyl, =0 (oxo), =S (thio), C6-C10 aryl, 4 -10 membered heterocyclic group, 4-10 membered heteroaryl group, 4-10 membered heterocyclic group or 4-10 membered heteroaryl group and C6-C10 aryl group, 4-10 membered heterocyclic acyl group and 4-10 membered hetero a substituent in the aroyl group;
R15、 R16各自独立地为 H; C1-C10焼基； C3-C10环垸基； 4-10元杂环基； 4-10元杂芳 基； 或者 R15、 R16与连接它们的 N原子一起形成 4-10元杂环基； 4-10元杂芳基； 其中， 所 述 C1-C10烷基、 C3-C10环垸基、 4-10元杂环基和 4-10元杂芳基可非必须地被 1个或多个 卤素； 羟基； 腈基； 氨基； C1-C10垸基； =0 (氧代)； =S (硫代)； C1-C10垸氧基取代； R7为 -(CH2)mR„、 -(CH2)mO(CH2)nRn或 -(CH2)mNHR11 ; R 15 and R 16 are each independently H; C1-C10 fluorenyl; C3-C10 cyclodecyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and attached thereto N atoms together form a 4-10 membered heterocyclic group; 4-10 membered heteroaryl; wherein The C1-C10 alkyl group, the C3-C10 cyclodecyl group, the 4-10 membered heterocyclic group and the 4-10 membered heteroaryl group may be optionally one or more halogens; a hydroxyl group; a nitrile group; an amino group; C10 fluorenyl; =0 (oxo); =S (thio); C1-C10 methoxy substituted; R 7 is -(CH 2 ) m R„, -(CH 2 ) m O(CH 2 ) n Rn or -(CH 2 ) m NHR 11 ;
其中， Ru为 H; 卤素； 硝基； 腈基； 羧基； -C(O)OCl-C10垸基； C2-C10烯基； C2-C10 炔基； C1-C10垸酰基； C1-C10垸基磺酰基； 氨基 C1-C10垸酰基； C1-C10垸基； C6-C10 芳基； 4-10元杂环基； 或 4-10元杂芳基； 上述 -C(O)OCl-C10垸基、 C2-C10烯基、 C2-C10 炔基、 C1-C10烷酰基、 C1-C10烷基磺酰基、 氨基 C1-C10垸酰基、 C1-C10垸基、 C6-C10 芳基、 4-10元杂环基或 4-10元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、氨基、腈基、羧基、 C1-C10烷氧基、 C1-C10烷酰氧基、 -C(O)OCl-C10烷基、 C1-C10 垸酰基、 C1-C10垸基磺酰基、 =0 (氧代)、 =S (硫代)和 C1-C10烷基中的取代基取代；Wherein, R u is H; halogen; nitro; nitrile; carboxyl; -C(O)OCl-C10 fluorenyl; C2-C10 alkenyl; C2-C10 alkynyl; C1-C10 nonanoyl; C1-C10垸Alkylsulfonyl; amino C1-C10 decanoyl; C1-C10 fluorenyl; C6-C10 aryl; 4-10 membered heterocyclic; or 4-10 membered heteroaryl; above -C(O)OCl-C10垸, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkanoyl, C1-C10 alkylsulfonyl, amino C1-C10 decanoyl, C1-C10 decyl, C6-C10 aryl, 4-10 The heterocyclic or 4-10 membered heteroaryl may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxyl, C1-C10 alkoxy, C1. -C10 alkanoyloxy, -C(O)OCl-C10 alkyl, C1-C10 decanoyl, C1-C10 decylsulfonyl, =0 (oxo), =S (thio) and C1-C10 alkane a substituent in the group;
Rs为 -(CH2)mR12、 -(CH2)mO(CH2)nR12或 -(CH2)mNHR12; Rs is -(CH 2 ) m R 12 , -(CH 2 ) m O(CH 2 ) n R 12 or -(CH 2 ) m NHR 12;
其中， R12为 H; 卤素； 硝基； 腈基； 羧基； =0 (氧代)； =S (硫代)； -C(O)OCl-C10 垸基； C2-C10烯基； C2-C10炔基； C1-C10垸酰基； C1-C10烷基磺酰基； 氨基 C1-C10烷 醜基； C1-C10烷基； Ph(CH2)m -; 0= ; 4-10元杂环基； 或 4-10元杂芳基； 上述Wherein R 12 is H; halogen; nitro; nitrile; carboxyl; =0 (oxo); =S (thio); -C(O)OCl-C10 fluorenyl; C2-C10 alkenyl; C10 alkynyl; C1-C10 decanoyl; C1-C10 alkylsulfonyl; amino C1-C10 alkyl oxa; C1-C10 alkyl; Ph(CH 2 ) m -; 0 = ; 4-10 membered heterocyclic Or 4-10 yuan heteroaryl;
-C(O)OCl-C10烷基、 C2-C10烯基、 C2-C10炔基、 C1-C10烷酰基、 C1-C10烷基磺酰基、 氨基 C1-C10垸酰基、 C1-C10烷基、 Ph(CH2)m - s」、 4-10元杂环基或 4-10元杂 芳基可非必须地被一个或多个选自卤素、三氟甲基、羟基、硝基、氨基、腈基、羧基、 C1-C10 垸氧基、 C1-C10垸酰氧基、 -C(O)OCl-C10垸基、 C1-C10垸酰基、 C1-C10垸基磺酰基、 = 0 (氧代)、 =S (硫代)和 C1-C10烷基中的取代基取代； -C(O)OCl-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkanoyl, C1-C10 alkylsulfonyl, amino C1-C10 decanoyl, C1-C10 alkyl, Ph(CH 2 ) m - s", 4-10 membered heterocyclyl or 4-10 membered heteroaryl may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, Nitrile group, carboxyl group, C1-C10 decyloxy group, C1-C10 decanoyloxy group, -C(O)OCl-C10 fluorenyl group, C1-C10 decanoyl group, C1-C10 decylsulfonyl group, = 0 (oxo generation) Substituted by a substituent in the =S (thio) and C1-C10 alkyl groups;
m和 n各自独立地为 0-5的整数， q为 0-4的整数；  m and n are each independently an integer of 0-5, and q is an integer of 0-4;
R13为卤素、 C1-C10烷氧基、 C6-C10芳氧基或 C1-C10烷酰氧基； R 13 is halogen, C1-C10 alkoxy, C6-C10 aryloxy or C1-C10 alkanoyloxy;
R14为氨基保护基， 优选为苄氧羰基或叔丁氧羰基。 R 14 is an amino protecting group, preferably a benzyloxycarbonyl group or a tert-butoxycarbonyl group.
11、 根据权利要求 10所述的 β-氨基羰基类化合物或其互变异构体、 对映体、 消旋体或 其药学上可接受的盐， 其中， 通式 II III VI或 VII所示的化合物为通式 ΠΑ ΙΠΑ VIA 或 VIIA  The β-aminocarbonyl compound or the tautomer, enantiomer, racemate or pharmaceutically acceptable salt thereof according to claim 10, wherein the formula II III VI or VII is represented by The compound is of the formula ΠΑ ΙΠΑ VIA or VIIA
Figure imgf000141_0001
Figure imgf000141_0001
其中， R,、 R2、 R3、 R4、 R5 R12、 Rn X和 q的定义同其在通式 II III、 VI 和 VII中的定义； Wherein R, R 2 , R 3 , R 4 , R 5 R 12 , Rn X and q are as defined in the formula II III, VI and VII;
R7为 -(CH^R! -(CH2)mO(CH2)nR1！或 -(CH m HR!！ R 7 is -(CH^R! -(CH 2 ) m O(CH 2 ) n R 1 ! or -(CH m HR!!
其中， Rii为 H; 卤素； 硝基； 腈基； 羧基； -C(0)OCl-C4垸基； C2-C4烯基； C2-C4 炔基； C1-C4垸酰基； C1-C4烷基磺酰基； 氨基 C1-C4垸酰基； C1-C4烷基； C6-C10芳基； 4-10元杂环基；或 4-10元杂芳基；上述 -C(0)OCl-C4烷基、 C2-C4炼基、 C2-C4炔基、 C1-C4 垸酰基、 C1-C4烷基磺酰基、 氨基 C1 -C4垸酰基、 C1-C4烷基、 C6-C10芳基、 4-10元杂环 基或 4-10元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈 基、 羧基、 C1-C4烷氧基、 C1-C4烷酰氧基、 -C(0)OCl-C4垸基、 C1-C4垸酰基、 C1-C4烷 基磺酰基、 =0 (氧代)、 =S (硫代)和 C1-C4烷基中的取代基取代； Wherein, Rii is H; halogen; nitro; nitrile; carboxy; -C(0)OCl-C4 fluorenyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 decanoyl; C1-C4 alkyl Sulfonyl; amino C1-C4 decanoyl; C1-C4 alkyl; C6-C10 aryl; 4-10 membered heterocyclic; or 4-10 membered heteroaryl; above-C(0)OCl-C4 alkyl , C2-C4 refining group, C2-C4 alkynyl group, C1-C4 decanoyl group, C1-C4 alkylsulfonyl group, amino C1-C4 decanoyl group, C1-C4 alkyl group, C6-C10 aryl group, 4-10 yuan Heterocycle The base or 4-10 membered heteroaryl may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxyl, C1-C4 alkoxy, C1-C4 alkane. Acyloxy, -C(0)OCl-C4 fluorenyl, C1-C4 decanoyl, C1-C4 alkylsulfonyl, =0 (oxo), =S (thio) and C1-C4 alkyl Substituent substitution;
其中， m和 n各自独立地为 0-5的整数；  Wherein m and n are each independently an integer of 0-5;
较佳地， 通式 ΠΑ、 IIIA、 VIA或 VIIA所示的化合物为通式 ΠΒ、 ΙΠΒ、 VIB或 VIIB所 示的化  Preferably, the compound of the formula ΠΑ, IIIA, VIA or VIIA is represented by the formula ΠΒ, ΙΠΒ, VIB or VIIB.
Figure imgf000142_0001
Figure imgf000142_0001
和 R4各自独立地为 H;卤素；三氟甲基；羟基；硝基；腈基；羧基； -C(0)OCl-C4 烷基；氨基； C1-C4垸氧基； C1 -C4烷基； C1-C4烷酰基； C1-C4垸酰氧基；磺酰基；或 C1-C4 垸基磺酰基； 上述 -C(0)OCl-C4烷基、 氨基、 C1-C4烷氧基、 C1-C4垸基、 C1-C4烷酰基、 And R4 are each independently H; halogen; trifluoromethyl; hydroxy; nitro; nitrile; carboxy; -C(0)OCl-C4 alkyl; amino; C1-C4 methoxy; C1-C4 alkyl C1-C4 alkanoyl; C1-C4 nonanoyloxy; sulfonyl; or C1-C4 mercaptosulfonyl; above -C(0)OCl-C4 alkyl, amino, C1-C4 alkoxy, C1- C4 thiol, C1-C4 alkanoyl,
C1-C4垸酰氧基、磺酰基或 C1-C4垸基磺酰基可非必须地被一个或多个选自卤素、三氟甲基、 羟基、硝基、氨基、腈基、羧基、 C1-C4垸基、 C1-C4垸氧基、 C1-C4垸酰氧基、 -C(0)OCl-C4 垸基、 C1-C4垸酰基、 磺酰基、 C1-C4烷基磺酰基、 苯基和苯甲基中的取代基取代； R,、 R2、 R3和 R4各自独立地优选为 H; 卤素； 羟基； 腈基； 氨基； C1-C4烷氧基； C1-C4烷基； 或 C1-C4垸酰基； R、 R2、 和 各自独立地更优选为 H或卤素； The C1-C4 nonanoyloxy group, the sulfonyl group or the C1-C4 mercaptosulfonyl group may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxyl, C1- C4 fluorenyl, C1-C4 decyloxy, C1-C4 nonanoyloxy, -C(0)OCl-C4 fluorenyl, C1-C4 decanoyl, sulfonyl, C1-C4 alkylsulfonyl, phenyl and Substituted in the benzyl group; R, R 2 , R 3 and R 4 are each independently preferably H ; halogen; hydroxy; nitrile; amino; C1-C4 alkoxy; C1-C4 alkyl; -C4 decanoyl; R, R 2 , and each independently more preferably H or halogen;
R5和 各自独立地为 -(CH2)mR9或 -(CH2)mCO(CH2)nR9, 其中， R9为 H; 卤素； 羟基； 硝基； 氨基； 腈基； 羧基； -C(0)OCl-C4烷基； C1-C4垸酰基； C1-C4烷基磺酰基； C1-C4 垸基； C2-C4烯基； C2-C4炔基； C6-C10芳酰基； C1-C4垸氧基； C6-C10芳基磺酰基、 -S02NR15R16、 -N 1SS02R,6; C6-C10芳基； 4-10元杂环基； 4-10元杂芳基； 4-10元杂环基 或 4-10元杂芳基并 C3-C8环烃基； 或者 4-10元杂环基或 4-10元杂芳基并 4-10元杂环基或And R 5 are each independently - (CH 2) m R 9 or - (CH 2) m CO ( CH 2) n R 9, wherein, R 9 is H; halo; hydroxy; nitro; amino; a nitrile group; Carboxy; -C(0)OCl-C4 alkyl; C1-C4 decanoyl; C1-C4 alkylsulfonyl; C1-C4 fluorenyl; C2-C4 alkenyl; C2-C4 alkynyl; C6-C10 aroyl C1-C4 methoxyl; C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -N 1S S0 2 R, 6 ; C6-C10 aryl; 4-10 membered heterocyclic group; 4-10 a heteroaryl group; a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group and a C3-C8 cycloalkyl group; or a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group and a 4 to 10 membered heterocyclic ring. Base or
4-10元杂芳基； 上述氨基、 -C(0)OCl-C4烷基、 C1-C4烷酰基、 C1-C4垸基磺酰基、 C1-C4 垸基、 C2-C4烯基、 C2-C4炔基、 C6-C10芳酰基、 C1-C4烷氧基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基 或 4-10元杂芳基并 C3-C8环烃基或者 4-10元杂环基或 4-10元杂芳基并 4-10元杂环基或 4-10 元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、 羟基、 硝基、 -NR15R16、、 腈基、 羧基、 C1-C4垸氧基、 -C(0)OCl-C4垸基、 -C(0)NR15R16、 C1-C4烷酰基、 C1-C4垸基磺酰 基、 -S02NR15R16、 -NR15S02R16、 C1-C4烷基、 羟基 C1-C4垸基、 氨基 C1-C4垸基、 C6-C10 芳基 C1-C4垸基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基； 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取 代基取代； R9优选为 H; 羟基； 腈基； C2-C4烯基； C6-C10芳酰基； C6-C10芳基； 4-10元 杂环基； 4-10元杂芳基； 4-10元杂环基或 4-10元杂芳基并 C3-C8环烃基； 或者 4-10元杂环 基或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基； 上述 C2-C4烯基、 C6-C10芳酰基、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C3-C8环烃 基或者 4-10元杂环基或 4-10元杂芳基并 4-10元杂环基或 4-10元杂芳基可非必须地被一个 或多个选自卤素、三氟甲基、羟基、硝基、 -NR15R16、腈基、羧基、 C1-C4烷氧基、 -C(0)0C1-C4 烷基、 -C(0)NR15R16、 C1-C4烷酰基、 C1-C4烷基磺酰基、 -S02NR15R16、 -NR15S02R16、 C1-C4 烷基、 羟基 C1-C4烷基、 氨基 C1-C4烷基、 C6-C10芳基 C1-C4垸基、 =0 (氧代)、 = S (硫 代)、 C6-C10芳基、 4-10元杂环基或 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10 芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取代基取代； 4-10 membered heteroaryl; the above amino group, -C(0)OCl-C4 alkyl group, C1-C4 alkanoyl group, C1-C4 mercaptosulfonyl group, C1-C4 fluorenyl group, C2-C4 alkenyl group, C2- C4 alkynyl, C6-C10 aroyl, C1-C4 alkoxy, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aryl, 4-10 A heterocyclic group, a 4-10 membered heteroaryl group, a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl and C3-C8 cycloalkyl group or a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group. And a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group may optionally be one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile group, carboxyl group , C1-C4 methoxy, -C(0)OCl-C4 fluorenyl, -C(0)NR 15 R 16 , C1-C4 alkanoyl, C1-C4 decylsulfonyl, -S0 2 NR 15 R 16 -NR 15 S0 2 R 16 , C1-C4 alkyl, hydroxy C1-C4 fluorenyl, amino C1-C4 fluorenyl, C6-C10 aryl C1-C4 fluorenyl, =0 (oxo), =S ( Thio), C6-C10 aryl, 4-10 membered heterocyclic; 4-10 membered heteroaryl, 4-10 membered heterocyclyl or 4-10 membered heteroaryl and C6-C10 aryl, 4- 10-membered heterocyclyl group substituted 4-10 membered heteroaryl group and aromatic acyl substituent; R 9 Selected as H; hydroxy; nitrile; C2-C4 alkenyl; C6-C10 aroyl; C6-C10 aryl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; 4-10 membered heterocyclic Or a 4-10 membered heteroaryl and C3-C8 cycloalkyl; or a 4-10 membered heterocyclic or 4-10 membered heteroaryl and 4-10 membered heterocyclic or 4-10 membered heteroaryl; -C4 alkenyl, C6-C10 aroyl, C6-C10 aryl, 4-10 membered heterocyclyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl or 4-10 membered heteroaryl and C3 -C8 cycloalkyl or 4-10 membered heterocyclyl or 4-10 membered heteroaryl and 4-10 membered heterocyclyl or 4-10 membered heteroaryl optionally substituted by one or more selected from halogen, Fluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile, carboxyl, C1-C4 alkoxy, -C(0)0C1-C4 alkyl, -C(0)NR 15 R 16 , C1- C4 alkanoyl, C1-C4 alkylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C1-C4 Alkyl, hydroxy C1-C4 alkyl, amino C1-C4 alkyl, C6-C10 aryl C1-C4 fluorenyl, =0 (oxo), = S (thio), C6-C10 aryl, 4- 10 membered heterocyclic or 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6-C10 aryl, 4-10 membered heterocyclic acyl group and 4-10 membered heteroaryl a substituent in the acyl group;
或者， R5和 Re与连接它们的 X—起形成 C6-C10芳基； C3-C10环烃基； C3-C10环烃 基并 C3-C10环烃基； C3-C10环烃基并 C6-C10芳基； C6-C10芳基并 C3-C10环烃基； 4-10 元杂环基； 4-10元杂芳基； 4-10元杂环基螺环； 4-10元杂芳基螺环； [4-10元杂环基或 4-10 元杂芳基]并 [C3-C10环烃基]; [C3-C10环烃基]并 [4-10元杂环基或 4-10元杂芳基]; [4-10元 杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]; [C6-C10芳基]并 [4-10元杂环 基或 4-10元杂芳基]; [4-10元杂环基或 4-10元杂芳基]并 [C6-C10芳基]; [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]; 或者Or, R 5 and Re together with the X to which they are bonded form a C6-C10 aryl group; a C3-C10 cycloalkyl group; a C3-C10 cycloalkyl group and a C3-C10 cycloalkyl group; a C3-C10 cycloalkyl group and a C6-C10 aryl group; C6-C10 aryl and C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; 4-10 membered heterocyclyl spiro; 4-10 membered heteroaryl spiro; a 10-membered heterocyclic group or a 4-10 membered heteroaryl][C3-C10cycloalkyl]; [C3-C10cycloalkyl][4-10 membered heterocyclic or 4-10 membered heteroaryl]; [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [4-10 membered heterocyclic group or 4-10 membered heteroaryl]; [C6-C10 aryl] and [4-10 membered hetero Cycloalkyl or 4-10 membered heteroaryl]; [4-10 membered heterocyclyl or 4-10 membered heteroaryl] and [C6-C10 aryl]; [4-10 membered heterocyclyl or 4-10 (heteroaryl)][4-10 membered heterocyclic or 4-10 membered heteroaryl][4-10 membered heterocyclic or 4-10 membered heteroaryl];
[4-10元杂环基或 4-10元杂芳基]并 [4-10元杂环基或 4-10元杂芳基]并 [C6-C10芳基]; 上述 基团可非必须地被一个或多个 R'取代， R'选自 -(CH2)m R10； -(CH2)mCO(CH2)nR10； -(CH2)mO(CH2)nRlo; -(CH2)mNHC(0)(CH2)nRio; 和 -(CH2)mNSO2(C¾)nR10; [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [4-10 membered heterocyclic group or 4-10 membered heteroaryl] and [C6-C10 aryl]; the above group may not be necessary The ground is replaced by one or more R', R' is selected from -(CH 2 ) m R 10 ; -(CH 2 ) m CO(CH 2 ) n R 10 ; -(CH 2 ) m O(CH 2 ) n R lo ; -(CH 2 ) m NHC(0)(CH 2 ) n Rio; and -(CH 2 ) m NSO 2 (C3⁄4) n R 10;
其中， 所述 Ru)为氢、 卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C4垸氧 基、 C6-C10芳氧基、 C1-C4烷酰氧基、 -C(0)OCl-C4烷基、 -C(0)NH2、 C1-C4烷酰基、 C1-C4 烷基磺酰基、 C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C4垸 基、羟基 C1-C4垸基、氨基 C1-C4烷基、 C6-C10芳基 C1-C4烷基、 =0 (氧代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳 Wherein the Ru) is hydrogen, halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C4 decyloxy, C6-C10 aryloxy, C1-C4 alkanoyloxy, -C(0)OCl-C4 alkyl, -C(0)NH 2 , C1-C4 alkanoyl, C1-C4 alkylsulfonyl, C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C4 fluorenyl, hydroxy C1-C4 fluorenyl, amino C1-C4 alkyl, C6-C10 aryl C1-C4 alkyl, =0 (oxo) , =S (thio), C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6-C10
Ph  Ph
基、 4-10元杂环酰基、 4-10元杂芳酰基或一^-COEt ; 上述氨基、 C1-C4烷氧基、 C6-C10芳 氧基、 C1-C4垸酰氧基、 -C(0)0C1-C4垸基、 -C(0)NH2、 C1-C4垸酰基、 C1-C4垸基磺酰基、a 4-10 membered heterocyclic acyl group, a 4-10 membered heteroaroyl group or a ^-COEt; the above amino group, C1-C4 alkoxy group, C6-C10 aryloxy group, C1-C4 nonanoyloxy group, -C (0) 0C1-C4 fluorenyl, -C(0)NH 2 , C1-C4 decanoyl, C1-C4 decylsulfonyl,
C6-C10芳基磺酰基、 -S02NR15R16、 -NR15S02R16、 C6-C10芳酰基、 C1-C4垸基、羟基 C1-C4 垸基、 氨基 C1-C4烷基、 C6-C10芳基 C1-C4烷基、 C6-C10芳基、 4-10元杂环基、 4-10元 杂芳基、 4-10元杂环基或 4-10元杂芳基并 C6-C10芳基、 4-10元杂环酰基、 4-10元杂芳酰 Ph C6-C10 arylsulfonyl, -S0 2 NR 15 R 16 , -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C4 fluorenyl, hydroxy C1-C4 fluorenyl, amino C1-C4 alkyl, C6-C10 aryl C1-C4 alkyl, C6-C10 aryl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered heteroaryl and C6 -C10 aryl, 4-10 membered heterocyclic acyl group, 4-10 membered heteroaroyl group Ph
基或一 -COEt可非必须地被一个或多个选自卤素、三氟甲基、羟基、硝基、 -NR15R16、腈基、 羧基、 C1-C4垸氧基、 C6-C10芳氧基、 C1-C4垸酰氧基、 -C(0)OCl-C4垸基、 -C(0)NR15R16 、The base or mono-COEt may optionally be selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, nitro, -NR 15 R 16 , nitrile, carboxyl, C1-C4 decyloxy, C6-C10 aryl Oxyl, C1-C4 nonanoyloxy, -C(0)OCl-C4 fluorenyl, -C(0)NR 15 R 16 ,
C1-C4烷酰基、 C1-C4垸基磺酰基、 C6-C10芳基磺酰基、 -S02N 15Ri6. -NR15S02R16、 C6-C10 芳酰基、 C1-C4垸基、羟基 C1-C4垸基、氨基 C1-C4垸基、 C6-C10芳基 C1-C4垸基、 =0 (氧 代)、 =S (硫代)、 C6-C10芳基、 4-10元杂环基、 4-10元杂芳基、 4- 10元杂环基或 4-10元杂 芳基并 C6-C10芳基、 4-10元杂环酰基和 4-10元杂芳酰基中的取代基取代； 所述 R1Q优选为 卤素、 三氟甲基、 羟基、 硝基、 氨基、 腈基、 羧基、 C1-C4烷氧基、 苯氧基、 C1-C4烷酰氧 基、 -C(0)0C1-C4垸基、 -C(0)NH2、 C C4垸酰基、 C1-C4垸基磺酰基、 苯磺酰基、 苯甲酰 基、 -S02 R15R16、 -NR15S02R16、 C1-C4垸基、 羟基 C1-C4烷基、 氨基 C1-C4垸基、 苄基、C1-C4 alkanoyl, C1-C4 mercaptosulfonyl, C6-C10 arylsulfonyl, -S0 2 N 15 Ri 6 . -NR 15 S0 2 R 16 , C6-C10 aroyl, C1-C4 fluorenyl, Hydroxy C1-C4 fluorenyl, amino C1-C4 fluorenyl, C6-C10 aryl C1-C4 fluorenyl, =0 (oxo), =S (thio), C6-C10 aryl, 4-10 meta a ring group, a 4-10 membered heteroaryl group, a 4- 10 membered heterocyclic group or a 4-10 membered heteroaryl group, a C6-C10 aryl group, a 4-10 membered heterocyclic acyl group, and a 4-10 membered heteroaroyl group. Substituted by a substituent; the R 1Q is preferably halogen, trifluoromethyl, hydroxy, nitro, amino, nitrile, carboxy, C1-C4 alkoxy, phenoxy, C1-C4 alkanoyloxy, -C (0) 0C1-C4 fluorenyl, -C(0)NH 2 , C C4 decanoyl, C1-C4 decylsulfonyl, phenylsulfonyl, benzoyl, -S0 2 R 15 R 16 , -NR 15 S0 2 R 16 , C1-C4 fluorenyl, hydroxy C1-C4 alkyl, amino C1-C4 fluorenyl, benzyl,
=0 (氧代)、 =S (硫代)、 苯基、 4-10元杂环基、 4-10元杂芳基、 4-10元杂环基或 4-10元杂 =0 (oxo), =S (thio), phenyl, 4-10 membered heterocyclic, 4-10 membered heteroaryl, 4-10 membered heterocyclic or 4-10 membered
Ph  Ph
芳基并 C6-C10芳基、 4-10元杂环酰基、 4-10元杂芳酰基或一 -COEt ; Aryl-C6-C10 aryl, 4-10 membered heterocyclic acyl, 4-10 membered heteroaroyl or mono-COEt ;
R15、 R16各自独立地为 H; C1-C4垸基； C3-C10环烷基； 4-10元杂环基； 4-10元杂芳 基； 或者 R15、 R16与连接它们的 N原子一起形成 4-10元杂环基； 4-10元杂芳基； 其中， 所 述 C1-C4烷基、 C3-C10环垸基、 4-10元杂环基和 4-10元杂芳基可非必须地被 1个或多个卤 素； 羟基； 腈基； 氨基； C1-C4浣基； =0 (氧代)； =S (硫代)； C1-C4烷氧基取代； R 15 and R 16 are each independently H; C1-C4 fluorenyl; C3-C10 cycloalkyl; 4-10 membered heterocyclic; 4-10 membered heteroaryl; or R 15 , R 16 and attached thereto N atoms together form a 4-10 membered heterocyclic group; 4-10 membered heteroaryl; wherein The C1-C4 alkyl group, the C3-C10 cyclodecyl group, the 4-10 membered heterocyclic group and the 4-10 membered heteroaryl group may be optionally one or more halogens; a hydroxyl group; a nitrile group; an amino group; C4 fluorenyl; =0 (oxo); =S (thio); C1-C4 alkoxy substituted;
R8为 -(CH2)mR12、 -(CH2)mO(CH2)nR12或 -(CH2)mNHR12; R 8 is -(CH 2 ) m R 12 , -(CH 2 ) m O(CH 2 ) n R 12 or -(CH 2 ) m NHR 12;
R,2 ¾ H; 卤素； 硝基； 腈基； 羧基； =0 (氧代)； =S (硫代)； -C(0)0C1-C4垸基； C2-C4 烯基； C2-C4炔基； C1-C4烷酰基； C1-C4烷基磺酰基； 氨基 C1-C4垸酰基； C1-C4烷基； 、 R, 2 3⁄4 H; halogen; nitro; nitrile; carboxyl; =0 (oxo); =S (thio); -C(0)0C1-C4 fluorenyl; C2-C4 alkenyl; C2-C4 Alkynyl; C1-C4 alkanoyl; C1-C4 alkylsulfonyl; amino C1-C4 decanoyl; C1-C4 alkyl;
Ph(CH2)m -; V； 。^； 4-10元杂环基； 或 4-10元杂芳基； 上述 -C(0)0C1-C4垸基、 C2-C4 烯基、 C2-C4炔基、 C1-C4烷酰基、 C1-C4烷基磺酰基、 氨基 C1-C4垸酰基、 C1-C4烷基、Ph(CH 2 ) m -; V; ^; 4-10 membered heterocyclic group; or 4-10 membered heteroaryl; above -C(0)0C1-C4 fluorenyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkanoyl, C1 -C4 alkylsulfonyl group, amino C1-C4 decanoyl group, C1-C4 alkyl group,
Ph(CH2)m -、 0、 °<5、 4-10元杂环基或 4-10元杂芳基可非必须地被一个或多个选自卤素、 三氟甲基、羟基、硝基、氨基、 腈基、羧基、 C1-C4烷氧基、 C1-C4烷酰氧基、 -C(0)OCl-C4 烷基、 C1-C4垸酰基、 C1-C4垸基磺酰基、 =θ (氧代)、 =S (硫代) C1-C4垸基中的取代基取 代； R12优选为 H; 卤素； =0 (氧代)； C1-C4垸酰基； C1-C4焼基； Ph(CH2)m-; 0； 。 ； 吲哚； 二氢吲哚； 吡咯； 呋喃； 噻吩； 噻唑； 咪唑； 噁唑； 异噁唑； 吡唑； 吡啶； 吡嗪； 嘧 啶； 哒嗪； 吡喃； 吲哚； 或喹啉； R12更优选为 H; 卤素； =0 (氧代)； C1-C4垸基； 苯基； 苄基； 0; n引噪； 二氢吲哚； 或吡咯； R12最优选为 H; Ph(CH 2 ) m -, 0, °<5, 4-10 membered heterocyclic or 4-10 membered heteroaryl may be optionally selected from one or more selected from the group consisting of halogen, trifluoromethyl, hydroxy, and nitro Base, amino, nitrile, carboxyl, C1-C4 alkoxy, C1-C4 alkanoyloxy, -C(0)OCl-C4 alkyl, C1-C4 decanoyl, C1-C4 decylsulfonyl, = Substituted by a substituent in the θ (oxo), =S (thio) C1-C4 fluorenyl group; R 12 is preferably H; halogen; =0 (oxo); C1-C4 decanoyl; C1-C4 fluorenyl; Ph(CH 2 ) m - ; 0; ; hydrazine; dihydroanthracene; pyrrole; furan; thiophene; thiazole; imidazole; oxazole; isoxazole; pyrazole; pyridine; pyrazine; pyrimidine; pyridazine; pyran; hydrazine; or quinoline; 12 and more preferably is H; halogen; = 0 (oxo); C1-C4 alkyl with; phenyl; benzyl; 0; n-cited noise; indoline; or pyrrole; 12 and most preferably R & lt H;
m和 n各自独立地优选为 0-3的整数； 最优选为 0、 1或 2; q优选为 0-2的整数；  m and n are each independently preferably an integer of 0 to 3; most preferably 0, 1 or 2; q is preferably an integer of 0 to 2;
R13为卤素、 C1-C4烷氧基、 C6-C10芳氧基或 C1-C4烷酰氧基；R 13 is halogen, C1-C4 alkoxy, C6-C10 aryloxy or C1-C4 alkanoyloxy;
4为氨基保护基， 优选为苄氧羰基或叔丁氧裁基。  4 is an amino protecting group, preferably a benzyloxycarbonyl group or a tert-butoxy group.
12、 一种包含通式 I所示的 β-氨基羰基类化合物或其互变异构体、 对映体、 消旋体或其 药学上可接受的盐中的一种或多种的药物组合物。  12. A pharmaceutical combination comprising a β-aminocarbonyl compound of the formula I or a tautomer, an enantiomer, a racemate or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof Things.
13、权利要求 1~8中任一项所述的 β-氨基羰基化合物或其互变异构体、对映体、消旋体 或其药学上可接受的盐在 (i)制备作为 DPP-4抑制剂的药物或 (ii)制备治疗 II型糖尿病、高血 糖症、 肥胖症或胰岛素抵抗症的药物中的用途。  The β-aminocarbonyl compound according to any one of claims 1 to 8, or a tautomer thereof, an enantiomer, a racemate thereof or a pharmaceutically acceptable salt thereof, as (i) prepared as DPP- Use of a 4 inhibitor drug or (ii) a medicament for the treatment of type 2 diabetes, hyperglycemia, obesity or insulin resistance.
14、 根据权利要求 13所述的用途， 其中， 该化合物进一步与抗糖尿病药物联用。  14. The use according to claim 13, wherein the compound is further used in combination with an anti-diabetic agent.
PCT/CN2014/000303 2013-03-20 2014-03-20 Β-aminocarbonyl compound, preparation method, pharmaceutical composition and use thereof WO2014146494A1 (en)

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