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WO2014146494A1 - Composé β-aminocarbonyle, procédé de préparation, composition pharmaceutique et utilisation correspondants - Google Patents

Composé β-aminocarbonyle, procédé de préparation, composition pharmaceutique et utilisation correspondants 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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WIPO (PCT)
Prior art keywords
group
membered
membered heteroaryl
aryl
alkyl
Prior art date
Application number
PCT/CN2014/000303
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English (en)
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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Publication date
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/zh
Publication of WO2014146494A1 publication Critical patent/WO2014146494A1/fr

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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
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—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
    • 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

La présente invention concerne le domaine de la chimie médicinale. La présente invention concerne, en particulier, un nouveau composé β-aminocarbonyle tel que représenté par la formule générale I, ou un tautomère, un énantiomère, un racémate et un sel pharmaceutiquement acceptable de celui-ci, un procédé de préparation et une composition pharmaceutique corrrespondants et son utilisation en tant qu'inhibiteur de la dipeptidylpeptidase IV (DPP-4). Le composé, ou une composition pharmaceutique correspondante, peut être utilisé en tant qu'inhibiteur de la DPP-4 pour traiter le diabète de type II, l'hyperglycémie, l'obésité ou les syndromes d'insulinorésistance.
PCT/CN2014/000303 2013-03-20 2014-03-20 Composé β-aminocarbonyle, procédé de préparation, composition pharmaceutique et utilisation correspondants WO2014146494A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998035939A1 (fr) * 1997-02-18 1998-08-20 Sanwa Kagaku Kenkyusho Co., Ltd. Derives de diamide malonique et utilisation de ces derniers
WO1999033798A1 (fr) * 1997-12-25 1999-07-08 Yamanouchi Pharmaceutical Co., Ltd. Derives heterocycliques azotes
CN1427826A (zh) * 2000-03-10 2003-07-02 布里斯托尔-迈尔斯斯奎布公司 基于环丙基稠合的吡咯烷二肽基肽酶iv抑制剂、它们的制备方法及用途
WO2004089362A1 (fr) * 2003-04-11 2004-10-21 Novo Nordisk A/S 2-cyanopyrroles et leurs analogues en tant qu'inhibiteurs de dipeptidylpeptidase-iv (dp-iv)
WO2006097175A1 (fr) * 2005-03-18 2006-09-21 Santhera Pharmaceuticals (Schweiz) Ag Inhibiteurs de la dpp-iv
CN1870990A (zh) * 2003-11-04 2006-11-29 默克公司 作为糖尿病治疗或预防用二肽基肽酶iv抑制剂的稠合苯基丙氨酸衍生物
WO2007053819A2 (fr) * 2005-10-31 2007-05-10 Bristol-Myers Squibb Company Inhibiteurs à base d'amide et de bêta-amino de pyrrolidinyle de la dipeptidyl peptidase iv et procédés

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0585999A (ja) * 1991-09-27 1993-04-06 Suntory Ltd ２−インダニルグリシン及びその関連化合物
CN104059068B (zh) * 2013-03-20 2017-02-08 中国科学院上海药物研究所 β‑氨基羰基类化合物、其制备方法、药物组合物及其用途

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998035939A1 (fr) * 1997-02-18 1998-08-20 Sanwa Kagaku Kenkyusho Co., Ltd. Derives de diamide malonique et utilisation de ces derniers
WO1999033798A1 (fr) * 1997-12-25 1999-07-08 Yamanouchi Pharmaceutical Co., Ltd. Derives heterocycliques azotes
CN1427826A (zh) * 2000-03-10 2003-07-02 布里斯托尔-迈尔斯斯奎布公司 基于环丙基稠合的吡咯烷二肽基肽酶iv抑制剂、它们的制备方法及用途
WO2004089362A1 (fr) * 2003-04-11 2004-10-21 Novo Nordisk A/S 2-cyanopyrroles et leurs analogues en tant qu'inhibiteurs de dipeptidylpeptidase-iv (dp-iv)
CN1870990A (zh) * 2003-11-04 2006-11-29 默克公司 作为糖尿病治疗或预防用二肽基肽酶iv抑制剂的稠合苯基丙氨酸衍生物
WO2006097175A1 (fr) * 2005-03-18 2006-09-21 Santhera Pharmaceuticals (Schweiz) Ag Inhibiteurs de la dpp-iv
WO2007053819A2 (fr) * 2005-10-31 2007-05-10 Bristol-Myers Squibb Company Inhibiteurs à base d'amide et de bêta-amino de pyrrolidinyle de la dipeptidyl peptidase iv et procédés

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
DATABASE 1016671-30-9 23 April 2008 (2008-04-23) *
DATABASE REGISTRY 1 August 2012 (2012-08-01), accession no. 385032-76-7 *
DATABASE REGISTRY 10 November 2004 (2004-11-10), accession no. 77882-83-4 *
DATABASE REGISTRY 10 October 1996 (1996-10-10), accession no. 81864-04-0 *
DATABASE REGISTRY 11 April 2012 (2012-04-11), accession no. 366526-73-9 *
DATABASE REGISTRY 18 December 2006 (2006-12-18), accession no. 15767-44-1 *
DATABASE REGISTRY 20 November 2012 (2012-11-20), accession no. 404369-99-8 *
DATABASE REGISTRY 29 October 2004 (2004-10-29), accession no. 71523-83-2 *
DATABASE REGISTRY 31 July 1999 (1999-07-31), accession no. 29636-40-2 *
DATABASE REGISTRY 6 November 1984 (1984-11-06), accession no. 2582-63-4 *
DATABASE REGISTRY 9 December 2007 (2007-12-09), accession no. 57188-30-6 *
DATABASE REIGSTRY 20 November 2004 (2004-11-20), accession no. 73867-86-0 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104876851A (zh) * 2015-05-15 2015-09-02 南京大学 一类含吲哚-3羧酸骨架的哌嗪类衍生物的制备方法及在抗癌药物中的应用
CN106810537A (zh) * 2015-11-27 2017-06-09 中国科学院大连化学物理研究所 一种适用于水油两相体系手性催化剂及其制备和应用
CN106810537B (zh) * 2015-11-27 2019-05-07 中国科学院大连化学物理研究所 一种适用于水油两相体系手性催化剂及其制备和应用
JP2020520924A (ja) * 2017-05-17 2020-07-16 デナリ セラピューティクス インコーポレイテッドＤｅｎａｌｉ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｉｎｃ． キナーゼ阻害剤およびその使用
JP7064512B2 (ja) 2017-05-17 2022-05-10 デナリ セラピューティクス インコーポレイテッド キナーゼ阻害剤およびその使用
CN110386927A (zh) * 2018-04-20 2019-10-29 中国科学院上海药物研究所 组蛋白乙酰转移酶（hat）抑制剂及其用途
CN110386927B (zh) * 2018-04-20 2022-09-23 中国科学院上海药物研究所 组蛋白乙酰转移酶（hat）抑制剂及其用途
CN112961113A (zh) * 2020-04-14 2021-06-15 北京新康哌森医药科技有限公司 一种盐酸氨溴索杂质的制备方法
JP2023514236A (ja) * 2020-07-31 2023-04-05 深▲川▼市橄欖生物医薬科技有限公司 ピラジン化合物およびその調製方法と使用
JP7466664B2 (ja) 2020-07-31 2024-04-12 深▲川▼市橄欖生物医薬科技有限公司 ピラジン化合物およびその調製方法と使用
CN118851979A (zh) * 2024-09-25 2024-10-29 潍坊市海欣药业有限公司 一种阿普斯特的制备方法

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