WO2016066134A1 - 作为dpp-4抑制剂的苯并六元环衍生物及其应用 - Google Patents

作为dpp-4抑制剂的苯并六元环衍生物及其应用 Download PDF

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WO2016066134A1
WO2016066134A1 PCT/CN2015/093384 CN2015093384W WO2016066134A1 WO 2016066134 A1 WO2016066134 A1 WO 2016066134A1 CN 2015093384 W CN2015093384 W CN 2015093384W WO 2016066134 A1 WO2016066134 A1 WO 2016066134A1
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group
compound
solution
alkoxy
reaction
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PCT/CN2015/093384
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English (en)
French (fr)
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李洪林
蒋华良
徐玉芳
李佳
赵振江
李静雅
徐洪玲
李诗良
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华东理工大学
中国科学院上海药物研究所
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Application filed by 华东理工大学, 中国科学院上海药物研究所 filed Critical 华东理工大学
Priority to JP2017523808A priority Critical patent/JP6731917B2/ja
Priority to EP15855852.8A priority patent/EP3214079B1/en
Priority to RU2017117559A priority patent/RU2702644C2/ru
Priority to CA2966250A priority patent/CA2966250C/en
Priority to AU2015341177A priority patent/AU2015341177B2/en
Priority to DK15855852.8T priority patent/DK3214079T3/da
Priority to BR112017009012-0A priority patent/BR112017009012B1/pt
Priority to SG11201703557UA priority patent/SG11201703557UA/en
Priority to KR1020177014842A priority patent/KR102637487B1/ko
Priority to US15/523,058 priority patent/US10479798B2/en
Publication of WO2016066134A1 publication Critical patent/WO2016066134A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/10—Aza-phenanthrenes
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C—CHEMISTRY; METALLURGY
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
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    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/08—Naphthothiopyrans; Hydrogenated naphthothiopyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry; in particular, the present invention relates to a novel benzo six-membered ring derivative, a method for its synthesis and its use in the preparation of a medicament for the treatment of type 2 diabetes and related diseases.
  • Diabetes Mellitus is a metabolic disease characterized by elevated levels of glucose (blood sugar) in the blood. It is a slow-progressive disease caused by genetic factors and environmental factors. As people's living standards improve, the number of people with diabetes increases rapidly. According to the International Diabetes Federation, there were about 371 million people with diabetes in the world in 2012, and the number of people with diabetes in China reached 90 million, making it the country with the largest number of patients worldwide (Wild, S.; Roglic, G.; Green, A.; Sicree, R.; King, H. Diabetes Care. 2004, 27, 1047-1053.). About 3.8 million people die of diabetes every year in the world, and rank third in the second place after cancer and cardiovascular disease along with AIDS.
  • diabetes can be divided into type 1 and type 2.
  • Type 1 diabetes mainly causes endogenous insulin secretion deficiency due to autoimmune destruction of islet ⁇ cells, that is, insulin is absolutely lacking, and patients need to be treated with insulin.
  • Type 2 diabetes is caused by a decrease in insulin secretion or an insulin resistance (Insulin Resistance) due to islet ⁇ -cell dysfunction, etc., that is, the relative lack of insulin leads to abnormal metabolism of sugar, protein and fat.
  • insulin resistance Insulin Resistance
  • the treatment of diabetes mainly uses a variety of oral hypoglycemic agents and insulin supplements to delay the progression of diabetes.
  • these methods sometimes fail to achieve the desired therapeutic effect, and there are side effects such as hypoglycemia and cardiovascular disease, and there is no protective effect on damaged islet cells.
  • Dipeptidyl peptidase-4 (DPP-4) has been shown to be an effective target for the treatment of type 2 diabetes, which rapidly degrades glucagon-like peptide-1 (glucagon-like peptide-1). 1) and a variety of important incretins such as glucose-dependent insulinotropic polypeptide (GIP), resulting in insufficient insulin secretion. Therefore, DPP-4 inhibitors can increase the activity of GLP-1 and GIP, promote insulin secretion, and lower blood sugar.
  • GIP glucose-dependent insulinotropic polypeptide
  • DPP-4 inhibitors can lower blood sugar levels, increase glucose tolerance, and have no side effects such as weight gain and hypoglycemia.
  • DPP-4 inhibitors that have been used clinically include sitagliptin, saxagliptin, vildagliptin, alogliptin, and linagliptin ( Linagliptin) (Havale, SH; Pal, M. Bioorg. Med. Chem. 2009, 17, 1783-1802; Gupta, R.; Walunj, SS; Tokala, RK; Parsa, KV; Singh, SK; Pal, M. Curr.Drug.Targets, 2009, 10, 71-87.).
  • hypoglycemic drugs which are DPP-4 inhibitors, have dominated the market for hypoglycemic drugs.
  • Merck-Dentin's sales of selestatin reached $13.1 billion in 2009, making it the only drug that has broken through 10 billion yuan.
  • the object of the present invention is to provide a compound having a novel structure, high efficiency, low toxicity, capable of being a novel DPP-4 inhibitor, a pharmaceutical composition comprising the compound, a preparation method of the compound, and preparation of the compound Use in medicines for preventing or treating DPP-4 related diseases.
  • the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:
  • X is selected from the group consisting of CH 2 , O, S, NH;
  • A is an unsubstituted benzene ring or a benzene ring having 1 to 5 substituents, and each substituent is independently selected from a halogen, a cyano group, a hydroxyl group, a C 1-6 alkyl group or a halogen, preferably F, more preferably. substituted with 1 to 5 F is C 1 ⁇ 6 alkyl group, C 1 ⁇ 6 alkoxy or halogen, preferably F, more preferably from 1 to 5 F substituted C 1 ⁇ 6 alkoxy;
  • A may also be selected from nitrogen-containing, sulfur five- or six-membered saturated or unsaturated heterocyclic rings having from 1 to 4 substituents, each substituent being independently selected from the group consisting of halogen, cyano, and boronic acid;
  • the A heterocycle is selected from the following structures:
  • Ring B is absent or is selected from an aromatic benzene ring, an aromatic heterocyclic ring, a saturated or unsaturated five-membered six-membered ring, a five- or six-membered saturated or unsaturated heterocyclic ring containing nitrogen, oxygen and sulfur, and a substituent R 1 carbonyl group is independently selected from alkoxycarbonyl, halo, cyano, hydroxy, C 1 ⁇ 6 alkyl group, C 1 ⁇ 10 alkoxy (preferably C 1 ⁇ 6 alkoxy), C 2 ⁇ 10 containing ethylenic, acetylenic bond , optionally substituted benzyloxy, C 1-10 alkylcarbonyloxy, C 1-3 alkoxy methoxy, disubstituted OCH 2 CH 2 O and OCH 2 O, COOH, C 1 ⁇ 6 alkoxycarbonyl, carbamoyl, amino, NR 2 R 3 , C 1-5 alkylcarboxamide, C 3 to 5 alkyl
  • R 2 , R 3 are independently selected from C 1-6 alkyl, or R 2 , R 3 together form a substituted or unsubstituted five- or six-membered cycloalkyl, or a substituted or unsubstituted five containing N, O A unitary or six-membered heterocyclic group.
  • the invention provides a compound of formula (II), or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:
  • X is selected from the group consisting of CH 2 , O, S, NH;
  • A is a benzene ring having 1 to 5 substituents, and each substituent is independently selected from a halogen, a cyano group, a hydroxyl group, a C 1-6 alkyl group or is substituted by a halogen, preferably F, more preferably 1 to 5 F. the C 1 ⁇ 6 alkyl group, C 1 ⁇ 6 alkoxy or halogen, preferably F, more preferably from 1 to 5 F substituted C 1 ⁇ 6 alkoxy;
  • R 4 is independently selected from the group consisting of H, hydroxyl, F, and cyano;
  • R 5 is halogen, cyano, hydroxy, mercapto, or C 1 ⁇ 6 alkyl group having 1 to 5 F atoms, C 1 ⁇ 6 alkyl group, C 1 ⁇ 6 alkoxy, hydroxy, C 1 ⁇ 10 alkyl group A Acyloxy, C 1-3 alkoxy methoxy, COOH, C 1-6 alkoxycarbonyl, carbamoyl, cyanomethylformyl, acetamidomethylformyl, 2-pyrrolyl, formyl-methoxy-methyl, 4-formyl pyran, 4-formyl morpholine, 1-formyl piperazine, C 1 ⁇ 6 alkylthio group having 1 to 5, or F atoms, C 1 ⁇ 6 alkylthio Base, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, acetylamino, methanesulfonamide, methylcarbamoyl, N-prop
  • the invention provides a compound of formula (III), or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:
  • X is selected from O, S, NH;
  • R 4 is independently selected from the group consisting of H and hydroxyl
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, decyl, C 1-2 alkoxy, C 1-2 alkylcarbonyloxy, C 1-3 alkoxy methoxy, COOH, C 1-2 alkoxycarbonyl, carbamoyl, cyanomethylformyl, acetamidomethylformyl, 2-pyrrolyl, methoxycarbonyl, 4-pyranoyl, 4-morpholine formyl, 1-piperazine formyl, methylthio, methylsulfinyl, methylsulfonyl, amino, acetylamino, methanesulfonylamino, methylcarbamoyl, N-propylsulfonyl Amine, N-butylsulfonyl lactam, 4-morphinolinyl, N-methylpiperazin-4-yl, piperazinyl, 3-methylsulfonylpiperazinyl
  • R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, Cl, F, and cyano.
  • the invention provides a compound selected from the group consisting of or a pharmaceutically acceptable salt or prodrug thereof:
  • the invention provides a compound selected from the group consisting of or a pharmaceutically acceptable salt or prodrug thereof:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first aspect of the invention, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier or Shape agent.
  • the pharmaceutical composition is a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, powders.
  • the present invention provides the use of a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for inhibiting DPP-4, treatment Or a drug that prevents diseases related to dipeptidyl peptidase-4 (DPP-4), or as a diuretic or a drug for treating and preventing inflammation.
  • a compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for inhibiting DPP-4, treatment Or a drug that prevents diseases related to dipeptidyl peptidase-4 (DPP-4), or as a diuretic or a drug for treating and preventing inflammation.
  • the dipeptidyl peptidase-4 (DPP-4) associated disease is diabetes, impaired glucose tolerance, intestinal disease, ulcerative colitis, Crohn's disease, obesity or metabolic syndrome.
  • the diabetes is non-insulin dependent type 2 diabetes.
  • the invention provides a process for the preparation of a compound of the first aspect of the invention, the method comprising the steps of:
  • the inventors After extensive and intensive study, has unexpectedly been found that a number of DPP-4 inhibitory activity of new derivatives of benzo six-membered ring; molecular-level activity evaluation, the compounds of the present invention, the DPP-4 inhibition activity IC 50 The value reaches nM level; thus, a new DPP-4 inhibitor with novel structure and excellent activity is obtained; after animal experiment, it is found that the compound of the present invention can have a very beneficial in vivo effect compared with the compound having similar activity in the prior art. , for example, excellent long-term effectiveness. The present invention has been completed on this basis.
  • alkyl refers to a saturated branched or straight-chain alkyl group having a carbon chain length of from 1 to 10 carbon atoms, and preferred alkyl groups include 2-8, 1-6, 1-4 carbon atoms, 3 An alkyl group of -8 carbon atoms and 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, heptyl, and the like.
  • the alkyl group may be substituted by one or more (e.g., 2, 3, 4 or 5) substituents, for example by halogen or haloalkyl.
  • the alkyl group may be an alkyl group substituted with 1 to 5 fluorine atoms, or the alkyl group may be an alkyl group substituted with a fluoroalkyl group.
  • alkoxy refers to an oxy group substituted with an alkyl group.
  • Preferred alkoxy groups are alkoxy groups of 1 to 6 carbon atoms, more preferably alkoxy groups of 1 to 4 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and the like.
  • halogen atom or halogen means fluoro, chloro, bromo and iodo.
  • Aryl means a monocyclic, bicyclic or tricyclic aromatic radical containing from 6 to 14 carbon atoms and includes phenyl, naphthyl, phenanthryl, anthryl, fluorenyl, fluorenyl, tetrahydronaphthyl, Hydrogenated fluorenyl and the like.
  • the aryl group may be optionally substituted with from 1 to 4 (for example, 1, 2, 3 or 4) substituents selected from the group consisting of halogen, C 1-4 aldehyde group, C 1-6 alkyl group, cyano group, Nitro, amino, hydroxy, hydroxymethyl, halogen-substituted alkyl (e.g., trifluoromethyl), carboxyl, C 1-4 alkoxy, ethoxycarbonyl, N(CH 3 ), and C 1-4 acyl Etham, heterocyclic or heteroaryl.
  • substituents selected from the group consisting of halogen, C 1-4 aldehyde group, C 1-6 alkyl group, cyano group, Nitro, amino, hydroxy, hydroxymethyl, halogen-substituted alkyl (e.g., trifluoromethyl), carboxyl, C 1-4 alkoxy, ethoxycarbonyl, N(CH 3 ), and C 1-4 acyl Etham, heterocyclic or
  • aralkyl refers to an alkyl group substituted with an aryl group, such as a C1-6 alkyl group substituted with a phenyl group.
  • aryl groups include, but are not limited to, arylmethyl, arylethyl, and the like, such as benzyl, phenethyl, and the like.
  • an aryl group may be substituted with from 1 to 3 groups selected from the group consisting of halogen, -OH, C1-4 alkoxy, C 1-4 alkyl, -NO 2 , -NH 2 , -N(CH 3 2 , carboxyl, and ethoxylated groups.
  • 5- or 6-membered saturated or unsaturated heterocyclic ring as used herein includes, but is not limited to, a heteroalicyclic or heteroaryl ring containing from 1 to 3 heteroatoms selected from O, S and N, including but not limited to furyl. , thienyl, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, morpholinyl and the like.
  • heteroaryl ring or “heteroaryl” means having 5 to 14 ring atoms and having 6, 10 or 14 electrons shared on the ring system. Further, the ring atom contained is a carbon atom and optionally 1-3 hetero atoms from oxygen, nitrogen, and sulfur.
  • Useful heteroaryl groups include piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, including but not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidinyl and the like.
  • the 5- or 6-membered heterocyclic ring may be optionally substituted with from 1 to 5 (e.g., 1, 2, 3, 4 or 5) substituents selected from the group consisting of halogen, C 1-4 aldehyde, C 1- 6 straight or branched alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), carboxyl, C 1-4 alkoxy, ethoxylated , N(CH 3 ) and C1-4 acyl.
  • 1 to 5 e.g., 1, 2, 3, 4 or 5
  • substituents selected from the group consisting of halogen, C 1-4 aldehyde, C 1- 6 straight or branched alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), carboxyl, C 1-4 alkoxy, ethoxylated , N(CH 3 ) and C1-4 acyl
  • substituent to which it is modified may be optionally substituted with from 1 to 5 (eg, 1, 2, 3, 4 or 5) substituents selected from the group consisting of halogen, C. 1-4 aldehyde, C 1-6 linear or branched alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), carboxyl, C 1- 4 alkoxy, ethoxycarbonyl, N(CH 3 ) and C1-4 acyl.
  • substituents selected from the group consisting of halogen, C. 1-4 aldehyde, C 1-6 linear or branched alkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), carboxyl, C 1- 4 alkoxy, ethoxycarbonyl, N(CH 3 ) and C1-4 acyl.
  • the benzo six-membered ring derivative of the present invention is a compound of the formula I or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:
  • X is selected from the group consisting of CH 2 , O, S, NH;
  • A is an unsubstituted benzene ring or a benzene ring having 1 to 5 substituents, and each substituent is independently selected from a halogen, a cyano group, a hydroxyl group, a C 1-6 alkyl group or a halogen, preferably F, more preferably. substituted with 1 to 5 F is C 1 ⁇ 6 alkyl group, C 1 ⁇ 6 alkoxy or halogen, preferably F, more preferably from 1 to 5 F substituted C 1 ⁇ 6 alkoxy;
  • A may also be selected from nitrogen-containing, sulfur five- or six-membered saturated or unsaturated heterocyclic rings having from 1 to 4 substituents, each substituent being independently selected from the group consisting of halogen, cyano, and boronic acid;
  • the A heterocycle is selected from the following structures:
  • Ring B is selected from the group consisting of a non-existing or aromatic benzene ring, an aromatic heterocyclic ring, a saturated or unsaturated five-membered six-membered ring, or a five- or six-membered saturated or unsaturated heterocyclic ring containing nitrogen, oxygen and sulfur
  • the substituent R 1 carbonyl group is independently selected from alkoxycarbonyl, halo, cyano, hydroxy, C 1 ⁇ 6 alkyl group, C 1 ⁇ 10 alkoxy (preferably C 1 ⁇ 6 alkoxy), C 2 ⁇ 10 containing ethylenic, acetylenic bond , optionally substituted benzyloxy, C 1-10 alkylcarbonyloxy, C 1-3 alkoxy methoxy, disubstituted OCH 2 CH 2 O and OCH 2 O, COOH, C 1 ⁇ 6 alkoxycarbonyl, carbamoyl, amino, NR 2 R 3 , C 1-5 alkylcarboxamide
  • R 2 , R 3 are independently selected from C 1-6 alkyl, or R 2 , R 3 together form a substituted or unsubstituted five- or six-membered cycloalkyl, or a substituted or unsubstituted five containing N, O A unitary or six-membered heterocyclic group.
  • the compound of the invention is a compound of formula (II), or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:
  • X is selected from the group consisting of CH 2 , O, S, NH;
  • A is a benzene ring having 1 to 5 substituents, and each substituent is independently selected from a halogen, a cyano group, a hydroxyl group, a C 1-6 alkyl group or is substituted by a halogen, preferably F, more preferably 1 to 5 F. the C 1 ⁇ 6 alkyl group, C 1 ⁇ 6 alkoxy or halogen, preferably F, more preferably from 1 to 5 F substituted C 1 ⁇ 6 alkoxy;
  • R 4 is independently selected from the group consisting of H, hydroxyl, F, and cyano;
  • R 5 is halogen, cyano, hydroxy, mercapto, or C 1 ⁇ 6 alkyl group having 1 to 5 F atoms, C 1 ⁇ 6 alkyl group, C 1 ⁇ 6 alkoxy group, C 1 ⁇ 3 alkoxy methoxy Base, hydroxy, COOH, C 1-6 alkoxycarbonyl, carbamoyl, cyanomethylformyl, acetamidomethylformyl, 2-pyrrolyl, methoxycarbonyl, 4-pyridyl formyl pyran, 4-formyl morpholine, 1-formyl piperazine, C 1 ⁇ 6 alkylthio group having 1 to 5, or F atoms, C 1 ⁇ 6 alkylthio group, C 1 ⁇ 6 alkyl sulfinyl group, C 1-6 alkylsulfonyl, amino, acetylamino, methanesulfonylamino, methylcarbamoyl, N-propyl
  • the absolute configuration is IIa.
  • the compound of the present invention is a compound of the formula (III) or a pharmaceutically acceptable salt or prodrug thereof, or an optically active isomer or solvate thereof:
  • X is selected from O, S, NH;
  • R 4 is independently selected from the group consisting of H and hydroxyl
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, decyl, C 1-2 alkoxy, C 1-2 alkylcarbonyloxy, C 1-3 alkoxy methoxy, COOH, C 1-2 alkoxycarbonyl, carbamoyl, cyanomethylformyl, acetamidomethylformyl, 2-pyrrolyl, methoxycarbonyl, 4-pyranoyl, 4-morpholine formyl, 1-piperazine formyl, methylthio, methylsulfinyl, methylsulfonyl, amino, acetylamino, methanesulfonylamino, methylcarbamoyl, N-propylsulfonyl Amine, N-butylsulfonyl lactam, 4-morphinolinyl, N-methylpiperazin-4-yl, piperazinyl, 3-methylsulfonylpiperazinyl
  • R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, Cl, F, and cyano.
  • the compounds of the invention are as follows:
  • the invention also provides a compound as shown below:
  • the compounds all contain more than one chiral carbon and may exist as optically pure isomers and enantiomers, and the invention includes all forms.
  • the invention also relates to a process for the preparation of the above formulae (I) to (III), which is now described by the preparation method of (III):
  • the reduction of the amino compound (III) is carried out by a usual reduction process such as catalytic hydrogenation reduction in a solvent such as methanol or ethanol, using a Raney nickel, a metal Pd or a metal platinum, etc.; a conventional metal and an acid and an acid salt.
  • the reducing conditions, commonly used metals include Zn, Fe, the acid used includes hydrochloric acid, sulfuric acid, acetic acid, acid salts such as ammonium chloride and the like.
  • the reduction reaction temperature is 20 to 80 °C.
  • the nitro compound (IV) is prepared by reduction of the nitro double bond compound (III), using sodium borohydride in a mixed solvent, the mixed solvent is THF and methanol, the ratio is 20:1 to 1:1; the reduction reaction temperature is 20 ⁇ 80 ° C.
  • the aldehyde group compound (VII) of the electron-rich group X is obtained by condensation.
  • the basic catalyst includes an organic base such as triethylamine, diisopropylethylamine, and trivinyldiamine, and the metal base includes a format reagent, butyl lithium, LDA, and the like.
  • the reaction temperature is -80 ° C to 80 ° C.
  • Nitrovinylbenzene (VI) is prepared by the condensation of substituted benzaldehyde and nitromethane.
  • the base used includes inorganic base NaOH, KOH, and the organic base includes triethylamine, diisopropylethylamine, trivinyldiamine.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula I, II or III of the present invention or a pharmaceutically acceptable salt thereof, in addition to the novel compounds of the present invention.
  • a pharmaceutically acceptable carrier or excipient e.g., a pharmaceutically acceptable styrene, a pharmaceutically acceptable styrene, a pharmaceutically acceptable styrene, a pharmaceutically acceptable salt thereof, in addition to the novel compounds of the present invention.
  • a pharmaceutically acceptable carrier or excipient e.g., a pharmaceutically acceptable carrier or excipient.
  • Examples of pharmaceutically acceptable salts of the compounds of the invention include, but are not limited to, inorganic and organic acid salts such as the hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate salts. , fumarate, mandelate and oxalate; and inorganic and formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methyl glucosamine Organic base salt.
  • inorganic and organic acid salts such as the hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate salts. , fumarate, mandelate and oxalate
  • bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methyl glucosamine Organic base salt.
  • compositions of the present invention may be formulated in a form suitable for various routes of administration, including but not limited to, formulated for oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal , in the form of intracranial, nasal or topical routes of administration for the treatment of DPP-4 related diseases.
  • the compounds of the invention are formulated for oral administration.
  • the amount administered is an amount effective to ameliorate or eliminate one or more conditions.
  • an effective amount is an amount sufficient to ameliorate or in some way alleviate the symptoms associated with the disease.
  • Such doses can be administered as a single dose or can be administered according to an effective therapeutic regimen.
  • the amount administered may cure the disease, but administration is usually to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired improvement in symptoms.
  • the dosage of the drug will be determined by the age of the patient, the health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.
  • the pharmaceutical preparation of the present invention can be administered to any mammal as long as they can obtain the therapeutic effect of the compound of the present invention.
  • the mammal is a human.
  • the compounds of the invention or pharmaceutical combinations thereof are useful for the treatment of diseases associated with the prevention of dipeptidyl peptidase-4 (DPP-4).
  • DPP-4 related diseases mainly include: diabetes, especially non-insulin dependent type 2 diabetes, impaired glucose tolerance, intestinal disease, ulcerative colitis, Crohn's disease, obesity or metabolic syndrome .
  • the compounds of the invention may also be used in the prevention and treatment of diuretics or inflammation.
  • the pharmaceutical preparations of the invention can be made in a known manner. For example, it is manufactured by a conventional mixing, granulating, tableting, dissolving, or freeze drying process. In the manufacture of oral formulations, the mixture can be selectively milled by combining the solid adjuvant with the active compound. If necessary or necessary, after adding an appropriate amount of auxiliary agent, the mixture of particles is processed to obtain a tablet or tablet core.
  • Suitable excipients are, in particular, fillers, such as sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, including corn starch. , wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, or polyvinylpyrrolidone.
  • fillers such as sugars such as lactose or sucrose, mannitol or sorbitol
  • cellulose preparations or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch pastes, including corn starch. , wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl
  • a disintegrating agent such as the above-mentioned starch, and carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added.
  • Adjuvants are especially flow regulators and lubricants, for example, silica, talc, stearates such as calcium magnesium stearate, stearic acid or polyethylene glycol.
  • the tablet core can be provided with a suitable coating that is resistant to gastric juice. For this purpose, a concentrated sugar solution can be applied.
  • This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture.
  • a suitable cellulose solution such as cellulose acetate phthalic acid or hydroxypropyl methylcellulose phthalic acid can be used.
  • a dye or pigment can be added to the coating of the tablet or tablet core. For example, a combination for identifying or for characterizing the dosage of an active ingredient.
  • prodrugs of the compounds of the invention are also included within the scope of the invention.
  • the term "prodrug” as used herein has the same meaning as commonly understood by one of ordinary skill in the art, that is, a compound having pharmacological activity obtained by chemical structural modification is inactive or less active in vitro, and is enzymatic in vivo. Or a non-enzymatic conversion that releases the active drug to exert a pharmacological effect.
  • the prodrug itself has no biological activity or low activity, and becomes an active substance after being metabolized in the body, thereby increasing the bioavailability of the drug, enhancing the targeting, and reducing the toxicity and side effects of the drug.
  • the prodrug of the compound of the present invention includes a derivative such as an ester or an amide obtained by chemically modifying the compound of the present invention.
  • the present invention also provides a method of treating or preventing a dipeptidyl peptidase-4 (DPP-4)-related disease, including but not limited to diabetes In particular, non-insulin dependent type 2 diabetes, impaired glucose tolerance, intestinal disease, ulcerative colitis, Crohn's disease, obesity or metabolic syndrome.
  • the method includes The subject in need thereof obtains a pharmaceutically acceptable salt, or a pharmaceutical composition of the present invention, with a compound of the formula I, II or III of the present invention.
  • Methods of administration include, but are not limited to, various methods of administration well known in the art, which can be determined based on the actual circumstances of the patient. These methods include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, nasal or topical routes of administration.
  • the present invention includes a compound of the formula I, II or III of the present invention or a pharmaceutically acceptable salt thereof for the preparation of a disease associated with the treatment or prevention of dipeptidyl peptidase-4 (DPP-4), including Not limited to) the use of diabetes, especially in non-insulin dependent type 2 diabetes, impaired glucose tolerance, intestinal disease, ulcerative colitis, Crohn's disease, obesity or metabolic syndrome DPP-4 mediated diseases; Use in the preparation of a medicament for inhibiting DPP-4; and use in the preparation of a medicament as a diuretic and for the treatment and prevention of inflammation.
  • DPP-4 dipeptidyl peptidase-4
  • the compound of the present invention is a novel structure of DPP-4 inhibitor
  • the compound of the present invention is excellent in inhibitory activity against DPP-4;
  • the compound of the present invention can replace the existing hypoglycemic drugs, has great industrialization and commercialization prospects and market value, and has significant economic benefits.
  • 2.7-Dimethoxy-1-naphthaldehyde (6.0 g, 27.9 mmol) was weighed into 45 ml of dry dichloromethane. AlCl 3 (11.1 g, 83.4 mmol) was added in portions. The mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was poured into 150 ml of brine, and the organic phase was extracted with ethyl acetate (2*150 ml) and the organic phase was washed twice with brine. (2*150 ml) dried over anhydrous sodium sulfate and evaporated to dryness. The yield was 61.3%.
  • LC-MS 203.05 (M + 1) +, 201.05 (M-1) -.
  • the above compound (6 g, 22.8 mmol) was weighed into 5 ml of water, 4 ml of concentrated sulfuric acid, and then added with 80 ml of diethyl ether. The mixture was stirred at room temperature for 4 d. g yellow solid. The yield was 35%.
  • 1,1-dichloromethyl ether (0.62 g, 0.0054 mol) was weighed in a 250 mL round bottom flask, dissolved in an appropriate amount of dichloromethane, and titanium tetrachloride (2.0 g, 0.0102) was added at 0 °C. Mol), stirring at 0 ° C for 15 min; weigh 6,7-dimethoxy-2-naphthol (1 g, 0.0049 mol) dissolved in a suitable amount of dichloromethane solution, added dropwise to the above In the solution, the solution changes from light yellow to red. After the dropwise addition, the solution is allowed to react at room temperature overnight.
  • the crude compound 15-2 obtained above was dissolved in 10 mL of an ethanol solution, and 6 mL of 6N hydrochloric acid and zinc powder (1.10 g, 1.70 mmol) was added to the solution, and the reaction was carried out at normal temperature and normal pressure overnight until the reaction solution was a clear and transparent solution. After the reaction, saturated NaHCO 3 was added to the solution, and the solution was neutralized to neutrality, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous Na 2 SO 4 ; Column chromatography gave 920 mg of white product in a two step yield of 84%. LC-MS: 330.10 (M+1) + .
  • the compound 6-methoxy-2-naphthylamine (7 g, 0.04044 mol), triethylamine (6 g, 0.06067 mol) was weighed into a 100 mL reaction flask, and 15 mL of a dichloromethane solution was added to the reaction flask at 0 The reaction was carried out for 15 min at °C; methanesulfonyl chloride (7 g, 0.06067 mol) was added dropwise, and the reaction was carried out for 30 min at 0 °C, and the mixture was monitored by TLC. After the reaction was completed, an appropriate amount of aqueous sodium hydroxide solution was added, and ethyl acetate was extracted and saturated brine.
  • 1,1-Dichloromethyl ether (1.374 g, 0.0118 mol) was weighed into a 250 mL eggplant-shaped flask, 30 mL of dichloromethane was added to the solvent, and TiCl 4 (2.2 mL, 0.0199 mol) was added to the solution. Stirring at 0 ° C for 15 min; weighed compound 16-1 (2 g, 0.0080 mol) was dissolved in an appropriate amount of dichloromethane, added dropwise to the above reaction solution, stirred at room temperature for 36 h, after the reaction was completed, an appropriate amount of 1 N was added.
  • the compound (0.5 g, 0.0012 mol) was weighed into a 250 mL round bottom flask, and 150 mL of a mixture of THF/CH 3 OH (10:1) was added to the bottle to dissolve the solid, and sodium borohydride was added to the solution in portions. (459mg, 0.0121mol), the bottle mouth plus drying tube, the reaction liquid quickly changed from bright orange red to pale yellow, under normal temperature and normal pressure conditions, the reaction was 20min; after the reaction was completed, the reaction liquid was quenched with water The reaction was extracted with ethyl acetate and dried over anhydrous sodium sulfate.
  • the compound obtained above was dissolved in 30 ml of ethanol solution, Zn powder (1.388 g, 21.353 mmol) was added, 6 ml of 6N HCl solution was added, and the reaction was carried out under normal temperature and pressure for 2-3 hours, and the TLC plate was monitored. After the reaction was completed, The reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was evaporated. Crude).
  • 1,1-Dichloromethyl ether (3.65 g, 0.0318 mol) was weighed into a 500 mL eggplant-shaped flask, 30 mL of dichloromethane was added to the solvent, and TiCl 4 (5.8 mL, 0.0530 mol) was added to the solution. The mixture was stirred at 0 ° C for 15 min; 6-bromo-2-methoxynaphthalene (5 g, 0.0212 mol) was weighed into an appropriate amount of dichloromethane, and added dropwise to the above reaction solution, and stirred at room temperature for 36 h.
  • the compound 18-6 (350 mg, 0.7917 mmol) was weighed into a 250 mL round bottom flask, and 33 ml of a mixture of THF/CH 3 OH (10:1) was added to the bottle to dissolve the solid, and boron was added to the solution in portions.
  • Sodium hydride (200mg, 5.284mmol), with a dry tube at the mouth of the bottle, reacted under normal temperature and normal pressure for 20min, the reaction solution changed from deep red to pale yellow; after the reaction was completed, water was added to the reaction solution to quench the reaction, acetic acid The ethyl ester was extracted, dried over anhydrous sodium sulfate, and the solution was applied to the next step.
  • the compound obtained above was dissolved in 30 ml of ethanol solution, Zn powder (835 mg, 12.85 mmol) was added, 6 ml of 6N HCl solution was added, and the reaction solution was stirred for 2-3 hours under normal temperature and normal pressure, and the reaction solution was mixed with saturated sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness.
  • the compound 19-1 (3.2 g, 0.01211 mol) was weighed into 250 ml of dry dichloromethane; AlCl 3 (18.2529 g, 0.1369 mol) was added in portions, and stirred under normal temperature and normal pressure for 36 h. The mixture was poured into brine, extracted with ethyl acetate, and the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. g, the yield was 41.25%.
  • the compound obtained above was dissolved in 30 ml of ethanol solution, Zn powder (1.388 g, 21.353 mmol) was added, 6 ml of 6N HCl solution was added, and the reaction was carried out under normal temperature and pressure for 2-3 hours, and the TLC plate was monitored. After the reaction was completed, The reaction solution is saturated The mixture was neutralized with a sodium hydrogencarbonate solution, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness.
  • the reaction was carried out for 20 min under normal temperature and normal pressure; after the reaction was completed, water was added to the reaction solution to quench the reaction, and ethyl acetate was extracted. The aqueous sodium sulfate was dried, and dried, and used directly for the next reaction.
  • the crude nitrile 59 is dissolved in 80 ml of ethanol solution, Zn powder (3.45 g, 0.053 mol) is added, 16 ml of 6N HCl solution is added, and the reaction is carried out under normal temperature and pressure for 2-3 hours, and the reaction is completed by TLC plate.
  • the solution was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate.
  • EtOAc EtOAc EtOAc EtOAc EtOAc The rate is 32.7%.
  • the compound 23-2 (2.38 g, 6.779 mmol) was weighed into a 50 mL round bottom flask, and 20 ml of a mixture of THF/CH 3 OH (10:1) was added to the bottle, and the solid was dissolved and added to the solution in portions.
  • Sodium borohydride (317 mg, 11.391 mmol), with a dry tube at the mouth of the bottle, under normal temperature and normal pressure, react for 20 min until the solution is clarified; after the reaction is complete, the reaction solution is quenched with water, extracted with ethyl acetate, anhydrous Dry over sodium sulfate, spin dry the solution and use directly for the next reaction.
  • the compound 24-2 (2.50 g, 6.779 mmol) was weighed into a 50 mL round bottom flask, and 20 ml of a mixture of THF/CH 3 OH (10:1) was added to the bottle, and the solid was dissolved and added to the solution in portions.
  • Sodium borohydride (317 mg, 11.391 mmol), with a dry tube at the mouth of the bottle, under normal temperature and normal pressure, react for 20 min until the solution is clarified; after the reaction is complete, the reaction solution is quenched with water, extracted with ethyl acetate, anhydrous Dry over sodium sulfate, spin dry the solution and use directly for the next reaction.
  • the compound obtained above was dissolved in 50 ml of ethanol solution, Zn powder (78 mg, 1.2 mmol) was added, 2 ml of 6N HCl solution was added, and the reaction was carried out at 50 ° C for 2 h, and the reaction solution was neutralized with a saturated sodium hydrogencarbonate solution, acetic acid.
  • the compound 30-1 (52 mg, 0.120 mmol) was weighed into a 50 mL round bottom flask, and 5 ml of a mixture of THF/CH 3 OH (10:1) was added to the bottle to dissolve the solid, and boron was added to the solution in portions.
  • Sodium hydride (9.08 mg, 0.240 mmol), with a dry tube at the mouth of the bottle, under normal temperature and normal pressure, react for 20 min until the solution is clarified; after the reaction is complete, the reaction solution is quenched with water, extracted with ethyl acetate, anhydrous Dry over sodium sulfate, spin dry the solution and use directly for the next reaction.
  • DPP4 dipeptidyl peptidase 4
  • alias CD26; ADABP; ADCP2; DPPIV; TP103
  • English full name dipeptidyl-peptidase 4 (CD26, adenosine deaminase complexing protein.
  • MATERIALS Human DPP4, which was expressed in insect cells using the baculovirus expression system. Substrate Gly-Pro-AMC.
  • DPP4 can specifically hydrolyze the substrate Gly-Pro-AMC to produce product AMC.
  • AMC is excited by 355nm ultraviolet light to generate 460nm emission light, and the fluorescence value at 460nm per unit time is dynamically measured, and DPP4 activity is calculated.
  • the experiment used MERK-0431 as a control compound.
  • the sample was dissolved in DMSO, stored at low temperature, and the concentration of DMSO in the final system was controlled to a range that did not affect the activity of the assay.
  • the activity of the sample was tested by initial screening at a single concentration, for example 20 ⁇ g/ml.
  • the inhibition rate is greater than 50%
  • the test activity dose dependence ie IC 50 /EC 50 value
  • the model used for fitting is sigmoidaldose-response (varible slope)
  • the bottom and top of the fitted curve are set to 0 and 100.
  • each sample is provided with a duplicate hole (n ⁇ 2) in the test, and the result is expressed by Standard Deviation (SD) or Standard Error (SE).
  • the results of the activity data show that the compounds of the present invention have an inhibitory IC 50 value of DPP-4 of about 50 nM, which is comparable to the control compound; and some of these compounds can even reach levels below 10 nM (see table below).
  • evaluation of the activity of the enzyme level shows that the activity of the compound of the present invention can be achieved even better than the existing drug.

Abstract

本发明涉及作为DPP-4抑制剂的苯并六元环衍生物及其应用。具体而言，本发明涉及式I所示化合物、含有式I化合物的药物组合物及所述化合物在制备治疗DPP-4相关疾病或抑制DPP-4的药物中的用途。

Description

作为DPP-4抑制剂的苯并六元环衍生物及其应用 技术领域
本发明涉及药物化学领域；具体地说，本发明涉及新型的苯并六元环衍生物，其合成方法及其在制备治疗2型糖尿病以及相关疾病的药物中的应用。
背景技术
糖尿病(Diabetes Mellitus，DM)是一种血液中葡萄糖(血糖)水平增高为特征的代谢疾病，是由遗传因素与环境因素共同作用而引起的一种缓慢进展性疾病。随着人们生活水平的提高，糖尿病患者人数快速增加。据国际糖尿病联盟统计，2012年全球约有3.71亿糖尿病患者，而中国糖尿病人数达到9000万，成为全球患病人数最多的国家(Wild,S.；Roglic,G.；Green,A.；Sicree,R.；King,H.Diabetes Care.2004,27,1047-1053.)。每年全世界约有380万人死于糖尿病，与艾滋病一起并列排在仅次于肿瘤、心血管疾病之后第三位。
根据发病机制，糖尿病可分为1型和2型。1型糖尿病主要由于自身免疫对胰岛β细胞破坏后造成内源性胰岛素分泌不足，即胰岛素绝对缺乏，患者需要通过胰岛素来治疗。2型糖尿病是由于胰岛β细胞功能障碍等原因引起胰岛素分泌减少或者是胰岛素抵抗(Insulin Resistance)，即，胰岛素相对缺乏而导致糖、蛋白质和脂肪代谢异常。
对糖尿病的治疗临床上主要采用多种口服降糖药和胰岛素补充来延缓糖尿病进程。然而，这些方法有时无法达到预期治疗效果，且存在诱发低血糖、心血管疾病等副作用，对损伤的胰岛细胞也没有保护作用。随着对糖尿病的发病机制的深入了解，依据发病关键靶点作用机制寻找有效的降糖药物成为研究热点。
二肽基肽酶-4(Dipeptidyl peptidase-4，DPP-4)已经证明是治疗2型糖尿病的有效靶点，它能迅速降解肠胰岛素血糖素样肽-1(glucagon-like peptide 1,GLP-1)和葡萄糖依赖性胰岛素释放肽(glucose-dependent insulinotropic polypeptide,GIP)等多种重要的肠促胰岛素(Incretin)，从而导致胰岛素分泌不足。因此，DPP-4抑制剂可以提高GLP-1和GIP的活性，促进胰岛素分泌，降低血糖。
临床试验表明，DPP-4抑制剂可以降低血糖水平，增加葡萄糖耐量，且没有出现体重增加和低血糖等副作用。目前，已应用于临床的DPP-4抑制剂有西格列汀(Sitagliptin)、沙格列汀(Saxagliptin)、维格列汀(Vildagliptin)、阿格列汀(Alogliptin)和利格列汀(Linagliptin)(Havale,S.H.；Pal,M.Bioorg.Med.Chem.2009,17,1783-1802；Gupta,R.；Walunj,S.S.；Tokala,R.K.；Parsa,K.V.；Singh,S.K.；Pal,M.Curr.Drug.Targets,2009,10,71-87.)。作为DPP-4抑制剂的降糖药物已经是降糖药物市场的主导，例如默沙东公司的西格列汀在2009年销售额达到131亿美元，是唯一突破百亿元降糖药物。
然而，目前所有上市的DPP-4抑制剂都处于专利保护期内，还有多种新型DPP-4抑制剂处于临床元研究阶段。因此，本领域急需研发新型、高效、低毒性的DPP-4抑制剂。
发明内容
本发明的目的在于提供一种具备全新结构的、高效、低毒、能够作为新型DPP-4抑制剂的化合物，包含所述化合物的药物组合物、所述化合物的制备方法以及所述化合物在制备预防或治疗DPP-4相关疾病的药物中的用途。
在第一方面，本发明提供通式I所示化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物：
Figure PCTCN2015093384-appb-000001
式中：
X选自CH2、O、S、NH；
A是未取代的苯环或带有1～5个取代基的苯环，每个取代基独立的选自卤素、氰基、羟基、C1～6烷基或被卤素、优选F，更优选1～5个F取代的C1～6烷基、C1～6烷氧基或被卤素、优选F，更优选1～5个F取代的C1～6烷氧基；
A还可选自具有1-4个取代基的含氮、硫五元或六元饱和或不饱和杂环，各取代基独立选自卤素、氰基、硼酸基；
A杂环选自以下结构：
Figure PCTCN2015093384-appb-000002
R为H、卤素、氰基、羟基、C1～6烷基或含1～5个F原子C1～6烷基、C1～6烷氧基或含1～5个F原子C1～6烷氧基，n＝1-2；
环B不存在或选自芳香苯环、芳杂环、饱和或不饱和的五元六元环、含氮、氧和硫的五元或六元饱和或不饱和杂环，其取代基R1独立选自羰基、卤素、氰基、羟基、C1～6烷基、C1～10烷氧基(优选C1～6烷氧基)、C2～10含烯键、炔键的烷氧基、任选取代的苄氧基、C1～10烷基甲酰氧基、C1～3烷氧基甲氧基、双取代基OCH2CH2O和OCH2O、COOH、C1～6烷氧甲酰基、氨基甲酰基、氨基、NR2R3、C1～5烷基甲酰胺基、C3～5烷基内酰胺基、C1～6烷基磺酰胺基、C3～5烷基内磺酰胺基、巯基、C1～5烷基巯基、C1～5烷基磺酰基、C3～5环烷基磺酰基、C1～5烷基亚磺酰基，m＝1～4；
R2、R3独立选自C1～6烷基，或者，R2、R3一起形成取代或未取代的五元或六元环烷基、或含N、O的取代或未取代的五元或六元杂环基。
在优选的实施方式中，本发明提供通式(II)所示化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物：
Figure PCTCN2015093384-appb-000003
其中，
X选自CH2、O、S、NH；
A是带有1～5个取代基的苯环，每个取代基独立的选自卤素、氰基、羟基、C1～6烷基或被卤素、优选F，更优选1～5个F取代的C1～6烷基、C1～6烷氧基或被卤素、优选F，更优选1～5个F取代的C1～6烷氧基；
R4独立选自H、羟基、F、氰基；
R5为卤素、氰基、羟基、巯基、C1～6烷基或含1～5个F原子C1～6烷基、C1～6烷氧基、羟基、C1～10烷基甲酰氧基、C1～3烷氧基甲氧基、COOH、C1～6烷氧甲酰基、氨基甲酰基、氰基甲基甲酰基、乙酰氨基甲基甲酰基、2-吡咯甲酰基、甲氧基甲酰甲基、4-吡喃甲酰基、4-吗啡啉甲酰基、1-哌嗪甲酰基、C1～6烷硫基或含1～5个F原子C1～6烷硫基、C1～6烷亚磺酰基、C1～6烷磺酰基、氨基、乙酰氨基、甲磺酰胺基、甲氨基甲酰胺基、N-丙磺酰内胺、N-丁磺酰内胺、4-吗啡啉基、N-甲基哌嗪-4-基、哌嗪基、3-甲磺酰基哌嗪基、3,3-二氟四氢吡咯基、2-氨基甲酰基哌啶基、3-吡唑氨基，q＝1～4。
在优选的实施方式中，本发明提供通式(III)所示化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物：
Figure PCTCN2015093384-appb-000004
其中，
X选自O、S、NH；
R4独立选自H、羟基；
R6、R7为独立选自氢、卤素、氰基、羟基、巯基、C1～2烷氧基、C1～2烷基甲酰氧基、C1～3烷氧基甲氧基、COOH、C1～2烷氧甲酰基、氨基甲酰基、氰基甲基甲酰基、乙酰氨基甲基甲酰基、2-吡咯甲酰基、甲氧基甲酰甲基、4-吡喃甲酰基、4-吗啡啉甲酰基、1-哌嗪甲酰基、甲硫基、甲基亚磺酰基、甲磺酰基、氨基、乙酰氨基、甲磺酰胺基、甲氨基甲酰胺基、N-丙磺酰内胺、N-丁磺酰内胺、4-吗啡啉基、N-甲基哌嗪-4-基、哌嗪基、3-甲磺酰基哌嗪基、3,3-二氟四氢吡咯基、2-氨基甲酰基哌啶基、3-吡唑氨基；
R8、R9和R10独立选自氢、Cl、F、氰基。
在另一优选的实施方式中，本发明提供选自下组的化合物或其药学上可接受的盐或前药：
Figure PCTCN2015093384-appb-000005
Figure PCTCN2015093384-appb-000006
在其它优选的实施方式中，本发明提供选自下组的化合物或其药学上可接受的盐或前药：
Figure PCTCN2015093384-appb-000007
在第二方面，本发明提供一种药物组合物，所述药物组合物含有本发明第一方面所述的化合物或其药学上可接受的盐或前药，以及药学上可接受的载体或赋形剂。
在优选的实施方式中，所述药物组合物是适于口服的剂型，包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。
在第三方面，本发明提供本发明第一方面所述的化合物或其药学上可接受的盐的用途，所述化合物或其药学上可接受的盐用于制备抑制DPP-4的药物、治疗或预防二肽基肽酶-4(DPP-4)相关疾病的药物，或作为利尿剂或治疗和预防炎症的药物。
在优选的实施方式中，所述二肽基肽酶-4(DPP-4)相关的疾病是糖尿病、糖耐量异常、肠道病、溃疡性结肠炎、克隆氏病、肥胖或代谢综合征。
在进一步优选的实施方式中，所述糖尿病是非胰岛素依赖的2-型糖尿病。
在第四方面，本发明提供本发明第一方面所述化合物的制备方法，所述方法包括以下步骤：
Figure PCTCN2015093384-appb-000008
其中，X、A、R、B、R1如上文所定义。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的 各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
发明人经过广泛而深入的研究，出乎意料地发现一批具有DPP-4抑制活性的新型苯并六元环衍生物；经分子水平活性评价，本发明化合物对DPP-4的抑制活性IC50值达到nM级别；从而得到结构全新、活性优异的新DPP-4抑制剂；经过动物实验研究，发现本发明的化合物相比于现有技术中具有类似活性的化合物还能具备非常有益的体内效果，例如优异的长效性。在此基础上完成了本发明。
基团定义
本文中涉及到的一些基团定义如下：
本文中，“烷基”指碳链长度为1-10个碳原子的饱和的支链或直链烷基，优选的烷基包括2-8、1-6、1-4个碳原子、3-8个碳原子、1-3个碳原子不等的烷基。烷基的例子包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、庚基等。
烷基可以被1个或多个(例如2、3、4或5个)取代基取代，例如被卤素或卤代烷基取代。例如，烷基可以是被1-5个氟原子取代的烷基，或者烷基可以是被氟代烷基取代的烷基。
本文中，“烷氧基”指被烷基取代的氧基。优选的烷氧基是1-6个碳原子的烷氧基，更优选为1-4个碳原子的烷氧基。烷氧基的例子包括但不限于甲氧基、乙氧基、丙氧基等。
本文中，“卤素原子”或“卤素”指氟、氯、溴和碘。
“芳基”指含有6到14个碳原子的单环、双环或三环芳族基团，包括苯基、萘基、菲基、蒽基、茚基、茀基、四氢化萘基、二氢化茚基等。芳基可任选地被1-4个(例如，1、2、3或4个)选自以下的取代基取代：卤素、C1-4醛基、C1-6烷基、氰基、硝基、氨基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、羧基、C1-4烷氧基、乙氧甲酰基、N(CH3)和C1-4酰基等、杂环基或杂芳基等。
本文中，“芳烷基”指被芳基取代的烷基，例如被苯基取代的C1-6烷基。芳烷基的例子包括但不限于芳基甲基、芳基乙基等，例如苄基、苯乙基等。
例如，芳基可以被1-3个选自以下的基团取代：卤素、-OH、C1-4烷氧基、C1-4烷基、-NO2、-NH2、-N(CH3)2、羧基、和乙氧甲酰基等。
本文所用的“5元或6元饱和或不饱和杂环”包括但不限于含有1-3个选自O、S和N的杂原子的杂脂环或杂芳环，包括但不限于呋喃基、噻吩基、吡咯基、吡咯烷基、吡唑基、咪唑基、三唑基、噁唑基、吡喃基、吡啶基、嘧啶基、吡嗪基、哌啶基、吗啉基等。
本文所用“杂芳环”或“杂芳基”是指含有5-14个环原子，并且有6个，10个或14个电子在环体系上共用。而且所含环原子是碳原子和从氧、氮、硫中任选的1-3个杂原子。有用的杂芳基包括哌嗪基、吗啉基、哌啶基、吡咯烷基、噻吩基、呋喃基、吡喃基、吡咯基、咪唑基、吡唑基、吡啶基、包括但不限制于2-吡啶基、3-吡啶基和4-吡啶基、吡嗪基、嘧啶基等。
5元或6元杂环可任选地被1-5个(例如，1、2、3、4或5个)选自以下的取代基取代：卤 素、C1-4醛基、C1-6直链或支链烷基、氰基、硝基、氨基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、羧基、C1-4烷氧基、乙氧甲酰基、N(CH3)和C1-4酰基。
本文中，“任选取代的”指其所修饰的取代基可任选地被1-5个(例如，1、2、3、4或5个)选自以下的取代基取代：卤素、C1-4醛基、C1-6直链或支链烷基、氰基、硝基、氨基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、羧基、C1-4烷氧基、乙氧甲酰基、N(CH3)和C1-4酰基。
本发明所述苯并六元环衍生物是通式I所示化合物或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物：
Figure PCTCN2015093384-appb-000009
式中：
X选自CH2、O、S、NH；
A是未取代的苯环或带有1～5个取代基的苯环，每个取代基独立的选自卤素、氰基、羟基、C1～6烷基或被卤素、优选F，更优选1～5个F取代的C1～6烷基、C1～6烷氧基或被卤素、优选F，更优选1～5个F取代的C1～6烷氧基；
A还可选自具有1-4个取代基的含氮、硫五元或六元饱和或不饱和杂环，各取代基独立选自卤素、氰基、硼酸基；
A杂环选自以下结构：
Figure PCTCN2015093384-appb-000010
R为H、卤素、氰基、羟基、C1～6烷基或含1～5个F原子C1～6烷基、C1～6烷氧基或含1～5个F原子C1～6烷氧基，n＝1-2；
环B选自不存在或芳香苯环、芳杂环、饱和或不饱和五元六元环、或含氮、氧和硫的五元或六元饱和或不饱和杂环，其取代基R1独立选自羰基、卤素、氰基、羟基、C1～6烷基、C1～10烷氧基(优选C1～6烷氧基)、C2～10含烯键、炔键的烷氧基、任选取代的苄氧基、C1～10烷基甲酰氧基、C1～3烷氧基甲氧基、双取代基OCH2CH2O和OCH2O、COOH、C1～6烷氧甲酰基、氨基甲酰基、氨基、NR2R3、C1～5烷基甲酰胺基、C3～5烷基内酰胺基、C1～6烷基磺酰胺基、C3～5烷基内磺酰胺基、巯基、C1～5烷基巯基、C1～5烷基磺酰基、C3～5环烷基磺酰基、C1～5烷基亚磺酰 基，m＝1～4；
R2、R3独立选自C1～6烷基，或者，R2、R3一起形成取代或未取代的五元或六元环烷基、或含N、O的取代或未取代的五元或六元杂环基。
在具体实施例中，本发明的化合物是通式(II)所示化合物或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物：
Figure PCTCN2015093384-appb-000011
其中，
X选自CH2、O、S、NH；
A是带有1～5个取代基的苯环，每个取代基独立的选自卤素、氰基、羟基、C1～6烷基或被卤素、优选F，更优选1～5个F取代的C1～6烷基、C1～6烷氧基或被卤素、优选F，更优选1～5个F取代的C1～6烷氧基；
R4独立选自H、羟基、F、氰基；
R5为卤素、氰基、羟基、巯基、C1～6烷基或含1～5个F原子C1～6烷基、C1～6烷氧基、C1～3烷氧基甲氧基、羟基、COOH、C1～6烷氧甲酰基、氨基甲酰基、氰基甲基甲酰基、乙酰氨基甲基甲酰基、2-吡咯甲酰基、甲氧基甲酰甲基、4-吡喃甲酰基、4-吗啡啉甲酰基、1-哌嗪甲酰基、C1～6烷硫基或含1～5个F原子C1～6烷硫基、C1～6烷亚磺酰基、C1～6烷磺酰基、氨基、乙酰氨基、甲磺酰胺基、甲氨基甲酰胺基、N-丙磺酰内胺、N-丁磺酰内胺、4-吗啡啉基、N-甲基哌嗪-4-基、哌嗪基、3-甲磺酰基哌嗪基、3,3-二氟四氢吡咯基、2-氨基甲酰基哌啶基、3-吡唑氨基，q＝1～4。
在结构通式(II)中，化学构型如IIa和IIb所示，A和NH2为反式构型，饱和六元环上两个手性碳以*标记：
Figure PCTCN2015093384-appb-000012
在优选的实施方式中，绝对构型为IIa。
在具体的实施方式中，本发明的化合物是通式(III)所示化合物或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物：
Figure PCTCN2015093384-appb-000013
其中，
X选自O、S、NH；
R4独立选自H、羟基；
R6、R7为独立选自氢、卤素、氰基、羟基、巯基、C1～2烷氧基、C1～2烷基甲酰氧基、C1～3烷氧基甲氧基、COOH、C1～2烷氧甲酰基、氨基甲酰基、氰基甲基甲酰基、乙酰氨基甲基甲酰基、2-吡咯甲酰基、甲氧基甲酰甲基、4-吡喃甲酰基、4-吗啡啉甲酰基、1-哌嗪甲酰基、甲硫基、甲基亚磺酰基、甲磺酰基、氨基、乙酰氨基、甲磺酰胺基、甲氨基甲酰胺基、N-丙磺酰内胺、N-丁磺酰内胺、4-吗啡啉基、N-甲基哌嗪-4-基、哌嗪基、3-甲磺酰基哌嗪基、3,3-二氟四氢吡咯基、2-氨基甲酰基哌啶基、3-吡唑氨基；
R8、R9和R10独立选自氢、Cl、F、氰基。
本发明化合物的通用制备方法如下：
Figure PCTCN2015093384-appb-000014
在优选的实施方式中，本发明的化合物如下所示：
Figure PCTCN2015093384-appb-000015
Figure PCTCN2015093384-appb-000016
在其它优选的实施方式中，本发明还提供如下所示的化合物：
Figure PCTCN2015093384-appb-000017
Figure PCTCN2015093384-appb-000018
化合物都含一个以上手性碳，可以以光学纯异构体和对映异构体存在，本发明包括所有形式。
本领域技术人员鉴于本发明的教导以及现有技术知识可以知晓，可以在本发明化合物的官能团上进行衍生，从而得到能在体内转化为母体化合物的衍生物。
本发明也涉及前面通式(I)～(III)的制备方法，现以(III)的制备方法进行描述：
Figure PCTCN2015093384-appb-000019
氨基化合物(III)的还原采用通常的还原工艺，比如在溶剂如甲醇、乙醇中的催化加氢还原反应，催化剂采用雷尼镍、金属Pd或金属铂等；常规的金属和酸及酸式盐还原条件，常用金属包括Zn、Fe，所用酸包括盐酸、硫酸、醋酸，酸式盐如氯化铵等。还原反应温度在20～80℃。
Figure PCTCN2015093384-appb-000020
硝基化合物(IV)由硝基双键化合物(III)还原制备，采用硼氢化钠在混合溶剂中进行，混合溶剂为THF和甲醇，比例20:1～1:1；还原反应温度在20～80℃。
Figure PCTCN2015093384-appb-000021
硝基双键化合物(III)(X＝S,O,NH,CH2)的制备采用类似迈克尔加成方法，在中性～碱性条件下由硝基乙烯基苯(VI)和相应邻位富电子基团X的醛基化合物(VII)缩合而得。碱性催化剂包括有机碱三乙胺、二异丙基乙胺、三乙烯基二胺，金属碱包括格式试剂、丁基锂、LDA等。反应温度-80℃～80℃。
Figure PCTCN2015093384-appb-000022
硝基乙烯基苯(VI)由取代苯甲醛和硝基甲烷缩合制备，所用碱包括无机碱NaOH、KOH，有机碱包括三乙胺、二异丙基乙胺、三乙烯基二胺。
在本发明的结构全新的化合物的基础上，本发明还提供了一种药物组合物，该组合物含有治疗有效量的本发明式I、II或III所示化合物或其药学上可接受的盐，以及药学上可接受的载体或赋形剂。
本发明化合物的药学上可接受的盐的例子包括但不限于无机和有机酸盐，例如盐酸盐、氢溴酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐和草酸盐；以及与碱例如钠羟基、三(羟基甲基)胺基甲烷(TRIS，胺丁三醇)和N-甲基葡糖胺形成的无机和有机碱盐。
虽然每个人的需求各不相同，本领域技术人员可确定本发明药物组合物中每种活性成分的最佳剂量。
本发明的药物组合物可被配制成适合各种给药途径的制剂形式，包括但不限于被配制成用于口服，肠外，皮下，静脉，肌肉，腹腔内，透皮，口腔，鞘内，颅内，鼻腔或外用途径给药的形式，用于治疗DPP-4相关疾病。在优选的实施方式中，本发明的化合物配制成口服给 药形式。给药量是有效地改善或消除一个或多个病症的药量。对于特定疾病的治疗，有效量是足以改善或以某些方式减轻与疾病有关的症状的药量。这样的药量可作为单一剂量施用，或者可依据有效的治疗方案给药。给药量也许可治愈疾病，但是给药通常是为了改善疾病的症状。一般需要反复给药来实现所需的症状改善。药的剂量将根据病人的年龄，健康与体重，并行治疗的种类，治疗的频率，以及所需治疗效益来决定。
本发明的药物制剂可以给予任何哺乳动物，只要他们能获得本发明化合物的治疗效果。在具体的实施方式中，所述哺乳动物中是人。
本发明的化合物或其药物组合可用于治疗与预防二肽基肽酶-4(DPP-4)相关的疾病。在具体的实施方式中，DPP-4相关的疾病主要包括：糖尿病，尤其是非胰岛素依赖的2-型糖尿病、糖耐量异常、肠道病、溃疡性结肠炎、克隆氏病、肥胖或代谢综合征。本发明化合物还可以用于利尿剂或炎症的预防和治疗。
本发明的药物制剂可用已知的方式制造。例如，由传统的混合，制粒，制锭，溶解，或冷冻干燥过程制造。制造口服制剂时，可结合固体辅料和活性化合物，选择性研磨混合物。如果需要或必要时加入适量助剂后，加工颗粒混合物，获得片剂或锭剂芯。
合适的辅料特别是填料，例如糖类如乳糖或蔗糖，甘露醇或山梨醇；纤维素制剂或钙磷酸盐，例如磷酸三钙或磷酸氢钙；以及粘结剂，例如淀粉糊，包括玉米淀粉，小麦淀粉，大米淀粉，马铃薯淀粉，明胶，黄芪胶，甲基纤维素，羟丙基甲基纤维素，羧甲基纤维素钠，或聚乙烯吡咯烷酮。如果需要，可增加崩解剂，比如上面提到的淀粉，以及羧甲基淀粉，交联聚乙烯吡咯烷酮，琼脂，或褐藻酸或其盐，如海藻酸钠。辅助剂特别是流动调节剂和润滑剂，例如，硅石，滑石，硬脂酸盐类，如镁硬脂酸钙，硬脂酸或聚乙二醇。如果需要，可以给锭剂核芯提供可以抵抗胃液的合适包衣。为此，可以应用浓缩糖类溶液。这个溶液可以含有阿拉伯树胶，滑石，聚乙烯吡咯烷酮，聚乙二醇和/或二氧化钛，漆溶液和合适的有机溶剂或溶剂混合物。为了制备耐胃液的包衣，可使用适当的纤维素溶液，例如醋酸纤维素邻苯二甲酸或羟丙基甲基纤维素邻苯二甲酸。可向药片或锭剂核芯的包衣加入染料或色素。例如，用于识别或为了表征活性成分剂量的组合。
基于本发明的化合物，本领域技术人员可以知晓本发明化合物的前药也应该包括在本发明的范围内。本文所用的术语“前药”具有与本领域普通技术人员通常理解的相同的含义，即，具有药理学活性的化合物经过化学结构修饰后得到的在体外无活性或活性较小、在体内经酶或非酶的转化释放出活性药物而发挥药效的化合物。前药本身没有生物活性或活性很低，经过体内代谢后变为有活性的物质，从而能够增加药物的生物利用度、加强靶向性、降低药物的毒性和副作用。在具体的实施方式中，本发明化合物的前药包括对本发明化合物进行化学修饰得到的酯、酰胺等衍生物。
在本发明的化合物以及药物组合物的基础上，本发明还提供一种治疗或预防二肽基肽酶-4(DPP-4)相关的疾病的方法，所述疾病包括(但不限于)糖尿病，尤其是非胰岛素依赖的2-型糖尿病、糖耐量异常、肠道病、溃疡性结肠炎、克隆氏病、肥胖或代谢综合征。该方法包括给 予需要的对象以本发明的式I、II或III所示化合物获取药学上可接受的盐，或本发明的药物组合物。
给药方法包括但不限于本领域周知的各种给药方法，可根据患者的实际情况加以确定。这些方法包括但不限于肠外，皮下，静脉，肌肉，腹腔内，透皮，口腔，鞘内，颅内，鼻腔或外用途径给药。
进一步地，本发明包括本发明的式I、II或III所示化合物或其药学上可接受的盐在制备治疗或预防二肽基肽酶-4(DPP-4)相关的疾病，包括(但不限于)糖尿病，尤其是非胰岛素依赖的2-型糖尿病、糖耐量异常、肠道病、溃疡性结肠炎、克隆氏病、肥胖或代谢综合征DPP-4介导的疾病的药物中的用途；制备抑制DPP-4的药物中的用途；以及制备作为利尿剂和治疗和预防炎症的药物中的用途。
本发明的优点：
1.本发明的化合物是一种结构全新的DPP-4抑制剂；
2.本发明的化合物对DPP-4的抑制活性优异；
3.本发明的化合物能够替代现有的降血糖药物，具备极大的产业化和商品化前景以及市场价值，经济效益显著。
以下结合具体实施案例对本发明的技术方案进一步描述，但以下实施案例不构成对本发明的限制，所有依据本发明的原理和技术手段采用的各种施用方法，均属于本发明范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例
1、trans-(2RS,3RS)-3-氨基-2-(2,4,5-三氟苯基)色满-5-酚(化合物-1)
Figure PCTCN2015093384-appb-000023
中间体1-1的合成：
将2,4,5-三氟苯甲醛(10g,62.46mmol)，硝基甲烷(4mL)，甲醇(10mL)制备成溶液；将 甲醇(60mL)，水(30mL)，氢氧化钠(2.5N,30mL)制备成溶液，保持温度在5℃；将前一种溶液逐滴加入到后一种溶液中，滴加约30-60min，始终保持溶液温度在5-10℃；滴加完后将上述溶液滴入到氯化锌(42.6g,31.25mmol)，浓盐酸(13mL)，水(17mL)的混合溶液中，滴加时保持温度0-10℃，滴完常温反应2-4h；反应完后，减压抽滤，用40％的甲醇溶液多次洗涤滤饼，即得产物9.8g，产率为77％。GC-MS：203.
1H-NMR(400MHz,CDCl3):δ7.95(d,J＝14.0Hz,1H),7.65(d,J＝14.0Hz,1H),7.36(d,J＝7.2Hz,J＝16.0Hz,1H),7.09(d,J＝6.4Hz,J＝16.0Hz,1H)。
中间体1-2的合成：
称取AlCl3(82.9g，600mmol)于1L的圆底烧瓶中，加入500mL的二氯甲烷溶解，室温条件下搅拌。称取2,6-二甲氧基苯甲醛(19.92g，120mmol)溶解于200ml的二氯甲烷中，缓慢滴加到上述圆底烧瓶中(滴加1h)，滴加完毕后继续搅拌12h，TLC跟踪待反应结束后加入稀盐酸(2mol/L,600mL)淬灭,分离有机相，水相用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤旋干溶剂，柱层析分离(PE:EA＝9:1)，得到12.5g黄色固体，产率78.3％。GC-MS,138.
1H-NMR(400MHz,CDCl3):δ10.37(s,1H),7.32(t,J＝8.4Hz,1H),7.26(s,1H),6.41(d,J＝8.0Hz,1H).
中间体1-3的合成：
称取中间体1-1(0.88g，4mmol)和中间体1-2(0.5g，3.6mmol)于50ml的圆底烧瓶中，加入二氧六环溶解(15mL)后加入DABCO(0.2g,1.8mmol)，并氩气保护。在室温条件下搅拌24h，TLC跟踪直到原料化合物5反应完全，用饱和氯化铵溶液(30mL)淬灭反应，然后用乙酸乙酯(3*30ml)萃取，有机相用饱和食盐水洗涤，然后用无水硫酸钠干燥，旋干溶剂，粗品直接快速住层析分离(PE:EA＝4：1)，得到深黄色油状液体230mg，产率19.6％。GC-MS,323.
1H-NMR(400MHz,CDCl3):δ10.94(s,1H),8.36(s,1H),7.70(m,1H),6.46(m,1H)，7.21(t，J＝8.4Hz，1H),6.80(s，1H),6.54(d，J＝8.4Hz，1H),6,.32(d，J＝8.0Hz，1H)。
中间体1-4的合成：
称取中间体1-3(3.2g，10mmol)于500mL的圆底烧瓶中，加入THF/CH3OH(10:1)220ml混合溶液溶解，磁力搅拌。加入硼氢化钠(NaBH4)(490mg，13mmol)室温搅拌20min，反应结束后加入10ml的水淬灭反应，旋干溶剂后加入100ml的水，乙酸乙酯萃取，无水硫酸钠干燥，柱层析分离(PE:EA＝10：1)得到1.4g淡黄色固体，产率43.7％。
1H-NMR(400MHz,DMSO-d6):δ9.89(s,1H),7.73-7.64(m,2H),7.00(t,J＝8.0Hz，1H),6.51(d,J＝7.6Hz，1H)，6.40(t，J＝8.0Hz，1H),5.71(d，J＝8.0Hz，1H),5.64-5.59(m，1H),3.31(dd，J＝8.8Hz,J＝16.8Hz，1H),3.22(dd，J＝5.6Hz,J＝16.8Hz，1H)。
(2RS,3RS)-3-氨基-2-(2,4,5-三氟苯基)色满-5-酚(化合物-1)的合成：
称取化合物6(325mg，1mmol)和锌粉(780mg，12mmol)于10mL的乙醇溶液中，加入6N的盐酸溶液3.2mL反应1小时。反应结束后过滤，滤液用饱和碳酸氢钠中和到PH＝8，水相用乙酸乙酯萃取，有机相用无水硫酸钠干燥，柱层析分离(PE:EA＝2:1)得到230mg的白色固体粉末，产率77.9％。
1HNMR(400MHz,DMSO-d6):δ9.50(s,1H),7.61-7.53(m,2H),6.88(t,J＝8.0Hz，1H),6.40(d, J＝8.0Hz，1H)，6.26(t，J＝8.0Hz，1H),4.74(d，J＝9.2Hz，1H),3.23-3.17(m，1H),2.93(dd，J＝5.2Hz,J＝16.4Hz，1H)，2.36(dd，J＝10.4Hz,J＝16.4Hz，1H).LCMS(M+1)+296.06。
2、trans-(8RS,9RS)-9-氨基-8-(2,4,5-三氟苯基)-9,10-二氢吡喃[2,3-f]色满-2(8H)-酮(化合物-2)
Figure PCTCN2015093384-appb-000024
称取化合物7(177mg，0.6mmol)于三氟乙酸(1mL)中，加入Pd(OAc)2(1.68mg，0.0075mmol)和丙炔酸乙酯(117mg，1.8mmol)，冰浴搅拌5min后，继续室温搅拌22h，反应结束后用10％的碳酸氢钠溶液中和，水相用乙酸乙酯萃取，有机相无水硫酸钠干燥，旋干溶剂，柱层析分离得到35mg白色固体粉末，产率18.5％。
1H-NMR(400MHz,DMSO-d6):δ8.00(d,J＝9.2Hz，1H),7.69-7.60(m,2H),7.49(d，J＝8.4Hz，1H),6.86(d,J＝8.4Hz，1H)，6.31(d，J＝9.2Hz，1H),4.96(d，J＝9.2Hz，1H),3.30(m，1H),3.17(dd，J＝5.6Hz,J＝16.8Hz，1H)，2.65(dd，J＝10.4Hz,J＝16.8Hz，1H)，1.72(m，2H)。LCMS(M+1)+348.18。
3、(8R,9S)-9-氨基-4-甲基-8-(2,4,5-三氟苯基)-9,10-二氢吡喃[2,3-f]色满-2(8H)-酮(化合物-3)
Figure PCTCN2015093384-appb-000025
称取化合物7(1.7g，5.26mmol)于100ml的圆底烧瓶中，用50ml 60％的硫酸溶液溶解，加入乙酰乙酸乙酯(2.55g，23.67mmol)后于55摄氏度条件下继续搅拌24小时，反应结束后加入40mL的冰水化合物，用饱和碳酸氢钠中和，乙酸乙酯萃取，柱层析分离(CH3OH:CH2Cl2＝1:8)，得到1.02g白色粉末固体，产率54％。
1HNMR(400MHz,DMSO-d6):δ7.68-7.59(m,2H),7.55(d，J＝8.8Hz，1H),6.88(d,J＝8.8Hz，1H)，6.23(s,1H),4.96(d，J＝9.2Hz，1H),3.39-3.34(m，1H),3.17(dd，J＝5.6Hz,J＝16.8Hz，1H)，2.67(dd，J＝10.0Hz,J＝16.8Hz，1H)。LCMS(M+1)+362.04。
手性柱拆分达到化合物-3。
4、trans-(2RS,3RS)-3-氨基-2-(2,4,5-三氟苯基)色满-6-酚(化合物-4)
Figure PCTCN2015093384-appb-000026
中间体4-1的合成：
称取化合物2,5-二羟基苯甲醛(1.38g，10mmol)，中间体1-1(6.09g，30mmol)，DABCO(0.56g，5mmol)于25ml的圆底烧瓶中，氩气保护60℃条件下搅拌过夜，得到2.4g红色固体，产率74％。
1H-NMR(400MHz,DMSO-d6):δ9.14(s,1H),7.72-7.65(m,2H),7.76-6.74(m,2H),6.61-6.60(m,2H)，5.66(d,J＝7.6Hz,1H),5.63-5.58(m,1H),3.51(dd,J＝8.4Hz,J＝12.4Hz,1H),3.3(d,J＝5.6Hz,1H)。
中间体4-2的合成：
称取4-1(167mg，0.5mmol)于25mL的圆底烧瓶中，加入THF/CH3OH(10：1)27.5mL溶解后室温搅拌，分批加入硼氢化钠继续搅拌20min。反应结束后，加入0.1ml的水淬灭反应，减压旋干溶剂，余下水后加入2ml的饱和氯化铵溶液，乙酸乙酯萃取，柱层析分离(PE:EA＝5：1)得到50mg的红色固体，产率31％。
1H-NMR(400MHz,DMSO-d6):δ9.14(s,1H),7.72-7.65(m,2H),7.76-6.74(m,2H),6.61-6.60(m,2H)，5.66(d,J＝7.6Hz,1H),5.63-5.58(m,1H),3.51(dd,J＝8.4Hz,J＝12.4Hz，1H),3.3(d，J＝5.6Hz，1H)。
(2RS,3RS)-3-氨基-2-(2,4,5-三氟苯基)色满-6-酚(化合物-4)的合成：
称取4-2(975mg，3mmol)和Zn粉(2.34g，36mmol)于17ml的乙醇溶液中，搅拌加入6N的HCl溶液11ml，反应1h后，反应液用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝1：1),得到439mg产物，产率49.6％。
1H-NMR(400MHz,DMSO-d6):δ9.50(s,1H),7.61-7.53(m,2H)，6.88(t,J＝8.0Hz，1H),6.40(d,J＝8.0Hz，1H)，6.26(t，J＝8.0Hz，1H),4.74(d，J＝9.2Hz，1H),3.23-3.17(m，1H),2.93(dd，J＝5.2Hz,J＝16.4Hz，1H)，2.36(dd，J＝10.4Hz,J＝16.4Hz，1H)。LCMS(M+1)+296.11。
5、(2S,3R)-9-甲氧基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-5)
Figure PCTCN2015093384-appb-000027
中间体5-1的合成：
称取化合物2,7-二甲氧基萘(870mg,4.62mmol)于2mL的DMF溶剂中，加入POCl3(796mg，5.2mmol)后60摄氏度条件下搅拌过夜，形成了棕色溶液。反应结束后加入20ml的冰水，混合物室温条件下继续搅拌过夜，反应完全后过滤，滤饼用甲醇重结晶。得到690mg灰色晶体。产率75.5％。LC-MS:217.10(M+1)+。
1H-NMR(400MHz,DMSO-d6):δ10.76(s,1H),8.69(d,J＝2.0Hz,1H),8.22(d,J＝8.8Hz，1H),7.87(d,J＝9.2Hz，1H),7.40(d,J＝9.2Hz，1H),7.12(d,J＝9.2Hz，J＝1.6Hz 1H),4.04(s,3H),3.88(s,3H).
中间体5-2的合成：
称取2.7-二甲氧基-1-萘甲醛(6.0g，27.9mmol)于45ml干燥的二氯甲烷中。分批加入AlCl3(11.1g,83.4mmol).室温条件下搅拌16h，反应结束后反应液倒入到150ml的食盐水中，乙酸乙酯萃取(2*150ml)有机相用食盐水继续洗涤两遍(2*150ml)无水硫酸钠干燥真空旋干固体，乙醇重结晶得到3.2g淡黄色晶体。产率61.3％。LC-MS:203.05(M+1)+,201.05(M-1)-。
1H-NMR(400MHz,DMSO-d6):δ11.93(s,1H),10.81(s,1H)，8.46(d,J＝2.0Hz,1H),8.04(d,J＝8.8Hz，1H),7.79(d,J＝8.8Hz，1H),7.09-7.04(m，2H),3.89(s,3H),4.04(s,3H),3.88(s,3H)。
中间体5-3的合成：
称取化合物7-甲氧基-2-羟基-1-萘甲醛(101mg，0.5mmol)，中间体1-1(506mg，2.5mmol，5eq)，DABCO(56mg，0.5mmol)于50ml的圆底烧瓶中，氩气保护条件下加热到80℃搅拌过夜，反应结束后加入20ml的二氯甲烷溶解，直接柱层析分离(PE:EA＝6：1)，得到51mg的淡黄色固体，产率26.4％。LC-MS:388.10(M+1)+。
1H-NMR(400MHz,CDCl3):δ8.82(s,1H),7.78(d,J＝8.8Hz,1H),7.69(d,J＝8.8Hz,1H),7.34(d,J＝2.0Hz，1H)，7.12(dd,J＝2.4Hz,J＝8.8Hz,1H),7.07-6.99(m,2H),6.98(s,1H),6.90(d,J＝9.2Hz,1H),4.04(s,3H)。
中间体5-4的合成：
称取化合物5-3(38.7mg，0.1mmol)于10mL的圆底烧瓶中，加入THF/CH3OH(10:1)的混合 液5.5ml溶解，加入硼氢化钠(10mg，0.26mmol)后磁力搅拌室温条件下搅拌20min。反应结束后加入少量的水淬灭反应。旋干溶剂，加入饱和氯化铵溶液10ml，乙酸乙酯萃取，无水硫酸钠干燥，得到20mg的灰白色固体，产率51.4％。
1H-NMR(400MHz,CDCl3):δ7.73(d,J＝9.2Hz,1H),7.66(d,J＝9.6Hz,1H),7.31-7.25(m,1H),7.10(dd,J＝2.4Hz，J＝8.8Hz，1H)，7.05-6.98(m,3H),5.75(d,J＝8.4Hz,1H),5.31-5.26(m,1H),3.94(s.3H),3.85(dd,J＝8.4Hz，J＝16.4Hz，1H),3.55(d,J＝6.0Hz,J＝16.4Hz，1H).
(2S,3R)-9-甲氧基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-5)合成：
称取中间体5-4(233.4mg，0.6mmol)Zn粉(468mg，7.2mmol)于3.4ml的乙醇溶液中，搅拌加入6N的HCl溶液2ml，50摄氏度条件下反应1h后，反应液用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝1：1),得到49mg产物，产率22.8％。手性柱拆分得到化合物5。LC-MS：360.10(M+1)+。
1H-NMR(400MHz,DMSO-d6):δ7.91-7.84(m,1H),7.80(d,J＝8.8Hz,1H),7.68(d,J＝8.4Hz,1H),7.64-7.62(m,1H),7.17(dd,J＝4.0Hz，J＝1.6Hz，1H)，7.07(dd,J＝2.4Hz，J＝6.4Hz，1H)，6.95(d,J＝8.8Hz,1H),5.48(d,J＝9.6Hz,1H),5.08-5.01(m,1H),3.77(dd,J＝16.4Hz，J＝10.8Hz，1H),3.55(d,J＝5.6Hz,J＝16.4Hz，1H).
6、(2S,3R)-8-甲氧基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-6)
Figure PCTCN2015093384-appb-000028
中间体6-1的合成：
称取2,6-二羟基萘(5g，31.2mmol)和二苯甲脒(8.7g，44.35mmol)于130摄氏度条件下氩气保护搅拌5h，TLC板跟踪，待反应冷却到室温后加入30ml的丙酮，沉淀过滤干燥得到红色粉末。得到5.5g红色固体粉末，产率70％。
1H-NMR(400MHz,DMSO-d6):δ15.37(d，J＝3.2Hz,1H),8.46(d,J＝2.0Hz,1H),9.60(d,J＝2.8Hz，1H),9.53(s,1H),8.37(d,J＝10.0Hz，1H),7.78(d,J＝7.2Hz,1H),7.59(d,J＝7.6Hz,2H),7.49(t, J＝7.6Hz,J＝8.0Hz,2H),7.31(t,J＝7.6Hz,J＝7.2Hz,1H),7.11(m,2H),6.98(d,J＝10.2Hz,1H)。
称取以上化合物(6g，22.8mmol)于5ml水，4ml的浓硫酸中，加入80ml的乙醚室温搅拌4d，分离得到上层的乙醚层，用乙醚多次萃取，合并有机相，旋干溶剂得到1.5g黄色固体。产率35％。
1H-NMR(400MHz,DMSO-d6):δ10.76(s,1H),8.78(d,J＝8.8Hz，1H),7.94(d,J＝9.2Hz，1H),7.19-7.13(m，3H)。
中间体6-2的合成：
称取2,6-二羟基-1-萘甲醛(564mg，3mmol)，K2CO3(1.34g，9mmol)于6ml的DMF溶剂中，室温搅拌1h，加入碘甲烷(1.28g，9mmol)后室温搅拌过夜，反应结束后加入硫代硫酸钠淬灭反应，乙酸乙酯萃取，旋干溶剂后乙醇重结晶得到430mg固体，产率66.4％。LC-MS:217.10(M+1)+.
1H-NMR(400MHz,DMSO-d6):δ10.74(s,1H),9.02(d,J＝9.2Hz,1H),8.23(d,J＝9.2Hz，1H),7.58(d,J＝9.2Hz，1H),7.39(s,1H),7.31(d,J＝9.6Hz，1H),4.03(s,3H),3.86(s,3H).
中间体6-3的合成：
称取2.6-二甲氧基-1-萘甲醛(11.50g，0.0532mol)于250ml干燥的二氯甲烷中；分批加入AlCl3(21.3g,0.1597mol).，40℃条件下搅拌36h，反应结束后，反应液倒入食盐水中，乙酸乙酯萃取，有机相用饱和食盐水继续洗涤两遍，无水硫酸钠干燥，真空旋干得固体，乙醇重结晶得到淡黄色固体。LC-MS:203.10(M+1)+,201.10(M-1)-。
1HNMR(400MHz,DMSO-d6):δ10.78(s,1H),8.86(d,J＝9.2,1H),8.04(d,J＝8.8Hz,1H),7.35(d,J＝2.8Hz,1H),7.28(dd,J1＝9.2Hz,J2＝2.8Hz,1H),7.22(d,J＝8.8,1H),3.86(s,3H)
中间体6-4的合成：
称取化合物7-甲氧基-2-羟基-1-萘甲醛(101mg，0.5mmol)，化合物1-1(506mg，2.5mmol，1.5eq)，DABCO(56mg，0.5mmol)于50ml的圆底烧瓶中，加入适量的DCM，70℃搅拌过夜，反应结束后用二氯甲烷：石油醚＝1：2过柱层析色谱，即得红色固体产物。LC-MS:388.10(M+1)+.
1HNMR(400MHz,CDCl3):δ8.82(s,1H),8.01(d,J＝9.2Hz,1H),7.77(d,J＝8.8Hz,1H),7.34(dd,J＝9.2Hz,J＝2.4Hz,1H)，7.12(dd,J＝2.8Hz,1H),7.05-7.00(m,2H),6.97(s,1H),3.93(s,3H)
中间体6-5的合成：
称取化合物42(500mg，1.292mmol)于250mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1)的混合液55ml，将固体溶解，分批向溶液中加入硼氢化钠(100mg,2.642mmol)，瓶口加上干燥管，常温常压的条件下，反应20min；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，直接用于下一步反应。
(2S,3R)-8-甲氧基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-6)的合成：
将上述所得的化合物溶于100ml的乙醇溶液中，加入Zn粉(835mg，12.85mmol)，加入6N的HCl溶液6ml，50℃条件下反应2h后，反应液用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝2：1)，得到白色产物6-6(175mg,37.8％)。 HPLC手性柱拆分得到化合物6。LC-MS(M+1)+：360.15。
1H NMR(400MHz,DMSO-d6):δ7.76(d,J＝9.2Hz,1H),7.70-7.57(m,3H),7.30(d,J＝2.4Hz,1H),7.21(dd,J1＝9.0Hz,J2＝2.4Hz,1H),7.04(d,J＝8.8Hz,1H),4.89(d,J＝8.8Hz,1H),3.86(s,3H),3.44-3.38(m,1H),3.34(dd,J1＝16.2Hz,J2＝5.6Hz,1H),2.86(dd,J1＝17.2Hz,J2＝10.0Hz,1H),1.76(s,2H).
7、(2S,3R)-8-溴-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-7)
Figure PCTCN2015093384-appb-000029
中间体7-1的合成：
称取TiCl4(7.97g，42mmol)和1,1，-二氯甲基醚(2.53g，22mmol)于20ml二氯甲烷中0摄氏度条件下搅拌15min。称取6-溴-2-羟基萘(4.46g，20mmol)于60ml的二氯甲烷中，逐滴加入到上述反应液中室温搅拌12h，待反应结束后加入200ml 1N的盐酸，二氯甲烷萃取，有机相用水洗涤干燥直接得到产物3.4g，产率67.7％。LC-MS:250.95(M-1)-.
1H-NMR(400MHz,DMSO-d6):δ11.91(s,1H),10.77(s,1H),8.93(d,J＝8.8Hz，1H),8.17(d,J＝2.0Hz，1H),8.11(d,J＝9.2Hz，1H),7.73(dd,J＝8.8Hz，J＝2.0Hz，1H),7.31(d,J＝8.8Hz，1H)。
中间体7-2的合成：
称取化合物6-溴-2-羟基-1-萘甲醛(40mg，0.16mmol)，化合物1-1(162.4mg，0.8mmol)，DABCO(9mg，0.08mmol)于10ml的圆底烧瓶中，氩气保护加热到60℃搅拌过夜，反应结束后加入10ml的二氯甲烷溶解，直接柱层析分离，得到28mg的淡黄色固体，产率40％。LC-MS:437.95(M+1)+,436.05(M-1)-.
1H NMR(400MHz,DMSO-d6):δ9.00(s,1H),8.37(d,J＝9.2Hz,1H),8.23(d,J＝1.6Hz,1H),8.03(d,J＝9.2Hz,1H),7.80(dd,J1＝9.2Hz,J2＝1.6Hz,1H),7.76-7.69(m,1H),7.65-7.59(m,1H),7.21(d,J＝8.8Hz,1H),7.03(s,1H).
中间体7-3的合成：
称取7-2(217mg,0.5mmol)于50ml的反应瓶中，加入THF：CH3OH＝(10：1，11ml)溶解，磁力搅拌缓慢加入硼氢化钠(76mg，2mmol)室温搅拌20min，反应结束后，加入少量水淬灭反应，减压旋干溶剂，加入10ml水，用乙酸乙酯(10ml*3)萃取，合并有机相，直接柱层析分离，得到60mg淡黄色固体产物，产率27.5％。
1HNMR(400MHz,CDCl3):δ7.99(s,1H),7.67-7.64(m,3H),7.28-7.22(m,1H),7.16(d,J＝9.2Hz,1H)，7.06-7.00(m,1H),5.78(d,J＝7.6Hz,1H),5.31-5.26(m,1H),3.90(dd,J＝8.4Hz, J＝16.8Hz,1H),3.59(dd,J＝6.0Hz,J＝16.8Hz,1H).
(2S,3R)-8-溴-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-7)的合成：
称取7-3(44mg，0.1mmol)和锌粉(78mg，1.2mmol)于6ml的乙醇溶液中，加几滴DMF，使其溶解，室温搅拌加入6N的盐酸溶液1.5ml，升高温度到50摄氏度反应过夜，反应结束后用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶剂，柱层析分离(PE:EA＝1:1)得到17mg产物，产率41.5％。手性拆分得到化合物7。LC-MS：408.05(M+1)+。
1HNMR(400MHz,CDCl3):δ7.94(d,J＝2.0Hz,1H),7.67(d,J＝8.8Hz,1H),7.59-7.56(m,2H),7.38-7.32(m,1H),7.12(d,J＝8.8Hz,1H)，7.05-6.98(m,1H),5.03(d,J＝8.0Hz,1H),3.44-3.36(m,2H),2.96-2.88(m,1H),1.45(s,2H)。
8、trans-(2RS,3RS)-9-溴-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-8)
Figure PCTCN2015093384-appb-000030
中间体8-1的合成：
称取TiCl4(797mg,4.2mmol)和1,1-二氯甲基醚(253mg，2.2mmol)于2ml的二氯甲烷中，0摄氏度条件下搅拌15min。称取7-溴-2-羟基萘(446mg，2mmol)于6ml的二氯甲烷中，逐滴加入到上述反应液中，室温搅拌12h，反应结束后加入20ml 1N的盐酸溶液，乙酸乙酯萃取，无水硫酸钠干燥，直接得到产物440mg，产率87.6％。LC-MS:253.00(M+1)+,251.00(M-1)-.
1HNMR(400MHz,DMSO-d6):δ11.94(s,1H),10.74(s,1H),8.93(d,J＝2.0Hz，1H),8.14(d,J＝8.8Hz，1H),7.85(d,J＝8.4Hz，1H),7.73(dd,J＝8.8Hz，J＝2.0Hz，1H),7.29(d,J＝9.2Hz，1H)。
中间体8-2的合成：
称取化合物7-溴-2-羟基-1-萘甲醛(300mg，1.2mmol)，化合物1-1(1.22mg，6mmol)，DABCO(134.4mg，1.2mmol)于25ml的圆底烧瓶中，氩气保护加热到70℃搅拌过夜，反应结束后加入50ml的二氯甲烷溶解，直接柱层析分离，得到212mg的淡黄色固体，产率40.6％。LC-MS:438.00(M+1)+.
1HNMR(400MHz,CDCl3):δ8.77(s,1H),8.25(m,1H),7.83(d,J＝8.8Hz,1H,7.76(d,J＝8.4Hz,1H),7.57(dd,J＝6.0Hz，J＝8.8Hz，1H)，7.07-6.99(m,4H)。
中间体8-3的合成：
称取8-2(261mg,0.6mmol)于50ml的反应瓶中，加入THF：CH3OH(10：1，22ml)溶解，磁力搅拌缓慢加入硼氢化钠(45.6mg，1.2mmol)室温搅拌20min，反应结束后，加入少量水淬灭反应，减压旋干溶剂，加入10ml水，用乙酸乙酯(10ml*3)萃取，合并有机相，直接柱层析分离，得到65mg淡黄色固体产物，产率24.8％。
1HNMR(400MHz,CDCl3):δ7.92(s,1H),7.72-7.68(m,2H),7.52(dd,J＝1.6,J＝8.8,1H),7.15(d,J＝8.8,1H),7.06-6.95(m,2H),5.80(d,J＝7.2Hz,1H)，5.31-5.26(m,1H),3.87(dd,J＝16.4Hz,J＝8.0Hz,1H),3.54(dd,J＝5.6Hz,J＝16.4Hz,1H).
化合物-8的合成：
称取8-2(44mg，0.1mmol)和锌粉(78mg，1.2mmol)于6ml的乙醇溶液中，加几滴DMF，使其溶解，室温搅拌加入6N的盐酸溶液1.5ml，升高温度到50摄氏度反应过夜，反应结束后用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶剂，柱层析分离(PE:EA＝1:1)得到20mg产物，产率48.8％。LC-MS(M+1)+：408.00。
1HNMR(400MHz,CDCl3):δ8.00(s,1H),7.84(d,J＝8.4Hz,1H),7.76(d,J＝8.8Hz,1H),7.71-7.59(m,2H),7.52(d,J＝8.8Hz,J＝2.0Hz,1H),7.13(d,J＝8.8Hz,1H),4.96(d,J＝9.2Hz,1H),3.49-3.43(m,1H),3.36(m,1H),2.86(d,J＝10.0Hz,J＝10.8Hz,1H),1.45(s,2H).
9、trans-(2RS,3RS)-8-氰基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-9)
Figure PCTCN2015093384-appb-000031
中间体9-1的合成：
称取TiCl4(398.5mg，2.1mmol)和1,1-二氯甲基醚(126.5mg，1.1mmol)于2ml二氯甲烷中0摄氏度条件下搅拌15min。称取6-氰基-2-萘酚(169mg，1mmol)于6ml的二氯甲烷中，逐滴加入到上述反应液中室温搅拌12h，待反应结束后加入20ml 1N的盐酸，二氯甲烷萃取，有机相用水洗涤干燥直接得到产物350mg，产率75.4％。LC-MS:196.05(M-1)-.
1HNMR(400MHz,DMSO-d6):δ12.22(s,1H),10.76(s,1H),9.11(d,J＝9.2Hz，1H),8.50(d,J＝2.0Hz，1H),8.22(d,J＝8.8Hz，1H),7.88(dd,J＝9.2Hz，J＝2.4Hz，1H),7.39(d,J＝9.2Hz，1H)
中间体9-2的合成：
称取化合物6-氰基-2-羟基-1-萘甲醛(197mg，1mmol)，化合物1-1(609mg，3mmol)，DABCO(112mg，1mmol)于微波反应加热到11℃搅拌25min，反应结束后加入10ml的二氯甲烷溶解，直接柱层析分离，得到102mg的淡黄色固体，产率26.7％。LC-MS:381.05(M-1)-.
1HNMR(400MHz,CDCl3):δ8.80(s,1H),8.19(m,2H),7.93(d,J＝8.8Hz,1H),7.82(dd,J＝9.2Hz,J＝1.6Hz,1H)，7.19(d,J＝9.2Hz,1H),7.09-7.00(m,3H)。
中间体9-3的合成：
称取9-2(176mg,0.5mmol)于50ml的反应瓶中，加入THF：CH3OH(10：1，22ml)溶解，磁力搅拌缓慢加入硼氢化钠(76mg，2mmol)室温搅拌20min，反应结束后，加入少量水淬灭反应，减压旋干溶剂，加入10ml水，用乙酸乙酯(10ml*3)萃取，合并有机相，直接柱层析分离，得到57mg淡黄色固体产物，产率32.2％。
1HNMR(400MHz,DMSO-d6):δ8.57(d,J＝1.6Hz,1H),8.09(d,J＝8.8Hz,1H),7.98(d,J＝9.2Hz,1H),7.87(d,J＝8.8Hz,J＝1.6Hz,1H),7.80-7.70(m,2H),7.36(s,J＝9.2Hz,1H),5.96(d,J＝8.0Hz,1H)，5.85(dd,J＝6.8Hz,J＝14.8Hz,1H),3.85(d,J＝7.2Hz,2H).
化合物-9的合成：
称取9-3(38.4mg，0.1mmol)和锌粉(78mg，1.2mmol)于10ml的乙醇溶液中，室温搅拌后加入6N的盐酸溶液1.5ml，升高温度到50摄氏度反应过夜，反应结束后用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶剂，柱层析分离(PE:EA＝1:1)得到17mg产物，产率48％。LC-MS(M+1)+：355.10。
1HNMR(400MHz,DMSO-d6):δ8.50(d,J＝1.6Hz,1H),8.00(d,J＝8.8Hz,1H),7.88(d,J＝8.8Hz,1H),7.81(d,J＝8.8Hz,J＝1.6Hz,1H),7.72-7.59(m,2H),7.25(d,J＝8.8Hz,1H),5.00(d,J＝9.2Hz,1H),3.45-3.36(m,2H),2.90(d,J＝8.8Hz,J＝16Hz,1H)。
10、trans-(2RS,3RS)-8-羟基甲酰基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-10)
Figure PCTCN2015093384-appb-000032
称取化合物9(35.4mg，0.1mmol)于45％硫酸溶液(1.8mL)中，回流搅拌过夜。反应结束后，用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，柱层析分离(DCM：CH3OH＝10:1)，得到8mg白色粉末，产率22％。LC-MS(M+1)+：374.10
1HNMR(400MHz,DMSO-d6):δ8.49(d,J＝1.6Hz,1H),8.13(dd,J＝8.8Hz,J＝1.6Hz,1H),7.87(d,J＝8.8Hz,1H),7.79(d,J＝9.2Hz,1H),7.49-7.43(m,1H),7.32-7.25(m,1H),7.15(d,J＝8.8Hz,1H),5.17(d,J＝8.4Hz,1H),4.6(s,1H),3.64(m,1H),3.44(dd,J＝8.8Hz,J＝16.4Hz,J＝5.6Hz,1H,3.05(dd,J＝16.4Hz,J＝9.2Hz,1H)。
11、trans-(2RS,3RS)-9-氰基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-11)
Figure PCTCN2015093384-appb-000033
中间体11-1的合成：
称取7-溴-2-萘酚(2.22g，10mmol)、CuCN(1.08g，12mmol)于3ml的DMF中溶解。氩气保护条件下加热到160℃回流3h，跟踪反应待反应结束后冷却到室温，加入20ml的水，乙酸乙酯萃取。乙醇-水体系重结晶，得到1.4g棕色粉末，产率83％。
1HNMR(400MHz,DMSO-d6):δ10.18(s,1H),8.35(s,1H),7.97(d,J＝8.0Hz，1H),,7.91(d,J＝8.4Hz,1H),7.52(dd,J＝8.4Hz，J＝1.6Hz，1H),7.29-7.27(m,2H)
中间体11-2的合成：
称取TiCl4(3.99mg，21mmol)和1,1-二氯甲基醚(1.265mg，11mmol)于20ml二氯甲烷中0摄氏度条件下搅拌15min。称取7-氰基-2-萘酚(1.69mg，10mmol)于40ml的二氯甲烷中，逐滴加入到上述反应液中室温搅拌12h，待反应结束后加入20ml 1N的盐酸，二氯甲烷萃取，有机相用水洗涤干燥直接得到产物500mg，产率25.3％。LC-MS:196.10(M-1)-。
1HNMR(400MHz,DMSO-d6):δ12.11(s,1H),10.77(s,1H),8.25(d,J＝9.2Hz,1H),8.22(d,J＝8.8Hz,1H),8.10(d,J＝8.4Hz,1H),7.74(dd,J＝8.4Hz,J＝1.6Hz,1H),7.45(d,J＝9.2Hz,1H)
中间体11-3的合成：
称取化合物7-氰基-2-羟基-1-萘甲醛(197mg，1mmol)，1-1(609mg，3mmol)，DABCO(112mg，1mmol)于微波反应加热到11℃搅拌25min，反应结束后加入10ml的二氯甲烷溶解，直接柱层析分离，得到112mg的淡黄色固体，产率29.3％。LC-MS:383.15(M+1)+,381.00(M-1)-.
1H NMR(400MHz,DMSO-d6):δ9.21(s,1H),9.11(s,1H),8.16(d,J＝9.2Hz,1H),8.12(d,J＝8.8Hz,1H),7.81(d,J＝8.4Hz,1H),7.76-7.71(m,1H),7.69-7.61(m,1H),7.35(d,J＝8.8Hz,1H),6.99(s,1H),7.06(s,3H).
中间体11-4的合成：
称取11-3(176mg,0.5mmol)于50ml的反应瓶中，加入THF：CH3OH(10：1，22ml)溶解，磁力搅拌缓慢加入硼氢化钠(76mg，2mmol)室温搅拌20min，反应结束后，加入少量水淬灭反应，减压旋干溶剂，加入10ml水，用乙酸乙酯(10ml*3)萃取，合并有机相，直接柱层析分离，得到57mg淡黄色固体产物，产率32.2％。
化合物11的合成：
称取11-4(38.4mg，0.1mmol)和锌粉(78mg，1.2mmol)于10ml的乙醇溶液中，室温搅拌后加入6N的盐酸溶液1.5ml，升高温度到50摄氏度反应过夜，反应结束后用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶剂，柱层析分离(PE:EA＝1:1)得到17mg产物，产率48％。LC-MS(M+1)+：355.10。
12、(2S,3R)-8,9-二甲氧基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-12)
Figure PCTCN2015093384-appb-000034
中间体12-1的合成：
称1，1-二氯甲醚(0.62g,0.0054mol)于250mL的圆底烧瓶中，溶于适量的二氯甲烷中，在0℃的条件下,加入四氯化钛(2.0g,0.0102mol)，0℃的条件下搅拌15min；称取6，7-二甲氧基-2-萘酚(1g,0.0049mol)溶于适量的二氯甲烷溶液中，将其逐滴加入到上述的溶液中，溶液由淡黄色变为红色，滴毕，使溶液在室温的条件下反应过夜；反应完全后，将溶液倒入50mL的1N盐酸溶液中，常温搅拌1h，乙酸乙酯萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，旋干溶液，柱层析分离，即得产品。LC-MS:233.10(M+1)+,231.10(M-1)-.
1HNMR(400MHz,CDCl3):δ12.85(s,1H),10.75(s,1H),7.82(d,J＝9.2Hz,1H),7.64(s,1H),7.10(s,1H),6.99(d,J＝8.8,1H),4.05(s,3H),3.99(s,3H)
中间体12-2的合成：
称取6，7-二甲氧基-2-氰基-1-萘醛(200mg,0.8618mmol)，化合物1-1(875mg,4.3103mmol)，DABCO(97mg,0.8661mmol)于耐压管中，外界的条件下搅匀、压实，在微波的条件下，120℃反应30min；反应完后，加入二氯甲烷溶解固体，柱层析分离(DCM:PE＝1:2)，即得产品。LC-MS:418.10(M+1)+.
1H NMR(400MHz,DMSO-d6):δ9.12(s,1H),7.85(d,J＝8.8Hz,1H),7.75-7.68(m,1H),7.72(s,1H),7.53-7.46(m,1H),7.34(s,1H),6.95(s,1H),6.94(d,J＝8.4Hz,1H),4.04(s,3H),3.87(s,3H).
中间体12-3的合成：
称取化合物47(50mg，0.1200mmol)于50mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1)的混合液5ml，将固体溶解，分批向溶液中加入硼氢化钠(10mg,0.2642mmol)，瓶口加上干燥管，常温常压的条件下，反应20min；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，直接用于下一步反应。
中间体12-4的合成：
将上述所得的化合物溶于50ml的乙醇溶液中，加入Zn粉(8.35mg，1.285mmol)，加入6N的HCl溶液2ml，50℃条件下反应2h后，反应液用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝2：1)，得到白色产物。LC-MS(M+1)+： 390.15。
1H NMR(500MHz,DMSO-d6):δ7.70-7.57(m,2H),7.55(d,J＝8.8Hz,1H),7.28(s,1H),7.10(s,1H),6.90(d,J＝8.8Hz,1H),4.87(d,J＝9.2Hz,1H),3.92(s,3H),3.86(s,3H),3.44-3.38(m,1H),3.32(dd,J1＝15.0Hz,J2＝5.6Hz,1H),2.82(dd,J1＝16.4Hz,J2＝10.0Hz,1H),1.62(s,2H).
化合物12：反式构型化合物12-4手性柱拆分得到化合物12。
13、trans-(2RS,3RS)-9-(4-(甲磺酰基)苯基)-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-13)
Figure PCTCN2015093384-appb-000035
中间体13-1的合成：
将8-2(300mg,0.69mmol)，4-甲磺酰基苯硼酸(276mg,1.38mmol)溶于甲苯(2.8mL)；向溶液中5％的四三苯基膦钯(39.9mg)；通氩气15min；在氩气保护下，80℃反应1h；用注射器加入NaHCO3溶液(2M,1.4mL)、乙醇(1.4mL)，继续反应24h；反应结束后，向溶液中加入适量的水，用乙酸乙酯萃取，水多次洗涤有机相，饱和NaCl水溶液洗涤，无水Na2CO3干燥，用石油醚：乙酸乙酯＝2：1的展开剂过柱层析色谱柱，即得产物274mg，产率为77.7％。LC-MS:512.10(M+1)+.
1HNMR(400MHz,DMSO-d6):δ9.30(s,1H),8.75(s,1H),8.25(d,J＝8.8Hz,2H),8.09(d,J＝8.8Hz,2H),8.06(d,J＝8.4Hz,2H),7.90(dd,J1＝8.0Hz,J2＝1.2Hz,1H),7.73-7.67(m,1H),7.71-7.54(m,1H),7.19(d,J＝9.2Hz,1H),7.03(s,1H),3.30(s,3H)
中间体13-2的合成：
将化合物7(250mg,0.4892mmol)溶液溶于3mL无水甲醇中，再加入30mL的无水四氢呋喃，多次分批加入硼氢化钠(74mg,1.955mmol)，常温下搅拌约20min，反应结束，将溶剂旋干，直接进行下一步反应。
化合物13的合成：
将化合物8(250mg,0.5175mmol)，溶于5mL的乙醇溶液中，向溶液中加入12mL的6N盐酸和锌粉(406.1mg,6.210mmol)，在55℃下加热反应过夜，直至反应溶液为澄清透明的溶液；反应完后向溶液中加入饱和的NaHCO3,中和溶液至中性，用乙酸乙酯萃取，饱和盐水洗涤，无水Na2SO4干燥；用乙酸乙酯：石油醚＝1：2过柱层析色谱，即得产物。LC-MS(M+1)+：484.20。
1HNMR(400MHz,DMSO-d6):δ8.15(s,1H),8.11(d,J＝8.8Hz,2H),8.05(d,J＝8.4Hz,2H),8.01(d,J＝8.4Hz,1H),7.08-7.77(m,2H),7.72-7.65(m,1H),7.63-7.58(m,1H),7.15(d,J＝8.8Hz,1H),4.98(d,J＝8.8Hz,1H),3.58-3.46(m,1H),3.26(s,3H),3.01-2.95(m,1H)
14、(2S,3R)-9-(3-(甲磺酰基)苯基)-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-14)
Figure PCTCN2015093384-appb-000036
中间体14-1的合成：
将8-2(500mg,1.15mmol)，3-甲磺酰基苯硼酸(459.8mg,2.30mmol)溶于甲苯(4.6mL)；向溶液中5％的四三苯基膦钯(66.4mg)；通氩气15min；在氩气保护下，80℃反应1h；用注射器加入NaHCO3溶液(2M,2.3mL)、乙醇(2.3mL)，继续反应24h；反应结束后，向溶液中加入适量的水，用乙酸乙酯萃取，水多次洗涤有机相，饱和NaCl水溶液洗涤，无水Na2CO3干燥，用石油醚：乙酸乙酯＝2：1的展开剂过柱层析色谱柱，即得产物。LC-MS:512.10(M+1)+.
1HNMR(400MHz,DMSO-d6):δ9.30(s,1H),8.73(s,1H),8.46(s,1H),8.34(d,J＝8.80Hz,1H),8.09(d,J＝9.2Hz,1H),8.07(d,J＝8.8Hz,1H),8.01(d,J＝8.0Hz,1H),7.92(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.84(t,J＝8.0Hz,1H),7.77-7.67(m,1H),7.63-7.57(m,1H),7.19(d,J＝8.8Hz,1H),7.03(s,1H),3.36(s,3H)
中间体14-2的合成：
将14-1(250mg,0.4892mmol)溶液溶于3mL无水甲醇中，再加入30mL的无水四氢呋喃，多次分批加入硼氢化钠(74mg,1.955mmol)，常温下搅拌约20min，反应结束，加入水萃灭反应，将溶剂旋干，乙酸乙酯萃取，无水Na2CO3干燥，旋干，直接进行下一步反应。
化合物14的合成：
将14-2(250mg,0.5175mmol)，溶于5mL的乙醇溶液中，向溶液中加入12mL的6N盐酸和锌粉(406.1mg,6.210mmol)，在55℃下加热反应过夜，直至反应溶液为澄清透明的溶液；反应完后向溶液中加入饱和的NaHCO3,中和溶液至中性，用乙酸乙酯萃取，饱和盐水洗涤，无水Na2SO4干燥；用乙酸乙酯：石油醚＝1：2过柱层析色谱，即得白色产物。LC-MS：484.10(M+1)+。
1HNMR(400MHz,DMSO-d6):δ8.32(s,1H),8.21(d,J＝7.6Hz,1H),8.14(s,1H),8.02(d,J＝8.4Hz,1H),7.98(d,J＝7.6Hz,1H),7.83-7.78(m,3H),7.73-7.69(m,1H),7.67-7.61(m,1H),7.14(d,J＝8.8Hz,1H),4.97(d,J＝9.2Hz,1H),3.58-3.52(m,1H),3.50-3.44(m,1H)，3.35(s,3H), 2.98(dd,J1＝16.2Hz,J2＝10.0Hz,1H)
所得反式构型产物通过手性色谱柱拆分，得到化合物14。
15、trans-(2RS,3RS)-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-15)
Figure PCTCN2015093384-appb-000037
中间体15-1的合成：
称取化合物2-羟基-1-萘甲醛(6g，34.87mmol)，化合物1-1(6.37g，31.32mmol)，DABCO(3.9g，34.87mmol)于250ml的圆底烧瓶中，加入100mL的乙酸乙酯，氩气保护加热到70℃搅拌过夜，反应结束后，旋干乙酸乙酯，加入适量的二氯甲烷溶解，直接柱层析分离，得到1.5g的红色固体，产率13％。LC-MS:358.10(M+1)+.
1H NMR(400MHz,DMSO-d6):δ9.02(s,1H),8.40(d,J＝8.4Hz,1H),8.05(d,J＝9.2Hz,1H),7.94(d,J＝8.0Hz,1H),7.75-7.64(m,2H),7.64-7.57(m,1H),7.53(t,J＝8.0Hz,1H),7.16(d,J＝8.8Hz,1H),7.03(s,1H).
中间体15-2的合成：
称取15-1(1.2g,3.4mmol)于100ml的反应瓶中，加入THF：CH3OH(10：1，55ml)溶解，磁力搅拌缓慢加入硼氢化钠(0.38g，10.1mmol)室温搅拌20min，反应结束后，加入少量水淬灭反应，减压旋干溶剂，加入10ml水，用乙酸乙酯(10ml*3)萃取，合并有机相，无水硫酸钠干燥，旋干溶剂，直接用于下一步。
化合物15的合成：
将上述所得粗品化合物15-2溶于10mL的乙醇溶液中，向溶液中加入6mL的6N盐酸和锌粉(1.10g,1.70mmol)，常温常压下反应过夜，直至反应溶液为澄清透明的溶液；反应完后向溶液中加入饱和的NaHCO3,中和溶液至中性，用乙酸乙酯萃取，饱和盐水洗涤，无水Na2SO4干燥；用乙酸乙酯：石油醚＝1：2过柱层析色谱，即得920mg白色产物，两步产率为84％。LC-MS:330.10(M+1)+.
1H NMR(400MHz,DMSO-d6):7.87(d,J＝3.6Hz,1H),7.85(d,J＝4.0Hz,1H),7.72(d,J＝8.8Hz,1H),7.70-7.59(m,2H),7.55(t,J＝7.6Hz,1H),7.40(t,J＝7.6Hz,1H),7.09(d,J＝8.8Hz,1H),4.93(d,J＝9.2Hz,1H),3.45-3.34(m,2H),2.88(dd,J1＝15.8Hz,J2＝9.2Hz,1H),1.69(s,2H).
16、N-((2S,3R)-2-氨基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-8)-甲磺酰胺(化合物-16)
Figure PCTCN2015093384-appb-000038
中间体16-1的合成：
称取化合物6-甲氧基-2-萘胺(7g，0.04044mol)，三乙胺(6g，0.06067mol)于100mL的反应瓶中，向反应瓶中加入15mL的二氯甲烷溶液，在0℃条件下反应15min；逐滴加入甲磺酰氯(7g，0.06067mol)，0℃条件下反应30min，TLC板监测，反应完全后，加入适量的氢氧化钠水溶液，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，柱层析分离(PE:EA＝2：1)，得紫色的固体5.6g，产率为55.2％。LC-MS:252.10(M+1)+,250.10(M-1)+.
1H NMR(400MHz,DMSO-d6):δ9.78(s,1H),7.79(d,J＝12.0Hz,1H),7.77(d,J＝12.0Hz,1H),7.63(d,J＝1.6Hz,1H),7.35(dd,J1＝8.8Hz,J2＝2.0Hz,1H),7.29(d,J＝2.4Hz,1H),7.15(dd,J1＝8.8Hz,J2＝2.4Hz,1H),3.86(s,3H),3.00(s,3H).
中间体16-2的合成：
称取1,1-二氯甲基醚(1.374g,0.0118mol)于250mL的茄形瓶中，加入30mL的二氯甲烷将其溶剂，向溶液中加入TiCl4(2.2mL,0.0199mol)，0℃条件下搅拌15min；称取化合物16-1(2g，0.0080mol)于适量的的二氯甲烷中溶解，逐滴加入到上述反应液中，室温搅拌36h，反应结束后加入适量的1N的盐酸溶液，乙酸乙酯萃取，无水硫酸钠干燥，柱层析分离(PE：EA＝2：1)，即得白色固体1.515g，产率为68.2％。LC-MS:280.10(M+1)+,278.05(M-1)+
1H NMR(400MHz,DMSO-d6):δ10.74(s,1H),9.98(s,1H),9.06(d,J＝9.2,1H),8.25(d,J＝9.2Hz,1H),7.72(d,J＝2.0Hz,1H),7.59(d,J＝9.2Hz,1H),7.50(dd,J1＝9.2Hz,J2＝2.0Hz,1H),4.05(s,3H),3.06(s,3H).
中间体16-3的合成：
称取化合物16-2(1.5g，0.0054mol)于250mL的反应瓶中，向反应瓶中加入适量的干燥的二氯甲烷，直至底物完全溶解；向反应液中分批加入三氯化铝(4.869g，0.03652mol)，瓶口加上干燥管，常温常压的条件下反应36h；反应结束后，向反应液中加入适量的水，搅拌一段时间，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，柱层析分离(PE：EA＝1：1)，得橘黄色固体1.021g，产率为71.6％。LC-MS:266.10(M+1)+,264.00(M-1)-.
1H NMR(400MHz,DMSO-d6):δ11.83(s,1H),10.78(s,1H),9.91(s,1H),8.93(d,J＝9.2Hz, 1H),8.09(d,J＝9.2Hz,1H),7.68(d,J＝2.0Hz,1H),7.48(dd,J1＝9.2Hz,J2＝2.4Hz,1H),7.24(d,J＝8.8Hz,1H),3.04(s,1H).
中间体16-4的合成：
称取化合物2-羟基-6-甲磺酰胺基-1-萘甲醛(900mg，3.3957mmol)，化合物1-1(1.032g，5.0936mmol)，DABCO(380mg，3.3957mmol)于50ml的圆底烧瓶中，加入适量的EA，70℃搅拌过夜，反应结束后用二氯甲烷：石油醚＝2：1柱层析分离，即得深红色固体850mg,产率为52.7％。LC-MS:449.00(M-1)-.
1H NMR(400MHz,DMSO-d6):δ10.03(s,1H),8.99(s,1H),8.39(d,J＝9.2Hz,1H),7.99(d,J＝9.2Hz,1H),7.76-7.68(m,2H),7.63-7.54(m,2H),7.14(d,J＝9.2Hz,1H),7.00(s,1H),3.07(s,1H).
中间体16-5的合成：
称取化合物16-4(800mg，1.777mmol)于250mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1)的混合液55ml，将固体溶解，分批向溶液中加入硼氢化钠(673mg,17.77mmol)，瓶口加上干燥管，常温常压的条件下反应20min，反应液由深红的变为淡黄色；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，直接用于下一步反应。
化合物16的合成：
将上述所得的化合物溶于40ml的乙醇溶液中，加入Zn粉(1150mg，17.692mmol)，加入6N的HCl溶液10ml，常温常压条件下反应2-3h后，反应液用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝1：2)，得到白色产物170mg，两步产率为22.7％。LC-MS:423.10(M+1)+。
1H NMR(500MHz,DMSO-d6):δ7.84(d,J＝9.0Hz,1H),7.69-7.62(m,3H),7.62-7.58(m,1H),7.44(dd,J1＝9.0Hz,J2＝2.0Hz,1H),7.08(d,J＝9.0Hz,1H),4.92(d,J＝9.0Hz,1H),3.44-3.40(m,1H),3.34(dd,J1＝16.3Hz,J2＝6.0Hz,1H),3.01(s,3H),2.86(dd,J1＝16.3Hz,J2＝10.5Hz,1H).
所得反式构型产物通过手性色谱柱拆分，得到化合物16。
17、(2S,3R)-8-甲磺酰基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-17)
Figure PCTCN2015093384-appb-000039
中间体17-1的合成：
称取1,1-二氯甲基醚(4.8g,0.04224mol)于500mL的茄形瓶中，加入30mL的二氯甲烷将其溶剂，0℃条件下向溶液中加入TiCl4(14g,0.07040mol)，0℃条件下搅拌15min； 称取6-甲氧基-2-甲磺酰基萘(4g，0.01693mol)于适量的的二氯甲烷中完全溶解，逐滴加入到上述反应液中，室温搅拌36h，TLC板监测，反应结束后加入适量的1N的盐酸溶液将反应液调制酸性，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，柱层析分离或重结晶，即得白色(偏微红色)产物3.275g，产率为73.5％。
中间体17-2的合成：
称取2-甲氧基-6-甲磺酰基萘-1-萘甲醛(3.2g，0.01211mol)于250ml干燥的二氯甲烷中；分批加入AlCl3(18.2529g,0.1369mol).，常温常压条件下搅拌36h，反应结束后，反应液倒入食盐水中，乙酸乙酯萃取，有机相用饱和食盐水继续洗涤两遍，无水硫酸钠干燥，真空旋干得固体，柱层析分离(PE：EA＝3：1)得白色固体1.250g，产率为41.25％。
中间体17-3的合成：
称取化合物6-甲磺酰基萘-1-甲酰基-2-萘酚(1.250g,0.0062mol)，化合物1-1(1.851g,0.0074mol)，DABCO(652mg,6.2mmol)于50mL的茄形瓶中，加入适量的乙酸乙酯将固体溶解，加热回流，反应完后柱层析分离(DCM：PE＝1：1)，即得红色产物0.5g，产率为18.6％。
中间体17-4的合成：
称取化合物(0.5g，0.0012mol)于250mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1)的混合液150mL，将固体溶解，分批向溶液中加入硼氢化钠(459mg,0.0121mol)，瓶口加上干燥管，反应液很快由发亮的橙红色变为淡黄色，常温常压的条件下，反应20min；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液得白色固体，直接用于下一步反应。
化合物17的合成：
将上述所得的化合物溶于30ml的乙醇溶液中，加入Zn粉(1.388g，21.353mmol)，加入6N的HCl溶液6ml，常温常压条件下反应2-3h后，TLC板监测，反应完全后，反应液用饱和碳酸氢钠溶液中和，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝1：1)，得到白色产物450mg(粗品)。
所得反式构型产物通过手性色谱柱拆分，得到化合物17。
1H NMR(500MHz,DMSO-d6):δ8.52(d,J＝2.0Hz,1H),8.08(d,J＝9.0Hz,1H),8.01(d,J＝9.0Hz,1H),7.97(dd,J1＝8.5Hz,J2＝2.0Hz,1H),7.72-7.67(m,1H),7.66-7.60(m,1H),7.26(d,J＝9.0Hz,1H),4.99(d,J＝9.5Hz,1H),3.47-3.43(m,1H),3.42(dd,J1＝17.5Hz,J2＝5.5Hz,1H),3.26(s,3H),2.93(dd,J1＝15.8Hz,J2＝10.0Hz,1H),1.74(s,2H).
18、trans-(2RS,3RS)-8-吗啉-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-18)
Figure PCTCN2015093384-appb-000040
中间体18-1的合成：
称取1,1-二氯甲基醚(3.65g,0.0318mol)于500mL的茄形瓶中，加入30mL的二氯甲烷将其溶剂，向溶液中加入TiCl4(5.8mL,0.0530mol)，0℃条件下搅拌15min；称取6-溴-2–甲氧基萘(5g，0.0212mol)于适量的的二氯甲烷中，逐滴加入到上述反应液中，室温搅拌36h，反应结束后加入适量的1N的盐酸溶液，乙酸乙酯萃取，无水硫酸钠干燥，柱层析分离(PE：EA＝4：1)，即得浅黄色产物3.145g，产率为56.2％。LC-MS:265.00(M+1)+.
1H NMR(400MHz,CDCl3):δ10.83(s,1H),9.15(d,J＝9.2,1H),7.92(d,J＝9.2Hz,1H),7.89(d,J＝2.0Hz,1H),7.64(dd,J1＝9.2Hz,J2＝2.0Hz,1H),7.29(d,J＝9.2Hz,1H),4.04(s,3H).
中间体18-2的合成：
称取6-溴-2-甲氧基-1-萘甲醛18-1(3.145g，0.0119mol)，乙二醇(4.437g，0.0715mol)，对甲基苯磺酸(123mg，0.0007mol)于100mL的反应瓶中，向瓶中加入适量的甲苯，加上分水器，150℃条件下回流反应过夜，反应完后，向溶液中加入氢氧化钠的水溶液将溶液调成碱性，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，柱层析分离(PE：EA＝6：1)，得淡黄色固体2.275g，产率为67％。LC-MS:309.05(M+1)+.
中间体18-3的合成：
称取化合物18-2(2.28g，0.0074mol)，Xantphos(0.214g，0.0004mol)，醋酸钯(0.083g，0.0004mol)，碳酸铯(4.824g，0.0148mol)于100mL的二颈瓶中，氩气置换气体，在抽气的情况下，用注射器加入10mL的甲苯，再注入吗啉(0.967g，0.0111mol)，继续抽气，氩气置换气体30min，氩气保护条件下，80℃反应过夜；TLC板监测，反应完全后，加入适量的水，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，柱层析(PE:EA＝2：1)分离，得黄色固体，直接用于下一步。
中间体18-4的合成：
称取化合物27-3于反应瓶中，加入适量的乙醇，向反应液中加入适量的1N的盐酸溶液，在60℃的条件下，加热回流2-3h，反应完后加入适量的氢氧化钠水溶液，有亮黄色固体析出，抽滤，滤饼柱层析分离(PE：EA＝2:1)，得亮黄色固体1.6g，两步产率为80％。LC-MS:272.20(M+1)+.
1H NMR(400MHz,CDCl3):δ10.85(s,1H),9.18(d,J＝9.6Hz,1H),7.92(d,J＝8.8Hz,1H),7.38(dd,J1＝9.6Hz,J2＝2.4Hz,1H),7.24(d,J＝9.2Hz,1H),7.05(d,J＝2.4Hz,1H),4.02(s,3H),3.91(t,J＝4.8Hz,4H),3.24(t,J＝4.8Hz,4H).
中间体18-5的合成：
称取2-甲氧基-6-吗啉-1-萘甲醛18-4(1.6g，0.0059mol)于250mL的反应瓶中，向反应瓶中加入适量的干燥的二氯甲烷，直至底物完全溶解；向反应液中分批加入三氯化铝(4.869g，0.03652mol)，瓶口加上干燥管，常温常压的条件下反应36h；反应结束后，向反应液中加入适量的水，搅拌一段时间，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干，柱层析分离(PE：EA＝1：1)，得黄色固体720mg，产率为47％。LC-MS:258.10(M+1)+,256.15(M-1)-.
1H NMR(400MHz,DMSO-d6):δ11.66(s,1H),10.77(s,1H),8.80(d,J＝9.6Hz,1H),7.98(d,J＝8.8Hz,1H),7.47(dd,J1＝9.6Hz,J2＝2.4Hz,1H),7.22(d,J＝2.4Hz,1H),7.16(d,J＝9.2Hz,1H),3.79(t,J＝4.4Hz,4H),3.18(t,J＝4.4Hz,4H).
中间体18-6的合成：
称取化合物2-羟基-6-吗啉-1-萘甲醛(720mg，2.800mmol)，化合物1-1(568mg，2.798mmol)，DABCO(313mg，2.795mmol)于50ml的圆底烧瓶中，加入适量的EA，70℃搅拌过夜，反应结束后用二氯甲烷：石油醚＝1：1柱层析分离，即得深红色固体350mg,产率为28.3％。LC-MS:443.10(M+1)+.
1H NMR(400MHz,DMSO-d6):δ8.96(s,1H),8.26(d,J＝9.2Hz,1H),7.86(d,J＝8.8Hz,1H),7.74-7.67(m,1H),7.57-7.50(m,2H),7.23(d,J＝2.0Hz,1H),7.05(d,J＝9.2Hz,1H),6.96(s,1H),3.80(t,J＝4.4Hz,4H),3.22(t,J＝4.4Hz,4H).
中间体18-7的合成：
称取化合物18-6(350mg，0.7917mmol)于250mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1)的混合液33ml，将固体溶解，分批向溶液中加入硼氢化钠(200mg,5.284mmol)，瓶口加上干燥管，常温常压的条件下反应20min，反应液由深红的变为淡黄色；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，直接用于下一步反应。
化合物18的合成：
将上述所得的化合物溶于30ml的乙醇溶液中，加入Zn粉(835mg，12.85mmol)，加入6N的HCl溶液6ml，常温常压条件下反应2-3h后，反应液用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝1：2)，得到淡黄色产物80mg，两步产率为26.7％。
1H NMR(400MHz,DMSO-d6):δ7.72(d,J＝9.2Hz,1H),7.70-7.58(m,2H),7.55(d,J＝8.8 Hz,1H),7.40(dd,J1＝9.2Hz,J2＝2.0Hz,1H),7.19(d,J＝2.0Hz,1H),6.99(d,J＝8.8Hz,1H),4.87(d,J＝9.2Hz,1H),3.79(t,J＝4.4Hz,4H),3.43-3.39(m,2H),3.18(t,J＝4.4Hz,4H),2.83(dd,J1＝16.4Hz,J2＝10.0Hz,1H),1.74(s,2H).
19、(2S,3R)-9-甲氧基-8-甲磺酰基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-19)
Figure PCTCN2015093384-appb-000041
中间体19-1的合成：
称取1,1-二氯甲基醚(4.8g,0.04224mol)于500mL的茄形瓶中，加入30mL的二氯甲烷将其溶剂，0℃条件下向溶液中加入TiCl4(14g,0.07040mol)，0℃条件下搅拌15min；称取2，7-甲氧基-6-甲磺酰基萘(4g，0.01693mol)于适量的的二氯甲烷中完全溶解，逐滴加入到上述反应液中，室温搅拌36h，TLC板监测，反应结束后加入适量的1N的盐酸溶液将反应液调制酸性，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，柱层析分离或重结晶，即得白色(偏微红色)产物3.275g，产率为73.5％。
中间体19-2的合成：
称取化合物19-1(3.2g，0.01211mol)于250ml干燥的二氯甲烷中；分批加入AlCl3(18.2529g,0.1369mol).，常温常压条件下搅拌36h，反应结束后，反应液倒入食盐水中，乙酸乙酯萃取，有机相用饱和食盐水继续洗涤两遍，无水硫酸钠干燥，真空旋干得固体，柱层析分离(PE：EA＝3：1)得白色固体1.250g，产率为41.25％。
中间体19-3的合成：
称取化合物化合物19-2(1.250g,0.0062mol)，化合物1-1(1.851g,0.0074mol)，DABCO(652mg,6.2mmol)于50mL的茄形瓶中，加入适量的乙酸乙酯将固体溶解，加热回流，反应完后柱层析分离(DCM：PE＝1：1)，即得红色产物0.5g，产率为18.6％。
中间体19-4的合成：
称取化合物19-3(0.5g，0.0012mol)于250mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1)的混合液150mL，将固体溶解，分批向溶液中加入硼氢化钠(459mg,0.0121mol)，瓶口加上干燥管，反应液很快由发亮的橙红色变为淡黄色，常温常压的条件下，反应20min；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液得白色固体，直接用于下一步反应。
化合物19的合成：
将上述所得的化合物溶于30ml的乙醇溶液中，加入Zn粉(1.388g，21.353mmol)，加入6N的HCl溶液6ml，常温常压条件下反应2-3h后，TLC板监测，反应完全后，反应液用饱和 碳酸氢钠溶液中和，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝1：1)，得到白色产物450mg(粗品)。
所得反式构型产物通过手性色谱柱拆分，得到化合物19。
1H NMR(500MHz,DMSO-d6):δ8.41(s,1H),7.92(d,J＝9.0Hz,1H),7.72-7.67(m,1H),7.65-7.60(m,1H),7.33(s,1H),7.05(d,J＝9.0Hz,1H),4.97(d,J＝9.0Hz,1H),4.08(s,3H),3.46-3.42(m,1H),3.39(dd,J1＝16.3Hz,J2＝5.0Hz,1H),3.30(s,3H),2.86(dd,J1＝16.0Hz,J2＝9.5Hz,1H),1.67(s,2H).
20、N-((2RS,3RS)-2-氨基-9-甲氧基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-8)-甲磺酰胺(化合物-20)
Figure PCTCN2015093384-appb-000042
中间体20-1的合成：
称取化合物2-溴-3，6-二甲氧基萘(3g，0.0113mol)，N，N′-二甲基乙二胺(0.509g，0.00565mol)，碘化亚铜(0.215g，0.0011mol)，磷酸钾(4.68g，0.03384mol)，甲磺酰胺(1.61g，0.0169mol)于250mL的二颈瓶中，氩气置换气体，在抽气的情况下，用注射器加入95mL的乙腈，继续抽气，氩气置换气体30min，氩气保护条件下，80℃反应36h；TLC板监测，反应结束后，加水淬灭反应，EA萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，旋干，柱层析分离(PE:EA＝3:1)，得1.89g白色固体，产率为59.6％。LC-MS:282.10(M+1)+,280.05(M-1)+.
1H NMR(400MHz,CDCl3):δ7.86(s,1H),7.65(d,J＝9.6Hz,1H),7.09(s,1H),7.05(s,1H),7.04(d,J＝3.2Hz,1H),6.94(s,1H),3.98(s,3H),3.90(s,3H),2.97(s,3H).
中间体20-2的合成：
称取1,1-二氯甲基醚(1.10g,0.0096mol)于100mL的茄形瓶中，加入15mL的二氯甲烷将其稀释，0℃条件下向溶液中加入TiCl4(3.02g,0.0159mol)，0℃条件下搅拌15min；称取N-(3，6-二甲氧基萘–2-)甲磺酰胺62(1.79g,0.0064mol)于适量的的二氯甲烷中完全溶解，逐滴加入到上述反应液中，室温搅拌过夜，TLC板监测，反应结束后加入适量的1N的盐酸溶液将反应液调制酸性PH＝5-6，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥， 柱层析分离，即得橘黄色产物1.5g，产率为76.1％。LC-MS:310.10(M+1)+,308.10(M-1)+.
1H NMR(400MHz,DMSO-d6):δ10.75(s,1H),9.15(s,1H),8.76(s,1H),8.22(d,J＝9.2Hz,1H),7.82(s,1H),7.41(d,J＝9.2Hz,1H),4.04(s,3H),3.95(s,3H),3.04(s,3H).
中间体20-3的合成：
称取无水AlCl3(4g，0.0299mol)于250mL的茄形瓶中，在冷却的条件下，向瓶中加入60mL的DCM，待固体溶解后，常温常压的条件下，向瓶中加入N-(5-甲酰基-3，6-二甲氧基萘–2-)甲磺酰胺20-2(1.85g，0.0060mol)，常温常压条件下反应；TLC板跟踪，反应结束后，向反应液中加入适量1N HCl，EA萃取，柱层析分离，即得白色的固体1.3g，产率为73％。LC-MS:296.10(M+1)+,294.10(M-1)-.
1H NMR(400MHz,DMSO-d6):δ12.03(s,1H),10.81(s,1H),9.11(s,1H),8.65(s,1H),8.11(d,J＝9.2Hz,1H),7.92(s,1H),7.15(d,J＝8.8Hz,1H),3.92(s,3H),3.50(s,3H).
中间体20-4的合成：
称取N-(5-甲酰基–3-二甲氧–6-羟基萘–2-)甲磺酰胺20-3(1g,0.0034mol)，(E)-1-(2,4,5–三氟苯基)–2–硝基烯1-1(688mg,0.0034mol)，DABCO(88mg,0.007mmol)于100mL的茄形瓶中，向瓶中加入35mL的EA，90℃条件下反应过夜，TLC板跟踪,反应结束后，柱层析分离(PE：DCM＝1:3)，得红色固体420mg,产率为25.8％。LC-MS:481.15(M+1)+,479.10(M-1)-.
1H NMR(400MHz,DMSO-d6):δ9.18(s,1H),9.16(s,1H),7.95(d,J＝8.8Hz,1H),7.83(s,1H),7.89(s,1H),7.75-7.68(m,1H),7.56-7.49(m,1H),6.99(s,1H),6.98(d,J＝9.6Hz,1H),4.11(s,3H),3.06(s,3H).
中间体20-5的合成：
称取N-[2-(2,4,5-三氟苯基)-3-硝基-6-甲氧基-2H-苯并[f]色满-7-]甲磺酰胺65(420mg，0.8749mmol)于100mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1)的混合液35mL，将固体溶解，分批向溶液中加入硼氢化钠(132mg,3.4996mmol)，反应液很快由橘黄色变为淡黄色溶液，瓶口加上干燥管，常温常压的条件下，反应20min；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干，直接用于下一步反应。
化合物20的合成：
将上述所得的N-[2-(2,4,5-三氟苯基)-3-硝基-6-甲氧基-3,4-二氢-2H-苯并[f]色满-7-]甲磺酰胺66粗品溶于20ml的乙醇溶液中，加入Zn粉(2.6g，0.040mol)，加入6N的HCl溶液2.6mL，常温常压条件下反应2-3h后，TLC板监测，反应完全后，反应液用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝1：2)。
21、(2S,3R)-2-氨基-9-甲氧基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-8-腈(化合物-21)
Figure PCTCN2015093384-appb-000043
中间体21-1的合成：
称取1,1-二氯甲基醚(4.8g,0.04224mol)于500mL的茄形瓶中，加入30mL的二氯甲烷将其溶剂，0℃条件下向溶液中加入TiCl4(14g,0.07040mol)，0℃条件下搅拌15min；称取3，6-二甲氧基萘腈(4g，0.02816mol)于适量的的二氯甲烷中完全溶解，逐滴加入到上述反应液中，室温搅拌36h，TLC板监测，反应结束后加入适量的1N的盐酸溶液将反应液调制酸性，二氯甲烷萃取，饱和食盐水洗涤，无水硫酸钠干燥，柱层析分离或重结晶，即得白色产物4.275g，产率为94.5％。
1HNMR(400MHz,DMSO-d6):δ10.71(s,1H),8.77(s,1H),8.50(s,1H),8.29(d,J＝8.4Hz,1H),7.55(d,J＝8.8Hz,1H),4.10(s,3H),3.98(s,3H)。
中间体21-2的合成：
称取6-氰基-2，7-二甲氧基–1-萘甲醛21-1(3.3g，0.01369mol)于250mL的反应瓶中，向瓶中加入150mL干燥的二氯甲烷；分批加入AlCl3(18.2529g,0.1369mol).，常温常压条件下搅拌36h，反应结束后，反应液倒入食盐水中，乙酸乙酯萃取，有机相用饱和食盐水继续洗涤两遍，无水硫酸钠干燥，真空旋干得固体，柱层析分离(PE：EA＝3：1)得淡粉红色固体1.250g，产率为40.2％。
1HNMR(400MHz,DMSO-d6):δ12.14(s,1H),10.68(s,1H),8.58(s,1H),8.35(s,1H),8.03(d,J＝9.2Hz,1H),7.11(d,J＝9.2Hz,1H),3.93(s,3H)。
中间体21-3的合成：
称取化合物6-氰基-2-羟基-7-甲氧基-1-萘甲醛21-2(1.250g,0.0055mol)，(E)-1-(2,4,5–三氟苯基)–2–硝基烯1-1(1.341g,0.0066mol)，DABCO(616mg,5.5mmol)于50mL的茄形瓶中，加入适量的乙酸乙酯将固体溶解，90℃反应过夜，反应完后柱层析分离(DCM：PE＝1：1)，即得橙黄色产物1g，产率为44.1％。
1H NMR(400MHz,DMSO-d6):δ9.18(s,1H),8.48(s,1H),8.03(d,J＝9.2Hz,1H),7.92(s,1H),7.76-7.70(m,1H),7.62-7.55(m,1H),7.10(d,J＝8.8Hz,1H),7.04(s,1H),4.16(s,1H)。
中间体21-4的合成：
称取2-(2，4，5–三氟苯基)-3–硝基–6–甲氧基–-3H–苯并[f]色满–7–腈21-3(2.2g，0.0053mol)于250mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1)的混合液150mL，将固体溶解，分批向溶液中加入硼氢化钠(606mg,0.0160mol)，反应液很快由发亮的橙红色变为淡黄色，瓶口加上干燥管，常温常压的条件下，反应20min；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液得白色固体，直接用于下一步反应。
化合物21的合成：
将上述方法1所得的2-(2，4，5–三氟苯基)-3–硝基–6–甲氧基–3，4–二氢-2H–苯并[f]色满–7–腈59粗品溶于80ml的乙醇溶液中，加入Zn粉(3.45g，0.053mol)，加入6N的HCl溶液16ml，常温常压条件下反应2-3h后，TLC板监测，反应完全后，反应液用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝1：1)，得到白色产物670mg，产率为32.7％。
所得反式构型产物通过手性色谱柱拆分，得到化合物21，LCMS(M+1)+,384.21。
1H NMR(500MHz,DMSO-d6):δ8.41(s,1H),7.75(d,J＝9.0Hz,1H),7.69-7.65(m,1H),7.64-7.58(m,1H),7.25(s,1H),7.04(d,J＝9.0Hz,1H),4.96(d,J＝9.0Hz,1H),4.03(s,3H),3.44-3.39(m,1H),3.35(dd,J1＝16.5Hz,J2＝5.5Hz,1H),2.82(dd,J1＝16.5Hz,J2＝10.0Hz,1H),1.72(s,2H).
22、trans-(2RS,3RS)-9-甲氧基-3-(2-氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-22)
Figure PCTCN2015093384-appb-000044
中间体22-1的合成：
将2–氟苯甲醛(7.747g,62.46mmol)，硝基甲烷(4mL)，甲醇(10mL)制备成溶液；将甲醇(60mL)，水(30mL)，氢氧化钠(2.5N,30mL)制备成溶液，保持温度在5℃；将前一种溶液逐滴加入到后一种溶液中，滴加约30-60min，始终保持溶液温度在5-10℃；滴加完后将上述溶液滴入到氯化锌(42.6g,31.25mmol)，浓盐酸(13mL)，水(17mL)的混合溶液中，滴加时保持温度0-10℃，滴完常温反应2-4h；反应完后，减压抽滤，用40％的甲醇溶液多次洗涤滤饼，即得淡黄色产物8.1g，产率为77.7％。GC-MS：167.
1H NMR(400MHz,CDCl3):δ8.06(d,J＝14.0,1H),7.74(d,J＝14.0,1H),7.54(d,J＝7.6Hz,1H),7.49(t,J＝6.8Hz,1H),7.25(t,J＝6.8Hz,1H),7.19(t,J＝9.6Hz,1H)。
中间体22-2的合成：
称取7-甲氧基-2-羟基-1-萘醛5-2(4.85g,24.003mmol)，化合物22-1(6g,35.928mmol)，于50mL圆底烧瓶中，加入乙酸乙酯20mL，加热溶解溶解后加入DABCO(2.7g,24.107mmol)，80℃下加热回流12h，溶液变为橙色，抽滤并用乙酸乙酯洗涤即得产物2.38g，产率为28％。
1H NMR(400MHz,DMSO-d6):δ9.18(s,1H),7.92(d,J＝8.8Hz,1H),7.81(d,J＝8.8Hz,1H),7.78(d,J＝2.0Hz,1H),7.44(m,1H),7.36(t,J＝3.6Hz,1H),7.32(d,J＝8.8Hz,1H),7.11(m,1H),7.03(s,1H),6.94(d,J＝8.8Hz,1H),4.02(s,3H),2.88(s,1H)。
中间体22-3的合成：
称取化合物6(2.38g，6.779mmol)于50mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1) 的混合液20ml，将固体溶解，分批向溶液中加入硼氢化钠(317mg，11.391mmol)，瓶口加上干燥管，常温常压的条件下，反应20min至溶液澄清；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，直接用于下一步反应。
化合物22的合成：
将上述所得的化合物溶于50ml的乙醇溶液中，加入Zn粉(4.53g，69.692mmol)，加入6N的HCl溶液8ml，50℃条件下反应2h后，用硅藻土抽滤锌粉，将溶剂悬干溶解于饱和的氢氧化钠溶液中，二氯甲烷萃取，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝2：1)，得到白色产物150mg。LC-MS:324.15(M+1)+.
1H NMR(400MHz,DMSO-d6):δ7.76(d,J＝8.8Hz,1H),7.63(d,J＝8.8Hz,1H),7.54(t,J＝7.6Hz,1H),7.45(m,1H),7.30(d,J＝2.4Hz,1H),7.26(d,J＝8.0Hz,1H),7.13(d,J＝2.0Hz,1H),7.05(m,1H),6.93(d,J＝8.8Hz,1H),5.01(d,J＝8.8Hz,1H),3.90(s,3H),2.85(m,1H),1.79(d,J＝3.2Hz,2H).
23、trans-(2RS,3RS)-9-甲氧基-3-(4-氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-23)
Figure PCTCN2015093384-appb-000045
中间体23-1的合成：
将4–氟苯甲醛(7.747g,62.46mmol)，硝基甲烷(4mL)，甲醇(10mL)制备成溶液；将甲醇(60mL)，水(30mL)，氢氧化钠(2.5N,30mL)制备成溶液，保持温度在5℃；将前一种溶液逐滴加入到后一种溶液中，滴加约30-60min，始终保持溶液温度在5-10℃；滴加完后将上述溶液滴入到氯化锌(42.6g,31.25mmol)，浓盐酸(13mL)，水(17mL)的混合溶液中，滴加时保持温度0-10℃，滴完常温反应2-4h；反应完后，减压抽滤，用40％的甲醇溶液多次洗涤滤饼，即得产物8.1g，产率为77.7％。GC-MS：167。
1H NMR(400MHz,DMSO-d6):δ8.23(d,J＝13.6,1H),8.16(d,J＝13.6,1H),7.96(m,2H),7.35(t,J＝8.8Hz,2H)。
中间体23-2的合成：
称取7-甲氧基-2-羟基-1-萘醛(4.85g,24.003mmol)，化合物5-2(6g,35.928mmol)，于50mL圆底烧瓶中，加入乙酸乙酯20mL，加热溶解溶解后加入DABCO(2.7g,24.107mmol)，80℃下加热回流12h，溶液变为橙色，抽滤并用乙酸乙酯洗涤即得产物2.38g，产率为28％。
1H NMR(400MHz,DMSO-d6):δ9.12(s,1H),7.93(d,J＝8.8Hz,1H),7.81(d,J＝8.8Hz,1H),7.74(s,1H),7.51(m,2H),7.19(t,J＝8.4Hz,2H),7.12(dd,J1＝9.2Hz,J2＝2.0Hz,1H),6.98(d,J＝8.8Hz,1H),6.80(s,1H),4.01(s,3H)。
中间体23-3的合成：
称取化合物23-2(2.38g，6.779mmol)于50mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1)的混合液20ml，将固体溶解，分批向溶液中加入硼氢化钠(317mg，11.391mmol)，瓶口加上干燥管，常温常压的条件下，反应20min至溶液澄清；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，直接用于下一步反应。
化合物23的合成：
将上述所得的化合物溶于50ml的乙醇溶液中，加入Zn粉(4.53g，69.692mmol)，加入6N的HCl溶液8ml，50℃条件下反应2h后，用硅藻土抽滤锌粉，将溶剂悬干溶解于饱和的氢氧化钠溶液中，二氯甲烷萃取，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝2：1)，得到白色产物150mg。LC-MS:324.15(M+1)+.
1H NMR(400MHz,DMSO-d6):δ7.75(d,J＝8.8Hz,1H),7.63(d,J＝8.8Hz,1H),7.52(m,2H),7.25(t,J＝8.8Hz,2H),7.11(d,J＝2.0Hz,1H),7.04(m,1H),6.94(d,J＝8.8Hz,1H),4.71(d,J＝8.8Hz,1H),3.90(s,3H),2.78(m,1H),1.54(s,2H)。
24、trans-(2RS,3RS)-9-甲氧基-3-(2，4-二氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-24)
Figure PCTCN2015093384-appb-000046
中间体24-1的合成：
将2，4–二氟苯甲醛(8.871g,62.46mmol)，硝基甲烷(4mL)，甲醇(10mL)制备成溶液；将甲醇(60mL)，水(30mL)，氢氧化钠(2.5N,30mL)制备成溶液，保持温度在5℃；将前一种溶液逐滴加入到后一种溶液中，滴加约30-60min，始终保持溶液温度在5-10℃；滴加完后将上述溶液滴入到氯化锌(42.6g,31.25mmol)，浓盐酸(13mL)，水(17mL)的混合溶液中，滴加时保持温度0-10℃，滴完常温反应2-4h；反应完后，减压抽滤，用40％的甲醇溶液多次洗涤滤饼，即得产物8.1g，产率为77.7％。GC-MS：185。
1H NMR(400MHz,DMSO-d6):δ8.14(d,J＝13.6,1H),8.09(d,J＝4.8,1H),8.06(d,J＝2.8Hz,1H),7.49(m,1H),7.25(t,J＝6.8Hz,1H),7.28(m,1H)。
中间体24-2的合成：
称取7-甲氧基-2-羟基-1-萘醛(2.7g,13.362mmol)，化合物5-2(3.7g,19.997mmol)，于50mL圆底烧瓶中，加入乙酸乙酯20mL，加热溶解溶解后加入DABCO(1.5g,13.393mmol)，80℃下加热回流12h，溶液变为橙色，抽滤并用乙酸乙酯洗涤即得产物1.5g，产率为30.4％。
1H NMR(400MHz,DMSO-d6):δ9.17(s,1H),7.93(d,J＝8.8Hz,1H),7.82(d,J＝8.8Hz,1H),7.77(d,J＝2.0Hz,1H),7.40(m,2H),7.13(dd,J1＝8.8Hz，J2＝2.4Hz,1H),6.99(s,1H),6.94(d,J＝8.8Hz,1H),4.02(s,3H),2.81(s,1H)。
中间体24-3的合成：
称取化合物24-2(2.50g，6.779mmol)于50mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1)的混合液20ml，将固体溶解，分批向溶液中加入硼氢化钠(317mg，11.391mmol)，瓶口加上干燥管，常温常压的条件下，反应20min至溶液澄清；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，直接用于下一步反应。
化合物24的合成：
将上述所得的化合物溶于50ml的乙醇溶液中，加入Zn粉(4.53g，69.692mmol)，加入6N的HCl溶液8ml，50℃条件下反应2h后，用硅藻土抽滤锌粉，将溶剂悬干溶解于饱和的氢氧化钠溶液中，二氯甲烷萃取，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝2：1)，得到白色产物160mg。LC-MS:342.20(M+1)+.
1H NMR(400MHz,DMSO-d6):δ7.78(d,J＝8.8Hz,1H),7.65(d,J＝9.2Hz,1H),7.60(t,J＝6.8Hz,1H),7.32(m,1H),7.17(m,1H),7.11(s,1H),7.05(dd,J1＝8.8Hz，J2＝2.4Hz,1H),6.93(d,J＝8.8Hz,1H),5.04(d,J＝8.8Hz,1H),3.91(s,3H),2.90(m,1H)。
25、trans-(2RS,3RS)-9-甲氧基-3-(2，5-二氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-25)
Figure PCTCN2015093384-appb-000047
中间体25-1的合成：
将2，5–二氟苯甲醛(8.871g,62.46mmol)，硝基甲烷(4mL)，甲醇(10mL)制备成溶液；将甲醇(60mL)，水(30mL)，氢氧化钠(2.5N,30mL)制备成溶液，保持温度在5℃；将前一种溶液逐滴加入到后一种溶液中，滴加约30-60min，始终保持溶液温度在5-10℃；滴加完后将上述溶液滴入到氯化锌(42.6g,31.25mmol)，浓盐酸(13mL)，水(17mL)的混合溶液中，滴加时保持温度0-10℃，滴完常温反应2-4h；反应完后，减压抽滤，用40％的甲醇溶液多次洗涤滤饼，即得产物8.1g，产率为77.7％。GC-MS：185。
1H NMR(400MHz,DMSO-d6):δ8.21(d,J＝13.6,1H),8.04(d,J＝13.6,1H),7.92(m,1H),7.47(m,2H)。
中间体25-2的合成：
称取7-甲氧基-2-羟基-1-萘醛(2.7g,13.362mmol)，化合物5-2(3.7g,19.997mmol)，于50mL圆底烧瓶中，加入乙酸乙酯20mL，加热溶解溶解后加入DABCO(1.5g,13.393mmol)，80℃下加热回流12h，溶液变为橙色，抽滤并用乙酸乙酯洗涤即得产物1.5g，产率为30.4％。
1H NMR(400MHz,DMSO-d6):δ9.17(s,1H),7.93(d,J＝8.8Hz,1H),7.82(d,J＝9.2Hz,1H),7.77(d,J＝2.0Hz,1H),7.40(m,2H),7.13(dd,J1＝9.2Hz，J2＝2.4Hz,1H),6.99(s,1H),6.94(d,J＝8.8Hz,1H),4.02(s,3H),2.78(s,1H)。
中间体25-3的合成：
称取化合物25-2(2.50g，6.779mmol)于50mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1)的混合液20ml，将固体溶解，分批向溶液中加入硼氢化钠(317mg，11.391mmol)，瓶口加上干燥管，常温常压的条件下，反应20min至溶液澄清；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，直接用于下一步反应。
化合物25的合成：
将上述所得的化合物溶于50ml的乙醇溶液中，加入Zn粉(4.53g，69.692mmol)，加入6N的HCl溶液8ml，50℃条件下反应2h后，用硅藻土抽滤锌粉，将溶剂悬干溶解于饱和的氢氧化钠溶液中，二氯甲烷萃取，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝2：1)，得到白色产物170mg。LC-MS:342.20(M+1)+.
1H NMR(400MHz,DMSO-d6):δ7.68(d,J＝8.8Hz,1H),7.56(d,J＝8.8Hz,1H),7.30(m,1H),7.23(m,2H),7.04(s,1H),6.97(dd,J1＝8.8Hz，J2＝2.4Hz,1H),6.85(d,J＝8.8Hz,1H),4.89(d,J＝8.8Hz,1H),3.82(s,3H),3.21(m,1H),2.76(m,1H)。
26、trans-(2RS,3RS)-9-甲氧基-3-(2-氯苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-26)
Figure PCTCN2015093384-appb-000048
中间体26-1的合成：
将2-氯苯甲醛(8.744g,62.46mmol)，硝基甲烷(4mL)，甲醇(10mL)制备成溶液；将甲醇(60mL)，水(30mL)，氢氧化钠(2.5N,30mL)制备成溶液，保持温度在5℃；将前一种溶液逐滴加入到后一种溶液中，滴加约30-60min，始终保持溶液温度在5-10℃；滴加完后将上述溶液滴入到氯化锌(42.6g,31.25mmol)，浓盐酸(13mL)，水(17mL)的混合溶液中，滴加时保持温度0-10℃，滴完常温反应2-4h；反应完后，减压抽滤，用40％的甲醇溶液多次洗涤滤饼，即得产物8.1g，产率为77.7％。GC-MS：183。
中间体26-2的合成：
称取7-甲氧基-2-羟基-1-萘醛(2.7g,13.362mmol)，化合物5-2(3.7g,19.997mmol)，于50mL圆底烧瓶中，加入乙酸乙酯20mL，加热溶解溶解后加入DABCO(1.5g,13.393mmol)，80℃下加热回流12h，溶液变为橙色，抽滤并用乙酸乙酯洗涤即得产物1.5g，产率为30.6％。
1H NMR(400MHz,DMSO-d6):δ9.21(s,1H),7.91(d,J＝8.8Hz,1H),7.81(d,J＝8.8Hz,1H),7.62(d,J＝7.6Hz,1H),7.39(m,2H),7.24(t,J＝7.6Hz,1H),7.13(dd,J1＝8.8Hz，J2＝2.0Hz,1H),7.08(s,1H),6.90(d,J＝8.8Hz,1H),4.03(s,3H),2.83(s,1H)。
中间体26-3的合成：
称取化合物26-2(2.49g，6.779mmol)于50mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1)的混合液20ml，将固体溶解，分批向溶液中加入硼氢化钠(317mg，11.391mmol)，瓶口加上 干燥管，常温常压的条件下，反应20min至溶液澄清；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，直接用于下一步反应。
化合物26的合成：
将上述所得的化合物溶于50ml的乙醇溶液中，加入Zn粉(4.53g，69.692mmol)，加入6N的HCl溶液8ml，50℃条件下反应2h后，用硅藻土抽滤锌粉，将溶剂悬干溶解于饱和的氢氧化钠溶液中，二氯甲烷萃取，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝2：1)，得到白色产物170mg。LC-MS:340.10(M+1)+.
1H NMR(400MHz,DMSO-d6):δ7.68(d,J＝8.8Hz,1H),7.55(d,J＝8.8Hz,1H),7.46(m,2H),7.33(t,J＝4.0Hz,2H),7.04(s,1H),6.96(dd,J1＝8.8Hz，J2＝1.6Hz,1H),6.85(d,J＝8.8Hz,1H),5.09(d,J＝8.4Hz,1H),3.82(s,3H),3.17(m,2H),2.80(m,1H)。
27、trans-(2RS,3RS)-9-甲氧基-3-(2，4-二氯苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-27)
Figure PCTCN2015093384-appb-000049
中间体27-1的合成：
将2，4–二氯苯甲醛(10.866g,62.46mmol)，硝基甲烷(4mL)，甲醇(10mL)制备成溶液；将甲醇(60mL)，水(30mL)，氢氧化钠(2.5N,30mL)制备成溶液，保持温度在5℃；将前一种溶液逐滴加入到后一种溶液中，滴加约30-60min，始终保持溶液温度在5-10℃；滴加完后将上述溶液滴入到氯化锌(42.6g,31.25mmol)，浓盐酸(13mL)，水(17mL)的混合溶液中，滴加时保持温度0-10℃，滴完常温反应2-4h；反应完后，减压抽滤，用40％的甲醇溶液多次洗涤滤饼，即得产物8.1g，产率为77.7％。GC-MS：217。
1H NMR(400MHz,DMSO-d6):δ8.31(d,J＝13.6,1H),8.18(d,J＝8.4,1H),8.07(d,J＝8.4Hz,1H),7.84(d,J＝2.0Hz,1H),7.58(m,1H)。
中间体27-2的合成：
称取7-甲氧基-2-羟基-1-萘醛(4.0g,19.802mmol)，化合物5-2(6.5g,29.954mmol)，于50mL圆底烧瓶中，加入乙酸乙酯20mL，加热溶解溶解后加入DABCO(2.2g,19.802mmol)，80℃下加热回流12h，溶液变为橙色，抽滤并用乙酸乙酯洗涤即得产物3.0g，产率为37.8％。
中间体27-3的合成：
称取化合物27-2(2.72g，6.779mmol)于50mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1)的混合液20ml，将固体溶解，分批向溶液中加入硼氢化钠(317mg，11.391mmol)，瓶口加上干燥管，常温常压的条件下，反应20min至溶液澄清；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，直接用于下一步反应。
化合物27的合成：
将上述所得的化合物溶于50ml的乙醇溶液中，加入Zn粉(4.53g，69.692mmol)，加入6N的HCl溶液8ml，50℃条件下反应2h后，用硅藻土抽滤锌粉，将溶剂悬干溶解于饱和的氢氧化钠溶液中，二氯甲烷萃取，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝2：1)，得到白色产物170mg。LC-MS:374.15(M+1)+.
1H NMR(400MHz,DMSO-d6):δ7.77(d,J＝8.8Hz,1H),7.70(d,J＝2.0Hz,1H),7.64(d,J＝8.8Hz,1H),7.59(d,J＝8.4Hz,1H),7.51(m,1H),7.12(d,J＝2.0Hz,1H),7.05(dd,J1＝8.8Hz，J2＝2.4Hz,1H),6.92(d,J＝8.8Hz,1H),5.13(d,J＝8.8Hz,1H),3.90(s,3H),3.015(s,2H),2.88(m,1H)。
28、trans-(2RS,3RS)-8，9-二甲氧基-3-(2，4-二氟苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-28)
Figure PCTCN2015093384-appb-000050
中间体28-1的合成：
称取6，7-二甲氧基-2-羟基-1-萘醛(200mg,0.862mmol)，化合物2(319mg,1.724mmol)，于50mL圆底烧瓶中，加入乙酸乙酯20mL，加热溶解溶解后加入DABCO(97mg,0.862mmol)，80℃下加热回流12h，溶液变为橙色，抽滤并用乙酸乙酯洗涤即得产物150mg，产率为44％。
中间体28-2的合成：
称取化合物8(48mg，0.120mmol)于50mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1)的混合液5ml，将固体溶解，分批向溶液中加入硼氢化钠(9.08mg，0.240mmol)，瓶口加上干燥管，常温常压的条件下，反应20min至溶液澄清；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，直接用于下一步反应。
化合物28的合成：
将上述所得的化合物溶于50ml的乙醇溶液中，加入Zn粉(78mg，1.2mmol)，加入6N的HCl溶液2ml，50℃条件下反应2h后，反应液用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝2：1)，得到白色产物15mg。LC-MS:272.20(M+1)+.
1HNMR(400MHz,DMSO-d6):δ7.59(m,2H),7.31(m,2H),7.16(m,1H),7.10(s,1H),6.89(d,J＝8.8Hz,1H),4.90(d,J＝8.8Hz,1H),3.92(s,3H),3.86(s,3H),3.43(d,J＝5.6Hz,1H),3.29(d,J＝5.2Hz,1H),2.83(q,J＝9.6Hz,1H)。
29、trans-(2RS,3RS)-8，9-二甲氧基-3-苯基-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-29)
Figure PCTCN2015093384-appb-000051
中间体29-1的合成：
将苯甲醛(6.620g,62.46mmol)，硝基甲烷(4mL)，甲醇(10mL)制备成溶液；将甲醇(60mL)，水(30mL)，氢氧化钠(2.5N,30mL)制备成溶液，保持温度在5℃；将前一种溶液逐滴加入到后一种溶液中，滴加约30-60min，始终保持溶液温度在5-10℃；滴加完后将上述溶液滴入到氯化锌(42.6g,31.25mmol)，浓盐酸(13mL)，水(17mL)的混合溶液中，滴加时保持温度0-10℃，滴完常温反应2-4h；反应完后，减压抽滤，用40％的甲醇溶液多次洗涤滤饼，即得产物6.8g，产率为73％。GC-MS：149。
1HNMR(400MHz,DMSO-d6):δ8.19(q,J＝13.6Hz,2H),7.87(d,J＝7.2Hz,2H),7.56-7.47(m,3H)。
中间体29-2的合成：
称取6，7-二甲氧基-2-羟基-1-萘醛(200mg,0.862mmol)，化合物2(257mg,1.724mmol)，于50mL圆底烧瓶中，加入乙酸乙酯20mL，加热溶解溶解后加入DABCO(97mg,0.862mmol)，80℃下加热回流12h，溶液变为橙色，抽滤并用乙酸乙酯洗涤即得产物150mg，产率为44％。
中间体29-3的合成：
称取化合物8(43.57mg，0.120mmol)于50mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1)的混合液5ml，将固体溶解，分批向溶液中加入硼氢化钠(9.08mg，0.240mmol)，瓶口加上干燥管，常温常压的条件下，反应20min至溶液澄清；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，直接用于下一步反应。
化合物29的合成：
将上述所得的化合物溶于50ml的乙醇溶液中，加入Zn粉(78mg，1.2mmol)，加入6N的HCl溶液2ml，50℃条件下反应2h后，反应液用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝4：1)，得到白色产物14mg。
30、trans-(2RS,3RS)-8，9-二甲氧基-3-(2，4-二氯苯基)-2,3-二氢-1H-苯并[f]色满-2-胺(化合物-30)
Figure PCTCN2015093384-appb-000052
中间体30-1的合成：
称取6，7-二甲氧基-2-羟基-1-萘醛(200mg,0.862mmol)，化合物12-1(374mg,1.724mmol)，于50mL圆底烧瓶中，加入乙酸乙酯20mL，加热溶解溶解后加入DABCO(97mg,0.862mmol)，80℃下加热回流12h，溶液变为橙色，抽滤并用乙酸乙酯洗涤即得产物150mg，产率为44％。
中间体30-2的合成：
称取化合物30-1(52mg，0.120mmol)于50mL的圆底烧瓶中，向瓶中加入THF/CH3OH(10:1)的混合液5ml，将固体溶解，分批向溶液中加入硼氢化钠(9.08mg，0.240mmol)，瓶口加上干燥管，常温常压的条件下，反应20min至溶液澄清；反应完全后，反应液中加入水淬灭反应，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，直接用于下一步反应。
化合物30的合成：
将上述所得的化合物溶于50ml的乙醇溶液中，加入Zn粉(78mg，1.2mmol)，加入6N的HCl溶液2ml，50℃条件下反应2h后，反应液用饱和碳酸氢钠溶液中和，乙酸乙酯萃取，无水硫酸钠干燥，旋干溶液，柱层析分离(PE:EA＝4：1)，得到白色产物16mg。LC-MS:404.05(M+1)+.
1HNMR(400MHz,DMSO-d6):δ7.69(s,1H),7.59(d,J＝8.4Hz,1H),7.57(d,J＝9.2Hz,1H),7.50(d,J＝8.4Hz,1H),7.28(s,1H),7.10(s,1H),6.90(d,J＝8.8Hz,1H),5.09(d,J＝8.8Hz,1H),3.91(s,3H),3.86(s,3H),3.47(q,J＝7.6Hz,1H),3.27(q,J＝7.2Hz,1H),2.87(q,J＝9.2Hz,1H)。
实施例31.本发明化合物的DPP4抑制活性
发明人通过以下实验在酶水平检测了本发明化合物对DPP4的抑制活性：
酶水平活性评价：
名称:DPP4(二肽基肽酶4)；别名:CD26；ADABP；ADCP2；DPPIV；TP103；英文全称:dipeptidyl-peptidase 4(CD26,adenosine deaminase complexing protein。
筛选方法:
方法名称:DPP4活性测定，荧光。
仪器：酶标仪,Envision(PerkinElmer,USA)。
材料：人源DPP4，本实验利用杆状病毒表达系统在昆虫细胞中表达得到。底物为 Gly-Pro-AMC。
过程：
DPP4可特异性水解底物Gly-Pro-AMC生成产物AMC，AMC经355nm的紫外光激发产生460nm的发射光，动态测量单位时间内460nm波长处荧光值线性变化，计算得到DPP4活性。实验采用MERK-0431作为对照化合物。
样品处理：
样品用DMSO溶解，低温保存，DMSO在最终体系中的浓度控制在不影响检测活性的范围之内。
数据处理及结果说明:
初筛选择单浓度条件下，例如20μg/ml，对样品的活性进行测试。对于在一定条件下表现出活性的样品，例如抑制率大于50％，测试活性剂量依赖关系，即IC50/EC50值，通过样品活性对样品浓度进行非线性拟合得到，计算所用软件为Graphpad Prism 4，拟合所使用的模型为sigmoidaldose-response(varible slope)，对于大多数抑制剂筛选模型，将拟合曲线底部和顶部设定为0和100。一般情况下，每个样品在测试中均设置复孔(n≥2)，在结果中以标准偏差(Standard Deviation,SD)或者标准误差(Standard Error,SE)表示。
活性数据结果显示本发明化合物对DPP-4的抑制IC50值达到nM级别，约为50nM左右，与对照化合物相当；而其中有些化合物甚至能够达到10nM以下的水平(见下表)。
活性数据：化合物对DPP-4的抑制IC50值
Figure PCTCN2015093384-appb-000053
Figure PCTCN2015093384-appb-000054
Figure PCTCN2015093384-appb-000055
因此，酶水平的活性评价显示本发明化合物的活性能够达到，甚至优于已有的药物。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (14)

  1. 通式I所示化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物：
    Figure PCTCN2015093384-appb-100001
    式中：
    X选自CH2、O、S、NH；
    A是未取代的苯环或带有1～5个取代基的苯环，每个取代基独立的选自卤素、氰基、羟基、C1～6烷基或被卤素、优选F，更优选1～5个F取代的C1～6烷基、C1～6烷氧基或被卤素、优选F，更优选1～5个F取代的C1～6烷氧基；
    A还可选自具有1-4个取代基的含氮、硫五元或六元饱和或不饱和杂环，各取代基独立选自卤素、氰基、硼酸基；
    A杂环选自以下结构：
    Figure PCTCN2015093384-appb-100002
    R为H、卤素、氰基、羟基、C1～6烷基或含1～5个F原子C1～6烷基、C1～6烷氧基或含1～5个F原子C1～6烷氧基，n＝1-2；
    环B不存在或选自芳香苯环、芳杂环、饱和或不饱和的五元六元环、含氮、氧和硫的五元或六元饱和或不饱和杂环，其取代基R1独立选自羰基、卤素、氰基、羟基、C1～6烷基、C1～10烷氧基(优选C1～6烷氧基)、C2～10含烯键、炔键的烷氧基、任选取代的苄氧基、C1～10烷基甲酰氧基、C1～3烷氧基甲氧基、双取代基OCH2CH2O和OCH2O、COOH、C1～6烷氧甲酰基、氨基甲酰基、氨基、NR2R3、C1～5烷基甲酰胺基、C3～5烷基内酰胺基、C1～6烷基磺酰胺基、C3～5烷基内磺酰胺基、巯基、C1～5烷基巯基、C1～5烷基磺酰基、C3～5环烷基磺酰基、C1～5烷基亚磺酰基，m＝1～4；
    R2、R3独立选自C1～6烷基，或者，R2、R3一起形成取代或未取代的五元或六元环烷基、或含N、O的取代或未取代的五元或六元杂环基。
  2. 如权利要求1所述的化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物：
    Figure PCTCN2015093384-appb-100003
    式中：
    X选自CH2、O、S、NH；
    A是带有1～5个取代基的苯环，每个取代基独立的选自卤素、氰基、羟基、C1～6烷基或被卤素、优选F，更优选1～5个F取代的C1～6烷基、C1～6烷氧基或被卤素、优选F，更优选1～5个F取代的C1～6烷氧基；
    A还可选自具有1-4个取代基的含氮、硫五元或六元饱和或不饱和杂环，各取代基独立选自卤素、氰基、硼酸基；
    A杂环选自以下结构：
    Figure PCTCN2015093384-appb-100004
    R为H、卤素、氰基、羟基、C1～6烷基或含1～5个F原子C1～6烷基、C1～6烷氧基或含1～5个F原子C1～6烷氧基，n＝1-2；
    环B选自芳香苯环、芳杂环、饱和或不饱和的五元六元环、含氮、氧和硫的五元或六元饱和或不饱和杂环，其取代基R1独立选自卤素、氰基、羟基、C1～6烷基、C1～6烷氧基、C1～3烷氧基甲氧基、双取代基OCH2CH2O和OCH2O、COOH、C1～6烷氧甲酰基、氨基甲酰基、氨基、NR2R3、C1～5烷基甲酰胺基、C3～5烷基内酰胺基、C1～6烷基磺酰胺基、C3～5烷基内磺酰胺基、巯基、C1～5烷基巯基、C1～5烷基磺酰基、C3～5环烷基磺酰基、C1～5烷基亚磺酰基，m＝1～4；
    R2、R3独立选自C1～6烷基，或者，R2、R3一起形成取代或未取代的五元或六元环烷基、或含N、O的取代或未取代的五元或六元杂环基。
  3. 如权利要求2所述的化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物，其特征在于，所述化合物是通式(II)所示化合物：
    Figure PCTCN2015093384-appb-100005
    其中，
    X选自CH2、O、S、NH；
    A是带有1～5个取代基的苯环，每个取代基独立的选自卤素、氰基、羟基、C1～6烷基或被卤素、优选F，更优选1～5个F取代的C1～6烷基、C1～6烷氧基或被卤素、优选F，更优选1～5个F取代的C1～6烷氧基；
    R4独立选自H、羟基、F、氰基；
    R5为卤素、氰基、羟基、巯基、C1～6烷基或含1～5个F原子C1～6烷基、C1～6烷氧基、羟基、C1～10烷基甲酰氧基、C1～3烷氧基甲氧基、COOH、C1～6烷氧甲酰基、氨基甲酰基、氰基甲基甲酰基、乙酰氨基甲基甲酰基、2-吡咯甲酰基、甲氧基甲酰甲基、4-吡喃甲酰基、4-吗啡啉甲酰基、1-哌嗪甲酰基、C1～6烷硫基或含1～5个F原子C1～6烷硫基、C1～6烷亚磺酰基、C1～6烷磺酰基、氨基、乙酰氨基、甲磺酰胺基、甲氨基甲酰胺基、N-丙磺酰内胺、N-丁磺酰内胺、4-吗啡啉基、N-甲基哌嗪-4-基、哌嗪基、3-甲磺酰基哌嗪基、3,3-二氟四氢吡咯基、2-氨基甲酰基哌啶基、3-吡唑氨基，q＝1～4。
  4. 如权利要求2所述的化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物，其特征在于，所述化合物是通式(II)所示化合物：
    Figure PCTCN2015093384-appb-100006
    其中，
    X选自CH2、O、S、NH；
    A是带有1～5个取代基的苯环，每个取代基独立的选自卤素、氰基、羟基、C1～6烷基或被卤素、优选F，更优选1～5个F取代的C1～6烷基、C1～6烷氧基或被卤素、优选F，更优选1～5个F取代的C1～6烷氧基；
    R4独立选自H、羟基、F、氰基；
    R5为卤素、氰基、羟基、巯基、C1～6烷基或含1～5个F原子C1～6烷基、C1～6烷氧基、羟基、C1～3烷氧基甲氧基、COOH、C1～6烷氧甲酰基、氨基甲酰基、氰基甲基甲酰基、乙酰氨基甲基甲酰基、2-吡咯甲酰基、甲氧基甲酰甲基、4-吡喃甲酰基、4-吗啡啉甲酰基、1-哌嗪甲酰基、C1～6烷硫基或含1～5个F原子C1～6烷硫基、C1～6烷亚磺酰基、C1～6烷磺酰基、氨基、乙酰氨基、甲磺酰胺基、甲氨基甲酰胺基、N-丙磺酰内胺、N-丁磺酰内胺、4-吗啡啉基、N-甲基哌嗪-4-基、哌嗪基、3-甲磺酰基哌嗪基、3,3-二氟四氢吡咯基、2-氨基甲酰基哌啶基、3-吡唑氨基，q＝1～4。
  5. 如权利要求2所述的化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物，其特征在于，所述化合物是通式(III)所示化合物：
    Figure PCTCN2015093384-appb-100007
    其中，
    X选自O、S、NH；
    R4独立选自H、羟基；
    R6、R7为独立选自氢、卤素、氰基、羟基、巯基、C1～2烷氧基、C1～2烷基甲酰氧基、C1～3烷氧基甲氧基、COOH、C1～2烷氧甲酰基、氨基甲酰基、氰基甲基甲酰基、乙酰氨基甲基甲酰基、2-吡咯甲酰基、甲氧基甲酰甲基、4-吡喃甲酰基、4-吗啡啉甲酰基、1-哌嗪甲酰基、甲硫基、甲基亚磺酰基、甲磺酰基、氨基、乙酰氨基、甲磺酰胺基、甲氨基甲酰胺基、N-丙磺酰内胺、N-丁磺酰内胺、4-吗啡啉基、N-甲基哌嗪-4-基、哌嗪基、3-甲磺酰基哌嗪基、3,3-二氟四氢吡咯基、2-氨基甲酰基哌啶基、3-吡唑氨基；
    R8、R9和R10独立选自氢、Cl、F、氰基。
  6. 如权利要求2所述的化合物，或其药学上可接受的盐或前药，或其光学活性异构体或溶剂化物，其特征在于，所述化合物是通式(III)所示化合物：
    Figure PCTCN2015093384-appb-100008
    其中，
    X选自O、S、NH；
    R4独立选自H、羟基；
    R6、R7为独立选自氢、卤素、氰基、羟基、巯基、C1～2烷氧基、C1～3烷氧基甲氧基、COOH、C1～2烷氧甲酰基、氨基甲酰基、氰基甲基甲酰基、乙酰氨基甲基甲酰基、2-吡咯甲酰基、甲氧基甲酰甲基、4-吡喃甲酰基、4-吗啡啉甲酰基、1-哌嗪甲酰基、甲硫基、甲基亚磺酰基、甲磺酰基、氨基、乙酰氨基、甲磺酰胺基、甲氨基甲酰胺基、N-丙磺酰内胺、N-丁磺酰内胺、4-吗啡啉基、N-甲基哌嗪-4-基、哌嗪基、3-甲磺酰基哌嗪基、3,3-二氟四氢吡咯基、2-氨基甲酰基哌啶基、3-吡唑氨基；
    R8、R9和R10独立选自氢、Cl、F、氰基。
  7. 选自下组的化合物或其药学上可接受的盐或前药：
    Figure PCTCN2015093384-appb-100009
    Figure PCTCN2015093384-appb-100010
  8. 选自下组的化合物或其药学上可接受的盐或前药：
    Figure PCTCN2015093384-appb-100011
  9. 一种药物组合物，其特征在于，所述药物组合物含有权利要求1-8中任一项所述的化合物或其药学上可接受的盐或前药，以及药学上可接受的载体或赋形剂。
  10. 如权利要求9所述的药物组合物，其特征在于，所述药物组合物是适于口服的剂型，包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。
  11. 权利要求1-8中任一项所述的化合物或其药学上可接受的盐的用途，所述化合物或其药学上可接受的盐用于制备抑制DPP-4的药物、治疗或预防二肽基肽酶-4(DPP-4)相关疾病的药物，或作为利尿剂或治疗和预防炎症的药物。
  12. 如权利要求11所述的用途，其特征在于，所述二肽基肽酶-4(DPP-4)相关的疾病是糖尿病、糖耐量异常、肠道病、溃疡性结肠炎、克隆氏病、肥胖或代谢综合征。
  13. 如权利要求12所述的用途，其特征在于，所述糖尿病是非胰岛素依赖的2-型糖尿病。
  14. 权利要求1-8中任一项所述化合物的制备方法，所述方法包括以下步骤：
    Figure PCTCN2015093384-appb-100012
    其中，X、A、R、B、R1如权利要求1-8所定义。
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CN107899073B (zh) * 2017-12-27 2021-03-30 北京大学第一医院 骨水泥、其制备方法和用途
CN110240586B (zh) * 2018-03-09 2023-01-24 山东百极地长制药有限公司 2,3-二氢-1H-苯并[f]色满-2-胺衍生物的制备方法
CN110237068A (zh) * 2018-03-09 2019-09-17 山东百极地长制药有限公司 苯并六元环衍生物作为dpp-4长效抑制剂的应用
CN110372663A (zh) * 2018-04-13 2019-10-25 山东百极地长制药有限公司 含硫杂环化合物及其作为dpp4抑制剂衍生物的应用
CN113801087A (zh) * 2020-06-12 2021-12-17 山东百极地长制药有限公司 作为dpp-4抑制剂的苯并六元环衍生物及其应用
CN113801088B (zh) * 2020-06-12 2024-04-26 山东百极地长制药有限公司 苯并六元环衍生物及其应用
CN115611843A (zh) * 2021-07-15 2023-01-17 山东百极地长制药有限公司 一种dpp4抑制活性化合物的多晶型及其制备方法
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