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WO2015172732A1 - 作为二肽基肽酶-iv抑制剂的氨基四氢吡喃衍生物 - Google Patents

作为二肽基肽酶-iv抑制剂的氨基四氢吡喃衍生物 Download PDF

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Publication number
WO2015172732A1
WO2015172732A1 PCT/CN2015/079016 CN2015079016W WO2015172732A1 WO 2015172732 A1 WO2015172732 A1 WO 2015172732A1 CN 2015079016 W CN2015079016 W CN 2015079016W WO 2015172732 A1 WO2015172732 A1 WO 2015172732A1
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alkyl
group
substituted
compound according
cycloalkyl
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English (en)
French (fr)
Inventor
李德群
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Chengdu Bestchiralbio Limited-Liability Co
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Chengdu Bestchiralbio Limited-Liability Co
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Priority to JP2017512091A priority Critical patent/JP2017515903A/ja
Priority to US15/311,267 priority patent/US20170217964A1/en
Priority to EP15792063.8A priority patent/EP3144310A4/en
Publication of WO2015172732A1 publication Critical patent/WO2015172732A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the present invention relates to compounds which can be used for inhibiting dipeptidyl peptidases, and processes for their preparation, and the use of such compounds, alone or in combination with other drugs, for the treatment of diseases associated with dipeptidyl peptidase activity.
  • type 2 diabetes As people's diets and lifestyles change, the number of people with diabetes is increasing. There are about 194 million people with diabetes in the world. It is estimated that by 2030, the number of patients with diabetes will rise to 366 million.
  • the treatment of type 2 diabetes is mainly small molecule oral drugs. Sulfonylureas, glinides, biguanides and thiazolidinediones are commonly used drugs for type 2 diabetes, but long-term use of these hypoglycemic drugs It can lead to adverse reactions such as hypoglycemia, increased body mass, and ⁇ -cell dysfunction. Ultimately, insulin or combination therapy with insulin is still needed.
  • Glucagon-like peptide-1 is an incretin that stimulates and protects islet beta cells, promotes insulin synthesis and secretion, and reduces postprandial blood glucose.
  • Dipeptidyl peptidase 4 (DPP-4) is a highly specific serine protease present in the form of a dimer that specifically recognizes the alanine residue at the 2nd position of the N-terminus of GLP-1, and from here Excision of the dipeptide inactivates GLP-1. Inhibition of DPP-4 can enhance the activity of GLP-1 and reduce the symptoms of hyperglycemia in patients with type 2 diabetes.
  • DPP-4 inhibitors can be divided into three stages: the inhibitors developed in the first stage have strong inhibitory effects on DPP-4, but are not highly selective for related enzymes such as DPP-7, DPP-8 and DPP-9.
  • Etc. increase mortality; inhibition of canine DPP-8 or DPP-9 produces gastrointestinal toxicity; inhibition of human DPP-8 or DPP-9 attenuates T cell activity and affects immune function. Therefore, new drug development requires compounds with higher selectivity for DPP-4.
  • the inhibitors developed in the second stage have high inhibitory activity and high selectivity to DPP-4, and generally the IC50 value for DPP-8 or DPP-9 should be more than 1000 times the IC50 value for DPP-4.
  • the inhibitors developed in the third stage not only have high activity and high selectivity, but also the action time of the drug can last for more than 24 hours.
  • DPP-4 inhibitors have received extensive attention in the treatment of diabetes because they inhibit the activity of DPP-4. At the same time, the development of various high-efficiency, low-toxicity and high-selectivity DPP-4 inhibitors has also become a research hotspot.
  • Another object of the present invention is to provide a pharmaceutical composition of the compound of the present invention, a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof.
  • a further object of the invention is to provide the use of a compound of the invention in the manufacture of a medicament for a disease associated with DPP-4 enzyme activity.
  • a further object of the present invention is to provide a method for treating a disease associated with DPP-4 enzyme activity using a compound of the present invention, a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, or a combination thereof .
  • the invention provides a compound represented by formula (I), a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof:
  • Ar is a substituted or unsubstituted aryl or heteroaryl group
  • R 1 is hydrogen, substituted or unsubstituted alkyl
  • R 2a and R 2b are each independently selected from hydrogen, or
  • R 2a and R 2b are each independently selected from substituted or unsubstituted alkyl, alkoxy, cycloalkyl, heterocycloalkyl;
  • R 2a and R 2b together with the nitrogen atom to which they are attached form a heterocycloalkyl group, and the heterocycloalkyl group may be optionally substituted;
  • A is selected from:
  • R 3a and R 3b are each independently selected from hydrogen, substituted or unsubstituted C 1-10 alkyl
  • R 4 is:
  • X is CR 8 or N
  • R 7 and R 7 is oxo, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or two or more R 7 form a bridged alkyl group Group
  • W is CR 8 , O, N;
  • R 6 is selected from H, a hydroxyl group, or
  • R 6 is selected from substituted or unsubstituted C 1-8 alkyl, C 1-8 alkyl-R 9 , C 3-14 cycloalkyl, 3-14 membered heterocycloalkyl, C(O)-C 1 -8 alkyl, C 1-8 haloalkyl, C 1-8 alkyl hydroxy, C(O)NR 9 R 10 , C 1-8 cyanoalkyl, C(O)R 9 , C 0-8 alkane -C(O)-C 0-8 alkyl-NR 9 R 10 , C 0-8 alkyl-C(O)OR 9 , NR 9 R 10 , SO 2 -C 1-8 alkyl, C 1 -8 alkyl-C 3-14 cycloalkyl, C(O)-C 1-8 alkyl-C 3-14 cycloalkyl, C 1-8 alkoxy;
  • R 8 is hydrogen or halogen
  • R 9 and R 10 are each independently selected from H, C 1-8 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocycloalkyl, C 6-14 aryl, 5-14 membered heteroaryl , alkoxy, C(O)C 1-4 alkyl, C 1-8 alkylamino, C 1-6 alkylhydroxy;
  • n 0, 1 or 2;
  • n 0, 1 or 2;
  • R 5 is selected from the group consisting of H, halogen, cyano, amino, nitro, or
  • R 5 is selected from a substituted or unsubstituted C 1-10 alkyl group, a C 1-10 alkoxy group, a C 2-10 alkenyl group, a (CH 2 ) p -aryl group, a (CH 2 ) p -heteroaryl group, (CH 2 ) p -cycloalkyl, (CH 2 ) p -heterocycloalkyl, (CH 2 ) p -NR 11 R 12 , (CH 2 ) p -SO 2 NR 11 R 12 , (CH 2 ) p -SO 2 R 13 , (CH 2 ) p -NR 11 SO 2 R 13 , (CH 2 ) p -OR 13 , (CH 2 ) p -OCOR 13 , (CH 2 ) p -OCONR 11 R 12 , (CH 2) p -CONR 11 R 12, (CH 2) p -NR 13 CONR 11 R 12, (CH 2) p -CO
  • R 11 and R 12 are independently selected from the group consisting of hydrogen, (CH 2 ) q -phenyl, (CH 2 ) q -C 3-8 cycloalkyl, C 1-6 alkyl, wherein the alkyl group is optionally 1 - 5 substituents selected from fluorine or hydroxy, and wherein phenyl and cycloalkyl are optionally 1-5 independently selected from halo, hydroxy, trifluoromethyl, C 1-6 alkyl or C 1 -6 alkoxy substituted;
  • R 11 and R 12 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from piperidine, piperazine, morpholine, pyrrole or azetidine, wherein said heterocyclic ring is optionally 1-3 independent a substituent selected from a halogen, a hydroxyl group, a C 1-6 alkyl group or a C 1-6 alkoxy group;
  • Each R 13 is independently C 1-6 alkyl, wherein the alkyl group is optionally substituted with from 1 to 5 substituents selected from fluoro or hydroxy;
  • p 0, 1, 2, 3, 4, 5 or 6;
  • q 0, 1, or 2.
  • Ar is phenyl optionally substituted with 1-5 R 14 ;
  • Each R 14 is independently selected from the group consisting of halogen, hydroxy, cyano, nitro, nitroso, amino, imino, carboxy, fluorenyl, or
  • Each R 14 is independently selected from substituted or unsubstituted alkyl, acyl, amide, ester, acyl, phenoxy, benzyl, benzyloxy, sulfonyl, sulfinyl, cycloalkyl, Heterocycloalkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkylamino, aryl, heteroaryl.
  • Ar must be non-1-3 substituents independently selected from F, Cl, Br, I, -CH 3, -CF 3, -OCF 3 phenyl substituents.
  • Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl.
  • R 2a and R 2b are independently selected from the group consisting of hydrogen, C 1-10 alkyl, alkoxy, C 3-14 cycloalkyl, 3-14 membered heterocycloalkyl;
  • alkyl group is optionally substituted with from 1 to 6 substituents independently selected from halo, hydroxy, trifluoromethyl;
  • the alkoxy group is optionally substituted with from 1 to 6 substituents independently selected from halogen or hydroxy;
  • the cycloalkylalkyl group is optionally selected from 1 to 3 independently from halogen, hydroxy, cyano, nitro, carboxy, C 1-6 alkyl, C 1-6 alkyloxycarbonyl or C 1-6 alkoxy a substituent substituted with a group wherein the alkyl group and the alkoxy group are substituted with from 1 to 5 fluorines;
  • Heterocyclyl optionally substituted with 1-3 groups independently selected from oxo, halogen, hydroxy, cyano, nitro, carboxy, C 1-6 alkyl, C 1-6 alkyloxycarbonyl or C 1-6 a substituent of an alkoxy group;
  • R 2a and R 2b together with the nitrogen atom to which they are attached form a heterocyclic ring selected from piperidine, piperazine, morpholine, pyrrole or azetidine, wherein the heterocyclic ring is optionally 1-3 independent Substituted with a substituent selected from a halogen, a hydroxyl group, a C 1-6 alkyl group or a C 1-6 alkoxy group, wherein each alkyl group and alkoxy group are substituted with from 1 to 5 fluorines.
  • R 2a and R 2b are, independently, selected from hydrogen, C 1-6 alkyl optionally substituted with 1-3 fluoro or hydroxy;
  • R 2a and R 2b together with the nitrogen atom to which they are attached form a heterocyclic ring selected from piperidine, piperazine, morpholine, pyrrole or azetidine.
  • R 2a and R 2b is hydrogen.
  • R 3a and R 3b are each independently selected from hydrogen, C 1-6 alkyl optionally substituted with from 1 to 6 fluorine atoms.
  • R 3a and R 3b are hydrogen.
  • R 5 is H.
  • R 4 is:
  • X is CR 8 or N
  • R 7 and R 7 is oxo, or both R 7 form a bridged alkyl group
  • W is CR 8 , O, N;
  • R 6 is selected from H, a hydroxyl group, or
  • R 6 is selected from substituted or unsubstituted C 1-8 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C(O)-C 1-6 alkyl, C(O)NR 9 R 10 , C(O)R 9 , NR 9 R 10 , SO 2 -C 1-8 alkyl;
  • R 8 is hydrogen or halogen
  • R 9 and R 10 are each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl;
  • n 0, 1 or 2;
  • n 0, 1, or 2.
  • a compound of formula Ic is shown in the absolute stereochemical configuration shown, having Ar and NR 2a R 2b in the trans orientation on three stereo-formed tetrahydropyran carbon atoms marked with * Substituents, Ar and A substituents in the trans direction, and NR 2a R 2b and A substituents in the cis direction:
  • A is selected from:
  • R 4 and R 5 are as defined above.
  • R 5 is H.
  • Typical compounds of the invention include, but are not limited to:
  • the compounds of formula (I) contain a chiral center and thus may exist in different enantiomeric and diastereomeric forms.
  • the compounds of the invention have an asymmetric center of carbon atoms labeled *. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially purified compounds are included within the scope of the invention.
  • the invention includes isotopically labeled compounds which are equivalent to those described by formula (I), but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number common in nature.
  • isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18, respectively. O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Compounds of the invention, prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs containing such isotopes and/or other isotopes of other atoms are within the scope of the invention.
  • Certain isotopically-labeled compounds of the invention, such as those incorporating radioisotopes (e.g., 3 H and 14 C), are useful in drug and/or substrate tissue distribution assays. Ruthenium, i.e., 3 H and carbon-14, i.e., 14 C isotopes, are particularly preferred because they are easy to prepare and detect.
  • isotopically labeled compounds of the formula (I) of the present invention and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopes in the following schemes and/or the procedures disclosed in the examples and preparations. Labeled reagents.
  • the compounds of formula (I) are capable of further producing pharmaceutically acceptable formulations comprising salts, solvates of the compounds of formula (I), including but not limited to acid addition salts and/or base salts.
  • the invention also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I), or a therapeutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient therefor. All of these forms belong to the invention.
  • Alkyl in the present invention refers to a structural unit of a group and other groups such as a halogen-substituted alkyl group and an alkoxy group, and may be linear or branched. Included are linear alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, undecyl, dodecyl and the like.
  • the term also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following groups: -CH (CH 3) 2, -CH (CH 3) (CH 2 CH 3), - CH (CH 2 CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 2 CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 C(CH 2 CH 3 ) 3 , -CH(CH 3 )-CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 3) 2, -CH 2 CH 2 CH (CH 3) (CH 2 CH 3), - CH 2 CH 2 CH (CH 3) 2, -CH 2 CH 2 C (CH 3) 3, -CH 2 CH 2 C(CH 3 ) 3 , -CH(CH 3 )CH 2 CH(CH 3 3) 3,
  • alkenyl refers to an alkyl group as defined above wherein two adjacent carbon atoms are joined by a double bond.
  • alkynyl relates to an alkyl group wherein two adjacent carbon atoms are joined by a triple bond.
  • halogen means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • alkoxy refers to an (alkyl) O- group wherein alkyl is as defined herein.
  • hydroxy refers to the group -OH.
  • amino refers to the group -NH 2.
  • amino refers to the group -NH-.
  • nitro refers to the group -NO 2 .
  • nitroso refers to the group -NO.
  • trifluoromethyl refers to the group -CF 3.
  • mercapto refers to the group -SH.
  • aryl refers to an aromatic ring in which each atom forming a ring is a carbon atom.
  • the aryl ring can be formed from five, six, seven, eight, nine or more than nine carbon atoms.
  • the aryl group can be optionally substituted.
  • An example package of an aryl group include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracenyl, fluorenyl and fluorenyl.
  • heteroaryl or optional “heteroaromatic” refers to an aromatic group which includes one or more ring heteroatoms of the optional nitrogen, oxygen and sulfur.
  • heteroaryl or “heteroaryl” moiety containing N refers to an aromatic group in which at least one of the backbone atoms of the ring is a nitrogen atom.
  • heteroaryl groups include the following:
  • the heteroaryl group can be mono- or di-radical (ie, a heteroarylene group).
  • cycloalkyl refers to a monocyclic or polycyclic radical containing only carbon and hydrogen, and is optionally saturated, partially unsaturated or fully unsaturated.
  • the cycloalkyl group includes a group having 3 to 10 ring atoms.
  • Illustrative examples of cycloalkyl groups include the following:
  • the cycloalkyl group is a monoradical or a diradical (for example, a cycloalkylene group), and if it is a "lower cycloalkyl group", it has 3 to 8 carbon atoms.
  • heterocycloalkyl refers to a heteroatom having at least one selected from the group consisting of O, N and S and optionally containing one or more double or triple bond non-aromatic cycloalkyl groups.
  • the cycloheteroalkyl group as a whole may have 3 to 14 ring atoms and contain 1 to 5 hetero atoms (for example, 3 to 6 ring atoms in the case of a monocyclic heterocycloalkyl group, in the case of a polycyclic heterocycloalkyl group) Has 7-14 ring atoms).
  • Heterocycloalkyl groups can be covalently attached to a defined chemical structure at any heteroatom or carbon atom that results in a stable structure.
  • heterocycloalkyl group can be oxidized (e.g., morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S, S-dioxide).
  • Heterocycloalkyl groups may also contain one or more oxo groups, such as phthalimido, piperidinone, oxazolidinone, 2,4(1H,3H)-dioxo-pyrimidinyl , pyridine-2(1H)-keto group and the like.
  • heterocycloalkyl groups also include morpholinyl, thiomorpholinyl, pyranyl, imidazolidinyl, imidazolinyl, oxazolidinyl, isoxazolidinyl, pyrazolidinyl, pyrazolinyl, Pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiazolyl, perhydroisodecyl, piperidinyl, azetidine, N-methylazetidinyl, piperazine Zinyl, N-methylpiperazinyl, diazepine, and the like.
  • acyl denotes a -CO- group
  • exemplary acyl groups include acetyl, trifluoroacetyl, benzoyl and the like.
  • amido refers to a chemical moiety having the formula -C(O)NHR or -NHC(O)R, wherein R is selected from alkyl, cycloalkyl, heterocycloalkyl (via ring carbon bonding), aryl A heteroaryl group (bonded through a ring carbon).
  • ester group refers to a chemical moiety having the formula -COOR wherein R is selected from alkyl, cycloalkyl, heterocycloalkyl (via ring carbon bonding), aryl, heteroaryl (via ring carbon bonding) ).
  • acyl ester group refers to a chemical moiety having the formula -CO-COOR wherein R is selected from alkyl, cycloalkyl, heterocycloalkyl (via ring carbon bonding), aryl, heteroaryl (via ring Carbon bonding).
  • the compounds of the invention may also be administered in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids.
  • a basic compound encompassed within the term “pharmaceutically acceptable salt” refers to a non-toxic salt of a compound of the invention which is usually prepared by reacting the free base with a suitable organic or inorganic acid.
  • a suitable solvent such as tetrahydrofuran, methanol, toluene, pyridine, DMF or DMSO
  • reagents such as sodium borohydride, borane or sodium triacetoxyborohydride
  • the reaction is carried out in the presence of a Lewis acid such as titanium tetrachloride or titanium tetraisopropylate.
  • the reaction can also be promoted by the addition of an acid such as acetic acid.
  • intermediate III can be a salt, such as a trifluoroacetate or hydrochloride, and a base such as N,N-diisopropylethylamine or triethylamine can be conveniently added to the reaction mixture. .
  • the protecting group is then removed, for example in the case of Boc with trifluoroacetic acid or methanolic hydrochloric acid or in the case of Fmoc with triethylamine, diethylamine, piperidine or morpholine in DMF, NMP or acetonitrile And then introducing the R a and R b groups by a suitable method (when both R a and R b are not hydrogen) (for example, under basic conditions, intermediate IV reacts with R a Cl and/or R b Cl) To give a compound of formula (I).
  • Intermediate II can be obtained by methods known to those skilled in the art.
  • the aldehyde a and the nitromethane are obtained in the presence of a base to obtain a nitro alcohol b, and the obtained nitro alcohol is treated with an oxidizing agent such as Dess-martin to obtain a nitroketone c.
  • Nitroketone c is reacted with 3-iodo-2-(iodomethyl)prop-1-ene under heating to give d.
  • the resulting d is reduced by a reducing agent such as sodium borohydride to give both cis and trans products wherein the cis product can be readily converted to the trans product using a base such as DBU.
  • trans products e1 and e2 were separated by a chiral column by HPLC to give e2. Then, e2 is reduced with zinc and an acid such as hydrochloric acid to give an aminopyran f, and the amino group is protected with a protecting group such as Boc to give g.
  • oxidizing reagents such as osmium tetroxide and N-methyl? The porphyrin N-oxide is treated with g to give the bishydroxy compound h, which is subsequently oxidized with sodium periodate to give the intermediate IIa.
  • Intermediate III can be prepared according to General Procedure 3.
  • the pyrrolidin i protected by Boc or other protecting agent can be converted to pyrrolidone j by oxidation, such as Swern oxidation.
  • j is heated in the presence of DMF-DMA to provide k.
  • a suitable solvent such as ethanol
  • hydrazine is added and heated to obtain intermediate 1. 1 is reacted with LR 2 , and after L is removed, it is removed by suitable conditions.
  • Deprotection groups are provided to provide intermediates IIIa and IIIb, and IIIa and IIIb can be separated by methods familiar to those skilled in the art such as column chromatography.
  • DIPEA N,N-diisopropylethylamine
  • NMO N-methyl-N-oxidized morpholine
  • Dess-martin periodinane (184 g) was added to a solution of the nitroethanol (68.1 g) prepared in the step 1 in dichloromethane over 30 minutes at 10 °C. Stirring was continued for 24 h, then the reaction mixture was poured into a mixture of sodium bicarbonate (441 g) and sodium thiosulfate (489 g) in water (4.2 L). The aqueous layer was neutralized with HCl (6N, 1.5 L) until no more bubbles were formed, extracted with dichloromethane and washed once with sodium bicarbonate. The combined organic layers were dried with EtOAc EtOAc m.
  • the product obtained in the previous step (440 mg, 2.2 mmol) was dissolved in ethanol, and zinc powder (1.2 g, 18.9 mmol) was added, and 6N hydrochloric acid (6 ml, 36 mmol) was added with vigorous stirring. After 3 h, the pH was adjusted to 10 with 2N sodium hydroxide and extracted three times with diethyl ether and dried over anhydrous sodium sulfate.
  • the product obtained in the step 7 was dissolved in 7 ml of acetone, 3.5 ml of water and 14 ml of t-butanol were added, and then 0.258 ml of a 2.5% solution of osmium tetroxide in t-butanol was added. After stirring for 10 min at room temperature, 0.14 ml of NMO was added, and the mixture was stirred at room temperature for 48 h, then a saturated sodium thiosulfate solution was added and stirred for half an hour, then extracted with ethyl acetate and dried over anhydrous sodium sulfate. 510mg product, directly proceed to the next reaction.
  • tert-Butyl 3-oxopyrrolidine-l-carboxylate (40 g, 216 mmol) was dissolved in 300 mL DMF-DMA and heated at 105 ° C for 40 min. The solution was evaporated under reduced pressure.
  • N-Boc-pyrazolopyrrolidine (100 mg, 0.478 mmol) was dissolved in 3 ml of anhydrous tetrahydrofuran, and sodium hydride (30 mg, 0.718 mmol, 60% dispersion in oil) was added and stirred at room temperature for 1 h, then morphosulfonyl chloride was added.
  • Example 2 The method for synthesizing the compound 2 of the present invention was carried out in the same manner as in Example 1, except that the morpholinesulfonyl chloride in Example 1 was replaced with piperidinyl chloride to give a white solid.
  • ESI-MS 468.3 (M + 1).
  • Example 1 Method for synthesizing the compound 5 of the present invention Referring to Example 1, the morpholinesulfonyl chloride of Example 1 was replaced with 4-cyclopentylpiperazin-1-yl-sulfonyl chloride to give a white solid.
  • Example 1 Method for synthesizing the compound 9 of the present invention Referring to Example 1, the morpholinesulfonyl chloride of Example 1 was replaced with 4-(methylsulfonyl)piperazine-1-sulfonyl chloride to give a white solid. ESI-MS: 547.5 (M+1).
  • the compound 10 of the present invention is obtained by reacting Compound 1 with ethyl bromide under basic conditions as a pale yellow solid.
  • ESI-MS 498.5 (M+1).
  • Compound 11 of the present invention is obtained by reacting Compound 1 with isopropyl bromide under basic conditions as an off-white solid.
  • ESI-MS 554.3 (M+1).
  • Compound 12 of the present invention is obtained by reacting Compound 1 with butyl bromide under basic conditions as a white solid.
  • Example 1 Method for synthesizing the compound 15 of the present invention Referring to Example 1, the morpholinesulfonyl chloride of Example 1 was replaced with perhydroindole-1-sulfonyl chloride to give a white solid.
  • ESI-MS 508.2 (M+1).
  • a suitable amount of DPP-4 enzyme (SIGMA), a 3-fold concentration-diluted sample cartridge HEPES buffer was added to the reaction system, and a blank control (without enzyme and sample cartridge), a negative control (without sample), and a positive control (positive) were set up.
  • the control was MK-3102), reacted at room temperature for 10 min, and the substrate Gly-Pro-7-amido-4-methylcoumarin (SIGMA) was added thereto, and the reaction was carried out at room temperature for 30 min in the dark, and fluorescence was detected at an excitation wavelength of 355 nm and an emission wavelength of 460 nm.
  • Table 1 Results of in vitro activity test of DPP-4 for example compounds and comparative compounds such as Siteagliptin
  • the compounds of the present invention have a significant inhibitory effect on the DPP-4 enzyme.
  • the compounds 1, 4 and the like of the present invention have better metabolic stability than MK-3102, suggesting that the compound of the present invention is expected to be developed as a long-acting hypoglycemic drug.

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Abstract

提供一种通式(I)所示的氨基四氢吡喃类衍生物、其制备方法及含有该衍生物的药物组合物，以及其制备治疗剂特别是制备二肽基肽酶-IV抑制剂的用途。

Description

作为二肽基肽酶-IV抑制剂的氨基四氢吡喃衍生物 技术领域
本发明涉及可以用于抑制二肽基肽酶的化合物，和其制备方法，以及该类化合物单独或和其他药物联合使用在治疗与二肽基肽酶活性相关的疾病中的应用。
背景技术
随着人们饮食和生活方式的改变，糖尿病患者数量在不断增加。全世界现有糖尿病患者约1.94亿，预计到2030年，糖尿病患病人数将升至3.66亿。长期以来，2型糖尿病的治疗以小分子口服药物为主，磺酰脲类、格列奈类、双胍类和噻唑烷二酮类是2型糖尿病的常用治疗药物，但长期使用这些降糖药物会导致患者发生低血糖、体质量增加、β-细胞功能损伤等不良反应，最终仍需采用胰岛素或与胰岛素联合治疗。
胰高血糖素样肽-1(GLP-1)是一种肠促胰岛素，它通过刺激和保护胰岛β细胞，促进胰岛素的合成和分泌，降低餐后血糖。二肽基肽酶4(DPP-4)是一种以二聚体形式存在的高特异性丝氨酸蛋白酶，可特异性识别GLP-1的N末端第2位的丙氨酸残基，并从此处切除二肽使GLP-1失活。抑制DPP-4能增强GLP-1的活性，降低2型糖尿病患者的高血糖症状。
DPP-4抑制剂的发展可分3个阶段：第一阶段开发的抑制剂对DPP-4的抑制作用强，但对DPP-7、DPP-8和DPP-9等相关酶选择性不高。研究发现对DPP-7的抑制会导致休眠期T细胞死亡；对大鼠DPP-8或DPP-9的抑制可引起秃毛、血小板减少、网状细胞减少、脾脏扩大以及多器官组织病理学改变等，增加死亡率；对犬DPP-8或DPP-9的抑制会产生肠胃毒性；对人DPP-8或DPP-9的抑制会减弱T细胞的活性，影响机体免疫功能。因此，新药开发要求化合物对DPP-4具有较高的选择性。第二阶段开发的抑制剂对DPP-4具有高抑制活性和高选择性，一般对DPP-8或DPP-9的IC50值应在其对DPP-4的IC50值的1000倍以上。第三阶段开发的抑制剂，不仅具有高活性和高选择性，而且药物的作用时间能持续24h以上。
近年来涌现了许多新结构类型、强效、高选择性DPP-4抑制剂，如默克公司研发的磷酸西格列汀(sitagliptin phosphate)，2006年在美国上市；诺华公司研究开发的维格列汀(vildagliptin)，2007年于欧洲上市；百时美施贵宝公司与阿斯利康公司合作开发的沙格列汀(saxagliptin)，2009年在美国上市；武田公司的苯甲酸阿格列汀(alogliptin benzoate)，2010年于日本上市；勃林格殷格翰公司的利格列汀(linagliptin)，2011年在美国上市；三菱田边与第一三共合作开发的特格列汀(teneligliptin)，2012年于日本上市；LG Life Sciences公司的吉格列汀(gemigliptin)，2012年韩国上市；Sanwa Kagaku Kenkyusho公司的阿格列汀(anagliptin)，2012年于日本上市。此外，尚有多个品种处于临床试验阶段。
DPP-4抑制剂因能抑制DPP-4的活性，在糖尿病的治疗中受到广泛的关注。同时，开发各种高效低毒、高选择性的DPP-4抑制剂也成为研究的热点。
发明内容
本发明的目的在于提供一类3-氨基四氢吡喃类化合物、其药学上可接受的盐、水合物、溶剂化物或立体异构体作为新型DPP-4抑制剂。
本发明的另一个目的是提供本发明的化合物、其药学上可接受的盐、水合物、溶剂化物或立体异构体的药物组合物。
本发明的又一个目的是提供本发明化合物在制备与DPP-4酶活性相关的疾病的药物中的应用。
本发明进一步的目的在于提供一种用本发明的化合物、其药学上可接受的盐、水合物、溶剂化物或立体异构体，或者其组合物治疗与DPP-4酶活性相关的疾病的方法。
本发明一方面提供一种式(I)表示的化合物、其药学上可接受的盐、水合物、溶剂化物或立体异构体：
Figure PCTCN2015079016-appb-000001
或其药学上可接受的盐、水合物、溶剂化物、立体异构体；其中
Ar为取代或未取代的芳基、杂芳基；
R1为氢、取代或未取代的烷基；
R2a和R2b各自独立地选自氢，或者
R2a和R2b各自独立地选自取代或未取代的烷基、烷氧基、环烷基、杂环烷基；或者
R2a和R2b与它们所连接的氮原子一起形成杂环烷基，并且，杂环烷基可被任意取代；
A选自：
Figure PCTCN2015079016-appb-000002
R3a和R3b各自独立地选自氢、取代或未取代的C1-10烷基；
R4为：
Figure PCTCN2015079016-appb-000003
X为CR8或N；
其中可能存在0-3个R7，并且R7为氧代、卤素、取代或未取代的烷基、取代或未取代的烷氧基，或者两个或多个R7形成桥连的烷基基团；
W为CR8、O、N；
R6选自H、羟基，或者
R6选自取代或未取代的C1-8烷基、C1-8烷基-R9、C3-14环烷基、3-14元杂环烷基、C(O)-C1-8烷基、C1-8卤代烷基、C1-8烷基羟基、C(O)NR9R10、C1-8氰基烷基、C(O)R9、C0-8烷基-C(O)-C0-8烷基-NR9R10、C0-8烷基-C(O)OR9、NR9R10、SO2-C1-8烷基、C1-8烷基-C3-14环烷基、C(O)-C1-8烷基-C3-14环烷基、C1-8烷氧基；
R8为氢或卤素；
R9和R10各自独立地选自H、C1-8烷基、C3-14环烷基、3-14元杂环烷基、C6-14芳基、5-14元杂芳基、烷氧基、C(O)C1-4烷基、C1-8烷基氨基、C1-6烷基羟基；
m为0、1或2；
n为0、1或2；
R5选自H、卤素、氰基、氨基、硝基，或者
R5选自取代或未取代的C1-10烷基、C1-10烷氧基、C2-10烯基、(CH2)p-芳基、(CH2)p-杂芳基、(CH2)p-环烷基、(CH2)p-杂环烷基、(CH2)p-NR11R12、(CH2)p-SO2NR11R12、(CH2)p-SO2R13、(CH2)p-NR11SO2R13、(CH2)p-OR13、(CH2)p-OCOR13、(CH2)p-OCONR11R12、(CH2)p-CONR11R12、(CH2)p-NR13CONR11R12、(CH2)p-COOH、(CH2)p-COR13、(CH2)p-CO2C1-6烷基、(CH2)p-NR11COOR13；
其中，R11和R12独立地选自氢、(CH2)q-苯基、(CH2)q-C3-8环烷基、C1-6烷基，其中烷基任选被1-5个选自氟或羟基的取代基取代，并且其中苯基和环烷基任选被1-5个独立地选自卤素、羟基、三氟甲基、C1-6烷基或C1-6烷氧基取代；
或者R11和R12与它们所连接的氮原子一起形成选自哌啶、哌嗪、吗啉、吡咯或氮杂环丁烷的杂环，其中所述杂环任选被1-3个独立地选自卤素、羟基、C1-6烷基或C1-6烷氧基的取代基取代；
每个R13独立地为C1-6烷基，其中烷基任选被1-5个选自氟或羟基的取代基取代；
p为0、1、2、3、4、5或6；
q为0、1或2。
在本发明化合物的一种实施方案中，Ar为非必须地被1-5个R14取代的苯基；
每个R14独立地选自卤素、羟基、氰基、硝基、亚硝基、氨基、亚氨基、羧基、巯基，或者
每个R14独立地选自取代或未取代的烷基、酰基、酰胺基、酯基、酰基酯基、苯氧基、苄基、苄氧基、磺酰基、亚磺酰基、环烷基、杂环烷基、烯基、炔基、烷氧基、烯氧基、烷基氨基、芳基、杂芳基。
在一类这样的实施方案中，Ar为非必须地被1-3个独立地选自F、Cl、Br、I、-CH3、-CF3、-OCF3的取代基取代的苯基。
在另一类这样的实施方案中，Ar为2，5-二氟苯基或2，4，5-三氟苯基。
在本发明的第二种实施方案中，R2a和R2b独立地选自氢、C1-10烷基、烷氧基、C3-14环烷基、3-14元杂环烷基；
其中，烷基任选被1-6个独立地选自卤素、羟基、三氟甲基的取代基取代；
烷氧基任选被1-6个独立地选自卤素或羟基的取代基取代；
环烷烷基任选被1-3个独立地选自卤素、羟基、氰基、硝基、羧基、C1-6烷基、C1-6烷基氧基羰基或C1-6烷氧基的取代基取代，其中烷基和烷氧基被1-5个氟取代；
杂环基任选被1-3个独立地选自氧代、卤素、羟基、氰基、硝基、羧基、C1-6烷基、C1-6烷基氧基羰基或C1-6烷氧基的取代基取代；
或者R2a和R2b与它们所连接的氮原子一起形成选自哌啶、哌嗪、吗啉、吡咯或氮杂环丁烷的杂环，其中所述杂环任选被1-3个独立地选自卤素、羟基、C1-6烷基或C1-6烷氧基的取代基取代，其中每个烷基和烷氧基被1-5个氟取代。
在一类这样的实施方案中，R2a和R2b独立地选自氢、任选被1-3个氟或羟基取代的C1-6烷基；或者
R2a和R2b与它们所连接的氮原子一起形成选自哌啶、哌嗪、吗啉、吡咯或氮杂环丁烷的杂环。
在另一类这样的实施方案中，R2a和R2b为氢。
在本发明化合物的第三种实施方案中，R3a和R3b各自独立地选自氢、任选被1-6个氟原子取代的C1-6烷基。
在一类这样的实施方案中，R3a和R3b为氢。
在本发明化合物的第四种实施方案中，A为：
Figure PCTCN2015079016-appb-000004
在该类的子类中，R5为H。
在本发明化合物的第五种实施方案中，R4为：
Figure PCTCN2015079016-appb-000005
X为CR8或N；
其中可能存在0-2个R7，并且R7为氧代，或者两个R7形成一个桥连的烷基基团；
W为CR8、O、N；
R6选自H、羟基，或者
R6选自取代或未取代的C1-8烷基、C3-8环烷基、3-8元杂环烷基、C(O)-C1-6烷基、C(O)NR9R10、C(O)R9、NR9R10、SO2-C1-8烷基；
R8为氢或卤素；
R9和R10各自独立地选自H、C1-6烷基、C3-8环烷基、3-8元杂环烷基；
m为0、1或2；
n为0、1或2。
在本发明化合物的第六种实施方案中，提供了所示立体化学构型的结构式Ia和Ib的化合物，其在两个用*标记的立体形成的四氢吡喃碳原子上具有反式方向的Ar和NR2aR2b取代基：
Figure PCTCN2015079016-appb-000006
其中Ar，NR2aR2b和A如上文所定义。
在一类这样的第六种实施方案中，提供了所示立体化学构型的结构式Ia的化合物，其在两个用*标记的立体形成的四氢吡喃碳原子上具有反式方向的Ar和NR2aR2b取代基：
Figure PCTCN2015079016-appb-000007
在第二类这样的第六种实施方案中，提供了所示绝对立体化学构型的结构式Ic和Id的化合物，其在三个用*标记的立体形成四氢吡喃碳原子上具有反式方向的Ar和NR2aR2b取代基， 反式方向的Ar和A取代基，以及顺式方向的NR2aR2b和A取代基：
Figure PCTCN2015079016-appb-000008
在该类的子集中，提供了所示绝对立体化学构型的结构式Ic的化合物，其在三个用*标记的立体形成四氢吡喃碳原子上具有反式方向的Ar和NR2aR2b取代基，反式方向的Ar和A取代基，以及顺式方向的NR2aR2b和A取代基：
Figure PCTCN2015079016-appb-000009
在该类的子集中，A选自：
Figure PCTCN2015079016-appb-000010
其中R4和R5如上文所定义。
在该类的子集中，R5为H。
本发明的典型化合物包括，但不限于：
Figure PCTCN2015079016-appb-000011
Figure PCTCN2015079016-appb-000012
式(I)化合物含有手性中心，因此可能存在不同的对映体和非对映体形式。特别地，在式Ia，Ib，Ic和Id中，本发明化合物具有标记为*的碳原子不对称中心。每个这样的不对称中心将独立地产生两种旋光异构体，所有可能的旋光异构体和非对映异构体混合物以及纯的或部分纯化的化合物都包含在本发明的范围内。
本发明包括同位素标记的化合物，它们等同于式(I)所描述的那些，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢，碳，氮，氧，磷，硫，氟和氯的同位素，分别例如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(如3H和14C)的那些可用于药物和/或底物组织分布测定。氚、即3H和碳-14、即14C同位素是特别优选的，因为它们容易制备和检测。进而，被更重的同位素取代，例如氘，即2H，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下可能是优选的。同位素标记的本发明式(I)化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。
式(I)化合物能够进一步生成药学上可接受的制剂，包含式(I)化合物的盐、溶剂化物，盐包括但不限于酸加成盐和/或碱盐。
本发明还提供药物制剂，包含治疗有效量的式(I)化合物或其治疗学上可接受的盐和其药学上可接受的载体、稀释剂或赋形剂。所有这些形式都属于本发明。
本文所用下列定义是适用的。
“烷基”在本发明中是指一个基团和其他基团例如卤素取代的烷基和烷氧基的结构单元，并可以使直链的或支链的。包括直链烷基如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基等。该术语还包括直链烷基的支链异构体，包括但不限于例如下面的基团：-CH(CH3)2、-CH(CH3)(CH2CH3)、-CH(CH2CH3)2、-C(CH3)3、-CH2CH(CH3)2、-CH2CH(CH3)(CH2CH3)、-CH2CH(CH2CH3)2、-CH2C(CH3)3、-CH2C(CH2CH3)3、-CH(CH3)-CH(CH3)(CH2CH3)、-CH2CH2CH(CH3)2、-CH2CH2CH(CH3)(CH2CH3)、-CH2CH2CH(CH2CH3)2、-CH2CH2C(CH3)3、-CH2CH2C(CH2CH3)3、-CH(CH3)CH2CH(CH3)2、-CH(CH3)CH(CH3)CH(CH3)2、-CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3)等。因此，术语烷基包括伯烷基、仲烷基和叔烷基。优选的烷基包括C1-12直链烷基及C3-10支链烷基。
术语“烯基”是指其中两个相邻碳原子通过双键连接的上面所定义的烷基。
术语“炔基”涉及其中两个相邻碳原子通过三键连接的烷基。
术语“卤素”是指氟原子、氯原子、溴原子、碘原子。
术语“烷氧基”是指(烷基)O-基团，其中烷基是在此定义的。
术语“羟基”是指基团-OH。
术语“氨基”是指基团-NH2。术语“亚氨基”是指基团-NH-。
术语“硝基”是指基团-NO2。术语“亚硝基”是指基团-NO。
术语“三氟甲基”是指基团-CF3。
术语“羧基”是指基团-COOH。
术语“巯基”是指基团-SH。
术语“芳基”是指其中形成环的每个原子是碳原子的芳香族环。芳基环可以由五个、六个、七个、八个、九个或超过九个碳原子形成。芳基基团可以是任选取代的。芳基基团的实例包 括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。
术语“杂芳基”或选择性的“杂芳香族基”是指芳香族基团，其中包括自选氮，氧和硫的一个或更多个环杂原子。含有N的“杂芳香族基”或“杂芳基”部分是指芳香族基团，其中环的骨架原子至少一个是氮原子。杂芳基基团的说明性实例包括以下几个部分：
Figure PCTCN2015079016-appb-000013
等。根据结构，杂芳基基团可以是单自由基或双自由基的(即，杂亚芳基基团)。
术语“环烷基”是指单环的或多环的自由基，其仅含有碳和氢，并且任选地是饱和的，部分不饱和的或完全不饱和的。环烷基基团包括具有3到10个环原子的基团。环烷基基团的说明性实例包括以下的部分：
Figure PCTCN2015079016-appb-000014
等。根据结构，环烷基基团是单自由基或者双自由基的(例如，环亚烷基基团)，如果是“低级环烷基”则具有3到8个碳原子。
术语“杂环烷基”是指至少有一个选自O、N和S的杂原子且任选含有一条或多条双键或三键非芳族环烷基。环杂烷基作为整体可以具有3-14个环原子并且含有1-5个杂原子(例如就单环杂环烷基而言具有3-6个环原子，就多环杂环烷基而言具有7-14个环原子)。杂环烷基可以在产生稳定结构的任意杂原子或碳原子上与所定义的化学结构共价连接。杂环烷基上的一个或多个N或S原子可以被氧化(例如吗啉N-氧化物、硫吗啉S-氧化物、硫吗啉S，S-二氧化物)。杂环烷基还可以含有一个或多个氧代基团，例如邻苯二酰亚氨基、哌啶酮基、恶唑烷酮基、2，4(1H，3H)-二氧代-嘧啶基、吡啶-2(1H)-酮基等。杂环烷基的实例还包括吗啉基、硫吗啉基、吡喃基、咪唑烷基、咪唑啉基、恶唑烷基、异恶唑烷基、吡唑烷基、吡唑啉基、吡咯烷基、吡咯啉基、四氢呋喃基、四氢噻吩基、四氢噻唑基、全氢异吲哚基、哌啶基、氮杂环丁烷、N-甲基氮杂环丁烷基、哌嗪基、N-甲基哌嗪基、二氮杂卓基等。
术语“氧代”是指双键氧(即，＝O)。
术语“酰基”表示-CO-基团，示例性酰基包括乙酰基、三氟乙酰基、苯甲酰基等。
术语“酰胺基”是指具有式-C(O)NHR或-NHC(O)R的化学部分，其中R选自烷基、环烷基、杂环烷基(通过环碳键合)、芳基、杂芳基(通过环碳键合)。
术语“酯基”是指具有式-COOR的化学部分，其中R选自烷基、环烷基、杂环烷基(通过环碳键合)、芳基、杂芳基(通过环碳键合)。
术语“酰基酯基”是指具有式-CO-COOR的化学部分，其中R选自烷基、环烷基、杂环烷基(通过环碳键合)、芳基、杂芳基(通过环碳键合)。
本发明化合物还可以以药学可接受的盐的形式给药。术语“药学可接受的盐”是指由药学可接受的无毒碱或酸制备的盐，所述碱或酸包括无机或有机碱和无机或有机酸。包含在术语“药学可接受的盐”内的碱性化合物是指通常通过使游离碱与合适的有机或者无机酸反应进行制备的本发明化合物的无毒盐。
具体实施方式
制备本发明化合物的方法：
式(I)化合物可按照流程1制备，其中各个取代基如发明概述中所定义：
流程1
Figure PCTCN2015079016-appb-000015
在中间体III存在下，合适溶剂中例如四氢呋喃、甲醇、甲苯、吡啶、DMF或DMSO，使用试剂例如硼氢化钠、癸硼烷或者三乙酰氧基硼氢化钠，通过中间体II的还原胺化，提供中间体IV。该反应在路易斯酸如四氯化钛或者四异丙基醇钛存在下进行。该反应还可以通过加入酸如醋酸得到促进。在一些情况下，中间体III可以为盐，例如三氟醋酸盐或盐酸盐，可以方便地将碱，例如N，N-二异丙基乙胺或三乙胺，加入到反应混合物中。然后脱去保护基，例如在Boc的情况下用三氟乙酸或盐酸甲醇溶液，或者在Fmoc的情况下用三乙胺、二乙基胺、哌啶或吗啉在DMF、NMP或乙腈中反应，然后用合适的方法引入Ra和Rb基团(当Ra和Rb不都为氢时)(比如在碱性条件下，中间体IV与RaCl和/或RbCl反应)，得到式(I)化合物。
流程2
Figure PCTCN2015079016-appb-000016
中间体II可以用本领域技术人员已知的方法获得。醛a与硝基甲烷在碱存在下，得到硝基醇b，利用氧化剂如Dess-martin处理得到的硝基醇，得到硝基酮c。硝基酮c与3-碘代-2-(碘代甲基)丙-1-烯在加热条件下反应得到d。得到的d被还原剂如硼氢化钠还原，得到顺式和反式两种产物，其中的顺式产物用碱如DBU异构可以很容易地转变成反式产物。将得到的反式产物e1和e2用手性柱通过HPLC进行拆分，得到e2。然后，用锌和酸例如盐酸还原e2，得到胺基吡喃f，用保护基如Boc保护氨基得到g。用氧化试剂如四氧化锇和N-甲基吗 啉N-氧化物处理g得到双羟基化合物h，随后用高碘酸钠氧化，得到中间体IIa。
流程3
Figure PCTCN2015079016-appb-000017
中间体III可以按照一般流程3加以制备。被Boc或其他保护剂保护的吡咯烷醇i可以通过氧化，例如Swern氧化，转化成吡咯烷酮j。j在DMF-DMA存在下，加热，提供k，其在合适的溶剂，例如乙醇中，加入肼，加热，得到中间体1。1与L-R2反应，L离去后，再用合适的条件脱去保护基，提供中间体IIIa和IIIb，并且IIIa和IIIb可以通过本领域技术人员熟悉的方法如柱层析分离。
下列实施例目的是描述特定的发明实施方式，但决不限制说明书或权利要求书的范围。本领域技术人员可以理解，原料可以不同，可以采用额外步骤来生成由本发明涵盖的化合物，正如下列实施例所示例的。下列实施例仅供阐述目的，既不打算、也不应当以任意方式被解释为限制发明。本领域技术人员将认识到的是，可以进行变化和修改，而不违背本发明的精神或范围。
缩写表
DMF：N，N-二甲基甲酰胺
DMSO：二甲基亚砜
Boc：叔丁氧羰基
Fmoc：芴甲氧羰酰基
NMP：N-甲基吡咯烷酮
DBU：1，8-二氮杂环[5，4，0]十一烯-7
HPLC：高效液相色谱法
DMF-DMA：N，N-二甲基甲酰胺二甲基缩醛
DIPEA：N，N-二异丙基乙胺
NMO：N-甲基-N-氧化吗啉
实施例1
Figure PCTCN2015079016-appb-000018
制备化合物1：(2R，3S，5R)-2-(2，5-二氟苯基)-5-[2-(吗啉磺酰基)-2，6-二氢吡咯并[3，4-c]吡唑-5(4H)-基]四氢-2H-吡喃-3-胺
A制备中间体
Figure PCTCN2015079016-appb-000019
步骤1.制备1-(2，5-二氟苯基)-2-硝基乙醇
Figure PCTCN2015079016-appb-000020
在5℃下，向氢氧化钠(1N，428ml)的甲醇(214ml)溶液慢慢滴加2，5-二氟苯甲醛(50g，0.35mol)和硝基甲烷(22.4ml，0.414mol)的甲醇溶液50ml(大于1h)，加完后，再加入冰醋酸(24ml)中和反应液，然后加入乙醚，有机层用饱和碳酸钠(30ml)和饱和食盐水(30ml)洗涤，无水硫酸镁干燥有机层并浓缩，得到1-(2，5-二氟苯基)-2-硝基乙醇，其无需进一步纯化即可用于步骤2。
步骤2.制备2-硝基-1-(2，5-二氟苯基)乙酮
Figure PCTCN2015079016-appb-000021
在10℃下，在30分钟内将dess-martin高碘烷(184g)分三批加入到步骤1中制备的硝基乙醇(68.1g)的二氯甲烷溶液中。继续搅拌24h，然后将反应混合物倾倒在碳酸氢钠(441g)和硫代硫酸钠(489g)在水(4.2L)中的混合液内。使用HCl(6N，1.5L)中和水性层，至不再产生气泡，二氯甲烷萃取，碳酸氢钠溶液洗涤一次。通过无水硫酸镁干燥合并的有机层，过滤，蒸干，通过色谱法(硅胶，石油醚∶乙酸乙酯10∶1到6∶1梯度洗脱)纯化，得到所需要的硝基酮54g。1H NMR(400MHz，CDCl3)δ7.74-7.70(m，1H)，7.43-7.37(m，1H)，7.28-7.22(m，1H)，5.82(d，J＝3.6Hz，2H)。
步骤3.制备3-碘代-2-(碘代甲基)-异丙基-1-烯
Figure PCTCN2015079016-appb-000022
将3-氯代-2-(氯代甲基)丙-1-烯(5.75ml，54.7mmol)和碘化钠(45g，301mmol)在丙酮(400ml)中的反应液在室温下搅拌20h，减压蒸干，将其分配在二氯甲烷和水中。通过无水硫酸钠干燥有机层，过滤，蒸干得到3-碘代-2-(碘代甲基)丙-1-烯，为淡红色的油状化合物。
步骤4.制备6-(2，5-二氟苯基)-3-亚甲基-5-硝基-3，4-二氢-2H-吡喃
Figure PCTCN2015079016-appb-000023
将3-碘代-2-(碘代甲基)-异丙基-1-烯(16.8g，54.7mmol)溶于50ml DMF中，加入DIPEA20ml，然后缓慢滴加2-硝基-1-(2，5-二氟苯基)乙酮(10g，49.7mmol)，加完后室温搅拌2h，加入400ml水，乙酸乙酯萃取三次，合并有机层，无水硫酸钠干燥，柱层析(石油醚∶二氯甲烷20％-30％梯度洗脱)，得到3g产物。1H NMR(400MHz，DMSO-d6)δ7.50-7.29(m，3H)，5.41(brs，1H)，5.34(brs，1H)，4.74(s，2H)，3.58(brs，2H)。
步骤5.制备(2R，3S)-2-(2，5-二氟苯基)-5-亚甲基-3-硝基四氢-2H-吡喃
Figure PCTCN2015079016-appb-000024
向6-(2，5-二氟苯基)-3-亚甲基-5-硝基-3，4-二氢-2H-吡喃(9.1g，35.96mmo)在氯仿(480ml)和异丙醇90ml的溶液中加入硅胶(100-200目)58g和硼氢化钠(5.2g，136.6mmol)，室温 搅拌过夜。然后缓慢加入稀盐酸(69ml，2N)淬灭反应，并过滤。用乙酸乙酯洗涤硅胶。使用碳酸氢钠洗涤有机层，无水硫酸钠干燥。旋于后柱层析(石油醚∶乙醚＝16∶1到15∶1梯度洗脱)，得到反式-2-(2，5-二氟苯基)-5-亚甲基-3-硝基四氢呋喃-2H-吡喃5.5g和顺式-2-(2，5-二氟苯基)-5-亚甲基-3-硝基四氢呋喃-2H-吡喃2.4g。将顺式构型的产物，溶于50ml四氢呋喃中，加入120微升DBU。室温搅拌0.5h后，柱层析(石油醚∶乙醚＝16∶1到15∶1洗脱)，又得到1.6g反式产物。将一部分反式产物(1g)通过HPLC(ChiralCel OD)进行拆分得到对映异构体(2R，3S)-5-亚甲基-3-硝基-2-(2，4，5-三氟苯基)四氢-2H-吡喃440mg。1H NMR(400MHz，CDCl3)δ7.17-7.13(m，1H)，7.06-7.03(m，2H)，5.14-5.11(m，2H)，5.08(d，J＝9.6Hz，1H)，4.82-4.73(m，1H)，4.39(d，J＝12.7Hz，1H)，4.24(d，J＝12.8Hz，1H)，3.13(d，J＝7.9Hz，2H)。
步骤6.制备(2R，3S)-2-(2，5-二氟苯基)-5-亚甲基四氢-2H-吡喃-3-氨基
Figure PCTCN2015079016-appb-000025
将上一步得到的产物(440mg，2.2mmol)溶于乙醇中，加入锌粉(1.2g，18.9mmol)，剧烈搅拌下加入6N盐酸(6ml，36mmol)。3h后，用2N氢氧化钠调节PH值到10，用乙醚萃取三次，无水硫酸钠干燥后，减压蒸去乙醚得到无色透明油状液体376mg，直接进行下一步反应。
步骤7.制备[(2R，3S)-5-亚甲基-2-(2，5-二氟苯基)四氢-2H-吡喃-3-基]氨基甲酸叔丁酯
Figure PCTCN2015079016-appb-000026
将上一步得到的无色透明油状液体溶于二氯甲烷中，加入二碳酸二叔丁酯(507mg，2.34mmol)，室温搅拌过夜，减压蒸去二氯甲烷得到464mg产品，直接进行下一步反应。
步骤8.制备[(2R，3S)-5-羟基-5-(羟基甲基)-2-(2，5-二氟苯基)四氢-2H-吡喃-3-基]氨基甲酸叔丁酯
Figure PCTCN2015079016-appb-000027
将步骤7得到的产品溶于7ml丙酮中，加入3.5ml水和14ml叔丁醇，然后加入0.258ml2.5％的四氧化锇的叔丁醇溶液。室温下搅拌10min后，加入NMO 0.184ml，于室温反应48h后，加入饱和硫代硫酸钠溶液，搅拌半小时，然后加入乙酸乙酯萃取，无水硫酸钠干燥后，减压蒸干溶剂，得到510mg产品，直接进行下一步反应。
步骤9.制备[(2R，3S)-5-氧代-2-(2，5-二氟苯基)四氢-2H-吡喃-3-基]氨基甲酸叔丁酯
Figure PCTCN2015079016-appb-000028
将上一步的产品溶于10ml四氢呋喃中，加入高碘酸钠(327mg，1.53mmol)的水溶液4ml，混合物搅拌4h。浓缩后柱层析(10％到20％的乙酸乙酯在氯仿中)，得到410mg白色固体。1H NMR(400MHz，CDCl3)δ7.23(d，J＝3.3Hz，1H)，7.05-7.00(m，2H)，4.83(d，J＝8.0Hz，1H)，4.71(d，J＝9.0Hz，1H)，4.31(dd，J＝16.3，1.5Hz，1H)，4.18-3.99(m，2H)，3.06(dd，J＝16.6，5.1Hz，1H)，2.75-2.68(m，1H)，1.31(s，9H)；ESI-MS：272.1(M+1-56)。
B.制备中间体
Figure PCTCN2015079016-appb-000029
步骤1.制备
Figure PCTCN2015079016-appb-000030
将3-氧代吡咯烷-1-羧酸叔丁酯(40g，216mmol)溶于300ml DMF-DMA中，在105℃下加热40分钟。冷却减压蒸发该溶液，使用己烷处理，过滤得到橙色固体41g，干燥，无需纯化即可用于下一步反应。
步骤2.制备
Figure PCTCN2015079016-appb-000031
将上一步的到的橙色固体41g溶于200ml甲苯中，40度下缓慢滴加水合肼15ml(80％含量)，滴加完后，室温反应2h，将反应液冷却有白色固体析出，过滤得到的固体并用正庚烷洗涤得到37.2g产品。
步骤3.制备
Figure PCTCN2015079016-appb-000032
将上一步得到的37.2g白色固体溶于甲醇中，加入5N盐酸，于室温下搅拌6h，浓酸后加入氨水甲醇溶液(2N)，调节PH至微碱性，加入二氯甲烷200ml，加入三乙胺40ml，于室温滴加二碳酸二叔丁酯64g的二氯甲烷(40ml)溶液，反应半小时后，旋干，柱层析(甲醇∶氨水∶乙酸乙酯＝135∶15∶350)，得到20g白色固体。1H NMR(400MHz，CDCl3)δ8.03(brs，1H)，7.34(d，J＝12.8Hz，1H)，4.50(t，J＝16.6Hz，4H)，1.53(s，9H)。
C.制备中间体
Figure PCTCN2015079016-appb-000033
步骤1.制备
Figure PCTCN2015079016-appb-000034
将N-Boc吡唑并吡咯烷(100mg，0.478mmol)溶于3ml无水四氢呋喃中，加入氢化钠(30mg，0.718mmol，60％dispersion in oil)于室温搅拌1h后，加入吗啉磺酰氯(133.23mg，0.718mmol)，过夜反应，旋干后，加入水和乙酸乙酯，有机层干燥后，柱层析(石油醚∶乙酸乙酯＝1∶1)，得到147mg油状液体。1H NMR(400MHz，CDCl3)δ7.67(d，J＝15.4Hz，1H)，4.49-4.39(m，4H)，3.73-3.66(m，4H)，3.34-3.21(m，4H)，1.47(s，9H)。
步骤2.制备
Figure PCTCN2015079016-appb-000035
向上一步的产物中加入4ml二氯甲烷，和1ml三氟乙酸，室温反应2h后，旋干得到80mg产品，无需纯化，直接进行下一步反应。
D.制备化合物1：(2R，3S，5R)-2-(2，5-二氟苯基)-5-[2-(吗啉磺酰基)-2，6-二氢吡咯并[3，4-c]吡唑-5(4H)-基]四氢-2H-吡喃-3-胺
Figure PCTCN2015079016-appb-000036
在室温下，将中间体[(2R，3S)-5-氧代-2-(2，5-二氟苯基)四氢-2H-吡喃-3-基]氨基甲酸叔丁酯(101mg，0.31mmol)和2-(N-磺酰基吗啉)-2，4，5，6-四氢吡咯并[3，4-c]吡唑(80mg，0.31mmol)溶于6ml无水甲醇中，于室温加入11.4mg癸硼烷，搅拌过夜，旋干浓缩后，加入二氯甲烷4ml，三氟乙酸1ml，室温搅拌2h，浓缩后，柱层析(甲醇∶二氯甲烷＝1∶20)，得到101mg白色固体。1H NMR(400MHz，MeOD)δ7.87(s，1H)，7.30-7.05(m，3H)，4.37-4.27(m，2H)，4.00-3.86(m，4H)，3.76-3.64(m，4H)，3.43(t，J＝10.7Hz，1H)，3.31-3.23(m，4H)，3.13-3.04(m，1H)，2.99-2.91(m，1H)，2.54-2.46(m，1H)，1.54(q，J＝11.7Hz，1H)；ESI-HRMS：calcd for C20H26F2N5O4S， 470.1674，found，470.1667。
实施例2
Figure PCTCN2015079016-appb-000037
制备化合物2：(2R，3S，5R)-2-(2，5-二氟苯基)-5-[2-(哌啶磺酰基)-2，6-二氢吡咯并[3，4-c]吡唑-5(4H)-基]四氢-2H-吡喃-3-胺
本发明化合物2的合成方法参考实施例1，将实施例1中的吗啉磺酰氯换成哌啶磺酰氯，得到白色固体。1H NMR(400MHz，DMSO-d6)δ7.89(s，1H)，7.21(m，3H)，4.16(d，J＝9.6Hz，1H)，4.12-4.11(m，1H)，3.76(d，J＝15.2Hz，4H)，3.26(t，J＝10.6Hz，1H)，3.17-3.14(m，4H)，2.95-2.86(m，2H)，2.34-2.31(m，1H)，1.50-1.37(m，7H).ESI-MS：468.3(M+1)。
实施例3
制备化合物3：(2R，3S，5R)-2-(2，5-二氟苯基)-5-[2-(吡咯磺酰基)-2，6-二氢吡咯并[3，4-c]吡唑-5(4H)-基]四氢-2H-吡喃-3-胺
Figure PCTCN2015079016-appb-000038
本发明化合物3的合成方法参考实施例1，将实施例1中的吗啉磺酰氯换成吡咯磺酰氯，得到淡黄色固体。1H NMR(400MHz，DMSO-d6)δ8.28(s，2H)，8.10(s，1H)，7.37-7.31(m，3H)，4.59(d，J＝10.0Hz，1H)，4.42-4.26(m，5H)，3.54-3.52(m，3H)，3.35(t，J＝6.4Hz，4H)，2.67-2.64(m，1H)，1.89(dd，J＝23.4，11.6Hz，1H)，1.76-1.73(m，4H).ESI-MS：454.7(M+1)。
实施例4
制备化合物4：(2R，3S，5R)-2-(2，5-二氟苯基)-5-[2-(N-甲基哌嗪磺酰基)-2，6-二氢吡咯并[3，4-c]吡唑-5(4H)-基]四氢-2H-吡喃-3-胺
Figure PCTCN2015079016-appb-000039
本发明化合物4的合成方法参考实施例1，将实施例1中的吗啉磺酰氯换成N-甲基哌嗪磺酰氯，得到白色固体。1H NMR(400MHz，MeOD)δ7.86(s，1H)，7.25-7.14(m，3H)，4.37(d，J＝9.4Hz，1H)，4.31-4.29(m，1H)，3.92-3.90(m，4H)，3.44(t，J＝10.5Hz，1H)，3.33(br s，4H)，3.12-3.20(m，2H)，2.50(br s，5H)，2.30(s，3H)，1.58(dd，J＝23.2，11.7Hz，1H).ESI-MS：483.1(M+1)。
实施例5
制备化合物5：(2R，3S，5R)-2-(2，5-二氟苯基)-5-[2-(4-环戊基哌嗪-1-基-磺酰基)-2，6-二氢吡咯并[3，4-c]吡唑-5(4H)-基]四氢-2H-吡喃-3-胺
Figure PCTCN2015079016-appb-000040
本发明化合物5的合成方法参考实施例1，将实施例1中的吗啉磺酰氯换成4-环戊基哌嗪-1-基-磺酰氯，得到白色固体。1H NMR(400MHz，MeOD)δ7.86(s，1H)，7.26-7.10(m，3H)，4.33(d，J＝9.6Hz，1H)，4.30-4.28(m，1H)，3.91-3.90(m，4H)，3.43(t，J＝10.7Hz，1H)，3.33(br s，4H)，3.10-3.04(m，1H)，3.01-2.95(m，1H)，2.58-2.49(m，6H)，1.92-1.87(m，2H)，1.74-1.70(m，2H)，1.62-1.50(m，3H)，1.41-1.31(m，2H).ESI-MS：537.4(M+1)。
实施例6
制备化合物6：(2R，3S，5R)-2-(2，5-二氟苯基)-5-[2-(3-氧代哌嗪-1-基-磺酰基)-2，6-二氢吡咯并[3，4-c]吡唑-5(4H)-基]四氢-2H-吡喃-3-胺
Figure PCTCN2015079016-appb-000041
本发明化合物6的合成方法参考实施例1，将实施例1中的吗啉磺酰氯换成3-氧代哌嗪-1-基-磺酰氯，得到白色固体。ESI-MS：483.1(M+1)。
实施例7
制备化合物7：(2R，3S，5R)-2-(2，5-二氟苯基)-5-[2-(3-羟基氮杂丁烷-1-磺酰基)-2，6-二氢吡咯并[3，4-c]吡唑-5(4H)-基]四氢-2H-吡喃-3-胺
Figure PCTCN2015079016-appb-000042
本发明化合物7的合成方法参考实施例1，将实施例1中的吗啉磺酰氯换成3-羟基氮杂丁烷-1-磺酰氯，得到白色固体。ESI-MS：456.1(M+1)。
实施例8
制备化合物8：(2R，3S，5R)-2-(2，5-二氟苯基)-5-[2-(1-异丙基哌啶-4-磺酰基)-2，6-二氢吡咯并[3，4-c]吡唑-5(4H)-基]四氢-2H-吡喃-3-胺
Figure PCTCN2015079016-appb-000043
本发明化合物8的合成方法参考实施例1，将实施例1中的吗啉磺酰氯换成1-异丙基哌啶-4-磺酰氯，得到淡黄色固体。ESI-MS：510.2(M+1)。
实施例9
制备化合物9：(2R，3S，5R)-2-(2，5-二氟苯基)-5-[2-(4-(甲基磺酰基)哌嗪-1-磺酰基)-2，6-二氢吡咯并[3，4-c]吡唑-5(4H)-基]四氢-2H-吡喃-3-胺
Figure PCTCN2015079016-appb-000044
本发明化合物9的合成方法参考实施例1，将实施例1中的吗啉磺酰氯换成4-(甲基磺酰基)哌嗪-1-磺酰氯，得到白色固体。ESI-MS：547.5(M+1)。
实施例10
制备化合物10：(2R，3S，5R)-2-(2，5-二氟苯基)-N-乙基-5-[2-(吗啉磺酰基)-2，6-二氢吡咯并[3，4-c]吡唑-5(4H)-基]四氢-2H-吡喃-3-胺
Figure PCTCN2015079016-appb-000045
本发明化合物10是由化合物1在碱性条件下与溴乙烷反应得到的，为淡黄色固体。ESI-MS：498.5(M+1)。
实施例11
制备化合物11：(2R，3S，5R)-2-(2，5-二氟苯基)-N，N-二异丙基-5-[2-(吗啉磺酰基)-2，6-二氢吡咯并[3，4-c]吡唑-5(4H)-基]四氢-2H-吡喃-3-胺
Figure PCTCN2015079016-appb-000046
本发明化合物11是由化合物1在碱性条件下与异丙基溴反应得到的，为灰白色固体。ESI-MS：554.3(M+1)。
实施例12
制备化合物11：(2R，3S，5R)-2-(2，5-二氟苯基)-N，N-二丁基-5-[2-(吗啉磺酰基)-2，6-二氢吡咯并[3，4-c]吡唑-5(4H)-基]四氢-2H-吡喃-3-胺
Figure PCTCN2015079016-appb-000047
本发明化合物12是由化合物1在碱性条件下与丁基溴反应得到的，为白色固体。ESI-MS：581.6(M+1)。
实施例13
制备化合物13：(2R，3S，5R)-2-(2，5-二氟苯基)-5-[2-(氮杂环丁烷-1-磺酰基)-2，6-二氢吡咯并[3，4-c]吡唑-5(4H)-基]四氢-2H-吡喃-3-胺
Figure PCTCN2015079016-appb-000048
本发明化合物13的合成方法参考实施例1，将实施例1中的吗啉磺酰氯换成N-杂丁烷-1-磺酰氯，得到白色固体。1H NMR(400MHz，MeOD)δ7.82(s，1H)，7.23-7.04(m，3H)，4.34-4.28(m，2H)，4.06(t，J＝7.8Hz，4H)，3.96-3.92(m，4H)，3.46(t，J＝10.7Hz，1H)，3.15-3.07(m，1H)，3.01-2.94(m，1H)，2.53-2.49(m，1H)，2.23-2.15(m，2H)，1.56(q，J＝11.7Hz，1H)。ESI-MS：440.4(M+1)。
实施例14
制备化合物14：(2R，3S，5R)-2-(2，5-二氟苯基)-5-[2-(4-甲基哌嗪-1-磺酰基)-2，6-二氢吡咯并[3，4-c]吡唑-5(4H)-基]四氢-2H-吡喃-3-胺
Figure PCTCN2015079016-appb-000049
本发明化合物14的合成方法参考实施例1，将实施例1中的吗啉磺酰氯换成4-甲基哌啶-1-磺酰氯，得到白色固体。1H NMR(400MHz，MeOD)δ7.89(s，1H)，7.26-7.17(m，3H)，4.16-4.11(m，2H)，3.76(d，J＝14.5Hz，4H)，3.70-3.67(m，2H)，3.26(t，J＝10.6Hz，1H)，2.94-2.83(m，2H)，2.66(t，J＝11.7Hz，2H)，2.34-2.31(m，1H)，1.65-1.62(m，2H)，1.45-1.36(m，2H)，1.11-1.01(m，2H)，0.84(d，J＝6.5Hz，3H)。ESI-MS：482.1(M+1)。
实施例15
制备化合物15：(2R，3S，5R)-2-(2，5-二氟苯基)-5-[2-(全氢吲哚-1-磺酰基)-2，6-二氢吡咯并[3，4-c]吡唑-5(4H)-基]四氢-2H-吡喃-3-胺
Figure PCTCN2015079016-appb-000050
本发明化合物15的合成方法参考实施例1，将实施例1中的吗啉磺酰氯换成全氢吲哚-1-磺酰氯，得到白色固体。1H NMR(400MHz，MeOD)δ7.92(s，1H)，7.27-7.18(m，3H)，4.20(d，J＝9.6Hz，1H)，4.15-4.12(m，1H)，3.76(d，J＝12.1Hz，4H)，3.40-3.36(m，3H)，3.27(t，J＝10.8Hz，2H)，3.22-3.18(m，3H)，2.99-2.90(m，2H)，2.36-2.33(m，1H)，2.15-2.12(m，2H)，1.45-1.35(m，6H)。ESI-MS：508.2(M+1)。
生物学评价
测试1
本发明化合物对DPP-4酶抑制活性测试：
反应体系中加入适量DPP-4酶(SIGMA)、3倍浓度梯度稀释的样品盒HEPES缓冲液，同时设立空白对照(不含酶和样品盒)、阴性对照(不含样品)和阳性对照(阳性对照物为MK-3102)，室温反应10min，加入底物Gly-Pro-7-amido-4-methylcoumarin(SIGMA)，室温避光反应30min，检测荧光，激发波长355nm，发射波长460nm。
根据荧光测量值计算抑制率，抑制率＝[1-(样品-空白)/(阴性-空白)]*100％，应用Xlfit软件中的4ParameteriLogistic Model计算IC50值。实验结果见表1所示。
表1：实例化合物以及Sitagliptin等对比化合物的DPP-4体外活性测试结果
Figure PCTCN2015079016-appb-000051
结论：本发明化合物对DPP-4酶具有显著的抑制作用。
另一方面，在人肝微粒体稳定性试验中，本发明化合物1、4等与MK-3102相比，具有更好的代谢稳定性，提示本发明化合物有望开发成为长效降糖药物。

Claims (21)

  1. 结构式I的化合物：
    Figure PCTCN2015079016-appb-100001
    其中，
    Ar为取代或未取代的芳基、杂芳基；
    R1为氢、取代或未取代的烷基；
    R2a和R2b各自独立地选自氢，或者
    R2a和R2b各自独立地选自取代或未取代的烷基、烷氧基、环烷基、杂环烷基；或者
    R2a和R2b与它们所连接的氮原子一起形成杂环烷基，并且，杂环烷基可被任意取代；
    A选自：
    Figure PCTCN2015079016-appb-100002
    R3a和R3b各自独立地选自氢、取代或未取代的C1-10烷基；
    R4为：
    Figure PCTCN2015079016-appb-100003
    X为CR8或N；
    其中可能存在0-3个R7，并且R7为氧代、卤素、取代或未取代的烷基、取代或未取代的烷氧基，或者两个或多个R7形成桥连的烷基基团；
    W为CR8、O或N；
    R6选自H、羟基，或者
    R6选自取代或未取代的C1-8烷基、C1-8烷基-R9、C3-14环烷基、3-14元杂环烷基、C(O)-C1-8烷基、C1-8卤代烷基、C1-8烷基羟基、C(O)NR9R10、C1-8氰基烷基、C(O)R9、C0-8烷基-C(O)-C0-8烷基-NR9R10、C0-8烷基-C(O)OR9、NR9R10、SO2-C1-8烷基、C1-8烷基-C3-14环烷基、C(O)-C1-8烷基-C3-14环烷基、C1-8烷氧基；
    R8为氢或卤素；
    R9和R10各自独立地选自H、C1-8烷基、C3-14环烷基、3-14元杂环烷基、C6-14芳基、5-14元杂芳基、烷氧基、C(O)C1-4烷基、C1-8烷基氨基、C1-6烷基羟基；
    m为0、1或2；
    n为0、1或2；
    R5选自H、卤素、氰基、氨基、硝基，或者
    R5选自取代或未取代的C1-10烷基、C1-10烷氧基、C2-10烯基、(CH2)p-芳基、(CH2)p-杂芳基、(CH2)p-环烷基、(CH2)p-杂环烷基、(CH2)p-NR11R12、(CH2)p-SO2NR11R12、(CH2)p-SO2R13、(CH2)p-NR11SO2R13、(CH2)p-OR13、(CH2)p-OCOR13、(CH2)p-OCONR11R12、(CH2)p-CONR11R12、(CH2)p-NR13CONR11R12、(CH2)p-COOH、(CH2)p-COR13、(CH2)p-CO2C1-6烷基、(CH2)p-NR11COOR13；
    其中，R11和R12独立地选自氢、(CH2)q-苯基、(CH2)q-C3-8环烷基、C1-6烷基，其中烷基任选被1-5个选自氟或羟基的取代基取代，并且其中苯基和环烷基任选被1-5个独立地选自卤素、羟基、三氟甲基、C1-6烷基或C1-6烷氧基取代；
    或者R11和R12与它们所连接的氮原子一起形成选自哌啶、哌嗪、吗啉、吡咯或氮杂环丁烷的杂环，其中所述杂环任选被1-3个独立地选自卤素、羟基、C1-6烷基或C1-6烷氧基的取代基取代；
    每个R13独立地为C1-6烷基，其中烷基任选被1-5个选自氟或羟基的取代基取代；
    p为0、1、2、3、4、5或6；
    q为0、1或2；
    或其药学上可接受的盐、水合物、溶剂化物或立体异构体。
  2. 根据权利要求1所述的化合物，其中，Ar为非必须地被1-5个R14取代的苯基；
    每个R14独立地选自卤素、羟基、氰基、硝基、亚硝基、氨基、亚氨基、羧基、巯基，或者
    每个R14独立地选自取代或未取代的烷基、酰基、酰胺基、酯基、酰基酯基、苯氧基、苄基、苄氧基、磺酰基、亚磺酰基、环烷基、杂环烷基、烯基、炔基、烷氧基、烯氧基、烷基氨基、芳基、杂芳基。
  3. 根据权利要求2所述的化合物，其中，Ar为非必须地被1-3个独立地选自F、C1、Br、I、-CH3、-CF3、-OCF3取代基取代的苯基。
  4. 根据权利要求3所述的化合物，其中，Ar为2，5-二氟苯基或2，4，5-三氟苯基。
  5. 根据权利要求1所述的化合物，其中，R2a和R2b独立地选自氢、C1-10烷基、烷氧基、C3-14环烷基、3-14元杂环烷基；
    其中，烷基任选被1-6个独立地选自卤素、羟基、三氟甲基的取代基取代；
    烷氧基任选被1-6个独立地选自卤素或羟基的取代基取代；
    环烷基任选被1-3个独立地选自卤素、羟基、氰基、硝基、羧基、C1-6烷基、C1-6烷基氧基羰基或C1-6烷氧基的取代基取代，其中烷基和烷氧基可被1-5个氟取代；
    杂环烷基任选被1-3个独立地选自氧代、卤素、羟基、氰基、硝基、羧基、C1-6烷基、C1-6烷基氧基羰基或C1-6烷氧基的取代基取代；
    或者R2a和R2b与它们所连接的氮原子一起形成选自哌啶、哌嗪、吗啉、吡咯或氮杂环丁烷的杂环，其中所述杂环任选被1-3个独立地选自卤素、羟基、C1-6烷基或C1-6烷氧基的取代基取代，其中每个烷基和烷氧基任选被1-5个氟取代。
  6. 根据权利要求5所述的化合物，其中，R2a和R2b独立地选自氢、任选被1-3个氟或羟基取代的C1-6烷基；或者
    R2a和R2b与它们所连接的氮原子一起形成选自哌啶、哌嗪、吗啉、吡咯或氮杂环丁烷的杂环。
  7. 根据权利要求6所述的化合物，其中，R2a和R2b为氢。
  8. 根据权利要求1所述的化合物，其中，R3a和R3b各自独立地选自氢、任选被1-6个氟原子取代的C1-6烷基。
  9. 根据权利要求8所述的化合物，其中，R3a和R3b为氢。
  10. 根据权利要求1所述的化合物，其中，A为：
    Figure PCTCN2015079016-appb-100004
  11. 根据权利要求10所述的化合物，其中，R5为H。
  12. 根据权利要求1所述的化合物，其中R4为：
    Figure PCTCN2015079016-appb-100005
    X为CR8或N；
    其中可能存在0-2个R7，并且R7为氧代，或者两个R7形成一个桥连的烷基基团；
    W为CR8、O或N；
    R6选自H、羟基，或者
    R6选自取代或未取代的C1-8烷基、C3-8环烷基、3-8元杂环烷基、C(O)-C1-6烷基、C(O)NR9R10、C(O)R9、NR9R10、SO2-C1-8烷基；
    R8为氢或卤素；
    R9和R10各自独立地选自H、C1-6烷基、C3-8环烷基、3-8元杂环烷基；
    m为0、1或2；
    n为0、1或2。
  13. 根据权利要求1-12任一项所述的化合物，其中，式I化合物如结构式Ia或Ib所示，其在两个用*标记的立体形成的碳原子上具有所示的绝对立体化学构型：
    Figure PCTCN2015079016-appb-100006
  14. 根据权利要求13所述的化合物，其中，式I化合物如结构式Ia所示，其在两个用*标记的立体形成的碳原子上具有所示的绝对立体化学构型：
    Figure PCTCN2015079016-appb-100007
  15. 根据权利要求14所述的化合物，其中，所述式Ia化合物如结构式Ic和Id所示，其在两个用*标记的立体形成的碳原子上具有所示的绝对立体化学构型：
    Figure PCTCN2015079016-appb-100008
  16. 根据权利要求15所述的化合物，其中，所述式Ia化合物如结构式Ic所示，其在两个用*标记的立体形成的碳原子上具有所示的绝对立体化学构型：
    Figure PCTCN2015079016-appb-100009
  17. 根据权利要求16所述的化合物，其中A选自
    Figure PCTCN2015079016-appb-100010
  18. 根据权利要求17所述的化合物，其中R5为H。
  19. 根据权利要求1所述的化合物，其选自下列的化合物：
    Figure PCTCN2015079016-appb-100011
    Figure PCTCN2015079016-appb-100012
  20. 治疗与DPP-4抑制作用相关的疾病、障碍或综合症的方法，所述方法包括给需要其的个体施用根据权利要求1-19的任意一项的化合物或其前药或包含式(I)化合物或其前药及药学上可接受的赋形剂的药物组合物。
  21. 如权利要求20中所述的治疗方法，其中所述的疾病、障碍或综合症选自胰岛素抵抗、高血糖、2型糖尿病的病症，其中的个体是包括人的动物。
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