CN106916091A - Cathepsin K inhibitor and application thereof - Google Patents

Cathepsin K inhibitor and application thereof Download PDF

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CN106916091A
CN106916091A CN201510995960.0A CN201510995960A CN106916091A CN 106916091 A CN106916091 A CN 106916091A CN 201510995960 A CN201510995960 A CN 201510995960A CN 106916091 A CN106916091 A CN 106916091A
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compound
alkyl
independently
bicyclic
methyl
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CN106916091B (en
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周平健
王晓军
阳传文
林继华
曹生田
杨新业
张英俊
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Guangdong HEC Pharmaceutical
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Dongguan Het Pharm Research And Development Co Ltd
Guangdong HEC Pharmaceutical
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
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    • C07C317/00—Sulfones; Sulfoxides
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    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/70—Sulfur atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07—ORGANIC CHEMISTRY
    • 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
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/66—Nitrogen atoms not forming part of a nitro radical
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • 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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Abstract

Cathepsin K inhibitor and application thereof.It is used to treat or prevent the compound and its pharmaceutical composition of tissue protease dependency illness the present invention relates to a class, these compounds and the composition comprising these compounds can serve as the treatment-related disease of bone resorption inhibitor.Wherein, described cathepsin includes but is not limited to cathepsin K.

Description

Cathepsin K inhibitor and application thereof
Invention field
The invention belongs to pharmaceutical field.It is used to treat or prevent the compound and its drug regimen of tissue protease dependency illness the present invention relates to a class Thing.These compounds and the composition comprising these compounds can serve as the treatment-related disease of bone resorption inhibitor.
Background technology
Osteoporosis is a kind of common disease, frequently-occurring disease of the elderly especially in climacteric and postmenopausal women.With the change of contemporary spectrum of disease, Osteoporosis is classified as one of big disease of person in middle and old age three by WHO, and the 7th is occupied in common disease.About 50% over the women of 50 years old and 20% Male suffer osteoporosis the fracture for causing.The Common drugs for the treatment of osteoporosis have anti-bone information medicine, promoting bone growing medicine, preceding two at present The double action medicine of person, biological medicament or other drugs, but the most side effect of medicine is larger, and new medicine is in being badly in need of.
Cathepsin (Cathepsin) is the Major Members of cysteine proteinase family, and more than 20 kinds are had found in living nature, main in human body There are 11 kinds, they are closely related with various major diseases such as human tumor, osteoporosis, arthritis.The Main Subtype of cathepsin has Cathepsin B, F, H, L, K, S, W and Z.Cathepsin S is mainly expressed in antigen presenting cell, because cathepsin S is adjusted Section Antigen-presenting role, so being considered as the important target spot for adjusting immune response.Cathepsin L participates in many special physiology courses, such as swashs Plain former activation, antigen presentation, development of histoorgan etc..Cathepsin B is in liver,spleen,kidney, bone, nerve cell, interstitial into fiber finer Born of the same parents, macrophage etc. are all distributed, and in being stored in lysosome in the form of the proenzyme, participate in many special physiology courses, such as the activation of prohormone, Antigen presentation, histoorgan development etc..
Cathepsin K (cat K are also abbreviated as known to it) is also referred to as cathepsin O and cathepsin O 2.Cathepsin K is selected Selecting property ground great expression in osteoclast, its physiological action substrate type i collagen of content up to 95% exactly in organic bone matrix, in addition it is also The osteopontin and osteonectin that can be degraded in bone matrix, are the most strong a kind of cysteine proteinases of expression quantity highest in osteoclast, bone resorption activity, It, to being significantly larger than various enzymes into the degradation capability of ossein, is a key enzyme during bone information, in being also osteoporosis research in recent years One focus.In human body, effect of the cathepsin K to physiology course is particularly significant and extremely complex.Current FDA does not ratify any One anti-cathepsin K inhibitor, but the cathepsin K inhibitor for having correlation carries out clinical research.
Current progress is faster the Odanacatib of Mo Shadong, but because it also has preferable inhibition to cathepsin S, to many The Selective depression effect for planting cathepsin is undesirable, thus also occurs in that some discomforting side effect signs in clinical studies.In order to keep away Exempt from broad spectrum activity to suppress to cause other side effects beyond clinic, therefore still need the cathepsin K inhibitor that design synthesizes some high selectivities.
Summary of the invention
It is used to treat or prevent the compound or its pharmaceutical composition of tissue protease dependency illness the present invention relates to a class.The compounds of this invention or medicine Compositions have preferable inhibitory activity to cathepsin K, and poor to the inhibitory activity of other hypotypes such as cathepsin B, L and S etc., Show selectivity very high.
Cathepsin K, as a key enzyme during bone information, is a popular target spot in bone loss disorders research in recent years, but by There is homology very high in the presence of the various hypotypes of cathepsin, especially cathepsin B, L and S and cathepsin K, and in human body Very important physiological action is inside suffered from, cathepsin K inhibitor is easy to cause effect of missing the target in human body, produces serious side effect. Therefore, the selectivity for how improving cathepsin K inhibitor is to develop the problem that such inhibitor must pull against.The compounds of this invention is not only to group Knitting Proteinase K has preferable inhibitory activity, while the cathepsin B high to homology, the inhibition of L and S are poor, shows choosing high Selecting property, reduces due to the side effect of missing the target that compound selectively causes, and is used to treat bone as cathepsin K inhibitor so as to substantially increase The possibility of matter osteoporosis drug development.
The present invention provides a kind of compound, and it is compound shown in formula (I), or the stereoisomer of compound shown in formula (I), geometric isomer, Dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein, R1、R2, E and n there is implication described in the invention.
In some embodiments, R1It is H, D, F, Cl or Br.
In some embodiments, ring E is that 3-8 former molecular monocycle carbocyclic rings, 5-10 former molecular spiral shell carbon is bicyclic, 5-10 atom group Into bridge carbon is bicyclic, 3-8 former molecular monocyclic heterocycles, 5-10 former molecular miscellaneous bicyclic, the 5-10 former molecular bridge of spiral shell are miscellaneous bicyclic or 5-6 former molecular hetero-aromatic ring；Wherein, described monocycle carbocyclic ring, spiral shell carbon is bicyclic, bicyclic bridge carbon, monocyclic heterocycles, the miscellaneous bicyclic, bridge of spiral shell are miscellaneous double Ring and hetero-aromatic ring are optionally independently by one or more R3Replaced；The R3With implication described in the invention.
In some embodiments, ring E is that 5-6 former molecular monocycle carbocyclic rings, 7-10 former molecular spiral shell carbon is bicyclic, 7-10 atom group Into bridge carbon is bicyclic, 5-6 former molecular monocyclic heterocycles, 7-10 former molecular miscellaneous bicyclic, the 7-10 former molecular bridge of spiral shell are miscellaneous bicyclic or 5-6 former molecular hetero-aromatic ring；Wherein, described monocycle carbocyclic ring, spiral shell carbon is bicyclic, bicyclic bridge carbon, monocyclic heterocycles, the miscellaneous bicyclic, bridge of spiral shell are miscellaneous double Ring and hetero-aromatic ring are optionally independently by one or more R3Replaced；The R3With implication described in the invention.
In some embodiments, ring E is following structure：
Wherein, each X1、X2、Y1And Y3It independently is CH2, O, S, S (=O), S (=O)2Or NH；Each Y2And Y4Independently be CH or N；Described t, e, f, n1, r and R3With implication described in the invention.
In some embodiments, ring E is following subformula：
Wherein, R3, f, n1 and r there is implication described in the invention.
In some embodiments, each R2It independently is halogen, cyano group, nitro, halo C1-4Alkyl, C3-8Cycloalkyl, 3-8 atom composition Heterocyclic radical, C6-10Aryl, 5-10 former molecular heteroaryl ,-SR4a,-S (=O) R4a,-S (=O)2R4a,-C (=O) R4b,-C (=O) OR4c、 -OR4c、-NR4dR4eOr=NR4f；Wherein, described alkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl individually optional ground quilt One or more are selected from oxo (=O), cyano group, nitro, hydroxyl, amino, halogen, C1-4Alkyl, halo C1-4Alkyl, C1-4Alkoxy or C1-4 The substitution base of alkyl amino is replaced；Wherein, described R4a、R4b、R4c、R4d、R4eAnd R4fWith implication described in the invention.
In some embodiments, each R2Independently be fluorine, chlorine, bromine, cyano group, nitro, difluoromethyl, trifluoromethyl, the fluoro ethyls of 2,2- bis-, Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, imidazolinyl, oxazole Alkyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-pyrimidine base, 1,3- oxazines quinolines base, phenyl, pyrrole radicals, pyridine radicals, pyrimidine Base ,-S (=O)2R4a,-C (=O) R4b,-C (=O) OR4c、-OR4c、-NR4dR4eOr=NR4f, wherein, described difluoromethyl, 2,2- difluoro second Base, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Oxyranyle, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, imidazolinyl, Oxazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-pyrimidine base, 1,3- oxazines quinolines base, phenyl, pyrrole radicals, pyridine radicals and Pyrimidine radicals is selected from oxo (=O), cyano group, nitro, hydroxyl, amino, fluorine, chlorine, bromine, methyl, ethyl, three by one or more individually optionally The substitution base of methyl fluoride, difluoromethyl, methoxyl group, methylamino or dimethylamino is replaced；Wherein, described R4a、R4b、R4c、R4d、 R4eAnd R4fWith implication described in the invention.
In some embodiments, each R2Independently be fluorine, cyano group, nitro, difluoromethyl, trifluoromethyl, tetrahydrofuran base, pyrrolidinyl, Imidazolinyl, piperidyl, piperazinyl, morpholinyl ,-S (=O)2CH3,-C (=O) CH3,-C (=O) OH ,-C (=O) OCH3、-OH、-OCH3、 -NH2Or=NOH, wherein, described tetrahydrofuran base, pyrrolidinyl, imidazolinyl, piperidyl, piperazinyl and morpholinyl individually optional ground quilt One or more oxo (=O) groups are replaced.
In some embodiments, each R3It independently is H, oxo (=O), halogen, hydroxyl, cyano group, nitro, C1-4Alkyl, halo C1-4 Alkyl, C1-4Alkoxy, amino or C1-4Alkyl amino.
In some embodiments, each R3Independently be H, oxo (=O), fluorine, chlorine, bromine, hydroxyl, cyano group, nitro, methyl, ethyl, Difluoromethyl, trifluoromethyl, methoxyl group, amino, methylamino or dimethylamino.
In some embodiments, each R4aAnd R4bIt independently is H, hydroxyl, C1-4Alkyl, halo C1-4Alkyl, C1-4Alkoxy, amino or C1-4Alkyl amino；
Each R4c、R4dAnd R4eIt independently is H, C1-4Alkyl, halo C1-4Alkyl, C1-4Alkanoyl or C1-4Alkyl sulphonyl；
Each R4fIt independently is H, hydroxyl, cyano group, C1-4Alkyl, C1-4Alkoxy or halo C1-4Alkyl.
In some embodiments, each R4aAnd R4bIt independently is H, hydroxyl, methyl, ethyl, propyl group, butyl, trifluoromethyl, difluoro first Base, methoxyl group, amino, methylamino or dimethylamino；
Each R4c、R4dAnd R4eIt independently is H, methyl, ethyl, propyl group, butyl, trifluoromethyl, methylacyl or methyl sulphonyl；
Each R4fIt independently is H, hydroxyl, cyano group, methyl, ethyl, methoxyl group or trifluoromethyl.
In some embodiments, n is 1,2,3 or 4.
In some embodiments, t is 1 or 2.
In some embodiments, e is 0 or 1.
In some embodiments, f is 1,2 or 3.
In some embodiments, each n1 and r independently are 0,1,2 or 3.
On the other hand, the invention provides a kind of compound, it is the structure of one of：
Or its stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, water Compound, solvate, metabolite, pharmaceutically acceptable salt or prodrug.
On the one hand, the present invention provides a kind of pharmaceutical composition, comprising compound of the present invention；Described pharmaceutical composition can further include medicine Acceptable carrier on, excipient, diluent, at least one in assistant agent and medium.
In some embodiments, pharmaceutical composition of the present invention is further optionally included and is selected from：Organic diphosphonic acid compound (such as Allan phosphoric acid Sodium), estrogenic agents (such as Evista), erss conditioning agent (such as estradiol, with reference to estrogen), androgen receptor modifier, Osteoclast proton triphosphatase inhibitor, HMG-CoA reductase inhibitor, integrain receptor antagaonists, osteoblast anabolic agent, Activated vitamin D (double hydroxyvitamins D (calcitriol) of such as 1 α-hydroxyvitamin D (alfacalcidol), 1,25-), phytoestrogen (Eprazinone), drop calcium Plain class (such as Calcitonin Salmon), Strontium Ranelate, Odanacatib, ONO5334, MIV-711, MIV-710 and its medicinal salt and mixture it is another Plant material.
On the one hand, the purposes of compound of the present invention or pharmaceutical composition of the present invention in medicine is prepared, wherein, the medicine is used for The activity of inhibiting cathepsin；Further, described cathepsin includes but is not limited to cathepsin K.
On the one hand, the purposes of compound of the present invention or pharmaceutical composition of the present invention in medicine is prepared, wherein, the medicine is used for The Cathepsin dependent diseases for the treatment of, treatment or mitigation patient.
On the one hand, the purposes of compound of the present invention or pharmaceutical composition of the present invention in medicine is prepared, wherein, the medicine is used for Treatment, prevention, mitigation or reduction of patient osteoporosis, osteitis deformans, the increase of bone update abnormal, periodontal disease, tooth loss, fracture, class wind Wet arthritis, osteoarthritis, periprosthetic osteolysis, incomplete ostosis, metastatic bone disease, malignant hypercalcemia, multiple marrow Knurl, multiple sclerosis, myasthenia gravis, psoriasis, ordinary day born of the same parents sore, exophthalmic goiter, systemic loupus erythematosus, asthma, pain, Atherosclerosis, bone lesion, stock have enough to meet the need the disease of abnormal increase, the hypercalcinemia of malignant tumour, obesity or Bone tumour.
" Cathepsin dependent diseases or illness " refers to depending on one or more pathological conditions of cathepsin active." cathepsin K according to Bad property disease or illness " refers to depending on the active illness of cathepsin K.The illness relevant with Cathepsin K activities include osteoporosis, The Osteoporosis of glucocorticoid inducible, osteitis deformans, the increase of bone update abnormal, periodontal disease, tooth loss, fracture, rheumatoid arthritis, bone Arthritis, periprosthetic osteolysis, incomplete ostosis, metastatic bone disease, malignant hypercalcemia and Huppert's disease.Wanted with the present invention When asking the compound of protection to treat such illness, required therapeutic dose will be changed with specific disease, and those skilled in the art can be easily It is determined.
Content noted earlier only outlines certain aspects of the invention, but the content being not limited in terms of these aspects and others will be made more below Specific complete description.
Detailed description of the invention book
Definition and general terms
Certain embodiments of the present invention will now be described in more detail, the example is by the structural formula enclosed and chemical formula explanation.It is all of the invention is intended to cover Substitute, change and equivalent technical solutions, they are included in the scope of the invention such as claim definition.Those skilled in the art will appreciate that It is many to can be used in the practice present invention with similar or equivalent method described herein and material.The present invention is not limited to method described herein and material. One or more in the document, patent and similar material for being combined it is different from the application or in the case of contradicting it is (including but not limited to defined Term, term application, described technology, etc.), it is defined by the application.
It will further be appreciated that some features of the invention, are clearly visible, it is described in multiple independent embodiments, but it is also possible to There is provided in combination in single embodiment.Conversely, various features of the invention, for brevity, are described in single embodiment, But can also be provided individually or with any suitable sub-portfolio.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have and are generally understood that identical contains with those skilled in the art of the invention Justice.All patents of the present invention and public publication are integrally incorporated the present invention by reference.
Unless otherwise indicated, following definition used herein should be applied.For purposes of the present invention, chemical element and periodic table of elements CAS Version, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle refers to " Organic Chemistry ", Thomas Sorrell,University Science Books,Sausalito:1999, and " March's Advanced Organic Chemistry " by Michael B. Smith and Jerry March,John Wiley&Sons,New York:Description in 2007, entire contents are incorporated herein by reference.
There is obvious conflict unless otherwise indicated or in context, article " " used herein, " one (kind) " and " described " are intended to include " extremely It is few one " or " one or more ".Therefore, these articles used herein refer to the article of one or more than one (i.e. at least one) object. For example, " component " refers to one or more components, it is possible to have more than one component be taken into account in the implementation method of the embodiment use or Use.
Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.Study subject, for example, also refer to primate Animal (such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc..In some implementations In scheme, the study subject is primate.In other embodiments, the study subject is people.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some embodiments, " patient " is Refer to people.
Term "comprising" is open language, i.e., including the content specified by the present invention, but be not precluded from otherwise content.
" stereoisomer " refers to but atom or the group spatially different compound of arrangement mode with identical chemical constitution.Stereoisomer bag Enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer are included, Etc..
" chirality " be have with its mirror image can not overlap property molecule；And " achirality " refer to can be overlap with its mirror image molecule.
" enantiomter " refers to the two of compound isomers that can not be overlapped but be mutually mirror.
" diastereoisomer " refers to have two or more chiral centres and its molecule not stereoisomer of mirror image each other.Diastereoisomer has Different physical properties, such as fusing point, boiling point, spectral quality and reactivity.Non-enantiomer mixture can operate such as electrophoresis by high resolution analysis And chromatogram, such as HPLC separates.
Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；And Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley＆Sons, Inc., New York, 1994.
Many organic compounds exist with optical active forms, i.e., they have the ability for rotating the plane of linearly polarized light.In description optics During reactive compound, absolute configuration of the molecule on one or more chiral centre is represented using prefix D and L or R and S.Prefix d and L or (+) and (-) are the symbols for the rotation of linearly polarized light caused by appointed compound, wherein (-) or l represent that compound is left-handed.Prefix For the compound of (+) or d is dextrorotation.A kind of specific stereoisomer is enantiomter, and the mixture of this isomers is referred to as enantiomerism Body mixture.The 50 of enantiomter:50 mixtures are referred to as racemic mixture or racemic modification, when chemical reaction or during selected without three-dimensional When selecting property or stereospecificity, such case is may occur in which.
Any asymmetric atom (for example, carbon etc.) that the present invention discloses compound can exist in the form of racemic or enantiomer enrichment, for example (R)-, (S)-or (R, S)-configuration be present.In certain embodiments, each asymmetric atom has at least 50% in terms of (R)-or (S)-configuration Enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, At least 95% enantiomeric excess, or at least 99% enantiomeric excess.
According to the selection of starting material and method, the compounds of this invention can be for example outer to disappear with possible isomers or their mixture The form of rotation body and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) is present.Optically active (R)-or (S)-isomers Can be used chiral synthon or chiral reagent to prepare, or split using routine techniques.If compound contains a double bond, substitution base may for E or Z configurations；If containing dibasic cycloalkyl in compound, the substitution base of cycloalkyl may have cis or trans configuration.
The mixture of any stereoisomer of gained can be separated into pure or substantially pure geometry according to the difference in component physicochemical properties Isomers, enantiomter, diastereoisomer, for example, separating different stereoisomers by chromatography and/or Steppecd crystallization.
The racemic modification of any gained end-product or intermediate can be split into light by method familiar to the person skilled in the art with known method Enantiomer is learned, e.g., is separated by its diastereoisomeric salt for obtaining.Racemic product can also be separated by chiral chromatogram, e.g., Use the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, enantiomter can be prepared by asymmetric syntheses, for example, referring to Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)； Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA, Weinheim,Germany,2007)。
Term " dynamic isomer " or " tautomeric form " refer to that can build (low energy barrier) mutually inversion of phases by low energy with different-energy Constitutional isomer.If tautomerism is possible (as in the solution), the chemical balance of dynamic isomer can be reached.For example, proton change Isomers (protontautomer) (also referred to as Prototropic tautomers (prototropic tautomer)) includes what is carried out by proton migration Mutual inversion of phases, such as keto-enol isomerization and imine-enamine isomerizations.Valence tautomerism body (valence tautomer) is included by some bondings electricity The mutual inversion of phases for recombinating to carry out of son.The instantiation of ketoenol tautomerization is pentane -2,4- diketone and the amyl- 3- alkene -2- ketone tautomerisms of 4- hydroxyls The change of body.Tautomeric another example is phenol-keto tautomerism.One instantiation of phenol-keto tautomerism is pyridine -4- alcohol and pyridine The change of -4 (1H) -one dynamic isomers.Unless otherwise noted, all tautomeric forms of the compounds of this invention are within the scope of the present invention.
In each several part of this specification, the substitution base that the present invention discloses compound is disclosed according to radical species or scope.Particularly point out, the present invention includes Each independent sub-combinations thereof of each member of these radical species and scope.For example, term " C1-C4Alkyl " or " C1-4Alkyl " is referred in particular to solely Vertical disclosed methyl, ethyl, C3Alkyl and C4Alkyl.
In each several part of the invention, connect substituent is described.When the structure clearly needs linking group, for the Ma Ku cited by the group Assorted variable is interpreted as linking group.If for example, the structure needs linking group and the Markush group definition for the variable lists " alkane Base " or " aryl ", then it should be understood that being somebody's turn to do alkylidene group or arylene group that " alkyl " or " aryl " represents connection respectively.
As described in the invention, compound of the invention optionally can be replaced by one or more substitution bases, such as general formula compound above, Or as the special example in embodiment the inside, subclass, and the class compound that the present invention is included.Should be appreciated that " optionally substituted " this term and " take In generation, is non-substituted " this term can exchange and use.In general, term is " substituted " to represent one or more the hydrogen atom quilts given in structure Specific substitution base is replaced；Before term " optionally " is whether located at term " substituted ", one or more hydrogen atoms that expression is given in structure Can be replaced or unsubstituted by specifically substitution base.Unless other aspects show that an optional substituted radical can have a substitution base in group Each commutable position is replaced.When more than one position can be selected from one or more substitution base institutes of specific group in given structural formula Substitution, then substitution base can be replaced with identical or different in each position." one or more " mean to be taken by one or more substitution base Generation, it is preferable that refer to be replaced by 1,2,3,4,5 or 6 substitution bases.When replacing base number to be more than 1, the substitution base is mutually solely Vertical, can be identical or different specific substituted radical.
Wherein, substitution base of the present invention can be, but be not limited to：Hydrogen, oxo (=O), alkyl, fluorine, chlorine, bromine, amino, hydroxyl, Carboxyl, alkoxy, alkylamino, haloalkyl, aldehyde radical, cyano group, alkyl acyl, alkyl sulphonyl, acylamino-, sulfonamido, hydroxyl substitution Alkyl, hydroxyl substitution haloalkyl, aryl, heterocyclic radical, heteroaryl, cycloalkyl or nitro etc..
Terminology used in the present invention " alkyl " includes the univalence hydrocarbyl of 1-12 carbon atom saturated straight chain or side chain.Some of them embodiment is, alkyl base 1-4 carbon atom is contained in group；Other embodiment is that alkyl group contains 1-3 carbon atom.Alkyl group further example includes, But be not limited to, methyl, ethyl, propyl group (including n-propyl and isopropyl), butyl (including normal-butyl, 2- methyl-propyls, 1- methyl-propyls and The tert-butyl group) etc..Term " alkyl " and its prefix " alkane " are being used herein as, the saturated carbon chains all comprising straight chain and side chain.
Term " haloalkyl " represents the situation that alkyl can be replaced by one or more identical or different halogen atoms.Wherein alkyl group has such as Implication of the present invention, such example includes, but is not limited to trifluoromethyl, 1- chloroethyls, difluoromethyl, Dichloroethyl, 2,2- difluoro second Base, 3,3,3- trifluoro propyls, the fluoro- 2- methyl-propyls of 2- etc..
Term " amino " refers to-NH2。
Term " alkylamino " or " alkyl amino " include " N- alkyl aminos " and " N, N- dialkyl amido ", and wherein amino group is separately by one Individual or two identical or different alkyl groups are replaced, and wherein alkyl group has implication as described in the present invention.Such example includes, but simultaneously It is not limited to, methylamino, ethylamino, dimethylamino, lignocaine etc..
Term " aminoacyl " refers to group-C (=O) NH2, wherein amino group (- NH2) further can be replaced by one or more alkyl groups.
Term " alkyl acyl ", " alkyl sulphonyl " refer respectively to group " alkyl-C (=O)-" and group " alkyl-S (=O)2- ", wherein, it is described The specific implication described in the invention of alkyl.Alkyl acyl includes but is not limited to methylacyl, ethyl acyl group etc..Alkyl sulphonyl includes but does not limit In methyl sulphonyl, ethylsulfonyl etc..
Term " alkoxy " used in the present invention refers to that alkyl group is connected in the agent structure of molecule by oxygen atom, wherein, described alkane Base has implication described in the invention.Such embodiment is included, but is not limited to, methoxyl group, ethyoxyl, propoxyl group etc..
Term " cycloalkyl " or " carbocyclic ring " they refer to the saturation or part unsaturation ring of monovalence or multivalence, and described ring is nonaromatic, and not comprising miscellaneous Atom；Wherein, described carbocyclic ring includes 3-12 monocyclic or 5-12 two rings or three rings of carbon atom of carbon atom.It is double with 5-12 atom Carbocyclic ring can be two rings [4,5], [5,5], [5,6] or [6,6] system, while it can be two rings [5,6] or [6,6] body to have 9 or 10 bicyclic carbocyclic rings of atom System.Suitable group of naphthene base is included, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of group of naphthene base further includes, but It is not limited to, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyls, cyclohexyl, cyclohexadienyl, suberyl, cyclooctyl etc..
Term " aryl " can be monocyclic, bicyclic or three rings carbocyclic ring systems, wherein, at least one ring is aromatic, and each ring includes 3-7 Individual atom.Term " aryl " can be exchanged with term " aromatic rings " and used, and such as aromatic rings can include phenyl, naphthyl and anthryl.
Term " heteroaryl ", " hetero-aromatic ring " is used interchangeably herein, refer to the up to 15 monocyclic, bicyclic or tricyclic systems of the stabilization of atom, Wherein at least one ring is armaticity, and at least one ring includes 1 to 4 hetero atom selected from O, N and S.Heteroaryl as defined in the range of this Include without limitation：Oxazolyl, pyranose, pyrazinyl, pyrazolyl, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, tetrazole radical, thiazolyl, Thienyl, triazolyl and furyl.If the heteroaryl includes nitrogen-atoms, it should be understood that this definition also includes its corresponding N- oxide.
Term " heterocyclic radical ", " heterocycle ", " miscellaneous alicyclic " or " heterocycle " are used interchangeably herein, bicyclic all referring to monocyclic, three rings or four Member ring systems, one or more atoms are selected from the hetero atom of N, O, S, P and are replaced individually optionally in its middle ring.Described heterocycle can be Full saturation or comprising one or more degrees of unsaturation, but be definitely not the fragrant same clan.Heterocyclic system can be connected on any hetero atom or carbon atom So as to form the compound of stabilization on to main structure.Unless otherwise indicated, heterocycle of the present invention includes N, S or P optionally by one or many Individual oxo (=O) group replaces and obtains as NO, NO2, SO, SO2, PO, PO2Group, meanwhile ,-the CH in heterocycle2- group can With optionally by-C (=O)-replacement." heterocyclic radical " equally also includes heterocyclic group with saturation or part unsaturation ring or heterocycle and the formed group of conjunction. The example of heterocycle is included, but is not limited to, piperidyl, piperazinyl, pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, four Hydrogen pyranose, dihydro pyranyl, azelidinyl, oxetanylmethoxy, glycidyl, morpholinyl, oxygen azatropylidene base, diazepine base, sulphur nitrogen Miscellaneous Zhuo Ji, pyrrolinyl, 2H- pyranoses, 4H- pyranoses, dioxane hexyl, 1,3- dioxies amyl group, dihydro-thiophene base, dihydro pyrazine base, Dihydropyridine base, pyrazoline base, dihydro-pyrimidin base, pyrrolin base, Isosorbide-5-Nitrae-dithiane base, etc..
Term " volution base ", " volution ", " spiral shell bicyclic group " or " spiral shell is bicyclic " are used interchangeably herein, refer to unit price or multivalence saturation or part not Saturated ring system, one of ring originates from specific ring carbon atom on another ring, and each ring includes 3-7 atom.For example, As described by formula i, ring A and ring B shares a carbon atom in two member ring systems of saturation, is referred to as " volution " or " spiral shell is bicyclic ".
Each ring in spiral shell bicyclic group can be carbocylic radical or heterocyclic radical.Spiral shell is bicyclic can be connected to body junction from any hetero atom or carbon atom On structure, or spiral shell is bicyclic and other rings are condensed and form three rings or tetracyclic ring system.Wherein, " spiral shell carbon is bicyclic " or " spiral shell carbon bicyclic group " refers to by carbon atom The spiral shell bicyclic group of composition, such example is included, but is not limited to, spiral shell [4.4] nonyl, spiral shell [2.4] heptane base, spiral shell [3,4] octyl, spiral shell [4,5] Certain herbaceous plants with big flowers alkyl etc.." spiral shell is miscellaneous bicyclic " or " the miscellaneous bicyclic group of spiral shell " refer in described volution at least one ring comprising 1,2,3 or 4 selected from N, O, S Hetero atom, as NO, NO obtained from optionally being replaced by one or more oxos (=O) including N or S herein2, SO, SO2Group, Such example is included but is not limited to, 2- oxygen -8- azaspiro [4,5] decyl, 2,7- diaza spiros [4.4] nonyl, 7- oxygen -2- azaspiro [4.5] decane Base, 4- azaspiros [2.4] heptane base, 4- oxaspiros [2.4] heptane base etc..Meanwhile ,-the CH in spiral shell bicyclic group2- group can optionally by-C (=O)- Substitute.
Term " bridge bicyclic group " represents saturation or the undersaturated bridged-ring system in part, is related to the bicyclic system of non-aromatic, as shown in formula j, i.e. ring R1 and ring r2 has an alkane chain or a miscellaneous alkane chain, and wherein p is 1,2,3 or 4.Such system can be comprising independent or conjugation not Saturation state, but its core texture does not include aromatic rings or aromatic ring (but aromatic series can be as substitution base thereon), and each ring bag Containing 3-7 atom.
Bridge bicyclic group includes bridge carbon bicyclic group and the miscellaneous bicyclic group of bridge.Bridge is bicyclic can be connected in agent structure from any hetero atom or carbon atom, Or bicyclic being condensed with other rings of bridge and form three rings or tetracyclic ring system." bridge carbon is bicyclic " or " bridge carbon bicyclic group " refers to the bridge pair being made up of carbon atom Ring group, such example is included, but is not limited to, bicyclic [2.2.1] heptane base etc.." bridge is miscellaneous bicyclic " or " the miscellaneous bicyclic group of bridge " refers to described bridged ring In at least one ring include 1,2,3 or 4 hetero atoms selected from N, O, S, herein including N or S optionally by one or more oxos (=O) As NO, NO obtained from replacing2, SO, SO2Group, such example includes but is not limited to, 2- methyl-miscellaneous two ring [2.2.1] heptane base etc.. Meanwhile ,-the CH in the bridge bicyclic group2- group can optionally by-C (=O)-replacement.
The descriptions such as " 3-8 former molecular carbocyclic ring ", " 5-10 former molecular spiral shell carbon is bicyclic " represent the number of the annular atom of composition ring structure, Wherein, described annular atom includes the hetero atom such as carbon atom and N, O, S, P, and the species of atom depends on the species of the specific group for being formed. For example, " 3-8 former molecular carbocyclic ring " refers to the cycloalkyl being made up of 3-8 carbon atom；" 3-7 former molecular heterocycle " refers to by 3-7 Individual former molecular heterocyclic radical, wherein, the heterocyclic radical includes 1,2,3 or 4 hetero atoms selected from N, O, S, P.When the ring structure During by specific substituent group, the atom number of base is replaced not to be included in the number of described annular atom.For example, when pentamethylene is by an oxo (=O) During substituent group, oxygen atom is not included in annular atom.
As described in the present invention, substituent R by one be bonded the member ring systems formed on the ring at the center of being connected to represent substituent R can be any on ring May replace or any rational position is replaced.For example, formula a represents any position that may be substituted on ring A can be replaced by R, such as formula b, Shown in formula c, formula d and formula e；Meanwhile, R can also be replaced any commutable position on ring D, and in formula f, ring D is specially ring The spirane structure that B and ring C are formed, then R can be replaced on any commutable position on ring A, ring B or ring C.
As described in the present invention, attachment point can be connected any attachable position on ring with molecule remainder.For example, formula g represents A rings Upper any position that may be connected can be connected as the point of connection with the remainder of molecule, such as formula g-1, formula g-2, formula g-3 and formula g-4 institute Show.
In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode that uses in the whole text herein " each ... and ... independently be ", " ... and ... be each independently " and " ... with ... separately for " can exchange, and should be interpreted broadly, its both can refer in different groups, Do not influenceed mutually between expressed specific option between same-sign, it is also possible to represent in identical group, expressed tool between same-sign Do not influenceed mutually between body option.For example, each R in formula hcSpecific option can be with identical, it is also possible to it is different and expressed each other Specific item is also different；It is and in the case of difference, the specific option of each k also can be identical or different.
Term " pharmaceutically acceptable " refer to when give people apply when pharmaceutical formulation and it is general do not produce allergy or similar unsuitable reaction, The molecular entity and composition of such as digestive discomfort, dizziness etc..Preferably, term " pharmaceutically acceptable " used herein refers to federal supervisor It is structure or national government approval or that American Pharmacopeia or pharmacopeias of other general accreditations are lifted in animal, be more in particular in human body in use.
Term " carrier " refers to diluent, assistant agent, excipient or the matrix together applied with the compound.These pharmaceutical carriers can be sterile liquid, Such as water and oils, including oil, animal, plant or synthesis source, such as peanut oil, soybean oil, mineral oil, sesame oil etc..Water and water Property solution saline solutions and aqueous glucose and glycerite be preferably used as carrier, particularly Injectable solution.Suitable pharmaceutical carrier is described in In " Remington ' s Pharmaceutical Sciences " of E.W.Martin.
" hydrate " of the invention refers to compound or its salt provided by the present invention, and it also includes chemical quantity or non-chemically equivalent passes through Non-covalent molecular Between the water that combines of power, can also say it is that solvent molecule is associated matter that water is formed.
" solvate " of the invention refers to the associated matter that one or more solvent molecules are formed with compound of the invention.Form the molten of solvate Agent is included, but is not limited to, water, isopropanol, ethanol, methyl alcohol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethylaminoethanol.
" ester " of the invention refers to the internal hydrolyzable ester that compound shown in the formula (I) containing hydroxyl is formed.Such ester is for example in human or animal body Interior hydrolysis produces the pharmaceutically acceptable ester of parent alcohol.The group of hydrolyzable ester includes in compound body shown in formula (I) containing hydroxyl, but not It is limited to, phosphate, acetoxymethoxy, 2,2- dimethylpropionyloxymethoxies, alkanoyl, benzoyl, the acyl group of benzene first and second, alkoxy Carbonyl, dialkyl carbamoyl and N- (di-alkyaminoethyl group)-N- alkyl-carbamoyls etc..
" nitrogen oxides " of the invention refers to that, when compound contains several amine functional groups, nitrogen-atoms that can be by 1 or more than 1 aoxidizes to form N- oxidations Thing.The particular example of N- oxides is the N- oxides of tertiary amine or the N- oxides of nitrogen heterocyclic ring nitrogen-atoms.Available oxidant such as hydrogen peroxide or Peracid (such as peroxycarboxylic acid) process corresponding amine formed N- oxides (referring to Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).Especially, N- oxides can be prepared (Syn.Comm.1977,7,509-514) with the method for L.W.Deady, Wherein for example in atent solvent such as dichloromethane, amines is set to be reacted with m- chloroperoxybenzoic acid (MCPBA).
In addition, unless showing in terms of other, the structural formula of compound described in the invention includes the enriched isotope of one or more different atoms. Compound of the present invention including isotope marks, they are equal to those described in formula (I), but one or more atoms by atomic mass or mass number Atom different from the common atomic mass of nature or mass number is replaced.The example of the isotope that can be introduced into the compounds of this invention include hydrogen, The isotope of carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, respectively for example2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F and36Cl.The compounds of this invention of other isotopes containing above-mentioned isotope and/or other atoms, its pro-drug and the compound or institute The pharmaceutically acceptable salt for stating pro-drug belongs to the scope of the present invention.The compounds of this invention of some isotope marks, for example introduce radioactivity Isotope is (for example3H and14C) those can be used for medicine and/or substrate tissue measure of spread.Tritium, i.e.3H and carbon-14, i.e.14C isotopes It is particularly preferred, because they easily prepare and detect.And hydrogen atom is replaced by heavier isotope, such as deuterium, i.e.2H, due to metabolic stability Property the benefit that can be provided in treatment higher, for example extend Half-life in vivo or reduce volume requirements, thus be probably in some cases preferred. Compound and its pro-drug can typically be prepared shown in the formula (I) of the present invention of isotope marks, carry out following flows and/or embodiment institute During disclosed technique, the reagent of nonisotopic labels is replaced with the reagent of the isotope marks being readily obtained.
" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One metabolite of compound can be with Identified by technology known to art, its activity can experimentally be characterized by adopting as described in the present invention. Such product can be by the way that to drug compound, by aoxidizing, reduction, hydrolysis, amidated, desamido- effect, esterification, degreasing, enzyme splits Solution etc. method is obtained.Correspondingly, metabolite of the present invention including compound, including compound of the invention and mammal are fully contacted one Metabolite produced by the section time.
The various pharmaceutically acceptable salt forms of the compounds of this invention are all useful.Term " pharmaceutically acceptable salt " refers to those salt forms pair Be for those skilled in the art it will be apparent that i.e. their substantially nontoxic and pharmacokinetic properties needed for providing, palatability, absorption, Distribution, metabolism are drained.Other factors, more practical in nature, also critically important for selecting, these are：The cost of raw material, crystallization Easily, the mobility of yield, stability, hygroscopicity and result bulk drug.Simply, pharmaceutical composition can by active ingredient with pharmaceutically Acceptable carrier is prepared.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of compound of the invention.Pharmaceutically acceptable salt is in institute Category field is known to us, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences,66:Described in 1-19,1977..The salt that pharmaceutically acceptable nontoxic acid is formed is included, but is not limited to, The inorganic acid salt to be formed is reacted with amino group hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, nitrate etc., and organic acid Salt such as acetate, propionate, glycollate, oxalates, maleate, malonate, succinate, fumarate, tartrate, citron Hydrochlorate, benzoate, mandelate, mesylate, esilate, tosilate, sulfosalicylate etc., or by books document Described other method such as ion-exchange obtains these salt.
Other pharmaceutically acceptable salts include adipate, malate, 2 hydroxy propanoic acid, alginates, ascorbate, aspartate, Benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, glucosulfone acid Salt, lauryl sulfate, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthic acid Salt, caproate, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactate, laruate, lauryl sulfate, malate, Malonate, mesylate, 2- naphthalene sulfonates, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acids salt, picrate, pivalate, propionate, stearate, rhodanate, undecylate, valerate, etc..By suitable When the salt that obtains of alkali include alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.
The present invention is also intended to contemplate the quaternary ammonium salt that the compound of any group comprising N is formed.Water-soluble or oil-soluble or dispersion product can lead to Quaternization is crossed to obtain.Alkali metal or alkali salt include sodium salt, lithium salts, sylvite, calcium salt, magnesium salts；Transition metal or its salt include molysite, Zinc salt, mantoquita, manganese salt, aluminium salt etc..Pharmaceutically acceptable salt is further included appropriate, nontoxic ammonium, quaternary ammonium salt and gegenions shape Into amine cation, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and fragrant sulphur Acidulants.Amine salt, such as but not limited to N, N '-dibenzyl-ethylenediamin, chloroprocanine, choline, ammonia, diethanol amine and other hydroxyalkyl amines, Ethylenediamine, N- methyl glucamines, procaine, N- benzyl-1-phenylethylamines, -1 '-ylmethyl of the p- chlorobenzyl -2- pyrrolidines of 1--benzimidazole, diethyl Amine and other alkylamines, piperazine and three (methylol) aminomethanes.
Term " blocking group " or " Pg " refer to a substitution base with other reacted with functional groups when, be commonly used to block or protect special function Property.For example, the feature that " blocking group of amino " refers to a substitution base to be connected to block or protect amino in compound with amino group, properly Amido protecting group include acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group (CBZ) and 9- fluorenes methylenes oxygen carbonyl (Fmoc). Similarly, " hydroxy-protective group " refer to the substitution base of hydroxyl for blocking or protecting the feature of hydroxyl, suitable blocking group include acetyl group and Silicyl." carboxy protective group " refer to the substitution base of carboxyl for blocking or protecting the feature of carboxyl, general carboxyl-protecting group includes -CH2CH2SO2Ph, cyano ethyl, 2- (TMS) ethyl, 2- (TMS) ethoxyl methyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..The description general for blocking group refers to document： T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski, Protecting Groups,Thieme,Stuttgart,2005.
In this manual, if there is any difference between chemical name and chemical constitution, structure is dominant.
The abbreviation of any blocking group used in the present invention, amino acid and other compounds, unless otherwise indicated, all so that they are usually used, Generally acknowledged abbreviation is defined, or reference IUPAC-IUB Commission on Biochemical Nomenclature (referring to Biochem.1972,11： 942-944)。
Unless other aspects show, all of stereoisomer of compound of the invention, geometric isomer, dynamic isomer, nitrogen oxides, hydration Thing, solvate, metabolite, salt and pharmaceutically acceptable prodrug belong to the scope of the present invention.Specifically, salt is pharmaceutically acceptable Salt.Term is " pharmaceutically acceptable " to include that material or composition must be adapted to chemistry or toxicologically, other components and use with composition preparation It is relevant in the mammal for the treatment of.The salt of compound of the invention is also included for preparing or purifying the intermediate of compound shown in formula (I) or formula (I) The salt of the enantiomter that shown compound is separate, but it is not necessarily pharmaceutically acceptable salt.
Compound of the invention, composition, and application thereof
Compound of the invention can individually or preferably together with pharmaceutical acceptable carrier or diluent, optionally in standard medicine together with known auxiliary agent such as alum It is administered in mammal, preferably people in the pharmaceutical composition for learning practice.The compound can be administered orally with delayed or parenteral, including intravenous, flesh Interior, intraperitoneal, subcutaneous, rectally and local administration.
In tablet for oral administration, conventional carrier includes lactose and cornstarch, and is usually added into lubricant, such as magnesium stearate.For with capsule For the oral administration that form is carried out, useful diluent includes lactose and dry cornstarch.For the oral application of the compounds of this invention, institute The compound of selection can be administered in the form of such as tablet or capsule or in the form of the aqueous solution or suspension.For carrying out in the form of tablets or capsules Oral administration for, can be by the pharmaceutically useful inert carrier of active pharmaceutical ingredient and oral, non-toxic such as lactose, starch, sucrose, glucose, methyl fibre Dimension element, magnesium stearate, Dicalcium Phosphate, calcium sulfate, mannitol, sorbierite etc. mutually merge；For the oral administration for carrying out in liquid form, can Mutually merge with pharmaceutically useful carrier such as ethanol, glycerine, water etc. of any oral, non-toxic with by oral drug components.Additionally, when needing or being required, also Can be to being mixed into suitable adhesive, lubricant, disintegrant and colouring agent in the mixture.Suitable adhesive includes starch, gelatin, natural sugar such as Glucose or beta lactose, corn sweetener, natural and synthesis natural gum as Arabic gum, bassora gum or mosanom, carboxy methyl cellulose, polyethylene glycol, Wax etc..The lubricant that can be used for these formulations includes enuatrol, odium stearate, magnesium stearate, Sodium Benzoate, sodium acetate, sodium chloride etc..Disintegration Agent includes starch, methylcellulose, agar, bentonite, xanthans etc. without limitation.When needing with aqueous suspension to carry out oral application, will Active component mutually merges with lubricant and supensoid agent.If it is desired, it is possible to add some sweeteners and/or flavouring.For intramuscular, intraperitoneal, skin For lower and intravenous application, the sterile solution of active component is generally prepared, and suitable regulation and buffering should be carried out to the pH of the solution.For quiet In arteries and veins for application, the total concentration of solute should be controlled so that said preparation is isotonic.
Compound of the invention can also be administered in the form of liposomal delivery system, for example small individual layer capsule of the liposomal delivery system, big list Layer capsule and multilayer capsule.Liposome can be formed with many phosphatide such as cholesterol, stearylamine or phosphatid ylcholine.
Compound of the invention can also be transmitted by using the monoclonal antibody as separate carrier, and compound molecule is coupled on the antibody. Compound of the invention can also mutually be coupled with as the soluble polymer of the pharmaceutical carrier that can be targetted.Such polymer may include polyvinylpyrrolidone, Pyran co-polymer, poly- hydroxypropylmethacrylamide-phenol, poly- hydroxy-ethyl aspartarnide-phenol or the polyethylene glycol oxide replaced by palmitoyl residues - polylysin.Additionally, the biodegradable polymer of controlled release that compound of the invention can also be used to obtain medicine with a class is mutually coupled, the polymer Such as copolymer of PLA, polyglycolic acid, PLA and polyglycolic acid, poly epsilon caprolactone lactone, poly butyric, poe, polyacetals, poly- dihydro The crosslinking of pyrans, polybutylcyanoacrylate and hydrogel or amphipathic nature block polymer.
Compound of the invention can also be strangeer with for treatment or pre- preventing bone rarefaction, the osteoporosis of glucocorticoid inducible, osteitis deformans, bone Normal increases, periodontal disease, tooth loss, fracture, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, ostosis are incomplete, metastatic The known substance combination of bone disease, malignant hypercalcemia and Huppert's disease.Compound disclosed in this invention with for treat or pre- preventing bone rarefaction Or the combination of the material of other bone disorders is also within the scope of the invention.Those skilled in the art can the characteristic of medicine and disease according to involved by which understands The combination of a little materials is useful.Such material includes following material：Organic diphosphonic acid compound；Estrogenic agents；Androgen receptor is adjusted Agent；Osteoclast proton triphosphatase inhibitor；HMG-CoA reductase inhibitor；Integrain receptor antagaonists；Osteoblast anabolic agent, Such as PTH；And its pharmaceutically useful salt and mixture.A kind of preferred combination is the combination of compound of the invention and organic diphosphonic acid compound.It is another Preferred combination is the combination of compound of the invention and estrogenic agents.Another preferred combination is compound of the invention and androgen receptor The combination of conditioning agent.Another preferred combination is the combination of compound of the invention and osteoblast anabolic agent.
The nonrestrictive example of organic diphosphonic acid compound used herein includes alendronic acid, BP, Clodronate, Etidronic Acid, Yi Ban Phosphonic acids, her card phosphonic acids, minodronic acid, Neridronic Acid, olpadronic acid, pamidronic acid, pyrrole phosphonic acids, Risedronic Acid, Tiludronic Acid and zoledronic acid with And its pharmaceutically useful salt and ester.Particularly preferred bisphosphonate compound is Alendronate, especially the sodium of alendronic acid, potassium, calcium, magnesium or ammonium salt. The example of preferred bisphosphonate compound is the sodium salt of alendronic acid, the especially sodium salt of the hydration of alendronic acid.The salt can be by the water of whole molal quantity or non- The water hydration of whole molal quantity.The example of preferred bisphosphonate compound is the sodium salt of the hydration of alendronic acid, especially Monosodium alendronate trihydrate. The precise dosage of organic diphosphonic acid compound is by with age, size, the sex of administration time table, selected specific diphosphonate, mammal or people Change to physical condition, the property of condition being treated and the order of severity and other related medical science and physical factors.
" SERM " is referred to not considering mechanism, can disturb or suppress the compound of the combination of estrogen and acceptor.Estrogen is received The example of body conditioning agent without limitation include estrogen, progestational hormone, estradiol, Droloxifene, Raloxifene, lasofoxifene, TSE-424, he not Former times sweet smell, Idoxifene, LY353381, Toremifene, fulvestrant, 4- [7- (2,2- dimethyl -1- oxopropoxy -4- methyl -2- [4- [2- (1- piperidyls) Ethyoxyl] phenyl] -2H-1- chromene -3- bases)-phenyl -2,2- dimethyl propylenes acid esters and 4,4 '-dihydroxy benaophenonel-dinitrophenyl group-hydrazone.
" erss conditioning agent " can be the compound of selectivity excitement or antagonising oestrogen receptors β (ER β).Exciting ER β increased by ER β The transcription of the tryptophan hydroxylase gene (TPH, the key enzyme in thrombocytin synthesis) that the event of mediation is carried out.
" androgen receptor modifier " is referred to not considering mechanism, can disturb or suppress the compound of the combination of androgen and acceptor.Androgen receptor is adjusted The example of agent includes Finasteride and other 5a- reductase inhibitors, Nilutamide, Flutamide, Bicalutamide, Liarozole and abiraterone acetate.
" osteoclast proton triphosphatase inhibitor " refers to the inhibitor of proton triphosphatase, its top film for being found in osteoclast On, and it has been reported that it plays an important role during bone information.This kind of inhibitor can serve as bone resorption inhibitor, for treating and preventing bone Matter is loose and related metabolic diseases.
" HMG-CoA reductase inhibitor " refers to the inhibitor of 3- hydroxy-3-methyl glutaryl-CoA reductases.The HMG-CoA that can be used is reduced The example of enzyme inhibitor includes Lovastatin, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin and cerivastatin without limitation.It is preferred that Ground, the HMG-CoA reductase inhibitor is selected from Health food and Simvastatin, and most preferably Simvastatin.Term used herein HMG-CoA reductase inhibitor includes all pharmaceutically useful lactone of the compound with HMG-CoA reductase inhibitory activity with the sour form opened (i.e. Wherein lactonic ring is opened so as to form free acid) and salt and ester-formin, therefore, within the scope of the invention also include using such salt, ester, open Acid and lactone form.
" integrain receptor antagaonists " used above refer to can selective antagonism, suppress or offset physiologic ligand and αvβ3The combination of integrin Compound, can selective antagonism, suppress or offset physiologic ligand and αvβ5The compound of the combination of integrin, with antagonism, suppression or can offset Physiologic ligand and αvβ3Integrin and αvβ5The compound of the combination of integrin, and with antagonism, suppression or can offset on capillary endothelial cells The active compound of the specific integrin of expression.The term further relates to αvβ6、αvβ8、α1β1、α2β1、α5β1、α6β1And α6β4Integrin it is short of money Anti-agent.The term further relates to αvβ3、αvβ5、αvβ6、αvβ8、α1β1、α2β1、α5β1、α6β1And α6β4Any combination of antagonist of integrin.
" osteoblast anabolic agent " refers to building the material of bone, such as PTH.Have shown that parathyroid hormone (PTH) or its amino terminals fragment and The intermittent administration of analog can prevent, prevent, the bone lesion in part de-rotation thing and human body and stimulate bon e formation.
The compounds of this invention can also suppress with selected from the NSAIDs such as inhibitor of selective cyclooxygenase-2 inhibitor, Interleukin -1β, LOX/COX Another material combination of agent, vitamin D, novel vitamin D analogues, calcium, the RANKL inhibitor of synthesis etc..
" NSAIDs " or NSAIDs, through cyclo-oxygenase COX-1 and COX-2, can suppress new old from arachidonic acid to proinflammatory prostaglandins Metabolism.Non-limiting NSAIDs examples include：Acetylsalicylic acid, brufen, NAP, Ciclofenaziae, Etodolac, fenoprofen, BTS-18322, indocin, Ketoprofen, ketorolac, Meloxicam, Nabumetone, first promazine, piroxicam, sulindac, toluoyl pyridine second Acid, diflunisal, first chloramines benzoic ether and phenylbutazone.
" selective cyclooxygenase-2 inhibitor " or cox 2 inhibitor, refer to a kind of NSAIDs (NSAID), can suppress that pain and body can be caused The COX-2 coenzyme of interior inflammation.The non-limiting example of cox 2 inhibitor includes：Celecoxib, Etoricoxib cloth, SC 69124, rofecoxib cut down Ground former times cloth and Prexige cloth.
" inhibitor of Interleukin -1β " or IL-1 beta inhibitors are the soluble factors produced by monocyte, macrophage and other cells, and it activates T- Lymphocyte simultaneously strengthens their reactions to mitogen or immunizing antigen.The non-limiting example of IL-1B inhibitor includes diacerein and Rhein.
" LOX/COX inhibitor " refers to the inhibitor for participating in arachidonic acid pathway.The non-limiting example of LOX/COX inhibitor is Licofelone.
" vitamin D " includes but is not limited to vitamine D3 (Vitamin D3) and calciferol (ergocalciferol), and they are biological naturally occurring, hydroxylatings Active metabolite vitamin D：La- hydroxy-vitamine Ds；25-hydroxy-vitamin D and la, the biological inactive precursor of 25-hydroxy-vitamin D.Calciferol There is identical biopotency in the mankind with vitamine D3.When calciferol or vitamine D3 enter circulation, can be by Cytochrome P450-Wei Sheng Plain D-25- hydroxylases hydroxylation, obtains 25-hydroxy-vitamin D.Metabolite 25-hydroxy-vitamin D is biologically inactive, and it can quilt in kidney Cytochrome P450-monooxygenase, 25 (OH) D-la- hydroxylases are further hydroxylated, and obtain 1,25- dihydroxyvitamin Ds.When serum calcium is reduced, can increase Plus the production of Yue shapes side glandular hormone (PTH), it passes through to increase 25- hydroxy vitamins and is converted to 1,25- dihydroxyvitamin Ds to adjust pot dynamic equilibrium and increasing Heal slurry calcium level.
In embodiments of the invention, the appropriate amount of vitamin D compounds is selected, to provide administration interim enough vitamin D nutrition thing, and Do not interfere with cathepsin K inhibitor and obtain the ability for suppressing bone information effect.
" novel vitamin D analogues of synthesis " include the compound of non-naturally occurring generation vitamin D sample effect.
" calcium " includes but is not limited to calcium carbonate, calcium citrate or any other compounds comprising element calcium.It is again bone knot necessary to calcium is human health Required for structure is complete.The Ionizing sections of blood calcium are physiologically important, and tight by parathyroid hormone (PTH) and 1,25- dihydroxyvitamin D Thickly maintain.Like this, blood calcium reduces (or only dietary calcium is insufficient) can promptly influence the level of PTH and 1,25- dihydroxyvitamin D, together Sample can negatively affect bone health, thus supplement Ca supply is intended to reduction PTH levels, is removed from skeleton storage with reducing hook, similarly has Beneficial to bone health.
" RANKL inhibitor " refers to the inhibitor of receptor agents NF- κ beta ligands (RANKL).RANKL is the key of osteoclast formation and maturation Stimulant.The non-limiting examples of RANKL inhibitor include AMG-162.
If be configured to the combination product of fixed dosage, dosage model is checked and approved at it with other using the compound of the invention within dosage range as described below Pharmacy activator () within enclosing.Compound of the invention can be used with known pharmaceutically acceptable reagent order.
The term " administration " and its modification (for example " applying " compound) used when compound of the invention is related to are referred to the compound or compound Prodrug is incorporated into the system of the animal for needing to be treated.When compound of the invention or its prodrug with one or more other active materials (such as cell Poison agent) the form of combination when being provided, while " administration " and its modification each should be read to include the compound or its prodrug and other materials with It is introduced sequentially into.Present invention prodrug including the compounds of this invention in the range of it.
Terms used herein " composition " include with specified amount include specify composition product and can directly or indirectly by the combination institute of specified quantitative special component Any product for producing.
Terms used herein " therapeutically effective amount " refers to that researcher, animal doctor, doctor or other clinics doctor can be caused in tissue, system, animal or people The reactive compound or the amount of pharmaceutical substances of biology or medicinal response sought by teacher.
" treatment " or " treatment " of terms used herein disease includes：Disease is prevented, even if the disease must occur or be prone to the disease but go back The mammal for not experiencing or showing the symptom of the disease does not form the clinical symptoms of the disease；Inhibit disease, that is, prevent or reduce disease or The development of its clinical symptoms；Or alleviate disease, i.e. so that disease or its clinical symptoms disappear.
Terms used herein " bone information " refers to process of the osteoclast by its bone of degrading.
Present invention additionally comprises the pharmaceutical composition for treating osteoporosis or other bone disorders, its compound of the invention for including therapeutically effective amount, and Comprising or not comprising pharmaceutically useful carrier or diluent.Proper combination of the invention includes that the pH levels for example 7.4 include the compounds of this invention and can The aqueous solution of pharmaceutical carrier such as salt solution.The solution can be incorporated into the blood of patient by local bolus injection.
When compound of the invention is administered in human patientses, the daily dose is typically determined by the attending doctor of evolution, and the dosage is general with each Age of patient, the order of severity of body weight and response and patient symptom and change.
In an application example, the compound of Sq is delivered medicine to the mammal treated to cathepsin dependent conditions.When due to meaning When the illness for going out is used, oral dose of the invention is for about 0.01mg/kg/ days to about 100mg/kg/ days, it is therefore preferable to 0.01 to 10mg/kg/ days, And most preferably 0.1 to 5.0mg/kg/ days.For oral administration, said composition be preferably with comprising 0.01,0.05,0.1,0.5,1.0, 2.5th, the form of 5.0,10.0,15.0,25.0,50.0,100 and 500 milligrams of tablets of active component is provided, for the patient being treated, Dosage is adjusted according to symptom.Medicine generally comprises about 0.01mg to about 500mg active components, preferably comprising about 1mg to about 100mg's Active component.During being input into constant speed, most preferred intravenous dosages are for about 0.1 to about 10mg/kg/ minutes.Compound of the invention can be advantageously It is administered in single daily dose form, or total daily dose can be administered in the form of the fractionated dose of daily two, three or four times.Additionally, Preferred compounds of the invention can be in intranasal form administered by using suitable intranasal vehicles, or can be many with those of ordinary skill in the art These well known transdermal skin patches forms are administered by cutaneous routes to it.For the administration carried out in transdermal delivery system form, it is administered Dosage during dosage certainly by continuously rather than being off and on administered.
Compound of the invention can be combined with the other materials of the illness for treating tissue proteases mediate.Over the course for the treatment of, each group of such combination Point can with split or single combination in the form of different time points is by separate administrable or is administered simultaneously.Therefore, the present invention should be understood comprising institute There is such simultaneously or alternate therapeutic scheme, and term " administration " also has and explains accordingly.It should be understood that the compounds of this invention be used for The scope of the combination of the other materials of the illness for the treatment of tissue proteases mediate includes being related to any medicine of the illness of estrogen function with for treatment in principle Any combinations of compositions.
Therefore, within the scope of the invention including the combination of compound of the presently claimed invention and second material selected from following material is used in combination： Organic diphosphonic acid compound；Estrogenic agents；Androgen receptor modifier；Osteoclast proton triphosphatase inhibitor；HMG-CoA Reductase inhibitor；Integrain receptor antagaonists；Osteoblast anabolic agent, such as PTH；And its pharmaceutically useful salt and mixture.
The pharmaceutically useful salt of the compounds of this invention includes the conventional salt nontoxic with the compounds of this invention of inorganic or organic acid formation.For example, nontoxic conventional salt bag Include these and derive from the inorganic acid such as salt of hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid etc. and by organic acid such as acetic acid, propionic acid, amber Acid, glycolic, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, flutter acid, maleic acid, hydroxymaleic acid, phenylacetic acid, paddy Propylhomoserin, benzoic acid, salicylic acid, p-aminobenzene sulfonic acid, 2- acetoxy-benzoics, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, The prepared salt of isethionic acid, trifluoroacetic acid etc..The pharmaceutically useful salt of the compounds of this invention can be with conventional chemical processes by comprising alkalescence or acidic moiety Compound of the invention synthesize.In general, the salt of alkali compounds is by ion-exchange chromatography or by by free alkali and stoichiometry or mistake The required inorganic acid or organic acid into salt of amount is reacted to be prepared in the various combinations of suitable solvent or solvent.Similarly, acidification The salt of compound is formed by being reacted with suitable inorganic or organic base.
General synthetic method
Usually, compound of the invention can be prepared by method described in the invention, unless there are further instruction, wherein replacing base Definition as shown in formula (I) compound.Following reaction scheme and embodiment are used to that present disclosure to be further illustrated.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used to suitably prepare many other chemical combination of the invention Thing, and be considered as within the scope of the present invention for preparing other methods of compound of the invention.For example, according to those non-examples of the invention The synthesis of the compound of card can be completed successfully by those skilled in the art by method of modifying, such as appropriate protection interference group, by profit With other known reagents except described in the invention, or reaction condition is made into some conventional modifications.In addition, it is disclosed in this invention reaction or Known reaction condition is also admittedly applied to the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all of temperature is set to degree Celsius.Reagent is bought in goods providers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all not by being further purified when using, Unless other aspects show.General reagent is resided well space from Shantou Xi Long chemical plant, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Chemical Company, Qingdao Teng Long chemical reagent Co., Ltd and Haiyang Chemical Plant, Qingdao are commercially available.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by metallic sodium backflow.Anhydrous methylene chloride and chloroform are through over hydrogenation Calcium backflow is dried to obtain.Ethyl acetate, petroleum ether, n-hexane, DMAC N,N' dimethyl acetamide and N,N-dimethylformamide are through anhydrous sodium sulfate thing First drying is used.
Below reaction is usually that a drying tube (unless other aspects show) is covered under nitrogen or argon gas positive pressure or on anhydrous solvent, and reaction bulb is all beyond the Great Wall Suitable rubber stopper, substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.Spectroscopic data of the nuclear magnetic resonance passes through Bruker Avance 400 nuclear magnetic resonance spectrometers or the nuclear magnetic resonance spectrometers of Bruker Avance III HD 600 are determined, with CDC13,d6-DMSO,CD3OD or d6- Acetone is solvent (report is in units of ppm), with TMS (0ppm) or chloroform (7.26ppm) as reference standard.When there is multiplet Wait, following abbreviation will be used：S (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplets), ddd (doublet of doublet Of doublets, in pairs doublet), ddt (doublet of doublet of triplets, in pairs triplet), dddd (doublet of doublet of doublet of Doublets, in pairs double doublet).Coupling constant, is represented with hertz (Hz).
The condition of Algorithm (MS) data determination is：Agilent 6120Quadrupole HPLC-MS (pillar models：Zorbax SB-C18, 2.1x 30mm, 3.5 μm, 6min, flow velocity is 0.6mL/min, mobile phase：5%-95% (the CH containing 0.1% formic acid3CN) (0.1% first is being contained The H of acid2O the ratio in))), detected with UV in 210/254nm, with electron spray ionisation pattern (ESI).
The characteristic manner of compound purity is：The preparative high performance liquid chromatographies of Agilent 1260 (Pre-HPLC) or the preparatives of Calesep Pump 250 High performance liquid chromatography (Pre-HPLC) (pillar model：NOVASEP, 50/80mm, DAC), detected with UV in 210nm/254nm.
The use of brief word below is through the present invention：
DCM dichloromethane；DMF N,N-dimethylformamides；HATU 2- (7- azos BTA)-N, N, N, N- tetramethylurea hexafluoro Phosphate；；CDCl3Deuterochloroform；Acetone-d6Deuterated acetone；DMSO dimethyl sulfoxides；NH4Cl ammonium chlorides；NBS N- bromos Succimide；NCS N- chlorosuccinimides；NIS N- N-iodosuccinimides；OTf TFMS bases；OTs is to toluene sulphur Acidic group
Synthetic schemes
The synthetic schemes 1 of intermediate
Midbody compound (1) can be prepared by the method described by the synthetic schemes 1 of intermediate, wherein, R1With as described in the present invention Implication.Compound (1a) and compound (1b) first react generation group with imine moiety in the basic conditions (such as in the presence of potassium carbonate), then in go back original reagent Reduction obtains compound (1c) in the presence of (such as zinc borohydride).Compound (1c) is with 1- amino -1- cyclopropyl cyanogen or its salt (such as hydrochloride) in condensation reagent Compound (1d) is condensed to yield in the presence of (such as HATU) and alkali (such as N, N- diisopropylethylamine etc.).Compound (1d) is being urged with connection pinacol borate Agent (such as 1,1'- double (diphenylphosphine) ferrocene) palladium chloride dichloromethane complex) and alkali (such as potassium acetate, potassium carbonate) in the presence of react and obtain centre Body compound (1).
The synthetic schemes 2 of intermediate
Midbody compound (2) can be prepared by the method described by the synthetic schemes 2 of intermediate, wherein, Hal is Cl, Br or I, L1 For leaving groups such as trifyl, p-toluenesulfonyls, E and R2With implication as described in the present invention.Compound (2a) is in NBS, NCS Or reacted in the presence of the halide reagent such as NIS and obtain halogenated compound (2b).Compound (2b) and R2To there is coupling in H anti-under suitable reagent Compound (2c) should be obtained；For example, working as R2During for nitrogen heterocycle, compound (2b) and R2H in alkali (such as potassium carbonate or potassium phosphate), catalyst (such as Cuprous iodide) and part (such as N, N'- dimethyl -1,2- ethylenediamines) in the presence of, react and obtain corresponding carbon nitrogen coupled product.Compound (2c) exists Demethylating obtains hydroxy compounds (2d) in the presence of Boron tribromide.Compound (2d) and acid anhydrides (such as trifluoromethanesulfanhydride anhydride) or acyl chlorides (such as tolysulfonyl Chlorine) in the presence of alkali (such as triethylamine or pyridine) occur condensation reaction obtain midbody compound (2).
Synthetic schemes 1
Target compound (4) can be prepared by the method described by synthetic schemes 1, wherein, L is OTf, OTs, halogen (such as Br, Cl) Deng leaving group, R1、R2, E and n there is implication as described in the present invention.Midbody compound (1) and compound (3) are at alkali (such as potassium carbonate) With catalyst (such as 1,1'- double (diphenylphosphine) ferrocene) palladium chloride dichloromethane complex) in the presence of reaction obtain objective body compound (4).
Embodiment
The synthesis of intermediate (A)
(S)-N- (1- anocy clopropyls) -4- methyl-the 2- ((fluoro- 1- (4- (4 of (S) -2,2,2- three, 4,5,5- tetramethyls -1,3,2- dioxaborolane -2- bases) phenyl) ethyl) ammonia Base) pentanamide
Step 1：(S) -2- (((S) -1- (4- bromophenyls) -2,2,2- trifluoroethyls) amino) -4- methylvaleric acids
To adding 4 '-bromo- 2,2,2- trifluoroacetophenones (1.2g, 4.75mmol), L-Leu methyl ester hydrochloride (1.03g, 5.7 in dry reaction flask Mmol), potassium carbonate (1.64g, 11.9mmol) and methyl alcohol (12mL), nitrogen protection, reaction mixture stirring reaction 18 hours at 55 DEG C. After reaction solution is cooled into room temperature, filtering, filtrate remains reaction.
To the acetonitrile solution (0.903g, 30mL, 9.5mmol) that zinc borohydride is added in three neck round bottom flask, reaction bulb is cooled to -40 DEG C, to Above-mentioned filtrate is slowly added dropwise in reaction bulb, after dripping off, reaction system is reacted 4 hours at -40 DEG C.It is quenched to water (20mL) is added in reaction solution Reaction, is 3 with the pH of dilute hydrochloric acid solution (10mL, 1mol/L) regulation system.Then acetonitrile is removed under reduced pressure, water is mutually extracted with ethyl acetate (60 ML), merge organic phase, washed with saturated aqueous common salt (20mL), anhydrous sodium sulfate drying.Filtering, decompression boils off solvent, and crude product is through silica gel Column chromatography purifies (ethyl acetate/dichloromethane (V/V)=1/30), obtains light yellow solid (1.64g, 90%).
MS(ESI,pos.ion)m/z:369.0(M+2).
Step 2：(S) -2- (((S) -1- (4- bromophenyls) -2,2,2- trifluoroethyls) amino)-N- (1- anocy clopropyls) -4- methylpentanamides
To addition (S) -2- (((S) -1- (4- bromophenyls) -2,2,2- trifluoroethyls) amino) -4- methylvaleric acids (736mg, 2.0mmol) in two mouthfuls of round-bottomed flasks, 1- amino -1- cyclopropyl cyanogen hydrochloride (308mg, 2.6mmol) and DMF (8mL).0 DEG C is cooled to, under nitrogen protection, HATU is sequentially added (798mg, 2.1mmol) and DIPEA (0.99mL, 6.0mmol), reaction system is stirred 2.0 hours at 0 DEG C.To reaction Saturated sodium bicarbonate aqueous solution (60mL) is added in system, is extracted with ethyl acetate (30mL × 3), merge organic phase, with saturated aqueous common salt (30 ML × 2) wash, anhydrous sodium sulfate drying.Filtering, decompression boils off solvent, and crude product purifies (ethyl acetate/dichloromethane (V/V) through silica gel column chromatography =1/50), obtain white solid (750mg, 82%).
MS(ESI,pos.ion)m/z:433.1(M+2).
Step 3：(S)-N- (1- anocy clopropyls) -4- methyl -2- ((the fluoro- 1- of (S) -2,2,2- three (4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) phenyl) Ethyl) amino) pentanamide
To in bottle with two necks add (S) -2- (((S) -1- (4- bromophenyls) -2,2,2- trifluoroethyls) amino)-N- (1- anocy clopropyls) -4- methylpentanamides (0.48g, 1.0mmol), connection pinacol borate (0.305g, 1.2mmol), (1,1'- double (diphenylphosphine) ferrocene) palladium chloride dichloromethane complex (0.067 G, 0.08mmol), potassium acetate (0.35g, 3.6mmol) and DMF (10mL) under nitrogen protection, are heated to 85 DEG C and react 3 hours.React Finish, be cooled to room temperature, add water and be quenched, extracted with ethyl acetate (60mL × 2), organic phase washed with water (60mL × 2) and saturated aqueous common salt (60 ML) wash, anhydrous sodium sulfate drying.Filtering, decompression boils off solvent, and crude product purifies (dichloromethane/ethyl acetate (V/V) through silica gel column chromatography =30/1), obtain white solid (0.16g, 61%).
MS(ESI,pos.ion)m/z:480.2(M+1).
The synthesis of intermediate (B)
(S) the fluoro- 4- methyl -2- of-N- (1- anocy clopropyls) -4- ((the fluoro- 1- of (S) -2,2,2- three (4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) phenyl) second Base) amino) pentanamide
Synthesized reference document Bioorg.Med.Chem.Lett., 2008,18,923-928 and the J.Org.Chem. of intermediate (B), 2009,74, 1605–1610。
MS(ESI,pos.ion)m/z:498.2(M+1)；
1H NMR(400MHz,CDCl3)δ(ppm)6.96–6.92(m,2H),6.87–6.83(m,1H),6.83–6.79(m,1H),6.61–6.56 (m, 1H), 4.19 (s, 1H), 3.92 (s, 1H), 2.31-2.26 (m, 1H), 2.23 (d, J=7.0Hz, 1H), 1.56 (d, J=6.8Hz, 3H), 1.48 (d, J=6.8Hz, 3H), 1.21 (s, 12H), 0.94-0.89 (m, 2H), 0.85-0.79 (m, 2H)
Embodiment 1
(S) fluoro- 4- methyl -2- (((S) -2 of-N- (1- anocy clopropyls) -4-, 2, the fluoro- 1- of 2- tri- (4- (4'- (2- oxo-pyrrolidine -1- bases) -1', 3'- dihydros spiral shell [pentamethylene -1,2'- Indenes] -7'- bases) phenyl) ethyl) amino) pentanamide
Step 1:4'- (2- oxo-pyrrolidine -1- bases) -1', 3'- dihydros spiral shell [pentamethylene -1,2'- indenes] -7'- base triflates
To the addition iodo- 1' of 4'-, 3'- dihydros spiral shell [pentamethylene -1,2'- indenes] -7'- bases triflate (522mg, 1.77 in a pressure-resistant teat glass Mmol) [synthetic method referenced patent WO 2014082379, the 113-115 pages synthetic route of intermediate 1-8], 2-Pyrrolidone (151mg, 1.77 Mmol), potassium phosphate (0.75g, 3.54mmol), cuprous iodide (17mg, 0.09mmol) and dry toluene (10mL), add under nitrogen flowing Enter N, N'- dimethyl-ethylenediamines (8.0mg, 0.09mmol) are heated to 130 DEG C of reactions overnight after sealing.Reaction is finished, and is cooled to room temperature, plus Water quenching is gone out, and is extracted with ethyl acetate (30mL × 2), and organic phase is washed with saturated aqueous common salt (10mL), anhydrous sodium sulfate drying.Decompression is boiled off Solvent, crude product purifies (petroleum ether through silica gel column chromatography:Ethyl acetate (V/V)=5:1) faint yellow title compound as oil (606mg, 85%), is obtained. MS(ESI,pos.ion)m/z:404.1(M+1).
Step 2:(S) the fluoro- 4- methyl -2- of-N- (1- anocy clopropyls) -4- ((the fluoro- 1- of (S) -2,2,2- three (4- (4'- (2- oxo-pyrrolidine -1- bases) -1', 3'- dihydros spiral shell [ring penta Alkane -1,2'- indenes] -7'- bases) phenyl) ethyl) amino) pentanamide
To addition 4'- (2- oxo-pyrrolidine -1- bases) -1', 3'- dihydros spiral shell [pentamethylene -1,2'- indenes] -7'- bases triflate (430mg, 1.00 in bottle with two necks Mmol), the fluoro- 4- methyl -2- of (S)-N- (1- anocy clopropyls) -4- ((the fluoro- 1- of (S) -2,2,2- three (4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) Phenyl) ethyl) amino) pentanamide (497mg, 1.00mmol), (1,1'- double (diphenylphosphine) ferrocene) palladium chloride dichloromethane complex (67mg, 0.08mmol), wet chemical (1.5mL, 2mmol/L) and DMF (10mL), under nitrogen protection, are heated to 85 DEG C and react 3 hours. Reaction is finished, and is cooled to room temperature, is added water and is quenched, and is extracted with ethyl acetate (60mL × 2), organic phase washed with water (60mL × 2) and saturation Saline solution (60mL) is washed, anhydrous sodium sulfate drying.Decompression boils off solvent, and crude product purifies (dichloromethane through silica gel column chromatography:Ethyl acetate (V/V)=1:1) titled compound as white solid (0.42g, 68%), is obtained.
MS(ESI,pos.ion)m/z:625.3(M+1)；
1H NMR(400MHz,CDCl3) δ (ppm) 7.49 (s, 1H), 7.46 (d, J=8.2Hz, 2H), 7.40 (d, J=8.2Hz, 2H), 7.23 (d, J= 8.1Hz, 1H), 7.14 (d, J=8.1Hz, 1H), 4.18-4.10 (m, 1H), 3.84 (t, J=6.9Hz, 2H), 3.71-3.64 (m, 1H), 2.95 (s, 2H), 2.84 (s, 2H), 2.63 (t, J=8.0Hz, 2H), 2.30-2.20 (m, 2H), 1.71-1.57 (m, 8H), 1.51 (d, J=12.3Hz, 3H), (m, the 2H) of 1.45 (d, J=12.8Hz, 3H), 1.31-1.25 (m, 2H), 1.07-0.92
Embodiment 2
The fluoro- 4- methyl -2- of (2S)-N- (1- anocy clopropyls) -4- ((the fluoro- 1- of (1S) -2,2,2- three (4- (8- (2- oxo-pyrrolidine -1- bases) -1,2,3,4- tetrahydrochysene -1,4- methanonaphthalenes - 5- bases) phenyl) ethyl) amino) pentanamide
Step 1:5- methoxyl group -1,4- dihydro -1,4- methanonaphthalenes
To magnesium chips (600mg, 24.9mmol), one small iodine and anhydrous tetrahydro furan (10mL) is added in dry reaction bulb, backflow is installed Condenser pipe, and protected with nitrogen, after first adding the bromo- 1- of 2- fluoro- 3- methoxybenzenes (0.5g) initiation reactions, then by the other fluoro- 3- methoxies of the bromo- 1- of 2- It is rearmounted that base benzene (2.5g, 12.2mmol) and the 1,3- cyclopentadiene (1.05g.17.56mmol) of new distillation are dissolved in anhydrous tetrahydro furan (20mL) Slowly it is added dropwise in constant pressure funnel, keeps the micro- backflow of reaction system.Completion of dropping, reaction system continues heating reflux reaction 1 hour.Reaction It is quenched with saturated aqueous ammonium chloride (10mL) after cooling, is extracted with ethyl acetate (60mL × 2), organic phase saturated aqueous common salt (30mL) is washed Wash, anhydrous sodium sulfate drying.Decompression boils off solvent, and crude product purifies (petroleum ether wash-out), obtains colourless liquid title compound through silica gel column chromatography (1.43g, 56%).
MS(ESI,pos.ion)m/z:173.1(M+1).
Step 2：5- methoxyl group -1,2,3,4- tetrahydrochysene -1,4- methanonaphthalenes
To addition 5- methoxyl groups-Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-methanonaphthalene (0.82g, 0.47mmol), unifor (5.25g, 2.82mmol) in reaction bulb With sodium acetate (3.82g, 2.82mmol), tetrahydrofuran (30mL) is added, reactant mixture heated overnight at reflux under nitrogen atmosphere.React Cheng Hou, is cooled to room temperature, filters off solids, and filtrate decompression concentration obtains crude product and purifies (petroleum ether wash-out) through silica gel column chromatography, obtains colourless Liquid title compound (0.65g, 80%).
MS(ESI,pos.ion)m/z:175.1(M+1).
Step 3：The bromo- 8- methoxyl groups -1,2,3,4- tetrahydrochysenes -1,4- methanonaphthalenes of 5-
5- methoxyl group -1,2,3,4- tetrahydrochysenes-Isosorbide-5-Nitrae-methanonaphthalene (0.85g, 0.48mmol) are dissolved in anhydrous acetonitrile (20mL), are then added in batches at room temperature Enter NBS (0.93g, 0.52mmol), reacted at room temperature after adding 3 hours.Water (20mL) is added, and (80mL × 2) is extracted with dichloromethane, Organic phase is washed with saturated aqueous common salt (30mL), anhydrous sodium sulfate drying.Decompression boils off solvent, and crude product purifies (petroleum ether through silica gel column chromatography Wash-out), obtain weak yellow liquid title compound (0.96g, 83%).
MS(ESI,pos.ion)m/z:254.0(M+2).
Step 4：1- (8- methoxyl group -1,2,3,4- tetrahydrochysene -1,4- methanonaphthalene -5- bases) pyrrolidin-2-one
By bromo- 8- methoxyl group -1 of 5-, 2,3,4- tetrahydrochysenes-Isosorbide-5-Nitrae-methanonaphthalene (0.50g, 1.97mmol), pyrrolidin-2-one (0.37g, 3.95mmol), iodate Cuprous (0.037g, 0.20mmol) and potassium carbonate (0.54g, 3.95mmol) mix with dry toluene (8mL), and reaction bulb is protected with nitrogen, so After add N, N'- dimethyl -1,2- ethylenediamines (0.070g, 0.79mmol), reactant mixture is heated to 120 DEG C and reacts 15 hours.After the completion of reaction, Room temperature is cooled to, ethyl acetate (80mL) is added, is washed with saturated aqueous common salt (30mL × 2), anhydrous sodium sulfate drying.Decompression boils off solvent, Crude product purifies (petrol ether/ethyl acetate (V/V)=2/1) through silica gel column chromatography, obtains faint yellow title compound as oil (0.42g, 82%).
MS(ESI,pos.ion)m/z:258.1(M+1).
Step 5：1- (8- hydroxyl -1,2,3,4- tetrahydrochysene -1,4- methanonaphthalene -5- bases) pyrrolidin-2-one
To addition 1- (8- methoxyl group -1,2,3,4- tetrahydrochysene -1,4- methanonaphthalene -5- bases) pyrrolidin-2-ones (0.42g, 1.63mmol) and dichloromethane in two mouthfuls of bottles Alkane (20mL), nitrogen protection, reactant mixture is cooled to -20 DEG C, be slowly added dropwise Boron tribromide dichloromethane solution (3.3mL, 3.3mmol, 1mol/L), after dripping, reactant mixture continues to react 2.5 hours.It is carefully added into water (10mL) and reaction is quenched, and is extracted with dichloromethane (30mL × 2), organic phase is washed with saturated aqueous common salt (30mL), anhydrous sodium sulfate drying.Decompression boils off solvent, and crude product is through silica gel column chromatography Purifying (petrol ether/ethyl acetate (V/V)=1/1), obtains weak yellow liquid title compound (0.41g, 98%).
MS(ESI,pos.ion)m/z:244.1(M+1).
Step 6：8- (2- oxo-pyrrolidine -1- bases) -1,2,3,4- tetrahydrochysene -1,4- methanonaphthalene -5- base triflates
To addition 1- (8- hydroxyl -1,2,3,4- tetrahydrochysenes-Isosorbide-5-Nitrae-methanonaphthalene -5- bases) pyrrolidin-2-one (0.20g, 0.82mmol), pyridine (0.066 in two mouthfuls of bottles ML, 1.64mmol) and anhydrous methylene chloride (15mL), nitrogen protection, 0 DEG C is cooled to, trifluoromethanesulfanhydride anhydride (0.28g, 0.98mmol) is added dropwise, Then it is warmed to room temperature reaction 1 hour.Add water (10mL) that reaction is quenched, and (30mL × 2) are extracted with dichloromethane, organic phase saturated common salt Water (30mL) is washed, anhydrous sodium sulfate drying.Decompression boils off solvent, and crude product purifies (petrol ether/ethyl acetate (V/V) through silica gel column chromatography =1/1), obtain weak yellow liquid title compound (0.22g, 71%).
MS(ESI,pos.ion)m/z:376.1(M+1).
Step 7：The fluoro- 4- methyl -2- of (2S)-N- (1- anocy clopropyls) -4- ((the fluoro- 1- of (1S) -2,2,2- three (4- (8- (2- oxo-pyrrolidine -1- bases) -1,2,3,4- tetrahydrochysenes - 1,4- methanonaphthalene -5- bases) phenyl) ethyl) amino) pentanamide
To addition 8- (2- oxo-pyrrolidine -1- bases) -1,2,3,4- tetrahydrochysene -1,4- methanonaphthalene -5- bases triflates (375mg, 1.00 in bottle with two necks Mmol), the fluoro- 4- methyl -2- of (S)-N- (1- anocy clopropyls) -4- ((the fluoro- 1- of (S) -2,2,2- three (4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) Phenyl) ethyl) amino) pentanamide (497mg, 1.00mmol), (1,1'- double (diphenylphosphine) ferrocene) palladium chloride dichloromethane complex (67mg, 0.08mmol), wet chemical (1.5mL, 2mmol/L) and DMF (10mL), under nitrogen protection, are heated to 85 DEG C and react 3 hours. Reaction is finished, and is cooled to room temperature, is added water and is quenched, and is extracted with ethyl acetate (60mL × 2), organic phase washed with water (60mL × 2) and saturation Saline solution (60mL) is washed, anhydrous sodium sulfate drying.Decompression boils off solvent, and crude product purifies (dichloromethane/ethyl acetate through silica gel column chromatography (V/V) titled compound as white solid (0.39g, 65%)=1/1), is obtained.
MS(ESI,pos.ion)m/z:597.2(M+1)；
1H NMR(400MHz,CDCl3) δ (ppm) 7.49 (s, 1H), 7.46 (d, J=8.2Hz, 2H), 7.40 (d, J=8.2Hz, 2H), 7.23 (d, J= 8.1Hz, 1H), 7.14 (d, J=8.1Hz, 1H), 4.18-4.10 (m, 1H), 3.84 (s, 3H), 3.83-3.79 (m, 1H), 3.77-3.69 (m, 2H), 3.62 (s, 1H), 3.33 (s, 1H), 2.60 (t, J=8.1Hz, 2H), 2.30-2.15 (m, 2H), 1.92 (dd, J=7.8,3.6Hz, 2H), 1.51 (d, J= 12.3Hz, 3H), 1.45 (d, J=12.8Hz, 3H), 1.33-1.22 (m, 6H), 1.07-0.92 (m, 2H)
Embodiment 3
(S) fluoro- 4- methyl -2- (((S) -2 of-N- (1- anocy clopropyls) -4-, 2, the fluoro- 1- of 2- tri- (4- (4'- (2- oxo-pyrrolidine -1- bases) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- Indenes] -7- bases) phenyl) ethyl) amino) pentanamide
Step 1：7- methoxyl group -1- methylene -2,3- dihydro -1H- indenes
To addition potassium tert-butoxide (3.50g, 30.86mmol), methyltriphenylphosphonium iodide phosphorus (13.7g, 33.9mmol) and anhydrous tetrahydrochysene in reaction bulb Furans (200mL), and protected with nitrogen, react 1 hour at room temperature.Then by 7- methoxyl group -2,3- dihydro -1H- 1-Indanones (5.0g, 30.86 Mmol anhydrous tetrahydro furan (20mL) solution) is added drop-wise in reaction bulb, and completion of dropping, reactant mixture is stirred at room temperature overnight.Reaction Complete, add water (80mL) be quenched, extracted with ethyl acetate (80mL × 3), organic phase washed with saturated aqueous common salt (60mL), anhydrous sulphur Sour sodium is dried.Decompression boils off solvent, and crude product purifies (dichloromethane/petroleum ether (V/V)=1/100), obtains colourless liquid title through silica gel column chromatography Compound (3.80g, 77%).
MS(ESI,pos.ion)m/z:161.1(M+1).
Step 2：7'- methoxyl groups -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes]
To in dry reaction bulb, anhydrous DCM (80mL) and diethyl zinc (71.3mL, 71.28mmol, 1.0mol/L), reaction system are added - 20 DEG C are cooled to, trifluoroacetic acid (5.2mL, 71.28mmol) is added dropwise.Add, reactant mixture stirring reaction is added dropwise after 1 hour at 0 DEG C Diiodomethane (5.8mL, 71.28mmol), adds and continues to react 40 minutes at 0 DEG C, by 7- methoxyl group -1- methylene -2,3- dihydro -1H- indenes (3.8 G, 23.76mmol) anhydrous methylene chloride (20mL) solution be added drop-wise in reaction bulb, reactant mixture is raised to and is stirred at room temperature 3 hours.React Into to addition saturation NH in reactant mixture4Cl solution (50mL), is quenched with dichloromethane (80mL × 3) and taken, with saturated brine (80mL × 2) Washing, anhydrous sodium sulfate drying.Filtering, after filtrate decompression concentration, crude product column chromatography purifies (petroleum ether/dichloromethane (V/V)=100/1), Obtain weak yellow liquid title compound (8.3g, 67%).
MS (ESI, pos.ion) m/z:175.1(M+1).
Step 3：Bromo- 7'- methoxyl groups -2', the 3'- dihydro spiral shells of 4'- [cyclopropane -1,1'- indenes]
7'- methoxyl groups -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] (2.5g, 14.35mmol) is dissolved in anhydrous acetonitrile (30mL), is then divided at room temperature Criticize and add NBS (2.76g, 15.5mmol), reacted at room temperature after adding 3 hours.Water (40mL) is added, and (80mL is extracted with dichloromethane × 2), organic phase is washed with saturated aqueous common salt (30mL), anhydrous sodium sulfate drying.Decompression boils off solvent, and crude product purifies (stone through silica gel column chromatography Oily ether wash-out), obtain weak yellow liquid title compound (2.9g, 80%).
MS (ESI, pos.ion) m/z:254.0(M+2).
Step 4：1- (7'- methoxyl groups -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -4'- bases) pyrrolidin-2-one
By bromo- 7'- methoxyl groups -2', the 3'- dihydro spiral shells of 4'- [cyclopropane -1,1'- indenes] (0.50g, 2.0mmol), pyrrolidin-2-one (0.37g, 3.95mmol), iodine Change cuprous (0.037g, 0.20mmol) and potassium carbonate (0.54g, 3.95mmol) mix with dry toluene (8mL), reaction bulb is protected with nitrogen, N is subsequently adding, N'- dimethyl -1,2- ethylenediamines (0.070g, 0.79mmol), reactant mixture is heated to 120 DEG C and reacts 15 hours.Reaction is completed Afterwards, room temperature is cooled to, ethyl acetate (80mL) is added, is washed with saturated aqueous common salt (30mL × 2), anhydrous sodium sulfate drying.Decompression boils off molten Agent, crude product purifies (petrol ether/ethyl acetate (V/V)=2/1) through silica gel column chromatography, obtains faint yellow title compound as oil (0.43g, 85%). MS(ESI,pos.ion)m/z:258.1(M+1).
Step 5：1- (7'- hydroxyls -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -4'- bases) pyrrolidin-2-one
To addition 1- (7'- methoxyl groups -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -4'- bases) pyrrolidin-2-one (0.43g, 1.63mmol) and two in two mouthfuls of bottles Chloromethanes (20mL), nitrogen protection, reactant mixture is cooled to -20 DEG C, be slowly added dropwise Boron tribromide dichloromethane solution (3.3mL, 3.3mmol, 1mol/L), after dripping, reactant mixture continues to react 2.5 hours, is carefully added into water (10mL) and reaction is quenched, and extracted with dichloromethane (30mL × 2), organic phase is washed with saturated aqueous common salt (30mL), anhydrous sodium sulfate drying.Decompression boils off solvent, and crude product is through silica gel column chromatography Purifying (petrol ether/ethyl acetate (V/V)=1/1), obtains weak yellow liquid title compound (0.41g, 98%).
MS(ESI,pos.ion)m/z:244.1(M+1).
Step 6：4'- (2- oxo-pyrrolidine -1- bases) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -7'- base triflates
To addition 1- (7'- hydroxyls -2', 3'- dihydro spiral shell [cyclopropane -1,1'- indenes] -4'- bases) pyrrolidin-2-one (0.40g, 1.64mmol), pyridine in two mouthfuls of bottles (0.132mL, 3.3mmol) and anhydrous methylene chloride (15mL), nitrogen protection, is cooled to 0 DEG C, and trifluoromethanesulfanhydride anhydride (0.56g, 2.0 is added dropwise Mmol), then it is warmed to room temperature reaction 1 hour.Add water (10mL) that reaction is quenched, and (30mL × 2) are extracted with dichloromethane, organic phase is used Saturated aqueous common salt (30mL) is washed, anhydrous sodium sulfate drying.Decompression boils off solvent, and crude product purifies (petroleum ether/acetic acid second through silica gel column chromatography Ester (V/V)=1/1), obtain weak yellow liquid title compound (0.43g, 70%).
MS(ESI,pos.ion)m/z：376.1(M+1)；
Step 7：(S) the fluoro- 4- methyl -2- of-N- (1- anocy clopropyls) -4- ((the fluoro- 1- of (S) -2,2,2- three (4- (4'- (2- oxo-pyrrolidine -1- bases) -2', 3'- dihydros spiral shell [ring third Alkane -1,1'- indenes] -7- bases) phenyl) ethyl) amino) pentanamide
To in bottle with two necks add 4'- (2- oxo-pyrrolidine -1- bases) -2', 3'- dihydros spiral shell [cyclopropane -1,1'- indenes] -7'- bases triflate (375mg, 1.00mmol), the fluoro- 4- methyl -2- of (S)-N- (1- anocy clopropyls) -4- ((the fluoro- 1- of (S) -2,2,2- three (4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- Base) phenyl) ethyl) amino) pentanamide (497mg, 1.00mmol), (1,1'- double (diphenylphosphine) ferrocene) palladium chloride dichloromethane complex (67 Mg, 0.08mmol), wet chemical (1.5mL, 2mmol/L) and DMF (10mL) under nitrogen protection, are heated to 85 DEG C of reactions 3 Hour.Reaction is finished, and is cooled to room temperature, is added water and is quenched, and is extracted with ethyl acetate (60mL × 2), organic phase washed with water (60mL × 2) With saturated aqueous common salt (60mL) washing, anhydrous sodium sulfate drying.Decompression boils off solvent, and crude product purifies (dichloromethane/second through silica gel column chromatography Acetoacetic ester (V/V)=1/1), obtain titled compound as white solid (0.4g, 68%).
MS(ESI,pos.ion)m/z:597.2(M+1)；
1H NMR(400MHz,CDCl3) δ (ppm) 7.49 (s, 1H), 7.46 (d, J=8.2Hz, 2H), 7.40 (d, J=8.2Hz, 2H), 7.23 (d, J= 8.1Hz, 1H), 7.14 (d, J=8.1Hz, 1H), 4.18-4.10 (m, 1H), 3.84 (s, 3H), 3.83-3.79 (m, 1H), 3.77-3.69 (m, 2H), 3.62 (s, 1H), 3.33 (s, 1H), 2.60 (t, J=8.1Hz, 2H), 2.45 (t, J=8.1Hz, 2H), 2.10-1.96 (m, 4H), 1.92 (dd, J=7.8, 3.6Hz,2H),1.07–0.92(m,2H),1.14–1.08(m,2H),0.73–0.68(m,2H),0.56-0.48(m,2H).
Embodiment 4
The fluoro- 4- methyl -2- of (2S)-N- (1- anocy clopropyls) -4- ((the fluoro- 1- of (1S) -2,2,2- three (4- (8- (mesyl) -1; 2; 3,4- tetrahydrochysene -1,4- methanonaphthalene -5- bases) benzene Base) ethyl) amino) pentanamide
Step 1：5- methoxyl groups -8- (mesyl) -1,2,3,4- tetrahydrochysene -1,4- methanonaphthalenes
By bromo- 8- methoxyl group -1 of 5-, 2,3,4- tetrahydrochysenes-Isosorbide-5-Nitrae-methanonaphthalene (0.50g, 1.97mmol), iodate Asia ketone (75mg, 0.39mmol) and L- dried meat ammonia Sour sodium (54mg, 0.39mmol) mixes with anhydrous DMSO (5mL), reaction bulb with nitrogen protect, be subsequently adding methyl sulfinic acid sodium (0.61g, 6.0mmol), reactant mixture be heated to 90 DEG C react 24 hours.After the completion of reaction, room temperature is cooled to, adds ethyl acetate (80mL), used Saturated aqueous common salt (30mL × 2) is washed, anhydrous sodium sulfate drying.Decompression boils off solvent, and crude product purifies (petroleum ether/acetic acid through silica gel column chromatography Ethyl ester (V/V)=1/1), obtain faint yellow title compound as oil (0.30g, 62%).
MS(ESI,pos.ion)m/z:253.1(M+1).
Step 2：8- (mesyl) -1,2,3,4- tetrahydrochysene -1,4- methanonaphthalene -5- alcohol
To addition 5- methoxyl groups -8- (mesyl) -1,2,3,4- tetrahydrochysene -1,4- methanonaphthalenes (0.3g, 1.22mmol) and dichloromethane (20 in two mouthfuls of bottles ML), nitrogen protection, reactant mixture is cooled to -20 DEG C, and the dichloromethane solution (3.3mL, 3.3mmol, 1mol/L) of Boron tribromide is slowly added dropwise, After dripping, reactant mixture continues to react 2.5 hours.It is carefully added into water (10mL) and reaction is quenched, and (30mL × 2) is extracted with dichloromethane, Organic phase is washed with saturated aqueous common salt (30mL), anhydrous sodium sulfate drying.Decompression boils off solvent, and crude product purifies (petroleum ether through silica gel column chromatography / ethyl acetate (V/V)=1/1), obtain weak yellow liquid title compound (0.28g, 98%).
MS(ESI,pos.ion)m/z:239.1(M+1).
Step 3：8- (mesyl) -1,2,3,4- tetrahydrochysene -1,4- methanonaphthalene -5- base triflates
To addition 8- (mesyl) -1,2,3,4- tetrahydrochysenes-Isosorbide-5-Nitrae-methanonaphthalene -5- alcohol (0.28g, 1.2mmol), pyridine (0.066mL, 1.64 in two mouthfuls of bottles Mmol) and anhydrous methylene chloride (15mL), nitrogen protection, is cooled to 0 DEG C, trifluoromethanesulfanhydride anhydride (0.5g, 1.79mmol) is added dropwise, then It is warmed to room temperature reaction 1 hour.Add water (10mL) that reaction is quenched, and (30mL × 2) are extracted with dichloromethane, organic phase saturated aqueous common salt (30 ML) wash, anhydrous sodium sulfate drying.Decompression boils off solvent, and crude product purifies (petrol ether/ethyl acetate (V/V)=1/1) through silica gel column chromatography, Obtain weak yellow liquid title compound (0.33g, 75%).
MS(ESI,pos.ion)m/z:371.1(M+1).
Step 4：The fluoro- 4- methyl -2- of (2S)-N- (1- anocy clopropyls) -4- ((the fluoro- 1- of (1S) -2,2,2- three (4- (8- (mesyl) -1,2,3,4- tetrahydrochysene -1,4- methanonaphthalenes - 5- bases) phenyl) ethyl) amino) pentanamide
To in bottle with two necks add 8- (mesyl) -1,2,3,4- tetrahydrochysenes -1,4- methanonaphthalenes -5- bases triflate (375mg, 1.00mmol), (S) the fluoro- 4- methyl -2- of-N- (1- anocy clopropyls) -4- ((the fluoro- 1- of (S) -2,2,2- three (4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) phenyl) second Base) amino) pentanamide (497mg, 1.00mmol), (1,1'- double (diphenylphosphine) ferrocene) palladium chloride dichloromethane complex (67mg, 0.08 Mmol), wet chemical (1.5mL, 2mmol/L) and DMF (10mL), under nitrogen protection, are heated to 85 DEG C and react 3 hours.Instead Should finish, be cooled to room temperature, add water and be quenched, be extracted with ethyl acetate (60mL × 2), organic phase washed with water (60mL × 2) and saturated common salt Water (60mL) is washed, anhydrous sodium sulfate drying.Decompression boils off solvent, and crude product purifies (dichloromethane/ethyl acetate (V/V) through silica gel column chromatography =1/1), obtain titled compound as white solid (0.41g, 70%).
MS(ESI,pos.ion)m/z:592.2(M+1)；
1H NMR(400MHz,CDCl3) δ (ppm) 7.49 (s, 1H), 7.46 (d, J=8.2Hz, 2H), 7.40 (d, J=8.2Hz, 2H), 7.23 (d, J= 8.1Hz, 1H), 7.14 (d, J=8.1Hz, 1H), 4.18-4.10 (m, 1H), 3.83-3.79 (m, 1H), 3.77-3.69 (m, 2H), 3.35 (s, 3H), 2.60 (t, J=8.1Hz, 2H), 2.30-2.15 (m, 2H), 1.51 (d, J=12.3Hz, 3H), 1.45 (d, J=12.8Hz, 3H), 1.33-1.22 (m, 6H),1.07–0.92(m,2H).
Embodiment 5
(S) fluoro- 4- methyl -2- (((S) -2 of-N- (1- anocy clopropyls) -4-, 2, the fluoro- 1- of 2- tri- (4- ((E) -8- (oximido) -5,6,7,8- naphthane -2- bases) phenyl) ethyl) amino) Pentanamide
Step 1：(E) bromo- 3,4- dihydronaphthalene -1 (2H) the -one oximes of -7-
To addition bromo- 3, the 4- dihydros -2H-1- naphthalenones (3.0g, 13.3mmol) of 7-, hydroxylamine hydrochloride (1.1g, 16mmol), sodium acetate (1.31 in reaction bulb G, 16mmol) and ethanol (60mL), reactant mixture is heated to reflux 2 hours.Reaction is completed, and be concentrated under reduced pressure solvent, adds water (20mL) With ethyl acetate (60mL), divide liquid, organic phase is washed with saturated aqueous common salt (60mL), anhydrous sodium sulfate drying.Decompression boils off solvent, obtains Pale solid title compound (3.0g, 95%).
MS(ESI,pos.ion)m/z:242.0(M+2).
Step 2：(S) fluoro- 4- methyl -2- (((S) -2 of-N- (1- anocy clopropyls) -4-, the fluoro- 1- of 2,2- tri- (4- ((E) -8- (oximido) -5,6,7,8- naphthane -2- bases) phenyl) second Base) amino) pentanamide
To addition bromo- (2H) -one of 3,4- dihydronaphthalene -1 oximes (240mg, 1.0mmol) of (E) -7-, (S)-N- (1- anocy clopropyls) -4- methyl in bottle with two necks - 2- ((the fluoro- 1- of (S) -2,2,2- three (4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) phenyl) ethyl) amino) pentanamide (534mg, 1.12 Mmol), (1,1'- double (diphenylphosphine) ferrocene) palladium chloride dichloromethane complex (67mg, 0.08mmol), wet chemical (1.5mL, 2 Mmol/L) and DMF (10mL), under nitrogen protection, it is heated to 85 DEG C and reacts 3 hours.Reaction is finished, and is cooled to room temperature, is added water and is quenched, Extracted with ethyl acetate (60mL × 2), organic phase washed with water (60mL × 2) and saturated aqueous common salt (60mL) are washed, anhydrous sodium sulfate drying. Filtering, decompression boils off solvent, and crude product purifies (dichloromethane/ethyl acetate (V/V)=1/1), obtains white solid title compound through silica gel column chromatography Thing (0.34g, 65%).
MS(ESI,pos.ion)m/z:531.2(M+1)；
1H NMR(400MHz,CDCl3) δ (ppm) 7.94 (d, J=0.9Hz, 1H), 7.40 (dd, J=8.4,1.2Hz, 1H), 7.15 (d, J=8.1Hz, 1H),6.96-6.92(m,2H),6.87-6.83(m,1H),6.83-6.79(m,1H),6.61-6.56(m,1H),4.19(s,1H),3.92(s,1H), 2.68-2.61 (m, 4H), 2.31-2.26 (m, 1H), 2.23 (d, J=7.0Hz, 1H), 1.78-1.68 (m, 2H), 1.56 (d, J=6.8Hz, 3H), 1.48 (d, J=6.8Hz, 3H), 0.94-0.89 (m, 2H), 0.85-0.79 (m, 2H)
Embodiment 6-7
Using corresponding raw material, the compound of embodiment 6-7 is prepared according to the method described in synthetic schemes of the present invention or embodiment 1-5, specifically Characterize data is as follows：
The pharmacological evaluation method of testing of biological Examples cathepsin
The external inhibitory activity experimental technique of cathepsin K：
With 45000 times of enzyme working solutions of dilution, 10 μM of Z-Phe-Arg-AMC is used as substrate.According to the experiment condition for having optimized, 15 are used Microlitre reaction system, after 25 DEG C of test compound and enzyme are incubated 15 minutes, determines the dynamics slope in reaction at 25 DEG C 15 minutes, asks calculation Go out IC of the compound to human cathepsin K50Value.
The external inhibitory activity experimental technique of cathepsin B：
Using the Cathepsin B of 0.01ng/ μ L as enzyme reaction final concentration, using final concentration of 10 μM of Z-Phe-Arg-AMC as substrate, plus Enter to 25 DEG C of test compound and enzyme in the reaction system after being incubated 15 minutes, determine the kinetic parameter reacted at 25 DEG C in 10 minutes, ask calculation Go out IC of the test compound to human cathepsin B50Value.
The external inhibitory activity experimental technique of cathepsin L：
Using the Cathepsin L of 0.01ng/ μ L as enzyme reaction final concentration, final concentration of 10 μM of Z-Phe-Arg-AMC as substrate, plus Enter to 25 DEG C of test compound and enzyme the reaction system after being incubated 15 minutes, determine the kinetic parameter reacted at 25 DEG C in 10 minutes, ask and calculate IC of the test compound to human cathepsin L50Value.
The external inhibitory activity experimental technique of cathepsin S：
Using the Cathepsin S of 0.25ng/ μ L as enzyme reaction final concentration, final concentration of 20 μM of Z-VVR-AMC is added to as substrate Reaction system after test compound and the incubation 15 minutes of 25 DEG C of enzyme, determines the kinetic parameter reacted at 25 DEG C in 10 minutes, asks and calculates candidate IC of the compound to human cathepsin S50Value.
The external activity test data of the compounds of this invention of table 1
Conclusion
Knowable to upper table data, the compounds of this invention has preferable inhibitory activity to cathepsin K, and to cathepsin B, histone The inhibitory activity of enzyme L and cathepsin S is poor, shows selectivity very high.Due to the high selectivity of the compounds of this invention, reduce because changing The side effect of missing the target that compound is selective and causes, dredges as cathepsin K inhibitor so as to substantially increase the compounds of this invention for treating sclerotin The possibility of loose disease drug exploitation.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specific example " or " some show It is real that the description of example " etc. means that the specific features, structure, material or the feature that are described with reference to the embodiment or example are contained in of the invention at least one In applying example or example.In this manual, the schematic representation to above-mentioned term is necessarily directed to identical embodiment or example.And, retouch Specific features, structure, material or the feature stated can in an appropriate manner be combined in any one or more embodiments or example.Additionally, not In the case of conflicting, those skilled in the art can be by the different embodiments or example described in this specification and different embodiments or example Feature be combined and combine.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is exemplary, it is impossible to be interpreted as right Limitation of the invention, one of ordinary skill in the art can be changed to above-described embodiment, change, replacing and modification within the scope of the invention.

Claims (10)

1. a kind of compound, it is compound shown in formula (I), or the stereoisomer of compound shown in formula (I), geometric isomer, dynamic isomer, Nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Wherein,
R1It is H, D, F, Cl or Br；
Ring E is 3-8 former molecular monocycle carbocyclic ring, 5-10 former molecular spiral shell carbon is bicyclic, the individual former molecular bridge carbon of 5-10 is bicyclic, 3-8 Individual former molecular monocyclic heterocycles, 5-10 former molecular miscellaneous bicyclic, the 5-10 former molecular bridge of spiral shell is miscellaneous bicyclic or 5-6 original is molecular miscellaneous Aromatic ring；Wherein, described monocycle carbocyclic ring, spiral shell carbon is bicyclic, bicyclic bridge carbon, monocyclic heterocycles, the miscellaneous bicyclic, bridge of spiral shell is miscellaneous bicyclic and hetero-aromatic ring is optionally independent Ground is by one or more R3Replaced；
Each R2It independently is halogen, cyano group, nitro, halo C1-4Alkyl, C3-8Cycloalkyl, 3-8 former molecular heterocyclic radical, C6-10Aryl, 5-10 former molecular heteroaryl ,-SR4a,-S (=O) R4a,-S (=O)2R4a,-C (=O) R4b,-C (=O) OR4c、-OR4c、-NR4dR4eOr =NR4f；Wherein, described alkyl, haloalkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl are selected from oxygen by one or more individually optionally Generation (=O), cyano group, nitro, hydroxyl, amino, halogen, C1-4Alkyl, halo C1-4Alkyl, C1-4Alkoxy or C1-4The substitution of alkyl amino Base is replaced；
N is 1,2,3 or 4；
Wherein, each R3It independently is H, oxo (=O), halogen, hydroxyl, cyano group, nitro, C1-4Alkyl, halo C1-4Alkyl, C1-4Alcoxyl Base, amino or C1-4Alkyl amino；
Each R4aAnd R4bIt independently is H, hydroxyl, C1-4Alkyl, halo C1-4Alkyl, C1-4Alkoxy, amino or C1-4Alkyl amino；
Each R4c、R4dAnd R4eIt independently is H, C1-4Alkyl, halo C1-4Alkyl, C1-4Alkanoyl or C1-4Alkyl sulphonyl；
Each R4fIt independently is H, hydroxyl, cyano group, C1-4Alkyl or halo C1-4Alkyl.
2. compound according to claim 1, wherein,
Ring E is 5-6 former molecular monocycle carbocyclic ring, 7-10 former molecular spiral shell carbon is bicyclic, the individual former molecular bridge carbon of 7-10 is bicyclic, 5-6 Individual former molecular monocyclic heterocycles, 7-10 former molecular miscellaneous bicyclic, the 7-10 former molecular bridge of spiral shell is miscellaneous bicyclic or 5-6 original is molecular miscellaneous Aromatic ring；Wherein, described monocycle carbocyclic ring, spiral shell carbon is bicyclic, bicyclic bridge carbon, monocyclic heterocycles, the miscellaneous bicyclic, bridge of spiral shell is miscellaneous bicyclic and hetero-aromatic ring is each independent Ground is by one or more R3Replaced；
Wherein, each R3It independently is H, oxo (=O), fluorine, chlorine, bromine, hydroxyl, cyano group, nitro, methyl, ethyl, difluoromethyl, three Methyl fluoride, methoxyl group, amino, methylamino or dimethylamino.
3. compound according to claim 2, wherein,
Ring E is following subformula：
Wherein, each X1、X2、Y1And Y3It independently is CH2, O, S, S (=O), S (=O)2Or NH；
Each Y2And Y4It independently is CH or N；
Each R3It independently is H, oxo (=O), fluorine, methyl or ethyl；
T is 1 or 2；
E is 0 or 1；
F is 1,2 or 3；
Each n1 and r independently are 0,1,2 or 3.
4. compound according to claim 1, wherein,
Each R2Independently be fluorine, chlorine, bromine, cyano group, nitro, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, It is Oxyranyle, tetrahydrofuran base, pyrrolidinyl, imidazolinyl, piperidyl, piperazinyl, morpholinyl, phenyl, pyrrole radicals, pyridine radicals, phonetic Piperidinyl ,-S (=O)2R4a,-C (=O) R4b,-C (=O) OR4c、-OR4c、-NR4dR4eOr=NR4f, wherein, described difluoromethyl, cyclopropyl, Cyclobutyl, cyclopenta, cyclobutyl, Oxyranyle, tetrahydrofuran base, pyrrolidinyl, imidazolinyl, piperidyl, piperazinyl, morpholinyl, Phenyl, pyrrole radicals, pyridine radicals and pyrimidine radicals individually optionally by one or more be selected from oxo (=O), cyano group, nitro, hydroxyl, amino, fluorine, The substitution base of chlorine, bromine, methyl, trifluoromethyl, methoxyl group, methylamino or dimethylamino is replaced；
Each R4aAnd R4bIt independently is H, hydroxyl, methyl, ethyl, trifluoromethyl, methoxyl group, amino, methylamino or dimethylamino；
Each R4c、R4dAnd R4eIt independently is H, methyl, ethyl, trifluoromethyl, methylacyl or methyl sulphonyl；
Each R4fIt independently is H, hydroxyl, cyano group, methyl, ethyl or trifluoromethyl.
5. compound according to claim 1, wherein, ring E is following subformula：
Each R2Independently be fluorine, cyano group, nitro, difluoromethyl, trifluoromethyl, tetrahydrofuran base, pyrrolidinyl, imidazolinyl, piperidyl, Piperazinyl, morpholinyl ,-S (=O)2CH3,-C (=O) CH3,-C (=O) OH ,-C (=O) OCH3、-OH、-OCH3、-NH2Or=NOH, its In, described tetrahydrofuran base, pyrrolidinyl, imidazolinyl, piperidyl, piperazinyl and morpholinyl are individually optionally by one or more oxos (=O) Group is replaced；
Each R3It independently is H, oxo (=O), methyl or methoxy；
F is 1,2 or 3；
Each n1 and r independently are 0,1,2 or 3.
6. compound according to claim 1, its structure for including one of：
Or its stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, Hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug.
7. a kind of pharmaceutical composition, comprising the compound described in claim 1-6 any one；It is further comprising pharmaceutically acceptable carrier, tax At least one of shape agent, diluent, assistant agent and medium.
8. purposes of the pharmaceutical composition described in the compound or claim 7 described in claim 1-6 any one in medicine is prepared, wherein, institute Medicine is stated for the activity of inhibiting cathepsin；Wherein, the cathepsin is cathepsin K.
9. purposes of the pharmaceutical composition described in the compound or claim 7 described in claim 1-6 any one in medicine is prepared, wherein, institute State medicine lost for processing, treating or mitigating the osteoporosis of patient, osteitis deformans, increases of bone update abnormal, periodontal disease, tooth, fractured, Rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, ostosis not exclusively, metastatic bone disease, malignant hypercalcemia or multiple Myeloma bone disease.
10. purposes of the pharmaceutical composition described in the compound or claim 7 described in claim 1-6 any one in medicine is prepared, wherein, institute Medicine is stated for processing, treating or mitigating the Cathepsin dependent diseases of patient.
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Citations (4)

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EP1586564B1 (en) * 2003-01-21 2012-11-28 Ono Pharmaceutical Co., Ltd. 8-azaprostaglandin derivatives and medicinal uses thereof
CN103086923A (en) * 2013-01-21 2013-05-08 吉林大学 Hydrazine cathepsin K inhibitor and application thereof in treating osteoporosis
WO2015120580A1 (en) * 2014-02-11 2015-08-20 Merck Sharp & Dohme Corp. Cathepsin cysteine protease inhibitors

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EP1586564B1 (en) * 2003-01-21 2012-11-28 Ono Pharmaceutical Co., Ltd. 8-azaprostaglandin derivatives and medicinal uses thereof
CN101061093A (en) * 2004-11-23 2007-10-24 默克弗罗斯特加拿大有限公司 Cathepsin cysteine protease inhibitors
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