CN106928113A - Cathepsin K inhibitor and application thereof - Google Patents

Abstract

The present invention relates to cathepsin K inhibitor and application thereof；In particular it relates to a class is used to treat or prevent the compound and its pharmaceutical composition of tissue protease dependency illness, 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 inhibitors and uses thereof

Technical Field

The invention belongs to the field of medicine. The present invention relates to a class of compounds and pharmaceutical compositions thereof for the treatment or prevention of cathepsin dependent disorders. These compounds and compositions comprising these compounds are useful as bone resorption inhibitors for the treatment of related diseases.

Background

Osteoporosis is a common and frequently occurring disease in the elderly, especially in menopausal and postmenopausal women. With the change of disease spectrum in the present generation, WHO ranks osteoporosis as one of three diseases of middle-aged and old people, and the disease is 7 th in common diseases. Approximately 50% of women aged 50 years and 20% of men suffer from osteoporosis-induced fractures. At present, common medicines for treating osteoporosis comprise bone absorption resisting medicines, bone formation promoting medicines, double-action medicines of the first two medicines, biological medicines or other medicines, but most of the medicines have large side effects, and novel therapeutic medicines are in urgent need.

Cathepsin (Cathepsin) is a major member of the cysteine protease family, more than 20 of which have been found in the biological world, and 11 of which are present in humans, and is closely associated with a variety of major diseases such as human tumors, osteoporosis, and arthritis. The major subtypes of cathepsin are cathepsin B, F, H, L, K, S, W and Z. Cathepsin S is mainly expressed in antigen presenting cells and is considered to be an important target for the regulation of immune responses due to the regulation of antigen presentation by cathepsin S. Cathepsin L is involved in many specific physiological processes such as prohormone activation, antigen presentation, development of tissues and organs, and the like. Cathepsin B is distributed in liver, spleen, kidney, bone, nerve cell, interstitial fibroblast, macrophage, etc., is stored in lysosome in the form of zymogen, and is involved in many special physiological processes such as prohormone activation, antigen presentation, tissue organ development, etc.

Cathepsin K (which is also known by the abbreviation cat K) is also known as cathepsin O and cathepsin O2. Cathepsin K is selectively expressed in a large amount in osteoclasts, and the physiological action substrate of the cathepsin K is type I collagen with the content of 95 percent in organic bone matrix, and in addition, the cathepsin K can degrade osteopontin and osteopontin in the bone matrix, is cysteine protease with the highest expression level and the highest bone-dissolving activity in osteoclasts, has the capability of degrading osteogenic collagen far higher than that of various enzymes, is a key enzyme in the bone resorption process, and is a hot spot in the research of osteoporosis in recent years. In the human body, cathepsin K is important and extremely complex for the role of physiological processes. The FDA currently does not approve any one of the anti-cathepsin K inhibitors, but there are related cathepsin K inhibitors that are undergoing clinical studies.

The Odanacatibib of Musacodon, which is the most advanced research at present, has better inhibition effect on cathepsin S and undesirable selective inhibition effect on various cathepsins, so that certain disconcerting side effect signs also appear in clinical research. In order to avoid the side effects of broad-spectrum inhibition, which are not clinical, the design and synthesis of some cathepsin K inhibitors with high selectivity are still needed.

Summary of The Invention

The present invention relates to a class of compounds or pharmaceutical compositions thereof for the treatment or prevention of cathepsin dependent disorders. The compound or the pharmaceutical composition has good inhibition activity on cathepsin K, has poor inhibition activity on other subtypes such as cathepsin B, L, cathepsin S and the like, and shows very high selectivity.

Cathepsin K is a key enzyme in the bone resorption process and is a hot target in the research of osteoporosis diseases in recent years, but due to the existence of various subtypes of cathepsin, especially, cathepsin B, L and S have high homology with cathepsin K and have very important physiological effects in human bodies, cathepsin K inhibitors can easily cause off-target effect in human bodies and generate serious side effects. Therefore, how to improve the selectivity of cathepsin K inhibitors is a difficult problem that must be overcome in the development of such inhibitors. The compound has better inhibition activity on cathepsin K, has poorer inhibition effect on cathepsin B, L and cathepsin S with high homology, shows high selectivity, and reduces off-target side effect caused by compound selectivity, thereby greatly improving the possibility of developing medicaments for treating osteoporosis as cathepsin K inhibitors.

The invention provides a compound which is a compound shown in a formula (I), or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown in the formula (I),

wherein R is¹、R²、R³、R⁴、R⁵M and n have the meanings described in the present invention.

In some embodiments, each R is¹And R²Independently is H or C_1-4Alkyl, wherein said alkyl is optionally substituted with one or more halogen atoms;

or, R¹、R²And the carbon atoms connected with the carbon atoms form a saturated carbocycle or heterocycle consisting of 3-8 atoms, wherein the carbocycle or heterocycle is independently and optionally substituted by one or more selected from H, halogen and C_1-4Alkyl or halo C_1-4Alkyl substituents.

In some embodiments, each R is¹And R²Independently H, methyl, ethyl, propyl or butyl, wherein said methyl, ethyl, propyl and butyl groups independently are optionally substituted with one or more fluorine atoms;

or, R¹、R²Together with the carbon atom to which they are attached form 5-7 atomsA saturated carbocyclic ring of a subgroup, wherein the carbocyclic ring is optionally substituted with one or more substituents selected from H, fluoro, chloro, methyl or trifluoromethyl.

In some embodiments, each R is¹And R²Independently H or butyl, wherein said butyl is optionally substituted with one or more fluorine atoms; or, R¹、R²Together with the carbon atom to which they are attached form a six-membered carbocyclic ringOr a seven membered carbocyclic ringWherein said six-membered and seven-membered carbocyclic rings are independently optionally substituted by one or more fluorine atoms.

In some embodiments, R³Is C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkylsulfonyl radical, C_1-4Alkyl acyl radical, C_3-6Cycloalkyl or heteroaryl of 5 to 7 atoms, or R³Is of the sub-structure:

wherein, X¹、X²Y and r have the meanings described in the invention;

wherein R is³Alkyl, haloalkyl, alkylsulfonyl, alkanoyl, cycloalkyl, heteroaryl of 5 to 7 atoms, subformula II-a and subformula II-b as defined in (a), are independently optionally substituted by one or more substituents selected from H, oxo (═ O), fluoro, chloro, bromo, cyano, hydroxy, nitro, methyl, ethyl, propyl, butyl, hydroxyethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, methylsulfonyl, acetyl, carboxy, methylsulfonylamino, carboxamido, carbamoyl, 2-hydroxypropane, hydroxy-2-yl or 2, 2-difluoro-1-hydroxyethyl.

In some embodiments, R³Is methyl, ethyl, propyl, butyl, trifluoromethyl, difluoromethyl, methylsulfonyl, ethylsulfonyl, acetyl, pyrazolyl, pyrrolyl, thiazolyl, triazolyl, tetrazolyl, oxazolyl, pyridyl, pyrimidinyl or pyrazinyl, or R³Is of the sub-structure:

wherein, X¹、X²Y and r have the meanings described in the invention;

wherein R is³The methyl, ethyl, propyl, butyl, difluoromethyl, methylsulfonyl, ethylsulfonyl, acetyl, pyrazolyl, pyrrolyl, thiazolyl, triazolyl, tetrazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, sub-formula II-a and sub-formula II-b described in (1), are independently optionally substituted with one or more substituents selected from H, fluoro, chloro, bromo, cyano, hydroxy, nitro, methyl, ethyl, propyl, butyl, hydroxyethyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, 2-hydroxypropan-2-yl or 2, 2-difluoro-1-hydroxyethyl.

In some embodiments, R³Is methylsulfonyl, ethylsulfonyl, pyrazolyl, pyrrolyl, thiazolyl, triazolyl, oxazolyl or pyridyl, or R³Is of the sub-structure:

R³the methylsulfonyl, ethylsulfonyl, pyrazolyl, pyrrolyl, thiazolyl, triazolyl, oxazolyl, pyridyl and each of the sub-formulae independently optionally substituted with one or more groups selected from oxo(═ O), fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, butyl, hydroxyethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, methylsulfonyl, formyl, carbamoyl, 2-hydroxypropan-2-yl or 2, 2-difluoro-1-hydroxyethyl.

In some embodiments, each R is⁴Independently H, halogen, cyano, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkoxy or halo C_1-4An alkyl group.

In some embodiments, each R is⁴Independently H, fluoro, chloro, bromo, cyano, hydroxy, amino, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, difluoromethyl, 2-difluoroethyl or trifluoromethyl.

In some embodiments, each R is⁵Independently H, halogen, nitro, cyano, hydroxy, amino, C_1-4Alkyl, halo C_1-4Alkyl or C_1-4An alkoxy group.

In other embodiments, each R is⁵Independently H, fluoro, chloro, bromo, methyl, ethyl or trifluoromethyl.

In some embodiments, X¹Is O, S, CH₂Or NH.

In some embodiments, X²Is O, S or CH₂。

In some embodiments, Y is O, S, CR^5aR^5bOr NR^5c(ii) a Wherein each R is^5aAnd R^5bIndependently is H, nitro, cyano, hydroxy or C_1-4An alkyl group; r^5cIs H, cyano, hydroxy, C_1-4Alkyl, halo C_1-4Alkyl or C_1-4An alkoxy group.

In some embodiments, r is 0, 1,2, or 3.

In some embodiments, each m and n is independently 0, 1,2, 3, or 4.

In another aspect, the present invention provides a compound having the structure of one of:

or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

In one aspect, the invention provides a pharmaceutical composition comprising a compound described herein; the pharmaceutical composition may further comprise at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.

In some embodiments, the pharmaceutical composition of the present invention further optionally comprises a compound selected from the group consisting of: an organic bisphosphonate (e.g., sodium alendronate), an estrogen receptor modulator (e.g., raynaxifen), an estrogen receptor beta modulator (e.g., estradiol, conjugated estrogens), an androgen receptor modulator, an osteoclast proton atpase inhibitor, an HMG-CoA reductase inhibitor, an integrin receptor antagonist, an osteoblast anabolic agent, an active vitamin D (e.g., 1 α -hydroxyvitamin D (α -calciferol), 1, 25-dihydroxyvitamin D (calcitriol)), a phytoestrogen (eplerenone), a calcitonin (e.g., paclobulin), strontium ranelate, odanactib, ONO5334, MIV-711, MIV-710, and pharmaceutically acceptable salts and mixtures thereof.

In one aspect, the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for inhibiting the activity of a cathepsin; further, the cathepsin includes, but is not limited to, cathepsin K.

In one aspect, the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for treating, preventing, alleviating or alleviating a cathepsin dependent disease in a patient.

In one aspect, the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for treating, preventing, reducing or alleviating osteoporosis, paget's disease, increased bone turnover, periodontal disease, tooth loss, bone fracture, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete osteogenesis, metastatic bone disease, hypercalcemia of malignancy, multiple myeloma, multiple sclerosis, myasthenia gravis, psoriasis, pemphigus vulgaris, Grave's goiter, systemic lupus erythematosus, asthma, pain, atherosclerosis, bone loss, increased abnormal femoral turnover, hypercalcemia of malignancy, obesity or a disease of bone metastasis in a patient.

"cathepsin dependent disease or disorder" refers to a pathological condition that is dependent on the activity of one or more cathepsins. "cathepsin K dependent diseases or conditions" refers to conditions which are dependent on the activity of cathepsin K. Conditions associated with cathepsin K activity include osteoporosis, glucocorticoid-induced osteoporosis, paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete osteogenesis, metastatic bone disease, malignant hypercalcemia, and multiple myeloma. In treating such conditions with the presently claimed compounds, the amount of treatment required will vary with the particular disease, and can be readily determined by one skilled in the art.

The foregoing has outlined only certain aspects of the present invention but is not limited in that these and other aspects will be more fully described in the following detailed description.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; andEliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% 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 in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, e.g., by chromatographic methods and/or fractional crystallization methods to separate the different stereoisomers.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemases and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)^ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of NotreDame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A PracticalApproach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (lowenergy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C₁-C₄Alkyl "or" C_1-4Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl and C₄An alkyl group.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent; the term "optionally" whether preceded by the term "substituted" or not, indicates that the given structure is unsubstituted or that one or more hydrogen atoms in the structure may be replaced by a particular substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. "one or more" means substituted with one or more substituents, preferably 1,2, 3, 4,5 or 6 substituents. When the number of the substituents is more than 1, the substituents are independent of each other and may be the same or different specific substituents.

Wherein, the substituent described in the present invention can be, but is not limited to: hydrogen, oxo (═ O), alkyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, alkoxy, alkylamino, haloalkyl, aldehyde, cyano, alkanoyl, alkylsulfonyl, acylamino, sulfonamido, hydroxyl-substituted alkyl, hydroxyl-substituted haloalkyl, aryl, heterocyclic, heteroaryl, cycloalkyl or nitro, and the like.

The term "alkyl" as used herein includes saturated straight or branched chain monovalent hydrocarbon groups of 1 to 12 carbon atoms. In some of these embodiments, the alkyl group contains 1 to 4 carbon atoms; in other embodiments, the alkyl group contains 1 to 3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, 2-methylpropyl, 1-methylpropyl and tert-butyl), and the like. The term "alkyl" and its prefix "alkane" as used herein, both include straight and branched saturated carbon chains.

The term "haloalkyl" denotes a situation where an alkyl group may be substituted by one or more of the same or different halogen atoms. Wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, trifluoromethyl, 1-chloroethyl, difluoromethyl, dichloroethyl, 2, 2-difluoroethyl, 3,3, 3-trifluoropropyl, 2-fluoro-2-methylpropyl, and the like.

The term "amino" refers to the group-NH₂。

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the amino groups are each independently substituted by one or two identical or different alkyl groups, wherein the alkyl groups have the meaning as described herein. Examples include, but are not limited to, methylamino, ethylamino, dimethylamino, diethylamino, and the like.

The term "aminoacyl" refers to the group-C (═ O) NH₂Wherein the amino group (-NH)₂) May be further substituted with one or more alkyl groups.

The terms "alkanoyl", "alkylsulfonyl" and "alkanoyl" refer to the radicals "alkyl-C (═ O) -" and the radicals "alkyl-S (═ O), respectively₂- ", wherein said alkyl group has the meaning as described in the present invention. Alkyl acyl groups include, but are not limited to, methyl acyl, ethyl acyl, and the like. Alkylsulfonyl groups include, but are not limited to, methylsulfonyl, ethylsulfonyl, and the like.

The term "alkoxy" as used herein means an alkyl group attached to the main structure of the molecule through an oxygen atom, wherein the alkyl group has the meaning described herein. Such examples include, but are not limited to, methoxy, ethoxy, propoxy, and the like.

The term "cycloalkyl" or "carbocyclic" refers to a monovalent or polyvalent saturated or partially unsaturated ring, which is non-aromatic and does not contain heteroatoms; wherein said carbocyclic ring comprises a monocyclic ring of 3 to 12 carbon atoms or a bicyclic or tricyclic ring of 5 to 12 carbon atoms. Examples of cycloalkyl groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term "aryl" may be a monocyclic, bicyclic or tricyclic carbocyclic ring system in which at least one ring is aromatic and each ring contains 3 to 7 atoms. The term "aryl" may be used interchangeably with the term "aromatic ring", e.g., aromatic rings may include phenyl, naphthyl and anthracenyl.

The terms "heteroaryl", "heteroaromatic ring" are used interchangeably herein and refer to a stable monocyclic, bicyclic or tricyclic ring system having up to 15 atoms in which at least one ring is aromatic and at least one ring contains 1 to 4 heteroatoms selected from O, N and S. Heteroaryl groups within this definition include, without limitation: oxazolyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thienyl, triazolyl (including, but not limited to, 1H-1,2, 4-triazol-1-yl, and the like), and furanyl. If the heteroaryl group contains a nitrogen atom, it should be understood that the definition also includes its corresponding N-oxide.

The terms "heterocyclyl", "heterocycle", "heteroalicyclic" or "heterocyclic" are used interchangeably herein and all refer to a monocyclic, bicyclic, tricyclic or tetracyclic ring system wherein one or more atoms of the ring is independently optionally substituted with a heteroatom selected from N, O, S, P. The heterocyclic ring may be fully saturated or contain one or more unsaturations, but is by no means aromatic. The heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable compound. Unless otherwise indicated, the heterocycles described herein include N, S or P optionally substituted with one or more oxo (═ O) groups to give, for example, NO₂，SO，SO₂，PO，PO₂Of the group of (A) and (B) simultaneously, -CH in the heterocycle₂-the group may optionally be replaced by-C (═ O) -. "Heterocyclyl" also includes heterocyclic groups fused to saturated or partially unsaturated rings or heterocycles. Examples of heterocycles include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, azetidinyl, oxetanyl, glycidyl, morpholinyl, oxazepinyl, diazepinyl, thiazepinyl, pyrrolinyl2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxolyl, dihydrothienyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, 1, 4-dithianyl, and the like.

"carbocyclic ring of 3 to 8 atoms", "spirocarbocyclic ring of 5 to 10 atoms", and the like, describe the number of ring atoms making up the ring structure, wherein the ring atoms include carbon atoms and heteroatoms such as N, O, S, P, the type of atoms depending on the particular group formed. For example, "a carbocyclic ring of 3 to 8 atoms" refers to a cycloalkyl group of 3 to 8 carbon atoms; "heterocyclic ring of 3 to 7 atoms" means a heterocyclic group of 3 to 7 atoms, wherein the heterocyclic group contains 1,2, 3 or 4 heteroatoms selected from N, O, S, P. When the ring structure is substituted with a specific group, the number of atoms of the substituent is not included in the number of ring atoms. For example, when cyclopentane is substituted with one oxo (═ O) group, the oxygen atom is not included in the ring atoms.

The ring system formed by the ring with the substituent R bonded to the center, as described herein, represents that the substituent R may be substituted at any substitutable or any reasonable position on the ring. For example, formula a represents any possible substituted position on the phenyl ring that may be substituted with R, as shown in formula b, formula c, formula d and formula e.

In addition, unless otherwise expressly indicated, the descriptions "… and … are each independently," "… and … are each independently," and "… and … are each independently" used throughout this document are interchangeable and should be broadly construed to mean that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other. Description of "… optionalThe term "independently" in "independently also means that the options are independent and do not affect each other. For example, each R in formula h^cThe specific options can be the same or different, and the specific items expressed mutually are different; the specific options for each k may be the same or different in different cases.

The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastrointestinal upset, dizziness and the like, when administered to a human. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by a federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

The term "carrier" refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, particularly injectable solutions. Suitable pharmaceutical carriers are described in e.w. martin, "Remington's pharmaceutical sciences".

The "hydrate" of the present invention refers to the compound or salt thereof provided by the present invention, which further comprises water bonded by non-covalent intermolecular forces in a chemical amount or in a non-chemical equivalent amount, and may be said to be an association of solvent molecules with water.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.

The "ester" of the present invention means an in vivo hydrolysable ester formed by a compound of formula (I) containing a hydroxyl group. Such esters are, for example, pharmaceutically acceptable esters which are hydrolysed in the human or animal body to yield the parent alcohol. The group of the in vivo hydrolysable ester of the compound of formula (I) containing a hydroxyl group includes, but is not limited to, phosphate, acetoxy, methoxy, 2-dimethylpropionyloxy, methoxyalkanoyl, benzoyl, alkoxycarbonyl, dialkylcarbamoyl, N- (dialkylaminoethyl) -N-alkylcarbamoyl and the like.

"nitroxide" in the context of the present invention means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form the N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4 th edition, Jerry March, pages). In particular, the N-oxide may be prepared by the method of L.W.Deady (Syn.Comm.1977,7,509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms. The invention includes isotopically-labeled compounds, which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹³C、¹¹C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the invention, e.g. by incorporation of radioactive isotopes(e.g. in³H and¹⁴C) can be used in drug and/or substrate tissue distribution assays. Tritium, i.e.³H and carbon-14, i.e.¹⁴The C isotopes are particularly preferred because of their ease of preparation and detection. And the hydrogen atoms being replaced by heavier isotopes, e.g. deuterium, i.e.²H, may be preferred in some cases because of the higher metabolic stability that may provide therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements. Isotopically-labelled compounds of formula (I) of the present invention and prodrugs thereof can generally be prepared by substituting a readily available isotopically-labelled reagent for a non-isotopically-labelled reagent in the course of performing the procedures disclosed in the schemes and/or in the examples below.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

Various pharmaceutically acceptable salt forms of the compounds of the present invention are useful. The term "pharmaceutically acceptable salts" means those salt forms that are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, as will be apparent to those skilled in the art. Other factors, more practical in nature, are also important for selection, these are: cost of raw materials, ease of crystallization, yield, stability, hygroscopicity and, as a result, flowability of the drug substance. Briefly, the pharmaceutical composition can be prepared by combining the active ingredient with a pharmaceutically acceptable carrier.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, descriptive acceptable salts in detail in J. pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, nitrate and the like, and organic acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, citrate, benzoate, mandelate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, sulfosalicylate and the like, or obtained by other methods described in the literature such as ion exchange.

Other pharmaceutically acceptable salts include adipates, malates, 2-hydroxypropionic acid, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodiates, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, picrates, pivalates, Propionate, stearate, thiocyanate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄A salt.

The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali metals or basesThe earth metal salt includes sodium salt, lithium salt, potassium salt, calcium salt, and magnesium salt; transition metals or transition metal salts include iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates. Amine salts such as, but not limited to, N '-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methyl reduced glucamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1' -ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris (hydroxymethyl) aminomethane.

The term "protecting group" or "Pg" refers to a substituent that when reacted with another functional group, is typically used to block or protect a particular functionality. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

In this specification, a structure is dominant if there is any difference between the chemical name and the chemical structure.

Abbreviations for any protecting groups, amino acids and other compounds used in the present invention shall be based on their commonly used, accepted abbreviations unless otherwise indicated, or refer to IUPAC-IUB Commission on biochemical nomenclature (see biochem.1972, 11: 942-944).

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the present invention. In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes materials or compositions which must be compatible chemically or toxicologically, with the other components comprising the formulation, and with the mammal being treated. Salts of the compounds of the present invention also include, but are not necessarily pharmaceutically acceptable salts of intermediates used in the preparation or purification of the compounds of formula (I) or isolated enantiomers of the compounds of formula (I).

Compounds, compositions, and uses of the invention

The compounds of the present invention may be administered to a mammal, preferably a human, alone or preferably together with a pharmaceutically acceptable carrier or diluent, optionally together with well-known adjuvants such as alum, in pharmaceutical compositions of standard pharmaceutical practice. The compounds may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration.

In tablets for oral use, commonly used carriers include lactose and corn starch, and a lubricant, such as magnesium stearate, is usually added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. For oral use of the compounds of the invention, the selected compound may be administered, for example, in the form of a tablet or capsule or in the form of an aqueous solution or suspension. For oral administration in the form of tablets or capsules, the active pharmaceutical ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral pharmaceutical composition can be combined with any orally non-toxic pharmaceutically acceptable carrier such as ethanol, glycerol, water, and the like. In addition, when necessary or desired, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants useful in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. When aqueous suspensions are required for oral use, the active ingredient is combined with a lubricant and a suspending agent. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous applications, sterile solutions of the active ingredients are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the formulation isotonic.

The compounds of the invention may also be administered in the form of liposomal delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a number of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of the invention may also be delivered by the use of monoclonal antibodies as separate carriers to which the compound molecules are coupled. The compounds of the invention may also be coupled to soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention may also be coupled to a class of biodegradable polymers useful for obtaining controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymers of hydrogels.

The compounds of the invention may also be used in combination with known substances for the treatment or prevention of osteoporosis, glucocorticoid-induced osteoporosis, paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete osteogenesis, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma. Combinations of the disclosed compounds with agents useful for treating or preventing osteoporosis or other bone disorders are also within the scope of the invention. One skilled in the art would know which combinations of substances are useful based on the nature of the drugs and diseases involved. Such materials include the following: an organic diphosphonic acid compound; an estrogen receptor modulator; androgen receptor modulators; osteoclast proton atpase inhibitors; HMG-CoA reductase inhibitors; an integrin receptor antagonist; osteoblastic anabolic agents, such as PTH; and pharmaceutically acceptable salts and mixtures thereof. One preferred combination is a combination of a compound of the invention and an organic bisphosphonic acid compound. Another preferred combination is a combination of a compound of the invention and an estrogen receptor modulator. Another preferred combination is a combination of a compound of the invention and an androgen receptor modulator. Another preferred combination is a combination of a compound of the invention and an osteoblast anabolic agent.

Non-limiting examples of organic bisphosphonic acid compounds for use herein include alendronate, sodium incadronate, clodronate, etidronate, ibandronic acid, incadronic acid, minodronate, neridronic acid, olpadronic acid, pamidronic acid, piridronic acid, risedronic acid, tiludronic acid, and zoledronic acid, and pharmaceutically acceptable salts and esters thereof. Particularly preferred bisphosphonic acid compounds are alendronate, especially the sodium, potassium, calcium, magnesium, or ammonium salts of alendronic acid. Examples of preferred bisphosphonic acid compounds are the sodium salts of alendronic acid, especially the hydrated sodium salts of alendronic acid. The salt may be hydrated by an entire mole of water or by an entire mole of water. Examples of more preferred bisphosphonic acid compounds are hydrated sodium salts of alendronic acid, especially monosodium alendronate trihydrate. The exact dosage of the organic bisphosphonate will vary with the schedule of administration, the particular bisphosphonate selected, the age, size, sex and physical condition of the mammal or human, the nature and severity of the condition being treated, and other relevant medical and physical factors.

"Selective estrogen receptor modulators" refers to compounds that, regardless of mechanism, can interfere with or inhibit the binding of estrogen to the receptor. Examples of estrogen receptor modulators include, without limitation, estrogen, progestin, estradiol, droloxifene, raloxifene, lasofoxifene, TSE-424, tamoxifen, idoxifene, LY353381, toremifene, fulvestrant, 4- [7- (2, 2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy ] phenyl ] -2H-1-benzopyran-3-yl) -phenyl-2, 2-dimethylpropionate, and 4, 4' -dihydroxybenzophenone-2, 4-dinitrophenyl-hydrazone.

An "estrogen receptor beta modulator" is a compound that can selectively agonize or antagonize estrogen receptor beta (ER β). Agonism of ER β increases transcription of tryptophan hydroxylase gene (TPH, a key enzyme in serotonin synthesis) by ER β -mediated events.

"androgen receptor modulators" refers to compounds that, regardless of mechanism, can interfere with or inhibit the binding of androgens to the receptor. Examples of androgen receptor modulators include finasteride and other 5 a-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.

"osteoclast proton atpase inhibitor" refers to an inhibitor of proton atpase, which is found on the apical membrane of osteoclasts and has been reported to play an important role in the bone resorption process. Such inhibitors may be useful as bone resorption inhibitors for the treatment and prevention of osteoporosis and related metabolic diseases.

"HMG-CoA reductase inhibitor" refers to an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductase inhibitors that may be used include, without limitation, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cerivastatin. Preferably, the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin, and most preferably is simvastatin. The term HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open acid forms of compounds having HMG-CoA reductase inhibitory activity (i.e., wherein the lactone ring is opened to form the free acid) as well as salt and ester forms, and thus the use of such salts, esters, open acid and lactone forms is also included within the scope of the present invention.

As used above, "integrin receptor antagonists" means that the physiological ligand and α can be selectively antagonized, inhibited or counteracted_vβ₃Integrin binding compounds that selectively antagonize, inhibit or neutralize physiological ligand α_vβ₅Integrin binding compounds which antagonize, inhibit or counteract the binding of physiological ligands to α_vβ₃Integrins and α_vβ₅Integrin-bound compounds, and compounds that antagonize, inhibit, or counteract the activity of specific integrins expressed on capillary endothelial cells the term also relates to α_vβ₆、α_vβ₈、α₁β₁、α₂β₁、α₅β₁、α₆β₁And α₆β₄Antagonists of integrins the term also relates to α_vβ₃、α_vβ₅、α_vβ₆、α_vβ₈、α₁β₁、α₂β₁、α₅β₁、α₆β₁And α₆β₄Antagonists of any combination of integrins.

"osteoblast anabolic agent" refers to a substance that can build bone, such as PTH. Intermittent administration of parathyroid hormone (PTH) or its amino-terminal fragments and analogs has been shown to prevent, arrest, partially reverse bone loss and stimulate bone formation in animals and humans.

The compounds of the present invention may also be used in combination with another agent selected from the group consisting of non-steroidal anti-inflammatory drugs such as selective cyclooxygenase-2 inhibitors, inhibitors of interleukin-1 β, LOX/COX inhibitors, vitamin D, synthetic vitamin D analogs, calcium, RANKL inhibitors, and the like.

"non-steroidal anti-inflammatory drugs" or NSAIDs inhibit the metabolism of arachidonic acid to pro-inflammatory prostaglandins by the cyclooxygenase enzymes COX-1 and COX-2. Non-limiting examples of NSAIDs include: acetylsalicylic acid, ibuprofen, naproxen, cyfluperazine, etodolac, fenoprofen, flurbiprofen, indolofenamide, ketoprofen, ketorolac, meloxicam, nabumetone, mepromazine, piroxicam, sulindac, toluoylpicolinic acid, diflunisal, meclofenamate, and phenylbutazone.

"Selective cyclooxygenase-2 inhibitor" or COX-2 inhibitor "refers to a non-steroidal anti-inflammatory drug (NSAID) that inhibits COX-2 coenzymes that cause pain and inflammation in the body. Non-limiting examples of COX-2 inhibitors include: lexib, etoricoxib, parecoxib, rofecoxib, valdecoxib, and lumiracoxib.

An "inhibitor of interleukin-1 β" or IL-1 β inhibitor is a soluble factor produced by monocytes, macrophages and other cells that activates T-lymphocytes and potentiates their response to mitogens or immune antigens. Non-limiting examples of IL-1B inhibitors include diacerein and rhein.

"LOX/COX inhibitor" refers to an inhibitor that participates in the arachidonic acid pathway. A non-limiting example of a LOX/COX inhibitor is lincomron.

"vitamin D" includes, but is not limited to, vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol), which are naturally occurring, hydroxylated bioactive metabolites, vitamin D: la-hydroxy vitamin D; 25-hydroxyvitamin D and la, a biologically inactive precursor of 25-hydroxyvitamin D. Vitamin D2 and vitamin D3 have the same biological potency in humans. When vitamin D2 or vitamin D3 enters the circulation, it is hydroxylated by cytochrome P450-vitamin D-25-hydroxylase to give 25-hydroxyvitamin D. The metabolite 25-hydroxyvitamin D is biologically inactive and can be further hydroxylated in the kidney by cytochrome P450-monooxygenase, 25(OH) D-la-hydroxylase, to give 1, 25-dihydroxyvitamin D. When serum calcium is reduced, -like paraglandular hormone (PTH) production is increased, which regulates pan homeostasis and increases plasma calcium levels by increasing the conversion of 25-hydroxy vitamin to 1, 25-dihydroxy vitamin D.

In an embodiment of the invention, the appropriate amount of vitamin D compound is selected to provide sufficient vitamin D nutrition during the dosing interval without interfering with the ability of the cathepsin K inhibitor to obtain a bone resorption inhibiting effect.

"synthetic vitamin D analogs" include non-naturally occurring compounds that produce a vitamin D-like effect.

"calcium" includes, but is not limited to, calcium carbonate, calcium citrate, or any other compound containing elemental calcium. Calcium is essential for human health and is required for the integrity of the skeletal structure. The ionized portion of serum calcium is physiologically important and is tightly maintained by parathyroid hormone (PTH) and 1, 25-dihydroxy vitamin D. As such, a decrease in blood calcium (or simply inadequate dietary calcium) can rapidly affect PTH and 1, 25-dihydroxy vitamin D levels, as well as adversely affect bone health, and thus the supply of supplemental calcium tends to reduce PTH levels to reduce hook removal from skeletal storage, as well as to contribute to bone health.

"RANKL inhibitor" refers to an inhibitor of the receptor active agent NF- κ β ligand (RANKL). RANKL is a key stimulator of osteoclast formation and maturation. Non-limiting examples of RANKL inhibitors include AMG-162.

When formulated as a fixed dose combination product, the compounds of the present invention are used within the dosage ranges described below and other pharmaceutically active agent(s) within their approved dosage ranges. The compounds of the invention may be used sequentially with known pharmaceutically acceptable agents.

The term "administering" and variations thereof (e.g., "administering" a compound) as used in reference to a compound of the invention refers to introducing the compound or a prodrug of the compound into the system of an animal in need of treatment. When a compound of the invention or a prodrug thereof is provided in combination with one or more other active substances (e.g., cytotoxic agents), "administration" and variations thereof are each understood to include the simultaneous and sequential introduction of the compound or prodrug thereof and the other substance. The present invention includes within its scope prodrugs of the compounds of the present invention.

The term "composition" as used herein includes a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

The term "treatment" or "management" of a disease as used herein includes: preventing a disease, i.e., a mammal that either develops or is predisposed to developing the disease but does not yet experience or exhibit symptoms of the disease does not develop clinical symptoms of the disease; inhibiting the disease, i.e., preventing or reducing the development of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

The term "bone resorption" as used herein refers to the process by which osteoclasts degrade bone.

The invention also includes pharmaceutical compositions for treating osteoporosis or other bone conditions comprising a therapeutically effective amount of a compound of the invention, with or without a pharmaceutically acceptable carrier or diluent. Suitable compositions of the invention include aqueous solutions comprising a compound of the invention and a pharmaceutically acceptable carrier, e.g., saline, e.g., at a pH level of 7.4. The solution may be introduced into the blood of a patient by a topical bolus injection.

When the compounds of the present invention are administered to human patients, the daily dosage will generally be determined by the prescribing physician and will generally vary with the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.

In one example of use, a suitable amount of the compound is administered to a mammal being treated for a cathepsin dependent condition. When used for the indicated conditions, the oral dosage of the present invention is from about 0.01 mg/kg/day to about 100 mg/kg/day, preferably from 0.01 to 10 mg/kg/day, and most preferably from 0.1 to 5.0 mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The medicament generally comprises from about 0.01mg to about 500mg of active ingredient, preferably from about 1mg to about 100mg of active ingredient. During infusion at a constant rate, the most preferred intravenous dose is from about 0.1 to about 10 mg/kg/minute. The compounds of the invention may advantageously be administered in a single daily dose form, or the total daily dose may be administered in divided doses of two, three or four times daily. In addition, preferred compounds of the present invention may be administered in intranasal form by using suitable intranasal matrices, or they may be administered by transdermal routes using such transdermal patch forms as are well known to those of ordinary skill in the art. For administration in the form of a transdermal delivery system, the dose administered will, of course, be administered continuously rather than intermittently during the dosage regimen.

The compounds of the present invention may be used in combination with other agents useful in the treatment of cathepsin-mediated conditions. The components of such combinations may be administered separately or simultaneously at different time points during the course of therapy, in divided or single combination forms. The invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly. It will be appreciated that the scope of combinations of the compounds of the present invention with other agents useful in the treatment of cathepsin mediated conditions includes in principle any combination with any pharmaceutical composition useful in the treatment of conditions involving oestrogen function.

Thus, it is within the scope of the present invention to use a combination of the claimed compounds of the present invention in combination with a second material selected from the group consisting of: an organic diphosphonic acid compound; an estrogen receptor modulator; androgen receptor modulators; osteoclast proton atpase inhibitors; HMG-CoA reductase inhibitors; an integrin receptor antagonist; osteoblastic anabolic agents, such as PTH; and pharmaceutically acceptable salts and mixtures thereof.

Pharmaceutically acceptable salts of the compounds of the present invention include conventional salts of the compounds of the present invention which are non-toxic and formed with inorganic or organic acids. For example, non-toxic conventional salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like, as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid and the like. Pharmaceutically acceptable salts of the compounds of the invention can be synthesized from the compounds of the invention which contain a basic or acidic moiety using conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess amount of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

General synthetic methods

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined for the compounds of formula (I), unless otherwise specified. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

In the examples described below, all temperatures are given in degrees celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu chemical Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaihua factory.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N-dimethylacetamide and N, N-dimethylformamide were used by being dried beforehand over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. NMR spectral data were measured by Bruker Avance400 NMR spectrometer or Bruker Avance III HD 600 NMR spectrometer, CDC1₃,d₆-DMSO,CD₃OD or d₆Acetone as solvent (reported in ppm) with TMS (0ppm) or chloroform (7.26ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton, singlet), d (doublet, triplet), t (triplet ), m (multiplet, multiplet), br (broad, doublet), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet), ddd (doublet of doublets), ddt (doublet of doublet of doublets, doublet of doublets), dddd (doublet of doublets ). Coupling constants are expressed in hertz (Hz).

The conditions for low resolution Mass Spectrometry (MS) data determination were: agilent 6120Quadrupole HPLC-MS (column model: Zorbax SB-C18,2.1X 30mm,3.5 μm,6min, flow rate 0.6mL/min, mobile phase 5% -95% (CH with 0.1% formic acid)₃CN) in (H containing 0.1% formic acid)₂Proportion in O)), at 210/254nm with UV detection, using electrospray ionization mode (ESI).

The purity of the compound is characterized in the following way: agilent 1260 preparative high performance liquid chromatography (Pre-HPLC) or Calesep Pump 250 preparative high performance liquid chromatography (Pre-HPLC) (column model: NOVASEP,50/80mm, DAC) with UV detection at 210nm/254 nm.

The following acronyms are used throughout the invention:

EA ethyl acetate; HCl hydrochloric acid; HATU 2- (7-azobenzotriazol) -N, N-tetramethyluronium hexafluorophosphate; boc-t-butoxycarbonyl; (Boc)₂Di-tert-butyl O-dicarbonate; CDCl₃Deuterated chloroform; acetone-d₆Deuterated acetone; DMF N, N-dimethylformamide; THF tetrahydrofuran; k₂CO₃Potassium carbonate

Synthetic schemes

Synthesis scheme 1 of intermediates

The intermediate compound (1) can be prepared by the method described in the synthesis scheme 1 of the intermediate, wherein T is Cl or OH, n and R¹、R²And R⁵Have the meaning as described in the present invention. Compound (1a) is first reacted with di-tert-butyl dicarbonate ((Boc) under basic conditions, for example under the action of sodium hydroxide₂O) to obtain a compound with a protecting group, and then condensing the compound with 1-amino-1-cyclopropyl cyanide or a salt thereof (such as hydrochloride) under the action of a condensation reagent (such as HATU) and a base (such as N, N-diisopropylethylamine and the like) to obtain a compound (1 b). The compound (1b) is deprotected under the action of an acid, and then reacted with the compound (1c) under appropriate conditions (e.g., under the action of a base such as triethylamine, pyridine, etc.) to obtain an intermediate compound (1).

Synthesis scheme 2 of intermediates

The intermediate compound (2) can be prepared by the method described in the synthesis scheme 2 of the intermediate, wherein n, R¹、R²And R⁵Have the meaning as described in the present invention. TransformingThe compound (1) reacts with pinacol diboron under the action of a catalyst (such as 1,1' -bis (diphenylphosphino) ferrocene) palladium dichloride dichloromethane complex) to obtain an intermediate compound (2).

Synthesis scheme 3 of intermediates

The intermediate compound (3) can be prepared by the method described in scheme 3 for the synthesis of intermediates, wherein m, R³And R⁴Have the meaning as described in the present invention. Compound (3a) and R³H is subjected to coupling reaction under the action of alkali (such as potassium carbonate and potassium phosphate), a catalyst (such as cuprous iodide) and a ligand (such as N, N' -dimethylethylenediamine) to obtain an intermediate compound (3).

Synthesis scheme 1

The target compound (4) can be prepared by the method described in FIG. 1, wherein m, n, R¹、R²、R³、R⁴And R⁵Have the meaning as described in the present invention. The intermediate compound (2) and the intermediate compound (3) react under the action of a base (such as potassium carbonate) and a catalyst (such as 1,1' -bis (diphenylphosphino) ferrocene) palladium dichloride dichloromethane complex) to obtain a target compound (4).

Synthesis scheme 2

The target compound (4) can also be prepared by the method described in FIG. 2, wherein m, n, R¹、R²、R³、R⁴And R⁵Have the meaning as described in the present invention. The intermediate compound (1) and the compound (5) react under the action of a base (such as potassium carbonate) and a catalyst (such as palladium tetratriphenylphosphine) to obtain a target compound (4).

Examples

Synthesis of intermediate (A)

N- (1- ((1-cyanocyclopropyl) carbamoyl) cyclohexyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

Step 1: 1- ((tert-butoxycarbonyl) amino) cyclohexanecarboxylic acid

A round-bottom flask was charged with sodium hydroxide solution (43mL,4mol/L), THF (40mL) and 1-aminocyclohexanecarboxylic acid (5.0g,34.96mmol), di-tert-butyl dicarbonate (9.13g,41.96mmol) was added to the flask at 0 deg.C, and after dropwise addition, the reaction was stirred at room temperature overnight. Water (100mL) was added to the reaction system, and the reaction system was acidified with hydrochloric acid (50mL,1mol/L), followed by extraction with ethyl acetate (50 mL. times.2), and the organic phases were combined, washed with saturated brine (100 mL. times.2), and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure gave the crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) ═ 4/1) to give the title compound as a white solid (7.3g, 86%).

Step 2: 1- ((1-Cyanocyclopropyl) carbamoyl) cyclohexyl) carbamic acid tert-butyl ester

1- ((tert-butoxycarbonyl) amino) cyclohexanecarboxylic acid (301mg,1.24mmol), 1-amino-1-cyclopropylcyano hydrochloride (294mg,2.48mmol), HATU (471mg,1.24mmol) and DMF (6mL) were charged to a two-necked flask, and triethylamine (0.52mL,3.72mmol) was added under nitrogen at 0 ℃ to stir the reaction at 0 ℃ for 4 hours. Water (50mL) was added to the reaction system, followed by extraction with ethyl acetate (50 mL. times.2), and the organic phases were combined, washed with saturated brine (50 mL. times.2), and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure gave the crude product which was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) ═ 8/1) to give the title compound as a white solid (0.34g, 90%).

MS(ESI,pos.ion)m/z:208.2(M-100+1).

And step 3: 1-amino-N- (1-cyanocyclopropyl) cyclohexanecarboxamide hydrochloride

To a two-necked flask was added tert-butyl 1- ((1-cyanocyclopropyl) carbamoyl) cyclohexyl) carbamate (340mg,1.11mmol) and ethyl acetate (10mL), followed by ethyl acetate hydrochloride solution (2mL,8mmol,4mol/L) and stirred at room temperature under nitrogen for 15 minutes. After completion of the reaction, the solvent was spin-dried to give the title compound (231mg, 85.4%) as a white solid, which was used in the next reaction without further purification.

And 4, step 4: 4-bromo-N- (1- ((1-cyanocyclopropyl) carbamoyl) cyclohexyl) benzamide

To a two-necked flask were added 1-amino-N- (1-cyanocyclopropyl) cyclohexylcarboxamide hydrochloride (730mg,3.0mmol) and anhydrous tetrahydrofuran (15mL), followed by addition of 4-bromobenzoyl chloride (1.32g,6.00mmol) and triethylamine (1.65mL,12.00mmol) at 0 ℃ and finally 4, 4-dimethylaminopyridine (18mg,0.15mmol), and the reaction was allowed to react at room temperature overnight. After completion of the reaction, saturated brine (100mL) was added, extraction was performed with ethyl acetate (30 mL. times.3), and the organic phases were combined, washed with saturated brine (50 mL. times.2), and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure gave the crude product which was purified by silica gel column chromatography (dichloromethane/ethyl acetate (V/V) ═ 10/1) to give the title compound as a white solid (758mg, 65%).

MS(ESI,pos.ion)m/z:391.2(M+2).

And 5: n- (1- ((1-cyanocyclopropyl) carbamoyl) cyclohexyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

To a two-necked flask were added 4-bromo-N- (1- ((1-cyanocyclopropyl) carbamoyl) cyclohexyl) benzamide (0.78g,2.0mmol), pinacol diboron diborate (0.61g,2.4mmol), (1,1' -bis (diphenylphosphino) ferrocene) dichloropalladium dichloromethane complex (0.067g,0.08mmol), potassium acetate (0.7g,7.2mmol) and DMF (10mL), and heated to 85 ℃ for 3 hours under nitrogen. After completion of the reaction, it was cooled to room temperature, quenched with water, extracted with ethyl acetate (60 mL. times.2), and the organic phase was washed successively with water (60 mL. times.2) and saturated brine (60mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography (dichloromethane/ethyl acetate (V/V) ═ 30/1) to give the title compound as a white solid (0.59g, 68%).

MS(ESI,pos.ion)m/z:438.2(M+1).

Synthesis of intermediate (B)

N- (1-cyanocyclopropyl) -1- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoylamino) cycloheptylcarboxamide

With reference to the synthesis of intermediate (a), intermediate (B) is prepared from the appropriate starting materials.

Example 1

N- (1- ((1-cyanocyclopropyl) carbamoyl) cyclohexyl) -4'- (2-oxopyrrolidin-1-yl) - [1,1' -biphenyl ] -4-carboxamide

Step 1: 1- (4-bromophenyl) pyrrolidin-2-one

To a two-necked flask was added 1-bromo-4-iodobenzene (1.10g,3.77mmol), 2-pyrrolidone (488mg,5.74mmol), potassium carbonate (1.05g,7.52mmol), cuprous iodide (0.072g,0.38mmol), N, N' -dimethylethylenediamine (0.068g,0.76mmol) and anhydrous toluene (20mL), and the mixture was heated under reflux for 6 hours. The reaction mixture was cooled to room temperature, poured into water (100mL), stirred, extracted with ethyl acetate (50 mL. times.3), and the organic phase was dried over anhydrous sodium sulfate. Filtration and removal of the solvent under reduced pressure gave the crude product which was purified by silica gel column chromatography (ethyl acetate/dichloromethane (V/V) ═ 1/7) to give the title compound as a pale yellow oil (0.73g, 80%).

MS(ESI,pos.ion)m/z:242.0(M+2).

Step 2: n- (1- ((1-cyanocyclopropyl) carbamoyl) cyclohexyl) -4'- (2-oxopyrrolidin-1-yl) - [1,1' -biphenyl ] -4-carboxamide

Into a two-necked flask was added 1- (4-bromophenyl) pyrrolidin-2-one (240mg,1.00mmol), N- (1- ((1-cyanocyclopropyl) carbamoyl) cyclohexyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzamide (437mg,1.00mmol), (1,1' -bis (diphenylphosphino) ferrocene) dichloropalladium dichloromethane complex (67mg,0.08mmol), aqueous potassium carbonate solution (1.5mL,2mmol/L) and DMF (10mL), and heated to 85 ℃ under nitrogen for 3 hours. After completion of the reaction, it was cooled to room temperature, quenched with water, extracted with ethyl acetate (60 mL. times.2), and the organic phase was washed successively with water (60 mL. times.2) and saturated brine (60mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography (dichloromethane/ethyl acetate (V/V) ═ 2/1) to give the title compound (0.29g, 62%) as a white solid.

MS(ESI,pos.ion)m/z:471.2(M+1)；

¹H NMR(400MHz,CDCl₃)(ppm):8.40(s,1H),7.85(d,J＝8.4Hz,2H),7.76(d,J＝8.8Hz,2H),7.69(d,J＝8.4Hz,2H),7.64(d,J＝8.8Hz,2H),6.16(s,1H),3.94(t,J＝7.0Hz,2H),2.67(t,J＝8.1Hz,2H),2.32-2.17(m,4H),2.00(dd,J＝18.1,7.7Hz,2H),1.75(d,J＝13.8Hz,2H),1.55(dd,J＝8.2,5.8Hz,2H),1.31-1.24(m,6H).

Example 2

N- (1- ((1-cyanocyclopropyl) carbamoyl) cycloheptyl) -4'- (2-oxopyrrolidin-1-yl) - [1,1' -biphenyl ] -4-carboxamide

Referring to the synthesis of example 1, step 2, starting from 1- (4-bromophenyl) pyrrolidin-2-one (240mg,1.00mmol) and N- (1-cyanocyclopropyl) -1- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzamido) cycloheptylcarboxamide (437mg,1.00mmol), the title compound was prepared as a white solid (39mg, 49.2%).

MS(ESI,pos.ion)m/z:485.2(M+1)；

¹H NMR(600MHz,CDCl₃)(ppm):8.08(s,1H),7.81(d,J＝8.4Hz,2H),7.73(d,J＝8.7Hz,2H),7.67(d,J＝8.4Hz,2H),7.62(d,J＝8.7Hz,2H),6.19(s,1H),3.92(t,J＝7.0Hz,2H),2.65(t,J＝8.1Hz,2H),2.39-2.25(m,2H),2.24-2.18(m,2H),2.14(dd,J＝14.8,7.4Hz,2H),1.71(dd,J＝14.2,7.1Hz,2H),1.65-1.60(m,4H),1.52(dd,J＝8.2,5.7Hz,2H),1.31-1.18(m,4H).

Example 3

N- (1- ((1-cyanocyclopropyl) carbamoyl) cycloheptyl) -4'- (2-oxoazetidin-1-yl) - [1,1' -biphenyl ] -4-carboxamide

Step 1: 1- (4-bromophenyl) azetidin-2-ones

Referring to the synthesis of example 1, step 1, starting from azetidin-2-one (267mg,3.77mmol) and 1-bromo-4-iodobenzene (1.10g,3.77mmol), the title compound was prepared as a yellow oil (700mg, 82%).

Step 2: n- (1- ((1-cyanocyclopropyl) carbamoyl) cycloheptyl) -4'- (2-oxoazetidin-1-yl) - [1,1' -biphenyl ] -4-carboxamide

Referring to the synthesis of example 1, step 2, starting from 1- (4-bromophenyl) azetidin-2-one (38mg,0.166mmol) and N- (1-cyanocyclopropyl) -1- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzamido) cycloheptylcarboxamide (75mg,0.166mmol), the title compound was prepared as a white solid (43mg, 55%).

MS(ESI,pos.ion)m/z:471.2(M+1)；

¹H NMR(600MHz,CDCl₃)(ppm):8.05(s,1H),7.80(d,J＝8.0Hz,2H),7.62(dd,J＝13.1,8.2Hz,4H),7.36(d,J＝8.1Hz,2H),6.28(s,1H),3.69(d,J＝5.4Hz,2H),2.59(t,J＝5.8Hz,2H),2.39-2.21(m,2H),2.13(dd,J＝14.4,8.0Hz,2H),2.12-1.96(m,4H),1.78-1.42(m,4H),1.33-1.19(m,4H).

Example 4

N- (1- ((1-cyanocyclopropyl) carbamoyl) cycloheptyl) -4'- (methylsulfonyl) - [1,1' -biphenyl ] -4-carboxamide

Into a two-necked flask was added 4-bromo-N- (1- ((1-cyanocyclopropyl) carbamoyl) cycloheptyl) benzamide (60mg,0.15mmol) [ Steps 1-4 in the Synthesis of Synthesis Process reference intermediate (A) ]]And N, N-dimethylformamide (6mL), 4-methanesulfonylphenylboronic acid (33mg,0.16mmol) was added, and tetratriphenylphosphine palladium (14.0mg,0.012mmol) and K were added under nitrogen blanket₂CO₃Aqueous solution (0.15mL,0.30mmol,2mol/L), and reacted at 90 ℃ for 1 hour after completion of the reaction, cooled to room temperature, added with saturated brine (60mL), extracted with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated brine (30mL × 2), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure,the crude product was purified by silica gel column chromatography (dichloromethane/ethyl acetate (V/V) ═ 2/1) to give the title compound as a white solid (47mg, 67.1%).

MS(ESI,pos.ion)m/z:480.1(M+1)；

¹H NMR(600MHz,DMSO-d₆)(ppm):8.45(s,1H),8.19(s,1H),8.05-8.02(m,2H),8.00(dd,J＝8.5,5.4Hz,4H),7.85(d,J＝8.4Hz,2H),3.27(s,3H),2.09(dd,J＝14.1,8.5Hz,2H),2.03(dd,J＝14.2,7.8Hz,2H),1.56-1.50(m,6H),1.41(dd,J＝8.1,5.3Hz,2H),1.25(d,J＝14.8Hz,2H),1.03(dd,J＝8.2,5.4Hz,2H).

Example 5

N- (1- ((1-cyanocyclopropyl) carbamoyl) cycloheptyl) -4'- (2-oxoimidazolidin-1-yl) - [1,1' -biphenyl ] -4-carboxamide

Step 1: 1- (4-bromophenyl) imidazolidin-2-one

To a two-necked flask, p-bromoiodobenzene (1.42g,5.0mmol) and N-butanol anhydrous (20mL) were added, 2-imidazolidinone (2.15g,25.0mmol) was further added, potassium carbonate (3.1g,22.0mmol) and cuprous iodide (143mg,0.75mmol) were further added, and finally N, N-dimethylethylenediamine (0.24mL,2.2mmol) was added dropwise to the reaction mixture and heated to 100 ℃ for reaction for 4 hours. The reaction was stopped, cooled to room temperature, and then saturated brine (80mL) was added, followed by extraction with ethyl acetate (30 mL. times.3), and the organic phases were combined, washed with saturated brine (50 mL. times.3), and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure gave the crude product which was purified by silica gel column chromatography (n-hexane/ethyl acetate (V/V) ═ 4/1) to give the title compound as a pale white solid (700g, 60%).

MS(ESI,pos.ion)m/z:243.0(M+2).

Step 2: n- (1- ((1-cyanocyclopropyl) carbamoyl) cycloheptyl) -4'- (2-oxoimidazolidin-1-yl) - [1,1' -biphenyl ] -4-carboxamide

To a two-necked flask were added 1- (4-bromophenyl) imidazolidin-2-one (241mg,1.00mmol), N- (1- ((1-cyanocyclopropyl) carbamoyl) cycloheptyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzamide (440mg,1.00mmol), (1,1' -bis (diphenylphosphino) ferrocene) dichloropalladium dichloromethane complex (67mg,0.08mmol), aqueous potassium carbonate solution (1.5mL,2mmol/L) and DMF (10mL), and heated to 85 ℃ for 3 hours under nitrogen protection. After completion of the reaction, it was cooled to room temperature, quenched with water, extracted with ethyl acetate (60 mL. times.2), and the organic phase was washed successively with water (60 mL. times.2) and saturated brine (60mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography (dichloromethane/ethyl acetate (V/V) ═ 2/1) to give the title compound (0.29g, 60%) as a white solid.

MS(ESI,pos.ion)m/z:486.1(M+1)；

¹H NMR(600MHz,DMSO-d₆)(ppm):8.44(s,1H),8.07(s,1H),7.91(d,J＝8.3Hz,2H),7.73(d,J＝8.3Hz,2H),7.68(q,J＝8.9Hz,4H),7.00(s,1H),3.95-3.84(m,2H),3.64-3.54(m,2H),2.13-2.01(m,4H),1.61-1.54(m,8H),1.40(q,J＝5.3Hz,2H),1.03(q,J＝5.4Hz,2H).

Example 6

(S) -N- (1- ((1-cyanocyclopropyl) amino) -4-fluoro-4-methyl-1-oxopent-2-yl) -4'- (2-oxopyrrolidin-1-yl) -3- (trifluoromethyl) - [1,1' -diphenyl ] -4-carboxamide

Step 1: (S) -2-amino-N- (1-cyanocyclopropyl) -4-fluoro-4-methylpentanamide hydrochloride

Tert-butyl (S) - (1- ((1-cyanocyclopropyl) amino) -4-fluoro-4-methyl-1-oxopent-2-yl) carbamate (synthetic method reference Bioorg. Med. chem. Lett.,2008,18, 923-. After completion of the reaction, ethyl acetate was distilled off under reduced pressure, dried toluene was added, and toluene was further distilled off under reduced pressure to give the title compound (325mg, 99.0%) as a pale yellow oil, which was used directly in the next reaction.

Step 2: (S) -4-bromo-N- (1- ((1-cyanocyclopropyl) amino) -4-fluoro-4-methyl-1-oxopentan-2-yl) -2- (trifluoromethyl) benzamide

6-bromo-2-trifluoromethylbenzoic acid (269mg,1.00mmol) was dissolved in anhydrous N, N-dimethylformamide (6mL) and dichloromethane (6mL), and (S) -2-amino-N- (1-cyanocyclopropyl) -4-fluoro-4-methylpentanamide hydrochloride (325mg,1.30mmol) was added, and (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (532mg,1.40mmol) and diisopropylethylamine (840mg,6.50mmol) were added at 0 deg.C and reacted for 1 hour at 0 deg.C. After completion of the reaction, saturated brine (50mL) was added, extraction was performed with ethyl acetate (30 mL. times.3), and the organic phases were combined, washed with saturated brine (50 mL. times.3), and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure gave the crude product which was purified by silica gel column chromatography (n-hexane/ethyl acetate (V/V) ═ 4/1) to give the title compound as a white solid (245mg, 52.78%).

MS(ESI,pos.ion)m/z:465.1(M+2).

And step 3: (S) -N- (1- ((1-cyanocyclopropyl) amino) -4-fluoro-4-methyl-1-oxopentan-2-yl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2- (trifluoromethyl) benzamide

To a two-necked flask were added (S) -4-bromo-N- (1- ((1-cyanocyclopropyl) amino) -4-fluoro-4-methyl-1-oxopentan-2-yl) -2- (trifluoromethyl) benzamide (0.93g,2.0mmol), pinacol diboron diborate (0.61g,2.4mmol), (1,1' -bis (diphenylphosphino) ferrocene) dichloropalladium dichloromethane complex (0.067g,0.08mmol), potassium acetate (0.7g,7.2mmol) and DMF (10mL), and heated to 85 ℃ for 3 hours under nitrogen protection. After completion of the reaction, it was cooled to room temperature, quenched with water, extracted with ethyl acetate (60 mL. times.2), and the organic phase was washed successively with water (60 mL. times.2) and saturated brine (60mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography (dichloromethane/ethyl acetate (V/V) ═ 30/1) to give the title compound (0.71g, 70%) as a white solid.

MS(ESI,pos.ion)m/z:512.2(M+1).

And 4, step 4: (S) -N- (1- ((1-cyanocyclopropyl) amino) -4-fluoro-4-methyl-1-oxopent-2-yl) -4'- (2-oxopyrrolidin-1-yl) -3- (trifluoromethyl) - [1,1' -diphenyl ] -4-carboxamide

To a two-necked flask were added (S) -N- (1- ((1-cyanocyclopropyl) amino) -4-fluoro-4-methyl-1-oxopentan-2-yl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2- (trifluoromethyl) benzamide (108mg,0.21mmol) and N, N-dimethylformamide (10mL), followed by 1- (4-bromophenyl) pyrrolidin-2-one (60mg,0.24mmol) and tetratriphenylphosphine palladium (12.7mg,0.011mmol) under nitrogen, and K was added₂CO₃An aqueous solution (0.22mL,0.44mmol,2mol/L) was added dropwise to the reaction mixture, and the reaction was carried out at 90 ℃ for 1 hour, after completion of the reaction, saturated saline (60mL) was added, extraction was carried out with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated saline (30mL × 3), dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the crude product was subjected to silica gel column chromatography (dichloromethane/ethyl acetate (V/V) ═ 5/1) to give the title compound as a white solid (66mg, 58%).

MS(ESI,pos.ion)m/z:545.2(M+1)；

¹H NMR(400MHz,CDCl₃)(ppm):7.87(s,1H),7.80-7.70(m,3H),7.58(t,J＝10.5Hz,4H),6.83(t,J＝6.9Hz,1H),4.90-4.71(m,1H),3.93(t,J＝7.0Hz,2H),2.67(t,J＝8.1Hz,2H),2.67(t,J＝8.1Hz,2H),2.31-2.26(m,1H),2.26-2.20(m,2H),1.60-1.50(m,2H),1.48(s,3H),1.45(s,3H),1.28(d,J＝11.4Hz,2H).

Examples 7 to 13

The compounds of examples 7 to 13 were prepared according to the synthetic schemes of the invention or the methods described in examples 1 to 6 using the corresponding starting materials, and the specific characterization data are as follows

Pharmacological experiment test method of biological embodiment cathepsin

Cathepsin K in vitro inhibition activity test method:

an 45000-fold dilution of the enzyme working solution was used, 10. mu.M of Z-Phe-Arg-AMC being used as substrate. According to optimized experimental conditions, a 15 microliter reaction system is used, a test compound and an enzyme are incubated for 15 minutes at 25 ℃, the kinetic slope of the reaction at 25 ℃ within 15 minutes is measured, and the IC of the compound on human cathepsin K is calculated₅₀The value is obtained.

Cathepsin B in vitro inhibition activity test method:

0.01 ng/. mu.L of Cathepsin B was used as the final concentration of the enzyme reaction, and Z-Phe-Arg-AMC as the substrate at a final concentration of 10. mu.M was added to the reaction system after incubation of the test compound with the enzyme at 25 ℃ for 15 minutes, and kinetic parameters were measured at 25 ℃ during the reaction for 10 minutes to calculate the IC of the test compound for human Cathepsin B₅₀The value is obtained.

Cathepsin L in vitro inhibitory activity test method:

0.01 ng/. mu.L of Cathepsin L is used as the final concentration of enzyme reaction, and Z-Phe-Arg-AMC with the final concentration of 10. mu.M is used as a substrate, and the substrate is added into a reaction system in which a test compound and an enzyme are incubated at 25 ℃ for 15 minutes, kinetic parameters in the reaction at 25 ℃ for 10 minutes are measured, and IC of the test compound on human Cathepsin L is calculated₅₀The value is obtained.

Cathepsin S in vitro inhibition activity test method:

0.25 ng/. mu.L of Cathepsin S is used as the final concentration of enzyme reaction, Z-VVR-AMC with the final concentration of 20. mu.M is used as a substrate, the substrate is added into a reaction system formed by incubating a test compound and an enzyme at 25 ℃ for 15 minutes, kinetic parameters of the reaction at 25 ℃ within 10 minutes are measured, and IC of a candidate compound on human Cathepsin S is calculated₅₀The value is obtained.

Table 1 in vitro activity test data for compounds of the invention

Conclusion

As can be seen from the data in the above table, the compound of the present invention has a good inhibitory activity against cathepsin K, but has a poor inhibitory activity against cathepsin B, cathepsin L and cathepsin S, and exhibits very high selectivity. Due to the high selectivity of the compound, off-target side effects caused by the selectivity of the compound are reduced, so that the possibility of developing the compound serving as a cathepsin K inhibitor for treating osteoporosis is greatly improved.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (9)

1. A compound of formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I),

wherein,

each R¹And R²Independently is H or C_1-4Alkyl, wherein said alkyl is optionally substituted with one or more halogen atoms;

or, R¹、R²And the carbon atoms connected with the carbon atoms form a saturated carbocycle or heterocycle consisting of 3-8 atoms, wherein the carbocycle or heterocycle is independently and optionally substituted by one or more selected from H, halogen and C_1-4Alkyl or halo C_1-4Alkyl is substituted by a substituent;

R³is C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkylsulfonyl radical, C_1-4Alkyl acyl radical, C_3-6Cycloalkyl or heteroaryl of 5 to 7 atoms, or R³Is of the sub-structure:

wherein, X¹is-O-, -S-, -CH₂-or-NH-;

X²is-O-, -S-or-CH₂-；

r is 0, 1,2 or 3;

y is O, S, CR^5aR^5bOr NR^5c；

Wherein each R is^5aAnd R^5bIndependently is H, nitro, cyano, hydroxy or C_1-4An alkyl group;

R^5cis H, cyano, hydroxy, C_1-4Alkyl, halo C_1-4Alkyl or C_1-4An alkoxy group;

wherein R is³Alkyl, haloalkyl, alkylsulfonyl, alkanoyl, cycloalkyl, heteroaryl of 5 to 7 atoms, subformula II-a and subformula II-b as defined in (a), are independently optionally substituted by one or more groups selected from H, oxo (═ O), fluoro, chloro, bromo, cyano, hydroxy, nitro, methyl, ethyl, propyl, butyl, hydroxyethyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, methylsulfonyl, acetyl, carboxy, methylsulfonylamino, carboxamido, carbamoyl, 2-hydroxypropan-2-yl or 2, 2-difluoro-1-hydroxy-ethylSubstituted by a substituent of the radical ethyl;

each R⁴Independently is H, fluoro, chloro, bromo, cyano, hydroxy, amino, methyl, methoxy, or trifluoromethyl;

each R⁵Independently is H, fluoro, chloro, bromo, methyl, ethyl or trifluoromethyl;

each m and n is independently 0, 1,2, 3 or 4.

2. The compound of claim 1, wherein,

each R¹And R²Independently H, methyl, ethyl, propyl or butyl, wherein said methyl, ethyl, propyl and butyl groups independently are optionally substituted with one or more fluorine atoms;

or, R¹、R²And the carbon atoms to which they are attached, together form a saturated carbocyclic ring of 5 to 7 atoms in which the carbocyclic ring is optionally substituted by one or more substituents selected from H, fluoro, chloro, methyl or trifluoromethyl.

3. The compound of claim 1, wherein,

R³is methyl, ethyl, propyl, butyl, trifluoromethyl, difluoromethyl, methylsulfonyl, ethylsulfonyl, acetyl, pyrazolyl, pyrrolyl, thiazolyl, triazolyl, tetrazolyl, oxazolyl, pyridyl, pyrimidinyl or pyrazinyl, or R³Is of the sub-structure:

wherein, X¹is-CH₂-or-NH-;

X²is-O-or-CH₂-；

r is 0, 1 or 2;

y is O or S;

wherein R is³The methyl group, ethyl group, propyl group, butyl group, difluoromethyl group, methylsulfonyl group, ethylsulfonyl group, and ethyl group as defined in (1)Acyl, pyrazolyl, pyrrolyl, thiazolyl, triazolyl, tetrazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, sub-formula II-a and sub-formula II-b are independently optionally substituted with one or more substituents selected from H, fluoro, chloro, bromo, cyano, hydroxy, nitro, methyl, ethyl, propyl, butyl, hydroxyethyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, 2-hydroxypropan-2-yl or 2, 2-difluoro-1-hydroxyethyl.

4. The compound of claim 3, wherein,

R³is methylsulfonyl, ethylsulfonyl, pyrazolyl, pyrrolyl, thiazolyl, triazolyl, oxazolyl or pyridyl, or R³Is of the sub-structure:

wherein R is³The methylsulfonyl, ethylsulfonyl, pyrazolyl, pyrrolyl, thiazolyl, triazolyl, oxazolyl, pyridyl and each sub-formula described in (1) are independently optionally substituted with one or more substituents selected from the group consisting of H, fluoro, chloro, bromo, hydroxy, methyl, ethyl, hydroxyethyl, methoxy, 2-hydroxypropan-2-yl or 2, 2-difluoro-1-hydroxyethyl.

5. The compound of claim 1, comprising the structure of one of:

or a stereoisomer thereofGeometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs.

6. A pharmaceutical composition comprising a compound of any one of claims 1-5; it further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.

7. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6 in the manufacture of a medicament for inhibiting cathepsin activity; wherein the cathepsin is cathepsin K.

8. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6 for the manufacture of a medicament for the treatment, prevention, alleviation or alleviation of osteoporosis, paget's disease, abnormal increase in bone turnover, periodontal disease, tooth loss, bone fracture, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, incomplete osteogenesis, metastatic bone disease, hypercalcemia of malignancy, or multiple myeloma disease in a patient.

9. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6 in the manufacture of a medicament for the treatment, prevention, alleviation or amelioration of a cathepsin dependent disease in a patient.