CN106478564A - Cathepsin K inhibitor and application thereof - Google Patents

Abstract

The present invention relates to inhibitor of cathepsin K and application thereof, specially one class is used for treatment or the compound (shown in formula (I)) of protease dependency disease, the including but not limited to inhibitor of cathepsin K are organized in prevention.Described compound and its pharmaceutical composition can serve as bone resorption inhibitor therapy-related disease.

Description

Cathepsin K inhibitor and application thereof

Background technology

Osteoporosises are old people's especially one of menopause and postmenopausal women commonly encountered diseases and frequently-occurring diseases.With work as For the change of spectrum of disease, WHO is classified as osteoporosis as one of big disease of person in middle and old age three, occupies the 7th in commonly encountered diseases.About 50% suffers osteoporosis the fracture causing over the women of 50 years old and 20% male.Treat osteoporotic common medicine at present Thing has anti-bone resorption medicine, promoting bone growing medicine, the above two dual function medicine, biological medicament and other drugs, but medicine Side effect is larger mostly, and new medicine is in urgent need.

Cathepsin (Cathepsin) is the Major Members of cysteine proteinase family, has been found that 20 in biosphere Remaining kind, is primarily present 11 kinds in human body, their close phases with multiple major disease such as human tumor, osteoporosises, arthritis Close.The Main Subtype of cathepsin Cathepsin B, F, H, L, K, S, W and Z in a organized way.Cathepsin S is mainly expressed in antigen In in delivery cell, because cathepsin S adjusts Antigen-presenting role, so being considered as the important target spot adjusting immunoreation. Cathepsin L participates in many special physiological process, such as incretogenous activation, antigen presentation, growth of histoorgan etc..Group Knit Cathepsin B to be all distributed in liver,spleen,kidney, bone, neurocyte, Stromal fibroblasts, macrophage etc., with the shape of proenzyme Formula is stored in lysosome, participates in many special physiological process, and such as incretogenous activation, antigen presentation, histoorgan is developed Deng.

Cathepsin K (being also abbreviated as cat K known to it) is also referred to as cathepsin O and cathepsin O 2. Cathepsin K optionally great expression in osteoclast, its physiological action substrate content exactly in organic bone matrix reaches 95% NTx, in addition it can also be degraded osteopontin and the osteonectin in bone matrix, is expression in osteoclast A kind of amount highest, bone resorption activity cysteine proteinase the strongest, it is significantly larger than various enzymes to the degradation capability becoming ossein, It is one of bone resorption process key enzyme, be also one of osteoporosises research in recent years focus.FDA does not ratify at present Any one anti-cathepsin K inhibitor, but the cathepsin inhibitors having correlation are carrying out clinical research.

Progress is the odanacatib of Mo Shadong faster at present, but due to also occurring in that some orders in clinical research The uneasy side effect sign of people, still in clinical stage.In human body, cathepsin K is very heavy to the effect of physiological process Want and extremely complex.In order to avoid broad spectrum activity suppression causes the other side effect beyond clinic, therefore design synthesis high selection The highly efficient depressor of property is extremely urgent.

Content of the invention

The present invention relates to a class is used for treatment or compound or the pharmaceutical composition of protease dependency disease are organized in prevention. The compounds of this invention has good inhibitory activity, IC to cathepsin K₅₀Value is all in nanomole level, and the group to other hypotypes The inhibitory activity knitting protease such as B, L and S etc., on micromolar levels, shows very high selectivity to cathepsin K. Cathepsin K, as one of bone resorption process key enzyme, is one of bone loss disorders research in recent years hot topic Target spot, but the presence due to the multiple hypotype of cathepsin, especially cathepsin B, these three cathepsins of L and S and K There is very high homology, and have very important physiological action in human body, cathepsin K inhibitor holds in human body very much Easily cause effect of missing the target, produce serious side effect, thus being one in terms of selectivity to exploitation cathepsin K inhibitor Challenge.The compounds of this invention not only has good inhibitory activity to cathepsin K, simultaneously also high to homology histone Enzyme B, L and S show very high selectivity, reduce the side effect of missing the target causing due to compound selectivity, thus significantly Improve and be used for treating the probability of osteoporosis agents exploitation as cathepsin K inhibitor.

The present invention provides a kind of compound, and it has the compound as shown in formula (I), or the stereoisomerism of shown compound Body, tautomer, geometric isomer, nitrogen oxides, prodrug or pharmaceutically acceptable salt,

Wherein, W, R³、R^3a、R²、R^2a、R⁴、R^4aAnd R⁵There is implication as described in the present invention.

In some embodiments, ring W is as follows one of subformula：

Wherein, * represents and R⁵Connected one end；

X is-O- ,-S- ,-C (=O)-or-N (R⁶)-；

V, Z and Y are each independently C (R⁹) or N；

Wherein R¹、R⁶And R⁹There is implication as described in the present invention.

In some embodiments, R¹For aryl, heteroaryl, cycloalkyl or heterocyclic radical；Wherein said aryl, heteroaryl, cycloalkanes Base and heterocyclic radical individually optional by 1,2,3,4 or 5 R^1aReplaced；Wherein R^1aThere is implication as described in the present invention.

In some embodiments, R¹For C_6-10Aryl, C_1-9Heteroaryl, C_3-12Cycloalkyl or C_2-12Heterocyclic radical；Wherein said each R¹ Individually optionally by 1,2,3,4 or 5 R^1aReplaced；

Wherein R^1aThere is implication as described in the present invention.

In some embodiments, R¹It is as follows subformula：

Wherein, each X¹、X²、X³、X⁹And X¹⁰It independently is CH or N；

Each X⁴、X⁵、X⁶、X⁷And X⁸It independently is-CH₂- ,-C (=O)-,-O- ,-S- ,-S (=O)-,-S (=O)₂- or- NH-；

Wherein said each R¹Individually optionally by 1,2,3,4 or 5 R^1aReplaced；Wherein R^1aHave as described in the present invention Implication.

In some embodiments, wherein R¹It is as follows subformula：

Wherein said each R¹ Individually optionally by 1,2,3,4 or 5 R^1aReplaced；Wherein R^1aThere is implication as described in the present invention.

In some embodiments, each R^1aIndependently be hydrogen, alkyl, haloalkyl, halogen, cyano group, oxo, alkoxyl, aryl, Heteroaryl, cycloalkyl, heterocyclic radical ,-SR¹⁴、-OR¹⁴、-SO₂-N(R¹³)(R^13a)、-N(R^13a)-SO₂-R¹⁴、-N(R¹³)(R^13a)、-C (=O)-C (=O)-N (R¹³)(R^13a) ,-C (=O)-N (R¹³)(R^13a)、-N(R¹³)-C (=O) R^14a,-C (=O)-OR¹⁴、-C (=O)-R^14aOr-SO₂R¹⁴；Each R^1aDescribed in aryl, heteroaryl, cycloalkyl, heterocyclic radical, alkyl, haloalkyl, alcoxyl Base ,-SR¹⁴、-OR¹⁴、-SO₂-N(R¹³)(R^13a)、-N(R^13a)-SO₂-R¹⁴、-N(R¹³)(R^13a) ,-C (=O)-C (=O)-N (R¹³) (R^13a) ,-C (=O)-N (R¹³)(R^13a)、-N(R¹³)-C (=O) R^14a,-C (=O)-OR¹⁴,-C (=O)-R^14aWith-SO₂R¹⁴Solely Stand optionally by 1,2,3,4 or 5 R^1bReplaced；

Each R^1bIt independently is hydrogen, alkyl, haloalkyl, thiazolinyl, alkynyl, alkoxyl, halogen, nitro, cyano group, hydroxyl, oxygen Generation ,-OR¹⁵、-SO₂R¹⁵、-N(R¹⁶)(R^16a) ,-C (=O)-N (R¹⁶)(R^16a), aryl, heteroaryl, cycloalkyl or heterocyclic radical；Institute The each R stating^1bOptionally further by 1,2,3,4 or 5 independently selected from hydroxyl, nitro, cyano group, alkyl, haloalkyl, halogen The substituent group of element, oxo, alkoxyl, aryl, heteroaryl, cycloalkyl, heterocyclic radical and amino is replaced；Wherein R¹⁵、R¹³、R^13a、 R¹⁴、R^14a、R¹⁶And R^16aThere is implication as described in the present invention.

In some embodiments, wherein each R^1aIt independently is hydrogen, C_1-6Alkyl, C_1-6Haloalkyl, halogen, cyano group, oxo, C_1-6Alkoxyl, C_6-10Aryl, C_1-9Heteroaryl, C_3-12Cycloalkyl, C_2-12Heterocyclic radical ,-SR¹⁴、-OR¹⁴、-SO₂-N(R¹³) (R^13a)、-N(R^13a)-SO₂-R¹⁴、-N(R¹³)(R^13a) ,-C (=O)-C (=O)-N (R¹³)(R^13a) ,-C (=O)-N (R¹³) (R^13a)、-N(R¹³)-C (=O) R^14a,-C (=O)-OR¹⁴,-C (=O)-R^14aOr-SO₂R¹⁴；Each R^1aDescribed in C_6-10Aryl, C_1-9Heteroaryl, C_3-12Cycloalkyl, C_2-12Heterocyclic radical, C_1-6Alkyl, C_1-6Haloalkyl, C_1-6Alkoxyl ,-SR¹⁴、-OR¹⁴、-SO₂- N(R¹³)(R^13a)、-N(R^13a)-SO₂-R¹⁴、-N(R¹³)(R^13a) ,-C (=O)-C (=O)-N (R¹³)(R^13a) ,-C (=O)-N (R¹³)(R^13a)、-N(R¹³)-C (=O) R^14a,-C (=O)-OR¹⁴,-C (=O)-R^14aWith-SO₂R¹⁴Individually optionally by 1,2,3, 4 or 5 R^1bReplaced；

Each R^1bIt independently is hydrogen, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_1-6Alkoxyl, halogen, nitre Base, cyano group, hydroxyl, oxo ,-OR¹⁵、-SO₂R¹⁵、-N(R¹⁶)(R^16a) ,-C (=O)-N (R¹⁶)(R^16a)、C_6-10Aryl, C_1-9Miscellaneous Aryl, C_3-12Cycloalkyl or C_2-12Heterocyclic radical；Described each R^1bIndividually optionally by 1,2,3,4 or 5 be selected from hydroxyl, nitro, Cyano group, C_1-6Alkyl, C_1-6Haloalkyl, halogen, oxo, C_1-6Alkoxyl, C_6-10Aryl, C_1-9Heteroaryl, C_3-12Cycloalkyl, C_2-12The substituent group of heterocyclic radical and amino is replaced；Wherein R¹⁵、R¹³、R^13a、R¹⁴、R^14a、R¹⁶And R^16aHave as described herein Implication.

In some embodiments, each R^1aIt independently is hydrogen, C_1-4Alkyl, C_1-4Haloalkyl, halogen, cyano group, oxo, C_1-4Alcoxyl Base ,-SR¹⁴、-OR¹⁴、-SO₂-N(R¹³)(R^13a)、-N(R^13a)-SO₂-R¹⁴、-N(R¹³)(R^13a) ,-C (=O)-C (=O)-N (R¹³)(R^13a)、- C (=O)-N (R¹³)(R^13a)、-N(R¹³)-C (=O) R^14a,-C (=O)-OR¹⁴,-C (=O)-R^14a、-SO₂R¹⁴Or subformula as follows：

Wherein, each Y¹、Y²、Y³、Y⁹And Y¹⁰It independently is CH or N；

Each Y⁴、Y⁵、Y⁶、Y⁷And Y⁸It independently is-CH₂- ,-C (=O)-,-O- ,-S- ,-S (=O)-,-S (=O)₂- or- NH-；

Wherein said each R^1aIndividually optionally by 1,2,3,4 or 5 R^1bReplaced；

Each R^1bIt independently is hydrogen, C_1-4Alkyl, C_1-4Haloalkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_1-4Alkoxyl, halogen, nitre Base, cyano group, hydroxyl, oxo ,-OR¹⁵、-SO₂R¹⁵、-N(R¹⁶)(R^16a) ,-C (=O)-N (R¹⁶)(R^16a) or structure shown below Formula： Wherein, each Z¹、Z²、Z³、Z⁹And Z¹⁰It independently is CH or N；

Each Z⁴、Z⁵、Z⁶、Z⁷And Z⁸It independently is-CH₂- ,-C (=O)-,-O- ,-S- ,-S (=O)-,-S (=O)₂- or- NH-；

Described each R^1bIt is selected from hydroxyl, nitro, cyano group, C by 1,2,3,4 or 5 individually optionally_1-4Alkyl, C_1-4Halo Alkyl, halogen, oxo, C_1-4Alkoxyl, phenyl, 5-6 unit's heteroaryl, the replacement of 4-7 unit cycloalkyl, 4-7 circle heterocycles base and amino Base is replaced；

Wherein R¹⁵、R¹³、R^13a、R¹⁴、R^14a、R¹⁶And R^16aThere is implication as described in the present invention.

In some embodiments, each R^1aIt independently is hydrogen, ethyl, methyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, cyanogen Base, trifluoromethyl, 2,2- bis- fluoro ethyl, 3,3,3- trifluoro propyl, fluorine, chlorine, bromine, oxo, methoxyl group, positive propoxy, ethyoxyl, Tert-butoxy, 2- methyl propoxyl group, isopropoxy ,-SR¹⁴、-OR¹⁴、-SO₂-N(R¹³)(R^13a)、-N(R^13a)-SO₂-R¹⁴、-N (R¹³)(R^13a) ,-C (=O)-C (=O)-N (R¹³)(R^13a) ,-C (=O)-N (R¹³)(R^13a)、-N(R¹³)-C (=O) R^14a、-C (=O)-OR¹⁴,-C (=O)-R^14a、-SO₂R¹⁴Or subformula as follows：

Wherein said each R^1aIndividually optionally by 1,2,3,4 or 5 R^1bReplaced；

Each R^1bIt independently is hydrogen, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, cyclopropyl, cyclobutyl, ring Hexyl, cyclopenta, difluoromethyl, trifluoromethyl, 2,2- bis- fluoro ethyl, 3,3,3- trifluoro propyl, vinyl, acrylic, allyl Base, acetenyl, propinyl, propargyl, methoxyl group, fluorine, chlorine, bromine, nitro, cyano group, hydroxyl, oxo ,-OR¹⁵、-SO₂R¹⁵、-N (R¹⁶)(R^16a) ,-C (=O)-N (R¹⁶)(R^16a) or structure shown below formula：

Described each R^1bIt is selected from hydroxyl, nitro, cyano group, methyl, ethyl, just by 1,2,3,4 or 5 individually optionally Propyl group, isopropyl, normal-butyl, the tert-butyl group, difluoromethyl, trifluoromethyl, 2,2- bis- fluoro ethyl, 3,3,3- trifluoro propyl, fluorine, Chlorine, bromine, oxo, methoxyl group, ethyoxyl, isopropoxy, tert-butoxy, phenyl, pyridine radicals, thiazolyl, thienyl, di azoly, Triazolyl, tetrazole radical, oxetanes, tetrahydrofuran base, THP trtrahydropyranyl, morpholinyl, piperidyl, cyclobutyl, cyclopenta, The substituent group of epoxy six ring group, cyclohexyl and amino is replaced；

Wherein R¹⁵、R¹³、R^13a、R¹⁴、R^14a、R¹⁶And R^16aThere is implication as described in the present invention.

R in some embodiments^4aFor hydrogen, C_2-6Alkyl or C_2-6Thiazolinyl；Wherein said C_2-6Alkyl and C_2-6Thiazolinyl is individually optional Ground is selected from halogen, C by 1,2,3,4,5 or 6_3-6Cycloalkyl, cyano group, C_6-10Aryl, C_1-9Heteroaryl and C_2-9The replacement of heterocyclic radical Base is replaced；

R⁴For hydrogen, C_2-6Alkyl ,-C (R⁷)(R^7a)-R⁸、C_3-9Heterocyclic radical or C_2-6Thiazolinyl；Wherein said C_2-6Alkyl and C_2-6Alkene Base is selected from halogen, C by 1,2,3,4,5 or 6 individually optionally_3-6Cycloalkyl, cyano group, C_6-10Aryl, C_1-9Heteroaryl and C_3-9Miscellaneous The substituent group of ring group is replaced；

Or R⁴And R^4aForm a nitrogenous C together with the nitrogen-atoms being connected with them_3-9Heterocyclic radical；Wherein said C_3-9Heterocycle Base is optionally selected from C by 1,2,3,4 or 5_1-6Alkyl, C_1-6Hydroxy alkyl, cyano group ,-C (R¹⁰)(R^10a)-C (=O)-N (R¹²) (R^12a) ,-C (=O)-OR^8a, oxo, C_1-6The substituent group of haloalkyl and halogen is replaced；

Wherein R¹⁰、R^10a、R¹²、R^12a、R^8a、R⁷、R^7aAnd R⁸There is implication as described in the present invention.

In some embodiments, R^4aFor hydrogen, ethyl, n-pro-pyl or isopropyl；

R⁴For ethyl, n-pro-pyl, isopropyl ,-C (R⁷)(R^7a)-R⁸, 5-6 circle heterocycles base or vinyl；

Or R⁴And R^4aForm following subformula together with the nitrogen-atoms being connected with them： Wherein R⁴And R^4aThe member ring systems being formed together with the nitrogen-atoms being connected with them are optionally selected from C by 1,2,3,4 or 5_1-4Alkyl, C_1-4Hydroxy alkyl, oxo, cyano group ,-C (R¹⁰)(R^10a)-C (=O)-N (R¹²)(R^12a) ,-C (=O)-OR^8a、C_1-4Haloalkyl Replaced with the substituent group of halogen；Wherein R¹⁰、R^10a、R¹²、R^12a、R^8a、R⁷、R^7aAnd R⁸There is implication as described in the present invention.

In some embodiments, R⁷And R^7aIt is each independently hydrogen, C_1-6Alkyl ,-C (R¹⁰)(R^10a)-C (=O)-N (R¹²) (R^12a) ,-C (=O)-OR^8a、C_2-9Heterocyclic radical or C_2-6Thiazolinyl；

Or R⁷And R^7aForm a C together with the carbon atom being connected with them_3-6Carbocyclic ring or C_2-6Heterocycle；Wherein said C_3-6Carbon Ring and C_2-6Heterocycle is selected from C by 1,2,3,4,5 or 6 individually optionally_1-6Alkyl, C_1-6Hydroxy alkyl, C_1-6Haloalkyl, oxygen Generation, cyano group ,-C (=O)-OR^8aOr the substituent group of halogen is replaced；

R⁸For C_1-6Alkyl, cyano group ,-N (R¹²)(R^12a) ,-C (=O)-C (=O)-N (R¹²)(R^12a) ,-C (=O)-N (R¹²) (R^12a) ,-C (=O)-OR^8a、C_3-6Heterocyclic radical or C_2-6Thiazolinyl；

Wherein R¹⁰、R^10a、R¹²、R^12a, and R^8aThere is implication as described in the present invention.

In some embodiments, R⁷And R^7aIt is each independently hydrogen, C_1-4Alkyl ,-C (R¹⁰)(R^10a)-C (=O)-N (R¹²) (R^12a) ,-C (=O)-OR^8a、C_3-6Heterocyclic radical or C_2-6Thiazolinyl；

Or R⁷And R^7aFormed together with the carbon atom being connected with them cyclopropyl, cyclopenta, cyclobutyl, cyclohexyl, Quinoline base, piperidyl or pyrrolidinyl；Wherein said cyclopropyl, cyclopenta, cyclobutyl, cyclohexyl, morpholinyl, piperidyl and pyrroles Alkyl is selected from C by 1,2,3,4 or 5 individually optionally_1-4Alkyl, C_1-4Hydroxy alkyl, C_1-4Haloalkyl, oxo, cyano group ,-C (=O)-OR^8aReplaced with the substituent group of halogen；

R⁸For hydrogen, C_1-4Alkyl, cyano group ,-N (R¹²)(R^12a) ,-C (=O)-C (=O)-N (R¹²)(R^12a) ,-C (=O)-N (R¹²)(R^12a) ,-C (=O)-OR^8a、C_3-6Heterocyclic radical or C_2-6Thiazolinyl；

Wherein R¹⁰、R^10a、R¹²、R^12a, and R^8aThere is implication as described in the present invention.

In some embodiments, each R^8a、R¹⁰、R^10a、R¹²And R^12aIt independently is hydrogen or C_1-6Alkyl；Wherein said C_1-6Alkyl Optionally it is selected from halogen, hydroxyl, amino, carboxyl, cyano group, C by 1,2,3,4,5 or 6_3-6Cycloalkyl, C_6-10Aryl, C_1-9Heteroaryl Base and C_2-9The substituent group of heterocyclic radical is replaced.

In some embodiments, each R^8a、R¹⁰、R^10a、R¹²And R^12aIt independently is hydrogen or C_1-4Alkyl；Wherein said C_1-4Alkyl Optionally it is selected from halogen, hydroxyl, amino, carboxyl, cyano group, C by 1,2,3,4 or 5_3-6Cycloalkyl, C_6-10Aryl, C_1-9Heteroaryl And C_2-9The substituent group of heterocyclic radical is replaced.

In some embodiments, each R^8a、R¹⁰、R^10a、R¹²And R^12aIndependently be hydrogen, methyl, ethyl, n-pro-pyl, isopropyl, 1- methyl-propyl, 2- methyl-propyl or the tert-butyl group；Wherein said methyl, ethyl, n-pro-pyl, isopropyl, 1- methyl-propyl, 2- first Base propyl group and the tert-butyl group are selected from fluorine, chlorine, bromine, hydroxyl, amino, carboxyl, cyano group, hexamethylene by 1,2,3,4,5 or 6 individually optionally Base, cyclopenta, cyclobutyl, cyclopropyl, suberyl, phenyl, pyridine radicals, thiazole, di azoly, triazolyl, piperidyl, furyl, The substituent group of tetrahydrofuran base, azelidinyl, oxetanylmethoxy and morpholinyl is replaced.

In some embodiments, R³、R^3a、R²And R^2aIt is each independently hydrogen or C_1-6Alkyl；Wherein said C_1-6Alkyl is optional Ground is selected from halogen, hydroxyl, amino, carboxyl, cyano group, C by 1,2,3,4,5 or 6_3-6Cycloalkyl, C_6-10Aryl, C_6-10Heteroaryl and C_2-9The substituent group of heterocyclic radical is replaced；

Or R²、R^2aAnd form a C together with the carbon atom being connected with them_3-9Carbocyclic ring or C_2-9Heterocycle；Wherein said C_3-9Carbon Ring and C_2-9Heterocycle is selected from C by 1,2,3,4,5 or 6 individually optionally_1-6Alkyl, C_2-6Thiazolinyl, C_1-6Hydroxy alkyl, C_1-6Halo The substituent group of alkyl, hydroxyl, amino, carboxyl, cyano group and halogen is replaced；

Or R³、R^3aAnd form one together with the carbon atom being connected with them>C (=O), C_3-9Carbocyclic ring or C_2-9Heterocycle；Wherein Described C_3-9Carbocyclic ring and C_2-9Heterocycle is selected from C by 1,2,3,4,5 or 6 individually optionally_1-6Alkyl, C_2-6Thiazolinyl, C_1-6Hydroxyl alkane Base, C_1-6The substituent group of haloalkyl, hydroxyl, amino, carboxyl, cyano group and halogen is replaced.

In some embodiments, R³、R^3a、R²And R^2aIt is each independently hydrogen, methyl, ethyl, n-pro-pyl, isopropyl, 1- first Base propyl group, 2- methyl-propyl or the tert-butyl group；Wherein said methyl, ethyl, n-pro-pyl, isopropyl, 1- methyl-propyl, 2- methyl-prop Base and the tert-butyl group individually optionally by 1,2,3,4,5 or 6 be selected from fluorine, chlorine, bromine, hydroxyl, amino, carboxyl, cyano group, cyclohexyl, Cyclopenta, cyclobutyl, cyclopropyl, suberyl, phenyl, pyridine radicals, thiazolyl, di azoly, triazolyl, piperidyl, furyl, four The substituent group of hydrogen furyl, azelidinyl, oxetanylmethoxy and morpholinyl is replaced；

Or R²、R^2aAnd form cyclohexyl, cyclopenta, cyclobutyl, cyclopropyl, a ring together with the carbon atom being connected with them Heptyl, piperidyl, pyrrolidinyl, piperazinyl, THP trtrahydropyranyl, morpholinyl or tetrahydrofuran base；Wherein said cyclohexyl, ring penta Base, cyclobutyl, cyclopropyl, suberyl, piperidyl, pyrrolidinyl, piperazinyl, THP trtrahydropyranyl, morpholinyl and tetrahydrofuran base Individually optionally by 1,2,3,4 or 5 independently selected from C_1-4Alkyl, C_2-4Thiazolinyl, C_1-4Hydroxy alkyl, C_1-4Haloalkyl, hydroxyl The substituent group of base, amino, carboxyl, cyano group, fluorine, chlorine and bromine is replaced；

Or R³、R^3aAnd form one together with the carbon atom being connected with them>C (=O), cyclohexyl, cyclopenta, cyclobutyl, Cyclopropyl, suberyl, piperidyl, pyrrolidinyl, piperazinyl, THP trtrahydropyranyl, morpholinyl or tetrahydrofuran base, wherein said ring Hexyl, cyclopenta, cyclobutyl, cyclopropyl, suberyl, piperidyl, pyrrolidinyl, piperazinyl, THP trtrahydropyranyl, morpholinyl and four Hydrogen furyl is selected from C by 1,2,3,4 or 5 individually optionally_1-4Alkyl, C_1-4Hydroxy alkyl, C_1-4Haloalkyl, hydroxyl, ammonia The substituent group of base, carboxyl, cyano group and halogen is replaced.

In some embodiments, each R⁶And R^6aIt independently is hydrogen or C_1-6Alkyl；Wherein said C_1-6Alkyl optionally by 1,2, 3rd, 4,5 or 6 independently selected from halogen, hydroxyl, amino, carboxyl, cyano group, C_3-6Cycloalkyl, C_6-10Aryl, C_1-9Heteroaryl and C_2-9The substituent group of heterocyclic radical is replaced.

In some embodiments, each R⁶And R^6aIt independently is hydrogen or C_1-4Alkyl；Wherein said C_1-4Alkyl optionally by 1,2, 3rd, 4,5 or 6 independently selected from halogen, hydroxyl, amino, carboxyl, cyano group, C_3-6Cycloalkyl, C_6-10Aryl, C_1-9Heteroaryl and C_2-9The substituent group of heterocyclic radical is replaced.

In some embodiments, each R⁶And R^6aIt independently is hydrogen, methyl, ethyl, n-pro-pyl, isopropyl, 1- methyl-propyl, 2- Methyl-propyl or the tert-butyl group；Wherein said methyl, ethyl, n-pro-pyl, isopropyl, 1- methyl-propyl, 2- methyl-propyl and tertiary fourth Base is selected from fluorine, chlorine, bromine, hydroxyl, amino, carboxyl, cyano group, cyclohexyl, cyclopenta, ring by 1,2,3,4,5 or 6 individually optionally Butyl, cyclopropyl, suberyl, phenyl, pyridine radicals, thiazole, di azoly, triazolyl, piperidyl, furyl, tetrahydrofuran base, nitrogen The substituent group of heterocycle butyl, oxetanylmethoxy and morpholinyl is replaced.

In some embodiments, each R⁹It independently is hydrogen, halogen, cyano group, hydroxyl, C_1-4Alkoxyl ,-N (R⁶)(R^6a)、C_1-4Halogen Substituted alkyl or C_1-4Alkyl；Wherein said C_1-4Alkyl is optionally selected from halogen, C by 1,2,3,4,5 or 6_3-6Cycloalkyl, C_6-10 Aryl, C_1-9Heteroaryl and C_2-9The substituent group of heterocyclic radical is replaced；Wherein, R⁶And R^6aThere is implication as described in the present invention.

In some embodiments, each R⁹Independently be hydrogen, fluorine, chlorine, bromine, cyano group, hydroxyl, methoxyl group, amino, methyl, ethyl, Isopropyl or trifluoromethyl.

In some embodiments, R⁵For hydrogen, C_1-4Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_1-6Alkoxyl, halogen, nitro, cyanogen Base ,-N (R⁶)(R^6a) or C_1-4Haloalkyl；Wherein R⁶And R^6aThere is implication as described in the present invention.

In some embodiments, each R⁵It independently is hydrogen, fluorine, chlorine, bromine, cyano group, hydroxyl, nitro, amino, methyl, ethyl, different Propyl group, the tert-butyl group, methoxyl group, ethyoxyl, difluoromethyl or trifluoromethyl.

In some embodiments, each R¹⁶And R^16aIt independently is hydrogen, C_1-4Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_6-10Aryl, C_1-9 Heteroaryl, C_3-6Cycloalkyl ,-SO₂R¹⁷、-N(R¹⁸)(R^18a)、C_1-4Haloalkyl or C_2-9Heterocyclic radical；Wherein R¹⁷、R¹⁸And R^18aTool There is implication as described in the present invention.

In some embodiments, each R¹⁶And R^16aIt independently is hydrogen or C_1-4Alkyl.

In some embodiments, each R¹⁷、R¹⁸And R^18aIt independently is hydrogen, C_1-4Alkyl, C_1-4Haloalkyl, C_2-6Thiazolinyl, C_2-6 Alkynyl, C_6-10Aryl, C_1-9Heteroaryl, C_3-6Cycloalkyl or C_2-9Heterocyclic radical.

In some embodiments, each R¹⁷、R¹⁸And R^18aIndependently be hydrogen, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, The tert-butyl group, trifluoromethyl, 2,2- difluoromethyl, 2,2- bis- fluoro ethyl, 3,3,3- trifluoro propyl, phenyl, cyclobutyl, cyclohexyl, Morpholinyl, oxetanyl, azelidinyl, tetrahydrofuran base or THP trtrahydropyranyl.

In some embodiments, each R¹⁵、R^15a、R¹³、R^13a、R¹⁴And R^14aIt independently is hydrogen, C_1-4Alkyl, C_1-4Haloalkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_6-10Aryl, C_1-9Heteroaryl, C_3-6Cycloalkyl or C_2-9Heterocyclic radical.

In some embodiments, each R¹⁵、R¹³、R^13a、R¹⁴And R^14aIt independently is hydrogen, C_1-4Alkyl, C_1-4Haloalkyl, C_2-6Alkene Base, C_2-6Alkynyl, phenyl, 5-6 unit's heteroaryl, C_3-6Cycloalkyl or 4-7 circle heterocycles base.

In some embodiments, each R¹⁵、R^15a、R¹³、R^13a、R¹⁴And R^14aIt independently is hydrogen, methyl, ethyl, n-pro-pyl, isopropyl Base, normal-butyl, the tert-butyl group, trifluoromethyl, 2,2- difluoromethyl, 2,2- bis- fluoro ethyl, 3,3,3- trifluoro propyl, phenyl, ring fourth Base, cyclohexyl, morpholinyl, oxetanyl, azelidinyl, tetrahydrofuran base or THP trtrahydropyranyl.

In some embodiments, compound of the present invention, it is the compound shown in formula (Ia) or compound shown in it Stereoisomer, tautomer, geometric isomer, nitrogen oxides or pharmaceutically acceptable salt；

Wherein X, Z, Y, V, R¹、R⁵、R³、R^3a、R²、R^2a、R⁴And R^4aThere is implication as described in the present invention.

In some embodiments, compound of the present invention, it is the compound shown in formula (II) or compound shown in it Stereoisomer, tautomer, geometric isomer, nitrogen oxides or pharmaceutically acceptable salt；

Wherein X, Z, Y, V, R¹、R⁵、R³、R^3a、R²、R^2a、R⁷And R^7aThere is implication as described in the present invention.

In some embodiments, compound of the present invention, it is the compound shown in formula (III) or compound shown in it Stereoisomer, tautomer, geometric isomer, nitrogen oxides or pharmaceutically acceptable salt；

Wherein X, Z, Y, V, R¹、R⁵、R²And R^2aThere is implication as described in the present invention.

In some embodiments, compound of the present invention, it is the compound shown in formula (IV) or compound shown in it Stereoisomer, tautomer, geometric isomer, nitrogen oxides or pharmaceutically acceptable salt；

Wherein R¹、R⁵、R²And R^2aThere is implication as described in the present invention.

In some embodiments, compound of the present invention, it is as follows one of compound, or compound shown in it Stereoisomer, tautomer, geometric isomer, nitrogen oxides or pharmaceutically acceptable salt：

On the one hand, the present invention provides a kind of pharmaceutical composition, comprises compound of the present invention and pharmaceutically acceptable Carrier, excipient, diluent, at least one in adjuvant and vehicle.

In some embodiments, pharmaceutical composition of the present invention, further optionally comprise organic bisphosphonate compound Thing (as Allan sodium phosphate), estrogenic agents (as Evista), erss regulator are (as estradiol, combination Estrogen), androgen receptor modifier, osteoclast proton triphosphatase inhibitor, HMG-CoA reductase inhibitor, Integrain receptor antagaonists, osteoblast anabolic agent, activated vitamin D are (as 1 α-hydroxyvitamin D (alfacalcidol), 1,25- Double hydroxyvitamin D (Calcitriol)), phytoestrogen (eprazinone), calcitonin class (as Miacalcic), Strontium Ranelate, difficult to understand work as Card is for another kind of material of (Odanacatib), ONO5334, MIV-711, MIV-710 and its medicinal salt and mixture.

On the one hand, compound of the present invention or pharmaceutical composition of the present invention purposes in preparing medicine, Wherein, described medicine is used for inhibiting cathepsin activity.

On the one hand, compound of the present invention or pharmaceutical composition of the present invention purposes in preparing medicine, Wherein, described medicine is used for treating Cathepsin dependent diseases.

In some embodiments, compound of the present invention or pharmaceutical composition of the present invention are in preparing medicine Purposes, described medicine is used for the activity of inhibiting cathepsin K.

In some embodiments, compound of the present invention or pharmaceutical composition of the present invention are in preparing medicine Purposes, described medicine is used for treating, prevents, mitigating or reduction of patient osteoporosises, Paget, bone update anomalies increase, Periodontal, tooth loss, fracture, rheumatoid arthritiss, osteoarthritis, periprosthetic osteolysis, osteogenesis not exclusively, turn Shifting property osteopathia, malignant hypercalcemia, multiple myeloma, multiple sclerosis, myasthenia graviss, psoriasiss, ordinary sky born of the same parents Skin ulcer, exophthalmic goiter, systemic lupus erythematosus (sle), asthma, pain, atherosclerosiss, bone lesion, the abnormal increasing of stock turnover Plus, the disease of the hypercalcemia of malignant tumor, obesity or Bone tumour.

" Cathepsin dependent diseases or disease " refers to depend on the disease of one or more cathepsin active Disease of science." cathepsin K dependence disease or disease " refers to depend on the disease of the activity of cathepsin K.With The relevant disease of Cathepsin K activities includes osteoporosises, the Osteoporosis of glucocorticoid inducible, Paget, bone Update anomalies increase, periodontal, tooth loss, fracture, rheumatoid arthritiss, osteoarthritis, periprosthetic osteolysis, bone Generate incomplete, metastatic bone disease, malignant hypercalcemia and multiple myeloma.With present invention chemical combination required for protection When thing is treated to such disease, required therapeutic dose will be changed with specific disease, and those skilled in the art are permissible Easily it is determined.

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects and other aspect Content is made more specific complete description below.

Detailed description of the invention book

Definition and general terms

Describe certain embodiments of the present invention in detail now, the example is by the structural formula enclosed and chemical formula explanation.This Invention intention covers all of replacement, modification and equivalent technical solutions, and they are included in as the present invention of claim definition In the range of.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method described herein and material Trample the present invention.The present invention is not limited to method described herein and material.In the document being combined, patent and similar material one Or many different from the application or conflicting in the case of (including but not limited to defined term, term application, described Technology, etc.), be defined by the application.

It will further be appreciated that some features of the present invention, it is clearly visible, carry out in multiple independent embodiments Description is but it is also possible to provide in combination in single embodiment.Conversely, the various features of the present invention, for brevity, Single embodiment is described but it is also possible to individually or with the sub-portfolio being arbitrarily suitable for provide.

Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.All patents according to the present invention and public publication are integrally incorporated this by reference Bright.

Unless otherwise indicated it should application is used herein obtains following definition.For purposes of the present invention, chemical element with Periodic table of elements CAS version, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can be joined Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley&Sons,New York:Description in 2007, entire contents are incorporated herein by.

There are unless otherwise stated or in context obvious conflict, article " " used herein, " one (kind) " " described " is intended to including " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (being at least one) object.For example, " component " refers to one or more components it is possible to have more than one Component be taken into account in the embodiment of described embodiment using or use.

Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.Tested right As for example also referring to primate (the such as mankind, sex), cattle, sheep, goat, horse, dog, cat, rabbit, rat, little Mus, fish, bird etc..In certain embodiments, described study subject is primate.In other embodiments, described it is subject to Examination to as if people.

Term " patient " used in the present invention refers to people's (including adult and child) or other animals.In some enforcements In scheme, " patient " refers to people.

Term "comprising" is open language, that is, include the content specified by the present invention, but be not precluded from otherwise Content.

" stereoisomer " refers to there is identical chemical constitution, but the spatially different change of arrangement mode of atom or group Compound.Stereoisomer includes enantiomer, diastereomer, conformer (rotamer), geometric isomer (cis/trans) isomer, atropisomer, etc.." chiral " be have with its mirror image can not overlapping property molecule；And " non-handss Property " refers to molecule that can be overlapping with its mirror image." enantiomer " refer to two of a compound can not be overlapping but be mutually The isomer of mirror image relationship." diastereomer " refers to two or more chiral centres and its molecule not mirror image each other Stereoisomer.Diastereomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Diastereomeric Isomer mixture can be by high resolution analysises operation as electrophoresis and chromatograph, and such as HPLC is separating.Used in the present invention vertical Body chemistry definition and rule typically follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；And Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley＆Sons, Inc., New York, 1994.Permitted Many organic compound are existed with optical active forms, and that is, they have the ability making the plane of linearly polarized light rotate.? During description optically active compound, represent that molecule is exhausted with regard to one or more chiral centre using prefix D and L or R and S To configuration.Prefix d and l or (+) and (-) are the symbols for linearly polarized light rotation caused by appointed compound, wherein (-) or l Represent that compound is left-handed.Prefix be (+) or the compound of d be dextrorotation.A kind of specific stereoisomer is that mapping is different Structure body, the mixture of this isomer is referred to as enantiomeric mixture.The 50 of enantiomer:50 mixture are referred to as raceme Mixture or racemic modification, when chemical reaction or during there is no stereo selectivity or stereospecificity when, may occur in which this Situation.Any asymmetric atom (for example, carbon etc.) of the open compound of the present invention can be enriched with raceme or enantiomer Form exists, for example (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration aspect there is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer Excessive.

According to the selection of starting material and method, the compounds of this invention can with one of possible isomer or they Mixture, the form of such as racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits ?.Optically active (R)-or (S)-isomer using chiral synthon or chiral reagent preparation, or can be torn open using routine techniquess Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing dibasic cycloalkanes in compound Base, the substituent group of cycloalkyl may have cis or trans configuration.

The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or substantially pure geometric isomer, enantiomer, diastereomer, for example, by chromatography and/or fractional crystallization Method.

With known method, the racemic modification of any gained end-product or intermediate can be passed through those skilled in the art Familiar method splits into optical antipode, e.g., by carrying out to its diastereoisomeric salt obtaining separating.Racemic product Thing can also be separated by chiral chromatogram, e.g., using the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomer can be prepared by asymmetric synthesis, for example, refers to Jacques, et al., Enantiomers, Racemates and Resolutions(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.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007).

Term " tautomer " or " tautomeric form " refer to that Tong Guo the mental retardation with different-energy builds (low Energy barrier) mutual inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical equilibrium of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include migrating, by proton, the mutual inversion of phases to carry out, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the restructuring of some bonding electronss Lai The mutual inversion of phases carrying out.The instantiation of ketoenol tautomerization is pentane -2,4- diketone and 4- hydroxyl amyl- 3- alkene -2- ketone is mutual The change of tautomeric.Another example tautomeric is phenol-keto tautomerism.One of phenol-keto tautomerism is specifically real Example is pyridine -4- alcohol and the change of pyridine -4 (1H) -one tautomer.Unless otherwise noted, the compounds of this invention is all Tautomeric forms are within the scope of the present invention.

In each several part of this specification, the substituent group of the open compound of the present invention is open according to radical species or scope.Special Do not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.For example, term “C₁-C₆Alkyl " refers in particular to individually disclosed methyl, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

In each several part of the present invention, describe connect substituent.When this structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.For example, if this structure needs linking group and for this The Markush group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively The alkylidene group connecting or arylene group.

As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, such as General formula compound above, or as special example inside embodiment, subclass, and the class compound that the present invention is comprised. Should be appreciated that " optionally substituted " this term and " substituted or non-substituted " this term can exchange use.In general, art Before language " optionally " is whether located at term " substituted ", represent that one or more of given structure hydrogen atom can be by Concrete substituent group is replaced.Unless other aspects show, an optional substituted radical can have a substituent group in group Each commutable position is replaced.When in given structural formula, more than one position can be selected from one of concrete group Or multiple substituent group is replaced, then substituent group can replace in each position identical or differently.Wherein said substituent group Can be, but be not limited to：Hydrogen, oxo (=O), alkyl, fluorine, chlorine, bromine, amino, hydroxyl, carboxyl, alkoxyl, alkylamino, halogen Substituted alkyl, aldehyde radical, cyano group, heterocyclic radical, H-C (H)₂- O-C (=O)-C (H)₂-, H₂N-C(H)₂-, H-C (H)₂-SO₂-C(H)₂-, HO-C(H)₂-, HO- (CH₂)-C (=O)-, NH₂- C (=O)-, CN-C (H)₂- C (=O)-, heteroaryl, cycloalkyl or nitro etc..

Terminology used in the present invention " alkyl " includes the univalence hydrocarbyl of 1-20 carbon atom saturated straight chain or side chain, wherein alkane Base can be replaced by one or more substituent groups described in the invention individually optionally.Some of them embodiment is, alkyl Group contains 1-10 carbon atom, and other embodiment is that alkyl group contains 1-8 carbon atom, other embodiment It is that alkyl group contains 1-6 carbon atom, other embodiment is that alkyl group contains 1-4 carbon atom, other Embodiment is that alkyl group contains 1-3 carbon atom, and other embodiment is that alkyl group contains 2-6 carbon atom.Alkane Base group further example includes, but is not limited to, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, 2- methyl-propyl Or isobutyl group, 1- methyl-propyl or sec-butyl, the tert-butyl group, n-pentyl, 2- amyl group, 3- amyl group, 2- methyl -2- butyl, 3- methyl - 2- butyl, 3- methyl isophthalic acid-butyl, 2-methyl-1-butene base, n-hexyl, 2,3- dimethyl -2- butyl, 3,3- dimethyl -2- fourths Base, n-heptyl, n-octyl, etc..Term " alkyl " and its prefix " alkane " are being used herein as, and all comprise the saturation of straight chain and side chain Carbochain.

Term " thiazolinyl " refers to comprise 2 to 10 carbon atoms and the straight or branched of at least one carbon-carbon double bond is non-aromatic Alkyl.There is preferably 1 carbon-carbon double bond, and there may be up to 4 non-aromatic carbon-carbon double bonds.Therefore, " C_2-6Thiazolinyl " Refer to the thiazolinyl with 2 to 6 carbon atoms.Thiazolinyl includes vinyl, acrylic, cyclobutenyl and cyclohexenyl group.It is being related to alkane In description above base, the straight chain of this thiazolinyl, side chain or annulus can comprise double bond and if point out it is substituted Thiazolinyl when can be substituted.

Term " alkynyl " refers to comprise the straight or branched hydrocarbon comprising 2 to 10 carbon atoms of at least one triple carbon-carbon bonds Base.There may be up to 3 triple carbon-carbon bonds.Therefore, " C_2-6Alkynyl " refers to the alkynyl with 2 to 6 carbon atoms.Alkynyl bag Include acetenyl, propinyl and butynyl.In being related to described form above alkyl, the straight chain of this alkyl, side chain or ring Shape partly can comprise three keys, and if points out it is can be substituted during substituted alkyl.

Term " haloalkyl " represents the situation that alkyl can be replaced by one or more identical or different halogen atoms. Wherein alkyl group has implication as described in the present invention, and such example includes, but is not limited to trifluoromethyl, 1- chloroethene Base, difluoromethyl, Dichloroethyl, 2,2- bis- fluoro ethyls, 3,3,3- trifluoro propyls, 2- fluoro- 2- methyl-propyl etc..

Term " hydroxy alkyl " represents the situation that alkyl can be replaced by one or more hydroxyls.Wherein alkyl group tool There is implication as described in the present invention, such example includes, but is not limited to hydroxymethyl, 1- hydroxyethyl, two (hydroxyl) second Base, 2,2- bis- (hydroxyl) ethyl etc..

Term " amino " refers to-NH₂.

Term " oxo " refers to=O.

Term " ring " inclusion carbocyclic ring, heterocycle, aromatic ring, hetero-aromatic ring, volution, condensed ring, etc., wherein said carbocyclic ring, heterocycle, virtue Ring, hetero-aromatic ring, volution, condensed ring group has implication as described in the present invention.

Term " alkylamino " or " alkyl amino " inclusion " N- alkyl amino " and " N, N- dialkyl amido ", wherein amino Group is separately replaced by one or two alkyl group, and wherein alkyl group has implication as described in the present invention. Such example includes, but is not limited to, methylamino, ethylamino, dimethylamino, lignocaine etc..

Term " aminoalkyl " refers to the alkyl group that amino group replaces, and wherein alkyl group has as described herein Implication.Some of them embodiment is that aminoalkyl is amino C_1-6Alkyl group.Other embodiment is, amino C_1-3Alkane Base group.Suitable aminoalkyl groups can be, but is not limited to, amino methyl, amino-ethyl, aminopropyl etc..

Term " alkoxyl " used in the present invention, is related to alkyl, as defined in the present invention, by oxygen atom even It is connected in main carbochain.Such embodiment includes, but is not limited to, methoxyl group, ethyoxyl, propoxyl group etc..

Term " aryl " can be monocyclic, the carbocyclic ring system of bicyclic or three rings, and wherein, at least one member ring systems is aromatic series , each of which member ring systems comprise 3-7 atom.Term " aryl " can exchange with term " aromatic rings " and use, such as fragrance Ring can include phenyl, naphthyl and anthracene.Depending on structure, aryl can be monoradical or divalent group, i.e. arlydene.

Term " heteroaryl ", " hetero-aromatic ring " is used interchangeably herein, has stablizing of up to 10 atoms in each ring Monocyclic, bicyclic or tricyclic, wherein at least one ring be aromatics and comprise 1 to 4 be selected from O, N and S hetero atom.This As defined in the range of heteroaryl include without limitation：Benzimidazolyl, benzofuranyl, benzofuraxan base, benzopyrazoles base, Benzotriazole base, benzothienyl, benzoxazolyl group, carbazyl, carbolinyl, cinnolines base, furyl, indolinyl, indole Base, indolizine base (indolazinyl), indazolyl, isobenzofuran-base, isoindolyl, isoquinolyl, isothiazolyl, different Oxazolyl, naphtho- pyridine radicals, di azoly, oxazolyl, oxazoline, isoxazolines, pyranose, pyrazinyl, pyrazolyl, pyridazinyl, Pyridopyridine base, pyridine radicals, pyrimidine radicals, pyrrole radicals, quinazolyl, quinolyl, quinoxalinyl, tetrazole radical, tetrazolo pyridine Base, thiadiazolyl group, thiazolyl, thienyl, triazolyl, dihydrobenzo imidazole radicals, dihydro benzo furyl, dihydrobenzo thiophene Base, dihydrobenzo oxazolyl, indolinyl, dihydroquinoline base, methylenedioxybenzenes, benzothiazolyl, benzothienyl, quinoline Quinoline base, isoquinolyl, oxazolyl, 2,3,3a, 7a- tetrahydrochysene -1H- isoindolyl, 1,2,3,4- tetrahydric quinoline group, pteridyl, fast Purine base and tetrahydroquinoline.It is bicyclo- in heteroaryl substituent, and ring is non-aromatic ring or in the case of not comprising hetero atom, It should be understood that it passes through aromatic ring respectively or is attached by comprising heteroatomic ring.If this heteroaryl comprises nitrogen Atom, then it should be understood that this definition also comprises its corresponding N- oxide.

Term " cycloalkyl " or " carbocyclic ring " refer to monovalence or multivalence, non-aromatic, saturation or partly unsaturated cyclic hydrocarbon, and not Comprise hetero atom, definitely not aryl, the bicyclo- including the monocyclic of 3-12 carbon atom or 7-12 carbon atom or three rings.Tool The bicyclic carbocyclic ring having 7-12 atom can be bicyclo- [4,5], [5,5], [5,6] or [6,6] system, have simultaneously 9 or 10 former The bicyclic carbocyclic ring of son can be bicyclo- [5,6] or [6,6] system.Suitable group of naphthene base includes, but is not limited to, cycloalkyl, Cycloalkenyl group and cycloalkynyl radical.The example of group of naphthene base further includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, 1- Cyclopenta -1- thiazolinyl, 1- cyclopenta -2- thiazolinyl, 1- cyclopenta -3- thiazolinyl, cyclohexyl, 1- cyclohexyl -1- thiazolinyl, 1- hexamethylene Base -2- thiazolinyl, 1- cyclohexyl -3- thiazolinyl, cyclohexadienyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, Cyclo-dodecyl, adamantyl etc..

Term " heterocyclic radical ", " heterocycle ", " miscellaneous alicyclic " or " heterocycle " is used interchangeably herein, all referring to monocyclic, Bicyclic, three rings or tetracyclic ring system, on its medium ring, one or more atoms are replaced by hetero atom individually optionally, and ring can be Fully saturated or comprise one or more degrees of unsaturation, but definitely not heteroaryl.Heterocyclic system can in any hetero atom or It is connected on person's carbon atom in main structure thus forming stable compound.One or more ring hydrogen atoms are individually optionally Replaced by one or more substituent groups described in the invention.Some of them embodiment is, " heterocyclic radical ", " heterocycle ", " heterolipid Ring race " or " heterocycle " group are monocyclic (the 1-6 carbon atoms and be selected from N, the 1-3 hetero atom of O, P, S, here of 3-7 yuan of rings N, S or P are optionally replaced by one or more oxygen atoms and obtain as NO, NO₂, SO, SO₂, PO, PO₂Group, meanwhile ,- CH₂- group can be optionally by-C (=O)-replacement；When described ring is three-membered ring, only one of which hetero atom), or 7-10 former molecular bicyclic (4-9 carbon atom and selected from N, the 1-3 hetero atom of O, P, S, in this N, S or P optionally by One or more oxygen atoms are replaced to be obtained as NO, NO₂, SO, SO₂, PO, PO₂Group, meanwhile ,-CH₂- group can be optional Ground is by-C (=O)-replacement；).Depending on structure, heterocyclic radical can be divalent group, i.e. sub- heterocyclic radical.

" heterocyclic radical " can be carbon-based or hetero atom base." heterocyclic radical " equally also includes heterocyclic group and saturation or part not Saturated rings or heterocycle simultaneously close formed group.The example of heterocycle includes, but is not limited to, 1,2,3,6- tetrahydro pyridyl, piperazine Piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, Tetrahydro thiapyran base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, glycidyl, azacycloheptyl, oxa- Suberyl, thia suberyl, N- morpholinyl, 2- morpholinyl, morpholinyl, thio-morpholinyl, homopiperazine base, piperidyl, oxygen nitrogen Miscellaneous Zhuo Ji, diazepine base, sulfur azatropylidene base, pyrrolin -1- base, 2- pyrrolinyl, 3- pyrrolinyl, 2H- pyranose, 4H- Pyranose, dioxacyclohexyl, 1,3- dioxy amyl group, dithiane base, dithiode alkyl, dihydro-thiophene base, 1,2,3,4- tetrahydrochysene Isoquinolyl, 1,2,6- thiadiazine alkane 1,1- dioxy -2- base, hexahydro -2H- [1,4] dioxin [2,3-c] pyrrole radicals, 1,1- bis- Oxidation thio-morpholinyl, N- pyridine radicals carbamide, dioxolanyl, dihydro pyrazine base, dihydropyridine base, pyrazoline base, dihydro Pyrimidine radicals, pyrrolin base, 1,4- dithiane base, morpholinyl, decahydro indyl, decahydro isoindolyl, etc..

As described in the present invention, substituent R is bonded, by one, the member ring systems formed on the ring at the center of being connected to and represents substituent R Can any on ring may replace or any rational position is replaced.For example, formula a represents any possible quilt on A ring or B ring The position replacing all can be replaced by R, such as formula b, formula c, formula d, formula e, formula f, formula g, and shown in formula h.

In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode that herein adopts in the whole text " each ... and ... independently be ", " ... and ... be each independently " and " ... and ... separately for " can be exchanged, and should do extensively Reason and good sense solution, it both may refer in different groups, does not affect mutually between same-sign between expressed concrete option, Can represent in identical group, not affect mutually between expressed concrete option between same-sign.

Term " pharmaceutically acceptable " refer to when give people apply when pharmaceutical formulation and typically do not produce allergy Or similar unsuitable reaction, the such as molecular entity of gastrointestinal upset, dizziness etc. and compositionss.Preferably, art used herein That language " pharmaceutically acceptable " refers to federal regulator or national government approval or American Pharmacopeia or other general accreditations Pharmacopeia lift in animal, be more in particular in human body used in.

Term " carrier " refers to diluent, adjuvant, excipient or the substrate together applied with described compound.These medicines carry Body can be sterile liquid, such as water and oils, including oil, animal, plant or synthesis source, such as Oleum Arachidis hypogaeae semen, Semen sojae atricolor Oil, mineral oil, Oleum sesami etc..Water and aqueous solution saline solution and aqueous glucose are preferably used as carrier, spy with glycerite It is not Injectable solution.Suitable pharmaceutical carrier is described in the " Remington ' s Pharmaceutical of E.W.Martin In Sciences ".

" hydrate " of the present invention refers to compound or its salt provided by the present invention, and it also includes chemical quantity or non-chemically The water that equivalent is combined by non-covalent intermolecular forces, also can say it is the associated complex that solvent molecule is water is formed.

" solvate " of the present invention refers to the association that the compound of one or more solvent molecules and the present invention is formed Thing.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.

" ester " of the present invention refers to that the formula containing hydroxyl (I)-compound shown in formula (IV) can form hydrolyzable ester in vivo. Such ester is the pharmaceutically acceptable ester that hydrolysis produces parent alcohol for example in human or animal's body.Formula containing hydroxyl (I)- In compound body shown in formula (IV), the group of hydrolyzable ester includes, but not limited to phosphate, acetoxymethoxy, and 2,2- Dimethylpropionyloxymethoxy, alkanoyl, benzoyl, benzene first and second acyl group, alkoxy carbonyl, dialkyl carbamoyl and N- (di-alkyaminoethyl group)-N- alkyl-carbamoyl etc..

" nitrogen oxides " of the present invention refer to when compound contains several amine functional group, can 1 or former more than the nitrogen of 1 Son oxidation forms N- oxide.The particular example of N- oxide is the N- oxide of tertiary amine or the N- oxidation of nitrogen heterocyclic ring nitrogen-atoms Thing.Available oxidant such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) process corresponding amine formed N- oxide (referring to Advanced Organic Chemistry, Wiley Interscience, the 4th edition, Jerry March, pages).Especially It is that N- oxide can be prepared (Syn.Comm.1977,7,509-514) with the method for L.W.Deady, wherein for example molten in inertia In agent such as dichloromethane, amines are made to react with metachloroperbenzoic acid (MCPBA).

In addition, unless other aspects show, the structural formula of compound described in the invention includes one or more differences Atom enriched isotope.The present invention includes isotope-labeled compound, and they are equal to described in formula (I)-formula (IV) Those, but one or more atom is different from the former of the common atomic mass of nature or mass number by atomic mass or mass number Son is replaced.The isotopic example being introduced in the compounds of this invention includes the same of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine Position element, respectively for example²H、³H、¹³C、¹¹C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶Cl.Containing above-mentioned isotope and/or The pharmacy of the isotopic the compounds of this invention of other, its prodrug and described compound or described prodrug of other atoms Upper acceptable salt broadly falls into the scope of the present invention.Some isotope-labeled the compounds of this invention, such as introducing radioactivity are same Position element is (for example³H and¹⁴C) those can be used for medicine and/or substrate tissue measure of spread.Tritium, i.e.³H and carbon-14, i.e.¹⁴The same position of C Element is particularly preferred, because they are easily prepared and detect.And then, replaced by heavier isotope, such as deuterium, i.e.²H, by In the higher benefit that can provide in treatment of metabolic stability, for example, extend Half-life in vivo or reduce volume requirements, thus It is probably preferably in some cases.Compound and its prodrug one shown in isotope-labeled formula (I)-formula (IV) of the present invention As can be prepared, when carrying out following flow processs and/or embodiment with technique disclosed in preparation example, same be readily obtained The reagent of the plain labelling in position replaces nonisotopically labelled reagent.

" metabolite " refers to specific compound or its salt in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention Adopt as stating and experimentally characterized.Such product can be by being administered compound through peroxidating, reducing, water Solution, amidated, desamido- acts on, esterification, degreasing, and enzymatic lysises etc. method obtains.Correspondingly, the present invention includes compound Metabolite, be fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.

The various pharmaceutically acceptable salt forms of the compounds of this invention are all useful.Term is " pharmaceutically acceptable Salt " refers to that those salt forms are it will be apparent that being that they are substantially nontoxic and be provided that required for pharmaceutical chemistry man Pharmacokinetic property, palatability, absorption, distribution, metabolism or excretion.Other factors, more practical in nature, for choosing Select also critically important, these are：The stream of the cost of raw material, easy, yield, stability, the hygroscopicity of crystallization and result crude drug Dynamic property.Simply, pharmaceutical composition can be prepared with pharmaceutically acceptable carrier by effective ingredient.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt of compound and the inorganic salt of the present invention.Medicine On, acceptable salt is known to us in art, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66: 1-19,1977. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, anti-with amino group The inorganic acid salt that should be formed has hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, nitrate etc., and acylate As acetate, propionate, glycollate, oxalates, maleate, malonate, succinate, fumarate, tartrate, Citrate, benzoate, mandelate, mesylate, esilate, toluene fulfonate, sulfosalicylate etc., or pass through On books document, described additive method such as ion exchange is obtaining these salt.

Other pharmaceutically acceptable salts include adipate, malate, 2 hydroxy propanoic acid, alginate, ascorbic acid Salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, camsilate, ring Amyl group propionate, digluconate, lauryl sulfate, formates, fumarate, gluceptate, glycerol phosphorus Hydrochlorate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonate salt, lactobionate, breast Hydrochlorate, laruate, lauryl sulfate, malate, 2- naphthalene sulfonate, nicotinate, oleate, palmitate, pamoate, Pectate, persulfate, 3- phenylpropionic acid salt, picrate, pivalate, stearate, rhodanate, undecylate, Valerate, etc..Alkali metal, alkaline-earth metal, ammonium and N are included by the salt that suitable alkali obtains⁺(C_1-4Alkyl)₄Salt.

The present invention is also intended to contemplate the quaternary ammonium salt that the compound of the group of any comprised N is formed.Water solublity or oil soluble Property or dispersion product can be obtained by quaternization.Alkali metal or alkali salt include sodium salt, lithium salts, potassium salt, calcium salt, Magnesium salt, iron salt, zinc salt, mantoquita, manganese salt, aluminium salt etc..Pharmaceutically acceptable salt further includes suitable, nontoxic ammonium, Quaternary ammonium salt and the amine cation of gegenions formation, such as halogenide, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, Nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.Amine salt, such as but not limited to N, N '-dibenzyl-ethylenediamin, the general Shandong of chlorine Caine, choline, ammonia, diethanolamine and other hydroxyalkyl amine, ethylenediamine, N- methyl glucamine, procaine, N- benzyl benzene Ethamine, 1- p- chlorobenzyl -2- pyrrolidine -1 '-ylmethyl-benzimidazole, diethylamine and other alkylamine, piperazine and three (hydroxyl first Base) aminomethane；Alkali salt, such as but not limited to barium, calcium and magnesium；Transition metal salt, such as but not limited to zinc.

When term " blocking group " or " Pg " refer to a substituent group and other reacted with functional groups, it is commonly used to hinder Feature disconnected or that protection is special.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or in protection compound amino feature, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group (CBZ) and 9- fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to the replacement of hydroxyl Base is used for blocking or protect the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl-protecting group Group " refers to the substituent group of carboxyl for blocking or protecting the feature of carboxyl, general carboxyl-protecting group includes- CH₂CH₂SO₂Ph, cyano ethyl, 2- (TMS) ethyl, 2- (TMS) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group refers to document：T W.Greene,Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.

In this manual, if there is any difference between chemical name and chemical constitution, structure is dominant.

The abbreviation of any blocking group used in the present invention, aminoacid and other compound, unless otherwise stated, all with Abbreviation that they are usually used, generally acknowledging is defined, or with reference to IUPAC-IUB Commission on Biochemical Nomenclature (referring to Biochem.1972,11：942-944).

Unless other aspects show, all of stereoisomer of compound of the present invention, geometric isomer, tautomerism Body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug broadly fall into the model of the present invention Enclose.

The compound of the present invention, compositionss, and application thereof

The compound of the present invention optionally can be helped with known individually or preferably together with pharmaceutical acceptable carrier or diluent Agent such as Alumen is administered together in mammal in the pharmaceutical composition of standard pharmaceutical practice, preferably people.This compound is permissible It is administered orally with delayed or parenteral, including intravenouss, intramuscular, intraperitoneal, subcutaneous, rectally and topical routes of administration.

In tablet for oral administration situation, conventional carrier includes Lactose and corn starch, and is usually added into lubrication Agent such as magnesium stearate.For the oral administration being carried out with capsule form, useful diluent includes Lactose and the jade being dried Rice starch.For the oral application of therapeutic compounds of the present invention, selected compound can be by with such as tablet or glue The form of the form of capsule or aqueous solution or suspension is administered.For the oral administration carrying out in the form of tablets or capsules Speech, can be by pharmaceutically useful inert carrier such as Lactose, starch, sucrose, glucose, the methyl of active pharmaceutical ingredient and oral, non-toxic Cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, Mannitol, Sorbitol etc. mutually merge；For carry out in liquid form For oral administration, can be by pharmaceutically useful the carrier such as ethanol, glycerol, water etc. of oral drug components and any oral, non-toxic Mutually merge.Additionally, when needing or being required, can also be mixed into in this mixture suitable binding agent, lubricant, disintegrating agent and Coloring agent.Suitable binding agent includes starch, gelatin, natural sugar such as glucose or beta lactose, corn sweetener, natural and conjunction The natural gum such as arabic gum, Tragacanth or sodium alginate, carboxy methyl cellulose, Polyethylene Glycol, wax etc. becoming.Can be used for these agent The lubricant of type includes enuatrol, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride etc..The non-limit of disintegrating agent Property ground processed includes starch, methylcellulose, agar, Bentonite, xanthan gum etc..When need to be carried out with aqueous suspension oral should Used time, active component is merged with lubricant and suspensoid phase.If it is desired, it is possible to adding some sweeting agents and/or rectifying Taste agent.For intramuscular, intraperitoneal, the application of subcutaneous and intravenouss, generally prepare the sterile solution of active component, and tackle The pH of this solution carries out suitable regulation and buffering.For intravenouss application, the total concentration of solute should be controlled so that this system Agent is isotonic.

The compound of the present invention can also be administered in the form of liposomal delivery system, described liposome transmission system System such as little monolayer capsule, big monolayer capsule and multilamellar capsule.Can with many phospholipid such as cholesterol, stearylamine or phosphatidylcholine Lai Form liposome.

The compound of the present invention can also be transmitted by using the monoclonal antibody as separate carrier, compound Molecule is coupled on this antibody.The compound of the present invention can also with as can targeting pharmaceutical carrier soluble polymer Mutually it is coupled.Such polymer may include Polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropylmethacrylamide-phenol, Poly- hydroxy-ethyl aspartarnide-phenol or the polyethylene glycol oxide-polylysin being replaced by palmitoyl residues.Additionally, the present invention The biodegradable polymer phase that compound can also be used for obtaining the controlled release of medicine with a class is coupled, and described polymer is for example The copolymer of polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid, poly epsilon caprolactone lactone, poly butyric, poe, bunching Aldehyde, the crosslinking of poly- dihydropyran, polybutylcyanoacrylate and hydrogel or amphipathic nature block polymer.

The compound of the present invention can also be dredged with the sclerotin for treatment or pre- preventing bone rarefaction, glucocorticoid inducible Pine, Paget, the increase of bone update anomalies, periodontal, tooth loss, fracture, rheumatoid arthritiss, osteoarthritis, vacation Osteolysises around body, osteogenesis not exclusively, the known substance of metastatic bone disease, malignant hypercalcemia and multiple myeloma Matter is combined.Compound disclosed in this invention is combined with the material for treatment or pre- preventing bone rarefaction or other bone disorders Within the scope of the invention.Those skilled in the art can understand the group of which material according to the characteristic of involved medicine and disease Conjunction is useful.Such material includes following material：Organic diphosphonic acid compound；Estrogenic agents；Androgen receptor Body regulator；Osteoclast proton triphosphatase inhibitor；HMG-CoA reductase inhibitor；Integrin receptor antagonism Agent；Osteoblast anabolic agent, such as PTH；And its pharmaceutically useful salt and mixture.A kind of preferred combination is the chemical combination of the present invention Thing and the combination of organic diphosphonic acid compound.Another kind of preferably combination is compound and the estrogenic agents of the present invention Combination.Another kind of preferably combination is the compound of the present invention and the combination of androgen receptor modifier.Another kind of preferred Combination is the compound of the present invention and the combination of osteoblast anabolic agent.

" organic diphosphonic acid compound " includes following chemical formula without limitation：

Wherein n is the integer from 0 to 7, and wherein A and X is independently selected from H, OH, halogen, NH₂, SH, phenyl, C₁-C₃₀Alkane Base, C₃-C₃₀Side chain or cycloalkyl, the bicyclic ring structures comprising two or three N, C₁-C₃₀The alkyl of replacement, C₁-C₁₀Alkyl replaces NH₂、C₃-C₁₀Side chain or the NH of cycloalkyl substituted₂、C₁-C₁₀The NH that dialkyl group replaces₂、C₁-C₁₀Alkoxyl, C₁-C₁₀Alkyl takes The sulfydryl in generation, thiophenyl, halosphenylsulfanyl, C₁-C₁₀Alkyl replace phenyl, pyridine radicals, furyl, pyrrolidinyl, imidazole radicals, Imidazopyridyl and benzyl, wherein when n is 0, A and X can not be both selected from H or OH；Or A and X and the carbon being attached thereto Atom forms a C together₃-C₁₀Ring.

In above-mentioned chemical formula, described alkyl can be straight chain, side chain or ring-type, can be right for this chemical formula The enough atoms being provided are selected.C₁-C₃₀The alkyl replacing may include various substituent groups, and nonrestrictive example includes this It is selected from phenyl, pyridine radicals, furyl, pyrrolidinyl, imidazole radicals, NH a bit₂、C₁-C₁₀Alkyl or the NH of dialkyl group replacement₂、OH、SH And C₁-C₁₀The group of alkoxyl.

Above-mentioned chemical formula also includes carbocyclic ring, aromatics and the hetero atom structures of complexity for A and/or X substituent group, in fact Example includes naphthyl, quinolyl, isoquinolyl, adamantyl and chlorophenylsulfanyl without limitation.

Pharmaceutically useful salt and the derivant of this bisphosphonate compound can also be used here.The non-limiting examples bag of salt Include these be selected from alkali metal salt, alkali salt (alkaline metal), ammonium salt and single-, two-, three-or four-C₁-C₃₀- The material of the ammonium salt of alkyl-replacement.Preferably salt is the salt that these are selected from sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt.More preferably Be sodium salt.The non-limiting examples of derivant include the material that these are selected from ester, hydrate and amide.

It should be noted that referring here to term " bisphosphonate compound " used during the therapeutic agent of the present invention and " di 2 ethylhexyl phosphonic acid Class compound " refers to also include double phosphinic acid compounds, two-phosphinic acid compounds, bis-phosphonic acids compounds and these materials Salt and derivant.Unless stated otherwise, otherwise it is not intended to when being directed to use with bisphosphonate compound or diphosphonic acids The scope of the present invention is limited.Because those of ordinary skill in the art using mixing nomenclature, remove non-specifically at present Illustrate, be otherwise to be counted based on sour effective weight in the specified weight being related to bisphosphonate compound of the present invention or percentage ratio 's.For example, " the about 5mg being counted based on alendronic Acid effective weight is selected from alendronate, its pharmaceutically useful salt to phrase And the bisphosphonate compound of the suppression bone resorption of its mixture " amount that refers to selected bisphosphonate compound is in 5mg Calculated on the basis of alendronic Acid.

The non-limiting examples of bisphosphonate compound used herein include following material：Alendronic Acid, 4- amino -1- Hydroxy butylidene -1,1- di 2 ethylhexyl phosphonic acid.The nonrestrictive example of bisphosphonate compound includes alendronic Acid, BP, chlorine Phosphonic acids, etidronic acid, ibandronic acid, her card phosphonic acids, minodronic acid, neridronic acid, olpadronic acid, pamidronic acid, piridronic acid, profit Plug phosphonic acids, tiludronic acid and zoledronic acid and its pharmaceutically useful salt and ester.Particularly preferred bisphosphonate compound is A Lun phosphine The sodium of hydrochlorate, especially alendronic Acid, potassium, calcium, magnesium or ammonium salt.The example of preferably bisphosphonate compound is the sodium of alendronic Acid The sodium salt of the hydration of salt, especially alendronic Acid.This salt can be hydrated by the water of the water of whole molal quantity or non-whole molal quantity.More excellent The example of the bisphosphonate compound of choosing is the sodium salt of the hydration of alendronic Acid, especially Monosodium alendronate trihydrate.

The precise dosage of organic diphosphonic acid compound will be with administration time table, selected specific diphosphate, suckling The age of animal or people, size, sex and physical condition, the property of condition being treated and the order of severity and other related doctor Learn and physical factors and change.It is thus impossible to predefine accurate pharmacy effective dose, it can be by care-giver or clinicist Easily to be determined.Suitable quantity can be determined by conventional animal model experiment and people's clinical research.Typically For, the amount selecting suitable bisphosphonate compound is to obtain bone resorption inhibitory action, i.e. using the diphosphine of bone resorption amount of suppression Acid compound.For people, the effective oral dose of bisphosphonate compound is typically about 1.5 to about 6000 μ g/kg body weight, and It is preferably about 10 to about 2000 μ g/kg body weight.For Monosodium alendronate trihydrate, can be administered is common People is with dosage generally 2mg/ days to about 40mg/ days it is therefore preferable to about 5mg/ days to about 40mg/ days.In U.S., go through at present Monosodium alendronate trihydrate to be used for preventing osteoporotic dosage be 5mg/ days, for treating osteoporotic dosage 10mg/ days, and be 40mg/ days for treating the dosage of Paget.

In selective dosage regimen, this bisphosphonate compound can with the other intervals in addition to daily carry out to Medicine, for example can with Per-Hop behavior once, Per-Hop behavior is administered once twice, every two weeks and is monthly administered once.Weekly Dosage regimen in, Monosodium alendronate trihydrate will with 35mg/ week or 70mg/ week dosage be administered.

" selective estrogen receptor modulatorss " refer to not consider mechanism, can disturb or suppress estrogen and receptor In conjunction with compound.The example of estrogenic agents includes estrogen, progestogen, estradiol, Qu Luoxi without limitation Sweet smell, raloxifene, lasofoxifene, TSE-424, tamoxifen, idoxifene, LY353381, toremifene, fulvestrant, 4- [7- (2,2- dimethyl -1- oxopropoxy -4- methyl -2- [4- [2- (piperidino) ethyoxyl] phenyl] -2H-1- benzo pyrrole Mutter -3- base)-phenyl -2,2- dimethyl propylene acid esters and 4,4 '-dihydroxy benaophenonel-dinitrophenyl group-hydrazone.

" erss regulator " is can be with the compound of selectivity excitement or antagonising oestrogen receptors β (ER β).Swash Dynamic ER β increased the tryptophan hydroxylase gene (TPH, the key enzyme in serotonin synthesis) carrying out by the beta mediated event of ER Transcription.In PCT Patent Application -- the WO 01/82923 disclosed in November 8 calendar year 2001 and WO disclosed in 20 days Mays in 2002 It can be found that the example of estrogen receptor beta-agonists, two patent documentations are all fully incorporated herein by here in 02/41835 Reference.

" androgen receptor modifier " refers to not consider mechanism, can disturb or suppress androgen and the combination of receptor Compound.The example of androgen receptor modifier includes finasteride and other 5α-reductase inhibitor, nilutamide, fluorine His amine, bicalutamide, liarozole and abiraterone acetate.

" osteoclast proton triphosphatase inhibitor " refers to the inhibitor of proton triphosphatase, and it is sent out Now on the top film of osteoclast, and it has been reported that it plays an important role during bone resorption.This proton pump generation Table can be used for treating and preventing the attractive mesh of the design of bone resorption inhibitor of osteoporosises and related metabolic diseases Mark.

" HMG-CoA reductase inhibitor " refers to the inhibitor of 3- hydroxy-3-methyl glutaryl-CoA reductase.Permissible To be readily determined the compound to HMG-CoA reductase with inhibitory activity with mensure well-known in prior art.Can The example of the HMG-CoA reductase inhibitor to use includes lovastatin, simvastatin, pravastatin, fluorine without limitation Cut down statin, atorvastatin and cerivastatin.Term HMG-CoA reductase inhibitor used herein is included with HMG- The all pharmaceutically useful lactone of the compound of CoA reductase active and open-(i.e. wherein lactonic ring is opened sour form Thus forming free acid) and salt and ester-formin, therefore, also include using such salt, ester within the scope of the invention, open Acid and lactone form.

This HMG-CoA reductase inhibitor is preferably chosen from Health food and simvastatin, and most preferably pungent cuts down Statin.Herein, it is related to term during HMG-CoA reductase inhibitor " pharmaceutically useful salt " and refer to chemical combination used by the present invention The nontoxic salt of thing, it generally can be prepared by free acid is carried out reaction with suitable organic base or inorganic base, special It is not these by the cation salt that for example sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethyl-ammonium are formed and by amine such as ammonia, second two Amine, N- methylglucamine, lysine, arginine, ornithine, choline, N, N '-dibenzyl-ethylenediamin, chloroprocaine, diethanol Amine, procaine, N- benzyl-1-phenylethylamine, 1- p-chlorobenzyl -2- pyrrolidine -1 '-base-tolimidazole, diethylamine, piperazine and These salt that three (hydroxymethyl) aminomethane is formed.The other example of the salt form of HMG-CoA reductase inhibitor is non- Restrictively include acetate, benzene sulfonate, benzoate, bicarbonate, disulfate, biatrate, borate, bromination Thing, Ca-EDTA salt, camsilate, carbonate, chloride, clavulanate, citrate, dihydrochloride, ethylenediamine Tetraacetate, ethanedisulphonate, estolate, esilate, fumarate, gluceptate, gluconate, glutamic acid Salt, glycollylarsanilate, hexyl resorcin salt, Kazakhstan amine (hydrabamine), hydrobromate, hydrochlorate, hydroxyl naphthalene Formates, iodide, different thiosulfate, lactate, Lactobionate, laruate, malate, maleate, mandelic acid Salt, mesylate, Methylsulfate, mucate, naphthalene sulfonate, nitrate, oleate, oxalates, pamoate (pamaote), Palmitate, pantothenate (panthothenate), phosphate/diphosphate, Polygalacturonate, salicylate, stearic acid Salt, basic acetate, succinate, tannate, tartrate, teoclate, toluene fulfonate, triethiodide compound and valeric acid Salt.

The ester derivant of described HMG-CoA reductase inhibitor can be used as prodrug, and described prodrug ought be absorbed into homoiothermy Can be cleaved and so that curative effect of medication is improved in the way of discharging medicament forms when in the blood flow of animal.

" integrain receptor antagaonists " used above refer to join with selectivity antagonism, suppression or counteracting physiology Body and α_vβ₃The compound of the combination of integrin, with selectivity antagonism, suppression or physiologic ligand and α can be offset_vβ₅Integrin egg The compound of white combination, with antagonism, suppression or physiologic ligand and α can be offset_vβ₃Integrin and α_vβ₅The knot of integrin The compound closed and the activity of the specific integrin that can be expressed on capillary endothelial cells with antagonism, suppression or counteracting Compound.This term further relates to α_vβ₆、α_vβ₈、α₁β₁、α₂β₁、α₅β₁、α₆β₁And α₆β₄The antagonist of integrin.This term is also It is related to α_vβ₃、α_vβ₅、α_vβ₆、α_vβ₈、α₁β₁、α₂β₁、α₅β₁、α₆β₁And α₆β₄Any combination of antagonist of integrin.

" osteoblast anabolic agent " refers to build the material of bone, such as PTH.Have shown that parathyroid hormone Or the intermittent administration of its amino terminals segment and analog can prevent, stop, in part de-rotation thing and human body (PTH) Bone lesion and stimulate bone formation.

It is being related to the term " administration " that uses during the compound of the present invention and its modification (for example " applying " compound) refers to Be that the prodrug of this compound or compound is incorporated in the system of animal needing to be treated.Compound as the present invention Or its prodrug is when with being provided in the form of the combining of one or more other active substance (such as cytotoxic agent), " administration " And its modification each should be read to include while this compound or its prodrug and other materials and is introduced sequentially into.The present invention The prodrug of the compounds of this invention is included in the range of it.

Terms used herein " compositionss " include with specified amount comprise specify composition product and can be direct or indirect Any product produced by the combination of specified quantitative special component.

" treatment " or " process " of terms used herein disease includes：Prevent disease, even if this disease must occurring or inclining Also do not experience or the mammal of the symptom that shows this disease does not form the clinic of this disease in this disease occurs Symptom；Inhibit disease, that is, stop or reduce the development of disease or its clinical symptoms；Or alleviate disease, i.e. make disease Or its clinical symptoms disappears.

Terms used herein " bone resorption " refers to the process by its bone of degrading for the osteoclast.

Present invention additionally comprises for the pharmaceutical composition treating osteoporosises or other bone disorders, it comprises therapeutically effective amount The present invention compound, and comprise or do not comprise pharmaceutically useful carrier or diluent.The proper combination of the present invention includes The such as pH level 7.4 comprises the compounds of this invention and the aqueous solution of pharmaceutical acceptable carrier such as saline.Can be pushed away by local This solution is incorporated in the blood of patient note.

When the compound of the present invention is administered in human patientses, this daily dose is typically determined by the attending doctor of evolution Determine, and this dosage typically changes with the order of severity at the age of each patient, body weight and response and patients symptomatic.

In an application example, the compound of Sq is delivered medicine to cathepsin dependent conditions are treated Mammal.When being used due to pointed disease, the oral dose of the present invention is for daily per kilogram of body weight about 0.01mg (mg/kg/ days) to about 100mg/kg/ days it is therefore preferable to 0.01 to 10mg/kg/ sky, and be most preferably 0.1 to 5.0mg/kg/ my god.For oral administration, said composition is preferably to comprise 0.01,0.05,0.1,0.5,1.0,2.5, 5.0th, the form of the tablet of 10.0,15.0,25.0,50.0,100 and 500 milligrams of active component is provided, for treated For patient, according to symptom, dosage is adjusted.Medicine generally comprises about 0.01mg to about 500mg active component, preferably Comprise about 1mg to the active component of about 100mg.During being inputted with constant speed, most preferred intravenous dosages are about 0.1 to about 10mg/kg/ minute.The compound of the present invention can be advantageously administered with single daily dose form, or can be by must Daily dose to be administered in the form of the fractionated dose of daily two, three or four times.Furthermore, it is possible to by using suitable intranasal Preferred compounds of the invention in intranasal form is administered by substrate, or can be with those of ordinary skill in the art's many institute's weeks These transdermal skin patches forms known are administered to it by cutaneous routes.For giving of being carried out with transdermal delivery system form For medicine, the dosage that is administered is during dosage certainly by continuous rather than be administered off and on.

The compound of the present invention can be with the other materials combination of the disease for treatment tissue proteases mediate.In treatment During, each component of such combination can with split or single combination in the form of different time points by separate administrable or It is administered simultaneously.Therefore, the present invention should be understood to comprise all such simultaneously or alternate therapeutic scheme, and term " is given Medicine " also has corresponding explanation.It should be understood that in the compounds of this invention and the disease for treatment tissue proteases mediate The combination of other materials scope include in principle with for treatment be related to estrogen function disease any medicine group Any combinations of compound.

Therefore, include within the scope of the invention of the presently claimed invention compound being used in combination and selected from following material The combination of second material：Organic diphosphonic acid compound；Estrogenic agents；Androgen receptor modifier；Osteoclast Proton triphosphatase inhibitor；HMG-CoA reductase inhibitor；Integrain receptor antagaonists；Osteoblast anabolic agent, As PTH；And its pharmaceutically useful salt and mixture.

The pharmaceutically useful salt of the compounds of this invention includes the routine nontoxic with inorganic or organic acid formation the compounds of this invention Salt.For example, nontoxic conventional salt includes these and derives from mineral acid example hydrochloric acid, hydrobromic acid, sulphuric acid, sulfamic acid, phosphoric acid, nitric acid etc. Deng salt and by organic acid for example acetic acid, propanoic acid, succinic acid, glycolic, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, Ascorbic acid, flutter acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzene sulfonic acid, 2- second Acyloxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, hydroxyethylsulfonic acid., trifluoroacetic acid etc. Prepared salt.The pharmaceutically useful salt of the compounds of this invention can with conventional chemical processes by comprise alkalescence or acidic moiety this Bright compound is synthesizing.In general, the salt of alkali compoundss is by ion exchange chromatography or to pass through free alkali and change Learn metering or excess the required mineral acid of one-tenth salt or organic acid is carried out in the various combinations of suitable solvent or solvent Reaction is being prepared.Similarly, the salt of acid compound is by carrying out reaction come shape with suitable inorganic or organic base Become.

General synthetic method

Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, the wherein definition of substituent group such as formula (I)-compound shown in formula (IV).Following reaction scheme and embodiment be used for into One step illustrates present disclosure.

Those skilled in the art will realize that：Chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds of many present invention, and other methods of the compound for preparing the present invention are considered as the model in the present invention Within enclosing.For example, according to the present invention, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art Completed by method of modifying, such as suitable protection disturbs group, by using reagent known to other except described in the invention , or modification reaction condition being made some routines.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the present invention.

The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, not through being further purified, unless other aspects show during use.General reagent is from western Gansu Province, Shantou chemical industry Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, dragon chemistry examination is risen in Qingdao Agent company limited, and Haiyang Chemical Plant, Qingdao is commercially available.

Anhydrous tetrahydro furan, dioxane, toluene, ether is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, normal hexane, N,N-dimethylacetamide and N, N- Dimethylformamide is to be dried in advance through anhydrous sodium sulfate to use.

Hereinafter reaction is usually to cover a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb all suitable rubber closures beyond the Great Wall, substrate is squeezed into by syringe.Glass drying oven is all dried.

Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.Spectroscopic data of the nuclear magnetic resonance Surveyed by Bruker Avance 400 nuclear magnetic resonance spectrometer or Bruker Avance III HD 600 nuclear magnetic resonance spectrometer Fixed, with CDC1₃,d₆-DMSO,CD₃OD or d₆- acetone is solvent (report is in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.When multiplet occurs, by using following abbreviation：S (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, double triplets), ddd (doublet of Doublet of doublets, doublet in pairs), ddt (doublet of doublet of triplets, triple in pairs Peak), dddd (doublet of doublet of doublet of doublets, double doublet in pairs).Coupling constant, uses Hertz (Hz) represents.

The condition of Algorithm (MS) data determination is：Agilent 6120Quadrupole HPLC-MS (pillar Model：Zorbax SB-C18,2.1x30mm, 3.5 μm, 6min, flow velocity is 0.6mL/min, mobile phase：5%-95% (contains The CH3CN of 0.1% formic acid) ratio in (H2O containing 0.1% formic acid))), detected with UV in 210/254nm, use electron spray Ionization pattern (ESI).

The characteristic manner of compound purity is：Agilent 1260 preparative high performance liquid chromatography (Pre-HPLC) or Calesep Pump 250 preparative high performance liquid chromatography (Pre-HPLC) (pillar model：NOVASEP, 50/80mm, DAC), 210nm/254nm is detected with UV.

The use of brief word runs through the present invention below：

EDC 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride

HATU 2- (7- azo BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester

KOH potassium hydroxide

Pd(Ph₃P)₄(triphenyl phosphorus) palladium

Pd(dppf)Cl₂·CH₂Cl₂[1,1 '-bis- (diphenylphosphine) ferrocene] palladium chloride (II) dichloromethane complex

DMF N, N- dimethyl sulfoxide

NaOH sodium hydroxide

CDCl₃Deuterochloroform

H₂O₂Hydrogen peroxide

TFA trifluoroacetic acid

Synthetic schemes

Synthetic schemes 1

The compounds of this invention can be obtained by the synthetic method of synthetic schemes 1：Compound (1.1) and corresponding amine (1.0) in the basic conditions, such as triethylamine, diisopropylethylamine etc. occurs condensation reaction to generate compound (1.2), reacts institute Include but is not limited to 2- (7- azo BTA)-N, N, N with condensing agent ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU), EDC etc.；

Compound (1.2) occurs deprotection reaction to generate compound (1.3)；

Compound (1.4) in the presence of base, occurs saponification to generate sour (1.5) accordingly, inorganic base used by reaction Including but not limited to sodium hydroxide, KOH etc.；

Compound (1.3) and compound (1.4) occur condensation reaction to generate compound (1.6)；

Compound (1.6) and borating agent (1.7) pass through to occur Suzuki coupling reaction to generate target compound (1.8), Used catalyst includes but is not limited to Pd (Ph₃P)₄,Pd(dppf)Cl₂·CH₂Cl₂Deng；Wherein R⁰For easy leaving group, such as halogen Element ,-OTf etc.；R^2a, R², R⁷, R^7a, R¹, R⁵, X, V, Y and Z have implication as described in the present invention.

Embodiment

Embodiment 1N- (1- ((1- anocy clopropyl) carbamoyl) cyclohexyl) -5- (4- (mesyl) phenyl)-benzene And furan -2- Methanamide

Step 1：5- bromobenzofuran -2- carboxylic acid, ethyl ester

The addition bromo- Benzaldehyde,2-hydroxy of 5- (15g, 74.63mmol) in bis- mouthfuls of bottles of 250mL, bromoacetate (18.7g, 111.9mmol), potassium carbonate (31g, 223.9mmol) and dry DMF (80mL), it is little that reactant mixture is heated to 130 DEG C of reactions 5 Shi Fanying completes.Filter, filtrate reduced in volume, residue with Ethyl acetate (100mL) dissolve, with saturated salt washing (50mL × 3), anhydrous sodium sulfate drying.Filter, decompression boils off solvent, and crude product is through silica gel column chromatography (ethyl acetate:Petroleum ether=1:20, V/V), faint yellow solid 16.6g, yield 83% are obtained.

MS(ESI,pos.ion)m/z:269.9(M+2)；

Step 2：5- bromobenzofuran -2- formic acid

Add 5- bromobenzofuran -2- carboxylic acid, ethyl ester (4g, 14.86mmol) and methanol (50mL) in bis- mouthfuls of bottles of 100mL, It is subsequently adding NaOH solution (22.3mL, 44.6mmol), reactant mixture is stirred at room temperature overnight.Concentrating under reduced pressure major part is molten Agent, residue adds water (20mL), adjusts pH value 3～4, sucking filtration with 2mol/L dilute hydrochloric acid solution, obtains white after vacuum drying Solid 3.30g, yield：92%

MS(ESI,pos.ion)m/z:241.9(M+2)；

Step 3：The bromo- N- of 5- (1- ((1- anocy clopropyl) carbamoyl) cyclohexyl) benzofuran-2-carboxamides

In 50mL round-bottomed flask add 1- amino-N- (1- anocy clopropyl) cyclohexyl carboxamide hydrochloride (1.46g, 6.0mmol) it is dissolved in anhydrous DMF (18mL), addition 5- bromo- 1- coumarilic acid (1.11g, 4.62mmol), add HATU (1.75g, 4.62mmol) and at 0 DEG C, then triethylamine (2.5ml, 13.85mmol) is added dropwise to In reactant liquor, and react 1 hour at 0 DEG C.Reaction is finished, and adds saturated aqueous common salt (100mL), with ethyl acetate (30mL × 3) Extraction, merges organic faciess, is washed with saturated aqueous common salt (50mL × 2), anhydrous sodium sulfate drying.Filter, decompression boils off solvent, slightly Product silica gel column chromatography (dichloromethane:Ethyl acetate=50:1, V/V) white solid 430mg, yield 21.6%, are obtained.

MS (ESI, pos.ion) m/z:430.3(M+1)；

Step 4：N- (1- ((1- anocy clopropyl) carbamoyl) cyclohexyl) -5- (4,4,5,5- tetramethyl -1,3,2- Dioxy -2- boryl) benzofuran-2-carboxamides

In 50mL bottle with two necks by bromo- for 5- N- (1- ((1- anocy clopropyl) carbamoyl) cyclohexyl) benzofuran- 2- Methanamide (427mg, 1.0mmol) is dissolved in anhydrous DMF (10mL), adds connection boric acid pinacol ester (330mg, 1.3mmol) and [double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex (82mg, 0.1mmol), then it is rapidly added potassium acetate (344mg, 3.5mmol), react 3.5 hours at 90 DEG C under nitrogen protection.Instead Room temperature should be cooled to, add saturated aqueous common salt (100mL), with ethyl acetate (30mL × 3) extraction, merge organic faciess, eaten with saturation Saline (50mL × 2) washs, anhydrous sodium sulfate drying.Filter, decompression boils off solvent, crude product silica gel column chromatography (dichloromethane: Ethyl acetate=40:1, V/V) white solid 330mg, yield 69.2%, are obtained.

MS(ESI,pos.ion)m/z:478.1(M+1)；

Step 5：N- (1- ((1- anocy clopropyl) carbamoyl) cyclohexyl) -5- (4- (mesyl) phenyl)-benzene And furan -2- Methanamide

The bromo- N- of 5- (1- ((1- anocy clopropyl) carbamoyl)-cyclohexyl) benzo is added in 50mL twoport flask Furan -2- Methanamide (50mg, 0.116mmol) is dissolved in ethanol (2mL) and toluene (6mL), adds 4- mesyl phenylboric acid (26mg, 0.129mmol), and add tetra-triphenylphosphine palladium (12mg, 0.012mmol), wet chemical under nitrogen protection (0.14ml, 0.28mmol) is added dropwise in reactant liquor, and reacts 1 hour at 95 DEG C.Reaction is finished, and adds saturated aqueous common salt (20mL), extracted with ethyl acetate (20mL × 3), merge organic faciess, washed with saturated aqueous common salt (20mL × 2), anhydrous slufuric acid Sodium is dried.Filter, decompression boils off solvent, crude product silica gel column chromatography (dichloromethane:Ethyl acetate=3:1, V/V), obtain white Color powder solid 50mg, yield 85%.

MS(ESI,pos.ion)m/z:506.2(M+1)；

¹H NMR(400MHz,DMSO-d₆) δ 8.90 (s, 1H), 8.80 (s, 1H), 8.53 (s, 1H), 8.07 (d, J= 7.4Hz, 2H), 8.03 (d, J=9.9Hz, 4H), 7.92 (d, J=8.1Hz, 1H), 7.80 7.65 (m, 2H), 3.35 (s, 3H), 2.03-1.89 (m, 4H), 1.55-1.47 (m, 6H), 1.26 (dd, J=8.1,5.4Hz, 2H), 1.08 (dd, J=8.2, 5.5Hz,2H).

Embodiment 2N- (1- ((1- anocy clopropyl) carbamoyl) cyclohexyl) the fluoro- 5- of -6- (4- (mesyl) benzene Base)-benzofuran-2-carboxamides

Step 1：5- bromo- 4- Fluorobenzofur -2- carboxylic acid, ethyl ester

The fluoro- Benzaldehyde,2-hydroxy of the bromo- 4- of 5- (16.3g, 74.63mmol), bromoacetate is added in bis- mouthfuls of bottles of 250mL (18.7g, 111.9mmol), potassium carbonate (31g, 223.9mmol) and dry DMF (80mL), according to the synthesis of embodiment 1 step 1 Prepared by method, crude product is through silica gel column chromatography (ethyl acetate:Petroleum ether=1:20, V/V) faint yellow solid 16.1g, yield, are obtained 75%.

MS(ESI,pos.ion)m/z:287.9(M+2)；

Step 2：5- bromo- 4- Fluorobenzofur -2- formic acid

5- bromo- 4- Fluorobenzofur -2- carboxylic acid, ethyl ester (4.26g, 14.86mmol), methanol is added in bis- mouthfuls of bottles of 100mL (50mL) with NaOH solution (22.3mL, 44.6mmol), according to the synthetic method preparation of embodiment 1 step 2, after vacuum drying To white solid 3.46g, yield 90%.

MS(ESI,pos.ion)m/z:259.9(M+2)；

Step 3：The bromo- N- of 5- (1- ((1- anocy clopropyl) formoxyl) cyclohexyl) -6 Fluorobenzofur -2- Methanamides

5- bromo- 6- Fluorobenzofur -2- formic acid (280mg, 1.08mmol), 1- amino-N- is added in 50mL two-mouth bottle (1- (1- anocy clopropyl) carboxamide hydrochloride (375mg, 1.54mmol) and DMF (6mL), at nitrogen protects 0 DEG C, add HATU (411mg, 1.08mmol), is subsequently adding triethylamine (0.50mL, 3.24mmol), according to the synthesis side of embodiment 1 step 3 Prepared by method, crude product is through silica gel column chromatography (dichloromethane:Ethyl acetate=20:1, V/V) 70mg white solid, yield, are obtained 11.8%.

MS (ESI, pos.ion) m/z:449.6(M+1)；

Step 4：N- (1- ((1- anocy clopropyl) carbamoyl) cyclohexyl) the fluoro- 5- of -6- (4- (mesyl) benzene Base)-benzofuran-2-carboxamides

The bromo- N- of 5- (1- ((1- anocy clopropyl) formoxyl) cyclohexyl) -6 fluorobenzene furan is added in 50mL two-mouth bottle Mutter -2- Methanamide (50mg, 0.111mmol), to mesyl phenylboric acid (22mg, 0.111mmol), [1,1'- double (diphenyl Phosphino-) ferrocene] palladium chloride (10mg, 0.011mmol) and DMF (6mL).Under nitrogen protection, add wet chemical (0.11mL,2mol/L).According to the synthetic method preparation of embodiment 1 step 5, crude product is through silica gel column chromatography (ethyl acetate:Two Chloromethanes=1:7, V/V) white solid 44mg, yield 76%, are obtained.

MS (ESI, pos.ion) m/z:524.3(M+1)；

¹H NMR(400MHz,CDCl₃) δ 8.07 7.97 (m, 3H), 7.72 (dd, J=7.0,1.9Hz, 3H), 7.50 (s, 1H), 7.38 (d, J=10.0Hz, 1H), 6.58 (s, 1H), 3.11 (s, 3H), 2.24 (d, J=14.1Hz, 2H), 2.00 (d, J =11.0Hz, 2H), 1.79 1.69 (m, 4H), 1.63 (s, 2H), 1.54 (d, J=2.5Hz, 2H), 1.25 (s, 2H).

Embodiment 3N- (1- ((1- anocy clopropyl) carbamoyl) cyclohexyl) -5- (2- oxo-pyrrolidine -1- base) benzene And furan -2- Methanamide

Step 1：5- bromobenzofuran -2- carboxylic acid, ethyl ester

The addition bromo- Benzaldehyde,2-hydroxy of 5- (15g, 74.63mmol) in bis- mouthfuls of bottles of 250mL, bromoacetate (18.7g, 111.9mmol), potassium carbonate (31g, 223.9mmol) and dry DMF (80mL), according to the synthetic method system of embodiment 1 step 1 Standby, crude product is through silica gel column chromatography (ethyl acetate:Petroleum ether=1:20, V/V) faint yellow solid 16.6g, yield 83%, are obtained.

MS(ESI,pos.ion)m/z:269.9(M+2)；

Step 2：5- bromobenzofuran -2- formic acid

Add 5- bromobenzofuran -2- carboxylic acid, ethyl ester (4g, 14.86mmol) and methanol (50mL) in bis- mouthfuls of bottles of 100mL, It is subsequently adding NaOH solution (22.3mL, 44.6mmol), according to the synthetic method preparation of embodiment 1 step 2, after vacuum drying To white solid 3.30g, yield 92%

MS(ESI,pos.ion)m/z:241.9(M+2)；

Step 3：The bromo- N- of 5- (1- ((1- anocy clopropyl) carbamoyl) cyclohexyl) benzofuran-2-carboxamides

In 50mL round-bottomed flask by 1- amino-N- (1- anocy clopropyl) cyclohexyl carboxamide hydrochloride (1.46g, 6.0mmol) it is dissolved in anhydrous DMF (18mL), addition 5- bromo- 1- coumarilic acid (1.11g, 4.62mmol), add HATU (1,75g, 4.62mmol) and at 0 DEG C, then triethylamine (2.5ml, 13.85mmol) is added dropwise to In reactant liquor, according to the synthetic method preparation of embodiment 1 step 3, crude product silica gel column chromatography (dichloromethane:Ethyl acetate= 50:1, V/V) white solid 430mg, yield 21.6%, are obtained.

MS (ESI, pos.ion) m/z:430.3(M+1)；

Step 4：N- (1- ((1- anocy clopropyl) carbamoyl) cyclohexyl) -5- (2- oxo-pyrrolidine -1- base) benzene And furan -2- Methanamide

By bromo- for 5- N- (1- ((1- anocy clopropyl) carbamoyl) cyclohexyl) benzofuran-2-carboxamides (100mg, 0.23mmol) it is dissolved in 4mL dry toluene, add 2-Pyrrolidone (25mg, 0.291mmol), and add under nitrogen protection Hydro-Giene (Water Science). (4.4mg, 0.023mmol) and potassium carbonate (64mg, 0.465mmol), then N, N '-dimethyl ethylenediamine (4.1mg, 0.046mmol) is added dropwise in reactant liquor, and tube sealing is overnight at 130 DEG C.Reaction is finished, and cools down and add 60mL saturation Saline solution, with ethyl acetate (20mL × 3) extraction, merges organic faciess, is washed with saturated aqueous common salt (30mL × 2), anhydrous slufuric acid Sodium is dried.Filter, decompression boils off solvent, crude product silica gel column chromatography (dichloromethane:Ethyl acetate=2:1, V/V), obtain white Color solid 35mg, yield 35.0%.

MS (ESI, pos.ion) m/z:435.1(M+1)；

¹H NMR(400MHz,CDCl₃) δ 8.12 (s, 1H), 7.87 (d, J=2.0Hz, 1H), 7.80 (dd, J=9.1, 2.2Hz, 1H), 7.54 (d, J=9.0Hz, 1H), 7.48 (s, 1H), 6.59 (s, 1H), 3.95 (t, J=7.0Hz, 2H), 2.67 (t, J=8.1Hz, 2H), 2.24 (dd, J=14.9,7.2Hz, 4H), 2.08 1.96 (m, 2H), 1.81 1.70 (m, 2H), 1.53 (dt, J=20.1,10.2Hz, 4H), 1.31 1.22 (m, 4H).

Embodiment 4N- (1- ((1- anocy clopropyl) carbamoyl) cyclohexyl) -5- (2- (1,1- dioxo Quinoline) thiazole-4-yl) benzofuran-2-carboxamides

Step 1：4- (4- bromo thiazole -2- base) thiomorpholine

2,4- bis- bromo thiazole (500mg, 2.06mmol) and thiomorpholine (5mL), reaction is added in 50mL twoport flask After mixture is heated to 90 DEG C of reactions 4.5 hours under nitrogen protection, reaction completes, and cools down and adds water (20mL), use acetic acid Ethyl ester (20mL × 3) extracts, and merges organic faciess, is washed with saturated aqueous common salt (10mL × 2), anhydrous sodium sulfate drying.Filter, subtract Pressure boils off solvent, crude product silica gel column chromatography (petroleum ether:Ethyl acetate=10:1, V/V), obtain faint yellow solid 450mg, receive Rate 87.0%.

MS (ESI, pos.ion) m/z:265.9(M+2)；

Step 2：4- (4- bromo thiazole -2- base) thiomorpholine 1,1- dioxide

Add 4- (4- bromo thiazole -2- base) thiomorpholine (360mg, 1.36mmol) in 50mL twoport flask, then will The solution that Disodium tungstate (Na2WO4) dihydrate (13.8mg) and tetrabutyl Ammonium hydrogen sulfate (38mg) are dissolved in dichloromethane (10mL) adds reaction bulb In, it is cooled to 0 DEG C with ice-water bath, Deca H in reaction bulb₂O₂(0.45mL, 30%) solution, completion of dropping, reactant mixture exists 3h is stirred, TLC monitoring raw material reaction is complete, and reactant liquor is poured in frozen water (10mL), with ethyl acetate (30mL × 3) extraction under room temperature Take, merge organic faciess, anhydrous sodium sulfate drying.Filter, decompression boils off solvent, crude product silica gel column chromatography (dichloromethane:Second Acetoacetic ester=2:1, V/V) purification, obtains white solid 260mg, yield 65%.

MS(ESI,pos.ion)m/z:297.9(M+2)；

Step 3：N- (1- ((1- anocy clopropyl) carbamoyl) cyclohexyl) -5- (2- (1,1- dioxothiomorpholin Base) thiazole-4-yl) benzofuran-2-carboxamides

In 50mL bottle with two necks add 4- (4- bromo thiazole -2- base) thiomorpholine 1,1- dioxide (65mg, 0.22mmol), N- [1- [(1- anocy clopropyl) carbamoyl] -4,4- difiuorocyclohexyl] -6- (4,4,5,5- tetramethyl - 1,3,2- bis- dislike borine -2- base) benzofuran-2-carboxamides (125mg, 0.26mmol), tetrakis triphenylphosphine palladium (15mg, 0.013mmol) with DMF (8mL), add wet chemical (0.3mL, 0.6mmol, 2mol/L), mixing under nitrogen protection Thing 85 DEG C reaction 2 hours after, be cooled to room temperature, add water (60mL) be quenched, with ethyl acetate (50mL × 2) extraction, organic faciess Washed with water (80mL × 2) and saturated aqueous common salt (80mL), after sodium sulfate is dried, solvent, residue column chromatography (dichloromethane are evaporated off Alkane:Methanol=10:1, V/V) faint yellow solid 70mg, yield 56%, are obtained.

MS(ESI,pos.ion)m/z:568.1(M+1)；

¹H NMR(400MHz,CDCl₃) δ 8.18 (s, 1H), 8.11 (s, 1H), 7.94 (dd, J=8.7,1.6Hz, 1H), 7.61 7.51 (m, 2H), 6.92 (s, 1H), 6.60 (s, 1H), 4.20 (s, 4H), 3.23 (d, J=5.0Hz, 4H), 2.26 (d, J =13.7Hz, 2H), 2.05 (d, J=13.0Hz, 2H), 1.79 1.72 (m, 2H), 1.57 1.50 (m, 4H), 0.91 0.86 (m,4H).

Embodiment 5N- (1- ((1- anocy clopropyl) carbamoyl) cyclohexyl) -5- (4- (mesyl) phenyl) - 1H- indole 2-carboxamides

Step 1：5- bromo- 1H- indole-2-carboxylic acid

5- bromo- 1H- indole -2-carboxylic ethyl ester (5.36g, 20.0mmol) and methanol is added in bis- mouthfuls of bottles of 100mL (50mL), it is subsequently adding NaOH solution (25mL, 50mmol), according to the synthetic method preparation of embodiment 1 step 2, obtain white Solid, obtains after vacuum drying:4.32g, yield 90%.

MS(ESI,pos.ion)m/z:240.9(M+2)；

Step 2：The bromo- N- of 5- (1- ((1- anocy clopropyl) formoxyl) cyclohexyl) -1H- indole 2-carboxamides

6- bromo- 1H- indole-2-carboxylic acid (283mg, 1.18mmol), 1- amino-N- (1- is added in 50mL two-mouth bottle ((1- anocy clopropyl) formoxyl) -1H- indole 2-carboxamides (375mg, 1.54mmol) and DMF (6mL), nitrogen protects 0 DEG C Under, add HATU (449mg, 1.18mmol), be then added dropwise to triethylamine (0.55mL, 3.55mmol), according to embodiment 1 step 3 synthetic method preparation, crude product is through silica gel column chromatography (dichloromethane:Ethyl acetate=50:1, V/V), obtain white solid 110mg, yield 22%.

MS(ESI,pos.ion)m/z:430.1(M+2)；

Step 3：N- (1- ((1- anocy clopropyl) carbamoyl) cyclohexyl) -5- (4- (mesyl) phenyl) -1H- Indole 2-carboxamides

The bromo- N- of 5- (1- ((1- anocy clopropyl) formoxyl) cyclohexyl) -1H- indole -2- is added in 50mL two-mouth bottle Methanamide (100mg, 0.23mmol), to mesyl phenylboric acid (44mg, 0.22mmol), [1,1'- double (diphenylphosphino) two Luxuriant ferrum] palladium chloride (18mg, 0.022mmol) and DMF (6mL).Under nitrogen protection, add the wet chemical of 2mol/L (0.23mL).According to the synthetic method preparation of embodiment 1 step 5, crude product is through silica gel column chromatography (ethyl acetate:Dichloromethane =1:3, V/V) white solid 40mg, yield 34%, are obtained.

MS (ESI, pos.ion) m/z:505.5(M+1)；

¹H NMR(400MHz,DMSO-d₆) δ 11.82 (s, 1H), 8.57 (s, 1H), 7.98 (dd, J=26.1,8.5Hz, 5H), 7.83 7.72 (m, 2H), 7.45 (dd, J=8.4,1.4Hz, 1H), 7.37 (s, 1H), 3.26 (s, 3H), 2.51 (d, J= 1.6Hz, 2H), 2.03 (t, J=12.7Hz, 2H), 1.87 1.73 (m, 2H), 1.55 (s, 4H), 1.44 (dd, J=8.0, 5.4Hz, 2H), 1.06 (dd, J=8.1,5.5Hz, 2H).

Embodiment 6 (S)-N- (1- ((1- anocy clopropyl) amino) -4- fluoro- 4- methyl isophthalic acid-oxo-pentane -2- base) -6- Fluoro- 5- (2- oxo-pyrroli -1- base) benzofuran-2-carboxamides

Step 1：5- bromo- 6- Fluorobenzofur -2- carboxylic acid, ethyl ester

In the bottle with two necks of a 50mL, the fluoro- Benzaldehyde,2-hydroxy of the bromo- 4- of 5- (1.0g, 4.57mmol) is dissolved in dimethyl In Methanamide (10mL), add bromoacetate (1.14g, 6.85mmol) and potassium carbonate (1.9g, 13.7mmol), according to enforcement The synthetic method preparation of example 1 step 1, by crude product in silica gel column chromatography purification (petroleum ether:Ethyl acetate=20:1, V/V), obtain To white solid 840mg, yield 62.5%.

MS (ESI, pos.ion) m/z:287.9(M+2)；

Step 2：5- bromo- 6- Fluorobenzofur -2- carboxylic acid

Bromo- for 5- 6- Fluorobenzofur -2- carboxylic acid, ethyl ester (820mg, 2.85mmol) in the solution of methanol (17mL), to The NaOH aqueous solution (4.3mL, 2mol/L) adding in solution, according to the synthetic method preparation of embodiment 1 step 2, obtains white Solid 650mg, yield 88.0%.

MS (ESI, pos.ion) m/z:259.9(M+2)；

Step 3：(S) the bromo- N- of -5- ((1- anocy clopropyl) amino) -4- fluoro- 4- methyl isophthalic acid-oxygen-pentane -2- base) -6- Fluoro- 5- (2- oxygen-pyrrolidin-1-yl) benzofuran-2-carboxamides

5- bromo- 6- Fluorobenzofur -2- carboxylic acid (260mg, 1mmol) and the fluoro- 4- methylvaleric acid of (S)-methyl 2- amino -4- Hydrochlorate (325mg, 1.3mmol) is dissolved in DMF (5mL) and the mixed solution of dichloromethane (5mL), adds HATU (532mg, 1.4mmol) and DIPEA (840mg, 6.5mmol), according to the synthetic method system of embodiment 1 step 3 Standby, by crude product in silica gel column chromatography purification (petroleum ether:Ethyl acetate=3:1, V/V) white solid 270mg, yield, are obtained 59.4%.

MS (ESI, pos.ion) m/z:455.1(M+2)；

Step 4：(S)-N- (1- ((1- anocy clopropyl) amino) -4- fluoro- 4- methyl isophthalic acid-oxygen-pentane -2- base) -6- is fluoro- 5- (2- oxygen-pyrrolidin-1-yl) benzofuran-2-carboxamides

In 10mL tube sealing, add the bromo- N- of (S) -5- ((1- anocy clopropyl) amino) -4- fluoro- 4- methyl isophthalic acid-oxygen-penta Alkane -2- base) the fluoro- 5- of -6- (2- oxygen-pyrrolidin-1-yl) benzofuran-2-carboxamides (270mg, 0.6mmol), pyrrolidine -2- Ketone (76mg, 0.9mmol), potassium carbonate (166mg, 1.2mmol), Hydro-Giene (Water Science). (6mg, 0.03mmol), N, N'- dimethyl second two Amine (15mg, 0.17mmol) and toluene (3mL), are stirred overnight in 130 DEG C of nitrogen protections.Synthesis side according to embodiment 3 step 4 Prepared by method, crude product silica gel column chromatography purification (petroleum ether:Ethyl acetate=1:1, V/V) white solid 50mg, yield, are obtained 18.2%.

MS (ESI, pos.ion) m/z:459.3(M+1)；

¹H NMR(400MHz,CDCl₃):δ:7.70 (d, J=7.4Hz, 1H), 7.47 (s, 1H), 7.36 (d, J=9.5Hz, 3H), 4.74 (dd, J=12.7,7.2Hz, 1H), 3.88 (t, J=7.1Hz, 2H), 2.67 (t, J=8.1Hz, 2H), 2.28 (dt, J=14.3,7.5Hz, 3H), 1.56 1.20 (m, 2H).

Embodiment 7-14

Using corresponding raw material and intermediate, the synthetic method according to embodiment 1 or 4 or 5 or 6 prepares embodiment 7- 14 compound, embodiments data is as follows

The method of the selective experiment of biological Examples 1 cathepsin

Cathepsin K vitro inhibition activity experiment method

With the enzyme working solution of 45000 times of dilutions, 10 μM of Z-Phe-Arg-AMC is substrate.According to the experiment bar having optimized Part, using 15 microlitres of reaction systems, after incubation 15min at a temperature of test compound and enzyme are placed in 25 DEG C, anti-at measuring 25 DEG C Answer the kinetics slope in 15min, seek the IC calculating compound to human cathepsin K₅₀Value.

Cathepsin B's vitro inhibition activity experiment method

Using the Cathepsin B of 0.01ng/ μ L as enzyme reaction final concentration, final concentration of 10 μM of Z-Phe-Arg-AMC As substrate, it is added to the reaction system after 25 DEG C of incubation 15min of test compound and enzyme, in reaction 10min at measuring 25 DEG C Kinetic parameter, seek the IC calculating test compound to human cathepsin B₅₀Value.

Cathepsin L's vitro inhibition activity experiment method

Using the Cathepsin L of 0.01ng/ μ L as enzyme reaction final concentration, final concentration of 10 μM of Z-Phe-Arg-AMC As substrate, it is added to the reaction system after 25 DEG C of incubation 15min of test compound and enzyme, in reaction 10min at measuring 25 DEG C Kinetic parameter, seek the IC calculating test compound to human cathepsin L₅₀Value.

Cathepsin S vitro inhibition activity experiment method

Using the Cathepsin S of 0.25ng/ μ L as enzyme reaction final concentration, final concentration of 20 μM of Z-VVR-AMC conduct Substrate, is added to the reaction system after 25 DEG C of incubation 15min of test compound and enzyme, dynamic in reaction 10min at measuring 25 DEG C Mechanics parameter, seeks the IC calculating candidate compound to human cathepsin S₅₀Value.

The external activity test data of table 2 the compounds of this invention

Can be seen that the compounds of this invention from the data of table 2 has good inhibitory activity, IC to cathepsin K₅₀Value is all In nanomole level, and to the inhibitory activity of the cathepsin such as B, L and S etc. of other hypotypes on micromolar levels, to tissue E.C. 3.4.21.64 shows very high selectivity.The compounds of this invention not only has good inhibitory activity to cathepsin K, with When also high to homology cathepsin B, L and S show very high selectivity, reduce due to compound poor selectivity The side effect of missing the target causing, opens thus substantially increasing and being used for treating osteoporosis agents as cathepsin K inhibitor The probability sent out.

The pharmacokineticss test of biological Examples 2 the compounds of this invention

1. laboratory animal:Healthy adult male SD rat, row vein intravenous and oral gavage are entered in packet respectively.

2. medicine ordinance:Weigh a certain amount of testing compound, add 5%DMSO, 10%Kolliphor HS15 and 85%Saline is configured to settled solution.

3. administration and sample collecting:Fasting 12h before animal administration, water freely drinks.3h feed after administration.Pass through SD respectively Rat hindlimb peduncular veins intravenous (IV, 1mg/kg) administration and the administration of oral gavage (PO, 5mg/kg).Blood collection is that big rat-tail is quiet Arteries and veins take a blood sample, blood sampling volume about 200-400 μ L/ time point, blood sampling time point be 0,0.083,0.25,0.5,1,2,4,6,8,24h.Often After individual time point collection whole blood, put in K2EDTA anticoagulant test tube, be put in the couveuse of bag on the rocks and preserve.All samples exist In 15min, in 4600r/min, 4 DEG C, it is centrifuged 5min, separated plasma.Sample is stored in -80 DEG C, to be measured.

4. analysis method:Using the content in the different compounds of LC/MS/MS method mensure upon administration rat plasma.

Experimental result shows：The compounds of this invention after oral administration in rat body blood drug level and exposed amount level equal Height, bioavailability is higher, long half time, has good Pharmacokinetic Characteristics.

Claims (10)

1. a kind of compound, it has the compound as shown in formula (I), or the stereoisomer of shown compound, tautomerism Body, geometric isomer, nitrogen oxides, prodrug or pharmaceutically acceptable salt,

Wherein,

Ring W is as follows one of subformula：

Wherein, * represents and R⁵Connected one end；

X is-O- ,-S- ,-C (=O)-or-N (R⁶)-；

V, Z and Y are each independently C (R⁹) or N；

R^4aFor hydrogen, C_2-6Alkyl or C_2-6Thiazolinyl；Wherein said C_2-6Alkyl and C_2-6Thiazolinyl is individually optionally by 1,2,3,4,5 or 6 Individual selected from halogen, C_3-6Cycloalkyl, cyano group, C_6-10Aryl, C_1-9Heteroaryl and C_2-9The substituent group of heterocyclic radical is replaced；

R⁴For C_2-6Alkyl ,-C (R⁷)(R^7a)-R⁸、C_3-9Heterocyclic radical or C_2-6Thiazolinyl；Wherein said C_2-6Alkyl and C_2-6Thiazolinyl is independent Optionally it is selected from halogen, C by 1,2,3,4,5 or 6_3-6Cycloalkyl, cyano group, C_6-10Aryl, C_1-9Heteroaryl and C_3-9Heterocyclic radical Substituent group is replaced；

Or R⁴And R^4aForm a nitrogenous C together with the nitrogen-atoms being connected with them_3-9Heterocyclic radical；Wherein said C_3-9Heterocyclic radical is appointed Selection of land is selected from C by 1,2,3,4 or 5_1-6Alkyl, C_1-6Hydroxy alkyl, cyano group ,-C (R¹⁰)(R^10a)-C (=O)-N (R¹²) (R^12a) ,-C (=O)-OR^8a, oxo, C_1-6The substituent group of haloalkyl and halogen is replaced；

R⁷And R^7aIt is each independently hydrogen, C_1-6Alkyl ,-C (R¹⁰)(R^10a)-C (=O)-N (R¹²)(R^12a) ,-C (=O)-OR^8a、 C_2-9Heterocyclic radical or C_2-6Thiazolinyl；

Or R⁷And R^7aForm a C together with the carbon atom being connected with them_3-6Carbocyclic ring or C_2-6Heterocycle；Wherein said C_3-6Carbocyclic ring and C_2-6Heterocycle is selected from C by 1,2,3,4,5 or 6 individually optionally_1-6Alkyl, C_1-6Hydroxy alkyl, C_1-6Haloalkyl, oxo, cyanogen Base ,-C (=O)-OR^8aReplaced with the substituent group of halogen；

R⁸For C_1-6Alkyl, cyano group ,-N (R¹²)(R^12a) ,-C (=O)-C (=O)-N (R¹²)(R^12a) ,-C (=O)-N (R¹²) (R^12a) ,-C (=O)-OR^8a、C_3-6Heterocyclic radical or C_2-6Thiazolinyl；

Each R⁶、R^6a、R³、R^3a、R²、R^2a、R^8a、R¹⁰、R^10a、R¹²And R^12aIt independently is hydrogen or C_1-6Alkyl；Wherein said C_1-6Alkyl Optionally it is selected from halogen, hydroxyl, amino, carboxyl, cyano group, C by 1,2,3,4,5 or 6_3-6Cycloalkyl, C_6-10Aryl, C_1-9Heteroaryl Base and C_2-9The substituent group of heterocyclic radical is replaced；

Or R²、R^2aAnd form a C together with the carbon atom being connected with them_3-9Carbocyclic ring or C_2-9Heterocycle；Wherein said C_3-9Carbocyclic ring and C_2-9Heterocycle is selected from C by 1,2,3,4,5 or 6 individually optionally_1-6Alkyl, C_2-6Thiazolinyl, C_1-6Hydroxy alkyl, C_1-6Haloalkyl, The substituent group of hydroxyl, amino, carboxyl, cyano group and halogen is replaced；

Or R³、R^3aAnd form one together with the carbon atom being connected with them>C (=O), C_3-9Carbocyclic ring or C_2-9Heterocycle；Wherein said C_3-9Carbocyclic ring and C_2-9Heterocycle is selected from C by 1,2,3,4,5 or 6 individually optionally_1-6Alkyl, C_2-6Thiazolinyl, C_1-6Hydroxy alkyl, C_1-6 The substituent group of haloalkyl, hydroxyl, amino, carboxyl, cyano group and halogen is replaced；

Each R⁹It independently is hydrogen, halogen, cyano group, hydroxyl, C_1-4Alkoxyl ,-N (R⁶)(R^6a)、C_1-4Haloalkyl or C_1-4Alkyl；Its Described in C_1-4Alkyl is optionally selected from halogen, C by 1,2,3,4,5 or 6_3-6Cycloalkyl, C_6-10Aryl, C_1-9Heteroaryl and C_2-9 The substituent group of heterocyclic radical is replaced；

R⁵For hydrogen, C_1-4Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_1-4Alkoxyl, halogen, nitro, cyano group ,-N (R⁶)(R^6a) or C_1-4Halogen Substituted alkyl；

R¹For aryl, heteroaryl, cycloalkyl or heterocyclic radical；Wherein said aryl, heteroaryl, cycloalkyl and heterocyclic radical are individually optional Ground is by 1,2,3,4 or 5 R^1aReplaced；

Each R^1aIt independently is hydrogen, alkyl, haloalkyl, halogen, cyano group, oxo, alkoxyl, aryl, heteroaryl, cycloalkyl, miscellaneous Ring group ,-SR¹⁴、-OR¹⁴、-SO₂-N(R¹³)(R^13a)、-N(R^13a)-SO₂-R¹⁴、-N(R¹³)(R^13a) ,-C (=O)-C (=O)-N (R¹³)(R^13a) ,-C (=O)-N (R¹³)(R^13a)、-N(R¹³)-C (=O) R^14a,-C (=O)-OR¹⁴,-C (=O)-R^14aOr- SO₂R¹⁴；Each R^1aDescribed in aryl, heteroaryl, cycloalkyl, heterocyclic radical, alkyl, haloalkyl, alkoxyl ,-SR¹⁴、-OR¹⁴、- SO₂-N(R¹³)(R^13a)、-N(R^13a)-SO₂-R¹⁴、-N(R¹³)(R^13a) ,-C (=O)-C (=O)-N (R¹³)(R^13a) ,-C (=O)- N(R¹³)(R^13a)、-N(R¹³)-C (=O) R^14a,-C (=O)-OR¹⁴,-C (=O)-R^14aWith-SO₂R¹⁴Individually optionally by 1,2, 3rd, 4 or 5 R^1bReplaced；

Each R^1bIndependently be hydrogen, alkyl, haloalkyl, thiazolinyl, alkynyl, alkoxyl, halogen, nitro, cyano group, hydroxyl, oxo ,- OR¹⁵、-SO₂R¹⁵、-N(R¹⁶)(R^16a) ,-C (=O)-N (R¹⁶)(R^16a), aryl, heteroaryl, cycloalkyl or heterocyclic radical；Described Each R^1bIt is selected from hydroxyl, nitro, cyano group, alkyl, haloalkyl, halogen, oxo, alcoxyl by 1,2,3,4 or 5 individually optionally The substituent group of base, aryl, heteroaryl, cycloalkyl, heterocyclic radical and amino is replaced；

Each R¹⁶And R^16aIt independently is hydrogen, C_1-4Alkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_6-10Aryl, C_1-9Heteroaryl, C_3-6Cycloalkanes Base ,-SO₂R¹⁷、-N(R¹⁸)(R^18a)、C_1-4Haloalkyl or C_2-9Heterocyclic radical；

Each R¹⁵、R¹³、R^13a、R¹⁴、R^14a、R¹⁷、R¹⁸And R^18aIt independently is hydrogen, C_1-4Alkyl, C_1-4Haloalkyl, C_2-6Thiazolinyl, C_2-6 Alkynyl, C_6-10Aryl, C_1-9Heteroaryl, C_3-6Cycloalkyl or C_2-9Heterocyclic radical.

2. compound according to claim 1, wherein,

R^4aFor hydrogen, ethyl, n-pro-pyl or isopropyl；

R⁴For ethyl, n-pro-pyl, isopropyl ,-C (R⁷)(R^7a)-R⁸, 5-6 circle heterocycles base or vinyl；

Or R⁴And R^4aForm following subformula together with the nitrogen-atoms being connected with them： Wherein R⁴And R^4aThe member ring systems being formed together with the nitrogen-atoms being connected with them are optionally selected from C by 1,2,3,4 or 5_1-4Alkyl, C_1-4Hydroxy alkyl, oxo, cyano group ,-C (R¹⁰)(R^10a)-C (=O)-N (R¹²)(R^12a) ,-C (=O)-OR^8a、C_1-4Haloalkyl Replaced with the substituent group of halogen；

R⁷And R^7aIt is each independently hydrogen, C_1-4Alkyl ,-C (R¹⁰)(R^10a)-C (=O)-N (R¹²)(R^12a) ,-C (=O)-OR^8a、 C_3-6Heterocyclic radical or C_2-6Thiazolinyl；

Or R⁷And R^7aFormed together with the carbon atom being connected with them cyclopropyl, cyclopenta, cyclobutyl, cyclohexyl, morpholinyl, Piperidyl or pyrrolidinyl；Wherein said cyclopropyl, cyclopenta, cyclobutyl, cyclohexyl, morpholinyl, piperidyl and pyrrolidinyl It is selected from C by 1,2,3,4 or 5 individually optionally_1-4Alkyl, C_1-4Hydroxy alkyl, C_1-4Haloalkyl, oxo, cyano group ,-C (= O)-OR^8aReplaced with the substituent group of halogen；

R⁸For C_1-4Alkyl, cyano group ,-N (R¹²)(R^12a) ,-C (=O)-C (=O)-N (R¹²)(R^12a) ,-C (=O)-N (R¹²) (R^12a) ,-C (=O)-OR^8a、C_3-6Heterocyclic radical or C_2-6Thiazolinyl；

Each R^8a、R¹⁰、R^10a、R¹²And R^12aIt independently is hydrogen or C_1-4Alkyl；Wherein said C_1-4Alkyl is optionally by 1,2,3,4 or 5 Individual selected from halogen, hydroxyl, amino, carboxyl, cyano group, C_3-6Cycloalkyl, C_6-10Aryl, C_1-9Heteroaryl and C_2-9The replacement of heterocyclic radical Base is replaced.

3. compound according to claim 1, wherein,

Each R⁶、R^6a、R³、R^3a、R²And R^2aIt independently is hydrogen, methyl, ethyl, n-pro-pyl, isopropyl, 1- methyl-propyl, 2- methyl Propyl group or the tert-butyl group；Wherein said methyl, ethyl, n-pro-pyl, isopropyl, 1- methyl-propyl, 2- methyl-propyl and the tert-butyl group are only Stand and be optionally selected from fluorine, chlorine, bromine, hydroxyl, amino, carboxyl, cyano group, cyclohexyl, cyclopenta, ring fourth by 1,2,3,4,5 or 6 Base, cyclopropyl, phenyl, pyridine radicals, thiazolyl, di azoly, triazolyl, piperidyl, furyl, tetrahydrofuran base, azetidin The substituent group of base, oxetanylmethoxy and morpholinyl is replaced；

Or R²、R^2aAnd form cyclohexyl, cyclopenta, cyclobutyl, cyclopropyl, a cycloheptyl together with the carbon atom being connected with them Base, piperidyl, pyrrolidinyl, piperazinyl, THP trtrahydropyranyl, morpholinyl or tetrahydrofuran base；Wherein said cyclohexyl, ring penta Base, cyclobutyl, cyclopropyl, suberyl, piperidyl, pyrrolidinyl, piperazinyl, THP trtrahydropyranyl, morpholinyl and tetrahydrofuran base It is selected from C by 1,2,3,4 or 5 individually optionally_1-4Alkyl, C_2-4Thiazolinyl, C_1-4Hydroxy alkyl, C_1-4Haloalkyl, hydroxyl, ammonia The substituent group of base, carboxyl, cyano group, fluorine, chlorine and bromine is replaced；

Or R³、R^3aAnd form one together with the carbon atom being connected with them>C (=O), cyclohexyl, cyclopenta, cyclobutyl, ring third Base, suberyl, piperidyl, pyrrolidinyl, piperazinyl, THP trtrahydropyranyl, morpholinyl or tetrahydrofuran base, wherein said hexamethylene Base, cyclopenta, cyclobutyl, cyclopropyl, suberyl, piperidyl, pyrrolidinyl, piperazinyl, THP trtrahydropyranyl, morpholinyl and tetrahydrochysene Furyl is selected from C by 1,2,3,4 or 5 individually optionally_1-4Alkyl, C_1-4Hydroxy alkyl, C_1-4Haloalkyl, hydroxyl, amino, The substituent group of carboxyl, cyano group and halogen is replaced；

Each R⁹It independently is hydrogen, fluorine, chlorine, bromine, cyano group, hydroxyl, methoxyl group, amino, methyl, ethyl, isopropyl or trifluoromethyl；

Each R⁵It independently is hydrogen, fluorine, chlorine, bromine, cyano group, hydroxyl, nitro, amino, methyl, ethyl, isopropyl, the tert-butyl group, methoxy Base, ethyoxyl, difluoromethyl or trifluoromethyl.

4. compound according to claim 1, wherein,

R¹For C_6-10Aryl, C_1-9Heteroaryl, C_3-12Cycloalkyl or C_2-12Heterocyclic radical；Wherein said each R¹Individually optionally by 1,2, 3rd, 4 or 5 R^1aReplaced；

Each R^1aIt independently is hydrogen, C_1-6Alkyl, C_1-6Haloalkyl, halogen, cyano group, oxo, C_1-6Alkoxyl, C_6-10Aryl, C_1-9 Heteroaryl, C_3-12Cycloalkyl, C_2-12Heterocyclic radical ,-SR¹⁴、-OR¹⁴、-SO₂-N(R¹³)(R^13a)、-N(R^13a)-SO₂-R¹⁴、-N(R¹³) (R^13a) ,-C (=O)-C (=O)-N (R¹³)(R^13a) ,-C (=O)-N (R¹³)(R^13a)、-N(R¹³)-C (=O) R^14a,-C (=O)- OR¹⁴,-C (=O)-R^14aOr-SO₂R¹⁴；Each R^1aDescribed in C_6-10Aryl, C_1-9Heteroaryl, C_3-12Cycloalkyl, C_2-12Heterocyclic radical, C_1-6Alkyl, C_1-6Haloalkyl, C_1-6Alkoxyl ,-SR¹⁴、-OR¹⁴、-SO₂-N(R¹³)(R^13a)、-N(R^13a)-SO₂-R¹⁴、-N (R¹³)(R^13a) ,-C (=O)-C (=O)-N (R¹³)(R^13a) ,-C (=O)-N (R¹³)(R^13a)、-N(R¹³)-C (=O) R^14a、-C (=O)-OR¹⁴,-C (=O)-R^14aWith-SO₂R¹⁴Individually optionally by 1,2,3,4 or 5 R^1bReplaced；

Each R^1bIt independently is hydrogen, C_1-6Alkyl, C_1-6Haloalkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_1-6Alkoxyl, halogen, nitro, cyanogen Base, hydroxyl, oxo ,-OR¹⁵、-SO₂R¹⁵、-N(R¹⁶)(R^16a) ,-C (=O)-N (R¹⁶)(R^16a)、C_6-10Aryl, C_1-9Heteroaryl, C_3-12Cycloalkyl or C_2-12Heterocyclic radical；Described each R^1bIndividually optionally by 1,2,3,4 or 5 be selected from hydroxyl, nitro, cyano group, C_1-6Alkyl, C_1-6Haloalkyl, halogen, oxo, C_1-6Alkoxyl, C_6-10Aryl, C_1-9Heteroaryl, C_3-12Cycloalkyl, C_2-12Heterocycle The substituent group of base and amino is replaced；

Each R¹⁶And R^16aIt independently is hydrogen or C_1-4Alkyl；

Each R¹⁵、R¹³、R^13a、R¹⁴And R^14aIt independently is hydrogen, C_1-4Alkyl, C_1-4Haloalkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, phenyl, 5-6 unit's heteroaryl, C_3-6Cycloalkyl or 4-7 circle heterocycles base.

5. compound according to claim 1,

R¹It is as follows subformula：

Wherein, each X¹、X²、X³、X⁹And X¹⁰It independently is CH or N；

Each X⁴、X⁵、X⁶、X⁷And X⁸It independently is-CH₂- ,-C (=O)-,-O- ,-S- ,-S (=O)-,-S (=O)₂- or-NH-；

Wherein said each R¹Individually optionally by 1,2,3,4 or 5 R^1aReplaced；

Each R^1aIt independently is hydrogen, C_1-4Alkyl, C_1-4Haloalkyl, halogen, cyano group, oxo, C_1-4Alkoxyl ,-SR¹⁴、-OR¹⁴、-SO₂- N(R¹³)(R^13a)、-N(R^13a)-SO₂-R¹⁴、-N(R¹³)(R^13a) ,-C (=O)-C (=O)-N (R¹³)(R^13a) ,-C (=O)-N (R¹³) (R^13a)、-N(R¹³)-C (=O) R^14a,-C (=O)-OR¹⁴,-C (=O)-R^14a、-SO₂R¹⁴Or subformula as follows： Wherein, each Y¹、Y²、Y³、Y⁹With Y¹⁰It independently is CH or N；

Each Y⁴、Y⁵、Y⁶、Y⁷And Y⁸It independently is-CH₂- ,-C (=O)-,-O- ,-S- ,-S (=O)-,-S (=O)₂- or-NH-；

Wherein said each R^1aIndividually optionally by 1,2,3,4 or 5 R^1bReplaced；

Each R^1bIt independently is hydrogen, C_1-4Alkyl, C_1-4Haloalkyl, C_2-6Thiazolinyl, C_2-6Alkynyl, C_1-4Alkoxyl, halogen, nitro, cyanogen Base, hydroxyl, oxo ,-OR¹⁵、-SO₂R¹⁵、-N(R¹⁶)(R^16a) ,-C (=O)-N (R¹⁶)(R^16a) or structure shown below formula： Wherein, each Z¹、Z²、Z³、Z⁹And Z¹⁰It independently is CH or N；

Each Z⁴、Z⁵、Z⁶、Z⁷And Z⁸It independently is-CH₂- ,-C (=O)-,-O- ,-S- ,-S (=O)-,-S (=O)₂- or-NH-；

Described each R^1bIt is selected from hydroxyl, nitro, cyano group, C by 1,2,3,4 or 5 individually optionally_1-4Alkyl, C_1-4Haloalkyl, halogen Element, oxo, C_1-4Alkoxyl, phenyl, 5-6 unit's heteroaryl, the substituent group of 4-7 unit cycloalkyl, 4-7 circle heterocycles base and amino are taken Generation.

6. compound according to claim 1, wherein

R¹It is as follows subformula：

Wherein said each R¹Individually optionally by 1,2,3,4 or 5 R^1aReplaced；

Each R^1aIt independently is hydrogen, ethyl, methyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, cyano group, trifluoromethyl, 2,2- bis- Fluoro ethyl, 3,3,3- trifluoro propyl, fluorine, chlorine, bromine, oxo, methoxyl group, positive propoxy, ethyoxyl, tert-butoxy, 2- methyl-prop Epoxide, isopropoxy ,-SR¹⁴、-OR¹⁴、-SO₂-N(R¹³)(R^13a)、-N(R^13a)-SO₂-R¹⁴、-N(R¹³)(R^13a) ,-C (=O)-C (=O)-N (R¹³)(R^13a) ,-C (=O)-N (R¹³)(R^13a)、-N(R¹³)-C (=O) R^14a,-C (=O)-OR¹⁴,-C (=O)- R^14a、-SO₂R¹⁴Or subformula as follows：

Wherein said each R^1aIndividually optionally by 1,2,3,4 or 5 R^1bReplaced；

Each R^1bIt independently is hydrogen, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, cyclobutyl, cyclopropyl, hexamethylene Base, cyclopenta, difluoromethyl, trifluoromethyl, 2,2- bis- fluoro ethyl, 3,3,3- trifluoro propyl, vinyl, acrylic, pi-allyl, Acetenyl, propinyl, propargyl, methoxyl group, fluorine, chlorine, bromine, nitro, cyano group, hydroxyl, oxo ,-OR¹⁵、-SO₂R¹⁵、-N(R¹⁶) (R^16a) ,-C (=O)-N (R¹⁶)(R^16a) or structure shown below formula：

Described each R^1bIt is selected from hydroxyl, nitro, cyano group, methyl, ethyl, just by 1,2,3,4 or 5 individually optionally Propyl group, isopropyl, normal-butyl, the tert-butyl group, difluoromethyl, trifluoromethyl, 2,2- bis- fluoro ethyl, 3,3,3- trifluoro propyl, fluorine, Chlorine, bromine, oxo, methoxyl group, ethyoxyl, isopropoxy, tert-butoxy, phenyl, pyridine radicals, thiazolyl, thienyl, di azoly, Triazolyl, tetrazole radical, oxetanes, tetrahydrofuran base, THP trtrahydropyranyl, morpholinyl, piperidyl, cyclobutyl, cyclopenta, ring The substituent group of oxygen six ring group, cyclohexyl and amino is replaced.

7. compound according to claim 1, it is different for the solid of the compound shown in formula (III) or compound shown in it Structure body, tautomer, geometric isomer, nitrogen oxides or pharmaceutically acceptable salt；

8. a kind of compound, it is as follows one of structure, or the stereoisomer of compound shown in it, tautomer, Geometric isomer, nitrogen oxides or pharmaceutically acceptable salt：

9. a kind of pharmaceutical composition, comprises the compound described in any one of claim 1-8 and pharmaceutically acceptable carrier, tax At least one in shape agent, diluent, adjuvant and vehicle；

Further optionally comprise organic bisphosphonate compound, estrogenic agents, erss regulator, hero Hormone receptor modulator, osteoclast proton triphosphatase inhibitor, HMG-CoA reductase inhibitor, integrin are subject to Body antagonist, osteoblast anabolic agent, vitamin D, phytoestrogen, calcitonin class, Strontium Ranelate, Ao Dangka replace, ONO5334, MIV-711, MIV-710 and another kind of material of its medicinal salt and mixture.

10. the compound described in any one of claim 1-8 or the pharmaceutical composition described in claim 9 are in preparing medicine Purposes, wherein, described medicine is used for inhibiting cathepsin activity or treatment Cathepsin dependent diseases, especially for The activity of inhibiting cathepsin K；And/or

Described medicine is used for treating, prevents, mitigates or reduction of patient osteoporosises, Paget, the increase of bone update anomalies, tooth All diseases, tooth loss, fracture, rheumatoid arthritiss, osteoarthritis, periprosthetic osteolysis, osteogenesis not exclusively, transfer Property osteopathia, malignant hypercalcemia, multiple myeloma, multiple sclerosis, myasthenia graviss, psoriasiss, ordinary sky born of the same parents' skin ulcer, Exophthalmic goiter, systemic lupus erythematosus (sle), asthma, pain, atherosclerosiss, bone lesion, the abnormal increase of stock turnover, evil The disease of the hypercalcemia, obesity or Bone tumour of property tumor.