CN100478331C

CN100478331C - Inhibitors of cathepsin s

Info

Publication number: CN100478331C
Application number: CNB2004800307122A
Authority: CN
Inventors: 刘宏; A·查特吉; D·C·塔利; P·B·阿尔佩尔; B·布尔苏拉亚; 郭建华; D·伍德曼西; D·穆特尼克; D·S·卡拉纽斯凯; 贺耘
Original assignee: IRM LLC
Current assignee: IRM LLC
Priority date: 2003-08-20
Filing date: 2004-08-19
Publication date: 2009-04-15
Anticipated expiration: 2024-08-19
Also published as: CN1871216A

Abstract

The present invention provides compounds, compositions and methods for the selective inhibition of cathepsin S. In a preferred aspect, cathepsin S is selectively inhibited in the presence of at least one other cathepsin isozyme. The present invention also provides methods for treating a disease state in a subject by selectively inhibiting cathepsin S.

Description

Cathepsin S inhibitor

The cross reference of related application

The application has required in the U.S. Patent application No.60/496 of submission on August 20th, 2003, and 980 right of priority for all purposes, all is incorporated herein by reference its instruction at this.

Background of invention

L-Cysteine HCL Anhydrous is represented the enzymic protein of the nucleophilic sulfydryl catalysis peptide bond hydrolysis of the cysteine residues that a class can be by enzyme active sites.More mammiferous normal processes and lysis and cysteine protease activity are linked up, it includes but not limited to: osteoporosis, osteoarthritis (Inui, T., O.Ishibashi, J Biol Chem 1997,272 (13), 8109-12; Saftig, P., E.Hunziker etc., Adv Exp Med Biol 2000+ADs 2000,477,293-303; Saftig, P., E.Hunziker etc., Proc Natl Acad Sci USA 1998,95 (23), 13453-8), periodontopathy, Paget's disease, atherosclerosis (Jormsjo, S., D.M.Wuttge etc., Am J Pathol 2002161 (3), 939-45), multiple sclerosis (Beck, H., G.Schwarz etc., Eur J Immunol 2001,31 (12), 3726-36), rheumatoid arthritis (Nakagawa, T.Y., W.H.Brissette etc., Immunity 1999,10 (2), 207-17; Hou, W.S., Z.Li etc., Am J Pathol 2001,159 (6), 2167-77), juvenile onset diabetes, lupus, asthma (Cimerman, N., P.M.Brguljan etc., Pflugers Arch 2001,442 (6 supplementary issues 1), R204-6), tissue rejection, alzheimer's disease (Lemere, C.A., J.S.Munger etc., Am J Pathol 1995,146 (4), 848-60), Parkinson's disease (Liu, Y., L.Fallon etc., Cell 2002,111 (2), 209-18), neuronal degeneration, shock (Jaeschke, H., M.A.Fisher etc., J Immunol 1998,160 (7), 3480-6), cancer (Fernandez, P.L., X.Farre etc., Int J Cancer 2001,95 (1), 51-5), malaria (Malhotra, P., P.V.Dasaradhi etc., Mol Microbiol 2002,45 (5), 1245-54), chagas disease (Eakin, A.E., A.A.Mills etc., J Biol Chem 1992,267 (11), 7411-20), leishmaniasis, schistosomicide and tsetse fly disease (Caffrey, C.R., S.Scory etc., Curr Drug Targets2000,1 (2), 155-62; Lalmanach, G., A.Boulange etc., Biol Chem 2002,383 (5), 739-49).

Kethepsin is a subclass of L-Cysteine HCL Anhydrous, belongs to enzyme classification EC 3.4.22 (Barrett, A.J., N.D.Rawlings etc., Handbook of proteolytic enzymes. London, Academic Press).Kethepsin lysosomal, endosome with extracellular protein degradation in the main effect of performance, and therefore relevant with the numerous disease process.For example, inferred cathepsin B [EC 3.4.22.1] in metastases, play a role (Berquin, I.M. and B.F.Sloane Adv Exp Med Biol 1996,389,281-94).

Cathepsin S [EC 3.4.22.27] is mainly expressed in special antigen presenting cell such as scavenger cell and dendritic cell.Shown that suitable MHC II class antigen presentation needs cathepsin S (Shi, G.P., J.A.Villadangos etc., Immunity 1999,10 (2) 197-206).Because its necessity effect in the antigen presentation of MHC II class, cathepsin S is associated with inflammation, sacroiliitis and atherosclerosis.Cathepsin K [EC 3.4.22.38] in coupling the selective expression in the osteoclast of ability of cathepsin K degraded type i collagen show its (Bromme that in normal and pathogenic bone reconstruction, plays a role, D., K.Okamoto etc., J Biol Chem 1996,271 (4), 2126-32).In the art, need optionally suppress specific L-Cysteine HCL Anhydrous to treat the Compounds and methods for of more mammiferous pathogenicity bo illnesss.The present invention has satisfied this demand and some other demand.

Summary of the invention

The invention provides and be used for optionally compound, composition and the method for inhibition of histone enzyme S.Compound of the present invention has selectivity to cathepsin S under the situation that has other tissue protein enzyme isoenzyme.In a preferred embodiment, compound of the present invention has selectivity to cathepsin S under the situation that has cathepsin K, L, B or its combination.The present invention also provides by existing under the situation of other tissue protein enzyme isoenzyme inhibition of histone enzyme S optionally to come the method that the morbid state of individuality is treated.One preferred aspect, inhibition of histone enzyme S optionally under the situation that has cathepsin K, L, B or its combination.

On the one hand, the invention provides the compound of formula I:

Or its pharmaceutically useful salt or prodrug, wherein:

Q is selected from following heterocycle: azetidinyl, pyrrolidyl, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl and indolinyl, it is by 0-2 R ^QReplace, wherein Q by theheterocyclic nitrogen atom and-C (=O)-link to each other; And NR ²⁵R ²⁶

Each R ^QBe independently selected from OH, F, Cl ,-S (=O) ₂CH ₃-, ethanoyl ,=O, C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, CF ₃, OCF ₃And NR ¹⁰R ¹¹

A is selected from-O-CR ¹R ²-,-NH-CR ¹R ²-,-CR ³R ⁴-O-and-CR ³R ⁴-CR ¹R ²-;

R ¹And R ³Be selected from H independently of one another, C ₁-C ₆Alkoxyl group is by 0-2 R ^1aThe C that replaces ₁-C ₆Alkyl, wherein said C ₁-C ₆Alkyl can randomly contain be selected from-O-,-S-,-S (=O)-and-S (=O) ₂-heteroatoms; C ₂-C ₆Alkenyl, C ₃-C ₆Alkynyl is by 0-2 R ^QThe C that replaces ₃-C ₇Cycloalkyl and by 0-2 R ^QThe C that replaces ₇-C ₁₁Bicyclic alkyl; By 0-3 R ¹³The phenyl that replaces contains 1-4 the first heteroaryl of heteroatomic 5-to 6-that is selected from N, O and S independently of one another, and wherein said heteroaryl is by 0-3 R ¹³Replace;

Each R ^1aBe independently selected from by 0-3 R ¹³The C that replaces ₆-C ₁₀Aryl; Contain 1-4 heteroatomic 5-to 6-unit's monocycle or 8-to 10-unit bicyclic heteroaryl that is selected from N, O and S independently of one another, wherein said heteroaryl is by 0-3 R ¹³Replace; By 0-2 R ^QThe C that replaces ₃-C ₈Cycloalkyl; By 0-2 R ^QThe C that replaces ₇-C ₁₁Bicyclic alkyl; And C ₁-C ₃Perfluoroalkyl;

R ²And R ⁴Be selected from H, F, OH, C independently of one another ₁-C ₆Alkyl and C ₁-C ₆Alkoxyl group;

R ⁵Be selected from H; C (=O) OR ¹⁴C (=O) NR ¹⁵R ¹⁶By 0-2 R ¹³The phenyl that replaces; With contain heteroatomic 5-to the 6-unit heteroaryl that 1-4 is selected from N, O and S independently of one another, wherein said heteroaryl is by 0-2 R ¹³Replace; C ₃-C ₇Cycloalkyl; By 0-2 R ²¹The C that replaces ₁-C ₆Alkyl, wherein said C ₁-C ₆Alkyl can randomly contain be selected from-O-,-S-,-S (=O)-,-S (=O) ₂-and-NR ²²-heteroatoms;

R ⁶, R ⁷, R ⁸And R ⁹Be selected from H and C independently of one another ₁-C ₆Alkyl;

Perhaps, R ⁵And R ⁷The common C that forms ₅-C ₇Cycloalkyl, wherein said C ₅-C ₇Methylene radical in the cycloalkyl can randomly be selected from-O-,-S-,-S (=O)-and-S (=O) ₂-heteroatoms substitute;

Each R ¹⁰Be independently selected from H, C ₁-C ₄Alkyl, (C ₁-C ₄Alkyl)-C (=O)-and (C ₁-C ₄Alkyl)-S (=O) ₂-;

Each R ¹¹Be independently selected from H and C ₁-C ₄Alkyl;

Each R ¹²Be independently selected from H; C ₃-C ₈Cycloalkyl; By 0-3 R ¹³The phenyl that replaces; Contain 1-4 the first heteroaryl of heteroatomic 5-to 6-that is selected from N, O and S independently of one another, the first heteroaryl of wherein said 5-to 6-is by 0-3 R ¹³Replace; With by 0-1 R ¹⁹The C that replaces ₁-C ₆Alkyl;

Each R ¹³Be independently selected from H, OH, F, Cl, Br, CN, NO ₂, COOR ¹⁷, C (=O) NR ¹⁷R ¹⁸, S (=O) ₂NR ¹⁷R ¹⁸, ethanoyl ,-SCH ₃,-S (=O) CH ₃,-S (=O) ₂CH ₃,-NR ¹⁰R ¹¹, C ₁-C ₆Alkoxyl group, C ₁-C ₃Perfluoroalkyl, C ₁-C ₃Perfluoro alkoxy and C ₁-C ₆Alkyl;

Each R ¹⁴Be independently selected from H, C ₃-C ₇Cycloalkyl, by 0-1 R ¹⁹The C that replaces ₁-C ₄Alkyl and by 0-3 R ¹³The phenyl that replaces;

Each R ¹⁵Be independently selected from H, C ₃-C ₈Cycloalkyl, by 0-3 R ¹³The phenyl that replaces and by 0-1 R ¹⁹The C that replaces ₁-C ₆Alkyl;

Each R ¹⁶Be independently selected from H and C ₁-C ₄Alkyl;

Perhaps, the R on identical N atom ¹⁵And R ¹⁶Common formation contains 1-2 heteroatomic C that is selected from N, O and S independently of one another ₅-C ₇Heterocycle;

R ¹⁷And R ¹⁸Be selected from H, C independently of one another ₁-C ₄Alkyl and C ₃-C ₆Cycloalkyl;

Each R ¹⁹Be independently selected from H, C ₃-C ₇Cycloalkyl, by 0-3 R ¹³The phenyl that replaces and contain 1-4 heteroatomic 5-to 6-unit heteroaryl that is selected from N, O and S independently of one another, wherein said 5-to 6-unit heteroaryl is by 0-3 R ¹³Replace;

Ar is selected from by 0-3 R ²⁰The phenyl that replaces and contain 1-4 heteroatomic 5-to 10-unit heteroaryl that is selected from N, O and S independently of one another; Wherein said heteroaryl is by 0-3 R ²⁰Replace;

Each R ²⁰Be independently selected from H, F, Cl, Br, CN, OR ¹³, SCH ₃, S (=O) CH ₃, S (=O) ₂CH ₃, S (=O) ₂NR ¹⁷R ¹⁸, NR ¹⁰R ¹¹, ethanoyl ,-S (=O) ₂NH (C=O) CH ₃, C (=O) NR ¹⁷R ¹⁸, CO ₂R ¹⁷, C (=NH) NH ₂, C ₁-C ₆Alkyl, CF ₃, OCF ₃And OCF ₂H;

Perhaps, R ²⁰And R ⁹Common formation contains individual N, O and the heteroatomic 5-to 7-of the S unit heterocycle of being selected from independently of one another of 1-2; Wherein said 5-to 7-unit's heterocycle and Ar is monolateral condenses (ortho-fused); The first heterocycle of wherein said 5-to 7-can be randomly by 0-2 R ²⁴Replace;

Each R ²¹Be independently selected from H; OH; F; Cl; CN; NO ₂C (=O) OR ¹⁴C (=O) NR ¹⁵R ¹⁶NR ²²R ²³C ₁-C ₃Perfluoro alkoxy; C ₁-C ₄Alkoxyl group; C ₂-C ₄Alkenyl; C ₂-C ₄Alkynyl; By 0-3 R ¹³The phenyl that replaces; Contain 1-4 the first heteroaryl of heteroatomic 5-to 6-that is selected from N, O and S independently of one another, wherein said heteroaryl is by 0-3 R ¹³Replace; Contain 1-2 heteroatomic C that is selected from N, O and S independently of one another ₃-C ₈Heterocycle, wherein said heterocycle is by 0-2 R ¹³Replace and be saturated or part undersaturated; And C ₃-C ₈Cycloalkyl;

R ²²Be independently selected from H, ^tBOC, Cbz, C ₃-C ₈Cycloalkyl, (C ₁-C ₆Alkyl)-C (=O)-, (C ₁-C ₆Alkyl)-S (=O) ₂-, by 0-1 R ¹⁹The C that replaces ₁-C ₆Alkyl, by 0-3 R ¹³The phenyl that replaces, contain 1-4 heteroatomic 5-to 6-unit heteroaryl that is selected from N, O and S independently of one another, wherein said 5-to 6-unit heteroaryl is by 0-3 R ¹³Replace;

Each R ²³Be independently selected from H and C ₁-C ₄Alkyl;

Each R ²⁴Be independently selected from C ₁-C ₄Alkyl, F, Cl and C ₁-C ₄Alkoxyl group, CF ₃And OCF ₃

Perhaps, two R ²⁴Can be combined to form C ₃-C ₆Cycloalkyl;

R ²⁵And R ²⁶Be selected from C independently of one another ₁-C ₆Alkyl, wherein said C ₁-C ₆Alkyl can randomly contain be selected from-O-,-S-,-S (=O)-,-S (=O) ₂-and-NR ₂₂-heteroatoms.

Second aspect the invention provides a kind of pharmaceutical composition that comprises above-mentioned formula I compound and pharmaceutically acceptable vehicle.

The third aspect, the invention provides a kind of in its Mammals of needs the active method of inhibition of histone enzyme S optionally, it comprises above-mentioned formula I compound or its pharmaceutically useful salt or prodrug to described administration treatment significant quantity.

When reading appended accompanying drawing and detailed description hereinafter, it is more obvious that these aspects and others, purpose and embodiment will become.

Brief Description Of Drawings

Fig. 1 has described MHC II antigen presentation.

Detailed Description Of The Invention

I. definition

Unless otherwise indicated, otherwise all scientific and technical terminologies used herein generally have the implication identical with the common implication of understanding of the technical field of the invention those of ordinary skill. Generally speaking, nomenclature used herein and organic and laboratory operation analytical chemistry all are well-known in the art and commonly used.

As used in disclosure thing, unless in the context that uses this term, carried out special adjustment, following abbreviation and term have defined implication:

The Ac acetyl group

The Bn benzyl

The Boc tert-butoxycarbonyl

Cbz or Z benzyloxycarbonyl

DCC N, N '-dicyclohexylcarbodiimide

The DCM carrene

The DIBAL diisobutylaluminium hydride

DIC N, N '-DIC

DIEA or DIPEA diisopropyl ethyl amine

DMAP 4-(dimethylamino) pyridine

The DMF dimethyl formamide

The DMSO dimethyl sulfoxide (DMSO)

EDC or EDCI 1-ethyl-3-(dimethylaminopropyl)-carbodiimide

Fmoc 9-fluorenyl methoxy carbonyl

HATU O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-

The tetramethylurea hexafluorophosphate

The HOBt I-hydroxybenzotriazole

KHMDS hexamethyldisilane base potassamide

The LAH lithium aluminium hydride reduction

The LDA lithium diisopropylamine

LHMDS hexamethyldisilane base lithium amide

The m-CPBA metachloroperbenzoic acid

The MW microwave

NaHMDS hexamethyldisilane base Sodamide

The PG protecting group

The PTSA p-methyl benzenesulfonic acid

The Py pyridine

RT or rt room temperature

The TEA triethylamine

The Tf trifyl

The TFA trifluoroacetic acid

THF hydrogen furans

The Tol p-methylphenyl

The definition of the term " rudimentary " that is connected with organic group or compound respectively in the context and is mentioned be to be side chain or unbranchedly to have at the most 7 and comprise 7, preferably at the most 4 and comprise the compound or the group of 4 and (as unbranched form) one or two carbon atom.

The definition of the term " perfluoro " that is connected with organic group or compound respectively in the context and is mentioned be compound or group with at least two available hydrogen that replaced by fluorine.For example, the perfluoro phenyl refers to 1,2,3,4, the 5-pentafluorophenyl group, and perfluoro methane refers to 1,1, the 1-trifluoromethyl, the perfluoro methoxyl group refers to 1,1, the 1-trifluoromethoxy.

Alkyl is side chain or unbranched, and contains 1-7 carbon atom, preferably contains 1-4 carbon atom.Alkyl is represented for example methyl, ethyl, propyl group, butyl, sec.-propyl or isobutyl-.

Alkenyl is represented the alkenyl of the straight or branched of 2 to 7 carbon atoms, preferred 2-4 carbon atom, for example vinyl, propenyl, pseudoallyl, butenyl, isobutenyl or butadienyl.

Alkynyl is represented the alkynyl of the straight or branched of 2 to 7 carbon atoms, preferred 2-4 carbon atom, for example ethynyl, proyl, different proyl, butynyl or isobutyl alkynyl.

Alkyl, alkenyl or alkynyl can be replaced by 3 substituting groups at the most, and described substituting group is selected from alkoxyl group, aryl, heterocyclic radical, hydroxyl, halogen, cyano group, randomly substituted amino, randomly substituted amino-oxy or trifluoromethyl.

Alkylidene group is represented the alkylidene group of the straight or branched of 1 to 7 carbon atom, i.e. the bivalent hydrocarbon radical of 1 to 7 carbon atom; For example, be formula-(CH ₂) _nThe straight-chain alkyl-sub-of divalent group, wherein n is 1,2,3,4,5,6 or 7.Alkylidene group is preferably represented the straight-chain alkyl-sub-of 1 to 4 carbon atom, for example methylene radical, ethylidene, propylidene or butylidene chain, or by C ₁-C ₃-alkyl (preferable methyl) is single replace or on identical or different carbon atom by C ₁-C ₃The dibasic methylene radical of-alkyl (preferable methyl), ethylidene, propylidene or butylidene chain, the sum of carbon atom are at most 7 and comprise 7.

Alkoxyl group (or alkyl oxy) preferably contains 1-7 carbon atom, more preferably contains 1-6 carbon atom, represents for example oxyethyl group, propoxy-, isopropoxy, isobutoxy, preferred methoxyl group.Alkoxyl group comprises cycloalkyl oxy and cycloalkyl-alkyl oxy.

Halogen (halo) is preferably represented chlorine or fluorine, but also can be bromine or iodine.

Aryl is represented monocyclic, bicyclic or tricyclic aryl, for example, and phenyl or be selected from alkyl, alkoxyl group, aryl, hydroxyl, halogen, cyano group, amino, amino-alkyl, trifluoromethyl, alkylenedioxy group and oxygen base-C by 1,2 or 3 ₂-C ₃-alkylidene group list-, two-or the three-phenyl that replaces; They all can randomly further be substituted, and for example are substituted like that as defined above; Or 1-or 2-naphthyl; Or 1-or 2-phenanthryl.Alkylenedioxy group is the divalent substituent that is connected on two adjacent carbonss of phenyl, for example methylene radical dioxy base or ethylidene dioxy base.Oxygen base-C ₂-C ₃-alkylidene group also is the divalent substituent that is connected on two adjacent carbonss of phenyl, for example oxygen base ethylidene or oxygen base propylidene.Oxygen base-C ₂-C ₃An example of-alkylidene group-phenyl is 2,3-Dihydrobenzofuranes-5-base.

Preferred aryl groups is naphthyl, phenyl or alkoxy, phenyl, halogen, alkyl or trifluoromethyl list-or dibasic phenyl, especially phenyl or alkoxy, halogen or trifluoromethyl list-or dibasic phenyl, and phenyl particularly.

Example as the substituted phenyl of R has for example 4-chlorobenzene-1-base; 3; 4-dichlorobenzene-1-base; 4-anisole-1-base; 4-methylbenzene-1-base; 4-amino methyl benzene-1-base; 4-methoxy ethyl amino methyl benzene-1-base; 4-hydroxyethyl amino methyl benzene-1-base; 4-hydroxyethyl-(methyl)-amino methyl benzene-1-base; 3-amino methyl benzene-1-base; 4-N-acetylamino methylbenzene-1-base; 4-amino-benzene-1-base; 3-amino-benzene-1-base; 2-amino-benzene-1-base; 4-phenyl-benzene-1-base; 4-(imidazoles-1-yl)-benzene-Ji; 4-(imidazoles-1-ylmethyl)-benzene-1-base; 4-(morpholine-1-yl)-benzene-1-base; 4-(morpholine-1-ylmethyl)-benzene-1-base; 4-(2-methoxy ethyl amino methyl)-benzene-1-base and 4-(tetramethyleneimine-1-ylmethyl)-benzene-1-base; (4-thienyl)-benzene-1-base; 4-(3-thienyl)-benzene-1-base; 4-(4-methylpiperazine-1-yl)-benzene-1-base and 4-(piperidyl)-phenyl and 4-(pyridyl)-phenyl, it randomly is substituted on heterocycle.

Benzyl is represented phenyl-CH ₂-group.Substituted benzyl means the benzyl that phenyl ring is wherein replaced by one or more loop systems substituting groups.Representational benzyl comprises 4-bromobenzyl, 4-methoxy-benzyl, 2,4-dimethoxy-benzyl etc.

Heteroaryl is represented monocycle or bicyclic heteroaryl, for example pyridyl, indyl, indazolyl, quinoxalinyl, quinolyl, isoquinolyl, benzothienyl, benzofuryl, benzopyranyl, benzo thiapyran base, furyl, pyrryl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazyl, pyrazolyl, imidazolyl, thienyl or substituted, any by in these groups of for example alkyl, nitro or halogen list-or two-replace especially.Pyridyl is represented 2-, 3-or 4-pyridyl, advantageously 2-or 3-pyridyl.Thienyl is represented 2-or 3-thienyl.Quinolyl is preferably represented 2-, 3-or 4-quinolyl.Isoquinolyl is preferably represented 1-, 3-or 4-isoquinolyl.Preferred respectively expression 3-benzopyranyl of benzopyranyl, benzo thiapyran base or 3-benzo thiapyran base.Thiazolyl is preferably represented 2-or 4-thiazolyl, and 4-thiazolyl most preferably.Triazolyl is 1-, 2-or 5-(1,2, the 4-triazolyl) preferably.Tetrazyl is the 5-tetrazyl preferably.

Heteroaryl is any in pyridyl, indyl, quinolyl, pyrryl, thiazolyl, isoxazolyl, triazolyl, tetrazyl, pyrazolyl, imidazolyl, thienyl, furyl, benzothiazolyl, benzofuryl, isoquinolyl, benzothienyl, oxazolyl, indazolyl or these groups substituted, especially coverlet-or two-replace preferably.

Dibenzyl can be preferably xenyl for example, promptly 2,3 or the 4-xenyl, 4-xenyl preferably, it is randomly replaced by for example alkyl, alkoxyl group, halogen, trifluoromethyl or cyano group separately, perhaps heterocycle-carbocyclic ring dibenzyl, preferably for example thienyl phenyl, pyrryl phenyl and pyrazolyl phenyl.

Cycloalkyl is represented randomly the saturated cyclic hydrocarbon that contain 3 to 10 ring carbon that replaced by alkyl and the cyclopentyl that is advantageously randomly replaced by alkyl, cyclohexyl, suberyl or ring octyl group.

Amino can randomly be replaced by for example alkyl.

Carbocyclic ring represents to have the undersaturated cyclic hydrocarbon of saturated or part of 5 to 7 ring memberses, and wherein 1 to 2 ring members can randomly be substituted by one of following group :-O-,-S-,-S (=O)-,-S (=O) ₂-and-NR-, wherein R is a group of the present invention.

Heterocyclic radical represents to contain the saturated cyclic hydrocarbon of one or more, preferred 1 or 2 heteroatoms that is selected from O, N or S and 3 to 10, preferred 5 to 8 annular atomses; For example, tetrahydrofuran base, tetrahydro-thienyl, Pyrrolidine base, piperidyl, piperazinyl or morpholino; They all can randomly be substituted, and for example are substituted like that about aryl is described as mentioned.

The pharmaceutically useful salt of acidic cpd of the present invention is the salt that forms with alkali, be cationic salts such as an alkali metal salt and alkaline earth salt, as sodium salt, lithium salts, sylvite, calcium salt, magnesium salts and ammonium salt, as ammonium salt, leptodactyline, diethyl ammonium salt and three-(hydroxymethyl)-methyl-ammonium salt.

Similarly, if basic group such as pyridyl constitute the part of structure, then the acid salt of acid salt such as mineral acid, organic carboxyl acid and organic sulfonic acid, for example hydrochloric acid, methylsulfonic acid, toxilic acid also is possible.

" treatment " refers to and alleviates or palliate a disease and/or the method for its simultaneous phenomenon.

" inhibition " and " inhibitor " refers to compound or the method that stops specific function or function.

" inhibition constant ", K _i, be the dissociation constant of enzyme-inhibitor complex, perhaps inhibitor is to the inverse of the binding affinity of enzyme.For the inhibition of classics, K _iValue be far longer than enzyme concn and can by under a plurality of inhibitor concentration the monitoring competitive substrate speed of reaction measure K _iThen, carry out match with following Nonlinear regression equation to suppressing speed:

v_{i} / v_{o} = \frac{K_{m} + [S]}{K_{m} (1 + [I] / K_{i}) + [S]}

V wherein _oBe not have the initial rate that substrate is handled under the situation of inhibitor, v _iBe the initial rate that substrate is handled under inhibitor concentration [I], K _mBe stable state Michaelis-Menton constant (Fersht, A. Structure and Mechanism in Protein Science. New York, W.H.Freeman and Company, 1999), and [S] is the concentration of competition substrate.

About the above-mentioned classical hypothesis that suppresses to have done is that free inhibitor concentration equals total inhibitor concentration.For having the K that approximates enzyme concn [E] greatly _iInhibitor, the hypothesis that free inhibitor concentration equals total inhibitor concentration no longer is correct, must carry out match to measure apparent inhibition constant K with described method with another alternative equation _i ^App(Kuzmic, P., K.C.Elrod etc., AnalBiochem 2000,286 (1) 45-50):

v_{i} / v_{o} = \frac{[E] - [I] - {K_{i}}^{app} + SQRT ({([E] - [I] - {K_{i}}^{app})}^{2} + 4 [E] {K_{i}}^{app})}{2 [E]}

Can be in order to the apparent inhibition constant K of following relational expression by competitive inhibitor _i ^AppDetermine to suppress constant K _i:

K_{i} = \frac{{K_{i}}^{app}}{1 + [S] / K_{m}} .

The multi-loop system that wherein any two adjacent rings have two (for example only having two) total adjacent atom is called as " monolateral condensing ".Such loop systems has n common limit and 2n common atom.

" treatment significant quantity " refer to the generation of one or more symptoms that are enough to prevent the illness of being treated or illness or can alleviate to a certain extent the compound amount of being used of one or more symptoms of the illness for the treatment of or illness.

" composition " used herein is intended to comprise the product of the special component that comprises specified quantitative and any product that can directly or indirectly be produced by the combination of the special component of specified quantitative." pharmaceutically useful " means described carrier, thinner or vehicle must be compatible with other composition in the preparation and harmless to its recipient.

" individuality " refers to animal such as Mammals, includes but not limited to primate (for example people), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse etc.In some aspects, described individuality is the people.

II. introduction

Cathepsin S is a kind of by the L-Cysteine HCL Anhydrous that is associated with more mammiferous normal processes and lysis.Particularly, because cathepsin S plays a role in the antigen presentation of MHC II class, it is by directly related with inflammation, sacroiliitis and atherosclerosis.One preferred aspect, the invention provides the active compound of inhibition of histone enzyme S.The present invention also provides by the activity of inhibition of histone enzyme S the method for treatment some diseases state in Mammals.One preferred aspect, compound of the present invention inhibition of histone enzyme S optionally under the situation that has at least a tissue protein enzyme isoenzyme.

III. compound

A. the preparation of compound

In one embodiment, arylamino ethylamine 1A (schema 1) used among the present invention can be as E.Altman etc., J.Med Chem.2002,45, preparing by oxazolidine-2-ketone being carried out the decarboxylation open loop like that described in 2352-54 and the reference wherein quoted with aromatic amine.

Schema 1

Another synthetic route of used diamines is as shown in schema 2 among the present invention.

Schema 2

A) [BH ₃THF, 0 ℃ of THF] or [i) TEA, isobutyl chlorocarbonate, THF, 0 ℃; Ii) NaBH ₄, H ₂O, 0 ℃ to room temperature];

B) i) Dess-Martin crosses iodine alkane (periodinane), DCM; Ii) NHR ⁹Ar, NaCNBH ₃, AcOH, MeOH;

C) remove PG.

Can use the BH of corresponding mixed acid anhydride ₃Method or NaBH ₄Reduction obtains 2A (schema 2) with the amino acid reduction [referring to R.C.Larock A guide to functional group preparations 548-552 page or leaf, Wiley-VCH, 1989] of N-protected.Alcohol can be oxidized to aldehyde then, the aldehyde that obtains is carried out reductive amination with amine, obtain 2B.Can use then the suitable reagent of protecting group this intermediate deprotection,, use TFA for example for Boc.

Indoline synthetic method used among the present invention has extensive description in the literature, and is well-known to those skilled in the art.Typical method includes but not limited to disclosed method in following reference: (a) G.W.Gribble etc., and Synthesis 1977,859; (b) A.Smith etc., Chem.Commun.1965,427; (c) G.W.Gribble etc., J.Am.Chem.Soc.1974,96,7812; (d) J.G.Berger Synthesis 1974,508; (e) L.J.Dolby etc., J.Heterocycl.Chem.1966,3,124; (f) W.A.Remers etc., J.Org.Chem.1971,36,279; (g) S.O ' Brien etc., J.Chem.Soc.1960,4609; (h) Y.Kikugawa etc., Synthesis 1978,477.

Among the present invention used can not be commercially available α-and the synthetic method of beta-amino acids extensive description is arranged in the literature, and be well-known to those skilled in the art.Suitable method includes but not limited to disclosed method in following reference: (a) D.J.Ager etc., Currentopinion in drug discovery ﹠amp; Development 2001,4,800-807; (b) R.O.Duthaler Tetrahedron 1994,50,1539-1650; (c) M.J.O ' Donnell AldrichimicaActa 2001,34,3-15; (d) K.B.Sharpless etc., J.Am.Chem.Soc.1998,120,1207-17; (e) E.Juaristi etc., Aldrichimica Acta 1994,27,3-11; (f) D.C.ColeTetrahedron 1994,50,9517-9582 and the reference of wherein being quoted.

Wherein A is-NH-CR in formula I ¹R ²Compound of the present invention can be by the path of preparing shown in the schema 3.With polystyrene aldehyde (polystyrene aldehyde) (PAL) resin with single aryl diamine (NH ₂CH ₂CH ₂NR ⁹Ar) carry out reductive amination, obtain resin 3A (schema 3).The use standard conditions [as A.R.Chamberlin, Chem.Rev.1997,97, described in the 2243-2266] and with the amino acid acidylate of this material, then product is used the piperidines deprotection with N-protected, obtain 3B.Under the standard coupling condition with after the QCOCl acidylate, use TFA cracking from the resin to get off, obtain urea 3C.

Schema 3

a)i)NH ₂CH ₂CH ₂NR ⁹Ar，AcOH，DMF.rt；

ii)NaHB(OAc) ₃，DMF；

b)i)FmocHNCHR ¹CO ₂H，HOBt，DIC，DMF，rt；

The ii) DMF solution of 20% piperidines;

C) QCOCl i), alkali, DMF, rt;

ii)TFA/DCM/H ₂O。

A=-CR in formula I wherein ³Specifying as shown in schema 4 of the The compounds of this invention of H-O-.

Schema 4

Schema 5

The synthetic method of mono-substituted succinate derivative is being well-known in the art, and it is disclosed in many reference, comprising: (a) D.A.Evans etc., J.Org.Chem.1999,64,6411; (b) D.W.C.MacMillan etc., J.Am.Chem.Soc.2001,123,2912; (c) S.Azam etc., J.Chem.Soc.Perkin Trans.1 1996,621; (d) A.Abell etc., Org.Lett.2002,4,3663; (e) R.J.Cherney etc., Bioorg.Med.Chem.Lett.2003,13,1297; (f) G.Shapiro etc., Tetrahedron Lett.1992,33,2447; (g) N.J.S.Harmat etc., Tetrahedron Lett.2000,41,1261.In schema 5, summarized a kind of representational method, wherein used acyl chlorides, obtained structure 5A oxazolidone chiral auxiliary(reagent) acidylate.With corresponding enolate alkylation, carry out LiOH/H with bromo-acetic acid tert-butyl then ₂O ₂The cracking of chiral auxiliary(reagent) of mediation obtains the mono-substituted monomester succinate 5C of enantiomer-pure.

Cis-2, the dibasic succinate derivative of 3-can use the chemical process described in the schema 6 to obtain, and it obtains by following method is made amendment: (a) M.J.Crimmin etc., Synlett 1993,137; (b) C.Xue etc., J.Org Chem.2002,67,865, be introduced into this paper as a reference.Use 2.2 equivalent highly basic to handle intermediate 5C, form enolate, use 1.5 equivalent R then ³X (wherein X=OTf, I, Br etc.) cancellation is carried out exclusively obtaining cis diastereomer 6A after the chromatography.

Schema 6

Trans-2, the dibasic succinate derivative of 3-can be as M.J.Crimmin etc., and Synlett1993 obtains by carry out the selectivity counter-rotating in C-3 carbon center described in 137.

Perhaps, can be according to (a) H.Oikiwa etc., Tetrahedron Lett.1996,37,6169; (b) B.Wirz etc., Tetrahedron:Asymnietty 1997,8,187 and the reference wherein quoted described in method split the succsinic acid that racemic succinate is converted into the enantiomorph enrichment by Dynamics of Enzyme Catalysis.

A=-CHR in formula I wherein ³-CHR ¹-The compounds of this invention can described in schema 7, be prepared.

Schema 7

A=-O-CR in formula I wherein ³Specifying as shown in schema 8 of the The compounds of this invention of H-.

Schema 8

B. preferred compound

The active compound of inhibition of histone enzyme S can be at U.S. Provisional Application No.60/457, finds in 848 and 60/457,595 (both all submit on March 24th, 2003) and 60/478,625 (the submitting on June 13rd, 2003).Each content in first to file is incorporated herein by reference.

On the one hand, the invention provides the compound of formula I:

Or its pharmaceutically useful salt or prodrug, wherein:

Each R ¹¹Be independently selected from H and C ₁-C ₄Alkyl;

Each R ¹⁶Be independently selected from H and C ₁-C ₄Alkyl;

Each R ²⁰Be independently selected from H, F, Cl, Br, CN, OR ¹², SCH ₃, S (=O) CH ₃, S (=O) ₂CH ₃, S (=O) ₂NR ¹⁷R ¹⁸, NR ¹⁰R ¹¹, ethanoyl ,-S (=O) ₂NH (C=O) CH ₃, C (=O) NR ¹⁷R ¹⁸, CO ₂R ¹⁷, C (=NH) NH ₂, C ₁-C ₆Alkyl, CF ₃, OCF ₃And OCF ₂H;

Perhaps, R ²⁰And R ⁹Common formation contains individual N, O and the heteroatomic 5-to 7-of the S unit heterocycle of being selected from independently of one another of 1-2; Wherein said 5-to 7-unit's heterocycle and Ar is monolateral condenses; The first heterocycle of wherein said 5-to 7-can be randomly by 0-2 R ²⁴Replace;

Each R ²³Be independently selected from H and C ₁-C ₄Alkyl;

Each R ²⁴Be independently selected from C ₁-C ₄Alkyl, F, Cl and C ₁-C ₄Alkoxyl group, CF ₃And OCF ₃Perhaps, two R ²⁴Can be combined to form C ₃-C ₆Cycloalkyl;

Compound of the present invention is a cathepsin S inhibitor.Aspect particularly preferred, cathepsin S inhibitor does not have restraining effect to cathepsin K, L, B or its combination.

One preferred aspect, the invention provides the compound of formula Ia:

Wherein:

R ¹Be independently selected from H; By 0-1 R ^1aThe C that replaces ₁-C ₆Alkyl, wherein said C ₁-C ₆Alkyl can randomly contain be selected from-O-,-S-and-S (=O) ₂-heteroatoms; C ₂-C ₆Alkenyl; By 0-2 R ^QThe C that replaces ₃-C ₇Cycloalkyl; With by 0-2 R ^QThe C that replaces ₇-C ₁₁Bicyclic alkyl; By 0-3 R ¹³The phenyl that replaces; Contain 1-4 the first heteroaryl of heteroatomic 5-to 6-that is selected from N, O and S independently of one another, wherein said heteroaryl is by 0-3 R ¹³Replace;

R ⁴Be selected from H, F, OH and C ₁-C ₆Alkyl.

Another preferred aspect, the invention provides the compound of formula Ib:

Wherein:

R ¹Be selected from C ₁-C ₆Alkyl, by 1 R ^1aThe C that replaces ₁-C ₄Alkyl, wherein said C ₁-C ₄Alkyl can randomly contain be selected from-O-,-S-and-S (=O) ₂-heteroatoms;

R ^1aBe selected from by 0-3 R ¹³The phenyl that replaces, by 0-2 R ^QThe C that replaces ₃-C ₇Cycloalkyl and by 0-2 R ^QThe C that replaces ₇-C ₁₁Bicyclic alkyl;

Another preferred aspect, the invention provides the compound of formula Ic:

Wherein:

R ³Be selected from C ₁-C ₆Alkyl; By 1 R ^1aThe C that replaces ₁-C ₄Alkyl, wherein said C ₁-C ₄Alkyl can randomly contain be selected from-O-,-S-and-S (=O) ₂-heteroatoms; By 0-2 R ^QThe C that replaces ₃-C ₇Cycloalkyl; By 0-2 R ^QThe C that replaces ₇-C ₁₁Bicyclic alkyl; By 0-3 R ¹³The phenyl that replaces;

R ^1aBe selected from by 0-3 R ¹³The phenyl that replaces, by 0-2 R ^QThe C that replaces ₃-C ₇Cycloalkyl and by 0-2 R ^QThe C that replaces ₇-C ₁₁Bicyclic alkyl.

Another preferred aspect, the invention provides the compound of formula Id:

Wherein:

R ⁵Be selected from H; By 0-2 R ¹³The phenyl that replaces; C ₃-C ₇Cycloalkyl; By 0-1 R ²¹The C that replaces ₁-C ₆Alkyl, wherein said C ₁-C ₆Alkyl can randomly contain be selected from-O-,-S-,-S (=O) ₂-heteroatoms;

Each R ²¹Be independently selected from H; OH; F; C (=O) OR ¹⁴C (=O) NR ¹⁵R ¹⁶NR ²²R ²³By 0-3 R ¹³The phenyl that replaces; And C ₃-C ₇Cycloalkyl;

Ar is selected from by 0-3 R ²⁰The phenyl that replaces;

Each R ²⁰Be independently selected from H, F, Cl, Br, CN, OR ¹², SCH ₃, S (=O) CH ₃, S (=O) ₂CH ₃, S (=O) ₂NR ¹⁷R ¹⁸, NR ¹⁰R ¹¹, ethanoyl, C (=O) NR ¹⁷R ¹⁸, CO ₂R ¹⁷, C (=NH) NH ₂, C ₁-C ₆Alkyl, CF ₃, OCF ₃

Perhaps, R ²⁰And R ⁹The common 5-unit heterocycle that contains 1 nitrogen-atoms that forms, wherein said 5-unit's heterocycle and Ar is monolateral condenses; The first heterocycle of wherein said 5-can be randomly by 0-2 R ²⁴Replace.

On the other hand, the invention provides the compound of formula Ie:

Wherein:

R ²Be H;

R ³Be selected from H, C independently of one another ₁-C ₆Alkyl, by 1 R ^1aThe C that replaces ₁-C ₄Alkyl;

R ^1aBe selected from by 0-2 R ^QThe C that replaces ₃-C ₇Cycloalkyl and by 0-2 R ^QThe C that replaces ₇-C ₁₁Bicyclic alkyl;

R ⁵Be selected from H, by 0-2 R ¹³The phenyl, the C that replace ₃-C ₇Cycloalkyl, by 0-1 R ²¹The C that replaces ₁-C ₆Alkyl, wherein said C ₁-C ₆Alkyl can randomly contain be selected from-O-,-S-,-S (=O) ₂-heteroatoms;

Each R ²¹Be independently selected from H, OH, C (=O) OR ¹⁴, C (=O) NR ¹⁵R ¹⁶, NR ²²R ²³, by 0-3 R ¹³The phenyl and the C that replace ₃-C ₈Cycloalkyl;

Ar is selected from by 0-3 R ²⁰The phenyl that replaces;

Perhaps, R ²⁰And R ⁹The common 5-unit heterocycle that contains 1 nitrogen-atoms that forms; Wherein said 5-unit's heterocycle and Ar is monolateral condenses; The first heterocycle of wherein said 5-can be randomly by 0-2 R ²⁴Replace.

Q preferably has following array structure:

1-indolinyl 4-morpholinyl

1-pyrrolidyl 4-thio-morpholinyl

1-piperazinyl piperidino

(or 4-piperazinyl).

Below listed preferred formula I compound:

1. morpholine-4-formic acid (S)-2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indoles-1-yl)-ethylamino formyl radical]-ethyl ester;

2. morpholine-4-formic acid { 2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indoles-1-yl)-ethylamino formyl radical]-ethyl }-acid amides;

3. morpholine-4-formic acid { 2-cyclohexyl-1-(S)-[2-(4-fluoro-phenyl amino)-ethylamino formyl radical]-ethyl }-acid amides;

4. morpholine-4-formic acid { 2-cyclohexyl-1-(S)-[2-(4-methoxyl group-phenyl amino)-ethylamino formyl radical]-ethyl }-acid amides;

(5.[2-4-fluoro-phenyl amino)-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

6.2-(R)-cyclohexyl methyl-N-[2-(4-fluoro-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

7.[4-(R)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-tetrahydrochysene-furans-3-(R)-yl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

8.2-(R)-cyclohexyl methyl-N-[2-(5-fluoro-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

9.3-(R)-cyclohexyl methyl-N-[2-(4-fluoro-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

10.[1-(R)-benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indoles-1-yl)-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

11. morpholine-4-formic acid 2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethylamino formyl radical]-ethyl ester;

12. morpholine-4-formic acid 2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethylamino formyl radical]-ethyl ester;

13.2-(R)-cyclohexyl methyl-4-morpholine-4-base-4-oxo-N-[2-(4-trifluoromethoxy-phenyl amino)-ethyl]-butyramide;

14.2-(R)-cyclohexyl methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

15.2-(R)-cyclopentyl-methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

16.2-(R)-cyclopentyl-methyl-3-(R)-methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

17. morpholine-4-formic acid { 2-benzyl sulfenyl-1-(R)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethylamino formyl radical]-ethyl }-acid amides;

18. morpholine-4-formic acid { 1-(R)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethylamino formyl radical]-2-phenyl methanesulfonamide acyl group-ethyl }-acid amides;

19. (R)-2-cyclohexyl methyl-N-[2-(4-methoxyl group-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

20.2-(R)-cyclohexyl methyl-4-morpholine-4-base-4-oxo-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-butyl }-butyramide;

21.2-(R)-(2-cyclohexyl-ethyl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

22.2-(R)-cyclohexyl methyl-4-morpholine-4-base-4-oxo-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide;

23.2-(R)-cyclohexyl methyl-4-morpholine-4-base-4-oxo-N-{3-phenyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide;

24.2-(R)-cyclohexyl methyl-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

25.5,5-dimethyl-2-(R)-(2-morpholine-4-base-2-oxo-ethyl)-caproic acid [1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-acid amides;

26.4,4-dimethyl-2-(R)-(2-morpholine-4-base-2-oxo-ethyl)-valeric acid [1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-acid amides;

27.2-(R)-cyclopentyl-methyl-4-morpholine-4-base-4-oxo-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-butyl }-butyramide;

28.2-(R)-cyclohexyl methyl-N-{3-methylsulfonyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

29.2-(R)-cyclohexyl methyl-N-{3-methylsulfonyl-1-(R)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

30.2-(R)-(2-morpholine-4-base-2-oxo-ethyl)-5-phenyl-pentanoic acid the 2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-acid amides;

31.2-(R)-cyclopentyl-methyl-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

32.N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-2-(R)-styroyl-butyramide;

33.2-(R)-(2-cyclopentyl-ethyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

34.N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-2-(S)-phenyl-butyramide;

35.2-(S)-cyclohexyl-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

36.2-(R)-(2-cyclopentyl-ethyl)-4-morpholine-4-base-4-oxo-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide;

37.2-(R)-(2-cyclopentyl-ethyl)-4-morpholine-4-base-4-oxo-N-{3-phenyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide;

38.4-morpholine-4-base-4-oxo-2-(R)-styroyl-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide;

39.4-morpholine-4-base-4-oxo-2-(S)-phenyl-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-butyl }-butyramide;

40.4-morpholine-4-base-4-oxo-2-(S)-phenyl-N-{3-phenyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide;

41.2-(S)-(4-fluoro-phenyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

42.2-(S)-(4-chloro-phenyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

43.2-(R)-(4-chloro-phenyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

44.4-morpholine-4-base-4-oxo-2-(S)-phenyl-N-[1-(S)-phenyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-butyramide;

45.2-(R)-cyclohexyl methyl-4-morpholine-4-base-4-oxo-N-[1-(S)-phenyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-butyramide;

46.2-(R)-(2-cyclopentyl-ethyl)-4-morpholine-4-base-4-oxo-N-[1-(S)-phenyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-butyramide;

47.2-(R)-(2-morpholine-4-base-2-oxo-ethyl)-penta-obtusilic acid the 2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-acid amides;

48.2-(S)-(4-chloro-phenyl)-4-morpholine-4-base-4-oxo-N-[1-(S)-phenyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-butyramide;

49. (R)-5,5-dimethyl-2-(2-morpholine-4-base-2-oxo-ethyl)-caproic acid [2-(5-methyl-isoxazole-3-base amino)-ethyl]-acid amides;

50.2-(R)-cyclohexyl methyl-4-(cis-2,6-dimethyl-morpholine-4-yl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-oxo-butyramide;

51.2-(R)-cyclohexyl methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-oxo-4-thiomorpholine-4-base-butyramide;

(52.4-4-ethanoyl-piperazine-1-yl)-2-(R)-cyclohexyl methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-oxo-butyramide;

53.2-(S)-(4-methoxyl group-phenyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

54.2-(R)-cyclohexyl methyl-N-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

55.N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide;

56.-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-2-(R)-(4-trifluoromethyl-phenyl)-butyramide;

57.N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-2-(S)-p-methylphenyl-butyramide;

58.2-(R)-cyclohexyl methyl-4-(1,1-dioxo-thiomorpholine-4-yl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-oxo-butyramide;

59.2-(R)-(3-ethyl-3-hydroxyl-cyclohexyl methyl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

60.N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide;

61.N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-2-(S)-phenyl-butyramide;

62.2-(S)-(4-fluoro-phenyl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

63.2-(S)-(4-methoxyl group-phenyl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

64.2-(S)-(4-fluoro-phenyl)-N-{1-(S)-[(6-methoxyl group-pyridin-3-yl amino)-methyl]-2-methyl-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

65.N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-2-(R)-spiral shell [2.5] suffering-6-ylmethyl-butyramide;

(66.N-[2-5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide;

67.2-(S)-(4-fluoro-phenyl)-N-{1-(S)-[(3-methylsulfonyl-phenyl amino)-methyl]-2-methyl-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

68.N-[1-(S)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-ylmethyl)-2-methyl-propyl group]-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide;

69.N-[1-(S)-cyclopropyl-2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-ethyl]-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide;

70.N-[1-(S)-cyclopropyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide;

71.2-(R)-(4-methylsulfonyl-phenyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

72. (S, S)-morpholine-4-formic acid 2-cyclohexyl-1-[2-(4-methoxyl group-phenyl amino)-1-methyl-ethylamino formyl radical]-ethyl }-acid amides;

73. morpholine-4-formic acid { 2-cyclopentyl-1-(S)-[2-(4-methoxyl group-phenyl amino)-1-(S)-methyl-ethylamino formyl radical]-ethyl }-acid amides;

74. morpholine-4-formic acid (2-cyclohexyl-1-(S)-{ 3-methylsulfonyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group formamyl }-ethyl)-acid amides;

75. morpholine-4-formic acid (2-cyclohexyl-1 (S)-{ 1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group formamyl }-ethyl)-acid amides;

76. morpholine-4-formic acid 2-cyclohexyl-1-(S)-[the 2-methyl isophthalic acid-(S)-(pyridin-3-yl amino methyl)-propyl group formamyl]-ethyl }-acid amides;

77. morpholine-4-formic acid { 2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(5-methyl-isoxazole-3-base amino)-ethylamino formyl radical]-ethyl }-acid amides;

78. morpholine-4-formic acid { 1-(S)-[2-(benzothiazole-2-base is amino)-1-(S)-methyl-ethylamino formyl radical]-2-cyclohexyl-ethyl }-acid amides;

79. morpholine-4-formic acid 1-(S)-[2-(benzoxazole-2-base is amino)-1-(S)-methyl-ethylamino formyl radical]-2-cyclohexyl-ethyl }-acid amides;

80. (S, S)-morpholine-4-formic acid 2-cyclohexyl-1-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-methyl-ethylamino formyl radical]-ethyl }-acid amides;

81. morpholine-4-formic acid { 2-cyclohexyl-1-(S)-[1-(S)-cyclopropyl-2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-ethylamino formyl radical]-ethyl }-acid amides;

82. morpholine-4-formic acid { 2-cyclohexyl-1-(S)-[1-(S)-cyclopropyl-2-(5-fluoro-3,3-Spirocyclopropyl-2,3-dihydro-indoles-1-yl)-ethylamino formyl radical]-ethyl }-acid amides;

83.[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

84.[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-carboxylamine 3,3-dimethyl-1-(S)-(morpholine-4-carbonyl)-butyl ester;

(85.[2-4-difluoro-methoxy-phenyl amino)-1-(S)-methyl-ethyl]-carboxylamine 3,3-dimethyl-1-(S)-(morpholine-4-carbonyl)-butyl ester;

86.{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

87.{3-phenyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

88.{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-butyl }-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

(89.[2-4-ethanoyl sulfamyl-phenyl amino)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

(90.[2-5-fluoro-2,2-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

91.[1-(S)-methyl-2-(5-methyl-isoxazole-3-base amino)-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

92. (S, S)-[1-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-base-methyl)-propyl group]-carboxylamine 1-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

(93.[2-5-fluoro-2,2-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-(2,6-cis-dimethyl-morpholine-4-yl)-2-oxo-ethyl ester;

94. (S, S)-[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indoles-1-yl)-1-methyl-ethyl]-carboxylamine 2-(4-ethanoyl-piperazine-1-yl)-1-cyclohexyl methyl-2-oxo-ethyl ester;

(95.[2-5-fluoro-2,2-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-(4-methylsulfonyl-piperazine-1-yl)-2-oxo-ethyl ester;

(96.[2-5-fluoro-2,2-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-oxo-2-thiomorpholine-4-base-ethyl ester;

(97.[2-5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-(2,6-cis-dimethyl-morpholine-4-yl)-2-oxo-ethyl ester;

(98.[2-5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 2-(4-ethanoyl-piperazine-1-yl)-1-(S)-cyclohexyl methyl-2-oxo-ethyl ester;

(99.[2-5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-(4-methylsulfonyl-piperazine-1-yl)-2-oxo-ethyl ester;

(100.[2-5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-oxo-2-thiomorpholine-4-base-ethyl ester;

(101.[2-5-fluoro-3,3-spiral shell-cyclopropyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

(102.[2-5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-oxo-2-piperidines-1-base-ethyl ester;

(103.[2-5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-oxo-2-tetramethyleneimine-1-base-ethyl ester;

(104.[2-5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 2-cyclohexyl-1-(S)-formyl-dimethylamino-ethyl ester;

(105.[2-5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-(1,1-dioxo-1 λ ⁶-thiomorpholine-4-yl)-2-oxo-ethyl ester;

(106.[2-5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 2-cyclohexyl-1-(S)-[(2-methoxyl group-ethyl)-methyl-formamyl]-ethyl ester;

(107.[2-5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 2-azetidine-1-base-1-(S)-cyclohexyl methyl-2-oxo-ethyl ester;

108.[1-(S)-cyclopropyl-2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

109.[1-(S)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-ylmethyl)-2-methyl-propyl group]-carboxylamine 2-morpholine-4-base-2-oxo-1-(R, S)-phenyl-ethyl ester;

110.[1-(S)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-ylmethyl)-2-methyl-propyl group]-carboxylamine 2-morpholine-4-base-2-oxo-1-(R)-phenyl methanesulfonamide acyl group methyl-ethyl ester;

111.[1-(S)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-ylmethyl)-2-methyl-propyl group]-carboxylamine 1-(S)-cyclohexyl-2-morpholine-4-base-2-oxo-ethyl ester.

Compound of the present invention can be obtained with the free form form, and is perhaps obtained with its salt form, and condition is to have salt forming group, and is perhaps obtained with ester-formin, and condition is to have into ester group.

Can transform salify with the compound of the present invention that pharmaceutically useful alkali, for example aqueous alkali metal hydroxide will have an acidic-group, advantageously transform existing under ether or alcohol solvent, the situation as low-level chain triacontanol.The salt of gained can be converted into free cpds, for example by transforming with acid treatment.These salt or other salt also can be used for the compound that purifying obtains.Can obtain ammonium salt by reacting with the amine that suits, for example diethylamine etc.

In some aspects, the compound with basic group of the present invention can be changed into acid salt, especially pharmaceutically useful salt.For example can form these salt with following acid: mineral acid, as mineral acid, for example sulfuric acid, phosphoric acid or haloid acid, perhaps organic carboxyl acid is as (C ₁-C ₄) the paraffinic hydrocarbons carboxylic acid, it for example is unsubstituted or is replaced by halogen, acetate for example is as saturated or undersaturated di-carboxylic acid, for example oxalic acid, succsinic acid, toxilic acid or fumaric acid, as hydroxycarboxylic acid, for example oxyacetic acid, lactic acid, oxysuccinic acid, tartrate or citric acid, as amino acid, for example aspartic acid or L-glutamic acid, or organic sulfonic acid, as (C ₁-C ₄)-alkylsulphonic acid (for example methylsulfonic acid) unsubstituted or substituted (for example being replaced) aryl sulfonic acid by halogen.The salt that forms with hydrochloric acid, methylsulfonic acid and toxilic acid preferably.

Because the substantial connection between the compound of free cpds and its salt or ester-formin, so when relating to a kind of compound in this article, also mean its corresponding salt or ester simultaneously, condition is that this is possible or suitable under described situation.

The compound that comprises their salt also can be obtained with its hydrate forms, perhaps comprises to be used for it is carried out other solvent of crystalline.

The compound that comprises free hydroxyl group of the present invention can also exist with the form of the ester of pharmaceutically useful, physiology cleavable, and such form is also included within the scope of the present invention.Such pharmaceutically useful ester is the prodrug ester derivative preferably, and it can be converted to the corresponding compound that comprises free hydroxyl group of the present invention by solvolysis or cracking under physiological conditions.Suitable pharmaceutically useful prodrug ester is those derived from carboxylic acid, carbonic acid monoesters or carbamic ester, preferably derived from the ester of substituted lower alkanols alkanoic acid or aryl carboxylic acid randomly.

It is obvious to the skilled person that some compound of the present invention has unsymmetrical carbon (optical center) or two key; Racemoid, diastereomer, enantiomorph, geometrical isomer and each isomer include within the scope of the invention.

The invention provides the optionally compound of inhibition of histone enzyme S.Some preferred aspect, the invention provides under the situation that has tissue protein enzyme isoenzyme such as cathepsin A, B, C, D, E, F, G, H, K, L, M, O, P, Q, R, V, W and X the optionally compound of inhibition of histone enzyme S.One preferred aspect, the invention provides under the situation that has cathepsin K, L, B or its combination the optionally compound of inhibition of histone enzyme S.

The cathepsin S that the compound of the present invention that can be used for treated tissue proteolytic enzyme S dependency illness preferably has less than 10 μ M suppresses constant.More preferably, the cathepsin S that has less than 1.0 μ M of the compound of the present invention that can be used for treated tissue proteolytic enzyme S dependency illness suppresses constant.Most preferably, the cathepsin S that has less than 0.1 μ M of the compound of the present invention that can be used for treated tissue proteolytic enzyme S dependency illness suppresses constant.

One preferred aspect, optionally the compound of the present invention of inhibition of histone enzyme S has the tissue protein enzyme isoenzyme that suppresses big at least 10 times of constant than its cathepsin S and suppresses constant under the situation that has the tissue protein enzyme isoenzyme.One preferred aspect, optionally the compound of the present invention of inhibition of histone enzyme S has the tissue protein enzyme isoenzyme that suppresses big at least 100 times of constant than its cathepsin S and suppresses constant under the situation that has the tissue protein enzyme isoenzyme.One most preferred aspect, optionally the compound of the present invention of inhibition of histone enzyme S has the tissue protein enzyme isoenzyme that suppresses big at least 1000 times of constant than its cathepsin S and suppresses constant under the situation that has the tissue protein enzyme isoenzyme.

IV. composition

Pharmaceutical composition of the present invention is that those are suitable for through intestines such as oral or rectum, transdermal, thereby local and parenteral is applied to Mammals inhibition of histone enzyme S activity that comprises the people and the pharmaceutical composition that is used for the treatment of the cathepsin S dependent conditions, the particularly chronic neuropathic pain of wherein said illness (referring to WO 03/020287), alzheimer's disease and some autoimmune conditions include but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves disease, myasthenia gravis, systemic lupus erythematous, rheumatoid arthritis and Hashimoto thyroiditis; Allergic disorder includes but not limited to asthma; With the allogeneic immune response, include but not limited to the rejection of organ graft or tissue grafts.

More specifically, pharmaceutical composition comprises the compound of the present invention of inhibition of histone enzyme S significant quantity.

Pharmacologically active chemical compounds of the present invention can be used for pharmaceutical compositions, described pharmaceutical composition comprise the described compound of significant quantity and with it coupling or with it blended be suitable for vehicle or carrier through intestines or parenteral application.

Preferably tablet and gelatine capsule agent, it comprises activeconstituents and a) thinner, for example lactose, glucose, sucrose, N.F,USP MANNITOL, sorbyl alcohol, Mierocrystalline cellulose and/or glycine; B) lubricant, for example silicon-dioxide, talcum powder, stearic acid, its magnesium salts or calcium salt and/or polyoxyethylene glycol; For tablet, also comprise c) tackiness agent, for example neusilin, starch paste, gelatin, tragakanta, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone; If desired, also can comprise d) disintegrating agent, for example starch, agar, Lalgine or its sodium salt or effervescent mixture; And/or e) absorption agent, tinting material, correctives and sweeting agent.Injectable composition preferably waits aqueous solution or the suspension of opening, and suppository is preferably made by fats emulsion or suspension.Assistant agent can be sterilized and/or be contained to described composition, as sanitas, stablizer, wetting agent or emulsifying agent, chaotropic agent (solutionpromoter), be used to regulate the salt and/or the buffer reagent of osmotic pressure.In addition, it can also contain other material that therapeutic value is arranged.Described composition is respectively according to the mixing of routine, granulation or coating method preparation, and contains the 0.1-75% that has an appointment, the preferred activeconstituents of about 1-50%.

Can be with method as known in the art to tablet bag film-coat or enteric coated.

The suitable formulations that is used for the transdermal application comprises the compound of the present invention and the carrier of significant quantity.Preferred carrier comprises and is used to help by accepting the absorbable pharmacology acceptable solvent of main body skin.For example, transdermal device is a form of bandage, and described form of bandage comprises back sheet, contain described compound and randomly carrier-containing storage storehouse, randomly be used for control and predetermined speed compound being delivered to the control speed barrier of the skin of accepting main body and being used for this device is fixed on means on the skin in for some time that prolongs.Also can use the matrix-type transdermal preparation.

Be used for topical application, for example be applied to skin and the eye the suitable formulations aqueous solution preferably well known in the art, ointment, ointment or gelifying agent.Such preparation can contain solubilizing agent, stablizer, increase tensile material, buffer reagent and sanitas.

Described pharmaceutical preparation contains independent or in the above defined compound of the present invention of the inhibition of histone enzyme S significant quantity of other therapeutical agent combination.

With other activeconstituents coupling the time, compound of the present invention can be used simultaneously, use before it or use after it with other activeconstituents, and they are used independently or use together in identical pharmaceutical preparation by identical or different route of administration.

The dosage of the active compound of being used depends on kind, body weight, age and individual instances and the administration form of warm-blooded animal (Mammals).Mammiferous unitary dose for oral administration to about 50 to 70kg can contain 5 to the 500mg activeconstituentss of having an appointment.

One preferred aspect, pharmaceutical composition of the present invention provides the compound of formula I.

In one aspect of the invention, the composition that comprises The compounds of this invention and pharmaceutically acceptable vehicle of the present invention inhibition of histone enzyme S optionally under the situation that has other kethepsin isozyme.One preferred aspect, the invention provides under the situation that has cathepsin K, L, B or its combination the optionally composition of inhibition of histone enzyme S.

In another aspect of the present invention, the cathepsin S that the composition of the present invention that can be used for treated tissue proteolytic enzyme S dependency illness preferably has less than 10 μ M suppresses constant.More preferably, the cathepsin S that has less than 1.0 μ M of the composition of the present invention that can be used for treated tissue proteolytic enzyme S dependency illness suppresses constant.Most preferably, the cathepsin S that has less than 0.1 μ M of the composition of the present invention that can be used for treated tissue proteolytic enzyme S dependency illness suppresses constant.

One preferred aspect, the compound of composition utilization of the present invention inhibition of histone enzyme S optionally under the situation that has the tissue protein enzyme isoenzyme has the tissue protein enzyme isoenzyme that suppresses big at least 10 times of constant than its cathepsin S and suppresses constant.One preferred aspect, optionally the compound of the present invention of inhibition of histone enzyme S has the tissue protein enzyme isoenzyme that suppresses big at least 100 times of constant than its cathepsin S and suppresses constant under the situation that has the tissue protein enzyme isoenzyme.One most preferred aspect, optionally the compound of the present invention of inhibition of histone enzyme S has the tissue protein enzyme isoenzyme that suppresses big at least 1000 times of constant than its cathepsin S and suppresses constant under the situation that has the tissue protein enzyme isoenzyme.

V. method

Because compound of the present invention is as the activity of cathepsin S inhibitor, they particularly can be used as the material of treatment and prevention and cathepsin S level rising diseases associated and medical condition in Mammals.For example, compound of the present invention can be used for treating alzheimer's disease and some autoimmune conditions, includes but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves disease, myasthenia gravis, systemic lupus erythematous, rheumatoid arthritis and Hashimoto thyroiditis; Allergic disorder includes but not limited to asthma; With the allogeneic immune response, include but not limited to the rejection of organ graft or tissue grafts.

Can estimate its beneficial effect with pharmacology test in the external and body as known in the art and as herein described.

Above-mentioned character can advantageously use Mammals for example rat, mouse, dog, rabbit, monkey or isolated organ and tissue and natural or test in vitro and in vivo by the Mammals enzyme preparation of for example recombinant technology preparation in proof.Compound of the present invention can be with the solution form, for example preferably use and use in intestines or parenteral, preferred oral approach body so that aqueous solution or suspension form body are outer, for example to use in the form of the suspension or the aqueous solution or the form body with the capsule fortreating AIDS preparation.The dosage of external application can be about 10 ^-5Mole is to 10 ^-9Volumetric molar concentration.According to the difference of route of administration, the dosage of using in the body can be for about 0.1 to 100mg/kg.

The arthritis effect that compound of the present invention is used for the treatment of rheumatoid arthritis can use model, (people such as R.E.Esser described before for example, J.Rheumatology 1993,20,1176) rat assist agent arthritis model or determine with model like this model class.The effect that compound of the present invention is used for the treatment of osteoarthritis can use model, described before for example (people such as Colombo, Arth.Rheum.1993,26,875-886) rabbit part lateral meniscus surgical blanking model or determine with model like this model class.The effect of described compound in model can be as described above (people such as O ' Byrne, Inflamm.Res.1995,44, S177-S118) carry out quantitatively with the histological score method.

The invention still further relates in Mammals and to use compound of the present invention and their pharmaceutically useful salt or its pharmaceutical composition to be used for inhibition of histone enzyme S and be used for the treatment of cathepsin S dependency illness, the method for cathepsin S dependency illness as herein described, for example inflammation, rheumatoid arthritis and osteoarthritis for example.

One preferred aspect, the present invention relates in Mammals, treat the method for rheumatoid arthritis, osteoarthritis and inflammation (and above-mentioned other disease), it comprises to its compound of the present invention of the corresponding significant quantity of administration of needs.

One preferred aspect, method of the present invention provides the compound of formula I.

The method that can be used for treated tissue proteolytic enzyme S dependency illness of the present invention is preferably used has the compound that suppresses constant less than 10 μ M cathepsin Ss.More preferably, the method that can be used for treated tissue proteolytic enzyme S dependency illness of the present invention is used and is had the compound that suppresses constant less than 1.0 μ M cathepsin Ss.Most preferably, the method that can be used for treated tissue proteolytic enzyme S dependency illness of the present invention is used and is had the compound that suppresses constant less than 0.1 μ M cathepsin S.

In addition, the invention still further relates in Mammals the optionally active method of inhibition of histone enzyme S, it comprises to its compound of the present invention of administration inhibition of histone enzyme S significant quantity of needs.One preferred aspect, method of the present invention is used under the situation that has tissue protein enzyme isoenzyme such as cathepsin A, B, C, D, E, F, G, H, K, L, M, O, P, Q, R, V, W and X the optionally compound of inhibition of histone enzyme S.One preferred aspect, method of the present invention is used under the situation that has cathepsin K, L, B or its combination the optionally compound of inhibition of histone enzyme S.

One preferred aspect, the compound that method of the present invention is used inhibition of histone enzyme S optionally under the situation that has the tissue protein enzyme isoenzyme has the tissue protein enzyme isoenzyme that suppresses big at least 10 times of constant than its cathepsin S and suppresses constant.One preferred aspect, optionally the compound of the present invention of inhibition of histone enzyme S has the tissue protein enzyme isoenzyme that suppresses big at least 100 times of constant than its cathepsin S and suppresses constant under the situation that has the tissue protein enzyme isoenzyme.One most preferred aspect, optionally the compound of the present invention of inhibition of histone enzyme S has the tissue protein enzyme isoenzyme that suppresses big at least 1000 times of constant than its cathepsin S and suppresses constant under the situation that has the tissue protein enzyme isoenzyme.

VI. embodiment

A. compound

Universal method.Be illustrated as anhydrous all solvents and all be buy from manufacturer and be that form when obtaining with it is used.All other reagent of buying all are that the form when receiving is used.Unless otherwise indicated, otherwise institute respond all and under positive nitrogen pressure, to carry out.Silica gel chromatography is to use prepacked column and the instrument that can carry out linear solvent gradient elution and fraction collection automatically to carry out. ¹The HNMR spectroscopic data is following to be reported: based on the chemical shift (using residual proton (protio) solvent as interior mark) of δ scale, (s=is unimodal for multiplicity, d=is bimodal, t=triplet, q=quartet, m=multiplet), integration and be the coupling constant of unit with the hertz. ¹³C spectrum be write down with the APT assay format and be that unit is reported with ppm, with residual solvent as interior mark.

Synthesizing of reference example 1. (S)-2-(4-methoxyl group-phenyl amino)-1-methylethyl amine

Steps A: (S)-preparation of 2-(tert-butoxycarbonyl amino)-propionic aldehyde.(523mg, 2.98mmol 1.0eq) are dissolved in the 45mL methylene dichloride with (S)-(-)-2-(tert-butoxycarbonyl amino)-1-propyl alcohol in being furnished with the 100mL round-bottomed flask of magnetic stirring bar.In this clarifying homogeneous solution, disposable adding Dess-Martin crosses iodine alkane, and (1.523g, 3.591mmol 1.2eq), at room temperature stirred the white reaction mixture of muddiness 2 hours.Finish until reaction with the tlc monitoring reaction.Reaction mixture is diluted with the 100mL ethyl acetate.(2M 20mL) joins in the reaction mixture, separates organic layer with sodium sulfite solution.With 3 * 30mL EtOAc washing water layer.The organic layer that merges is washed with 50mL 1M NaOH, use saturated NaCl (30mL) to wash and use MgSO subsequently ₄Dry.Filter and rotary evaporation, obtain required product, be yellow oil (475mg, 92% productive rate, R _f=0.63,1: 1 hexane/ethyl acetate).

Step B:[2-(4-methoxyl group-phenyl amino)-(1S)-methyl-ethyl]-preparation of t-butyl carbamate.In being furnished with the 100mL round-bottomed flask of magnetic stirring bar, with (S)-2-(tert-butoxycarbonyl amino)-propionic aldehyde (473mg, 2.74mmol) and P-nethoxyaniline (1.031g, 8.371mmol 3.0eq) are dissolved among the MeOH of 0 ℃ of 45mL.Randomly, (469 μ L, 8.21mmol is 3.0eq) to promote reaction can to add acetate by syringe.In the dark solution that is stirring, add sodium cyanoborohydride (326mg, 5.82mmol, 1.89eq).Observing gas emits with color and disappears.Reaction is gone through slowly be warming up to room temperature in 30 minutes, by the LC/MS monitoring reaction.When reacting completely, with 1M NaOH cancellation mixture, with 3 * 50mL ethyl acetate extraction.With the organism saturated NaHCO of 50mL that obtains ₃, the saturated NaCl of 40mL washing, use MgSO ₄Dry.The evaporation of acetic acid ethyl ester obtains the 728mg brown oil.Carry out purifying by automatization ISCO chromatography, obtain clarifying [2-(4-methoxyl group-phenyl amino)-(1S)-methyl-ethyl]-t-butyl carbamate (583mg, 2.079mmol, 76% productive rate) of oily matter form.HPLC-MS:C ₁₅H ₂₄N ₂O ₃(M+H ⁺) calculated value 281.2, measured value 281.5. ¹H NMR (CDCl ₃, 400MHz) δ 1.21 (d, 6H, J=6.6Hz), 1.47 (s, 9H), 3.05 (dd, 1H, J=12.2,7.3Hz), 3.13 (dd, 1H, J=12.2,4.6Hz), 3.76 (s, 3H), 3.93 (wide s, 1H), 4.62 (wide s, 1H), 6.60 (d, 2H, J=6.8Hz), 6.80 (2H, d, J=6.8Hz).

Step C: in being furnished with the 25mL round-bottomed flask of magnetic stirring bar, at room temperature, (383mg 1.37mmol) adds in the 10mL trifluoroacetic acid solution (dichloromethane solution of 10v/v%) with [2-(4-methoxyl group-phenyl amino)-(1S)-methyl-ethyl]-t-butyl carbamate.Afterreaction became dark purple/black in 5 minutes.To react at room temperature to be stirred to and react completely by the HPLC/MS judgement.Evaporation removes and desolvates, and obtains 2-(4-methoxyl group-phenyl amino)-(1S)-methyl-ethyl-ammonium; Three fluoro-acetates for brown oil (394mg, 1.34mmol, 98% productive rate), are directly used in next step reaction with it.HPLC-MS:C ₁₀H ₁₆N ₂₀O (M+H ⁺) calculated value 181.1, measured value 181.5.

Reference example 2. (R)-3-benzyloxy-N ¹-(4-methoxyl group-phenyl)-propane-1, the 2-diamines

Steps A: with the N-Boc-OBn-Serine (750mg, 2.54mmol), P-nethoxyaniline (344mg, 2.79mmol) and HOBt (377mg 2.79mmol) puts into a 50mL round-bottomed flask and use CH ₂Cl ₂(6mL) handle.Then, (535mg 2.79mmol) handles and stirs 2 hours should to react usefulness EDCI.Then, this reaction is diluted and the water extracting twice, with 1M HCl extracting twice, with 1M NaOH extracting twice with ethyl acetate.Then, with organism MgSO ₄Dry also removing desolvated, and obtains 450mg (44%) white solid: ¹H NMR (CDCl ₃, 400MHz) δ 1.49 (s, 9H), 3.63-3.72 (m, 1H), 3.81 (s, 3H), 4.00-4.08 (m, 1H), and 4.47-4.50 (m, 1H), 4.55-4.70 (m, 2H), 5.45-5.60 (m, 1H), 6.87 (d, 2H, J=8.8), 7.30-7.41 (m, 7H), 8.20-8.33 (m, 1H); HPLC-MS:C ₂₂H ₂₈N ₂O ₅(M+H ⁺) calculated value 401.2, measured value 401.4.

Step B: (400mg 1.00mmol) joins in the solution (1M) of ice-cooled borine in THF will to derive from the product of steps A.Remove cooling bath and will react stirring 24 hours, at this moment use 5%NaHSO ₄The reagent that cancellation is excessive.To react with ethyl acetate dilution and with 1M NaOH extracting twice.With organism MgSO ₄Dry also removing desolvated.The resistates of gained contains the material that has lost the Boc group and still has the material (proving by HPLC-MS) of Boc group with some.This oily matter was handled and stirred 3 hours with MeOH (2mL) and 4M HCl (2mL).Then, distribute except that desolvating and will being reflected between ethyl acetate and the 1M NaOH.Water is used ethyl acetate extraction twice again, with the organism MgSO that merges ₄Dry also removing desolvated.

Reference example 3. (S)-N1-(4-trifluoromethoxy-phenyl)-propane-1,2-diamines synthetic

Steps A: (S)-2-(benzyloxycarbonyl group amino)-propionic aldehyde

(5g 23.9mmol) is dissolved in CH with (S)-2-(benzyloxycarbonyl group amino)-propyl alcohol ₂Cl ₂Cross iodine alkane (12.26g, 1.1eq) processing (200mL) and with Dess-Martin.This mixture was stirred 2 hours, use the Sulfothiorine cancellation then, under vacuum, remove and desolvate.Then, (1M 500mL) and between the ethyl acetate (500mL) separates at sodium hydroxide with resistates.With organism salt water washing, dry (MgSO ₄) and vaporising under vacuum, obtain clarifying oily matter, it is directly used in next step without being further purified.

Step B:[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-benzyl carbamate

(S)-2-(benzyloxycarbonyl group amino)-propionic aldehyde is dissolved in the methyl alcohol (300mL).To wherein add acetate (4mL, 2.9eq), with the 4-trifluoro-methoxyaniline (9.6mL 3eq) handles this mixture and it was stirred 15 minutes, then, have under some effervescive situations to wherein add sodium cyanoborohydride (4.36g, 2.9eq.).This mixture was stirred 3 hours, under vacuum, remove then and desolvate.Then it is separated between hydrochloric acid (1M, 500mL * 2) and ethyl acetate (500mL).Organism is washed dry (MgSO with sodium bicarbonate (500mL), salt solution (500mL) ₄) and vaporising under vacuum, obtain clarifying oily matter, by silica gel chromatography it is carried out purifying, carry out gradient elution with the 0-100% ethyl acetate/hexane.

Step C:(S)-and N1-(4-trifluoromethoxy-phenyl)-propane-1, the 2-diamines

[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-benzyl carbamate (23.9mmol) is dissolved in the ethanol (200mL), is placed under the nitrogen then.Adding 10% palladium carbon (0.5g) also spends the night the stirring under hydrogen (normal atmosphere) of this mixture.When reacting completely, with the mixture diatomite filtration.(5 * 50mL) washings, vacuum-evaporation then obtain brown oil (productive rate in 3 steps is 72% for 4.03g, 17.21mmol) with ethanol with diatomite.

Reference example 4.2,2-dimethyl-5-fluorine indoline synthetic

Steps A: (9.02g, 42.7mmol) solution in THF (112mL) is cooled to-60 ℃ with the N-Boc-4-fluoroaniline with the cryocool instrument.(63mL 106.7mmol) handles this solution pentane solution by dripping 1.7M t-BuLi.After consuming the first equivalent alkali, form yellow solution.Make reaction be warming up to-20 ℃ and it was stirred 2.5 hours under this temperature.Then, by drip methallyl bromide (5.67g, 42.7mmol) solution in THF (35mL) this reaction is handled and with it-20 ℃ of following restir 1.5 hours.Then, will react cancellation by adding entry.After reaching room temperature, will react with ethyl acetate and handle and water and salt solution extraction, use MgSO ₄Dry also filtration.Remove then and desolvate,, carry out gradient elution, obtain 11.3g (80% productive rate) [4-fluoro-2-(2-methyl-allyl group)-phenyl]-t-butyl carbamate, be white solid with the hexane solution of 0-25% ethyl acetate with resistates purifying on silica gel; ¹H NMR (CDCl ₃, 400MHz) δ 1.50 (s, 9H), 1.72 (s, 3H), 3.28 (s, 2H), 4.71 (s, 1H), 4.92 (s, 1H), 6.32-6.50 (m, 1H), 6.86 (dd, 1H, J ₁=3.0, J ₂=9.1), 6.93 (ddd, 1H, J ₁=3.0, J ₂=8.5, J ₃=11.5), and 7.65-7.82 (m, 1H); HPLC-MS:C ₁₅H ₂₀FNO ₂(M+H ⁺-tBu) calculated value 210.1, measured value 210.3.

Step B: (1.10g 4.14mmol) handled and stirs 4 hours with phenylmethylether (5mL), methylene dichloride (5mL) and trifluoroacetic acid (5mL) with the sample of [4-fluoro-2-(2-methyl-allyl group)-phenyl]-t-butyl carbamate.Except that desolvating and reaction being transferred in the microwave reaction bottle with methylsulfonic acid (3mL).Reaction is heated to 170 ℃ reaches 10 minutes.With reaction be cooled to room temperature and with its cancellation to excessive carrying out among the 1M NaOH that stirs.With water ethyl acetate extraction twice, with the organism MgSO that merges ₄Dry also filtration.Oily matter purifying on silica gel with gained carries out gradient elution with 0-70% tertiary butyl ethyl ether and hexane, obtains 2 of 450mg (66% productive rate), 2-dimethyl-5-fluorine indoline; ¹H NMR (CDCl ₃, 400MHz) δ 1.08 (s, 6H), 2.58 (s, 2H), 6.24 (dd, 1H, J ₁=4.4, J ₂=8.4), and 6.43-6.48 (m, 1H), 6.53-6.56 (m, 1H); HPLC-MS:C ₁₀H ₁₂FN (M+H ⁺) calculated value 166.1, measured value 166.4.

Reference example 5.3,3-dimethyl-5-fluorine indoline synthetic

According to S.Coulton etc., the method described in the WO9925709 is synthesized, and it is adjusted.(5g 24.12mmol) joins and contains aluminum chloride (7g is in microwave tube 52.4mmol) with N-(4-fluoro-phenyl)-N-(2-methyl-allyl group)-ethanamide.This pipe closed the lid and be heated to 150 ℃ under microwave reach 20 minutes.Water and ethyl acetate are carried out aftertreatment to these slurries, organic layer are extracted for 3 times with saturated sodium bicarbonate solution washing and with the organic layer dried over mgso.Then, solution is filtered and rotary evaporation, obtain pure 1-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-ethyl ketone with quantitative yield.Reach 10 minutes and convert it into free indoline by being suspended in whole 5g products among the 20mL 6M HCl and in microwave, being heated to 200 ℃.After the cooling, the 5-fluoro-3 of gained, 3-dimethyl-2,3-dihydro-1H-indoles is separated out crystallization with quantitative yield with hydrochloride form.This material is identical with the compound of being reported before.

Synthesizing of reference example 6. (S)-[1-cyclopropyl-2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-ethyl]-benzyl carbamate

Steps A: (S)-the cyclopropyl glycine is according to the D.J.Bayston through adjusting etc., US6, institute's reported method preparation in 191,306.(16.8g, sample 76.7mmol) is with THF (200mL), water (100mL) and 10%Pd/C (4.76g) processing with (R)-styroyl-(S)-cyclopropyl glycine.In carrying out stirred mixture, add formic acid (17mL) and will react the stirring spend the night.Then, desolvate by removing by filter catalyzer with Celite pad and removing by rotary evaporation.With this material for several times and dry under vacuum, obtain 4.75g (54% productive rate) desired substance, be solid with the methyl alcohol coevaporation, with it without being further purified direct use.

(4.75g 41mmol) is dissolved among the 130mL 1N NaOH and (5.92g 49.5mmol) handles with chloroformic acid benzyl ester under vigorous stirring with the material of above step gained.To react to stir and spend the night, use dichloromethane extraction then twice.Discard organism, water is also used dichloromethane extraction three times with dense HCl acidifying.With the organism MgSO that merges ₄Dry and remove and desolvate, obtain 7.38g (72% yield) (S)-benzyloxycarbonyl amino-cyclopropyl-acetate, be white solid.

Step B: (3.2g, 12.8mmol) solution in THF (20mL) cools off in ice/water-bath and uses 1M BH with (S)-benzyloxycarbonyl amino-cyclopropyl-acetate ₃(16.7mL 16.7mmol) handles solution in THF.To react and stir 4 hours, handle with 1M HCl then, until stopping bubbling.To react to stir and spend the night, remove organic solvent by rotary evaporation.Resistates is handled with ethyl acetate and it is transferred in the separating funnel.Aqueous phase discarded with 1M NaOH washed twice, is used MgSO with organism ₄Dry also removing desolvated.With resistates purifying on silica gel, carry out gradient elution with the hexane solution of 0-100% ethyl acetate, obtain 1.5g (50% productive rate) (S)-(1-cyclopropyl-2-hydroxyl-ethyl)-benzyl carbamate, be white solid; ¹H NMR (CDCl ₃, 400MHz) δ 0.26-0.37 (m, 1H), 0.34-0.44 (m, 1H), 0.47-0.61 (m, 2H), 0.83-0.94 (m, 1H), 2.95-3.04 (m, 1H), 3.70 (dd, 1H, J ₁=5.8, J ₂=11.1), 3.79-3.88 (m, 1H), 5.00-5.12 (m, 1H), 5.10 (s, 2H), 7.29-7.31 (m, 5H); HPLC-MS:C ₁₃H ₁₇NO ₃(M+H ⁺) calculated value 236.1, measured value 236.3.

Step C: use with reference example 3 similar modes and make (S)-[1-cyclopropyl-2-(5-fluoro-3 with 67% productive rate, 3-dimethyl-2,3-dihydro-indoles-1-yl)-ethyl]-benzyl carbamate, different is that 3-dimethyl-5-fluorine indoline (WO 9925709) is as the coupling companion with pure and mild 1 equivalent 3 that derives from above step; HPLC-MS:C ₂₃H ₂₇FN ₂O ₂(M+H ⁺) calculated value 383.2, measured value 383.4.

Reference example 7.5-fluoro-3,3-Spirocyclopropyl-indoline synthetic

Steps A: (5g, 30.2mmol) solution in DMF (60mL) cools off in ice/water-bath and (1.44g 60.6mmol) handles by add sodium hydride in batches with the 5-fluoro indigo red.After adding last portion, will react stirring 15 minutes, use then that (5.32g 45.3mmol) handles and stir 1 hour to methoxy-benzyl chlorine.Then, will react cancellation by the excessive methyl alcohol of slow adding.After stopping bubbling, reaction is poured in the water (100mL), use twice of ethyl acetate extraction.Organism is merged, use MgSO ₄Dry also removing desolvated.Resistates by the silica gel chromatography purifying, is carried out gradient elution with the hexane solution of 0-100% ethyl acetate, obtain 7.1g (82%) 5-fluoro-1-(4-methoxyl group-benzyl)-1H-indoles-2, the 3-diketone; ¹H NMR (CDCl ₃, 400MHz) δ 3.79 (s, 3H), 4.86 (s, 2H), 6.75 (dd, 1H, J ₁=3.6, J ₂=8.6), and 6.84-6.90 (m, 2H), 7.19 (ddd, 1H, J ₁=J ₂=8.6, J ₃=3.6), and 7.22-7.27 (m, 1H), 7.26-7.31 (m, 2H); HPLC-MS:C ₁₆H ₁₂FNO ₃(M+H ⁺) calculated value 286.1, measured value 286.3.

Step B: (7.1g, 24.9mmol) solution in hydrazine hydrate (35mL) and ethanol (15mL) refluxes and spends the night, twice of dilute with water and usefulness ethyl acetate extraction with 5-fluoro-1-(4-methoxyl group-benzyl)-1H-indoles-2,3 diketone.With the organism Na that merges ₂SO ₄Drying is filtered and is concentrated.Resistates by the silica gel chromatography purifying, is carried out gradient elution with the hexane solution of 0-100% ethyl acetate, obtain 6.1g (90%) 5-fluoro-1-(4-methoxyl group-benzyl)-1, the 3-dihydro-indol-2-one; ¹H NMR (CDCl ₃, 400MHz) δ 3.59 (s, 2H), 3.77 (s, 3H), 4.83 (s, 2H), 6.63 (dd, 1H, J ₁=4.2, J ₂=8.6), and 6.82-6.91 (m, 3H), 6.96-7.01 (m, 1H), 7.19-7.23 (m, 1H), 7.27-7.31 (m, 1H); HPLC-MS:C ₁₆H ₁₄FNO ₂(M+H ⁺) calculated value 272.1, measured value 272.3.

Step C: with 5-fluoro-1-(4-methoxyl group-benzyl)-1,3-dihydro-indol-2-one (6.12g, 22.6mmol) solution in DMF (65mL) cools off in ice/water-bath and by add ethylene dibromide (6.35g in batches, 33.8mmol), add sodium hydride then (1.09g 45mmol) handles in batches.0 ℃ down stir 1 hour after, reaction is cooled to-78 ℃ and handle with excessive methanol.After stopping bubbling, reaction is poured in the water (100mL) and with twice of ethyl acetate extraction.Organism is merged, use Na ₂SO ₄Dry also removing desolvated.Resistates by the silica gel chromatography purifying, is carried out gradient elution with the hexane solution of 0-100% ethyl acetate, obtain 4.1g (61%) 5-fluoro-1-(4-methoxyl group-benzyl)-Spirocyclopropyl oxindole; ¹H NMR (CDCl ₃, 400MHz) δ 1.54 (dd, 2H, J ₁=4.0, J ₂=7.8), 1.83 (dd, 2H, J ₁=4.3, J ₂=8.1), 3.77 (s, 3H), 4.91 (s, 2H), 6.57 (dd, 1H, J ₁=2.5, J ₂=8.0), 6.69 (dd, 1H, J ₁=4.2, J ₂=8.5), 6.81 (dd, 1H, J ₁=2.5, J ₂=9.3), and 6.83-6.87 (m, 2H), 7.22-7.25 (m, 2H); HPLC-MS:C ₁₈H ₁₆FNO ₂(M+H ⁺) calculated value 298.1, measured value 298.3.

Step D: (3.38g, 11.4mmol) solution in TFA (20mL) stirs down at 60 ℃ and spends the night with 5-fluoro-1-(4-methoxyl group-benzyl)-Spirocyclopropyl oxindole.Remove then and desolvate, will react with ethyl acetate and dilute and use saturated NaHCO ₃Solution washing to washing lotion is neutral.Then, with organic phase salt water washing, use Na ₂SO ₄Dry also removing desolvated.Resistates by the silica gel chromatography purifying, is carried out gradient elution with the hexane solution of 0-100% ethyl acetate, obtain 1.94g (96%) 5-fluoro-Spirocyclopropyl oxindole; ¹H NMR (MeOD, 400MHz) δ 1.76-1.86 (m, 4H), 6.91-6.94 (m, 1H), 7.07-7.11 (m, 2H); HPLC-MS:C ₁₀H ₈FNO (M+H ⁺) calculated value 178.2, measured value 178.3.

Step e: the sample (172mg, 97 μ mol) of 5-fluoro-Spirocyclopropyl oxindole is cooled off in ice/water-bath and (1.94mL 1.9mmol) handles with 1.0M LAH solution.To react and at room temperature stir 15 minutes, stir 3 hours down at 50 ℃ then, go back with ice/water-bath cooling at last.To react with 1M NaOH (1.9mL), water (1.9mL) processing then.To react with diatomite filtration and use MgSO ₄Dry.After the filtration, remove and desolvate, the not purified direct use of 5-fluoro-Spirocyclopropyl indoline crude product material.

In addition, at (1) Jackson, A.H. etc., Tetrahedron (1968), 24 (1), 403-13; (2) Jansen, A.B.A. etc., Tetrahedron (1965), 21 (6), 1327-31; (3) Bermudez, J. etc., J.Med.Chem. (1990), 33 (7), 1929-32; (4) Nishio, T. etc., Helv.Chim.Acta (1990), 73 (6), 1719-23; (5) Nishio, T. etc., J.Chem.Soc., Perkin Trans 1 (1991), (1), 141-3; (6) Kucerovy, A. etc., Synth.Commun. (1992), 22 (5), 729-33; (7) Kato, M. etc., Chem.Pharm.Bull. (1995), 43 (8), among the 1351-7 also to other 3,3-spiral shell-the synthetic of cycloalkyl indoline is described.

Reference example 8.2,2,5-trifluoro indoline synthetic

Steps A: under inert atmosphere, go through 15 minutes will be at the 5-fluoro-1H-of the solution form among dry DMF indoles-2,3 diketone (956mg, 5.79mmol, 1eq) be added drop-wise to the sodium hydride (278mg that is stirring, 11.6mmol, 2eq) in the slurries in dry DMF, carry out enough pressure release to adapt to H ₂Gas is emitted.The mixture of gained was stirred 1 hour, in reaction, add methoxy-benzyl chlorine by syringe.Then, with about 2 hours of solution stirring, by adding entry, being extracted in the ethyl acetate it is carried out aftertreatment then.Wash organic layer with water twice, use MgSO then ₄Dry.Carry out purifying by column chromatography, use the ethyl acetate/hexane wash-out, obtain 5-fluoro-1-(4-methoxyl group-benzyl)-1H-indoles-2, the 3-diketone is red solid (1.3g, 80% productive rate). ¹H NMR(CDCl ₃)δ(ppm)：7.3-7.24(m，3H)，7.20(td，J＝8.7，2.7Hz，1H)，6.9-6.86(m，2H)，6.76(dd，J＝8.6，3.6Hz，1H)，3.81(s，2H)，3.78(s，3H)。LC/MS＝286.1(M+1)。

Step B: (200mg, 0.701mmol 1eq) are dissolved among the dry DCM of 10mL and are placed under the inert atmosphere will to derive from the product of steps A.(339mg, 2.103mmol 3eq) also will react stirring and spend the night to add DAST by syringe.By adding saturated sodium bicarbonate aqueous solution aftertreatment is carried out in reaction, with organic layer MgSO ₄Drying is filtered, and rotary evaporation is to doing.The crude product material of gained is passed through purified by flash chromatography, use ethyl acetate/hexane as solvent systems. ¹H NMR(CDCl ₃)δ(ppm)：7.3-7.28(m，1H)，7.22(d，J＝8.7Hz，2H)，7.09(td，J＝8.7，1.3Hz，1H)，6.87(d，J＝8.7Hz，2H)，6.73(m，1H)，4.83(s，2H)，3.79(s，3H)。LC/MS＝308.1(M+1)。

Step C: (1.178g, 3.83mmol 1eq) are dissolved in the 75mL dry THF and are placed under the inert atmosphere will to derive from the product of step B.Under-78 ℃, at positive N ₂Depress to the LiAlH that wherein adds solid form ₄(291mg, 7.66mmol, 2eq).To be reflected under this temperature and stir 30 minutes, and it be gone through be warming up to room temperature in 6 hours.By dripping water, adding the 4 equivalent KOH aqueous solution then aftertreatment is carried out in this reaction.With this slurries with the dilution of 500mL water and with 2 * 200mL ethyl acetate extraction.Organic layer is merged, use MgSO ₄Drying is filtered and rotary evaporation is extremely done.The crude product material of gained is passed through purified by flash chromatography, as solvent systems, obtain 320mg pure substance (28%) with ethyl acetate/hexane. ¹H NMR(CD ₃OD)δ(ppm)：7.21(d，J＝8.8Hz，2H)，7.06(dd，J＝8.2，1.3Hz，1H)，6.89(m，1H)，6.84(d，J＝8.7Hz，2H)，6.77(dd，J＝8.6，4.3Hz，1H)，4.83(s，2H)，3.73(s，3H)，3.12(s，2H)。LC/MS＝294.1(M+1)。

Step D: will derive from product (50mg, 0.1704mmol, 1eq) the usefulness 1mL TFA absorption of step C.This solution is placed microwave tube, and sealing is heated to 175 ℃ and reaches 5 minutes.With the dark solution of gained with the saturated sodium bicarbonate neutralization and with 2 * 50mL ethyl acetate extraction.With organic layer MgSO ₄Drying is filtered and rotary evaporation is extremely done.The solid of gained is dissolved in 50: 50 the DMSO/MeOH mixture and by preparation HPLC purifying.Obtain 23.8mg white solid (81%). ¹H NMR(DMSO D ₆)δ(ppm)：10.41(s，1H)，7.13(dd，J＝8.6，2.4Hz，1H)，7.01(td，J＝8.6，2.7Hz，1H)，6.8(dd，J＝8.5，4.5Hz，1H)，3.5(s，2H)。

Embodiment 1. morpholines-4-formic acid (S)-2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indoles-1-yl)-ethylamino formyl radical]-ethyl ester

(4.00g is 23.4mmol) at 0.5MH to L-Cyclohexylalanine under 0 ℃, that stirring ₂SO ₄Slowly drip NaNO in the suspension (120mL) ₂(12.1g is at 40mL H for the aqueous solution ₂Among the O).Be added dropwise to complete after about 1 hour, at this moment make solution be warming up to room temperature.After 16 hours, (3 * 100mL) extractions are with the organic extract 1M NaHSO that merges with ether with reaction mixture ₄(1 * 200mL) and salt solution (1 * 100mL) washing, use anhydrous Na then ₂SO ₄Dry.Under vacuum, remove and desolvate, with crude product Et ₂O/ pentane (10mL/100mL) recrystallization, obtain 2.1g (52% productive rate) (S)-cyclohexyl lactic acid, be thin white needles thing.

(558mg is 3.42mmol) at CH to (the S)-cyclohexyl lactic acid that is stirring ₂Cl ₂In suspension in add 2-(5-fluoro-2,3-dihydro-indoles-1-yl)-ethylamine (616mg, 3.42mmol), HATU (1.429g, 3.76mmol) and DIEA (1.79mL, 10.3mmol).With reaction mixture stirred for several hour at room temperature, up to showing that by LCMS raw material disappears.Add ethyl acetate (100mL), with solution 1M NaHSO ₄(2 * 100mL), saturated NaHCO ₃The aqueous solution (2 * 100mL) and salt solution (1 * 100mL) washing.Under vacuum, remove and desolvate, with the crude product material by silica gel chromatography (purifying of hexane/EtOAc) obtains 320mg 3-cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indoles-1-yl)-ethyl]-2-(S)-hydroxyl-propionic acid amide, be white powder.

To the 3-cyclohexyl-N-[2-that is stirring (5-fluoro-2,3-dihydro-indoles-1-yl)-ethyl]-(263mg is 0.79mmol) at CH for 2-(S)-hydroxyl-propionic acid amide ₂Cl ₂Add in the solution (2.0mL) pyridine (0.1mL) and chloroformic acid 4-nitro phenyl ester (202mg, 1.01mmol).To react at room temperature to stir and spend the night, at this moment show that by LCMS raw material disappears.The crude product material by the silica gel chromatography purifying, is obtained corresponding mixed carbonate ester, be white powder.

(50mg 0.094mmol) is dissolved in CH with the carbonic ether that obtains ₂Cl ₂(1.0mL), add excessive morpholine (0.1mL), will react at room temperature stirred for several hour, up to showing that by LCMS raw material disappears.Under vacuum, remove and desolvate, the crude product material is passed through the reversed-phase HPLC purifying.HPLC-MS:C ₂₄H ₃₄FN ₃O ₄(M+H ⁺) calculated value 448.25, measured value 448.5.

Embodiment 2. morpholines-4-formic acid { 2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indoles-1-yl)-ethylamino formyl radical]-ethyl }-acid amides

According to the method described in the embodiment 4 so that 2-(5-fluoro-2,3-dihydro-indoles-1-yl)-ethylamine is that raw material has synthesized title compound.

HPLC-MS:C ₂₄H ₃₅FN ₄O ₃(M+H ⁺) calculated value 447.27, measured value 447.5.

Embodiment 3. morpholines-4-formic acid { 2-cyclohexyl-1-(S)-[2-(4-fluoro-phenyl amino)-ethylamino formyl radical]-ethyl }-acid amides

With N1-(4-fluorophenyl)-ethane-1, the 2-diamines is that raw material has synthesized title compound according to the method described in the embodiment.

HPLC-MS:C ₂₂H ₃₃FN ₄O ₃(M+H ⁺) calculated value 421.25, measured value 421.5.

Embodiment 4. morpholines-4-formic acid { 2-cyclohexyl-1-(S)-[2-(4-methoxyl group-phenyl amino)-ethylamino formyl radical]-ethyl }-acid amides

Steps A: with aldehyde-functionalized polystyrene resin (" Pal-resin ", 16.76g; @1.05mmol/g 17.6mmol) expanded 10 minutes in DMF (50mL).Be added in N1-(4-methoxyl group-phenyl)-ethane-1 among the DMF (150mL), 2-diamines (5.85g, 35mmol is according to schema 1 preparation), add subsequently acetate (8.1mL, 8eq), with mixture stirring at room 1 hour.Add sodium triacetoxy borohydride (11.2g, 52.8mmol eq.) then, with mixture jolting at room temperature 16 hours.Resin filter with reductive amination also washs (DMF * 3, the equal amount of mixture of ethanol/methylene * 4, acetonitrile * 3) then.

Step B: resin (17.6mmol) is expanded in dimethyl formamide (50mL), add Fmoc-CHA-OH (20.45g, 3eq), HOBt (8.08g, 3eq) and DIC (4.58mL, solution 3eq).With mixture jolting 3 hours, washing (dimethyl formamide * 3, the equal amount of mixture of ethanol/methylene * 4, acetonitrile * 3) then.

Synthesizing on Argonaut Quest 210 of end product carried out, and it has the automatization wash module can finish washing automatically.

Step C:Fmoc deprotection

(250mg 0.163mmol) weighs and puts into reaction vessel, puts into stirring rod subsequently, and the piperidines (solution of 4mL 20%) that is used in then in the dimethyl formamide is handled, and mixture was stirred 1 hour with resin.Washing resin (3 * dimethyl formamide, 3 * methylene dichloride) then.

Step D: the formation of urea

(3eq, solution 0.490mmol) join in the resin (0.163mmol) will to be dissolved in morpholine formyl chloride in the methylene dichloride (10mL).(3eq 0.490mmol), will react and stir 3 hours, with dimethyl formamide washing 4 times, use washed with dichloromethane 4 times then, use nitrogen drying then to add DIEA.

Step e: cracking

With resin with the mixture of trifluoroacetic acid, methylene dichloride and water (45: 45: 10,10mL) handle.It was stirred 1 hour, and then handle, stirred 5 minutes, and then washing once, is filled in the bottle.Vaporising under vacuum solvent, LCMS system (7.5 fens clock methods, gradient are the 10-90% acetonitrile/water that the contains 0.35% trifluoroacetic acid) purifying that instructs with the Waters mass spectrum then.Then compound is analyzed, be condensed into solid by lyophilize then.

HPLC-MS:C ₂₃H ₃₆FN ₄O ₄(M+H ⁺) calculated value 433.27, measured value 433.5.

Embodiment 5.[2-(4-fluoro-phenyl amino)-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester

(4.00g is 23.4mmol) at 0.5MH to L-Cyclohexylalanine under 0 ℃, that stirring ₂SO ₄Slowly drip NaNO in the suspension (120mL) ₂(12.1g is at 40mL H for the aqueous solution ₂Among the O).Finish dropping after about 1 hour, at this moment make solution be warming up to room temperature.After 16 hours, (3 * 100mL) extractions are with the organic extract 1M NaHSO that merges with ether with reaction mixture ₄(1 * 200mL) and salt solution (1 * 100mL) washing, use anhydrous Na then ₂SO ₄Dry.Under vacuum, remove and desolvate, with crude product Et ₂O/ pentane (10mL/100mL) recrystallization, obtain 2.1g (52% productive rate) (S)-cyclohexyl lactic acid, be thin white needles thing.

To (the S)-cyclohexyl lactic acid that is stirring (300mg, 1.74mmol), morpholine (0.15mL, 1.74mmol) and DIEA (0.91mL is 5.23mmol) at CH ₂Cl ₂(728mmol 1.92mmol), at room temperature stirs reaction mixture and to spend the night to add HATU in the solution (3mL).Add EtOAc (100mL), with the saturated NaHCO of solution ₃(2 * 100mL), salt solution (1 * 100mL) washing, use Na ₂SO ₄Drying concentrates under vacuum, obtains corresponding amide, is colorless oil, with its not purified direct use.

The acid amides (1.74mmol) that obtains is dissolved in the pyridine (5mL), and adding chloroformic acid 4-nitro phenyl ester (405mg, 2.21mmol).Reaction mixture was stirred 4 hours down at 70 ℃, at this moment show that by LCMS raw material disappears.Then reaction is cooled to room temperature, adds EtOAC (100mL), organic layer 1M NaHSO ₄Na is used in washing ₂SO ₄Dry.(purifying of hexane/EtOAc) obtains 550mg carbonic acid nitro phenyl ester (productive rate of two-step reaction is 78%), is white powder by silica gel chromatography with the crude product material.

To the N1-that is stirring (4-fluorophenyl)-ethane-1,2-diamines 2HCl (110mg, 0.48mmol) and DIEA (0.34mL, 1.93mmol) be added in the suspension in THF (2.0mL) the carbonic acid nitro phenyl ester that obtains in the final step (196mg, 0.48mmol).Reaction mixture is at room temperature stirred, after 18 hours, show that by LCMS raw material disappears.Evaporating solvent, (purifying of hexane/EtOAc) carries out the purifying second time by reversed-phase HPLC subsequently, obtains the title compound of embodiment 5, is white powder (55mg, 27% productive rate) by silica gel chromatography with the crude product material.

HPLC-MS:C ₂₂H ₃₂FN ₃O ₄(M+H ⁺) calculated value 422.24, measured value 422.5.

Embodiment 6.2-(R)-cyclohexyl methyl-N-[2-(4-fluoro-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide

With (R)-2-(cyclohexyl methyl) succsinic acid-1-methyl esters (470mg, 2.06mmol) (AcrosOrganics) with morpholine (350mg, 4.00mmol, 2eq.) and HATU (745mg, 2.26mmol) processing.In exsiccant methylene dichloride (5mL), (1mL 5.741mmol) handles with diisopropyl ethyl amine with agent dissolves.To react to stir and spend the night.By the LC/MS monitoring reaction, will react directly by preparation type LC/MS purifying.Obtain product, be clarifying oily matter (460mg, 1.54mmol, 75%).(460mg 1.54mmol) is dissolved in MeOH (10mL) and H with the product that obtains ₂In 2: 1 mixtures of O (5mL), be placed in 0 ℃ the ice bath.(45mg, 1.87mmol 1.2eq.), stirred 8 hours disposable adding lithium hydroxide, slowly were warming up to 23 ℃.After reacting completely, remove methyl alcohol by evaporation.Add ethyl acetate (75mL), solution is extracted with 1M HCl (50mL).With 2 * 75mL ethyl acetate extraction water, the organic phase that merges is washed with saturated sodium bicarbonate (50mL) and saturated sodium-chloride (50mL), use dried over mgso, filter also evaporation, obtain the 220mg product, be yellow oil (0.77mmol, 50% productive rate).Product (the 220mg that a part is obtained, 0.77mmol), N1-(4-fluoro-phenyl)-ethane-1,2-diamines (193mg, 0.85mmol, 1.1eq. according to schema 1 preparation) and HATU (280mg, 0.85mmol 1.1eq.) are dissolved in the exsiccant methylene dichloride (4mL), (400 μ L 5.741mmol) handle with diisopropyl ethyl amine.The reaction mixture stirring is spent the night, monitor by LC/MS.Reaction mixture directly by preparation type LC/MS purifying, is obtained 56mg (0.10mmol, 13%) title compound, is white solid: ¹H NMR (CDCl ₃, 400MHz) δ 0.74-1.96 (m, 13H), 2.42-2.98 (m, 3H), 3.21-3.98 (m, 12H), 7.11-7.36 (m, 4H); HPLC-MS:C ₂₃H ₃₄FN ₃O ₃(M+H ⁺) calculated value 420.5, measured value 420.5.

Embodiment 7.[4-(R)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-tetrahydrochysene-furans-3-(R)-yl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester

Steps A: 1-(4-(R)-azido--tetrahydrochysene-furans-3-(R)-yl)-5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles and 1-(4-(R)-azido--tetrahydrochysene-furans-3-(S)-yl)-5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles synthetic

(232mg 1.8mmol) is dissolved in the methylene dichloride (10mL), and in ice/water-bath cooling eventually, (917mg 2.2mmol) handles to cross iodine alkane with Dess-Martin with 3-(R)-azido--4-(R)-hydroxyl tetrahydrofuran sample.Make to react and be warming up to room temperature and stirred the demonstration of TLC analysis at this moment reaction end 1 hour.Then with the ketone solution that obtains with 5-fluoro-3,3-dimethyl indoline (328mg, 2.0mmol) and acetate (148mg, 2.7mmol) solution-treated in methyl alcohol (10mL) and THF (5mL).(170mg 2.7mmol) handles and stirs and spend the night will to react the usefulness sodium cyanoborohydride then.Removing volatiles under vacuum will react and use up in ethyl acetate then, with 1M NaOH extraction.Organism Na ₂SO ₄Drying is removed and is desolvated.Resistates by the silica gel chromatography purifying, is carried out linear gradient elution with the hexane solution of 0-50% ethyl acetate, obtain 155mg (31%) trans-isomer(ide) and 50mg (10%) trans-isomer(ide).

1-(4-(R)-azido--tetrahydrochysene-furans-3-(R)-yl)-5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles: ¹H NMR (400MHz, CDCl ₃) δ 6.77 (m, 2H), 6.38 (dd, J=6.0,4.0Hz, 1H), 4.31 (m, 1H), 4.09 (dd, J=10.0,5.8Hz, 1H), 4.03 (m, 3H), 3.83 (dd, J=10.0,3.2Hz, 1H), 3.45 (d, J=8.2Hz, 1H), 3.26 (d, J=8.2Hz, 1H), 1.32 (s, 3H), 1.31 (s, 3H); HPLC-MS:C ₁₄H ₁₇FN ₄O ₂(M+H ⁺) calculated value 277.3, measured value 277.4.

1-(4-(R)-azido--tetrahydrochysene-furans-3-(S)-yl)-5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles: ¹H NMR (400MHz, CDCl ₃) δ 6.77 (m, 2H), 6.44 (dd, J=8.5,4.0Hz, 1H), 4.11 (m, 2H), 4.02 (m, 3H), 3.75 (dd, J=8.6,2.6Hz, 1H), 3.23 (d, J=8.3Hz, 1H), 3.07 (d, J=8.4Hz, 1H), 1.29 (s, 3H), 1.27 (s, 3H); HPLC-MS:C ₁₄H ₁₇FN ₄O ₂(M+H ⁺) calculated value 277.3, measured value 277.4.

((55mg is 0.20mmol) with methyl alcohol (5mL) and PtO for 3-dihydro-1H-indoles sample for 4-(R)-azido--tetrahydrochysene-furans-3-(R)-yl)-5-fluoro-3,3-dimethyl-2 with 1-for step B. ₂(2.4mg 0.01mmol) handles.Make hydrogen stream by reacting bubbling 5 minutes, will be reflected under the hydrogen bag pressure power and stir 3 hours.Reaction atmosphere is changed into nitrogen, react by one deck diatomite filtration.Remove and to desolvate, take out resistates, with the material that obtains under condition of high vacuum degree dry 1 hour.To react then with Virahol (10mL) and (S)-carbonic acid 1-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester 4-nitro-phenyl ester (81mg, 0.20mmol) and diisopropyl ethyl amine (38mg, 0.3mmol) processing.To react and at room temperature stir 24 hours, stir 4 hours down at 60 ℃ then.Removing volatiles under vacuum will react and use up in ethyl acetate then, with 1M HCl extraction.With organism Na ₂SO ₄Drying is removed and is desolvated.Resistates by the silica gel chromatography purifying, is carried out linear gradient elution with the hexane solution of 0-100% ethyl acetate, obtain the described material of 64mg (62%); ¹H NMR (400MHz, CDCl ₃) δ 7.16 (d, J=8.0Hz, 1H), 6.72 (dd, J=8.4,2.6Hz, 1H), 6.66 (ddd, J=8.9,8.9,2.7Hz, 1H), 6.39 (dd, J=8.6,4.1Hz, 1H), 5.08 (dd, J=10.3,3.0Hz, 1H), 4.44 (m, 1H), 4.03 (m, 2H), 3.70 (m, 2H), and 3.44-3.64 (m, 7H), 3.32 (d, J=6.6Hz, 1H), 3.29 (m, 1H), 3.24 (d, J=8.4Hz, 1H), 1.55 (m, 8H), 1.25-1.37 (m, 2H), 1.29 (s, 3H), 1.27 (s, 3H), 1.12 (m, 2H), 0.78-0.93 (m, 1H); HPLC-MS:C ₂₈H ₄₀FN ₃O ₅(M+H ⁺) calculated value 518.6, measured value 518.6.

With similar response hierarchy with 1-(4-(R)-azido--tetrahydrochysene-furans-3-(S)-yl)-5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles is converted into accordingly [4-(S)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-tetrahydrochysene-furans-3-(R)-yl]-carboxylamine (S)-1-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester.HPLC-MS:C ₂₈H ₄₀FN ₃O ₅(M+H ⁺) calculated value 518.6, measured value 518.6.

Embodiment 8.2-(R)-cyclohexyl methyl-N-[2-(5-fluoro-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-4-morpholine-4-base-4-oxo-butyramide

Synthesize title compound according to the method described in the embodiment 6, be pale solid.HPLC-MS:C ₂₆H ₃₈FN ₃O ₃(M+H ⁺) calculated value 460.3, measured value 460.5.

Embodiment 9.3-(R)-cyclohexyl methyl-N-[2-(4-fluoro-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide

Steps A: (R)-2-(cyclohexyl methyl) succsinic acid-1-methyl esters (211mg that will derive from Acros Organics, 0.93mmol) usefulness (500 μ L, 2.87mmol, 3.1eq.) diisopropyl ethyl amine, HATU (360mg, 1.096mmol, 1.2eq.) with (N-(4-fluoro-phenyl)-ethane-1,2-diamines) (210mg, 0.93mmol, 1eq.) handle.With each agent dissolves in exsiccant methylene dichloride (5mL).To react and stir 5 hours, monitor by LC/MS.Remove volatile matter, will react by automatic normal phase chromatography (the 0-100% ethyl acetate gets the hexane solution gradient) direct purification.Obtain (R)-2-cyclohexyl methyl-N-[2-(4-fluoro-phenyl amino)-ethyl]-the succinamic acid methyl esters, be clarifying oily matter (220mg, 0.60mmol, 65%).

Step B: with (R)-2-cyclohexyl methyl-N-[2-(4-fluoro-phenyl amino)-ethyl]-(220mg, 0.60mmol 1.0eq.) are dissolved in MeOH (4.5mL) and H to the succinamic acid methyl esters ₂In the mixture of O (3mL), be placed in 0 ℃ the ice bath.(30mg, 1.25mmol 2.1eq.), stirred 8 hours disposable adding lithium hydroxide, slowly were warming up to 23 ℃.By LC/MS judge react completely after, remove methyl alcohol by evaporation.In the solution that obtains, add ethyl acetate (75mL), with 1M HCl (50mL) extraction.With 2 * 75mL ethyl acetate extraction water, the organism that merges is washed with saturated sodium bicarbonate (50mL) and saturated sodium-chloride (50mL), use dried over mgso, filter and evaporation, obtain 183mg (R)-2-cyclohexyl methyl-N-[2-(4-fluoro-phenyl amino)-ethyl]-succinamic acid, for yellow oil (0.52mmol, 86%), it is directly used in following reaction.

Step C: with (R)-2-cyclohexyl methyl-N-[2-(4-fluoro-phenyl amino)-ethyl]-succinamic acid (220mg, 0.52mmol) with morpholine (110 μ L, 1.26mmol, 2.4eq.) and HATU (238mg, 0.72mmol, 1.4eq.) processing.In exsiccant methylene dichloride (4mL), (315 μ L, 1.81mmol 3.5eq.) handle with diisopropyl ethyl amine with each agent dissolves.React completely by the LC/MS judgement, the evaporation volatile matter will react the purifying with preparation type LC/MS, obtain 131mg (0.25mmol, 40%) pale solid.HPLC-MS:C ₂₃H ₃₄FN ₃O ₃(M+H ⁺) calculated value 420.3, measured value 420.5.

Embodiment 10.[1-(R)-benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indoles-1-yl)-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester

According to the method described in the embodiment 5 so that 1-(R)-benzyloxymethyl-2 (5-fluoro-2,3-dihydro-indoles-1-yl)-ethylamine is that raw material has synthesized title compound.

¹H-NMR(CD ₃OD)δ7.35(m，5H)，6.78(m，1H)，6.66(m，1H)，6.42(m，1H)，5.28(m，1H)，4.52(m，2H)，3.99(m，1H)，3.60(m，11H)，3.43(m，1H)，3.14(m，2H)，2.87(m，2H)，1.80(m，1H)，1.67(m，5H)，1.42(m，2H)，1.18(m，3H)，0.92(m，2H)。HPLC-MS:C ₃₂H ₄₂FN ₃O ₅(M+H ⁺) calculated value 568.31, measured value 568.6.

Embodiment 11.[2-(5-fluoro-2,3-dihydro-indoles-1-yl)-1-(R)-methylol-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester

(50mg 0.088mmol) is dissolved in the methyl alcohol (about 1-2mL) of minimum, adds the 10%Pd/C of catalytic amount with the title compound of embodiment 10.Air purge from reaction vessel is come out, introduce H by air bag ₂Gas.With reaction mixture at H ₂After this stirred for several hour under the atmosphere monitors raw material by LCMS and disappears.Filter Pd/C, the crude product material by the reversed-phase HPLC purifying, is obtained title compound (30mg, 71% productive rate).

¹H-NMR(CD ₃OD)δ6.78(m，1H)，6.71(m，1H)，6.49(m，1H)，5.28(m，1H)，3.88(m，1H)，3.62(m，9H)，3.47(m，3H)，3.12(m，2H)，2.89(m，2H)，1.80(m，1H)，1.67(m，5H)，1.45(m，2H)，1.19(m，3H)，0.92(m，2H)。HPLC-MS:C ₂₅H ₃₆FN ₃O ₅(M+H ⁺) calculated value 478.26, measured value 478.5.

Embodiment 12. morpholines-4-formic acid 2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethylamino formyl radical]-ethyl ester

According to embodiment 1 described method so that 2-(5-fluoro-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethylamine is that raw material has synthesized title compound.

HPLC-MS:C ₂₅H ₃₆FN ₃O ₄(M+H ⁺) calculated value 462.27, measured value 462.2.

Embodiment 13.2-(R)-cyclohexyl methyl-4-morpholine-4-base-4-oxo-N-[2-(4-trifluoromethoxy-phenyl amino)-ethyl]-butyramide

Synthesize title compound according to the method described in the embodiment 6, be pale solid.HPLC-MS:C ₂₄H ₃₄F ₃N ₃O ₄(M+H ⁺) calculated value 486.3, measured value 486.4.

Embodiment 14.2-(R)-cyclohexyl methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide

Synthesize title compound according to the method described in the embodiment 6, be pale solid.HPLC-MS:C ₂₅H ₃₆F ₃N ₃O ₄(M+H ⁺) calculated value 500.3, measured value 500.4.

Embodiment 15.2-(R)-cyclopentyl-methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide

Synthesize title compound according to the method described in the embodiment 21, be the light brown solid.HPLC-MS:C ₂₄H ₃₄F ₃N ₃O ₄(M+H ⁺) calculated value 486.3, measured value 486.4.

Embodiment 16.2-(R)-cyclopentyl-methyl-3-(R)-methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide

Steps A: (620mg, 1.49mmol 1.0eq.) are dissolved among the THF (35mL), cool off in 0 ℃ of ice-water with 4-(4-(S)-benzyl-2-oxo-oxazolidines-3-yl)-3-(R)-cyclopentyl-methyl-4-oxo-tert-butyl acetate.In reaction mixture, be added in hydrogen peroxide (31w/w%) in the water (7.5mL) (654 μ L, 5.97mmol, 4.0eq.) and LiOH (72mg, 2.98mmol, 2.0eq.).To be reflected under 0 ℃ and stir, and judge by LC/MS to react completely.In reaction, add saturated sodium sulfite (18mL) and sodium bicarbonate (18mL).Evaporate THF by rotary evaporation, use CH ₂Cl ₂(3 * 75mL) aqueous layer extracted are removed chiral auxiliary(reagent).Under 0 ℃, water layer is acidified to pH～1 with 6M HCl, with ethyl acetate (4 * 75mL) extractions.With the organic extract MgSO that merges ₄Drying, filtration and evaporation obtain 281mg (1.10mmol, 73%) 2-(R)-cyclopentyl-methyl-succsinic acid 4-tert-butyl ester, are clarifying oily matter, and it directly is used among the step B.HPLC-MS:C ₁₄H ₂₄O ₄(M+Na ⁺) calculated value 279.3, measured value 279.3.

Step B: (138mg, 0.54mmol 1.0eq.) are dissolved among the exsiccant THF (3mL), are cooled to-78 ℃ in acetone/the dry ice bath with 2-(R)-cyclopentyl-methyl-succsinic acid 4-tert-butyl ester.In reaction, add lithium diisopropylamine (2.0M, in THF, 600 μ L, 1.20mmol 2.2eq.), stirred 1 hour down at-78 ℃.(40 μ L, 0.65mmol 1.2eq.), will be reflected at-78 ℃ and stir 2 hours down to add methyl iodide.Under-78 ℃, add MeOH (2mL) and react with cancellation.Remove THF and MeOH by rotary evaporation, be dissolved in the ethyl acetate (30mL).With 1M HCl (20mL), saturated NaHCO ₃(20mL) with salt water washing organic layer.Organic layer with dried over mgso, filtration and evaporation, is obtained the clarifying oily matter of 130mg (0.51,96%).Obtain 3: 1 mixtures of raw material and required product 2-(R)-cyclopentyl-methyl-3-(R)-methyl-succsinic acid 4-tert-butyl ester by this reaction.This material directly uses.HPLC-MS:C ₁₅H ₂₆O ₄(M+Na ⁺) calculated value 293.3, measured value 293.3.

Step C: prepared 3-(R)-cyclopentyl-methyl-2-(R)-methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl according to embodiment 21]-the succinic diamide tert-butyl acrylate.Separated product directly is used in it in next step reaction.HPLC-MS:C ₂₅H ₃₇F ₃N ₂O ₄(M+H ⁺) calculated value 487.3, measured value 487.4.

Step D: prepared 3-(R)-cyclopentyl-methyl-2-(R)-methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl according to embodiment 21]-succinamic acid.Separated product directly is used in it in next step reaction.HPLC-MS:C ₂₁H ₂₉F ₃N ₂O ₄(M+H ⁺) calculated value 431.2, measured value 431.4.

Step e: prepared title compound 2-(R)-cyclopentyl-methyl-3-(R)-methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl according to embodiment 21]-4-morpholine-4-base-4-oxo-butyramide.By the HPLC separated product that mass spectrum instructs, after evaporation and lyophilize, obtain 12mg white solid (0.020mmol, the productive rate in 3 steps is 3.6%).HPLC-MS:C ₂₅H ₃₆F ₃N ₃O ₄(M+H ⁺) calculated value 500.3, measured value 500.5.

Embodiment 17. morpholines-4-formic acid { 2-benzyl sulfenyl-1-(R)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethylamino formyl radical]-ethyl }-acid amides

Steps A: (1.21g, 5.75mmol 1.0eq.) are suspended in acetonitrile (18mL) and the water (1.5mL), use Et with 2-(R)-amino-3-benzyl sulfenyl-propionic acid ₃N handles, and stirs 20 minutes down at 23 ℃.Add the morpholine formyl chloride by syringe, stirred 3 hours, monitor by LC/MS.After reacting completely, will react with ethyl acetate (150mL) dilution, with 1M HCl (50mL), saturated NaHCO ₃(50mL) with the salt solution extraction.Organic layer with dried over mgso, filtration and evaporation, is obtained 2.80g 3-(R)-benzyl sulfenyl-2-[(morpholine-4-carbonyl)-amino]-propionic acid, be light yellow oil, it directly is used in next step.HPLC-MS:C ₁₅H ₂₀N ₂O ₄S (M+H ⁺) calculated value 325.1, measured value 325.3.

Step B: at room temperature, with 3-benzyl sulfenyl-2-(R)-[(morpholine-4-carbonyl)-amino]-propionic acid (182mg, 0.56mmol, 1.2eq.), derive from the N of schema 1a ¹-(4-trifluoromethoxy-phenyl)-(S)-propane-1, the 2-diamines (110mg, 0.47mmol, 1.0eq.) and HATU (185mg, 0.56mmol 1.2eq.) are dissolved in CH ₂Cl ₂(2mL).(245 μ L, 1.41mmol 3.0eq.), monitor the mixture that obtains to reacting completely by LC/MS to add DIPEA by syringe.After reacting completely, evaporating solvent, the HPLC direct purification by mass spectrum instructs obtains 22mg (0.03mmol, 5%) pale solid (list-tfa salt).HPLC-MS:C ₂₅H ₃₁F ₃N ₄O ₄S (M+H ⁺) calculated value 541.2, measured value 541.3.

Embodiment 18. morpholines-4-formic acid { 1-(R)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethylamino formyl radical]-2-phenyl methanesulfonamide acyl group-ethyl }-acid amides

Steps A: with 3-benzyl sulfenyl-2-(R)-[(morpholine-4-carbonyl)-amino]-(780mg, 2.41mmol 1.0eq.) are dissolved in CH to propionic acid ₂Cl ₂In, be placed in 0 ℃ of ice-water-bath.(1.62g, 7.22mmol 3eq.), stir it disposable adding mCPBA (77%), react completely until monitoring by LC/MS.With methyl-sulfide (5mL) cancellation reaction, evaporating solvent.HPLC direct purification by mass spectrum instructs obtains 2-(R)-[(morpholine-4-carbonyl)-amino]-3-phenyl methanesulfonamide acyl group-propionic acid, is clarifying oily matter (73mg, 0.21mmol, 9%).HPLC-MS:C ₁₅H ₂₀N ₂O ₆S (M+H ⁺) calculated value 357.1, measured value 357.3.

Step B: at room temperature, with 2-(R)-[(morpholine-4-carbonyl)-amino]-3-phenyl methanesulfonamide acyl group-propionic acid (73mg, 0.21mmol, 1.0eq.), derive from the N of schema 1a ¹-(4-trifluoromethoxy-phenyl)-(S)-propane-1, the 2-diamines (48mg, 0.21mmol, 1.0eq.), EDC (59mg, 0.31mmol, 1.5eq.) and HOBT (38mg, 0.25mmol 1.2eq.) are dissolved in CH ₂Cl ₂In.By syringe add N-methylmorpholine (225 μ L, 2.05mmol, 10eq.), complete by the LC/MS monitoring reaction.Evaporating solvent by the HPLC purifying that mass spectrum instructs, obtains 44mg (0.06mmol, 31%) pale solid with reaction, is list-tfa salt.HPLC-MS:C ₂₅H ₃₁F ₃N ₄O ₆S (M+H ⁺) calculated value 573.2, measured value 573.3.

Embodiment 19. (R)-2-cyclohexyl methyl-N-[2-(4-methoxyl group-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide

C ₂₄H ₃₇N ₃O ₄；HPLC-MS：432.5(M+H ⁺)。

Embodiment 20.2-(R)-cyclohexyl methyl-4-morpholine-4-base-4-oxo-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-butyl }-butyramide

Use suitable diamines to synthesize this compound with the method that is similar to embodiment 6.HPLC-MS:C ₂₇H ₄₀F ₃N ₃O ₄(M+H ⁺) calculated value 528.3, measured value 528.6.

Embodiment 21.2-(R)-(2-cyclohexyl-ethyl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide

Steps A: (3.4g, 20.0mmol 1.0eq.) are dissolved in exsiccant CH with 4-cyclohexyl-butyric acid ₂Cl ₂(10mL), in ice-water bath, be cooled to 0 ℃.Add several DMF (～100 μ L), then by syringe slowly add thionyl chloride (2.07mL, 20.0mmol, 1eq.).Make reaction mixture be warming up to room temperature and stirred 2 hours.Evaporating solvent directly is used in the 4-cyclohexyl-butyryl chloride that obtains among the step B without being further purified.

Step B: use 4-cyclohexyl-butyryl chloride according to Evans, D.A. etc., Tetrahedron 1988,44, and the description in 5525 is carried out.Separate (S)-4-benzyl-3-(4-cyclohexyl-butyryl radicals)-oxazolidines-2-ketone (5.65g, 17.15mmol, 88%), be white solid.HPLC-MS:C ₂₀H ₂₇NO ₃(M+Na ⁺) calculated value 352.3, measured value 352.1.

Step C: use (S)-4-benzyl-3-(4-cyclohexyl-butyryl radicals)-oxazolidines-2-ketone according to Evans, D.A. etc., J.Org.Chem.1999, the description in 64,6411 is carried out.Separate 3-(R)-(4-(S)-benzyl-2-oxo-oxazolidine-3-the carbonyl)-5-cyclohexyl-valeric acid tert-butyl ester (2.5g, 5.63mmol, 84%) obtain clarifying the oily matter form and＞20: 1 non-enantiomer mixture: ¹H NMR (CDCl ₃, 400MHz) δ 0.66-0.78 (m, 2H), 0.96-1.14 (m, 6H), 1.30 (s, 9H), and 1.32-1.56 (m, 7H), 2.34 (dd, 1H, J=16.8,4.0Hz), 2.61 (dd, 1H, J=12.4,6.0Hz), 2.66 (dd, 1H, J=16.8,10.4Hz), 3.21 (dd, 1H, J=13.6,3.2Hz), 3.96-3.21 (m, 3H), 4.55 (m, 1H), 7.13-7.23 (m, 5H).

Step D: (2.01g, 4.53mmol is 1.0eq) with 45: 50: 5 CH with 3-(R) (4-(S)-benzyl-2-oxo-oxazolidines-3-carbonyl)-5-cyclohexyl-valeric acid tert-butyl ester ₂Cl ₂: TFA: H ₂The O solution-treated.By the LC/MS monitoring reaction, afterreaction was complete in 1 hour.Evaporating solns obtains 3-(R)-(4-(S)-benzyl-2-oxo-oxazolidines-3-carbonyl)-5-cyclohexyl-valeric acid of quantitative yield, is yellow oil. ¹H NMR(CDCl ₃，400MHz)δ0.80-0.91(m，2H)，1.09-1.27(m，6H)，1.44-1.53(m，1H)，1.61-1.73(m，6H)，2.12(s，2H)，2.35(dd，1H，J＝17.2，4.0Hz)，2.49(dd，1H，J＝13.6，9.6Hz)，2.71(dd，1H，J＝17.6，10.8Hz)，3.03(dd，1H，J＝13.6，3.2Hz)，3.87-3.97(m，3H)，4.43(m，1H)，6.90-7.10(m，5H)。

Step e: with 3-(R)-(4-(S)-benzyl-2-oxo-oxazolidines-3-carbonyl)-5-cyclohexyl-valeric acid (1.76g, 4.53mmol, 1.0eq.) be dissolved among the DMF (10mL), with HATU (1.3g, 5.0mmol, 1.1eq.), morpholine (680 μ L, 7.77mmol, 1.7eq.) and DIPEA (870 μ L, 5.0mmol, 1.1eq.) processing.Perhaps the monovalent morpholine can be in reaction, re-used, CH can be used ₂Cl ₂As reaction solvent.By the LC/MS monitoring reaction.With ethyl acetate (50mL) diluted reaction mixture, with 0.5MHCl (2 * 10mL), saturated NaHCO ₃Extract with salt solution.With organic layer MgSO ₄Drying, filtration and evaporation.Directly be used in crude mixture in the step F, or by normal phase silica gel chromatography method purifying, hexane solution with the 20-50% ethyl acetate carries out gradient elution, obtain 1-(4-(S)-benzyl-2-oxo-oxazolidines-3-yl)-2-(R)-(2-cyclohexyl-ethyl)-4-morpholine-4-base-butane-1, the 4-diketone, be white solid (1.91g, 4.18mmol, 92%): ¹H NMR (CDCl ₃, 400MHz) δ 0.80-0.91 (m, 2H), 1.09-1.27 (m, 6H), 1.44-1.53 (m, 1H), 1.61-1.73 (m, 6H), 2.12 (s, 2H), 2.35 (dd, 1H, J=17.2,4.0Hz), 2.49 (dd, 1H, J=13.6,9.6Hz), 2.71 (dd, 1H, J=17.6,10.8Hz), 3.03 (dd, 1H, J=13.6,3.2Hz), 3.48-3.72 (m, 8H), 3.87-3.97 (m, 3H), 4.43 (m, 1H), 6.90-7.10 (m, 5H), 8.02 (s, 1H).

Step F: use with the identical mode of embodiment 16 steps A and remove chiral auxiliary(reagent).Separate obtaining 2-(R)-(2-cyclohexyl-ethyl)-4-morpholine-4-base-4-oxo-butyric acid, be white solid (1.0g, 3.36mmol, 80%).HPLC-MS:C ₁₆H ₂₇NO ₄(M+H ⁺) calculated value 298.2, measured value 298.1.

Step G: with 2-(R)-(2-cyclohexyl-ethyl)-4-morpholine-4-base-4-oxo-butyric acid (98mg, 0.33mmol 1.0eq.) are dissolved among the DMF (2mL), with HATU (137mg, 0.36mmol, 1.1eq.), (S)-N ¹-(4-trifluoromethoxy-phenyl)-propane-1, the 2-diamines (85mg, 0.36mmol, 1.1eq.) and DIPEA (63 μ l, 0.36mmol 1.1eq.) handle.Perhaps, according to the solvability of raw material, can use CH ₂Cl ₂As reaction solvent.By the LC/MS monitoring reaction.With reaction mixture with ethyl acetate (20mL) dilution, with 0.5M HCl (2 * 10mL), saturated NaHCO ₃Extract with salt solution.With organic layer MgSO ₄Drying, filtration and evaporation.Perhaps, the HPLC purifying that the crude reaction thing directly can be instructed by mass spectrum.The HPLC that instructs by mass spectrum obtains title compound after evaporation and lyophilize, be white solid: ¹H NMR (CD ₃OD, 400MHz) δ 0.74-0.82 (m, 2H), 1.08-1.65 (m, 13H), 1.21 (d, J=6.8Hz, 3H), 2.38 (dd, J=4.8,15.6Hz, 1H), 2.65 (m, 1H), 2.74 (dd, J=9.6,15.6Hz, 1H), 3.10 (m, 2H), 3.54-3.66 (m, 8H), 4.11 (m, 1H), 6.45 (m, 2H), 6.97 (m, 2H).HPLC-MS:C ₂₆H ₃₈F ₃N ₃O ₄(M+H ⁺) calculated value 514.3, measured value 514.2.

Embodiment 22.2-(R)-cyclohexyl methyl-4-morpholine-4-base-4-oxo-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide

Synthesized this compound with method similar to Example 6.HPLC-MS:C ₂₆H ₃₈F ₃N ₃O ₄(M+H ⁺) calculated value 514.3, measured value 514.6.

Embodiment 23.2-(R)-cyclohexyl methyl-4-morpholine-4-base-4-oxo-N-{3-phenyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide

Synthesized this compound with method similar to Example 6.HPLC-MS:C ₃₂H ₄₂F ₃N ₃O ₄(M+H ⁺) calculated value 590.3, measured value 590.6.

Embodiment 24.2-(R)-cyclohexyl methyl-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide

Synthesized this compound with method similar to Example 6.HPLC-MS:C ₂₇H ₄₀F ₃N ₃O ₄(M+H ⁺) calculated value 528.3, measured value 528.6.

Embodiment 25.5,5-dimethyl-2-(R)-(2-morpholine-4-base-2-oxo-ethyl)-caproic acid [1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-acid amides

With to Chatterjee, A.K. etc., J.Am.Chem.Soc.2003,125 (37), the preparation 5 of improving one's methods of 11360-11370, the 5-dimethyl-oneself-the 2-olefin(e) acid.With 4,4-dimethyl-1-amylene (5.0mL, 34.77mmol, 1.5eq.) and vinylformic acid (1.54mL, 22.51mmol, 1.0eq.) ([1,3-two (2,4 to join ruthenium catalyst, the 6-trimethylphenyl)-and 2-imidazolidine subunit] dichloro [[2-(1-methyl ethoxy-) phenyl] methylene radical-] ruthenium, 282mg, 0.45mmol is 2mol%) at CH ₂Cl ₂In solution, being heated under nitrogen atmosphere refluxes reaches 12 hours.With the brown solution CH that obtains ₂Cl ₂Dilution is with 1M NaOH (3 * 15mL) washings.Organic phase with 4M HCl (20mL) acidifying, is used EtOAc (3 * 25mL) extractions.With the organism that merges with the salt water washing, use MgSO ₄Drying, filtration and evaporation obtain intermediate 5, the 5-dimethyl-oneself-the 2-olefin(e) acid, be light brown oily thing (3.16g, 22.21mmol, 99%): ¹H NMR (CDCl ₃, 400MHz) δ 0.94 (s, 9H), 2.11 (d, 2H, J=8.0Hz), 5.82 (d, 1H, J=16.0Hz), 7.12 (dt, 1H, J=16.0,8.0Hz).

With 5,5-dimethyl-own-2-olefin(e) acid is reduced into 5,5-dimethyl-caproic acid by the method described in the embodiment 26 step B.

With 5,5-dimethyl-caproic acid is converted into title compound with the method described in the embodiment 21.

¹H NMR(CD ₃OD，400MHz)δ0.80(s，9H)，1.18(m，2H)，1.21(d，J＝6.8Hz，3H)，1.43-1.52(m，2H)，2.40(dd，J＝4.8，16Hz，1H)，2.61(m，1H)，2.76(dd，J＝9.6，15.6Hz，1H)，3.11(m，2H)，3.52-3.65(m，8H)，4.10(m，1H)，6.64(m，2H)，6.98(m，2H)。HPLC-MS:C ₂₄H ₃₆F ₃N ₃O ₄(M+H ⁺) calculated value 488.3, measured value 488.2.

Embodiment 26.4,4-dimethyl-2-(R)-(2-morpholine-4-base-2-oxo-ethyl)-valeric acid [1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-acid amides

Steps A: (13.35mL, 73.6mmol 1.05eq.) are dissolved among the THF (30mL), are cooled to-78 ℃ in acetone-the dry ice bath with diethyl phosphoryl methyl acetate.Go through slowly added in 20 minutes n-BuLi (solution of 1.6M in hexane) (45.8mL, 73.2mmol, 1.05eq.).(6.0g, 69.6mmol 1.0eq.), stirred 20 minutes down at-78 ℃, were warming up to room temperature and stirred and spend the night to add trimethyl-acetaldehyde in reaction.Add entry (30mL) cancellation, with ether (3 * 100mL) extractions.With the organism salt water washing that merges, use MgSO ₄Drying is filtered and evaporation, obtains 4, and 4-dimethyl-penta-2-olefin(e) acid methyl esters is colourless liquid (8.52g, 60.0mmol, 86%), and it directly is used in next step reaction. ¹H NMR(CDCl ₃，400MHz)δ0.89(s，9H)，3.64(s，3H)，5.64(d，1H，J＝16.0Hz)，6.88(d，1H，J＝16.0Hz)。

Step B: with 4, (8.52g 60.0mmol) is dissolved in MeOH (30mL) and the ethyl acetate (30mL) 4-dimethyl-penta-2-olefin(e) acid methyl esters.In reaction, add palladium carbon (10wt%) (～50mg) and place (1atm) under the hydrogen capsule.To react and stir 12 hours, use nitrogen wash, filter by Celite pad.Evaporation obtains 4, and 4-dimethyl-methyl valerate (7.0g, 48.5mmol, 81%) is colorless oil: ¹H NMR (CDCl ₃, 400MHz) δ 0.89 (s, 9H), 1.53-1.57 (m, 2H), 2.26-2.30 (m, 2H), 3.67 (s, 3H).

Step C: with 4, (7.0g, 48.5mmol is 1.0eq.) with NaOH (4.0g, 100mmol, 2.1eq.) solution-treated in water (5mL) for 4-dimethyl-methyl valerate.This homogeneous phase solution was stirred 4-5 hour.To react and use CH ₂Cl ₂CH is used in dilution ₂Cl ₂(50mL * 3) aqueous layer extracted.Water layer is acidified to pH～1.5 with 6M HCl, with ethyl acetate (50mL * 3) extraction.The ethyl acetate that merges is partly used MgSO ₄Drying, filtration and evaporation obtain 4, and 4-dimethyl-valeric acid (5.35g, 41.1mmol, 85%) is colorless oil: ¹H NMR (CDCl ₃, 400MHz) δ 0.89 (s, 9H), 1.53-1.57 (m, 2H), 2.26-2.30 (m, 2H).

Use the method described in the embodiment 21 with 4,4-dimethyl-valeric acid is converted into title compound.

¹H NMR(CD ₃OD，400MHz)δ0.90(s，9H)，1.18(d，J＝6.8Hz 3H)，1.20-1.29(m，2H)，1.77(dd，J＝9.2，14Hz，1H)，2.39(dd，J＝6.4，15.6Hz，1H)，2.61(dd，J＝8.4，15.6Hz，1H)，2.82(m，1H)，2.99-3.05(m，1H)，3.21(dd，J＝6.8，12.8Hz，1H)，3.50-3.65(m，8H)，4.04(m，1H)，6.63-6.66(m，2H)，6.96-6.99(m，2H)。HPLC-MS:C ₂₃H ₃₄F ₃N ₃O ₄(M+H ⁺) calculated value 474.3, measured value 474.2.

Embodiment 27.2-(R)-cyclopentyl-methyl-4-morpholine-4-base-4-oxo-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-butyl }-butyramide

According to embodiment 21 synthetic these compounds.HPLC-MS:C ₂₆H ₃₈F ₃N ₃O ₄(M+H ⁺) calculated value 514.3, measured value 514.5.

Embodiment 28.2-(R)-cyclohexyl methyl-N-{3-methylsulfonyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide.

According to embodiment 6 synthetic these compounds.HPLC-MS:C ₂₇H ₄₀F ₃N ₃O ₆S (M+H ⁺) calculated value 592.3, measured value 592.5.

Embodiment 29.2-(R)-cyclohexyl methyl-N-{3-methylsulfonyl-1-(R)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide

Separation from embodiment 28 synthetic obtains this compound as in a small amount diastereomer.HPLC-MS:C ₂₇H ₄₀F ₃N ₃O ₆S (M+H ⁺) calculated value 592.3, measured value 592.5.

Embodiment 30.2-(R)-(2-morpholine-4-base-2-oxo-ethyl)-5-phenyl-pentanoic acid { 2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl] propyl group }-acid amides

Synthesized this compound according to embodiment 21.HPLC-MS:C ₂₉H ₃₈F ₃N ₃O ₄(M+H ⁺) calculated value 550.3, measured value 550.5.

Embodiment 31.2-(R)-cyclopentyl-methyl-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide

Synthesized this compound according to embodiment 21. ¹H NMR(CD ₃OD，400MHz)δ0.96(d，J＝6.8Hz，3H)，0.98(d，J＝6.8Hz，3H)，1.03-1.93(m，12H)，2.39(dd，J＝4.4，15.2Hz，1H)，2.70-2.76(m，1H)，3.11(dd，J＝8.4，12.8Hz，1H)，3.26(dd，J＝4.0，12.4Hz，1H)，3.52-3.66(m，8H)，3.87(m，1H)，6.59-6.63(m，2H)，6.98-7.00(m，2H)。HPLC-MS:C ₂₆H ₃₈F ₃N ₃O ₄(M+H ⁺) calculated value 514.3, measured value 514.2.

Embodiment 32.N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-2-(R)-styroyl-butyramide

According to embodiment 21 synthetic these compounds. ¹H NMR(CD ₃OD，400MHz)δ0.97(d，J＝6.8Hz，3H)，1.0(d，J＝6.8Hz，3H)，1.70-1.94(m，3H)，2.43(dd，J＝3.2，14.8Hz，1H)，2.55-2.60(m，2H)，2.80(m，1H)，3.14(dd，J＝9.2，13.2Hz，1H)，3.28(m，1H)，3.51-3.63(m，8H)，3.93(m，1H)，4.61(bs，1H)，6.60(m，2H)，6.95(m，2H)，7.05-7.18(m，5H)。HPLC-MS:C ₂₈H ₃₆F ₃N ₃O ₄(M+H ⁺) calculated value 536.3, measured value 536.5.

Embodiment 33.2-(R)-(2-cyclopentyl-ethyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide

Use synthetic this compound of allyl group cyclopentenes according to embodiment 25.

¹H NMR(CD ₃OD，400MHz)δ0.97(d，J＝6.8Hz，3H)，1.0(d，J＝6.8Hz，3H)，1.30-1.69(m，12H)，1.90(m，1H)，2.38(m，1H)，2.75-2.82(m，2H)，3.11(dd，J＝8.4，12.4Hz，1H)，3.26(dd，J＝4.4，12.4Hz，1H)，3.54-3.67(m，8H)，3.89(m，1H)，6.59-6.65(m，2H)，6.97-7.00(m，2H)。HPLC-MS:C ₂₇H ₄₀F ₃N ₃O ₄(M+H ⁺) calculated value 528.3, measured value 528.5.

Embodiment 34.N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-2-(S)-phenyl-butyramide

According to embodiment 21 synthetic these compounds.HPLC-MS:C ₂₆H ₃₂F ₃N ₃O ₄(M+H ⁺) calculated value 508.2, measured value 508.4.

Embodiment 35.2-(S)-cyclohexyl-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide

According to embodiment 21 synthetic these compounds.HPLC-MS:C ₂₆H ₃₈F ₃N ₃O ₄(M+H ⁺) calculated value 514.3, measured value 514.4.

Embodiment 36.2-(R)-(2-cyclopentyl-ethyl)-4-morpholine-4-base-4-oxo-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide

According to embodiment 25 synthetic these compounds. ¹H NMR(CD ₃OD，400MHz)δ1.13(t，J＝6.8Hz，3H)，1.14-1.84(m，14H)，2.55(dd，J＝3.6，14.8Hz，1H)，2.87-2.95(m，2H)，3.31(d，J＝6.8Hz)，3.69-3.81(m，8H)，4.05(m，1H)，6.82-6.85(m，2H)，7.15-7.17(m，2H)。HPLC-MS:C ₂₆H ₃₈F ₃N ₃O ₄(M+H ⁺) calculated value 514.3, measured value 514.3.

Embodiment 37.2-(R)-(2-cyclopentyl-ethyl)-4-morpholine-4-base-4-oxo-N-{3-phenyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide

According to embodiment 25 synthetic these compounds. ¹H NMR(CD ₃OD，400MHz)δ1.15(m，2H)，1.47-2.10(m，14H)，5.57(m，1H)，2.70-2.99(m，3H)，3.12-3.35(m，2H)，3.69-3.84(m，8H)，4.20(m，1H)，6.80-6.82(m，2H)，7.14-7.16(m，2H)，7.31-7.40(m，5H)。HPLC-MS:C ₃₂H ₄₂F ₃N ₃O ₄(M+H ⁺) calculated value 590.3, measured value 590.3.

Embodiment 38.4-morpholine-4-base-4-oxo-2-(R)-styroyl-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide

According to embodiment 21 synthetic these compounds. ¹H NMR(CD ₃OD，400MHz)δ0.98(t，J＝7.2Hz，3H)，1.45-1.90(m，4H)，2.40-2.50(m，1H)，2.58-2.62(m，2H)，2.80-2.82(m，2H)，3.19(d，J＝6.8Hz，2H)，3.51-3.65(m，8H)，3.95(m，1H)，6.68-6.70(m，2H)，6.98-6.99(m，2H)，7.00-7.21(m，5H)。HPLC-MS:C ₂₇H ₃₄F ₃N ₃O ₄(M+H ⁺) calculated value 522.3, measured value 522.2.

Embodiment 39.4-morpholine-4-base-4-oxo-2-(S)-phenyl-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-butyl }-butyramide

According to embodiment 21 synthetic these compounds. ¹H NMR(CD ₃OD，400MHz)δ0.81(t，J＝7.2Hz，3H)，1.20-1.43(m，4H)，2.52(dd，J＝4.8，16Hz，1H)，2.85-2.95(m，2H)，3.11(dd，J＝10，16Hz，1H)，3.38-3.50(m，8H)，3.86(m，1H)，3.92(dd，J＝4.8，10.4Hz，1H)，6.34-6.36(m，2H)，6.78-6.80(m，2H)，7.15-7.26(m，5H)。HPLC-MS:C ₂₆H ₃₂F ₃N ₃O ₄(M+H ⁺) calculated value 508.3, measured value 508.2.

Embodiment 40.4-morpholine-4-base-4-oxo-2-(S)-phenyl-N-{3-phenyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide

According to embodiment 21 synthetic these compounds. ¹H NMR(CD ₃OD，400MHz)δ1.76-1.90(m，2H)，2.58-2.65(m，2H)，2.72-2.77(m，1H)，3.00-3.10(m，2H)，3.24-3.30(m，1)，3.49-3.66(m，8H)，3.97(m，1H)，4.09(dd，J＝4.8，10.4Hz，1H)，5.43-6.46(m，2H)，6.87-6.89(m，2H)，7.18-7.40(m，10H)。HPLC-MS:C ₃₁H ₃₄F ₃N ₃O ₄(M+H ⁺) calculated value 570.3, measured value 570.2.

Embodiment 41.2-(S)-(4-fluoro-phenyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide

According to embodiment 21 synthetic these compounds.HPLC-MS:C ₂₆H ₃₁F ₄N ₃O ₄(M+H ⁺) calculated value 526.2, measured value 526.5.

Embodiment 42.2-(S)-(4-chloro-phenyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide

According to embodiment 21 synthetic these compounds.HPLC-MS:C ₂₆H ₃₁ClF ₃N ₃O ₄(M+H ⁺) calculated value 542.2, measured value 542.5.

Embodiment 43.2-(R)-(4-chloro-phenyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide

Separation from embodiment 42 synthetic obtains this compound as minor by-products.HPLC-MS:C ₂₆H ₃₁ClF ₃N ₃O ₄(M+H ⁺) calculated value 542.2, measured value 542.5.

Embodiment 44.4-morpholine-4-base-4-oxo-2-(S)-phenyl-N-[1-(S)-phenyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-butyramide

According to embodiment 21 synthetic these compounds.HPLC-MS:C ₂₉H ₃₀F ₃N ₃O ₄(M+H ⁺) calculated value 542.2, measured value 542.5.

Embodiment 45.2-(R)-cyclohexyl methyl-4-morpholine-4-base-4-oxo-N-[1-(S)-phenyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-butyramide

According to embodiment 6 synthetic these compounds.HPLC-MS:C ₃₀H ₃₈F ₃N ₃O ₄(M+H ⁺) calculated value 562.3, measured value 562.5.

Embodiment 46.2-(R)-(2-cyclopentyl-ethyl)-4-morpholine-4-base-4-oxo-N-[1-(S)-phenyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-butyramide

According to embodiment 25 synthetic these compounds. ¹H NMR(CD ₃OD，400MHz)δ1.15-1.64(m，2H)，1.42-1.85(m，12H)，2.44(dd，J＝3.6，10.8Hz，1H)，2.83-2.92(m，2H)，3.55-3.65(m 9H)，5.28(t，J＝7.2Hz，1H)，6.77-6.80(m，2H)，7.12-7.14(m，2H)，7.39-7.53(m，5H)。HPLC-MS:C ₃₀H ₃₈F ₃N ₃O ₄(M+H ⁺) calculated value 562.3, measured value 562.5.

Embodiment 47.2-(R)-(2-morpholine-4-base-2-oxo-ethyl)-penta-obtusilic acid the 2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-acid amides

According to embodiment 21 synthetic these compounds. ¹H NMR(CD ₃OD，400MHz)δ0.97(d，J＝6.8Hz，3H)，0.98(d，J＝6.8Hz，3H)，1.88-1.93(m，1H)，2.15-2.32(m，2H)，2.40(dd，J＝4，16Hz，1H)，2.73-2.82(m，1H)，2.85-2.90(m，1H)，31.0-3.13(m，1H)，3.24-3.31(m，1H)，3.51-3.67(m，8H)，3.90(m，1H)，4.97-5.08(m，2H)，5.74-5.81(m，1H)，6.61-6.63(m，2H)，6.98-7.01(m，2H)。HPLC-MS:C ₂₃H ₃₂F ₃N ₃O ₄(M+H ⁺) calculated value 472.3, measured value 472.2.

Embodiment 48.2-(S)-(4-chloro-phenyl)-4-morpholine-4-base-4-oxo-N-[1-(S)-phenyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-butyramide

According to embodiment 21 synthetic these compounds. ¹H NMR(CD ₃OD，400MHz)δ2.63(dd，J＝4.4，15.6Hz，1H)，3.26(dd，J＝10.0，16Hz，1H)，3.42-3.69(m，9H)，4.14-4.21(m，1H)，5.13(dd，J＝6，8.8Hz，1H)，6.50-6.53(m，2H)，6.97-7.00(m，2H)，7.27-7.52(m，10H)。HPLC-MS:C ₂₉H ₂₉ClF ₃N ₃O ₄(M+H ⁺) calculated value 576.2, measured value 576.1.

Embodiment 49. (R)-5,5-dimethyl-2-(2-morpholine-4-base-2-oxo-ethyl)-caproic acid [2-(5-methyl-isoxazole-3-base amino)-ethyl]-acid amides

C ₂₀H ₃₄N ₄O ₄；HPLC-MS：395.5(M+H ⁺)。

Embodiment 50.2-(R)-cyclohexyl methyl-4-(cis-2,6-dimethyl-morpholine-4-yl)-N[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-oxo-butyramide

Use cis-2 according to embodiment 6, the 6-thebaine synthesizes this compound. ¹H NMR(CD ₃OD，400MHz)δ0.79-0.85(m，2H)，1.06-1.21(m，14H)，1.42-1.82(m，6H)，2.22-2.40(m，2H)，2.61-2.76(m，3H)，3.01-3.13(m，2H)，3.36-3.55(m，2H)，3.77-3.81(m，1H)，4.05(m，1H)，4.26-4.29(m，1H)，6.62-6.65(m，2H)，6.95-6.97(m，2H)。HPLC-MS:C ₂₇H ₄0F ₃N ₃O ₄(M+H ⁺) calculated value 528.3, measured value 528.6.

Embodiment 51.2-(R)-cyclohexyl methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-oxo-4-thiomorpholine-4-base-butyramide

Use synthetic this compound of thiomorpholine according to embodiment 6. ¹H NMR(CD ₃OD，400MHz)δ0.81-0.85(m，2H)，1.08-1.23(m，5H)，1.19(d，J＝6.8Hz，3H)，1.42-1.83(m，6H)，2.35(dd，J＝4.4，15.6Hz，1H)，2.50-2.76(m，6H)，3.09(dd，J＝5.6，12.4Hz，1H)，3.20(dd，J＝7.6，12.8Hz，1H)，3.66-3.85(m，4H)，4.01-4.07(m，1H)，6.73-6.75(m，2H)，7.01-7.03(m，2H)。HPLC-MS:C ₂₅H ₃₆F ₃N ₃O ₄(M+H ⁺) calculated value 516.2, measured value 516.5.

Embodiment 52.4-(4-ethanoyl-piperazine-1-yl)-2-(R)-cyclohexyl methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-oxo-butyramide

Use synthetic this compound of 1-ethanoyl-piperazine according to embodiment 6. ¹H NMR(CD ₃OD，400MHz)δ0.74-0.78(m，2H)，0.98-1.16(m，5H)，1.11(d，J＝6.8Hz，3H)，1.36-1.76(m，6H)，2.01(s，3H)，2.30-2.35(m，1H)，2.59-2.72(m，2H)，2.98(dd，J＝6.0，12.8Hz，1H)，3.07-3.09(m，2H)，3.35-3.54(m，8H)，3.96-4.01(m，1H)，6.59-6.61(m，2H)，6.90-6.92(m，2H)。HPLC-MS:C ₂₇H ₃₉F ₃N ₃O ₄(M+H ⁺) calculated value 541.3, measured value 541.6.

Embodiment 53.2-(S)-(4-methoxyl group-phenyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide

According to embodiment 21 synthetic these compounds.HPLC-MS:C ₂₇H ₃₄F ₃N ₃O ₅(M+H ⁺) calculated value 538.3, measured value 538.5.

Embodiment 54.2-(R)-cyclohexyl methyl-N-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-4-morpholine-4-base-4-oxo-butyramide

HPLC-MS：C ₂₈H ₄₂FN ₃O ₃(M+1)＝488.4。

Embodiment 55.N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide

According to embodiment 21 synthetic these compounds.HPLC-MS:C ₂₇H ₃₁F ₆N ₃O ₄(M+H ⁺) calculated value 576.2, measured value 576.5.

Embodiment 56.N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-2-(R)-(4-trifluoromethyl-phenyl)-butyramide

In embodiment 55 synthetic, synthesized this compound as minor by-products.HPLC-MS:C ₂₇H ₃₁F ₆N ₃O ₄(M+H ⁺) calculated value 576.2, measured value 576.5.

Embodiment 57.N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-2-(S)-p-methylphenyl-butyramide

According to embodiment 21 synthetic these compounds.HPLC-MS:C ₂₇H ₃₄F ₃N ₃O ₄(M+H ⁺) calculated value 522.3, measured value 522.5.

Embodiment 58.2-(R)-cyclohexyl methyl-4-(1,1-dioxo-thiomorpholine-4-yl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-oxo-butyramide

Synthesized this compound with method similar to Example 6.Title compound with oxone (OXONE) oxidation embodiment 51 obtains sulfone.Use is at McCarthy, Org.Synth. such as J.R., CV9, the method described in 446. ¹H NMR(CD ₃OD，400MHz)δ0.73-0.79(m，2H)，1.00-1.19(m，7H)，1.10(d，J＝6.8Hz)，1.34-1.75(m，6H)，2.34-2.37(m，1H)，2.64-2.71(m，2H)，2.94-3.08(m，7H)，3.79-4.01(m，5H)，6.53-6.56(m，2H)，6.87-6.89(m，2H)。HPLC-MS:C ₂₅H ₃₆F ₃N ₃O ₅S (M+H ⁺) calculated value 548.2, measured value 548.2.

Embodiment 59.2-(R)-(3-ethyl-3-hydroxyl-cyclohexyl methyl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide

¹H NMR(CD ₃OD，400MHz)δ0.70(t，J＝7.6Hz，3H)，0.95-1.57(m，13H)，1.12(d，J＝6.8Hz，3H)，2.30(dd，J＝4.4，15.6Hz，1H)，2.58-2.64(m，1H)，2.72(m，1H)，3.00(dd，J＝5.2，12.4Hz，1H)，3.07(dd，J＝7.6，12.4Hz，1H)，3.38-3.57(m，8H)，4.02-4.04(m，1H)，6.58-6.61(m，2H)，6.91-6.93(m，2H)。HPLC-MS:C ₂₇H ₄₀F ₃N ₃O ₅(M+H ⁺) calculated value 544.3, measured value 544.2.

Embodiment 60.N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide

According to embodiment 21 synthetic these compounds.HPLC-MS:C ₂₅H ₂₇F ₆N ₃O ₄(M+H ⁺) calculated value 548.2, measured value 548.4.

Embodiment 61.N-[1-(S)-methyl-2-(4-trifluoromethyl-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-2-(S)-phenyl-butyramide

According to embodiment 21 synthetic these compounds.HPLC-MS:C ₂₄H ₂₈F ₃N ₃O ₄(M+H ⁺) calculated value 480.2, measured value 480.4.

Embodiment 62.2-(S)-(4-fluoro-phenyl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide

According to embodiment 21 synthetic these compounds.HPLC-MS:C ₂₄H ₂₇F ₄N ₃O ₄(M+H ⁺) calculated value 498.2, measured value 498.4.

Embodiment 63.2-(S)-(4-methoxyl group-phenyl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide

According to embodiment 21 synthetic these compounds.HPLC-MS:C ₂₅H ₃₀F ₃N ₃O ₅(M+H ⁺) calculated value 510.2, measured value 510.4.

Embodiment 64.2-(S)-(4-fluoro-phenyl)-N-{1-(S)-[(6-methoxyl group-pyridine 3-base is amino)-methyl]-2-methyl-propyl group }-4-morpholine-4-base-4-oxo-butyramide

Steps A: with 2-(S)-(4-fluoro-phenyl)-4-morpholine-4-base-4-oxo-butyric acid (2.00g, 7.11mmol, 1.0eq.), 2-(S)-amino-3-methyl-butane-1-alcohol (1.59g, 7.33mmol, 1.03eq.) and HATU (2.41g, 7.33mmol 1.03mmol) are dissolved in CH ₂Cl ₂In and at room temperature stir.By syringe add diisopropyl ethyl amine (3.9mL, 21.98mmol, 3.1eq.), by the LC/MS monitoring reaction.After reacting completely, evaporation reaction, with ethyl acetate (100mL) dilution, with 0.5M HCl (2 * 30mL), saturated NaHCO ₃Extract with salt solution.With organic layer MgSO ₄Drying, filtration and evaporation.Handle with column chromatography, with the hexane solution gradient elution of (0-100%) EtOAc, obtain 2-(S)-(4-fluoro-phenyl)-N-(1-(S)-methylol-2-methyl-propyl group)-4-morpholine-4-base-4-oxo-butyramide, be clarifying oily matter (1.06g, 2.89mmol, 41%).HPLC-MS:C ₁₉H ₂₇FN ₂O ₄(M+H ⁺) calculated value 367.2, measured value 367.4; TLC (the R of 1: 1 hexane/EtOAc) _f=0.15.

Step B: with 2-(S)-(4-fluoro-phenyl)-N-(1-(S)-methylol-2-methyl-propyl group)-(2.31g, 6.30mmol 1.0eq.) are dissolved in CH to 4-morpholine-4-base-4-oxo-butyramide ₂Cl ₂Also at room temperature stir (32mL).Disposable adding Dess-Martin cross iodine alkane (2.67g, 6.30mmol, 1.0eq.), by LC/MS and TLC monitoring reaction.After reacting completely,, use 1M Na with EtOAc (200mL) diluting reaction ₂S ₂O ₃(100mL), NaHCO ₃(100mL) with the salt solution extraction.With organic phase MgSO ₄Drying, filtration and evaporation obtain 2-(S)-(4-fluoro-phenyl)-N-(1-(S)-formyl radical-2-methyl-propyl group)-4-morpholine-4-base-4-oxo-butyramide (1.41g, 3.89mmol, 62%), and it directly is used in next step.HPLC-MS:C ₁₉H ₂₅FN ₂O ₄(M+H ⁺) calculated value 365.2, measured value 365.4.

Step C: at room temperature; with 2-(S)-(4-fluoro-phenyl)-N-(1-(S)-formyl radical-2-methyl-propyl group)-4-morpholine-4-base-4-oxo-butyramide (350mg; 0.96mmol; 1.0eq.) and 5-amino-2-methoxyl group-pyridine (240 μ L; 1.92mmol, 2.0eq.) be dissolved among the MeOH (2.5mL), add acetate (106mL by syringe; 1.92mmol, 2.0eq.).Disposable adding sodium cyanoborohydride (121mg, 1.92mmol, 2.0eq.), by the LC/MS monitoring reaction.After reacting completely, evaporating solvent also is dissolved among the EtOAc (100mL), uses the salt water washing, uses MgSO ₄Drying is filtered and evaporation.HPLC purifying by preparation type mass spectrum instructs obtains title compound after evaporation and lyophilize, be white solid (2.6mg, 5.6 mol, 0.6%).HPLC-MS:C ₂₅H ₃₃FN ₄O ₄(M+H ⁺) calculated value 473.3, measured value 473.5.

Embodiment 65.N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-2-(R)-spiral shell [2.5] suffering-6-ylmethyl-butyramide

Steps A: use from Della J.Org.Chem.1993 such as E.W., 58,2110 method is that raw material has synthesized 4-methylene radical-naphthenic acid ethyl ester (9.0g, 65.1mmol with the 4-oxo-naphthenic acid ethyl ester of commercially available acquisition, 91%), it directly is used in next step reaction. ¹H NMR(CHCl ₃，400MHz)δ1.23-1.27(m，3H)，1.55-1.62(m，2H)，1.97-2.09(m，4H)，2.31-2.46(m，3H)，4.09-4.19(m，2H)，4.64(s，2H)。

Step B: described in the reduction reaction such as above-mentioned reference of the 4-methylene radical-naphthenic acid ethyl ester that carries out with LAH.By the distillation purifying product, obtain (4-methylene radical-cyclohexyl)-methyl alcohol, be clarifying oily matter (overall yield of steps A and B is 50% for 3.67g, 29.09mmol).

Step C: as Boehm, J.Med.Chem.1995 such as M.F. described in 38,3146 carry out (4-methylene radical-cyclohexyl)-methyl alcohol Cyclopropanatedly, obtain spiral shell [2.5] suffering-6-base-methyl alcohol (340mg, 2.42mmol, 75%), are faint yellow oily thing. ¹H NMR(CHCl ₃，400MHz)δ0.17-0.27(m，4H)，0.88-0.91(m，2H)，1.09-1.25(m，2H)，1.52-1.54(m，2H)，1.69-1.75(m，3H)，3.49-3.51(m，2H)。

Step D: (2.57g, 18.3mmol 1.0eq.) are dissolved in CH with spiral shell [2.5] suffering-6-base-methyl alcohol ₂Cl ₂(30mL) and be placed in ice-water-bath of 0 ℃.(7.9g, 36.6mmol 2.0eq.), under agitation make reaction be warming up to room temperature and reach 4 hours to add pyridinium dichromate (PCC).Crude reaction is filtered by Celite pad, use CH ₂Cl ₂Washing and evaporation.The crude product substance dissolves in ether, by diatomite filtration, is washed for several times with ether.Evaporating solvent obtains spiral shell [2.5] octane-6-formaldehyde, for brown oil (2.98g, quantitative), with its direct use. ¹H NMR(CHCl ₃，400MHz)δ0.17-0.27(m，4H)，0.88-0.91(m，2H)，1.09-1.25(m，2H)，1.52-1.54(m，2H)，1.69-1.75(m，3H)，9.44(d，1H，J＝1.2Hz)。

Prepare 4-(4-(S)-benzyl-2-oxo-oxazolidines-3-yl)-4-oxo-3-(R)-spiral shell [2.5] suffering-6-ylmethyl-tert-butyl acetate according to the method described in the embodiment 26.Use Trzeciak, the improving one's methods of method described in the Synthesis such as A. 1996,1443 with this tert-butyl ester deprotection.Under nitrogen atmosphere, with 4-(4-(S)-benzyl-2-oxo-oxazolidines-3-yl)-4-oxo-3-(R)-spiral shell [2.5] suffering-6-ylmethyl-tert-butyl acetate (40mg, 0.09mmol, 1.0eq.) be dissolved in the exsiccant diox (5mL), add Et by syringe subsequently ₃N (200 μ L, 1.43mmol, 16eq.) and TMS-Otf (200 μ L, 1.11mmol, 12.3eq.).Reaction mixture at room temperature stirred spend the night, be heated to 65 ℃ then and reach 1.5 hours.After reacting completely, add 2mL water, the evaporation volatile matter.Product is diluted water and salt solution extraction with ether.With organic layer MgSO ₄Drying, filtration and evaporation, (50mg quantitatively), is white solid, and it directly is used in next step to obtain 4-(4-(S)-benzyl-2-oxo-oxazolidines-3-yl)-4-oxo-3-(R)-spiral shell [2.5] suffering-6-ylmethyl-butyric acid.HPLC-MS:C ₂₃H ₂₉NO ₅(M+Na ⁺) calculated value 422.2, measured value 422.1.According to the method described in the embodiment 21 4-(4-(S)-benzyl-2-oxo-oxazolidines-3-yl)-4-oxo-3-(R)-spiral shell [2.5] suffering-6-ylmethyl-butyric acid is converted into title compound.

N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-2-(R)-spiral shell [2.5] suffering-6-ylmethyl-butyramide: ¹H NMR (CD ₃OD, 400MHz) δ 0.05-.10 (m, 4H), 0.63-1.63 (m, 10H), 1.05 (d, J=4.0Hz, 3H), 2.23 (dd, J=4.8,15.6Hz, 1H), 2.55 (dd, J=9.6,15.6Hz, 1H), 2.65 (m, 1H), 2.92 (dd, J=6.0,12.8Hz, 1H), 3.02 (dd, J=7.2,12.4Hz, 1H), and 3.32-3.51 (m, 8H), 3.92-3.96 (m, 1H), and 6.50-6.53 (m, 2H), 6.81-6.85 (m, 2H).HPLC-MS:C ₂₇H ₃₈F ₃N ₃O ₄(M+H ⁺) calculated value 526.3, measured value 526.5.

Embodiment 66.N-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide

HPLC-MS：C ₂₈H ₃₃F ₄N ₃O ₃(M+1)536.4。

Embodiment 67.2-(S)-(4-fluoro-phenyl)-N-{1-(S)-[(3-methylsulfonyl-phenyl amino)-methyl]-2-methyl-propyl group }-4-morpholine-4-base-4-oxo-butyramide

According to embodiment 64 synthetic these compounds.HPLC-MS:C ₂₆H ₃₄FN ₃O ₅S (M+H ⁺) calculated value 520.2, measured value 520.5.

Embodiment 68.N-[1-(S)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-ylmethyl)-2-methyl-propyl group]-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide

According to embodiment 21 synthetic these compounds.HPLC-MS:C ₃₀H ₃₇F ₄N ₃O ₃(M+H ⁺) calculated value 564.3, measured value 564.5.

Embodiment 69.N-[1-(S)-cyclopropyl-2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-ethyl]-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide

¹H NMR (CD ₃OD, 400MHz) δ 0.32-0.44 (m, 2H), 0.45-0.58 (m, 2H), 0.88 (s, 3H), 0.92-1.01 (m, 1H), 1.07 (s, 3H), and 1.17-1.30 (m, 1H), 2.64 (dd, 1H, J=8.7,17.3), 2.74 (d, 1H, J=8.4), 2.91 (d, 1H, J=8.8), 3.02 (dd, 1H, J=3.8,13.8), 3.15-3.28 (m, 2H), 3.42-3.68 (m, 10H), 4.11 (dd, 1H, J=4.6,9.8), (6.27 dd, 1H, J=4.4,8.0), 6.56-6.63 (m, 2H), 7.44 (d, 2H, J=8.0), 7.50 (d, 2H, J=8.4); HPLC-MS:C ₃₀H ₃₅F ₄N ₃O ₃(M+H ⁺) calculated value 562.3, measured value 562.5.

Embodiment 70.N-[1-(S)-cyclopropyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide

¹H NMR (400MHz, MeOD) δ 7.43 (d, J=8.5Hz, 2H), 7.40 (d, J=8.6Hz, 2H), and 6.74-6.79 (m, 2H), 6.30-6.36 (m, 2H), 4.00 (dd, J=10.1,4.6Hz, 1H), 3.30-3.57 (m, 8H), 3.17-3.26 (m, 1H), and 3.00-3.15 (m, 3H), 2.53 (dd, J=16.2,4.6Hz, 1H), and 0.80-0.90 (m, 1H), 0.38-0.45 (m, 1H), and 0.28-0.36 (m, 1H), 0.13-0.23 (m, 2H); HPLC-MS:C ₂₇H ₂₉F ₆N ₃O ₄(M+H ⁺) calculated value 574.5, measured value 574.4.

Embodiment 71.2-(R)-(4-methylsulfonyl-phenyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide

According to embodiment 21 synthetic these compounds, it is as separated the obtaining of diastereomer in a small amount.HPLC-MS:C ₂₇H ₃₄F ₃N ₃O ₆S (M+H ⁺) calculated value 586.2, measured value 586.4.

Embodiment 72. (S, S)-morpholine-4-formic acid 2-cyclohexyl-1-[2-(4-methoxyl group-phenyl amino)-1-methyl-ethylamino formyl radical]-ethyl }-acid amides

¹H NMR(CD ₃OD，400MHz)δ7.02(d，J＝8.6Hz，2H)，6.75(dt，J＝9.1，3.5Hz，2H)，4.2(dd，J＝9，6.8Hz，1H)，4.08(dt，J＝13，6.8Hz，1H)，3.6(m，4H)，3.36(m，4H)，3.15(m，2H)，1.68(m，5H)，1.49(m，2H)，1.18(d，J＝6.8Hz，3H)，1.16(m，3H)，0.89(m，2H)。HPLC-MS：C ₂₄H ₃₈N ₄O ₄(M+1)＝447.3。

Embodiment 73. morpholines-4-formic acid { 2-cyclopentyl-1-(S)-[2-(4-methoxyl group-phenyl amino)-1-(S)-methyl-ethylamino formyl radical]-ethyl }-acid amides

HPLC-MS：C ₂₃H ₃₆N ₄O ₄(M+1)＝433.3。

Embodiment 74. morpholines-4-formic acid (2-cyclohexyl-1-(S)-{ 3-methylsulfonyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group formamyl }-ethyl)-acid amides

According to embodiment 17 synthetic these compounds.HPLC-MS:C ₂₆H ₃₉F ₃N ₄O ₆S (M+H ⁺) calculated value 593.3, measured value 593.5.

Embodiment 75. morpholines-4-formic acid (2-cyclohexyl-1 (S)-{ 1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group formamyl }-ethyl)-acid amides

According to embodiment 17 synthetic these compounds.HPLC-MS:C ₂₅H ₃₇F ₃N ₄O ₄(M+H ⁺) calculated value 515.3, measured value 515.5.

Embodiment 76. morpholines-4-formic acid 2-cyclohexyl-1-(S)-[the 2-methyl isophthalic acid-(S)-(pyridin-3-yl amino methyl)-propyl group formamyl]-ethyl }-acid amides

According to embodiment 64 synthetic these compounds.HPLC-MS:C ₂₄H ₃₉N ₅O ₃(M+H ⁺) calculated value 446.3, measured value 446.4.

Embodiment 77. morpholines-4-formic acid { 2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(5-methyl-isoxazole-3-base amino)-ethylamino formyl radical]-ethyl }-acid amides; C ₂₁H ₃₅N ₅O ₄HPLC-MS:422.5 (M+H ⁺).

Embodiment 78. morpholines-4-formic acid { 1-(S)-[2-(benzothiazole-2-base is amino)-1-(S)-methyl-ethylamino formyl radical]-2-cyclohexyl-ethyl }-acid amides; C ₂₄H ₃₅N ₅O ₃S; HPLC-MS:474.5 (M+H ⁺).

Embodiment 79. morpholines-4-formic acid 1-(S)-[2-(benzoxazole-2-base is amino)-1-(S)-methyl-ethylamino formyl radical]-2-cyclohexyl-ethyl }-acid amides;

C ₂₄H ₃₅N ₅O ₄；HPLC-MS：458.5(M+H ⁺)。

Embodiment 80. (S, S)-morpholine-4-formic acid 2-cyclohexyl-1-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-methyl-ethylamino formyl radical]-ethyl }-acid amides

HPLC-MS：C ₂₇H ₄₁FN ₄O ₃(M+1)＝489.3。

Embodiment 81. morpholines-4-formic acid { 2-cyclohexyl-1-(S)-[1-(S)-cyclopropyl-2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-ethylamino formyl radical]-ethyl }-acid amides

¹H NMR (400MHz, MeOD) δ 7.85 (d, J=8.8Hz, 1H), 6.70 (m, 2H), 6.44 (m, 1H), 6.26 (d, J=8.0Hz, 1H), 4.27 (m, 1H), 3.62 (m, 3H), 3.53 (m, 1H), 3.26-3.38 (m, 7H), 3.09 (dd, J=8.4,3.1Hz, 1H), 3.04 (d, J=8.4Hz, 1H), 1.57-1.76 (m, 5H), 1.27 (s, 3H), 1.23 (s, 3H), 1.04-1.50 (m, 6H), 0.96 (m, 1H), 0.76-0.89 (m, 2H), 0.56 (m, 1H), 0.45 (m, 1H), 0.34 (m, 2H); HPLC-MS:C ₂₉H ₄₃FN ₄O ₃(M+H ⁺) calculated value 515.7, measured value 515.5.

Embodiment 82. morpholines-4-formic acid { 2-cyclohexyl-1-(S)-[1-(S)-cyclopropyl-2-(5-fluoro-3,3-Spirocyclopropyl-2,3-dihydro-indoles-1-yl)-ethylamino formyl radical]-ethyl }-acid amides

¹H NMR (400MHz, MeOD) δ 7.85 (d, J=8.7Hz, 1H), 6.65 (ddd, J=9.3,9.3,2.6Hz, 1H), 6.40 (dd, J=8.5,4.1Hz, 1H), 6.31 (dd, J=8.5,2.6Hz, 1H), 6.23 (d, J=7.9Hz, 1H), 4.26 (m, 1H), 3.62 (m, 4H), 3.50 (m, 2H), 3.36 (m, 10H), 3.14 (dd, J=13.8,4.6Hz, 1H), 1.66 (m, 4H), 1.43 (m, 1H), 1.34 (m, 1H), 1.15 (m, 2H), 0.819-1.08 (m, 6H), 0.56 (m, 1H), 0.46 (m, 1H), 0.34 (m, 2H); HPLC-MS:C ₂₉H ₄₂FN ₄O ₃(M+H ⁺) calculated value 513.7, measured value 513.5.

Embodiment 83.[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester

HPLC-MS:C ₂₄H ₃₅F ₃N ₃O ₅(M+H ⁺) calculated value 502.3, measured value 502.4.

Embodiment 84.[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-carboxylamine 3,3-dimethyl-1-(S)-(morpholine-4-carbonyl)-butyl ester

¹H NMR (400MHz, CDCl ₃) δ 7.00 (d, J=8.6Hz, 2H), 6.56 (d, J=8.7Hz, 2H), 5.38 (d, J=9.9Hz, 1H), 4.04-4.20 (m, 1H), and 3.87-3.97 (m, 1H), 3.42-3.80 (m, 8H), 3.10-3.20 (m, 1H), 1.81 (dd, J=15.0,10.1Hz, 1H), and 1.42-1.50 (m, 1H), 1.24 (d, J=6.7Hz, 3H), 0.95 (s, 9H); HPLC-MS:C ₂₂H ₃₃F ₃N ₃O ₅(M+H ⁺) calculated value 476.5, measured value 476.3.

Embodiment 85.[2-(4-difluoro-methoxy-phenyl amino)-1-(S)-methyl-ethyl]-carboxylamine 3,3-dimethyl-1-(S)-(morpholine-4-carbonyl)-butyl ester

¹H NMR (400MHz, CDCl ₃) δ 6.92-6.96 (m, 2H), 6.53-6.58 (m, 2H), 6.358 (dd, J=42.6,42.6Hz, 1H), 5.35-5.41 (m, 1H), 3.98-4.13 (m, 1H), 3.84-3.98 (m, 1H), 3.40-3.80 (m, 8H), and 3.10-3.20 (m, 1H), 1.81 (dd, J=14.9,10.2Hz, 1H), and 1.42-1.50 (m, 1H), 1.24 (d, J=6.7Hz, 3H), 0.95 (s, 9H); HPLC-MS:C ₂₂H ₃₄F ₂N ₃O ₅(M+H ⁺) calculated value 458.5, measured value 458.3.

Embodiment 86.{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester

According to synthetic this compound described in the embodiment 5.HPLC-MS:C ₂₆H ₃₈F ₃N ₃O ₅(M+H ⁺) calculated value 530.3, measured value 530.5.

Embodiment 87.{3-phenyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester

According to synthetic this compound described in the embodiment 5.HPLC-MS:C ₃₁H ₄₀F ₃N ₃O ₅(M+H ⁺) calculated value 592.3, measured value 592.6.

Embodiment 88.{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-butyl }-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester

Embodiment 89.[2-(4-ethanoyl sulfamyl-phenyl amino)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

C ₂₅H ₃₈N ₄O ₇S；HPLC-MS：539.5(M+H ⁺)。

Embodiment 90.[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

C ₂₇H ₄₀FN ₃O ₄；HPLC-MS：490.6(M+H ⁺)。

Embodiment 91.[1-(S)-methyl-2-(5-methyl-isoxazole-3-base amino)-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

C ₂₁H ₃₄N ₄O ₅；HPLC-MS：423.5(M+H ⁺)。

Embodiment 92. (S, S)-[1-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-base-methyl)-propyl group]-carboxylamine 1-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester

¹H NMR(CDCl ₃，400MHz)δ6.74(m，2H)，6.38(s，1H)，5.33(d，J＝7.86Hz，1H)，4.98(s，1H)，3.94(m，1H)，3.68(m，5H)，3.57(m，3H)，3.22(d，J＝8.35Hz，1H)，3.22(d，J＝8.35Hz，1H)，3.1(m，2H)，2.99(dd，J＝13.6，6.8Hz，1H)，1.7(m，7H)，1.44(m，2H)，1.26(m，10H)，1.14(m，3H)，0.91(m，2H)。HPLC-MS：C ₂₇H ₄₁FN ₄O ₃(M+1)＝504.3。(118636)

Embodiment 93.[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-(2,6-cis-dimethyl-morpholine-4-yl)-2-oxo-ethyl ester;

C ₂₉H ₄₄FN ₃O ₄；HPLC-MS：518.6(M+H ⁺)； ¹H-NMR(400MHz)□(DMSO-D ₆)7.23(m，1H)，6.79(m，1H)，6.68(m，1H)，6.35(m，1H)，5.19(m，1H)，4.11(m，1H)，3.66(m，2H)，2.79(m，1H)，2.62(m，4H)，2.19(m，1H)，1.70(m，1H)，1.53(m，4H)；1.24(m，3H)；1.02(m，18H)，0.88(m，2H)。

Embodiment 94. (S, S)-[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indoles-1-yl)-1-methyl-ethyl]-carboxylamine 2-(4-ethanoyl-piperazine-1-yl)-1-cyclohexyl methyl-2-oxo-ethyl ester; C ₂₉H ₄₃FN ₄O ₄HPLC-MS:531.7 (M+H ⁺).

Embodiment 95.[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-(4-methylsulfonyl-piperazine-1-yl)-2-oxo-ethyl ester; C ₂₈H ₄₃FN ₄O ₅S; HPLC-MS:567.6 (M+H ⁺).

Embodiment 96.[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-oxo-2-thiomorpholine-4-base-ethyl ester; C ₂₇H ₄₀FN ₃O ₃S; HPLC-MS:506.5 (M+H ⁺).

Embodiment 97.[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-(2,6-cis-dimethyl-morpholine-4-yl)-2-oxo-ethyl ester; C ₂₉H ₄₄FN ₃O ₄, HPLC-MS:518.6 (M+H ⁺).

Embodiment 98.[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 2-(4-ethanoyl-piperazine-1-yl)-1-(S)-cyclohexyl methyl-2-oxo-ethyl ester; C ₂₉H ₄₃FN ₄O ₄HPLC-MS:531.7 (M+H ⁺).

Embodiment 99.[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl]-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-(4-methylsulfonyl-piperazine-1-yl)-2-oxo-ethyl ester; C ₂₈H ₄₃FN ₄O ₅S; HPLC-MS:567.6 (M+H ⁺).

Embodiment 100.[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-oxo-2-thiomorpholine-4-base-ethyl ester; C ₂₇H ₄₀FN ₃O ₃S; HPLC-MS:506.5 (M+H ⁺).

Embodiment 101.[2-(5-fluoro-3,3-spiral shell-cyclopropyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester.

¹H NMR (400MHz, MeOD) δ 6.66 (m, 1H), 6.41 (dd, J=8.5,4.1Hz, 1H), 6.32 (dd, J=8.5,2.5Hz, 1H), 5.24 (m, 1H), 3.83 (m, 1H), 3.45-3.77 (m, 10H), 3.41 (d, J=8.6Hz, 1H), 3.15 (dd, J=13.7,7.0Hz, 1H), 3.00 (dd, J=13.7,5.8Hz, 1H), and 1.59-1.81 (m, 6H), 1.37-1.50 (m, 2H), 1.21 (d, J=6.8Hz.3H), 1.12-1.26 (m, 3H), 0.95 (m, 6H); HPLC-MS:C ₂₇H ₃₉FN ₃O ₄(M+H ⁺) calculated value 488.6, measured value 488.4.

Embodiment 102.[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-oxo-2-piperidines-1-base-ethyl ester; C ₂₈H ₄₂FN ₃O ₃HPLC-MS:488.5 (M+H ⁺).

Embodiment 103.[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-oxo-2-tetramethyleneimine-1-base-ethyl ester; C ₂₇H ₄₀FN ₃O ₃HPLC-MS:474.5 (M+H ⁺).

Embodiment 104.[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 2-cyclohexyl-1-(S)-formyl-dimethylamino-ethyl ester; C ₂₅H ₃₈FN ₃O ₃HPLC-MS:448.5 (M+H ⁺).

Embodiment 105.[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-(1,1-dioxo-1 λ ⁶-thiomorpholine-4-yl)-2-oxo-ethyl ester; C ₂₇H ₄₀FN ₃O ₅S; HPLC-MS:538.5 (M+H ⁺).

Embodiment 106.[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 2-cyclohexyl-1-(S)-[(2-methoxyl group-ethyl)-methyl-formamyl]-ethyl ester; C ₂₇H ₄₂FN ₃O ₄HPLC-MS:491.5 (M+H ⁺).

Embodiment 107.[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 2-azetidine-1-base-1-(S)-cyclohexyl methyl-2-oxo-ethyl ester; C ₂₆H ₃₈FN ₃O ₃HPLC-MS:460.5 (M+H ⁺).

Embodiment 108.[1-(S)-cyclopropyl-2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester.

¹H NMR (400MHz, CDCl ₃) δ 6.67-6.74 (m, 2H), 6.34-6.41 (m, 1H), 5.27-5.33 (m, 1H), and 5.03-5.09 (m, 1H), 3.40-3.75 (m, 8H), 3.13-3.26 (m, 4H), 1.55-1.81 (m, 6H), 1.30-1.46 (m, 2H), 1.26 (s, 3H), 1.24 (s, 3H), 1.03-1.25 (m, 3H), 0.78-0.99 (m, 3H), 0.43-0.58 (m, 2H), 0.27-0.41 (m, 2H); HPLC-MS:C ₂₉H ₄₃FN ₃O ₄(M+H ⁺) calculated value 516.3, measured value 516.5.

Embodiment 109.[1-(S)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-ylmethyl)-2-methyl-propyl group]-carboxylamine 2-morpholine-4-base-2-oxo-1-(R, S)-phenyl-ethyl ester.

According to using synthetic this compound of (L)-amygdalic acid described in the embodiment 5.Isolated in form with non-enantiomer mixture obtains this compound.HPLC-MS:C ₂₈H ₃₆FN ₃O ₄(M+H ⁺) calculated value 498.3, measured value 498.3.

Embodiment 110.[1-(S)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-ylmethyl)-2-methyl-propyl group]-carboxylamine 2-morpholine-4-base-2-oxo-1-(R)-phenyl methanesulfonamide acyl group methyl-ethyl ester.

Steps A: as preceding according to Deechongkit, S.; You, S.-L.; Kelly, J.W.Org.Lett.2004 uses (S)-Racemic glycidol acid methyl 110a and benzyl sulfhydrate to carry out this reaction described in 6,497.Separate obtaining (R)-3-benzyl sulfenyl-2-hydroxyl-methyl propionate 110b (7.41g, 31.41mmol, 92%), be heavy-gravity oily matter.MS:C ₁₁H ₁₄O ₃S (M+H ⁺) calculated value 227.1, measured value 227.3.

Step B: as preceding according to Deechongkit, S.; You, S.-L.; Kelly, J.W.Org.Lett.2004 uses (R)-3-benzyl sulfenyl-2-hydroxyl-methyl propionate 110b and lithium hydroxide to carry out this reaction described in 6,497.Separate obtaining (R)-3-benzyl sulfenyl-2-hydroxyl-propionic acid 110c (3.08g, 14.51mmol, 46%), be heavy-gravity oily matter.MS:C ₁₀H ₁₂O ₃S (M+Na ⁺) calculated value 235.1, measured value 235.3.

Step C: described in front embodiment 5, use (R)-3-benzyl sulfenyl-2-hydroxyl-propionic acid 110c to carry out this reaction.Separate obtaining (R)-3-benzyl sulfenyl-2-hydroxyl-1-morpholine-4-base-propane-1-ketone 110d (3.41g, 11.87mmol, 67%), be heavy-gravity oily matter.MS:C ₁₄H ₁₉NO ₃S (M+H ⁺) calculated value 282.1, measured value 282.4.

Step D: with oxone (2KHSO ₅KHSO ₄K ₂SO ₄) (10.55g, 17.17mmol 3.0eq.) are dissolved in H ₂O (25ml, 0.7M) in, go through 30 minutes with its join (R)-3-benzyl sulfenyl-2-hydroxyl-1-morpholine-4-base-propane-1-ketone 110d under 0 ℃ (1.61g, 5.73mmol, methanol solution 1.0eq.) (25ml, 0.3M) in.By the LC/MS monitoring reaction to reacting completely.After judging reaction safety (～12 hours), vaporising under vacuum MeOH.With the solution H that obtains ₂CH is used in O (30ml) dilution ₂Cl ₂(3 * 50ml) extractions.Merge organic layer, use MgSO ₄Dry also filtration.Under vacuum, remove organic solvent, obtain (R)-2-hydroxyl-1-morpholine-4-base-3-phenyl methanesulfonamide acyl group-propane-1-ketone 110e, be heavy-gravity oily matter (1.60g, 5.11mmol, 89%), with it without being further purified direct use.MS:C ₁₄H ₁₉NO ₅S (M+H ⁺) calculated value 314.1, measured value 314.3.

Step e: described in front embodiment 5, use (R)-2-hydroxyl-1-morpholine-4-base-3-phenyl methanesulfonamide acyl group-propane-1-ketone 110e to carry out this reaction.After the column chromatography processing, separate obtaining (R)-carbonic acid 2-morpholine-4-base-2-oxo-1-phenyl methanesulfonamide acyl group methyl-ethyl ester 4-nitro-phenyl ester 110f (1.98g, 4.14mmol, 81%), be white solid.MS:C ₂₁H ₂₂N ₂O ₉S (M+H ⁺) calculated value 479.1, measured value 479.3.

Be the feedstock production title compound as described in example 5 above with the mixed carbonate ester, it obtains so that the white solid form is separated.HPLC-MS:C ₃₀H ₄₀FN ₃O ₆S (M+H ⁺) calculated value 590.3, measured value 590.2.

Embodiment 111.[1-(S)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-ylmethyl)-2-methyl-propyl group]-carboxylamine 1-(S)-cyclohexyl-2-morpholine-4-base-2-oxo-ethyl ester.

According to synthesizing this compound with (L)-tetrahydrochysene amygdalic acid described in the embodiment 5.HPLC-MS:C ₂₈H ₄₂FN ₃O ₄(M+H ⁺) calculated value 504.3, measured value 504.6.

B. kethepsin suppresses activity test

Cathepsin S

Screen the best substrate-ethanoyl-Histidine-proline(Pro)-Xie Ansuan-Methionin-amino formamyl tonka bean camphor (Harris that has determined cathepsin S by combinatorial libraries to the fluorescence peptide substrates; J.L.; B.J.Backes etc.; Proc Natl Acad Sci USA 2000; 97 (14), 7754-9).Total reaction volume with 30 μ l has been carried out kinetic measurement in the microtiter plate of 384-hole.The cathepsin S that with final concentration is 0.3-3nM (reactive site) was hatched under room temperature 20 minutes in the damping fluid that contains 100mM NaAc (pH5.5), 1mM EDTA, 100mM NaCl, 0.01% Bian Ze-35 with the compound of 12 kinds of different concns.Do not exist the 24 parts of ground of the control reaction same form under the inhibitor situation to carry out.By adding the final concentration initiation reaction of substrate-ethanoyl-Histidine-proline(Pro)-Xie Ansuan-Methionin-amino formamyl tonka bean camphor to 50 μ M.By under the emission wavelength of the excitation wavelength of 380nm and 450nm the hydrolysis rate of measuring substrate being monitored in the increase of fluorescence, the aniline key in the described fluorescence substrate is produced by enzymatic lysis.By enzyme carry out curve determine the apparent inhibition constant of compound (Kuzmic, P., K.C.Elrod etc., Anal Biochem 2000,286 (1), 45-50), calculate the inhibition constant of competitive inhibitor then with it.

Cathepsin K

Screen the best substrate-ethanoyl-Methionin-Histidine-proline(Pro)-Methionin-amino formamyl tonka bean camphor (Harris that has determined cathepsin K by combinatorial libraries to the fluorescence peptide substrates; J.L.; B.J.Backes etc.; Proc Natl Acad Sci USA 2000; 97 (14), 7754-9).Total reaction volume with 30 μ l has been carried out kinetic measurement in the microtiter plate of 384-hole.The cathepsin K that with final concentration is 3.5nM (reactive site) was hatched under room temperature 20 minutes in the damping fluid that contains 100mM NaAc (pH5.5), 1mM EDTA, 100mM NaCl, 0.01% Bian Ze-35 with the compound of 12 kinds of different concns.Do not exist the 24 parts of ground of the control reaction same form under the inhibitor situation to carry out.By adding the final concentration initiation reaction of substrate-ethanoyl-Methionin-Histidine-proline(Pro)-Methionin-amino formamyl tonka bean camphor to 40 μ M.By under the emission wavelength of the excitation wavelength of 380nm and 450nm the hydrolysis rate of measuring substrate being monitored in the increase of fluorescence, the aniline key in the described fluorescence substrate is produced by enzymatic lysis.By enzyme carry out curve determine the apparent inhibition constant of compound (Kuzmic, P., K.C.Elrod etc., Anal Biochem 2000,286 (1), 45-50), calculate the inhibition constant of competitive inhibitor then with it.

Cathepsin L

Screen the best substrate-ethanoyl-Histidine-Methionin-phenylalanine-Methionin-amino formamyl tonka bean camphor (Harris that has determined cathepsin L by combinatorial libraries to the fluorescence peptide substrates; J.L.; B.J.Backes etc.; Proc Natl Acad Sci USA 2000; 97 (14), 7754-9).Total reaction volume with 30 μ l has been carried out kinetic measurement in the microtiter plate of 384-hole.The cathepsin L that with final concentration is 0.1nM (reactive site) hatched under room temperature 20 minutes in the damping fluid that contains 100mM NaAc (pH5.5), 1mM EDTA, 100mM NaCl, 0.01% Bian Ze-35 with the compound of 12 kinds of different concns.Do not exist the 24 parts of ground of the control reaction same form under the inhibitor situation to carry out.By adding the final concentration initiation reaction of substrate-ethanoyl-Histidine-Methionin-phenylalanine-Methionin-amino formamyl tonka bean camphor to 20 μ M.By under the emission wavelength of the excitation wavelength of 380nm and 450nm the hydrolysis rate of measuring substrate being monitored in the increase of fluorescence, the aniline key in the described fluorescence substrate is produced by enzymatic lysis.By enzyme carry out curve determine the apparent inhibition constant of compound (Kuzmic, P., K.C.Elrod etc., Anal Biochem 2000,286 (1), 45-50), calculate the inhibition constant of competitive inhibitor then with it.

Cathepsin B

Screen the best substrate-ethanoyl-Histidine-proline(Pro)-Xie Ansuan-Methionin-amino formamyl tonka bean camphor (Harris that has determined cathepsin B by combinatorial libraries to the fluorescence peptide substrates; J.L.; B.J.Backes etc.; Proc Natl Acad Sci USA 2000; 97 (14), 7754-9).Total reaction volume with 30 μ l has been carried out kinetic measurement in the microtiter plate of 384-hole.The cathepsin B that with final concentration is 1.5nM (reactive site) hatched under room temperature 20 minutes in the damping fluid that contains 100mM NaAc (pH5.5), 1mM EDTA, 100mM NaCl, 0.01% Bian Ze-35 with the compound of 12 kinds of different concns.Do not exist the 24 parts of ground of the control reaction same form under the inhibitor situation to carry out.By adding the final concentration initiation reaction of substrate-ethanoyl-Histidine-proline(Pro)-Xie Ansuan-Methionin-amino formamyl tonka bean camphor to 10 μ M.By under the emission wavelength of the excitation wavelength of 380nm and 450nm the hydrolysis rate of measuring substrate being monitored in the increase of fluorescence, the aniline key in the described fluorescence substrate is produced by enzymatic lysis.By enzyme carry out curve determine the apparent inhibition constant of compound (Kuzmic, P., K.C.Elrod etc., Anal Biochem 2000,286 (1), 45-50), calculate the inhibition constant of competitive inhibitor then with it.

The preferred cathepsin S of The compounds of this invention suppresses constant less than 10 μ M.The preferred inhibition constant of The compounds of this invention is less than 1.0 μ M.The most preferred inhibition constant of The compounds of this invention is less than 0.1 μ M.

The ratio that the cathepsin S that suppresses constant and same compound with the tissue protein enzyme isoenzyme of The compounds of this invention suppresses constant has been determined under the situation that has the tissue protein enzyme isoenzyme selectivity to cathepsin S.Cathepsin S had this ratio of preferred compound of the present invention optionally greater than 10.Cathepsin S had this ratio of the preferred compound of the present invention optionally greater than 100.Cathepsin S had this ratio of most preferred of the present invention optionally greater than 1000.

Table I: the testing data of cathepsin S inhibitor

Embodiment	K _iCathepsin S ^a	With respect to the selectivity of cathepsin K to cathepsin S ^b	With respect to the selectivity of cathepsin L to cathepsin S ^b	With respect to the selectivity of cathepsin B to cathepsin S ^b
Embodiment	K _iCathepsin S ^a				1	+	-	-	+
2	+++	++	+	+++	1	+	-	-	+
2	+++	++	+	+++	3	+++	++	+	++
4	+++	++	+	+++	3	+++	++	+	++
4	+++	++	+	+++	5	+	+	+	+
6	+	+	+	+	5	+	+	+	+
6	+	+	+	+	7	+	+	+	+
8	+++	++	++	+++	7	+	+	+	+
8	+++	++	++	+++	9	+	+	+	+
10	+++	++	+++	+++	9	+	+	+	+
10	+++	++	+++	+++	11	++	++	++	++

Embodiment	K _iCathepsin S ^a	With respect to the selectivity of cathepsin K to cathepsin S ^b	With respect to the selectivity of cathepsin L to cathepsin S ^b	With respect to the selectivity of cathepsin B to cathepsin S ^b
Embodiment	K _iCathepsin S ^a				12	++	+	+	++
13	++	++	++	++	12	++	+	+	++
13	++	++	++	++	14	+++	++	++	+++
15	+++	++	++	+++	14	+++	++	++	+++
15	+++	++	++	+++	16	++	+	+	++
17	+++	++	+	++	16	++	+	+	++
17	+++	++	+	++	18	+++	+++	++	++
19	++	++	++	++	18	+++	+++	++	++
19	++	++	++	++	20	+++	+	+	+++
21	+++	++	+++	+++	20	+++	+	+	+++
21	+++	++	+++	+++	22	+++	+	+	+++
23	+++	+	-	++	22	+++	+	+	+++
23	+++	+	-	++	24	+++	-	+	+++
25	++	++	++	++	24	+++	-	+	+++
25	++	++	++	++	26	++	-	++	++
27	+++	+	++	+++	26	++	-	++	++
27	+++	+	++	+++	28	+++	+	+	+++
29	+++	+	+	++	28	+++	+	+	+++
29	+++	+	+	++	30	+++	++	+	++
31	+++	+	++	+++	30	+++	++	+	++
31	+++	+	++	+++	32	+++	-	+	+++
33	+++	+++	+	+++	32	+++	-	+	+++
33	+++	+++	+	+++	34	+++	+	+	+++
35	+++	+	++	+++	34	+++	+	+	+++
35	+++	+	++	+++	36	+++	++	+	+++
37	+++	++	+	++	36	+++	++	+	+++
37	+++	++	+	++	38	+++	-	-	+++
39	+++	+	++	+++	38	+++	-	-	+++
39	+++	+	++	+++	40	+++	+	++	+++
41	+++	+	++	+++	40	+++	+	++	+++
41	+++	+	++	+++	42	+++	+++	++	+++
43	++	++	++	++	42	+++	+++	++	+++
43	++	++	++	++	44	++	+	++	++
45	+++	++	++	+++	44	++	+	++	++
45	+++	++	++	+++	46	+++	+++	++	+++
47	++	-	+	+	46	+++	+++	++	+++
47	++	-	+	+	48	++	+	++	++
49	+	+	+	+	48	++	+	++	++
49	+	+	+	+	50	+++	++	-	+++
51	+++	++	+	+++	50	+++	++	-	+++
51	+++	++	+	+++	52	++	+	++	++
53	++	++	++	++	52	++	+	++	++
53	++	++	++	++	54	+++	+++	++	+++
55	++	+++	++	++	54	+++	+++	++	+++
55	++	+++	++	++	56	-	-	-	-
57	++	++	++	++	56	-	-	-	-

Embodiment	K _iCathepsin S ^a	With respect to the selectivity of cathepsin K to cathepsin S ^b	With respect to the selectivity of cathepsin L to cathepsin S ^b	With respect to the selectivity of cathepsin B to cathepsin S ^b
Embodiment	K _iCathepsin S ^a				58	++	++	+	++
59	+	+	+	+	58	++	++	+	++
59	+	+	+	+	60	+	+	+	+
61	+	+	+	+	60	+	+	+	+
61	+	+	+	+	62	++	++	++	++
63	++	++	++	++	62	++	++	++	++
63	++	++	++	++	64	++	+	+	++
65	++	++	++	++	64	++	+	+	++
65	++	++	++	++	66	+	-	-	+
67	+	+	+	+	66	+	-	-	+
67	+	+	+	+	68	+++	++	+++	+++
69	++	+	++	++	68	+++	++	+++	+++
69	++	+	++	++	70	++	++	++	++
71	+	-	++	+	70	++	++	++	++
71	+	-	++	+	72	+++	++	+	++
73	+++	+	+	++	72	+++	++	+	++
73	+++	+	+	++	74	+++	+	-	+
75	+++	+	-	+	74	+++	+	-	+
75	+++	+	-	+	76	++	+	-	+
77	++	+	+	++	76	++	+	-	+
77	++	+	+	++	78	+	+	-	+
79	+	+	-	+	78	+	+	-	+
79	+	+	-	+	80	+++	+++	+	+++
81	+++	++	+	+++	80	+++	+++	+	+++
81	+++	++	+	+++	82	+++	++	-	++
83	++	++	++	++	82	+++	++	-	++
83	++	++	++	++	84	+	-	+	+
85	+	-	+	+	84	+	-	+	+
85	+	-	+	+	86	+++	++	++	+++
87	+++	++	++	+++	86	+++	++	++	+++
87	+++	++	++	+++	88	+++	+	++	+++
89	+	+	+	+	88	+++	+	++	+++
89	+	+	+	+	90	++	++	++	++
91	+	+	+	+	90	++	++	++	++
91	+	+	+	+	92	+++	+++	+++	+++
93	+	+	-	+	92	+++	+++	+++	+++
93	+	+	-	+	94	+	+	+	+
95	+	+	+	+	94	+	+	+	+
95	+	+	+	+	96	+	+	+	+
97	+	+	-	+	96	+	+	+	+
97	+	+	-	+	98	+	+	+	+
99	+	+	+	+	98	+	+	+	+
99	+	+	+	+	100	+	+	+	+
101	++	++	++	++	100	+	+	+	+
101	++	++	++	++	102	+++	+++	+++	+++
103	+++	++	+++	+++	102	+++	+++	+++	+++

Embodiment	K _iCathepsin S ^a	With respect to the selectivity of cathepsin K to cathepsin S ^b	With respect to the selectivity of cathepsin L to cathepsin S ^b	With respect to the selectivity of cathepsin B to cathepsin S ^b
Embodiment	K _iCathepsin S ^a				104	++	++	++	++
105	++	+	+	++	104	++	++	++	++
105	++	+	+	++	106	++	++	++	++
107	++	++	++	++	106	++	++	++	++
107	++	++	++	++	108	+++	+++	+++	+++
109	+	-	+	+	108	+++	+++	+++	+++
109	+	-	+	+	110	+	+	+	+
111	+++	+	++	+++	110	+	+	+	+
111	+++	+	++	+++

^aThe cathepsin S of formula I compound suppresses constant :+,＜10 μ M; ++,＜1.0 μ M; +++,＜0.1 μ M.

^bCompare the selectivity of formula I compound to cathepsin S with another kind of kethepsin :+,＞10; ++,＞100; +++,＞1000.

Although for the mode of more clearly having understood explanation by way of example and embodiment above-mentioned the present invention has been carried out detailed description to a certain degree, it is evident that and to carry out some variation and adjustment in the scope of claims.In addition, each reference that this paper provided all is incorporated herein by reference, its degree just looks like that each reference is incorporated herein by reference the same by each.

Claims

1. the compound of formula I:

Or its pharmaceutically useful salt, wherein:

R ¹And R ³Be selected from H independently of one another; C ₁-C ₆Alkoxyl group; By 0-2 R ^1aThe C that replaces ₁-C ₆Alkyl, wherein said C ₁-C ₆Alkyl randomly contain be selected from-O-,-S-,-S (=O)-and-S (=O) ₂-heteroatoms; C ₂-C ₆Alkenyl; C ₃-C ₆Alkynyl; By 0-2 R ^QThe C that replaces ₃-C ₇Cycloalkyl; With by 0-2 R ^QThe C that replaces ₇-C ₁₁Bicyclic alkyl; By 0-3 R ¹³The phenyl that replaces; Contain 1-4 the first heteroaryl of heteroatomic 5-to 6-that is selected from N, O and S independently of one another, wherein said heteroaryl is by 0-3 R ¹³Replace;

R ⁵Be selected from H; C (=O) OR ¹⁴C (=O) NR ¹⁵R ¹⁶By 0-2 R ¹³The phenyl that replaces; With contain heteroatomic 5-to the 6-unit heteroaryl that 1-4 is selected from N, O and S independently of one another, wherein said heteroaryl is by 0-2 R ¹³Replace; C ₃-C ₇Cycloalkyl; By 0-2 R ²¹The C that replaces ₁-C ₆Alkyl, wherein said C ₁-C ₆Alkyl randomly contain be selected from-O-,-S-,-S (=O)-,-S (=O) ₂-and-NR ²²-heteroatoms;

Perhaps, R ⁵And R ⁷The common C that forms ₅-C ₇Cycloalkyl, wherein said C ₅-C ₇Methylene radical in the cycloalkyl randomly is selected from-O-,-S-,-S (=O)-and-S (=O) ₂-heteroatoms substitute;

Each R ¹¹Be independently selected from H and C ₁-C ₄Alkyl;

Each R ¹⁶Be independently selected from H and C ₁-C ₄Alkyl;

Perhaps, R ²⁰And R ⁹Common formation contains 1-2 the first heterocycle of heteroatomic 5-to 7-that is selected from N, O and S independently of one another; Wherein said 5-to 7-unit's heterocycle and Ar is monolateral condenses; The first heterocycle of wherein said 5-to 7-is randomly by 0-2 R ²⁴Replace;

R ²²Be independently selected from H, ^tBOC, Cbz, C ₃-C ₈Cycloalkyl, (C ₁-C ₆Alkyl)-C (=O)-, (C ₁-C ₆Alkyl)-S (=O) ₂-, by 0-1 R ¹⁹The C that replaces ₁-C ₆Alkyl, by 0-3 R ¹³The phenyl that replaces and contain 1-4 heteroatomic 5-to 6-unit heteroaryl that is selected from N, O and S independently of one another, wherein said 5-to 6-unit heteroaryl is by 0-3 R ¹³Replace;

Each R ²³Be independently selected from H and C ₁-C ₄Alkyl;

Perhaps, two R ²⁴Can be combined to form C ₃-C ₆Cycloalkyl;

R ²⁵And R ²⁶Be selected from C independently of one another ₁-C ₆Alkyl, wherein said C ₁-C ₆Alkyl randomly contain be selected from-O-,-S-,-S (=O)-,-S (=O) ₂-and-NR ₂₂-heteroatoms.

2. the compound of claim 1, wherein said compound has following formula:

Wherein:

R ¹Be independently selected from H; By 0-1 R ^1aThe C that replaces ₁-C ₆Alkyl, wherein said C ₁-C ₆Alkyl randomly contain be selected from-O-,-S-and-S (=O) ₂-heteroatoms; C ₂-C ₆Alkenyl; By 0-2 R ^QThe C that replaces ₃-C ₇Cycloalkyl; With by 0-2 R ^QThe C that replaces ₇-C ₁₁Bicyclic alkyl; By 0-3 R ¹³The phenyl that replaces; Contain 1-4 the first heteroaryl of heteroatomic 5-to 6-that is selected from N, O and S independently of one another, wherein said heteroaryl is by 0-3 R ¹³Replace;

R ⁴Be selected from H, F, OH and C ₁-C ₆Alkyl.

3. the compound of claim 1, wherein said compound has following formula:

Wherein:

4. the compound of claim 1, wherein said compound has following formula:

Wherein:

R ³Be selected from C ₁-C ₆Alkyl; By 1 R ^1aThe C that replaces ₁-C ₄Alkyl, wherein said C ₁-C ₄Alkyl randomly contain be selected from-O-,-S-and-S (=O) ₂-heteroatoms; By 0-2 R ^QThe C that replaces ₃-C ₇Cycloalkyl; With by 0-2 R ^QThe C that replaces ₇-C ₁₁Bicyclic alkyl; By 0-3 R ¹³The phenyl that replaces;

5. the compound of claim 1, wherein said compound has following formula:

Wherein:

R ¹Be selected from C ₁-C ₆Alkyl, by 1 R ^1aThe C that replaces ₁-C ₄Alkyl, wherein said C ₁-C ₄Alkyl randomly contain be selected from-O-,-S-and-S (=O) ₂-heteroatoms;

R ⁵Be selected from H; By 0-2 R ¹³The phenyl that replaces; C ₃-C ₇Cycloalkyl; By 0-1 R ²¹The C that replaces ₁-C ₆Alkyl, wherein said C ₁-C ₆Alkyl randomly contain be selected from-O-,-S-,-S (=O) ₂-heteroatoms;

Ar is selected from by 0-3 R ²⁰The phenyl that replaces;

Perhaps, R ²⁰And R ⁹The common 5-unit heterocycle that contains 1 nitrogen-atoms that forms, wherein said 5-unit's heterocycle and Ar is monolateral condenses; The first heterocycle of wherein said 5-is randomly by 0-2 R ²⁴Replace.

6. the compound of claim 1, wherein said compound has following formula:

Wherein:

R ²Be H;

R ⁵Be selected from H, by 0-2 R ¹³The phenyl, the C that replace ₃-C ₇Cycloalkyl, by 0-1 R ²¹The C that replaces ₁-C ₆Alkyl, wherein said C ₁-C ₆Alkyl randomly contain be selected from-O-,-S-,-S (=O) ₂-heteroatoms;

Ar is selected from by 0-3 R ²⁰The phenyl that replaces;

Perhaps, R ²⁰And R ⁹The common 5-unit heterocycle that contains 1 nitrogen-atoms that forms; Wherein said 5-unit's heterocycle and Ar is monolateral condenses; The first heterocycle of wherein said 5-is randomly by 0-2 R ²⁴Replace.

7. the compound of claim 2, wherein:

Each R ²¹Be independently selected from H, OH, C (=O) OR ¹⁴, C (=O) NR ¹⁵R ¹⁶, NR ²²R ²³, by 0-3 R ¹³The phenyl and the C that replace ₃-C ₇Cycloalkyl.

8. the compound of claim 7, wherein:

R ¹Be independently selected from by 1 R ^1aThe C that replaces ₁-C ₄Alkyl, wherein said C ₁-C ₄Alkyl randomly contain be selected from-O-,-S-and-S (=O) ₂-heteroatoms; C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl is by 0-2 R ^QThe C that replaces ₃-C ₇Cycloalkyl and by 0-2 R ^QThe C that replaces ₇-C ₁₁Bicyclic alkyl; By 0-3 R ¹³The phenyl that replaces;

Each R ^1aBe independently selected from by 0-3 R ¹³The phenyl that replaces, by 0-2 R ^QThe C that replaces ₃-C ₈Cycloalkyl and by 0-2 R ^QThe C that replaces ₇-C ₁₁Bicyclic alkyl;

R ⁴Be H, F, OH, methyl, ethyl, propyl group or butyl;

Ar is by 0-3 R ²⁰The phenyl that replaces; With contain heteroatomic 5-to the 6-unit heteroaryl that 1-2 is selected from N, O and S independently of one another; Wherein said heteroaryl is by 0-2 R ²⁰Replace.

9. the compound of claim 8, wherein:

Q is selected from following heterocycle: azetidinyl, pyrrolidyl, piperidyl, piperazinyl, 4-ethanoyl piperazinyl, 4-methyl sulphonyl piperazinyl, morpholinyl, thio-morpholinyl, 1,1-dioxo-1 λ ⁶-thio-morpholinyl, 2,6-dimethylated morpholinyl and 3, the 5-dimethylated morpholinyl, wherein Q by theheterocyclic nitrogen atom and-C (=O) link to each other;

R ¹Be independently selected from cyclohexyl methyl, 4,4-dimethyl-cyclohexyl methyl, spiral shell [2,5] suffering-6-ylmethyl, spiral shell [3,5] ninth of the ten Heavenly Stems-7-ylmethyl, the cyclohexyl ethyl, cyclopentyl-methyl, the cyclopentyl ethyl, cyclobutylmethyl, the cyclobutyl ethyl, the cyclopropyl methyl, the cyclopropyl ethyl, allyl group, butenyl, cyclopentyl, cyclohexyl, tertiary butyl methyl, tertiary butyl ethyl, 4-ethyl-4-hydroxyl-cyclohexyl methyl, styroyl, phenyl propyl, phenyl, the 4-fluorophenyl, the 4-aminomethyl phenyl, the 4-trifluoromethyl, the 4-chloro-phenyl-, the 4-p-methoxy-phenyl, 4-Trifluoromethoxyphen-l and 4-methyl sulphonyl phenyl;

R ⁴Be H or methyl;

R ⁵Be selected from H, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, cyclopropyl, cyclopropyl methyl, sulfonyloxy methyl ylmethyl, methyl sulphonyl ethyl, hydroxymethyl, hydroxyethyl, styroyl, benzyl, phenyl and benzyloxymethyl;

Ar is by 0-3 R ²⁰The phenyl that replaces, by 0-2 R ²⁰Replace the De isoxazolyl, by 0-2 R ²⁰The pyridyl that replaces;

Each R ²⁰Be independently selected from H, F, Cl, OCH ₃, CH ₃, SCH ₃, S (=O) ₂CH ₃, S (=O) ₂NH ₂, ethanoyl, C (=O) NH ₂, CO ₂H, OCF ₃And OCHF ₂

Perhaps, R ²⁰And R ⁹The common 5-unit heterocycle that contains 1 nitrogen-atoms that forms; Wherein said 5-unit's heterocycle and Ar is monolateral condenses; The first heterocycle of wherein said 5-is randomly by 0-2 R ²⁴Replace;

Each R ²⁴Be independently selected from methyl and F;

Perhaps, two R ²⁴Be combined to form cyclopropyl and cyclobutyl.

10. the compound of claim 3, wherein:

Each R ²¹Be independently selected from H, OH, C (=O) OR ¹⁴, C (=O) NR ¹⁵R ¹⁶, NR ²²R ²³, C ₁-C ₄Alkoxyl group, by 0-3 R ¹³The phenyl and the C that replace ₃-C ₈Cycloalkyl.

11. the compound of claim 10, wherein:

Q is selected from following heterocycle: azetidinyl, pyrrolidyl, piperidyl, piperazinyl, 4-ethanoyl piperazinyl, 4-methyl sulphonyl piperazinyl, morpholinyl, thio-morpholinyl, 1,1-dioxo-1 λ ⁶-thio-morpholinyl, 2,6-dimethylated morpholinyl and 3, the 5-dimethylated morpholinyl, wherein Q by theheterocyclic nitrogen atom and-C (=O)-link to each other;

R ¹Be independently selected from cyclohexyl methyl, 4,4-dimethyl-cyclohexyl methyl, spiral shell [2.5] suffering-6-ylmethyl, spiral shell [3.5] ninth of the ten Heavenly Stems-7-ylmethyl, cyclohexyl ethyl, cyclopentyl-methyl, cyclopentyl ethyl, cyclobutylmethyl, cyclobutyl ethyl, cyclopropyl methyl, cyclopropyl ethyl, tertiary butyl methyl, tertiary butyl ethyl, phenyl methyl alkylsulfonyl methyl and dibenzylsulfide ylmethyl;

R ⁵Be selected from H, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, cyclopropyl, cyclopropyl methyl, sulfonyloxy methyl ylmethyl, methyl sulphonyl ethyl, hydroxymethyl, hydroxyethyl, benzyloxymethyl, styroyl, benzyl and phenyl;

Ar is by 0-3 R ²⁰The phenyl that replaces, by 0-2 R ²⁰The pyridyl that replaces and by 0-2 R ²⁰Replace the De isoxazolyl;

Each R ²⁰Be independently selected from H, F, Cl, CH ₃, OCH ₃, SCH ₃, S (=O) ₂CH ₃, S (=O) ₂NH ₂, ethanoyl, C (=O) NH ₂, CO ₂H, OCF ₃And OCHF ₂

Perhaps, R ²⁰And R ⁹The common 5-unit heterocycle that contains 1 nitrogen-atoms that forms; Wherein said 5-is first assorted

Ring condenses with Ar is monolateral; The first heterocycle of wherein said 5-is randomly by 0-2 R ²⁴Replace; Each R ²⁴Be independently selected from methyl, ethyl and F;

Perhaps, two R ²⁴Be combined to form cyclopropyl and cyclobutyl.

12. the compound of claim 4, wherein:

Each R ²¹Be independently selected from H, OH, C (=O) OR ¹⁴, C (=O) NR ¹⁵R ¹⁶, NR ²²R ²³, C ₁-C ₄Alkoxyl group, by 0-3 R ¹³The phenyl and the C that replace ₃-C ₈Cycloalkyl;

R ⁷Be H.

13. the compound of claim 12, wherein:

Q is selected from following heterocycle: azetidinyl, pyrrolidyl, piperidyl, piperazinyl, 4-ethanoyl piperazinyl, 4-methyl sulphonyl piperazinyl, morpholinyl, thio-morpholinyl, 1,1-dioxo-1 λ ⁶-thio-morpholinyl, 2,6-dimethylated morpholinyl and 3, the 5-dimethylated morpholinyl, wherein Q by theheterocyclic nitrogen atom and-C (=O)-link to each other; And NR ²⁵R ²⁶

R ³Be independently selected from cyclohexyl methyl, 4,4-dimethyl-cyclohexyl methyl, spiral shell [2.5] suffering-6-ylmethyl, spiral shell [3.5] ninth of the ten Heavenly Stems-7-ylmethyl, cyclohexyl ethyl, cyclopentyl-methyl, cyclopentyl ethyl, cyclobutylmethyl, cyclobutyl ethyl, cyclopropyl methyl, cyclopropyl ethyl, tertiary butyl methyl, tertiary butyl ethyl, phenyl, cyclohexyl, cyclopentyl, 4,4-Dimethylcyclohexyl, phenyl methyl alkylsulfonyl methyl and dibenzylsulfide ylmethyl;

Ar is by 0-3 R ²⁰The phenyl that replaces and by 0-2 R ²⁰Replace the De isoxazolyl;

Each R ²⁰Be independently selected from H, F, Cl, OCH ₃, CH ₃, SCH ₃, S (=O) ₂CH ₃, S (=O) ₂NH ₂,-S (=O) ₂NH (C=O) CH ₃, ethanoyl, C (=O) NH ₂, CO ₂H, OCF ₃And OCHF ₂

Each R ²⁴Be independently selected from methyl and F;

Perhaps, two R ²⁴Be combined to form cyclopropyl and cyclobutyl;

R ²⁵And R ²⁶Be selected from C independently of one another ₁-C ₄Alkyl; Wherein said C ₁-C ₆Alkyl randomly contains and is selected from-heteroatoms of O-.

14. the compound of claim 1, wherein said compound is selected from:

Morpholine-4-formic acid (S)-2-cyclohexyl-1-[2-(5-fluoro-2,3-dihydro-indoles-1-yl)-ethylamino formyl radical]-ethyl ester;

Morpholine-4-formic acid { 2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indoles-1-yl)-ethylamino formyl radical]-ethyl }-acid amides;

Morpholine-4-formic acid { 2-cyclohexyl-1-(S)-[2-(4-fluoro-phenyl amino)-ethylamino formyl radical]-ethyl }-acid amides;

Morpholine-4-formic acid { 2-cyclohexyl-1-(S)-[2-(4-methoxyl group-phenyl amino)-ethylamino formyl radical]-ethyl }-acid amides;

[2-(4-fluoro-phenyl amino)-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

2-(R)-cyclohexyl methyl-N-[2-(4-fluoro-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

[4-(R)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-tetrahydrochysene-furans-3-(R)-yl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

2-(R)-cyclohexyl methyl-N-[2-(5-fluoro-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

3-(R)-cyclohexyl methyl-N-[2-(4-fluoro-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

[1-(R)-benzyloxymethyl-2-(5-fluoro-2,3-dihydro-indoles-1-yl)-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

Morpholine-4-formic acid 2-cyclohexyl-1-(S)-[2-(5-fluoro-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethylamino formyl radical]-ethyl ester;

2-(R)-cyclohexyl methyl-4-morpholine-4-base-4-oxo-N-[2-(4-trifluoromethoxy-phenyl amino)-ethyl]-butyramide;

2-(R)-cyclohexyl methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

2-(R)-cyclopentyl-methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

2-(R)-cyclopentyl-methyl-3-(R)-methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

Morpholine-4-formic acid { 2-benzyl sulfenyl-1-(R)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethylamino formyl radical]-ethyl }-acid amides;

Morpholine-4-formic acid { 1-(R)-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethylamino formyl radical]-2-phenyl methanesulfonamide acyl group-ethyl }-acid amides;

(R)-2-cyclohexyl methyl-N-[2-(4-methoxyl group-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

2-(R)-cyclohexyl methyl-4-morpholine-4-base-4-oxo-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-butyl }-butyramide;

2-(R)-(2-cyclohexyl-ethyl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

2-(R)-cyclohexyl methyl-4-morpholine-4-base-4-oxo-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide;

2-(R)-cyclohexyl methyl-4-morpholine-4-base-4-oxo-N-{3-phenyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide;

2-(R)-cyclohexyl methyl-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

5,5-dimethyl-2-(R)-(2-morpholine-4-base-2-oxo-ethyl)-caproic acid [1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-acid amides;

4,4-dimethyl-2-(R)-(2-morpholine-4-base-2-oxo-ethyl)-valeric acid [1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-acid amides;

2-(R)-cyclopentyl-methyl-4-morpholine-4-base-4-oxo-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-butyl }-butyramide;

2-(R)-cyclohexyl methyl-N-{3-methylsulfonyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

2-(R)-cyclohexyl methyl-N-{3-methylsulfonyl-1-(R)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

2-(R)-(2-morpholine-4-base-2-oxo-ethyl)-5-phenyl-pentanoic acid the 2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-acid amides;

2-(R)-cyclopentyl-methyl-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

The N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-2-(R)-styroyl-butyramide;

2-(R)-(2-cyclopentyl-ethyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

The N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-2-(S)-phenyl-butyramide;

2-(S)-cyclohexyl-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

2-(R)-(2-cyclopentyl-ethyl)-4-morpholine-4-base-4-oxo-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide;

2-(R)-(2-cyclopentyl-ethyl)-4-morpholine-4-base-4-oxo-N-{3-phenyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide;

4-morpholine-4-base-4-oxo-2-(R)-styroyl-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide;

4-morpholine-4-base-4-oxo-2-(S)-phenyl-N-{1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-butyl }-butyramide;

4-morpholine-4-base-4-oxo-2-(S)-phenyl-N-{3-phenyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-butyramide;

2-(S)-(4-fluoro-phenyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

2-(S)-(4-chloro-phenyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

2-(R)-(4-chloro-phenyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

4-morpholine-4-base-4-oxo-2-(S)-phenyl-N-[1-(S)-phenyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-butyramide;

2-(R)-cyclohexyl methyl-4-morpholine-4-base-4-oxo-N-[1-(S)-phenyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-butyramide;

2-(R)-(2-cyclopentyl-ethyl)-4-morpholine-4-base-4-oxo-N-[1-(S)-phenyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-butyramide;

2-(R)-(2-morpholine-4-base-2-oxo-ethyl)-penta-obtusilic acid the 2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-acid amides;

2-(S)-(4-chloro-phenyl)-4-morpholine-4-base-4-oxo-N-[1-(S)-phenyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-butyramide;

(R)-5,5-dimethyl-2-(2-morpholine-4-base-2-oxo-ethyl)-caproic acid [2-(5-methyl-isoxazole-3-base amino)-ethyl]-acid amides;

2-(R)-cyclohexyl methyl-4-(cis-2,6-dimethyl-morpholine-4-yl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-oxo-butyramide;

2-(R)-cyclohexyl methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-oxo-4-thiomorpholine-4-base-butyramide;

4-(4-ethanoyl-piperazine-1-yl)-2-(R)-cyclohexyl methyl-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-oxo-butyramide;

2-(S)-(4-methoxyl group-phenyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

2-(R)-cyclohexyl methyl-N-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

The N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide;

-the 2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-2-(R)-(4-trifluoromethyl-phenyl)-butyramide;

The N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-2-(S)-p-methylphenyl-butyramide;

2-(R)-cyclohexyl methyl-4-(1,1-dioxo-thiomorpholine-4-yl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-oxo-butyramide;

2-(R)-(3-ethyl-3-hydroxyl-cyclohexyl methyl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide;

N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-2-(S)-phenyl-butyramide;

2-(S)-(4-fluoro-phenyl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

2-(S)-(4-methoxyl group-phenyl)-N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-butyramide;

2-(S)-(4-fluoro-phenyl)-N-{1-(S)-[(6-methoxyl group-pyridin-3-yl amino)-methyl]-2-methyl-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

N-[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-2-(R)-spiral shell [2.5] suffering-6-ylmethyl-butyramide;

N-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide;

2-(S)-(4-fluoro-phenyl)-N-{1-(S)-[(3-methylsulfonyl-phenyl amino)-methyl]-2-methyl-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

N-[1-(S)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-ylmethyl)-2-methyl-propyl group]-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide;

N-[1-(S)-cyclopropyl-2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-ethyl]-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide;

N-[1-(S)-cyclopropyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-4-morpholine-4-base-4-oxo-2-(S)-(4-trifluoromethyl-phenyl)-butyramide;

2-(R)-(4-methylsulfonyl-phenyl)-N-{2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-4-morpholine-4-base-4-oxo-butyramide;

(S, S)-morpholine-4-formic acid 2-cyclohexyl-1-[2-(4-methoxyl group-phenyl amino)-1-methyl-ethylamino formyl radical]-ethyl }-acid amides;

Morpholine-4-formic acid { 2-cyclopentyl-1-(S)-[2-(4-methoxyl group-phenyl amino)-1-(S)-methyl-ethylamino formyl radical]-ethyl }-acid amides;

Morpholine-4-formic acid (2-cyclohexyl-1-(S)-{ 3-methylsulfonyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group formamyl }-ethyl)-acid amides;

Morpholine-4-formic acid (2-cyclohexyl-1 (S)-{ 1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group formamyl }-ethyl)-acid amides;

Morpholine-4-formic acid 2-cyclohexyl-1-(S)-[the 2-methyl isophthalic acid-(S)-(pyridin-3-yl amino methyl)-propyl group formamyl]-ethyl }-acid amides;

Morpholine-4-formic acid { 2-cyclohexyl-1-(S)-[1-(S)-methyl-2-(5-methyl-isoxazole-3-base amino)-ethylamino formyl radical]-ethyl }-acid amides;

Morpholine-4-formic acid { 1-(S)-[2-(benzothiazole-2-base is amino)-1-(S)-methyl-ethylamino formyl radical]-2-cyclohexyl-ethyl }-acid amides;

Morpholine-4-formic acid 1-(S)-[2-(benzoxazole-2-base is amino)-1-(S)-methyl-ethylamino formyl radical]-2-cyclohexyl-ethyl }-acid amides;

(S, S)-morpholine-4-formic acid 2-cyclohexyl-1-[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-methyl-ethylamino formyl radical]-ethyl }-acid amides;

Morpholine-4-formic acid { 2-cyclohexyl-1-(S)-[1-(S)-cyclopropyl-2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-ethylamino formyl radical]-ethyl }-acid amides;

Morpholine-4-formic acid { 2-cyclohexyl-1-(S)-[1-(S)-cyclopropyl-2-(5-fluoro-3,3-Spirocyclopropyl-2,3-dihydro-indoles-1-yl)-ethylamino formyl radical]-ethyl }-acid amides;

[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

[1-(S)-methyl-2-(4-trifluoromethoxy-phenyl amino)-ethyl]-carboxylamine 3,3-dimethyl-1-(S)-(morpholine-4-carbonyl)-butyl ester;

[2-(4-difluoro-methoxy-phenyl amino)-1-(S)-methyl-ethyl]-carboxylamine 3,3-dimethyl-1-(S)-(morpholine-4-carbonyl)-butyl ester;

The 2-methyl isophthalic acid-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

{ 3-phenyl-1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-propyl group }-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

{ 1-(S)-[(4-trifluoromethoxy-phenyl amino)-methyl]-butyl }-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

[2-(4-ethanoyl sulfamyl-phenyl amino)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

[1-(S)-methyl-2-(5-methyl-isoxazole-3-base amino)-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

(S, S)-[1-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-base-methyl)-propyl group]-carboxylamine 1-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-(2,6-cis-dimethyl-morpholine-4-yl)-2-oxo-ethyl ester;

(S, S)-[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indoles-1-yl)-1-methyl-ethyl]-carboxylamine 2-(4-ethanoyl-piperazine-1-yl)-1-cyclohexyl methyl-2-oxo-ethyl ester;

[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-(4-methylsulfonyl-piperazine-1-yl)-2-oxo-ethyl ester;

[2-(5-fluoro-2,2-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-oxo-2-thiomorpholine-4-base-ethyl ester;

[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-(2,6-cis-dimethyl-morpholine-4-yl)-2-oxo-ethyl ester;

[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 2-(4-ethanoyl-piperazine-1-yl)-1-(S)-cyclohexyl methyl-2-oxo-ethyl ester;

[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-(4-methylsulfonyl-piperazine-1-yl)-2-oxo-ethyl ester;

[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-oxo-2-thiomorpholine-4-base-ethyl ester;

[2-(5-fluoro-3,3-spiral shell-cyclopropyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-oxo-2-piperidines-1-base-ethyl ester;

[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-oxo-2-tetramethyleneimine-1-base-ethyl ester;

[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 2-cyclohexyl-1-(S)-formyl-dimethylamino-ethyl ester;

[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-(1,1-dioxo-1 λ ⁶-thiomorpholine-4-yl)-2-oxo-ethyl ester;

[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 2-cyclohexyl-1-(S)-[(2-methoxyl group-ethyl)-methyl-formamyl]-ethyl ester;

[2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-1-(S)-methyl-ethyl]-carboxylamine 2-azetidine-1-base-1-(S)-cyclohexyl methyl-2-oxo-ethyl ester;

[1-(S)-cyclopropyl-2-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-yl)-ethyl]-carboxylamine 1-(S)-cyclohexyl methyl-2-morpholine-4-base-2-oxo-ethyl ester;

[1-(S)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-ylmethyl)-2-methyl-propyl group]-carboxylamine 2-morpholine-4-base-2-oxo-1-(R, S)-phenyl-ethyl ester;

[1-(S)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-ylmethyl)-2-methyl-propyl group]-carboxylamine 2-morpholine-4-base-2-oxo-1-(R)-phenyl methanesulfonamide acyl group methyl-ethyl ester; With

[1-(S)-(5-fluoro-3,3-dimethyl-2,3-dihydro-indoles-1-ylmethyl)-2-methyl-propyl group]-carboxylamine 1-(S)-cyclohexyl-2-morpholine-4-base-2-oxo-ethyl ester.

15. a pharmaceutical composition, described composition comprise the compound and the vehicle of claim 1.

16. the formula I compound of claim 1 is used for the purposes of the active medicine of inhibition of histone enzyme S in preparation.

17. the purposes of claim 16, the cathepsin S of wherein said formula I compound suppress constant less than 10 μ M.

18. the purposes of claim 17, the cathepsin S of wherein said formula I compound suppress constant less than 1.0 μ M.

19. the purposes of claim 18, the cathepsin S of wherein said formula I compound suppress constant less than 0.1 μ M.

20. the purposes of claim 16 is wherein optionally suppressed at the proteolytic enzyme S of situation undertissue that has at least a other kethepsin.

21. the purposes of claim 20, wherein said formula I compound suppresses at least 10 times greatly of constants to the inhibition constant of described at least a other kethepsin than the cathepsin S of described formula I compound.

22. the purposes of claim 21, wherein said formula I compound suppresses at least 100 times greatly of constants to the inhibition constant of described at least a other kethepsin than the cathepsin S of described formula I compound.

23. the purposes of claim 22, wherein said formula I compound suppresses at least 1000 times greatly of constants to the inhibition constant of described at least a other kethepsin than the cathepsin S of described formula I compound.

24. the purposes of claim 16, wherein said compound is selected from the compound of claim 14.